Small molecule inhibitors of ubiquitin specific protease 1 (usp1) and uses thereof

Patent metadata

Field	Value
Publication number	US-2024190839-A1
Application number	US-202318340978-A
Country	US
Kind code	A1
Filing date	Jun 26, 2023
Priority date	Nov 12, 2021
Publication date	Jun 13, 2024
Grant date	—

Abstract

The disclosure provides for small molecules inhibitory compounds of ubiquitin specific protease 1 (USP1) and compositions comprising the same. The disclosure further provides methods for targeting ubiquitin specific protease 1 (USP1) and methods of treating diseases or disorders related to USP1, such as cancer.

First claim

1 . A compound having the structure of Formula (IVa), or a pharmaceutically acceptable salt thereof,

wherein,
Y 1 is N or CR Y1 ;
Y 2 is N or CR Y2 ;
Y 3 is N or CR Y3 ;
Y 4 is N or CR Y4 ;
R 1 is hydrogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 2-7 heterocycloalkyl;
each of R 4 and R 4′ is independently selected from hydrogen, halo, —CN, —OR 11 , —SR 11 , —N(R 12 )(R 11 ), optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-8 cycloalkyl, and optionally substituted C 2-7 heterocycloalkyl; or R 4 and R 4′ taken together form an oxo; or R 4 and R 4′ taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
each of R 5 and R 5′ is independently selected from hydrogen, halo, —CN, —OR 11 , —SR 11 , —N(R 12 )(R 11 ), optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-8 cycloalkyl, and optionally substituted C 2-7 heterocycloalkyl; or R 5 and R 5′ taken together form an oxo; or R 5 and R 5′ taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
each of R 6 and R 6′ is independently selected from hydrogen, halo, —CN, —OR 11 , —SR 11 , —N(R 12 )(R 11 ), optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-8 cycloalkyl, and optionally substituted C 2-7 heterocycloalkyl; or R 6 and R 6′ taken together form an oxo; or R 6 and R 6′ taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
each of R 8 and R 9 is independently selected from hydrogen, halo, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl; or R 8 and R 9 taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
ring A is monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocycloalkyl, or bicyclic heterocycloalkyl;
each of R A is independently selected from halogen, —NO 2 , oxo, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, —OR 11 , —SR 11 , —N(R 12 )(R 11 ), —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —OC(O)N(R 12 )(R 11 ), —C(O)N(R 12 )(R 11 ), —N(R 12 )C(O)R 12 , —N(R 12 )C(O)OR 12 , —N(R 12 )C(O)N(R 12 )(R 11 ), —N(R 12 ) 2 S(O) 2 (R 12 ), —S(O)R 12 , —S(O) 2 R 12 , and —S(O) 2 N(R 12 )(R 11 );
R 11 is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted —C 1-4 alkylene-C 3-8 cycloalkyl, optionally substituted —C 1-4 alkylene-C 2-7 heterocycloalkyl, optionally substituted —C 1-4 alkylene-phenyl, or optionally substituted —C 1-4 alkylene-heteroaryl;
each of R 12 is independently selected from hydrogen, —NO 2 , —CN, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, —OH, oxo, amino, —NO 2 , —CN, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkyl;
R B1 is optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;
each of R Y1 , R Y2 , R Y3 and R Y4 is independently selected from hydrogen, halo, —CN, —NO 2 , —OR 11 , —SR 11 , —N(R 12 )(R 11 ), optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, —OR 11 , —SR 11 , —N(R 12 )(R 11 ), —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —OC(O)N(R 12 )(R 11 ), —C(O)N(R 12 )(R 11 ), —N(R 12 )C(O)R 12 , —N(R 12 )C(O)OR 12 , —N(R 12 )C(O)N(R 12 )(R 11 ), —N(R 12 )S(O) 2 (R 12 ), —S(O)R 12 , —S(O) 2 R 12 , —S(O) 2 N(R 12 )(R 11 ), optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, and optionally substituted bicyclic heteroaryl; or
R Y1 and R Y2 are taken together with the carbons to which they are attached to form an optionally substituted C 3-8 cycloalkyl or optionally substituted C 2-9 heterocycloalkyl; or
R Y3 and R Y4 are taken together with the carbons to which they are attached to form an optionally substituted C 3-8 cycloalkyl or optionally substituted C 2-9 heterocycloalkyl;
m is 0, 1, 2, 3, or 4; and
p is 0 or 1.

2 .- 46 . (canceled)

47 . A compound having the structure of Formula (VI), or a pharmaceutically acceptable salt thereof,

wherein,
ring C is an optionally substituted 5 membered heteroaryl;
ring D is an aromatic, saturated or partially saturated 6 membered carbocycle or heterocycle, wherein each of the carbocycle or heterocycle is optionally substituted; each of R 8 and R 9 is independently selected from hydrogen, halo, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl; or R 8 and R 9 taken together form an oxo; or R 8 and R 9 taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl; ring A is phenyl, naphthyl, monocyclic heteroaryl, bicyclic heteroaryl, cycloalkyl or heterocycloalkyl;
each of R A is independently selected from halogen, —NO 2 , oxo, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, —OR 11 , —SR 11 , —N(R 12 )(R 11 ), —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —OC(O)N(R 12 )(R 11 ), —C(O)N(R 12 )(R 11 ), —N(R 12 )C(O)R 12 , —N(R 12 )C(O)OR 12 , —N(R 12 )C(O)N(R 12 )(R 11 ), —N(R 12 ) 2 S(O) 2 (R 12 ), —S(O)R 12 , —S(O) 2 R 12 , and —S(O) 2 N(R 12 )(R 11 );
R 11 is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted —C 1-4 alkylene-C 3-8 cycloalkyl, optionally substituted —C 1-4 alkylene-C 2-7 het

Assignees

• Insilico Medicine Ip Ltd

Inventors

• Wu Jianping
• Qin Luoheng
• Liu Jinxin

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title