K-Ras modulators

Patent metadata

Field	Value
Publication number	US-11358940-B2
Application number	US-201816605643-A
Country	US
Kind code	B2
Filing date	Apr 20, 2018
Priority date	Apr 20, 2017
Publication date	Jun 14, 2022
Grant date	Jun 14, 2022

Abstract

Provided herein are the K-Ras inhibitors of the formulae:Also provided are compositions comprising thereof for treating cancer.

First claim

What is claimed is:

1. A compound having formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is phenyl, indolinyl, indazolyl, benzimidazolyl, benzoxazolyl, azaindolyl, purinyl, indolyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl,

R 1 is independently halogen, —CX 1 3 , —CHX 1 2 , —CH 2 X 1 , —CN, —SO n1 R 1D , —SO v1 NR 1A R 1B , —NHNR 1A R 1B , —ONR 1A R 1B , —NHC=(O)NHNR 1A R 1B , —NHC(O)NR 1A R 1B , —N(O) m1 , —NR 1A R 1B , —C(O)R 1C , —C(O)—OR 1C , —C(O)NR 1A R 1B , —OR 1D , —NR 1A SO 2 R 1D , —NR 1A C(O)R 1C , —NR 1A C(O)OR 1C , —NR 1A OR 1C , —OCX 1 3 , —OCHX 1 2 , —OCH 2 X 1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; or two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
z1 is an integer from 0 to 4;
L 2 is —S(O) 2 —, —C(O)NH—, or —C(O)NHCH 2 —;
L 3 is a bond, —S(O) 2 —, —N(R 3 )—, —O—, —S—, —C(O)—, —C(O)N(R 3 )—, —N(R 3 )C(O)—, —N(R 3 )C(O)NH—, —NHC(O)N(R 3 )—, —C(O)O—, —OC(O)—, unsubstituted alkylene, unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted arylene, or unsubstituted heteroarylene;
R 3 is independently hydrogen, —CX 3 3 , —CHX 3 2 , —CH 2 X 3 , —C(O)R 3A , —C(O)OR 3A , —C(O)NR 3A R 3B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L 4 is a bond, —S(O) 2 —, —N(R 4 )—, —O—, —S—, —C(O)—, —C(O)N(R 4 )—, —N(R 4 )C(O)—, —N(R 4 )C(O)NH—, —NHC(O)N(R 4 )—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene;
R 4 is independently hydrogen, —CX 4 3 , —CHX 4 2 , —CH 2 X 4 , —C(O)R 4A , —C(O)OR 4A , —C(O)NR 4A R 4B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is independently:

wherein R 13 is hydrogen, halogen, substituted or unsubstituted alkyl; and z13 is an integer from 0 to 3;
each R 1A , R 1B , R 1C , R 1D , R 3A , R 3B , R 4A , and R 4B is independently hydrogen, —CX 3 , —CN, —COOH, —CONH 2 , —CHX 2 , —CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R 3A and R 3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
each X, X 1 , X 3 , and X 4 is independently —F, —Cl, —Br, or —I;
n1 is independently an integer from 0 to 4; and
m1 and v1 are independently 1 or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Ring A is indolinyl, indazolyl, benzimidazolyl, benzoxazolyl, azaindolyl, purinyl, indolyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl,

R 1 is independently halogen, —CX 1 3 , —CHX 1 2 , —CH 2 X 1 , —CN, —SO n1 R 1D , —SO v1 NR 1A R 1B , —NHNR 1A R 1B , —ONR 1A R 1B , —NHC=(O)NHNR 1A R 1B , —NHC(O)NR 1A R 1B , N(O) m1 , —NR 1A R 1B , —C(O)R 1C , —C(O)—OR 1C , —C(O)NR 1A R 1B , —OR 1D , —NR 1A SO 2 R 1D , —NR 1A C(O)R 1C , —NR 1A C(O)OR 1C , —NR 1A OR 1C , —OCX 1 3 , —OCHX 1 2 , —OCH 2 X 1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; or two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
z1 is an integer from 0 to 4;
L 3 is a bond, —S(O) 2 —, —N(R 3 )—, —O—, —S—, —C(O)—, —C(O)N(R 3 )—, —N(R 3 )C(O)—, —N(R 3 )C(O)NH—, —NHC(O)N(R 3 )—, —C(O)O—, —OC(O)—, unsubstituted alkylene, unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted arylene, or unsubstituted heteroarylene;
R 3 is independently hydrogen, —CX 3 3 , —CHX 3 2 , —CH 2 X 3 , —C(O)R 3A , —C(O)OR 3A , —C(O)NR 3A R 3B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L 4 is a bond, —S(O) 2 —, —N(R 4 )—, —O—, —S—, —C(O)—, —C(O)N(R 4 )—, —N(R 4 )C(O)—, —N(R 4 )C(O)NH—, —NHC(O)N(R 4 )—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene;
R 4 is independently hydrogen, —CX 4 3 , —CHX 4 2 , —CH 2 X 4 , —C(O)R 4A , —C(O)OR 4A , —C(O)NR 4A R 4B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each R 1A , R 1B , R 1C , R 1D , R 3A , R 3B , R 4A , and R 4B is independently hydrogen, —CX 3 , —CN, —COOH, —CONH 2 , —CHX 2 , —CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R 3A and R 3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
each X, X 1 , X 3 , and X 4 is independently —F, —Cl, —Br, or —I;
n1 is independently an integer from 0 to 4; and
m1 and v1 are independently 1 or 2.

3. The compo

Assignees

• Univ California
• Leidos Biomedical Res Inc

Inventors

• Mccormick Frank
• Renslo Adam
• Turner David
• Maciag Anna E
• Dyba Marcin
• Vo Elizabeth D
• Saavedra Joseph
• Kumari Vandana

Classifications

• C07C255/56

  containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton · CPC title

• C07D237/08

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• A61K31/4192

  1,2,3-Triazoles · CPC title

• C07C237/32

  having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title