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

• US 8,957,068 B2
• Filed: 09/26/2012
• Issued: 02/17/2015
• Est. Priority Date: 09/27/2011
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Caferro, Thomas Raymond, Cho, Young Shin, Costales, Abran Q., Lei, Huangshu, Lenoir, Francois, Levell, Julian Roy, Liu, Gang, Palermo, Mark G., Pfister, Keith Bruce, Sendzik, Martin, Shafer, Cynthia, Shultz, Michael David, Smith, Troy, Sutton, James Clifford, Toure, Bakary-Barry, Yang, Fan, Zhao, Qian
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US14/347,481
• Publication Number:
  US 20140235620A1
• Time in Patent Office: 874 Days
• Field of Search: 540/575, 544/122, 544/295, 544/296, 544/323, 544/324, 514/218, 514/235.8, 514/249, 514/252.19, 514/255.05, 514/275
• US Class Current: 514/218
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/08 Bridged systems
• CPC Class Codes: C07D 498/10 Spiro-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

The invention is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R¹-R⁶ are defined herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.

Claims

1. A compound of formula (I)

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

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

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 CF₃;

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 R¹ is hydrogen, fluoro or chloro and R² is hydrogen, fluoro, chloro, or methyl;

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7 wherein R¹ and R² 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, —

SO₂R^b, —

NHC(O)R^b, and —

NR^bR^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 R⁶ 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 R⁶ 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 R⁶ 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 R⁶ is substituted with one —

CH₂R^a, —

C(O)R^a, —

NHC(O)R^a, —

NHC(O)R^b, —

C(O)NHR^a, C(O)NHR^b, —

OR^a, —

NR^aR^b, —

SO₂NR^bR^b, —

SO₂R^a, or —

SO₂R^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 R⁶ is optionally substituted phenyl;

or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 19 wherein the phenyl is substituted with one —

CH₂R^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)

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 R¹ and R² is independently hydrogen, deuterium, halo, hydroxyl, NH₂, 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 NH₂;

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, NH₂, 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, SO₂R^b, NHC(O)R^b, and NR^bR^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, NH₂, 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, CD₃, CF₃, CH₂F, or CHF₂ and

R⁶ 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, SO₂R^b, NHC(O)R^b, and NR^bR^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, NH₂, and C_1-3 alkyl;

—

CH₂R^a;

—

OR^a;

—

C(O)R^a;

—

NR^aR^b;

—

COOR^a;

—

SO₂R^a;

NHC(O)R^a; and

—

SO₂NR^bR^b;

or

R^5b and R⁶ are joined together forming an optionally substituted C_3-7 cycloalkyl group or an optionally substituted group of formula (a);

26. The compound according to claim 25 wherein

R¹ is hydrogen, fluoro, chloro, or methyl;

R² 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 CF₃;

or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 26 wherein R⁶ 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.