Combination therapies for treatment of cancer

Patent metadata

Field	Value
Publication number	US-10111874-B2
Application number	US-201514858766-A
Country	US
Kind code	B2
Filing date	Sep 18, 2015
Priority date	Sep 18, 2014
Publication date	Oct 30, 2018
Grant date	Oct 30, 2018

Abstract

Combination therapies for treatment of cancers associated with mutations in the KRAS gene are provided. Compositions comprising therapeutic agents for treatment of cancers associated with mutations in the KRAS gene are also provided.

First claim

The invention claimed is:

1. A method for treating a KRAS G12C mutant cancer, the method comprising administering an effective amount of a KRAS G12C mutant modulating compound and an additional therapeutic agent to a subject in need thereof, wherein the KRAS G12C mutant modulating compound has the following structure (I′b):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
X and Y are each independently N or CR 6 ;
Z is N or CR 6a ;
L 1 is a bond;
L 2 is a bond or alkylene;
R′ is R 1 and R″ is R 2c ; or R′ is H and R″ is R 1 ;
R 1 is substituted or unsubstituted aryl or heteroaryl;
R 2a , R 1b and R 2C are each independently H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, 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, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl;
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, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl;
R 6 is, at each occurrence, independently H, 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 or arylalkyloxy;
R 6a is H or C 1 -C 6 alkyl;
represents a double or triple bond;
Q is —C(═O)-, —C(═NR 8′ )—, —NR 8 C(═O)-, —S(═O) 2 - or —NR 8 S(═O) 2 -;
R 8 is H, C 1 -C 6 alkyl or hydroxylalkyl;
R 8′ is H, —OH, —CN or C 1 -C 6 alkyl; and
when is a double bond then R 9 and R 10 are each independently H, cyano, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl or R 9 and R 10 join to form a carbocyclic or heterocyclic ring,
provided at least one of X, Y and Z is N,

wherein the KRAS mutant cancer is a pancreatic cancer, a colorectal cancer or a lung cancer.

2. The method of claim 1 , wherein the additional therapeutic agent is a phosphatidylinositol-3 kinase (PI3K) inhibitor.

3. The method of claim 2 , wherein the phosphatidylinositol kinase (PI3K) inhibitor is GDC0941, MLN1117, BYL719 (Alpelisib) or BKM120 (Buparlisib).

4. The method of claim 1 , wherein the additional therapeutic agent is a protein kinase inhibitor.

5. The method of claim 4 , wherein the protein kinase inhibitor is Afatinib, Axitinib, Bevacizumab, Bostutinib, Cetuximab, Crizotinib, Dasatinib, Erlotinib, Fostamatinib, Gefitinib, Imatinib, Lapatinib, Lenvatinib, Ibrutinib, Nilotinib, Panitumumab, Pazopanib, Pegaptanib, Ranibizumab, Ruxolitinib, Sorafenib, Sunitinib, SU6656, Trastuzumab, Tofacitinib, Vandetanib or Vemurafenib.

6. A method for inducing apoptosis in a cell population comprising a KRAS G12C mutant protein, the method comprising administering an effective amount of a KRAS G12C mutant modulating compound and an additional therapeutic agent to the cell population, wherein the KRAS G12C mutant modulating compound has the following structure (I′b):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
X and Y are each independently N or CR 6 ;
Z is N or CR 6a ;
L 1 is a bond;
L 2 is a bond or alkylene;
R′ is R 1 and R″ is R 2c ; or R′ is H and R″ is R 1 ;
R 1 is substituted or unsubstituted aryl or heteroaryl;
R 2a , R 2b and R 2C are each independently H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, 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, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl;
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, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl;
R 6 is, at each occurrence, independently H, 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 or arylalkyloxy;
R 6a is H or C 1 -C 6 alkyl;
represents a double or triple bond;
Q is —C(═O)—, —C(═NR 8′ )-, —NR 8 C(═O)-, —S(═O) 2 - or —NR 8 S(═O) 2 -;
R 8 is H, C 1 -C 6 alkyl or hydroxylalkyl;
R 8′ is H, —OH, —CN or C 1 -C 6 alkyl; and
when is a double bond then R 9 and R 10 are each independently H, cyano, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl or R 9 and R 10 join to form a carbocyclic or heterocyclic ring,
provided at least one of X, Y and Z is N.

7. A method for inhibiting G12C mutant protein in a subject, the method comprising administering an effective amount of a KRAS G12C mutant modulating compound and an additional therapeutic agent to the subject, wherein the KRAS G12C mutant modulating compound has the following structure (I′b):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
X and Y are each independently N or CR 6 ;
Z is N or CR 6a ;
L 1 is a bond;
L 2 is a bond or alkylene;
R′ is R 1 and R″ is R 2c ; or R′ is H and R″ is R 1 ;
R 1 is substituted or unsubstituted aryl or heteroaryl;
R 2a , R 2b and R 2C are each independently H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, 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, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl;
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, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl;
R 6 is, at each occurrence, independently H, 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 or arylalkyloxy;
R 6a is H or C 1 -C 6 alkyl;
represents

Assignees

• Araxes Pharma Llc

Inventors

• Janes Matthew Robert
• Patricelli Matthew Peter
• Li Liansheng
• Ren Pingda
• Liu Yi

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P1/18

  for pancreatic disorders, e.g. pancreatic enzymes · CPC title