US 12,606,566 B2 · Substituted cyclopenta[4,5]pyrrolo[1,2-a]pyrazines as bruton's tyrosine kinase inhibitors

Substituted cyclopenta[4,5]pyrrolo[1,2-a]pyrazines as bruton's tyrosine kinase inhibitors

AssigneesShanghai Synergy Pharmaceutical Sciences Co., Ltd, Zhejiang Huahai Pharmaceutical Co., Ltd.

InventorsXin Xu, Jia Chen, Guan Wang, Linli Zhang, Qingyun Jiang, Chenghao Xi, Kang Sun, Xiaojuan Zhang, Chunqiao Chen, Shuai Li, Qiang Li, Liangze Xia, Ying Wang, Xiaoer Xia

Life of this patent

Estimating the term…

Abstract

A compound of formula (I) as Bruton's tyrosine kinase inhibitor, a preparation method therefor, and an application thereof in the field of medicine. The Bruton's tyrosine kinase inhibitor may be used for preventing and/or treating a disease related to Bruton's tyrosine kinase mediation, such as an autoimmune disease, cancer, or an inflammatory disease. Through experimental research, the provided compound has high selectivity with respect to a Bruton's tyrosine kinase target, and can exhibit a uniquely advantageous medicinal effect in an in vivo animal experiment.

Claims14

Dependent claims

A compound of formula (I):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:
R1 is halogen, CN, C1-6 alkyl, CF3, NH2, NHC1-6 alkyl, or OC1-6 alkyl;
R2 is C1-3 alkyl;
R3 is C1-3 alkyl;
X is N;
R is OH;
R0 is H;
A is
R4 is C1-6 alkyl;
R5 is H or C1-3 alkyl;
X1 is N;
T is a nitrogen-containing 5- or 6-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl is substituted by one T1 substituent, one T2 substituent, or one T1 substituent and one T2 substituent;
T1 is C1-6 alkyl;
and
T2 is C1-6 alkyl or 3- to 6-membered heterocycloalkyl.

13 more elements

A process for preparing a compound of formula I-12:

wherein:
R1 is halogen, CN, C1-6 alkyl, CF3, NH2, NHC1-6 alkyl, or OC1-6 alkyl;
R2 is C1-3 alkyl;
R3 is C1-3 alkyl;
X is N;
R0 is H;
R4 is C1-6 alkyl;
X1 is N;
T is a nitrogen-containing 5- or 6-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl is substituted by one T1 substituent, one T2 substituent, or one T1 substituent and one T2 substituent;
T1 is C1-6 alkyl;
and
T2 is C1-6 alkyl or 3- to 6-membered heterocycloalkyl;
wherein the process comprises the following steps:
(1) reacting a compound of formula I-1:
wherein:
X1 is N;
and
T is a nitrogen-containing 5- or 6-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl is substituted by one T1 substituent, one T2 substituent, or one T1 substituent and one T2 substituent;
with a reducing agent 1 selected from the group consisting of borane dimethyl sulfoxide, borane tetrahydrofuran, lithium aluminum hydride, and reducing iron powder, to provide a compound of formula I-2:
wherein:
X1 is N;
and
T is a nitrogen-containing 5- or 6-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl is substituted by one T1 substituent, one T2 substituent, or one T1 substituent and one T2 substituent;
(2) reacting the compound of formula I-2 provided in step (1) above with a compound of formula Int 3:
wherein:
R4 is C1-6 alkyl;
in the presence of a catalyst selected from the group consisting of 1,1′-binaphthyl-2,2′-bis(diphenylphosphine), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, cuprous iodide, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, palladium acetate, 1,10-phenanthroline, tetrakis(triphenylphosphine)palladium, and tris(dibenzylideneacetone)dipalladium, to provide a compound of formula I-3:
wherein:
R4 is C1-6 alkyl;
X1 is N;
and
T is a nitrogen-containing 5- or 6-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl is substituted by one T1 substituent, one T2 substituent, or one T1 substituent and one T2 substituent;
(3) reacting the compound of formula I-3 provided in step (2) above with bis(pinacolato)diboron in the presence of a catalyst selected from the group consisting of 1,1′-binaphthyl-2,2′-bis(diphenylphosphine), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, cuprous iodide, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, palladium acetate, 1,10-phenanthroline, tetrakis(triphenylphosphine)palladium, and tris(dibenzylideneacetone)dipalladium, to provide a compound of formula I-4:
wherein:
R4 is C1-6 alkyl;
X1 is N;
and
T is a nitrogen-containing 5- or 6-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl is substituted by one T1 substituent, one T2 substituent, or one T1 substituent and one T2 substituent;
(4) reacting the compound of formula I-4 provided in step (3) above with a compound of formula I-10:
wherein:
R1 is halogen, CN, C1-6 alkyl, CF3, NH2, NHC1-6 alkyl, or OC1-6 alkyl;
R2 is C1-3 alkyl;
R3 is C1-3 alkyl;
X is N;
and
R0 is H;
in the presence of a catalyst selected from the group consisting of 1,1′-binaphthyl-2,2′-bis(diphenylphosphine), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, cuprous iodide, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, palladium acetate, 1,10-phenanthroline, tetrakis(triphenylphosphine)palladium, and tris(dibenzylideneacetone)dipalladium, to provide a compound of formula I-11:
wherein:
R1 is halogen, CN, C1-6 alkyl, CF3, NH2, NHC1-6 alkyl, or OC1-6 alkyl;
R2 is C1-3 alkyl;
R3 is C1-3 alkyl;
X is N;
R0 is H;
R4 is C1-6 alkyl;
R1 is H or C1-3 alkyl;
X1 is N;
T is a nitrogen-containing 5- or 6-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl is substituted by one T1 substituent, one T2 substituent, or one T1 substituent and one T2 substituent;
T1 is C1-6 alkyl;
and
T2 is C1-6 alkyl or 3- to 6-membered heterocycloalkyl;
and
(5) reacting the compound of formula I-11 provided in step (4) above with a reducing agent 2 selected from the group consisting of potassium borohydride, sodium borohydride, sodium cyanoborohydride, and sodium triacetylborohydride, to provide a compound of formula I-12:
wherein:
R1 is halogen, CN, C1-6 alkyl, CF3, NH2, NHC1-6 alkyl, or OC1-6 alkyl;
R2 is C1-3 alkyl;
R3 is C1-3 alkyl;
X is N;
R0 is H;
R4 is C1-6 alkyl;
X1 is N;
T is a nitrogen-containing 5- or 6-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl is substituted by one T1 substituent, one T2 substituent, or one T1 substituent and one T2 substituent;
T1 is C1-6 alkyl;
and
T2 is C1-6 alkyl or 3- to 6-membered heterocycloalkyl.

71 more elements

Dependencies are inferred from the claim text.

Facts

Application

18/002,133Filed 18 Jun 2021

Priority

CN 202010558345.418 Jun 2020

Published

US 2023/0348471 A12 Nov 2023

Granted

21 Apr 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/4985
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: pyrazines or piperazines…
A61P 11/00
Drugs for disorders of the respiratory system
A61P 19/02
Drugs for skeletal disorders: for joint disorders, e.g. arthritis, arthrosis