Anti-proliferative agents for treating PAH

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is CH or N;

R 1 is C 1 -C 2 alkyl or C 1 -C 2 fluoroalkyl;

R 2 is C 1 -C 4 alkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of —OH, C 1 -C 2 alkoxy, and F;

R 3 is 4- to 8-membered heterocyclyl, C 3 -C 8 cycloalkyl, (4- to 8-membered heterocyclyl)-C 1 -C 4 alkyl-, or (C 3 -C 8 cycloalkyl)-C 1 -C 4 alkyl-,

wherein each of the 4- to 8-membered heterocyclyl and the 4- to 8-membered heterocyclyl moiety in (4- to 8-membered heterocyclyl)-C 1 -C 4 alkyl- is optionally substituted with 1 or 2 R 5 ,

wherein each of the C 3 -C 8 cycloalkyl and the C 3 -C 8 cycloalkyl moiety in (C 3 -C 8 cycloalkyl)-C 1 -C 4 alkyl- is optionally substituted with 1 or 2 R 5 and further optionally substituted with 1 —N(R 6 ) 2 , and

wherein each of the C 1 -C 4 alkyl moieties in (4- to 8-membered heterocyclyl)-C 1 -C 4 alkyl- and (C 3 -C 8 cycloalkyl)-C 1 -C 4 alkyl- is optionally substituted with 1, 2, or 3 R 5 ;

R 4 is a moiety having the structure of

each R 5 is independently selected from the group consisting of —F, —OH, —CN, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkyl-, C 1 -C 4 fluoroalkoxy-C 1 -C 4 alkyl-, C 1 -C 4 alkoxy-C 1 -C 4 fluoroalkyl, and C 1 -C 4 fluoroalkoxy-C 1 -C 4 fluoroalkyl-;

each R 6 is independently selected from the group consisting of H and C 1 -C 2 alkyl;

each R 7 is independently H or C 1 -C 2 alkyl; and

each R 8 is independently H, F, or C 1 -C 2 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A is CH or N;

R 1 is CH 3 or C 1 fluoroalkyl;

R 2 is CH 3 ;

R 3 is 5- to 7-membered heterocyclyl, C 3 -C 6 cycloalkyl, (5- to 7-membered heterocyclyl)-C 1 -C 4 alkyl-, or (C 3 -C 6 cycloalkyl)-C 1 -C 4 alkyl-,

wherein each of the 5- to 7-membered heterocyclyl and the 5- to 7-membered heterocyclyl moiety in (5- to 7-membered heterocyclyl)-C 1 -C 4 alkyl- is optionally substituted with 1 R 5 ,

wherein each of the C 3 -C 6 cycloalkyl and the C 3 -C 6 cycloalkyl moiety in (C 3 -C 6 cycloalkyl)-C 1 -C 4 alkyl- is optionally substituted with 1 or 2 R 5 and further optionally substituted with 1 —N(R 6 ) 2 , and

wherein each of the C 1 -C 4 alkyl moieties in (5- to 7-membered heterocyclyl)-C 1 -C 4 alkyl- and (C 3 -C 6 cycloalkyl)-C 1 -C 4 alkyl- is optionally substituted with 1, 2, or 3 R 5 ;

R 4 is a moiety having the structure of

each R 5 is independently selected from the group consisting of —F, —OH, —CN, C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 fluoroalkoxy, C 1 -C 2 alkoxy-C 1 -C 2 alkyl-, C 1 -C 2 fluoroalkoxy-C 1 -C 2 alkyl-, C 1 -C 2 alkoxy-C 1 -C 2 fluoroalkyl-, and C 1 -C 2 fluoroalkoxy-C 1 -C 2 fluoroalkyl-;

each R 6 is independently selected from the group consisting of H and C 1 -C 2 alkyl; and

each R 7 is independently H or CH 3 , provided that no more than two R 7 are CH 3 .

3. The compound of claim 1 , wherein the compound is a compound of Formula II:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula III:

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:

A is CH or N;

R 3 is 5- to 7-membered heterocyclyl optionally substituted with 1 R 5 ; and

R 5 is selected from the group consisting of F, OH, —CN, C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 fluoroalkoxy, C 1 -C 2 alkoxy-C 1 -C 2 alkyl-, C 1 -C 2 fluoroalkoxy-C 1 -C 2 alkyl-, C 1 -C 2 alkoxy-C 1 -C 2 fluoroalkyl-, and C 1 -C 2 fluoroalkoxy-C 1 -C 2 fluoroalkyl-.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of 2-azaspiro[3.3]heptanyl, tetrahydrofuranyl, pyrrolidinyl, and piperidinyl, wherein each of the heterocyclyl selections is optionally substituted with 1 R 5 ; and R 5 is selected from the group consisting of F, OH, —CN, C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 fluoroalkoxy, C 1 -C 2 alkoxy-C 1 -C 2 alkyl-, C 1 -C 2 fluoroalkoxy-C 1 -C 2 alkyl-, C 1 -C 2 alkoxy-C 1 -C 2 fluoroalkyl-, and C 1 -C 2 fluoroalkoxy-C 1 -C 2 fluoroalkyl-.

7. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is 2-azaspiro[3.3]heptan-6-yl optionally substituted with 1 R 5 that is selected from the group consisting of C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy-C 1 -C 2 alkyl-, and C 1 -C 2 fluoroalkoxy-C 1 -C 2 alkyl-.

8. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:

A is CH or N;

R 3 is C 3 -C 6 cycloalkyl optionally substituted with 1 or 2 R 5 and further optionally substituted with 1 —N(R 6 ) 2 ;

each R 5 is independently selected from the group consisting of F, OH, —CN, C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 fluoroalkoxy, C 1 -C 2 alkoxy-C 1 -C 2 alkyl-, C 1 -C 2 fluoroalkoxy-C 1 -C 2 alkyl-, C 1 -C 2 alkoxy-C 1 -C 2 fluoroalkyl, and C 1 -C 2 fluoroalkoxy-C 1 -C 2 fluoroalkyl-; and

each R 6 is independently selected from the group consisting of H and C 1 -C 2 alkyl.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[3.1.0]hexanyl, wherein each of the selections is optionally substituted with 1 or 2 R 5 and further optionally substituted with 1 —N(R 6 ) 2 .

10. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3 is cyclobutyl optionally substituted with 1 or 2 R 5 ; and each R 5 is independently selected from the group consisting of F, OH, C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 fluoroalkoxy, C 1 -C 2 alkoxy-C 1 -C 2 alkyl-, C 1 -C 2 fluoroalkoxy-C 1 -C 2 alkyl-, C 1 -C 2 alkoxy-C 1 -C 2 fluoroalkyl, and C 1 -C 2 fluoroalkoxy-C 1 -C 2 fluoroalkyl-.

11. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3 is cyclopentyl optionally substituted with 1 or 2 R 5 ; and each R 5 is independently selected from the group consisting of F, OH, C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 fluoroalkoxy, C 1 -C 2 alkoxy-C 1 -C 2 alkyl-, C 1 -C 2 fluoroalkoxy-C 1 -C 2 alkyl-, C 1 -C 2 alkoxy-C 1 -C 2 fluoroalkyl, and C 1 -C 2 fluoroalkoxy-C 1 -C 2 fluoroalkyl-.

12. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3 is cyclopentyl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is CH.

14. The compound of any claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is N.

15. A compound selected from the group consisting of:

6-acetyl-8-cyclobutyl-2-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

6-acetyl-8-cyclopentyl-2-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

6-acetyl-8-(2-azaspiro[3.3]heptan-6-yl)-2-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

6-acetyl-2-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-5-methyl-8-[(1R,2S)-2-methylcyclopentyl]pyrido[2,3-d]pyrimidin-7(8H)-one;

3-acetyl-1-cyclopentyl-7-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-4-methyl-1,6-naphthyridin-2(1H)-one;

6-acetyl-8-[(1S,2R,5R)-bicyclo[3.1.0]hexan-2-yl]-2-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

6-acetyl-8-[(1R,2S,5S)-bicyclo[3.1.0]hexan-2-yl]-2-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

6-acetyl-8-[(1R,2S)-2-fluoro-2-methylcyclopentyl]-2-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

6-acetyl-8-[(1S,2R)-2-fluoro-2-methylcyclopentyl]-2-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one; and

6-acetyl-8-[2-(2,2-difluoroethyl)-2-azaspiro[3.3]heptan-6-yl]-2-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one,

or a pharmaceutically acceptable salt thereof.

16. A compound of claim 1 that is selected from the group consisting of:

6-acetyl-8-cyclobutyl-2-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

6-acetyl-8-cyclopentyl-2-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

6-acetyl-2-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-5-methyl-8-[(1R,2S)-2-methylcyclopentyl]pyrido[2,3-d]pyrimidin-7(8H)-one;

3-acetyl-1-cyclopentyl-7-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-4-methyl-1,6-naphthyridin-2(1H)-one; and

6-acetyl-8-[2-(2,2-difluoroethyl)-2-azaspiro[3.3]heptan-6-yl]-2-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one,

or a pharmaceutically acceptable salt thereof.

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

18. A pharmaceutical composition comprising a compound of claim 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. A method for treating a disease or disorder in a subject, which method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from the group consisting of pulmonary hypertension, pulmonary arterial hypertension, pulmonary hypertension with left heart disease, pulmonary hypertension with lung disease and/or hypoxemia, pulmonary hypertension due to chronic thrombotic and/or embolic disease, and diseases associated with pulmonary hypertension including sarcoidosis, histiocytosis X, lymphangiomatosis and compression of pulmonary vessels.

20. The method of claim 19 , wherein the disease or disorder is pulmonary arterial hypertension.

21. A compound that is 3-acetyl-1-cyclopentyl-7-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-4-methyl-1,6-naphthyridin-2(1H)-one, or a pharmaceutically acceptable salt thereof.

22. A compound that is 3-acetyl-1-cyclopentyl-7-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-4-methyl-1,6-naphthyridin-2(1H)-one.

23. A crystalline form of 3-acetyl-1-cyclopentyl-7-{[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino}-4-methyl-1,6-naphthyridin-2(1H)-one.

24. The crystalline form of claim 23 , wherein the crystalline form is anhydrous.

25. The crystalline form of claim 24 , wherein the crystalline form (designated as Form I) has a powder X-ray diffraction pattern (CuKα radiation) comprising at least two characteristic peaks, in terms of 2θ, selected from at 8.0±0.2°; 18.6±0.2°; 19.1±0.2°; and 21.3±0.2°.

26. The crystalline form of claim 25 , having a powder X-ray diffraction pattern (CuKα radiation) comprising at least three characteristic peaks, in terms of 2θ, selected from at 8.0±0.2°; 18.6±0.2°; 19.1±0.2°; and 21.3±0.2°.

27. The crystalline form of claim 26 , having a powder X-ray diffraction pattern (CuKα radiation) comprising four characteristic peaks, in terms of 2θ, selected from at 8.0±0.2°; 18.6±0.2°; 19.1±0.2°; and 21.3±0.2°.

28. A pharmaceutical composition comprising a compound of claim 21 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

29. A pharmaceutical composition comprising a compound of claim 24 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

30. A method for treating a disease or disorder in a subject, which method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from the group consisting of pulmonary hypertension, pulmonary arterial hypertension, pulmonary hypertension with left heart disease, pulmonary hypertension with lung disease and/or hypoxemia, pulmonary hypertension due to chronic thrombotic and/or embolic disease, and diseases associated with pulmonary hypertension including sarcoidosis, histiocytosis X, lymphangiomatosis and compression of pulmonary vessels.