Substituted aminopurine compounds, compositions thereof, and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-10646493-B2
Application number	US-201916514749-A
Country	US
Kind code	B2
Filing date	Jul 17, 2019
Priority date	Oct 6, 2014
Publication date	May 12, 2020
Grant date	May 12, 2020

Abstract

Provided herein are Aminopurine Compounds having the following structures:

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 a cancer, for example, melanoma.

First claim

What is claimed is:

1. A method for treating melanoma, comprising administering to a patient having melanoma an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt, tautomer, stereoisomer or enantiomer thereof,
wherein:
R 1 is substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, or substituted or unsubstituted non-aromatic heterocyclyl;
R 2 is H or substituted or unsubstituted C 1-3 alkyl;
R 3 is phenyl, substituted with one or more halogen, optionally further substituted with one or more substituents independently selected from substituted or unsubstituted C 1-3 alkyl, CN, and —OR′, wherein each R′ is independently substituted or unsubstituted C 1-3 alkyl;
wherein when an alkyl group is substituted, it is substituted with a substituent selected from the group consisting of chloro; iodo; bromo; fluoro; alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; acyl; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH) 2 ; and O(alkyl)aminocarbonyl;
wherein when a group other than an alkyl group is substituted, it is substituted with a substituent selected from the group consisting of chloro; iodo; bromo; fluoro; alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; acyl; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aryloxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxo; B(OH) 2 , O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic, or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic; monocyclic or fused or non-fused polycyclic aryl or heteroaryl; aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy; and
provided that the compound is not
4-[2-[(1-methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]-9H-purin-9-yl]-cis-cyclohexanecarboxamide, or
4-[8-[(2,4-difluorophenyl)amino]-2-[(trans-4-hydroxycyclohexyl)amino]-9H-purin-9-yl]-cis-cyclohexanecarboxamide,
wherein said compound of formula (I) is administered to said patient one to four times a day in a dose of about 0.005 mg/kg to about 10 mg/kg of said patient's body weight.

2. The method of claim 1 , wherein the dose is about 0.01 mg/kg to about 5 mg/kg of said patient's body weight, about 0.05 mg/kg to about 1 mg/kg of said patient's body weight, about 0.1 mg/kg to about 0.75 mg/kg of said patient's body weight or about 0.25 mg/kg to about 0.5 mg/kg of said patient's body weight.

3. The method of claim 1 , wherein the dose is about 0.25 mg/kg to about 0.5 mg/kg of said patient's body weight.

4. The method of claim 1 , wherein R 1 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydro-thiopyrandioxide, piperidyl, oxepanyl, or oxaspiroheptyl, optionally substituted with one or more substituents independently selected from F, OH, SO 2 CH 3 , SO 2 -tosyl, C(═O)CH 3 , C(═O)OCH 3 , C(═O)O-tert-butyl, C(═O)O-isopropyl, C(═O)NHCH 3 , C(═O)NH-phenyl, methyl, ethyl, isopropyl, CH 2 OH, phenyl, pyridyl, or benzyl.

5. The method of claim 1 , wherein R 2 is CH 3 .

6. The method of claim 1 , wherein R 3 is 2,4,6-trihalogen substituted phenyl.

7. The method of claim 1 , wherein the compound is (1s,4s)-4-(8-(3-chlorophenylamino)-2-(isopropylamino)-9H-purin-9-yl)cyclohexanecarboxamide.

8. The method of claim 1 , wherein the compound is (1R,4s)-4-(8-(2,4-dichloro-6-fluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide.

9. The method of claim 1 , wherein the compound is (1R,4s)-4-(8-(2,4-dichloro-6-fluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide.

10. The method of claim 1 , wherein the compound is (1R,4s)-4-(8-(2,6-dichloro-4-cyanophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide.

11. The method of claim 1 , wherein the compound is (1s,4s)-4-(2-(cyclobutylamino)-8-(2,6-dichloro-4-cyanophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide.

12. The method of claim 1 , wherein the compound is (1s,4s)-4-(2-(cyclobutylamino)-8-(2,6-dichloro-4-cyanophenylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide.

13. The method of claim 1 , wherein the compound is (1s,4s)-4-(2-(3,3-difluorocyclobutylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide.

14. The method of claim 1 , wherein the compound is (1s,4s)-4-(2-(cyclopentylamino)-8-(2,6-dichloro-4-cyanophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide.

15. The method of claim 1 , wherein the compound is (1S,4s)-4-(8-(2,6-dichloro-4-fluorophenylamino)-2-((R)-3,3-difluorocyclopentylamino)-9H-purin-9-yl)cyclohexanecarboxamide.

16. The method of claim 1 , wherein the compound is (1R,4s)-4-(2-(((3R,4 S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.

17. The method of claim 1 , wherein the compound is (1R,4S)-4-(8-(2,4-dichloro-6-fluorophenyl amino)-2-((1 S,3R)-3-hydroxycyclohexylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide.

18. The method of claim 1 , wherein the compound is (1S,4s)-4-(2-(((3 S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.

19. The method of claim 1 , wherein the compound is (1S,4s)-4-(8-((4-chloro-2,6-difluorophenyl)amino)-2-(((3 S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.

20. The method of claim 1 , wherein the compound is (1s,4s)-4-(8-(4-chloro-2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.

Assignees

• Signal Pharm Llc

Inventors

• Alexander Matthew
• Bahmanyar Sogole
• Boylan John Frederick
• Hansen Joshua
• Huang Dehua
• Hubbard Robert
• Jeffy Brandon
• Leisten Jim
• Moghaddam Mehran
• Raheja Raj K
• Raymon Heather
• Schwarz Kimberly
• Sloss Marianne
• Torres Eduardo
• Tran Tam Minh
• Xu Shuichan
• Zhao Jingjing

Classifications

• C07D473/32 Primary

  Nitrogen atom · CPC title

• A61K31/52 Primary

  Purines, e.g. adenine · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D239/50

  Three nitrogen atoms · CPC title