Heterocyclic compounds, compositions thereof, and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-2025250287-A1
Application number	US-202519049918-A
Country	US
Kind code	A1
Filing date	Feb 10, 2025
Priority date	Aug 11, 2022
Publication date	Aug 7, 2025
Grant date	—

Abstract

Provided herein are compounds having the following structure:wherein the substituents are as defined herein, compositions comprising an effective amount of a compound, and methods for modulating activity of KRAS G12D and/or G12V.

First claim

1 . A compound having Formula (I):

or a pharmaceutically acceptable salt, tautomer, isotopologue, stereoisomer, enantiomer, atropisomer, or prodrug thereof,
wherein
ring A is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
ring B is unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl;
X is N, or C—R 8 ;
each of R 0 is, independently, H, halogen, amino, —CN, —OH, unsubstituted or substituted C 1-4 alkyl, unsubstituted or substituted C 1-4 alkenyl, unsubstituted or substituted C 1-4 alkynyl, unsubstituted or substituted C 1-4 alkoxy, unsubstituted or substituted C 3-5 cycloalkyl, unsubstituted or substituted 3-member to 5-member heterocyclyl, unsubstituted or substituted C 1-4 alkylamino, carboxy, nitro, thiol, or thioether; or one or more pairs of the R 0 groups, together with the atom to which they are attached to, form unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
each of R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , and R 7b , is, independently, H, halogen, unsubstituted or substituted amino, —CN, —OH, unsubstituted or substituted C 1-4 alkyl, unsubstituted or substituted C 1-4 alkoxy, unsubstituted or substituted C 3-5 cycloalkyl, unsubstituted or substituted 3-member to 5-member heterocyclyl, unsubstituted or substituted C 1-4 alkylamino, carboxy, nitro, thiol, or thioether; optionally, R 3a , and R 3b , together with the atom to which they are attached to, form unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl; or R 4a , and R 4b , together with the atom to which they are attached to, form unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl; or R 6a , and R 6b , together with the atom to which they are attached to, form unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl; or R a , and R 7b , together with the atom to which they are attached to, form unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl; or optionally, R 3a , and R 4a , together with the atoms to which they are attached to, form unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl; or R 4a , and R 5 , together with the atoms to which they are attached to, form unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl; or R 5 , and R 6a , together with the atoms to which they are attached to, form unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl; or R 6a , and R a , together with the atoms to which they are attached to, form unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl;
R 8 is H, halogen, unsubstituted or substituted C 1-4 alkyl, unsubstituted or substituted C 1-4 alkenyl, unsubstituted or substituted C 3-5 cycloalkyl, unsubstituted or substituted C 1-4 alkoxyl, unsubstituted or substituted C 1-4 halogenated alkyl, unsubstituted or substituted C 3-5 halogenated cycloalkyl, unsubstituted or substituted C 1-4 halogenated alkoxyl, CN, OH, or amino;
t is 0, or 1;
u is 1, 2, 3, or 4; and
each of m, and q is, independently, an integer between 0 and the maximum number of the substituent groups allowed on rings A, and B, respectively.

2 . The compound of claim 1 , wherein X is N, C—H, C—Cl, or C—CF 3 .

3 . The compound of claim 2 , wherein ring A is substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzo[b]thiophenyl, or substituted or unsubstituted benzo[d]thiazolyl; and
ring B is substituted or unsubstituted hexahydro-1H-pyrrolizinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted aminomethylcyclopropyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted oxabicyclo[2.1.1]hexanyl, substituted or unsubstituted oxabicyclo[2.2.1]heptanyl.

4 . The compound of claim 0 , wherein ring A is

5 . The compound of claim 4 , wherein ring B is

wherein each of R a and R b is, independently, substituted or unsubstituted C 1-4 alkyl; substituted or unsubstituted C 3-5 cycloalkyl; or R a and R b together with the N they are attached to form a substituted or unsubstituted heterocycle containing N, O or S; and
R c is H, halogen, CN, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 3-5 cycloalkyl, substituted or unsubstituted C 1-4 alkoxyl.

6 . The compound of claim 5 , wherein the compound is a compound having formula (II):

7 - 9 . (canceled)

10 . The compound of claim 5 , wherein the compound is a compound having formula (III):

11 .- 18 . (canceled)

19 . The compound of claim 5 , wherein the compound is a compound having formula (IV):

20 .- 24 . (canceled)

25 . The compound of claim 5 , wherein the compound is a compound having formula (V):

26 . (canceled)

27 . The compound of claim 5 , wherein the compound is a compound having formula (VI):

28 . (canceled)

29 . The compound of claim 0 , wherein the compound is a compound having formula (VII):

30 .- 37 . (canceled)

38 . The compound of claim 5 , wherein the compound is a compound having formula (VIII):

39 .- 40 . (canceled)

41 . The compound of claim 5 , wherein the compound is a compound having formula (IX):

42 . (canceled)

43 . The compound of claim 5 , wherein the compound is a compound having formula (Ia):

or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, atropisomer, isotopologue, or prodrugs thereof,
wherein:
ring C is unsubstituted or substituted C 3-6 cycloalkyl, or unsubstituted or substituted 3-membered to 6-membered heterocyclyl;
each of u and v is, independently, an integer; and
the sum of u and v is 1, 2, 3, or 4.

44 . The compound of claim 1 , wherein the compound is selected from

Assignees

• Beigene Switzerland Gmbh

Inventors

• Yu Chao
• Chen Jie
• Bian Yichao
• Li Xiaoyu
• Sun Hanzi
• Liu Huaqing
• Wang Ce
• Wang Zhiwei

Classifications

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D498/16

  Peri-condensed systems · CPC title