	US 12,338,228 B2
	NLRP3 modulators
Scott Hunter Watterson, Pennington, NJ (US); Daniel O'Malley, New Hope, PA (US); Ashvinikumar V. Gavai, Princeton Junction, NJ (US); Patrice Gill, Levittown, PA (US); Steven P. Seitz, Swarthmore, PA (US); and Hua Gong, King of Prussia, PA (US)
Assigned to Innate Tumor Immunity, Inc., Princeton, NJ (US)
Appl. No. 17/422,510
Filed by Innate Tumor Immunity, Inc., Princeton, NJ (US)
PCT Filed Jan. 13, 2020, PCT No. PCT/US2020/013265 § 371(c)(1), (2) Date Jul. 13, 2021, PCT Pub. No. WO2020/150116, PCT Pub. Date Jul. 23, 2020.
Claims priority of provisional application 62/791,967, filed on Jan. 14, 2019.
Prior Publication US 2022/0089566 A1, Mar. 24, 2022
Int. Cl. C07D 401/10 (2006.01); A61K 31/4709 (2006.01); A61K 45/06 (2006.01); A61P 35/00 (2006.01); C07D 401/04 (2006.01); C07D 401/14 (2006.01); C07D 405/14 (2006.01); A61K 31/47 (2006.01)

CPC C07D 401/10 (2013.01) [A61K 31/4709 (2013.01); A61K 45/06 (2013.01); A61P 35/00 (2018.01); C07D 401/14 (2013.01); C07D 405/14 (2013.01)]

12 Claims

1. A compound of Formula (I), (II) or (III):

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

W is independently selected from: —Y—R⁶, -Q-Y-R⁶,Q-R^6a, and R^6b;

Q is independently selected from: NR⁵, CHR⁵, O, and S;

Y is independently selected from: C_1-10alkylene, C_2-10alkenylene, and C_2-10alkynylene, each of which is substituted with 0 to 4 R^eand/or each of which is optionally interrupted by one of the following:

(i) O;

(ii) N(R^f);

(iii) C_3-6cycloalkylene substituted with 0 to 4 R⁸;

(iv) phenylene substituted with 0 to 4 R^d;

(v) heteroarylene consisting of 5 to 10 ring atoms, wherein from 1 to 4 ring atoms are each independently selected from N, N(R^f), O, and S, and which is substituted with 0 to 4 R^d, or

(vi) heterocycloalkylene consisting of 3 to 10 ring atoms, wherein from 1 to 3 ring atoms are each independently selected from N, N(R^f), O and S(O)_1-2, and which is substituted with 0 to 4 R^g;

R¹and R³are, at each occurrence, independently selected from: H, halogen, cyano, C_1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, and C_1-4haloalkoxy;

R^1ais independently selected from: halogen, cyano, C_1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, and C_1-4haloalkoxy;

R²is independently a heteroaryl consisting of 5 ring atoms, wherein from 1 to 4 ring atoms are each independently selected from N, NH, O, and S, wherein the heteroaryl is substituted with 0 to 3 R^d,

R^4ais independently selected from: halogen, cyano, C_1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, C_1-4haloalkoxy, N(C_1-4alkyl)₂, and —(C_0-3alkylene)-heteroaryl consisting of 5 ring atoms, wherein from 1 to 4 ring atoms are each independently selected from N, NH, N(C_1-4alkyl), O, and S, wherein the heteroaryl is substituted with 0 to 3 R^d,

R⁴is independently H or R^4a,

R⁵is independently H or C_1-4alkyl;

R⁶is independently selected from: —OR^a, C_1-4haloalkoxy, —C(O)R^a, —CO₂R^a, —SO_1-2(R^h), —CONRⁱR^j, cyano and R^6a;

R^6ais independently selected from: phenyl substituted with 0 to 4 R^d, heteroaryl consisting of 5 to 10 ring atoms, wherein from 1 to 4 ring atoms are each independently selected from N, N(R^f), O, and S, wherein the heteroaryl is substituted with 0 to 4 R^d; C_3-10cycloalkyl substituted with 0 to 4 R^g; and heterocyclyl consisting of 3 to 10 ring atoms, wherein from 1 to 3 ring atoms are each independently selected from N, N(R^f), O and S(O)_1-2, wherein the heterocyclyl is substituted with 0 to 4 R^g;

R^6bis independently selected from: C_1-6alkoxy, C_1-4haloalkoxy, —C(O)R^a, —CO₂R^a, —SO_1-2(R^h),—CONRⁱR^j, phenyl substituted with 0 to 4 R^d; heteroaryl consisting of 5 to 10 ring atoms, wherein from 1 to 4 ring atoms are each independently selected from N, N(R^f), O, and S, wherein the heteroaryl is substituted with 0 to 4 R^d; C_3-10cycloalkyl substituted with 0 to 4 R^g; and heterocyclyl selected from

wherein the heterocyclyl is substituted with 0 to 2 R^g;

R⁷is independently H, halogen, cyano, C_1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, or C_1-4haloalkoxy;

R^7ais halogen;

R^ais independently selected from: H; C_1-8alkyl substituted with 0 to 2 R^e; —(C_0-3alkylene)-C_3-10cycloalkyl, wherein the cycloalkyl is substituted with 0 to 4 R^g; —(C_0-3alkylene)-heterocyclyl consisting of 3 to 10 ring atoms, wherein from 1 to 3 ring atoms are each independently selected from N(R^f), O, and S, wherein the heterocyclyl is substituted with 0 to 4 R^g; —(C_0-3alkylene)-(C_6-10aryl), wherein the aryl is substituted with 0 to 4 R^d, and —(C_0-3alkylene) -heteroaryl consisting of 5 to 10 ring atoms, wherein from 1 to 4 ring atoms are each independently selected from N, N(R^f), O, and S, wherein the heteroaryl is substituted with 0 to 4 R^d,

R^band R^care, at each occurrence, independently R^aor —C(O)R^a;

R^dis independently selected from: halogen, OH, cyano, C_1-4alkoxy, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, —C(O)O(C_1-4alkyl), NH₂, N(C_1-4alkyl)₂,—C(O)NH₂, —C(O)N(C_1-4alkyl)₂, C_2-6alkenyl, C_2-6alkynyl, and C_1-6alkyl substituted with 0 to 2 R^e;

R^eis independently selected from: F, OH, cyano, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, and C_1-4alkyl substituted with 0 to 1 Rⁿ;

R^fis independently selected from: H, C_1-4alkyl, —C(O)(C_1-4alkyl), and —C(O)O(C_1-4alkyl);

R^gis independently oxo or R^d,

R^his independently selected from: C_1-6alkyl, C_1-4haloalkyl, —(C_0-3alkylene)-phenyl, and —(C_0-3alkylene)-heteroaryl consisting of 5 to 6 ring atoms, wherein from 1-4 ring atoms are each independently selected from N, N(R^f), O, and S;

Rⁱand R^jare, at each occurrence, independently H or R^h, or Rⁱand R^jtogether with the nitrogen atom to which each is attached forms a ring consisting of 5 to 6 ring atoms, wherein the ring includes: (a) from 3 to 5 ring carbon atoms, each of which is substituted with from 1 to 2 substituents independently selected from H and R^m; and (b) from 0 to 2 ring heteroatoms (in addition to the nitrogen atom attached to Rⁱand R^j), which are each independently selected from N(R^f), O, and S;

R^mis independently oxo or R^e; and

Rⁿis independently selected from: OH, CONH₂and C_1-4alkoxy.