Compounds and pharmaceutical compositions thereof for the treatment of diseases

1. A method of treating ovarian, breast, prostate, or lung cancer, comprising administering to a subject in need thereof an effective amount of a compound according to Formula I:

wherein,

X is N or CR 4 ;

one of Y 1 , Y 2 and Y 3 is N and the other two are C;

Z is

—NR 5a R 5b ,

—NR 5c —, wherein the N atom and R 3b together with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one double bond and further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, or

N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, optionally substituted with one, two or three independently selected R 6 groups;

R 1 is H, halo, C 1-4 alkyl, or C 1-4 alkoxy optionally substituted with C 1-4 alkoxy, phenyl, —CN, —C(═O)OH, or —C(═O)—C 1-4 alkoxy;

R 2 is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected R 7 groups;

R 3a and R 3b are independently selected from

halo,

C 1-4 alkyl,

C 1-4 alkoxy optionally substituted with one or more independently selected halo, —OH or C 1-4 alkoxy,

NR 5a R 5b , and

—OH;

R 4 is H or C 1-4 alkyl;

R 5a is H or C 1-4 alkyl;

R 5b is selected from

C 1-6 alkyl optionally substituted with one or more independently selected R 9 ,

C 3-7 cycloalkyl optionally substituted with one or more independently selected R 10 ,

4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more oxo, and

5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl;

R 5c is selected from C 3-7 cycloalkyl, and C 1-6 alkyl optionally substituted with one or more independently selected halo;

each R 6 is independently selected from

oxo,

halo,

—CN,

—OH,

—NR 11a R 11b

phenyl,

C 3-7 cycloalkyl,

C 2-4 alkynyl,

—C(═O)—C 1-4 alkoxy,

C 1-4 alkoxy optionally substituted with one or more halo or phenyl,

C 1-4 alkyl optionally substituted with one or more halo, —OH, or C 1-4 alkoxy, and

4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S;

each R 7 is selected from

halo,

—CN,

C 1-6 alkyl optionally substituted with one or more independently selected

halo,

—CN,

—OH,

C 1-4 alkoxy optionally substituted with one or more independently selected halo,

—NR 11c R 11d ,

—C(═O)R 2 , or

4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S,

C 1-4 alkoxy,

C 3-7 cycloalkyl,

4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with —C(═O)C 1-4 alkoxy or C 1-4 alkyl optionally substituted with —CN,

—NR 13a R 13b , and

—C(═O)NR 13c R 13d ;

each R 8a and R 8b is independently selected from H and C 1-4 alkyl optionally substituted with one —OH or C 1-4 alkoxy;

each R 9 is independently selected from

halo,

—CN,

—NR 11e R 11f

—OH,

C 1-4 alkoxy,

—S(═O) 2 —C 1-4 alkyl,

4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, and

5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl;

each R 10 is independently selected from

halo,

C 1-4 alkyl optionally substituted with one or more independently selected halo, —OH, or C 1-4 alkoxy,

—OH,

C 1-4 alkoxy, and

—NR 11g R 11h ;

each R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g , and R 11h is independently selected from H and C 1-4 alkyl; each R 12 is

—NR 14a R 14b , wherein each R 14a and R 14b is independently selected from H and C 1-4 alkyl,

—OH,

C 1-4 alkoxy optionally substituted with one or more independently selected C 3-7 cycloalkyl, halo, —NR 15a R 15b or 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S,

—O-(4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S), or

—O—(C 3-7 monocyclic cycloalkyl);

each R 13a , R 13b , R 13c , and R 13d , is independently selected from H and C 1-4 alkyl; and

each R 15a and R 15b is independently selected from H and C 1-4 alkyl;

or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein R 1 is H, halo, C 1-4 alkyl, or C 1-4 alkoxy optionally substituted with C 1-4 alkoxy; each R 7 is selected from

halo,

—CN,

—C 1-4 alkyl optionally substituted with one or more independently selected

halo,

—CN,

—OH,

C 1-4 alkoxy optionally substituted with one or more independently selected halo,

—NR 11c R 11d ,

—C(═O)R 12 , or

4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S,

C 1-4 alkoxy,

C 3-7 cycloalkyl,

4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with —C(═O)C 1-4 alkoxy or C 1-4 alkyl optionally substituted with —CN,

NR 13a R 13b , and

—C(═O)NR 13c R 13d ; and

each R 12 is

NR 14a R 14b , wherein each R 14′ and R 14b is independently selected from H and C 1-4 alkyl,

—OH,

C 1-4 alkoxy optionally substituted with one or more independently selected C 3-7 cycloalkyl, or halo,

—O-(4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S), or

—O—(C 3-7 monocyclic cycloalkyl).

3. The method according to claim 1 , wherein R 2 is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted with one or more independently selected R 7 groups.

4. The method according to claim 1 , wherein the compound is according to any one of Formulae Va-Vf:

5. The method according to claim 1 , wherein R 7 is C 1-4 alkyl.

6. The method according to claim 1 , wherein R 3b is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 )2, each of which is optionally substituted with one or more independently selected halo, —OH or C 1-4 alkoxy.

7. The method according to claim 1 , wherein R 3a is halo, —OH, C 1-4 alkoxy, or C 1-4 alkoxy substituted with one or more independently selected halo, —OH or C 1-4 alkoxy.

8. The method according to claim 1 , wherein the compound is according to any one of Formulae VIIIa-VIIId:

9. The method according to claim 1 , wherein Z is —NR 5a R 5b .

10. The method according to claim 1 , wherein R 5a is H, —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .

11. The method according to claim 1 , wherein R 5b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

12. The method according to claim 1 , wherein R b is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH(CH 3 )CH 2 CH 3 , or —CH(CH 3 )CH(CH 3 ) 2 , each of which is substituted with one or more independently selected R 9 .

13. The method according to claim 12 , wherein R 9 is F, Cl, —CN, —OH, —O—CH 3 , —O—CH 2 CH 3 , —O—CH(CH 3 ) 2 , —S(═O) 2 —CH 3 , —S(═O) 2 —CH 2 CH 3 , or —S(═O) 2 —CH(CH 3 ) 2 .

14. A method of treating ovarian, breast, prostate, or lung cancer, comprising administering to a subject in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt thereof according to Formula I:

wherein,

X is N or CR 4 ;

one of Y 1 , Y 2 and Y 3 is N and the other two are C;

Z is

—NR 5a R 5b ,

—NR 5e —, wherein the N atom and R 3b together with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one double bond and further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, or

N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, optionally substituted with one, two or three independently selected R 6 groups;

R 1 is H, halo, C 1-4 alkyl, or C 1-4 alkoxy optionally substituted with C 1-4 alkoxy, phenyl, —CN, —C(═O)OH, or —C(═O)—C 1-4 alkoxy;

R 2 is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected R 7 groups;

R 3a and R 3b are independently selected from

halo,

C 1-4 alkyl,

C 1-4 alkoxy optionally substituted with one or more independently selected halo, —OH or C 1-4 alkoxy,

—NR 5a R 5b , and

—OH;

R 4 is H or C 1-4 alkyl;

R 5a is H or C 1-4 alkyl;

R 5b is selected from

C 1-6 alkyl optionally substituted with one or more independently selected R 9 ,

C 3-7 cycloalkyl optionally substituted with one or more independently selected R 10 ,

4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more oxo, and

5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl;

R 5c is selected from C 3-7 cycloalkyl, and C 1-6 alkyl optionally substituted with one or more independently selected halo;

each R 6 is independently selected from

oxo,

halo,

—CN,

—OH,

—NR 11a R 11b

phenyl,

C 3-7 cycloalkyl,

C 2-4 alkynyl,

—C(═O)—C 1-4 alkoxy,

C 1-4 alkoxy optionally substituted with one or more halo or phenyl,

C 1-4 alkyl optionally substituted with one or more halo, —OH, or C 1-4 alkoxy, and

4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S;

each R 7 is selected from

halo,

—CN,

C 1-6 alkyl optionally substituted with one or more independently selected

halo,

—CN,

—OH,

C 1-4 alkoxy optionally substituted with one or more independently selected halo,

—NR 11c R 11d ,

—C(═O)R 2 , or

4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S,

C 1-4 alkoxy,

C 3-7 cycloalkyl,

4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with —C(═O)C 1-4 alkoxy or C 1-4 alkyl optionally substituted with —CN,

—NR 13a R 13b , and

—C(═O)NR 13c R 13d ;

each R 8a and R 5b is independently selected from H and C 1-4 alkyl optionally substituted with one —OH or C 1-4 alkoxy;

each R 9 is independently selected from

halo,

—CN,

—NR 11e R 11f

—OH,

C 1-4 alkoxy,

—S(═O) 2 —C 1-4 alkyl,

4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, and

5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl;

each R 10 is independently selected from

halo,

C 1-4 alkyl optionally substituted with one or more independently selected halo, —OH, or C 1-4 alkoxy,

—OH,

C 1-4 alkoxy, and

—NR 11g R 11h ;

each R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g , and R 11h is independently selected from H and C 1-4 alkyl; each R 2 is

—NR 14a R 14b , wherein each R 14a and R 14b is independently selected from H and alkyl,

—OH,

C 1-4 alkoxy optionally substituted with one or more independently selected C 3-7 cycloalkyl, halo, —NR 15a R 15b or 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S,

—O-(4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S), or

—O—(C 3-7 monocyclic cycloalkyl);

each R 13 , R 3b , R 13c , and R 131 , is independently selected from H and C 1-4 alkyl; and

each R 15a and R 11b is independently selected from H and C 1-4 alkyl.

15. The method according to claim 1 , further comprising administering a therapeutic agent.

16. The method according to claim 15 , wherein the therapeutic agent is for the treatment of ovarian, breast, prostate, or lung cancer.

17. The method according to claim 15 , wherein the therapeutic agent is paclitaxel.

18. The method according to claim 1 , wherein the method is for treating breast cancer.

19. The method according to claim 1 , wherein the method is for treating ovarian cancer.

20. The method according to claim 14 , further comprising administering a therapeutic agent.

21. The method according to claim 20 , wherein the therapeutic agent is for the treatment of ovarian, breast, prostate, or lung cancer.

22. The method according to claim 20 , wherein the therapeutic agent is paclitaxel.

23. The method according to claim 14 , wherein the disease method is for treating breast cancer.

24. The method according to claim 14 , wherein the method is for treating ovarian cancer.

25. The method according to claim 1 , wherein the method is for treating prostate cancer.

26. The method according to claim 1 , wherein the method is for treating lung cancer.

27. The method according to claim 14 , wherein the method is for treating prostate cancer.

28. The method according to claim 14 , wherein the method is for treating lung cancer.

29. A method of inhibiting a Salt-Inducible Kinase comprising administering to a subject in need thereof an effective amount of a compound according to Formula I:

wherein,

X is N or CR 4 ;

one of Y 1 , Y 2 and Y 3 is N and the other two are C;

Z is

—NR 5a R 5b ,

—NR 5c —, wherein the N atom and R 3b together with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one double bond and further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, or

N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, optionally substituted with one, two or three independently selected R 6 groups;

R 1 is H, halo, C 1-4 alkyl, or C 1-4 alkoxy optionally substituted with C 1-4 alkoxy, phenyl, —CN, —C(═O)OH, or —C(═O)—C 1-4 alkoxy;

R 2 is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected R 7 groups;

R 3a and R 3b are independently selected from

halo,

C 1-4 alkyl,

C 1-4 alkoxy optionally substituted with one or more independently selected halo, —OH or C 1-4 alkoxy,

—NR 5a R 5b , and

—OH;

R 4 is H or C 1-4 alkyl;

R 5a is H or C 1-4 alkyl;

R 5b is selected from

C 1-6 alkyl optionally substituted with one or more independently selected R 9 ,

C 3-7 cycloalkyl optionally substituted with one or more independently selected R 10 ,

4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more oxo, and

5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl;

R 5c is selected from C 3-7 cycloalkyl, and C 1-6 alkyl optionally substituted with one or more independently selected halo;

each R 6 is independently selected from

oxo,

halo,

—CN,

—OH,

—NR 11a R 11b

phenyl,

C 3-7 cycloalkyl,

C 2-4 alkynyl,

—C(═O)—C 1-4 alkoxy,

C 1-4 alkoxy optionally substituted with one or more halo or phenyl,

C 1-4 alkyl optionally substituted with one or more halo, —OH, or C 1-4 alkoxy, and

4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S;

each R 7 is selected from

halo,

—CN,

C 1-6 alkyl optionally substituted with one or more independently selected

halo,

—CN,

—OH,

C 1-4 alkoxy optionally substituted with one or more independently selected halo,

—NR 11c R 11d ,

—C(═O)R 2 , or

4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S,

C 1-4 alkoxy,

C 3-7 cycloalkyl,

4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with —C(═O)C 1-4 alkoxy or C 1-4 alkyl optionally substituted with —CN,

—NR 13a R 13b , and

—C(═O)NR 13c R 13a ; each R 8a and R 5b is independently selected from H and C 1-4 alkyl optionally substituted with one —OH or C 1-4 alkoxy;

each R 9 is independently selected from

halo,

—CN,

—NR 11e R 11f

—OH,

C 1-4 alkoxy,

—S(═O)—C 1-4 alkyl,

4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, and

5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl;

each R 10 is independently selected from

halo,

C 1-4 alkyl optionally substituted with one or more independently selected halo, —OH, or C 1-4 alkoxy,

—OH,

C 1-4 alkoxy, and

NR 11g R 11h ;

each R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g , and R 11h is independently selected from H and C 1-4 alkyl; each R 12 is

—NR 14a R 14b , wherein each R 14a and R 14b is independently selected from H and C 1-4 alkyl,

—OH,

C 1-4 alkoxy optionally substituted with one or more independently selected C 3-7 cycloalkyl, halo, —NR 15a R 15b or 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S,

—O-(4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S), or

—O—(C 3-7 monocyclic cycloalkyl);

each R 13a , R 13b , R 13c , and R 13d , is independently selected from H and C 1-4 alkyl; and

each R 15a and R 15b is independently selected from H and C 1-4 alkyl;

or a pharmaceutically acceptable salt thereof.