Heterocyclic derivatives as modulators of kinase activity

Patent metadata

Field	Value
Publication number	US-10287300-B2
Application number	US-201715818035-A
Country	US
Kind code	B2
Filing date	Nov 20, 2017
Priority date	Nov 16, 2012
Publication date	May 14, 2019
Grant date	May 14, 2019

Abstract

The invention provides novel imidazol-piperidinyl derivatives of the formula (I)

in which R 1 , R 2 , W, X 1 , X 2 , X 3 , X 4 and n have the meanings indicated in formula I, and their manufacture and use for the treatment of hyperproliferative diseases, such as cancer.

First claim

We claim:

1. A method of treating breast, bladder, neuroblastoma, pancreatic, renal or lung cancer, comprising administering to a subject a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof,
wherein:
X 1 is N,
X 2 is CH 2 or NH,
X 3 is CH 2 or CO,
X 4 is O, CH 2 or NH,
W is N or CH,
R 1 is Ar or Het,
R 2 is [C(R 3 ) 2 ] p Het 1 or [C(R 3 ) 2 ] p N(R 3 ) 2 ,
R 3 is H or alkyl with 1, 2, 3, or 4 C-atoms, which is optionally substituted;
Ar is phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, phenyl, CON(R 3 ) 2 , COOR 3 , NHCOA, NHSO 2 A, CHO, COA, SO 2 N(R 3 ) 2 , SO 2 A, [C(R 3 ) 2 ] p OR 3 , [C(R 3 ) 2 ] p N(R 3 ) 2 and/or [C(R 3 ) 2 ] p CN,
Het is furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl or quinolyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R 3 ) 2 ] p OR 3 , [C(R 3 ) 2 ] p —N(R 3 ) 2 , NO 2 , CN, [C(R 3 ) 2 ] p COOR 3 , CON(R 3 ) 2 , NR 3 COA, NR 3 SO 2 A, SO 2 N(R 3 ) 2 , S(O) m A and/or O[C(R 3 ) 2 ] q N(R 3 ) 2 ,
Het 1 is dihydropyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydrofuranyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, azepanyl, morpholinyl, hexahydropyridazinyl, hexahydropyrimidinyl, [1,3]dioxolanyl, tetrahydropyranyl, pyridyl or piperazinyl, which is unsubstituted or mono- or disubstituted by A,
A is unbranched or branched alkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/or CH 2 -groups may be replaced by N-, O- and/or S-atoms and wherein 1-7H-atoms may be replaced by F or Cl,
Hal is F, Cl, Br or I,
each m is independently 0, 1 or 2,
each n is independently 0, 1 or 2,
each p is independently 0, 1, 2, 3 or 4,
each q is independently 2, 3 or 4.

2. The method of claim 1 , wherein the cancer is bladder cancer, breast cancer, pancreatic cancer, or neuroblastoma.

3. The method of claim 1 , wherein the cancer is breast cancer.

4. The method of claim 1 , wherein R 3 is H or methyl.

5. The method of claim 1 , wherein Ar is phenyl which is unsubstituted or mono- or disubstituted by Hal and/or A.

6. The method of claim 1 , wherein Het is pyridyl or pyrimidyl, which is unsubstituted or monosubstituted by A.

7. The method of claim 1 , wherein Het 1 is pyrrolidinyl, azetidinyl or piperidinyl.

8. The method of claim 1 , wherein R 1 is

9. The method of claim 1 , wherein R 2 is

10. The method of claim 1 , wherein
X 3 is CO;
X 4 is CH 2 or NH; and
W is N or CH.

11. The method of claim 10 , wherein
R 1 is Ar,
each R 3 is independently H or methyl,
Ar is phenyl which is unsubstituted or mono- or disubstituted by Hal and/or A,
Het 1 is pyrrolidinyl, azetidinyl or piperidinyl,
each A is independently unbranched or branched alkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/or CH 2 -groups may be replaced by N- and/or O-atoms and wherein 1-7H-atoms may be replaced by F or Cl,
or Cyc,

Cyc is cyclic alkyl with 3-7 C-atoms,
each n is independently 0 or 1, and
each p is independently 0, 1, 2, 3 or 4.

12. The method of claim 1 , wherein
X 3 is CH 2 .

13. The method of claim 12 , wherein,
X 4 is CH 2 or NH,
R 1 is Ar,
each R 3 is independently H or methyl,
Ar is phenyl which is unsubstituted or mono- or disubstituted by Hal and/or A,
Het 1 is pyrrolidinyl, azetidinyl or piperidinyl,
each A is independently unbranched or branched alkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/or CH 2 -groups may be replaced by N- and/or O-atoms and wherein 1-7H-atoms may be replaced by F or Cl,
or Cyc,

Cyc is cyclic alkyl with 3-7 C-atoms,
each n is independently 0 or 1, and
each p is independently 0, 1, 2, 3 or 4.

14. The method of claim 11 , wherein the compound of formula I is a compound of formula I-h:

or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

15. The method of claim 1 , wherein the compound of formula I is a compound of formula I-g:

or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

16. The method of claim 1 , wherein the compound of formula I is a compound of formula I-i:

or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

17. The method of claim 1 , wherein the compound of formula (I) is selected from:
2-(1-(2,3-dihydro-1H-pyrrolo[2,3]pyrimidin-4-yl)piperazin-4-yl)-2-(4-(trifluoro-methyl)phenyl)ethanamine (“A2”)
2-(1-(6,7-dihydro-5H-cyclopenta[b]pyrimidin-4-yl)piperazin-4-yl)-2-(4-(trifluoromethyl)phenyl)ethanamine (“A3”)
{2-(4-Chlorophenyl)-2-[4-(7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine (“A4”)
[2-[4-(7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-ethyl]-dimethylamine (“A5”)
[2-[4-(6,7-Dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-ethyl]-dimethylamine (“A6”)
{2-(4-Chlorophenyl)-2-[4-(6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine (“A7”)
{2-(4-Chlorophenyl)-2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine (“A8”)
Dimethyl-[2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethyl-phenyl)-ethyl]-amine (“A9”)
2-[4-(7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-ethylamine (“A10”)
2-(4-Chlorophenyl)-2-[4-(7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-ethylamine (“A11”)
[2-[4-(7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-2-(3-fluoro-4-trifluoromethylphenyl)-ethyl]-dimethylamine (“A12”)
2-(4-Chloro-phenyl)-2-[4-(6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethylamine (“A13”)
2-[4-(6,7-Dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-fluorophenyl)-ethylamine (“A14”)
{2-(4-Chloro-3-fluoro-phenyl)-2-[4-(6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine (“A15”)
2-[4-(5,6,7,8-Tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethyl-phenyl)-ethylamine (“A16”)
2-(4-Chloro-phenyl)-2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethylamine (“A17”)
{2-(4-Chloro-3-fluoro-phenyl)-2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine (“A18”)
{2-(3-Fluoro-4-trifluoromethyl-phenyl)-2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine (“A19”)
2-(4-fluorophenyl)-2-[4-(7,8-dihydro-6H-pyrimido[5,

Assignees

• Merck Patent Gmbh

Inventors

• Lan Ruoxi
• Huck Bayard R
• Chen Xiaoling
• Xiao Yufang

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P29/00

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

• A61P27/06

  Antiglaucoma agents or miotics · CPC title