Isoindolin-1-one glucokinase activators

专利摘要:
The present invention provides an isoindolin-1-one-substituted propionamide glucokinase activator that increases insulin secretion in the treatment of type II diabetes.
公开号:KR20030064817A
申请号:KR10-2003-7007869
申请日:2001-12-07
公开日:2003-08-02
发明作者:구에르틴케빈리처드
申请人:에프. 호프만-라 로슈 아게；
IPC主号:

专利说明:

Isoindolin-1-one glucokinase activator {ISOINDOLIN-1-ONE GLUCOKINASE ACTIVATORS}
[1] Glucokinase (GK) is one of four hexokinases found in mammals (Colowick, SP, The Enzymes , Vol. 9 (P. Boyer, ed.), Academic Press, New York, NY, pages 1- 48, 1973). Hexokinase catalyzes the first step in glucose metabolism, namely the reaction in which glucose is converted to glucose-6-phosphate. Glucokinase has a finite cell distribution, found mainly in β-cells of the pancreas and parenchymal cells of the liver. GK is also a rate-regulating enzyme for glucose metabolism in these two cell types known to play an important role in systemic glucose homeostasis (Chipkin, SR, Kelly, KL and Ruderman, NB, Joslin's Diabetes (CR Khan and GC). Wier, eds.), Lea and Febiger, Philadelphia, PA, pages 97-115, 1994). The concentration of glucose in which GK exhibits half-maximal activity is about 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations (<1 mM). Therefore, the flow of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting levels (5 mM) to carbohydrate-containing postprandial levels (about 10 to 15 mM) (Printz, RG, Magnuson, MA). and Granner, DK, Ann. Rev. Nutrition , Vol. 13 (RE Olson, DM Bier and DB McCormick, eds.), Annual Review, Inc., Palo Alto, CA, pages 463-496, 1993). This finding contributed to the hypothesis that GK acts as a glucose detector in β-cells and hepatocytes 10 years ago (Meglasson, MD and Matschinsky, FM, Amer. J. Physiol ., 246 , E1-E13, 1984). ). Recently, studies on transgenic animals have shown that GK actually plays an important role in systemic glucose homeostasis. Animals that do not express GK die within days of severe diabetes, whereas animals that overexpress GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell 83 , 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J. , 10 , 1213-1218, 1996). Increased glucose exposure leads to increased insulin secretion in β-cells by GK and increased glycogen deposition and possibly reduced glucose production in hepatocytes.
[2] The finding that type II maturity-onset diabetes of the young (MODY-2) in adolescence is caused by the loss of functional mutations in the GK gene suggests that GK also acts as a glucose detector in humans. (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J. , 309 , 167-173, 1995). Another evidence supporting the important role of GK in regulating glucose metabolism in humans has been demonstrated by the identification of patients expressing mutant forms of GK with increased enzymatic activity. Such patients exhibit fasting hypoglycemia associated with inappropriately elevated levels of plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New England J. Med ., 338 , 226- 230, 1998). Although no mutation of the GK gene is found in the majority of patients with type II diabetes, compounds that increase the sensitivity of the GK detector system by activating GK will also be useful in the treatment of hyperglycemia, which is also characteristic of all type II diabetes. Glucokinase activators will increase the flow of glucose metabolism in β-cells and hepatocytes, which will lead to increased insulin secretion. Such agents will be useful for treating type II diabetes.
[3] The present invention provides an amide compound of formula I, a pharmaceutically acceptable salt or N-oxide thereof:
[4]
[5] Where
[6] A is unsubstituted phenyl; Or phenyl monosubstituted or disubstituted, or monosubstituted with lower alkyl sulfonyl, lower alkyl thio or nitro;
[7] R ¹ is cycloalkyl having 3 to 9 carbon atoms or lower alkyl having 2 to 4 carbon atoms;
[8] R ² is an unsubstituted or monosubstituted 5 or 6 membered heteroaromatic ring which is linked to the amine group represented by the formula by a ring carbon atom, wherein the 5 or 6 membered heteroaromatic ring is 1 selected from the group consisting of sulfur, oxygen and nitrogen Comprising from 3 heteroatoms, one heteroatom is nitrogen adjacent to the linking ring carbon atom, which ring may be monocyclic or condensed with phenyl at two of the ring carbons, and the monosubstituted heteroaromatic ring Is a halo, lower alkyl, nitro, cyano, perfluoro-lower alkyl, hydroxy,-(CH ₂ ) _n -OR ³ ,-(CH at a position on a ring carbon atom other than the ring carbon atom adjacent to the linking carbon atom ₂ ) _n -C (O) -OR ³ ,-(CH ₂ ) _n -C (O) -NH-R ³ , -C (O) C (O) -OR ³ and-(CH ₂ ) _n -NHR ³ (wherein, R ³ is hydrogen or lower alkyl; n is 0, 1, 2, 3, or 4) a mono-substituted with a substituent selected from the group consisting of: .
[9] Preferably, R ² is a 5 or 6 membered heteroaromatic ring which is linked by a ring carbon atom to the amine group represented by formula (I), wherein the 5 or 6 membered heteroaromatic ring is 1 to 1 selected from the group consisting of sulfur, oxygen and nitrogen Three heteroatoms, one heteroatom, is a nitrogen adjacent to the linking carbon atom. This ring may be monocyclic or condensed with phenyl at two of the ring carbons. According to an aspect of the present invention, adjacent nitrogen in a heteroaromatic ring comprising nitrogen may be in the form of an N-oxide wherein the nitrogen adjacent to the ring carbon atom is converted to N-oxide. On the other hand, the compound of formula (I) may be in the form of a pharmaceutically acceptable salt.
[10] Compounds of formula I have been found to activate glucokinase in vitro. Glucokinase activators are useful for increasing insulin secretion in the treatment of type II diabetes.
[11] The invention also relates to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier and / or adjuvant. The invention also relates to the use of this compound as a therapeutically active substance and its use for the manufacture of a medicament for the treatment or prevention of type II diabetes. The invention also relates to a process for the preparation of compounds of formula (I). The present invention also relates to a method of preventing or treating type II diabetes, comprising administering a compound of formula (I) to a human or animal.
[12] In more detail, the present invention provides a compound comprising the amide of formula I as described above, an N-oxide and a pharmaceutically acceptable salt of this amide.
[13] In compounds of formula I, "*" represents an asymmetric carbon atom in this compound. The compounds of formula (I) may exist as racemates at the asymmetric carbon atoms shown. However, preference is given to "S" enantiomers in which the amide is in the "S" configuration at the unsymmetrical carbon. When the phenyl ring A is monosubstituted with lower alkyl sulfonyl, nitro or lower alkyl thio, it is preferred to be substituted at the 5 or 6 position as shown in formula (I). Thus, when A is phenyl substituted with nitro, it is preferred that this substitution is in the 5 or 6 position, such as 5-nitro phenyl and 6-nitro phenyl.
[14] In one embodiment of formula I, the R ² ring as described above is a single, or monocyclic (uncondensed) ring. When R ² is a monocyclic ring, it is preferably substituted or unsubstituted pyridine. In another embodiment of Formula (I), the R ² ring as described above is condensed with phenyl, which is a bicyclic ring.
[15] The term "lower alkyl" as used throughout this application refers to straight and branched chain alkyl groups having 1 to 10 carbon atoms, preferably 3 to 9 carbon atoms, especially 2 to 4 carbon atoms, such as propyl, isopropyl and heptyl. It includes.
[16] As used herein, the term "cycloalkyl" refers to a 3-9 membered, preferably 5-8 membered cycloalkyl ring such as cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
[17] As used herein, "perfluoro-lower alkyl" refers to any lower alkyl group in which all hydrogens of the lower alkyl group have been substituted or replaced with fluoro. Preferred perfluoro-lower alkyl groups of these are trifluoromethyl, pentafluoroethyl, heptafluoropropyl, and the like.
[18] As used herein, "lower alkyl thio" means a lower alkyl group as defined above which is attached to the rest of the molecule via the sulfur atom of the thio group.
[19] As used herein, "lower alkyl sulfonyl" means a lower alkyl group as defined above which is attached to the rest of the molecule via the sulfur atom of the sulfonyl group.
[20] The term "halogen" as used herein is used interchangeably with the word "halo" and refers to all four halogens, fluorine, chlorine, bromine and iodine, unless otherwise noted.
[21] As used herein, the term "N-oxide" refers to a negatively charged oxygen atom covalently bonded to a positively charged nitrogen in a heteroaromatic ring.
[22] As used herein, “heteroaromatic ring” means a 5 or 6 membered unsaturated carbocyclic ring in which one or more carbon atoms have been replaced with a heteroatom such as oxygen, nitrogen or sulfur. The heteroaromatic ring may be monocyclic or bicyclic, ie a ring formed by condensation of two rings.
[23] The heteroaromatic ring defined by R ² is an unsubstituted or monosubstituted 5 or 6 membered heteroaromatic ring having 1 to 3 heteroatoms selected from the group consisting of sulfur, oxygen and nitrogen and the amide represented by the ring carbon atom in the formulae. It may be linked to the amine of the group. At least one heteroatom is nitrogen and is adjacent to the linking carbon atom. If present, other heteroatoms may be sulfur, oxygen or nitrogen. The ring defined by R ² may be monocyclic. Such heteroaromatic rings include, for example, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl and imidazolyl. Preferred heteroaromatic rings are pyridinyl. The ring defined by R ² may be bicyclic, ie may be condensed with phenyl at two of the free ring carbons. Examples of such rings are benzimidazolyl, benzothiazolyl, quinolinyl, benzoxazolyl and the like. The ring defined by R ² is linked to an amide group via a ring carbon atom to form an amide of formula (I). The ring carbon atom of the heteroaromatic ring which is linked via an amide bond to form a compound of formula (I) may not contain any substituents. When R ² is an unsubstituted or monosubstituted 5-membered heteroaromatic ring, the preferred ring is one comprising a nitrogen heteroatom adjacent to the linking ring carbon and a second heteroatom adjacent to the linking ring carbon.
[24] As used herein, -C (O) OR ³ is And the like.
[25] As used herein, the term “pharmaceutically acceptable salts” refers to pharmaceuticals such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, para-toluene sulfonic acid, and the like. And any salts with both pharmaceutically acceptable acids, either inorganic or organic, which are acceptable. The term "pharmaceutically acceptable salts" also includes any pharmaceutically acceptable base salt, such as amine salts, trialkyl amine salts, and the like. Such salts can be prepared very easily using standard techniques by those skilled in the art.
[26] Prodrugs of compounds of formula I are also part of the present invention. Prodrug means a metabolic precursor of a drug that, when administered to a patient, breaks down into a drug and an acceptable byproduct. The compounds of the present invention can be prepared with any conventional prodrug. One specific prodrug of the present invention is N-oxide as described above. Any individual compound of the present invention may generally be obtained as a prodrug.
[27] During the reaction process provided in the Schemes and Discussion section below, various functional groups such as free carboxylic acid or hydroxy groups can be protected by conventional hydrolyzable ester or ether protecting groups. As used herein, the term “hydrolyzable ester or ether protecting group” means any ester or ether commonly used to protect carboxylic acids or alcohols that can be hydrolyzed to provide hydroxyl or carboxyl groups, respectively. Representative ester groups useful for this purpose are those in which the acyl moiety is derived from lower alkanoic acid, aryl lower alkanoic acid or lower alkane dicarboxylic acid. Among them activated acids which can be used to generate these groups are acid anhydrides, acid halides, preferably acid chlorides or acid bromide derived from aryl or lower alkanoic acid. Examples of anhydrides are anhydrides derived from monocarboxylic acids such as acetic anhydride, benzoic anhydride, and lower alkane dicarboxylic anhydrides such as succinic anhydride as well as chloro formates such as preferably trichloro and ethylchloro formate. Suitable ether protecting groups for alcohols are, for example, tetrahydropyranyl ethers such as 4-methoxy-5,6-dihydroxy-2H-pyranyl ether. Others are aroylmethyl ethers, for example benzyl, benzhydryl or trityl ether or α-lower alkoxy lower alkyl ethers, for example alkyl silylethers such as methoxymethyl or allyl ether or trimethylsilyl ether There is.
[28] Similarly, the term "amino protecting group" refers to a conventional amino protecting group that can be cleaved to produce a free amino group. Preferred protecting groups are conventional amino protecting groups used for peptide synthesis. Particular preference is given to amino protecting groups which can cleave under weakly acidic conditions of about pH 2.0 to 3. Particularly preferred amino protecting groups are t-butyl carbamate (BOC), benzyl carbamate (CBZ) and 9-fluorenylmethyl carbamate (FMOC).
[29] In a preferred compound of formula (I), R ¹ is cycloalkyl having 5 to 8 carbon atoms and R ² is an unsubstituted or monosubstituted 5 or 6 membered heteroaromatic ring linked by an amine group represented by the formula by a ring carbon atom, This 5 or 6 membered heteroaromatic ring comprises one or two heteroatoms selected from the group consisting of sulfur, oxygen and nitrogen, one heteroatom is nitrogen adjacent to the linking ring carbon atom and the ring is a monocyclic ring, Or condensed with phenyl at two of the ring carbons, wherein the monosubstituted heteroaromatic ring is in the group consisting of halo and lower alkyl (formula AB) at positions on a ring carbon atom other than the ring carbon atom adjacent to the linking carbon atom. Monosubstituted with selected substituents. R ² described in Formula AB may be a monocyclic ring (Formula A) or may be a bicyclic ring (Formula B) via condensation with phenyl. In the compounds of the formula A, it is particularly preferred that R ² is substituted or unsubstituted pyridine. It is also preferred that R ¹ is cyclohexyl. Preferably, phenyl A is unsubstituted.
[30] In a preferred compound of formula (I), R ¹ is cyclohexyl and R ² is a monocyclic ring (Formula A-1). It is preferred that phenyl A is not substituted in the compound of formula A-1. It is particularly preferred that R ² is substituted or unsubstituted pyridine.
[31] In one embodiment of Formula A-1, R ² is unsubstituted pyridine and in other embodiments R ² is monosubstituted pyridine. Preferably, the substituent is halo, such as bromine, fluoro or chloro, or lower alkyl, such as methyl.
[32] In one embodiment of Formula A-1, R ² is monosubstituted pyrimidine. Preferably, the substituent is lower alkyl such as methyl and phenyl A is unsubstituted. R ² may also be unsubstituted pyrimidine of formula A-1. Preferably, phenyl A is unsubstituted or substituted with lower alkyl sulfonyl at the 4 or 7 position.
[33] In one embodiment of Formula A-1, R ² is unsubstituted thiazole. In this preferred compound, A is phenyl unsubstituted or substituted with chloro at the 5 and 6 positions, substituted with nitro at the 5 or 6 position, or substituted with halo or lower alkyl sulfonyl at the 4 or 7 position. .
[34] In one embodiment of Formula A-1, R ² is monosubstituted thiazole. Preferably, the substituent is halo, A is unsubstituted phenyl, substituted with chloro at the 5 and 6 positions, substituted with nitro at the 5 or 6 position, or halo or lower alkyl sulfon at the 4 or 7 position. Phenyl substituted with ponyl.
[35] In one embodiment of Formula (A-1), R ² is unsubstituted pyrazine. Preferably, A is phenyl unsubstituted or substituted with halo or lower alkyl sulfonyl at the 4 or 7 position.
[36] In one embodiment of Formula A-1, wherein R ¹ is cyclohexyl and R ² is a monocyclic ring, R ² is unsubstituted imidazole, and preferably, phenyl A is unsubstituted phenyl.
[37] In other embodiments of Formula I or Formula A, phenyl A is unsubstituted and R ² is a monocyclic ring, preferably R ² is substituted or unsubstituted thiazole (Formula A-2). In some compounds of Formula A-2, R ¹ is cyclopentyl, alternatively R ¹ is cycloheptyl, and alternatively R ¹ is cyclooctyl.
[38] In a preferred compound of formula I, R ² is a bicyclic heteroaromatic ring via condensation with phenyl at ^two of the ring carbons and R ¹ is cyclohexyl (formula B-1). In the compound of formula B-1, phenyl A is preferably unsubstituted. Also preferably, R ² is benzothiazole, benzimidazole, benzoxazole or quinoline, all of which are preferably unsubstituted.
[39] In one preferred aspect of the invention, A is unsubstituted phenyl or fluoro, lower alkyl sulfonyl or lower alkyl thio at the 4 or 7 position, chloro at the 5 or 6, or 5 and 6 positions, or 5 Or phenyl which may be substituted with bromo or nitro at the 6 position. In another preferred embodiment, A is unsubstituted phenyl, phenyl which may be mono- or di-substituted with halo, or phenyl which may be mono-substituted with lower alkyl sulfonyl or nitro. Most preferably, A is unsubstituted phenyl or phenyl monosubstituted with halo, preferably fluoro.
[40] In one preferred embodiment of the invention, R ¹ is cycloalkyl having 3 to 9, preferably 5 to 8 carbon atoms. Most preferred residue R ¹ is cyclopentyl or cyclohexyl.
[41] In one preferred embodiment of the invention, R ² is unsubstituted or monosubstituted 5 or linked to an amine group represented by the formula by a ring carbon atom comprising 1 or 2 heteroatoms selected from the group consisting of sulfur, oxygen and nitrogen Is a 6-membered heteroaromatic ring, one heteroatom is nitrogen adjacent to the linking ring carbon atom, which ring may be a monocyclic ring or may be condensed with phenyl at two of the ring carbons, said monocyclic heteroaromatic ring being linked And mono-substituted with a substituent selected from the group consisting of halo and lower alkyl sulfonyl at positions on ring carbon atoms other than ring carbon atoms adjacent to the carbon atoms. In another preferred embodiment, R ² is a heteroaromatic ring selected from the group consisting of thiazolyl, quinolinyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, benzimidazolyl, benzothiazolyl and benzoxazolyl, These heteroaromatic rings may be optionally substituted with halo, preferably chloro or bromo, or lower alkyl, preferably methyl. More preferred heteroaromatic ring residues R ² are selected from the group consisting of thiazolyl, pyrimidyl, pyrazinyl and pyridyl, and these heteroaromatic rings are halo, preferably bromo or chloro, or lower alkyl, preferably methyl Optionally substituted with Most preferred residue R ² is an unsubstituted heteroaromatic ring selected from the group consisting of thiazolyl, pyrimidyl, pyrazinyl and pyridyl; Or a monosubstituted heteroaromatic ring selected from the group consisting of thiazolyl substituted with chloro and pyridyl substituted with chloro, bromo or lower alkyl, preferably methyl.
[42] Preferred compounds according to the invention
[43] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide,
[44] (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide,
[45] (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide,
[46] (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide,
[47] (S) -3-cyclohexyl-2- (7-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide,
[48] (R) -N- (5-bromo-pyridin-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
[49] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-5-chloro-pyridin-2-yl-propionamide,
[50] (S) -3-cyclohexyl-2- (I-oxo-1,3-dihydro-isoindol-2-yl) -N-4-methyl-pyridin-2-yl-propionamide,
[51] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-5-methyl-pyridin-2-yl-propionamide,
[52] 3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide,
[53] (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide,
[54] (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide,
[55] (S) -N-3-cyclohexyl-N- (2-methyl-pyrimidin-4-yl) -2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide ,
[56] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
[57] (R) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
[58] (S) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
[59] (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
[60] (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
[61] (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
[62] (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
[63] (S) -3-cyclohexyl-2- (7-methylsulfonyl-I-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
[64] (S) -3-cyclohexyl-2- (5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
[65] (S) -3-cyclohexyl-2- (6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
[66] (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
[67] (S) -N- (5-bromo-thiazol-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
[68] (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydroisoindol-2-yl) Propionamide,
[69] (S) -N- (5-Bromo-thiazol-2-yl) -3-cyclohexyl--2- (5,6-dichloro-1-oxo-1,3-dihydroisoindole-2- 1) -propionamide,
[70] (S) -N- (5-Chloro-thiazol-2-yl) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydroisoindol-2-yl) -propion amides,
[71] (S) -N- (5-Chloro-thiazol-2-yl) -3-cyclohexyl-2- (7-chloro-1-oxo-1,3-dihydroisoindol-2-yl) -propion amides,
[72] (S) -N- (5-Chloro-thiazol-2-yl) -3-cyclohexyl-2- (5-nitro-1-oxo-1,3-dihydroisoindol-2-yl) -propion amides,
[73] (S) -N- (5-Chloro-thiazol-2-yl) -3-cyclohexyl-2- (6-nitro-1-oxo-1,3-dihydroisoindol-2-yl) -propion amides,
[74] (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) Propionamide,
[75] (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) Propionamide,
[76] (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
[77] (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
[78] (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
[79] (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
[80] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
[81] (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
[82] (S) -3-cyclohexyl-N- (1H-imidazol-2-yl) -2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
[83] 3-cyclopentyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
[84] N- (5-Chloro-thiazol-2-yl) -3-cyclopentyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
[85] 3-cycloheptyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
[86] N- (5-Chloro-thiazol-2-yl) -3-cycloheptyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
[87] 3-cyclooctyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
[88] (S) -N-benzothiazol-2-yl-3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
[89] (S) -N- (1H-benzimidazol-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
[90] (S) -N-benzoxazol-2-yl-3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
[91] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-quinolin-2-yl-propionamide,
[92] (S) -3-cyclohexyl-2- (7-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
[93] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N- (1-oxy-pyridin-2-yl) -propionamide and
[94] In the group consisting of (S) -3-cyclohexyl-2- (7-chloro-1-oxo-l, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide Is selected.
[95] Most preferred compounds according to the invention are
[96] 3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide,
[97] N- (5-Chloro-thiazol-2-yl) -3-cyclopentyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
[98] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-5-chloro-pyridin-2-yl-propionamide,
[99] (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
[100] (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
[101] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
[102] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide,
[103] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
[104] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-5-methyl-pyridin-2-yl-propionamide and
[105] Consisting of (R) -N- (5-bromo-pyridin-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide Selected from the group.
[106] Compounds of the present invention can be prepared according to the following Schemes 1-3.
[107]
[108] Wherein Phenyl A, R ¹ , R ² and R ³ are as defined in formula (I)
[109]
[110] (Wherein
[111] Ra is halo and Rb is H or halo;
[112] Ra is nitro and Rb is H; or
[113] Ra is lower alkyl thio or lower alkyl sulfonyl and Rb is H)
[114]
[115] Compounds of the invention may be prepared by reacting a substituted ortho-phenylene dialdehyde of Formula 1 or 1 'with an amino acid derivative of Formula 2 or 2' in a suitable solvent such as acetonitrile to obtain a carboxylic acid derivative of Formula 3 or 3 '. Can be. The compound of formula 3 or 3 'can then be coupled with a suitable heteroaromatic amine, H ₂ NR ² , under reaction conditions customary for amide bond formation to yield the compound of formula I.
[116] Compounds of formula I wherein phenyl A is substituted with halo (obtained from halo phthalic acid) or nitro are obtained as described in Scheme 2 above, wherein the compound of formula 4 is a suitable substituted phthalic acid commercially available. Substituted ortho-phenylene dialdehydes of Formula 1 or 1 'may be prepared by reduction of phthalic acid of Formula 4 to diol intermediates, followed by oxidation to provide compounds of Formula 1'.
[117] Compounds of formula I wherein phenyl A is substituted with lower alkyl sulfonyl can be prepared by the following multistep treatment starting from phthalic acid of formula 4 wherein Ra is fluoro and Rb is hydrogen:
[118] a) conversion of sulfuric acid with methanol to the corresponding dimethyl ester,
[119] b) providing a compound of formula 4 wherein Ra is lower alkyl thio by nucleophilic substitution of fluorine with sodium trimethoxide in a suitable solvent such as dimethylsulfoxide,
[120] c) reduction of the resulting phthalic acid of formula 4 to diol, wherein Ra is lower alkyl thio, followed by oxidation of the corresponding ortho-phenylene dialdehyde of formula 1 wherein Ra is lower alkyl thio,
[121] d) reaction of the amino acid of formula (2) with ortho-phenylene dialdehyde of formula (1) wherein Ra is lower alkyl thio in refluxing acetonitrile to obtain a mixture of lower alkyl thio and lower alkyl thio carboxylic isomers of formula (3), and
[122] e) providing a compound of Formula I wherein Ra is lower alkyl thio by coupling with H ₂ NR ² .
[123] The compound of formula (I), wherein Ra is lower alkyl sulfonyl and Rb is hydrogen, first oxidizes the lower alkyl isomer of step d) as described above with hydrogen peroxide to lower the formula (3) (Ra is lower alkyl sulfonyl and Rb is hydrogen). After forming the alkyl sulfonyl carboxylic acid, the resulting carboxylic acid of formula 3 is coupled with H ₂ NR ² to provide a compound of formula I wherein Ra is lower alkyl sulfonyl.
[124] Compounds of formula (I) in which R ¹ is C ₃ -C ₉ cycloalkyl or C ₂ -C ₄ alkyl (R, S or racemic form) are described above when the compounds of formula 2 or 2 'are commercially available amino acids As obtained. In addition, amino acids of formula (2) or (2 ') can be obtained according to Scheme 3 from the compound of formula (5). Compounds of formula 5 are prepared according to the procedures of literature (see, eg, O'Donnell, MJ; Polt, RL J. Org. Chem. 47, 2663-2666, 1982) and substituted with the desired R ¹ Reacting with basic alkyl halide reagents under basic conditions, it is possible to obtain any amino acid of formula 2 after acidic hydrolysis. Alkyl halide reagents are commercially available or can be prepared using conventional methods.
[125] Compounds of formula (I), in which R ² is described in formula (I), give the desired heteroaromatic amine (commercially available or prepared by conventional methods) under the usual conditions of reacting the amine with an acid. It can be prepared by coupling to a derivative. N-oxide heteroaromatic amines (eg, 2-aminopyridine-N-oxide) can be coupled to a compound of Formula 3 or 3 ', or R ^{2 in which the} corresponding compound of Formula I is not substituted by known methods. Oxidation in the ring can yield an N-oxide.
[126] If it is desired to prepare the R or S isomers of the compounds of formula (I), the compounds may be separated into these isomers by conventional physical or chemical means. One physical separation means involves resolution of an enantiomeric pair of compounds of formula (I) using high performance liquid chromatography equipped with a chromatography column loaded with a chiral agent. Preferred chemical means among them are the reaction of intermediate carboxylic acids of formula 3 or 3 'with an optically active base. This digestion can be carried out using any conventional optically active base. Preferred optically active bases among them are optically active amines such as alpha-methylbenzylamine, quinine, dehydroabiethylamine and alpha-methylnaphthylamine. This decomposition can be carried out using any conventional technique used to decompose organic acids with optically active organic amine bases.
[127] In the decomposition step, the compound of formula 3 or 3 'is reacted with an optically active base in an inert organic solvent medium to produce a salt of optically active amine having both the R and S isomers of formula 3 or 3'. In the formation of these salts, temperature and pressure are not critical and salt formation can occur at room temperature and atmospheric pressure. The R and S salts can be separated by conventional methods such as fractional crystallization. After crystallization, each of the salts can be converted to the compounds of formula 3 or 3 'in the R and S configurations, respectively, by hydrolysis with acids. Preferred acids among them are dilute aqueous acids, ie 0.001 to 2N aqueous acids, such as aqueous sulfuric acid or aqueous hydrochloric acid. The arrangement of compounds of formula 3 or 3 'made by this decomposition process is carried out throughout the scheme to yield the desired R or S isomers of formula I or II. Separation of the R and S isomers can also be accomplished using enzymatic ester hydrolysis of any lower alkyl ester derivative of Formula 3 or 3 '(see, eg, Ahmar, M .; Girard, C .; Bloch). , R, Tetrahedron Lett, 7053, 1989), resulting in the formation of the corresponding chiral acids and chiral esters. This ester and acid can be separated by conventional methods of separating the acid from the ester. Another preferred method for the degradation of the racemates of the compounds of formula 3 or 3 'is through the formation of the corresponding diastereomeric esters or amides. The diastereomeric esters or amides are selected from the group consisting of Or by coupling with a chiral amine. This reaction can be carried out using conventional methods of coupling carboxylic acids with alcohols or amines. The corresponding diastereomers of the derivatives of the carboxylic acids of formula (3) or (3 ') can then be separated using conventional separation methods such as HPLC. The resulting pure diastereomeric esters or amides are then hydrolyzed to yield the corresponding pure R or S isomers. This hydrolysis reaction can be carried out using a conventionally known method of hydrolyzing an ester or an amide without racemization.
[128] Based on the ability to activate glucokinase, the compounds of formula I of the present invention can be used as a medicament for the treatment of type II diabetes. Therefore, as mentioned above, a medicament comprising a compound of formula (I) is also an object of the present invention and may comprise one or more compounds of formula (I), and optionally one or more other therapeutically useful substances, for example, It is also an object of the present invention to prepare such a medicament, which comprises preparing the compound of formula I in a dosage form by admixing a pharmaceutically acceptable carrier and / or adjuvant.
[129] The pharmaceutical compositions can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard or soft gelatin capsules, solutions, emulsifiers or suspensions. Administration can also be performed rectally, eg using suppositories; Topically or percutaneously, for example using ointments, creams, gels or solutions; Alternatively, for example, it can be done parenterally, eg, intravenously, intramuscularly, subcutaneously, intradural or percutaneously using injection solutions. Administration can also be carried out sublingually, or, for example, with an aerosol in the form of a spray. In preparing tablets, coated tablets, dragees or hard gelatin capsules, the compounds of the present invention may be mixed with pharmaceutically inert, inorganic or organic excipients. Examples of suitable excipients for tablets, dragees or hard gelatin capsules include lactose, corn starch or derivatives thereof, talc or stearic acid or salts thereof. Suitable excipients for use in soft gelatin capsules include, for example, vegetable oils, waxes, fats, semisolid or liquid polyols, and the like; Depending on the nature of the active ingredient, no excipients may be required in soft gelatin capsules. Excipients that can be used in the preparation of solutions and syrups include, for example, water, polyols, saccharose, invert sugar and glucose. In the case of injections, excipients which can be used include, for example, water, alcohols, polyols, glycerin and vegetable oils. For suppositories and for topical or transdermal use, excipients that can be used include, for example, natural or hardened oils, waxes, fats and semisolid or liquid polyols. The pharmaceutical composition may also include preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for changing the osmotic pressure, buffers, coatings or antioxidants. As mentioned above, they may also include other therapeutically useful agents. It is a prerequisite that all auxiliaries used in the preparation of the preparations are nontoxic.
[130] Preferred forms of use are intravenous, intramuscular or oral administration, with oral administration being most preferred. The dosage in which the compound of formula I is administered in an effective amount depends on the nature of the particular active ingredient, the age and requirements of the patient, and the mode of application. In general, dosages of about 1 to 100 mg / kg body weight / day are contemplated.
[131] The invention will be better understood from the following examples, which are intended to illustrate and are not intended to limit the scope of the invention as defined in the appended claims.
[132] Synthetic Example
[133] Example 1
[134] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[135]
[136] Step A: (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid
[137] A mixture of (S)-(+)-α-aminocyclohexanepropionic acid hydrate (5.00 g; 29.2 mmol) and phthalic acid dicarboxaldehyde (4.21 g; 31.3 mmol) in acetonitrile (120 mL) was refluxed under nitrogen for 20 hours. It was. The mixture was cooled to room temperature and further cooled to 0 ° C. The solid was filtered off and washed once with cold acetonitrile (50 mL) to give (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydroisoindol-2-yl)-as a white solid. 6.54 g (78%) propionic acid was obtained: calcd for EI-HRMS m / e C ₁₇ H ₂₁ N0 ₃ (M ⁺ ) 287.1521, found 287.1521.
[138] Step B: (S) -3-cyclohexyl-2- (I-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[139] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (prepared in Step A, 286 mg) in anhydrous methylene chloride (10 mL); 1.0 mmol), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (BOP, 500 mg; 1.1 mmol) and 2-aminothiazole (125 mg) 1.2 mmol) was added dropwise to N, N-diisopropylethylamine (0.55 mL; 3.1 mmol) at 0 ° C. The mixture was warmed to room temperature and stirred overnight. The mixture was then partitioned with water and the organic layer was washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to afford a crude residue. Fast Chromatography (Biotage 40S; eluent: 3% methanol / methylene chloride) gave (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindole) as light brown foam. 325 mg (75%) of 2-yl) -N-thiazol-2-yl-propionamide were obtained: calcd. For EI-HRMS m / e C ₂₀ H ₂₃ N ₃ 0 ₂ S (M ⁺ ) 369.1511 Found: 369.1513.
[140] Example 2
[141] (S) -N- (5-Chloro-thiazol-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide
[142]
[143] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydroisoindol-2-yl) -N-thiazol-2-yl-propion outlined in Example 1, step B) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (Step A of Example 1) in a similar manner to the method used for the preparation of the amide. 120 mg; 0.42 mmol) and 2-amino-5-chlorothiazole hydrochloride (90 mg; 0.51 mmol) were subjected to BOP coupling to yield N- (5-chloro-thiazole as a white solid in 59% yield. The title compound was prepared by obtaining -2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide: EI-HRMS m / e Calcd for C ₂₀ H ₂₂ ClN ₃ 0 ₂ S (M ⁺ ) 403.1121, found 403.1124.
[144] Example 3
[145] (S) -N- (5-Bromo-thiazol-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide
[146]
[147] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide in anhydrous carbon tetrachloride (1.0 mL) (Prepared in Example 1; 21 mg; 0.06 mmol) and benzoyl peroxide (1 mg; 0.004 mmol) were added to a suspension of N-bromosuccinimide (11 mg; 0.06 mmol). The mixture was stirred at 95 ° C. in a sealed tube. After 1.5 h, N-bromosuccinimide (2 mg) and benzoyl peroxide (1 mg) were added and the mixture was further stirred for 30 minutes. The mixture was cooled to rt and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with water. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (Biotage 12S, eluent: 20% ethyl acetate / hexanes) to give N- (5-bromo-thiazol-2-yl) -3-cyclohexyl-2- as a gray foam. 15 mg (58%) of (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide were obtained: EI-HRMS m / e C ₂₀ H ₂₃ BrN ₃ 0 ₂ S (M ⁺ Calculated 447.0616, found 447.0623.
[148] Example 4
[149] (S) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[150]
[151] Step A: 4,5-dichloro-1,2-di-hydroxymethyl benzene
[152] 4,5-dichlorophthalic acid (5.013 g) in tetrahydrofuran (35 mL) to a stirred solution of borane-tetrahydrofuran complex (45 mL of 1.5M solution in tetrahydrofuran / diethyl ether) cooled to 0 ° C. under nitrogen. 21.1 mmol) was added dropwise over 20 minutes. After the addition was completed, the mixture was stirred at 0 ° C. for 2.5 hours. The mixture was quenched by the slow addition of methanol until gas evolution ceased. The mixture was stirred at rt for 30 min and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution followed by brine solution. The organic extract was dried (sodium sulfate), filtered and concentrated in vacuo to give 4.41 g (100%) of 4,5-dichloro-1,2-di-hydroxymethyl benzene as a white solid: ES-LRMS C ₈ H ₇ Calcd for Ci ₂ 0 ₂ (M ⁺ -1) 205, found 205.
[153] Step B: 4,5-dichlorophthalic acid-1,2-dicarboxaldehyde
[154] To a stirred solution of oxalyl chloride (2.6 mL; 29.2 mmol) in anhydrous methylene chloride (35 mL) at −78 ° C. under nitrogen was added dropwise a solution of dimethyl sulfoxide (4.2 mL; 59.1 mmol) in methylene chloride (10 mL). . After stirring the solution for 10 minutes, a solution of 4,5-dichloro-1,2-di-hydroxymethyl benzene (2.50 g; 12.1 mmol) dissolved in 16 ml of 1: 1 methylene chloride / dimethyl sulfoxide was added dropwise. It was. The resulting mixture was stirred at -78 ° C for 2 hours. Triethylamine (30 mL; 17.6 mmol) was slowly added dropwise over 15 minutes and the mixture was allowed to warm to room temperature for 2 hours. The mixture was diluted with cold water (150 mL) and extracted with methylene chloride. The extract was washed with 1N HCl, dried over sodium sulfate and concentrated to give 2.58 g of 4,5-dichlorophthalic acid-1,2-dicarboxaldehyde as a yellow solid: ES-LRMS C ₈ H ₃ O ₂ (M ⁺ - Calcd for 1), found 201.
[155] Step C: (S) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid
[156] (S)-(+)-α-aminocyclohexanepropionic acid hydrate (1.05 g; 5.83 mmol) and 4,5-dichlorophthalic acid dicarboxaldehyde (prepared in Step B; 1.25 g; 5.86) in acetonitrile (35 mL) mmol) was refluxed under argon for 72 h. The mixture was then cooled to room temperature and left for 2 hours. The solid was filtered off and washed once with cold acetonitrile to afford (S) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydro-isoindole-2 as light brown solid. 1.33 g (64%) of -yl) -propionic acid were obtained: calcd for EI-HRMS m / e C ₁₇ H ₁₉ Cl ₂ NO ₃ (M ⁺ ) 355.0742, found 355.0747.
[157] Step D: (S) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propion amides
[158] (S) -3cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propion outlined in Example 1, step B) (S) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid ( Prepared in Step C; 248 mg; 0.70 mmol) and 2-aminothiazole (91 mg; 0.88 mmol) by BOP coupling as (S) -3-cyclohexyl-2- as beige foam in 35% yield. (5,6-Dichloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide was obtained: EI-HRMS m / e C ₂₀ H Calcd for ₂₁ Cl ₂ N ₃ 0 ₂ S (M ⁺ ) 437.0731, found 437.0725.
[159] Example 5
[160] (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydroisoindol-2-yl) Propionamide
[161]
[162] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 1, step B) Similar to the method used to prepare propionamide, (S) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid ( Example 4, prepared in Step C; 250 mg; 0.70 mmol) and 2-amino-5-chlorothiazole hydrochloride (154 mg; 0.88 mmol) were BOP coupled to give N- as a beige solid in 37% yield. (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide The title compound was prepared by: EI-HRMS m / e calcd for C ₂₀ H ₂₀ Cl ₃ N ₃ O ₂ S (M ⁺ ) 471.0342, found 471.0345.
[163] Example 6
[164] (S) -N- (5-Bromo-thiazol-2-yl) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydro-isoindole-2- 1) -propionamide
[165]
[166] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 1, step B) (S) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid in a similar manner to that used for the preparation of propionamide (Prepared in Example 4, Step C; 248 mg; 0.70 mmol) and 2-amino-5-bromothiazole hydrochloride (154 mg; 0.89 mmol) were BOP-coupled to give N as a beige solid in 40% yield. -(5-Bromo-thiazol-2-yl) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide The title compound was prepared by obtaining: EI-HRMS m / e calcd for C ₂₀ H ₂₀ BrCl ₂ N ₃ 0 ₂ S (M ⁺ ) 514.9837, found 514.9836.
[167] Example 7
[168] (S) -N- (1H-benzimidazol-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide
[169]
[170] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- outlined in Example 9, step B) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (Example 1, step) in a similar manner to the method used for preparing propionamide Prepared in A, 287 mg; 1.0 mmol) and 2-amino-benzimidazole (119 mg; 1.0 mmol) were subjected to BOP coupling to crude N- (5-bromo-thiazol-2-yl) -3 The title compound was prepared by providing -cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide. The crude product was purified by reverse phase HPLC (Rainin Dynamax SD-1 instrument) using a gradient of 100% acetonitrile in 10% acetonitrile / water / 0.1% trifluoroacetic acid on a C18 column. The combined fractions containing the product were concentrated to remove most of acetonitrile and then extracted with ethyl acetate. The extract was dried (sodium sulfate) and concentrated in vacuo to give N- (1H-benzimidazol-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindole- as white solid. 240 mg (60%) of 2-yl) -propionamide was obtained: calcd. For EI-HRMS m / e C ₂₄ H ₂₆ N ₄ O ₂ (M ⁺ ) 402.2056, found 402.2056.
[171] Example 8
[172] (S) -N-benzothiazol-2-yl-3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide
[173]
[174] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (Example 1, step) in a similar manner to the method used for preparing propionamide Prepared in A, 144 mg; 0.5 mmol) and 2-amino-benzothiazole (81 mg; 0.55 mmol) were subjected to BOP coupling to give crude N-benzothiazol-2-yl-3-cyclohexyl-2- The title compound was prepared by providing (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide. The crude product was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 35% ethyl acetate / hexanes) to give N-benzothiazol-2-yl-3-cyclohexyl- as a white solid. 185 mg (44%) of 2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide were obtained: EI-HRMS m / e C ₂₄ H ₂₅ N ₃ O ₂ S ( M ⁺ ) calculated 419.1667, found 419.1661.
[175] Example 9
[176] (R) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[177]
[178] Step A: (R) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid
[179] A mixture of (R)-(+)-α-aminocyclohexanepropionic acid hydrochloride (2.69 g; 15.7 mmol) and phthalic acid dicarboxaldehyde (2.5Og; 14.6 mmol) in acetonitrile (60 mL) was refluxed under nitrogen for 42 hours. It was. The mixture was cooled to room temperature and further cooled to 0 ° C. The solid was filtered off and washed once with cold acetonitrile to afford 2.65 g of (R) -3-cyclohexyl-2- (1-oxo-1,3-dihydroisoindol-2-yl) -propionic acid as a white solid. 63%) were obtained: calcd for EI-HRMS m / e C ₁₇ H ₂₁ NO ₃ (M ⁺ ) 287.1521, found 287. 1523.
[180] Step B: (R) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[181] (R) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (prepared in Step A, 144) in methylene chloride anhydrous (3 mL) at room temperature Mg; 0.5 mmol), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (BOP, 268 mg; 0.55 mmol) and 2-aminothiazole ( To a solution of 50 mg; 0.5 mmol), N, N-diisopropylethylamine (0.20 mL; 1.15 mmol) was added dropwise. The mixture was stirred for 1 hour. The mixture was then diluted with methylene chloride and washed with water. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford a crude residue. (R) -3cyclohexyl-2- (1-oxo-1,3-dihydro-isoindole) as off-white foam by flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 30% ethyl acetate / hexane) 150 mg (81%) of -2-yl) -N-thiazol-2-yl-propionamide were obtained: calcd for EI-HRMS m / e C ₂₀ H ₂₃ N ₃ O ₂ S (M ⁺ ) 369.1511 Found: 369.1511.
[182] Example 10
[183] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-quinolin-2-yl-propionamide
[184]
[185] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 1, step B) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (Example 1, step) in a similar manner to the method used for preparing propionamide Prepared in A; 288 mg; 1.0 mmol) and 2-aminoquinoline (180 mg; 1.2 mmol) were BOP coupled to 3-cyclohexyl-2- (1-oxo-1, as a white solid in 99% yield. The title compound was prepared by obtaining 3-dihydro-isoindol-2-yl) -N-quinolin-2-yl-propionamide: EI-HRMS m / e C ₂₆ H ₂₇ N ₃ O ₂ (M ⁺ ) Calcd for 413.2103, found 413.2103.
[186] Example 11
[187] 11.1. (S) -3-cyclohexyl-2- (5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide and
[188] 11.2. (S) -3-cyclohexyl-2- (6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[189]
[190] Step A: 4-nitro-1,2-di-hydroxymethyl benzene
[191] 4-nitrophthalic acid in tetrahydrofuran (50 mL) over 20 minutes in a stirred solution of borane-tetrahydrofuran complex (70 mL of 1.5 M solution in tetrahydrofuran / diethyl ether) cooled to 0 ° C. under nitrogen. 7.01 g; 33.2 mmol) was added dropwise. After the addition was completed, the mixture was stirred at 0 ° C. for 3.5 hours. The mixture was allowed to warm to room temperature and then refluxed for 18 hours. The mixture was cooled to rt, quenched with methanol and concentrated in vacuo. The residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution followed by brine solution. The organic extract was dried (sodium sulfate), filtered and concentrated in vacuo to give 5.61 g (92%) of 4-nitro-1,2-di-hydroxymethyl benzene as a white solid: ES-LRMS C ₈ H ₈ NO ₄ Calcd for (M ⁺ -1) 182, found 182.
[192] Step B: 4-nitro-ortho-phenylene-1,2-dicarboxaldehyde
[193] To a stirred solution of oxalyl chloride (4.90 mL; 55.0 mmol) in anhydrous methylene chloride (60 mL) at −78 ° C. under nitrogen was added dropwise a solution of dimethyl sulfoxide (8.20 mL; 115 mmol) in methylene chloride (20 mL). After the solution was stirred for 10 minutes, a solution of 4-nitro-1,2-di-hydroxymethyl benzene (3.99 g; 21.8 mmol) dissolved in 20 mL of 1: 1 methylene chloride / dimethyl sulfoxide was added dropwise. The resulting mixture was stirred at -78 ° C for 3 hours. Triethylamine (60 mL; 426 mmol) was added slowly over 15 minutes and the mixture was allowed to warm to room temperature for 2 hours. The mixture was diluted with cold water (300 mL) and extracted with methylene chloride. The extract was washed with 1N HCI, dried over sodium sulfate and concentrated to give crude 4-nitro-ortho-phenylene-1,2-dicarboxaldehyde, which was subjected to flash chromatography (Biotage 40M, eluent: 35% ethyl). Further purification with acetate / hexanes yielded 2.5 g (64%) of 4-nitro-1,2-dicarboxaldehyde, assessed to approximately 40% purity by NMR: ES-LRMS C ₈ H ₄ NO ₄ (M Calcd for ⁺ -1), found 178.
[194] Step C: (S) -3-cyclohexyl-2- (5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid
[195] (S)-(+)-α-aminocyclohexanepropionic acid hydrate (0.708 g; 3.93 mmol) and 4-nitrophthalic acid dicarboxaldehyde (prepared in step B; 2.02 g; 3.95 mmol) in acetonitrile (20 mL) The mixture of was heated to reflux under argon. An additional amount of (S)-(+)-α-aminocyclohexanepropionic acid hydrate (0.775 g; 4.30 mmol) was added over 2 hours and the mixture was refluxed overnight. The mixture was cooled to room temperature, the solids were filtered off and washed once with cold acetonitrile to give (S) -3-cyclohexyl-2- (5-nitro-1-oxo-1,3-dihydro in a 1: 2.7 ratio. Isoindol-2-yl) -propionic acid and regioisomer (S) -3-cyclohexyl-2- (6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid Obtained beige solid (0.511 g) was obtained. The filtrate was then concentrated in vacuo and the residue was recrystallized from acetonitrile to give (S) -3-cyclohexyl-2- (5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid A second crop of this richer product (1.01 g) was obtained. Calcd for ES-LRMS C ₁₇ H ₁₉ N ₂ O ₅ (M ⁺ -1) of the mixture, 331, found 331.
[196] Step D: (S) -3-cyclohexyl-2- (5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide and (S) -3-cyclohexyl-2- (6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[197] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 1, step B) (S) -3-cyclohexyl-2- (5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (approximately similar to the method used for the preparation of propionamide) 1: 1 regioisomer mixture prepared in step C; 301 mg; 0.91 mmol) and 2-aminothiazole (116 mg; 1.12 mmol) BOP coupled and chromatographed (Biotage 40M, eluent: 30% ethyl) 131 mg of 3-cyclohexyl-2- (5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide) EI-HRMS m / e calcd for C ₂₀ H ₂₂ N ₄ 0 ₄ S (M ⁺ ) 414.1362, found 414.1362; And regioisomer 3-cyclohexyl-2- (6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide 121 mg: EI- HRMS m / e calcd for C ₂₀ H ₂₂ N ₄ O ₄ S (M ⁺ ) 414.1362, found 414.1368.
[198] Example 12
[199] 12.1. (S) -N- (5-Chloro-thiazol-2-yl) -3-cyclohexyl-2- (5-nitro-1-oxo-1,3-dihydroisoindol-2-yl) -propion Amides and
[200] 12.2. (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)- Propionamide
[201]
[202] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydroisoindol-2-yl) -N-thiazol-2-yl-propion outlined in Example 1, step B) (S) -3-cyclohexyl-2- (5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (about 1) A mixture of 1,5,6-positionisomers, prepared in step C; 307 mg; 0.92 mmol) and 2-amino-5-chlorothiazole hydrochloride (360 mg; 2.04 mmol) were subjected to BOP coupling and chromatography ( Biotage 40M, eluent: 25% ethyl acetate / hexanes) to (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (5-nitro-1-oxo-1 , 3-dihydroisoindol-2-yl) -propionamide 134 mg: calcd for EI-HRMS m / e C ₂₀ H ₂₁ ClN ₄ 0 ₄ S (M ⁺ ) 448.0972, found 448.0970; And regioisomer (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (6-nitro-1-oxo-1,3-dihydro-isoindole-2- Il) -propionamide 111 mg: EI-HRMS m / e calcd for C ₂₀ H ₂₁ ClN ₄ 0 ₄ S (M ⁺ ) 448.0972, found 448.0972.
[203] Example 13
[204] 13.1. (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydroisoindol-2-yl)- Propionamide and
[205] 13.2. (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) Propionamide
[206]
[207] Step A: 3-Fluoro-1,2-di-hydroxymethyl benzene
[208] 3-fluorophthalic acid in tetrahydrofuran (40 mL) over 15 minutes to a stirred solution of borane-tetrahydrofuran complex (50 mL of 1.5 M solution in tetrahydrofuran / diethyl ether) cooled to 0 ° C. under argon. (4.51 g; 24.0 mmol) was added dropwise. After the end of the addition, the mixture was stirred at 0 ° C. for 2 hours. The mixture was warmed to room temperature and then refluxed for 20 hours. The mixture was cooled to rt, quenched with methanol (30 mL) and concentrated in vacuo. The residue was taken up in ethyl acetate (150 mL) and washed with saturated sodium bicarbonate solution. The aqueous layer was further extracted with ethyl acetate (2X125 mL) and the combined extracts were washed with brine solution. The organic extract was dried (sodium sulfate), filtered and concentrated in vacuo to yield 3.73 g (99%) of 3-fluoro-1,2-di-hydroxymethyl benzene as a white solid: ES-LRMS C ₈ H ₈ FO Calcd for ₂ (M ⁺ -1) 155, found 155.
[209] Step B: 3-fluorophthalic acid dicarboxaldehyde
[210] To a stirred solution of oxalyl chloride (2.80 mL; 31.5 mmol) in anhydrous methylene chloride (35 mL) at −78 ° C. under nitrogen was added dropwise a solution of dimethyl sulfoxide (4.6 mL; 64.7 mmol) in methylene chloride (10 mL). . After stirring the solution for 30 minutes, a solution of 3-fluoro-1,2-di-hydroxymethyl benzene (2.00 g; 12.8 mmol) dissolved in 20 ml of 1: 1 methylene chloride / dimethyl sulfoxide was added dropwise. . The reaction mixture was stirred at -78 ° C for 2.5 h. Triethylamine (35 mL; 248.6 mmol) was added slowly over 15 minutes and the mixture was stirred at −78 ° C. for 30 minutes, then warmed to room temperature over 4 hours. The mixture was poured into cold water (200 mL) and extracted with methylene chloride. The extract was washed with 1N HCI and brine, then dried (sodium sulfate) and concentrated to afford crude 3-fluorophthalic acid dicarboxaldehyde, which was not purified further: ES-LRMS C ₈ H ₄ FO ₂ (M Calcd for ⁺ -1), found 151.
[211] Step C: (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid
[212] (S)-(+)-α-aminocyclohexanepropionic acid hydrate (0.565 g; 3.14 mmol) and 3-fluorophthalic acid dicarboxaldehyde (prepared in step B; 1.60 g; 3.16 mmol) in acetonitrile (20 mL) ) Was heated to reflux under argon. An additional amount of (S)-(+)-α-aminocyclohexanepropionic acid hydrate (0.437 g; 2.43 mmol) was added over 7 hours and the mixture was refluxed for 72 hours. The mixture was cooled to room temperature for 3 hours and then stored in the refrigerator for 1 hour. The solid was filtered off and washed once with cold acetonitrile to give (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydroisoindole-2 in a ratio of about 1: 1. White solid consisting of -yl) -propionic acid and regioisomer (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid 1.39 g, 77%) was calculated: calcd for ES-LRMS C ₁₇ H ₁₉ FNO ₃ (M ⁺ -1) 304, found 304.
[213] Step D: (S) -N- (5-Chloro-thiazol-2-yl) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindole-2 -Yl) -propionamide and (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro- Isoindol-2-yl) -propionamide
[214] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydroisoindol-2-yl) -N-thiazol-2-yl-propion outlined in Example 9, step B) (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (approximately similar to the method used for the preparation of the amide) A mixture of 1: 1 regioisomers, prepared in step C; 501 mg; 1.64 mmol) and 2-amino-5-chlorothiazole hydrochloride (643 mg; 3.64 mmol) and BOP coupled and normal HPLC (waters prep ( Waters Prep.) 500, loaded on a column containing methylene chloride, eluent: 20% ethyl acetate / hexanes) to (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl- 2- (4-Fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide 194 mg: EI-HRMS m / e C ₂₀ H ₂₁ ClFN ₃ O ₂ S (M ⁺ Calculated for 421.1027, found 421.1024; And regioisomer (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindole-2 -Yl) -propionamide 173 mg: Calcd for EI-HRMS m / e C ₂₀ H ₂₁ ClFN ₃ O ₂ S (M ⁺ ) 421.1027, found 421.1031.
[215] Example 14
[216] 3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide
[217]
[218] (R) -3cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propion outlined in Example 9, step B) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (Example 1, Step A) in a similar manner to that used for the preparation of the amide. 287 mg; 1.00 mmol) and 4-aminopyrimidine (108 mg; 1.14 mmol) were subjected to BOP coupling and flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 50% ethyl acetate / hexane) To give 271 mg (74%) of 3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide as a white foam. Was: EI-HRMS m / e calcd for C ₂₁ H ₂₄ N ₄ 0 ₂ (M ⁺ ) 364.1899, found 364.1893.
[219] Example 15
[220] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide
[221]
[222] (R) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (Example 1, step) in a similar manner to the method used for preparing propionamide Prepared in A; 287 mg; 1.00 mmol) and 2-aminopyrazine (95 mg; 1.00 mmol) are BOP coupled and flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 50% ethyl acetate / hexanes) 350 mg (96%) of (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide as a white foam ) Was obtained: calcd for EI-HRMS m / e C ₂₁ H ₂₄ N ₄ O ₂ (M ⁺ ) 364.1899. Found 364.1908.
[223] Example 16
[224] (S) -N-Benzoxazol-2-yl-3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide
[225]
[226] (R) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (Example 1, step) in a similar manner to the method used for preparing propionamide Prepared in A; 144 mg; 0.50 mmol) and 2-aminobenzoxazole (67 mg; 0.50 mmol) were BOP coupled and flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 50% ethyl acetate / (S) -N-benzoxazol-2-yl-3cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide as a white foam (96%) were obtained: Calcd for EI-HRMS m / e C ₂₄ H ₂₅ N ₃ O ₃ (M ⁺ ) 403.1896, found 403.1895.
[227] Example 17
[228] 3-cyclopentyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[229]
[230] Step A: 3-cyclopentyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid
[231] A mixture of 2-amino-3-cyclopentyl-propionic acid (0.800 g; 5.09 mmol) and phthalic acid dicarboxaldehyde (0.684 g; 5.10 mmol) in acetonitrile (30 mL) was refluxed under nitrogen for 3 hours. The mixture was cooled to room temperature and the solid was filtered off and washed once with cold acetonitrile (5 mL) to afford 3-cyclopentyl-2- (1-oxo-1,3-dihydro-isoindole-2- as white solid. Il) -propionic acid was obtained 1.16 g (83%): calcd for EI-HRMS m / e C ₁₆ H ₁₉ NO ₃ (M ⁺ ) 273.1365, found 273.1374.
[232] Step B: 3-cyclopentyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[233] (R) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) 3-cyclopentyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (prepared in Step A; 273 mg) in a similar manner to the method used for preparing propionamide; 1.00 mmol) and 2-aminothiazole (100 mg; 1.00 mmol) were subjected to BOP coupling and flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 40% ethyl acetate / hexanes) to 3-cyclo as a white solid. 132 mg (37%) of pentyl-2- (1-oxo-1,3-dihydroisoindol-2-yl) -N-thiazol-2-yl-propionamide were obtained: ES-HRMS m / e Calcd for C ₁₉ H ₂₁ N ₃ 0 ₂ SNa (M ⁺ + Na ⁺ ) 378.1247, found 378.1250.
[234] Example 18
[235] N- (5-Chloro-thiazol-2-yl) -3-cyclopentyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide
[236]
[237] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 1, step B) 3-cyclopentyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (prepared in Example 1, Step A) in a manner analogous to the method used for the preparation of propionamide ; 277 mg; 1.01 mmol) and 2-amino-5-chlorothiazole hydrochloride (397 mg; 2.30 mmol) by BOP coupling and flash chromatography (Biotage 40M eluent: 20% ethyl acetate / hexanes) to a light yellow solid 290 mg (74% N- (5-chloro-thiazol-2-yl) -3-cyclopentyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide ) Was obtained: calcd. For E-HRMS m / e C ₁₉ H ₂₁ N ₃ 0 ₂ S (M ⁺ ) 389.0965, found 389.0966.
[238] Example 19
[239] 3-cycloheptyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[240]
[241] Step A: Cycloheptane Methanol
[242] Cycloheptancarboxylic acid (10.05 g; 69.3 mmol) in 30 ml tetrahydrofuran was added to a solution of borane-tetrahydrofuran complex (95 ml 1.5 M solution in tetrahydrofuran / ether) at 0 ° C. under argon. After 2 hours, the mixture was quenched by careful addition of methanol and concentrated in vacuo. The residue was taken up in ethyl acetate and washed successively with 1N HCl, saturated sodium bicarbonate and brine solution. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo to yield 9.19 g (100%) of cycloheptane methanol as colorless oil.
[243] Step B: Cycloheptylmethyl Iodide
[244] Dilute iodine (23.52 g; 92.7 mmol) over 10 minutes in a solution of triphenylphosphine (24.59 g; 92.8 mmol) and imidazole (6.40 g; 93.1 mmol) in methylene chloride (100 mL) cooled to 0 ° C. Added. Then a solution of cycloheptane methanol (9.14 g; 71.3 mmol) dissolved in methylene chloride (50 mL) was added over 5 minutes. The cooling bath was removed and the mixture was warmed to room temperature and stirred overnight. The mixture was diluted with methylene chloride and washed with water, and the organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product was chromatographed (eluent: hexane) to give 15.35 g (93%) of cycloheptylmethyl iodide as an oil.
[245] Step C: 2- (Benzhydrylidene-amino) -3-cycloheptyl-propionic acid t-butyl ester
[246] To a stirred solution of (benzhydrylidene-amino) -acetic acid t-butyl ester (2.56 g; 8.68 mmol) in 30 mL tetrahydrofuran at -78 ° C under argon (10.0 mL; in cyclohexane 1.5M solution) was added dropwise. After 30 minutes a solution of cycloheptylmethyl iodide (prepared in Step B; 3.48 g; 14.6 mmol) in 20 ml of tetrahydrofuran was added dropwise and the mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was quenched with saturated ammonium chloride solution (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was chromatographed (Biotage 40M; eluent: 5% ethyl acetate / hexanes) to give 2.56 g (73%) of 2- (benzhydrylidene-amino) -3-cycloheptyl-propionic acid t-butyl ester as pale yellow oil. ) Was obtained.
[247] Step D: 2-Amino-3-cycloheptyl-propionic acid
[248] To a solution of 2- (benzhydrylidene-amino) -3-cycloheptyl-propionic acid t-butyl ester (1.34 g; 3.31 mmol) in methanol (5 mL) is added 1ON HCl solution (15 mL) and the mixture is refluxed. Heated. After 15 hours, the mixture was cooled to room temperature, transferred to a separatory funnel and washed with ethyl acetate. The aqueous layer was neutralized with concentrated ammonium hydroxide solution and the white solid was filtered off and air dried to give 329 mg of 2-amino-3-cycloheptyl-propionic acid.
[249] Step E: 3-cycloheptyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid
[250] A solution of phthalic acid dicarboxaldehyde (248 mg; 1.80 mmol) and 2-amino-3-cycloheptyl-propionic acid (318 mg; 1.72 mmol) in acetonitrile was heated to reflux for 18 hours. The mixture was then cooled to room temperature and stored in the refrigerator for 3 hours. The solid was filtered off, rinsed with cold acetonitrile and air dried to afford 424 mg (82%) of 3-cycloheptyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid as a beige solid. ) Was obtained: calcd for EI-HRMS m / e C ₁₈ H ₂₃ NO ₃ (M ⁺ ) 301.1678, found 301.1668.
[251] Step F: 3-cycloheptyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[252] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 1, step B) 3-cycloheptyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (prepared in Step E; 173 mg) in a similar manner to the method used for preparing propionamide; 0.58 mmol) and 2-aminothiazole (97 mg; 0.94 mmol) were subjected to BOP coupling and flash chromatography (Biotage 40S, eluent: 35% ethyl acetate / hexanes) to give 3-cycloheptyl-2- (as a white foam. 217 mg (99%) of 1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide were obtained: EI-HRMS m / e C ₂₁ H ₂₅ Calcd for N ₃ 0 ₂ S (M ⁺ ) 383.1667, found 383.1660.
[253] Example 20
[254] N- (5-Chloro-thiazol-2-yl) -3-cycloheptyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide
[255]
[256] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 1, step B) 3-cycloheptyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (prepared in Step E; 177 mg) in a similar manner to the method used for preparing propionamide; 0.59 mmol) and 2-amino-5-chlorothiazole hydrochloride (168 mg; 0.95 mmol) were subjected to BOP coupling and flash chromatography (Biotage 40M, eluent: 20% ethyl acetate / hexanes) to give N- ( 99 mg (40%) of 5-chloro-thiazol-2-yl) -3-cycloheptyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide were obtained. : EI-HRMS m / e calcd for C ₂₁ H ₂₄ ClN ₃ O ₂ S (M ⁺ ) 417.1278, found 417.1289.
[257] Example 21
[258] 3-cyclooctyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[259]
[260] Step A: Cyclooctylmethyl Iodide
[261] Triphenylphosphine (9.23 g; 35.2 mmol) was added to the solution of cyclooctylmethanol (5.00 g; 35.2 mmol) and iodine (8.93 g; 35.2 mmol) in dry methylene chloride (100 mL) at room temperature over 10 minutes. It was. After 1 h the mixture was diluted with methylene chloride and washed with water, followed by saturated sodium bisulfite solution, and the organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product was chromatographed (eluent: hexane) to give 5.35 g (60%) of cyclooctylmethyl iodide as an oil.
[262] Step B: 2- (Benzhydrylidene-amino) -3-cyclooctyl-propionic acid t-butyl ester
[263] To a solution of (benzhydrylidene-amino) -acetic acid t-butyl ester (3.00 g; 10.1 mmol) in 60 mL tetrahydrofuran at -78 ° C under argon (11.5 mL; 1.5 in cyclohexane) M solution) was added dropwise. After 30 minutes, a solution of cycloheptylmethyl iodide (prepared in Step A; 3.83 g; 15.2 mmol) was added dropwise through a syringe and the mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was quenched with saturated sodium bicarbonate solution and most of the tetrahydrofuran was vacuumed off. The mixture was diluted with water and extracted with methylene chloride. The combined extracts were dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was chromatographed (eluent: 4% ethyl acetate / hexanes) to yield 3.34 g (79%) of 2- (benzhydrylidene-amino) -3-cyclooctyl-propionic acid t-butyl ester as light yellow oil. .
[264] Step C: 2-Amino-3-cyclooctyl-propionic acid
[265] To a solution of 2- (benzhydrylidene-amino) -3-cyclooctyl-propionic acid t-butyl ester (2.00 g) in methanol (15 mL) was added 1ON HC1 solution (30 mL) and the mixture was heated to reflux. After 20 hours, the mixture was cooled to room temperature, diluted with 20 mL of water and transferred to a separating funnel and washed with ethyl acetate. The aqueous layer was then neutralized with 1ON sodium hydroxide solution and further cooled to 0 ° C. The white solid was filtered off and air dried to afford 590 mg of 2-amino-3-cyclooctyl-propionic acid.
[266] Step D: 3-cyclooctyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid
[267] A solution of phthalic acid dicarboxaldehyde (349 mg; 2.60 mmol) and 2-amino-3-cyclooctyl-propionic acid (500 mg; 2.51 mmol) in acetonitrile (20 mL) was heated to reflux for 3 hours. The mixture was then hot filtered to remove insoluble matters, then cooled to room temperature and then further cooled to 0 ° C. The solid was filtered off, rinsed with cold acetonitrile and air dried to afford 480 mg (62%) of 3-cyclooctyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid as a white solid. Obtained: EI-HRMS m / e calcd for C ₁₉ H ₂₅ NO ₃ (M ⁺ ) 315.1834, found 315.1840.
[268] Step E: 3-cyclooctyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[269] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) 3-cyclooctyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (prepared in step D; 200 mg) in a similar manner to the method used for preparing propionamide; 0.65 mmol) and 2-aminothiazole (70 mg; 0.70 mmol) were BOP-coupled and flash chromatography (eluent: 30% ethyl acetate / hexanes) gave 3-cyclooctyl-2- (1-oxo- as a white foam). 226 mg (88%) of 1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide were obtained: EI-HRMS m / e C ₂₂ H ₂₇ N ₃ O ₂ Calcd for S (M ⁺ ) 397.1824, found 397.1825.
[270] Example 22
[271] (R) -N- (5-Bromo-pyridin-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide
[272]
[273] (R) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (Example 1, step) in a similar manner to the method used for preparing propionamide Prepared in A; 287 mg; 1.00 mmol) and 2-amino-5-bromopyridine (173 mg; 1.00 mmol) were BOP coupled and flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 30%) Ethyl acetate / hexane) to give (S) -N- (5-bromo-pyridin-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindole-) as a white foam. 243 mg (55%) of 2-yl) -propionamide were obtained: calcd for EI-HRMS m / e C ₂₂ H ₂₄ BrN ₃ O ₂ (M ⁺ ) 441.1052, found 441.1036.
[274] Example 23
[275] 23.1. (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide and
[276] 23.2. (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[277]
[278] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid and in a similar manner to that used for the preparation of propionamide and (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (499 mg; 1.63 mmol, 1: 1 regioisomer ) And 2-aminothiazole (376 mg; 3.64 mmol) by BOP coupling and flash chromatography (Biotage 40M; eluent: 30% ethyl acetate / hexanes) to (S) -3-cyclohexyl-2- (4-Fluoro-1-oxo-1,3-dihydroisoindol-2-yl) -N-thiazol-2-yl-propionamide (221 mg): EI-HRMS m / e C ₂₀ H ₂₂ Calcd for FN ₃ 0 ₂ S (M ⁺ ) 387.1417, found 387.1422; And impure (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide This was further purified by spin chromatography (eluent: 35% ethyl acetate / hexanes) to give pure (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3 as pure white foam). 48 mg of -dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide were obtained: for EI-HRMS m / e C ₂₀ H ₂₂ FN ₃ O ₂ S (M ⁺ ) Calc. 387.1417, found 387.1415.
[279] Example 24
[280] (S) -3-cyclohexyl-N- (1H-imidazol-2-yl) -2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide
[281]
[282] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 1, step B) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (Example 1, step) in a similar manner to the method used for preparing propionamide Prepared in A; 287 mg; 1.00 mmol) and 2-aminoimidazole (241 mg; 1.79 mmol) by BOP coupling and flash chromatography (Biotage 40M; eluent: 4% methanol / methylene chloride) (S) Obtain 320 mg of 3-cyclohexyl-N- (1H-imidazol-2-yl) -2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide, and then This was recrystallized from ethyl acetate / hexanes to give 290 mg of pure material: calcd for EI-HRMS m / e C ₂₀ H ₂₄ N ₄ 0 ₂ (M ⁺ ) 352.1899, found 352.1895.
[283] Example 25
[284] 25.1. (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-l, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide and
[285] 25.2. (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide
[286]
[287] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid and in a similar manner to that used for the preparation of propionamide and (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (331 mg; 1.08 mmol, of 1: 1 position isomer Mixture) and 2-aminopyrazine (232 mg; 2.41 mmol) by BOP coupling and flash chromatography (Biotage 40M; eluent: 30% ethyl acetate / hexanes) to (S) -3-cyclohexyl-2- (4 -Fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide and (S) -3-cyclohexyl-2- (7-fluoro Rho-I-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide is obtained, which is 40% acetonitrile / water / 0.1% on a C18 column. Further purification by reverse phase HPLC (Rynein Dynamax SD-1 equipment) using a gradient of 100% acetonitrile in trifluoroacetic acid to give pure (S) -3-cyclohexyl-2- (7-fluoro as pure white foam). -1-oxo-1,3-dihydroisoindol-2-yl) -N-thiazol-2-yl-propionamide 39 mg: EI-HRMS m / e C ₂₁ H ₂₃ FN ₄ O ₂ (M ⁺ Calcd for 382.1805, found 382.1794; And regioisomer (S) -3cyclohexyl-2- (7-fluoro-1-oxo-l, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide 43 Mg: EI-HRMS m / e calcd for C ₂₁ H ₂₃ FN ₄ O ₂ (M ⁺ ) 382.1805, found 382.1810.
[288] Example 26
[289] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide
[290]
[291] (R) -3-cyclohexyl-2 (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propion outlined in Example 9, step B) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (Example 1, Step A) in a similar manner to that used for the preparation of the amide. 287 mg; 1.00 mmol) and 2-aminopyridine (94 mg; 1.00 mmol) by BOP coupling and flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 45% ethyl acetate / hexanes); 186 mg of (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydroisoindol-2-yl) -N-pyridin-2-yl-propionamide was obtained as a white foam: EI -HRMS m / e calcd for C ₂₂ H ₂₅ N ₃ 0 ₂ (M ⁺ ) 363.1947, found 363.1935.
[292] Example 27
[293] (S) -N-3-cyclohexyl-N- (2-methyl-pyrimidin-4-yl) -2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide
[294]
[295] (R) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (Example 1, step) in a similar manner to the method used for preparing propionamide Prepared in A; 150 mg; 0.52 mmol) and 2-amino-6-methylpyrimidine (57 mg; 0.52 mmol) are BOP coupled and flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 65%) Ethyl acetate / hexane) to give (S) -3-cyclohexyl-N- (2-methyl-pyrimidin-4-yl) -2- (1-oxo-1,3-dihydro-isoindole-) as a white foam. 109 mg of 2-yl) -propionamide were obtained: calcd. For EI-HRMS m / e C ₂₂ H ₂₆ N ₄ O ₂ (M ⁺ ) 378.2056. Found 378.2054.
[296] Example 28
[297] 28.1 (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide and
[298] 28.2. (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[299]
[300] Step A: 3-fluorophthalic acid dimethyl ester
[301] Hydrochloric acid was bubbled into 3-fluorophthalic acid (2.00 g; 10.9 mmol) in methanolic anhydride for 2 minutes at room temperature. The mixture was heated to reflux. After 1 hour of reflux, 1 ml of concentrated sulfuric acid was added and refluxing continued for 22 hours. The mixture was cooled to room temperature and then neutralized with saturated sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate. The extract was dried (sodium sulfate), filtered and concentrated in vacuo to yield 1.70 g of 3-fluorophthalic acid dimethyl ester as an oil.
[302] Step B: 3-thiomethylphthalic acid
[303] A mixture of 3-fluorophthalic acid dimethyl ester (2.27 g; 10.7 mmol) and sodium thiomethoxide (6.34 g; 85.9 mmol) in DMSO (20 mL) was heated at 50 ° C. After 24 hours, crushed ice was added and the resulting mixture was acidified with 1N HCl. The solution was extracted with ethyl acetate and the extract was washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by reverse phase HPLC (Rynenin Dynamax SD-1 equipment) using a gradient of 0% acetonitrile / water / 0.1% trifluoroacetic acid to 100% acetonitrile on a C18 column to afford 3-thiomethylphthalic acid 802. Mg was obtained.
[304] Step C: 3-thiomethyl-1,2-di-hydroxymethyl benzene
[305] 3-thiomethylphthalic acid (0.739 g; 3.48 mmol in 20 ml of tetrahydrofuran) to a stirred solution of borane-tetrahydrofuran complex (14.0 ml of 1.5 M solution in tetrahydrofuran / diethyl ether) cooled to 0 ° C. under argon. ) Solution was added. After the addition was completed, the mixture was refluxed for 15 hours. The mixture was cooled to rt, quenched with methanol (20 mL), refluxed for 2 h and concentrated in vacuo. The residue was partitioned between 1N HCl and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the combined extracts were washed with saturated sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated in vacuo to afford crude 3-thiomethyl-1,2-di-hydroxymethyl benzene. This was purified by flash chromatography (Biotage 40M; eluent: 25% to 50% gradient of ethyl acetate / hexanes) to give 454 mg of pure 3-thiomethyl-1,2-di-hydroxymethyl benzene.
[306] Step D: 3-thiomethylphthalic acid dicarboxaldehyde
[307] To a stirred solution of oxalyl chloride (0.42 mL; 4.72 mmol) in anhydrous methylene chloride (5 mL) under argon was added dropwise a solution of dimethyl sulfoxide (0.70 mL; 9.67 mmol) in methylene chloride (2 mL). . After the solution was stirred for 10 minutes, a solution of 3-thiomethyl-1,2-di-hydroxy benzene (0.415 g; 2.25 mmol) dissolved in 3 mL of 1: 1 methylene chloride / dimethyl sulfoxide was added dropwise. The resulting mixture was stirred at -78 ° C for 2 hours. After triethylamine (5.5 mL; 17.4 mmol) was added dropwise, the mixture was gradually warmed to room temperature and stirred for 20 hours. The mixture was poured into ice water and the layers separated. The extract was washed with brine, then dried (sodium sulfate) and concentrated to afford crude 3-thiomethylphthalic acid dicarboxaldehyde, which was not purified further.
[308] Step E: (S) -3-cyclohexyl-2- (4-methylthio-1-oxo-1,3-dihydro-isoindol-2-yl) propionic acid
[309] (S)-(+)-α-aminocyclohexanepropionic acid hydrate (0.125 g; 0.70 mmol) in acetonitrile (5 mL) and crude 3-thiomethylphthalic acid dicarboxaldehyde (prepared in step D; 0.250 g; 1.4 mmol) was heated to reflux for 18 hours under argon. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage 40S; eluent: 5% methanol / methylene chloride) to give (S) -3-cyclohexyl-2- (4-methylthio-1-oxo in about 1: 1 ratio. -1,3-Dihydro-isoindol-2-yl) -propionic acid and regioisomer (S) -3-cyclohexyl-2- (7-methylthio-1-oxo-1,3-dihydro-isoindole 260 mg of 2-yl) -propionic acid were obtained.
[310] Step F: (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid
[311] (S) -3-cyclohexyl-2- (4-methylthio-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid and regioisomers in formic acid (4 mL) at 0 ° C. S) -3-cyclohexyl-2- (7-methylthio-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (0.790 g; 2.37 mmol; about 1: 1 mixture) 30% hydrogen peroxide solution (1.3 mL; 12.7 mmol) was added dropwise to the solution. The mixture was warmed to rt and stirred for 19 h. The mixture was concentrated under a stream of nitrogen to remove formic acid to afford crude (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)- Propionic acid and regioisomer (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid were obtained.
[312] Step G: (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-l, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propion amides
[313] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1,3-dihydroisoindol-2-yl) -propionic acid and in a similar manner to the method used for preparing propionamide and Regioisomer (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (112 mg; 0.31 mmol) and 2- Aminothiazole (54 mg; 0.52 mmol) was BOP coupled and flash chromatography (Biotage 40M; eluent: ethyl acetate / methylene chloride: gradient of 15% to 50% ethyl acetate) gave (S) -3-cyclohexyl -2- (4-Methylsulfonyl-1-oxo-l, 3-dihydroisoindol-2-yl) -N-thiazol-2-yl-propionamide 51 mg: EI-HRMS m / e C ₂₁ Calcd for H ₂₅ N ₃ 0 ₄ S ₂ (M ^{+ -2} ) 445.1130, found 445.1125; And (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-l, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide 39 Mg: calcd for EI-HRMS m / e C ₂₁ H ₂₅ N ₃ O ₄ S ₂ (M ⁺ ) 447.1286, found 447.1280.
[314] Example 29
[315] 29.1. (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide and
[316] 29.2. (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide
[317]
[318] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid in a similar manner to the method used for preparing propionamide And regioisomer (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (200 mg; 0.55 mmol) and 2 -Aminopyrazine (88 mg; 0.91 mmol) BOP coupled and flash chromatography (Biotage 40S; eluent: ethyl acetate / methylene chloride, gradient: 20% to 60%) yields a crude mixture, which is a C18 column. Further purification by reverse phase HPLC (Rynein Dynamax SD-1 equipment) using a gradient of 90% acetonitrile in 10% acetonitrile / water / 0.1% trifluoroacetic acid in phase (S) -3-cyclohexyl-2 -(4-methylsulfonyl-1-oxo-1,3-di Hydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide 21 mg: calcd for EI-HRMS m / e C ₂₂ H ₂₄ N ₄ O ₄ SNa (M ⁺ + Na ⁺ ) 465.1567, Found 465.1570; And (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide 13 mg : EI-HRMS m / e calcd for C ₂₂ H ₂₄ N ₄ O ₄ SNa (M ⁺ + Na ⁺ ) 465.1567, found 465.1568.
[319] Example 30
[320] 30.1. (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide and
[321] 30.2. (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide
[322]
[323] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1,3-dihydroisoindol-2-yl) -propionic acid and in a similar manner to the method used for preparing propionamide and Regioisomer (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (200 mg; 0.55 mmol) and 4- Aminopyrimidine (89 mg; 0.91 mmol) was subjected to BOP coupling and flash chromatography (Biotage 40S; eluent: ethyl acetate / methylene chloride, gradient: 25% to 70% ethyl acetate) as a foam (S) -3- Cyclohexyl-2- (4-methylsulfonyl-1-oxo-1,3-dihydroisoindol-2-yl) -N-pyrimidin-4-yl-propionamide 83 mg: EI-HRMS m / e Calcd for C ₂₂ H ₂₄ N ₄ 0 ₄ SNa (M ⁺ + Na ⁺ ) 465.1567, found 465.1568; And (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propion as foam Amide 77 mg: EI-HRMS m / e calcd for C ₂₂ H ₂₆ N ₄ O ₄ SNa (M ⁺ + Na ⁺ ) 465.1567, found 465.1572.
[324] Example 31
[325] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-5-methyl-pyridin-2-yl-propionamide
[326]
[327] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 1, step B) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid Example 1, Step A in a similar manner to the method used for preparing propionamide Manufactured in; 287 mg; 1.00 mmol) and 2-amino-5-methylpyridine (143 mg; 1.32 mmol) were subjected to BOP coupling and flash chromatography (Biotage 40S; eluent: 30% ethyl acetate / hexanes) as a white foam (S) -3 352 mg of -cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-5-methyl-pyridin-2-yl-propionamide were obtained: EI-HRMS m / e calcd for C ₂₃ H ₂₇ N ₃ 0 ₂ (M ⁺ ) 377.2103, found 377.2107.
[328] Example 32
[329] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-4-methyl-pyridin-2-yl-propionamide
[330]
[331] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 1, step B) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (Example 1, step) in a similar manner to the method used for preparing propionamide Prepared in A; 287 mg; 1.00 mmol) and 2-amino-4-methylpyridine (143 mg; 1.32 mmol) by BOP coupling and flash chromatography (Biotage 40S; eluent: 30% ethyl acetate / hexanes) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-4-methyl-pyridin-2-yl-propionamide 344 mg as a white foam Obtained: EI-HRMS m / e calcd for C ₂₃ H ₂₇ N ₃ 0 ₂ (M ⁺ ) 377.2103. Found 377.2106.
[332] Example 33
[333] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-5-chloro-pyridin-2-yl-propionamide
[334]
[335] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 1, step B) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (Example 1, step) in a similar manner to the method used for preparing propionamide Prepared in A; 287 mg; 1.00 mmol) and 2-amino-5-chloropyridine (129 mg; 1.00 mmol) were BOP coupled and flash chromatography (eluent: 25% ethyl acetate / hexanes) as a white foam ( 160 mg of S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-5-chloro-pyridin-2-yl-propionamide was obtained: EI-HRMS m / e calcd for C ₂₂ H ₂₄ N ₃ 0 ₂ ClNa (M ⁺ + Na ⁺ ) 420.1449, found 420.1451.
[336] Example 34
[337] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N- (1-oxy-pyridin-2-yl) -propionamide
[338]
[339] (R) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (Example 1, step) in a similar manner to the method used for preparing propionamide Prepared in A; 287 mg; 1.00 mmol) and 2-aminopyridine N-oxide (110 mg; 1.00 mmol) are BOP coupled and flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 2% methanol / (S) -N- (pyridin-N-oxide-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) as an off-white foam 340 mg (55%) of) -propionamide were obtained. NMR indicated that the product was not pure and was further added by reverse phase HPLC (Rynein Dynamax SD-1 instrument) using a gradient of 10% acetonitrile / water / 0.1% trifluoroacetic acid to 100% acetonitrile on a C18 column. Purification to pure (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N- (1-oxy-pyridin-2-yl) -propionamide 188 mg was obtained: Calcd for ES-LRMS m / e C ₂₂ H ₂₅ N ₃ O ₃ (M ⁺ + H ⁺ ) 380, found 380.
[340] Example 35
[341] 35.1. (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide and
[342] 35.2. (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide
[343]
[344] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid ( A mixture of about 1: 1 regioisomers, prepared in Example 13, step C; 501 mg; 1.64 mmol) and 2-aminopyridine (643 mg; 3.64 mmol) were BOP coupled and 40% acetonitrile / on C18 column. Purification by reverse phase HPLC (Rynein Dynamax SD-1 equipment) using a gradient of 70% acetonitrile in water / 0.1% trifluoroacetic acid (S) -3-cyclohexyl-2- (4-fluoro-1 -Oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide 157 mg: EI-HRMS m / e C ₂₂ H ₂₄ FN ₃ O ₂ Na (M ⁺ + Na ⁺ ) calculated 404.1745, found 404.1748; And regioisomer (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydroisoindol-2-yl) -N-pyridin-2-yl-propionamide 99 mg : EI-HRMS m / e calcd for C ₂₂ H ₂₄ FN ₃ O ₂ Na (M ⁺ + Na ⁺ ) 404.1745, found 404.1749.
[345] Example 36
[346] 36.1. (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide and
[347] 36.2. (S) -3-cyclohexyl-2- (7-chloro-1-oxo-l, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[348]
[349] Step A: 3-Chloro-1,2-di-hydroxymethyl benzene
[350] Example 3, in a yield of 97% via borane reduction of 3-chlorophthalic acid, in a similar manner to the method used for the preparation of 3-fluoro-1,2-di-hydroxymethyl benzene described in step A). -Chloro-1,2-di-hydroxymethyl benzene was prepared. 3-chlorophthalic acid is described by Fertel, LB et al. J. Org. Chem. 58 (1), 261-263, 1993].
[351] Step B: 3-Chlorophthalic Acid Dicarboxaldehyde
[352] Of 3-chloro-1,2-di-hydroxymethyl benzene (prepared in step A) in a similar manner to that used for the preparation of 3-fluorophthalic acid dicarboxaldehyde described in Example 13, step B). 3-chlorophthalic acid dicarboxaldehyde was prepared via oxidation, and the product of this control was used in the next step without further purification.
[353] Step C: (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid and (S) -3-cyclohexyl-2 -(7-Chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid
[354] (S) -3cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid and (S) as described in Example 13, step C) In a similar manner to that used for the preparation of 3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid, (S)-(+ ) -α-aminocyclohexanepropionic acid hydrate is condensed with 3-chlorophthalic acid dicarboxaldehyde (prepared in step B) to give (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3 -Dihydro-isoindol-2-yl) -propionic acid and (S) -3-cyclohexyl-2- (7-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (Approximately 1: 1 mixture) was prepared.
[355] Step D: (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide and (S) -3-cyclohexyl-2- (7-chloro-1-oxo-l, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide
[356] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (approximately similar to the method used for preparing propionamide) A mixture of 1: 1 regioisomers, prepared in step C; 326 mg; 1.0 mmol) and 2-aminothiazole (231 mg; 2.23 mmol) were BOP coupled and chromatographed (Biotage 40M column, eluent: ethyl acetate Gradient from 5% to 30% of hexane) (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazole -2-yl-propionamide 132 mg: calcd for EI-HRMS m / e C ₂₀ H ₂₂ ClN ₃ O ₂ S (M ⁺ + Na ⁺ ) 426.1013, found 426.1016; And regioisomer (S) -3-cyclohexyl-2- (7-chloro-1-oxo-l, 3-dihydroisoindol-2-yl) -N-thiazol-2-yl-propionamide 91 mg : EI-HRMS m / e calcd for C ₂₀ H ₂₂ ClN ₃ O ₂ SNa (M ⁺ + Na ⁺ ) 426.1013, found 426.1017.
[357] Example 37
[358] 37.1. (S) -N- (5-Chloro-thiazol-2-yl) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydroisoindol-2-yl) -propion Amides and
[359] 37.2. (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (7-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)- Propionamide
[360]
[361] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (approximately similar to the method used for preparing propionamide) A mixture of 1: 1 regioisomers, prepared in Example 36, step C; 151 mg; 0.47 mmol) and 2-amino-5-chlorothiazole hydrochloride (186 mg; 1.05 mmol) were subjected to BOP coupling and chromatography ( Biotage 40M column, eluent: gradient from 5% to 20% of ethyl acetate / hexanes) (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (4- Chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide 67 mg: Calcd for EI-HRMS m / e C ₂₀ H ₂₁ Cl ₂ N ₃ O ₂ S (M ⁺ ) 437.0731, found 437.0727; And regioisomer (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (7-chloro-1-oxo-1,3-dihydro-isoindole-2- Il) -propionamide 46 mg: Calcd for EI-HRMS m / e C ₂₀ H ₂₁ Cl ₂ N ₃ O ₂ S (M ⁺ + Na ⁺ ) 437.0731, found 437.0726.
[362] Example 38
[363] 38.1. (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide and
[364] 38.2. (S) -3-cyclohexyl-2- (7-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide
[365]
[366] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (approximately similar to the method used for the preparation of propionamide) A mixture of 1: 1 regioisomers, prepared in Example 36, step C; 201 mg; 0.62 mmol) and 2-aminopyridine (132 mg; 1.39 mmol) were BOP coupled and chromatographed (Biotage 40S column, eluent). : 30% ethyl acetate / hexanes) to (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridine-2- 107 mg of mono-propionamide: calcd for EI-HRMS m / e C ₂₂ H ₂₄ C1N ₃ O ₂ (M ⁺ ) 397.1557, found 397.1563; And regioisomer (S) -3-cyclohexyl-2- (7-chloro-1-oxo-l, 3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide 46 mg : EI-HRMS m / e Calcd for ₂₂ H ₂₄ ClN ₃ O ₂ (M ⁺ ) 397.1557. Found 397.1551.
[367] Example 39
[368] 39.1. (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide and
[369] 39.2. (S) -3-cyclohexyl-2- (7-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide
[370]
[371] (S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl- as outlined in Example 9, step B) (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -propionic acid (approximately similar to the method used for preparing propionamide) A mixture of 1: 1 regioisomers, prepared in Example 36, step C; 243 mg; 0.76 mmol) and 2-aminopyrazine (170 mg; 1.77 mmol) were BOP coupled and chromatographed (Biotage 40M column, eluent). : 20% ethyl acetate / hexanes) to (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazine-2- Yl-propionamide 53 mg: calcd for EI-HRMS m / e C ₂₁ H ₂₃ ClN ₄ O ₂ (M ⁺ ) 398.1510, found 398.1520; And regioisomer (S) -3-cyclohexyl-2- (7-chloro-1-oxo-l, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide 41 mg : EI-HRMS m / e calcd for C ₂₁ H ₂₃ ClN ₄ O ₂ (M ⁺ ) 398.1510, found 398.1507.
[372] Biologically Active Examples
[373] All compounds of the present invention, including the compounds disclosed in the Examples, activated glucokinase in vitro by the procedure of the following biological activity test A. In this way, the compounds increase the flow rate of glucose metabolism which increases insulin secretion. Therefore, compounds of formula (I) are glucokinase activators useful for increasing insulin secretion.
[374] Biological Activity Example A: In Vitro Glucokinase Activity
[375] Glucokinase Activity: The production of glucose-6-phosphate from Leuconostoc mesenteroides as a coupling enzyme inhibits glucose-6-phosphate dehydrogenase (G6PDH, 0.75 to 1 k units / mg; Indiana, Indiana, USA). Glucokinase (GK) was analyzed by coupling to the production of NADH by Boehringer Mannheim, Poles (Scheme 4).
[376]
[377] Recombinant human liver GK1 is Lee. Expressed as Glutathione S-transferase fusion protein (GST-GK) (see Liang et al., 1995) in E. coli , a manufacturer-supplied procedure (Armer, Piscataway, NJ) Purified by chromatography on glutathione-sepharose 4B affinity column using Amersham Pharmacia Biotech. Previous studies have demonstrated that the enzymatic properties of native GK and GST-GK are essentially identical (see Liang et al., 1995 and Neat et al., 1990).
[378] Assays were performed in flat bottom 96-well tissue culture plates from Costar (Cambridge, Mass., USA) with a final culture volume of 120 μL at 25 ° C. Culture mixtures included: 25 mM Hepes buffer (pH 7.1), 25 mM KCl, 5 mM D-glucose, 1 mM ATP, 1.8 mM NAD, 2 mM MgCl ₂ , 1 μM Sorbitol-6-Phosphate, 1 mM Dithiotray Tall, test drug or 10% DMSO, 1.8 units / ml G6PDH and GK (see below). All organic reagents were more than 98% pure and were from Boehringer Mannheim, while D-glucose and Hepes were from Sigma Chemical Co., St. Louis, Missouri. Test compounds were dissolved in DMSO and added to a 12 μl volume of the culture mixture without GST-GK to give a final DMSO concentration of 10%. The mixture was pre-incubated for 10 minutes in a temperature control room of a SPECTRAmax 250 microplate spectrophotometer (Molecular Devices Corp., Sunnyvale, Calif.), Followed by temperature equilibration and then 20 μl. GST-GK was added to initiate the reaction.
[379] After enzyme addition, the absorbance (OD) increase at 340 nm was monitored over a 10 minute incubation period as a measure of GK activity. Sufficient GST-GK was added to increase OD ₃₄₀ by 0.08 to 0.1 units over a 10 minute incubation period in wells containing 10% DMSO but no test compound. Preliminary experiments confirmed that during this time the GK response was the primary reaction, even in the presence of an activator that produced a five-fold increase in GK activity. GK activity in control wells was compared to activity in wells containing test GK activators and the concentration of activator resulting in a 50% increase in GK activity, ie SC _1.5, was calculated.
[380] The compounds of the present invention described in the Synthesis Examples exhibited SC _1.5 of 30 μM or less except for the compound of Example 9, which exhibited SC _1.5 of 36 μM. These results indicate GK activator activity.
[381] References to Biologically Active Example A:
[382] Liang, Y., Kesavan, P., Wang, L., Niswender, K., Tanizawa, Y., Permut, MA, Magnuson, M. and Matschinsky, FM, Variable effects of maturity-onset-diabetes-of -youth (MODY) -associatedglucokinase mutations on the substrate interactions and stability of the enzyme, Biochem. J. 309 : 167-173, 1995; and
[383] See, K., Keenan, RP and Tippett, PS, Observation of a kinetic slow transition in monomeric glucokinase, Biochemistry 29 ; 770-777, 1990.
[384] Biological Activity Example B: In Vivo Activity
[385] In Vivo Glucokinase Activator Screening Protocol
[386] C57BL / 6J mice were orally administered a glucokinase (GK) activator at 50 mg / kg body weight by gavage following a 2 hour fasting period. Blood glucose was measured fivefold during the study period after six hours of administration.
[387] Mice (n = 6) were weighed and starved for 2 hours before oral treatment. The GK activator was combined with Gelucire vehicle at 6.76 mg / ml (Ethanol: Glusir 44/14: PEG400 Sufficient 4:66:30 (v / w / v)). Mice were administered orally at 7.5 μl combination / g body weight equivalent to a 50 mg / kg dose. Immediately prior to dosing, the animal's tail was cut out slightly (about 1 mm) and 15 μl of blood was collected in the analytical heparinized capillary tube to obtain a full dose (zero time) blood glucose reading. After administration of the GK activator, additional blood glucose readings were taken at the same tail wound at 1, 2, 4 and 6 hours after administration. The mean blood glucose values of the 6 vehicle treated mice were compared with the 6 GK activator treated mice over a 6 hour study period to analyze the results. The compound was considered active if it showed a statistically significant (p ≦ 0.05) decrease in blood glucose relative to the vehicle for a series of two assay points.
[388] The compounds of Examples 1, 18, 22, 23.1, 25.1, 26, 14, 15, 31 and 33 were tested and when administered orally according to the assay described in Biologically active Example B, these compounds exhibited excellent in vivo gluco It was found to have kinase activator activity.
[389] Example A
[390] Tablets comprising the following ingredients were prepared in conventional manner:
[391] ingredientMg / tablet Compound of formula (I)10.0-100.0 Lactose125.0 Corn starch75.0 talc4.0 Magnesium stearate1.0
[392] Example B
[393] Capsules containing the following ingredients were prepared in conventional manner:
[394] ingredientMg / capsules Compound of formula (I)25.0 Lactose150.0 Corn starch20.0 talc5.0

权利要求:
Claims (24)
[1" claim-type="Currently amended] Amide compounds of formula I, their pharmaceutically acceptable salts or N-oxides:
Formula I

Where
A is unsubstituted phenyl; Or phenyl monosubstituted or disubstituted, or monosubstituted with lower alkyl sulfonyl, lower alkyl thio or nitro;
R ¹ is cycloalkyl having 3 to 9 carbon atoms or lower alkyl having 2 to 4 carbon atoms;
R ² is an unsubstituted or monosubstituted 5 or 6 membered heteroaromatic ring linked by an amine group represented by a ring carbon atom, wherein the 5 or 6 membered heteroaromatic ring is 1 to 1 selected from the group consisting of sulfur, oxygen and nitrogen Comprising three heteroatoms, one heteroatom is a nitrogen adjacent to the linking ring carbon atom, which ring may be monocyclic or condensed with phenyl at two of the ring carbons, said monosubstituted heteroaromatic ring Halo, lower alkyl, nitro, cyano, perfluoro-lower alkyl, hydroxy,-(CH ₂ ) _n -OR ³ ,-(CH ₂ ) at positions of ring carbon atoms other than the ring carbon atoms adjacent to the linking carbon atom _n- C (O) -OR ³ ,-(CH ₂ ) _n -C (O) -NH-R ³ , -C (O) C (O) -OR ³ and-(CH ₂ ) _n -NHR ³ ( Wherein R ³ is hydrogen or lower alkyl; n is monosubstituted with a substituent selected from the group consisting of 0, 1, 2, 3 or 4.
[2" claim-type="Currently amended] The method of claim 1,
Amide or a pharmaceutically acceptable salt thereof.
[3" claim-type="Currently amended] The method of claim 2,
Phenyl unsubstituted by A; Or a substituent selected from the group consisting of fluoro, lower alkyl sulfonyl and lower alkyl thio at the 4 or 7 position, chloro at the 5 or 6 position, or chloro at the 5 and 6 position, or bromo or nitro at the 5 or 6 position; A compound that is phenyl which may be substituted.
[4" claim-type="Currently amended] The method according to any one of claims 1 to 3,
Wherein the amide is in the S configuration at the asymmetric carbon shown in the formula.
[5" claim-type="Currently amended] The method according to any one of claims 1, 2 and 4,
Phenyl unsubstituted by A; Or phenyl which may be mono- or di-substituted with halo, or mono-substituted with lower alkyl sulfonyl or nitro.
[6" claim-type="Currently amended] The method according to any one of claims 1, 2 and 4,
A is unsubstituted phenyl or monosubstituted phenyl.
[7" claim-type="Currently amended] The method according to any one of claims 1 to 6,
R ¹ is cycloalkyl having 3 to 9 carbon atoms.
[8" claim-type="Currently amended] The method according to any one of claims 1 to 6,
R ¹ is cyclopentyl or cyclohexyl.
[9" claim-type="Currently amended] The method according to any one of claims 1 to 8,
R ² is an unsubstituted or monosubstituted 5 or 6 membered heteroaromatic ring linked by an amine group represented by a ring carbon atom, wherein the 5 or 6 membered heteroaromatic ring is selected from the group consisting of sulfur, oxygen and nitrogen; Comprising two heteroatoms, one heteroatom being a nitrogen adjacent to the linking ring carbon atom, which is a monocyclic ring or condensed with phenyl at two of the ring carbons, said monosubstituted heteroaromatic ring being linked A compound monosubstituted with a substituent selected from the group consisting of halo and lower alkyl at positions on ring carbon atoms other than ring carbon atoms adjacent to the carbon atoms.
[10" claim-type="Currently amended] The method according to any one of claims 1 to 8,
In the group consisting of thiazolyl, quinolinyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, benzimidazolyl, benzothiazolyl and benzoxazolyl, wherein R ² may be monosubstituted with halo or lower alkyl And a heteroaromatic ring selected.
[11" claim-type="Currently amended] The method according to any one of claims 1 to 8,
R ² is a heteroaromatic ring selected from the group consisting of thiazolyl, pyrimidyl, pyrazinyl and pyridyl, which may be monosubstituted with halo or lower alkyl.
[12" claim-type="Currently amended] The method according to any one of claims 1 to 8,
Unsubstituted heteroaromatic ring wherein R ² is selected from the group consisting of thiazolyl, pyrimidyl, pyrazinyl and pyridyl; Or a monosubstituted heteroaromatic ring selected from thiazolyl substituted with chloro and pyridyl substituted with a substituent selected from the group consisting of chloro, bromo and lower alkyl.
[13" claim-type="Currently amended] The method of claim 1,
Phenyl unsubstituted by A; Or phenyl which may be mono- or di-substituted with halo, or mono-substituted with lower alkyl sulfonyl or nitro;
R ¹ is cycloalkyl having 5 to 8 carbon atoms;
R ² is an unsubstituted or monosubstituted 5 or 6 membered heteroaromatic ring linked by an amine group represented by a ring carbon atom, wherein the 5 or 6 membered heteroaromatic ring is selected from sulfur, oxygen and nitrogen. Wherein said heteroatom is condensed with phenyl at two of the ring carbons, said monosubstituted heteroaromatic ring being adjacent to the linking carbon atom; A compound mono-substituted with a substituent selected from the group consisting of halo and lower alkyl at positions on a ring carbon atom other than the ring carbon atom.
[14" claim-type="Currently amended] The method according to any one of claims 1 to 13,
(S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (7-chloro-1-oxo-l, 3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide,
(R) -N- (5-bromo-pyridin-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
(S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-5-chloro-pyridin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-4-methyl-pyridin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-5-methyl-pyridin-2-yl-propionamide,
3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide,
(S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide,
(S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide,
(S) -N-3-cyclohexyl-N- (2-methyl-pyrimidin-4-yl) -2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide ,
(S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
(R) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
(S) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
(S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
(S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
(S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
(S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
(S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
(S) -3-cyclohexyl-2- (5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
(S) -3-cyclohexyl-2- (6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
(S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
(S) -N- (5-bromo-thiazol-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
(S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl ) -Propionamide,
(S) -N- (5-bromo-thiazol-2-yl) -3-cyclohexyl-2- (5,6-dichloro-1-oxo-1,3-dihydroisoindol-2-yl ) -Propionamide,
(S) -N- (5-Chloro-thiazol-2-yl) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)- Propionamide,
(S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (7-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)- Propionamide,
(S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)- Propionamide,
(S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)- Propionamide,
(S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) Propionamide,
(S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) Propionamide,
(S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
(S) -3-cyclohexyl-N- (1H-imidazol-2-yl) -2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
3-cyclopentyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
N- (5-Chloro-thiazol-2-yl) -3-cyclopentyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
3-cycloheptyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
N- (5-Chloro-thiazol-2-yl) -3-cycloheptyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
3-cyclooctyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
(S) -N-benzothiazol-2-yl-3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
(S) -N- (1H-benzimidazol-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl-propionamide,
(S) -N-benzoxazol-2-yl-3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
(S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-quinolin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (7-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N- (1-oxy-pyridin-2-yl) -propionamide and
In the group consisting of (S) -3-cyclohexyl-2- (7-chloro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide Selected compound.
[15" claim-type="Currently amended] The method according to any one of claims 1 to 13,
3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide,
N- (5-Chloro-thiazol-2-yl) -3-cyclopentyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide,
(S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-5-chloro-pyridin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (4-fluoro-1-oxo-l, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
(S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide,
(S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide,
(S) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -N-5-methyl-pyridin-2-yl-propionamide and
Consisting of (R) -N- (5-bromo-pyridin-2-yl) -3-cyclohexyl-2- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide Compound selected from the group.
[16" claim-type="Currently amended] A pharmaceutical composition comprising the compound according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier and / or adjuvant.
[17" claim-type="Currently amended] 16. A process for the preparation of a pharmaceutical composition according to claim 16 comprising mixing a compound of formula (I) according to any one of claims 1 to 15 with a pharmaceutically acceptable carrier and / or adjuvant.
[18" claim-type="Currently amended] The method according to any one of claims 1 to 15,
Compounds for use as therapeutically active substances.
[19" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 15 for the treatment or prevention of type II diabetes.
[20" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 15 for the manufacture of a medicament for the treatment or prophylaxis of type II diabetes.
[21" claim-type="Currently amended] A method for preventing or treating type II diabetes, comprising administering a compound according to any one of claims 1 to 15 to a human or animal.
[22" claim-type="Currently amended] To a compound of formula 3 under conventional reaction conditions for the formation of an amide bond A process for the preparation of a compound according to any one of claims 1 to 15 comprising coupling with a suitable heteroaromatic amine of to obtain a compound of formula (I):

Formula I

In the above formulas,
*, A, R ¹ and R ² are as defined in claim 1.
[23" claim-type="Currently amended] A compound prepared by the process according to claim 22.
[24" claim-type="Currently amended] Invention as defined herein.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-12-13|Priority to US25527300P

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2000-12-13|Priority to US60/255,273

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2001-09-13|Priority to US31871501P

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2001-09-13|Priority to US60/318,715

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2001-12-07|Application filed by 에프. 호프만-라 로슈 아게

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2001-12-07|Priority to PCT/EP2001/014404

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2003-08-02|Publication of KR20030064817A

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2005-10-11|Application granted

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2005-10-11|Publication of KR100520651B1

优先权:

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申请号 | 申请日 | 专利标题

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US25527300P| true| 2000-12-13|2000-12-13|

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US60/255,273|2000-12-13|

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US31871501P| true| 2001-09-13|2001-09-13|

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US60/318,715|2001-09-13|

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PCT/EP2001/014404|WO2002048106A2|2000-12-13|2001-12-07|Isoindolin-1-one glucokinase activators|