Protac small molecule compound and use thereof

Patent metadata

Field	Value
Publication number	US-2022331435-A1
Application number	US-202017763949-A
Country	US
Kind code	A1
Filing date	Sep 25, 2020
Priority date	Sep 25, 2019
Publication date	Oct 20, 2022
Grant date	—

Abstract

The present invention discloses a compound of general formula I, or a pharmaceutically acceptable salt, a stereoisomer, an ester, a prodrug, a solvate and a deuterated compound thereof, a composition comprising the compound of general formula I, and use of the compound of general formula I, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof for preparing a medicament for treating a disease associated with the serine/threonine kinase family (MAP4Ks), and preferably for preparing a medicament for treating a disease associated with hematopoietic progenitor kinase 1 (HPK1).

First claim

1 . A compound of general formula I, or a pharmaceutically acceptable salt, a stereoisomer, an ester, a prodrug, a solvate and a deuterated compound thereof:

wherein the MAP4Ks family inhibitor is selected from: a HPK1 inhibitor, an MAP4K2 inhibitor, an MAP4K3 inhibitor, an MAP4K4 inhibitor, an MAP4K5 inhibitor, and an MAP4K6 inhibitor;
q is selected from integers between 1 and 5;
the Cereblon protein ligand is a small molecular ligand of Cereblon protein in an E3 ubiquitin ligase complex;
L is a linking group between the Cereblon protein ligand and the MAP4K family inhibitor;
preferably, the L is -A 1 -A 2 . . . -A t -,
wherein A 1 , A 2 . . . A t are independently selected from:
CR L1 R L2 , O, S, S═O, S(═O) 2 , S(O) 2 O, OS(O) 2 , OS(O) 2 O, NR L3 , S(═O) 2 NR L3 , S(═O)NR L3 , C(═O)NR L3 , OC(O)NR L3 , NR L3 C(═O), NR L3 C(═O)NR L4 , NR L3 S(═O) 2 NR L4 , C(═O), CR L1 ═CR L2 , C═C, C≡C, SiR L1 R L2 , P(═O)R L1 , P(═O)OR L1 , NR L3 C(═N—CN)NR L4 , NR L3 C(═N—CN), NR L3 C(═C—NO 2 )NR L4 , C 3-11 cyclohydrocarbyl, C 3-11 heterocyclohydrocarbyl, succinimide,

 CH 2 CH 2 O—, —OCH 2 CH 2 —,

 or are absent, wherein any hydrogen atom of the cyclohydrocarbyl and the heterocyclohydrocarbyl may be substituted with 1-6 R L1 or R L2 ;
when A 1 , A 2 . . . A t are CR L1 R L2 or SiR L1 R L2 , R L1 and R L2 may be independently linked to other A to form cyclohydrocarbyl or heterocyclohydrocarbyl, and preferably, the cyclohydrocarbyl or heterocyclohydrocarbyl is optionally substituted with 1-11 R L5 groups;
R L1 , R L2 , R L3 , R L4 and R L5 are independently selected from H, halogen, C 1-8 alkyl, O(C 1-8 alkyl), S(C 1-8 alkyl), NH(C 1-8 alkyl), N(C 1-8 alkyl) 2 , C 3-11 cyclohydrocarbyl, C 3-11 heterocyclohydrocarbyl, O(C 1-8 cyclohydrocarbyl), S(C 1-8 cyclohydrocarbyl), NH(C 1-8 cyclohydrocarbyl), N(C 1-8 cyclohydrocarbyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 (C 1-8 alkyl), P(═O)(OC 1-8 alkyl)(C 1-8 alkyl), P(═O)(OC 1-8 alkyl) 2 , C 1-8 alkynyl, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , Si(OH) 3 , Si(C 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , C(═O)(C 1-8 alkyl), CO 2 H, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NH(C 1-8 alkyl), SO 2 N(C 1-8 alkyl) 2 , S(═O)N(C 1-8 alkyl) 2 , C(═O)NH(C 1-8 alkyl), C(═O)N(C 1-8 alkyl) 2 , N(C 1-8 alkyl)C(═O)NH(C 1-8 alkyl), N(C 1-8 alkyl)C(═O)N(C 1-8 alkyl) 2 , NHC(═O)NH(C 1-8 alkyl), NHC(═O)N(C 1-8 alkyl) 2 , NHC(═O)NH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl)SO 2 N(C 1-8 alkyl) 2 , NHSO 2 NH(C 1-8 alkyl), NHSO 2 N(C 1-8 alkyl) 2 and NHSO 2 NH 2 ;
X 3 is selected from O, S, —NR— and —CHR—;
R is selected from H and C 1-3 alkyl substituted with 1 or 2 —OH;
i is selected from integers between 1 and 6;
Y is selected from —O—, —S— and —NR—, or is absent; and
t is selected from integers between 1 and 100, and preferably, t is selected from integers between 1 and 50.

2 . The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1 , wherein the MAP4K family inhibitor is selected from a HPK1 inhibitor.

3 . The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1 , wherein the linking group L is

wherein s is selected from integers between 1 and 6;
CON is selected from

 or is absent;
W 1 and W 2 are independently selected from

n is selected from integers between 1 and 10, and preferably from integers between 1 and 4;
m is selected from integers between 0 and 10, and preferably from integers between 2 and 7;
X 1 is selected from O, S and —NR—; and
X 2 is selected from O, S, —NR—, —S(O)—, —S(O) 2 O—, —OS(O) 2 — and —OS(O) 2 O—.

4 . The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1 , wherein the linking group L is selected from

Ar is selected from N-containing six-membered aryl;
g is selected from 0 and 1;
k is selected from integers between 1 and 10, and preferably from integers between 1 and 4; and
p is selected from integers between 1 and 10, and preferably from integers between 1 and 2.

5 . The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1 , wherein the Cereblon protein ligand is selected from: an amide compound, a phthalimide compound, thalidomide and a derivative thereof, lenalidomide and a derivative thereof, and pomalidomide and a derivative thereof, and preferably, the Cereblon protein ligand moiety has a general formula as follows:

wherein C 1 , C 2 , C 3 and C 4 are independently selected from C and N;
T is selected from O and S;
V is selected from —O—, —S—, wherein R′ and R″

 are independently selected from C 0-10 alkyl, cyclohydrocarbyl and heterocyclohydrocarbyl;
G and Z are independently selected from H, —OH, C 1-10 linear/branched alkyl, C 3-10 cyclohydrocarbyl, O-containing heterocyclohydrocarbyl, N-containing heterocyclohydrocarbyl and S-containing heterocyclohydrocarbyl; and
q is selected from integers between 1 and 3, such as 1, 2 or 3.

6 . The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 5 , wherein C 1 , C 2 , C 3 and C 4 are C; or, when C 1 is C, at least one of C 2 , C 3 and C 4 is N; or, when C 2 is C, at least one of C 1 , C 3 and C 4 is N; or, when C 3 is C, at least one of C 1 , C 2 and C 4 is N; or, when C 4 is C, at least one of C 1 , C 2 and C 3 is N.

7 . The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 6 , wherein C 1 , C 2 , C 3 and C 4 are C;
T is O; V is selected from —CH 2 —,

 and —NH—; and
G and Z are independently selected from H, —CH 3 and —CH 2 CH 3 .

8 . The compound, or the pharmaceutically acceptable salt,

Assignees

• Zhuhai Yufan Biotechnologies Co Ltd
• Univ Tsinghua

Inventors

• Liao Xuebin
• Sun Shuhao
• Lin Xingyu
• Liu Yahui

Classifications

• A61K47/55 Primary

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61K38/177

  Receptors; Cell surface antigens; Cell surface determinants · CPC title

• A61P13/12

  of the kidneys · CPC title