Small molecule inhibitors of the mcl-1 oncoprotein and uses therof

Abstract

Compounds that inhibit Myeloid Cell Leukemia-1 (Mcl-1) oncoprotein, and methods of using the same, are provided for treating disease.

1 .- 8 . (canceled) 
     
     
         9 . A compound of formula (IV): 
       
         
           
           
               
               
           
         
         wherein R 41  is a substituent selected from the group consisting of H and optionally substituted alkyl, aryl, and cycloalkyl; 
         Z 41  and Z 42  each can independently represent a substituent selected from the group consisting of H, cyano, OR 42 , COOR 42 , CONR 42 OR 42 , CONR 42 R 42 , CON(R 42 )—S(O) 2 R 42 , 
       
       
         
           
           
               
               
           
         
       
       and optionally substituted alkyl and aryl;
 each R 42  can independently represent a substituent selected from the group consisting of H and optionally substituted alkyl and aryl; 
 A 41  is a bond or a substituent selected from the group consisting of S(═O), S(═O) 2 , and C(═O); 
 X 41  is a substituent selected from the group consisting of optionally substituted alkyl, aryl, cycloalkyl, and heterocycloalkyl; or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. 
 
     
     
         10 . The compound of  claim 9 , wherein the compound is selected from the group consisting of 4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
 4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid, 
 2-hydroxy-4-(N-isobutylphenylsulfonamido)benzoic acid, 
 2-hydroxy-4-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid, 
 4-(4-bromo-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid, 
 2-hydroxy-4-(N-isobutyl-4-(p-tolyloxy)phenylsulfonamido)benzoic acid, 
 4-(4-(3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid, 
 4-(4-(2,4-dichlorophenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid, 
 2-hydroxy-4-(4-phenoxyphenylsulfonamido)benzoic acid, 
 3-(N-isobutylphenylsulfonamido)benzoic acid, 
 3-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid, 
 2-hydroxy-5-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid, 
 5-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid, 
 methyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate, 
 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(phenylsulfonyl)benzamide, 
 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(methylsulfonyl)benzamide, 
 4-(N-isobutyl-4-phenoxyphenylsulfonamido)-2-((4-(((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)carbamoyl)benzyl)oxy)benzoic acid, 
 4-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid, 
 4-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid, 
 2-hydroxy-4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid, 
 2-hydroxy-4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid, 
 4-(N-cyclopentyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid, 
 4-(N-cyclopentylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid, 
 4-(4-(4-chloro-3,5-dimethylphenoxy)-N-cyclopentylphenylsulfonamido)-2-hydroxybenzoic acid, 
 3-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid, 
 3-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid, 
 3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid, 
 phenyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate, 
 acetoxymethyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate, 
 N-(4-cyano-3-hydroxyphenyl)-N-isobutyl-4-phenoxybenzenesulfonamide, 
 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, 
 4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, 
 3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid, 
 4-(4-fluoro-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid, 
 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoic acid, 
 4-(N-benzyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid, 
 4-(N-benzylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid, 
 4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid, 
 3-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid, 
 2-hydroxy-5-(N-isobutylphenylsulfonamido)benzoic acid, 
 2-hydroxy-5-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid, 
 N-(4-(2H-tetrazol-5-yl)phenyl)-N-isobutyl-4-phenoxybenzenesulfonamide, 
 N,2-dihydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzamide, 
 N-isobutyl-N-(4-(3-oxo-2,3-dihydroisoxazol-5-yl)phenyl)-4-phenoxybenzenesulfonamide, 
 5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid, 
 5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. 
 
     
     
         11 . The compound of  claim 9 , wherein Z 41  and Z 42  each can independently represent a substituent selected from the group consisting of OR 42  and COOR 42 . 
     
     
         12 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. 
     
     
         13 . A method of treating a condition by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method comprising administering a therapeutically effective amount of a compound of  claim 9  or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. 
     
     
         14 .- 16 . (canceled) 
     
     
         17 . A method of treating a condition by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method comprising administering a therapeutically effective amount of one or more compounds selected from the group consisting of:
 4-(N-isobutylphenylsulfonamido)benzoic acid,   4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,   4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,   2-hydroxy-4-(N-isobutylphenylsulfonamido)benzoic acid,   2-hydroxy-4-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,   4-(4-bromo-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,   2-hydroxy-4-(N-isobutyl-4-(p-tolyloxy)phenylsulfonamido)benzoic acid,   4-(4-(3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,   4-(4-(2,4-dichlorophenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,   2-hydroxy-4-(4-phenoxyphenylsulfonamido)benzoic acid,   3-(N-isobutylphenylsulfonamido)benzoic acid,   3-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,   2-hydroxy-5-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,   5-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,   methyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,   4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(phenylsulfonyl)benzamide,   4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(methylsulfonyl)benzamide,   4-(N-isobutyl-4-phenoxyphenylsulfonamido)-2-((4-(((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)carbamoyl)benzyl)oxy)benzoic acid,   4-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,   4-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,   2-hydroxy-4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,   2-hydroxy-4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,   4-(N-cyclopentyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,   4-(N-cyclopentylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,   4-(4-(4-chloro-3,5-dimethylphenoxy)-N-cyclopentylphenylsulfonamido)-2-hydroxybenzoic acid,   3-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,   3-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,   3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,   phenyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,   acetoxymethyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,   N-(4-cyano-3-hydroxyphenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,   4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,   4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,   3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,   4-(4-fluoro-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,   2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoic acid,   4-(N-benzyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,   4-(N-benzylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,   4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,   3-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,   2-hydroxy-5-(N-isobutylphenylsulfonamido)benzoic acid,   2-hydroxy-5-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,   N-(4-(2H-tetrazol-5-yl)phenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,   N,2-dihydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzamide,   N-isobutyl-N-(4-(3-oxo-2,3-dihydroisoxazol-5-yl)phenyl)-4-phenoxybenzenesulfonamide,   5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,   5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.   
     
     
         18 . A method of treating a condition by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method comprising administering a therapeutically effective amount of a compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. 
     
     
         19 . The method of  claim 18 , wherein the condition is selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma. 
     
     
         20 . The method of  claim 18 , wherein the condition is selected from the group consisting of myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer. 
     
     
         21 . A pharmaceutical composition for treating a condition alleviated by inhibiting Mcl-1 protein activity, the pharmaceutical composition comprising one or more compounds according to  claim 12 , and a pharmaceutically acceptable carrier. 
     
     
         22 . The method of  claim 13 , wherein the condition is selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma. 
     
     
         23 . The method of  claim 13 , wherein the condition is selected from the group consisting of myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer. 
     
     
         24 . A pharmaceutical composition for treating a condition alleviated by inhibiting Mcl-1 protein activity, the pharmaceutical composition comprising one or more compounds according to  claim 9 , and a pharmaceutically acceptable carrier. 
     
     
         25 . The method of  claim 17 , wherein the condition is selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma. 
     
     
         26 . The method of  claim 17 , wherein the condition is selected from the group consisting of myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer. 
     
     
         27 . A pharmaceutical composition for treating a condition alleviated by inhibiting Mcl-1 protein activity, the pharmaceutical composition comprising one or more compounds according to  claim 10 , and a pharmaceutically acceptable carrier.