COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH STING ACTIVITY
This disclosure features compounds of Formula I (and their 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 compounds 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:
X 1 is selected from the group consisting of O, S, N, NR 2 , and CR 5 ;
X 2 is selected from the group consisting of O, S, N, NR 4 , and CR 5 ;
Y 1 is N or CR 1a ;
Y 2 is N or CR 1b ;
Y 3 is N or CR 1c ; provided that one of Y 1 , Y 2 , and Y 3 is N;
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 the 6-membered ring comprising Y 1 , Y 2 , and Y 3 is heteroaryl;
R 1a , R 1b , R 1c , and R 1d are each independently selected from the group consisting of: H; R c ; R h ; and -(L 1 ) b1 -R h ;
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 ;
Q 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 R h ;
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 R h ;
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 R h ; and
C 6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of R c and R h ;
each L A 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);
a1 is 0, 1, 2, 3, or 4;
provided that -(L A ) a1 - cannot contain bond(s) between O, N, or S(O) 0 atoms, unless an N—N bond is further attached to C(O);
Q 2 is selected from the group consisting of: R g , H, and R c ;
R 3 is selected from the group consisting of: H; R d ; and R h ;
W is selected from the group consisting of: (i) C(═O); (ii) C(═S); (iii) S(O) 1-2 ; (iv) C(═NR d ) or C(═N—CN); (v) C(═NH); (vi) C(═CH—NO 2 ); (vii) S(═O)(═N(R d )); and (viii) S(═O)(═NH);
Z and A are defined according to (AA) or (BB) below:
(AA)
Z is —N(H)— or —N(R d )—;
A is selected from the group consisting of:
—H;
C 1-10 alkyl which is optionally substituted with 1-6 R b ; and
—(Y A1 ) nA —Y A2 wherein:
nA is 0 or 1;
Y A1 is C 1-6 alkylene optionally substituted with 1-3 R b ; and
Y A2 is 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 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 ;
C 6-10 aryl optionally substituted with 1-4 R c ; and
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 ;
Z and A, taken together, form:
and
Ring E is a saturated or partially unsaturated ring of 3-16 ring atoms, wherein 0-3 ring atoms are heteroatoms (in addition to the nitrogen atom already present), 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 1-4 substituents independently selected from the group consisting of: oxo, R c , R h , and -(L g ) bg -R h ;
each occurrence of R a and R h 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 W; 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 ; —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 W 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 1-3 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 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 3-8 cycloalkyl or C 3-8 cycloalkenyl, each of which is optionally substituted with 1-4 R i ;
heterocyclyl or heterocycloalkenyl 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 heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R ;
heteroaryl of 5-6 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 ; and
C 6 aryl optionally substituted with 1-4 R ;
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 1 , L 2 , and L g 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′ and R″ is independently selected from the group consisting of: H; —OH; and C 1-4 alkyl,
provided that one or both of (a) and (b) applies:
(a) Q 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 R h ; and
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 R h ; or
(b) Q 2 is —R g ,
further provided that the compound is other than:
2 . The compound of claim 1 , wherein Q 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 R h ; and
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 R h .
3 . The compound of claim 1 or 2 , wherein Q 1 is 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 R h .
4 . The compound of any one of claims 1 - 3 , wherein:
(i) Q 1 is heterocyclylene 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 is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c , and R h ; or
(ii) Q 1 is heterocyclylene of 4-8 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 is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R c .
5 . The compound of any one of claims 1 - 4 , wherein Q 1 is:
(i) a group of Formula (Q1a):
which is optionally substituted with 1-2 R c , wherein:
aa represents the point of attachment to -(L A ) a1 ;
m1 and m2 are independently 0, 1, or 2;
Q A and Q B are independently CH, CR c , or N, provided that 1-2 of Q A and Q B is N;
optionally m1 and m2 are each 1; and
optionally Q A and Q B are both N;
or
(ii)
6 . The compound of claim 1 , wherein Q 1 is:
(i) 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 R h ;
(ii) heteroarylene of 5-6 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 heteroarylene is optionally substituted with 1-2 R c ; or
(iii) pyrazolylene which is optionally substituted with R c .
7 . The compound of any one of claims 1 - 6 , wherein a1 is 0.
8 . The compound of any one of claims 1 - 6 , wherein a1 is 1 or 2.
9 . The compound of any one of claims 1 - 6 , wherein a1 is 1; and L A is C 1-3 alkylene optionally substituted with 1-2 R a ,
10 . The compound of any one of claims 1 - 9 , wherein Q 2 is:
(i) a moiety 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 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 ;
(ii) a moiety selected from the group consisting of:
heteroaryl of 5-6 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 1-3 substituents independently selected from the group consisting of R c , R h , and -(L g ) bg -R h ; and
C 6 aryl optionally substituted with 1-3 substituents independently selected from the group consisting of R c , R h , and -(L g ) bg -R h ;
(iii) a moiety selected from the group consisting of: phenyl and pyridyl, each optionally substituted with 1-3 substituents independently selected from the group consisting of R c and R h ; or
(iv) a moiety selected from the group consisting of:
wherein leis selected from the group consisting of: R c and R h .
11 . The compound of any one of claims 1 - 9 , wherein Q 2 is:
(i) a moiety 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 ; and
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 ;
(ii) a moiety selected from the group consisting of:
monocyclic C 3-8 cycloalkyl which is optionally substituted with 1-3 substituents independently selected from the group consisting of oxo, R c , and R h ; and
monocyclic heterocyclyl of 4-8 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 heterocyclyl is optionally substituted with 1-3 substituents independently selected from the group consisting of oxo, R c , and R h ;
(iii) a moiety selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and piperidinyl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of oxo, R c , and R h , wherein the ring nitrogen atom of the pyrrolidinyl and piperidinyl is further optionally substituted with R d ; or
(iv) a moiety selected from the group consisting of:
wherein each R Q is independently selected from the group consisting of: R c and R h .
12 . The compound of any one of claims 1 - 9 , wherein Q 2 is R c .
13 . The compound of any one of claims 1 - 9 or 12 , wherein Q 2 is C 1-10 alkyl which is optionally substituted with 1-6 independently selected R a .
14 . The compound of any one of claims 1 - 9 or 12 - 13 , wherein Q 2 is unsubstituted C 1-6 alkyl; or wherein Q 2 is methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, or iso-butyl.
15 . The compound of any one of claims 1 - 9 or 12 - 13 , wherein Q 2 is:
(i) C 1-10 alkyl substituted with 1-6 independently selected R a ;
(ii) C 1-6 alkyl which is substituted with 1-6 independently selected halo;
(iii) C 1-6 alkyl which is substituted with —OH, C 1-4 alkoxy, or C 1-4 haloalkoxy; or
(iv) a moiety selected from the group consisting of:
16 . The compound of any one of claims 1 - 15 , wherein:
(i) Y 1 is N; Y 2 is CR 1b ; and Y 3 is CR 1c ; or
(ii) Y 1 is N; Y 2 is CH; and Y 3 is CH.
17 . The compound of any one of claims 1 - 15 , wherein:
(i) Y 1 is CR 1a ; Y 2 is CR 1b ; and Y 3 is N; or
(ii) Y 1 is CH; Y 2 is CH; and Y 3 is N.
18 . The compound of any one of claims 1 - 17 , wherein:
(i) X 1 is NR 2 ; and X 2 is CR 5 ; or
(ii) X 1 is NH; and X 2 is CH.
19 . The compound of any one of claims 1 - 18 , wherein W is C(═O).
20 . The compound of any one of claims 1 - 19 , wherein Z and A are defined according to (AA).
21 . The compound of any one of claims 1 - 20 , wherein A is —(Y A1 ) nA —Y A2 or Y A2 .
22 . The compound of any one of claims 1 - 21 , wherein Y A2 :
(i) a moiety selected from the group consisting of:
C 6-10 aryl optionally substituted with 1-4 R c ; and
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 ;
(ii) C 6-10 aryl optionally substituted with 1-4 R c ;
(iii) C 6 aryl optionally substituted with 1-3 R c ;
(iv)
or
(v) any groups of (i)-(iv), wherein each R c present in Y A2 is C 1-6 alkyl substituted with 1-3 independently selected halo; or each R c present in Y A2 is —CF 3 .
23 . The compound of any one of claims 1 - 20 , wherein A is —H or C 1-4 alkyl which is optionally substituted with 1-3 R b .
24 . The compound of claim 1 , wherein the compound is a compound of Formula (I-a):
or a pharmaceutically acceptable salt thereof, wherein:
R 6 is H or R d ;
m1 and m2 are independently 0, 1, or 2;
Q A and Q B are independently CH, CR c , or N, provided that 1-2 of Q A and Q B is N;
a1 is 0 or 1; and
L A is C 1-3 alkylene optionally substituted with 1-2 W,
optionally wherein m1 and m2 are each 1;
optionally wherein Q A and Q B are both N; and
optionally wherein A is —(Y A1 ) nA —Y A2 , optionally wherein Y A2 is selected from the group consisting of:
C 6 aryl optionally substituted with 1-3 R c ; and
heteroaryl of 5-6 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 1-3 R c .
25 . The compound of claim 1 , wherein the compound is a compound of Formula (I-b):
or a pharmaceutically acceptable salt thereof, wherein:
R 6 is H or R d ;
Q 1 is pyrazolylene optionally substituted with R c ;
a1 is 0 or 1; and
L A is C 1-3 alkylene optionally substituted with 1-2 R a ;
optionally wherein Q 2 is selected from the group consisting of:
heteroaryl of 5-6 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 1-3 substituents independently selected from the group consisting of R c , R h , and -(L g ) bg -R h ; and
C 6 aryl optionally substituted with 1-3 substituents independently selected from the group consisting of R c , R h , and -(L g ) bg -R h ;
optionally wherein A is:
(i) C 1-4 alkyl which is optionally substituted with 1-3 R h ; or
(ii) —(Y A1 ) nA —Y A2 , optionally wherein Y A2 is selected from the group consisting of:
C 6 aryl optionally substituted with 1-3 R c ; and
heteroaryl of 5-6 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 1-3 R c .
26 . The compound of claim 24 or 25 , wherein R 2 is H; and R 5 is H.
27 . The compound of any one of claims 24 - 26 , wherein:
(i) Y 1 is N; Y 2 is CR 1b ; and Y 3 is CR 1c ; or
(ii) Y 1 is CR 1a ; Y 2 is CR 1b ; and Y 3 is N.
28 . The compound of any one of claims 24 - 27 , wherein Y A2 is C 6 aryl optionally substituted with 1-3 R c ; or
29 . The compound of claim 1 , wherein:
(i) (a) applies;
(ii) (b) applies; or
(iii) both (a) and (b) apply.
30 . The compound of claim 1 , wherein the compound is selected from the group consisting of the compounds delineated in Table C 1 or a pharmaceutically acceptable salt thereof.
31 . A pharmaceutical composition comprising a compound of any one of claims 1 - 30 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
32 . A method for inhibiting STING activity, the method comprising contacting STING with a compound as claimed in any one of claims 1 - 30 , or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as claimed in claim 31 .
33 . 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 - 30 , or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as claimed in claim 31 .
34 . 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 - 30 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 31 .