Antimalarial hexahydropyrimidine analogues

Patent metadata

Field	Value
Publication number	US-2022289685-A1
Application number	US-202017632336-A
Country	US
Kind code	A1
Filing date	Aug 17, 2020
Priority date	Aug 19, 2019
Publication date	Sep 15, 2022
Grant date	—

Abstract

A series of 2-imino-6-methylhexahydropyrimidin-4-one derivatives, and analogues thereof, substituted in the 6-position by an arylcarbonylaminophenyl or heteroarylcarbonylaminophenyl moiety, being potent inhibitors of the growth and propagation of the Plasmodium falciparum parasite in human blood, are beneficial as pharmaceutical agents, especially in the treatment of malaria.

First claim

1 . A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein
W represents C(O) or S(O) 2 ;
Z represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents;
R 1 represents C 3-7 cycloalkyl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, C 4-9 heterobicycloalkyl, C 4-9 spiroheterocycloalkyl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; and
R 2 , R 3 and R 4 independently represent hydrogen, halogen or trifluoromethyl.

2 . A compound as claimed in claim 1 represented by formula (IIA), or a pharmaceutically acceptable salt thereof:

wherein
V represents N or CH;
R 15 and R 16 independently represent hydrogen, halogen, cyano, nitro, C 1-6 alkyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, difluoro-methoxy, trifluoromethoxy, phenoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, amino(C 1-6 )alkyl, di(C 1-6 )alkylamino(C 1-6 )-alkyl, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkyl-aminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1 -6)alkylaminosulfonyl or di(C 1-6 )alkylsulfoximino; and
R 1 , R 2 and R 3 are as defined in claim 1 .

3 . A compound as claimed in claim 2 wherein R 15 represents hydrogen, halogen, cyano, trifluoromethyl or trifluoromethoxy.

4 . A compound as claimed in claim 2 wherein R 16 represents hydrogen, halogen, cyano, trifluoromethyl, C 1-6 alkoxy, trifluoromethoxy or C 1-6 alkylsulfonyl.

5 . A compound as claimed in claim 1 wherein R 1 represents C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one, two or three substituents independently selected from halogen and C 1-6 alkyl.

6 . A compound as claimed in claim 1 represented by formula (IIB), or a pharmaceutically acceptable salt thereof:

wherein
R 11 represents hydrogen or methyl;
R 12 represents hydrogen or methyl;
R 13 represents hydrogen or methyl; and
Z, R 2 and R 3 are as defined in claim 1 .

7 . A compound as claimed in claim 1 represented by formula (IIC), or a pharmaceutically acceptable salt thereof:

wherein
R 11 represents hydrogen or methyl.

8 . A compound as claimed in claim 1 , wherein Z represents phenyl, naphthyl, furyl, benzofuryl, pyrrolyl, indolyl, pyrazolyl, imidazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, imidazo[1,2-a]pyrazinyl, oxadiazolyl, [1,2,4]-triazolo[4,3-a]pyridinyl, tetrazolo[1,5-a]pyridinyl, pyridinyl, quinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, pyrimidinyl, pyrazinyl or quinoxalinyl, any of which groups may be optionally substituted by one, two or three substituents independently selected from halogen, cyano, C 1-6 alkyl, trifluoromethyl, C 2-6 alkynyl, cyclopropyl, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, methylenedioxy, C 1-6 alkylsulfonyl, di(C 1-6 )alkylamino, morpholinyl, pyrazolyl, imidazolyl and (C 1 -6)alkylimidazolyl.

9 . A compound as claimed in claim 1 wherein R 2 represents chloro.

10 . A compound as claimed in claim 1 which is
N-{2-Chloro-3-[(4S)-2-imino-4-methyl-6-oxo-1-(tetrahydropyran-4-yl)hexahydropyrimidin-4-yl]-phenyl}benzamide trifluoroacetic acid salt;
5-Chloro-N-{2-chloro-3-[(4S)-2-imino-4-methyl-6-oxo-1-(tetrahydropyran-4-yl)hexahydro-pyrimidin-4-yl]phenyl}pyridine-2-carboxamide trifluoroacetic acid salt;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-4-fluorobenzamide hydrochloride;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-2,4-difluorobenzamide hydrochloride;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-pyridine-4-carboxamide hydrochloride;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-pyridine-2-carboxamide hydrochloride;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-pyridine-3-carboxamide hydrochloride;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-1-methylpyrazole-3-carboxamide hydrochloride;
4-Chloro-N-(2-chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyltetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-benzamide hydrochloride;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-4-cyanobenzamide hydrochloride;
3-Chloro-N-(2-chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyltetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-benzamide hydrochloride;
2-Chloro-N-(2-chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyltetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-benzamide hydrochloride;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-5-fluoropyridine-2-carboxamide hydrochloride;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-pyrazine-2-carboxamide hydrochloride;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-pyrimidine-2-carboxamide hydrochloride;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-pyrimidine-4-carboxamide hydrochloride;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide hydrochloride;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-5-(trifluoromethyl)pyridine-2-carboxamide hydrochloride;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-pyridazine-3-carboxamide hydrochloride;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-3-cyanobenzamide hydrochloride;
N-(2-Chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyl-tetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-6-(trifluoromethyl)pyridine-3-carboxamide hydrochloride;
3-Chloro-N-(2-chloro-3-{(4S)-2-imino-4-methyl-1-[(2R*,4R*)-2-methyltetrahydropyran-4-yl]-6-oxo-hexahydropyrimidin-4-yl}phenyl)-5-methylbenzamide hydrochloride;
N-{2-Chloro-3-[(4S)-1-(4,4-difluorocyclohexyl)-2-imino-4-methyl-6-oxohexahydropyrimidin-4-yl]phenyl}-3-cyanobenzamide hydrochloride;
N-(2-Chloro-3-{(4S)-1-[(2S*,6R*)-2,6-dimethyltetrahydropyran-4-yl]-2-imino-4-methyl-6-oxohexahydro-pyrimidin-4-yl}phenyl)-3-cyano-benzamide hydrochloride;
N-(2-Chloro-3-{(4S)-1-[(1R*,3R*)-4,4-difluoro-3-methylcyclohexyl]-2-imino-4-methyl-6-oxohexahydro-pyrimidin

Assignees

• UCB Biopharma SRL

Inventors

• De Haro Garcia Teresa
• Lowe Martin Alexander
• Maccoss Malcolm
• Taylor Richard David
• Zhu Zhaoning
• Chappell Rose Elizabeth

Classifications

• C07D239/22 Primary

  with hetero atoms directly attached to ring carbon atoms · CPC title

• C07D407/14

  containing three or more hetero rings · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K47/06

  Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite · CPC title