	US 12,152,018 B2
	Compounds and compositions for treating conditions associated with STING activity
Shankar Venkatraman, Lansdale, PA (US); Jason Katz, Newton, MA (US); William R. Roush, Boston, MA (US); and Hans Martin Seidel, Concord, MA (US)
Assigned to IFM Due, Inc., Boston, MA (US)
Filed by IFM Due, Inc., Boston, MA (US)
Filed on Jan. 7, 2022, as Appl. No. 17/570,936.
Claims priority of provisional application 63/135,336, filed on Jan. 8, 2021.
Prior Publication US 2022/0242852 A1, Aug. 4, 2022
Int. Cl. C07D 401/14 (2006.01); C07D 209/40 (2006.01); C07D 403/10 (2006.01); C07D 403/14 (2006.01); C07D 405/14 (2006.01)

CPC C07D 403/14 (2013.01) [C07D 209/40 (2013.01); C07D 401/14 (2013.01); C07D 403/10 (2013.01); C07D 405/14 (2013.01)]

36 Claims

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

X¹is NR²;

X²is CR⁵;

each

is independently a single bond or a double bond, provided that the five-membered ring comprising X¹and X²is heteroaryl, and

the 6-membered ring

is aromatic;

R^1a, R^1b, R^1c, and R⁵are each independently selected from the group consisting of: H; R^c; R^h; and -(L¹)_b1-R^h;

each occurrence of R²is independently selected from the group consisting of: H; R^d; R^g; and -(L²)_b2-R^g;

Q¹is selected from the group consisting of:

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(O)_0-2, and wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of R^cand R^h; and

C₆arylene optionally substituted with 1-4 substituents independently selected from the group consisting of R^cand R^h

each L^Ais independently selected from the group consisting of: C_1-3alkylene 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)₀atoms, unless an N—N bond is further attached to C(O);

Q²is R^g;

R³is selected from the group consisting of: H; R^d; and R^h;

W is:

(i) C(═O);

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:

C_1-10alkyl which is optionally substituted with 1-6 R^b; and

-(Y^A1)_nA-Y^A2, wherein:

nA is 0 or 1;

Y^A1is C_1-6alkylene optionally substituted with 1-3 R^b, and

Y^A2is selected from the group consisting of:

monocyclic C_3-8cycloalkyl or C_3-8cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R^c; 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(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; or

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^aand R^bis independently selected from the group consisting of: —OH; -halo; —NR^eR^f; C_1-4alkoxy; C_1-4haloalkoxy; —C(═O)O(C_1-4alkyl); —C(═O)(C_1-4alkyl); —C(═O)OH; —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4alkyl); and cyano;

each occurrence of R^cis independently selected from the group consisting of: halo; cyano; C_1-10alkyl which is optionally substituted with 1-6 independently selected R^a; C_2-6alkenyl; C_2-6alkynyl; C_1-4alkoxy; C_1-4haloalkoxy; —S(O)_1-2(C_1-4alkyl); —S(O)(═NH)(C_1-4alkyl); —NR^eR^f; —OH; —S(O)_1-2NR′R″; —C_1-4thioalkoxy; —NO₂; —C(═O)(C_1-10alkyl); —C(═O)O(C_1-4alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF₅;

each occurrence of R^dis independently selected from the group consisting of: C_1-6alkyl optionally substituted with 1-3 independently selected R^a; —C(O)(C_1-4alkyl); —C(O)O(C_1-4alkyl); —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4alkyl); —OH; and C_1-4alkoxy;

each occurrence of R^eand R^fis independently selected from the group consisting of: H; C_1-6alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, and Rⁱ; —C(O)(C_1-4alkyl); —C(O)O(C_1-4alkyl); —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4alkyl); —OH; and C_1-4alkoxy;

each occurrence of R^gis independently selected from the group consisting of:

C_3-12cycloalkyl or C_3-12cycloalkenyl, 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_6-10aryl 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^his independently selected from the group consisting of:

C_3-8cycloalkyl or C_3-8cycloalkenyl, each of which is optionally substituted with 1-4 Rⁱ;

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 Rⁱ;

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 Rⁱ; and

C₆aryl optionally substituted with 1-4 Rⁱ,

each occurrence of Rⁱis independently selected from the group consisting of: C_1-6alkyl; C_1-4haloalkyl; C_1-4alkoxy; C_1-4haloalkoxy; and halo;

each occurrence of L¹, L², and L^gis selected from the group consisting of: —O—, —NH—, —NR^d, —S(O)_0-2, C(O), and C_1-3alkylene 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_1-4alkyl.