Malic enzyme inhibitors

Abstract

The present invention relates to novel compounds useful as malic enzyme (ME) inhibitors, processes for their preparation and use of these compounds for the therapeutic treatment of disorders mediated by ME such as cancers (e.g. pancreatic ductal adenocarcinoma (PDAC)) in humans.

1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein
 X is CH; 
 R 1  is selected from hydrogen, —CH 3 , —COOH, fluoro and —CN; 
 R 2  is selected from hydrogen, —CH 3 , —COOH, fluoro and —CN; and 
 Y is selected from: 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , wherein Y is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , wherein R 1  and R 2  are hydrogen. 
     
     
         4 . The compound of  claim 1 , wherein
 R 1  and R 2  both are hydrogen; and   Y is selected from:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein
 R 1  and R 2  both are hydrogen; and   Y is selected from:   
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein Y is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 6 , wherein R 1  and R 2  both are hydrogen. 
     
     
         8 . The compound of  claim 1 , wherein Y is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 8 , wherein R 1  and R 2  both are hydrogen. 
     
     
         10 . A compound selected from:
 1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-phenylethanone,   4-(4-Hydroxyphenyl)piperazin-1-yl]-(1H-indol-3-yl)-methanone,   1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-(3,4,5-trimethoxyphenyl)-ethanone,   2-(4-Hydroxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,   1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-[4-(2-methoxyethoxy)-phenyl]-ethanone,   [4-(4-Hydroxyphenyl)-piperazin-1-yl]-[1-(2-methoxyethyl)-piperidin-4-yl]-methanone,   [4-(4-Hydroxyphenyl)-piperazin-1-yl]-(1H-indazol-3-yl)-methanone,   Acridin-9-yl-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-methanone,   [4-(4-Hydroxyphenyl)-piperazin-1-yl]-[5-(2-methoxyethoxy)-1H-indol-3-yl]-methanone,   1-[4-(2-Fluoro-4-hydroxy-phenyl)-piperazin-1-yl]-2-phenyl ethanone,   3-(4-Butoxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propan-1-one,   (5-Butoxy-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,   (1-Benzyl-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,   N-{(S)-1-Benzyl-2-[4-(4-hydroxyphenyl)-piperazin-1-yl]-2-oxoethyl}-acetamide,   1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-phenyl-ethane-1,2-dione,   (1-Butyl-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,   N-{(1R)-2-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-oxo-1-phenylethyl}acetamide,   (2,6-diphenyl-4-pyridyl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone,   Anthracen-9-yl-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,   [4-(4-Hydroxyphenyl)-piperazin-1-yl]-phenanthren-9-yl-methanone,   1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-3-naphthalen-2-yl-propan-1-one,   [4-(4-Hydroxyphenyl)-piperazin-1-yl]-quinolin-3-yl-methanone,   Anthracen-1-yl-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,   (1-Benzylindol-4-yl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone,   (3,5-Diphenylphenyl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone,   1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-ethanone,   [4-(4-Hydroxyphenyl)-piperazin-1-yl]-imidazo[1,2-a]yridine-8-yl-methanone,   [4-(4-Hydroxyphenyl)-piperazin-1-yl]-(1H-indol-4-yl)-methanone,   [4-(4-Hydroxyphenyl)-piperazin-1-yl]-[3-(4-trifluoromethylphenyl)-imidazo[1,2-a]yridine-8-yl]-methanone,   2-Hydroxy-5-(4-phenylacetylpiperazin-1-yl)-benzoic acid,   [4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-morpholino-6-phenyl-4-pyridyl)methanone,   [4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-phenyl-4-pyridyl)methanone,   [4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-morpholino-4-pyridyl)methanone,   (2-Chloro-6-morpholino-4-pyridyl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone,   5-[4-(2,6-Diphenylpyridine-4-carbonyl)piperazin-1-yl]-2-hydroxy-benzonitrile,   5-[4-(2,6-Diphenylpyridine-4-carbonyl)piperazin-1-yl]-2-hydroxy-benzoic acid,   3-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-2-pyridyl]benzoic acid,   1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-3,3-diphenyl-prop-2-en-1-one,   3-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-6-morpholino-2-pyridyl]benzoic acid,   4-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-6-morpholino-2-pyridyl]benzoic acid,   1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-3-naphthalen-1-yl-propan-1-one,   3-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-1H-quinolin-4-one,   1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-(2-phenoxyphenyl)ethanone,   [4-(4-Hydroxyphenyl)piperazin-1-yl]-[2-(1-piperidyl)-4-pyridyl]methanone,   1-[4-(4-Hydroxy-3-methyl-phenyl)-piperazin-1-yl]-2-phenylethanone,   3-Anthracen-9-yl-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propan-1-one,   2-(3,5-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,   2-(2,4-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,   2-(5-Fluoro-1H-indol-3-yl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,   2-(2-Bromophenylsulfanyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,   (2-Chloro-6-methylphenyl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,   (5-Fluoro-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,   1-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-2-(3,4,5-trifluoro-phenyl)-ethanone,   1-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-3-methyl-3-phenyl-butan-1-one, and   pharmaceutically acceptable salts, stereoisomers, and/or deuterated analogs thereof.   
     
     
         11 . The compound of  claim 10 , selected from:
 4-(4-Hydroxyphenyl)piperazin-1-yl]-(1H-indol-3-yl)-methanone,   2-(5-Fluoro-1H-indol-3-yl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,   2-(3,5-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,   2-(2,4-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone, and   pharmaceutically acceptable salts, stereoisomers, and/or deuterated analogs thereof.   
     
     
         12 . The compound of  claim 10 , selected from:
 [4-(4-Hydroxyphenyl)-piperazin-1-yl]-[1-(2-methoxyethyl)-piperidin-4-yl]-methanone,   [4-(4-Hydroxyphenyl)-piperazin-1-yl]-(1H-indazol-3-yl)-methanone,   Acridin-9-yl-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-methanone,   [4-(4-Hydroxyphenyl)-piperazin-1-yl]-[5-(2-methoxyethoxy)-1H-indol-3-yl]-methanone,   1-[4-(2-Fluoro-4-hydroxy-phenyl)-piperazin-1-yl]-2-phenylethanone,   3-(4-Butoxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propenone,   3-(4-Butoxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propan-1-one,   [4-(4-Hydroxyphenyl)-piperazin-1-yl]-phenanthren-9-yl-methanone,   [4-(4-Hydroxyphenyl)-piperazin-1-yl]-(1H-indol-4-yl)-methanone,   [4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-morpholino-6-phenyl-4-pyridyl)methanone,   [4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-morpholino-4-pyridyl)methanone,   (2-Chloro-6-morpholino-4-pyridyl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone, and   pharmaceutically acceptable salts, stereoisomers, and/or deuterated analogs thereof.   
     
     
         13 . The compound of  claim 10 , selected from:
 1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-phenylethanone,   4-(4-Hydroxyphenyl)piperazin-1-yl]-(1H-indol-3-yl)-methanone,   2-(4-Hydroxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,   1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-[4-(2-methoxyethoxy)-phenyl]-ethanone,   Anthracen-9-yl-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,   1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-ethanone,   3-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-2-pyridyl]benzoic acid,   1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-3,3-diphenyl-prop-2-en-1-one,   3-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-6-morpholino-2-pyridyl]benzoic acid,   4-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-6-morpholino-2-pyridyl]benzoic acid,   1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-3-naphthalen-1-yl-propan-1-one,   3-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-1H-quinolin-4-one,   1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-(2-phenoxyphenyl)ethanone,   [4-(4-Hydroxyphenyl)piperazin-1-yl]-[2-(1-piperidyl)-4-pyridyl]methanone,   1-[4-(4-Hydroxy-3-methyl-phenyl)-piperazin-1-yl]-2-phenylethanone,   3-Anthracen-9-yl-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propan-1-one,   2-(3,5-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,   2-(2,4-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,   2-(5-Fluoro-1H-indol-3-yl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,   2-(2-Bromophenylsulfanyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,   (2-Chloro-6-methylphenyl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,   (5-Fluoro-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,   1-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-2-(3,4,5-trifluoro-phenyl)-ethanone,   1-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-3-methyl-3-phenyl-butan-1-one,   and pharmaceutically acceptable salts, stereoisomers, and/or deuterated analogs thereof.   
     
     
         14 . A method of treating a subject having cancer, comprising administering to the subject a malic enzyme inhibitor, wherein the malic enzyme inhibitor is a compound of  claim 1 . 
     
     
         15 . The method of  claim 14 , wherein the malic enzyme is malic enzyme 3 (ME3), malic enzyme 2 (ME2) and/or malic enzyme 1 (ME1). 
     
     
         16 . The method of  claim 15 , wherein the malic enzyme is malic enzyme 3. 
     
     
         17 . The method of  claim 14 , wherein the cancer is selected from leukemia, brain cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testis cancer, thyroid cancer, and urothelial cancer. 
     
     
         18 . A method of treating a subject having cancer, comprising administering to the subject a malic enzyme inhibitor, wherein the malic enzyme inhibitor is a compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein
 X is CH; 
 R 1  is selected from hydrogen, CH 3 , —COOH, fluoro and CN; 
 R 2  is selected from hydrogen, CH 3 , —COOH, fluoro and CN; and 
 Y is selected from substituted or unsubstituted C 1-5  alkyl, substituted or unsubstituted C 2-4  alkenyl, substituted or unsubstituted 5 to 14 membered heteroaryl ring containing one, two or three heteroatoms each independently selected from nitrogen, oxygen, and sulfur, substituted or unsubstituted 5 to 14 membered heterocycloalkyl group containing one, two or three heteroatoms each independently selected from nitrogen and oxygen, substituted or unsubstituted C 3-15  cycloalkyl, substituted or unsubstituted C 3-15  cycloalkylC 1-6 alkyl, substituted or unsubstituted C 6-14  aryl, substituted or unsubstituted C 6-14 arylC 1-6 alkyl, substituted or unsubstituted C 6-14 arylC 2-5 alkenyl, substituted or unsubstituted 5 to 14 membered heteroarylC 1-6 alkyl, and substituted or unsubstituted 5 to 14 membered heterocycloalkylC 1-6 alkyl. 
 
       
     
     
         19 . The method of  claim 18 , wherein the malic enzyme is malic enzyme 3 (ME3), malic enzyme 2 (ME2) and/or malic enzyme 1 (ME1). 
     
     
         20 . The method of  claim 19 , wherein the malic enzyme is malic enzyme 3. 
     
     
         21 . The method of  claim 18 , wherein the cancer is selected from leukemia, brain cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testis cancer, thyroid cancer, and urothelial cancer. 
     
     
         22 . The compound of  claim 1 , for use in the treatment of a subject having cancer by inhibiting the malic enzyme. 
     
     
         23 . The compound of  claim 22 , wherein the malic enzyme is malic enzyme 3 (ME3), malic enzyme 2 (ME2), and/or malic enzyme 1 (ME1). 
     
     
         24 . The compound of  claim 23 , wherein the malic enzyme is malic enzyme 3. 
     
     
         25 . The compound of  claim 22 , wherein the cancer is selected from leukemia, brain cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testis cancer, thyroid cancer, and urothelial cancer. 
     
     
         26 . A compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein 
         X is CH; 
         R 1  is selected from hydrogen, CH 3 , —COOH, fluoro and CN; 
         R 2  is selected from hydrogen, CH 3 , —COOH, fluoro and CN; 
         Y is selected from substituted or unsubstituted C 1-5  alkyl, substituted or unsubstituted C 2-4  alkenyl, substituted or unsubstituted 5 to 14 membered heteroaryl ring containing one, two or three heteroatoms each independently selected from nitrogen, oxygen, and sulfur, substituted or unsubstituted 5 to 14 membered heterocycloalkyl group containing one, two or three heteroatoms each independently selected from nitrogen and oxygen, substituted or unsubstituted C 3-15  cycloalkyl, substituted or unsubstituted C 3-15  cycloalkylC 1-6 alkyl, substituted or unsubstituted C 6-14  aryl, substituted or unsubstituted C 6-14 arylC 1-6 alkyl, substituted or unsubstituted C 6-14 arylC 2-5 alkenyl, substituted or unsubstituted 5 to 14 membered heteroarylC 1-6 alkyl, and substituted or unsubstituted 5 to 14 membered heterocycloalkylC 1-6 alkyl, for use in the treatment of a subject having cancer by inhibiting a malic enzyme. 
       
     
     
         27 . The compound of  claim 26 , wherein the malic enzyme is malic enzyme 3 (ME3), malic enzyme 2 (ME2), and/or malic enzyme 1 (ME1). 
     
     
         28 . The compound of  claim 27 , wherein the malic enzyme is malic enzyme 3. 
     
     
         29 . The compound of  claim 26 , wherein the cancer is selected from leukemia, brain cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testis cancer, thyroid cancer, and urothelial cancer. 
     
     
         30 . A medicament comprising a compound according to  claim 1  for treating a subject having cancer by inhibiting a malic enzyme. 
     
     
         31 . The medicament of  claim 30 , wherein the malic enzyme is malic enzyme 3 (ME3), malic enzyme 2 (ME2), and/or malic enzyme 1 (ME1). 
     
     
         32 . The medicament of  claim 31 , wherein the malic enzyme is malic enzyme 3 (ME3). 
     
     
         33 . The medicament of  claim 30 , wherein the cancer is selected from leukemia, brain cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testis cancer, thyroid cancer, and urothelial cancer. 
     
     
         34 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         35 . A method of inhibiting a malic enzyme in a subject comprising administering to the subject in need thereof, a compound of  claim 1 . 
     
     
         36 . The method of  claim 35 , wherein the subject has cancer. 
     
     
         37 . The method of  claim 36 , wherein the cancer is selected from leukemia, brain cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testis cancer, thyroid cancer, and urothelial cancer. 
     
     
         38 . The method of  claim 35 , wherein the malic enzyme is malic enzyme 3 (ME3), malic enzyme 2 (ME2), and/or malic enzyme 1 (ME1). 
     
     
         39 . The method of  claim 38 , wherein the malic enzyme is malic enzyme 3 (ME3). 
     
     
         40 . A method of inhibiting a malic enzyme in a subject comprising administering to the subject in need thereof, a compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein
 X is CH; 
 R 1  is selected from hydrogen, CH 3 , —COOH, fluoro and CN; 
 R 2  is selected from hydrogen, CH 3 , —COOH, fluoro and CN; 
 Y is selected from substituted or unsubstituted C 1-5  alkyl, substituted or unsubstituted C 2-4  alkenyl, substituted or unsubstituted 5 to 14 membered heteroaryl ring containing one, two or three heteroatoms each independently selected from nitrogen, oxygen, and sulfur, substituted or unsubstituted 5 to 14 membered heterocycloalkyl group containing one, two or three heteroatoms each independently selected from nitrogen and oxygen, substituted or unsubstituted C 3-15  cycloalkyl, substituted or unsubstituted C 3-15  cycloalkylC 1-6 alkyl, substituted or unsubstituted C 6-14  aryl, substituted or unsubstituted C 6-14 arylC 1-6 alkyl, substituted or unsubstituted C 6-14 arylC 2-5 alkenyl, substituted or unsubstituted 5 to 14 membered heteroarylC 1-6 alkyl, and substituted or unsubstituted 5 to 14 membered heterocycloalkylC 1-6 alkyl. 
 
       
     
     
         41 . The method of  claim 40 , wherein the subject has cancer. 
     
     
         42 . The method of  claim 41 , wherein the cancer is selected from leukemia, brain cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testis cancer, thyroid cancer, and urothelial cancer. 
     
     
         43 . The method of  claim 40 , wherein the malic enzyme is malic enzyme 3 (ME3), malic enzyme 2 (ME2), and/or malic enzyme 1 (ME1). 
     
     
         44 . The method of  claim 44 , wherein the malic enzyme is malic enzyme 3 (ME3).