Animal and human anti-trypanosomonal and anti-leishmania agents

Patent metadata

Field	Value
Publication number	US-10420772-B2
Application number	US-201816000969-A
Country	US
Kind code	B2
Filing date	Jun 6, 2018
Priority date	Jun 2, 2016
Publication date	Sep 24, 2019
Grant date	Sep 24, 2019

Abstract

Provided herein are Aminopurine compounds 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 an Aminopurine Compound, and methods for treating or preventing animal and human protozoal infections.

First claim

What is claimed is:

1. A method for the treatment of trypanosomosis, trypanosomiasis, or leishmaniasis, the method comprising administering to a subject having trypanosomosis, trypanosomiasis, or leishmaniasis an effective amount of a 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 each of R 1a , R 1b and R 1c is independently (C 1-4 )alkyl, or (C 1-4 )alkyl(OR); or R 1a and R 1b and the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, and R 1c is (C 1-4 )alkyl;
R 2 is cycloalkyl or aryl, substituted with at least one NR 2 , OR, CN, NRC(O)R, CH 2 OR, CH 2 NR 2 , CH 2 NRCOR, CH 2 NRCOOR′, or heterocyclylalkyl;
R 3 is phenyl or pyridyl, optionally substituted with at least one halogen, CN, (C 1-2 )alkyl, or O(C 1-2 )alkyl, wherein the alkyl is optionally fluorinated;
R is H or (C 1-4 ) alkyl; and
R′ is (C 1-4 )alkyl.

2. The method of claim 1 , wherein R 1 is CR 1a R 1b R 1c , wherein each of R 1a , R 1b and R 1c is independently (C 1-2 )alkyl.

3. The method of claim 1 , wherein R 1 is t-butyl, C(CH 3 ) 2 CH 2 CH 3 , or C(CH 3 ) 2 CH 2 OH.

4. The method of claim 1 , wherein R 1 is CR 1a R 1b R 1c , and wherein R 1a and R 1b and the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, and R 1c is (C 1-4 )alkyl.

5. The method of claim 4 , wherein R 1a and R 1b and the carbon to which they are attached form a cyclopropyl, cyclobutyl, cyclohexyl, or tetrahydropyranyl.

6. The method of claim 4 , wherein R 1c is CH 3 .

7. The method of claim 1 , wherein R 1 is 1-methylcyclopropyl, 1-methylcyclobutyl, 1-methylcyclpentyl or 1-methyl-tetrahydropyranyl.

8. The method of claim 1 , wherein R 2 is (C 3-7 )cycloalkyl, substituted with at least one NR 2 , OR, CN, NRC(O)R, CH 2 OR, CH 2 NR 2 , CH 2 NRC(O)R, CH 2 NRC(O)OR′ or heterocyclylalkyl.

9. The method of claim 8 , wherein R 2 is cyclobutyl, cyclopentyl, or cyclohexyl.

10. The method of claim 8 , wherein R 2 is substituted with at least one NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, OCH 3 , CN, NHC(O)CH 3 , N(CH 3 )C(O)CH 3 , CH 2 OH, CH 2 OCH 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 NHC(O)CH 3 , CH 2 N(CH 3 )C(O)CH 3 , CH 2 NHC(O)OCH 3 , CH 2 N(CH 3 )C(O)OCH 3 , CH 2 -piperidyl, or CH 2 -morpholinyl.

11. The method of claim 8 , wherein R 2 is cyclohexyl, substituted with NH 2 , OH, CN, NHC(O)CH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 NHC(O)CH 3 , CH 2 NHC(O)OCH 3 , CH 2 -piperidyl, or CH 2 -morpholinyl.

12. The method of claim 1 , wherein R 2 is aryl, substituted with at least one NR 2 , OR, CN, NRC(O)R, CH 2 OR, CH 2 NR 2 , CH 2 NRCOR, or CH 2 NRCOOR′.

13. The method of claim 12 , wherein R 2 is phenyl, substituted with at least one NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, OCH 3 , CN, NHC(O)CH 3 , N(CH 3 )C(O)CH 3 , CH 2 OH, CH 2 OCH 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 NHC(O)CH 3 , CH 2 N(CH 3 )C(O)CH 3 , CH 2 NHC(O)OCH 3 , or CH 2 N(CH 3 )C(O)OCH 3 .

14. The method of claim 12 , wherein R 2 is phenyl, substituted with CH 2 NH 2 .

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

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

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

18. The method 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 method of claim 18 , wherein R 3 is substituted with at least one F, Cl, CHF 2 , CF 3 , or OCF 3 .

20. The method of claim 18 , wherein R 3 is substituted with at least one Cl, or CF 3 .

21. The method of claim 1 , wherein the compound is:
9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,
9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclobutyl)-9H-purine-2,8-diamine,
9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-tert-pentyl-9H-purine-2,8-diamine,
9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclopentyl)-9H-purine-2,8-diamine,
N8-(3-chlorophenyl)-9-((1s,4s)-4-((dimethylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,
9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-(pyridin-2-yl)-9H-purine-2,8-diamine,
9-((1r,4r)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,
9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(pyridin-2-yl)-9H-purine-2,8-diamine,
9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(2,3-difluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,
(1s,4s)-4-(8-(3-chlorophenylamino)-2-(1-methylcyclopentylamino)-9H-purin-9-yl)cyclohexanol,
N-(((1s,4s)-4-(8-(3-chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methyl)acetamide,
9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(1-methylcyclopentyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-pentyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
methyl ((1s,4s)-4-(8-(3-chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methylcarbamate,
9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(1-methylcyclopentyl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
9-((1r,4r)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
9-((1 r,4r)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-p-tolyl-9H-purine-2,8-diamine,
((1s,4 s)-4-(8-(3-chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methanol,
9-((1R, 3 S)-3-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,
N8-(3-chlorophenyl)-9-((1s,4s)-4-((methylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,
9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-pentyl-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
(1s,4s)-4-(2-(4-methyltetrahydro-2H-pyran-4-ylamino)-8-(3-(trifluoromethyl)phenylamino)-9H-purin-9-yl)cyclohexanecarbonitrile,
N-((1s,4s)-4-(8-(3-chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)acetamide,
((1r,4r)-4-(8-(3-chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methanol,
9-((1s,4s)-4-aminocyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,
9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
9-((1s,4s)-4-aminocyclohexyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
9-((1r,4r)-4-aminocyclohexyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(

Assignees

• Celgene Corp

Inventors

• Canan Stacie S
• Hawryluk Natalie Anne
• Witty Michael John

Classifications

• A61P43/00

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

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/52 Primary

  Purines, e.g. adenine · CPC title

• C07C211/36

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