Antimalarial hexahydropyrimidine analogues

Patent metadata

Field	Value
Publication number	US-11479546-B2
Application number	US-201917044550-A
Country	US
Kind code	B2
Filing date	Apr 2, 2019
Priority date	Apr 6, 2018
Publication date	Oct 25, 2022
Grant date	Oct 25, 2022

Abstract

The application relates to a series of 2-imino-6-methylhexahydropyrimidin-4-one derivatives and 3-imino-5-methyl-1,2,4-thiadiazinane 1,1-dioxide derivatives of formula (I), substituted by an arylaminophenyl or heteroarylaminophenyl moiety. The compounds are potent inhibitors of the growth and propagation of the Plasmodium falciparum parasite in human blood and thus useful as pharmaceutical agents for the treatment of malaria.

First claim

The invention claimed is:

1. A compound of formula (I) 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 2-6 alkyl, optionally substituted by hydroxy; or R 1 represents C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, 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 wherein Z represents phenyl, naphthyl, 2,3-dihydroindolyl, 2,3-dihydrobenzoxazinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, pyrazolo-[3,4-b]pyridinyl, indazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, imidazo-[4,5-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl or pyrazinyl, any of which groups may be optionally substituted by one, two or three substituents independently selected from halogen, cyano, C 1-6 alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyanocyclobutyl, phenyl, azetidinyl, oxopyrrolidinyl, morpholinyl, oxazolyl, methyloxadiazolyl, triazolyl, methyltetrazolyl, oxo, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, phenoxy, methylenedioxy, difluoromethylenedioxy, C 1-6 alkylsulfonyl, di(C 1-6 )alkylamino, C 2-6 alkylcarbonyl, C 2-6 alkoxycarbonyl and di(C 1-6 )alkylsulfoximino.

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

wherein
R 15 and R 16 independently represent hydrogen, halogen, cyano, nitro, C 1-6 alkyl, difluoromethyl, trifluoromethyl, phenyl, oxopyrrolidinyl, oxazolyl, methyloxadiazolyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, phenoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, amino, 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, am inocarbonyl, C 1-6 alkylaminocarbonyl, 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 .

4. A compound as claimed in claim 3 wherein R 15 represents hydrogen, halogen, cyano, C 1-6 alkyl, trifluoromethyl, phenyl, oxopyrrolidinyl, oxazolyl, methyloxadiazolyl, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, phenoxy, C 1-6 alkylsulfonyl, C 2-6 alkoxycarbonyl or di(C 1-6 )alkylsulfoximino.

5. A compound as claimed in claim 3 wherein R 16 represents hydrogen, halogen, cyano, C 1-6 alkyl, trifluoromethyl or C 1-6 alkoxy.

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

wherein
V represents N or CH;
R 25 represents methyl, cyclopropyl, difluoromethoxy or difluoroethoxy; and
R 1 , R 2 and R 3 are as defined in claim 1 .

7. A compound as claimed in claim 1 wherein R 1 represents C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, C 4-9 heterobicycloalkyl or C 4-9 spiroheterocycloalkyl, any of which groups may be optionally substituted by one, two or three substituents independently selected from halogen, cyano, C 1-6 alkyl, trifluoromethyl and hydroxy.

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

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

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

10. A compound as claimed in claim 1 which is
(6S)-6-(3-Anilino-2-chloro-phenyl)-3-[(1-hydroxy-cyclopropyl)methyl]-2-imino-6-methylhexahydropyrimidin-4-one;
(6S)-6-(3-Anilino-2-chloro-phenyl)-2-imino-6-methyl-3-(tetrahydropyran-4-yl)-hexahydropyrimidin-4-one;
(6S)-6-(3-Anilino-2-chloro-phenyl)-2-imino-6-methyl-3-(tetrahydropyran-4-ylmethyl)-hexahydropyrimidin-4-one;
(6S)-6-(3-Anilino-2-chloro-phenyl)-3-cyclohexyl-2-imino-6-methylhexahydropyrimidin-4-one;
(6S)-6-(3-Anilino-2-chloro-phenyl)-2-imino-6-methyl-3-[(3S or 3R*)-tetrahydrofuran-3-yl]hexahydropyrimidin-4-one;
(6S)-6-(3-Anilino-2-chloro-phenyl)-2-imino-6-methyl-3-[(3S or 3R*)-tetrahydrofuran-3-yl]hexahydropyrimidin-4-one;
(6S)-6[2-Chloro-3-(3-chloro-anilino)phenyl]-2-imino-6-methyl-3-(tetrahydropyran-4-yl)hexahydropyrimidin-4-one;
(6S)-6[2-Chloro-3-(3-methyl-anilino)phenyl]-2-imino-6-methyl-3-(tetrahydropyran-4-yl)hexahydropyrimidin-4-one;
3-{2-Chloro-3-[(4S)-2-imino-4-methyl-6-oxo-1-(tetrahydro-pyran-4-yl)hexahydropyrimidin-4-yl]anilino}benzonitrile;
(6S)-6[2-Chloro-3-(4-fluoro-3-methylanilino)phenyl]-2-imino-6-methyl-3-(tetrahydropyran-4-yl)hexahydropyrimidin-4-one;
(6S)-6-{2-Chloro-3-[4-(tri-fluoromethyl)anilino]phenyl}-2-imino-6-methyl-3-(tetrahydro-pyran-4-yl)hexahydropyrimidin-4-one;
(6S)-6-[2-Chloro-3-(4-fluoro-anilino)phenyl]-2-imino-6-methyl-3-(tetrahydropyran-4-yl)hexahydropyrimidin-4-one;
(6S)-6-(3-Anilino-2-chloro-phenyl)-3-(3-hydroxy-3-methyl-cyclobutyl)-2-imino-6-methyl-hexahydropyrimidin-4-one;
(6S)-6-{2-Chloro-3-[(6-methyl-pyridin-3-yl)amino]phenyl}-2-imino-6-methyl-3-(tetrahydro-pyran-4-yl)hexahydropyrimidin-4-one;
(6S)-6-[2-Chloro-3-(2-chloro-anilino)phenyl]-2-imino-6-methyl-3-(tetrahydropyran-4-yl)hexahydropyrimidin-4-one;
(6S)-6-{2-Chloro-3-[2-(trifluoromethyl)anilino]-phenyl}-2-imino-6-methyl-3-(tetrahydropyran-4-yl)-hexahydropyrimidin-4-one;
2-{2-Chloro-3-[(4S)-2-imino-4-methyl-6-oxo-1-(tetrahydro-pyran-4-yl)hexahydropyrimidin-4-yl]anilino}benzonitrile;
4-{2-Chloro-3-[(4S)-2-imino-4-methyl-6-oxo-1-(tetrahydro-pyran-4-yl)hexahydropyrimidin-4-yl]anilino}benzonitrile;
(6S)-6-{2-Chloro-3-[(2-methyl-pyrimidin-5-yl)amino]phenyl}-2-imino-6-methyl-3-(tetrahydro-pyran-4-yl)hexahydropyrimidin-4-one;
(6S)-6-[2-Chloro-3-(pyridin-3-ylamino)phenyl]-2-imino-6-methyl-3-(tetrahydropyran-4-yl)hexahydropyrimidin-4-one;
(6S)-6-[2-Chloro-3-(quinolin-5-ylamino)phenyl]-2-imino-6-methyl-3-(tetrahydropyran-4-yl)hexahydropyrimidin-4-one;
(6S)-6-{2-Chloro-3-[2-fluoro-5-(trifluoromethoxy)anilino]-phenyl}-2-imino-6-methyl-3-(tetrahydropyran-4-yl)-hexahydropyrimidin-4-one;
(6S)-6-[2-Chloro-3-(3-fluoro-5-methoxyanilino)phenyl]-2-imino-6-methyl-3-(tetrahydro-pyran-4-yl)hexahydropyrimidin-4-one;
2-Chloro-4-{2-chloro-3-[(4S)-2-imino-4-methyl-6-oxo-1-(tetrahydropyran-4-yl)-hexahydropyrimidin-4-yl]-anilino}benzonitrile;
(6S)-6-(2-Chloro-3-{[6-(morpholin-4-yl)pyridin-3-yl]amino}phenyl)-2-imino-6-methyl-3-(tetrahydropyran-4-yl)hexahydropyrimidin-4-one;
(6S)-6-(2-Chloro-3-{[2-(trifluoromethyl)pyridin-3-yl]amino}phenyl)-2-imino-6-methyl-3-(tetrahydropyran-4-yl)hexahydropyrimidin-4-one;
(6S)-6-[2-Chloro-3-(5-fluoro-2-methoxyanilino)phenyl]-2-imino-6-methyl-3-(tetrahydro-pyran-4-yl)hexahydropyrimidin-4-one;
(6S)-6-{2-Chl

Assignees

• UCB Biopharma SRL

Inventors

• De Haro Garcia Teresa
• King Lloyd Malcolm
• Lowe Martin Alexander
• Maccoss Malcolm
• Taylor Richard David
• Zhu Zhaoning

Classifications

• C07D401/12

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

• C07D493/08

  Bridged systems · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D471/04

  Ortho-condensed systems · 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