Pyrazolo compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12110276-B2
Application number	US-202218057738-A
Country	US
Kind code	B2
Filing date	Nov 21, 2022
Priority date	Nov 24, 2021
Publication date	Oct 8, 2024
Grant date	Oct 8, 2024

Abstract

This disclosure relates to compounds and methods of using said compounds, as well as pharmaceutical compositions containing such compounds, for treating diseases and conditions mediated by TEAD, such as cancer.

First claim

What is claimed is:

1. A compound of formula (I-AB):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
L′ is *—N(R 1 )-L-**, wherein * denotes the point of attachment to Z, and ** denotes the point of attachment to

R 1 is H or C 1-6 alkyl;
X 1 is N or CR s , wherein R s is selected from H, deuterium, —CN, halo, C 1-15 alkyl, C 1-6 alkynyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —OR f , C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ;
wherein each of R d , R e and R f are independently H, C 1-6 alkyl, or C 3-20 cycloalkyl, wherein each of C 1-6 alkyl and C 3-20 cycloalkyl are independently optionally substituted with one or more halo, oxo, —OH, or —CN;
wherein the C 1-15 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more R t1 , wherein R t1 is independently, at each occurrence, selected from halo, oxo, —OH, —OR 1 , —CN, —NR d R e , and 3 to 15 membered heterocyclyl optionally substituted with one or more —OH; wherein R f1 is —C(O)CH 2 NR d R e , —C(O)C 1-6 alkyl, —P(O)(OH) 2 ; wherein R d and R e are each independently H or C 1-6 alkyl, and the C 1-6 alkyl of R d or R e is optionally substituted with one or more halo, oxo, —OH, or —CN; and
wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R t2 , wherein R t2 is independently, at each occurrence, selected from halo, oxo, —OH, —CN, C(O)NH 2 , —C(O)NR d R e , —NR d R e , C 1-6 alkoxyl, 3 to 6 membered heterocyclyl, C 3-6 cycloalkyl, and C 1-6 alkyl; wherein the C 1-6 alkyl of R t2 is optionally substituted with one or more —OH, C 1-6 alkoxyl, halo, oxo, —S(O) 2 CH 3 , or —NR d R e ; wherein R d and R e are each independently H, —C(O)CH 3 , —C(O)C 1-6 alkyl, or C 1-6 alkyl;

X 2 , X 3 , and X 4 are each independently N, CH, or CD, provided that: 1) only one of X 1 , X 2 , X 3 , and X 4 is N; or 2) X 1 is N, X 2 is CH, X 3 is CH, and X 4 is N; or 3) X 1 is CR s and X 2 , X 3 , and X 4 are each independently CH or CD;
B is phenyl or 5 to 6 membered heteroaryl, wherein the phenyl or 5 to 6 membered heteroaryl of B are each independently optionally substituted with one or more R, wherein R is independently at each occurrence selected from halo, C 1-15 alkyl, C 1-6 alkoxy, and S(R y ) 5 , wherein each R y is halo, and wherein the C 1-15 alkyl or C 1-6 alkoxy of R t is optionally substituted with one or more halo;
Z is —C(O)R x , wherein R x is C 2-6 alkenyl, optionally substituted with one or more substituents selected from C 1-6 alkyl, deuterium, —OH, C 1-6 alkoxyl, and halo; or R x is C 1-6 alkyl, optionally substituted with one or more halo; or R x is C 1-6 alkynyl optionally substituted with —OH; or R x is cyclobutenyl, dihydrofuranyl, bicyclobutanyl, or cyclopentenyl; or
Z is S(O) 2 R x1 , wherein R x1 is C 2-6 alkenyl; and
L is methylene, optionally substituted with one or more C 1-6 alkyl.

2. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-A):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R a , R b , and R c are each independently H, deuterium, —OH, C 1-6 alkoxyl, halo, or C 1-5 alkyl.

3. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (A-1):

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

4. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-A-1):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
R a , R b , and R c are each independently H, halo, deuterium, —OH, C 1-6 alkoxyl, or C 1-5 alkyl; and
R t is selected from halo, C 1-15 alkyl, C 1-6 alkoxy, and S(R y ) 5 , wherein each R y is halo, and wherein the C 1-15 alkyl or C 1-6 alkoxy of R t is optionally substituted with one or more halo.

5. The compound of claim 2 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-A-5):

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

6. The compound of claim 5 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-A-12):

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

7. The compound of claim 6 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-A-13):

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

8. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the R of B is —SF 5 , —O—CHF 2 , or —O—CF 3 .

9. The compound of claim 1 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is —C(O)R x and R x is C 2-6 alkenyl optionally substituted with one or more substituents selected from C 1-6 alkyl, deuterium, —OH, C 1-6 alkoxyl, and halo; or R x is C 1-6 alkyl optionally substituted with one or more halo.

10. The compound of claim 1 , or a stereoisomer or tautomer thereof or a pharmaceutically acceptable salt thereof, wherein X 1 is CR s ; and X 2 , X 3 , and X 4 are CH.

11. The compound of claim 1 , or a stereoisomer or tautomer thereof or a pharmaceutically acceptable salt thereof, wherein X 1 is CR s ; X 2 and X 3 are CH; and X 4 is N.

12. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R s is H, halo, or —CN.

13. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R s is —OR f , wherein R f is C 3-20 cycloalkyl optionally substituted with one or more —OH.

14. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R s is C 1-15 alkyl or C 1-15 alkoxy, wherein the C 1-15 alkyl or C 1-15 alkoxy of R s are each independently optionally substituted with one or more R t1 , wherein R t1 is independently, at each occurrence, selected from halo, oxo, —OH, —OR f1 , —CN,

Assignees

• Genentech Inc

Inventors

• Zbieg Jason Robert
• Smith Russell Tyler
• Beroza Paul Powell
• Verma Vishal Anil
• Zhu Bing-Yan
• Beveridge Ramsay
• Barton Lisa Marie
• Chan Bryan Ka Ip
• Colwell Curtis
• Bouayad-Gervais Samir
• Dey Anwesha
• Evangelista Marie Anne

Classifications

• C07F9/095

  Compounds containing the structure P(=O)-O-acyl, P(=O)-O-heteroatom, P(=O)-O-CN · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D231/56 Primary

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title