Compounds and compositions for treating conditions associated with STING activity

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, wherein:

Z is CH;

each of Y 1 and Y 2 is an independently selected CR 1 , and Y 3 is N;

Y 4 is C;

X 1 is NR 2 ;

X 2 is CH;

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; and wherein the ring-that includes Z, Y 1 , Y 2 , Y 3 , and Y 4 :

 is aromatic;

W is selected from the group consisting of:

(i) C(═O);

(ii) C(═S);

(iv) C(═NR d ); and

(v) C(═NH);

Q-A is defined according to (A) or (B) below:

(A)

Q is NH or N(C 1-6 alkyl) wherein the C 1-6 alkyl is optionally substituted with 1-2 independently selected R a , and

A is:

(i) —(Y A1 ) n —Y A2 , wherein:

n is 0;

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, and wherein one or more of the heteroaryl ring carbon atoms are 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 b ),N(R d ), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected R b ,

OR

(ii) —Z 1 —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

(B)

Q and A, taken together, form:

 wherein denotes point of attachment to W; and

E is a ring including from 3-16 ring atoms, wherein aside from the nitrogen atom present, from 0-3 additional ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected R b ,

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; C 2-6 alkynyl; C 1-4 haloalkyl; C 1-4 alkoxy; C 1-4 haloalkoxy; —(C 0-3 alkylene)-C 3-6 cycloalkyl optionally substituted with from 1-4 independently selected R g ; —(C 0-3 alkylene)-C 6-10 aryl optionally substituted with from 1-4 independently selected R g ; —(C 0-3 alkylene)-5-10 membered heteroaryl, wherein from 1-3 ring atoms of the heteroaryl are heteroatoms each independently selected from the group consisting of N, NH, NR d , O, and S, wherein the heteroaryl is optionally substituted with from 1-4 independently selected R g ; —(C 0-3 alkylene)-5-10 membered heterocyclyl, wherein from 1-3 ring atoms of the heterocyclyl are heteroatoms each independently selected from the group consisting of N, NH, NR d , O, and S, wherein the heterocyclyl is optionally substituted with 1-4 independently selected R g ; —S(O) 1-2 (C 1-4 alkyl); —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″);

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 ), and O;

(iv) —C(O)(C 1-4 alkyl);

(v) —C(O)O(C 1-4 alkyl);

(vi) —CON(R′)(R″);

(vii) —S(O) 1-2 (NR′R″);

(viii) —S(O) 1-2 (C 1-4 alkyl);

(ix) —OH;

(x) C 1-4 alkoxy; and

(xi) H;

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; (C 0-3 alkylene)-C 6-10 aryl optionally substituted with 1-4 independently selected C 1-4 alkyl; and (C 0-3 alkylene)-C 3-6 cycloalkyl optionally substituted with from 1-4 independently selected C 1-4 alkyl;

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

(i) halo;

(ii) cyano;

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

(iv) C 2-6 alkenyl;

(v) C 2-6 alkynyl;

(vi) C 1-4 haloalkyl;

(vii) C 1-4 alkoxy;

(viii) C 1-4 haloalkoxy;

(ix) —(C 0-3 alkylene)-C 3-6 cycloalkyl optionally substituted with from 1-4 independently selected C 1-4 alkyl;

(x) —(C 0-3 alkylene)-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 ), and O;

(xi) —S(O) 1-2 (C 1-4 alkyl);

(xii) —NR e R f ;

(xiii) —OH;

(xiv) —S(O) 1-2 (NR′R″);

(xv) —C 1-4 thioalkoxy;

(xvi) —NO 2 ;

(xvii) —C(═O)(C 1-4 alkyl);

(xviii) —C(═O)O(C 1-4 alkyl);

(xix) —C(═O)OH;

(xx) —C(═O)N(R′)(R″);

(xxi) —(C 0-3 alkylene)-C 6-10 aryl optionally substituted with from 1-4 independently selected C 1-4 alkyl; and

(xxii) —(C 0-3 alkylene)-5-10 membered heteroaryl, wherein from 1-3 ring atoms of the heteroaryl are heteroatoms each independently selected from the group consisting of N, NH, NR d , O, and S, wherein the heteroaryl is optionally substituted with from 1-4 independently selected C 1-4 alkyl;

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); —CN; —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; 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 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 e and R f ), which are each independently selected from the group consisting of N(R d ), O, and S;

each occurrence of R g is independently selected from the group consisting of: halo; cyano; C 1-6 alkyl optionally substituted with from 1-2 independently selected R a ; C 1-4 haloalkyl; C 1-6 alkoxy optionally substituted with 1-2 independently selected R a ; C 1-4 haloalkoxy; S(O) 1-2 (C 1-4 alkyl); —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″); and

each occurrence of R′ and R″ is independently selected from the group consisting of: H and C 1-4 alkyl; 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(R d ), O, and S, and

provided that when Q-A is defined according to (A), and A is C 6 aryl mono-substituted with C 4 alkyl, then the ring that includes Z, Y 1 , Y 2 , Y 3 , and Y 4 must be substituted with one or more R 1 that is other than hydrogen.

2. The compound of claim 1 , wherein W is C(═O).

3. The compound of claim 1 , wherein Q and A are defined according to (A).

4. The compound of claim 3 , wherein A is —(Y A1 ) n —Y A2 .

5. The compound of claim 4 , wherein Y A2 is C 6-20 aryl, which is optionally substituted with from 1-4 R c .

6. The compound of claim 4 , wherein Y A2 is 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, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected R c .

7. The compound of claim 4 , wherein Y A2 is C 3-20 cycloalkyl, which is optionally substituted with from 1-4 R b .

8. The compound of claim 4 , wherein Y A2 is heterocyclyl including from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected R b .

9. The compound of claim 1 , wherein Q and A are defined according to (B).

10. The compound of claim 1 , wherein

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; C 2-6 alkynyl; C 1-4 haloalkyl; C 1-4 alkoxy; C 1-4 haloalkoxy —S(O) 1-2 (C 1-4 alkyl); —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″).

11. A compound selected from the group consisting of the following compounds

Compound

#

Final Structure

115

116

132

133

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135

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143

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387

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable excipients.