US2016039825A1PendingUtilityA1
S1p and/or atx modulating agents
Est. expiryMar 15, 2033(~6.6 yrs left)· nominal 20-yr term from priority
A61P 35/00A61P 29/00C07D 487/04A61K 31/198A61P 25/00A61P 19/02A61K 36/9068C07D 519/00A61P 11/06
52
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Claims
Abstract
Compounds of formula (I), and pharmaceutically acceptable salts thereof, can modulate the activity of one or more SIP receptors and/or the activity of autotaxin (ATX).
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound represented by formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
L is —C(O)—, —O—C(O)—, —NR 6 —C(O)—, or —S(O) 2 —;
L 2 is a bond, —O—, or —NR—; provided that L 2 is not —O— when R 2 is structure (iv);
R, for each occurrence, is independently hydrogen or a C 1-4 alkyl;
R 1 is a C 1-8 alkylene;
R 2 is selected form the group consisting of:
R 3 is hydrogen, —CN, C 1-8 alkyl, C 1-8 haloalkyl, —(CR 10 R 11 ) m —N(R 16 ) 2 , —(CR 10 R 11 ) m —OR 15 , —(CR 10 R 11 ) m —C(O)OR 15 , —(CR 10 R 11 ) m —C(O)N(R 16 ) 2 , —(CR 10 R 11 ) m —S(O) 2 N(R 16 ) 2 , —(CR 10 R 11 ) m —S(O) 2 NHS(O) 2 R 15 , —C(O)N(R 15 )—S(O) 2 R 15 , —S(O) 2 OR 15 , —C(O)NHC(O)R 15 , —Si(O)OH, —B(OH) 2 , —N(R 15 )S(O) 2 R 15 , —O—P(O)(OR 15 ) 2 , —P(O)(OR 15 ) 2 , —S(O) 2 NHC(O)R 15 , —C(O)NHS(O) 2 R 15 , —C(O)NHOH, —C(O)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -L 1 -R 4 ; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R 5 ; provided that when R 2 is structure (ii), (iii), (iv), or (xi), R 3 is not hydrogen; and provided that when R 2 is structure (iv), R 3 is not pyrrolidinyl, piperidinyl, an N-methylpyrrolidinyl, an N-acetyl-pyrrolidinyl, an N-methylpiperidinyl, or an N-acetyl-piperidinyl;
L 1 is C 1-8 alkylene, —C(O)—, —C(O)O—, —C(O)NR—, —S(O) 2 NR—, or —C(O)NR—S(O) 2 —;
R 4 is C 1-8 alkyl, C 3-8 cycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R 4 may be optionally substituted with from one to four R 5 ;
R 5 is halo, cyano, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, —(CR 10 R 11 ) m —N(R 16 ) 2 —, —(CR 10 R 11 ) m —OR 15 , —(CR 10 R 11 ) m —C(O)OR 15 , —C(O)N(R 16 ) 2 , —C(O)N(R 15 )—S(O) 2 R 15 , —S(O) 2 OR 15 , —C(O)NHC(O)R 15 , —Si(O)OH, —B(OH) 2 , —N(R 15 )S(O) 2 R 15 , —S(O) 2 N(R 15 ) 2 , O P(O)(OR 15 ) 2 , —P(O)(OR 15 ) 2 , —S(O) 2 NHC(O)R 15 , —C(O)NHS(O) 2 R 15 , C(O)NHOH, C(O)NHCN, —C(O)R 15 , a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, ═O, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkylamido, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, sulfamoyl, N—C 1-4 alkylsulfamoyl, and N,N—(C 1-4 dialkyl)-sulfamoyl;
R 6 is hydrogen or a C 1-8 alkyl;
R 7 , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkoxy, C 3-8 halocycloalkoxy, C 1-8 alkanoyl, amino, N—(C 1-8 alkyl)amino, N,N-di-(C 1-8 alkyl)amino, C 1-8 alkoxycarbonyl, C 1-8 alkanoyloxy, carbamoyl, N—(C 1-8 alkyl)carbamoyl, N,N-di-(C 1-8 alkyl)carbamoyl, C 1-8 alkylamido, mercapto, C 1-8 alkylthio, C 1-8 alkylsulfonyl, sulfamoyl, N—(C 1-8 alkyl)sulfamoyl, N,N-di-(C 1-8 alkyl)sulfamoyl, and C 1-8 alkylsulfonamido;
R 8 , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkoxy, C 3-8 halocycloalkoxy, C 1-8 alkanoyl, amino, N—(C 1-8 alkyl)amino, N,N-di-(C 1-8 alkyl)amino, C 1-8 alkoxycarbonyl, C 1-8 alkanoyloxy, carbamoyl, N—(C 1-8 alkyl)carbamoyl, N,N-di-(C 1-8 alkyl)carbamoyl, C 1-8 alkylamido, mercapto, C 1-8 alkylthio, C 1-8 alkylsulfonyl, sulfamoyl, N—(C 1-8 alkyl)sulfamoyl, N,N-di-(C 1-8 alkyl)sulfamoyl, and C 1-8 alkylsulfonamido;
R 9 , for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-8 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 cycloalkoxy, C 3-8 halocycloalkoxy, C 1-8 alkanoyl, amino, N—(C 1-8 alkyl)amino, N,N-di-(C 1-8 alkyl)amino, C 1-8 alkoxycarbonyl, C 1-8 alkanoyloxy, carbamoyl, N—(C 1-8 alkyl)carbamoyl, N,N-di-(C 1-8 alkyl)carbamoyl, C 1-8 alkylamido, mercapto, C 1-8 alkylthio, C 1-8 alkylsulfonyl, sulfamoyl, N—(C 1-8 alkyl)sulfamoyl, N,N-di-(C 1-8 alkyl)sulfamoyl, C 1-8 alkylsulfonamido, C 6-10 aryl, C 1-8 alkoxy-C 1-6 alkyl, and tri-(C 1-8 alkyl)silyl;
R 9a is hydrogen or R 9 ; or R 9a and R 6 , together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R 9 ;
R 10 and R 11 , for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, C 1-4 alkyl, or C 1-4 haloalkyl;
R 15 for each occurrence is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R 15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carboxyl, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkylamido, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, sulfamoyl, N—(C 1-4 alkyl)sulfamoyl, and N,N—(C 1-4 dialkyl)-sulfamoyl;
R 16 is C 1-8 alkoxy, or R 15 ; or two R 16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carboxyl, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkylamido, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, sulfamoyl, N—C 1-4 alkylsulfamoyl, and N,N—(C 1-4 dialkyl)-sulfamoyl;
h is 0, 1, or 2;
n, for each occurrence, is independently 0, 1, 2, 3, or 4;
m, for each occurrence, is independently 0 or an integer from 1 to 6;
p is 0, 1, 2, or 3;
q is 1, 2, 3, or 4;
r is 1, 2, or 3; and
t is 0 or 1, provided that the compound is not:
3-(5-(2-(4-isopropylphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)propanoic acid;
2-(2,3-difluorophenyl)-1-(2-((dimethylamino)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone;
3-(5-((2-fluorophenethyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)propanoic acid;
3-(5-((4-methylbenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)propanoic acid;
3-(5-(2-(2-chloro-4-fluorophenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)propanoic acid;
N-(3-fluorobenzyl)-2-(pyrrolidine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamide;
1-(2-(4-methylpiperazine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-3-(p-tolyl)propan-1-one;
methyl 5-((3-fluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate;
methyl 5-((4-fluorophenethyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate;
3-(5-(2-(3-(methylthio)phenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanoic acid;
3-(5-(2-(4-chlorophenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanoic acid;
3-(5-(2-(2,3-difluorophenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanoic acid;
1-(2-(pyridin-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-2-(3-(trifluoromethyl)phenyl)ethanone;
1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-2-(3-(trifluoromethyl)phenyl)ethanone;
1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-2-(2-fluorophenyl)ethanone;
N-(3-fluorobenzyl)-2-(pyrrolidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxamide;
5-(2-(3,4-difluorophenyl)acetyl)-N-(2-hydroxyethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide;
3-(5-(2-(2-methoxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanoic acid;
3-(5-(2-(4-ethoxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanoic acid;
1-(2-((1,4-oxazepan-4-yl)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-2-(4-methoxyphenyl)ethanone;
3-(5-(2-(2-methoxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)propanoic acid;
3-(2-methoxyphenyl)-1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)propan-1-one;
2-(2-methoxyphenyl)-1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)ethanone;
2-(4-ethoxyphenyl)-1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)ethanone;
methyl 5-(3-(3-methoxyphenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate;
N2-cyclopropyl-N5-(3-methoxybenzyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-2,5(4H)-dicarboxamide;
5-((1-(3-methoxyphenyl)ethyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid;
4-(4-chlorophenyl)-1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepin-8(9H)-yl)butan-1-one;
N-(2-fluorophenethyl)-6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepine-8(9H)-carboxamide;
1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepin-8(9H)-yl)-2-(4-ethoxyphenyl)ethanone;
1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepin-8(9H)-yl)-2-(o-tolyl)ethanone;
N-(4-chlorobenzyl)-6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepine-8(9H)-carboxamide;
1-ethyl-6-methyl-N-(4-methylbenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide;
N-(4-fluorobenzyl)-6-methyl-1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide;
1-ethyl-N-(4-fluorobenzyl)-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide;
1-ethyl-N-(3-methoxybenzyl)-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide;
2-(2-aminophenyl)-1-(1,6-dimethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethanone;
2-(4-aminophenyl)-1-(1,6-dimethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethanone;
N-(3-methoxybenzyl)-6-methyl-1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide;
1-isopropyl-6-methyl-N-(4-methylbenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide;
1-isopropyl-N-(3-methoxybenzyl)-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide;
6-methyl-N-(4-methylbenzyl)-1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide;
5-(((4-methoxybenzyl)oxy)carbonyl)-2-methyl-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid;
2-(3-bromophenyl)-2-methyl-1-(2-methyl-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)propan-1-one;
1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-2-(3-methoxyphenyl)ethanone;
2-(4-fluorophenyl)-1-(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone;
2-(p-tolyl)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone;
3-(m-tolyl)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propan-1-one;
3-(p-tolyl)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propan-1-one;
2-(2-chloro-6-fluorophenyl)-1-(3-isopropyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone;
4-(3-oxo-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propyl)benzonitrile;
2-(2-fluorophenyl)-1-(3-isopropyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-methylpropan-1-one;
3-(2-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propan-1-one;
2-(3,4-dimethoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone;
2-(3-chloro-4-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone;
2-(2-chloro-4-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone;
3-(4-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7 (8H)-yl)propan-1-one;
3-(3-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7 (8H)-yl)propan-1-one;
2-(2-fluorophenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7 (8H)-yl)ethanone;
2-(2-chloro-6-fluorophenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7 (8H)-yl)ethanone;
1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7 (8H)-yl)-2-(2-fluorophenyl)-2-methylpropan-1-one;
3-(3-chloro-4-methylphenyl)-1-(3-isopropyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7 (8H)-yl)propan-1-one;
3-(2,5-dimethoxyphenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7 (8H)-yl)propan-1-one;
3-(3-chloro-4-methylphenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7 (8H)-yl)propan-1-one;
1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7 (8H)-yl)-5-(p-tolyl)pentan-1-one;
2-(2-chloro-6-fluorophenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7 (8H)-yl)ethanone;
3-(2-ethoxyphenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7 (8H)-yl)propan-1-one;
3-(2-methoxyphenyl)-1-(3-(tetrahydrofuran-2-yl)-8,9-dihydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepin-7(6H)-yl)propan-1-one;
2-(3,4-dichlorophenyl)-1-(3-(tetrahydrofuran-2-yl)-8,9-dihydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepin-7(6H)-yl)ethanone;
2-([1,1′-biphenyl]-4-yl)-1-(3-isopropyl-8,9-dihydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepin-7(6H)-yl)ethanone;
2-(2-chloro-6-fluorophenyl)-1-(3-methyl-8,9-dihydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepin-7(6H)-yl)ethanone;
2-(3-fluorophenyl)-1-(3-methyl-8,9-dihydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepin-7(6H)-yl)ethanone;
1-(3-isopropyl-8,9-dihydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepin-7(6H)-yl)-2-(4-(methylthio)phenyl)ethanone;
2-(2-chloro-6-fluorophenyl)-1-(3-(hydroxymethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone;
2-(2-chlorophenyl)-1-(3-(hydroxymethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone;
5-(4-bromophenyl)-1-(1-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)pentan-1-one;
3-(4-ethoxyphenyl)-1-(1-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)propan-1-one;
2-(2-ethoxyphenoxy)-1-(1-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)ethanone;
1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-2-(3-fluorophenoxy)ethanone;
3-(5-(2-(3,4-dimethylphenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanoic acid;
3-(5-(2-(2,3-dimethylphenoxy)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)propanoic acid;
3-(5-(2-(2,3-dimethylphenoxy)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)propanoic acid;
2-(4-ethylphenoxy)-1-(2-(pyrrolidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)ethanone;
1-(2-(4-methylpiperazine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-2-(m-tolyloxy)ethanone;
methyl 5-(2-(3,4-dimethylphenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate;
5-(2-((3-methoxyphenyl)amino)butanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonitrile;
5-(2-(2-(sec-butyl)phenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonitrile;
1-(2,3-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)-2-(4-fluorophenyl)ethanone;
2-(2-chloro-6-fluorophenyl)-1-(2,3-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone;
methyl 3-ethyl-5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylate;
methyl 3-ethyl-5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylate;
3-(5-(2-(3-hydroxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanoic acid;
3-(5-(3-(4-hydroxyphenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)propanoic acid;
3-(5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)propanoic acid;
3-(5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanoic acid;
methyl 5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate;
5-(2-(2-hydroxyphenyl)acetyl)-N-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide;
2-(2-hydroxyphenyl)-1-(2-(pyrrolidine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone;
7-(3-(2-hydroxyphenyl)propanoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide;
2-(3-chloro-4-hydroxyphenyl)-1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepin-8(9H)-yl)ethanone;
1-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-2-(2-hydroxyphenoxy)ethanone; or
1-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-3-(2-hydroxyphenyl)propan-1-one.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected form the group consisting of:
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 1, and r is 1 or 2.
5 - 12 . (canceled)
13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (II):
14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is —C(O)—, —O—C(O)—, or —NR—C(O)—.
15 . (canceled)
16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by structural formula (III):
wherein:
R 1 is a C 1-8 alkylene;
R 3 is hydrogen, —CN, C 1-8 alkyl, C 1-8 haloalkyl, —(CR 10 R 11 ) m —N(R 16 ) 2 , —(CR 10 R 11 ) m —OR 15 , —(CR 10 R 11 ) m —C(O)OR 15 , —(CR 10 R 11 ) m —C(O)N(R 16 ) 2 , —(CR 10 R 11 ) m —S(O) 2 N(R 16 ) 2 , —(CR 10 R 11 ) m —S(O) 2 NHS(O) 2 R 15 , —C(O)N(R 15 )—S(O) 2 R 15 , —S(O) 2 OR 15 , —C(O)NHC(O)R 15 , —Si(O)OH, —B(OH) 2 , —N(R 15 )S(O) 2 R 15 , —O—P(O)(OR 15 ) 2 , —P(O)(OR 15 ) 2 , —S(O) 2 NHC(O)R 15 , —C(O)NHS(O) 2 R 15 , —C(O)NHOH, —C(O)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or L 1 -R 4 ; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R 5 ;
L 1 is C 1-8 alkylene, —C(O)—, —C(O)O—, —C(O)NR—, —S(O) 2 NR—, or —C(O)NR—S(O) 2 —;
R, for each occurrence, is independently hydrogen or C 1-4 alkyl;
R 4 is C 1-8 alkyl, C 3-8 cycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R 4 may be optionally substituted with from one to four R 5 ;
R 5 is halo, cyano, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, —(CR 10 R 11 ) m —N(R 16 ) 2 , —(CR 10 R 11 ) m —OR 15 , —(CR 10 R 11 ) m —C(O)OR 15 , —C(O)N(R 16 ) 2 , —C(O)N(R 15 )—S(O) 2 R 15 , —S(O) 2 OR 15 , —C(O)NHC(O)R 15 , —Si(O)OH, —B(OH) 2 , —N(R 15 )S(O) 2 R 15 , —S(O) 2 N(R 15 ) 2 , O P(O)(OR 15 ) 2 , —P(O)(OR 15 ) 2 , —S(O) 2 NHC(O)R 15 , —C(O)NHS(O) 2 R 15 , C(O)NHOH, C(O)NHCN, —C(O)R 15 , a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, ═O, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkylamido, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, sulfamoyl, N—C 1-4 alkylsulfamoyl, and N,N—(C 1-4 dialkyl)-sulfamoyl;
R 9 , for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-8 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 cycloalkoxy, C 3-8 halocycloalkoxy, C 1-8 alkanoyl, amino, N—(C 1-8 alkyl)amino, N,N-di-(C 1-8 alkyl)amino, C 1-8 alkoxycarbonyl, C 1-8 alkanoyloxy, carbamoyl, N—(C 1-8 alkyl)carbamoyl, N,N-di-(C 1-8 alkyl)carbamoyl, C 1-8 alkylamido, mercapto, C 1-8 alkylthio, C 1-8 alkylsulfonyl, sulfamoyl, N—(C 1-8 alkyl)sulfamoyl, N,N-di-(C 1-8 alkyl)sulfamoyl, C 1-8 alkylsulfonamido, C 6-10 aryl, C 1-8 alkoxy-C 1-6 alkyl, and tri-(C 1-8 alkyl)silyl;
R 10 and R 11 , for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, C 1-4 alkyl, or C1-4haloalkyl;
R 15 for each occurrence is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R 15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carboxyl, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkylamido, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, sulfamoyl, N—(C 1-4 alkyl)sulfamoyl, and N,N—(C 1-4 dialkyl)-sulfamoyl;
R 16 is C 1-8 alkoxy, or R 15 ; or two R 16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carboxyl, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkylamido, C 1-4 alkylsulfonamido, sulfamoyl, N—C 1-4 alkylsulfamoyl, and N,N—(C 1-4 dialkyl)-sulfamoyl;
m, for each occurrence, is independently 0 or an integer from 1 to 6; and
q is 1, 2, 3, or 4.
17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, —CN, C 1-8 alkyl, C 1-8 haloalkyl, —(CR 10 R 11 ) m —N(R 16 ) 2 , —(CR 10 R 11 ) m —OR 15 , —(CR 10 R 11 ) m —C(O)OR 15 , —(CR 10 R 11 ) m —C(O)N(R 16 ) 2 , a 5 to 14 membered heteroaryl, or L 1 -R 4 ; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R 5 .
18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 16 , for each occurrence, is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, or two R 16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carboxyl, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkylamido, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, sulfamoyl, N—C 1-4 alkylsulfamoyl, and N,N—(C 1-4 dialkyl)-sulfamoyl.
19 .- 28 . (canceled)
29 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
L is —O—C(O)—, —NR 6 —C(O)—, or —C(O)—; L 2 is a bond, —O—, or —NR—; R 1 is C 1-4 alkylene; R 2 is selected form the group consisting of:
p is 1 or 2; and
r is 1 or 2.
30 . The compound of claim 29 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is methylene or ethylene; and R 2 is selected from
31 . (canceled)
32 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 7 , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, cyano, carboxy, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 alkanoyl, amino, N—(C 1-8 alkyl)amino, C 1-8 alkoxycarbonyl, C 1-8 alkanoyloxy, carbamoyl, N—(C 1-8 alkyl)carbamoyl, N,N-di-(C 1-8 alkyl)carbamoyl, and C 1-8 alkylamido; R 8 , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, cyano, carboxy, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 alkanoyl, amino, N—(C 1-8 alkyl)amino, C 1-8 alkoxycarbonyl, C 1-8 alkanoyloxy, carbamoyl, N—(C 1-8 alkyl)carbamoyl, N,N-di-(C 1-8 alkyl)carbamoyl, and C 1-8 alkylamido; h is 0 or 1; n is 0 or 1; and t is 0 or 1.
33 .- 35 . (canceled)
36 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 , for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-8 haloalkoxy, C 1-8 alkanoyl, C 1-8 alkoxycarbonyl, C 1-8 alkanoyloxy, carbamoyl, N—(C 1-8 alkyl)carbamoyl, N,N-di-(C 1-8 alkyl)carbamoyl, C 1-8 alkylamido, mercapto, C 1-8 alkylsulfonyl, sulfamoyl, N—(C 1-8 alkyl)sulfamoyl, N,N-di-(C 1-8 alkyl)sulfamoyl, C 1-8 alkylsulfonamido, C 6-10 aryl, and C 1-8 alkoxy-C 1-6 alkyl; and q is 1, 2, or 3.
37 - 40 . (canceled)
41 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or C 1-4 alkyl; R 6 is hydrogen or a C 1-4 alkyl; R 9a is hydrogen or R 9 ; or R 9a and R 6 , together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R 9 .
42 .- 43 . (canceled)
44 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, R 3 is hydrogen, —CN, C 1-8 alkyl, C 1-8 haloalkyl, —(CR 10 R 11 ) m —N(R 16 ) 2 , —(CR 10 R 11 ) m —OR 15 , —(CR 10 R 11 ) m —C(O)OR 15 , —(CR 10 R 11 ) m —C(O)N(R 16 ) 2 , —(CR 10 R 11 ) m —S(O) 2 N(R 16 ) 2 , —C(O)NHS(O) 2 R 15 , a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -L 1 -R 4 ; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R 5 groups selected from C 1-4 alkyl, —OH, C 1-4 alkoxy, hydroxy(C 1-4 alkyl), —COOH, —COO—C 1-4 alkyl, —CH 2 COOH, and —CH 2 COO—C 1-4 alkyl;
L 1 is C 1-8 alkylene, —C(O)—, —C(O)O—, —C(O)NR—, —S(O) 2 NR—, or —C(O)NR—S(O) 2 —;
R, for each occurrence, is independently hydrogen or a C 1-4 alkyl;
R 4 is C 1-8 alkyl, C 3-8 cycloalkyl, a 5 to 14 membered heteroaryl, or a 3 to 15 membered heterocyclyl, wherein R 4 may be optionally substituted with from one to four R 5 groups selected from halo, cyano, C 1-8 alkyl, C 1-8 haloalkyl, —COOH, —C(O)O—(C 1-4 alkyl), C 1-4 alkoxy, —OH, hydroxyC 1-4 alkyl, —NH 2 , (C 1-4 alkyl)amino, C 3-8 cycloalkyl, and a 3 to 15 membered heterocyclyl selected from 3-azabicyclo[3.1.0]hexanyl, azetidinyl, morpholinyl, piperidinyl, or pyrrolidinyl, wherein the heterocyclyl may be optionally substituted with one or two substituents independently selected from the group consisting of optionally substituted with C 1-4 alkyl, —OH, and COOH;
R 10 and R 11 , for each occurrence, are independently hydrogen, carboxy, C 1-4 alkyl, or C 1-4 haloalkyl;
R 15 for each occurrence is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, wherein R 15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, C 1-4 alkyl, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, and carboxyl;
Each R 16 is independently selected from hydrogen, C 1-8 alkoxy, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R 16 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carboxyl carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, and C 1-4 alkylamidol;
or two R 16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carboxyl, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, and C 1-4 alkylamidol; and
m, for each occurrence, is independently 0 or 1.
45 .- 46 . (canceled)
47 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
L is —O—C(O)—, —NR 6 —C(O)—, or —C(O)—; L 2 is a bond; R 1 is C 1-4 alkylene; R 2 is
R 3 is —(CR 10 R 11 ) m —C(O)OR 15 , a 3 to 15 membered heterocyclyl selected from 8-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct-2-enyl, 3,8-diazabicyclo[3.2.1]octanyl, 1,4-diazepanyl, 4,7-diazaspiro[2.5]octanyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydropyrido[2,1-c][1,4]oxazinyl, octahydropyrrolo[1,2-a]pyrazinyl, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-c], piperidin-2-only, piperidinyl, piperizinyl, pyrrolidinyl, 1,2,3,6-tetrahydropyridinyl, wherein heterocyclyl is optionally substituted with one to four groups selected from C 1-4 alkyl, hydroxyC 1-4 alkyl, —COOH, —COO—C 1-4 alkyl, —CH 2 COOH, and —CH 2 COO—C 1-4 alkyl; or -L 1 -R 4 ;
L 1 is —C(O)—,
R 4 is 3 to 15 membered heterocyclyl selected from 9-azabicyclo[3.3.1]nonanyl, 8-azabicyclo[3.2.1]octanyl, azetidinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,9-diazabicyclo[3.3.1]nonanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.2]octanyl, 3,6-diazabicyclo[3.2.1]octanyl, 6,9-diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, 5,8-diazaspiro[3.5]nonanyl, 4,7-diazaspiro[2.5]octanyl, 1,4-diazepanyl, 4,5-dihydrothiazolyl, morpholinyl, octahydropyrrolo[1,2-a]pyrazinyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[2,3-b]pyrrolyl, piperazin-2-onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl, tetrahydro-2H-pyranyl, wherein the heterocyclyl may be optionally substituted with from one to four groups selected from halo, —CN, C 1-4 alkyl, —CF 3 , —COOH, —COOCH 3 , —COO-t-butyl, —OH, —CH 2 CH 2 OH, —OCH 3 , —NH 2 , and —NHCH 3 ;
each R 9 is independently selected from halo and C 1-8 haloalkyl;
R 9a is hydrogen;
R 10 and R 11 , for each occurrence, are independently hydrogen or C 1-4 alkyl;
R 15 is hydrogen or C 1-4 alkyl;
m is 0 or 1;
n is 0 or 1;
q is 1, 2, or 3;
p is 1 or 2;
r is 1 or 2; and
t is 0 or 1.
48 . The compound of any one of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
L is —O—C(O)— L 2 is a bond; R 1 is methylene; R 2 is
R 3 is —C(O)OR 15 ; —CR 10 R 11 —C(O)OR 15 a 3 to 15 membered heterocyclyl selected from azetidinyl, morpholinyl, piperazin-2-onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydropyrido[2,1-c][1,4]oxazinyl, octahydropyrrolo[1,2-a]pyrazinyl, and octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-c], wherein the heterocyclyl is optionally substituted with one to four groups selected from C 1-4 alkyl, hydroxyC 1-4 alkyl, —COOH, —COO—C 1-4 alkyl, —CH 2 COOH, and —CH 2 COO—C 1-4 alkyl; or -L 1 -R 4 ;
L 1 is —C(O)—,
R 4 is 3 to 15 membered heterocyclyl selected azetidinyl, morpholinyl, piperazin-2-onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl, tetrahydro-2H-pyranyl, the heterocyclyl may be optionally substituted with from one to four groups selected from halo, C 1-4 alkyl, —CF 3 , —COOH, —COOCH 3 , —COO-t-butyl;
each R 9 is independently selected from halo and C 1-4 haloalkyl;
R 9a is hydrogen;
R 10 and R 11 , for each occurrence, are independently hydrogen or C 1-4 alkyl;
R 15 is hydrogen or C 1-4 alkyl; and
q is 1, 2, or 3.
49 . (canceled)
50 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
51 . A method of preventing, treating, or reducing symptoms of a condition mediated by ATX activity in a mammal comprising administering to said mammal an effective amount of a compound represented by formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
L is —C(O)—, —O—C(O)—, —NR 6 —C(O)—, or —S(O) 2 —;
L 2 is a bond, —O—, or —NR—;
R, for each occurrence, is independently hydrogen or a C 1-4 alkyl;
R 1 is a C 1-8 alkylene;
R 2 is selected form the group consisting of:
R 3 is hydrogen, —CN, C 1-8 alkyl, C 1-8 haloalkyl, —(CR 10 R 11 ) m —N(R 16 ) 2 , (CR 10 R 11 ) m —OR 15 , —(CR 10 R 11 ) m —C(O)OR 15 , —(CR 10 R 11 ) m —C(O)N(R 16 ) 2 , —(CR 10 R 11 ) m —S(O) 2 N(R 16 ) 2 , —(CR 10 R 11 ) m —S(O) 2 NHS(O) 2 R 15 , —C(O)N(R 15 )—S(O) 2 R 15 , —S(O) 2 OR 15 , —C(O)NHC(O)R 15 , —Si(O)OH, —B(OH) 2 , —N(R 15 )S(O) 2 R 15 , —O—P(O)(OR 15 ) 2 , —P(O)(OR 15 ) 2 , —S(O) 2 NHC(O)R 15 , —C(O)NHS(O) 2 R 15 , —C(O)NHOH, —C(O)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -L 1 -R 4 ; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R 5 ;
L 1 is C 1-8 alkylene, —C(O)—, —C(O)O—, —C(O)NR—, S(O) 2 NR—, or C(O)NR—S(O) 2 —;
R 4 is C 1-8 alkyl, C 3-8 cycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R 4 may be optionally substituted with from one to four R 5 ;
R 5 is halo, cyano, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, —(CR 10 R 11 ) m —N(R 16 ) 2 , —(CR 10 R 11 ) m —OR 15 , —(CR 10 R 11 ) m —C(O)OR 15 , —C(O)N(R 16 ) 2 , —C(O)N(R 15 )—S(O) 2 R 15 , —S(O) 2 OR 15 , —C(O)NHC(O)R 15 , —Si(O)OH, —B(OH) 2 , —N(R 15 )S(O) 2 R 15 , —S(O) 2 N(R 15 ) 2 , O P(O)(OR 15 ) 2 , —P(O)(OR 15 ) 2 , —S(O) 2 NHC(O)R 15 , —C(O)NHS(O) 2 R 15 , C(O)NHOH, C(O)NHCN, —C(O)R 15 , a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, ═O, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkylamido, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, sulfamoyl, N—C 1-4 alkylsulfamoyl, and N,N—(C 1-4 dialkyl)-sulfamoyl;
R 6 is hydrogen or a C 1-8 alkyl;
R 7 , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkoxy, C 3-8 halocycloalkoxy, C 1-8 alkanoyl, amino, N—(C 1-8 alkyl)amino, N,N-di-(C 1-8 alkyl)amino, C 1-8 alkoxycarbonyl, C 1-8 alkanoyloxy, carbamoyl, N—(C 1-8 alkyl)carbamoyl, N,N-di-(C 1-8 alkyl)carbamoyl, C 1-8 alkylamido, mercapto, C 1-8 alkylthio, C 1-8 alkylsulfonyl, sulfamoyl, N—(C 1-8 alkyl)sulfamoyl, N,N-di-(C 1-8 alkyl)sulfamoyl, and C 1-8 alkylsulfonamido;
R 8 , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkoxy, C 3-8 halocycloalkoxy, C 1-8 alkanoyl, amino, N—(C 1-8 alkyl)amino, N,N-di-(C 1-8 alkyl)amino, C 1-8 alkoxycarbonyl, C 1-8 alkanoyloxy, carbamoyl, N—(C 1-8 alkyl)carbamoyl, N,N-di-(C 1-8 alkyl)carbamoyl, C 1-8 alkylamido, mercapto, C 1-8 alkylthio, C 1-8 alkylsulfonyl, sulfamoyl, N—(C 1-8 alkyl)sulfamoyl, N,N-di-(C 1-8 alkyl)sulfamoyl, and C 1-8 alkylsulfonamido;
R 9 , for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-8 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 cycloalkoxy, C 3-8 halocycloalkoxy, C 1-8 alkanoyl, amino, N—(C 1-8 alkyl)amino, N,N-di-(C 1-8 alkyl)amino, C 1-8 alkoxycarbonyl, C 1-8 alkanoyloxy, carbamoyl, N—(C 1-8 alkyl)carbamoyl, N,N-di-(C 1-8 alkyl)carbamoyl, C 1-8 alkylamido, mercapto, C 1-8 alkylthio, C 1-8 alkylsulfonyl, sulfamoyl, N—(C 1-8 alkyl)sulfamoyl, N,N-di-(C 1-8 alkyl)sulfamoyl, C 1-8 alkylsulfonamido, C 6-10 aryl, C 1-8 alkoxy-C 1-6 alkyl, and tri-(C 1-8 alkyl)silyl;
R 9a is hydrogen or R 9 ; or R 9a and R 6 , together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R 9 ;
R 10 and R 11 , for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, C 1-4 alkyl, or a C 1-4 haloalkyl;
R 15 for each occurrence is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R 15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carboxyl, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkylamido, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, sulfamoyl, N—(C 1-4 alkyl)sulfamoyl, and N,N—(C 1-4 dialkyl)-sulfamoyl;
R 16 is C 1-8 alkoxy, or R 15 ; or two R 16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carboxyl, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkylamido, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, sulfamoyl, N—C 1-4 alkylsulfamoyl, and N,N—(C 1-4 dialkyl)-sulfamoyl;
h is 0, 1, or 2;
n, for each occurrence, is independently 0, 1, 2, 3, or 4;
m, for each occurrence, is independently 0 or an integer from 1 to 6;
p is 0, 1, 2, or 3;
q is 1, 2, 3, or 4;
r is 1, 2, or 3; and
t is 0 or 1.
52 .- 62 . (canceled)
63 . A method of preventing, treating, or reducing chronic pain in a mammal comprising administering to said mammal an effective amount of a compound represented by formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
L is —C(O)—, —O—C(O)—, —NR—C(O)—, or —S(O) 2 —;
R, for each occurrence, is independently hydrogen or a C 1-4 alkyl;
R 1 is a C 1-8 alkylene;
R 2 is selected form the group consisting of:
R 3 is hydrogen, —CN, C 1-8 alkyl, C 1-8 haloalkyl, —(CR 10 R 11 ) m —N(R 16 ) 2 , —(CR 10 R 11 ) m —OR 15 , —(CR 10 R 11 ) m —C(O)OR 15 , —(CR 10 R 11 ) m —C(O)N(R 16 ) 2 , —(CR 10 R 11 ) m —S(O) 2 N(R 16 ) 2 , —(CR 10 R 11 ) m —S(O) 2 NHS(O) 2 R 15 , —C(O)N(R 15 )—S(O) 2 R 15 , —S(O) 2 OR 15 , —C(O)NHC(O)R 15 , —Si(O)OH, —B(OH) 2 , —N(R 15 )S(O) 2 R 15 , —O—P(O)(OR 15 ) 2 , —P(O)(OR 15 ) 2 , —S(O) 2 NHC(O)R 15 , —C(O)NHS(O) 2 R 15 , —C(O)NHOH, —C(O)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -L 1 -R 4 ; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R 5 ;
L 1 is C 1-8 alkylene, —C(O)—, —C(O)O—, —C(O)NR—, —S(O) 2 NR—, or —C(O)NR—S(O) 2 —;
R 4 is C 1-8 alkyl, C 3-8 cycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R 4 may be optionally substituted with from one to four R 5 ;
R 5 is halo, cyano, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, —(CR 10 R 11 ) m —N(R 16 ) 2 , —(CR 10 R 11 ) m —OR 15 , —(CR 10 R 11 ) m —C(O)OR 15 , —C(O)N(R 16 ) 2 , —C(O)N(R 15 )—S(O) 2 R 15 , —S(O) 2 OR 15 , —C(O)NHC(O)R 15 , —Si(O)OH, —B(OH) 2 , —N(R 15 )S(O) 2 R 15 , —S(O) 2 N(R 15 ) 2 , O P(O)(OR 15 ) 2 , —P(O)(OR 15 ) 2 , —S(O) 2 NHC(O)R 15 , —C(O)NHS(O) 2 R 15 , C(O)NHOH, C(O)NHCN, —C(O)R 15 , a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, ═O, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkylamido, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, sulfamoyl, N—C 1-4 alkylsulfamoyl, and N,N—(C 1-4 dialkyl)-sulfamoyl;
R 7 , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkoxy, C 3-8 halocycloalkoxy, C 1-8 alkanoyl, amino, N—(C 1-8 alkyl)amino, N,N-di-(C 1-8 alkyl)amino, C 1-8 alkoxycarbonyl, C 1-8 alkanoyloxy, carbamoyl, N—(C 1-8 alkyl)carbamoyl, N,N-di-(C 1-8 alkyl)carbamoyl, C 1-8 alkylamido, mercapto, C 1-8 alkylthio, C 1-8 alkylsulfonyl, sulfamoyl, N—(C 1-8 alkyl)sulfamoyl, N,N-di-(C 1-8 alkyl)sulfamoyl, and C 1-8 alkylsulfonamido;
R 8 , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkoxy, C 3-8 halocycloalkoxy, C 1-8 alkanoyl, amino, N—(C 1-8 alkyl)amino, N,N-di-(C 1-8 alkyl)amino, C 1-8 alkoxycarbonyl, C 1-8 alkanoyloxy, carbamoyl, N—(C 1-8 alkyl)carbamoyl, N,N-di-(C 1-8 alkyl)carbamoyl, C 1-8 alkylamido, mercapto, C 1-8 alkylthio, C 1-8 alkylsulfonyl, sulfamoyl, N—(C 1-8 alkyl)sulfamoyl, N,N-di-(C 1-8 alkyl)sulfamoyl, and C 1-8 alkylsulfonamido;
R 9 , for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-8 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 cycloalkoxy, C 3-8 halocycloalkoxy, C 1-8 alkanoyl, amino, N—(C 1-8 alkyl)amino, N,N-di-(C 1-8 alkyl)amino, C 1-8 alkoxycarbonyl, C 1-8 alkanoyloxy, carbamoyl, N—(C 1-8 alkyl)carbamoyl, N,N-di-(C 1-8 alkyl)carbamoyl, C 1-8 alkylamido, mercapto, C 1-8 alkylthio, C 1-8 alkylsulfonyl, sulfamoyl, N—(C 1-8 alkyl)sulfamoyl, N,N-di-(C 1-8 alkyl)sulfamoyl, C 1-8 alkylsulfonamido, C 6-10 aryl, C 1-8 alkoxy-C 1-6 alkyl, and tri-(C 1-8 alkyl)silyl;
R 10 and R 11 , for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, C 1-4 alkyl, or a C 1-4 haloalkyl;
R 15 for each occurrence is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R 15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carboxyl, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkylamido, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, sulfamoyl, N—(C 1-4 alkyl)sulfamoyl, and N,N—(C 1-4 dialkyl)-sulfamoyl;
R 16 is C 1-8 alkoxy, or R 15 ; or two R 16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carboxyl, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkylamido, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, sulfamoyl, N—C 1-4 alkylsulfamoyl, and N,N—(C 1-4 dialkyl)-sulfamoyl;
h is 0, 1, or 2;
n, for each occurrence, is independently 0, 1, 2, 3, or 4;
m, for each occurrence, is independently 0 or an integer from 1 to 6;
p is 0, 1, 2, or 3;
q is 1, 2, 3, or 4;
r is 1, 2, or 3; and
t is 0 or 1, provided that the compound is not 2-(4-fluorophenyl)-1-(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone.
64 .- 76 . (canceled)Join the waitlist — get patent alerts
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