Substituted quinazolines as inhibitors of KRAS G12C

Patent metadata

Field	Value
Publication number	US-11878985-B2
Application number	US-202017125955-A
Country	US
Kind code	B2
Filing date	Dec 17, 2020
Priority date	Oct 10, 2013
Publication date	Jan 23, 2024
Grant date	Jan 23, 2024

Abstract

Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I):or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein R1, R2a, R3a, R3b, R4a, R4b, G1, G2, L1, L2, m1, m2, A, B, W, X, Y, Z and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

First claim

The invention claimed is:

1. A method for covalently binding the cysteine 12 residue of a KRAS G12C protein in a human subject with a KRAS G12C-mutated cancer, wherein the method comprises administering to the human subject in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the following structure (I):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,
wherein:
A is CR 1 or CR 2b ;
B is CR 1 or CR 2 C;
R 1 is heterocyclyl, heteroaryl or aryl, wherein the heterocyclyl, aryl or heteroaryl is optionally 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 hydroxylalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, aminylsulfone, aminylcarbonyl, aminylcarbonylC 1 -C 6 alkyl, aminylcarbonylC 3 -C 8 cycloalkyl, C 1 -C 6 alkylaminylcarbonyl, C 3 -C 8 cycloalkylaminylcarbonyl, C 3 -C 8 cycloalkylalkyl and C 3 -C 8 cycloalkyl, C 3 -C 8 fused cycloalkyl and heteroaryl;
R 2a is H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, heteroaryl or aryl;
R 2b , when present, is H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, heteroaryl or aryl;
R 2c , when present, is H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, heteroaryl or aryl;
W is CR 6 ;
X is N;
Y is CR 6 ;
each R 6 is independently H, oxo, cyano, cyanoalkyl, amino, aminylalkyl, aminylalkylaminyl, aminylcarbonyl, aminylsulfonyl, —CO 2 NR a R b , wherein R a and R b are each independently H or C 1 -C 6 alkyl or R a and R b join to form a carbocyclic or heterocyclic ring, alkylaminyl, haloalkylaminyl, hydroxylalkyaminyl, amindinylalkyl, amidinylalkoxy, amindinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, C 1 -C 6 alkoxy, aminylalkoxy, alkylaminylalkoxy, alkylcarbonylaminylalkoxy, C 1 -C 6 alkyl, heterocyclyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylaminyl, heterocyclylalkylaminyl, heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylaminyl, heteroarylalkylaminyl, aryl, aryloxy, arylaminyl, arylalkylaminyl, arylalkyloxy or a bond to L;
Z is N;
L 1 is a bond or NR 7 ;
R 7 is H or C 1 -C 6 alkyl;
G 1 is CH or N;
each R 3a is independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
each R 3b is independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
each R 4a is independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
each R 4b is independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
G 2 is CH or N;
L 2 is a bond or alkylene;
m 1 is 1, 2 or 3;
m 2 is 1, 2 or 3;
E is:

wherein:
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;
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, heteroaryl or hydroxylalkyl or R 9 and R 10 join to form a carbocyclic or heterocyclic ring;
when is a triple bond then R 9 is absent and R 10 is H, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl;
with the proviso that:
(1) (a) W is CR 6 , where R 6 is a bond to L 1 ; or
(b) Y is CR 6 , where R 6 is a bond to L 1 ; and

(2) if R 1 is pyridinyl, then at least one of R 2a , R 2b or R 2c is not H.

2. The method of claim 1 , wherein the KRAS G12C-mutated cancer is selected from the group consisting of a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer and lung cancer.

3. The method of claim 1 , wherein the compound has the following structure (I′a):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,
wherein:
(i) R′ is R 1 ; and
R″ is R 2c ; or
(ii) R′ is H; and
R″ is R 1 .

4. The method of claim 3 , wherein the compound has the following structure (I′b), structure (I′c), structure (I′d), or structure (I′e):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

5. The method of claim 4 , wherein the compound has the following structure (I′f), structure (I′g), structure (I′h), structure (I′i), structure (I′j), structure (I′l), or structure (I′m):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

6. The method of claim 5 , wherein Q is —C(═O)—.

7. The method of claim 5 , wherein Q is —S(═O) 2 —, —NR 8 C(═O)— or —NR 8 S(═O) 2 —.

8. The method of claim 7 , wherein R 8 is H or hydroxylalkyl.

9. The method of claim 5 , wherein:
(i) R 9 is H; or
(ii) R 10 is H; or
iii) R 9 is H and R 10 is H.

10. The method of claim 5 , wherein R 10 is alkylaminylalkyl or hydroxylalkyl.

11. The method of claim 5 , wherein the compound has the following structure (I′j):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

12. The method of claim 11 , wherein

13. The method of claim 12 , wherein R 1 is heteroaryl.

14. The method of claim 13 , wherein L 1 is a bond.

15. The method of claim 14 , wherein L 2 is a bond.

16. The method of claim 15 , wherein:
R 2a is Cl; and
R 2b is F.

17. The method of claim 16 , wherein:
Y is CR 6 , wherein R 6 is heterocyclylalkyloxy.

18. The method of claim 17 , wherein one of R 3a , R 3b , R 4a , and R 4b is CH 3 and the other seven of R 3a , R 3b , R 4a , and R 4b are independently H.

19. The method of claim 18 , wherein R 1 is thiophenyl, pyridinyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl, benzodioxazolyl, benzoimidazolyl, quinolinyl, tetrahydroquinolinyl, quinazolinyl, indazolyl, benzothiophenyl or dihydrobenzodioxinyl.

20. The method of claim 19 , wherein the KRAS G12C-mutated cancer is selected from the group consisting of a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.

21. The method of claim 13 , where

Assignees

• Araxes Pharma Llc

Inventors

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

Classifications

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• C07D215/46

  with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms · CPC title

• C07D215/54

  attached in position 3 · CPC title

• C07D217/22

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring · CPC title

• C07D239/84

  Nitrogen atoms · CPC title