2,5-disubstituted 3-methyl pyrazines and 2,5,6-trisubstituted 3-methyl pyrazines as allosteric SHP2 inhibitors

Patent metadata

Field	Value
Publication number	US-12565476-B2
Application number	US-202318124352-A
Country	US
Kind code	B2
Filing date	Mar 21, 2023
Priority date	Jul 12, 2016
Publication date	Mar 3, 2026
Grant date	Mar 3, 2026

Abstract

The present disclosure is directed to inhibitors of SHP2, such as pyrazine compounds having the formula:

and their use in the treatment of disease. Also disclosed are pharmaceutical compositions comprising the same.

First claim

The invention claimed is:

1 . A compound of Formula I-W:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof,
wherein:
ring A is 5- to 12-membered cycloalkyl, 5- to 12-membered heterocycloalkyl, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl, wherein the 5- to 12-membered cycloalkyl, 5- to 12-membered heterocycloalkyl, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl is monocyclic or polycyclic;
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)NR 5 R 6 , C(O)OR 5 , NR 5 R 6 , NR 5 C(O)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 6 , ═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 , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, monocyclic heterocyclyl, polycyclic heterocyclyl, spiroheterocyclyl, or heteroaryl, 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, monocyclic heterocyclyl, polycyclic heterocyclyl, spiroheterocyclyl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of CN, NO 2 , R 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 , ═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, and heteroaryl;
Y 1 is —S—, —S(O)—, or —S(O) 2 —;
R 2 is F, Br, I, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OH, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
wherein the heterocyclyl or heteroaryl contains 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of N, S, O, and P;
wherein the heterocyclyl or heteroaryl is not attached via a nitrogen heteroatom; 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, heterocyclyl, or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , R 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 , heterocyclyl, aryl, and heteroaryl;

Y 2 is —NR a —;
R a is H, D, C 1 -C 6 alkyl, —(CH 2 ) n aryl, OH, C 3 -C 8 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl is optionally substituted with one or more NH 2 substituents;
R 3 is C 1 -C 6 alkyl, —(CH 2 ) n R b , C 3 -C 8 cycloalkyl, monocyclic 3- to 12-membered heterocyclyl, polycyclic 3- to 12-membered heterocyclyl, or 5- to 12-membered spiroheterocyclyl, wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, monocyclic 3- to 12-membered heterocyclyl, polycyclic 3- to 12-membered heterocyclyl, or 5- to 12-membered spiroheterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, (CH 2 ) n OH, NHR b , OR b , heterocyclyl, and spiroheterocyclyl; or
R a and R 3 , taken together with the nitrogen atom to which they are attached, form a monocyclic 3- to 12-membered heterocyclyl, polycyclic 3- to 12-membered heterocyclyl, or 5- to 12-membered spiroheterocyclyl, wherein the monocyclic 3- to 12-membered heterocyclyl, polycyclic 3- to 12-membered heterocyclyl, or 5- to 12-membered spiroheterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, CH 2 F, CHF 2 , CF 3 , (CH 2 ) n NH 2 , (CH 2 ) n OH, C(O)NHR b , C(O)NH(CH 2 ) n C(O)OR b , C(O)OR b , NHR b , NHC(O)OR b , OR b , ═O, heterocyclyl, and heteroaryl;
R 4 is H, D, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, CHFOH, CF 2 OH, C(O)R b , C(O)NR 5 R 6 , C(O)NH(CH 2 ) n R b , C(O)OR 5 , NH 2 , NH(CH 2 ) n OH, NHC(O)R 5 , NHC(O)NHR 5 , NHNHR 5 , NHOR 5 , NHS(O) 2 R 5 , NHS(O) 2 NHR 5 , OH, ONR 5 R 6 , S(O) 2 NR 5 R 6 , S(O) 2 OH, C 3 -C 8 cycloalkyl, heterocyclyl, or aryl;
wherein the heterocyclyl contains 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of N, S, O, and P;
wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NH 2 , OR b , and ═O; and
wherein the aryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NH 2 , and OH;

each R b is independently H, D, C 1 -C 6 alkyl, —(CH 2 ) n aryl, C 2 -C 6 alkenyl, OH, C 3 -C 8 cycloalkyl, heterocyclyl, or heteroaryl;
wherein each heterocyclyl and heteroaryl independently contains 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of N, S, O, and P; and
wherein each C 1 -C 6 alkyl, aryl portion of —(CH 2 ) n aryl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, heterocyclyl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, R 5 , CH 2 F, CHF 2 , —(CH 2 ) n OH, C(O)NR 5 R 6 , NR 5 R 6 , NR 5 C(O)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 , aryl, and heteroaryl;

each R S is independently H, D, CN, NO 2 , C 1 -C 6 alkyl, CF 3 , 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, monocyclic 3- to 12-membered heterocyclyl, or polycyclic 3- to 12-membered heterocyclyl;
each R 6 is independently H, D, halogen, CN, NO 2 , C 1 -C 6 alkyl, CF 3 , 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, monocyclic 3- to 12-membered heterocyclyl, 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, OR b , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, monocyclic 3- to 12-membered heterocyclyl, 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, monocyclic 3- to 12-membered heterocyclyl, and polycyclic 3- to 12-membered 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, OR b , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, monocyclic 3- to 12-membered heterocyclyl, 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, monocyclic 3- to 12-membered heterocyclyl, and polycyclic 3- to 12-membered 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 m is independently 1, 2, 3, 4, 5, or 6; and
each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

2 . The compound of claim 1 , wherein the compound is of Formula I:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof,
wherein:
ring A is 5- to 12-membered heterocycloalkyl, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl is monocyclic o

Assignees

• Revolution Medicines Inc

Inventors

• Koltun Elena S
• Mellem Kevin
• Gill Adrian
• Kiss Gert
• Semko Christopher
• Aay Naing
• Buckl Andreas
• Jogalekar Ashutosh
• Won Walter

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D477/26

  with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 4 · CPC title

• C07D401/04 Primary

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

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title