NLRP3 modulators
The present invention provides compounds of Formula (I): wherein all of the variables are as defined herein. These compounds are modulators of NLRP3, which may be used as medicaments for the treatment of proliferative disorders, such as cancer in a subject (e.g., a human).
1. A compound of Formula (I):
or a tautomer or a pharmaceutically acceptable salt thereof, wherein:
R 1 is independently C 3-6 cycloalkyl substituted with 0-3 halogen;
R 2 , R 3 and R 5 are, at each occurrence, independently selected from: H, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;
R 4 is independently 5-membered heteroaryl including from 1-4 ring atoms are each independently selected from N, N(R a ), O, and S, wherein the heteroaryl is substituted with from 0-3 R b ;
R 6 is independently heterocyclyl including from 5 to 6 ring atoms, wherein from 1 to 3 ring atoms are each independently selected from N(R c ), O, and S, wherein the heterocyclyl is substituted with from 0 to 3 R d ; or heteroaryl including from 5 to 6 ring atoms, wherein from 1 to 4 ring atoms are each independently selected from N, N(R c ), O, and S, wherein the heteroaryl is substituted with from 0 to 3 R d ;
R 7 is independently H or C 1-4 alkyl;
Y is independently C 1-3 alkylene;
R a and R c are, at each occurrence, independently selected from: H and C 1-4 alkyl; and
R b and R d are, at each occurrence, independently selected from: halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy.
2. A compound according to claim 1 , wherein:
R 1 is independently C 3-4 cycloalkyl;
R 2 , R 3 and R 5 are, at each occurrence, independently selected from: H, halogen and C 1-4 alkyl;
R 4 is independently pyrazolyl, thienyl or isothiazolyl;
R 6 is independently selected from: thiazolyl substituted with 0 to 2 R d , pyridyl substituted with 0 to 2 R d , and
Y is independently C 1-2 alkylene; and
R d is, at each occurrence, independently selected from: halogen, C 1-4 alkyl, and C 1-4 alkoxy.
3. A compound according to claim 2 , wherein the compound is of Formula (II):
or a tautomer or a pharmaceutically acceptable salt thereof; wherein:
R 1 is independently selected from: cyclopropyl, and cyclobutyl;
R 6 is independently selected from: thiazolyl substituted with 0 to 2 R d , pyridyl substituted with 0 to 2 R d , and
Y is is independently —CH 2 — or —CH 2 CH 2 —; and
R d is, at each occurrence, independently halogen, C 1-4 alkyl or C 1-4 alkoxy.
4. A compound according to claim 2 , wherein
R 1 is independently selected from: cyclopropyl, and cyclobutyl;
R 6 is independently selected from: thiazolyl substituted with 0 to 1 R d , pyridyl substituted with 0 to 1 R d , and
Y is is independently —CH 2 — or —CH 2 CH 2 —; and
R d is independently F, Cl or OCH 3 .
5. A compound according to claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as claimed in claims 1 and one or more pharmaceutically acceptable excipients.
7. A method of treating cancer selected from breast cancer, colon cancer, rectal cancer, colorectal cancer, pancreatic cancer, prostate cancer, melanoma, head and neck cancer, skin cancer, and acute monocytic leukemia cells, comprising administering to a subject in need of such treatment an effective amount of a compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 .
8. The method of claim 7 , wherein the cancer is selected from breast cancer, colon cancer, rectal cancer, colorectal cancer, pancreatic cancer, and prostate cancer.
9. The method of claim 7 , wherein the cancer is selected from hormone receptor positive breast cancer, microsatellite stable colon or rectal cancer, pancreatic cancer and prostate cancer.
10. The method of claim 7 , wherein the compound is administered in combination with one or more additional cancer therapies.
11. The method of claim 10 , wherein the one or more additional cancer therapies comprise surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.
12. The method of claim 10 , wherein the additional cancer therapy comprises one or more agents selected from nivolumab, pembrolizumab, PDR001, MEDI-0680, cemiplimab, JS001, BGB-A317, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGD013, IBI308, BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, LY3300054, CK-301, urelumab, PF-05082566, MEDI6469, TRX518, varlilumab, CP-870893, BMS-986016, MGA271, lirilumab, IPH2201, emactuzumab, INCB024360, galunisertib, ulocuplumab, BKT140, Bavituximab, CC-90002, bevacizumab, MNRP1685A, ipilimumab, MK-1308, AGEN-1884, and tremelimumab.
13. The method of claim 10 , wherein the additional cancer therapy comprises one or more agents selected from nivolumab, ipilimumab, pembrolizumab, atezolizumab, durvalumab and avelumab.
14. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as claimed in claim 2 and one or more pharmaceutically acceptable excipients.
15. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as claimed in claim 3 and one or more pharmaceutically acceptable excipients.
16. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as claimed in claim 4 and one or more pharmaceutically acceptable excipients.
17. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as claimed in claim 5 and one or more pharmaceutically acceptable excipients.