Nlrp3 modulators

A compound of Formula (I):

• or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein:
• is independently selected from:
• R1 is, at each occurrence, independently:
• (i) H;
• (ii) halo;
• (iii) X—R5, wherein X is C1-6 alkylene, and R5 is H, OH, cyano, C1-4 alkoxy, C1-4 haloalkoxy, —C(O)ORa, —NRbRc, or —C(O)NRbRk;
• (iv) C1-6 alkyl substituted with 1 to 6 F;
• (v) C3-6 cycloalkyl substituted with 0 to 6 F;
• (vi) (C1-3 alkylene)-aryl, wherein the aryl is substituted with 0 to 3 Rd;
• or
• (vii) (C1-3 alkylene)-heteroaryl including from 5 to 6 ring atoms, wherein from 1 to 4 ring atoms are each independently selected from N, N(Rf), O, and S, wherein the heteroaryl is substituted with 0 to 3 Rd;
• R1a is independently H, C1-6 alkyl substituted with 0 to 6 F, or C3-6 cycloalkyl substituted with 0 to 6 F;
• R2 is, at each occurrence, independently:
• (i) H;
• (ii) —Y—R6;
• (iii) —C(O)—Y—R6;
• wherein:
• Y is independently C1-8 alkylene substituted with from 0 to 4 Re;
• and
• R6 is, at each occurrence, independently:
• H, OH, CN, ORa, —C(O)Ra, —C(O)ORa, —NRbRc, —C(O)NRbRk, —SO1-2Rh
• or heteroaryl including from 5 to 10 ring atoms, wherein from 1-4 ring atoms are each independently selected from N, N(Rf), O, and S, wherein the heteroaryl is substituted with from 0 to 3 Rd;
• (iv) —(Y1)n—Y2—(Y3)p—R7, wherein:
• n is independently 0, 1 or 2;
• p is independently 0 or 1;
• each of Y1 and Y3 is, independently, C1-3 alkylene substituted with from 0 to 2 Re;
• Y2 is independently C3-6 cycloalkylene substituted with from 0 to 4 Rg, or heterocycloalkylene including from 3-8 ring atoms, wherein from 1-2 ring atoms are each independently selected from N, N(Rf) and O, and wherein the heterocycloalkylene is substituted with from 0 to 4 Rg, and
• R7 is H, OH, —ORa, —C(O)ORa, —NRbRc, —C(O)NRbRk, or heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are each independently selected from N, N(Rf), O, and S, and wherein the heteroaryl is substituted with from 0 to 4 Rg;
• or
• (v) —Z1—Z2—Z3—R8, wherein:
• Z1 is C1-3 alkylene substituted with from 0 to 6 F;
• Z2 is —N(Rf)—, —O—, or —S—;
• Z3 is C2-5 alkylene substituted with from 0 to 6 F;
• and
• R8 is OH, ORa, —C(O)Ra, —C(O)ORa;
• —NRbRc, —C(O)NRbRk, or heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are each independently selected from N, N(Rf), O, and S, wherein the heteroaryl is substituted with from 0 to 3 Rd;
• R3 is independently halo or —(C0-3 alkylene)-(5-membered heteroaryl) wherein the heteroaryl includes 1 to 4 ring carbon atoms and 1 to 4 ring heteroatoms are each independently selected from:
• N, N(Rf), O, and S, and is substituted with from 0 to 3 Rg;
• provided that when R3 is furanyl, R2 is other than C1-4 alkyl;
• R4 is independently selected from:
• H, halo, cyano, OH, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, —C(O)OH, —C(O)ORa, —NRjRk, —C(O)NRjRk, —SO1-2Rh, and C1-4 alkyl substituted with from 0 to 2 Re;
• Ra is, at each occurrence, independently:
• (i) C1-6 alkyl substituted with from 0 to 3 Re;
• (ii) —(C0-3 alkylene)-C3-6 cycloalkyl, wherein the cycloalkyl is substituted with from 0 to 4 Rg;
• (iii) —(C0-3 alkylene)-heterocyclyl including from 3 to 10 ring atoms, wherein from 1 to 3 ring atoms are each independently selected from N(Rf), O, and S(O)0-2, wherein the heterocyclyl is substituted with from 0 to 4 Rg;
• (iv) —(C0-3 alkylene)—(C6-10 aryl), wherein the aryl is substituted with from 0 to 5 Rd;
• or
• (v) —(C0-3 alkylene)-heteroaryl including from 5 to 10 ring atoms, wherein from 1 to 4 ring atoms are each independently selected from N, N(Rf), O, and S, wherein the heteroaryl is substituted with from 0 to 3 Rd;
• Rb is, at each occurrence, independently H or Ra;
• Rc is, at each occurrence, independently selected from:
• H, —C(O)Ra, —C(O)ORa, —C(O)NjRk, —S(O)1-2Rh, C1-6 alkyl substituted with from 0 to 2 Re, —(C0-3 alkylene)-(phenyl substituted with from 0 to 4 Rn), and —(C0-3 alkylene)-heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are each independently selected from N, N(Rf), O, and S, wherein the heteroaryl is substituted with from 0 to 3 Rn;
• alternatively, Rb and Rc, together with the nitrogen atom to which each is attached form heterocyclyl including from 3 to 10 ring atoms, wherein from 1 to 3 ring atoms are each independently selected from N(Rf), O, and S, and wherein the heterocyclyl is substituted with from 0 to 4 Rg;
• Rd is, at each occurrence, independently selected from:
• halo, OH, cyano, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, —C(O)(C1-4 alkyl), —C(O)OH, —C(O)O(C1-4 alkyl), —NRjRk, —N(Rm)(C(O)(C1-4 alkyl), —N(Rm)(C(O)O(C1-4 alkyl), —C(O)NRjRk, —S(O)1-2Rh, —S(O)1-2NRhRj, C1-6 alkyl substituted with from 0 to 2 Re, and —(C0-3 alkylene)-Rp;
• Re is, at each occurrence, independently selected from:
• halo, OH, cyano, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, —C(O)ORa, —OC(O)Rh, —NRbRc, and —CONRbRk;
• Rf is, at each occurrence, independently selected from:
• H, OH, C1-4 alkyl, C1-4 alkoxy, —C(O)(C1-4 alkyl), —C(O)(C1-4 haloalkyl), —C(O)O(C1-4 alkyl), —C(O)NRjRk, —S(O)1-2Rh, and —(C0-3 alkylene)-phenyl;
• Rg is, at each occurrence, independently oxo or Rd;
• Rh is, at each occurrence, independently selected from C1-6 alkyl substituted with 0 to 2 Rn, C1-4 haloalkyl, and —(C0-3 alkylene)-Rp;
• Rj and Rm are, at each occurrence, independently H or C1-4 alkyl;
• Rk is, at each occurrence, independently selected from H, C1-4 alkyl, and —(C0-2 alkylene)-phenyl;
• Rn is, at each occurrence, independently selected from:
• halo, OH, C1-6 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, cyano, —C(O)OH, —C(O)O(C1-4 alkyl), —NRjRk, and —CONRjRk;
• and
• Rp is, at each occurrence, independently selected from:
• C3-6 cycloalkyl substituted with from 0 to 4 C1-4 alkyl;
• heterocyclyl including from 3-10 ring atoms, wherein from 1 to 3 ring atoms are each independently selected from NH, N(C1-4 alkyl), O, and S, wherein the heterocyclyl is substituted with 0 to 4 independently selected C1-4 alkyl;
• phenyl substituted with 0 to 3 Rn;
• and heteroaryl including from 5 to 10 ring atoms, wherein from 1 to 4 ring atoms are each independently selected from N, NH, N(C1-4 alkyl), O, and S, wherein the heteroaryl is substituted with 0 to 3 Rn.