Spirocyclic tetrahydroquinazolines

Patent metadata

Field	Value
Publication number	US-11312724-B2
Application number	US-202117200342-A
Country	US
Kind code	B2
Filing date	Mar 12, 2021
Priority date	Jan 8, 2020
Publication date	Apr 26, 2022
Grant date	Apr 26, 2022

Abstract

The present disclosure provides compounds represented by Formula I:wherein R3, A, A1, A2, A3, E, E1, E2, L, Q, Z, andare as defined in the specification, and the pharmaceutically acceptable salts and solvates thereof. Compounds of Formula I are KRAS inhibitors and are thus useful to treat cancer and other diseases.

First claim

What is claimed is:

1. A compound of Formula VII:

wherein:
Z is

X represents a 6- to 12-membered monocyclic or bicyclic heterocyclo;
R 1 is selected from the group consisting of —C(═O)R 1a , —C(═O)—CR 4a ═CR 4b R 4c , —C(═O)—C≡CR 5a , —S(═O) 2 CR 4e ═CR 4f R 4g , and —S(═O) 2 —C≡CR 5b ;
R 1a is selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 3 -C 6 cycloalkyl;
R 4a , R 4b , and R 4c are independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (amino)C 1 -C 4 alkyl, (hydroxy)C 1 -C 4 alkyl, (alkoxy)C 1 -C 4 alkyl, and (optionally substituted heterocyclo)C 1 -C 4 alkyl;
R 5a is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (amino)C 1 -C 4 alkyl, (hydroxy)C 1 -C 4 alkyl, (alkoxy)C 1 -C 4 alkyl, and (optionally substituted heterocyclo)C 1 -C 4 alkyl;
R 4e , R 4f , and R 4g are independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (amino)C 1 -C 4 alkyl, (hydroxy)C 1 -C 4 alkyl, (alkoxy)C 1 -C 4 alkyl, and (optionally substituted heterocyclo)C 1 -C 4 alkyl;
R 5b is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (amino)C 1 -C 4 alkyl, (hydroxy)C 1 -C 4 alkyl, (alkoxy)C 1 -C 4 alkyl, and (optionally substituted heterocyclo)C 1 -C 4 alkyl;
R 2a is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, (cyano)C 1 -C 4 alkyl, (hydroxy)C 1 -C 4 alkyl, (alkoxy)C 1 -C 4 alkyl, (amino)C 1 -C 4 alkyl, (optionally substituted heterocyclo)C 1 -C 4 alkyl, (optionally substituted aryl)C 1 -C 4 alkyl, (optionally substituted hetereoaryl)C 1 -C 4 alkyl, C 2 -C 4 alkynyl, heteroalkyl, cyano, —C(═O)OR 5c , —C(═O)NR 5d R 5e , and —NR 5f R 5g ;
R 2b and R 2c are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; or
R 2b and R 2c are attached to the same carbon atom and are taken together to form a —C(═O)— group;
R 5c is selected from the group consisting hydrogen and C 1 -C 4 alkyl;
R 5d and R 5e are independently selected from the group consisting hydrogen and C 1 -C 4 alkyl; or
R 5d and R 5e taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered heterocyclo;
R 5f and R 5g are independently selected from the group consisting hydrogen and C 1 -C 4 alkyl; or
R 5f and R 5g taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered heterocyclo;
L is selected from the group consisting of —O—, —S—, and —N(R 7 )—; or L is a bond;
R 7 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
R 3 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, (amino)C 1 -C 4 alkyl, (hydroxy)C 1 -C 4 alkyl, (alkoxy)C 1 -C 4 alkyl, (carboxamido)C 1 -C 4 alkyl, (optionally substituted heterocyclo)C 1 -C 4 alkyl, (optionally substituted aryl)C 1 -C 4 alkyl, and (optionally substituted hetereoaryl)C 1 -C 4 alkyl;
A is —CH 2 —;
E is —CH 2 —;
E 1 is —CH 2 —;
E 2 is —O—;
Q is selected from the group consisting of ═C(R 10 )— and ═N—;
R 10 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl; and
R 11a , R 11b , R 11c , and R 11d are independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and (hydroxy)C 1 -C 4 alkyl,
or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1 of Formula VIII:

or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1 of Formula IX:

or a pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 1 , wherein Q is ═N—; and L is —O—, or a pharmaceutically acceptable salt or solvate thereof.

5. The compound of claim 1 , wherein R 3 is selected from the group consisting of (amino)C 1 -C 4 alkyl, (carboxamido)C 1 -C 4 alkyl, and (optionally substituted heterocyclo)C 1 -C 4 alkyl, or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of claim 1 , wherein R 3 is:

wherein:
X is selected from the group consisting of —O— and —CR 18a R 18b ;
each R 17 is independently selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and (hydroxyl)C 1 -C 3 alkyl;
R 18a and R 18b are each independently selected from the group consisting of hydrogen, halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and (hydroxyl)C 1 -C 3 alkyl; or
R 18a and R 18b taken together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl;
u is 1, 2, or 3; and
v is 0, 1, or 2,
with the proviso that u is 2 or 3 when X is —O—.

7. The compound of claim 1 , wherein R 3 is selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.

8. The compound of claim 1 , wherein Z is selected from the group consisting of:

wherein R 2a is —CH 2 CN, or a pharmaceutically acceptable salt or solvate thereof.

9. The compound of claim 1 , wherein R 1 is selected from the group consisting of —C(═O)—CR 4a ═CHR 4b , —C(═O)—CCR 5a , and —S(═O) 2 CH═CHR 4f , or a pharmaceutically acceptable salt or solvate thereof.

10. The compound of claim 1 , wherein R 1 is selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.

11. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

12. The compound of claim 5 , wherein R 3 is (optionally substituted heterocyclo)C 1 -C 4 alkyl, or a pharmaceutically acceptable salt or solvate thereof.

13. The compound of claim 10 , wherein R 1 is:

or a pharmaceutically acceptable salt or solvate thereof.

14. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt

Assignees

• Ascentage Pharma Suzhou Co Ltd
• Ascentage Pharma Group Corp Ltd

Inventors

• Li Chao
• Tang Guozhi
• Chen Jianyong
• Jiao Lingling
• Li Liugen

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• C07D471/10 Primary

  Spiro-condensed systems · CPC title