Anti-Wolbachia pyrido[2,3-d]pyrimidine compounds

Patent metadata

Field	Value
Publication number	US-11518760-B2
Application number	US-201816478281-A
Country	US
Kind code	B2
Filing date	Jan 17, 2018
Priority date	Jan 17, 2017
Publication date	Dec 6, 2022
Grant date	Dec 6, 2022

Abstract

The present invention relates to compounds of Formulae (I) and (II) as defined herein, and salts and solvates thereof.The present invention also relates to pharmaceutical compositions comprising compounds of Formulae (I) and (II), and to the use of compounds of Formulae (I) and (II) in the treatment or prevention of filarial worm infection, as well as other diseases or conditions in which filarial worm infection is implicated.

First claim

The invention claimed is:

1. A compound, or a salt or solvate thereof, according to Formula Ia:

wherein,
R 6 is selected from hydrogen, methyl, or ethyl;
R 7 is hydrogen; or
R 6 and R 7 , together with the atoms to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl ring;
X 4 is N;
R 2 is NR c1 R d1 or is selected from

 each of which may optionally be substituted with one or more R e , wherein each R e is selected from hydroxyl, ═O, halogen, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, O—C 1-6 alkyl, C 3-6 cycloalkyl, and —NR c R d ;
where R c1 is C 1-6 alkyl, and R d1 is selected from C 3-6 cycloalkyl, C 1-6 alkyl and C 6-11 aryl, wherein said C 1-6 alkyl, C 6-11 aryl, and C 3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-11 aryl, C 1-6 alkyl and O—C 1-6 alkyl;
R b is selected from hydroxyl, halogen, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, and O—C 1-6 alkyl;
R c is independently selected from hydrogen, hydroxyl, halogen, CN, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl;
R d is independently selected from hydrogen, hydroxyl, halogen, CN, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl, C 6-11 aryl; and
R 4 and R 5 are independently selected from hydrogen, hydroxyl, halogen, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 1-6 alkyl.

2. A compound according to claim 1 , or a salt or solvate thereof, wherein R 4 and R 5 are hydrogen.

3. A compound according to claim 1 , or a salt or solvate thereof, wherein R b is selected from fluoro, chloro, and CF 3 .

4. A compound according to claim 1 , wherein R 6 and R 7 are both hydrogen.

5. A compound according to claim 1 , or a salt or solvate thereof, wherein R 2 is selected from

each of which may optionally be substituted with one or more R e .

6. A compound according to claim 1 , or a salt or solvate thereof, wherein each R e is independently selected from fluoro, chloro, CN, CF 3 , OCF 3 , and methyl.

7. A compound, or a salt or solvate thereof, selected from:
N 2 -isopropyl-N 2 ,N 4 -dimethyl-N 4 -((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine;
N 2 -isopropyl-N 2 -methyl-N 4 -(2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine;
N 2 -isopropyl-N 2 -methyl-N 4 -(2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine methanesulfonate;
2-(azetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
3-methyl-1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)azetidin-3-ol;
2-(2-methylazetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(2,2-dimethylazetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
N 2 -cyclopropyl-N 2 -methyl-N 4 -(2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine;
2-morpholino-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine methanesulfonate;
2-(3,3-difluoropyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(3,3-difluoropyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine methanesulfonate;
2-(4-fluoropiperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(4,4-difluoropiperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(4-chloropiperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(3-fluoroazetidin-1-yl)-N-[2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(3,3-difluoroazetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(3-(trifluoromethyl)azetidin-1-yl)-N-[2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
(S)-2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
(R)-2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(4-chloropiperidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidine;
2-(4,4-difluoropiperidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidin;
3-methyl-4-(4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine;
2-(3,3-difluoropyrrolidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidine;
2-(3-(trifluoromethyl)azetidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidine;
2-((4-chloropiperidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-((4,4-difluoropiperidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-((3-methylmorpholino)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-((3,3-difluoropyrrolidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine
2-((3-(trifluoromethyl)azetidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-((4-chloropiperidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-((4,4-difluoropiperidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-((3-methylmorpholino)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-((3,3-difluoropyrrolidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-((3-(trifluoromethyl)azetidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(4-(methylsulfonyl)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(4,4-dimethylpiperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-4-carbonitrile;
2-(4-(trifluoromethyl)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyr-imidin-4-amine;
N-((2-(trifluoromethyl)pyridin-3-yl)methyl)-2-(3-(trifluoromethyl)pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-4-amine;
1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)azetidine-3-carbonitrile;
1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carbonitrile;
2-(2,2-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(3,3-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(2-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine;
2-(3-fluoropyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-am

Assignees

• Liverpool School Tropical Medicine
• Univ Liverpool
• Eisai R&D Man Co Ltd

Inventors

• Ward Stephen A
• Taylor Mark J
• O'Neill Paul M
• Hong Weiqian David
• Benayoud Farid

Classifications

• C07D239/86

  with hetero atoms directly attached in position 4 · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07D471/04 Primary

  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