Aromatic sulfone hydroxamic acid metalloprotease inhibitor

专利摘要:
The present invention demonstrates excellent inhibitory activity against matrix metalloprotease (MMP) enzymes such as one or more of MMP-2, MMP-9 and MMP-13, while the inhibitory activity against one or more MMP-1 is substantially less Which comprises administering to a host suffering from a disease associated with pathological matrix metalloprotease activity an effective amount of an aromatic sulfonic hydroxamic acid. The enzyme inhibitor to be administered is structurally equivalent to, or is a pharmaceutically acceptable salt thereof: (I) Wherein R 1 and R 2 are both hydrazido or R 1 and R 2 together with the atoms to which they are attached contain 1, 2 or 3 heteroatoms in the ring which are oxygen, sulfur or nitrogen Form a 5- to 8-membered ring; R < 3 > is an optionally substituted aryl or an optionally substituted heteroaryl radical. The present invention also discloses pharmaceutical compositions using the metalloprotease inhibitor compounds having selective activity, methods of making such compounds and inhibitors.
公开号:KR20010031773A
申请号:KR1020007004839
申请日:1998-11-12
公开日:2001-04-16
发明作者:바르타토마스이；베커다니엘피；보엠테리엘；테크레션조게리에이；빌라밀클라라아이；맥도날드조세프제이；프레스코존엔；젯맨다니엘피
申请人:월리암스 로저에이；지디.썰.앤；
IPC主号:

专利说明:

[0001] AROMATIC SULFONE HYDROXAMIC ACID METALLOPROTEASE INHIBITOR [0002]
The connective tissue, extracellular matrix components and basement membrane are necessary components in all mammals. Such components are biological materials that provide stiffness, differentiation, adhesion, and in some cases elasticity to biological systems, including humans and other mammals. Connective tissue components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. Such biochemical materials constitute or are components of such structures as skin, bone, teeth, tendons, cartilage, basement membrane, blood vessels, cornea and vitreous humor.
The turnover and / or repair action of connective tissue is regulated under normal conditions and is in equilibrium. If for any reason the balance is lost, a number of diseases will occur. Inhibition of enzymes responsible for equilibrium loss provides a regulatory mechanism of said tissue degradation, thereby providing a therapy for said disease.
The degradation of the connective tissue or connective tissue component is carried out by the action of a native tissue cell and / or a proteinase that is released from the infiltrating inflammatory or tumor cell. The major enzyme involved in this function is zinc metalloproteinase (metalloprotease).
Metalloprotease enzymes are usually divided into classes that include several members with different names. Examples include: collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3); Collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC 3.4.24.22), proteoglycanase, martiraiicin (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24) (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) And membrane MMP (MMP-14). MMP is an abbreviation or acronym for the term Matrix Metalloprotease, and the attached numbers provide the differentiation between specific members of the MMP family.
Unregulated connective tissue degradation by metalloprotease is a hallmark of many pathological diseases. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; Corneal ulcer, epidermal ulcer or gastric ulcer; Tumor metastasis, invasion or angiogenesis; Periodontal disease; Proteinuria; Alzheimer's disease; Coronary artery thrombosis and bone disease. A defective injury recovery process also occurs. This can lead to mild restoration, adhesion and scarring by improperly healing the trauma. This latter defect can cause scarring and / or permanent disability as well as post-surgical adhesion.
Metalloprotease is also implicated in the biosynthesis of tumor necrosis factor (TNF), and inhibition of the production or action of TNF and related compounds is an important clinical mechanism of disease treatment. For example, TNF-α is a cytokine that is thought to be initially produced as a 28 kD cell-associated molecule. TNF-a is released into the 17 kD active form, which can mediate a number of deleterious consequences both in vitro and in vivo. For example, TNF may be used in the treatment of inflammation, rheumatoid arthritis, autoimmune diseases, multiple sclerosis, transplant rejection, fibrosis, cancer, infectious diseases, malaria, mycobacterial infections, meningitis, fever, psoriasis, cardiovascular / pulmonary effects such as ischemic reperfusion It occurs during shocks such as post-traumatic, congestive heart failure, hemorrhage, coagulation, oxygen-excess alveolar injury, radial injury, and septic shock and blood shock, causing and / or causing the effects of acute- It can be a cause. Chronic release of active TNF may cause cachexia and anorexia. TNF can be fatal, and TNF can help regulate the growth of tumor cells.
The TNF-alpha convertase is a metalloprotease involved in the formation of soluble TNF-a. Inhibition of the TNF-alpha converting agent (TACE) inhibits the production of active TNF-a. Compounds that inhibit both MMP activity and TNF- [alpha] production are disclosed in WIPO International Publication Nos. WO 94/24140, WO 94/02466 and WO 97/20824. Compounds that inhibit MMPs such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF (Gearing et al., Nature 376, 555-557 (1994)), McGeehan et al. [Nature 376, 558-561 (1994)). There is still a need for effective MMP inhibitors. There is also a need for effective TNF-alpha converting agent inhibitors.
MMP is also implicated in other biochemical processes in mammals. Examples of ovulation control, delivery uterus after degeneration, possibly implantation, cleavage and α ₁ in the amyloid plaques in APP (β- amyloid precursor protein) may be mentioned the deactivation of the protease inhibitor (α ₁ -PI). The inhibition of the metalloprotease makes it possible to control fertility and to treat or prevent Alzheimer's disease. In addition, maintaining or increasing the level of biochemical agents such as endogenous or administered serine protease inhibitor drugs or alpha ₁ -PI may be useful for the treatment and / or prevention of diseases such as type, emphysema, inflammatory diseases and aging diseases such as loss of skin or organ stretch and elasticity, Prevention continues.
The inhibition of selective MMP may also be desirable in other cases. Selective inhibition of stromelysin, gelatinase A or B, or collagenase III, particularly in the treatment of diseases which appear to be inhibition of relatively the most important enzymes or enzymes when compared to collagenase I (MMP-1) An example of an approach is to inhibit the treatment and / or metastasis of cancer and / or inhibit angiogenesis. Agents that do not inhibit collagenase I may have an excellent therapeutic profile. Osteoarthritis, another widespread disease thought to be caused by MMP-13 released from cells such as inflammatory cartilage cells at least in part by cartilage degradation of the joints, is one of its mode of action, inhibition of MMP-13 It can be best treated by administration of medicines. See, for example, Mitchell et al. Clin. Invest., 97: 761-768 (1996) and Reboul et al. Clin. Invest., 97: 2011-2019 (1996).
Inhibitors of metalloprotease are known. Examples include natural biochemical substances such as tissue metalloproteinase inhibitors (TIMP), [alpha] ₂ -macroglobulin and analogs or derivatives thereof. The endogenous inhibitor is a high molecular weight protein molecule that forms an inert complex with a metalloprotease. A number of smaller similar peptide compounds that inhibit metalloprotease have been described. The mercaptoamide peptidyl derivatives showed ACE inhibition both in vitro and in vivo. Angiotensin converting enzyme (ACE) promotes the production of angiotensin II, which is a powerful step-up substance in mammals. When the enzyme is inhibited, blood pressure is lowered.
Amide or peptidyl amide-based metalloprotease (MMP) inhibitors containing thiol groups are described, for example, in WO 95/12389, WO 96/11209 and U.S. Pat. 4,595,700. ≪ / RTI > MMP inhibitors, including hydroxamate groups, are disclosed in numerous patent application publications, such as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386, which disclose carbon skeletal compounds, and WO 90/05719, As in the case of Schwartz et al. [Progr. Med. Chem., 29: 271-334 (1992)], hydroxamates having a peptidyl backbone or similar backbone skeleton are disclosed in WO93 / 20047, WO95 / 09841 and WO96 / 06074 And Rasmussen et al. [Pharmacol. Ther., 75 (1): 69-75 (1997)] and Denis et al. [Invest. New Drugs, 15 (3): 175-185 (1997).
One possible problem associated with known MMP inhibitors is that such compounds often exhibit the same or similar inhibitory effects on each of the MMP enzymes. For example, a similar peptide hydroxamate, known as batimastat, is present at about 1 to about 20 nanomolar (nM) for each of MMP-1, MMP-2, MMP-3, MMP- there is a report showing that the IC ₅₀ value. Another similar peptide hydroxamate, Marimastat, is another broad spectrum MMP inhibitor with an enzyme inhibition spectrum very similar to batimastat, except that it exhibits an IC ₅₀ value of 230 nM for MMP-3 . Rasmussen et al., Pharmacol. Ther., 75 (1): 69-75 (1997).
Meta-analysis of data from I / II studies in patients with progressive rapid-progressive therapy-resistant solid tumor tumors (colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer) using marimastatum revealed that a biologically active surrogate marker Specific antigens that are used as a dose-limiting dose. Although marimastat demonstrates the efficacy of several criteria through these markers, toxic side effects have emerged. The most common drug-related toxicities of Mariamast in these clinical trials were musculoskeletal pain and stiffness, which often originated from the small joints of the hands and spread to the arms and shoulders. Short treatment discontinuation for 1 to 3 weeks, followed by dose reduction, will result in continued treatment. Rasmussen et al., Pharmacol. Ther., 75 (1): 69-75 (1997). The lack of specificity of the inhibitory effect between MMPs may be the cause of this effect.
International Patent Application Publication No. WO 98/38163 (issued Sep. 3, 1998) discloses a number of hydroxamate inhibitor groups of MMP and TACE. The compounds of WO 98/38163 comprise one or two substituents adjacent to the hydroxamate functional group and substituents which may be aromatic sulfonyl groups adjacent to said one or two substituents.
International Patent Application Publication No. WO 98/37877 (published Sep. 3, 1998) includes an aromatic sulfonyl group adjacent to the heterocyclic ring which contains a 5- to 7-membered heterocyclic ring adjacent to the hydroxamate functional group ≪ / RTI > is disclosed.
Although a number of known MMP inhibitors such as hydroxamate, batimastat and marimastat of WO 98/37877 and WO 98/38163 exhibit broad spectrum activity against MMP, such compounds are particularly selective for their inhibitory activity It is not. This lack of selectivity may be the cause of musculoskeletal pain and stiffness observed when using the compounds. It may also be therapeutically advantageous to use medicines with selectivity in their activity in comparison to common active substances so that the treatment can be more closely aligned with the pathological disease manifested by the mammalian host. The following disclosures describe methods for treating diseased host cells associated with pathological matrix metalloprotease activity using compounds that selectively inhibit one or more MMPs while exhibiting less activity against one or more MMP-1 .
SUMMARY OF THE INVENTION
The present invention relates to a method of treatment comprising administering an effective amount of an aromatic sulphonated hydroxamic acid metalloprotease inhibitor to a diseased mammalian host associated with pathological metalloprotease activity. In particular, the molecule exhibits excellent inhibitory activity for one or more matrix metalloproteinase (MMP) enzymes such as MMP-2, MMP-9 and MMP-13, . "Substantially less" that is, in in vitro inhibition assays below, compared to the IC ₅₀ values for MMP-1 in the present compound, IC ₅₀ values for one or more of MMP-2, MMP-9 or MMP-13 (For example, IC ₅₀ MMP-2: IC ₅₀ MMP-1) is less than about 1:10, preferably less than about 1: 100, and most preferably less than about 1: 1000. The present invention also relates to certain compounds which selectively inhibit the activity of one or more of MMP-2, MMP-9 and MMP-13 while substantially inhibit the activity of one or more of MMP-1, ≪ / RTI >
Briefly, one embodiment of the present invention is a method of treating a mammalian host suffering from a disease associated with pathological metalloprotease activity, as described above, with an effective amount of an aromatic sulfone hydroxamic acid metalloprotease inhibitor that selectively inhibits matrix metalloprotease activity Or a pharmaceutically acceptable salt thereof. The enzyme inhibitor to be administered corresponds in structure to the following formula I, or a pharmaceutically acceptable salt thereof:
Wherein,
R ¹ and R ² are both hydrazido or R ¹ and R ² together with the atom to which they are attached form a 5- to 8-membered ring containing one, two or three heteroatoms, such as oxygen, sulfur or nitrogen, ≪ / RTI >
R < ³ > is an optionally substituted aryl or an optionally substituted heteroaryl radical. When R ³ is a substituted aryl or heteroaryl radical, the substituent is selected from the group consisting of aryl, heteroaryl, aralkyl, heteroaralkyl, aryloxy, arylthio, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralka Alkylthioalkyl, arylthioalkyl, alkylthioalkyl, aralkylthioalkyl, aralkylthioalkyl, arylthioalkyl, arylthioalkyl, arylthioalkyl, arylthioalkyl, arylthioalkyl, arylthioalkyl, arylthioalkyl, A thioaryl radical, a sulfoxide or sulfone of thio substituent, and a fused ring structure comprising two or more 5 or 6 ring members selected from the group consisting of aryl, heteroaryl, carbocyclic and heterocyclic .
Substituents attached to the aryl or heteroaryl radicals that comprise the R < ³ > radicals may be substituted with one or more substituents (i.e., the substituting substituents are optionally substituted). When the aryl or heteroaryl radical is substituted and the substituting moiety (group, substituent, or radical) itself is substituted, the latter substituent may be cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, Alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbamoyl, aryloxycarbonyl, aryloxycarbonyl, hydroxy, haloalkyl, trifluoromethylalkyl, Heteroaryloxy, heteroarylthio, heteroarylalkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, Aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylthio, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcycloalkyl, Alkylthioalkyl, arylthioalkylthio, arylthioalkylthio, arylthioalkylthio, arylthioalkylthio, arylthioalkylthio, arylthioalkylthio, arylthioalkylthio, arylthioalkylthio, arylthioalkylthio, arylthioalkylthio, arylthioalkylthio, Wherein the amino nitrogen is (i) unsubstituted or (ii) substituted or unsubstituted alkyl, alkoxycarbonylalkylthio, alkoxycarbonylalkylthio, amino, 1 > independently selected from the group consisting of aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and alkanoyl groups Or (iii) amino nitrogen and two substituents attached thereto are substituted with 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, or (A) unsubstituted or (b) aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, , Alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzo fused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, Benzo-fused heterocycloalkoxy, benzo-fused cycloalkylcarbonyl, heterocycloalkylcarbonyl, and cycloalkylcarbonyl groups, carbonylamino wherein the carbonylamino is optionally substituted with one or two groups independently selected from the group consisting of Nitrogen may be either (i) unsubstituted, (ii) a reactive amine of an amino acid, or (iii) alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, 1, 2, 3, 4, or 5 substituents selected from the group consisting of lower alkyl, halogen, lower alkyl, halogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, alkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, Or (iv) the carboxamido and the two substituents attached thereto are taken together to form a ring that is itself unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl Aryl, aralkyl, heteroaralkyl and amino groups wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, and heteroaryl Or (iii) the amino nitrogen and the two substituents attached thereto form a 5 to 8 membered heterocyclo or heteroaryl ring, A 5- or 8-membered heterocyclo, heteroaryl or benzo fused heterocycloalkyl ring which is optionally substituted with one or two radicals selected from the group consisting of aminoalkyl, (Ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl groups, or (iii) Wherein the aminoalkyl nitrogen and the two substituents attached to it form a 5 to 8 membered heterocyclo or heteroaryl ring.
In a preferred embodiment, R ¹ and R ² together with the atoms to which they are attached form a six-membered ring.
The length of the R ³ radical is preferably longer than the length of the pentyl group [a- (CH ₂ ) ₄ CH ₃ chain], more preferably about the length of the hexyl group [a- (CH ₂ ) ₅ CH ₃ chain] It is longer. The length of the R ₃ radical is preferably less than the length of the eicosyl group [a- (CH ₂ ) ₁₉ CH ₃ chain], more preferably less than the length of the stearyl group [a- (CH ₂ ) ₁₇ CH ₃ chain] . Preferred R < ³ > groups include two or more 5-membered or 6-membered rings. The R ³ group may be attached to the 6-membered ring at the SO ₂ -bond 1-position and the substituent-bonded 4-position, or around the axis drawn through the SO ₂ -bond 1 -position and the substituent- , The widest extent of which has a width of from about 1 furanyl ring to about 2 phenyl rings in the direction of rotation at the crossing of the axis.
And the R ³ radical is a 5 or 6 membered ring at its 4-position in the case of a 6 membered ring, or at its 3- or 4- position in the case of a 5 membered ring, An aryl group, a C ₃ -C ₁₄ alkyl group, an N-piperidyl group, an N-piperazyl group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenyl azo group and a benzamido group Or a monocyclic aryl or heteroaryl group which is itself substituted by a substituted substituent. Substituents on the 5-membered or 6-membered aryl or heteroaryl group may be substituted on their own, as discussed above.
Preferred compounds for use in the present method are those having a structure corresponding to the formula (II), or a pharmaceutically acceptable salt thereof:
Wherein,
R ¹⁴ is selected from the group consisting of a hydrido, a pharmaceutically acceptable cation or C (W) R ¹⁵ wherein W is O or S and R ¹⁵ is C ₁ -C ₆ -alkyl, aryl, C ₁ -C ₆ -alkoxy, aryl -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aryloxy, aralkyl, -C ₁ -C ₆ - alkoxy, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl and amino C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkoxycarbonyl, C ₁ -C ₆ - alkoxycarbonyl, and C ₁ -C ₆ - the group consisting of alkanoyl radicals Or (iii) amino C ₁ -C ₆ -alkyl nitrogen and the two substituents attached thereto are substituted by one or two substituents independently selected from a 5 to 8 membered heterocyclo or heteroaryl ring Lt; / RTI >
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
the sum of m + n + p is 1, 2, 3 or 4;
(a) X, one of Y and Z is selected from ^{C (O), NR 6,} O, S, S (O), S (O) 2 and NS (O) group consisting of ₂ R ^7, X, The remaining two of Y and Z are CR ⁸ R ⁹ , and CR ¹⁰ R ¹¹ ,
(b) X and Z or Z and Y together ^{NR 6 C (O), NR} 6 S (O), NR 6 S (O) 2, NR 6 S, NR 6 O, SS, NR 6 NR 6, and OC (O), the other of X, Y and Z being CR ⁸ R ⁹ , or
(c) n is 0, and X, Y and Z together form a group of formula:

[Wherein,
The wavy line is the bond to the atom of the indicated ring;
R ⁶ and R ^{6 '} are independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkanoyl, C ₆ -aryl-C ₁ -C ₆ -alkyl, aroyl, bis (C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl) -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkyl, C ₁ -C ₆ - haloalkyl, C ₁ -C ₆ - perfluoroalkyl, C ₁ -C ₆ - trifluoromethyl alkyl, C ₁ -C ₆ - perfluoroalkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₈ - heterocycloalkyl, C ₃ -C ₈ - heterocycloalkyl-carbonyl, C ₆ - aryl, C ₅ -C ₆ - heterocycloalkyl, C ₅ -C ₆ - heteroaryl, C ₃ -C ₈ - cycloalkyl- C ₁ -C ₆ -alkyl, C ₆ -aryloxy-C ₁ -C ₆ -alkyl, heteroaryloxy-C ₁ -C ₆ -alkyl, heteroaryl-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, C ₆ -arylsulfonyl, C ₁ -C ₆ -alkylsulfonyl, C ₅ -C ₆ -heteroarylsulfonyl, carboxy-C ₁ -C ₆ -alkyl, C ₁ -C ₄ - alkoxy-carbonyl -C ₁ -C ₆ - alkyl, aminocarbonyl, C _l -C ₆ -alkyl already noka Viterbo carbonyl, C ₆ - Reel already noka Viterbo carbonyl, C ₅ -C ₆ - heterocycloalkyl already noka Viterbo carbonyl, C ₆ - arylthio -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, C ₆ - arylthio -C ₃ -C ₆ - alkenyl, C ₁ -C ₄ - alkylthio -C ₃ -C ₆ - alkenyl, C ₅ -C ₆ - heteroaryl, -C ₁ -C ₆ - alkyl, halo -C ₁ -C ₆ - alkanoyl, hydroxy -C _l -C ₆ - alkanoyl, thiol -C ₁ -C ₆ - alkanoyl, C ₃ -C ₆ - alkenyl, C ₃ -C ₆ - alkynyl C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkyl, C ₁ -C ₅ -alkoxycarbonyl, aryloxycarbonyl, NR ⁸ R ⁹ -C ₁ -C ₅ -alkylcarbonyl, hydroxy -C ₁ -C ₅ - alkyl, aminocarbonyl (where aminocarbonyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of an alkanoyl group), a hydroxy-aminocarbonyl, aminosulfonyl group (wherein, aminosulfonyl Nitrogen is (i) _{Or, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - Al 1 is independently selected from the group consisting of alkanoyl groups Amino-C ₁ -C ₆ -alkylsulfonyl, wherein the amino-C ₁ -C ₆ -alkylsulfonyl is (i) unsubstituted or (ii) substituted by C ₁ - C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - alkanoyl group substituted by one or two radicals independently selected from the group consisting of ) and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ -cycloalkyl and a C ₁ -C ₆ -alkanoyl group); R 1 is selected from the group consisting of:
R ⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyl, C ₁ -C ₆ -carboxyalkyl and C ₁ -C ₆ -hydroxyalkyl group;
R ^8, R ^9, R ¹⁰ and R ¹¹ are also hideurayi, hydroxy, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl -C ₁ -C ₆ - Alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl, thiol-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylthio-C ₁ -C ₆ -alkylcycloalkyl, C ₁ -C ₆ -alkyl, heterocycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, aralkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy carboxylic carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, arylthio ₁ -C -C ₆ - alkyl, heteroarylthio -C ₁ -C ₆ - alkyl, -C ₁ -C ₆ with a sulfoxide or sulfone, perfluoroalkyl of said thio substituents -methyl-alkyl, trifluoromethyl -C ₁ -C ₆ - Alkyl, halo-C ₁ -C ₆ -alkyl, alkoxycarbonylamino-C ₁ -C ₆ -alkyl Kill and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of alkanoyl search) with independently selected from the group consisting of; Or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ and the carbon to which they are bonded form a carbonyl group or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ or R ⁸ and R ¹⁰ are atoms to which they are bonded Or a 5-to 8-membered heterocyclic ring containing one or two heteroatoms of nitrogen, oxygen, or sulfur, or a 5- to 8-membered carbocyclic ring with the proviso that R ⁸ and R ⁹ , or only one of R < ¹⁰ > and R < ¹¹ > is hydroxy;
R ¹² and R ^{12 'are} also hideurayi, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl, C ₂ -C ₆ - alkynyl, C ₂ -C _6-alkenyl, thiol -C ₁ -C ₆ - alkyl, cycloalkyl, cycloalkyl -C ₁ -C ₆ - alkyl, heterocycloalkyl -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy-carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, arylthio -C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, the sulfoxide or sulfone of said thio substituent, perfluoro-C ₁ -C ₆ -alkyl, trifluoromethyl-C ₁ -C ₆ -alkyl, halo -C ₁ -C ₆ - alkyl, alkoxycarbonylamino -C ₁ -C ₆ - alkyl and Mino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl, and C ₁ - C ₆ - Al 1 is independently selected from the group consisting of alkanoyl, or substituted with two radicals) with independently selected from the group consisting of;
R ¹³ is selected from the group consisting of: hydrido, benzyl, phenyl, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl and C ₁ -C ₆ -hydroxyalkyl groups do]
Lt; RTI ID = 0.0 > of: < / RTI >
G-A-R-E-Y is preferably a substituent having a length longer than the length of the pentyl group, more preferably a length longer than the hexyl group. The substituent G-A-R-E-Y preferably has a length less than the length of the eicosyl group, more preferably less than the length of the stearyl group.
In this substituent,
G is an aryl or heteroaryl group;
A is selected from the group consisting of:
(1) -O-;
(2) -S-;
(3) -NR ¹⁷ -;
(4) -CO-N (R ¹⁷ ) or -N (R ¹⁷ ) -CO-, wherein R ¹⁷ is hydrogen, C ₁ -C ₄ -alkyl, or phenyl;
(5) -CO-O- or -O-CO-;
(6) -O-CO-O-;
(7) -HC = CH-;
(8) -NH-CO-NH-;
(9) -C C-;
(10) -NH-CO-O- or -O-CO-NH-;
(11) -N = N-;
(12) -NH-NH-; And
(13) -CS-N (R ¹⁸ ) - or -N (R ¹⁸ ) -CS-, wherein R ¹⁸ is hydrogen, C ₁ -C ₄ -alkyl, or phenyl; or
(14) A is absent and G is directly bonded to R;
R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Cycloalkyl, thioalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl substituents are unsubstituted or (ii) Alkoxy, C ₁ -C ₂ -alkylene-dioxy, hydroxycarbamoyl, perhaloalkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, One or two radicals selected from the group consisting of haloalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkylcarbonylalkyl, A residue selected from the group consisting of substituted), R A is not an alkyl or alkoxyalkyl when -O- or -S-;
E is selected from the group consisting of:
(1) -CO- (R ¹⁹⁾ or - (R ¹⁹⁾ -CO- (wherein, R ¹⁹ is a heterocycloalkyl, or a cycloalkyl group Im);
(2) -CONH- or -HNCO-;
(3) -CO-;
(4) -SO ₂ -R ¹⁹ - or -R ¹⁹ -SO ₂ -;
(5) -SO ₂ -
(6) -NH-SO ₂ - or -SO ₂ -NH-; or
(7) E is absent and R is directly bonded to Y;
Y is not present or is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, Cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups wherein the aryl, heteroaryl, or heterocycloalkyl group is optionally substituted with one or more groups selected from the group consisting of (i) Or (ii) an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, and amino group wherein the amino nitrogen is either (i) unsubstituted or (ii) independently selected from hydrido, ≪ / RTI > wherein one or two radicals are optionally replaced by one or two groups as defined above).
Particularly preferred compounds for use in the present process are those which are structurally equivalent or are pharmaceutically acceptable,
Wherein,
m, n, p, X, Z, Y and R ¹⁴ are as defined for formula II above and the R ³ radical as defined below is a subset of the GAREY substituents discussed previously.
Thus, R < ³ > is a 5 or 6 membered ring, at its 4-position if it is a 6 membered ring and at its 3- or 4- 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4-fluorothiophene Phenoxy, 4-trifluoromethoxy-phenoxy, 4-trifluoromethylphenoxy, 4- (trifluoromethylthio) -phenoxy, 4- (trifluoromethylthio) 4-isopropoxyphenoxy, (2-methyl-1,3-benzothiazol-5-yl) oxy, 4- ( 3-methylphenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy, 4-chloro-3 4-fluoro-3-chlorophenoxy, 4- (lH-1,2,4-triazol-1-yl) phenoxy, 3,5-difluorophenoxy, 3,4 - dichlorophenoxy, 4 3-methylphenoxy, 4-bromophenoxy, 4-methylthiophenoxy, 4-phenylphenoxy, 4-benzylphenoxy, 6-quinolinyloxy 3-methylphenoxy, 3-methoxyphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, N- N-piperazinyl, and 4-benzyloxyphenoxy groups. The term " heteroaryl "
More particularly preferred compounds for use in the present process are those having a structure corresponding to the formula (IV) or a pharmaceutically acceptable salt thereof:
Wherein,
R ³ is as defined in formula (I), more preferably is as defined in formula (II), wherein said R ³ group is a GAREY substituent and more preferably is as defined in formula (III);
Z is O, S, NR ⁶ , SO, SO ₂ , and NSO ₂ R ⁷ wherein R ⁶ is selected from the group consisting of: hydrido, C ₁ -C ₅ -alkyl, C ₁ -C ₅ -alkanoyl, benzyl, benzoyl, C ₃ -C ₅ - alkynyl, C ₃ -C ₅ - alkenyl, C ₁ -C ₃ - alkoxy -C ₁ -C ₄ - alkyl, C ₃ -C ₆ - cycloalkyl, heteroaryl, -C ₁ -C ₆ -alkyl, C ₁ -C ₅ - hydroxyalkyl, C ₁ -C ₅ - alkyl, carboxyl, C ₁ -C ₅ - alkoxy C ₁ -C ₅ -alkyl-carbonyl, and NR ⁸ R ⁹ -C ₁ -C ₅ -Alkylcarbonyl or NR ⁸ R ⁹ -C ₁ -C ₅ -alkyl, wherein R ⁸ and R ⁹ are independently selected from the group consisting of hydrido, C ₁ -C ₅ -alkyl, C ₁ -C ₅ -alkoxycarbonyl or aryl C ₁ -C ₅ -alkoxycarbonyl, or NR ⁸ R ⁹ together form a heterocyclic ring comprising 5 to 8 atoms in the ring; R ⁷ is selected from the group consisting of arylalkyl, Aryl, heteroaryl, heterocyclo, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyl, C ₁ -C ₆ -carboxyalkyl and C ₁ -C ₆ -hydro Roxy alkyl group From the group is a group selected from the group consisting of selected).
A group of compounds which are even more preferred for use in the present process are those which correspond in structure to the following formula V, or a pharmaceutically acceptable salt thereof:
Wherein,
Z is as previously defined in formula IV;
W and Q are independently oxygen (O), NR ⁶ or sulfur (S), R ⁶ is as defined in formula IV;
q is 0 or 1, and when q is 0, the trifluoromethyl group is directly bonded to the phenyl ring shown.
The compounds of formulas I to V, or a pharmaceutically acceptable salt of one of these compounds, are used in the process. Also compounds of formula II, III, IV and V, and pharmaceutically acceptable salts thereof, are contemplated as the compounds of the invention.
The present invention also relates to precursors or intermediate compounds useful in the preparation of compounds of Formulas (I) through (V). This intermediate compound corresponds in structure to the following formula VI:
Wherein,
m, n, p, X, Z and Y are as defined in formula II above;
g is 0, 1 or 2;
R ²⁴ is R ³ as defined in formula I, III or IV, or a substituent GAREY (formula VIA) of formula II, or a coupling substituent having reactivity in coupling with other moieties, for example, R ^{3 '} substituted with a possible leaving group D, an aryl or heteroaryl group (formula VIB).
Examples of the substitutable leaving group D in the parent haekjeok include halo (fluoro, chloro, bromo, or iodo), nitro, azido, phenyl sulfoxides also, aryloxy, C ₁ -C ₆ - alkoxy, C ₁ - C ₆ -alkylsulfonate or arylsulfonate group and a trisubstituted ammonium group wherein the three substituents are independently aryl, -C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkyl.
R ²⁰ is selected from the group consisting of: (a) -OR ²¹ wherein R ²¹ is selected from the group consisting of a hydrido, C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl and a pharmaceutically acceptable cation, Or (b) -NH-OR ²² , wherein R ²² is an optionally removable protecting group such as 2-tetrahydropyranyl, C ₁ -C ₆ -acyl, aroyl, benzyl, p-methoxybenzyloxy (MOZ), benzyloxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkoxy-CH ₂ -, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkoxy-CH ₂ , trisubstituted silyl group or o-nitrophenyl group, peptide synthetic resin, etc.). The trisubstituted silyl group is substituted by C ₁ -C ₆ -alkyl, aryl, or ar-C ₁ -C ₆ -alkyl.
Particularly preferred precursor intermediates or intermediate compounds of formula (VI) are intermediate compounds of formula (VII)
Wherein m, n, p, g, X, Z, Y, D and R ²⁰ are as defined in Formula VI.
Several advantages and advantages of the present invention include providing compounds and compositions that are effective as inhibitors of matrix metalloproteinase activity, inhibition of metalloproteinases associated with diseases and disorders associated with uncontrolled degradation of connective tissue And to provide such effective compounds and compositions.
More specifically, the advantages of the present invention include, but are not limited to, rheumatoid arthritis, osteoarthritis, septic arthritis, corneal ulcer, epidermal ulcer or gastric ulcer, tumor metastasis, invasion or angiogenesis, periodontal disease, Such as one or more MMP-2, MMP-9 and MMP-13, associated with a pathological disorder such as inflammation, thrombosis, and bone disease.
The advantage of the present invention is that the metalloproteinases associated with the disease, such as MMP-2, MMP-9 or MMP-13, selectively inhibit, while at the same time inhibiting other metalloproteinases such as MMP- Compositions and methods effective for treating such pathological conditions by minimizing adverse effects resulting from the inhibition of the pathology of the disease, which is necessary or desirable for normal body function.
Another advantage of the present invention is to provide a process for preparing such compounds.
Another advantage is to provide a method of treating pathological diseases associated with abnormal matrix metalloproteinase activity.
Another advantage of the present invention is to provide a method for producing such a composition.
Other advantages and benefits of the present invention will be apparent to those skilled in the art from the following disclosure.
The present invention relates to a method for treating a disease associated with a proteinase (protease) inhibitor, more particularly a pathological matrix metalloproteinase activity, and in particular to a method for treating a disease associated with an aromatic sulfonic hydroxamic acid A selective inhibitor itself, a protease inhibitor composition, a synthetic intermediate of a protease inhibitor, and a method for producing a protease inhibitor.
In accordance with the present invention, certain aromatic sulfonic hydroxamic acids (hydroxamates) have been found to be effective in inhibiting matrix metalloproteinases (MMPs) which are believed to be associated with uncontrolled or pathological degradation of connective tissue. In particular, the specific aromatic sulfonic hydroxamate is one or more enzymes, such as MMP-2, MMP-9 and MMP-13, which are present in abnormal amounts or concentrations, Lt; / RTI > Such pathological activity includes assisting tumor and tumor cells in penetrating the basement membrane and developing into new or improved blood supply (i.e., angiogenesis).
In addition, the aromatic sulfonamide hydroxamate selectively inhibits one or more of MMP-2, MMP-9, and MMP-13 without excessively inhibiting other collagenases essential for normal bodily functions such as tissue turnover and repair . More specifically, the inventive aromatic sulfone hydroxamates of the invention, or pharmaceutically acceptable salts thereof, inhibit one or more of MMP-2, MMP-9 and MMP-13 in an in vitro assay that may predict in vivo activity Lt; RTI ID = 0.0 > activity. ≪ / RTI > In addition, the present aromatic sulfonamide hydroxamate, or a salt thereof, has selectivity for one or more MMP-2, MMP-9 and MMP-13, but the inhibitory effect on MMP-1 is limited or minimal.
Thus, for one or more of MMP-2, MMP-9 and MMP-13 and MMP-1, there is a significant difference in the activity of the compounds used in the method. These significant differences are analyzed using in vitro inhibition assays discussed in the Examples. A significant difference in the active surface is that the compound has an IC _{50 of at} least about 0.1-fold, more preferably at least about 0.01-fold, and most preferably at least about 0.001-fold greater for MMP-1 than for one or more of MMP-2, MMP-9 and MMP- Value. Indeed, some compounds exhibit selectivity differences in the number of 100,000 times, which is measured by the IC ₅₀ value and exceeds the analytical limit. This selectivity is illustrated in the following inhibition table.
Alternatively, the present compounds may inhibit the activity of MMP-2 as compared to MMP-9 or MMP-13 and MMP-1. Similarly, the compounds can inhibit the activity of MMP-13 and MMP-2 while the inhibition of MMP-1 and MMP-9 is less. In addition, the compounds can inhibit the activity of MMP enzymes while having less effect on tumor necrosis factor release.
The selectivity of the present compounds can be understood by considering the therapeutic use of the present compounds, regardless of theory. For example, inhibition of MMP-1 is considered undesirable because of its role as a housekeeping enzyme that helps maintain normal connective tissue turnover and repair. Inhibition of MMP-1 can lead to toxic or side effects such as joint or connective tissue deterioration and pain. On the other hand, MMP-13 was thought to be closely related to the destruction of joint components in diseases such as osteoarthritis. Thus, potent and selective inhibition of MMP-13 in comparison to MMP-1 inhibition may be beneficial because the MMP-13 inhibitor not only has a positive effect on the progression of the disease in the patient, Very desirable.
Inhibition of MMP-2 and MMP-9 may be desirable for inhibiting tumor growth, metastasis, invasion and / or angiogenesis. Compared to MMP-1, the profile of selective inhibition of MMP-2 and MMP-9 can provide therapeutic advantages.
Another advantage of the present compounds is the selectivity associated with tumor necrosis factor release and / or tumor necrosis factor receptor release, which provides physicians with other factors that help to select the best agent for a particular patient. Without being bound by theory, it is believed that there are several factors in the type of selectivity considered.
First, the presence of the tumor necrosis factor may be desirable for the control of cancer in an organism, unless the tumor necrosis factor (TNF) is present in a toxic excess. Thus, unregulated inhibition of TNF release may lead to adverse effects, and may even be considered to cause adverse side effects, even in cancer patients. In addition, selectivity associated with inhibition of the release of tumor necrosis factor receptors may also be desirable. The presence of the receptor may be desirable to maintain a modulated tumor necrosis level in the mammal by binding to excess TNF.
The selective MMP inhibitor compounds of the present invention useful in the present methods can be administered in a variety of routes to provide appropriate therapeutic blood levels of inhibitors that are enzymatically active. The compounds can be administered, for example, by the oral (IG, PO) or intravenous (IV) route. Oral administration is advantageous if the patient is a hospital patient, is not hospitalized, and is able to eat enough medication at physically necessary intervals. This is true even when the patient is treated with one or more medicines for more than one disease. IV drug administration, on the other hand, is advantageous in hospital settings where dosages, and thus blood levels, can be well controlled. The inhibitor may also be formulated for IM administration if desired. Such routes of administration may be desirable for delivering medicines on a regular basis to a patient who is physically weak, has poorly obeyed records, or is in need of certain blood drug levels.
Accordingly, the present invention provides, in one embodiment, an effective dose of the present aromatic sulfonate hydroxamic acid metalloprotease inhibitor, or a pharmaceutically acceptable salt thereof, to a diseased mammalian host associated with pathological matrix metalloprotease activity And to a method of treatment which comprises administering a therapeutically effective amount of the compound. The present aromatic sulfonamide hydroxamate inhibitor compounds useful in this method inhibit the activity of one or more MMP-2, MMP-9 and MMP-13 in an in vitro assay as discussed in detail below and shown above, Lt; RTI ID = 0.0 > MMP-1. ≪ / RTI > Aromatic sulfone hydroxamate inhibitor compounds for use in the present process correspond in structure to the following formula I:
(I)

In one embodiment, R ¹ and R ² are both hydrazido. In another embodiment, R < ¹ > and R < ² > together with the atoms to which they are attached form a 5- to 8-membered ring containing one, two or three heteroatoms, do.
R ¹ and R ² together with the atom to which they are bonded form a 5-membered to 8-membered ring containing 1, 2 or 3 heteroatoms, together with the atoms to which they are bonded, one Or a 5-to 8-membered ring containing two heteroatoms. The heterocyclic ring itself may also be substituted with up to 6 C ₁ -C ₆ -alkyl groups, groups comprising other 5 to 8 member carbocyclic or heterocyclic rings, or amino groups, or one Or two oxo (carbonyl) groups.
R < ³ > in formula (I) is an optionally substituted aryl or an optionally substituted heteroaryl radical. Wherein said R ³ radical is selected from the group consisting of aryl, heteroaryl, aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl Arylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, aralkylthioaryl radical, sulfoxide or sulfone of thio substituent, and aryl, heteroaryl, heteroaryl, heteroaryl, And a fused ring structure comprising two or more 5-membered or 6-membered rings selected from the group consisting of aryl, carbocyclic and heterocyclic.
The substituent constituting R ³ itself is unsubstituted; Alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, heteroaryloxy, heteroaryl or heterocyclylalkyl, each of which is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, cyano, perfluoroalkyl, trifluoromethylalkyl, Heteroarylthio, aralkoxy, aralkylthio, aralkylamino, heteroaryl, heteroarylthio, heteroarylthio, heteroarylthio, heteroarylthio, aralkylthio, aralkylthio, aralkylthio, aralkylthio, heterocycloalkylthio, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, Alkanoyl, alkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, Alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxyalkyl Wherein the amino nitrogen is (i) unsubstituted, or (ii) alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, Substituted with one or two substituents independently selected from the group consisting of alkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and alkanoyl groups; iii) the amino nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing 0 to 2 additional heteroatoms which are nitrogen, oxygen or sulfur, (a) is unsubstituted or substituted with one or more substituents selected from the group consisting of (b) aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, Benzo fused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzo fused heterocycloalkoxy, benzo fused cycloalkylcarbonyl, heterocycloalkyl, Alkylcarbonyl, and cycloalkylcarbonyl group), carbonylamino (wherein the carboxamido is (i) unsubstituted or (ii) reacts with an amino acid Amine, or (iii) an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzo fused heterocycloalkyl, benzo fused heterocycloalkyl, benzo fused cycloalkyl , And N, N-dialkyl-substituted alkylamino-alkyl groups, or (iv) substituted with one or two radicals selected from the group consisting of And wherein the two substituents attached to the phenyl ring and the two substituents attached thereto are each independently unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl And amino groups wherein amino nitrogen is unsubstituted or substituted with one or two substituents independently selected from the group consisting of (ii) alkyl, aryl, and heteroaryl, or (iii) amino nitrogen And wherein the two substituents attached thereto form a 5- or 8-membered heterocyclo or heteroaryl ring), or a 5- to 8-membered heterocycle substituted with one or two radicals independently selected from the group consisting of , A heteroaryl or benzo fused heterocycloalkyl ring), and an aminoalkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) alkyl, aryl, aralkyl (Iii) aminoalkyl nitrogen and two substituents attached thereto are substituted with one or two substituents independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl groups; 5 to 8 membered heterocyclo or heteroaryl ring). ≪ / RTI > The compounds of formula I may also be used in the form of pharmaceutically acceptable salts.
The length of the R ³ radical is longer than the length of the pentyl group [a- (CH ₂ ) ₄ CH ₃ chain], and more preferably longer than the length of the hexyl group [a- (CH ₂ ) ₅ CH ₃ chain]. The length of the R ³ group is preferably an eicosyl group [eicosyl; a- (CH ₂ ) ₁₉ CH ₃ chain] and more preferably less than the length of the stearyl group [a- (CH ₂ ) ₁₇ CH ₃ chain]. The R ³ radical may be an SO ₂ -linked 1-position and a substituent-bonded 4-position of a 6-membered ring, or an SO ₂ -linked 1 -position of a 5-membered ring and an axis drawn through a 3- or 4- When rotated around it, it delimits a three-dimensional volume whose widest size has a width of about one furanyl ring to about two phenyl rings in the direction of rotation at the crossing of the axis.
For illustrative purposes, when the SO ₂ -binding R ³ radical is 4-phenoxyphenyl, the present compound may be represented as a phenoxyphenylsulfone derivative of the preferred 5-to 8-membered ring N-hydroxycarboxamide . Thus, exemplary compounds include:
N-hydroxy-1-methyl- [4- (phenoxyphenylsulfonyl)] - 4-piperidinecarboxamide,
N-hydroxy- [4- (phenoxyphenylsulfonyl)] tetrahydro-2H-pyran-4-carboxamide,
N-hydroxy-1-methyl- [2,6-dioxo-4- (phenoxyphenylsulfonyl)] - 4-piperidinecarboxamide,
Hydroxy-2,2-dimethyl- [5- (phenoxyphenyl-sulfonyl)] - 1,3-dioxane-5-carboxamide,
N-hydroxy-1,2-dimethyl-6-oxo- [4- (phenoxyphenyl-sulfonyl)] - 4-piperidinecarboxamide,
Hydroxy-2,2,6,6-tetramethyl- [4- (phenoxyphenyl-sulfonyl)] - 4-piperidinecarboxamide,
Hydroxy-1,3-dimethyl- [5- (phenoxyphenyl-sulfonyl)] - hexahydro-5-pyrimidinecarboxamide,
Amino-N-hydroxy- [5- (phenoxyphenylsulfonyl)] - 1,4,5,6-tetrahydro-5-pyrimidinecarboxamide,
N-hydroxy-1,1-dioxo [4- (phenoxyphenylsulfonyl)] - 1 (λ6) 2,6-thiadiazine-
Hydroxy-2-oxo [5- (phenoxyphenylsulfonyl)] - hexahydro-5-pyrimidinecarboxamide,
N-hydroxy- [2- (phenoxyphenylsulfonyl)] tetrahydro-2-furancarboxamide,
N-hydroxy-1-methyl- [2- (phenoxyphenylsulfonyl)] - 2-pyrrolidinecarboxamide,
N-hydroxy-2-methyl- [4- (phenoxyphenylsulfonyl)] - 4-piperidinecarboxamide,
N-hydroxy- [3- (phenoxyphenylsulfonyl)] - 8-azabicyclo [3.2.1] octane-3-carboxamide,
N-hydroxy-1,1-dioxo- [4- (phenoxyphenylsulfonyl)] - hexahydro-1 (lambda 6) -thiopyran-
N-hydroxy- [3- (phenoxyphenylsulfonyl)] tetrahydro-3-furancarboxamide,
N-hydroxy- [3- (phenoxyphenylsulfonyl)] - 3-pyrrolidinecarboxamide,
Hydroxy-4 - [[4- (phenylthio) phenyl] sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide, monohydrochloride,
Hydroxy-4 - [[4- (phenylthio) phenyl] sulfonyl] -1- (2-propynyl) -4- piperidinecarboxamide, monomethanesulfonate,
4- [[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide,
(4-pyridinylmethyl) -4 - [[4- [4- (trifluoromethyl) phenoxy] phenyl] -sulfonyl] -4-piperidinecarboxamide, hydro Chloride,
4- [[4- [4-trifluoromethyl] phenoxy] phenyl] -sulfonyl] -4-piperidinecarboxamide, dihydroxy- Chloride,
Phenyl] -sulfonyl] -4-piperidinecarboxamide, di (2-pyridinylmethyl) -4 - [[4- Hydrochloride,
4- [4- [4- (trifluoromethoxy) phenoxy] phenyl] -sulfonyl] -4-piperidinecarboxamide, dihydrochloride ,
4- [4- [4- (trifluoromethoxy) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide, monohydroxy- Chloride,
(2-methoxyethyl) -4 - [[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl) -4-piperidinecarboxamide, monohydro Chloride,
4- [4 - [(trifluoromethyl) thio] phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide , Monohydrochloride,
1 -cyclopropyl-N-hydroxy-4 - [[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide, monohydrochloride and the like.
Examples of the R ¹ and R ² groups forming the heterocyclic ring together with the various aromatic sulfonic hydroxamic acid compounds of the present invention include the following table and detailed descriptions of the rings of the 5- to 8-membered rings, For example.
In a more preferred embodiment, R ¹ and R ² in formula (I) together with the atoms to which they are attached form a 5-to 8-membered ring comprising one, two or three heteroatoms. Most preferably, said ring is a six-membered ring containing one heteroatom located at the 4-position relative to the position to which the SO ₂ group is attached. Other preferred compounds for use in this method correspond in structure to one or more of the following formulas II, III, IV or V discussed below.
In one embodiment, the preferred compounds used in the present process have a structure corresponding to formula II:
≪ RTI ID = 0.0 &

Wherein,
R ¹⁴ is selected from the group consisting of a hydrido, a pharmaceutically acceptable cation or C (W) R ¹⁵ wherein W is O or S and R ¹⁵ is C ₁ -C ₆ -alkyl, aryl, C ₁ -C ₆ -alkoxy, aryl -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aryloxy, aralkyl, -C ₁ -C ₆ - alkoxy, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl and amino C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkoxycarbonyl, C ₁ -C ₆ - alkoxycarbonyl, and C ₁ -C ₆ - the group consisting of alkanoyl radicals Or (iii) amino C ₁ -C ₆ -alkyl nitrogen and the two substituents attached thereto are substituted by one or two substituents independently selected from a 5 to 8 membered heterocyclo or heteroaryl ring Lt; / RTI >
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
the sum of m + n + p is 1, 2, 3 or 4;
(a) X, one of Y and Z is selected from ^{C (O), NR 6,} O, S, S (O), S (O) 2 and NS (O) group consisting of ₂ R ^7, X, The remaining two of Y and Z are CR ⁸ R ⁹ , and CR ¹⁰ R ¹¹ ,
(b) X and Z or Z and Y together ^{NR 6 C (O), NR} 6 S (O), NR 6 S (O) 2, NR 6 S, NR 6 O, SS, NR 6 NR 6, and OC (O), the other of X, Y and Z being CR ⁸ R ⁹ , or
(c) n is 0, and X, Y and Z together form a group of formula:

[Wherein,
The wavy line is the bond to the atom of the indicated ring;
R ⁶ and R ^{6 '} are independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkanoyl, C ₆ -aryl-C ₁ -C ₆ -alkyl, aroyl, bis (C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl) -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkyl, C ₁ -C ₆ - haloalkyl, C ₁ -C ₆ - perfluoroalkyl, C ₁ -C ₆ - trifluoromethyl alkyl, C ₁ -C ₆ - perfluoroalkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₈ - heterocycloalkyl, C ₃ -C ₈ - heterocycloalkyl-carbonyl, C ₆ - aryl, C ₅ -C ₆ - heterocycloalkyl, C ₅ -C ₆ - heteroaryl, C ₃ -C ₈ - cycloalkyl- C ₁ -C ₆ -alkyl, C ₆ -aryloxy-C ₁ -C ₆ -alkyl, heteroaryloxy-C ₁ -C ₆ -alkyl, heteroaryl-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, C ₆ -arylsulfonyl, C ₁ -C ₆ -alkylsulfonyl, C ₅ -C ₆ -heteroarylsulfonyl, carboxy-C ₁ -C ₆ -alkyl, C ₁ -C ₄ - alkoxy-carbonyl -C ₁ -C ₆ - alkyl, aminocarbonyl, C _l -C ₆ -alkyl already noka Viterbo carbonyl, C ₆ - Reel already noka Viterbo carbonyl, C ₅ -C ₆ - heterocycloalkyl already noka Viterbo carbonyl, C ₆ - arylthio -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, C ₆ - arylthio -C ₃ -C ₆ - alkenyl, C ₁ -C ₄ - alkylthio -C ₃ -C ₆ - alkenyl, C ₅ -C ₆ - heteroaryl, -C ₁ -C ₆ - alkyl, halo -C ₁ -C ₆ - alkanoyl, hydroxy -C _l -C ₆ - alkanoyl, thiol -C ₁ -C ₆ - alkanoyl, C ₃ -C ₆ - alkenyl, C ₃ -C ₆ - alkynyl C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkyl, C ₁ -C ₅ -alkoxycarbonyl, aryloxycarbonyl, NR ⁸ R ⁹ -C ₁ -C ₅ -alkylcarbonyl, hydroxy -C ₁ -C ₅ - alkyl, aminocarbonyl (where aminocarbonyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of an alkanoyl group), a hydroxy-aminocarbonyl, aminosulfonyl group (wherein, aminosulfonyl Nitrogen is (i) _{Or, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - Al 1 is independently selected from the group consisting of alkanoyl groups Amino-C ₁ -C ₆ -alkylsulfonyl, wherein the amino-C ₁ -C ₆ -alkylsulfonyl is (i) unsubstituted or (ii) substituted by C ₁ - C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - alkanoyl group substituted by one or two radicals independently selected from the group consisting of ) and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ -cycloalkyl and a C ₁ -C ₆ -alkanoyl group); R 1 is selected from the group consisting of:
R ⁷ is selected from the group consisting of benzyl, phenyl, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyl, and C ₁ -C ₆ -hydroxyalkyl groups;
R ^8, R ^9, R ¹⁰ and R ¹¹ are also hideurayi, hydroxy, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl -C ₁ -C ₆ - Alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl, thiol-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylthio-C ₁ -C ₆ -alkylcycloalkyl, C ₁ -C ₆ -alkyl, heterocycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, aralkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy carboxylic carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, arylthio ₁ -C -C ₆ - alkyl, heteroarylthio -C ₁ -C ₆ - alkyl, -C ₁ -C ₆ with a sulfoxide or sulfone, perfluoroalkyl of said thio substituents -methyl-alkyl, trifluoromethyl -C ₁ -C ₆ - Alkyl, halo-C ₁ -C ₆ -alkyl, alkoxycarbonylamino-C ₁ -C ₆ -alkyl Kill and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of alkanoyl search) with independently selected from the group consisting of; Or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ and the carbon to which they are bonded form a carbonyl group or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ or R ⁸ and R ¹⁰ are atoms to which they are bonded Or a 5-to 8-membered heterocyclic ring containing one or two heteroatoms of nitrogen, oxygen, or sulfur, or a 5- to 8-membered carbocyclic ring with the proviso that R ⁸ and R ⁹ , or only one of R < ¹⁰ > and R < ¹¹ > is hydroxy;
R ¹² and R ^{12 'are} also hideurayi, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl, C ₂ -C ₆ - alkynyl, C ₂ -C _6-alkenyl, thiol -C ₁ -C ₆ - alkyl, cycloalkyl, cycloalkyl -C ₁ -C ₆ - alkyl, heterocycloalkyl -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy-carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, arylthio -C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, the sulfoxide or sulfone of said thio substituent, perfluoro-C ₁ -C ₆ -alkyl, trifluoromethyl-C ₁ -C ₆ -alkyl, halo -C ₁ -C ₆ - alkyl, alkoxycarbonylamino -C ₁ -C ₆ - alkyl and Mino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl, and C ₁ - C ₆ - Al 1 is independently selected from the group consisting of alkanoyl, or substituted with two radicals) with independently selected from the group consisting of;
R ¹³ is selected from the group consisting of: hydrido, benzyl, phenyl, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl and C ₁ -C ₆ -hydroxyalkyl groups do]
Lt; RTI ID = 0.0 > of: < / RTI >
G-A-R-E-Y is preferably a substituent having a length longer than the length of the pentyl group, more preferably a length longer than the hexyl group. The substituent G-A-R-E-Y preferably has a length less than the length of the eicosyl group, more preferably less than the length of the stearyl group.
In this substituent,
G is an aryl or heteroaryl group;
A is selected from the group consisting of:
(1) -O-;
(2) -S-;
(3) -NR ¹⁷ -;
(4) -CO-N (R ¹⁷ ) or -N (R ¹⁷ ) -CO-, wherein R ¹⁷ is hydrogen, C ₁ -C ₄ -alkyl, or phenyl;
(5) -CO-O- or -O-CO-;
(6) -O-CO-O-;
(7) -HC = CH-;
(8) -NH-CO-NH-;
(9) -C C-;
(10) -NH-CO-O- or -O-CO-NH-;
(11) -N = N-;
(12) -NH-NH-; And
(13) -CS-N (R ¹⁸ ) - or -N (R ¹⁸ ) -CS-, wherein R ¹⁸ is hydrogen, C ₁ -C ₄ -alkyl, or phenyl; or
(14) A is absent and G is directly bonded to R;
R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Cycloalkyl, thioalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl substituents are unsubstituted or (ii) Alkoxy, C ₁ -C ₂ -alkylene-dioxy, hydroxycarbamoyl, perhaloalkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, One or two radicals selected from the group consisting of haloalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkylcarbonylalkyl, A residue selected from the group consisting of substituted), R A is not an alkyl or alkoxyalkyl when -O- or -S-;
E is selected from the group consisting of:
(1) -CO- (R ¹⁹⁾ or - (R ¹⁹⁾ -CO- (wherein, R ¹⁹ is a heterocycloalkyl, or a cycloalkyl group Im);
(2) -CONH- or -HNCO-;
(3) -CO-;
(4) -SO ₂ -R ¹⁹ - or -R ¹⁹ -SO ₂ -;
(5) -SO ₂ -
(6) -NH-SO ₂ - or -SO ₂ -NH-; or
(7) E is absent and R is directly bonded to Y;
Y is either not present or is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, Wherein the aryl, heteroaryl, or heterocycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of (i) alkyl, alkenyl, alkenyl, alkynyl, Wherein the amino nitrogen is (i) unsubstituted or (ii) is independently selected from the group consisting of hydrido, alkyl, and aralkyl groups; Substituted with one or two radicals selected from the group consisting of < RTI ID = 0.0 > (I) < / RTI >
The substituent -G-A-R-E-Y preferably comprises 2 to 4 carbocyclic or heterocyclic rings, including an aryl or heteroaryl group, G. More preferably, each of said rings is a six-membered ring. Also preferred are compounds of formula II wherein: (a) A is -O- or -S-, (b) R is aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, (c) E is absent , (d) Y is a compound selected from the group consisting of hydride, alkyl, alkoxy, perfluoroalkoxy and perfluoroalkylthio groups.
A more preferred compound for use in the present method has a structure corresponding to formula III:
(III)

Wherein,
R ³ is a 5-membered or 6-membered monocyclic aryl or heteroaryl group, at its 4-position if it is a 6-membered ring and at its 3- or 4- 4-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, Phenoxy, 4-trifluoromethoxy-phenoxy, 4-trifluoromethylphenoxy, 4- (trifluoromethylthio) -phenoxy, 4- (trifluoromethyl Thiophenoxy, 4-isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazol- 3-methylphenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy (4-methoxyphenoxy) , 4-fluoro-3-chlorophenoxy, 4- (lH-1,2,4-triazol-1-yl) phenoxy, 3,5- difluoro 4-methylphenoxy, 4-methylthiophenoxy, 4-phenylphenoxy, 4-fluorophenoxy, 4-chloropentylphenoxy, 3-methylphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-methoxyphenoxy, 3- Lt; / RTI > is substituted with a substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl,
R ¹⁴ is a hydride, a pharmaceutically acceptable cation or a C (W) R ¹⁵ wherein W is O or S and R ¹⁵ is C ₁ -C ₆ -alkyl, aryl, C ₁ -C ₆ -alkoxy, heteroaryl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aryloxy, aralkyl, -C ₁ -C ₆ - alkoxy, aralkyl, -C ₁ -C ₆ - alkyl , Heteroaryl and amino C ₁ -C ₆ -alkyl groups wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkoxycarbonyl, C ₁ -C ₆ - alkoxycarbonyl, and C ₁ -C ₆ - alkanoyl radical consisting of Or (iii) amino C ₁ -C ₆ -alkyl nitrogen and two substituents attached thereto are substituted by one or two substituents independently selected from the group consisting of a 5- to 8-membered heterocyclo or heteroaryl ring Lt; / RTI >
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
the sum of m + n + p is 1, 2, 3 or 4;
(a) X, one of Y and Z is selected from ^{C (O), NR 6,} O, S, S (O), S (O) 2 and NS (O) group consisting of ₂ R ^7, X, The remaining two of Y and Z are CR ⁸ R ⁹ , and CR ¹⁰ R ¹¹ ,
(b) X and Z or Z and Y together ^{NR 6 C (O), NR} 6 S (O), NR 6 S (O) 2, NR 6 S, NR 6 O, SS, NR 6 NR 6, and OC (O), the other of X, Y and Z being CR ⁸ R ⁹ , or
(c) n is 0, and X, Y and Z together form a group of formula:

[Wherein,
The wavy line is the bond to the atom of the indicated ring;
R ⁶ and R ^{6 '} are independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkanoyl, C ₆ -aryl-C ₁ -C ₆ -alkyl, aroyl, bis (C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl) -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkyl, C ₁ -C ₆ - haloalkyl, C ₁ -C ₆ - perfluoroalkyl, C ₁ -C ₆ - trifluoromethyl alkyl, C ₁ -C ₆ - perfluoroalkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₈ - heterocycloalkyl, C ₃ -C ₈ - heterocycloalkyl-carbonyl, C ₆ - aryl, C ₅ -C ₆ - heterocycloalkyl, C ₅ -C ₆ - heteroaryl, C ₃ -C ₈ - cycloalkyl- C ₁ -C ₆ -alkyl, C ₆ -aryloxy-C ₁ -C ₆ -alkyl, heteroaryloxy-C ₁ -C ₆ -alkyl, heteroaryl-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, C ₆ -arylsulfonyl, C ₁ -C ₆ -alkylsulfonyl, C ₅ -C ₆ -heteroarylsulfonyl, carboxy-C ₁ -C ₆ -alkyl, C ₁ -C ₄ - alkoxy-carbonyl -C ₁ -C ₆ - alkyl, aminocarbonyl, C _l -C ₆ -alkyl already noka Viterbo carbonyl, C ₆ - Reel already noka Viterbo carbonyl, C ₅ -C ₆ - heterocycloalkyl already noka Viterbo carbonyl, C ₆ - arylthio -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, C ₆ - arylthio -C ₃ -C ₆ - alkenyl, C ₁ -C ₄ - alkylthio -C ₃ -C ₆ - alkenyl, C ₅ -C ₆ - heteroaryl, -C ₁ -C ₆ - alkyl, halo -C ₁ -C ₆ - alkanoyl, hydroxy -C _l -C ₆ - alkanoyl, thiol -C ₁ -C ₆ - alkanoyl, C ₃ -C ₆ - alkenyl, C ₃ -C ₆ - alkynyl C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkyl, C ₁ -C ₅ -alkoxycarbonyl, aryloxycarbonyl, NR ⁸ R ⁹ -C ₁ -C ₅ -alkylcarbonyl, hydroxy -C ₁ -C ₅ - alkyl, aminocarbonyl (where aminocarbonyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of an alkanoyl group), a hydroxy-aminocarbonyl, aminosulfonyl group (wherein, aminosulfonyl Nitrogen is (i) _{Or, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - Al 1 is independently selected from the group consisting of alkanoyl groups Amino-C ₁ -C ₆ -alkylsulfonyl, wherein the amino-C ₁ -C ₆ -alkylsulfonyl is (i) unsubstituted or (ii) substituted by C ₁ - C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - alkanoyl group substituted by one or two radicals independently selected from the group consisting of ) and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ -cycloalkyl and a C ₁ -C ₆ -alkanoyl group); R 1 is selected from the group consisting of:
R ⁷ is selected from the group consisting of benzyl, phenyl, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyl, and C ₁ -C ₆ -hydroxyalkyl groups;
R ^8, R ^9, R ¹⁰ and R ¹¹ are also hideurayi, hydroxy, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl -C ₁ -C ₆ - Alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl, thiol-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylthio-C ₁ -C ₆ -alkylcycloalkyl, C ₁ -C ₆ -alkyl, heterocycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, aralkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy carboxylic carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, arylthio ₁ -C -C ₆ - alkyl, heteroarylthio -C ₁ -C ₆ - alkyl, -C ₁ -C ₆ with a sulfoxide or sulfone, perfluoroalkyl of said thio substituents -methyl-alkyl, trifluoromethyl -C ₁ -C ₆ - Alkyl, halo-C ₁ -C ₆ -alkyl, alkoxycarbonylamino-C ₁ -C ₆ -alkyl Kill and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of alkanoyl search) with independently selected from the group consisting of; Or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ and the carbon to which they are bonded form a carbonyl group or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ or R ⁸ and R ¹⁰ are atoms to which they are bonded Or a 5-to 8-membered heterocyclic ring containing one or two heteroatoms of nitrogen, oxygen, or sulfur, or a 5- to 8-membered carbocyclic ring with the proviso that R ⁸ and R ⁹ , or only one of R < ¹⁰ > and R < ¹¹ > is hydroxy;
R ¹² and R ^{12 'are} also hideurayi, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl, C ₂ -C ₆ - alkynyl, C ₂ -C _6-alkenyl, thiol -C ₁ -C ₆ - alkyl, cycloalkyl, cycloalkyl -C ₁ -C ₆ - alkyl, heterocycloalkyl -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy-carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, arylthio -C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, the sulfoxide or sulfone of said thio substituent, perfluoro-C ₁ -C ₆ -alkyl, trifluoromethyl-C ₁ -C ₆ -alkyl, halo -C ₁ -C ₆ - alkyl, alkoxycarbonylamino -C ₁ -C ₆ - alkyl and Mino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl, and C ₁ - C ₆ - Al 1 is independently selected from the group consisting of alkanoyl, or substituted with two radicals) with independently selected from the group consisting of;
R ¹³ is selected from the group consisting of: hydrido, benzyl, phenyl, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl and C ₁ -C ₆ -hydroxyalkyl groups A group selected from the group consisting of Again, the use of a compound of formula (III) as a pharmaceutically acceptable salt is also contemplated.
With respect to compounds of formula (III) (also applied to compounds of formula (II), the following compounds are preferred, which are independently preferred: (a) the sum of m + n + p is 1 or 2, more preferably 2 ego; (b) Z is O, S or NR < ⁶ >; (c) R ⁶ is C ₃ -C ₆ -cycloalkyl, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl, C ₁ -C ₆ -alkoxy-C C ₁ -C ₆ -alkyl, amino-C ₁ -C ₆ -alkyl, aminosulfonyl, heteroaryl-C ₁ -C ₆ -alkyl, aryloxycarbonyl, and C ₁ -C ₆ -alkoxycarbonyl ≪ / RTI > (d) m = n = 0, p = 1, and Y is NR ⁶ . Other preferred compounds of formula II and III are those wherein R ¹⁴ is hydrazido or C (W) R ¹⁵ wherein W is O and R ¹⁵ is C ₁ -C ₆ -alkyl, aryl, C ₁ - C ₆ -alkoxy, heteroaryl-C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₆ -alkyl, or an aryloxy group.
Even more preferred compounds for use in this method correspond in structure to the following formula IV:
(IV)

Wherein,
R ³ is as defined in formulas I and III, more preferably as defined in formula II, wherein the R ³ radical is the substituent GAREY, most preferably R ³ is as defined in formula III Is the same;
Z is O, S, NR ⁶ , SO, SO ₂ , and NSO ₂ R ⁷ wherein R ⁶ is selected from the group consisting of: hydrido, C ₁ -C ₅ -alkyl, C ₁ -C ₅ -alkanoyl, benzyl, benzoyl, C ₃ -C ₅ - alkynyl, C ₃ -C ₅ - alkenyl, C ₁ -C ₃ - alkoxy -C ₁ -C ₄ - alkyl, C ₃ -C ₆ - cycloalkyl, heteroaryl, -C ₁ -C ₆ -alkyl, C ₁ -C ₅ - hydroxyalkyl, C ₁ -C ₅ - alkyl, carboxyl, C ₁ -C ₅ - alkoxy C ₁ -C ₅ -alkyl-carbonyl, and NR ⁸ R ⁹ -C ₁ -C ₅ -Alkylcarbonyl or NR ⁸ R ⁹ -C ₁ -C ₅ -alkyl, wherein R ⁸ and R ⁹ are independently selected from the group consisting of hydrido, C ₁ -C ₅ -alkyl, C ₁ -C ₅ -alkoxycarbonyl or aryl C ₁ -C ₅ -alkoxycarbonyl, or NR ⁸ R ⁹ together form a heterocyclic ring comprising 5 to 8 atoms in the ring; R ⁷ is selected from the group consisting of arylalkyl, Aryl, heteroaryl, heterocyclo, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyl, C ₁ -C ₆ -carboxyalkyl and C ₁ -C ₆ -hydro Roxy alkyl group From the group is a group selected from the group consisting of selected). Z is most preferably O or NR < ^{6 &} gt ;. Here too, the use of a compound of formula IV as a pharmaceutically acceptable salt is also contemplated.
This group of compounds which are even more preferred for use in the present process corresponds in structure to the following formula V:
(V)

Wherein,
Z is as previously defined in formula IV;
W and Q are independently oxygen (O), NR ⁶ or sulfur (S), R ⁶ is as defined in formula IV;
q is 0 or 1, and when q is 0, Q is not present and the trifluoromethyl group is directly bonded to the phenyl ring shown. Here too, the use of a compound of formula (V) as a pharmaceutically acceptable salt is contemplated.
Particularly preferred compounds within the group defined by formula V have the structural formulas shown below in terms of structure:



Also particularly preferred compounds are those of the formula:

Several particularly preferred compounds having structures corresponding to Formulas I through V are illustrated in the tables and examples provided below.
As can be seen above, the compounds of formulas II, III, IV and V, and the pharmaceutically acceptable salts thereof, are themselves regarded as the compounds of the present invention.
In a preferred embodiment, SO ₂ - bonded R ³ radical is that of its own one of the other single-ring aryl or heteroaryl group, or a carbon atom number of 3 to about 16 chain lengths (more preferably, a length of about 14 or less carbon atoms C ₆ H ₅ -S-] group, phenylazo [C ₆ H ₅ -N ₂ -] group, N-piperidyl [C ₅ H _10] An aryl or heteroaryl group which is a 5-membered or 6-membered monocyclic ring substituted by an N-piperazine [NC ₄ H ₉ N-] group or a benzamido [-NHC (O) C ₆ H ₅ ] to be. Wherein the SO ₂ -bonded monocyclic aryl or heteroaryl R ³ group is substituted at its 4-position for the 6-membered ring and at its 3- or 4-position for the 5-membered ring.
The SO ₂ -bonded aryl or heteroaryl group of the R ³ radical is preferably itself substituted at the 4-position for a 6-membered ring or at the 3- or 4-position for a 5-membered ring. Particularly preferred substituents are monocyclic aryl or heteroaryl which may be unsubstituted or substituted on its own, phenoxy, thiophenoxy, phenylazo, N-piperidyl, N-piperazyl, or benzamido.
The 4- and 3-positions of the rings discussed herein are numbered from substituent bonding sites as compared to the authorized ring numbering positions used in the heteroaryl nomenclature, as discussed further below. Herein, even though longer substituents having a total length of less than or equal to the eicosyl group may be accepted, a single atom such as a halogen residue (fluoro, chloro, bromo, or iodo) Preferred substituents include chain lengths such as phenyl, C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, trifluorothiomethyl or carboxyethyl groups.
Particularly preferred examples of substituted SO ₂ -bonded R ³ radicals include 4- (phenyl) phenyl [biphenyl], 4- (4'-methoxyphenyl) -phenyl, 4- (phenoxy) 4 - [(4'-trifluoromethylthio) phenoxy] phenyl, 4 - [(4'-trifluoromethyl) phenyl] 4 - [(4'-trifluoromethyl) phenoxy] phenyl, 4 - [(4'-trifluoromethyl) thiophenyl] (4'-trifluoromethoxy) thiophenyl] phenyl, 4- [(4'-phenyl) -N-piperidyl] phenyl, 4- Acetyl) -N-piperazinyl] phenyl and 4- (benzamido) phenyl.
As long as the SO ₂ -bonded aryl or heteroaryl radical of the R ³ group is preferably itself replaced by a six-membered ring, two naming systems are used herein together to facilitate understanding of the substituent position. The first system uses the position number for the ring directly bonded to the SO ₂ - group, while the second system uses the position number for the substituent of one or more six-membered rings bonded to the SO ₂ -bonded aryl or heteroaryl radical, Or para. It is believed that the ortho, meta and para positional nomenclature is not commonly used in aliphatic ring systems, but will make the description of the compounds easier to understand when used in conjunction with the numerical designation system for the first ring bound to the SO ₂ - group. When the R < ³ > radical is not a 6-membered ring, the substitution position is numbered from the bonding position for an aromatic or heteroaromatic ring. Certified chemical nomenclature is used in naming specific compounds.
Thus, the SO ₂ in the discussion-coupled aryl or 1-position of the heteroaryl groups are SO ₂ - where the groups are bonded to the ring. The 4- and 3-positions of the rings discussed herein are numbered from the substituent bonding position from the SO ₂ - bond as compared to the formulated ring numbering position used for heteroaryl nomenclature.
Together with the longest chain of atoms, the R ³ radical, including its own substituent, has a longer total length than the saturated chain (pentyl group) of 5 carbon atoms, preferably a saturated chain of 6 carbon atoms (I.e., having a length of at least about heptyl chain). The R ³ radical also has a length of less than the length of the saturated chain of about 20 carbon atoms [the eicosyl group (formerly spelled with eicosyl)], more preferably the saturated chain (stearyl group) of about 18 carbon atoms I have. Most preferably, the length of the R < ³ > group is the length of the chain of 8 to about 12 carbon atoms, even if more valency is present in the ring structure or substituent. The length requirements are further discussed below.
The R < ³ > radical (group or moiety) has a length longer than the length of the pentyl group, except for certain residues that constitute it, more generally. This R ³ radical also has a length less than the length of the eicosyl (didecyl) group. That is, R ³ has a minimum length longer than the saturated chain of 5 carbon atoms, preferably a minimum length longer than the hexyl group, but less than the length of the saturated chain of 20 carbon atoms, preferably less than 18 carbon atoms Lt; / RTI > chain length. Most preferably, R < ³ > is longer than the octyl group and has a length less than the lauryl group.
More specifically, the R < ³ > group has the minimum length of the hexyl group when the substituent is composed of only two rings which can be fused or can be covalently bonded together by exocyclic bonds. When R ³ does not include two bonds or fused rings, for example when the R ³ radical comprises an alkyl or a second, third or fourth ring substituent, R ³ has a longer length than the hexyl group . Examples of such two-ring R ³ groups are 2-naphthyl or 2-quinolinyl (each having a chain length of 6 carbon atoms) and 8-purinyl (having a chain length of 5 carbon atoms). Without being bound by theory, it is believed that the presence of multiple rings at R ³ enhances the selectivity of the enzyme activity inhibitor profile.
The length of the radical chain is measured along the longest linear atomic chain in the radical along the skeletal atom around the ring if necessary. Each atom of the chain, for example carbon, oxygen, sulfur or nitrogen, is assumed to be carbon for ease of calculation.
Such a length may be determined by measuring the desired, generally staggered chain, if necessary, using the published coupling angle, coupling length and atomic radius, or by comparing the coupling angle, length and atomic radius to the permitted presentation values Can be easily determined by making a model using a purchasable kit. The length of the radical (substituent) is also the same as that of the unsaturated bond, although the above measurement method is preferable, the unsaturated bond has the same length as the saturated bond, and the bonding angle of the unsaturated bond is the same as the bonding angle of the saturated bond , It can be measured somewhat less accurately. For example, using this measurement method, the phenyl or pyridyl group has a chain length of 4 carbon atoms, similar to the propoxy group, while the biphenyl group has a chain length of about 8 carbon atoms.
In addition, R ³ SO ₂ group of the six membered ring - when rotated about an axis drawn through the engaged position and the substituent bonded 3-or 4-position-bonded 1-position and 4-position, or 5-SO ₂ of ring , Bounding the three-dimensional volume, the widest dimension of which has a width of about one furanyl ring to about two phenyl rings in the direction of rotation at the crossing of the axis.
Thus, the 2-naphthyl substituent or the 8-furanyl substituent will be of the order of magnitude of about R ^{3 when} viewed on the basis of the above rotational width, and the criteria discussed above. On the other hand, the 1-naphthyl group or the 7- or 9-purinyl group is too large on rotation to be excluded from the R ³ group.
As a result of the above length and width requirements, it was found that 4- (phenyl) phenyl [4- (4'-methoxyphenyl) (Phenylthio) phenyl], 4- (azophenyl) phenyl, 4 - [(4'-trifluoromethylthio) 4 - [(4'-trifluoromethoxy) phenoxy] phenyl, 4 - [(4'-trifluoromethyl) thiophenyl] Phenyl, 4 - [(4'-acetyl) -N-piperazine] phenyl, 4 - [(4'-trifluoromethoxy) thiophenyl] Lt; / RTI > phenyl and 4- (benzamido) phenyl are particularly preferred R < ³ > radicals. The substituent also with a substituent containing a longest chain length that contain atoms of 5 or less, except for a single atom, or preferably a hydrogen meta- or para-position, or at both of the second ring from the group SO ₂ It can be replaced by itself.
Without being bound by theory, it is believed that the length of the R ³ radical substituent attached to the SO ₂ group generally plays an important role in the overall activity of the present inhibitor compounds on the MMP enzyme. The length of the R ³ radical group also appears to play an important role in the selective activity of inhibitor compounds on certain MMP enzymes.
In a particularly preferred embodiment, R ³ is a PhR ²³ group wherein Ph is phenyl. The phenyl ring (Ph) of the PhR ²³ group may be substituted by other single ring aryl or heteroaryl group, piperidyl group, piperazinyl group, phenoxy group, thiophenoxy [C ₆ H ₅ -S-] group, phenylazo [C ₆ H ₅ -N ₂ -] group or a benz amido _{[NHC (O) C 6 H} 5] by a group R ²³ which can date its para-substituted at a position (4-position).
In one embodiment of a particularly preferred aromatic sulfonamide hydroxamate inhibitor compound, the R ²³ substituent is phenoxy and is selected from the group consisting of halogen, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ alkyl group, a dimethylamino group, a carboxyl C ₁ -C _A C ₁ -C ₃ alkylene group, a C ₁ -C ₄ alkoxycarbonyl C ₁ -C ₃ alkylene group, a trifluoromethylthio group, a trifluoromethoxy group, a trifluoromethyl group, and a carboxy C ₁ -C ₃ alkylene group Substituted at its para-position with a residue selected from the group or substituted at the meta- and para-positions with a methylenedioxy group. It is to be understood that the R < ²³ > substituent may be substituted with a residue from the above list. Substitution at said para-position is preferred.
The present invention also relates to intermediates useful in the preparation of compounds of Formulas (I) through (V). This intermediate compound corresponds in structure to the following formula VI:
(VI)

Wherein,
g is 0, 1 or 2;
R ²⁰ is selected from the group consisting of: (a) -OR ²¹ wherein R ²¹ is selected from the group consisting of a hydrido, C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl and a pharmaceutically acceptable cation, Or (b) -NH-OR ²² , wherein R ²² is an optionally removable protecting group such as 2-tetrahydropyranyl, C ₁ -C ₆ -acyl, aroyl, benzyl, p-methoxybenzyl MOZ) carbonyl -C ₁ -C ₆ - alkoxy, trisubstituted silyl group or an o- inde nitro group, peptide synthesis resin and the like, wherein trisubstituted silyl group is C ₁ -C ₆ - alkyl, aryl, aralkyl or -C ₁ - Lt; ₆ >-alkyl;
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
the sum of m + n + p is 1, 2, 3 or 4;
(a) X, one of Y and Z is selected from ^{C (O), NR 6,} O, S, S (O), S (O) 2 and NS (O) group consisting of ₂ R ^7, X, The remaining two of Y and Z are CR ⁸ R ⁹ , and CR ¹⁰ R ¹¹ ,
(b) X and Z or Z and Y together ^{NR 6 C (O), NR} 6 S (O), NR 6 S (O) 2, NR 6 S, NR 6 O, SS, NR 6 NR 6, and OC (O), the other of X, Y and Z being CR ⁸ R ⁹ , or
(c) n is 0, and X, Y and Z together form a group of formula:

[Wherein,
The wavy line is the bond to the atom of the ring shown,
R ⁶ and R ^{6 '} are independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkanoyl, C ₆ -aryl-C ₁ -C ₆ -alkyl, aroyl, bis (C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl) -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkyl, C ₁ -C ₆ - haloalkyl, C ₁ -C ₆ - perfluoroalkyl, C ₁ -C ₆ - trifluoromethyl alkyl, C ₁ -C ₆ - perfluoroalkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₈ - heterocycloalkyl, C ₃ -C ₈ - heterocycloalkyl-carbonyl, C ₆ - aryl, C ₅ -C ₆ - heterocycloalkyl, C ₅ -C ₆ - heteroaryl, C ₃ -C ₈ - cycloalkyl- C ₁ -C ₆ -alkyl, C ₆ -aryloxy-C ₁ -C ₆ -alkyl, heteroaryloxy-C ₁ -C ₆ -alkyl, heteroaryl-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, C ₆ -arylsulfonyl, C ₁ -C ₆ -alkylsulfonyl, C ₅ -C ₆ -heteroarylsulfonyl, carboxy-C ₁ -C ₆ -alkyl, C ₁ -C ₄ - alkoxy-carbonyl -C ₁ -C ₆ - alkyl, aminocarbonyl, C _l -C ₆ -alkyl already noka Viterbo carbonyl, C ₆ - Reel already noka Viterbo carbonyl, C ₅ -C ₆ - heterocycloalkyl already noka Viterbo carbonyl, C ₆ - arylthio -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, C ₆ - arylthio -C ₃ -C ₆ - alkenyl, C ₁ -C ₄ - alkylthio -C ₃ -C ₆ - alkenyl, C ₅ -C ₆ - heteroaryl, -C ₁ -C ₆ - alkyl, halo -C ₁ -C ₆ - alkanoyl, hydroxy -C _l -C ₆ - alkanoyl, thiol -C ₁ -C ₆ - alkanoyl, C ₃ -C ₆ - alkenyl, C ₃ -C ₆ - alkynyl C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkyl, C ₁ -C ₅ -alkoxycarbonyl, aryloxycarbonyl, NR ⁸ R ⁹ -C ₁ -C ₅ -alkylcarbonyl, hydroxy -C ₁ -C ₅ - alkyl, aminocarbonyl (where aminocarbonyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of an alkanoyl group), a hydroxy-aminocarbonyl, aminosulfonyl group (wherein, aminosulfonyl Nitrogen is (i) _{Or, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - Al 1 is independently selected from the group consisting of alkanoyl groups Amino-C ₁ -C ₆ -alkylsulfonyl, wherein the amino-C ₁ -C ₆ -alkylsulfonyl is (i) unsubstituted or (ii) substituted by C ₁ - C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - alkanoyl group substituted by one or two radicals independently selected from the group consisting of ) and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ -cycloalkyl and a C ₁ -C ₆ -alkanoyl group); R 1 is selected from the group consisting of:
R ⁷ is selected from the group consisting of benzyl, phenyl, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyl, and C ₁ -C ₆ -hydroxyalkyl groups;
R ^8, R ^9, R ¹⁰ and R ¹¹ are also hideurayi, hydroxy, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl -C ₁ -C ₆ - Alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl, thiol-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylthio-C ₁ -C ₆ -alkylcycloalkyl, C ₁ -C ₆ -alkyl, heterocycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, aralkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy carboxylic carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, arylthio ₁ -C -C ₆ - alkyl, heteroarylthio -C ₁ -C ₆ - alkyl, -C ₁ -C ₆ with a sulfoxide or sulfone, perfluoroalkyl of said thio substituents -methyl-alkyl, trifluoromethyl -C ₁ -C ₆ - Alkyl, halo-C ₁ -C ₆ -alkyl, alkoxycarbonylamino-C ₁ -C ₆ -alkyl Kill and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of alkanoyl search) with independently selected from the group consisting of; Or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ and the carbon to which they are bonded form a carbonyl group or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ or R ⁸ and R ¹⁰ are atoms to which they are bonded Or a 5-to 8-membered heterocyclic ring containing one or two heteroatoms of nitrogen, oxygen, or sulfur, or a 5- to 8-membered carbocyclic ring with the proviso that R ⁸ and R ⁹ , or only one of R < ¹⁰ > and R < ¹¹ > is hydroxy;
R ¹² and R ^{12 'are} also hideurayi, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl, C ₂ -C ₆ - alkynyl, C ₂ -C _6-alkenyl, thiol -C ₁ -C ₆ - alkyl, cycloalkyl, cycloalkyl -C ₁ -C ₆ - alkyl, heterocycloalkyl -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy-carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, arylthio -C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, the sulfoxide or sulfone of said thio substituent, perfluoro-C ₁ -C ₆ -alkyl, trifluoromethyl-C ₁ -C ₆ -alkyl, halo -C ₁ -C ₆ - alkyl, alkoxycarbonylamino -C ₁ -C ₆ - alkyl and Mino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl, and C ₁ - C ₆ - Al 1 is independently selected from the group consisting of alkanoyl, or substituted with two radicals) with independently selected from the group consisting of;
R ¹³ is selected from the group consisting of: hydrido, benzyl, phenyl, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl and C ₁ -C ₆ -hydroxyalkyl groups do]
Lt; RTI ID = 0.0 > of: < / RTI >
R ²⁴ is R ³ as defined in formula I, III or IV, or a substituent GAREY of formula II (formula VIA). Alternatively, R ²⁴ is a coupling substituent having a reactivity in coupling with another moiety, such as an R ^{3 '} , aryl, or heteroaryl group (Formula VIB) substituted with a nucleophilically replaceable leaving group D.
(VIA)

[Chemical Formula VIB]

Examples of the substitutable leaving group D in the parent haekjeok include halo (fluoro, chloro, bromo, or iodo), nitro, azido, phenyl sulfoxides also, aryloxy, C ₁ -C ₆ - alkoxy, C ₁ - C ₆ -alkylsulfonate or arylsulfonate group and a trisubstituted ammonium group wherein the three substituents are independently aryl, -C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkyl. Additional coupling substituents include, but are not limited to, amino and hydroxyl groups that can be coupled with a carbonyl-containing moiety to form esters, urethanes, carbonates, amides, and ureas. Similarly, a carboxyl-coupling substituent can be used to form an ester, thioester, or amide. Thus, a coupling substituent is useful to convert a coupling substituent-containing aryl or heteroaryl group to a substituent such as the GAREY substituent discussed above by formation of a covalent bond.
Compounds of formula VI can be coupled with other moieties in the R ^{3 '} coupling substituent to form compounds wherein the newly formed R ³ group is a group of formula I, III, IV or -GAREY. Examples of such couplings are nucleophilic substitution to form bonds of ethers and thioethers with esters, amides, ureas, carbonates, urethanes, and the like.
A particularly preferred precursor intermediate for the intermediate compound of formula (VI) is an intermediate compound of formula (VII)
(VII)

Wherein m, n, p, g, X, Z, Y, D and R ²⁰ are as defined in Formula VI.
R ²⁰ is preferably -NH-OR ²² wherein R ²² is an optionally removable protecting group such as 2-tetrahydropyranyl, C ₁ -C ₆ -acyl, aroyl, benzyl, p-methoxy (MOZ) carbonyl-C ₁ -C ₆ -alkoxy, o-nitrophenyl group, a peptide synthetic resin (for example, a so-called Merrifield peptide resin available from Sigma Chemical Co.) Particularly preferred is 2-tetrahydropyranyl. Thus, the -NH-OR ²² group (R ²⁰ ) in formulas VI and VII appears to be the reaction product of hydroxylamine in which oxygen is attached to a selectively removable protecting group and a carboxyl group.
With respect to each of the compounds of formulas VI and VII, the subscript " g " is used to denote the oxidation state of the sulfur atom. When g is 0, the sulfur is not oxidized and the exemplified compounds are sulfide reaction products of sulfur-containing synthons, as generally illustrated in the Examples below. When g is 1, the sulfur is oxidized to sulfoxide, while when g is 2, the sulfur is oxidized to the sulfone as also illustrated below. Compounds of formula (VI) or (VII), wherein g is 0 or 1, are usually themselves intermediates in the preparation of analogous compounds wherein g is 2, and this intermediate is the preferred sulfone.
Accordingly, preferred intermediates correspond to the following formula VIIA in terms of structure.
In describing molecules and groups in detail, the description of molecules may be combined to produce a word or phrase describing a structural group, or may be combined to describe a structural group. Such statements are used in this document. Typical illustrative examples include such terms as aralkyl (or arylalkyl), heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, aralkoxyalkoxycarbonyl, and the like. Specific examples of the compounds included in the latter alkoxyalkoxycarbonyl include C ₆ H ₅ -CH ₂ -CH ₂ -O-CH ₂ -O- (C = O) (wherein C ₆ H ₅ - represents phenyl Lt; / RTI > It is also to be understood that the structural groups may have one or more of the art's technical words or phrases, for example the heteroaryloxyalkylcarbonyl may also be denoted by the term heteroaryloxyalkanoyl. Such combinations are used herein in the description of the methods, compounds and compositions of the present invention, and further examples are described below. The following list provides illustrative examples of words or phrases used herein and is not intended to be limiting to the examples.
The term " alkyl ", as used herein, alone or in combination signifies a straight or branched chain alkyl radical having from 1 to about 12 carbon atoms, preferably from 1 to about 10, more preferably from 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl,
The term " alkenyl ", alone or in combination, signifies a straight or branched chain having from 2 to about 12 carbon atoms, preferably from 2 to about 10, more preferably from 2 to about 6, Means a hydrocarbon radical. Examples of suitable alkenyl radicals include but are not limited to ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, -Butenyl, decenyl, and the like.
The term " alkynyl ", alone or in combination, signifies a straight-chain hydrocarbon having at least one triple bond of from 2 to about 12 carbon atoms, preferably from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms Radical. ≪ / RTI > Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl and the like.
The term " carbonyl " or " oxo ", alone or in combination, signifies a -C (= O) - group in which the remaining two bonds (valences) may be independently substituted. The term carbonyl is also meant to include the hydrated carbonyl group -C (OH) ₂ -.
The term " thiol " or " sulfhydryl ", alone or in combination, signifies a-SH group. The term " thio " or " thia ", alone or in combination, I. E. An ether group in which the ether oxygen is replaced by a sulfur atom.
The term " amino ", alone or in combination signifies an amine or -NH ₂ group, whereas the term monosubstituted amino, alone or in combination, refers to a substituted amine -N (H) (substituent) group in which one hydrogen atom is replaced by a substituent And the disubstituted amine means -N (substituent) ₂ wherein two hydrogen atoms of the amino group are replaced by a substituent independently selected.
Amines, amino groups and amides can be represented by primary (I °), secondary (II °), tertiary (III °) or unsubstituted, monosubstituted or N, N-disubstituted to be. Quaternary amine (ammonium) (IV °) means nitrogen with four substituents [-N ⁺ (substituent) ₄ ] with a positive charge and a counter ion, whereas N-oxides are oxygen in which one substituent is oxygen ^{group-represented} by [-N ⁺ (substituent) ₃ -O]; That is, the charge is internally offset.
The term " cyano ", alone or in combination, signifies a -C-triple bond -N (-C N) group. The term " azido ", alone or in combination, signifies an -N-triple bond -N (-N≡N) group. The term " hydroxyl ", alone or in combination, means an -OH group. The term " nitro ", alone or in combination, signifies the -NO ₂ group. The term " azo ", alone or in combination, means an -N = N-group in which the bond at the terminal position can be independently substituted.
The term " hydrazino ", alone or in combination, means an -NH-NH- group in which the remaining two bonds (valences) below may be independently substituted. The hydrogen atom of the hydrazino group may be independently substituted by a substituent, and the nitrogen atom may form an acid addition salt or quaternized.
Alone or in combination The term "sulfonyl" is -SO ₂ where the remaining two bond (valence) below may be substituted independently - group. The term " sulfoxido ", alone or in combination, means an -SO- group in which the remaining two bonds (valences) may be independently substituted.
Alone or the combination term "sulfone" is -SO ₂ where the remaining two bond (valence) below may be substituted independently - group. The term " sulfenamide ", alone or in combination, means a -SON = group in which the remaining three bonds (valences) below may be independently substituted. The term " sulfide ", alone or in combination, means an-S- group in which the remaining two bonds (valences) may be independently substituted.
The term " alkoxy ", alone or in combination, means an alkyl ether radical as defined above. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
The term " cycloalkyl ", alone or in combination, refers to a cyclic alkyl radical having from 3 to about 8 carbon atoms. The term " cycloalkylalkyl " means an alkyl radical as defined above which is substituted by a cycloalkyl radical having from 3 to about 8, preferably from 3 to about 6 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The heterocyclic (heterocyclo) or heterocyclo moiety, such as a heterocyclo carbonyl, heterocyclooxycarbonyl, heterocycloalkoxycarbonyl or heterocycloalkyl group, may be saturated or unsaturated, containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Or some unsaturated monocyclic, bicyclic or tricyclic heterocycle. This moiety may be optionally substituted on the at least one ring carbon atom by halogen, alkyl, alkoxy, oxo, and the like and / or by alkyl, aralkoxycarbonyl, alkanoyl, aryl or arylalkyl on the secondary nitrogen atom May be optionally substituted by oxido on the tertiary nitrogen atom (i.e., = N-) and are linked through a carbon atom. In addition, a tertiary nitrogen atom having three substituents may be bonded to form an N-oxide [= N (O) -] group.
The term " aryl ", alone or in combination, signifies a fused ring system comprising a 5- or 6-membered carbocyclic aromatic ring containing moiety or two or three rings having all carbon atoms in the ring; Means a carbocyclic aryl radical. Examples of carbocyclic aryl radicals include phenyl, indenyl, and naphthyl radicals.
The term " heteroaryl ", alone or in combination, refers to a fused or fused ring containing a 5- or 6-membered aromatic ring containing moiety or two or three rings having one or more carbon atoms and also one or more heteroatoms such as sulfur, oxygen and nitrogen in the ring Ring system (radical). Examples of such heterocyclic or heteroaryl groups include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol- Benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl, triazolyl, oxazolyl, oxadiazoyl, thiazolyl, (E.g., 2-quinolinyl, 3-quinolinyl, 1-oxy-2-quinolinyl, etc.), isoindolyl (For example, 1,2,3,4-tetrahydro-2-quinolyl, etc.), tetrahydroquinolinyl (for example, benzyloxycarbonyl) 1,2,3,4-tetrahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxalinyl, 2-benzofurancarbonyl, benzothiophenyl, 1-, 2-, 4- or 5-benzimidazolyl, and the like.
When the aryl or heteroaryl radical is a substituted moiety (group, substituent or radical), it can be substituted on its own and the last mentioned substituent is cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio Alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthiol, aralkyl, aryl, aryl, heteroaryl, heterocyclyl, heterocyclyl, Heteroarylthio, aralkoxy, heteroarylthio, heteroarylthio, heteroarylalkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy , Aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylthio, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, aryl Alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, arylthioalkylthioaryl, arylthioalkylthioaryl, arylthioalkylthioaryl, arylthioalkylthioaryl, arylthioalkylthioarylthio, Alkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,
Wherein the amino nitrogen is selected from the group consisting of (i) unsubstituted or (ii) alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, (Iii) wherein the two substituents attached to the amino nitrogen and the nitrogen to which they are attached are selected from the group consisting of nitrogen, oxygen, or sulfur, wherein the substituents are independently selected from the group consisting of oxygen, Form a 5-to 8-membered heterocyclo or heteroaryl ring containing two additional heteroatoms and wherein the ring itself is either (a) unsubstituted or (b) aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl , Hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzo fused heterocycloalkyl, hydroxyalkoxy Alkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzo fused heterocycloalkoxy, benzo fused cycloalkylcarbonyl, heterocycloalkylcarbonyl, and cycloalkylcarbonyl groups, or Wherein the carbonylamino nitrogen is either (i) unsubstituted or (ii) a reacted amine of an amino acid, or (iii) an alkyl, hydroxyalkyl, hydroxyheteroaralkyl Cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzo fused heterocycloalkyl, benzo fused heterocycloalkyl, benzo fused cycloalkyl, and N, N-dialkyl substituted alkylamino-alkyl groups (Iv) the carboxamido and the two substituents attached thereto are substituted with one or two radicals selected from the group consisting of Wherein the amino nitrogen is (i) unsubstituted or optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, (ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and the substituent bonded thereto are 5- to 8-membered heterocyclo or hetero Heteroaryl, or benzo-fused heterocycloalkyl ring substituted with one or two radicals independently selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxy, lower alkoxy, The aminoalkyl nitrogen may be unsubstituted or substituted with (i) unsubstituted or (ii) alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, (Iii) wherein the aminoalkyl nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, optionally substituted with one or two substituents independently selected from the group consisting of ). ≪ / RTI >
The term " aralkyl ", alone or in combination, means an alkyl radical as defined above wherein one hydrogen atom is replaced by an aryl radical as defined above such as benzyl, 2-phenylethyl, and the like.
The term " aralkoxycarbonyl ", alone or in combination, means a radical of the formula aralkyl-O-C (O) - in which the term "aralkyl" has the abovementioned meaning. An example of an aralkoxycarbonyl radical is benzyloxycarbonyl.
The term " aryloxy " means a radical of the formula aryl-O-, wherein the term aryl has the abovementioned meaning. The phenoxy radical is an exemplary aryloxy radical.
The terms " heteroaralkyl " and " heteroaryloxy " refer to radicals structurally similar to aryloxy and aralkyl from a heteroaryl radical. Examples of such radicals include 4-picolinyl and 2-pyrimidoxime, respectively.
The term " alkanoyl " or " alkylcarbonyl ", alone or in combination, signifies an acyl radical derived from an alkanecarboxylic acid, including formyl, acetyl, propionyl, butyryl, valeryl, And a reel.
The term " cycloalkylcarbonyl " refers to a monocyclic or bridged cycloalkcarboxylic acid, such as those derived from cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, or the like, Benz-fused monocyclic cycloalkanes which may be substituted by alkanoylamino such as tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl, Means an acyl group derived from a carboxylic acid.
The term " aralkanoyl " or " aralkylcarbonyl " refers to phenyl acetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl) acetyl, 4-chlorohydrocinnamoyl, Means an acyl radical derived from an aryl-substituted alkanecarboxylic acid, such as aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl, and the like.
The term " aroyl " or " arylcarbonyl " means an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals include aromatic carboxylic acids, optionally substituted benzoic acids or naphthoic acids such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4- (benzyloxycarbonyl) benzoyl, 1-naphthoyl, 2- 2-naphthoyl, 3-hydroxy-2-naphthoyl, 3- (benzyloxyformoyl) -2-naphthoyl, 2-naphthoyl and the like.
The term " cycloalkylalkoxycarbonyl " means an acyl group of di-cycloalkylalkyl-O-CO-, wherein cycloalkylalkyl has the previously given significance. The term " aryloxyalkanoyl " means an acyl radical of formula aryl-O-alkanoyl, wherein the aryl and alkanoyl have the previously described significance. The term " heterocyclooxycarbonyl " means an acyl group having the formula heterocyclo-O-CO-, wherein heterocyclo has the same meaning as described above.
The term " heterocycloalkanoyl " is an acyl radical of a formula heterocyclo-substituted alkanecarboxylic acid, wherein the heterocyclo has the previously described meaning. The term " heterocycloalkoxycarbonyl " means an acyl radical of formula heterocyclo-substituted alkane-O-CO-, wherein heterocyclo has the meaning indicated above. The term " heteroaryloxycarbonyl " means an acyl radical represented by the formula heteroaryl-O-CO-, wherein the heteroaryl has the previously described significance.
The term " aminocarbonyl " (carboxamide) alone or in combination refers to an amino-substituted carbonyl (carbamoyl) group derived from a carboxylic acid and a reacted amine wherein the amino (amino nitrogen) a is (-NH ₂₎ or, as described above, hydrogen, alkyl, aryl, aralkyl, cycloalkyl, one selected from the group consisting of alkyl radicals, such as two or a substituted primary or secondary amino group containing substituents. Hydroxamate is an N-hydroxycarboxamide.
The term " aminoalkanoyl " means an acyl group derived from an amino-substituted alkanecarboxylic acid, wherein the amino group is optionally substituted with a substituent independently selected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radical, Which may be primary or secondary amino groups.
The term " halogen " means fluoride, chloride, bromide or iodide. The term " haloalkyl " means an alkyl radical having the meaning mentioned above wherein one or more hydrogens are substituted with a halogen. Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like.
The term " perfluoroalkyl " means an alkyl group in which each hydrogen is replaced by a fluorine atom. Examples of such perfluoroalkyl groups other than the trifluoromethyls described above are perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl.
The term " perfluoroalkoxy ", alone or in combination, refers to a perfluoroalkyl ether radical as defined above. Examples of perfluoroalkoxy groups in addition to trifluoromethoxy (F ₃ CO-) are perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy and perfluorodecoxy.
The term " perfluoroalkylthio ", alone or in combination, signifies a perfluoroalkyl thioether radical, the term perfluoroalkyl being as defined above.
Examples of such perfluoroalkylthio groups other than trifluoromethylthio (F ₃ CS-) are perfluorobutylthio, perfluoroisopropylthio, perfluorododecylthio and perfluorodecylthio.
The term " aromatic ring ", as combined, such as substituted-aromatic cyclic sulfone or substituted-aromatic cyclic sulfoxide, means aryl or heteroaryl as defined above.
The term " pharmaceutically acceptable " is used herein adjectival to mean that the modified noun is suitable for use in a pharmaceutical product. Pharmaceutically acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to, suitable alkali metal (Ia family) salts, alkaline earth metal (IIa family) salts, and other physiologically acceptable metal ions. Examples of ions include aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, which are common valencies. Preferred organic ions include, in part, trimethylamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) Including protonated tertiary amines and quaternary ammonium cations. Examples of pharmaceutically acceptable acids include, but are not limited to, hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, acetic, formic, tartaric, maleic, malic, citric, isocitric, succinic, lactic, gluconic, Pyruvic acid, oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid and the like.
As used in the reaction schemes to be described below, " M " represents a leaving group such as a halogen, a phosphate ester or a sulfate ester.
Preparation of useful compounds
Reaction schemes A to C and Reaction Schemes 1 to 19 described below are useful compounds in the present invention; I. E., Compounds of formulas I, II, III, IV and V, and analogous cyclic inhibitors. In addition, the preparation of compounds of formula (VI) and (VII) was shown. Compounds of formula (VI) and (VII) can be used as intermediates in the preparation of compounds of formula (I), (II), (III), (IV) and (V) or pro- drugs or MMP inhibitors.
In Schemes A to C, the symbol J independently represents R ²⁰ or other synthetically useful groups such as amides, acid chlorides, mixed anhydrides, and the like. In Scheme C, n is 0, 1 or 2 and preferably 1 or 2. N of this scheme corresponds to g of formula (VI) and (VII) and is 0, 1 or 2. The symbol m is 1 or 2. The symbol r is independently 1, 2 or 3. The symbol P represents also a protecting group which may be a ring of the group R < ^{6 &} gt ;. In Scheme A, the positional isomers are indicated as linkages via rings according to standard methods in order to simplify and clarify the description. The later reaction schemes typically show only one positional isomer, but the regioisomers are represented by the structure and reaction in the manner consistent with Formulas I, II, III, IV, V, VI, VII above. Likewise, the symbol B represents O, S, SO, SO ₂ and NR ⁶ . The symbols C and C 'are independently an electron nucleophilic group or a group capable of participating in the condensation reaction. It should be noted here that the 6-membered rings are shown for illustrative purposes, but that the procedures and / or reagents are applicable to the manufacture of 5- to 8-membered rings and represent combinations permitting them.
The structures in Schemes 1-19 are also shown with the compounds representing other compounds of the invention. The aromatic rings in Scheme C are aryl and heteroaryl. The moiety of -A-R-E-Y is as described above. The reaction indicated with a spiro-heterocyclic nitrogen atom may not be applicable to such compounds with sulfur or oxygen.
Scheme A shows the reduction of a heteroaryl compound to a carboxyl derivative in Step 1. [ Typically, the first product is a hydrogen-containing amine heterocycle if the starting material is aromatic or an R ⁶ -containing heterocycle if the partially unsaturated heterocycle is the starting material.
Compound 2 can be treated in various ways according to the needs of the chemist. In step 2, nitrogen can be protected, for example, by preparing carbobenzoxy (Z) or tert-butoxycarbonyl derivatives. Such acylation can be carried out by methods known in the art, particularly by amino acid and peptide synthesis techniques. The acylation process with the activated carboxyl group- or activated sulfonyl group-containing reagent for the preparation of the target compound is carried out in the same manner. Examples of such acylating groups are carbonyl azides, halides, anhydrides, mixed anhydrides, carbodiimide derivatives or other less conventional activating ester groups, such as hydroxybenzotriazole derivatives. Such acylation may be carried out in the presence of a base containing a mild base such as triethylamine or N-ethylmorpholine, if necessary. Their use for the preparation of some activated ester reagents and for the preparation of other compounds useful in the present invention are described below. It should be recalled that the group which constitutes P and acts as a selectively removable protecting group may also be included as part of group R < ^{6 &} gt ;.
. Step 4 of Scheme A shows the alkylation or acylation of compound 2 to prepare compound 5. Acylation and alkylation processes are as described herein. In step 5, base J can be changed as needed. An example of such a modification is the exchange of esters for THP-protected hydroxamate conversion of the THP-protected hydroxamate to the hydroxamate or conversion of the acid to the protected hydroxamate.
Steps 3, 7 and 8 show the preparation of the target compounds or sulfur-containing derivatives of the intermediates for these compounds. The starting materials for the above steps (e.g., Compounds 2, 5 and 6) can be treated with a base to deprotonate the carbon alpha to carbonyl functionality. These anions can react with electron-nucleophilic sulfur to form sulfone, sulfoxide or sulfide. These e-nucleophile, for ^{example, R 24 S-SR 24,} R 24 SO 2 C 1, R 24 SC 1, R 24 SOC 1, R 24 S (O) may be in the form of -SR ^24, wherein R ²⁴ is a coupling substituent R ^{3 '} as defined above or containing an aryl or heteroaryl sulfur-containing material, which can be used to prepare one of the R ²⁴ -containing groups. The preparation of the anion requires a base, and a strong base such as one of the metal amides, hydrides or alkyls mentioned herein may be required. The solvent is non-magnetic and the polar aprotic solvent is preferred along with an inert atmosphere. R ³ is used instead of R ²⁴ for convenience of explanation in the following reaction formula.
It should be noted that this process produces sulfide (thioether), sulfoxide or sulfone depending on the starting material. In addition, the sulfide can be oxidized to the sulfoxide or sulfone and the sulfoxide can be oxidized to the corresponding sulfone derivative thereof. The choice of position within the synthesis sequence to change the oxidation state of the sulfur as well as the crystals to change the oxidation state depends on the discretion of the skilled chemist of the art. The oxidation method of sulfur is described below.
Scheme A, steps 6, 9, 10, and 12 independently represent interconversion of J internal units. Examples of such interconversions include conversion of the ester to a hydroxamic acid or a hydroxamic acid gum derivative, conversion of the carboxylic acid to an activated carbonyl derivative or hydroxamic acid or hydroxamic acid derivative (a prodrug or protected derivative) Removal of the protecting group from the rhamcate derivative is included. The preparation of an activated carbonyl compound by reaction with a nucleophile such as hydroxamic acid, protected hydroxamic acid or a hydroxamic acid pre-agent is described below and is the conversion of the protected hydroxamic acid derivative to hydroxamic acid. For example, the preparation of the derived product, hydroxybenzotriazole / carbodiimide, is mentioned herein. The preparation or hydrolysis of esters, amides, amide derivatives, acid chlorides, acid anhydrides, mixed anhydrides, etc. is a synthetic method well known in the art and has not been discussed in detail here. Step 6 shows the conversion of compound 4 to compound 9 without first being converted to compound 7.
Scheme B shows an alternative preparation of the target compound. The reagent shown on the arrow in Step 1 is a reagent having two activating groups other than the above-mentioned hetero atom (B). Here again, the specific reagents shown are intended to illustrate the reagents which have been chosen to clarify the reaction, or which enable the production of heteroatomic positions and 5-, 7- and 8-membered ring size compounds. Such reagents are readily selectable by those skilled in the art.
Step 1 C and C 'in the reagent are groups that can be independently converted into an electron nucleophile or an electron nucleophile. These groups include halides, sulfonic acid esters, epoxides, thioepoxides, hydroxyl groups and the like. This reagent reacts with a nucleophilic anion of sulfur containing a carbonyl compound such as Compound 1. [ Anions are formed by deprotonation of Compound 1, and examples of bases suitable for such deprotonation are described below. The treatment with the nucleophilic reagent is carried out under alkalinizing conditions known in the art, which is mentioned herein. The product of this reaction may be Compound 2 or Compound 3; That is, the reaction can be carried out in one port or two-step process as required.
Step 3 shows the interconversion of J groups as needed as described for Scheme A. In step 4, C represents, for example, a nucleophile as described above, and C 'uses a reagent which exhibits a nucleophile or an electron nucleophile such as hydroxyl, thiol or R ⁶ -amino. C 'may independently be a nucleophile or an electron nucleophile if m is 2, i.e., the C' group need not be the same when m is 2. When m is 2, treatment with 2 moles of base provides the skilled chemist with an alternative method of making compound 5. When C 'is hydroxyl, thiol, or R ⁶ -amino and m is 2, one of ordinary skill in the art may condense Compound 4, for example an aldehyde or ketone, under reducing conditions, or form a target compound with subsequent reduction. As described above, a compound with m = 2 can be prepared in one step (one-pot process) or in two steps, allowing the chemist the choice of allowing the reagents to be the same (1 port) or different (2 steps) .
Scheme B also shows the interconversion of J internal groups, the oxidation state of the R < ⁶ > group, on the sulfur and nitrogen, to yield the target compound. Such methods and processes are mentioned for the reaction of Scheme A.
Scheme C shows the nucleophilic substitution of group D as defined herein. This reaction is carried out in a manner similar to the substitution reaction mentioned here. The choice of the oxidation state of the sulfur is by one skilled in the art, but sulfoxide or sulfone groups are preferred, and sulfone is most preferred. Substitution can be carried out before or after the methylene beside the carbonyl group reacts to form a spiro-heterocyclic group.
Although steps 1, 2 and 3 can also be carried out with a single nucleophile (Nu), even if the nucleophilic substitution can be carried out with a nucleophile (Nu), the product of this reaction can be modified by methods known in the art, -AREY is generated.
A non-limiting description of such a process is provided where D is fluoride. The fluoride leaving group can be directly substituted with an anion such as 4-trifluoromethylphenol, 4-trifluoromethoxyphenol, or 4-trifluoromethylthiophenol to obtain the desired compound. This is a one-pot process from compound 4. Other compounds included in AREY may be prepared by replacing the fluoride leaving group with ammonia which provides an amine and then acylating it in the manner described for example by 4-trifluoromethylbenzoyl chloride to give another target compound . The R ⁶ functional group can be modified and / or further modified in the compounds or steps in the reaction schemes according to the needs of those skilled in the art to produce the desired compound. The interconversion to a different R ⁶ group of a dual-purpose counterpart such as a long-term or short-term protecting group is mentioned. Many different routes, including the production of synthetic intermediates and / or useful conversions, are well known in the art. Some non-limiting examples of such conversions or reactions include: reduction; Nucleophilic substitution / substitution reaction; Conversion or production of a carboxylic acid or a sulfonic acid, an amide, an ester, an acid halide, a mixed anhydride and the like; Electron nucleophilic substitution / substitution reaction; Oxidation; Cyclic ring opening, ring opening / closing, ring opening / closing, ring opening, sulfonyl or carbonyl groups and / or carbon-hydrogen bonds affected by one or both of these groups. The selection of the method of preparation or conversion of the desired compound and the order of the reaction is made by those skilled in the art. If a particular order or method turns out to be undesirable, it is expected that alternatives will be selected and used. The selection of the final R ⁶ phase of the manufacture / addition of the units in a single step using an approximate inhibitor strategy or the stepwise strategy.
Thus, typically, the choice of starting materials and reaction conditions is variable as is well known to those skilled in the art. Typically, the condition of any single set is not limited because it can be modified as needed. The conditions are also selected as necessary to suit the particular purpose, such as small or large scale manufacturing. In both cases, the use of a less stable or less environmentally friendly substance or reagent is usually minimized. Examples of such materials are diazomethane, diethyl ether, heavy metal salts, dimethyl sulfide, chloroform, benzene, and the like.
This reaction can be carried out in a dry inert atmosphere such as nitrogen or argon if necessary. Selective reactions known to those skilled in the art can be carried out in a dry atmosphere such as dry air, while other synthetic steps such as aqueous acid or base ester or amide hydrolysis can be carried out under laboratory air. In addition, some processes in this synthesis can be carried out in a pressure vessel at atmospheric pressure, atmospheric pressure or subatmospheric pressure. The use of ancillary equipment in the control of gaseous reagents such as hydrogen, ammonia, trimethylamine, methylamine, oxygen and the like can also help prevent air or moisture from leaking into ongoing reactions. It is to be readily understood that additional or alternative methods, conditions, reactions or systems can be ascertained and used by ordinary skill in chemistry.
The reaction described is typically carried out in an inert atmosphere such as nitrogen or argon at a temperature of from -25 C to the solvent reflux temperature. The solvent or solvent mixture may vary widely depending on reagents and other conditions and may include polar or polar aprotic solvents as listed or a mixture of such solvents. The reaction may be carried out to effect reactions such as metallization or anion formation using a strong base at low temperatures such as dry ice / acetone or, if desired, liquid nitrogen temperatures.
In some cases, amines such as triethylamine, pyridine, or other non-reactive bases may serve as reagents and / or solvents and / or co-solvents. In some cases, in the above reaction and in other reactions in the above formula, a protecting group may be used to maintain or retain groups within other portions of the molecule at a location other than the desired reaction center. Examples of such groups that may be retained or retained by one skilled in the art include amines, other hydroxyls, thiols, acids, and the like. Such a protecting group may include an acyl group, an arylalkyl group, a carbamoyl group, an ether, an alkoxyalkyl ether, a cycloalkyloxy ether, an arylalkyl group, a silyl group including a trisubstituted silyl group, an ester group and the like. Examples of such protecting groups include acetyl, trifluoroacetyl, tetrahydropyran (THP), benzyl, tert-butoxycarbonyl (BOC or TBOC), benzyloxycarbonyl (Z or CBZ), tert- butyldimethylsilyl ) Or a methoxyethoxymethylene (MEM) group. The preparation of such protected compounds and their removal are known in the art. The protecting group may also be used as a substituent in the target compound whose application is a drug rather than as a synthetic intermediate.
Many reactions or processes involve bases which can serve as reactants, reagents, deprotecting agents, acid scavengers, salt formation reagents, solvents, co-solvents, and the like. Examples of the base that can be used include metal hydroxides such as sodium, potassium, lithium, cesium or magnesium hydroxide, oxides such as sodium, potassium, lithium, calcium or magnesium oxide, sodium, potassium, lithium, cesium, Metal carbonate such as calcium or magnesium carbonate, metal bicarbonate such as sodium bicarbonate or potassium bicarbonate, alkylamine, arylalkylamine, alkylarylalkylamine, heterocyclic amine or heteroatom (II), tertiary (III) organic amines, such as alkylamines, arylamines, ammonium hydroxides or quaternary ammonium hydroxides. By way of non-limiting example, such an amine may be selected from the group consisting of triethylamine, trimethylamine, diisopropylamine, methyldiisopropylamine, diazabicyclononane, tribenzylamine, dimethylbenzylamine, morpholine, N- N, N'-dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline, tetramethylethylenediamine and the like. Non-limiting examples of ammonium hydroxides typically made from amines and water include ammonium hydroxide, triethylammonium hydroxide, trimethylammonium hydroxide, methyldiisopropylammonium hydroxide, tribenzylammonium hydroxide , Dimethylbenzyl ammonium hydroxide, morpholinium hydroxide, N-methylmorpholinium hydroxide, N, N'-dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide and the like . Non-limiting examples of quaternary ammonium hydroxides include tetraethylammonium hydroxide, tetramethylammonium hydroxide, dimethyldiisopropyl-ammonium hydroxide, benzylmethyldiisopropylammonium hydroxide, methyldiazabicyclo- nonyl N, N, N ', N'-tetramethylpiperazinium hydroxide and N-ethyl-N', N'-tetramethylpiperazinium hydroxide, ammonium hydroxide, - hexylpiperidinium hydroxide, and the like.
Sodium hydride, sodium hydride, sodium hydride, potassium hydride, lithium hydride, aluminum hydride, diisobutylaluminum hydride (DIBAL) sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, Metal hydrides, amides or alcoholates such as potassium diisopropylamide and the like may also be suitable reagents.
Alkyl or aryl lithium reagents such as methyllithium, phenyllithium, tert-butyllithium, lithium acetylide or butyllithium, Grignard reagents such as methylmagnesium bromide or methylmagnesium chloride, organic cadmium reagents such as dimethylcadmium, The depurring agent may also act as a base to catalyze salt formation induction or reaction. Quaternary ammonium hydroxides or mixed salts are also useful for assisting phase transfer coupling or acting as phase transfer reagents. The pharmaceutically acceptable base may be reacted with an acid to form the desired pharmaceutically acceptable salt. It should also be noted that optically active salts which can be used for optical resolution can be prepared using optically active bases.
Typically, the reaction medium contains a single solvent, a single or a mixture of different types of solvents, or may be used as a reagent in a single or mixed solvent system. The solvent may be quantum, non-magnetic, or bipolar non-quantum. Non-limiting examples of quantum solvents include water, methanol (MeOH), denatured or 95% pure or anhydrous alcohol, isopropanol, and the like. Typical aprotic solvents include acetone, tetrahydrofuran (THF), dioxane, diethyl ether, tert-butyl methyl ether (TBME), aromatic such as xylene, toluene or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloro Ethane, methylene chloride, ethylene dichloride (EDC), hexane, heptane, isooctane, cyclohexane and the like. The polar aprotic solvent includes dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, DMSO, hexamethylphosphorus triamide (HMPA), nitromethane, tetramethylurea, N-methylpyrrolidone and the like . Non-limiting examples of reagents that can be used as solvents or as part of a mixed solvent system include organic or inorganic mono- or multi-proton acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, Alcohols or amines for the preparation of pyridine, N-methyl morpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, esters or amides or thiols for the preparation of the desired products.
Here, the preparation of the desired compound may require oxidation of nitrogen or sulfur to an N-oxide derivative or a sulfoxide or sulfone. Reagents for such processes include, but are not limited to, peroxymonosulfate (OXONE TM), hydrogen peroxide, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, peracetic acid, tert- butyl peroxide, Chlorite, sodium hypochlorite, hypochlorous acid, sodium metaperiodate, periodic acid, and the like, and weaker agents most useful in the production of sulfone and sulfoxide. The pure or mixed, quantum, aprotic, bipolar aprotic solvents may be selected from a choice of, for example, methanol / water.
The oxidation reaction can be carried out at a temperature of about -78 ° C to about 50 ° C, and is usually selected in the range of -10 ° C to about 40 ° C. Sulfoxide is best prepared with one equivalent of oxidizing agent. Performing the reaction in an inert gas atmosphere with or without a degassed solvent may be desirable in the case of the more active oxidizing agent, but is not required. It should be noted that the oxidation of the sulfide to the sulfone can be carried out via the sulfoxide in one or two steps, depending on the needs of the chemist.
The reduction reaction is well known in the art and a useful method is hydrogenation. In this case (catalytic reduction), metal catalysts such as Rh, Pd, Pt, Ni and the like may be present with or without additional supports such as carbon, barium carbonate and the like. The solvent may be either a quantum or non-amorphous pure solvent or a mixed solvent as needed. The reduction can be carried out in a special hydrogenation equipment well known in the art at atmospheric pressure, at atmospheric pressure, or at multi-atmospheric pressure with about 40 pounds per square inch (psi).
It is also a process for the preparation of compounds useful for the reductive alkylation of amines or active methylene compounds. Such alkylation can be carried out under reductive hydrogenation conditions as indicated above using, for example, aldehydes or ketones. Hydride transfer reagents such as sodium cyanoborohydride, aluminum hydride, lithium aluminum hydride, borane, sodium borohydride, diisobutyl aluminum hydride and the like are also useful as reagents for reducing alkyl. The acyl group can be reduced in a manner analogous to producing a substituted amine.
An alternative method of alkylating carbon or nitrogen is direct alkylation. As is well known in the art, such alkylation can be carried out by treating an activated carbon containing one or more hydrogens with a base to form the corresponding anion and adding an electron-nucleophilic reagent to effect the SN2 reaction. Amines to be alkylated are treated similarly except that dephen quantitation is not required. Electron nucleophiles include halogen derivatives, sulfonate esters, epoxides, and the like.
The bases and solvents for the alkylation reaction are as described above. Closed bases are preferred to the extent that competition with the electron nucleophiles is minimized. Further preferred bases are metal hydrides, amide anions or organometallic bases such as n-butyllithium. Solvents, solvent mixtures or solvent / reagent mixtures mentioned are satisfactory, but examples of preferred classes are aprotic or polar aprotic solvents such as acetone, acetonitrile, DMP and the like.
Acids are used in many reactions during various syntheses. For example, the THP-protecting group is removed and used in the production of hydroxamic acid. The acid can be a mono-, di- or tri-quantum organic or inorganic acid. Examples of acids include hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, hydrobromic acid, hydrofluoric acid, carbonic acid, phosphorous acid, p- toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, difluoroacetic acid, , Methanesulfonic acid, benzenesulfonic acid, 2,6-dimethylbenzenesulfonic acid, trichloroacetic acid, nitrobenzoic acid, dinitrobenzoic acid, trinitrobenzoic acid and the like. These may also be Lewis acids such as aluminum chloride, boron trifluoride, antimony pentafluoride and the like. Acids of quantum properties can also be used to catalyze hydrolysis and exchange reactions of esters, amides, and the like.
Conversion to a hydroxamic acid or hydroxamic acid derivative of a protected carboxylic acid such as an ester or amide such as an O-arylalkyl ether or an O-cycloalkoxyalkyl ether group is useful. When hydroxylamine is used, treatment of the ester or amide with one or more equivalents of hydroxylamine hydrochloride, at room temperature or above, in a solvent, a quantum or partially quantum solvent as described above, It can provide rocky mountains. This exchange process can be catalyzed by the addition of additional acids. Alternatively, a hydroxylamine can be formed from a hydroxylamine hydrochloride, which can be exchanged with an ester or amide using a base such as a salt of an alcohol used as a solvent, such as sodium methoxide in methanol. As described above, the exchange may be carried out with a protected hydroxylamine such as tetrahydropyranylhydroxyamine (THPONH ₂ ), benzylhydroxylamine (BnONH ₂ ), etc., in which case tetrahydropyranyl (THP) or Benzyl (Bn) hydroxamic acid derivatives are compounds as shown in Schemes A, B, and C. Removal of the protecting group, if necessary, for example, after further modification or after storage in other parts of the molecule, may be effected by acid hydrolysis of the THP group as described above or by hydrogen and metal catalysts such as palladium, platinum, palladium on carbon or nickel Is accomplished by standard methods well known in the art, such as the elimination of benzyl groups.
When R < ²⁰ > is hydroxyl; That is, when the intermediate is a carboxylic acid, a standard coupling reaction can be used. For example, the acid can be converted to an acid chloride, mixed anhydride or activated ester, such as hydroxybenzotriazole, and treated in the presence of a base that is non-competitive with a hydroxylamine or a compound that is nitrogen acylated with a protected hydroxylamine. This is the same product as described above. Coupling of this nature is well known in the art, particularly in the art relating to peptide and amino acid chemistry.
Wherein the desired compound possesses one or more asymmetric carbon atoms and can exist in the form of optical isomers, enantiomers, diastereoisomers and mixtures of racemates or non-racemic mixtures. The compounds may also be further classified as ortho, meta and para isomers, cis and trans isomers, syn and anti isomers, E and Z isomers, tautomer isomers, alpha and beta isomers, equatorial isomer and other isomeric forms such as isomers due to blocked rotation. The isomer may be in equilibrium with the mammal or other isomer in the test system. Such compounds may also be present as isomerically equilibrium systems with water or solvents, for example as hydrated ketones or aldehydes, which are known in the art. All isomers are included as compounds of the present invention.
The above-described chemical reactions are usually the most extensive for the preparation of the compounds of the present invention




Tables 1 to 150 below show structural formulas representing various target aromatic sulfonic hydroxynaphthalate inhibitor compounds or substituents. Each of the compounds is represented by a series of preferred moieties or groups which constitute various substituents which can be attached to the general formula or formula and then to the position explicitly indicated in the general structure. Substituent symbols such as R1 and R2 and R3 are as shown in the respective tables,





































Desirable inhibitor compounds include those having a disease associated with pathological matrix metalloprotease activity; Rat; rabbit; dog; Words; Such as primates, such as monkeys, chimpanzees or humans.
Also contemplated is the use of metalloprotease inhibitor compounds which are intended for the treatment of disease states which may be influenced by the activity of the metalloprotease TNF-alpha converting agent. Examples of such disease states are acute state reactions of shock and sepsis, coagulation, bleeding and cardiovascular effects, fever and inflammation, anorexia and cachexia.
In treating disease states associated with pathological matrix metalloprotease activity, the intended MMP inhibitor compound may be used in the form of an amine salt derived from an inorganic or organic acid. Exemplary salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, nisulfate, butyrate, camphorate, camphorsulfonate, digluconate, But are not limited to, cyclopentanone, cyclopentanone, cyclopentane propionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, heptadate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, Methoxy sulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate , Propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoe It can be given.
Also, basic nitrogen-containing groups include methyl, ethyl, propyl and lower alkyl halides such as butyl chloride, bromide, and iodine; Dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodine, aralkyl halides such as benzyl and phenethyl bromide, ≪ / RTI > and other improved water-solubility. Whereby a product soluble or dispersible in water or oil is obtained as intended. A salt is formed by mixing the basic compound with the desired acid.
Still other compounds useful in the present invention may also form salts as acids. Examples include alkali metal or alkaline earth metal salts such as sodium, potassium, calcium or magnesium; Or an organic base or a basic quaternary ammonium salt.
In either case, the salt may also be used as an adjuvant in the separation, purification or degradation of the compound of the present invention.
The total daily dose administered in single or divided doses to the host mammal may be, for example, from 0.001 to 30 mg per kg of body weight per day, and more usually from 0.01 to 10 mg per kilogram of body weight. The dosage unit composition may contain the above amount or about several times its amount constituting the daily dose. Suitable doses may be administered in divided doses several times per day. Also, if the person prescribing the drug intends to do so, the total daily dose may be increased by several doses per day.
Methods of administration for treating a disease with the compounds and / or compositions of the present invention may vary depending on factors such as the type of patient, age, weight, sex, diet and medical condition, the severity of the disease, the route of administration, Including, for example, the pharmacological and toxicological profile of the drug, the drug delivery system used, and whether the compound is administered as part of a drug combination. Therefore, the administration method practically used can be very diverse, and thus can be deviated from the above-mentioned preferable administration method.
The compounds of the present invention may be formulated into pharmaceutical compositions. Such compositions may be administered orally, parenterally, intranasally, or locally, as unitary dosage forms containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and excipients, depending on the purpose have. Local administration may also include the use of transdermal administration, such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrasternal injection or infusion methods. The preparation of the drug is described in Hoover, John E., Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania; 1975 and Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to known methods using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be solutions in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, 1,3-butanediol. Acceptable excipients and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterilized fixed oils are commonly used as a solvent or suspending medium. For this purpose, fixed oils of any combination, including synthetic mono- or diglycerides, may be used. Also, fatty acids such as oleic acid are used in injectable preparations. Dimethylacetamide, surfactants including ionic and nonionic detergents, polyethylene glycol can be used. Mixtures of wetting agents and solvents such as those mentioned above are also useful.
Suppositories for rectal administration of drugs are drugs which are solid at normal temperatures but liquid at rectal temperatures and therefore suitable for administration as drugs such as cocoa butter, synthetic mono-, di- or triglycerides, fatty acids and polyethylene glycols, Can be prepared by mixing with non-polar excipients.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of the invention are usually mixed with one or more adjuvants appropriate for the indicated route of administration. When administered by mouth, the desired aromatic sulfonamide hydroxymate inhibitor compound is selected from the group consisting of lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, And calcium salt, gelatin, acacia rubber, sodium alginate, polyvinyl pyrrolidone, and / or polyvinyl alcohol, and may be tableted or encapsulated for conventional administration. Such capsules or tablets may contain a release-controlling agent in which the active compound may be dispersed in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents such as sodium citrate, magnesium or calcium carbonate or dicarbonate. Tablets and pills may additionally be prepared by intestinal care.
For therapeutic purposes, formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. The solutions and suspensions may be made into sterile powders or granules containing one or more of the carriers or diluents referred to for use in preparations for oral administration. The desired aromatic sulfonamide hydroxymate inhibitor compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical arts.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art such as water. The composition may also contain adjuvants such as wetting agents, emulsifying agents and suspending agents, sweetening agents, flavoring agents and fragrances.
The amount of active ingredient that can be mixed with the carrier material to produce a single dosage form will vary depending upon the mammalian host being treated and the particular mode of administration.
Best Mode for Implementing the Invention
Without further elaboration, one of ordinary skill in the art would be able to make best use of the present invention, as described above. The preferred embodiments below are therefore to be construed as merely illustrative, and not limitative of the remainder of the disclosure.
Example 1: Preparation of N-hydroxy-2 - [(4-phenoxyphenyl) sulfonyl] acetamide

Part A: To a solution of 3-bromopyruvic acid hydrate (1.95 g, 11.7 mmol) in methanol (50 mL) cooled to 0 ° C was added 4- (phenoxy) benzenethiol (2.35 g, 11.7 mmol). The solution was stirred for 15 minutes then concentrated in vacuo. The residue was partitioned between ethyl acetate and H ₂ O and the organic layer was dried over magnesium sulfate. Concentration in vacuo afforded the crude sulfide as a yellow solid which was used without further purification.
Part B: To a solution of the crude sulfide of Part A (1.2 g, < 2.6 mmol) in methanol / H ₂ O cooled to 0 & (Oxone ; 3.5 g, 5.72 mmol). The solution was stirred for 1 hour and then filtered to give an excess of oxone . One by concentration of the filtrate the residue was dissolved in ethyl acetate and washed with saturated NaHCO ₃ and saturated NaCl and dried over magnesium sulfate. After concentration in vacuo, the resulting residue was dissolved in methanol and thionyl chloride (1.9 mL, 26 mmol) was added. Chromatography (ethyl acetate / hexanes on silica) gave the solid sulfone (350 mg, 44%). ^{MS (CI) MH +: C} 15 calculated in the H ₁₄ O ₅ S: 307, Found: 307.
Part C: To a solution of sulfone (350 mg, 1.1 mmol) in methanol (2 mL) and THF (THF; 2 mL) was added 50% aqueous hydroxylamine (1 mL). The solution was stirred overnight. Trituration with ethyl acetate gave the title compound as a white solid (270 mg, 77%). HPLC purity: > 97%. ^{MS (CI) MH +: C} 14 calculated in the H ₁₃ NO ₅ S: 308, Found: 308.
Example 2: Preparation of N-hydroxy-2-methyl-2 - [(4-phenoxyphenyl) sulfonyl] propanamide

To a solution of 4- (phenoxy) benzenethiol (3.8 g, 18.8 mmol) in methanol (60 mL) cooled to 0 ° C was added t-butyl bromoacetate (2.8 mL, 18.8 mmol) and triethylamine 2.6 mL, 19.0 mmol). The solution was stirred for 30 min and then concentrated in vacuo. The residue was partitioned between ethyl acetate and H ₂ O and the organic layer was washed with saturated NaCl and dried over magnesium sulfate. And concentrated in vacuo to give an oil-phosphorus sulfide. To a solution of the sulfide in dichloromethane (85 mL) was added m-chloroperbenzoic acid (13.8 g, 43.2 mmol) over 15 min. The solution was stirred at room temperature for 2 hours. The reaction was stopped by adding aqueous Na ₂ SO ₄ . After 30 minutes, the solution was washed with celite Lt; / RTI > The filtrate was washed with 25% aqueous hydroxyamine, 1 N HCl, and saturated NaCl and dried over magnesium sulfate. Chromatography (ethyl acetate / hexanes on silica) gave the sulfones as white solids (4.0 g, 68%).
Part B: Sodium hydride (730 mg of a 60% dispersion in mineral oil, 18.4 mmol) was added to a solution of Part A sulfone (3.2 g, 9.3 mmol) in THF (65 mL) cooled to 0 ° C. After 10 minutes, methyl iodide (2.28 mL, 36.8 mmol) was added dropwise and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with H ₂ O and concentrated in vacuo. The aqueous residue was diluted with ethyl acetate and the organic phase was washed with H ₂ O and then dried over Na ₂ SO ₄ . Concentration in vacuo yielded a gray colored white solid (3.2 g, 92%). HPLC purity: 95%.
Part C: To a solution of the dimethyl compound of Part B (3.2 g, 8.5 mmol) in anisole (10 mL) was added trifluoroacetic acid (30 mL) and the solution was stirred for 30 min. Concentrated in vacuo and then triturated (ethyl ether) to give the acid as a white solid (750 mg, 28%). HPLC purity: 99%. ^{MS (CI) MH +: C} 16 H 16 O 5 S Calcd of: 321, Found: 321.
To a solution of the acid of Part C (723 mg, 2.26 mmol) in DMF (DMF; 4.5 mL) was added N-hydroxybenzotriazole.H ₂ O (HOBT; 366 mg, 2.71 mmol) -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC; 476 mg, 2.49 mmol). The solution was stirred at room temperature for 1 hour and then 50% aqueous hydroxyamine (0.40 mL, 6.8 mmol) was added. After 15 minutes the solution was partitioned between ethyl acetate and H ₂ O. The organic layer was washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . Reverse phase chromatography (acetonitrile / H ₂ O on silica) gave the title compound as a white foam (434 mg, 57%). HPLC purity: 99%, MS (CI) M + Li ⁺ : Calcd for C ₁₆ H ₁₇ NO ₅ O: 342, found 342.
Example 3: Preparation of 1,1-dimethylethyl ester 4 - [(hydroxyamino) carbonyl] -4 - [(phenoxyphenyl) sulfonyl] -1-piperidinecarboxylic acid

Part A: A solution of 4- (phenoxy) benzenethiol (2.03 g, 10.0 mmol) in DMSO (DMSO; 20 mL) was heated to 65 <0> C for 5 h. The solution was left at room temperature for 18 hours. The solution was extracted with ethyl acetate and the combined organic layers were washed with H ₂ O and saturated NaCl and dried over magnesium sulfate. And concentrated in vacuo to give the disulfide which is a yellow oil (2.3 g, quantitative yield).
Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mmol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF Lt; / RTI &gt; The solution was stirred at room temperature overnight and concentrated in vacuo to give a light oil. The oil was filtered through silica gel (7: 3 ethyl acetate / hexanes) and concentrated in vacuo to give a clear colorless oil, BOC-piperidine compound (26.2 g, quantitative yield).
Part C: To a solution of diisopropylamine (2.8 mL, 20 mmol) in THF (30 mL) cooled to -78 ° C was added n-butyllithium (12.5 mL, 20 mmol) dropwise. After 15 min, the BOC-piperidine compound of Part B (2.6 g, 10 mmol) in THF (10 mL) was added dropwise. After 1.5 h, the solution was cooled to-60 C and a solution of the disulfide of Part A (2.0 g, 10 mmol) in THF (7 mL). The solution was stirred at room temperature for 2 hours. The solution was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with H ₂ O and saturated NaCl and dried over magnesium sulfate. Chromatography (ethyl acetate / hexane on silica) gave the oil sulfide (1.8 g, 40%).
Part D: To a solution of Part C sulfide (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to 0 C m-chloroperbenzoic acid (1.7 g, 7.9 mmol) was added. The solution was stirred for 1.5 h, then diluted with H ₂ O and extracted with dichloromethane. The organic layer was washed with 10% Na ₂ SO ₄ , H ₂ O, and saturated NaCl and dried over magnesium sulfate. Chromatography (ethyl acetate / hexanes on silica) gave the solid sulfone (1.15 g, 59%).
Part E: To a solution of Part D sulfone (800 mg, 1.63 mmol) in THF (9 mL) and ethanol (9 mL) NaOH in H ₂ O (3 mL) (654 mg, 16.3 mmol) was added. The solution was heated at 65 &lt; 0 &gt; C for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in H ₂ O. After acidification to pH 4 with 2N HCl, the solution was extracted with ethyl acetate and the organic layer was washed with saturated NaCl and then dried over magnesium sulfate. And concentrated in vacuo to give the acid as a white foam (790 mg, quantitative yield). Anal Calcd for C ₂₃ H ₂₇ NO ₇ S: C, 59.86; H, 5.90; N, 3.04; S, 6.95. Found: C, 59.49; H, 6.37; N, 2.81; S, 6.59.
Part F: To a solution of the acid of Part G (730 mg, 1.58 mmol) in DMF (9 mL) was added HOBT (256 mg, 1.90 mmol) followed by EDC (424 mg, 2.21 mmol), 4-methylmorpholine 0.521 mL, 4.7 mmol) and 50% aqueous hydroxylamine (1.04 mL, 15.8 mmol). The solution was stirred for 20 hours and N-hydroxybenzotriazole.H ₂ O (256 mg), EDC (424 mg) and 50% aqueous hydroxyamine (1.04 mL) were added additionally. After stirring for an additional 24 hours, the solution was diluted with H ₂ O and extracted with ethyl acetate, then the organic layer was washed with saturated NaCl and dried over magnesium sulfate. Reverse phase chromatography (acetonitrile / H ₂ O on silica) afforded the title compound as a white solid (460 mg, 61%). HPLC purity: &gt; 99%. Anal. Calcd for C ₂₃ H ₂₈ N ₂ O ₇ S: C, 57.97; H, 5.92; N, 5.88; S, 6.73. Found: C, 57.95; H, 6.02; N, 5.81; S, 6.85.
Example 4: Preparation of N-hydroxy-4 - [(4-phenoxyphenyl) sulfonyl] -4-piperidinecarboxamide, monohydrochloride

Part A: A solution of 4- (phenoxy) benzenethiol (2.03 g, 10.0 mmol) in DMSO (20 mL) was heated to 65 <0> C for 5 h. The solution was left at room temperature for 18 hours. The solution was extracted with ethyl acetate and the combined organic layers were washed with H ₂ O and saturated NaCl and dried over magnesium sulfate. Concentration in vacuo afforded the disulfide as a yellow oil (2.3 g, quantitative yield).
Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF Lt; / RTI &gt; The solution was stirred at room temperature overnight and concentrated in vacuo to give light oil. The oil was filtered through silica gel (on silica, ethyl acetate / hexanes) and then concentrated in vacuo to give a clear colorless oil, BOC-piperidine compound (26.2 g, quantitative yield).
Part C: To a solution of diisopropylamine (2.8 mL, 20 mmol) in THF (30 mL) cooled to -78 ° C was added n-butyllithium (12.5 mL, 20 mmol) dropwise. After 15 min, the BOC-piperidine compound of Part B (2.6 g, 10 mmol) in THF (10 mL) was added dropwise. After 1.5 hours, the solution was cooled to-60 C and a disulphide of Part A (2.0 g, 10 mmol) in THF (7 mL) was added. The solution was stirred at room temperature for 2 hours. The solution was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with H ₂ O and saturated NaCl and dried over magnesium sulfate. Chromatography (ethyl acetate / hexane on silica) gave the oil sulfide (1.8 g, 40%).
Part D: To a solution of Part C sulfide (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to 0 C m-chloroperbenzoic acid (1.7 g, 7.9 mmol) was added. The solution was stirred for 1.5 h, then diluted with H ₂ O and extracted with dichloromethane. The organic layer was washed with 10% Na ₂ SO ₃ , H ₂ O, and saturated NaCl and dried over magnesium sulfate. Chromatography (ethyl acetate / hexanes on silica) gave the solid sulfone (1.15 g, 59%).
Part E: To a solution of Part D sulfone (800 mg, 1.63 mmol) in THF (9 mL) and ethanol (9 mL) NaOH in H ₂ O (3 mL) (654 mg, 16.3 mmol) was added. The solution was heated at 65 &lt; 0 &gt; C for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in H ₂ O. After acidification to pH 4 with 2 N HCl, the solution was extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over magnesium sulfate. And concentrated in vacuo to give the acid as a white foam (790 mg, quantitative yield). Anal Calcd for C ₂₃ H ₂₇ NO ₇ S: C, 59.86; H, 5.90; N, 3.04; S, 6.95. Found: C, 59.49; H, 6.37; N, 2.81; S, 6.59.
Part F: To a solution of the acid of Part G (730 mg, 1.58 mmol) in DMF (9 mL) was added HOBT (256 mg, 1.90 mmol) followed by EDC (424 mg, 2.21 mmol), 4-methylmorpholine 0.521 mL, 4.7 mmol) and 50% aqueous hydroxylamine (1.04 mL, 15.8 mmol). The solution was stirred for 20 hours and additional HOBT (256 mg), EDC (424 mg) and 50% aqueous hydroxylamine (1.04 mL) were added. After stirring for an additional 24 h, the solution was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over magnesium sulfate. By reverse phase HPLC (acetonitrile / H ₂ O) to obtain a hydroxide roksa formate as a white solid (460 mg, 61%). HPLC purity: &gt; 99%. Anal. Calcd for C ₂₃ H ₂₈ N ₂ O ₇ S: C, 57.97; H, 5.92; N, 5.88; S, 6.73. Found: C, 57.95; H, 6.02; N, 5.81; S, 6.85.
Part G: HCl gas was sparged for 5 minutes into a solution of the hydroxamate of Part F (385 mg, 0.808 mmol) in ethyl acetate (25 mL) cooled to 0 ° C. After standing for 30 minutes, the solution was concentrated in vacuo. Trituration with ethyl ether afforded the title compound as a white solid (330 mg, quantitative yield). ^{MS (CI) MH +: C} 18 H 20 N 2 O 5 S Calcd of: 377, _{found: 377. HRMS: C 18 H 20} N 2 O 5 S Calcd for: 377.1171, Found: 377.1170. _{C 18 H 20 N 2 O 5} S · 1.1HCl · 0.25H ₂ O for analysis calcd: C, 51.35; H, 5.71; N, 6.65; S, 7.62; Cl, 9.26. Found: C, 51.58; H, 5.09; N, 6.55; S, 8.02; Cl, 9.09.
Example 5: Preparation of (E) N-hydroxy-2 - [(4-phenoxyphenyl) sulfonyl] -3-phenyl-2-propenamide

Part A: To a solution of 4- (phenoxy) benzenethiol (5.00 g, 24.7 mmol) in methanol (100 mL) cooled to 0 C was added t-butyl bromoacetate (3.99 mL, 24.7 mmol). Triethylamine (3.60 mL, 25.8 mmol) was then added and the solution was stirred for 40 min. The solution was concentrated in vacuo and the resulting residue was dissolved in ethyl acetate and washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . And concentrated in vacuo to give an oil-phosphorus sulfide (7.9 g, quantitative yield).
Part B: To a solution of oxone sulfide (7.9 g, 24.7 mmol) of Part A in methanol (180 mL) and H ₂ O (20 mL) (38.4 g, 62.5 mmol) was added and the mixture was stirred for 22 hours. The mixture was acidified to pH 4 with 2.5 N NaOH and then stripped to remove insoluble salts. Concentrated to embellish according to one-half volume and partitioned between ethyl acetate and H ₂ O. The organic layer was washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (ethyl acetate / hexanes on silica) afforded the sulfone as a yellow solid (5.79 g, 67%).
Part C: To a solution of Part B sulfone (2.5064 g, 7.20 mmol) and benzaldehyde (0.748 mL, 7.36 mmol) in benzene (20 mL) was added acetic acid (0.15 mL) and piperidine (0.05 mL). The solution was heated at reflux for 2 hours and the concentrate collected via a Dean-Stark trap. After refluxing for another 1.5 hours, the solution was returned to room temperature and stirred for 18 hours. The solution was diluted with ethyl acetate and washed with H ₂ O and saturated NaCl and then dried over Na ₂ SO ₄ . Chromatography (ethyl acetate / hexanes on silica) followed by trituration (ethyl ether / hexanes) gave the unsaturated sulfones as white solids (1.97 g, 73%). HPLC purity: &gt; 98%.
Part D: HCl gas was sparged in a solution of Part C unsaturated sulfone (0.5053 g, 1.16 mmol) for 1 hour. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with H ₂ O and dried over Na ₂ SO ₄ . Concentrate in vacuo to give the oil phosphoric acid (0.41 g, 93%).
Part E: To a solution of the acid of Part D (461 mg, 1.21 mmol) was added thionyl chloride (3.0 mL) and the solution was heated to 100 &lt; 0 &gt; C for 1 h. And concentrated in vacuo to give the acid chloride as an amber oil (380 mg, 79%).
Part F: To a solution of the acid chloride (380 mg, 0.95 mmol) in Part E in THF (20 mL) was added 50% aqueous hydroxylamine (1.7 mL, 9.5 mmol). The solution was stirred at 0 &lt; 0 &gt; C for 1 hour. The solution was diluted with ethyl acetate, washed with H ₂ O and saturated NaCl, and dried over Na ₂ SO ₄ . Purification by reverse phase chromatography (acetonitrile / H ₂ O on silica) and trituration (ethyl ether / hexane) gave the title compound as a white solid (131 mg, 35%). HPLC purity: &gt; 97%.
Example 6: Preparation of N-hydroxy-4 - [(4-phenoxyphenyl) sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide, monohydrochloride

Part A: A solution of 4- (phenoxy) benzenethiol (2.03 g, 10.0 mmol) in DMSO (20 mL) was heated to 65 <0> C for 5 h. The solution was left at room temperature for 18 hours. The solution was extracted with ethyl acetate and the combined organic layers were washed with H ₂ O and saturated NaCl and dried over magnesium sulfate. Concentration in vacuo afforded the disulfide as a yellow oil (2.3 g, quantitative yield).
Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF Lt; / RTI &gt; The solution was stirred at room temperature overnight and concentrated in vacuo to give a light oil. The oil was filtered through silica gel (ethyl acetate / hexanes) and concentrated in vacuo to give a clear colorless oil, BOC-piperidine compound (26.2 g, quantitative yield).
Part C: To a solution of diisopropylamine (2.8 mL, 20 mmol) in THF (30 mL) cooled to -78 ° C was added n-butyllithium (12.5 mL, 20 mmol) dropwise. After 15 min, the BOC-piperidine compound of Part B (2.6 g, 10 mmol) in THF (10 mL) was added dropwise. After 1.5 h, the solution was cooled to-60 C and a solution of Part A disulfide (2.0 g, 10 mmol) in THF (7 mL) was added. The solution was stirred at room temperature for 2 hours. The solution was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with H ₂ O and saturated NaCl and dried over magnesium sulfate. Chromatography (silica gel, ethyl acetate / hexane) gave the oil sulfide (1.8 g, 40%).
Part D: To a solution of Part C sulfide (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to 0 C m-chloroperbenzoic acid (1.7 g, 7.9 mmol) was added. The solution was stirred for 1.5 h, then diluted with H ₂ O and extracted with dichloromethane. The organic layer was washed with 10% Na ₂ SO ₄ , H ₂ O, and saturated NaCl and dried over magnesium sulfate. Chromatography (ethyl acetate / hexanes on silica) gave the solid sulfone (1.15 g, 59%).
Part E: HCl gas was sparged for 5 minutes into a solution of Part D sulfone (3.56 g, 7.0 mmol) in ethyl acetate (100 mL) cooled to 0 &lt; 0 &gt; C. Concentrated in vacuo and triturated with ethyl ether to give the amine solid hydrochloride salt as a white solid (3.5 g, quantitative yield). ^{MS (CI) MH +: C} 20 calculated in the H ₂₃ NO ₅ S: 390, Found: 390.
Part F: Propargyl bromide (892 mg, 6 mmol) was added to a solution of the amine hydrochloride salt of Part E (2.6 g, 6 mmol) and K ₂ CO ₃ (1.66 g, 12 mmol) in DMF (50 mL) And the solution was stirred at room temperature for 4 hours. The solution was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over magnesium sulfate. Chromatography (ethyl acetate / hexanes on silica) afforded the white solid propargylamine (2.15 g, 82%).
Part G: NaOH (2.0 g, 50 mmol) was added to a solution of Part F of the solution of part F (2.15 g, 5 mmol) in THF (30 mL) and ethanol (30 mL) Lt; / RTI &gt; The solution was concentrated in vacuo and the aqueous residue was acidified to pH 5. The resulting precipitate was vacuum filtered to give the acid as a white solid (2.04 g, quantitative yield).
Part H: To a solution of the acid of Part G (559 mg, 1.4 mmol) in dichloromethane (5 mL) was added triethylamine (0.585 mL, 4.2 mmol) and 50% aqueous hydroxylamine (0.925 mL, 14.0 mmol) Followed by bromotris (pyrrolidino) phosphonium hexafluorophosphate (PyBroP ; 718 mg, 1.54 mmol). The solution was stirred at room temperature for 4 hours. The solution was diluted with H ₂ O and extracted with dichloromethane. The organic layer was washed with saturated NaCl and dried over magnesium sulfate. Reverse phase chromatography (acetonitrile / H ₂ O on silica) afforded the hydroxamic acid as a white solid (140 mg, 25%). C ₂₁ H ₂₂ N ₂ O ₅ S for analysis calcd: C, 60.85; H, 5.37; N, 6.76; S, 7.74. Found: C, 60.47; H, 5.35; N, 6.61; S, 7.46.
Part I: To a solution of Part H hydroxamate (121 mg, 0.292 mmol) in methanol (2 mL) cooled to 0 C was added acetyl chloride (0.228 mL, 0.321 mmol) in methanol (1 mL). After stirring at room temperature for 30 min, the solution was concentrated under a stream of N _2. Trituration with ethyl ether gave the title compound as a white solid (107 mg, 81%). Anal. Calcd for C ₂₁ H ₂₂ N ₂ O ₅ S · HCl · 0.3H ₂ O Calcd .: C, 55.27; H, 5.21; N, 6.14. Found: C, 54.90; H, 5.37; N, 6.07.
Example 7: Preparation of N- [4 - [[2- (hydroxyamino) -2-oxoethyl] sulfonyl] phenyl]

Part A: Thionyl chloride (24.0 mL, 0.327 mmol) was added dropwise to a suspension of 2- (4-aminophenylthio) acetic acid (20.00 g, 0.109 mmol) in methanol (100 mL) cooled to 0 ° C. Additional methanol (100 mL) was added and the suspension was heated under reflux for 2 hours. The solution was concentrated in vacuo and the residue was dissolved in H ₂ O and neutralized with saturated NaHCO ₃ . The organic layer was washed aqueous layer was extracted with ethyl acetate combined with saturated NaCl and dried over Na ₂ SO _4. And concentrated in vacuo to give the methyl ester as a dark purple oil (22.75 g, quantitative yield). HPLC purity: 99%.
Part B: Benzoyl chloride (3.24 mL, 27.89 mmol) was added to a solution of the methyl ester of Part A (5.00 g, 25.35 mmol) and triethylamine (7.07 mL, 50.70 mmol) in dichloromethane (50 mL) And the mixture was stirred at room temperature for 2 hours. The solution was concentrated in vacuo and ethyl acetate and the residue was partitioned between THF and H ₂ O. The organic layer was washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . And concentrated in vacuo to give the benzamide (7.06 g, 92%) as a purple solid. HPLC purity: 98%. MS (CI) M + Li ⁺ : Calcd for C ₁₆ H ₁₅ NO ₃ S: 308, found: 308.
Part C: To a solution of the benzamide of Part B (4.00 g, 13.27 mmol) in THF (100 mL) and H ₂ O (10 mL) cooled to 0 ° C was added oxone (Potassium monopersulfate; 24.47 g, 39.81 mmol). The slurry was stirred at room temperature overnight (about 18 hours). The mixture was filtered to remove excess oxone Was removed and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with H ₂ O and saturated NaCl, then dried over Na ₂ SO ₄ . And concentrated in vacuo to give the sulfone as a pink solid (4.11 g, 93%). HPLC purity: 98%. MS (CI) M + Li ^+: calcd C ₁₆ of the H ₁₅ NO ₅ S: 340, Found: 340.
Part D: To a solution of the sulfone of Part C (400 mg, 1.2 mmol) in THF (9 mL) was added 50% aqueous hydroxylamine (5.0 mL). The solution was stirred for 8 h and concentrated in vacuo. Trituration with hot ethyl ether afforded the title compound as an off-white solid (348 mg, 78%). HPLC purity: 97%. ^{MS (CI) MH +: C} 17 H 14 N 2 O 5 S Calcd of: 335, Found: 335.
Example 8: Preparation of N- [4 - [[2- (hydroxyamino) -2-oxo-1- (piperidin-4-yl) ethyl] sulfonyl] phenyl] benzamide, monohydrochloride

Part A: To a solution of diethanolamine (22.16 g, 0.211 mol) in THF (100 mL) cooled to 0 C was added di-t-butyl dicarbonate (46.0 g, 0.211 mol) Lt; / RTI &gt; The solution was concentrated in vacuo and the resulting residue was filtered through a pad of silica (5% methanol / 95% dichloromethane) to give the diol as a clear oil (45.06 g, quantitative yield). ^{MS (CI) MH +: C} 9 H 19 O 4 S Calcd of: 206, Found: 206.
Part B: Thionyl chloride (24.0 mL, 0.327 mmol) was added dropwise to a solution of 2- (4-aminophenylthio) acetic acid (20.00 g, 0.109 mmol) in methanol (100 mL) cooled to 0 ° C. After additional methanol (100 mL) was added, the suspension was heated at reflux for 2 hours. The composition was concentrated in vacuo and the residue was dissolved in H ₂ O and neutralized with saturated NaHCO ₃ . The organic layer was washed aqueous layer was extracted with ethyl acetate combined with saturated NaCl and dried over Na ₂ SO _4. Concentration in vacuo yielded the methyl ester as a dark purple oil (22.75 g, quantitative yield). HPLC purity: 99%.
Part C: Benzoyl chloride (3.24 mL, 27.89 mmol) was added to a solution of the methyl ester of Part B (5.00 g, 25.35 mmol) and triethylamine (7.07 mL, 50.70 mmol) in dichloromethane (50 mL) And the mixture was stirred at room temperature for 2 hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate, THF and H ₂ O. The organic layer was washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . And concentrated in vacuo to give the benzamide (7.06 g, 92%) as a purple solid. HPLC purity: 98%.
Part D: To a solution of Part C benzamide (4.00 g, 13.27 mmol) in THF (100 mL) and H ₂ O (10 mL) cooled to 0 ° C was added oxone (24.47 g, 39.81 mmol). The slurry was stirred at room temperature overnight (about 18 hours). The mixture was filtered to remove excess oxone Was removed and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . And concentrated in vacuo to give the sulfone as a pink solid (4.11 g, 93%). HPLC purity: 98%.
Part E: To a solution of the diol of Part A (1.03 g, 5.00 mmol) in THF (100 mL) and the methyl ester of Part D (2.00 g, 6.00 mmol) was added 1,1 '- (azodicarbonyl) dipiperidine (5.05 g, 20.00 mmol). To the slurry was added trimethylphosphine (20.00 mL of a 1.0 M solution in THF, 20.00 mmol). The mixture was stirred at room temperature for 1 hour and then heated at 40 &lt; 0 &gt; C for 18 hours. The slurry was returned to room temperature, then ethyl ether was added and the insoluble solids were filtered off. The filtrate was concentrated in vacuo and the resulting residue was dissolved in ethyl acetate, washed with H ₂ O and saturated NaCl, then dried over Na ₂ SO ₄ . Chromatography (on silica, ethyl acetate / hexanes) gave the piperidine compound as a yellow solid (600 mg, 24%). ^{MS (CI) MH +: C} 25 H 30 N 2 O 7 S Calcd of: 503, Found: 503.
Part F: Potassium silanolate (970 mg, 7.56 mmol) was added to a solution of the piperidine compound (950 mg, 1.89 mmol) in Part E in THF (10 mL) and the solution was stirred at room temperature for 72 hours . The solution was diluted with H ₂ O, acidified to pH 2 using 1 M HCl and extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over Na ₂ SO _4. Concentration in vacuo afforded the acid as a yellow solid (772 mg, 84%).
Part G: HOBT (240 mg, 1.77 mmol), 4-methylmorpholine (0.488 mL, 4.44 mmol), O-tetrahydropyran (538 mg, 4.54 mmol) and EDC (397 mg, 2.07 mmol). The solution was stirred at room temperature for 2 hours. Concentrated in vacuo and then the residue was partitioned between ethyl acetate and H ₂ O. The organic layer was washed with saturated NaCl and dried over Na ₂ SO _4. Chromatography (on silica, ethyl acetate / hexanes) afforded protected hydroxylamine which was a white solid (608 mg, 70%). HPLC purity: &gt; 99%.
Part H: To a solution of the protected hydroxylamine (596 g, 1.01 mmol) in Part G in dioxane (3 mL) and methanol (1 mL) was added 4 M HCl in dioxane (2.50 mL, 10.14 mmol) The solution was stirred at room temperature for 50 minutes. Trituration with ethyl ether afforded the title compound as a white solid (433 mg, 98%). HPLC purity: 98%. ^{MS (CI) MH +: C} 19 H 21 N 3 O 5 S Calcd of: 404, Found: 404.
Example 9: Preparation of N-hydroxy-4 - [[4- (phenylthio) phenyl] sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide, monohydrochloride

Part A: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF Lt; / RTI &gt; The solution was stirred at room temperature overnight (about 18 hours) and concentrated in vacuo to give light oil. The oil was filtered through silica gel (ethyl acetate / hexanes) and concentrated in vacuo to give the BOC-piperidine compound as a clear colorless oil (26.2 g, quantitative yield).
Part B: A solution of 4-fluorothiophenol (50.29 g, 390 mmol) in DMSO (500 mL) was heated to 65 [deg.] C for 6 hours. The reaction was quenched with wet ice and the resulting solid was combined by vacuum filtration to give the disulfide which is a white solid (34.4 g, 68.9%).
Part C: Lithium diisopropylamine (41.33 mL, 74 mmol) was added to a solution of the BOC-piperidine compound (16 g, 62 mmol) in Part A in THF (300 mL) Was stirred at 0 &lt; 0 &gt; C for 1.5 hours. To the solution was added the disulfide of Part B (15.77 g, 62 mmol) and the resulting solution was stirred at room temperature for 20 hours. H ₂ O was added to quench the reaction and the solution was concentrated in vacuo. The aqueous residue was extracted with ethyl acetate and the organic layer was washed with 0.5 N KOH, H ₂ O, and saturated NaCl. Chromatography (on silica, hexane / ethyl acetate) gave the oil sulfide (18.0 g, 75%).
Part D: To a solution of Part C sulfide (16.5 g, 43 mmol) in dichloromethane (500 mL) cooled to 0 C was added 3-chloroperbenzoic acid (18.0 g, 86 mmol) and the solution stirred for 20 h . The solution was diluted with H ₂ O and extracted with dichloromethane. The organic layer was washed with 10% Na ₂ SO ₄ , H ₂ O, and saturated NaCl and dried over magnesium sulfate. Chromatography (ethyl acetate / hexane on silica) gave the solid sulfone (10.7 g, 60%).
Part E: HCl gas was stirred in a solution of Part D of sulfone (10 g, 24.0 mmol) in ethyl acetate (250 mL) for 10 minutes and then at room temperature for 4 hours. Concentration in vacuo afforded the amine hydrochloride salt as a white solid (7.27 g, 86%).
Part F: To a solution of the amine hydrochloride salt of Part E (5.98 g, 17.0 mmol) in DMF (120 mL) was added potassium carbonate (4.7 g, 34.0 mmol) followed by propargyl bromide (2.02 g, 17.0 mmol) Was added and the solution was stirred at room temperature for 4 hours. The solution was partitioned between ethyl acetate and H ₂ O and the organic layer was washed with H ₂ O and saturated NaCl and dried over magnesium sulphate. Chromatography (on silica, ethyl acetate / hexanes) afforded a yellow oil, propargylamine (5.2 g, 86%).
Part G: DMF was added thiophenol (0.80 mL, 7.78 mmol) and _{CsCO 3 (2.79 g, 8.56 mmol} ) in propargyl amine of part F solution of (15 mL) and the solution heated to 70 ℃ for 6 hours Respectively. The solution was partitioned between ether and H ₂ O. The organic layer was washed with H ₂ O and saturated NaCl and dried over magnesium sulfate. Chromatography (ethyl acetate / hexanes on silica) afforded the S-phenoxyphenyl compound as an oil (1.95 g, 56%).
Part H: KOH (1.37 g, 24.5 mmol) was added to a solution of Part G of S-phenoxyphenol (1.81 g, 4.06 mmol) in ethanol (21 mL) and H ₂ O (3.5 mL) Gt; 105 &lt; / RTI &gt; The solution was acidified to pH 1 with concentrated HCl solution and then concentrated to give the acid as a yellow residue (1.82 g) which was used without further purification.
To a solution of the acid of Part H (1.82 g, 4.06 mmol) in acetonitrile (20 mL) was added O-tetrahydro-2H-pyran-2-yl-hydroxylamine (723 mg, 6.17 mmol) Amine (0.67 mL, 4.86 mmol). To the stirred solution was added EDC (1.18 g, 6.17 mmol) and the solution was stirred for 18 hours. The solution was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with H ₂ O, saturated NaHCO ₃ and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate / hexanes) afforded the protected hydroxamate as a white solid (1.32 g, 63%).
Part J: To a solution of the protected hydroxamate of Part I (9.65 g, 18.7 mmol) in methanol (148 mL) cooled to 0 ° C was added acetyl chloride (4.0 mL, 56.2 mmol) Lt; / RTI &gt; Concentrated in vacuo and triturated with ethyl ether to give the title compound as a white solid (8.10 g, 94%). ^{MS (CI) MH +: C} 21 H 22 N 2 O 4 calculated in S _2: 431, Found: 431.
Example 10: Synthesis of 4 - [[4- (1,3-benzodioxol-5-yloxy) phenyl] sulfonyl] -N-hydroxy- 1- (2-propynyl) -4-piperidinecarboxylic acid Preparation of radium midium and monohydrochloride

Part A: Sesamol (5.52 g, 40 mmol) and potassium carbonate (5.52 g, 40 mmol) were added to a solution of the propargylamine (7.0 g, 19.8 mmol) from Example 9, Part F in DMF (30 mL) And the solution was heated to 85 &lt; 0 &gt; C for 48 hours. The solution was partitioned between ethyl acetate and H ₂ O. The organic layer was dried over magnesium sulfate. Chromatography (ethyl acetate / hexane on silica) gave the sulfide of the oil (9.38 g, quantitative yield).
Part B: To a solution of Part A sulfide (2.72 g, 5.92 mmol) in ethanol (30 mL) and H ₂ O (5 mL) was added potassium hydroxide (2.0 g, 36 mmol) And heated. The solution was acidified to pH = 3 using concentrated HCl. The solution was concentrated in vacuo and the residue was dissolved in acetonitrile (30 mL). To this solution was added O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.05 g, 9.0 mmol), triethylamine (1 mL) and EDC (1.72 g, 9.0 mmol) Stir for 18 hours. Concentrated in vacuo and the solution was diluted with saturated NaHCO ₃ and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. Chromatography (on silica, ethyl acetate / hexanes) afforded the protected hydroxamic acid as an oil (2.86 g, 93%).
Part C: To a solution of the protected hydroxamate of Part B (2.86 g, 5.27 mmol) in methanol (40 mL) was added acetyl chloride (1.13 mL, 15.8 mmol) and the solution was stirred for 3 h. The solution was concentrated in vacuo. Reverse phase chromatography (acetonitrile / H ₂ O (HCl) on silica) afforded the title compound as a white solid (2.2 g, 84%). ^{MS (CI) MH +: C} 22 H 22 N Calcd the ₂ O ₇ S: 459, Found: 459.
Example 11: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-phenyl-1-piperidinyl) phenyl] sulfonyl] -2H-pyran-4-carboxamide, monohydrochloride

Part A: To a solution of Na (8.97 g, 390 mmol) in methanol (1 L) at 0 ° C was added 4-fluorothiophenol (50 g, 390 mmol) and methyl chloroacetate (34.2 mL, 390 mmol) The solution was stirred at room temperature for 4 hours. The solution was filtered to remove the salt and the filtrate was concentrated in vacuo to give the sulfide as a colorless oil (75.85 g, 97%).
Part B: To a solution of Part A sulfide (75.85 g, 380 mmol) in methanol (1 L) and H ₂ O (100 mL) (720 g, 1.17 mol) was added and the solution was stirred for 2 hours. The reaction mixture was filtered to remove excess salts and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with H ₂ O, saturated NaHCO ₃ and saturated NaCl, then dried over magnesium sulfate. Concentration in vacuo afforded the sulfone as a white solid (82.74 g, 94%).
Part C: To a solution of Part B sulfones (28.5 g, 123 mmol) in N, N-dimethylacetamide (200 mL) was added potassium carbonate (37.3 g, 270 mmol), bis- (2- bromoethyl) ether 19.3 mL, 147 mmol), 4-dimethylaminopyridine (750 mg, 6 mmol) and tetrabutylammonium bromide (1.98 g, 6 mmol) were added and the solution stirred at room temperature for 72 hours. The solution was poured into 1N HCl (300 mL) and the resulting precipitate was collected by vacuum filtration. Recrystallization (ethyl acetate / hexane) gave a tetrahydropyran compound as a beige solid (28.74 g, 77%).
Part D: DMSO (10 mL) of a solution of the tetrahydropyran compound (1.21 g, 4.0 mmol) of Part _{C Cs 2 CO 3 (3.26 g} , 10.0 mmol) and 4-phenylpiperidine (640 mg, 4.0 mmol ) Was added and the solution was heated at 90 &lt; 0 &gt; C for 2 hours. The solution was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with 5% aqueous KHSO ₄ , saturated NaHCO ₃ and saturated NaCl and dried over magnesium sulfate. And concentrated in vacuo to give the amine as a white solid (1.2 g, 67%).
Part E: To a solution of Part D amine (815 mg, 1.84 mmol) in methanol (5 mL) and THF (5 mL) was added 50% aqueous NaOH (2 mL) and the solution was stirred at room temperature for 18 hours . The solution was concentrated in vacuo and the residue was diluted with H ₂ O and acidified to pH 7. The resulting precipitate was collected by vacuum filtration to give an acid which was a white solid (680 mg, 86%).
Part F: PyBroP (810 mg, 1.73 mmol), N-methylmorpholine (0.5 mL, 4.3 mmol) was added to a solution of the acid of Part E (620 mg, 1.44 mmol) in dichloromethane (10 mL) and DMF And O-tetrahydro-2H-pyran-2-yl-hydroxylamine (190 mg, 1.59 mmol) were added and the solution was stirred at room temperature for 4 hours. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with H ₂ O and saturated NaCl, then dried over Na ₂ SO ₄ . Chromatography (on silica, ethyl acetate / hexanes) afforded the protected hydroxamate as a white solid (630 mg, 83%). ^{MS (CI) MH +: C} 28 H 36 N 2 Calculated for O ₆ S: 529, Found: 529.
Part G: To a solution of the protected hydroxamate of Part F (600 mg, 1.14 mmol) in dioxane (1.5 mL) and methanol (1.5 mL) was added 4 N HCl in dioxane (1.5 mL) And stirred for 2 hours. The solution was poured into ethyl ether and the resulting precipitate was combined by vacuum filtration to give the title compound as a beige solid (500 mg, 91%). ^{MS (CI) M + Li +} : C 23 H 28 N 2 O 5 S Calcd of: 445, Found: 445.
Example 12: Preparation of 1-acetyl-N-hydroxy-4 - [(4-phenoxyphenyl) sulfonyl] -4-piperidinecarboxamide

Part A: To a solution of the sulfone of Example 6, Part D (2.75 g, 5.6 mmol) in THF (10 mL) and ethanol (10 mL) was added NaOH (2.25 g, 56 mmol) And heated for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in H ₂ O and extracted with ethyl ether. The aqueous solution was acidified to pH 2 and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. And concentrated in vacuo to give the crude amorphous acid. A solution of the acid in dichloromethane (6 mL) and trifluoroacetic acid (6 mL) was stirred at room temperature for 1 hour. Concentration in vacuo afforded the amine hydrochloride salt as a solid (2.3 g, quantitative yield).
Part B: To a solution of the amine hydrochloride salt of Part A (2.3 g, <5.6 mmol) in acetone (10 mL) and H ₂ O (10 mL) cooled to 0 ° C was added triethylamine (1.17 mL, 8.4 mmol) And acetyl chloride (0.60 mL, 8.4 mmol) were added and the solution was stirred at room temperature for 18 hours. The solution was concentrated in vacuo to remove the acetone and the aqueous solution was extracted with ethyl ether. The aqueous layer was acidified to pH 2 and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give the N-acetyl compound as a white solid (1.5 g, 65.2%).
To a solution of Part B N-acetyl compound (0.6 g, 1.49 mmol) in DMF (10 mL) was added EDC (401 mg, 2.1 mmol) followed by 50% aqueous hydroxylamine (0.9 mL) and 4 -Methylmorpholine (0.7 mL, 6.4 mmol) was added and the solution was stirred at room temperature for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with H ₂ O and dried over magnesium sulfate. Purification by reverse phase chromatography (acetonitrile / H ₂ O on silica) afforded the title compound as a white solid (101 mg, 16%). ^{MS (CI) MH +: C} 20 H 22 N 2 O 6 S Calcd of: 419, Found: 419.
Example 13: Preparation of 4 - [[4- (cyclohexylthio) -phenyl] sulfonyl] -N-hydroxy-1- (2-propynyl) -4-piperidinecarboxamide, monohydrochloride

Part A: Potassium carbonate (3.81 g, 27.6 mmol) and cyclohexylmercaptan (3.37 mL, 27.6 mmol) were added to a solution of the propargylamine (6.5 g, 18.4 mmol) from Example 9, Part F in DMF (10 mL) ). The solution was heated to 100 &lt; 0 &gt; C for 6.5 hours. The solution was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. Chromatography (on silica, hexane / ethyl acetate) gave the sulfide which is a yellow oil (6.05 g, 73%).
Part B: To a solution of Part B sulfide (612 mg, 1.4 mmol) in ethanol (8.4 mL) and H ₂ O (1.4 mL) was added potassium hydroxide (470 mg, 8.4 mmol) . The solution was acidified to pH 3 and concentrated in vacuo. The residue was dissolved in acetonitrile (10 mL) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (230 mg, 2.0 mmol) and triethylamine (0.5 mL) EDC (380 mg, 2.0 mmol) was added and the solution was stirred at room temperature for 18 hours. The solution was concentrated in vacuum The residue was diluted with saturated NaHCO ₃ and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. Chromatography (on silica, ethyl acetate / hexanes) afforded the protected hydroxamic acid as an oil (246 mg, 34%).
Part C: To a solution of the protected hydroxamate of Part B (246 mg, 0.47 mmol) in methanol (4 mL) was added acetyl chloride (0.11 mL, 1.5 mmol) and the solution was stirred at room temperature for 3 hours. After concentration in vacuo, the residue was subjected to reverse phase chromatography (acetonitrile / H ₂ O (HCl) on silica) to give the title compound as a white solid (223 mg, quantitative yield).
Example 14: Preparation of N-hydroxy-1-methyl-4 - [(phenoxyphenyl) sulfonyl] -4-piperidinecarboxamide, monohydrochloride

Part A: To a solution of the sulfone of Example 6, Part D (2.67 g, 5.5 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred at room temperature for 2 hours. The solution was concentrated in vacuo and the residue was triturated with ethyl ether to give the crude aminotrifluoroacetic acid salt. Formaldehyde (37% aqueous solution, 2.0 mL, 27.5 mmol) and borane pyridine (2.2 mL, 22 mmol) were added to a solution of the crude amine salt in methanol (10 mL) and the solution was stirred at room temperature for 18 hours. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and dried over magnesium sulfate. Concentrated in vacuo to give the N-methyl compound as a yellow oil (2.17 g, 98%).
Part B: NaOH (2.0 g, 50 mmol) was added to a solution of Part A N-methyl compound (2.17 g, 5.4 mmol) in ethanol (10 mL) and THF (10 mL) Lt; 0 &gt; C. The solution was concentrated in vacuo. The residue was dissolved in H ₂ O and extracted with ethyl ether. The aqueous solution was acidified to pH 2 and the resulting solid was combined by vacuum filtration to give the acid as a white solid (1.8 g, 90%).
Part C: To a solution of the acid of Part B (0.5 g, 1.3 mmol) in DMF (10 mL) was added EDC (1.06 g, 5.5 mmol) followed by O-tetrahydro-2H-pyran- Amine (490 mg, 4.2 mmol) and 4-methylmorpholine (0.76 mL) were added and the solution was stirred at room temperature for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with H ₂ O and dried over magnesium sulphate. And concentrated in vacuo to give the crude protected hydroxamate. To a solution of the crude hydroxamic acid in methanol (10 mL) was added acetyl chloride (0.28 mL, 3.9 mmol) and the solution was stirred at room temperature for 3 hours. The solution was concentrated in vacuo. MS (CI) MH ^& lt ^{; +} & gt ^; : C ₁₉ H ₂₂ N ₂ O ₅ (261 mg, 46%) as a white solid by reverse phase chromatography on silica (acetonitrile / H ₂ O (0.0125% HCl) Calcd for S: 391, Found: 391.
Example 15: Synthesis of N-hydroxy-4 - [[4- (4-methoxyphenoxy) phenyl] sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide, monohydrochloride Manufacturing

Part A: To a solution of the propargylamine (2.00 g, 5.66 mmol) from Example 9, Part F in DMF (10 mL) was added cesium carbonate (4.7 g, 14.5 mmol) and 4-methoxythiophenol 1.80 g, 14.5 mmol) and the solution was heated to 95 &lt; 0 &gt; C for 24 h. The solution was diluted with ethyl acetate and washed with 1 N NaOH and saturated NaCl, then dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / hexane) gave the solid phenoxy compound (2.67 g, quantitative yield).
Part B: To a solution of the phenoxy compound of Part A (2.40 g, 5.25 mmol) in ethanol (30 mL) and H ₂ O (6 mL) was added potassium hydroxide (2.0 g, 31.37 mmol) And heated for 4 hours. The solution was acidified to pH 3 with concentrated HCl and the residue was collected by vacuum filtration to give crude which was used without further purification.
Part C: To a solution of the acid of Part B (2.25 g, 5.25 mmol) in acetonitrile (30 mL) was added triethylamine (1 mL) and O-tetrahydro-2H-pyran- g, 9.0 mmol). After stirring the solution for 15 minutes, EDC (1.72 g, 9.0 mmol) was added to the solution and stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated NaHCO ₃ , H ₂ O and saturated NaCl and dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / hexanes) gave the protected hydroxamate as a white solid (0.93 g, 33%).
Part D: To a solution of the protected hydroxamate (0.93 g, 1.7 mmol) in Part C in methanol (15 mL) was added acetyl chloride (0.36 mL, 5.1 mmol) and the solution was stirred for 3 h. The solution was concentrated in vacuo to give the title compound as a white solid (650 mg, 82%).
Anal Calcd for C ₂₂ H ₂₄ N ₂ O ₆ SHCl: C, 54.84; H, 5.24; N, 5.82; S, 6.67; Cl, 6.67. Found: C, 53.10; H, 5.07; N, 5.59; S, 7.04; Cl, 6.32.
Example 16: Synthesis of 4 - [[4- (4-butoxy-1-piperidinyl) phenyl] sulfonyl] -tetrahydro-N-hydroxy-2H-pyran-4-carboxamide, monohydrochloride Produce

Part A: DMSO (25 mL) of Example 11, a solution of the tetrahydropyran compound (1.95 g, 6.46 mmol) of Part _{C, Cs 2 CO 3 (7.4} g, 22.6 mmol) and 4-butoxy As piperidine ( 1.25 g, 6.46 mmol) and the solution was heated to 90 &lt; 0 &gt; C for 1 hour. The solution was quenched with H ₂ O and extracted with ethyl acetate. The organic layer was washed with 5% aqueous KHSO ₄ , saturated NaHCO ₃ and saturated NaCl and dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / dichloromethane) gave the amine as a yellow oil (1.85 g, 65%).
Part B: To an amine solution of Part A (1.65 g, 3.76 mmol) in THF (10 mL) was added potassium trimethylsilanolate (530 mg, 4.13 mmol) and the solution stirred at ambient temperature for 22 h. The solution was concentrated in vacuo and the crude residue was used directly in the next reaction.
To a solution of Part B (1.74 g, 3.76 mmol) in dichloromethane (10 mL) was added PyBroP (2.10 g, 4.51 mmol), N-methylmorpholine (1.24 mL, 11.3 mmol) and O- Hydro-2H-pyran-2-yl-hydroxylamine (484 mg, 4.14 mmol) was added and the solution was stirred at ambient temperature for 30 minutes. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with H ₂ O and saturated NaCl, then dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / hexane / methanol) was performed to give the protected hydroxamate as a colorless oil (1.5 g, 76% in two steps).
Part D: To a solution of the protected hydroxamate of Part C (1.25 g, 2.4 mmol) in dioxane (3 mL) was added 4N HCl in dioxane (3 mL) and the solution was stirred for 15 min. Methanol (3 mL) was added to the solution and then stirred at ambient temperature for 5 hours. The solution was poured into ethyl ether and the resulting precipitate was collected by vacuum filtration to give the title compound as a white solid (1.0 g, 88%). ^{MS (CI) MH +: C} 21 H 32 N ₂ O ₆ S of the calculated: 441, found: 441.
Example 17: Preparation of 1-cyclopropyl-N-hydroxy-4 - [(4-phenoxyphenyl) sulfonyl] -4-piperidinecarboxamide, monohydrochloride

Part A: To a solution of the amine hydrochloride salt of Example 6, Part E (2.13 g, 5.0 mmol) in methanol (25 mL), 3 A molecular sieve, acetic acid (2.86 mL, 50 mmol) Lt; / RTI &gt; To this solution was added ((1-ethoxycyclopropyl) oxy) -trimethylsilane (6.08 mL, 30 mmol) followed by sodium cyanoborohydride (1.41 g, 22.0 mmol) and the solution was refluxed for 18 h And heated. Excess salts and sieves were collected by filtration and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with 1 N NaOH, H ₂ O and saturated NaCl, and dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / hexane) gave cyclopropylamine (1.90 g, 86%) as a white solid.
Part B: To a solution of Part A cyclopropylamine (1.9 g, 4.2 mmol) in THF (12 mL) and ethanol (12 mL) was added NaOH (1.71 g, 4.3 mmol) in H ₂ O And the solution was heated at 62 [deg.] C for 20 hours. The solution was concentrated in vacuo and the residue was diluted with H ₂ O and acidified to pH 5 with 1N HCl. The resulting solid was collected by vacuum filtration to give the acid as a white solid (1.49 g, 82%). ^{MS (CI) MH +: C} 21 H 23 NO 5 S Calcd of: 402, found: 402. HRMS: calcd for C ₂₁ H ₂₃ NO ₅ S: 402.1375, Found: 402.1350.
To a solution of Part C acid (1.49 g, 3.4 mmol) in dichloromethane (50 mL) was added triethylamine (1.42 mL, 10.21 mmol) followed by 50% aqueous hydroxylamine (2.25 mL, 34.0 mmol) and PyBroP 3.17 g, 6.8 mmol) and the solution was stirred for 72 hours. The mixture was diluted with H ₂ O and the organic layer was separated, washed with saturated NaCl and dried over magnesium sulfate. After concentration in vacuo, by performing the reverse-phase chromatography (silica phase, acetonitrile / H ₂ O) to give the hydroxy roksa mate.
The free base (830 mg, 2.0 mmol) was dissolved in methanol (20 mL) and acetyl chloride (0.17 mL, 2.0 mmol) was added to prepare the hydrochloride salt. The solution was stirred at 0 &lt; 0 &gt; C for 10 min. The resulting white solid was collected by vacuum filtration and washed with cold ethyl ether to give the title compound (595 mg, 66%). HRMS: C ₂₁ H ₂₄ N Calcd the ₂ O ₅ S: 416.1407, Found: 416.1398. _{C 21 H 24 N 2 O 5} S Calcd for: C, 55.68; H, 5.56; N, 6.18; S, 7.08; Cl, 7.83. Found: C, 55.39; H, 5.72; N, 6.15; S, 7.29; Cl, 8.17.
Example 18: Preparation of N-hydroxy-1- (methylsulfonyl) -4- (phenoxyphenyl) -sulfonyl] -4-piperidinecarboxamide

Part A: To a solution of the amine hydrochloride salt of Example 6, Part E (1.06 g, 2.5 mmol) in dichloromethane (10 mL) was added triethylamine (0.76 mL, 5.5 mmol) and methanesulfonyl chloride (0.23 mL , 3.0 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and the residue was fractionated with ethyl acetate and H ₂ O. The organic layer was washed with H ₂ O and saturated NaCl, and dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / hexanes) gave solid methanesulfonamide (2.1 g, 58%).
Part B: To a solution of Part A methanesulfonamide (2.0 g, 4.15 mmol) in ethanol (12 mL) and H ₂ O (12 mL) was added NaOH (1.66 g, 41.5 mmol) And heated for 18 hours. The solution was concentrated in vacuo and the residual aqueous solution was acidified to pH 4. The solution was extracted with ethyl acetate, and the organic layer was washed with saturated NaCl and dried over magnesium sulfate. Concentration in vacuo afforded the acid in the form of a yellow foam (1.46 g, 80%).
Part C: To a solution of the acid of Part B (1.46 g, 3.38 mmol) in dichloromethane (50 mL) was added triethylamine (1.41 mL, 10.1 mmol), 50% aqueous hydroxylamine (2.2 mL, 33.8 mmol) PyBroP (3.16 g, 6.76 mmol) was added and the solution was stirred at ambient temperature for 72 hours. The solution was diluted with H ₂ O, the organic layer was separated, washed with saturated NaCl, and dried over magnesium sulfate. Reverse phase chromatography (silica phase, acetonitrile / H ₂ O) was performed and triturated with ethyl ether to give the title compound as a white solid (160 mg, 11%). C ₁₉ H ₂₂ N ₂ O ₇ S ₂ Analysis Calcd: C, 50.21; H, 4.88; N, 6.16; S, 14.11. Found: C, 48.72; H, 5.36; N, 5.61; S, 12.81.
Example 19: Preparation of 4 - [[4- (cyclohexylthio) phenyl] sulfonyl] -N-hydroxyl-4-piperidinecarboxamide, monohydrochloride

Part A: K ₂ CO ₃ (5.0 g, 36.0 mmol) and cyclohexylmercaptan (4.4 mL, 36.0 mmol) were added to a solution of the sulfone of Example 9, Part D (10.1 g, 24.0 mmol) in DMF ) Was added and the solution was heated at 85 &lt; 0 &gt; C for 6.5 h. The solution was fractionated between ethyl acetate and H ₂ O. The organic layer was washed with saturated NaCl and dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / hexane) gave the sulfide in oil form (8.2 g, 67%).
Part B: To a solution of sulfide (2.32 g, 4.5 mmol) in ethanol (10 mL) and THF (10 mL) was added NaOH (1.81 g, 45 mmol) in H ₂ O (10 mL) Lt; RTI ID = 0.0 &gt; 65 C &lt; / RTI &gt; The solution was concentrated in vacuo and the aqueous residue was acidified to pH 2. The solution was extracted with dichloromethane and dried over magnesium sulfate. Concentration in vacuo afforded the acid as a white solid (830 mg, 38%).
To a solution of the acid of Part B (2.0 g, 4.0 mmol) in dichloromethane (25 mL) was added N-methylmorpholine (1.32 mL, 12.0 mmol), PyBroP (2.12 g, 2.12 mmol) Hydroxylamine (2.6 mL, 40 mmol) was added and the solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O and the layers were separated. The organic layer was washed with saturated NaCl and dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / methanol) was performed to give the hydroxamate as a white solid (1.4 g, 70%).
Part D: To a solution of Part C hydroxamate (1.31 g, 2.63 mmol) in ethyl acetate (70 mL) cooled to 0 C, HCl gas was bubbled through for 30 min. The solution was concentrated in vacuo. Reverse phase chromatography (silica phase, acetonitrile / H ₂ O (HCl)) gave the title compound as a white solid (378 mg, 33%). C ₁₈ H ₂₆ N ₂ O ₄ S ₂ Calculated analysis: C, 49.70; H, 6.26; N, 6.44; S, 14.74; Cl, 8.15. Found: C, 48.99; H, 6.34; N, 6.24; S, 14.66; Cl, 8.56.
Example 20: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-phenyl-1-piperazinyl) phenyl] sulfonyl] -2H-pyran-4-carboxamide, dichloride

Part A: embodiment of DMSO (20 mL) Example 11 To a solution of the tetrahydropyran compound (1.96 g, 6.5 mmol) of Part _{C, Cs 2 CO 3 (4.9} g, 15 mmol) and 4-phenyl-piperazine (1.1 mL, 7.15 mmol) and the solution was heated to 90 &lt; 0 &gt; C for 45 min. The solution was quenched by addition of H ₂ O and extracted with ethyl acetate. The organic layer was washed with 5% aqueous KHSO ₄ , saturated NaHCO ₃ and saturated NaCl and dried over magnesium sulfate. Concentration in vacuo afforded an amide of a beige solid (1.7 g, 59%).
Part B: To a solution of the amine of Part A (1.5 g, 3.38 mmol) in THF (20 mL) was added potassium trimethylsilanolate (480 mg, 3.72 mmol) and the solution stirred at ambient temperature for 22 hours. Concentration in vacuo afforded the acid salt, which was used in the next step without purification.
To a solution of Part B acid salt (1.58 g, 3.38 mmol) in dichloromethane (10 mL) and DMF (3 mL) was added PyBroP (1.89 g, 4.06 mmol), N- methylmorpholine (1.1 mL, 10.1 tetrahydro-2H-pyran-2-yl-hydroxylamine (435 mg, 3.72 mmol) and the solution stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo, the residue was partitioned between ethyl acetate and H ₂ O, and the organic layer was washed with H ₂ O and saturated NaCl, then dried over magnesium sulfate. Chromatography (silica phase, dichloromethane / methanol) was performed to give the protected hydroxamate as a white foam (1.7 g, 95% in two steps).
Part D To a solution of the protected hydroxamate of Part C (1.28 g, 2.4 mmol) in dioxane (5 mL) and methanol (5 mL) was added 4 N HCl in dioxane (5 mL) Was stirred at ambient temperature for 2 hours. The solution was poured into ethyl ether and the resulting precipitate was collected by vacuum filtration to give the title compound as a white solid (900 mg, 73%). MS (CI) MH ⁺ : Calculated C ₂₂ H ₂₇ N ₃ O ₅ S : 446, found 446.
Example 21: Preparation of 4 - [[4- (cyclohexylthio) phenyl] sulfonyl] -1-cyclopropyl) -N-hydroxy-4-piperidinecarboxamide, monohydrochloride

Part A: K ₂ CO ₃ (5.0 g, 36.0 mmol) and cyclohexylmercaptan (4.4 mL, 36.0 mmol) were added to a solution of the sulfone of Example 9, Part D (10.1 g, 24.0 mmol) in DMF ) Was added and the solution was heated at 85 &lt; 0 &gt; C for 6.5 h. The solution was fractionated with ethyl acetate and H ₂ O. The organic layer was washed with saturated NaCl and dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / hexane) gave the sulfide in oil form (8.2 g, 67%).
Part B: To a solution of the sulfide of Part B (8.2 g, 17.0 mmol) in ethyl acetate (100 mL) cooled to 0 C, HCl gas was bubbled through for 30 min. The solution was concentrated in vacuo to afford the amine as a white solid (5.99 g, 79%). ^{MS (CI) MH +: C} 20 calculated in the H ₂₉ NO ₄ S: 412, Found: 412.
Part C: To a solution of the amide (2.24 g, 5.0 mmol) in Part B in methanol (20 mL) was added acetic acid (2.86 mL, 50 mmol) followed by (1-ethoxycyclopropyl) oxytrimethylsilane (6.03 mL, 30 mmol ), And sodium borohydride (1.41 g, 22.5 mmol) were added and the solution was refluxed for 18 hours. The solution was concentrated in vacuo, the residue was dissolved in ethyl acetate, washed with 1 N NaOH, H ₂ O and saturated NaCl, and dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / hexane) gave the cyclopropylamine as a white solid (1.97 g, 87%).
Part D: To a solution of Part C cyclopropylamine (1.9 g, 4.2 mmol) in ethanol (10 mL) and THF (10 mL) was added NaOH (1.68 g, 42.0 mmol) in H ₂ O And the solution was heated at 68 [deg.] C for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH 2. The resulting solid was collected and washed with ethyl ether to give an acid as a white solid (1.61 g, 81%). HRMS: C ₂₁ H ₂₉ NO ₄ Calcd of S _2: 424.1616, Found: 424.1615.
Part E: N-Methylmorpholine (1.0 g, 9.0 mmol), PyBroP (1.54 g, 3.3 mmol) and 50% aqueous H 2 O Loxylamine (2.0 mL, 30 mmol) was added and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo. The residue was partitioned between ethyl acetate and H ₂ O, and the organic layer was washed with H ₂ O and saturated NaCl, then dried over magnesium sulfate. Filtration through a pad of silica (ethyl acetate / methanol) gave a white solid of hydroxamate (1.07 g, 80%).
Part F: To a solution of Part F hydroxamate (1.07 g, 2.4 mmol) in cold methanol (2 mL), acetyl chloride (0.27 mL, 3.6 mmol) was added and the solution stirred for 30 min. The solution was concentrated in vacuo. Reverse phase chromatography (acetonitrile / H ₂ O (HCl)) was performed to give the title compound as a white solid (245 mg, 21%).
Example 22: Preparation of 4 - [[4 - [(4-fluorophenyl) thio] phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide, monohydrochloride

Part A: Potassium carbonate (2.39 mg, 17.3 mmol) and 4-fluorothiophenol (3.0 mL, 28.1 mmol) were added to a solution of the sulfone of Example 9, Part D (6.0 g, 14.4 mmol) in DMF ) Was added and the solution was stirred at ambient temperature for 18 hours. The solution was diluted with ethyl acetate, washed with 1 N NaOH and saturated NaCl, and dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / hexanes) gave the solid sulfide (6.6 g, 87%).
Part B: ethanol (90 mL) and H ₂ O (20 mL) to a solution of of the Part A sulfide (6.6 g, 12.6 mmol), was added sodium hydroxide (5.04 g, 126 mmol), and the solution 70 ℃ Lt; / RTI &gt; for 18 hours. The mixture was acidified to pH 4 and the solution was extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / ethanol) gave the solid acid (4.8 g, 79%).
Part C: To a solution of the acid of Part B (4.8 g, 10.0 mmol) in DMF (30 mL) was added 4-methylmorpholine (3.03 g, 30.0 mmol) followed by O-tetrahydro-2H- (5.55 g, 12.0 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and saturated NaCl, and dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / hexanes) gave the protected hydroxamate as a white solid (4.0 g, 67%).
Part D: To a solution of the protected hydroxamate (4.0 g, 6.7 mmol) in Part D in ethyl acetate (120 mL), HCl gas was bubbled through for 5 minutes and stirred at ambient temperature for 1.5 hours. The resulting solid was collected by vacuum filtration to give the title compound as a white solid (1.90 g, 64%). ^{MS (CI) MH +: C} 18 H 19 N 2 O 4 Calcd of S ₂ F: 411, Found: 411.
Example 23: Synthesis of N-hydroxy-4 - [[4- [4- (1H-imidazol-1-yl) phenoxy] phenyl] sulfonyl] -1- (2-propynyl) &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;

To a solution of the amine salt of Example 9, Part F (3.00 g, 8.49 mmol) in DMF (13 mL), K ₂ CO ₃ (2.35 g, 17.0 mmol) and 4- (imidazol- Yl) phenol (2.72 g, 17.0 mmol) was added and the solution was heated to 85 <0> C for 64 h. The solution was concentrated, followed by fractionation of the residue with ethyl acetate and H ₂ O. The organic layer was washed with H ₂ O and saturated NaCl, and dried over magnesium sulfate. Chromatography (silica phase, chloroform / methanol) was performed to give the ethyl ester as a white foam (2.36 g, 56%).
Part B: KOH (1.80 g, 32.1 mmol) was added to a solution of the ethyl ester of Part A (2.36 g, 5.33 mmol) in ethanol (2.8 mL) and H ₂ O (4.6 mL) / RTI &gt; The solution was acidified to pH 1 with concentrated HCl solution and concentrated to give an acid as a tan solid (2.87 g) which was used without further purification.
To a solution of the acid of Part B (2.87 g, 5.33 mmol) in acetonitrile (24 mL) was added O-tetrahydro-2H-pyran-2-yl-hydroxylamine (870 mg, 7.45 mmol), EDC (1.43 g, 7.45 mmol) and N-methylmorpholine (1.21 mL, 11.0 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated and the residue was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with H ₂ O and saturated NaCl and dried over magnesium sulfate. Chromatography (chloroform, methanol) was performed to give the protected hydroxylamine as a white solid (1.62 g, 53%).
Part D: To a solution of the protected hydroxylamine of Part C (1.60 g, 2.83 mmol) in methanol (23 mL), acetyl chloride (0.61 mL, 8.52 mmol) was added and the solution stirred for 1 hour. The solution was concentrated in vacuo. Reverse phase chromatography (silica phase, acetonitrile / H ₂ O) was performed to give the title compound as a white solid (975 mg, 62%). MS (CI) MH ⁺ : Calcd for C ₂₄ H ₂₅ N ₄ O ₅ S: 481, found: 481. Anal Calcd for C ₂₄ H ₂₅ N ₄ O ₅ S 2HCl: C, 52.08; H, 4.73; N, 10.12; S, 5.79; Cl, 12.81. Found: C, 51.59; H, 4.84; N, 10.93; S, 5.51; Cl, 11.98.
Example 24: Synthesis of 4 - [[4 - [(4-fluorophenyl) thiophenyl] sulfonyl] -N-hydroxy-1- (2-propynyl) -4-piperidinecarboxamide, Preparation of chloride

Part A: Potassium carbonate (3.18 g, 22.98 mmol) and 4-fluorothiophenol (2.95 g, 12.98 mmol) were added to a solution of the propargylamine of Example 9, Part F (4.06 g, 11.49 mmol) in DMF , 22.98 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was diluted with ethyl acetate, washed with 1 N NaOH and saturated NaCl, and then dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / hexane) gave the solid sulfide (4.46 g, 84%).
Part B: NaOH (3.86 g, 97.0 mmol) was added to a solution of the sulfide of Part A (4.46 g, 9.7 mmol) in tetrahydropyran (90 mL), H ₂ O (30 mL) and ethanol And the solution was heated to 65 [deg.] C for 2 hours. The solution was concentrated in vacuo, the residue was dissolved in H ₂ O and acidified to pH 4 with 2 N HCl. The resulting residue was vacuum filtered and collected to give an acid as a white solid (4.0 g, 95%).
Part C: To a solution of the acid of Part B (4.0 g, 9.2 mmol) in DMF (50 mL) and 4-methylmorpholine (2.8 g, 27.7 mmol) O- tetrahydro-2H- Hydroxylamine (6.88 g, 46.1 mmol) and PyBroP (5.16 g, 11.1 mmol) were added and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with H ₂ O and saturated NaCl and dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / hexane) gave the protected hydroxamate as a white solid (2.8 g, 56%).
Part D: To a solution of the protected amine (2.8 g, 5.1 mmol) in Part C in ethyl acetate (100 mL) was bubbled HCl gas for 10 min and the solution was stirred for 1 h. The solution was concentrated in vacuo and the solid recrystallized (ethanol) to give the title compound as a white solid (1.12 g, 45%). ^{MS (CI) MH +: C} 21 H 21 N 2 O 4 Calcd of S ₂ F: 449, Found: 449.
Example 25: Preparation of 4 - [[4 - [(4-chlorophenyl) thio] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the tetrahydropyran compound of Example 11, Part C (8.0 g, 26.5 mmol) in THF (250 mL), potassium trimethylsilanate (10.2 g, 79.5 mmol) Lt; / RTI &gt; The reaction was quenched by the addition of H ₂ O, acidified to pH 2.5 and the solution was extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried with Na ₂ SO _4. Concentration in vacuo afforded the acid salt of a white solid (5.78 g, 76%).
To a solution of Part A acid salt (5.4 g, 18.7 mmol) in DMF (35 mL) was added HOBT (3.04 g, 22.5 mmol), N-methylmorpholine (6.2 mL, 56.2 mmol), O- -2H-pyran-2-yl-hydroxylamine (6.8 g, 58.1 mmol) and EDC (5.0 g, 26.2 mmol) and the solution stirred at ambient temperature for 3 hours. The solution was concentrated in vacuo, the residue was partitioned between ethyl acetate and H ₂ O and the organic layer was washed with 5% aqueous KHSO ₄ , H ₂ O, saturated NaHCO ₃ and saturated NaCl, then dried over Na ₂ SO ₄ . Concentration in vacuo afforded the protected hydroxamate as a white solid (6.34 g, 87%).
To a solution of p-chlorothiophenol (2.71 g, 18.7 mmol) in DMF (10 mL) was added K ₂ CO ₃ (2.6 g, 18.7 mmol) followed by the protected hydroxamate of Part B (2.9 g, 7.5 mmol) and the solution was heated at 75 &lt; 0 &gt; C for 5 hours. The solution was concentrated in vacuo, the residue was partitioned between ethyl acetate and H ₂ O, and the organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (silica phase, ethyl acetate / hexane / methanol) gave the sulfide in the form of a white foam (3.56 g, 93%). MS (CI) MH ⁺ : Calcd for C ₂₃ H ₂₆ ClNO ₆ S ₂ : 512, found 512.
Part D: To a solution of the sulfide of Part C (3.5 g, 6.8 mmol) in dioxane (10 mL) was added 4 N HCl in dioxane (10 mL). After stirring for 10 minutes, methanol (10 mL) was added while stirring was continued for 1 hour. The solution was concentrated in vacuo. Recrystallization (acetone / hexane) was performed to give the title compound as a white solid (2.4 g, 83%). ^{MS (CI) MH +: C} 18 calculated in the H ₁₈ ClNO ₅ S: 428, Found: 428.
Example 26: Synthesis of tetrahydro-N-hydroxy-4 - [[4- [4- (1H-1,2,4- triazol-1-yl) phenoxy] phenyl] sulfonyl] Preparation of 4-carboxamide, monohydrochloride

Part A: To a solution of the protected hydroxamate of Example 25, Part B (2.9 g, 7.5 mmol) in DMF (10 mL) was added 4- (1,2,4-triazole- was added 1-yl) phenol (2.47 g, 15 mmol), followed by _{Cs 2 CO 3 (7.33 g,} 22.5 mmol) and the solution was heated at 95 ℃ for 5 hours. The solution was concentrated in vacuo and the residue was fractionated with ethyl acetate and H ₂ O. The organic layer was washed with saturated NaCl, dried with Na ₂ SO _4. Chromatography (silica phase, ethyl acetate / hexane / methanol) gave the phenol of the white solid (3.16 g, 80%).
Part B: To a solution of Part A phenol (2.8 g, 5.3 mmol) in dioxane (10 mL) was added 4 N HCl in dioxane (10 mL). After stirring for 5 minutes, methanol (10 mL) was added and stirring was continued for 1 hour. The solution was then poured into ethyl ether and the resulting precipitate was collected by vacuum filtration to give the title compound as a white solid (2.44 g, 96%). ^{MS (CI) MH +: C} 20 H 20 N 4 O 6 S Calcd of: 445, Found: 445.
Example 27: Preparation of 1-cyclopropyl-4 - [[4 - [(4-fluorophenyl) thio] phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide, monohydrochloride

Part A: To a solution of the sulfide (7.06 g, 13.5 mmol) from Example 9, Part D in ethyl acetate (150 mL) was bubbled with HCl gas for 7 min and the solution was stirred at 0 <0> C for 15 min. The solution was concentrated in vacuo to afford the amine as a white solid (6.43 g, quantitative yield).
Part B: To a solution of the amine of Part A (6.4 g, 13.9 mmol) in methanol (65 mL) was added acetic acid (7.96 mL, 139 mmol) and a spoonful of 3A molecular sieves. To this mixture was added (1-ethoxycyclopropyl) -oxytrimethylsilane (16.8 mL, 84 mmol) followed by sodium cyanoborohydride (3.9 g, 62 mmol). The solution was heated under reflux for 6 hours. The solution was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O, 2 N NaOH and saturated NaCl, and dried over magnesium sulfate. Filtration through silica pad (hexane / ethyl acetate) afforded the cyclopropylamine as a white solid (6.49 g, quantitative yield).
Part C: NaOH (5.5 g, 138 mmol) in H ₂ O (23 mL) was added to a solution of the cyclopropylamine (6.4 g, 13.8 mmol) in Part B in ethanol (30 mL) and THF And the solution was heated to 65 [deg.] C for 12 hours. The solution was concentrated in vacuo and the aqueous layer was acidified to pH 2 with 2 N HCI. The resulting white precipitate was collected by filtration to give an acid as a white solid (5.2 g, 87%). ^{MS (CI) MH +: C} 21 H 22 NO 4 Calcd of S ₂ F: 436, Found: 436.
To a solution of the acid of Part C (2.27 g, 5.2 mmol) in DMF (60 mL) was added HOBT (845 mg, 6.2 mmol) followed by N-methylmorpholine (1.71 mL, 15.6 mmol), EDC tetrahydro-2H-pyran-2-yl-hydroxylamine (913 mg, 7.8 mmol) was added and the solution was stirred at ambient temperature for 72 hours. The solution was concentrated in vacuo, the residue was dissolved in dichloromethane, washed with H ₂ O and saturated NaCl, and then dried over magnesium sulfate. Chromatography (silica phase, hexane / ethyl acetate) was performed to give the protected hydroxamate as a white solid (1.95 g, 70%).
Part E: To a solution of the protected hydroxamate (3.2 g, 6.0 mmol) in Part D in cold methanol (100 mL) was added acetyl chloride (1.3 mL, 18.0 mmol) in methanol (30 mL) And stirred at ambient temperature for 4 hours. The solution was concentrated in vacuo and the residue was triturated with ethyl ether to give the title compound as a white solid (2.86 g, 98%). MS (CI) MH ⁺ : C ₂₁ H ₂₃ N ₂ O ₄ Calcd for S ₂ F: 451, found 451.
Anal. Calcd for C ₂₁ H ₂₃ N ₂ O ₄ S ₂ F 0.25 H ₂ O HCl: C, 51.32; H, 5.02; N, 5.70; S, 13.05; Cl, 7.21. Found: C, 50.99; H, 4.91; N, 5.65; S, 13.16; Cl, 7.83.
Example 28: Preparation of N-hydroxy-4 - [[4- (phenylthio) phenyl] sulfonyl] -1- (2-propenyl) -4-piperidinecarboxamide, monohydrochloride

To a solution of the amine hydrochloride salt of Example 9, Part E (4.78 g, 10.8 mmol) in DMF (25 mL) was added K ₂ CO ₃ (2.98 g, 21.6 mmol) and allyl bromide (0.935 mL, 10.8 mmol) and the solution was stirred at ambient temperature for 5 hours. The solution was partitioned between ethyl acetate and H ₂ O, and the organic layer was washed with H ₂ O and saturated NaCl and dried over magnesium sulfate. Filtration through silica pad (hexane / ethyl acetate) gave the allylamine in oil (4.80 g, quantitative yield).
Part B: addition of ethanol (25 mL) and NaOH (4.3 g, 108 mmol) in THF (25 mL) of a solution of allylamine (4.8 g, 10.8 mmol) of Part _{A, H 2 O (20 mL} ) and , And the solution was heated to 65 [deg.] C for 18 hours. The solution was concentrated in vacuo and diluted with H ₂ O. The aqueous solution was acidified to pH 3. The resulting precipitate was collected by vacuum filtration to give an acid which was a beige solid (4.1 g, 84%). ^{MS (CI) MH +: C} 21 calculated in the _{H 23 NO 4 O 2: 418} , Found: 418.
To a solution of the acid of Part B (4.1 g, 9.0 mmol) in DMF (90 mL) was added HOBT (1.46 g, 11.0 mmol) followed by N-methylmorpholine (2.97 mL, 2.7 mmol) Pyrrol-2-yl-hydroxylamine (1.58 g, 13.5 mmol) and EDC (2.42 g, 13.0 mmol) were added and the solution was stirred for 72 h. The solution was concentrated in vacuo. The residue was dissolved in dichloromethane, washed with H ₂ O and saturated NaCl, and then dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / methanol) was performed to give the protected hydroxylamine of a white solid (4.11 g, 88%).
Part D: To a solution of the protected hydroxylamine of Part C (4.11 g, 8.0 mmol) in ethyl acetate (100 mL) cooled to 0 C was added acetyl chloride (1.71 mL, 24.0 mmol) Lt; / RTI &gt; for 4 h. The solution was concentrated in vacuo and triturated with ethyl ether to give the title compound as a white solid (3.53 g, 95%). _{C 21 H 24 N 2 O 4} S HCl 0.5 H ₂ O analysis for Calcd _2: C, 52.76; H, 5.48; N, 5.86; S, 13.42; Cl, 7.42. Found: C, 52.57; H, 5.69; N, 6.29; S, 12.59; Cl, 7.80.
Example 29: Preparation of 1- (cyclopropylmethyl) -N-hydroxy-4 - [(4-phenoxyphenyl) sulfonyl] -4-piperidinecarboxamide, monohydrochloride

To a solution of the amine hydrochloride salt of Example 6, Part E (2.13 g, 5.0 mmol) in DMF (10 mL), K ₂ CO ₃ (1.4 g, 10.0 mmol) and bromomethylcyclopropane mL, 5.0 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was partitioned between ethyl acetate and H ₂ O, and the organic layer was washed with H ₂ O and saturated NaCl, then dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / hexanes) gave solid cyclopropylmethylamine (2.09 g, 91%).
Part B: To a solution of Part A cyclopropylmethylamine (2.0 g, 4.4 mmol) in ethanol (12 mL) and THF (12 mL) was added NaOH (1.75 g, 44 mmol) in H ₂ O And the solution was heated to 65 &lt; 0 &gt; C for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH 5. The resulting precipitate was collected by vacuum filtration to give an acid as a white solid (1.58 g, 79%). HRMS: calcd for C ₂₂ H ₂₅ NO ₅ S: 414.1375, Found: 414.1334.
Part C: To a solution of the acid of Part B (1.58 g, 3.5 mmol) in dichloromethane (50 mL) was added triethylamine (1.46 mL, 10.5 mmol) followed by 50% aqueous hydroxylamine (2.3 mL, And PyBroP (3.26 g, 6.99 mmol) were added and the solution was stirred at ambient temperature for 72 hours. The solution was washed with H ₂ O and saturated NaCl and dried over magnesium sulfate. Reverse phase chromatography (silica phase, acetonitrile / H ₂ O) was carried out to obtain the hydromate of white solid (3.2 g, quantitative yield).
Part D: Acetyl chloride (0.25 mL, 3.5 mmol) in methanol (5 mL) was added to a solution of Part C hydroxamate (1.5 g, 3.5 mmol) in cold methanol (20 mL) And stirred for 15 minutes. The solution was stirred at ambient temperature for an additional 30 minutes and concentrated in vacuo. Trituration with ethyl ether gave the title compound as a white solid (229 mg, 7%).
Example 30: Preparation of N-hydroxy-1- (2-methoxyethyl) -4 - [(4-phenoxyphenyl) sulfonyl] -4-piperidinecarboxamide, monohydrochloride

Part A: To a solution of the amine HCl salt of Example 6, Part E (2.5 g, 5.87 mmol) and K ₂ CO ₃ (1.6 g, 11.57 mmol) in N, N-dimethylformamide (25 mL) Moiety methyl methyl ether (0.66 mL, 7.0 mmol) was added and stirred at ambient temperature for 18 hours. N, N-Dimethylformamide was evaporated in a high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over Mg ₂ SO ₄ . Concentration in vacuo yielded 2.63 g (quantitative yield) of light yellow gel-like methoxylethylamine.
Part B: To a solution of Part A methoxylethylamine (2.63 g, 5.87 mmol) in tetrahydrofuran (18 mL) and ethanol (18 mL) was added NaOH (2.1 g, 5.25 mmol) in H ₂ O ). The solution was heated under reflux for 12 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether (2 x 100 mL) and acidified to pH 2. The resulting precipitate was vacuum filtered to give an acid as a white solid (2.4 g, quantitative yield).
Part C: A solution of the acid of Part B (2.0 g, 4.33 mmol) in N, N-dimethylformamide (20 mL) containing N-methylmorpholine (1.8 mL, 16.4 mmol) (3.1 g, 16.2 mmol) was added to a solution of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.767 g, 6.44 mmol) Lt; / RTI &gt; for 20 h. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with H ₂ O and dried over Mg ₂ SO ₄ . Concentration in vacuo afforded the amide in off-white foam (1.60 g, 71.1%).
Part D: To a solution of the amide of Part C (1.58 g, 3.05 mmol) in methanol (20 mL) cooled to 0 C was added acetyl chloride (0.65 mL, 9.15 mmol) and the resulting solution was stirred at the same temperature for 3 h Lt; / RTI &gt; The solution was concentrated and subjected to reverse phase chromatography (C-18 silica phase, acetonitrile / H ₂ O + 0.01% HCl) to give the hydromamate HCl salt as a white solid (0.65 g, 45.5%). _{C 21 H 26 N 2 O 6} S.HCl.0.75H of analysis ₂ O Calcd: C, 52.06; H, 5.93; N, 5.78; S, 6.62. Found: C, 51.94; H, 5.67; N, 5.91; S, 6.66. _{HSMS: C 21 H 26 N 2} O 6 S Calculated for: 435.1590, Found: 435.1571.
Example 31: Preparation of N-hydroxy-4 - [(4-phenoxyphenyl) sulfonyl] -1- (1-pyrrolidinyl acetyl) -4-piperidinecarboxamide, monohydrochloride

Part A: tetrahydrofuran (10 mL) and ethanol in Example 6, a solution of the sulfone (2.75 g, 5.6 mmol) of Part _{D, H 2 O (20 mL} ) of NaOH (2.25 g, 56 of the (10 mL) mmol) were added and the solution was heated to 70 &lt; 0 &gt; C for 20 h. The solution was concentrated in vacuo and dissolve the dried residue was taken up in H ₂ O. The aqueous layer was extracted with ether, acidified to pH 2, and extracted with ethyl acetate. The combined organic layers were washed again with H ₂ O and dried over Mg ₂ SO ₄ . Concentration in vacuo afforded the BOC-acid as a white foam (2.3 g, 88.8%).
Part B: Trifluoroacetic acid (6 mL, 77.8 mmol) was added to a solution of Part A BOC-acid (2.3 g, 4.98 mmol) in dichloromethane (6 mL) and the resulting solution was stirred at ambient temperature for 1 hour Lt; / RTI &gt; Concentration in vacuo afforded the amine in the form of a white foam (2.44 g, quantitative yield).
Part C: To a solution of the amine of Part B (2.4 g, 4.9 mmol) and triethylamine (3.5 mL, 24.4 mmol) in acetone (15 mL) and H ₂ O (15 mL) was added chloroacetyl chloride (1.2 mL, 14.7 mmol ) Was added and the solution was stirred at ambient temperature for 20 hours. The acetone was then evaporated and the aqueous layer was acidified to pH 2. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and dried over Mg ₂ SO ₄ . And concentrated in vacuo to give the chloroacetylamide in the pale yellow gel state (2.78 g, quantitative yield).
Part D: To a solution of N, N- dimethylformamide (20 mL) chloroacetyl amide (2.78 g, 4.93 mmol) and _{K 2 CO 3 (5 g,} 36 mmol) of Part C, pyrrolidine (3 mL , 36 mmol). The solution was then stirred at ambient temperature for 18 hours. The N, N-dimethylformamide was then evaporated under high vacuum and the reversed phase chromatography (C-18 silica phase, acetonitrile / H ₂ O + 0.01% HCl) was performed to give pyrrolidine acetylamide (0.25 g, 10.7%).
Part E: N-Methylmorpholine (0.14 mL, 1.27 mmol), 1-hydroxybenzotriazole (0.17 g, 1.2 mmol) and O-tetrahydro-2H-pyranylhydroxylamine (0.15 g, 1.26 To a solution of the pyrrolidine acetylamide of Part D (0.25 g, 0.53 mmol) in N, N-dimethylformamide (4 mL) containing 1 - [3- (dimethylamino) 3-ethylcarbodiimide chloride (0.23 g, 1.2 mmol) was added. The solution was then stirred at ambient temperature for 18 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , H ₂ O and dried over Mg ₂ SO ₄ . Concentration in vacuo afforded the THP amide in the form of a white foam (0.25 g, 83.3%).
Part F: To a solution of the amide of Part E (0.25 g, 0.437 mmol) in methanol (4 mL) cooled to 0 C acetyl chloride (0.075 mL, 1.05 mmol) was added and the resulting solution was stirred at ambient temperature for 2.5 h Lt; / RTI &gt; The solution was concentrated and subjected to reverse phase chromatography (C-18 silica phase, acetonitrile / H ₂ O + 0.01% HCl) to give the hydromamate HCl salt as a white solid (80 mg, 29%). Anal Calcd for C ₂₄ H ₂₉ N ₃ O ₆ S.HCl 0.9H ₂ O Calcd: C, 53.36; H, 5.98; N, 7.78. Found: C, 53.61; H, 5.71; N, 7.94. HSMS: Calcd for C ₂₄ H ₂₉ N ₃ O ₆ S: 488.1855, found 488.1835.
Example 32: Preparation of 1-cyclopropyl-N-hydroxy-4 - [[4- (phenylthio) phenyl] sulfonyl] -4-piperidinecarboxamide, monohydrochloride

Part A: A solution of 4-fluorothiophenol (50.29 g, 0.39 mmol) in dimethylsulfoxide (500 mL) was heated to 65 <0> C for 5 h. The solution was cooled to ambient temperature and poured into vigorously stirred ice water. The precipitate was filtered and washed twice with water. Drying under high vacuum yielded disulfide as a yellow oil (34.39 g, 68.9%) at ambient temperature.
To a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in tetrahydrofuran (5 mL) was added ethylisonipecotate (15.7 g, 0.1 mol) in tetrahydrofuran (100 mL) Was added dropwise over 20 min. The resulting solution was stirred overnight (about 18 hours) at ambient temperature and concentrated in vacuo to give light oil. The oil was filtered through silica gel (ethyl acetate / hexanes) and concentrated in vacuo to give the BOC-piperidine compound as a clear colorless oil (26.2 g, quantitative yield).
Part C: Lithium diisopropylamide (41.33 mL, 74 mmol) was added to a solution of the BOC-piperidine compound (15.96 g, 62 mmol) in Part B in tetrahydrofuran (300 mL) . The solution was then stirred at -40 &lt; 0 &gt; C for 1 h and at 0 &lt; 0 &gt; C for 1.5 h. The solution was again cooled to -40 C and disulfide of Part A (15.77 g, 62 mmol) in tetrahydrofuran (20 mL) was added. The resulting solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with H ₂ O and saturated NaCl and dried over MgSO ₄ . Chromatography (silica phase, ethyl acetate / hexanes) gave the sulfide in oil form (18 g, 75%).
Part D: m-Chloroperbenzoic acid (18.5 g, 107 mmol) was added to a solution of the sulfide (16.5 g, 43 mmol) of Part C in dichloromethane (500 mL) After 2 h, the solution was diluted with dichloromethane, washed with 1 N KOH, H ₂ O and dried over MgSO ₄ . Concentration in vacuo gave solid sulphone (21 g, quantitative yield).
Part E: To a solution of Part D sulfone (40 g, 96 mmol) and powdered K ₂ CO ₃ (26 g, 188 mmol) in N, N-dimethylformamide (200 mL) Phenol (19.8 mL, 192 mmol) was added and the resulting composition was stirred at ambient temperature for 36 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with H ₂ O and dried over magnesium sulfate. Chromatography (silica phase, ethyl acetate / hexane) gave the phenylthiophenyl Boc-sulfone as a white solid (44.34 g, 91%).
Part F: To a solution of the phenylthiophenyl Boc-sulfone (8.6 g, 17 mmol) in Part E in dichloromethane (30 mL) cooled to 0 C trifluoroacetic acid (TFA; 30 mL) The solution was stirred at ambient temperature for 2 hours. Concentration in vacuo afforded an amine TFA salt of pale yellow gel (8.7 g, quantitative yield).
Part G: To a solution of the amine TFA salt of Part F (6 g, 11.9 mmol) was added acetic acid (6.8 mL, 119 mmol). After stirring for 5 minutes at ambient temperature, (1-ethoxycloropropyl) oxytriomethylsilane (14.3 mL, 71.4 mmol) was added and after 5 minutes sodium cyanoborane hydrate (3.35 g, 53.55 mmol) Respectively. The solution was then heated under reflux for 18 hours. The methanol was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N NaOH, H ₂ O, and dried over Mg ₂ SO ₄ . Concentration in vacuo yielded an off-white powder, cyclopropylamine (4.9 g, 92.6%).
Part H: tetrahydrofuran NaOH (4.3 g, 100 mmol) of (12.5 mL) and ethanol (12.5 mL) of Part G cyclopropylamine To a solution of (4.88 g, 10.95 mmol), H 2 O (25 mL) Was added. The solution was heated to 50-55 [deg.] C for 12 hours and stirred at ambient temperature for 18 hours. The solution was acidified to pH 2 and concentrated in vacuo to give a mixture of the acid and NaCl as a white solid. Tetrahydropyranylamine (1.95 g, 16.3 mmol), N-methylmorpholine (2.4 mL, 21.9 mmol) and 1- [3- (dimethylamino) propyl) piperazine were added to a solution of the mixture in acetonitrile ] -3-ethylcarbodiimide hydrochloride (3.14 g, 16.3 mmol) were added in sequence. The solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with H ₂ O and dried over Mg ₂ SO ₄ . Concentration in vacuo afforded tetrahydropyranyl (THP) amide as a white solid (3.0 g, 53.1%).
Part I: To a cooled solution of THP amide (3 g, 5.8 mmol) in Part H in methanol (45 mL) to 0 C was added acetyl chloride (1.5 mL, 21.1 mmol) and the solution was stirred at ambient temperature for 2.5 h Lt; / RTI &gt; The precipitate was vacuum filtered to give the hydroxamate HCl salt as a white solid (1.844 g, 68.3%). Anal. Calcd for C ₂₁ H ₂₄ N ₂ O ₄ S ₂ .HCl: C, 53.78; H, 5.37; N, 5.97; S, 13.67. Found: C, 53.40; H, 5.26; N, 5.95; S, 13.68.
Example 33: Preparation of N-hydroxy-1-methyl-4 - [[4- (phenylthio) phenyl] sulfonyl] -4-piperidinecarboxamide, monohydrochloride

To a solution of the amine TFA salt (2.67 g, 5.14 mmol) from Example 32, Part F in methanol (20 mL) and 37% formaldehyde (2.0 mL, 25.7 mmol) in aqueous solution was added borane pyridine (2.6 mL, 25.7 mmol) Was added at ambient temperature. The solution was then stirred at ambient temperature for 18 hours. The solution was acidified to destroy excess reagent. The methanol was evaporated and the residue was partitioned between aqueous NaHCO ₃ and ethyl acetate. The NaHCO ₃ aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with H ₂ O and dried over Mg ₂ SO ₄ . Concentration in vacuo afforded methylamine in off-white foam (1.6 g, 76%).
Part B: To a solution of Part A methylamine (1.63 g, 3.88 mmol) in ethanol (20 mL) was added KOH (1.31 g, 23.2 mmol) in H ₂ O (4 mL) C for 8 hours, heated to 70 &lt; 0 &gt; C for 4 hours, and then stirred at ambient temperature for 18 hours. The solution was acidified and concentrated in vacuo to give a mixture of the acid and NaCl as a white solid. Tetrahydropyranylamine (0.92 g, 7.76 mmol), N-methylmorpholine (1.05 mL, 7.76 mmol) and 1- [3 (tert-butyldimethylsilyloxy) - (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.5 g, 7.76 mmol) were added in turn. The solution was stirred at ambient temperature for 72 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , H ₂ O and dried over Mg ₂ SO ₄ . Concentration in vacuo and chromatography (silica phase, dichloromethane / methanol) gave the THP amide as a white solid (0.46 g, 24.2%).
Part C: To a cooled solution of THP amide (0.22 g, 0.45 mmol) in Part B in methanol (5 mL) to 0 C was added acetyl chloride (0.096 mL, 13.5 mmol) Lt; / RTI &gt; The solution was concentrated in vacuo and subjected to reverse phase chromatography (C-18 silica phase, acetonitrile / H ₂ O + 0.01% HCl) to give the hydroxamate HCl salt as a white solid (0.12 g, 60.6%). _{HSMS: C 19 H 22 N 2} O 4 calculated in S _2: 407.1099, Found: 407.1105.
Example 34: Preparation of N-hydroxy-1- (1-methylethyl) -4 - [[4- (phenylthio) phenyl] sulfonyl] -4-piperidinecarboxamide, monohydrochloride

Part A: To a solution of the BOC-sulfone of Example 32, Part E (11.19 g, 22.12 mmol) in ethyl acetate (150 mL) cooled to 0 C, HCl gas was bubbled through for 20 min. The solution was further stirred at the same temperature for 40 minutes. Concentrated in vacuo and triturated with ether to give the amine HCl salt (9.88 g, quantitative yield).
Part B: To a solution of the HCl salt of Part A (4.7 g, 10.6 mmol), triethylamine (2.0 mL, 14.4 mmol) and acetone (2.0 mL, 27.2 mmol) in dichloromethane (100 mL) was added sodium triacetoxylboro Hydride (5.7 g, 26.9 mmol) followed by acetic acid (1.5 mL, 26.9 mmol) was added at ambient temperature. The solution was stirred for 18 hours and titrated with 1 N NaOH and ether. The aqueous layer was extracted with ether and the combined organic layers were washed with 1 N NaOH, H ₂ O and dried over Mg ₂ SO ₄ . Concentration in vacuo afforded isopropylamine in the form of a white foam (4.58 g, 96.2%).
Part C: NaOH (2.1 g, 5.25 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) of Part B of isopropyl amine to a solution of (4.58 g, 10.2 mmol), H 2 O (20 mL) Was added. The solution was heated to 60 &lt; 0 &gt; C for 13.5 hours and stirred at ambient temperature for 18 hours. The solution was acidified and concentrated in vacuo to give a mixture of the acid and NaCl as a white solid. To a solution of the mixture in N, N-dimethylformamide (75 mL) was added 1- hydroxybenzotriazole (1.94 g, 14.4 mmol), O-tetrahydropyranylamine (1.8 g, 15.1 mmol) Methyl morpholine (3.37 mL, 30.7 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (2.74 g, 14.3 mmol) were added in turn. The solution was stirred at ambient temperature for 48 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , H ₂ O and dried over Mg ₂ SO ₄ . Concentration in vacuo and chromatography (silica phase, dichloromethane / methanol) gave the THP amide as a white solid (3.78 g, 71.3%).
Part D: To a solution of Part C THP amide (1.15 g, 2.2 mmol) in methanol (20 mL) was added acetyl chloride (0.096 mL, 13.5 mmol) and the resulting solution was stirred at ambient temperature for 2.5 h. The solution was concentrated in vacuo and subjected to reverse phase chromatography (acetonitrile / H ₂ O + 0.01% HCl on C-18 silica) to give the hydromamate HCl salt as a white solid (0.69 g, 66.3%). _{C 21 H 26 N 2 O 4} S 2 .HCl.H ₂ O for analysis calcd: C, 51.58; H, 5.98; N, 5.73; S, 13.11. Found: C, 51.76; H, 5.47; N, 5.72; S, 12.68.
Example 35: Preparation of N-hydroxy-1- (2-methoxyethyl) -4 - [[4- (phenylthio) phenyl] sulfonyl] -4-piperidinecarboxamide, monohydrochloride

Part A: N, to a solution of N- dimethylformamide (40 mL) in Example 34, Part A amine HCl salt (4.3 g, 9.43 mmol) and _{K 2 CO 3 (2.62 g,} 19.0 mmol) of 2- Bromoethyl methyl ether (1.9 mL, 20.2 mmol) was added. The solution was stirred at ambient temperature for 48 hours. N, N-Dimethylformamide was then evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over Mg ₂ SO ₄ . Concentration in vacuo afforded the methoxylethylamine as a white foam (4.26 g, 95.3%).
Part B: To a solution of Part A methoxylethylamine (4.26 g, 9.2 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) was added NaOH (3.7 g, 92.5 mmol) in H ₂ O ). The resulting solution was heated at 60 &lt; 0 &gt; C for 12 h and stirred at ambient temperature for 18 h. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether (2 x 100 mL) and acidified to pH 2. The resulting precipitate was vacuum filtered to give an acid as a white solid (3.5 g, 87.5%).
Part C: N-Methylmorpholine (2.6 mL, 23.4 mmol), 1-hydroxybenzotriazole (3.16 g, 23.4 mmol) and O-tetrahydro-2H-pyran- To a solution of the acid of Part B (3.4 g, 7.8 mmol) in N, N-dimethylformamide (20 mL) containing potassium carbonate Carbodiimide hydrochloride (4.47 g, 23.4 mmol) was added. The solution was stirred at ambient temperature for 36 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , H ₂ O and dried over Mg ₂ SO ₄ . Concentration in vacuo afforded an amide which was an off-white solid (2.98 g, 71.5%).
Part D: To a cooled solution of the amide of Part C (2.98 g, 5.6 mmol) in methanol (40 mL) at 0 C was added acetyl chloride (1.19 mL, 16.8 mmol) and the resulting solution was stirred at ambient temperature for 3 h Lt; / RTI &gt; The solution was concentrated and subjected to reverse phase chromatography (C-18 silica phase, acetonitrile / H ₂ O + 0.01% HCl) to give the hydromamate HCl salt as a white solid (2.29 g, 84.6%). _{C 21 H 26 N 2 O 6} S.HCl.0.9H of analysis ₂ O Calcd: C, 50.12; H, 5.77; N, 5.57; S, 12.74. Found: C, 50.41; H, 5.85; N, 5.73; S, 12.83.
Example 36: Preparation of 1-acetyl-N-hydroxy-4 - [[4- (phenylthio) phenyl] sulfonyl] -4-piperidinecarboxamide, monohydrochloride

Part A: in tetrahydrofuran (25 mL) and ethanol (25 mL) of Example 32, a solution of phenyl thiophenyl BOC- sulfone (7 g, 1.29 mmol) of Part _{E, H 2 O (50 mL} ) NaOH (5.1 g, 12.9 mmol). The solution was heated under reflux for 20 hours. While cooling, the solution was concentrated in vacuo and dissolve the dried residue was taken up in H ₂ O. The aqueous layer was extracted with ether, acidified to pH 2, and extracted with ethyl acetate. The combined organic layers were washed again with H ₂ O and dried over Mg ₂ SO ₄ . Concentration in vacuo afforded BOC-acid as a white foam (3.9 g, 60%).
Part B: To a solution of Part A BOC-acid (2.3 g, 4.98 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (6 mL, 77.8 mmol) and the solution was stirred at ambient temperature for 1 hour Lt; / RTI &gt; Concentration in vacuo afforded the amine in the form of a white foam (2.44 g, quantitative yield).
Part C: acetone (20 mL) and H ₂ O (20 mL) the solution was cooled to 0 ℃ of Part B amine (5.0 g, 12.08 mmol) and triethylamine (8.7 mL, 60.4 mmol), acetyl chloride (4.6 mL, 36 mmol) and the solution was stirred at ambient temperature for 40 h. The acetone was evaporated and the aqueous layer was acidified to pH 2. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and dried over Mg ₂ SO ₄ . Concentration in vacuo afforded the acetylamide in pale yellow foam (5 g, quantitative yield).
Part D: N-Methylmorpholine (5.3 mL, 47.6 mmol), 1-hydroxybenzotriazole (4.8 g, 35.7 mmol) and O-tetrahydro-2H-pyran-1 -hydroxylamine (2.8 g, 23.5 mmol) was added to a solution of the acetylamide (5 g, 11.9 mmol) of Part C in N, N-dimethylformamide (50 mL) containing 1- [3- (dimethylamino) (6.8 g, 35.7 mmol) was added and the solution was stirred at ambient temperature for 20 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , KHSO ₄ , H ₂ O and dried over Mg ₂ SO ₄ . Concentration in vacuo afforded the THP amide in the form of a white foam (6.07 g, 98.2%).
Part E: To a cooled solution of THP amide (6.07 g, 11.7 mmol) in Part D in methanol (100 mL) to 0 C was added acetyl chloride (2.5 mL, 35.1 mmol) and the solution was stirred at ambient temperature for 3 h Lt; / RTI &gt; The solution was concentrated and chromatographed (silica phase, methanol / dichloromethane) to give the hydroxamate HCl salt as a white solid (3.3 g, 65%). Anal Calcd for C ₂₄ H ₂₉ N ₃ O ₆ S.HCl 0.9H ₂ O Calcd: C, 53.36; H, 5.98; N, 7.78. Found: C, 53.61; H, 5.71; N, 7.94. HSMS: Calcd for C ₂₄ H ₂₉ N ₃ O ₆ S: 488.1855, found 488.1835.
Example 37: Synthesis of 1-acetyl-4 - [[4- (1,3-benzodioxol-5-yloxy) phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide, monohydro Preparation of chloride

Part A: To a solution of the sulfone of Example 32, Part D (25 g, 67.3 mmol) and powdered K ₂ CO ₃ (23.3 g, 16.9 mmol) in N, N-dimethylformamide was added sesamol (23.24 g, 16.8 mmol) at ambient temperature and the solution was heated to 90 &lt; 0 &gt; C for 24 h. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N NaOH, H ₂ O, dried over MgSO ₄ and chromatographed (silica, ethyl acetate / hexane) to give ceasaryl BOC-sulfones as white foam (33.6 g, 93.6% ).
Part B: To a solution of the sesamol BOC-sulfone (29.31 g, 54.93 mmol) in Part E in ethanol (60 mL) and tetrahydrofuran (60 mL) was added NaOH (21.97 g, 544 mmol ). The solution was then heated to 60 &lt; 0 &gt; C for 9 hours and then stirred at ambient temperature for 12 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH 2. It was then extracted with ethyl acetate and the combined organic layers were washed with H ₂ O and dried over MgSO ₄ . Concentration in vacuo afforded the acid as a white solid (25.3 g, 91%).
Part C: To a solution of the acid of Part F (20.3 g, 40.15 mmol) in ethyl acetate cooled to 0 C, HCl gas was bubbled through. After 1.5 h, the white precipitate was vacuum filtered to give the amine solid HCl salt as a white solid (16 g, 93.6%).
Part D: To a solution of the amine HCl salt of Part G (8.1 g, 19.01 mmol) in acetone (150 mL) and H ₂ O (150 mL) and triethylamine (13.2 mL, 95.05 mmol) Acetyl chloride (5.4 mL, 76 mmol) was added. The solution was stirred at ambient temperature for 18 hours. The acetone was evaporated and the aqueous layer was acidified to pH 2. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and dried over Mg ₂ SO ₄ . Concentration in vacuo afforded the acetylamide in pale yellow foam (9.24 g, quantitative yield).
Part E: To a solution of acetylamide (9.1 g, 20.33 mmol) from Part D in N, N-dimethylformamide (40 mL), N-methylmorpholine (6.7 mL, 61 mmol), 1-hydroxybenzotriazole 3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (4.85 g, 40 mmol) was added to a solution of 2- (11.65 g, 60 mmol). The resulting solution was stirred at ambient temperature for 20 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , KHSO ₄ , H ₂ O and dried over Mg ₂ SO ₄ . Concentration in vacuo and chromatography (silica phase, ethyl acetate / hexanes) gave the THP amide as a white foam (10 g, 89.7%).
Part F: To a solution of 4 N HCl in dioxane (20 mL) was added a solution of the amide of Part E (5.0 g, 9.1 mmol) in methanol (5 mL) and dioxane (15 mL). The solution was stirred at ambient temperature for 30 minutes. The white precipitate was vacuum filtered to give the hydroxamate HCl salt as a white solid (3.3 g, 65%). Anal. Calcd for C ₂₁ H ₂₂ N ₂ O ₈ S.HCl: C, 54.34; H, 5.15; N, 5.49; S, 6.43. Found: C, 54.54; H, 4.79; N, 6.06; S, 6.93. HSMS: C ₂₁ H ₂₂ N Calcd the ₂ O ₈ S: 463.1175, Found: 463.118.
Example 38: Synthesis of 4 - [[4- (3,4-dimethoxyphenoxy) phenyl] sulfonyl] -N-hydroxy-1- (2-propynyl) -4-piperidinecarboxamide, Preparation of Hydrochloride

Part A: HCl gas was bubbled through a solution of the sulfone of Example 32, Part D (10 g, 24 mmol) in ethyl acetate at 0 &lt; 0 &gt; C. After 4 h, the white precipitate was vacuum filtered to give the amine HCl salt as a white solid (7.27 g, 86%).
Part B: To a solution of the amine HCl salt of Part A (5.98 g, 17 mmol) and powdered K ₂ CO ₃ (4.7 g, 34 mmol) in N, N-dimethylformamide (120 mL) (2.022 g, 17 mmol) was added at ambient temperature and then stirred for 4 hours. The solution was diluted with ethyl acetate, washed with H ₂ O and saturated NaCl, and dried over Mg ₂ SO ₄ . Concentration in vacuo and chromatography (silica phase, ethyl acetate / hexanes) afforded the propargylamine as a white solid (5.2 g, 86%)
Part C: A solution of Part B propargylamine (8 g, 22.63 mmol) and powdered K ₂ CO ₃ (8.8 g, 56.6 mmol) in N, N-dimethylformamide (150 mL) Dimethoxyphenol (6.98 g, 45 mmol) was added at ambient temperature. The composition was heated to 90 DEG C for 36 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N NaOH and H ₂ O and dried over Mg ₂ SO ₄ . Chromatography (silica phase, ethyl acetate / hexane) afforded phenoxypropargylamine as a pale yellow gel (10 g, 90.9%).
Part D: A solution of NaOH (8.2 g, 200 mmol) in H ₂ O (30 mL) from an addition funnel was added to a solution of Part C phenoxypropargylamine (10 mL) in ethanol (15 mL) and tetrahydrofuran g, 20.5 mmol) at ambient temperature. The resulting solution was then heated to 60 DEG C for 48 hours and heated at ambient temperature for 48 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH = 2. Vacuum filtration of the white precipitate gave the acid as a white solid (9.4 g, quantitative yield).
Part E: To a solution of the acid of Part D (9.4 g, 20.5 mmol), N-methylmorpholine (6.8 mL, 62 mmol), 1-hydroxybenzotriazole (8.3 g, , 60 mmol) and O-tetrahydro-2H-pyran-1 -ylhydroxylamine (4.8 g, 40 mmol) in DMF (5 mL) was added 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride (11.7 g, 60 mmol). The resulting solution was then stirred for 20 hours at ambient temperature. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO ₃ and H ₂ O and dried over Mg ₂ SO ₄ . Concentration in vacuo and chromatography (silica phase, ethyl acetate / hexanes) afforded THP amide as a white foam (10 g, 89.7%).
Part F: To a solution of 4N HCl in dioxane (38 mL, 152 mmol) was added a solution of the amide of Part E (8.5 g, 15.2 mmol) in methanol (8 mL) and dioxane (24 mL). The resulting composition was stirred for 80 minutes at ambient temperature. Concentration in vacuo and titration with ether gave the hydroxamate HCl salt as a white solid (7.7 g, quantitative yield). _{HSMS: C 23 H 26 N 2} O 7 S Calculated for: 475.1461, found 45.1539.
Example 39: Synthesis of 4 - [[4- (3,5-dimethoxyphenoxy) phenyl] sulfonyl] -N-hydroxy-1- (2-propynyl) -4-piperidinecarboxamide, Preparation of Hydrochloride

Part A: To a solution of the propargylamine (2 g, 5.6 mmol) from Part B of Example 38 and powdered K ₂ CO ₃ (1.9 g, 13.7 mmol) in N, N-dimethylformamide (20 mL) , 3,5-dimethoxyphenol (2.18 g, 13.7 mmol) was added at ambient temperature. The resulting composition was heated to 90 DEG C for 36 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N NaOH and H ₂ O and dried over MgSO ₄ . Chromatography (silica phase, ethyl acetate / hexane) gave phenoxypropargylamine as a pale yellow gel (2.76 g, quantitative yield).
Part B: ethanol (5 mL) and tetrahydrofuran (5 mL) NaOH (2.3 of a solution of the phenoxy propargyl amine (2.75 g, 5.6 mmol) of Part A _{of, H 2 O (10 mL)} g, 56 mmol) at ambient temperature. The solution was then heated to 60 DEG C for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH = 2. Vacuum filtration of the white precipitate gave the acid as a white solid (2 g, 77.2%).
Hydroxybenzotriazole (1.74 g, 13.2 mmol) and O-tetrahydro-2H-pyran-yl-hydroxylamine (1.02 g, 8.6 mmol) To a solution of the acid of Part B (2 g, 4.3 mmol) in N, N-dimethylformamide (20 mL) containing 1 - [3- (dimethylamino) propyl] -3-ethylcarbodiie MeOH (2.47 g, 12.9 mmol) was added. The resulting composition was stirred at ambient temperature for 20 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO ₃ and H ₂ O and dried over Mg ₂ SO ₄ . Concentration in vacuo and chromatography (silica phase, ethyl acetate / hexanes) afforded THP amide as a white foam (2.4 g, quantitative yield).
Part D: To a solution of 4N HCl in dioxane (13 mL, 52 mmol) was added a solution of the THP amide of Part C (2.43 g, 4.35 mmol) in methanol (2 mL) and dioxane (6 mL) The composition was stirred at ambient temperature for 80 minutes. Vacuum filtration of the precipitate and washing with ether gave the hydroxamate HCl salt as a white solid (1.25 g, 56.3%). Analytical Calcd for C ₂₃ H ₂₆ N ₂ O ₇ S.1.5HCl: C 52.20; H 5.24; N 5.29. Found: C 52.00; H 5.05; N 5.17.
Example 40: Preparation of 4 - [[4- (1,3-benzodioxol-5-yloxy) phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide, monohydrochloride

Part A: To a solution of the N-BOC carboxylic acid compound from Example 37 Part B (1.25 g, 2.47 mmol), N-methylmorpholine (1.00 g, 9.89 mmol) in N, N- dimethylformamide 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.616 g, 3.21 mmol) was added to a solution of 1-hydroxybenzotriazole hydrate (0.40 g, 2.96 mmol) Respectively. After 5 min, a solution of O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.39 g, 3.33 mmol) in N, N-dimethylformamide (2 mL) was added. After 2 days, the pale yellow solution was concentrated in vacuo to give a residue which was dissolved in ethyl acetate, washed successively with water (3x) and brine, and dried over sodium sulfate. The residue was concentrated and chromatographed on silica gel eluting with ethyl acetate / hexanes (20/80) to give THP-protected hydroxamate as an oil (1.54 g, 100%).
Part B: To a solution of Part A THP-protected hydroxamate (1.49 g, 2.46 mmol) in dioxane (9 mL) and methanol (3 mL) was added 4N HCl in dioxane (10 mL, 40 mmol) . After 1.5 h at ambient temperature, the suspension was treated with diethyl ether (15 mL) and filtered to give the title hydroxamate (1.00 g, 89%) as a colorless powder. MS (CI) MH ⁺ : Anal. Calcd for C ₁₉ H ₂₀ N ₂ SO ₇ : 421, found: 421. Anal Calcd for C ₁₉ H ₂₀ N ₂ SO ₇ HCl: C 49.95; H 4.63; N 6.13; Cl 7.76; S 7.02. Found: C 49.82; H 4.60; N 5.98; Cl 17.38; S 7.10.
Example 41: Synthesis of N-hydroxy-4 - [[4- (3-methylphenoxy) phenyl] sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide, monohydrochloride Produce

Part A: the N, N- dimethylformamide (30 mL) Example 9 of the part F of propargyl amine (8.0 mg, 22.6 mmol) and K ₂ CO ₃ in the solution, m- cresol (3.5 g, 33.9 mmol) and the solution was stirred at 90 &lt; 0 &gt; C for 18 h. The solution was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl, dried over MgSO _4. Chromatography (silica phase, eluted with 10% ethyl acetate / hexanes) gave the 3-methylphenoxyphenyl compound as a solid (10.3 g, 98%). MS: C ₂₄ H ₂₈ Calculated for NSO ₅ : 441.1688, found 442.1697.
Part B: To a solution of the 3-methylphenoxyphenyl compound of Part A (10.3 g, 22.0 mmol) in tetrahydrofuran (50 mL) and ethanol (50 mL) was added NaOH (8.9 g, 22.3 mmol) The solution was heated at 65 &lt; 0 &gt; C for 24 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH = 3. Vacuum filtration of the resulting precipitate gave the acid as a white solid (9.0 g, 91%). MS: C ₂₂ H ₂₄ Calculated for NSO ₅ = 414.1375. Found = 414.1389.
Hydroxybenzotriazole (3.24 g, 23.9 mmol), N-methylmorpholine (6.58 mL, 59.9 mmol) and O-tetrahydrobenzo [b] thiophene were added to a solution of the acid of Part B (9.0 g, 19.5 mmol) 3- (ethylamino) propyl] -3-ethylcarbodiimide hydrochloride (5.35 g, 27.9 mmol) was added to a solution of . The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over MgSO _4. Chromatography (silica phase, eluted with 40% ethyl acetate / hexanes) gave the desired THP-protected hydroxamate as a solid (6.9 g, 67%). Analytical Calcd for C ₂₇ H ₃₃ N ₂ SO ₆揃 0.1H ₂ O: C 62.92, H 6.49, N 5.43, S 6.23. Found: C 62.69, H 6.47, N 5.57, S 6.33. MS: Calcd for C ₂₇ H ₃₃ N ₂ SO ₆ : 513.2059, found 513.2071.
Part D: To a solution of Part C THP-protected hydroxamate (6.4 mg, 12.5 mmol) in dioxane (56 mL) and methanol (19 mL) was added 4N HCl / dioxane (40 mL). After stirring at ambient temperature for 1 hour, the solution was concentrated in vacuo. Trituration with ethyl ether gave the title compound as a white solid (5.66 g, 97.4%). MS: C ₂₂ H ₂₄ N ₂ Calculated for SO ₅ +1: 429.1484, found M + 1: 429.1493.
Example 42: Synthesis of 4 - [[4- (1,3-benzodioxol-5-yloxy) phenyl] sulfonyl] -N-hydroxy-1- (methylsulfonyl) -4-piperidinecarboxamide Manufacture of Mead

Part A: To a solution of the sulfone of Part D of Example 32 (25 g, 67.3 mmol) in N, N-dimethylformamide was added potassium carbonate (23.3 g, 0.169 mol) and sesamol (23.2 g, 0.164 mol ). The solution was immersed in an oil bath at 90 占 폚 and stirred for 25 hours. Ethyl acetate was added to the solution and the organic phase was washed with water, 1 N NaOH and water, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel eluting with ethyl acetate / hexanes (15/85) gave the ethyl ester compound as an oil (29.3 g, 82%).
Part B: To a solution of the ethyl ester (29.3 mg, 54.93 mmol) from Part A in ethanol (60 mL) and tetrahydrofuran (60 mL) was added NaOH (21.9 g, 0.549 mol) Was added and the solution was heated at 65 &lt; 0 &gt; C for 10 h. The solution was concentrated in vacuo and the aqueous residue was acidified to pH = 3. The solution was extracted with ethyl acetate. The solution was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the acid as a yellow foam (25.6 g, 92.1%).
Part C: To a solution of the acid of Part B (20.3 g, 40.15 mmol) in ethyl acetate at O <0> C, gaseous HCl was bubbled through for 20 min. The solution was stirred at 0 &lt; 0 &gt; C for 1.5 h. The precipitate formed was filtered and washed with ether to give the amine hydrochloride as a white solid (16.0 g, 93.5%).
Part D: Methanesulfonyl chloride (2.0 g, 25.0 mol) was added to a solution of the amine hydrochloride of Part C (7.5 g, 17.0 mmol) in methylene chloride (200 mL) and the solution was stirred at ambient temperature for 18 h Lt; / RTI &gt; The solution was washed with water and saturated NaCl, dried over magnesium sulphate and concentrated in vacuo to give the acid as a white solid (6.97 g, 85%).
Hydroxybenzotriazole (2.43 g, 18.0 mmol), N-methylmorpholine (4.94 mL, 45.0 mmol) and O-tetrahydrobenzo [b] thiophene were added to a solution of the acid of Part D (7.37 g, 15.0 mmol) Yl) -hydroxylamine (2.65 g, 22.5 mmol) was added followed by the addition of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (4.02 g, 21.0 mmol) . The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over MgSO _4. Chromatography (silica, eluted with 50% ethyl acetate / hexanes) gave the desired THP-protected hydroxamate as a solid (7.54 g, 85%).
Part F: To a solution of THP-protected hydroxamate (6.32 mg, 10.8 mmol) in Part E in dioxane (75 mL) and methanol (25 mL) was added 4N HCl / dioxane (30 mL). After stirring at ambient temperature for 1 hour, the solution was concentrated in vacuo. Trituration with ethyl ether gave the title compound. Chromatography (silica phase, 5% methanol / ethyl acetate) gave the hydroxamate as a white solid (4.32 g, 80%). _{MS: C 22 H 22 N 2} S 2 O Calcd ₉ +1: 499.0845. Found: 499.0848.
Example 43: Synthesis of 4 - [[4- (3,4-dimethylphenoxyl) phenyl] sulfonyl] -N-hydroxy-1- (2-propynyl) -4-piperidinecarboxamide, monohydro Preparation of chloride

Part A: A mixture of the fluoro compound from Example 9, Part F (2.0 g, 5.66 mmol), 3,4-dimethylphenol (2.0 g, 16.5 mmol) and potassium carbaldehyde in N, N-dimethylformamide (15 mL) (2.3 g, 16.5 mmol) was heated at 90 &lt; 0 &gt; C under nitrogen atmosphere overnight (about 18 h). The brown mixture was concentrated in vacuo and purified by chromatography (silica phase, ethyl acetate / hexanes) to give the 3,4-dimethylphenoxyphenyl compound as a clear yellow oil (2.0 g, 79% yield). Analytical Calcd for C ₂₅ H ₂₉ NO ₅ S: C 65.91; H 6.42; N 3.04; S 7.04. Found: C 65.76; H 6.37; N 3.03; S 7.00.
Part B: A solution of the 3,4-dimethylphenoxyphenyl compound of Part A (2.0 g, 4.93 mmol) and potassium hydroxide (1.7 g, 29.7 mmol) in a mixture of ethanol (25 mL) and water (4 mL) And the mixture was stirred under reflux for 4 hours. The solution was cooled with an ice bath, then acidified with concentrated hydrochloric acid and concentrated to give a crude residue. Tetrahydro-2H-pyran-2-yl-hydroxylamine (0.88 g, 7.50 mmol), triethylamine (0.81 mL, 5.81 mmol) and 1- (3-hydroxyphenyl) -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were stirred overnight at ambient temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution, water and saturated salt solution. After drying over magnesium sulphate, the filtrate as THP-protected hydroxamate was concentrated to give a yellow foam.
Part C: The THP-protected hydroxamate of Part B (920 mg, 1.75 mmol) was dissolved in methanol (16 mL). Acetyl chloride (0.37 mL, 5.3 mmol) was added. After 3 hours, by reverse phase HPLC after concentration, the title compound was obtained as a white solid (611 mg, 79%). MS (EI) MH ^+: calcd for _{C 23 H 26 N 2 O 5} S: 443, Found: 443.
Example 44: Preparation of 4 - [[4- (4-chlorophenyl) thiophenyl] sulfonyl] -1- (propynyl) -4-piperidinecarboxylic acid, monohydrochloride and 4- 4-chlorophenyl) thiophenyl] sulfonyl] -N-hydroxy-1- (propynyl) -4-piperidinecarboxamide, monohydrochloride

Part A: To a solution of the fluoro compound from Example 9, Part F (2.0 g, 5.66 mmol), 4-chlorothiophenol (1.0 g, 6.94 mmol) and potassium carbamoylborate in N, N-dimethylformamide (12 mL) (1.1 g, 8.00 mmol) was stirred at ambient temperature under a nitrogen atmosphere overnight (about 18 hours). The mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified by chromatography (silica phase, ethyl acetate / hexanes) to give the 4-chlorophenylthiophenyl compound as a white solid (2.0 g, 75% yield). Anal. Calcd for C ₂₃ H ₂₄ NO ₄ S ₂ C ₁ : C 57.791; H 5.06; N 2.93; S 13.42; Cl 7.42. Found: C 57.57; H 5.11; N 2.94; S 13.19; Cl 7.73.
Part B: Chlorophenylthiophenyl compound from Part A (2.04 g, 4.27 mmol) was diluted with ethanol (30 mL) and water (5 mL). Potassium hydroxide (1.55 g, 27.7 mmol) was added and the mixture was heated under reflux for 3 hours. After completion of the reaction, the solution was cooled and acidified with concentrated HCl to a pH of 1-3. The solvent was removed by rotary evaporation and the residue azeotroped until dry by repeated addition of acetonitrile. The acid hydrochloride was further dried over a vacuum line and then carried over the coupling reaction. It was assumed that saponification was quantitative.
Part C: Carboxylic acid hydrochloride (4.27 mmol) from the previous part was suspended in acetonitrile (20 mL). After addition of N-methylmorpholine (about 1.0 mL), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (585 mg, 5 mmol) was added. After 5 minutes, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDC; 955 mg, 5 mmol) was added. After stirring the mixture overnight (about 18 hours), the solvent was removed by rotary evaporation, the residue was diluted with half-saturated NaHCO ₃ solution (50 mL), and the product extracted with ethyl acetate (2 x 100 mL) Respectively. In this example, difficult to process emulsions complicated compound recovery. The combined organic layers were dried over MgSO ₄ , filtered through silica, concentrated and chromatographed (flash silica, ethyl acetate / hexanes) to afford the title O-THP-protected hydroxamate (162 mg, 7% , &Lt; / RTI &gt; ester) as a foam. 450. collection amount due to the poor, the silica filter cake 1:: MS (EI) MH +: C 21 H 22 N 2 O 4 Calculated for Cl ₂ S: 450, found by extracting with ethyl acetate: methanol 1 4-piperidinecarboxylic acid, monohydrochloride (540 mg, 26%) was obtained as a colorless oil.
Part D: O-THP-protected hydroxamate (441 mg, 0.80 mmol) from Part C was dissolved in methanol (2 mL). Acetyl chloride (0.2 mL, 3 mmol) was added. After 3 hours, by reverse phase HPLC after concentration, the title hydroxamate compound was obtained as a pink solid (162 mg, 44%). ^{MS (EI) MH +: C} 21 H 22 N 2 O 4 calculated in S _2: 465, Found: 465.
Example 45: Preparation of 4 - [[4- (cyclopentylthio) -phenyl] sulfonyl] -N-hydroxy-1- (2-propynyl) -4-piperidinecarboxamide, monohydrochloride

Part A: Part F of Example 9 of propargyl amine (3.05 g, 8.5 mmol) of _{K 2 CO 3 (1.38 g,} 10 mmol), N, N- dimethylformamide (6 mL) and cyclopentyl mercaptan (1.02 mL, 10 mmol). The mixture was heated to 80 &lt; 0 &gt; C for 4 hours and to 95 &lt; 0 &gt; C for 2.5 hours and monitored by TLC. Aqueous work-up was carried out using water (10 mL) and ethyl acetate (2 x 100 mL). The combined organic layers were dried over magnesium sulfate, concentrated, and chromatographed (flash silica; ethyl acetate / hexane eluant) to give the cyclopentylmercaptil compound as an oil (3.2 g, 86%).
Part B: The cyclopentylmercaptile compound from Part A (3.12 g, 7.13 mmol) was diluted with ethanol (50 mL) and water (8 mL). Potassium hydroxide (2.59 g, 46.3 mmol) was added and the mixture was heated at reflux for 3.5 hours. After completion of the reaction, the solution was cooled and acidified with concentrated HCl to a pH of 1-3. The solvent was removed by rotary evaporation and the residue azeotroped until dry by repeated addition of acetonitrile. The carboxylic acid hydrochloride was further dried over the vacuum line and then carried over the coupling reaction. It was assumed that saponification was quantitative.
Part C: Carboxylic acid hydrochloride (7.13 mmol) from Part B was suspended in acetonitrile (50 mL). After addition of N-methylmorpholine (about 2.0 mL), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.05 g, 9 mmol) was added. After 5 min, EDC (1.72 g, 9 mmol) was added. After the mixture was stirred overnight (about 18 hours), the solvent was removed by rotary evaporation. The residue was diluted with semi-saturated NaHCO ₃ solution (50 mL) and the product was extracted with ethyl acetate (2 x 100 mL). Dry the combined organic layers over MgSO _4, filtered through silica, concentrated, and chromatographed (flash silica, ethyl acetate / hexane), while concentrated, O-THP- protected hydroxy roksa formate (2.0 g, 51%, Ester) as a foam.
Part D: O-THP-protected hydroxamate (2.00 g, 3.95 mmol) from Part C was dissolved in methanol (16 mL). Acetyl chloride (0.86 mL, 12 mmol) was added over 2 min. The reaction was stirred at ambient temperature for 4 hours, then concentrated with repeated additions of chloroform and acetonitrile and dried. The title compound precipitated as a white solid (1.77 g, 98%). ^{MS (EI) MH +: C} 20 H 26 N 2 O 4 calculated in S _2: 422, Found: 422.
Example 47: Synthesis of N-hydroxy-4 - [[4- (phenylthio) phenyl] sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide, Preparation of hydroxy-4 - [[4- (phenylsulfinyl) phenyl] sulfonyl-1- (2-propynyl) -4-piperidinecarboxamide

chloropiperbenzoic acid (57-86%, 120 mg) was added to a solution of N-hydroxy-4 - [[4- (phenylthio) phenyl] sulfonyl] -1- -Propyl) -4-piperidinecarboxamide (title compound, Example 9) (215 mg, 0.5 mmol). The reaction was slowly warmed to ambient temperature and after 16 h the mixture was passed through a micron filter and concentrated. A gradient of 30 min gradient starting with 80:20 acetonitrile and 50:50 dilution) was added to 5 (5 mL) of reverse phase HPLC (Delta Pak 50 x 300 mm; 15 micron C ₁₈ 100 angstrom; dilute HCl The major component of the branch was separated. Due to the first and second peaks from the column, two compounds of 14 (6%) and 16 mg (7%) were obtained while concentrating, and based on their NMR spectra, N-hydroxy- - [[4- (phenylsulfinyl) phenyl] sulfonyl-1- (2-propynyl) -4-piperidinecarboxamide as a partial isomer. The third peak was not confirmed. The fourth peak was identified by NMR as N-hydroxy-4 - [[4- (phenylthio) phenyl] sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide, (147 mg, 66%). MS (EI) MH +: 447. was last peak comprises a number of 3-chloro-benzoic acid 73 mg: Calculated for _{C 21 H 22 N 2 O 5} S 2: 447, Found.
Example 48: Preparation of N-hydroxy-2,2-dimethyl-5 - [(4-phenoxyphenyl) sulfonyl] -1,3-dioxane-4-carboxamide

Part A: A fresh sodium methoxide solution was prepared by slowly adding hexane-washed sodium sulphate (9.4 g, 410 mmol) to methanol (1.0 L) at 0 ° C. To this cooled solution was added 4-fluorothiophenol (50.0 g, 390 mmol) followed by the addition of methyl 2-chloroacetate (42.3 g, 390 mmol). After raising the temperature to ambient temperature, the reaction was stirred overnight (about 18 hours). The methanol was removed in vacuo and the residue was dissolved in ethyl acetate (300 mL). The organic layer was washed with water (2 × -200 mL), dried over MgSO _4. Concentration afforded the methyl ester sulfide product as a clear oil (71.8 g, 92%).
Part B: To a solution of the methyl ester sulfide product of Part A (71.8 g, 358 mmol) in 70% methanol / H ₂ O (1.0 L) Oxone ^TM (660 g, 1.08 mol) was added slowly. The mixture was stirred at ambient temperature overnight (about 18 hours). Excess Oxone ^™ was removed by filtration, and methanol was removed from the filtrate under vacuum. The remaining aqueous solution was extracted with ethyl acetate (3 x 300 mL). The organic layer was washed with water (2 × -300 mL), dried over MgSO _4. Concentration afforded the sulfone product as a tan oil (82 g, 98%).
Part C: To the prepared slurry of potassium bicarbonate (1.0 g, 9.8 mmol) in 37% formaldehyde solution was added the sulfone product of Part B (28.6 g, 123 mmol). The reaction was stirred for 1 hour and then a saturated solution of sodium sulfate (20 mL) was added. After stirring for 30 min, the mixture was extracted with diethyl ether (4 x 100 mL). The organic layer was dried over MgSO _4. Chromatography (silica phase, ethyl acetate / hexanes) gave the sulfondiol product as a clear oil (15.3 g, 42%).
Part D: The sulfone diol product of Part C (1.3 g, 4.5 mmol) was dissolved in acetone (2 mL) with 2,2-dimethoxypropane (1.1 mL, 9.0 mmol) and p- toluenesulfonic acid monohydrate (0.03 mg, 40 mL) and the resulting composition was refluxed for 6 hours. After cooling, the mixture was neutralized with solid Na ₂ CO ₃ (pH 7 or less), filtered and concentrated. The residue was dissolved in chloroform (50 mL) and washed with water (2 x -30 mL). Dried over MgSO ₄ and concentrated, to give the dimethyl ketal product as an opaque, an oil (1.4 g, 94%).
Part E: Phenol (0.6 g, 6.3 mmol) and cesium carbonate (2.0 g, 6.3 mmol) were added to a solution of the dimethyl ketal product of Part D (1.4 g, 4.2 mmol) in N, N- dimethylformamide Solution. The mixture was heated at 90 &lt; 0 &gt; C for 5 h, diluted with water (20 mL) and extracted with ethyl acetate (4 x -100 mL). The organic layer was washed with brine (1 x -100 mL) and water (1 x -100 mL). Concentration afforded phenol-O-phenol dimethyl ketal as a dark brown oil (1.51 g, 88%).
Part F: To a solution of the phenol-O-phenol dimethyl ketal product (1.5 g, 3.4 mmol) in Part E in tetrahydrofuran (10 mL) was added aqueous lithium hydroxide (0.34 g, 14.8 mmol, 5 mL of H ₂ O ). The reaction was stirred for 2 hours then diluted with water (15 mL) and acidified to pH = 3 with 30% HCl _aq . The acidic solution was extracted with diethyl ether (3 x 100 mL). Dried over MgSO _4, and concentrated to give the carboxylic acid as a brown oil product (1.5 g, quantitative yield).
Part G: To a solution of the carboxylic acid product of Part F (1.3 g, 3.3 mmol) and N-hydroxybenzotriazole hydrate (0.54 g, 4.0 mmol) in DMF (15 mL) was added 4-methylmorpholine Tetrahydro-2H-pyran-2-yl-hydroxylamine (1.2 g, 10.2 mmol) and EDC (0.88 g, 4.6 mmol), respectively. After stirring overnight, the DMF was removed in vacuo and the residue was dissolved in ethyl acetate / water (1: 1, 50 mL). The organic layer was washed with brine (1 × -20 mL) and water (1 × -20 mL), dried over MgSO _4. The THP-protected hydroxylamine product was obtained as a white solid (0.36 g, 22%) and as decarboxylated byproduct (0.27 g, 24%) by chromatography (silica phase, ethyl acetate / hexane).
Part H: To a solution of the THP-protected hydroxylamine product of Part G (0.36 g, 0.73 mmol) in dioxane (3 mL) and methanol (1 mL) was added 4N HCl in dioxane (2 mL) . The reaction was stirred for 5 minutes and then the solvent was removed in vacuo. Chromatography (reverse phase C-18, acetonitrile / water) gave the title compound as a white solid (0.13 g, 44%). MS (FAB) M ⁺ H Calcd for C ₁₉ H ₂₁ NO ₇ S: 408, found 408.
Example 49: Preparation of tetrahydro-N-hydroxy-4 - [[4- (phenylthio) phenyl] sulfonyl] -2H-thiopyran-4-carboxamide

Part A: To a solution of methyl 2-chloroacetate (322 g, 2.96 mol) in N, N-dimethylacetamide (1.0 L) was added thiophenol (400 g, 3.12 mol) and potassium carbonate (408 g, mol). The reaction was stirred at ambient temperature overnight (about 18 hours). After dilution with a minimum amount (800 mL) of water, the mixture was extracted with ethyl acetate (4 x 1 L). The organic layer was washed with water (1 × -800 mL), dried over MgSO _4, and concentrated to afford the sulfide product as a clear oil (614 g, quantitative yield).
Part B: To a solution of sulfide (75.85 g, 0.38 mol) from Part A in methanol (1000 mL) was added water (100 mL) at 20 &lt; (720 g, 1.17 mol). And the heat release point up to 67 ° C was noted. After 2 hours, the reaction was filtered and the cake was washed well with methanol. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over MgSO _4, filtered and concentrated in vacuo to give the sulfone as a crystalline solid (82.74 g, 94%).
Part C: To a solution of the sulfone of Part B (60.0 g, 258 mmol) in DMA (350 mL) was added dibromoethyl thioether (76.9 g, 310 mmol) followed by potassium carbonate (78.3 g, 568 mmol). The mixture was stirred for 5 minutes before the catalytic amounts of 4-dimethylaminopyridine and tetrabutylammonium bromide were added. The reaction was stirred overnight (about 18 hours) then poured into a stirred solution of 10% HCl _aq (2.5 L). The resulting precipitate was filtered and washed with hexane to remove excess thioether. Drying under vacuum for one night (about 18 hours) yielded methyl ester thiopyran-Ph-pF as yellow powder (76.1 g, 93%).
Part D: To a solution of the methyl ester thiopyran-Ph-pF in Part C in N, N-dimethylacetamide (25 mL), cesium carbonate (6.1 g, 18.9 mmol) and thiophenol (2.1 g, 18.9 mmol ). The mixture was stirred at 90 &lt; 0 &gt; C for 2 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 100 mL). After washing the organic layer with brine (1 × -75 mL) and water (1 × -75 mL), dried over MgSO _4. Chromatography (silica phase, ethyl acetate / hexanes) gave the phenyl-S-phenylmethyl ester as a pale yellow solid (3.6 g, 71%).
Part E: Potassium trimethylsilanate (1.24 g, 9.7 mmol) was added to a solution of phenyl-S-phenylmethyl ester (3.6 g, 8.8 mmol) in Part D in tetrahydrofuran (15 mL). The mixture was stirred at ambient temperature for 2 to 3 hours or until solid precipitate was expressed. After the hydrolysis was complete, N-methylmorpholine (2.9 mL, 26.4 mmol) was added followed by PyBrop (4.9 g, 10.6 mmol). The solution was stirred for 10 minutes. Aqueous hydroxylamine (0.32 g, 9.7 mmol) was added and the mixture was stirred for a further 2 h. After completion, the solvent was removed in vacuo. Chromatography of the residue (reverse phase C-18, acetonitrile / water) gave the title compound as an off-white solid (0.82 g, 23%). ^{MS (FAB) M + H:} C 18 calculated in the _{H 19 NO 4 S 3: 410} , Found: 410.
Example 50: Preparation of 4 - [(4-fluorophenyl) sulfonyl] tetrahydro-N - [(tetrahydro-2H-pyran-2-yl) oxy] -2H-thiopyran-4-carboxamide

Part A: Thiophenol (400 g, 3.12 mol) and potassium carbonate (408 g, 2.96 mol) were added to a solution of methyl 2-chloroacetate (322 g, 2.96 mol) in N, N-dimethylacetamide Solution. The reaction was stirred at ambient temperature overnight (about 18 hours). After diluting with a minimal amount of water (800 mL), the mixture was extracted with ethyl acetate (4 x 1 L). Followed by washing the organic layer with water (1 × -800 mL), dried over MgSO _4, and concentrated to afford the sulfide product as a clear oil (614 g, quantitative yield).
Part B: To a solution of sulfide (75.85 g, 0.38 mol) from Part A in methanol (100 mL) was added water (100 mL) at 20 &lt; (720 g, 1.17 mol). And the heat release point up to 67 ° C was noted. After 2 hours, the reaction was filtered and the cake was washed well with methanol. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over MgSO _4, filtered and concentrated in vacuo to give the methyl ester sulfone as a crystalline solid (82.74 g, 94%).
To a solution of the methyl ester sulfone product of Part B (60.0 g, 258 mmol) in N, N-dimethylacetamide (350 mL) was added 2,2-dibromoethyl thioether (76.9 g, 310 mmol) Was added followed by potassium carbonate (78.3 g, 568 mmol). The mixture was stirred for 5 minutes before the catalytic amounts of 4-dimethylaminopyridine and tetrabutylammonium bromide were added. The reaction was stirred overnight (about 18 hours) then poured into a stirred solution of 10% HCl _aq (2.5 L). The resulting precipitate was filtered and washed with hexane to remove excess thioether. Drying under vacuum for one night (about 18 hours) gave the thiopyranemethyl ester as a yellow powder (76.1 g, 93%).
Part D: To a solution of the thiopyranemethyl ester of Part C (30.0 g, 94 mmol) in tetrahydrofuran (250 mL) was added potassium trimethylsilonate (28.9 g, 226 mmol). The mixture was stirred at ambient temperature for 2 to 3 hours or until solid precipitate was expressed. After the hydrolysis was complete, the solvent was removed in vacuo. Water (200 mL) was added and the mixture was washed with diethyl ether (1 x -200 mL). The water layer was cooled to 0 &lt; 0 &gt; C and 10% HCl _aq was slowly added until a precipitate formed. The solid was collected and dried with phosphorus pentoxide under vacuum to give the thiopyranecarboxylic acid as a yellow solid (17.8 g, 62%).
Part E: To a solution of the thiopyranecarboxylic acid of Part D (17.8 g, 58.5 mmol) in N, N-dimethylformamide (100 mL) was added N- methylmorpholine (19.3 mL, 176 mmol) , N-hydroxybenzotriazole hydrate (9.5 g, 70.2 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (10.3 g, 87.8 mmol) and 1- ) -3-ethylcarbodiimide hydrochloride (16.8 g, 87.8 mmol). The mixture was stirred for 3 hours and then diluted with water (100 mL). The mixture was extracted with ethyl acetate (4 x -200 mL). The organic layers were washed with a saturated aqueous potassium carbonate solution (1 x -200 mL), 1% HCl _aq, and brine (1 x -200 mL). Dried over MgSO _4, and the title compound was obtained by concentration in vacuo an off-white solid (30.8 g, quantitative yield). MS (FAB) M ⁺ H: C ₁₇ H ₂₂ FNO ₅ Calculated for S ₂ : 404, found: 404.
Example 51: Preparation of tetrahydro-N-hydroxy-4 - [[4 - [(4-methoxyphenyl) thio] phenyl] sulfonyl] -2H-thiopyran-4-carboxamide

Part A: To a solution of the title compound of example 50 (6.0 g, 14.9 mmol) in N, N-dimethylacetamide (25 mL) was added 4-methoxythiophenol (2.5 g, 17.8 mL) Potassium carbonate (6.2 g, 44.7 mmol) was added. The reaction was heated at 60 &lt; 0 &gt; C for 3 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (4 x 100 mL). Washing the organic layer with water (2 × -50 mL), dried over MgSO _4. Concentration in vacuo afforded the THP-protected phenyl-Sphenyl-OMe product as a pale yellow solid (9.2 g, quantitative yield).
Part B: To a solution of THP-protected phenyl-Sphenyl-OMe product (9.2 g, 14.9 mmol) from Part A in dioxane was slowly added 4N HCl in dioxane (10 mL). After stirring overnight (about 18 hours), the solvent was removed. Chromatography of the resulting residue (reverse phase C-18, acetonitrile / water) gave the title compound as a white solid (1.84 g, 28.3%). ^{MS (FAB) M + H:} C 19 calculated in the _{H 21 NO 5 S 3: 440} , Found: 440.
Example 52: Preparation of tetrahydro-N-hydroxy-4 - [(4-phenylthio) phenyl] sulfonyl] -2H-thiopyran-4-carboxamide-1,1-dioxide

Part A: To a solution of the title compound of Example 50 (13.0 g, 24.5 mmol) in methylene chloride (100 mL) cooled to 0 C was slowly added 50-60% m-chloroperbenzoic acid (17.1 g, 49.5 mmol) . The mixture was stirred at 0 &lt; 0 &gt; C for 1 hour and then further stirred for 3 hours as the temperature rose to ambient conditions. Water (200 mL) was added and the mixture was neutralized with 10% ammonium hydroxide (100 mL). The organic layer was washed with water (1 × -200 mL), dried over MgSO _4. Concentration in vacuo gave an orange oil (3.5 g, 33%). The water / 10% ammonium hydroxide solution was saturated with sodium chloride and extracted with ethyl acetate (2x400 mL). The organic layer was dried over MgSO ₄ and concentrated to give the THP-protected sulfone-thiopyran-p F compound as an orange foam (6.1 g, 57%).
Part B: To a solution of THP-protected sulfone-thiopyran-pF (9.6 g, 22 mmol) from Part A in N, N-dimethylacetamide (120 mL) was added thiophenol (2.9 g, 26.4 mL) After addition, potassium carbonate (9.1 g, 66 mmol) was added. The reaction was heated at 60 &lt; 0 &gt; C for 4 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (4 x 100 mL). Washing the organic layer with water (2 × -50 mL), dried over MgSO _4. Chromatography (silica phase, ethyl acetate / hexanes) gave the THP-protected phenyl-S-phenyl product as an orange oil (5.1 g, 43%).
Part C: To a solution of the THP-protected phenyl-S-phenyl product from Part B (5.1 g, 9.4 mmol) in dioxane was slowly added 4N HCl in dioxane (10 mL). After stirring overnight (about 18 hours), the solvent was removed. Chromatography of the resulting residue (reverse phase C-18, acetonitrile / water) gave the title compound as a pink solid (1.2 g, 29%). ^{MS (FAB) M + H:} C 18 H 19 NO 6 Calcd of S _3: 442, Found: 442.
Example 53: Synthesis of tetrahydro-N-hydroxy-4 - [[4- [4- (1H-1,2,4-triazol-1-yl) phenoxy] phenyl] sulfonyl] -2H- -4-carboxamide 1,1-dioxide, monohydrochloride

Part A: To a solution of the title compound of Example 50 (13.0 g, 24.5 mmol) in methylene chloride (100 mL) cooled to 0 C was slowly added 50-60% m-chloroperbenzoic acid (17.1 g, 49.5 mmol) . The mixture was stirred at 0 &lt; 0 &gt; C for 1 hour and then further stirred for 3 hours as the temperature rose to ambient temperature. Water (200 mL) was added and the mixture was neutralized with 10% ammonium hydroxide (100 mL). The organic layer was washed with water (1 × -200 mL), dried over MgSO _4. Concentration in vacuo gave an orange oil (3.5 g, 33%). The water / 10% ammonium hydroxide solution was saturated with sodium chloride and extracted with ethyl acetate (2x400 mL). The organic layer was dried over MgSO _4, and concentrated to THP- protected sulfone-thiopyran the -pF was obtained as an orange foam (6.1 g, 57%).
Part B: To a solution of THP-protected sulfone-thiopyran-PF (6.0 g, 13.8 mmol) from Part A in N, N-dimethylformamide (25 mL) was added 4- (1H- Yl) phenol (4.4 g, 27.5 mmol) followed by the addition of cesium carbonate (13.4 g, 41.4 mmol). The reaction was heated at 95 &lt; 0 &gt; C for 5 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (4 x 100 mL). Washing the organic layer with water (2 × -50 mL), dried over MgSO _4. Concentration afforded the THP-protected phenyl-O-phenyltriazole product as a tan solid (9.7 g, quantitative yield).
Part C: To a solution of crude THP-protected phenyl-O-phenyltriazole product (8.0 g, 13.8 mmol) from Part B in acetonitrile (40 mL), 10% HCl _aq (100 mL) . After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a tan solid (1.3 g, 18%). MS (FAB) M ⁺ H: C ₂₀ H ₂₁ ClN ₄ O ₇ S ₂ : 493, found 493.
Example 54: 4 - [[4- [4- (2-aminoethyl)] phenoxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-thiopyran- -Dioxido &lt; / RTI &gt; monohydrochloride

Part A: To a solution of the title compound of Example 50 (13.0 g, 24.5 mmol) in methylene chloride (100 mL) cooled to 0 C was slowly added 50-60% m-chloroperbenzoic acid (17.1 g, 49.5 mmol) . The mixture was stirred at 0 &lt; 0 &gt; C for 1 hour and then further stirred for 3 hours as the temperature rose to ambient conditions. Water (200 mL) was added and the mixture was neutralized with 10% ammonium hydroxide (100 mL). The organic layer was washed with water (1 × -200 mL), dried over MgSO _4. Concentration in vacuo gave an orange oil (3.5 g, 33%). The water / 10% ammonium hydroxide solution was saturated with sodium chloride and extracted with ethyl acetate (2x400 mL). The organic layer was dried over MgSO _4, and concentrated to THP- protected sulfone-thiopyran the -pF was obtained as an orange foam (6.1 g, 57%).
Part B: To a solution of THP-protected sulfone-thiopyran-pF (6.0 g, 13.8 mmol) from Part A in N, N-dimethylacetamide (25 mL) Cesium carbonate (13.6 g, 42 mmol) was then added. The reaction was heated at 95 &lt; 0 &gt; C for 5 hours. N, N-dimethylacetamide was removed in vacuo to give a brown solid (20 g). Chromatography (reverse phase, C-18, acetonitrile / water) gave the THP-protected tyramine product as a tan oil (1.0 g, 13%).
Part C: To a solution of crude THP-protected thiamine product (1.0 g, 1.8 mmol) from Part B in acetonitrile (40 mL), 10% HCl _aq (100 mL) was slowly added. After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a tan solid (0.9 g, 99%). ^{MS (FAB) M + H:} C 20 H 25 ClN 2 O 7 Calcd of S _2: 469, Found: 469.
Example 55: Preparation of 4 - [(4-fluorophenyl) sulfonyl] tetrahydro-N - [(tetrahydro-2H-pyran-2-yl) oxy] -2H-pyran-4-carboxamide

Part A: In a drying facility under nitrogen, sodium metal (8.97 g, 0.39 mol) was added to methanol (1000 mL) at 2 占 폚. The reaction was stirred for 45 minutes, at which time sodium was dissolved at ambient temperature. The solution was cooled to 5 [deg.] C and p-fluorothiophenol (41.55 mL, 0.39 mmol) was added followed by methyl 2-chloroacetate (34.2 mL, 0.39 mol). The reaction was stirred at ambient temperature for 4 hours, filtered and concentrated in vacuo to give the sulfide as a clear colorless oil (75.85 g, 97%).
Part B: To a solution of sulfide (75.85 g, 0.38 mol) from Part A in methanol (1000 mL) was added water (100 mL) at 20 &lt; (720 g, 1.17 mol). And the heat release point up to 67 ° C was noted. After 2 hours, the reaction was filtered and the cake was washed well with methanol. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over MgSO _4, filtered and concentrated in vacuo to give the sulfone as a crystalline solid (82.74 g, 94%).
Part C: To a solution of the sulfone from Part B (28.5 g, 0.123 mol) in N, N-dimethylacetamide (200 mL) was added potassium carbonate (37.3 g, 0.27 mol), bis- Ethyl) ether (19.3 mL, 0.147 mol), 4-dimethylaminopyridine (0.75 g, 6 mmol) and tetrabutylammonium bromide (1.98 g, 6 mmol). The reaction was stirred at ambient temperature overnight (about 18 hours). The reaction was slowly poured into 1N HCl (300 mL), the resulting solid was filtered, and the cake was washed well with hexane. The solid was recrystallized from ethyl acetate / hexanes to give the pyran compound as a beige solid (28.74 g, 77%). MS (ES +) MH +: C 13 H 15 O 5 Calcd of S ₁ F _1: 303, Found: 303.
Part D: The pyran compound from Part C (8.0 g, 26.5 mmol) was dissolved in dry tetrahydrofuran (250 mL) and dried in a dry tetrahydrofuran (15 mL) solution in the presence of potassium trimethylcyclonate 10.2 g, 79.5 mmol) was added at ambient temperature. After 90 minutes, water (100 mL) was added and the solution was concentrated in vacuo. The residue was dissolved in water and extracted with ethyl acetate to remove unreacted starting material. The aqueous solution was treated with 6N HCl until pH = 1. The slurry was extracted with ethyl acetate, washed the combined extracts with water, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The residue was heated in diethyl ether, the solid was filtered off and dried to give the carboxylic acid as a crystalline solid (5.78 g, 76%). HRMS (ES-) MH of C ₁₂ H ₁₃ O ₅ S ₁ F ₁ Calcd: 287.04, found 287.04.
Part E: In a drying facility under nitrogen, the carboxylic acid (9.1 g, 31.6 mmol) from Part D was dissolved in dry N, N-dimethylformamide (70 mL) and the remaining reagents were added to the solution Hydroxybenzotriazole hydrate (5.1 g, 37.9 mmol), N-methylmorpholine (10.4 mL, 94.8 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (11.5 g, 98 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (8.48 g, 44.2 mmol). After 3 h at ambient temperature, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, 5% KHSO ₄ , saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexane) gave the title compound as a crystalline solid (9.7 g, 80%). HRMS (ES +) MH +: C 17 H 22 NO 6 Calcd of S ₁ F _1: 388.12, Found: 388.12.
Example 56: Preparation of 4 - [[4- (3,4-difluorophenoxy) phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (2.0 g, 5.2 mmol) in N, N-dimethylacetamide (6 mL) was added 3,4-difluorophenol (1.0 g, 7.7 mmol) , Cesium carbonate (6.6 g, 20.2 mmol) was added. The reaction was heated at 95 &lt; 0 &gt; C for 5 hours. N, N-dimethylacetamide was removed in vacuo to give a brown solid (8.3 g, quant.). The THP-protected difluoro product in solution was obtained by chromatography (reverse phase, C-18, acetonitrile / water).
Part B: To the collected THP-protected difluoro product from A in acetonitrile / water (50 mL) was slowly added 10% HCl _aq (100 mL). After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (1.02 g, 48.6%). ^{MS (FAB) M + H:} C 18 calculated in the H ₁₇ FNO ₆ S: 414, Found: 414.
Example 57: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-iodophenoxy) phenyl] sulfonyl] -2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (2.0 g, 5.2 mmol) in N, N-dimethylacetamide (6 mL) was added 4-iodophenol (1.7 g, 7.8 mmol) Carbonitrile (6.6 g, 20.2 mmol). The reaction was heated at 95 &lt; 0 &gt; C for 5 hours. The N, N-dimethylacetamide was removed in vacuo to give a brown solid (5.7 g, quant.). The THP-protected iodo product in solution was obtained by chromatography (reverse phase, C-18, acetonitrile / water).
Part B: To a solution of the crude THP-protected iodo product from Part A in acetonitrile / water (40 mL) was slowly added 10% HCl _aq (100 mL). After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (2.6 g, 99%). ^{MS (FAB) M + H:} C 18 calculated in the H ₁₈ INO ₆ S: 504, Found: 504.
Example 58: Preparation of tetrahydro-N-hydroxy-4 - [[4- (2,4,5-trifluorophenoxy) phenyl] sulfonyl] -2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (2.0 g, 5.2 mmol) in N, N-dimethylacetamide (6 mL) was added 2,4,5-trifluorophenol (1.2 g, 7.8 mmol) After addition, cesium carbonate (10.1 g, 31.0 mmol) was added. The reaction was heated at 95 &lt; 0 &gt; C for 32 hours. The N, N-dimethylacetamide was removed in vacuo to give a brown solid (5.7 g, quant.). The THP-protected phenol product (1.2 g, 44%) was obtained by chromatography (reverse phase, C-18, acetonitrile / water).
Part B: To a solution of the crude THP-protected phenol product (1.2 g, 2.3 mmol) from Part A in acetonitrile / water (40 mL) was slowly added 10% HCl _aq (100 mL). After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (0.79 g, 79%). ^{MS (FAB) M - H:} C 18 H 16 F 3 Calculated for NO ₆ S: 430, Found: 430.
Example 59: Preparation of 4 - [[4- (3,5-dichlorophenoxy) phenyl] sulfonyl] -tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: 3,5-Dichlorophenol (1.3 g, 7.8 mmol) was added to a solution of the title compound of Example 55 (2.0 g, 5.2 mmol) in N, N-dimethylacetamide (6 mL) Cesium carbonate (6.6 g, 20.2 mmol) was added. The reaction was heated at 95 &lt; 0 &gt; C for 12 h. The N, N-dimethylacetamide was removed in vacuo to give a brown solid (5.7 g, quant.). The residue was dissolved in acetonitrile / water (20 mL) and acidified to pH = 6. A white precipitate formed and was collected to give the THP-protected product as a white cake (1.8 g, 64%).
Part B: To THP-protected product (1.8 g, 3.4 mmol) from Part A in acetonitrile / water (20 mL) was slowly added 10% HCl _aq (40 mL). After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (0.71 g, 47%). ^{MS (FAB) M + H:} C 18 H 17 Calcd for Cl ₂ NO ₆ S: 447, Found: 447.
Example 59: Synthesis of tetrahydro-N-hydroxy-4 - [[4- [[5- (trifluoromethyl) -2-pyridinyl] thio] phenyl] sulfonyl] -2H- Preparation of midmonohydrochloride

To a solution of the title compound of Example 55 (2.0 g, 5.2 mmol) in N, N-dimethylacetamide (6 mL) was added 5- (trifluoromethyl) -2-pyridinylthiophenol , 7.8 mmol) followed by potassium carbonate (2.2 g, 15.6 mmol). The reaction was heated at 65 &lt; 0 &gt; C for 12 h. The N, N-dimethylacetamide was removed in vacuo to give a brown solid (5.4 g, quant.). The THP-protected product in solution was obtained by chromatography (reverse phase, C-18, acetonitrile / water).
Part B: To a solution of the crude THP-protected product from Part A in acetonitrile / water (40 mL) was slowly added 10% HCl _aq (40 mL). After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (0.20 g, 8%). ^{MS (FAB) M + H:} C 18 H 17 F 3 N 2 O 5 Calcd of S _2: 463, Found: 463.
Example 60: Preparation of 4 - [[4- (3,4-dichlorophenyl) thio] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (2.0 g, 5.2 mmol) in N, N-dimethylacetamide (6 mL) was added 3,4-dichlorothiophenol (1.4 g, 7.8 mmol) , Potassium carbonate (2.2 g, 15.6 mmol). The reaction was heated at 70 &lt; 0 &gt; C for 6 hours. N, N-dimethylacetamide was removed in vacuo to give a brown solid (5.6 g, quant.). The THP-protected product in solution was obtained by chromatography (reverse phase, C-18, acetonitrile / water).
Part B: To a solution of the THP-protected product from Part A in acetonitrile / water (40 mL) was slowly added 10% HCl _aq (40 mL). After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (1.5 g, 62%). ^{MS (FAB) M + H:} C 18 H 17 Cl 2 Calcd of NO ₅ S: 463, Found: 463.
Example 61: Synthesis of 4 - [[4- [[2-amino-4- (trifluoromethyl) phenyl] thio] phenyl] sulfonyl] tetrahydro-N-hydroxy- , Preparation of monohydrochloride

To a solution of the title compound of Example 55 (2.0 g, 5.2 mmol) in N, N-dimethylacetamide (6 mL) was added 2-amino-4- (trifluoromethyl) thiophenol hydrochloride g, 7.8 mmol) followed by the addition of potassium carbonate (3.6 g, 26 mmol). The reaction was heated at 70 &lt; 0 &gt; C for 8 hours. The dimethylacetamide was removed in vacuo to give a brown solid (14 g, quant.). The THP-protected product in solution was obtained by chromatography (reverse phase, C-18, acetonitrile / water).
Part B: To a solution of the THP-protected product in acetonitrile / water (40 mL) was slowly added 10% HCl _aq (40 mL). After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (1.3 g, 52%). MS (FAB) M ⁺ H Calcd: C ₁₈ H ₁₇ Cl ₂ NO ₆ S: 477, found 477.
Example 62: Preparation of tetrahydro-4 - [[4- (4-phenyl-1-piperidinyl) phenyl] sulfonyl] -2H-pyran-4-carboxamide, monohydrochloride

Part A: In a drying facility under nitrogen, sodium metal (8.97 g, 0.39 mol) was added to methanol (1000 mL) at 2 占 폚. The reaction was stirred for 45 minutes, at which time sodium was dissolved at ambient temperature. The solution was cooled to 5 [deg.] C and p-fluorothiophenol (41.55 mL, 0.39 mmol) was added followed by methyl 2-chloroacetate (34.2 mL, 0.39 mol). The reaction was stirred at ambient temperature for 4 hours, filtered and concentrated in vacuo to give the sulfide as a clear colorless oil (75.85 g, 97%).
Part B: To a solution of sulfide (75.85 g, 0.38 mol) from Part A in methanol (1000 mL) was added water (100 mL) at 20 &lt; (720 g, 1.17 mol). And the heat release point up to 67 ° C was noted. After 2 hours, the reaction was filtered and the cake was washed well with methanol. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over MgSO _4, filtered and concentrated in vacuo to give the sulfone as a crystalline solid (82.74 g, 94%).
Part C: To a solution of the sulfone from Part B (28.5 g, 0.123 mmol) in N, N-dimethylacetamide (200 mL) was added potassium carbonate (37.3 g, 0.27 mol), bis- Ethyl) ether (19.3 mL, 0.147 mol), 4-dimethylaminopyridine (0.75 g, 6 mmol) and tetrabutylammonium bromide (1.98 g, 6 mmol). The reaction was stirred at ambient temperature overnight (about 18 hours). The reaction was slowly poured into 1N HCl (300 mL), the resulting solid was filtered, and the cake was washed well with hexane. The solid was recrystallized from ethyl acetate / hexanes to give the title compound as a beige solid (28.74 g, 77%). MS (ES +) MH +: C 13 H 15 O 5 Calcd of S ₁ F _1: 303, Found: 303.
Part D: To a solution of the pyrane compound (1.21 g, 4.0 mmol) from Part C in dimethylsulfoxide (10 mL) was added cesium carbonate (3.26 g, 10 mmol) and methyl 4- Phenylpiperidine (0.64 g, 4.0 mmol) was added. The slurry was stirred at 90 &lt; 0 &gt; C for 2 hours. The reaction was cooled, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with 5% KHSO _4, saturated NaHCO _3, brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The resulting solid was slurried in diethyl ether, filtered and dried to yield the N-substituted piperidine as a white solid (1.2 g, 67%). MS (FAB +) MH +: C 24 H 29 N 1 O 5 Calculated for S _1: 444, Found: 444.
Part E: To a slurry of N-substituted piperidine (815 mg, 1.84 mmol) from Part D in methanol (5 mL) and tetrahydrofuran (5 mL) was added 50% sodium hydroxide . After 24 hours at ambient temperature, the reaction was concentrated in vacuo. The slurry was diluted with water (10 mL) and 6N HCl was added until pH = 7. Vacuum filtration of the resulting precipitate gave the acid as a white solid (705 mg, 89%). MS (FAB +) MH +: C 23 H 27 Calcd of _{N 1 O 5 S 1: 430} , Found: 430.
Part F: In a drying apparatus under nitrogen, the carboxylic acid (620 mg, 1.44 mmol) from Part E was slurried in methylene chloride (10 mL) and N, N-dimethylformamide (3 mL) The reagents were added to the slurry in the following order: bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (810 mg, 1.73 mmol), N-methylmorpholine (0.5 mL, 4.34 mmol) Hydro-2H-pyran-2-yl-hydroxylamine (190 mg, 1.59 mmol). After 4 h at ambient temperature, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexanes) afforded the THP-protected hydroxamate as a white solid (630 mg, 83%). MS (FAB +) MH +: C 28 H 22 N 2 O 6 calculated in S _1: 529, Found: 529.
Part G: To a slurry of THP-protected hydroxamate (600 mg, 1.14 mmol) from Part F in dioxane (1.5 mL) was added 4N HCl dioxane solution (1.5 mL) and methanol (1.5 mL) . After 2 h at ambient temperature, the reaction was poured into diethyl ether (100 mL). Vacuum filtration of the resulting precipitate gave the title compound as a pale beige solid (500 mg, 91%). MS (FAB +) M + Li : C 23 H 28 N 2 Calculated for O ₅ S _1: 445, Found: 445.
Example 63: Synthesis of 4 - [[4- [4- (1,3-benzodioxol-5-yloxy) -1-piperidinyl] phenyl] sulfonyl] tetrahydro-N-hydroxy- -4-carboxamide, &lt; / RTI &gt; monohydrochloride

Part A: In a drying apparatus under nitrogen, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyl dicarbonate (43.65 g, 0.2 mol) was added at such a rate as to keep the temperature below 30 ° C. After stirring at ambient temperature for 4 hours, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, 5% KHSO ₄ , saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give BOC piperidine as a white solid (37.7 g , 94%).
Part B: BOC piperidine from Part A (5.0 g, 24.8 mmol) in dry tetrahydrofuran (100 mL) was cooled to 0 <0> C and treated with triphenylphosphine (9.77 g, 37.3 mmol). After stirring at 0 C for 15 min, sesamol (5.15 g, 37.3 mmol) was added to the reaction followed by dropwise addition of diethyl azodicarboxylate (5.87 mL, 37.7 mmol). The reaction was stirred at 0 &lt; 0 &gt; C for 30 minutes and then at ambient temperature for 20 hours. The reaction was concentrated in vacuo. The residue was slurried in diethyl ether, triphenylphosphine oxide was removed by filtration, and the filtrate was concentrated in vacuo. The BOC piperidine substituted by chromatography (silica phase, ethyl acetate / hexanes) was obtained as a white solid (3.14 g, 39%).
Part C: To a slurry of the substituted BOC piperidine (3.14 g, 9.8 mmol) from Part B in dioxane (15 mL) was added 4N HCl dioxane solution (15 mL). After 3 h at ambient temperature, the reaction was concentrated in vacuo. The residue was slurried in diethyl ether and the hydrochloride was obtained as a white solid (2.3 g, 100%) by vacuum filtration of the resulting precipitate.
Part D: To a slurry of the hydrochloride from Part C (0.93 g, 3.6 mmol) in N, N-dimethylformamide (10 mL) was added cesium carbonate (2.93 g, 9 mmol) and the title compound of Example 55 (1.16 g, 3.0 mmol). The slurry was stirred at 90 &lt; 0 &gt; C for 24 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, 5% KHSO ₄ , saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The THP-protected hydroxamate substituted by chromatography (silica phase, ethyl acetate / hexane) was obtained as a white solid (640 mg, 36%). MS (FAB +) MH &lt; + &gt;: Calcd for C ₂₉ H ₃₆ N ₂ O ₉ S ₁ : 589, found: 589.
Part E: To a slurry of THP-protected hydroxamate (600 mg, 1.02 mmol) from Part D in dioxane (3 mL) was added 4N HCl dioxane solution (3 mL) and methanol (3 mL) . After 1 hour at ambient temperature, the reaction was poured into diethyl ether (100 mL). Vacuum filtration of the resulting precipitate gave the title compound as a pale beige solid (440 mg, 80%). HRMS (ES &lt; + &gt;) MH &lt; + &gt; of C ₂₄ H ₂₈ N ₂ O ₈ S ₁ : 505.16, found 505.16.
Example 64: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-methoxyphenoxy) phenyl] sulfonyl] -2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (3.48 g, 9 mmol) in N, N-dimethylformamide (20 mL) was added cesium carbonate (8.8 g, 27 mmol) and p-methoxyphenol 2.23 g, 18 mmol). The slurry was stirred at 95 &lt; 0 &gt; C for 24 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated under vacuum. Chromatography (silica phase, ethyl acetate / hexane) gave the substituted THP-protected hydroxamate (3.82 g, 86%) as a beige foam. MS (FAB +) MH &lt; + &gt;: C ₂₄ H ₂₉ N ₁ O ₈ S ₁ calcd: 492, found 492.
Part B: To a slurry of THP-protected hydroxamate (3.6 g, 7.33 mmol) from Part A in dioxane (18 ml) was added 4 N HCl dioxane solution (18 mL) and methanol (18 mL). After 15 minutes at ambient temperature, the reaction was diluted with ethyl acetate, washed with water and washed with Na₂SO₄&Lt; / RTI &gt; filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexane) to give the title compound as a white solid (2.1 g, 70%). HRMS (ES &lt; + &gt;) MH + : C₁₉H₂₁N_OneO₇S_One: 408.11, found: 408.11.
Example 65: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-methoxyphenylthio) phenyl] sulfonyl] -2H-pyran-4-carboxamide

To a solution of the title compound of Example 55 (3.1 g, 8 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (1.33 g, 9.6 mmol) and p- methoxybenzenethiol (1.48 mL, 12 mmol). The slurry was stirred at 65 &lt; 0 &gt; C for 24 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated under vacuum. Chromatography (silica phase, ethyl acetate / hexanes) gave the substituted THP-protected hydroxamate (4.1 g, 100%) as a white foam. HRMS (ES +) M + NH 4 +: C 24 H 29 N 1 O 7 Calcd of S _2: 525.17, Found: 525.17.
Part B: To a slurry of THP-protected hydroxamate (4.0 g, 7.9 mmol) from Part A in dioxane (20 ml) was added 4N HCl dioxane solution (20 mL) and methanol (20 mL). After 15 minutes at ambient temperature, the reaction was diluted with ethyl acetate, washed with water and washed with Na₂SO₄&Lt; / RTI &gt; filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexane) to give the title compound as a white solid (2.21 g, 67%). HRMS (ES &lt; + &gt;) MH + : C₁₉H₂₁N_OneO₆S₂Lt; / RTI &gt; Calculated: 424.09, Found: 424.09.
Example 66: Preparation of 4 - [(4-fluorophenyl) sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a slurry of the title compound of Example 55 (530 mg, 1.38 mmol) in dioxane (5 mL) was added 4N HCl dioxane solution (5 mL) and methanol (5 mL). After 15 minutes at ambient temperature, the reaction was concentrated in vacuo. Purification by reverse phase chromatography (silica phase, acetonitrile / water) gave the title compound (140 mg, 34%) as a beige solid. HRMS (ES &lt; + &gt;) M + NH₄ ⁺ : C₁₂H₁₄N_OneO₅S_OneF₂Lt; / RTI &gt;: 321.09, found 321.09.
Example 67: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-piperidinyloxy) phenyl] sulfonyl] -2H-pyran-4-carboxamide, monohydrochloride

Part A: In a nitrogen-free drying apparatus, 4-hydroxy-Nt- (butoxycarbonyl) piperidine (844 mg, 4.2 mmol) was dissolved in dry N, N-dimethylformamide % Sodium hydride (210 mg, 5.25 mmol). The slurry was stirred at ambient temperature for 2 hours. At 5 [deg.] C, the title compound of Example 55 (1.35 g, 3.5 mmol) was added and the reaction was heated to 50 [deg.] C for 3 h. The reaction was cooled, quenched with water and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated under vacuum. Chromatography (silica phase, ethyl acetate / hexanes) gave the substituted THP-protected hydroxamate (283 mg, 14%) as a white foam. MS (FAB +) MH &lt; + &gt;: Calcd for C ₂₇ H ₄₀ N ₂ O ₉ S ₁ : 569, found: 569.
Part B: To a slurry of THP-protected hydroxamate (530 mg, 0.93 mmol) from Part A in dioxane (5 ml) was added 4N HCl dioxane solution (5 mL) and methanol (5 mL). After 15 minutes at ambient temperature, the reaction was concentrated in vacuo. Purification by reverse phase chromatography (silica phase, acetonitrile / 0.01% HCl buffered water) gave the title compound (240 mg, 62%) as a beige solid. HRMS (ES &lt; + &gt;) MH + : C₁₇H₂₄N₂O₆S_OneFound: 385.14 Found: 385.14.
Example 68: Preparation of tetrahydro-N-hydroxy-4 - [[4 - [(4-phenylmethyl) amino] phenyl] sulfonyl] -2H-pyran-4-carboxamide, monohydrochloride

Part A: In a solid phase reaction vessel, benzylamine (11.0 mL, 100 mmol) was added to dry 1-methyl-2-pyrrolidinone (40 mL) with swollen resin II (5.0 g, 4.55 mmol as described above) . The reaction was heated to 100 &lt; 0 &gt; C for 48 hours with shaking. The resin was transferred to a frit and washed 4 times with N, N-dimethylformamide (30 mL), 4 times with methanol (30 mL), 4 times with methylene chloride (30 mL), and then dried. The dried resin was transferred to a flask and 95% trifluoroacetic acid / 5% water solution (50 mL) was added. The slurry was stirred for 1 hour, filtered, and the cake was washed with methylene chloride. The combined filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and the pH was brought to pH 7 by addition of saturated sodium bicarbonate solution. The organic layer was washed with Na₂SO₄&Lt; / RTI &gt; filtered, and concentrated in vacuo. Purification by reverse phase chromatography (silica phase, acetonitrile / 0.01% HCl buffered water) gave the title compound as a reddish solid (1.01 g, 52%). HRMS (ES &lt; + &gt;) M + NH₄ ⁺ : C₁₉H₂₂N₂O₅S_OneFound: 408.16 Found: 408.16.
Example 69: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-trifluoromethoxy) phenoxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (3.1 g, 8 mmol) in N, N-dimethylacetamide (20 mL) was added cesium carbonate (8.8 g, 27 mmol) and p- (trifluoromethoxy) 2.1 mL, 16 mmol). The slurry was stirred at 95 &lt; 0 &gt; C for 19 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated under vacuum. Chromatography (silica phase, ethyl acetate / hexanes) gave the substituted THP-protected hydroxamate (4.2 g, 96%) as a white foam. HRMS (ES +) MH +: C 24 H 26 N 1 O 8 calculated value of S ₁ F _3: 546.14, Found: 546.14.
Part B: To a slurry of THP-protected hydroxamate (4.0 g, 7.3 mmol) from Part A in dioxane (20 ml) was added 4N HCl dioxane solution (20 mL) and methanol (20 mL). After 15 minutes at ambient temperature, the reaction was diluted with ethyl acetate, washed with water and washed with Na₂SO₄&Lt; / RTI &gt; filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexane) to give the title compound as a white solid (2.2 g, 65%). HRMS (ES &lt; + &gt;) M + NH₄ ⁺ : C₁₉H₁₈N_OneO₇S_OneF₃Lt; / RTI &gt; 479.11, found 479.11.
Example 70: Preparation of 4 - [[4- (3,5-difluorophenoxy) phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

To a solution of the title compound of Example 55 (3.1 g, 8 mmol) in N, N-dimethylacetamide (20 mL) was added cesium carbonate (8.8 g, 27 mmol) and 3,5- difluorophenol (2.1 g, 16 mmol). The slurry was stirred at 95 &lt; 0 &gt; C for 48 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated under vacuum. Chromatography (silica phase, ethyl acetate / hexane) gave the substituted THP-protected hydroxamate (3.23 g, 81%) in beige foam. HRMS (ES &lt; + &gt;) MH &lt; + &gt;: C ₂₃ H ₂₅ N ₁ O ₇ S ₁ F ₂ : 498.14, found 498.14.
Part B: To a slurry of THP-protected hydroxamate (3.2 g, 6.3 mmol) from Part A in dioxane (20 ml) was added 4 N HCl dioxane solution (20 mL) and methanol (20 mL). After 15 minutes at ambient temperature, the reaction was diluted with ethyl acetate, washed with water and washed with Na₂SO₄&Lt; / RTI &gt; filtered, and concentrated in vacuo. The residue was slurried in diethyl ether and the resulting precipitate was vacuum filtered to give the title compound as a white solid (1.5 g, 57%). HRMS (ES &lt; + &gt;) M + NH₄ ⁺ : C₁₈H₁₇N_OneO₆S_OneF₂: 431.11, found: 431.11.
Example 71: Preparation of 4 - [[4- (3,4-dichlorophenoxy) phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (3.1 g, 8 mmol) in N, N-dimethylacetamide (20 mL) was added cesium carbonate (8.8 g, 27 mmol) and 3,4-dichlorophenol (2.61 g, 16 mmol). The slurry was stirred at 95 &lt; 0 &gt; C for 41 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated under vacuum. Chromatography (silica phase, ethyl acetate / hexanes) gave the substituted THP-protected hydroxamate (4.17 g, 98%) as a white foam. HRMS (ES +) M + NH 4 +: C 23 H 25 N 1 O 7 S 1 calculated for Cl _2: 547.11, Found: 547.10.
Part B: To a slurry of THP-protected hydroxamate (3.5 g, 6.6 mmol) from Part A in dioxane (20 ml) was added 4 N HCl dioxane solution (20 mL) and methanol (20 mL). After 15 minutes at ambient temperature, the reaction was diluted with ethyl acetate, washed with water and washed with Na₂SO₄&Lt; / RTI &gt; filtered, and concentrated in vacuo. The residue was slurried in diethyl ether and the resulting precipitate was vacuum filtered to give the title compound as a white solid (2.98 g, 100%). HRMS (ES &lt; + &gt;) M + NH₄ ⁺ : C₁₈H₁₇N_OneO₆S_OneCl₂Found: 463.05, found 463.05.
Example 72: Preparation of tetrahydro-N-hydroxy-4 - [[4- [4 - [(phenylmethyl) oxy] phenoxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide

To a solution of the title compound of Example 55 (2.7 g, 7 mmol) in N, N-dimethylacetamide (20 mL) was added cesium carbonate (6.48 g, 21 mmol) and 4- (benzyloxy) phenol , 14 mmol). The slurry was stirred at 95 &lt; 0 &gt; C for 6 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated under vacuum. Chromatography (silica phase, ethyl acetate / hexane) gave the substituted THP-protected hydroxamate (3.94 g, 99%) as a white foam. HRMS (ES +) M + NH 4 +: C 30 H 33 N calculated value of ₁ O ₈ S _1: 585.23, Found: 585.23.
Part B: To a slurry of THP-protected hydroxamate (1.42 g, 2.5 mmol) from Part A in dioxane (6.3 ml) was added 4 N HCl dioxane solution (6.3 mL) and methanol (6.3 mL). After 15 minutes at ambient temperature, the reaction was diluted with ethyl acetate, washed with water and washed with Na₂SO₄&Lt; / RTI &gt; filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexane) to give the title compound as a white solid (0.56 g, 46%). HRMS (ES &lt; + &gt;) MH + : C₂₅H₂₅N_OneO₇S_OneFound: 484.14 Found: 484.14.
Example 73: Preparation of tetrahydro-N-hydroxy-4 - [[4- [4- (trifluoromethoxy) phenylthio] phenyl] sulfonyl] -2H-pyran-4-carboxamide

To a solution of the title compound of Example 55 (3.1 g, 8 mmol) in N, N-dimethylformamide (20 mL) was added calcium carbonate (2.21 g, 16 mmol) and p- (trifluoromethoxy) benzenethiol (2.33 g, 12 mmol). The slurry was stirred at 70 &lt; 0 &gt; C for 2 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated under vacuum. Chromatography (silica phase, ethyl acetate / hexanes) gave the substituted THP-protected hydroxamate (4.4 g, 98%) as a white solid. HRMS (ES +) M + NH 4 +: C 24 H 26 N 1 O 7 Calcd of S ₂ F _3: 579.14, Found: 579.14.
Part B: To a slurry of THP-protected hydroxamate (4.15 g, 7.4 mmol) in dioxane (20 ml) from Part A was added 4N HCl dioxane solution (20 mL) and methanol (20 mL). After 15 minutes at ambient temperature, the reaction was diluted with ethyl acetate, washed with water and washed with Na₂SO₄&Lt; / RTI &gt; filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexane) to give the title compound as a white solid (3.0 g, 85%). HRMS (ES &lt; + &gt;) M + NH₄ ⁺ : C₁₉H₁₈N_OneO₆S₂F₃Lt; / RTI &gt;: 495.09, found 495.09.
Example 74: Preparation of phenylmethyl-4 - [[2- (hydroxyamino) -2-oxoethyl] sulfonyl] phenyl] carbamate

Part A: Thionyl chloride (24 mL, 0.33 mol) was slowly added to a suspension of 2- (4-aminophenylthio) acetic acid (20.0 g, 0.11 mmol) in methanol (100 mL) cooled to 0 ° C. Additional methanol (100 mL) was added and the cooling bath was removed. The resulting mixture was heated to reflux for 2 hours. The reaction mixture was then cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in H ₂ O and neutralized with saturated NaHCO ₃ . The aqueous reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Concentration in vacuo afforded the methyl ester sulfide (22.75 g, quantitative yield) of the dark purple oil.
Part B: To a solution of Part A methyl ester sulphide (10.0 g, 50.7 mmol) in dichloromethane (100 mL) was added N-methylmorpholine (11.2 mL, 101.4 mmol) followed by N- (benzyloxycarbonyl Oxy) succinimide (12.6 g, 50.7 mmol). The resulting mixture was stirred overnight at ambient temperature (about 18 hours) and then concentrated in vacuo. The residue was dissolved in ethyl acetate and then washed with H ₂ O, 5% KHSO ₄ , saturated NaCl, and dried over Na ₂ SO ₄ . Concentration in vacuo afforded benzyloxycarbamate sulfide (16.2 g, 96%) as a black oil.
Part C: To a solution of the benzyloxycarbamate sulfide (16.2 g, 48.7 mmol) in Part B in H ₂ O (10 mL) and tetrahydrofuran (100 mL) was added Oxone (90.0 g, 146.4 mmol) was added and the resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O, saturated NaCl, and dried over Na ₂ SO ₄ . Concentration in vacuo afforded benzyloxycarbamatesulfone (15.6 g, 88%) as a tan solid.
Part D: To a solution of Part C benzyloxycarbamatesulfone (0.25 g, 0.69 mmol) in tetrahydrofuran (3 mL) was added 50% aqueous hydroxylamine (1.5 mL). The resulting mixture was stirred at ambient temperature for 24 hours. The mixture was then diluted with ethyl acetate (30 mL), washed with H ₂ O, saturated NaCl, and dried over Na ₂ SO ₄ . Concentrated in vacuo and then washed with hot diethyl ether to give the title compound (0.20 g, 80%) as a pale pink solid. MS MH ^& lt ^{; + &} gt ^; : Calcd for C ₁₆ H ₁₇ O ₆ N ₂ S: 365, found 365.
Example 75: Preparation of N-hydroxy-2 - [[4 - [[(phenylamino) carbonyl] amino] phenyl] sulfonyl] acetamide

Part A: Hydrogen gas was bubbled through a suspension of Example 74 Part C benzyloxycarbamatesulfone (13.4 g, 36.8 mmol) and 4% Pd / C in tetrahydrofuran (100 mL). After stopping the H ₂ absorption, the mixture was purged with N ₂ and then washed with tetrahydrofuran to give Celite Pad. The filtrate was concentrated in vacuo to give aniline of brown solid (8.1 g, 96%).
Part B: To a suspension of Part A aniline (0.50 g, 2.2 mmol) in dichloromethane (4 mL) was added phenyl isocyanate (0.36 mL, 3.3 mmol). The mixture was stirred at ambient temperature overnight (about 18 hours) and then diluted with dichloromethane (50 mL). The mixture was then washed with H ₂ O, saturated NaCl, and dried over Na ₂ SO ₄ . Chromatography (silica gel, ethyl acetate / hexanes) gave the urea as a white solid (0.59 g, 78%).
Part C: To a solution of the compound of Part B (0.32 g, 0.92 mL) in tetrahydrofuran (3 mL) was added 50% aqueous hydroxylamine (1.5 mL). The resulting mixture was stirred at ambient temperature for 24 hours. The mixture was then diluted with ethyl acetate (30 mL), then washed with H ₂ O, saturated NaCl, and dried over Na ₂ SO ₄ . Concentrated in vacuo and washed with hot diethyl ether to give the title compound (0.24 g, 76%) as a pale pink solid. _{^{MS MH +: C 15 H 16}} O 5 N ₃ S of the calculated: 350, found: 350.
Example 78: Synthesis of 5- [4- (3,4-dimethylphenoxy) phenyl] sulfonyl] -N ⁵ -hydroxy-1,3-dimethylhexahydro-5-pyrimidinecarboxamide, dihydrochloride Produce

Part A: To a solution of 1,3,5-trimethylhexahydro-1,3,5-triazine (1.21 mL, 8.61 mmol) and the solution of Example 55 Part B (2.00 g, 8.61 mmol) in benzene (20 mL) Trifluoroacetic acid (0.66 mL, 8.61 mmol) was slowly added. The resulting mixture was refluxed for 1 hour, heated and cooled to ambient temperature. The mixture was then extracted with 2N HCl. The aqueous layer was neutralized with saturated NaHCO ₃ and extracted with diethyl ether. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Concentration in vacuo afforded a clear oil of tetrahydropyrimidine (2.31 g, 81%).
Part B: N, N- dimethylformamide (5.0 mL) of Part A of the tetrahydro-pyrimidine (1.26 g, 3.81 mmol) 3,4- dimethyl-phenol To a solution of (0.559 g, 4.58 mmol) and Cs ₂ CO ₃ (3.72 g, 11.43 mmol). The resulting mixture was heated at 90 &lt; 0 &gt; C for 16 hours. After cooling to ambient temperature, the reaction was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate) gave the biaryl ether of the pale amber oil (1.40 g, 85%).
Part C: Potassium trimethylsilanolate (0.360 g, 2.81 mmol) was added to a solution of the nonaryl ether of Part B (0.936 g, 2.16 mmol) in tetrahydrofuran (5.0 mL). The resulting mixture was stirred at ambient temperature for 48 hours and then the solvent was removed. The resulting residue was dissolved in dichloromethane (5.0 mL) and then N-methylmorpholine (0.712 mL, 6.48 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.278 g, 2.38 mmol). After stirring at ambient temperature for 10 minutes, PyBroP (1.21 g, 2.59 mmol). Stirred overnight (about 18 hours) at ambient temperature and the resulting mixture was then diluted with dichloromethane (50 mL) and washed with H ₂ O. Remove the organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate) gave a white solid of hydroxamate (0.970 g, 87%).
Part F: To a suspension of Part E hydroxamate (0.667 g, 1.29 mmol) in methanol (1.0 mL) and dioxane (3.0 mL) was added a solution of 4N HCl in dioxane (3.22 mL, 12.9 mmol). After stirring at ambient temperature for 30 minutes, the reaction mixture was concentrated in vacuo. Reverse phase chromatography to give (0.379 g, 58%) of the (silica phase, acetonitrile / H ₂ O / trifluoroacetic acid) In a white solid was obtained. _{^{MS MH +: C 21 H 28}} O 5 N ₃ S of the calculated: 434, found: 434.
Example 79: Preparation of 4 - [[4- (4-chloro-3-methylphenoxy) phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide, monohydrochloride

Part A: Thionyl chloride (85.0 mL, 1.16 mmol) was slowly added dropwise to a suspension of isoniphenic acid (50.5 g, 0.39 mol) in methanol (300 mL) cooled to 0 ° C. After the addition was complete, the cooling bath was removed and the mixture was heated to reflux for 2 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. After suspending the resulting solid in ethyl acetate and washed with saturated NaHCO _3. The aqueous layer was concentrated in vacuo and the resulting solid was dissolved in hot ethyl acetate and extracted from the salt. The organic layer was then concentrated in vacuo to give the methyl ester of the white solid (55.4 g, quantitative yield).
Part B: To a solution of di-t-butyl dicarbonate (15.3 g, 70.0 mmol) in tetrahydrofuran (100 mL) was added the methyl ester of Part A (10.0 g, 70.0 mmol). The resulting mixture was stirred overnight at ambient temperature (about 18 hours) and then concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexanes) gave Boc-piperidine methyl ester (10.1 g, 59%) as a pale yellow oil.
Part C: To a solution of Boc-piperidine methyl ester (23.31 g, 0.096 mol) in Part B in tetrahydrofuran (500 mL) cooled to -40 ° C was added lithium diisopropylamide (57.5 mL, 2.0 M in THF , 0.115 mmol) was slowly added. The resulting mixture was stirred at -40 &lt; 0 &gt; C for 1 hour and then at 0 &lt; 0 &gt; C for 30 minutes. The mixture was then re-cooled to-40 C and a solution of disulfide (24.37 g, 0.096 mol) from Example A part A in tetrahydrofuran (60 mL) was added slowly. The resulting mixture was allowed to warm slowly to ambient temperature overnight (about 18 hours) and then H ₂ O (200 mL) was added. The mixture was then concentrated in vacuo and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with 0.5 M NaOH, H ₂ O, saturated NaCl, and dried over Na ₂ SO ₄ . Chromatography (silica phase, ethyl acetate / hexane) gave the sulfide (28.1 g, 79%) of the amber oil.
Part D: m-Chloroperoxybenzoic acid (48 g, 0.152 mol) was added to a solution of Part C of Sulfide (28.2 g, 0.076 mol) in dichloromethane (250 mL) cooled to 0 ° C. The resulting mixture was stirred at 0 &lt; 0 &gt; C for 1 hour and then at ambient temperature for 2.5 hours. The mixture was then diluted with H ₂ O and 10% NH ₄ OH. The organic layer was washed with 10% NH ₄ OH, H ₂ O and dried over Na ₂ SO ₄ . Chromatography (silica phase, ethyl acetate / hexanes) gave the sulfone (24.7 g, 81%) as a white solid.
Part E: N, N- dimethylformamide (15 mL) of Part D of the sulfone (3.00 g, 7.47 mmol) solution of 4-chloro-3-methylphenol (1.28 g, 8.96 mmol) and Cs ₂ CO ₃ of ( 7.30 g, 22.42 mmol). The resulting mixture was heated at 80 &lt; 0 &gt; C for 8 hours. The mixture was concentrated in vacuo and the residue partitioned between H ₂ O and ethyl acetate. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate / hexane) gave the beeraryl ether of the clear oil (3.26 g, 83%).
Part F: Potassium dimethylsilanolate (1.01 g, 7.87 mmol) was added to a solution of the beadaryl ether of Part E (3.17 g, 6.05 mmol) in tetrahydrofuran (30 mL). The resulting mixture was stirred at ambient temperature for 20 hours. Additional tetrahydrofuran (40 mL) was added and the mixture was stirred at ambient temperature for 36 hours. Additional potassium trimethylsilanolate (0.233 g, 1.82 mmol) was added and the mixture was stirred at ambient temperature for 23 hours. The tetrahydrofuran was removed and the resulting residue was suspended in dichloromethane (30 mL). To the suspension was added N-methylmorpholine (2.00 mL, 18.15 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.780 g, 6.66 mmol) followed by PyBroP (3.38 g, 7.26 mmol). The mixture was stirred at ambient temperature for 24 hours and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with H ₂ O, saturated NaCl, and dried over Na ₂ SO ₄ . Chromatography (silica phase, ethyl acetate / hexanes) gave the hydroxamate (2.98 g, 81%) as an off-white foam.
Part G: To a solution of Part F hydroxamate (2.98 g, 4.89 mmol) in methanol (6 mL) and dioxane (14 mL) was added 4 N HCl solution in dioxane (10 mL). The resulting mixture was stirred at ambient temperature for 3.5 hours, then diethyl ether (40 mL) was added and the precipitate was collected by filtration to give the title compound (2.00 g, 88%) as a light pink solid. MS MH ^& lt ^{; + &} gt ^; : Calcd for C ₁₉ H ₂₂ O ₅ N ₂ ClS: 425, found: 425.
Example 80: Preparation of 4 - [[4- (4-chloro-3-methylphenoxy) phenyl] sulfonyl] -4- (hydroxyamino) carbonyl] -1-piperidine acetic acid, monohydrochloride

Part A: acetonitrile (4.0 mL) Example 80 title compound (0.250 g, 0.542 mol) t- butyl bromoacetate To a suspension (0.088 mL, 0.542 mmol) and _{K 2 CO 3 (0.150 g,} 1.08 mmol) of of Was added. The resulting mixture was stirred at ambient temperature for 18 hours, then washed with ethyl acetate to give Celite Pad. The filtrate was then concentrated in vacuo. Reverse phase chromatographed (silica phase, acetonitrile / H ₂ O / trifluoroacetic acid) to a white solid t- butyl ester (0.156 g, 53%) was obtained.
Part B: Treatment of the t-butyl ester of Part A (0.156 g, 0.289 mmol) with a solution of 4N HCl in dioxane (1.5 mL) and addition of additional dioxane (2 mL) to the resulting mixture at ambient temperature Stir for 3.5 hours. After stirring at ambient temperature for 8 hours, the reaction mixture was concentrated in vacuo. The residue was reprocessed with 4 N HCl solution in dioxane (1.5 mL) at ambient temperature for 4 hours. Diethyl ether was added to the reaction mixture and the precipitate was collected by filtration to give the title compound (0.111 g, 74%) as an off-white solid. _{^{MS MH +: C 21 H 24}} O 7 Calcd for N ₂ SCl: 483, Found: 483.
Example 81: Synthesis of 4 - [[4- (4-chloro-3-methylphenoxy) phenyl] sulfonyl] -N-hydroxy- 1- (2- propynyl) -4-piperidinecarboxamide, Preparation of monohydrochloride

Part A: acetonitrile (8.0 mL) of Example 79 to obtain the title compound (0.500 g, 1.08 mmol) in propargyl bromide (0.126 mL, toluene 80% solution, 1.13 mmol) and K ₂ CO ₃ suspension (0.300 g, 2.17 mmol). The resulting mixture was stirred at ambient temperature for 24 hours, then washed with methanol to give Celite Filter through a pad, and the filtrate was concentrated in vacuo. Chromatography (silica phase, ethyl acetate) gave N-propargylhydroxamate (0.200 g, 40%) as a tan solid.
Part B: To a solution of Part A N-propargylhydroxamate (0.200 g, 0.432 mmol) in H ₂ O (0.5 mL) and acetonitrile (3.0 mL) was added concentrated HCl (0.05 mL). The resulting mixture was stirred at ambient temperature for 5 minutes and concentrated in vacuo to give the title compound (0.200 g, 93%) as a pink solid. _{^{MS MH +: C 22 H 24}} O 5 Calculated for N ₂ SCl: 463, Found: 463.
Example 82: Synthesis of 4 - [[4- (4-chloro-3-methylphenoxy) phenyl] sulfonyl] -N-hydroxy-1- (2-propenyl) -4- piperidinecarboxamide, Preparation of monohydrochloride

Part A: To a suspension of the title compound of Example 79 (0.500 g, 1.08 mmol) in acetonitrile (8.0 mL) was added allyl bromide (0.093 mL, 1.08 mmol) and K ₂ CO ₃ (0.300 g, 2.17 mmol) . The resulting mixture was stirred at ambient temperature for 22 hours. Additional allyl bromide (0.054 mL, 1 M in acetonitrile, 0.054 mmol) was added and stirring continued at ambient temperature for 6 hours. The resulting mixture was washed with ethyl acetate to give Celite Filter through a pad, and the filtrate was concentrated in vacuo. Chromatography (silica phase, methanol / ethyl acetate) gave N-allyl hydroxamate (0.080 g, 15%) as an off-white solid.
Part B: To a solution of Part A N-allyl hydroxamate (0.080 g, 0.172 mmol) in H ₂ O (1.0 mL) and acetonitrile (3.0 mL) was added concentrated HCl (0.05 mL). The resulting mixture was stirred at ambient temperature for 10 minutes and concentrated in vacuo to give the title compound as a white solid (0.100 g, quantitative yield). _{^{MS MH +: C 22 H 26}} O 5 N 2 SCl Calculated for: 465, Found: 465.
Example 83: Preparation of 4 - [[4- (4-fluoro-3-methylphenoxy) phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide, monohydrochloride

Part A: Potassium trimethylsilanolate (4.79 g, 37.36 mmol) was added to a solution of the sulfone of Example 79 part D (5.00 g, 12.45 mmol) in tetrahydrofuran (100 mL). The resulting mixture was stirred at ambient temperature for 1.5 hours and diluted with H ₂ O and diethyl ether (100 mL). The aqueous layer was extracted with diethyl ether, it washed the combined organic layers with H ₂ O. The aqueous layers were combined, acidified with 2N HCl (pH = 2) and extracted with ethyl acetate. The combined organic layers are washed with saturated NaCl, dried over Na ₂ SO _4, to give the acid (4.61 g, 96%) as an off-white solid.
Part B: To a suspension of the acid of Part A (0.830 g, 2.14 mmol) in dichloromethane (10 mL) was added N-methylmorpholine (0.706 mL, 6.42 mmol) and O-tetrahydro-2H-pyran- (0.276 g, 2.35 mmol). After stirring at ambient temperature for 5 minutes, PyBroP (1.20 g, 2.57 mmol) and the resulting mixture was stirred at ambient temperature for 19 hours. The mixture was concentrated in vacuo and the residue partitioned between H ₂ O and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, washed the combined organic layers with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate) gave p-fluorosulfone as a crystalline solid (0.993 g, 95%).
Part C: To a solution of Part B p-fluorosulfone (0.485 g, 0.996 mmol) in N, N-dimethylformamide (5 mL) was added 4- fluoro-3-methylphenol (0.133 mL, 1.20 mmol) ₂ CO ₃ (0.973 g, 2.99 mmol). The resulting mixture was heated at 60 &lt; 0 &gt; C for 17 hours. Additional 4-fluoro-3-methylphenol (0.055 mL, 0.498 mmol) was added and the temperature of the reaction mixture was raised to 80 &lt; 0 &gt; C for 4 h and then to 100 &lt; 0 &gt; C for 3 h. Additional 4-fluoro-3-methylphenol (0.133 mL, 1.20 mmol) was added and the reaction mixture was heated to 100 &lt; 0 &gt; C for 7.5 h. Adding additional Cs ₂ CO _3, and heating was continued at 100 ℃ for 17 hours. The reaction was cooled to ambient temperature and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate / hexanes) gave protected hydroxamate (0.490 g, 83%) which was an off-white solid.
Part D: To a solution of the protected hydroxamate of Part C (0.479 g, 0.808 mmol) in methanol (1 mL) and dioxane (3 mL) was added a solution of 4N HCl in dioxane (2.02 mL, 8.08 mmol) . The resulting mixture was stirred at ambient temperature for 1.5 hours. Diethyl ether (5 mL) was added and the precipitate was collected by filtration to give the title compound (0.323 g, 90%) as an off-white solid. _{^{MS MH +: C 19 H 22}} O 5 N ₂ of SF Calcd: 409, Found: 409.
Example 84: Preparation of 4 - [[4- (3-chloro-4-fluorophenoxy) phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide, monohydrochloride

To a solution of p-fluorosulfone (0.485 g, 0.996 mmol) from Example 83 Part B in N, N-dimethylformamide (5.0 mL) was added 4-fluoro-3-chlorophenol (0.176 g, 1.20 mmol ) and _{Cs 2 CO 3 (0.973 g,} 2.99 mmol) was added. The resulting mixture was heated at 60 &lt; 0 &gt; C for 17 h, then additional 4-fluoro-3-chlorophenol (0.073 g, 0.498 mmol) was added and the reaction mixture was heated at 80 &Lt; 0 &gt; C. After heating to 90 &lt; 0 &gt; C for 7 h, additional 4-fluoro-3-chlorophenol (0.176 mL, 1.20 mmol) was added and heating continued at 90 <0> C for 7.5 h. The addition of Cs ₂ CO ₃ and the mixture was added (0.973 g, 2.99 mmol) was heated at 90 ℃ for 24 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate / hexanes) gave protected hydroxamate (0.550 g, 90%) which was an off-white solid.
Part B: To a solution of Part A protected hydroxamate (0.530 g, 0.864 mmol) in methanol (1 mL) and dioxane (3 mL) was added a solution of 4N HCl in dioxane (2.00 mL, 8.00 mmol) . The resulting mixture was stirred at ambient temperature for 1.5 hours. Diethyl ether (5 mL) was added and the precipitate was collected by filtration to give the title compound (0.377 g, 94%) as an off-white solid. MS MH ^& lt ^{; + &} gt ^; : Calcd for C ₁₉ H ₁₉ O ₅ N ₂ SFCl: 429, found 429.
Example 85: Synthesis of 4 - [[4- (4-chlorophenoxy) phenyl] sulfonyl] -N-hydroxy-1- (2-propynyl) -4-piperidinecarboxamide, monohydrochloride Produce

Part A: N, N- dimethylformamide (20 mL) Example 79 Part D, of the sulfone (4.53 g, 11.28 mmol) solution of 4-chlorophenol (4.41 g, 13.54 mmol) and Cs ₂ CO ₃ (11.03 g of , 33.85 mmol). The resulting mixture was heated at 90 &lt; 0 &gt; C for 5 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate / hexanes) afforded the biaryl ether (4.60 g, 78%) as a white solid.
Part B: To a solution of the biaryl ether of Part A (4.57 g, 8.96 mmol) in dioxane (10 mL) was added 4 N HCl solution in dioxane (10 mL). The resulting mixture was stirred at ambient temperature for 2.5 hours and then additional dioxane (10 mL) was added. After stirring at ambient temperature for 1.5 hours, the mixture was concentrated in vacuo. The resulting solid was suspended in dioxane (20 mL) and reprocessed with 4 N HCl solution in dioxane (10 mL). The mixture was stirred at ambient temperature for 1 hour, methanol (1 mL) was added and stirring continued at ambient temperature. After 1 hour, the mixture was concentrated in vacuo to give the amine as a white solid (4.09 g, quantitative yield).
Part C: acetonitrile (20 mL) Part B amine (4.00 g, 8.96 mmol) in propargyl bromide (1.05 mL, toluene 80% solution, 9.41 mmol) and K ₂ CO ₃ (2.60 g suspension in, 18.82 mmol). The resulting mixture was stirred at ambient temperature for 18 hours, washed with ethyl acetate to give Celite After filtering through the pad, the filtrate was concentrated in vacuo to afford N-propargylamine (4.14 g, quantitative yield) as a sticky foam.
Part D: To a suspension of Part C N-propargylamine (4.14 g, 8.96 mmol) in tetrahydrofuran (20 mL) was added potassium trimethylsilanolate (1.26 g, 9.86 mmol). The resulting mixture was stirred at ambient temperature for 17 hours and additional tetrahydrofuran (5 mL) and potassium trimethylsilanolate (0.350 g, 2.73 mmol) were added. After stirring at ambient temperature for 4 hours, additional tetrahydrofuran (5 mL) was added and stirring continued at ambient temperature for 24 hours. Additional potassium trimethylsilanolate (0.115 g, 0.896 mmol) was added and the mixture was stirred at ambient temperature for 24 hours while adding additional potassium trimethylsilanolate and the resulting mixture was added at ambient temperature for 24 hours Lt; / RTI &gt; The tetrahydrofuran is removed and the residue is suspended in dichloromethane (20 mL).
Methylmorpholine (2.96 mL, 26.9 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.15 g, 9.86 mmol) were added to a suspension of dichloromethane and then PyBroP (5.01 g, 10.75 mmol). The resulting mixture was stirred overnight at ambient temperature and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate / hexanes) gave the protected hydroxamate (3.29 g, 69%) as an off-white foam.
Part E: To a solution of Part D protected hydroxamate (3.27 g, 6.13 mmol) in methanol (7 mL) and dioxane (21 mL) was added 4 N HCl solution in dioxane (10 mL). The resulting mixture was stirred at ambient temperature for 4 hours and then diethyl ether (75 mL) was added. The solid was collected by filtration and washed with diethyl ether to give the title compound (2.95 g, 99%) as an off-white solid. _{^{MS MH +: C 21 H 22}} O 5 Calculated for N ₂ SCl: 449, Found: 449.
Example 86: Preparation of 4 - [[4- (phenylthio) phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide, monohydrochloride

Part A: To a solution of the sulfone (0.500 g, 1.25 mmol) from Example 79 Part D in N, N-dimethylformamide (3.0 mL) was added thiophenol (0.154 mL, 1.50 mmol) and K ₂ CO ₃ mmol). The resulting mixture was stirred at ambient temperature for 24 hours and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate / hexane) gave the clear viscous oil, bialylthioether (0.480 g, 78%).
Part B: Potassium trimethylsilanolate (0.682 g, 5.31 mmol) was added to a solution of the vialylthioether of Part A (2.01 g, 4.09 mmol) in tetrahydrofuran (40 mL). The resulting mixture was stirred at ambient temperature for 23 hours and then concentrated in vacuo. The residue was then suspended in dichloromethane (20 mL), followed by addition of N-methylmorpholine (1.35 mL, 12.27 mmol) and 50% aqueous hydroxylamine (0.265 mL, 4.50 mmol) followed by PyBroP (2.29 g, 4.91 mmol). The resulting mixture was stirred at ambient temperature for 16 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and H ₂ O. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. A portion of the sample was subjected to reverse phase chromatography (silica phase, acetonitrile / H ₂ O / trifluoroacetic acid) to yield hydroxamate (0.190 g) as an off-white solid.
Part C: To a solution of Part B hydroxamate (0.181 g, 0.367 mmol) in methanol (1 mL) and dioxane (5 mL) was added 4 N HCl solution in dioxane (3 mL). The resulting mixture was stirred at ambient temperature for 3 hours and then concentrated in vacuo to give the title compound as an off-white solid (0.170 g, quantitative yield). _{^{MS MH +: C 18 H 21}} O 4 Calculated for N ₂ S _2: 393, Found: 393.
Example 87: Preparation of 4 - [(hydroxyamino) carbonyl] -4 - [[4- (phenylthio) phenyl] sulfonyl] -1-piperidine acetic acid, monohydrochloride

Part A: Compound of Example 86 (0.322 g, 0.751 mmol) t- butyl bromoacetate (0.121 mL, 0.751 mmol) and _{K 2 CO 3 (0.207 g,} 1.50 mmol) in a solution of acetonitrile (4.0 mL) . The resulting mixture was stirred at ambient temperature for 18 hours, washed with ethyl acetate and washed with Celite Filter through a pad, and the filtrate was concentrated in vacuo. Reverse phase chromatography (silica phase, acetonitrile / H ₂ O / trifluoroacetic acid) gave t-butyl ester as an off-white solid (0.150 g, 40%).
Part B: The t-butyl ester of Part A (0.145 g, 0.286 mmol) was treated with a 4 N HCl solution in dioxane (3 mL). The resulting mixture was stirred at ambient temperature for 7 hours, diethyl ether was added and the precipitate was collected by filtration. Purification by reverse phase chromatography (silica phase, acetonitrile / H ₂ O / HCl) gave the title compound (0.060 g, 43%) as an off-white solid. _{^{MS MH +: C 20 H 23}} O 6 Calculated for N ₂ S _2: 451, Found: 451.
Example 88: Preparation of 4 - [[4- (4-chlorophenoxy) phenyl] sulfonyl] -4 - [(hydroxyamino) carbonyl] -1-piperidine acetic acid, monohydrochloride

Part A: To a suspension of 4-bromopiperidine hydrobromide (40.0 g, 0.16 mmol) in tetrahydrofuran (200 mL) was slowly added triethylamine (45.4 mL, 0.33 mol) Butyl dicarbonate (37.4 g, 0.17 mol) was added in several portions. The resulting mixture was stirred at ambient temperature for 17 hours, then filtered and concentrated in vacuo. The solid was washed with hexane and then collected by filtration to give Boc-piperidine compound (45.8 g, &gt; 100%) of an amber oil.
Part B: To a solution of 4-fluorophenol (25.0 g, 0.20 mmol) in acetone (150 mL) degassed with N ₂ was added Cs ₂ CO ₃ (79.7 g, 0.25 mmol). After degassing for 5 minutes the resulting mixture with N _2, the part A Boc- piperidin a Compound (43.1 g, 0.16 mol) was added. The resulting mixture was stirred at ambient temperature for 22 hours, then washed with acetone to give Celite Pad. The residue was washed with diethyl ether and the solid was collected by filtration to give the sulfide (47.6 g, 93%) of a yellow oil.
Part C: m-Chloroperoxybenzoic acid (80 g, 57-86%) was added to a solution of Part B of Sulfide (47.3 g, 0.15 mol) in dichloromethane (350 mL) cooled to 0 ° C. Additional dichloromethane (50 mL) was added and the mixture was stirred at 0 &lt; 0 &gt; C for 1 h and then at ambient temperature for 1.5 h. The reaction mixture was diluted with H ₂ O and aqueous sodium metabisulfite (4.0 g in 50 mL). The mixture was concentrated in vacuo and then extracted with diethyl ether and ethyl acetate. The combined organic layers were washed with 10% NH ₄ OH, saturated NaCl, dried over Na ₂ SO _4. Recrystallization from ethyl acetate gave a white solid of the sulfone (18.9 g, 36%).
Part D: N, N- dimethylformamide (40 mL) of Part C sulfonamide To a solution of (8.00 g, 23.3 mmol) 4- chlorophenol (3.59 g, 27.96 mmol) and K ₂ CO ₃ (22.77 g of, 69.90 mmol). The resulting mixture was heated at 60 캜 for 4 hours and then heated to 80 캜 for 7 hours. The reaction was cooled to ambient temperature and concentrated in vacuo. To the residue was added H ₂ O (100 mL) and the solid was collected by filtration to give the bearyl ether (10.5 g, 99%) as an off-white solid.
Part E: To a solution of the beadaryl ether of Part D (5.00 g, 11.1 mmol) in tetrahydrofuran (50 mL) cooled to 0 C was added lithium bis ( Trimethylsilyl) amide (13.3 mL, 1 M in tetrahydrofuran, 13.3 mmol). The resulting mixture was stirred at 0 &lt; 0 &gt; C for 30 min and then dimethyl carbonate (1.40 mL, 16.6 mmol) was slowly added at such a rate that the temperature of the reaction mixture never exceeded 2 [deg.] C. The resulting mixture was then slowly warmed to ambient temperature.
After 17 hours, the reaction was re-cooled to 0 ° C and additional lithium bis (trimethylsilyl) amide (5.50 mL, 1 M in tetrahydrofuran, 5.50 mmol) was slowly added at a rate such that the reaction temperature never exceeded 2 ° C . After stirring for 30 min, dimethyl carbonate (0.048 mL, 0.570 mmol) was added and stirring was continued at 0 &lt; 0 &gt; C for 45 min. Additional lithium bis (trimethylsilyl) amide (0.500 mL, 1 M in tetrahydrofuran, 0.500 mmol) was added slowly and after 1 hour additional dimethyl carbonate (0.010 mL, 0.119 mmol) was added. On the 0 ℃ stirred for 20 minutes, addition of saturated NH ₄ Cl and then was The reaction mixture was concentrated in vacuo. The residue was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl, dried over Na ₂ SO _4. Recrystallization from methanol afforded the methyl ester of the white crystalline solid (3.56 g, 63%).
Part F: To a solution of the methyl ester of Part E (3.54 g, 6.94 mmol) in methanol (6 mL) and dioxane (18 mL) was added 4 N HCl solution in dioxane (10 mL). The resulting mixture was stirred at ambient temperature for 5 hours and then concentrated in vacuo to give an amine (3.10 g, quantitative yield) as an off-white solid.
Part G: To a solution of the amine of Part F (1.50 g, 3.36 mmol) in acetonitrile (15 mL) was added t-butyl bromoacetate (0.570 mL, 3.53 mmol) and K ₂ CO ₃ (1.16 g, 8.40 mmol) Respectively. The resulting mixture was stirred at ambient temperature for 3 hours, then washed with ethyl acetate to give Celite Pad. The filtrate was concentrated in vacuo to give the t-butyl ester of pale yellow oil (1.83 g, &gt; 100%).
Part H: To a solution of Part G t-butyl ester (1.76 g, 3.36 mmol) in tetrahydrofuran (15 mL) was added potassium trimethylsilanolate (0.475 g, 3.70 mmol). The resulting mixture was stirred at ambient temperature overnight (about 18 hours) and additional tetrahydrofuran (10 mL) was added. After stirring overnight (about 18 hours) at ambient temperature, additional potassium trimethylsilanolate (0.475 g, 3.70 mmol) was added. After stirring at ambient temperature for 4 hours and the resulting mixture was diluted with H ₂ O. The reaction mixture was acidified with 1N HCl (pH-7) and then concentrated in vacuo. The solid was washed with diethyl ether and then with H ₂ O to give an off-white solid (0.579 g, 32%).
Part I: To a suspension of the acid of Part H (0.579 g, 1.17 mmol) in dichloromethane (5 mL) was added N-methylmorpholine (0.386 mL, 3.51 mmol) and O- tetrahydro-2H-pyran- After adding hydroxylamine (0.151 g, 1.29 mmol), PyBroP (0.655 g, 1.40 mmol). The resulting mixture was stirred overnight at ambient temperature (about 18 hours) and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate / hexanes) afforded protected hydroxamate (0.510 g, 72%) as a white foam.
Part J: The protected hydroxamate of Part I (0.510 g, 0.837 mmol) was treated with a 4 N HCl solution in dioxane (10 mL). The resulting mixture was stirred at ambient temperature for 24 h before diethyl ether (20 mL) was added and the solid was collected by filtration to give the title compound as a white solid (0.370 g, 87%). _{^{MS MH +: C 20 H 22}} O 7 Calcd for N ₂ SCl: 469, Found: 469.
Example 89: Preparation of 4 - [[4- (4-chlorophenoxy) phenyl] sulfonyl] -N-hydroxy-1- [2- (4-morpholinyl) ethyl] -4-piperidinecarboxamide Meade, dihydrochloride

Part A: To a solution of the amine of Example 88 part F (1.00 g, 2.24 mmol) in acetonitrile (10 mL) was added 4- (2-chloroethyl) morpholine (0.438 g, 2.35 mmol) and K ₂ CO ₃ g, 8.96 mmol). The resulting mixture was stirred at ambient temperature for 1.5 hours, then a catalytic amount of NaI was added and stirring was continued for 21 hours at ambient temperature. The temperature of the reaction mixture was then raised to 60 DEG C for 29 hours. After cooling to ambient temperature, the reaction mixture was washed with ethyl acetate to give Celite Pad. The filtrate was concentrated in vacuo to give an oily solid ester (1.15 g, 98%).
Part B: To a solution of the ester of Part A (1.15 g, 2.20 mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.579 g, 4.51 mmol). The reaction mixture was stirred at ambient temperature for 4 hours, then additional tetrahydrofuran (10 mL) was added and stirring continued at ambient temperature overnight (about 18 hours). The reaction mixture was diluted with H ₂ O (10 mL) and acidified (pH-7) with 1N HCl. The resulting precipitate was collected by filtration to give an off-white acid (0.753 g, 72%).
To a suspension of Part B acid (0.750 g, 1.47 mmol) in dichloromethane (7 mL) was added N-methylmorpholine (0.500 mL, 4.55 mmol) and O- tetrahydro- Loxylamine (0.198 g, 1.62 mmol) was added followed by PyBroP (0.822 g, 1.76 mmol). The resulting mixture was stirred at ambient temperature for 24 hours and then additional N-methylmorpholine (0.242 mL, 2.21 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.052 g, mmol) and PyBroP (0.343 g, 0.735 mmol). The resulting mixture was stirred at ambient temperature for 23 hours and then additional O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.017 g, 0.145 mmol) and PyBroP (0.073 g, 0.157 mmol). The resulting mixture was stirred at ambient temperature overnight (about 18 hours) and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, methanol / chloroform) gave protected hydroxamate (0.750 g, 84%) which was an off-white solid.
Part D: The protected hydroxamate (0.730 g, 1.20 mmol) from Part C was treated with a solution of 4N HCl in methanol (1 mL) and dioxane (10 mL). The resulting mixture was stirred at ambient temperature for 1 hour, then diethyl ether (20 mL) was added and the solid was collected by filtration to give the title compound (0.625 g, 87%) as a light yellow solid. _{^{MS MH +: C 24 H 31}} O 6 Calculated for N ₃ SCl: 525, Found: 525.
Example 90: Synthesis of 4 - [[4- (4-chlorophenoxy) phenyl] sulfonyl] -N ⁴ -hydroxy-N ¹ - (1-methylethyl) -1,4-piperidinecarboxamide Manufacturing

Part A: To a suspension of the amine of Example 88 Part F (0.600 g, 1.34 mmol) in dichloromethane (5 mL) was added triethylamine (0.411 mL, 2.95 mmol) and isopropyl isocyanate (0.198 g, 2.01 mmol) . The resulting mixture was stirred at ambient temperature for 2 hours and then diluted with dichloromethane (50 mL). The mixture was washed with H ₂ O, saturated NaCl and dried over Na ₂ SO _{4 to} give an off-white solid (0.670 g,> 100%).
Part B: To a solution of the compound of Part A (0.640 g, 1.29 mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.199 g, 1.55 mmol). The resulting mixture was stirred at ambient temperature for 17 hours while adding additional potassium trimethylsilanolate (0.015 g, 0.117 mmol). The resulting mixture was further stirred for 24 hours, and N _{2 was} then blown onto the mixture to remove the tetrahydrofuran. To a suspension of the residue in dichloromethane (5 mL) was added N-methylmorpholine (0.426 mL, 3.87 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.181 g, 1.55 mmol) After that, PyBroP (0.902 g, 1.94 mmol). The resulting mixture was stirred at ambient temperature for 7 hours and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate / hexanes) gave protected hydroxamate (0.330 g, 44%) which was an off-white solid.
Part C: To a solution of the protected hydroxamate of Part B (0.330 g, 0.569 mmol) in methanol (1 mL) and dioxane (3 mL) was added 4 N HCl solution in dioxane (10 mL). The resulting mixture was stirred at ambient temperature for 3.5 hours and then diethyl ether was added. The solid was collected by filtration to give the title compound as a white solid (0.259 g, 92%). _{^{MS MH +: C 22 H 27}} O 6 Calculated for N ₃ SCl: 496, Found: 496.
Example 91: Synthesis of 4- [4 '- (4-chloro [1,1'-biphenyl] -4-yl) sulfonyl] -N-hydroxy-4-piperidinecarboxamide, monohydrochloride Produce

Part A: K ₂ CO ₃ (12.41 g, 89.80 mmol) was added to a solution of 4-bromothiophenol (16.98 g, 89.80 mmol) in acetone (200 mL) degassed with N ₂ . The Boc- piperidine compound (21.57 g, 81.64 mmol) of Example 88 Part A after degassing for 5 minutes, and the resulting mixture was added to N _2. The resulting mixture was stirred at ambient temperature for 19 hours, then washed with acetone to give Celite Pad. The residue was washed with diethyl ether and the solid was collected by filtration to give the sulfide (31.7 g, &gt; 100%) of the green oil.
Part B: m-Chloroperoxybenzoic acid (56.35 g, 50-60%, 163.28 mmol) was added to a solution of Part A of Sulfide (31.68 g, 81.64 mol) in dichloromethane (200 mL) Respectively. The resulting mixture became very viscous and additional dichloromethane (100 mL) was added. The mixture was stirred at 0 &lt; 0 &gt; C for 1.5 hours and then at ambient temperature for 1.5 hours. The reaction mixture was diluted with H ₂ O (300 mL) and aqueous sodium metabisulfite (8.00 g, 42.08 mmol in 50 mL of H ₂ O). The dichloromethane was removed in vacuo and the aqueous reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with 10% NaOH, saturated NaCl, dried over Na ₂ SO _4. Concentration in vacuo afforded the sulfone of the yellow oil (33.42 g, &gt; 100%).
Part C: To a solution of the sulfone (7.80 g, 19.34 mol) in Part B in tetrahydrofuran (100 mL) cooled to 0 C was added lithium bis (trimethylsilyl) amide at a rate such that the temperature of the reaction mixture never exceeded 2 [ Amide (23.8 mL, 1 M in tetrahydrofuran, 23.9 mmol). The resulting mixture was stirred at 0 ° C for 30 minutes and then a solution of methyl chloroformate (2.30 mL, 29.8 mmol) in tetrahydrofuran (5 mL) was added at such a rate that the temperature of the reaction mixture never exceeded 2 ° C . The resulting mixture was then allowed to slowly set to ambient temperature. The mixture was diluted with saturated NH ₄ Cl and the tetrahydrofuran was removed in vacuo. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate / hexanes) gave the ester as a yellow solid (6.33 g, 69%).
Part D: dimethoxyethane (50 mL) of the ester of part C (4.74 g, 10.28 mmol) solution in 4-chlorophenylboronic acid (1.77 g, 11.30 mmol), an aqueous _{Cs 2 CO 3 (25 mL,} 2.0 M, 50.0 mmol) and tetrakis (triphenylphosphine) palladium (0) (1 g) were added. The resulting mixture was stirred at ambient temperature for 3 days. The reaction mixture was washed with ethyl acetate, and Celite Filter through a pad, and the filtrate was concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexane) gave the biphenyl compound as an off-white solid (4.16 g, 82%).
Part E: To a solution of the biphenyl compound of Part D (1.50 g, 3.04 mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.468 g, 3.65 mmol). The resulting mixture was stirred at ambient temperature for 1 hour, additional tetrahydrofuran (5 mL) was added and the reaction mixture was stirred overnight at ambient temperature (about 18 hours). Additional tetrahydrofuran (15 mL) was added and the reaction mixture was further stirred at ambient temperature for 26 h. Additional potassium trimethylsilanolate (0.040 g, 0.304 mmol) was added and the mixture was stirred at ambient temperature overnight (about 18 hours) and the solvent was removed by blowing N ₂ over the reaction mixture.
To the residue suspension in dichloromethane (20 mL) was added N-methylmorpholine (1.00 mL, 9.12 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.427 g, 3.65 mmol) After that, PyBroP (2.13 g, 4.56 mmol). The resulting mixture was stirred at ambient temperature for 24 hours and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate / hexanes) gave the protected hydroxamate (1.25 g, 71%) as a white solid.
Part F: To a solution of the protected hydroxamate of Part E (1.25 g, 2.16 mmol) in methanol (1 mL) and dioxane (3 mL) was added 4 N HCl solution in dioxane (10 mL). The resulting mixture was stirred at ambient temperature for 3.5 hours, then diethyl ether (20 mL) was added. The solid was collected by filtration to give the title compound as a white solid (0.900 g, 97%). MS MH ^& lt ^{; + &} gt ^; : C ₁₈ H ₂₀ O ₄ N ₂ SCl Calcd: 395, found 395.
Example 92: Preparation of N-hydroxy-4 - [[4- (methylphenylamino) phenyl] sulfonyl-4-piperidinecarboxamide, monohydrochloride

Part A: toluene (4 mL) of Example 91 Part ester (1.00 g, 2.17 mmol) solution of N- methylaniline (0.282 mL, 2.60 mmol), Cs 2 CO 3 (0.990 g, 3.04 mmol) in C, tris (Dibenzylideneacetone) dipalladium (0) (0.018 g, 0.02 mmol) and (R) - (+) - 2,2'-bis (diphenylphosphino) 1,1'-binaphthyl (BINAP; 0.021 g, 0.033 mmol). The resulting mixture was heated to 100 &lt; 0 &gt; C for 20 hours. After cooling to ambient temperature, diethyl ether was added and the mixture was washed with diethyl ether to give Celite Filter through a pad, and the filtrate was concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexanes) gave the yellow sticky aniline (0.930 g, 88%).
Part B: To a solution of Part A of aniline (0.930 g, 1.90 mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.293 g, 2.28 mmol). The resulting mixture was stirred at ambient temperature for 19 hours and then additional potassium trimethylsilanolate (0.024 g, 0.190 mmol) was added. After stirring overnight at ambient temperature (about 18 hours), N ₂ was blown onto the mixture to remove the solvent.
To a suspension of the residue in dichloromethane (10 mL) was added N-methylmorpholine (0.627 mL, 5.70 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.267 g, 2.28 mmol) After that, PyBroP (1.33 g, 2.85 mmol). The resulting mixture was stirred at ambient temperature for 2 days and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate / hexanes) gave the protected hydroxamate as a white solid (0.860 g, 79%).
Part C: To a solution of the protected hydroxamate of Part B (0.890 g, 1.55 mmol) in methanol (1 mL) and dioxane (3 mL) was added 4 N HCl solution in dioxane (5 mL). The resulting mixture was stirred at ambient temperature for 1 hour and then diethyl ether (15 mL) was added. The solid was collected by filtration to give the title compound as a white solid (0.529 g, 80%). _{^{MS MH +: C 19 H 24}} O 4 Calculated for N ₃ S: 390, Found: 390.
Example 93: Preparation of 4 - [[4- (4-chlorophenoxy) phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide, monohydrochloride

Part A: To a suspension of resin I (4.98 g, 5.87 mmol) in 1-methyl-2-pyrrolidinone (45 mL) in a peptide flask was added the acid of Example 83 Part A (4.55 g, 11.74 mmol) 1-yloxy-tris-pyrrolidino-phosphono hexafluorophosphate (6.11 g, 11.74 mmol) and N-methylmorpholine (2.58 mL, 23.48 mmol) were added. The resulting mixture was stirred at ambient temperature for 14 hours. The resin was then collected by filtration, and stored by removing the filtrate, washing the resin with N, N- dimethylformamide, H ₂ O, N, N- dimethylformamide, methanol, dichloromethane and finally diethyl ether Respectively. The resin was dried under vacuum at ambient temperature to yield bound p-fluorosulfone as a yellow solid (6.72 g, 95%).
The filtrate was diluted with H ₂ O and extracted with ethyl acetate. The aqueous layer was acidified (pH = 2.0) with 2N HCl and then extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. The resulting residue was dissolved in 1-methyl-2-pyrrolidinone (40 mL) and the resin, followed by N-methylmorpholine (1.50 mL, 13.64 mmol) and benzotriazol- Pyrrolidino-phosphonium hexafluorophosphate (3.05 g, 5.86 mmol) was added. The resulting mixture was stirred at ambient temperature for 3.5 hours. Then, the resin was collected by filtration, washed with N, N- dimethylformamide, H ₂ O, N, N- dimethylformamide, methanol, dichloromethane and finally diethyl ether. The resin was vacuum dried at ambient temperature to afford resin bound p-fluorosulfone (6.34 g, 89%) as a pale orange solid. By cleavage of a small portion of the sulfone as a resin bound p- fluoro-95% trifluoroacetic acid / H ₂ O was measured for a load (0.78 mmol / g).
Part B: To a suspension of resin bound p-fluorosulfone (0.700 g, 0.546 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was added p- chlorophenol (0.702 g, 5.46 mmol) and Cs ₂ CO ₃ (1.78 g, 5.46 mmol). The resulting mixture was heated to 110 &lt; 0 &gt; C for 13 hours. Then the resin was collected by filtration, N, N- dimethylformamide, H ₂ O, N, was continuously washed with N- dimethylformamide, 2N HCl, N, N- dimethylformamide, methanol and dichloromethane. The resulting resin was re-run under the above reaction conditions for 3 hours. It was then collected by washing the resin was filtered off, continuous in N, N- dimethylformamide, H ₂ O, N, N- dimethylformamide, 2N HCl, N, N- dimethylformamide, methanol and dichloromethane. The solid was then vacuum dried at ambient temperature to give resin-bound hydroxamate (0.692 g, 91%) as an orange solid.
Part C: the resin-bonded part of the B-hydroxy roksa formate (0.692 g, 0.540 mmol) was treated with 95% trifluoroacetic acid at ambient temperature for 1 hour with acetic acid _{/ H 2 O (3 mL)} . The resin was filtered and washed with 95% trifluoroacetic acid / H ₂ O (3 mL) and then with dichloromethane (2 × 3 mL) to. The filtrate was then evaporated. A hydroxyl roksa mate by reverse phase chromatography (silica phase, acetonitrile / H ₂ O / trifluoroacetic acid) was obtained. The resulting solid was dissolved in acetonitrile (5 mL) and H ₂ O (0.5 mL) and treated with concentrated HCl. The resulting mixture was stirred at ambient temperature for 5 minutes and concentrated in vacuo to give the title compound (0.220 g, 91%) as an off-white solid. _{^{MS MH +: C 18 H 20}} O 5 Calculated for N ₂ SCl: 411, Found: 411.
Example 94: Preparation of tetrahydro-N-hydroxy-4 - [(4-phenoxyphenyl) sulfonyl] -2H-pyran-4-carboxamide

Part A: To a stirred solution of the methyl ester compound of Example 55, Part C (0.96 g, 3.2 mmol) in N, N-dimethylformamide (30 mL) was added phenol (0.3 g, 3.2 mmol) followed by cesium carbonate Nate (3.2 g, 10 mmol) was added. The resulting composition was heated to 7O &lt; 0 &gt; C for 5 hours. The solution was allowed to stand at ambient temperature for 18 hours, diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with semi-saturated NaCl and dried over sodium sulfate. The solvent was removed by rotary evaporation to give the desired phenoxy compound (1.1 g, 92%).
Part B: Sodium hydroxide (1 g, 25 mmol) was added to a solution of the phenoxy compound of Part A (1.1 g, 2.9 mmol) in THF (10 mL) and ethanol (10 mL). The resulting solution was stirred at ambient temperature for 1 hour. The solution was then heated to 80 DEG C for 1 hour. The solvent was removed by rotary evaporation and the resulting sodium salt was acidified with 1N HCl (50 mL) and extracted with ethyl acetate. The organic layer was dried over Na ₂ SO _4. The solvent was removed by rotary evaporation to give the desired phenoxycarboxylic acid (1.1 g, 99%).
Part C: To a stirred solution of Part B phenoxycarboxylic acid (1.1 g, 3 mmol) in DMF (7 mL) was added N-hydroxybenzotriazole-H ₂ O (0.623 g, 4.6 mmol) followed by 1 - [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.634 g, 3.3 mmol). After 10 minutes, 50% aqueous hydroxylamine solution (2 mL, 30 mmol) was added and the solution stirred at ambient temperature for 18 hours. The solution was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with H ₂ O, followed by _semi- saturated NaCl, and dried over Na ₂ SO ₄ . The title compound (0.37 g, 33%) as a white solid by reverse phase chromatography (silica phase, acetonitrile / H ₂ O) was obtained. ^{HRMS (ES +) MH +:} C 18 calculated in the H ₁₉ NO ₆ S: 378.1011, Found: 378.0994.
Example 95: Preparation of tetrahydro-N-hydroxy-4 - [[4- (phenylthio) phenyl] sulfonyl] -2H-pyran-4-carboxamide

Part A: To a stirred solution of the methyl ester of Example 55, Part C (1.02 g, 3.4 mmol) in N, N-dimethylformamide (20 mL) under nitrogen atmosphere was added thiophenol (0.37 g, 3.4 mmol) Cesium carbonate (3.3 g, 10.1 mmol) was added and the solution was heated to 70 &lt; 0 &gt; C for 17 h. The solution was allowed to stand at ambient temperature for 1 hour, diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with half saturated NaCl, dried over Na ₂ SO _4. S-Phenyl compound (0.6 g, 41%) was obtained by chromatography (silica phase, ethyl acetate / hexane).
Part B: NaOH (0.8 g, 20 mmol) was added to a stirred solution of Part A S-phenyl compound (0.6 g, 1.4 mmol) in THF (10 mL) and ethanol (10 mL). The solution was heated to 80 &lt; 0 &gt; C for 1 hour. The solution was allowed to stand at ambient temperature for 18 hours. The solvent was removed by rotary evaporation, the resulting sodium salt was acidified with IN HCl (25 mL), extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was removed by rotary evaporation to give the desired S-phenylcarboxylic acid (0.6 g, quantitative yield).
Part C: N-Hydroxybenzotriazole-H ₂ O (0.30 g, 2.2 mmol) was added to a stirred solution of Part B, S-phenylcarboxylic acid (0.6 g, 1.5 mmol) in DMF 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.32 g, 1.6 mmol) was added. After 10 minutes, 50% aqueous hydroxylamine solution (1.5 mL, 22 mmol) was added and the solution stirred at ambient temperature for 42 hours. The solution was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with H ₂ O, followed by semi-saturated NaCl, and dried over sodium sulfate. The title compound (0.15 g, 26%) was obtained as a white solid by reverse phase chromatography (silica phase, acetonitrile / H ₂ O). ^{HRMS (ES +) MH +:} C 18 calculated in the _{H 19 NO 5 S 2: 394.0783} , Found: 394.0753.
Example 96: Preparation of 4 - [[4- (3,4-dimethylphenoxy) phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

To a stirred solution of the methyl ester of Example 55, Part C (1.04 g, 3.3 mmol) in N, N-dimethylformamide (30 mL) was added 3,4-dimethylphenol (0.4 g, 3.3 mmol) Cesium carbonate (3.2 g, 10 mmol) was then added. The resulting solution was heated to 88 [deg.] C for 5 hours. The solution was concentrated by rotary evaporation, diluted with H ₂ O and extracted with ethyl acetate. The organic layer was dried over MgSO _4. The solvent was removed by rotary evaporation to give the desired dimethylphenoxy compound (1.2 g, 91%).
Part B: NaOH (1 g, 25 mmol) was added to a solution of the dimethylphenoxy compound of Part A (1.2 g, 3 mmol) in THF (10 mL) and ethanol (10 mL). The resulting solution was heated to 80 &lt; 0 &gt; C for 1 hour. The solvent was removed by rotary evaporation and the resulting sodium salt was acidified with 1N HCl (50 mL) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was removed by rotary evaporation to give the desired dimethylphenoxycarboxylic acid (1.2 g, quantitative yield).
Part C: To a stirred solution of Part B dimethylphenoxycarboxylic acid (1.2 g, 3 mmol) in DMF (7 mL) was added N-hydroxybenzotriazole-H₂O (0.623 g, 4.6 mmol) followed by 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.634 g, 3.3 mmol). After 10 minutes, 50% aqueous hydroxylamine solution (2 mL, 30 mmol) was added and the solution stirred at ambient temperature for 18 hours. The solution was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with H₂O, followed by semi-saturated NaCl, and washed with Na₂SO₄Lt; / RTI &gt; Purification by reverse phase chromatography (silica phase, acetonitrile / H₂O) to give the title compound (0.52 g, 43%) as a white solid. HRMS (ES⁺) MH⁺: C₂₀H₂₃NO₆Calcd for S: 406.1324, found 406.1302.
Example 97: Synthesis of tetrahydro-N-hydroxy-4 - [[4 - [(6-methyl-3-pyridinyl) oxy] phenyl] sulfonyl] -2H- Manufacturing

To a stirred solution of the methyl ester of Example 55, Part C (1.02 g, 3.4 mmol) in N, N-dimethylformamide (20 mL) was added 5-hydroxy-2-methyl- 5 mmol) followed by cesium carbonate (3.2 g, 10 mmol). The resulting solution was heated to 70 &lt; 0 &gt; C for 5 hours. The solution was allowed to stand at ambient temperature for 4 days, diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with semi-saturated NaCl and dried over sodium sulfate. The solvent was removed by rotary evaporation to give a heavy oil from which the desired white methylpyridine compound (1.2 g, 94%) was crystallized at ambient temperature under vacuum.
Part B: Potassium trimethylsilanoate (0.5 g, 3.5 mmol) was added to a solution of Part A methyl pyridine (1.2 g, 3.2 mmol) in THF (13 mL). The resulting solution was stirred at ambient temperature for 18 hours, during which the gel was formed. The solvent was removed by rotary evaporation to give the desired methyl pyridinecarboxylic acid (1.4 g, quantitative yield).
Part C: To a stirred solution of Part B methyl pyridinecarboxylic acid (1.4 g, 3.2 mmol) in methylene chloride (10 mL) was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1.79 g, 3.8 (0.97 g, 9.6 mmol) followed by O-tetrahydro-2H-pyran-yl-hydroxylamine (0.41 g, 3.5 mmol) was added and the solution was stirred at ambient temperature for 1.5 hours Lt; / RTI &gt; The solution was filtered to remove the precipitate and the solvent was removed by rotary evaporation. Chromatography (silica phase, ethyl acetate / hexane) gave O-tetrahydropyranemethylpyridine (1.48 g, 97%) as a white solid.
Part D: Methanol (3 mL) was added to a stirred solution of Part C O-tetrahydropyranemethylpyridine (1.48 g, 3.1 mmol) in 4N HCl in dioxane (5 mL). The solution was stirred at ambient temperature for 3 hours and poured into ethyl ether. The resulting precipitate was collected by vacuum filtration. The title compound (0.64 g, 53%) was obtained as a white solid by reverse phase chromatography (silica phase, acetonitrile / H ₂ O / HCl). ^{HRMS (ES +) MH +:} C 18 H 20 N Calcd the ₂ O ₆ S: 393.1120, Found: 393.1110.
Example 98: Preparation of tetrahydro-N-hydroxy-4 - [[4 - [(6-methyl-2-pyridinyl) oxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide

To a stirred solution of the methyl ester of Example 55, Part C (1.0 g, 3.3 mmol) in N, N-dimethylformamide (20 mL) was added 2-hydroxy-6-methyl- 5 mmol) followed by cesium carbonate (3.2 g, 10 mmol). The resulting solution was heated to 70 &lt; 0 &gt; C for 5 hours. The solution was allowed to stand at ambient temperature for 11 hours, at which time additional 2-hydroxy-6-methyl-pyridine (0.3 g, 2.7 mmol) was added to the stirred solution and the resulting solution was heated Respectively. The solution was concentrated by rotary evaporation, diluted with saturated NaCl in H ₂ O and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was removed by rotary evaporation to give the desired methyl pyridine (0.63 g, 49%) as a white solid by chromatography (silica phase, ethyl acetate / methanol).
Part B: To a solution of the methyl pyridine (0.63 g, 1.6 mmol) in Part A in THF (13 mL) was added potassium trimethylsilanoate (0.5 g, 3.5 mmol). The resulting solution was stirred at ambient temperature for 18 hours. The formed precipitate was removed by filtration, washed with methylene chloride, and dried in vacuo to give methyl pyridinecarboxylate potassium salt (0.4 g, 55%).
Part C: To a stirred solution of Part B methylpyridinecarboxylate (0.4 g, 0.9 mmol) in N, N-dimethylformamide (5 mL) was added bromo-tris-pyrrolidino-phosphonium hexafluoro (0.5 g, 1 mmol) followed by 4-methylmorpholine (0.27 g, 2.6 mmol) followed by a 50% hydroxylamine aqueous solution (0.6 mL, 9 mmol). The resulting solution was stirred at ambient temperature for 32 hours. The solution was concentrated by rotary evaporation and the title compound (0.162 g, 47%) was obtained as a white solid by reverse phase chromatography (silica phase, acetonitrile / H ₂ O). ^{HRMS (ES +) MH +:} C 18 H 20 N Calcd the ₂ O ₆ S: 393.1120, Found: 393.1119.
Example 99: Synthesis of tetrahydro-N-hydroxy-4 - [[4- [4- (1H-imidazol-1-yl) phenoxy] phenyl] sulfonyl] -2H- Preparation of monohydrochloride

Part A: To a solution of the THP pyran fluoro compound from Example 55, Part C (2.0 g, 5.2 mmol) in N, N-dimethylacetamide (6 mL) was added 4- (l, 3-imidazole) g, 33.3 mmol) followed by cesium carbonate (32.5 g, 99.9 mmol). The reaction was heated to 65 &lt; 0 &gt; C for 12 hours. The dimethylacetamide was removed in vacuo to give a brown solid. The THP-protected product in solution was obtained by reverse phase chromatography (silica phase, acetonitrile / water).
Part B: 10% HCl _aq (100 mL) was added slowly to a solution of the crude THP-protected product from Part A in acetonitrile / water (100 mL). After stirring overnight (approximately 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound (6.0 g, 41%) as a brown solid. ^{MS (FAB) M + H:} C 218 H 21 N 3 O 6 calculated in S _1: 444, Found: 444.
Example 100: Preparation of 4 - [[4- (4-chlorophenoxy) phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: p-Chlorophenol (1.93 g, 15 mmol) was added to a stirred solution of the THP pyran fluoro compound of Example 55, Part C (2.9 g, 7.5 mmol) in N, N- dimethylformamide (15 mL) , Followed by cesium carbonate (7.3 g, 22.5 mmol). The resulting composition was heated to 90 DEG C for 1.5 hours. The solution was allowed to stir at ambient temperature for 18 hours and to the stirred solution was added dimethylformamide (20 mL) followed by cesium carbonate (2 g, 6.2 mmol). The resulting composition was heated to 95 캜 for 3 hours. The solution was then allowed to stand at ambient temperature for 20 hours, at which time it was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with semi-saturated NaCl and dried over sodium sulfate. The solvent was removed by rotary evaporation. Chromatography (silica phase, ethyl acetate / hexane) afforded p-chlorophenoxyphenyl THP-protected hydroxamate compound (2.9 g, 78%).
Part B: To a solution of the p-chlorophenoxyphenyl THP-protected hydroxamate compound (2.9 g, 5.7 mmol) in Part A in dioxane (5 mL) was added 4N HCl in dioxane (5 mL, 20 mmol) Methanol (7.5 mL) was added. The resulting solution was stirred at ambient temperature for 1 hour. The solvent was removed by rotary evaporation. The title compound (1.35 g, 58%) as a white solid by reverse phase chromatography (silica phase, acetonitrile / H ₂ O) was obtained. ^{MS (FAB) MH +: C} 18 calculated in the H ₁₈ NO ₆ SCl: 412, Found: 412.
Example 101: Preparation of 4 - [[4- (3-chlorophenoxy) phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: p-Chlorophenol (5 g, 39 mmol) was added to a stirred solution of the THP pyran fluoro compound of Example 55, Part C (5.0 g, 13 mmol) in N, N- dimethylformamide (20 mL) , Followed by cesium carbonate (17 g, 52 mmol). The resulting solution was heated to 95 &lt; 0 &gt; C for 7 hours. The solution was allowed to stand at ambient temperature for 7 hours, diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with semi-saturated NaCl and dried over sodium sulfate. The solution was concentrated by rotary evaporation. Chromatography (silica phase, ethyl acetate / hexane) gave m-chlorophenoxyphenyl THP-protected hydroxamate compound (5.2 g, 82%).
Part B: To a solution of m-chlorophenoxyphenyl THP-protected hydroxamate compound (5.2 g, 10 mmol) in Part A in dioxane (5 mL) was added 4N HCl in dioxane (5 mL, 20 mmol) Methanol (10 mL) was then added. The resulting solution was stirred at ambient temperature for 1 hour. The solvent was removed by rotary evaporation to give the title compound (3.4 g, 79%) as a white solid. ^{HRMS (ES +) M + NH} 4 +: C 18 H 18 NO Calcd for ₆ SCl: 429.0887, Found: 429.0880.
Example 102: Preparation of methyl 4- [4 - [(tetrahydro-4 - [(hydroxyamino) carbonyl] -2H-pyran-4-yl] sulfonyl] phenoxy] benzenepropanoate

To a stirred solution of the THP pyran fluoro compound from Example 55, Part C (5.0 g, 13 mmol) in N, N-dimethylformamide (45 mL) was added methyl 3- (4- hydroxyphenyl) (7 g, 39 mmol) followed by cesium carbonate (17 g, 52 mmol). The resulting composition was heated to 95 캜 for 7 hours. The solution was allowed to stand at ambient temperature for 7 hours. The solution was then diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with semi-saturated NaCl and dried over sodium sulfate. The solution was concentrated by rotary evaporation. Methyl propanoate phenoxyphenyl THP-protected hydroxamate compound (5.6 g, 79%) was obtained by chromatography (silica phase, ethyl acetate / hexane).
Part B: To a solution of the methyl propanoate phenoxyphenyl THP-protected hydroxamate compound (5.6 g, 10 mmol) in Part A in methanol (5 mL) was added 4N HCl in dioxane (5 mL, 20 mmol) Respectively. The resulting solution was stirred at ambient temperature for 0.5 hour. The solvent was removed by rotary evaporation. The residue was dissolved in methylene chloride / ethyl acetate and the compound precipitated with hexane. The precipitate was washed with hexane and dried in vacuo to give the title compound (3.8 g, 80%) as a white solid. ^{HRMS (ES +) M +:} C 22 calculated in the H ₂₅ NO ₈ S: 464.138, found: 464.135.
Example 103: Preparation of 4 - [[4 - [(4-fluorophenyl) thio] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a stirred solution of the THP pyran fluoro compound of Example 55, Part C (2.9 g, 7.5 mmol) in N, N-dimethylformamide (25 mL) under a nitrogen atmosphere was added cesium carbonate , 15 mmol) followed by 4-fluoro-thiophenol (1.9 g, 15 mmol). The resulting composition was heated to 95 캜 for 7 hours. Cesium carbonate (1.2 g, 3.8 mmol) was added after 1 hour of heating and again at 2 hours. The solution was allowed to stand at ambient temperature for 9 hours, concentrated by rotary evaporation, diluted with H ₂ O containing 30% brine, and extracted with ethyl acetate. The organic layer was washed with semi-saturated NaCl and dried over sodium sulfate. The solution was concentrated by rotary evaporation. Chromatography (silica phase, ethyl acetate / hexane) to then reverse phase chromatography (acetonitrile / H ₂ O) -S- phenyl phenyl THP- protected hydroxy roksa formate compound (1.9 g, 55%) as a fluoro-p- .
Part B: To a solution of Part A of p-fluorophenyl-S-phenyl THP-protected hydroxamate compound (1.9 g, 4 mmol) in methanol (5 mL) was added 4N HCl in dioxane (5 mL, 20 mmol) Was added. The resulting solution was stirred at ambient temperature for 0.5 hour. The solvent was removed by rotary evaporation and the residue was dissolved in methylene chloride and precipitated with hexane. The precipitate was vacuum dried to give the title compound (1.5 g, 89%) as a white solid. ^{HRMS (ES +) M + NH} 4 +: C 18 calculated in the _{H 18 NO 5 S 2 F:} 429.0954, Found: 429.0948.
Example 104: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-pyridinylthio) phenyl] sulfonyl] -2H-pyran-4-carboxamide, monohydrochloride

Part A: Potassium carbonate (2.6 g, 19 mmol) was added to a stirred solution of the THP pyran fluoro compound of Example 55, Part C (2.9 g, 7.5 mmol) in N, N-dimethylformamide (20 mL) 4-Mercaptopyridine (1.7 g, 15 mmol) was added. The resulting composition was heated to 75 DEG C for 5 hours. Potassium carbonate (0.26 g, 1.9 mmol) was added after 1 hour of heating and again at 2 hours. The solution was allowed to stand at ambient temperature for 14 hours. The solution was concentrated by rotary evaporation, diluted with H ₂ O containing 30% brine, and extracted with ethyl acetate. The organic layer was washed with half saturated NaCl, dried over Na ₂ SO _4. The solution was concentrated by rotary evaporation. The mercapto pyridine THP-protected hydroxamate compound (1.2 g, 33%) was obtained by chromatography (silica phase, ethyl acetate / hexane).
Part B: 12.5 N HCl (0.4 mL, 5 mmol) followed by methanol (3 mL) was added to a solution of Part A mercaptopyridine THP-protected hydroxamate compound (1.2 g, 2.5 mmol) in acetonitrile Lt; / RTI &gt; The resulting solution was stirred at ambient temperature for 1 hour. The precipitate was filtered off, washed with methanol, then ethyl ether, and dried in vacuo to give the title compound (0.92 g, 86%) as a white solid. ^{HRMS (ES +) M + NH} 4 +: C 17 H 18 N 2 O 5 S 2 Calculated for: 395.0735, Found: 395.0734.
Example 105: Preparation of 4- [4 - [[tetrahydro-4 - [(hydroxyamino) carbonyl] -2H-pyran-4-yl] sulfonyl] phenoxy] benzenepropanoic acid

Part A: To a stirred solution of the title compound of Example 102 (0.1 g, 0.2 mmol) in methanol (0.5 mL) was added aqueous 1M Li (OH) ₂ (0.43 mL, 0.43 mmol). After standing at ambient temperature for 24 hours, the solution was refluxed for 20 hours. The solution was lyophilized to give the title compound (9 mg, 9%) as a white solid by reverse phase chromatography. MS (FAB) M + Li ^+: calcd C ₂₁ of the H ₂₃ NO ₈ S: 456, Found: 456.
Example 106: Synthesis of tetrahydro-N-hydroxy-4 - [[4- [[1- (2-propynyl) -4-piperidinyl] oxy] phenyl] sulfonyl] -2H- Preparation of radium midium and monohydrochloride

Part A: Slurried NaH (60% 1.59 g, 40 mmol) in N, N-dimethylformamide (50 mL) was added to a heat dried 3-neck flask under a nitrogen atmosphere. The slurry was cooled to 0 C using an ice bath and N-Boc-4-hydroxypiperidine (8 g, 40 mmol) followed by N, N-dimethylformamide rinse (10 mL) was added. The ice bath was removed and the stirred solution was allowed to reach ambient temperature over 2 hours. The stirred solution was again cooled to 0 C and the methyl ester compound of Example 55, Part C (10 g, 33 mmol) dissolved in N, N-dimethylformamide (40 mL) was added. The ice bath was removed and the solution was stirred at ambient temperature for 48 hours. The solution was concentrated by rotary evaporation. The solution was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After chromatography (silica phase, ethyl acetate / hexane / methanol), the crude N-Boc methyl ester was treated with 1N HCl in methanol. The solvent was removed by rotary evaporation. The residue was then dissolved in acetonitrile (21 mL) and H ₂ O (21 mL) was added. A reverse phase chromatography piperidine methyl ester (4.9 g, 35%) was purified by (silica phase, acetonitrile / H ₂ O) was obtained as the HCl salt.
Part B: To a stirred suspension of the piperidine methyl ester HCl salt of Part A (1.8 g, 4 mmol) in acetonitrile (24 mL) was added potassium carbonate (1.8 g, 13 mmol) followed by propargyl bromide 0.58 mL 80% solution, 5.2 mmol). The mixture was stirred at ambient temperature for 18 hours. The solution was concentrated by rotary evaporation, diluted with H ₂ O and extracted with ethyl acetate. The organic layer was dried over Na ₂ SO _4, and concentrated by rotary evaporation. Chromatography (silica phase, methylene chloride / methanol) gave the propargylpiperidine methyl ester compound (1.1 g, 63%).
Part C: Potassium trimethylsilanoate (0.57 g, 4 mmol) was added to a solution of the Part B propargyl piperidine methyl ester compound (1.1 g, 2.7 mmol) in THF (3 mL). After 5 min, THF (12 mL) was added and after 10 min a second THF (15 mL) was added. The resulting solution was stirred at ambient temperature for 18 hours, during which the gel was formed. The solvent was removed by rotary evaporation, the residue was diluted with H ₂ O and washed with ethyl acetate. The aqueous layer was acidified and chromatographed (silica phase, acetonitrile / H ₂ O) and lyophilized to give the desired propargylpiperidinecarboxylic acid (0.64 g, 59%).
Part D: To a stirred solution of Part C propargylpiperidinecarboxylic acid (0.64 g, 1.6 mmol) in N, N-dimethylformamide (5 mL) was added 1-hydroxybenzotriazole (0.3 g, 2.3 mmol) followed by 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride (0.33 g, 1.7 mmol) followed by O-tetrahydro-2H-pyran- (0.57 g, 4.8 mmol). The solution was stirred at ambient temperature for 42 hours, concentrated by rotary evaporation, diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then brine, dried over Na ₂ SO _4. The solution was concentrated by rotary evaporation and reverse phase chromatography (silica phase, acetonitrile / H ₂ O) and lyophilization gave the title compound (0.2 g, 30%) as a white solid. ^{HRMS (ES +) MH +:} C 20 H 26 N 2 O 6 S Calcd for: 423.159, found: 423.159.
Example 107: Preparation of 4 - [[4 - [(1-acetyl-4-piperidinyl) oxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a stirred suspension of the piperidine methyl ester HCl salt of Example 106, Part A (1.8 g, 4 mmol) in pyridine (2 mL) was added acetic anhydride (1.7 g, 16 mmol). The mixture was stirred at ambient temperature for 20 minutes. The solution was concentrated by rotary evaporation and chromatographed (silica phase, ethyl acetate / methanol) to give the acetylpiperidine methyl ester compound (1.5 g, 83%).
Part B: To a solution of the acetylpiperidine methyl ester compound of Part A (1.5 g, 3.3 mmol) in THF (5 mL) was added potassium trimethylsilanoate (0.86 g, 6 mmol). After 5 min, THF (15 mL) was added and a second THF (15 mL) was added after 10 min. The resulting solution was stirred at ambient temperature for 18 hours. The precipitate was separated by filtration to give the desired acetylpiperidine carboxylic acid (1.5 g, 98%).
Part C: To a stirred solution of Part B acetylpiperidinecarboxylic acid (0.9 g, 2 mmol) in dimethylacetamide (5 mL) was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1 tetrahydro-2H-pyran-2-yl-hydroxylamine (1.5 mL, 23 mmol) was added followed by the addition of a solution of 4-methylmorpholine (0.6 g, 6 mmol) And stirred at ambient temperature for 48 hours. The title compound (0.1 g, 12%) was obtained as a white solid by reverse phase chromatography (silica phase, H ₂ O / acetonitrile). ^{MS (FAB) MH +: C} 19 H 26 N 2 O 7 S Calcd of: 427, Found: 427.
Example 108: Preparation of 4 - [[4- (3-chloro-4-fluorophenoxy) phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a stirred solution of the THP pyran fluoro compound of Example 55, Part C (3.2 g, 7.7 mmol) in N, N-dimethylacetamide (15 mL) was added 3-chloro-4-fluorophenol mL, 12 mmol) followed by cesium carbonate (5 g, 15.5 mmol). The reaction was heated at 95 [deg.] C for 2 hours. Cesium carbonate (2.5 g, 8 mmol) was added and the reaction was heated at 95 [deg.] C for 6 h. The solution was allowed to stand at ambient temperature for 8 hours. The crude reaction was then filtered to remove cesium chloride and the coprecipitated product. The filter cake was suspended in H ₂ O and acidified to pH 6 with HCl. After foaming stopped, the precipitate was removed by filtration, and washed with H ₂ O, dissolved in H ₂ O / acetonitrile and chromatographed on a reverse phase HPLC column (H ₂ O / acetonitrile) to give 3-chloro-4- Fluorophenoxy THP-protected hydroxamate (1.4 g, 35%) was obtained.
Part B: To a stirred solution of Part A of 3-chloro-4-fluorophenoxy THP-protected hydroxamate (1.4 g, 2.7 mmol) in acetonitrile (10 mL) was added 1N aqueous HCl (10 mL) . The solution was stirred at ambient temperature for 1 hour. The acetonitrile was evaporated at ambient temperature under a steady stream of nitrogen until a medium precipitate formed. The precipitate was filtered and the cake was washed with H ₂ O and then diethyl ether and then vacuum dried to give the title compound (12.5 g, 96%) as a white solid. The compound was recrystallized from acetone / hexane to give white crystals (10.9 g, 86%). _{HRMS (ES) M + NH 4} +: C 18 H 19 NO Calcd for ₆ SFCl: 447.079, found: 447.080.
Example 109: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-phenoxy) phenyl] sulfonyl] -2H-thiopyran-4-carboxamide

Part A: To a solution of the methyl ester thiopyrane compound of Example 50, Part C (MW 318, 3 g, 1.0 eq) in N, N-dimethylacetamide (DMA: 40 mL) cesium carbonate (12 g, 1.5 eq.) And phenol (1.5 g). The mixture was heated to 95 [deg.] C for 6 hours. The reaction was cooled to ambient temperature and the reaction mixture was filtered, then the N, N-dimethylacetamide was removed by rotary evaporation. The residue was dissolved in 10% aq. HCl (100 mL) and extracted with ethyl acetate (2x). The ethyl acetate extract was dried over sodium sulfate and removed under reduced pressure to give an oil. The oil was purified on silica gel to give 2 g of methyl ester. ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: To a solution of the methyl ester compound of Part A (MW 392, 2 g) in THF (20 mL) was added potassium trimethylsilanoate (MW 128, 1.6 g, 1.2 eq.). The mixture was stirred at ambient temperature for 2 to 3 hours until solid precipitate formed. After completion of the hydrolysis, N-methylmorpholine (2 mL) was added followed by PyBrop (2.3 g, 1.2 eq). The solution was stirred for 10 minutes, then aqueous hydroxylamine was added and stirred for a further 2 hours. After completion of the reaction (2 hours), the solvent was removed by rotary evaporation. The residue was dissolved in water / acetonitrile, acidified with TFA (pH = 2) and then purified on preparative RPHPLC to give 1 g of the title compound as a white solid. ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C 18 H 19 NO 5 Calcd of S _2: 393, Found: 393.
Example 110: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-phenoxy) phenyl] sulfonyl-2H-sulfonylpyran-

Part A: To a solution of Example 109, Part A compound (2 g) in tetrahydrofuran (50 mL) was added water (50 mL). While vigorously stirring, Oxone (8 g, 3 eq). The progress of the reaction was monitored by RPHPLC. After 3 hours, water was added and the product was extracted with ethyl acetate (100 mL, 2X). The ethyl acetate was dried over sodium sulfate. After removal of the solvent under reduced pressure, 1.8 g of phenoxymethyl ester compound was obtained as a white solid. ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: To a solution of the phenoxymethyl ester compound of Part A (MW 590, 2 g) in tetrahydrofuran (20 mL) was added potassium trimethylsilanoate (MW 128, 1.2 g, 1.2 eq.). The mixture was stirred for 2 to 3 hours until solid precipitate formed. After completion of the hydrolysis, N-methylmorpholine (2 mL) was added followed by PyBrop (2.3 g, 1.2 eq). The solution was stirred for 10 minutes, then aqueous hydroxylamine was added and stirred for a further 2 hours. After completion of the reaction (2 hours), the solvent was removed by rotary evaporation. The residue was dissolved in water / acetonitrile, acidified with trifluoroacetic acid (pH = 2) and then purified on preparative RPHPLC to give 500 mg of the title compound as a white solid. ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C 18 H 19 NO 7 Calculated for S _2: 425, Found: 425.
Example 111: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-phenoxy) phenyl] sulfonyl 2H-sulfonylpyran-

Part A: To a solution of Example 109, Part A methyl ester (2 g) in acetic acid / water (25/5 mL) was added hydrogen peroxide (2 mL, 30% solution). The progress of the vigorously stirred solution was monitored by RPHPLC. After 3 hours, water was added and the product was extracted with ethyl acetate (100 mL, 2x). The ethyl acetate was dried over sodium sulfate. After removal of the solvent under reduced pressure, 2.1 g of methyl ester sulfoxyphenyl phenyl-O-phenyl compound was obtained as a white solid. ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: Potassium trimethylsilanoate (MW 128, 1.2 g, 1.2 eq.) Was added to a solution of the methyl ester sulfoxydipyran phenyl-O-phenyl compound (MW 578, 1.8 g) in Part A in tetrahydrofuran (25 mL) Was added. The mixture was stirred for 2 to 3 hours until solid precipitate formed. After completion of the hydrolysis, N-methylmorpholine (2 mL) was added followed by PyBrop (2.3 g, 1.2 eq). The solution was stirred for 10 minutes, then aqueous hydroxylamine was added and further stirred for 2 hours. After completion of the reaction (12 hours), the solvent was removed by rotary evaporation. The residue was dissolved in water / acetonitrile, acidified with trifluoroacetic acid (pH = 2) and purified on preparative RPHPLC to give 500 mg of the title compound as a white solid. ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C 18 H 19 NO 6 Calcd of S _2: 409, Found: 409.
Example 112: Preparation of tetrahydro-N-hydroxy-4 - [[4- (1-acetyl-4- (4- piperazinphenoxy) phenyl] sulfonyl 2H-thiopyran-4-carboxamide

Part A: To a solution of the methyl ester thiopyran compound from Example 50, Part C (MW 318, 5 g, 1.0 eq) in N, N-dimethylacetamide (70 mL), cesium carbonate (MW 5.5 g, 1.5 (2 mL, 2 M in THF) and 1-acetyl-4- (4-hydroxyphenyl) piperazine (4.9 g) were added. The mixture was stirred and heated to 90 &lt; 0 &gt; C for 6 hours. The reaction mixture was filtered, and then N, N-dimethylacetamide was removed by rotary evaporation. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (2x). The ethyl acetate was dried over sodium sulfate and removed under reduced pressure to give an oil. The oil was purified on silica gel to give 3 g of methyl ester. ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: To a solution of the methyl ester compound of Part A (MW 433, 3 g) in tetrahydrofuran (50 mL) was added potassium trimethylsilanoate (MW 128, 0.9 g, 1.2 eq.). The mixture was stirred for 2 to 3 hours until solid precipitate formed. After completion of the hydrolysis, N-methylmorpholine (2 mL) was added followed by PyBrop (3.5 g, 1.2 eq.). The solution was stirred for 10 minutes, then aqueous hydroxylamine was added and further stirred for 2 hours. After completion of the reaction (2 hours), the solvent was removed by rotary evaporation. The residue was dissolved in water / acetonitrile, acidified (pH = 2) with trifluoroacetic acid and purified on preparative RPHPLC to give 1.2 g of the title compound as a white solid. ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: Calcd for C ₂₄ H ₂₉ N ₃ O ₆ S ₂ : 519, found 519.
Example 113: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-thiophenoxy) phenyl] sulfonyl 2H-thiopyran-4-carboxamide

Part A: Water / hydrogen peroxide (8 mL, 4 mL / 4 mL, 30% solution) was added to a solution of the methyl ester thiopyran compound (5 g) from Example 50, Part C in acetic acid (40 mL). The progress of the vigorously stirred solution was monitored by RPHPLC. After 3 h at ambient temperature, water was added and the product was extracted with ethyl acetate (100 mL, 2x). The ethyl acetate was dried over sodium sulfate. After the solvent was removed under reduced pressure, 4.5 g of methyl ester sulfoxydepyran Ph-pF was obtained as a white solid. ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: Cesium carbonate (4.5 g MW, 1.1 eq.) And thiophenol (1.5 eq.) Were added to a methyl ester sulfoxydepyran Ph-pF (MW 318, 5 g, 1.0 eq.) Solution of Part A in DMA g, 1.05 eq.). The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and then N, N-dimethylacetamide was removed by rotary evaporation. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (2x). The ethyl acetate was dried over sodium sulfate and removed under reduced pressure to give an oil. The oil was purified on a preparative RPHPLC to give 2 g of methyl ester sulfoxy dephenyl phenyl-S-Ph compound. ¹ H-NMR, MS and HPLC were consistent with the desired compound.
Part C: Potassium trimethylsilanoate (MW 128, 1.5 g, 2 eq.) Was added to a solution of the Part B methyl ester sulfoxydepyran phenyl-S-Ph (MW 590, 5 g) in tetrahydrofuran . The mixture was stirred for 2 to 3 hours until solid precipitate formed. After completion of the hydrolysis, N-methylmorpholine (6 mL) was added followed by PyBrop (4 g, 1.1 eq.). The solution was stirred for 10 minutes, then aqueous hydroxylamine was added and stirring was continued for another 2 hours. After completion of the reaction (12 hours), the solvent was removed by rotary evaporation. The residue was dissolved in water / acetonitrile, acidified with trifluoroacetic acid (pH = 2) and then purified on preparative RPHPLC to give 1.9 g of the title compound as a white solid. ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C 18 calculated in the _{H 19 NO 5 S 3: 425} , Found: 425.
Example 114: Preparation of tetrahydro-N-hydroxy-4 - [[4- [4- (4-hydroxyphenyl) thiophenoxy) phenyl] sulfonyl 2H-thiopyran-4-carboxamide

To a solution of the title compound of Example 50 (MW 402, 5 g, 1.0 eq) in N, N-dimethylacetamide (70 mL) was added 4- hydroxythiophenol (MW 126, 1.6 g, 1.3 eq.), Potassium carbonate (MW 138, 5 g, 2.0 eq) was then added. The reaction was heated at 65 &lt; 0 &gt; C for 3 h until HPLC indicated the reaction was complete. The reaction mixture was filtered and the N, N-dimethylacetamide was removed in vacuo. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (2x). The ethyl acetate was dried over sodium sulfate and removed under reduced pressure to give the p-OH thiophenoxy compound as a crude oil. ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: The crude p-OH thiophenoxy compound of Part A was stirred in HCl / dioxane (50 mL) for 2 hours. The solvent was removed and the residue was dried, dissolved in water / acetonitrile, acidified (pH = 2) with trifluoroacetic acid and then purified on preparative RPHPLC to give 2.1 g of the title compound as a yellow solid. ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C 18 calculated in the _{H 19 NO 5 S 3: 425} , Found: 425.
Example 115: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-aminophenyl) thiophenoxy] phenyl] sulfonyl 2H-thiopyran-4-carboxamide

Part A: To a solution of 4-aminothiophenol (MW 126, 1.6 g, 1.3 eq) in the title compound of Example 50 (MW 402, 5 g, 1.0 eq.) In N, N-dimethylacetamide Potassium (MW 138, 5 g, 2.0 eq) was added. The reaction was heated to 65 &lt; 0 &gt; C for 3 h until HPLC indicated the reaction was complete. The reaction mixture was filtered and the N, N-dimethylacetamide was removed in vacuo. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (2x). The ethyl acetate was dried over sodium sulfate and removed under reduced pressure to give the p-NH ₂ thiophenoxy compound as a crude oil. ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: The crude p-NH ₂ thiophenoxy compound of Part A was stirred in HCl / dioxane (50 mL) for 2 hours. The solvent was removed and the residue was dried, dissolved in water / acetonitrile, acidified (pH = 2) with trifluoroacetic acid and then purified on preparative RPHPLC to give 2.1 g of the title compound as a yellow solid. ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C 18 H 20 N 2 O 4 S 3 C 2 calculated in the HF ₃ O _2: 538, Found: 538.
Example 116: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-tyramine) phenoxy] phenyl] sulfonyl 2H-thiopyran-4-carboxamide

Part A: To a solution of the title compound of Example 50 (MW 402,5 g, 1.0 eq) in N, N-dimethylacetamide (50 mL) was added tyramine (3 g, 2 eq) followed by cesium carbonate , 2.0 eq.). The reaction was heated at 95 &lt; 0 &gt; C for 5 h until HPLC indicated the reaction was complete. The reaction mixture was filtered and the N, N-dimethylacetamide was removed in vacuo. The solvent was removed and the residue was dried, dissolved in water / acetonitrile, acidified (pH = 2) with trifluoroacetic acid (TFA) and then purified on preparative RPHPLC to afford 2.5 g of crude methyl ester as a yellow solid &Lt; / RTI &gt; ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: The crude methyl ester from Reaction Part A was stirred in aqueous HCl (50 mL) for 1 hour. The solvent was removed and the residue was dried, dissolved in water / acetonitrile, acidified with TFA (pH = 2) and then purified on preparative RPHPLC to give 2.2 g of the trifluoroacetic acid salt of the title compound as a yellow foam solid &Lt; / RTI &gt; ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C ₂₀ H ₂₄ N ₂ O ₅ S ₂ C ₂ HF ₃ O ₂ : 550, found: 550.
Example 117: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-hydroxyphenylglycine)] phenyl] sulfonyl 2H-thiopyran-4-carboxamide

To a solution of the title compound of Example 50 (MW 402, 5 g, 1.0 eq) in N, N-dimethylacetamide (50 mL) was added hydroxyphenylglycine (3 g, 2 eq.) Followed by cesium carbonate Nate (10 g, 2.0 eq) was added. The reaction was heated to 95 &lt; 0 &gt; C for 5 h until HPLC indicated the reaction was complete. The reaction mixture was filtered and the N, N-dimethylacetamide was removed in vacuo. The solvent was removed and the residue was dried, dissolved in water / acetonitrile, acidified with trifluoroacetic acid (pH = 2) and then purified on preparative RPHPLC to give 2.0 g of crude methyl ester as a tan solid. ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: The crude methyl ester of Reaction Part A was stirred in aqueous HCl (50 mL) for 1 hour. The solvent was removed and the residue was dried, dissolved in water / acetonitrile, acidified (pH = 2) with trifluoroacetic acid and then purified on preparative RPHPLC to give the title compound trifluoro 2.2 g of acetic acid salt was obtained. ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C ₂₀ H ₂₂ N ₂ O ₇ S ₂ C ₂ HF ₃ O ₂ : 580, found: 580.
Example 118: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-hydroxyphenylglycine)] phenyl] sulfonyl 2H-thiopyran-4-carboxamide

Part A: To a stirred solution of Example 115 (0.25 g) in N-Boc N-hydroxysuccinyl glycine (2.1 g, 2 eq) and THF (25 mL) containing N- methyl morpholine (2 mL) and 4- dimethylaminopyridine Of a solution of the title compound (MW 518, 2.5 g, 1.0 eq) in DMF (5 mL) was stirred for 12 h. After the RPHPLC showed completion of the reaction, the solvent was removed under reduced pressure to give an oil. While stirring for a further 1 to 2 hours, a 10% aqueous solution of hydrochloric acid was added. The solution was then purified on a preparative RPHPLC to give 1.2 g of trifluoroacetic acid salt as a white foam / solid. ¹ H NMR, MS and HPLC were consistent with the desired compound. The solid was then dried under reduced pressure, then suspended in ethyl ether and 4N HCl / dioxane (20 mL) was added. The HCl salt was filtered off and washed with ethyl ether to give the title compound (1.1 g) as a tan solid. ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C 20 H 23 N 3 O 5 S 3 C 2 calculated in the HF ₃ O _2: 595, Found: 595.
Example 119: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-pyridinylthio) phenyl] sulfonyl] -2H-thiopyran-4-carboxamide, monohydrochloride

Part A: To a solution of the title compound of Example 50 (MW 402, 5 g, 1.0 eq) in N, N-dimethylacetamide (50 mL) was added 4- thiopyridine (3 g, 2 eq) followed by cesium carbonate (10 g, 2.0 eq). The reaction was heated to 75 &lt; 0 &gt; C for 5 h until HPLC indicated the reaction was complete. The reaction mixture was filtered and the N, N-dimethylacetamide was removed in vacuo. The residue was dried, dissolved in water / acetonitrile, acidified (pH = 2) with trifluoroacetic acid and purified on preparative RPHPLC to afford 2.0 g of crude S-pyridyl THP protected thiopyran compound as a brown solid Respectively. ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: S-Pyridyl of Part A The THP-protected thiopyran compound was stirred in aqueous HCl (50 mL) for 1 hour. The solvent was removed and the residue was dried, dissolved in water / acetonitrile, acidified (pH = 2) with trifluoroacetic acid and then purified on preparative RPHPLC to give the title compound trifluoro Acetic acid salt. ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C ₁₇ H ₁₈ N ₂ O ₄ S ₃ HCl: 447, found 447.
Example 120: Preparation of 4 - [[4 - [(4-aminophenyl) thio] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (MW 387,5 g, 1.0 eq) in N, N-dimethylacetamide (50 mL) was added 4- aminothiophenol (3 g, 2 eq) followed by potassium carbonate 10 g, 2.0 eq.). The reaction was heated to 60 &lt; 0 &gt; C for 5 h until HPLC indicated the reaction was complete. The reaction mixture was filtered and the DMA removed in vacuo. The solvent was removed and the residue was dried and dissolved in water / acetonitrile, acidified (pH = 2) with trifluoroacetic acid and purified on preparative RPHPLC to give crude 4-amino-S-Ph THP-protected 2.0 g of the thiopyran was obtained. ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: 4-Amino-S-Ph THF-protected thiopyran compound of Part A was stirred in aqueous HCl (50 mL) for 1 hour. The solvent was removed and the residue was dried, dissolved in water / acetonitrile, acidified (pH = 2) with trifluoroacetic acid and then purified on preparative RPHPLC to give the title compound trifluoro 1.4 g of acetic acid salt was obtained. ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C 18 H 20 N 2 O 5 Calcd of S _2: 408, Found: 408.
Example 121: Preparation of tetrahydro-N-hydroxy-4 - [[4- [(2-methyl-5-benzothiazolyl) oxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (MW 387, 10 g, 1.0 eq) in DMA (50 mL) was added hydroxymethylbenzothiazole (8 g, 1.5 eq.) Followed by cesium carbonate (20 g, 2.0 eq.). The reaction was heated to 90 &lt; 0 &gt; C for 5 h until HPLC indicated the reaction was complete. The reaction mixture was cooled and then filtered and N, N-dimethylacetamide was discarded. The filter cake was placed in 10% aqueous HCl and stirred for 30 minutes to remove the cesium salt. The desired solid was separated from the solution as gum. The gum was dissolved in ethyl acetate (100 mL), washed with water and dried over sodium sulfate. The solvent was removed in vacuo to give an oil which was dissolved in water / acetonitrile, acidified (pH = 2) with trifluoroacetic acid and then purified on preparative RPHPLC to give a 2-methyl-5-benzothiazolyloxy compound Respectively. ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: 2-Methyl-5-benzothiazolyloxy compound of Part A was stirred in aqueous HCl (20 mL) / acetonitrile (20 mL) for 1 hour. The solvent was concentrated and the separated solid was filtered to give 6.5 g of the title compound. ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C 20 H 20 N 2 O 6 Calcd of S _2: 448, Found: 448.
Example 122: Preparation of 4 - [[4- (4-chloro-3-fluorophenoxy) phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (MW 387, 10 g, 1.0 eq) in N, N-dimethylacetamide (50 mL) was added 4- chloro-3-fluorophenol (7 g, 1.4 eq) Cesium carbonate (20 g, 2.0 eq) was then added. The reaction was heated at 90 &lt; 0 &gt; C for 5 h until HPLC indicated the reaction was complete. The reaction mixture was cooled and then filtered and the DMA was discarded. The filter cake was placed in 10% aqueous HCl and stirred for 30 minutes to remove the cesium salt. The desired 4-chloro-3-fluorophenoxy compound (11 g) was isolated from the solution and filtered. ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: The 4-chloro-3-fluorophenoxy compound (3.4 g) of Part A was stirred in aqueous HCl (20 mL) / acetonitrile (20 mL) for 1 hour. The solvent was concentrated and the separated solid was filtered to give 2.0 g of the title compound. ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C 18 calculated in the H ₁₇ ClFNO ₆ S: 429, Found: 429.
Phenoxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide, 4- [ Preparation of trifluoroacetic acid salt

To a solution of the title compound of Example 55 (MW 387, 5 g, 1.0 eq) in DMA (50 mL) was added l-acetyl-4- (4- hydroxyphenyl) piperazine (3 g, Cesium carbonate (10 g, 2.0 eq) was then added. The reaction was heated to 90 &lt; 0 &gt; C for 5 h until HPLC indicated the reaction was complete. The reaction mixture was filtered and the DMA removed in vacuo. The residue was dissolved in water / acetonitrile, acidified (pH = 2) with TFA and then purified on preparative RPHPLC to give 3.1 g of crude 4-acetyl-1-piperazinylphenoxy compound as a brown solid. ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: 4-Acetyl-1-piperazinylphenoxy compound of Reaction Part A was stirred in aqueous HCl (50 mL) for 1 hour. The solvent was removed and the residue was dried, dissolved in water / acetonitrile, acidified with TFA (pH = 2) and then purified on preparative RPHPLC to give 2.0 g of the title compound trifluoroacetate as a tan foam . ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C ₂₄ H ₂₉ N ₃ O ₇ SC ₂ HF ₃ O ₂ : 617, found 617.
Example 124: N, N-Dimethyl-5- [4 - [[tetrahydro-4 - [(hydroxyamino) carbonyl] -2H-pyran-4-yl] sulfonyl] phenoxy] -2-carboxamide, &lt; / RTI &gt; trifluoroacetic acid salt

Part A: To a solution of the title compound of Example 55 (MW 387,5 g, 1.0 eq) in DMA (50 mL) was added 5-hydroxy-2-indoldimethylcarboxylate (3 g, 2 eq) followed by Cs ₂ CO ₃ (10 g, 2.0 eq) was added. The reaction was heated to 90 &lt; 0 &gt; C for 5 h until HPLC indicated the reaction was complete. The reaction mixture was filtered and the DMA removed in vacuo. The residue was dissolved in water / acetonitrile, acidified with TFA (pH = 2) and then purified on preparative RPHPLC to give 2.1 g of crude THP-protected pyranhydroxamate compound as a brown solid. ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: THP protected pyran hydroxamate compound of Part A was stirred in aqueous HCl (50 mL) for 1 hour. The solvent was removed and the residue was dried, dissolved in water / acetonitrile, acidified with TFA (pH = 2) and then purified on preparative RPHPLC to give 1.5 g of the trifluoroacetic acid salt of the title compound as a tan solid . ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C 23 H 25 N 3 O 7 S Calcd of: 487, Found: 487.
Example 125: Preparation of tetrahydro-N-hydroxy-4 - [[4- [4- (1-methylethyl) phenoxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (MW 387, 5 g, 1.0 eq) in DMA (50 mL) was added 4-isopropylphenol (3 g, 2 eq) followed by cesium carbonate Equivalent). The reaction mixture was heated to 90 &lt; 0 &gt; C for 8 hours until HPLC indicated the reaction was complete. The reaction mixture was filtered and the DMA portion was discarded. The filter cake was placed in 10% aqueous HCl and stirred for 30 minutes to remove the cesium salt. The separated solid isopropylphenoxyphenyl THP-protected hydroxamate (3.5 g) was filtered off. ¹ H NMR, MS and HPLC were consistent with the desired compound.
Part B: To a stirred solution of aqueous HCl (20 mL) and acetonitrile (20 mL) was added the crude Isopropyl-phenoxyphenyl THP-protected hydroxamate of Part A and the resulting mixture was stirred for 1 to 2 hours Lt; / RTI &gt; The solvent was concentrated on a solution surface through a stream of nitrogen. The solid was filtered and dried to give 2.2 g of the title compound as a tan solid. ¹ H NMR, MS and HPLC were consistent with the desired compound. MS (CI) M + H: C 21 calculated in the H ₂₅ NO ₆ S: 419, Found: 419.
Example 126: Preparation of resin II:
Step 1: Coupling of the compound of Example 55, Part D, to Resin I
A 500 mL round bottom flask was charged with resin I (Floyd et al. Tetrahedron Lett. 1996, 37, 8045-8048] (8.08 g, 9.7 mmol) and 1-methyl-2-pyrrolidinone (50 mL). A magnetic stirring bar was put and the resin slurry was stirred slowly. A solution of the compound of Example 55, Part D (5.58 g, 19.4 mmol) in 1-methyl-2-pyrrolidinone (35 mL) was added to the slurry followed by the addition of benzotriazol- -Pyrrolidino-phosphonium hexafluorophosphate (10.1 g, 19.4 mmol) was added in one portion. Once the hexafluorophosphate salt was dissolved, 4-methylmorpholine (4.26 mL, 39 mmol) was added dropwise. The reaction slurry was stirred at room temperature for 24 hours and then the resin was collected in a fired disc funnel and washed with N, N-dimethylformamide, methanol, methylene chloride and diethyl ether (3 x 30 mL of each solvent). The resin was vacuum dried to obtain 10.99 g of polymer-bound hydroxymate as a brown polymeric solid. The theoretical load on the polymer was 0.91 mmol / g. The FTIR electron microscope showed bands at 1693 and 3326 cm ^-1 indicating hydroxamate carbonyl and nitrogen-hydrogen stretch, respectively.
Step 2: Preparation of resin III: reaction of nucleophile with resin II
Resin II (50 mg, 0.046 mmol) was weighed into an 8 mL glass vial and a 0.5 M solution of the nucleophile in 1-methyl-2-pyrrolidinone (1 mL) was added to the reaction vessel. For phenol and thiophenol nucleophiles, cesium carbonate (148 mg, 0.46 mmol) was added and, for the substituted piperazine nucleophile, potassium carbonate (64 mg, 0.46 mmol) was added. The vial stopper was capped, heated to 70-145 ° C for 24-48 hours and then cooled to room temperature. The resin was then drained and washed with 1-methyl-2-pyrrolidinone, 1-methyl-2-pyrrolidinone / water (1: 1), water, 10% acetic acid / water, methanol and methylene chloride mL, each solvent).
Step 3: Cleavage of hydroxamic acid from polymer support
Resin III was treated with a trifluoroacetic acid / water mixture (19: 1, 1 mL) at room temperature for 1 hour. During this time, the resin became dark red. The resin was then drained, washed with trifluoroacetic acid / water (19: 1) and methylene chloride (2 x 1 mL each solvent), and the combined filtrates were collected in a zero pointed vial. The volatiles were removed in vacuo and a toluene / methylene chloride mixture (2 mL each) was added to the residue. The mixture was again concentrated in vacuo. The product was characterized by an electron spray mass spectrometer.
Was synthesized from resin II using the conditions of step 2 with a nucleophile indicating the following hydroxamic acid and released from the polymer using the reaction conditions of step 3.



Example XX: Large scale manufacture of resin IIIa
Resin II (5 g, 0.91 mmol) was weighed into an oven-dried cedar round bottom flask equipped with a temperature probe, overhead stirring paddle and nitrogen inlet. Anhydrous 1-methyl-2-pyrrolidine (35 mL) was added to the flask followed by ethyl isonipecotate (7.0 mL, 45.5 mmol). The resin slurry was slowly stirred with an overhead stirrer and the mixture was heated to 80 DEG C with a heating mantle for 65 hours. The flask was then cooled to ambient temperature.
The resin was collected in a sintered-disc glass funnel and washed with N, N-dimethylformamide, methanol and methylene chloride (3 x 30 mL each solvent). The resin was dried under vacuum to give 5.86 g of resin IIIa as a grayish white resin bead. The theoretical load of the polymer was 0.81 mmol / g. TFA cleavage was performed on 50 mg of resin IIIa as described in Step 3 to yield 10.4 mg of a grayish white solid which was not distinguishable from the reaction product of ethyl isonipecotate of Example 211 by spectroscopy .
Example YY: Large scale manufacture of resin IIIb
Resin IIIb was prepared following the procedure described for the preparation of Resin IIIa except that ethyl isonipecotate was replaced by ethylnipecotate. The yield after drying in vacuo was 5.77 g of resin IIIb as pale yellow resin beads. The theoretical load of the polymer was 0.81 mmol / g. TFA cleavage carried out on 50 mg of resin IIIb as described in Step 3 afforded 14.7 mg of a grayish white solid which was not distinguishable by spectroscopy from the reaction product of the ethylenepecotate of Example 212 Respectively.
Step 4: Hydrolysis of polymer-bound esters: preparation of resin IVa
The resin IIIa (5.8 g, 4.5 mmol) was weighed into a cedar round bottom flask equipped with an overhead stirring pedal. 1,4-dioxane was added to the flask, and the resin slurry was stirred for 15 minutes. Then, a 4 M solution of KOH (5 mL, 20 mmol) was added and the mixture was stirred for 44 hours. The resin was then collected in a sintered-disc glass funnel and washed with dioxane / water (9: 1), water, 10% acetic acid / water, methanol and methylene chloride (3 x 30 mL each solvent). The resin was dried under vacuum to give 5.64 g of resin IVa as a grayish white polymer bead. The FTIR microscope showed a band at 1732 and 1704 cm ^-1 and a broad band at 2500-3500 cm ^-1 . The theoretical load of polymer-bound acid was 0.84 mmol / g.
Preparation of resin Ivb:
Using the procedure described in step 4, resin IIIb (5.71 g, 4.5 mmol) was converted to 5.61 g of resin IVb. The FTIR microscope showed a band at 1731 and 1705 cm ^-1 and a wide band at 2500-3500 cm ^-1 . The theoretical load of polymer-bound acid was 0.84 mmol / g.
Step 5: Amide bond formation: preparation of resin V
The resin IVa or resin IVb (50 mg, 0.042 mmol) was weighed into a reaction vessel in which the glass raw material was dissolved and the vessel was capped under nitrogen. A 0.5 M solution of 1-methyl-2-pyrrolidinone (0.3 mL, Of hydroxybenzotriazole was added followed by the addition of a 0.5 M solution of diisopropylcarbodiimide in 1-methyl-2-pyrrolidinone (0.3 mL, 0.15 mmol). The resin was stirred for 15 minutes using a table top stirring plate and then a 0.7 M solution of the amine in 1-methyl-2-pyrrolidinone (0.3 mL, 0.21 mmol) was added. The reaction mixture was stirred for 6 hours, then the resin was filtered off and washed with 1-methyl-2-pyrrolidinone (3X1 mL). The reaction was repeated using the same reagent as the above reagent. The reaction mixture was stirred for 16 hours, then the resin was filtered off and washed with 1-methyl-2-pyrrolidinone, methanol and methylene chloride (3 x 1 mL each solvent).
The following hydroxamic acid was synthesized using the amine exemplified in step 5 reaction conditions and the exemplified polymer-bound acid and then released from the polymer using the reaction conditions of step 3.



Large scale manufacture of resin IIIc
Resin II (3.01 g, 2.74 mmol) was weighed into an oven-dried cedar round bottom flask equipped with an overhead stirring pedal, temperature probe, and nitrogen inlet. After addition of 1-methyl-2-pyrrolidinone (25 mL), pyrazine (2.36 mL, 27.4 mmol) and cesium carbonate (8.93 g, 27.4 mmol) were added. Additional 1-methyl-2-pyrrolidinone (10 mL) was added and the reaction mixture was heated to 100 &lt; 0 &gt; C and stirred for 18 hours. The flask was cooled to ambient temperature and the resin was collected in a sintered-disc funnel and washed with N, N-diethylformamide / water (1: 1), water, 10% acetic acid / water, methanol and methylene chloride Solvent). After drying under vacuum, the yield was 3.14 g of resin IIIb as pale yellow resin beads. The theoretical load of the polymer was 0.86 mmol / g. TFA cleavage was carried out on 50 mg of resin IIIb as described in Step 3 to yield 21 mg of a grayish white solid which was indissoluble by the spectroscopy from the compound of Example 209. [
Step 6: Amide bond formation with resin IIIc: Preparation of resin VI
Carboxylic acid (0.215 mmol) and 1-hydroxybenzotriazole (44 mg, 0.326 mmol) were placed in a reaction vessel in which the glass raw material was dissolved. The vessel was capped under nitrogen and after addition of 1-methyl-2-pyrrolidinone diisopropylcarbodiimide (0.034 mL, 0.215 mmol) was added. The solution was stirred on a table top shaker for 15 minutes and then resin IIIc (50 mg, 0.043 mmol) was added in one portion. The reaction mixture was stirred for 16 h, then the resin was filtered and washed with 1-methyl-2-pyrrolidinone, methanol and methylene chloride (3 x 1 mL each solvent). For the N-9-fluorenylmethoxycarbonyl-protected amino acid, the resin was further treated with piperidine / N, N-dimethylformamide solution (1: 4, 1 mL) for 30 minutes. The resin was filtered off and washed with N, N-dimethylformamide, methanol and methylene chloride (3 x 1 mL each solvent).
The following hydroxamic acid was synthesized from resin IIIc using step 6 with the indicated carboxylic acid and then released from the polymer using the reaction conditions of step 3.

Step 7: Preparation of resin VII
Resin IIIc (1.0 g, 0.86 mmol) was weighed into an oven dried 100 mL round bottom flask and a bulkhead with a magnetic stirring bar and a nitrogen spat was added. Methylene chloride (10 mL) was added and the resin slurry was slowly stirred. After p-Nitrophenyl chloroformate (0.867 g, 4.3 mmol) was added in one portion, diisopropylethylamine (0.75 mL, 4.3 mmol) was added dropwise. Mild warmth was detected when added. The reaction was stirred at ambient temperature for 18 hours and then the resin was collected in a sintered-disc glass funnel and washed with methylene chloride, methanol and methylene chloride (3 x 10 mL each solvent).
The polymer-bound product was dried under vacuum to give 1.25 g of resin VII as a brown resin bead. FTIR microscopy showed bands at 1798, 1733, 1696 and 1210 cm ^-1 . The theoretical load of the polymer was 0.75 mmol / g.
Step 8: Reaction of resin VII with an amine: Preparation of resin VIII
A small glass vial of 8 mL was charged directly to resin VII (50 mg, 0.038 mmol) and a small magnetic stirrer and a 0.5 M solution of amine in 1-methyl-2-pyrrolidinone (1 mL) was added. The vial was capped and heated to 50 &lt; 0 &gt; C. The resin slurry was gently agitated for 15 hours and then the small vial was cooled to ambient temperature. The resin was collected in a reaction vessel in which the glass raw material was dissolved and washed with 1-methyl-2-pyrrolidinone, methanol and methylene chloride (3 x 10 mL each solvent).
The following hydroxamic acid was synthesized from resin VII using the reaction conditions of step 8 with the indicated amine and then released from the polymer using the reaction conditions of step 3.

Example XXX: Preparation of 4 - [(4-bromophenyl) -sulfonyl] tetrahydro-2H-pyran-4-carboxylic acid
Part A: Preparation of the following compounds
A 60% sodium hydride oil dispersion (4.0 g, 0.1 mole) was weighed into an oven-dried cedar 500 mL round bottom flask in a nitrogen glove bag and the flask was charged with nitrogen inlet, temperature probe, overhead stirring paddle and rubber septum Respectively. Anhydrous tetrahydrofuran (200 mL) was added to the flask and it was cooled in an ice bath. 4-Bromothiophenol (18.91 g, 0.1 mole) was added dropwise and the temperature was kept below 7 ° C. It has been noticed that the gas is generated violently during the addition. After the addition was complete, the mixture was stirred for 10 minutes while cooling. Methylbromoacetate (9.5 mL, 0.1 mol) was then added dropwise and the temperature was maintained below 7 &lt; 0 &gt; C. The reaction was stirred for 10 minutes while cooling, then the ice bath was removed and the mixture was further stirred for 30 minutes. The reaction was quenched by the addition of 5 mL water and the solvent was removed on a rotary evaporator. The organic layer was washed with 5% hydrochloric acid / water (1 x 200 mL), saturated sodium bicarbonate (1 x 200 mL) and brine (1 x 200 mL). The organic layer was washed with water mL). The organic phase was dried over magnesium sulfate and concentrated to give 24.53 g of product (94%) as a yellow oil. ¹ H NMR was consistent with the desired structure. Mass spectrum indicated m / z 260 (M + H).
Part B: Preparation of the following compounds
The compound of Part A (24.5 g, 0.094 mol) was weighed into a 1.0 L round bottom flask equipped with overhead stirring paddle and temperature probe, then 550 mL of methanol was added followed by 55 mL of water to give solution Lt; / RTI &gt; The flask was immersed in an ice bath and the temperature was once dropped below 5 ° C and Oxone (144.5 g, 0.235 mol) was added dropwise over 5 minutes. A slight increase in temperature was detected at 8 ° C. The reaction was stirred while cooling for 10 minutes and then the ice bath was removed. After 4 hours, the reversed phase high pressure liquid chromatography showed a single component at 13.6 min. The reaction mixture was filtered and the solid washed thoroughly with methanol. The combined filtrate was concentrated on a rotary evaporator and the residue was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was washed with water (3 x 200 mL), saturated sodium bicarbonate (1 x 200 mL ) And brine (1 x 200 mL), then the organic phase was dried over magnesium sulfate and concentrated to give 25 g of product as a tan solid. Trituration with hexane afforded 24.3 g of pure sulfone (88%) as a grayish white solid. ¹ H NMR was consistent with the desired structure. The mass spectrum indicated m / z 293 (M + H).
Part C: Preparation of the following compounds
A 60% sodium hydroxide oil dispersion (5.76 g, 0.144 mol) was weighed into an oven-dried cedar 1.0 L round bottom flask in a nitrogen glove bag and the flask was charged with nitrogen inlet, temperature probe, overhead stirring paddle and rubber septum Respectively. Anhydrous N, N-dimethylformamide (250 mL) was added to the flask, mechanical stirring was started, and the mixture was heated to 50 &lt; 0 &gt; C. A solution of the above Part B compound (17.59 g, 0.06 mol) and 40 mL of dibromodiethyl ether (14.5 g, 0.06 mol) in N, N-dimethylformamide was added dropwise to the sodium hydroxide slurry, 55 [deg.] C and hydrogen was steadily evaporated. After the addition was complete, the temperature of the reaction mixture was increased to 65 DEG C and the mixture was stirred for 2 hours. The flask was then cooled to ambient temperature and the flask was impregnated with an ice bath. When the temperature fell below 20 ° C, 0.5 L ice water was added.
The mixture was transferred to a 4.0 L separatory funnel, 1.0 L of water was further added and the mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with 5% hydrogen chloride / water (1 x 200 mL), saturated sodium bicarbonate (1 x 200 mL) and brine (1 x 200 mL), dried over magnesium sulfate and concentrated in vacuo to give 18.2 g of crude product were obtained. Recrystallization from ethyl acetate / hexane gave 6.53 g of pure product as yellowish brown crystals (30%). ¹ H NMR was consistent with the desired structure. The mass spectrum indicated m / z 363 (M + H).
Part D: Preparation of the title compound
A solution of the above Part C compound (4.57 g, 12.6 mmol) in 50 mL of dry tetrahydrofuran in an oven dried 100 mL round bottom flask was stirred at ambient temperature under nitrogen and 4.84 g of potassium trimethylsilanolate (37.7 mmol) was added in one portion. The mixture was stirred for 2 hours and then 10 mL of water was added dropwise. The volatiles were removed in vacuo and the residue was partitioned between 100 mL ethyl ether and 100 mL water. The aqueous layer was acidified to less than pH 2 using concentrated hydrogen chloride, causing a white precipitate. The mixture was extracted with ethyl acetate (3 x 75 mL), and the combined ethyl acetate layers were dried over magnesium sulfate and concentrated in vacuo to give 4.15 g of pure product (94%) as a white solid. _{^{1 H NMR (CDCl 3 / CD}} 3 OD) 2.10 (m, 4H), 3.28 (m, 2H), 3.90 (m, 2H), 7.60 (m, 4H). Mass spectrum indicated m / z 349 (M + H).
Step 9: Attachment to Resin I: Preparation of Resin IX
According to the procedure outlined in the previous step 1, 3.13 g of the title compound of the above preparation was reacted with 3.73 g of resin I to give 5.19 g of polymer-bound hydroxamate as a tan polymeric solid. The theoretical load of the polymer was 0.86 mmol / g. FTIR microscopy showed bands at 1693 and 3332 cm ^-1 , indicating hydroxamate carbonyl and nitrogen-hydrogen stretch, respectively.
Step 10: Palladium catalysed reaction of resin IX with boronic acid: preparation of resin VII
An 8 mL glass solid phase reaction vessel was charged with resin IX (50 mg, 0.043 mmol). The resin was washed with dry dimethoxyethane (2 x 3 mL). 0.017 M solution of palladium tetrakis (triphenylphosphine) (0.6 mL, 0.01 mmol) was added to the vessel followed by a 0.6 M solution of boronic acid in 1: 1 dimethoxyethane / ethanol (0.6 mL, 0.36 mmol) A 2 M solution of potassium (0.4 mL, 0.8 mmol) was added. The solution was kept under argon pressure and heated at 90 &lt; 0 &gt; C for 16 hours. The solution was cooled to ambient temperature and the resin was filtered and washed with 1-methyl-2-pyrrolidinone, 1-methyl-2-pyrrolidinone / water (1: 1), water, , Methanol and methylene chloride (3 x 3 mL each solvent).
The following hydroxamic acid was synthesized from resin IX using the reaction conditions of step 10 with the exemplified boric acid and then cleaved from the polymer using the reaction conditions of step 3.

Example 233: Preparation of monomethanesulfonate salt: To a solution of N-hydroxy-4 - [[4- (phenylthio) phenyl] -sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide Meade, monomethanesulfonate
First manufacturing
Part A: A solution of the compound of Example 9, Part J (2.1 g, 4.5 mmol) in hot water (200 mL) at ambient temperature was treated with NaHCO₃ Lt; / RTI &gt; After stirring for 20 min, the resulting white solid was isolated by filtration, washed with water and dried in a vacuum oven at 37 [deg.] C to give the free base of the title compound (1.7 g, 86%) as a white solid. Analysis: C₂₁H₂₂N₂O₄S₂· O · 3% H₂Calculated for O: C, 57.86; H, 5.23; N, 6.43; S, 14.71. Found: C, 57.84; H, 4.96; N, 6.39; S, 14.89.
Part B: Methanesulfonic acid (0.28 mL, 4.1 mmol) was added to a solution of the free base of Part A (1.6 g, 3.7 mmol) in methanol (10 mL) at ambient temperature. After 3 h, the resulting solid was isolated by filtration, washed with methanol and dried in an oven at ambient temperature to give the monomethanesulfonic acid title compound (1.6 g, 81%) as a white solid. _{Analysis: C 21 H 22 N 2 O} 4 calculated in _{S 2 · CH 4 O 3:} C, 48.51; H, 5.18; N, 5.14; S, 17.66. Found: C, 48.88; H, 5.15; N, 5.23; S, 17.81.
Second Manufacturing
Methanesulfonic acid (0.91 mL, 14 mmol) was added to a solution of the protected hydroxamate of Example 9, Part A (6.0 g, 12 mmol) in methanol (37 mL) under a nitrogen atmosphere. After 1 hour, the precipitate was isolated by filtration, washed with methanol and dried in a vacuum oven at 40 &lt; 0 &gt; C for 1 day to give the title compound as a white solid (5.5 g, 89% Methanesulfonate The title compound is obtained.
Methanesulfonate salts of other cyclic amine compounds described herein can be similarly prepared using the above two preparation methods.
Examples 234-280:
The compounds of Examples 234-280 were prepared as described for the compounds of Examples 129-199.

Examples 281-288:
The following hydroxamic acid was synthesized from resin IX using step 10 with the exemplified boronic acid and then cleaved from the polymer using step 3 as previously described in examples 213-232.
Examples 289-294:
Step 11: Preparation of Resin XI
Resin IIIc (50 mg, 0.043 mmol) was placed in a reaction vessel in which the glass raw material was dissolved. Diisopropylethylamine (75 [mu] L, 0.43 mmol) was added after addition of a 0.43 M solution of isocyanate in 1-methyl-2-pyrrolidinone (1 mL, 0.43 mmol). The vessel was capped under nitrogen and stirred on a table top shaker and heated to 50 &lt; 0 &gt; C for 48 hours. Next, the vessel was cooled to ambient temperature, and the resin was filtered to obtain a mixture of 1-methyl-2-pyrrolidinone, 1: 1 1-methyl-2-pyrrolidinone / water, water, 1: 9 acetic acid / And washed with methylene chloride (3 x 1 mL each solvent).
The following hydroxamic acid was synthesized from resin IIIc using Step 11 with the exemplified isocyanate and then released from the polymer using the reaction conditions in Step 3.

Examples 295-300:
Step 12: Synthesis of Resin XII
Resin VII (50 mg, 0.038 mmol) and cesium carbonate (122 mg, 0.38 mmol) were placed in a reaction vessel in which the glass raw material was dissolved. Phenol in a 0.43 M solution in 1-methyl-2-pyrrolidinone (1 mL, 0.43 mmol) was added and the vessel was then capped under nitrogen. The reaction mixture was stirred on a table top shaker and heated to 50 &lt; 0 &gt; C for 48 hours. Next, the vessel was cooled to ambient temperature, and the resin was filtered to obtain a mixture of 1-methyl-2-pyrrolidinone, 1: 1 1-methyl-2-pyrrolidinone / water, water, 1: 9 acetic acid / And washed with methylene chloride (3 x 1 mL each solvent).
The following hydroxamic acid was synthesized from resin IIIc using Step 11 with the exemplified isocyanate and then released from the polymer using the reaction conditions in Step 3.
Examples 301-323:
Large-scale manufacture of resin Xa
The reaction vessel in which the glass raw material was dissolved was charged with 0.008 M solution of tetrakis- (triphenylphosphine) palladium (0) and resin IX (1 g, 0.86 mmol) in ethylene glycol dimethyl ether (5 mL, 0.04 mmol). 2-formylbenzeneboronic acid in a 1 M solution in a 1: 1 mixture of ethanol and ethylene glycol dimethyl ether (6 mL, 6 mmol) was added followed by 1 M cesium carbonate in water (2 mL, 2 mmol) . The vessel was sealed under argon and heated to 90 &lt; 0 &gt; C for 16 hours. After this, the vessel was cooled to ambient temperature and the resin was filtered and washed with solvents dimethylformamide, 1: 1 dimethylformamide / water, dimethylformamide, water, methanol and methylene chloride (3 x 5 mL each solvent) Respectively. The resin was dried in vacuo to give 1.025 g of product as a tan polymerizable solid. The theoretical load of the polymer was 0.84 mmol. TFA cleavage was performed on 35 mg of resin Xa as described in step 3 to yield 11.2 mg of a tan solid.
Large scale production of resin Xb
Preparation of Resin Xb was made in the same manner as described for the preparation of Resin Xa except that 3-formylbenzeneboronic acid was used in place of 2-formylbenzeneboronic acid. After drying under vacuum, the yield was 1.052 g of resin Xb as yellowish brown resin beads. The theoretical load of the polymer was 0.84 mmol / g. TFA cleavage was performed on 20 mg of resin Xb as described in step 3 to yield 6.5 mg of a tan solid.
Large-scale manufacture of resin Xc
The preparation of Resin Xc was the same as that described for the preparation of Resin Xa except that 4-formylbenzeneboronic acid was used in place of 2-formylbenzeneboronic acid. After drying under vacuum, the yield was 1.03 g of Resin Xc as yellowish brown resin beads. The theoretical load of the polymer was 0.84 mmol / g. TFA cleavage was performed on 28 mg of resin Xb as described in step 3 to yield 9.4 mg of a tan solid.
Step 13: Synthesis of Resin XIII
Resins Xa, Xb or Xc (50 mg, 0.042 mmol) were placed in a reaction vessel in which the glass raw material was dissolved. A 0.2 M solution of amine in trimethylorthoformate (1 mL, 0.2 mmol) was added and the vessel was capped under nitrogen. The reaction mixture was stirred on the table top shaker for 3 hours. Next, a 0.5 M solution of sodium triacetoxyborohydride in 1-methyl-2-pyrrolidinone (0.8 mL, 0.4 mmol) was added to the vessel and the mixture was further stirred for 40 hours. After this, the resin was filtered and washed with 1-methyl-2-pyrrolidinone, methanol, water, methanol and methylene chloride (3X1 mL each solvent) in this order.
The following hydroxamic acid was synthesized according to the procedure outlined in Step 13 using the exemplified resin-bound aldehyde and the exemplified amine and then released from the polymer using the reaction conditions in Step 3:

Large-scale manufacture of resin Xd
The preparation of Resin Xd was the same as that described for the preparation of Resin Xa except that 4-carboxybenzeneboronic acid was used instead of 2-formylbenzeneboronic acid. After drying under vacuum, the yield was 1.07 g of resin Xd as a yellowish polymerizable solid. The theoretical load of the polymer was 0.83 mmol / g. TFA cleavage was performed on 23.5 mg of resin Xd as described in step 3 to yield 4.9 mg of a tan solid.
Step 14: Synthesis of Resin XIV
Resin Xd (50 mg, 0.042 mmol) was placed in a reaction vessel in which the glass raw material was dissolved. The resin was washed with 1-methyl-2-pyrrolidinone (2 X 3 mL) and then treated with a solution of benzotriazol-1-yl-oxy-tris -Pyrrolidinophosphonium hexafluorophosphate was added followed by the addition of a 0.7 M solution of amine in 1-methyl-2-pyrrolidinone (0.3 mL, 0.21 mmol) and 1-methyl-2- A 1.0 M solution of diisopropylethylamine in Rardidinone (0.4 mL, 0.4 mmol) was added. The vessel was capped under nitrogen and the reaction mixture was stirred on a table top shaker for 24 hours. The resin was then filtered and washed with 1-methyl-2-pyrrolidinone (3 X 1 mL). A 1.0 M solution of benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate in 1-methyl-2-pyrrolidinone (0.2 mL, 0.2 mmol) Reaction with amine by addition of a 0.7 M solution of amine in pyrrolidinone (0.3 mL, 0.21 mmol) and a 1.0 M solution of diisopropylethylamine in 1-methyl-2-pyrrolidinone (0.4 mL, 0.4 mmol) . The vessel was capped under nitrogen and the reaction mixture was stirred on a table top shaker for 8 hours. Subsequently, the resin was filtered to obtain 1-methyl-2-pyrrolidinone, 1: 1 1-methyl-2-pyrrolidinone / water, water, 1: 9 acetic acid / water, methanol, methylene chloride ).
The following hydroxamic acid was synthesized according to the following procedure, summarized in Step 14, using Resin Xd and the exemplified amine, and then released from the polymer using the procedure in Step 3:

Amino] -1-piperidinyl] -phenyl] sulfonyl] tetrahydro-2H-pyran -4-carboxylic acid
Part A: To a solution of the product of Example 11 part B (10.0 g, 34.7 mmol) in 1-methyl-2-pyrrolidinone (70 mL) was added 4- (Nt-butoxycarbonylamino) piperidine g, 52.1 mmol) followed by the addition of diisopropylethylamine (6.0 mL, 34.7 mmol). The resulting mixture was heated to 80 &lt; 0 &gt; C for 24 hours and then cooled to ambient temperature. The crude mixture was poured into 700 mL water and the cloudy aqueous layer was extracted with ethyl acetate (3 X 150 mL). The combined organic layers were washed with 5% potassium hydrogen sulfate (2 X 150 mL) and brine (2 X 150 mL), dried over magnesium sulfate and concentrated in vacuo to give the crude ester as a solid foam (13.04 g, 78% Respectively.
Part B: To a solution of the ester of Part A (5.74 g, 11.9 mmol) in a mixture of ethanol (80 mL) and tetrahydrofuran (40 mL) was added 2 N sodium hydroxide (60 mL, 120 mmol). The resulting solution was heated to 60 &lt; 0 &gt; C for 1 hour and then cooled to ambient temperature. The solution was concentrated in vacuo and the residue partitioned between water (300 mL) and ethyl acetate (200 mL). The aqueous layer was separated and acidified to pH 2 with concentrated hydrochloric acid. The resulting white precipitate was collected by vacuum filtration and dried in vacuo to give the carboxylic acid (4.88 g, 88%) as a white solid foam.
Part C: To a suspension of carboxylic acid from Part B (4.88 g, 10.4 mmol) in methylene chloride (35 mL) was added trifluoroacetic acid (35 mL), resulting in the dissolution of the solid. After 15 minutes at ambient temperature, the solution was concentrated in vacuo. The product was titrated as diethyl ether to give an amino acid (4.92 g, 98%) as a grayish white solid.
Part D: A suspension of the amino acid from Part C (4.92 g, 10.21 mmol) in a mixture of 10% sodium carbonate / water (35 mL), water (100 mL) and dioxane (100 mL) was cooled with an ice bath. To the cooled suspension was added a solution of 9-fluorenylmethylsuccinimidyl carbonate (3.79 g, 11.23 mmol) in dioxane (50 mL). After the addition was complete, the ice bath was removed and the mixture was warmed to ambient temperature. After 1 h, the solution was concentrated in vacuo and the residue was partitioned between water (300 mL) and ethyl acetate (200 mL). The aqueous layer was separated and acidified to pH 2 with concentrated hydrochloric acid. The white precipitate formed was collected by vacuum filtration, washed with hexane and dried in vacuo to give the title compound (5.46 g, 91%) as a white solid.
Step 15: Preparation of Resin XVI.
Part A: Following the procedure outlined in step 1 above, the product of example 336 (2.4 g, 4.06 mmol) was reacted with resin I (1.7 g, 2.03 mmol) to give Resin XV (2.82 g) as a tan polymeric solid . The theoretical load of the polymer was 0.71 mmol / g.
Part B: Resin XV (2.76 g, 1.96 mmol) from above Part A was suspended in a 1: 4 piperidine / dimethylformamide solution (20 mL) in a reaction vessel in which the glass raw material had been dissolved and placed in a table top shaker Lt; / RTI &gt; The resin was filtered and a 1: 4 mixture of additional piperidine / dimethylformamide (20 mL) was added to the kettle. The slurry was stirred for 30 minutes at ambient temperature. Thereafter, the resin was filtered and washed with dimethylformamide, methanol and methylene chloride (3 x 20 mL each solvent). After drying in vacuo, the title compound was obtained as a yellowish polymeric solid (2.30 g).
Step 16: Acylation / sulfonylation of Resin XVI
Resin XVI (50 mg, 0.043 mmol) was washed with 1-methyl-2-pyrrolidinone (2 X 1 mL) in a reaction vessel in which the glass raw material was dissolved. Next, an acylating agent or a sulfonylating reagent of 0.22 M solution in 1-methyl-2-pyrrolidinone (1 mL, 0.22 mmol) was added to the resin, diisopropylethylamine (40 μL, 0.22 mmol) Respectively. The vessel was capped under nitrogen and stirred on a table top shaker at ambient temperature for 16 hours. Next, the resin was filtered and washed with 1-methyl-2-pyrrolidinone, water, 1: 9 acetic acid / water, methanol and methylene chloride (3 X 1 mL each solvent).
The following hydroxamic acid was synthesized from Resin XVI using Step 16 with the exemplified acylation or sulfonylation reagent and then released from the polymer using the reaction conditions in Step 3.

Examples 365-371:
Reductive alkylation of resin XVI
In a reaction vessel in which the glass raw material was dissolved, Resin XVI (50 mg, 0.043 mmol) was washed with methylene chloride (2 x 1 mL). Next, a 1 M solution of aldehyde or ketone in methylene chloride (1 mL, 1 mmol) was added to the resin. The vessel was capped under nitrogen and stirred on a table top shaker at ambient temperature for 3 hours. The resin was filtered and washed with methylene chloride (3 X 1 mL). The resin was then treated with resin in a 1 M solution of aldehyde or ketone in methylene chloride (1 mL, 1 mmol). The resin was filtered and washed with methylene chloride (3 x 1 mL each solvent). Subsequently, a 1 M solution of sodium triacetoxyborohydride in 1-methyl-2-pyrrolidinone (1 mL, 1 mmol) was added to the resin and the reaction was stirred overnight. After this time, the resin was filtered and washed with 1-methyl-2-pyrrolidinone, methanol, water, 1: 9 acetic acid / water, methanol and methylene chloride (3 x 1 mL each solvent).
The following hydroxamic acid was synthesized from Resin XVI using Step 17 with the aldehyde or ketone exemplified and then released from the polymer using the reaction conditions in Step 3.
Example 372: Preparation of 4 - [[4- (4-butoxyphenoxy) -phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide
To a solution of the product of example 55 (3.1 g, 8 mmol) in dimethylacetamide (20 mL) was added cesium carbonate (7.28 g, 24 mmol) and 4-butoxyphenol (2.66 g, 16 mmol) Was added. The slurry was stirred at 95 &lt; 0 &gt; C for 19 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexane) gave TFP hydroxamate (3.96 g, 93%) which was substituted as a grayish white foam. HRMS (ES +) M + NH 4 +: C 27 H 35 N 1 O 8 calculated value of S ₁ F: 551.24, Found: 551.24.
Part B: To a solution of THP hydroxamate (3.9 g, 7.3 mmol) from Part A in 1,4-dioxane (20 mL) was added 4 N HCl dioxane solution (20 mL) and methanol Respectively. After 15 minutes at ambient temperature, the reaction was diluted with ethyl acetate, washed with water, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexanes) to give the title compound (2.75 g, 84%) as a white solid. HRMS (ES &lt; + &gt;) M + H ⁺ C ₂₂ H ₂₇ N ₁ O ₇ S ₁ : 450.16, found 450.16.
Example 373: Preparation of tetrahydro-N-hydroxy-4 - [[4- [3- (trifluoromethyl) phenoxy] phenyl] -sulfonyl] -2H-pyran-4-carboxamide
Part A: To a solution of the product of Example 55 (3.1 g, 8 mmol) in dimethylacetamide (20 mL) was added cesium carbonate (7.28 g, 24 mmol) and m- (trifluoromethyl) , 16 mmol). The slurry was stirred at 95 &lt; 0 &gt; C for 19 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. THP hydroxamate (4.1 g, 97%) was obtained as a white foam by chromatography (silica phase, ethyl acetate / hexane). HRMS (ES &lt; + &gt;) M + H ⁺ C ₂₄ H ₂₆ N ₁ O ₇ S ₁ F ₃ : 530.15, found 530.14.
Part B: To a solution of THP hydroxamate (3.9 g, 7.4 mmol) from Part A in 1,4-dioxane (20 mL) was added 4 N HCl dioxane solution (20 mL) and methanol Respectively. After 15 minutes at ambient temperature, the reaction was diluted with ethyl acetate, washed with water, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexanes) to give the title compound (1.9 g, 58%) as a white solid. HRMS (ES &lt; + &gt;) M + H ^{+ Calcd for} C ₁₉ H ₁₈ N ₁ O ₆ S ₁ F ₃ : 446.09, found 446.09.
Example 374: Preparation of tetrahydro-N-hydroxy-4 - [[4- [4- (methylthio) phenoxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide
To a solution of the product of example 55 (3.1 g, 8 mmol) in dimethylacetamide (20 mL) was added cesium carbonate (7.28 g, 24 mmol) and 4- (methylthio) phenol mmol). The slurry was stirred at 95 &lt; 0 &gt; C for 24 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. THP hydroxamate (4.1 g, 100%) was obtained as a white foam by chromatography (silica phase, ethyl acetate / hexane). HRMS (ES &lt; + &gt;) M + H ⁺ C ₂₄ H ₂₉ N ₁ O ₇ S ₂ : 508.15, found 508.15.
Part B: To a solution of THP hydroxamate (4.0 g, 7.9 mmol) from Part A in 1,4-dioxane (20 mL) was added 4N HCl dioxane solution (20 mL) and methanol Respectively. After 15 minutes at ambient temperature, the reaction was diluted with ethyl acetate, washed with water, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexane) to give the title compound (1.9 g, 57%) as a white solid. HRMS (ES &lt; + &gt;) M + H ^{+ Calcd for} C ₁₉ H ₂₁ N ₁ O ₆ S ₂ : 424.09, found 424.09.
Example 375: Preparation of tetrahydro-N-hydroxy-4 - [[4- [4- (phenylmethyl) phenoxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide
To a solution of the product of example 55 (2.7 g, 7 mmol) in dimethylacetamide (15 mL) was added cesium carbonate (6.84 g, 21 mmol) and 4-hydroxydiphenylmethane (2.8 g, 14 mmol) mmol). The slurry was stirred at 95 &lt; 0 &gt; C for 19 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexanes) afforded THP hydroxamate (3.7 g, 96%) which was substituted as a pale yellow foam. HRMS (ES +) M + H + C 30 H 33 N 1 O 7 calculated in S _1: 552.21, Found: 552.21.
Part B: To a solution of THP hydroxamate (3.5 g, 6.4 mmol) from Part A in 1,4-dioxane (16 mL) was added 4N HCl dioxane solution (16 mL) and methanol (16 mL) Respectively. After 15 minutes at ambient temperature, the reaction was diluted with ethyl acetate, washed with water, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexanes) to give the title compound (1.95 g, 67%) as a white solid. HRMS (ES &lt; + &gt;) M + H ^{+ Calcd for} C ₂₅ H ₂₅ N ₁ O ₆ S ₁ : 468.15, found 468.15.
Example 376: Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-hydroxyphenoxy) phenyl] sulfonyl] -2H-pyran-4-carboxamide
To a solution of the product of Example 55 (2.7 g, 7 mmol) in dimethylacetamide (20 mL) was added cesium carbonate (6.84 g, 21 mmol) and 4- (benzyloxy) phenol mmol). The slurry was stirred at 95 [deg.] C for 6 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. THP hydroxamate (3.94 g, 99%) was obtained as a white foam by chromatography (silica phase, ethyl acetate / hexane). HRMS (ES +) M + NH 4 + C 30 H 33 N calculated value of ₁ O ₈ S _1: 585.23, Found: 585.23.
Part B: To a solution of THP hydroxamate (1.5 g, 2.64 mmol) from Part A in glacial acetic acid (5 mL) was added concentrated HCl (5 mL) and the reaction was heated to 60 C for 20 min. The reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate. It washed three times with the ethyl acetate extract with water, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexanes) to give the title compound (810 mg, 78%) as a white solid. HRMS (ES +) M + NH 4 + C 18 H 19 N 1 O 7 calculated in S _1: 468.15, Found: 468.15.
Example 377: Synthesis of tetrahydro-N-hydroxy-4 - [[4- [4 - [(1- methylethyl) thio] phenoxy] -phenyl] -sulfonyl] -2H- Manufacturing
Part A: 2-Iodopropane (7.0 g, 41 mmol) was added to a suspension of 4-hydroxythiophenol (5.0 g, 40 mmol) and potassium carbonate (8.0 g, 58 mmol) in dimethylformamide . The slurry was stirred at ambient temperature for 1 hour. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed twice as water, washed with 10% hydrochloric acid solution, brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexanes) gave the substituted phenol (5.1 g, 76%) as a clear colorless oil.
To a solution of the product of example 55 (3.1 g, 8 mmol) in dimethylacetamide (20 mL) was added cesium carbonate (7.28 g, 24 mmol) and phenol from part A (2.7 g, 16 mmol) Was added. The slurry was stirred at 95 &lt; 0 &gt; C for 15 h. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. THP hydroxamate (4.15 g, 97%) was obtained as a white foam by chromatography (silica phase, ethyl acetate / hexane). HRMS (ES &lt; + &gt;) M + H ^{+ Calcd for} C ₂₆ H ₃₃ N ₁ O ₇ S ₂ : 536.18, found: 538.17.
To a solution of THP hydroxamate (3.9 g, 7.3 mmol) from Part A in 1,4-dioxane (18 mL) was added 4 N HCl dioxane solution (18 mL) and methanol (18 mL) Respectively. After 15 minutes at ambient temperature, the reaction was diluted with ethyl acetate, washed with water, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexanes) to give the title compound (2.32 g, 71%) as a grayish white solid. HRMS (ES +) M + H + C 21 H 25 N 1 O 6 S 2 Calculated for: 452.12, Found: 452.12.
Example 378: Preparation of tetrahydro-N-hydroxy-4 - [[4- [4- (1-methylethoxy) phenoxy) -phenyl] sulfonyl] -2H-pyran-4-carboxamide
Potassium carbonate (8.3 g, 60 mmol) and 2-iodopropane (5 mL, 50 mmol) were added to a solution of benzoic acid, 4-hydroxyphenyl ester (8.57 g, 40 mmol) in dimethylacetamide ). The slurry was stirred at 60 &lt; 0 &gt; C for 1 hour. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed three times as water, washed with brine, isopropoxy compound (9.7 g, 95%) was dried by Na ₂ SO _4, filtered, and concentrated under vacuum to a pale gray solid .
Part B: A 2.5 N sodium hydroxide solution (26 mL, 65 mmol) was added to a slurry of isopropoxy compound (9.7 g, 38 mmol) from Part A in 1,4-dioxane (20 mL) Was added. The slurry was stirred at 60 &lt; 0 &gt; C for 4 hours. The reaction was cooled and 6 N hydrochloric acid solution was added until pH = 5. The reaction was extracted with methylene chloride. Was the organic layer was washed four times with ammonium hydroxide solution 5%, washed with water, brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo to give the phenol (5.4 g, 94%) as an orange oil .
To a solution of the product of example 55 (3.1 g, 8 mmol) in dimethylacetamide (20 mL) was added cesium carbonate (7.28 g, 24 mmol) and phenol from part B (2.4 g, 16 mmol) Was added. The slurry was stirred at 95 &lt; 0 &gt; C for 21 hours. The reaction was concentrated in vacuo. Washing the residue dissolved in ethyl acetate and with water three times, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexanes) afforded THP hydroxamate (3.65 g, 88%) which was substituted as a grayish white foam. HRMS (ES &lt; + &gt;) M + H ^{+ Calcd for} C ₂₆ H ₃₃ N ₁ O ₈ S ₁ : 520.20, found 520.20.
Part D: To a solution of THP hydroxamate (3.5 g, 6.7 mmol) from Part C in 1,4-dioxane (17 mL) was added 4N HCl dioxane solution (17 mL) and methanol Respectively. After 15 minutes at ambient temperature, the reaction was diluted with ethyl acetate, washed with water, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexanes) to give the title compound (2.2 g, 80%) as a grayish white solid. HRMS (ES &lt; + &gt;) M + H ⁺ C ₂₁ H ₂₅ N ₁ O ₇ S ₁ : 436.14, found 436.14.
Example 379: Preparation of tetrahydro-N-hydroxy-4 - [[4- [4 - [(trifluoromethyl) phenoxy] -phenyl] sulfonyl] -2H-pyran-4-carboxamide
Part A: In a dry apparatus under nitrogen, sodium hydroxide (60% oil dispersion) (11.0 g, 0.275 mol) was added to a solution of 4- [4- (trifluoromethyl) phenoxy ] -Phenol &lt; / RTI &gt; (50.0 g, 0.197 mol) in THF. After 15 minutes, a solution of dimethylthiocarbamoyl chloride (32.0 g, 0.259 mol) in dry dimethylformamide (100 mL) was added. The reaction was stirred at ambient temperature for 16 hours. The reaction was poured into 10% hydrochloric acid solution (1 L). The resulting precipitate was vacuum filtered to give the thione compound (67.0 g, 100%) as a white solid.
Part B: The thiono compound from Part A (70 g, 0.2 mol) was safely shielded and heated to 317 [deg.] C for 3 min. The reaction was exothermic to 330 ° C. The heat was removed and the reaction was cooled to ambient temperature to give thiocarbamate (70 g, 100%) as a brown solid.
Part C: To a solution of thiocarbamate (65.0 g, 0.19 moles) from Part B in methanol (510 mL) with a nitrogen stream under surface was added 2.5 N aqueous sodium hydroxide solution (160 mL, 0.4 mol). The slurry was stirred for 2 h at 74 &lt; 0 &gt; C. The reaction was cooled and the methanol was removed in vacuo. The residue was diluted with water (100 mL) and extracted four times with diethyl ether. Nitrogen sub-surface stream was added to the aqueous solution and sodium chloroacetate (22.2 g, 0.19 mol) was added. The reaction was stirred at ambient temperature and after 30 minutes the nitrogen stream was removed. After 12 hours, the solution was cooled and 6 N hydrochloric acid was added until pH = 1. The slurry was extracted four times with ethyl acetate. The combined ethyl acetate extracts washed with 0.1 N hydrochloric acid, water, brine, dried with Na ₂ SO _4, filtered, and was concentrated in vacuo to give the thio acid (61.0 g, 98%) as a tan solid.
Part D: To a solution of thioacetic acid (54.45 g, 0.166 mol) from Part C in tetrahydrofuran (370 mL) was added water (45 mL) and Oxone (306 g, 0.498 mol) Respectively. It was found that heat was generated up to 42 캜. After 2 hours, the reaction was filtered, the cake was washed well with tetrahydrofuran and water (250 mL) was added to the filtrate. The filtrate was concentrated in vacuo. The slurry was extracted four times with ethyl acetate. Washed three times with water The combined extracts were washed with brine, dried over MgSO _4, filtered and to give the sulfone (60.0 g, 100%) as a beige solid and concentrated under vacuum.
Part E: A solution of the sulfone (119.52 g, 0.332 mol) from Part D in methanol (660 mL) and 4 N hydrochloric acid in dioxane solution (20 mL) was stirred for 12 hours at ambient temperature. The reaction was heated to boiling and slowly cooled to ambient temperature. The resulting crystals were filtered, washed well with cold methanol and dried to give methyl ester (89.4 g, 72%) as a white solid.
Part F: To a solution of the methyl ester from Part E (64.5 g, 0.180 moles) in dimethylacetamide (360 mL) was added potassium carbonate (66.8 g, 0.48 mol), bis- (2- bromoethyl) ether , 0.305 mol), 4-dimethylaminopyridine (1.1 g, 9 mmol) and tetrabutylammonium bromide (2.9 g, 9 mmol). The reaction was stirred at ambient temperature overnight. The reaction was slowly poured into 1 N HCl (500 mL). The resulting precipitate was filtered, washed with water and then with hexane. The solid was recrystallized from methanol to give the pyran compound (62.8 g, 79%) as a white solid. MS (ES +) M + NH 4 + C 20 H 19 O 56 calculated in S ₁ F _3: 462.12, Found: 462.12.
Part G: In a nitrogen-free drying apparatus, the pyran compound (64.0 g, 0.144 mol) from Part F was dissolved in dry tetrahydrofuran (250 mL) and potassium trimethylsilonate (55.9 g, &lt; / RTI &gt; 0.432 mol) was added at ambient temperature. After 2 hours, water (200 mL) was added and the solution was concentrated in vacuo. The slurry was extracted with ethyl acetate to remove unreacted starting material. The aqueous solution was treated with 6 N HCl until pH = 1 and the combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was heated in diethyl ether and the resulting solid was filtered and dried to give carboxylic acid (56.3 g, 91%) as a white solid. MS (ES +) M + NH ₄ ⁺ C ₁₉ H ₁₇ O ₆ S ₁ F ₃ : 448.10, found 448.10.
Part H: In a nitrogen-free drying apparatus, the carboxylic acid (49.0 g, 0.144 mol) from Part G was dissolved in dry dimethylformamide (280 mL) and the remaining reagents were added to the solution in the following order: (37.5 mL, 0.342 mol), O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (41.3 g, 0.353 mol), N-methylmorpholine , And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (30.6 g, 0.160 mol). After 4 h at ambient temperature, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, water, 5% KHSO _4, saturated NaHCO _3, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo as a white foam THP hydroxide roksa formate (62.6 g, 100%). HRMS (ES +) M + NH 4 + C 24 H 26 NO 7 Calculated for S ₁ F _3: 547.17, Found: 547.17.
Part I: To a solution of THP hydroxamate (58.5 g, 0.11 mol) from Part H in 1,4-dioxane (280 mL) was added 4N HCl dioxane solution (280 mL) and methanol Respectively. After 15 minutes at ambient temperature, the reaction was diluted with ethyl acetate, washed with water, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexane) to give the title compound (42.79 g, 87%) as a white solid. HRMS (ES +) M + NH 4 + C 19 calculated in the _{H 18 NO 6 S 1 F 3} : 463, Found: 463.
Example 380: Preparation of 4 - [[4 - ([1,1'-biphenyl] -4-yloxy] phenyl) sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide
Part A: To a solution of the product of Example 55 (2.0 g, 5.2 mmol) in dimethylacetamide (8 mL) was added 4-phenylphenol (Aldrich, 1.3 g, 7.8 mmol) followed by cesium carbonate , 20.8 mmol). The reaction was heated at 95 [deg.] C for 5 hours. The dimethylacetamide was removed in vacuo to give a brown solid (5.3 g, quant.). Chromatography (reverse phase, C-18, acetonitrile / water) gave the THP protected biphenyl product in solution.
Part B: To THP protected biphenyl product collected from A in acetonitrile / water (50 mL) was slowly added 10% HCl _aq (100 mL). After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (2.0 g, 83%). MS (FAB) calcd for C ₂₄ H ₂₃ NO ₆ S M ⁺ H: 454, found: 454.
Example 381: Preparation of tetrahydro-N-hydroxy-4 - [[4- [[4- (trifluoromethyl) phenyl] thio] phenyl] -sulfonyl] -2H-pyran-4-carboxamide
Part A: To a solution of the product of Example 55 (2.0 g, 5.2 mmol) in dimethylacetamide (6 mL) was added 4-trifluoromethylthiophenol (Maybridge, 2.0 g, 11.2 mmol) (2.9 g, 20.8 mmol). The reaction was heated at 65 [deg.] C for 12 hours. Dimethyl acetamide was removed in vacuo to give a brown solid (6.5 g, quant.). Chromatography (reverse phase, C-18, acetonitrile / water) gave the THP protected trifluoromethyl product in solution.
Part B: To a solution of the crude THP protected trifluoromethyl product collected from A in acetonitrile / water (40 mL) was slowly added 10% HCl _aq (100 mL). After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a tan solid (0.75 g, 31%). MS (FAB) Calcd for C ₁₉ H ₁₈ FNO ₅ S ₂ M ⁺ H: 462, found 462.
Example 382: Synthesis of tetrahydro-N-hydroxy-4 - [[4- [4 - [(trifluoromethyl) thio] phenoxy] phenyl] -sulfonyl] -2H- Produce
Part A: 4- (Trifluoromethylthio) thiophenol (Aldrich, 1.5 g, 7.8 mmol) was added to a solution of the product of Example 55 (2.0 g, 5.2 mmol) in dimethylacetamide (6 mL) Cesium carbonate (6.8 g, 20.8 mmol) was added. After the addition of a catalytic amount of potassium fluoride, the reaction was heated at 95 DEG C for 12 hours. Dimethyl acetamide was removed in vacuo to give a brown solid (7.2 g, quant.). Chromatography (reverse phase, C-18, acetonitrile / water) gave the THP protected trifluoromethyl thio product in solution.
Part B: To a solution of the crude THP protected trifluoromethylthio product collected from A in acetonitrile / water (40 mL) was slowly added 10% HCl _aq (100 mL). After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a tan solid (0.60 g, 24%). MS (FAB) M ^- H: Calcd for C ₁₉ H ₁₈ FNO ₆ S ₂ : 476, found 476.
Example 380: Synthesis of 4 - [[4- [4-chloro-3- (trifluoromethyl) phenoxy] phenyl] sulfonyl-tetrahydro-N-hydroxy-2H- Produce
Part A: To a solution of the product of Example 55 (2.0 g, 5.2 mmol) in dimethylacetamide (6 ml) was added 4-chloro-3-trifluoromethylphenol (Avocado, 1.5 g, 7.8 mmol) , Cesium carbonate (6.8 g, 20.8 mmol) were added. The reaction was heated at 95 [deg.] C for 12 hours. Removal of dimethylacetamide in vacuo yielded a brown solid (7.6 g, quant.). Chromatography (reverse phase, C-18, acetonitrile / water) gave the THP protected product in solution.
Part B: To a solution of the crude THP protected product from A in acetonitrile / water (40 ml) was slowly added 10% aqueous HCl (100 ml). After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (0.92 g, 37%). MS (FAB) M ⁺ H Calcd for C ₁₉ H ₁₇ ClF ₃ NO ₆ S: 480, found 480.
Example 384: Preparation of 4 - [[4- [4- (1,1-dimethylethyl) -phenoxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide
Part A: To a solution of the product of Example 55 (5.0 g, 12.9 mmol) in dimethylacetamide (25 ml) was added 4-t-butylphenol (Avocado, 2.9 g, 19.4 mmol) followed by cesium carbonate (20.4 g, 20.8625 mmol). The reaction was heated at 95 [deg.] C for 12 hours. Removal of dimethylacetamide in vacuo yielded a brown solid (9.4 g, quant.). Chromatography (reverse phase, C-18, acetonitrile / water) gave the THP protected product in solution.
Part B: To a solution of the crude THP protected product from A in acetonitrile / water (60 ml) was slowly added 10% aqueous HCl (100 ml). After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (0.28 g, 5%). ^{MS (FAB) M + H:} C 22 calculated in the H ₂₇ NO ₆ S: 434, Found: 434.
Example 385: Preparation of 4 - [[4- [3,5-bis (trifluoromethyl) phenoxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide
Part A: To a solution of the product of Example 55 (3.0 g, 7.7 mmol) in dimethylacetamide (15 ml) was added 3,5-ditrifluoromethylphenol (2.9 g, 19.4 mmol) (20.4 g, 20.8625 mmol) was added. The reaction was heated at 95 [deg.] C for 12 hours. Removal of dimethylacetamide in vacuo yielded a brown solid (14.7 g, quant.). Chromatography (reverse phase, C-18, acetonitrile / water) gave the THP protected product in solution.
Part B: To a solution of the crude THP protected product from A in acetonitrile / water (60 ml) was slowly added 10% aqueous HCl (100 ml). After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (1.2 g, 31%). ^{MS (FAB) M + H:} C 20 H 17 F 6 NO calcd for ₆ S: 514, Found: 514.
Example 386: Synthesis of tetrahydro-N-hydroxy-4 - [[4- [3-methyl-4- (1- methylethyl) phenoxy] phenyl] -sulfonyl] -2H- Manufacturing
Part A: To a solution of the product of Example 55 (4.0 g, 10.3 mmol) in dimethylacetamide (20 ml) was added 4-isopropyl-3-methylphenol (Aldirch, 2.3 g, 15.5 mmol) Carbonate (16.8 g, 51.5 mmol). The reaction was heated at 95 [deg.] C for 12 hours. Removal of dimethylacetamide in vacuo yielded a brown solid (18.3 g, quant.). Chromatography (reverse phase, C-18, acetonitrile / water) gave the THP protected product in solution.
Part B: To a solution of the crude THP protected product from A in acetonitrile / water (40 ml) was slowly added 10% aqueous HCl (100 ml). After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a tan solid (1.8 g, 40%). ^{MS (FAB) M - H:} C 22 H 27 F 3 Calculated for NO ₆ S: 432, Found: 432.
Example 387: Synthesis of tetrahydro-N-hydroxy-4 - [[4 - [(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin- ] Oxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide
Part A: To a solution of the product of Example 55 (5.0 g, 12.9 mmol) in dimethylacetamide (25 ml) was added 2,2,3,3-tetrafluoro-6-hydroxybenzodioxene (Oakwood, 4.3 g , 19.4 mmol) followed by the addition of cesium carbonate (21.0 g, 64.5 mmol). The reaction was heated at 95 [deg.] C for 5 hours. Removal of dimethylacetamide in vacuo yielded a brown solid (11.3 g, quant.). Chromatography (reverse phase, C-18, acetonitrile / water) gave the THP protected product in solution.
Part B: To the collected THP protected product from A in acetonitrile / water (50 ml) was slowly added 10% aqueous HCl (100 ml). After stirring overnight (about 18 hours), the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (3.5 g, 54%). ^{MS (FAB) M - H:} C 20 H 17 F 4 Calcd of NO ₈ S: 506, Found: 506.
Example 388: N-Hydroxy-1- [2- (4-morpholinyl) -ethyl] -4 - [[4- [4- (trifluoromethyl) phenoxy] Preparation of 4-piperidinecarboxamide, dihydrochloride
Part A: To a suspension of 4-bromopiperidine hydrobromide (107.0 g, 0.436 mol) in tetrahydrofuran (11) was added slowly triethylamine (122 ml, 0.872 mol) followed by di-tert- butyl Dicarbonate (100 g, 0.458 mol) was added, which was added in several portions. The resulting mixture was stirred at ambient temperature for 22 hours, then filtered and concentrated in vacuo. The solid was washed with hexanes and then collected by filtration to give Boc-piperidine compound as an amber oil (124 g, &gt; 100%).
Part B: The _{Cs 2 CO 3 (159 g,} 0.488 mol) to a solution of phenol (50.0 g, 0.390 mol) of 4-fluoro degassed with N _2, acetone (400 ml) was added. The resulting mixture was degassed with N ₂ for 5 minutes, the blood was added to Part A Boc- piperidine compound (85.9 g, 0.325 mol). The resulting mixture was stirred at ambient temperature for 18 hours and then filtered through a pad of the brand name Celite, washing with acetone. The filtrate was concentrated in vacuo to give the sulfide as a yellowish brown residue (98.5 g, 97%).
Part C: To a solution of the sulfide (8.00 g, 25.7 mmol) in Part B in dichloromethane (90 ml) and methanol (15 ml) was added in two portions monoperoxyphthalic acid magnesium salt hexahydrate (19.1 g, 38.6 mmol) Was added. The resulting mixture was stirred at ambient temperature for 1.5 hours and then filtered. Washing the filtrate with saturated NaHCO _3, then washed with saturated NaCl. The combined aqueous layers were extracted with dichloromethane (100 ml). Drying the combined organic layers over Na ₂ SO ₄ and then concentrated in vacuo. The resulting solid was washed with hexane and then dissolved in dichloromethane and filtered through a pad of the brand name Celite, washing with dichloromethane. The filtrate was concentrated in vacuo and recrystallized from ethyl acetate to give the sulfone (4.45 g, 50%) as a white crystalline solid.
Part D: N, N- dimethylformamide in (40 ml) solution of sulfone _{Cs 2 CO 3 (19.9 g,} 61.2 mmol) and α, α, α- trifluoromethyl of (7.00 g, 20.4 mmol) of Part C -p-cresol (3.97 g, 24.5 mol). The resulting mixture was heated at &lt; RTI ID = 0.0 &gt; 80 C &lt; / RTI &gt; After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The resulting residue was treated with H ₂ O and the solid was collected by filtration. The solid was then washed with hexane and then washed with methanol to give biaryl ether (8.60 g, 87%) as a tan solid.
Part E: To a solution of the nonaryl ether of Part D (8.59 g, 17.7 mmol) in tetrahydrofuran (100 ml) cooled to 0 ° C was added lithium bis (trimethyl Silyl) amide (22.0 ml, 1.0 M in tetrahydrofuran, 22.0 mmol) was slowly added. The resulting mixture was stirred for 1 hour at 0 ° C and then a solution of methyl chloroformate (2.05 ml, 26.6 mmol) in tetrahydrofuran (5.0 ml) was slowly added at a rate such that the temperature of the reaction mixture did not exceed 4 ° C Was added. After the addition was complete, the mixture was slowly warmed to ambient temperature. The addition of saturated NH ₄ Cl (50 ml), followed by removal of tetrahydrofuran under vacuum. Water (50 ml) was added to the residue and the residue was extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl, dried over Na ₂ SO _4. Recrystallization from methanol gave methyl ester (7.66 g, 80%) as a pale yellow crystalline solid.
Part F: To a solution of the methyl ester of Part E (7.66 g, 14.1 mmol) in dioxane (30 ml) and methanol (10 ml) was added a solution of 4N HCl in dioxane (10 ml, 40 mmol). After stirring for 2 h at ambient temperature, additional 4 N HCl in dioxane (10 ml, 40 mmol) was added. After stirring for 2.5 h at ambient temperature, the reaction mixture was concentrated in vacuo to give the amine as a grayish white solid (6.80 g, &gt; 100%).
Part G: K ₂ CO ₃ (3.46 g, 25.0 mmol), 4- (2-chloroethyl) morpholine hydrochloride (1.22 g, g, 6.56 mmol) and a catalytic amount of NaI. The resulting mixture was heated at reflux for 22 hours. After cooling to ambient temperature, the reaction mixture was filtered through a pad of the brand name Celite while washing with ethyl acetate. The filtrate was concentrated in vacuo to give morpholine ethylamine (3.45 g, &gt; 100%) as a tan solid.
Part H: Potassium trimethylsilanolate (1.60 g, 12.50 mmol) was added to a solution of morpholine ethylamine (3.45 g, 6.25 mmol) in Part G in tetrahydrofuran (60 ml). After stirring for 25 h at ambient temperature, H ₂ O was added. The reaction mixture was then neutralized with 1N HCl (pH 7). The tetrahydrofuran was removed in vacuo and the resulting precipitate was collected by filtration and washed with diethyl ether to give an amino acid (2.87 g, 85%) as a grayish white solid.
Part I: To a suspension of the amino acid of Part H (2.87 g, 5.29 mmol) in dichloromethane (25 ml) was added N-methylmorpholine (1.74 ml, 15.9 mmol), O- (tetrahydrofuranyl) hydroxylamine g, 5.82 mmol) and the trade name PyBroP (2.96 g, 6.35 mmol). After stirring at ambient temperature for 19 h, N-methylmorpholine (0.872 ml, 7.94 mmol), O- (tetrahydrofuranyl) hydroxylamine (0.310 g, 2.65 mmol) and the trade name PyBroP (1.48 g, 3.17 mmol ) Was added. The resulting mixture was stirred at ambient temperature for 3 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and H ₂ O. The organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, methanol / chloroform) gave protected hydroxamate (2.62 g, 77%) as a grayish white solid.
Part J: To a solution of the protected hydroxamate of Part I (2.62 g, 4.08 mmol) in dioxane (9 ml) and methanol (3 ml) was added a solution of 4N HCl in dioxane (10 ml, 40.0 mmol) did. The resulting mixture was stirred at ambient temperature for 2 hours and then diethyl ether (20 ml) was added. The resulting solid was collected by filtration to give the title compound (2.31 g, 90%) as a grayish white solid. MS MH ^& lt ^{; + &} gt ^; : C ₂₅ H ₃₁ O ₆ N ₃ Calculated for SF ₃ : 558, found 558.
Example 389: N-Hydroxy-1- (4-pyridinylmethyl) -4 - [[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide Meade, dihydrochloride
Part A: To a suspension of the amine of part F of Example 388 (1.50 g, 3.13 mmol) in acetonitrile (10 ml) was added K ₂ CO ₃ (1.73 g, 12.5 mmol) and 4-picolyl chloride hydrochloride , 3.44 mmol). After stirring for 21.5 hours at reflux, the reaction mixture was filtered through a pad of the brand name Celite while washing with ethyl acetate. The filtrate was concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexane) gave picolylamine (1.44 g, 86%) as clear gum.
Part B: To a solution of picolylamine (1.44 g, 2.69 mmol) in Part A in tetrahydrofuran (20 ml) was added potassium trimethylsilanolate (0.690 g, 5.38 mmol). The resulting mixture was stirred at ambient temperature for 20 hours, then N ₂ was blown onto the reaction mixture to remove the tetrahydrofuran. Water (8 ml) was added and the reaction mixture was neutralized with 2N HCl (pH 7). The resulting precipitate was collected by filtration to give an amino acid (1.31 g, 94%) as a white solid.
Part C: To a suspension of the amino acid of Part B (1.31 g, 2.52 mmol) in N, N-dimethylformamide (10 ml) was added 1- hydroxybenzotriazole (0.408 g, 3.02 mmol), N- methylmorpholine (0.476 g, 3.78 mmol) and 1-3 - [(dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.867 g, 7.56 mmol), O- (tetrahydrofuranyl) hydroxylamine 3.53 mmol). The resulting mixture was stirred at ambient temperature for 3 days and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The combined organic layers were washed with saturated NaHCO ₃ , then with saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (silica phase, ethyl acetate / hexane) gave protected hydroxamate (1.24 g, 79%) as a white foam.
Part D: To a solution of the protected hydroxamate of Part C (1.24 g, 2.00 mmol) in dioxane (6 ml) and methanol (2 ml) was added a solution of 4N HCl in dioxane (5.00 ml, 20.0 mmol) did. After stirring at ambient temperature for 2.5 hours, the reaction mixture was concentrated in vacuo. The resulting foam was then re-treated with a solution of 4N HCl in dioxane (3 ml) for 15 minutes, then diethyl ether was added and the resulting precipitate was collected by filtration to give a grayish white solid To give the title compound (1.04 g, 85%). MS MH ^& lt ^{; + &} gt ^; : C ₂₅ H ₂₅ O ₅ N ₃ Calculated for SF ₃ : 536, found 536.
Example 390: Synthesis of N-hydroxy-1- (3-pyridinylmethyl) -4 - [[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide Meade, dihydrochloride
Part A: To a suspension of the amine of Example 38 part F (1.00 g, 2.08 mmol) in acetonitrile (10 ml) was added K ₂ CO ₃ (1.15 g, 8.33 mmol) and 3-picolyl chloride hydrochloride , 2.29 mmol). After stirring for 12 h at reflux, the reaction mixture was filtered through a pad of brand name Celite while washing with ethyl acetate. The filtrate was concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexane) gave picolylamine (0.740 g, 67%) as a pale yellow foam.
Part B: Potassium trimethylsilanolate (0.355 g, 2.77 mmol) was added to a solution of picolylamine (0.740 g, 1.38 mmol) in Part A in tetrahydrofuran (10 ml). The resulting mixture was stirred at ambient temperature for 17 hours, then potassium trimethylsilanolate (0.044 g, 0.343 mmol) was further added and the resulting mixture was stirred for 2 hours at ambient temperature. N ₂ was bubbled through the reaction mixture to remove the tetrahydrofuran. Water (5 ml) was added and the reaction mixture was neutralized with 2N HCl (pH 7). The resulting precipitate was collected by filtration and concentrated to dryness in vacuo with acetone to give the amino acid (0.700 g, 97%) as a grayish white solid.
Part C: To a suspension of the amino acid of Part B (0.700 g, 1.34 mmol) in N, N-dimethylformamide (10 ml) was added 1-hydroxybenzotriazole (0.218 g, 1.61 mmol) (0.360 g, 2.01 mmol) and 1-3 - [(dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.442 ml, 4.02 mmol) 1.88 mmol). The resulting mixture was stirred at ambient temperature for 23 hours and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The combined organic layers were washed with H ₂ O, saturated NaHCO ₃ , saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (silica phase, ethyl acetate / hexane) gave protected hydroxamate (0.500 g, 60%) as a grayish white foam.
Part D: To a solution of the protected hydroxamate of Part C (0.500 g, 0.807 mmol) in dioxane (1.5 ml) and methanol (0.5 ml) was added a solution of 4N HCl in dioxane (3.0 ml, 12.00 mmol) did. After stirring at ambient temperature for 2 hours, ethyl ether was added and the resulting precipitate was collected by filtration to give the title compound (0.363 g, 74%) as a yellow solid. MS MH ^& lt ^{; + &} gt ^; : C ₂₅ H ₂₅ O ₅ N ₃ Calculated for SF ₃ : 536, found 536.
Example 391: Synthesis of N-hydroxy-1- (2-pyridinylmethyl) -4 - [[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide Meade, dihydrochloride
Part A: To a suspension of the amine of Example 388 Part F (1.26 g, 2.63 mmol) in acetonitrile (10 ml) was added K ₂ CO ₃ (1.45 g, 10.5 mmol) and 2-picolyl chloride hydrochloride , 2.89 mmol). After stirring for 12 h at reflux, the reaction mixture was filtered through a pad of brand name Celite while washing with ethyl acetate. The filtrate was concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexane) gave picolylamine (1.40 g, 99%) as an amber oil.
Part B: To a solution of picolylamine (1.40 g, 2.62 mmol) in Part A in tetrahydrofuran (20 ml) was added potassium trimethylsilanolate (0.672 g, 5.24 mmol). The resulting mixture was stirred at ambient temperature for 15 hours. N ₂ was bubbled through the reaction mixture to remove the tetrahydrofuran. Water (5 ml) was added and the reaction mixture was neutralized with 2N HCl (pH 7). The resulting precipitate was collected by filtration and concentrated to dryness in vacuo with acetonitrile to give amino acid (1.07 g, 79%) as a grayish white solid.
To a suspension of the amino acid of Part B (1.07 g, 2.06 mmol) in N, N-dimethylformamide (10 ml) was added 1-hydroxybenzotriazole (0.333 g, 2.47 mmol), N- methylmorpholine 3-ethylcarbodiimide hydrochloride (0.553 g, 3.09 mmol) and O- (tetrahydrofuranyl) hydroxylamine (0.369 g, 2.88 mmol). The resulting mixture was stirred at ambient temperature for 19 hours and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The combined organic layers were washed with H ₂ O, saturated NaHCO ₃ , saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (silica phase, methanol / dichloromethane) afforded protected hydroxamate (1.03 g, 81%) as a white solid.
Part D: To a solution of the protected hydroxamate of Part C (1.03 g, 1.66 mmol) in dioxane (3.0 ml) and methanol (1.0 ml) was added a solution of 4N HCl in dioxane (3.0 ml, 12.00 mmol) did. After stirring at ambient temperature for 1.5 hours, diethyl ether was added and the resulting precipitate was collected by filtration to give the title compound (0.970 g, 96%) as a pale pink solid. MS MH ^& lt ^{; + &} gt ^; : C ₂₅ H ₂₅ O ₅ N ₃ Calculated for SF ₃ : 536, found 536.
Example 392: Preparation of N-hydroxy-4 - [[4 - [(4-methoxyphenyl) amino] phenyl] sulfonyl] -4-piperidinecarboxamide, monohydrochloride
Part A: exemplary _{Cs 2 CO 3 (0.990 g,} 3.04 mmol), BINAP (0.061 g, 0.098 mmol), tris (di-benzylidene acetone) to the ester (1.00 g, 2.17 mmol) of Example 91 Part C dipal lithium ( O) (0.060 g, 0.07 mmol), p-anisidine (0.320 g, 2.60 mmol) and toluene (4 ml). The resulting mixture was heated to 100 &lt; 0 &gt; C for 22 hours. After cooling to ambient temperature, the reaction mixture was filtered through a pad of brand name Celite while diethyl ether was added and washed with ethyl acetate. The filtrate was concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexane) gave aniline (0.810 g, 74%) as an orange foam.
Part B: Potassium trimethylsilanolate (0.238 g, 1.86 mmol) was added to a solution of Part A aniline (0.780 g, 1.55 mmol) in tetrahydrofuran (4.0 ml). The resulting mixture was stirred at ambient temperature for 17 hours and then additional potassium trimethylsilanolate (0.020 g, 0.1955 mmol) was added. After stirring for 24 hours at ambient temperature, potassium trimethylsilanolate (0.040 g, 0.310 mmol) was added. After stirring for 26 hours at ambient temperature, N ₂ was blown on the mixture to remove the solvent. N-Methylmorpholine (0.511 ml, 4.65 mmol) and O- (tetrahydrofuranyl) hydroxylamine (0.218 g, 1.86 mmol) were added to a suspension of the residue in dichloromethane (10 ml) (1.08 g, 2.33 mmol). The resulting mixture was stirred at ambient temperature for 2 days and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The combined organic layers were washed with saturated NaCl, dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate / hexane) gave protected hydroxamate (0.600 g, 66%) as a grayish white solid.
Part C: To a solution of the protected hydroxamate of Part B (0.580 g, 0.984 mmol) in dioxane (3 ml) and methanol (1 ml) was added a solution of 4N HCl in dioxane (2.5 ml, 10.0 mmol) did. The resulting mixture was stirred at ambient temperature for 1 hour and then diethyl ether (10 ml) was added. The solid was collected by filtration to give the title compound (0.437 g, 100%) as a white solid. _{^{MS MH +: C 19 H 24}} O 5 N ₃ S of the calculated: 406, found: 406.
Example 393: Preparation of N-hydroxy-4 - [[4 - [[4- (trifluoromethoxy) phenyl] amino] phenyl] sulfonyl] -4-piperidinecarboxamide, monohydrochloride
Part A: performed in a solution of the ester (3.27 g, 7.09 mmol) of Example 91 Part _{C Cs 2 CO 3 (3.23 g} , 9.92 mmol), BINAP (0.066 g, 0.107 mmol), tris (di-benzylidene acetone) (0.065 g, 0.071 mmol), 4-trifluoro-methoxyaniline (1.15 ml, 8.51 mmol) and toluene (14 ml) were added. The resulting mixture was heated to 100 &lt; 0 &gt; C for 22 hours. After cooling to ambient temperature, the mixture was washed with ethyl acetate and filtered through a pad of brand name Celite, and the filtrate was concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexane) afforded aniline (3.59 g, 91%) as a tan solid.
Part B: Potassium trimethylsilanolate (0.331 g, 2.58 mmol) was added to a solution of Part A aniline (1.03 g, 1.84 mmol) in tetrahydrofuran (10 ml). The resulting mixture was stirred at ambient temperature for 24 hours and then additional potassium trimethylsilanolate (0.118 g, 0.092 mmol) was added. After stirring at ambient temperature for 24 hours, N ₂ was blown on the mixture to remove the solvent. Water was added and the reaction mixture was acidified with 1N HCl (pH 3). Extract the aqueous reaction mixture with ethyl acetate, drying the combined organic layers with sat. NaCl and dried over Na ₂ SO _4. Concentration in vacuo afforded the acid as a tan solid (1.01 g, 100%).
Part C: To a suspension of the acid of Part B (1.00 g, 1.84 mmol) in N, N-dimethylformamide (10 ml) was added 1-hydroxybenzotriazole (0.298 g, 2.21 mmol), N-methylmorpholine 0.607 ml, 5.52 mmol), O- (tetrahydrofuranyl) hydroxylamine (0.323 g, 2.76 mmol) and 1-3 - [(dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride 2.58 mmol). The resulting mixture was stirred at ambient temperature for 17 hours and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The combined organic layers were washed with H ₂ O, saturated NaHCO ₃ , saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (silica phase, ethyl acetate / hexane) gave protected hydroxamate (0.960 g, 81%) as a white solid.
Part D: To a solution of Part C protected hydroxamate (0.960 g, 1.49 mmol) in dioxane (3 ml) and methanol (1 ml) was added a solution of 4N HCl in dioxane (4.0 ml, 16.0 mmol) did. The resulting mixture was stirred at ambient temperature for 2.5 hours. The solvent was then removed by bubbling N ₂ over the reaction mixture. Diethyl ether (20 ml) was added and the precipitate was collected by filtration to give the title compound as a pale pink solid (0.716 g, 100%). _{^{MS MH +: C 19 H 21}} O 5 Calculated for N ₃ SF _3: 460, Found: 460.
Example 394: Synthesis of N-hydroxy-1- (2-methoxyethyl) -4 - [[4 - [[4- (trifluoromethoxy) phenyl] amino] phenyl] sulfonyl] -4- Preparation of carboxamide, monohydrochloride
Part A: To a solution of the aniline (2.55 g, 4.57 mmol) from Example 392 Part A in dioxane (9.0 ml) and methanol (3.0 ml) was added a solution of 4N HCl in dioxane (10 ml, 40 mmol) did. After stirring for 2 h at ambient temperature, the reaction mixture was concentrated in vacuo to give the amine (2.36 g, &gt; 100%) as a tan solid.
Part B: K ₂ CO ₃ (1.26 g, 9.09 mmol) and 2-bromoethyl methyl ether (0.313 ml, 3.33 mmol) were added to a suspension of the amine of Part A (1.50 g, 3.03 mmol) in acetonitrile (12 ml) Was added. After stirring at reflux for 23 hours, Cs ₂ CO ₃ was added (2.96 g, 9.09 mmol). After 6 h at reflux, the reaction mixture was filtered through a pad of the brand name Celite, washing with dichloromethane. The filtrate was concentrated in vacuo. Chromatography (silica phase, methanol / dichloromethane) provided methoxyethylamine (1.13 g, 72%) as a tan solid.
Part C: Potassium trimethylsilanolate (0.561 g, 4.38 mmol) was added to a solution of the methoxyethylamine of Part B (1.13 g, 2.19 mmol) in tetrahydrofuran (20 ml). The resulting mixture was stirred at ambient temperature for 18 hours and then potassium trimethylsilanolate (0.140 g, 1.09 mmol) was further added. After stirring for 5 hours at ambient temperature, N ₂ was bubbled through the mixture to remove the tetrahydrofuran. Water (8 ml) was added and the reaction mixture was neutralized with 1N HCl (pH 7). The solid was collected by filtration and concentrated to dryness under vacuum with acetonitrile to give the amino acid as a grayish solid (0.900 g, 82%).
Part D: To a suspension of Part C amino acid (0.900 g, 1.79 mmol) in N, N-dimethylformamide (8.0 ml) was added 1-hydroxybenzotriazole (0.290 g, 2.15 mmol) 0.580 ml, 5.37 mmol), O- (tetrahydrofuranyl) hydroxylamine (0.315 g, 2.69 mmol) and 1-3 - [(dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride 2.51 mmol). The resulting mixture was stirred at ambient temperature for 16 hours and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The combined organic layers were washed with H ₂ O, saturated NaHCO ₃ , saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (silica phase, methanol / dichloromethane) provided protected hydroxamate (0.870 g, 81%) as a grayish white solid.
Part E: To a solution of the protected hydroxamate (0.870 g, 1.45 mmol) in Part D in dioxane (3 ml) and methanol (1 ml) was added a solution of 4N HCl in dioxane (10 ml, 40.0 mmol) did. The resulting mixture was stirred at ambient temperature for 2.0 hours. The reaction mixture was concentrated in vacuo and then treated again with 4N HCl (3 ml) for 30 min. The solvent was then removed by bubbling N ₂ over the reaction mixture. Diethyl ether (30 ml) was added and the precipitate was collected by filtration to give the title compound as a pale pink solid (0.771 g, 96%). _{^{MS MH +: C 22 H 27}} O 6 Calculated for N ₃ SF _3: 518, Found: 518.
Example 395: Preparation of N-hydroxy-4 - [[4 - [[4- (trifluoromethoxy) phenyl] amino] phenyl] sulfonyl] -4-piperidinecarboxamide, monohydrochloride
Part A: performed in a solution of the ester (3.16 g, 6.85 mmol) of Example 91 Part _{C Cs 2 CO 3 (3.13 g} , 9.59 mmol), BINAP (0.064 g, 0.103 mmol), tris (di-benzylidene acetone) (0.063 g, 0.069 mmol), α, α, α-trisfluoro-methylaniline (1.03 ml, 8.22 mmol) and toluene (14 ml) were added. The resulting mixture was heated to 100 &lt; 0 &gt; C for 17 hours. After cooling to ambient temperature, the mixture was washed with dichloromethane and filtered through a pad of brand name Celite, and the filtrate was concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexane) gave aniline (3.08 g, 83%) as a pale orange foam.
Part B: Potassium trimethylsilanolate (0.473 g, 3.69 mmol) was added to a solution of Part A aniline (1.00 g, 1.84 mmol) in tetrahydrofuran (10 ml). The resulting mixture was stirred at ambient temperature for 25 hours, then N ₂ was blown on the mixture to remove the solvent. Water was added and the reaction mixture was acidified with 1 N HCI (pH 3). The aqueous layer was extracted with ethyl acetate, washed the combined organic layers with sat. NaCl and dried over Na ₂ SO _4. Concentration in vacuo afforded the acid (1.00 g, &gt; 100%) as an orange foam.
Part C: To a suspension of the acid of Part B (0.972 g, 1.84 mmol) in N, N-dimethylformamide (10 ml) was added 1-hydroxybenzotriazole (0.298 g, 2.21 mmol), N-methylmorpholine 0.607 ml, 5.52 mmol), O- (tetrahydrofuranyl) hydroxylamine (0.323 g, 2.76 mmol) and 1-3 - [(dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride 2.58 mmol). The resulting mixture was stirred at ambient temperature for 18 hours and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The combined organic layers were washed with H ₂ O, saturated NaHCO ₃ , saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (silica phase, ethyl acetate / hexane) gave protected hydroxamate (0.970 g, 84%) as a white solid.
Part D: To a solution of Part C protected hydroxamate (0.950 g, 1.51 mmol) in dioxane (3 ml) and methanol (1 ml) was added a solution of 4N HCl in dioxane (4.0 ml, 16.0 mmol) did. The resulting mixture was stirred at ambient temperature for 1.5 hours. Diethyl ether (20 ml) was added and the precipitate was collected by filtration to give the title compound as a white solid (0.630 g, 87%). _{^{MS MH +: C 19 H 21}} O 4 Calculated for N ₃ SF _3: 444, Found: 444.
Example 396: Synthesis of N-hydroxy-1- (2-methoxyethyl) -4 - [[4 - [[4- (trifluoromethyl) phenyl] amino] phenyl] sulfonyl] -4- Preparation of carboxamide, monohydrochloride
Part A: To a solution of the aniline (2.07 g, 3.82 mmol) from Example 395 Part A in dioxane (9.0 ml) and methanol (3.0 ml) was added a solution of 4 N HCl in dioxane (10 ml, 40 mmol) Was added. After stirring for 2 h at ambient temperature, the reaction mixture was concentrated in vacuo to give the amine as a yellow solid (1.89 g,> 100%).
Part B: K ₂ CO ₃ (1.58 g, 11.46 mmol) and 2-bromoethyl methyl ether (0.395 ml, 4.20 mmol) were added to a suspension of the amine of Part A (1.83 g, 3.82 mmol) in acetonitrile (12 ml) Was added. After stirring for 18 hours at reflux, the reaction mixture was filtered through a pad of the brand name Celite, washing with dichloromethane and the filtrate was concentrated in vacuo. Chromatography (silica phase, methanol / dichloromethane) afforded methoxyethylamine (1.58 g, 83%) as a grayish white solid.
Part C: To a solution of Part B methoxyethylamine (1.58 g, 3.15 mmol) in tetrahydrofuran (30 ml) was added potassium trimethylsilanolate (0.810 g, 6.31 mmol). The resulting mixture was stirred for 3 days at ambient temperature and then N ₂ was blown on the mixture to remove the solvent. Water (10 ml) was added and the reaction mixture was neutralized with 1 N HCI (pH 7). The solid was collected by filtration and concentrated to dryness in vacuo with acetonitrile to give the amino acid as a pink solid (1.32 g, 86%).
Part D: To a suspension of Part C amino acid (1.32 g, 2.71 mmol) in N, N-dimethylformamide (12 ml) was added 1-hydroxybenzotriazole (0.439 g, 3.25 mmol) (0.727 g, 4.07 mmol) and 1-3 - [(dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.894 ml, 8.13 mmol), O- (tetrahydrofuranyl) hydroxylamine 3.79 mmol). The resulting mixture was stirred at ambient temperature for 20 hours and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The combined organic layers were washed with H ₂ O, saturated NaHCO ₃ , saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (silica phase, methanol / ethyl acetate) provided protected hydroxamate (1.39 g, 88%) as a grayish white solid.
Part E: To a solution of the protected hydroxamate (1.40 g, 2.39 mmol) in Part D in dioxane (3 ml) and methanol (1 ml) was added a solution of 4N HCl in dioxane (5.98 ml, 23.9 mmol) did. The resulting mixture was stirred for 2.5 hours at ambient temperature. The reaction mixture was dried by blowing N ₂ over the reaction mixture. Diethyl ether (25 ml) was added and the precipitate was collected by filtration. The resulting solid was dissolved in methanol (1 ml) and treated with 4N HCl in dioxane (1.5 ml). After stirring at ambient temperature for 1.5 h, the reaction mixture was slowly added to diethyl ether (50 ml). The resulting precipitate was collected by filtration to give the title compound as a grayish white solid (1.08 g, 84%). _{^{MS MH +: C 22 H 27}} O 5 Calculated for N ₃ SF _3: 502, Found: 502.
Example 397: Preparation of ethyl 1- (2-methoxyethyl) -3-phenylpropoxy) phenyl] sulfonyl] -4-piperidinecarboxylate
Part A: A solution of methoxyethylamine, ethyl-4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidinecarboxylate (1.5 g, 4.0 mmol), 3-phenyl-1-propanol (2.2 ml, 16 mmol) and K ₂ CO ₃ (2.2 g, 16 mmol) was heated at 135 ° C for 1 day at 125 ° C for 3 days. The mixture was concentrated in vacuo, then diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate and concentrated in vacuo to give a crude oil. The oil was purified by flash chromatography (20:80 hexanes / ethyl acetate) to give the ether as a brown oil (1.35 g, 67%).
Part B: A mixture of the ether of Part A (1.3 g, 2.7 mmol) and a 50% aqueous NaOH solution (2.1 g, 27 mmol), EtOH (23 ml) and H ₂ O (12 ml) in THF Lt; RTI ID = 0.0 &gt; 60 C &lt; / RTI &gt; for a period of time. The material was concentrated in vacuo and triturated with diethyl ether to give a solid. The solids were dissolved in water, cooled with an ice bath and acidified with concentrated hydrochloric acid. The precipitate was separated by filtration, washed with cold water and dried at ambient temperature in a vacuum oven for 3 days to give crude acid.
(1.1 g), N-hydroxybenzotriazole (0.36 g, 2.7 mmol), 4-methylmorpholine (0.74 ml, 6.7 mmol) and O-tetrahydro- A mixture of 2H-pyran-2-yl-hydroxylamine (0.39 g, 3.3 mmol) and 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride (0.60 g, 3.1 mmol) And stirred at ambient temperature under a nitrogen atmosphere. The mixture was concentrated in vacuo and dissolved in a solution of saturated NaHCO ₃ (90 ml), ethyl acetate (25 ml) and a few drops of 2 N NaOH. The aqueous layer was extracted with further ethyl acetate. The combined ethyl acetate layer was saturated NaHCO ₃ solution, washed with water and brine. After drying over magnesium sulphate, the filtrate was concentrated in vacuo to give a dark yellow oil. The oil was purified by flash chromatography (40:60 acetonitrile / toluene) to give the protected hydroxamate as a yellow oil (0.32 g, 25%). MS MH ^& lt ^{; + &} gt ^; : Calcd for C ₂₉ H ₄₀ N ₂ O ₇ S: 561, found 561.
Part C: To a solution of the protected hydroxamate (0.28 g, 0.50 mmol) in Part 2B in methanol (4.0 ml) was added acetyl chloride (0.11 ml, 1.5 mmol) and the solution was stirred at ambient temperature Lt; / RTI &gt; The solution was diluted with diethyl ether and concentrated. The solid was triturated with diethyl ether and dried in a vacuum oven at 40 &lt; 0 &gt; C to give the title compound as a grayish white solid (0.15 g, 20%). _{^{MS MH +: C 24 H 32}} N 2 O ₆ S of the calculated: 477, found: 477.
Example 398: Preparation of 1-cyclopropyl-N-hydroxy-4 - [[4- (2-phenoxyethoxy) phenyl] sulfonyl] -4-piperidinecarboxamide, monohydrochloride
Part A: To a solution of the product of part E of part 9 (14.36 g, 40 mmol) in methanol (50 ml) was added acetic acid (24.5 g, 400 mmol), a 4 A molecular sieve -Oxytrimethylsilane (25.8 ml, 148 mmol) and sodium cyanoborohydride (7.05 g, 112 mmol) were added. The solution was heated at reflux for 8 hours. The precipitated solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with H ₂ O (400 ml) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, and dried over MgSO ₄ filtered, and concentrated in vacuo. The solid was filtered and washed with H ₂ O / diethyl ether to give the desired cyclopropylamine {ethyl-4 - [(4-fluorophenyl-sulfonyl)] - 1 -cyclopentane as a white solid (11.83 g, 81.5% Propyl-4-piperidinecarboxylate}. MH ⁺ MS: calcd for C ₁₇ H ₂₂ NO ₄ SF: 356, Found: 356.
Part B: A solution of Part A cyclopropylamine (2.0 g, 5.6 mmol), ethylene glycol phenyl ether (2.8 ml, 23 mmol), and cesium carbonate (7.3 g, 23 mmol) in DMAC (10 ml) Lt; RTI ID = 0.0 &gt; 125-135 C &lt; / RTI &gt; for 18 hours under a nitrogen atmosphere. The mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, dried over magnesium sulfate, concentrated in vacuo, dissolved in diethyl ether, precipitated as hydrochloride salt and dried in a vacuum oven at 40 &lt; 0 &gt; C. The solids were dissolved in a mixture of water, acetonitrile and ethanol and the pH was adjusted to 12 with 1 N NaOH solution. The mixture was concentrated in vacuo to remove ethanol and acetonitrile. The solid was separated by filtration, washed with water and dried in a vacuum oven at 50 &lt; 0 &gt; C to give the ether as a white solid (1.8 g, 68%). MS ^+: C ₂₅ H ₃₁ NO ₆ S Calcd of: 474, found: 474. Analysis: C ₂₅ H ₃₁ NO ₆ S Calcd for: C, 63.40; H, 6.60; N, 2.96; S, 6.77, found: C, 63.35; H, 6.59, N, 2.99; S, 6.61.
Part C: A mixture of the ether of Part B (1.8 g, 3.7 mmol) and a 50% aqueous NaOH solution (3.0 g, 37 mmol), EtOH (32 ml) and H ₂ O (16 ml) in THF (32 ml) Lt; RTI ID = 0.0 &gt; 60 C &lt; / RTI &gt; for a period of time. The material was concentrated in vacuo and triturated with diethyl ether to give a solid. The tan solid was dissolved in a mixture of water, ethanol and THF, the pH adjusted to 3 with concentrated hydrochloric acid, concentrated in vacuo, triturated with water and dried in a vacuum oven at 50 C to give crude crude solid (2.3 g, ).
(2.3 g), N-hydroxybenzotriazole (1.9 g, 14 mmol), 4-methylmorpholine (1.6 ml, 14 mmol), O-tetra (1.1 g, 9.4 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.7 g, 14 mmol) in DMF Lt; / RTI &gt; and stirred at ambient temperature under a nitrogen atmosphere for one day. The mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic layer was washed with 1 N NaOH solution, water, and brine, dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography (20:80 to 40:60 ethyl acetate / toluene) to yield a white solid 0.43 g, 21%) to give the protected hydroxamate. _{^{MS MH +: C 28 H 36}} N 2 O 7 S Calcd of: 545, found: 545. _{Analysis: C 28 H 36 N 2 O} 7 S Calcd for: C, 61.74; H, 6.66; N, 5.14; S, 5.89, found: C, 61.72; H, 6.75; N, 5.06; S, 5.91
The aqueous layer was acidified to pH 3, and the solid was collected by filtration and dried to separate additional compound to give a white solid (0.80 g).
Part D: Protected hydroxamate (0.80 g, 1.5 mmol) from Part C was added to an ambient temperature solution of acetyl chloride (0.31 ml, 4.4 mmol) in methanol (11 ml) under a nitrogen atmosphere. After stirring for 2.5 h, the precipitate was collected by filtration, washed with diethyl ether and dried in a vacuum oven at 45 <0> C to give the title compound as a white solid (0.58 g, 79%). _{MS MH +: C 23 H 28} N ₂ O ₆ S of the calculated: 461, found: 461. _{Analysis: C 23 H 28 N 2 O} 6 Calcd for and S 1.5HCl: C, 53.62; H, 5.77; N, 5.44; S, 6.22, found: C, 53.47; H, 5.79; N, 5.41; S, 6.16
Example 399: Synthesis of hydroxy-1- (3-pyridinylmethyl) -4 - [[4- [4- (trifluoromethoxy) phenoxy] phenyl [sulfonyl] -4-piperidinecarboxamide, Preparation of dihydrochloride
Part A: An amine hydrochloride salt of the product of Example 410 (2.4 g, 4.6 mmol), 3-picolyl chloride (1.5 g, 8.8 mmol) and potassium carbonate (4.3 g, 31 mmol) in DMF (12 ml) Was heated at 50 &lt; 0 &gt; C for 1 day under a nitrogen atmosphere. The mixture was concentrated in vacuo, dissolved in water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (50: 50 ethyl acetate / hexanes) to give 3-picolylamine (1.6 g, 60%) as an amber oil. MS MH &lt; + &gt;: Calcd for C ₂₇ H ₂₇ N ₂ O ₆ SF ₃ : 565, found 565. Analysis: C ₂₇ H ₂₇ N ₂ O ₆ Calculated for SF ₃ : C, 57.44; H, 4.82; N, 4.96; S, 5.68, found: C, 57.49; H, 5.10; N, 4.69; S, 5.67
Part B: 3-Picolylamine (1.5 g, 2.6 mmol) and a 50% aqueous solution of NaOH (2.1 g, 26 mmol), EtOH (22 ml) and H ₂ O (11 ml) in Part 4A in THF Was heated at 65 &lt; 0 &gt; C under a nitrogen atmosphere for 24 h. The material was concentrated in vacuo and triturated with diethyl ether to give a solid. The tan solid was dissolved in water and the pH was adjusted to 1 with concentrated hydrochloric acid. The mixture was concentrated in vacuo and dried in a vacuum oven at 45 &lt; 0 &gt; C to give a crude white solid (2.5 g). MS MH &lt; + &gt;: C ₂₅ H ₂₃ N ₂ O ₆ Calculated for SF ₃ : 537, found 537
Part C: N-Hydroxybenzotriazole (1.0 g, 7.7 mmol), 4-methylmorpholine (0.64 ml, 7.7 mmol), Part B crude white acid (2.5 g) in DMF (40 ml) (0.60 g, 5.1 mmol) and 1- (3-dimethyl-aminopropyl) -3-ethylcarbodiimide hydrochloride (1.5 g, 7.7 mmol ) Was stirred for 5 days at ambient temperature under a nitrogen atmosphere. The mixture was concentrated in vacuo, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography (5:95 methanol / chloroform) to give the protected hydroxamate as a white foam (1.1 g, 66%). MS MH &lt; + &gt;: C ₃₀ H ₃₂ N ₃ O ₇ Calculated for SF ₃ : 636, found 636.
Part D: An ambient temperature solution of acetyl chloride (0.34 ml, 4.7 mmol) and protected hydroxamate (1.0 g, 1.6 mmol) in Part C in methanol (11 ml) was stirred under a nitrogen atmosphere for 2.5 h, Pour into ethyl ether. The solid was separated by filtration and dried in a vacuum oven at 46 &lt; 0 &gt; C to give the title compound as a white solid (0.85 g, 87%). _{Analysis: C 25 H 24 N 3 O} 6 SF ₃ and the calculated 2.2HCl: C, 47.53; H, 4.18; N, 6.65; S, 5.08, found: C, 47.27; H, 4.34; N, 6.60; S, 5.29. MS MH &lt; + &gt;: C ₂₅ H ₂₄ N ₃ O ₆ Calculated for SF ₃ : 552, found 552.
Example 400: Synthesis of N-hydroxy-4- [4- (4-methoxyphenoxy) phenyl] sulfonyl] -1- (2-pyridinylmethyl) -4-piperidinecarboxamide, dihydrochloride Manufacturing
Part A: Potassium carbonate (2.48 g, 19 mmol) and N, N-dimethylformamide were added to a stirred solution of ethyl 4 - [(4-fluorophenylsulfonyl)] - 4-piperidinecarboxylate hydrochloride (2.02 g, 5.76 mmol) N-dimethylformamide (12 ml). 2-Picolylhydrochloride (1.0 g, 6.1 mmol) was added and the mixture was stirred at 40 &lt; 0 &gt; C for 24 h. The reaction mixture was diluted with water (80 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over magnesium sulfate, concentrated and chromatographed (ethyl acetate) to give the desired pyridine ester as an oil (2.30 g, quant.).
Part B: Pyridine ethyl ester (2.30 g, 5.76 mmol) from Part A was added to a solution of potassium carbonate (1.29 g, 9 mmol), 4-methoxyphenol (1.12 g, 9.0 mmol) and N, N-dimethylformamide 3 ml), and the mixture was heated at a temperature of 75 to 80 캜 for 24 hours. Additional 4-methoxyphenol (300 mg) and potassium carbonate (350 mg) were added and the mixture was stirred at 90 &lt; 0 &gt; C for additional 3 hours. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over magnesium sulfate and concentrated to give the desired ester as an oil (2.85 g, quant.) By chromatography.
Part C: The ester of Part B (2.85 g) was mixed with ethanol (18 ml), water (6 ml) and potassium hydroxide (2.24 g, 40 mmol). The mixture was refluxed and heated for 4.5 hours. Cooled to 0 占 폚, and acidified with concentrated hydrochloric acid water. The solvent was removed and the resulting solid was azeotropically dried with acetonitrile. Vacuum was maintained until the weight was constant.
The crude acid hydrochloride was treated with N-methylmorpholine (1 ml), 1-hydroxybenzotriazole (0.945 g, 7 mmol), O-tetrahydropyranylhydroxylamine (0.82 g, 7 mmol) and Was stirred with N, N-dimethylformamide (21 ml). After 10 minutes, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.34 g, 7 mmol) was added and the mixture was stirred overnight. The reaction was then diluted with semi-saturated aqueous sodium bicarbonate (100 ml) and extracted with ethyl acetate (200 ml, then 50 ml). The combined organic layers were dried over magnesium sulfate, concentrated and chromatographed (9: 1 ethyl acetate: hexane) to give O-tetrahydropyranyl protected hydroxamate (2.82 g, 88%) as a yellow oil.
Part D: O-tetrahydropyranyl protected hydroxamate (2.82 g, 5 mmol) in Part C was diluted with methanol (20 ml). Acetyl chloride (2.1 ml, 30 mmol) was added over 2 min. The reaction was stirred at ambient temperature for 4 hours and then concentrated to give 2.59 g of crude dihydrochloride salt which was recrystallized from ethanol / water to give 525 mg (18%) of the title hydroxamate . ^{MS (EI) MH +: C} 25 H 27 N calculated in ₃ O ₆ S: 498, Found: 498.
Example 401: Preparation of N-hydroxy-4- [4- (4-cyclohexylthio) phenyl] sulfonyl] -1- (2-methoxyethyl) -4-piperidinecarboxamide, hydrochloride
Part A: Ethyl-4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidinecarboxylate (5.5 g, 14 mmol) was added to powdered potassium carbonate g, 20 mmol), N, N-dimethylformamide (7 ml) and cyclohexylmercaptan (2.4 ml, 20 mmol) and stirred at ambient temperature for 2 days. The temperature was raised from 45 캜 to 50 캜 and stirring was continued for 24 hours. Additional potassium carbonate (1.0 g) and cyclohexylmercaptan (1.0 ml) were introduced and the reaction was heated for an additional 16 h. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (100 ml, then 25 ml). The combined organic layers were dried, concentrated and chromatographed (ethyl acetate) to give the desired sulfide (3.59 ml, 53%) as a yellow oil.
Part B: Sulfide from Part A (3.59 gm, 7.4 mmol) was saponified followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride coupling (Example 401, Part C To yield 2.16 g (54%) of the desired tetrahydropyranyl protected hydroxamate as an oil.
Part C: Tetrahydropyranyl protected hydroxamate of Part B (2.16 g, 4 mmol) was diluted with methanol (16 ml). Acetyl chloride (1.1 ml, 16 mmol) was added over 1 min. The reaction was stirred for 4 hours, then concentrated and azeotroped with acetonitrile to give 1.11 g of crude product which was recrystallized from pure ethanol to give 804 mg of the title compound. ^{MS (EI) MH +: C} 21 H 32 N 2 O 5 Calcd of S _2: 457, Found: 457.
Example 402: Preparation of N-Hydroxyl-1- (2-methoxyethyl) -4 - [[(phenylmethoxy) phenyl] -sulfonyl] -4-piperidinecarboxamide
Part A: Ethyl-4 - [(4-fluorophenylsulfonyl)] - 1- (2- methoxyethyl) -4-piperidinecarboxylate (1.58 g, 4.5 mmol) was added to powdered potassium carbonate g, 18 mmol), N, N-dimethylformamide (5 ml) and benzyl alcohol (1.94 ml, 18 mmol) and stirred at 140 ° C for 16 hours. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (125 ml, then 25 ml). The combined organic layers were dried, concentrated and chromatographed (ethyl acetate) to give the desired ethyl ester (1.16 ml, 56%) as a roy oil.
Part B: The ethyl ester from Part A (1.16 gm, 2.5 mmol) was saponified and then coupled with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride coupling To afford the desired tetrahydropyranyl-protected hydroxamate as an oil (880 mg, 80%).
Part C: Tetrahydropyranyl protected hydroxamate (880 mg, 2.0 mmol) of Part B was diluted with methanol (8 ml). Acetyl chloride (0.68 ml, 10 mmol) was added over 1 min. The reaction was stirred for 3 hours and then concentrated and azeotroped with acetonitrile to give the crude product which was then added with enough saturated aqueous sodium hydrogen carbonate (25 ml) to neutralize the hydrogen chloride, Extract with ethyl acetate (100 ml, then 50 ml) and convert to the free base. The organic phase was dried with magnesium sulfate, concentrated and chromatographed (9: 1 dichloromethane: methanol, 1% ammonium hydroxide) to give the desired hydroxamate (327 mg, 36%) as free. ^{MS (EI) MH +: C} 22 H 28 N 2 O 6 S Calcd of: 447, Found: 447.
Example 403: Preparation of N-hydroxy-1- (1-methylethyl) -4 - [[4- (2-phenylethoxy) phenyl] sulfonyl] -4-piperidinecarboxamide
Part A: Ethyl-4 - [(4-fluorophenylsulfonyl)] - 1- (1-methylethyl) -4-piperidinecarboxylate (2.75 g, 7.7 mmol) was added to powdered potassium carbonate , 19 mmol), N, N-dimethylformamide (10 ml) and 2-phenylethanol (2 ml, 19 mmol) and stirred at 85 ° C for 24 hours. Additional potassium carbonate (1.3 g) and 2- = phenylethanol were added and the temperature was raised to 110 [deg.] C for 48 hours and then to 125 [deg.] C for 4 hours. The mixture was diluted with water (100 ml) and extracted with ethyl acetate (200 ml, then 25 ml). The combined organic layers were dried, concentrated and chromatographed (ethyl acetate) to give the desired ethyl ester (3.19 ml, 90%) as an oil.
Part B: The ethyl ester from Part A (3.19 gm, 6.9 mmol) was saponified and then coupled with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride coupling To afford the title compound as an oil, 2.27 g (64%). &Lt; RTI ID = 0.0 &gt;
Part C: Tetrahydropyranyl protected hydroxamate (2.27 mg, 4.4 mmol) of Part B was diluted with methanol (16 ml). Acetyl chloride (0.68 ml, 10 mmol) was added over 1 min. The reaction was stirred for 3 hours and then concentrated and azeotroped with acetonitrile to give the crude product which was then added with enough saturated aqueous sodium hydrogen carbonate (25 ml) to neutralize the hydrogen chloride, Extraction with ethyl acetate (100 ml, then 50 ml) and conversion to the free base. The organic phase was dried over magnesium sulfate, concentrated and chromatographed (819 mg, 42%) as a free glass with chromatography (9: 1 dichloromethane: methanol, 1% ammonium hydroxide). ^{MS (EI) MH +: C} 23 H 30 N ₂ O ₅ of S calculated: 449, found: 449.
Example 404: Preparation of N-hydroxy-4 - [(4-phenylthiophenyl) sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide phosphate
(430 mg, 1.0 mmol) was dissolved in methanol (15 ml) and the mixture was stirred at room temperature for 2 hours. . Concentrated phosphoric acid (67 [mu] L) was added and the solution was then concentrated in vacuo. The residue was recrystallized from methanol, separated by filtration and recrystallized twice from methanol / methyl t-butyl ether to give the title compound as a solid (215 mg, 41%). Anal. Calcd for C ₂₁ H ₂₂ N ₂ O ₄ .H ₃ PO ₄ : C, 47.72; H, 4.77; N, 5.30, found: C, 47.63; H, 5.04; N, 4.82
Example 405: Preparation of N-hydroxy-4 - [(4-phenylthiophenyl) sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide p-toluenesulfonate
(516 mg, 1.0 mmol) was reacted with p-toluenesulfonic acid monohydroxy-4 - [(4-phenylthiophenyl) sulfonyl] -1- (200 mg, 1.05 mmol) and the mixture was dissolved in methanol (3 ml). After 4 h, the resulting white precipitate is collected by filtration to give 488 mg (81%) of the title tosylate salt, which has spectroscopic properties.
Example 406: Synthesis of 4 - [[4 - [(2,3-dihydro-1H-inden-2-yl) amino] phenyl] sulfonyl] -N- Preparation of monohydrochloride
Part A: To a solution of the product of Example 9 Part D (0.979 g, 2.36 mmol), 2-aminoindan hydrochloride (1.00 g, 5.89 mmol) and cesium carbonate (1.92 mmol) in N, N- dimethylformamide g, 5.89 mmol) in DMF (5 mL) was heated to 95 &lt; 0 &gt; C for 22 h. The reaction was then cooled, diluted with ethyl acetate (50 ml), washed three times with water, once with brine, and then dried over sodium sulfate. The residue was concentrated and chromatographed on silica gel. Purification 4-Aminosulfone derivative (450 mg, 36%) was eluted with ethyl acetate / hexanes (30/70). ^{MS (EI) MH +: C} 28 H 36 N 2 O 6 S Calcd of: 529, _{found: 529. HRMS M +: C 28} H 36 N 2 O 6 S Calculated for: 528.2294, Found: 528.2306
Part B: To a solution of the ethyl ester of Part A (450 mg, 0.85 mmol) in ethanol (3 ml), water (2 ml) and tetrahydrofuran (3 ml) was added sodium hydroxide (340 mg, 8.5 mmol) , The solution was heated to 60 &lt; 0 &gt; C for 26 hours. The solution was cooled and then diluted with water (10 ml) and diluted with 10% aqueous hydrochloric acid (3 ml) to obtain a pH of 2. The resulting solution was extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, and dried over sodium sulfate to yield the desired carboxylic acid (376 mg, 88%) as a pale brown foam. Anal. Calcd for C ₂₆ H ₃₂ N ₂ O ₆ S: C, 62.38; H, 6.44; N, 5.60; S, 6.40, found: C, 62.48; H, 6.69, N, 5.42; S, 6.27.
Part C: To a solution of the carboxylic acid of Part B (305 mg, 0.609 mmol) in N, N-dimethylformamide (2 mL) was added 4-methylmorpholine (247 mg, 2.44 mmol), N-hydroxybenzotri Pyridine (99 mg, 0.73 mmol) and 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride (152 mg, 0.79 mmol) followed by O- (tetrahydro- -2-yl) hydroxylamine (97 mg, 0.82 mmol). After stirring for 2 days at ambient temperature, the solution is concentrated to an oil. Water was added and the mixture was extracted with ethyl acetate. The organic extracts were washed with water and brine, and dried over sodium sulfate. The brown foam formed by concentration was chromatographed on silica gel. Elution with ethyl acetate / hexanes (40/60) yielded the protected hydroxamate derivative (0.38 g, 100%) as colorless glass. _{^{MS MH +: C 31 H 41}} N 3 O 7 S Calcd of: 600, Found: 600.
Part D: To a solution of the protected hydroxamate of Part C (350 mg, 0.584 mmol) in methanol (3 ml) and 1,4-dioxane (1.5 ml) was added 4 N HCl / ml, 6 mmol) and the solution was stirred for 3 hours at ambient temperature. Concentration and trituration of the resulting residue with diethyl ether afforded the title compound as a solid which was filtered and dried at 51 [deg.] C for 40 h (249 mg, 94%). ^{HRMS (ESI) MH +: C} 21 H 25 N 3 O 4 S Calcd for: 416.1644, Found: 416.1647.
Example 407: Preparation of 4 - [[4 - [(dimethylamino) phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide, monohydrochloride
Part A: To a solution of the product of Example 9 Part D (0.979 g, 2.36 mmol), 2-aminoindan hydrochloride (1.00 g, 5.89 mmol) and cesium carbonate (1.92 mmol) in N, N- dimethylformamide g, 5.89 mmol) in DMF (5 mL) was heated to 95 &lt; 0 &gt; C for 22 h. The reaction was then cooled, diluted with ethyl acetate (50 ml), washed three times with water, once with brine, and then dried over sodium sulfate. Concentration and the resultant residue was chromatographed on silica gel. The 4-N, N-dimethylaminosulfone derivative (590 mg, 57%) was eluted with ethyl acetate / hexane (30/70) along with the product of example 406. ^{MS (EI) MH +: C} 21 H 32 N 2 O ₆ S of the calculated: 441, found: 441. HRMS: C ₂₁ H ₃₂ N ₂ O ₆ S Calculated for: 440.1981, Found: 440.1978.
Part B: To a solution of Part A ethyl ester (580 mg, 1.3 mmol) in ethanol (4 ml), water (3 ml) and tetrahydrofuran (4 ml) was added sodium hydroxide (520 mg, 13 mmol) , And the solution was heated to 62 [deg.] C for 5 hours. The solution was cooled and then diluted with water (5 ml) and acidified (pH 2) by diluting with 10% aqueous hydrochloric acid (5 ml). The resulting solution was extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, and dried over sodium sulfate to give the desired carboxylic acid (520 mg, 97%) as a pale brown foam. _{^{MS MH +: C 19 H 28}} N 2 O ₆ S of the calculated: 413, found: 413.
Part C: To a solution of the carboxylic acid of Part B (500 mg, 1.21 mmol) in N, N-dimethylformamide (4 ml) was added 4- methylmorpholine (490 mg, 4.8 mmol), N-hydroxybenzotri (Tetrahydro-2H-pyran-2-ylamine) was prepared by the same procedure as that described for the synthesis of 4- (2-methoxyphenyl) -2-yl) hydroxylamine (192 mg, 1.63 mmol). After stirring for 2 days at ambient temperature, the solution is concentrated to an oil. Water (25 ml) was added and the mixture was extracted with ethyl acetate. The organic extracts were washed with water and brine, and dried over sodium sulfate. The brown oil produced by concentration was crystallized from a mixture of ethyl acetate, hexane and methylene chloride (1: 1: 2) to give the protected hydroxamate derivative (506 mg, 82%) as a colorless solid. _{^{MS MH +: C 24 H 37}} N 3 O 7 S Calcd of: 512, Found: 512.
Part D: To a solution of the protected hydroxamate of Part C (477 mg, 0.932 mmol) in methanol (3 ml) and 1,4-dioxane (3 ml) was added 4 N HCl / ml, 9.3 mmol) and the solution was stirred for 3 hours at ambient temperature. Concentration and trituration of the resulting residue with diethyl ether afforded the title compound as a solid which was filtered and dried at 51 [deg.] C for 40 h (372 mg, 100%). ^{HRMS (ESI) MH +: C} 14 H 21 N 3 O 4 S Calcd for: 328.1331, Found: 328.1343
Example 408: 1-Cyclopropyl-4 - [[4- [(2,3-dihydro-1,4-benzodioxin-6-yl) oxy] phenyl] sulfonyl] Preparation of 4-piperidinecarboxamide, monohydrochloride
Part A: To a solution of the product of Example 398 Part A (1.36 g, 3.47 mmol) in N, N-dimethylformamide (8 ml) was added 6-hydroxybenzo-1,4-dioxane (792 mg, 5.21 mmol ) Was added followed by cesium carbonate (2.83 g, 8.69 mmol) and the solution was heated at 100 &lt; 0 &gt; C for 20 h. The solution was partitioned between ethyl acetate and H ₂ O. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . Filtration through a silica pad (ethyl acetate / hexane) gave the phenoxyphenyl compound (1.81 g, quantitative yield) as an orange oil. MS (CI) MH ⁺ : Calcd for C ₂₅ H ₂₉ NO ₇ S: 488, found 488.
Part B: To a solution of the phenoxy phenol compound (1.81 g, <3.47 mmol) in Part A in tetrahydrofuran (10 ml) and ethanol (10 ml) was added sodium hydroxide in H ₂ O (5 ml) mmol) were added. The solution was heated to 60 &lt; 0 &gt; C for 20 hours. The solution is concentrated in vacuo and the aqueous residue is acidified to pH 2 with 10% HCl. The resulting solid was collected by vacuum filtration to give the acid as a yellow solid (1.23 g, 72%). MS (CI) MH ⁺ : Calcd for C ₂₃ H ₂₅ NO ₇ S: 460, found 460. HRMS: Calcd for C ₂₃ H ₂₅ NO ₇ S: 460.1430, found 460.1445.
To a suspension of the acid of Part B (1.21 g, 2.46 mmol) in N, N-dimethylformamide (20 ml) was added N-hydroxybenzotriazole (399 mg, 2.95 mmol), 4- methylmorpholine 0.81 ml, 7.38 mmol) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (432 mg, 3.69 mmol). After stirring for 1 hour, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (660 mg, 3.44 mmol) was added and the solution stirred at ambient temperature for 20 hours. The solution was partitioned between ethyl acetate and H ₂ O and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na ₂ SO _4. Chromatography (silica phase, ethyl acetate / hexane) gave protected hydroxamate (940 mg, 70%) as a yellow oil. ^{MS (CI) MH +: C} 28 H 34 N calculated value of ₂ O ₂ S: 559, Found: 559.
Part D: To a solution of the Part C protected hydroxamate (920 mg, 1.68 mmol) in 1,4-dioxane (15 mL) was added 4 N HCl in 1,4-dioxane (10 mL). After stirring at ambient temperature for 2 hours, the resulting precipitate was collected by vacuum filtration and washed with ethyl ether to give the title compound (510 mg, 60%) as a white solid. _{C 23 H 26 N 2 O 7} MS (CI) MH ⁺ calculated for S: 475, found: 475. HRMS C ₂₃ H ₂₆ NO ₇ S Calcd: 475.1539, Found: 475.1553. Anal. Value for C ₂₃ H ₂₆ N ₂ O ₇ S 揃 1.15HCl 揃 0.5H ₂ O: C, 52.57; H, 5.40; N, 5.33; Cl, 7.76, found: C, 52.62; H, 5.42; N, 5.79; Cl, 7.71.
Example 409: Preparation of N-hydroxy-4 - [[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide, monohydrochloride
Part A: To a solution of the product of Example 9, Part D (1.5 g, 3.61 mmol) in N, N-dimethylformamide (10 mL) was added cesium carbonate (2.94 g, 9.03 mmol) and α, Was added p-cresol (877 mg, 5.41 mmol). This solution was heated to 90 &lt; 0 &gt; C for 20 hours. After separating the solution with ethyl acetate and H ₂ 0, and the organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Filtration through a silica pad (ethyl acetate) yielded diaryl ether (2.30 g, quantitative yield) as a yellow oil. MS (CI) MH ^{&lt; +} & gt ^; calculated for C ₂₆ H ₃₀ NO ₇ SF ₃ : 558, found: 558.
Part B: tetrahydrofuran (10 mL) and ethanol (10 mL) of sodium hydroxide (1.44 g, 36.1 mmol) of diaryl ether (2.30 g, <3.61 mmol) H 2 0 (5 mL) to a solution of Part A of Was added and the solution was heated to 60 &lt; 0 &gt; C for 18 hours. The solution was concentrated, the aqueous residue was acidified with 10% HCl to pH = 2, then extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na ₂ SO _4. And concentrated in vacuo to yield the above acid as a solid (2.11 g, quantitative yield). MS (CI) MH ^{&lt; +} & gt ^; calculated for C ₂₄ H ₂₆ NO ₇ SF ₃ : 530, found: 530.
Part C: To a solution of the acid of Part B (2.11 g, <3.61 mmol) in N, N-dimethylformamide (10 mL) was added N-hydroxybenzotriazole (586 mg, 4.33 mmol) 1.19 mL, 10.83 mmol) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (634 mg, 5.41 mmol). After stirring for 1 hour, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (969 mg, 5.05 mmol) was added and the solution stirred for 18 hours. The solution was separated with ethyl acetate and H ₂ O. The aqueous layer was washed with ethyl acetate and the combined organic layers were washed with H ₂ O and saturated NaCl and dried over MgSO ₄ . Chromatography yielded protected hydroxamate (1.40 g, 62%) as a clear colorless oil. MS (CI) MH ^{&lt; +} & gt ^; calculated for C ₂₉ H ₃₅ N ₂ O ₈ SF ₃ : 629, found: 629.
Part D: To a solution of Part C protected hydroxamate (1.40 g, 2.23 mmol) in 1,4-dioxane (10 mL) was added 4 N HCl in 1,4-dioxane (15 mL) The solution was diluted with ethyl ether and the resulting precipitate was collected by vacuum filtration to give the title compound (747 mg, 70%) as a white solid. HPLC purity: 97.5%. _{C 19 H 19 N 2 O MS} (CI) MH ⁺ calculated for ₅ SF _3: 445, Found: 445. C ₁₉ H ₁₉ N HRMS calculated for ₂ O ₅ SF _3: 445.1045, Found: 445.1052. Anal. Calcd for C ₁₉ H ₁₉ N ₂ O ₅ SF ₃ .0.5H ₂ O .1HCl: C, 46.58; H, 4.32; N, 5.72; S, 6.55; Cl, 7.24, found: C, 46.58; H, 3.82; N, 5.61; S, 6.96, Cl, 7.37.
Example 410: Preparation of N-hydroxy-4 - [[4 - [(trifluoromethoxy) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide, monohydrochloride
Part A: To a solution of the product of Example 9, Part D (1.5 g, 3.61 mmol) in N, N-dimethylformamide (10 mL) was added cesium carbonate (2.94 g, 9.03 mmol) and 4- (trifluoromethoxy) Phenol (0.70 mL, 5.41 mmol). This solution was heated to 90 &lt; 0 &gt; C for 20 hours. After separating the solution with ethyl acetate and H ₂ 0, and the organic layer was washed with saturated NaCl, dried over Na ₂ SO _4. Filtration through a silica pad (ethyl acetate) yielded phenoxy phenol (2.11 g, quantitative yield) as a yellow oil. MS (CI) MH ^{&lt; +} & gt ^; calculated for C ₂₆ H ₃₀ NO ₈ SF ₃ : 596, found: 596.
Part B: tetrahydrofuran (10 mL) and ethanol (10 mL) of sodium hydroxide (1.44 g, 36.1 mmol) in of part phenoxy phenol (2.11 g, <3.61 mmol) H 2 0 (5 mL) to a solution of A Was added and the solution was heated to 60 &lt; 0 &gt; C for 18 hours. The solution was concentrated, the aqueous residue was acidified with 10% HCl to pH = 2, then extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na ₂ SO _4. And concentrated in vacuo to yield the above acid as a solid (2.2 g, quantitative yield). MS (CI) MH &lt; ⁺ & gt ^; calculated for C ₂₄ H ₂₆ NO ₈ SF ₃ : 546, found: 546.
Part C: To a solution of the acid of Part B (2.2 g) in N, N-dimethylformamide (10 mL) was added N-hydroxybenzotriazole (586 mg, 4.33 mmol), 4-methylporphorine mmol) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (634 mg, 5.41 mmol). After stirring for 30 minutes, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (969 mg, 5.05 mmol) was added and the solution stirred for 18 hours. The solution was separated with ethyl acetate and H ₂ O. The aqueous layer was washed with ethyl acetate and the combined organic layers were washed with H ₂ O and saturated NaCl and dried over MgSO ₄ . Chromatography (silica, ethyl acetate / hexanes) gave the protected hydroxamate (1.26 g, 53%) as a clear colorless oil.
Part D: To a solution of the protected hydroxamate (1.26 g, 1.96 mmol) in Part C in 1,4-dioxane (10 mL) was added 4N HCl in 1,4-dioxane (10 mL) Was stirred for 2 hours. The solution was diluted with ethyl ether and the resulting precipitate was collected by vacuum filtration to give the title compound as a white solid (455 mg, 47%). HPLC purity: 98%. _{C 19 H 19 N 2 O 6} SF 3 MS (CI) MH + calculated for: 461, Found: 461. C ₁₉ H ₁₉ N ₂ O HRMS calcd for ₆ SF _3: 461.0994, Found: 461.0997. Anal. Calcd for C ₁₉ H ₁₉ N ₂ O ₆ SF ₃ .1.0HCl: C, 45.93; H, 4.06; N, 5.64; S, 6.45; Cl, 6.45, found: C, 46.23; H, 4.07; N, 5.66; S, 6.59, Cl, 7.03.
Example 411: Synthesis of 1-cyclopropyl-4 - [[4- [(2,3-dihydro-1,4-benzodioxin-6-yl) amino] phenyl] sulfonyl] -Piperidinecarboxamide, &lt; / RTI &gt; monohydrochloride &lt; RTI ID = 0.0 &gt;
Part A: To a solution of the ester of Example 91, Part C (1.57 g, 3.40 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (10 mL). After stirring for 1 hour, the resulting precipitate was collected by vacuum filtration to give amine hydrochloride (1.16 g, 86%) as a white solid.
Part B: To a slurry of the amine hydrochloride of Part A (1.16 g, 2.91 mmol) in methanol (10 mL) was added acetic acid (1.68 mL, 29.1 mmol) followed by (1-ethyloxycyclopropyl) oxytrimethylsilane mL, 17.5 mmol) and sodium cyanoborohydride (823 mg, 13.1 mmol). This solution was heated to reflux for 6 hours. The solution was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with H ₂ O, aqueous sodium hydroxide and saturated NaCl, then dried over MgSO ₄ . Concentration in vacuo afforded the N-cyclopropyl compound (1.03 g, 88%) as a white solid.
Part C: To a solution of Part B N-cyclopropyl compound (1.0 g, 2.49 mmol) in toluene (6 mL) was added cesium carbonate (1.14 g, 3.49 mmol), tris (dibenzylideneacetone) dipalladium (0) mg, 0.075 mmol), R- (+) - 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (69 mg, 0.112 mmol) and 1,4- -Amine (451 mg, 2.99 mmol) was added and the solution was heated to 100 &lt; 0 &gt; C for 19 h. The solution was diluted with ethyl ether and filtered through Super Cel (trade name). The filtrate was concentrated and chromatographed (silica, ethyl acetate / hexane) to give the aniline compound as an orange oil (561 mg, 48%). MS (CI) MH ^{&lt; +} & gt ^; calculated for C ₂₄ H ₂₈ N ₂ O ₆ S: 473, found 473.
Part D: To a solution of the aniline compound of Part C (550 mg, 1.16 mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate (297 mg, 3.48 mmol) and the solution was stirred at ambient temperature for 18 h Lt; / RTI &gt; The solution was concentrated, the residue obtained was suspended in H ₂ O. The solid was collected by vacuum filtration to give the crude acid (282 mg).
Part E: To a solution of the crude D (282 mg, 0.62 mmol) of Part D in N, N-dimethylformamide (10 mL) was added N-hydroxybenzotriazole (100 mg, 0.74 mmol) (0.20 mL, 1.86 mmol) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (108 mg, 0.93 mmol). After stirring for 30 minutes, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (166 mg, 0.87 mmol) was added and the solution stirred for 72 hours. The solution was separated into ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with H ₂ O and saturated NaCl and dried over Na ₂ O ₄ . Chromatography (silica, ethyl acetate / hexanes) afforded protected hydroxamate (150 mg, 43%) as a white solid. _{C 28 H 35 N 3 O 7} MS (CI) MH ⁺ calculated for S: 558, found: 558.
Part F: To a solution of Part E protected hydroxamate (133 mg, 0.24 mmol) in 1,4-dioxane (5 mL) was added 4N HCl in 1,4-dioxane (10 mL) Was stirred for 1.5 hours. The solution was diluted with ethyl ether and the resulting residue was collected by vacuum filtration to give the title hydroxamate (80 mg, 66%) as a white solid. C ₂₃ H ₂₇ N ₃ O MS for ₆ S (CI) MH ⁺ calculated: 474, _{found: 474. C 23 H 27 N 3} O HRMS calcd for ₆ S: 474.1699, Found: 474.1715. Anal. Value for C ₂₃ H ₂₇ N ₃ O ₆ S 揃 1.5HCl 揃 1.5H ₂ O: C, 49.75; H, 5.72; N, 7.57; S, 5.77; Cl, 9.58, found: C, 49.78; H, 5.52; N, 8.05; S, 9.16; Cl, 5.76.
Example 412: Synthesis of 1-cyclopropyl-4 - [[4- [4- [[4- (2,3-dimethylphenyl) -1- piperazinyl] carbonyl] -1- piperidinyl] Fluoro-N- &lt; / RTI &gt; hydroxy-4-piperidinecarboxamide, trihydrochloride
Part A: To a solution of isonipecotinic acid (10.5 g, 81.3 mmol) in H ₂ O (325 mL) was added sodium carbonate (8.37 g, 81.3 mmol) and the solution was stirred until homogeneous. To this solution, di-tert-butyl dicarbonate (18.22 g, 83.5 mmol) in 1,4-dioxane (77 mL) was added dropwise and the resulting solution was stirred at ambient temperature for 72 hours. The solution was concentrated in vacuo and the resulting aqueous solution was washed with ethyl ether. The aqueous solution was acidified to pH = 2 with concentrated HCl. This solution was extracted with ethyl ether and concentrated in vacuo to give a white solid. This was recrystallized (ethyl acetate) to give N-Boc-isonipecotinic acid (10 g, 54%) as a white solid.
Part B: To a solution of Part A of N-Boc-isonipecotinic acid (2.14 g, 9.33 mmol) in dichloromethane (19 mL) was added 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide (1.82 g, 9.49 mmol), N-hydroxybenzotriazole (1.32 g, 9.77 mmol) and l- (2,3-xylyl) piperazine monohydrochloride (2.47 g, 10.89 mmol). After stirring for 30 minutes, diisopropylethylamine (0.74 mL, 20.7 mmol) was added and the solution was stirred for 18 hours. After the solution was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 1M HCl, saturated NaHCO ₃ and saturated NaCl. The solution was dried with MgSO _4. Recrystallization (ethyl acetate / hexanes) gave the amide as a grayish white solid (2.65 g, 71%).
Part C: Trifluoroacetic acid (5 mL) was added to a solution of the amide of Part B (1.0 g, 3.75 mmol) in dichloromethane (5 mL) and the solution was stirred for 15 min. The solution was concentrated in vacuo and the resulting oil was dissolved in N, N-dimethylacetamide (10 mL). To this solution, the product of Example 398, Part A (979 mg, 2.50 mmol) and cesium carbonate (3.67 g, 11.25 mmol) was added and the solution was heated at 110 <0> C for 17 h. The solution was separated with ethyl acetate and H ₂ O. The organic layer was washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . And concentrated in vacuo to give the piperidine compound as a white solid (1.89 g, quantitative yield). C ₃₅ H ₄₈ N ₄ O MS for S ₅ (CI) MH ⁺ calculated: 637, found: 637.
Part D: To a solution of the piperidine compound (1.89 g) in Part C in ethanol (8 mL) and tetrahydrofuran (8 mL) was added sodium hydroxide (1.0 g, 25 mmol) in H ₂ O . The solution was heated to 50 &lt; 0 &gt; C for 8 hours and 62 [deg.] C for 8 hours. The solution was concentrated in vacuo and the residue was diluted with H ₂ O and acidified to pH = 3 with 3M HCl. The resulting precipitate was collected by vacuum filtration to give the acid as a white solid (1.16 g, 65%). _{C 33 H 44 N 4 MS (} CI) MH ⁺ calculated for O ₅ S: 609, found: 609.
Part E: To a solution of the Part D acid (1.16 g, 1.62 mmol) in N, N-dimethylformamide (10 mL) was added N-hydroxybenzotriazole (262 mg, 1.94 mmol), 4- methylmorpholine mL, 8.2 mmol) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (284 mg, 2.4 mmol). After stirring for 45 minutes, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (334 mg, 2.2 mmol) was added and the solution stirred at ambient temperature for 18 hours. The solution was separated into ethyl acetate and H ₂ O, and the organic layer was washed with H ₂ O and saturated NaCl, then dried over Na ₂ O ₄ . Crude (dichloromethane) gave the protected hydroxamate (850 mg, 75%) as a white solid. _{C 38 H 53 N 5 O MS} (CI) MH ⁺ calculated for ₆ S: 708, _{found: 708. C 38 H 53 N 5} O 6 analysis value for _{S · 0.5H 2 O: C,} 63.66; H, 7.59; N, 9.77; S, 4.47, found: C, 63.68; H, 7.54; N, 9.66; S, 4.67.
Part F: To a solution of the protected hydroxamate (746 mg, 1.07 mmol) in Part E in methanol (10 mL) was added 4M HCl in 1,4-dioxane (10 mL) and the solution was stirred for 1 hour Respectively. The resulting solid was collected by vacuum filtration and washed with ethyl ether to give the title compound as a white solid (650 mg, 83%). _{C 33 H 45 N 5 O MS} (CI) MH + calculated for ₅ S: 624, _{found: 624. C 33 H 49 N 5} O HRMS calculated for ₅ S: 624.3220, Found: 624.3253. C ₃₃ H ₄₅ N ₅ O ₅ analysis value for _{S · 3.5HCl · H 2 O:} C, 51.82; H, 6.59; N, 9.16. Found: C, 52.04; H, 6.30; N, 8.96.
Example 413: 4 - [[4- [4 - [[4- (2,3-Dimethylphenyl) -1-piperazinyl] carbonyl] -1- piperidinyl] phenyl] sulfonyl] Preparation of hydroxy-1- (2-methoxyethyl) -4-piperidinecarboxamide, trihydrochloride
Part A: To a solution of isonipecotinic acid (10.5 g, 81.3 mmol) in H ₂ O (325 mL) was added sodium carbonate (8.37 g, 81.3 mmol) and the solution was stirred until homogeneous. To this solution, di-tert-butyl dicarbonate (18.22 g, 83.5 mmol) in 1,4-dioxane (77 mL) was added dropwise and the resulting solution was stirred at ambient temperature for 72 hours. The solution was concentrated in vacuo and the resulting aqueous solution was washed with ethyl ether. The aqueous solution was acidified to pH = 2 with concentrated HCl. This solution was extracted with ethyl ether and concentrated in vacuo to give a white solid. This was recrystallized (ethyl acetate) to give N-Boc-isonipecotinic acid (10 g, 54%) as a white solid.
Part B: To a solution of Part A of N-Boc-isonipecotinic acid (2.14 g, 9.33 mmol) in dichloromethane (19 mL) was added 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide (1.82 g, 9.49 mmol), N-hydroxybenzotriazole (1.32 g, 9.77 mmol) and l- (2,3-xylyl) piperazine monohydrochloride (2.47 g, 10.89 mmol). After stirring for 30 minutes, diisopropylethylamine (0.74 mL, 20.7 mmol) was added and the solution was stirred for 18 hours. After the solution was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 1M HCl, saturated NaHCO ₃ and saturated NaCl. The solution was dried with MgSO _4. Recrystallization (ethyl acetate / hexanes) gave the amide as a grayish white solid (2.65 g, 71%).
Part C: Trifluoroacetic acid (5 mL) was added to a solution of the amide of Part B (965 mg, 2.41 mmol) in dichloromethane (5 mL) and the solution was stirred for 15 min. The solution was concentrated in vacuo and the resulting oil was dissolved in N, N-dimethylacetamide (10 mL). To this solution was added ethyl-4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidinecarboxylate (600 mg, 1.61 mmol) and cesium carbonate g, 8.43 mmol) and the solution was heated at 110 &lt; 0 &gt; C for 20 h. The solution was separated with ethyl acetate and H ₂ O. The organic layer was washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . Concentration in vacuo afforded the piperidine compound (1.26 g, quantitative yield) as a white solid. _{C 35 H 50 N 4 O MS} (CI) MH ⁺ calculated for ₆ S: 655, found: 655.
Part D: To a solution of the piperidine compound (1.26 g) in Part C in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (644 mg, 16 mmol) in H ₂ O . The solution was heated to 60 &lt; 0 &gt; C for 8 hours and 62 &lt; 0 &gt; C for 8 hours. The solution was concentrated in vacuo and the residue was diluted with H ₂ O and acidified to pH = 3 with 3M HCl. The resulting precipitate was collected by vacuum filtration to give the acid as a white solid (650 mg, 65%). _{C 33 H 46 N 4 O MS} (CI) MH ⁺ calculated for ₆ S: 627, found: 627.
Part E: To a solution of the Part D acid (620 g, 0.94 mmol) in N, N-dimethylformamide (10 mL) was added N-hydroxybenzotriazole (152 mg, 1.13 mmol), 4- methylmorpholine mL, 4.7 mmol) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (165 mg, 1.4 mmol). After stirring for 45 minutes, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (252 mg, 1.32 mmol) was added and the solution stirred at ambient temperature for 18 hours. The solution was separated into ethyl acetate and H ₂ O, and the organic layer was washed with H ₂ O and saturated NaCl, then dried over Na ₂ SO ₄ . Concentration in vacuo afforded protected hydroxamate (641 mg, 94%) as a white solid. _{C 38 H 55 N 5 O 7} MS (CI) MH ⁺ calculated for S: 726, found: 726.
Part F: To a solution of the protected hydroxamate (630 mg, 0.87 mmol) in Part E in methanol (8 mL) was added 4M HCl in 1,4-dioxane (10 mL) and the solution was stirred for 1 hour Respectively. The resulting solid was collected by vacuum filtration and washed with ethyl ether to give the title compound (624 mg, 83%) as a white solid. _{C 33 H 47 N 5 O MS} (CI) MH ⁺ calculated for ₆ S: 642, found: 642.
Example 414: N-Hydroxy-4 - [[4- [4- (1-methylethyl) phenoxy] phenyl] sulfonyl] -1- (2- propynyl) -4- piperidinecarboxamide , Preparation of monohydrochloride
Part A: To a solution of the product of Example 9, Part E (6.0 g, 15.4 mmol) and powdered K ₂ CO ₃ (8.0 g, 38.5 mmol) in N, N-dimethylformamide (70 mL) Phenol (5.24 g, 38.5 mmol) was added at ambient temperature and the solution was heated to 90 &lt; 0 &gt; C for 32 h. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N NaOH and H ₂ O and dried over MgSO ₄ . Silica chromatography, eluting with ethyl acetate / hexanes, gave the diaryl ether (6.89 g, 87%) as a pale yellow gel.
Part B: To a solution of Part A diaryl ether (6.89 g, 14.7 mmol) in ethanol (14 mL) and tetrahydrofuran (14 mL) was added NaOH (5.88 g, 147 mmol) in H ₂ O mmol) was added at ambient temperature. The solution was heated to 60 &lt; 0 &gt; C for 17 hours and ambient temperature for 24 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH = 2. The white precipitate was filtered under vacuum to give the acid as a white solid (6.56 g, quantitative yield).
Part C: To a solution of the acid of Part B (6.56 g, 14.86 mmol), N-methylmorpholine (6.5 mL, 59.4 mmol), 1-hydroxybenzotriazole (6.0 g, 3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (8.5 g, 44.6 mmol) was added to a solution of 4- Was added and the solution was stirred at ambient temperature for 20 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO ₃ and H ₂ O and dried over MgSO ₄ . Concentration in vacuo and silica gel chromatography eluting with ethyl acetate / hexanes afforded tetrahydropyranyl-protected hydroxamate (8.03 g, quantitative yield) as a white foam.
Part D: To a solution of 4N HCl in dioxane (37 mL, 149 mmol) was added tetrahydrothiopyranyl-protected hydroxamate (8.03 g, 14.9 mmol) in Part C in methanol (5 mL) and dioxane (15 mL) Was added and the solution was stirred at ambient temperature for 3 hours. Concentration in vacuo and trituration with diethyl ether afforded the title compound (5.0 g, 71.1%) as a white solid. Anal. Calcd for C ₂₄ H ₂₈ N ₂ O ₅ S · HCl · 0.9H ₂ O: C, 56.61; H, 6.10; N, 5.50; S, 6.30, found: C, 56.97; H, 6.05; N, 5.41; S, 5.98. _{C 24 H 28 N 2 O 5} S HRMS MH + calculated for: 457.1797, Found: 457.1816.
Example 415: Synthesis of 4 - [[4- (1,3-benzodioxol-5-yloxy) phenyl] sulfonyl] -N-hydroxy-1- (2- methoxyethyl) -4- Preparation of carboxamide, monohydrochloride
Part A: To a solution of the product of Example 9, Part D (25 g, 67.3 mmol) and powdered K ₂ CO ₃ (23.3 g, 169 mmol) in N, N-dimethylformamide (150 mL) g, 168 mmol) at ambient temperature and the solution was heated to 90 &lt; 0 &gt; C for 25 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N NaOH and H ₂ O and dried over MgSO ₄ . Silica chromatography, eluting with ethyl acetate / hexanes, gave the desired diaryl ether (33.6 g, 93.6%) as a pale yellow gel.
Part B: To a solution of Part A diaryl ether (4.0 g, 7.4 mmol) in dichloromethane (7 mL) cooled to 0 C was added trifluoroacetic acid (7 mL) and the solution was stirred at ambient temperature for 2 hours Lt; / RTI &gt; Concentration under vacuum afforded the amine trifluoroacetic acid salt as a pale yellow gel. To a solution of the trifluoroacetic acid salt and K ₂ CO ₃ (3.6 g, 26 mmol) in N, N-dimethylformamide (50 mL) was added 2-bromoethyl methyl ether (1.8 mL, 18.7 mmol) The solution was stirred at ambient temperature for 36 hours. N, N-Dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water, dried over MgSO _4. Concentration in vacuo afforded methoxyethylamine (3.7 g, quantitative yield) as a pale yellow gel.
Part C: To a solution of the methoxyethylamine (3.7 g, 7.5 mmol) in Part B in ethanol (7 mL) and tetrahydrofuran (7 mL) was added NaOH in aq. H ₂ O (15 mL) 75 mmol) at ambient temperature. The solution was heated to 60 &lt; 0 &gt; C for 19 hours and ambient temperature for 12 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH = 2. The white precipitate was filtered under vacuum to give the acid as a white solid (4.0 g, quantitative yield).
Part D: To a solution of the acid from Part C (4.0 g, 7.5 mmol), N-methylmorpholine (3.3 mL, 30 mmol), 1-hydroxybenzotriazole (3.0 g, 30 mmol) in N, N- dimethylformamide (Dimethylguanyl) propyl] -3-ethylcarbodiimide hydrochloride (4.3 g, 22.5 mmol) was added to a solution of 1- Was added and the solution was stirred at ambient temperature for 4 days. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO ₃ and H ₂ O and dried over MgSO ₄ . Concentration in vacuo and silica gel chromatography eluting with ethyl acetate / hexanes yielded tetrahydropyranyl-protected hydroxamate (2.40 g, 57.1%) as a white foam.
Part E: Tetrahydropyranyl-protected hydroxamate (2.4 g, 4.3 mmol) in Part D in methanol (2 mL) and dioxane (6 mL) was added to a 4N HCl solution in dioxane (11 mL, 43 mmol) Was added and the solution was stirred at ambient temperature for 3 hours. Concentrated in vacuo and triturated with ether to give hydroxamate hydrochloride (1.88 g, 85.8%) as a white solid. C ₂₂ H ₂₆ N ₂ O analysis value for _{8 S · HCl · H 2 O} : C, 49.58; H, 5.48; N, 5.26; S, 6.02, found: C, 49.59; H, 5.53; N, 5.06; S, 5.71. _{C 22 H 26 N 2 HRMS MH} + calculated for O ₈ S: 479.1488, Found: 479.1497.
Example 416: Synthesis of N-hydroxy-1- (2-methoxyethyl) -4 - [[4- [4- (trifluoromethoxy) phenoxy] phenyl] sulfonyl] -4-piperidinecarbox Amide, monohydrochloride
Part A: To a solution of the product of Example 9, Part D (30 g, 161 mmol) in dichloromethane (50 mL) cooled to 0 C was added trifluoroacetic acid (25 mL) And stirred for 1 hour. Concentration under vacuum afforded the amine trifluoroacetic acid salt as a pale yellow gel. To a solution of the trifluoroacetic acid salt and K ₂ CO ₃ (3.6 g, 26 mmol) in N, N-dimethylformamide (50 mL) cooled to 0 ° C was added 2-bromoethyl methyl ether (19 mL, 201 mmol ) And the solution was stirred at ambient temperature for 36 hours. N, N-Dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water, dried over MgSO _4. Concentration in vacuo afforded methoxyethylamine (26.03 g, 86.8%) as a pale yellow gel.
Part B: To a solution of Part A methoxyethylamine (6.0 g, 16.0 mmol) and powdered K ₂ CO ₃ (4.44 g, 32 mmol) in N, N-dimethylformamide (30 mL) (5.72 g, 32 mmol) was added at ambient temperature and the solution was heated to 90 &lt; 0 &gt; C for 25 h. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N NaOH and H ₂ O and dried over MgSO ₄ . Trifluoromethoxyphenoxyphenylsulfone (7.81 g, 91.5%) as a pale yellow gel was obtained by silica chromatography eluting with ethyl acetate / hexane.
NaOH in ethanol (14 mL) and tetrahydrofuran (14 mL) fluoro in the tree of the part B Romero ethoxy phenoxyphenyl sulfone (7.81 g, 14.7 mmol) was added, from the addition funnel, H ₂ O (28 mL): Part C (5.88 g, 147 mmol) at ambient temperature. The solution was then heated to 60 &lt; 0 &gt; C for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH = 2. The white precipitate was filtered under vacuum to give the acid as a white solid (5.64 g, 73.3%).
Part D: To a solution of the acid of Part C (5.64 g, 10.8 mmol), N-methylmorpholine (4.8 mL, 43.1 mmol), 1-hydroxybenzotriazole (4.38 g, 3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (6.2 g, 32.4 mmol) was added to a solution of the compound of Example 1 (32.4 mmol) and O-tetrahydropyranylhydroxylamine Was added and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO ₃ and H ₂ O and dried over MgSO ₄ . Concentration in vacuo and silica gel chromatography eluting with ethyl acetate / hexanes yielded tetrahydropyranyl-protected hydroxamate (6.65 g, quantitative yield) as a white foam.
Part E: Tetrahydropyranyl-protected hydroxamate (6.65 g, 11.03 mmol) in Part D in methanol (3 mL) and dioxane (9 mL) was added to a solution of 4N HCl in dioxane (28 mL, Was added and stirred at ambient temperature for 3 hours. Concentrated in vacuo and triturated with diethyl ether to give the title compound as a white solid (4.79 g, 78.2%). Anal. Calcd for C ₂₂ H ₂₅ N ₂ O ₇ SF ₃ .HCl .0.5H ₂ O: C, 46.85; H, 4.83; N, 4.97; S, 5.69, found: C, 46.73; H, 4.57; N, 4.82; S, 5.77.
Example 417: Synthesis of N-hydroxy-1- (2-methoxyethyl) -4 - [[4- [4- (1-methylethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarbox Amide, monohydrochloride
Part A: To a solution of ethyl 4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidinecarboxylate ( 4-isopropylphenol (1.07 g, 7.8 mmol) was added at ambient temperature to a solution of 1.47 g, 3.9 mmol) and powdered K ₂ CO ₃ (1.6 g, 11.7 mmol) And heated. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N NaOH and H ₂ O and dried over MgSO ₄ . Silica chromatography, eluting with ethyl acetate / hexanes, gave the diaryl ether (1.77 g, 92.2%) as a pale yellow gel.
Part B: To a solution of Part A diaryl ether (1.77 g, 3.6 mmol) in ethanol (3.5 mL) and tetrahydrofuran (3.5 mL) was added NaOH (1.46 g, 36 mmol) in H ₂ O Lt; / RTI &gt; The solution was then heated to 60 &lt; 0 &gt; C for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with diethyl ether and acidified to pH = 2. The white precipitate was filtered under vacuum to give the acid as a white solid (1.39 g, 83.7%).
Part C: To a solution of the acid of Part B (1.39 g, 3.0 mmol), N-methylmorpholine (1 mL, 9 mmol), 1-hydroxybenzotriazole (1.22 g, (Dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.72 g, 9.0 mmol) was added to a solution of 5-bromo-5-methoxybenzaldehyde Was added and the solution was stirred at ambient temperature for 48 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO ₃ and H ₂ O and dried over MgSO ₄ . Concentration in vacuo and purification by silica chromatography eluting with ethyl acetate / hexanes afforded tetrahydropyranyl-protected hydroxamate (1.65 g, 98.2%) as a white foam.
Part D: To a solution of 4N HCl in dioxane (7.35 mL, 29.4 mmol) was added tetrahydrothiopyranyl-protected hydroxamate (1.65 g, 2.94 mmol) in Part C in methanol (1 mL) and dioxane (3 mL) Was added and the solution was stirred at ambient temperature for 3 hours. Concentration in vacuo and trituration with diethyl ether afforded the title compound (1.2 g, 79.5%) as a white solid. Anal. Value for C ₂₄ H ₃₂ N ₂ O ₆ S · HCl · 0.5H ₂ O: C, 55.22; H, 6.56; N, 5.37; S, 6.14, found: C, 55.21; H, 6.41; N, 5.32; S, 6.18.
Example 418: Synthesis of N-hydroxy-1- (2-methoxyethyl) -4 - [[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarbox Amide, monohydrochloride
Part A: To a solution of ethyl 4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidinecarboxylate ( 4-Trifluoromethylphenol (5.72 g, 32 mmol) was added at ambient temperature to a solution of 6 g, 16.0 mmol) and powdered K ₂ CO ₃ (4.44 g, 32 mmol) / RTI &gt; The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N NaOH and H ₂ O and dried over MgSO ₄ . Silica chromatography, eluting with ethyl acetate / hexanes, gave the diaryl ether (2.66 g, 32.1%) as a pale yellow gel.
Part B: To a solution of Part A diaryl ether (1.5 g, 2.9 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was added NaOH (1.22 g, 29 mmol) in H ₂ O Lt; / RTI &gt; The solution was then heated to 60 &lt; 0 &gt; C for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with diethyl ether and acidified to pH = 2. The white precipitate was filtered under vacuum to give the desired acid (1.0 g, 70.9%) as a white solid.
Part C: To a solution of the acid of Part B (1.0 g, 2.05 mmol), N-methylmorpholine (0.68 mL, 6.1 mmol), 1-hydroxybenzotriazole (0.84 g, (Dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.18 g, 6 mmol) was added to a solution of the compound of Example 1 (6.1 g, 6.15 mmol) and O-tetrahydropyranylhydroxylamine Was added and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO ₃ and H ₂ O and dried over MgSO ₄ . Concentration in vacuo and silica gel chromatography eluting with ethyl acetate / hexanes afforded tetrahydropyranyl-protected hydroxamate (1.16 g, 96.7%) as a white foam.
Part D: To a solution of 4N HCl in dioxane (5 mL, 20 mmol) was added tetrahydrothiopyranyl-protected hydroxamate (1.16 g, 2 mmol) in Part C in methanol (1 mL) and dioxane (3 mL) Was added and the solution was stirred at ambient temperature for 3 hours. Concentrated in vacuo and triturated with diethyl ether to give the title compound as a white solid (0.79 g, 74.5%). Anal. Calcd for C ₂₂ H ₂₅ N ₂ O ₆ SF ₃ .HCl: C, 49.03; H, 4.86; N, 5.20; S, 5.95, found: C, 48.85; H, 4.60; N, 5.22; S, 6.13.
Example 419: N-Hydroxy-1- (2-methoxyethyl) -4 - [[4- [4 - [(trifluoromethyl) thio] phenoxy] phenyl] sulfonyl] Preparation of dihydrocarboxamide, monohydrochloride
Part A: To a solution of ethyl 4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidinecarboxylate ( 4- (trifluoromethylthio) phenol (3.9 g, 20 mmol) was added at ambient temperature to a solution of 5 g, 13.4 mmol) and powdered K ₂ CO ₃ (3.7 g, Lt; 0 &gt; C for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N NaOH and H ₂ O and dried over MgSO ₄ . Silica chromatography, eluting with ethyl acetate / hexanes, gave the desired diaryl ether (5.94 g, 81.04%) as a pale yellow gel.
Part B: To a solution of Part A diaryl ether (5.94 g, 210 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added NaOH (4.34 g, 108 mmol) in H ₂ O Lt; / RTI &gt; The solution was then heated to 60 &lt; 0 &gt; C for 24 hours and ambient temperature for an additional 24 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with diethyl ether and acidified to pH = 2. The white precipitate was filtered under vacuum to give the acid as a white solid (5.5 g, quantitative yield).
Part C: The acid of Part B (5.5 g, 10.8 mmol), N-methylmorpholine (3.6 mL, 32.4 mmol), 1-hydroxybenzotriazole (4.4 g, 3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (6.2 g, 32.4 mmol) was added to a solution of 2- Was added and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO ₃ and H ₂ O and dried over MgSO ₄ . Concentration in vacuo and purification by silica chromatography eluting with ethyl acetate / hexanes afforded tetrahydropyranyl-protected hydroxamate (4.66 g, 69.8%) as a white foam.
Part D: To a solution of 4N HCl in dioxane (20 mL, 79 mmol) was added tetrahydrothiopyranyl-protected hydroxamate (4.65 g, 7.9 mmol) in Part C in methanol (2.5 mL) and dioxane (8 mL) Was added and stirred at ambient temperature for 3 hours. Concentrated in vacuo and triturated with diethyl ether to give the title compound as a white solid (3.95 g, 92.1%). _{C 22 H 25 N 2 O 6} S 2 analysis value for _{F 3 · HCl: C, 46.27} ; H, 4.59; N, 4.91; S, 11.23, found: C, 46.02; H, 4.68; N, 4.57; S, 11.11.
Example 420: Synthesis of N-hydroxy-1- (1-methylethyl) -4 - [[4- [4- (1-methylethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide , Preparation of monohydrochloride
Part A: To a solution of the product of Example 9, Part D (30 g, 161 mmol) in dichloromethane (40 mL) cooled to 0 C was added trifluoroacetic acid (30 mL) And stirred for 1 hour. Concentration in vacuo afforded the trifluoroacetic acid salt as a pale yellow gel. To a solution of the trifluoroacetic acid salt and triethylamine (28 mL, 201 mmol) in dichloromethane (250 mL) cooled to 0 ° C was added acetone (24 mL, 320 mmol) and sodium triacetoxyborohydride (68 g , 201 mmol) was added in small portions followed by acetic acid (18.5 mL, 320 mmol) and the solution was stirred at ambient temperature for 48 hours. The dichloromethane was then evaporated under high vacuum and the residue was diluted with diethyl ether. The organic layer was washed with 1N NaOH and water, dried over MgSO _4. Concentration in vacuo afforded isopropylamine (21.03 g, 72.8%) as a pale yellow gel.
Part B: To a solution of Part A isopropylamine (4 g, 11.2 mmol) and powdered K ₂ CO ₃ (3.09 g, 22.4 mmol) in N, N-dimethylformamide (30 mL) was added 4-isopropylphenol 3.05 g, 22 mmol) at ambient temperature and the solution was heated to 90 &lt; 0 &gt; C for 25 h. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N NaOH and H ₂ O and dried over MgSO ₄ . The desired diaryl ether (5.10 g, 96.2%) was obtained as a pale yellow gel by silica chromatography eluting with ethyl acetate / hexanes.
Part C: To a solution of the diaryl ether (5.10 g, 10.77 mmol) in Part B in ethanol (10 mL) and tetrahydrofuran (10 mL) was added NaOH (4.3 g, 108 mmol) in H ₂ O mmol) was added at ambient temperature. The solution was then heated to 60 &lt; 0 &gt; C for 24 hours and ambient temperature for an additional 24 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with diethyl ether and acidified to pH = 2. The white precipitate was filtered under vacuum to give the desired acid (4.80 g, quantitative yield) as a white solid.
Part D: The acid of Part C (4.80 g, 10.8 mmol), N-methylmorpholine (3.6 mL, 32.4 mmol), 1-hydroxybenzotriazole (4.4 g, 3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (6.17 g, 32.4 mmol) was added to a solution of 2- Was added and the solution was stirred at ambient temperature for 7 days. The solution was filtered to remove unreacted starting material, and the filtrate was concentrated under high vacuum. The residue was dissolved in ethyl acetate and the organic layer was washed with saturated aqueous NaHCO ₃ and H ₂ O and then dried over MgSO ₄ . Concentration in vacuo and silica gel chromatography eluting with ethyl acetate / hexanes afforded tetrahydropyranyl-protected hydroxamate (2.45 g, 41.7%) as a white foam.
Part E: Tetrahydropyranyl-protected hydroxamate (2.45 g, 11.03 mmol) in Part D in methanol (4 mL) and dioxane (8 mL) was added to a solution of 4N HCl in dioxane (11.2 mL, 45 mmol) Was added and stirred at ambient temperature for 3 hours. Concentration in vacuo and trituration with diethyl ether afforded the title compound (2.01 g, 89.7%) as a white solid. Anal. Value for C ₂₄ H ₃₂ N ₂ O ₅ S · HCl · 0.5H ₂ O: C, 56.96; H, 6.77; N, 5.54; S, 6.34, found: C, 56.58; H, 6.71; N, 5.44; S, 6.25.
Example 421 Synthesis of 4 - [[4- (1,3-benzodioxol-5-yloxy) phenyl] sulfonyl] -1-cyclopropyl-N-hydroxy-4-piperidinecarboxamide, mono Preparation of Hydrochloride
Part A: K ₂ CO ₃ (4.55 g, 33 mmol) and sesamol (4.55 g, 33 mmol) were added to a solution of the product of Example 9, Part D (9.0 g, 22.0 mmol) in DMF (30 mL) . The solution was stirred at 90 占 폚 for 24 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. The desired ester (9.3 g, 79%) as an oil was obtained by silica gel chromatography eluting with 10% ethyl acetate / hexanes. HRMS MH ^& lt ^{; +} & gt ^; calculated for C ₂₆ H ₃₁ NSO ₉ : 534.1798, found: 534.1796.
Part B: A solution of the ester of Part A (9.3 g, 17 mmol) in ethyl acetate (100 mL) cooled to 0 ° C was bubbled with HCl gas for 10 minutes. The reaction was stirred at this temperature for 0.5 h. The solution was concentrated in vacuo to give the hydrochloride (7.34 g, 92%). MS MH ⁺ calculated for _{C 21 H 23 NSO 7: 434.1273} , Found: 434.1285.
Part C: To a solution of the hydrochloride of Part B (7.34 g, 15.6 mmol) in methanol (60 mL) was added acetic acid (8.94 mL, 156 mmol), a portion of 4-A molecular sieve (about 2 g), (1-ethoxycyclo Propyl) oxytrimethylsilane (18.82 mL, 93.6 mmol) and sodium cyanoborohydride (4.41 g, 70.2 mmol). This solution was refluxed for 8 hours. The precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. The desired cyclopropylamine (7.9 g, 100%) as a solid was obtained by silica gel chromatography eluting with 100% ethyl acetate. MS MH ^{&lt; + &} gt ^; calculated for C ₂₄ H ₂₇ NSO ₇ : 474.1586, found 474.1599.
Part D: To a solution of Part C cyclopropylamine (7.9 g, 16.7 mmol) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution of NaOH (6.68 g, 166.8 mmol) in water , And the solution was heated at 60 占 폚 for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH = 3. The resulting precipitate was filtered to obtain the desired carboxylic acid (6.14 g, 76%). MS MH ⁺ calculated for C ₂₂ H ₂₅ NSO _7: 446.1273, Found: 446.1331.
Part E: To a solution of the carboxylic acid of Part D (6.14 g, 12.7 mmol) in DMF (60 mL) was added 1-hydroxybenzotriazole (2.06 g, 15.2 mmol) and N- methylmorpholine (4.2 mL, 38.0 mmol ) And O-tetrahydropyranyl hydroxylamine (2.23 g, 19.0 mmol) followed by the addition of 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride (3.41 g, 17.8 mmol) Was added. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. The desired tetrahydropyranyl-protected hydroxamate (6.67 g, 96%) as a solid was obtained by silica gel chromatography eluting with 40% ethyl acetate / hexanes.
Part F: To a solution of Part E tetrahydropyranyl-protected hydroxamate (6.67 g, 12.0 mmol) in dioxane (70 mL) was added 4N HCl / dioxane (6.6 mL). After stirring at ambient temperature for 3 hours, the solution was concentrated in vacuo. C18 reverse phase column chromatography eluting with acetonitrile / (HCl) water gave a white solid (4.21 g, 69%). _{C 22 H 24 N 2 MS MH} + calculated for SO _7: 461.1382, Found: 461.1386.
Example 422: Preparation of 1-cyclopropyl-4 - [[4- (4-ethoxyphenoxy) phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide, monohydrochloride
Part A: K ₂ CO ₃ (4.00 g, 28.8 mmol) and 4-ethoxyphenol (3.99 g, 28.8 mmol) were added to a solution of the product of Example 9, Part D (8.0 g, 19.2 mmol) in DMF (30 mL) Was added. The solution was stirred at 90 占 폚 for 24 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. The desired ester (9.62 g, 94%) as an oil was obtained by silica gel chromatography eluting with 10% ethyl acetate / hexanes. MS MH ^{&lt; + &} gt ^; calculated for C ₂₇ H ₃₅ NSO ₈ : 534.2162, found: 534.2175.
Part B: A solution of the ester of Part A (9.62 g, 18 mmol) in ethyl acetate (100 mL) cooled to 0 ° C was bubbled with HCl gas for 5 minutes. The reaction was stirred at this temperature for 0.5 h. The solution was then concentrated in vacuo to give the hydrochloride (8.1 g, 96%). MS MH ⁺ calculated for C ₂₂ H ₂₇ NSO _6: 434.1637, Found: 434.1637.
Part C: To a solution of Part B hydrochloride (8.1 g, 17.2 mmol) in methanol (70 mL) was added acetic acid (9.86 mL, 172 mmol), a portion of 4-A molecular sieve (about 2 g), (1-ethoxycyclo Propyl) oxytrimethylsilane (20.7 mL, 103 mmol) and sodium cyanoborohydride (4.86 g, 74.4 mmol). This solution was refluxed for 8 hours. The precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with 1N NaOH and saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. Trituration with diethyl ether afforded the desired cyclopropylamine (6.84 g, 84%) as a white solid.
Part D: To a solution of Part C cyclopropylamine (6.84 g, 14.0 mmol) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution of NaOH (5.60 g, 140 mmol) in water , And the solution was heated at 60 占 폚 for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH = 3. Filtration afforded the desired acid (6.07 g, 88%). MS MH ⁺ calculated for C ₂₂ H ₂₇ NSO _6: 446, Found: 446.
Part E: To a solution of the Part D acid (6.07 g, 12.6 mmol) in DMF (60 mL) was added 1-hydroxybenzotriazole (2.04 g, 15.1 mmol), N- methylmorpholine (4.15 mL, 37.8 mmol) (3.38 g, 17.6 mmol) was added after the addition of O- tetrahydropyranylhydroxylamine (2.21 g, 18.9 mmol) followed by the addition of 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride Respectively. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. Silica gel chromatography eluting with 60% ethyl acetate / hexanes gave the desired tetrahydropyranyl-protected hydroxamate (6.29 g, 92%) as a white foam. _{C 28 H 36 N 2 MS MH} + calculated for SO _7: 545.2321, Found: 545.2316.
Part F: To a solution of Part E tetrahydropyranyl-protected hydroxamate (2.84 g, 5.0 mmol) in dioxane (40 mL) was added 4N HCl / dioxane (30 mL). After stirring at ambient temperature for 2.5 hours, the solution was concentrated in vacuo. The resulting solid was triturated with diethyl ether and filtered to give the desired hydroxamate (2.33 g, 90%) as a white solid. _{C 23 H 28 N 2 MS M} + calculated for SO _6: 460.1677, Found: 460.1678.
Example 423: Preparation of 4 - [[4- (cyclohexylthio) phenyl] sulfonyl] -N-hydroxy-1- (methylsulfonyl) -4-piperidinecarboxamide
Part A: K ₂ CO ₃ (4.99 g, 36.0 mmol) and cyclohexylmercaptan (4.40 g, 36.0 mmol) were added to a solution of the product of Example 9, Part D (10.0 g, 24.0 mmol) in DMF (20 mL) . The solution was stirred at 90 &lt; 0 &gt; C for 48 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. Trituration with ethanol gave the desired sulfide (7.16 g, 58%) as a white solid.
Part B: To a solution of Part A of Sulfide (9.46 g, 18.5 mmol) in ethanol (30 mL) and tetrahydrofuran (30 mL) was added a solution of NaOH (7.39 g, 185 mmol) in water (15 mL) The solution was heated at 65 &lt; 0 &gt; C for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH = 3.5. The white solid obtained was collected by filtration and washed with H ₂ O and ethyl ether to give the desired carboxylic acid (8.57 g, 95%).
Part C: A solution of the carboxylic acid of Part B (8.3 g, 17.0 mmol) in ethyl acetate (200 mL) cooled to 0 ° C was bubbled with HCl gas for 15 minutes. The reaction was then stirred at this temperature for 0.5 hour. The solution was concentrated in vacuo and the residue was triturated with diethyl ether to give the desired hydrochloride (7.03 g, 98%) as a white solid. C ₁₈ H ₂₅ NS MS MH ⁺ calculated for ₂ O _4: 384.1303, Found: 384.1318.
To a solution of Part D: Part C hydrochloride (1.0 g, 2.4 mmol) was added N-methylmorpholine (654 mL, 5.9 mmol) followed by a solution of mesyl chloride (280 mL, 3.6 mmol) in methylene chloride (20 mL) Was added. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O (400 mL) and extracted with methylene chloride. The organic layer was washed with water and saturated NaCl, dried over MgSO _4, filtered and concentrated under vacuum to give the desired as a foam methanesulfonamide (1.0 g, quantitative yield).
Part E: 1-Hydroxybenzotriazole (474 mg, 3.5 mmol), N-methylmorpholine (956 mL, 8.7 mmol) was added to a solution of Part D of methanesulfonamide (1.3 g, 2.9 mmol) in DMF ) And tetrahydropyranyl hydroxylamine (509 mg, 4.3 mmol) were added, followed by the addition of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (778 mg, 4.06 mmol) Respectively. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. Silica gel chromatography eluting with 30% ethyl acetate / hexanes gave the desired tetrahydropyranyl-protected hydroxamate (1.05 g, 82%) as a white foam.
Part F: To a solution of Part E tetrahydropyranyl-protected hydroxamate (1.05 g, 1.97 mmol) in dioxane (30 mL) was added 4N HCl / dioxane (10 mL). After stirring at ambient temperature for 2.5 hours, the solution was concentrated in vacuo. C18 reverse phase column chromatography eluting with acetonitrile / (HCl) water gave a white solid (602 mg, 64%). _{C 19 H 28 N 2 MS M} + calculated for S ₃ O _6: 477, Found: 477.
Example 424: Preparation of N-hydroxy-1- (methylsulfonyl) -4 - [[4- (phenylthio) phenyl] sulfonyl] -4-piperidinecarboxamide
Part A: K ₂ CO ₃ (20 g, 144 mmol) and thiophenol (22.2 g, 144 mmol) were added to a solution of the product of Example 9, part D (40.0 g, 96.0 mmol) in DMF (200 mL) . The solution was stirred at ambient temperature for 24 hours. The solution was then diluted with H ₂ O (1 L) and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. The desired sulphide (44.4 g, 91%) was obtained as a white solid by silica chromatography eluting with 15% ethyl acetate / hexanes.
Part B: A solution of the sulfide (31.2 g, 6.6 mmol) in Part A in ethyl acetate (500 mL) cooled to 0 ° C was bubbled with HCl gas for 30 min. The reaction was stirred at this temperature for 1.5 hours. The solution was concentrated in vacuo and the resulting solid was triturated with diethyl ether to give the hydrochloride (26.95 g, 96%) as a white solid.
To a solution of Part C: Part B hydrochloride (2.0 g, 4.7 mmol) was added N-methylmorpholine (1.29 mL, 11.7 mmol) followed by a solution of mesyl chloride (550 mL, 7.05 mmol) in methylene chloride (35 mL) Was added. The solution was stirred at ambient temperature for 48 hours. The solution was diluted with H ₂ O (400 mL) and extracted with methylene chloride. The organic layer was washed with water and saturated NaCl, dried over MgSO _4, filtered and concentrated to give the desired as a white solid, methanesulfonamide (2.17 g, 96%) was obtained under vacuum.
Part D: To a solution of Part C of methanesulfonamide (2.1 g, 4.3 mmol) in ethanol (25 mL) and tetrahydrofuran (25 mL) was added a solution of NaOH (1.72 g, 43 mmol) in water , And the solution was heated at 60 占 폚 for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH = 3.5. The resulting precipitate was filtered to give the desired carboxylic acid (2.1 g, quantitative yield) as a white solid.
Part E: 1-Hydroxybenzotriazole (705 mg, 5.2 mmol), N-methylmorpholine (1.54 mL, 12.9 mmol) was added to a solution of the carboxylic acid of Part D (1.98 g, 4.3 mmol) in DMF (Dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.17 g, 6.1 mmol) was added to a solution of 1- [3- (dimethylamino) Was added. The solution was stirred at ambient temperature for 5 days. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. C18 reverse phase column chromatography eluting with acetonitrile / (HCl) water gave the desired tetrahydropyranyl-protected hydroxamate (1.86 g, 80%) as a white solid. _{C 24 H 30 N 2 HRMS MH} + calculated for S ₃ O _7: 555.1293, Found: 555.1276.
Part F: To a solution of Part E tetrahydropyranyl-protected hydroxamate (1.86 g, 3.5 mmol) in dioxane (30 mL) and methanol (10 mL) was added 4N HCl / dioxane (20 mL) . After stirring at ambient temperature for 2.5 hours, the solution was concentrated in vacuo. C18 reverse phase column chromatography eluting with acetonitrile / (HCl) water gave the title compound (1.48 g, 91%) as a white solid. _{C 19 H 22 N 2 HRMS MH} + calculated for S ₃ O _6: 471.0718, Found: 471.0728.
Example 425: 1-Cyclopropyl-N-hydroxy-4 - [[4- [4- (trifluoromethoxy) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide, monohydrochloride Manufacturing
Part A: To a solution of the product of Example 398, Part A (6.97 g, 19.6 mmol) in DMF (500 mL) was added K ₂ CO ₃ (3.42 g, 18.0 mmol) and 4- (trifluoromethoxy) , 24.8 mmol). This solution was stirred at 90 占 폚 for 40 hours. The solution was diluted with H ₂ O (600 mL) and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl, dried with MgSO _4, filtered and concentrated in vacuo to give the diaryl ether (8.5 g, quantitative yield) as a desired oil. HRMS MH ^& lt ^{; +} & gt ^; calculated for C ₂₄ H ₂₆ NSO ₆ F ₃ : 514.1511, found: 514.1524.
Part B: To a solution of Part A diaryl ether (8.4 g, 16.4 mmol) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution of NaOH (6.54 g, 164 mmol) in water , And the solution was heated at 60 占 폚 for 18 hours. The solution was concentrated under vacuum to remove most of the organic solvent and the aqueous residue was acidified to pH = 4.0. The resulting precipitate was filtered to give the desired hydrochloride (5.01 g, 63%) as a white solid. C ₂₂ H ₂₂ NSO HRMS MH ⁺ calculated for ₆ F _3: 486.1198, Found: 486.1200.
Part C: 1-Hydroxybenzotriazole (1.65 g, 12.3 mmol), N-methylmorpholine (3.4 mL, 30.9 mmol) was added to a solution of Part B hydrochloride (5.0 g, 10.3 mmol) in DMF (80 mL) (1.60 g, 12.3 mmol) was added to a solution of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride ). The solution was stirred at ambient temperature for 42 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. Silica gel chromatography eluting with 30% ethyl acetate / hexanes gave the desired tetrahydropyranyl-protected hydroxamate (5.41 g, 89%) as a white solid.
Part D: To a solution of Part C tetrahydropyranyl-protected hydroxamate (5.4 g, 9.2 mmol) in dioxane (80 mL) and methanol (20 mL) was added 4N HCl / dioxane (50 mL) . The reaction was stirred at ambient temperature for 2.5 hours and the solution was concentrated in vacuo. Trituration with diethyl ether gave the title compound (4.02 g, 81%) as a white solid. _{C 22 H 23 N 2 HRMS MH} + calculated for SO ₃ F _6: 501.1307, Found: 501.1324.
Example 426: Preparation of 1-cyclopropyl-4 - [(4-ethoxyphenyl) sulfonyl] -N-hydroxy-4-piperidinecarboxamide, monohydrochloride
To a solution of the product of Example 398, Part A (5.87 g, 16.5 mmol) in DMF (50 mL) was added K ₂ CO ₃ (3.42 g, 24.7 mmol) and α, α, α- (trifluoromethyl) -p-cresol (4.01 g, 24.7 mmol). The solution was stirred at 90 &lt; 0 &gt; C for 48 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo to give the crude product (8.39 g) containing large amount of starting material (%). To this material (8.39 g) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution of NaOH (6.75 g, 169 mmol) in water (20 mL) and the solution was heated Respectively. The solution was concentrated in vacuo and the aqueous residue was acidified to pH = 3.5. The resulting precipitate was filtered to give the desired hydrochloride (5.04 g, 64%) as a waxy solid.
Part B: 1-Hydroxybenzotriazole (1.73 g, 12.8 mmol), N-methylmorpholine (3.5 mL, 31.8 mmol) was added to a solution of Part A hydrochloride (5.0 g, 10.3 mmol) in DMF (80 mL) (1.86 g, 15.9 mmol) followed by the addition of O- tetrahydropyranylhydroxylamine hydrochloride (1.86 g, 15.9 mmol) followed by the addition of 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride ). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. Silica gel chromatography eluting with 30% ethyl acetate / hexanes gave the desired tetrahydropyranyl-protected hydroxamate (1.5 g, 32%) as a white solid.
Part C: To a solution of Part B tetrahydropyranyl-protected hydroxamate (1.5 g, 3.3 mmol) in dioxane (30 mL) and methanol (15 mL) was added 4N HCl / dioxane (50 mL) . The reaction was stirred at ambient temperature for 2 hours and then the solution was concentrated in vacuo. The residue was triturated with diethyl ether to give the title compound as a white solid (1.09 g, 81%). _{C 17 H 24 N 2 MS MH} + calculated for SO _5: 369, Found: 369.
Example 427: 1-Cyclopropyl-N-hydroxy-4 - [[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide, monohydrochloride Manufacturing
Part A: To a solution of the product of Example 398, Part A (5.96 g, 15.0 mmol) in DMF (100 mL) was added K ₂ CO ₃ (12.34 g, 38.0 mmol) and α, α, α-trifluoromethylphenol 3.65 g, 22.5 mmol). The solution was stirred at 90 &lt; 0 &gt; C for 28 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo to give the aryl ether (7.54 g, quantitative yield) as a desired oil.
Part B: To a solution of the aryl ether of Part A (7.54 g, 15.0 mmol) in ethanol (40 mL) and tetrahydrofuran (40 mL) was added a solution of NaOH (6.06 g, 151.0 mmol) in water (20 mL) The solution was heated at 60 &lt; 0 &gt; C for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH = 2.0. The resulting precipitate was filtered to obtain the desired hydrochloride (7.98 g, quantitative yield) as a white solid. C ₂₂ H ₂₂ MS MH ⁺ calculated for NSO ₅ F _3: 470, Found: 470.
Part C: 1-Hydroxybenzotriazole (2.44 g, 18.0 mmol) and N-methylmorpholine (3.4 mL, 30.9 mmol) were added to a solution of Part B hydrochloride (7.60 g, 15.0 mmol) in DMF (100 mL) (2.63 g, 22.5 mmol) followed by the addition of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (4.02 g, 21.0 mmol ). The solution was stirred at ambient temperature for 96 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. The desired tetrahydropyranyl-protected hydroxamate (5.93 g, 69%) was obtained as a white solid by silica chromatography eluting with 30% ethyl acetate / hexanes.
Part D: To a solution of Part C tetrahydropyranyl-protected hydroxamate (3.8 g, 6.7 mmol) in dioxane (100 mL) was added 4N HCl / dioxane (30 mL). The reaction was stirred at ambient temperature for 2 hours and then the solution was concentrated in vacuo. Trituration with diethyl ether afforded the title compound (3.33 g, 96%) as a white solid. _{C 22 H 23 N 2 MS MH} + calculated for SO ₅ F _3: 485, Found: 485.
Example 428: Synthesis of N-hydroxy-1- (1-methylethyl) -4 - [[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide , Preparation of monohydrochloride
Part A: To a solution of the product of Example 9, Part D (30.0 g, 80.8 mmol) in methylene chloride (100 mL) was added trifluoroacetic acid (30 mL) in methylene chloride (40 mL). The solution was stirred at ambient temperature for 2 hours. The solution was concentrated in vacuo. To a residue that was dissolved in methylene chloride (150 mL) was added triethylamine (28.0 mL, 277 mmol), acetone (24.0 mL, 413 mmol), sodium cyanoborohydride (68 g, 323.1 mmol) and acetic acid , 308 mmol) at 0 &lt; 0 &gt; C. The reaction mixture was stirred at ambient temperature for 18 hours. The solution was diluted with 1N NaOH and extracted with ethyl ether. The organic layer was washed with 1N NaOH, water and saturated NaCl, dried over MgSO _4, filtered and concentrated under vacuum to give the desired isopropylamine (21.03 g, 72%).
Part B: To a solution of the isopropylamine (4.04 g, 11.0 mmol) of Part A in DMF (50 mL) was added CsCO ₃ (10.75 g, 33.3 mmol) and a mixture of alpha, alpha, alpha -trifluoro-p- , 16.5 mmol). This solution was stirred at 90 占 폚 for 40 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. The desired diaryl ether (5.35 g, 97%) was obtained as an oil by silica gel chromatography eluting with 30% ethyl acetate / hexanes. HRMS for C ₂₄ H ₂₈ NSO ₅ F ₃ MH ⁺ Calcd: 500.1640, found: 500.1678.
Part C: To a solution of Part B diaryl ether (5.3 g, 10.6 mmol) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution of NaOH (4.2 g, 106.0 mmol) in water , And the solution was heated at 60 占 폚 for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH = 3.0. The resulting precipitate was filtered to obtain the desired hydrochloride (5.38 g, quantitative yield) as a white solid. C ₂₂ H ₂₄ NSO MS MH ⁺ calculated for ₅ F _3: 472.1406, Found: 472.1407.
Part D: 1-Hydroxybenzotriazole (1.72 g, 12.3 mmol), N-methylmorpholine (3.5 mL, 32.0 mmol) was added to a solution of Part C of hydrochloride (5.4 g, 10.6 mmol) in DMF (1.88 g, 15.9 mmol) followed by the addition of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (2.8 g, 15.0 mmol ). The solution was stirred at ambient temperature for 144 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. Silica gel chromatography eluting with 2% methanol / ethyl acetate gave the desired tetrahydropyranyl-protected hydroxamate (2.74 g, 45%) as a white solid. HRMS MH ^& lt ^{; +} & gt ^; calculated for C ₂₇ H ₃₃ N ₂ SO ₅ F ₃ : 571.2090, found: 571.2103.
Part E: To a solution of Part D tetrahydropyranyl-protected hydroxamate (2.7 g, 4.7 mmol) in dioxane (50 mL) was added 4 N HCl / dioxane (20 mL). The reaction was stirred at ambient temperature for 2 hours. Filtration afforded the title compound as a white solid (2.08 g, 84%). _{C 22 H 25 N 2 MS MH} + calculated for SO ₅ F _3: 487, Found: 487.
Example 429: Synthesis of 1-ethyl-N-hydroxy-4 - [[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide, monohydrochloride Produce
Part A: A solution of the product of Example 9, part D (48 g, 115.0 mmol) in ethyl acetate (750 mL) cooled to 0 C was allowed to foam with gaseous HCl for 45 min, Lt; / RTI &gt; The solution was concentrated in vacuo to yield a residue which was triturated with diethyl ether to give the desired hydrochloride salt as a white solid (32.76 g, 81%).
Part B: To a solution of the hydrochloride salt of Part A (15.8 g, 45.0 mmol) in DMF (75 mL) was added K ₂ CO ₃ (12.4 g, 90.0 mmol) and bromoethane (3.4 mL, 45.0 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O (200 mL) and extracted with ethyl acetate. The organic layer was washed with water, washed with saturated NaCl, dried over MgSO _4, filtered, and then provided to the oil the desired amine was concentrated in vacuo (15.4 g, quantitative).
To a solution of Part B ethylamine (5.2 g, 15.0 mmol) in DMF (50 mL) was added CsCO ₃ (12.21 g, 37.5 mmol) and α, α, α-trifluoro-p- , 23.0 mmol). The solution was stirred at 90 &lt; 0 &gt; C for 25 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water, washed with saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. The desired diaryl ether was provided as an oil (7.3 g, quantitative yield) by chromatography on silica gel, eluting with 20% ethyl acetate / hexanes.
Part D: To a solution of diaryl ether (7.3 g, 15.0 mmol) from Part C in ethanol (40 mL) and tetrahydrofuran (40 mL) was added a solution of NaOH (6.0 g, 150 mmol) in water Was added and the solution was heated at 60 [deg.] C for 16 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH = 4.0. The resulting precipitate was filtered to yield the desired hydrochloride salt as a white solid (5.96 g, 80%). C ₂₁ H ₂₂ NSO HRMS MH ⁺ calculated for ₅ F _3: 458.1249, Found: 458.1260.
Part E: To a solution of the hydrochloride salt of Part D (5.96 g, 12.0 mmol) in DMF (80 mL) was added 1- hydroxybenzotriazole (1.96 g, 14.0 mmol), N-methylmorpholine (3.9 mL, 36.0 mmol (Dimethylarnine) propyl] -3-ethylcarbodiimide hydrochloride (3.24 g, 17.0 mmol) was added to the solution, followed by addition of O-tetrahydropyranylhydroxylamine hydrochloride (2.11 g 18.0 mmol) Was added. The solution was stirred at ambient temperature for 168 hours. The insoluble material was removed by filtration, the filtrate was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried with MgSO _4, filtered and concentrated in vacuo. Chromatography on silica gel eluting with 70% ethyl acetate / hexanes afforded the desired tetrahydropyranyl-protected hydroxamate as a white solid (2.80 g, 41%).
Part F: To a solution of the tetrahydropyranyl-protected hydroxamate (2.8 g, 5.0 mmol) in Part E in dioxane (80 mL) was added 4 N HCl / dioxane (20 mL). The reaction was stirred at ambient temperature for 5 hours and the solution was concentrated in vacuo. Trituration with diethyl ether gave the title compound as a white solid (2.08 g, 84%). _{C 21 H 23 N 2 MS MH} + calculated for SO ₅ F _3: 473, Found: 473.
Example 430: Synthesis of 1-ethyl-N-hydroxy-4 - [[4- [4- (1- methylethyl) phenoxy] phenyl] -sulfonyl] -4- piperidinecarboxamide, monohydrochloride Manufacturing
Part A: A solution of the product of Example 9, Part D (48 g, 115.0 mmol) in ethyl acetate (750 mL) cooled to 0 ° C was allowed to foam with gaseous HCl for 45 min. The reaction was stirred at that temperature for 7 hours. The solution was concentrated in vacuo to give a residue which was triturated with diethyl ether to give the desired hydrochloride salt as a white solid (32.8 g, 81%).
Part B: To a solution of the hydrochloride salt of Part A (15.8 g, 45.0 mmol) in DMF (75 mL) was added K ₂ CO ₃ (12.4 g, 90.0 mmol) and bromoethane (3.4 mL, 45.0 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O (200 mL) and extracted with ethyl acetate. The organic layer was washed with water, washed with saturated NaCl, dried over MgSO _4, filtered, and then provided to the oil the desired amine was concentrated in vacuo (15.4 g, quantitative).
Part C: To a solution of Part B ethylamine (5.2 g, 15.0 mmol) in DMF (50 mL) was added CsCO ₃ (12.2 g, 37.5 mmol) and 4-isopropylphenol (3.15 g, 23.0 mmol). The solution was stirred at 90 &lt; 0 &gt; C for 5 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water, washed with saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. The desired diaryl ether was provided as an oil (6.2 g, 95%) by chromatography on silica gel eluting with 20% ethyl acetate / hexanes. C ₂₅ H ₃₃ HRMS MH ⁺ calculated for N ₃ SO _5: 460.2158, Found: 460.2160.
Part D: To a solution of diaryl ether (6.2 g, 13.0 mmol) from Part C in ethanol (40 mL) and tetrahydrofuran (40 mL) was added a solution of NaOH (5.1 g, 130 mmol) in water Was added and the solution was heated at 60 [deg.] C for 16 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH = 4.0. The resulting precipitate was filtered and washed with H ₂ O and diethyl ether to yield the desired hydrochloride salt as a white solid (6.0 g, quant.). HRMS for C ₂₃ H ₂₉ NSO ₅ MH ⁺ Calcd: 432.1845, found: 432.1859.
Part E: To a solution of Part D hydrochloride (6.08 g, 13.0 mmol) in DMF (80 mL) was added 1-hydroxybenzotriazole (2.11 g, 15.6 mmol), N- methylmorpholine (4.3 mL, 39.0 mmol (Dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (3.49 g, 18.2 mmol) was added to the solution, followed by the addition of O-tetrahydropyranylhydroxylamine hydrochloride (2.28 g, 19.5 mmol) Was added. The solution was stirred at ambient temperature for 168 hours. The insoluble material was removed by filtration, the filtrate was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried with MgSO _4, filtered and concentrated in vacuo. Chromatography on silica gel eluting with 50% ethyl acetate / hexanes gave the desired tetrahydropyranyl-protected hydroxamate as a white solid (1.7 g, 25%). _{C 28 H 38 N 2 HRMS MH} + calculated for SO _5: 531.2529, Found: 531.2537.
Part F: To a solution of the tetrahydropyranyl-protected hydroxamate (1.7 g, 3.0 mmol) in Part E in dioxane (60 mL) was added 4 N HCl / dioxane (10 mL). The reaction was stirred at ambient temperature for 4 hours and the solution was concentrated in vacuo. Chromatography on a C18 reversed phase column eluting with acetonitrile / (HCl) water gave the title compound as a white solid (860 mg, 59%). _{C 23 H 30 N 2 HRMS MH} + calculated for SO _5: 447.1954, Found: 447.1972.
Example 431: Synthesis of 1-cyclopropyl-N-hydroxy-4 - [[4- [4- (1-methylethyl) phenoxy] phenyl] -sulfonyl] -4-piperidinecarboxamide, Preparation of Hydrochloride
To a solution of the product of Example 398, Part A (4.0 g, 10.2 mmol) in DMF (40 mL), K ₂ CO ₃ (12.46 g, 38.0 mmol) and 4- isopropylphenol (4.99 g, 15.3 mmol ). The solution was stirred at 90 &lt; 0 &gt; C for 24 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water, washed with saturated NaCl, dried over MgSO _4, filtered and concentrated in vacuo. Chromatography on silica gel eluting with 30% ethyl acetate / hexanes provided the desired diaryl ether as a white solid (3.89 g, 76%). HRMS MH ^& lt ^{; +} & gt ^; calculated for C ₂₆ H ₃₃ NSO ₅ : 472.2158, found 472.2171.
Part B: To a solution of diaryl ether (3.89 g, 8.20 mmol) from Part A in ethanol (40 mL) and tetrahydrofuran (40 mL) was added a solution of NaOH (3.30 g, 82.5 mmol) in water Was added and the solution was heated at &lt; RTI ID = 0.0 &gt; 60 C &lt; / RTI &gt; The solution was concentrated in vacuo to remove most of the organic solvent and the aqueous residue was acidified to pH = 3.0. The resulting precipitate was filtered and washed with H ₂ O and diethyl ether to yield the desired hydrochloride salt as a white solid (7.98 g, quant.). MS MH ⁺ calculated for C ₂₄ H ₂₉ NSO _5: 444, Found: 444.
To a solution of the hydrochloride salt of Part B (3.6 g, 7.0 mmol) in DMF (70 mL) was added 1-hydroxybenzotriazole (1.22 g, 9.0 mmol), N-methylmorpholine (2.3 mL, 21.0 mmol (Dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (2.01 g, 10.4 mmol) was added to the reaction solution after the addition of O-tetrahydropyranylhydroxylamine hydrochloride (1.23 g, 10.5 mmol) Was added. The solution was stirred at ambient temperature for 15 days. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried with MgSO _4, filtered and concentrated in vacuo. Chromatography on silica gel eluting with 15% ethyl acetate / hexanes afforded the desired tetrahydropyranyl-protected hydroxamate as a white solid (3.51 g, 92%). HRMS MH ⁺ calculated for _{C 29 H 38 N 2 SO 6} : 543.2529, Found: 543.2539.
Part D: To a solution of Part C tetrahydropyranyl-protected hydroxamate (3.51 g, 6.0 mmol) in methanol (10 mL) and dioxane (200 mL) was added 4 N HCl / dioxane (30 mL) Respectively. Stir at ambient temperature for 2.5 hours and concentrate the solution in vacuo. Trituration with diethyl ether gave the title compound as a white solid (2.56 mg, 86%). _{C 24 H 30 N 2 MS MH} + calculated for SO _5: 459.1875, Found: 459.1978.
Example 432: Synthesis of N-hydroxy-4 - [[4- [4- (1-methylethoxy) phenoxy] phenyl] sulfonyl] -1- (1-methylethyl) -4-piperidinecarboxamide Meade, monohydrochloride
Part A: To a solution of ethyl 4 - [(4-fluorophenylsulfonyl)] - l- (1-methylethyl) -4-piperidinecarboxylate (2.0 g) in N, N- dimethylformamide &lt; / RTI &gt; g, 5.4 mmol). Indian Chem. 4-isopropyloxyphenol (1.63 g, 10.7 mmol) and cesium carbonate (7 g, 21.5 mmol), which may be prepared according to the method of Soc., 73, 1996, 507-511, The suspension was stirred at 60 &lt; 0 &gt; C for 16 hours. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1 N sodium hydroxide, water and brine, and dried over magnesium sulfate. The organic phase was concentrated. The resulting residue was purified by chromatography on silica gel eluting with ethyl acetate / hexane to yield the aryl ether (1.06 g, 39%).
Part B: To a solution of the aryl ether (1.06 g, 2.1 mmol) in ethanol (20 mL) and water (20 mL) was added sodium hydroxide (0.84 g, 21 mmol) and the mixture was heated at 65 < . The solvent was then removed in vacuo. Water (50 mL) was added, the mixture was again concentrated in vacuo, and the resulting mixture was acidified with 2 N HCl to pH = 4-5. The solid precipitate was collected by filtration and washed with diethyl ether to yield the desired carboxylic acid (3.13 g, 100%).
Part C: A solution of the carboxylic acid of Part B (1.0 g, 2.0 mmol) in thionyl chloride (5 mL) was refluxed for 2 hours. The solvent was removed in vacuo. To the resulting residue in DMF (10 mL) was added N-methylmorpholine (0.66 mL, 6.0 mmol) and O-tetrahydropyranylhydroxylamine hydrochloride (351 mg, 3.0 mmol). The solution was stirred at ambient temperature for 18 hours. The suspension was filtered and the filtrate was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried with MgSO _4, filtered and concentrated in vacuo. Chromatography on silica gel eluting with 90% ethyl acetate / hexanes afforded the desired tetrahydropyran-protected hydroxamate as a white solid (280 mg, 23%). HRMS MH ^& lt ^{; +} & gt ^; calculated for C ₂₉ H ₄₀ N ₂ SO ₇ : 561.2634, found: 561.2653.
Part D: To a solution of Part C tetrahydropyranyl-protected hydroxamate (275 mg, 0.48 mmol) in dioxane (15 mL) was added 4 N HCl / dioxane (5 mL). After stirring at ambient temperature for 2 hours, the solution was concentrated in vacuo. Trituration with diethyl ether and filtration of the resulting solid yielded the title compound as a white solid (193 mg, 76%). _{C 24 H 32 N 2 MS MH} + calculated for SO _6: 477, Found: 477.
Example 433: Preparation of 4 - [[4 - [(2-fluorophenyl) -thio] phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide, monohydrochloride
Part A: To a solution of the product of Example 9, Part D (6.0 g, 14.4 mmol) in N, N-dimethylformamide (30 mL) was added 2-fluorothiophenol (2.22 g, 17.3 mmol) and calcium carbonate 2.40 g, 17.3 mmol) and the resulting suspension was stirred at ambient temperature for 48 hours. The reaction mixture was then diluted with ethyl acetate (200 mL) and diluted with 1N sodium hydroxide and sodium chloride (3X). The organic phase was concentrated and the resulting residue was purified by chromatography on silica gel eluting with ethyl acetate / hexane (1: 4) to give the desired arylsulfide as a white solid (8.0 g, 100%).
Part B: Sodium hydroxide (6.1 g, 152 mmol) was added to a solution of the ethyl ester of Part A (8.0 g, 15 mmol) in ethanol (90 mL) and water (20 mL) Lt; / RTI &gt; Volatile organics were removed in vacuo and the resulting aqueous mixture was acidified with 2 N HCl to pH = 3-4. Solid &lt; / RTI &gt; sodium chloride was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with NaCl and dried with magnesium sulfate. The solvent was removed to yield the desired carboxylic acid (4.92 g, 68%).
Part C: To a solution of the carboxylic acid of Part B (4.92 g, 9.93 mmol) in N, N-dimethylformamide (100 mL) was added 4-methylmorpholine (1.52 g, 15.0 mmol), N-hydroxybenzotri (Tetrahydro-2H-pyran-2-ylamine) was obtained after addition of a sol (1.62 g, 12.0 mmol) and 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride -Yl) hydroxylamine (2.24 g, 15.0 mmol). After stirring at ambient temperature for 16 hours, the reaction mixture was concentrated and the resulting residue was dissolved in ethyl acetate (200 mL) and washed with water and brine. Concentration and purification by chromatography on silica gel yielded the protected hydroxamate derivative (4.9 mg, 83%).
Part D: To a ice-bath-cooled solution of the protected hydroxamate of Part C (4.9 g, 8.25 mmol) in ethyl acetate (30 mL) was hydrogenated with hydrogen chloride gas for 10 minutes. The mixture was then allowed to stand at ambient temperature for 2 hours and then the solvent was removed in vacuo. Fresh ethyl acetate (30 mL) was added and removed in vacuo and the procedure was repeated. Ethyl acetate (50 mL) was then added and the solid obtained by filtration was purified by reverse phase chromatography eluting with acetonitrile / water (20/80 to 100% acetonitrile gradient) to give the title compound 1.9 g, 43%). C ₁₈ H ₁₉ FN ₂ O ₄ S ₂ Anal. Calcd for HCl: C, 48.37; H, 4.51; N, 6.27; Cl, 7.93. Found: C, 48.14; H, 4.33; N, 6.21; Cl, 8.64. _{C 18 H 19 FN HRMS (ESI} ) for the ₂ O ₄ S ₂ MH ⁺ calculated: 411.0849, found 411.0844.
Example 434: Synthesis of 4 - [[4 - [(2-fluorophenyl) -thio] phenyl] sulfonyl] -N-hydroxy- 1- (2-propynyl) -4- piperidinecarboxamide, Preparation of monohydrochloride
Part A: To a solution of the product of Example 9, Part F (4.46 g, 12.6 mmol) in N, N-dimethylformamide (30 mL) was added 2- fluorothiophenol (1.94 g, 15.1 mmol) and calcium carbonate 2.09 g, 15.1 mmol) and the resulting suspension was stirred at ambient temperature for 48 hours. The reaction mixture was then diluted with ethyl acetate (200 mL), washed with 1 N sodium hydroxide (200 mL) and brine (3X). The organic phase was concentrated to give the desired aryl sulfide (5.2 g, 90%).
Part B: Sodium hydroxide (5.0 g, 125 mmol) was added to a solution of the ethyl ester of Part A (5.1 g, 11.4 mmol) in ethanol (90 mL) and water (30 mL) Lt; / RTI &gt; The organics were removed in vacuo and the resulting aqueous mixture was acidified with 2 N HCl to pH = 3-4. Solid &lt; / RTI &gt; sodium chloride was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with NaCl and dried with magnesium sulfate. The solvent was removed to yield the desired carboxylic acid (4.5 g, 94%).
Part C: To a solution of the carboxylic acid of Part B (4.5 g, 11.0 mmol) in N, N-dimethylformamide (50 mL) was added 4- methylmorpholine (1.62 g, 16.0 mmol), N-hydroxybenzotri (Tetrahydro-2H-pyran-2-ylamine) was prepared by the addition of a solution of 1.74 g (12.8 mmol) of the above compound and 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride -Yl) hydroxylamine (2.39 g, 16.0 mmol). After stirring at ambient temperature for 16 hours, the reaction mixture was concentrated and the resulting residue was dissolved in ethyl acetate (200 mL) and washed with water and brine. Concentration and purification by chromatography on silica gel yielded the protected hydroxamate derivative used directly in the next step
Part D: To a ice-bath-cooled solution of the protected hydroxamate of Part C (4.9 g, 8.25 mmol) in ethyl acetate (30 mL) was hydrogenated with hydrogen chloride gas for 10 minutes. The mixture was then allowed to stand at ambient temperature for 2 hours and then the solvent was removed in vacuo. Fresh ethyl acetate (30 mL) was added and removed in vacuo and the procedure was repeated. Ethyl acetate (50 mL) was then added and the filtrate collected and the resulting solid was purified by reverse phase chromatography eluting with acetonitrile / water (20/80 to 100% acetonitrile gradient) to give the title compound (1.85 g, 35% for Parts C and D). C ₂₁ HRMS (ESI) for the _{H 21 FN 2 O 4 S 2} MH + calculated: 449.1005, found 449.1023.
Example 435: Synthesis of 4 - [[4- (4-ethoxyphenoxy) -phenyl] sulfonyl] -N-hydroxy-1- (2-propynyl) -4-piperidinecarboxamide, monohydro Preparation of chloride
Part A: To a solution of the product of Example 9, Part F (8.00 g, 22.6 mmol) in N, N-dimethylformamide (50 mL) was added 4- ethoxyphenol (9.38 g, 70 mmol) and cesium carbonate g, 70 mmol) and the resulting suspension was stirred at 75 &lt; 0 &gt; C for 20 hours. The reaction mixture was then diluted with ethyl acetate (1000 mL) and washed with 1 N sodium hydroxide, water and brine. The organic phase was concentrated and the resulting residue was purified by chromatography on silica gel eluting with ethyl acetate / hexane (1: 2) to give the desired diaryl ether (10.5 g, 99%).
Part B: Sodium hydroxide (8.9 g, 222 mmol) was added to a solution of the ethyl ester of Part A (10.5 g, 22.3 mmol) in ethanol (70 mL) and water (60 mL) Lt; / RTI &gt; Volatile organics were removed in vacuo and the resulting aqueous mixture was acidified with 2 N HCl to pH = 3-4. Solid &lt; / RTI &gt; sodium chloride was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with NaCl and dried with magnesium sulfate. The solvent was removed to yield the desired carboxylic acid (10 g, 100%).
Part C: To a solution of the carboxylic acid of Part B (10 g, 22.5 mmol) in N, N-dimethylformamide (50 mL) was added 4- methylmorpholine (3.42 g, 33.8 mmol), N-hydroxybenzotri (Tetrahydro-2H-pyran-2-ylamine) was prepared by the addition of triethylamine (3.66 g, 27.1 mmol) and 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride (6.05 g, 31.6 mmol) -Yl) hydroxylamine (5.05 g, 33.8 mmol). After stirring at ambient temperature for 16 hours, the reaction mixture was concentrated and the resulting residue was dissolved in ethyl acetate (200 mL) and washed with water and brine. Concentration and purification by chromatography on silica gel eluting with ethyl acetate / hexane (1: 1) yielded the protected hydroxamate derivative used directly in the next step (6.5 g, 53%).
Part D: To a solution of the protected hydroxamate of Part C in methanol / 1,4-dioxane (1: 3, 70 mL) was added 4 N HCl / 1,4-dioxane (30 mL) Was stirred at ambient temperature for 4 hours. The solvent was then removed in vacuo. Methanol (40 mL) was added and then removed in vacuo. Diethyl ether (100 mL) was added and the resulting solid was collected by filtration to give the title compound (4.3 g, 72%). C ₂₃ H ₂₆ N ₂ O ₆ S HCl Analytical calculated for H ₂ O: C, 53.85; H, 5.70; N, 5.46; Cl, 6.91; S, 6.25. Found: C, 53.65; H, 5.72; N, 5.41; Cl, 6.86; S, 6.48. ₂₃ H ₂₆ N ₂ C MS (ESI) MH ⁺ calculated for O ₆ S: 459, found 459.
Example 436: Synthesis of N-hydroxy-4 - [[4- [4- (methylsulfonyl) phenoxy] phenyl] -sulfonyl] -1- (2- propynyl) -4-piperidinecarboxamide , Preparation of monohydrochloride
Part A: To a solution of the product of Example 9, Part F (2.5 g, 6.4 mmol) in N, N-dimethylformamide (15 mL) was added 4- methylsulfonylphenol (3.5 g, 20.3 mmol) 8.7 g, 27 mmol) was added and the resulting suspension was stirred at 90 &lt; 0 &gt; C for 16 h. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate (500 mL) and washed with 1 N sodium hydroxide, water and brine. The organic phase was concentrated and the resulting residue was purified by chromatography on silica gel eluting with ethyl acetate / hexane (1: 1) to give the desired aryl ether (2.5 g, 77%).
Part B: Sodium hydroxide (2.0 g, 49 mmol) was added to a solution of the ethyl ester of Part A (2.5 g, 4.9 mmol) in ethanol (50 mL) and water (30 mL) Lt; / RTI &gt; The solvent was removed in vacuo. Water (50 mL) was added, the mixture was again concentrated in vacuo, and the resulting mixture was acidified with 2 N HCl to pH = 4-5. The solid precipitate was collected by filtration to give the desired carboxylic acid (1.57 g, 67%).
Part C: To a solution of the carboxylic acid of Part B (1.57 g, 3.3 mmol) in N, N-dimethylformamide (15 mL) was added 4- methylmorpholine (0.5 g, 4.9 mmol), N-hydroxybenzotri (Tetrahydro-2H-pyran-2-ylamine) was prepared by the same procedure as described in Example 1, except that the sol (0.53 g, 3.9 mmol) and 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride -Yl) hydroxylamine (0.74 g, 4.9 mmol). After stirring at ambient temperature for 16 hours, the reaction mixture was concentrated and the resulting residue was dissolved in ethyl acetate (200 mL) and washed with water and brine. Concentrated, and purified by chromatography on silica gel eluting with ethyl acetate / hexanes, gave the protected hydroxamate derivative (1.5 g, 79%) which was used directly in the next step.
Part D: To a solution of the protected hydroxamate of Part C (1.5 g, 2.60 mmol) in methanol / 1,4-dioxane (1: 3, 40 mL) was added 4 N HCl / ML) was added and the solution was stirred at ambient temperature for 3 hours. The solvent was then removed in vacuo. Methanol (30 mL) was added and then removed in vacuo. Diethyl ether (100 mL) was added and the resulting solid was collected by filtration to give the title compound (1.35 g, 98%). C ₂₂ H ₂₄ N ₂ O ₇ S ₂ Anal. Calcd for HCl: C, 49.95; H, 4.76; N, 5.30; Cl, 6.70; S, 12.12. Found: C, 49.78; H, 4.56; N, 5.25; Cl, 6.98; S, 11.98. C ₂₂ HRMS (ESI) for the _{H 24 N 2 O 7 S 2} MH + calculated: 493.1103, found 493.1116.
Example 437: Synthesis of N-hydroxy-4 - [[4 - [(phenylmethyl) amino] phenyl] sulfonyl] -1- (2-propynyl-4-piperidinecarboxamide, monohydrochloride
To a solution of the product of Example 9, Part F (2.5 g, 6.4 mmol) in N, N-dimethylformamide (30 mL) was added benzylamine (3.44 g, 32.1 mmol) and cesium carbonate (10.5 g, 32.3 mmol) mmol) was added and the resulting suspension was stirred at 100 &lt; 0 &gt; C for 16 h. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate (500 mL), washed with water and brine, and dried over magnesium sulfate. The organic phase was concentrated and the resulting residue was purified by chromatography on silica gel eluting with ethyl acetate / hexane (1: 1) to give the desired benzyl aniline derivative (2.5 g, 88%).
Part B: Sodium hydroxide (2.27 g, 56.7 mmol) was added to a solution of the ethyl ester of Part A (2.5 g, 5.67 mmol) in ethanol (50 mL) and water (30 mL) Lt; / RTI &gt; The solvent was removed in vacuo. Water (50 mL) was added, the mixture was again concentrated in vacuo, and the resulting mixture was acidified with 2 N HCl to pH = 4-5. The solid precipitate was collected by filtration and rinsed with diethyl ether to yield the desired carboxylic acid (2.3 g, 98%).
Part C: To a solution of the carboxylic acid of Part B (2.3 g, 5.57 mmol) in N, N-dimethylformamide (15 mL) was added 4-methylmorpholine (0.85 g, 8.36 mmol), N-hydroxybenzotri (Tetrahydro-2H-pyran-2-ylamine) was prepared following the addition of sol (0.9 g, 6.69 mmol) and 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride -Yl) hydroxylamine (1.25 g, 8.36 mmol). After stirring at ambient temperature for 16 h, the reaction mixture was concentrated and the resulting residue was dissolved in ethyl acetate and washed with water and brine. Concentration and purification by chromatography on silica gel eluting with ethyl acetate / hexanes yielded the protected hydroxamate derivative used directly in the next step.
Part D: To a ice-bath-cooled solution of the protected hydroxamate of Part C (4.9 g, 8.25 mmol) in ethyl acetate (50 mL) was bubbled with hydrogen chloride gas for 10 minutes. The solvent was then removed in vacuo. Ethyl acetate (100 mL) was added and then removed in vacuo. Ethyl acetate (100 mL) was then added and the resulting solid was collected by filtration to give the title compound (1.6 g, 62% for steps C and D). _{C 22 H 25 N 3 O HRMS} (ESI) MH ⁺ calculated for ₄ S: 428.1644, found 428.1652.
Example 438: 1-Ethyl-N-hydroxy-4 - [[4- [[4- [trifluoromethyl) phenyl] methoxy] -phenyl] sulfonyl] -4- piperidinecarboxamide, Preparation of monohydrochloride
Part A: To a solution of the product of Example 429, Part B (1.0 g, 2.9 mmol) in N, N-dimethylformamide (30 mL) was added 4- (trifluoromethyl) benzyl alcohol (1.53 g, And cesium carbonate (2.85 g, 8.74 mmol) were added and the resulting suspension was stirred at 95-100 C for 8 hours. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1 N sodium hydroxide, water and brine. The organic phase was concentrated and the resulting residue was purified by chromatography on silica gel eluting with ethyl acetate / hexanes to yield the desired aryl ether (0.8 g, 54%).
Part B: To a solution of the ethyl ester of Part A (0.8 g, 1.5 mmol) in ethanol (50 mL) and water (50 mL) was added sodium hydroxide (1.0 g, 25 mmol) Lt; / RTI &gt; The solvent was removed in vacuo. Water (50 mL) was added and the mixture was acidified to pH = 4 with 2 N HCI. The solid precipitate was collected by filtration to give the desired carboxylic acid (0.75 g, 99%).
Part C: To a solution of the carboxylic acid of Part B (0.75 g, 1.54 mmol) in N, N-dimethylformamide (10 mL) was added 4-methylmorpholine (0.47 g, 4.6 mmol), N-hydroxybenzotri (Tetrahydro-2H-pyran-2-ylamine) was prepared by the addition of a solution of the sol (0.25 g, 1.85 mmol) and 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride -Yl) hydroxylamine (0.35 g, 2.3 mmol). After stirring at ambient temperature for 16 hours, the reaction mixture was concentrated and the resulting residue was dissolved in ethyl acetate (200 mL) and washed with water and brine. Concentration, purification by chromatography on silica gel eluting with ethyl acetate / hexanes yielded the protected hydroxamate derivative (250 mg, 57%).
Part D: To a solution of the protected hydroxamate of Part C (250 mg, 0.43 mmol) in methanol / 1,4-dioxane (1: 3, 20 mL) was added 4 N HCl / ML) was added and the solution was stirred at ambient temperature for 3 hours. The solvent was then removed in vacuo. Additional ethyl acetate was added and removed in vacuo. Diethyl ether (100 mL) was added and the resulting solid was collected by filtration to give the title compound (190 mg, 82%). ₂₂ H ₂₅ F ₃ N ₂ C MS (CI) MH ⁺ calculated for O ₅ S: 487, found 487.
Example 439: 1-Cyclopropyl-N-hydroxy-4 - [[4- [4- (1-methylethoxy) phenoxy] -phenyl] -sulfonyl] -4- piperidinecarboxamide, Preparation of monohydrochloride
Part A: To a solution of the product of Example 398, Part A (2.49 g, 7.0 mmol) in N, N-dimethylformamide (30 mL) was added [J. Indian Chem. 4-isopropoxyphenol (1.28 g, 8.4 mmol) and cesium carbonate (5.48 g, 16.8 mmol), which may be prepared according to the method of Soc., 73, 1996, 507-511, Stir at 16O &lt; 0 &gt; C for 16 h. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1 N sodium hydroxide, water and brine. The organic phase was concentrated and the resulting residue was purified by chromatography on silica gel eluting with ethyl acetate / hexanes to yield the desired aryl ether (2.8 g, 82%).
Part B: Sodium hydroxide (2.3 g, 57 mmol) was added to a solution of the ethyl ester of Part A (2.8 g, 5.7 mmol) in ethanol (50 mL) and water (50 mL) Lt; / RTI &gt; The solvent was removed in vacuo. Water (50 mL) was added and the mixture was acidified to pH = 4 with 2 N HCI. The solid precipitate was collected by filtration to give the desired carboxylic acid (1.4 g, 53%).
Part C: To a solution of the carboxylic acid of Part B (1.4 g, 3.1 mmol) in N, N-dimethylformamide (15 mL) was added 4-methylmorpholine (0.92 g, 9.1 mmol), N-hydroxybenzotri (0.49 g, 3.66 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.82 g, 4.26 mmol) followed by O- (tetrahydro- -Yl) hydroxylamine (0.68 g, 4.5 mmol). After stirring at ambient temperature for 16 h, the reaction mixture was concentrated and the resulting residue was dissolved in ethyl acetate and washed with water and brine. Concentration and purification by chromatography on silica gel eluting with ethyl acetate / hexanes yielded the protected hydroxamate derivative used directly in the next step.
Part D: To a solution of the protected hydroxamate of Part C in methanol / 1, 4-dioxane (1: 3, 20 mL) was added 4 N HCl / 1,4-dioxane (10 mL) Was stirred at ambient temperature for 3 hours. The solvent was then removed in vacuo. Additional ethyl acetate was added and removed in vacuo. Diethyl ether was added and the resulting solid was collected by filtration to give the title compound (0.3 g, 19% for parts C and D). C ₂₄ H ₃₀ N ₂ O ₆ S Anal. Calcd for HCl: C, 56.41; H, 6.11; N, 5.48. Found: C, 56.04; H, 5.82; N, 5.44. _{C 24 H 30 N 2 O MS} (CI) MH ⁺ calculated for ₆ S: 475, 475 silchi.
Example 440: Synthesis of 4 - [[4- [2- (4-chlorophenyl) -ethyl] amino] phenyl] -sulfonyl] -1-ethyl-N-hydroxy- Preparation of Hydrochloride
Part A: To a solution of the product of Example 429, Part B (1.0 g, 2.91 mmol) in N, N-dimethylformamide (20 mL) was added 4- chlorophenethylamine (0.91 g, 5.8 mmol) and cesium carbonate 3.80 g, 11.6 mmol) was added and the resulting suspension was stirred at 90 &lt; 0 &gt; C for 24 hours. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1 N sodium hydroxide, water and brine. The organic phase was concentrated and the resulting residue was purified by chromatography on silica gel eluting with ethyl acetate / hexanes to yield the desired aryl ether (0.8 g, 58%).
Part B: Sodium hydroxide (1.0 g, 25 mmol) was added to a solution of the ethyl ester of Part A (0.8 g, 1.7 mmol) in ethanol (50 mL) and water (50 mL) Lt; / RTI &gt; The solvent was removed in vacuo. Water (50 mL) was added and the mixture was acidified to pH = 4 with 2 N HCI. The solid precipitate was collected by filtration to give the desired carboxylic acid (0.75 g, 92%).
Part C: To a solution of the carboxylic acid of Part B (0.75 g, 1.7 mmol) in N, N-dimethylformamide (20 mL) was added 4- methylmorpholine (0.51 g, 5.1 mmol), N-hydroxybenzotri (Tetrahydro-2H-pyran-2-ylamine) was obtained after addition of a sol (0.27 g, 2.0 mmol) and 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride -Yl) hydroxylamine (0.37 g, 2.5 mmol). After stirring at ambient temperature for 16 h, the reaction mixture was concentrated and the resulting residue was dissolved in ethyl acetate and washed with water and brine. Concentration and purification by chromatography on silica gel eluting with ethyl acetate / hexanes yielded the protected hydroxamate derivative used directly in the next step.
Part D: To a solution of the protected hydroxamate of Part C in methanol / 1,4-dioxane was added 4 N HCl / 1,4-dioxane (10 mL) and the solution was stirred at ambient temperature for 3 hours Respectively. The solvent was then removed in vacuo. Additional ethyl acetate was added and removed in vacuo. Diethyl ether was added and the resulting solid was collected by filtration to give the title compound (30 mg, 4% for both Part C and D).
Example 441: Synthesis of N-hydroxy-1- (2-methoxyethyl) -4 - [[4 - [[[4- (trifluoromethoxy) Preparation of piperidine carboxamide, monohydrochloride
Part A: To a solution of ethyl 4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidinecarboxylate ( (Trifluoromethyloxy) benzylamine (1.0 g, 5.2 mmol) and cesium carbonate (1.7 g, 5.2 mmol) and the resulting suspension was stirred at 90 &lt; 0 &gt; C for 24 h Lt; / RTI &gt; The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1 N sodium hydroxide, water and brine. The organic phase was concentrated and the resulting residue was purified by chromatography on silica gel eluting with ethyl acetate / hexanes to give the desired trifluoromethoxy compound (0.6 g, 30%).
Part B: To a solution of the ethyl ester of Part A (0.6 g, 1.1 mmol) in ethanol (30 mL), water (30 mL) and tetrahydrofuran (15 mL) was added sodium hydroxide (0.44 g, 11 mmol) , And the mixture was heated to 60 [deg.] C for 16 hours. The solvent was removed in vacuo. Water (50 mL) was added and the mixture was acidified to pH = 4 with 2 N HCI. The solid precipitate was collected by filtration to give the desired carboxylic acid (0.5 g, 88%).
Part C: To a solution of the carboxylic acid of Part B (0.50 g, 0.98 mmol) in N, N-dimethylformamide (10 mL) was added 4-methylmorpholine (0.15 g, 1.5 mmol), N-hydroxybenzotri (0.16 g, 1.2 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.27 g, 1.4 mmol) followed by O- (tetrahydro- -Yl) hydroxylamine (0.22 g, 1.5 mmol). After stirring at ambient temperature for 16 h, the reaction mixture was concentrated and the resulting residue was dissolved in ethyl acetate and washed with water and brine. Concentration and purification by chromatography on silica gel eluting with ethyl acetate / hexanes yielded the protected hydroxamate derivative (110 mg, 18%).
Part D: To a solution of the protected hydroxamate (110 mg, 0.18 mmol in Part C) in methanol / 1, 4-dioxane (1: 4, 20 mL) was added 4 N HCl / ) Was added and the solution was stirred at ambient temperature for 3 hours then the solvent was removed in vacuo. Additional methanol (20 mL) was added and then removed in vacuo. Diethyl ether was added and the resulting solid The product was collected by filtration to give the title compound (30 mg, 31%). C ₂₃ H ₂₈ F ₃ N ₃ O ₆ S MS (ESI) MH ⁺ Calcd: 532,
Example 442: Synthesis of N-hydroxy-4 - [[4- [4- (1-methylethoxy) phenoxy] phenyl] sulfonyl] -1- (2- methoxyethyl) -4- Preparation of radium midium and monohydrochloride
Part A: To a solution of ethyl 4 - [(4-fluorophenyl-sulfonyl)] - l- (2-methoxyethyl) -4-piperidinecarboxylate in 20 ml N, N- dimethylformamide (2.0 g, 5.4 mmol) in dichloromethane [J. Indian Chem. 4-isopropoxyphenol (1.63 g, 10.7 mmol) and cesium carbonate (7 g, 21.5 mmol), which may be prepared according to the method of Soc., 73, 1996, 507-511, Stir at 16O &lt; 0 &gt; C for 16 h. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1N sodium hydroxide, water and brine and dried over magnesium sulfate. The organic phase was concentrated and the resulting residue was purified by chromatography on silica gel eluting with ethyl acetate / hexanes to give the desired aryl ether (1.37 g, 50%).
Part B: Sodium hydroxide (1.08 g, 27 mmol) was added to a solution of the ethyl ester of Part A (1.37 g, 2.7 mmol) in ethanol (30 mL) and water (30 mL) Lt; / RTI &gt; The solvent was then removed in vacuo. Water (50 mL) was added, the mixture was again concentrated in vacuo, and the resulting mixture was acidified with 2 N HCl to pH = 4-5. The solid precipitate was collected by filtration and rinsed with diethyl ether to yield the desired carboxylic acid (1.25 g, 100%).
Part C: To a solution of the carboxylic acid of Part B (1.25 g, 2.7 mmol) in N, N-dimethylformamide (15 mL) was added 4- methylmorpholine (0.82 g, 8.1 mmol), O- (tetrahydro- Pyrrolidinio-phosphonium hexafluorophosphate (PyBroP, 1.51 g, 3.3 mmol) was added after the addition of 2-pyran-2-yl) hydroxylamine (0.61 g, 4.1 mmol) . After stirring at ambient temperature for 16 h, the reaction mixture was concentrated and the resulting residue was dissolved in ethyl acetate and washed with water and brine. Concentration, and purification by chromatography on silica gel eluting with ethyl acetate / hexane yielded the hydroxamate derivative (1.0 g, 63%).
Part D: To a ice-bath-cooled solution of the protected hydroxamate (1.0 g, 1.7 mmol) of Part C in ethyl acetate (20 mL) was bubbled with hydrogen chloride gas for 5 minutes. After stirring at ambient temperature for 5 hours, the solvent was removed in vacuo. Ethyl acetate (30 mL) was added and removed in vacuo. Ethyl acetate (30 mL) was added again and the resulting solid was collected by filtration to give the title compound (0.5 g, 56%). C ₂₄ H ₃₂ N ₂ O ₇ S HCl 1.5 Anal. Calcd for H ₂ O: C, 51.84; H, 6.53; N, 5.04; Cl, 6.38; S, 5.77. Found: C, 51.87; H, 6.12; N, 4.92; Cl, 6.38; S, 5.84. C ₂₄ H ₃₂ N MS MH ⁺ calculated for ₂ O ₇ S: 493, found 493.
Example 443: Synthesis of N-hydroxy-1- (2-pyridinylmethyl) -4- [4- (4-trifluoromethoxyphenoxy) phenyl] sulfonyl] -4-piperidinecarboxamide, di Preparation of Hydrochloride
Part A: Aryl fluoride (6.22 g, 15 mmol) from Example 9, Part D was added to a solution of powdered calcium carbonate (3.04 g, 22 mmol), 4- (trifluoromethoxy) phenol (3.92 g, 322 mmol) , And N, N-dimethylformamide (7 ml), and the mixture was stirred at 90 占 폚 for 16 hours. Additional 4- (trifluoromethoxy) -phenol (1 g) and calcium carbonate (800 mg) were added and the reaction continued at 115 ° C for an additional 20 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL, then 2 x 25 mL). The combined organic layers were dried using magnesium sulfate, concentrated and chromatographed to yield the desired aryl ether as an oil (9.6 g, approximately quantitative).
Part B: The aryl ether from Part A (9.6 g, about 15 mmol) was dissolved in ethyl acetate (45 mL). HCl solution in dioxane (4 N, 12 mL) was added and the mixture was stirred at ambient temperature for 3 hours. Thin layer chromatography indicates that the deprotection is incomplete. Aqueous dark HCl (4 mL) was added and the reaction was heated several times with a heating gun to reflux. The solution was concentrated and azeotroped with acetonitrile to give the desired piperidine hydrochloride salt as a foam (9.6 g). Nuclear magnetic resonance spectroscopy indicated some contaminating 4- (trifluoromethoxy) phenol, which had to be removed from Part A.
The piperidine hydrochloride salt (6.0 g) was dissolved in ethyl acetate (125 mL) and washed with aqueous sodium hydroxide (2 g NaOH in 50 mL water). The organic layer was dried over magnesium sulfate and filtered through a pad of silica gel. The phenolic contaminants were eluted. The desired piperidine was then liberated from the filter cake by eluting with methanol (approximately 100 mL) containing 1% aqueous ammonium hydroxide. The filtrate was concentrated and azeotroped with acetonitrile to give 3.3 g (7.3 mmol).
Part C: Piperidine (1.24 g, 2.7 mmol) from Part B was added to a solution of powdered calcium carbonate (828 mg, 6.0 mmol), 2-picolyl hydrochloride (492 mg, 3.0 mmol) Was mixed with dimethylformamide (3 mL) and the mixture was stirred at ambient temperature for 2 hours and then heated at 50 &lt; 0 &gt; C for additional 2 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (150 mL, then 50 mL). The combined organic layers were dried using magnesium sulfate, concentrated and chromatographed to give the desired ester as an oil (1.13 g, 74%).
Part D: The ester from Part C (1.1 g, 2.0 mmol) was mixed with ethanol (6 mL), water (2 mL), and potassium hydroxide (0.90 g, 16 mmol). The mixture was refluxed and heated for 4 h. The solution was then cooled to 0 &lt; 0 &gt; C and acidified using aqueous concentrated hydrochloric acid. The solvent was removed and the resulting solid was dried by azeotroping with acetonitrile. Vacuum was allowed to reach a constant weight.
(0.405 g, 3 mmol), O-tetrahydropyranylhydroxylamine (0.35 g, 3.0 mmol), and N, N-dimethylformamide N-dimethylformamide (9 ml). After 10 minutes, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.57 g, 3.0 mmol) was added and the product was stirred overnight. The reaction was then diluted with half-saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (100 mL, then 25 mL). The combined organic layers were dried with magnesium sulfate, concentrated and chromatographed (9: 1 ethyl acetate: methanol) to give the desired tetrahydropyranyl-protected hydroxamate as a yellow oil (1.20 g, 95% ).
Part E: Tetrahydropyranyl-protected hydroxamate (1.20 g, 1.90 mmol) was diluted with methanol (9 mL). Acetyl chloride (0.78 mL, 11 mmol) was added over 2 min. The reaction was stirred at ambient temperature for 2 h and then concentrated to give the desired dihydrochloride salt as a crystalline solid (1.20 g, quantitative yield). C ₂₅ H ₂₄ F ₃ N ₃ O ₆ S 2HCl Anal. Calcd for 1/3 H ₂ O: C, 47.58; H, 4.07; N, 6.66. Found: C, 47.31; H, 4.14; N, 6.80.
Example 444: Inhibition of in vitro metalloproteinases
The activity of the compounds prepared in the manner described in the above examples was determined according to Knight et al., FEBS Lett. 296 (3): 263 (1992)]. Briefly, 4-aminophenylmercylacetate (APMA) or trypsin-activated MMPs were incubated with various concentrations of inhibitory compounds at room temperature for 5 minutes.
More specifically, recombinant human MMP-13, MMP-1, MMp-2, and MMP-9 enzymes were prepared in the recipient's laboratory following conventional laboratory procedures. [V.A. Luckow, Insect Cell Expression Technology, pages 183-218, in Protein engineering: Principles and Practice, J.L. MMP-13 from full-length cDNA was expressed as an enzyme precursor using baculovirus as described by Cleland et al., Wiley-Liss, Inc., (1996). For further details on the use of the baculovirus expression system [Luckow et al., J. Virol., 67: 4566-4579 (1993)]; [O'Reillu et al., Baculovirus Expression Vectors: A Laboratorial Manual, W.H. Freeman and Company, New York, (1992); And King et al., The Baculovirus Expression System: A Laboratory Guide, Chapman &amp; Hall, London (1992). The expressed enzyme was first purified with a heparin agarose column and then purified with a chelating zinc chloride column. The enzyme precursor was activated with APMA for use in the assay.
[Washington University, St. Louis. Louis, MO] Harold Welgus provided MMP-1 expressed in transfected HT-1080. The enzyme was activated using APMA and then purified with a hydroxamic acid column. Dr. Welgus also provided transfected HT-1080 cells expressing MMP-9. Transfected HT-1080 cells expressing MMP-2 were obtained from the same university. Provided by Gregory. Studies conducted using MMP-2 in the presence of 0.02% 2-mercaptoethanol are presented in the table below together with an asterisk. More specific details regarding the manufacture and use of such enzymes can be found in the scientific literature describing these enzymes. See, e.g., Enzyme Nomenclature, Academic Press, San Diego, Ca (1992) and citations therein; and Frije et al., J. Biol. Chem., 26 (24): 16766-16773 (1994). The substrate of the enzyme is a methoxy coumarin-containing polypeptide having the following sequence:
MCA-ProLeuGlyLeuDpaAlaArgNH ₂
Wherein MCA is methoxy coumarin and Dpa is 3- (2,4-dinitrophenyl) -L-2,3-diaminopropionyl alanine. This substrate is commercially available from Baychem under the product M-1895.
Buffer used in the assay contained lauryl ether la in pH 7.5 100 mM Tris-HCl, 100 mM NaCl, 10 mM CaCl 2 and 0.05 percent polyethyleneglycol (23). Analysis was performed at room temperature, and the inhibitory compound was dissolved using dimethyl sulfoxide (DMSO) at a final concentration of 1%.
The analyzed inhibitory compounds in the analyzed DMSO / buffer solution were analyzed by Micoroflour The same amount of DMSO / buffer without inhibitor was compared with the control group using White Plates (Dynatech). The inhibitor or control solution was maintained on the plate for 10 minutes and the substrate was added to a final concentration of 4 [mu] M.
In the absence of inhibitory activity, the fluorescent peptides were cleaved at the Gly-Leu peptide bond and the highly fluorescent peptides were isolated from the 2,4-dinitrophenyl inhibitor resulting in increased fluorescence intensity (excitation at 328 nm / 415 nm Lt; / RTI &gt; Using a Perkin Elmer L550 plate reader, the inhibition was measured by a decrease in fluorescence intensity as a function of inhibitor concentration. IC ₅₀ values were calculated from these values. In a suitable place by significant digits three IC _50, are shown in Tables A and B inhibition of the results.
Inhibition Table A (nM)
Example MMP-13 MMP-2 MMP-1 MMP-9
No. IC ₅₀ (nM) IC ₅₀ (nM) IC ₅₀ (nM) IC ₅₀ (nM)
1 5.1 2.6 6600 31.6
2 0.25 0.1 220 1.4
3 0.3 0.2 1140
4 0.35 0.23 1090 5
5 4800 1800> 10000
6 0.25 0.15 327
7 37.2 1.8 &gt; 10000 235
8 24.1 4 &gt; 10000 290
9 0.5 0.2 9000 1.5
10 0.4 0.2 1600 0.3
11 6 4.4> 10000
12 <0.1 <0.1 464
13 0.6 0.4> 10000 8
14 0.1 <0.1 464
15 0.4 0.2 3600 0.2
16 2.4 100 &gt; 10000 2500
17 0.3 0.2 400 0.3
18 0.5 0.3 800
19 9 13.9> 10000
20 1.7 23.5 10000
21 0.6 1.3> 10000
22 1.2 0.9> 10000
23 0.2 <0.1 2275
24 0.4 1 &gt; 10000 3.7
25 3 2.6> 10000
26 0.5 0.2 7700 7
27 0.45 0.4> 10000 4
28 &lt; 0.1 &lt; 0.1770
29 0.3 0.15 &gt; 10,000
Inhibition Table B (nM)
Example MMP-13 MMP-2 MMP-9 MMP-13
No. IC ₅₀ (nM) IC ₅₀ (nM) IC ₅₀ (nM) IC ₅₀ (nM)
30 350 0.1 0.3 0.1
31 370 &lt; 0.1 0.2
32 &gt; 10000 0.1 2.5 0.2
33 &gt; 10000 0.5 9.4 0.8
34> 10000 1.1 1.2
35 &gt; 10000 0.3 3 0.5
36 7300 0.4 8 0.6
37 1000 0.2 0.3
38 &gt; 10000 2.0 135 22
39 &gt; 10000 230 24.5
40 4400 0.4 2.4 1.9
41 1200 0.15 0.2
42 2200 0.2 1.3 0.4
43 7000 0.4 0.8
44a &gt; 10000 &lt; 0.1 0.2
44b &gt; 10000 8000 &gt; 10000
45 8800 2.5 1.7
46 710000 - - 710000
47a &gt; 10000 7 14.6
47b &gt; 10000 3000 3100
48 210 0.2 0.25
49 &gt; 10000 76.9 90.0
51 5500 0.7 1.3
52 &gt; 10000 2.7 5.9
53 &gt; 10000 0.3 92 1.5
54> 10000 60 120
55 1200 0.1 0.3
56 1500 &lt; 0.1 0.15
57 1200 <0.1 0.2
58> 10000 83 30
59> 10000 130 180
60> 10000 64 147
61> 10000 1500 2000
62> 10000> 10000> 10000
63> 10000 18.1 530 1.5
64 1470 &lt; 0.1 0.15
65 8000 0.6 4.4 0.7
66> 10000 4590 36000
67 1600 239 268
68 &gt; 10000 5.3 130 6
69 1140 &lt; 0.1 0.2 &lt; 0.1
70 1500 0.2 7.3 0.8
71 3600 0.35 5 0.8
72 2100 &lt; 0.1 0.3
73 1140 &lt; 0.1 0.2 &lt; 0.1
74 &gt; 10000 130 480
75 &gt; 10000 60 900
78 &gt; 10000 6 50 10
79> 10000 1 1.7
80 3000 0.1 1.8 0.2
81 3300 0.1 0.3
82 4000 0.1 0.3
83 8000 1.2 5 1.5
84 8000 1.8 2.5
85 500 &lt; 0.1 0.4 &lt; 0.1
86> 10000 2.5 3.5
87 7200 0.8 13.9 0.35
88 1100 0.2 0.5 0.2
89 1200 0.15 0.4 0.25
90 1200 0.1 0.1
91 1800 1.5 40 2.1
92 &gt; 10000 1800 2430
93 8000 0.4 3.5 0.7
94 268 &lt; 0.1 0.4 &lt; 0.1
95 &gt; 10000 1 3.6 0.5
96 5000 0.2 1.3 0.3
97 4000 8.2 16.7
98 &gt; 10000 37 23.4
99> 10000 0.4 1
100 435 &lt; 0.1 0.3 0.15
101 1800 0.3 2.9 0.45
102 2000 <0.1 0.2
103> 10000 0.8 10 0.7
104> 10000 1.5 42.8 0.65
105> 10000 3500 114 0.85
106 &gt; 10000 27.1 12.1
107 &gt; 10000 12.1 6
108 2000 0.4 0.4
109 500 0.1 0.7 0.3
110 2700 0.4 10 0.5
111 3700 0.5 1.3
112 1000 7 3.2
113> 10000 0.9 4
114 3000 0.65 31.6 0.4
115 4500 0.3 31.6 0.6
116 2350 2 15.3 5.5
117 3700 0.6 45.4 4.8
118 2850 0.3 50 0.8
119 &gt; 10000 1.5 30 1.7
120 4000 0.4 0.4
121 1200 <0.1 0.2
122 600 0.1 0.15
123 3600 1.8 27.8 1.8
124 1000 0.5 1.1
125 &gt; 10000 0.4 7 0.5
126 8000 11.3 10
127> 10000 37 40
128 &gt; 10000 23.8 20
129 &gt; 10000 &gt; 100 1000
130 &gt; 10000 57.7 45.9
131 &gt; 10000 650 10
132> 10000 420
133 &gt; 10000 90 27
134 9000 29 4
135> 10000 500 65
136> 10000 445 40
137> 10000 300 34.7
138> 10000> 100> 100
139 &gt; 10000 1000 25.4
140> 10000 1000 60
141> 10000> 100> 100
142> 10000 600 70
143 &gt; 10000 900 23.9
144> 10000 800 30.7
145> 10000> 100> 100
146 &gt; 10000 650 32.6
147> 10000 2700 31
148> 10000 2400 31
149> 10000 1600 15.5
150 &gt; 10000 1300 14.5
151> 10000 1500 35
152 &gt; 10000 2400 16.5
153 &gt; 10000 2700 13.5
154> 10000 1600 27
155> 10000> 1000> 100
156> 10000 3300 27.8
157> 10000 6000 90
158> 10000 5000 80
159> 10000 2500 15.6
160 &gt; 10000 4700 33.7
161> 10000> 1000> 100
162> 10000> 1000> 100
163> 10000 4000 77.4
164> 10000 1750 20
165 &gt; 10000 330 13.6
166> 10000> 1000> 100
167> 10000> 1000> 100
168> 10000> 1000> 100
169 10000> 1000> 100
170 10000> 1000> 100
171> 10000> 1000> 100
172> 10000> 1000> 100
173> 10000> 1000> 100
174 8000 900> 100
175 10000> 1000> 100
176> 10000 400 25
177> 10000 400 21
178> 10000 540> 100
179> 10000 440 100
180 5000 128 4
181 10000 121 6.1
182 &gt; 10000 240 4
183> 10000 288 40
184> 10000 94 7
185 &gt; 10000 210 17.5
186> 10000 120 10
187> 10000 290 12.1
188 &gt; 10000 350 9.4
189 3700 94 8
190 &gt; 10000 220 10.6
191> 10000 350 4
192> 10000 330 10
193> 10000 390 6
194 10000 165 8
195 10000 100 14.5
196> 10000 240 25
197 7000 145 8
198 &gt; 10000 270 14.5
199 &gt; 10000 155 1.4
200 &gt; 10000 24 17.5
201 &gt; 10000 22.4 13.6
202 &gt; 10000 54 9.15
203 8500 31 30
204> 10000 25 27.1
205 7300 12.7 2
206> 10000> 10.0 20
207> 10000 30.6 28
208> 10000 27 27
209> 10000 19 20
210 &gt; 10000 27 20
211> 10000 33 24
212> 10000 33 20
213 310 &lt; 1.0 &lt; 1.0
214 1100 &lt; 1.0 &lt; 1.0
215 &lt; 1.0 &lt; 1.0
216 1000 &lt; 1 &lt; 1.0
217 600 &lt; 1.0 &lt; 1.0
218 &gt; 10000 &lt; 1.0 &lt; 1.0
219 &gt; 10000 &lt; 1.0 &lt; 1.0
220 145 &lt; 1.0 1.0
221 1600 &lt; 1.0 &lt; 1.0
222 100 <1.0 <1.0
223 1100 &lt; 1.0 &lt; 1.0
224 &gt; 10000 18.1 16.7
225> 10000 54 70
226 &gt; 10000 18.6 6
227 &gt; 10000 &lt; 1 &lt; 1
228 600 &lt; 1.0 &lt; 1.0
229 &gt; 10000 &lt; 1 &lt; 1
230 &gt; 10000 &gt; 100 &gt; 100
231 650 &lt; 1.0 &lt; 1.0
232 <100 <1.0 <1.0
Example 445: In vivo angiogenesis assay
The study of angiogenesis depended on a reliable and reproducible model for stimulation and inhibition of angiogenic responses. Micropocket analysis of the cornea provided an angiogenic model in the rat cornea. [A Model of Angiogenesis in the Mouse Cornea; Kenyon, BM, et al., Investigative Ophthalmology & Visual Science, July 1996, Vol. 37, No. 8].
In this assay, uniform sized Hydron containing sucralate and bFGF Pellets were prepared and surgically implanted into the substrate mouse cornea adjacent to the temporal corneal limbus. 10 [mu] g recombinant bFGF, 10 mg sucralfate and 12% Hydron in ethanol A suspension of 20 [mu] l sterile saline containing 10 [mu] l was prepared to form pellets. The slurry is then placed on a 10 x 10 mm piece of sterile nylon mesh. After drying, the nylon fibers of the net were separated to release the pellets.
A 7 week old C57Bl / 6 female mouse was anesthetized and the pupil was extruded with jeweler's forceps on a precision scientific instrument to prepare a corneal pocket. Using a dissecting microscope, the cornea was incised approximately 0.6 mm in length and centered parallel to the lateral rectus insert with a # 15 surgical knife. Using a modified cataract chart, a laminated micropocket was cut toward the temporal corneal limbus. The pocket is stretched to within 1.0 mm of the temporal corneal limbus. A single pellet is placed on the corneal surface at the bottom of the pocket with a forceps on a precision scientific instrument. The pellet is then delivered to the temporal extremities of the pocket. The antibiotic ointment was then applied to the eye.
Routine bases were dosed into the mice during the analysis period. The dose of the animal was based on the in vivo utilization of the compound and overall efficiency. An example of the dosage is 10 to 50 mg / g (mpk) bid, po. to be. Angiogenesis of the corneal stroma begins on about the third day and can continue up to the fifth day under the influence of the compound being analyzed. On day 5, angiogenesis inhibition was recorded by observing the progression of angiogenesis with a slit lamp microscope.
The mice were anesthetized and the study eye was again extruded. The maximum blood vessel length of the angiogenesis stretched from the pellet to the limbus was measured. In addition, the peripheral zone of adjacent angiogenesis was measured in terms of time (the arc of 30 degrees equals one clock time). The area of angiogenesis is calculated as follows.
Five to six mice were used for each compound in each study. The study mice were then compared with control mice and the differences in angiogenic areas were recorded as mean values. Mice of each group studied in this way constitute an "n" value of 1, with values of "n" greater than 1 representing multiple studies in which the mean results are provided in the table. Exemplary compounds typically exhibit inhibition rates of about 25 to about 75%, while excipient controls show an inhibition of 0%.
Data for the four compounds of the above example at doses of 10 and 50 mpk are shown below.
Inhibition rate of angiogenesis
Dose
Example 10 mpk 50 mpk
Marimastat - 48 (n = 6)
4 18 (n = 3) 41 (n = 6)
9 50 (n = 2) 46 (n = 3)
10 47 (n = 1) 54 (n = 2)
24 53 (n = 1) 78 (n = 1)
Example 446: In vivo PC-3 tumor reduction
PC-3 human pancreatic cancer cells (ATCC CRL 1435) were cultured in a 90% pool in F12 / MEM (Gibco) containing 7% FBS (Gibco). Cells were mechanically harvested with rubber scrapers and washed twice with cold media. The shed cells were resuspended in a low temperature medium containing 30% Matrigel (Collaborative Research) and the cell containing medium was kept on ice until use.
Seven to nine major Balb / c nu / nu mice were anesthetized with abertin [2,2,2-tribromethanol / t-amyl alcohol (1 g / l) diluted 1:60 into phosphate buffered saline) , 3-5 x 10 &lt; ⁶ &gt; cells in 0.2 ml medium were injected into the left flank of each mouse. The cells were injected in the morning, whereas the administration of the inhibitor started at 6 pm. From day 0 (cell implantation day) to day 25-30, animals were fed a meal with BID, and animals were euthanized and tumor weight was measured.
The compound was administered at a dose of 10 mg / ml in 0.5% methylcellulose / 0.1% polysorbate 80, followed by two doses of 50 mg / kg (mpk) per day or 10 mg / kg (mpk) . Tumor measurements were initiated on day 7 and continued every 3-4 days until completion of the study. Groups of 10 mice were used in each study, and 9 to 10 survived. Mice of each group studied in this way constitute an "n" value of 1, with values of "n" greater than 1 representing multiple studies in which the mean results are provided in the table. The results of these studies on the various compounds mentioned above are shown below as the mean of tumor weight reduction.
Mean tumor weight reduction%
Example 10 mpk 50 mpk
Marimastat <5 39 (n = 2)
4 33 (n = 2) 43 (n = 2)
9 40 (n = 1) 60 (n = 1)
10 nt 59 (n = 1)
Example 447: Tumor necrosis factor analysis
Cell culture.
The cells used in the assay are the human monocytic cell line U-937 (ATCC CRL-1593). Cells were cultured in RPMI containing 10% FCS and PSG supplement (R-10) to prevent overgrowth. Was analyzed as follows:
1. Cells were counted and collected by centrifugation. The pellet 1.540 × 10 ⁶ cells / ㎖ reproduction was suspended in R-10 supplement to a concentration of.
2. The test compound in 65 [mu] l R-10 was added to the appropriate wells of a 96-well plate tissue culture plate. The DMSO stock (100 mM compound) was first diluted to provide a 400 uM solution, from which an additional 3-fold serial 5 dilutions were made. A final compound test concentration of 100 μM, 33.3 μM, 11.1 μM, 3.7 μM, 1.2 μM and 0.4 μM was obtained with each dilution of 65 μL (triplicate).
3. Count the cells, wash and resuspend in 130 [mu] l (200,000 cells / well) and add to the wells.
4. Incubate at 37 ° C for 45 minutes to 1 hour in a container saturated with 5% CO ₂ in water.
5. R-10 (65 μl) containing 160 ng / ml PMA (Sigma) was added to each well.
6. The test system was incubated at 37 ° C and 100% humidity in 5% CO ₂ overnight (18-20 hours).
7. Carefully remove 150 μl of the supernatant from each well for use in the ELISA assay.
For toxicity, 250 μl of PMS solution, 5 ml of TMS [CellTiter 96 AQueous One Solution Cell Proliferation Assay Cat. # G358 / 0,1 (Promega Biotech)] and 5 ml R-10 was added to each well containing the remaining supernatant and cells, and the cells were incubated until the color disappeared in a 5% CO ₂ baeang it was incubated at 37 ℃. The system was excited at 570 nm and read at 630 nm.
TNF receptor II ELISA assay
1. 2 μg / ml mouse anti-human TNFrII antibody (R & D Systems # MAB226) in 1 × PBS (pH 7.1, Gibco) was plated at 100 μl / well on a NUNC-Immuno Maxisorb plate. The plates were incubated overnight at 4 ° C (about 18-20 hours).
2. The plate was washed with PBS-Tween (1 x PBS containing 0.05% Tween).
3. 200 [mu] l of 5% BSA in PBS was added and blocked at 37 [deg.] C for 2 hours in a water saturated atmosphere.
4. Wash the plate with PBS-Tween.
5. Samples and control were added to each well (100 [mu] l each). The standard is 0, 50, 100, 200, 300 and 500 pg recombinant human TNFrII (R &amp; D Systems # 226-B2) in 100 [mu] l of 0.5% BSA in PBS. Between 400 and 500 pg the assay is linear.
6. Incubate at 37 ° C for 1.5 hours in a saturated atmosphere.
7. The plate was washed with PBS-Tween.
8. Add 100 [mu] l of goat anti-human TNFrII polyclonal (1.5 [mu] g / ml R &amp; D Systems # AB226-PB in 0.5% BSA in PBS).
9. Incubate at 37 ° C for 1 hour in a saturated atmosphere.
10. The plate was washed with PBS-Tween.
11. Add 100 μl anti-goat IgG-peroxidase (1: 50,000 in 0.5% BSA in PBS, Sigma # A5420).
12. Incubate at 37 ° C for 1 hour in a saturated atmosphere.
13. Wash the plate with PBS-Tween.
14. Add 10 μl KPL TMB developer, develop at room temperature (usually about 10 minutes), terminate with phosphoric acid, excite at 450 nm and read at 570 nm.
TNFα ELISA analysis
Saran Wrapped tightly wrapped, Immulon 2 plates of 0.1 ㎖ / well _{0.1 M NaHCO 3 pH 8.0 1 ㎍} / ㎖ overnight with Genzyme mAb (about 18-20 hours) in the buffer, was coated at 4 ℃.
The coating solution was filicked out, and Saran Wrapped and blocked with 0.3 ml / well blocking buffer at 4 &lt; 0 &gt; C overnight.
The wells were washed four times thoroughly with wash buffer, and all wash buffer was removed completely. 0.1 ml / well of each sample or rhTNFα standard was added. If necessary, the sample is diluted with a suitable diluent (for example tissue culture medium). The standards were diluted with the same diluent. Three standards and samples were required.
Gt; 37 C &lt; / RTI &gt; for 1 hour in a corroded container.
The plate was washed as above. A 1: 200 dilution of genzyme rabbit anti-hTNF was added at 0.1 ml / well.
The incubation was repeated.
Washing was repeated. 1 μg / ml Jacksom goat anti-rabbit IgG (H + L) -peroxidase was added at 0.1 ml / well.
Followed by incubation at 37 DEG C for 30 minutes.
Washing was repeated. Peroxidase-ABS solution was added to 0.1 ml / well.
And incubated at room temperature for 5-20 minutes.
The OD was read at 405 nm.
The 12 reagents are as follows:
Genzyme mouse anti-human TNF Monoclonal (Cat. # 80-3399-01),
Genzyme Rabbit anti-human TNF Polyclonal (Cat. # IP-300),
Genzyme Recombinant Human TNF (Cat. # TNF-H),
Jackson Immunoresearch Peroxidase-conjugated goat anti-rabbit IgG (H + L) (Cat. # 111-035-144),
Kirkegaard / Perry peroxidase ABTS solution (Cat. # 50-66-01),
Immulon 2 96-well microtiter plate,
The blocking solution is 1 mg / ml gelatin in PBS containing 1 X thimerazole.
The wash buffer was washed with 0.5 ml Tweem &lt; RTI ID = 0.0 &gt; 20.
result:
Example No.MTS Toxicity TD ₅₀ (micromolar)TNFRII release IC ₅₀ (micromolar)TNFa release IC ₅₀ (micromolar) DMSO469101327356995379100> 100> 100> 100> 100> 100100> 100100> 10080100> 100> 100> 100> 100> 100> 100> 100> 100> 100> 100> 100> 100> 50> 50> 50> 50> 50> 80> 80> 80> 5080
Example 448: Pharmacokinetic (PK) evaluation of MMP inhibitors in rats
Separate the femoral artery (all 8 mice) and the femoral vein (4 out of 8), pipet PE50 tubing and lock with 3.0 silk suture. Subsequent measurements require two catheters, the venous line used for infusion of the compound (in the case of a rat receiving the compound via the intravenous (IV) route) and the arterial line used for the collection of blood samples. The rats were then placed in a minimally moveable confinement box and allowed to awaken from the anesthesia for approximately 30 minutes. Blood samples (400 [mu] l) were taken from the arterial cannula at 0 hour (before dosing).
One group of rats (4 rats per group) received 2 ml / kg (10 mg / ml, 0.1% Tween (10 mg / ml, 10% EtOH, 50% PEG 400, dissolved in 40% saline) in the remaining groups of rats. Administered intravenously. &Lt; / RTI &gt; Blood samples were taken from the arterial cannula at 15, 30, 60, 120, 240 and 360 minutes in the oral group and an additional 3 minute samples were taken from the IV group. After each sample, PBS containing 10 units / ml heparin is poured into the cannula. At the end of the study at 6 hours, animals were euthanized with excessive anesthesia or carbon monoxide choking. Blood samples were analyzed at each time point for MMP-13 enzyme inhibitory activity and the circulating concentrations of compound plus and active metabolites were estimated based on standard curves. The pharmacokinetic (PK) parameters were calculated with the VAX computer program CSTRIP. The parameters are defined in textbooks such as Goodman and Gilman's The Pharmacological Basis of Therapeutics, eighth ed., McGraw-Hill, Ins., New York (1993) and references therein.

From the foregoing, it can be seen that many changes and modifications can be effected without departing from the spirit and scope of the novel concept of the invention. It should be understood that the specific embodiments illustrated are not limiting. The specification is intended to cover by the appended claims all such modifications as fall within the scope of the claims.

权利要求:
Claims (142)
[1" claim-type="Currently amended] (MMP) -2, MMP-9 and MMP-13, while the inhibitory activity against MMP-1 is substantially less than that of metal Or a pharmaceutically acceptable salt thereof, with an effective amount of a protease inhibitor compound, or a pharmaceutically acceptable salt thereof, in a mammalian host afflicted with a disease associated with a pathological matrix metalloprotease (MMP) activity, wherein the pathological matrix metalloprotease activity Treatment of diseased mammalian hosts:
(I)

[Wherein,
R ¹ and R ² are both hydrazido or R ¹ and R ² together with the atom to which they are attached form a 5- to 8-membered ring containing one, two or three heteroatoms, such as oxygen, sulfur or nitrogen, &Lt; / RTI &gt;
R ³ is an optionally substituted aryl or optionally substituted heteroaryl radical, wherein when the aryl or heteroaryl radical is substituted, the substituent is selected from the group consisting of (a) optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl Alkoxyalkyl, arylalkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylthiazoaryl, arylhydrazino, arylthio, Alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, aralkylthioaryl radical, sulfoxide or sulfone of thio substituent, and aryl, heteroaryl, cycloalkyl and heterocycloalkyl. A fused ring structure comprising two or more 5-membered or 6-membered rings selected, (b) a fused ring structure selected from the group consisting of cyano, perfluoro Haloalkyl, alkoxy, nitro, thiol, hydroxycarbonyl &lt; / RTI &gt;&lt; RTI ID = 0.0 &gt; Aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkyl Alkylthio, aralkylamino, heterocyclo, heteroaryl, arylthio, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, arylthio, arylthio, arylthio, Alkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, arylox Alkoxyalkylthio, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino wherein the amino nitrogen Is selected from the group consisting of (i) unsubstituted or (ii) alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl And (iii) amino nitrogen and two substituents attached thereto are substituted with 0 to 2 additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, or And wherein the ring itself forms a 5- or 8-membered heterocyclo or heteroaryl ring containing (a) unsubstituted or (b) aryl, alkyl, heteroaryl, aralkyl , Heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzo fused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, Substituted with one or two groups independently selected from the group consisting of alkyl, alkoxy, alkylcarbonyl, arylcarbonyl, arylcarbonyl, arylcarbonyl, arylcarbonyl, Carbonylamino wherein the carbonylamino nitrogen is either (i) unsubstituted, (ii) is a reactive amine of an amino acid, or (iii) is alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, Benzyl fused heterocycloalkyl, benzo fused heterocycloalkyl, benzo fused cycloalkyl, and N, N-dialkyl (Iv) the carboxamido and the two substituents bonded thereto are taken together, either unsubstituted or substituted by one or more radicals selected from the group consisting of alkyl, alkoxycar Wherein the amino nitrogen is (i) unsubstituted, or (ii) alkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halogen, nitro, , Or (iii) amino nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, optionally substituted with one or two substituents independently selected from the group consisting of Membered heterocyclo, heteroaryl or benzo fused heterocycloalkyl ring substituted with one or two radicals independently selected from the group consisting of ), And an aminoalkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) independently of the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl groups , Or (iii) the aminoalkyl nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, optionally substituted with one or two substituents selected from Optionally substituted with one or more substituents selected.
[2" claim-type="Currently amended] The compound according to claim 1, wherein R ¹ and R ² together with the atom to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms in the ring, which is oxygen, sulfur or nitrogen, Lt; / RTI &gt;
[3" claim-type="Currently amended] ^3. A compound according to claim 2, wherein R &lt; ³ &gt; is a 5-membered or 6-membered monocyclic aryl or heteroaryl group, 6-membered ring in its 4-position, Position, one further monocyclic aryl or heteroaryl group, a C ₃ -C ₁₄ alkyl group, an N-piperidyl group, an N-piperazinyl group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, &Lt; / RTI &gt; and benzamido groups.
[4" claim-type="Currently amended] 4. The method of claim 3, wherein R &lt; ³ &gt; comprises two or more 5-membered or 6-membered rings.
[5" claim-type="Currently amended] The compound according to claim 3, wherein R ³ is a SO ₂ -bond 1-position and a substituent-bond 4-position of a 6-membered ring, or a SO ₂ -bond 1 -position and a substituent- Dimensional volume having a width of from about 1 furanyl ring to about 2 phenyl rings in the direction of rotation at the cross-section of the axis when the ring is rotated about the axis drawn through the ring.
[6" claim-type="Currently amended] The method according to claim 3, wherein R ³ is longer than the length of the pentyl group and less than the length of the eicosyl group.
[7" claim-type="Currently amended] A metalloprotease inhibitor compound that is structurally equivalent to the following formula II and which inhibits the activity of at least one of MMP-2, MMP-9 and MMP-13 while exhibiting a substantially lower inhibitory activity of MMP-1, or A pharmaceutically acceptable salt thereof is administered to a mammalian host afflicted with a disease associated with pathologic matrix metalloproteinase (MMP) activity, comprising administering to the mammalian host an effective amount of a disease-associated mammalian host associated with pathological matrix metalloprotease activity Treatment:
&Lt; RTI ID = 0.0 &

Wherein,
R ¹⁴ is selected from the group consisting of a hydrido, a pharmaceutically acceptable cation or C (W) R ¹⁵ wherein W is O or S and R ¹⁵ is C ₁ -C ₆ -alkyl, aryl, C ₁ -C ₆ -alkoxy, aryl -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aryloxy, aralkyl, -C ₁ -C ₆ - alkoxy, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl and amino C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkoxycarbonyl, C ₁ -C ₆ - alkoxycarbonyl, and C ₁ -C ₆ - the group consisting of alkanoyl radicals Or (iii) amino C ₁ -C ₆ -alkyl nitrogen and the two substituents attached thereto are substituted by one or two substituents independently selected from a 5 to 8 membered heterocyclo or heteroaryl ring Lt; / RTI &gt;
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
the sum of m + n + p is 1, 2, 3 or 4;
(a) X, one of Y and Z is selected from ^{C (O), NR 6,} O, S, S (O), S (O) 2 and NS (O) group consisting of ₂ R ^7, X, The remaining two of Y and Z are CR ⁸ R ⁹ , and CR ¹⁰ R ¹¹ ,
(b) X and Z or Z and Y together ^{NR 6 C (O), NR} 6 S (O), NR 6 S (O) 2, NR 6 S, NR 6 O, SS, NR 6 NR 6, and OC (O), the other of X, Y and Z being CR ⁸ R ⁹ , or
(c) n is 0, and X, Y and Z together form a group of formula:

[Wherein,
The wavy line is the bond to the atom of the indicated ring;
R ⁶ and R ^{6 '} are independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkanoyl, C ₆ -aryl-C ₁ -C ₆ -alkyl, aroyl, bis (C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl) -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkyl, C ₁ -C ₆ - haloalkyl, C ₁ -C ₆ - perfluoroalkyl, C ₁ -C ₆ - trifluoromethyl alkyl, C ₁ -C ₆ - perfluoroalkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₈ - heterocycloalkyl, C ₃ -C ₈ - heterocycloalkyl-carbonyl, C ₆ - aryl, C ₅ -C ₆ - heterocycloalkyl, C ₅ -C ₆ - heteroaryl, C ₃ -C ₈ - cycloalkyl- C ₁ -C ₆ -alkyl, C ₆ -aryloxy-C ₁ -C ₆ -alkyl, heteroaryloxy-C ₁ -C ₆ -alkyl, heteroaryl-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, C ₆ -arylsulfonyl, C ₁ -C ₆ -alkylsulfonyl, C ₅ -C ₆ -heteroarylsulfonyl, carboxy-C ₁ -C ₆ -alkyl, C ₁ -C ₄ - alkoxy-carbonyl -C ₁ -C ₆ - alkyl, aminocarbonyl, C _l -C ₆ -alkyl already noka Viterbo carbonyl, C ₆ - Reel already noka Viterbo carbonyl, C ₅ -C ₆ - heterocycloalkyl already noka Viterbo carbonyl, C ₆ - arylthio -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, C ₆ - arylthio -C ₃ -C ₆ - alkenyl, C ₁ -C ₄ - alkylthio -C ₃ -C ₆ - alkenyl, C ₅ -C ₆ - heteroaryl, -C ₁ -C ₆ - alkyl, halo -C ₁ -C ₆ - alkanoyl, hydroxy -C _l -C ₆ - alkanoyl, thiol -C ₁ -C ₆ - alkanoyl, C ₃ -C ₆ - alkenyl, C ₃ -C ₆ - alkynyl C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkyl, C ₁ -C ₅ -alkoxycarbonyl, aryloxycarbonyl, NR ⁸ R ⁹ -C ₁ -C ₅ -alkylcarbonyl, hydroxy -C ₁ -C ₅ - alkyl, aminocarbonyl (where aminocarbonyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of an alkanoyl group), a hydroxy-aminocarbonyl, aminosulfonyl group (wherein, aminosulfonyl Nitrogen is (i) _{Or, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - Al 1 is independently selected from the group consisting of alkanoyl groups Amino-C ₁ -C ₆ -alkylsulfonyl, wherein the amino-C ₁ -C ₆ -alkylsulfonyl is (i) unsubstituted or (ii) substituted by C ₁ - C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - alkanoyl group substituted by one or two radicals independently selected from the group consisting of ) and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ -cycloalkyl and a C ₁ -C ₆ -alkanoyl group); R 1 is selected from the group consisting of:
R ⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyl, C ₁ -C ₆ -carboxyalkyl and C ₁ -C ₆ -hydroxyalkyl group;
R ^8, R ^9, R ¹⁰ and R ¹¹ are also hideurayi, hydroxy, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl -C ₁ -C ₆ - Alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl, thiol-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylthio-C ₁ -C ₆ -alkylcycloalkyl, C ₁ -C ₆ -alkyl, heterocycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, aralkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy carboxylic carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, arylthio ₁ -C -C ₆ - alkyl, heteroarylthio -C ₁ -C ₆ - alkyl, -C ₁ -C ₆ with a sulfoxide or sulfone, perfluoroalkyl of said thio substituents -methyl-alkyl, trifluoromethyl -C ₁ -C ₆ - Alkyl, halo-C ₁ -C ₆ -alkyl, alkoxycarbonylamino-C ₁ -C ₆ -alkyl Kill and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of alkanoyl search) with independently selected from the group consisting of; Or R ⁸ and R ⁹ , or R ¹⁰ and R ¹¹ and the carbon to which they are attached form a carbonyl group, or R ⁸ and R ⁹ , or R ¹⁰ and R ¹¹ , or R ⁸ and R ¹⁰ , A 5- to 8-membered heterocyclic ring containing 1 or 2 hetero atoms such as nitrogen, oxygen, or sulfur, or a 5-to 8-membered carbocyclic ring, with R &lt; ⁸ &gt; And R ⁹ , or only one of R ¹⁰ and R ¹¹ is hydroxy;
R ¹² and R ^{12 'are} also hideurayi, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl, C ₂ -C ₆ - alkynyl, C ₂ -C _6-alkenyl, thiol -C ₁ -C ₆ - alkyl, cycloalkyl, cycloalkyl -C ₁ -C ₆ - alkyl, heterocycloalkyl -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy-carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, arylthio -C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, the sulfoxide or sulfone of said thio substituent, perfluoro-C ₁ -C ₆ -alkyl, trifluoromethyl-C ₁ -C ₆ -alkyl, halo -C ₁ -C ₆ - alkyl, alkoxycarbonylamino -C ₁ -C ₆ - alkyl and Mino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl, and C ₁ - C ₆ - Al 1 is independently selected from the group consisting of alkanoyl, or substituted with two radicals) with independently selected from the group consisting of;
R ¹³ is selected from the group consisting of: hydrido, benzyl, phenyl, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl and C ₁ -C ₆ -hydroxyalkyl groups do] Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt;
G-A-R-E-Y is a substituent having a length greater than the length of the pentyl group and less than the length of the eicosyl group,
G is an aryl or heteroaryl group;
A is selected from the group consisting of:
(1) -O-;
(2) -S-;
(3) -NR ¹⁷ -;
(4) -CO-N (R ¹⁷ ) or -N (R ¹⁷ ) -CO-, wherein R ¹⁷ is hydrogen, C ₁ -C ₄ -alkyl, or phenyl;
(5) -CO-O- or -O-CO-;
(6) -O-CO-O-;
(7) -HC = CH-;
(8) -NH-CO-NH-;
(9) -C C-;
(10) -NH-CO-O- or -O-CO-NH-;
(11) -N = N-;
(12) -NH-NH-; And
(13) -CS-N (R ¹⁸ ) - or -N (R ¹⁸ ) -CS-, wherein R ¹⁸ is hydrogen, C ₁ -C ₄ -alkyl, or phenyl; or
(14) A is absent and G is directly bonded to R;
R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Cycloalkyl, thioalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl substituents are unsubstituted or (ii) Alkoxy, C ₁ -C ₂ -alkylene-dioxy, hydroxycarbamoyl, perhaloalkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, One or two radicals selected from the group consisting of haloalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkylcarbonylalkyl, A residue selected from the group consisting of substituted), R A is not an alkyl or alkoxyalkyl when -O- or -S-;
E is selected from the group consisting of:
(1) -CO- (R ¹⁹⁾ or - (R ¹⁹⁾ -CO- (wherein, R ¹⁹ is a heterocycloalkyl, or a cycloalkyl group Im);
(2) -CONH- or -HNCO-;
(3) -CO-;
(4) -SO ₂ -R ¹⁹ - or -R ¹⁹ -SO ₂ -;
(5) -SO ₂ -;
(6) -NH-SO ₂ - or -SO ₂ -NH-; or
(7) E is absent and R is directly bonded to Y;
Y is either not present or is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, Wherein the aryl, heteroaryl, or heterocycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of (i) alkyl, alkenyl, alkenyl, alkynyl, Wherein the amino nitrogen is (i) unsubstituted or (ii) is independently selected from the group consisting of hydrido, alkyl, and aralkyl groups; Substituted with one or two radicals selected from the group consisting of &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt;
[8" claim-type="Currently amended] 8. The method of claim 7, wherein the -G-A-R-E-Y substituent comprises 2 to 4 carbocyclic or heterocyclic rings.
[9" claim-type="Currently amended] 9. The method of claim 8, wherein each of the two to four rings is six.
[10" claim-type="Currently amended] 8. The method of claim 7, wherein the -G-A-R-E-Y substituent has a length greater than the length of the hexyl group and less than the length of the stearyl group.
[11" claim-type="Currently amended] 8. The method of claim 7, wherein A is -O- or -S-.
[12" claim-type="Currently amended] 8. The method of claim 7, wherein R is aryl, heteroaryl, cycloalkyl or heterocycloalkyl group.
[13" claim-type="Currently amended] 8. The method of claim 7, wherein E is absent.
[14" claim-type="Currently amended] 8. The method of claim 7, wherein Y is selected from the group consisting of hydride, alkyl, alkoxy, perfluoroalkoxy and perfluoroalkylthio groups.
[15" claim-type="Currently amended] A metalloprotease inhibitor compound which corresponds in structure to Formula III and which inhibits the activity of one or more of MMP-2, MMP-9 and MMP-13 while exhibiting a substantially less inhibitory activity on MMP-1, or A pharmaceutically acceptable salt thereof is administered to a mammalian host afflicted with a disease associated with pathologic matrix metalloproteinase (MMP) activity, comprising administering to the mammalian host an effective amount of a disease-associated mammalian host associated with pathological matrix metalloprotease activity Treatment:
(III)

Wherein,
R ³ is a 5 or 6 membered ring at its 4-position for a six membered ring and at its 3- or 4-position for a five membered ring, thiophenoxy, 4-chloro 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4-fluorothiophenoxy, (Trifluoromethylthio) phenoxy, 4-trifluoromethoxyphenoxy, 4-trifluoromethylphenoxy, 4- (trifluoromethylthio) phenoxy, 4- 4-isopropoxyphenoxy, (2-methyl-1,3-benzothiazol-5-yl) oxy, 4- (1H-imidazol- 3-methylphenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy, 4-chloro-3-methylphenoxy, 4- (1H-1,2,4-triazol-1-yl) phenoxy, 3,5-difluorophenoxy, 3,4-dichlorophenoxy, 4-cyclopentane Phenoxy, 4-bromo-3-methylphenoxy, 4-bromophenoxy, 4-methylthiophenoxy, 4-phenylphenoxy, 4-benzylphenoxy, 6-quinolinyloxy, 4- Amino-3-methylphenoxy, 3-methoxyphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy and 4-benzyloxyphenoxy groups Lt; / RTI &gt; is a monocyclic aryl or heteroaryl group that is itself substituted with a substituent selected from the group consisting of &lt; RTI ID = 0.0 &gt;
R ¹⁴ is a hydride, a pharmaceutically acceptable cation or a C (W) R ¹⁵ wherein W is O or S and R ¹⁵ is C ₁ -C ₆ -alkyl, aryl, C ₁ -C ₆ -alkoxy, heteroaryl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aryloxy, aralkyl, -C ₁ -C ₆ - alkoxy, aralkyl, -C ₁ -C ₆ - alkyl , Heteroaryl and amino C ₁ -C ₆ -alkyl groups wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkoxycarbonyl, C ₁ -C ₆ - alkoxycarbonyl, and C ₁ -C ₆ - alkanoyl radical consisting of Or (iii) amino C ₁ -C ₆ -alkyl nitrogen and two substituents attached thereto are substituted by one or two substituents independently selected from the group consisting of a 5- to 8-membered heterocyclo or heteroaryl ring Lt; / RTI &gt;
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
the sum of m + n + p is 1, 2, 3 or 4;
(a) X, one of Y and Z is selected from ^{C (O), NR 6,} O, S, S (O), S (O) 2 and NS (O) group consisting of ₂ R ^7, X, The remaining two of Y and Z are CR ⁸ R ⁹ , and CR ¹⁰ R ¹¹ ,
(b) X and Z or Z and Y together ^{NR 6 C (O), NR} 6 S (O), NR 6 S (O) 2, NR 6 S, NR 6 O, SS, NR 6 NR 6, and OC (O), the other of X, Y and Z being CR ⁸ R ⁹ , or
(c) n is 0, and X, Y and Z together form a group of formula:

[Wherein,
The wavy line is the bond to the atom of the indicated ring;
R ⁶ and R ^{6 '} are independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkanoyl, C ₆ -aryl-C ₁ -C ₆ -alkyl, aroyl, bis (C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl) -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkyl, C ₁ -C ₆ - haloalkyl, C ₁ -C ₆ - perfluoroalkyl, C ₁ -C ₆ - trifluoromethyl alkyl, C ₁ -C ₆ - perfluoroalkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₈ - heterocycloalkyl, C ₃ -C ₈ - heterocycloalkyl-carbonyl, C ₆ - aryl, C ₅ -C ₆ - heterocycloalkyl, C ₅ -C ₆ - heteroaryl, C ₃ -C ₈ - cycloalkyl- C ₁ -C ₆ -alkyl, C ₆ -aryloxy-C ₁ -C ₆ -alkyl, heteroaryloxy-C ₁ -C ₆ -alkyl, heteroaryl-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, C ₆ -arylsulfonyl, C ₁ -C ₆ -alkylsulfonyl, C ₅ -C ₆ -heteroarylsulfonyl, carboxy-C ₁ -C ₆ -alkyl, C ₁ -C ₄ - alkoxy-carbonyl -C ₁ -C ₆ - alkyl, aminocarbonyl, C _l -C ₆ -alkyl already noka Viterbo carbonyl, C ₆ - Reel already noka Viterbo carbonyl, C ₅ -C ₆ - heterocycloalkyl already noka Viterbo carbonyl, C ₆ - arylthio -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, C ₆ - arylthio -C ₃ -C ₆ - alkenyl, C ₁ -C ₄ - alkylthio -C ₃ -C ₆ - alkenyl, C ₅ -C ₆ - heteroaryl, -C ₁ -C ₆ - alkyl, halo -C ₁ -C ₆ - alkanoyl, hydroxy -C _l -C ₆ - alkanoyl, thiol -C ₁ -C ₆ - alkanoyl, C ₃ -C ₆ - alkenyl, C ₃ -C ₆ - alkynyl C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkyl, C ₁ -C ₅ -alkoxycarbonyl, aryloxycarbonyl, NR ⁸ R ⁹ -C ₁ -C ₅ -alkylcarbonyl, hydroxy -C ₁ -C ₅ - alkyl, aminocarbonyl (where aminocarbonyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of an alkanoyl group), a hydroxy-aminocarbonyl, aminosulfonyl group (wherein, aminosulfonyl Nitrogen is (i) _{Or, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - Al 1 is independently selected from the group consisting of alkanoyl groups Amino-C ₁ -C ₆ -alkylsulfonyl, wherein the amino-C ₁ -C ₆ -alkylsulfonyl is (i) unsubstituted or (ii) substituted by C ₁ - C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - alkanoyl group substituted by one or two radicals independently selected from the group consisting of ) and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ -cycloalkyl and a C ₁ -C ₆ -alkanoyl group); R 1 is selected from the group consisting of:
R ⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyl, C ₁ -C ₆ -carboxyalkyl and C ₁ -C ₆ -hydroxyalkyl group;
R ^8, R ^9, R ¹⁰ and R ¹¹ are also hideurayi, hydroxy, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl -C ₁ -C ₆ - Alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl, thiol-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylthio-C ₁ -C ₆ -alkylcycloalkyl, C ₁ -C ₆ -alkyl, heterocycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, aralkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy carboxylic carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, arylthio ₁ -C -C ₆ - alkyl, heteroarylthio -C ₁ -C ₆ - alkyl, -C ₁ -C ₆ with a sulfoxide or sulfone, perfluoroalkyl of said thio substituents -methyl-alkyl, trifluoromethyl -C ₁ -C ₆ - Alkyl, halo-C ₁ -C ₆ -alkyl, alkoxycarbonylamino-C ₁ -C ₆ -alkyl Kill and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of alkanoyl search) with independently selected from the group consisting of; Or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ and the carbon to which they are bonded form a carbonyl group or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ or R ⁸ and R ¹⁰ are atoms to which they are bonded Or a 5-to 8-membered heterocyclic ring containing one or two heteroatoms of nitrogen, oxygen, or sulfur, or a 5- to 8-membered carbocyclic ring with the proviso that R ⁸ and R ⁹ , or only one of R &lt; ¹⁰ &gt; and R &lt; ¹¹ &gt; is hydroxy;
R ¹² and R ^{12 'are} also hideurayi, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl, C ₂ -C ₆ - alkynyl, C ₂ -C _6-alkenyl, thiol -C ₁ -C ₆ - alkyl, cycloalkyl, cycloalkyl -C ₁ -C ₆ - alkyl, heterocycloalkyl -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy-carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, arylthio -C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, the sulfoxide or sulfone of said thio substituent, perfluoro-C ₁ -C ₆ -alkyl, trifluoromethyl-C ₁ -C ₆ -alkyl, halo -C ₁ -C ₆ - alkyl, alkoxycarbonylamino -C ₁ -C ₆ - alkyl and Mino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl, and C ₁ - C ₆ - Al 1 is independently selected from the group consisting of alkanoyl, or substituted with two radicals) with independently selected from the group consisting of;
R ¹³ is selected from the group consisting of: hydrido, benzyl, phenyl, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl and C ₁ -C ₆ -hydroxyalkyl groups do] Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt;
[16" claim-type="Currently amended] 16. The method of claim 15, wherein the sum of m + n + p is 1 or 2.
[17" claim-type="Currently amended] 16. The method of claim 15, wherein Z is O, S or NR ⁶ in.
[18" claim-type="Currently amended] 16. The method of claim 15 wherein, R ⁶ is C ₃ -C ₆ - cycloalkyl, C ₁ -C ₆ - alkyl, C ₃ -C ₆ - alkenyl, C ₃ -C ₆ - alkynyl, C ₁ -C ₆ - C ₁ -C ₆ -alkyl, amino-C ₁ -C ₆ -alkyl, aminosulfonyl, heteroaryl-C ₁ -C ₆ -alkyl, aryloxycarbonyl, and C ₁ -C ₆ -alkoxycarbonyl &Lt; / RTI &gt;
[19" claim-type="Currently amended] The method of claim 15, wherein m = n = 0, and p = 1, Y is a NR ⁶ method.
[20" claim-type="Currently amended] A metalloprotease inhibitor compound which corresponds in structure to the formula (IV) and inhibits the activity of one or more of MMP-2, MMP-9 and MMP-13 while the inhibitory activity on MMP-1 is substantially less, or A pharmaceutically acceptable salt thereof is administered to a mammalian host afflicted with a disease associated with pathologic matrix metalloproteinase (MMP) activity, comprising administering to the mammalian host an effective amount of a disease-associated mammalian host associated with pathological matrix metalloprotease activity Treatment:
(IV)

Wherein,
R ³ is an optionally substituted aryl or optionally substituted heteroaryl radical, wherein when the aryl or heteroaryl radical is substituted, the substituent is selected from the group consisting of (a) optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl Alkoxyalkyl, arylalkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylthiazoaryl, arylhydrazino, arylthio, Alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, aralkylthioaryl radical, sulfoxide or sulfone of thio substituent, and aryl, heteroaryl, cycloalkyl and heterocycloalkyl. Or a fused ring structure comprising two or more 5-membered or 6-membered rings selected, or (b) a fused ring structure selected from the group consisting of cyano, Halo, alkyl, alkoxy, nitro, thiol, hydroxy, alkoxy, alkoxy, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, Aryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, Alkoxy, alkanoyl, arylcarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, , Alkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, Aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino (wherein the arylthioalkylthioaryl, arylthioalkylthioaryl, Amino nitrogen is optionally substituted with one or more substituents selected from the group consisting of (i) unsubstituted or (ii) alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaryl Alkanoyl and an alkanoyl group, or (iii) an amino nitrogen and two additional substituents attached thereto are substituted by 0 to 2 further substituents selected from the group consisting of nitrogen, oxygen or sulfur (A) unsubstituted or substituted with one or more substituents selected from the group consisting of aryl, alkyl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, Alkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, And one or two groups independently selected from the group consisting of carbonyl, hydroxycarbonyl, aryloxycarbonyl, benzo fused heterocycloalkoxy, benzo fused cycloalkylcarbonyl, heterocycloalkylcarbonyl, and cycloalkylcarbonyl groups Wherein the carbonylamino nitrogen is (i) unsubstituted or (ii) is a reactive amine of an amino acid, or (iii) alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, Alkyl, trifluoromethylalkyl, heterocycloalkyl, benzo fused heterocycloalkyl, benzo fused heterocycloalkyl, benzo fused cycloalkyl, and N, N-dialkyl-substituted alkylamino-alkyl groups, or (iv) the carboxamido nitrogen and the two substituents attached thereto together are unsubstituted or substituted with one or more substituents independently selected from the group consisting of (I) unsubstituted or (ii) substituted or unsubstituted alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and amino groups, , Aryl, and heteroaryl, or (iii) the amino nitrogen and the two substituents attached thereto are substituted with one or two substituents independently selected from the group consisting of a 5- to 8-membered heterocyclo or heteroaryl ring Lt; RTI ID = 0.0 &gt; of-5-to 8-membered heterocyclo, &lt; / RTI &gt; substituted by one or two radicals independently selected from the group consisting of And aminoalkyl groups wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl groups (Iii) the aminoalkyl nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, optionally substituted with one or two substituents independently selected from the group consisting of Lt; / RTI &gt; is independently optionally substituted with one or more substituents independently selected from the group consisting of:
Z is O, S, NR ⁶ , SO, SO ₂ , and NSO ₂ R ⁷ wherein R ⁶ is selected from the group consisting of: hydrido, C ₁ -C ₅ -alkyl, C ₁ -C ₅ -alkanoyl, benzyl, benzoyl, C ₃ -C ₅ - alkynyl, C ₃ -C ₅ - alkenyl, C ₁ -C ₃ - alkoxy -C ₁ -C ₄ - alkyl, C ₃ -C ₆ - cycloalkyl, heteroaryl, -C ₁ -C ₆ -alkyl, C ₁ -C ₅ - hydroxyalkyl, C ₁ -C ₅ - alkyl, carboxyl, C ₁ -C ₅ - alkoxy C ₁ -C ₅ -alkyl-carbonyl, and NR ⁸ R ⁹ -C ₁ -C ₅ -Alkylcarbonyl or NR ⁸ R ⁹ -C ₁ -C ₅ -alkyl, wherein R ⁸ and R ⁹ are independently selected from the group consisting of hydrido, C ₁ -C ₅ -alkyl, C ₁ -C ₅ -alkoxycarbonyl or aryl C ₁ -C ₅ -alkoxycarbonyl, or NR ⁸ R ⁹ together form a heterocyclic ring comprising 5 to 8 atoms in the ring; R ⁷ is selected from the group consisting of arylalkyl, Aryl, heteroaryl, heterocyclo, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyl, C ₁ -C ₆ -carboxyalkyl and C ₁ -C ₆ -hydro Roxy alkyl group From the group is a group selected from the group consisting of selected).
[21" claim-type="Currently amended] 21. The compound of claim 20, wherein R &lt; ³ &gt; is a 5 or 6 membered ring, at its 4-position if it is a 6 membered ring, or at its 3- or 4- A heterocyclic group, a heteroaryl group, a C ₃ -C ₁₄ alkyl group, an N-piperidyl group, an N-piperazinyl group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenyl azo group and a benzamido group Lt; / RTI &gt; is a monocyclic aryl or heteroaryl group that is itself substituted with a substituent selected from &lt; RTI ID = 0.0 &gt;
[22" claim-type="Currently amended] 21. The method of claim 20, wherein R ³ is longer than the length of the pentyl group and less than the length of the eicosyl group.
[23" claim-type="Currently amended] The method of claim 20, wherein Z is O, S or NR ⁶ in.
[24" claim-type="Currently amended] 24. The method of claim 23 wherein, R ⁶ is C ₃ -C ₆ - cycloalkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkyl, C ₃ -C ₆ - alkenyl , C ₃ -C ₆ -alkynyl, amino-C ₁ -C ₆ -alkyl, aminosulfonyl, heteroaryl-C ₁ -C ₆ -alkyl, aryloxycarbonyl, and C ₁ -C ₆ -alkoxycarbonyl &Lt; / RTI &gt;
[25" claim-type="Currently amended] 21. The compound of claim 20, wherein the R &lt; ³ &gt; radical is a substituent GAREY,
At this time,
G is an aryl or heteroaryl group;
A is selected from the group consisting of:
(1) -O-;
(2) -S-;
(3) -NR ¹⁷ -;
(4) -CO-N (R ¹⁷ ) or -N (R ¹⁷ ) -CO, wherein R ¹⁷ is hydrogen, C ₁ -C ₄ -alkyl, or phenyl;
(5) -CO-O- or -O-CO-;
(6) -O-CO-O-;
(7) -HC = CH-;
(8) -NH-CO-NH-;
(9) -C C-;
(10) -NH-CO-O- or -O-CO-NH-;
(11) -N = N-;
(12) -NH-NH-; And
(13) -CS-N (R ¹⁸ ) - or -N (R ¹⁸ ) -CS, wherein R ¹⁸ is hydrogen, C ₁ -C ₄ -alkyl or phenyl; or
(14) A is absent and G is directly bonded to R;
R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Cycloalkyl, thioalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl substituents are unsubstituted or (ii) Alkoxy, C ₁ -C ₂ -alkylene-dioxy, hydroxycarbamoyl, perhaloalkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, One or two radicals selected from the group consisting of haloalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkylcarbonylalkyl, A residue selected from the group consisting of substituted), R A is not an alkyl or alkoxyalkyl when -O- or -S-;
E is selected from the group consisting of:
(1) -CO- (R ¹⁹⁾ or - (R ¹⁹⁾ -CO (wherein, R ¹⁹ is a heterocycloalkyl, or a cycloalkyl group Im);
(2) -CONH- or -HNCO-;
(3) -CO-;
(4) -SO ₂ -R ¹⁹ - or -R ¹⁹ -SO ₂ -;
(5) -SO ₂ -;
(6) -NH-SO ₂ - or -SO ₂ -NH-; or
(7) E is absent and R is directly bonded to Y;
Y is either not present or is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, Wherein the aryl, heteroaryl, or heterocycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of (i) alkyl, alkenyl, alkenyl, alkynyl, Wherein the amino nitrogen is (i) unsubstituted or (ii) is independently selected from the group consisting of hydrido, alkyl, and aralkyl groups; Substituted with one or two radicals selected from the group consisting of &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt;
[26" claim-type="Currently amended] 26. The method of claim 25, wherein the -G-A-R-E-Y substituent comprises 2 to 4 carbocyclic or heterocyclic rings.
[27" claim-type="Currently amended] 27. The method of claim 26, wherein each of the two to four rings is six.
[28" claim-type="Currently amended] 26. The method of claim 25, wherein the -G-A-R-E-Y substituent is longer than the hexyl group and less than the length of the stearyl group.
[29" claim-type="Currently amended] 26. The method of claim 25, wherein A is -O- or -S-.
[30" claim-type="Currently amended] 26. The method of claim 25, wherein R is aryl, heteroaryl, cycloalkyl or heterocycloalkyl group.
[31" claim-type="Currently amended] 26. The method of claim 25, wherein E is absent.
[32" claim-type="Currently amended] 26. The method of claim 25, wherein Y is selected from the group consisting of hydride, alkyl, alkoxy, perfluoroalkoxy and perfluoroalkylthio groups.
[33" claim-type="Currently amended] 20. The compound according to claim 20, wherein R &lt; ³ &gt; is a 5 or 6 membered ring at its 4-position if it is a 6 membered ring and at its 3- or 4- 4-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4- Phenoxy, 4-trifluoromethoxy-phenoxy, 4-trifluoromethylphenoxy, 4- (trifluoromethylthio) -phenoxy, 4- (trifluoromethylthio) 3-fluorophenoxy, 4-isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazol- , 4-methylphenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy, 4-fluorophenoxy, 4-fluoro-3-chlorophenoxy, 4- (lH-1,2,4-triazol-1-yl) phenoxy, 3,5-difluorophenoxy , 3,4-dichloro Phenoxy, 4-cyclopentylphenoxy, 4-bromo-3-methylphenoxy, 4-bromophenoxy, 4-methylthiophenoxy, 3-methoxyphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, N- Is a radical consisting of a single ring aryl or heteroaryl group that is itself substituted with a substituent selected from the group consisting of piperidyl, N-piperazinyl, and 4-benzyloxyphenoxy groups.
[34" claim-type="Currently amended] 21. The method of claim 20, wherein the inhibitor corresponds in structure to the formula:

[35" claim-type="Currently amended] A metalloprotease inhibitor compound that corresponds in structure to Formula V and substantially inhibits the activity of one or more MMP-2, MMP-9, and MMP-13, while the inhibitory activity on MMP-1 is substantially less, or A pharmaceutically acceptable salt thereof is administered to a mammalian host afflicted with a disease associated with pathologic matrix metalloproteinase (MMP) activity, comprising administering to the mammalian host an effective amount of a disease-associated mammalian host associated with pathological matrix metalloprotease activity Treatment:
(V)

Wherein,
Z is O, S or NR &lt; ⁶ &gt;;
W and Q are independently oxygen (O), NR ⁶ or sulfur (S) and R ⁶ is C ₃ -C ₆ -cycloalkyl, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ - alkynyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, aminosulfonyl, heteroaryl, -C ₁ -C ₆ - alkyl, aryl Oxycarbonyl, and C ₁ -C ₆ -alkoxycarbonyl;
q is 0 or 1, and when q is 0, Q is not present and the trifluoromethyl group is directly bonded to the phenyl ring shown.
[36" claim-type="Currently amended] 36. The method of claim 35, wherein q is 0.
[37" claim-type="Currently amended] 36. The method of claim 35, wherein W is oxygen (O).
[38" claim-type="Currently amended] 38. The method of claim 37, wherein q is 0.
[39" claim-type="Currently amended] 38. The method of claim 37, wherein q is 1 and Q is oxygen (O).
[40" claim-type="Currently amended] 38. The method of claim 37, wherein q is 1 and Q is S.
[41" claim-type="Currently amended] 36. The method of claim 35 wherein said inhibitor is structurally equivalent to the formula:

[42" claim-type="Currently amended] 36. The method of claim 35 wherein said inhibitor is structurally equivalent to the formula:

[43" claim-type="Currently amended] 36. The method of claim 35 wherein said inhibitor is structurally equivalent to the formula:

[44" claim-type="Currently amended] 36. The method of claim 35 wherein said inhibitor is structurally equivalent to the formula:

[45" claim-type="Currently amended] 36. The method of claim 35 wherein said inhibitor is structurally equivalent to the formula:

[46" claim-type="Currently amended] 36. The method of claim 35 wherein said inhibitor is structurally equivalent to the formula:

[47" claim-type="Currently amended] 36. The method of claim 35 wherein said inhibitor is structurally equivalent to the formula:

[48" claim-type="Currently amended] 36. The method of claim 35 wherein said inhibitor is structurally equivalent to the formula:

[49" claim-type="Currently amended] 36. The method of claim 35 wherein said inhibitor is structurally equivalent to the formula:

[50" claim-type="Currently amended] 36. The method of claim 35 wherein said inhibitor is structurally equivalent to the formula:

[51" claim-type="Currently amended] 36. The method of claim 35 wherein said inhibitor is structurally equivalent to the formula:

[52" claim-type="Currently amended] In terms of structure, a compound corresponding to formula (II), or a pharmaceutically acceptable salt thereof:
&Lt; RTI ID = 0.0 &

Wherein,
R ¹⁴ is selected from the group consisting of a hydrido, a pharmaceutically acceptable cation or C (W) R ¹⁵ wherein W is O or S and R ¹⁵ is C ₁ -C ₆ -alkyl, aryl, C ₁ -C ₆ -alkoxy, aryl -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aryloxy, aralkyl, -C ₁ -C ₆ - alkoxy, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl and amino C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkoxycarbonyl, C ₁ -C ₆ - alkoxycarbonyl, and C ₁ -C ₆ - the group consisting of alkanoyl radicals Or (iii) amino C ₁ -C ₆ -alkyl nitrogen and the two substituents attached thereto are substituted by one or two substituents independently selected from a 5 to 8 membered heterocyclo or heteroaryl ring Lt; / RTI &gt;
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
the sum of m + n + p is 1, 2, 3 or 4;
(a) X, one of Y and Z is selected from ^{C (O), NR 6,} O, S, S (O), S (O) 2 and NS (O) group consisting of ₂ R ^7, X, The remaining two of Y and Z are CR ⁸ R ⁹ , and CR ¹⁰ R ¹¹ ,
(b) X and Z or Z and Y together ^{NR 6 C (O), NR} 6 S (O), NR 6 S (O) 2, NR 6 S, NR 6 O, SS, NR 6 NR 6, and OC (O), the other of X, Y and Z being CR ⁸ R ⁹ , or
(c) n is 0, and X, Y and Z together form a group of formula:

[Wherein,
The wavy line is the bond to the atom of the indicated ring;
R ⁶ and R ^{6 '} are independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkanoyl, C ₆ -aryl-C ₁ -C ₆ -alkyl, aroyl, bis (C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl) -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkyl, C ₁ -C ₆ - haloalkyl, C ₁ -C ₆ - perfluoroalkyl, C ₁ -C ₆ - trifluoromethyl alkyl, C ₁ -C ₆ - perfluoroalkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₈ - heterocycloalkyl, C ₃ -C ₈ - heterocycloalkyl-carbonyl, C ₆ - aryl, C ₅ -C ₆ - heterocycloalkyl, C ₅ -C ₆ - heteroaryl, C ₃ -C ₈ - cycloalkyl- C ₁ -C ₆ -alkyl, C ₆ -aryloxy-C ₁ -C ₆ -alkyl, heteroaryloxy-C ₁ -C ₆ -alkyl, heteroaryl-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, C ₆ -arylsulfonyl, C ₁ -C ₆ -alkylsulfonyl, C ₅ -C ₆ -heteroarylsulfonyl, carboxy-C ₁ -C ₆ -alkyl, C ₁ -C ₄ - alkoxy-carbonyl -C ₁ -C ₆ - alkyl, aminocarbonyl, C _l -C ₆ -alkyl already noka Viterbo carbonyl, C ₆ - Reel already noka Viterbo carbonyl, C ₅ -C ₆ - heterocycloalkyl already noka Viterbo carbonyl, C ₆ - arylthio -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, C ₆ - arylthio -C ₃ -C ₆ - alkenyl, C ₁ -C ₄ - alkylthio -C ₃ -C ₆ - alkenyl, C ₅ -C ₆ - heteroaryl, -C ₁ -C ₆ - alkyl, halo -C ₁ -C ₆ - alkanoyl, hydroxy -C _l -C ₆ - alkanoyl, thiol -C ₁ -C ₆ - alkanoyl, C ₃ -C ₆ - alkenyl, C ₃ -C ₆ - alkynyl C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkyl, C ₁ -C ₅ -alkoxycarbonyl, aryloxycarbonyl, NR ⁸ R ⁹ -C ₁ -C ₅ -alkylcarbonyl, hydroxy -C ₁ -C ₅ - alkyl, aminocarbonyl (where aminocarbonyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of an alkanoyl group), a hydroxy-aminocarbonyl, aminosulfonyl group (wherein, aminosulfonyl Nitrogen is (i) _{Or, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - Al 1 is independently selected from the group consisting of alkanoyl groups Amino-C ₁ -C ₆ -alkylsulfonyl, wherein the amino-C ₁ -C ₆ -alkylsulfonyl is (i) unsubstituted or (ii) substituted by C ₁ - C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - alkanoyl group substituted by one or two radicals independently selected from the group consisting of ) and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ -cycloalkyl and a C ₁ -C ₆ -alkanoyl group); R 1 is selected from the group consisting of:
R ⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyl, C ₁ -C ₆ -carboxyalkyl and C ₁ -C ₆ -hydroxyalkyl group;
R ^8, R ^9, R ¹⁰ and R ¹¹ are also hideurayi, hydroxy, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl -C ₁ -C ₆ - Alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl, thiol-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylthio-C ₁ -C ₆ -alkylcycloalkyl, C ₁ -C ₆ -alkyl, heterocycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, aralkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy carboxylic carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, arylthio -C C ₁ -C ₆ -alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, sulfoxide or sulfone of said thio substituent, perfluoro-C ₁ -C ₆ -alkyl, trifluoromethyl-C ₁ -C ₆ -Alkyl, halo-C ₁ -C ₆ -alkyl, alkoxycarbonylamino-C ₁ -C ₆ -alkyl Kill and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of alkanoyl search) with independently selected from the group consisting of; Or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ and the carbon to which they are bonded form a carbonyl group or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ or R ⁸ and R ¹⁰ are atoms to which they are bonded Or a 5-to 8-membered heterocyclic ring containing one or two heteroatoms of nitrogen, oxygen, or sulfur, or a 5- to 8-membered carbocyclic ring with the proviso that R ⁸ and R ⁹ , or only one of R &lt; ¹⁰ &gt; and R &lt; ¹¹ &gt; is hydroxy;
R ¹² and R ^{12 'are} also hideurayi, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl, C ₂ -C ₆ - alkynyl, C ₂ -C _6-alkenyl, thiol -C ₁ -C ₆ - alkyl, cycloalkyl, cycloalkyl -C ₁ -C ₆ - alkyl, heterocycloalkyl -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy-carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, arylthio -C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, the sulfoxide or sulfone of said thio substituent, perfluoro-C ₁ -C ₆ -alkyl, trifluoromethyl-C ₁ -C ₆ -alkyl, halo -C ₁ -C ₆ - alkyl, alkoxycarbonylamino -C ₁ -C ₆ - alkyl and Mino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl, and C ₁ - C ₆ - Al 1 is independently selected from the group consisting of alkanoyl, or substituted with two radicals) with independently selected from the group consisting of;
R ¹³ is selected from the group consisting of: hydrido, benzyl, phenyl, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl and C ₁ -C ₆ -hydroxyalkyl groups do] Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt;
G-A-R-E-Y is a substituent having a length longer than the length of the pentyl group and less than the length of the eicosyl group,
At this time,
G is an aryl or heteroaryl group;
A is selected from the group consisting of:
(1) -O-;
(2) -S-;
(3) -NR ¹⁷ -;
(4) -CO-N (R ¹⁷ ) or -N (R ¹⁷ ) -CO-, wherein R ¹⁷ is hydrogen, C ₁ -C ₄ -alkyl, or phenyl;
(5) -CO-O- or -O-CO-;
(6) -O-CO-O-;
(7) -HC = CH-;
(8) -NH-CO-NH-;
(9) -C C-;
(10) -NH-CO-O- or -O-CO-NH-;
(11) -N = N-;
(12) -NH-NH-; And
(13) -CS-N (R ¹⁸ ) - or -N (R ¹⁸ ) -CS, wherein R ¹⁸ is hydrogen, C ₁ -C ₄ -alkyl or phenyl; or
(14) A is absent and G is directly bonded to R;
R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Cycloalkyl, thioalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl substituents are unsubstituted or (ii) Alkoxy, C ₁ -C ₂ -alkylene-dioxy, hydroxycarbamoyl, perhaloalkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, One or two radicals selected from the group consisting of haloalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkylcarbonylalkyl, A residue selected from the group consisting of substituted), R A is not an alkyl or alkoxyalkyl when -O- or -S-;
E is selected from the group consisting of:
(1) -CO- (R ¹⁹⁾ or - (R ¹⁹⁾ -CO- (wherein, R ¹⁹ is a heterocycloalkyl, or a cycloalkyl group Im);
(2) -CONH- or -HNCO-;
(3) -CO-;
(4) -SO ₂ -R ¹⁹ - or -R ¹⁹ -SO ₂ -;
(5) -SO ₂ -;
(6) -NH-SO ₂ - or -SO ₂ -NH-; or
(7) E is absent and R is directly bonded to Y;
Y is either not present or is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, Wherein the aryl, heteroaryl, or heterocycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of (i) alkyl, alkenyl, alkenyl, alkynyl, Wherein the amino nitrogen is (i) unsubstituted or (ii) is independently selected from the group consisting of hydrido, alkyl, and aralkyl groups; Substituted with one or two radicals selected from the group consisting of &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt;
[53" claim-type="Currently amended] 53. The compound of claim 52, wherein the -G-A-R-E-Y substituent comprises 2 to 4 carbocyclic or heterocyclic rings.
[54" claim-type="Currently amended] 53. The compound of claim 52, wherein each of the two to four rings is six.
[55" claim-type="Currently amended] 53. The compound of claim 52, wherein the -G-A-R-E-Y substituent is longer than the hexyl group and less than the length of the stearyl group.
[56" claim-type="Currently amended] 53. The compound of claim 52, wherein A is -O- or -S-.
[57" claim-type="Currently amended] 53. The compound of claim 52, wherein R is aryl, heteroaryl, cycloalkyl or heterocycloalkyl.
[58" claim-type="Currently amended] 53. The compound of claim 52, wherein E is absent.
[59" claim-type="Currently amended] 53. The compound of claim 52, wherein Y is selected from the group consisting of hydride, alkyl, alkoxy, perfluoroalkoxy and perfluoroalkylthio groups.
[60" claim-type="Currently amended] 53. The compound of claim 52, wherein R &lt; ¹⁴ &gt; is hydrazide.
[61" claim-type="Currently amended] 53. The method of claim 52, C (W) R ^15, and W is O in, R ¹⁵ is C ₁ -C ₆ - alkyl, aryl, C ₁ -C ₆ - alkoxy, heteroaryl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₆ -alkyl, or an aryloxy group.
[62" claim-type="Currently amended] In terms of structure, a compound corresponding to formula III, or a pharmaceutically acceptable salt thereof:
(III)

Wherein,
R ³ is a 5 or 6 membered ring at its 4-position for a six membered ring and at its 3- or 4-position for a five membered ring, thiophenoxy, 4-chloro 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4-fluorothiophenoxy, (Trifluoromethylthio) phenoxy, 4-trifluoromethoxyphenoxy, 4-trifluoromethylphenoxy, 4- (trifluoromethylthio) phenoxy, 4- 4-isopropoxyphenoxy, (2-methyl-1,3-benzothiazol-5-yl) oxy, 4- (1H-imidazol- 3-methylphenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy, 4-chloro-3-methylphenoxy, 4- (1H-1,2,4-triazol-1-yl) phenoxy, 3,5-difluorophenoxy, 3,4-dichlorophenoxy, 4-cyclopentane Phenoxy, 4-bromo-3-methylphenoxy, 4-bromophenoxy, 4-methylthiophenoxy, 4-phenylphenoxy, 4-benzylphenoxy, 6-quinolinyloxy, 4- Amino-3-methylphenoxy, 3-methoxyphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy and 4-benzyloxyphenoxy groups Lt; / RTI &gt; is a monocyclic aryl or heteroaryl group that is itself substituted with a substituent selected from the group consisting of &lt; RTI ID = 0.0 &gt;
R ¹⁴ is a hydride, a pharmaceutically acceptable cation or a C (W) R ¹⁵ wherein W is O or S and R ¹⁵ is C ₁ -C ₆ -alkyl, aryl, C ₁ -C ₆ -alkoxy, heteroaryl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aryloxy, aralkyl, -C ₁ -C ₆ - alkoxy, aralkyl, -C ₁ -C ₆ - alkyl , Heteroaryl and amino C ₁ -C ₆ -alkyl groups wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkoxycarbonyl, C ₁ -C ₆ - alkoxycarbonyl, and C ₁ -C ₆ - alkanoyl radical consisting of Or (iii) amino C ₁ -C ₆ -alkyl nitrogen and two substituents attached thereto are substituted by one or two substituents independently selected from the group consisting of a 5- to 8-membered heterocyclo or heteroaryl ring Lt; / RTI &gt;
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
the sum of m + n + p is 1, 2, 3 or 4;
(a) X, one of Y and Z is selected from ^{C (O), NR 6,} O, S, S (O), S (O) 2 and NS (O) group consisting of ₂ R ^7, X, The remaining two of Y and Z are CR ⁸ R ⁹ , and CR ¹⁰ R ¹¹ ,
(b) X and Z or Z and Y together ^{NR 6 C (O), NR} 6 S (O), NR 6 S (O) 2, NR 6 S, NR 6 O, SS, NR 6 NR 6, and OC (O), the other of X, Y and Z being CR ⁸ R ⁹ , or
(c) n is 0, and X, Y and Z together form a group of formula:

[Wherein,
The wavy line is the bond to the atom of the indicated ring;
R ⁶ and R ^{6 '} are independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkanoyl, C ₆ -aryl-C ₁ -C ₆ -alkyl, aroyl, bis (C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl) -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkyl, C ₁ -C ₆ - haloalkyl, C ₁ -C ₆ - perfluoroalkyl, C ₁ -C ₆ - trifluoromethyl alkyl, C ₁ -C ₆ - perfluoroalkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₈ - heterocycloalkyl, C ₃ -C ₈ - heterocycloalkyl-carbonyl, C ₆ - aryl, C ₅ -C ₆ - heterocycloalkyl, C ₅ -C ₆ - heteroaryl, C ₃ -C ₈ - cycloalkyl- C ₁ -C ₆ -alkyl, C ₆ -aryloxy-C ₁ -C ₆ -alkyl, heteroaryloxy-C ₁ -C ₆ -alkyl, heteroaryl-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, C ₆ -arylsulfonyl, C ₁ -C ₆ -alkylsulfonyl, C ₅ -C ₆ -heteroarylsulfonyl, carboxy-C ₁ -C ₆ -alkyl, C ₁ -C ₄ - alkoxy-carbonyl -C ₁ -C ₆ - alkyl, aminocarbonyl, C _l -C ₆ -alkyl already noka Viterbo carbonyl, C ₆ - Reel already noka Viterbo carbonyl, C ₅ -C ₆ - heterocycloalkyl already noka Viterbo carbonyl, C ₆ - arylthio -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, C ₆ - arylthio -C ₃ -C ₆ - alkenyl, C ₁ -C ₄ - alkylthio -C ₃ -C ₆ - alkenyl, C ₅ -C ₆ - heteroaryl, -C ₁ -C ₆ - alkyl, halo -C ₁ -C ₆ - alkanoyl, hydroxy -C _l -C ₆ - alkanoyl, thiol -C ₁ -C ₆ - alkanoyl, C ₃ -C ₆ - alkenyl, C ₃ -C ₆ - alkynyl C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkyl, C ₁ -C ₅ -alkoxycarbonyl, aryloxycarbonyl, NR ⁸ R ⁹ -C ₁ -C ₅ -alkylcarbonyl, hydroxy -C ₁ -C ₅ - alkyl, aminocarbonyl (where aminocarbonyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of an alkanoyl group), a hydroxy-aminocarbonyl, aminosulfonyl group (wherein, aminosulfonyl Nitrogen is (i) _{Or, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - Al 1 is independently selected from the group consisting of alkanoyl groups Amino-C ₁ -C ₆ -alkylsulfonyl, wherein the amino-C ₁ -C ₆ -alkylsulfonyl is (i) unsubstituted or (ii) substituted by C ₁ - C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - alkanoyl group substituted by one or two radicals independently selected from the group consisting of ) and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ -cycloalkyl and a C ₁ -C ₆ -alkanoyl group); R 1 is selected from the group consisting of:
R ⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyl, C ₁ -C ₆ -carboxyalkyl and C ₁ -C ₆ -hydroxyalkyl group;
R ^8, R ^9, R ¹⁰ and R ¹¹ are also hideurayi, hydroxy, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl -C ₁ -C ₆ - Alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl, thiol-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylthio-C ₁ -C ₆ -alkylcycloalkyl, C ₁ -C ₆ -alkyl, heterocycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, aralkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy carboxylic carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, arylthio -C C ₁ -C ₆ -alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, sulfoxide or sulfone of said thio substituent, perfluoro-C ₁ -C ₆ -alkyl, trifluoromethyl-C ₁ -C ₆ -Alkyl, halo-C ₁ -C ₆ -alkyl, alkoxycarbonylamino-C ₁ -C ₆ -alkyl Kill and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of alkanoyl search) with independently selected from the group consisting of; Or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ and the carbon to which they are bonded form a carbonyl group or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ or R ⁸ and R ¹⁰ are atoms to which they are bonded Or a 5-to 8-membered heterocyclic ring containing one or two heteroatoms of nitrogen, oxygen, or sulfur, or a 5- to 8-membered carbocyclic ring with the proviso that R ⁸ and R ⁹ , or only one of R &lt; ¹⁰ &gt; and R &lt; ¹¹ &gt; is hydroxy;
R ¹² and R ^{12 'are} also hideurayi, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl, C ₂ -C ₆ - alkynyl, C ₂ -C _6-alkenyl, thiol -C ₁ -C ₆ - alkyl, cycloalkyl, cycloalkyl -C ₁ -C ₆ - alkyl, heterocycloalkyl -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy-carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, arylthio -C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, the sulfoxide or sulfone of said thio substituent, perfluoro-C ₁ -C ₆ -alkyl, trifluoromethyl-C ₁ -C ₆ -alkyl, halo -C ₁ -C ₆ - alkyl, alkoxycarbonylamino -C ₁ -C ₆ - alkyl and Mino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl, and C ₁ - C ₆ - Al 1 is independently selected from the group consisting of alkanoyl, or substituted with two radicals) with independently selected from the group consisting of;
R ¹³ is selected from the group consisting of: hydrido, benzyl, phenyl, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl and C ₁ -C ₆ -hydroxyalkyl groups do] Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt;
[63" claim-type="Currently amended] 63. The compound of claim 62, wherein the sum of m + n + p is 1 or 2.
[64" claim-type="Currently amended] 63. The method of claim 62, wherein the compound which Z is O, S or NR ^6.
[65" claim-type="Currently amended] 63. The method of claim 62 wherein, R ⁶ is C ₃ -C ₆ - cycloalkyl, C ₁ -C ₆ - alkyl, C ₃ -C ₆ - alkenyl, C ₃ -C ₆ - alkynyl, C ₁ -C ₆ - C ₁ -C ₆ -alkyl, amino-C ₁ -C ₆ -alkyl, aminosulfonyl, heteroaryl-C ₁ -C ₆ -alkyl, aryloxycarbonyl, and C ₁ -C ₆ -alkoxycarbonyl &Lt; / RTI &gt;
[66" claim-type="Currently amended] 63. The method of claim 62, wherein m = n = 0, and p = 1, Y is NR ⁶ A compound.
[67" claim-type="Currently amended] 63. The compound of claim 62, wherein R &lt; ¹⁴ &gt; is hydrazide.
[68" claim-type="Currently amended] 63. The method of claim 62, wherein, C (W) R ^15, and W is O in, R ¹⁵ is C ₁ -C ₆ - alkyl, aryl, C ₁ -C ₆ - alkoxy, heteroaryl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₆ -alkyl, or an aryloxy group.
[69" claim-type="Currently amended] A compound corresponding in structure to the formula (IV), or a pharmaceutically acceptable salt thereof:
(IV)

Wherein,
R ³ is a 5 or 6 membered ring at its 4-position for a six membered ring, or at its 3- or 4-membered ring for a five membered ring, An aryl group, a C ₃ -C ₁₄ alkyl group, an N-piperidyl group, an N-piperazinyl group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenyl azo group and a benzamido group Lt; / RTI &gt; is a monocyclic aryl or heteroaryl group that is substituted by itself;
Z is O, S, NR ⁶ , SO, SO ₂ , and NSO ₂ R ⁷ wherein R ⁶ is selected from the group consisting of: hydrido, C ₁ -C ₅ -alkyl, C ₁ -C ₅ -alkanoyl, benzyl, benzoyl, C ₃ -C ₅ - alkynyl, C ₃ -C ₅ - alkenyl, C ₁ -C ₃ - alkoxy -C ₁ -C ₄ - alkyl, C ₃ -C ₆ - cycloalkyl, heteroaryl, -C ₁ -C ₆ -alkyl, C ₁ -C ₅ - hydroxyalkyl, C ₁ -C ₅ - alkyl, carboxyl, C ₁ -C ₅ - alkoxy C ₁ -C ₅ -alkyl-carbonyl, and NR ⁸ R ⁹ -C ₁ -C ₅ -Alkylcarbonyl or NR ⁸ R ⁹ -C ₁ -C ₅ -alkyl, wherein R ⁸ and R ⁹ are independently selected from the group consisting of hydrido, C ₁ -C ₅ -alkyl, C ₁ -C ₅ -alkoxycarbonyl or aryl C ₁ -C ₅ -alkoxycarbonyl, or NR ⁸ R ⁹ together form a heterocyclic ring comprising 5 to 8 atoms in the ring; R ⁷ is selected from the group consisting of arylalkyl, Aryl, heteroaryl, heterocyclo, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyl, C ₁ -C ₆ -carboxyalkyl and C ₁ -C ₆ -hydro Roxy alkyl group From the group is a group selected from the group consisting of selected).
[70" claim-type="Currently amended] 70. The compound of claim 69, wherein R &lt; ³ &gt; is greater than the length of the pentyl group and less than the length of the eicosyl group.
[71" claim-type="Currently amended] 70. The compound of claim 69, wherein Z is O, S or NR &lt; ⁶ &gt;.
[72" claim-type="Currently amended] The method of claim 69 wherein, R ⁶ is C ₃ -C ₆ - cycloalkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkyl, C ₃ -C ₆ - alkenyl , C ₃ -C ₆ -alkynyl, amino-C ₁ -C ₆ -alkyl, aminosulfonyl, heteroaryl-C ₁ -C ₆ -alkyl, aryloxycarbonyl, and C ₁ -C ₆ -alkoxycarbonyl &Lt; / RTI &gt;
[73" claim-type="Currently amended] 70. The method of claim 69, wherein the R &lt; ³ &gt; radical is a substituent GAREY,
At this time,
G is an aryl or heteroaryl group;
A is selected from the group consisting of:
(1) -O-;
(2) -S-;
(3) -NR ¹⁷ -;
(4) -CO-N (R ¹⁷ ) or -N (R ¹⁷ ) -CO-, wherein R ¹⁷ is hydrogen, C ₁ -C ₄ -alkyl, or phenyl;
(5) -CO-O- or -O-CO-;
(6) -O-CO-O-;
(7) -HC = CH-;
(8) -NH-CO-NH-;
(9) -C C-;
(10) -NH-CO-O- or -O-CO-NH-;
(11) -N = N-;
(12) -NH-NH-; And
(13) -CS-N (R ¹⁸ ) - or -N (R ¹⁸ ) -CS-, wherein R ¹⁸ is hydrogen, C ₁ -C ₄ -alkyl, or phenyl; or
(14) A is absent and G is directly bonded to R;
R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Cycloalkyl, thioalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl substituents are unsubstituted or (ii) Alkoxy, C ₁ -C ₂ -alkylene-dioxy, hydroxycarbamoyl, perhaloalkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, One or two radicals selected from the group consisting of haloalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkylcarbonylalkyl, A residue selected from the group consisting of substituted), R A is not an alkyl or alkoxyalkyl when -O- or -S-;
E is selected from the group consisting of:
(1) -CO- (R ¹⁹⁾ or - (R ¹⁹⁾ -CO- (wherein, R ¹⁹ is a heterocycloalkyl, or a cycloalkyl group Im);
(2) -CONH- or -HNCO-;
(3) -CO-;
(4) -SO ₂ -R ¹⁹ - or -R ¹⁹ -SO ₂ -;
(5) -SO ₂ -;
(6) -NH-SO ₂ - or -SO ₂ -NH-; or
(7) E is absent and R is directly bonded to Y;
Y is either not present or is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, Wherein the aryl, heteroaryl, or heterocycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of (i) alkyl, alkenyl, alkenyl, alkynyl, Wherein the amino nitrogen is (i) unsubstituted or (ii) is independently selected from the group consisting of hydrido, alkyl, and aralkyl groups; Substituted with one or two radicals selected from the group consisting of &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt;
[74" claim-type="Currently amended] 70. The compound of claim 69, wherein said -G-A-R-E-Y substituent comprises 2 to 4 carbocyclic or heterocyclic rings.
[75" claim-type="Currently amended] 70. The compound of claim 69, wherein each of the two to four rings is six.
[76" claim-type="Currently amended] 70. The compound of claim 69, wherein the -G-A-R-E-Y substituent is longer than the hexyl group and less than the length of the stearyl group.
[77" claim-type="Currently amended] 70. The compound of claim 69, wherein A is -O- or -S-.
[78" claim-type="Currently amended] 70. The compound of claim 69, wherein R is aryl, heteroaryl, cycloalkyl or heterocycloalkyl.
[79" claim-type="Currently amended] 70. The compound of claim 69, wherein E is absent.
[80" claim-type="Currently amended] 70. The compound of claim 69, wherein Y is selected from the group consisting of hydrido, alkyl, alkoxy, perfluoroalkoxy and perfluoroalkylthio groups.
[81" claim-type="Currently amended] 70. The compound of claim 69, wherein R &lt; ³ &gt; is a 5 or 6 membered ring at its 4-position if it is a 6 membered ring and at its 3- or 4- 4-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4- (Trifluoromethylthio) phenoxy, 4- (trifluoromethylthio) phenoxy, 4-trifluoromethylphenoxy, 4- 4-isopropoxyphenoxy, (2-methyl-1,3-benzothiazol-5-yl) oxy, 4- (3-methylphenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy, 4-chloro- 3-chlorophenoxy, 4- (lH-1,2,4-triazol-1-yl) phenoxy, 3,5- difluorophenoxy, 3, 4-dichlorophe 4-methylphenoxy, 4-methylphenoxy, 4-phenylphenoxy, 4-benzylphenoxy, 6-quinolyloxy, 3-methoxyphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, N- A monocyclic aryl or heteroaryl group that is itself substituted with a substituent selected from the group consisting of piperidyl, N-piperazinyl, and 4-benzyloxyphenoxy groups.
[82" claim-type="Currently amended] 70. The method of claim 69, wherein said R ³ group is selected from the group consisting of PhR ²³ wherein Ph is other single ring aryl or heteroaryl group, piperidyl group, piperazinyl group, phenoxy group, thiophenoxy group, phenyl azo group and benzamido group Wherein R &lt; ²³ &gt; is a phenyl ring substituted at the 4-position thereof by R &lt; ²³ &gt;
[83" claim-type="Currently amended] Wherein the R ²³ group is selected from the group consisting of halogen, a C ₁ -C ₄ -alkoxy group, a C ₁ -C ₄ alkyl group, a dimethylamino group, a carboxyl C ₁ -C ₃ alkylene group, a C ₁ -C ₄ alkoxycarbonyl C ₁ C ₁ -C ₃ alkylene group, trifluoromethylthio group, trifluoromethoxy group, trifluoromethyl group and carboxamido C ₁ -C ₃ alkylene group, or may be substituted by meta- and Substituted at the para-position with a methylenedioxy group.
[84" claim-type="Currently amended] 85. The compound of claim 83, wherein said R &lt; ²³ &gt; group is substituted at the para-position.
[85" claim-type="Currently amended] 85. The compound according to claim 84, wherein the R &lt; ²³ &gt; group is phenoxy.
[86" claim-type="Currently amended] 70. The compound of claim 69, wherein said inhibitor is structurally equivalent to the formula:

[87" claim-type="Currently amended] In terms of structure, a compound corresponding to formula V, or a pharmaceutically acceptable salt thereof:
(V)

Wherein,
Z is a formula O, S or NR &lt; ⁶ &gt;;
W and Q are independently oxygen (O), NR ⁶ or sulfur (S) and R ⁶ is C ₃ -C ₆ -cycloalkyl, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ - alkynyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, aminosulfonyl, heteroaryl, -C ₁ -C ₆ - alkyl, aryl Oxycarbonyl, and C ₁ -C ₆ -alkoxycarbonyl;
q is 0 or 1, and when q is 0, Q is not present and the trifluoromethyl group is directly bonded to the phenyl ring shown.
[88" claim-type="Currently amended] 87. The compound of claim 87, wherein q is 0.
[89" claim-type="Currently amended] 87. The compound of claim 87, wherein W is oxygen (O).
[90" claim-type="Currently amended] 90. The compound of claim 89, wherein q is 0.
[91" claim-type="Currently amended] 90. The compound of claim 89, wherein q is 1 and Q is oxygen (O).
[92" claim-type="Currently amended] 90. The compound of claim 89, wherein q is 1 and Q is S.
[93" claim-type="Currently amended] 87. The compound of claim 87, wherein said inhibitor is structurally equivalent to the formula:

[94" claim-type="Currently amended] 87. The compound of claim 87, wherein said inhibitor is structurally equivalent to the formula:

[95" claim-type="Currently amended] 87. The compound of claim 87, wherein said inhibitor is structurally equivalent to the formula:

[96" claim-type="Currently amended] 87. The compound of claim 87, wherein said inhibitor is structurally equivalent to the formula:

[97" claim-type="Currently amended] 87. The compound of claim 87, wherein said inhibitor is structurally equivalent to the formula:

[98" claim-type="Currently amended] 87. The compound of claim 87, wherein said inhibitor is structurally equivalent to the formula:

[99" claim-type="Currently amended] 87. The compound of claim 87, wherein said inhibitor is structurally equivalent to the formula:

[100" claim-type="Currently amended] 87. The compound of claim 87, wherein said inhibitor is structurally equivalent to the formula:

[101" claim-type="Currently amended] 87. The compound of claim 87, wherein said inhibitor is structurally equivalent to the formula:

[102" claim-type="Currently amended] 87. The compound of claim 87, wherein said inhibitor is structurally equivalent to the formula:

[103" claim-type="Currently amended] 87. The compound of claim 87, wherein said inhibitor is structurally equivalent to the formula:

[104" claim-type="Currently amended] An intermediate compound corresponding in structure to the following formula VI:
(VI)

Wherein,
g is 0, 1 or 2;
R ³ is an optionally substituted aryl or optionally substituted heteroaryl radical, wherein when the aryl or heteroaryl radical is substituted, the substituent is selected from the group consisting of (a) optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl Alkoxyalkyl, arylalkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylthiazoaryl, arylhydrazino, arylthio, Alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, aralkylthioaryl radical, sulfoxide or sulfone of thio substituent, and aryl, heteroaryl, cycloalkyl and heterocycloalkyl. Or a fused ring structure comprising two or more 5-membered or 6-membered rings selected, or (b) a fused ring structure selected from the group consisting of cyano, Halo, alkyl, alkoxy, nitro, thiol, hydroxy, alkoxy, alkoxy, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, Aryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, Alkoxy, alkanoyl, arylcarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, , Alkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, Aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino (wherein the arylthioalkylthioaryl, arylthioalkylthioaryl, Amino nitrogen is optionally substituted with one or more substituents selected from the group consisting of (i) unsubstituted or (ii) alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaryl Alkanoyl and alkanoyl groups, or (iii) amino nitrogen and two substituents attached thereto are substituted with 0 to 2 additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, (A) unsubstituted or substituted with one or more substituents selected from the group consisting of aryl, alkyl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, Alkyl, cycloalkyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzo fused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl Substituted with one or two groups independently selected from the group consisting of hydrogen, alkylcarbonyl, arylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, ), Carbonylamino wherein the carbonylamino nitrogen is either (i) unsubstituted or (ii) is a reactive amine of an amino acid, or (iii) alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, Heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and N, N- &lt; RTI ID = 0.0 &gt; Alkyl substituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and the two substituents bonded thereto are taken together, either unsubstituted or substituted by one or more radicals selected from the group consisting of alkyl, Wherein the amino nitrogen is (i) unsubstituted, or (ii) alkyl, aryl, and / or heterocycloalkyl, Heteroaryl, or (iii) the amino nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, 5-membered to 8-membered heterocyclyl, heteroaryl or benzo-fused heterocycloalkyl optionally substituted with one or two radicals independently selected from the group consisting of And aminoalkyl groups wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl groups (Iii) the aminoalkyl nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, optionally substituted with one or two substituents independently selected from the group consisting of Lt; / RTI &gt; is independently optionally substituted with one or more substituents independently selected from the group consisting of:
Or an aryl or heteroaryl group substituted with a nucleophilically replaceable leaving group;
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
the sum of m + n + p is 1, 2, 3 or 4;
(a) X, one of Y and Z is selected from ^{C (O), NR 6,} O, S, S (O), S (O) 2 and NS (O) group consisting of ₂ R ^7, X, The remaining two of Y and Z are CR ⁸ R ⁹ , and CR ¹⁰ R ¹¹ ,
(b) X and Z or Z and Y together ^{NR 6 C (O), NR} 6 S (O), NR 6 S (O) 2, NR 6 S, NR 6 O, SS, NR 6 NR 6, and OC (O), the other of X, Y and Z being CR ⁸ R ⁹ , or
(c) n is 0, and X, Y and Z together form a group of formula:

[Wherein,
The wavy line is the bond to the atom of the indicated ring;
R ⁶ and R ^{6 '} are independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkanoyl, C ₆ -aryl-C ₁ -C ₆ -alkyl, aroyl, bis (C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl) -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkyl, C ₁ -C ₆ - haloalkyl, C ₁ -C ₆ - perfluoroalkyl, C ₁ -C ₆ - trifluoromethyl alkyl, C ₁ -C ₆ - perfluoroalkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₈ - heterocycloalkyl, C ₃ -C ₈ - heterocycloalkyl-carbonyl, C ₆ - aryl, C ₅ -C ₆ - heterocycloalkyl, C ₅ -C ₆ - heteroaryl, C ₃ -C ₈ - cycloalkyl- C ₁ -C ₆ -alkyl, C ₆ -aryloxy-C ₁ -C ₆ -alkyl, heteroaryloxy-C ₁ -C ₆ -alkyl, heteroaryl-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, C ₆ -arylsulfonyl, C ₁ -C ₆ -alkylsulfonyl, C ₅ -C ₆ -heteroarylsulfonyl, carboxy-C ₁ -C ₆ -alkyl, C ₁ -C ₄ - alkoxy-carbonyl -C ₁ -C ₆ - alkyl, aminocarbonyl, C _l -C ₆ -alkyl already noka Viterbo carbonyl, C ₆ - Reel already noka Viterbo carbonyl, C ₅ -C ₆ - heterocycloalkyl already noka Viterbo carbonyl, C ₆ - arylthio -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, C ₆ - arylthio -C ₃ -C ₆ - alkenyl, C ₁ -C ₄ - alkylthio -C ₃ -C ₆ - alkenyl, C ₅ -C ₆ - heteroaryl, -C ₁ -C ₆ - alkyl, halo -C ₁ -C ₆ - alkanoyl, hydroxy -C _l -C ₆ - alkanoyl, thiol -C ₁ -C ₆ - alkanoyl, C ₃ -C ₆ - alkenyl, C ₃ -C ₆ - alkynyl C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkyl, C ₁ -C ₅ -alkoxycarbonyl, aryloxycarbonyl, NR ⁸ R ⁹ -C ₁ -C ₅ -alkylcarbonyl, hydroxy -C ₁ -C ₅ - alkyl, aminocarbonyl (where aminocarbonyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of an alkanoyl group), a hydroxy-aminocarbonyl, aminosulfonyl group (wherein, aminosulfonyl Nitrogen is (i) _{Or, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - Al 1 is independently selected from the group consisting of alkanoyl groups Amino-C ₁ -C ₆ -alkylsulfonyl, wherein the amino-C ₁ -C ₆ -alkylsulfonyl is (i) unsubstituted or (ii) substituted by C ₁ - C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - alkanoyl group substituted by one or two radicals independently selected from the group consisting of ) and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ -cycloalkyl and a C ₁ -C ₆ -alkanoyl group); R 1 is selected from the group consisting of:
R ⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyl, C ₁ -C ₆ -carboxyalkyl and C ₁ -C ₆ -hydroxyalkyl group;
R ^8, R ^9, R ¹⁰ and R ¹¹ are also hideurayi, hydroxy, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl -C ₁ -C ₆ - Alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl, thiol-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylthio-C ₁ -C ₆ -alkylcycloalkyl, C ₁ -C ₆ -alkyl, heterocycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, aralkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy carboxylic carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, arylthio ₁ -C -C ₆ - alkyl, heteroarylthio -C ₁ -C ₆ - alkyl, -C ₁ -C ₆ with a sulfoxide or sulfone, perfluoroalkyl of said thio substituents -methyl-alkyl, trifluoromethyl -C ₁ -C ₆ - Alkyl, halo-C ₁ -C ₆ -alkyl, alkoxycarbonylamino-C ₁ -C ₆ -alkyl Kill and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of alkanoyl search) with independently selected from the group consisting of; Or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ and the carbon to which they are bonded form a carbonyl group or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ or R ⁸ and R ¹⁰ are atoms to which they are bonded Or a 5-to 8-membered heterocyclic ring containing one or two heteroatoms of nitrogen, oxygen, or sulfur, or a 5- to 8-membered carbocyclic ring with the proviso that R ⁸ and R ⁹ , or only one of R &lt; ¹⁰ &gt; and R &lt; ¹¹ &gt; is hydroxy;
R ¹² and R ^{12 'are} also hideurayi, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl, C ₂ -C ₆ - alkynyl, C ₂ -C _6-alkenyl, thiol -C ₁ -C ₆ - alkyl, cycloalkyl, cycloalkyl -C ₁ -C ₆ - alkyl, heterocycloalkyl -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy-carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, arylthio -C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, the sulfoxide or sulfone of said thio substituent, perfluoro-C ₁ -C ₆ -alkyl, trifluoromethyl-C ₁ -C ₆ -alkyl, halo -C ₁ -C ₆ - alkyl, alkoxycarbonylamino -C ₁ -C ₆ - alkyl and Mino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl, and C ₁ - C ₆ - Al 1 is independently selected from the group consisting of alkanoyl, or substituted with two radicals) with independently selected from the group consisting of;
R ¹³ is selected from the group consisting of: hydrido, benzyl, phenyl, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl and C ₁ -C ₆ -hydroxyalkyl groups do] Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt;
R ²⁰ is selected from the group consisting of: (a) -OR ²¹ wherein R ²¹ is selected from the group consisting of a hydrido, C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl and a pharmaceutically acceptable cation, Or (b) -NH-OR ²² , wherein R ²² is an optionally removable protecting group.
[105" claim-type="Currently amended] The method of claim 104, wherein, R ³ is a substituent GAREY
[here,
G is an aryl or heteroaryl group;
A is selected from the group consisting of:
(1) -O-;
(2) -S-;
(3) -NR ¹⁷ -;
(4) -CO-N (R ¹⁷ ) or -N (R ¹⁷ ) -CO-, wherein R ¹⁷ is hydrogen, C ₁ -C ₄ -alkyl, or phenyl;
(5) -CO-O- or -O-CO-;
(6) -O-CO-O-;
(7) -HC = CH-;
(8) -NH-CO-NH-;
(9) -C C-;
(10) -NH-CO-O- or -O-CO-NH-;
(11) -N = N-;
(12) -NH-NH-; And
(13) -CS-N (R ¹⁸ ) - or -N (R ¹⁸ ) -CS-, wherein R ¹⁸ is hydrogen, C ₁ -C ₄ -alkyl, or phenyl; or
(14) A is absent and G is directly bonded to R;
R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Cycloalkyl, thioalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl substituents are unsubstituted or (ii) Alkoxy, C ₁ -C ₂ -alkylene-dioxy, hydroxycarbamoyl, perhaloalkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, One or two radicals selected from the group consisting of haloalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkylcarbonylalkyl, A residue selected from the group consisting of substituted), R A is not an alkyl or alkoxyalkyl when -O- or -S-;
E is selected from the group consisting of:
(1) -CO- (R ¹⁹⁾ or - (R ¹⁹⁾ -CO- (wherein, R ¹⁹ is a heterocycloalkyl, or a cycloalkyl group Im);
(2) -CONH- or -HNCO-;
(3) -CO-;
(4) -SO ₂ -R ¹⁹ - or -R ¹⁹ -SO ₂ -;
(5) -SO ₂ -;
(6) -NH-SO ₂ - or -SO ₂ -NH-; or
(7) E is absent and R is directly bonded to Y;
Y is not present or is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, Cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups wherein the aryl, heteroaryl, or heterocycloalkyl group is optionally substituted with one or more groups selected from the group consisting of (i) Or (ii) an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, and amino group wherein the amino nitrogen is either (i) unsubstituted or (ii) independently selected from hydrido, Substituted with one or two radicals which are the same or different and are selected from the group consisting of hydrogen,
Lt; / RTI &gt;
[106" claim-type="Currently amended] 107. The intermediate compound of claim 104, wherein the -G-A-R-E-Y substituent comprises 2 to 4 carbocyclic or heterocyclic rings.
[107" claim-type="Currently amended] 106. The intermediate compound of claim 106, wherein each of the two to four rings is six.
[108" claim-type="Currently amended] 106. The intermediate compound of claim 104, wherein the -G-A-R-E-Y substituent is longer than the hexyl group and has a length less than the length of the stearyl group.
[109" claim-type="Currently amended] 104. The compound of claim 104, wherein A is -O- or -S-.
[110" claim-type="Currently amended] 104. The intermediate compound of claim 104, wherein R is aryl, heteroaryl, cycloalkyl or heterocycloalkyl group.
[111" claim-type="Currently amended] 106. The intermediate compound of claim 104, wherein E is absent.
[112" claim-type="Currently amended] 104. The intermediate compound of claim 104, wherein Y is selected from the group consisting of hydride, alkyl, alkoxy, perfluoroalkoxy, and perfluoroalkylthio groups.
[113" claim-type="Currently amended] 104. The intermediate compound of claim 104, wherein R &lt; ¹⁴ &gt; is hydrazide.
[114" claim-type="Currently amended] The method of claim 104 wherein, C (W) R ^15, and W is O in, R ¹⁵ is C ₁ -C ₆ - alkyl, aryl, C ₁ -C ₆ - alkoxy, heteroaryl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₆ -alkyl, or an aryloxy group.
[115" claim-type="Currently amended] 103. The compound of claim 103, wherein R &lt; ³ &gt; is a 5 or 6 membered ring at its 4-position if it is a 6-membered ring and at its 3- or 4- 4-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4- (Trifluoromethylthio) phenoxy, 4- (trifluoromethylthio) phenoxy, 4-trifluoromethylphenoxy, 4- 4-isopropoxyphenoxy, (2-methyl-1,3-benzothiazol-5-yl) oxy, 4- (3-methylphenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy, 4-chloro- 3-chlorophenoxy, 4- (lH-1,2,4-triazol-1-yl) phenoxy, 3,5- difluorophenoxy, 3, 4-dichloro 4-methylphenoxy, 4-methylphenoxy, 4-phenylphenoxy, 4-benzylphenoxy, 6-quinolyloxy, 3-methoxyphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, and 4- Lt; / RTI &gt; is a monocyclic aryl or heteroaryl group that is itself substituted with a substituent selected from the group consisting of a benzyloxyphenoxy group.
[116" claim-type="Currently amended] The method of claim 103, wherein the protecting group can selectively remove the 2-tetrahydropyranyl, C ₁ -C ₆ - acyl, aroyl, benzyl, p- methoxybenzyl oxycarbonyl, benzyloxycarbonyl, C ₁ - C ₆ - alkoxycarbonyl, C ₁ -C ₆ - alkoxy _{-CH 2 -, C 1 -C 6} - alkoxy -C ₁ -C ₆ - alkoxy -CH ₂ - and the intermediates are selected from the group consisting of o- nitro group compound.
[117" claim-type="Currently amended] The method of claim 103, wherein the even substitutable leaving group selected from halo, nitro, azido to the parent haekjeok, phenyl sulfoxides also, aryloxy, C ₁ -C ₆ - alkoxy, C ₁ -C ₆ - alkyl sulfonate or aryl sulfonate Group and a trisubstituted ammonium group wherein the three substituents are independently aryl, ar-C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkyl.
[118" claim-type="Currently amended] 108. The compound of claim 103, wherein g is 0.
[119" claim-type="Currently amended] Intermediate compounds corresponding in structure to formula VII:
(VII)

Wherein,
g is 0, 1 or 2;
D is a nucleophilically replaceable leaving group;
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
the sum of m + n + p is 1, 2, 3 or 4;
(a) X, one of Y and Z is selected from ^{C (O), NR 6,} O, S, S (O), S (O) 2 and NS (O) group consisting of ₂ R ^7, X, The remaining two of Y and Z are CR ⁸ R ⁹ , and CR ¹⁰ R ¹¹ ,
(b) X and Z or Z and Y together ^{NR 6 C (O), NR} 6 S (O), NR 6 S (O) 2, NR 6 S, NR 6 O, SS, NR 6 NR 6, and OC (O), the other of X, Y and Z being CR ⁸ R ⁹ , or
(c) n is 0, and X, Y and Z together form a group of formula:

[Wherein,
The wavy line is the bond to the atom of the indicated ring;
R ⁶ and R ^{6 '} are independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkanoyl, C ₆ -aryl-C ₁ -C ₆ -alkyl, aroyl, bis (C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl) -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkyl, C ₁ -C ₆ - haloalkyl, C ₁ -C ₆ - perfluoroalkyl, C ₁ -C ₆ - trifluoromethyl alkyl, C ₁ -C ₆ - perfluoroalkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₈ - heterocycloalkyl, C ₃ -C ₈ - heterocycloalkyl-carbonyl, C ₆ - aryl, C ₅ -C ₆ - heterocycloalkyl, C ₅ -C ₆ - heteroaryl, C ₃ -C ₈ - cycloalkyl- C ₁ -C ₆ -alkyl, C ₆ -aryloxy-C ₁ -C ₆ -alkyl, heteroaryloxy-C ₁ -C ₆ -alkyl, heteroaryl-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, C ₆ -arylsulfonyl, C ₁ -C ₆ -alkylsulfonyl, C ₅ -C ₆ -heteroarylsulfonyl, carboxy-C ₁ -C ₆ -alkyl, C ₁ -C ₄ - alkoxy-carbonyl -C ₁ -C ₆ - alkyl, aminocarbonyl, C _l -C ₆ -alkyl already noka Viterbo carbonyl, C ₆ - Reel already noka Viterbo carbonyl, C ₅ -C ₆ - heterocycloalkyl already noka Viterbo carbonyl, C ₆ - arylthio -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, C ₆ - arylthio -C ₃ -C ₆ - alkenyl, C ₁ -C ₄ - alkylthio -C ₃ -C ₆ - alkenyl, C ₅ -C ₆ - heteroaryl, -C ₁ -C ₆ - alkyl, halo -C ₁ -C ₆ - alkanoyl, hydroxy -C _l -C ₆ - alkanoyl, thiol -C ₁ -C ₆ - alkanoyl, C ₃ -C ₆ - alkenyl, C ₃ -C ₆ - alkynyl C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkyl, C ₁ -C ₅ -alkoxycarbonyl, aryloxycarbonyl, NR ⁸ R ⁹ -C ₁ -C ₅ -alkylcarbonyl, hydroxy -C ₁ -C ₅ - alkyl, aminocarbonyl (where aminocarbonyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of an alkanoyl group), a hydroxy-aminocarbonyl, aminosulfonyl group (wherein, aminosulfonyl Nitrogen is (i) _{Or, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - Al 1 is independently selected from the group consisting of alkanoyl groups Amino-C ₁ -C ₆ -alkylsulfonyl, wherein the amino-C ₁ -C ₆ -alkylsulfonyl is (i) unsubstituted or (ii) substituted by C ₁ - C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - alkanoyl group substituted by one or two radicals independently selected from the group consisting of ) and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ -cycloalkyl and a C ₁ -C ₆ -alkanoyl group); R 1 is selected from the group consisting of:
R ⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyl, C ₁ -C ₆ -carboxyalkyl and C ₁ -C ₆ -hydroxyalkyl group;
R ^8, R ^9, R ¹⁰ and R ¹¹ are also hideurayi, hydroxy, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl -C ₁ -C ₆ - Alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl, thiol-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylthio-C ₁ -C ₆ -alkylcycloalkyl, C ₁ -C ₆ -alkyl, heterocycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, aralkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy carboxylic carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, arylthio -C C ₁ -C ₆ -alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, sulfoxide or sulfone of said thio substituent, perfluoro-C ₁ -C ₆ -alkyl, trifluoromethyl-C ₁ -C ₆ -Alkyl, halo-C ₁ -C ₆ -alkyl, alkoxycarbonylamino-C ₁ -C ₆ -alkyl Kill and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of alkanoyl search) with independently selected from the group consisting of; Or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ and the carbon to which they are bonded form a carbonyl group or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ or R ⁸ and R ¹⁰ are atoms to which they are bonded Or a 5-to 8-membered heterocyclic ring containing one or two heteroatoms of nitrogen, oxygen, or sulfur, or a 5- to 8-membered carbocyclic ring with the proviso that R ⁸ and R ⁹ , or only one of R &lt; ¹⁰ &gt; and R &lt; ¹¹ &gt; is hydroxy;
R ¹² and R ^{12 'are} also hideurayi, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl, C ₂ -C ₆ - alkynyl, C ₂ -C _6-alkenyl, thiol -C ₁ -C ₆ - alkyl, cycloalkyl, cycloalkyl -C ₁ -C ₆ - alkyl, heterocycloalkyl -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy-carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, arylthio -C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, the sulfoxide or sulfone of said thio substituent, perfluoro-C ₁ -C ₆ -alkyl, trifluoromethyl-C ₁ -C ₆ -alkyl, halo -C ₁ -C ₆ - alkyl, alkoxycarbonylamino -C ₁ -C ₆ - alkyl and Mino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl, and C ₁ - C ₆ - Al 1 is independently selected from the group consisting of alkanoyl, or substituted with two radicals) with independently selected from the group consisting of;
R ¹³ is selected from the group consisting of: hydrido, benzyl, phenyl, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl and C ₁ -C ₆ -hydroxyalkyl groups do] Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt;
R ²⁰ is selected from the group consisting of: (a) -OR ²¹ wherein R ²¹ is selected from the group consisting of a hydrido, C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl and a pharmaceutically acceptable cation, Or (b) -NH-OR ²² , wherein R ²² is an optionally removable protecting group.
[120" claim-type="Currently amended] The method of claim 119, wherein the protecting group can selectively remove the 2-tetrahydropyranyl, C ₁ -C ₆ - acyl, aroyl, benzyl, p- methoxybenzyl oxycarbonyl, benzyloxycarbonyl, C ₁ - C ₆ - alkoxycarbonyl, C ₁ -C ₆ - alkoxy _{-CH 2 -, C 1 -C 6} - alkoxy -C ₁ -C ₆ - alkoxy -CH ₂ - and the intermediates are selected from the group consisting of o- nitro group compound.
[121" claim-type="Currently amended] Wherein said nucleophilically replaceable leaving group D is selected from the group consisting of halo, nitro, azido, phenylsulfoxy, aryloxy, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylsulfonate or aryl A sulfonate group and a trisubstituted ammonium group wherein the three substituents are independently aryl, ar-C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkyl.
[122" claim-type="Currently amended] 119. The intermediate compound of claim 119, wherein said halo group is fluoro.
[123" claim-type="Currently amended] 119. The intermediate compound of claim 119, wherein g is zero.
[124" claim-type="Currently amended] 52. A pharmaceutical composition comprising a compound of claim 52 dissolved or dispersed in a pharmaceutically acceptable carrier.
[125" claim-type="Currently amended] 62. A pharmaceutical composition comprising a compound of claim 62 dissolved or dispersed in a pharmaceutically acceptable carrier.
[126" claim-type="Currently amended] 69. A pharmaceutical composition comprising a compound of claim 69 dissolved or dispersed in a pharmaceutically acceptable carrier.
[127" claim-type="Currently amended] A pharmaceutical composition comprising a compound of claim 87 dissolved or dispersed in a pharmaceutically acceptable carrier.
[128" claim-type="Currently amended] A method for preparing a metalloprotease inhibitor compound or intermediate compound corresponding in structure to the following formula VIA, comprising the step of coupling an intermediate compound corresponding to formula VIB in structure to another moiety:
(VIA)

[Chemical Formula VIB]
Wherein,
g is 0, 1 or 2;
R ^{3 'is} an aryl or heteroaryl group that is substituted with a coupling substituent reactive with respect to the coupling with the other residue;
R ³ is an optionally substituted aryl or optionally substituted heteroaryl radical, wherein when the aryl or heteroaryl radical is substituted, the substituent is selected from the group consisting of (a) optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl Alkoxyalkyl, arylalkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylthiazoaryl, arylhydrazino, arylthio, Alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, aralkylthioaryl radical, sulfoxide or sulfone of thio substituent, and aryl, heteroaryl, cycloalkyl and heterocycloalkyl. A fused ring structure comprising two or more 5-membered or 6-membered rings selected, (b) a fused ring structure selected from the group consisting of cyano, perfluoro Haloalkyl, alkoxy, nitro, thiol, hydroxycarbonyl &lt; / RTI &gt;&lt; RTI ID = 0.0 &gt; Aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkyl Alkylthio, aralkylamino, heterocyclo, heteroaryl, arylthio, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, arylthio, arylthio, arylthio, Alkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, arylox Alkoxyalkylthio, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino wherein the amino nitrogen Is selected from the group consisting of (i) unsubstituted or (ii) alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl And (iii) amino nitrogen and two substituents attached thereto are substituted with 0 to 2 additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, or And wherein the ring itself forms a 5- or 8-membered heterocyclo or heteroaryl ring containing (a) unsubstituted or (b) aryl, alkyl, heteroaryl, aralkyl , Heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzo fused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, Substituted with one or two groups independently selected from the group consisting of alkyl, alkoxy, alkylcarbonyl, arylcarbonyl, arylcarbonyl, arylcarbonyl, arylcarbonyl, Carbonylamino wherein the carbonylamino nitrogen is either (i) unsubstituted, (ii) is a reactive amine of an amino acid, or (iii) is alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, Benzyl fused heterocycloalkyl, benzo fused heterocycloalkyl, benzo fused cycloalkyl, and N, N-dialkyl (Iv) the carboxamido and the two substituents bonded thereto are taken together, either unsubstituted or substituted by one or more radicals selected from the group consisting of alkyl, alkoxycar Wherein the amino nitrogen is (i) unsubstituted, or (ii) alkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halogen, nitro, , Or (iii) amino nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, optionally substituted with one or two substituents independently selected from the group consisting of Membered heterocyclo, heteroaryl or benzo fused heterocycloalkyl ring substituted with one or two radicals independently selected from the group consisting of ), And an aminoalkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) independently of the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl groups , Or (iii) the aminoalkyl nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, optionally substituted with one or two substituents selected from Lt; / RTI &gt; is optionally substituted in its own case with one or more substituents selected;
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
the sum of m + n + p is 1, 2, 3 or 4;
(a) X, one of Y and Z is selected from ^{C (O), NR 6,} O, S, S (O), S (O) 2 and NS (O) group consisting of ₂ R ^7, X, The remaining two of Y and Z are CR ⁸ R ⁹ , and CR ¹⁰ R ¹¹ ,
(b) X and Z or Z and Y together ^{NR 6 C (O), NR} 6 S (O), NR 6 S (O) 2, NR 6 S, NR 6 O, SS, NR 6 NR 6, and OC (O), the other of X, Y and Z being CR ⁸ R ⁹ , or
(c) n is 0, and X, Y and Z together form a group of formula:

[Wherein,
The wavy line is the bond to the atom of the indicated ring;
R ⁶ and R ^{6 '} are independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkanoyl, C ₆ -aryl-C ₁ -C ₆ -alkyl, aroyl, bis (C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl) -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkyl, C ₁ -C ₆ - haloalkyl, C ₁ -C ₆ - perfluoroalkyl, C ₁ -C ₆ - trifluoromethyl alkyl, C ₁ -C ₆ - perfluoroalkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₈ - heterocycloalkyl, C ₃ -C ₈ - heterocycloalkyl-carbonyl, C ₆ - aryl, C ₅ -C ₆ - heterocycloalkyl, C ₅ -C ₆ - heteroaryl, C ₃ -C ₈ - cycloalkyl- C ₁ -C ₆ -alkyl, C ₆ -aryloxy-C ₁ -C ₆ -alkyl, heteroaryloxy-C ₁ -C ₆ -alkyl, heteroaryl-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, C ₆ -arylsulfonyl, C ₁ -C ₆ -alkylsulfonyl, C ₅ -C ₆ -heteroarylsulfonyl, carboxy-C ₁ -C ₆ -alkyl, C ₁ -C ₄ - alkoxy-carbonyl -C ₁ -C ₆ - alkyl, aminocarbonyl, C _l -C ₆ -alkyl already noka Viterbo carbonyl, C ₆ - Reel already noka Viterbo carbonyl, C ₅ -C ₆ - heterocycloalkyl already noka Viterbo carbonyl, C ₆ - arylthio -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, C ₆ - arylthio -C ₃ -C ₆ - alkenyl, C ₁ -C ₄ - alkylthio -C ₃ -C ₆ - alkenyl, C ₅ -C ₆ - heteroaryl, -C ₁ -C ₆ - alkyl, halo -C ₁ -C ₆ - alkanoyl, hydroxy -C _l -C ₆ - alkanoyl, thiol -C ₁ -C ₆ - alkanoyl, C ₃ -C ₆ - alkenyl, C ₃ -C ₆ - alkynyl C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkyl, C ₁ -C ₅ -alkoxycarbonyl, aryloxycarbonyl, NR ⁸ R ⁹ -C ₁ -C ₅ -alkylcarbonyl, hydroxy -C ₁ -C ₅ - alkyl, aminocarbonyl (where aminocarbonyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of an alkanoyl group), a hydroxy-aminocarbonyl, aminosulfonyl group (wherein, aminosulfonyl Nitrogen is (i) _{Or, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - Al 1 is independently selected from the group consisting of alkanoyl groups Amino-C ₁ -C ₆ -alkylsulfonyl, wherein the amino-C ₁ -C ₆ -alkylsulfonyl is (i) unsubstituted or (ii) substituted by C ₁ - C ₆ - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl and C ₁ -C ₆ - alkanoyl group substituted by one or two radicals independently selected from the group consisting of ) and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, C ₃ -C ₈ -cycloalkyl and a C ₁ -C ₆ -alkanoyl group); R 1 is selected from the group consisting of:
R ⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyl, C ₁ -C ₆ -carboxyalkyl and C ₁ -C ₆ -hydroxyalkyl group;
R ^8, R ^9, R ¹⁰ and R ¹¹ are also hideurayi, hydroxy, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl -C ₁ -C ₆ - Alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl, thiol-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylthio-C ₁ -C ₆ -alkylcycloalkyl, C ₁ -C ₆ -alkyl, heterocycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, aralkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy carboxylic carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, arylthio ₁ -C -C ₆ - alkyl, heteroarylthio -C ₁ -C ₆ - alkyl, -C ₁ -C ₆ with a sulfoxide or sulfone, perfluoroalkyl of said thio substituents -methyl-alkyl, trifluoromethyl -C ₁ -C ₆ - Alkyl, halo-C ₁ -C ₆ -alkyl, alkoxycarbonylamino-C ₁ -C ₆ -alkyl Kill and amino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl and C ₁ -C ₆ - substituted by one or two radicals independently selected from the group consisting of alkanoyl search) with independently selected from the group consisting of; Or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ and the carbon to which they are bonded form a carbonyl group or R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ or R ⁸ and R ¹⁰ are atoms to which they are bonded Or a 5-to 8-membered heterocyclic ring containing one or two heteroatoms of nitrogen, oxygen, or sulfur, or a 5- to 8-membered carbocyclic ring with the proviso that R ⁸ and R ⁹ , or only one of R &lt; ¹⁰ &gt; and R &lt; ¹¹ &gt; is hydroxy;
R ¹² and R ^{12 'are} also hideurayi, C ₁ -C ₆ - alkyl, aryl, aralkyl, -C ₁ -C ₆ - alkyl, heteroaryl, heteroaralkyl, C ₂ -C ₆ - alkynyl, C ₂ -C _6-alkenyl, thiol -C ₁ -C ₆ - alkyl, cycloalkyl, cycloalkyl -C ₁ -C ₆ - alkyl, heterocycloalkyl -C _l -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, hydroxy-carbonyl -C ₁ -C ₆ - alkyl, hydroxy-carbonyl are -C ₁ -C ₆ - alkyl, amino-carbonyl -C ₁ -C ₆ - alkyl, aryloxy -C ₁ -C ₆ - alkyl, heteroaryloxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, arylthio -C ₁ -C ₆ -Alkyl, heteroarylthio-C ₁ -C ₆ -alkyl, the sulfoxide or sulfone of said thio substituent, perfluoro-C ₁ -C ₆ -alkyl, trifluoromethyl-C ₁ -C ₆ -alkyl, halo -C ₁ -C ₆ - alkyl, alkoxycarbonylamino -C ₁ -C ₆ - alkyl and Mino -C ₁ -C ₆ - alkyl group (wherein, aminoalkyl nitrogen is (i) _{unsubstituted, (ii) C 1 -C 6} - alkyl, aralkyl, -C ₁ -C ₆ - alkyl, cycloalkyl, and C ₁ - C ₆ - Al 1 is independently selected from the group consisting of alkanoyl, or substituted with two radicals) with independently selected from the group consisting of;
R ¹³ is selected from the group consisting of: hydrido, benzyl, phenyl, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkenyl and C ₁ -C ₆ -hydroxyalkyl groups do] Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt;
R ²⁰ is selected from the group consisting of: (a) -OR ²¹ wherein R ²¹ is selected from the group consisting of a hydrido, C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl and a pharmaceutically acceptable cation, Or (b) -NH-OR ²² , wherein R ²² is an optionally removable protecting group.
[129" claim-type="Currently amended] 129. The method of claim 128, further comprising the step of recovering said product.
[130" claim-type="Currently amended] The method according to claim 128, wherein, R ²⁰ is -NH-OR ²² (wherein, R ²² is a protecting group being optionally removed as possible).
[131" claim-type="Currently amended] The method of claim 130, wherein the protecting group can selectively remove the 2-tetrahydropyranyl, C ₁ -C ₆ - acyl, aroyl, benzyl, p- methoxybenzyl oxycarbonyl, benzyloxycarbonyl, C ₁ - C ₆ - alkoxycarbonyl, C ₁ -C ₆ - alkoxy _{-CH 2 -, C 1 -C 6} - alkoxy -C ₁ -C ₆ - alkoxy -CH ₂ -, the group consisting of o- nitro group and a peptide synthesis resin &Lt; / RTI &gt;
[132" claim-type="Currently amended] 133. The method of claim 128, wherein the coupling substituent is a nucleophilically substitutable leaving group.
[133" claim-type="Currently amended] According to claim 122, wherein the even substitutable leaving group selected from halo, nitro, azido to the parent haekjeok, phenyl sulfoxides also, aryloxy, C ₁ -C ₆ - alkoxy, C ₁ -C ₆ - alkyl sulfonate or aryl sulfonate Group and a trisubstituted ammonium group wherein the three substituents are independently aryl, ar -C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkyl.
[134" claim-type="Currently amended] 128. The method of claim 128, wherein g is 2.
[135" claim-type="Currently amended] 128. The method of claim 128, wherein said R &lt; ³ &gt; aryl or heteroaryl group is an aryl group.
[136" claim-type="Currently amended] 128. The method of claim 128, wherein said intermediate corresponding to structure VI in structure is in structural aspect:
[Formula VIIA]
Wherein,
D is a nucleophilically replaceable leaving group selected from halo, nitro, azido, phenylsulfoxy, aryloxy, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylsulfonate or arylsulfonate groups, And a trisubstituted ammonium group wherein the three substituents are independently aryl, ar-C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkyl.
[137" claim-type="Currently amended] 129. The method of claim 128, further comprising the step of recovering said product.
[138" claim-type="Currently amended] The method of claim 128, wherein the method includes an additional step of selective removal of the protecting group, R ^22.
[139" claim-type="Currently amended] The method of claim 138, wherein the method of removing the protective group, R ²² and then perform an additional step of recovery of the product.
[140" claim-type="Currently amended] 144. The method of claim 139, wherein said protecting group, R &lt; ²² &gt; is a 2-tetrahydropyranyl group.
[141" claim-type="Currently amended] 129. The method of claim 129, wherein after recovery, R &lt; ²¹ &gt; is hydraido and the product is reacted with a hydroxylamine or a compound wherein the oxygen is selected from the group consisting of 2-tetrahydropyranyl, C ₁ -C ₆ -acyl, aroyl, -methoxy-benzyloxycarbonyl, benzyloxycarbonyl, C ₁ -C ₆ - alkoxycarbonyl, C ₁ -C ₆ - alkoxy _{-CH 2 -, C 1 -C 6} - alkoxy -C ₁ -C ₆ - alkoxy -CH ₂ -, o- nitro group and a further step of reacting a hydroxylamine and further for selectively removing protecting groups and capable of reacting with selected from the group consisting of a peptide synthesis resin to form a hydroxamic acid or protected hydroxyl roksa formate product &Lt; / RTI &gt;
[142" claim-type="Currently amended] 143. The method of claim 141, comprising the further step of recovering the formed product.