3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH

1. A compound of formula (I)

wherein:

R 1 and R 2 are each independently hydrogen, deuterium, halo, hydroxyl, NH 2 , aryl, heteroaryl, or optionally substituted C 1-4 alkyl,

wherein said C 1-4 alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, and NH 2 ;

R 3a is hydrogen, deuterium, C 1-6 alkyl, phenyl, or benzyl and

R 3b is hydrogen, deuterium, or C 1-6 alkyl; or

R 3a and R 3b are joined together forming an optionally substituted 3-7 membered cycloalkyl ring or an optionally substituted 4-7 membered heterocyclic ring,

wherein said cycloalkyl and heterocyclic rings are each optionally substituted with one or two substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH 2 , and C 1-3 alkyl;

R 4a is hydrogen, C 1-6 alkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted heteroaryl, or methylene-dibenzene,

wherein said phenyl, benzyl, and heteroaryl rings are optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, C 1-4 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenoxy, —COOR b , —SO 2 R b , —NHC(O)R b , and —NR b R b and

R 4b is hydrogen, deuterium, or C 1-3 alkyl; or

R 4a and R 4b are joined together forming an optionally substituted 3-7 membered cycloalkyl ring or an optionally substituted 4-7 membered heterocyclic ring,

wherein said cycloalkyl and heterocyclic rings are optionally substituted with one or two substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH 2 , and C 1-3 alkyl,

provided that only one of R 3a and R 3b and R 4a and R 4b are joined together forming a ring;

R 5a is hydrogen or deuterium;

R 5b is hydrogen, deuterium, methyl, ethyl, CD 3 , CF 3 , CH 2 F, or CHF 2 and

R 6 is optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, or optionally substituted C 3-10 cycloalkyl,

wherein said C 1-6 alkyl is optionally substituted with one substituent selected from the group consisting of hydroxyl, C 1-3 alkoxy and −OR a ,

wherein said aryl, heteroaryl, heterocyclic and C 3-10 cycloalkyl are optionally substituted with one to three substituents each independently selected from the group consisting of: halo; hydroxyl; cyano; nitro; C 1-4 alkoxy; C 1-3 haloalkyl; C 1-3 haloalkoxy; C 1-6 alkyl; C 3-6 cycloalkyl optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, and C 1-3 haloalkyl; phenyl optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenoxy, —COOR b , —SO 2 R b , —NHC(O)R b , and NR b R b ; 5-6 membered heteroaryl optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy; 5-6 membered heterocyclic optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH 2 , and C 1-3 alkyl; —CH 2 R a ; —OR a ; —C(O)R a ; —NR a R b ; —COOR a ; —SO 2 R a ; —SO 2 R b ; —NHC(O)R a ; —NHC(O)R b ; —C(O)NR a R b ; —C(O)NHR b ; and —SO 2 NR b R b ; or R 5b and R 6 are joined together forming an optionally substituted C 3-7 cycloalkyl group or an optionally substituted group of formula (a):

wherein n is 1, 2, or 3 and

said C 3-7 cycloalkyl and group of formula (a) are optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, benzyloxy, —COOR b , —SO 2 R b , —NHC(O)R b , and —NR b R b ;

each R a is independently optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, or optionally substituted C 3-7 cycloalkyl,

wherein said phenyl and heteroaryl are optionally substituted with one to three substituents each independently selected from the group consisting of halo, hydroxyl, cyano, nitro, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, and C 1-3 alkyl,

wherein said heterocyclic is optionally substituted with one to three substituents each independently selected from the group consisting of halo, hydroxyl, oxo, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-4 alkyl, C 3-5 cycloalkyl, —C(O)R b , and —NR b R b , and

wherein said C 3-7 cycloalkyl is optionally substituted with one to three substituents each independently selected from the group consisting of halo, hydroxyl, oxo, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, and C 1-3 alkyl; and

each R b is independently hydrogen or C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 of the formula (III)

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 of the formula (IV)

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3 wherein R 3a and R 3b are both hydrogen; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4 wherein R 5a is hydrogen and R 5b is hydrogen, methyl, ethyl, or CF 3 ; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5 wherein R 5b is methyl; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 wherein R 1 is hydrogen, fluoro or chloro and R 2 is hydrogen, fluoro, chloro, or methyl; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7 wherein R 1 and R 2 are both hydrogen; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8 wherein R 4a is hydrogen, C 1-6 alkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted heteroaryl, or methylene-dibenzene,

wherein said phenyl, benzyl, and heteroaryl rings are optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenoxy, —COOR b , —SO 2 R b , —NHC(O)R b , and —NR b R b and

R 4b is hydrogen or C 1-3 alkyl; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9 wherein R 4b is hydrogen or methyl; or a pharmaceutically acceptable salt thereof.

11. The compound according claim 10 wherein R 4b is hydrogen; or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 11 R 4a is hydrogen, methyl, ethyl, isopropyl, phenyl, 4-fluorophenyl, 4-methoxyphenyl, biphenyl, benzyl, or pyridinyl; or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 12 wherein R 4a is isopropyl; or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 wherein R 6 is methyl, C 5-10 cycloalkyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazolyl, optionally substituted pyrazolyl, optionally substituted thiazolyl, optionally substituted 1,3,4-oxadiazolyl, optionally substituted 1,2,4-oxadiazolyl, optionally substituted isoxazolyl, thienyl, oxazolyl, quinolinyl, optionally substituted benzimidazolyl, benzthiazolyl, benzoxazolyl, tetrazolo[1,5-a]pyridinyl, imidazo[2,1-b][1,3,4]thiadiazolyl, optionally substituted piperidinyl, optionally substituted piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted tetrahydro-thiopyran1,1-dioxide, 1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydro-benzo[1,4]dioxinyl, 5,6,7,8-tetrahydro-[1,2,4]trazolo[4,3-a]pyrazinyl, 4,5,6,7-tetrahydro-benzothiazolyl, indolizinyl, cyclopropyl, cyclopentyl, or cyclohexyl, wherein said phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, pyrazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, isoxazolyl, benzimidazolyl, piperidinyl, piperazinyl, and tetrahydro-thiopyran1,1-dioxide are each optionally substituted with one or two substituents as defined in formula (I).

15. The compound according to claim 14 wherein R 6 is optionally substituted with one or two substituents each independently selected from the group consisting of: halo; hydroxy; nitro; C 1-4 alkoxy; C 1-3 haloalkyl; C 1-3 haloalkoxy; C 1-6 alkyl; C 3-6 cycloalkyl optionally substituted with one substituent selected from the group consisting of: cyano, C 1-3 alkyl, and C 1-3 alkoxy; phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, methyl, cyano, and methoxy; and 5-6 membered heteroaryl optionally substituted with one or two methyl groups; or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 15 wherein R 6 is optionally substituted 1,3,4-oxadiazolyl or optionally substituted 1,2,4-oxadiazolyl; or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 14 wherein R 6 is substituted with one —CH 2 R a , —C(O)R a , —NHC(O)R a , —NHC(O)R b , —C(O)NHR a , C(O)NHR b , —OR a , —NR a R b , —SO 2 NR b R b , —SO 2 R a , or —SO 2 R b group; or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 17 wherein Ra is

(a) phenyl optionally substituted with one or two substituents each independently selected from the group consisting of fluoro, chloro and bromo;

(b) optionally substituted 5-6 membered heteroaryl;

(c) C 5-7 cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of fluoro, hydroxy, methyl, and C 1-3 haloalkoxy; or

(d) a heterocyclic group selected from the group consisting of: piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydro-thiopyran1,1-dioxide, 1,4-diazepanyl, 4,7-diaza-spiro[2.5]octanyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 3,8-diaza-bicyclo[4.2.0]octanyl, octahydro-pyrrolo[1,2-a]pyrazinyl, octahydro-pyrido[1,2-a]pyrazinyl, octahydro-pyrrolo[3,4-c]pyrrolyl, and 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazinyl each of which is optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxy, fluoro, amino, dimethylamino, C 1-3 haloalkoxy, C 1-3 alkyl, and C 3-5 cycloalkyl; or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 18 wherein R 6 is optionally substituted phenyl; or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 19 wherein the phenyl is substituted with one —CH 2 R a , —C(O)R a , or —C(O)NHR a group in the para position; or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 2 of the formula (V)

wherein R 4a is phenyl and R 4b is hydrogen; or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 1 selected from the group consisting of:

(S)-4-isopropy-3-(2-(((S)-1-(4-(2-yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;

N-(4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)phenyl)cyclohexanecarboxamide;

(S)-3-(2-(((S)-1-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-4-isopropyl-3-(2-(((S)-1-(4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;

2-fluoro-N-(4-hydroxy-4-methylcyclohexyl)-4-((S)-1-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)benzamide;

(S)-3-(2-((S)-1-(4-((4-amino-4-methylpiperidin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-((S)-1-(4-((4-(dimethylamino)piperidin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-4-isopropyl-3-(2-((S)-1-(4-((4-methylpiperazin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;

(S)-4-isopropyl-4-methyl-3-(2-((S)-1-(4-((4-methylpiperazin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;

(S)-4-isopropyl-3-(2-((S)-1-(6-phenylpyridin-3-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;

(S)-3-(2-((S)-1-(4-benzoylphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-4-isopropyl-3-(2-(((S)-1-(5-phenyl-1,3,4-thiadiazol-2-yl)ethyl)amino) pyrimidin-4-yl)oxazolidin-2-one;

(4S)-4-isopropyl-3-(2-(1-(5-phenylpyrimidin-2-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;

3-(5-fluoro-2-((1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;

(S)-4-isopropyl-3-(2-(((S)-1-(1-(3-methoxyphenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;

(S)-3-(2-(((S)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-4-isopropyl-3-(2-(((S)-1-(3-(m-tolyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;

(S)-3-(2-(((S)-1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-((S)-1-(5-(4-fluoro-2-methylphenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-4-Isopropyl-3-{2-[(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amino]-pyrimidin-4-yl}-oxazolidin-2-one;

(S)-4-isopropyl-3-(2-((S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;

(S)-3-(2-((S)-1-(2-fluoro-4-isopropylphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-((S)-1-(4-isobutoxy-3-methylphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-(((S)-1-(4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(5-fluoro-2-(((S)-1-(4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

2-fluoro-N-(trans-4-hydroxycyclohexyl)-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide;

(S)-3-(5-fluoro-2-((S)-1-(3-fluoro-4-(piperidine-1-carbonyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

N-cyclohexyl-2-fluoro-4-((S)-1-(5-fluoro-4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide;

N-cyclohexyl-2-fluoro-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide; and

(S)-3-(5-fluoro-2-((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethylami no)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one; or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 1 selected from the group consisting of:

(S)-3-(2-(((S)-1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-(((S)-1-(4-((4,4-difluoropiperidin-1-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(5-fluoro-2-(1-(4-phenoxyphenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;

(S)-3-(2-((S)-1-(4-(4-fluorophenoxy)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-((S)-1-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-(((S)-1-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-((S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-((S)-1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-((S)-1-(5-(4-fluorophenoxy)pyrazin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-4-isopropyl-3-(2-((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one; and

(S)-3-(2-((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one; or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 1 selected from the group consisting of:

(S)-3-(2-(1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)-5-fluoropyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one;

(S)-3-(6-chloro-2-(1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;

(S)-3-(2-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino) pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

2-chloro-N-cyclopentyl-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide;

(S)-3-(2-((S)-1-(4-((3,3-difluoropiperidin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-((S)-1-(4-(4,7-diazaspiro[2.5]octan-4-ylmethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-((S)-1-(4-((4-acetylpiperazin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(2-(((S)-1-(4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;

(S)-3-(5-fluoro-2-(((S)-1-(4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one; and

2-fluoro-N-(trans-4-hydroxycyclohexyl)-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide; or a pharmaceutically acceptable salt thereof.

25. The compound according to claim 1 wherein

each R 1 and R 2 is independently hydrogen, deuterium, halo, hydroxyl, NH 2 , aryl, heteroaryl, or optionally substituted C 1-4 alkyl,

wherein said C 1-4 alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, and NH 2 ;

R 3a is hydrogen, deuterium, C 1-6 alkyl, phenyl, or benzyl and

R 3b is hydrogen, deuterium, or C 1-6 alkyl; or

R 3a and R 3b are joined together forming an optionally substituted 3-7 membered cycloalkyl ring or an optionally substituted 4-7 membered heterocyclic ring,

wherein said cycloalkyl and heterocyclic rings are each optionally substituted with one or two substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH 2 , and C 1-3 alkyl;

R 4a is hydrogen, C 1-6 alkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted heteroaryl, or methylene-dibenzene,

wherein said phenyl, benzyl, and heteroaryl rings are optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenoxy, COOR b , SO 2 R b , NHC(O)R b , and NR b R b and

R 4b is hydrogen, deuterium, or C 1-3 alkyl; or

R 4a and R 4b are joined together forming an optionally substituted 3-7 membered cycloalkyl ring or an optionally substituted 4-7 membered heterocyclic ring,

wherein said cycloalkyl and heterocyclic rings are optionally substituted with one or two substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH 2 , and C 1-3 alkyl,

provided that only one of R 3a and R 3b and R 4a and R 4b are joined together forming a ring;

R 5a is hydrogen or deuterium;

R 5b is hydrogen, deuterium, methyl, ethyl, CD 3 , CF 3 , CH 2 F, or CHF 2 and

R 6 is optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, or optionally substituted C 5-10 cycloalkyl,

wherein said C 1-6 alkyl is optionally substituted with one substituent selected from the group consisting of hydroxyl, C 1-3 alkoxy and −OR a ;

wherein said aryl, heteroaryl, heterocyclic and C 5-10 cycloalkyl are optionally substituted with one to three substituents each independently selected from the group consisting of: halo; hydroxyl; cyano; nitro; C 1-3 alkoxy; C 1-3 haloalkyl; C 1-3 haloalkoxy; C 1-6 alkyl; C 3-6 cycloalkyl; phenyl optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenoxy, COOR b , SO 2 R b , NHC(O)R b , and NR b R b ; 5-6 membered heteroaryl; 5-6 membered heterocyclic optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH 2 , and C 1-3 alkyl; —CH 2 R a ; —OR a ; —C(O)R a ; —NR a R b ; —COOR a ; —SO 2 R a ; NHC(O)R a ; and —SO 2 NR b R b ; or

R 5b and R 6 are joined together forming an optionally substituted C 3-7 cycloalkyl group or an optionally substituted group of formula (a):

wherein n is 1, 2, or 3 and

said C 3-7 cycloalkyl and group of formula (a) are optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, benzyloxy, COOR b , SO 2 R b , NHC(O)R b , and NR b R b ;

each R a is independently optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted 4-7 membered heterocyclic,

wherein said phenyl and heteroaryl are optionally substituted with one to three substituents each independently selected from the group consisting of halo, hydroxyl, cyano, nitro, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, and C 1-3 alkyl,

wherein said 4-7 membered heterocyclic is optionally substituted with one to three substituents each independently selected from the group consisting of halo, hydroxyl, oxo, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, and C 1-3 alkyl; and

each R b is independently hydrogen or C 1-6 alkyl; or a pharmaceutically acceptabble salt thereof.

26. The compound according to claim 25 wherein

R 1 is hydrogen, fluoro, chloro, or methyl;

R 2 is hydrogen;

R 3a is hydrogen, methyl, or phenyl;

R 3b is hydrogen or methyl;

R 4a is hydrogen, C 1-4 alkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted heteroaryl, or methylene-dibenzene;

R 4b is hydrogen or methyl;

R 5a is H; and

R 5b is hydrogen, methyl, ethyl, or CF 3 ; or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 26 wherein R 6 is isopropyl, optionally substituted aryl, optionally substituted pyrazolyl, optionally substituted pyridinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or optionally substituted C 5-10 cycloalkyl; or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.