Animal and human anti-malarial agents

Patent metadata

Field	Value
Publication number	US-10016436-B2
Application number	US-201715611108-A
Country	US
Kind code	B2
Filing date	Jun 1, 2017
Priority date	Jun 2, 2016
Publication date	Jul 10, 2018
Grant date	Jul 10, 2018

Abstract

Provided herein are Purine Comounds of Formula (I)

or pharmaceutically acceptable salts, tautomers, isotopologues, or stereoisomers thereof, wherein R 1 , R 2 , and R 3 are as defined herein, compositions comprising an effective amount of a Purine Compound, and methods for treating or preventing malaria comprising the administration of an effective amount of a Purine Compound.

First claim

What is claimed is:

1. A Purine Compound of formula (I),

or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, wherein
R 1 is CR 1a R 1b R 1c , wherein R 1a and R 1b are (C 1-4 )alkyl and R 1c is H or (C 1-4 )alkyl; or R 1a and R 1b form a 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, and R 1c is H or (C 1-4 )alkyl;
R 2 is L-R 2a or L-R 2b ,
L is a bond or (C 1-2 alkyl);
R 2a is 3-6 membered N-containing heterocyclyl or heteroaryl, each optionally substituted with one or more (C 1-4 )alkyl, or (C 1-4 )alkyl-NR 2 ,
R 2b is (C 1-4 branched or unbranched alkyl)-NR 2 ,
R 3 is phenyl or pyridyl, substituted with at least one halogen, CN, (C 1-4 )alkyl, or O(C 1-4 )alkyl, wherein the alkyl is optionally fluorinated; and
R is H or (C 1-4 ) alkyl;
provided the Purine Compound is not
4-(2-(isopropylamino)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-9-yl)pyrrolidin-2-one;
N 2 -cyclopentyl-N 8 -(2-fluorophenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine; or
N 2 -cyclohexyl-N 8 -(2-fluorophenyl)-9-(piperidin-4-ylmethyl)-9H-purine-2,8-diamine.

2. The Purine Compound of claim 1 , wherein R 1 is CR 1a R 1b R 1c , wherein R 1a and R 1b are (C 1-2 )alkyl and R 1c is H or (C 1-4 )alkyl.

3. The Purine Compound of claim 2 , wherein R 1 is isopropyl or t-butyl.

4. The Purine Compound of claim 1 , wherein R 1 is CR 1a R 1b R 1c , and R 1a and R 1b form a 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, and R 1c is H or (C 1 - 2 )alkyl.

5. The Purine Compound of claim 4 , wherein R 1a and R 1b form a cyclopropyl, cyclobutyl, cyclopentyl or tetrahydropyranyl.

6. The Purine Compound of claim 4 , wherein R 1c is H or CH 3 .

7. The Purine Compound of claim 4 , wherein R 1 is cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl, 1-methyl-cyclopropyl, 1-methyl-cyclobutyl, 1-methyl-cylopentyl, 1-methyl-tetrahydropyranyl or 4-methyl-tetrahydropyranyl.

8. The Purine Compound of claim 1 , wherein R 2 is L-R 2a and R 2a is selected from azetidyl, pyrolidinyl, piperidyl, piperazinyl, imidazolyl, octahydrocyclopenta[c]pyrrolyl, or octahydro-1H-isoindolyl.

9. The Purine Compound of claim 8 , wherein L is a bond, —CH 2 — or —CH 2 CH 2 —.

10. The Purine Compound of claim 8 , wherein R 2 is substituted with CH 3 , CH 2 CH 3 , or CH 2 CH 2 NH 2 .

11. The Purine Compound of claim 8 , wherein R 2 is azetidyl, piperidyl, pyrrolidyl, octahydrocyclopenta[c]pyrrolyl, octahydro-1H-isoindolyl, CH 2 -pyrrolidyl, CH 2 CH 2 -pyrrolidyl, CH 2 -piperidyl, CH 2 CH 2 -piperidyl, CH 2 CH 2 -imidazolyl, or CH 2 CH 2 -piperazinyl.

12. The Purine Compound of claim 1 , wherein R 2 is L-R 2b and R 2b is CH 2 NR 2 ,CH 2 CH 2 NR 2 , CH(CH 3 )NR 2 , or C(CH 3 ) 2 NR 2 .

13. The Purine Compound of claim 12 , wherein L is a bond, —CH 2 — or —CH 2 CH 2 —.

14. The Purine Compound of claim 12 , wherein R 2 is CH 2 CH 2 NH 2 , CH 2 CH 2 NH(CH 3 ), CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH(CH 3 )NH 2 , or CH 2 C(CH 3 ) 2 NH 2 .

15. The Purine Compound of claim 1 , wherein R 3 is phenyl substituted with at least one halogen, CN, fluorinated (C 1-2 )alkyl, or O-fluorinated(C 1-2 )alkyl.

16. The Purine Compound of claim 15 , wherein R 3 is substituted with at least one F, Cl, CN, CHF 2 , CF 3 , or OCF 3 .

17. The Purine Compound of claim 15 , wherein R 3 is meta-substituted phenyl.

18. The Purine Compound of claim 1 , wherein R 3 is pyridyl, substituted with at least one halogen, fluorinated (C 1-2 )alkyl, or O-fluorinated(C 1-2 )alkyl.

19. The Purine Compound of claim 18 , wherein R 3 is substituted with at least one Cl, or CF 3 .

20. The Purine Compound of claim 1 , wherein the Purine Compound is:
9-(2-(1H-imidazol-1-yl)ethyl)-N2-tert-butyl-N8-(3-chlorophenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(piperidin-4-yl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(piperidin-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
9-(1-(2-aminoethyl)piperidin-4-yl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
9-(1-(2-aminoethyl)piperidin-4-yl)-N2-tert-butyl-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3,4-dichlorophenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(4-chlorophenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3,4-dichlorophenyl)-9-(pyrrolidin-3-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(pyrrolidin-3-yl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(pyrrolidin-3-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
9-(3-aminopropyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(4-chlorophenyl)-9-(pyrrolidin-3-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(2-(pyrrolidin-1-yl)ethyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
4-(2-(tert-butylamino)-9-(piperidin-4-yl)-9H-purin-8-ylamino)benzonitrile,
N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-(piperidin-4-yl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-(2-(piperidin-1-yl)ethyl)-9H-purine-2,8-diamine,
N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-(2-(pyrrolidin-1-yl)ethyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(2-(pyrrolidin-3-yl)ethyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(2-(pyrrolidin-2-yl)ethyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3,5-dichlorophenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(piperidin-4-yl)-N8-(4-(trifluoromethoxy)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(2-(piperazin-1-yl)ethyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(piperidin-4-ylmethyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(pyrrolidin-3-ylmethyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-(piperidin-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3-chloro-5-fluorophenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3-chloro-5-(trifluoromethyl)phenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3,5-difluorophenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(piperidin-4-yl)-N8-(3-(trifluoromethoxy)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(5-chloropyridin-3-yl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(piperidin-4-yl)-N8-(2-(trifluoromethyl)pyridin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(3-(dimethylamino)propyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3-(difluoromethyl)phenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-cyclopropyl-N8-(3,5-dichlorophenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
9-(1-(2-aminoethyl)piperidin-4-yl)-N2-tert-butyl-N8-(3,5-dichlorophenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3,4-dichlorophenyl)-9-(1-methylpiperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3,4-dichlorophenyl)-9-(1-ethylpiperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3,5-dichlorophenyl)-9-(pyrrolidin-3-yl)-9H-purine-2,8-diamine,
9-(1-(2-aminoethyl)piperidin-4-yl)-N2-tert-butyl-N8-(3-chloro-5-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N8-(3-chloro-5-(trifluoromethyl)phenyl)-N2-cyclopropyl-9-(piperidin-4-yl)-9H-purine-

Assignees

• Celgene Corp

Inventors

• Canan Stacie S
• Hawryluk Natalie Anne

Classifications

• A61P33/06

  Antimalarials · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07C211/36

  containing at least two amino groups bound to the carbon skeleton · CPC title

• C07D473/32

  Nitrogen atom · CPC title

• C07D231/02

  not condensed with other rings · CPC title