SOS1 inhibitors

Patent metadata

Field	Value
Publication number	US-12304915-B2
Application number	US-202218071384-A
Country	US
Kind code	B2
Filing date	Nov 29, 2022
Priority date	Dec 20, 2019
Publication date	May 20, 2025
Grant date	May 20, 2025

Abstract

The present invention relates to methods of treating cancer using compounds that inhibit Son of sevenless homolog 1 (SOS1) activity and pharmaceutical compositions containing such compounds.

First claim

What is claimed is:

1. A method for inhibiting SOS1 activity in a cell, comprising contacting the cell in which inhibition of SOS1 activity is desired with an effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is hydroxyl, C1-C6 alkyl, alkoxy, —N(R 6 ) 2 , —NR 6 C(O)R 6 , —C(O)N(R 6 ) 2 , —SO 2 alkyl, —SO 2 NR 6 alkyl, cycloalkyl, -Q-heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are each optionally substituted with one or more R 2 or L-R 2 ;
each Q is independently a bond, O, or NR 6 ;
X is N;
each R 2 is independently C1-C3 alkyl, oxo, hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , —SO 2 alkyl, —NR 6 C(O)C1-C3 alkyl, —C(O)cycloalkyl, —C(O)C1-C3 alkyl, —C(O)heterocyclyl, aryl, heteroaryl or heterocyclyl, wherein the cycloalkyl, the heterocyclyl, the aryl, the heteroaryl or the heterocyclyl are each optionally substituted with one or more R 11 ;
R 3 is hydrogen, C1-C6 alkyl, alkoxy, —N(R 10 ) 2 , -L-N(R 10 ) 2 , cycloalkyl, haloalkyl or heterocyclyl, wherein the C1-C6 alkyl, the cycloalkyl and the heterocyclyl, are each optionally substituted with one or more R 9 ;
Y is a bond or heteroarylene;
R 4 is aryl or heteroaryl, each optionally substituted with one or more R 5 ;
each R 5 is independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, haloalkyl-OH, —N(R 6 ) 2 , -L-N(R 6 ) 2 or -SO 2 alkyl;
L is C1-C3 alkylene;
each R 6 is independently hydrogen, C1-C3 alkyl, haloalkyl, or cycloalkyl;
R 8 is C1-C2 alkyl or halo-C1-C2 alkyl;
each R 9 is independently hydroxy, halogen, amino, cyano, alkoxy, or C1-C3 alkyl;
each R 10 is independently hydrogen, C1-C3 alkyl or cycloalkyl;
each R 11 is independently C1-C3 alkyl, halogen or haloalkyl; and
R 12 is hydrogen, halogen or C1-C3 alkyl,
or a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein the cell harbors an activating mutation in a RAS family-member gene.

3. The method according to claim 1 , wherein the cell harbors an activating mutation in SOS1 gene.

4. The method according to claim 1 , wherein the cell harbors an activating mutation in NF-1 or NF-2 gene.

5. A method for treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is hydroxyl, C1-C6 alkyl, alkoxy, —N(R 6 ) 2 , —NR 6 C(O)R 6 , —C(O)N(R 6 ) 2 , —SO 2 alkyl, —SO 2 NR 6 alkyl, cycloalkyl, -Q-heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are each optionally substituted with one or more R 2 or L-R 2 ;
each Q is independently a bond, O, or NR 6 ;
X is N;
each R 2 is independently C1-C3 alkyl, oxo, hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , —SO 2 alkyl, —NR 6 C(O)C1-C3 alkyl, —C(O)cycloalkyl, —C(O)C1-C3 alkyl,—C(O)heterocyclyl, aryl, heteroaryl or heterocyclyl, wherein the cycloalkyl, the heterocyclyl, the aryl, the heteroaryl or the heterocyclyl are each optionally substituted with one or more R 11 ;
R 3 is hydrogen, C1 C6 alkyl, alkoxy, —N(R 10 ) 2 , -L-N(R 10 ) 2 , cycloalkyl, haloalkyl or heterocyclyl, wherein the C1-C6 alkyl, the cycloalkyl and the heterocyclyl, are each optionally substituted with one or more R 9 ;
Y is a bond or heteroarylene;
R 4 is aryl or heteroaryl, each optionally substituted with one or more R 5 ;
each R 5 is independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, haloalkyl-OH, —N(R 6 ) 2 , -L-N(R 6 ) 2 or -SO 2 alkyl;
L is C1-C3 alkylene;
each R 6 is independently hydrogen, C1-C3 alkyl, haloalkyl, or cycloalkyl;
R 8 is C1-C2 alkyl or halo-C1-C2 alkyl;
each R 9 is independently hydroxy, halogen, amino, cyano, alkoxy, or C1-C3 alkyl;
each R 10 is independently hydrogen, C1-C3 alkyl or cycloalkyl;
each R 11 is independently C1-C3 alkyl, halogen or haloalkyl; and
R 12 is hydrogen, halogen or C1-C3 alkyl, or
a pharmaceutically acceptable salt or solvate thereof, alone or combined with a pharmaceutically acceptable carrier, excipient or diluents,
wherein the cancer is a Ras family-associated cancer, a SOS1-associated cancer or a NF-1/NF-2 associated cancer.

6. The method according to claim 5 , wherein R 1 is alkoxy or -Q-heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more R 2 or L-R 2 .

7. The method according to claim 6 , wherein R 1 is -Q-heterocyclyl, and wherein Q is a bond or —O— and the heterocyclyl is morpholinyl, piperazinyl, or piperazinone.

8. The method according to claim 7 , wherein R 1 is -Q-heterocyclyl, and wherein the heterocyclyl is bridged morpholinyl, bridged piperazinyl, or bridged piperazinone.

9. The method according to claim 6 , wherein R 1 is -Q-heterocyclyl, and wherein the heterocyclyl is spirocyclic ring system containing two or more rings.

10. The method according to claim 9 , wherein the spirocyclic ring system comprises two rings each containing a heteroatom.

11. The method according to claim 9 , wherein the spirocyclic ring system contains a ring with no heteroatom.

12. The method according to claim 5 , wherein R 1 is heteroaryl, wherein the heteroaryl is optionally substituted with one or more R 2 or L-R 2 .

13. The method according to claim 12 , wherein the heteroaryl is a bicyclic or tricyclic ring system comprising a non-aromatic ring.

14. The method according to claim 13 , wherein the bicyclic or tricyclic ring system is 5,6,7,8-tetrahydro-[1,2,4]triazolopyrazinyl, 5,6,7,8-tetrahydroimidazopyrazinyl, 2,4,5,6-tetrahydropyrrolopyrazolyl, 1,2,3,4-tetrahydrobenzo[4,5]imidazopyrazinyl or 4,5,6,7-tetrahydropyrazolopyrazinyl.

15. The method according to claim 5 , wherein R 1 is hydroxyl.

16. The method according to claim 5 , wherein R 1 is —N(R 6 ) 2 .

17. The method according to claim 5 , wherein R 1 is —NR 6 C(O)R 6 .

18. The method according to claim 5 , wherein R 1 is —C(O)N(R 6 ) 2 .

19. The method according to claim 5 , wherein R 1 is cycloalkyl optionally substituted with one or more R 2 .

20. The method according to claim 19 , wherein the cycloalkyl is cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with one or more R 2 .

21. The method according to claim 20 , wherein the cyclobutyl, cyclopentyl or the cyclohexyl are substituted with one R 2 , wherein R 2 is C1-C3 alkyl, alkoxy, halogen, hydroxyl or —N(R 6 ) 2 .

22. The method according to claim 5 , wherein R 1 is -Q-heterocyclyl optionally substituted with one or more R 2 .

23. The method according to claim 22 , wherein Q is a bond and the heterocyclyl is morpholinyl, piperdinyl, piperazinyl, N-methylpiperazinyl, piperazin-2-one, 1-methyl-piperazin-2-one, diazepanyl,

Assignees

• Mirati Therapeutics Inc

Inventors

• Marx Matthew Arnold
• Ketcham John Michael
• Smith Christopher Ronald
• Lawson John David
• Burns Aaron Craig
• Wang Xiaolun
• Kulyk Svitlana
• Ivetac Anthony

Classifications

• C07D237/34

  with nitrogen atoms directly attached to carbon atoms of the nitrogen-containing ring, e.g. hydrazine radicals · CPC title

• C07D471/08

  Bridged systems · CPC title

• C07D498/10

  Spiro-condensed systems · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title