Smarca degraders and uses thereof

Patent metadata

Field	Value
Publication number	US-2025170248-A1
Application number	US-202519022628-A
Country	US
Kind code	A1
Filing date	Jan 15, 2025
Priority date	Jun 28, 2021
Publication date	May 29, 2025
Grant date	—

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

First claim

1 . A compound of formula I-a:

or a pharmaceutically acceptable salt thereof, wherein:
each of Ring V, Ring W, and Ring Y is independently a fused ring selected from 6-membered aryl, 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 4-9 membered saturated or partially unsaturated monocyclic, bicyclic, or bridged bicyclic carbocyclyl or heterocyclyl with 1-4 heteroatoms independently selected from, nitrogen, oxygen, and sulfur;
R w is selected from

or hydrogen;
Ring Z is phenyl, a 5-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of R and R y is independently hydrogen, Rz, halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —Si(R) 3 , —S(O) 2 R, —S(O) 2 N(R) 2 , —S(O)R, —CF(R) 2 , —CF 2 R, —CF 3 , —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)NROR, —C(R) 2 NRC(O)R, —C(R) 2 NRC(O)N(R) 2 , —OC(O)R, —OC(O)N(R) 2 , —OP(O)(R) 2 , —OP(O)(OR) 2 , —OP(O)(OR)N(R) 2 , —OP(O)(N(R) 2 ) 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)N(R) 2 , —NRS(O) 2 R, —NP(O)R 2 , —NRP(O)(OR) 2 , —NRP(O)(OR)N(R) 2 , —NRP(O)(N(R) 2 ) 2 , or —NRS(O) 2 R; or
two R groups or two R y groups are optionally taken together to form an optionally substituted 5-7 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same atom are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring or an optionally substituted 3-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur;

each R z is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L x is a covalent bond or a C 1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(S)—, —C(R) 2 —, —CFR—, —CF 2 —, —NR—, —S—, —S(O) 2 — or —CR═CR—; and
x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;
y is 0, 1, 2, 4, or 5;
L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C 1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —N(R)—, —Si(R) 2 —, —Si(OH)(R)—, —Si(OH) 2 —, —P(O)(OR)—, —P(O)(R)—, —P(O)(N(R) 2 )—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, —N(R)C(O)O—,

each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
r is 0, 1,2,3,4,5,6,7,8,9,or 10;
X is —C(O)—, —C(O)NR—, —SO 2 —, —SO 2 NR—, or an optionally substituted 5-membered heterocyclic ring;
X 1 is a covalent bond or bivalent group selected from —O—, —C(O)—, —C(S)—, —C(R) 2 —, —NR—, —S(O)—, or —SO 2 —;
X 2 is an optionally substituted bivalent group selected from C 1-6 saturated or unsaturated alkylene, phenylenyl, a 5-6 membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R 1 is R Z , —C(R) 2 Rz, —OR, —SR, —N(R) 2 , —C(R) 2 OR, —C(R) 2 N(R) 2 , —C(R) 2 NRC(O)R, —C(R) 2 NRC(O)N(R) 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)N(R) 2 , or —NRSO 2 R;
R 2 is hydrogen, halogen, —CN,

Ring A is a ring selected from phenyl, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-9 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of R 3 is independently hydrogen, Rz, halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —Si(R) 3 , —SO 2 R, —SO 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)OR, —C(R) 2 NRC(O)R, —C(R) 2 NRC(O)N(R) 2 , —OC(O)R, —OC(O)N(R) 2 , —OP(O)(R) 2 , —OP(O)(OR) 2 , —OP(O)(OR)N(R) 2 , —OP(O)(N(R) 2 ) 2 , —N(R)C(O)OR, —N(R)C(O)R, —NRC(O)N(R) 2 , —N(R)SO 2 R, —NP(O)(R) 2 , —N(R)P(O)(OR) 2 , —N(R)P(O)(OR)N(R) 2 , —N(R)P(O)(N(R) 2 ) 2 , or —N(R)SO 2 R; or
two R 3 groups are optionally taken together to form an optionally substituted 5-7 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

n is 0, 1, 2, 4, or 5.

2 . The compound of claim 1 , wherein R w is

and Ring Z is phenyl or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

3 . The compound of any one of claims 1-2 , wherein Ring V is a fused 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

4 . The compound of any one of claims 1-3 , wherein Ring W is a fused 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 4-9 membered saturated or partially unsaturated monocyclic, bicyclic, or bridged bicyclic heterocyclyl with 1-4 heteroatoms independently selected from, nitrogen, oxygen, and sulfur.

5 . The compound of any one of cl

Assignees

• Kymera Therapeutics Inc

Inventors

• Zhang Yi
• Fleming Paul R
• Zhu Xiao
• Weiss Matthew M

Classifications

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• C12N9/104

  Aminoacyltransferases (2.3.2) · CPC title

• C12Y203/02

  Aminoacyltransferases (2.3.2) · CPC title