Therapeutically active compounds and their methods of use

1. A compound having Formula I or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

A is t-butyl, or optionally substituted cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl or 1,2,3,6-tetrahydropyridinyl;

ring B is an optionally substituted 5-6 member monocyclic heteroaryl;

R 1 and R 3 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, and CN, wherein any alkyl portion of R 1 is optionally substituted with —OH, NH 2 , NH(C 1 -C 4 alkyl), or N(C 1 -C 4 alkyl) 2 ;

R 2 is selected from: —(C 1 -C 6 alkyl), —(C 2 -C 6 alkenyl or alkynyl), —(C 1 -C 6 alkylene)-N(R 6 )—(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-N(R 6 )—(C 0 -C 6 alkylene)-Q, —(C 1 -C 6 alkylene)-N(R 6 )(R 6 ), —(C 1 -C 6 alkylene)-N(R 6 )—S(O) 1-2 —(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-N(R 6 )—S(O) 1-2 —(C 0 -C 6 alkyl)-Q, —(C 1 -C 6 alkylene)-S(O) 1-2 —N(R 6 )(R 6 ), —(C 1 -C 4 alkylene)-S(O) 1-2 —N(R 6 )—(C 1 -C 6 alkylene)-Q, —C(O)N(R 6 )—(C 1 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —C(O)N(R 6 )—(C 1 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-O—(C 0 -C 6 alkylene)-Q, —(C 1 -C 6 alkylene)-O—C(O)—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-O—C(O)—(C 0 -C 6 alkyl)-Q, —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-Q, —(C 0 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —(C 0 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-Q, —(C 1 -C 6 alkylene)-O—C(O)—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-O—C(O)—(C 0 -C 6 alkylene)-Q, —(C 0 -C 6 alkylene)-C(O)N(R 6 )—(C 1 -C 6 alkyl), —(C 0 -C 6 alkylene)-C(O)N(R 6 )—(C 0 -C 6 alkylene)-Q, —(C 1 -C 6 alkylene)-N(R 6 )C(O)—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-N(R 6 )C(O)—(C 0 -C 6 alkylene)-Q, —(C 0 -C 6 alkylene)-S(O) 0-2 —(C 1 -C 6 alkyl), —(C 0 -C 6 alkylene)-S(O) 0-2 —(C 0 -C 6 alkylene)-Q, —(C 1 -C 6 alkylene)-N(R 6 )—C(O)—N(R 6 )—(C 1 -C 6 alkyl), —(C 0 -C 6 alkylene)-Q, —(C 0 -C 6 alkylene)-C(O)—(C 1 -C 6 alkyl), —(C 0 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-Q, wherein:

any alkyl or alkylene moiety present in R 2 is optionally substituted with one or more —OH, —O(C 1 -C 4 alkyl) or halo;

any terminal methyl moiety present in R 2 is optionally replaced with —CH 2 OH, CF 3 , —CH 2 F, —CH 2 Cl, C(O)CH 3 , C(O)CF 3 , CN, or CO 2 H;

each R 6 is independently selected from hydrogen and C 1 -C 6 alkyl;

R 4 and R 5 are independently selected from hydrogen and C 1 -C 6 alkyl; and

Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl; and Q is optionally substituted; or

R 1 and R 3 are optionally taken together with the carbon to which they are attached to form C(═O); or

R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl, or optionally substituted heterocyclyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein R 1 is independently selected from hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 OH, CN, or R 1 and R 3 are taken together to form ═O.

3. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein R 1 and R 2 are taken together to form carbocyclyl or heterocyclyl, either of which is optionally substituted with up to 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, ═O, —OH, and —C(O)C 1 -C 4 alkyl.

4. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein R 2 is selected from: —(C 1 -C 4 alkyl) optionally substituted with fluoro or —OH; —(C 0 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —(C 0 -C 2 alkylene)-N(R 6 )—(C 1 -C 6 alkyl), —(C 0 -C 2 alkylene)-Q, and —O—(C 0 -C 2 alkylene)-Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, ═O, —C(O)—C 1 -C 4 alkyl, —CN, and halo.

5. The compound of claim 4 or a pharmaceutically acceptable salt or hydrate thereof, wherein Q is selected from pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl and oxetanyl, wherein Q is optionally substituted with up to 2 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, ═O, fluoro, chloro, and bromo.

6. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein R 1 and R 2 are taken together to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.1]heptanyl or azetidinyl, any of which is optionally substituted with up to 2 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, —OH, —C(O)CH 3 , fluoro, and chloro.

7. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein A is selected from t-butyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl, and 1,2,3,6-tetrahydropyridinyl, wherein said cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl, and 1,2,3,6-tetrahydropyridinyl are optionally substituted with up to two substituents independently selected from —OH, ═O, and CH 3 .

8. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein ring B is selected from pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, wherein ring B is optionally substituted with up to two substituents independently selected from halo, —C 1 -C 4 alkyl, —C 2 -C 4 alkynyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 hydroxyalkyl, C 3 -C 6 cycloalkyl, —(C 0 -C 2 alkylene)-O—C 1 -C 4 alkyl, —O—(C 1 -C 4 alkylene)-C 3 -C 6 cycloalkyl, —NH—S(O) 2 —(C 1 -C 4 alkyl), —S(O) 2 NH(C 1 -C 4 alkyl), —S(O) 2 —NH—(C 3 -C 6 cycloalkyl), —S(O) 2 -(saturated heterocyclyl), —CN, —S(O) 2 —(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —OH, C(O)—O—(C 1 -C 4 alkyl), saturated heterocyclyl, and —NH 2 .

9. A compound having Structural Formula II:

or a pharmaceutically acceptable salt or hydrate thereof,

wherein:

A′ is selected from cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl and 1,2,3,6-tetrahydropyridinyl, wherein A′ is optionally substituted with up to two substituents independently selected from —OH, ═O, and CH 3 ; or A′ is t-butyl;

ring B′ is selected from pyridin-3-yl, pyridin-4-yl, pyridazin-4-yl, isoxazol-4-yl, isoxazol-3-yl, thiazol-5-yl, pyrimidin-5-yl and pyrazol-4-yl, wherein ring B′ is optionally substituted with one to two substituents independently selected from halo; —CN; —OH; C 1 -C 4 alkyl optionally substituted with halo, CN or —OH; —S(O) 2 —C 1 -C 4 alkyl; —S(O)—C 1 -C 4 alkyl; —S(O) 2 —NH—C 1 -C 4 alkyl; —S(O) 2 —NH—CH 2 —CF 3 ; —S(O) 2 —N(C 1 -C 4 alkyl) 2 ; —S(O) 2 -azetidin-1-yl; —O—C 1 -C 4 alkyl; —CH 2 —O—CH 3 , morpholin-4-yl, cyclopropyl, cyclopropyl-C 1 -C 4 alkyl, cyclopropyl-C 1 -C 4 alkoxy, cyclopropyl-CN, —S(O) 2 —NH-cyclopropyl; —S(O) 2 —NH—CH 2 -cyclopropyl; —C(O)—C 1 -C 4 alkyl, —C(O)—O—CH 3 ; and

—C(R 1a )(R 2a )(R 3a ) is selected from C 1 -C 6 alkyl optionally substituted with halo, —OCH 3 , —P(O) 3 2− or —OH; —(C 0 -C 1 alkylene)-cycloalkyl, wherein the alkylene is optionally substituted with methyl and the cycloalkyl is optionally substituted with —OH, —CH 2 OH, halo, —OCH 3 or methyl; saturated or partially saturated —(C 0 -C 1 alkylene)-heterocyclyl wherein the heterocyclyl is optionally substituted with halo, —S(O) 2 —CH 2 —C(O)—C 1 -C 6 alkyl, —S(O) 2 —C 1 -C 6 alkyl, —C(O)—O—C 1 -C 6 alkyl, —C(O)—N(CH 3 ) 2 or methyl; —C(O)—O—C 1 -C 6 alkyl; —C(O)—(C 0 -C 1 alkylene)-cyclopropyl; and C(O)-benzyl.

10. The compound of claim 9 or a pharmaceutically acceptable salt or hydrate thereof, wherein A′ is selected from t-butyl, cyclohexenyl, cyclohexyl, cyclopentyl, cyclobutyl, 3-cyclohex-2-enonyl, 3-hydroxy-1-cyclohexenyl, 3-hydroxycyclohexyl, 3-methylcyclohexyl, cyclohexan-3-onyl, 3,5-dimethylcyclohexyl, 5,6-dihydropyridin-2(1H)-onyl, and 4-5,6-dihydropyridin-2(1H)-onyl.

11. The compound of claim 9 or a pharmaceutically acceptable salt or hydrate thereof, wherein ring B′ is selected from 2-(morpholin-4-yl)pyridin-4-yl, 2-dimethylaminopyridin-4-yl, 5 chloropyridin-3-yl, 5-cyanopyridin-3-yl, 5-cyanopyridin-3-yl, 5-cyanopyridin-4-yl, 5-fluoropyridin-3-yl, 2-(1-hydroxyisopropyl)pyridin-4-yl, 5-trifluoromethypyridin-3-yl, 2-trifluoromethylpyridin-4-yl, 2-difluoromethylpyridin-4-yl, 2-chloropyridin-4-yl, 6-chloropyridin-4-yl, 6-cyanopyridin-4-yl, 2-cyanopyridin-4-yl, 6-cyclopropylpyridin-4-yl, 6-ethoxypyridin-4-yl, 6-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 5,6-difluoropyridin-3-yl, 6-fluoropyridin-4-yl, 6-methylpyridin-4-yl, 2-difluoromethylpyridin-4-yl, 6-trifluoromethylpyridin-4-yl, 2-(1-methoxycyclopropyl)pyridin-4-yl, 2-cyclopropylpyridin-4-yl, 2-(propan-1-one)pyridin-4-yl, 2-(1-methylcyclopropyl)pyridin-4-yl, 2-(1-cyanocyclopropyl)pyridin-4-yl, 2-(1-cyanoisopropyl)pyridin-4-yl, isoxazol-4-yl, pyridin-4-yl, picolinat-2-yl, pyrimidin-5-yl, 1-propylpyrazol-4-yl, 6-methyl-pyridazin-4-yl, and thiazol-5-yl.

12. The compound of claim 9 or a pharmaceutically acceptable salt or hydrate thereof, wherein the moiety represented by C(R 1a )(R 2a )(R 3a ) is selected from 2-methylcyclopropyl, —(CH 2 ) 3 CH 3 , —CH(CH 3 )—C(CH 3 ) 3 , —CH(CH 3 )—CH 2 OCH 3 , —CH(CH 3 )—CH(CH 3 ) 2 , —CH(CH 3 )—CH 2 CH 3 , —CH 2 C(CH 3 ) 2 —CH 2 OH, —CH 2 C(OH)(CH 3 ) 3 , CH 2 C(CH 3 ) 3 , —CH 2 CF 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 )—CH 2 CH 3 , —CH 2 CH 2 CH(CH 3 ) 2 , —CH 2 -cyclopropyl, isopropyl, and t-butyl.

13. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13 , further comprising a second therapeutic agent useful in the treatment of cancer.

15. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, selected from the group consisting of:

16. The compound of claim 1 or pharmaceutically acceptable salt or hydrate thereof, wherein ring A is cyclohexyl or cyclohexenyl, wherein said cyclohexyl or cyclohexenyl is optionally substituted with one occurrence of —OH.

17. The compound of claim 9 or pharmaceutically acceptable salt or hydrate thereof, wherein ring A′ is cyclohexyl or cyclohexenyl, wherein said cyclohexyl or cyclohexenyl is optionally substituted with one occurrence of —OH.