US2015038484A1PendingUtilityA1
Indole and indazole compounds that activate ampk
Est. expiryApr 10, 2032(~5.7 yrs left)· nominal 20-yr term from priority
Inventors:Samit Kumar BhattacharyaKimberly O. CameronMatthew S. DowlingDilinie FernandoDavid Christopher EbnerKevin James FilipskiDaniel Wei-Shung KungEsther Cheng Yin LeeAaron SmithMeihua Mike Tu
A61P 3/06A61P 35/00A61P 3/10A61P 3/04A61P 3/00A61P 13/12C07D 403/04C07D 209/30C07D 209/42A61K 31/4155C07D 401/12C07D 401/04C07D 401/10C07D 413/12A61K 31/416A61K 31/404C07D 405/12C07D 403/12C07D 401/14C07D 231/56C07D 405/10C07D 403/10C07D 413/14C07D 405/14C07D 405/04
51
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Claims
Abstract
The present invention relates to indole and indazole compounds of Formula (I) that activate 5′ adenosine monophosphate-activated protein kinase (AMPK). The invention also encompasses pharmaceutical compositions containing these compounds and methods for treating or preventing diseases, conditions, or disorders ameliorated by activation of AMPK.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A method of treating or preventing chronic kidney disease, diabetic nephropathy, acute kidney injury or polycystic kidney disease in a human comprising administering to the human in need of such treatment a therapeutically effective amount of a compound of Formula (I), wherein
X is N or CH;
R 1 is —C(O)OR A , —C(O)NR B R C , —S(O 2 )OR A , —S(O 2 )NHC(O)R D , 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, or 1H-tetrazol-5-yl;
R A is H or (C 1 -C 6 )alkyl;
R B and R C are independently H, (C 1 -C 6 )alkyl, or —S(O 2 )R D ;
R D is (C 1 -C 6 )alkyl, —CF 3 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, mercapto, nitro, or NR E R F ;
R E and R F are independently H or (C 1 -C 6 )alkyl;
R 2 , R 3 , and R 4 are independently H, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 8 )alkyl, mercapto, nitro, —NR G R H or (NR G R H )carbonyl;
R G and R H are independently H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylcarbonyl;
R 5 is H or (C 1 -C 6 )alkyl;
L is a bond, O, S, NR A , (C 1 -C 6 )alkylene, (C 2 -C 6 )alkenylene, or (C 2 -C 6 )alkynylene;
A is phenyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydro-1H-indenyl, imidazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiazolyl, wherein each is optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, aryl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkyl, arylcarbonyl, aryloxy, carboxy, carboxy(C 1 -C 6 )alkoxy, carboxy(C 1 -C 6 )alkyl, cyano, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkylcarbonyl, (C 3 -C 8 )cycloalkyloxy, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, heteroaryl, heteroaryl(C 1 -C 6 )alkoxy, heteroaryl(C 1 -C 6 )alkyl, heteroarylcarbonyl, heteroaryloxy, (C 3 -C 7 )heterocycle, (C 3 -C 7 )heterocycle(C 1 -C 6 )alkoxy, (C 3 -C 7 )heterocycle(C 1 -C 6 )alkyl, (C 3 -C 7 )heterocyclecarbonyl, (C 3 -C 7 )heterocyclecarbonyl(C 1 -C 6 )alkyl, (C 3 -C 7 )heterocycleoxy, hydroxy, hydroxy(C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR J R K , (NR J R K )carbonyl, —NR M R N , —NR M R N (C 1 -C 6 )alkoxy, (NR M R N )carbonyl, (NR M R N )carbonyl(C 1 -C 6 )alkyl, or (NR M R N )carbonyl(C 1 -C 6 )alkoxy; wherein the aryl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkyl, arylcarbonyl, and aryloxy are optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR M R N , or (NR M R N )carbonyl; wherein the halo(C 1 -C 6 )alkyl is optionally substituted with 1 or 2 hydroxy groups; wherein the (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkylcarbonyl, and (C 3 -C 8 )cycloalkyloxy are optionally substituted with 1, 2, or 3 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR M R N , or (NR M R N )carbonyl; wherein the heteroaryl, heteroaryl(C 1 -C 6 )alkoxy, heteroaryl(C 1 -C 6 )alkyl, heteroarylcarbonyl, and heteroaryloxy, are optionally substituted with 1, 2, or 3 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR M R N , or (NR M R N )carbonyl; and wherein the (C 3 -C 7 )heterocycle, (C 3 -C 7 )heterocycle(C 1 -C 6 )alkoxy, (C 3 -C 7 )heterocycle(C 1 -C 6 )alkyl, (C 3 -C 7 )heterocyclecarbonyl, (C 3 -C 7 )heterocyclecarbonyl(C 1 -C 6 )alkyl, and (C 3 -C 7 )heterocycleoxy, are optionally substituted with 1, 2, or 3 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxysulfonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR M R N , (NR M R N )carbonyl, or oxo;
R J and R K are independently H or (C 1 -C 6 )alkyl; and
R M and R N are independently H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylcarbonyl; or R M and R N together with the nitrogen they are attached to form a 3 to 8 membered ring;
or a pharmaceutically acceptable salt thereof.
2 . The method according to claim 1 wherein
X is N or CH;
L is a bond or (C 2 -C 6 )alkynylene;
A is
R 1 is —C(O)OR A , —C(O)NR B R C , —S(O 2 )OR A ;
R A is H;
R B and R C are independently H or —S(O 2 )R D ;
R D is (C 1 -C 6 )alkyl, —CF 3 , or phenyl;
R 2 , R 3 , and R 4 are independently H, (C 1 -C 6 )alkyl, cyano, or halogen;
R 5 is H;
R 6 , R 7 , R 9 , and R 10 are independently H, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, cyano, halogen, hydroxy, or hydroxy(C 1 -C 6 )alkyl;
R 8 is H, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, aryl, carboxy(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyloxy, halo(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkoxy, (C 3 -C 7 )heterocycle, (C 3 -C 7 )heterocycle(C 1 -C 6 )alkoxy, (C 3 -C 7 )heterocyclecarbonyl(C 1 -C 6 )alkyl, (C 3 -C 7 )heterocycleoxy, hydroxy(C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, —NR M R N , (NR M R N )carbonyl(C 1 -C 6 )alkyl, or (NR M R N )carbonyl(C 1 -C 6 )alkoxy; wherein the aryl is optionally substituted with 1 substituent that is (C 1 -C 6 )alkoxy or hydroxy; wherein the halo(C 1 -C 6 )alkyl is optionally with 1 hydroxy group; wherein the (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, and (C 3 -C 8 )cycloalkyloxy are optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(C 1 -C 6 )alkyl, or (NR M R N )carbonyl; and wherein the (C 3 -C 7 )heterocycle and (C 3 -C 7 )heterocycle(C 1 -C 6 )alkoxy are optionally substituted with 1 substituent that is (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylsulfonyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, or oxo; and
R M and R N are independently H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylcarbonyl; or R M and R N together with the nitrogen they are attached to form a 3 to 8 membered ring;
or a pharmaceutically acceptable salt thereof.
3 . A method of treating or preventing chronic kidney disease, diabetic nephropathy, acute kidney injury or polycystic kidney disease in a human comprising administering to the human in need of such treatment a therapeutically effective amount of a compound of Formula (II), wherein
wherein
X is N or CH;
L is a bond, O, S, NR A , (C 1 -C 6 )alkylene, (C 2 -C 6 )alkenylene, or (C 2 -C 6 )alkynylene;
R 1 is —C(O)OR A , —C(O)NR B R C , —S(O 2 )OR A , —S(O 2 )NHC(O)R D , 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, or 1H-tetrazol-5-yl;
R A is H or (C 1 -C 6 )alkyl;
R B and R C are independently H, (C 1 -C 6 )alkyl, or —S(O 2 )R D ;
R D is (C 1 -C 6 )alkyl, —CF 3 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, mercapto, nitro, or NR E R F ;
R E and R F are independently H or (C 1 -C 6 )alkyl;
R 2 , R 3 , and R 4 are independently H, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 8 )alkyl, mercapto, nitro, —NR G R H , or (NR G R H )carbonyl;
R G and R H are independently H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylcarbonyl;
R 5 is H or (C 1 -C 6 )alkyl;
R 6 , R 7 , R 9 , and R 10 are independently H, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR J R K , or (NR J R K )carbonyl;
R J and R K are independently H or (C 1 -C 6 )alkyl;
R 8 is H, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, aryl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkyl, arylcarbonyl, aryloxy, carboxy, carboxy(C 1 -C 6 )alkoxy, carboxy(C 1 -C 6 )alkyl, cyano, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkylcarbonyl, (C 3 -C 8 )cycloalkyloxy, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, heteroaryl, heteroaryl(C 1 -C 6 )alkoxy, heteroaryl(C 1 -C 6 )alkyl, heteroarylcarbonyl, heteroaryloxy, (C 3 -C 7 )heterocycle, (C 3 -C 7 )heterocycle(C 1 -C 6 )alkoxy, (C 3 -C 7 )heterocycle(C 1 -C 6 )alkyl, (C 3 -C 7 )heterocyclecarbonyl, (C 3 -C 7 )heterocyclecarbonyl(C 1 -C 6 )alkyl, (C 3 -C 7 )heterocycleoxy, hydroxy, hydroxy(C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR M R N , —NR M R N (C 1 -C 6 )alkoxy, (NR M R N )carbonyl, (NR M R N )carbonyl(C 1 -C 6 )alkyl, or (NR M R N )carbonyl(C 1 -C 6 )alkoxy; wherein the aryl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkyl, arylcarbonyl, and aryloxy are optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR M R N , or (NR M R N )carbonyl; wherein the halo(C 1 -C 6 )alkyl is optionally substituted with 1 or 2 hydroxy groups; wherein the (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkylcarbonyl, and (C 3 -C 8 )cycloalkyloxy are optionally substituted with 1, 2, or 3 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR M R N , or (NR M R N )carbonyl; wherein the heteroaryl, heteroaryl(C 1 -C 6 )alkoxy, heteroaryl(C 1 -C 6 )alkyl, heteroarylcarbonyl, and heteroaryloxy, are optionally substituted with 1, 2, or 3 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR M R N , or (NR M R N )carbonyl; and wherein the (C 3 -C 7 )heterocycle, (C 3 -C 7 )heterocycle(C 1 -C 6 )alkoxy, (C 3 -C 7 )heterocycle(C 1 -C 6 )alkyl, (C 3 -C 7 )heterocyclecarbonyl, (C 3 -C 7 )heterocyclecarbonyl(C 1 -C 6 )alkyl, and (C 3 -C 7 )heterocycleoxy, are optionally substituted with 1, 2, or 3 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxysulfonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR M R N , (NR M R N )carbonyl, or oxo; and
R M and R N are independently H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylcarbonyl; or R M and R N together with the nitrogen they are attached to form a 3 to 8 membered ring;
or a pharmaceutically acceptable salt thereof.
4 . The method according to claim 3 wherein
X is CH;
L is a bond;
R 1 is —C(O)OR A ;
R A is H;
R 2 is H or F;
R 3 is Cl, F, or CN;
R 4 and R 5 are H;
R 6 and R 7 are independently H, F, or methoxy;
R 9 and R 10 are H; and
R 8 is hydroxy(C 1 -C 6 )alkoxy;
or a pharmaceutically acceptable salt thereof.
5 . The method according to claim 3 wherein
X is CH;
L is a bond;
R 1 is —C(O)OR A ;
R A is H;
R 2 is H or F;
R 3 is Cl, F, or CN;
R 4 and R 5 are H;
R 6 and R 7 are independently H, F, or methoxy;
R 9 and R 10 are H; and
R 8 is (C 1 -C 6 )alkoxy;
or a pharmaceutically acceptable salt thereof.
6 . The method according to claim 3 wherein
X is CH;
L is a bond;
R 1 is —C(O)OR A ;
R A is H;
R 2 is H or F;
R 3 is Cl, F, or CN;
R 4 and R 5 are H;
R 6 and R 7 are independently H, F, or methoxy;
R 9 and R 10 are H; and
R 8 is hydroxy(C 1 -C 6 )alkyl;
or a pharmaceutically acceptable salt thereof.
7 . The method according to claim 3 wherein
X is CH;
L is a bond;
R 1 is —C(O)OR A ;
R A is H;
R 2 is H or F;
R 3 is Cl, F, or CN;
R 4 and R 5 are H:
R 6 and R 7 are independently H, F, or methoxy;
R 9 and R 10 are H;
R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is hydroxy;
or a pharmaceutically acceptable salt thereof.
8 . The method according to claim 3 wherein
X is CH;
L is a bond;
R 1 is —C(O)OR A ;
R A is H;
R 2 is H or F;
R 3 is Cl, F, or CN;
R 4 and R 5 are H;
R 6 and R 7 are independently H, F, or methoxy;
R 9 and R 10 are H;
R 8 is (C 3 -C 7 )heterocycle wherein the (C 3 -C 7 )heterocycle is azetidinyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylsulfonyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, or oxo;
or a pharmaceutically acceptable salt thereof.
9 . The method according to claim 3 wherein
X is CH;
L is a bond;
R 1 is —C(O)OR A ;
R A is H;
R 2 is H or F;
R 3 is Cl, F, or CN;
R 4 and R 5 are H;
R 6 and R 7 are independently H, F, or methoxy;
R 9 and R 10 are H;
R 8 is (C 3 -C 7 )heterocycle(C 1 -C 6 )alkoxy, wherein the (C 3 -C 7 )heterocycle is azetidinyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylsulfonyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, or oxo;
or a pharmaceutically acceptable salt thereof.
10 . The method according to claim 3 wherein
X is CH;
L is a bond;
R 1 is —C(O)OR A ;
R A is H;
R 2 is H or methoxy;
R 3 is Cl, F, or CN;
R 4 and R 5 are H;
R 6 and R 7 are independently H, F, or methoxy;
R 9 and R 10 are H;
R 8 is (C 3 -C 8 )cycloalkyl wherein the (C 3 -C 8 )cycloalkyl is cyclopropyl or cyclobutyl substituted with hydroxy(C 1 -C 6 )alkyl;
or a pharmaceutically acceptable salt thereof.
11 . The method according to claim 3 wherein
X is CH;
L is a bond;
R 1 is —C(O)OR A ;
R A is H;
R 2 is H or F;
R 3 is Cl, F, or CN;
R 4 and R 5 are H;
R 6 and R 7 are independently H, F, or methoxy;
R 9 and R 10 are H;
R 8 is (C 3 -C 8 )cycloalkyl wherein the (C 3 -C 8 )cycloalkyl is cyclobutyl substituted with hydroxy;
or a pharmaceutically acceptable salt thereof.
12 . The method according to claim 11 wherein the compound is
6-chloro-5-[2-fluoro-4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid;
6-chloro-5-[3-fluoro-4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid; or
6-chloro-5-[4-(1-hydroxycyclobutyl)-3-methoxyphenyl]-1H-indole-3-carboxylic acid;
or a pharmaceutically acceptable salt thereof.
13 . The method according to claim 11 wherein the compound is 6-chloro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
14 . The method according to claim 11 wherein the compound is
15 . A method of treating or preventing chronic kidney disease, diabetic nephropathy, acute kidney injury or polycystic kidney disease in a human comprising administering to the human in need of such treatment a therapeutically effective amount of a compound of Formula (III), wherein
X is N or CH;
L is a bond, O, S, NR A , (C 1 -C 6 )alkylene, (C 2 -C 6 )alkenylene, or (C 2 -C 6 )alkynylene;
R 1 is —C(O)OR A , —C(O)NR B R C , —S(O 2 )OR A , —S(O 2 )NHC(O)R D , 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, or 1H-tetrazol-5-yl;
R A is H or (C 1 -C 6 )alkyl;
R B and R C are independently H, (C 1 -C 6 )alkyl, or —S(O 2 )R D ;
R D is (C 1 -C 6 )alkyl, —CF 3 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, mercapto, nitro, or NR E R F ;
R E and R F are independently H or (C 1 -C 6 )alkyl;
R 2 , R 3 , and R 4 are independently H, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 8 )alkyl, mercapto, nitro, —NR G R H , or (NR G R H )carbonyl;
R G and R H are independently H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylcarbonyl;
R 5 is H or (C 1 -C 6 )alkyl;
R 6 , R 7 , and R 10 are independently H, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR J R K , or (NR J R K )carbonyl;
R J and R K are independently H or (C 1 -C 6 )alkyl;
R 8 is H, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, aryl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkyl, arylcarbonyl, aryloxy, carboxy, carboxy(C 1 -C 6 )alkoxy, carboxy(C 1 -C 6 )alkyl, cyano, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkylcarbonyl, (C 3 -C 8 )cycloalkyloxy, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, heteroaryl, heteroaryl(C 1 -C 6 )alkoxy, heteroaryl(C 1 -C 6 )alkyl, heteroarylcarbonyl, heteroaryloxy, (C 3 -C 7 )heterocycle, (C 3 -C 7 )heterocycle(C 1 -C 6 )alkoxy, (C 3 -C 7 )heterocycle(C 1 -C 6 )alkyl, (C 3 -C 7 )heterocyclecarbonyl, (C 3 -C 7 )heterocyclecarbonyl(C 1 -C 6 )alkyl, (C 3 -C 7 )heterocycleoxy, hydroxy, hydroxy(C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR M R N , —NR M R N (C 1 -C 6 )alkoxy, (NR M R N )carbonyl, (NR M R N )carbonyl(C 1 -C 6 )alkyl, or (NR M R N )carbonyl(C 1 -C 6 )alkoxy; wherein the aryl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkyl, arylcarbonyl, and aryloxy are optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR M R N , or (NR M R N )carbonyl; wherein the halo(C 1 -C 6 )alkyl is optionally substituted with 1 or 2 hydroxy groups; wherein the (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkylcarbonyl, and (C 3 -C 8 )cycloalkyloxy are optionally substituted with 1, 2, or 3 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR M R N , or (NR M R N )carbonyl; wherein the heteroaryl, heteroaryl(C 1 -C 6 )alkoxy, heteroaryl(C 1 -C 6 )alkyl, heteroarylcarbonyl, and heteroaryloxy, are optionally substituted with 1, 2, or 3 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR M R N , or (NR M R N )carbonyl; and wherein the (C 3 -C 7 )heterocycle, (C 3 -C 7 )heterocycle(C 1 -C 6 )alkoxy, (C 3 -C 7 )heterocycle(C 1 -C 6 )alkyl, (C 3 -C 7 )heterocyclecarbonyl, (C 3 -C 7 )heterocyclecarbonyl(C 1 -C 6 )alkyl, and (C 3 -C 7 )heterocycleoxy, are optionally substituted with 1, 2, or 3 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxysulfonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR M R N , (NR M R N )carbonyl, or oxo; and R M and R N are independently H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylcarbonyl; and
R M and R N together with the nitrogen they are attached to form a 3 to 8 membered ring;
or a pharmaceutically acceptable salt thereof.
16 . The method according to claim 15 wherein
X is CH;
L is a bond;
R 1 is —C(O)OR A ;
R A is H;
R 2 is H or halogen;
R 3 is (C 1 -C 6 )alkyl, cyano, or halogen;
R 4 is H;
R 5 is H;
R 6 and R 7 are H;
R 10 is H or (C 1 -C 6 )alkoxy;
R 8 is (C 3 -C 7 )heterocycle wherein the (C 3 -C 7 )heterocycle is morpholinyl or pyrrolidinyl where the pyrrolidinyl is optionally substituted with (C 1 -C 6 )alkoxy or hydroxy;
or a pharmaceutically acceptable salt thereof.
17 . The method according to claim 15 wherein the compound is
6-chloro-5-[6-(dimethylamino)-2-methoxypyridin-3-yl]-1H-indole-3-carboxylic acid;
6-chloro-5-[2-methoxy-6-(morpholin-4-yl)pyridin-3-yl]-1H-indole-3-carboxylic acid;
6-chloro-5-{2-methoxy-6-[(3R)-3-methoxypyrrolidin-1-yl]pyridin-3-yl}-1H-indole-3-carboxylic acid;
6-chloro-5-{2-methoxy-6-[(3S)-3-methoxypyrrolidin-1-yl]pyridin-3-yl}-1H-indole-3-carboxylic acid;
6-chloro-5-{6-[(3S)-3-hydroxypyrrolidin-1-yl]-2-methoxypyridin-3-yl}-1H-indole-3-carboxylic acid; or
6-chloro-5-{6-[(3R)-3-hydroxypyrrolidin-1-yl]-2-methoxypyridin-3-yl}-1H-indole-3-carboxylic acid;
or a pharmaceutically acceptable salt thereof.Cited by (0)
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