Methods and compositions for inhibition of Ras

Patent metadata

Field	Value
Publication number	US-10011600-B2
Application number	US-201515508387-A
Country	US
Kind code	B2
Filing date	Sep 25, 2015
Priority date	Sep 25, 2014
Publication date	Jul 3, 2018
Grant date	Jul 3, 2018

Abstract

Inhibitors of Ras protein, methods to modulate the activity of Ras protein, and methods of treatment of disorders mediated by Ras protein are provided. A method for regulating activity of a K-Ras, H-Ras or N-Ras mutant protein with a compound is described. Disorders that can be treated include cancer, such as hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer, or lung cancer.

First claim

What is claimed is:

1. A compound having the following structure (I):

or a pharmaceutically acceptable salt thereof, wherein:
A is CR 2b ;
B is CR 1 ;
G 1 and G 2 are each independently N or CH;
W is CR 6 ;
X is N;
Y is CR 6 ;
Z is N;
L 1 is a bond or NR 7 ;
L 2 is a bond or alkylene;
R 1 is H, cyano, halo, heterocyclyl, heteroaryl, aryloxy or aryl;
R 2a and R 2b are each independently H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl or aryl;
R 3a and R 3b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkynyl, hydroxylalkyl, aminoalkyl, alkylaminoalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or R 3a and R 3b join to form a carbocyclic or heterocyclic ring; or R 3a is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkynyl, hydroxylalkyl, aminoalkyl, alkylaminoalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl, and R 3b joins with R 4b to form a carbocyclic or heterocyclic ring;
R 4a and R 4b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkynyl, hydroxylalkyl, aminoalkyl, alkylaminoalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or R 4a and R 4b join to form a carbocyclic or heterocyclic ring; or R 4a is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkynyl, hydroxylalkyl, aminoalkyl, alkylaminoalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl, and R 4b joins with R 3b to form a carbocyclic or heterocyclic ring;
R 7 is H or C 1 -C 6 alkyl;
R 6 is, at each occurrence, independently H, oxo, cyano, cyanoalkyl, amino, aminylalkyl, aminylalkylaminyl, aminocarbonyl, alkylaminyl, haloalkylamino, hydroxylalkyamino, amindinylalkyl, amidinylalkoxy, amindinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, C 1 -C 6 alkoxy, aminylalkoxy, alkylcarbonylaminylalkoxy, C 1 -C 6 alkyl, heterocyclyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, heteroarylalkylamino, aryl, aryloxy, arylamino, arylalkylamino, arylalkyloxy or a bond to L 1 ;
m 1 and m 2 are each independently 1, 2 or 3;
indicates a single or double bond such that all valences are satisfied; and
T is a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein;

wherein a heteroaryl comprises one to six heteroatoms selected from nitrogen, oxygen and sulfur;
wherein a heterocyclyl comprises one to six heteroatoms selected from nitrogen, oxygen and sulfur;
wherein at least one of W, X, Y or Z is CR 6 where R 6 is a bond to L 1 ; and
provided that when R 1 , R 2a , and R 2b are all independently selected from H and halo, then X and Z are both N and at least one of R 3a , R 3b , R 4a or R 4b is not H, and provided that at least one of R 2a or R 2b is not H when R 1 is pyridyl.

2. The compound of claim 1 , wherein the compound has one of the following structures (ID, (I′k), (I′l) or (I′m):

3. The compound of claim 1 , wherein R 1 is aryl.

4. The compound of claim 3 , wherein R 1 is phenyl or naphthyl.

5. The compound of claim 1 , wherein R 1 is substituted with one or more substituents selected from halo, cyano, cyanoC 1 -C 6 alkyl, cyanoC 3 -C 8 cycloalkyl, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkylcycloalkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylaminyl, C 1 -C 6 alkylcarbonylaminyl, C 1 -C 6 hydroxyl alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, aminosulfone, aminocarbonyl, aminocarbonylC 1 -C 6 alkyl, aminocarbonylC 3 -C 8 cycloalkyl, C 1 -C 6 alkylaminocarbonyl, C 3 -C 8 cycloalkylaminocarbonyl, C 3 -C 8 cycloalkylalkyl and C 3 -C 8 cycloalkyl, C 3 -C 8 fusedcycloalkyl and heteroaryl.

6. The compound of claim 5 , wherein R 1 is substituted with one or more substituents selected from fluoro, chloro, bromo, cyano, hydroxyl, hydroxylmethyl, methoxy, methoxymethyl, ethyl, isopropyl, trifluoromethyl, aminocarbonyl and cyclopropyl.

7. The compound of claim 1 , wherein R has one of the following structures:

8. The compound of claim 1 , wherein R 2a , when present, is halo.

9. The compound of claim 1 , wherein R 2a , when present, is C 1 -C 6 alkyl.

10. The compound of claim 1 , wherein R 2b , when present, is halo.

11. The compound of claim 1 , wherein L 1 is a bond.

12. The compound of claim 1 , wherein L 2 is a bond.

13. The compound of claim 1 , wherein R 3a , R 3b , R 4a and R 4b are H.

14. The compound of claim 1 , wherein W is CR 6 , wherein R 6 is a bond to L 1 .

15. The compound of claim 1 , wherein R 6 is H, cyano, C 1 -C 6 alkoxy, amino, aminylalkyl or C 1 -C 6 alkyl.

16. The compound of claim 1 , wherein the compound is selected from the group consisting of:

17. The compound of claim 1 , wherein the compound is selected from the group consisting of:

18. The compound of claim 1 , wherein T is selected from the group consisting of:
H, —NH 2 , —OH, —NHR 5 ,

Assignees

• Araxes Pharma Llc

Inventors

• Li Liansheng
• Feng Jun
• Long Yun Oliver
• Ren Pingda
• Liu Yi

Classifications

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C12N9/14

  Hydrolases (3) · CPC title