Pyrazoline compounds

Abstract

Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I: wherein R 1 , R 2 , R 3A , R 3B , R 4 , R 5 , R 6 , R 7 , R 8 , and X are as defined in the detailed description of the invention. Corresponding pharmaceutical compositions, methods of treatment, and intermediates are also disclosed.

1 . A compound, or a pharmaceutically acceptable salt of the compound, wherein the compound has the structure of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is selected from the group consisting of —CH 2 — and —O—; 
 R 1  is selected from the group consisting of cyclopentyl and phenyl; wherein the R 1  cyclopentyl and phenyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, methyl, ethyl, propyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl and trifluoromethyl; 
 R 2  is selected from the group consisting of hydrogen and alkyl; 
 R 3A  and R 3B  are independently selected from the group consisting of hydrogen and alkyl; 
 R 4 , R 6 , and R 7  are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, and alkoxy; 
 R 5  is selected from the group consisting of hydrogen, —(CH 2 ) m OR 50 , —(CH 2 ) m C(O)R 50 , —(CH 2 ) m C(O)OR 50 , —(CH 2 ) m C(O)NR 51 R 52 , —(CH 2 ) m NR 51 R 52 , —(CH 2 ) m N(R 51 )C(O)R 52 , and —(CH 2 ) m S(O) n R 50 ; 
 m is 0, 1, 2, 3, 4, 5, or 6; 
 n is 0, 1, or 2; 
 R 50  is selected from the group consisting of hydrogen and alkyl; 
 R 51  and R 52  are independently selected from the group consisting of hydrogen and alkyl; or R 51  and R 52  together with the nitrogen to which they are attached form a five- or six-membered ring heterocyclyl; 
 wherein the R 50 , R 51  and R 52  alkyl substituents and the R 51 /R 52  heterocyclyl substituent may be independently and optionally substituted with one or more substituents selected from the group consisting of halogen, pyrolidinyl, —OR 53 , —C(O)R 53 , —C(O)OR 53 , —C(O)NR 54 R 55 , —NR 54 R 55 , —N(R 56 )C(O)R 53 ; —S(O) p R 53 , and —S(O) p NR 54 R 55 ; 
 p is 0, 1, or 2; 
 R 53  is selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, and carboxyalkyl; 
 R 54  and R 55  are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, and carboxyalkyl; or R 54  and R 55  together with the nitrogen to which they are attached form a five- or six-membered ring heterocyclyl; 
 R 56  is selected from the group consisting of hydrogen and alkyl; and 
 R 8  is selected from the group consisting of phenyl, pyridinyl and pyrimidinyl; wherein the phenyl, pyridinyl and pyrimidinyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, carboxyalkyl, alkoxy, haloalkoxy, cyanoalkoxy, amino, alkylamino, dialkylamino, and alkoxycarbonyl 
 with the proviso that 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid is not included. 
 
     
     
         2 - 66 . (canceled) 
     
     
         67 . A compound, or a pharmaceutically acceptable salt of the compound, wherein the compound has the structure of Formula II: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is selected from the group consisting of —CH 2 — and —O—; 
 Z is selected from the group consisting of —C(R 81 )— and —N—; 
 R 1  is selected from the group consisting of cyclopentyl and phenyl; wherein the R 1  cyclopentyl and phenyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, methyl, ethyl, propyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl and trifluoromethyl; 
 R 2  is selected from the group consisting of hydrogen or (C 1 -C 4 )-alkyl; 
 R 5  is selected from the group consisting of —(CH 2 ) m OR 50 , —(CH 2 ) m C(O)OR 50 , and —(CH 2 ) m C(O)NR 51 R 52 ; wherein: 
 m is 0, 1, 2, or 3; 
 R 50  is selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl; 
 R 51  and R 52  are independently selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl; 
 wherein the R 50 , R 51  and R 52  (C 1 -C 6 )-alkyl substituents may be independently and optionally substituted with one or more substituents selected from the group consisting of halogen, —OR 53 , —C(O)R 53 , —C(O)OR 53 , —C(O)NR 54 R 55 , —NR 54 R 55 , —N(R 56 )C(O)R 53 ; —S(O) p R 53 , and —S(O) p NR 54 R 55 ; 
 p is 0, 1 or 2; 
 R 53  is selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, halo-(C 1 -C 6 )-alkyl, hydroxy-(C 1 -C 6 )-alkyl, and carboxy-(C 1 -C 6 )-alkyl; 
 R 54  and R 55  are independently selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, halo-(C 1 -C 6 )-alkyl, hydroxy-(C 1 -C 6 )-alkyl, and carboxy-(C 1 -C 6 )-alkyl; and 
 R 81 , R 82 , R 83 , R 84 , and R 85  are independently selected from the group consisting of hydrogen, chloro, fluoro, cyano, hydroxy, carboxy, methyl, ethyl, trichloromethyl, trifluoromethyl, cyanomethyl, hydroxymethyl, carboxymethyl, methoxy, amino, methylamino, and dimethylamino 
 with the proviso that 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid is not included. 
 
     
     
         68 . (canceled) 
     
     
         69 . A compound according to  claim 67 , wherein R 2  is hydrogen. 
     
     
         70 . A compound according to  claim 69 , wherein:
 R 5  is —(CH 2 ) m C(O)OR 50 ; wherein:   m is 0, 1, 2, or 3;   R 50  is selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl; wherein the R 50  (C 1 -C 6 )-alkyl substituent may be independently and optionally substituted with one or more substituents selected from the group consisting of halogen, —OR 53 , —C(O)R 53 , —C(O)OR 53 , —C(O)NR 54 R 55 , —NR 54 R 55 , —N(R 56 )C(O)R 53 ; —S(O) p R 53 , and —S(O) p NR 54 R 55 ;   p is 0, 1 or 2;   R 53  is selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, halo-(C 1 -C 6 )-alkyl, hydroxy-(C 1 -C 6 )-alkyl, and carboxy-(C 1 -C 6 )-alkyl; and   R 54  and R 55  are independently selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, halo-(C 1 -C 6 )-alkyl, hydroxy-(C 1 -C 6 )-alkyl, and carboxy-(C 1 -C 6 )-alkyl.   
     
     
         71 . A compound according to  claim 69 , wherein:
 R 5  is —(CH 2 ) m C(O)0R 50 ; wherein:   m is 0, 1, or 2;   R 50  is selected from the group consisting of hydrogen and (C 1 -C 4 )-alkyl; wherein the R 50  (C 1 -C 4 )-alkyl substituent may be independently and optionally substituted with one or more substituents selected from the group consisting of halogen, —OR 53 , —C(O)R 53 , and —C(O)OR 53 ; and   R 53  is selected from the group consisting of hydrogen and (C 1 -C 4 )-alkyl.   
     
     
         72 . A compound according to  claim 69 , wherein:
 Z is selected from the group consisting of —C(R 81 )— and —N—;   R 1  is selected from the group consisting of cyclopentyl and phenyl; wherein the R 1  cyclopentyl and phenyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, methyl, and trifluoromethyl;   R 5  is —(CH 2 ) m C(O)OR 50 ; wherein:   m is 0, 1, or 2;   R 50  is selected from the group consisting of hydrogen and (C 1 -C 4 )-alkyl; wherein the R 50  (C 1 -C 4 )-alkyl substituent may be independently and optionally substituted with one or more substituents selected from the group consisting of halogen, —OR 53 , —C(O)R 53 , and —C(O)OR 53 ; and   R 53  is selected from the group consisting of hydrogen and (C 1 -C 4 )-alkyl; and   R 81 , R 82 , R 83 , R 84 , and R 85  are independently selected from the group consisting of hydrogen, chloro, fluoro, cyano, hydroxy, carboxy, methyl, ethyl, cyanomethyl, hydroxymethyl, carboxymethyl, methoxy, amino, methylamino, and dimethylamino.   
     
     
         73 . A compound according to  claim 69 , wherein:
 Z is selected from the group consisting of —C(R 81 )— and —N—;   R 1  is selected from the group consisting of cyclopentyl and phenyl; wherein the R 1  cyclopentyl and phenyl substituents may be optionally substituted with fluoro;   R 5  is —(CH 2 ) m C(O)OR 50 ; wherein:   m is 0;   R 50  is selected from the group consisting of hydrogen and (C 1 -C 4 )-alkyl; and   R 81  and R 85  are each hydrogen; and   R 82 , R 83 , and R 84  are independently selected from the group consisting of chloro, cyano, and methyl.   
     
     
         74 . A compound according to  claim 69 , wherein:
 X is —CH 2 —;   Z is —C(R 81 )—;   R 1  is selected from the group consisting of cyclopentyl and phenyl; wherein the R 1  phenyl substituent may be optionally substituted with fluoro;   R 5  is —(CH 2 ) m C(O)OR 50 ; wherein:   m is 0;   R 50  is hydrogen;   R 81 , R 84  and R 85  are each hydrogen; and   R 82  and R 83  are independently selected from the group consisting of chloro, cyano, and methyl.   
     
     
         75 . A compound according to  claim 74 , wherein R 82  is selected from the group consisting of chloro and methyl; and R 83  is cyano. 
     
     
         76 . A compound according to  claim 74 , wherein R 82  is chloro and R 83  is cyano. 
     
     
         77 . A compound according to  claim 74 , wherein R 1  is cyclopentyl. 
     
     
         78 . A compound according to  claim 74 , wherein R 1  is phenyl; wherein the R 1  phenyl substituent may be optionally substituted with fluoro. 
     
     
         79 . A compound according to  claim 74 , wherein R 1  is phenyl; wherein the R 1  phenyl substituent may be optionally substituted with fluoro at the para position. 
     
     
         80 . A compound according to  claim 69 , wherein:
 X is —O—;   Z is —C(R 81 )—;   R 1  is selected from the group consisting of cyclopentyl and phenyl; wherein the R 1  phenyl substituent may be optionally substituted with fluoro;   R 5  is —(CH 2 ) m C(O)OR 50 ; wherein:   m is 0;   R 50  is hydrogen;   R 81 , R 84  and R 85  are each hydrogen; and   R 82  and R 83  are independently selected from the group consisting of chloro, cyano, and methyl.   
     
     
         81 . A compound according to  claim 80 , wherein R 82  is selected from the group consisting of chloro and methyl; and R 83  is cyano. 
     
     
         82 . (canceled) 
     
     
         83 . A compound according to  claim 80 , wherein R 1  is cyclopentyl. 
     
     
         84 - 85 . (canceled) 
     
     
         86 . A compound according to  claim 69 , wherein:
 X is —CH 2 —;   Z is —N—;   R 1  is selected from the group consisting of cyclopentyl and phenyl; wherein the R 1  phenyl substituent may be optionally substituted with fluoro;   R 5  is —(CH 2 ) m C(O)OR 50 ; wherein:   m is 0;   R 50  is hydrogen;   R 81 , R 84  and R 85  are each hydrogen; and   R 82  and R 83  are independently selected from the group consisting of chloro, cyano, and methyl.   
     
     
         87 .- 91 . (canceled) 
     
     
         92 . A compound according to  claim 69 , wherein:
 X is —O—;   Z is —N—;   R 1  is selected from the group consisting of cyclopentyl and phenyl; wherein the R 1  phenyl substituent may be optionally substituted with fluoro;   R 5  is —(CH 2 ) m C(O)OR 50 ; wherein:   m is 0;   R 50  is hydrogen;   R 81 , R 84  and R 85  are each hydrogen; and   R 82  and R 83  are independently selected from the group consisting of chloro, cyano, and methyl.   
     
     
         93 .- 97 . (canceled) 
     
     
         98 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         99 . The composition of  claim 98 , further comprising a therapeutically effective amount of one or more compounds selected from the group consisting of diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, beta blockers, alpha blockers, alpha-beta blockers, aldosterone receptor antagonists and renin inhibitors. 
     
     
         100 . The composition of  claim 99 , wherein the diuretics are selected from the group consisting of loop diuretics, thiazide-type diuretics, phthalamide-type diuretics, quinazoline-type diuretics and potassium sparing diuretics. 
     
     
         101 .- 110 . (canceled) 
     
     
         111 . A method of treating a condition selected from the group consisting of cardiovascular conditions, renal conditions, liver conditions, vascular conditions, inflammatory conditions, pain, retinopathy, neuropathy (such as peripheral neuropathy), insulinopathy, edema, endothelial dysfunction and baroreceptor dysfunction comprising administering a therapeutically effective amount of a compound of  claim 1  to a subject in need thereof. 
     
     
         112 .- 113 . (canceled) 
     
     
         114 . The method of  claim 111 , wherein the cardiovascular condition is hypertension. 
     
     
         115 . (canceled) 
     
     
         116 . The method of  claim 111 , wherein the renal condition is nephrapathy. 
     
     
         117 . A compound, or a pharmaceutically acceptable salt of the compound, selected from the group consisting of:
 2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid;   3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-methylbenzonitrile;   3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-(trifluoromethyl)benzonitrile;   2-chloro-4-(3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)benzonitrile;   2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide.   2-(4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid;   2-(4-cyano-3-methylphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid;   2-(5-cyano-6-methylpyridin-2-yl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid;   2-(4-cyano-3-methoxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid;   N-(-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazol-7-yl)acetamide;   methyl 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate;   2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3a-methyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid;   2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-N-(2-(methylsulfonyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide;   2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-N-(2-hydroxyethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide;   2-(4-cyano-3-methylphenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid.   2-(3-chloro-4-cyanophenyl)-3-cyclobutyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid;   2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid;   2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid.   2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid;   2-(3-chloro-4-cyanophenyl)-3-(3-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid;   2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-furyl)-N[2-(methylsulfonyl)ethyl]-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide;   2-(3-chloro-4-cyanophenyl)-N-[2-(methylsulfonyl)ethyl]-3-(2-methyl-1,3-thiazol-5-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide.   2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid;   2-[4-cyano-3-(trifluoromethyl)phenyl]-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid;   2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid; and   2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid.