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 is selected from the group consisting of a bond, CR 1 , C(R 3 ) 2 , N, and NR 2 ;

each of Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of O, S, CR 1 , C(R 3 ) 2 , N, and NR 2 ;

Y 4 is C or N;

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 Y 4 , X 1 , and X 2 is heteroaryl;

W is defined according to (A) or (B) below:

(A)

W is Q 1 -Q 2 -A, wherein

Q 1 is selected from the group consisting of:

(a) phenyl optionally substituted with from 1-2 independently selected R q1 ; and

(b) heteroaryl including from 5-6 ring atoms, wherein from 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 ring is optionally substituted with from 1-4 independently selected R q1 ;

Q 2 is selected from the group consisting of: a bond, —NH-, —N(C 1-3 alkyl)-, -O-, —C(═O), and S(O) 0-2 -;

A is:

-(i) —(Y A1 ) n —Y A2 , wherein:

n is 0 or 1;

Y A1 is C 1-6 alkylene, which is optionally substituted with from 1-6 R a ; and

Y A2 is:

(a) C 3-20 cycloalkyl, which is optionally substituted with from 1-4 R b ,

(b) C 6-20 aryl, which is optionally substituted with from 1-4 R c ;

(c) heteroaryl including from 5-20 ring atoms, wherein from 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 ring is optionally substituted with from 1-4 independently selected R c ; or

(d) heterocyclyl including from 3-16 ring atoms, wherein from 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 ring is optionally substituted with from 1-4 independently selected R b ,

OR

(ii) -Z 3 -Z 2 -Z 3 , wherein:

Z 1 is C 1-3 alkylene, which is optionally substituted with from 1-4 R a ;

Z 2 is N(H)—, —N(R d )—, —O—, or —S—; and

Z 3 is C 2-7 alkyl, which is optionally substituted with from 1-4 R a ;

OR

(iii) C 1-10 alkyl, which is optionally substituted with from 1-6 independently selected R a ,

OR

(B)

W is selected from the group consisting of:

(a) C 7-20 bicyclic or polycyclic aryl, which is optionally substituted with from 1-4 R c ; and

(b) bicyclic or polycyclic heteroaryl including from 7-20 ring atoms, wherein from 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 ring is optionally substituted with from 1-4 independently selected R c ;

each occurrence of R 1 is independently selected from the group consisting of

H;

halo;

cyano;

C 1-6 alkyl optionally substituted with 1-2 R a ;

C 2-6 alkenyl optionally substituted with 1-2 R a ;

C 2-6 alkynyl optionally substituted with 1-2 R a ;

C 1-4 haloalkyl;

C 1-4 alkoxy;

C 1-4 haloalkoxy;

-L 3 -L 4 -R i ;

—S(O) 1-2 (C 1-4 alkyl),

—S(O)(═NH)(C 1-4 alkyl),

SF 5 ,

—NR e R f , —OH,

oxo,

—S(O) 1-2 (NR′R″), —C 1-4 thioalkoxy,

—NO 2 , —C(═O)(C 1-4 alkyl), —C(═O)O(C 1-4 alkyl), —C(═O)OH, and —C(═O)N(R′)(R″);

or a pair of R 1 on adjacent atoms, taken together with the atoms connecting them, form a ring including from 3-10 ring atoms, wherein from 0-2 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 ring is optionally substituted with from 1-4 substituents each independently selected from C 1-6 alkyl, halo, C 1-6 haloalkyl, —OH, NR e R f , C 1-6 alkoxy, and C 1-6 haloalkoxy,

each occurrence of R 2 is independently selected from the group consisting of:

(i) C 1-6 alkyl, which is optionally substituted with from 1-2 independently selected R a ;

(ii) C 3-6 cycloalkyl;

(iii) heterocyclyl including from 3-10 ring atoms, wherein from 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 ;

(iv) C 6-10 aryl;

(v) heteroaryl including from 5-10 ring atoms, wherein from 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 ;

(vi) —C(O)(C 1-4 alkyl);

(vii) —C(O)O(C 1-4 alkyl);

(viii) —CON(R′)(R″);

(ix) —S(O) 1-2 (NR′R″);

(x) —S(O) 1-2 (C 1-4 alkyl);

(xi) —OH;

(xii) C 1-4 alkoxy; and

(xiii) H;

or a pair of R 1 and R 2 on adjacent atoms, taken together with the atoms connecting them, form a ring including from 3-10 ring atoms, wherein from 0-2 ring atoms (in addition to the nitrogen atom to which the R 2 is attached) 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 ring is optionally substituted with from 1-4 substituents each independently selected from C 1-6 alkyl, halo, C 1-6 haloalkyl, —OH, NR e R f , C 1-6 alkoxy, and C 1-6 haloalkoxy,

each occurrence of R 3 is independently selected from H; C 1-6 alkyl optionally substituted with from 1-6 independently selected R a ; C 1-4 haloalkyl; OH; —F; —Cl; —Br; NR e R f ; C 1-4 alkoxy; C 1-4 haloalkoxy; —C(═O)(C 1-4 alkyl); —C(═O)O(C 1-4 alkyl); —C(═O)OH; —C(═O)N(R′)(R″); —S(O) 1-2 (NR′R″); —S(O) 1-2 (C 1-4 alkyl); cyano; and C 3-6 cycloalkyl optionally substituted with from 1-4 independently selected C 1-4 alkyl; or

two R 3 on the same carbon combine to form an oxo; or

a pair of R 3 , taken together with the atom(s) connecting them, form a ring including from 3-10 ring atoms, wherein from 0-2 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 ring is optionally substituted with from 1-4 substituents each independently selected from C 1-6 alkyl, halo, C 1-6 haloalkyl, —OH, NR e R f , C 1-6 alkoxy, and C 1-6 haloalkoxy; or

a pair of R 1 and R 3 on adjacent atoms, taken together with the atoms connecting them, form a ring including from 3-10 ring atoms, wherein from 0-2 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 ring is optionally substituted with from 1-4 substituents each independently selected from C 1-6 alkyl, halo, C 1-6 haloalkyl, —OH, NR e R f , C 1-6 alkoxy, and C 1-6 haloalkoxy; or

or a pair of R 2 and R 3 on adjacent atoms, taken together with the atoms connecting them, form a ring including from 3-10 ring atoms, wherein from 0-2 ring atoms (in addition to the nitrogen atom to which the R 2 is attached) 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 ring is optionally substituted with from 1-4 substituents each independently selected from C 1-6 alkyl, halo, C 1-6 haloalkyl, —OH, NR e R f , C 1-6 alkoxy, and C 1-6 haloalkoxy;

R 4 is selected from H and C 1-6 alkyl;

R 5 is selected from H and halo;

R 6 is selected from H; C 1-6 alkyl; —OH; C 1-4 alkoxy; C(═O)H; C(═O)(C 1-4 alkyl); CN; C 6-10 aryl optionally substituted with from 1-4 independently selected C 1-4 alkyl; and heteroaryl including from 5-10 ring atoms, wherein from 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 ring is optionally substituted with from 1-4 independently selected C 1-4 alkyl;

each occurrence of R q1 is independently selected from the group consisting of:

(a) halo; (b) cyano; (c) C 1-10 alkyl which is optionally substituted with from 1-6 independently selected R a ; (d) C 2-6 alkenyl; (e) C 2-6 alkynyl; (f) C 3-6 cycloalkyl; (g) C 1-4 alkoxy; (h) C 1-4 haloalkoxy; (i) —S(O) 1-2 (C 1-4 alkyl); (j) —NR e R f ; (k) OH; (l) —S(O) 1-2 (NR′R″); (m) —C 1-4 thioalkoxy; (n) —NO 2 ; (o) —C(═O)(C 1-4 alkyl); (p) —C(═O)O(C 1-4 alkyl); (q) —C(═O)OH; (r) —C(═O)N(R′)(R″); and (s) oxo;

each occurrence of R a is independently selected from the group consisting of: —OH; —F; —Cl; —Br; 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; —CON(R′)(R″); —S(O) 1-2 (NR′R″); —S(O) 1-2 (C 1-4 alkyl); cyano; and C 3-6 cycloalkyl optionally substituted with from 1-4 independently selected C 1-4 alkyl;

each occurrence of R b is independently selected from the group consisting of: C 1-10 alkyl optionally substituted with from 1-6 independently selected R a ; C 1-4 haloalkyl; OH; oxo; —F; —Cl; —Br; NR e R f ; C 1-4 alkoxy; C 1-4 haloalkoxy; —C(═O)(C 1-4 alkyl); —C(═O)O(C 1-4 alkyl); —C(═O)OH; —C(═O)N(R′)(R″); —S(O) 1-2 (NR′R″); —S(O) 1-2 (C 1-4 alkyl); cyano; and -L 1 -L 2 -R h ;

each occurrence of R c is independently selected from the group consisting of:

(a) halo;

(b) cyano;

(c) C 1-10 alkyl which is optionally substituted with from 1-6 independently selected R a ;

(d) C 2-6 alkenyl;

(e) C 2-6 alkynyl;

(g) C 1-4 alkoxy;

(h) C 1-4 haloalkoxy;

(i) —S(O) 1-2 (C 1-4 alkyl);

(j) —NR e R f ;

(k) OH;

(l) —S(O) 1-2 (NR′R″);

(m) —C 1-4 thioalkoxy;

(n) —NO 2 ;

(o) —C(═O)(C 1-4 alkyl);

(p) —C(═O)O(C 1-4 alkyl);

(q) —C(═O)OH;

(r) —C(═O)N(R′)(R″);

(s) -L 1 -L 2 -R h ; and

(t) oxo;

R d is selected from the group consisting of: C 1-6 alkyl; C 3-6 cycloalkyl; —C(O)(C 1-4 alkyl); —C(O)O(C 1-4 alkyl); —CON(R′)(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 from 1-2 substituents each independently selected from halo, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, and CN; C 1-6 haloalkyl; C 3-6 cycloalkyl; —C(O)(C 1-4 alkyl); —C(O)O(C 1-4 alkyl); —CON(R′)(R″); —S(O) 1-2 (NR′R″); —S(O) 1-2 (C 1-4 alkyl); —OH; and C 1-4 alkoxy; or R e and R f together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C 1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R e and R f ), which are each independently selected from the group consisting of N(R d ), NH, 0, and S;

-L 1 is a bond or C 1-3 alkylene optionally substituted with from 1-2 substituents each independently selected from the group consisting of halo, NR e R f , OH, C 1-4 alkoxy, and CN;

-L 2 is -O-, —N(H)—, —S(O) 0-2 -, or a bond;

R h is selected from:

C 3-8 cycloalkyl optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, C 1-4 alkyl, hydroxyC 1-4 alkyl, and C 1-4 haloalkyl (in certain embodiments, it is provided that when R h is C 3-6 cycloalkyl optionally substituted with from 1-4 substituents independently selected C 1-4 alkyl, -L 1 is a bond, or -L 2 is -O-, —N(H)—, or —S—);

heterocyclyl, wherein the heterocyclyl includes from 3-16 ring atoms, wherein from 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 , wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, C 1-4 alkyl, hydroxyC 1-4 alkyl, and C 1-4 haloalkyl;

heteroaryl including from 5-10 ring atoms, wherein from 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 ring is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, C 1-4 alkyl, hydroxyC 1-4 alkyl, and C 1-4 haloalkyl; and

C 6-10 aryl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, C 1-4 alkyl, hydroxyC 1-4 alkyl, and C 1-4 haloalkyl;

-L 3 is a bond; C 1-3 alkylene optionally substituted with from 1-2 substituents each independently selected from the group consisting of halo, NR e R f , OH, C 1-4 alkoxy, and CN; CH═CH; or CC;

-L 4 is —O—, —N(H)—, —S(O) 0-2 —, or a bond;

R i is selected from:

C 3-8 cycloalkyl optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, C 1-4 alkyl, hydroxyC 1-4 alkyl, and C 1-4 haloalkyl;

heterocyclyl, wherein the heterocyclyl includes from 3-16 ring atoms, wherein from 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 , wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, C 1-4 alkyl, hydroxyC 1-4 alkyl, and C 1-4 haloalkyl;

heteroaryl including from 5-10 ring atoms, wherein from 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 ring is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, C 1-4 alkyl, hydroxyC 1-4 alkyl, and C 1-4 haloalkyl; and

C 6-10 aryl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, C 1-4 alkyl, hydroxyC 1-4 alkyl, and C 1-4 haloalkyl; and

each occurrence of R′ and R″ is independently selected from the group consisting of: H, C 1-4 alkyl, and C 6-10 aryl optionally substituted with from 1-2 substituents selected from halo, C 1-4 alkyl, and C 1-4 haloalkyl; or R′ and R″ together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from the group consisting of H and C 1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R′ and R″), which are each independently selected from the group consisting of N(H), N(C 1-6 alkyl), 0, and S;

provided that the compound is other than a compound selected from the group consisting of:

and

further provided that when Z, Y 2 , and Y 3 are each CH; Y 4 is C; Y 3 is CH or C-OH; X 1 is NH; and X 2 is CH, then W cannot be:

pyrimidinyl substituted with from 1-2 substituents each independently selected from the group consisting of: methyl; —CH 2 NH 2 ; —CH 2 N(H)Me; —CH 2 CH 2 NH 2 ; —CH 2 CH 2 N(H)Me; —N(H)Me; —N(H)Et; —N(H)CH 2 CH 2 NH 2 ; —N(H)CH 2 CH 2 OH; —N(H)iPr; —N(H)CH 2 CN; cyano; C(═O)OH; and —Cl;

thiazolyl substituted with —CH 2 NH 2 ; or

pyridinyl substituted with from 1-2 substituents each independently from the group consisting of: NH 2 ; methyl; and Br.

2 . The compound of claim 1 , wherein the ring that includes Z, Y 1 , Y 2 , Y 3 , and Y 4 is aromatic.

3 . The compound of claim 1 or 2 , wherein X 1 is NR 2 , such as NH.

4 . The compound of any one of claims 1 - 3 , wherein X 2 is CR 5 , such as CH.

5 . The compound of any one of claims 1 - 4 , wherein W is defined according to (A).

6 . The compound of any one of claims 1 - 5 , wherein Q 1 is heteroaryl including from 5-6 ring atoms, wherein from 1-4 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 ring is optionally substituted with from 1-4 independently selected R q1 .

7 . The compound of any one of claims 1 - 6 , wherein Q 2 is a bond.

8 . The compound of any one of claims 1 - 7 , wherein A is —(Y A1 ) n —Y A2 .

9 . The compound of any one of claims 1 - 8 , wherein Y A2 is C 6-10 aryl, which is optionally substituted with from 1-3 R c , such as wherein Y A2 is C 6 aryl, which is optionally substituted with from 1-3 R c ; or

wherein Y A2 is C 7-15 bicyclic or tricyclic aryl which is optionally substituted with from 1-3 R c , such as wherein Y A2 is naphthyl, tetrahydronaphthyl, indacenyl, or 1′,3′-dihydrospiro[cyclopropane-1,2′-indene] such as

each of which is optionally substituted with from 1-3 R c .

10 . The compound of any one of claims 1 - 4 , wherein W is defined according to (B).

11 . The compound of claim 10 , wherein W is bicyclic or polycyclic heteroaryl including from 7-20 ring atoms, wherein from 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 ring is optionally substituted with from 1-4 independently selected R c .

12 . The compound of claim 11 , wherein W 2 is selected from the group consisting of:

wherein:

W a , W b , W c , W d , W e , W f , and W g are each independently selected from the group consisting of: N, CH, and CR c , provided that from 1-4 of W a -W g is N, and no more than 4 of W a -W g are CR c ;

W h and W i are independently selected from the group consisting of N, NH, NR d , O, S, CH, and CR c ;

W j and W o are independently N or C;

W k , W l , W m , and W n are independently N, CH, or CR c , provided that:

from 1-4 of W h -W o are heteroatoms,

no more than 4 of W h -W o are CR c , and

when one of W h and W i is N, the other one of W h and W i is CH, CR c , O or S;

each is independently a single bond or a double bond, provided that the 5-membered ring including W i , W j , W o , and W h is aromatic, and the 6-membered ring including W o , W j , W k , W l , W m , and W n is aromatic.

13 . The compound of any one of claims 1 - 12 , wherein the

moiety is

14 . The compound of any one of claims 1 - 12 , wherein from 1-2 of Y 1 , Y 2 , and Y 3 is independently N or NR 2 , such as N.

15 . The compound of any one of claim 1 - 12 or 14 , wherein the

moiety is

wherein the asterisk denotes point of attachment to Y 4 .

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 any one of claims 1 - 16 , or a pharmaceutically acceptable salt thereof, 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 .