Fused ring compounds

Patent metadata

Field	Value
Publication number	US-12084429-B2
Application number	US-202117644993-A
Country	US
Kind code	B2
Filing date	Dec 17, 2021
Priority date	Nov 9, 2018
Publication date	Sep 10, 2024
Grant date	Sep 10, 2024

Abstract

This invention pertains to fused ring compounds of Formula (I), as further detailed herein, which are used for the inhibition of Ras proteins, as well as compositions comprising these compounds and methods of treatment by their administration.

First claim

What is claimed is:

1. A compound having a Formula (II):

or a pharmaceutically acceptable salt thereof;
wherein,
R 2 is NH 2 ;
R 3 and R 4 are each independently selected from the group consisting of H, NH 2 , halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 1-6 alkylamino, and cyclopropyl;
R 5 is selected from the group consisting of H, NH 2 , halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 1-6 alkylamino, and C 3-7 cycloalkyl,
or wherein R 4 and R 5 , together with the atoms to which they are each bonded, form C 6-14 aryl or 5- to 10-membered heteroaryl; each of which is optionally substituted with 1 to 4 substituents, wherein each substituent is independently selected from the group consisting of OH, NH 2 , halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy;
R 7 is selected from the group consisting of H, cyano, and halo; and R 8 and R 9 are each independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, and halo; wherein C 1-6 alkyl is optionally substituted with one substituent selected from the group consisting of: methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), an alkyl or aryl sulfonate leaving group, C 1-6 alkanoylamino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 6-12 dialkylamino, and C 1-6 haloalkoxy;
or
R 7 and R 8 together form a triple bond between the carbons to which they are attached, or R 7 and R 8 together with the carbons to which they are each bonded form a C 3-7 cycloalkenyl optionally substituted with one or two halo substituents; and Ry is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, cyano, and halo; wherein C 1-6 alkyl is optionally substituted with one substituent selected from the group consisting of: C 1-6 alkanoylamino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 6-12 dialkylamino, and C 1-6 haloalkoxy;
X is 4- to 7-membered heterocyclyl optionally substituted with 1 to 4 substituents, wherein each substituent is independently selected from the group consisting of OH, NH2, halo, cyano, carboxy, carbamoyl, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 carbamoylalkyl, C 1-6 carboxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and 4- to 7-membered heterocyclyl; wherein two geminal substituents may be taken together to form C 3-7 spirocycloalkyl or 4- to 7-membered spiroheterocyclyl;
Y is Y 1 ;
Y 1 is H;
U is C(R 6a );
V is C(R 6b );
W is C(R 6c );
each of R 6a , R 6b , and R 6c are independently selected from the group consisting of H, OH, NH 2 , halo, cyano, carbamoyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl substituted with a 4- to 10-membered heterocyclyl substituent, C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 haloalkylthio, C 2-6 alkynyl, C 1-6 alkylamino, C 6-14 aryl, C 1-6 aminoalkyl, C 1-6 carbamoylalkyl, C 1-6 carboxyalkyl, C 1-6 cyanoalkyl, C 3-7 cycloalkyl, C 1-6 haloalkoxy, C 1-6 haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; and
n is selected from the group consisting of 0, 1, and 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are independently selected from the group consisting of H, halo, C 1-6 alkyl, C 1-6 haloalkyl, and cyclopropyl and R 5 is selected from the group consisting of H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, and C 3-7 cycloalkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 , together with the atoms to which they are each bonded, form an unsubstituted C 6 aryl or 5- to 10-membered heteroaryl; or wherein R 4 and R 5 , together with the atoms to which they are each bonded, form a Ce aryl or 5- to 10-membered heteroaryl substituted with 1 substituent, independently selected from the group consisting of halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy.

4. A compound having a Formula (IV):

or a pharmaceutically acceptable salt thereof;
wherein,
R 1 is an electrophilic moiety capable of forming a covalent bond with a cysteine residue at position 12 of a K-Ras G12C mutant protein;
X is 4- to 7-membered heterocyclyl optionally substituted with 1 to 4 substituents, wherein each substituent is independently selected from the group consisting of OH, NH 2 , halo, cyano, carboxy, carbamoyl, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 carbamoylalkyl, C 1-6 carboxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and 4- to 7-membered heterocyclyl; wherein two geminal substituents may be taken together to form C 3-7 spirocycloalkyl or 4- to 7-membered spiroheterocyclyl;
Y is Y 1 ;
Y 1 is H;
U is C(R 6a );
V is C(R 6b );
W is C(R 6c );
each of R 6a , R 6b , and R 6c are independently selected from the group consisting of H, OH, NH 2 , halo, cyano, carbamoyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl substituted with a 4- to 10-membered heterocyclyl substituent, C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 haloalkylthio, C 2-6 alkynyl, C 1-6 alkylamino, C 6-14 aryl, C 1-6 aminoalkyl, C 1-6 carbamoylalkyl, C 1-6 carboxyalkyl, C 1-6 cyanoalkyl, C 3-7 cycloalkyl, C 1-6 haloalkoxy, C 1-6 haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl;
n is selected from the group consisting of 0, 1, and 2; and
R 11 is selected from the group consisting of:

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 6a is H.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of:

7. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of:

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of

9. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein X is

10. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein

Assignees

• Genentech Inc

Inventors

• Malhotra Sushant
• Xin Jianfeng
• Do Steven
• Terrett Jack

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K9/0053

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

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title