Sting agonist compounds and methods of use

A compound of Formula (IA′)

• or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein:
• W1, X1, Y1, Z1, W2, X2, Y2, and Z2 are each independently O, S, C, or N;
• X3 and X4 are each independently S or NR;
• X5 is N or CRA2;
• X6 is N or CRA1;
• X9 is N or CR4;
• r and s are each independently 0 or 1;
• p is 1 or 2;
• the total of r and s is 1 or 2;
• RA1 and RA2 are each independently H, halogen, amino, amino(C1-4 alkyl)-, hydroxy, —O—P(O)(OH)2, —O—P(O)(RIRII)2, —N(Re)(Rf), —CO2Rf, —N(Rf)CORb, —N(Rg)SO2(C1-4 alkyl)-N(Re)(Rf), —N(Rg)CO(C1-4 alkyl)-N(Rh)(Rf), optionally substituted (C1-6 alkyl), optionally substituted (C1-6 alkyl)oxy-, optionally substituted (C1-6 alkyl)amino-, and optionally substituted (C1-6 alkyl)(C1-4 alkyl)amino-,
• wherein the (C1-6 alkyl) of said optionally substituted (C1-6 alkyl), optionally substituted (C1-6 alkyl)oxy-, optionally substituted (C1-6 alkyl)amino- and optionally substituted (C1-6 alkyl)(C1-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, —O—P(O)(OH)2, —O—P(O)(RIRII)2, C1-4 alkoxy-, —N(Re)(Rf), —CO2(Rf), —CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH)2, —O—P(O)(RIRII)2, amino, (C1-6 alkyl)amino-, (C1-6 alkyl)(C1-6 alkyl)amino-, —(C1-6 alkyl)-NH2, halo(C1-6 alkyl), hydroxy-(C1-4 alkyl)-, —(C1-4 alkyl)-O—P(O)(OH)2, —(C1-4 alkyl)-O—P(O)(RIRII)2, halo(C1-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, —(C2-4 alkoxy)-O—P(O)(OH)2, —(C2-4 alkoxy)-O—P(O)(RIRII)2, —C1-4 alkyl-(C1-4 alkoxy), and C1-4 alkoxy-(C1-4 alkoxy)-;
• when r is 0, RB1 and RB2 are each independently H, optionally substituted C1-6 alkyl, halo(C1-6 alkyl), optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroaryl,
• wherein said optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, nitro, —Rc, —OH, —O—P(O)(OH)2, —O—P(O)(RIRII)2—ORc, —NH2, —NRcRc, —NRcRd, —OCORc, —CO2H, —CO2Rc, —SORc, —SO2Rc, —CONH, —CONRcRd, —SO2NH2, —SO2NRcRd, —OCONH2, —OCONRcRd, —NRdCORc, —NRdSORc, —NRdCO2Rc, and —NRdSO2Rc;
• when s is 0, RC1 is absent, H, halogen, or C1-4 alkyl and RC2 is absent or optionally substituted C1-4 alkyl, wherein said optionally substituted C1-4 alkyl group is optionally substituted by a substituent selected from —ORc, —NRcRd, —CO2Rc, —CONRcRd, —SO2NRcRd, and —OCONRcRd;
• when r is 1, RB1 and RB2 are each independently —CH2—, and B, taken together with RB1 and RB2, forms a linking group, wherein B is a bond or B is -halo(C1-10 alkyl)-, optionally substituted —C1-10 alkyl-, optionally substituted —C2-10 alkenyl-, optionally substituted —C2-10 alkynyl-, optionally substituted —C1-6 alkyl-O—C1-6 alkyl-, optionally substituted —C1-6 alkyl-NRa—C1-6 alkyl-, optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted —C1-4 alkyl-(C3-6 cycloalkyl)-C1-4 alkyl-, optionally substituted —C1-4 alkyl-phenyl-C1-4 alkyl-, optionally substituted —C1-4 alkyl-(4-6 membered heterocycloalkyl)-C1-4 alkyl-, or optionally substituted —C1-4 alkyl-(5-6 membered heteroaryl)-C1-4 alkyl-,
• wherein the alkyl moiety of said optionally substituted —C1-10 alkyl-, optionally substituted —C2-10 alkenyl-, optionally substituted —C2-10 alkynyl-, optionally substituted —C1-6 alkyl-O—C1-6 alkyl-, optionally substituted —C1-6 alkyl-NRa—C1-6 alkyl-, optionally substituted —C1-4 alkyl-(C3-6 cycloalkyl)-C1-4 alkyl-, optionally substituted —C1-4 alkyl-phenyl-C1-4 alkyl-, optionally substituted —C1-4 alkyl-(4-6 membered heterocycloalkyl)-C1-4 alkyl-, or optionally substituted —C1-4 alkyl-(5-6 membered heteroaryl-C1-4 alkyl)- is optionally substituted by 1 or 2 substituents each independently selected from halogen, halo(C1-4 alkyl), —OH, —O—P(O)(OH)2, —O—P(O)(RIRII)2, —ORc, —NH2, —NRcRd, —OCORc, —CO2H, —CO2Rc, —SORc, —SO2Rc, —CONH2, —CONRcRd, —SO2NH2, —SO2NRcRd, —OCONH2, —OCONRcRd, —NRdCORc, —NRdSORc, —NRdCO2Rc, and —NRdSO2Rc, and
• the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted —C1-4 alkyl-(C3-6 cycloalkyl)-C1-4 alkyl-, optionally substituted —C1-4 alkyl-phenyl-C1-4 alkyl-, optionally substituted —C1-4 alkyl-(4-6 membered heterocycloalkyl)-C1-4 alkyl-, or optionally substituted —C1-4 alkyl-(5-6 membered heteroaryl)-C1-4 alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH)2, —O—P(O)(ORIRII)2, amino, (C1-4 alkyl)amino-, (C1-4 alkyl)(C1-4 alkyl)amino-, C1-4 alkyl, halo(C1-4 alkyl), halo(C1-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, —(C2-4 alkoxy)-O—P(O)(OH)2, —(C2-4 alkoxy)-O—P(O)(RIRII)2, and C1-4 alkoxy-(C1-4 alkoxy)-;
• when s is 1, W1 and Z2 are each independently C or N, RC1 and RC2 are each independently —CH2—, and D taken together with RC1 and RC2, forms a linking group, wherein D is -halo(C1-12 alkyl)-, optionally substituted —C1-12 alkyl-, optionally substituted —C2-12 alkenyl-, optionally substituted —C2-12 alkynyl-, optionally substituted —C1-6 alkyl-O—C1-6 alkyl-, optionally substituted —C1-6 alkyl-NRa—C1-6 alkyl-, optionally substituted —C1-6 alkyl-(C3-6 cycloalkyl)-C1-6 alkyl-, optionally substituted —C1-6 alkyl-phenyl-C1-6 alkyl-, optionally substituted —C1-6 alkyl-(4-6 membered heterocycloalkyl)-C1-6 alkyl-, or optionally substituted —C1-6 alkyl-(5-6 membered heteroaryl)-C1-6 alkyl-,
• wherein the alkyl moiety of said optionally substituted —C1-12 alkyl-, optionally substituted —C1-6 alkenyl-, optionally substituted —C2-12 alkynyl-, optionally substituted —C1-6 alkyl-O—C1-6 alkyl-, optionally substituted —C1-6 alkyl-NRa—C1-6 alkyl-, optionally substituted —C1-6 alkyl-(C3-6 cycloalkyl)-C1-6 alkyl-, optionally substituted —C1-6 alkyl-phenyl-C1-6 alkyl-, optionally substituted —C1-6 alkyl-(4-6 membered heterocycloalkyl)-C1-6 alkyl-, or optionally substituted —C1-6 alkyl-(5-6 membered heteroaryl)C1-6 alkyl- is optionally substituted by 1 or 2 substituents each independently selected from halogen, halo(C1-4 alkyl), —OH, —O—P(O)(OH)2, —O—P(O)(RIRII)2, —ORc, —NH2, —NRcRd, —OCORc, —CO2H, —CO2Rc, —SORc, —SO2Rc, —CONH2, —CONRcRd, —SO2NH2, —SO2NRcRd, —OCONH2, —OCONRcRd, —NRdCORc, —NRdSORc, —NRdCO2R, and —NRdSO2R, and
• the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted —C1-6 alkyl-(C3-6 cycloalkyl)-C1-6 alkyl-, optionally substituted —C1-6 alkyl-phenyl-C1-6 alkyl-, optionally substituted —C1-6 alkyl-(4-6 membered heterocycloalkyl)-C1-6 alkyl-, or optionally substituted —C1-6 alkyl-(5-6 membered heteroaryl)-C1-6 alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH)2, O—P(O)(RIRII)2, amino, (C1-4 alkyl)amino-, (C1-4 alkyl)(C1-4 alkyl)amino-, C1-4 alkyl, halo(C1-4 alkyl), halo(C1-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, —(C2-4 alkoxy)-O—P(O)(OH)2, —(C2-4 alkoxy)-O—P(O)(RIRII)2, and C1-4 alkoxy-(C1-4 alkoxy)-;
• R3 and R5 are each independently —CON(Rd)(Rf), —CH2N(Rd)(Rf), —N(Rd)(Rf), —N(Rd)CO(Rf), —CH2N(Rd)CO(Rf), or
• one of R3 and R5 is —CON(Rd)(Rf), —CH2N(Rd)(Rf), —N(Rd)(Rf), —N(Rd)CO(Rf), or —CH2N(Rd)CO(Rf), and the other of R3 and R5 is H, COOH, or —CO2Rc;
• R4 and R6 are each independently selected from H, halogen, halo(C1-6 alkyl), halo(C1-6 alkoxy)-, hydroxy, —O—P(O)(OH)2, O—P(O)(RIRII)2, —NH2, —NRcRd, —NRcRd, —CORc, —CO2Rc, —N(Rd)CORc, —N(Rd)SO2Rc, —N(Rg)SO2(C1-2 alkyl)-N(Rh)(Rf), —N(Rg)CO(C1-2 alkyl)-N(Rh)(Rf), optionally substituted (C1-6 alkyl), optionally substituted (C1-6 alkyl)oxy-, optionally substituted (C1-6 alkyl)amino-, and optionally substituted (C1-6 alkyl)(C1-4 alkyl)amino-,
• wherein the (C1-6 alkyl) of said optionally substituted (C1-6 alkyl), optionally substituted (C1-6 alkyl)oxy-, optionally substituted (C1-6 alkyl)amino- and optionally substituted (C1-6 alkyl)(C1-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from —OH, —O—P(O)(OH)2, —O—P(O)(RIRII)2, —ORc, —NH2—NRcRc, —NRcRd, —CO2H, —CO2Rc, —OCORc, —CO2H, —CO2Rc, —SORc, —SO2Rc—CONH2, —CONRcRd, —SO2NH2, —SO2NRcRd, —OCONH2, —OCONRcRd, —NRdCORc, —NRdSORc, —NRdCO2Rc, —NRdSO2Rc, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH)2, —O—P(O)(RIRII)2, amino, (C1-4 alkyl)amino-, (C1-4 alkyl)(C1-4 alkyl)amino-, C1-4 alkyl, halo(C1-4 alkyl), hydroxy-(C1-4 alkyl)-, —(C1-4 alkyl)-O—P(O)(OH)2, —(C1-4 alkyl)-O—P(O)(RIRII)2, halo(C1-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, —(C2-4 alkoxy)-O—P(O)(OH)2, —(C2-4 alkoxy)-O—P(O)(RIRII)2, C1-4 alkoxy-(C1-4 alkoxy)-, —CORd, —CON(Rd)(Rf), and —CO2Rd,
• R14 is absent, H, halogen, or optionally substituted C1-4 alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, —ORc, —NRcRd, —CO2Rc, —CONRcRd, —SO2NRcRd, and —OCONRcRd;
• R16 is absent, H, halogen, or C1-4 alkyl;
• R15 and R17 are each independently absent, H, cyclopropyl, halogen or optionally substituted C1-4 alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, —ORc, —NRcRd, —CO2Rc, —CONRcRd, —SO2NRcRd, and —OCONRcRd;
• or R15 and R19 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring;
• or R16 and R17 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring;
• R18 and R19 are each independently absent, H, halogen, optionally substituted C1-4 alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, —ORc, —NRcRd, —CO2Rc, —CONRcRd, —SO2NRcRd, and —OCONRcRd;
• or R17 and R18 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring;
• Ra is H, —Rc, —CORc, —CO2H, —CO2Rc, —SORc, —SO2Rc—CONH2, —CONRcRd, —SO2NH2, —CH2—CO2Rc, or —SO2NRcRd;
• each Rb is independently C1-4 alkyl, halo(C1-4 alkyl), —(C1-4 alkyl)-OH, —(C1-4 alkyl)-O—P(O)(OH)2, —(C1-4 alkyl)-O—P(O)(RIRII)2, —(C1-4 alkyl)-O—(C1-4 alkyl), —(C1-4 alkyl)-N(Re)(Rf), —(C1-4 alkyl)-O—CO(C1-4 alkyl), or —(C1-4 alkyl)-CO—O—(C1-4 alkyl);
• each Rc is independently H, C1-4 alkyl, halo(C1-4 alkyl), —(C1-4 alkyl)-OH, —(C1-4 alkyl)-O—P(O)(OH)2, —(C1-4 alkyl)-O—P(O)(RIRII)2, —(C1-4 alkyl)-O—(C1-4 alkyl), —(C1-4 alkyl)-N(Re)(Rf), —(C1-4 alkyl)-O—CO(C1-4 alkyl), —(C1-4 alkyl)-CO—O—(C1-4 alkyl), optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally substituted —C1-4 alkyl-C3-6 cycloalkyl, optionally substituted —C1-4 alkyl-phenyl, optionally substituted —C1-4 alkyl-4-6 membered heterocycloalkyl, optionally substituted —C1-4 alkyl-5-6 membered heteroaryl, or optionally substituted —C1-4 alkyl-9-10 membered heteroaryl,
• wherein the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or 9-10 membered heteroaryl moiety of said optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally substituted —C1-4 alkyl-C3-6 cycloalkyl, optionally substituted —C1-4 alkyl-phenyl, optionally substituted —C1-4 alkyl-4-6 membered heterocycloalkyl, optionally substituted —C1-4 alkyl-5-6 membered heteroaryl, or optionally substituted —C1-4 alkyl-9-10 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH)2, —O—P(O)(RR)2, amino, (C1-4 alkyl)amino-, (C1-4 alkyl)(C1-4 alkyl)amino-, C1-4 alkyl, halo(C1-4 alkyl), halo(C1-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, —(C2-4 alkoxy)-O—P(O)(OH)2, —(C2-4 alkoxy)-O—P(O)(RIRII)2, C1-4 alkoxy-(C1-4 alkoxy)-, —CORd, —CON(Rd)(Rf), and —CO2Rd;
• each Rd is independently H, hydroxy, or C1-4 alkyl;
• each Re is independently H, (C1-4 alkyl), —CO(C1-4 alkyl), —OCO(C1-4 alkyl), —CO2(C1-4 alkyl), —(C1-4 alkyl)amino, —(C1-4 alkyl)-C1-4 alkoxy, —CO-(optionally substituted 5-6 membered heterocycloalkyl), —CO—(C1-4 alkyl)-(optionally substituted 5-6 membered heterocycloalkyl), —CO-(optionally substituted 5-6 membered heteroaryl), —CO—(C1-4 alkyl)-(optionally substituted 5-6 membered heteroaryl),
• wherein the optionally substituted 5-6 membered heterocycloalkyl or optionally substituted 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH)2, —O—P(O)(RIRII)2, amino, (C1-4 alkyl)amino-, (C1-4 alkyl)(C1-4 alkyl)amino-, C1-4 alkyl, halo(C1-4 alkyl), halo(C1-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, —(C2-4 alkoxy) O—P(O)(OH)2, —(C2-4 alkoxy)-O—P(O)(R1R)2, C1-4 alkoxy-(C1-4 alkoxy)-, —CORd, —CON(Rd)(Rf), and —CO2Rd;
• each R is independently H, hydroxy, or (C1-4 alkyl);
• Rg and Rh are each independently H or (C1-4 alkyl) or R9 and Rh, taken together with the atom or atoms through which they are connected, form a 5-6 membered ring;
• and
• each RI and RII are independently (C1-6 alkyl)oxy-;
• provided that at least one of (i), (ii), or (iii), applies:
• (i) when s is 0, r is 1, (a) Z1, Z2, Y1 and Y2 are each N, W1, W2, X1 and X2 are each C;
• or (b) W1, W2, X1 and X2 are each N, Z1, Z2, Y1 and Y2 are each C;
• or (c) Z1 and Y1 are each N, W1 and X1 are each C;
• or (d) Z2 and Y2 are each N, W2 and X2 are each C;
• or (e) W1 and X1 are each N, Z1 and Y1 are each C;
• or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S or X9 is N;
• or
• (ii) when s is 0, r is 1, (a) Z1, Z2, Y1 and Y2 are each N, W1, W2, X1 and X2 are each C;
• or (b) W1, W2, X1 and X2 are each N, Z1, Z2, Y1 and Y2 are each C, then R14 is a C1-4 alkyl substituted with halogen, —OR, —NRcRd, —CO2R, —CONRcRd, —SO2NRcRd, and —OCONRcRd wherein R is H;
• or
• (iii) when s is 0, r is 1, (a) Z1 and Y1 are each N, W1 and X1 are each C;
• or (b) Z2 and Y2 are each N, W2 and X2 are each C;
• or (c) W1 and X1 are each N, Z1 and Y1 are each C;
• or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, X6, and X9 is N and RA1 or RA2 is halogen, hydroxy, optionally substituted (C1-6 alkyl), substituted (C1-6 alkyl)oxy-, optionally substituted (C1-6 alkyl)amino-, or optionally substituted (C1-6 alkyl)(C1-4 alkyl)amino-,
• wherein the (C1-6 alkyl) of said optionally substituted (C1-6 alkyl), substituted (C1-6 alkyl)oxy-, optionally substituted (C1-6 alkyl)amino-, or optionally substituted (C1-6 alkyl)(C1-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, —O—P(O)(OH)2, —O—P(O)(RIRII)2, —N(Re)(Rf), —CO2(Rf), —CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH)2, —O—P(O)(RIRII)2, amino, (C1-6 alkyl)amino-, (C1-6 alkyl)(C1-6 alkyl)amino-, —(C1-6 alkyl)-NH2, halo(C1-6 alkyl), hydroxy-(C1-4 alkyl)-, —(C1-4 alkyl)-O—P(O)(OH)2, —(C1-4 alkyl)-O—P(O)(RIRII)2, halo(C1-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, —(C2-4 alkoxy)-O—P(O)(OH)2, —(C2-4 alkoxy)-O—P(O)(RR)2, —C1-4 alkyl-(C1-4 alkoxy), and C1-4 alkoxy-(C1-4 alkoxy)-.