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:

L A is -(L 1 ) a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4 ) a4 -(L 5 ) a5 -*, wherein * represents the point of attachment to Q 1 ;

a1, a2, a3, a4, and a5 are each independently 0 or 1,

provided that a1+a2+a3+a4+a5≥1, and

each of L 1 , L 3 , and L 5 is independently selected from the group consisting of: —O—, —N(H)—, —N(R d )—, S(O) 0-2 , and —C(═O)—;

provided that when one or both of a2 and a4 is 0, then the combinations of L 1 , L 3 , and L 5 cannot form O—O, N—O, N—N, O—S, S—S, or N—S(O) 0 bonds, and

further provided that L A cannot include a cyclic group directly attached to the 6-membered ring containing Y 1 , Y 2 , and Y 3 ;

each of L 2 and L 4 is independently selected from the group consisting of:

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

C 3-10 cycloalkylene or C 3-10 cycloalkenylene, each of which is optionally substituted with 1-3 R c provided the C 3-10 cycloalkylene or C 3-10 cycloalkenylene is not directly connected to the 6-membered ring containing Y 1 , Y 2 , and Y 3 ; and

heterocyclylene or heterocycloalkenylene, each having 4-10 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R d ), O, and S(O) 0-2 , wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-3 R c , provided the heterocyclylene or heterocycloalkenylene is not directly connected to the 6-membered ring containing Y 1 , Y 2 , and Y 3 ;

Q 1 is —R g ;

Y 1 , Y 2 , and Y 3 are each 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 ;

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 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 g ) bg -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 g ) bg -R g ;

R 6 is selected from the group consisting of: H; R d ; and R g ;

W is selected from the group consisting of:

(i)

Ring B1 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 B1 is optionally substituted with 1-2 substituents independently selected from the group consisting of oxo and R c , provided that Ring B1 is attached to the C(═O)NR 6 group via a ring carbon atom;

each L AA is independently selected from the group consisting of: C 1-3 alkylene optionally substituted with 1-2 R a ; —O—; —NH—; —NR d ; —S(O) 0-2 ; and C(O);

aa1 is 0, 1, or 2;

Ring C 1 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, R c , and (L AA ) aa1 -R g ;

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, R c , and (L AA ) aa1 -R g ;

heteroarylene 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 heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of R c and (L AA ) aa1 -R g ; and

C 6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of R c and (L AA ) aa1 -R g ;

R 7 is selected from the group consisting of: R g and -(L 7 ) b7 -R g ;

each L 7 is independently selected from the group consisting of: C 1-3 alkylene optionally substituted with 1-2 R a1 ; —O—; —NH—; —NR d ; —S(O) 0-2 ; and C(O); and

b7 is 1, 2, or 3;

Ring B2 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 AB 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);

aa2 is 0, 1, 2, or 3;

Ring C 2 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 ;

(iii) heteroaryl of 5 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 ; provided the heteroaryl is attached to the C(═O)NR 6 group via a ring carbon atom;

P 1 , P 2 , P 3 , P 4 , and P 5 are each independently selected from the group consisting of: N, NH, NR d , NR 71 , CH, CRC, CR 71 , and C(═O);

each occurrence of R 71 is independently -(L AC ) aa3 -R 8 , wherein:

each L AC is independently selected from the group consisting of: C 1-3 alkylene optionally substituted with 1-4 R a ; —O—; —NR N ; —S(O) 0-2 ; C(O); C(O)O; OC(O); NR N C(O); C(O)NR N ;

NR N C(O)NR N ; NR N C(O)O; and OC(O)NR N ;

aa3 is 0, 1, 2, or 3;

each occurrence of R 8 is independently R g or C 1-10 alkyl optionally substituted with 1-6 R a1 ; and

each occurrence of R N is independently H or R d ;

(v) a bicyclic or polycyclic ring system selected from the group consisting of:

bicyclic or polycyclic C 5-15 cycloalkyl or C 5-15 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c , and -(L AD ) bB -R g ;

bicyclic or polycyclic heterocyclyl or heterocycloalkenyl of 7-15 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 heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c , and -(L AD ) bB -R g ;

bicyclic or polycyclic heteroaryl of 8-15 ring atoms, wherein 1-6 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: oxo, R c , and -(L AD ) bB -R g ; and

bicyclic or polycyclic C 8-15 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R c , and -(L AD ) bB -R g ,

provided the bicyclic or polycyclic heteroring is attached to the C(═O)NR 6 group via a ring carbon atom;

each occurrence of L AD 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 ; and

bB is 0, 1, 2, or 3;

AND

L AE 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 a ;

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 AF 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);

aa4 is 0, 1, 2, or 3; and

Ring C 4 is R g ;

each occurrence of R a and 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 b and 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 c and R 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, halo, C 1-4 alkoxy, and C 1-4 haloalkoxy; —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 , and 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 , and 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 oxo, R c , and R h ; and

C 6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c , and 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 1 ;

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 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; and halo;

each occurrence of 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 ;

each occurrence of bg is 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 . The compound of claim 1 , wherein a2 is 1.

3 . The compound of claim 1 , wherein L 2 is straight-chain C 1-6 alkylene, straight-chain C 2-6 alkenylene, or straight-chain C 2-6 alkynylene, each of which is optionally substituted with 1-6 R b ,

optionally wherein L 2 is straight-chain C 1-6 alkylene, which is optionally substituted with 1-6 R b ;

optionally wherein L 2 is straight-chain C 1-3 alkylene, which is optionally substituted with 1-3 R b .

4 . The compound of claim 1 , wherein L 2 is selected from the group consisting of:

C 3-10 cycloalkylene or C 3-10 cycloalkenylene, each of which is optionally substituted with 1-3 R c ; and

heterocyclylene or heterocycloalkenylene, each having 4-10 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R d ), O, and S(O) 0-2 , wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-3 R c .

5 . The compound of claim 1 , wherein at is 1.

6 . The compound of claim 1 , wherein L 1 is selected from the group consisting of: —O—, —N(H)—, —N(R d )—, and —S—,

optionally wherein L 1 is —O—.

7 . The compound of claim 1 , wherein a1 is 0.

8 . The compound of claim 1 , wherein a3 is 1.

9 . The compound of claim 1 , wherein L 3 is selected from the group consisting of: —O—, —N(H)—, —N(R d )—, and —S—,

optionally wherein L 3 is —O—.

10 . The compound of claim 1 , wherein a3 is 0.

11 . The compound of claim 1 , wherein a4 is 1.

12 . The compound of claim 1 , wherein:

a1 and a2 are each 1;

optionally, wherein:

a1 and a2 are each 1;

L 1 is —O—, —N(H)—, or —N(R d )—; and

L 2 is selected from the group consisting of:

straight-chain C 1-3 alkylene, which is optionally substituted with 1-3 R b ,

C 3-8 cycloalkylene, which is optionally substituted with 1-3 R c ; and

heterocyclylene having 4-8 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R d ), O, and S(O) 0-2 , wherein the heterocyclylene is optionally substituted with 1-3 R c ;

optionally wherein:

a1 and a2 are each 1;

L 1 is —O—; and

L 2 is straight-chain C 1-3 alkylene, which is optionally substituted with 1-3 R b ,

optionally wherein:

a1 and a2 are each 1;

L 1 is —O—; and L 2 is C 3-8 cycloalkylene, which is optionally substituted with 1-3 R c ; optionally

wherein L 2 is:

which is optionally substituted with 1-2 R c , wherein n1 and n2 are independently 0, 1, or 2; Q 2 is CH, CR c , or N; and the asterisk represents the point of attachment to -(L 3 ) a3 -;

optionally wherein n1 and n2 are independently 0 or 1, optionally 0; and Q 2 is CH; optionally wherein n1 and n2 are 0 and Q 2 is CH; optionally wherein L 2 is cyclobutane-diyl optionally substituted with 1-2 R c ; optionally wherein L 2 is cyclobutane-1,3-diyl optionally substituted with 1-2 R c ; optionally wherein L 2 is unsubstituted cyclobutane-diyl; optionally wherein L 2 is unsubstituted cyclobutane-1,3-diyl.

13 . The compound of claim 12 , wherein a3, a4, and a5 are each 0, optionally wherein L A is —O—CH 2 CH 2 —*, or

(such as

wherein * represents the point of attachment to Q 1 .

14 . The compound of claim 1 , wherein a1 is 0; a2 is 1; optionally wherein L 2 is straight-chain C 1-6 alkylene, which is optionally substituted with 1-6 R b , optionally wherein L 2 is straight-chain C 1-3 alkylene, which is optionally substituted with 1-3 R b .

15 . The compound of claim 14 , wherein a3 is 1; optionally, wherein L 3 is selected from the group consisting of: is —O—, —N(H)—, and —N(R d )—, optionally wherein L 3 is —O—.

16 . The compound of claim 14 , wherein a4 is 0; and a5 is 0, optionally wherein L A is —CH 2 CH 2 —O—*, wherein * represents to point of attachment to Q 1 .

17 . The compound of claim 1 , wherein Q 1 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 1-3 R c ; and

phenyl optionally substituted with 1-3 R c .

18 . The compound of claim 1 , wherein Q 1 is 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 ;

optionally wherein Q 1 is

wherein m1 and m2 are each independently 0, 1, or 2; and wherein Q 1 is optionally substituted with 1-2 R c ; and

optionally wherein each R d present in Q 1 is independently selected from the group consisting of:

—C(O)O(C 1-4 alkyl); and C 1-6 alkyl optionally substituted with 1-3 independently selected R a .

19 . The compound of claim 1 , wherein Y 1 is CR 1 ; Y 2 is CR 1 ; and/or Y 3 is CR 1 .

20 . The compound of claim 1 , wherein X 1 is NR 2 ; and X 2 is CR 5 ; optionally wherein X 1 is NH; and X 2 is CH.

21 . The compound of claim 1 , wherein R 6 is H.

22 . The compound of claim 1 , wherein W has formula (A-1) (A-2), or (A-4); optionally wherein W has formula (A-1); optionally wherein W has formula (A-2); optionally wherein W has formula (A-4).

23 . The compound of claim 1 , wherein W is defined according to (iii), (iv), or (v); optionally wherein W is defined according to (iii); optionally wherein W is defined according to (iv); optionally wherein W is defined according to (v).

24 . 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.

25 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

26 . A method for inhibiting STING activity, the method comprising contacting STING with a compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof.

27 . 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 claim 1 , or a pharmaceutically acceptable salt thereof.

28 . 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 claim 1 , or a pharmaceutically acceptable salt thereof.