Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases

Abstract

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-xL proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-xL protein.

1 - 16 . (canceled) 
     
     
         17 . A compound having Formula (V): 
       
         
           
           
               
               
           
         
       
       or a therapeutically acceptable salt thereof, wherein
 X is heteroaryl; wherein the heteroaryl represented by X is optionally substituted with one, two, three, or four R 4 ; 
 R x , at each occurrence, is independently selected from the group consisting of R 5 , OR 5 , SR 5 , S(O)R 5 , SO 2 R 5 , C(O)R 5 , CO(O)R 5 , OC(O)R 5 , OC(O)OR 5 , NH 2 , NHR 5 , N(R 5 ) 2 , NHC(O)R 5 , NR 5 C(O)R 5 , NHS(O) 2 R 5 , NR 5 S(O) 2 R 5 , NHC(O)OR 5 , NR 5 C(O)OR 5 , NHC(O)NH 2 , NHC(O)NHR 5 , NHC(O)N(R 5 ) 2 , NR 5 C(O)NHR 5 , NR 5 C(O)N(R 5 ) 2 , C(O)NH 2 , C(O)NHR 5 , C(O)N(R 5 ) 2 , C(O)NHOH, C(O)NHOR 5 , C(O)NHSO 2 R 5 , C(O)NR 5 SO 2 R 5 , SO 2 NH 2 , SO 2 NHR 5 , SO 2 N(R 5 ) 2 , CO(O)H, C(O)H, OH, CN, N 3 , NO 2 , F, Cl, Br and I; 
 L 1  is selected from the group consisting of (CR 6 R 7 ) q , (CR 6 R 7 ) s —O—(CR 6 R 7 ) r , (CR 6 R 7 ) s —C(O)—(CR 6 R 7 ) r , (CR 6 R 7 ) s —S—(CR 6 R 7 ) r , (CR 6 R 7 ) s —S(O) 2 —(CR 6 R 7 ) r , (CR 6 R 7 ) s —NR 6A C(O)—(CR 6 R 7 ) r , (CR 6 R 7 ) s —C(O)NR 6A —(CR 6 R 7 ) r , (CR 6 R 7 ) s —NR 6A —(CR 6 R 7 ) r , (CR 6 R 7 ) s —S(O) 2 NR 6A —(CR 6 R 7 ) r , and (CR 6 R 7 ) s —NR 6A S(O) 2 —(CR 6 R 7 ) r ; and 
 Y 2  is selected from the group consisting of C 3-11  branched chain alkyl, C 3-7  cycloalkyl, C 4-7  cycloalkenyl, phenyl, and C 3-7  heterocyclyl; wherein the C 3-7  cycloalkyl, C 4-7  cycloalkenyl, phenyl, and C 3-7  heterocyclyl are optionally fused to one or two rings selected from the group consisting of C 3-8  cycloalkane, C 3-8  cycloalkene, benzene, C 5-6  heteroarene, C 3-8  heterocycloalkane, and C 3-8  heterocycloalkene; wherein Y 2  is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of R 8 , OR 8 , SR 8 , S(O)R 8 , SO 2 R 8 , C(O)R 8 , CO(O)R 8 , OC(O)R 8 , OC(O)OR 8 , NH 2 , NHR 8 , N(R 8 ) 2 , NHC(O)R 8 , NR 8 C(O)R 8 , NHS(O) 2 R 8 , NR 8 S(O) 2 R 8 , NHC(O)OR 8 , NR 8 C(O)OR 8 , NHC(O)NH 2 , NHC(O)NHR 8 , NHC(O)N(R 8 ) 2 , NR 8 C(O)NHR 8 , NR 8 C(O)N(R 8 ) 2 , C(O)NH 2 , C(O)NHR 8 , C(O)N(R 8 ) 2 , C(O)NHOH, C(O)NHOR 8 , C(O)NHSO 2 R 8 , C(O)NR 8 SO 2 R 8 , SO 2 NH 2 , SO 2 NHR 8 , SO 2 N(R 8 ) 2 , CO(O)H, C(O)H, OH, CN, N 3 , NO 2 , F, Cl, Br and I; or 
 L 1  is a bond; and 
 Y 2  is selected from the group consisting of C 3-7  cycloalkyl, C 4-7  cycloalkenyl, phenyl, and C 3-7  heterocyclyl; wherein the C 3-7  cycloalkyl, C 4-7  cycloalkenyl, phenyl, and C 3-7  heterocyclyl represented by Y 2  are optionally fused to one or two rings selected from the group consisting of C 3-8  cycloalkane, C 3-8  cycloalkene, benzene, C 5-6  heteroarene, C 3-8  heterocycloalkane, and C 3-8  heterocycloalkene; wherein each Y 2  and each ring fused to Y 2  are optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of R 8 , OR 8 , SR 8 , S(O)R 8 , SO 2 R 8 , C(O)R 8 , CO(O)R 8 , OC(O)R 8 , OC(O)OR 8 , NH 2 , NHR 8 , N(R 8 ) 2 , NHC(O)R 8 , NR 8 C(O)R 8 , NHS(O) 2 R 8 , NR 8 S(O) 2 R 8 , NHC(O)OR 8 , NR 8 C(O)OR 8 , NHC(O)NH 2 , NHC(O)NHR 8 , NHC(O)N(R 8 ) 2 , NR 8 C(O)NHR 8 , NR 8 C(O)N(R 8 ) 2 , C(O)NH 2 , C(O)NHR 8 , C(O)N(R 8 ) 2 , C(O)NHOH, C(O)NHOR 8 , C(O)NHSO 2 R 8 , C(O)NR 8 SO 2 R 8 , SO 2 NH 2 , SO 2 NHR 8 , SO 2 N(R 8 ) 2 , CO(O)H, C(O)H, OH, CN, N 3 , NO 2 , F, Cl, Br and I; 
 Z 1  is selected from the group consisting of C(O)OR 9 , C(O)NR 10 R 11 , C(O)R 11 , NR 10 C(O)R 11 , NR 10 C(O)NR 10 R 11 , OC(O)NR 10 R 11 , NR 10 C(O)OR 9 , C(═NOR 10 )NR 10 R 11 , NR 10 C(═NCN)NR 10 R 11 , NR 10 S(O) 2 NR 10 R 11 , S(O) 2 R 9 , S(O) 2 NR 10 R 11 , N(R 10 )S(O) 2 R 11 , NR 10 C(═NR 11 )NR 10 R 11 , C(═S)NR 10 R 11 , C(═NR 10 )NR 10 R 11 , halogen, NO 2 , and CN; or 
 Z 1  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         R 1 , at each occurrence, is independently selected from the group consisting of halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 1-6  haloalkyl; 
         R 2 , at each occurrence, is independently selected from the group consisting of deuterium, halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 1-6  haloalkyl; 
         two R 2  that are attached to the same carbon atom, together with said carbon atom, optionally form a ring selected from the group consisting of heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl; 
         R 3 , at each occurrence, is independently selected from the group consisting of halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 1-6  haloalkyl; 
         R 4 , at each occurrence, is independently selected from the group consisting of NR 12 R 13 , OR 12 , CN, NO 2 , halogen, C(O)OR 12 , C(O)NR 12 R 13 , NR 12 C(O)R 13 , NR 12 S(O) 2 R 14 , NR 12 S(O)R 14 , S(O) 2 R 14 , S(O)R 14  and R 14 ; 
         R 5 , at each occurrence, is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; 
         R 6A  is independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 1-6  haloalkyl; 
         R 6  and R 7 , at each occurrence, are each independently selected from the group consisting of hydrogen, R 15 , OR 15 , SR 15 , S(O)R 15 , SO 2 R 15 , C(O)R 15 , CO(O)R 15 , OC(O)R 15 , OC(O)OR 15 , NH 2 , NHR 15 , N(R 15 ) 2 , NHC(O)R 15 , NR 15 C(O)R 15 , NHS(O) 2 R 15 , NR 15 S(O) 2 R 15 , NHC(O)OR 15 , NR 15 C(O)OR 15 , NHC(O)NH 2 , NHC(O)NHR 15 , NHC(O)N(R 15 ) 2 , NR 15 C(O)NHR 15 , NR 15 C(O)N(R 15 ) 2 , C(O)NH 2 , C(O)NHR 15 , C(O)N(R 15 ) 2 , C(O)NHOH, C(O)NHOR 15 , C(O)NHSO 2 R 15 , C(O)NR 15 SO 2 R 15 , SO 2 NH 2 , SO 2 NHR 15 , SO 2 N(R 15 ) 2 , CO(O)H, C(O)H, OH, CN, N 3 , NO 2 , F, Cl, Br and I; 
         R 8 , at each occurrence, is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R 8  C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 1-6  haloalkyl are optionally substituted with one, two, three, four, five, or six substituents independently selected from the group consisting of R 16 , OR 16 , SR 16 , S(O)R 16 , SO 2 R 16 , C(O)R 16 , CO(O)R 16 , OC(O)R 16 , OC(O)OR 16 , NH 2 , NHR 16 , N(R 16 ) 2 , NHC(O)R 16 , NR 16 C(O)R 16 , NHS(O) 2 R 16 , NR 16 S(O) 2 R 16 , NHC(O)OR 16 , NR 16 C(O)OR 16 , NHC(O)NH 2 , NHC(O)NHR 16 , NHC(O)N(R 16 ) 2 , NR 16 C(O)NHR 16 , NR 16 C(O)N(R 16 ) 2 , C(O)NH 2 , C(O)NHR 16 , C(O)N(R 16 ) 2 , C(O)NHOH, C(O)NHOR 16 , C(O)NHSO 2 R 16 , C(O)NR 16 SO 2 R 16 , SO 2 NH 2 , SO 2 NHR 16 , SO 2 N(R 16 ) 2 , CO(O)H, C(O)H, OH, CN, N 3 , NO 2 , F, Cl, Br and I; wherein the R 8  aryl, heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, NH 2 , C(O)NH 2 , SO 2 NH 2 , C(O)H, (O), OH, CN, NO 2 , OCF 3 , OCF 2 CF 3 , F, Cl, Br and I; 
         R 9  is selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, cycloalkyl, phenyl and (CH 2 ) 1-4  phenyl; and 
         R 10  and R 11 , at each occurrence, are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, C 1-6  haloalkyl, phenyl and (CH 2 ) 1-4 -phenyl; or 
         R 10  and R 11 , or R 10  and R 9 , together with the atom to which each is attached are combined to form a heterocyclyl; 
         R k , at each occurrence, is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  heterocycloalkyl, C 3-7  cycloalkyl and C 1-6  haloalkyl; wherein the R k  C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl are optionally substituted with aryl, heterocyclyl, cycloalkyl, or cycloalkenyl; 
         R 12  and R 15 , at each occurrence, are each independently selected from the group consisting of hydrogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  haloalkyl and (CH 2 ) 1-4  phenyl; 
         R 14 , at each occurrence, is independently selected from the group consisting of C 1-6  alkyl, C 2-4  alkenyl, C 2-4  alkynyl and C 1-4  haloalkyl; 
         R 12  and R 15 , or R 12  and R 14 , at each occurrence, together with the atom to which each is attached, are optionally combined to form a heterocyclyl; 
         R 15 , at each occurrence, is independently selected from the group consisting of C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  haloalkyl, C 1-4  hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R 15  C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  haloalkyl, and C 1-4  hydroxyalkyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  haloalkyl, C 1-4  hydroxyalkyl, C 1-4  alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl, NH 2 , C(O)NH 2 , SO 2 NH 2 , C(O)H, C(O)OH, (O), OH, CN, NO 2 , OCF 3 , OCF 2 CF 3 , F, Cl, Br and I; 
         R 16 , at each occurrence, is independently selected from the group consisting of C 1-4  alkyl, C 2-6  alkenyl, C 2-4  alkynyl, C 1-4  haloalkyl, C 1-4  hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R 16  C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  haloalkyl, and C 1-4  hydroxyalkyl are optionally substituted with one substituent independently selected from the group consisting of OCH 3 , OCH 2 CH 2 OCH 3 , and OCH 2 CH 2 NHCH 3 ; 
         q is 1,2, or 3; 
         s is 0, 1, or 2; 
         r is 0, 1, or 2; 
         wherein the sum of s and r is 0, 1, or 2; 
         m is 0, 1, 2, or 3; 
         n is 0, 1, 2,3,4, 5, or 6; 
         o is 0, 1, 2,3, or 4; and 
         p is 0, 1, or 2. 
       
     
     
         18 . The compound or therapeutically acceptable salt of  claim 17 , wherein X is benzo[d]thiazolyl; which is optionally substituted with one, two, three or four R 4 . 
     
     
         19 . The compound or therapeutically acceptable salt of  claim 17 , wherein:
 Z 1  is   
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound or therapeutically acceptable salt of  claim 17 , wherein:
 L 1  is (CR 6 R 7 ) q ; and   Y 2  is selected from the group consisting of C 3-7  cycloalkyl, C 4-7  cycloalkenyl, phenyl, and C 3-7  heterocycloalkyl; wherein
 R 6  and R 7 , at each occurrence, are R 15  or hydrogen; and 
 q is 1,2, or 3. 
   
     
     
         21 . The compound or therapeutically acceptable salt of  claim 17 , wherein:
 L 1  is selected from the group consisting of (CR 6 R 7 ) s —NR 6A C(O)—(CR 6 R 7 ) r , (CR 6 R 7 ) s —C(O)NR 6A —(CR 6 R 7 ) r , (CR 6 R 7 ) s —NR 6A —(CR 6 R 7 ) r , (CR 6 R 7 ) s —S(O) 2 —NR 6A —(CR 6 R 7 ) r , and (CR 6 R 7 ) s —NR 6A S(O) 2 —(CR 6 R 7 ) r ;   s is 0;   r is 0 or 1;   R 6A  is independently selected from the group consisting of hydrogen, and C 1-6  alkyl; and   R 6  and R 7 , at each occurrence, are hydrogen.   
     
     
         22 . The compound or therapeutically acceptable salt of  claim 17 , wherein the compound is selected from the group consisting of:
 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(4-phenoxyphenyl)pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(3-phenoxyphenyl)pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(4-nitrophenoxy)phenyl]pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(4-chlorophenoxy)phenyl]pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(3-benzylphenyl)pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylmethyl)-2-methylphenyl]pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(4-methyl-3-phenoxyphenyl)pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-5-phenoxyphenyl)pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-phenoxyphenyl)pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-4-phenoxyphenyl)pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylmethoxy)-2-methylphenyl]pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexylmethoxy)-2-methylphenyl]pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-cyano-3-(cyclohexyloxy)phenyl]pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-chloro-3-(cyclohexyloxy)phenyl]pyridine-2-carboxylicacid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylamino)-2-methylphenyl]pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-fluorophenyl]pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-(trifluoromethyl)phenyl]pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)oxy]-2-methylphenyl}pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[methyl(phenyl)amino]phenyl}pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)(methyl)amino]-2-methylphenyl}pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(cyclohexylcarbonyl)(methyl)amino]-2-methylphenyl}pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[(1-methylcyclohexyl)carbonyl]amino}phenyl)pyridine-2-carboxylic acid;   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[(cyclohexylsulfonyl)(methyl)amino]phenyl}pyridine-2-carboxylic acid; and   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[2-(tricyclo[3.3.1.1 3,7 ]dec-1-ylpyrrolidin-1-yl]phenyl}pyridine-2-carboxylic acid.   
     
     
         23 . A pharmaceutical composition, comprising the compound or therapeutically acceptable salt of  claim 17 , and an excipient. 
     
     
         24 . A pharmaceutical composition, comprising the compound or therapeutically acceptable salt of  claim 22 , and an excipient. 
     
     
         25 . A method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, a lymphoid malignancy of T cell or B cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non small cell lung cancer, prostate cancer, small cell lung cancer, or spleen cancer in a patient, said method comprising administering to the patient a therapeutically effective amount of the compound or therapeutically acceptable salt thereof of  claim 17 . 
     
     
         26 . A method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, a lymphoid malignancy of T cell or B cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non small cell lung cancer, prostate cancer, small cell lung cancer, or spleen cancer in a patient, said method comprising administering to the patient a therapeutically effective amount of the compound or therapeutically acceptable salt thereof of  claim 22 .