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

Patent metadata

Field	Value
Publication number	US-2017042902-A1
Application number	US-201615335619-A
Country	US
Kind code	A1
Filing date	Oct 27, 2016
Priority date	Oct 6, 2014
Publication date	Feb 16, 2017
Grant date	—

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

1 - 20 . (canceled)

21 . 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, enantiomer, or isotopologue 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 substitutents 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;

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.

22 . The method of claim 21 , wherein R 1 is substituted or unsubstituted C 1-8 alkyl.

23 . The method of claim 22 , wherein R 1 is substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylpentyl, 3-methylpentyl, isopentyl, or neopentyl.

24 . The method of claim 22 , wherein R 1 is substituted with one or more substituents independently selected from halogen and OR, wherein each R is independently H or substituted or unsubstituted C 1-3 alkyl.

25 . The method of claim 22 , wherein R 1 is substituted with one or more substituents independently selected from F, OH, and OCH 3 .

26 . The method of claim 22 , wherein R 1 is ethyl, isopropyl, isobutyl, tert-butyl, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 CH(CH 3 )OH, CH 2 CH(CH 3 )OCH 3 , CH(CH 3 )CH 2 OH, CH(CH 3 )CH 2 OCH 3 , CH 2 C(F 2 )CH 2 OH, CH 2 C(F 2 )CH 2 OCH 3 , CH(CF 3 )CH 2 OH, CH(CF 3 )CH 2 OCH 3 , CH(CH 2 OH)CH 2 CH 3 , CH(CH 2 OCH 3 )CH 2 CH 3 , CH 2 C(CH 3 ) 2 CH 2 OH, or CH 2 C(CH 3 ) 2 CH 2 OCH 3 .

27 . The method of claim 22 , wherein R 1 is isopropyl, isobutyl, tert-butyl, CH 2 CF 3 , CH 2 CH(CH 3 )OH, CH(CH 3 )CH 2 OH, CH(CH 3 )CH 2 OCH 3 , CH 2 C(F 2 )CH 2 OH, CH(CF 3 )CH 2 OH, CH(CH 2 OH)CH 2 CH 3 , or CH 2 C(CH 3 ) 2 CH 2 OH.

28 . The method of claim 21 , wherein R 1 is substituted or unsubstituted cycloalkyl.

29 . The method of claim 28 , wherein R 1 is substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

30 . The method of claim 28 , wherein R 1 is substituted with one or more substituents independently selected from halogen, OR, SO 2 R′, substituted or unsubstituted C 1-3 alkyl, and substituted or unsubstituted heterocyclyl, wherein each R is independently H or substituted or unsubstituted C 1-3 alkyl, and each R′ is independently substituted or unsubstituted C 1-3 alkyl.

31 . The method of claim 28 , wherein R 1 is substituted with one or more substituents independently selected from F, OH, OCH 3 , SO 2 CH 3 , methyl, and a substituted or unsubstituted 5-membered heterocyclyl.

32 . The method of claim 31 , wherein the 5-membered heterocyclyl is pyrroldinedionyl, or oxadiazolyl.

33 . The method of claim 28 , wherein R 1 is cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, optionally substituted with one or more substituents independently selected from F, OH, OCH 3 , SO 2 CH 3 , methyl, pyrrolidinedionyl, and oxadiazolyl.

34 . The method of claim 21 , wherein R 1 is substituted or unsubstituted cycloalkylalkyl.

35 . The method of claim 34 , wherein R 1 is substituted or unsubstituted (C 1-3 alkyl)-(C 1-8 cycloalkyl).

36 . The method of claim 34 , wherein R 1 is substituted or unsubstituted CH 2 -cyclopropyl, CH 2 -cyclobutyl, CH 2 -cyclopentyl, CH 2 -cyclohexyl, or CH 2 -cycloheptyl.

37 . The method of claim 34 , wherein R 1 is substituted with one or more substituents independently selected from (C 1-3 alkyl)OR or OR, wherein each R is independently H or substituted or unsubstituted C 1-3 alkyl.

38 . The method of claim 34 , wherein is CH 2 -cyclopropyl, CH 2 -cyclobutyl, CH 2 -cyclopentyl, or CH 2 -cyclohexyl, optionally substituted with one or more CH 2 OH or OH.

39 . The method of claim 21 , wherein R 1 is substituted or unsubstituted non-aromatic heterocyclyl.

40 . The method of claim 39 wherein R 1 is substituted or unsubstituted oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydro-thiopyrandioxide, piperidyl, oxepanyl, or oxaspiroheptyl.

41 . The method of claim 39 wherein R 1 is substituted with one or more substituents independently selected from halogen, OR, SO 2 R 4 , C(═O)R 5 , C(═O)OR 6 , C(═O)NRR 7 , substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted or alkylaryl, wherein each R is independently H or substituted or unsubstituted C 1-3 alkyl; R 4 is substituted or unsubstituted C 1-3 alkyl, or substituted or unsubstituted aryl; R 5 is substituted or unsubstituted C 1-3 alkyl; R 6 is substituted or unsubstituted C 1-6 alkyl; and R 7 is substituted or unsubstituted C 1-3 alkyl, or substituted or unsubstituted aryl.

42 . The method of claim 39 wherein 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.

43 . The method of claim 21 , wherein R 2 is H.

44 . The method of claim 21 , wherein R 2 is CH 3 .

45 . The method of claim 21 , wherein R 3 is ortho-halogen substituted phenyl.

46 . The method of claim 21 , wherein R 3 is para-halogen substituted phenyl.

47 . The method of claim 21 , wherein R 3 is para-CN substituted phenyl.

48 . The method of claim 21 , wherein R 3 is ortho, ortho-dihalogen substituted phenyl.

49 . The method of claim 21 , wherein R 3 is ortho, para-dihalogen substituted phenyl.

50 . The method of claim 21 , wherein R 3 is 2,4,6-trihalogen substituted phenyl.

51 . The method of claim 21 , wherein R 3 is ortho-halogen, para-CN substituted phenyl.

52 . The method of claim 21 , wherein R 3 is

wherein
each Hal is independently halogen;
each R 8 is independently substituted or unsubstituted C 1-3 alkyl, CN, or OR′;
each R′ is independently substituted or unsubstituted C 1-3 alkyl;
m is 1-3;
and p is 0-2.

53 . The method of claim 52 , wherein each Hal is independently Cl or F.

54 . The method of claim 52 , wherein each R 8 is independently CH 3 , CF 3 , CN, or OCH 3 .

55 . The method of claim 52 , wherein m is 2 o

Assignees

• Signal Pharm Llc

Inventors

• Alexander Matthew
• Bahmanyar Sogole
• 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
• Boylan John Frederick

Classifications

• C07D473/32 Primary

  Nitrogen atom · CPC title

• A61K31/5377

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/52 Primary

  Purines, e.g. adenine · CPC title

• C07D239/50

  Three nitrogen atoms · CPC title