1,2,4-triazol-5-ones 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, branched C3-C8alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, 4-8 membered heterocyclic ring and heteroaryl, wherein each A moiety may be further substituted with one, two, or three R3 moieties;

W is C5-C6heteroaryl, phenyl, —NHC(O)R6, —NHC(O)R7, —NHC(O)N(R8)R9 or —C(O)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties;

Q1 is CH or N;

X1 and X2 are individually and independently hydrogen, or C1-C6 alkyl;

Y is NR4 or O;

Z is N or CR11;

each R1 and R2 is individually and independently hydrogen, C1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain is partially or completely deuterated, 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 halogen;

each R3 is individually and independently hydrogen, 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;

R4 is hydrogen, C1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl;

each R5 is individually and independently hydrogen, C1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, halogen, cyano, fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, —(CH 2 ) m —C(O)NR8(R9), —(CH 2 ) m —C(O)R7, —(CH 2 ) m —OR8, —(CH 2 ) m —NR8(R9), or —(CH 2 ) m —R7, wherein each alkylene is optionally substituted with C1-C4 alkyl;

Each R6 is individually and independently hydrogen, C1-C6 alkyl, branched C3-C8 alkyl, C3-C8 cycloalkyl, —(CH 2 ) m —CN, —(CH 2 ) m —OR8, —(CH 2 ) m —NR8(R9), or —(CH 2 ) m —R7, wherein each alkylene is optionally substituted with C1-C4 alkyl;

each R7 is independently and individually selected from the group consisting of

and wherein the symbol (##) is the point of attachment to respective W, R5 or R6 moieties containing a R7 moiety;

each R7 is optionally substituted with —(R10) p ;

each R8 and R9 is individually and independently hydrogen, C1-C6 alkyl, fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, or branched C3-C8 alkyl;

each R10 is individually and independently C1-C6 alkyl, —(CH 2 ) m —CN, —(CH 2 ) m —OR3, —(CH 2 ) m —NR8(R9), or —(CH 2 ) m —C(O)—R6, wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl;

wherein each alkylene is optionally substituted with C1-C4 alkyl;

R11 is hydrogen, C1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl;

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, or 2.

2. The compound of claim 1 , wherein W is selected from the group consisting of pyrazolyl, phenyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl, pyridinyl, —NHC(O)R6, —NHC(O)R7, —NHC(O)N(R8)R9, and —C(O)N(R8)R9.

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 A is C1-C6 alkyl, branched C3-C8alkyl, C3-C8carbocyclyl, phenyl or a 4-8 membered heterocyclic ring and q is 0 or 1.

5. The compound of claim 4 , wherein W is pyrazolyl or pyridinyl, optionally substituted with —(R5) p .

6. The compound of claim 5 wherein Y is NR4 and R4 is hydrogen.

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

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

wherein the A moiety is selected from C1-C6 alkyl, branched C3-C8alkyl, C3-C8carbocyclyl, phenyl or a 4-8 membered heterocyclic ring.

8. The compound of claim 7 , wherein W is pyrazolyl or pyridinyl, optionally substituted with —(R5) p .

9. The compound of claim 8 , wherein R4 is hydrogen.

10. The compound of claim 1 , wherein the compound is a compound of Formula Ic,

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

wherein q is 0 or 1.

11. The compound of claim 2 , wherein the compound is a compound of Formula Id,

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

12. The compound of claim 2 , wherein the compound is a compound of Formula Ie,

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

wherein the A moiety is selected from C1-C6 alkyl, branched C3-C8alkyl, C3-C8carbocyclyl, phenyl or a 4-8 membered heterocyclic ring.

13. The compound of claim 12 , wherein W is pyrazolyl, optionally substituted with —(R5) p .

14. The compound of claim 13 , wherein R4 is hydrogen.

15. The compound of claim 1 , wherein the compound is a compound of Formula If,

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

wherein q is 0 or 1.

16. The compound of claim 2 , wherein the compound is a compound of Formula Ig,

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

wherein the A moiety is selected from C1-C6 alkyl, branched C3-C8alkyl, C3-C8carbocyclyl, phenyl or a 4-8 membered heterocyclic ring.

17. The compound of claim 16 , wherein W is pyrazolyl or pyridinyl, optionally substituted with —(R5) p .

18. The compound of claim 1 , wherein the compound is a compound of Formula Ih,

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

19. The compound of claim 1 is selected from the group consisting of 3-(4-fluorobenzyl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-benzyl-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(4-fluorobenzyl)-1-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(tert-butyl)-1-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-isopropyl-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-cyclohexyl-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(tert-butyl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(tert-butyl)-1-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(tert-butyl)-1-(6-methyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(tert-butyl)-1-(6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, N-(4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)acetamide, 3-(tert-butyl)-1-(6-methyl-54(2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(tert-butyl)-4-methyl-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(tert-butyl)-1-(6-methyl-5-(2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(2-methoxyethyl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(2-methoxypropan-2-yl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(methoxymethyl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(tert-butyl)-1-(5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(tert-butyl)-1-(6-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazol-5(4H)-one, N-(4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)-1-methylpiperidine-4-carboxamide, 3-isobutyl-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(tert-butyl)-1-(6-methyl-5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 1-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(tert-butyl)-1H-1,2,4-triazol-5(4H)-one, 1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(tert-pentyl)-1H-1,2,4-triazol-5(4H)-one, 4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)pyridin-3-yl)oxy)-N-methylpicolinamide, 1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(1-methylcyclopropyl)-1H-1,2,4-triazol-5(4H)-one, 3-(4-fluorophenyl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(4-fluorophenyl)-1-(6-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)-1,1-dimethylurea, 3-(tert-butyl)-1-(4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, N-(4-((6-(3-(4-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide, 3-(tert-butyl)-1-(4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-cyclopentyl-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-cyclopropyl-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-neopentyl-1H-1,2,4-triazol-5(4H)-one, 3-cyclobutyl-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(tert-butyl)-1-(5-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(tert-butyl)-1-(6-methyl-5-((2-(oxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(tert-butyl)-1-(6-methyl-5-((6′-(4-methylpiperazin-1-yl)-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(tert-butyl)-1-(6-methyl-5-((2′-(4-methylpiperazin-1-yl)-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(1-hydroxy-2-methylpropan-2-yl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-1H-1,2,4-triazol-5(4H)-one, N-(4-((6-(3-(2-methoxypropan-2-yl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-methylpyridin-3-yl)oxy)pyridin-2-yl)acetamide, N-(4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide, 3-(1-methoxy-2-methylpropan-2-yl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 3-(tert-butyl)-1-(6-methyl-5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one, 4-(tert-butyl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-imidazol-2(3H)-one, and 5-(tert-butyl)-3-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1,3,4-oxadiazol-2(3H)-one.

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

21. The compound 3-(tert-butyl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one.

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

23. The compound 3-isopropyl-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one.

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

25. The compound 1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(tert-pentyl)-1H-1,2,4-triazol-5(4H)-one.

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

27. The compound.

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

29. The compound 4-(tert-butyl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-imidazol-2(3H)-one.

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

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

32. The composition of claim 31 further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers.

33. A method of treating gastrointestinal stromal tumors, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers, osteosarcomas, multiple myelomas, cervical carcinomas, cancers that are metastatic to bone, papillary thyroid carcinoma, non-small cell lung cancer, colonic cancers, rheumatoid arthritis, osteoarthritis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, mastocytosis, and mast cell leukemia, the method comprising administering to a human patient in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

34. A method of treating glioblastomas, breast cancers, pancreatic cancers, or cancers that are metastatic to bone, the method comprising administering to a human patient in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

35. The method of claim 33 , wherein the compound is administered orally, parenterally, by inhalation, or subcutaneously.

36. The method of claim 34 , wherein the compound is administered orally, parenterally, by inhalation, or subcutaneously.