US 12,503,436 B2 · Compounds and compositions for treating conditions associated with STING activity

Abstract

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.

A compound of Formula (I):

or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:
LA is -(L1)a1-(L2)a2(L3)a3-(L4)a4-(L5)a5-*, wherein * represents the point of attachment to Q1;
a1, a2, a3, a4, and a5 are each independently 0 or 1,
provided that at +a2+a3+a4+a5≥1, and
each of L1, L3, and L5 is independently selected from the group consisting of:
—O—, —N(H)—, —N(Rd)—, S(O)0-2, and —C(═O)—;
provided that when one or both of a2 and a4 is 0, then the combinations of L1, L3, and L5 cannot form O—O, N—O, N—N, O—S, S—S, or N—S(O)0 bonds, and
each of L2 and L4 is independently selected from the group consisting of:
straight-chain C1-6 alkylene, straight-chain C2-6 alkenylene, or straight-chain C2-6 alkynylene, each of which is optionally substituted with 1-6 Rb;
C3-10 cycloalkylene or C3-10 cycloalkenylene, each of which is optionally substituted with 1-3 Rc provided the C3-10 cycloalkylene or C3-10 cycloalkenylene is not directly connected to the 6-membered ring containing Y1, Y2, and Y3;
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(Rd), O, and S(O)0-2, wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-3 Rc, provided that the heterocyclylene or heterocycloalkenylene is not directly connected to the 6-membered ring containing Y1, Y2, and Y3;
Q1 is —Rg;
Y1, Y2, and Y3 are each independently selected from the group consisting of CR1, C(═O), N, and NW;
X1 is NH;
X2 is CH;
each is independently a single bond or a double bond, provided that the five-membered ring comprising X1 and X2 is heteroaryl, and that the six-membered ring comprising Y1, Y2, and Y3 is aryl or heteroaryl;
further provided that LA cannot include a cyclic group directly attached to the 6-membered ring containing Y1, Y2, and Y3;
each occurrence of R1 is independently selected from the group consisting of:
H;
Rc;
Rg;
and -(Lg)bg-Rg;
each occurrence of R2 is independently selected from the group consisting of:
H;
Rd;
Rg;
and -(Lg)bg-Rg;
R6 is selected from the group consisting of:
H;
Rd;
and Rg;
W is selected from the group consisting of:
H;
C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl, each of which is optionally substituted with 1-6 Ra2, wherein one or more of the internal optionally substituted methylene group can be replaced by one or more heteroatom selected from O or S, wherein when W is alkenyl or alkynyl, the heteroatom is not directly connected to the sp2 or sp carbon;
monocyclic C3-8 cycloalkyl or C3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;
and
monocyclic 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(Rd), 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 RC, provided that when W is heterocyclyl or heterocycloalkenyl, the heterocyclyl or heterocycloalkenyl is attached to the C(═O)NR6 group via a ring carbon atom;
each occurrence of Ra and Ra2 is independently selected from the group consisting of:
—OH;
—halo;
—NReRf;
C1-4 alkoxy;
C1-4 haloalkoxy;
—C(═O)O(C1-4 alkyl);
—C(═O)(C1-4 alkyl);
—C(═O)OH;
—CONR′R″;
—S(O)1-2NR′R”;
—S(O)1-2(C1-4 alkyl);
and cyano;
each occurrence of Rb and Rc is independently selected from the group consisting of:
halo;
cyano;
C1-10 alkyl which is optionally substituted with 1-6 independently selected Ra;
C2-6 alkenyl;
C2-6 alkynyl;
C1-4 alkoxy;
C1-4 haloalkoxy;
—S(O)1-2(C1-4 alkyl);
—S(O)(=NH)(C1-4 alkyl);
—NReRf;
—OH;
—S(O)1-2NR′R″;
—C1-4 thioalkoxy;
—NO2;
—C(═O)(C1-10 alkyl);
—C(═O)O(C1-4 alkyl);
—C(═O)OH;
—C(═O)NR′R″;
—NR′C(═O)(C1-4 alkyl) and —SF5;
each occurrence of Rd is independently selected from the group consisting of:
C1-6 alkyl optionally substituted with 1-3 independently selected Ra;
—C(O)(C1-4 alkyl);
—C(O)O(C1-4 alkyl);
—CONR′R″;
—S(O)1-2NR′R″;
—S(O)1-2(C1-4 alkyl);
—OH;
and C1-4 alkoxy;
each occurrence of Re and Rf is independently selected from the group consisting of:
H;
C1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, halo, C1-4 alkoxy, and C1-4 haloalkoxy;
—C(O)(C1-4 alkyl);
—C(O)O(C1-4 alkyl);
—CONR′R″;
—S(O)1-2NR′R″;
—S(O)1-2(C1-4 alkyl);
—OH;
and C1-4 alkoxy;
each occurrence of Rg is independently selected from the group consisting of:
C3-12 cycloalkyl or C3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc, and Rh;
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(Rd), 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, Rc, and Rh;
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(Rd), 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, Rc, and Rh;
and
C6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc, and Rh;
each occurrence of Rh is independently selected from the group consisting of:
C3-12 cycloalkyl or C3-12 cycloalkenyl, each of which is optionally substituted with 1-4 Ri;
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(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 Ri;
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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Ri;
and
C6-10 aryl optionally substituted with 1-4 Ri;
each occurrence of Ri is independently selected from the group consisting of:
C1-6 alkyl;
C1-4 haloalkyl;
C1-4 alkoxy;
C1-4 haloalkoxy;
and halo;
each occurrence of Lg is independently selected from the group consisting of:
—O—, —NH—, —NRd, —S(O)0-2, C(O), and C1-3 alkylene optionally substituted with 1-3 Ra;
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 C1-4 alkyl.

114 more elements

Compounds and compositions for treating conditions associated with STING activity

Life of this patent

Compounds and compositions for treating conditions associated with STING activity

Life of this patent

Abstract

Claims86