Heteroaryl pyridone and aza-pyridone compounds with electrophilic functionality

1. A compound selected from Formula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:

X 1 is CR 1 or N;

X 2 is CR 2 or N;

X 3 is CR 3 or N;

R 1 , R 2 and R 3 are independently selected from H, F, Cl, CN, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, and C 1 -C 3 alkyl;

X 4 , X 5 , X 6 , and X 7 are independently selected from CH and N;

Y 1 and Y 2 are independently selected from CH and N;

Z is O or NR, where R is H or C 1 -C 3 alkyl;

Q is selected from the groups having the structure:

where R 4 is selected from —CH═CH 2 , —C(CH 3 )═CH 2 , —C(CN)═CH 2 , —C≡CCH 3 , and —C≡CH; and R 5 is selected from H and C 1 -C 3 alkyl;

R 6a , R 6b , R 7a , and R 7b are independently selected from H, F, Cl, CN, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, and C 1 -C 3 alkyl;

or R 6a and R 7a form a five-, six-, or seven-membered carbocyclyl or heterocyclyl ring;

or R 5 and R 6a form a five-, six-, or seven-membered heterocyclyl ring;

or if Z is nitrogen, then Z and R 7a , or Z and R 6a form a five-, six-, or seven-membered heterocyclyl ring;

R 8 is selected from H, F, Cl, CN, —CH 2 OH, —CH(CH 3 )OH, —C(CH 3 ) 2 OH, —CH(CF 3 )OH, —CH 2 F, —CHF 2 , —CH 2 CHF 2 , —CF 3 , —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, cyclopropyl, cyclopropylmethyl, 1-hydroxycyclopropyl, imidazolyl, pyrazolyl, 3-hydroxy-oxetan-3-yl, oxetan-3-yl, and azetidin-1-yl;

R 9 is selected from the structures:

where the wavy line indicates the site of attachment; and

where alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CN, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —C(CH 3 ) 2 CH, —CH(OH)CH(CH 3 ) 2 , —C(CH 3 ) 2 CH 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CH 2 OP(O)(OH) 2 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH(CH 3 )CN, —C(CH 3 ) 2 CN, —CH 2 CN, —CO 2 H, —COCH 3 , —CO 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —N(CH 3 )COCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , —NO 2 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 N(CH 3 ) 2 , —OP(O)(OH) 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , —S(O) 3 H, cyclopropyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, pyrrolidin-1-yl, and morpholino.

2. The compound of claim 1 wherein X 1 is N.

3. The compound of claim 1 wherein X 2 is N.

4. The compound of claim 1 wherein X 3 is N.

5. The compound of claim 1 wherein X 1 and X 3 are N, X 1 and X 2 are N, or X 2 and X 3 are N.

6. The compound of claim 1 wherein X 1 and X 3 are CH, and X 2 is CF.

7. The compound of claim 1 wherein X 4 is N.

8. The compound of claim 1 wherein X 4 and X 5 are N.

9. The compound of claim 1 wherein Y 1 is CH and Y 2 is N.

10. The compound of claim 1 wherein Y 1 is N and Y 2 is CH.

11. The compound of claim 1 wherein Y 1 and Y 2 are each CH.

12. The compound of claim 1 wherein R 4 is —CH═CH 2 .

13. The compound of claim 1 wherein R 5 is H or —CH 3 .

14. The compound of claim 1 wherein R 6a , R 6b , R 7a , and R 7b are H.

15. The compound of claim 1 wherein R 8 is —CH 2 OH.

16. The compound of claim 1 wherein R 9 is selected from:

17. The compound of claim 1 selected from Formula Ia:

18. The compound of claim 17 selected from Formula Ib:

19. The compound of claim 17 wherein the group:

is selected from:

20. The compound of claim 1 selected from Formula Ic:

21. The compound of claim 20 selected from Formula Id:

22. The compound of claim 1 selected from:

N-{2-[(6-{[5-(2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0 2,6 ] dodeca-2(6),7-dien-10-yl}-3-(hydroxymethyl)pyridin-4-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}pyridin-2-yl)oxy]ethyl}prop-2-enamide;

N-(cyanomethyl)-1-(4-{[5-(2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0 26 ] dodeca-2(6),7-dien-10-yl}-3-(hydroxymethyl)pyridin-4-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}pyrimidin-2-yl)pyrrolidine-3-carboxamide;

N-[2-[[6-[[5-[5-fluoro-2-(hydroxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]prop-2-enamide;

N-[2-[[6-[[5-[2-(6-tert-butyl-8-fluoro-1-oxo-phthalazin-2-yl)-3-(hydroxymethyl)-4-pyridyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]prop-2-enamide;

N-[2-[[6-[[5-[5-fluoro-2-(hydroxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]amino]ethyl]prop-2-enamide; and

N-[2-[[6-[[5-[5-fluoro-2-(hydroxymethyl)-3-(4-oxo-6,7, 8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]but-2-ynamide.

23. The compound of claim 1 selected from:

N-[(1S)-2-[[6-[[5-[2-(7,7-dimethyl-4-oxo-1,2,6, 8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-3-yl)-3-(hydroxymethyl)-4-pyridyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]-1-methyl-ethyl]prop-2-enamide;

N-[(1S)-2-[[6-[[5-[5-fluoro-2-(hydroxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]-1-methyl-ethyl]prop-2-enamide;

N-[2-[[6-[[5-[2-(7,7-dimethyl-4-oxo-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-3-yl)-3-(hydroxymethyl)-4-pyridyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]amino]ethyl]prop-2-enamide;

N-[2-[[6-[[5-[2-(7,7-dimethyl-4-oxo-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-3-yl)-3-(hydroxymethyl)-4-pyridyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]-methyl-amino]ethyl]prop-2-enamide;

N-[2-[[6-[[5-[5-fluoro-2-(hydroxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]-methyl-amino]ethyl]prop-2-enamide;

N-[2-[[6-[[5-[2-(7,7-dimethyl-4-oxo-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-3-yl)-3-(hydroxymethyl)-4-pyridyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]-N-methyl-prop-2-enamide;

N-[2-[[6-[[5-[5-fluoro-2-(hydroxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]-N-methyl-prop-2-enamide;

N-[(3S)-1-[6-[[5-[2-(7,7-dimethyl-4-oxo-1,2,6,8-tetrahydrocyclopenta [3,4]pyrrolo[3,5-b]pyrazin-3-yl)-3-(hydroxymethyl)-4-pyridyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]-3-piperidyl]prop-2-enamide;

N-[(3S)-1-[6-[[5-[5-fluoro-2-(hydroxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]-3-piperidyl]prop-2-enamide;

N-[2-[[6-[[5-[2-(7,7-dimethyl-4-oxo-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-3-yl)-3-(hydroxymethyl)-4-pyridyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]but-2-ynamide;

2-cyano-N-[2-[[6-[[5-[5-fluoro-2-(hydroxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]prop-2-enamide; and

2-cyano-N-[2-[[6-[[5-[2-(7,7-dimethyl-4-oxo-1,2,6,8-tetrahydrocyclopenta [3,4]pyrrolo[3,5-b]pyrazin-3-yl)-3-(hydroxymethyl)-4-pyridyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]prop-2-enamide.

24. A pharmaceutical composition comprised of a compound of claim 1 and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

25. A process for making a pharmaceutical composition which comprises combining a compound of claim 1 with a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

26. A method of treating a disease or disorder which comprises administering a therapeutically effective amount of the pharmaceutical composition of claim 24 to a patient with a disease or disorder selected from systemic and local inflammation, arthritis, inflammation related to immune suppression, organ transplant rejection, allergies, ulcerative colitis, Crohn's disease, dermatitis, asthma, systemic lupus erythematosus, extra-renal lupus, Sjögren's Syndrome, multiple sclerosis, scleroderma/systemic sclerosis, idiopathic thrombocytopenic purpura (ITP), anti-neutrophil cytoplasmic antibodies (ANCA) vasculitis, chronic obstructive pulmonary disease (COPD), and psoriasis.

27. The method of claim 26 wherein the disease or disorder is rheumatoid arthritis.

28. The method of claim 26 further comprising administering an additional therapeutic agent selected from an anti-inflammatory agent, an immunomodulatory agent, chemotherapeutic agent, an apoptosis-enhancer, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, and an agent for treating immunodeficiency disorders.

29. The method of claim 28 wherein the additional therapeutic agent is a Bcl-2 inhibitor.

30. The method of claim 29 wherein the Bcl-2 inhibitor is venetoclax.

31. The method of claim 28 wherein the additional therapeutic agent is a Btk inhibitor.

32. The method of claim 31 wherein the Btk inhibitor is ibrutinib.

33. The method of claim 28 wherein the additional therapeutic agent is a JAK inhibitor.

34. The method of claim 28 wherein the additional therapeutic agent is an anti-CD20 antibody.

35. The method of claim 34 wherein the anti-CD20 antibody is obinutuzumab or rituximab.

36. A kit for treating a condition mediated by Bruton's tyrosine kinase, comprising:

a) a pharmaceutical composition of claim 24 ; and

b) instructions for use.