COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH STING ACTIVITY
This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:
Z, Y 1 , Y 2 , and Y 3 are independently selected from the group consisting of CR 1 , C(═O), N, and NR 2 ;
X 1 is selected from the group consisting of O, S, N, NR 2 , and CR 1 ;
X 2 is selected from the group consisting of O, S, N, NR 4 , and CR 5 ;
provided that when each one of Z, Y 1 , and Y 2 is CR 1 , then Y 3 cannot be N, or
when each one of Z, Y 1 , Y 2 , and Y 3 is CR 1 , then at least one R 1 is other than H;
each is independently a single bond or a double bond, provided that the five-membered ring comprising X 1 and X 2 is heteroaryl, and that the six-membered ring comprising Z, Y 1 , Y 2 , and Y 3 is aryl or heteroaryl;
each R 1 is independently selected from the group consisting of: H; R e ; R g ; and -(L 1 ) b1 -R g ;
each R 2 is independently selected from the group consisting of: H; R d ; R g ; and -(L 2 ) b2 -R g ,
R 4 is selected from the group consisting of: H and R d ;
R 5 is selected from the group consisting of: H; R c ; and R h ,
R 6 is selected from the group consisting of: H; R d ; and R h ,
Ring B is a heteroarylene of 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R d ), O, and S, wherein the heteroarylene of Ring B is optionally substituted with 1-2 substituents independently selected from the group consisting of: oxo and R c , provided that Ring B is attached to the C(═O)NR 6 group via a ring carbon atom;
each L A is independently selected from the group consisting of: C 1-3 alkylene optionally substituted with 1-4 R a1 ; —O—; —NH—; —NR d ; —S(O) 0-2 ; and C(O);
a1 is 0, 1, 2, or 3;
Ring C is selected from the group consisting of:
C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R c ;
heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R c ;
heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R c ; and
C 6-10 aryl optionally substituted with 1-4 R c ;
each occurrence of R a and R a1 is independently selected from the group consisting of: —OH; -halo; —NR e R f ; C 1-4 alkoxy; C 1-4 haloalkoxy; —C(═O)O(C 1-4 alkyl); —C(═O)(C 1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O) 1-2 NR′R″; —S(O) 1-2 (C 1-4 alkyl); and cyano;
each occurrence of R c is independently selected from the group consisting of: halo; cyano; C 1-10 alkyl which is optionally substituted with 1-6 independently selected R a ; C 2-6 alkenyl; C 2-6 alkynyl; C 1-4 alkoxy; C 1-4 haloalkoxy; —S(O) 1-2 (C 1-4 alkyl); —S(O)(═NH)(C 1-4 alkyl); —NR e R f ; —OH; —S(O) 1-2 NR′R″; —C 1-4 thioalkoxy; —NO 2 ; —C(═O)(C 1-10 alkyl); —C(═O)O(C 1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF 5 ;
each occurrence of R d is independently selected from the group consisting of: C 1-6 alkyl optionally substituted with 1-3 independently selected R a ; —C(O)(C 1-4 alkyl); —C(O)O(C 1-4 alkyl); —CONR′R″; —S(O) 1-2 NR′R″; —S(O) 1-2 (C 1-4 alkyl); —OH; and C 1-4 alkoxy;
each occurrence of R e and R f is independently selected from the group consisting of: H; C 1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, and R i ; —C(O)(C 1-4 alkyl); —C(O)O(C 1-4 alkyl); —CONR′R″; —S(O) 1-2 NR′R″; —S(O) 1-2 (C 1-4 alkyl); —OH; and C 1-4 alkoxy;
each occurrence of R g is independently selected from the group consisting of:
C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c , R h , and -(L g ) bg -R h ;
heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c , R h , and -(L g ) bg -R h ;
heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R c , R h , and -(L g ) bg -R h ; and
C 6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R c , R h , and -(L g ) bg -R h ;
each occurrence of R h is independently selected from the group consisting of:
C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each of which is optionally substituted with 1-4 R i ;
heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R i ;
heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R i ; and
C 6-10 aryl optionally substituted with 1-4 R i ;
each occurrence of R i is independently selected from the group consisting of: C 1-6 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-6 alkyl-O—C 1-6 alkyl-; C 1-4 haloalkyl-O—C 1-6 alkyl-; halo; cyano; —OH; —NR′R″; and C 3-6 cycloalkyl;
each occurrence of L 1 , L 2 , and L g is independently selected from the group consisting of: —O—, —NH—, —NR d , —S(O) 0-2 , C(O), and C 1-3 alkylene optionally substituted with 1-3 R a ;
b1, b2, and bg are each independently 1, 2, or 3; and
each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C 1-4 alkyl.
2 . A compound of Formula II:
or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:
X 1 is selected from the group consisting of O, S, N, NR 2 , and CR 1 ;
X 2 is selected from the group consisting of O, S, N, NR 4 , and CR 5 ;
each is independently a single bond or a double bond, provided that the five-membered ring comprising X 1 and X 2 is heteroaryl;
R 1 is selected from the group consisting of: H; R c ; R g ; and -(L) b1 -R g ;
R 2 is selected from the group consisting of: H; R d ; R g ; and -(L 2 ) b2 -R g ;
R 4 is selected from the group consisting of: H and R d ;
R 5 is selected from the group consisting of: H; R c ; and R h ;
R 6 is selected from the group consisting of: H; R d ; and R h ;
Ring B is a heteroarylene of 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R d ), O, and S, wherein the heteroarylene of Ring B is optionally substituted with 1-2 substituents independently selected from the group consisting of: oxo and R c , provided that Ring B is attached to the C(═O)NR 6 group via a ring carbon atom;
each L A is independently selected from the group consisting of: C 1-3 alkylene optionally substituted with 1-4 R a1 ; —O—; —NH—; —NR d ; —S(O) 0-2 ; and C(O);
a1 is 0, 1, 2, or 3;
Ring C is selected from the group consisting of:
C 3-12 cycloalkylene or C 3-12 cycloalkenylene, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R c ,
heterocyclylene or heterocycloalkenylene of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R c ,
heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroarylene is optionally substituted with 1-4 R c ; and
C 6-10 aryl optionally substituted with 1-4 R c ;
each occurrence of R a and R a1 is independently selected from the group consisting of: -halo; —NR e R f ; C 1-4 alkoxy; C 1-4 haloalkoxy; —C(═O)O(C 1-4 alkyl); —C(═O)(C 1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O) 1-2 NR′R″; —S(O) 1-2 (C 1-4 alkyl); and cyano;
each occurrence of R c is independently selected from the group consisting of: halo; cyano; C 1-10 alkyl which is optionally substituted with 1-6 independently selected R a ; C 2-6 alkenyl; C 2-6 alkynyl; C 1-4 alkoxy; C 1-4 haloalkoxy; —S(O) 1-2 (C 1-4 alkyl); —S(O)(═NH)(C 1-4 alkyl); —NR e R f ; —OH; —S(O) 1-2 NR′R″; —C 1-4 thioalkoxy; —NO 2 ; —C(═O)(C 1-10 alkyl); —C(═O)O(C 1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF 5 ;
each occurrence of R d is independently selected from the group consisting of: C 1-6 alkyl optionally substituted with 1-3 independently selected R a ; —C(O)(C 1-4 alkyl); —C(O)O(C 1-4 alkyl); —CONR′R″; —S(O) 1-2 NR′R″; —S(O) 1-2 (C 1-4 alkyl); —OH; and C 1-4 alkoxy;
each occurrence of R e and R f is independently selected from the group consisting of: H; C 1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, and R i ; —C(O)(C 1-4 alkyl); —C(O)O(C 1-4 alkyl); —CONR′R″; —S(O) 1-2 NR′R″; —S(O) 1-2 (C 1-4 alkyl); —OH; and C 1-4 alkoxy;
each occurrence of R g is independently selected from the group consisting of:
C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c , R h , and -(L g ) bg -R h ;
heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c , R h , and -(L g ) bg -R h ;
heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R c , R h , and -(L g ) bg -R h ; and
C 6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R c , R h , and -(L g ) bg -R h ;
each occurrence of R h is independently selected from the group consisting of:
C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each of which is optionally substituted with 1-4 R i ;
heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R i ;
heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R i ; and
C 6-10 aryl optionally substituted with 1-4 R i ;
each occurrence of R i is independently selected from the group consisting of: C 1-6 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-6 alkyl-O—C 1-6 alkyl-; C 1-4 haloalkyl-O—C 1-6 alkyl-; halo; cyano; —OH; —NR′R″; and C 3-6 cycloalkyl;
each occurrence of L 1 , L 2 , and L g is independently selected from the group consisting of: —O—, —NH—, —NR d , —S(O) 0-2 , C(O), and C 1-3 alkylene optionally substituted with 1-3 R a ;
b1, b2, and bg are each independently 1, 2, or 3; and
each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C 1-4 alkyl;
provided that:
1) Ring C is other than: unsubstituted morpholinyl, unsubstituted pyrrolidinyl, unsubstituted tetrahydrofuranyl, unsubstituted cyclopentyl, monosubstituted oxetanyl, methylfuranyl, unsubstituted thiophenyl, or methylpyrrolyl; or
2) -(L A ) a1 -Ring C is other than: unsubstituted benzyl or phenyl that is optionally substituted with one substituent selected from the group consisting of: —F, —OMe, and -OEt.
3 . A compound of Formula IT
or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:
X 1 is selected from the group consisting of O, S, N, NR 2 , and CR 1 ;
X 2 is selected from the group consisting of O, S, N, NR 4 , and CR 5 ;
each is independently a single bond or a double bond, provided that the five-membered ring comprising X 1 and X 2 is heteroaryl;
R 1 , R 1a , R 1b , and R 1c are each independently selected from the group consisting of: H; R c ; R g ; and -(L 1 ) b1 -R g ;
R 2 is independently selected from the group consisting of: H; R d ; R g ; and -(L 2 ) b2 -R g ;
R 4 is selected from the group consisting of: H and R d ,
R 5 is selected from the group consisting of: H; R c ; and R h ,
R 6 is selected from the group consisting of: H; R d ; and R h ,
Ring B is a heteroarylene of 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R d ), O, and S, wherein the heteroarylene of Ring B is optionally substituted with 1-2 substituents independently selected from the group consisting of: oxo and R c , provided that Ring B is attached to the C(═O)NR 6 group via a ring carbon atom;
each L A is independently selected from the group consisting of: C 1-3 alkylene optionally substituted with 1-4 R a1 ; —O—; —NH—; —NR d ; —S(O) 0-2 ; and C(O);
a1 is 0, 1, 2, or 3;
Ring C is selected from the group consisting of:
C 3-12 cycloalkylene or C 3-12 cycloalkenylene, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R c ,
heterocyclylene or heterocycloalkenylene of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R c ,
heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroarylene is optionally substituted with 1-4 R c ; and
C 6-10 arylene optionally substituted with 1-4 R c ;
each occurrence of R a and R a1 is independently selected from the group consisting of: -halo; —NR e R f ; C 1-4 alkoxy; C 1-4 haloalkoxy; —C(═O)O(C 1-4 alkyl); —C(═O)(C 1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O) 1-2 NR′R″; —S(O) 1-2 (C 1-4 alkyl); and cyano;
each occurrence of R c is independently selected from the group consisting of: halo; cyano; C 1-10 alkyl which is optionally substituted with 1-6 independently selected R a ; C 2-6 alkenyl; C 2-6 alkynyl; C 1-4 alkoxy; C 1-4 haloalkoxy; —S(O) 1-2 (C 1-4 alkyl); —S(O)(═NH)(C 1-4 alkyl); —NR e R f ; —OH; —S(O) 1-2 NR′R″; —C 1-4 thioalkoxy; —NO 2 ; —C(═O)(C 1-10 alkyl); —C(═O)O(C 1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF 5 ;
each occurrence of R d is independently selected from the group consisting of: C 1-6 alkyl optionally substituted with 1-3 independently selected R a ; —C(O)(C 1-4 alkyl); —C(O)O(C 1-4 alkyl); —CONR′R″; —S(O) 1-2 NR′R″; —S(O) 1-2 (C 1-4 alkyl); —OH; and C 1-4 alkoxy;
each occurrence of R e and R f is independently selected from the group consisting of: H; C 1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, and R i ; —C(O)(C 1-4 alkyl); —C(O)O(C 1-4 alkyl); —CONR′R″; —S(O) 1-2 NR′R″; —S(O) 1-2 (C 1-4 alkyl); —OH; and C 1-4 alkoxy;
each occurrence of R g is independently selected from the group consisting of:
C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c , R h , and -(L g ) bg -R h ;
heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c , R h , and -(L g ) bg -R h ;
heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R c , R h , and -(L g ) bg -R h ; and
C 6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R c , R h , and -(L g ) bg -R h ;
each occurrence of R h is independently selected from the group consisting of:
C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each of which is optionally substituted with 1-4 R i ;
heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R i ;
heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R i ; and
C 6-10 aryl optionally substituted with 1-4 R i ;
each occurrence of R i is independently selected from the group consisting of: C 1-6 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-6 alkyl-O—C 1-6 alkyl-; C 1-4 haloalkyl-O—C 1-6 alkyl-; halo; cyano; —OH; —NR′R″; and C 3-6 cycloalkyl;
each occurrence of L 1 , L 2 , and L g is independently selected from the group consisting of: —O—, —NH—, —NR d , —S(O) 0-2 , C(O), and C 1-3 alkylene optionally substituted with 1-3 R a ;
b1, b2, and bg are each independently 1, 2, or 3; and
each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C 1-4 alkyl;
provided that when Ring B is unsubstituted
wherein aa is the point of connection to (L A ) a1 ; and (L A ) a1 is unsubstituted CH 2 , then Ring C is other than unsubstituted pyridyl, unsubstituted pyrrolyl, or phenyl which is optionally substituted with one substituent selected from the group consisting of: —F, —Cl, -Me, —OMe, or —CN.
4 . The compound of claim 1 , wherein the compound is a compound of Formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein: Ria, R 1b , R 1c , and R 1d are each an independently selected R 1 .
5 . The compound of claim 1 , wherein one of Z, Y 1 , and Y 2 is N; and each remaining one of Z, Y 1 , Y 2 , and Y 3 is an independently selected CR 1 .
6 . The compound of any one of claims 1 - 5 , wherein X 1 is NR 2 ; and X 2 is CR 5 , such as: wherein X 1 is NH; and X 2 is CH.
7 . The compound of any one of claims 1 - 6 , wherein 1-2 R 1 is independently selected from the group consisting of: R c1 and R g1 ; and each remaining R 1 is H, wherein R c1 is an independently selected R c ; and R g1 is an independently selected R g .
8 . The compound of claim 7 , wherein each R c1 is an independently selected halo or cyano, such as —F, —Cl, or —CN, such as —F or —Cl, such as —F; and each R g1 is independently heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 R c .
9 . The compound of claim 4 , wherein R 1a and R 1d are H; and R 1b and R 1c are independently selected halo, such as —F or —Cl, such as —F, such as wherein R 1b and R 1c are —F; or wherein R 1b is —F; and R 1c is —Cl; or wherein R 1b is —Cl; and R 1c is —F; or
wherein R 1a and R 1d are H; one of R 1b and R 1c is H; and the other one of R 1b and R 1c is halo, such as —F or —Cl, such as —F, such as wherein R 1c is H, and R 1b is halo; or wherein R 1c is halo, and R 1b is H; or
wherein R 1a and R 1d are H; R 1c is halo or H, such as —F, —Cl, or H; and R 1b is heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 R c ; or
R 1a and R 1d are H; R 1c is halo or H, such as —F, —Cl, or H; and R 1b is heteroaryl of 5-6, such as 5, ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein the heteroaryl is substituted with one occurrence of R h1 or -(L g ) bg -R h and further optionally substituted with 1-2 R c ; or
wherein R 1a and R 1d are H; R 1c is halo or H, such as —F, —Cl, or H; and R 1b is phenyl optionally substituted with 1-4 R c , such as phenyl optionally substituted with 1-2 substituents each independently selected from the group consisting of: C 1-6 alkyl optionally substituted with 1-6 R a ; -halo; -cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy.
10 . The compound of any one of claims 1 - 9 , wherein Ring B has Formula B1 or B2:
wherein:
B 4 is C or N;
B 1 , B 2 , and B 3 are each independently CH, CR c , NH, N(R d ), N, O, or S;
provided that 0-2 of B 1 , B 2 , and B 3 is CR c ;
aa is the point of attachment to (L A ) a1 ; and
each is independently a single bond or a double bond provided that the ring including B 1 -B 4 is a heteroaryl.
11 . The compound of claim 10 , wherein Ring B has Formula B1, optionally wherein: Ring B selected from the group consisting of:
12 . The compound of claim 10 , wherein Ring B has Formula B2, optionally wherein the heteroarylene of Ring B is
each of which is optionally substituted with R c .
13 . The compound of any one of claims 1 - 12 , wherein a1 is 0; or wherein a1 is 1, and optionally wherein L A is C 1-3 alkylene, such as CH 2 or CH(Me), optionally substituted with 1-4 R a1 .
14 . The compound of any one of claims 1 - 13 , wherein Ring C is selected from the group consisting of:
heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R c ; and
C 6-10 aryl optionally substituted with 1-4 R c ; such as:
wherein Ring C is selected from the group consisting of:
heteroaryl of 5-6 ring atoms, wherein 1-3, such as 1-2, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R C ; and
phenyl optionally substituted with 1-4 R C ;
such as:
Ring C is
wherein Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are independently CH, CR c , or N, provided that at least two of Q 1 -Q 5 are CH.
15 . The compound of claim 1 , wherein the compound is a compound of Formula (Ia-1-1):
or a pharmaceutically acceptable salt thereof, wherein:
B 4 is C or N;
B 1 , B 2 , and B 3 are each independently CH, CR c , NH, N(R d ), N, O, or S;
provided that 0-2 of B 1 , B 2 , and B 3 is CR c ;
each is independently a single bond or a double bond provided that the ring including B 1 -B 4 is a heteroaryl; and
Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are independently CH, CR c , or N, provided that at least two of Q 1 -Q 5 are CH.
16 . The compound of claim 1 , wherein the compound is selected from the group consisting of the compounds delineated in Table C1, or a pharmaceutically acceptable salt thereof.
17 . A pharmaceutical composition comprising a compound of claims 1 - 16 and one or more pharmaceutically acceptable excipients.
18 . A method for inhibiting STING activity, the method comprising contacting STING with a compound as claimed in any one of claims 1 - 16 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 17 .
19 . A method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as claimed in any one of claims 1 - 16 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 17 .
20 . A method of treatment of disease, disorder, or condition associated with STING, such as a disease, disorder, or condition, in which increased STING signaling, such as excessive STING signaling, contributes to the pathology and/or symptoms and/or progression of the disease, such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 16 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 17 .