HK1063314B

HK1063314B - Isoindolin-1-one glucokinase activators

Info

Publication number: HK1063314B
Application number: HK04106031.4A
Authority: HK
Inventors: 凯文．理查德．格廷
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2000-12-13
Filing date: 2001-12-07
Publication date: 2006-10-06

Description

Isoindolin-1-one glucokinase activators

Glucokinase (GK) is one of The four hexokinases found in mammals [ colwick, s.p., The Enzymes, vol.9(p.boyer eds.) Academic Press, New York, NY, pages 1-48, 1973 ]. Hexokinase catalyzes the first step in glucose metabolism, the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, which is found primarily in pancreatic beta-cells and hepatic parenchymal cells. Furthermore, GK is the rate-limiting enzyme for glucose metabolism in these two cell types, which have been reported to play an important role in the homeostasis of glucose in the whole body [ Chipkin, s.r., Kelly, k.l., and Ruderman, n.b. job's diabetes (c.r.khan, and g.c. wier editions), Lea and Febiger, philiadelphia, PA, pp 97-115, 1994 ]. At half the time when GK showed the highest activity, the concentration of glucose was approximately 8 mM. While at very low concentrations (< 1mM) the other three hexokinases are saturated. Thus, when eating a carbohydrate-containing meal, as the blood glucose concentration increases from fasting (5mM) to postprandial (approximately equal to 10-15mM) levels, the glucose flux through the GK pathway increases [ Printz, r.g., Magnuson, m.a., and Granner, d.k., afzn.rev.nutrition vol.13(r.e.olson, d.m.bier, and d.b.mccormick editors), Annual Review, inc. These findings benefit from the assumption 10 years ago: GK functions as a glucose sensor in β -cells and hepatocytes (Meglasson, m.d. and matchshinsky, f.m.amer. journal of physiology (j. physiol.)246, E1-E13, 1984). In recent years, studies in transgenic animals have demonstrated that GK does play a critical role in glucose homeostasis throughout the body. Animals that do not express GK die within a few days of birth from severe diabetes, while animals that overexpress GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al, Cell (Cell)83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al, FASEB J., 10, 1213. cake 1218, 1996). The increase in glucose exposure is coupled to increased insulin secretion by GK in beta cells, increased glycogen deposition and perhaps decreased glucose production by GK in liver parenchymal cells.

Type II juvenile maturity onset diabetes mellitus (MODY-2) was found to be caused by loss of function following mutation of the GK gene, suggesting that GK also functions as a glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L., et al, J. Biochem. J., 309, 167-. Further evidence is provided to support the important role of GK in the regulation of glucose metabolism in humans by identifying patients expressing mutant GK with increased enzymatic activity. These patients exhibit fasting hypoglycemia associated with abnormally elevated plasma insulin levels (Glaser, b., Kesavan, p., Heyman, m. et al, New England j. med.338, 226-. Although no mutation in the GK gene is found in most type II diabetic patients, compounds that activate GK and thereby increase the sensitivity of the GK sensor system are still used to treat the hyperglycemic symptoms of all type II diabetes. Glucokinase activators increase the flux of glucose metabolism in beta-cells and hepatocytes, which is accompanied by increased insulin secretion. These drugs will be used to treat type II diabetes.

The present invention provides a compound comprising an amide of the formula:

wherein A is unsubstituted phenyl, or phenyl mono-or di-substituted with halogen, or phenyl mono-substituted with lower alkylsulfonyl, lower alkylthio or nitro;

R¹is cycloalkyl having 3 to 9 carbon atoms or lower alkyl having 2 to 4 carbon atoms;

R²an unsubstituted or monosubstituted five-or six-membered heteroaromatic ring which is attached to the indicated amine group through a ring carbon atom, which five-or six-membered heteroaromatic ring contains 1 to 3 heteroatoms selected from sulfur, nitrogen and oxygen, one of which is nitrogen, which is adjacent to the attached ring carbon atom, which ring may be monocyclic or fused on two of its ring carbon atoms with a phenyl group, said monosubstituted heteroaromatic ring being monosubstituted at a position of the ring carbon atom which is not adjacent to the attached carbon atom with a substituent selected from: halogen, lower alkyl, nitro, cyano, perfluoro-lower alkyl; hydroxy, - (CH)₂)_n-OR³，-(CH₂)_n-C(O)-OR³，-(CH₂)_n-C(O)-NH-R³，-C(O)C(O)-OR³Or is- (CH)₂)_n-NHR³(ii) a Wherein R is³Is hydrogen or lower alkyl; n is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt or N-oxide thereof.

R²Preferably a five-or six-membered heteroaromatic ring which is linked via a ring carbon atom to the amine group shown in formula I, which five-or six-membered heteroaromatic ring contains 1 to 3 heteroatoms selected from sulfur, oxygen and nitrogen, one of whichOne heteroatom is nitrogen, which is adjacent to the attached ring carbon atom. The ring may be monocyclic or fused to a phenyl group at two ring carbon atoms. According to one embodiment of the invention, adjacent nitrogens in the nitrogen-containing heteroaromatic ring may form N-oxides, wherein the nitrogens adjacent to the ring carbon atoms are converted to N-oxides. In another aspect, the compounds of formula I may form pharmaceutically acceptable salts.

It has been found that the compounds of formula I activate glucokinase in vitro. Glucokinase activators are used to increase insulin secretion in the treatment of type II diabetes.

The invention also relates to pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier and/or adjuvant. In addition, the invention relates to the use of these compounds as therapeutically active substances and to their use for the preparation of medicaments for the treatment or prophylaxis of type II diabetes. The invention also relates to a preparation method of the compound shown in the formula I. Furthermore, the present invention relates to a method for the prevention or treatment of type II diabetes, comprising administering a compound of formula I to a human being or animal.

More specifically, the present invention provides a compound comprising an amide of formula I as described above or an N-oxide of an amide of formula I as described above, as well as pharmaceutically acceptable salts thereof.

In the compounds of formula I, "-" denotes an asymmetric carbon atom in the compound. The compounds of formula I may be presented as racemates on the asymmetric carbon atoms indicated. However, the amide is preferably the "S" enantiomer with the "S" configuration at the asymmetric carbon atom. When the phenyl ring A is mono-substituted with lower alkylsulfonyl, nitro or lower alkylthio, it is preferably substituted at the 5-or 6-position as shown in formula I. Thus, when A is nitro substituted phenyl, it is preferred that the substitution is at the 5 or 6 position, for example 5-nitrophenyl and 6-nitrophenyl.

In one embodiment of formula I, R as described above²The rings are single, or monocyclic (unfused rings). When R is²When monocyclic, substituted or unsubstituted pyridines are preferred. In another embodiment of formula I, R as described above²The ring is bicyclic, i.e., fused to a phenyl group.

The term "lower alkyl" as used throughout this application includes straight and branched chain alkyl groups having 1 to 10, preferably 3 to 9 carbon atoms, especially 2 to 4 carbon atoms, such as propyl, isopropyl, heptyl.

The term "cycloalkyl" as used herein refers to a 3-to 9-membered cycloalkyl ring, preferably a 5-to 8-membered cycloalkyl ring, such as cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

As used herein, "perfluoro-lower alkyl" refers to any lower alkyl group wherein all hydrogens of the lower alkyl group are substituted or replaced with fluorine. Preferred perfluoro-lower alkyl groups are trifluoromethyl, pentafluoroethyl, heptafluoropropyl, and the like.

"lower alkylthio" as used herein refers to a lower alkyl group, as defined above, which is attached to the remainder of the molecule through the sulfur atom of the thio group.

As used herein, "lower alkylsulfonyl" refers to a lower alkyl group, as defined above, which is bonded to the remainder of the molecule through the sulfur atom in the sulfonyl group.

The term "halogen" as used herein is used interchangeably with "halo" and, unless otherwise indicated, denotes all four halogens, i.e., fluorine, chlorine, bromine and iodine.

The term "N-oxide" as used herein refers to a negatively charged oxygen atom that is covalently attached to a positively charged nitrogen atom in a heteroaromatic ring.

As used herein, "heteroaryl ring" refers to a five or six membered unsaturated carbocyclic ring (carbaciclic ring) in which one or more carbons are replaced by a heteroatom such as oxygen, nitrogen or sulfur. The heteroaromatic ring may be monocyclic or bicyclic, i.e., formed by the fusion of two rings.

R²The heteroaromatic ring as defined may be an unsubstituted or monosubstituted, five-or six-membered heteroaromatic ring having from 1 to 3 heteroatoms selected from sulfur, nitrogen and oxygen, which is bonded via a ring carbon atom to the amide group shownTo the amine group of (a). Wherein at least one heteroatom is nitrogen, which is adjacent to the attached ring carbon atom. The other heteroatom, if present, may be sulfur, oxygen or nitrogen. R²The defined ring may be a single ring. Such heteroaryl rings include, for example, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, and imidazolyl. R²The defined ring may be bicyclic, i.e., may be fused to a phenyl group at two of its free ring carbon atoms. Examples of such rings are benzimidazolyl, benzothiazolyl, quinolynyl, benzoxazolyl, and the like. R²The defined ring is attached to the amide group via a ring carbon atom to form an amide of formula I. The ring carbon atoms in the heteroaromatic ring that are attached via an amide to form a compound of formula I cannot contain any substituents. When R is²In the case of unsubstituted or mono-substituted five-membered heteroaromatic rings, preferred rings are those in which the nitrogen heteroatom is adjacent to the attached ring carbon atom and the second heteroatom is adjacent to the attached ring carbon atom.

As used herein, -C (O) OR³RepresentsAnd the like.

The term "pharmaceutically acceptable salt" as used herein includes any salt formed with inorganic or organic pharmaceutically acceptable acids, 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, p-toluenesulfonic acid and the like. The term "pharmaceutically acceptable salt" also includes any pharmaceutically acceptable base salt, such as amine salts, trialkylamine salts, and the like. These salts can be readily formed by one of ordinary skill in the art using standard techniques.

Prodrugs of compounds of formula I are also part of the invention. Prodrugs refer to metabolic precursors of a drug that degrade into the drug and acceptable by-products when administered to a patient. The compounds of the present invention may be prepared as any conventional prodrug. One particular prodrug of the present invention is the above-described N-oxide. Each of the compounds of the present invention generally gives prodrugs.

During the reactions provided in the reaction schemes and discussion that follow, multiple functional groups, such as free carboxylic acid or hydroxyl groups, may be protected by hydrolyzable conventional ester or ether protecting groups. The term "hydrolyzable ester or ether protecting group" as used herein refers to any ester or ether conventionally used to protect carboxylic acids or alcohols, which can hydrolyze to produce hydroxyl or carboxyl groups, respectively. Examples of ester groups useful for this purpose are those where the acyl moiety is derived from a lower alkane, aryl lower alkane, or lower alkane dicarboxylic acid. Among the activated acids that may be used to form these groups are acid anhydrides, acid halides, preferably acid chlorides or acid bromides derived from aryl or lower alkanoic acids. Examples of anhydrides are anhydrides derived from monocarboxylic acids, such as acetic anhydride, benzoic anhydride, and lower alkanedicarboxylic anhydrides, such as succinic anhydride, and chloroformates, such as preferably trichloro, ethyl chloroformate. 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, such as benzyl, benzhydryl or trityl ethers or α -lower alkoxy lower alkyl ethers, for example, methoxymethyl or allyl ethers or alkylsilyl ethers, such as trimethylsilyl ether.

Likewise, the term "amino protecting group" refers to any conventional amino protecting group that can be cleaved to yield a free amino group. Preferred protecting groups are conventional amino protecting groups used in peptide synthesis. Particularly preferred are those amino protecting groups that are cleavable under moderately acidic conditions at a pH of 2.0-3. Particularly preferred amino protecting groups are t-Butylcarbamate (BOC), benzylcarbamate (CBZ), and 9-Fluorenylmethylcarbamate (FMOC).

In preferred compounds of formula I, R¹Is cycloalkyl having 5 to 8 carbon atoms, R²Is an unsubstituted or mono-substituted five-or six-membered heteroaromatic ring which is linked to the indicated amine group via a ring carbon atom and which contains 1 to 2 heteroatoms selected from sulfur, oxygen and nitrogen, one of which is nitrogen and which is adjacent to the linked ring carbon atom, which ring may be monocyclic or fused on two of its ring carbon atoms to a phenyl groupAnd (c) mono-substituted heteroaryl ring is mono-substituted at a position on a ring carbon atom not adjacent to the linking carbon atom with a substituent selected from halogen or lower alkyl (formula AB). In formula AB the R²May be a monocyclic ring (formula A) or may be a bicyclic ring (formula B) formed by fusion with a phenyl group. In the compound of formula A, R²Particularly preferred are substituted or unsubstituted pyridines. Also preferred is R¹Is cyclohexyl. Phenyl A is preferably unsubstituted.

In a preferred compound of formula I, R¹Is cyclohexyl, R²Is a monocyclic ring (formula A-1). In the compounds of formula A-1, preferably phenyl A is unsubstituted. Particular preference is given to R²Is substituted or unsubstituted pyridine.

In one embodiment of formula A-1, R²Is unsubstituted pyridine, and in another embodiment, R²Is a mono-substituted pyridine. The substituents are preferably halogen, such as bromine, fluorine or chlorine, or lower alkyl, such as methyl.

In one embodiment of formula A-1, R²Is a mono-substituted pyrimidine. The substituents are preferably lower alkyl groups such as methyl, phenyl A being unsubstituted. R of the formula A-1²Also unsubstituted pyrimidines. Preferably, phenyl A is unsubstituted or substituted in the 4 or 7 position by lower alkylsulfonyl.

In one embodiment of formula A-1, R²Is unsubstituted thiazole. In preferred such compounds a is unsubstituted phenyl, or phenyl substituted in the 5 and 6 positions by chloro, or phenyl substituted in the 5 or 6 position by nitro, or phenyl substituted in the 4 or 7 position by halogen or lower alkylsulfonyl.

In one embodiment of formula A-1, R²Is a mono-substituted thiazole. Preferably the substituents are halogen, a is unsubstituted phenyl, or phenyl substituted in the 5 and 6 positions by chlorine, or phenyl substituted in the 5 or 6 position by nitro, or phenyl substituted in the 4 or 7 position by halogen or lower alkylsulfonyl.

In one embodiment of formula A-1In, R²Is unsubstituted pyrazine. A is preferably unsubstituted phenyl, or phenyl substituted in the 4 or 7 position by halogen or lower alkylsulfonyl.

At R¹Is cyclohexyl and R²In one embodiment of formula A-1, which is monocyclic, R²Is unsubstituted imidazole, and phenyl and A are preferably unsubstituted phenyl.

In another embodiment of formula I or formula A, phenyl A is unsubstituted, R is²Is a monocyclic ring, preferably R²Is substituted or unsubstituted thiazole (formula A-2). In some compounds of formula A-2, R¹Is cyclopentyl, other R¹Being cycloheptyl, some further R¹Is a cyclooctyl group.

In a preferred class of compounds of formula I, R²Is a bicyclic heteroaromatic ring fused at two ring carbon atoms thereof to a phenyl group, R¹Is cyclohexyl (formula B-1). In the compounds of formula B-1, preferably phenyl A is unsubstituted. Further preferred is R²Is benzothiazole, benzimidazole, benzoxazole, or quinoline, preferably all unsubstituted.

In a preferred embodiment of the invention a is unsubstituted phenyl, or phenyl substituted in the 4 or 7 position by fluoro, lower alkylsulfonyl or lower alkylthio, or phenyl substituted in the 5 or 6 position or in the 5 and 6 positions by chloro, or phenyl substituted in the 5 or 6 position by bromo or nitro. In another preferred embodiment, a is unsubstituted phenyl, or phenyl mono-or di-substituted with halogen, or phenyl mono-substituted with lower alkylsulfonyl or nitro. Most preferably, A is unsubstituted phenyl, or phenyl monosubstituted by halogen, preferably by fluorine.

In a preferred embodiment of the invention, R¹Are cycloalkyl radicals having 3 to 9, preferably 5 to 8, carbon atoms. Most preferred is R¹Is cyclopentyl or cyclohexyl.

In a preferred embodiment of the invention, R²Is an unsubstituted or mono-substituted five-or six-membered heteroaromatic ring, process for its preparationA five-or six-membered heteroaromatic ring containing 1 to 2 heteroatoms selected from sulfur, oxygen or nitrogen, one of which is nitrogen, which is adjacent to the attached ring carbon atom, which ring is monocyclic, or is fused at two of its ring carbon atoms to a phenyl group, said monosubstituted heteroaromatic ring being monosubstituted at the position of the ring carbon atom not adjacent to said attached carbon atom with a substituent selected from halogen or lower alkyl. In another preferred embodiment, R²Is selected from thiazolyl, quinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, benzimidazolyl, benzothiazolyl or benzoxazolyl, said heteroaromatic ring being optionally mono-substituted with halogen, preferably bromine or chlorine, or lower alkyl, preferably methyl. More preferably a residue R²Selected from thiazolyl, pyrimidinyl, pyrazinyl, pyridyl, said heteroaromatic ring being optionally mono-substituted by halogen, preferably bromo or chloro, or lower alkyl, preferably methyl. Most preferred is residue R²Is an unsubstituted heteroaromatic ring selected from thiazolyl, pyrimidinyl, pyrazinyl or pyridinyl, or a monosubstituted heteroaromatic ring selected from thiazolyl substituted with chlorine, or chlorine, bromine or lower alkyl, preferably pyridinyl substituted with methyl.

Preferred compounds of the invention are selected from the group consisting of:

(S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyridin-2-ylpropanamide,

(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-ylpropanamide,

(S) -3-cyclohexyl-2- (4-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyridin-2-ylpropanamide,

(S) -3-cyclohexyl-2- (7-chloro-1-oxo-1, 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-ylpropanamide,

3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrimidin-4-ylpropanamide,

(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-ylpropanamide,

(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-dihydro-isoindol-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-ylpropanamide,

(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) propanamide,

(S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-quinolin-2-ylpropanamide,

(S) -3-cyclohexyl-2- (7-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-ylpropanamide,

(S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N- (1-oxy-pyridin-2-yl) -propionamide, and

(S) -3-cyclohexyl-2- (7-chloro-1-oxo-1, 3 dihydro-isoindol-2-yl) -N-thiazol-2-ylpropanamide.

Most preferred compounds of the invention are selected from the group consisting of:

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-ylpropanamide,

(S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-ylpropanamide,

(S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-ylpropanamide,

(S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-5-methyl-pyridin-2-yl-propionamide, and

(R) -N- (5-bromo-pyridin-2-yl) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide.

The compounds of the present invention may be prepared by the following reaction scheme, wherein phenyl A, R¹，R²And R³As described in formula I.

Reaction scheme

Reaction scheme 1

Reaction scheme 2

Ra-halogen, Rb-H or halogen

Ra ═ nitro, Rb ═ H

Ra ═ lower alkylthio, lower alkylsulfonyl, Rb ═ H

Reaction scheme 3

The compounds of the invention can be obtained by reacting a substituted o-phenylene dialdehyde 1 or 1 ' with an amino acid derivative 2 or 2 ' in a suitable solvent, for example acetonitrile, to give a carboxylic acid derivative 3 or 3 '. 3 or 3' can then be reacted with the appropriate heteroaromatic amine H under the customary reaction conditions for amide bond formation to give compounds of the formula I₂N-R²And (3) coupling.

Compounds of formula I wherein phenyl A is substituted with halogen (derived from halophthalic acid) or nitro are obtained as described in scheme 2, supra, wherein 4 is a suitable commercially available substituted phthalic acid. Substituted o-phenylene dialdehydes 1 or 1 'can be prepared by reducing phthalic acid 4 to a diol intermediate, which is then oxidized to give 1'.

Compounds of formula I wherein phenyl a is substituted by lower alkylsulfonyl can be prepared starting from phthalic acid wherein Ra is fluorine and Rb is hydrogen, by the following multi-step reaction:

a) conversion to the corresponding dimethyl ester with sulfuric acid in methanol;

b) nucleophilic displacement of fluorine with sodium thiomethoxide in a suitable solvent such as dimethylsulfoxide to give 4 wherein Ra is lower alkylthio;

c) reducing the resulting phthalic acid 4, wherein Ra is lower alkylthio, to give a diol, which is then oxidized to the corresponding o-phenylene dialdehyde 1, wherein Ra is lower alkylthio;

d) reacting ortho-phenylene dialdehyde 1 wherein Ra is lower alkylthio with amino acid 2 in refluxing acetonitrile to give lower alkylthio, a mixture of lower alkylthio carboxylic acid isomers 3; and

e) and H₂N-R²Coupling to form a compound of formula I wherein Ra is lower alkylthio.

Compounds of formula I wherein Ra is lower alkylsulfonyl and Rb is hydrogen may be obtained by first oxidizing the lower alkyl isomer of step (d) above with hydrogen peroxide to form a lower alkylsulfonylcarboxylic acid of formula 3 (Ra is lower alkylsulfonyl and Rb is hydrogen), and then reacting the resulting carboxylic acid of formula 3 with H₂N-R²Coupling to give a compound of formula I wherein Ra is lower alkylsulfonyl.

R¹Is C₃-C₉Cycloalkyl or C₂-C₄Alkyl (R type, S type)Or racemic form) of a compound of formula I, wherein 2 or 2' is an appropriate commercially available amino acid. Amino acids 2 or 2' can also be obtained from 5 according to scheme 3.5 prepared according to the literature methods (see O' Donnell, M.J.; Polt, R.L.J.org.chem.1982, 47, 2663-2666), 5 can be reacted under basic conditions with the appropriate reagents having the desired R¹The alkyl halide reagent reacts, and any amino acid 2 is obtained after acid hydrolysis. The haloalkane reagents are commercially available or can be prepared by conventional methods.

Under the conventional conditions for reacting amines with acids, wherein R²The compounds of formula I, which are described in formula I, can be obtained by 3 or 3' coupling of the desired heteroaromatic amine, which is commercially available or can be prepared by conventional methods, with a carboxylic acid derivative. The N-oxide of a heteroaromatic amine (e.g., 2-aminopyridine-N-oxide) can be coupled to 3 or 3' or the unsubstituted R can be oxidized by known methods to obtain the N-oxide²The corresponding compounds of formula I can be obtained from the ring.

If it is desired to produce the R or S isomers of the compounds of formula I, these compounds can be resolved into their isomers using conventional physical or chemical methods. One physical method for resolution involves separation of the partner pairs of the compound of formula I with a high performance liquid chromatography device equipped with a column packed with a chiral reagent. The preferred chemistry is to react the intermediate carboxylic acid 3 or 3' with an optically active base. Any conventional optically active base can be used to perform the resolution. Among the preferred optically active bases are optically active amine bases such as alpha-methylbenzylamine, quinine, dehydroabietylamine, and alpha-methylnaphthylamine. Any conventional technique for resolving organic acids using optically active organic amine bases can be used to carry out the reaction.

In the resolution step, 3 or 3 'is reacted with an optically active base in an inert organic solvent medium to produce a salt of the optically active amine of 3 or 3' with two R and S isomers. In forming these salts, temperature and pressure are not critical, and the salt formation can be carried out at room temperature and atmospheric pressure. The R and S salts may be separated by conventional methods such as fractional crystallization. After crystallization, each salt can be converted to 3 or 3' with R and S configurations, respectively, by acid hydrolysis. Preferred acids are dilute aqueous acids, i.e., from about 0.001N to 2N aqueous acid, such as aqueous sulfuric acid or aqueous hydrochloric acid. The 3 or 3' configuration prepared by this resolution method can be used throughout the reaction scheme to prepare the desired R or S isomer of formula I or II. The separation of the R and S isomers can also be obtained by enzymatic ester hydrolysis of any lower alkyl ester derivative of 3 or 3' (see e.g. Ahmar, M.; Girard, C.; Bloch, R, Tetrahedron Lett, 1989, 7053), which results in the formation of the corresponding chiral acid and chiral ester. The ester and acid are separated by conventional methods for separating the acid from the ester. Another preferred method of resolution of the racemate of compound 3 or 3' is by formation of the corresponding diastereomeric ester or amide. These diastereomeric esters or amides can be prepared by coupling a 3 or 3' carboxylic acid with a chiral alcohol or a chiral amine. The reaction can be carried out by conventional coupling methods of carboxylic acids with alcohols or amines. The corresponding diastereoisomers of the 3 or 3' carboxylic acid derivatives may then be separated using any conventional method, for example HPLC. The resulting pure diastereomeric esters or amides can then be hydrolyzed to yield the corresponding pure R or S isomers. The hydrolysis reaction can be carried out by a conventionally known method of hydrolyzing an ester or amide without racemization.

The compounds of formula I above may be used as medicaments for the treatment of type II diabetes, depending on their ability to activate glucokinase. Thus, as mentioned above, medicaments containing a compound of formula I are also an object of the present invention, as well as a process for the preparation of such medicaments, which comprises bringing one or more compounds of formula I and, if desired, one or more other therapeutically valuable substances into a galenical administration form, for example by combining a compound of formula I with pharmaceutically acceptable carriers and/or adjuvants.

The pharmaceutical compositions can be administered orally, for example in the form of tablets, coated tablets, dragees, hard or soft gelatine capsules, solutions, emulsions or suspensions. Administration can also be effected rectally, e.g., using suppositories; topical or transdermal administration, for example using ointments, creams, gels or solutions; or parenterally, e.g., intravenously, intramuscularly, subcutaneously, intrathecally, or transdermally, using injectable solutions. Also, administration may be sublingual or as an aerosol, e.g., spray. For the preparation of tablets, coated tablets, dragees, hard gelatin capsules, the compounds of the present invention may be mixed with pharmaceutically inert, organic or inorganic excipients. Examples of suitable excipients for tablets, coated tablets, dragees, hard gelatine capsules include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof. Suitable excipients for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols and the like; however, depending on the nature of the active ingredient, there may be cases where the soft gelatin capsule does not require any excipients at all. For the preparation of solutions and syrups, excipients which may be used include, for example, water, polyols, sugars, invert sugar and glucose. For the preparation of injectable solutions, excipients which may be used include, for example, water, alcohols, polyols, glycerol, and vegetable oils. For the preparation of suppositories and for topical or transdermal administration, excipients which may be used include, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols. The pharmaceutical compositions may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. As mentioned above, they may also contain other therapeutically valuable active agents. It is a prerequisite that all adjuvants used in the preparation of the formulation are non-toxic.

Preferred dosage forms for use are intravenous, intramuscular or oral administration, most preferably oral administration. The effective dose of the compound of formula I to be administered will depend on the nature of the particular active ingredient, the age and requirements of the patient and the mode of administration. In general, dosages of about 1-100mg/kg body weight/day are contemplated.

The invention will be better understood from the following examples, which are intended for the purpose of illustration and are not intended to limit the invention as defined by the appended claims.

Synthetic examples

Example 1(S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

Step A: (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid

A mixture of (S) - (+) - α -aminocyclohexanepropionic acid hydrate (5.00 g; 29.2mmol) and o-phthalaldehyde (o-phthalaldehyde) (4.21 g; 31.3mmol) was refluxed under nitrogen pressure in acetonitrile (120mL) for 20 h. The mixture was cooled to room temperature and further cooled to 0 ℃. The solid was filtered off and washed once with cold acetonitrile (50mL) to give 6.54g (78%) of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydroisoindol-2-yl) -propionic acid as a white solid: EI-HRMS m/e C₁₇H₂₁NO₃(M⁺) Calculated value of 287.1521, actual value of 287.1521.

And B: (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

To a solution of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in step A, 286 mg; 1.0mmol), O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate (BOP, 500 mg; 1.1mmol) and 2-aminothiazole (125 mg; 1.2mmol) in anhydrous dichloromethane (10mL) was added N, N-diisopropylethylamine (0.55 mL; 3.1mmol) dropwise at 0 ℃. The mixture was warmed to room temperature and stirred overnight. The mixture was then partitioned with water, the organic layer washed with brine, dried (MgSO₄) Filtered and concentrated in vacuo to give a crude residue. Flash chromatography (Biotage 40S; eluent: 3% methanol/dichloromethane) afforded 325mg (75%) of (S) -3-cyclohexyl 2- (1-oxo-1, 3-dihydro-isoindole) as a light brown foam-2-yl) -N-thiazol-2-yl-propionamide: EI-HRMS m/e C₂₀H₂₃N₃O₂S(M⁺) Calculated value of 369.1511, actual value of 369.1513.

Example 2(S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) propionamide

This compound was prepared in analogy to the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydroisoindol-2-yl) -N-thiazol-2-yl-propionamide described in example 1, step B by coupling via BOP (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in example 1, step A; 120 mg; 0.42mmol) and 2-amino-5-chlorothiazole hydrochloride (90 mg; 0.51mmol) to give N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (1-oxo-1) as white solid, 3-dihydro-isoindol-2-yl) propionamide, yield 59%: EI-HRMS m/eC₂₀H₂₂ClN₃O₂S(M⁺) Calculated value of 403.1121, actual value of 403.1124.

Example 3(S) -N- (5-bromo-thiazol-2-yl) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) propionamide

To a suspension of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (prepared in example 1; 21 mg; 0.06mmol) and N-bromosuccinimide (11 mg; 0.06mmol) in anhydrous carbon tetrachloride (1.0mL) was added benzoyl peroxide (1 mg; 0.004 mmol). The mixture was stirred in a sealed tube at 95 ℃. After 1.5h, N-bromosuccinimide (2mg) and benzoyl peroxide (1mg) were added and the mixture was stirred for 30 min. The mixture was then cooled to room temperature and the solvent removed in vacuo. Removing residuesThe residue was taken up in ethyl acetate and washed with water. The organic extract phase 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/hexane) to give 15mg (58%) of N- (5-bromo-thiazol-2-yl) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) propionamide as a gray foam: EI-HRMS m/e C₂₀H₂₃BrN₃O₂S(M⁺) Calculated value of 447.0616, actual value of 447.0623.

Example 4(S) -3-cyclohexyl-2- (5, 6-dichloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-ylpropanamide

Step A: 4, 5-dichloro-1, 2-di-hydroxytoluene

To a stirred solution of borane tetrahydrofuran complex (45mL of a 1.5M solution in tetrahydrofuran/diethyl ether) cooled to 0 deg.C under a nitrogen atmosphere was added dropwise a solution of 4, 5-dichlorophthalic acid (5.013 g; 21.1mmol) in tetrahydrofuran (35mL) over 20 minutes. After the addition was complete, the mixture was stirred at 0 ℃ for 2.5 h. The mixture was quenched by slowly adding methanol until gas evolution ceased. The mixture was stirred at room temperature for 30 minutes and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with saturated sodium bicarbonate solution and then with brine solution. The organic extract phase was dried (sodium sulfate), filtered and concentrated in vacuo to give 4.41g (100%) of 4, 5-dichloro-1, 2-di-hydroxytoluene as a white solid: ES-LRMS C₈H₇Cl₂O₂(M⁺-1) has a calculated value of 205 and an actual value of 205.

And B: 4, 5-Dichlorophthalic-1, 2-dicarbaldehyde (4, 5-dichlorphthalic-1, 2-dicarbaxaldehydes)

To a stirred solution of oxalyl chloride (2.6 mL; 29.2mmol) in anhydrous dichloromethane (35mL) under nitrogen at-78 deg.C was added dimethyl sulfoxide dropwise(4.2 mL; 59.1mmol) in dichloromethane (10 mL). The solution was stirred for 10 minutes and then a solution of 4, 5-dichloro-1, 2-di-hydroxytoluene (2.50 g; 12.1mmol) dissolved in 16mL of 1: 1 dichloromethane/dimethyl sulfoxide was added dropwise. The resulting mixture was stirred at-78 ℃ for 2 h. Triethylamine (30 mL; 17.6mmol) was added slowly over 15 minutes and the mixture was allowed to warm to room temperature for 2 h. The mixture was diluted with ice water (150mL) and extracted with dichloromethane. The extract was washed with 1N HCI, dried over sodium sulfate and concentrated to give 2.58g of 4, 5-dichlorophthalaldehyde-1, 2-dicarbaldehyde as a yellow solid: ES-LRMS C₈H₃O₂(M⁺-1) the calculated value is 201 and the actual value is 201.

And C: (S) -3-cyclohexyl-2- (5, 6-dichloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid

A mixture of (S) - (+) - α -aminocyclohexanepropionic acid hydrate (1.05 g; 5.83mmol) and 4, 5-dichlorophthalaldehyde (prepared in step B; 1.25 g; 5.86mmol) in acetonitrile (35mL) was refluxed under argon for 72 h. The mixture was then allowed to cool and stand at room temperature for 2 h. The solid was filtered off and washed once with cold acetonitrile to give 1.33g (64%) of (S) -3-cyclohexyl-2 (5, 6-dichloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid as a light brown solid: EI-HRMS m/e C₁₇H₁₉Cl₂NO₃(M⁺) Calculated value of 355.0742, actual value of 355.0747.

Step D: (S) -3-cyclohexyl-2- (5, 6-dichloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

Following a procedure analogous to that for the preparation of (S) -3 cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 1, described in step B), coupling via BOP (S) -3-cyclohexyl-2- (5, 6-dichloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in step C; 248 mg; 0.70mmol) and 2-aminothiazole (91 mg; 0.88mmol) gave (S) -3-cyclohexyl-2- (5, 6-dichloro-1-oxo-1, 3-dihydroisoindol-2-yl) -N-thiazole-2-yl- Mesityl-propionamide, yield 35%: EI-HRMS m/eC₂₀H₂₁Cl₂N₃O₂S(M⁺) Calculated value of 437.0731, actual value of 437.0725.

Example 5(S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (5, 6-dichloro-1-oxo-1, 3-dihydroisoindol-2-yl) -propionamide

Preparation of this compound (S) -3-cyclohexyl-2- (5, 6-dichloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (prepared in example 4, step C; 250 mg; 0.70mmol) and 2-amino-5-chlorothiazole hydrochloride (154 mg; 0.88mmol) were coupled via BOP in analogy to the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (described in example 1, step B) to give N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (5, 6-dichloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide, yield 37%: EI-HRMS m/eC₂₀H₂₀Cl₃N₃O₂S(M⁺) Calculated value of 471.0342, actual value of 471.0345.

Example 6(S) -N- (5-bromo-thiazol-2-yl) -3-cyclohexyl-2- (5, 6-dichloro-1-oxo-1, 3-dihydroisoindol-2-yl) -propionamide

Preparation of this compound (S) -3-cyclohexyl-2- (5, 6-dichloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (prepared in example 4, step C; 248 mg; 0.70mmol) and 2-amino-5-bromothiazole hydrochloride (154 mg; 0.89mmol) were coupled via BOP in analogy to the procedure for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (described in example 1, step B) to give N- (5-bromo-thiazol-2-yl) -3-cyclohexyl-2- (5, 6-dichloro-1-oxo-1, 3 dihydro-isoindol-2-yl) -propionamide, yield 40%: EI-HRMS m/eC₂₀H₂₀BrCl₂N₃O₂S(M⁺) Calculated value of 514.9837, actual value of 514.9836.

Example 7(S) -N- (1H-benzimidazol-2-yl) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide

Preparation of this compound following a procedure analogous to that for (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (described in example 9, step B), coupling via BOP (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in example 1, step A, 287 mg; 1.0mmol) and 2-amino-benzimidazole (119 mg; 1.0mmol) afforded crude N- (5-bromo-thiazol-2-yl) -3-cyclohexyl-2- (5, 6-dichloro-1-oxo-1, 3-dihydro-isoindol-2-yl) propionamide. The crude product was subjected to reverse phase HPLC (Rainin Dynamax SD-1 apparatus) with a gradient of 10% acetonitrile/water/0.1% trifluoroacetic acid to 100% acetonitrile at C₁₈The crude product was purified on the column. The combined fractions containing the product were concentrated to remove most of the acetonitrile and then extracted with ethyl acetate. The extract was dried (sodium sulfate) and concentrated in vacuo to give 240mg (60%) of (S) -N- (1H-benzimidazol-2-yl) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide as a white solid: EI-HRMS m/e C₂₄H₂₆N₄O₂(M⁺) Calculated value of 402.2056, actual value of 402.2056.

Example 8(S) -N-benzothiazol-2-yl-3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide

The preparation of this compound is analogous to the preparation of the (S) -3-ringMethod of hexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B) by coupling via BOP (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in example 1, step A, 144 mg; 0.5mmol) and 2-amino-benzothiazole (81 mg; 0.55mmol) to give crude N-benzothiazol-2 yl-3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide. The crude product was purified by flash chromatography (Merck silica gel 60, 230 mesh 400, eluent: 35% ethyl acetate/hexane) to give 185mg (44%) (S) -N-benzothiazol-2-yl-3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide as a white solid: EI-HRMS m/eC₂₄H₂₅N₃O₂S(M⁺) Calculated value of 419.1667, actual value of 419.1661.

Example 9(R) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

Step A: (R) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid

A mixture of (R) - (+) -a-aminocyclohexanepropionic acid hydrochloride (2.69 g; 15.7mmol) and o-phthalaldehyde (2.50 g; 14.6mmol) in acetonitrile (60mL) was refluxed under nitrogen for 42 h. The mixture was cooled to room temperature and further cooled to 0 ℃. The solid was filtered off and washed once with cold acetonitrile to give 2.65g (63%) of (R) -3-cyclohexyl-2- (1-oxo-1, 3-dihydroisoindol-2-yl) -propionic acid as a white solid: EI-HRMS m/e C₁₇H₂₁NO₃(M⁺) Calculated value of 287.1521, actual value of 287.1523.

And B: (R) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

To (R) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in step A,144 mg; 0.5mmol), O-benzotriazol-1-yl-N, N' -tetramethyluronium hexafluorophosphate (BOP, 268 mg; 0.55mmol) and 2-aminothiazole (50 mg; 0.5mmol) in anhydrous dichloromethane (3mL) was added dropwise N, N-diisopropylethylamine (0.20 mL; 1.15 mmol). The mixture was stirred for 1 h. The mixture was then diluted with dichloromethane and washed with water. Drying the organic layer (Na)₂SO₄) Filtered and concentrated in vacuo to give a crude residue. Flash chromatography (Merck silica gel 60, 230 mesh 400, eluent: 30% ethyl acetate/hexane) afforded 150mg (81%) of (R) -3 cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide as a milky white foam: EI-HRMS m/e C₂₀H₂₃N₃O₂S(M⁺) Calculated value of 369.1511, actual value of 369.1511.

Example 10(S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-quinolin-2-yl-propionamide

Preparation of this compound (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (described in example 1, step B) was coupled via BOP to (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in example 1, step A, 288 mg; 1.0mmol) and 2-aminoquinoline (180 mg; 1.2mmol) in analogy to the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-quinolin-2-yl-propionamide as white solid, yield 99%: EI-HRMS m/e C₂₆H₂₇N₃O₂(M⁺) Calculated value of 413.2103, actual value of 413.2103.

Example 11

(S) -3-cyclohexyl-2- (5-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide and 11.2.(S) -3-cyclohexyl-2- (6-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

Step A: 4-nitro-1, 2-di-hydroxymethyl-benzene

To a stirred solution of borane tetrahydrofuran complex (70mL of a 1.5M solution in tetrahydrofuran/diethyl ether) cooled to 0 deg.C under a nitrogen atmosphere was added dropwise a solution of 4-nitrophthalic acid (7.01 g; 33.2mmol) in tetrahydrofuran (50mL) over 20 minutes. After the addition was complete, the mixture was stirred at 0 ℃ for 3.5 h. The mixture was warmed to room temperature and then refluxed for 18 h. The mixture was cooled to room temperature, quenched by addition of methanol and concentrated in vacuo. The residue was taken up in ethyl acetate, washed with saturated sodium bicarbonate solution and then with brine solution. The organic extract phase was dried (sodium sulfate), filtered and concentrated in vacuo to give 5.61g (92%) of 4-nitro-1, 2-bis-hydroxymethylbenzene as a white solid: ES-LRMSC₈H₈NO₄(M⁺-1) has a calculated value of 182 and an actual value of 182.

And B: 4-Nitro-o-benzene-1, 2-dicarbaldehyde (4-nitro-ortho-phenylene-1, 2-dicarbaxaldehydes)

To a stirred solution of oxalyl chloride (4.90 mL; 55.0mmol) in anhydrous dichloromethane (60mL) at-78 deg.C under nitrogen was added dropwise a solution of dimethyl sulfoxide (8.20 mL; 115mmol) in dichloromethane (20 mL). The solution was stirred for 10 minutes and then a solution of 4-nitro-1, 2-bis- (hydroxymethyl) benzene (3.99 g; 21.8mmol) dissolved in 20mL of 1: 1 dichloromethane/dimethyl sulfoxide was added dropwise. The resulting mixture was stirred at-78 ℃ for 3 h. Triethylamine (60 mL; 426mmol) was added slowly over 15 minutes and the mixture was allowed to warm to room temperature for 2 h. The mixture was diluted with ice water (300mL) and extracted with dichloromethane. The extract was washed with 1N HCI, dried over sodium sulfate, and concentrated to give crude 4-nitro-o-benzene-1, 2-dicarboxaldehyde, which was further purified by flash chromatography (Biotage 40M, eluent: 35% ethyl acetate/hexanes) to give 2.5g (64%) of 4-nitro-1, 2-dicarboxaldehyde as a yellow solid, which was evaluated by NMRPurity about 40%: ES-LRMS C₈H₄NO₄(M⁺-1) has a calculated value of 178 and an actual value of 178.

And C: (S) -3-cyclohexyl-2- (5-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid

A mixture of (S) - (+) - α -aminocyclohexanepropionic acid hydrate (0.708 g; 3.93mmol) and 4-nitro-phthalaldehyde (prepared in step B; 2.02 g; 3.95mmol) in acetonitrile (20mL) was heated to reflux under argon. The balance of (S) (+) - α -aminocyclohexanepropionic acid hydrate (0.775 g; 4.30mmol) was added in portions over 2 hours, and the mixture was refluxed overnight. The mixture was cooled to room temperature and the solid was filtered off and washed once with cold acetonitrile to give a light brown solid (0.511g) consisting of (S) -3-cyclohexyl-2- (5-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid and the regioisomer (regioisomer) (S) -3-cyclohexyl-2- (6-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid in a ratio of 1: 2.7. The filtrate was then concentrated in vacuo and the residue recrystallized from acetonitrile to give a second crop of product (1.01g) which was further enriched in (S) -3-cyclohexyl-2- (5-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid, C in the mixture₁₇H₁₉N₂O₅(M⁺ES-LRMS of-1) calculated 331, actual 331.

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

Following a procedure analogous to that for the preparation of (S) -3 cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 1, described in step B), coupling via BOP (S) -3-cyclohexyl-2- (5-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (approx. 1: 1 regioisomer mixture, prepared in step C; 301 mg; 0.91mmol) and 2-aminothiazole (116 mg; 1.12mmol), purification by chromatography (Biotage 40M, eluent: 30% ethyl acetate/hexane) to yield 131mg of 3-cyclohexyl-2- (5-nitro).1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide: EI-HRMS m/e C₂₀H₂₂N₄O₄S(M⁺) Calculated value of 414.1362, found 414.1362, and 121mg regioisomer 3-cyclohexyl-2- (6-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide: EI-HRMS m/e C₂₀H₂₂N₄O₄S(M⁺) Calculated value of 414.1362, actual value of 414.1368.

Example 12

(S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (5-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide and 12.2.(S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (6-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 1, described in step B), coupling via BOP (S) -3-cyclohexyl-2- (5-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (5, 6-regioisomer mixture of about 1: 1, prepared in step C; 307 mg; 0.92mmol) and 2-amino-5-chlorothiazole hydrochloride (360 mg; 2.04mmol) and, after chromatographic purification (Biotage 40M, eluent: 25% ethyl acetate/hexane), to give 134mg of (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (5-nitro-1-oxo-1, 3-dihydroisoindol-2-yl) -propionamide: EI-HRMS m/e C₂₀H₂₁ClN₄O₄S(M⁺) Calculated value of 448.0972, found 448.0970, and 111mg of regioisomer (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (6-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide: EI-HRMS m/e C₂₀H₂₁ClN₄O₄S(M⁺) Calculated value of 448.0972, actual value of 448.0972.

Example 13

(S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydroisoindol-2-yl) -propionamide and 13.2.(S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (7-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide

Step A: 3-fluoro-1, 2-bis- (hydroxymethyl) benzene

To a stirred solution of borane tetrahydrofuran complex (50mL of a 1.5M solution in tetrahydrofuran/diethyl ether) cooled to 0 deg.C under a nitrogen atmosphere was added dropwise a solution of 3-fluorophthalic acid (4.51 g; 24.0mmol) in tetrahydrofuran (40mL) over 15 minutes. After the addition was complete, the mixture was stirred at 0 ℃ for 2 h. The mixture was warmed to room temperature and then refluxed for 20 h. The mixture was cooled to room temperature, quenched by addition of methanol (30mL) and concentrated in vacuo. The residue was taken up in ethyl acetate (150mL) and washed with saturated sodium bicarbonate solution. The aqueous layer was further extracted with ethyl acetate (2X 125mL) and the combined extracts were further washed with brine solution. The organic extract phase was dried (sodium sulfate), filtered and concentrated in vacuo to give 3.73g (99%) of 3-fluoro-1, 2-bis- (hydroxymethyl) benzene as a white solid: ES-LRMSC₈H₈FO₂(M⁺Calculated value of-1) is 155, actual value is 155.

And B: 3-fluoro-phthalaldehyde

To a stirred solution of oxalyl chloride (2.80 mL; 31.5mmol) in anhydrous dichloromethane (35mL) at-78 deg.C under a nitrogen atmosphere was added dropwise a solution of dimethyl sulfoxide (4.6 mL; 64.7mmol) in dichloromethane (10 mL). The solution was stirred for 30 minutes and then a solution of 3-fluoro-1, 2-bis- (hydroxymethyl) benzene (2.00 g; 12.8mmol) dissolved in 20mL of 1: 1 dichloromethane/dimethyl sulfoxide was added dropwise. The resulting mixture was stirred at-78 ℃ for 2.5 h. Triethylamine (35 mL; 248.6mmol) was slowly added over 15 minutes, the mixture was stirred at-78 deg.C for 30 minutes, and the mixture was allowed to warm to 4 hoursAnd (4) room temperature. The mixture was poured into ice water (200mL) and extracted with dichloromethane. The extract was washed with 1N HCI and brine, dried over sodium sulfate, and concentrated to give crude 3-fluoro-phthalaldehyde which was not further purified: ES-LRMS C₈H₄FO₂(M⁺-1) has a calculated value of 151 and an actual value of 151.

And C: (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid

A mixture of (S) - (+) - α -aminocyclohexanepropionic acid hydrate (0.565 g; 3.14mmol) and 3-fluorophthalaldehyde (prepared in step B; 1.60 g; 3.16mmol) in acetonitrile (20mL) was heated under reflux under argon. The balance of (S) - (+) - α -aminocyclohexylpropionic acid hydrate (0.437 g; 2.43mmol) was added in portions over 7 hours, and the mixture was refluxed for 72 hours. The mixture was allowed to cool to room temperature, held for 3h, and then stored in a refrigerator for 1 h. The solid was filtered off and washed once with cold acetonitrile to give a white solid consisting of (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydroisoindol-2-yl) -propionic acid and the regioisomer (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid in a ratio of about 1: 1 (1.39g, 77%): ES-LRMS C₁₇H₁₉FNO₃(M⁺-1) has a calculated value of 304 and an actual value of 304.

Step D: (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydro-isoindol-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

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydroisoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), coupling of (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) propionic acid (ca.1: 1 mixture of regioisomers, prepared in step C; 501 mg; 1.64mmol) and 2-amino-5-chlorothiazole hydrochloride (643 mg; 3.64mmol) via BOP was performed by normal phase HPLC (Waters Prep.500, packed with dichloromethane, eluent: 20% ethyl acetate/hexane).After purification, 194mg of(s) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide: EI-HRMS m/eC₂₀H₂₁ClFN₃O₂S(M⁺) Calculated value of 421.1027, actual value of 421.1024; and 137mg of the regioisomer (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (7-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide: EI-HRMS m/e C₂₀H₂₁ClFN₃O₂S(M⁺) Calculated value of 421.1027, actual value of 421.1031.

Example 14

3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide

Following a procedure analogous to that for the preparation of (R) -3 cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), coupling via BOP (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in example 1, step A; 287 mg; 1.00mmol) and 4-aminopyrimidine (108 mg; 1.14mmol) gave 271mg (74%) of 3-cyclohexyl-2- (1-oxo-1) after purification by flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 50% ethyl acetate/hexane, 3 dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide white foam: EI-HRMS m/e C₂₁H₂₄N₄O₂(M⁺) Calculated value of 364.1899, actual value of 364.1893.

Example 15(S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide

In analogy to the preparation of (R) -3 cyclohexyl-2-, (Method of 1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), coupling via BOP (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in example 1, step a; 287 mg; 1.00mmol) and 2-aminopyrazine (95 mg; 1.00mmol), by flash chromatography (Merck silica gel 60, 230-: 50% ethyl acetate/hexane) to yield 350mg (96%) (S) -3-cyclohexyl-2- (1-oxo-1, 3 dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide as a white foam: EI-HRMS m/e C₂₁H₂₄N₄O₂(M⁺) Calculated value of 364.1899, actual value of 364.1908.

Example 16

(S) -N-benzoxazol-2-yl-3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) propanamide

Following a procedure analogous to that for the preparation of (R) -3 cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), coupling via BOP (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in example 1, step A; 144 mg; 0.50mmol) and 2-aminobenzoxazole (67 mg; 0.50mmol) gave, after purification by flash chromatography (Merck silica gel 60, 230-mesh 400, eluent: 50% ethyl acetate/hexane), 161mg (96%) of (S) -N-benzoxazol-2-yl-3-cyclohexyl-2- (1-oxo-1, 3-isoindol-2-yl) -propionic acid -oxo-1, 3-dihydro-isoindol-2-yl) -propionamide white foam: EI-HRMS m/e C₂₄H₂₅N₃O₃(M⁺) Calculated value of 403.1896, actual value of 403.1895.

Example 173-cyclopentyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

Step A: 3-cyclopentyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid

A mixture of 2-amino-3-cyclopentyl-propionic acid (0.800 g; 5.09mmol) and o-phthalaldehyde (0.684 g; 5.10mmol) in acetonitrile (30mL) was refluxed under nitrogen for 3 h. The mixture was cooled to room temperature and the solid was filtered and washed once with cold acetonitrile (5mL) to give 1.16g (83%) of 3-cyclopentyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid as a white solid: EI-HRMS m/eC₁₆H₁₉NO₃(M⁺) Calculated value of 273.1365, actual value of 273.1374.

And B: 3-cyclopentyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

Following a procedure analogous to that for the preparation of (R) -3 cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), coupling via BOP (3-cyclopentyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in step A; 273 mg; 1.00mmol) and 2-aminothiazole (100 mg; 1.00mmol) and purification by flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 40% ethyl acetate/hexane) gave 132mg (37%) of 3-cyclopentyl-2- (1-oxo-1, 3-dihydroisoindol-2-yl) -N-thiazol-2-yl-propionamide as a white solid: EI-HRMS m/e C₁₉H₂₁N₃O₂SNa(M⁺+Na⁺) Calculated value of 378.1247, actual value of 378.1250.

Example 18

N- (5-chloro-thiazol-2-yl) -3-cyclopentyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide

Preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazole in analogy-2-yl-propionamide (described in example 1, step B) 3-cyclopentyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in example 1, step A; 277 mg; 1.01mmol) and 2-amino-5-chlorothiazole hydrochloride (397 mg; 2.30mmol) were coupled via BOP and, after purification by flash chromatography (Biotage 40M eluent: 20% ethyl acetate/hexane), 290mg (74%) of N- (5-chloro-thiazol-2-yl) -3-cyclopentyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide are obtained as a light yellow solid: EI-HRMS m/e C₁₉H₂₁N₃O₂S(M⁺) Calculated value of 389.0965, actual value of 389.0966.

Example 19

3-cycloheptyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

Step A: cycloheptane methanol

To a stirred solution of borane tetrahydrofuran complex at 0 deg.C (95mL of a 1.5M solution in tetrahydrofuran/diethyl ether) under argon was added cycloheptane carboxylic acid (10.05 g; 69.3mmol) in 30mL of tetrahydrofuran. After 2h, the reaction mixture was quenched by careful addition of methanol and the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and washed successively with 1N HCl, saturated sodium bicarbonate solution and brine solution. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo to give 9.19g (100%) of cycloheptanemethanol as a colorless oil.

And B: cycloheptyl methyl iodide

To a stirred solution of triphenylphosphine (24.59 g; 92.8mmol) and imidazole (6.40 g; 93.1mmol) in dichloromethane (100mL) cooled to 0 deg.C was added iodine (23.52 g; 92.7mmol) in portions over 10 minutes. A solution of cycloheptanemethanol (9.14 g; 71.3mmol) dissolved in dichloromethane (50mL) was then added over 5 minutes. The ice bath was removed and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with dichloromethane, washed with water, the organic layer dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product was purified by chromatography (eluent: hexane) to give 15.35g (93%) of cycloheptyl iodomethane as an oil.

And C: 2- (Diphenylmethylene-amino) -3-cycloheptyl-propionic acid tert-butyl ester

To a stirred solution of (diphenylmethylene-amino) -acetic acid tert-butyl ester (2.56 g; 8.68mmol) in 30mL of tetrahydrofuran under a nitrogen atmosphere at-78 deg.C was added dropwise a solution of lithium diisopropylamide (10.0 mL; 1.5M solution in cyclohexane). After 30 minutes, a solution of cycloheptyl iodomethane (prepared in step B; 3.48 g; 14.6mmol) in 20mL of tetrahydrofuran was added dropwise, the mixture warmed to room temperature and stirred for 18 h. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL). The phases were separated and the aqueous layer was taken up in ethyl acetate. The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by chromatography (Biotage 40M; eluent: 5% ethyl acetate/hexane) to yield 2.56g (73%) of tert-butyl 2- (diphenylmethylene-amino) -3-cycloheptyl-propionate as a pale yellow oil.

Step D: 2-amino-3-cycloheptyl-propionic acid

To a solution of tert-butyl 2- (diphenylmethylene-amino) -3-cycloheptyl-propionate (1.34 g; 3.31mmol) in methanol (5mL) was added 10N HCl solution (15mL) and the mixture was heated to reflux. After 15h, the mixture was cooled to room temperature, transferred to a separatory funnel and washed with ethyl acetate. The aqueous layer was then neutralized with concentrated ammonium hydroxide solution and the white solid was filtered off and air dried to give 329mg of 2-amino-3 cycloheptyl-propionic acid.

Step E: 3-cycloheptyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid

A solution of o-phthalaldehyde (248 mg; 1.80mmol) and 2-amino-3 cycloheptyl-propionic acid (318 mg; 1.72mmol) in acetonitrile was heated to reflux for 18 h. The mixture was then cooled to room temperature and stored in a refrigerator for 3 h. The solid was filtered off. Rinsed with cold acetonitrile and air dried to give 424mg (82%) 3-cycloheptyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) propionic acid as an off-white solid: EI-HRMS m/e C₁₈H₂₃NO₃(M⁺) Calculated value of 301.1678, actual value of 301.1668.

Step F: 3-cycloheptyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl propionamide

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (described in example 1, step B), coupling of 3-cycloheptyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in step E; 173 mg; 0.58mmol) and 2-aminothiazole (97 mg; 0.94mmol) via BOP, purification by flash chromatography (Biotage 40S, eluent: 35% ethyl acetate/hexane) gave 217mg (99%) of 3-cycloheptyl-2- (1-oxo-1 as a white foam, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide: EI-HRMS m/e C₂₁H₂₅N₃O₂S(M⁺) Calculated value of 383.1667, actual value of 383.1660.

Example 20

N- (5-chloro-thiazol-2-yl) -3-cycloheptyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) propionamide

In analogy to the procedure for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 1, described in step B) 3-cycloheptyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in step E; 177 mg; 0.59mmol) and 2-amino-5-chlorothiazole hydrochloride (168 mg; 0.95mmol) were coupled via BOP and after purification by flash chromatography (Biotage 40S, eluent: 20% ethyl acetate/hexane) 99mg (40%) of N- (5-chlorothiazol-2-yl) -3-cycloheptyl-2- (1- Oxo-1, 3-dihydro-isoindol-2-yl) -propionamide: EI-HRMS m/e C₂₁H₂₄ClN₃O₂S(M⁺) Calculated value of 417.1278, actual value of 417.1289.

Example 21

3-cyclooctyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

Step A: cyclooctyl methyl iodide

To a stirred solution of cyclooctylmethanol (5.00 g; 35.2mmol) and iodine (8.93 g; 35.2mmol) in dry dichloromethane (100mL) at room temperature was added triphenylphosphine (9.23 g; 35.2mmol) in portions over 10 minutes. After 1h, the mixture was diluted with dichloromethane, washed with water, then with saturated sodium bisulfite solution, the organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product was purified by chromatography (eluent: hexane) to give 5.35g (60%) of cyclooctyl iodomethane as an oil.

And B: 2- (Diphenylmethylene-amino) -3-cyclooctyl-propionic acid tert-butyl ester

To a stirred solution of (diphenylmethylene-amino) -acetic acid tert-butyl ester (3.00 g; 10.1mmol) in 60mL tetrahydrofuran was added dropwise a lithium diisopropylamide solution (11.5 mL; 1.5M solution in cyclohexane) under argon-78 ℃. After 30 minutes, cyclooctyl iodomethane solution (prepared in step A; 3.83 g; 15.2mmol) was added dropwise via syringe, the mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution. Most of the tetrahydrofuran was removed in vacuo. The mixture was diluted with water and extracted with dichloromethane. The combined extracts were dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by chromatography (eluent: 4% ethyl acetate/hexane) to yield 3.34g (79%) of tert-butyl 2- (diphenylmethylene-amino) -3-cyclooctyl-propionate as a pale yellow oil.

And C: 2-amino-3-cyclooctyl-propionic acid

To a solution of tert-butyl 2- (diphenylmethylene-amino) -3-cyclooctyl-propionate (2.00g) in methanol (15mL) was added 10N HCl solution (30mL), and the mixture was heated to reflux. After 20h, the mixture was cooled to room temperature, diluted with 20mL of water, transferred to a separatory funnel and washed with ethyl acetate. The aqueous layer was then neutralized with 10N sodium hydroxide solution and further cooled to room temperature. The white solid was filtered off and air dried to give 590mg of 2-amino-3-cyclooctyl-propionic acid.

Step D: 3-cyclooctyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid

A solution of o-phthalaldehyde (349 mg; 2.60mmol) and 2-amino-3-cycloheptyl-propionic acid (500 mg; 2.51mmol) in acetonitrile (20mL) was heated to reflux for 3 h. The mixture was then filtered hot to remove insoluble material, then cooled to room temperature and further cooled to 0 ℃. The solid was filtered off. Rinsed with cold acetonitrile and air dried to give 480mg (62%) of 3-cyclooctyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid as a white solid: EI-HRMS m/e C₁₉H₂₅NO₃(M⁺) Calculated value of 315.1834, actual value of 315.1840.

Step E: 3-cyclooctyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

In analogy to the procedure for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B) 3-cyclooctyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in step D; 200 mg; 0.65mmol) and 2-aminothiazole (70 mg; 0.70mmol) were coupled via BOP and after purification by flash chromatography (30% ethyl acetate/hexane), 226mg (88%) 3-cyclooctyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazole-2-yl-propionate were obtained as a white foam And (3) propionamide: EI-HRMS m/e C₂₂H₂₇N₃O₂S(M⁺) Calculated value of 397.1824, actual value of 397.1825.

Example 22

(R) -N- (5-bromo-pyridin-2-yl) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide

Following a procedure analogous to that for the preparation of (R) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in step 1, step A; 287 mg; 1.00mmol) and 2-amino-5-bromopyridine (173 mg; 1.00mmol) were coupled via BOP and, after purification by flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 30% ethyl acetate/hexane), 243mg (55%) of (S) -N- (5-bromo-pyridin-2-yl) were obtained as a white foam -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide: EI-HRMS m/e C₂₂H₂₄BrN₃O₂S(M⁺) Calculated value of 441.1052, actual value of 441.1036.

Example 23

(S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide and 23.2.(S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), coupling via BOP (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) propionic acid and (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) propionic acid (499 mg; 1.63mmol, regioisomeric mixture in a ratio of 1: 1) with 2-aminothiazole (376 mg; 3.64mmol), by flash chromatography (Biotage 40M; eluent): 30% ethyl acetate/hexanes) to give (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydroisoindol-2-yl) -N-thiazol-2-yl-propionamide (221 mg): EI-HRMS m/e C₂₀H₂₂FN₃O₂S(M⁺) Calculated value of 387.1417, actual value of 387.1422; and impure (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1, 3 dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide, which is further purified by radial chromatography (eluent: 35% ethyl acetate/hexane) to give 48mg pure (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1, 3 dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide as a white foam: EI-HRMS m/e C₂₀H₂₂N₃O₂S(M⁺) Calculated value of 387.1417, actual value of 387.1415.

Example 24

(S) -3-cyclohexyl-N- (1H-imidazol-2-yl) -2- (1-oxo-1, 3-dihydro-isoindol-2-yl) propionamide

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (described in example 1, step B), 3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in step A of example 1; 287 mg; 1.00mmol) and 2-aminoimidazole (241 mg; 1.79mmol) were coupled via BOP to give, after purification by flash chromatography (Biotage 40M eluent: 4% methanol/dichloromethane), 320mg of (S) -3-cyclohexyl-N- (1H-imidazol-2-yl) -2- (1-oxo-1, 3-dihydro-isoindol-2-yl) propionamide, which is then recrystallized from ethyl acetate/hexane to give 209mg of pure material: EI-HRMS m/eC₂₀H₂₄N₄O₂(M⁺) Calculated value of 352.1899, actual value of 352.1895.

Example 25

(S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide and 25.2.(S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), coupling via BOP (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) propionic acid and (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) propionic acid (331 mg; 1.08mmol, regioisomeric mixture in the ratio 1: 1) with 2-aminopyrazine (232 mg; 2.41mmol), after purification by flash chromatography (Biotage 40M; eluent: 30% ethyl acetate/hexane), the (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydroisoindol-2-yl) -N-thiazol-2-yl-propionamide and (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide were obtained, which were further purified by reverse phase HPLC (Rainin Dynamax SD-1 apparatus) with a gradient of 40% acetonitrile/water/0.1% trifluoroacetic acid to 100% acetonitrile on a C18 column to yield 39mg of pure, N-thiazolyl-2-yl-propionamide, White foam of (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1, 3-dihydroisoindol-2-yl) -N-thiazol-2-yl-propionamide: EI-HRMS m/e C₂₁H₂₃FN₄O₂(M⁺) Calculated value of 382.1805, actual value of 382.1810.

Example 26

(S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide

Coupling via BOP according to a procedure analogous to that for the preparation of (R) -3-cyclohexyl-2 (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B)(S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in step A of example 1; 287 mg; 1.00mmol) and 2-aminopyridine (94 mg; 1.00mmol) to give, after purification by flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 45% ethyl acetate/hexane), 186mg of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydroisoindol-2-yl) -N-pyridin-2-yl-propionamide as a white foam: EI-HRMS m/e C₂₂H₂₅N₃O₂(M⁺) Calculated value of 363.1947, actual value of 363.1935.

Example 27

(S) -N-3-cyclohexyl-N- (2-methyl-pyrimidin-4-yl) -2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide

Following a procedure analogous to that for the preparation of (R) -3-cyclohexyl-2 (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in step A of example 1; 150 mg; 0.52mmol) and 2-amino-6-methylpyrimidine (57 mg; 0.52mmol) were coupled via BOP and, after purification by flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 65% ethyl acetate/hexane), 109mg of (S) -3-cyclohexyl-N- (2-methyl-pyrimidine-4-one) were obtained as a white foam Yl) -2- (1-oxo-1, 3-dihydro-isoindol-2-yl) propionamide: EI-HRMS m/e C₂₂H₂₆N₄O₂(M⁺) Calculated value of 378.2056, actual value of 378.2054.

Example 28

28.1(S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide and 28.2.(S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1, 3 dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

Step A: 3-Fluorophthalic acid dimethyl ester

Hydrochloric acid was bubbled through a stirred solution of 3-fluorophthalic acid (2.00 g; 10.9mmol) in anhydrous methanol at room temperature for 2 minutes. The mixture is heated and refluxed. After refluxing for 1h, 1mL of concentrated sulfuric acid was added and refluxing was continued for 22 h. 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 give 1.70g of 3-fluorophthalic acid dimethyl ester as an oil.

And B: 3-Thiomethylphthalic acid

A mixture of dimethyl 3-fluorophthalate (2.27 g; 10.7mmol) and sodium thiomethoxide (6.34 g; 85.9mmol) in DMSO (20mL) was heated to 50 ℃. After 24h, crushed ice was added and the resulting mixture was acidified with 1N HCl. The solution was extracted with ethyl acetate, the extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by reverse phase HPLC (Rainin DynamaxSD-1 apparatus) with a gradient of 0% acetonitrile/water/0.1% trifluoroacetic acid to 100% acetonitrile on a C18 column to give 802mg of 3-thiomethylphthalic acid.

And C: 3-thiomethyl-1, 2-bis- (hydroxymethyl) benzene

To a stirred solution of borane tetrahydrofuran complex (14.0mL of a 1.5M solution in tetrahydrofuran/diethyl ether) cooled to 0 deg.C under argon was added a solution of 3-thiomethylphthalic acid (0.739 g; 3.48mmol) in 20mL of tetrahydrofuran. After the addition was complete, the mixture was refluxed for 15 h. The mixture was cooled to room temperature, quenched with methanol (20mL), refluxed for 2h, 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 washed with saturated sodium bicarbonate solution, brine, dried (sodium sulfate), filtered and concentrated in vacuo to give crude 3-thiomethyl-1, 2-bis- (hydroxymethyl) benzene which was purified by flash chromatography (Biotage 40M; eluent: 25% -50% ethyl acetate/hexane gradient) to give 454mg of pure 3-thiomethyl-1, 2-bis- (hydroxymethyl) benzene.

Step D: 3-Thiomethyl-o-phthalaldehyde

To a stirred solution of oxalyl chloride (0.42 mL; 4.72mmol) in anhydrous dichloromethane (5mL) was added dropwise a solution of dimethyl sulfoxide (0.70 mL; 9.67mmol) in dichloromethane (2mL) under argon at-78 ℃. The solution was stirred for 10 minutes and then a solution of 3-thiomethyl-1, 2-bis- (hydroxymethyl) benzene (0.415 g; 2.25mmol) dissolved in 3mL of 1: 1 dichloromethane/dimethylsulfoxide was added dropwise. The resulting mixture was stirred at-78 ℃ for 2 h. Triethylamine (5.5 mL; 17.4mmol) was added dropwise and the mixture was gradually warmed to room temperature and stirred for 20 h. The mixture was poured into ice water and the phases were separated. The extract was washed with brine, dried over sodium sulfate and concentrated to give crude 3-thiomethyl-phthalaldehyde without further purification.

Step E: (S) -3-cyclohexyl-2- (4-methylsulfanyl-1-oxo-1, 3-dihydro-isoindol-2-yl) propionic acid

A mixture of (S) - (+) - α -aminocyclohexanepropionic acid hydrate (0.125 g; 0.70mmol) and crude 3-thiomethyl phthaldehyde (prepared in step D; 0.250 g; 1.4mmol) in acetonitrile (5mL) was heated to reflux under argon for 18 h. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage 40S; eluent: 5% methanol/dichloromethane) to give 260mg of (S) -3-cyclohexyl-2- (4-methylsulfanyl-1-oxo-1, 3-dihydroisoindol-2-yl) -propionic acid and the regioisomer (S) -3-cyclohexyl-2- (7-methylsulfanyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid in a ratio of about 1: 1.

Step F: (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid

To a solution of (S) -3-cyclohexyl-2- (4-methylsulfanyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid and the regioisomer (S) -3-cyclohexyl-2- (7-methylsulfanyl-1-oxo-1, 3 dihydro-isoindol-2-yl) -propionic acid (0.790 g; 2.37 mmol; a mixture of about 1: 1) in formic acid (4mL) at 0 deg.C was added dropwise a 30% hydrogen peroxide solution (1.3 mL; 12.7 mmol). The mixture was warmed to room temperature and stirred for 19 h. The mixture was concentrated under a stream of nitrogen to remove formic acid, yielding 0.901g of crude (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid and the regioisomer (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid.

Step G: (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1, 3 dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), coupling via BOP (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1, 3-dihydroisoindol-2-yl) -propionic acid and the regioisomer (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (112 mg; 0.31mmol) with 2-aminothiazole (54 mg; 0.52mmol), after purification by flash chromatography (Biotage 40M; eluent: ethyl acetate/dichloromethane: gradient 15% -50% ethyl acetate), 51mg of(s) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1, 3 dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide: EI-HRMS m/e C₂₁H₂₅N₃O₄S₂(M^+-2) Calculated value of 445.1130, actual value of 445.1125, and 39mg(s) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1, 3 dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide: EI-HRMS m/eC₂₁H₂₅N₃O₄S₂(M⁺) Calculated value of 447.1286, actual value of 447.1280.

Example 29

(S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide and 29.2.(S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), coupling via BOP (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid and the regioisomer (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (200 mg; 0.55mmol) and 2-aminopyrazine (88 mg; 0.91mmol), after purification by flash chromatography (Biotage 40M; eluent: ethyl acetate/dichloromethane: gradient 20% -60%) the crude mixture was obtained, which was further purified by reverse phase HPLC (Rainin Dynamax SD-1 device) on a C18 column with a gradient of 10% acetonitrile/water/0.1% trifluoroacetic acid to 90% acetonitrile to give 21mg of(s) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide: EI-HRMS m/e C₂₂H₂₄N₄O₄SNa(M⁺+Na⁺) Calculated value of 465.1567, actual value of 465.1570, and 13mg of(s) -3-cyclohexyl-2 (7-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide: EI-HRMS m/eC₂₂H₂₄N₄O₄SNa(M⁺+Na⁺) Calculated value of 465.1567, actual value of 465.1568.

Example 30

(S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide and 30.2.(S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide

Preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), coupling via BOP (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid and the regioisomer (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (200 mg; 0.55mmol) and 4-aminopyrimidine (89 mg; 0.91mmol), after purification by flash chromatography (Biotage 40S; eluent: ethyl acetate/dichloromethane: gradient 25% -70% ethyl acetate), 83mg of foamed (S) -3-cyclohexyl-2- (4-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide were obtained: EI-HRMS m/e C₂₂H₂₆N₄O₄SNa(M⁺+Na⁺) Calculated value of 465.1567, found 465.1568, and 77mg of foamy (S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrimidin-4-yl-propionamide: EI-HRMS m/e C₂₂H₂₆N₄O₄SNa(M⁺+Na⁺) Calculated value of 465.1567, actual value of 465.1572.

Example 31

(S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-5-methyl-pyridin-2-yl-propionamide

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (described in example 1, step B), coupling via BOP (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in step A of example 1; 287 mg; 1.00mmol) and 2-amino-5-methylpyridine (143 mg; 1.32mmol) gave, after purification by flash chromatography (Biotage 40S; eluent: 30% ethyl acetate/hexane), 352mg of (S) -3-cyclohexyl-2- (1-oxo-1), 3-dihydro-isoindol-2-yl) -N-5-methyl-pyridin-2-yl-propionamide: EI-HRMS m/e C₂₃H₂₇N₃O₂(M⁺) Calculated value of 377.2103, actual value of 377.2107.

Example 32

(S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-4-methyl-pyridin-2-yl-propionamide

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (described in example 1, step B), coupling via BOP (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in step A of example 1; 287 mg; 1.00mmol) and 2-amino-4-methylpyridine (143 mg; 1.32mmol) and purification by flash chromatography (Biotage 40S; eluent: 30% ethyl acetate/hexane) gave 344mg of (S) -3-cyclohexyl-2- (1-oxo-1), 3-dihydro-isoindol-2-yl) -N-4-methyl-pyridin-2-yl-propionamide: EI-HRMS m/e C₂₃H₂₇N₃O₂(M⁺) Calculated value of 377.2103, actual value of 377.2106.

Example 33

(S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-5-chloro-pyridin-2-yl-propionamide

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (described in example 1, step B), coupling via BOP (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in step A of example 1; 287 mg; 1.00mmol) and 2-amino-5-chloropyridine (129 mg; 1.00mmol), purification by flash chromatography (eluent: 25% ethyl acetate/hexane)To give 160mg of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-5-chloro-pyridin-2-yl-propionamide as a white foam: EI-HRMS m/e C₂₂H₂₄N₃O₂ClNa(M⁺+Na⁺) Calculated value of 420.1449, actual value of 420.1451.

Example 34

(S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N- (1-oxy-pyridin-2-yl) -propionamide

Following a procedure analogous to that for the preparation of (R) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (prepared in step A of example 1; 287 mg; 1.00mmol) and 2-aminopyridine N-oxide (110 mg; 1.00mmol) were coupled via BOP and, after purification by flash chromatography (Merck silica gel 60, 230-400 mesh, eluent: 2% methanol/ethyl acetate), 340mg (55%) of (S) -N- (pyridine-N-oxide-2-one) were obtained as a milky foam -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide. NMR showed that the product was impure, so that it was further purified by reverse phase HPLC (Rainin Dynamax SD-1 apparatus) with a gradient of 10% acetonitrile/water/0.1% trifluoroacetic acid to 100% acetonitrile on a C18 column to give 188mg of pure (S-3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindolin-2-yl) -N- (1-oxy-pyridin-2-yl) -propionamide ES-LRMS m/e C₂₂H₂₅N₃O₃(M⁺+H⁺) The calculated value of (1) is 380, and the actual value is 380.

Example 35

(S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide and 35.2.(S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (described in example 9, step B), coupling via BOP (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) propionic acid (mixture of regioisomers in a ratio of about 1: 1, prepared in example 13, step C; 501mg, 1.64mmol) and 2-aminopyridine (643 mg; 3.64mmol), via reverse phase HPLC (Rainin Dynamax SD-1 apparatus) with a gradient of 40% acetonitrile/water/0.1% trifluoroacetic acid to 70% acetonitrile, after purification on a C18 column, 157mg(s) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide: ES-LRMS m/e C₂₂H₂₄FN₃O₂Na(M⁺+Na⁺) Calculated value of 404.1745, actual value of 404.1748; and 99mg of the regioisomer (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide: EI-HRMS m/eC₂₂H₂₄FN₃O₂Na(M⁺+Na⁺) Calculated value of 404.1745, actual value of 404.1749.

Example 36

(S) -3-cyclohexyl-2- (4-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide and 36.2.(S) -3-cyclohexyl-2- (7-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

Step A: 3-chloro-1, 2-bis- (hydroxymethyl) benzene

3-chloro-1, 2-bis- (hydroxymethyl) benzene was prepared in 97% yield by reducing 3-chlorophthalic acid with borane in analogy to the procedure described for the preparation of 3-fluoro-1, 2-bis- (hydroxymethyl) benzene in example 13, step A. 3-Chlorophthalic acid was prepared according to the literature method of Fertel, L.B., et al, J.org.chem.1993, 58(1), 261-263.

And B: 3-chloro-o-phthalaldehyde

3-Chlorophthalicarbaldehyde was prepared in a similar manner to that described for 3-fluorophthalcarbaldehyde in example 13, step B, by oxidation of 3-chloro-1, 2-bis- (hydroxymethyl) benzene (prepared in step A), and the crude product was used in the next step without further purification.

And 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

In a similar manner as described for the preparation of (S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid and (S) -3-cyclohexyl-2- (7-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid in example 13, step C, (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid and (S) -3-cyclo-3-cyclophthaldialdehyde prepared in step B was prepared by condensing (S) - (+) - α -aminocyclohexanepropionic acid hydrate with 3-chloro-phthalaldehyde Hexyl-2- (7-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid (mixture of about 1: 1).

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-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), coupling of (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) propionic acid (ca.1: 1 regioisomer mixture, prepared in step C; 326 mg; 1.0mmol) and 2-aminothiazole (231 mg; 2.23mmol) via BOP gave 132mg of (S) -3-ring after purification by chromatography (Biotage 40M column, eluent: 5% to 30% gradient of ethyl acetate/hexane).Hexyl-2- (4-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-ylpropanamide: ES-LRMS m/e C₂₀H₂₂ClN₃O₂S(M⁺+Na⁺) Calculated value of 426.1013, actual value of 426.1016; and 91mg of the regioisomer (S) -3-cyclohexyl-2- (7-chloro-1-oxo-1, 3-dihydroisoindol-2-yl) -N-thiazol-2-yl-propionamide: EI-HRMSm/e C₂₀H₂₂ClN₃O₂SNa(M⁺+Na⁺) Calculated value of 426.1013, actual value of 426.1017.

Example 37

(S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (4-chloro-1-oxo-1, 3-dihydroisoindol-2-yl) -propionamide and 37.2.(S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (7-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), coupling via BOP (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) propionic acid (regioisomer mixture in a ratio of about 1: 1, example 36, prepared in step C; 151 mg; 0.47mmol) and 2-amino-5-chlorothiazole hydrochloride (186 mg; 1.05mmol) and purification by chromatography (Biotage 40M column, eluent: 5% to 20% gradient ethyl acetate/hexane), yield 67mg of (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (4-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide: EI-HRMS m/eC₂₀H₂₁Cl₂N₃O₂S(M⁺+Na⁺) Calculated value of 437.0731, actual value of 437.0727; 46mg of the regioisomer (S) -N- (5-chloro-thiazol-2-yl) -3-cyclohexyl-2- (7-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) propionamide: EI-HRMS m/e C₂₀H₂₁Cl₂N₃O₂S(M⁺+Na⁺) Is/are as followsThe calculated value was 437.0731 and the actual value was 437.0726.

Example 38

(S) -3-cyclohexyl-2- (4-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide and 38.2.(S) -3-cyclohexyl-2- (7-chloro-1-oxo-1, 3-dihydroisoindol-2-yl) -N-pyridin-2-yl-propionamide

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (example 9, described in step B), coupling via BOP (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) propionic acid (regioisomer mixture in a ratio of about 1: 1, example 36, prepared in step C; 201 mg; 0.62mmol) and 2-aminopyridine (132 mg; 1.39mmol) gave, after purification by chromatography (Biotage 40S column, eluent: 30% ethyl acetate/hexane), 107mg of (S) -3-cyclohexyl-2- (4-chloro-1-oxo-2-yl) -1, 3-dihydro-isoindol-2-yl) -N-pyridin-2-ylpropanamide: EI-HRMS m/e C₂₂H₂₄ClN₃O₂(M⁺) Calculated value of 397.1557, actual value of 397.1563; 46mg of the regioisomer (S) -3-cyclohexyl-2- (7-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyridin-2-yl-propionamide: EI-HRMS m/eC₂₂H₂₄ClN₃O₂(M⁺) Calculated value of 397.1557, actual value of 397.1551.

Example 39

(S) -3-cyclohexyl-2- (4-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide and 39.2.(S) -3-cyclohexyl-2- (7-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide

Following a procedure analogous to that for the preparation of (S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide (described in example 9, step B), coupling via BOP (S) -3-cyclohexyl-2- (4-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) propionic acid (regioisomer mixture in a ratio of about 1: 1, prepared in example 36, step C; 243 mg; 0.76mmol) and 2-aminopyrazine (170 mg; 1.77mmol) gave 53mg of (S) -3-cyclohexyl-2- (4-chloro-1-oxo-2-yl) after purification by chromatography (Biotage 40M column, eluent: 20% ethyl acetate/hexane) -1, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-ylpropanamide: EI-HRMS m/e C₂₁H₂₃ClN₄O₂(M⁺) Calculated value of 398.1510, actual value of 398.1520; 41mg of the regioisomer (S) -3-cyclohexyl-2- (7-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-yl-propionamide: EI-HRMS m/eC₂₁H₂₃ClN₄O₂(M⁺) Calculated value of 398.1510, actual value of 398.1507.

Examples of biological Activity

All compounds of the present invention, including the compounds set forth in the examples, are capable of activating glucokinase in vitro as determined by the method of biological activity example a. In this manner, these compounds enhance the flux of glucose metabolism, which results in enhanced insulin secretion. Thus, the compounds of formula I are glucokinase activators useful for enhancing insulin secretion.

Biological activity example a: in vitro glucokinase Activity

Glucokinase assay: glucokinase (GK) was analyzed by coupling the production of glucose-6-phosphate with the production of NADH by glucose-6-phosphate dehydrogenase (G6PDH, 0.75-1 kunits/mg; Boehringer Mannheim, Indianapolis, IN) from Leuconostoc mesenteroides as a coupling enzyme (scheme 2).

Reaction scheme 2

Recombinant human liver GK1 was expressed in E.coli as glutathione S-transferase fusion protein (GST-GK) [ Liang et al, 1995] and chromatographed on glutathione Sepharose 4B affinity column using the method provided by the manufacturer (Amersham Pharmacia Biotech Piscataway, N.J.). Previous studies have demonstrated that the nature of the enzymes of native GK and GST-GK are essentially identical (Liang et al, 1995; Neet et al, 1990).

Assays were performed in 96-well flat-bottomed tissue culture plates from Costar (Cambridge, MA) at 25 ℃ in a final culture volume of 120. mu.l. The culture mixture contains: 25mM Hepes buffer (pH, 7.1), 25mM KCI, 5mM D-glucose, 1mM ATP, 1.8mM NAD, 2mM MgCl₂1 μ M sorbitol-6-phosphate, 1mM dithiothreitol, experimental drug or 10% DMSO, 1.8 units/ml G6PDH, and GK (see below). All organic reagents were > 98% pure, except D-glucose and Hepes from Sigma Chemical Co, St Louis, MO, others from Boehringer Mannheim. Test compounds were dissolved in DMSO and a volume of 12. mu.l of the GST-GK-free incubation mixture was added to a final DMSO concentration of 10%. The mixture was pre-incubated in a temperature-controlled bath of a SPECTRAmax 250 microplate spectrophotometer (Molecular devices corporation, Sunnyvale, Calif.) for 10 minutes, the temperature was equilibrated, and 20. mu.l GST-GK was added to initiate the reaction.

After addition of the enzyme, the increase in Optical Density (OD) at 340nm was monitored over a 10-minute incubation period as a measure of GK activity. Sufficient GST-GK was added to allow the OD of wells containing 10% DMSO without test compound to be in a 10 minute incubation period₃₄₀Increasing from 0.08 to 0.1 units. Preliminary experiments indicate that the GK response is linear over this period, even in the presence of an activator that produces a 5-fold increase in GK activity. The GK activity in control wells was compared to wells containing the test GK activator, and the concentration of activator that increased GK activity by 50%, i.e., SC, was calculated_1.5。

Except for SC of example 9_1.5SC of all other compounds described in the synthetic examples of the present invention at 36. mu.M_1.5Are below 30. mu.M. These results show the activity of GK activators.

Reference to bioactive example a:

liang, y., Kesavan, p., Wang, l., nisswender, k., Tanizawa, y., Permut, m.a., Magnuson, m., and matchinsky, f.m., variability effects of glucokinase mutations associated with maturity-onset diabetes (MODY) of young humans on the relationship of substrate interaction and enzyme stability (Variable effects of substrate-on-diabetes-of-your-Mouth (MODY) -associated glucokinase mutations and stability of enzymes), biochemical j.309: 167-173, 1995.

Neet, k., Keenan, r.p., and Tippett, p.s. observations of slow changes in the kinetics of monomeric glucokinase (initiation of a kinetic slow transition in monomeric glucokinase). Biochemistry 29; 770-777, 1990.

Biological activity example B: in vivo Activity

Glucokinase activator in vivo screening protocol: after fasting for 2 hours, C57BL/6J mice were orally administered with Glucokinase (GK) activator by gavage at a dose of 50mg/kg body weight. Blood glucose measurements were performed 5 times over a 6 hour study period after dosing.

Mice (n ═ 6) were weighed and fasted for 2 hours prior to oral administration. GK activator concentration was formulated at 6.76mg/ml (in Gelucire vehicle (ethanol: Gelucire 44/14: PEG400 q.s.4: 66: 30 v/w/v)). Mice were dosed orally with 7.5 μ L of formulation per gram of body weight, i.e. a dose equal to 50mg/kg of body weight. Immediately prior to dosing, each dose (0 hr) of blood glucose was obtained by cutting a small (-1 mm) section of the animal's tail and collecting 15 μ L of blood into a heparin coated capillary for analysis. Other blood glucose levels were obtained from the same tail wounds at 1, 2, 4 and 6 hours post-administration following GK activator administration. The results were analyzed by comparing the mean blood glucose values of 6 mice treated with vehicle and 6 mice treated with GK activator over a 6 hour study period. The compounds of the invention were considered to be active as they showed a statistically significant (p.ltoreq.0.05) reduction in blood glucose at two consecutive test time points compared to vehicle alone.

Following oral administration according to the assay described in biological activity example B, the compounds of examples 1, 18, 22, 23.1, 25.1, 26, 14, 15, 31, 33 were tested for excellent in vivo glucokinase activator activity.

Example A

Tablets containing the following ingredients may be prepared according to conventional methods:

component (A)	mg/tablet
component (A)	mg/tablet	A compound of formula I	10.0-100.0
Lactose	125.0	A compound of formula I	10.0-100.0
Lactose	125.0	Corn starch	75.0
Talc	4.0	Corn starch	75.0
Talc	4.0	Magnesium stearate	1.0

Example B

Capsules containing the following ingredients can be prepared according to conventional methods:

component (A)	mg/capsule
component (A)	mg/capsule	A compound of formula (I)	25.0
Lactose	150.0	A compound of formula (I)	25.0
Lactose	150.0	Corn starch	20.0
Talc	5.0	Corn starch	20.0

Claims

1. A compound comprising an amide of the formula:

wherein

A is unsubstituted phenyl, or phenyl mono-or di-substituted with halogen, or phenyl mono-substituted with lower alkylsulfonyl, lower alkylthio or nitro;

R²an unsubstituted or monosubstituted five-or six-membered heteroaromatic ring which is attached to the indicated amine group via a ring carbon atom, which five-or six-membered heteroaromatic ring contains 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, one of which is nitrogen, which is adjacent to the attached ring carbon atom, which ring may be monocyclic or fused on two of its ring carbon atoms with a phenyl group, said monosubstituted heteroaromatic ring being monosubstituted in the position of the ring carbon atom which is not adjacent to the attached carbon atom with a substituent selected from: halogen, lower alkyl, nitro, cyano, perfluoro-lower alkyl; hydroxy, - (CH)₂)_n-OR³，-(CH₂)_n-C(O)-OR³，-(CH₂)_n-C(O)-NH-R³，-C(O)C(O)-OR³Or is- (CH)₂)_n-NHR³；

R³Is hydrogen or lower alkyl; and

n is 0, 1, 2, 3 or 4;

wherein "lower alkyl" refers to straight and branched chain alkyl groups having 1 to 10 carbon atoms;

"" denotes an asymmetric carbon atom in the compound;

or a pharmaceutically acceptable salt thereof.

2. Compounds according to claim 1, wherein a is unsubstituted phenyl, or phenyl which may be substituted in position 4 or 7 by fluoro, lower alkylsulfonyl or lower alkylthio, or in position 5 or 6, or in positions 5 and 6 by chloro, or in position 5 or 6 by bromo or nitro, wherein "lower alkyl" is as defined in claim 1.

3. A compound according to claim 1 or 2 wherein the amide is in the S configuration at the asymmetric carbon atom indicated.

4. Compounds according to claim 1, wherein a is unsubstituted phenyl, or phenyl which may be mono-or di-substituted by halogen, or which may be mono-substituted by lower alkylsulfonyl or nitro, wherein "lower alkyl" is as defined in claim 1.

5. A compound according to claim 1, wherein a is unsubstituted phenyl, or phenyl monosubstituted by halogen.

6. A compound according to claim 1, wherein R is¹Is cycloalkyl having 3 to 9 carbon atoms.

7. A compound according to claim 1, wherein R is¹Is cyclopentyl or cyclohexyl.

8. A compound according to claim 1, wherein R is²Is an unsubstituted or mono-substituted five-or six-membered heteroaromatic ring which is attached to the indicated amine group via a ring carbon atom, which five-or six-membered heteroaromatic ring contains 1 or 2 heteroatoms selected from sulfur, oxygen or nitrogen, one of which is nitrogen, which is adjacent to the attached ring carbon atom, which ring is monocyclic or is fused on two of its ring carbon atoms with a phenyl group, said mono-substituted heteroaromatic ring being monosubstituted at a position of the ring carbon atom which is not adjacent to the attached carbon atom by a substituent selected from halogen or lower alkyl, wherein "lower alkyl" is as defined in claim 1.

9. A compound according to claim 1, wherein R is²Is a heteroaromatic ring selected from thiazolyl, quinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, benzimidazolyl, benzothiazolyl or benzoxazolyl, said heteroaromatic ring being optionally mono-substituted with halogen or lower alkyl, wherein "lower alkyl" is as defined in claim 1.

10. A compound according to claim 1, wherein R is²Is a heteroaromatic ring selected from thiazolyl, pyrimidinyl, pyrazinyl or pyridinyl, which heteroaromatic ring is optionally mono-substituted by halogen or lower alkyl, wherein "lower alkyl" is as defined in claim 1.

11. A compound according to claim 1, wherein R is²Is an unsubstituted heteroaromatic ring selected from thiazolyl, pyrimidinyl, pyrazinyl or pyridyl, or is a monosubstituted heteroaromatic ring selected from thiazolyl substituted by chlorine or pyridyl substituted by chlorine, bromine or lower alkyl, wherein "lower alkyl" is as defined in claim 1.

12. A compound according to claim 1, wherein a is unsubstituted phenyl, or phenyl which may be mono-or di-substituted with halogen, or which may be mono-substituted with lower alkylsulfonyl or nitro; r¹Is cycloalkyl having 5 to 8 carbon atoms; r²Is an unsubstituted or mono-substituted five-or six-membered heteroaromatic ring which is attached to the indicated amine group via a ring carbon atom, which five-or six-membered heteroaromatic ring contains 1 or 2 heteroatoms selected from sulfur, oxygen or nitrogen, one of which is nitrogen, which is adjacent to the attached ring carbon atom, which ring may be monocyclic or fused on two of its ring carbon atoms with a phenyl group, said mono-substituted heteroaromatic ring being monosubstituted at a position of the ring carbon atom which is not adjacent to the attached carbon atom by a substituent selected from halogen or lower alkyl, wherein "lower alkyl" is as defined in claim 1.

13. The compound of claim 1 selected from the group consisting of:

(S) -3-cyclohexyl-2- (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,

(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-methyl-pyridin-2-yl-propionamide,

3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrimidin-4-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-ylpropanamide,

(S) -3-cyclohexyl-2- (7-methylsulfonyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-ylpropanamide,

(S) -3-cyclohexyl-2- (6-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-thiazol-2-ylpropanamide,

(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-ylpropanamide,

n- (5-chloro-thiazol-2-yl) -3-cycloheptyl-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) -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- (7-chloro-1-oxo-1, 3 dihydro-isoindol-2-yl) -N-thiazol-2-yl-propionamide.

14. The compound of claim 1 selected from the group consisting of:

(S) -3-cyclohexyl-2- (4-fluoro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N-pyrazin-2-ylpropanamide,

(S) -3-cyclohexyl-2- (1-oxo-1, 3-dihydro-isoindol-2-yl) -N-5-methyl-pyridin-2-ylpropanamide, and

15. Pharmaceutical compositions comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable carrier and/or adjuvant.

16. A process for the preparation of a pharmaceutical composition according to claim 15, which comprises bringing a compound of formula I according to any one of claims 1 to 14 into association with a pharmaceutically acceptable carrier and/or adjuvant.

17. Compounds according to any of claims 1 to 14 for use as therapeutically active substances.

18. The use of compounds according to any of claims 1 to 14 for the preparation of medicaments for the treatment or prophylaxis of type II diabetes.

19. A process for preparing a compound of formula I, said process comprising:

reacting the compound of formula 3 under conventional reaction conditions for forming an amide bond

Wherein A and R¹As defined in claim 1;

and formula H₂N-R²Suitable for the coupling of heteroaromatic amines,

wherein R is²As defined in claim 1;

to give the compound of the formula I

Wherein^*，A，R¹And R²As defined in claim 1.