Substituted pyrazolopyrazines, imidazopyrazines and [1,2,4]triazolopyrazines as allosteric SHP2 inhibitors

Patent metadata

Field	Value
Publication number	US-11739093-B2
Application number	US-201916518798-A
Country	US
Kind code	B2
Filing date	Jul 22, 2019
Priority date	Jan 23, 2017
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

The present disclosure is directed to compounds of Formula IV:as inhibitors of SHP2 and their use in the treatment of diseases associated with SHP2. Also disclosed are pharmaceutical compositions comprising the same.

First claim

The invention claimed is:

1. A compound of Formula IV:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:

is:

wherein ring B is optionally substituted on any available carbon with one or two substituents independently selected from the group consisting of C 1 -C 6 alkyl, CH 2 F, CHF 2 , CF 3 , (CH 2 ) n NH 2 , (CH 2 ) n OH, heterocyclyl, and heteroaryl;

R 2 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR 5 R 6 , OH, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, or heterocyclyl;
wherein the heterocyclyl contains 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of nitrogen, phosphorous, oxygen, and sulfur;
wherein the heterocyclyl is not attached via a nitrogen atom; and
wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , NR 5 R 6 , NR 5 S(O)R 6 , NR 5 S(O)NR 5 R 6 , NR 5 S(O) 2 R 6 , NR 5 S(O) 2 NR 5 R 6 , OR 5 , ═O, SR 5 , S(O)R 5 , S(O)NR 5 R 6 , S(O) 2 R 5 , S(O) 2 NR 5 R 6 , heterocyclyl, aryl, heteroaryl, and R 5 ;

Y 2 is —NR a ', —NR a C(O)—, —NR a C(O)NR a —, —NR a C(O)O—, —NR a C(S)—, —NR a C(S)NR a —, or —NR a S(O) 2 —, wherein the bond on the left side of Y 2 is bound to the ring and the bond on the right side of Y 2 is bound to R 3 ;
R 3 and R a , together with the atom(s) to which they are attached, form a monocyclic or polycyclic 3- to 12-membered heterocyclyl or a spirocyclic 5- to 12-membered heterocyclyl;
wherein the monocyclic or polycyclic 3- to 12-membered heterocyclyl or spirocyclic 5- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, CH 2 F, CHF 2 , CF 3 , (CH 2 ) n NH 2 , (CH 2 ) n OH, ═O, heterocyclyl, and heteroaryl;

R 4 is:

wherein:
Y 1 is a direct bond, —CH 2 —, —C(═CH 2 )—, —NH—, —S—, —S(O)—, —S(O) 2 —, or —S(O) 2 NH—;
ring A is a monocyclic or polycyclic 5- to 12-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and
each R 1 is independently H, D, halogen, CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C(O)R 5 , C(O)OR 5 , NR 5 R 6 , NR 5 S(O)R 6 , NR 5 S(O)NR 5 R 6 , NR 5 S(O) 2 R 6 , NR 5 S(O) 2 NR 5 R 6 , OR 5 , SR 5 , S(O)R 5 , S(O)NR 5 R 6 , S(O) 2 R 5 , S(O) 2 NR 5 R 6 , C 3 -C 8 cycloalkyl, or C 4 -C 8 cycloalkenyl;
wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, and C 4 -C 8 cycloalkenyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , NR 5 R 6 , NR 5 S(O)R 6 , NR 5 S(O)NR 5 R 6 , NR 5 S(O) 2 R 6 , NR 5 S(O) 2 NR 5 R 6 , OR 5 , ═O, SR 5 , S(O)R 5 , S(O)NR 5 R 6 , S(O) 2 R 5 , S(O) 2 NR 5 R 6 , heterocyclyl, aryl, heteroaryl, and R 5 ;

each R 5 is independently H, D, halogen, CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR 7 R 8 , OR 7 , SR 7 , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, or a monocyclic or polycyclic 3- to 12-membered heterocyclyl;
each R 6 is independently H, D, halogen, CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR 7 R 8 , OR 7 , SR 7 , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, or a monocyclic or polycyclic 3- to 12-membered heterocyclyl;
each R 7 is independently H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, or a monocyclic or polycyclic 3- to 12-membered heterocyclyl;
wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, and 3- to 12-membered monocyclic or polycyclic heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of CN, NO 2 , NH 2 , OH, and SH;

each R 8 is independently H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, or a monocyclic or polycyclic 3- to 12-membered heterocyclyl;
wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, and 3- to 12-membered monocyclic or polycyclic heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of CN, NO 2 , NH 2 , OH, and SH; and

each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

with the provisos that:
(1) the heteroaryl of ring A is not furanyl or thiophenyl; and
(2) R a and R 3 , together with the atom(s) to which they are attached, do not form an optionally substituted piperazinyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein ring B is optionally substituted on any available carbon with one or two substituents independently selected from the group consisting of C 1 -C 6 alkyl, CH 2 F, CHF 2 , CF 3 , (CH 2 ) n NH 2 , and (CH 2 ) n OH.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 is C 1 -C 6 alkyl;
wherein the C 1 -C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NR 5 R 6 , and OR 5 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 is CH 3 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Y 2 is —NR a —, wherein the bond on the left side of Y 2 is bound to the ring and the bond on the right side of Y 2 is bound to R 3 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 3 and R a , together with the atom(s) to which they are attached, form a monocyclic or polycyclic 3- to 12-membered heterocyclyl;
wherein the monocyclic or polycyclic 3- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, CH 2 F, CHF 2 , CF 3 , (CH 2 ) n NH 2 , and (CH 2 ) n OH.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 3 and R a , together with the atom(s) to which they are attached, form a spirocyclic 5- to 12-membered heterocyclyl;
wherein the spirocyclic 5- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, CH 2 F, CHF 2 , CF 3 , (CH 2 ) n NH 2 , and (CH 2 ) n OH.

8. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the spirocyclic 5- to 12-membered heterocyclyl is optionally substituted with one or more independently selected C 1 -C 6 alkyl substituents.

9. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the spirocyclic 5- to 12-membered heterocyclyl is optionally substituted with one or more NH 2 substituen

Assignees

• Revolution Medicines Inc

Inventors

• Blank Brian R
• Pitzen Jennifer
• Wang Gang
• Won Walter S
• Tzitzilonis Christos
• Li Jie Jack
• Koltun Elena S
• Aay Naing
• Buckl Andreas
• Mellem Kevin
• Semko Christopher
• Jogalekar Ash
• Kiss Gert
• Gill Adrian

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title