COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH STING ACTIVITY

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;

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, and that the six-membered ring comprising Z, Y 1 , Y 2 , and Y 3 is aryl or heteroaryl;

each occurrence of R 1 and R 5 is independently selected from the group consisting of: H; R c ; R g ; and -(L 1 ) b1 -R g ;

each occurrence of R 2 and R 4 is independently selected from the group consisting of: H; R d ; R g ; and -(L 2 ) b2 -R g ;

R 6 is selected from the group consisting of: H; R d ; and R h , L B is selected from the group consisting of:

C 1-6 alkylene, C 2-6 alkenylene, or C 2-6 alkynylene, each of which is optionally substituted with 1-6 R a1 ;

monocyclic C 3-8 cycloalkylene or C 3-8 cycloalkenylene, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R c ; and

monocyclic heterocyclylene or heterocycloalkenylene of 3-8 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 , provided that the heterocycloylene or heterocycloalkenylene 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 R g ;

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′,

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 optionally substituted with 1-6 substituents independently selected from the group consisting of: —OH, NR′R″, C 1-4 alkoxy, C 1-4 haloalkoxy, cyano, and C 3-6 cycloalkyl optionally substituted with 1-2 independently selected halo; C 1-4 haloalkyl; C 1-4 alkoxy; C 1-4 haloalkoxy; halo; cyano; —OH; —NR′R″; and C 3-6 cycloalkyl optionally substituted with 1-2 independently selected halo;

each occurrence of L 1 , L 2 , and L 9 is 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 1 and R″ is independently selected from the group consisting of: H; —OH; and C 1-4 alkyl.

2 . The compound of claim 1 , wherein the compound is a compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein: R 1a , R 1b , R 1c , and R 1d are each an independently selected R 1 .

3 . 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 .

4 . The compound of any one of claims 1 - 3 , wherein X 1 is NR 2 ; and X 2 is CR 5 , optionally wherein X 1 is NH; and X 2 is CH.

5 . The compound of any one of claims 1 - 4 , wherein 1-2 R 1 is independently selected from the group consisting of: R 1 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 , optionally:

wherein each R 1 is independently selected from the group consisting of: halo; cyano; C 1-3 alkyl; C 1-4 alkoxy; and C 1-4 haloalkoxy, such as —F, —Cl, or —CN, such as wherein each R 1 is independently —F or —Cl, such as —F; and

each R g1 is heteroaryl of 5-10 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 substituents independently selected from the group consisting of R c , R h , and -(L g ) bg -R h .

6 . The compound of claim 2 , 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

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

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 5-6, 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 h or -(L g ) bg -R h , such as R h or —CH 2 R h , and further optionally substituted with 1-2 R c ; or

wherein R 1a is H; R 1d is halo, such as —F or —Cl; R 1c is H; and R 1b is R g .

7 . The compound of any one of claims 1 - 6 , wherein L B is C 1-6 alkylene, C 2-6 alkenylene, or C 2-6 alkynylene, each of which is optionally substituted with 1-6 R a1 .

8 . The compound of any one of claims 1 - 6 , wherein L B is selected from the group consisting of:

monocyclic C 3-8 cycloalkylene or cycloalkenylene, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R c ; and

monocyclic heterocyclylene or heterocycloalkenylene of 3-8 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 , provided that the heterocycloylene or heterocycloalkenylene is attached to the C(═O)NR 6 group via a ring carbon atom.

9 . The compound of any one of claims 1 - 8 , wherein a1 is 0; or wherein a1 is 1, and optionally wherein L A is —O—, —S(O) 2 —, C(═O), or CH 2 , such as —O—.

10 . The compound of any one of claims 1 - 9 , wherein Ring C is selected from the group consisting of:

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 ; such as:

wherein Ring C is selected from the group consisting of:

heteroaryl of 5-10 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 ; such as:

wherein Ring C is selected from the group consisting of:

heteroaryl of 5-6 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 aryl optionally substituted with 1-4 R c .

11 . The compound of claim 1 , wherein the compound is a compound of Formula (I-a1-1):

or a pharmaceutically acceptable salt thereof; or

wherein the compound is a compound of Formula (I-a1-2):

or a pharmaceutically acceptable salt thereof, optionally wherein L A is —O— or S(O) 2 , such as —O—.

12 . The compound of claim 1 , wherein the compound is a compound of Formula (I-2):

or a pharmaceutically acceptable salt thereof, wherein:

L q is CH 2 or a bond; and

each one of Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is independently CH, CR i , or N, provided that no more than 3 of Q 1 -Q 5 is N, and no more than 4 of Q 1 -Q 5 is CR i .

13 . 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.

14 . A pharmaceutical composition comprising a compound of claims 1 - 13 and one or more pharmaceutically acceptable excipients.

15 . A method for inhibiting STING activity, the method comprising contacting STING with a compound as claimed in any one of claims 1 - 13 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 14 .

16 . 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 - 13 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 14 .

17 . 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 - 13 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 14 .