Compounds and compositions for treating hematological disorders

1. A method of treating acute myeloid leukemia in a subject having a mutation in FLT-3 kinase, comprising administering a compound of Formula II:

or a pharmaceutically acceptable salt thereof;

wherein

X 1 and X 3 independently are CH or N; X 2 is CR 2 or N; provided one and not more than one of X 1 , X 2 or X 3 is N;

A is O or S;

Y is —CH 2 — or O;

Z is pyridyl, oxazolyl, or furanyl;

R 1 , at each occurrence, is independently halo or optionally substituted 4-6 membered heterocyclyl;

wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or —NR a R b ;

R 2 is hydrogen, optionally substituted cycloalkyl, optionally substituted or 4-6 membered heterocyclyl; wherein the substituent is alkyl, amino, halo or hydroxyl;

R 3 , at each occurrence, is alkyl or hydroxyl;

R a and R b are each independently hydrogen, alkyl, or acyl;

‘m’ and ‘n’ are each independently 0, 1 or 2; and

‘p’ is 0 or 1.

2. The method of claim 1 , wherein

A is O or S;

Y is —CH 2 — or O;

R 1 , at each occurrence, is independently halo or optionally substituted 4-6 membered heterocyclyl,

wherein the substituent is alkyl, aminoalkyl, halo, or —NR a R b ; where R a and R b are independently hydrogen, alkyl, or 4-6 membered heterocyclyl;

R 2 is hydrogen, cycloalkyl, or 4-6 membered heterocyclyl;

‘m’ is 0; and

‘n’ is 1.

3. The method of claim 1 , wherein

A is O or S;

Y is —CH 2 — or O;

R 1 , at each occurrence, is independently halo or optionally substituted 4-6 membered heterocyclyl;

wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl or —NR a R b ; where R a and R b are independently hydrogen, alkyl, or 4-6 membered heterocyclyl;

R 2 is hydrogen, cycloalkyl, or optionally substituted 4-6 membered heterocyclyl, where the substituent is selected from amino, halo or hydroxyl;

‘m’ and ‘n’ are independently 0, 1 or 2; and

‘p’ is 0 or 1.

4. The method of claim 1 , or a pharmaceutically acceptable salt

thereof, wherein the group

is

5. The method of claim 1 , wherein the compound of formula (II) is represented by formula (IIA):

or a pharmaceutically acceptable salt thereof.

6. The method of claim 5 , wherein

A is O or S;

Y is —CH 2 — or O;

R 1 , at each occurrence, is independently halo or optionally substituted 4-6 membered heterocyclyl,

wherein the substituent is alkyl, aminoalkyl, halo, or —NR a R b ; where R a and R b are independently hydrogen, alkyl, or 4-6 membered heterocyclyl;

R 2 is hydrogen, cycloalkyl, or 4-6 membered heterocyclyl;

‘m’ is 0; and

‘n’ is 1.

7. The method of claim 5 , wherein

A is O or S;

Y is —CH 2 — or O;

R 1 , at each occurrence, is independently halo or optionally substituted 4-6 membered heterocyclyl;

wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl or —NR a R b ; where R a and R b are independently hydrogen, alkyl, or 4-6 membered heterocyclyl;

R 2 is hydrogen, cycloalkyl, or optionally substituted 4-6 membered heterocyclyl, where the substituent is selected from amino, halo or hydroxyl; and

‘m’ and ‘n’ are independently 0, 1 or 2.

8. The method of claim 1 , wherein the compound of formula (II) is represented by formula (IIB):

or a pharmaceutically acceptable salt thereof.

9. The method of claim 8 , wherein

A is O or S;

Y is —CH 2 — or O;

R 1 , at each occurrence, is independently halo or optionally substituted 4-6 membered heterocyclyl,

wherein the substituent is alkyl, aminoalkyl, halo, or —NR a R b ; where R a and R b are independently hydrogen, alkyl, or 4-6 membered heterocyclyl;

R 2 is hydrogen, cycloalkyl, or 4-6 membered heterocyclyl; and

‘n’ is 1.

10. The method of claim 8 , wherein

A is O or S;

Y is —CH 2 — or O;

R 1 , at each occurrence, is independently halo or optionally substituted 4-6 membered heterocyclyl;

wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl or —NR a R b ; where R a and R b are independently hydrogen, alkyl, or 4-6 membered heterocyclyl;

R 2 is hydrogen, cycloalkyl, or optionally substituted 4-6 membered heterocyclyl, where the substituent is selected from amino, halo or hydroxyl; and

‘m’ and ‘n’ are independently 0, 1 or 2.

11. The method of claim 1 , wherein the compound of formula (II) is represented by formula (TIC):

or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , wherein R 1 is optionally substituted 4-6 membered heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or —NR a R b ; and R a and R b are independently hydrogen or acyl.

13. The method of claim 1 , wherein R 1 is optionally substituted 4-6 membered heterocyclyl; wherein the substituent is alkyl, aminoalkyl, halo, or —NR a R b ; and R a and R b are each independently hydrogen or acyl.

14. The method of claim 1 , wherein R 1 is optionally substituted 4-6 membered heterocyclyl; and the substituent is alkyl, aminoalkyl, halo, or —NR a R b ; where R a and R b are each independently hydrogen, alkyl, or 4-6 membered heterocyclyl.

15. The method of claim 1 , wherein R 1 is optionally substituted 4-6 membered heterocyclyl; and the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl or —NR a R b ; where R a and Rb are each independently hydrogen, alkyl, or 4-6 membered heterocyclyl.

16. The method of claim 12 , wherein R 1 is pyridyl, pyrazolyl, pyrrolidinyl or piperidinyl.

17. The method of claim 12 , wherein R 1 is optionally substituted pyrazolyl, wherein the substituent is alkyl, hydroxyl or —NR a R b .

18. The method of claim 1 , wherein R 1 is halo.

19. The method of claim 1 , wherein R 2 is hydrogen, cycloalkyl, or 4-6 membered heterocyclyl.

20. The method of claim 1 , wherein R 2 is hydrogen, cycloalkyl, or optionally substituted 4-6 membered heterocyclyl, where the substituent is selected from amino, halo and hydroxyl.

21. The method of claim 1 , wherein R 2 is optionally substituted 4-6 membered heterocyclyl selected from piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolyl, or furanyl; wherein the substituent is hydroxyl, halo, alkyl or amino.

22. The method of claim 1 , wherein R 2 is piperidinyl, pyrrolidinyl, morpholinyl, or piperazinyl.

23. The method of claim 1 , wherein R 2 is hydrogen.

24. The method of claim 1 , wherein R 2 is cycloalkyl.

25. The method of claim 24 , wherein R 2 is cyclopropyl.

26. The method of claim 1 , wherein R 3 is alkyl.

27. The method of claim 1 , wherein m is 0 and p is 1.

28. The method of claim 1 , wherein m is 0 or 2, and p is 0 or 1.

29. A method of treating acute myeloid leukemia in a subject having a mutation in FLT-3 kinase, comprising administering a compound selected from:

6′-amino-N-(2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3′-bipyridine]-6-

carboxamide;

6′-amino-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3′-

bipyridine]-6-carboxamide hydrochloride;

N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-

yl)oxazole-4-carboxamide hydrochloride;

N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide

hydrochloride;

N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-

yl)oxazole-4-carboxamide;

N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-

yl)picolinamide;

2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-

yl)oxazole-4-carboxamide;

6-chloro-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide;

N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-

yl)picolinamide;

2-(2-chloropyridin-4-yl)-N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-

4-carboxamide;

(S)-2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-3-ylamino)oxazolo[4,5-

b]pyridin-6-yl)oxazole-4-carboxamide;

6′-amino-N-(2-morpholinooxazolo[5,4-b]pyridin-5-yl)-[2,3′-bipyridine]-6-

carboxamide;

6′-amino-N-(2-morpholinothiazolo[4,5-c]pyridin-6-yl)-[2,3′-bipyridine]-6-

carboxamide;

6′-amino-N-(2-morpholinothiazolo[5,4-b]pyridin-5-yl)-[2,3′-bipyridine]-6-

carboxamide;

2-(2-methylpyridin-4-yl)-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-

carboxamide;

6′-amino-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-[2,3′-bipyridine]-6-

carboxamide;

N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide;

3-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-

6-yl)benzamide;

2-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-

6-yl)benzamide;

2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-

yl)oxazole-4-carboxamide;

N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-

yl)picolinamide;

N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-

yl)picolinamide;

N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-

yl)oxazole-4-carboxamide;

N-(2,5-dimorpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-

carboxamide;

N-(5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-

yl)oxazole-4-carboxamide;

N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-

yl)oxazole-4-carboxamide;

N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-hydroxypyridin-3-

yl)oxazole-4-carboxamide;

2-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-

6-yl)oxazole-4-carboxamide;

N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-hydroxypyridin-3-

yl)oxazole-4-carboxamide;

2-(2-methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-

6-yl)oxazole-4-carboxamide;

2-(2-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-

yl)oxazole-4-carboxamide;

2-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-

yl)oxazole-4-carboxamide;

N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(3-methylpyridin-4-

yl)oxazole-4-carboxamide;

2-(6-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-

yl)oxazole-4-carboxamide;

6-(1-methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-

b]pyridin-6-yl)picolinamide;

N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methylpyridin-3-

yl)oxazole-4-carboxamide;

(S)-N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

(R)-N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

(R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

(S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-

b]pyridin-6-yl)oxazole-4-carboxamide;

(S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-

b]pyridin-6-yl)picolinamide;

(S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-

b]pyridin-6-yl)picolinamide;

(S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-

b]pyridin-6-yl)oxazole-4-carboxamide;

(S)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(3-

hydroxypyrrolidin-1-yl)oxazole-4-carboxamide;

(S)-2-(3-aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-

6-yl)oxazole-4-carboxamide;

2-(2-methylpyridin-4-yl)-N-(5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-

b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride;

N-(2-(2,6-dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride;

N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-

yl)picolinamide hydrochloride;

6-(1-methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-

b]pyridin-6-yl)picolinamide;

N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-

yl)oxazole-4-carboxamide hydrochloride;

N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-

yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;

2-(2-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-

yl)oxazole-4-carboxamide;

2-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-

6-yl)oxazole-4-carboxamide;

N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methoxypyridin-4-

yl)oxazole-4-carboxamide;

2-(6-methoxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-

6-yl)oxazole-4-carboxamide;

2-(2-methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-

6-yl)oxazole-4-carboxamide;

(S)-N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

2-(6-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-

yl)oxazole-4-carboxamide;

2-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-

yl)oxazole-4-carboxamide;

(S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-

b]pyridin-6-yl)picolinamide;

(S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-

b]pyridin-6-yl)picolinamide;

(S)-6-(3-aminopyrrolidin-1-yl)-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-

yl)picolinamide;

(S)-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-

yl)picolinamide;

(S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-

b]pyridin-6-yl)oxazole-4-carboxamide;

(S)-N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

(S)-2-(3-aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-

b]pyridin-6-yl)oxazole-4-carboxamide;

N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-

yl)oxazole-4-carboxamide;

(S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-

b]pyridin-6-yl)oxazole-4-carboxamide;

(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

(S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-

hydroxypyrrolidin-1-yl)picolinamide;

(S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(3-

hydroxypyrrolidin-1-yl)oxazole-4-carboxamide;

(S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1-(2-

hydroxypropyl)-1H-pyrazol-4-yl)picolinamide;

(S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(1-(2-

hydroxypropyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide;

N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-

methoxypyridin-3-yl)oxazole-4-carboxamide;

(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-

methoxypyridin-3-yl)oxazole-4-carboxamide;

(R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-

methoxypyridin-3-yl)oxazole-4-carboxamide;

(S)-N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-

hydroxypyrrolidin-1-yl)picolinamide;

N-(5-(3-hydroxyazetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-

methylpyridin-4-yl)thiophene-2-carboxamide;

(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-

methylpyridin-4-yl)furan-2-carboxamide;

(S)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide

(R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-

methylpyridin-4-yl)furan-2-carboxamide;

N-(5-(azetidin-1-yl)-2-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-

b]pyridin-6-yl)oxazole-4-carboxamide;

2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-

6-yl)oxazole-4-carboxamide;

5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-

yl)furan-2-carboxamide;

N-(5-(azepan-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-

yl)oxazole-4-carboxamide;

2-(2-aminopyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-

yl)oxazole-4-carboxamide hydrochloride;

N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-

yl)oxazole-4-carboxamide;

(R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

(R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-

methylpyridin-4-yl)furan-2-carboxamide;

(S)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-

yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide

N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-

methylpyridin-4-yl)furan-2-carboxamide

N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride

N-(5-(1-methyl-1H-pyrazol-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

N-(5-(3-fluorophenyl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-

4-yl)oxazole-4-carboxamide;

N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-

methylpyridin-4-yl)furan-2-carboxamide;

N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-

methylpyridin-4-yl)furan-2-carboxamide;

(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-

methoxypyridin-3-yl)oxazole-4-carboxamide;

N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

(R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-

methoxypyridin-3-yl)oxazole-4-carboxamide;

N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-

methoxypyridin-3-yl)oxazole-4-carboxamide;

(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-

methylpyridin-4-yl)furan-2-carboxamide;

(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-

methylpyridin-4-yl)thiophene-2-carboxamide;

N-(5-(azetidin-1-yl)-2-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-

b]pyridin-6-yl)oxazole-4-carboxamide;

5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-

yl)furan-2-carboxamide;

N-(5-(azetidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-

yl)oxazole-4-carboxamide;

2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-

6-yl)oxazole-4-carboxamide;

N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-

methylpyridin-4-yl)furan-2-carboxamide;

(R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-

methylpyridin-4-yl)furan-2-carboxamide;

N-(5-(furan-3-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-

yl)oxazole-4-carboxamide;

N-(5-(3-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

N-(5-(4-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

(S)-N-(5-(3-aminopiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(1H-pyrazol-4-yl)thiazolo[4,5-

b]pyridin-6-yl)oxazole-4-carboxamide;

N-(5-(6-fluoropyridin-3-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

N-(5-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-2-morpholinothiazolo[4,5-b]pyridin-

6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;

N-(2-(3-hydroxypiperidin-1-yl)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

2-(2-acetamidopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-

morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;

N-(2-(3-hydroxypiperidin-1-yl)-5-(4-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-

yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;

2-(2-acetamidopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-

morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;

2-(2-aminopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-

b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride;

5-(2-aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-

b]pyridin-6-yl)furan-3-carboxamide hydrochloride;

2-(2-aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-

b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride;

2-(2-aminopyridin-4-yl)-N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-

b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride;

N-(5-(2-fluoropyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide;

N-(5-(4-fluoropiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-

yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;

N-(5-(4-aminopiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-

yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride; and

N-(5-(2-hydroxypyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-

methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride;

or a pharmaceutically acceptable salt thereof.

30. The method of claim 1 , wherein the compound of formula (II) is selected from:

6′-amino-N-(2-morpholinooxazolo[5,4-b]pyridin-5-yl)-[2,3′-bipyridine]-6-carboxamide;

N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;

N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide hydrochloride; and

(R)—N—(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;

or a pharmaceutically acceptable salt thereof.

31. The method of claim 1 , wherein the compound of formula (II) is selected from:

N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;

N-(5-(azepan-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;

(R)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; and

N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide, or a pharmaceutically acceptable salt thereof.

32. The method of claim 1 , wherein the mutation is an internal tandem duplication (ITD).

33. The method of claim 1 , wherein the mutation is selected from D835H, D835V, D835Y, K663Q, N841I, ITD, ITD and D835V, and ITD and F691L.

34. The method of claim 1 , wherein the AML is resistant to an FLT-3 inhibitor.

35. The method of claim 13 , wherein R 1 is pyridyl, pyrazolyl, pyrrolidinyl or piperidinyl.

36. The method of claim 13 , wherein R 1 is optionally substituted pyrazolyl, wherein the substituent is alkyl, hydroxyl or —NR a R b .

37. The method of claim 14 , wherein R 1 is pyridyl, pyrazolyl, pyrrolidinyl or piperidinyl.

38. The method of claim 14 , wherein R 1 is optionally substituted pyrazolyl, wherein the substituent is alkyl, hydroxyl or —NR a R b .

39. The method of claim 15 , wherein R 1 is pyridyl, pyrazolyl, pyrrolidinyl or piperidinyl.

40. The method of claim 15 , wherein R 1 is optionally substituted pyrazolyl, wherein the substituent is alkyl, hydroxyl or —NR a R b .

41. The method of claim 1 , wherein the compound of formula (II) is selected from:

or a pharmaceutically acceptable salt thereof.

42. The method of claim 1 , wherein the compound of formula (II) is

or a pharmaceutically acceptable salt thereof.

43. The method of claim 1 , wherein the compound of formula (II) is

44. The method of claim 1 , wherein the compound of formula (II) is

or a pharmaceutically acceptable salt thereof.

45. The method of claim 1 , wherein the compound of formula (II) is

46. The method of claim 1 , wherein the compound of formula (II) is

or a pharmaceutically acceptable salt thereof.

47. The method of claim 1 , wherein the compound of formula (II) is

48. The method of claim 1 , wherein the compound of formula (II) is

or a pharmaceutically acceptable salt thereof.

49. The method of claim 1 , wherein the compound of formula (II) is

50. The method of claim 1 , wherein the compound of formula (II) is

or a pharmaceutically acceptable salt thereof.

51. The method of claim 1 , wherein the compound of formula (II) is