Fused ring compounds

Patent metadata

Field	Value
Publication number	US-11760744-B2
Application number	US-201916642824-A
Country	US
Kind code	B2
Filing date	Aug 15, 2019
Priority date	Aug 16, 2018
Publication date	Sep 19, 2023
Grant date	Sep 19, 2023

Abstract

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

First claim

What is claimed is:

1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof;
wherein,
R 1 is

wherein each R 20 is independently selected from the group consisting of C 1-6 alkyl, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , halo, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 hydroxyalkyl, —OC(═O)CH═CH 2 , and hydroxy, and p is 0, 1, 2, 3, or 4;
Y 1 is absent;
Y 2 is C(H)(R 8 );
Y 3 is CH;
Z 1 is N;
Z 2 is C(-L-R 10a );
Z 3 is N;
R 4 and R 5 are each hydrogen;
R 8 is selected from the group consisting of H and C 1 -C 6 alkyl;
-L-R 10a is selected from the group consisting of

R 13 , R 14 , and R 15 are each H, or R 13 is F and R 14 and R 15 are each H;
X is substituted or unsubstituted piperazine, wherein the substituted piperazine is substituted with one or more groups selected from the group consisting of CH 3 , CH 2 CN, CH 2 OH, CN, CF 3 , CH 2 CF 3 , and CHF 2 ;
n is 0; and
------ represents a single bond or a double bond.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 20 is independently selected from the group consisting of C 1-6 alkyl, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , halo, C 1-6 haloalkyl, and C 3-6 cycloalkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

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 1 , having a formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 having a formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. A method of treating cancer mediated by a K-Ras G12C mutation, the method comprising administering to an individual in need thereof a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer, lung cancer, or is agnostic.

11. A method for treating cancer mediated by a K-Ras G12C mutation in an individual having such cancer, the method comprising:
determining if the individual has the mutation; and
if the individual is determined to have the mutation, then administering to the individual a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof;
wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer, lung cancer, or is agnostic.

12. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from the group consisting of H, methyl, ethyl, and isopropyl.

15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from the group consisting of H and methyl.

16. The compound of claim 1 , selected from the group consisting of:
1-(4-(7-(3-amino-2-fluoro-5,6-dimethylphenyl)-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Compound 11);
1-[(3S)-4-[(6S,7S)-7-(3-amino-2-fluoro-5,6-dimethyl-phenyl)-6-methyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydroquinazolin-4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one (Compound 11a);
1-[(3S)-4-[(6R,7R)-7-(3-amino-2-fluoro-5,6-dimethyl-phenyl)-6-methyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydroquinazolin-4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one (Compound 11b);
1-(4-(7-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Compound 12);
1-((S)-4-((6S,7S)-7-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Compound 12a);
1-((S)-4-((6R,7R)-7-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Compound 12b);
1-(4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (Compound 20);
1-(4-((6R,7R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (Compound 20a);
1-(4-((6S,7S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (Compound 20b);
1-(4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Compound 21);
1-((S)-4-((6S,7S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Compound 21a);
1-((S)-4-((6R,7R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Compound 21b);
1-(4-(7-(3-amino-2-fluoro-6-(trifluoromethyl)phenyl)-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Compound 23);
1-((S)-4-((6S,7S)-7-(3-amino-2-fluoro-6-(trifluoromethyl)phenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-o

Assignees

• Genentech Inc

Inventors

• Lu Aijun
• Malhotra Sushant
• Olivero Alan G
• Shao Cheng
• Zhang Yamin
• Do Steven

Classifications

• A61K9/0014 Primary

  Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00) · CPC title

• A61K31/517 Primary

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

• C07D403/12 Primary

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

• C07D401/04 Primary

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

• C07D403/14

  containing three or more hetero rings · CPC title