4-heteroaryl substituted benzoic acid compounds as RORgammaT inhibitors and uses thereof
The present invention relates to compounds according to Formula I (Formula I), and pharmaceutically acceptable salts or solvates thereof. Such compounds can be used in the treatment of RORgammaT-mediated diseases or conditions.
1. A compound according to Formula I
or a pharmaceutically acceptable salt or solvate thereof, wherein:
Y is CH, CR a , or N;
n=0, 1, 2, 3 or 4;
R a is (C 1-4 )alkyl or (C 3-7 )cycloalkyl;
R 1 is
(i) (C 3-12 )carbocyclyl(C 0-4 )alkyl, or
(ii) a 4- to 12-membered heterocyclyl(C 0-4 )alkyl,
each being substituted with (i) one occurrence of R 8 that is (C 3-7 ) cycloalkyl and (ii) optionally one, two, three, or four other occurrences of R 8 ;
R 2 is hydroxycarbonyl, hydroxycarbonyl(C 1-10 )alkyl, (C 1-10 )alkylsulfoxyaminocarbonyl, or carbamoyl;
R 3 is hydrogen, halogen, cyano, hydroxy, (C 1-4 )alkylcarbonyloxy, (C 1-4 ) alkylsulfonylamino, (C 1-4 ) alkylcarbonylamino, (C 1-4 )alkyl, or (C 1-4 )alkoxy, wherein (C 1-4 )alkyl and (C 1-4 )alkoxy are optionally substituted with one or more halogen;
R 4 -R 7 independently are hydrogen, halogen, amino, cyano, hydroxy, (C 1-3 )alkoxy, (C 1-4 )-alkyl, (C 0-10 )alkylaminocarbonyl, (C 0-6 )alkyoxycarbonylamino, (di)(C 1-6 )alkylaminocarbonyl, (C 1-6 )alkylcarbonylamino, (C 1-4 )alkylamino, or amino(C 1-4 )alkyl, wherein (C 1-3 )alkoxy and (C 1-4 )alkyl are optionally substituted with one or more halogen; or a group having the formula
optionally substituted with one or more of the following: (C 1-10 )alkyl, halogen, amino, cyano, hydroxy, (C 1-3 )alkoxy, and wherein m is 1, 2, 3, or 4; or
R 6 is additionally selected from:
(i) (C 3-7 )cycloalkyl or (C 3-5 )heterocycloalkyl, both optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, oxo (═O), (C 1-4 )alkyl or (C 1-3 )alkoxy;
(ii) (C 2-9 )heteroaryl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(iii) (C 6-14 )aryl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(iv) (C 3-5 )heterocycloalkylcarbonyl or (C 3-5 )heterocycloalkylcarbonyl(C 1-4 )alkyl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(v) (C 3-5 )heterocycloalkylamino, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(vi) (C 3-5 )cycloalkylaminocarbonyl or di(C 3-5 )cycloalkylaminocarbonyl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(vii) (C 3-5 )cycloalkylcarbonylamino, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(viii) (C 3-5 )cycloalkyl(C 1-4 )alkyl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(ix) (C 3-5 )cycloalkylamino, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(x) (C 3-5 )cycloalkylcarbonyl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(xi) (C 2-9 )heteroaryl(C 1-4 )alkyl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(xii) (C 2-9 )heteroarylcarbonyl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
and
R 8 is halogen, cyano, amino, hydroxy, di(C 1-3 )alkylamino, (C 1-4 )alkyl, (C 3-5 )heterocycloalkyl, (C 1-4 )alkenyl, (C 3-6 )cycloalkoxy or (C 1-3 )alkoxy, wherein (C 1-4 )alkyl and (C 1-3 )alkoxy are optionally substituted with one, two or three halogens.
2. The compound of claim 1 having Formula Ia
or a pharmaceutically acceptable salt or solvate thereof.
3. The compound of claim 1 having Formula Ib
or a pharmaceutically acceptable salt or solvate thereof.
4. The compound of claim 3 , wherein Y is N.
5. The compound of claim 3 having Formula Ic
or a pharmaceutically acceptable salt or solvate thereof.
6. The compound of claim 5 having Formula Id
or a pharmaceutically acceptable salt or solvate thereof.
7. The compound of claim 6 , wherein Y is N.
8. The compound of claim 2 having Formula Ie
wherein x is 1, 2, 3, 4 or 5; and at least one occurrence of R 8 is (C 3-7 )cycloalkyl;
or a pharmaceutically acceptable salt or solvate thereof.
9. The compound of claim 8 having Formula If
or a pharmaceutically acceptable salt or solvate thereof; wherein at least one occurrence of R 8 is (C 3-7 )cycloalkyl.
10. The compound of claim 9 having Formula Ig
or a pharmaceutically acceptable salt or solvate thereof; wherein at least one occurrence of R 8 is (C 3-7 )cycloalkyl.
11. The compound of claim 10 having Formula Ih
or a pharmaceutically acceptable salt or solvate thereof; wherein R 8 is (C 3-7 )cycloalkyl.
12. The compound of claim 1 , wherein Y is N.
13. The compound of claim 1 , wherein R 1 is
(i) (C 3-7 )cycloalkyl or (C 3-5 )heterocycloalkyl, both being substituted with (i) one occurrence of R 8 that is (C 3-7 )cycloalkyl and (ii) optionally one, two, three, or four other occurrences of or five R 8 ;
(ii) (C 2-9 )heteroaryl(C 0-4 )alkyl, being substituted with (i) one occurrence of R 8 that is (C 3-7 )cycloalkyl and (ii) optionally one, two, three, or four other occurrences of R 8 ; or
(iii) (C 6-14 )aryl(C 0-4 )alkyl, being substituted with (i) one occurrence of R 8 that is (C 3-7 )cycloalkyl and (ii) optionally one, two, three, or four other occurrences of R 8 .
14. The compound of claim 13 , wherein R 1 is (i) (C 2-9 )heteroaryl, or (ii) (C 6-14 )aryl, both substituted with (i) one occurrence of R 8 that is (C 3-7 )cycloalkyl and (ii) optionally one, two, three, or four other occurrences of R 8 .
15. The compound of claim 14 , wherein R 1 is (C 6-14 )aryl substituted with (i) one occurrence of R 8 that is (C 3-7 )cycloalkyl and (ii) optionally one other occurrence of R 8 .
16. The compound of claim 15 , wherein R 1 is phenyl substituted with (i) one occurrence of R 8 that is (C 3-7 )cycloalkyl and (ii) optionally one other occurrence of R 8 .
17. The compound of claim 16 , wherein R 2 is C(O)OH.
18. The compound of claim 1 , wherein R 6 is
19. A compound selected from:
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-formyl-1H-indazol-3-yl)benzoic acid;
3-fluoro-4-(1-(2-phenylpropanoyl)-1H-indazol-3-yl)benzoic acid;
3-fluoro-4-[1-(methoxyacetyl)-1H-indazol-3-yl]benzoic acid;
3-fluoro-4-[1-(pyridin-3-ylcarbonyl)-1H-indazol-3-yl]benzoic acid;
3-fluoro-4-{1-[(2-oxopyrrolidin-1-yl)acetyl]-1H-indazol-3-yl}benzoic acid;
3-fluoro-4-[1-(naphthalen-1-ylcarbonyl)-1H-indazol-3-yl]benzoic acid;
3-fluoro-4-{1-[(1-methyl-1H-indol-2-yl)carbonyl]-1H-indazol-3-yl}benzoic acid;
4-{1-[(2-bromo-3-methylphenyl)carbonyl]-1H-indazol-3-yl}-3-fluorobenzoic acid;
4-[1-(2,3-dihydro-1H-inden-4-ylcarbonyl)-1H-indazol-3-yl]-3-fluorobenzoic acid;
4-(1-{[3-(tertbutoxycarbonyl)-3-azabicyclo[3.1.0]hex-6-yl]carbonyl}-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-[1-(2,3-dihydro-1-benzofuran-7-ylcarbonyl)-1H-indazol-3-yl]-3-fluorobenzoic acid;
4-[1-(1-benzofuran-7-ylcarbonyl)-1H-indazol-3-yl]-3-fluorobenzoic acid;
4-{1-[(2-bromo-3-chlorophenyl)carbonyl]-1H-indazol-3-yl}-3-fluorobenzoic acid;
3-fluoro-4-(1-(tetrahydrofuran-2-carbonyl)-1H-indazol-3-yl)benzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(morpholine-4-carbonyl)-1H-indazol-3-yl)benzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-((2S,6R)-2,6-dimethylmorpholine-4-carbonyl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(4-oxopiperidine-1-carbonyl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
2-acetamido-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazol -3-yl)benzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl) benzoyl)-6-(3-hydroxyazetidin-1-yl)-1H-indazol-3-yl)benzoic acid;
4-(6-(azetidin-1-yl)-1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(cyclopropylamino)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(oxetan-3-ylamino)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(3-hydroxypyrrolidin-1-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-morpholino-1H-indazol-3-yl)benzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(methoxycarbonylamino)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(N-methylacetamido)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(cyclopropanecarboxamido)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(methylsulfonamido)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(3-methylureido)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(6-acetamido-1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(N-methylmethylsulfonamido)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(1,3-dimethylureido)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(2-oxo-imidazolidin-1-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(2-oxoazetidin-1-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(6-(2-carboxyethylamino)-1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(3-methyl-2-oxoimidazolidin-1-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(2-oxopyrrolidin-1-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(morpholine-4-carbonyl)-1H-indazol-3-yl)benzoic acid;
3-(4-carboxyphenyl)-1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazole-6-carboxylic acid;
sodium 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(5-methyloxazol-2-yl)-1H-indazol-3-yl)benzoate;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(5-methyloxazol-2-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(3-hydroxyprop-1-ynyl)-1H-indazol-3-yl)benzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(3-hydroxybut-1-ynyl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(6-(3-aminoprop-1-ynyl)-1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-ethynyl-1H-indazol-3-yl)benzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(5-(hydroxymethyl)oxazol-2-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(1-methyl-1H-imidazol-4-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(oxazol-2-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(6-(5-bromooxazol-2-yl)-1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
(E)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(N′-cyano-N,N-dimethylcarbamimidoyl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(4H-1,2,4-triazol-3-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(1-methyl-1H-imidazol-2-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-[1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-(1-methyl-1H-imidazol-5-yl)-1H-indazol-3-yl]benzoic acid;
4-[1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-(5-methylthiophen-3-yl)-1H-indazol-3-yl]benzoic acid;
4-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-pyrimidin-2-yl-1H-indazol-3-yl)benzoic acid;
4-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-pyrimidin-4-yl-1H-indazol-3-yl)benzoic acid;
4-[1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-(1-methyl-1H-imidazol-4-yl)-1H-indazol-3-yl]benzoic acid;
4-[1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-(1,3-thiazol-4-yl)-1H-indazol-3-yl]benzoic acid;
4-(6-[4-(aminomethyl)pyridin-2-yl]-1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-1H-indazol-3-yl)benzoic acid;
4-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-pyridin-2-yl-1H-indazol-3-yl)benzoic acid;
4-[1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-(1,3-thiazol-5-yl)-1H-indazol-3-yl]benzoic acid;
4-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-pyridin-4-yl-1H-indazol-3-yl)benzoic acid;
4-[1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-(4-cyanophenyl)-1H-indazol-3-yl]benzoic acid;
4-[1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-(3-cyanophenyl)-1H-indazol-3-yl]benzoic acid;
4-[1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-(2-cyanophenyl)-1H-indazol-3-yl]benzoic acid;
4-[1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-(2-fluorophenyl)-1H-indazol-3-yl]benzoic acid;
4-[1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-(3-fluorophenyl)-1H-indazol-3-yl]benzoic acid;
4-[1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-(4-fluorophenyl)-1H-indazol-3-yl]benzoic acid;
4-[1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-(1-methyl-1H-pyrazol-5-yl)-1H-indazol-3-yl]benzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(methylsulfonamidomethyl)-1H-indazol-3-yl)benzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(2,5-dioxoimidazolidin-4-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(4-chloro-1-(2-chloro-6-cyclopropylbenzoyl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-cyclopropylbenzoyl)-1H-indazol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-2-methyl-1H-indol-3-yl)-3-fluorobenzoic acid;
4-(2-methyl-1-(2-(trifluoromethyl)benzoyl)-1H-indol-3-yl)benzoic acid;
4-(1-(2-chloro-6-cyclopropylbenzoyl)-1H-indazol-3-yl)-3,5-difluorobenzoic acid;
4-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)-3,5-difluorobenzoic acid;
4-(6-(azetidine-1-carbonyl)-1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indol-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(3-methoxy-azetidine-1-carbonyl)-1H-indol-3-yl)-3-fluorobenzoic acid; and
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(oxetan-3-yl)-1H-indazol-3-yl)-3-fluorobenzoic acid.
20. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.
21. A method for treating a disease or condition mediated by RORgammaT in a subject, comprising administering to the subject an amount of a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, that is effective for treating the disease or condition mediated by RORgammaT in the subject, wherein the disease or condition is an autoimmune disease or inflammatory disease.
22. A method for treating a disease or condition mediated by RORgammaT in a subject, comprising administering to the subject an amount of a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, that is effective for treating the disease or condition mediated by RORgammaT in the subject, wherein the disease or condition is multiple sclerosis, inflammatory bowel disease, Crohn's disease, ankylosing spondylitis, psoriasis, rheumatoid arthritis, asthma, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis, or mucosal leishmaniasis.
23. The compound of claim 7 , wherein:
R 2 is C(O)OH;
R 3 is hydrogen or halogen; and
R 4 , R 5 , and R 7 are hydrogen or halogen.
24. The compound of claim 23 , wherein R 6 is (C 3-5 )heterocycloalkylcarbonyl or (C 3-5 )heterocycloalkylcarbonyl(C 1-4 )alkyl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy.
25. A pharmaceutical composition comprising a compound of claim 24 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
26. A compound according to the Formula:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
Y is CH, CR a , or N;
n=0, 1, 2, 3 or 4;
R a is (C 1-4 )alkyl or (C 3-7 )cycloalkyl;
R 1 is
(i) (C 3-12 )carbocyclyl(C 0-4 )alkyl, or
(ii) a 4- to 12-membered heterocyclyl(C 0-4 )alkyl,
each optionally substituted with one, two, three, four or five R 8 ;
R 2 is hydroxycarbonyl, hydroxycarbonyl(C 1-10 )alkyl, (C 1-10 )alkylsulfoxyaminocarbonyl, or carbamoyl;
R 3 is hydrogen, halogen, cyano, nitro, hydroxy, (C 1-4 )alkylcarbonyloxy, (C 1-4 ) alkylcarbonylamino, (C 1-4 )alkyl, or (C 1-4 )alkoxy, wherein (C 1-4 )alkyl and (C 1-4 )alkoxy are optionally substituted with one or more halogen;
R 4 , R 5 , and R 7 independently are hydrogen, halogen, amino, cyano, hydroxy, (C 1-3 )alkoxy, (C 1-4 )alkyl, (C 0-10 )alkylaminocarbonyl, (C 0-6 )alkyoxycarbonylamino, (di)(C 1-6 )alkylaminocarbonyl, (C 1-6 )alkylcarbonylamino, (C 1-4 )alkylamino, or amino(C 1-4 )alkyl, wherein (C 1-3 )alkoxy and (C 1-4 )alkyl are optionally substituted with one or more halogen; or a group having the formula
optionally substituted with one or more of the following: (C 1-10 )alkyl, halogen, amino, cyano, hydroxy, (C 1-3 )alkoxy, and wherein m is 1, 2, 3, or 4;
R 6 is:
(i) (C 3-7 )cycloalkyl or (C 3-5 )heterocycloalkyl, both optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, oxo (═O), (C 1-4 )alkyl or (C 1-3 )alkoxy;
(ii) (C 2-9 )heteroaryl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(iii) (C 6-14 )aryl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(iv) (C 3-5 )heterocycloalkylamino, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(v) (C 3-5 )cycloalkyl(C 1-4 )alkyl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(vi) (C 3-5 )cycloalkylamino, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(vii) (C 3-5 )cycloalkylcarbonyl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(viii) (C 2-9 )heteroaryl(C 1-4 )alkyl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(ix) (C 2-9 )heteroarylcarbonyl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
and
R 8 is halogen, cyano, amino, hydroxy, di(C 1-3 )alkylamino, (C 1-4 )alkyl, (C 3-5 )heterocycloalkyl, (C 1-4 )alkenyl, (C 3-6 )cycloalkoxy or (C 1-3 )alkoxy, wherein (C 1-4 )alkyl and (C 1-3 )alkoxy are optionally substituted with one, two or three halogens.
27. The compound of claim 26 , wherein:
Y is N;
R 2 is C(O)OH;
R 3 is hydrogen or halogen; and
R 4 , R 5 , and R 7 are hydrogen or halogen.
28. The compound of claim 27 , wherein R 6 is:
(i) (C 3-7 )cycloalkyl or (C 3-5 )heterocycloalkyl, both optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy;
(ii) (C 2-9 )heteroaryl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 )alkyl or (C 1-3 )alkoxy; or
(iii) (C 6-14 )aryl, optionally substituted with one or more groups selected from halogen, amino, amino(C 1-4 )alkyl, cyano, hydroxyl, (C 1-4 alkyl or (C 1-3 )alkoxy.
29. A pharmaceutical composition comprising a compound of claim 26 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.