Imidazole-containing inhibitors of ALK2 kinase

1. A compound represented by formula (I) or formula (II):

or a pharmaceutically acceptable salt thereof;

wherein:

A is a fused aromatic ring, heteroaromatic ring, partially unsaturated cycloalkyl ring, or partially unsaturated heterocycloalkyl ring optionally substituted by one or more occurrences of R 4 ;

W is C or N;

R a represents H or alkyl;

—R 1 —R 1a represents

wherein R 1a represents phenyl substituted by two or more occurrences of alkoxy, and the phenyl is further optionally substituted;

J represents H, halo, —OR 2 , —NR 2 R 3 , —C(O)NR 2 R 3 , —C(O)O(alkyl), —C(O)OH, aryl, or heteroaryl, wherein aryl or heteroaryl is optionally substituted by one or more occurrences of R 2a ;

R 2 represents optionally substituted alkyl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, or hydroxyalkyl;

R 3 represents H or alkyl; or

R 2 and R 3 , taken together, form a heterocycloalkyl ring, optionally substituted by one or more occurrences of R 2a ;

R 2a , independently for each occurrence, represents halo, hydroxyl, —C(O)H, oxo, —NH 2 , —C(O)NH 2 , —C(O)OH, —C(O)R 5 , —C(O)OR 5 , —C(O)NH(R 5 ), or optionally substituted alkyl, alkoxyl, hydroxyalkyl, heteroaryl, aryl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, or —N(alkyl) 2 ;

or any two geminal or vicinal occurrences of R 2a , taken together, may form a spiro or fused cycloalkyl ring;

R 4 , independently for each occurrence, represents halo, cyano, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, —CH 2 C(O)NH 2 , —C(O)R 5 , —C(O)OR 5 , or —S(O) 2 R 5 ; and

R 5 , independently for each occurrence, represents optionally substituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl.

2. The compound of claim 1 , wherein the compound is represented by formula (Ia) or formula (IIa):

wherein:

valence permitting, Q, T, U, and V each independently represent CH, CH 2 , N, NH, O, or SO 2 , wherein any hydrogen of a CH, CH 2 , or NH group is optionally replaced by an occurrence of R 4 ;

R 4 , independently for each occurrence, represents halo, cyano, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, —CH 2 C(O)NH 2 , —C(O)R 5 , —C(O)OR 5 , or —S(O) 2 R 5 ;

m is an integer from 0-4, as permitted by valence.

3. The compound of claim 2 , wherein the compound is represented by:

(a) formula (Ib) or (IIb):

wherein Q represents CH or N, and V represents CH or N;

(b) formula (Ic) or (IIc):

(c) formula (Id) or (IId):

wherein T represents CH 2 , NH, O, or SO 2 , and U represents CH 2 , NH, O, or SO 2 ; or

(d) formula (Ie) or (IIe):

4. The compound of claim 3 , wherein the compound is represented by formula (Ib) or (IIb); and wherein Q is N; and V is CH; or wherein Q is CH; and V is N.

5. The compound of claim 3 , wherein the compound is represented by formula (Id) or (IId); and wherein T is NH; and U is CH 2 ; or wherein T is CH 2 ; and U is NH.

6. The compound of claim 1 , wherein the compound is represented by formula (Ij) or formula (IIj):

wherein:

W is C or N;

valence permitting, X, Y, and Z each independently represent CH, CH 2 , CO, N, NH, O, S, or SO 2 , wherein any hydrogen of a CH, CH 2 , or NH group is optionally replaced by an occurrence of R 4 ;

R 4 , independently for each occurrence, represents cyano, halo, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, —CH 2 C(O)NH 2 , —C(O)R 5 , —C(O)OR 5 , or —S(O) 2 R 5 ;

n is an integer from 0-4, as permitted by valence.

7. The compound of claim 6 , wherein the compound is represented by formula (Ik) or (IIk):

wherein X, Y, and Z each independently represent CH, N, NH, O, S, or SO 2 .

8. The compound of claim 7 , wherein the compound is represented by:

(a) formula (Ik′) or (IIk′):

(b) formula (Ik″) or (IIk″):

wherein at least one of X and Z is selected from the group consisting of O, N, NH, and S; or

(c) formula (In) or (IIn):

wherein each of Y and Z are selected from the group consisting of O, N, NH, and S.

9. The compound of claim 8 , wherein the compound is represented by formula (Ik″) or (IIk″), and:

(a) one of X and Z is selected from the group consisting of O, NH, and S, and the other of X and Z is CH;

(b) X is selected from the group consisting of O, NH, and S;

(c) Z is selected from the group consisting of O, NH, and S;

(d) each of X and Z are selected from the group consisting of O, N, NH, and S; or

(e) one of X and Z is N and the other of X and Z is NH.

10. The compound of claim 6 , wherein the compound is represented by formula (Im) or (IIm):

wherein X, Y, and Z each independently represent CH 2 , CO, NH, O, S, or SO 2 .

11. The compound of claim 10 , wherein:

(a) each of X, Y, and Z is CH 2 ; or

(b) one of X, Y, and Z is N or O.

12. The compound of claim 1 , wherein R 4 , if present, is selected from the group consisting of optionally substituted alkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, and (heterocycloalkyl)alkyl.

13. The compound of claim 1 , wherein R a is H.

14. The compound of claim 1 , wherein —R 1 —R 1a represents

15. The compound of claim 1 , wherein R 1a is 3,4,5-trimethoxyphenyl.

16. The compound of claim 1 , wherein:

(a) J is aryl, optionally substituted by one or more occurrences of R 2a ; or

(b) J is —NR 2 R 3 .

17. The compound of claim 16 , wherein J is —NR 2 R 3 ; and:

(a) R 2 and R 3 , taken together, form a heterocycloalkyl ring, optionally substituted by one or more occurrences of R 2a ; or

(b) R 2 and R 3 , taken together, form a pyrrolidine ring, optionally substituted by one or more occurrences of R 2a .

18. The compound of claim 16 , wherein R 2a , independently for each occurrence, represents —C(O)NH 2 , —C(O)R 5 , hydroxyalkyl, heteroaryl, or aryl.

19. The compound of claim 1 , selected from the following table:

20. A compound represented by formula (III) or formula (IV):

or a pharmaceutically acceptable salt thereof;

wherein:

A is a fused aromatic ring, heteroaromatic ring, partially unsaturated cycloalkyl ring, or partially unsaturated heterocycloalkyl ring optionally substituted by one or more occurrences of R 4 ;

W is C or N;

B is CH or N;

D is CH or N;

provided that when B is CH, then D is N; or when D is CH, then B is N;

R a represents H or alkyl;

—R 1 —R 1a represents

wherein R 1a represents phenyl substituted by two or more occurrences of alkoxy, and the phenyl is further optionally substituted;

J represents H, halo, —OR 2 , —NR 2 R 3 , —C(O)NR 2 R 3 , —C(O)O(alkyl), —C(O)OH, aryl, or heteroaryl, wherein aryl or heteroaryl is optionally substituted by one or more occurrences of R 2a ;

R 2 represents optionally substituted alkyl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, or hydroxyalkyl;

R 3 represents H or alkyl; or

R 2 and R 3 , taken together, form a heterocycloalkyl ring, optionally substituted by one or more occurrences of R 2a ;

R 2a , independently for each occurrence, represents halo, hydroxyl, —C(O)H, oxo, —NH 2 , —C(O)NH 2 , —C(O)OH, —C(O)R 5 , —C(O)OR 5 , —C(O)NH(R 5 ), or optionally substituted alkyl, alkoxyl, hydroxyalkyl, heteroaryl, aryl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, or —N(alkyl) 2 ;

or any two geminal or vicinal occurrences of R 2a , taken together, may form a spiro or fused cycloalkyl ring;

R 4 , independently for each occurrence, represents halo, cyano, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, —CH 2 C(O)NH 2 , —C(O)R 5 , —C(O)OR 5 , or —S(O) 2 R 5 ; and

R 5 , independently for each occurrence, represents optionally substituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl.

21. A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

22. The compound of claim 20 , wherein the compound is represented by formula (IIIa) or formula (IVa):

wherein:

valence permitting, Q, T, U, and V each independently represent CH, CH 2 , N, NH, O, or SO 2 , wherein any hydrogen of a CH, CH 2 , or NH group is optionally replaced by an occurrence of R 4 ;

R 4 , independently for each occurrence, represents halo, cyano, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, —CH 2 C(O)NH 2 , —C(O)R 5 , —C(O)OR 5 , or —S(O) 2 R 5 ; and

m is an integer from 0-4, as permitted by valence.

23. The compound of claim 22 , wherein the compound is represented by:

(a) formula (IIIb) or (IVb):

wherein Q represents CH or N, and V represents CH or N;

(b) formula (IIIc) or (IVc):

(c) formula (IIId) or (IVd):

wherein T represents CH 2 , NH, O, or SO 2 ; and U represents CH 2 , NH, O, or SO 2 ; or

(d) formula (IIIe) or (IVe):

24. The compound of claim 23 , wherein the compound is represented by formula (IIIb) or (IVb); and wherein Q is N; and V is CH; or wherein Q is CH; and V is N.

25. The compound of claim 23 , wherein the compound is represented by formula (IIId) or (IVd); and wherein T is NH; and U is CH 2 ; or wherein T is CH 2 ; and U is NH.

26. The compound of claim 20 , wherein the compound is represented by formula (IIIj) or formula (IVj):

wherein:

W is C or N;

valence permitting, X, Y, and Z each independently represent CH, CH 2 , CO, N, NH, O, S, or SO 2 , wherein any hydrogen of a CH, CH 2 , or NH group is optionally replaced by an occurrence of R 4 ;

R 4 , independently for each occurrence, represents halo, cyano, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, —CH 2 C(O)NH 2 , —C(O)R 5 , —C(O)OR 5 , or —S(O) 2 R 5 ;

n is an integer from 0-4, as permitted by valence.

27. The compound of claim 26 , wherein the compound is represented by formula (IIIk) or (IVk):

wherein X, Y, and Z each independently represent CH, N, NH, O, S, or SO 2 .

28. The compound of claim 27 , wherein the compound is represented by:

(a) formula (IIIk′) or (IVk′):

(b) formula (IIIk″) or (IVk″):

wherein at least one of X and Z is selected from the group consisting of O, N, NH, and S; or

(c) formula (IIIn) or (IVn):

wherein each of Y and Z are selected from the group consisting of O, N, NH, and S.

29. The compound of claim 28 , wherein the compound is represented by formula (IIIk″) or (IVk″), and:

(a) one of X and Z is selected from the group consisting of O, NH, and S, and the other of X and Z is CH;

(b) X is selected from the group consisting of O, NH, and S;

(c) Z is selected from the group consisting of O, NH, and S;

(d) each of X and Z are selected from the group consisting of O, N, NH, and S; or

(e) one of X and Z is N and the other of X and Z is NH.

30. The compound of claim 28 , wherein the compound is represented by formula (IIIn) or (IVn), Y is N, and Z is NH.

31. The compound of claim 26 , wherein the compound is represented by formula (IIIm) or (IVm):

wherein X, Y, and Z each independently represent CH 2 , CO, NH, O, S, or SO 2 .

32. The compound of claim 31 , wherein:

(a) each of X, Y, and Z is CH 2 ; or

(b) one of X, Y, and Z is N or O.

33. The compound of claim 20 , wherein R 4 , if present, is selected from the group consisting of optionally substituted alkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, and (heterocycloalkyl)alkyl.

34. The compound of claim 20 , wherein R a is H.

35. The compound of claim 20 , wherein —R 1 —R 1a represents

36. The compound of claim 20 , wherein R 1a is 3,4,5-trimethoxyphenyl.

37. The compound of claim 20 , wherein:

(a) J is aryl, optionally substituted by one or more occurrences of R 2a ; or

(b) J is —NR 2 R 3 .

38. The compound of claim 37 , wherein J is —NR 2 R 3 ; and:

(a) R 2 and R 3 , taken together, form a heterocycloalkyl ring, optionally substituted by one or more occurrences of R 2a ; or

(b) R 2 and R 3 , taken together, form a pyrrolidine ring, optionally substituted by one or more occurrences of R 2a .

39. The compound of claim 37 , wherein R 2a , independently for each occurrence, represents —C(O)NH 2 , —C(O)R 5 , hydroxyalkyl, heteroaryl, or aryl.

40. The compound of claim 20 , selected from the following table:

41. The compound of claim 1 , wherein the optional substituents are selected from halogen, haloalkyl, hydroxyl, carbonyl, carboxyl, alkoxycarbonyl, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, alkenyloxy, alkynyloxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, alkylamino, dialkylamino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, silyl, silyloxy, heterocycloalkyl, cycloalkyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl.

42. The compound of claim 20 , wherein the optional substituents are selected from halogen, haloalkyl, hydroxyl, carbonyl, carboxyl, alkoxycarbonyl, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, alkenyloxy, alkynyloxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, alkylamino, dialkylamino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, silyl, silyloxy, heterocycloalkyl, cycloalkyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl.