Granted Patent B2

US 12,521,438 · App. 17/596,490 · Granted Jan 13, 2026

Inventors: Nan Ji (Arlington, MA); Yi Zhang (Belmont, MA); Michael D. Sintchak (Winchester, MA); Paul R. Fleming (Lexington, MA)

Assignee: Kymera Therapeutics, Inc.

A61K47/55A61K47/545A61P35/00

Abstract

Claims (44)

1 . A method of degrading one or more of SMARCA2, SMARCA4, and PB1 protein in a patient or biological sample comprising administering to said patient, or contacting said biological sample with a compound of formula I-h:

or a pharmaceutically acceptable salt thereof, wherein:

R x is —OR, wherein R is hydrogen or C 1-6 alkyl;

x is 1;

and

DIM is:

(i) a compound of formula I-xxx:

or a pharmaceutically acceptable salt thereof, wherein:

X1 is a bivalent group selected from —O— and —CR 2 —, wherein each R is independently H or C 1-6 alkyl;

X 2 is phenylenyl;

R 1 is —CR 2 , —CR 2 NR 2 , or —CR 2 N(R)C(O)R, wherein each R is independently hydrogen, or a group selected from C 1-6 aliphatic and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the C 1-6 aliphatic and a 5-6 membered heteroaryl is optionally substituted with one halogen;

R 2 is

Ring A is a ring selected from phenyl and a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of R 3 is independently hydrogen, C 1-6 aliphatic, or halogen; and

n is 0 or 1, or

2 . A method of treating one or more SMARCA2-mediated, SMARCA4-mediated, or PB1-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formula I-h:

or a pharmaceutically acceptable salt thereof, wherein:

R x is —OR, wherein R is hydrogen or C 1-6 alkyl;

x is 1;

L is

and

DIM is:

(i) a compound of formula I-xxx:

or a pharmaceutically acceptable salt thereof, wherein:

X1 is a bivalent group selected from —O— and —CR 2 —, wherein each R is independently H or C 1-6 alkyl;

X 2 is phenylenyl;

R 1 is —CR 2 , —CR 2 NR 2 , or —CR 2 N(R)C(O)R, wherein each R is independently hydrogen, or a group selected from C 1-6 aliphatic and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the C 1-6 aliphatic and a 5-6 membered heteroaryl is optionally substituted with one halogen or —OMe;

R 2 is

Ring A is a ring selected from phenyl and a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of R 3 is independently hydrogen, C 1-6 aliphatic, or halogen; and

n is 0 or 1, or

wherein the compound of formula I-h effectuates degradation of one or more of SMARCA2, SMARCA4, and PB1 protein in the patient, and wherein the one or more SMARCA2-mediated, SMARCA4-mediated, or PB1-mediated disorder is cancer.

3 . The method according to claim 2 , wherein the cancer is selected from lung cancer, breast cancer, pancreatic cancer, colorectal cancer, melanoma, leukemia, and malignant rhabdoid tumors (MRT).

4 . The method of claim 2 , wherein R x —OH.

5 . The method of claim 2 , wherein

6 . The method of claim 2 , wherein DIM is

7 . The method of claim 2 , wherein DIM is

8 . The method of claim 2 , wherein DIM is

9 . The method of claim 2 , wherein DIM is

10 . The method of claim 2 , wherein DIM is

11 . The method of claim 2 , wherein L is selected from:

12 . The method of claim 2 , wherein said compound of formula I-h is selected from:

or a pharmaceutically acceptable salt thereof.

13 . The method of claim 2 , wherein the compound or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition comprising a pharmaceutically acceptable carrier, adjuvant, or vehicle.

Assignments (1)

Continuity (5)

References Cited (400)