N-acyl-N′-(pyridin-2-yl) ureas and analogs exhibiting anti-cancer and anti-proliferative activities

1. A compound of Formula I:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof,

wherein

A is selected from the group consisting of C1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, and C3-C8carbocyclyl, and wherein each A moiety may be further substituted with one, two, or three R3 moieties;

W is —NHC(O)R5, —NHC(O)R6, —NHC(O)N(R7)R8 or —C(O)N(R7)R8;

X1 and X2 are individually and independently hydrogen, C1-C6 alkyl, fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated;

each R1 and R2 is individually and independently H, C1-C6 alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, hydroxyl, C1-C6 alkoxy, fluoroC1-C6alkoxy wherein the alkyl group is fully or partially fluorinated, or cyano;

each R3 is individually and independently H, halogen, C1-C6 alkyl, fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-C1-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano;

each R4 is individually and independently hydrogen, C1-C6 alkyl, or branched C3-C8 alkyl;

each R5 is individually and independently hydrogen, C1-C6 alkyl, branched C3-C8 alkyl, C3-C8 cycloalkyl, —(CH 2 ) m —CN, —(CH 2 ) m —OR7, —(CH 2 ) m —NR7(R8), or —(CH 2 ) m —R6, wherein each alkylene of R5 may be further substituted with one or more C1-C6alkyl;

each R6 is independently and individually selected from the group consisting of

 and wherein the symbol (##) is the point of attachment to respective R5 or W moieties containing a R6 moiety;

each R6 is optionally substituted with —(R9) p ;

each R7 and R8 is individually and independently H, C1-C6 alkyl, fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, —(CH 2 ) m —CN, —(CH 2 ) m —OR7, —(CH 2 ) m —NR7(R8), or —(CH 2 ) m —R6,

each R9 is individually and independently C1-C6 alkyl, —(CH 2 ) m —CN, —(CH 2 ) m —OR3, —(CH 2 ) m —NR7(R8), or —(CH 2 ) m —C(O)—R5, wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl;

each R10 is H, 4-(C1-C4alkyl)-piperazin-1-yl, morpholinyl, piperidinyl, pyrrolidinyl or azetidinyl;

each m is individually and independently 0, 1, 2, or 3;

each n is individually and independently 0, 1, 2, or 3;

each p is 0, 1, 2, or 3; and

each q is 0, 1, 2, or 3.

2. The compound of claim 1 , wherein X1 and X2 are individually and independently hydrogen or C1-C6 alkyl.

3. The compound of claim 2 , wherein the compound is a compound of Formula Ia,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

4. The compound of claim 3 , wherein R3 is C1-C6alkyl, hydrogen or C1-C6alkoxy.

5. The compound of claim 4 , wherein W is —NHC(O)R5, —NHC(O)R6 or —NHC(O)N(R7)R8.

6. The compound of claim 4 , wherein W is —C(O)N(R7)R8.

7. The compound of claim 2 , wherein the compound is a compound of Formula Ib:

wherein A is C3-C8 carbocyclyl.

8. The compound of claim 7 , wherein R3 is C1-C6alkyl, hydrogen, C1-C6alkoxy or fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated.

9. The compound of claim 8 , wherein W is —NHC(O)R5, —NHC(O)R6 or —NHC(O)N(R7)R8.

10. The compound of claim 8 , wherein W is —C(O)N(R7)R8.

11. The compound of claim 1 selected from the group consisting of N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclohexanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclopentanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-2-cyclohexylacetamide, N-((5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)cyclopentanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)isobutyramide, N-(4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide, N-((6-methyl-5-((2-propionamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-isobutyramidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)propionamide, N-((5-((2-isobutyramidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-methylcyclopropanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)-2-methoxy-2-methylpropanamide, 1-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, N-((5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-propionamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-(trifluoromethyl)cyclobutanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-2-methoxy-2-methylpropanamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-methoxycyclopropanecarboxamide, N-((5-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-methylcyclopropanecarboxamide, N-(4-((6-(3-(2-methoxy-2-methylpropanoyl)ureido)pyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide, 1-methyl-N-(4-((6-(3-(1-methylcyclopropanecarbonyl)ureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, N-methyl-4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)picolinamide, 1-methyl-N-((5-((2-propionamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclopropanecarboxamide, 2-methoxy-2-methyl-N-((5-((2-propionamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)propanamide, N-((5-((2-acetamidopyridin-4-yl)oxy)-4-methylpyridin-2-yl)carbamoyl)-2-methoxy-2-methylpropanamide, 1-methoxy-N-((5-((2-propionamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclopropanecarboxamide, N-(4-((6-(3-(2-methoxy-2-methylpropanoyl)ureido)pyridin-3-yl)oxy)pyridin-2-yl)-1-methylpiperidine-4-carboxamide, N-((5-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-methoxycyclopropanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)-4-methylpyridin-2-yl)carbamoyl)pivalamide, N-((5-(2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)-1-methylcyclobutanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-methylcyclobutanecarboxamide, 4-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide, N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)morpholine-4-carboxamide, (S)-3-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide, N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)azetidine-1-carboxamide, N-(4-((6-(3-(1-methoxycyclopropanecarbonyl)ureido)pyridin-3-yl)oxy)pyridin-2-yl)-1-methylpiperidine-4-carboxamide, N-((5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-methylcyclopropanecarboxamide, 1-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-((5-((2-(2-(pyrrolidin-1-yl)acetamido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-(2-(dimethylamino)acetamido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, 1-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-3-carboxamide, N-((5-((2-(2-cyanoacetamido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, N-(4-((6-(3-isobutyrylureido)pyridin-3-yl)oxy)pyridin-2-yl)-1-methylpiperidine-4-carboxamide, 4-((6-(3-(2-methoxy-2-methylpropanoyl)ureido)pyridin-3-yl)oxy)-N-methylpicolinamide, 1-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)-1H-imidazole-4-carboxamide, (1s,3s)-3-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)cyclobutanecarboxamide, (1r,3r)-3-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)cyclobutanecarboxamide, N-((5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamide, N-(4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)morpholine-4-carboxamide, 4-((6-(3-(1-methoxycyclopentanecarbonyl)ureido)pyridin-3-yl)oxy)-N-methylpicolinamide, N-(4-((6-(3-isobutyrylureido)pyridin-3-yl)oxy)pyridin-2-yl)-4-methylpiperazine-1-carboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-methoxycyclopentanecarboxamide, (R)-3-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide, 4-methyl-N-(4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide, N-(4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide, N-methyl-4-((6-(3-(1-(trifluoromethyl)cyclobutanecarbonyl)ureido)pyridin-3-yl)oxy)picolinamide, N-isopropyl-4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)picolinamide, N-cyclopropyl-4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)picolinamide, N-(1-methylpiperidin-4-yl)-4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)picolinamide, 4-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-1-carboxamide, 3-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)azetidine-1-carboxamide, N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide, N-((5-((2-(3-methylureido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, 4-ethyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide, 4-(4-methylpiperazin-1-yl)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-1-carboxamide, N-((5-((2-(3-(2-methoxyethyl)ureido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, and N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide.

12. A pharmaceutical composition, comprising a compound of claim 11 and a pharmaceutically acceptable carrier.

13. The compound of claim 1 selected from N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-2-methoxy-2-methylpropanamide, N-((5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamide, or N-(4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide.

14. A pharmaceutical composition, comprising a compound of claim 13 and a pharmaceutically acceptable carrier.

15. The compound of claim 1 selected from 4-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide, 4-ethyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide, N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide, 4-methyl-N-(4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide, 1-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, (S)-3-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide, (R)-3-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide, 3-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)azetidine-1-carboxamide, 4-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-1-carboxamide, N-(4-((6-(3-isobutyrylureido)pyridin-3-yl)oxy)pyridin-2-yl)-4-methylpiperazine-1-carboxamide, N-(4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)morpholine-4-carboxamide, or N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)morpholine-4-carboxamide.

16. A pharmaceutical composition, comprising a compound of claim 15 and a pharmaceutically acceptable carrier.

17. The compound of claim 1 selected from N-methyl-4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)picolinamide, 4-((6-(3-(2-methoxy-2-methylpropanoyl)ureido)pyridin-3-yl)oxy)-N-methylpicolinamide, or N-methyl-4-((6-(3-(1-(trifluoromethyl)cyclobutanecarbonyl)ureido)pyridin-3-yl)oxy)picolinamide.

18. A pharmaceutical composition, comprising a compound of claim 17 and a pharmaceutically acceptable carrier.

19. The compound of claim 1 wherein the compound is 4-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide.

20. A pharmaceutical composition, comprising the compound of claim 19 and a pharmaceutically acceptable carrier.

21. The compound of claim 1 , wherein the compound is 4-ethyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide.

22. A pharmaceutical composition, comprising the compound of claim 21 and a pharmaceutically acceptable carrier.

23. The compound of claim 1 , wherein the compound is N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide.

24. A pharmaceutical composition, comprising the compound of claim 23 and a pharmaceutically acceptable carrier.

25. The compound of claim 1 , wherein the compound is N-methyl-4-46-(3-pivaloylureido)pyridin-3-yl)oxy)picolinamide.

26. A pharmaceutical composition, comprising the compound of claim 25 and a pharmaceutically acceptable carrier.

27. The compound of claim 1 , wherein the compound is 4-((6-(3-(2-methoxy-2-methylpropanoyl)ureido)pyridin-3-yl)oxy)-N-methylpicolinamide.

28. A pharmaceutical composition, comprising the compound of claim 27 and a pharmaceutically acceptable carrier.

29. The compound of claim 1 , wherein the compound is 4-methyl-N-(4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide.

30. A pharmaceutical composition, comprising the compound of claim 29 and a pharmaceutically acceptable carrier.

31. The compound of claim 1 , wherein the compound is N-((5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamide.

32. A pharmaceutical composition, comprising the compound of claim 31 and a pharmaceutically acceptable carrier.

33. The compound of claim 1 , wherein the compound is compound N-((5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide.

34. A pharmaceutical composition, comprising the compound of claim 33 and a pharmaceutically acceptable carrier.

35. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

36. The composition of claim 35 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers.

37. A method of treating cancer, gastrointestinal stromal tumors, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, solid tumors, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers, osteosarcomas, multiple myelomas, cervical carcinomas, metastasis of primary tumor sites, cancers that are metastatic to bone, papillary thyroid carcinoma, non-small cell lung cancer, colonic cancers, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, mastocytosis, or mast cell leukemia, the method comprising administering to a patient in need thereof an effective amount of a compound of any of claim 1 .

38. A method of treating glioblastomas, breast cancers, pancreatic cancers, metastasis of primary tumor sites, or cancers that are metastatic to bone, the method comprising administering to a patient in need thereof an effective amount of a compound of claim 1 .

39. The method of claim 37 , wherein the compound is administered orally, parenterally, by inhalation, or subcutaneously.

40. The method of claim 38 , wherein the compound is administered orally, parenterally, by inhalation, or subcutaneously.