Jak1 selective inhibitors and uses thereof

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein R 1 is H, halo, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(0)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′;

R 2 is H, halo, or C 1-3 alkyl;

Cy is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R 3 , oxo, halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′, wherein R 3 is C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′; and

R and R′ are each independently H, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN.

2. The compound of claim 1 , wherein Cy is C 5-7 cycloalkyl, or 5-7 membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R 3 , oxo, halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′, wherein R 3 is C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 RR′.

3. The compound of claim 1 , wherein R 2 is hydrogen.

4. The compound of claim 1 , wherein the compound is selected from the group consisting of:

trans-4-[2-[(R)-1-Hydroxyethyl]-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl] cyclohexanecarbonitrile (1),

trans-4-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl] cyclohexanecarbonitrile (2),

2-[trans-4-[2-[(R)-1-Hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]cyclohexyl] acetonitrile (3),

2-[(2R,5S)-5-[2-[(R)-1-Hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-1-yl] tetrahydropyran-2-yl]acetonitrile (4),

3-[2-[(R)-1-Hydroxyethyl]-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (5),

(R)-4-[2-(1-Hydroxyethyl)-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]-N-(2,2,2-trifluoroethyl)piperidine-1-carboxamide (6),

2-[(2R,5S)-5-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (7),

2-[(2S,5S)-5-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (8),

2-[(2R,5S)-5-[2-Ethylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl] tetrahydropyran-2-yl]acetonitrile (9),

2-[(2R,5S)-5-[2-Furo[3,2-b]imidazo[4,5-d] pyridin-1-yl] tetrahydropyran-2-yl]acetonitrile (10), and

2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-1-yl] tetrahydropyran-2-yl] acetonitrile (11).

2-[(2R,5S)-5-[2-Ethylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (9),

2-[(2R,5S)-5-[2-Furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (10), and

2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (11).

5. A method of treating rheumatoid arthritis in a subject comprising administering to the subject a compound of claim 1 .

6. A compound of formula A1-14:

7. A process, comprising contacting a compound of formula V:

and a compound of formula VI:

in the presence of a (C 1-6 ) 3 alkyloxonium tetrafluoroborate at a sufficient temperature, and for a sufficient time to produce a compound of formula I:

wherein R 1 is H, halo, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′;

R 2 is H;

Cy is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R 3 , oxo, halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′, wherein R 3 is C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′; and

R and R′ are each independently H, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN.

8. The process of claim 7 , wherein the (C 1-6 ) 3 alkyloxonium tetrafluoroborate reagent is triethyloxonium tetrafluoroborate.

9. The process of claim 7 , wherein the compound of formula V is prepared by a process comprising reducing a compound of formula VII:

in the presence of a hydrogenation catalyst and hydrogen gas at a sufficient temperature, a sufficient pressure and for a sufficient time to produce a compound of formula V.

10. The process of claim 9 , wherein the hydrogenation catalyst is palladium on carbon.

11. The process of claim 9 , wherein the compound of formula VII is prepared by a process comprising contacting a compound of formula A1-14:

and a compound of formula VIII:

Cy-NH 2    VIII

in the presence of a base at a sufficient temperature, and for a sufficient time to produce the compound of formula VII.

12. The process of claim 11 , wherein the base is N,N-Diisopropylethylamine.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy is C 5-7 cycloalkyl, or 5-7 membered heterocyclyl, each optionally substitutued with 1, 2, or 3 substituents independently selected from the group consisting of R 3 , oxo, halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′, wherein R 3 is C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.

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

2-[(2R,5S)-5-[2-Ethylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (9),

2-[(2R,5S)-5-[2-Furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (10),

2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (11), and

pharmaceutically acceptable salts thereof.

16. A compound that is 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (11).

17. A pharmaceutically acceptable salt that is a pharmaceutically acceptable salt of 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (11).

18. A method of treating rheumatoid arthritis in a subject in need thereof comprising administering to the subject in need thereof an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

19. A compound of formula A1-14:

or a pharmaceutically acceptable salt thereof.

20. A process, comprising contacting a compound of formula V:

and a compound of formula VI:

in the presence of a (C 1-6 alkyl) 3 oxonium tetrafluoroborate at a sufficient temperature, and for a sufficient time to produce a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein R 1 is H, halo, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′;

R 2 is H;

Cy is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R 3 , oxo, halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′, wherein R 3 is C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′; and

R and R′are each independently H, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN.

21. The process of claim 20, wherein Cy is C 5-7 cycloalkyl or 5-7 membered heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R 3 , oxo, halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′, wherein R 3 is C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′.

22. The process of claim 20, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

2-[(2R,5S)-5-[2-Ethylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (9),

2-[(2R,5S)-5-[2-Furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (10),

2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (11), and

pharmaceutically acceptable salts thereof.