Irreversible bruton's tyrosine kinase inhibitor

Patent metadata

Field	Value
Publication number	US-10669238-B2
Application number	US-201616074970-A
Country	US
Kind code	B2
Filing date	Dec 22, 2016
Priority date	Feb 4, 2016
Publication date	Jun 2, 2020
Grant date	Jun 2, 2020

Abstract

The present invention provides an inhibitor of Bruton's tyrosine kinase, which is a compound of formula (I), or its pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug. The present invention also provides a pharmaceutical composition comprising the compound. The present invention also provides a method for inhibiting the activity of tyrosine kinase activity or for treating a disease, disorder, or condition, which would benefit from the inhibition of Bruton's tyrosine kinase(s), by using the Bruton's tyrosine kinase inhibitor, as well application of the Bruton's tyrosine kinase inhibitor for the same.

First claim

The invention claimed is:

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, or prodrug thereof, said compound having a structure of:

wherein,
ring A represents any monocyclic or fused-ring group selected from the group consisting of phenyl, thienyl, benzothienyl, and tetrahydrobenzothienyl;
R 1 is hydrogen;
R 2 is selected from the group consisting of

R 3 is selected from the group consisting of hydrogen, C1-C8 alkyl, halo, hydroxy, nitro, cyano, C1-C8 haloalkyl, amino, C1-C8 alkylamino, —(CO)—R 7 , heterocycloalkyl optionally substituted with R 8 , and heteroaryl optionally substituted with R 8 ;
each of R 4 , R 5 and R 6 is independently selected from the group consisting of hydrogen, halo, hydroxy, amino, nitro, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, heterocycloalkyl, aryl and heteroaryl, or any adjacent two of R 4 , R 5 and R 6 together form C3-C8 cycloalkyl or heterocycloalkyl;
R 7 is selected from the group consisting of C1-C8 alkoxy, C1-C8 alkylamino, C3-C8 cycloalkylamino, C2-C8 heteroalkylamino, C3-C8 heterocycloalkylamino, and heterocycloalkyl optionally substituted with halo, hydroxy, amino, nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, or amino protecting group;
R 8 is selected from the group consisting of C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino or C2-C8 alkanoyl.

2. The compound or a pharmaceutically acceptable salt, solvate, ester, acid, or prodrug thereof according to claim 1 , wherein R 3 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkylamino, —(CO)—R 7 , heterocycloalkyl optionally substituted with R 8 , and heteroaryl optionally substituted with R 8 ; and R 7 is selected from the group consisting of C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkylamino, C2-C6 heteroalkylamino, C3-C6 heterocycloalkylamino, and heterocycloalkyl optionally substituted with halo, hydroxy, amino, nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, or amino protecting group; R 8 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkanoyl, and C1-C8 alkylamino.

3. The compound or a pharmaceutically acceptable salt, solvate, ester, acid, or prodrug thereof according to claim 1 , wherein each of R 4 , R 5 and R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, heterocycloalkyl, or any adjacent two of R 4 , R 5 and R 6 together form C3-C6 cycloalkyl or heterocycloalkyl.

4. The compound or a pharmaceutically acceptable salt, solvate, ester, acid, or prodrug thereof according to claim 1 , wherein R 2 is selected from the group consisting of

5. The compound or a pharmaceutically acceptable salt, solvate, ester, acid, or prodrug thereof according to claim 1 , wherein
ring A represents any monocyclic or fused-ring group selected from the group consisting of phenyl, thiophene-2-yl, benzo[b]thiophene-2-yl, and 4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl;
R 3 is selected from the group consisting of hydrogen, methyl, dimethylamino, —(CO)—R 7 , and piperazinyl, morpholinyl, piperidyl, pyrrolidyl and pyrazolyl optionally substituted with R 8 ; and R 7 is selected from the group consisting of methoxy, dimethylamino, cyclopropylamino, N-(2-methoxyethyl)amino, N,N-bis(2-ethoxyethyl)amino, tetrahydropyran-4-ylamino, pyrrolidyl, piperidyl optionally substituted with hydroxyl or methoxy, morpholinyl, and piperazinyl with its nitrogen(s) being optionally substituted with methyl or Boc; R 8 is selected from the group consisting of methyl, ethyl, isopropyl, methoxy, acetyl, and dimethylamino;
each of R 4 , R 5 and R 6 is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, trifluoromethyl, methoxy, dimethylamino, morpholinyl, and pyrrolidyl, or any adjacent two of R 4 , R 5 and R 6 together form cyclohexyl, dioxolanyl, or dioxanyl.

6. The compound or a pharmaceutically acceptable salt, solvate, ester, acid, or prodrug thereof according to claim 1 , said compound having a structure of formula (Ia):

wherein,
R 1 is hydrogen,
R 2 is selected from the group consisting of

R 3 is selected from the group consisting of hydrogen, C1-C8 alkyl, halo, hydroxy, nitro, cyano, C1-C8 haloalkyl, amino, C1-C8 alkylamino, —(CO)—R 7 , and heterocycloalkyl optionally substituted with R 8 ;
each of R 4 , R 5 and R 6 is independently selected from the group consisting of hydrogen, halo, hydroxy, amino, nitro, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, heterocycloalkyl, aryl and heteroaryl, or any adjacent two of R 4 , R 5 and R 6 together form C3-C8 cycloalkyl or heterocycloalkyl;
R 7 is selected from the group consisting of C1-C8 alkoxy, C1-C8 alkylamino, C3-C8 cycloalkylamino, C2-C8 heteroalkylamino, C3-C8 heterocycloalkylamino, and heterocycloalkyl optionally substituted with halo, hydroxy, amino, nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, or amino protecting group;
R 8 is selected from the group consisting of C1-C8 alkyl.

7. The compound or a pharmaceutically acceptable salt, solvate, ester, acid, or prodrug thereof according to claim 6 , wherein R 3 is selected from the group consisting of hydrogen, C1-C6 alkyl, and —(CO)—R 7 , and heterocycloalkyl optionally substituted with C1-C6 alkyl; and R 7 is selected from the group consisting of C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkylamino, C2-C6 heteroalkylamino, C3-C6 heterocycloalkylamino, and optionally substituted heterocycloalkyl.

8. The compound or a pharmaceutically acceptable salt, solvate, ester, acid, or prodrug thereof according to claim 6 , wherein each of R 4 , R 5 and R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, heterocycloalkyl, or any adjacent two of R 4 , R 5 and R 6 together form C3-C6 cycloalkyl or heterocycloalkyl.

9. The compound or a pharmaceutically acceptable salt, solvate, ester, acid, or prodrug thereof according to claim 6 , said compound having a structure of formula (IIa):

wherein
R 1 is hydrogen; R 2 is

R 3 is heterocycloalkyl optionally substituted with C1-C6 alkyl, or —(CO)—R 7 , and R 7 is selected from the group consisting of C1-C6 alkylamino, C3-C6 cycloalkylamino, C3-C6 heterocycloalkylamino, and optionally substituted heterocycloalkyl; R 4 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkylamino, and heterocycloalkyl, and each of R 5 and R 6 is hydrogen, or any adjacent two of R 4 , R 5 and R 6 together form C3-C6 cycloalkyl or heterocycloalkyl.

10. The compound or a pharmaceutically acceptable salt, solvate, ester, acid, or prodrug thereof according to claim 1 , said compound having the structure of formula (Ib):

Assignees

• Hefei Inst Physical Sci Cas

Inventors

• Liu Jing
• Liu Qingsong
• Liang Qianmao
• Chen Yongfei
• Chen Cheng
• Wang Aoli
• Wu Hong
• Yu Kailin
• Wang Wei
• Hu Chen
• Wang Wenchao
• Qi shuang
• Wang Beilei
• Wang Li

Classifications

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D213/74 Primary

  Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P35/02

  specific for leukemia · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title