combination of pharmaceutical agents such as rsv inhibitors

专利摘要:
The present invention relates to pharmaceutical agents administered to a subject in combination or in series for the treatment of a respiratory syncytial virus (rsv) infection, wherein the treatment comprises administering a compound effective to inhibit rsv function and a compound additional or combinations of compounds with anti-rsv activity.
公开号:BR112020006334A2
申请号:R112020006334-7
申请日:2018-09-28
公开日:2020-09-24
发明作者:Brian C. SHOOK；In Jong Kim；Thomas P. Blaisdell；Jianming Yu；Joseph Panarese；Kai Lin；Michael H.J. Rhodin；Nicole V. McAllister；Yat Sun Or
申请人:Enanta Pharmaceuticals, Inc.；
IPC主号:

专利说明:

[001] [001] This application claims the benefit of US Interim Application No. 62/566,159, filed September 29, 2017, and US Interim Application No. 62/566,160, filed September 29, 2017. All the teachings of the above applications are, in the present invention, incorporated by reference. TECHNICAL FIELD
[002] [002] The present invention generally relates to compounds and pharmaceutical compositions useful as inhibitors of respiratory syncytial virus (RSV). Specifically, the present invention relates to benzodiazepine derivatives that can be used in combination with other pharmaceutical agents for the treatment of RSV infection. BACKGROUND OF THE INVENTION
[003] [003] Human respiratory syncytial virus (HRSV) is a single-stranded, negative-sense RNA paramyxovirus (KM. Empey, et al., Rev. Anti-Infective Agents, 2010, 50 (1 May), 1258- 1267). RSV is the leading cause of acute lower respiratory tract infections (ALRI) and affects patients of all ages. Symptoms in adults are usually not severe and are typically analogous to a mild cold. However, in infants and young children, the virus can cause lower respiratory tract infections, including bronchiolitis or pneumonia, many of which require hospitalization. Almost all children were infected by age 3 years. There are known high-risk groups in which RSV infection is more likely to progress to ALRI. Premature babies and/or infants who suffer from lung or heart disease are at increased risk of developing ALRI. Other high-risk groups include the elderly, adults with chronic heart and/or lung disease, stem cell transplant patients, and immunosuppressed patients.
[004] [004] Currently, there is no vaccine available to prevent HRSV infection. Palivizumab is a monoclonal antibody that is used prophylactically to prevent HRSV infection in high-risk babies, for example, premature babies and those with heart and/or lung disease. The high cost of palivizumab treatment limits its general-purpose use. Ribavirin has also been used to treat HRSV infections, but its effectiveness is limited. There is a great medical need for new and effective treatments for HRSV that can be generally used by all types of populations and age groups.
[005] [005] There have been several RSV fusion inhibitors that have been disclosed in the following publications: WO2010/103306, WO2012/068622, WO2013/096681, WO2014/060411, WO2013/186995, WO2013/186334, WO2013/186332, WO2012/080451, WO2012/080451 /080450, WO2012/080449, WO2012/080447, WO2012/080446 and J. Med. Chem. 2015, 58, 1630-1643. Examples of other N protein inhibitors for the treatment of HRSV have been disclosed in the following publications: WO 2004/026843, J. Med. Chem. 2006, 49, 2311-2319 and J. Med. Chem. 2007, 50, 1685-1692. Examples of L protein inhibitors for HRSV have been disclosed in the following publications: WO2011/005842 , WO2005/042530 , Antiviral Res. 2005, 65, 125-131 and Bioorg. Med. Chem. Lett. 2013, 23, 6789-6793 . Examples of nucleoside/polymerase inhibitors have been disclosed in the following publications: WO2013/242525 and J. Med. Chem. 2015, 58, 1862-1878.
[006] [006] It is necessary to develop effective treatments for HRSV. The present invention has identified compounds that are benzodiazepines - substituted with aminoheteroaryl and inhibit HRSV. The invention includes methods for preparing the compounds, as well as methods for using them in the treatment of disease. SUMMARY OF THE INVENTION
[007] [007] The present invention provides compounds represented by Formula (I) and pharmaceutically acceptable salts, esters or prodrugs, which can be used to treat or prevent viral infection (particularly HRSV).
[008] [008] Each preferred group indicated above may be taken in combination with one, any or all other preferred groups. BRIEF DESCRIPTION OF THE DRAWINGS
[009] [009] Figure 1 is a graphical representation of the drug configuration and combination of compounds across 96-well plates as described in the Examples.
[010] [010] Figure 2 is a graphical representation of the percentage of viral inhibition of compounds or combinations of compounds at each individual concentration or combination concentration tested as described in the examples. DETAILED DESCRIPTION OF THE INVENTION
[011] [011] In one embodiment of the present invention, it is a compound represented by Formula (I) as described above, or a pharmaceutically acceptable salt, ester or prodrug thereof.
[012] [012] The carbon atom at position 3 of the benzodiazepine ring system of the compounds of the invention is chiral. Thus, compounds of the invention may have the stereochemistry represented in formula (Ia) or (Ib): wherein R1, R2, R3, R4, R5, R6, A and n are previously defined.
[013] [013] A composition of the invention may comprise a compound of the invention as a racemic mixture of Formula Ia and Formula Ib, a pure enantiomer of Formula Ia or Formula Ib, or an excess of one enantiomer over the other. For example, the composition may comprise the compound in an enantiomeric excess of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90%. In one embodiment, the enantiomeric excess is at least 95%. In compounds of the invention with two or more chiral atoms, these compounds may be present in a composition as a pure stereoisomer or a mixture of stereoisomers, such as a racemic mixture or a mixture of diastereoisomers. In one embodiment, a composition of the invention comprises a racemic mixture, a single stereoisomer or enantiomers with an enantiomeric excess of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95%.
[014] [014] In a preferred embodiment, a compound of the invention is represented by Formula (Ib). Compositions of the invention preferably comprise a substantially pure compound of Formula (Ib) or a mixture of a compound of Formula (Ib) and the corresponding compound of Formula (Ia), with an enantiomeric excess of the compound of Formula (Ib) as discussed above .
[015] [015] In certain embodiments, the present invention pertains to compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein R1 is not hydrogen. In other embodiments, R1 is hydrogen, optionally substituted -C1-C8-alkoxy, or optionally substituted CH3. In certain embodiments, the present invention pertains to compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein R1 is optionally substituted -C1-C8-alkoxy, or optionally substituted CH3, such as, for example, CF3 .
[016] [016] In certain embodiments, the present invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein, R2 is hydrogen or optionally substituted CH3.
[017] [017] In certain embodiments, the present invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein, R5 is hydrogen or optionally substituted CH3.
[018] [018] In certain embodiments, the present invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein, R1 is hydrogen or optionally substituted CH3, R2 is hydrogen, and R5 is hydrogen.
[019] [019] In certain embodiments, the present invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein, R3 is optionally substituted aryl or heteroaryl. Preferably R3 is phenyl and optionally substituted with one to three substituents selected from the group consisting of hydrogen, halo, -CF3, -OCF3, -CH3, -SO2Me, and cyano.
[020] [020] In certain embodiments, the present invention pertains to compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein, A is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C3-C8 cycloalkyl or heterocyclyl of 3 to 8 members optionally substituted. Preferably A is optionally substituted aryl or optionally substituted heteroaryl. More preferably A is an optionally substituted monocyclic 5 membered heteroaryl, an optionally substituted monocyclic 6 membered heteroaryl or a fused 8 to 10 membered heteroaryl. In one embodiment, A is a five-membered nitrogen-containing heteroaryl group.
[021] [021] In another embodiment, the present invention relates to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is derived from one of the following by removal of two hydrogen atoms: wherein each of monocyclic heteroaryls shown above is optionally substituted where possible.
[022] [022] In certain embodiments, A is selected from, but not limited to, the groups set forth below, where one of the indicated valences is the point of attachment of the heteroaryl group to R4 and the other is the point of attachment to the atom of amino nitrogen. Each of these groups is optionally additionally substituted where possible. The A atom linking A to R4 can be a carbon atom or, when possible, a nitrogen atom:
[023] [023] Preferably, the optional substituents are independently selected from halo, -CH3, -CF3, -OCF3, -CN, -SO2Me, -CH2N(CH3)2, optionally substituted C1-C8-alkoxy, and -C( O)CH3. It should be understood that, depending on the heteroaryl group, there may be 0, 1, 2 or 3 substituents. In preferred embodiments, there are 0 to 2 substituents, and more preferably, 0 or 1 substituent.
[024] [024] In another particular embodiment, the present invention relates to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is derived from a fused bicyclic group selected from one of the following by the removal of two hydrogen atoms. N N No N N H O S H N N N N N H H O Y N N O N N N N
[025] [025] In this embodiment, A is bonded to the amino nitrogen atom and R4 through any available ring atom. In 5/6 fused rings, A is preferably attached to the amino nitrogen atom through an available atom on the 5-membered ring. In 6/6 fused rings, A is preferably attached to the amino nitrogen atom through a carbon atom of the nitrogen-containing ring.
[026] [026] In certain embodiments, A is selected from the groups set out below: wherein the point of attachment to the amino nitrogen atom is shown and R 4 is attached to any other available ring position and is preferably hydrogen. In one embodiment, R4 is bonded to a benzo ring atom. When A is naphthyl, R4 and the amino nitrogen atom are preferably bonded to carbon atoms of different rings. Each of the groups shown above is optionally substituted and preferably the optional substituents are independently selected from halo, -CH3, -CF3, -OCF3, -CN, -NH2, -OH, -CH2N(CH3)2, -C( O)CH3, -NH-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, -SO2-NH-(C1-C6)alkyl, -NH-SO2-(C1-C6)alkyl, and - C1-C8-alkoxy. Preferably, in addition to R4, there are 0, 1, 2 or 3 substituents, more preferably 0, 1 or 2 substituents, and most preferably 0 or 1 substituents.
[027] [027] In certain embodiments of the compounds of the invention, R4 is not hydrogen. In certain embodiments of the compounds of the invention, R4 is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 3- to 12-membered heterocycloalkyl, -C3-C12-
[028] [028] In certain embodiments of the compounds of the invention, R4 is a group derived from one of the following by removal of a hydrogen atom: wherein each of the above is optionally substituted where possible
[029] [029] In certain embodiments, R4 is selected from the groups shown below, each of which is optionally substituted.
[030] [030] In certain embodiments, R4 is optionally substituted by one or more substituents independently selected from halo, -CH3, -CF3, -OCF3, -CN, -NH2, -OH, -CH2N(CH3)2, -C (O)CH3, -NH-(C1-C6)alkyl, -NH-(C1-C6)alkyl (C1-C6)alkoxy optionally, -SO2-(C1-C6)alkyl, -SO2 -NH-(C1-C6)alkyl, optionally substituted -NH-SO2-(C1-C6)alkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C1-C8-alkyl optionally substituted, -C1-C8-alkenyl, optionally substituted -C3-C8-cycloalkyl, optionally substituted -C3-C8-cycloalkenyl, and optionally substituted -C1-C8-alkoxy. In another embodiment, the substituents are independently selected from CH3, CN, fluorine, chlorine, CH3O-, CH3C(O)-, CH3OCH2-, CH3OCH2CH2O-, -CF3, CF3O-, N O O , , , , , , , , , , , , , ,
[031] [031] In another embodiment, the substituents are independently selected from CH3, CN, fluorine, chlorine, CH3O-, CH3C(O)-, CH3OCH2-,
[032] [032] In certain embodiments, there are 0 to 4, 0 to 3, 0 to 2, 1 or 0 substituents. Preferably, there are 0 to 2 substituents, and more preferably, 0 or 1 substituent. More preferably optionally substituted groups may be more than one.
[033] [033] In certain embodiments of the compounds of the invention, A is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C3-C8 cycloalkyl, or optionally substituted 3- to 8-membered heterocyclyl, as described above. In this embodiment, R4 is an optionally substituted aryl, heteroaryl, 3- to 12-membered heterocycloalkyl, C3-C12-cycloalkyl, C3-C12 cycloalkenyl, aryl-O-, heteroaryl-O, aryl-
[034] [034] In certain embodiments of the compounds of the invention, each R6 is independently halo, optionally substituted methyl, CN or CF3. In certain embodiments, n is 0 to 3, 0 to 2, 1, or 0. More preferably, n is 0.
[035] [035] In certain embodiments of the compounds of the invention, A is a 5-membered monocyclic heteroaryl, optionally substituted with one to two substituents independently selected from the group consisting of halo, CF3, OCF3, SO2Me, cyano, -C1-C8 -optionally substituted alkoxy, and optionally substituted methyl; R1 is hydrogen or optionally substituted methyl; R2 is hydrogen; R3 is optionally substituted aryl, R4 is optionally substituted aryl or optionally substituted heteroaryl. R5 is hydrogen; n is 0. Preferably A is optionally substituted triazole, optionally substituted oxadiazolyl, optionally substituted oxazolyl, or optionally substituted thiadiazolyl.
[036] [036] In certain embodiments of the compounds of the invention, A is a 6-membered monocyclic heteroaryl optionally independently substituted with one to two substituents selected from the group consisting of halo, CF3, OCF3, SO2Me, cyano, -C1-C8- optionally substituted alkoxy, and optionally substituted methyl; R1 is hydrogen or optionally substituted methyl; R2 is hydrogen; R3 is optionally substituted aryl. R4 is optionally substituted aryl or optionally substituted heteroaryl. R5 is hydrogen; R6 is hydrogen. Preferably A is optionally substituted pyridyl or optionally substituted pyrimidyl.
[037] [037] In another embodiment of the invention is a compound represented by one of formulas (IIa-1), (IIa-2), (IIb-1) and (IIb-2) or a pharmaceutically acceptable salt, ester or prodrug thereof: wherein R2, R3, R4, R5, R6, A and n are previously defined.
[038] [038] In another embodiment of the invention is a compound represented by one of formulas (IIIa-1), (IIIa-2), (IIIb-1), and (IIIb-2) or a pharmaceutically acceptable salt, ester or prodrug acceptable thereof: wherein R3, R4, R6, A and n are previously defined.
[039] [039] In another embodiment of the invention is a compound represented by one of the formulas (IV-1) ~(IV-4), (IVa-1) ~(IVa-4), and (IVb-1) ~(IVb- 4), or a pharmaceutically acceptable salt, ester or prodrug thereof:
[040] [040] In another embodiment of the invention is a compound represented by one of the formulas (V-1) ~(V-3), (Va-1) ~(Va-3), and (Vb-1) ~(Vb- 3), or a pharmaceutically acceptable salt, ester or prodrug thereof: wherein, R1, R2, R3, R4, R5, R6 and n are previously defined.
[041] [041] In another embodiment of the invention is a compound represented by one of formulas (VIa-1)~ (VIa-8) and Formulas (VIb-1)~ (VIb-8), or a salt, ester or prodrug pharmaceutically acceptable of the same:
[042] [042] It will be appreciated that the description of the present invention should be interpreted in congruence with the laws and principles of chemical bonding. In some cases, it may be necessary to remove a hydrogen atom to accommodate a substituent at any location.
[043] [043] It is anticipated that the definition of any substituent or variable (eg, R1, R2, etc.) at a specific location in a molecule is independent of its definitions elsewhere in that molecule. For example, in formula (V-1) when n is 2, each of the two R6 groups can be the same or different.
[044] [044] It will further be appreciated that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric and optically active forms. It will further be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated as being within the scope of the present invention.
[045] [045] In certain embodiments, the present invention provides a method for preventing or treating RSV activities and for treating RSV infections. The method comprises administering a therapeutically effective amount of a compound of formula (I).
[046] [046] The present invention also provides the use of a compound of formula (I) for the preparation of a medicament for the prevention or treatment of RSV.
[047] [047] Thus, in one embodiment, a compound of formula (I), or pharmaceutically acceptable salt thereof, is combined with a steroidal anti-inflammatory compound, for example budesonide or fluticasone. In a preferred embodiment, the steroid is administered in low doses to minimize immunosuppressive effects. In another embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is combined with a non-steroidal anti-inflammatory compound, for example leukotriene antagonists such as Singulair (Merck) or Accolate (Astra Zeneca), phosphodiesterase-4 inhibitors such as roflumilast (Altana), TNF alpha inhibitors such as Enbrel (Amgen), Remicade (Centocor), Humira (Abbott) or CDP870 (Celltech) or NSAIDs. In another embodiment, a compound of formula (I) is combined with inhibitors of interleukin 8 or interleukin 9. The present invention also relates to a product containing a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an anti-inflammatory compound for simultaneous, separate or sequential use in the treatment of RSV.
[048] [048] The present invention also relates to a combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, with an anti-influenza compound and the use of such a combination in the treatment of concomitant RSV and influenza infections. . The present invention also relates to a product containing a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an anti-influenza compound for simultaneous, separate or sequential use in the treatment of concomitant RSV and influenza infections. Compounds of the invention can be administered in a variety of dosage forms. Thus, they can be administered orally, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. Compounds of the invention may also be administered parenterally, either subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The compounds may also be administered in the form of suppositories.
[049] [049] In certain embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered with one or more additional agents together in a single pharmaceutical composition. In certain embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered with one or more additional agents as two or more separate pharmaceutical compositions. for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in a pharmaceutical composition and at least one of the additional agents can be administered in a second pharmaceutical composition. If there are at least two additional agents, one or more additional agents may be in a first pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one of the other additional agent(s) may be be in a second pharmaceutical composition.
[050] [050] The order of administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, with one or more additional agents, may vary. In certain embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered prior to all additional agents. In other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered before at least one additional agent. In still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered concomitantly with one or more additional agents. In still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered following administration of at least one additional agent. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered following administration of all additional agents.
[051] [051] After a period of time, infectious agents such as RSV may develop resistance to one or more therapeutic agents. In certain embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to an RSV-infected individual who is resistant to one or more different anti-RSV agents (e.g., ribavirin). In certain circumstances, the development of resistant RSV strains is delayed when subjects are treated with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, compared to the development of RSV strains resistant to other RSV drugs. .
[052] [052] In one embodiment, compounds of the invention are administered by intranasal or intrabronchial administration. The present invention also provides an inhaler or nebulizer containing a medicament comprising (a) a benzodiazepine derivative of formula (I), as defined above, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier or diluent.
[053] [053] The present invention also provides a pharmaceutical composition containing a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. In certain embodiments, the invention provides pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and at least one additional anti-RSV agent, such as the anti-RSV agents, disclosed in this invention. Preferably, the combination formulations of the invention comprise a compound of Formula I or a pharmaceutically acceptable salt thereof and one or more additional anti-RSV agents that are bioavailable by the same route of administration. Under preferred conditions, the compound of Formula I or a pharmaceutically acceptable salt thereof and the additional anti-RSV agent(s) are orally available and the pharmaceutical composition is in a form suitable for oral administration.
[054] [054] The compounds and combinations of the invention are typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain, together with the active compound, diluents, for example lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants, for example silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; binding agents; for example starches, acacia, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents, for example starch, alginic acid, alginates or sodium starch glycollate; effervescent mixtures; dyes; sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulfates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in a known manner,
[055] [055] Liquid dispersions for oral administration can be syrups, emulsions and suspensions. Syrups may contain as carriers, for example, sucrose or sucrose with glycerin and/or mannitol and/or sorbitol.
[056] [056] Suspensions and emulsions may contain as carriers, for example, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, for example sterile water, olive oil, ethyl oleate, glycols, for example propylene glycol and, if desired, a suitable amount of sodium hydrochloride. lidocaine.
[057] [057] Solutions for injection or infusion may contain as a carrier, for example, sterile water or, preferably, may be in the form of isotonic, aqueous and sterile saline solutions.
[058] [058] The present invention also relates to novel compounds as defined above; or a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body. The present invention also relates to a pharmaceutical composition comprising a novel compound as defined above and a pharmaceutically acceptable diluent or carrier. Preferably, the pharmaceutical composition comprises a pharmaceutically acceptable salt of a novel compound as defined above. A pharmaceutically acceptable salt is as defined above. Novel compounds of the invention are typically administered in the manner defined above and the compounds are typically formulated for administration in the manner defined above.
[059] [059] Preferably, the pharmaceutical compositions comprise optically active isomers of the novel compounds of the invention. Thus, for example, preferred novel compounds of the invention containing only one chiral center include an R enantiomer in substantially pure form, an S enantiomer in substantially pure form, and enantiomeric mixtures that contain an excess of the R enantiomer or an excess of the S enantiomer. It is preferred that the pharmaceutical compositions contain a compound of the invention which is a substantially pure optical isomer. For the avoidance of doubt, the novel compounds of the invention can, if desired, be used in the form of solvates.
[060] [060] Yet another aspect of the present invention is a process of making any of the compounds outlined in the present invention, employing any of the synthetic means outlined in the present invention. Definitions
[061] [061] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this descriptive report and claims, unless they are limited to specific cases, individually or as part of a larger group.
[062] [062] The term "alkyl", as used in the present invention, refers to saturated, monovalent straight-chain or branched hydrocarbon radicals. Preferred alkyl radicals include C1-C6 alkyl and C1-C8 alkyl radicals. Examples of C1-C6 alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl radicals; and examples of C1-C8 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.
[063] [063] The term "alkenyl", as used in the present invention, refers to straight or branched chain hydrocarbon radicals that have at least one carbon-carbon double bond by the removal of a single hydrogen atom. Preferred alkenyl groups include C2-C6 alkenyl and C2-C8 alkenyl groups. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
[064] [064] The term "alkynyl", as used in the present invention, refers to straight or branched chain hydrocarbon radicals having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. Preferred alkynyl radicals include C2-C6 alkynyl and C2-C8 alkynyl radicals. Representative alkynyl radicals include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptylnyl, octylnyl, and the like.
[065] [065] It is understood that any alkyl, alkenyl, alkynyl and cycloalkyl moiety in the present invention described may also be an aliphatic group, an alicyclic group or a heterocyclic group. An "aliphatic" group is a non-aromatic moiety which may contain any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contain one or more units of unsaturation, e.g. double and/or triple bonds. An aliphatic group can be straight chain, branched or cyclic and preferably contains from about 1 to about 24 carbon atoms, more typically from about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, aliphatic groups include, for example, polyalkoxyalkyl, such as polyalkylene glycols, polyamines and polymines, for example. These aliphatic groups can be further substituted.
[066] [066] The term "alicyclic", as used in the present invention, denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2,2,1]heptyl, and bicyclo[2,2,2]octyl. Such alicyclic groups may be further substituted.
[067] [067] The term "alkynylene" refers to an alkynyl group from which an additional hydrogen atom has been removed to form a diradical group. Alkynylene groups include, but are not limited to, for example, ethynylene, propynylene, butynylene, 1-methyl-2-butyn-1-ylene, heptylene, octylene and the like.
[068] [068] The term "carbocycle" refers to a ring system that is saturated (e.g. "cycloalkyl"), partially saturated (e.g. "cycloalkenyl" or "cycloalkynyl") or fully unsaturated (e.g. "aryl" ) containing zero heteroatom ring atom. "Ring atoms" or "ring members" are the atoms joined to form the ring or rings. When a carbocycle group is a divalent moiety that bonds two other elements in a depicted chemical structure, the carbocycle group can be bonded to the other two elements through any two replaceable ring atoms. A C4-C6 carbocycle has 4 to 6 ring atoms.
[069] [069] The term "cycloalkyl", as used in the present invention, refers to a monocyclic or polycyclic saturated carbocyclic ring compound, and the carbon atoms may be optionally oxo-substituted. A polycyclic cycloalkenyl may comprise fused rings. Preferred cycloalkyl groups include C3-C8 cycloalkyl and C3-C12 cycloalkyl groups. Examples of C3-C8-cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and Examples of C3-C12-cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl,
[070] [070] The term "cycloalkenyl", as used in the present invention, refers to the monocyclic or polycyclic carbocyclic ring compound that has at least one carbon-carbon double bond and the carbon atoms may be optionally oxo-substituted. A polycyclic cycloalkenyl may comprise fused rings, covalently linked rings or a combination thereof. Preferred cycloalkenyl groups include C3-C8 cycloalkenyl and C3-C12 cycloalkenyl groups. Examples of C3-C8-cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like; and Examples of C3-C12-cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.
[071] [071] The term "heterocycloalkyl" and "heterocyclic" may be used interchangeably and refer to a 3, 4, 5, 6, 7 or 8 or 9 to 12 membered non-aromatic ring or a bi- or fused or bridged tricyclic or spiro system, wherein: (i) each ring contains between one and three heteroatoms independently selected from oxygen, sulfur, and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds, and each ring 6, 7, 8 or 9-12 member has 0 to 2 double bonds; (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized; (iv) the nitrogen heteroatom may optionally be quaternized; (v) any of the above rings may be fused to a benzene ring and (vi) the remaining ring atoms are carbon atoms which may optionally be oxo-substituted. Representative heterocycloalkyl groups include, but are not limited to, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothialinazolidinyl, quinoxalidinyl, pyridazinonyl, 2-azabicyclo 2,2,1] heptyl, 8-
[072] [072] The term "aryl", as used in the present invention, refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanil, indenil and the like. A polycyclic aryl is a polycyclic ring system comprising at least one aromatic ring. Polycyclic aryls may comprise fused rings, covalently linked rings or a combination thereof.
[073] [073] The term "heteroaryl", as used herein, refers to a mono- or polycyclic aromatic radical having one or more ring atoms selected from S, O and N; and the remaining ring atoms are carbon, where any N or S contained in the ring may be optionally oxidized. Preferred heteroaryl groups are monocyclic or bicyclic. Heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, iso-oxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl, and others similar. A polycyclic heteroaryl may comprise fused rings, covalently linked rings, or a combination thereof.
[074] [074] According to the invention, aromatic groups can be substituted or unsubstituted.
[075] [075] The term "arylalkyl", as used in the present invention, refers to the functional group in which an alkylene chain is attached to an aryl group. Examples include, but are not limited to, benzyl, phenethyl, and the like. The term "substituted arylalkyl" means an arylalkyl functional group in which the aryl group is substituted. Likewise, the term "heteroarylalkyl" means a functional group in which an alkylene chain is bonded to a heteroaryl group. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl, and the like. The term "substituted heteroarylalkyl" means a heteroarylalkyl functional group on which the heteroaryl group is substituted.
[076] [076] The term "alkoxy" used alone or in combination with other terms means, unless otherwise indicated, an alkyl group with the designated number of carbon atoms bonded to the rest of the molecule by an oxygen atom, as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologues and isomers. Preferred alkoxy are (C1-C3)alkoxy.
[077] [077] The term "halo" or halogen" alone or as part of another substituent, as used in the present invention, refers to a fluorine, chlorine, bromine or iodine atom.
[078] [078] The term "hydrogen" includes hydrogen and deuterium. Furthermore, the indication of an atom includes other isotopes of that atom, provided that the resulting compound is pharmaceutically acceptable.
[079] [079] The term "substituted", as used in the present invention, refers to the independent replacement of one, two, three or more hydrogen atoms therein by substituents, including, but not limited to, deuterium, tritium, -F, -Cl, -Br, -I, -OH, protected hydroxy, -NO2, -CN, -NH2, -N3, protected amino, alkoxy, thioalkoxy, oxo, thioxo, -C1-C12-alkyl, -C2-C12- alkenyl, -C2-C12-alkynyl, -C3-C12-cycloalkyl-halo-C1-C12-alkyl, -halo-C2-C12-alkenyl, -halo-C2-C12-alkynyl, -halo-C3-C12-cycloalkyl -NH-C1-C12-alkyl, -NH-C2-C12-alkenyl, -NH-C2-C12-alkynyl, -NH-C3-C12-cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-
[080] [080] The term "optionally substituted" as used in the present invention means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is not substituted. In another embodiment, the referenced group is optionally substituted with one or more additional groups selected individually and independently of groups described in the present invention.
[081] [081] According to the invention, any of the aryls, substituted aryls, heteroaryls and substituted heteroaryls described in the present invention can be any aromatic group. Aromatic groups may be substituted or unsubstituted.
[082] [082] It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described in the present invention may also be an aliphatic group or an alicyclic group.
[083] [083] An "aliphatic" group is a non-aromatic moiety composed of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms and optionally contains one or more units of unsaturation, for example , double bonds and/or triple bonds. Examples of aliphatic groups are functional groups such as alkyl, alkenyl, alkynyl, O, OH, NH, NH2, C(O), S(O)2, C(O)O, C(O)NH, OC(O) )O, OC(O)NH, OC(O)NH2, S(O)2NH, S(O)2NH2, NHC(O)NH2, NHC(O)C(O)NH, NHS(O)2NH, NHS (O)2NH2, C(O)NHS(O)2, C(O)NHS(O)2NH or C(O)NHS(O)2NH2, and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons ( optionally substituted) and groups in which one or more carbons of a non-aromatic hydrocarbon (optionally substituted) are replaced by a functional group. The carbon atoms of an aliphatic group may optionally be oxo-substituted. An aliphatic group can be straight chain, branched, cyclic or a combination thereof and preferably contains from about 1 to about 24 carbon atoms, more typically from about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups such as used in the present invention, aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines and polyimines, for example. Aliphatic groups may be optionally substituted.
[084] [084] The term "alicyclic", as used in the present invention, denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2,2,1]heptyl and bicyclo[2,2,2]octyl. Such alicyclic groups may be further substituted.
[085] [085] It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic or similar moiety described in the present invention may also be a divalent or multivalent group when used as a bond to connect two or more groups or substituents, which may be on the same or different atoms. One skilled in the art can quickly determine the valence of any such group from the context in which it occurs.
[086] [086] The term "hydroxy activating group", as used in the present invention, refers to a labile chemical moiety that is known in the prior art to activate a hydroxy group so that it moves away during synthetic procedures, such as in substitution or elimination reactions. Examples of hydroxy activating group include, but are not limited to, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate, and the like.
[087] [087] The term "activated hydroxy", as used in the present invention, refers to an activated hydroxy group with a hydroxy activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example. example.
[088] [088] The term "protected hydroxy", as used in the present invention, refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
[089] [089] The term "hydroxy protecting group", as used in the present invention, refers to a labile chemical moiety that is known in the prior art to protect a hydroxy group against unwanted reactions during synthetic procedures. After said synthetic procedure(s), the hydroxy protecting group as described in the present invention can be selectively removed. Hydroxy protecting groups, as known in the prior art, are described generally in T.H. Greene and P.G., S.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxy protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3- butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like. Preferred hydroxy protecting groups for the present invention are acetyl (Ac or -C(O)CH3), benzoyl (Bz or -C(O)C6H5), and trimethylsilyl (TMS or -Si(CH3)3), and the like.
[090] [090] The term "hydroxy prodrug group", as used in the present invention, refers to a modifying (promoiety) functional group that is known in the prior art to alter the physicochemical properties and, therefore, the biological properties of a parent drug in a transient manner, covering or masking the hydroxy group. After the aforementioned
[091] [091] The term "amino protecting group", as used in the present invention, refers to a labile chemical moiety that is known in the prior art to protect an amino group against unwanted reactions during synthetic procedures. After said synthetic procedure(s), the amino protecting group as described in the present invention can be selectively removed. Amino protecting groups as known in the art are described generally in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.
[092] [092] The term "protected amino", as used in the present invention, refers to an amino group protected with an amino protecting group, as defined above.
[093] [093] The term "leaving group" means a functional group or atom that can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
[094] [094] The compounds described in the present invention contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) - or (S) - or as (D) - or (L) - for amino acids. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers can be prepared from their respective optically active precursors by the procedures described above, or by resolving racemic mixtures. Resolution may be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization, or by some combination of these techniques, which are known to those skilled in the art. Additional details on resolutions can be found in Jacques et al., Enantiomers, Racemates and Resolutions (John Wiley & Sons, 1981). When the compounds described in the present invention contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both the E and Z geometric isomers. Likewise, all tautomeric forms must also be included. The configuration of any carbon-carbon double bond appearing in this present invention is selected for convenience only and is not intended to designate a specific configuration unless the text states; therefore, a carbon-carbon double bond in the present invention arbitrarily described as trans may be cis, trans, or a mixture of the two in any proportion.
[095] [095] Certain compounds of the present invention may also exist in different stable conformational forms that may be separable. Torsional asymmetry due to restricted rotation around an asymmetrical single bond, for example due to steric hindrance or ring tension, can allow separation of different conformers. The present invention includes each conformational isomer of these compounds and mixtures thereof.
[096] [096] The term "subject" as used in the present invention refers to a mammal. Therefore, an individual refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, and the like. Preferably, the subject is human. When the subject is human, the subject may be referred to in the present invention as a patient.
[097] [097] As used in the present invention, the term "pharmaceutically acceptable salt" refers to salts of compounds formed by the process of the present invention that are, within the scope of sound medical judgment, suitable for use in contact with human tissues. and lower animals, without toxicity, irritation, undue allergic response and the like, and are proportionate to a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.
[098] [098] Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). Salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately, by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, for example, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid. or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or using other methods used in the prior art, such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate,
[099] [099] Pharmaceutically acceptable salts can also be prepared by deprotonating the parent compound with a suitable base, thus forming the anionic conjugate base of the parent compound. In such salts, the counter-ion is a cation. Suitable cations include ammonium and metal cations, such as alkali metal cations, including Li+, Na+, K+ and Cs+, and alkaline earth metal cations, such as Mg2+ and Ca2+.
[0100] [0100] As used in the present invention, the term "pharmaceutically acceptable ester" refers to esters of compounds formed by the process of the present invention that hydrolyze in vivo and include those that readily decompose in the human body to leave the parent compound or a salt of the same. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than
[0101] [0101] The term "pharmaceutically acceptable prodrugs" as used in the present invention refers to prodrugs of compounds formed by the process of the present invention that are, within the scope of sound medical judgment, suitable for use in contact with human and lower animal tissues with undue toxicity, irritation, allergic response, and the like, proportionate to a reasonable risk/benefit ratio and effective for the intended use, as well as zwitterionic forms, whenever possible, of the compounds of the present invention . "Prodrug" as used in the present invention means a compound that is convertible in vivo by metabolic means (e.g. by hydrolysis) to provide any compound delineated by the formulas of the present invention. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, Vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed.). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry , Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).
[0102] [0102] Additional types of prodrugs are also covered. For example, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups can be derivatized using groups including, but not limited to, hemisuccinates, ethyl succinate, phosphate esters,
[0103] [0103] The term "treatment" as used in the present invention means alleviating, lessening, reducing, eliminating, modulating or ameliorating, i.e. causing regression of the disease state or condition. Treatment may also include inhibiting, i.e., arresting the development, of an existing disease state or condition and alleviating or ameliorating, i.e., causing regression of an existing disease state or condition, for example, when the disease state or condition of disease may already be present.
[0104] [0104] The term "prevention", as used in the present invention,
[0105] [0105] The terms "therapeutically effective amount" and "effective amount" are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the indicated biological or medicinal response. In the case of a combination therapy, i.e., the administration of two or more active pharmaceutical agents, a therapeutically effective amount is the amount of each agent in combination that produces the desired response, even if the amount of any agent in the combination is not sufficient. , by itself, to provide such an answer. for example, a therapeutically effective amount of a compound or combination of compounds is that amount of said compound or combination of compounds necessary to prevent, treat, alleviate or ameliorate one or more symptoms or conditions of the disease or prolong the survival of the subject under treatment . This response can occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determining an effective amount of a compound or a combination of two or more compounds is within the skill of those skilled in the art, in view of the disclosure provided in the present invention. The required therapeutically effective amount of the compounds described in the present invention as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the particular animal under consideration. The dose can be tailored to achieve the desired effect, but will depend on factors such as weight, diet, concurrent medication, and other factors that medical experts will recognize.
[0106] [0106] Various indicators for determining the effectiveness of a method for treating a viral infection, such as a paramyxovirus, are known to those skilled in the art. Examples of suitable indicators include, but are not limited to, reduced viral load, reduced viral replication, reduced viral RNA, reduced seroconversion time (undetectable virus in the patient's serum), reduced morbidity or mortality in clinical outcomes, and /or other disease response indicator.
[0107] [0107] In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective to reduce viral titers to essentially undetectable or very low levels, for example, to less than 1.7 log10 equivalent of plaque forming units (PFUe) / mL or less than 0.3 log10 equivalent of plaque forming units (PFUe) / mL. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may reduce viral load compared to viral load prior to administration of the combination (e.g., 60 hours after receiving the initial dosage of the combination) . In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described in the present invention, can reduce viral load to less than 1.7 Log10 (PFUe)/mL or less than 0.3 Log10 (PFUe) / mL. In some embodiments, a combination of compounds described in the present invention can achieve a reduction in the subject's serum viral titer in the range of about 1.5 log to about a 2.5 log reduction, about a 3 log reduction. to about a 4 log reduction or greater to about a 5 log reduction compared to the viral load before the combination is given, e.g. viral load is measured before the combination is given and several hours after receiving the dose combination dose (eg, 60 hours after receiving the initial combination dose).
[0108] [0108] The term "resistant", as used in the present invention, refers to a viral strain that exhibits a delayed, diminished and/or null response to therapeutic agent(s). For example, after treatment with an antiviral agent, the viral load of an individual infected with a resistant virus may be reduced to a lesser degree compared to the amount of viral load reduction exhibited by an individual infected with a non-resistant strain.
[0109] [0109] In addition, the compounds of the present invention, including the salts of the compounds, may exist in hydrated or non-hydrated (anhydrous) form or as solvates with other solvent molecules. Examples of non-limiting solvents include monohydrates, dihydrates, etc. Examples of non-limiting solvates include ethanol solvates, acetone solvates and the like.
[0110] [0110] "Solvates" means solvent addition forms that contain stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to retain a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed will be a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with one of the substances in which water retains its molecular state as H2O, this combination being capable of forming one or more hydrates.
[0111] [0111] As used in the present invention, the term "analog" refers to a chemical compound that is structurally similar to another, but differs slightly in composition (such as replacing an atom with an atom of a different element or in the presence of a particular functional group or the replacement of one functional group by another functional group). Thus, an analogue is a compound that is similar or comparable in functionality and appearance to the reference compound.
[0112] [0112] The term "aprotic solvent", as used in the present invention, refers to a solvent that is relatively inert to proton activity, that is, it does not act as a proton donor. Examples include, but are not limited to, hydrocarbons such as hexane and toluene, for example halogenated hydrocarbons such as, for example, methylene chloride, ethylene chloride, chloroform, chloroform and the like, heterocyclic compounds such as, for example tetrahydrofuran and N-methylpyrrolidinone and ethers such as diethyl ether, bis-methoxymethyl ether. Such solvents are well known to those skilled in the art and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending on factors such as solubility of the reactants, reactivity of the reactants and preferred temperature ranges, for example. Additional discussions of aprotic solvents can be found in organic chemistry textbooks or specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
[0113] [0113] The terms "protogenic organic solvent" or "protic solvent" as used in the present invention refer to a solvent that tends to supply protons, such as alcohol, e.g. methanol, ethanol, propanol, isopropanol, butanol , t-butanol Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending on factors such as the solubility of the reactants, reactivity of the reactants, and preferred temperature ranges, Additional discussions of protogenic solvents can be found in organic chemistry textbooks or specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th edition., edited by John A. Riddick et al., Vol. II, in the series Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
[0114] [0114] The combinations of substituents and variables provided for by this invention are only those that result in the formation of stable compounds. The term "stable", as used in the present invention, refers to compounds that have sufficient stability to allow production and that maintain the integrity of the compound for a period of time sufficient to be useful for the purposes detailed herein (e.g. , therapeutic or prophylactic administration to a subject).
[0115] [0115] The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high performance liquid chromatography or recrystallization. Furthermore, the various synthetic steps can be carried out in an alternating sequence or order to provide the desired compounds. In addition, solvents, temperatures, reaction durations, etc. outlined in the present invention are for illustrative purposes only and varying reaction conditions can produce the desired bridged macrocyclic products of the present invention. Synthetic chemical transformations and protecting group (protection and deprotection) methodologies useful in the synthesis of the compounds described in the present invention include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,
[0116] [0116] The compounds of this invention can be modified by attaching various functionalities through synthetic means in the present invention designed to improve selective biological properties. Such modifications include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and alter the rate of excretion. PHARMACEUTICAL COMPOSITIONS
[0117] [0117] The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof or a therapeutically effective amount of a combination of a compound of formula I or a pharmaceutically acceptable salt thereof and at least at least one additional anti-RSV agent formulated together with one or more pharmaceutically acceptable carriers. As used in the present invention, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or auxiliary formulation of any type. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; baby powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweeteners, flavors, preservatives and antioxidants may also be present. present in the composition, according to the judgment of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as in powdered form, ointments or drops), by buccal administration, or as an oral spray. or nasal.
[0118] [0118] The pharmaceutical compositions of this invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, by buccal, vaginal or implanted reservoir administration, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional pharmaceutically acceptable non-toxic carriers, adjuvants or carriers. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to increase the stability of the formulated compound or its delivery form. The term parenteral, as used in the present invention, includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
[0119] [0119] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular cottonseed, peanut, corn, wheat germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of sorbitan fatty acids and their mixtures. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
[0120] [0120] Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions can be formulated according to the known technique using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[0121] [0121] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media before of use.
[0122] [0122] To prolong the effect of a drug, it is often desirable to delay the absorption of the drug by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with low water solubility. The absorption rate of the drug then depends on its dissolution rate, which, in turn, may depend on the crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers, such as polylactide-polyglycolide. Depending on the drug to polymer ratio and the nature of the specific polymer employed, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions compatible with body tissues.
[0123] [0123] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature, but liquids at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.
[0124] [0124] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants, such as glycerol, d) disintegrating agents, such as agar, carbonate of calcium, tapioca or potato starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as, for example cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sucrose lauryl sodium sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
[0125] [0125] Solid compositions of a similar type can also be employed as fillers in soft and hard gelatine capsules, using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.
[0126] [0126] The active compounds can also be in microencapsulated form with one or more excipients, as noted above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, tablet lubricants and other tablet aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
[0127] [0127] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any suitable preservative or buffer as required. Ophthalmic formulations, eye drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
[0128] [0128] Ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites , silicic acid, talc and zinc oxide or mixtures thereof.
[0129] [0129] Powders and sprays may contain, in addition to the compounds of this invention, excipients, such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and powdered polyamide, or mixtures of these substances. Sprays can also contain customary propellants such as chlorofluorohydrocarbons.
[0130] [0130] Transdermal patches have the added benefit of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.
[0131] [0131] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon age, weight, severity of disease and mammalian species treated, particular compounds employed, and the specific use. for which these compounds are used. The determination of effective dosage levels, which are the dosage levels necessary to achieve the desired result, can be determined by one of ordinary skill in the art using routine methods, for example, human clinical trials and in vitro studies.
[0132] [0132] Unless defined otherwise, all technical and scientific terms used in the present invention are given the meaning commonly known to the person skilled in the art. All publications, patents, published patent applications and other references mentioned herein are incorporated by reference in their entirety. Combination and alternation therapy for RSV
[0133] [0133] In certain aspects, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described in the present invention, is used in combination with one or more additional agents. Under certain conditions, a compound of
[0134] [0134] Other examples of compounds that can be used in combination with a compound of formula (I), or a pharmaceutically acceptable salt thereof, include those provided in WO 2013/186333, published December 19, 2013; WO 2013/186332, published December 19, 2013; WO 2013/186335, published December 19, 2013; WO 2013/186334, published December 19, 2013; WO 2012/080447, published June 21, 2012; WO 2012/080449, published June 21, 2012; WO 2012/080450, published June 21, 2012; WO 2012/080451, published June 21, 2012; WO 2012/080446, published June 21, 2012; WO 2010/103306, published September 16, 2010; WO 2012/068622, published May 31,
[0135] [0135] In combination therapy, additional agents may be administered in amounts that have been shown to be effective for these additional agents. Such amounts are known in the state of the art; alternatively, they can be derived from viral load or replication studies using the parameters for "effective amount" set out above. Alternatively, the amount used may be less than the monotherapy effective amount for these additional agents. for example the amount used can be between 90% and 5% of that amount, for example 90%, 80%, 70%, 60%, 50%, 40%, 30%, 30%, 20%, 10% or 5 % or intermediate values between these points.
[0136] [0136] A potential advantage of using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agents, including pharmaceutically acceptable salts and prodrugs thereof, may be a reduction in the (s) required amount(s) of one or more compounds described above (including those shown in the table) including pharmaceutically acceptable salts and prodrugs thereof that are effective in treating a disease condition in the present disclosed invention (e.g., RSV), compared to the amount required to achieve the same therapeutic result when one or more compounds described above (including those shown in the table), including pharmaceutically acceptable salts thereof, are administered without a compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, the amount of a compound described above, including a pharmaceutically acceptable salt and prodrug thereof, may be less compared to the amount of the above compound, including a pharmaceutically acceptable salt and prodrug thereof, necessary to achieve the same reduction in viral load when given as monotherapy.
[0137] [0137] Another potential advantage of using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agents described above (including the table), including pharmaceutically acceptable salts and prodrugs of the The same is that the use of two or more compounds with different mechanisms of action can create a higher barrier to the development of resistant viral strains than the barrier when a compound is administered in monotherapy.
[0138] [0138] Additional advantages of using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agents described above (including the table), including pharmaceutically acceptable salts and prodrugs, may include little or no cross-resistance between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agents described above, including pharmaceutically acceptable salts and prodrugs thereof; different routes for eliminating a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agents described above, including pharmaceutically acceptable salts and prodrugs; little or no overlapping toxicity between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agents described above, including pharmaceutically acceptable salts and prodrugs thereof; little or no significant effect on cytochrome P450; and/or little or no pharmacokinetic interaction between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agents described above, including pharmaceutically acceptable salts and prodrugs.
[0139] [0139] It will be understood that administration of the combination of the invention may be by way of a single patient pack, or patient packs of each formulation, containing within an information leaflet instructing the patient on the correct use of the invention, is a resource desirable feature of this invention.
[0140] [0140] Unless otherwise defined, all technical and scientific terms used herein are given the meaning commonly known to one skilled in the art. All publications, patents, published patent applications and other references mentioned herein are incorporated by reference in their entirety. abbreviations
[0141] [0141] Abbreviations that have been used in the schematic descriptions and examples below are: ACN for acetonitrile; BAST for bis(2-methoxyethyl)amino-sulfur trifluoride; BME for 2-mercaptoethanol; BOP for benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate;
[0142] [0142] The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes illustrating the methods by which the compounds of the invention may be prepared, which serve as an illustration only and not to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications, including, without limitation, those relating to the chemical structures, substituents, derivatives, and/or methods of the invention, may be made without departing from the spirit of invention and the scope of the appended claims.
[0143] [0143] As shown in Scheme 1, new RSV analogs of compounds of formula 10 or 11 are prepared from compounds 1, 2 and 3. A procedure similar to that described by Sherrill and Sugg (J. Org. Chem. 1995, 60, 730-734) was adopted to arrive at the intermediate with formula 8.
[0144] [0144] Scheme 2 illustrates alternative methods, wherein n, R2, R3, R4, R5, R6 and A are defined as described above, to prepare compounds of formula (11). Following path 1, compound 12 is reacted with dihalide 13, where X is a halogen which may or may not be the same, via displacement of a halogen (X) or via suitable coupling conditions using Pd or Cu catalysts. to produce compounds of formula 14. Compound 14 is further reacted with appropriate coupling partners selected from, but not limited to, boronic acids, boronic esters, organotin reagents, organozinc reagents, organomagnesium reagents, organosilicon reagents, amines and alcohols, in combination with the appropriate Pd, Ni or Cu catalyst to provide compounds of formula 11. The above-mentioned reaction can also be carried out in a carbon monoxide atmosphere to provide corresponding ketones, amides and esters of formula 11. Compound 14 it can also react with an appropriate amine, alcohol or thiol to form 11 via a displacement reaction.
[0145] [0145] Scheme 3 illustrates methods, wherein n, R2, R3, R4, R5 and R6 are defined as described above, to prepare compounds of formulas 20, 21, 22 and 23. Following path 1, amine 8 is reacted with 1,1'-thiocarbonyldiimidazole (TCDI) to generate intermediate 17 which is reacted directly with hydrazides to produce compounds of formula 18. Compounds of formula 18 can be reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) to produce the formula oxadiazoles
[0146] [0146] Scheme 4 illustrates methods, wherein n, R2, R3, R4, R5 and R6 are defined as described above, to prepare compounds of formula 20 and (21). Compounds 8 can be reacted with oxadiazolones, with the presence of a coupling reagent such as, but not limited to, (Benzotriazol-1-yloxy)tris(dimethylamino)hexafluorophosphate (BOP) to provide compounds of formula 20 and can be further reacted by alkylation with reagents such as, but not limited to, alkyl halides, mesylates and tosylates or by reductive amination with aldehydes and ketones to install R2 , where R2 is defined as described above, to produce compounds of formula 21. Alternatively compounds 12 can be reacted with oxadiazolones, in the presence of (BOP) to produce compounds of formula
[0147] [0147] Scheme 5 illustrates methods, wherein n, R2, R3, R4, R5 and R6 are defined as described above, to prepare compounds of formula 23, 24, 26, and 27. Following path 1, the amine 8 is reacted with TCDI to generate intermediate 17 which is reacted with alpha-azido ketones to generate oxazole 23. Compound 23 can be further reacted by alkylation with reagents such as, but not limited to, alkyl halides, mesylates and tosylates. or via reductive amination with aldehydes and ketones to install R2, where R2 is defined as described above, to form compounds of formula 24. Following path 2, 8 is reacted with TCDI to generate the thiourea intermediate 25 which is further reacted with alpha -bromo ketones to form the thiazoles with a formula such as 26, which can be further reacted by alkylation with reagents such as, but not limited to, alkyl halides, mesylates and tosylates or by reductive amination with aldehydes and ketones to install R2 in that R2 is defined as described in previously to produce compounds of formula 27. Scheme 5
[0148] [0148] Scheme 6 illustrates methods, wherein n, R2, R3, R4, R5 and R6 are defined as described above, to prepare compounds of formula 29, 30, 32 and 33. Following path 1, amine 8 is reacted with isothiocyanates to produce intermediate (28) which further reacts with hydrazine to produce triazoles of formula 29. Compound 29 can be further reacted by alkylation with reagents such as, but not limited to, alkyl halides,
[0149] [0149] Scheme 7 illustrates methods, wherein n, R2, R3, R4, R5 and R6 are defined as described above, to prepare compounds of formulas 20 and 21. Amine 8 is reacted with BTC to produce intermediate isocyanate 34 which is further reacted with hydrazides to provide intermediates 35. The reaction of 35 with PPh3 and CCl4 provides the oxadiazoles 20 which can be further reacted via alkylation with reagents such as, but not limited to, alkyl halides, mesylates and tosylates or via amination reductive reaction with aldehydes and ketones to install R2, where R2 is defined as described above, to produce compounds of formula 33. Scheme 7
[0150] [0150] Scheme 8 illustrates methods, wherein n, R2, R3, R4, R5 and R6 are defined as described above, to prepare compounds of formula 37 and 38. Amine 8 is reacted with isothiocyanates to produce intermediate 28 which is further reacted with methyl iodide to produce intermediates 36. Reaction of 36 with hydroxylamine salt -HCl provides the 1,2,4-oxadiazoles 37 which can be further reacted by alkylation with reagents such as, but not limited to, halides of alkyl, mesylates and tosylates or via reductive amination with aldehydes and ketones to install R2, where R2 is defined as described above, to produce compounds of formula 38.
[0151] [0151] Scheme 8
[0152] [0152] Scheme 9 illustrates methods, wherein n, R1, R2, R3, R4, R5 and R6 are defined as described above, to prepare compounds of formula
[0153] [0153] Scheme 10 illustrates methods, wherein n, R1, R2, R3, R4, R5 and R6 are defined as described above, to prepare compounds of formula
[0154] [0154] Scheme 11 illustrates methods, wherein n, R3, R4, R5 and R6 are defined as described above, to prepare compounds of formula
[0155] [0155] The compounds and processes of the present invention will be better understood in connection with the following examples, which serve as an illustration only and are not intended to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications, including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention, may be made without departing from the spirit. of the invention and the scope of the appended claims. Unless otherwise indicated, each of the compounds in the examples below was prepared and tested as a racemic mixture or, where possible, a diastereomeric mixture. Example 1: Example 1 step a:
[0156] [0156] To a 250 mL flask equipped with a mechanical stirrer, 2-oxoacetic acid hydrate (9.2 g, 0.1 mol), benzyl carbamate (15.1 g, 0.1 mol) and 1H -benzo[d][1,2,3]triazole (9.2 g, 0.1 mol), and toluene (300 mL). The resulting solution was stirred for 2 h at 120 °C in an oil bath. The resulting mixture was filtered and the solid residue was washed with petroleum ether (3x), and dried in vacuo to yield 2-(1H-benzo[d][1,2,3]triazol-1-yl)-2 acid - (benzyloxycarbonylamino)acetic acid (28.6 g, 87%) as a white solid which was used without further purification. ESI-MS m/z: 327 [M+H]+. Example 1 step b:
[0157] [0157] To a 500 ml 3-neck round bottom flask was added 2-(1H-1,2,3-benzotriazol-1-yl)-2-[[(benzyloxy)carbonyl]amino]acetic acid ( 46.3 g, 91.94 mmol) and tetrahydrofuran (200 mL). The reaction mixture was cooled to 0°C and a solution of oxalyl chloride (17.6 g, 1.00 equiv) in tetrahydrofuran (40 mL) was added dropwise, followed by the addition of DMF (8 mL). The resulting solution was stirred for 2 h at 0 °C then treated with a THF solution (160 mL) of N-methylmorpholine (28.6 g, 280.7 mmol) and 2-benzoylaniline (22.3 g, 80.0 mmol) in portions at 0°C. The cold bath was removed and the resulting solution stirred for 30 minutes at room temperature. The solids were filtered off and the filtrate was evaporated to dryness to give benzyl N-[[(2-benzoylphenyl)carbamoyl](1H-1,2,3-benzotriazol-1-yl)methyl]carbamate (40 .4 g, 87%) as a yellow oil which was used without further purification. ESI-MS m/z: 504 [M-H]-. Example 1 step c:
[0158] [0158] To a 250-mL round bottom flask, benzyl N-[[(2-benzoylphenyl)carbamoyl](1H-1,2,3-benzotriazol-1-yl)methyl]carbamate (40, 4. g, 80.00 mmol), methanol (200 mL), and ammonia (200 mL). The reaction mixture was stirred for 3 h at room temperature, concentrated in vacuo, and the residue was diluted with EtOAc (200 mL). The resulting solution was washed with 1M sodium hydroxide (2x100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to yield benzyl N-[amino[(2-benzoylphenyl)carbamoyl]methyl]carbamate (30.2 g, 93%) as a yellow oil which was used without further purification. To a 500 mL round bottom flask was added benzyl N-[amino[(2-benzoylphenyl)carbamoyl]methyl]carbamate (30.2 g, 74.8 mmol), acetic acid (200 mL), and CH3COONH4 (28.00 g, 363.3 mmol). The reaction mixture was stirred for 16 h at room temperature, concentrated in vacuo, and the residue was diluted with EtOAc:ether = 1:3 (100 mL). The pH value of the solution was adjusted to 8 with 1M sodium hydroxide and the precipitate was collected by filtration to give 2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin (Z)-Benzyl-3-yl)carbamate (14.5 g, 50%) as a pink solid which was used without further purification. ESI-MS m/z: 386 [M+H]+. Example 1 step d:
[0159] [0159] In a 50 mL round bottom flask, 2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl-carbamate of (Z )-benzyl (300 mg, 0.60 mmol), HBr/HOAc (20 mL). The resulting solution was stirred for 30 minutes at 70°C in an oil bath. The resulting solution was diluted with 20 ml of ether. The solids were collected by filtration to yield 270 mg (crude) of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-
[0160] [0160] The crude (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one hydrobromide from step d (38.7 g) was dissolved in 50 mL of water, then NH3.H2O was slowly added in an ice bath to adjust the pH to 14. The solid was filtered and washed with a small amount of water. The solid was collected and dried under vacuum to give (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (16.8 g) as a yellow solid. and used without further purification. ESI-MS m/z: 252 [M+H]+. Example 1 step f:
[0161] [0161] A solution of methyl 3-hydroxybenzoate (4 g, 26.3 mmol), 2-bromoethyl methyl ether (7.3 g, 52.6 mmol) and K2CO3 in acetone (50 mL) was refluxed for 16 hours, the mixture was cooled to room temperature and filtered. The filtrate was concentrated, dissolved in DCM, and washed with saturated aqueous NaHCO3 (x2). The organic layer was dried (Na2SO4), concentrated, and purified by column chromatography (silica, petroleum ether: EtOAc) to yield the desired compound as a pale yellow oil (3.3 g, 59.6%). ESI-MS m/z: 252.2 [M+ MeCN+H]+. Example 1 step g:
[0162] [0162] A solution of the compound from step f (3.3 g, 15.7 mmol) in EtOH
[0163] [0163] Tryphosgene (3.7 g, 12.4 mmol) in THF (10 mL) was added dropwise to the solution of the compound from step g (1.3 g, 6.2 mmol) and Et3N (1.7 mL, 12.4 mmol) in THF (30 mL) at 0 ℃ and heated to reflux for 16 hours. The reaction was quenched with water and concentrated, and the resulting residue was dissolved in EtOAc. The organic layer was washed with water, dried (Na2SO4), and concentrated to give 5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one as a yellow solid (600 mg, 41%) which was used without further purification. ESI-MS m/z: 237.2 [M+H]+. Example 1 step i:
[0164] [0164] A solution of the compound from step h (350 mg, 1.48 mmol), BOP (654 mg, 1.48 mmol), (Z)-3-amino-5-phenyl-1H-benzo[e][ 1,4]diazepin-2(3H)-one (149 mg, 0.59 mmol) and DIPEA (305 mg, 2.37 mmol) in DMF (3 mL) was stirred for 36 hours at room temperature. Then the reaction mixture was purified by preparative HPLC to yield the title compound as a white solid (10 mg, 4%). ESI-MS m/z: 470.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.33(s, 3H), 3.68 (m, 2H), 4.11 – 4.21 (m, 2H), 5.16 (d, J = 8.6 Hz,
[0165] [0165] Example 2 was prepared using a procedure similar to that used to prepare Example 1 where 5-phenyl-1,3,4-oxadiazol-2(3H)-one was used in place of 5-(3-(2- methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 396.1 [M+H]+. Example 3:
[0166] [0166] Example 3 was prepared using a procedure similar to that used to prepare Example 1 where 5-(3-fluorophenyl)-1,3,4-oxadiazol-2(3H)-one was used in place of 5-(3 -(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 414.1 [M+H]+. Example 4:
[0167] [0167] Example 4 was prepared using a procedure similar to that used to prepare Example 1 where 5-(3-methoxyphenyl)-1,3,4-oxadiazol-2(3H)-one was used in place of 5-(3 -(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 426.2 [M+H]+. Example 5:
[0168] [0168] Example 5 was prepared using a procedure similar to that used to prepare Example 1 where 5-cyclopropyl-1,3,4-oxadiazol-2(3H)-one was used in place of 5-(3-(2- methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 360.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.78 - 0.93 (m, 2H), 1.02 (dt, J = 8.3, 3.2 Hz, 2H), 2.05 (tt, J = 8.4, 5.0 Hz, 1H), 5.04 (d, J = 8.7 Hz, 1H), 7.20 - 7.38 (m, 3H), 7.39 - 7.61 (m, 5H), 7.67 (ddd, J = 8.4, 7.0, 1.8 Hz, 1H), 8.67 (d, J = 8.7 Hz, 1H), 10.93 ( s, 1H). Example 6:
[0169] [0169] Example 6 was prepared using a procedure similar to that used to prepare Example 1 where 5-(2-fluorophenyl)-1,3,4-oxadiazol-2(3H)-one was used in place of 5-(3 -(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 414.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.19 (d, J = 8.4 Hz, 1H), 7.25 - 7.55 (m, 10H), 7.58 - 7.72 (m, 2H), 7.87 (m, 1H), 9.23 (d, J = 8.5 Hz, 1H), 11.00 (s, 1H). Example 7:
[0170] [0170] Example 7 was prepared using a procedure similar to that used to prepare Example 1 where 5-(4-fluorophenyl)-1,3,4-oxadiazol-2(3H)-one was used in place of 5-(3 -(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one.
[0171] [0171] Example 7a was separated from racemic Example 7 using a reversed-phase chiral column (Gemini-NX C18 110A). ESI-MS m/z: 414.2 [M+H]+. Example 7b:
[0172] [0172] Example 7b was separated from racemic Example 7 using a reversed-phase chiral column (Gemini-NX C18 110A). ESI-MS m/z: 414.2 [M+H]+. Example 8:
[0173] [0173] Example 8 was prepared using a procedure similar to that used to prepare Example 1 where 5-(4-methoxyphenyl)-1,3,4-oxadiazol-2(3H)-one was used in place of 5-(3 -(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 426.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.16 (d, J = 8.4 Hz, 1H), 7.09 – 7.19 (m, 2H), 7.24 – 7.42 (m, 3H), 7.43 - 7.60 (m, 5H), 7.69 (ddd, J = 8.6, 7.1, 1.8 Hz, 1H), 7.75 - 7.85 (m, 2H), 9.02 (d, J = 8.6 Hz, 1H), 10.99 (s, 1H). Example 9:
[0174] [0174] Example 9 was prepared using a procedure similar to that used to prepare Example 1 where 5-(2-methoxyphenyl)-1,3,4-oxadiazol-2(3H)-one was used in place of 5-(3 -(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 426.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.84 (s, 3H), 5.14 (d, J = 8.5 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H ), 7.15 - 7.40 (m, 4H), 7.42 - 7.58 (m, 6H), 7.67 (td, J = 7.4, 1.7 Hz, 2H), 8, 98 (d, J = 8.6 Hz, 1H), 10.98 (s, 1H). Example 10:
[0175] [0175] Example 10 was prepared using a procedure similar to that used to prepare Example 1 where 5-(furan-2-yl)-1,3,4-oxadiazol-2(3H)-one was used in place of 5- (3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 386.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.14 (d, J = 8.4 Hz, 1H), 6.72 (dd, J = 3.5, 1.8 Hz, 1H), 7.06 (dd, J = 3.5, 0.8 Hz, 1H), 7.22 - 7.40 (m, 3H), 7.40 - 7.61 (m, 5H), 7.66 (ddd, J = 8.5, 7.0, 1.8 Hz, 1H), 7.94 (dd, J = 1.8, 0.8 Hz, 1H), 9.21 (d, J = 8.5 Hz, 1H), 10.99 (s, 1H). Example 10a:
[0176] [0176] Example 10a was separated from racemic Example 10 using a reversed-phase chiral column (Gemini-NX C18 110A). ESI-MS m/z: 386.2 [M+H]+. Example 10b:
[0177] [0177] Example 10b was separated from racemic Example 10 using a reversed-phase chiral column (Gemini-NX C18 110A). ESI-MS m/z: 386.2 [M+H]+. Example 11:
[0178] [0178] Example 11 was prepared using a procedure similar to that used to prepare Example 1 where 5-(pyridin-2-yl)-1,3,4-oxadiazol-2(3H)-one was used in place of 5- (3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 397.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 5.20 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 2.3 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 7.22 - 7.33 (m, 2H), 7.33 - 7.42 (m, 2H), 7.42 - 7.60 (m, 5H), 7, 69 (ddd, J = 8.5, 7.2, 1.7 Hz, 1H), 7.94 - 8.05 (m, 2H), 8.71 (dt, J = 4.7, 1.4 Hz, 1H), 9.32 (d, J = 8.5 Hz, 1H), 11.01 (s, 1H). Example 12:
[0179] [0179] Example 12 was prepared using a procedure similar to that used to prepare Example 1 where 4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzonitrile was used in place of 5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 421.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.21 (d, J = 8.1 Hz, 1H), 7.23 - 7.42 (m, 3H), 7.42 - 7.61 (m, 5H), 7.69 (ddd, J = 8.5, 7.0, 1.8 Hz, 1H), 7.95 - 8.09 (m, 4H), 9.37 (d, J = 8, 3 Hz, 1H), 11.02 (s, 1H). Example 13:
[0180] [0180] Example 13 was prepared using a procedure similar to that used to prepare Example 1 where 5-(4-chlorophenyl)-1,3,4-oxadiazol-2(3H)-one was used in place of 5-(3 -(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 430.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 5.18 (d, J = 8.5 Hz, 1H), 7.23 - 7.41 (m, 3H), 7.41 - 7.60 (m, 5H), 7.61 - 7.75 (m, 3H), 7.79 - 7.89 (m, 2H), 9.20 (d, J = 8.5 Hz, 1H), 11.00 (s , 1H). Example 14:
[0181] [0181] Example 14 was prepared using a procedure similar to that used to prepare Example 1 where 5-(4-fluoro-3-methoxyphenyl)-1,3,4-oxadiazol-2(3H)-one was used in place of 5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 444.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.94 (s, 3H), 5.18 (d, J = 8.4 Hz, 1H), 7.23 – 7.63 (m, 11H), 7 .69 (ddd, J = 8.4, 7.0, 1.7 Hz, 1H), 9.12 (d, J = 8.5 Hz, 1H), 11.01 (s, 1H). Example 15:
[0182] [0182] Example 15 was prepared using a procedure similar to that used to prepare Example 1 where 5-(3-isopropoxyphenyl)-1,3,4-oxadiazol-2(3H)-one was used in place of 5-(3 -(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 454.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.30 (d, J
[0183] [0183] Example 16 was prepared using a procedure similar to that used to prepare Example 1 where 5-(naphthalen-2-yl)-1,3,4-oxadiazol-2(3H)-one was used in place of 5- (3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 446.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.22 (d, J = 8.4 Hz, 1H), 7.24 - 7.42 (m, 3H), 7.44 - 7.60 (m, 5H), 7.60 - 7.76 (m, 3H), 7.92 - 8.07 (m, 2H), 8.11 (dd, J = 8.0, 4.9 Hz, 2H), 8 .34 - 8.45 (m, 1H), 9.21 (d, J = 8.5 Hz, 1H), 11.03 (s, 1H). Example 17:
[0184] [0184] Example 17 was prepared using a procedure similar to that used to prepare Example 1 where 5-(naphthalen-1-yl)-1,3,4-oxadiazol-2(3H)-one was used in place of 5- (3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 446.3[M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.25 (d, J = 8.4 Hz, 1H), 7.24 - 7.43 (m, 3H), 7.43 - 7.61 (m, 5H), 7.60 - 7.77 (m, 4H), 8.07 (td, J = 7.6, 1.7 Hz, 2H), 8.15 (d, J = 8.2 Hz, 1H ), 9.02 - 9.13 (m, 1H), 9.23 (d, J = 8.4 Hz, 1H), 11.03 (s, 1H). Example 18:
[0185] [0185] Example 18 was prepared using a procedure similar to that used to prepare Example 1 where 5-methyl-1,3,4-oxadiazol-2(3H)-one was used in place of 5-(3-(2- methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 334.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.32 (s, 3H), 5.03 (d, J = 8.7 Hz, 1H), 7.20 – 7.37 (m, 3H), 7 .38 - 7.60 (m, 5H), 7.65 (ddd, J = 8.6, 7.0, 1.8 Hz, 1H), 8.73 (d, J = 8.7 Hz, 1H ), 10.92 (s, 1H). Example 19:
[0186] [0186] Example 19 was prepared using a procedure similar to that used to prepare Example 1 where 5-(5-methylthiophen-2-yl)-1,3,4-oxadiazol-2(3H)-one was used in place of 5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z: 416.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.52(s, 3H), 5.14 (d, J = 8.5 Hz, 1H), 6.95 (dd, J = 3.6, 1, 3 Hz, 1H), 7.23 - 7.61 (m, 9H), 7.68 (m, 1H), 9.11 (d, J = 8.5 Hz, 1H), 10.99 (s, 1H). Example 20: Example 20 step a:
[0187] [0187] A solution of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (5.1 g, 20.3 mmol), 1 ,1'-Thiocarbonyldiimidazole (5.4 g, 30.3 mmol) in DMF (20 mL) was stirred for 20 minutes before hydrazine monohydrate (2 mL) was added. The mixture was stirred for 30 minutes, diluted with EtOAc, and washed with water (x2). The organic layer was dried (Na2SO4) and concentrated to yield the desired compound as a pale yellow solid (5 g, 76%) which was used without further purification. ESI-MS m/z: 326.1 [M+H]+. Example 20 step b:
[0188] [0188] A solution of the compound from step a (100mg, 0.3mmol), 5-chlorofuran-2-carboxylic acid (54mg, 0.4mmol), HOBt (61mg, 0.48mmol) and EDCI (86 mg, 0.45 mmol) in DMF (2 mL) was stirred for 2 hours. The mixture was purified by C18 reversed phase column chromatography (MeCN:H2O) to yield the desired compound as a white solid (110 mg, 80%). ESI-MS m/z: 454.2 [M+H]+. Example 20 step c:
[0189] [0189] A solution of the compound from step b (110 mg, 0.24 mmol) and EDCI (70 mg, 0.36 mmol) in DMF (5 mL) was stirred for 30 minutes at 60 °C. It was purified by preparative HPLC to yield the title compound as a yellow solid (27 mg, 27%). ESI-MS m/z: 420.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 5.15 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 3.6 Hz, 1H), 7.17 (d, J = 3.6 Hz, 1H), 7.23 - 7.39 (m, 3H), 7.50 (m, 5H), 7.62 - 7.72 (m, 1H), 9.28 (d, J = 8.4 Hz,
[0190] [0190] A solution of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (200 mg, 0.8 mmol), 1.1 '-Thiocarbonyldiimidazole (178 mg, 1.0 mmol) in DMF (3 mL) was stirred for 20 minutes before tetrahydro-2H-pyran-4-carbohydrazide (159 mg, 1.1 mmol) was added. The resulting mixture was stirred for 30 minutes and used directly in the next step. ESI-MS m/z: 438.2 [M+H]+. Example 21 step b:
[0191] [0191] A solution of the compound from step a (350 mg, 0.8 mmol) and EDCI (192 mg, 1.0 mmol) in DMF (3 mL) was stirred for 60 minutes at 60 °C. It was purified directly by preparative HPLC to yield the title compound as a white solid (54 mg, 17%). ESI-MS m/z: 404.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.69 (tdd, J = 13.2, 10.9, 5.5 Hz, 2H), 1.80 - 1.95 (m, 2H), 3, 09 (tt, J = 10.9, 4.0 Hz, 1H), 3.45 (td, J = 11.3, 2.3 Hz, 2H), 3.88 (dt, J = 11.6, 3.6 Hz, 2H), 5.07 (d, J = 8.2 Hz, 1H), 7.21 - 7.40 (m, 3H), 7.41 - 7.61 (m, 5H), 7.67 (ddd, J = 8.5, 7.0, 1.8 Hz, 1H), 8.81 (d, J = 8.7 Hz, 1H), 10.95 (s, 1H).
[0192] [0192] Example 22 was prepared using a procedure similar to that used to prepare Example 21 where 2-phenylacetohydrazide was used in place of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 410.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 4.11 (s, 2H), 5.05 (d, J = 8.6 Hz, 1H), 7.23 – 7.41 (m, 8H), 7 .43 - 7.57 (m, 5H), 7.67 (ddd, J = 8.5, 6.9, 1.9 Hz, 1H), 8.78 (d, J = 8.7 Hz, 1H ), 10.85 - 11.02 (m, 1H). Example 23:
[0193] [0193] Example 23 was prepared using a procedure similar to that used to prepare Example 20 where 5-fluoropicolinic acid was used in place of 5-chlorofuran-2-carboxylic acid ESI-MS m/z: 415.0 [M+H ]+. 1H NMR (300 MHz, DMSO-d6) δ 5.20 (d, J = 7.9 Hz, 1H), 7.24 - 7.61 (m, 8H), 7.69 (m, 1H), 7 .94 (m, 1H), 8.09 (dd, J = 8.8, 4.4 Hz, 1H), 8.74 (d, J = 2.8 Hz, 1H), 9.32 (d, J = 8.4 Hz, 1H), 10.96 (s, 1H). Example 24:
[0194] [0194] Example 24 was prepared using a procedure similar to that used to prepare Example 20 where 5-cyanopicolinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 422.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.23 (d, J = 7.5 Hz, 1H), 7.24 - 7.42 (m, 3H), 7.52 (dq, J = 12, 0, 6.8, 5.5 Hz, 5H), 7.70 (t, J = 7.3 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H), 8.48 ( dd, J = 8.3, 2.1 Hz, 1H), 9.13 - 9.22 (m, 1H), 9.58 (d, J = 8.3 Hz, 1H), 11.04 (s , 1H). Example 25:
[0195] [0195] Example 25 was prepared using a procedure similar to that used to prepare Example 20 where 5-(trifluoromethyl)picolinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 465.3 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 5.21 (d, J = 7.6 Hz, 1H), 7.22 - 7.41 (m, 3H), 7.39 - 7.60 (m , 5H), 7.68 (m, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.38 (m, 1H), 9.11 (m, 1H), 9.52 (d, J = 8.3 Hz, 1H), 11.01 (s, 1H). Example 26:
[0196] [0196] Example 26 was prepared using a procedure similar to that used to prepare Example 20 where 6-methylpicolinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 411.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.54 (s, 3H), 5.18 (d, J = 8.5 Hz, 1H), 7.21 – 7.75 (m, 10H), 7 .74 - 7.92 (m, 2H), 9.27 (d, J = 8.5 Hz, 1H), 10.99 (s, 1H). Example 27:
[0197] [0197] Example 27 was prepared using a procedure similar to that used to prepare Example 21 where 4-(methylsulfonyl)benzohydrazide was used in place of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 474.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.21 (s, 1H), 7.23 - 7.43 (m, 3H), 7.43 - 7.61 (m, 5H), 7.69 ( ddd, J = 8.4, 7.0, 1.7 Hz, 1H), 8.02 - 8.19 (m, 4H), 9.37 (s, 1H), 10.96 (s, 1H) . Example 28:
[0198] [0198] Example 28 was prepared using a procedure similar to that used to prepare Example 20 where 4-(trifluoromethyl)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 464.1 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 5.19 (d, J = 11.2 Hz, 1H), 7.20-7.60 (m, 8H), 7.65-7.75 (m , 1H), 7.90 - 8.00 (m, 2H), 8.00-8.10 (m, 2H), 9.34 (d, J = 11.2 Hz, 1H), 11.02 ( s, 1H). Example 29:
[0199] [0199] Example 29 was prepared using a procedure similar to that used to prepare Example 20 where 3-(trifluoromethyl)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 464.3 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 5.19 (d, J = 11.2 Hz, 1H), 7.20-7.40 (m, 3H), 7.40-7.60 (m , 5H), 7.65-7.75 (m, 1H), 7.90-8.00 (m, 2H), 8.00-8.10 (m, 2H), 9.30-9.40 (d, J = 11.6 Hz, 1H), 11.02 (s, 1H). Example 30:
[0200] [0200] Example 30 was prepared using a procedure similar to that used to prepare Example 20 where 4-(trifluoromethoxy)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 480.2 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 5.17 (d, J = 8.4 Hz, 1H), 7.22 - 7.61 (m, 11H), 7.67 (m, 1H), 7.88 - 8.00 (m, 2H), 9.23 (d, J = 8.5 Hz, 1H), 11.00 (s, 1H). Example 31:
[0201] [0201] Example 31 was prepared using a procedure similar to that used to prepare Example 20 where 4-sulfamoylbenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 475.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.19 (s, 1H), 7.20-7.80 (m, 12H), 7.90-8.10 (m, 4H), 9.20- 9.60 (m, 1H). Example 32:
[0202] [0202] Example 32 was prepared using a procedure similar to that used to prepare Example 20 where 3-cyano-4-fluorobenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 439.1 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 5.18 (d, J = 8.2 Hz, 1H), 7.26 – 7.60 (m, 8H), 7.71 (dt, J = 14 .3, 7.9 Hz, 2H), 8.17 (m, 1H), 8.30 (dd, J = 6.0, 2.3 Hz, 1H), 9.30 (d, J = 8, 4 Hz, 1H), 11.02 (s, 1H).
[0203] [0203] Example 33 was prepared using a procedure similar to that used to prepare Example 20 where 4-cyano-3-fluorobenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 439.1 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 5.19 (s, 1H), 7.22 - 7.59 (m, 9H), 7.67 (m, 1H), 7.82 (m, 2H ), 8.12 (dd, J = 8.1, 6.7 Hz, 1H), 9.49 (s, 1H), 11.01 (s, 1H). Example 34:
[0204] [0204] Example 34 was prepared using a procedure similar to that used to prepare Example 20 where 4-cyano-3-methylbenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 435.2 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 2.57 (s, 3H), 5.19 (d, J = 8.3 Hz, 1H), 7.23 – 7.60 (m, 8H) , 7.62 - 7.81 (m, 2H), 7.87 - 8.00 (m, 2H), 9.36 (d, J = 8.4 Hz, 1H), 11.03 (s, 1H ). Example 35:
[0205] [0205] Example 35 was prepared using a procedure similar to that used to prepare Example 20 where 3-cyanobenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 421.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.20 (s, 1H), 7.25 - 7.33 (m, 1H), 7.37 (dd, J = 8.1, 2.2 Hz,
[0206] [0206] Example 36 was prepared using a procedure similar to that used to prepare Example 20 where 4-(1H-pyrazol-1-yl)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 462.3 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 5.19 (d, J = 8.4 Hz, 1H), 6.62 (t, J = 2.2 Hz, 1H), 7.24 - 7, 42 (m, 3H), 7.43 - 7.62 (m, 5H), 7.70 (ddd, J = 8.4, 7.1, 1.7 Hz, 1H), 7.83 (d, J = 1.7 Hz, 1H), 7.89 - 8.01 (m, 2H), 8.02 - 8.12 (m, 2H), 8.63 (d, J = 2.6 Hz, 1H ), 9.18 (d, J = 8.6 Hz, 1H), 11.01 (s, 1H). Example 37:
[0207] [0207] Example 37 was prepared using a procedure similar to that used to prepare Example 20 where nicotinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 397.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.19 (d, J = 8.4 Hz, 1H), 7.23 - 7.74 (m, 10H), 8.14 - 8.23 (m, 1H), 8.72 (d, J = 4.7 Hz, 1H), 9.01 (s, 1H), 9.26 (d, J = 8.4 Hz, 1H), 11.01 (s, 1H). Example 38:
[0208] [0208] Example 38 was prepared using a procedure similar to that used to prepare Example 20 where 2-cyanoisonicotinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 422.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.24 (s, 1H), 7.16 - 7.43 (m, 3H), 7.52 (hept, J = 7.6, 7.0 Hz, 5H), 7.70 (t, J = 7.3 Hz, 1H), 8.03 (dd, J = 5.1, 1.8 Hz, 1H), 8.33 (s, 1H), 8, 50 (s, 0H), 8.93 (d, J = 5.2 Hz, 1H), 9.61 (s, 1H), 11.09 (s, 1H). Example 39:
[0209] [0209] Example 39 was prepared using a procedure similar to that used to prepare Example 20 where 6-oxo-1,6-dihydropyridine-3-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 413.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 5.13 (d, J = 8.6 Hz, 1H), 6.45 - 6.53 (m, 1H), 7.24 - 7.39 (m, 3H), 7.42 - 7.59 (m, 5H), 7.68 (m, 1H), 7.76 - 7.84 (m, 2H), 9.00 (d, J = 8.7 Hz , 1H), 11.01 (s, 1H), 12.05 (s, 1H). Example 40:
[0210] [0210] Example 40 was prepared using a procedure similar to that used to prepare Example 20 where 2-oxo-1,2-dihydropyridine-4-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 413.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 5.18 (s, 1H), 6.53 – 6.63 (m, 2H), 7.24 – 7.40 (m, 3H), 7.42 – 7.59 (m, 6H), 7.68 (m, 1H), 9.41 (s, 1H), 11.39 (s, 2H). Example 41:
[0211] [0211] Example 41 was prepared using a procedure similar to that used to prepare Example 20 where 1H-benzo[d]imidazole-6-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 436.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.17 (d, J = 11.6 Hz, 1H), 7.20-7.40 (m, 3H), 7.40-7.60 (m, 5H), 7.60-7.85 (m, 3H), 8.01 (s, 1H), 8.37 (s, 1H), 9.06 (d, J=11.6Hz, 1H), 11.02 (s, 1H). Example 42:
[0212] [0212] Example 42 was prepared using a procedure similar to that used to prepare Example 20 where benzo[d]thiazole-6-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 453.2 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 5.21 (d, J = 8.4 Hz, 1H), 7.24 – 7.62 (m, 9H), 7.70 (ddd, J = 8 .5, 7.2, 1.8 Hz, 1H), 8.00 (dd, J = 8.6, 1.8 Hz, 1H), 8.25 (d, J = 8.6 Hz, 1H) , 8.69 (d, J = 1.7 Hz, 1H), 9.26 (d, J = 8.5 Hz, 1H), 9.54 (s, 1H), 11.02 (s, 1H) . Example 43:
[0213] [0213] Example 43 was prepared using a procedure similar to that used to prepare Example 20 where thieno[2,3-b]pyridine-2-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 453.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.53 (s, 2H), 5.19 (d, J = 6.3 Hz, 1H),
[0214] [0214] Example 44 was prepared using a procedure similar to that used to prepare Example 20 where 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 472.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.40 (s, 3H), 2.81 (dt, J = 28.9, 5.9 Hz, 4H), 3.68 (s, 2H), 5 .17 (d, J = 8.3 Hz, 1H), 7.22 - 7.60 (m, 8H), 7.65-7.70 (m, 1H), 9.44 (d, J = 8 .3 Hz, 1H), 11.00 (s, 1H). Example 45:
[0215] [0215] Example 45 was prepared using a procedure similar to that used to prepare Example 21 where piperidine-4-carbohydrazide was used in place of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 403.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.75 - 1.93 (m, 2H), 2.04 - 2.18 (m, 2H), 3.04 (q, J = 11.2 Hz, 2H), 3.20 (tt, J = 10.9, 4.0 Hz, 1H), 3.33 (d, J = 13.2 Hz, 2H), 5.07 (d, J = 8.4 Hz, 1H), 7.23 - 7.41 (m, 3H), 7.41 - 7.60 (m, 5H), 7.67 (ddd, J = 8.4, 7.0, 1.8 Hz, 1H), 8.55 (d, J = 10.8 Hz, 1H), 8.87 (d, J = 8.7 Hz, 2H), 10.97 (s, 1H). Example 46:
[0216] [0216] Example 46 was prepared using a procedure similar to that used to prepare Example 20 where 1-methylpiperidine-4-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 417.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.58 – 1.76 (m, 2H), 1.85 – 1.97 (m, 2H), 1.97 – 2.11 (m, 2H), 2.20 (s, 3H), 2.77 (td, J = 10.9, 5.3 Hz, 3H), 5.06 (d, J = 8.7 Hz, 1H), 7.18 - 7 .40 (m, 3H), 7.41 - 7.60 (m, 5H), 7.67 (ddd, J = 8.5, 7.0, 1.8 Hz, 1H), 8.75 (d , J = 8.7 Hz, 1H), 10.94 (s, 1H). Example 47:
[0217] [0217] Example 47 was prepared using a procedure similar to that used to prepare Example 21 where 1-acetylpiperidine-4-carbohydrazide was used in place of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 445.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.26-1.26 (m, 2H), 1.92-2.09 (m, 4H), 2.72 - 2.88 (m, 1H), 3.03 - 3.28 (m, 2H), 4.25 (d, J = 13.3 Hz, 1H), 5.07 (d, J = 7.8 Hz, 1H), 7.31 (dtd , J = 15.2, 7.9, 5.4 Hz, 2H), 7.40 - 7.61 (m, 4H), 7.67 (ddd, J = 8.4, 7.0, 1, 8 Hz, 1H), 8.83 (d, J = 8.7 Hz, 1H), 10.95 (s, 1H). Example 48:
[0218] [0218] Example 48 was prepared using a procedure similar to that used to prepare Example 20 where (S)-4-(tert-
[0219] [0219] Example 49 was prepared using a procedure similar to that used to prepare Example 20 where (R)-4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. The Boc-protected intermediate was deprotected using a procedure similar to that described in Example 48. ESI-MS m/z: 405.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.66 – 2.81 (m, 1H), 2.86 (d, J = 13.1 Hz, 1H), 3.41 – 3.71 (m, 3H), 3.79 - 3.90 (m, 1H), 3.96 (m, 1H), 5.06 (m, 1H), 7.20 - 7.38 (m, 3H), 7.38 – 7.58 (m, 5H), 7.65 (m, 1H), 8.45 (S, 0.23H), 8.79 – 8.89 (m, 1H), 10.94 (d, J = 6.0 Hz, 1H). Example 50:
[0220] [0220] Example 50 was prepared using a procedure similar to that used to prepare Example 20 where 2,4-difluorobenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 432.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.18 (d, J = 8.4 Hz, 1H), 7.20 - 7.61 (m, 10H), 7.61 - 7.77 (m, 1H), 7.92 (td, J = 8.6, 6.3 Hz, 1H), 9.22 (d, J = 8.5 Hz, 1H), 11.01 (s, 1H). Example 51:
[0221] [0221] Example 51 was prepared using a procedure similar to that used to prepare Example 20 where 5-methoxypicolinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 427.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.91 (s, 3H), 5.17 (d, J = 8.5 Hz, 1H), 7.22 – 7.61 (m, 9H), 7 .68 (m, 1H), 7.95 (d, J = 8.8 Hz, 1H), 8.41 (d, J = 2.9 Hz, 1H), 9.18 (d, J = 8, 6 Hz, 1H), 11.00 (s, 1H). Example 52:
[0222] [0222] Example 52 was prepared using a procedure similar to that used to prepare Example 20 where 6-methoxypicolinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 427.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.91 (s, 3H), 5.18 (d, J = 8.4 Hz, 1H), 6.97 (dd, J = 8.4, 0, 8 Hz, 1H), 7.21 - 7.73 (m, 10H), 7.87 (dd, J = 8.4, 7.4 Hz, 1H), 9.28 (d, J = 8.5 Hz,
[0223] [0223] Example 53 was prepared using a procedure similar to that used to prepare Example 20 where 6-fluoronicotinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 415.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.17 (d, J = 8.4 Hz, 1H), 7.22 - 7.59 (m, 9H), 7.67 (m, 1H), 8 .21(s, 0.518H), 8.37 (m, 1H), 8.66 (d, J = 2.4 Hz, 1H), 9.28 (d, J = 8.4 Hz, 1H), 11.01 (s, 1H). Example 54:
[0224] [0224] Example 54 was prepared using a procedure similar to that used to prepare Example 20 where 6-methoxynicotinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 427.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.93 (s, 3H), 5.16 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H ), 7.22 - 7.59 (m, 8H), 7.65-7.70 (m, 1H), 8.10 (dd, J = 8.7, 2.5 Hz, 1H), 8, 61 (d, J = 2.4 Hz, 1H), 9.14 (d, J = 8.5 Hz, 1H), 10.97 (s, 1H). Example 55:
[0225] [0225] Example 55 was prepared using a procedure similar to that used to prepare Example 20 where 2-fluoroisonicotinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 415.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.20 (s, 1H), 7.22 - 7.76 (m, 11H), 8.44 (d, J = 5.2 Hz, 1H). 9.48 (s, 1H), 11.00 (s, 1H). Example 56:
[0226] [0226] Example 56 was prepared using a procedure similar to that used to prepare Example 20 where 2-methoxyisonicotinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 427.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.91 (s, 3H), 5.18 (d, J = 8.2 Hz, 1H), 7.07 (t, J = 1.0 Hz, 1H ), 7.22 - 7.59 (m, 9H), 7.67 (ddd, J = 8.4, 7.0, 1.8 Hz, 1H), 8.34 (d, J = 5.3 Hz, 1H), 9.38 (d, J = 8.4 Hz, 1H), 11.02 (s, 1H). Example 57:
[0227] [0227] Example 57 was prepared using a procedure similar to that used to prepare Example 20 where 4-methoxypicolinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 427.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.91 (s, 3H), 5.19 (d, J = 8.4 Hz, 1H), 7.12 (dd, J = 5.8, 2, 5 Hz, 1H), 7.22 - 7.59 (m, 9H), 7.68 (m, 1H), 8.51 (d, J = 5.7 Hz, 1H), 9.27 (d, J = 8.5 Hz, 1H), 10.97 - 11.04 (m, 1H). Example 58:
[0228] [0228] Example 58 was prepared using a procedure similar to that used to prepare Example 20 where pyrazine-2-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 398.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.20 (d, J = 8.1 Hz, 1H), 7.22 - 7.59 (m, 8H), 7.67 (m, 1H), 8 .72 - 8.82 (m, 2H), 9.19 (d, J = 1.3 Hz, 1H), 9.46 (d, J = 8.3 Hz, 1H), 11.01 (s, 1H). Example 59:
[0229] [0229] Example 59 was prepared using a procedure similar to that used to prepare Example 20 where pyrimidine-2-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 398.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.23 (d, J = 8.4 Hz, 1H), 7.23 - 7.43 (m, 3H), 7.43 - 7.62 (m, 5H), 7.60 - 7.77 (m, 2H), 8.98 (d, J = 4.9 Hz, 2H), 9.47 (d, J = 8.4 Hz, 1H), 11, 01 (s, 1H). Example 60:
[0230] [0230] Example 60 was prepared using a procedure similar to that used to prepare Example 20 where pyrimidine-5-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 398.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.20 (d, J = 7.7 Hz, 1H), 7.21 - 7.59 (m, 8H), 7.67 (m, 1H),
[0231] [0231] Example 61 was prepared using a procedure similar to that used to prepare Example 20 where isonicotinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 397.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.21 (d, J = 8.3 Hz, 1H), 7.24 - 7.61 (m, 8H), 7.63 - 7.80 (m, 3H), 8.73 - 8.88 (m, 2H), 9.41 (d, J = 8.4 Hz, 1H), 11.02 (s, 1H). Example 62:
[0232] [0232] Example 62 was prepared using a procedure similar to that used to prepare Example 20 where pyridazine-3-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 398.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.24 (d, J = 8.2 Hz, 1H), 7.24 - 7.43 (m, 3H), 7.43 - 7.62 (m, 5H), 7.70 (ddd, J=8.4, 7.0, 1.7Hz, 1H), 7.89 (dd, J=8.6, 5.0Hz, 1H), 8.25 (dd, J = 8.6, 1.6 Hz, 1H), 9.36 (dd, J = 5.0, 1.6 Hz, 1H), 9.55 (d, J = 8.4 Hz, 1H), 11.04 (s, 1H). Example 63:
[0233] [0233] Example 63 was prepared using a procedure similar to that used to prepare Example 20 where pyrimidine-4-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 398.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.23 (s, 1H), 7.24 - 7.62 (m, 8H), 7.69 (m, 1H), 8.02 (dd, J = 5.3, 1.5 Hz, 1H), 8.99 (d, J = 5.3 Hz, 1H), 9.34 (d, J = 1.4 Hz, 1H), 9.60 (s, 1H), 11.03 (s, 1H). Example 64:
[0234] [0234] Example 64 was prepared using a procedure similar to that used to prepare Example 20 where 6-(methoxymethyl)picolinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 441.1 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 3.40 (s, 3H), 4.57 (s, 2H), 5.19 (d, J = 8.4 Hz, 1H), 7.22 - 7.59 (m, 10H), 7.68 (m, 1H), 7.86 - 8.05 (m, 2H), 9.29 (d, J = 8.5 Hz, 1H), 10.98 (s, 1H). Example 65:
[0235] [0235] Example 65 was prepared using a procedure similar to that used to prepare Example 20 where 1-methyl-1H-pyrazole-5-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 400.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 4.11 (s, 3H), 5.17 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H ), 7.22 - 7.74 (m, 10H), 9.24 (d, J = 8.4 Hz, 1H), 11.00 (s, 1H). Example 66:
[0236] [0236] Example 66 was prepared using a procedure similar to that used to prepare Example 20 where 1-methyl-1H-pyrazole-4-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 400.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.92 (s, 3H), 5.12 (d, J = 8.6 Hz, 1H), 7.21 – 7.60 (m, 8H), 7 .67 (m, 1H), 7.84 (d, J = 0.8 Hz, 1H), 8.28 (s, 1H), 8.92 (d, J = 8.6 Hz, 1H), 10 .96 (s, 1H). Example 67:
[0237] [0237] Example 67 was prepared using a procedure similar to that used to prepare Example 20 where 1-methyl-1H-imidazole-2-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 400.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.92 (s, 3H), 5.15 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 1.1 Hz, 1H ), 7.21 - 7.59 (m, 9H), 7.67 (m, 1H), 9.24 (d, J = 8.5 Hz, 1H), 10.96 (s, 1H). Example 68:
[0238] [0238] Example 68 was prepared using a procedure similar to that used to prepare Example 20 where 1-methyl-1H-imidazole-4-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 400.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.72 (s, 3H), 5.12 (d, J = 8.6 Hz, 1H),
[0239] [0239] Example 69 was prepared using a procedure similar to that used to prepare Example 20 where thiazole-2-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 403.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.20 (s, 1H), 7.23 - 7.61 (m, 8H), 7.69 (m, 1H), 7.99 - 8.15 ( m, 2H), 9.50 (s, 1H), 11.02 (s, 1H). Example 70:
[0240] [0240] Example 70 was prepared using a procedure similar to that used to prepare Example 20 where oxazole-2-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 387.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.34 (d, J = 14.0 Hz, 1H), 5.20 (d, J = 8.3 Hz, 1H), 7.22 - 7.62 (m, 10H), 7.69 (ddd, J = 8.4, 7.1, 1.8 Hz, 1H), 8.41 (d, J = 0.8 Hz, 1H), 9.61 ( d, J = 8.3 Hz, 1H), 11.03 (s, 1H). Example 71:
[0241] [0241] Example 71 was prepared using a procedure similar to that used to prepare Example 20 where 5-methylfuran-2-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 400.0 [M+H]+.
[0242] [0242] Example 72 was prepared using a procedure similar to that used to prepare Example 20 where 5-(methoxymethyl)furan-2-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 430.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.28 (s, 3H), 4.44 (s, 2H), 5.14 (s, 1H), 6.68 (d, J = 3.5 Hz , 1H), 7.02 (d, J = 3.4 Hz, 1H), 7.21 - 7.59 (m, 8H), 7.67 (m, 1H), 9.26 (s, 2H) . Example 73:
[0243] [0243] Example 73 was prepared using a procedure similar to that used to prepare Example 20 where 5-((dimethylamino)methyl)furan-2-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 443.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.79 (s, 6H), 4.50 (s, 2H), 5.15 (d, J = 8.4 Hz, 1H), 6.94 (d , J = 3.5 Hz, 1H), 7.13 (d, J = 3.5 Hz, 1H), 7.22 - 7.60 (m, 8H), 7.61 - 7.74 (m, 1H), 9.30 (d, J = 8.5 Hz, 1H), 10.33 (s, 1H), 10.99 (s, 1H). Example 74:
[0244] [0244] Example 74 was prepared using a procedure similar to that used to prepare Example 20 where 3-methylisoxazole-5-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 401.2 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 2.34 (s, 3H), 5.16 (s, 1H), 7.02 (s, 1H), 7.23-7.36 (m, 3H ), 7.43-7.56 (m, 5H), 7.66 (t, J = 7.4 Hz, 1H), 9.76 (s, 1H), 10.89 (s, 1H). Example 75:
[0245] [0245] Example 75 was prepared using a procedure similar to that used to prepare Example 20 where oxazole-5-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 387.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.17 (d, J = 8.3 Hz, 1H), 7.23 - 7.43 (m, 3H), 7.43 - 7.63 (m, 5H), 7.69 (td, J = 7.7, 7.0, 1.8 Hz, 1H), 7.85 (s, 1H), 8.69 (s, 1H), 9.41 (d , J = 8.4 Hz, 1H), 11.01 (s, 1H). Example 76:
[0246] [0246] Example 76 was prepared using a procedure similar to that used to prepare Example 20 where thiazole-5-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 403.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.15 (d, J = 8.2 Hz, 1H), 7.21 – 7.59 (m, 8H), 7.66 (m, 1H), 8 .35 (s, 1H), 9.27 (d, J = 7.9 Hz, 2H), 10.99 (s, 1H). Example 77:
[0247] [0247] Example 77 was prepared using a procedure similar to that used to prepare Example 20 where thiazole-4-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 403.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.18 (d, J = 8.5 Hz, 1H), 7.20 - 7.43 (m, 3H), 7.42 - 7.61 (m, 5H), 7.69 (ddd, J = 8.5, 7.0, 1.7 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 9.20 (d, J = 8.5 Hz, 1H), 9.30 (d, J = 1.9 Hz, 1H), 10.99 (s, 1H). Example 78:
[0248] [0248] Example 78 was prepared using a procedure similar to that used to prepare Example 20 where 2-ethoxy-2-oxoacetic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 392.21 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.31 (t, J = 7.1 Hz, 3H), 4.36 (q, J = 7.1 Hz, 2H), 5.18 (s, 1H ), 7.22 - 7.40 (m, 3H), 7.40 - 7.60 (m, 5H), 7.64-7.70 (m, 1H), 9.70 (s, 1H), 11.04 (s, 1H). Example 79: Example 79 step a:
[0249] [0249] A solution of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (300mg, 1.195mmol), BTC (116.7mg, 0.394mmol) and saturated NaHCO3 (3mL) in DCM (10mL) was stirred for 30 minutes at 0°C. It was diluted with water, extracted with DCM (x2). The organic layer was dried, concentrated to yield the desired compound as an orange solid (331mg, 100%) which was used without further purification. ESI-MS m/z: 278.1 [M+H]+. Example 79 step b:
[0250] [0250] A solution of the isocyanate from step a (331 mg, 1.20 mmol), formylhydrazine (108 mg, 1.79 mmol) and DIPEA (1 mL) in DMF (5 mL) was stirred for 2 hours. The reaction mixture was purified by C18 reversed phase column chromatography (MeCN:H2O) to yield the desired compound as a white solid (220 mg, 55%). ESI-MS m/z: 338.1 [M+H]+. Example 79 step c:
[0251] [0251] A solution of the compound from step b (190 mg, 0.56 mmol), PPh3 (443 mg, 1.69 mmol), CCl4 (0.4 mL), and TEA (0.5 mL) in MeCN ( 5 ml) was stirred for 30 minutes. Water was added and the aqueous phase was extracted with EtOAc (x2) and the organics were dried (Na2SO4), concentrated, and purified by preparative HPLC to yield the title compound as a yellow solid (12mg, 7%). ESI-MS m/z: 320.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.08 (d, J = 8.6 Hz, 1H), 7.18 – 7.78 (m, 9H), 8.57 (s, 1H), 8 .94 (d, J = 8.6 Hz, 1H), 10.96 (s, 1H). Example 80:
[0252] [0252] Example 80 was prepared using a procedure similar to that used to prepare Example 20 where 4-fluorobenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. The title compound was also used to prepare Example 7. Example 80 step b:
[0253] [0253] To an NMP solution (3 mL) of 2-(4-fluorobenzoyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin- 3-yl)hydrazine-1-carbothioamide (447 mg, 1.0 mmol), prepared in step a, was added TEA (0.28 mL, 2.0 mmol) followed by TsCl (229 mg, 1.2 mmol ). The mixture was stirred for 2 h at room temperature. DCM was added and the mixture was washed with water and brine. The organic phase was dried (Na2SO4), concentrated and purified by preparative HPLC yielding the desired compound as a pale yellow solid (142 mg, 33%). ESI-MS m/z: 430.1 [M+H]+. 1H-NMR (300 MHz, DMSO-d6) δ 5.37 (d, J = 7.6 Hz, 1H), 7.23 - 7.39 (m, 5H), 7.44 - 7.55 (m , 5H), 7.68 (m, 1H), 7.82 (dd, J = 8.7, 5.5 Hz, 2H), 9.16 (d, J = 7.7 Hz, 1H), 10 .98 (s, 1H). Example 81:
[0254] [0254] Example 81 was prepared using a procedure similar to that used to prepare Example 80 where benzoic acid was used in place of 4-fluorobenzoic acid. ESI-MS m/z: 412.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.40 (d, J = 7.6 Hz, 1H), 7.34 (dd, J = 19.8, 7.9 Hz, 3H), 7.42 – 7.64 (m, 8H), 7.63 – 7.74 (m, 1H), 7.73 – 7.94 (m, 2H), 9.16 (d, J = 7.7 Hz, 1H ), 10.98 (s, 1H). Example 82:
[0255] [0255] Example 82 was prepared using a procedure similar to that used to prepare Example 80 where 4-cyanobenzoic acid was used in place of 4-fluorobenzoic acid. ESI-MS m/z: 437.2 [M+H]+. 1H NMR (300 MHz, CD3OD: CDCl3= 2:1) δ 5.46 (s, 1H), 7.20-7.35 (m, 2H), 7.35-7.50 (m, 3H), 7.50-7.60 (m, 3H), 7.60-7.70 (m, 1H), 7.75-7.95 (m, 2H), 7.95-8.10 (m, 2H ). Example 83:
[0256] [0256] Example 83 was prepared using a procedure similar to that used to prepare Example 80 where isonicotinic acid was used in place of 4-fluorobenzoic acid. ESI-MS m/z: 413.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.41 (d, J = 7.4 Hz, 1H), 7.24 - 7.46 (m, 5H), 7.47 - 7.62 (m, 5H), 7.63 - 7.79 (m, 3H), 8.63 - 8.72 (m, 2H), 9.42 (d, J = 7.5 Hz, 1H), 11.03 (s , 1H). Example 84:
[0257] [0257] A solution of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (251 mg, 1.0 mmol) in DCM (20 mL) was added di(1H-imidazol-1-yl)methanethione (178 mg, 1.0 mmol) at 0 ℃. The ice bath was removed and the reaction stirred at room temperature for 30 minutes. Water was added to the mixture and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated to provide the desired product as a yellow foam (320 mg), which is used directly without further purification. ESI-MS m/z: 294.2 [M+H]+. Example 84 step b:
[0258] [0258] 2-azido-1-phenylethanone (161 mg, 1.0 mmol) and PPh3 (262 mg, 1.0 mmol) were added to the solution of the compound from step a (293 mg, 1.0 mmol) in dioxane (10 ml). The mixture was heated at 90 °C for 30 minutes under N2. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give the title product as a white solid (20 mg, 5%). ESI-MS m/z: 395.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.19 (d, J = 8.7 Hz, 1H), 7.12 - 7.31 (m, 3H), 7.31 - 7.58 (m, 11H), 7.66 (m, 1H), 8.65 (d, J = 8.7 Hz, 1H), 10.83 - 11.08 (m, 1H).
[0259] [0259] To a solution of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (251 mg, 1.0 mmol) in DMF ( 5 mL) was added di(1H-imidazol-1-yl)methanethione (214 mg, 1.2 mmol) at 0 °C. After stirring for 30 minutes, 2-amino-1-phenylethanone as the HCl salt (342 mg, 2.0 mmol) and TEA (303 mg, 3.0 mmol) were added. The mixture was stirred at room temperature for 30 minutes, then it was purified by C18 reversed phase column chromatography (MeCN:H2O) to give product as a yellow solid (180 mg, 42%). ESI-MS m/z: 429.3 [M+H]+. Example 85 step b:
[0260] [0260] A solution of the compound from step a (80 mg, 0.18 mmol) in 5 mL DCM was added to 50 mg H2SO4 (98%) at 0 °C. After stirring for 30 minutes, it was diluted with DCM and washed with water, dried (Na2SO4), concentrated, and purified by preparative HPLC to give the title product as a white solid (35 mg, 46%). ESI-MS m/z: 411.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.37 (d, J = 8.0 Hz, 1H), 7.10 – 7.59 (m, 14H), 7.66 (m, 1H), 8 .94 (d, J = 8.0 Hz, 1H), 10.90 (s, 1H).
[0261] [0261] A solution of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (200 mg, 0.80 mmol), benzoyl isothiocyanate (0.11 mL, 0.80 mmol) in DCM (10 mL) was stirred for 2 hours at room temperature. The reaction mixture was concentrated and the resulting residue was purified by column chromatography (silica, petroleum ether:EtOAc) to yield the desired compound as a yellow solid (390 mg, 100%). ESI-MS m/z: 415.2 [M+H]+. Example 86 step b:
[0262] [0262] A solution of the compound from step a (300mg, 0.73mmol) and NH2NH2.H2O (0.1mL) in EtOH (5mL) was stirred for 3 hours at 60°C. The reaction mixture was concentrated, diluted with water, extracted with EtOAc (x4), dried (Na2SO4), and concentrated. The crude product was purified by preparative HPLC to yield the title compound as a pink solid (30mg, 10%). ESI-MS m/z: 395.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.20 (d, J = 8.8 Hz, 1H), 7.21 - 7.72 (m, 13H), 7.78 - 7.88 (m, 2H), 8.37(s, 0.185H), 10.94 (s, 1H). Example 87:
[0263] [0263] To a 20 mL flask was placed (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (141 mg, 0.56 mmol ), 5-chloro-3-phenyl-1,2,4-thiadiazole (100 mg, 0.51 mmol), and TEA (0.14 mL, 1.02 mmol) in DMF (2.5 mL) and the resulting mixture was heated at 70°C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), concentrated, and purified via column chromatography (silica, hexanes:EtOAc) to yield the title compound (35 mg, 15%) as an off-white solid. . ESI-MS m/z: 412.1 [M+H]+. Example 88: Example 88 step a:
[0264] [0264] To a 20 mL flask was placed (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (324 mg, 1.29 mmol ), 3,5-dichloro-1,2,4-thiadiazole (200 mg, 1.29 mmol), and Et 3 N (0.36 mL, 2.58 mmol) in DMF (5 mL) and the resulting mixture was heated at 40 °C for 5 ha. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), concentrated, and purified via column chromatography (silica, hexanes: EtOAc) to yield the title compound (190 mg, 40%) as a yellow solid. . ESI-MS m/z: 370.0 [M+H]+. Example 88 step b:
[0265] [0265] To a 20 mL flask was placed the compound from step a (35 mg, 0.10 mmol) and morpholine (0.16 mL, 1.9 mmol) in dioxane (0.75 mL) and the resulting mixture was heated at 80 °C for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), concentrated, and purified via column chromatography (silica, hexanes: EtOAc) to yield the title compound (17 mg, 43%) as a yellow solid. ESI-MS m/z: 421.1 [M+H]+. Example 89:
[0266] [0266] Example 89 was prepared using a procedure similar to that used to prepare Example 87 where 5-chloro-3-phenyl-1,2,4-oxadiazole was used in place of 5-chloro-3-phenyl-1,2 ,4-thiadiazole. ESI-MS m/z: 396.1 [M+H]+. Example 90: Example 90 step a:
[0267] [0267] Solid di(1H-imidazol-1-yl)methanethione (196 mg, 1.1 mmol) was added to (Z)-3-amino-5-phenyl-1H-benzo[e][1,4] diazepin-2(3H)-one (251 mg,
[0268] [0268] To a solution of the compound from step a (248 mg, 0.8 mmol) was added 2-bromo-1-phenylethanone (158 mg, 0.8 mmol) and AcOK (94 mg, 0.96 mmol) in EtOH (20 mL). The mixture was stirred for 1 h at 80 °C, then poured into water. The mixture was extracted with EtOAc(x3), and the organic layer was dried (Na2SO4), concentrated, and the resulting residue was purified by C18 reverse phase column chromatography (MeCN:H2O) to yield the title compound as a yellow solid. clear (142 mg, 43%). ESI-MS m/z: 411.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.40 (d, J = 7.7 Hz, 1H), 7.10 - 7.60 (m, 12H), 7.63 - 7.75 (m, 3H), 8.74 (d, J = 7.8 Hz, 1H), 10.95 (s, 1H). Example 91: Example 91 step a:
[0269] [0269] A solution of (Z)-benzyl 2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl-carbamate (6.0 g, 7.8 mmol; from Example 1 step c), PMBCl (3.7 g, 23.4 mmol) and K2CO3 (4.3 g, 31.2 mmol) in DMF (100 mL) was heated to 50 °C for at night. The solution was poured into water and extracted with EtOAc. The organic layer was dried (Na2SO4), concentrated, and purified by column chromatography (silica, petroleum ether:EtOAc) to yield the desired product (5.0 g, 64%) as a yellow solid. ESI-MS m/z: 506.4 [M+H]+. Example 91 step b:
[0270] [0270] A solution of the compound from step a (5.8 g, 11.5 mmol) in 48% HBr/AcOH (50 mL) was heated at 70 °C for 30 minutes. Ether was added to the solution and the resulting solid was collected by filtration. The collected solid was added to saturated NaHCO3, and extracted with EtOAc. The organic layer was dried (Na2SO4), concentrated and the residue was purified by column chromatography (silica, DCM:MeOH) to give 3-amino-1-(4-methoxybenzyl)-5-phenyl-1,3-dihydro- 2H-benzo[e][1,4]diazepin-2-one (2.4 g, 56%) as yellow foam. ESI-MS m/z: 372.2 [M+H]+. Example 91 step c:
[0271] [0271] A solution of (Z)-3-amino-1-(4-methoxybenzyl)-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one, from step b, (185 mg, 0.5 mmol) and benzoyl isothiocyanate (82 mg, 0.5 mmol) in DCM (20 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by C18 reversed phase column chromatography (MeCN:H2O) to obtain the desired product as a yellow solid (155 mg, 58%). ESI-MS m/z: 535.3 [M+H]+. Example 91 step d:
[0272] [0272] Solid NaH (15mg, 0.58mmol) was added to the compound from step c (155mg, 0.29mmol) in THF (20ml) at 0°C. After stirring for 30 minutes, pure MeI (82 mg, 0.58 mmol) was added. The mixture was stirred at room temperature for 3 h. The solvent was removed and the residue was used directly in the next step. ESI-MS m/z: 549.3 [M+H]+. Example 91 step e:
[0273] [0273] The crude compound from step d was dissolved in ethanol (5 mL). Hydroxylamine hydrochloride (40 mg, 0.58 mmol) was added and the mixture was heated at 75 °C for 3 h. The resulting mixture was concentrated in vacuo and water was added. The resulting precipitate was filtered off to yield the desired compound (100 mg, 67%) as a pale yellow solid. ESI-MS m/z: 516.4 [M+H]+.
[0274] [0274] To compound from step e (100 mg, 0.19 mmol) in MeCN (10 mL) and water (10 mL) was added CAN (153 mg, 0.28 mmol). The resulting solution was stirred at room temperature for 4 h. The solution was diluted with 20 mL of EtOAc, washed with water, dried (Na2SO4), concentrated and purified by preparative HPLC to obtain the title product as a white solid (27 mg, 19%). ESI-MS m/z: 396.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6): δ 5.06 (d, J = 8.7 Hz, 1H), 7.20 – 7.80 (m, 12H), 7.93 – 8.14 (m , 3H), 10.96 (s, 1H). Example 92: Example 92 step a:
[0275] [0275] To a solution of Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (1.0 g, 4.0 mmol) in iPrOH (60 mL) was added 4,6-dichloropyrimidine (1.2 g, 2.0 mmol) and DIPEA (1.3 g, 2.5 mmol). The mixture was stirred for 18 h at 90 °C. The reaction was concentrated and the residue was triturated with Et2O (20 mL) and H2O (3 mL), and dried under vacuum to yield the desired compound as a white solid (800 mg, 55%). ESI-MS m/z: 364.2 [M+H]+. Example 92 step b:
[0276] [0276] To a solution of the compound from step a (109 mg, 0.30 mmol) in dioxane (4 mL) and H2O (1 mL) was added phenylboronic acid (73.2 mg, 0.60 mmol), Pd( dtbpf)Cl 2 (20 mg, 0.03 mmol) and KF (174 mg, 3.0 mmol). The mixture was heated at 100°C in the microwave for 1 h. The reaction mixture was purified directly by C18 reversed phase column chromatography (MeCN:H2O) to yield the desired compound as a white solid (22 mg, 18%). ESI-MS m/z: 406.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.65 (d, J = 7.6 Hz, 1H), 7.23 – 7.61 (m, 12H), 7.68 (m, 1H), 7 .96 - 8.11 (m, 2H), 8.47 (d, J = 1.1 Hz, 1H), 8.57 (s, 1H), 10.90 - 10.97 (m, 1H). Example 93:
[0277] [0277] To a solution of the compound from Example 92 step a (182 mg, 0.5 mmol) in DMF (5 mL) was added K2CO3 (138 mg, 1.0 mmol) and morpholine (2 mL). The mixture was heated at 140°C for 1h in the microwave, then poured into water and extracted with EtOAc(x3). The organic layer was dried (Na2SO4), concentrated, and purified by C18 reversed phase column chromatography (MeCN:H2O) to yield the title compound as a white solid (63 mg, 30%). ESI-MS m/z: 415.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.43 (m, 4H), 3.68 (dd, J = 5.8, 3.9 Hz, 4H), 5.59 (d, J = 8, 1 Hz, 1H), 6.05 - 6.12 (m, 1H), 7.20 - 7.60 (m, 8H), 7.66 (m, 1H), 7.78 (s, 1H), 7.97 (s, 1H), 10.86 (s, 1H). Example 94:
[0278] [0278] To a solution of the compound from Example 92 step a (182 mg, 0.5 mmol) in DMF (6 mL) was added K2CO3 (414 mg, 3.0 mmol) and phenol (282 mg, 3.0 mmol ). The mixture was heated for 3 h at 130 °C in the microwave. The reaction mixture was purified directly by C18 reversed phase column chromatography (MeCN:H2O) to yield the desired compound as a white solid (20 mg, 10%). ESI-MS m/z: 415.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.56 (s, 1H), 6.26 (s, 1H), 7.10 - 7.37 (m, 6H), 7.37 - 7.57 ( m, 7H), 7.64 (m, 1H), 8.07 (s, 1H), 8.52 (s, 1H), 10.86 (s, 1H). Example 95: Example 95 step a:
[0279] [0279] A solution of 3-amino-1-(4-methoxybenzyl)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one, from Example 91 step b , (500 mg, 1.35 mmol), 3-chloro-6-phenylpyridazine (257 mg, 1.35 mmol), Brettphos (72 mg, 0.14 mmol) and K2CO3 (372 mg, 2.70 mmol) in t-BuOH (5 mL) were stirred under nitrogen for 30 minutes at room temperature before 3rd generation Brettphos pre-catalyst (122 mg, 0.14 mmol) was added. The reaction was stirred for 12 hours at 90 °C. The mixture was diluted with EtOAc, washed with water (x2), dried
[0280] [0280] To a solution of the compound from step a (87 mg, 0.17 mmol) in anisole (5 mL) was added AlCl 3 (220 mg, 1.65 mmol) and the mixture was stirred for 3 hours at 70 °C. The reaction mixture was purified directly by preparative HPLC to yield the title compound as a white solid (31 mg, 47%). ESI-MS m/z: 406.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) 5.69 (d, J = 7.7 Hz, 1H), 7.25 - 7.70 (m, 13H), 7.91 - 7.98 (m, 3H ), 8.12 (d, J = 7.7 Hz, 1H), 10.92 (s, 1H). Example 96: Example 96 step a:
[0281] [0281] A solution of Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (500 mg, 2.0 mmol), 2,4- dichloropyrimidine (600mg, 4.0mmol), DIEA (1.5ml, 9.0mmol) in iPrOH (60ml) were heated at 90°C overnight. The reaction mixture was cooled to room temperature, diluted with DCM, and washed with water (x2). The organic layer was dried (Na2SO4), concentrated, and purified by C18 reversed phase column chromatography (MeCN:H2O) to yield the desired compound as a beige solid (530 mg, 41%). ESI-MS m/z: 364.1 [M+H]+. Example 96 step b:
[0282] [0282] A solution of the compound from step a (200 mg, 0.55 mmol), phenylboronic acid (300 mg, 2.46 mmol), Pd(dtbpf)Cl2 (80 mg, 0.06 mmol), KF(500 mg, 8.2 mmol) in H 2 O (1 mL) and 1,4-dioxane (5 mL) was heated at 100 °C in the microwave for 1.5 hours. The reaction mixture was purified by preparative HPLC to yield the title compound as a white solid (26 mg, 11%). ESI-MS m/z: 406.2 [M+H]+. 1H NMR (300 MHz, Methanol-d4) δ 5.80 (s, 1H), 6.79 (s, 1H), 7.28 - 7.58 (m, 21H), 7.70 (ddd, J = 8.4, 7.2, 1.6 Hz, 2H), 8.11 (d, J = 7.6 Hz, 3H), 8.25 (d, J = 6.1 Hz, 2H). Example 97: Example 97 step a:
[0283] [0283] A solution of 3-bromo-2-hydroxypyridine (2.0 g, 12 mmol), benzyl bromide (1.9 g, 12 mmol), and K2CO3 (4.9 g, 36 mmol) in DMF ( 100 ml) was stirred for 3 hours at room temperature. The reaction mixture was diluted with water and extracted with EtOAc (x3). The organic layer was dried
[0284] [0284] A solution of the compound from step a (87 mg, 0.33 mmol), Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (100 mg, 0.40 mmol), Pd(OAc) 2 (11 mg, 0.05 mmol), and CsCO 3 (220 mg, 0.66 mmol) in DMF (5 mL) was stirred for 5 h at 120 °C . The mixture was purified directly by preparative HPLC to yield the title compound as a white solid (5 mg, 4%). ESI-MS m/z: 435.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.48 (s, 1H), 7.64 (m, 1H), 7.56 - 7.21 (m, 14H) , 7.12 (dd, J = 5.9, 2.6 Hz, 1H), 6.58 (d, J = 6.9 Hz, 1H), 6.20 - 6.07 (m, 2H), 5.17 (s, 2H), 4.91 (d, J = 6.9 Hz, 1H). Example 98:
[0285] [0285] To a solution of Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (502 mg, 2.0 mmol) in iPrOH(20 mL) was added 2-chloroquinazoline (164 mg, 1.0 mmol) and TsOH (1.0 mmol). The mixture was stirred for 24 hours at 80°C. The reaction mixture was concentrated and purified by preparative HPLC to yield the desired compound as a white solid (17 mg, 4%). ESI-MS m/z: 445.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.63 (d, J = 7.9 Hz, 1H), 7.24 - 7.59 (m, 10H), 7.59 - 7.80 (m, 3H), 7.87 (d, J = 8.0 Hz, 1H), 8.48 (s, 1H), 9.23 (s, 1H), 10.92 (s, 1H).
[0286] [0286] To a solution of Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (502 mg, 2.0 mmol) in DMF (8 mL) 2,6-dichlorobenzo[d]oxazole (449 mg, 2.4 mmol) and TEA (404 mg, 2 mmol) were added. The mixture was stirred at 60 °C for 1 h, then poured into water. The mixture was extracted with EtOAc(x3), the organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC to yield the desired compound as a white solid (500 mg, 62%). ESI-MS m/z: 403.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.31 (d, J = 8.3 Hz, 1H), 7.12 - 7.76 (m, 12H), 9.50 (d, J = 8, 3 Hz, 1H), 10.98 (s, 1H). Example 100:
[0287] [0287] Example 100 was prepared using a procedure similar to that used to prepare Example 99 where 2-chlorobenzo[d]oxazole was used in place of 2,6-dichlorobenzo[d]oxazole. ESI-MS m/z: 369.1 [M+H]+. Example 101:
[0288] [0288] To a solution of Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (50 mg, 0.2 mmol) in DMSO (1 mL) was added 1-iodo-2-isothiocyanatobenzene (46 mg, 0.3 mmol), nBu4NBr (91 mg, 0.3 mmol), and CuBr (7 mg, 0.05 mmol) and the resulting mixture was stirred at 60oC for 2h. The reaction mixture was purified by preparative HPLC to yield the desired compound as a pale yellow solid (12 mg, 17%). ESI-MS m/z: 385.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.52 (d, J = 7.9 Hz, 1H), 7.05 (m, 1H), 7.14 – 7.61 (m, 10H), 7 .64 - 7.77 (m, 2H), 9.26 (d, J = 7.9 Hz, 1H), 10.96 (s, 1H). Example 102: Example 102 step a:
[0289] [0289] To a 100 mL round bottom flask was added 5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (1.05 g, 4.4 mmol ) and DMF (40 mL) and cooled to 0oC. The reaction mixture was treated with 60% NaH in oil (213 mg, 5.3 mmol), stirred for 20 min., allowed to warm to room temperature, treated with PMB-Cl (0.72 mL, 5.3 mmol) and stirred for 3.5 h. The reaction was cooled to 0oC, quenched by addition of saturated NH4Cl solution (10 mL), diluted with ethyl acetate-MTBE (100 mL) and filtered. The filtrate was washed with H 2 O (3 x 30 mL) and brine. Dry over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography (silica, hexanes:EtOAc) to yield the title compound (1.262 g) as a colorless solid. ESI MS m/z = 357.16 [M+H]+. Example 102 step b:
[0290] [0290] To a 25 mL round bottom flask were added the compound from step a (0.569 g, 1.0 equiv., 1.6 mmol) and THF (8 mL) and cooled to -65°C. The reaction mixture was treated with t-BuOK (1.68 mL, 1M in THF, 1.7 mmol) and stirred for 30 minutes. Methyl iodide (0.109 mL, 1.8 mmol) in THF (2 mL) was added to the reaction via cannula, slowly allowed to warm to 2°C over 1.5 hours and stirred at room temperature for 15 minutes. The reaction was cooled to 0oC, quenched by addition of saturated NH4Cl solution (2 mL), diluted with ethyl acetate, washed with H2O and brine. Dry over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography (silica, hexanes:acetone) to give the title compound (519.6 mg) as a colorless solid. ESI MS m/z = 371.17 [M+H]+. Example 102 step c:
[0291] [0291] To a 25 mL round bottom flask was added step b compound (0.1 g, 1.0 equiv., 0.27 mmol), DME (6 mL)-THF (1 mL), HMPA (0.28 mL, 1.62 mmol) and cooled to -40 °C. The reaction mixture was treated with KHMDS (mL, 0.5M in toluene, 1.08 mmol) and stirred for 100 min. Then trisyl azide (570 mg, 1.84 mmol) in THF (1.5 mL) was added to a reaction via cannula and stirred for 2 hours. The reaction mixture was treated with AcOH (0.28 mL, 4.86 mmol) and slowly allowed to warm to room temperature over 100 min. Then the reaction was diluted with ethyl acetate, washed with saturated NaHCO3 solution, H2O and brine. Dry over Na2SO4,
[0292] [0292] To a mixture of the compound from step c (62 mg, ~60% purity) and H2O (1 drop) in THF (0.9 mL) was added PPh3 (200 mg, 0.76 mmol), heated to 60oC for 2 hours and evaporated to dryness. The residue was purified by column chromatography (silica, DCM:MeOH) to give the title compound (14 mg) as a colorless solid. ESI MS m/z = 386.19 [M+H]+. Example 103:
[0293] [0293] Example 103 was prepared using a procedure similar to that used to prepare Example 99 where 2-chloro-6-fluorobenzo[d]oxazole was used in place of 2,6-dichlorobenzo[d]oxazole. ESI-MS m/z: 387.1 [M+H]+. Example 104:
[0294] [0294] Example 104 was prepared using a procedure similar to that used to prepare Example 99 where 2-chloro-5-fluorobenzo[d]oxazole was used in place of 2,6-dichlorobenzo[d]oxazole. ESI-MS m/z: 387.1 [M+H]+.
[0295] [0295] Example 105 was prepared using a procedure similar to that used to prepare Example 99 where 2-chloro-4-fluorobenzo[d]oxazole was used in place of 2,6-dichlorobenzo[d]oxazole. ESI-MS m/z: 387.1 [M+H]+. Example 106:
[0296] [0296] Example 106 was prepared using a procedure similar to that used to prepare Example 99 where 2-chloro-5-methylbenzo[d]oxazole was used in place of 2,6-dichlorobenzo[d]oxazole. ESI-MS m/z: 383.1 [M+H]+. Example 107:
[0297] [0297] Example 107 was prepared using a procedure similar to that used to prepare Example 20 where 5-(methylsulfonyl)picolinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 475.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.41 (s, 3H), 5.23 (d, J = 6.3 Hz, 1H), 7.26 – 7.42 (m, 2H), 7 .43 - 7.59 (m, 6H), 7.70 (td, J = 7.7, 7.0, 1.8 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H ), 8.49 (dd, J = 8.4, 2.4 Hz, 1H), 9.19 (d, J = 2.1 Hz, 1H), 9.59 (s, 1H), 11.04 (s, 1H). Example 108:
[0298] [0298] Example 108 was prepared using a procedure similar to that used to prepare Example 20 where 5-(dimethylamino)picolinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 440.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.02 (s, 6H), 5.14 (d, J = 8.6 Hz, 1H), 7.18 (m, 1H), 7.23 – 7 .39 (m, 3H), 7.42 - 7.57 (m, 5H), 7.62 - 7.79 (m, 2H), 8.16 (d, J = 3.0 Hz, 1H), 9.03 (d, J = 8.7 Hz, 1H), 10.98 (s, 1H). Example 109:
[0299] [0299] Example 109 was prepared using a procedure similar to that used to prepare Example 20 where 6-chloro-5-methoxypicolinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 461.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.97 (s, 3H), 5.16 (d, J = 8.5 Hz, 1H), 7.22 – 7.40 (m, 3H), 7 .42 - 7.57 (m, 5H), 7.61 - 7.79 (m, 2H), 7.98 (d, J = 8.5 Hz, 1H), 9.27 (d, J = 8 .5 Hz, 1H), 10.99 (s, 1H). Example 110:
[0300] [0300] Example 110 was prepared using a procedure similar to that used to prepare Example 20 where 5-fluoro-6-methylpicolinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 429.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.50 (s, 3H), 5.17 (d, J = 8.5 Hz, 1H),
[0301] [0301] Example 111 was prepared using a procedure similar to that used to prepare Example 20 where 3-morpholinobenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 481.2 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 3.15 (t, J = 4.9 Hz, 4H), 3.75 (dd, J = 6.0, 3.6 Hz, 4H), 5, 10 - 5.19 (m, 1H), 7.08 - 7.73 (m, 14H), 7.82 (s, 1H), 8.99 - 9.09 (m, 1H), 10.99 ( s, 1H). Example 112:
[0302] [0302] Example 112 was prepared using a procedure similar to that used to prepare Example 20 where 3-fluoro-4-morpholinobenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 499.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.11 (t, J = 4.7 Hz, 4H), 3.75 (dd, J = 6.0, 3.3 Hz, 4H), 5.10 – 5.17 (m, 1H), 7.12 – 7.40 (m, 4H), 7.41 – 7.73 (m, 8H), 9.07 (d, J = 7.8 Hz, 1H ), 11.00 (s, 1H). Example 113:
[0303] [0303] Example 113 was prepared using a procedure similar to that used to prepare Example 20 where 3-methyl-4-morpholinobenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 440.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.33 (s, 3H), 2.81 - 2.99 (m, 4H), 3.71 - 3.84 (m, 4H), 5.15 ( d, J = 8.6 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.25 - 7.39 (m, 3H), 7.43 - 7.57 (m , 5H), 7.59 - 7.73 (m, 3H), 9.03 (d, J = 8.6 Hz, 1H), 10.99 (s, 1H). Example 114:
[0304] [0304] Example 114 was prepared using a procedure similar to that used to prepare Example 20 where 5-morpholinopicolinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 482.2 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 3.31 (m, 4H), 3.77 (m, 4H), 5.17 (d, J = 8.3 Hz, 1H), 7.21 - 7.87 (m, 11H), 8.41 (d, J = 2.9 Hz, 1H), 9.13 (d, J = 8.4 Hz, 1H), 11.01 (s, 1H). Example 115:
[0305] [0305] Example 115 was prepared using a procedure similar to that used to prepare Example 20 where 6-morpholinicotinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 482.4[M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 3.52 – 3.60 (m, 4H), 3.70 (dd, J = 5.8, 3.8 Hz, 4H), 5.13 (d , J = 8.5 Hz, 1H), 6.98 (d, J = 9.1 Hz, 1H), 7.22 - 7.38 (m, 3H), 7.41 - 7.57 (m, 5H), 7.66 (ddd, J=8.5, 7.0, 1.7Hz, 1H), 7.90 (dd, J=9.0, 2.4Hz, 1H), 8.44 – 8.58 (m, 1H), 8.98 (d, J = 8.6 Hz, 1H), 10.98 (s, 1H). Example 116:
[0306] [0306] Example 116 was prepared using a procedure similar to that used to prepare Example 20 where 4-(cyclohexylamino)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 493.4[M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.48 – 1.05 (m, 5H), 1.60 (d, J = 12.5 Hz, 1H), 1.84 – 1.65 (m, 2H), 1.92 (d, J = 12.0 Hz, 2H), 3.20 (m, 1H), 5.11 (d, J = 8.7 Hz, 1H), 6.14 (d, J = 7.8 Hz, 1H), 6.72 - 6.50 (m, 2H), 7.38 - 7.22 (m, 3H), 7.56 - 7.41 (m, 7H), 7 .66 (m, 1H), 8.79 (d, J = 8.8 Hz, 1H), 10.95 (s, 1H). Example 117:
[0307] [0307] Example 117 was prepared using a procedure similar to that used to prepare Example 20 where 4-((2-methoxyethyl)amino)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 469.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.27 (d, J = 6.8 Hz, 5H), 3.49 (t, J = 5.6 Hz, 2H), 5.11 (d, J = 8.7 Hz, 1H), 6.34 (t, J = 5.6 Hz, 1H), 6.75 - 6.60 (m, 1H), 7.40 - 7.20 (m, 3H) , 7.58 - 7.40 (m, 7H), 7.66 (ddd, J = 8.6, 7.0, 1.7 Hz, 1H), 8.83
[0308] [0308] Example 118 was prepared using a procedure similar to that used to prepare Example 20 where 4-((2-methoxyethyl)(methyl)amino)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 483.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.98 (s, 3H), 3.25 (s, 3H), 3.64 - 3.43 (m, 4H), 5.12 (d, J = 8.7 Hz, 1H), 6.89 - 6.63 (m, 2H), 7.39 - 7.20 (m, 3H), 7.56 - 7.39 (m, 5H), 7.72 - 7.55 (m, 3H), 8.86 (d, J = 8.7 Hz, 1H), 10.97 (s, 1H). Example 119:
[0309] [0309] Example 119 was prepared using a procedure similar to that used to prepare Example 20 where 5-fluoro-2-morpholinobenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 499.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.75 - 2.97 (m, 4H), 3.56 - 3.84 (m, 4H), 5.17 (d, J = 8.6 Hz, 1H), 7.19 - 7.41 (m, 5H), 7.42 - 7.57 (m, 6H), 7.67 (ddd, J = 8.4, 7.0, 1.7 Hz, 1H), 9.17 (d, J = 8.6 Hz, 1H), 10.99 (s, 1H). Example 120:
[0310] [0310] Example 120 was prepared using a procedure similar to that used to prepare Example 20 where 2-morpholinicotinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 482.3 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 3.07 - 3.20 (m, 4H), 3.68 (m, 4H), 5.15 (d, J = 8.6 Hz, 1H), 7.04 (dd, J = 7.6, 4.8 Hz, 1H), 7.24 - 7.38 (m, 3H), 7.41 - 7.60 (m, 5H), 7.67 ( ddd, J = 8.5, 7.1, 1.8 Hz, 1H), 7.96 (dd, J = 7.6, 1.9 Hz, 1H), 8.35 (dd, J = 4, 8, 1.9 Hz, 1H), 9.16 (d, J = 8.6 Hz, 1H), 10.98 (s, 1H). Example 121:
[0311] [0311] Example 121 was prepared using a procedure similar to that used to prepare Example 20 where 4-(methylsulfonyl)-2-morpholinobenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 559.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.86 – 3.07 (m, 4H), 3.27 (s, 3H), 3.72 (t, J = 4.7 Hz, 4H), 5 .18 (d, J = 8.3 Hz, 1H), 7.24 - 7.39 (m, 3H), 7.42 - 7.71 (m, 8H), 7.92 (d, J = 8 .1 Hz, 1H), 9.31 (d, J = 8.5 Hz, 1H), 11.00 (s, 1H). Example 122:
[0312] [0312] Example 122 was prepared using a procedure similar to that used to prepare Example 20 where 2-chloro-4-
[0313] [0313] Example 123 was prepared using a procedure similar to that used to prepare Example 20 where 2-morpholino-4-(trifluoromethyl)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 549.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.97 (s, 3H), 5.18 (d, J = 8.3 Hz, 1H), 7.13 – 7.82 (m, 11H), 8 .22 (d, J = 1.9 Hz, 1H), 9.47 (d, J = 8.4 Hz, 1H), 11.00 (s, 1H). Example 124:
[0314] [0314] Example 124 was prepared using a procedure similar to that used to prepare Example 20 where 4-morpholinobenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 481.2 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ 3.22-3.24 (m, 4H), 3.73-3.75 (m, 4H), 5.12-5.14 (d, J = 8.0 Hz, 1H), 7.06 - 7.08 (m, 2H), 7.26 - 7.29 (m, 1H), 7.33 - 7.36 (m, 2H), 7.44 -7.49 (m, 5H), 7.51-7.77 (m, 1H), 8.93-8.95 (d, J = 8.0 Hz, 1H) 10.98 (s, 1H) . Example 124a:
[0315] [0315] Example 124a was separated from racemic Example 7 using a Chiralpak IC2*25cm, 5um Chiral-P(IC)004S90IC0SCJ-QF001 column. ESI-MS m/z: 481.2 [M+H]+.
[0316] [0316] Example 124b:
[0317] [0317] Example 124b was separated from racemic Example 7 using a Chiralpak IC2*25cm, 5um Chiral-P(IC)004S90IC0SCJ-QF001 column. ESI-MS m/z: 481.2 [M+H]+. Example 125:
[0318] [0318] Example 125 was prepared using a procedure similar to that used to prepare Example 20 where 2-morpholinobenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 481.3 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 2.90 (dd, J = 5.7, 3.4 Hz, 4H), 3.71 (t, J = 4.6 Hz, 4H), 5, 18 (d, J = 8.7 Hz, 1H), 7.08 - 7.24 (m, 2H), 7.24 - 7.42 (m, 3H), 7.42 - 7.61 (m, 6H), 7.61 - 7.83 (m, 2H), 9.10 (d, J = 8.8 Hz, 1H), 10.99 (s, 1H). Example 125a:
[0319] [0319] Example 125a was separated from racemic Example 7 using a Chiralpak IC2*25cm, 5umChiral-P(IC)004S90IC0SCJ-QF001 column. ESI-MS m/z: 481.3 [M+H]+. Example 125b:
[0320] [0320] Example 125b was separated from racemic Example 7 using a Chiralpak IC2*25cm column, 5umChiral-P(IC)004S90IC0SCJ-QF001. ESI-MS m/z: 481.3 [M+H]+. Example 126:
[0321] [0321] Example 126 was prepared using a procedure similar to that used to prepare Example 20 where 2-fluoro-4-morpholinbenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 499.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.90 (t, J = 4.5 Hz, 4H), 3.69 (td, J = 4.2, 2.0 Hz, 4H), 5.16 (d, J = 8.7 Hz, 1H), 6.92 - 7.03 (m, 2H), 7.24 - 7.39 (m, 3H), 7.42 - 7.59 (m, 5H ), 7.63 - 7.74 (m, 2H), 9.11 (d, J = 8.7 Hz, 1H), 10.98 (s, 1H). Example 126a:
[0322] [0322] Example 126a was separated from racemic Example 7 using a Chiralpak IB-3 100*3mm, 3μm column. ESI-MS m/z: 499.2 [M+H]+. Example 126b:
[0323] [0323] Example 126b was separated from racemic Example 7 using a Chiralpak IB-3 100*3mm, 3μm column. ESI-MS m/z: 499.2 [M+H]+. Example 127: Example 127 step a:
[0324] [0324] A solution of the compound 2-chloro-4-fluorobenzoic acid (5.2 g, 30 mmol), CuI (570 mg, 3 mmol), K2CO3 (1.8 g, 90 mmol) and morpholine (10 mL) in DMF (100 mL) was stirred for 2 hours at 90°C. The mixture was concentrated and purified by C18 reversed phase column chromatography (MeCN:H2O) to yield 4-fluoro-2-morpholinobenzoic acid as a white solid (900 mg, 13%). ESI-MS m/z: 226.0 [M+H]+. Example 127 step b:
[0325] [0325] Example 127 was prepared using a procedure similar to that used to prepare Example 20 where 4-fluoro-2-morpholinobenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 499.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.92 (d, J = 4.6 Hz, 4H), 3.71 (m, 4H), 5.17 (d, J = 8.7 Hz, 1H ), 6.91 – 7.06 (m, 2H), 7.23 – 7.41 (m, 3H), 7.42 – 7.62 (m, 5H), 7.63 – 7.77 (m , 2H), 9.13 (d, J = 8.8 Hz, 1H), 11.00 (s, 1H). Example 128: Example 128 step a:
[0326] [0326] A solution of 2-chloro-4-(1H-1,2,4-triazol-1-yl)benzoic acid (300 mg, 1.34 mmol) in morpholine (5 mL) was stirred at 120 °C for 2 hours. Water (20 mL) was added to the mixture and extracted with EtOAc(x3). The organic layer was dried and purified by C18 reversed phase column chromatography to yield 2-chloro-4-(1H-1,2,4-triazol-1-yl)benzoic acid as an off-white solid (200 mg, 54% ). ESI-MS m/z: 275.1 [M+H]+. Example 128 step b:
[0327] [0327] Example 128 was prepared using a procedure similar to that used to prepare Example 20 where 2-chloro-4-(1H-1,2,4-triazol-1-yl)benzoic acid was used in place of 5- chlorofuran-2-carboxylic acid. ESI-MS m/z: 548.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.97-2.99 (m, 4H), 3.74 (s, 4H), 5.16-5.18 (d, J = 8.0 Hz, 1H), 7.26 - 7.28 (m, 1H), 7.30 - 7.34 (m, 2H), 7.36 - 7.48 (m, 5H), 7.51-7.53 ( m, 3H), 7.54-7.60 (m, 1H), 8.29 (s, 1H), 9.17-9.19 (m, 1H), 9.44 (s, 1H)10, 99 (s, 1H). Example 129:
[0328] [0328] Example 129 was prepared using a procedure similar to that used to prepare Example 20 where 2-morpholino-4-(1H-pyrazol-1-yl)benzoic acid, which was prepared similarly to 2-chloro-4 -(1H-1,2,4-triazol-1-yl)benzoic acid from Example 128 step a, was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 547.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.96-2.98 (m, 4H), 3.73(s, 4H), 5.16-5.18 (d, J = 8.0 Hz, 1H), 6.59-6.60 (m, 1H), 7.26 - 7.36 (m, 2H), 7.44 - 7.48 (m, 2H), 7.51-7.54 ( m, 6H), 7.58-7.59 (m, 2H), 7.60-7.69 (m, 1H), 7.77-7.80 (m, 2H), 8.64 (s, 1H), 9.12-9.14 (m, 1H), 9.44 (s, 1H) 10.99 (s, 1H). Example 130:
[0329] [0329] Example 130 was prepared using a procedure similar to that used to prepare Example 20 where 2-morpholino-6-(trifluoromethyl)nicotinic acid, which was prepared similarly to 2-chloro-4-(1H-1, 2,4-triazol-1-yl)benzoic acid from Example 128 step a, was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 550.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.18-3.22 (m, 4H), 3.66-3.72 (m, 4H), 5.16-5.18 (d, J = 8 .0 Hz, 1H), 7.26 - 7.28 (m, 1H), 7.30 - 7.34 (m, 2H), 7.36 - 7.48 (m, 6H), 7.50- 7.70 (m, 1H), 8.18-8.20 (m, 1H), 9.33-9.35 (d, J = 8.0 Hz, 1H), 11.01 (s, 1H) . Example 131:
[0330] [0330] Example 131 was prepared using a procedure similar to that used to prepare Example 20 where 4-cyano-2-morpholinobenzoic acid, which was prepared similarly to 2-chloro-4-(1H-1,2,4) -triazol-1-yl)benzoic acid from Example 128 step a, was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 506.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.92-2.94 (m, 4H), 3.71-3.75 (m, 4H), 5.17-5.19 (d, J = 8 .0 Hz, 1H), 7.26 – 7.28 (m, 1H), 7.30 – 7.34 (m, 2H), 7.35 – 7.48 (m, 7H), 7.50- 7.59 (m, 1H), 7.65-7.69 (m, 1H), 9.29-9.31 (d, J = 8.0 Hz, 1H), 10.99 (s, 1H) . Example 132:
[0331] [0331] A solution of 3-chloropicolinic acid (1 g, 6.37 mmol) and H2SO4 (1 mL) in EtOH (20 mL) was refluxed for 3 hours. It was concentrated and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield ethyl 3-chloropicolinate as a yellow oil (0.85 g, 72%). ESI-MS m/z: 186.0 [M+H]+. Example 132 step b:
[0332] [0332] A solution of ethyl 3-chloropicolinate (400 mg, 2.16 mmol) in morpholine (neat) (2 ml) was stirred overnight at 120°C. It was concentrated in vacuo and the crude product was purified by preparative TLC (PE/EtOAc=2/1) to yield ethyl 3-morpholinopicolinate as a yellow solid (0.17 g, 35%). ESI-MS m/z: 237.1 [M+H]+. Example 132 step c:
[0333] [0333] A solution of ethyl 3-morpholinopicolinate (0.17 g, 0.72 mmol) and NH2NH2.H2O (1 mL) in EtOH (10 mL) was refluxed overnight. The crude product was purified by C18 reversed phase column chromatography
[0334] [0334] Example 132 was prepared using a procedure similar to that used to prepare Example 21 where 3-morpholinopicolinohydrazide was used in place of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 482.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.87 – 3.08 (m, 4H), 3.71 (dd, J = 5.7, 3.2 Hz, 4H), 5.20 (d, J = 8.5 Hz, 1H), 7.24 - 7.42 (m, 3H), 7.43 - 7.61 (m, 6H), 7.62 - 7.75 (m, 2H), 8 .35 (dd, J = 4.5, 1.3 Hz, 1H), 9.21 (d, J = 8.6 Hz, 1H), 11.00 (s, 1H). Example 133: Example 133 step a:
[0335] [0335] A solution of 4-chloronicotinic acid (1.00 g, 6.0 mmol), morpholine (1.26 g, 14.0 mmol) and K2CO3 (1.33 g, 9.6 mmol) in DMSO ( 5 ml) was stirred for 12 hours at 120°C. It was diluted with EtOH, the solid was filtered off. The filtrate was concentrated, and it was precipitated by addition of MeCN (20 mL) to yield 1.06 g (71%) as a white solid. ESI-MS m/z:
[0336] [0336] Example 133 was prepared using a procedure similar to that used to prepare Example 20 where potassium 4-morpholinonicotinate was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 482.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.03 (s, 4H), 3.69 (s, 4H), 5.15 (d, J = 8.7 Hz, 1H), 7.03 (d , J = 5.7 Hz, 1H), 7.29 (m, 1H), 7.35 (m, 2H), 7.39 - 7.62 (m, 5H), 7.67 (m, 1H) , 8.42 (d, 1H), 8.56 (s, 1H), 9.18 (d, 1H), 10.99 (s, 1H). Example 134:
[0337] [0337] Example 134 was prepared using a procedure similar to that used to prepare Example 20 where epotassium 4-(piperidin-1-yl)nicotinate, which was prepared similarly to potassium 4-morpholinonicotinate from Example 133 step a, was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 480.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.57 (s, 4H), 3.15 (s, 4H), 5.15 (d, 1H), 7.15 (d, J = 6.5 Hz , 1H), 7.19 - 7.40 (m, 3H), 7.40 - 7.60 (m, 5H), 7.62 - 7.71 (m, 1H), 8.35 (d, J = 6.5 Hz, 1H), 8.52 (s, 1H), 9.21 (d, J = 8.6 Hz, 1H), 10.99 (s, 1H). Example 135:
[0338] [0338] A solution of 3-chloro-5-fluoropicolinic acid (500 mg, 2.85 mmol), H2SO4 (1 mL) in EtOH (5 mL) was stirred at 80 °C for 4 hours. Then H2O (20 ml) was added to the mixture and extracted with EtOAc (x3). The organic layer was dried and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield ethyl 3-chloro-5-fluoropicolinate as an off-white solid (400 mg, 69%). ESI-MS m/z: 203.9 [M+H]+. Example 135 step b:
[0339] [0339] A solution of ethyl 3-chloro-5-fluoropicolinate (100mg, 0.49mmol), morpholine (43mg, 0.49mmol), K2CO3 (135mg, 0.98mmol) in DMSO (5 mL) was stirred at 100 °C for 2 hours. Then H2O (20 ml) was added to the mixture and extracted with EtOAc (x3). The organic layer was dried and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield ethyl 3-chloro-5-morpholinopicolinate as an off-white solid (120 mg, 91%). ESI-MS m/z: 270.9 [M+H]+. Example 135 step c:
[0340] [0340] A solution of ethyl 3-chloro-5-morpholinopicolinate (120 mg,
[0341] [0341] Example 135 was prepared using a procedure similar to that used to prepare Example 21 where 3-chloro-5-morpholinopicolinohydrazide was used in place of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 516.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.28-3.38 (m, 4H), 3.73-3.75 (m, 4H), 5.15-5.17 (d, J = 8 .0 Hz, 1H), 7.26-7.29 (m, 1H), 7.33 - 7.36 (m, 2H), 7.44 - 7.55 (m, 6H), 7.66- 7.69 (m, 1H), 8.40-8.41 (m, 1H), 9.15-9.17 (m, 1H), 10.99 (s, 1H). Example 136: Example 136 step a:
[0342] [0342] A solution of 3,5-difluoropicolinic acid (3.3 g, 20.75 mmol), H2SO4 (5 mL) in EtOH (20 mL) was stirred for 2 hours at 80 °C. Then solvent was removed. The residue was diluted with EtOAc and it was washed with brine (x2). The organic layer was concentrated to yield ethyl 3,5-difluoropicolinate as a pale yellow solid (3.44 g, 88%). ESI-MS m/z: 188.0 [M+H]+. Example 136 step b:
[0343] [0343] A solution of ethyl 3,5-difluoropicolinate (3.1 g, 16.6 mmol), morpholine (1.44 g, 16.6 mmol) and K2CO3 (6.87 g, 49.8 mmol) in DMF (4 ml) and DMSO (6 ml) was stirred overnight at room temperature. It was poured into water and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 and concentrated to yield a mixture of ethyl 5-fluoro-3-morpholinopicolinate and the ethyl 3-fluoro-5-morpholinopicolinate isomer as a pale yellow solid (3.37 g). ESI-MS m/z: 255.2 [M+H]+. Example 136 step c:
[0344] [0344] A solution of the mixture of isomers from step b (3.37 g, 13.3 mmol) and NaOH (796 mg, 19.9 mmol) in THF (10 mL) and H2O (15 mL) was stirred for 2 hours at room temperature. It was pH adjusted to 2-3 with HCl and purified by preparative HPLC (MeCN/H 2 O) to yield 817 mg of the desired compound 5-fluoro-3-morpholinopicolinic acid as a white solid. ESI-MS m/z: 227.0[M+H]+. Example 136 step d:
[0345] [0345] A solution of 5-fluoro-3-morpholinopicolinic acid (817 mg, 3.62 mmol) and NH2NHBoc (956 mg, 7.24 mol), DIPEA (934 mg, 7.24 mol) and HATU (1. 44 g, 3.80 mol) in DMF (10 mL) was stirred for half an hour at room temperature. It was diluted with H2O(x3), extracted with EtOAc and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield tert-butyl 2-(5-fluoro-3-morpholinopicolinoyl)hydrazine-1-carboxylate as white solid. ESI-MS m/z: 341.2[M+H]+. Example 136 step e:
[0346] [0346] A solution of tert-butyl 2-(5-fluoro-3-morpholinopicolinoyl)hydrazine-1-carboxylate in EA (10 mL) was added HCl (3 mL, conc.). Then it was stirred for half an hour at room temperature. Solvent was removed and the residue was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield 5-fluoro-3-morpholinopicolinohydrazide as a pale yellow solid (293 mg). ESI-MS m/z: 241.0[M+H]+. Example 136 step f:
[0347] [0347] The above compound (S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (A) was made in various ways, including the procedures described by Sherrill and Sugg (J. Org. Chem. 1995, 60, 730-734), Rittle and Evans (Tetrahedron Lett. 1987, 28, 521-522), and the method described below.
[0348] [0348] Pure (R)-3-chloro-1-phenylpropan-1-ol (12.6 g, 73.8 mmol) was dissolved in morpholine (60 mL) and the mixture was heated at 80°C overnight . The mixture was cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic layer was dried (Na2SO4), concentrated, and pumped under high vacuum for 3 h. The material (R)-3-morpholino-1-phenylpropan-1-ol (14.0 g, 86%) was used directly without further purification. Example 136 step g:
[0349] [0349] Solid p-nitrophenyl chloroformate (6.4 g, 41.1 mmol) was added to a DCM solution (200 mL) of (R)-3-morpholino-1-phenylpropan-1-ol (7.0 g, 31.6 mmol) and i-Pr2NEt (8.3 mL, 47.4 mmol) and the mixture was stirred at room temperature overnight. The mixture was diluted with DCM, and washed with water and brine, dried (Na2SO4), concentrated, and purified via column chromatography to yield the desired material (R)-3-morpholino-1-phenylpropyl(4-nitrophenyl) carbonate. (10.2 g, 84%) as a yellow gum that will be used directly in the next step. Example 136 step h:
[0350] [0350] Pure i-Pr2NEt (4.1 mL, 23.2 mmol) was added to a DMF solution (140 mL) of (R)-3-morpholino-1-phenylpropyl (4-nitrophenyl)carbonate (6, 9 g, 17.9 mmol) and racemic amine (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (4.5 g, 17, 9 mmol) and the mixture was heated at 60°C overnight. The mixture was cooled to room temperature, diluted with EtOAc, and washed with water and brine, dried (Na2SO4), concentrated, and purified via column chromatography (0-100% EtOAc/hexanes) to yield the (R)-3- morpholino-1-phenylpropyl((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate (3.92 g, 44% yield, first region and less polar) and ((R)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate from (R )-3-morpholino-1-phenylpropyl (3.56 g, 40% yield, second region and more polar) as pale yellow solid. ESI MS m/z = 499.2395 [M+H]+ for ((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3- R)-3-morpholino-1-phenylpropyl yl)carbamate at /z = 499.2379 [M+H]+ for ((R)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo (R)-3-morpholino-1-phenylpropyl [e][1,4]diazepin-3-yl)carbamate. Example 136 step i:
[0351] [0351] ((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate from (R)-3-morpholino-1 Pure phenylpropyl (4.4 g, 8.8 mmol) was dissolved in 33% HBr in AcOH (30 mL) and the mixture was stirred at room temperature. After 2 h, the mixture became heterogeneous and a solution was cooled with an ice bath and adjusted to pH ~ 8 by the dropwise addition of saturated aqueous NaHCO3. After the overnight period, the white solid precipitated which was filtered, washed with cold water, cold MeOH and dried under high vacuum to give (S)-3-amino-5-phenyl-1,3-dihydro-2H- pure benzo[e][1,4]diazepin-2-one (A) (2.81 g, 79% yield) as a white solid. ESI MS m/z = 252.1529 [M+H]+. ee% = 98.4% (retention time 9.39 min, Method A); [α]D = -195.56 (c = 0.19, MeOH). Example 136 step j:
[0352] [0352] Compound ((R)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate 1-Phenylpropyl (2.0 g, 4.0 mmol) was dissolved in MeOH (40 mL), then 25 wt% NaOMe in MeOH (2.2 mL) was slowly added. The resulting mixture was stirred at room temperature for 20 h and confirmed with 1H NMR that the diastereomer ratio was close to 1:1. Diluted with EtOAc, washed with brine, dried and evaporated. The residue was purified by combiflash eluting with 0-10% MeOH/DCM to obtain ((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3 (R)-3-morpholino-1-phenylpropyl -yl)carbamate (0.90 g, 45% yield) and ((R)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo recycled (R)-3-morpholino-1-phenylpropyl [e][1,4]diazepin-3-yl)carbamate (0.84 g, 42% yield). ((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate of (R)-3-morpholino-1-phenylpropyl was resubmitted to Example 136 step i to obtain the desired (S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one. Example 136 step k:
[0353] [0353] CDI (196 mg, 1.2 mmol) was added to a solution of (S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin- 2-one (A) (276 mg, 1.1 mmol) in MeCN (3 mL) and DMF (0.6 mL), then stirred for 1 hour at room temperature. The compound from step e (293 mg, 1.2 mmol) was added and then stirred for 48 hours. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield (S)-2-(5-fluoro-3-morpholinopicolinoyl)-N-(2-oxo-5-phenyl-2,3 -dihydro-1H-benzo[e][1,4]diazepin-3-yl)hydrazine-1-carboxamide as a pale yellow solid (371 mg). ESI-MS m/z: 518.3 [M+H]+. Example 136 step 1:
[0354] [0354] To a solution of (S)-2-(5-fluoro-3-morpholinopicolinoyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4] ]diazepin-3-yl)hydrazine-1-carboxamide (371 mg, 0.72 mmol), DMAP (20 mg) and TEA (181 mg, 1.78 mmol) in DCM (5 mL) was added TsCl (204 mg). , 1.07 mmol). It was stirred for 1 hour before being concentrated. The crude product was purified by preparative HPLC (MeCN/H2O) to yield (S)-3-((5-(5-fluoro-3-morpholinopyridin-2-yl)-1,3,4-oxadiazol-2-yl )amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one as a white solid (122 mg, 34%). ESI-MS m/z: 500.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.07 (s, 1H), 2.85 - 3.07 (m, 4H), 3.61 - 3.78 (m, 4H), 5.17 ( d, 1H), 7.06 - 7.81 (m, 9H), 8.34 (d, 1H), 9.21 (d, 1H), 10.97 (s, 1H). Examples 137 and 138: Examples 137 and 138 step a:
[0355] [0355] A solution of 3,5-difluoropicolinic acid (1.60 g, 10.0 mol), morpholine (0.870 g, 10.0 mol) and K2CO3 (2.42 g, 176 mol) in DMSO (15 mL ) was stirred for 1 hour at 100°C. It was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the mixture of 3-fluoro-5-morpholinopicolinic acid and 5-fluoro-3-morpholinopicolinic acid as a yellow solid (1.90 g, 84% ). ESI-MS m/z: 226.1 [M+H]+. Examples 137 and 138 step b:
[0356] [0356] Examples 137 and 138 were prepared using a procedure similar to that used to prepare Example 20 where 3-fluoro-5-morpholinopicolinic acid and 5-fluoro-3-morpholinopicolinic acid were used, respectively, in place of 5-chlorofuran acid. -2-carboxylic acid. Example 137: ESI-MS m/z: 500.3[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.32 (t, J = 4.9 Hz, 4H), 3.76 (t, J = 4.9 Hz, 4H), 5.17 (d, J = 8.5 Hz, 1H) 7.61 - 7.17 (m, 9H), 7.82 - 7.62 (m, 1H), 8.36 - 8.22 (m, 1H), 9.18 (d, J = 8.6 Hz, 1H), 10.99 (s, 1H). Example 138: ESI-MS m/z: 500.2[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.10 - 2.88 (m, 4H), 3.71 (dd, J = 5.9, 3.3 Hz, 4H), 5.19 (d, J = 8.6 Hz, 1H), 7.44 - 7.23 (m, 3H), 7.76 - 7.44 (m, 7H), 8.36 (d, J = 2.3 Hz, 1H ), 9.25 (d, J = 8.6 Hz, 1H), 11.00 (s, 1H). Example 139:
[0357] [0357] Example 139 was prepared using a procedure similar to that used to prepare Example 20 where 3-morpholino-5-(trifluoromethyl)picolinic acid, which was prepared similarly to 2-chloro-4-(1H-1, 2,4-triazol-1-yl)benzoic acid from Example 128 step a was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 550.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.09 (d, J = 4.6 Hz, 4H), 3.73 (d, J = 4.6 Hz, 3H), 5.22 (d, J = 8.4 Hz, 1H), 7.22 - 7.44 (m, 3H), 7.44 - 7.65 (m, 5H), 7.66 - 7.80 (m, 1H), 7, 91 (d, J = 1.9 Hz, 1H), 8.71 (s, 1H), 9.43 (d, J = 8.6 Hz, 1H), 11.01 (s, 1H). Example 140:
[0358] [0358] Example 140 was prepared using a procedure similar to that used to prepare Example 20 where 5-cyano-3-morpholinopicolinic acid, which was prepared similarly to 2-chloro-4-(1H-1,2,4) -triazol-1-yl)benzoic acid from Example 128 step a, was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 507.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.02-3.04(m, 4H), 3.71-3.73 (m, 4H), 5.19-5.21 (d, J=8 .0 Hz, 1H), 7.24 - 7.28 (m, 1H), 7.30 - 7.37 (m, 5H), 7.42 - 7.90 (m, 1H), 8.00- 8.13 (m, 1H), 8.47 (s, 1H), 9.42-9.44 (m, 2H), 10.99 (s, 1H). Example 141: Example 141 step a:
[0359] [0359] A solution of 3-fluoroisonicotinic acid (1.30 g, 1.0 mol), piperidine (1.16 g, 13.3 mol) and K2CO3 (2.25 g, 17.6 mol) in DMSO ( 15 ml) was stirred for 1 hour at 120°C. It was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield 3-(piperidin-1-yl)isonicotinic acid as a white solid (1.12 g, 49%). ESI-MS m/z: 207.1 [M+H]+. Example 141 step b:
[0360] [0360] Example 141 was prepared using a procedure similar to that used to prepare Example 20 where 3-(piperidin-1-yl)isonicotinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 480.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.97 (s, 3H), 5.18 (d, J = 8.3 Hz, 1H), 7.13 – 7.82 (m, 11H), 8 .22 (d, J = 1.9 Hz, 1H), 9.47 (d, J = 8.4 Hz, 1H), 11.00 (s, 1H). Example 142:
[0361] [0361] Example 142 was prepared using a procedure similar to that used to prepare Example 20 where 3-morpholinoisonicotinic acid, which was prepared similarly to 3-(piperidin-1-yl)isonicotinic acid from Example 141 step a, was used in the instead of 5-chlorofuran-2-carboxylic acid.
[0362] [0362] Example 143 was prepared using a procedure similar to that used to prepare Example 20 where 3-morpholinopyrazine-2-carboxylic acid, which was prepared similarly to 3-(piperidin-1-yl)isonicotinic acid from Example 141 step a, was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 483.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.27-3.33(m, 4H), 3.67-3.70 (m, 4H), 5.17-5.19 (d, J=8 .0 Hz, 1H), 7.26 – 7.28 (m, 1H), 7.30 – 7.36 (m, 2H), 7.44 – 7.55 (m, 5H), 8.22- 8.23 (m, 1H), 8.35 (s, 1H), 9.33-9.35 (d, J = 8.0 Hz, 1H), 10.99 (s, 1H). Example 144: Example 144 step a:
[0363] [0363] A solution of 2-chloro-6-methylnicotinic acid (855 mg, 5 mmol), K2CO3 (1.38 g, 10 mmol) and morpholine (2 mL) in DMF (20 mL) was stirred for 3 hours at 130°C. The solid was filtered off and the solvent was removed and the residue was washed with Et 2 O (50 mL) to yield 6-methyl-2-morpholinicotinic acid as a white solid (666 mg, 60%). ESI-MS m/z: 223.1 [M+H]+. Example 144 step b:
[0364] [0364] Example 144 was prepared using a procedure similar to that used to prepare Example 20 where 6-methyl-2-morpholinicotinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 496.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.43 (s, 3H), 3.14 (m, 4H), 3.64 - 3.74 (m, 4H), 5.16 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 7.24 - 7.41 (m, 3H), 7.41 - 7.62 (m, 5H), 7.69 (m, 1H), 7.86 (d, J = 7.7 Hz, 1H), 9.14 (d, J = 8.8 Hz, 1H), 11.00 (s, 1H). Example 145: Example 145 step a:
[0365] [0365] A solution of 2-chloro-5-fluoronicotinic acid (1050 mg, 6 mmol) and morpholine (3 mL) in DMF (15 mL) was stirred for 1 hour at 120°C. The solvent was removed to yield 5-fluoro-2-morpholinicotinic acid as a white solid (904 mg, 67%). ESI-MS m/z: 227.1 [M+H]+. Example 145 step b:
[0366] [0366] A solution of 5-fluoro-2-morpholinonicotinic acid (904 mg, 4 mmol) and H2SO4 (2 mL) in EtOH (50 mL) was stirred for 18 hours at 80°C. Then the pH was adjusted to 9, extracted with EtOAc(3x), dried Na2SO4, filtered to yield ethyl 5-fluoro-2-morpholinonicotinate as a white solid (762 mg, 75%). ESI-MS m/z: 255.1 [M+H]+. Example 145 step c:
[0367] [0367] A solution of ethyl 5-fluoro-2-morpholinonicotinate (762 mg, 3 mmol) and NH2NH2.H2O (3 mL) in EtOH (10 mL) was stirred for 18 hours at 80°C. The solvent was removed and washed with Et2O (20 mL) to yield 5-fluoro-2-morpholinicotinohydrazide as a white solid (480 mg, 67%). ESI-MS m/z: 241.2 [M+H]+. Example 145 step d:
[0368] [0368] Example 145 was prepared using a procedure similar to that used to prepare Example 21 where 5-fluoro-2-morpholinicotinohydrazide was used in place of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 500.1[M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.09
[0369] [0369] Example 146 was prepared using a procedure similar to that used to prepare Example 20 where 2-morpholino-5-(trifluoromethyl)nicotinic acid, which was prepared similarly to 3-(piperidin-1-yl)isonicotinic acid from Example 141 step a, was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 550.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.31 (d, J = 3.7 Hz, 4H), 3.68 (m, 4H), 5.14 (d, J = 6.1 Hz, 1H ), 7.19 - 7.39 (m, 3H), 7.41 - 7.57 (m, 5H), 7.66 (m, 1H), 8.15 (d, J = 2.4 Hz, 1H), 8.66 (m, 1H), 9.21 (s, 1H), 10.97 (s, 1H). Example 147: Example 147 step a:
[0370] [0370] A solution of 4-fluoro-2-(trifluoromethyl)benzoic acid (500 mg, 2.5 mol), HATU (1.90 g, 5 mmol), DIPEA (650 mg, 5 mmol) and BnOH (200 µL) in DMF (10 mL) was stirred for 0.5 hour. To it was added water, extracted by EtOAc to give 300 mg (crude) of benzyl 4-fluoro-2-(trifluoromethyl)benzoate as yellow oil, which was used directly in the next step. Example 147 step b:
[0371] [0371] A solution of benzyl 4-fluoro-2-(trifluoromethyl)benzoate (300 mg, crude) in morpholine (5 mL) was stirred for 1 hour at 100 °C. To the mixture was added water and extracted by EA to give the desired compound benzyl 4-morpholino-2-(trifluoromethyl)benzoate as yellow oil (1.07 g, crude). ESI-MS m/z: 366.2 [M+H]+. Example 147 step c:
[0372] [0372] A solution of benzyl 4-morpholino-2-(trifluoromethyl)benzoate (1.07 g, crude), NH 2 NH 2 .H 2 O (10 ml) in EtOH (10 ml) was stirred at 80°C for 1 hour. The solvent was removed and the crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound 4-morpholino-2-(trifluoromethyl)benzohydrazide as a white solid (139 mg). ESI-MS m/z: 290.1 [M+H]+. Example 147 step d:
[0373] [0373] Example 147 was prepared using a procedure similar to that used to prepare Example 21 where 4-morpholino-2-(trifluoromethyl)benzohydrazide was used in place of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 549.2[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ3.32 -
[0374] [0374] A solution of 2-chloro-3-fluorobenzoic acid (1 g, 5.75 mmol) and H2SO4 (1 mL) in EtOH (10 mL) was refluxed for 16 hours. It was concentrated and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield ethyl 2-chloro-3-fluorobenzoate as a yellow oil (1.1 g, 95%). ESI-MS m/z: 202.9[M+H]+. Example 148 step b:
[0375] [0375] A solution of ethyl 2-chloro-3-fluorobenzoate (1.1 g, 5.44 mmol) in morpholine (neat) (6 ml) was stirred overnight at 120°C. It was concentrated in vacuo and the crude product was purified by preparative TLC (PE/EA=2/1) to yield ethyl 3-fluoro-2-morpholinobenzoate as a yellow solid (0.25 g, 18%). ESI-MS m/z: 254.0[M+H]+. Example 148 step c:
[0376] [0376] A solution of ethyl 3-fluoro-2-morpholinobenzoate (0.25 g, 0.99 mmol) and NH2NH2. H2O (1 mL) in EtOH (10 mL) was refluxed overnight. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield 3-fluoro-2-morpholinobenzohydrazide as a white solid (0.16 g, 68%). ESI-MS m/z: 240.0[M+H]+. Example 148 step d:
[0377] [0377] Example 148 was prepared using a procedure similar to that used to prepare Example 21 where 3-fluoro-2-morpholinobenzohydrazide was used in place of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 499.0[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.02 (m, 4H), 3.55 - 3.73 (m, 4H), 5.19 (d, J = 8.5 Hz, 1H), 7 .24 - 7.62 (m, 11H), 7.62 - 7.74 (m, 1H), 9.18 (d, J = 8.6 Hz, 1H), 11.02 (s, 1H). Examples 149 and 150:
[0378] [0378] Examples 149 and 150 were prepared using a procedure similar to that used to prepare Example 20 where 2-fluoro-6-morpholinonicotinic acid and 6-fluoro-2-morpholinonicotinic acid, which were prepared similarly to 3-fluoro -5-morpholinopicolinic acid and 5-
[0379] [0379] A solution of 6-fluoro-2-morpholinicotinic acid, which was prepared similarly to 5-fluoro-2-morpholinnicotinic acid described in Example 145 step a, (280 mg, 1.22 mmol), tert. - butyl (161 mg, 1.22 mmol), HATU (464 mg, 1.22 mmol) and DIPEA (0.34 mL, 2.04 mmol) in DMF (5 mL) was stirred for 1 hour at room temperature. It was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield tert-butyl 2-(6-fluoro-2-morpholinonicotinoyl)hydrazine-1-carboxylate as a white solid (400 mg, 96%). ESI-MS m/z: 341.2 [M+H]+. Example 151 step b:
[0380] [0380] A solution of tert-butyl 2-(6-fluoro-2-morpholinonicotinoyl)hydrazine-1-carboxylate (400 mg, 1.18 mmol) and conc. (0.4 ml) in EA (2 ml) was stirred for 1 hour. It was concentrated, adjusted to pH=7-8 with saturated aqueous NaHCO3. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield 6-fluoro-2-morpholinonicotinohydrazide as a pale yellow solid (210 mg.75%). ESI-MS m/z: 241.2 [M+H]+. Example 151 step c:
[0381] [0381] CDI (160 mg, 0.96 mmol) was added to a solution of (S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin- 2-one (A) from Example 136 steps f/or i (242 mg, 0.96 mmol), in MeCN (3 mL) and DMF (0.6 mL), then stirred for 1 hour at room temperature. Then 6-fluoro-2-morpholinonicotinohydrazide (210 mg, 0.88 mmol) was added and then stirred for 48 hours at room temperature. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield (S)-2-(6-fluoro-2-morpholinonicotinoyl)-N-(2-oxo-5-phenyl-2,3 -dihydro-1H-benzo[e][1,4]diazepin-3-yl)hydrazine-1-carboxamide as a pale yellow solid (300 mg). ESI-MS m/z: 518.2 [M+H]+. Example 151 step d:
[0382] [0382] A solution of (S)-2-(6-fluoro-2-morpholinonicotinoyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4] diazepin-3-yl)hydrazine-1-carboxamide (300 mg, 0.58 mmol), TsCl (166 mg, 0.87 mmol) and TEA (117 mg, 1.16 mmol) in DCM (5 mL) was stirred for 1 hour before being concentrated. The crude product was purified by preparative HPLC (MeCN/H2O) to yield (S)-3-((5-(6-fluoro-2-morpholinopyridin-3-yl)-1,3,4-oxadiazol-2-yl )amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one as a white solid (59mg, 20%). ESI-MS m/z: 500.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.11 – 3.23 (m, 4H), 3.66 (m, 4H), 5.14 (d, J = 8.6 Hz, 1H), 6 .70 (m, 1H), 7.18 - 7.38 (m, 3H), 7.41 - 7.59 (m, 5H), 7.67 (m, 1H), 8.08 (m, 1H ), 9.14 (d, J = 8.6 Hz, 1H), 10.96 (s, 1H). Example 152: Example 152 step a:
[0383] [0383] A solution of 2-morpholino-4-(trifluoromethyl)benzoic acid (1.0 g, 0.35 mol), H2SO4 (3 mL) in EtOH (10 mL) was stirred for 4 hours at 80°C. It was diluted with water, extracted with EA(x3), washed with brine (x2). The organic layer was dried and concentrated to yield 869 mg (crude) of ethyl 2-morpholino-4-(trifluoromethyl)benzoate as yellow oil, which was used directly in the next step. ESI-MS m/z: 304.2 [M+H]+. Example 152 step b:
[0384] [0384] A solution of the compound from step 1 (869 mg, 2.87 mmol) and NH2NH2.H2O (5 mL) in EtOH (15 mL) was refluxed 13 hours. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a white solid (651 mg, 78%). ESI-MS m/z: 290.1 [M+H]+. Example 152 step c:
[0385] [0385] CDI (180 mg, 0.80 mmol) was added to a solution of (S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin- 2-one (A) from Example 136 steps f/or i (200 mg, 0.80 mmol) in MeCN (3 mL) and DMF (0.6 mL) and then stirred for 1 hour. The step b compound (315 mg, 1.10 mmol) was added and then stirred for 72 hours. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a light yellow solid (283 mg, 63%). ESI-MS m/z: 567.3 [M+H]+. Example 152 step d:
[0386] [0386] A solution of the compound from step c (283 mg, 0.50 mmol), TsCl (285 mg, 0.75 mmol) and TEA (0.5 mL) in DCM (5 mL) was stirred for 16 hours before to be concentrated. The crude product was purified by preparative HPLC (MeCN/H2O) to yield the title compound as a pale yellow solid (205mg, 75%). ESI-MS m/z: 549.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.95 (dd, J = 6.3, 3.0 Hz, 4H), 3.71 (dd, J = 5.7, 3.5 Hz, 4H) , 5.18 (d, J = 8.5 Hz, 1H), 7.18 - 7.63 (m, 10H), 7.67 (ddd, J = 8.5, 7.1, 1.7 Hz , 1H), 7.86 - 7.98 (m, 1H), 9.26 (d, J = 8.6 Hz, 1H), 10.97 (s, 1H). Example 153: Example 153 step a:
[0387] [0387] A solution of morpholine (0.85 g, 9.8 mmol) in DMF (20 mL) was added dropwise to methyl 2,6-dichloronicotinate (2 g, 9.8 mmol) in DMF (100 mL ). It was stirred for 1 hour at room temperature. The mixture was diluted with water, extracted with EA(x3) and washed with brine (x2). The organic layer was dried and concentrated. The residue was chromatographed (silica gel, PE:EA =10:1) to yield methyl 6-chloro-2-morpholinonicotinate as a pale yellow solid (0.6 g, 24%). ESI-MS m/z: 257.2 [M+H]+. Example 153 step b:
[0388] [0388] A solution of methyl 6-chloro-2-morpholinonicotinate (0.6 g, 2.34 mmol), Zn(CN) 2 (0.54 g, 4.68 mmol), Pd(PPh3) 4 ( 0.53 g, 0.46 mmol) in DMF (30 mL) was stirred for 2 hours at 80 °C under nitrogen. It was diluted with EA and washed with water (x2). The organic layer was dried, concentrated and purified by preparative TLC (PE/EA=3:1) to yield methyl 6-cyano-2-morpholinonicotinate. ESI-MS m/z: 248.2[M+H]+. Example 153 step c:
[0389] [0389] A solution of methyl 6-cyano-2-morpholinonicotinate, LiOH (0.1 g, 2.68 mmol) in THF (5 mL) and water (2 mL) was stirred at room temperature for 5 hours. The solvent was removed and the crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield 6-cyano-2-morpholinonicotinic acid as a white solid (0.4g). ESI-MS m/z: 234.2 [M+H]+. Example 153 step d:
[0390] [0390] Example 153 was prepared using a procedure similar to that used to prepare Example 151 where 6-cyano-2-morpholinonicotinic acid was used in place of 6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z: 507.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.21 (m, 4H), 3.71 (m, 4H), 5.19 (s, 1H), 7.33 (m, 3H), 7.50 (m, 5H), 7.62 (d, J = 7.8 Hz, 1H), 7.69 (m, 1H), 8.16 (d, J = 7.7 Hz, 1H), 9.38 (s, 1H), 10.91 (s, 1H). Example 154:
[0391] [0391] A solution of compound 1 (940 mg, 4 mmol) and H2SO4 (2 mL) in EtOH (20 mL) was stirred for 18 hours at 80°C. Then it was adjusted to pH 8~9, extracted with EA(3x), dried Na2SO4, filtered and concentrated to yield the desired compound as a white solid (1052 mg, 100%). ESI-MS m/z: X [M+H]+. Example 154 step b:
[0392] [0392] A solution of the compound from step a (526 mg, 2 mmol), cyclopropylboronic acid (860 mg, 10 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol) and K2CO3 (550 mg, 4 mmol ) in dioxane (12 mL) was heated to 70°C by microwave for 1.5 hours. Then it was poured into water and extracted with EA(3x). The residue was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a brown oil. (315 mg, 70%). ESI-MS m/z: 225.9 [M+H]+. Example 154 step c:
[0393] [0393] A solution of the compound from step b (315 mg,1.4 mmol) in morpholine (10 mL) was stirred for 2 hours at 80 °C. The solvents were removed and it was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a brown oil. (331 mg, 86%). ESI-MS m/z: 277.2 [M+H]+. Example 154 step d:
[0394] [0394] Example 154 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 6-cyclopropyl-2-morpholinonicotinate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 522.4 [M+H]+. 1H NMR (300 MHz, Methanol-d4) δ 0.87 - 1.13 (m, 4H), 2.04 (m, 1H), 3.22 (m, 4H), 3.77 (m, 4H) , 4.82 (s, 1H), 5.28 (s, 1H), 6.92 (d, J = 7.9 Hz, 1H), 7.22 - 7.71 (m, 9H), 7, 87 (d, J = 7.9 Hz, 1H). Example 155: Example 155 step a:
[0395] [0395] A solution of 2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (1.0 g, 5.78 mmol), H2SO4 (5 mL) in EtOH (20 mL) was stirred at 80°C for 4 hours. Then H2O (100 mL) was added to the mixture and extracted with EA(x3). The organic layer was dried and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield ethyl 2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate as yellow oil (950 mg, 81% ). ESI-MS m/z: 201.9 [M+H]+. Example 155 step b:
[0396] [0396] A solution of ethyl 2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (402 mg, 2.0 mmol) in morpholine (5 mL) was stirred at 100 °C for 2 hours. Then H2O (20 mL) was added to the mixture and extracted with EA(x3). The organic layer was dried and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield ethyl 2-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylate as yellow oil (450 mg, 89% ). ESI-MS m/z: 253.0 [M+H]+. Example 155 step c:
[0397] [0397] A solution of ethyl 2-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylate (400 mg, 1.58 mmol), iodomethane (1127 mg, 7.93 mmol), t-BuONa ( 303 mg, 3.16 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. Then H2O (20 mL) was added to the mixture and extracted with EA(x3). The organic layer was dried and flash purified to yield ethyl 1-methyl-2-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylate as yellow oil (320 mg, 76%). ESI-MS m/z: 267.0 [M+H]+. Example 155 step d:
[0398] [0398] Example 155 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 1-methyl-2-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylate was used in place of 2-morpholino Ethyl -4-(trifluoromethyl)benzoate. ESI-MS m/z: 512.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.21-3.23 (d, J = 6.0 Hz, 4H), 3.67-3.70 (m, 4H), 3.88 (s, 1H), 5.12-5.15 (d, J = 9.0 Hz, 1H), 6.40-6.42 (d, J = 6.0 Hz, 1H), 7.26-7.37 (m, 3H), 7.44 - 7.57 (m, 5H), 7.65 - 7.68 (m, 1H), 7.70-7.86 (m, 1H), 9.01-9 .04 (m, 1H), 10.96 (s, 1H). Example 156: Example 156 step a:
[0399] [0399] Ethyl 2-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylate, from Example 155 step b, (500 mg, 1.98 mmol) was dissolved in DMF (10 mL) and cooled in a bath. ice cold. NaH (105 mg, 2.62 mmol) was added and then SEMCl (420 mg, 2.52 mmol) was added. The mixture was warmed to room temperature and stirred for 2 hours. Water (10 mL) was added and the mixture was extracted with EA (20 mL ×3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated to yield 2-chloro-6-oxo-1-((2-
[0400] [0400] A solution of ethyl 2-chloro-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carboxylate (510 mg, 1.33 mmol) and NH2NH2 .H2O (10 mL) in EtOH (10 mL) was refluxed for 5 hours. The mixture was then cooled to room temperature and concentrated. The residue was purified by C18 reversed phase column chromatography (MeCN/H2O) to give 2-chloro-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carbohydrazide as a yellow solid (300 mg, 61%). ESI-MS m/z: 369.2 [M+H]+. Example 156 step c:
[0401] [0401] CDI (132 mg, 0.81 mmol) was added to a solution of (S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin- 2-one (A) from Example 136 steps f/or i (186 mg, 0.74 mmol) in MeCN (3 mL) and DMF (0.6 mL) and then stirred for 1 hour. Then 2-chloro-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carbohydrazide (300 mg, 0.81 mmol) was added and then stirred for 72 hours and then purified by C18 reversed phase column chromatography (MeCN/H2O) to yield (S)-2-(2-morpholino-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1 ,6-dihydropyridine-3-carbonyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)hydrazine-1-carboxamide as an off-white solid (300 mg, 63%). ESI-MS m/z: 646.4 [M+H]+. Example 156 step d:
[0402] [0402] A solution of (S)-2-(2-morpholino-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carbonyl)-N-(2 -oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)hydrazine-1-carboxamide (300 mg, 0.46 mmol), TsCl (132.8 mg, 0.69 mmol), DMAP(20 mg) and TEA (0.5 mL) in DCM (5 mL) was stirred for 2 hours and then concentrated. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield (S)-3-((5-(2-morpholino-6-oxo-1-((2-(trimethylsilyl)ethoxy)) methyl)-1,6-dihydropyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4] diazepin-2-one as a yellow solid (200 mg, 69%). ESI-MS m/z: 628.4 [M+H]+. Example 156 step e:
[0403] [0403] (S)-3-((5-(2-morpholino-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridin-3-yl)-1,3 ,4-oxadiazol-2-yl)amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (200 mg, 0.32 mmol) was dissolved in DCM (8 mL) and cooled to 0 °C and TFA (4 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was dissolved in DCM and then concentrated for two cycles. The residue was purified by preparative HPLC to yield (S)-3-((5-(2-morpholino-6-oxo-1,6-
[0404] [0404] Example 157 was prepared using a procedure similar to that used to prepare Example 151 where 4-cyano-2-morpholinobenzoic acid, which was prepared in Example 131, was used in place of 6-fluoro-2-morpholinicotinic acid. ESI-MS m/z: 506.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.94-2.97 (m, 4H), 3.67-3.74 (m, 4H), 5.20 (d, J = 8.3 Hz, 1H), 7.34 -7.75 (m, 11H), 7.86 (d, J = 8.0 Hz, 1H), 9.31 (d, J = 8.6 Hz, 1H), 11, 00 (s, 1H). Example 158: Example 158 step a:
[0405] [0405] A solution of ethyl 2-chloro-5-cyano-6-methylnicotinate (1 g, 4.5 mmol) and K2CO3 (1.24 g, 9 mmol) in morpholine (5 mL) was stirred for 3 hours at 100 oC. It was diluted with water and extracted with EA(x3). The organic layer was concentrated and the residue was purified by silica gel chromatography with EtOAc/PE to yield 970 mg of the desired compound as a yellow solid. ESI-MS m/z: 276.2 [M+H]+. Example 158 step b:
[0406] [0406] A solution of the compound from step 1 (100 mg, 0.36 mmol), LiOH.H2O (31 mg, 0.73 mmol), in THF (5 mL) and water (2 mL) was stirred at room temperature. during the night. Then adjusted the pH to 2 by 0.5M HCl. Solvent has been removed. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a pink solid (80 mg, 89%). ESI-MS m/z: 248.2 [M+H]+. Example 158 step c:
[0407] [0407] Example 158 was prepared using a procedure similar to that used to prepare Example 151 where 5-cyano-6-methyl-2-morpholinonicotinic acid was used in place of 6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z: 521.5 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.55 (s, 3H), 3.33 - 3.40 (m, 4H), 3.66 (m, 4H), 5.14 (d, J = 8.5 Hz, 1H), 7.21 - 7.42 (m, 3H), 7.39 - 7.59 (m, 5H), 7.67 (m, 1H), 8.16 (s, 1H ), 9.17 (d, J = 8.5 Hz, 1H), 10.98 (s, 1H). Example 159:
[0408] [0408] A solution of 4-fluoro-2-morpholinobenzoic acid, prepared in Example 127 step a (2.25 g, 10 mmol) and H2SO4 (10 mL) in EtOH (50 mL) was stirred for 18 hours at 80 °C . The solvent was removed, H2O(100ml) was added and extracted with EA(3x). The water layer was adjusted to pH 9~10 and extracted with EA(3x). The organic layers were combined and concentrated to yield ethyl 4-fluoro-2-morpholinobenzoate as a white solid (1270 mg, 50%). ESI-MS m/z: 254.1 [M+H]+. Example 159 step b:
[0409] [0409] Example 159 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 4-fluoro-2-morpholinobenzoate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 499.3 [M+H]+. 1H NMR (300 MHz, Methanol-d4) δ 2.94 – 3.04 (m, 4H), 3.77 – 3.87 (m, 4H), 5.30 (s, 1H), 6.82 – 7.02 (m, 2H), 7.23 - 7.83 (m, 10H). Example 160:
[0410] [0410] A solution of methyl 5-bromo-3-fluoropicolinate (1.0 g, 4.29 mmol), K2CO3 (1.2 g, 8.58 mmol) in morpholine (10 mL) was stirred at 120 °C for 2 hours. Then H2O (150 mL) was added to the mixture and extracted with EA(x3). The organic layer was dried and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a yellow oil (950 mg, 74%). ESI-MS m/z: 300.9 [M+H]+. Example 160 step b:
[0411] [0411] A solution of the compound from step a (900mg, 3.00mmol), Pd(PPh3)4 (693mg, 0.60mmol), Zn(CN)2 (696mg, 6.00mmol) in DMF (5 mL) was stirred at 120 °C for 2 hours. Then H2O (20 ml) was added to the mixture and extracted with EA(x3). The organic layer was dried and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a yellow oil (330 mg, 44%). ESI-MS m/z: 248.2 [M+H]+. Example 160 step c:
[0412] [0412] Example 160 was prepared using a procedure similar to that used to prepare Example 152 where methyl 5-cyano-3-morpholinopicolinate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 507.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.02-3.04 (m, 4H), 3.71-3.73 (m, 4H), 5.19-5.21 (d, J = 8 .0 Hz, 1H), 7.26-7.30 (m, 1H), 7.34-7.36 (m, 2H), 7.44 - 7.55 (m, 5H), 7.65 - 7.70(m, 1H), 8.13 (s, 1H), 8.72 (s, 1H), 9.42-9.45 (m, 1H), 10.98 (s, 1H). Example 161: Example 161 step a:
[0413] [0413] To a solution of methyl 5-chloropyrazine-2-carboxylate (1.0 g, 5.79 mmol) and morpholine (756 mg, 8.69 mmol) in DMSO (10 mL) was added K2CO3 (2. 4 g, 17.4 mmol). The mixture was heated at 100 °C for 4 hours and then cooled to room temperature. Water (20 ml) was added and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with water (20 ml) and brine (20 ml). It was then dried over anhydrous Na 2 SO 4 and concentrated to yield the desired product as a yellow solid (850 mg) which was used in the next step directly. ESI-MS m/z: 224.1 [M+H]+.
[0414] [0414] Example 161 was prepared using a procedure similar to that used to prepare Example 152 where methyl 5-morpholinopyrazine-2-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 483.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.62 – 3.79 (m, 8H), 5.17 (d, J = 7.8 Hz, 1H), 7.18 – 7.80 (m, 9H), 8.42 (s, 1H), 8.63 (s, 1H), 9.13 (d, J = 8.2 Hz, 1H), 10.83 - 10.93 (m, 1H). Example 162: Example 162 step a:
[0415] [0415] A solution of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (0.5 g, 1.97 mmol) in morpholine (5 mL) was stirred for 1 hour at room temperature. The mixture was concentrated. The residue was purified by preparative TLC (PE:EA =2:1) to yield the desired compound as a pale yellow solid (0.6 g, 100%). ESI-MS m/z: 306.2 [M+H]+. Example 162 step b:
[0416] [0416] A solution of the compound from step 1 (600 mg, 1.97 mmol), LiOH (189 mg, 7.88 mmol) in THF (5 mL) and water (5 mL) was stirred at 70 °C for 3 hours . The solvent was removed and the crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a white solid (0.45 g, 82%). ESI-MS m/z: 278.1 [M+H]+. Example 162 step c:
[0417] [0417] Example 162 was prepared using a procedure similar to that used to prepare Example 151 where 4-morpholino-2-(trifluoromethyl)pyrimidine-5-carboxylic acid was used in place of 6-fluoro-2-morpholinicotinic acid. ESI-MS m/z: 551.6 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.50 (m, 4H), 3.70 (m, 4H), 5.18 (d, J = 8.0 Hz, 1H), 7.22 - 7 .42 (m, 3H), 7.42 - 7.62 (m, 5H), 7.68 (m, 1H), 8.71 (s, 1H), 9.31 (d, J = 8.4 Hz, 1H), 11.02 (s, 1H). Example 163: Example 163 step a:
[0418] [0418] A mixture of 2-aminopyridine (940 mg, 10 mmol) and ethyl glyoxalate solution (50% solution in toluene) (2 mL, 10 mmol) was stirred at room temperature for 2 min. THF (20 mL) and DABCO (1.12 g, 10 mmol) were then added. The reaction mixture was cooled to 0–5 °C and TMSCN (1.25 mL, 1 mmol) was added. The mixture was heated under microwave irradiation at 120°C. After completion of a reaction (monitored by TLC, 15 min), the solvent was evaporated under vacuum. The residue was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound (600 mg) as a yellow oil. ESI-MS m/z: 206.0 [M+H]+. Example 163 step b:
[0419] [0419] A solution of the compound from step a (600mg, 2.92mmol), 1-bromo-2-(2-bromoethoxy)ethane (1.01g, 4.39mmol) and Cs2CO3 (2.85g, 8.76 mmol) in DMA (20 mL) was stirred for 4 hours at 120 °C. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a yellow solid (500 mg). ESI-MS m/z: 276.2 [M+H]+. Example 163 step c:
[0420] [0420] Example 163 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 3-morpholinoimidazo[1,2-a]pyridine-2-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI-MS m/z: 521.5 [M+H]+. 1H NMR (300 MHz, Methanol-d4) δ 3.90 (t, J = 4.6 Hz, 4H), 5.34 (s, 1H), 7.08 (td, J = 6.8, 1, 2 Hz, 1H), 7.26 - 7.33 (m, 1H), 7.34 - 7.70 (m, 10H), 8.46 (dt, J = 7.0, 1.2 Hz, 1H ).
[0421] [0421] A solution of methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate (1.0 g, 5.41 mmol) and Pd/C (200 mg) in MeOH (60 mL) was stirred for 1 hour at 25°C. Pd/C was filtered off and the filtrate was concentrated to yield the desired compound as a white solid (800 mg, 95%). Example 164 step b:
[0422] [0422] A solution of the compound from step a (775 mg, 5 mmol), 1-chloro-2-(2-chloroethoxy)ethane (1420 mg, 10 mmol), KI (1660 mg, 10 mmol) and K2CO3 (2070 mg.15 mmol) in DMF (60 mL) was stirred for 3 hours at 120 °C. The solvent was removed and it was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a pale yellow solid. (450 mg, 40%). ESI-MS m/z: 226.0 [M+H]+. Example 164 step c:
[0423] [0423] Example 164 was prepared using a procedure similar to that used to prepare Example 152 where methyl 1-methyl-4-morpholino-1H-pyrazole-3-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI-MS m/z: 485.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.94 (m, 4H), 3.68 (m, 4H), 3.86 (d, J = 2.2 Hz, 3H), 5.09 - 5 .19 (m, 1H), 7.23 - 7.41 (m, 3H), 7.38 - 7.75 (m, 7H), 9.05 (m, 1H), 10.91 (s, 1H ). Example 165: Example 165 step a:
[0424] [0424] A solution of ethyl 4-chloropyrimidine-5-carboxylate (0.90 g, 5.0 mmol) in morpholine (5 mL) was stirred for 1 hour at room temperature. The mixture was concentrated. The residue was purified by preparative TLC (PE:EA =2:1) to yield the desired compound as a pale yellow solid (869 mg, 74%). ESI-MS m/z: 238.1 [M+H]+. Example 165 step b:
[0425] [0425] Example 165 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 2-morpholinopyrimidine-5-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 483.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.69 (d, J = 4.9 Hz, 4H), 3.81 (t, J = 4.8 Hz, 4H), 5.14 (d, J = 8.4 Hz,
[0426] [0426] Example 166 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidine-5-carboxylate, which was prepared similarly to ethyl 2-morpholinopyrimidine-5-carboxylate, in Example 165 step a, was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 509.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.66 (t, J = 6.6 Hz, 2H), 1.84 (dd, J = 8.5, 4.3 Hz, 2H), 3.16 (dd, J = 13.4, 2.5 Hz, 2H), 4.29 (d, J = 13.0 Hz, 2H), 4.37 - 4.55 (m, 2H), 5.14 ( d, J = 8.5 Hz, 1H), 7.24 - 7.40 (m, 3H), 7.43 - 7.58 (m, 5H), 7.68 (ddd, J = 8.4, 7.2, 1.6 Hz, 1H), 8.74 (s, 2H), 9.06 (d, J = 8.5 Hz, 1H), 10.82 - 11.07 (m, 1H). Example 167: Example 167 step a:
[0427] [0427] A solution of morpholine (0.79 g) in DMF (20 mL) was added dropwise to ethyl 2,4-dichloropyrimidine-5-carboxylate (2 g, 9.1 mmol) in DMF (100 mL) . It was stirred for 1 hour at room temperature. The mixture was diluted with water, extracted with EA(x3), washed with brine (x2). The organic layer was dried and concentrated. The residue was chromatographed (silica gel, PE:EA =10:1) to yield the desired compound as a pale yellow solid (1.0 g, 41%). ESI-MS m/z: 272.2 [M+H]+. Example 167 step b:
[0428] [0428] A solution of the compound from step a (0.8 g, 3.0 mmol), cyclopropylboronic acid (360 mg, 4.2 mmol), Pd(DtBPF)Cl2 (196 mg, 0.3 mmol) and Cs2CO3 (1.47 g, 4.5 mmol) in dioxane (30 mL) was stirred for 3 hours at 100 °C under nitrogen. It was diluted with EA, washed with water (x2). The organic layer was dried, concentrated and purified by preparative TLC (PE/EA=3:1) to yield the desired compound as a yellow solid (420 mg, 50%). ESI-MS m/z: 278.2 [M+H]+. Example 167 step c:
[0429] [0429] A solution of the compound from step b (400mg, 1.44mmol), LiOH (140mg, 5.78mmol) in MeOH (2mL) and water (2mL) was stirred at room temperature for 5 hours. The solvent was removed and the crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a white solid (200 mg, 50%). ESI-MS m/z: 250.2 [M+H]+. Example 167 step d:
[0430] [0430] Example 167 was prepared using a procedure similar to that used to prepare Example 151 where 2-cyclopropyl-4-morpholinopyrimidine-5-carboxylic acid was used in place of 6-fluoro-2-morpholinicotinic acid. ESI-MS m/z: 523.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.85 – 1.10 (m, 4H), 2.06 (m, 1H), 3.37 (q, J = 3.6 Hz, 4H), 3 .64 (m, 4H), 5.13 (d, J = 8.5 Hz, 1H), 7.22 - 7.41 (m, 3H), 7.41 - 7.60 (m, 5H), 7.67 (m, 1H), 8.38 (s, 1H), 9.11 (d, J = 8.5 Hz, 1H), 10.98 (s, 1H). Example 168:
[0431] [0431] Example 168 was prepared using a procedure similar to that used to prepare Example 152 where methyl 5-bromo-3-morpholinopicolinate, prepared in Example 160 step a, was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI-MS m/z: 560.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.03 (t, J = 4.6 Hz, 4H), 3.72 (t, J = 4.6 Hz, 4H), 5.20 (d, J = 8.5 Hz, 1H), 7.25 - 7.60 (m, 8H), 7.69 (m, 1H), 7.86 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 1.8 Hz, 1H), 9.27 (d, J = 8.6 Hz, 1H), 10.99 (d, J = 12.7 Hz, 1H). Example 169:
[0432] [0432] A solution of methyl 5-bromo-3-morpholinopicolinate, prepared in Example 160 step a, (753 mg, 2.5 mmol), K2CO3 (1.73 g, 12.5 mmol), cyclopropylboronic acid (1 .07 g, 12.5 mmol) and Pd(dppf)Cl 2 (183 mg, 0.25 mmol) in dioxane (10 mL) was stirred for 1 hour at 80 °C in the microwave. It was concentrated in vacuo and diluted with water (100 mL). The resulting solution was extracted with EA (100 mLx3). The organic layer was dried and concentrated to yield 1.0 g (crude) of the desired compound, which was used directly in the next step. ESI-MS m/z: 263.0 [M+H]+. Example 169 step b:
[0433] [0433] Example 169 was prepared using a procedure similar to that used to prepare Example 152 where methyl 5-cyclopropyl-3-morpholinopicolinate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 522.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.89 (dt, J = 6.8, 3.3 Hz, 2H), 1.07 (dt, J = 8.6, 3.2 Hz, 2H) , 2.04 (tt, J = 8.7, 5.0 Hz, 1H), 2.98 (t, J = 4.6 Hz, 4H), 3.70 (t, J = 4.5 Hz, 4H), 5.19 (d, J = 8.7 Hz, 1H), 7.22 - 7.41 (m, 4H), 7.44 - 7.58 (m, 5H), 7.69 (ddd , J = 8.5, 7.1, 1.8 Hz,
[0434] [0434] A solution of 2,4,6-trifluorobenzoic acid (2.00 g, 10.1 mmol), H2SO4 (3 mL, 6 mmol) in EtOH (10 mL) was stirred for 12 hours at 80 °C. It was diluted with water, extracted with EA(x3), washed with brine (x2). The organic layer was dried and concentrated to yield 2.34 g (crude) of the desired compound as yellow oil, which was used directly in the next step. ESI-MS m/z: need [M+H]+. Examples 170 and 171 step b:
[0435] [0435] A solution of ethyl 2,4,6-trifluorobenzoate (2.34 g, 11.5 mmol), morpholine (999 mg, 11.5 mmol) and K2CO3 (2.76 g, 20.0 mmol) in DMF (10 mL) was stirred for 12 hours at 100 °C. It was diluted with water, extracted with EA(x3), washed with brine (x2). The organic layer was dried and concentrated to yield 2.31 g (crude) mixture of the desired compound as yellow oil, which was used directly in the next step. ESI-MS m/z: 272.1 [M+H]+. Examples 170 and 171 step c:
[0436] [0436] A solution of the compound from step b (2.31 g, 2.94 mmol) and NaOH (500 mg) in MeOH (5 mL) and water (5 mL) was stirred for 5 hours. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a white solid (1.79 g, 86%). ESI-MS m/z: 244.1 [M+H]+. Examples 170 and 171 step d:
[0437] [0437] Examples 170 and 171 were prepared using a procedure similar to that used to prepare Example 151 where 2,6-difluoro-4-morpholinobenzoic acid and 2,4-difluoro-6-morpholinobenzoic acid, respectively, were used in place of 6-fluoro-2-morpholinicotinic acid. Example 170: ESI-MS m/z: 517.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ3.30 (m, 4H), 3.72 (m, 4H), 5.15 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 12.9 Hz, 2H), 7.25 - 7.38 (m, 3H), 7.43 - 7.58 (m, 5H), 7.68 (ddd, J = 8.4, 7, 1, 1.7 Hz, 1H), 9.10 (d, J = 8.5 Hz, 1H), 10.99 (s, 1H). Example 171: ESI-MS m/z: 517.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.91 (t, J = 4.6 Hz, 4H), 3.61 (q, J = 3.9 Hz, 4H), 5.16 (d, J = 8.7 Hz, 1H), 6.75 - 7.12 (m, 2H), 7.21 - 7.42 (m, 3H), 7.42 - 7.61 (m, 5H), 7, 64 - 7.77 (m, 1H), 9.17 (d, J = 8.8 Hz, 1H), 10.99 (s, 1H). Example 172:
[0438] [0438] A solution of ethyl 2-chloro-4-morpholinopyrimidine-5-carboxylate, prepared similarly to the method described in Example 145 (0.54 g, 2 mmol), 1H-pyrazole (0.27 g, 4 mmol) and Cs2CO3 (1.30 g, 4 mmol) in DMF (20 mL) was stirred for 1 hour at room temperature. It was diluted with water and extracted with EA(x3). The organic layer was concentrated to yield a yellow solid (0.6 g, 99%). ESI-MS m/z: 304.1 [M+H]+. Example 172 step b:
[0439] [0439] A solution of the compound from step a (0.6 g, 1.98 mmol), LiOH (71 mg, 2.97 mmol), in THF (10 mL) and water (2 mL) was stirred at room temperature. for 16 hours. The solvent was removed and the crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a white solid (200 mg, 37%). ESI-MS m/z: 276.2 [M+H]+. Example 172 step c:
[0440] [0440] Example 172 was prepared using a procedure similar to that used to prepare Example 151 where 4-morpholino-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid was used in place of 6-fluoro- 2- morpholinonicotinic. ESI-MS m/z: 549.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.53 (m, 4H), 3.69 (m, 4H), 5.16 (d, J = 8.3 Hz, 1H), 6.55 – 6 .67 (m, 1H), 7.29 (m, 1H), 7.36 (m, 2H), 7.46 - 7.55 (m, 5H), 7.63 - 7.73 (m, 1H ), 7.86 (d, J = 1.6 Hz, 1H), 8.57 (s, 1H), 8.68 (d, J = 2.7 Hz, 1H), 9.19 (d, J = 8.5 Hz, 1H), 11.01 (s, 1H). Example 173:
[0441] [0441] Example 173 was prepared using a procedure similar to that used to prepare Example 151 where 4-morpholino-2-(1H-1,2,4-triazol-1-yl)pyrimidine-5-carboxylic acid, which was prepared similarly 4-morpholino-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, described in Example 172 step b, was used in place of 6-fluoro-2-morpholinicotinic acid. ESI-MS m/z: 550.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.55 (m, 4H), 3.69 (d, J = 4.7 Hz, 4H), 5.16 (d, J = 3.8 Hz, 1H ), 7.19 - 7.41 (m, 3H), 7.42 - 7.62 (m, 5H), 7.67 (m, 1H), 8.30 (s, 1H), 8.61 ( s, 1H), 9.19 (s, 1H), 9.49 (s, 1H), 10.91 (s, 1H). Example 174: Example 174 step a:
[0442] [0442] A solution of methyl 5-bromo-2-chloronicotinate (5.0 g, 20.0 mmol) in morpholine (20 mL) was stirred for 1 hour at 120 °C. It was concentrated and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a yellow solid (5.4 g, 90%). ESI-MS m/z: 302.9 [M+H]+. Example 174 step b:
[0443] [0443] A solution of the compound from step a (1.3 g, 4.3 mmol), LiOH (517 mg, 21.6 mmol) in THF/H 2 O (10 mL) (1/1) was stirred at room temperature. during the night. The solution was adjusted to pH 4 with 3N HCl and extracted with EA. The solution was concentrated and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired product as an off-white solid (1.1 g, 88%). ESI-MS m/z: 287.0 [M+H]+. Example 174 step c:
[0444] [0444] A solution of the compound from step b (1.1 g, 3.83 mmol), tert-butyl hydrazinecarboxylate (607 mg, 4.59 mmol), HATU (1.75 g, 4.60 mmol), DIPEA (1.48 g, 11.49 mmol) in DMF (20 mL) was stirred at room temperature for 1 hour. The solution was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired product as an off-white solid (1.3 g, 85%). ESI-MS m/z: 403.2 [M+H]+. Example 174 step d:
[0445] [0445] A solution of the compound from step c (1.3g, 3.24mmol), Zn(CN)2 (752mg, 6.28mmol), Pd(PPh3)4 (750mg, 0.62mmol ) in DMF (20 mL) was stirred at 120 °C for 1 hour. The solution was purified by C18 reversed phase column chromatography (MeCN/H2O) yielding tert-butyl 2-(5-cyano-2-morpholinonicotinoyl)hydrazine-1-carboxylate as an off-white solid (1.0 g, 89% ). ESI-MS m/z: 348.3 [M+H]+. Example 174 step e:
[0446] [0446] Example 174 was prepared using a procedure similar to that used to prepare Example 151. tert-Butyl 2-(5-cyano-2-morpholinonicotinoyl)hydrazine-1-carboxylate was used in place of 2-(6-fluoro tert-butyl -2-morpholinonicotinoyl)hydrazine-1-carboxylate. ESI-MS m/z: 507.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.30-3.40 (m, 4H), 3.65-3.67 (m, 4H), 5.14-5.16 (d, J = 6 .0 Hz, 1H), 7.26 - 7.30 (m, 1H), 7.33 - 7.36 (m, 2H), 7.44-7.55 (m, 5H), 7.65 - 7.69 (m, 1H), 8.25 (m, 1H), 8.69 - 8.70 (m, 1H), 9.22-9.24 (d, J = 8.0 Hz, 1H) , 10.99 (s, 1H). Example 175: Example 175 step a:
[0447] [0447] Methyl 5-bromo-2-chloronicotinate (1.2 g, 4.8 mmol) and potassium cyclopropyl trifluoroborate (2.13 g, 14.4 mmol) was dissolved in AcOH (30 mL) and water (30 ml). TFA (0.36 mL, 4.8 mmol) was added. The mixture was stirred at room temperature for 20 minutes. Mn(OAc)3·2H2O (11.6 g, 43.2 mmol) was added and the mixture was heated to 70 °C under a N2 atmosphere. After 48 hours, the mixture was cooled to room temperature and saturated Na2CO3 solution was added and then solid was filtered off. The filtrate was extracted with EA (200 mL×3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (PE:EA = 100:1 to 50:1) to yield the desired product as a white solid (269mg) and starting material (696mg). ESI-MS m/z: 292.0 [M+H]+. Example 175 step b:
[0448] [0448] The compound from step a (269 mg, 0.92 mmol) was dissolved in morpholine (3 mL) and heated at 100 °C for 1 hour. Water was added (10 mL) and the mixture was extracted with EA (20 mL×3) and the combined organic phase was dried and concentrated to yield the desired product as a yellow oil (400 mg,). ESI-MS m/z: 343.1 [M+H]+. Example 175 step c:
[0449] [0449] The compound from step b (400 mg, 1.17 mmol) was dissolved in THF
[0450] [0450] The compound from step c (300 mg, 0.92 mmol) was dissolved in DMF (5 mL) and BocNHNH 2 (242 mg, 1.83 mmol) was added. HATU (697 mg, 1.83 mmol) and DIPEA (0.3 mL) were added. The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added and the mixture was extracted with EA (15 mL×3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by gel chromatography (PE/EA = 3/1) to yield the desired product as a yellow solid (350 mg, 86%). ESI-MS m/z: 441.0 [M+H]+. Example 175 step e:
[0451] [0451] To a stirred solution of the compound from step 4 (350mg, 0.79mmol) and Zn(CN)2 (183mg, 1.58mmol) in DMF (5mL) was added Pd(PPh3)4 (183.28 mg, 0.158 mmol). The mixture was heated at 120 °C for 1 hour under a N2 atmosphere. Then it was cooled to room temperature, saturated FeSO4 solution was added and the mixture was extracted with EA (50 mL ×3). The combined organic phase was washed with water, brine and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to yield the desired compound as a yellow solid (290 mg, 95%). ESI-MS m/z: 388.4 [M+H]+. Example 175 step f:
[0452] [0452] Example 175 was prepared using a procedure similar to that used to prepare Example 151; tert-butyl 2-(5-cyano-6-cyclopropyl-2-morpholinonicotinoyl)hydrazine-1-carboxylate was used in place of tert-butyl 2-(6-fluoro-2-morpholinonicotinoyl)hydrazine-1-carboxylate. ESI-MS m/z: 547.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.95 – 1.23 (m, 4H), 2.24 – 2.48 (m, 1H), 3.18 – 3.43 (m, 4H), 3.64 (t, J = 4.8 Hz, 4H), 5.15 (d, J = 8.2 Hz, 1H), 7.22 - 7.61 (m, 8H), 7.68 (ddd , J = 8.5, 7.0, 1.8 Hz, 1H), 8.12 (s, 1H), 9.17 (d, J = 8.5 Hz, 1H), 10.98 (s, 1H). Example 176:
[0453] [0453] Example 176 was prepared using a procedure similar to that used to prepare Example 151; tert-Butyl 2-(5-cyano-6-ethyl-2-morpholinonicotinoyl)hydrazine-1-carboxylate, which was prepared similarly to 2-(5-cyano-6-cyclopropyl-2-morpholinonicotinoyl)hydrazine-1 - tert-butyl carboxylate as described in Example 175 step e, was used in place of tert-butyl 2-(6-fluoro-2-morpholinonicotinoyl)hydrazine-1-carboxylate. ESI-MS m/z: 535.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.23 (m, 3H),
[0454] [0454] A solution of ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate compound (1.69 g, 10 mmol), 1-bromo-2-(2-bromoethoxy) ethane (3.45 g, 15 mmol) and Cs2CO3 (9.77 g, 30 mmol) in DMA (30 mL) was stirred overnight at 120 °C. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound 700mg (crude). ESI-MS m/z: 240.1 [M+H]+. Example 177 step b:
[0455] [0455] Example 177 was prepared using a procedure similar to that used to prepare Example 152 where methyl 1-methyl-5-morpholino-1H-pyrazole-4-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI-MS m/z: 485.4 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 3.19 (dd, J = 5.7, 3.5 Hz, 4H), 3.83 (d, J = 6.5 Hz, 7H), 5.29 (s, 1H),
[0456] [0456] A solution of 1-methyl-4-nitro-1H-pyrazole-5-carboxylic acid (1.03 g, 6 mmol), EtBr (3 mL) and K2CO3 (1.66 g, 12 mmol) in DMF (30 mL) was stirred for 1 hour at 60 °C. Then it was poured into water and extracted with EA(3x) to yield the desired compound as a pale yellow solid. (995 mg, 83%). ESI-MS m/z: 200.2 [M+H]+. Example 178 step b:
[0457] [0457] A solution of the compound from step a (995 mg, 5 mmol) and Pd/C (200 mg) in EtOH (50 mL) was stirred for 3 hours at 25 °C. Pd/C was filtered off and the filtrate was concentrated to yield the desired compound as a light brown solid. (845 mg, 100%). ESI-MS m/z: 170.2 [M+H]+. Example 178 step c:
[0458] [0458] A solution of the compound from step b (845 mg, 5 mmol), 1-bromo-
[0459] [0459] Example 178 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 1-methyl-4-morpholino-1H-pyrazole-5-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI-MS m/z: 485.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.84 - 2.93 (m, 4H), 3.64 (m, 4H), 3.98 (s, 3H), 5.16 (d, J = 8.3 Hz, 1H), 7.24 - 7.62 (m, 9H), 7.63 - 7.75 (m, 1H), 9.26 (d, J = 8.4 Hz, 1H), 11.01 (s, 1H). Example 179: Example 179 step a:
[0460] [0460] A solution of ethyl 3-aminobenzofuran-2-carboxylate (1.03 g, 5 mmol) and NaH (480 mg, 12 mmol) in DMF (30 mL) was stirred for 0.5 hour at 0 °C Then 1-bromo-2-(2-bromoethoxy)ethane (1.38 g, 6 mmol) was added to the mixture, stirred for 1 hour at room temperature H 2 O (50 mL) and extracted with EA(3x) . The organic layer was concentrated and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a light brown oil. (530 mg, 40%). ESI-MS m/z: 276.2 [M+H]+. Example 179 step b:
[0461] [0461] Example 179 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 3-morpholinobenzofuran-2-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 521.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.32 (m, 4H), 3.74 (m, 4H), 5.17 (d, J = 8.4 Hz, 1H), 7.22 - 7 .75 (m, 12H), 7.86 - 8.00 (m, 1H), 9.31 (d, J = 8.5 Hz, 1H), 11.00 (s, 1H). Example 180: Example 180 step a:
[0462] [0462] A solution of ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate (500 mg, 2.25 mmol), 1-bromo-2-(2-bromoethoxy)ethane (1.38 g , 6 mmol) and
[0463] [0463] Example 180 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 3-morpholinothieno[2,3-b]pyridine-2-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI-MS m/z: 538.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.30 - 3.17 (m, 4H), 3.77 (d, J = 6.8 Hz, 4H), 5.19 (d, J = 8, 2 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.61 - 7.42 (m, 6H) , 7.68 (t, J = 7.6 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 8.66 (d, J = 4.6 Hz, 1H), 9 .40 (d, J = 8.1 Hz, 1H), 11.03 (s, 1H). Example 181: Example 181 step a:
[0464] [0464] A solution of ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate
[0465] [0465] Example 181 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 1-methyl-3-morpholino-1H-pyrazole-4-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI-MS m/z: 485.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.14-3.15 (m, 4H), 3.65-3.67 (m, 4H), 3.77 (s, 3H), 5.07- 5.09 (d, J = 8.0 Hz, 1H), 7.32-7.35 (m, 3H), 7.45-7.51 (m, 6H), 8.04 (s, 1H) , 8.90-8.93 (m, 1H), 10.86-11.07 (m, 1H). Example 182: Example 182 step a:
[0466] [0466] A solution of methyl 3-amino-5-bromothiophene-2-carboxylate
[0467] [0467] Example 182 was prepared using a procedure similar to that used to prepare Example 152 where methyl 5-bromo-3-morpholinothiophene-2-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 566.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.06-3.07 (m, 4H), 3.64-3.70 (m, 4H), 5.09-5.11 (d, J = 8 .0 Hz, 1H), 7.24-7.29 (m, 2H), 7.33-7.35 (m, 2H), 7.41-7.49 (m, 5H), 7.51- 7.68 (m, 1H), 9.11-9.13 (m, 1H), 10.94-10.99 (m, 1H). Example 183:
[0468] [0468] Example 183 was prepared using a procedure similar to that used to prepare Example 20 where 5-cyanothiophene-2-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 427.1 [M+H]+. Example 184:
[0469] [0469] Example 184 was prepared using a procedure similar to that used to prepare Example 20 where 4-(pyrrolidin-1-yl)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 465.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.98 (q, J = 4.7, 3.1 Hz, 4H), 3.35 (q, J = 4.7, 3.1 Hz, 4H) , 5.13 (d, J = 8.7 Hz, 1H), 6.32 - 6.78 (m, 2H), 7.22 - 7.42 (m, 3H), 7.42 - 7.59 (m, 5H), 7.58 - 7.77 (m, 3H), 8.85 (d, J = 8.7 Hz, 1H), 10.98 (s, 1H). Example 185:
[0470] [0470] Example 185 was prepared using a procedure similar to that used to prepare Example 20 where 3-fluoro-5-methoxypicolinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 455.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.93 (s, 3H), 5.17 (d, J = 8.5 Hz, 1H), 7.22 – 7.39 (m, 3H), 7 .40 - 7.58 (m, 5H), 7.60 - 7.72 (m, 2H), 8.32 (m, 1H), 9.26 (d, J = 8.5 Hz, 1H), 11.00 (s, 1H). Example 186:
[0471] [0471] Example 186 was prepared using a procedure similar to that used to prepare Example 20 where 4-(2-methyl-2H-tetrazol-5-yl)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z:
[0472] [0472] Example 187 was prepared using a procedure similar to that used to prepare Example 20 where 2-methylbenzo[d]thiazole-6-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 467.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.17 (s, 1H), 8.53 (d, J = 1.7 Hz, 1H), 8.04 (d , J = 8.5 Hz, 1H), 7.91 (dd, J = 8.6, 1.8 Hz, 1H), 7.66 (ddd, J = 8.4, 7.2, 1.7 Hz, 1H), 7.59 - 7.40 (m, 5H), 7.39 - 7.20 (m, 3H), 5.16 (s, 1H), 2.83 (s, 3H). Example 188:
[0473] [0473] Example 188 was prepared using a procedure similar to that used to prepare Example 20 where isobutyric acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 362.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.23 (d, J = 6.9 Hz, 6H), 3.02 (hept, J = 6.9 Hz, 1H), 5.04 (d, J = 8.7 Hz, 1H), 7.19 - 7.41 (m, 3H), 7.38 - 7.58 (m, 5H), 7.65 (ddd, J = 8.4, 7.0 , 1.8 Hz, 1H), 8.71 (d, J = 8.7 Hz, 1H), 10.93 (s, 1H). Example 189:
[0474] [0474] Example 189 was prepared using a procedure similar to that used to prepare Example 20 where pivalic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 376.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.29 (s, 9H), 5.03 (d, J = 8.6 Hz, 1H), 7.19 – 7.37 (m, 3H), 7 .39 - 7.58 (m, 5H), 7.65 (ddd, J = 8.4, 7.0, 1.8 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H ), 10.93 (s, 1H). Example 190:
[0475] [0475] Example 190 was prepared using a procedure similar to that used to prepare Example 20 where butyric acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 362.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.92 (t, J = 7.4 Hz, 3H), 1.64 (h, J = 7.4 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 5.03 (d, J = 8.3 Hz, 1H), 7.19 - 7.58 (m, 8H), 7.65 (ddd, J = 8.4, 7.0, 1.8 Hz, 1H), 8.72 (d, J = 8.5 Hz, 1H), 10.94 (s, 1H). Example 191:
[0476] [0476] Example 191 was prepared using a procedure similar to that used to prepare Example 20 where 2-methoxyacetic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 364.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.29 (s, 3H), 4.45 (s, 2H), 5.08 (d, J = 8.6 Hz, 1H), 7.20 -
[0477] [0477] Example 192 was prepared using a procedure similar to that used to prepare Example 20 where 4,4,4-trifluorobutanoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 416.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.58 - 2.81 (m, 2H), 2.98 (dd, J = 8.7, 6.5 Hz, 2H), 5.05 (d, J = 8.6 Hz, 1H), 7.19 - 7.38 (m, 3H), 7.38 - 7.60 (m, 5H), 7.63-7.68 (m, 1H), 8 .85 (d, J = 8.7 Hz, 1H), 10.95 (s, 1H). Example 193:
[0478] [0478] Example 193 was prepared using a procedure similar to that used to prepare Example 20 where 3-cyanopropanoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 373.1 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 2.89 (t, J = 6.8 Hz, 2H), 3.07 (t, J = 7.2 Hz, 2H), 5.04 (s, 1H), 7.18 - 7.37 (m, 3H), 7.38 - 7.58 (m, 5H), 7.62-7.67 (m, 1H), 8.88 (d, J = 4.9 Hz, 1H), 10.94 (s, 1H). Example 194:
[0479] [0479] Example 194 was prepared using a procedure similar to that used to prepare Example 20 where 2-(methylsulfonyl)acetic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 412.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.13 (s, 3H), 4.89 (s, 2H), 5.09 (d, J = 8.5 Hz, 1H), 7.20 – 7 .40 (m, 3H), 7.38 - 7.59 (m, 5H), 7.63-7.68 (m, 1H), 9.17 (d, J = 8.5 Hz, 1H), 10.97 (s, 1H). Example 195:
[0480] [0480] Example 195 was prepared using a procedure similar to that used to prepare Example 20 where 1-methylcyclopropane-1-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 374.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.77 – 0.92 (m, 2H), 1.00 – 1.10 (m, 2H), 1.39 (s, 3H), 5.00 ( d, J = 7.8 Hz, 1H), 7.18 - 7.58 (m, 8H), 7.61-7.67 (m, 1H), 8.62 (d, J = 8.1 Hz , 1H), 10.94 (s, 1H). Example 196:
[0481] [0481] Example 196 was prepared using a procedure similar to that used to prepare Example 20 where cyclobutanecarboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 374.3 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 1.79 – 2.12 (m, 2H), 2.13 – 2.39 (m, 4H), 3.58 (m, 1H), 5.05 (d, J = 8.7 Hz, 1H), 7.19 - 7.58 (m, 8H), 7.65 (m, 1H), 8.75 (d, J = 8.7 Hz, 1H) , 10.94 (s, 1H). Example 197:
[0482] [0482] Example 197 was prepared using a procedure similar to that used to prepare Example 20 where cyclopentanecarboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 388.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.52 – 1.83 (m, 6H), 1.87 – 2.07 (m, 2H), 3.08 – 3.25 (m, 1H), 5.03 (d, J = 8.6 Hz, 1H), 7.19 - 7.37 (m, 3H), 7.38 - 7.58 (m, 5H), 7.65 (m, 1H) , 8.69 (d, J = 8.7 Hz, 1H), 10.93 (s, 1H). Example 198:
[0483] [0483] Example 198 was prepared using a procedure similar to that used to prepare Example 20 where (R)-tetrahydrofuran-2-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 390.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.82 - 2.30 (m, 4H), 3.74 - 3.86 (m, 2H), 4.94 (m, 1H), 5.06 ( d, J = 8.5 Hz, 1H), 7.18 - 7.38 (m, 3H), 7.38 - 7.71 (m, 6H), 8.93 (m, 1H), 10.96 (s, 1H). Example 199:
[0484] [0484] Example 199 was prepared using a procedure similar to that used to prepare Example 20 where 3-phenylpropanoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 424.4 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 2.90 – 3.09 (m, 4H), 5.02 (s, 1H), 7.14 – 7.71 (m, 1H),
[0485] [0485] Example 200 was prepared using a procedure similar to that used to prepare Example 20 where 5-cyano-6-methylpicolinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 436.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.73 (s, 3H), 5.20 (d, J = 7.2 Hz, 1H), 7.21 – 7.40 (m, 3H), 7 .40 - 7.59 (m, 5H), 7.67 (ddd, J = 8.5, 7.2, 1.8 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H ), 8.38 (d, J = 8.2 Hz, 1H), 9.52 (d, J = 8.2 Hz, 1H), 11.01 (s, 1H). Example 201:
[0486] [0486] A solution of Example 7 (0.2 g, 0.48 mmol), K2CO3 (0.13 g, 0.96 mmol) MeI (68 mg, 0.48 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 6 h, it was diluted with EA and washed with brine. The organic phase was dried and concentrated. The residue was purified by preparative HPLC to yield the desired product as a white solid (31.2 mg, 15.2%). ESI-MS m/z: 428.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.44 (s, 3H), 5.23 (d, J = 8.6 Hz, 1H), 7.36 – 7.62 (m, 9H), 7 .77 (m, 2H), 7.83 - 7.96 (m, 2H), 9.22 (d, J = 8.7 Hz, 1H). Example 202:
[0487] [0487] Example 202 was prepared using a procedure similar to that used to prepare Example 20 where 4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoic acid was used in place of 5-chlorofuran-2- carboxylic. ESI-MS m/z: 530.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.19 (d, J = 8.4 Hz, 1H), 7.19 - 7.59 (m, 9H), 7.61 - 7.76 (m, 3H), 7.94 - 8.06 (m, 3H), 9.29 (d, J = 8.5 Hz, 1H), 11.01 (s, 1H). Example 203:
[0488] [0488] Example 203 was prepared using a procedure similar to that used to prepare Example 20 where 3,3,3-trifluoropropanoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 402.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 4.11 (q, J = 10.7 Hz, 2H), 5.07 (d, J = 8.4 Hz, 1H), 7.20 - 7.59 (m, 8H), 7.65 (ddd, J = 8.4, 7.0, 1.8 Hz, 1H), 9.13 (d, J = 8.5 Hz, 1H), 10.96 ( s, 1H). Example 204:
[0489] [0489] Example 204 was prepared using a procedure similar to that used to prepare Example 20 where 1-fluorocyclopropane-1-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z:
[0490] [0490] Example 205 was prepared using a procedure similar to that used to prepare Example 20 where (S)-2,2-dimethylcyclopropane-1-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 388.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 0.94-1.00 (m, 5H), 1.18 (s, 3H), 1.86-1.90 (m, 1H), 5.03- 5.05 (d, J = 8.0 Hz, 1H), 7.24 - 7.34 (m, 3H), 7.44 - 7.55 (m, 5H), 7.64 - 7.68 ( m, 1H), 8.70-8.73 (m, 1H), 10.93 (s, 1H). Example 206:
[0491] [0491] Example 206 was prepared using a procedure similar to that used to prepare Example 20 where 3,3-dimethylcyclobutane-1-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 402.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.10 (s, 3H), 1.20 (s, 3H), 1.99 - 2.16 (m, 4H), 3.56 (m, 1H) , 5.06 (d, J = 8.7 Hz, 1H), 7.22 - 7.38 (m, 3H), 7.41 - 7.58 (m, 5H), 7.66 (m, 1H ), 8.75 (d, J = 8.7 Hz, 1H), 10.95 (s, 1H). Example 207:
[0492] [0492] Example 207 was prepared using a procedure similar to that used to prepare Example 20 where (S)-tetrahydrofuran-2-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 390.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.93-2.01 (m, 2H), 2.15-2.22 (m, 2H), 3.79-3.83 (m, 2H), 4.93-5.08 (m, 2H), 7.25 - 7.35 (m, 3H), 7.44 - 7.53 (m, 5H), 7.64 - 7.68 (m, 1H ), 8.93-8.96 (m, 1H), 11.00 (s, 1H). Example 208:
[0493] [0493] Example 208 was prepared using a procedure similar to that used to prepare Example 20 where 2,2-dimethyl-3-phenylpropanoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 452.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.22 – 1.30 (m, 6H), 2.91 (s, 2H), 5.05 (d, J = 8.7 Hz, 1H), 6 .95 - 7.02 (m, 2H), 7.15 - 7.38 (m, 6H), 7.42 - 7.60 (m, 5H), 7.67 (m, 1H), 8.73 (d, J = 8.8 Hz, 1H), 10.96 (s, 1H). Example 209: Example 209 step a:
[0494] [0494] A solution of 3-amino-1-(4-methoxybenzyl)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one, from Example 91 step b , (0.37 g, 1 mmol), TCDI (196 mg, 1.1 mmol) in DMF (10 mL) was stirred for 0.5 hours. 4-Fluorobenzohydrazide (169 mg, 1.1 mmol) was added and then stirred for 3 hours. EDCI (764 mg, 4 mmol) was added and then stirred for 1 hour at 60 °C. Then it was flash purified to give product as a white solid (0.3 g, 56%). ESI-MS m/z: 534.3 [M+H]+. Example 209 step b:
[0495] [0495] A solution of the compound from step a (0.3 g, 0.56 mmol), K2CO3 (0.15 g, 1.12 mmol) MeI (95 mg, 0.68 mmol) in DMF (5 mL) . The mixture was stirred at room temperature for 6 h, it was diluted with EA and washed with brine. The organic phase was dried and concentrated to provide product as a yellow solid (0.3 g, 98%). ESI-MS m/z: 548.5 [M+H]+. Example 209 step c:
[0496] [0496] The mixture of step b compound (200 mg, 0.37 mmol) and AlCl 3 (490 mg, 3.7 mmol) in anisole (5 mL) was heated at 70 °C for 3 h under N 2 . Solvent has been removed. The residue was purified by preparative HPLC to provide product as a pale yellow solid (79.6 mg, 50.4%). ESI-MS m/z: 428.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.55 (s, 3H), 5.49 (s, 1H), 7.25 - 7.45 (m, 5H), 7.46 - 7.64 ( m, 5H), 7.65 - 7.77 (m, 1H), 7.93 (m, 2H), 11.06 (s, 1H).
[0497] [0497] Example 210 was prepared using a procedure similar to that used to prepare Example 20 where 4-(4-methylpiperazin-1-yl)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid ESI-MS m/ z: 494.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.15 (t, J = 4.9 Hz, 4H), 3.75 (dd, J = 6.0, 3.6 Hz, 4H), 5.10 – 5.19 (m, 1H), 7.08 – 7.73 (m, 14H), 7.82 (s, 1H), 8.99 – 9.09 (m, 1H), 10.99 (sec , 1H). Example 211:
[0498] [0498] Example 211 was prepared using a procedure similar to that used to prepare Example 20 where 6-(1H-pyrazol-1-yl)nicotinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 482.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.18 (d, J = 6.6 Hz, 1H), 6.64 (dd, J = 2.7, 1.7 Hz, 1H), 7.22 – 7.59 (m, 8H), 7.67 (ddd, J = 8.4, 7.1, 1.7 Hz, 1H), 7.90 (dd, J = 1.6, 0.7 Hz , 1H), 8.09 (dd, J = 8.6, 0.9 Hz, 1H), 8.36 (dd, J = 8.7, 2.3 Hz, 1H), 8.68 (dd, J = 2.6, 0.7 Hz, 1H), 8.86 (dd, J = 2.3, 0.8 Hz, 1H), 9.28 (d, J = 7.2 Hz, 1H), 11.01 (s, 1H). Example 212:
[0499] [0499] Example 212 was prepared using a procedure similar to that used to prepare Example 20 where 3-(1H-imidazol-1-yl)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 462.1 [M+H]+. H NMR (300 MHz, DMSO-d6) δ 5.21 (d, J = 8.4 Hz, 1H), 7.13 - 7.20 (m, 1H), 7.24 - 7.61 (m, 8H), 7.63 - 7.90 (m, 5H), 7.98 - 8.11 (m, 1H), 8.37 (s, 1H), 9.23 (d, J = 8.3 Hz , 1H), 11.02 (s, 1H). Example 213:
[0500] [0500] Example 213 was prepared using a procedure similar to that used to prepare Example 20 where 4-(1H-imidazol-1-yl)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 378.1 [M+H]+. H NMR (300 MHz, DMSO-d6) δ 1.49 (s, 6H), 2.44 (s, 1H), 5.07 (d, J = 8.6 Hz, 1H), 5.67 (s , 1H), 7.22 - 7.43 (m, 3H), 7.41 - 7.61 (m, 5H), 7.67 (m, 1H), 8.82 (d, J = 8.7 Hz, 1H), 10.92 - 10.99 (s, 1H). Example 214:
[0501] [0501] Example 214 was prepared using a procedure similar to that used to prepare Example 20 where 3,3-difluorocyclobutane-1-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z:
[0502] [0502] Example 215 was prepared using a procedure similar to that used to prepare Example 20 where tetrahydrofuran-3-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 390.1 [M+H]+. H NMR (300 MHz, DMSO-d6) δ 2.03 - 2.31 (m, 2H), 3.60 (m, 1H), 3.70 - 3.91 (m, 3H), 3.97 ( m, 1H), 5.07 (d, J = 8.7 Hz, 1H), 7.22 - 7.40 (m, 3H), 7.41 - 7.61 (m, 5H), 7.67 (m, 1H), 8.51 (s, 0.2H), 8.83 (d, J = 8.6 Hz, 1H), 10.97 (d, J = 8.6 Hz, 1H). Example 216:
[0503] [0503] Example 216 was prepared using a procedure similar to that used to prepare Example 20 where 3-fluoro-4-(1H-1,2,4-triazol-1-yl)benzoic acid was used in place of 5- chlorofuran-2-carboxylic acid. ESI-MS m/z: 481.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.19 (d, J = 7.5 Hz, 1H), 7.22 - 7.59 (m, 8H), 7.67 (ddd, J = 8, 5, 7.0, 1.7 Hz, 1H), 7.78 - 7.94 (m, 2H), 8.03 (t, J = 8.0 Hz, 1H), 8.36 (s, 1H ), 9.11 (d, J = 2.5 Hz, 1H), 9.32 (d, J = 8.2 Hz, 1H), 11.02 (s, 1H). Example 217:
[0504] [0504] Example 217 was prepared using a procedure similar to that used to prepare Example 20 where 3-methyl-4-(1H-1,2,4-triazol-1-yl)benzoic acid was used in place of 5- chlorofuran-2-carboxylic acid. ESI-MS m/z: 477.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H), 5.19 (d, J = 8.1 Hz, 1H), 7.22 – 7.74 (m, 10H), 7 .80 (dd, J = 8.4, 1.9 Hz, 1H), 7.91 (t, J = 1.2 Hz, 1H), 8.28 (s, 1H), 8.97 (s, 1H), 9.23 (d, J = 8.2 Hz, 1H), 11.01 (s, 1H). Example 218:
[0505] [0505] Example 218 was prepared using a procedure similar to that used to prepare Example 20 where 2-methyl-4-(1H-1,2,4-triazol-1-yl)benzoic acid was used in place of 5- chlorofuran-2-carboxylic acid. ESI-MS m/z: 477.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.67 (s, 3H), 5.20 (d, J = 7.9 Hz, 1H), 7.24 – 7.43 (m, 3H), 7 .44 - 7.64 (m, 5H), 7.64 - 7.78 (m, 1H), 7.95 (d, J = 16.1 Hz, 3H), 8.31 (s, 1H), 9.19 (d, J = 8.3 Hz, 1H), 9.41 (s, 1H), 11.01 (s, 1H). Example 219:
[0506] [0506] Example 219 was prepared using a procedure similar to that used to prepare Example 20 where 3-methoxy-4-(4-methyl-1H-
[0507] [0507] Example 220 was prepared using a procedure similar to that used to prepare Example 20 where 4-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid . ESI-MS m/z: 496.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.62 (dtd, J = 13.3, 9.0, 4.1 Hz, 2H), 1.91 - 2.09 (m, 2H), 3, 51 (ddd, J = 11.7, 9.5, 2.8 Hz, 2H), 3.88 (dt, J = 11.4, 4.6 Hz, 2H), 4.70 (td, J = 8.9, 4.5 Hz, 1H), 5.16 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 7.24 - 7, 43 (m, 3H), 7.42 - 7.62 (m, 5H), 7.63 - 7.84 (m, 3H), 9.02 (d, J = 8.5 Hz, 1H), 10 .98 (s, 1H). Example 221:
[0508] [0508] Example 221 was prepared using a procedure similar to that used to prepare Example 20 where pyrrolidine-3-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 489.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.98 (dt, J = 12.8, 7.0 Hz, 1H), 2.12 (ddd, J = 12.9, 8.7, 6.4 Hz, 1H), 2.99 (q, J = 8.2, 6.8 Hz, 3H), 3.27 (dd, J = 11.1, 7.8 Hz, 1H), 3.43 (q , J = 7.7 Hz, 1H), 5.04 - 5.10 (m, 1H), 7.24 - 7.39 (m, 3H), 7.43 - 7.59
[0509] [0509] Example 222 was prepared using a procedure similar to that used to prepare Example 20 where 7-azaspiro[3,5]nonane-2-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 443.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.63 (q, J = 5.1 Hz, 2H), 1.75 (dd, J = 7.2, 3.9 Hz, 2H), 2.03 (ddd, J = 12.6, 8.3, 2.2 Hz, 2H), 2.18 - 2.29 (m, 2H), 2.86 (dt, J = 34.9, 5.5 Hz , 4H), 3.59 (d, J = 8.6 Hz, 1H), 5.05 (d, J = 7.8 Hz, 1H), 7.22 - 7.40 (m, 3H), 7 .42 - 7.59 (m, 5H), 7.66 (ddd, J = 8.5, 7.1, 1.7 Hz, 1H), 8.40 (s, 1H), 8.77 (d , J = 8.7 Hz, 1H). Example 223:
[0510] [0510] Example 223 was prepared using a procedure similar to that used to prepare Example 20 where 3-methylpyrrolidine-3-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 403.3 [M+H]+. H NMR (300 MHz, DMSO-d6) δ 1.40 (s, 3H), 1.80 (m, 1H), 2.24 (m, 1H), 2.88 (d, J = 11.2 Hz , 1H), 2.94 - 3.16 (m, 3H), 3.23 (d, J = 11.2 Hz, 1H), 5.07 (d, J = 8.4 Hz, 1H), 7 .22 - 7.40 (m, 3H), 7.41 - 7.61 (m, 5H), 7.61 - 7.73 (m, 1H), 8.41 (s, 1H), 8.78 (d, J = 8.7 Hz, 1H), 11.10 (s, 1H). Example 224:
[0511] [0511] Example 224 was prepared using a procedure similar to that used to prepare Example 20 where 2-(4-methylpiperazin-1-yl)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 494.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 2.38 (d, J = 5.4 Hz, 4H), 2.89 (t, J = 4.6 Hz, 4H ), 5.18 (d, J = 8.5 Hz, 1H), 7.06 - 7.22 (m, 2H), 7.23 - 7.41 (m, 3H), 7.41 - 7, 59 (m, 6H), 7.59 - 7.75 (m, 2H), 9.03 (d, J = 8.6 Hz, 1H), 10.99 (s, 1H). Example 225:
[0512] [0512] Example 225 was prepared using a procedure similar to that used to prepare Example 20 where 6-(1H-1,2,4-triazol-1-yl)nicotinic acid was used in place of 5-chlorofuran-2- carboxylic. ESI-MS m/z: 464.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.17 (s, 1H), 7.20 – 7.39 (m, 3H), 7.39 – 7.61 (m, 5H), 7.60 – 7.72 (m, 1H), 8.05 (d, J = 8.6 Hz, 1H), 8.34 - 8.53 (m, 2H), 8.93 (d, J = 2.3 Hz , 1H), 9.30 (s, 1H), 9.46 (s, 1H), 11.03 (s, 1H). Example 226:
[0513] [0513] Example 226 was prepared using a procedure similar to that used to prepare Example 20 where 2-(pyridin-4-yl)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 473.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 4.94 (d, J = 8.5 Hz, 1H), 7.21 - 7.37 (m, 5H), 7.38 - 7.58 (m, 6H), 7.66 (tdd, J = 6.8, 3.6, 1.7 Hz, 3H), 7.84 (dd, J = 7.3, 1.9 Hz, 1H), 8.46 - 8.56 (m, 2H), 8.98 (d, J = 8.6 Hz, 1H), 10.93 (s, 1H). Example 227:
[0514] [0514] Example 227 was prepared using a procedure similar to that used to prepare Example 20 where piperidin-4-yl-L-proline was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 472.3 [M+H]+. H NMR (300 MHz, DMSO-d6) δ 1.42 (m, 2H), 1.82 (m, 6H), 2.09 (m, 1H), 2.62 - 2.79 (m, 2H) , 2.85 (s, 1H), 3.00 (m, 4H), 4.06 - 4.16 (m, 1H), 5.07 (d, J = 8.5 Hz, 1H), 7, 22 - 7.40 (m, 3H), 7.51 (q, J = 7.9, 6.9 Hz, 5H), 7.61 - 7.74 (m, 1H), 8.37 - 8, 44 (s, 1H), 8.82 (d, J = 8.7 Hz, 1H), 10.92 (s, 1H). Example 228:
[0515] [0515] A solution of Example 227 (188 mg, 0.4 mmol), HCHO (0.5 mL), NaBH(OAc) 3 (212 mg, 1.0 mmol) in THF (20 mL) was stirred for 1 hour at 50°C. Extracted with EA(3x), dried Na2SO4, filtered and purified by preparative HPLC (MeCN/H2O) to yield desired compound as a yellow solid (10 mg, 26%). ESI-MS m/z: 486.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.22 -
[0516] [0516] Example 229 was prepared using a procedure similar to that used to prepare Example 20 where 2-(2-methoxyethoxy)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 470.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.27 (s, 3H), 3.61 - 3.72 (m, 2H), 4.18 (dd, J = 5.6, 3.8 Hz, 2H), 5.15 (d, J = 8.5 Hz, 1H), 7.08 (td, J = 7.5, 1.0 Hz, 1H), 7.16 - 7.39 (m, 4H ), 7.41 - 7.57 (m, 6H), 7.67 (ddd, J = 8.4, 5.0, 1.8 Hz, 2H), 9.00 (d, J = 8.6 Hz, 1H), 10.98 (s, 1H). Example 230: Example 230 step a:
[0517] [0517] A solution of 3-amino-1-(4-methoxybenzyl)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one, from Example 91 step b , (1.0 g, 2.70 mmol), benzaldehyde (314 mg, 2.96 mmol), 4A molecular sieves (10 g) and MgSO4 (10 g) in 50 mL of DCM, was stirred at room temperature for the night under N2. Then the solid was filtered off and the filtrate was concentrated to give crude product, which was used directly in the next step. ESI-MS m/z: 460.3 [M+H]+. Example 230 step b:
[0518] [0518] A solution of the compound from step a (1.0 g, 2.18 mmol) in THF (20 mL) was added to NaHMDS (2.4 mL) in THF (5 mL) at -70 °C under N 2 . After stirring for 5 minutes, MeI (340 mg, 2.40 mmol) was added. The mixture was stirred at -70 °C for 2 h, then warmed to room temperature and stirred overnight. It was cooled by brine and solvent was removed. The residue was dissolved in 2N HCl (10 mL) and MeOH (5 mL). The mixture was stirred for 30 minutes, basified with 2N NaOH and extracted with EtOAc. It was purified by silica gel column to give product as a tin solid (160 mg). ESI-MS m/z: 386.1 [M+H]+. Example 230 step c:
[0519] [0519] To a solution of the compound from step b (150 mg, 0.39 mmol) and Et3N (79 mg, 0.78 mmol) in DCM (5 mL) was added thiophosgene (49 mg, 0.43 mmol) to 0 oC After stirring for 2 h at 0 °C, 4-fluorobenzohydrazide (200 mg, 1.3 mmol) was added. It was stirred for another hour before being concentrated. The residue was purified by C18 reversed phase column chromatography (MeCN/H2O) to give product as a yellow solid (70 mg). ESI-MS m/z: 582.4 [M+H]+.
[0520] [0520] The mixture of step c compound (70 mg, 0.12 mmol) and EDCI (44 mg, 0.24 mmol) in DMF (2 mL) was heated at 60 °C for 1 hour. Then it was purified by C18 reversed phase column chromatography (MeCN/H2O) to give product as a yellow solid (48 mg). ESI-MS m/z: 548.4 [M+H]+. Example 230 step g:
[0521] [0521] The mixture of step d compound (48 mg, 0.087 mmol) and AlCl 3 (200 mg, 1.5 mmol) in anisole (5 mL) was heated at 70 °C for 5 hrs under N 2 . Solvent has been removed. The residue was purified by preparative TLC to give product as a yellow solid (6mg). ESI-MS m/z: 428.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.25 (s, 3H), 7.05 – 7.31 (m, 3H), 7.34 – 7.62 (m, 8H), 7.75 – 7.90 (m, 2H), 8.23 (s, 1H), 11.02 (s, 1H). Example 231:
[0522] [0522] Example 231 was prepared using a procedure similar to that used to prepare Example 20 where 4-(1H-imidazol-1-yl)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 462.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 5.15 (s, 1H), 7.16 (s, 1H), 7.24-
[0523] [0523] Example 232 was prepared using a procedure similar to that used to prepare Example 20 where 6-(1H-imidazol-1-yl)nicotinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 463.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.23 (s, 1H), 5.19 (d, J = 8.3 Hz, 1H), 7.14 – 7.74 (m, 11H), 7 .97 - 8.07 (m, 2H), 8.36 (dd, J = 8.6, 2.3 Hz, 1H), 8.63 (s, 1H), 8.89 (d, J = 2 .2 Hz, 1H), 9.28 (d, J = 8.5 Hz, 1H), 11.02 (s, 1H). Example 233:
[0524] [0524] Example 233 was prepared using a procedure similar to that used to prepare Example 20 where 4-(4H-1,2,4-triazol-4-yl)benzoic acid was used in place of 5-chlorofuran-2- carboxylic. ESI-MS m/z: 463.0 [M+H]+. H-NMR-PH-ETA-A1-433-0: 1H NMR (300 MHz, DMSO-d6) δ 5.18 (d, J = 8.0 Hz, 1H), 7.22 – 7.60 (m , 8H), 7.68 (ddd, J = 8.4, 7.1, 1.7 Hz, 1H), 7.86 - 8.04 (m, 4H), 9.23 (s, 3H), 11.01 (s, 1H). Example 234:
[0525] [0525] Example 234 was prepared using a procedure similar to that used to prepare Example 20 where 2-(2-(dimethylamino)ethoxy)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 483.5 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 6H), 2.63 (t, J = 5.9 Hz, 2H), 4.13 (t, J = 5.9 Hz, 2H ), 5.14 (d, J = 8.6 Hz, 1H), 7.07 (td, J = 7.5, 1.0 Hz, 1H), 7.16 - 7.59 (m, 10H) , 7.61 - 7.73 (m, 2H), 8.96 (d, J = 8.7 Hz, 1H), 10.97 (s, 1H). Example 235:
[0526] [0526] Example 235 was prepared using a procedure similar to that used to prepare Example 20 where 2-((pyridin-2-ylmethyl)amino)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 496.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 4.60 (d, J = 5.4 Hz, 2H), 5.17 (d, J = 8.5 Hz, 1H), 6.68 - 6.83 (m, 2H), 7.22 - 7.81 (m, 14H), 8.02 (t, J = 5.5 Hz, 1H), 8.46 (s, 1H), 8.51 - 8, 60 (m, 1H), 9.15 (d, J = 8.5 Hz, 1H), 11.01 (s, 1H). Example 236:
[0527] [0527] A solution of methyl 4-hydroxybenzoate (1.52 g, 10 mmol), 2-methoxyethanol (1.52 g, 20 mmol), DIAD (5 mL) and PPh3 (5 mL) in THF (50 mL ) was stirred overnight at room temperature. It was used directly in the next step. ESI-MS m/z: 211.2 [M+H]+. Example 236 step b:
[0528] [0528] NaOH (50 mL, 3.0 M) was added to the reaction mixture in step a, and then stirred for 4 hours at room temperature. It was concentrated, and extracted with EA (x3) and washed with brine (x2). The water layers were combined and adjusted to pH 1-2 with HCl, then extracted with EA (x3) and washed with brine (x2). The organic layers were combined and concentrated to yield the desired compound as a white solid (900 mg, 46%). ESI-MS m/z: 196.8 [M+H]+. Example 236:
[0529] [0529] Example 236 was prepared using a procedure similar to that used to prepare Example 20 where 4-(2-methoxyethoxy)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 470.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.31 (s, 3H), 3.58 - 3.73 (m, 2H), 4.08 - 4.24 (m, 2H), 5.14 ( d, 1H), 7.05 – 7.18 (d, 2H), 7.18 – 7.38 (m, 3H), 7.40 –
[0530] [0530] Example 237 was prepared using a procedure similar to that used to prepare Example 20 where 2-(4-methylpiperazin-1-yl) nicotinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 495.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.16 (s, 6H), 2.36 (t, J = 4.7 Hz, 4H), 3.15 (dd, J = 5.6, 3, 7 Hz, 4H), 5.15 (d, J = 8.5 Hz, 1H), 6.99 (dd, J = 7.6, 4.8 Hz, 1H), 7.22 - 7.60 ( m, 8H), 7.67 (ddd, J=8.5, 7.1, 1.7Hz, 1H), 7.91 (dd, J=7.6, 1.9Hz, 1H), 8 .32 (dd, J = 4.8, 1.9 Hz, 1H), 9.12 (d, J = 8.7 Hz, 1H), 10.98 (s, 1H). Example 238:
[0531] [0531] Example 238 was prepared using a procedure similar to that used to prepare Example 20 where (R)-2-(methylamino)-2-phenylacetic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 439.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 4.84 (s, 1H), 5.03 (d, J = 8.6 Hz, 1H), 7.19 - 7 .58 (m, 13H), 7.65 (ddd, J = 8.4, 6.9, 1.9 Hz, 1H), 8.29 (s, 1H), 8.82 (dd, J = 8 .7, 2.4 Hz, 1H). Example 239:
[0532] [0532] Example 239 was prepared using a procedure similar to that used to prepare Example 20 where 2-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid . ESI-MS m/z: 496.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.62 (ddt, J = 11.6, 7.9, 4.7 Hz, 2H), 1.88 (dd, J = 12.4, 6.4 Hz, 2H), 3.38 - 3.51 (m, 2H), 3.81 (dt, J = 10.2, 4.6 Hz, 2H), 4.71 (tt, J = 7.4, 3.7 Hz, 1H), 5.14 (d, J = 8.6 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 7.22 - 7.59 (m, 10H), 7.60 - 7.74 (m, 2H), 9.05 (d, J = 8.6 Hz, 1H), 10.98 (s, 1H). Example 240:
[0533] [0533] Example 240 was prepared using a procedure similar to that used to prepare Example 20 where 2-(1,1-dioxydothiomorpholino)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 529.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.31 (s, 4H), 3.38 (d, J = 4.9 Hz, 4H), 5.17 (d, J = 8.7 Hz, 1H ), 7.19 – 7.39 (m, 5H), 7.42 – 7.58 (m, 6H), 7.64 – 7.81 (m, 2H), 9.27 (d, J = 8 .7 Hz, 1H), 11.00 (s, 1H). Example 241:
[0534] [0534] Example 241 was prepared using a procedure similar to that used to prepare Example 20 where 2-(piperidin-1-yl)nicotinic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 480.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.54 (d, J = 7.4 Hz, 6H), 3.10 (d, J = 5.5 Hz, 4H), 5.15 (d, J = 8.7 Hz, 1H), 6.94 (dd, J = 7.6, 4.8 Hz, 1H), 7.21 - 7.39 (m, 3H), 7.40 - 7.59 ( m, 5H), 7.67 (ddd, J=8.3, 7.0, 1.8Hz, 1H), 7.88 (dd, J=7.6, 1.9Hz, 1H), 8 .29 (dd, J = 4.8, 1.9 Hz, 1H), 9.11 (d, J = 8.7 Hz, 1H), 10.98 (s, 1H). Example 242:
[0535] [0535] Example 242 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 2-morpholinopicolinate, which was prepared similarly to ethyl 3-morpholinopicolinate in Example 132 step b, was used in place of 2- ethyl morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 482.1980 [M+H]+. Example 243:
[0536] [0536] Example 243 was prepared using a procedure similar to that used to prepare Example 161 where cis-2,6-dimethylmorpholine and 2-
[0537] [0537] Example 244 was prepared using a procedure similar to that used to prepare Example 161 where (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane and ethyl 2-chloro-4-fluorobenzoate were used in place of morpholine and methyl 5-chloropyrazine-2-carboxylate, respectively. ESI-MS m/z: 541.3 [M+H]+. Example 245: Example 245 step a:
[0538] [0538] A solution of methyl 2-fluoronicotinate (1 g, 6.5 mmol), (R)-3-methylmorpholine (722 mg, 7.2 mmol) and K2CO3 (1.79 g, 13.0 mmol) in DMSO (5 mL) was stirred for 1 hour at 100 °C. It was diluted with water, extracted with EA(x3), washed with brine(x2), the organic layers were combined, dried, concentrated to yield 1.2 g (crude) of the desired compound as a colorless oil, which was used directly in the next step. ESI-MS m/z: 237.1
[0539] [0539] A solution of the compound from step a (1.2 g, 5.0 mol) and NH2NH2.H2O (5 mL) in EtOH (10 mL) was refluxed 2 hours. It was concentrated and purified by preparative HPLC (MeCN/H2O) to yield the desired compound as a white solid (1 g, 83%). ESI-MS m/z: 237.1 [M+H]+. Example 245 step c:
[0540] [0540] Example 245 was prepared using a procedure similar to that used to prepare Example 21 where (R)-2-(3-methylmorpholino)nicotinohydrazide was used in place of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 496.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.00 (m, 3H), 3.03-3.04(m, 1H), 3.24-3.25(m, 1H), 3.38 - 3.79 (m, 5H), 5.15 (m, 1H), 7.03 (m, 1H), 7.32 (m, 3H), 7.41 - 7.60 (m, 5H), 7 .67 (m, 1H), 7.95 (m, 1H), 8.33 - 8.41 (m, 1H), 9.15 (m, 1H), 10.98 (s, 1H). Example 246:
[0541] [0541] Example 246 was prepared using a procedure similar to that used to prepare Example 245 where 3,3-difluoropiperidine was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 516.5 [M+H]+. H NMR (300 MHz, DMSO-d6) δ 1.83 (d, J = 7.3 Hz, 2H), 1.93 - 2.14 (m, 2H), 3.18 (d, J = 6, 1 Hz, 2H), 3.43 - 3.58 (m, 2H), 5.16 (d, J = 7.7 Hz, 1H), 7.08 (m, 1H), 7.22 - 7, 61 (m, 8H), 7.62 - 7.74 (m, 1H), 7.98 (m, 1H), 8.36 (m, 1H), 9.13 (d, J = 8.0 Hz , 1H), 11.00 (s, 1H). Example 247:
[0542] [0542] Example 247 was prepared using a procedure similar to that used to prepare Example 245 where (S)-3-methoxypyrrolidine was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 496.5 [M+H]+. H NMR (300 MHz, DMSO-d6) δ 1.84 - 2.01 (m, 2H), 3.10 - 3.50 (m, 7H), 3.96 (m, 1H), 5.14 ( m, 1H), 6.76 (m, 1H), 7.21 - 7.39 (m, 3H), 7.39 - 7.60 (m, 5H), 7.60 - 7.77 (m, 5H), 2H), 8.26 (m, 1H), 9.01 (m, 1H), 10.95 (s, 1H). Example 248:
[0543] [0543] Example 248 was prepared using a procedure similar to that used to prepare Example 245 where (1S,4S)-2-oxa-5-azabicyclo[2,2,1]heptane was used in place of (R)-3 -methylmorpholine. ESI-MS m/z: 494.5 [M+H]+. H NMR (300 MHz, DMSO-d6) δ 1.78 (s, 2H), 2.68 (m, 1H), 3.27 - 3.40 (m, 1H), 3.70 - 3.83 ( m, 2H), 4.53 (s, 1H), 4.70 - 4.80 (m, 1H), 5.13 (m, 1H), 6.84 (m, 1H), 7.21 - 7 .39 (m, 3H), 7.49 (m, 5H), 7.66 (m, 1H), 7.78 (m,
[0544] [0544] Example 249 was prepared using a procedure similar to that used to prepare Example 245 where 1,4-oxazepane was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 496.5 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.83 (m, 2H), 3.45 (m, 4H), 3.53 - 3.64 (m, 2H), 3.69 (m, 2H) , 5.13 (d, J = 8.6 Hz, 1H), 6.83 (m, 1H), 7.21 - 7.39 (m, 3H), 7.40 - 7.59 (m, 5H ), 7.66 (m, 1H), 7.77 (m, 1H), 8.27 (m, 1H), 9.02 (d, J = 8.6 Hz, 1H), 10.96 (s , 1H). Example 250:
[0545] [0545] Example 250 was prepared using a procedure similar to that used to prepare Example 160 where ethyl 3-oxa-8-azabicyclo[3.2.1]octane and 3-chloro-5-(trifluoromethyl)picolinate were used in the instead of morpholine and methyl 5-bromo-3-fluoropicolinate, respectively. ESI MS m/z = 576.2 [M+H]+. Example 251:
[0546] [0546] Example 251 was prepared using a procedure similar to that used to prepare Example 160 where 8-oxa-3-azabicyclo[3.2.1]octane and ethyl 3-chloro-5-(trifluoromethyl)picolinate were used in the instead of morpholine and methyl 5-bromo-3-fluoropicolinate, respectively. ESI MS m/z = 576.2 [M+H]+. Example 252:
[0547] [0547] Example 252 was prepared using a procedure similar to that used to prepare Example 160 where methyl 2-chloro-6-methylnicotinate was used in place of methyl 5-bromo-3-fluoropicolinate. ESI MS m/z = 496.2 [M+H]+. Example 253:
[0548] [0548] Example 253 was prepared using a procedure similar to that used to prepare Example 160 where ethyl 3-chloro-5-(trifluoromethyl)picolinate was used in place of methyl 5-bromo-3-fluoropicolinate. ESI-MS m/z: 550.2 [M+H]+. Example 254:
[0549] [0549] Example 254 was prepared using a procedure similar to that used to prepare Example 245 where 4-methoxypiperidine was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 510.5 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.53 (m, 2H), 1.85 (s, 1H), 2.85 - 2.99 (m, 2H), 3.23 (s, 6H) , 5.15 (d, J = 8.5 Hz, 1H), 6.96 (m, 1H), 7.21 - 7.59 (m, 8H), 7.67 (m, 1H), 7, 90 (m, 1H), 8.30 (m, 1H), 9.12 (d, J = 8.6 Hz, 1H), 10.97 (s, 1H). Example 255:
[0550] [0550] Example 255 was prepared using a procedure similar to that used to prepare Example 245 where piperidin-4-ol was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 496.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.47 (m, 2H), 1.68 – 1.81 (m, 2H), 2.83 – 2.97 (m, 2H), 3.57 – 3.70 (m, 1H), 4.66 (s, 1H), 5.15 (d, J = 8.6 Hz, 1H), 6.94 (m, 1H), 7.21 - 7.40 (m, 3H), 7.39 - 7.59 (m, 5H), 7.67 (m, 1H), 7.88 (m, 1H), 8.30 (m, 1H), 9.10 ( d, J = 8.6 Hz, 1H), 10.97 (s, 1H). Example 256:
[0551] [0551] Example 256 was prepared using a procedure similar to that used to prepare Example 245, where 4-fluoropiperidine was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 498.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.72 - 1.88 (m, 4H), 1.94 (d, J = 19.8 Hz, 4H), 3.11 (m, 4H), 4 .75 (m, 1H), 5.15 (d, J = 8.6 Hz, 2H), 7.01 (m, 2H), 7.32 (m, 6H), 7.39 - 7.62 ( m, 10H),
[0552] [0552] Example 257 was prepared using a procedure similar to that used to prepare Example 245, where (R)-3-methoxypyrrolidine was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 496.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.94 (m, 2H), 3.09 - 3.50 (m, 7H), 3.96 (m, 1H), 5.14 (m, 1H) , 6.76 (m, 1H), 7.21 - 7.39 (m, 3H), 7.39 - 7.60 (m, 5H), 7.60 - 7.77 (m, 2H), 8 .26 (m, 1H), 9.01 (m, 1H), 10.97 (s, 1H). Example 258:
[0553] [0553] Example 258 was prepared using a procedure similar to that used to prepare Example 245, where 3-methoxyazetidine was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 482.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.19 (s, 3H), 3.73 (m, 2H), 4.02 - 4.26 (m, 3H), 5.15 (d, J = 8.5 Hz, 1H), 6.84 (m, 1H), 7.21 - 7.40 (m, 3H), 7.39 - 7.60 (m, 5H), 7.67 (m, 1H ), 7.79 (dd, J = 7.6, 1.9 Hz, 1H), 8.28 (m, 1H), 9.09 (d, J = 8.5 Hz, 1H), 10.97 (s, 1H). Example 259:
[0554] [0554] Example 259 was prepared using a procedure similar to that used to prepare Example 245, where 3,3-difluoroazetidine was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 488.4 [M+H]+. H NMR (300 MHz, DMSO-d6) δ 4.41 (m, 4H), 5.18 (d, J = 8.3 Hz, 1H), 7.05 (m, 1H), 7.21 - 7 .78 (m, 9H), 7.97 (m, 1H), 8.37 (m, 1H), 9.20 (d, J = 8.5 Hz, 1H), 11.01 (s, 1H) . Example 260:
[0555] [0555] Example 260 was prepared using a procedure similar to that used to prepare Example 245, where piperidine-4-carbonitrile was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 505.3 [M+H]+. H NMR (300 MHz, DMSO-d6) δ 1.77 - 2.03 (m, 4H), 3.03 (m, 3H), 3.31 (d, J = 6.8 Hz, 2H), 5 .16 (s, 1H), 7.04 (m, 1H), 7.22 - 7.40 (m, 3H), 7.40 - 7.60 (m, 5H), 7.67 (m, 1H ), 7.97 (m, 1H), 8.34 (m, 1H), 9.21 (s, 1H), 9.80 (s, 1H). Example 261:
[0556] [0556] Example 261 was prepared using a procedure similar to that used to prepare Example 245, where (S)-3-methylmorpholine was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 496.5 [M+H]+. 1H NMR (400MHz,
[0557] [0557] Example 262 was prepared using a procedure similar to that used to prepare Example 245 where (R)-2-methylmorpholine was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 496.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.06 (d, J = 6.1 Hz, 3H), 2.53 - 2.62 (m, 1H), 2.84 (m, 1H), 3 .41 (m, 2H), 3.55 - 3.70 (m, 2H), 3.76 (s, 1H), 5.12 - 5.18 (m, 1H), 7.02 (m, 1H ), 7.22 - 7.41 (m, 3H), 7.42 - 7.57 (m, 5H), 7.67 (m, 1H), 7.95 (m, 1H), 8.25 - 8.36 (m, 1H), 9.09 - 9.20 (m, 1H). Example 263:
[0558] [0558] Example 263 was prepared using a procedure similar to that used to prepare Example 245 where (S)-2-methylmorpholine was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 496.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.08 (d, J = 6.2 Hz, 3H), 2.57 (d, J = 10.1 Hz, 1H), 2.86 (m, 1H ), 3.39 (m, 2H), 3.58 - 3.93 (m, 3H), 5.18 (d, J = 8.2 Hz, 1H), 7.03 (m, 1H), 7 .29 (m, 1H), 7.36 (m, 2H), 7.50 (m, 5H), 7.68 (m, 1H), 7.97 (d, J = 7.6 Hz, 1H) , 8.27 - 8.51 (m,
[0559] [0559] Example 264 was prepared using a procedure similar to that used to prepare Example 245 where (1R,4R)-2-oxa-5-azabicyclo[2,2,1]heptane was used in place of (R)-3 -methylmorpholine. ESI-MS m/z: 494.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.79 (s, 2H), 2.71 (m, 1H), 3.37 (m, 1H), 3.70 - 3.90 (m, 2H) , 4.54 (s, 1H), 4.76 (m, 1H), 5.15 (m, 1H), 6.85 (m, 1H), 7.24 - 7.41 (m, 3H), 7.44 - 7.60 (m, 5H), 7.67 (m, 1H), 7.80 (m, 1H), 8.29 (m, 1H), 9.03 (d, J = 8, 5 Hz, 1H), 10.98 (s, 1H). Example 265:
[0560] [0560] Example 265 was prepared using a procedure similar to that used to prepare Example 245 where 3-oxa-8-azabicyclo[3.2.1]octane was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 508.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.72-1.79 (m, 2H), 1.81-1.84 (m, 2H), 3.48-3.50 (m, 2H), 3.73-3.78 (m, 2H), 3.96-4.03(m, 2H), 5.14-5.16 (d, J=8.0, 1H), 6.94-6 .98 (m, 1H), 7.26-7.29 (m, 1H), 7.33-7.35 (m, 2H), 7.44-7.53 (m, 5H), 7.54 -7.55(m, 1H), 7.65-7.69 (m, 1H), 7.89-7.92 (m, 1H), 8.29-8.30-9.42 (m, 1H), 1H), 9.14-9.16 (d, J=8.0, 1H), 10.97 (s, 1H). Example 266:
[0561] [0561] Example 266 was prepared using a procedure similar to that used to prepare Example 245 where 8-oxa-3-azabicyclo[3.2.1]octane was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 508.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.63 - 1.80 (m, 2H), 1.89 (dd, J = 7.4, 4.6 Hz, 2H), 3.01 (dt, J = 12.5, 2.2 Hz, 2H), 3.28 (dd, J = 11.4, 3.3 Hz, 2H), 4.28 (dd, J = 4.4, 2.3 Hz , 2H), 5.15 (d, J = 8.6 Hz, 1H), 6.97 (dd, J = 7.6, 4.7 Hz, 1H), 7.32 (ddd, J = 18, 4, 7.4, 1.3 Hz, 3H), 7.41 - 7.60 (m, 5H), 7.67 (ddd, J = 8.4, 7.0, 1.7 Hz, 1H) , 7.85 (dd, J = 7.6, 1.9 Hz, 1H), 8.32 (dd, J = 4.8, 1.9 Hz, 1H), 9.12 (d, J = 8 .6 Hz, 1H), 10.97 (s, 1H). Example 267:
[0562] [0562] Example 267 was prepared using a procedure similar to that used to prepare Example 245 where (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole was used in place of (R)-3-methylmorpholine . ESI-MS m/z: 508.5 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 2.90 (dq, J = 7.5, 4.1 Hz, 2H), 3.16 (ddd, J = 10.8, 5.9, 3, 1 Hz, 2H), 3.37 - 3.60 (m, 4H), 3.80 (dd, J = 8.7, 6.2 Hz, 2H), 5.17 (d, J = 8.5 Hz, 1H), 6.84 (dd, J = 7.5, 4.8 Hz, 1H), 7.33 (dd, J = 18.6, 7.8 Hz, 3H), 7.42 - 7 .63 (m, 5H), 7.63 - 7.84 (m, 2H), 8.30 (dd, J = 4.7, 1.8 Hz, 1H), 9.07 (d, J = 8 .6 Hz, 1H), 10.98 (s, 1H). Example 268:
[0563] [0563] Example 268 was prepared using a procedure similar to that used to prepare Example 160 where 4-methoxypiperidine and ethyl 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and 5-bromo-3-fluoropicolinate. methyl, respectively. ESI-MS m/z: 578.2 [M+H]+. Example 269:
[0564] [0564] Example 269 was prepared using a procedure similar to that used to prepare Example 160 where ethyl 4-fluoropiperidine and 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and ethyl 5-bromo-3-fluoropicolinate. methyl, respectively. ESI-MS m/z: 566.2 [M+H]+. Example 270:
[0565] [0565] Example 270 was prepared using a procedure similar to that used to prepare Example 245 where 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 519.2
[0566] [0566] Example 271 was prepared using a procedure similar to that used to prepare Example 160 where ethyl 3-methoxyazetidine and 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and 5-bromo-3-fluoropicolinate. methyl, respectively. ESI MS m/z = 550.1830 [M+H]+. Example 272: Example 272 step a:
[0567] [0567] In an oven-dried flask, methyl 2-methyl-5-bromothiazole-4-carboxylate (0.5 g, 2.12 mmol) was dissolved in morpholine (4 ml, 46.4 mmol) and sealed. The reaction was heated to 60 °C and stirred overnight. The reaction mixture was concentrated, removing excess morpholine. The crude product was added to a silica gel column and eluted with 0% to 100% ethyl acetate/hexane to yield methyl 2-methyl-5-morpholinothiazole-4-carboxylate
[0568] [0568] Example 272 was prepared using a procedure similar to that used to prepare Example 152 where methyl 2-methyl-5-morpholinothiazole-4-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 502.2 [M+H]+. Example 273:
[0569] [0569] Example 273 was prepared using a procedure similar to that used to prepare Example 20 where 4-(1H-1,2,4-triazol-1-yl)benzoic acid was used in place of 5-chlorofuran-2- carboxylic. ESI MS m/z = 463.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 5.18-5.20 (d, J=8.0, 1H), 7.27-7.29 (m, 1H), 7.31-7.35 (m, 2H), 7.37-7.45 (m, 2H), 7.47 - 7.51 (m, 3H), 7.53 - 7.56 (m, 1H), 7.66 - 7 .70 (m, 2H), 7.71-7.99 (m, 2H), 8.00-8.09 (m, 1H), 9.22-9.24 (m, 1H), 9.42 (s, 1H), 11.00 (s, 1H). Example 274:
[0570] [0570] Example 274 was prepared using a procedure similar to that used to prepare Example 245 where azetidine-3-carbonitrile was used in place of (R)-3-methylmorpholine. ESI-MS m/z: 477.2 [M+H]+. 1H NMR (300 MHz, Methanol-d4) δ 3.69 (tt, J = 8.9, 6.0 Hz, 1H), 4.22 (ddd, J = 8.4, 6.2, 1.5 Hz, 2H), 4.35 (td, J = 8.8, 2.4 Hz, 2H), 5.30 (s, 1H), 6.95 (dd, J = 7.7, 4.9 Hz , 1H), 7.23 - 7.72 (m, 10H), 7.98 (dd, J = 7.7, 1.8 Hz, 1H), 8.32 (dd, J = 4.9, 1 .8 Hz, 1H), 8.52 (s, 2H). Example 275:
[0571] [0571] Example 275 was prepared using a procedure similar to that used to prepare Example 160 where ethyl 3-oxa-8-azabicyclo[3.2.1]octane and 2-chloro-6-(trifluoromethyl)nicotinate were used in the instead of morpholine and methyl 5-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 576.3 [M+H]+. Example 276:
[0572] [0572] Example 276 was prepared using a procedure similar to that used to prepare Example 160 where ethyl 3-oxa-8-azabicyclo[3.2.1]octane and 2-chloro-6-(trifluoromethyl)nicotinate were used in the instead of morpholine and methyl 5-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 576.3 [M+H]+. Example 277:
[0573] [0573] Example 277 was prepared using a procedure similar to that used to prepare Example 160 where (R)-2-methylmorpholine and ethyl 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and 5-bromo- Methyl 3-fluoropicolinate, respectively. ESI-MS m/z: 564.3 [M+H]+. Example 278:
[0574] [0574] Example 278 was prepared using a procedure similar to that used to prepare Example 160 where (S)-2-methylmorpholine and ethyl 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and 5-bromo- Methyl 3-fluoropicolinate, respectively. ESI-MS m/z: 564.3 [M+H]+. Example 279:
[0575] [0575] Example 279 was prepared using a procedure similar to that used to prepare Example 160 where 3-oxa-8-azabicyclo[3.2.1]octane and methyl 2-chloro-6-methylnicotinate were used in place of morpholine and 5-
[0576] [0576] Example 280 was prepared using a procedure similar to that used to prepare Example 160 where 8-oxa-3-azabicyclo[3.2.1]octane and methyl 2-chloro-6-methylnicotinate were used in place of morpholine methyl e2-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 522.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.77 (m, 4H), 2.39 (s, 3H), 3.44 – 3.53 (d, 2H), 3.70 – 3.81 ( m, 2H), 3.94 - 4.08 (d, 2H), 5.15 (d, 1H), 6.83 (d, 1H), 7.32 (d, 3H), 7.41 - 7 .60 (m, 5H), 7.67 (m, 1H), 7.79 (d, 1H), 9.10 (d, 1H), 10.98 (s, 1H). Example 281:
[0577] [0577] Example 281 was prepared using a procedure similar to that used to prepare Example 151, where 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-cyanobenzoic acid, which was prepared similarly to 4-cyano-2-morpholinobenzoic acid in Example 131, was used in place of 6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z: 532.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.60 – 1.82 (m, 2H), 1.95 – 2.11 (m, 2H), 2.80 – 2.99 (m, 4H), 4.19 - 4.35 (m, 2H), 5.18 (d, J = 8.6 Hz, 1H), 7.26 - 7.74 (m, 12H), 9.27 (dd, J = 8.5, 1.6 Hz, 1H), 11.00 (s, 1H). Example 282: Example 282 step a:
[0578] [0578] The solution of ethyl 3-chloro-5-(trifluoromethyl)picolinate (1 g, 4.0 mmol), pyridin-4-ylboronic acid (583 mg, 4.7 mmol), Pd(dppf)Cl 2 . DCM (1.8 g, 2.2 mol) and Na2CO3 (848 mg, 8.0 mol) in DMF (5 mL) was stirred for 1 hour at 130 °C. It was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield ethyl 5-(trifluoromethyl)-[3,4'-bipyridine]-2-carboxylate as a white solid (513 mg, 43%). ESI-MS m/z: 297.0 [M+H]+. Example 282 step b:
[0579] [0579] Example 282 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 5-(trifluoromethyl)-[3,4'-bipyridine]-2-carboxylate was used in place of 2-morpholino-4- ethyl (trifluoromethyl)benzoate. ESI-MS m/z: 542.2 [M+H]+. 1H NMR (300MHz,
[0580] [0580] Example 283 was prepared using a procedure similar to that used to prepare Example 20 where 2-(1H-pyrazol-1-yl)benzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 462.4 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ 4.89 (d, J = 8.6 Hz, 1H), 6.13 – 6.19 (m, 1H), 7.24 – 7.78 (m , 13H), 7.81 - 7.91 (m, 1H), 7.95 - 8.05 (m, 1H), 8.91 (d, J = 8.6 Hz, 1H), 10.94 ( s, 1H). Example 284:
[0581] [0581] Example 284 was prepared using a procedure similar to that used to prepare Example 159 where ethyl 2-(cis-2,6-dimethylmorpholino)-4-fluorobenzoate was used in place of ethyl 4-fluoro-2-morpholinobenzoate . ESI-MS m/z: 527.2 [M+H]+. Example 285:
[0582] [0582] Example 285 was prepared using a procedure similar to that used to prepare Example 151, where (R)-4-cyano-2-(3-methylmorpholino)benzoic acid, which was prepared similarly to 4-cyano- 2-morpholino benzoic in Example 131 was used in place of 6-fluoro-2-morpholinicotinic acid. ESI-MS m/z: 520.6 [M+H]+. Example 286:
[0583] [0583] Example 286 was prepared using a procedure similar to that used to prepare Example 160 where (R)-3-methylmorpholine and methyl 2-chloro-6-methylnicotinate were used in place of morpholine and 2-bromo-3-fluoropicolinate of methyl, respectively. ESI-MS m/z: 510.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 0.99-1.01 (m, 3H), 2.50-2.51 (m, 3H), 3.03-3.07 (m, 1H), 3.22-3.26 (m, 1H), 3.33-3.46 (m, 1H), 3.50-3.53 (m, 1H), 3.57-3.69 (m, 1H ), 3.73-3.78 (m, 2H), 5.14-5.16 (d, J=8.0, 1H), 6.89-6.91 (d, J=8.0, 1H), 7.26-7.36 (m, 3H), 7.44-7.55 (m, 5H), 7.65-7.70 (m, 1H), 7.82-7.84 ( m, 1H), 9.08-9.11 (d, J=12.0, 1H), 10.98 (s, 1H). Example 287:
[0584] [0584] Example 287 was prepared using a procedure similar to that used to prepare Example 20 where quinuclidine-4-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 390.1 [M+H]+. H NMR (300 MHz, DMSO-d6) δ 1.69 (m, 6H), 2.76 - 2.88 (m, 6H), 5.03 (d, J = 8.7
[0585] [0585] Example 288 was prepared using a procedure similar to that used to prepare Example 159 where ethyl 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-fluorobenzoate was used in place of ethyl 4-fluoro-2-morpholinobenzoate. ESI-MS m/z: 525.2 [M+H]+. Example 289:
[0586] [0586] Example 289 was prepared using a procedure similar to that used to prepare Example 151, where 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-cyanobenzoic acid, which was prepared similarly to 4-cyano-2-morpholinobenzoic acid in Example 131, was used in place of 6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z: 532.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.82-1.85 (m, 4H), 3.45-3.48 (m, 2H), 3.69-3.80 (m, 4H), 5.15-5.17 (m, 1H), 7.26-7.33 (m, 2H), 4.53-4.54 (m, 1H), 7.35-7.44 (m, 3H ), 7.46-7.55(m, 6H), 7.65-7.74 (m, 2H), 9.24-9.26 (d, J=8.0, 1H), 10.97 (s, 1H). Example 290:
[0587] [0587] Example 290 was prepared using a procedure similar to that used to prepare Example 162, where 8-oxa-3-azabicyclo[3.2.1]octane was used in place of morpholine. ESI-MS m/z: 551.6 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.69 (m, 4H), 3.22 (d, J = 12.9 Hz, 2H), 3.67 (m, 2H), 4.35 (s , 2H), 5.15 (d, J = 6.9 Hz, 1H), 7.26 (m, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.48 (m , 5H), 7.65 (m, 1H), 8.66 (s, 1H), 9.24 (d, J = 7.9 Hz, 1H), 10.98 (s, 1H). Example 291:
[0588] [0588] Example 291 was prepared using a procedure similar to that used to prepare Example 20 where 3-cyano-1H-indole-6-carboxylic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 460.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.19 (d, J = 8.6 Hz, 1H), 7.24 - 7.89 (m, 11H), 7.96 - 8.03 (m, 1H), 8.44 (s, 1H), 9.16 (d, J = 8.6 Hz, 1H), 11.02 (s, 1H), 12.52 (s, 1H). Example 292:
[0589] [0589] Example 292 was prepared using a procedure similar to that used to prepare Example 272. ESI-MS m/z: 489.1 [M+H]+.
[0590] [0590] Example 293 was prepared using a procedure similar to that used to prepare Example 282. ESI-MS m/z: 505.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.92 (m, 2H), 1.10 (m, 2H), 2.90 - 3.00 (m, 1H), 5.20-5.23( d, J = 7.8 Hz, 1H), 7.25 - 7.37 (m, 3H), 7.37 - 7.56 (m, 5H), 7.65 (m, 1H), 7.82 (s, 1H), 8.89 (s, 1H), 9.41 (d, J = 8.4 Hz, 1H), 10.98 (s, 1H). Example 294:
[0591] [0591] Example 294 was prepared using a procedure similar to that used to prepare Example 160 where (R)-3-methylmorpholine and ethyl 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and 5-bromo- Methyl 3-fluoropicolinate, respectively. ESI-MS m/z: 564.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.80 (d, J = 6.3 Hz, 3H), 2.71 – 2.83 (m, 2H), 3.35 (s, 2H), 3 .50 (m, 1H), 3.58 - 3.68 (m, 1H), 3.78 (m, 2H), 5.20 (d, J = 8.3 Hz, 1H), 7.22 - 7.38 (m, 3H), 7.40 - 7.58 (m, 5H), 7.61 - 7.75 (m, 1H), 8.04 (d, J = 1.9 Hz, 1H) , 8.45 (s, 0.29H), 8.72 - 8.78 (m, 1H), 9.37 (d, J = 8.5 Hz, 1H), 10.97 (s, 1H). Example 295:
[0592] [0592] Example 295 was prepared using a procedure similar to that used to prepare Example 160 where methyl 2-chloro-6-methoxynicotinate was used in place of methyl 2-bromo-3-fluoropicolinate. ESI-MS m/z: 512.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.11 - 3.27 (m, 4H), 3.62 (s, 4H), 3.87 (s, 3H), 5.13 (d, J = 8.6 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 7.18 - 7.40 (m, 3H), 7.40 - 7.58 (m, 5H), 7.61 - 7.74 (m, 1H), 7.83 (d, J = 8.3 Hz, 1H), 9.00 (d, J = 8.7 Hz, 1H), 10.88 (s , 1H). Example 296:
[0593] [0593] Example 296 was prepared using a procedure similar to that used to prepare Example 160 where ethyl 1-methylpiperazin-2-one and 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and 5-bromo- Methyl 3-fluoropicolinate, respectively. ESI-MS m/z: 577.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.86 (s, 3H), 3.34 (d, J = 4.6 Hz, 2H), 3.44 (m, 2H), 3.78 (s , 2H), 5.19 (d, J = 8.2 Hz, 1H), 7.22 - 7.39 (m, 3H), 7.40 - 7.57 (m, 5H), 7.61 - 7.71 (m, 1H), 7.93 (d, J = 1.9 Hz, 1H), 8.66 - 8.78 (m, 1H), 9.39 (d, J = 8.4 Hz , 1H), 10.97 (s, 1H). Example 297:
[0594] [0594] Example 297 was prepared using a procedure similar to that used to prepare Example 151. ESI-MS m/z: 552.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.18 (s, 6H), 3.25 (d, J = 5.2 Hz, 2H), 4.66 (s, 1H), 5.20 (d , J = 8.3 Hz, 1H), 7.20 - 7.40 (m, 3H), 7.40 - 7.62 (m, 6H), 7.67 (ddd, J = 8.5, 7 .1, 1.7 Hz, 1H), 7.92 (t, J = 5.2 Hz, 1H), 8.21 (dd, J = 1.8, 0.8 Hz, 1H), 9.48 (d, J = 8.4 Hz, 1H), 10.99 (s, 1H). Example 298: Example 298 step a:
[0595] [0595] A solution of 1H-benzo[d]imidazole-2-carboxylic acid (500 mg, 3.086 mmol), 1-bromo-2-methoxyethane (852 mg, 6.17 mmmol) and CS2CO3 (3.02 g, 9.258 mmol) in DMF(5 mL) was stirred for 3 hours at 60 °C. It was diluted with water, extracted with EA(x3), washed with brine (x2), The organic phase was dried, concentrated to yield 750 mg(crude) of the desired compound as yellow oil, which was used directly in the next step. ESI-MS m/z: 279.3 [M+H]+. Example 298 step b:
[0596] [0596] Example 298 was prepared using a procedure similar to that used to prepare Example 152 where 2-methoxyethyl 1-(2-methoxyethyl)-1H-benzo[d]imidazole-2-carboxylate was used in place of 2-morpholino Ethyl -4-(trifluoromethyl)benzoate. ESI-MS m/z: 494.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.16 (s, 3H), 3.72 (m, 2H), 4.85 (m, 2H), 5.23 (d, J = 7.5 Hz , 1H), 7.23 - 7.42 (m, 5H), 7.43 - 7.61 (m, 3H), 7.64 - 7.82 (m, 3H), 9.47 - 9.64 (m, 1H), 11.01 (s, 1H). Example 299:
[0597] [0597] Example 299 was prepared using a procedure similar to that used to prepare Example 151, where 3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-fluoropicolinic acid, which was prepared similarly to 5-fluoro-3-morpholinopicolinic acid in Example 136, was used in place of 6-fluoro-2-morpholinopicotinic acid. ESI-MS m/z: 526.5 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.71 (m, 2H), 1.92 - 2.11 (m, 2H), 2.94 (m, 4H), 4.28 (s, 2H) , 5.17 (d, 1H), 7.17 - 7.78 (m, 10H), 8.30 (m, 1H), 9.19 (d, 1H), 10.96 (s, 1H). Example 300:
[0598] [0598] To a stirred solution of methyl 4-bromo-2-hydroxybenzoate (1.5 g, 6.49 mmol), KI (108 mg, 0.65 mmol) and K2CO3 (2.69 g, 19. 47 mmol) in DMF (30 mL) was added 1-bromo-2-methylethane (902mg, 6.49 mmol). The mixture was heated at 80°C overnight and water (150 mL) was added. The mixture was extracted with EA (150 mL × 3) and the combined organic phase was washed with water, brine and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography (PE/EA = 5/1) to yield the desired compound as a yellow solid (1.7 g, 90%). ESI-MS m/z: 289.1 [M+H]+. Example 300 step b:
[0599] [0599] To a stirred solution of the compound from step a (1.7 g, 5.88 mmol) and Zn(CN) 2 (1.36 g, 11.76 mmol) in DMF (30 mL) was added Pd (PPh3)4 (1.36 g, 1.18 mmol). The mixture was heated at 120 °C for 2 hours under a N2 atmosphere. The mixture was cooled to room temperature and saturated FeSO4 solution was added. The mixture was extracted with EA (100 mL × 3) and the combined organic phase was washed with water, brine and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by gel chromatography to give the title compound as a white solid (1.2 g, 78%). ESI-MS m/z: 263.0 [M+H]+. Example 300 step c:
[0600] [0600] Example 300 was prepared using a procedure similar to that used to prepare Example 152 where methyl 4-cyano-2-(2-methoxyethoxy)benzoate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate . ESI-MS m/z: 495.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.27 (s, 3H), 3.67 (dd, J = 5.5, 3.7 Hz, 2H), 4.28 (dd, J = 5, 5, 3.8 Hz, 2H), 5.17 (d, J = 8.0 Hz, 1H), 7.18 - 7.59 (m, 9H), 7.58 - 7.77 (m, 2H ), 7.87 (d, J = 8.0 Hz, 1H), 9.20 (d, J = 8.4 Hz, 1H), 10.97 (s, 1H). Example 301:
[0601] [0601] Example 301 was prepared using a procedure similar to that used to prepare Example 151, where (R)-5-cyano-3-(3-methylmorpholino)picolinic acid, which was prepared similarly to 5-cyano- 3-morpholino picolinic in Example 140, in place of 6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z: 521.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.81 (d, J = 6.3 Hz, 3H), 2.65 - 2.76 (m, 1H), 3.40 - 3.51 (m, 3H), 3.54 - 3.68 (m, 1H), 3.78 (m, 2H), 5.20 (d, J = 8.3 Hz, 1H), 7.23 - 7.38 (m , 3H), 7.41 - 7.58 (m, 5H), 7.67 (m, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.78 (d, J = 1.7 Hz, 1H), 9.41 (d, J = 8.5 Hz, 1H), 10.98 (s, 1H).
[0602] [0602] Example 302 was prepared using a procedure similar to that used to prepare Example 136, where dimethylamine and ethyl 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and ethyl 3,5-difluoropicolinate, respectively. . ESI-MS m/z: 508.3 [M+H]+. Example 303:
[0603] [0603] Example 303 was prepared using a procedure similar to that used to prepare Example 136, where ethyl 3-aminopropanenitrile and 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and ethyl 3,5-difluoropicolinate , respectively. ESI-MS m/z: 533.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.85 (t, J = 6.5 Hz, 2H), 3.74 (q, J = 6.4 Hz, 2H), 5.20 (d, J = 8.3 Hz, 1H), 7.22 - 7.60 (m, 8H), 7.61 - 7.78 (m, 2H), 7.89 (t, J = 6.2 Hz, 1H) , 8.27 - 8.34 (m, 1H), 9.51 (d, J = 8.4 Hz, 1H), 11.00 (s, 1H). Example 304:
[0604] [0604] Example 304 was prepared using a procedure similar to that used to prepare Example 151, where 3-(8-oxa-3-
[0605] [0605] Example 305 was prepared using a procedure similar to that used to prepare Example 136, where ethyl 2-methoxyethan-1-amine and 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and 3.5 - ethyl difluoropicolinate, respectively. ESI-MS m/z: 538.5 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.28 (s, 3H), 3.52 (m, 2H), 3.58 (m, 2H), 5.20 (d, 1H), 7.22 – 7.40 (m, 3H), 7.40 – 7.60 (m, 6H), 7.68 (m, 1H), 7.82 (m, 1H), 8.22 – 8.28 (s , 1H), 9.50 (d, 1H), 11.00 (s, 1H). Example 306:
[0606] [0606] Example 306 was prepared using a procedure similar to that used to prepare Example 298 where 1H-imidazole-2-carboxylic acid was used in place of 1H-benzo[d]imidazole-2-carboxylic acid. ESI-MS m/z: 444.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.20 (s, 3H), 3.63 (m, 2H), 4.54 (m, 2H), 5.15 (d, J = 8.4 Hz , 1H), 7.10 (d, J = 1.1 Hz, 1H), 7.21 - 7.38 (m, 2H), 7.40 - 7.57
[0607] [0607] Example 307 was prepared using a procedure similar to that used to prepare Example 136, where methylamine and ethyl 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and ethyl 3,5-difluoropicolinate, respectively. . ESI-MS m/z: 494.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.97 (s, 3H), 5.18 (d, J = 8.3 Hz, 1H), 7.13 – 7.82 (m, 11H), 8 .22 (d, J = 1.9 Hz, 1H), 9.47 (d, J = 8.4 Hz, 1H), 11.00 (s, 1H). Example 308:
[0608] [0608] Example 308 was prepared using a procedure similar to that used to prepare Example 136, where 2-methoxy-N-methylethan-1-amine and ethyl 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and ethyl 3,5-difluoropicolinate, respectively. ESI-MS m/z: 566.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.04 (s, 6H), 2.85 (s, 3H), 3.31 (d, J = 2.2 Hz, 2H), 4.39 (s , 1H), 5.20 (d, J = 8.5 Hz, 1H), 7.20 - 7.42 (m, 3H), 7.41 - 7.61 (m, 5H), 7.68 ( ddd, J = 8.4, 7.1, 1.7 Hz, 1H), 7.96 - 8.10 (m, 1H), 8.36 - 8.47 (m, 1H), 9.26 ( d, J = 8.6 Hz, 1H), 10.99 (s, 1H). Example 309:
[0609] [0609] A solution of methyl 2-bromo-4-cyanobenzoate (480 mg, 2.0 mmol), thiophen-3-ylboronic acid (307 mg, 2.4 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol) and K2CO3 (552 mg, 4.0 mmol) in dioxane (10 mL) and H2O (2 mL) was stirred for 1 hour at 80 °C. Extracted with EA(3x), dried Na2SO4, and filtered to yield desired compound as a brown solid (389 mg, 80%). ESI-MS m/z: no sign. Example 309 step b:
[0610] [0610] Example 309 was prepared using a procedure similar to that used to prepare Example 152 where methyl 4-cyano-2-(thiophen-3-yl)benzoate was used in place of 2-morpholino-4-(trifluoromethyl)benzoate of ethyl. ESI-MS m/z: 503.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 4.96 (m, 1H), 6.98 – 7.07 (m, 1H), 7.24 – 7.80 (m, 1H), 7.90 – 8.06 (m, 3H), 9.11 (m, 1H), 10.96 (s, 1H). Example 310:
[0611] [0611] Example 310 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI-MS m/z: 444.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.16 (s, 3H), 3.69 (m, 2H), 4.67 (m, 2H), 5.15 (d, J = 8.4 Hz , 1H), 6.73 (d, J = 2.0 Hz, 1H), 7.20 - 7.39 (m, 3H), 7.41 - 7.59 (m, 5H), 7.59 - 7.73 (m, 2H), 9.27 (d, J = 8.4 Hz, 1H), 11.00 (s, 1H). Example 311: Example 311 step a:
[0612] [0612] A solution of 5-bromo-3-fluoropicolinic acid (1.0 g, 4.57 mmol) was dissolved in DMF (15 mL) and BocNHNH 2 (1.2 g, 9.14 mmol) was added. HATU (1.8 g, 4.80 mmol) and Et3N (5 mL) were added. The mixture was stirred at room temperature for 1 hour. Water (20 mL) was added and the mixture was extracted with EA (25 mL×3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (PE/EA=3/1) to yield the desired product as a white solid (1.3 g, 83%). Example 311 step b:
[0613] [0613] A solution of step a compound (1.3 g, 3.78 mmol), morpholine (658 mg, 7.56 mmol) and K2CO3 (1.3 g, 9.45 mmol) in DMSO (10 mL ) was stirred overnight at 100 °C. It was diluted with H2O, and extracted with EA(x3) and washed with brine(x2). The organic phase was combined and concentrated to yield 1.2 g (81%) of white product. ESI-MS m/z: 401.2 [M+H]+. Example 311 step c:
[0614] [0614] To the solution of the compound from step b (500 mg, 1.25 mmol) and ethynyltrimethylsilanes (368 mg, 3.75 mmol) in i-Pr2NH (6 mL) was added Pd(PPh3)2Cl2 (88 mg, 0 .13 mmol) and CuI (24 mg, 0.13 mmol). The mixture was heated at 80 °C for 3 hours and then cooled to room temperature. It was filtered and concentrated, then purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired product as a yellow solid (451 mg, 86%). ESI-MS m/z: 419.4 [M+H]+. Example 311 step d:
[0615] [0615] The solution of the compound from step c (451 mg, 1.08 mmol) and K2CO3 (298 mg, 2.16 mmol) in MeOH (10 mL) was stirred at room temperature for 1 hour. It was purified by silica gel column (PE/EA=3:1-1:1) to yield tert-butyl 2-(5-ethynyl-3-morpholinopicolinoyl)hydrazine-1-carboxylate as a yellow solid (348 mg , 93%). ESI-MS m/z: 347.3 [M+H]+.
[0616] [0616] Example 311 was prepared using a procedure similar to that used to prepare Example 151, where tert-butyl 2-(5-ethynyl-3-morpholinopicolinoyl)hydrazine-1-carboxylate was used in place of 6-fluoro-2 - morpholinonicotinohydrazide. ESI-MS m/z: 506.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.99 (d, 4H), 3.70 (d, 4H), 4.61 (s, 1H), 5.19 (d, 1H), 7.16 – 7.39 (m, 3H), 7.39 – 7.60 (m, 4H), 7.59 – 7.73 (m, 2H), 8.41 (d, 1H), 9.28 (d , J = 8.6 Hz, 1H), 10.97 (s, 1H). Example 312: Example 312 step a:
[0617] [0617] A solution of 5-bromo-3-fluoropicolinic acid (4.0 g, 18.26 mmol) and H2SO4 (10 mL) in EtOH (25 mL) was heated at 80 °C overnight and then cooled to room temperature. It was concentrated, diluted with H2O, and extracted with EA(x3) and washed with brine(x2). The organic phase was combined and concentrated to yield the desired compound as a yellow oil (4.45 g, 95%). ESI-MS m/z: 247.8 [M+H]+. Example 312 step b:
[0618] [0618] The solution of the compound from step a (4.45 g, 18.02 mmol) and K2CO3 (7.46 g, 54.06 mmol) in morpholine (20 mL) was stirred at room temperature for 1 hour. It was concentrated, diluted with H2O, and extracted with EA(x3) and washed with brine(x2). The organic phase was combined and concentrated, then purified by silica gel column (PE/EA=5:1) to yield the desired compound as a yellow solid (4.79 g, 85%). ESI-MS m/z: 315.2 [M+H]+. Example 312 step c:
[0619] [0619] The solution of step b compound (1.5 g, 3.18 mmol), cyclohexenylboronic acid (481 mg, 3.82 mmol), K2CO3 (878 mg, 6.36 mmol) and Pd(PPh3)4 (367mg, 0.318mmol) in DMF (8ml) was stirred overnight. It was filtered and purified by preparative HPLC (MeCN/H2O) to yield ethyl 5-(cyclohex-1-en-1-yl)-3-morpholinopicolinate as a yellow oil (440 mg, 44%). ESI-MS m/z: 317.3 [M+H]+. Example 312 step d:
[0620] [0620] Example 312 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 5-(cyclohex-1-en-1-yl)-3-morpholinopicolinate was used in place of 2-morpholino-4-( ethyl trifluoromethyl)benzoate. ESI-MS m/z: 562.3 [M+H]+. 1H NMR (300MHz,
[0621] [0621] A solution of ethyl 5-(cyclohex-1-en-1-yl)-3-morpholinopicolinate from example 312 step c (460 mg, 1.45 mmol) and Pd-C (100 mg) in 10 mL MeOH was stirred at room temperature for 3 h under H2. Pd/C was filtered off and the filtrate was concentrated to give ethyl 5-cyclohexyl-3-morpholinopicolinate as a yellow oil (500 mg). ESI-MS m/z: 319.3 [M+H]+. Example 313 step b:
[0622] [0622] Example 313 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 5-cyclohexyl-3-morpholinopicolinate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 564.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.39 (m, 5H), 1.76 (m,
[0623] [0623] The solution of methyl 5-bromo-3-morpholinopicolinate compound from example 160 step a (800 mg, 2.55 mmol), pyrrolidine (362 mg, 5.1 mmol), CuI (242 mg, 1.3 mmol), L-Proline (147 mg, 1.3 mmol) and K2CO3 (704 mg, 5.1 mmol) in DMSO (6 mL) was stirred at room temperature for 2 hours. It was filtered and then purified by preparative HPLC (MeCN/H2O) to yield ethyl 3-morpholino-5-(pyrrolidin-1-yl)picolinate as a yellow oil (376 mg, 48%). ESI-MS m/z: 306.2 [M+H]+. Example 314 step b:
[0624] [0624] Example 314 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 3-morpholino-5-(pyrrolidin-1-yl)picolinate was used in place of 2-morpholino-4-(trifluoromethyl)benzoate of ethyl. ESI-MS m/z: 551.4 [M+H]+. 1H NMR (400MHz,
[0625] [0625] Example 315 was prepared using a procedure similar to that used to prepare Example 309 where 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H) -one was used in place of thiophen-3-ylboronic acid. ESI-MS m/z: 528.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.47 (s, 3H), 5.12 (d, J = 8.3 Hz, 1H), 6.34 (d, J = 9.3 Hz, 1H ), 7.23 - 7.40 (m, 4H), 7.50 (m, 5H), 7.67 (m, 1H), 7.90 (d, J = 2.6 Hz, 1H), 7 .99 (d, J = 4.0 Hz, 3H), 9.27 (d, J = 8.4 Hz, 1H), 10.97 (s, 1H). Example 316: Example 316 step a:
[0626] [0626] A solution of 3-bromoisoquinolin-4-amine (980 mg, 4.4 mmol), Cs2CO3 (4.3 g, 13.2 mmol), 1-bromo-2-(2-bromoethoxy)ethane (1 .5 g, 6.7 mmol) in DMA (20 mL) was stirred at 120 °C overnight. Then H2O (20 mL) was added to the mixture and extracted with EA(x3). The organic phase was dried and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a brown solid (500 mg, 39%). ESI-MS m/z: 293.2 [M+H]+. Example 316 step b:
[0627] [0627] A solution of the compound from step a (470 mg, 1.6 mmol), Pd(dppf)Cl 2 (200 mg, 0.245 mmol) and TEA (2 mL) in MeOH (10 mL). The solution was stirred overnight at 100°C in CO(g) under 20 atm. The solid was filtered off. The filtrate was concentrated in vacuo, and was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield methyl 4-morpholinoisoquinoline-3-carboxylate as a black solid (1.0g). ESI-MS m/z: 273.3 [M+H]+. Example 316 step c:
[0628] [0628] Example 316 was prepared using a procedure similar to that used to prepare Example 152 where methyl 4-morpholinoisoquinoline-3-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 532.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.02 (d, J = 6.0 Hz, 4H), 3.78 (t, J = 4.5 Hz, 4H), 5.22 (d, J = 8.6 Hz, 1H), 7.22 - 7.60 (m, 8H), 7.68 (ddd, J = 8.4, 7.1, 1.7 Hz, 1H), 7.87 ( dddd, J = 32.0, 8.0, 6.9, 1.2 Hz, 2H), 8.18 - 8.30 (m, 1H), 8.37 (d, J = 8.3 Hz, 1H), 9.21 (d, J = 9.6 Hz, 2H), 10.99 (s, 1H). Example 317:
[0629] [0629] A solution of methyl 4-amino-2-fluorobenzoate (1.0 g, 5.9 mmol) and K2CO3 (1.6 g, 11.8 mmol) in morpholine (4 mL) was heated to 100°C overnight and then cooled to room temperature. Water (10 ml) was added and the mixture was extracted with EA (10 mlx3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed (silica, PE:EA =2:1) to yield the desired compound as a pink solid (990 mg, 71%). ESI-MS m/z: 237.2 [M+H]+. Example 317 step b:
[0630] [0630] To a solution of the compound from step a (990 mg, 4.2 mmol) and Cs2CO3 (2.05 g, 6.3 mmol) in DMF (5 mL) was added 1,4-dibromobutane (898 mg, 4 .2 mmol). The mixture was heated at 80 °C for 24 hours and then cooled to room temperature. Water (10 ml) was added and the mixture was extracted with EA (10 mlx3). And the combined organic phase was washed with water (20 mL) and brine (20 mL). It was then dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed (silica,PE:EA =5:1) to yield methyl 2-morpholino-4-(pyrrolidin-1-yl)benzoate as a pink solid (200 mg, 16%). ESI-MS m/z: 291.3 [M+H]+.
[0631] [0631] Example 317 was prepared using a procedure similar to that used to prepare Example 152 where methyl 2-morpholino-4-(pyrrolidin-1-yl)benzoate was used in place of 2-morpholino-4-(trifluoromethyl)benzoate of ethyl. ESI-MS m/z: 550.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.91 – 2.01 (m, 4H), 2.88 (m, 4H), 3.24 – 3.30 (m, 4H), 3.68 ( m, 4H), 5.12 (d, J = 8.9 Hz, 1H), 6.15 (d, J = 2.2 Hz, 1H), 6.29 (m, 1H), 7.24 - 7.41 (m, 3H), 7.41 - 7.57 (m, 6H), 7.66 (m, 1H), 8.80 (d, J = 8.9 Hz, 1H), 10.94 (s, 1H). Example 318: Example 318 step a:
[0632] [0632] A solution of 6-chloro-3-fluoropicolinic acid (525 mg, 3.0 mmol) and H2SO4 (1 mL) in EtOH (20 mL) was stirred for 2 hours at 80 °C. Then it was adjusted to pH 8~9, extracted with EA(3x), dried Na2SO4, filtered and concentrated to yield the desired compound as a white solid (610mg, 100%). ESI-MS m/z: 204.2 [M+H]+.
[0633] [0633] Example 318 step b:
[0634] [0634] A solution of compound from step a (406 mg, 2.0 mmol), cyclopropylboronic acid (860 mg, 10.0 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol) and Cs2CO3 (978 mg,3.0 mmol) in dioxane (20 mL) was heated at 120 °C for 2 hours. Then it was poured into water and extracted with EA(3x) to yield the desired crude compound as brown oil. (1 g). ESI-MS m/z: 209.9 [M+H]+. Example 318 step c:
[0635] [0635] A solution of step b compound (1 g, crude) in morpholine (30 mL) was stirred for 3 hours at 110°C. Solvents were removed and extracted with EA(3x) to yield crude desired product ethyl 6-cyclopropyl-3-morpholinopicolinate as brown oil. (1.2 g). ESI-MS m/z: 277.3 [M+H]+. Example 318 step d:
[0636] [0636] Example 318 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 6-cyclopropyl-3-morpholinopicolinate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 522.4 [M+H]+. 1H NMR (300 MHz, Methanol-d4) δ 1.01 (d, J = 5.8 Hz, 4H), 2.14 (m, 1H), 3.08 (m, 4H), 3.86 (m , 4H), 5.39 (s, 1H), 7.26 - 7.79 (m, 11H). Example 319:
[0637] [0637] Example 319 was prepared using a procedure similar to that used to prepare Example 309 where furan-3-ylboronic acid was used in place of thiophen-3-ylboronic acid. ESI-MS m/z: 487.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 5.09 (d, J = 8.4 Hz, 1H), 6.37 - 6.60 (m, 1H), 7.23 - 7.41 (m, 3H), 7.42 - 7.58 (m, 5H), 7.61 - 7.75 (m, 2H), 7.88 - 8.02 (m, 3H), 8.08 (d, J = 1.5 Hz, 1H), 9.19 (d, J = 8.4 Hz, 1H), 10.98 (s, 1H). Example 320:
[0638] [0638] Example 320 was prepared using a procedure similar to that used to prepare Example 309 where (3,5-dimethylisoxazol-4-yl)boronic acid was used in place of thiophen-3-ylboronic acid. ESI-MS m/z: 516.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.91 (d, J = 3.2 Hz, 3H), 2.17 (s, 3H), 5.08 (d, J = 8.1 Hz, 1H ), 7.22 - 7.37 (m, 3H), 7.41 - 7.60 (m, 5H), 7.60 - 7.71 (m, 1H), 7.98 (d, J = 1 .7 Hz, 1H), 8.02 - 8.15 (m, 2H), 9.33 (d, J = 8.4 Hz, 1H), 10.98 (s, 1H). Example 321:
[0639] [0639] Example 321 was prepared using a procedure similar to that used to prepare Example 169 where methyl 3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-bromopicolinate, prepared similarly to methyl 5-bromo-3-morpholinopicolinate in Example 160, was used in place of methyl 5-bromo-3-morpholinopicolinate. ESI-MS m/z: 548.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.18 (s, 2H), 1.6 (s, 2H), 2.15 (d, 1H), 4.25 - 5.15 (m, 3H) , 7.14 - 8.27 (m, 11H), 9.15 (d, 1H), 11.15 (d, 1H). Example 322:
[0640] [0640] Example 322 was prepared using a procedure similar to that used to prepare Example 316 where 2-bromoquinolin-3-amine was used in place of 3-bromoisoquinolin-4-amine. ESI-MS m/z: 532.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.94 – 3.12 (m, 4H), 3.74 (m, 4H), 5.22 (d, J = 7.9 Hz, 1H), 7 .27 (m, 1H), 7.32 - 7.40 (m, 2H), 7.41 - 7.58 (m, 5H), 7.66 (m, 3H), 7.97 (m, 2H ), 8.07 (s, 1H), 9.33 (d, J = 8.5 Hz, 1H), 10.89 (s, 1H). Example 323: Example 323 step a:
[0641] [0641] To a solution of methyl 5-bromo-3-morpholinothiophene-2-carboxylate, prepared in Example 182 step a, (900 mg, 2.9 mmol) in THF/H2O
[0642] [0642] To the solution of the compound from step a (400 mg, 1.37 mmol) and BocNHNH2 (362.1 mg, 2.74 mmol) in DMF (5 mL) was added HATU (1.04 g, 2.74 mmol) and DIPEA (0.5 mL). The mixture was stirred at room temperature for 1 hour. Water (5 mL) was added and the mixture was extracted with EA (20 mL ×3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (PE/EA = 10/1) to yield the desired compound as a yellow oil (230 mg, 41%). ESI-MS m/z: 408.1 [M+H]+. Example 323 step c:
[0643] [0643] Under N 2 atmosphere the compound from step b (230 mg, 0.57 mmol) was dissolved in DMF (4 mL) and Pd(PP3) 4 (131 mg, 0.11 mmol) and Zn(CN) 2 ( 131 mg, 1.13 mmol) was added. The mixture was heated at 120 °C for 2 hours. FeSO4 solution (20 mL) was added and the mixture was extracted with EA (20 mL×3). And the combined organic phase was washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (PE/EA = 5/1) to yield 2-(5-cyano-3-morpholinothiophene-2-carbonyl)hydrazine-1-
[0644] [0644] Example 323 was prepared using a procedure similar to that used to prepare Example 151 where tert-butyl 2-(5-cyano-3-morpholinothiophene-2-carbonyl)hydrazine-1-carboxylate was used in place of 6- fluoro-2-morpholinonicotinohydrazide. ESI-MS m/z: 512.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.02 - 3.12 (m, 4H), 3.61 - 3.71 (m, 4H), 5.13 (d, J = 8.3 Hz, 1H), 7.21 - 7.39 (m, 3H), 7.39 - 7.60 (m, 5H), 7.67 (ddd, J = 8.5, 7.0, 1.8 Hz, 1H), 7.92 (s, 1H), 9.36 (d, J = 8.4 Hz, 1H), 10.99 (s, 1H). Example 324: Example 324 step a:
[0645] [0645] A solution of 6-chloro-3-fluoropicolinic acid (1.40 g, 8 mmol), tert-butyl hydrazinecarboxylate (1.32 g, 10 mmol), DIPEA (3 mL) and HATU (3.80 g, 10 mmol) in DMF (50 mL) was stirred for 0.5 hours at 25 °C. Then it was cooled with H2O, extracted with EA (3x), dried with Na2SO4, filtered and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a white solid (1.74 g, 75 %). ESI-MS m/z: 600.9 [2M+Na]+. Example 324 step b:
[0646] [0646] A solution of compound from step a (725mg, 2.5mmol), Zn(CN)2 (580mg, 5mmol) and Pd(PPh3)4 (580mg, 0.5mmol) in DMA ( 20 mL) was heated at 140 °C for 1 h in the microwave. The mixture was filtered, extracted with EA(3x), the solvents removed and purified by C18 reverse phase column chromatography (MeCN/H2O) to yield the desired product as a yellow solid. (224 mg, 32%). ESI-MS m/z: 302.9 [M+H]+. Example 324 step c:
[0647] [0647] A solution of step b compound (224 mg, 0.8 mmol) in morpholine (10 mL) was stirred for 1 hour at 80 °C. Solvents were removed and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield tert-butyl 2-(6-cyano-3-morpholinopicolinoyl)hydrazine-1-carboxylate as a yellow solid. (208 mg, 75%). ESI-MS m/z: 348.3 [M+H]+. Example 324 step d:
[0648] [0648] Example 324 was prepared using a procedure similar to that used to prepare Example 151, where tert-butyl 2-(6-cyano-3-morpholinopicolinoyl)hydrazine-1-carboxylate was used in place of 6-fluoro-2 -morpholinonicotinohydrazide. ESI-MS m/z: 507.3 [M+H]+. H NMR (300
[0649] [0649] Example 325 was prepared using a procedure similar to that used to prepare Example 151, where 5-cyano-3-morpholinopicolinic acid, prepared in Example 140, was used in place of 6-fluoro-2-morpholinopicotinic acid. ESI-MS m/z: 507.2 [M+H]+. Example 326:
[0650] [0650] Example 326 was prepared using a procedure similar to that used to prepare Example 151, where (R)-5-cyano-3-(2-methylmorpholino) picolinic acid, which was prepared similarly to 5-cyano- 3-morpholinpicolinic acid in Example 140 was used in place of 6-fluoro-2-morpholinicotinic acid. ESI-MS m/z: 521.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.08 (d, 3H), δ 2.54 – 2.62 (d, 1H), 2.83 (m, 1H), 3.18 (m, 2H ), 3.57 – 3.74 (m, 2H), 3.74 – 3.89 (m, 1H), 5.21 (d, 1H), 7.25 – 7.42 (m, 3H), 7.43 - 7.59 (m, 5H), 7.69 (m, 1H), 8.13 (d, 1H), 8.72 (d, 1H), 9.43 (d, 1H), 11 .00 (s, 1H). Example 327:
[0651] [0651] Example 327 was prepared using a procedure similar to that used to prepare Example 160 where ethyl 1-methylpiperazine and 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and ethyl 5-bromo-3-fluoropicolinate. methyl, respectively. ESI-MS m/z: 563.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.19 (s, 3H), 2.49-2.50 (m, 4H), 3.05 (s, 4H), 5.19-5.21 ( d, J=8.0, 1H), 7.28-7.37 (m, 8H), 7.44-7.54 (m, 1H), 7.66-7.85 (m, 1H), 8.65 (s, 1H), 9.35-9.37 (d, J=8.0, 1H), 10.99 (s, 1H). Example 328:
[0652] [0652] Example 328 was prepared using a procedure similar to that used to prepare Example 160 where piperidin-4-ol and ethyl 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and 5-bromo-3- methyl fluoropicolinate, respectively. ESI-MS m/z: 564.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.54-1.61 (m, 2H), 1.79-1.82 (m, 2H), 2.82-2.87 (m, 2H), 3.21-3.24 (m, 2H), 3.60-3.65 (m, 1H), 4.66-4.67 (d, J=4.0, 1H), 5.19-5 .21 (d, J=4.0, 1H), 7.26-7.30 (m, 1H), 7.34-7.37 (m, 2H), 7.44-7.55 (m, 2H), 5H), 7.65-7.66 (m, 1H), 7.67-7.69 (m, 1H), 8.61 (s, 1H), 9.31-9.33(d, J= 8.0, 1H), 10.97 (s, 1H). Example 329:
[0653] [0653] Example 329 was prepared using a procedure similar to that used to prepare Example 151, where (S)-5-cyano-3-(2-methylmorpholino)picolinic acid, which was prepared similarly to 5-cyano- 3-morpholino picolinic in Example 140 was used in place of 6-fluoro-2-morpholinicotinic acid. ESI-MS m/z: 521.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.08 (d, 3H), 2.54 - 2.64 (m, 1H), 2.71 - 2.93 (m, 1H), 3.19 ( m, 2H), 3.61 - 3.91 (m, 3H), 5.22 (d, 1H), 7.22 - 7.41 (m, 3H), 7.43 - 7.61 (m, 5H), 7.69 (m, 1H), 8.13 (d, 1H), 8.72 (d, 1H), 9.43 (d, 1H), 11.00 (s, 1H). Example 330: Example 330 step a:
[0654] [0654] To a stirred solution of ethyl 2-amino-5-methylthiophene-3-carboxylate (2.0 g, 10.8 mmol) in DMA (20 mL) was added 1-bromo-2-(2- bromoethoxy) ethane (5.42 g, 27.5 mmol), Cs 2 CO 3 (11.4 g, 35 mmol) at room temperature. The mixture was refluxed overnight at 80°C. The mixture was cooled to room temperature, then poured into water and extracted with EA (3*100 ml). The organic phase was dried over Na2SO4. The residue was purified by silica gel chromatography (PE/EA = 4/1) to yield ethyl 5-methyl-2-morpholinothiophene-3-carboxylate as a white solid (700 mg, 28%). ESI-MS m/z: 256.2 [M+H]+. Example 330 step b:
[0655] [0655] Example 330 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 5-methyl-2-morpholinothiophene-3-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 501.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ2.38 (3H, d), 2.97 (4H, dd), 3.32 (4H, m), 5.12 (1H, d), 6.90 (1H, d), 7.44 (9H, m), 8.96 (1H, d), 10.96 (1H, s). Example 331: Example 331 step a:
[0656] [0656] A solution of ethyl 3-chloro-5-(trifluoromethyl)picolinate (3.8 g, 15 mmol) and PMBNH2 (4.94 g, 36 mol) in DMSO (50 mL) was stirred for 18 hours at 110°C. It was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a pale yellow solid (1.4 g, 27%).
[0657] [0657] The solution of the compound from step a (1.06 g, 3 mmol) and TFA (5 mL) in DCM (20 mL) was stirred for 1 hour at room temperature. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a pale yellow solid (585 mg, 83%). ESI-MS m/z: 235.2 [M+H]+. Example 331 step c:
[0658] [0658] The solution of step b compound (421 mg, 1.8 mmol), TMSCN (1.78 g, 18 mmol) and (CH2O)n (540 mg, 18 mmol) in MeCN (15 mL) was stirred for 18 hours at 90°C. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) yielding ethyl 3-((cyanomethyl)amino)-5-(trifluoromethyl)picolinate as a brown oil. (328 mg, 67%). ESI-MS m/z: 274.2 [M+H]+. Example 331d:
[0659] [0659] Example 331 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 3-((cyanomethyl)amino)-5-(trifluoromethyl)picolinate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI-MS m/z: 519.4 [M+H]+. H NMR (300 MHz, DMSO-d6) δ 4.76 (d, J = 6.4 Hz, 2H), 5.23 (s, 1H), 7.19 - 7.61 (m, 8H), 7 .63 -
[0660] [0660] A solution of tert-butyl 2-(5-bromo-3-morpholinopicolinoyl)hydrazine-1-carboxylate, prepared in Example 311 step b, (2.0 g, 6.0 mmol) was dissolved in DMSO ( 20 mL), then morpholine (1.04 g, 12.0 mmol) and K2CO3 (2.48 g, 18.0 mmol) were added. The mixture was stirred at room temperature overnight. It was concentrated, diluted with H 2 O, and extracted with EA(x3) and washed with brine(x2). The organic phase was combined and concentrated, then purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a light gray solid (1.96 g, 82%). ESI-MS m/z: 401.1 [M+H]+. Example 332 step b:
[0661] [0661] The solution of the compound from step a (700 mg, 1.8 mmol) was dissolved in 1-methylpyrrolidin-2-one (6 mL), then NaSCH3 (245 mg, 3.5 mmol) and K2CO3 (725 mg, 5.3 mmol) were added. The mixture was stirred at room temperature overnight. Water (10 mL) was added and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired product as a brown solid (515 mg, 80%). ESI-MS m/z: 369.1 [M+H]+. Example 332 step c:
[0662] [0662] A solution of the compound from step b (495 mg, 1.4 mmol) and Oxono (1.22 g, 2.0 mmol) in MeOH (3 mL), acetone (3 mL) and H2O (3 mL) was stirred for three hours at room temperature. It was concentrated, and extracted with EA(x3) and washed with brine(x2). The organic layers were combined and concentrated to yield 254 mg (47%) of tert-butyl 2-(5-(methylsulfonyl)-3-morpholinopicolinoyl)hydrazine-1-carboxylate as a yellow product. ESI-MS m/z: 401.2 [M+H]+. Example 332:
[0663] [0663] Example 332 was prepared using a procedure similar to that used to prepare Example 151, where tert-butyl 2-(5-(methylsulfonyl)-3-morpholinopicolinoyl)hydrazine-1-carboxylate was used in place of 6-fluoro -2-morpholinonicotinohydrazide. ESI-MS m/z: 560.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.09 (s, 4H), 3.39 (s, 3H), 3.75 (s, 4H), 5.22 (d, 1H), 7.29 (d, 1H), 7.33 - 7.40 (m, 2H), 7.41 - 7.60 (m, 5H), 7.63 - 7.75 (m, 1H), 7.98 (d , 1H), 8.76 (d, 1H), 9.44 (d, 1H), 10.99 (s, 1H). Example 333:
[0664] [0664] Example 333 was prepared using a procedure similar to that used to prepare Example 151, where 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-cyanopicolinic acid, which was prepared similarly to 5-cyano-3-morpholinopicolinic acid in Example 140, was used in place of 6-fluoro-2-morpholinopicolinic acid. ESI-MS m/z: 533.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.86 (s, 4H), 3.49 (m, 2H), 3.80 (m, 2H), 3.84 - 3.97 (d, 2H) , 5.21 (d, 1H), 7.23 - 7.40 (m, 3H), 7.40 - 7.60 (m, 5H), 7.68 (m, 1H), 8.04 (d , 1H), 8.58 (d, 1H), 9.39 (d, 1H), 11.00 (s, 1H). Example 334:
[0665] [0665] Example 334 was prepared using a procedure similar to that used to prepare Example 272 where methyl 4-bromo-1,2,5-thiadiazole-3-carboxylate was used in place of 2-methyl-5-bromothiazole-4 -methyl carboxylate. ESI-MS m/z: 560.5 [M+H]+. Example 335: Example 335 step a:
[0666] [0666] A solution of ethyl 5-amino-2-methylthiazole-4-carboxylate (1.7 g, 9.0 mmol), 1-bromo-2-methoxyethane (1.2 g, 9.0 mmol) and Cs2CO3 (4.4 g, 13.5 mmol) in DMF (10 mL) was heated at 50 °C for 7 hours and then cooled to room temperature. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield ethyl 5-((2-methoxyethyl)amino)-2-methylthiazole-4-carboxylate as an orange oil (850 mg, 3, 48 mmol, 39%). ESI-MS m/z: 245.2 [M+H]+. Example 335 step b:
[0667] [0667] Example 335 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 5-((2-methoxyethyl)amino)-2-methylthiazole-4-carboxylate was used in place of 2-morpholino-4- ethyl (trifluoromethyl)benzoate. ESI-MS m/z: 490.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.52 (s, 3H), 3.27 (s, 3H), 3.38 (d, J = 5.4 Hz, 2H), 3.52 (m , 2H), 5.11 (d, J = 8.7 Hz, 1H), 6.84 (m, 1H), 7.22 - 7.37 (m, 3H), 7.40 - 7.58 ( m, 5H), 7.67 (m, 1H), 8.89 (d, J = 8.7 Hz, 1H), 10.95 (s, 1H). Example 336: Example 336 step a:
[0668] [0668] In an oven-dried flask, methyl 5-bromothiazole-4-carboxylate (200 mg, 0.90 mmol) was dissolved in MeCN (2.4 mL). Morpholine (87 µL, 0.99 mmol) and DBU (0.2 mL, 1.35 mmol) were added to the flask sequentially. The vial was sealed and heated at 80 °C for 5 hours. The flask was cooled to room temperature and quenched with water. Extract aqueous layer (3x) with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified on silica gel (hexane/EtOAc: 0% to 80%), providing methyl 5-morpholinothiazole-4-carboxylate (120 mg, 58%) as a white solid. ESI MS m/z = 229.1 [M+H]+. Example 336 step b:
[0669] [0669] Example 336 was prepared using a procedure similar to that used to prepare Example 152 where methyl 5-morpholinothiazole-4-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 488.1537 [M+H]+. Example 337:
[0670] [0670] Example 337 was prepared using a procedure similar to that used to prepare Example 272 where ethyl 5-bromooxazole-4-carboxylate was used in place of methyl 2-methyl-5-bromothiazole-4-carboxylate. ESI MS m/z = 486.2 [M+H]+. Example 338: Example 338 step a:
[0671] [0671] To an oven-dried flask, methyl 5-morpholinothiazole-4-carboxylate, prepared in Example 336, (247 mg, 1.08 mmol) was dissolved in MeCN (5.4 mL). NBS (208 mg, 1.17 mmol) was added to the flask in one portion at room temperature. The reaction was allowed to stir at room temperature until the starting material was consumed. The reaction mixture was concentrated and purified over silica gel (hexane/EtOAc: 0% to 80%), yielding methyl 2-bromo-5-morpholinothiazole-4-carboxylate (256 mg, 77%) as a white solid. ESI MS m/z = 309.0 [M+H]+. Example 338 step b:
[0672] [0672] To a flask was added methyl 2-bromo-5-morpholinothiazole-4-carboxylate (212 mg, 0.69 mmol), cyclopropylboronic acid (65 mg, 0.76 mmol), K2CO3 (286 mg, 2 .07 mmol) and Pd(PPh3)4 (40 mg, 0.04 mmol). The vial was sealed and evacuated with nitrogen. Toluene (2.9 mL) and water (0.6 mL) were added to the vial with the syringe. The reaction mixture was heated to
[0673] [0673] Example 338 was prepared using a procedure similar to that used to prepare Example 152 where methyl 2-cyclopropyl-5-morpholinothiazole-4-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 528.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.72 - 1.00 (m, 2H), 1.08 (m, 2H), 2.33 (m, 1H), 2.82 - 3.16 ( m, 4H), 3.54 - 3.90 (m, 4H), 5.14 (d, J = 8.3 Hz, 1H), 7.22 - 7.41 (m, 3H), 7.41 - 7.60 (m, 5H), 7.67 (m, 1H), 9.07 (d, J = 8.4 Hz, 1H), 10.97 (s, 1H). Example 339:
[0674] [0674] Example 339 was prepared using a procedure similar to that used to prepare Example 272 where ethyl 5-bromo-2-(trifluoromethyl)thiazole-4-carboxylate was used in place of 2-methyl-5-bromothiazole-4- methyl carboxylate. ESI-MS m/z: 556.1 [M+H]+.
[0675] [0675] Example 340 was prepared using a procedure similar to that used to prepare Example 338 where phenylboronic acid was used in place of cyclopropylboronic acid. ESI MS m/z = 564.1823 [M+H]+. Example 341: Example 341 step a:
[0676] [0676] To an oven-dried flask, methyl 2-bromo-5-chlorothiazole-4-carboxylate (200 mg, 0.78 mmol) and Pd(Ph3P)4 (90 mg, 0.08 mmol) were added. The vial was sealed and evacuated and refilled with nitrogen (3x). To the sealed flask, THF (3.9 mL) and pyridin-2-ylzinc(II) bromide (1.9 mL, 0.94 mmol) were added sequentially. The flask was heated to 65°C overnight. The reaction mixture was allowed to cool and then diluted with water and EtOAc. The aqueous layer was extracted twice with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was added to the silica gel column and eluted with 0% to 100% ethyl acetate/hexane to give methyl 5-chloro-2-(pyridin-2-yl)thiazol-4-carboxylate (106 mg, 53% yield) as a solid. ESI MS m/z = 255.0 [M+H]+.
[0677] [0677] Example 341 was prepared using a procedure similar to that used to prepare Example 272 where methyl 5-chloro-2-(pyridin-2-yl)thiazol-4-carboxylate was used in place of 2-methyl-5- methyl bromothiazole-4-carboxylate. ESI MS m/z = 565.3 [M+H]+. Example 342: Example 342 step a:
[0678] [0678] To a flask was added methyl 2-bromo-5-chlorothiazole-4-carboxylate (200 mg, 0.78 mmol), (2-methoxyphenyl)boronic acid (142 mg, 0.94 mmol), Pd (Ph3P)4 (90mg, 0.08mmol) and K2CO3 (323mg, 2.34mmol). The vial was sealed and evacuated with nitrogen (3x). Toluene (3.2 mL) and water (650 µL) were added to the sealed vial. The flask was heated to 80°C and stirred overnight. The reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted twice with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was added to the silica gel column and eluted with 0% to 50% ethyl acetate/hexane to give methyl 5-chloro-2-(2-methoxyphenyl)thiazole-4-carboxylate (150 mg, 68% yield) as a white solid. ESI MS m/z = 284.0 [M+H]+. Example 342 step b:
[0679] [0679] Example 342 was prepared using a procedure similar to that used to prepare Example 272, where methyl 5-chloro-2-(2-methoxyphenyl)thiazole-4-carboxylate was used in place of 2-methyl-5-bromothiazole methyl -4-carboxylate. ESI MS m/z = 594.3 [M+H]+. Example 343:
[0680] [0680] Example 343 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 2-methylthiazole-4-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 417.1 [M+H]+. Example 344: Example 344 step a:
[0681] [0681] To an oven-dried flask, ethyl 2-methylthiazole-4-carboxylate (1.0 g, 5.84 mmol), dissolved in DMF (29 mL) in the open air to yield a yellow solution. 1,3,5-Trichloro-1,3,5-triazinane-2,4,6-trioneine (1.1 g, 4.67 mmol) was added to the solution and stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over NaSO4, filtered and concentrated. The crude product was added to the silica gel column and eluted with 0% to 20% ethyl acetate/hexane to give ethyl 5-chloro-2-methylthiazole-4-carboxylate (257 mg, 21% yield) as a oil . ESI MS m/z = 206.0 [M+H]+. Example 344:
[0682] [0682] Example 344 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 5-chloro-2-methylthiazole-4-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 451.1 [M+H]+. Example 345: Example 345 step a:
[0683] [0683] To an oven-dried flask, methyl 5-bromo-2-methylthiazole-4-carboxylate (600 mg, 2.54 mmol), 2-(3,6-dihydro-2H-pyran-4-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (587 mg, 2.80 mmol), K3PO4∙H2O (1.5 g, 6.61 mmol), and
[0684] [0684] Example 345 was prepared using a procedure similar to that used to prepare Example 152 where methyl 5-(3,6-dihydro-2H-pyran-4-yl)-2-methylthiazole-4-carboxylate was used instead of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 499.2 [M+H]+. Example 346:
[0685] [0685] To a round bottom flask, (S)-3-((5-(5-(3,6-dihydro-2H-pyran-4-yl)-2-methylthiazol-4-yl)-1, 3,4-oxadiazol-2-yl)amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (Example 345) (23 mg, 0.05 mmol) was dissolved in MeOH (2 mL) to give a clear solution. Palladium on carbon (5 mg, 0.05 mmol) was added to the reaction mixture in one portion. The vial was sealed and evacuated with a balloon of hydrogen. The reaction was stirred under hydrogen overnight. The reaction mixture was filtered through celite, washed with EtOAc, and concentrated, yielding (S)-3-((5-(2-methyl-5-(tetrahydro-2H-pyran-4-yl)thiazol-4- yl)-1,3,4-oxadiazol-2-yl)amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (17 mg, 74% yield) as a white solid. ESI MS m/z = 501.2 [M+H]+. Example 347:
[0686] [0686] Example 347 was prepared using a procedure similar to that used to prepare Example 345 where methyl 5-bromothiazole-4-carboxylate was used in place of methyl 5-bromo-2-methylthiazole-4-carboxylate. ESI MS m/z = 485.1 [M+H]+. Example 348: Example 348 step a:
[0687] [0687] In an oven-dried round-bottom flask, potassium iodide (706 mg, 4.25 mmol), potassium carbonate (588 mg, 4.25 mmol), and methyl 3-aminofuran-2-carboxylate ( 300 mg, 2.13 mmol) were dissolved in
[0688] [0688] Example 348 was prepared using a procedure similar to that used to prepare Example 152 where methyl 3-morpholinofuran-2-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 471.2 [M+H]+. Example 349: Example 349 step a:
[0689] [0689] In a round-bottomed flask equipped with a condenser, acid
[0690] [0690] Example 349 was prepared using a procedure similar to that used to prepare Example 152 where methyl 1-phenyl-1H-pyrazole-5-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 462.2 [M+H]+. Example 350: Example 350 step a:
[0691] [0691] In a round-bottomed flask equipped with a condenser, 1-phenyl-1H-pyrazole-3-carboxylic acid (0.25 g, 1.33 mmol) was dissolved in methanol
[0692] [0692] Example 350 was prepared using a procedure similar to that used to prepare Example 152 where methyl 1-phenyl-1H-pyrazole-3-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 462.2 [M+H]+. Example 351:
[0693] [0693] Example 351 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 2-morpholinothiazole-4-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 488.2 [M+H]+. Example 352:
[0694] [0694] Example 352 was prepared using a procedure similar to that used to prepare Example 20 where 2-iodobenzoic acid was used in place of 5-chlorofuran-2-carboxylic acid. ESI MS m/z = 522.0 [M+H]+. Example 353:
[0695] [0695] Example 353 was prepared using a procedure similar to that used to prepare Example 345 where 3-((5-(2-iodophenyl)-1,3,4-oxadiazol-2-yl)amino)-5-phenyl- 1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one was used in place of methyl 5-bromo-2-methylthiazole-4-carboxylate. ESI MS m/z = 478.2 [M+H]+. Example 354:
[0696] [0696] Example 354 was prepared using a procedure similar to that used to prepare Example 346 where 3-((5-(2-(3,6-dihydro-2H-pyran-4-yl)phenyl)-1,3, 4-oxadiazol-2-yl)amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one was used in place of (S)-3-(( 5-(5-(3,6-dihydro-2H-pyran-4-yl)-2-methylthiazol-4-yl)-1,3,4-oxadiazol-2-yl)amino)-5-phenyl-1 ,3-dihydro-2H-benzo[e][1,4]diazepin-2-one. ESI MS m/z = 480.3 [M+H]+. Example 355:
[0697] [0697] To a solution of 2-amino-3-fluorobenzonitrile (25 g, 0.18 mol) in THF (400 mL) was added PhMgBr (120 mL, 3 M) dropwise at 0 °C under N2 over 30 minutes . The reaction mixture was stirred for 2 h at room temperature. Then HCl/H2O (400 mL, 6 M) was added and the reaction mixture was stirred O/N at room temperature. LCMS showed the reaction was complete. The organic layer was removed, the residue phase was extracted with EA (x 3). The combined organic layer was washed with brine, dried over Na2SO4 and purified by silica gel chromatography (PE/EA = 1/0 - 10/1) to yield the desired compound as a yellow solid (31.5 g, 78%) . ESI-MS m/z: 216.0 [M+H]+. Example 355 step b:
[0698] [0698] 3-amino-9-fluoro-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one was prepared using a procedure similar to that used to prepare (Z) - 3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one in Example 1 where (2-amino-3-fluorophenyl)(phenyl)methanone was used in place of 2-benzoylaniline. ESI-MS m/z: 270.1 [M+H]+.
[0699] [0699] Example 355 was prepared using a procedure similar to that used to prepare Example 21 where 3-amino-9-fluoro-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin- 2-one and 2-morpholinobenzohydrazide were used in place of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one and tetrahydro-2H-pyran- 4-carbohydrazide, respectively. ESI-MS m/z: 499.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.83 – 2.93 (m, 4H), 3.69 (dd, J = 5.4, 3.4 Hz, 4H), 5.15 – 5, 24 (m, 1H), 7.11 - 7.18 (m, 3H), 7.25-7.32 (m, 1H), 7.40 - 7.72 (m, 8H), 9.02 ( d, J = 7.9 Hz, 1H), 10.92 (t, J = 13.9 Hz, 1H).
[0700] [0700] Example 355 (300mg, 0.60mmol) was purified by Chiral Separation to yield the product 355a as a pale yellow solid (102mg, 33%) and 355b as a pale yellow solid (103mg, 35%). Example 355a:
[0701] [0701] ESI-MS m/z: 499.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.88 (dd, J = 5.6, 3.5 Hz, 4H), 3.70 (dd, J = 5.6, 3.5 Hz, 4H) , 5.25 (d, J = 8.7 Hz, 1H), 7.07 - 7.24 (m, 3H), 7.30-7.37 (m, 1H), 7.41 - 7.72 (m, 8H), 9.13 (d, J = 8.7 Hz, 1H), 10.96 (s, 1H). Example 355b:
[0702] [0702] ESI-MS m/z: 499.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.83 - 2.93 (m, 4H), 3.65 - 3.75 (m, 4H), 5.25 (d, J = 8.6 Hz, 1H), 7.07 - 7.24 (m, 3H), 7.30-7.37 (m, 1H), 7.41 - 7.72 (m, 8H), 9.13 (d, J = 8.7 Hz, 1H), 10.96 (s, 1H). Example 356:
[0703] [0703] Example 355 was prepared using a procedure similar to that used to prepare Example 355 where 4-morpholinobenzohydrazide was used in place of 2-morpholinobenzohydrazide. ESI-MS m/z: 499.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.23 (t, J = 4.9 Hz, 4H), 3.74 (dd, J = 6.1, 3.6 Hz, 4H), 5.21 (d, J = 8.5 Hz, 1H), 7.01 - 7.13 (m, 2H), 7.18 (dd, J = 8.0, 1.3 Hz, 1H), 7.32 ( td, J = 8.0, 4.9 Hz, 1H), 7.40 - 7.72 (m, 8H), 8.96 (d, J = 8.6 Hz, 1H), 10.93 (s , 1H). Examples 357 and 358:
[0704] [0704] Examples 357 and 358 were prepared using a procedure similar to that used to prepare Example 355 where 2-morpholinonicotinohydrazide was used in place of 2-morpholinobenzohydrazide, followed by chiral separation.
[0705] [0705] Example 357: ESI-MS m/z: 500.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.15 (d, J = 5.0 Hz, 4H), 3.68 (d, J = 4.9 Hz, 4H), 5.25 (d, J = 8.5 Hz, 1H), 6.99
[0706] [0706] Examples 359 and 360 were prepared using a procedure similar to that used to prepare Example 355, where 3-morpholino-5-(trifluoromethyl)picolinohydrazide was used in place of 2-morpholinobenzohydrazide, followed by chiral separation.
[0707] [0707] Example 359: ESI-MS m/z: 568.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.07 (dd, J = 5.7, 3.2 Hz, 4H), 3.61 - 3.77 (m, 4H), 5.30 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.30-7.37 (m, 1H), 7.41 - 7.75 (m, 6H ), 7.89 (s, 1H), 8.69 (s, 1H), 9.43 (d, J = 8.4 Hz, 1H), 10.90 (s, 1H).
[0708] [0708] Example 360: ESI-MS m/z: 568.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.02 - 3.12 (m, 4H), 3.72 (dd, J = 5.9, 3.2 Hz, 4H), 5.29 (d, J = 8.3 Hz, 1H), 7.19 (dd, J = 7.9, 1.4 Hz, 1H), 7.30-7.37 (m, 1H), 7.41 - 7.70 (m, 6H), 7.89 (s, 1H), 8.69 (s, 1H), 9.43 (d, J = 8.5 Hz, 1H), 10.92 (s, 1H). Example 361:
[0709] [0709] Example 361 was prepared using a procedure similar to that used to prepare Example 325, except that (S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-2H-benzo[e][ 1,4]diazepin-2-one was used in place of (S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (A ). (S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one was prepared similarly to (S)-3 -amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (A). ESI-MS m/z: 525.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.03 (s, 4H), 3.72-3.80 (m, 4H), 5.23-5.31 (m, 1H), 7.18- 7.20 (m, 1H), 7.30-7.37 (m, 1H), 7.45 - 7.66 (m, 6H), 8.13-8.14 (m, 1H), 8. 73 (m, 1H), 9.41-9.49(m, 1H), 10.96 (s, 1H). Example 362:
[0710] [0710] Example 355 was prepared using a procedure similar to that used to prepare Example 355 where 2-amino-3-chlorobenzonitrile was used in place of 2-amino-3-fluorobenzonitrile. ESI-MS m/z: 499.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.83 – 2.93 (m, 4H), 3.62 – 3.77 (m, 4H), 5.18 (d, J = 8.5 Hz, 1H), 7.07 - 7.22 (m, 2H), 7.33 (d, J = 4.6 Hz, 2H), 7.41 - 7.61 (m, 6H), 7.67 (dd , J = 7.7, 1.6 Hz, 1H), 7.85 (q, J = 4.2 Hz, 1H), 9.13 (d, J = 8.7 Hz, 1H), 10.64 (s, 1H). Example 363:
[0711] [0711] Example 363 was prepared using a procedure similar to that used to prepare Example 86 where 4-fluorobenzoyl isothiocyanate was used in place of benzoyl isothiocyanate. ESI-MS m/z: 413.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.19 (d, J = 8.8 Hz, 1H), 7.15 - 7.72 (m, 12H), 7.79 - 7.93 (m, 2H), 10.97 (s, 1H), 12.26 (s, 1H). Example 364: Example 364 step a:
[0712] [0712] The solution of 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)thiourea from example 90 step a (1,2 g, 3.9 mol) and MeI (577 mg, 4.1 mmol) in MeOH (20 mL) was refluxed for 1 hour. It was concentrated to yield 1.4 g (crude) of the desired compound as an orange solid, which was used directly in the next step. ESI-MS m/z: 325.0 [M+H]+. Example 364 step b:
[0713] [0713] A solution of step a compound (150 mg, 0.463 mmol), 4-(1H-pyrazol-1-yl)benzohydrazide (103 mg, 0.51 mmol) in pyridine (5 mL) was refluxed for 1 hour in an oil bath. The crude product was purified by preparative HPLC (MeCN/H2O) to yield the title compound as a white solid (27 mg, 13%). ESI-MS m/z: 461.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.21 (d, J = 8.8 Hz, 1H), 6.55 (m, 1H), 7.22 – 7.58 (m, 9H), 7 .57 - 7.82 (m, 2H),
[0714] [0714] Example 365 was prepared using a procedure similar to that used to prepare Example 364 where 4-cyanobenzohydrazide was used in place of 4-(1H-pyrazol-1-yl)benzohydrazide. ESI-MS m/z: 420.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.21 (d, J = 8.6 Hz, 1H), 7.20 - 7.37 (m, 3H), 7.38 - 7.55 (m, 5H), 7.66 (m, 2H), 7.84 (d, J = 8.3 Hz, 2H), 7.93 - 8.08 (m, 2H), 10.97 (s, 1H), 12.66 (s, 1H). Example 366:
[0715] [0715] Example 366 was prepared using a procedure similar to that used to prepare Example 364 where isonicotinohydrazide was used in place of 4-(1H-pyrazol-1-yl)benzohydrazide. ESI-MS m/z: 396.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.23 (d, J = 8.6 Hz, 1H), 7.20 - 7.54 (m, 8H), 7.57 - 7.84 (m, 4H), 8.51 - 8.69 (m, 2H), 10.98 (d, J = 11.8 Hz, 1H), 12.62 (s, 1H). Example 367:
[0716] [0716] Example 367 was prepared using a procedure similar to that used to prepare Example 364 where 2-morpholinobenzohydrazide was used in place of 4-(1H-pyrazol-1-yl)benzohydrazide. ESI-MS m/z: 480.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.77 (m, 4H), 3.62 (s, 4H), 5.21 (d, J = 8.8 Hz, 1H), 7.10 (s , 2H), 7.21 - 7.29 (m, 2H), 7.29 - 7.36 (m, 2H), 7.46 (m, 5H), 7.59 - 7.68 (m, 2H ), 10.89 (s, 1H), 12.80 (s, 1H). Example 368:
[0717] [0717] Example 368 was prepared using a procedure similar to that used to prepare Example 84 where 4-(2-azidoacetyl)benzonitrile was used in place of 2-azido-1-phenylethane. ESI-MS m/z: 410.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ5.20 (s, 1H), 7.25-7.28 (m, 1H), 7.33 - 7.35 (m, 2H), 7.43 - 7 .49 (m, 6H), 7.51-7.55 (m, 3H), 7.64-7.86 (m, 2H), 9.00 (s, 1H), 10.95 (s, 1H ). Example 369:
[0718] [0718] Example 369 was prepared using a procedure similar to that used to prepare Example 84 where 2-azido-1-(4-fluorophenyl)ethan-1-one was used in place of 2-azido-1-phenylethane. ESI-MS m/z: 413.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ5.17-5.19 (d, J = 8.0, 1H), 7.10-7.14 (m, 1H), 7.19 - 7.26 ( m, 3H), 7.27 - 7.36 (m, 3H), 7.44-7.49 (m, 2H), 7.51-7.57 (m, 7H), 7.65-7, 69 (m, 1H), 8.70-8.73 (m, 1H), 10.95 (s, 1H). Example 370:
[0719] [0719] Example 370 was prepared using a procedure similar to that used to prepare Example 84 where 2-azido-1-(4-bromophenyl)ethan-1-one was used in place of 2-azido-1-phenylethane. ESI-MS m/z: 475.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ5.17-5.19 (d, J = 8.0 Hz, 1H), 7.25-7.29 (m, 2H), 7.33 - 7.35 (m, 2H), 7.44 - 7.49 (m, 7H), 7.51-7.59 (m, 2H), 7.61-7.68 (m, 1H), 8.75-8 .77 (d, J = 8.0 Hz, 1H), 10.93 (s, 1H). Example 371:
[0720] [0720] Example 371 was prepared using a procedure similar to that used to prepare Example 95 where 2-chloro-5-phenylpyrimidine was used in place of 3-chloro-6-phenylpyrizadine. ESI-MS m/z: 406.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.56 (d, J = 7.6 Hz, 1H), 7.30 (m, 2H), 7.47 (m, 10H), 7.62 - 7 .77 (m, 2H), 7.95 (s, 1H), 8.20 (d, J = 7.7 Hz, 1H), 8.37 (s, 1H), 10.95 (s, 1H) . Example 372:
[0721] [0721] Example 372 was prepared using a procedure similar to that used to prepare Example 86, where cyclopropanecarbonyl isothiocyanate was used in place of benzoyl isothiocyanate. ESI-MS m/z: 359.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.77 (d, J = 35.3 Hz, 4H), 1.77 (m, 1H), 5.03 (d, J = 9.0 Hz, 1H ), 7.19 - 7.37 (m, 3H), 7.39 - 7.55 (m, 5H), 7.63 (m, 1H), 8.19 (s, 1H), 10.86 ( s, 1H). Example 373:
[0722] [0722] Example 373 was prepared using a procedure similar to that used to prepare Example 95 where 2-chloro-5-(4-fluorophenyl)pyrazine was used in place of 3-chloro-6-phenylpyrizadine. ESI-MS m/z: 424.3 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 5.52 (d, J = 7.7 Hz, 1H), 7.27 (m, 3H), 7.33 - 7.41 (m, 2H), 7.42 - 7.60 (m, 5H), 7.67 (m, 1H), 7.90 - 8.03 (m, 2H) , 8.30 - 8.46 (m, 2H), 8.48 - 8.58 (m, 1H), 10.76 - 11.18 (m, 1H). Example 374:
[0723] [0723] Example 374 was prepared using a procedure similar to that used to prepare Example 95 where 3-chloro-6-(4-fluorophenyl)pyrizadine was used in place of 3-chloro-6-phenylpyrizadine. ESI-MS m/z: 424.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.64 (d, J = 6.2 Hz, 1H), 7.23 – 7.40 (m, 5H), 7.41 – 7.61 (m, 6H), 7.68 (m, 1H), 7.94 - 8.18 (m, 3H), 8.79 (s, 1H), 11.02 (s, 1H). Example 375:
[0724] [0724] Example 375 was prepared using a procedure similar to that used to prepare Example 95, where 3-chloro-6-(pyridin-4-yl)pyrizadine was used in place of 3-chloro-6-phenylpyrizadine. ESI-MS m/z: 407.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.73 (d, J = 7.5 Hz, 1H), 7.24 - 7.43 (m, 4H), 7.43 - 7.62 (m, 5H), 7.69 (m, 1H), 7.93 - 8.02 (m, 2H), 8.06 (d, J = 9.4 Hz, 1H), 8.38 (d, J = 7 .6 Hz, 1H), 8.62 - 8.72 (m, 2H), 10.93 (s, 1H). Example 376:
[0725] [0725] Example 376 was prepared using a procedure similar to that used to prepare Example 95, where 3-chloro-6-(4-methoxyphenyl)pyrizadine was used in place of 3-chloro-6-phenylpyrizadine. ESI-MS m/z: 436.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.79 (s, 3H), 5.68 (d, J = 7.8 Hz, 1H), 6.96 – 7.07 (m, 2H), 7 .28 (m, 2H), 7.36 (m, 2H), 7.43 - 7.53 (m, 4H), 7.67 (m, 1H), 7.83 - 7.95 (m, 3H ), 8.03 (d, J = 7.9 Hz, 1H), 8.44 (s, 1H), 10.92 (s, 1H). Example 377:
[0726] [0726] Example 377 was prepared using a procedure similar to that used to prepare Example 95 where 4-(6-chloropyridazin-3-yl)benzonitrile was used in place of 3-chloro-6-phenylpyrizadine. ESI-MS m/z: 431.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 5.74 (d, J = 7.4 Hz, 1H), 7.27 - 7.43 (m, 4H), 7.44 - 7.59 (m, 5H), 7.66 - 7.75 (m, 1H), 7.92 - 8.01 (m, 2H), 8.03 - 8.12 (m, 1H), 8.16 - 8.26 ( m, 2H), 8.37 (d, J = 7.4 Hz, 1H), 10.96 (s, 1H). Example 378:
[0727] [0727] Example 378 was prepared using a procedure similar to that used to prepare Example 95 where 4-(2-(6-chloropyridazin-3-yl)phenyl)morpholine was used in place of 3-chloro-6-phenylpyrizadine. ESI-MS m/z: 491.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.66 – 2.84 (m, 4H), 3.49 – 3.66 (m, 4H), 5.70 (m, 1H), 7.07 – 7.19 (m, 2H), 7.19 - 7.31 (m, 2H), 7.35 (m, 3H), 7.43 - 7.57 (m, 6H), 7.67 (m, 1H), 7.96 (m, 1H), 8.08 (d, J = 7.9 Hz, 1H), 10.68 (s, 1H). Example 379: Example 379 step a:
[0728] [0728] A solution of aniline (4.65 g, 50 mmol) in DCE (100 mL) was stirred for 10 minutes at 0 °C. Then BCl3 (55 ml, 55 mmol, 1M in DCM) was slowly added before being stirred for 30 minutes at 0 °C. 2-Fluorobenzonitrile (12 g, 100 mmol) and AlCl 3 (7.38 g, 55 mmol) were added and the mixture was heated at 80 °C overnight. Solid was filtered off and the filtrate was concentrated in vacuo, diluted with water (100ml) and extracted with EA (3x100ml). The organic phase was concentrated in vacuo. The crude product was used directly in the next step. ESI-MS m/z: 215.1 [M+H]+.
[0729] [0729] The solution of the compound from step a (8.79 g, 41.8 mmol) in HCl (60 mL) was stirred for 40 minutes at 0 °C. The solution was heated to 80 °C for one hour. The crude product was purified by Flash (MeCN/H2O) to yield the desired compound as a yellow solid (2.3 g, 27%). ESI-MS m/z: 216.1 [M+H]+. Example 379 step c:
[0730] [0730] To a solution of (COCl)2 (1.85 g, 14.2 mmol) was added 2-(1H-benzo[d][1,2,3]triazol-1-yl acid) dropwise. -2-(benzyloxycarbonylamino)acetic acid, prepared in Example 1 step a, (3.6 g, 11 mmol) and DMF (0.5 mL) in THF (100 mL) at 0 °C and stirred for 1 h, then ( 2-aminophenyl)(2-fluorophenyl)methanone (1.08 g, 5.0 mmol) and NMM (1.01 g, 10.0 mmol) were added to the mixture at 0 °C and stirred for 1 h at room temperature. Filtered and NH3.H2O (7N) in MeOH (50 mL) was added and stirred for 2h, extracted with EA (100 mL x 3), washed with aqueous NaOH (1N, 200 mL), dried (Na2SO4), concentrated and dissolved. by HOAc (50 mL), then NH4OAc (4.37 g, 31.0 mmol) was added and stirred for 18 h at room temperature. Solvents were removed and it was adjusted to pH 9~10, washed with Et2O (50 mL) to provide the desired compound as an off-white solid (940 mg, 47%). ESI-MS m/z: 404.1 [M+H]+. Example 379 step d:
[0731] [0731] The compound from step c (940 mg, 2.3 mmol) was dissolved in HBr/HOAc (3 mL) and stirred for 30 min at 70 °C. The reaction mixture was cooled to 0 °C and Et2O (30 mL) was added, filtered to provide the desired compound as a yellow solid (142 mg, 23%). ESI-MS m/z: 270.1 [M+H]+. Example 379 step e:
[0732] [0732] The solution of step d compound (142 mg, 0.53 mmol), TEA (1 mL) and TCDI (140 mg, 0.79 mmol) in DMF (20 mL) is stirred for 1 h at 25 °C. Then 4-fluorobenzohydrazide (120 mg, 0.78 mmol) and EDCI (764 mg, 4 mmol) were added to the mixture and stirred for 2 h at 60 °C. The mixture was cooled to 0 °C and H2O (60 mL) was added. Solid was collected and purified by preparative HPLC (MeCN/H2O) to give the title compound as a light yellow solid (21 mg, 9%). ESI-MS m/z: 432.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.17 (d, J = 8.6 Hz, 1H), 7.15 - 7.48 (m, 7H), 7.50 - 7.71 (m, 3H), 7.80 - 7.94 (m, 2H), 9.17 (d, J = 8.6 Hz, 1H), 11.08 (s, 1H). Example 380:
[0733] [0733] Example 380 was prepared using a procedure similar to that used to prepare Example 379, where 3-fluorobenzonitrile was used in place of 2-fluorobenzonitrile. ESI-MS m/z: 432.1 [M+H]+. 1H NMR (300MHz,
[0734] [0734] Example 381 was prepared using a procedure similar to that used to prepare Example 379 where isophthalonitrile was used in place of 2-fluorobenzonitrile. ESI-MS m/z: 439.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.18 (d, J = 8.3 Hz, 1H), 7.22 - 7.48 (m, 8H), 7.49 - 7.58 (m, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.81 - 7.96 (m, 2H), 9.18 (d, J = 8.4 Hz, 1H), 11, 06 (s, 1H). Example 382:
[0735] [0735] Example 382 was prepared using a procedure similar to that used to prepare Example 379 where 4-fluorobenzonitrile was used in place of 2-fluorobenzonitrile. ESI-MS m/z: 432.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 5.16 (d, J = 8.5 Hz, 1H), 7.24 – 7.50 (m, 7H), 7.51 – 7.64 (m, 2H), 7.70 (m, 1H), 7.82 - 7.95 (m, 2H), 9.16 (d, J = 8.5 Hz, 1H), 11.02 (s, 1H). Example 383: Example 383 step a:
[0736] [0736] A solution of methyl 2-aminothiophene-3-carboxylate (6.0 g, 38.4 mmol) was dissolved in DMA (40 mL), then 1-bromo-2-(2-bromoethoxy)ethane ( 26.5 g, 115 mmol) and Cs2CO3 (37.5 g, 115.0 mmol) were added. The mixture was stirred at 80 °C for 5 hours. It was diluted with H2O, and extracted with EA (x3) and washed with brine (x2). The organic phase was combined and concentrated, then purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as a brown liquid (8.0 g). ESI MS m/z = 227.9 [M+H]+. Example 383 step b:
[0737] [0737] A solution of iodosobenzene diacetate (4.83 g, 15 mmol) was added to the compound from step a (1.14 g, 5 mmol), TMSCF3 (2.13 g, 15 mmol) and KF (870 mg). ) in DMSO (40 mL) was stirred for 0.5 hours at room temperature. It was cooled by H 2 O (50 mL) and extracted with DCM(3x), dried Na 2 SO 4 , filtered to yield crude methyl 2-morpholino-5-(trifluoromethyl)thiophene-3-carboxylate as a brown oil. (5 g). ESI MS m/z = 296.2 [M+H]+. Example 383 step c:
[0738] [0738] Example 404 was prepared using a procedure similar to that used to prepare Example 152 where methyl 2-morpholino-5-(trifluoromethyl)thiophene-3-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl)benzoate of ethyl. ESI MS m/z = 555.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.11 – 3.21 (m, 4H), 3.67 – 3.77 (m, 4H), 5.12 (d, J = 8.5 Hz, 1H), 7.20 - 7.38 (m, 3H), 7.38 - 7.58 (m, 5H), 7.59 - 7.72 (m, 2H), 9.06 (d, J = 8.6 Hz, 1H), 10.97 (s, 1H). Example 384: Example 384 step:
[0739] [0739] A solution of methyl 2-morpholinothiophene-3-carboxylate, from step a, (5.0 g, 22 mmol), HBr (2 mL) and DMSO (2 mL) in EA (4 mL) was stirred at room temperature for 1 hour. The resulting solution was diluted with water and extracted with EA(x3). The organic phase was concentrated and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired product as a brown solid (1.6 g, 24%). ESI MS m/z = 306.2 [M+H]+. Example 384 step b:
[0740] [0740] The solution of step a compound (488 mg, 1.6 mmol), cyclopropylboronic acid (276 mg, 3.2 mmol), Pd(OAc) 2 (72 mg, 0.32 mmol),
[0741] [0741] Example 384 was prepared using a procedure similar to that used to prepare Example 152 where methyl 5-cyclopropyl-2-morpholinothiophene-3-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 527.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.60 – 0.75 (m, 2H), 0.84 – 1.02 (m, 2H), 2.01 – 2.16 (ddt, J = 13 .3, 8.5, 4.8 Hz, 1H), 2.93 – 3.02 (m, 4H), 3.65 – 3.74 (m, 4H), 5.08 – 5.18 (d , J = 8.6 Hz, 1H), 6.86 - 6.93 (d, J = 0.9 Hz, 1H), 7.23 - 7.40 (m, 3H), 7.41 - 7, 60 (m, 5H), 7.62 - 7.74 (ddd, J = 8.5, 7.0, 1.8 Hz, 1H), 8.92 - 9.01 (d, J = 8.6 Hz, 1H), 10.95 - 11.02 (s, 1H). Example 385: Example 385 step a:
[0742] [0742] A solution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate (10.0 g, 42.6 mmol) and morpholine (4.076 g, 46.86 mmol) was dissolved in MeCN (100 mL), and then DBU (9.712 g, 63.9 mmol) was added. The mixture was stirred at 80°C for 1 hour. It was concentrated, and purified by silica gel column with PE:EA=1:1 to yield the target compound as a yellow green solid (6.17 g, 60%). ESI MS m/z = 243.2 [M+H]+. Example 385 step b:
[0743] [0743] The solution of the compound from step a (6.17 g, 25.51 mmol) and NBS (4.9 g, 27.55 mmol) was dissolved in MeCN (100 mL), the mixture was stirred at room temperature for 1 hour. It was concentrated, and purified by chromatography on silica gel with PE:EA=3:1 to yield ethyl 2-bromo-5-morpholinothiazole-4-carboxylate as a pale yellow solid (7.53 g, 92%). ESI MS m/z = 320.9 [M+H]+. Example 385 step c:
[0744] [0744] To a stirred solution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate (300 mg, 0.97 mmol) and ZnEt 2 (229 mg, 1.87 mmol) in THF (10 mL) was added Pd(PPh3)4 (30 mg, 0.010 mmol) under nitrogen. The mixture was refluxed overnight and then concentrated. The reaction mixture was poured into ice-cold saturated water, extracted with EA (3 x 100 ml). The organic phase was dried over Na2SO4. The residue was purified by flash chromatography (MeCN/H 2 O) to give ethyl 2-ethyl-5-morpholinothiazole-4-carboxylate as a yellow solid (320 mg). ESI MS m/z = 271.2 [M+H]+. Example 385 step d:
[0745] [0745] Example 385 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 2-ethyl-5-morpholinothiazole-4-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 548.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ1.30 (3H, t), 2.95 (2H, t), 3.07 (4H, m), 3.72 (4H, dd), 5.15 (1H, d), 7.34 (3H, m), 7.52 (5H, m), 7.68 (1H, m), 9.07 (1H, d), 10.96 (1H, s). Example 386: Example 387: Example 387 step a:
[0746] [0746] Cyclobutylzinc(II) bromide (7.6 mL, 3.8 mmol) was added dropwise to a solution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate, prepared in Example 385, (1 g, 3.1 mmol) and Pd(PPh3)4 (361 mg, 0.031 mmol) in THF (10 mL) at 0°C under N2. The mixture was stirred for 16 hours under reflux. The solution was water-cooled, concentrated, extracted with EA (x3). The organic layers were combined, dried, concentrated. The crude product was purified by silica gel chromatography (PE-EA) to yield ethyl 2-cyclobutyl-5-morpholinothiazole-4-carboxylate as yellow oil (740 mg, 81%). ESI MS m/z = 297.3 [M+H]+. Example 387 step b:
[0747] [0747] Example 387 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 2-cyclobutyl-5-morpholinothiazole-4-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 542.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.89 (m, 1H), 1.97 - 2.07 (m, 1H), 2.20 - 2.31 (m, 2H), 2.38 ( m, 2H), 3.07 (m, 4H), 3.66 - 3.75 (m, 4H), 3.75 - 3.83 (m, 1H), 5.15 (d, J = 8, 6 Hz, 1H), 7.25 - 7.40 (m, 3H), 7.51 (m, 5H), 7.68 (m, 1H), 9.07 (d, J = 8.7 Hz, 1H), 10.88 - 11.03 (m, 1H). Example 388:
[0748] [0748] Example 388 was prepared using a procedure similar to that used to prepare Example 338 where 3-pyridylboronic acid was used in place of cyclopropylboronic acid. ESI MS m/z = 565.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.19-3.21 (m, 4H), 3.74-3.76 (m, 4H), 5.15-5.17 (d, J=8 .0, 1H), 7.27-7.37 (m, 5H), 7.45-7.57 (m, 6H), 7.66-7.69 (m, 1H), 8.21-8 .24 (m, 1H), 8.65-8.67 (m, 1H), 9.06-9.77 (m, 1H), 9.18-9.20 (m, 1H), 10.98 (s, 1H). Example 389: Example 389 step a:
[0749] [0749] A solution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate, prepared in Example 385, (1.0 g, 3.10 mmol), (5-fluoropyridin-2-yl) zinc bromide ( II) (1488 mg, 6.20 mmol), Pd(PPh3)4 (340 mg, 0.31 mmol) in THF (25 mL) was stirred at 65 °C for 5 h. Then H2O (20 mL) was added to the mixture and extracted with EA (x3). The organic phase was dried and purified by C18 reversed phase column chromatography to yield ethyl 2-(5-fluoropyridin-2-yl)-5-morpholinothiazole-4-carboxylate as a yellow solid (110 mg, 11%). Example 389 step b:
[0750] [0750] Example 389 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 2-(5-fluoropyridin-2-yl)-5-morpholinothiazole-4-carboxylate was used in place of 2-morpholino-4 - ethyl (trifluoromethyl)benzoate. ESI MS m/z = 583.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.32-3.34 (m, 4H), 3.74-3.75 (m, 4H), 5.16-5.18 (d, J=8 .0, 1H), 7.27-7.29 (m, 1H), 7.31-7.37 (m, 2H), 7.46-7.54 (m, 5H), 7.67-7 .69 (m, 1H), 7.93-7.94 (m,1H), 8.07-8.11 (m,1H), 8.65-8.66(m,1H), 9.17 -9.18(d, J=8.0, 1H), 10.99 (s, 1H). Example 390: Example 390 step a:
[0751] [0751] A solution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate, prepared in Example 385, (700 mg, 2.18 mmol), 6-(trifluoromethyl)pyridin-3-ylboronic acid (460 mg, 2.40 mmol), Pd(dppf)Cl2 (320 mg, 0.43 mmol) and Cs2CO3 (1.42 g, 4.37 mmol) was stirred for 2 h at 90 °C in DMF (30 mL). It was purified by silica gel chromatography (PE:EA=5:1) to yield ethyl 5-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)thiazol-4-carboxylate as a yellow solid (460 mg, 54%). ESI MS m/z = 388.2 [M+H]+. Example 390 step b:
[0752] [0752] Example 390 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 5-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)thiazol-4-carboxylate was used in place of 2- ethyl morpholino-4-(trifluoromethyl)benzoate.
[0753] [0753] To a flask, ethyl 5-bromo-2-(trifluoromethyl)thiazole-4-carboxylate (516 mg, 1.70 mmol), K2CO3 (352 mg, 2.55 mmol) and Pd(Ph3P) was added. 4 (392 mg, 0.34 mmol). Evacuation and refilling with N2 were carried out and sealing was carried out. Toluene (8 ml), ethanol (8 ml) and water (4 ml) were added via syringe. (E)-2-(3-Methoxyprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.432 mL, 2.036 mmol) was added via syringe. Flask heated to 80°C and shaken overnight. Dilution with water and extraction with EtOAc(3x) was performed. The organic layer was dried, filtered and concentrated. The crude product was added to the silica gel column and eluted with 0% to 50% ethyl acetate/hexane to yield (E)-5-(3-methoxyprop-1-en-1-yl)-2-(trifluoromethyl) ethyl)thiazole-4-carboxylate (264 mg, 53% yield) as an oil. Examples 394 and 395 step b: relative stereochemistry
[0754] [0754] To an oven dried flask was added ethyl (E)-4-(3-methoxyprop-1-en-1-yl)-2-(trifluoromethyl)thiazole-5-carboxylate (264 mg, 0.894 mmol ) and
[0755] [0755] Examples 394 and 395 were prepared using a procedure similar to that used to prepare Example 21 where ethyl 4-(2-(methoxymethyl)cyclopropyl)-2-(trifluoromethyl)thiazole-5-carboxylate was converted to its corresponding hydrazide , similar to that described in Example 152 step b, and was used in place of tetrahydro-2H-pyran-4-carbohydrazide. The racemic mixture was purified by chiral separation to yield the desired compound as a mixture of trans-isomers with respect to cyclopropane. (Column= YMC CHIRAL Cellulose-SB, 250*20mm (5 µM); Mobile Phase = 50% EtOH/50% Hexane; Flow Rate = 20 mL/min). ESI MS m/z = 555.1 [M+H]+.
[0756] [0756] A solution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate, prepared in Example 385, (1.0 g, 3.13 mmol), 1-methyl-1H-pyrazol-4-ylboronic acid ( 976 mg, 4.69 mmol), Cs2CO3 (863 mg, 6.25 mmol) and Pd(dppf)Cl2 (511 mg, 0.63 mmol) were dissolved in DMF (20 mL), then the mixture was stirred at 90°C overnight. It was concentrated, and purified by silica gel chromatography with PE:EA=1:1 to obtain ethyl 2-(1-methyl-1H-pyrazol-4-yl)-5-morpholinothiazol-4-carboxylate as a pale yellow solid. (211 mg, 21%). ESI MS m/z = 323.3 [M+H]+. Example 399 step b:
[0757] [0757] Example 399 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 2-(1-methyl-1H-pyrazol-4-yl)-5-morpholinothiazole-4-carboxylate was used in place of 2 ethyl -morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 568.5 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ3.17 – 3.02 (m, 4H), 3.77 – 3.67 (m, 4H), 3.91 (s, 3H), 5.16 (d , 1H), 7.40 - 7.23 (m, 3H), 7.59 - 7.40 (m, 5H), 7.69 (m, 1H), 7.87 (d, 1H), 8, 29 (s, 1H), 9.13 (d, 1H), 10.98 (s, 1H). Example 400:
[0758] [0758] Example 400 was prepared using a procedure similar to that used to prepare Example 21 where ethyl 2-bromo-5-morpholinothiazole-4-carboxylate was converted to the corresponding hydrazide, similar to that described in Example 152 step b, and used in the instead of tetrahydro-2H-pyran-4-carbohydrazide. ESI MS m/z = 568.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ
[0759] [0759] NaH (360 mg, 0.015 mol) was added to a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (2 g, 0.013 mol) in MeCN (30 ml) at 0 °C. The mixture was stirred for 20 minutes at 0 °C. Bromoethane (1.67 g, 0.015 mol) was added and the mixture was stirred overnight. The solution was cooled with water, concentrated. The crude product was purified via silica gel chromatography (DCM-MeOH) to yield the mixture as a yellow oil (1.25 g, 53%). ESI MS m/z = 184.3 [M+H]+. Example 401 step b:
[0760] [0760] The solution of the mixture from step 1 (1.25 g, 6.8 mmol), 1-bromo-2-(2-bromoethoxy)ethane (3.1 g, 13.6 mmol), Cs2CO3 (4, 44 g, 13.6 mmol) in DMA (20 mL) was stirred overnight at 100°C. The mixture was diluted with water, extracted with EA(x3). The organic layers were combined and washed with brine (x2), dried and concentrated. The residue was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield 1-ethyl-3-morpholino-1H-
[0761] [0761] Example 401 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 1-ethyl-3-morpholino-1H-pyrazole-4-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI MS m/z = 499.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.36 (m, 3H), 3.17 (d, J = 5.3 Hz, 4H), 3.61 – 3.74 (m, 4H), 4 .07 (m, 2H), 5.07 - 5.14 (m, 1H), 7.32 (m, 3H), 7.50 (m, 5H), 7.68 (m, 1H), 8. 09 (d, J = 2.3 Hz, 1H), 8.91 (m, 1H), 10.98 (s, 1H). Example 402:
[0762] [0762] Example 402 was prepared using a procedure similar to that used to prepare Example 401 where 1-bromo-2-methoxyethane was used in place of bromoethane. ESI MS m/z = 529.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.17 (m, 4H), 3.25 (s, 3H), 3.67 (m, 6H), 4.20 (m, 2H), 5.10 (d, J = 8.7 Hz, 1H), 7.25 - 7.39 (m, 3H), 7.42 - 7.58 (m, 5H), 7.68 (m, 1H), 8, 04 (s, 1H), 8.91 (d, J = 8.7 Hz, 1H), 10.96 (s, 1H). Example 403:
[0763] [0763] A solution of 3-amino-1-isopropyl-1H-pyrazole-4-carboxylic acid (1 g, 6 mmol) and H2SO4 (2 mL) in EtOH (5 mL) was refluxed for 5 hours. The solution was concentrated, adjusted to pH=8 with saturated aqueous Na2CO3, extracted with EA(x3). The organic layers were combined, dried, concentrated to yield the desired product 1.09 g (crude) as orange oil, which was used directly in the next step. ESI MS m/z = 198.3 [M+H]+. Example 403 step b:
[0764] [0764] The solution of step a compound (1.09 g, 5.5 mmol), 1-bromo-2-(2-bromoethoxy)ethane (2.5 g, 11 mmol) and Cs2CO3 (3.6 g , 11 mmol) in DMA (10 mL) was stirred overnight at 100 °C. The solution was diluted with water, extracted with EA(x3), washed with brine(x2). The organic phase was dried, concentrated. The residue was purified via silica gel chromatography (PE-EA) to yield ethyl 1-isopropyl-3-morpholino-1H-pyrazole-4-carboxylate as orange oil (1 g, 67%). ESI MS m/z = 268.4 [M+H]+. Example 403 step c:
[0765] [0765] Example 403 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 1-isopropyl-3-morpholino-1H-pyrazole-4-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI MS m/z = 513.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.41 (d, J = 6.6 Hz, 6H), 3.10 – 3.19 (m, 4H), 3.67 (m, 4H), 4 .43 (m, 1H), 5.10 (d, J = 8.7 Hz, 1H), 7.25 - 7.37 (m, 3H), 7.43 - 7.56 (m, 5H), 7.67 (m, 1H), 8.07 (s, 1H), 8.87 (d, J = 8.7 Hz, 1H), 10.96 (s, 1H). Example 404: Example 404 step a:
[0766] [0766] To a solution of ethyl 3-aminofuro[2,3-b]pyridine-2-carboxylate (500mg, 2.42mmol) in DMF (10mL) was added NaH (387mg, 9.68mmol) . It was stirred at room temperature for 10 minutes and then 1-bromo-2-(2-bromoethoxy)ethane (1.67 g, 7.28 mmol) was added. The solution was stirred at room temperature for 2 hours. Then H2O (20 mL) was added to the mixture and extracted with EA(x3). The organic phase was dried and purified by C18 reversed phase column chromatography to yield ethyl 3-morpholinofuro[2,3-b]pyridine-2-carboxylate as a yellow solid (310 mg, 46%). ESI MS m/z = 276.9 [M+H]+. Example 404 step b:
[0767] [0767] Example 404 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 3-morpholinofuro[2,3-b]pyridine-2-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI MS m/z = 522.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.36-3.39 (m, 4H), 3.73-3.76 (m, 4H), 5.18-5.20 (d, J=8 .0, 1H), 7.27-7.31 (m, 1H), 7.36-7.38 (m, 2H), 7.40-7.43 (m, 1H), 7.45-7 .49 (m, 2H), 7.52-7.56 (m, 3H), 7.67-7.71 (m, 1H), 8.42-8.46 (m, 2H), 9.39 -9.41 (d, J=8.0, 1H), 11.02 (s, 1H). Example 405: Example 405 step a:
[0768] [0768] A solution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate, prepared in Example 385, (700 mg, 2.19 mmol), cyclohexenylboronic acid (303 mg, 2.41 mmol), K2CO3 (604 mg, 4.38 mmol) and Pd(dppf)Cl 2 (160 mg, 0.219 mmol) was dissolved in DMF (5 mL), then the mixture was stirred at 100 °C overnight. It was concentrated, and purified by chromatography on silica gel with PE:EA=5:1 to obtain a yellow oil (571 mg, 81%). ESI MS m/z = 322.6 [M+H]+. Example 405 step b:
[0769] [0769] The solution of step a compound (700 mg, 2.19 mmol), cyclohexenylboronic acid (303 mg, 2.41 mmol), K2CO3 (604 mg, 4.38 mmol) and Pd(dppf)Cl2 (160 mg, 0.22 mmol) was dissolved in DMF (5 mL), then the mixture was stirred at 100 °C overnight. It was concentrated, and purified by silica gel column with PE:EA=5:1 to obtain ethyl 2-cyclohexyl-5-morpholinothiazole-4-carboxylate as a yellow oil (571 mg, 81%). ESI MS m/z = 324.6 [M+H]+. Example 405 step c:
[0770] [0770] Example 405 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 2-cyclohexyl-5-morpholinothiazole-4-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 570.5 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.55 – 1.16 (m, 5H), 1.90 – 1.63 (m, 3H), 2.04 (d, 2H), 3.15 – 3.00 (m, 4H), 3.82 - 3.61 (m, 4H), 5.15 (d, 1H), 7.43 - 7.23 (m, 3H), 7.62 - 7, 43 (m, 5H), 7.68 (m, 1H), 9.08 (d, 1H), 10.97 (s, 1H). Example 406:
[0771] [0771] The solution of step a compound (2.0 g, 6.25 mmol), ethynyltrimethylsilane (1420 mg, 12.50 mmol), Pd(PPh3) Cl2 (439 mg, 0.62 mmol), PPh3 ( 3.28 g, 12.50 mmol) and TEA (5 mL) in THF (50 mL) was stirred at room temperature for 20 minutes. Then CuI (2.4 g, 12.50 mmol) was added to the solution and stirred at 65 °C for 2 hours. Then H2O (20 mL) was added to the mixture and extracted with EA(x3). The organic phase was dried and purified by C18 reversed phase column chromatography to yield the desired compound as a yellow oil (1.25 g, 59%). ESI MS m/z = 339.0 [M+H]+. Example 406 step b:
[0772] [0772] The solution of step a compound (1.25 g, 3.70 mmol), LiOH (444 mg, 18.49 mmol) in H 2 O (10 mL), THF (10 mL) was stirred at room temperature for 5 hours and the solution was adjusted to pH 10. It was purified by C18 reversed phase column chromatography to yield the desired compound as a yellow solid (580 mg, 66%). ESI MS m/z = 238.9 [M+H]+. Example 406 step c:
[0773] [0773] Example 406 was prepared using a procedure similar to that used to prepare Example 151, where 2-ethynyl-5-morpholinothiazole-4-carboxylic acid was used in place of 6-fluoro-2-morpholinicotinic acid. ESI MS m/z = 512.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.17-3.20 (m, 4H), 3.71-3.73 (m, 4H), 4.91 (s, 1H), 5.14- 5.16 (d, J=8.0, 1H), 7.26-7.28 (m, 1H), 7.30-7.36 (m, 2H), 7.45-7.48 (m , 2H), 7.51-7.55 (m, 3H), 7.65-7.69 (m, 1H), 9.17-9.19 (d, J=8.0, 1H), 10 .97 (s, 1H). Example 407: Example 407 step a:
[0774] [0774] To a stirred solution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate, prepared in Example 385, (400 mg, 1.25 mmol) in Toluene (10 mL) was added tributyl (1-ethoxyvinyl ) stannane (905 mg, 2.5 mmol) and Pd(PPh3)4 (40 mg, 0.001 mmol) at room temperature under nitrogen. The mixture was refluxed for 2.5 hours at 110 °C under nitrogen and then concentrated. The reaction mixture was poured into water and extracted with EA (3 * 100 ml). The organic phase was dried over Na2SO4. The residue was purified by silica gel chromatography (PE/EA = 3/1) to yield the desired compound as a white solid (300 mg, 77%). ESI MS m/z = 313.2 [M+H]+. Example 407 step b:
[0775] [0775] To the solution of compound from step a (300 mg, 0.96 mmol) was added HCl (5 mL) in dioxane (8 mL) at room temperature. The resulting solution was stirred at room temperature for 5 h. The reaction mixture was poured into saturated liquid NaHCO3 and extracted with EA (3 * 100 mL). The organic phase was dried over Na2SO4 and purified to yield the desired compound as a white solid (150mg, 54%). ESI MS m/z = 285.4 [M+H]+. Example 407 step c:
[0776] [0776] To a stirred solution of BAST (2 mL, 1.04 mmol) in DCM (5 mL) was added step b compound (150 mg, 0.52 mmol) at room temperature. The resulting solution was stirred at room temperature for 3 days. During the period, additional BAST (5 mL) was added. The reaction mixture was poured into ice water and extracted with DCM (3 * 100 mL). The organic phase was dried over Na2SO4 and purified by silica gel chromatography (PE/EA = 1/1) to yield ethyl 2-(1,1-difluoroethyl)-5-morpholinothiazole-4-carboxylate as a yellow solid (160 mg, 100%). ESI MS m/z = 307.1 [M+H]+. Example 407 step d:
[0777] [0777] Example 407 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 2-(1,1-difluoroethyl)-5-morpholinothiazole-4-carboxylate was used in place of 2-morpholino-4-( ethyl trifluoromethyl)benzoate. ESI MS m/z = 552.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ1.24 (1H, s), 2.12 (3H, t), 3.20 (4H, m), 3.74 (4H, m), 5.15 (1H, d), 7.32 (3H, m), 7.50 (5H, m), 7.67 (1H, m), 9.20 (1H, d), 10.98 (1H, s). Example 408: Example 408 step a:
[0778] [0778] A solution of 6-methoxyquinoline-4-carboxylic acid (500 mg, 2.46 mmol) and H2SO4 (2 mL) in EtOH (10 mL) was stirred at 80 °C for 2 hours. Then H2O (20 mL) was added to the mixture and extracted with EA (x3). The organic layer was washed with NaHCO 3 , brine and dried over Na 2 SO 4 to give ethyl 6-methoxyquinoline-4-carboxylate as a yellow solid (450 mg, 79%). ESI MS m/z = 231.9 [M+H]+. Example 408 step b:
[0779] [0779] Example 408 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 6-methoxyquinoline-4-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 477.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.91 (s, 3H), 5.26 (s, 1H), 7.29-7.32 (m, 1H), 7.37-7.39 ( m, 2H), 7.45-7.49 (m,2H), 7.51-7.54 (m,4H), 7.68-7.72 (m,1H), 7.85-7, 86 (m,1H), 8.04-8.06 (m, 1H), 8.56-8.57 (m,1H), 8.91-8.93 (m,1H), 9.52 ( m, 1H), 10.93-10.94 (s, 1H). Example 409: Example 409 step a:
[0780] [0780] A solution of 6-bromoquinoline-4-carboxylic acid (500 mg, 2.0 mmol), EtOH (10 mL) and H2SO4 (2 mL) was stirred for 4 hours at 80°C. It was diluted with H2O, and extracted with EA (x3) and washed with brine (x2). The organic phase was combined and concentrated to yield a brown solid product (420 mg, 75%) which was used without further purification. ESI MS m/z = 280.2 [M+H]+. Example 409 step b:
[0781] [0781] A solution from step a (767 mg, 2.75 mmol), potassium trifluoro(methoxymethyl)borate (1.25 g, 8.25 mmol), Pd(OAc) 2 (123 mg, 0.55 mmol ), RuPhos (513 mg, 1.1 mmol), and Cs2CO3 (2.68 g, 8.25 mmol) was dissolved in degassed CPME (4.0 mL) and H2O (1.0 mL), then the mixture was was stirred at 100°C overnight under N2. It was concentrated, and purified by chromatography on silica gel with PE:EA=5:1 to obtain ethyl 6-(methoxymethyl)quinoline-4-carboxylate as an orange oil (206 mg, 30%). ESI MS m/z = 245.5 [M+H]+. Example 409 step c:
[0782] [0782] Example 409 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 6-(methoxymethyl)quinoline-4-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 491.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.33 (s, 3H), 4.67 (s, 2H), 5.28 (d, 1H), 7.28 - 7.44 (m, 2H) , 7.44 - 7.60 (m, 6H), 7.71 (m, 1H), 7.82 - 7.90 (m, 2H), 8.13 (d, 1H), 9.01 - 9 .14 (m, 2H), 9.54 (d, 1H), 11.06 (s, 1H). Example 410:
[0783] [0783] Example 410 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI MS m/z = 466.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.92 (s, 3H), 5.16 (d, J = 8.7 Hz, 1H), 6.80 (dd, J = 7.6, 2, 7 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.33 - 7.40 (m, 3H), 7.44 - 7.58 (m, 5H), 7, 66-7.70 (m, 1H), 8.33 (s, 1H), 8.73 (d, J = 7.6 Hz, 1H), 8.94 (d, J = 8.7 Hz, 1H ), 11.01 (s,
[0784] [0784] A solution of methyl 4-bromopyrazolo[1,5-a]pyridine-3-carboxylate (500 mg, 1.97 mmol), potassium trifluoro(2-methoxyethyl)borate (490 mg, 1.28 mmol ), RuPhos (734 mg, 1.58 mmol), Pd(OAc) 2 (177 mg, 0.79 mmol) and Cs2CO3 (1.92 g, 5.91 mmol) in CPME (8 mL) and water (2 mL) was stirred for 5 hours at 100 °C under N2. The mixture was diluted with water, extracted with EA(x3), The organic phase was dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to yield the desired compound as a yellow solid (140 mg, 30%). ESI MS m/z = 235.3 [M+H]+. Example 411 step b:
[0785] [0785] Example 411 was prepared using a procedure similar to that used to prepare Example 152 where methyl 4-(2-methoxyethyl)pyrazolo[1,5-a]pyridine-3-carboxylate was used in place of 2-morpholino- Ethyl 4-(trifluoromethyl)benzoate. ESI MS m/z = 494.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.15 (s, 2H), 3.41 (m, 2H), 3.47 (m, 2H), 5.16 (d, J = 8.6 Hz , 1H), 7.06 (m, 1H), 7.26 - 7.34 (m, 2H), 7.36 (m, 2H), 7.43 - 7.63 (m, 5H), 7. 68
[0786] [0786] Pd(dppf)Cl2 (0.7 g, 2.15 mmol) was added to ethyl 3-chloro-5-(trifluoromethyl)picolinate (1.64 g, 6.47 mmol), Cs2CO3 (2, 7 g, 8.6 mmol) and (E)-3-methoxyprop-1-enylboronic acid (0.5 g, 4.3 mmol) in DMF (30 mL) at room temperature under N 2 . The mixture was stirred for 2 hours at 100°C. The solution was diluted with EA, washed with brine. The organic phase was dried over anhydrous Na2SO4 and concentrated. The crude product was purified via silica gel chromatography (PE-EA) to yield the desired compound as a yellow solid (0.53 g, 43%). ESI MS m/z = 290.0 [M+H]+. Examples 412 and 413 step b:
[0787] [0787] The solution of the compound from step a (300 mg, 1.0 mmol) and NH2NH2.H2O (2 mL) in EtOH (5 mL) was refluxed for 2 hours. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield a mixture of A and B as a yellow solid (~20% of the olefin was reduced as A) (200mg, 70%). A ESI MS m/z = 276.3 [M+H]+. B ESI MS m/z = 278.3 [M+H]+.
[0788] [0788] Examples 412 and 413 were prepared using a procedure similar to that used to prepare Example 152 where (E)-3-(3-methoxyprop-1-en-1-yl)-5-(trifluoromethyl)picolinohydrazide and 3-( 3-Methoxypropyl)-5-(trifluoromethyl)picolinohydrazide was used in place of 2-morpholino-4-(trifluoromethyl)benzohydrazide. Example 418 ESI MS m/z = 535.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.32 (s, 3H), 4.11 (m, 2H), 5.22 (d, J = 8.4 Hz, 1H), 6.75 (m , 1H), 7.27 - 7.33 (m, 1H), 7.36 (m, 2H), 7.44 - 7.50 (m, 2H), 7.50 - 7.63 (m, 4H ), 7.69 (m, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.95 - 9.10 (m, 1H), 9.50 (d, J = 8, 4 Hz, 1H), 11.01 (s, 1H). Example 419 ESI MS m/z = 537.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.72 - 1.96 (m, 2H), 3.11 - 3.25 (m, 4H), 3.33 (s, 3H), 5.22 ( d, J = 7.9 Hz, 1H), 7.25 - 7.32 (m, 1H), 7.33 - 7.41 (m, 2H), 7.43 - 7.50 (m, 2H) , 7.50 - 7.60 (m, 3H), 7.68 (m, 1H), 8.27 (d, J = 2.1 Hz, 1H), 8.88 - 9.10 (m, 1H ), 9.47 (d, J = 8.4 Hz, 1H), 10.99 (s, 1H). Example 414: Examples 414 step a:
[0789] [0789] The compound 3-fluoro-5-(trifluoromethyl)picolinic acid (2.0 g, 9.56 mmol) was dissolved in DMF (8 mL) and BocNHNH 2 (2.5 g, 19.12 mmol) was added , and then DIPEA (2.5 g, 19.12 mmol) and HATU (3.8 g, 10.04 mmol) were added. The mixture was stirred at room temperature for 1 hour. Water (30 mL) was added and the mixture was extracted with EA (50 mL×3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by C18 reversed phase column chromatography to yield the desired product as a yellow solid (2.0 g, 65%). Example 414 step b:
[0790] [0790] A solution of tert-butyl 2-(3-fluoro-5-(trifluoromethyl)picolinoyl)hydrazinecarboxylate, prepared in step a, (400mg, 1.24mmol) and 1-methoxy-2-methylpropan-2 -amine (191 mg, 1.8 mmol) was dissolved in DMSO (10 mL). The mixture was stirred at 100°C for 4 hours. Water (10 mL) was added and it was purified by C18 reverse phase column chromatography (MeCN/H2O) to yield the desired product as a yellow solid (340 mg, 68%). ESI MS m/z = 406.6 [M+H]+. Example 414 step c:
[0791] [0791] The solution of step b compound (340 mg, 0.84 mmol) and ZnBr2 (371 mg, 1.67 mmol) in DCM (10 mL) was stirred for one hour at room temperature. It was concentrated, diluted with 150 ml of EA and washed with water (x3). The organic layer was concentrated to yield 1.65 g as a yellow oil. It was purified by C18 reversed-phase column chromatography (MeCN/H2O) to yield 200 mg of 3-((1-methoxy-2-methylpropan-
[0792] [0792] Example 414 was prepared using a procedure similar to that used to prepare Example 152 where 3-((1-methoxy-2-methylpropan-2-yl)amino)-5-(trifluoromethyl)picolinohydrazide was used in place of 2 -morpholino-4-(trifluoromethyl)benzohydrazide. ESI MS m/z = 566.5 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.29 – 1.47 (s, 6H), 3.30 – 3.32 (s, 3H), 3.43 – 3.53 (s, 2H), 5.18 - 5.26 (d, J = 8.2 Hz, 1H), 7.27 - 7.42 (m, 3H), 7.45 - 7.64 (m, 5H), 7.66 - 7.77 (m, 2H), 8.00 - 8.09 (s, 1H), 8.23 - 8.33 (d, J = 1.7 Hz, 1H), 9.48 - 9.57 ( d, J = 8.4 Hz, 1H), 10.96 - 11.11 (s, 1H). Example 415:
[0793] [0793] Example 415 was prepared using a procedure similar to that used to prepare Example 414 where 1-(methoxymethyl)cyclopropan-1-amine was used in place of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z = 564.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ2.38 (3H, d), 2.97 (4H, dd), 3.69 (4H, t), 5.12 (1H, d), 6.90 (1H, d), 7.41 (3H, m), 7.67 (5H, m), 8.96 (1H, d), 10.96 (1H, s). Example 416:
[0794] [0794] Example 416 was prepared using a procedure similar to that used to prepare Example 414 where 2-methoxy-2-methylpropan-1-amine was used in place of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z = 555.4 [M+H]+. H NMR (300 MHz, DMSO-d6) δ 1.18 (s, 6H), 3.09 (s, 2H), 3.34 (d, J = 4.7 Hz, 2H), 5.19 (d , J = 8.4 Hz, 1H), 7.21 - 7.59 (m, 9H), 7.60 - 7.85 (m, 2H), 8.22 (d, J = 1.8 Hz, 1H), 9.49 (d, J = 8.4 Hz, 1H), 10.99 (s, 1H). Examples 417 and 418:
[0795] [0795] Examples 417 and 418 were prepared using a procedure similar to that used to prepare Example 414 where (cis)-2-aminocyclobutanol hydrochloride was used in place of 1-methoxy-2-methylpropan-2-amine. The crude product was purified by C18 reversed phase column chromatography and preparative HPLC to yield 417 as a yellow solid, 14mg) and 418 as a yellow solid, 14mg). Example 417 ESI MS m/z = 550.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.60 - 1.82 (m, 1H), 1.91 (m, 1H), 2.16 (d, 2H), 4.19 (s, 1H) , 4.46 (s, 1H), 5.22 (d, 1H), 5.51 (d, 1H), 7.26 - 7.34 (m, 2H), 7.38 (m, 2H), 7.43 - 7.61 (m, 5H), 7.69 (m, 1H), 8.21 - 8.38 (m, 2H), 9.49 (d, 1H), 11.02 (s, 1H). Example 418 ESI MS m/z = 550.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.72 (m, 1H), 1.91 (m, 1H), 2.05 - 2.27 (m, 2H), 4.20 (s, 1H) , 4.46 (s, 1H), 5.22 (d, 1H), 5.51 (d, 1H), 7.25 - 7.34 (m, 1H), 7.34 - 7.43 (m , 1H), 7.43 - 7.62 (m, 7H),
[0796] [0796] Example 419 was prepared using a procedure similar to that used to prepare Example 414 where (S)-(tetrahydrofuran-2-yl)methanamine was used in place of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z = 564.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.60-1.64 (m, 1H), 1.81-1.88 (m, 2H), 1.97-2.01 (m, 1H), 3.33-3.37 (m, 1H), 3.51-3.54 (m, 1H), 3.65-3.70 (m, 1H), 3.75-3.80 (m, 1H ), 4.06-4.09 (m, 1H), 5.20-5.22 (d, J=8.0, 1H), 7.27-7.29 (m, 3H), 7.32 -7.38 (m, 5H), 7.45-7.49 (m, 1H), 7.51-7.54 (m, 1H), 7.61-7.86 (m, 1H), 8 .25 (s, 1H), 9.51-9.54(d, J=12.0, 1H), 10.99 (s, 1H). Example 420:
[0797] [0797] Example 420 was prepared using a procedure similar to that used to prepare Example 414 where (R)-(tetrahydrofuran-2-yl)methanamine was used in place of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z = 564.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.60-1.64 (m, 1H), 1.81-1.88 (m, 2H), 1.97-2.01 (m, 1H), 3.34-3.37 (m, 1H), 3.52-3.55 (m, 1H), 3.65-3.70 (m, 1H), 3.74-3.79 (m, 1H ), 4.06-4.09 (m, 1H), 5.20-5.22 (d, J=8.0, 1H), 7.27-7.29 (m, 3H), 7.32 -7.38 (m, 5H), 7.45-7.50 (m, 1H), 7.52-7.54 (m, 1H), 7.61-7.86 (m, 1H), 8 .26 (s, 1H), 9.51-9.53(d, J=8.0, 1H), 11.02 (s, 1H).
[0798] [0798] Example 421 was prepared using a procedure similar to that used to prepare Example 414 where furan-2-ylmethanamine was used in place of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z = 560.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 4.66-4.68 (d, J=8.0, 1H), 5.18-5.20 (d, J=8.0, 1H), 6 .40-6.42 (m, 2H), 7.25-7.28 (m, 3H), 7.30-7.36 (m, 5H), 7.43-7.70 (m, 3H) , 7.99-7.02 (m, 1H), 8.30 (s, 1H), 9.51-9.54(d, J=12.0, 1H), 11.01 (s, 1H) . Example 422:
[0799] [0799] Example 422 was prepared using a procedure similar to that used to prepare Example 414 where (1R,2S)-2-aminocyclopentan-1-ol was used in place of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z = 564.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.37 – 1.94 (m, 5H), 1.99 – 2.16 (m, 1H), 3.84 – 4.00 (m, 1H), 4.06 - 4.18 (dt, J = 7.6, 3.6 Hz, 1H), 4.94 - 5.03 (d, J = 4.5 Hz, 1H), 5.16 - 5, 25 (d, J = 8.4 Hz, 1H), 7.23 - 7.44 (m, 3H), 7.41 - 7.61 (m, 6H), 7.63 - 7.75 (ddd, J = 8.3, 7.1, 1.7 Hz, 1H), 8.03 - 8.12 (d, J = 7.4 Hz, 1H), 8.18 - 8.25 (m, 1H) , 9.43 - 9.52 (d, J = 8.5 Hz, 1H), 10.99 - 11.05 (s, 1H). Example 423:
[0800] [0800] Example 423 was prepared using a procedure similar to that used to prepare Example 414 where (1S,2R)-2-aminocyclopentan-1-ol was used in place of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z = 564.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.40 – 1.70 (m, 3H), 1.74 – 1.80 (s, 1H), 1.80 – 1.87 (s, 1H), 2.03 - 2.13 (m, 1H), 3.86 - 3.97 (t, J = 6.3 Hz, 1H), 4.07 - 4.16 (d, J = 5.4 Hz, 1H), 4.94 - 5.03 (d, J = 4.5 Hz, 1H), 5.16 - 5.25 (d, J = 8.4 Hz, 1H), 7.24 - 7.42 (m, 3H), 7.42 - 7.61 (m, 6H), 7.63 - 7.76 (ddd, J = 8.6, 7.0, 1.7 Hz, 1H), 8.04 – 8.13 (d, J = 7.5 Hz, 1H), 8.18 – 8.25 (d, J = 1.7 Hz, 1H), 9.42 – 9.51 (d, J = 8 .4 Hz, 1H), 10.98 - 11.04 (s, 1H). Example 424:
[0801] [0801] Example 424 was prepared using a procedure similar to that used to prepare Example 414 where 3-methyltetrahydrofuran-3-amine was used in place of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z = 564.2 [M+H]+. H NMR (400 MHz, DMSO-d6) δ 1.54 (s, 3H), 2.08 (m, 1H), 2.26 (m, 1H), 3.68 (d, J = 9.3 Hz , 1H), 3.82 (m, 1H), 3.94 (m, 2H), 5.20 (d, J = 8.3 Hz, 1H), 7.25 - 7.40 (m, 3H) , 7.43 - 7.63 (m, 6H), 7.69 (m, 1H), 8.10 (s, 1H), 8.32 (d, J = 1.8 Hz, 1H), 9, 58 (d, J = 8.4 Hz, 1H), 11.02 (s, 1H). Example 425:
[0802] [0802] (E)-ethyl 2-cyano-3-ethoxyacrylate (1.37 g, 8.1 mmol) in THF (10 mL) was added dropwise to the solution of 3-hydrazinylpyridine dihydrochloride (1, 5 g, 8.2 mmol) and NaOEt-EtOH (10.5 g, 32.4 mmol) at 0 °C. The mixture was stirred for 90 minutes at 0°C. 4M HCl in 1,4-dioxane (8.1 mL, 32.4 mmol) was added and the solution was refluxed for 2 hours. The solution was concentrated, adjusted to pH=10-13 with 1M NaOH, extracted with EA (x3). The organic layers were combined, dried and concentrated. The crude product was purified by C18 reversed phase column chromatography (MeCN/H2O) to yield the desired compound as an orange solid (360 mg, 19%). ESI MS m/z = 233.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.31 (m, 3H), 4.27 (m, 2H), 5.80 (s, 2H), 7.51 (m, 1H), 8.20 (m, 1H), 8.48 (m, 1H), 8.88 (s, 1H), 9.07 (d, J = 2.6 Hz, 1H). Example 425 step b:
[0803] [0803] NaH (88 mg, 2.21 mmol) was added to the solution of compound from step a (340 mg, 1.47 mmol) in DMF (10 mL) at 0 °C. The mixture was stirred for 40 minutes at 0 °C. 1-bromo-2-(2-bromoethoxy)ethane (674 mg, 2.93 mmol) was added and then the solution was stirred for 3 hours at room temperature. The solution was cooled with water, extracted with EA (x3), washed with brine (x2). The organic phase was dried, concentrated. The residue was purified via silica gel chromatography (PE-EA) to yield ethyl 3-morpholino-1-(pyridin-3-yl)-1H-pyrazol-4-carboxylate as a yellow solid (180 mg, 41%). ESI MS m/z = 303.3 [M+H]+. Example 425 step c:
[0804] [0804] Example 425 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 3-morpholino-1-(pyridin-3-yl)-1H-pyrazol-4-carboxylate was used in place of 2-morpholino Ethyl -4-(trifluoromethyl)benzoate. ESI MS m/z = 548.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.25 – 3.34 (m, 4H), 3.72 (m, 4H), 5.14 (d, J = 8.6 Hz, 1H), 7 .26 - 7.44 (m, 3H), 7.45 - 7.62 (m, 6H), 7.69 (m, 1H), 8.26 (m, 1H), 8.52 (m, 1H ), 8.97 (s, 1H), 9.03 - 9.17 (m, 2H), 10.99 (s, 1H). Example 426: Example 426 step a:
[0805] [0805] A solution of methyl 1H-indole-7-carboxylate (1 g, 5.71 mmol) in DMF (30 mL) was added NaH (274 mg, 6.86 mmol) at 0°C. After stirring for 45 minutes, 1-bromo-2-methoxyethane (946 mg, 6.86 mmol) was added and stirred for 16 hours at room temperature. It was cooled with water, extracted with EA (x3), washed with brine (x2). The organic phase was dried, and concentrated to yield the crude product methyl 1-(2-methoxyethyl)-1H-indole-7-carboxylate as a yellow oil (680 mg, 51%). ESI MS m/z = 233.9 [M+H]+. Example 426 step b:
[0806] [0806] Example 426 was prepared using a procedure similar to that used to prepare Example 152 where methyl 1-(2-methoxyethyl)-1H-indole-7-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI MS m/z = 493.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.08 (s, 3H), 3.37 (d, J = 5.2 Hz, 2H), 4.54 (t, J = 5.3 Hz, 2H ), 5.20 (d, J = 8.6 Hz, 1H), 6.61 (d, J = 3.2 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.26 - 7.33 (m, 1H), 7.34 - 7.57 (m, 9H), 7.69 (m, J = 8.4, 7.1, 1.7 Hz, 1H), 7.80 (m, J = 7.9, 1.2 Hz, 1H), 9.14 (d, J = 8.6 Hz, 1H), 11.01 (s, 1H). Example 427: Example 427 step a:
[0807] [0807] The solution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate compound, prepared in Example 385, (750 mg, 2.34 mmol), 2-fluorophenylboronic acid (530 mg, 3.51 mmol) , Pd (dppf) Cl 2 (188 mg, 0.23 mmol) and Cs 2 CO 3 (1395 mg, 4.68 mmol) in DMF (10 mL) was stirred at 80 °C for 4 h. Then H2O (20 mL) was added to the mixture and extracted with EA (x3). The organic phase was dried and purified by C18 reversed phase column chromatography to yield ethyl 2-(2-fluorophenyl)-5-morpholinothiazole-4-carboxylate as a yellow oil (680 mg, 87%). ESI MS m/z = 358.5 [M+H]+. Example 427 step b:
[0808] [0808] Example 427 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 2-(2-fluorophenyl)-5-morpholinothiazole-4-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI MS m/z = 582.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.21-3.23 (m, 4H), 3.73-3.75 (m, 4H), 5.16-5.18 (d, J=8 .0, 1H), 7.34-7.39 (m, 11H), 7.46-7.53 (m, 1H), 8.10-8.20 (m, 1H), 9.16-9 .18 (d, J=8.0, 1H), 10.99 (s, 1H). Example 428:
[0809] [0809] Example 428 was prepared using a procedure similar to that used to prepare Example 390, where 4-fluorophenylboronic acid was used in place of 6-(trifluoromethyl)pyridin-3-ylboronic acid. ESI MS m/z = 582.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.16-3.18 (m, 4H), 3.73-3.75 (m, 4H), 5.15-5.17 (d, J=8 .0, 1H), 7.34-7.38 (m, 5H), 7.46-7.48 (m, 6H), 7.51-7.53 (m, 1H), 7.90-7 .94 (m, 2H), 9.15-9.17 (d, J=8.0, 1H), 10.99 (s, 1H). Example 429:
[0810] [0810] Example 429 was prepared using a procedure similar to that used to prepare Example 390, where 4-pyridylboronic acid was used in place of 6-(trifluoromethyl)pyridin-3-ylboronic acid. ESI MS m/z = 565.2 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ 3.23-3.26 (m, 4H), 3.75-3.76 (m, 4H), 5.16-5.19 (d, J= 12.0, 1H), 7.35-7.38 (m, 1H), 7.47-7.50 (m, 2H), 7.52-7.54 (m, 5H), 7.80 ( m, 1H), 7.82 (m, 2H), 8.70-8.72 (m, 2H), 9.20-9.30 (m, 1H), 10.99 (s, 1H). Example 430: Example 430 step a:
[0811] [0811] NaH (421 mg, 0.011 mol) was added to a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1.25 g, 0.009 mol) in DMF (5 mL) at 0 °C. The mixture was stirred for 1 hour at 0 °C. Bromocyclobutane (2.16 g, 0.016 mol) was added and the mixture was stirred overnight at 50°C. The solution was cooled with water, extracted with EA (x3), washed with brine (x2). The organic phase was dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to yield the desired compound as a colorless oil (600 mg, 33%). ESI MS m/z = 210.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.24 (m, 3H), 1.73 (m, 2H), 2.27 (m, 2H), 2.34 - 2.50 (m, 2H) , 4.16 (m, 2H), 4.61 (m, 1H), 5.38 (s, 2H), 7.95 (s, 1H). Example 430 step b:
[0812] [0812] The solution of step a compound (600 mg, 2.87 mmol), 1-bromo-2-(2-bromoethoxy)ethane (1.32 g, 5.74 mmol), Cs2CO3 (1.87 g , 5.74 mmol) in DMA (10 mL) was stirred overnight at 100 °C. The mixture was diluted with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2), dried and concentrated. The residue was purified via silica gel chromatography (PE-EA) to yield ethyl 1-cyclobutyl-3-morpholino-1H-pyrazole-4-carboxylate as yellow oil (590 mg, 74%). ESI MS m/z = 280.3 [M+H]+. Example 430 step c:
[0813] [0813] Example 430 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 1-cyclobutyl-3-morpholino-1H-pyrazole-4-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI MS m/z = 525.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.75 (m, 2H), 2.28 – 2.37 (m, 2H), 2.42 – 2.48 (m, 2H), 3.13 – 3.21 (m, 4H), 3.67 (m, 4H), 4.79 (m, 1H), 5.10 (d, J = 8.7 Hz, 1H), 7.25 - 7.31 (m, 1H), 7.32 - 7.37 (m, 2H), 7.44 - 7.56 (m, 5H), 7.67 (m, 1H), 8.13 (s, 1H), 8.89 (d, J = 8.7 Hz, 1H), 10.96 (s, 1H). Example 431:
[0814] [0814] Example 431 was prepared using a procedure similar to that used to prepare Example 430, where 2-hydrazinylpyridine dihydrochloride was used in place of 3-hydrazinylpyridine dihydrochloride. ESI MS m/z = 548.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.32 – 3.40 (m, 4H), 5.14 (d, J = 8.5 Hz, 1H), 7.24 – 7.39 (m, 4H), 7.42 - 7.57 (m, 5H), 7.67 (m, 1H), 7.84 (m, 1H), 8.00 (m, 1H), 8.45 - 8.51 (m, 1H), 8.79 (s, 1H), 9.02 (d, J = 8.5 Hz, 1H), 10.98 (s, 1H). Example 432:
[0815] [0815] A solution of 4-iodo-tetrahydro-2H-pyran compound (3.18 g, 15 mmol) was added to ethyl 3-methyl-1H-pyrazole-5-carboxylate (770 mg, 5 mmol) and Cs2CO3 in DMF (30 mL) was stirred for 18 hours at 60 °C. It was cooled by H2O (50 mL) and extracted with EA (3x), dried Na2SO4, filtered and purified by C18 reversed phase column chromatography (MeCN/H2O) to yield 3-methyl-1-(tetrahydro-2H-pyran Ethyl -4-yl)-1H-pyrazol-5-carboxylate as a brown oil. (143 mg, 12%). Example 432 step b:
[0816] [0816] Example 432 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-carboxylate was used instead of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 484.2 [M+H]+. H NMR (300 MHz, Methanol-d4) δ 1.88 - 2.02 (m, 2H), 2.14 - 2.35 (m, 5H), 3.58 (m, 2H), 4.08 ( m, 2H), 5.19 - 5.36 (m, 2H), 6.63 (s, 1H), 7.25 - 7.62 (m, 8H), 7.68 (m, 1H). Example 433:
[0817] [0817] A solution of ethyl 3-chloroquinoxaline-2-carboxylate (500 mg, 2.12 mmol) in morpholine (5 mL was stirred for 1 hour at 100 °C. It was diluted with water, extracted with EA (x3) , washed with brine (x2) The organic phase was dried and concentrated to yield 450 mg (crude) of the desired compound as a yellow oil, which was used directly in the next step without further purification. ESI MS m/z = 287.5 [ M+H]+ Example 433 step b:
[0818] [0818] Example 433 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 3-morpholinoquinoxaline-2-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 533.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.33 - 3.49 (m, 4H), 3.76 (t, J = 4.6 Hz, 4H), 5.25 (d, J = 8, 4 Hz, 1H), 7.25 - 7.43 (m, 3H), 7.44 - 7.63 (m, 5H), 7.63 - 7.77 (m, 2H), 7.77 - 7 .91 (m, 2H), 7.98 - 8.06 (m, 1H), 9.54 (d, J = 8.5 Hz, 1H), 11.02 (s, 1H). Example 434:
[0819] [0819] A solution of 2-chloroquinoline-3-carboxylic acid compound (414 mg, 2 mmol) in MeOH (20 mL) and H2SO4 (1 mL) was stirred for 2 hours at 60°C. It was cooled by H 2 O (30 mL) to 0 °C and adjusted pH to 8~9, extracted with EA (3x), dried Na 2 SO 4 , filtered to yield the desired compound as a yellow solid (354 mg, 80%). ESI MS m/z = 222.2 [M+H]+. Example 435 step b:
[0820] [0820] The solution of the compound from step a (1.06 g, 3 mmol) in morpholine (20 mL) was stirred for 1 hour at 100 °C. Extracted with EA (3x), dried Na2SO4, filtered to yield desired compound as light yellow solid (326 mg, 75%). ESI MS m/z = 273.3 [M+H]+. Example 434 step c:
[0821] [0821] Example 434 was prepared using a procedure similar to that used to prepare Example 152 where methyl 2-morpholinoquinoline-3-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate.
[0822] [0822] 6-Bromoquinoline-4-carboxylic acid (502mg, 2.0mmol), tert-butyl hydrazinecarboxylate (528mg, 4.0mmol), HATU (836mg, 2.2mmol), DIPEA (774mg , 6.0 mmol) in DMF (5 mL) were stirred for 6 hours at room temperature. The solution was cooled with water, extracted with EA (x3), washed with brine (x2), the organic phase was dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to yield the desired compound as a yellow solid (680 mg, 93%). ESI MS m/z = 367.9 [M+H]+. Example 435 step b:
[0823] [0823] The solution of the compound from step a (680 mg, 1.86 mmol), Zn(CN)2 (432 mg, 3.72 mmol), Pd(PPh3)4 (215 mg, 0.18 mmol) in DMF (5 mL) was stirred for 2 hours at 120 °C. The mixture was diluted with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2),
[0824] [0824] Example 435 was prepared using a procedure similar to that used to prepare Example 151, where tert-butyl 2-(6-cyanoquinoline-4-carbonyl)hydrazine-1-carboxylate was used in place of 2-(6- tert-butyl fluoro-2-morpholinonicotinoyl)hydrazine-1-carboxylate. ESI MS m/z = 472.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ5.26-5.29 (d, J = 9.0 Hz, 1H), 7.28 – 7.39 (m, 3H), 7.44 – 7.56 (m, 5H), 7.67-7.72 (m, 1H), 8.01-8.03 (m, 1H), 8.17-8.20 (m, 1H), 8.28-8 .31 (m,1H), 9.24-9.26 (d, J = 6.0 Hz, 1H), 9.61-9.66 (m,2H), 11.06 (s, 1H). Example 436: (relative trans-stereochemistry)
[0825] [0825] Example 436 was prepared using a procedure similar to that used to prepare Example 420 where trans-4-methoxytetrahydrofuran-3-amine was used in place of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z = 580.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.35 (3H, s), 3.69 (2H, m), 3.88 (2H, m), 4.05 (1H, dd) , 4.33 (1H, d), 5.20 (1H, d), 7.32 (3H, m), 7.51 (5H, m), 7.67 (2H, d) , 7.80 (1H, d), 8.35 (1H, d), 9.58 (1H, d), 11.02 (1H, s).
[0826] [0826] To a stirred solution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate, prepared in Example 385, (400 mg, 1.25 mmol) in Toluene (10 mL) was added tributyl(1-ethoxyvinyl). )stannane (905 mg, 2.5 mmol) and Pd(PPh3)4 (40 mg, 0.001 mmol) at room temperature under nitrogen. The mixture was refluxed for 2.5 hours at 110 °C under nitrogen and then concentrated. The reaction mixture was poured into water and extracted with EA (3 x 100 mL). The organic phase was dried over Na2SO4. The residue was purified by silica gel chromatography (PE/EA = 3/1) to yield the desired compound as a white solid (300 mg, 77%). ESI MS m/z = 313.2 [M+H]+. Example 437 step b:
[0827] [0827] To the solution of the compound from step a (300 mg, 0.96 mmol) was added HCl (5 mL) in dioxane (8 mL) at room temperature. The resulting solution was stirred at room temperature for 5 h. The reaction mixture was poured into saturated liquid NaHCO3 and extracted with EA (3 x 100 mL). The organic phase was dried over Na2SO4 and purified to yield the desired compound product as a white solid (150mg, 55%). ESI MS m/z = 285.4
[0828] [0828] To a stirred solution of the compound from step b (200 mg, 0.7 mmol) in THF (6 mL) was added MeMgCl (0.27 mL, 0.77 mmol). The mixture was stirred at room temperature for 2.5 hours under nitrogen and then concentrated. The reaction mixture was poured into ice water and extracted with EA (3 x 60 mL). The organic phase was dried over Na2SO4 and purified by C18 reversed phase column chromatography (ACN/H2O = 1/5) to yield the compound desired as yellowish solid (175 mg, 83%). ESI MS m/z = 301.1 [M+H]+. Example 437 step d:
[0829] [0829] Example 437 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 2-(2-hydroxypropan-2-yl)-5-morpholinothiazole-4-carboxylate was used in place of 2-morpholino-4 - ethyl (trifluoromethyl)benzoate. ESI MS m/z = 456.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ1.48 (4 H, s), 3.02 (3 H, d), 3.67 (3 H, d), 5.12 (1 H, s), 7.32 (2H, d), 7.49 (5H, d), 8.35 (1H, d). Example 438:
[0830] [0830] NaH (61.5 mg, 1.54 mol) was added to the solution of ethyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate (250 mg, 1.28 mmol) in DMF (5 mL) at 0 °C. The mixture was stirred for 1 hour at 0 °C. 1-Bromo-2-methoxyethane (353 mg, 2.56 mmol) was added and the mixture was stirred overnight. The solution was cooled with water, extracted with EA (x3), washed with brine (x2). The organic phase was dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to yield the desired compound as a yellow oil (260 mg, 80%). ESI MS m/z = 254.3 [M+H]+. Example 438 step b:
[0831] [0831] Example 438 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 4-(2-methoxyethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 499.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.03 (m, 2H), 3.18 (s, 3H), 3.37 (s, 2H), 3.41 (m, 2H), 3.79 (m, 2H), 4.02 (m, 2H), 5.09 (d, J = 8.7 Hz, 1H), 7.24 - 7.32 (m, 1H), 7.34
[0832] [0832] 3-Azabicyclo[3.1.0]hexan-6-ol (220 mg, 1.62 mmol) was dissolved in THF (5 mL) and K2CO3 (289.8 mg, 2.1 mmol) was added . CbzCl (360 mg, 2.1 mmol) was then added and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EA. The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (PE:EA=10:1) to yield the desired product as a white solid (250mg, 66%). ESI MS m/z = 234.2 [M+H]+. Example 439 step b:
[0833] [0833] The compound from step a (250 mg, 1.07 mmol) was dissolved in DCM (8 mL) and cooled with ice bath. The proton sponge (689 mg, 3.21 mmol) was added and then trimethyloxonium tetrafluoroborate (238 mg, 1.6 mmol) was added. The mixture was warmed to room temperature and stirred overnight. Water was added and the mixture was extracted with EA. The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC (PE:EA = 2:1) to yield the desired product as a yellow oil (121mg, 46%) and starting material (50mg, 0.21mmol). ESI MS m/z = 248.3 [M+H]+. Example 439 step c:
[0834] [0834] The compound from step b (121 mg, 0.49 mmol) was dissolved in MeOH (10 mL) and Pd/C (20 mg) was added. The mixture was exchanged with H2 three times and then stirred overnight. The mixture was filtered and the filtrate was concentrated to yield 6-methoxy-3-azabicyclo[3.1.0]hexane as a white solid (30 mg, 55%). There was no LCMS signal from the product. Example 439 step d:
[0835] [0835] Example 439 was prepared using a procedure similar to that used to prepare Example 414, where 6-methoxy-3-azabicyclo[3.1.0]hexane was used in place of 1-methoxy-2-methylpropan-2- the mine. ESI MS m/z = 576.5 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1H NMR (300 MHz, DMSO-d6) δ 3.24 (s, 3H), 3.26-3.31 (m, 2H), 5.20 (d, J = 8.4 Hz, 1H), 7.18-7.40 (m, 3H), 7.40-7.61 (m, 6H), 7.68 (t, J = 7.9 Hz, 1H ), 8.37 (s, 1H), 9.26 (d, J = 8.5 Hz, 1H), 11.00 (s, 1H).
[0836] [0836] Example 440:
[0837] [0837] A solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1.55 g, 0.01 mol), 2-bromo-5-(trifluoromethyl)pyridine (2.25 g, 0.01 mol), Cs2CO3 (6.52 g, 0.02 mol) in DMF (20 mL) was stirred for 1 hour at 100 °C. The mixture was diluted with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2), dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to yield the desired compound as a yellow solid (1.95 g, 65%). ESI MS m/z = 301.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.31 (m, 3H), 4.14 - 4.40 (m, 2H), 5.96 (d, J = 4.0 Hz, 2H), 7 .86 (m, 1H), 8.36 (m, 1H), 8.74 (d, J = 3.7 Hz, 1H), 8.83 (d, J = 2.8 Hz, 1H). Example 440 step b:
[0838] [0838] NaH (360 mg, 0.015 mol) was added to the solution of the compound from step a (1.95 g, 6.5 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (1.645 g, 7. 2 mmol) in DMF (20 mL) at 0 °C. The mixture was stirred overnight at room temperature. The mixture was cooled with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2), dried and concentrated. The crude product was purified via silica gel chromatography (PE-EA) to yield the desired compound as a yellow solid (350 mg, 15%).
[0839] [0839] Example 440 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 3-morpholino-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-carboxylate was used in the instead of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 616.4 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 3.39 (m, 4H), 3.67 - 3.85 (m, 4H), 5.16 (d, J = 8.5 Hz, 1H), 7.25 - 7.40 (m, 3H), 7.45 - 7.62 (m, 5H), 7.65 - 7.73 (m, 1H), 8.01 (d, J = 8.7 Hz, 1H), 8.41 (m, 1H), 8.87 (s, 1H), 8.88 - 8.96 (m, 1H), 9.10 (d, J = 8.5 Hz, 1H ), 11.01 (s, 1H). Example 441:
[0840] [0840] Example 441 was prepared using a procedure similar to that used to prepare Example 435, where 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid was used in place of 6-bromoquinoline-4-carboxylic acid. ESI MS m/z = 461.3[M+H]+. 1H NMR (300 MHz, DMSO-d6) δ5.18-5.20 (d, J = 6.0 Hz, 1H), 7.27 – 7.39 (m, 1H), 7.43 – 7.46 (m, 2H), 7.49-7.54 (m, 6H), 7.66-7.71 (m, 1H), 8.64-8.70 (m, 2H), 9.01-9 .11(m,2H), 10.70 (s, 1H). 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid. Examples 442 and 443:
[0841] [0841] A 2M solution of trimethylaluminum in hexane (23 mL, 44.40 mmol) was added to a mixture of N,O-dimethylhydroxylamine hydrochloride (4.3 g, 44.40 mmol) in DCM (30 mL) and the reaction was stirred at 0 °C for 40 minutes. A solution of 3-morpholino-5-(trifluoromethyl)picolinic acid (9 g, 29.60 mmol) in DCM (20 mL) was added and the reaction mixture was stirred at 40 °C for 2 hours. After cooling to room temperature, the mixture was carefully quenched with 1N HCl and diluted with DCM. After 30 minutes under stirring the layers were separated and the organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to yield the desired compound as a yellow solid (9 g, 95%). ESI MS m/z = 320.3[M+H]+. Examples 442 and 443 step b:
[0842] [0842] A solution of the (3M) MeMgCl (10.3 mL, 31 mmol) in hexane was added dropwise to the compound from step a (9 g, 28.20 mmol) in THF at 0 °C under N 2 . It was stirred for 2 hours at 0 °C. The mixture was diluted with EA and quenched with saturated NH4Cl, the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to yield the desired compound as a yellow oil (7.2 g, 93%). ESI MS m/z = 275.2 [M+H]+. Examples 442 and 443 step c:
[0843] [0843] HBr-AcOH was added to the solution of the compound from step b (7.20 g, 26.3 mmol) in AcOH (20 mL), then pyridinium tribromide (9.20 g, 28.9 mmol) was added at room temperature. It was stirred for 2 hours at room temperature and filtered. The solid was washed with AcOH and partitioned between EA/saturated NaHCO 3 , the organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to yield the desired compound as a yellow solid (6.1 g, 66%). ESI MS m/z = 355.1 [M+H]+. Examples 442 and 443 step d:
[0844] [0844] The solution of the compound from step 3 (3 g, 8.52 mmol), NaN3 (0.61 g, 9.38 mmol) in acetone/H2O=2/1 (15 mL) was stirred for 1 hour at room temperature. The mixture was diluted with EA, washed with brine. The organic phase was dried over anhydrous Na2SO4 and concentrated to 10 ml in EA. It was used for the next step directly. ESI MS m/z = 316.1 [M+H]+. Examples 442 and 443 step e:
[0845] [0845] TCDI (1.97 g, 11.08 mmol) was added to the compound solution
[0846] [0846] EDCI (260 mg, 1.37 mmol) was added to the solution of step e compound (230 mg, 0.34 mmol) in DMF. It was stirred for 5 hours at 90 °C. The crude product was purified by preparative HPLC (MeCN/H2O) to yield the desired compound as a yellow solid (70 mg, 38%). ESI MS m/z = 549.4 [M+H]+. Examples 442 and 443 step g:
[0847] [0847] The compound from step f (70 mg, 0.13 mmol) was purified by preparative chiral HPLC to yield the title compound 442 (21 mg, 29 %) as a yellow solid and 443 (22 mg, 31 %) as yellow solid. Example 442 ESI MS m/z = 549.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.94 (m, 4H), 3.77 (m, 4H), 5.26 (d, J = 8.5 Hz, 1H), 7.25 – 7 .31 (m, 1H), 7.34 (m, 2H), 7.42 - 7.60 (m, 5H), 7.67 (m, 1H), 7.84 (d, J = 2.1 Hz, 2H), 8.58 - 8.71 (m, 1H), 9.20 (d, J = 8.6 Hz, 1H), 10.93 (s, 1H). Example 443 ESI MS m/z = 549.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.94 (m, 4H), 3.77 (m, 4H), 5.26 (d, J = 8.5 Hz, 1H), 7.23 - 7 .32 (m, 1H), 7.34 (m, 2H), 7.41 - 7.58 (m, 5H), 7.67 (m, 1H), 7.84 (d, J = 2.0 Hz, 2H), 8.63 (m, 1H), 9.20 (d, J = 8.6 Hz, 1H), 10.93 (s, 1H). Examples 444 and 445: Examples 444 and 445 step a:
[0848] [0848] A solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1.55 g, 0.01 mol), 5-fluoro-2-(trifluoromethyl)pyridine (1.65 g, 0.01 mol), Cs2CO3 (4.89 g, 0.015 mol) in DMF (8 mL) was stirred for 1 hour at 100 °C. The mixture was diluted with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2), dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to yield the desired compound mixture as a yellow solid (1.04 g, 35%). ESI MS m/z = 301.1[M+H]+. Examples 444 and 445 step b:
[0849] [0849] NaH (168 mg, 4.2 mmol) was added to the solution of the compound from step a (1.04 g, 3.5 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (966 mg, 4.2 mmol) in DMF (20 mL) at 0 °C. The mixture was stirred overnight. The mixture was cooled with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2), dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to yield the desired compound mixture as a white solid (280 mg, 22%). ESI MS m/z = 371.2 [M+H]+. Examples 444 and 445 step c:
[0850] [0850] Examples 444 and 445 were prepared using a procedure similar to that used to prepare Example 152 where ethyl 3-morpholino-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxylate and 5 ethyl-morpholino-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-carboxylate were used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. The isomers were separated by preparative HPLC (MeCN/H2O/0.1% FA). Example 444 ESI MS m/z = 616.5 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.31 (m, 4H), 3.74 (m, 4H), 5.16 (d, J = 8.5 Hz, 1H), 7.25 – 7 .42 (m, 3H), 7.51 (m, J 5H), 7.65 - 7.74 (m, 1H), 8.07 (d, J = 8.7 Hz, 1H), 8.51 (m, 1H), 9.09 - 9.16 (m, 2H), 9.32 (d, J = 2.5 Hz, 1H), 11.00 (s, 1H). Example 445 ESI MS m/z = 616.5 [M+H]+. 1H NMR (300MHz,
[0851] [0851] NaH (1.6 g, 0.04 mol) was added to the solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (3.10 g, 0.02 mol) in DMF (25 mL) at 0°C. Then (bromomethyl)cyclopropane (2.68 g, 0.02 mol) was added. The mixture was stirred for 3 hours at room temperature. The solution was cooled with water, extracted with EA (x3), washed with brine (x2), the organic phase was dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to yield the desired compound as a yellow oil (1.81 g, 43%). ESI MS m/z = 209.9 [M+H]+. Examples 446 and 447 step b:
[0852] [0852] The solution of step a compound (1.81 g, 8.66 mmol), 1-bromo-2-(2-bromoethoxy)ethane (6.0 g, 25.98 mmol) and Cs2CO3 (5. 64 g, 17.32 mmol) in DMA (20 mL) was stirred for 4 hours at 100 °C. The mixture was diluted with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2), dried, and concentrated. The residue was purified via silica gel chromatography (PE-EA) to yield the desired compound as an off-white solid (1.08 g, 45%). ESI MS m/z = 280.0 [M+H]+. Examples 446 and 447 step c:
[0853] [0853] The solution of the compound from step b (1.08 g, 3.87 mmol) and NH2NH2.H2O (10 mL) in EtOH (20 mL) was refluxed for 3 hours. The crude product was purified by preparative HPLC (MeCN/H2O) to yield the desired compound as a yellow oil (810 mg, 79%). ESI MS m/z = 260.0 [M+H]+. Examples 446 and 447 step d:
[0854] [0854] A solution of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (753 mg, 3.0 mmol), and di( 1H-imidazol-1-yl)methanethione (1.6 g, 9.0 mmol) in DMF (10 mL) was stirred for 1 hour at 0 °C and the compound from step c (810 mg, 3.05 mmol) was added to the solution and stirred at room temperature for 2 hours. The residue was purified by preparative HPLC (MeCN/H2O) to yield the desired compound as a yellow solid (950 mg, 57%). ESI MS m/z = 559.3 [M+H]+. Examples 446 and 447 step e:
[0855] [0855] EDCI (980 mg, 5.10 mmol) was added to the solution of the compound from step d (950 mg, 1.70 mmol) in DMF (5 mL). The mixture was stirred at 60 °C for 2 hours. The mixture was diluted with water, extracted with DCM (x3). The organic layers were combined and dried, concentrated. The residue was then purified by preparative TLC (EA) and preparative HPLC (MeCN/H 2 O/0.1% FA) to yield the desired compound as a yellow solid (500 mg, 56%). ESI MS m/z = 525.3 [M+H]+. Examples 446 and 447 step f:
[0856] [0856] The compound from step e (500mg, 0.95mmol) was separated by chiral HPLC to yield 446 as an off-white solid (101mg) and 447 as a yellow solid (162mg). Example 446: ESI MS m/z = 525.5 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.35-0.39 (m, 2H), 0.51-0.57 (m, 2H), 1.24-1.28 (m, 1H), 3.17-3.18 (m, 4H), 3.66-3.67 (m, 4H), 3.89-3.91 (m, 2H), 5.08-5.11 (d, J = 9.0 Hz, 1H), 7.26-7.36 (m, 3H), 7.44 - 7.54 (m, 5H), 7.65-7.70 (m, 1H), 8. 10 (s, 1H), 8.88-8.91 (d, J = 9.0 Hz, 1H), 10.96 (s, 1H). Example 447: ESI MS m/z = 525.4 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 0.36-0.38 (m, 2H), 0.52-0.55 (m, 2H), 1.08-1.40 (m, 1H) , 3.17-3.18 (m, 4H), 3.66-3.68 (m, 4H), 3.89-3.91 (m, 2H), 5.08-5.11 (d, J = 9.0 Hz, 1H), 7.28 (m, 3H), 7.33 - 7.36 (m, 5H), 7.46-7.52 (m, 1H), 8.10 (s , 1H), 8.88-8.91 (d, J = 9.0 Hz, 1H), 10.96 (s, 1H).
[0857] [0857] Example 448 was prepared using a procedure similar to that used to prepare Example 448, where 2,5-difluoropyridine was used in place of 2-bromo-5-(trifluoromethyl)pyridine. ESI MS m/z = 566.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.31 (m, 4H), 3.73 (m, 4H), 5.14 (d, J = 8.0 Hz, 1H), 7.25 – 7 .38 (m, 3H), 7.42 - 7.61 (m, 5H), 7.68 (m, 1H), 7.89 (m, 1H), 7.97 (m, 1H), 8. 52 (d, J = 2.9 Hz, 1H), 8.74 (s, 1H), 9.06 (d, J = 8.6 Hz, 1H). Example 449: Example 449 step a:
[0858] [0858] A solution of ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1.0 g, 3.73 mmol), methylboronic acid (448 mg, 7.46 mmol), Pd(dppf )Cl2 (545 mg, 0.746 mmol) and Cs2CO3 (2.42 g, 7.46 mmol) were dissolved in DMF (5.0 mL), then the mixture was stirred at 100 °C for two hours. It was concentrated, and purified by silica gel chromatography with PE:EA=5:1 to obtain the desired compound as an orange solid (589 mg, 77%). ESI MS m/z = 204.5 [M+H]+. Example 449 step b:
[0859] [0859] The solution of step a compound (434 mg, 2.13 mmol), BPO (515 mg, 2.13 mmol), and NBS (398 mg, 2.24 mmol) were dissolved in CCl4 (6 mL) at room temperature, then the mixture was stirred at 78 °C for one hour. Upon completion, the mixture was cooled with water, and extracted with EA (20 mLx2), the organic layer was combined, washed with water, saturated NaHCO3 solution (15 mL) and brine (15 mL) in turn, then dried. with anhydrous Na2SO4 and concentrated to obtain a yellow solid (415 mg, 69%) which was used without further purification. ESI MS m/z = 282.3 [M+H]+. Example 449 step c:
[0860] [0860] A mixture of NaH (96 mg, 3.99 mmol) in MeOH (5 mL) was stirred at 0 °C for 5 minutes, then step b compound (375 mg, 1.33 mmol) was added to the mixture. It was heated at 50 °C for one hour. Upon completion, the mixture was poured into ice-water glacial acetic acid solution, and extracted with EA (25 mLx2), the organic layer was combined, washed with brine (15 mL), then dried with anhydrous Na2SO4 and concentrated to obtain Methyl 5-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate as a pale yellow solid, which was used without further purification. ESI MS m/z = 220.5 [M+H]+. Example 449 step d:
[0861] [0861] Example 449 was prepared using a procedure similar to that used to prepare Example 152, where methyl 5-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate was used in place of 2-morpholino-4 - ethyl (trifluoromethyl)benzoate. ESI MS m/z = 480.3[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.38 (s, 3H), 4.56 (s, 2H), 5.17 (d, 1H), 7.04 (m, 1H), 7.25 – 7.33 (m, 1H), 7.37 (m, 2H), 7.42 – 7.58 (m, 5H), 7.69 (m, 1H), 7.95 – 8.04 (m , 1H), 8.42 (s, 1H), 8.84 (d, 1H), 8.98 (d, 1H), 10.90 (s, 1H). Example 450: Example 450 step a:
[0862] [0862] A solution of ethyl 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate (700 mg, 2.76 mmol), 2-[(E)-2-ethoxyethenyl]-4,4,5, 5-Tetramethyl-1,3,2-dioxaborolane (545 mg, 2.75 mmol), Pd(dppf)Cl2 (197 mg, 0.27 mmol) and Cs2CO3 (2.7 g, 8.29 mmol) in 1 ,4-dioxane (15 ml) and water (5 ml) were stirred for 1 hour at 80 °C. The reaction was then diluted by the addition of water. The resulting solution was extracted with EA. The crude product was purified by C18 reversed phase column chromatography to yield the desired compound (550 mg, 69%) as an off-white oil. ESI MS m/z = 290.1 [M+H]+.
[0863] [0863] A solution of compound from step a (400 mg, 1.38 mmol), HCl-dioxane (2 mL, 4N) in dioxane (2 mL) was stirred for 2 hours at room temperature. The reaction was then quenched by the addition of NaHCO3 and extracted with DCM. The organic layer was combined and dried over anhydrous sodium sulfate and concentrated in vacuo to yield the desired compound (388 mg, 107%) as a yellow oil, which was used without further purification. ESI MS m/z = 262.0 [M+H]+. Example 450 step c:
[0864] [0864] A solution of compound from step b (380 mg, 1.45 mmol) in THF (6 mL) was added BH3.THF (2.9 mL, 2.9 mmol) dropwise at 0 °C. It was stirred for 30 minutes at 0 °C. The reaction was then quenched by the addition of water and extracted with DCM. The organic layer was combined and concentrated in vacuo. The organic layer was purified by silica gel column to yield the desired compound 160 mg as an off-white oil. ESI MS m/z = 264.1 [M+H]+. Example 450 step d:
[0865] [0865] A solution of compound from step c (160 mg, 0.61 mmol), NH2NH2.H2O (2 mL) in EtOH (2 mL) was stirred for 1 hour at 80 °C. The reaction was then washed by the addition of water and extracted with DCM. The organic layer was combined and concentrated in vacuo to yield 3-(2-hydroxyethyl)-5-(trifluoromethyl)picolinohydrazide (100 mg, 66%) as an off-white oil. ESI MS m/z = 250.0 [M+H]+. Example 450 step e:
[0866] [0866] Example 450 was prepared using a procedure similar to that used to prepare Example 21, where 3-(2-hydroxyethyl)-5-(trifluoromethyl)picolinohydrazide was used in place of tetrahydro-2H-pyran-4-carbohydrazide. ESI MS m/z = 509.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.30 (d, J = 6.1 Hz, 2H), 3.70 (q, J = 5.8, 5.8, 5.6 Hz, 2H) , 4.69 (t, J = 5.3, 5.3 Hz, 1H), 5.21 (d, J = 6.5 Hz, 1H), 7.23 - 7.41 (m, 3H), 7.43 - 7.59 (m, 5H), 7.63 - 7.79 (m, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.92 - 9.05 ( m, 1H), 9.38 - 9.56 (m, 1H), 10.98 (s, 1H). Example 451:
[0867] [0867] Example 451 was prepared using a procedure similar to that used in Example 339, where (R)-1-methoxypropan-2-amine was used in place of morpholine. ESI MS m/z = 558.2 [M+H]+. Example 452:
[0868] [0868] Example 452 was prepared using a procedure similar to that used in Example 339 where (S)-2-methoxypropan-1-amine was used in place of morpholine. ESI MS m/z = 558.2 [M+H]+. Example 453: Example 453 step a:
[0869] [0869] Example 453 step a was prepared using a procedure similar to that used to prepare Example 345, where ethyl 5-bromo-2-(trifluoromethyl)thiazole-4-carboxylate was used in place of 5-bromo-2-methylthiazole methyl -4-carboxylate. Example 453 step b:
[0870] [0870] Example 453 step b was prepared using a procedure similar to that used to prepare Example 152 where 5-(3,6-dihydro-2H-pyran-4-
[0871] [0871] To an oven-dried round bottom flask, 2,2,3,3,3-pentafluoropropanamide (2 g, 12.27 mmol) was dissolved in THF (29.9 mL) under nitrogen to yield a colored solution . Lawesson's reagent (2.98 g, 7.36 mmol) was added to the reaction mixture. The reaction vessel was stirred at 80°C overnight. The reaction mixture was cooled and ethyl 3-bromo-2-oxopropanoate (1.92 mL, 15.33 mmol) was added. The flask was reheated to 80°C and shaken overnight. The mixture was poured into water and the aqueous layer was extracted with EtOAc. The organic phase was dried, filtered and concentrated. The crude product was added to the silica gel column and eluted with 0% to 50% ethyl acetate/hexane to give ethyl 2-(perfluoroethyl)thiazole-4-carboxylate (1.29 g, 38% yield) as a white solid. Example 454 step b:
[0872] [0872] A solution of ethyl 2-(perfluoroethyl)thiazole-4-carboxylate (1.29 g, 4.69 mmol) in THF (10.7 mL) was added to LDA (2.93 mL, 5.86 mL). mmol) in
[0873] [0873] Example 454 was prepared using a procedure similar to that used to prepare Example 272, where ethyl 5-bromo-2-(perfluoroethyl)thiazole-4-carboxylate was used in place of 2-methyl-5-bromothiazole-4 -methyl carboxylate. ESI-MS m/z: 606.1 [M+H]+. Example 455: Example 455 step a:
[0874] [0874] To a cold (-78 °C) solution of ethyl 5-morpholinothiazole-4-carboxylate (0.5 g, 2.06 mmol) in THF (5.2 mL) was added n-BuLi (1, 29 mL, 2.06 mmol) dropwise. The reaction was stirred for 15 minutes and cyclobutanone (0.15 mL, 2.06 mmol) was added via syringe. The reaction was stirred for 1 hour and then quenched by the addition of saturated ammonium chloride solution. The cold bath was removed and the reaction warmed to room temperature. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (2x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield the crude title compound. The crude product was added to the silica gel column and eluted with 0% to 50% ethyl acetate/hexane to yield ethyl 2-(1-hydroxycyclobutyl)-5-morpholinothiazole-4-carboxylate (427 mg, 66% yield) as a yellow solid. Example 455 step b:
[0875] [0875] Example 455 was prepared using a procedure similar to that used to prepare Example 152 where ethyl 2-(1-hydroxycyclobutyl)-5-morpholinothiazole-4-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI MS m/z = 558.2 [M+H]+. Example 456:
[0876] [0876] Example 456 was prepared using a procedure similar to that used to prepare Example 21, where (R)-5-(2-(methoxymethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)thiazole-4-carboxylate is ethyl, which was prepared similarly to ethyl 5-morpholino-2-(trifluoromethyl)thiazole-4-carboxylate in Example 339, was converted to the corresponding hydrazide and used to tetrahydro-2H-pyran-4-carbohydrazide. The racemic mixture was purified by chiral separation. (Column= YMC CHIRAL Cellulose-SB, 250*20mm (5 µM); Mobile Phase = 50% iPrOH/50% hexane; Flow rate = 20 mL/min). ESI MS m/z = 584.2 [M+H]+. Example 457:
[0877] [0877] Example 457 was prepared using a procedure similar to that used to prepare Example 21, where (S)-5-(2-(methoxymethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)thiazole-4-carboxylate is ethyl, which was prepared similarly to ethyl 5-morpholino-2-(trifluoromethyl)thiazole-4-carboxylate in Example 339, was converted to the corresponding hydrazide and used in place of tetrahydro-2H-pyran-4-carbohydrazide. The racemic mixture was purified by chiral separation. (Column= YMC CHIRAL Cellulose-SB, 250*20mm (5 µM); Mobile Phase = 50% iPrOH/50% hexane; Flow rate = 20 mL/min). ESI MS m/z = 584.2 [M+H]+. Example 458: Example 458 step a:
[0878] [0878] Example 458 step a was prepared using a procedure similar to that used to prepare Example 454, where 1-fluorocyclobutane-1-carboxamide was used in place of 2,2,3,3,3-pentafluoropropanamide to produce 2-( ethyl 1-fluorocyclobutyl)thiazole-4-carboxylate. Example 458 step b:
[0879] [0879] Ethyl 2-(1-fluorocyclobutyl)thiazole-4-carboxylate (230 mg, 1.0 mmol) was taken up in MeOH (2 mL) and 1M NaOH (2 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the aqueous layer was extracted 3x with EtOAc. The organic phase was dried, filtered and concentrated. 2-(1-Fluorocyclobutyl)thiazole-4-carboxylic acid (197 mg, 98% yield) was isolated as a white solid.
[0880] [0880] A solution of 2-(1-fluorocyclobutyl)thiazole-4-carboxylic acid (197 mg, 0.98 mmol) in tetrahydrofuran (11.5 mL) was cooled to -78°C under argon and treated with a n -butyllithium (1.29 mL, 2.06 mmol). The reaction mixture was allowed to warm to room temperature for 15 minutes, then cooled again to -78°C. A solution of bromine (55 µL, 1.08 mmol) in hexane (0.5 mL) was added. The reaction mixture was allowed to warm to room temperature, then cooled by adding 1N HCl. The mixture was extracted three times with methylene chloride, and the combined organic layer was dried over sodium sulfate and evaporated. The crude product was added to the silica gel column and eluted with 0% to 10% methanol/dichloromethane to give 5-bromo-2-(1-fluorocyclobutyl)thiazole-4-carboxylic acid (219 mg, 80% yield) as a white solid.
[0881] [0881] To a vial, 5-bromo-2-(1-fluorocyclobutyl)thiazole-4-carboxylic acid (218 mg, 0.78 mmol), HATU (355 mg, 0.93 mmol) and tert-butyl hydrazine carboxylate (123 mg, 0.93 mmol) was dissolved in DMF (7.2 mL) in free air to yield a yellow solution. DIPEA (272 µL, 1.56 mmol) was added to the reaction mixture in one portion. Stirring was carried out at room temperature for 2 hours. The reaction mixture was concentrated and the crude reaction mixture placed on the silica gel plug. The crude product was added to the silica gel column and eluted with 0% to 50% ethyl acetate/hexane to yield 2-(5-bromo-2-(1-fluorocyclobutyl)thiazole-4-carbonyl)hydrazine-1- tert-butyl carboxylate (270 mg, 88% yield) as a white solid. Example 458 step d:
[0882] [0882] To an oven-dried flask, tert-butyl 2-(5-bromo-2-(1-fluorocyclobutyl)thiazole-4-carbonyl)hydrazine-1-carboxylate (270 mg, 0.69 mmol) was dissolved. in morpholine (1370 µL) in open air to produce a colored suspension. K2CO3 (189 mg, 1.37 mmol) was added to the reaction mixture. Stirring was carried out at 80 °C for 3 hours. It was filtered and washed with DCM and the organic layer was concentrated. The crude product was added to the silica gel column and eluted with 0% to 50% ethyl acetate/hexane to yield 2-(2-(1-fluorocyclobutyl)-5-morpholinothiazole-4-carbonyl)hydrazine-1-carboxylate of tert-butyl (198 mg, 72% yield) as a white solid.
[0883] [0883] A solution of tert-butyl 2-(2-(1-fluorocyclobutyl)-5-morpholinothiazol-4-carbonyl)hydrazine-1-carboxylate (198 mg, 0.49 mmol) and hydrochloric acid, 37% ( 1.12 mL) in EtOH (11.2 mL) was stirred at room temperature for 1 hour. It was adjusted to pH=7-8 with aqueous saturated NaHCO3. Extraction was performed with DCM (3x). The organic layer was dried and concentrated. The crude product was added to the silica gel column and eluted with 0% to 10% methanol/dichloromethane to give 2-(1-ethoxycyclobutyl)-5-morpholinothiazole-4-carbohydrazide (51 mg, 32% yield) as a white solid. Example 458 step f:
[0884] [0884] Example 458 was prepared using a procedure similar to that used to prepare Example 21, where 2-(1-ethoxycyclobutyl)-5-morpholinothiazole-4-carbohydrazide was used in place of tetrahydro-2H-pyran-4-carbohydrazide. The racemic mixture was purified by chiral separation. (Column= YMC CHIRAL Cellulose-SB, 250*20mm (5 µM); Mobile phase = 50% i-PrOH/50% hexane; Flow rate = 20 mL/min). ESI MS m/z = 586.2 [M+H]+. Example 459:
[0885] [0885] To an oven-dried flask, tert-butyl 2-(5-bromo-2-(2-fluoropropan-2-yl)thiazol-4-carbonyl)hydrazine-1-carboxylate (166 mg, 0.43 mmol) was dissolved in morpholine (0.87 mL) in free air to give the yellow suspension. K2CO3 (120 mg, 0.87 mmol) was added to the reaction mixture and allowed to stir at 90 °C for four hours. The reaction mixture was filtered and washed with DCM. The filtrate was concentrated. The crude product was added to the silica gel column and eluted with 0% to 50% ethyl acetate/hexane to yield 2-(5-morpholino-2-(2-morpholinopropan-2-yl)thiazol-4-carbonyl) tert-butyl hydrazine-1-carboxylate (180 mg, 91% yield) as a white solid. Example 459 step b:
[0886] [0886] To a vial, tert-butyl 2-(5-morpholino-2-(2-morpholinopropan-2-yl)thiazol-4-carbonyl)hydrazine-1-carboxylate (180 mg, 0.395 mmol) was absorbed in DCM (0.6 ml) and TFA (0.6 ml). The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated and taken up in saturated aqueous DCM NaHCO3 (aq). The aqueous layer was extracted with DCM (2x). The organic phase was dried, filtered and concentrated. 5-morpholino-2-(2-morpholinopropan-2-yl)thiazol-4-carbohydrazide (135 mg, 96% yield) was carried forward without purification. Example 459 step c:
[0887] [0887] Example 459 was prepared using a procedure similar to that used to prepare Example 21, where 5-morpholino-2-(2-morpholinopropan-2-yl)thiazol-4-carbohydrazide was used in place of tetrahydro-2H-pyran -4- carbohydrazide. The racemic mixture was purified by chiral separation. (Column= YMC CHIRAL Cellulose-SB, 250*20mm (5 uM); Mobile phase = 50% i-PrOH/50% hexane; Flow rate = 20 mL/min). ESI MS m/z = 528.2 [M-C4H9NO]+. Example 460:
[0888] [0888] Example 460 step a was prepared using a similar procedure to 458 where 1-(trifluoromethyl)cyclopropane-1-carboxamide was used in place of 1-fluorocyclobutane-1-carboxamide. The racemic mixture was purified by chiral separation. (Column= YMC CHIRAL Cellulose-SB, 250*20mm (5 µM); Mobile Phase = 50% EtOH/50% Hexane; Flow Rate = 20 mL/min). ESI MS m/z = 596.2 [M+H]+. Example 461:
[0889] [0889] An oven-dried flask was charged with methyl 5-bromo-3-morpholinopicolinate (340 mg, 1.13 mmol), cesium fluoride (858 mg, 5.65 mmol), and copper(I) iodide. (1402 mg, 11.29 mmol). The vial was purged with nitrogen gas, then NMP (20 mL) was added via syringe. To this mixture was added (difluoromethyl)trimethylsilane (1402 mg, 11.29 mmol). The reaction mixture was heated at 120 °C for 24 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of silica gel and washed with EtOAc (50 mL). The filtrate was concentrated and purified by RP-HPLC (30-95% MeCN:water) to give methyl 5-(difluoromethyl)-3-morpholinopicolinate (30 mg, 10% yield) as a yellow oil. ESI MS m/z = 273.1 [M+H]+. Example 461 step b:
[0890] [0890] Example 461 was prepared using a procedure similar to that used to prepare Example 152 where methyl 5-(difluoromethyl)-3-morpholinopicolinate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z = 596.2 [M+H]+.
[0891] [0891] An oven-dried flask was charged with 3,5-dichloropyrizadine (100 mg, 0.67 mmol), phenylboronic acid (82 mg, 0.671 mmol), potassium fluoride (97 mg, 1.68 mmol), acetate of palladium (8 mg, 0.034 mmol), and Q-Phos (24 mg, 0.034 mmol). The vial was purged with nitrogen gas, then Toluene (5 mL) and water (1.2 mL) was added via syringe. The reaction mixture was heated at 70 °C for 22 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (4 mL). The reaction mixture was filtered through a pad of celite and concentrated. The residue was purified on silica gel (0-100% EtOAc:hexane) to give 3-chloro-5-phenylpyrizadine (110 mg, 86% yield) as a brown solid. ESI MS m/z = 191.1 [M+H]+. Example 462 step b:
[0892] [0892] An oven-dried flask was charged with 3-chloro-5-phenylpyrizadine (80 mg, 0.420 mmol), 3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4 ]diazepin-2-one (158 mg, 0.629 mmol), potassium tert-butoxide (141 mg, 1.259 mmol), SPhos (17 mg, 0.042 mmol), and SPhos-palladium G3 (33 mg, 0.042 mmol). The flask was purged with nitrogen gas, then
[0893] [0893] An oven dried flask was charged with 3,5-dichloropyrizadine (115 mg, 0.772 mmol). The vial was purged with nitrogen gas, then MeCN (5 mL) was added via syringe. Morpholine (0.22 mL, 2.57 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was purified by RP-HPLC (60-100% MeCN:water) to give 4-(6-chloropyridazin-4-yl)morpholine as a yellow oil (115 mg, 75% yield). ESI MS m/z = 200.2 [M+H]+. Example 463 step b:
[0894] [0894] An oven-dried flask was charged with 4-(6-chloropyridazin-4-yl)morpholine (120 mg, 0.601 mmol), 3-amino-5-phenyl-1,3-dihydro-2H-benzo[e] ][1,4]diazepin-2-one (76 mg, 0.301 mmol), potassium tert-butoxide
[0895] [0895] Example 464 was prepared using a procedure similar to that used in Example 160 where (R)-tetrahydrofuran-3-amine and ethyl 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and 5-bromo- Methyl 3-fluoropicolinate, respectively. ESI MS m/z = 550.1 M+H]+. Example 465:
[0896] [0896] Example 465 was prepared using a procedure similar to that used to prepare Example 430, where ethyl 5-amino-3-methylisothiazole-4-carboxylate was used in place of 3-amino-1-cyclobutyl-1H-pyrazole- 4- ethyl carboxylate. ESI MS m/z = 502.1 [M+H]+. Example 466:
[0897] [0897] Example 466 was prepared using a procedure similar to that used in Example 160 where 2-oxa-5-azabicyclo[4.1.0]heptane and ethyl 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and methyl 5-bromo-3-fluoropicolinate, respectively. ESI MS m/z = 562.1 [M+H]+. Example 467: (mixture of diastereomers)
[0898] [0898] Example 467 was prepared using a procedure similar to that used in Example 160 where ethyl 2-(trifluoromethyl)morpholine and 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and 5-bromo-3-fluoropicolinate of methyl, respectively. ESI MS m/z = 618.1 [M+H]+. Example 468:
[0899] [0899] Example 468 was prepared using a procedure similar to that used in Example 160 where ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine and 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and methyl 5-bromo-3-fluoropicolinate, respectively. ESI MS m/z = 598.1[M+H]+. Example 469:
[0900] [0900] Example 469 was prepared using a procedure similar to that used in Example 160 where oxetan-3-amine and ethyl 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and 5-bromo-3-fluoropicolinate from methyl, respectively. ESI MS m/z = 536.1 [M+H]+. Example 470:
[0901] [0901] Example 470 was prepared using a procedure similar to that used in Example 160 where (S)-tetrahydrofuran-3-amine and ethyl 3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholine and 5-bromo- Methyl 3-fluoropicolinate, respectively. ESI MS m/z = 550.1 [M+H]+. Example 471:
[0902] [0902] Example 471 was prepared using a procedure similar to that used to prepare Example 430, where ethyl 2-aminothiophene-3-carboxylate was used in place of ethyl 3-amino-1-cyclobutyl-1H-pyrazole-4-carboxylate ethyl. ESI MS m/z = 487.1 [M+H]+. Example 472:
[0903] [0903] Example 472 was prepared using a procedure similar to that used to prepare Example 471, where 1-bromo-2-methoxyethane was used in place of 1-bromo-2-(2-bromoethoxy)ethane. ESI MS m/z = 475.1 [M+H]+. Example 473:
[0904] [0904] Example 473 was prepared using a procedure similar to that used in Example 339, where 2-methoxyethan-1-amine was used in place of morpholine. ESI MS m/z = 544.1[M+H]+. Example 474:
[0905] [0905] Example 474 was prepared using a procedure similar to that used in Example 339, where (R)-tetrahydrofuran-3-amine was used in place of morpholine. ESI MS m/z = 556.1 [M+H]+. Example 475:
[0906] [0906] Example 475 was prepared using a procedure similar to that used in Example 339, where oxetan-3-ylmethanamine was used in place of morpholine. ESI MS m/z = 556.1 [M+H]+. Example 476: Example 476 step a:
[0907] [0907] To an 8 mL flask 4-fluoro-2-hydroxybenzonitrile (150 mg, 1.094 mmol) was dissolved in acetone (2188 µL). To a solution was added ethyl 2-bromoacetate (121 µL, 1.094 mmol) followed by potassium tert-butoxide (151 mg, 1.094 mmol). The vial was sealed with electrical tape and heated at 40 °C for 12 h. The reaction was allowed to cool to room temperature and water (2 mL) and EtOAc (2 mL) were added. The organic layer was separated and the aqueous layer was washed with EtOAc (2 x 2 mL). The combined organic layer was dried over MgSO4 and concentrated. The crude reaction mixture was purified by silica gel chromatography (80:20 Hex/EtOAc). The desired product, ethyl 3-amino-6-fluorobenzofuran-2-carboxylate, was obtained as a white solid (186 mg, 76% yield). Example 476 step b:
[0908] [0908] Example 476 was prepared using a procedure similar to that used to prepare Example 430 where ethyl 3-amino-6-fluorobenzofuran-2-carboxylate was used in place of 3-amino-1-cyclobutyl-1H-pyrazol-4 - ethyl carboxylate. ESI MS m/z = 539.2 [M+H]+. Example 477:
[0909] [0909] Example 477 was prepared using a procedure similar to that used to prepare Example 476, where 2-fluoro-6-hydroxybenzonitrile was used in place of 4-fluoro-2-hydroxybenzonitrile. ESI MS m/z = 539.2 [M+H]+. Example 478:
[0910] [0910] Example 478 was prepared using a similar procedure to 458 where 1-methylcyclobutane-1-carboxamide was used in place of 1-fluorocyclobutane-1-carboxamide. The racemic mixture was purified by chiral separation. (Column= YMC CHIRAL Cellulose-SB, 250*20mm (5 µM); Mobile Phase = 50% EtOH/50% Hexane; Flow Rate = 20 mL/min). ESI MS m/z = 556.3 [M+H]+. Example 479: Example 479 step a:
[0911] [0911] To a nitrogen-dispersed solution of methyl 5-bromo-2-methylthiazole-4-carboxylate (0.5 g, 2.012 mmol), (E)-2-(3-methoxyprop-1-en-1- yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.068 ml, 5.03 mmol), and potassium phosphate (1.525 g, 7.04 mmol) in dry THF (20 ml) tetrakis(triphenylphosphine)palladium(0) (0.470 g, 0.402 mmol) was added. After 2 minutes of additional spraying, the mixture was stirred at 66 °C for 16 h, during which time it was diluted with water (20 mL) and extracted 3x with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous MgSO4 , filtered, and concentrated in vacuo. The resulting residue was flash chromatographed on silica gel to give methyl (E)-5-(3-methoxyprop-1-en-1-yl)-2-methylthiazole-4-carboxylate (310.1mg, 1.364mmol, 67 .8% yield) (TLC 30% EtOAc in hexane, rf ~0.2) as yellowish oil. Example 479 step b:
[0912] [0912] An oven-dried 20mL flask was charged with methyl (E)-5-(3-methoxyprop-1-en-1-yl)-2-methylthiazole-4-carboxylate (257mg, 1.131mmol), palladium on carbon (120 mg, 0.113 mmol) and anhydrous MeOH (11.308 mL). The flask was then purged with hydrogen and then stirred under atmospheric hydrogen at room temperature overnight. The solvent was evaporated and the crude residue filtered through a plug of silica gel using 1:1 EtOAc:hexane as eluent. Then the crude residue was purified by column chromatography to give methyl 5-(3-methoxypropyl)-2-methylthiazole-4-carboxylate (195.1 mg, 0.851 mmol, 75% yield) as a colorless oil. Example 479 step c:
[0913] [0913] Example 479 was prepared using a procedure similar to that used to prepare Example 152 where methyl 5-(3-methoxypropyl)-2-methylthiazole-4-carboxylate was used in place of 2-morpholino-4-(trifluoromethyl) ethyl benzoate. ESI MS m/z = 489.2 [M+H]+.
[0914] [0914] Et2Zn (1M in hexane) (10.4 mL, 10.4 mmol) was added to PH-ETA-A1-770-1 (0.3 g, 1.04 mmol) at 0 °C in then CH2I2 (5.6 g, 20.8 mmol) was added under N2. The mixture was stirred for 1 day at room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (PE-EA) and preparative chiral HPLC to yield the desired compound as a yellow oil (0.23g, 73%). ESI MS m/z = 304.3 [M+H]+. Examples 480, 481, 482 and 483 step b:
[0915] [0915] The solution of the compound from step a (230 mg, 0.76 mmol) and NH2NH2.H2O (2 mL) in EtOH (5 mL) was stirred for 1 hour at room temperature. The crude product was purified by preparative Flash HPLC (MeCN/H 2 O) to yield the desired mixture of compounds as a yellow oil (150 mg, 68%). The mixture was separated by preparative chiral HPLC to yield A (67 mg, 45%) and B (70 mg, 47%). A: ESI MS m/z = 290.3 [M+H]+. B: ESI MS m/z = 290.3 [M+H]+. Examples 480, 481, 482 and 483 step c:
[0916] [0916] Examples 480 and 481 with hydrazide A from step b), and 482 and 483 (with hydrazide B from step b), were prepared using a procedure similar to that used to prepare Example 21, where hydrazide A and hydrazide B were used in the instead of tetrahydro-2H-pyran-4-carbohydrazide. Compounds 481 and 482 were separated by preparative chiral HPLC. Compounds 483 and 484 were separated by preparative chiral HPLC. Example 480: ESI MS m/z = 549.5 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.05 (m, 1H), 1.19 (m, 1H), 1.58 (m, 1H), 2.90 (m, 1H), 3.23 (s, 3H), 3.28 (d, J = 6.5 Hz, 1H), 3.46 (m, 1H), 5.22 (d, J = 8.2 Hz, 1H), 7.24 – 7.42 (m, 3H), 7.41 – 7.61 (m, 5H), 7.68 (m, 1H), 7.83 – 7.93 (m, 1H), 8.83 – 9 .04 (m, 1H), 9.44 (d, J = 8.4 Hz, 1H), 11.00 (s, 1H). Example 481: ESI MS m/z = 549.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.05 (m, 1H), 1.13 - 1.28 (m, 1H), 1.51 - 1.67 (m, 1H), 2.90 ( m, 1H), 3.23 (s, 3H), 3.26 - 3.31 (m, 1H), 3.46 (m, 1H), 5.22 (d, J = 8.3 Hz, 1H ), 7.24 - 7.41 (m, 3H), 7.42 - 7.60 (m, 5H),
[0917] [0917] A solution of ethyl 2-(trifluoromethyl)thiazole-4-carboxylate (1.3 g, 5.78 mmol) in THF (5 mL) was added dropwise to the LDA solution (5.8 mL, 11.56 mmol) in THF (10 mL) at -78 °C under N 2 . The mixture was stirred for 45 minutes at the same temperature. To it a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (5.58 g, 17.34 mmol) in THF (5 mL) was added dropwise and warmed to room temperature, stirred for 2 hours. The reaction was quenched with saturated ammonium chloride solution. Water was added and the mixture was extracted with EA (x3). The organic layer was combined, dried and concentrated. The residue was purified via silica gel chromatography (petroleum ether-ethyl acetate) to yield the desired compound as a yellow oil (900 mg, 51%). ESI MS m/z = 549.5 [M+H]+. Examples 484, 485, 486, and 487 step b:
[0918] [0918] The solution of step a compound (800 mg, 2.64 mmol), 2-oxa-5-aza-bicyclo[4.1.0]heptane hydrochloride (535 mg, 3.96 mmol) and DIPEA (0.8 ml) in DMSO (4 ml) was stirred overnight at 80°C. It was extracted with EA (25 mLx2), the organic layer combined, and dried over anhydrous Na2SO4, then concentrated and purified by silica gel column to yield the mixture of enantiomers as an orange oil (443 mg, 52%). The mixture was purified by preparative chiral HPLC to yield A (200 mg, 42%) and B (210 mg, 44%). ESI MS m/z = 549.5 [M+H]+. Examples 484, 485, 486 and 487step c:
[0919] [0919] Examples 484 and 485 (with step b ester A), and 486 and 487 (with step b ester B), were prepared using a procedure similar to that used to prepare Examples 480, 481, 482, and 483. Example 484: ESI MS m/z = 568.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.81 (m, 2H), 2.94 (m, 2H), 3.56 - 3.83 (m, 3H), 3.88 (m, 1H) , 5.15 (d, 1H), 7.13 - 7.41 (m, 3H), 7.41 - 7.61 (m, 5H), 7.61 - 7.83 (m, 1H), 9 .14 (d, 1H), 10.97 (s, 1H). Example 485: ESI MS m/z = 568.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.82 (s, 2H), 2.92 (m, 2H), 3.57 – 4.02 (m, 4H), 5.15 (d, 1H) , 7.32 (m, 3H), 7.51 (m, 5H), 7.67 (m, 1H), 9.14 (d, 1H), 10.97 (s, 1H). Example 486: ESI MS m/z = 568.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.73 - 0.92 (m, 2H), 2.92 (m, 2H), 3.64 (m, 1H), 3.67 - 3.82 ( m, 2H), 3.89 (m, 1H), 5.15 (d, 1H), 7.19 - 7.39 (m, 3H), 7.39 - 7.59 (m, 5H), 7 .68 (m, 1H), 9.14 (d, 1H), 10.97 (s, 1H). Example 487: ESI MS m/z = 568.4 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 0.82 (m, 2H), 2.93 (m, 2H), 3.65 (m, 1H), 3.68 - 3.81 (m, 2H) , 3.89 (m, 1H), 5.15 (d, 1H), 7.14 - 7.40 (m, 3H), 7.40 - 7.59 (m, 5H), 7.68 (m , 1H), 9.14 (d, 1H), 10.97 (s, 1H). Examples 488 and 489: Examples 488 and 489 step a:
[0920] [0920] To a stirred solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (4 g, 0.025 mol) in DMF (50 ml) was added Cs2CO3 (8.2 g, 0.025 mol) and 1, 1,1-Trifluoro-2-iodoethane (10.5 g, 0.055 mol) at room temperature. The mixture was stirred at 70°C overnight and then concentrated. The reaction mixture was filtered and the filtrate was poured into water and extracted with EA (3 x 150 mL). The organic phase was dried over Na2SO4. The residue was purified via silica gel chromatography (petroleum ether-ethyl acetate) to yield the desired compound as a yellow solid (2.5 g, 44%). ESI MS m/z = 238.2 [M+H]+. Examples 488 and 489 step b:
[0921] [0921] To a stirred solution of the compound from step 1 (2.5g, 0.011mol) in DMA (30ml) was added 1-bromo-2-(2-bromoethoxy)ethane (5.82g, 0.025mol ) and Cs2CO3 (5.5 g, 0.017 mol) at room temperature. The resulting solution was stirred at 100 °C for 6 hours and then concentrated. The reaction mixture was poured into water and extracted with EA (3 x 150 ml). The organic phase was dried over Na2SO4. The residue was purified via silica gel chromatography (petroleum ether-ethyl acetate) to yield the desired product as a yellow solid (700 mg, 21%). ESI MS m/z = 308.4 [M+H]+. Examples 488 and 489 step c:
[0922] [0922] To a stirred solution of the compound from step 2 (700 mg, 3.74 mmol) in EtOH (5 mL) was added NH2NH2.H2O (4 mL) at room temperature. The resulting solution was stirred at room temperature for 5 hours. The reaction mixture was purified by C18 reversed phase column chromatography (MeCN:H2O) (MeCN/H2O) to yield the desired product as a yellow solid (300 mg, 27%). ESI MS m/z = 294.1 [M+H]+. Examples 488 and 489 step d:
[0923] [0923] Examples 488 and 489 were prepared using a procedure similar to that used to prepare Example 21, where 3-morpholino-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carbohydrazide was used in place of tetrahydro -2H-pyran-4-carbohydrazide. Examples 488 and 489 were separated by preparative chiral HPLC. Example 488: ESI MS m/z = 553.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ3.12 – 3.23 (dd, J = 6.1, 3.4 Hz, 4H), 3.61 – 3.82 (m, 4H), 5.00 – 5.23 (m, 3H), 7.26 – 7.39 (m, 3H), 7.39 – 7.59 (m, 5H), 7.64 – 7.76 (m, J = 8, 5, 7.0, 1.8 Hz, 1H), 8.16 - 8.32 (s, 1H), 8.93 - 9.12 (d, J = 8.7 Hz, 1H), 10.90 – 11.12 (s, 1H). Example 489: ESI MS m/z = 553.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ3.10 – 3.26 (dd, J = 6.1, 3.4 Hz, 4H), 3.61 – 3.78 (m, 4H), 5.00 – 5.18 (dd, J = 8.8, 3.4 Hz, 3H), 7.13 – 7.38 (m, 3H), 7.39 – 7.62 (m, 5H), 7.65 – 7.76 (m, J = 8.5, 7.0, 1.8 Hz, 1H), 8.16 – 8.29 (s, 1H), 8.95 – 9.10 (d, J = 8.6 Hz, 1H), 10.83 - 11.10 (s, 1H). Example 490:
[0924] [0924] Example 490 was prepared using a similar procedure to 458 where 1-(trifluoromethyl)cyclobutane-1-carboxamide was used in place of 1-fluorocyclobutane-1-carboxamide. The racemic mixture was purified by chiral separation. (Column= YMC CHIRAL Cellulose-SB, 250*20mm (5 µM); Mobile Phase = 50% EtOH/50% Hexane; Flow Rate = 20 mL/min). ESI MS m/z = 610.2 [M+H]+.
[0925] [0925] Example 491 was prepared using a similar procedure to 430 where bromocyclopentane was used in place of bromocyclobutane. ESI MS m/z = 539.5 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.55 – 1.69 (m, 2H), 1.77 (m, 2H), 1.84 – 1.96 (m, 2H), 1.96 – 2.10 (m, 2H), 3.02 - 3.26 (m, 4H), 3.66 (m, 4H), 4.63 (m, 1H), 5.10 (d, J = 8, 7 Hz, 1H), 7.23 - 7.39 (m, 3H), 7.41 - 7.58 (m, 5H), 7.67 (m, 1H), 8.06 (s, 1H), 8.85 (d, J = 8.7 Hz, 1H), 10.96 (s, 1H). Example 492:
[0926] [0926] Example 492 was prepared using a similar procedure to 458 where MeOH was used in place of EtOH in step e. The racemic mixture was purified by chiral separation. (Column= YMC CHIRAL Cellulose-SB, 250*20mm (5 µM); Mobile Phase = 50% EtOH/50% Hexane; Flow Rate = 20 mL/min). ESI MS m/z = 572.2 [M+H]+. Example 493:
[0927] [0927] Example 493 was prepared using a procedure similar to that used to prepare Example 21, where (R)-5-((5-oxopyrrolidin-3-yl)amino)-2-(trifluoromethyl)thiazole-4-carboxylate is ethyl, which was prepared similarly to ethyl 5-morpholino-2-(trifluoromethyl)thiazole-4-carboxylate in Example 339, was converted to the corresponding hydrazide and used in place of tetrahydro-2H-pyran-4-carbohydrazide. The racemic mixture was purified by chiral separation. (Column= YMC CHIRAL Cellulose-SB, 250*20mm (5 µM); Mobile Phase = 50% iPrOH/50% hexane; Flow rate = 20 mL/min). ESI MS m/z = 569.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.33 (dd, J = 16.7, 5.3 Hz, 1H), 2.69 (dd, J = 16.7, 7.9 Hz, 1H) , 3.28 (dd, J = 10.2, 4.5 Hz, 1H), 3.70 (dd, J = 10.1, 7.0 Hz, 1H), 4.23 (q, J = 6 .1, 6.1, 6.0 Hz, 1H), 5.15 (d, J = 8.4 Hz, 1H), 7.24 - 7.39 (m, 3H), 7.42 - 7, 58 (m, 5H), 7.68 (ddd, J=8.4, 7.0, 1.8Hz, 1H), 7.81 (s, 1H), 9.15 (d, J=8, 6 Hz, 1H), 10.95 (s, 1H). Example 494:
[0928] [0928] Example 494 was prepared using a procedure similar to that used to prepare Example 21, where (R)-5-((2-oxopyrrolidin-3-yl)amino)-2-(trifluoromethyl)thiazole-4-carboxylate is ethyl, which was prepared similarly to ethyl 5-morpholino-2-(trifluoromethyl)thiazole-4-carboxylate in Example 339, was converted to the corresponding hydrazide and used in place of tetrahydro-2H-pyran-4-carbohydrazide. The racemic mixture was purified by chiral separation. (Column= YMC CHIRAL Cellulose-SB, 250*20mm (5 µM); Mobile Phase = 50% iPrOH/50% hexane; Flow rate = 20 mL/min). ESI MS m/z = 569.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 2.03 (dq, J = 12.2, 9.6, 9.6, 9.6 Hz, 1H), 2.62 (dt, J = 12.6 , 6.6, 6.6 Hz, 1H), 3.30 (d, J = 3.4 Hz, 2H), 4.26 (t, J = 9.3, 9.3 Hz, 1H), 5 ,16
[0929] [0929] A solution of ethyl 5-bromo-2-(trifluoromethyl)thiazole-4-carboxylate (500 mg, 1.65 mmol), LiOH (198 mg, 8.25 mmol) in THF (5 mL) and H2O (2 mL) was stirred for 1 hour at room temperature. It was adjusted to pH 4 with 3N HCl and flash purified (MeCN/H2O) to yield the desired acid as a yellow solid (410 mg, 90.3%). The acid (410 mg, 1.49 mmol), K2CO3 (411 mg, 2.98 mmol), BnBr (507 mg, 2.98 mmol) in DMF (5 mL) was stirred for 1 hour at room temperature and purified by Flash (MeCN/H 2O) to yield the desired compound as a yellow solid (505 mg, 92.8%). The compound had no signal on LCMS. Example 495 step b:
[0930] [0930] The solution of step 1 compound (580mg, 1.59mmol), morpholin-3-one (481mg, 4.76mmol), Pd2(dba)3 (164mg, 0.15mmol), Xantphos (184 mg, 0.31 mmol), Cs2CO3 (1.03 g, 3.18 mmol) in 1,4-dioxane (10 mL) was stirred at 100°C for 2 hours. The solution was concentrated and purified by TLC yielding the desired product as a yellow solid (140 mg, 22.81%). ESI MS m/z = 409.1 [M+H]+. Example 495 step c:
[0931] [0931] The solution of compound from step 2 (140 mg, 0.36 mmol), Pd/C (50 mg) in MeOH (10 mL) under H 2 was stirred at room temperature for 2 hours. The solid was filtered off and concentrated to yield 5-(3-oxomorpholino)-2-(trifluoromethyl)thiazole-4-carboxylic acid as a yellow solid (70 mg, 65.69%). ESI MS m/z = 297.2 [M+H]+. Example 495 step d:
[0932] [0932] The solution of step 3 compound (70 mg, 0.23 mmol), tert-butyl hydrazinecarboxylate (62 mg, 0.46 mmol), HATU (131 mg, 0.34 mmol), DIPEA (0. 5 ml) in DMF (2 ml) was stirred at room temperature for 2 hours. The solution was Flash purified (MeCN/H2O) to yield the desired product as a yellow oil (50 mg, 53.02%). ESI MS m/z = 354.9 [M-t-Bu]+. Example 495 step e:
[0933] [0933] The solution of compound from step 4 (50mg, 0.12mmol), TFA (2mL) in DCM (16mL) was stirred at room temperature for 1 hour. The solution was adjusted to pH 10 with saturated NaHCO3 solution and flash purified (MeCN/H2O) to yield 5-(3-oxomorpholino)-2-(trifluoromethyl)thiazol-4-
[0934] [0934] Example 495 was prepared using a procedure similar to that used to prepare Example 21, where 5-(3-oxomorpholino)-2-(trifluoromethyl)thiazole-4-carbohydrazide was used in place of tetrahydro-2H-pyran-4 -carbohydrazide. The racemic mixture was purified by chiral separation. (Column= YMC CHIRAL Cellulose-SB, 250*20mm (5 µM); Mobile Phase = 50% iPrOH/50% hexane; Flow rate = 20 mL/min). ESI MS m/z = 570.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 3.82-3.84 (m, 2H), 3.99-4.03 (m, 2H), 4.32 (s, 2H), 5.16- 5.19 (d, J = 9.0 Hz, 1H), 7.27 - 7.36 (m, 3H), 7.43 - 7.53 (m, 5H), 7.64-7.67 ( m, 1H), 9.43-9.46 (d, J = 9.0 Hz, 1H), 10.98 (s, 1H). Example 496:
[0935] [0935] Example 496 was prepared using a procedure similar to that used to prepare Example 430, where 1-bromo-2-methoxyethane was used in place of 1-bromo-2-(2-bromoethoxy)ethane. ESI MS m/z = 513.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.65 – 1.84 (m, 2H), 2.31 (m, 2H), 2.40 – 2.48 (m, 2H), 3.27 ( s, 3H), 3.39 (m, 2H), 3.51 (m, 2H), 4.72 (m, 1H), 5.10 (d, J = 8.6 Hz, 1H), 5, 40 (s, 1H), 7.24 - 7.31 (m, 1H), 7.32 - 7.38 (m, 2H), 7.43 - 7.57 (m, 5H), 7.67
[0936] [0936] Example 497 was prepared using a similar procedure to 458 where 3,3,3-trifluoro-2,2-dimethylpropanamide was used in place of 1-fluorocyclobutane-1-carboxamide. The racemic mixture was purified by chiral separation. (Column= YMC CHIRAL Cellulose-SB, 250*20mm (5 µM); Mobile Phase = 50% EtOH/50% Hexane; Flow Rate = 20 mL/min). ESI MS m/z = 598.2 [M+H]+. Example 498:
[0937] [0937] Example 498 was prepared using a similar procedure to 458 where 3,3,3-trifluoro-2,2-dimethylpropanamide and 2-methoxyethan-1-amine were used in place of 1-fluorocyclobutane-1-carboxamide and morpholine, respectively. The racemic mixture was purified by chiral separation. (Column= YMC CHIRAL Cellulose-SB, 250*20mm (5 µM); Mobile Phase = 50% EtOH/50% Hexane; Flow Rate = 20 mL/min). ESI MS m/z = 586.2 [M+H]+. Example 499:
[0938] [0938] Example 499 was prepared using a procedure similar to that used to prepare Example 21, where (R)-5-((tetrahydro-2H-pyran-3-yl)amino)-2-(trifluoromethyl)thiazol-4- ethyl carboxylate, which was prepared similarly to ethyl 5-morpholino-2-(trifluoromethyl)thiazole-4-carboxylate in Example 339, was converted to the corresponding hydrazide and used in place of tetrahydro-2H-pyran-4-carbohydrazide . The racemic mixture was purified by chiral separation. (Column= YMC CHIRAL Cellulose-SB, 250*20mm (5 µM); Mobile Phase = 50% iPrOH/50% hexane; Flow rate = 20 mL/min). ESI MS m/z = 570.1 [M+H]+. Examples 500-518
[0939] [0939] The following compounds were prepared according to the general method described in Examples 430, 458 and 499. Example 500: Example 501:
[0940] [0940] HEp-2 cells, (originally derived from tumors grown in weaned, irradiated and cortisone mice, which were injected with squamous cell carcinoma tissue from the larynx of a 56-year-old male, but later discovered to be indistinguishable from the cells HeLa by PCR DNA analysis) were used for the culture of genotype A, RSV “Long” strain. Vials were inoculated with RSV and viral stocks were collected when the cytopathic effect (CPE) was greater than 90%. Viral stocks in 25% sucrose medium were flash frozen using liquid nitrogen to increase viral stability. Virus stock titers were quantified by 50% tissue culture infectious dose (TCID50) using 8000 cells per well and 3-fold viral dilutions in a 96-well plate, cultured for 4 days. Virus stock titers were also quantified by a plaque forming unit assay as described.
[0941] [0941] After extensive parameter testing, the final assay is performed as follows: HEp-2 cells are seeded into the inner 60 wells of a 96-well plate at 8,000 cells per well in a volume of 50 µL using Medium (DMEM without phenol red, 1% L-Glut, 1% Pen/Estrep, 1% non-essential amino acids, 10% heat-inactivated FBS). Two-fold serial dilutions of control and test compounds are added to the wells in duplicate, in a total volume of 25 µL.
[0942] [0942] HEp-2 cells (originally derived from tumors grown in weaned, irradiated and cortisone mice, which were injected with squamous cell carcinoma tissue from the larynx of a 56-year-old male, but later found to be indistinguishable from HeLa cells by analysis of PCR DNA) were used for the culture of genotype B, strain 9320. The flasks were inoculated with RSV-B and viral stocks were collected when the cytopathic effect (CPE) was greater than 90%. Viral stocks in 25% sucrose medium were flash frozen using liquid nitrogen to increase viral stability. Virus stock titers were quantified by 50% tissue culture infectious dose (TCID50) using 8000 cells per well and 5-fold viral dilutions in a 96-well plate, cultured for 4 days. Virus stock titers were also quantified by a plaque forming unit assay as described.
[0943] [0943] The assay is performed as follows: A549 cells (originally derived from explant culture from carcinomatous lung tissue of a 58-year-old male) are seeded into the inner 60 wells of a 96-well plate at 3,000 cells per well in a volume of 50 µL using A549 growth medium (F-12K media, 1% Pen/Estrep, 1% non-essential amino acids, 10% heat-inactivated FBS). Two-fold serial dilutions of control and test compounds are added to the wells in duplicate, in a total volume of 25 µL.
[0944] [0944] Compounds were serially diluted 1.3-fold in DMSO in 7 columns or rows of a 96-well plate using a Well-Pro machine. Using a 1.3-fold dilution, the base of the inhibition curve (~3% viral inhibition) resides at one end of the dilution plate, while the opposite end of the dilution plate approaches the 90% viral inhibition point. . This allows for maximum resolution in the assay.
[0945] [0945] Figure 1 and Table 4 show, respectively, the plate configuration and concentrations of each drug as used in this assay. Figure 1 is a graphical representation of drug configuration and compound combination in 96-well plates. Plate X and plate Y detail the configuration of the individual compounds diluted in DMSO, while the assay plate describes the combination of compounds as they reside in the final assay plates, including the location of viral infection and controls. Table 4: Drug Concentration Scheme Ex. 253 AZ-27 GS-5806 ALS-8112 Palivizumab Ribavirin [M] [M] [nM] [M] [M] [M] Top 0.100 0.020 0.975 3.750 0.520 12,000 0.077 0.015 0,750 2,885 0,400 9,231 0,059 0.012 0.577 2,219 0,308 7,101 0,046 0,009 0.444 1,707 0,237 0.007 0,341 1,313 0,182 4,202 0,027 0,00 0,232
[0946] [0946] HEp-2 cells were seeded in wells of assay plates at
[0947] [0947] Figure 2 is a graphical representation of the percentage of viral inhibition of compounds or combinations of compounds at each individual concentration or combination concentration tested. When no compound is administered, there is 0% viral inhibition, while maximum concentrations of compounds administered in combination reach or approach 100% viral inhibition. This data is used to calculate a combination index that determines whether compounds are antagonistic, additive or synergistic using the Loewe additivity model. The results are shown in Table 5. Table 5: Composite Combination Index Values Average Combination Index (CI) at EC50 EC75 EC90 EC95 Avg. Example 253 + Example 253 0.8 0.8 0.9 0.9 0.9 Example 253 + ALS-8112 0.7 0.6 0.5 0.4 0.6 Example 253 + AZ-27 0.8 0.6 0.5 0.4 0.6 Example 253 + GS5806 0.9 0.7 0.6 0.5 0.7 Example 253 + Ribavirin 0.9 1.0 1.1 1.2 1.0 Example 253 + Palivizumab 0.8 0.8 0.7 0.6 0.7 Cl<0.9 = synergy Cl>1.1 = antagonism Cl 0.9-1.1 = additivity
[0948] [0948] The combinations of Example 253 and palivizumab, ribavirin, GS-5806, AZ-27 or ALS-8112 were additive to moderately synergistic. While this invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and detail may be made without departing from the scope of the invention encompassed by the appended claims.

权利要求:
Claims (26)
[1]
1. Method for treating a human respiratory syncytial virus infection in a subject in need thereof, characterized in that it comprises administering to the subject a compound represented by Formula (I): R5 O RN 2
N (R6)n R4 R1 A
N R3 (I), or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of: 1) hydrogen; 2) halogen; 3) CN; 4) -C1-C8 optionally substituted alkyl; and 5) -C1-C8 alkyl optionally substituted -O-R11; R2 and R5 are each independently selected from the group consisting of: 1) hydrogen; and 2) -C1-C8 optionally substituted alkyl; A is selected from the group consisting of: 1) optionally substituted -C3-C12 cycloalkyl; 2) optionally substituted -C3-C12 cycloalkenyl; 3) optionally substituted 3- to 12-membered heterocycloalkyl; 4) optionally substituted aryl; and 5) optionally substituted heteroaryl; R3 is hydrogen or R11; {//4014/1301WO/00376111/V1}
R4 is selected from the group consisting of: 1) -C3-C12 optionally substituted cycloalkyl; 2) optionally substituted -C3-C12 cycloalkenyl; 3) optionally substituted 3- to 12-membered heterocyclyl; 4) optionally substituted aryl; 5) optionally substituted heteroaryl; 6) optionally substituted aryl-O-; 7) optionally substituted heteroaryl-O; 8) optionally substituted aryl-C1-C4-alkyl; and 9) optionally substituted heteroaryl-C1-C4-alkyl; each R6 is the same or different and independently selected from hydrogen, halogen, hydroxyl, protected hydroxyl, cyano, amine, protected amine, nitro, optionally substituted -C1-C8 alkyl, optionally substituted -C1-C8 alkoxy, -NHC1- optionally substituted C8 alkyl, -S-(- optionally substituted C1-C8 alkyl) optionally substituted -SO2-(-C1-C8 alkyl) optionally substituted -SO2-NH-(-C1-C8 alkyl) optionally substituted -NH-SO2 -(-C1-C8 alkyl) optionally substituted, -CO2R12, -NR13R14, and -CO-NR13R14; R11 and R12 are each independently selected from the group consisting of: 1) -C1-C8 optionally substituted alkyl; 2) optionally substituted -C2 -C8 alkenyl; 3) optionally substituted -C2 -C8 alkynyl; 4) optionally substituted -C3-C8 cycloalkyl; 5) optionally substituted -C3-C8 cycloalkenyl; 6) optionally substituted 3- to 8-membered heterocycloalkyl; 7) optionally substituted aryl; and 8) optionally substituted heteroaryl;
{//4014/1301WO/00376111/V1}
R13 and R14 are each independently selected from hydrogen, –C1-C8-optionally substituted alkyl, –C2-C8-optionally substituted alkenyl, –C2-C8-optionally substituted alkynyl; –C3-C8-optionally substituted cycloalkyl, - C(O)R12, -S(O)2R12, and -S(O)2NHR12, and -C1-C8-optionally substituted alkoxy; alternatively, R13 and R14 are taken together with the nitrogen to which they are attached to form a heterocyclic ring; and n is 0, 1, 2, 3 or 4; and a second anti-respiratory syncytial virus agent, wherein the compound of Formula I and the second agent are administered in a combined amount that is therapeutically effective.
[2]
2. Method according to claim 1, characterized in that the compound of Formula (I) is represented by Formula Ia or Formula Ib, R5 R5
O R O R N 2 N 2
N N (R6)n A R4 (R6)n A R4 R1 R1
N N R3 R3 (Ia) (Ib), or a pharmaceutically acceptable salt thereof.
[3]
3. Method according to claim 1, characterized in that A is selected from one of the following by removing two hydrogen atoms: {//4014/1301WO/00376111/V1}
H
N N N N O
NH S NH NH N NH NH N NH
N N N S N N N N N
No
N Y Y N N
O O N
O O S
N O N N N N N
N N N N
N N
No
N N
H O S H
N N N
N N
H H O
Y N N O
N N
N N , where each of those shown above is optionally substituted where possible.
[4]
4. Method according to claim 1, characterized in that R4 is selected from one of the following, by removing a hydrogen atom:
Y N N N HN N O N O
N N
O S N
H
HN O S S N N N N N N N
No
N Y N O
H
N N H
N N N N N O
No
THE
HN HN NH HN NH HN O HN OH NH2
HN HN HN O O O NH2
H
O N O NH2 NH2
H H
N S S N O N N N N N , wherein each of the above is optionally substituted where possible.
{//4014/1301WO/00376111/V1}
[5]
Method according to claim 1, characterized in that R4 is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, -CH3, -CF3, -OCF3, -CN, -NH2, -OH, -CH2N(CH3)2, -C(O)CH3, -NH-(C1-C6)alkyl, optionally substituted -NH-(C1-C6)alkyl-(C1-C6)alkoxy, -SO2 -(C1-C6)alkyl, -SO2-NH-(C1-C6)alkyl, optionally substituted -NH-SO2-(C1-C6)alkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl , optionally substituted heteroaryl, optionally substituted -C1-C8-alkyl, optionally substituted -C1-C8-alkenyl, optionally substituted -C3-C8-cycloalkyl, optionally substituted -C3-C8-cycloalkenyl, and optionally substituted -C1-C8-alkoxy .
[6]
6. Method according to claim 1, characterized in that R4 is substituted by 1 to 3 substituents independently selected from the group consisting of CH3, CN, fluorine, chlorine, CH3O-, CH3C(O)-, CH3OCH2 -,
N O O O N N CH3OCH2CH2O-, -CF3, CF3O-, , , , , ,
N O N O N N
N N N OH N O N O , , , , O , ,
THE
N O N O N O N NH
NH NH , , , , OH , NH OCH3 NH OCH3 NH OCH3 NH OCH3 NH OCH3 , , , , , F3C MeO EtO HO NH OCH3 CF3 CF3 , , , , , , , , ,
F F F CF3 , , F, and .
{//4014/1301WO/00376111/V1}
[7]
7. Method according to claim 1, characterized in that the compound of Formula I is represented by Formulas IIa-1, IIa-2, IIb-1 or IIb-2, or a pharmaceutically acceptable salt thereof, R5 R5
O R O R N 2 N 2
N N (R6)n A R4 (R6)n A R4
H H
N N R3 R3 (IIa-1) (IIb-1) R5 R5
O R O R N 2 N 2
N N (R6)n A R4 (R6)n A R4 Me Me
N N R3 R3 (IIa-2) (IIb-2) wherein R2, R3, R4, R5, R6, n and A are as defined in claim 1.
[8]
8. Method according to claim 1, characterized in that the compound of Formula I is represented by Formulas IV-1, IV-2, IV-3, or IV-4, or a pharmaceutically acceptable salt thereof, R5 R5
O R O R N 2 N 2
N O N S (R6)n (R6)n R1 R4 R1 R4
N N N N N N R3 R3 (IV-1) (IV-2) R5 R5
O R O R 2 N 2
N H
N O N N (R6)n (R6)n R1 R4 R1 R4
N N N N N R3 R3 (IV-3) (IV-4) wherein R1, R2, R3, R4, R5, R6, and n are as defined in claim 1.
[9]
9. Method according to claim 1, characterized in that the compound of Formula I is represented by Formulas V-1, V-2, V-3, or V-4, { //4014/1301WO/00376111/ V1}
R5 R5
O R O R N 2 2
No
N Y N O (R6)n (R6)n R1 R1
N N N N R3 R4 R3 R4 (V-1) (V-2) R5 R5
O R O R N 2 N 2
H
N N N N (R6)n (R6)n R1 R1 R4
N N N N R3 R4 R3 (V-4) (V-3) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, and n are as defined in claim 1.
[10]
10. Method according to claim 1, characterized in that the compound of Formula I is selected from the compounds shown below or a pharmaceutically acceptable salt thereof: Example Structure Example Structure
H O H O
N N
NH NH 1 N
No
O O 2 N
No
THE
NO
H O H O
N N
NH NH 3 N
No
The F 4 N
No
The OMe
N N
H O H O
N N
NH NH 5 N
N O 6 N
No
The F
N N
H O H O
N N
NH NH 7a N
N O 7b N
No
THE
N N
F F {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH 8 N
N O 9 N
N O MeO
N N O Me
H O H O
N N
NH NH 10a N
No
THE
The 10b N
No
THE
THE
N N
H O H O
N N
NH NH 11 N
No
THE
N 12 N
No
THE
N N
CN
H O H O
N N
NH NH 13 N
N O 14 N
No
The OMe
N N Cl F
H O H O
N N
NH NH 15 N
No
O O 16 N
No
THE
N N
H O H O
N N
NH NH 17 N
N O 19 N
No
THE
s
N N
H O H O
N N
NH NH 20 N
No
THE
The 21 N
No
The NCl N
THE
H O
N H O
No
NH
N O NH 22 N
N 23 N
No
THE
No
No
F {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH 24 N
No
THE
N 25 N
No
THE
No
N N CN CF3
H O H O
N N
NH NH 26 N
No
THE
N 27 N
No
THE
N N SO2Me
H O H O
N N
NH 28 N
N O 29 N
No
The CF3
N N CF3
H O H O
N N
NH NH 30 N
N O 31 N
No
THE
N N OCF3 SO2NH2
H O H O
N N
NH NH 32 N
No
The CN 33 N
No
THE
F
N N
F CN
H O H O
N N
NH NH 34 N
N O 35 N
No
THE
CN
N N
CN
H O H O
N N
NH NH
NO 36 N 37 N
No
THE
N N N
No
No
H O H O
N N
NH NH 38 N
No
The CN 39 N
No
THE
N N NH
No
The {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH 40 N
No
O O 41 N
No
The H
No
N N
NH N
H O H O
N N
NH NH 42 N
No
THE
S 43 N
No
THE
s
N N N
No
H O H O
N N
NH NH 44 N
No
THE
S 45 N
No
THE
N N
N N NH
H O H O
N N
NH NH
N O 46 N
N O 47 N
No
N N
No
THE
H O H O
N N
NH NH 48 N
No
The H
N 49 N
No
The H
No
N N
The O
H O H O
N N
NH NH 50 N
No
The F 51 N
No
THE
No
N N F OMe
H O H O
N N
NH NH 52 N
No
O N OMe 53 N
No
THE
N N N
F
H O H O
N N
NH NH 54 N
N O 55 N
No
THE
F
N N N
N OMe {//4014/1301WO/00376111/V1}
H O H O
N N
NH
NH
N O 56 N
No
The OMe 57 N
No
No
No
Name
H O H O
N N
NH NH 58 N
No
THE
N 59 N
No
THE
No
N N
No
No
H O H O
N N
NH NH 60 N
N O 61 N
No
THE
N N N
No
No
H O H O
N N
NH NH 62 N
No
THE
N 63 N
No
THE
No
N N N
No
H O H O
N N
NH NH 64 N
No
THE
N O 65 N
No
THE
N N
N N
H O H O
N N
NH 66 N
No
The 67 N
No
THE
No
N N N
N N
H O H O
N N
NH 68 N
No
THE
N 69 N
No
THE
s
N N
N N
H O H O
N N
NH 70 N
No
THE
The 71 N
No
THE
THE
N N
N {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH 72 N
No
THE
The 73 N
No
THE
THE
N N
The No.
H O H O
N N
NH NH 74 N
No
THE
The 75 N
No
THE
THE
N N N
No
H O H O
N N
NH 76 N
No
THE
S 77 N
No
THE
N N S
N N
H O H O
N N
NH 80 N
N S 81 N
No
s
N N
F
H O H O
N N
NH NH 82 N
N S 83 N
No
s
N N
No
CN
H O H O
N N
NH NH 84 N
N O 85 N
No
s
H O H O
N N
NH 86 N
N NH 87 N
s
No
N N
H O H O
N N
NH 88 N
Y N 89 N
THE
No
N N N
The {//4014/1301WO/00376111/V1}
H O O
N H O N
NH N N 90 N
Y N 91 N
NH
H O H O
N N
NH 92 N
N 93 N
N N O
N N
H O
H O N
No
NH
NH
N N 94 N N O 95 N
No
H O H O
N N
THE
NH NH
N 96 N N 97 N
No
H O H O
N N
NH 98 N
No
N 99 N
No
The Cl
H O H O
N N
NH 100 N
N O 101 N
No
s
PMB H O
The No.
N NH2 NH Me 102 N 103 N
No
THE
F
H O
N H O
No
NH
NH
N O 104 N 105 N
No
THE
F
F {///4014/1301WO/00376111/V1}
H O H O
N N
NH
NH
N O 106 N 107 N
No
THE
No
N SO2Me
H O H O
N N
NH NH
N O 108 N N 109 N
No
The NCl
N N
AT THE
H O H O
N N
NH NH
The 110 N
No
THE
N 111 N
No
THE
No
N N
F
H O H O
N N
NH NH
N O N O 112 N F 113 N
N N
N N
The O
H O H O
N N
NH NH
N O N O 114 N N 115 N
No
N N
N N
The O
H O
H O N
No
NH
NH
N N O 116 N
The 117 N
N N
N NH
H O
H O H O
N N
NH NH
NO NO 118 N 119 N
No
F
No
N N
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 120 N
N 121 N
N N N N SO2Me
The O
H O H O
N N
NH NH
N N O
The 122 N 123 N
No
N N N CF3 Cl O
THE
H O H O
N N
NH NH
NO NO 124a N 124b N
N N
N N
The O
H O H O
N N
NH NH
NO NO 125a N
N 125b N
No
N N
The O
H O H O
N N
NH NH
NO NO 126a N 126b N
N N
F N F N
The O
H O H O
N N
NH NH
NO NO 127 N
N 128 N
No
N F N N N
No
The O
H O H O
N N
NH NH
NO NO 129 N
N 130 N
N N N N N CF3
No
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 131 N
N 132 N
No
No
N CN N
The O
H O H O
N N
NH NH
N O N O 133 N N N 134 N
N N
N N
THE
H O H O
N N
NH NH
NO NO 135 N N 136 N
No
No
No
N N F Cl
THE
THE
H O H O
N N
NH NH
NO NO 137 N N 138 N
No
No
No
N F
F N
The O
H O H O
N N
NH NH
NO NO 139 N
N N 140 N
No
N N CF3 N CN
The O
H O H O
N N
NH NH
NO NO 141 N
N 142 N
No
N N
N N
THE
H O H O
N N
NH NH
NO NO 143 N
N N 144 N
No
N N N N
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 145 N
No
F 146 N
N CF3
N N N N
The O
H O H O
N N
NH NH
NO NO 147 N 148 N
No
N F3C N N
The F
THE
H O H O
N N
NH NH
NO NO 149 N 150 N
No
No
N N F
F N N
The O
H O H O
N N
NH NH
NO NO 151 N
N 152 N
N N N F N CF3
The O
H O H O
N N
NH NH
NO NO 153 N
N 154 N
No
N N CN N N
The O
H O H O
N N
NH NH
NO NO 155 N
N 156 N
No
N N O N N O
H
The O
H O H O
N N
NH NH
NO NO 157 N
N 158 N
No
CN
N CN N N
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 159 N
N 160 N
No
No
N F N CN
The O
H O H O
N N
NH NH
N O N O 161 N N 162 N
N N
N N N N CF3
No
THE
THE
H O H O
N N
NH NH
NO NO 163 N
N N 164 N
No
No
No
No
N N
The O
H O H O
N N
NH NH
NO NO 165 N
N 166 N
No
N N
N N N N
The O
H O H O
N N
NH NH
N O N O 167 N N N 168 N
No
N N N N Br
The O
H O H O
N N
NH NH
N O N F
The 169 N
N N 170 N
No
N F N
THE
THE
H O H O
N N
NH NH
N O F N O 171 N
N 172 N
N N
N F N N
No
The No.
The {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
N O N O 173 N N N 174 N
No
CN
N N N N N N
No
The O
H O H O
N N
NH NH
NO NO 175 N
No
CN 176 N
No
CN
N N N N
The O
H O H O
N N
NH NH
N O N O 177 N N N 178 N
No
No
No
No
N N
The O
H O H O
N N
NH NH
NO NO 179 N
N O 180 N
No
s
No
N N
The O
H O H O
N N
NH NH
N O N O 181 N N N 182 N
No
S BR
No
N N
The O
H O H O
N N
NH NH
N O 183 N
No
THE
S 184 N
N CN N
No
H O
H O N
No
NH
NH
N O 185 N
No
THE
N 186 N
N N
No. No
F
N N {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH 187 N
No
THE
S 188 N
No
THE
N N
No
H O H O
N N
NH NH 189 N
N O 190 N
No
THE
N N
H O H O
N N
NH NH 191 N
No
THE
The 192 N
No
O N N CF3
H O H O
N N
NH NH 193 N
N O 194 N
No
The SO2Me
N CN N
H O H O
N N
NH 195 N
N O 196 N
No
THE
N N
H O H O
N N
NH 197 N
N O 198 N
No
THE
N N
THE
H O H O
N N
NH 199 N
N O 200 N
No
THE
No
N N
CN
H O
The No.
N NH
NH NO 201 N
N O 202 N
No
N N
F N CF3 {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH 203 N
N O 204 N
No
THE
N N CF3 F
H O H O
N N
NH 205 N
N O 206 N
No
THE
N N
H O H O
N N
NH 207 N
N O 208 N
No
THE
N N
THE
H O
H O N
No
NH
No
N O 209 N
N O 210 N
No
No
No
F
No
H O
H O N
N NH
NH NO
N O N 211 N
N 212 N
No
No
N N
No
H O H O
N N
NH NH 213 N
N O 214 N
No
THE
N N F
oh
F
H O H O
N N
NH
NH
N O 215 N
N O 216 N F
No
N N
No
THE
No
H O H O
N N
NH NH
NO NO 217 N 218 N
N N
N N
N N
N N {//4014/1301WO/00376111/V1}
H O
No
H O
N NH
NH NO
N O N 219 N O Me 220 N
AT THE
No
No
THE
H O H O
N N
NH NH 221 N
N O 222 N
No
THE
N NH N
NH
H O
H O N
N NH
NH NO 223 N
No
The NH 224 N
No
No
No
No
H O H O
N N
NH NH
N N O
The 225 N
N 226 N
No
No
No
No
N N
H O H O
N N
NH NH
NINTH
N 227 N N 228 N
N N
HN N
H O
N H O
NH N H
AT THE
N O F 229 N N 230 N N N
THE
THE
H O H O
N N
NH NH
NO NO 231 N 232 N
No
N N
N N N N {//4014/1301WO/00376111/V1}
H O
H O N
No
NH
NH NO
N O 233 N 234 N
No
No
N N O
N N
H O
N H O
NH N
N O NH
N N O 235 N 236 N
No
HN
AT THE
THE
H O
N H O
NH N
N O NH 237 N N 238 N
No
THE
No
N N
HN
No
H O H O
N N
NH NH
NINTH
No
N 239 N 240 N
THE
No
YOU
The O
H O H O
N N
NH NH
NO NO 241 N
N 242 N
No
N N N N
THE
H O H O
N N
NH
NH
N O N O 243 N N 244 N
No
N Cl N O Cl
The {//4014/1301WO/00376111/V1}
H O
H O N
No
NH
NH NO
N O N 245 N
N 246 N
N N
N N
THE
F F
H O
N H O
No
NH
NH
AT THE
AT THE
N 247 N 248 N
No
N N
N N
The MeO
H O H O
N N
NH NH
NO NO 249 N N 250 N
No
N N CF3
No
THE
THE
H O H O
N N
NH NH
NO NO 251 N
N N 252 N
N N CF3 N N
The O
H O H O
N N
NH NH
NO NO 253 N
N N 254 N
N N CF3 N N
The MeO
H O H O
N N
NH NH
NO NO 255 N N 256 N
No
N N N N
HO F {//4014/1301WO/00376111/V1}
H O H O
N N
NH
NH
NINTH
N 257 N 258 N
No
N N
No Me Me
H O H O
N N
NH NH
NO NO 259 N N 260 N
No
N N N N
F
F NC
H O
H O N
No
NH
NH
AT THE
N O N 261 N
N 262 N
N N
N N
THE
THE
H O
N H O
No
NH
NH
AT THE
AT THE
N 263 N 264 N
No
N N
N N
THE
THE
H O H O
N N
NH NH
NO NO 265 N
N 266 N
No
N N N N
The O
H O H O
N N
NH NH
NINTH
N 267 N 268 N
No
N H N N CF3
N O H MeO {//4014/1301WO/00376111/V1}
H O
H O N
No
NH
NH
AT THE
AT THE
N 269 N
No
N 270 N CF3 N N
No
No
F N
No
H O H O
N N
NH NH
NO NO 271 N
N N 272 N
No
N CF3 S
N N Me O O
H O
H O N
No
NH
NH
AT THE
N O 273 N 274 N
No
No
N N N N
No
NC
H O H O
N N
NH NH
NO NO 275 N
N 276 N
N N N CF3 N N CF3
The O
H O H O
N N
NH NH
NINTH
N N N N 277 N 278 N N CF3 N CF3
The O
H O H O
N N
NH NH
NO NO 279 N
N 280 N
No
N N N N
The O
H O H O
N N
NH NH
NO NO 281 N
N 282 N
No
N N CN CF3
The N {///4014/1301WO/00376111/V1}
H O
H O N
No
NH
NH NO
N O N 283 N
N 284 N
N F
N N
THE
H O H O
N N
NH NH
NO NO 285 N
N 286 N
No
N CN N N
The O
H O
H O N
No
NH
NH NO 287 N
N O 288 N
No
N F
N N
THE
H O H O
N N
NH NH
NO NO 289 N
N 290 N
N N N CN N N CF3
The O
H O
H O N
No
NH
NH NO
N O 291 N
H N 292 N
No
No
No
N S
No
CN
THE
H O H O
N N
NH NH
N N O
O 293 N N 294 N
No
No
N CF3 N CF3
THE
H O
H O N
No
NH
NH NO
N O N N 295 N
N 296 N N CF3 N N OMe
No
THE
The {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NINTH
N N 297 N 298 N
No
N CF3 N
HN
HO
THE
H O H O
N N
NH NH
NO NO 299 N
N N 300 N
No
F O CN
No
The O
H O H O
N N
NH NH
NO NO 301 N
N N 302 N N
N N CN CF3
No
THE
H O H O
N N
NH NH
NO NO 303 N
N N 304 N
No
N HN CF3 N CN
NC O
H O H O
N N
NH NH
NO NO 305 N
N N 306 N
No
No
N HN CF3
The O
H O
H O N
N NH
NH NO
N O N N 307 N N 308 N
N N CF3 HN CF3
HO
H O H O
N N
NH NH
NO NO 309 N
N N 310 N
No
N N CF3
S O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 311 N
N N 312 N
No
No
N N
The O
H O H O
N N
NH NH
NO NO 313 N
N N 314 N
No
No
N N N
The O
H O
N H O
No
NH
NH
AT THE
AT THE
N 315 N 316 N
No
No
CN
No
O N O
H O H O
N N
NH NH
NO NO 317 N
N 318 N
No
No
N N N
The O
H O H O
N N
NH NH
NO NO 319 N
N 320 N
No
CN CN
THE
No
THE
H O H O
N N
NH NH
NO NO 321 N
N N 322 N
No
No
N N
The O
H O H O
N N
NH NH
NO NO 323 N
No
S CN 324 N
No
N CN
N N
THE
The {///4014/1301WO/00376111/V1}
H O
H O N
No
NH
NH
AT THE
N O N N 325 N
N N 326 N
N CN
N CN
THE
THE
H O H O
N N
NH NH
NO NO 327 N
N N 328 N
No
N CF3 N CF3
No
NO
H O H O
N N
NH NH
NINTH
N N 329 N 330 N
No
N CN S
No
THE
THE
H O H O
N N
NH NH
NO NO 331 N
No
N 332 N
No
N HN CF3 SO2Me
No
THE
NC
H O H O
N N
NH NH
NO NO 333 N
N N 334 N
No
No
s
CN N
N N
THE
THE
H O H O
N N
NH NH
NO NO 335 N
N N 336 N
No
No
S S
HN N
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 337 N
N N 338 N
No
No
YOU
N N
The O
H O H O
N N
NH NH
NO NO 339 N
No
N CF3 340 N
No
No
S S
N N
The O
H O H O
N N
NH NH
NINTH
N 341 N
N N 342 N
No
No
Y Y N N MeO
The O
H O H O
N N
NH NH 343 N
No
THE
N 344 N
No
THE
No
N N
S S Cl
H O H O
N N
NH NH
NO NO 345 N
N N 346 N
No
No
S S
The O
H O H O
N N
NH NH
NO NO 347 N
N N 348 N
No
THE
s
No
The O
H O H O
N N
NH NH
NO NO 349 N N 350 N
N N
N N N {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH 351 N
No
THE
N O 352 N
No
THE
N N N
S I
H O H O
N N
NH NH
NO NO 353 N
N 354 N
No
The O
F H O F H O
N N
NH NH
NO NO 355a N
N 355b N
No
N N
The O
F F H O
H O N
No
NH NH
NO NO 356 N 357 N
No
No
N N N
THE
THE
F H O F H O
N N
NH NH
NO NO 358 N
N 359 N
No
N N N N CF3
The O
F H O F H O
N N
NH NH
NO NO 360 N
N N 361 N
No
N N CF3 N CN
O O Cl HO
N H O
No
NH
N NH
The 362 N
N 363 N
No
NH
No
N F
The {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
N NH 364 N 365 N
No
NH
N N
No
N CN
H O
H O N
No
NH
NH N NH 366 N
N NH 367 N
No
No
N N
THE
H O H O
N N
NH NH 368 N
N O 369 N
No
THE
CN F
H O
H O N
No
NH
NH N N 370 N
N O 371 N Br
H O
No
H O
N NH
NH N N 372 N
N NH 373 N
No
F
H O
N H O
No
NH
NH
N N
N N
N 374 375 N
No
F
H O H O
N N
NH NH
N N N N
N N 376 377 OMe CN {//4014/1301WO/00376111/V1}
H O
N H O
No
NH
N N O NH 378 N 379 N
No
THE
No
F N
F
H O H O
N N
NH NH
NO NO 380 N 381 N
N N
F F
F CN
H O H O
N N
NH NH
NO NO 382 N
N 383 N N CF3
s
F N
F O
H O H O
N N
NH NH
N O N O 384 N N 385 N
No
No
S S
N N
The O
H O H O
N N
NH NH
NINTH
F 386 N
N N 387 N
No
No
F
S S
N N
The O
H O H O
N N
NH NH
N O N N O
N 388 N
N N 389 N
No
N F
S S
N N
The O
H O H O
N N
NH NH
N O N N O 390 N
N N CF3 391 N
No
N CF3
S S
N HN
The O {///4014/1301WO/00376111/V1}
H O
H O N
No
NH
NH
AT THE
N O N N 392 N
No
N CF3 393 N CF3
S S
HN HN
The O
H O H O
N N
NH NH
NO NO 394 N
No
N CF3 395 N
No
N CF3
S S
The O
H O H O
N N
NH NH
NINTH
N N N 396 N
N CF3 397 N CF3
S S
HN
THE HO
H O
N H O
No
NH
NH
NINTH
N N N 398 N CF3 399 N
No
No
No
S S
HN N
HOO
H O H O
N N
NH NH
NO NO 400 N
No
N B 401 N
N N
Y N
N N
The O
H O H O
N N
NH NH
NO NO 402 N
N N O 403 N
N N
N N
N N
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 404 N
No
The N 405 N
No
No
s
N N
The O
H O H O
N N
NH NH
N O N O F 406 N
N N 407 N
No
N F
S S
N N
The O
H O H O
N N
NH NH
NO NO 408 N N 409 N
No
N N MeO MeO
H O
N H O
No
NH
NH
AT THE
AT THE
N 410 N N 411 N
N N
No
N MeO MeO
H O H O
N N
NH NH
NINTH
N N N N 412 N 413 N CF3 CF3 MeO MeO 412 413
H O H O
N N
NH NH
NO NO 414 N
No
N 415 N
No
N CF3 HN CF3
HN MeO MeO {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NINTH
N N N N 416 N 417 N HN CF3 CF3
HN MeO
HO
H O H O
N N
NH NH
NINTH
N N N N 418 N 419 N CF3 HN CF3
HN
THE
HO
H O H O
N N
NH NH
NINTH
N N N N 420 N 421 N HN CF3 HN CF3
The O
H O H O
N N
NH NH
NINTH
N N N N 422 N 423 N HN CF3 HN CF3
HO HO
H O
N H O
No
NH
NH
N O N O N
N N 424 N 425 N
N N HN CF3 N
No
THE
THE
H O H O
N N
NH NH
N O N O F 426 N N 427 N
No
No
s
N N O Me O {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 428 N
No
N F 429 N
No
N N
S S
N N
The O
H O H O
N N
NH NH
NINTH
N 430 N N N 431 N
N N
N N
N N
The O
H O H O
N N
NH NH
NO NO 432 N N 433 N
No
No
N N
N N
The O
H O H O
N N
NH NH
NO NO 434 N
N 435 N
No
No
N N
the NC
H O
N H O
No
NH
NH
NINTH
N N 436 N 437 N
No
N CF3 S OH
HN
N MeO
THE
THE
H O H O
N N
NH NH
NINTH
N N N 438 N N 439 N N CF3
N N OMe MeO {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NINTH
N N 440 N
N N CF3 441 N N
N N
No
the NC
H O H O
N N
NH NH
N O N O 442 N N 443 N N N CF3 CF3
No
The O
H O
H O N
No
NH
NH NO
N O N N 444 N
N N CF3 445 N
No
No
N N
N N
THE
The CF3
H O
H O N
No
NH
NH
AT THE
N O N 446 N N N 447 N N
No
N N
No
The O 447
H O H O
N N
NH NH
NINTH
N N 448 N
N N
F 449 N N
N N
N O MeO
H O H O
N N
NH NH
NINTH
N 450 N
N N 451 N
N CF3 CF3
s
HN
HO O {//4014/1301WO/00376111/V1}
H O
N H O
No
NH
NH
NINTH
N N 452 N CF3 453 N
No
N CF3
s
HN S
THE
THE
H O H O
N N
NH NH
NO NO HO 454 N
No
N CF2CF3 455 N
No
No
S S
N N
The O
H O H O
N N
NH NH
NINTH
N N N N 456 N CF3 457 N CF3
S S
N N O Me O Me
H O H O
N N
NH NH
NO NO EtO 458 N
N N 459 N
No
No
No
S S
N N
THE
The O
H O H O
N N
NH NH
NO NO 460 N
N N 461 N
No
N CF3 F
s
N N
F
The O
H O H O
N N
NH NH 462 N
N 463 N
N N O
N N {//4014/1301WO/00376111/V1}
H O
N H O
No
NH
NH
AT THE
N N N O 464 N 465 N
N N HN CF3
s
No
THE
THE
H O
H O N
No
NH
NH
AT THE
N O N N 466 N
No
N 467 N N CF3 N CF3
THE
The CF3
H O H O
N N
NH NH
NINTH
N N N N 468 N 469 N N CF3 CF3
HN
THE
THE
H O
N H O
No
NH
N NH
THE
N N N O 470 N 471 N
N HN CF3
s
No
THE
THE
H O H O
N N
NH NH
NO NO 472 N N 473 N
No
N CF3
S S
HN HN
The O
H O H O
N N
NH NH
NINTH
N N N N 474 N CF3 475 N
S CF3
s
HN HN
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 476 N
N O 477 N
No
THE
F
N N
O O F
H O H O
N N
NH NH
NO NO 478 N
N N 479 N
No
No
S S
No
The O
H O H O
N N
NH NH
NO NO 480 N
No
N 481 N
No
N CF3 CF3 MeO MeO
H O H O
N N
NH NH
NO NO 482 N
No
N 483 N
No
N CF3 CF3 MeO MeO
H O H O
N N
NH NH
NO NO 484 N
No
N CF3 485 N
No
N CF3
S S
N N
The O
H O H O
N N
NH NH
NINTH
N N 486 N
N CF3 487 N
N CF3
S S
N N
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
N O N O 488 N N N 489 N
N N CF3 CF3
N N
N N
The O
H O H O
N N
NH NH
NO NO CF3 490 N
N N 491 N
N N
Y N
N N
The O
H O
H O N
N NH
NH NO
N O N N OMe N CF3 492 N
N N 493 S
S HN
No
The No.
H O
H O
N H O
NH N
N O NH
N N N O N CF3 494 S 495 N
No
N CF3
HN S
No
The O
AT THE
H
H O H O
N N
NH NH
N O N O 496 N N N 497 N
No
N CF3
N S
HN N
The O
H O
H O N
No
NH
NH NO
N O N N 498 N
N N 499 N CF3 CF3 S
S HN
HN
THE
The {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NINTH
N N N N 500 N CF3 501 N CF3
S S
HN HN
The O
H O
H O N
No
NH
NH
NO NO F3C
N N 502 N
N N 503 N CF3 S
S HN
HN
THE
THE
H O
N H O
No
NH
NH
AT THE
N O N N CF3 504 N 505 N
No
No
s
HN S
HN
THE
THE
H O
H O N
No
NH
NH
AT THE
N O N 506 N
N N 507 N N
No
S HN
HN
THE
THE
H O H O
N N
NH NH
NINTH
F N 508 N N N F 509 N
N CF3
N S
N N
The O
H O H O
N N
NH NH
NINTH
N 510 N
N 511 N
No
N CF3
S S
N N
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO CF3 512 N
No
N 513 N
No
No
S S
N N
The O
H O H O
N N
NH NH
NINTH
N 514 N
N 515 N
No
No
S S
N HN
The O
H O
N H O
No
NH
NH
AT THE
N O N N NH2 516 N 517 N
No
No
s
HN S
No
THE
THE
H O
No
NH
N O F F 518 N
No
No
s
No
THE
[11]
A method according to any one of claims 1 to 10, characterized in that the second anti-respiratory syncytial virus agent is selected from the group consisting of an anti-RSV antibody, a fusion inhibitor, a N protein, a nucleoside or non-nucleoside inhibitor of RSV polymerase L, an IMPDH inhibitor, a siRNA, and an interferon.
[12]
12. Method according to claim 11, characterized in that the second anti-respiratory syncytial virus agent is selected from the group consisting of RSV-IGIV, palivizumab, motavizumab, MK-1654, I-cyclopropyl-3- [[1-(4-hydroxybutyl)benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-one (BMS-433771), 4,4"-bis-{4,6-bis acid -[3-(bis-carbamoylmethyl-sulfamoyl)- {//4014/1301WO/00376111/V1}
phenylamino]-(1,3,5)triazin-2-ylamino}-biphenyl-2,2"-disulfonic acid (RFI-641), 4,4'-Bis[4,6-di[3-aminophenyl-N ,N-bis(2-carbamoylethyl)-sulfonylimino]-1,3,5-triazine-2-ylamino]-biphenyl-2,2'-disulfonic acid, disodium salt (CL387626), 2-[[2-[[1] -(2-aminoethyl)-4-piperidinyl]amino]-4-methyl-1H-benzimidazol-1-yl]-6-methyl-3-pyridinol (JNJ-2408068), 2-[[6-[[[2] -(3-Hydroxypropyl)-5-methylphenyl]amino]methyl]-2-[[3-(morpholin-4-yl)propyl]amino]benzimidazol-1-yl]methyl]-6-methylpyridin-3-ol ( TMC-353121), 5,5'-bis[1-(((5-amino-1H-tetrazolyl)imino)methyl)]2,2',4"-methylidinetrisphenol (VP-14637, MDT-637), N -(2-hydroxyethyl)-4-methoxy-N-methyl-3-(6-methyl-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)benzenesulfonamide (P13), 2- ((2-((1-(2-aminoethyl)piperidin-4-yl)amino)-4-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6-methylpyridin-3-ol ( R170591), 1,4-bis(3-methylpyridin-4-yl)-1,4-diazepam (05), (R)-9b-(4-chlorophenyl)-1-(4-fluorobenzoyl)-2,3 -dihydro-1H-imidazo[r,2':1,2]pyrrolo[3,4-c]pyridin-5(9bH)-one (BTA9981), [2,2-bis(doco siloxyoxymethyl)propyl-5-acetaoamido-3,5-dideoxy-4,7,8,9-tetra-O-(sodium-oxysulfonyl)-D-glycero-D-galacto-2-nonulopyranoside]onate (MBX-300) , BTA-C286, N-(2-((S)-2-(5-((S)-3-aminopyrrolidin-1-yl)-6-methylpyrazolo[1,5-a]pyrimidin-2-yl) piperidine-1-carbonyl)-4-chlorophenyl)methanesulfonamide (GS-5806), an anti-RSV nanobody, a peptide fusion inhibitor (such as a peptide having the sequence DEFDASISQVNEKINQSLAFIRKSDELL (T-67), a peptide having the sequence FDASISQVNEKINQSLAFIRKSDELLHNVNAGKST (T-118), (S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3- yl)urea (RSV-604), STP-92, iKT-041, 6-{4-[(biphenyl-2-ylcarbonyl)amino]benzoyl}-N-cyclopropyl-5,6-dihydro-4H-thieno[3 ,2-d][1]benzazepine-2-carboxamide (IM-53403). N-cyclopropyl-5-(4-(2-(pyrrolidin-1-yl)benzamido)benzoyl)-5,6,7,10-tetrahydrobenzo[b]cyclopenta[d]azepine-9-carboxamide, 6-(4 -(2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)nicotinamido)benzoyl)-N-cyclopropyl-5,6-dihydro-4H-benzo[b]thieno[2,3-d] azepine-2-carboxamide, 4-amino-8-(3-{[2-(3,4-
{//4014/1301WO/00376111/V1}
dimethoxyphenyl)ethyl]amino}propyl)-6,6-dimethyl-2-(4-methyl-3-nitrophenyl)-1H-imidazo[4,5-h]-isoquinoline-7,9(6H,8H)- dione, AZ-27, ribavirin, 5-ethynyl-1-beta-D-ribofuranosilimidazole-4-carboxamide (EICAR), 4-hydroxy-3-beta-D-ribofuranosylpyrazole-5-carboxamide (pyrazofurin), 1-(( 2R,3R,4S,5R)-3,4-dihydroxy-5(hydroxymethyl)tetrahydrofuran-2-yl)-1H-1,2,4-triazol-3-carboximidamide (Taribavirin, viramidine), (2R,3R, 4R,5R)-5-(4-amino-2-oxopyrimidin-1-(2H)-yl)-2-(chloromethyl)-4-fluoro-2-((isobutyryloxy)methyl)tetrahydrofuran-3-yl isobutyrate, (2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-4-fluoro-2(hydroxymethyl)tetrahydrofuran-3-yl isobutyrate,((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl) methyl triphosphate, 4-amino-1-((2R,3R,4R,5R)-5-(chloromethyl)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H )-one, 1,3,4-thiadiazol-2-ylcyanamide (LI253963), tetrahydrofuran-3-yl-3-(3-(3-methoxy-4) -(oxazol-5-yl)phenyl)ureido)benzylcarbamate (VX-497), (4E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2 acid -benzofuran-5-yl)-4-methylhex-4-enoic acid (mycophenolic acid), 2-morpholin-4-ylethyl-(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo -1H-2-benzofuran-5-yl)-4-methylhex-4-enoate (Mycophenolate Mofetil), a Type 1 interferon, a Type 2 interferon, a Type 3 interferon, a double-stranded RNA oligonucleotide, 5- methyl-N-[4-(trifluoromethyl)phenyl]-isoxazole-4-carboxamide (leflumomide), N-(2-chloro-4-methylphenyl)-2-((1-(4-methoxyphenyl)-1H-benzo[ d]imidazol-2-yl)thio)propanamide (JMN3-003), an intratracheal formulation of recombinant human CClO (GC-100), high titer, human immunoglobulin (RI-001), a non-neutralizing mAb against G protein (mAb 131-2G), ALN-RSVO1, ALN-RSV02, Medi-559, Medi-534 and Medi-557, JNJ-53718678, AK-0529, RV521, BTA585, MIV-323, PC786, JNJ-64417184, ALS -8176,
{//4014/1301WO/00376111/V1}
ALS-8112, ALX-0171, or a pharmaceutically acceptable salt of any of the above.
[13]
A method according to any one of claims 1 to 12, characterized in that the compound of Formula I or a salt thereof and the second anti-respiratory syncytial virus agent are administered in a single composition or in separate compositions.
[14]
14. Pharmaceutical composition, characterized in that it comprises a compound represented by Formula (I): R5 O RN 2
N (R6)n R4 R1 A
N R3 (I), or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of: 1) hydrogen; 2) halogen; 3) CN; 4) -C1-C8 optionally substituted alkyl; and 5) optionally substituted -C1-C8 alkyl-O-R11; R2 and R5 are each independently selected from the group consisting of: 1) hydrogen; and 2) -C1-C8 optionally substituted alkyl; A is selected from the group consisting of: 1) optionally substituted -C3-C12 cycloalkyl; 2) optionally substituted -C3-C12 cycloalkenyl; 3) optionally substituted 3- to 12-membered heterocycloalkyl; {//4014/1301WO/00376111/V1}
4) optionally substituted aryl; and 5) optionally substituted heteroaryl; R3 is hydrogen or R11; R4 is selected from the group consisting of: 1) -C3-C12 optionally substituted cycloalkyl; 2) optionally substituted -C3-C12 cycloalkenyl; 3) optionally substituted 3- to 12-membered heterocyclyl; 4) optionally substituted aryl; 5) optionally substituted heteroaryl; 6) optionally substituted aryl-O-; 7) optionally substituted heteroaryl-O; 8) optionally substituted aryl-C1-C4-alkyl; and 9) optionally substituted heteroaryl-C1-C4-alkyl; each R6 is the same or different and independently selected from hydrogen, halogen, hydroxyl, protected hydroxyl, cyano, amine, protected amine, nitro, optionally substituted -C1-C8 alkyl, optionally substituted -C1-C8 alkoxy, -NHC1- optionally substituted C8 alkyl, -S-(- optionally substituted C1-C8 alkyl) optionally substituted -SO2-(-C1-C8 alkyl) optionally substituted -SO2-NH-(-C1-C8 alkyl) optionally substituted -NH- SO2-(-C1-C8 alkyl) optionally substituted, -CO2R12, -NR13R14, and -CO-NR13R14; R11 and R12 are each independently selected from the group consisting of: 1) -C1-C8 optionally substituted alkyl; 2) optionally substituted -C2 -C8 alkenyl; 3) optionally substituted -C2 -C8 alkynyl; 4) optionally substituted -C3-C8 cycloalkyl; 5) optionally substituted -C3-C8 cycloalkenyl;
{//4014/1301WO/00376111/V1}
6) optionally substituted 3- to 8-membered heterocycloalkyl; 7) optionally substituted aryl; and 8) optionally substituted heteroaryl; R13 and R14 are each independently selected from hydrogen, -C1-C8-optionally substituted alkyl, -C2-C8-optionally substituted alkenyl, -C2-C8-optionally substituted alkynyl; -C3-optionally substituted C8-cycloalkyl, -C(O)R12, -S(O)2R12, and -S(O)2NHR12, and- optionally substituted C1-C8-alkoxy; alternatively, R13 and R14 are taken together with the nitrogen to which they are attached to form a heterocyclic ring; and n is 0, 1, 2, 3 or 4; a second anti-respiratory syncytial virus agent; and a pharmaceutically acceptable carrier or excipient.
[15]
15. Pharmaceutical composition according to claim 14, characterized in that the compound of Formula (I) is represented by Formula Ia or Formula Ib, R5 R5
O R O R N 2 N 2
N N (R6)n A R4 (R6)n A R4 R1 R1
N N R3 R3 (Ia) (Ib), or a pharmaceutically acceptable salt thereof.
[16]
16. Pharmaceutical composition according to claim 14, characterized in that A is selected from one of the following by removing two hydrogen atoms: {//4014/1301WO/00376111/V1}
H
N N N N O
NH S NH NH N NH NH N NH
N N N S N N N N N
No
N Y Y N N
O O N
O O S
N O N N N N N
N N N N
N N
No
N N
H O S H
N N N
N N
H H O
Y N N O
N N
N N , where each of those shown above is optionally substituted where possible.
[17]
17. Pharmaceutical composition according to claim 14, characterized in that R4 is selected from one of the following by removing a hydrogen atom:
Y N N N HN N O N O
N N
O S N
H
HN O S S N N N N N N N
No
N Y N O
H
N N H
N N N N N O
No
THE
HN HN NH HN NH HN O HN OH NH2
HN HN HN O O O NH2
H
O N O NH2 NH2
H H
N S S N O N N N N N , wherein each of the above is optionally substituted where possible.
{//4014/1301WO/00376111/V1}
[18]
18. Pharmaceutical composition according to claim 14, characterized in that R4 is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, -CH3, -CF3, -OCF3, -CN, -NH2 , -OH, -CH2N(CH3)2, -C(O)CH3, -NH-(C1-C6)alkyl optionally substituted -NH-(C1-C6)alkyl-(C1-C6)alkoxy optionally substituted, - optionally substituted SO2-(C1-C6)alkyl, -SO2- optionally substituted NH-(C1-C6)alkyl, optionally substituted -NH-SO2-(C1-C6)alkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally aryl substituted, optionally substituted heteroaryl,– optionally substituted C1-C8-alkyl,– optionally substituted C1-C8-alkenyl, – optionally substituted C3-C8-cycloalkyl,– optionally substituted C3-C8-cycloalkenyl, and– optionally substituted C1-C8-alkoxy substituted.
[19]
19. Pharmaceutical composition according to claim 14, characterized in that R4 is substituted by 1 to 3 substituents independently selected from the group consisting of CH3, CN,
N O fluorine, chlorine, CH3O-, CH3C(O)-, CH3OCH2-, CH3OCH2CH2O-, -CF3, CF3O-, ,
AT THE
O O N N N N N OH , , , , , , ,
N O N N
N O N O N O N O N O , O , , ,
O N NH NH NH NH OCH3 NH OCH3 , , , OH , , , {//4014/1301WO/00376111/V1}
NH OCH3 NH OCH3 NH OCH3 NH OCH3 , , , , , , F3C MeO EtO HO F F CF3
F CF3 , , , , , , CF3 , , F, and .
[20]
20. Pharmaceutical composition according to claim 14, characterized in that the compound of Formula I is represented by Formulas IIa-1, IIa-2, IIb-1, or IIb-2, or a pharmaceutically acceptable salt thereof, R5 R5
O R O R N 2 N 2
N N (R6)n A R4 (R6)n A R4
H H
N N R3 R3 (IIa-1) (IIb-1) R5 R5
O R O R N 2 N 2
N N (R6)n A R4 (R6)n A R4 Me Me
N N R3 R3 (IIa-2) (IIb-2) wherein R2, R3, R4, R5, R6, n and A are as defined in claim 1.
[21]
21. Pharmaceutical composition according to claim 14, characterized in that the compound of Formula I is represented by Formulas IV-1, IV-2, IV-3, or IV-4, or a pharmaceutically acceptable salt thereof, R5 R5
O R O R N 2 N 2
N O N S (R6)n (R6)n R1 R4 R1 R4
N N N N N N R3 R3 (IV-1) (IV-2) R5 R5
O R O R 2 N 2
N H
N O N N (R6)n (R6)n R1 R4 R1 R4
N N N N N R3 R3 (IV-3) (IV-4) wherein R1, R2, R3, R4, R5, R6, and n are as defined in claim 1.
{//4014/1301WO/00376111/V1}
[22]
22. Pharmaceutical composition according to claim 14, characterized in that the compound of Formula I is represented by Formulas V-1, V-2, V-3, or V-4, R5 R5
O R O R N 2 2
No
N Y N O (R6)n (R6)n R1 R1
N N N N R3 R4 R3 R4 (V-1) (V-2) R5 R5
O R O R N 2 N 2
H
N N N N (R6)n (R6)n R1 R1 R4
N N N N R3 R4 R3 (V-4) (V-3) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, and n are as defined in claim 1.
[23]
23. Pharmaceutical composition according to claim 14, characterized in that the compound of Formula I is selected from the compounds shown below or a pharmaceutically acceptable salt thereof: Example Structure Example Structure
H O H O
N N
NH NH 1 N
No
O O 2 N
No
THE
NO
H O H O
N N
NH NH 3 N
No
The F 4 N
No
The OMe
N N
H O H O
N N
NH NH 5 N
N O 6 N
No
The F
N N {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH 7a N
N O 7b N
No
THE
N N
F F
H O H O
N N
NH NH 8 N
N O 9 N
N O MeO
N N O Me
H O H O
N N
NH NH 10a N
No
THE
The 10b N
No
THE
THE
N N
H O H O
N N
NH NH 11 N
No
THE
N 12 N
No
THE
N N
CN
H O H O
N N
NH NH 13 N
N O 14 N
No
The OMe
N N Cl F
H O H O
N N
NH NH 15 N
No
O O 16 N
No
THE
N N
H O H O
N N
NH NH 17 N
N O 19 N
No
THE
s
N N
H O H O
N N
NH NH 20 N
No
THE
The 21 N
No
The NCl N
The {//4014/1301WO/00376111/V1}
H O
N H O
No
NH
N O NH 22 N
N 23 N
No
THE
No
No
F
H O H O
N N
NH NH 24 N
No
THE
N 25 N
No
THE
No
N N CN CF3
H O H O
N N
NH NH 26 N
No
THE
N 27 N
No
THE
N N SO2Me
H O H O
N N
NH 28 N
N O 29 N
No
The CF3
N N CF3
H O H O
N N
NH NH 30 N
N O 31 N
No
THE
N N OCF3 SO2NH2
H O H O
N N
NH NH 32 N
No
The CN 33 N
No
THE
F
N N
F CN
H O H O
N N
NH NH 34 N
N O 35 N
No
THE
CN
N N
CN
H O H O
N N
NH NH
NO 36 N 37 N
No
THE
N N N
No
N {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH 38 N
No
The CN 39 N
No
THE
N N NH
No
THE
H O H O
N N
NH NH 40 N
No
O O 41 N
No
The H
No
N N
NH N
H O H O
N N
NH NH 42 N
No
THE
S 43 N
No
THE
s
N N N
No
H O H O
N N
NH NH 44 N
No
THE
S 45 N
No
THE
N N
N N NH
H O H O
N N
NH
NH
N O 46 N
N O 47 N
No
N N
No
THE
H O H O
N N
NH NH 48 N
No
The H
N 49 N
No
The H
No
N N
The O
H O H O
N N
NH NH 50 N
No
The F 51 N
No
THE
No
N N F OMe
H O H O
N N
NH NH 52 N
No
O N OMe 53 N
No
THE
N N N
F {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH 54 N
N O 55 N
No
THE
F
N N N
Name
H O
H O N
No
NH
NH
N O 56 N
No
The OMe 57 N
No
No
No
Name
H O H O
N N
NH NH 58 N
No
THE
N 59 N
No
THE
No
N N
No
No
H O H O
N N
NH NH 60 N
N O 61 N
No
THE
N N N
No
No
H O H O
N N
NH NH 62 N
No
THE
N 63 N
No
THE
No
N N N
No
H O H O
N N
NH NH 64 N
No
THE
N O 65 N
No
THE
N N
N N
H O H O
N N
NH NH
N 66 N
The 67 N
No
THE
No
N N N
N N
H O H O
N N
NH NH
N 68 N
THE
N 69 N
No
THE
s
N N
N N {//4014/1301WO/00376111/V1}
H O H O
N N
NH 70 N
No
THE
The 71 N
No
THE
THE
N N
No
H O H O
N N
NH NH 72 N
No
THE
The 73 N
No
THE
THE
N N
The No.
H O H O
N N
NH NH
N 74 N
THE
The 75 N
No
THE
THE
N N N
No
H O H O
N N
NH 76 N
No
THE
S 77 N
No
THE
N N S
N N
H O H O
N N
NH 80 N
N S 81 N
No
s
N N
F
H O H O
N N
NH NH 82 N
N S 83 N
No
s
N N
No
CN
H O H O
N N
NH NH 84 N
N O 85 N
No
s
H O H O
N N
NH 86 N
N NH 87 N
s
No
N N {//4014/1301WO/00376111/V1}
H O H O
N N
NH 88 N
Y N 89 N
THE
No
N N N
THE
H O O
N H O N
NH N N 90 N
s
N 91 N
NH
H O H O
N N
NH 92 N
N 93 N
N N O
N N
H O
H O N
No
NH
NH
N N
N 94 N O 95 N
No
H O H O
N N
THE
NH NH
N 96 N N 97 N
No
H O H O
N N
NH 98 N
No
N 99 N
No
The Cl
H O H O
N N
NH 100 N
N O 101 N
No
s
PMB H O
The No.
N NH2 NH Me 102 N 103 N
No
THE
F {///4014/1301WO/00376111/V1}
H O
N H O
No
NH
NH
N O 104 N 105 N
No
THE
F
F
H O
N H O
No
NH
NH
N O 106 N 107 N
No
THE
No
N SO2Me
H O H O
N N
NH NH
N O 108 N N 109 N
No
The NCl
N N
AT THE
H O H O
N N
NH NH
The 110 N
No
THE
N 111 N
No
THE
No
N N
F
H O H O
N N
NH NH
N O N O 112 N F 113 N
N N
N N
The O
H O H O
N N
NH NH
N O N O 114 N N 115 N
No
N N
N N
The O
H O H O
N N
NH NH
N N O 116 N
The 117 N
No
No
N NH
H O {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 118 N
N 119 N
No
F
N N
The O
H O H O
N N
NH NH
NO NO 120 N
N 121 N
N N N N SO2Me
The O
H O H O
N N
NH NH
N N O
The 122 N 123 N
No
N N N CF3 Cl O
THE
H O H O
N N
NH NH
NO NO 124a N 124b N
N N
N N
The O
H O H O
N N
NH NH
NO NO 125a N
N 125b N
No
N N
The O
H O H O
N N
NH NH
NO NO 126a N 126b N
N N
F N F N
The O
H O H O
N N
NH NH
NO NO 127 N
N 128 N
No
N F N N N
No
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 129 N
N 130 N
N N N N N CF3
No
The O
H O H O
N N
NH NH
NO NO 131 N
N 132 N
No
No
N CN N
The O
H O H O
N N
NH NH
N O N O 133 N N N 134 N
N N
N N
THE
H O H O
N N
NH NH
NO NO 135 N N 136 N
No
No
No
N N F Cl
THE
THE
H O H O
N N
NH NH
NO NO 137 N N 138 N
No
No
No
N F
F N
The O
H O H O
N N
NH NH
NO NO 139 N
N N 140 N
No
N N CF3 N CN
The O
H O H O
N N
NH NH
NO NO 141 N
N 142 N
No
N N
N N
The {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 143 N
N N 144 N
No
N N N N
The O
H O H O
N N
NH NH
NO NO 145 N
No
F 146 N
N CF3
N N N N
The O
H O H O
N N
NH NH
NO NO 147 N 148 N
No
N F3C N N
The F
THE
H O H O
N N
NH NH
NO NO 149 N 150 N
No
No
N N F
F N N
The O
H O H O
N N
NH NH
NO NO 151 N
N 152 N
N N N F N CF3
The O
H O H O
N N
NH NH
NO NO 153 N
N 154 N
No
N N CN N N
The O
H O H O
N N
NH NH
NO NO 155 N
N 156 N
No
N N O N N O
H
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 157 N
N 158 N
No
CN
N CN N N
The O
H O H O
N N
NH NH
NO NO 159 N
N 160 N
No
No
N F N CN
The O
H O H O
N N
NH NH
N O N O 161 N N 162 N
N N
N N N N CF3
No
THE
THE
H O H O
N N
NH NH
NO NO 163 N
N N 164 N
No
No
No
No
N N
The O
H O H O
N N
NH NH
NO NO 165 N
N 166 N
No
N N
N N N N
The O
H O H O
N N
NH NH
N O N O 167 N N N 168 N
No
N N N N Br
The O
H O H O
N N
NH NH
N O N F
The 169 N
N N 170 N
No
N F N
THE
The {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
N O F N O 171 N
N 172 N
N N
N F N N
No
No
The O
H O H O
N N
NH NH
N O N O 173 N N N 174 N
No
CN
N N N N N N
No
The O
H O H O
N N
NH NH
NO NO 175 N
No
CN 176 N
No
CN
N N N N
The O
H O H O
N N
NH NH
N O N O 177 N N N 178 N
No
No
No
No
N N
The O
H O H O
N N
NH NH
NO NO 179 N
N O 180 N
No
s
No
N N
The O
H O H O
N N
NH NH
N O N O 181 N N N 182 N
No
S BR
No
N N
The O
H O H O
N N
NH NH
N O 183 N
No
THE
S 184 N
N CN N
N {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
N O 185 N
No
The N 186 N
N N
No. No
F N N
H O H O
N N
NH NH 187 N
No
THE
S 188 N
No
THE
N N
No
H O H O
N N
NH NH 189 N
N O 190 N
No
THE
N N
H O H O
N N
NH NH 191 N
No
THE
The 192 N
No
O N N CF3
H O H O
N N
NH NH 193 N
N O 194 N
No
The SO2Me
N CN N
H O H O
N N
NH 195 N
N O 196 N
No
THE
N N
H O H O
N N
NH 197 N
N O 198 N
No
THE
N N
THE
H O H O
N N
NH 199 N
N O 200 N
No
THE
No
N N
CN {//4014/1301WO/00376111/V1}
H O
No
THE
N NH
NH NO 201 N
N O 202 N
No
N N
F N CF3
H O H O
N N
NH NH 203 N
N O 204 N
No
THE
N N CF3 F
H O H O
N N
NH 205 N
N O 206 N
No
THE
N N
H O H O
N N
NH 207 N
N O 208 N
No
THE
N N
THE
H O
H O N
No
NH
No
N O 209 N
N O 210 N
No
No
No
F
No
H O
H O N
N NH
NH NO
N O N 211 N
N 212 N
No
No
N N
No
H O H O
N N
NH NH 213 N
N O 214 N
No
THE
N N F
oh
F {///4014/1301WO/00376111/V1}
H O
H O N
No
NH
NH
N O 215 N
N O 216 N F
No
N N
The No.
No
H O H O
N N
NH NH
NO NO 217 N 218 N
N N
N N
N N
N N
H O
H O N
N NH
NH NO
N O N 219 N O Me 220 N
AT THE
No
No
THE
H O H O
N N
NH NH
N 221 N
N O 222 N
THE
N NH N
NH
H O
H O N
N NH
NH NO 223 N
No
The NH 224 N
No
No
No
No
H O H O
N N
NH NH
N N O
The 225 N
N 226 N
No
No
No
No
N N
H O H O
N N
NH NH
NINTH
N 227 N N 228 N
N N
HN N {//4014/1301WO/00376111/V1}
H O
No
H O
NH N H
N N O
The F
N 229 N 230 N N N
THE
THE
H O H O
N N
NH NH
NO NO 231 N 232 N
No
N N
N N N N
H O
H O N
No
NH
NH NO
N O N 233 N 234 N
No
AT THE
No
N N
H O
N H O
NH N
N O NH
N N O 235 N 236 N
No
HN
AT THE
THE
H O
N H O
NH N
N O NH 237 N N 238 N
No
THE
No
N N
HN
No
H O
N H O
No
NH
NH
NINTH
No
N 239 N 240 N
THE
No
YOU
THE
The {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 241 N
N 242 N
No
N N N N
THE
H O
N H O
No
NH
NH
AT THE
N O 243 N N 244 N
No
N Cl N O Cl
THE
H O
H O N
No
NH
NH NO
N O N 245 N
N 246 N
N N
N N
THE
F F
H O
N H O
No
NH
NH
AT THE
AT THE
N 247 N 248 N
No
N N
N N
The MeO
H O H O
N N
NH NH
NO NO 249 N N 250 N
No
N N N CF3
THE
THE
H O H O
N N
NH NH
NO NO 251 N
N N 252 N
N N CF3 N N
The O
H O H O
N N
NH NH
NO NO 253 N
N N 254 N
N CF3 N N
N O MeO {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 255 N N 256 N
No
N N N N
HOF
H O
N H O
No
NH
NH
AT THE
AT THE
N 257 N 258 N
No
N N
N MeO OMe
H O H O
N N
NH NH
NO NO 259 N N 260 N
No
N N N N
F
F NC
H O
H O N
No
NH
NH
AT THE
N O N 261 N
N 262 N
N N
N N
THE
THE
H O
N H O
No
NH
NH
AT THE
N N O 263 N 264 N
No
N N
N N
THE
THE
H O H O
N N
NH NH
NO NO 265 N
N 266 N
No
N N N N
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NINTH
N 267 N 268 N
No
N H N N CF3
N O H MeO
H O
H O N
No
NH
NH
AT THE
AT THE
N 269 N
No
N 270 N CF3 N N
No
No
F N
No
H O H O
N N
NH NH
NO NO 271 N
N N 272 N
No
N CF3 S
N N Me O O
H O
H O N
No
NH
NH
AT THE
N O 273 N 274 N
No
No
N N N
No
No
NC
H O H O
N N
NH NH
NO NO 275 N
N 276 N
N N N CF3 N N CF3
The O
H O H O
N N
NH NH
NINTH
N N N N 277 N 278 N N CF3 N CF3
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 279 N
N 280 N
No
N N N N
The O
H O H O
N N
NH NH
NO NO 281 N
N 282 N
No
N N CN CF3
The No.
H O
H O N
No
NH
NH NO
N O N 283 N
N 284 N
N F
N N
THE
H O H O
N N
NH NH
NO NO 285 N
N 286 N
No
N CN N N
The O
H O
H O N
No
NH
NH NO 287 N
N O 288 N
No
No
N N F
THE
H O H O
N N
NH NH
NO NO 289 N
N 290 N
N N N CN N N CF3
The O
H O
H O N
No
NH
NH NO
N O 291 N
H N 292 N
No
No
No
No
s
No
CN
The {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
N N O
O 293 N N 294 N
No
No
N CF3 N CF3
THE
H O
H O N
No
NH
NH NO
N O N N 295 N
N 296 N N CF3 N N OMe
No
THE
THE
H O H O
N N
NH NH
NINTH
N N 297 N 298 N
No
N CF3 N
HN
HO
THE
H O H O
N N
NH NH
NO NO 299 N
N N 300 N
No
F O CN
No
The O
H O H O
N N
NH NH
NO NO 301 N
N N 302 N N
N N CN CF3
No
THE
H O H O
N N
NH NH
NO NO 303 N
N N 304 N
No
N HN CF3 N CN
NC O
H O H O
N N
NH NH
NINTH
N 305 N
N N 306 N
No
N HN CF3
THE
The {//4014/1301WO/00376111/V1}
H O
H O N
N NH
NH NO
N O N N 307 N N 308 N N CF3
N HN CF3
HO
H O H O
N N
NH NH
N N O
THE
N 309 N
N N 310 N
N N CF3
ONLY
H O H O
N N
NH NH
NO NO 311 N
N N 312 N
No
No
N N
The O
H O H O
N N
NH NH
NO NO 313 N
N N 314 N
No
No
N N N
The O
H O
N H O
No
NH
NH
AT THE
N N O 315 N 316 N
No
No
CN
No
O N O
H O H O
N N
NH NH
NO NO 317 N
N 318 N
No
No
N N N
The O
H O H O
N N
NH NH
NO NO 319 N
N 320 N
No
CN CN
No
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 321 N
N N 322 N
No
No
N N
The O
H O H O
N N
NH NH
NO NO 323 N
No
S CN 324 N
No
N CN
N N
THE
THE
H O
H O N
No
NH
NH
AT THE
N O N N 325 N
N N 326 N
N CN
N CN
THE
THE
H O H O
N N
NH NH
NO NO 327 N
No
N 328 N
No
N CF3 N CF3
No
NO
H O H O
N N
NH NH
NINTH
N N 329 N 330 N
No
N CN S
No
THE
THE
H O H O
N N
NH NH
NO NO 331 N
No
N 332 N
No
N HN CF3 SO2Me
No
NC O {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 333 N
N N 334 N
No
No
s
CN N
N N
THE
THE
H O H O
N N
NH NH
NO NO 335 N
N N 336 N
No
No
S S
HN N
The O
H O H O
N N
NH NH
NO NO 337 N
N N 338 N
No
No
YOU
N N
The O
H O H O
N N
NH NH
NO NO 339 N
No
N CF3 340 N
No
No
S S
N N
The O
H O H O
N N
NH NH
NINTH
N 341 N
N N 342 N
No
No
Y Y N N MeO
The O
H O H O
N N
NH NH 343 N
No
THE
N 344 N
No
THE
No
N N
S S Cl
H O H O
N N
NH NH
NO NO 345 N
N N 346 N
No
No
S S
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 347 N
N N 348 N
No
THE
s
No
The O
H O H O
N N
NH NH
NINTH
N 349 N N 350 N N
N N N
H O H O
N N
NH NH 351 N
No
THE
N O 352 N
No
THE
N N N
S I
H O H O
N N
NH NH
NO NO 353 N
N 354 N
No
The O
F H O F H O
N N
NH NH
NO NO 355a N
N 355b N
No
N N
The O
F F H O
H O
N N
NH NH
NO NO 356 N 357 N
No
No
N N N
THE
THE
F H O F H O
N N
NH NH
NO NO 358 N
N 359 N
No
N N N N CF3
The O {///4014/1301WO/00376111/V1}
F H O F H O
N N
NH NH
NO NO 360 N
N N 361 N
No
N N CF3 CN
No
O O Cl HO
N H O
No
NH
N NH
The 362 N
N 363 N
No
NH
No
N F
THE
H O H O
N N
NH NH
N NH 364 N 365 N
No
NH
N N
No
N CN
H O
H O N
No
NH
NH N NH 366 N
N NH 367 N
No
No
N N
THE
H O H O
N N
NH NH 368 N
N O 369 N
No
THE
CN F
H O
H O N
No
NH
NH N N 370 N
N O 371 N Br
H O
No
H O
N NH
NH N N 372 N
No
NH 373 N
No
F {///4014/1301WO/00376111/V1}
H O O
N H
No
NH
NH
N N
N N
N 374 375 N
F N
H O H O
N N
NH NH
N N N N
N N 376 377 OMe CN
H O
N H O
No
NH
N N O NH 378 N 379 N
No
THE
No
F N
F
H O H O
N N
NH NH
NO NO 380 N 381 N
N N
F F
F CN
H O H O
N N
NH NH
AT THE
N O 382 N
N 383 N N CF3
F S
No
F O
H O H O
N N
NH NH
N O N O 384 N N 385 N
No
No
S S
N N
The O
H O H O
N N
NH NH
NINTH
F 386 N
No
N 387 N
No
No
F
S S
N N
The O {///4014/1301WO/00376111/V1}
H O H O
N N
NH NH
N O N N O
N 388 N
No
N 389 N
No
N F
S S
N N
The O
H O H O
N N
NH NH
N O N N O 390 N
N N CF3 391 N
No
N CF3
S S
N HN
The O
H O
H O N
No
NH
NH
AT THE
AT THE
N N 392 N
No
N CF3 393 N CF3
s
S HN
HN
THE
THE
H O H O
N N
NH NH
NO NO 394 N
No
N CF3 395 N
No
N CF3
S S
The O
H O H O
N N
NH NH
NINTH
N N N N 396 N CF3 397 N CF3
S S
HN
THE HO
H O H O
N N
NH
NH
NINTH
N N N 398 N CF3 399 N
No
No
No
s
HN S
No
HO
The {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 400 N
No
N B 401 N
N N
Y N
N N
The O
H O H O
N N
NH NH
NO NO 402 N
N N O 403 N
N N
N N
N N
The O
H O H O
N N
NH NH
NO NO 404 N
No
The N 405 N
No
No
s
N N
The O
H O H O
N N
NH NH
N O N O F 406 N
N N 407 N
No
N F
S S
N N
The O
H O H O
N N
NH NH
NO NO 408 N N 409 N
No
N N MeO MeO
H O
N H O
No
NH
NH
AT THE
N N O 410 N N 411 N
N N
No
N MeO MeO {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NINTH
N N N N 412 N 413 N CF3 CF3 MeO MeO 412 413
H O H O
N N
NH NH
NO NO 414 N
No
N 415 N
No
N HN CF3 CF3
HN MeO MeO
H O H O
N N
NH NH
NINTH
N N N N 416 N 417 N HN CF3 CF3
HN MeO
HO
H O H O
N N
NH NH
NINTH
N N N N 418 N 419 N CF3 HN CF3
HN
THE
HO
H O H O
N N
NH NH
NINTH
N N N N 420 N 421 N HN CF3 HN CF3
The O
H O H O
N N
NH NH
NINTH
N N N N 422 N 423 N HN CF3 HN CF3
HO HO {//4014/1301WO/00376111/V1}
H O H O
No
No
NH
NH
N O N O N
N N 424 N 425 N
N N HN CF3 N
No
The O
H O H O
N N
NH NH
N O N O F 426 N N 427 N
No
No
s
N N O Me O
H O H O
N N
NH NH
NO NO 428 N
No
N F 429 N
No
N N
S S
N N
The O
H O H O
N N
NH NH
NINTH
N 430 N N N 431 N
N N
N N
N N
The O
H O H O
N N
NH NH
NO NO 432 N N 433 N
No
No
N N
N N
The O
H O H O
N N
NH NH
NO NO 434 N
N 435 N
No
No
N N
The NC {//4014/1301WO/00376111/V1}
H O
No
NH
AT THE
H O N
N N
No
NH S OH
NO
N N 436 N 437 O HN CF3 MeO
THE
H O H O
N N
NH NH
NINTH
N N N 438 N N 439 N N CF3
N N O Me MeO
H O H O
N N
NH NH
NINTH
N N 440 N
N N CF3 441 N N
N N
No
the NC
H O H O
N N
NH NH
N O N O 442 N N 443 N N N CF3 CF3
No
The O
H O
H O N
No
NH
NH NO
N O N N CF3 444 N N N 445 N
No
No
N N
N N
THE
The CF3 {//4014/1301WO/00376111/V1}
H O
H O N
No
NH
NH
AT THE
N O N 446 N N N 447 N N
No
N N
No
THE
The 447
H O H O
N N
NH NH
NINTH
N N 448 N
N N
F 449 N N
N N
N O MeO
H O H O
N N
NH NH
NINTH
N N 450 N
No
N 451 N CF3
S CF3 HN
HOO
H O
N H O
No
NH
NH
AT THE
AT THE
N N 452 N CF3 453 N
No
N CF3
s
HN S
THE
THE
H O H O
N N
NH NH
NO NO HO 454 N
No
N CF2CF3 455 N
No
No
S S
N N
The O
H O H O
N N
NH NH
NINTH
N N N N 456 N CF3 457 N CF3
S S
N N OMe OMe {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO EtO 458 N
N N 459 N
No
No
No
S S
N N
THE
The O
H O H O
N N
NH NH
NO NO 460 N
N N 461 N
No
N CF3 F
s
N N
F
The O
H O H O
N N
NH NH 462 N
N 463 N
N N O
N N
H O
N H O
No
NH
NH
AT THE
N N N O 464 N 465 N
N N HN CF3
s
No
THE
THE
H O
H O N
No
NH
NH
AT THE
N O N N 466 N
No
N 467 N N CF3 N CF3
THE
The CF3
H O H O
N N
NH NH
NINTH
N N N N 468 N 469 N N CF3 CF3
HN
THE
The {//4014/1301WO/00376111/V1}
H O
N H O
No
NH
N NH
THE
N N N O 470 N 471 N
N HN CF3
s
No
THE
THE
H O H O
N N
NH NH
NO NO 472 N N 473 N
No
N CF3
S S
HN HN
The O
H O H O
N N
NH NH
NINTH
N N N N 474 N CF3 475 N
S CF3
s
HN HN
The O
H O H O
N N
NH NH
NO NO 476 N
N O 477 N
No
THE
F
N N
O O F
H O H O
N N
NH NH
NO NO 478 N
N N 479 N
No
No
S S
No
The O
H O H O
N N
NH NH
NO NO 480 N
No
N 481 N
No
N CF3 CF3 MeO MeO {//4014/1301WO/00376111/V1}
H O H O
N N
NH NH
NO NO 482 N
No
N 483 N
No
N CF3 CF3 MeO MeO
H O H O
N N
NH NH
NO NO 484 N
No
N CF3 485 N
No
N CF3
S S
N N
The O
H O H O
N N
NH NH
NINTH
N N 486 N
N CF3 487 N
N CF3
S S
N N
The O
H O H O
N N
NH NH
N O N O 488 N N N 489 N
N N CF3 CF3
N N
N N
The O
H O H O
N N
NH NH
NO NO CF3 490 N
No
N 491 N
N N
Y N
N N
The O
H O
H O N
N NH
NH NO
N O N N OMe N CF3 492 N
N N 493 S
S HN
No
The No.
H O {///4014/1301WO/00376111/V1}
H O
N H O
NH N
N O NH
N N N O N CF3 494 S 495 N
No
N CF3
HN S
No
The O
AT THE
H
H O H O
N N
NH NH
N O N O 496 N N N 497 N
No
N CF3
N S
HN N
The O
H O
H O N
No
NH
NH NO
N O N N 498 N
N N 499 N CF3 CF3 S
S HN
HN
THE
THE
H O H O
N N
NH NH
NINTH
N N N N 500 N CF3 501 N CF3
S S
HN HN
The O
H O
H O N
No
NH
NH
NO NO F3C
N N 502 N
N N 503 N CF3 S
S HN
HN
THE
THE
H O
N H O
No
NH
NH
AT THE
N O N N CF3 504 N 505 N
No
No
s
HN S
HN
THE
The {///4014/1301WO/00376111/V1}
H O
H O N
No
NH
NH
AT THE
N O N 506 N
N N 507 N N
No
S HN
HN
THE
THE
H O H O
N N
NH NH
NINTH
F N 508 N N N F 509 N
N CF3
N S
N N
The O
H O H O
N N
NH NH
NO NO 510 N
No
N 511 N
No
N CF3
S S
N N
The O
H O H O
N N
NH NH
NO NO CF3 512 N
No
N 513 N
No
No
S S
N N
The O
H O H O
N N
NH NH
NINTH
N 514 N
N 515 N
No
No
S S
N HN
The O
H O
N H O
No
NH
NH
AT THE
N O N N NH2 516 N 517 N
No
No
s
HN S
No
THE
The {///4014/1301WO/00376111/V1}
H O
No
NH
N O F F 518 N
No
No
s
No
THE
[24]
24. Pharmaceutical composition according to claim 23, characterized in that the compound of Formula I is that of Example 253 or a pharmaceutically acceptable salt thereof.
[25]
25. Pharmaceutical composition according to any one of claims 14 to 24, characterized in that the second anti-respiratory syncytial virus agent is selected from the group consisting of an anti-RSV antibody, a fusion protein inhibitor, an N protein inhibitor, an RSV polymerase inhibitor, an IMPDH inhibitor, and an interferon.
[26]
26. Pharmaceutical composition according to claim 25, characterized in that the second anti-respiratory syncytial virus agent is selected from the group consisting of RSV-IGIV, palivizumab, motavizumab, MK-1654, I-cyclopropyl-3 -[[1-(4-hydroxybutyl)benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-one (BMS-433771), 4,4"-bis-{4,6- acid bis-[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]-(1,3,5)triazin-2-ylamino}-biphenyl-2,2"-disulfonic acid (RFI-641), 4,4'- Bis[4,6-Di[3-aminophenyl-N,N-bis(2-carbamoylethyl)sulfonylimino]-1,3,5-triazine-2-ylamino]-biphenyl-2,2'-disulfonic acid, disodium salt (CL387626), 2-[[2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-4-methyl-1H-benzimidazol-1-yl]-6-methyl-3-pyridinol (JNJ- 2408068), 2-[[6-[[[2-(3-Hydroxypropyl)-5-methylphenyl]amino]methyl]-2-[[3-(morpholin-4-yl)propyl]amino]benzimidazol-1- yl]methyl]-6-methylpyridin-3-ol (TMC-353121), 5,5'-bis[1-(((5-amino-1H-tetrazolyl)imino)methyl)]2,2',4" -methylidinetrisphenol (VP-14637, MDT-637), N-(2-hyd roxyethyl)-4-methoxy-N-methyl-3-(6-methyl-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)benzenesulfonamide (P13), 2-((2- ((1-(2-aminoethyl)piperidin-4-yl)amino)-4-{//4014/1301WO/00376111/V1}
methyl-1H-benzo[d]imidazol-1-yl)methyl)-6-methylpyridin-3-ol (R170591), 1,4-bis(3-methylpyridin-4-yl)-1,4-diazepam ( 05), (R)-9b-(4-chlorophenyl)-1-(4-fluorobenzoyl)-2,3-dihydro-1H-imidazo[r,2':1,2]pyrrolo[3,4-c] pyridin-5(9bH)-one (BTA9981), [2,2-bis(docosyloxymethyl)propyl-5-acetaoamido-3,5-dideoxy-4,7,8,9-tetra-O-(sodiumoxysulfonyl) -D-glycero-D-galacto-2-nonulopyranoside]onate (MBX-300), BTA-C286, N-(2-((S)-2-(5-((S)-3-aminopyrrolidin-1 - yl)-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carbonyl)-4-chlorophenyl)methanesulfonamide (GS-5806), an anti-RSV nanobody, a peptide fusion inhibitor ( such as a peptide having the sequence DEFDASISQVNEKINQSLAFIRKSDELL (T-67), a peptide having the sequence FDASISQVNEKINQSLAFIRKSDELLHNVNAGKST (T-118), (S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2 ,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)urea (RSV-604), STP-92, iKT-041, 6-{4-[(biphenyl-2-ylcarbonyl) amino]benzoyl}-N-cyclopropyl-5,6-dihydro-4H-thieno[3,2-d][1]benzazepine-2-carboxamide (IM- 53403). N-cyclopropyl-5-(4-(2-(pyrrolidin-1-yl)benzamido)benzoyl)-5,6,7,10-tetrahydrobenzo[b]cyclopenta[d]azepine-9-carboxamide, 6-(4 -(2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)nicotinamido)benzoyl)-N-cyclopropyl-5,6-dihydro-4H-benzo[b]thieno[2,3-d] azepine-2-carboxamide, 4-amino-8-(3-{[2-(3,4-dimethoxyphenyl)ethyl]amino}propyl)-6,6-dimethyl-2-(4-methyl-3-nitrophenyl) -1 H-imidazo[4,5-h]-isoquinoline-7,9(6H,8H)-dione, AZ-27, ribavirin, 5-ethynyl-1-beta-D-ribofuranosilimidazole-4-carboxamide (EICAR) , 4-hydroxy-3-beta-D-ribofuranosylpyrazole-5-carboxamide (pyrazofurin), 1-((2R,3R,4S,5R)-3,4-dihydroxy-5(hydroxymethyl)tetrahydrofuran-2-yl)- 1H-1,2,4-Triazole-3-carboximidamide (Taribavirin, Vimidine), (2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1-(2H)-iI) - 2 -(chloromethyl)-4-fluoro-2-((isobutyryloxy)methyl)tetrahydrofuran-3-yl isobutyrate, (2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1 (2H) -yl)-2-(chloromethyl)-4-fluoro-2(hydroxymethyl)tetrahydrofuran-3-yl isobutyrate,((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2) H)-yl)-2-
{//4014/1301WO/00376111/V1}
(chloromethyl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methyl triphosphate, 4-amino-1-((2R,3R,4R,5R)-5-(chloromethyl)-3-fluoro-4-hydroxy- 5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one, 1,3,4-thiadiazol-2-ylcyanamide (LI253963), tetrahydrofuran-3-yl-3-(3-(3-methoxy) -4-(oxazol-5-yl)phenyl)ureido)benzylcarbamate (VX-497), (4E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro acid -2-benzofuran-5-yl)-4-methylhex-4-enoic (mycophenolic acid), 2-morpholin-4-ylethyl-(E)-6-(4-hydroxy-6-methoxy-7-methyl-3 -oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate (Mycophenolate Mofetil), a Type 1 interferon, a Type 2 interferon, a Type 3 interferon, a double-stranded RNA oligonucleotide, 5-Methyl-N-[4-(trifluoromethyl)phenyl]-isoxazole-4-carboxamide (leflumomide), N-(2-chloro-4-methylphenyl)-2-((1-(4-methoxyphenyl)-1H- benzo[d]imidazol-2-yl)thio)propanamide (JMN3-003), an intratracheal formulation of recombinant human CClO (GC-100), high titer, human immunoglobulin (RI-001), a non-neutralizing mAb against aa G protein (mAb 131-2G), ALN-RSVO1, ALN-RSV02, Medi-559, Medi-534 and Medi-557, JNJ-53718678, AK-0529, RV521, BTA585, MIV-323, PC786, JNJ- 64417184, ALS-8176, ALS-8112, ALX-0171, or a pharmaceutically acceptable salt of any of the above.
{//4014/1301WO/00376111/V1}

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法律状态:
2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201762566159P| true| 2017-09-29|2017-09-29|

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US201762566160P| true| 2017-09-29|2017-09-29|

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US62/566,160|2017-09-29|

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US62/566,159|2017-09-29|

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PCT/US2018/053361|WO2019067864A1|2017-09-29|2018-09-28|Combination pharmaceutical agents as rsv inhibitors|

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