COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH STING ACTIVITY
This disclosure features chemical entities (e.g., a compound or a 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 chemical entities 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:
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
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 ;
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 ;
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:
C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl, each of which is optionally substituted with 1-6 R a2 or R g ;
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 ; and
heteroaryl, 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 heteroaryl, heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R c ,
provided that when W is heteroaryl, heterocyclyl or heterocycloalkenyl, it is attached to the C(═O)NR 6 group via a ring carbon atom;
each occurrence of R a and R a2 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 h 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 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, 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 i ;
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 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 claims 1 or 2 , 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 claims 1 or 2 , 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 any one of claims 1-4 , wherein a1 is 1.
6 . The compound of any one of claims 1-5 , 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 any one of claims 1-3 , wherein a1 is 0.
8 . The compound of any one of claims 1-7 , wherein a3 is 1.
9 . The compound of any one of claims 1-8 , 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 any one of claims 1-7 , wherein a3 is 0.
11 . The compound of any one of claims 1-10 , 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 o , wherein n1 and n2 are independently 0, 1, or 2; Q 2 is CH, CR o , 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 claims 14 or 15 , 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 any one of claims 1-16 , 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 any one of claims 1-16 , 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 any one of claims 1-18 , wherein Y 1 is CR 1 ; Y 2 is CR 1 ; and/or Y 3 is CR 1 .
20 . The compound of any one of claims 1-19 , 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 any one of claims 1-20 , wherein R 6 is H.
22 . The compound of any one of claims 1-21 , wherein W is:
(i) C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl, each of which is optionally substituted with 1-6 R a2 or R g ;
optionally C 1-10 alkyl, which is optionally substituted with 1-6 R a2 or R g ; optionally C 1-4 alkyl, which is optionally substituted with 1-6 R a2 or R g ;
optionally wherein C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl is substituted with one R g , optionally wherein R g is cycloalkyl, heteroary or heterocyclyl.
23 . The compound of any one of claims 1-21 , wherein W is:
(i) 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 ; optionally C 3-12 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R c .
(ii) heteroaryl, 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 heteroaryl, heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R c ;
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 any one of claims 1-24 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
26 . A method for inhibiting STING activity, the method comprising contacting STING with a compound as claimed in any one of claims 1-24 , or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as claimed in claim 25 .
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 any one of claims 1-24 , or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as claimed in claim 25 .
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 any one of claims 1-24 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 25 .