Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof

Patent metadata

Field	Value
Publication number	US-9623028-B2
Application number	US-201514797548-A
Country	US
Kind code	B2
Filing date	Jul 13, 2015
Priority date	Jul 14, 2014
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

Abstract

Provided herein are methods for treating or preventing a cancer, in particular solid tumors and hematological cancers, comprising administering to a subject in need thereof an effective amount of a compound of formula (I):

First claim

What is claimed is:

1. A method for treating glioblastoma multiforme, comprising administering to a subject having glioblastoma multiforme an effective amount of Pyrrolopyrimidine Compound, wherein the Pyrrolopyrimidine Compound is a compound of formula (I):

and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and isotopologues thereof,
wherein:
R 1 is substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclyl;
R 2 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3 is substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl, and
L is NH or O;
provided
R 3 is not pyridyl when L is NH or when R 2 is pyrazolyl; and
the compound is not
N-methyl-N-[trans-3-[[5-(1-methyl-1H-pyrazol-4-yl)-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]cyclobutyl]-2-propenamide; or
N-methyl-N-[trans-3-[[5-(1-methyl-1H-pyrazol-3-yl)-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]cyclobutyl]-2-propenamide.

2. The method of claim 1 , wherein L is O.

3. The method of claim 1 , wherein R 1 is substituted or unsubstituted C 3-8 cycloalkyl.

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

5. The method of claim 3 , wherein the cycloalkyl is substituted with one or more —CN, halogen, —OR or a substituted or unsubstituted C 1-3 alkyl, wherein each R is independently —H or substituted or unsubstituted (C 1-4 )alkyl.

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

wherein
each R′ is independently —CN, halogen, —OR or C 1-3 alkyl;
R″ is —H or C 1-3 alkyl;
each R is independently H or substituted or unsubstituted (C 1-4 )alkyl; and
n is 0-2.

7. The method of claim 1 , wherein R 2 is substituted phenyl.

8. The method of claim 7 , wherein R 2 is phenyl, substituted with one or more substituted or unsubstituted C 1-6 alkyl, halogen, —CN, —OR 5 , —C(═O)NR 5 2 , —C(═O) (substituted or unsubstituted heterocyclyl), —C(═O) (substituted or unsubstituted alkylheterocyclyl), —NHC(═O)R 5 , —SO 2 NR 5 2 , or substituted or unsubstituted heteroaryl, wherein each R 5 is independently —H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkylheterocyclyl.

9. The method of claim 7 , wherein R 2 is phenyl, substituted with one or more —(C 1-3 alkyl), —(C 1-3 alkyl)NR 2 , —CF 3 , —Cl, —F, —CN, —OCH 3 , —OCF 3 , —C(═O)NR 2 , —C(═O)NR (substituted or unsubstituted cycloalkyl), —C(═O)NR(CH 2 ) 0-2 CR 2 (CH 2 ) 0-2 OR, —C(═O)NR(CH 2 ) 0-2 CR 2 (CH 2 ) 0-2 NR 2 , —C(═O)NR(CH 2 ) 0-2 CR 2 (CH 2 ) 0-2 C(═O)NR 2 , —C(═O)N (substituted or unsubstituted cycloalkyl)(CH 2 ) 0-2 OR, —C(═O)NR(CH 2 ) 0-3 (substituted or unsubstituted heterocyclyl), —C(═O)(CH 2 ) 0-3 (substituted or unsubstituted heterocyclyl), —C(═NR)NR 2 , —NRC(═O)R, —SO 2 NR 2 , —SO 2 R, or substituted or unsubstituted heterocyclyl, wherein each R is independently —H or substituted or unsubstituted (C 1-4 )alkyl.

10. The method of claim 9 , wherein each R is independently —H or —CH 3 .

11. The method of claim 7 , wherein R 2 is phenyl, substituted with one or more —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 NH 2 , —CF 3 , —Cl, —F, —CN, —OCH 3 , —OCF 3 , —C(═O)NH 2 , —C(═O)NHCH 3 , —C(═O)N(CH 3 ) 2 , —C(═O)NC(CH 3 ) 3 , —C(═O)NHCH 2 CH 2 F, —C(═O)NHCH 2 CHF 2 , —C(═O)NHCH 2 CF 3 , —C(═O)NHCH 2 CF 2 CH 3 , —C(═O)NHCH 2 CN, —C(═O)N(CH 3 )CH 2 CN, —C(═O)NHCH 2 CH 2 CN, —C(═O)N(CH 3 )CH 2 CH 2 CN, —C(═O)NH-cyclobutyl, —C(═O)NH-(hydroxy-cyclobutyl), —C(═O)NH-cyclopentyl, —C(═O)NH-(hydroxy-cyclopentyl), —C(═O)NHCH 2 CH 2 OH, —C(═O)NHCH 2 CH 2 OCH 3 , —C(═O)N(CH 3 )CH 2 CH 2 OH, —C(═O)N(CH 3 )CH 2 CH 2 OCH 3 , —C(═O)NHCH 2 CH 2 CH 2 OH, —C(═O)N(CH 3 )CH 2 CH 2 CH 2 OH, —C(═O)N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , —C(═O)NHCH 2 CH(CH 3 )OH, —C(═O)NHCH 2 C(CH 3 ) 2 OH, —C(═O)NHCH(CH 3 )CH 2 OH, —C(═O)NHC(CH 3 ) 2 CH 2 OH, —C(═O)NHCH 2 CH 2 NH 2 , —C(═O)NHCH 2 CH 2 NH(CH 3 ), —C(═O)NHCH 2 CH 2 N(CH 3 ) 2 , —C(═O)NHCH 2 C(═O)NH 2 , —C(═O)N(CH 3 )CH 2 C(═O)NH 2 , —C(═O)NHCH 2 CH 2 C(═O)NH 2 , —C(═O)N(CH 3 )CH 2 CH 2 C(═O)NH 2 , —C(═O)N(cyclopropyl)CH 2 CH 2 OH, —C(═O)NH-oxetanyl, —C(═O)N(CH 3 )-oxetanyl, —C(═O)NH-(methyl-oxetanyl), —C(═O)NH-azetidinyl, —C(═O)NH-(methylazetidinyl), —C(═O)NH-(1-acetylazetidinyl), —C(═O)NH-pyrrolidyl, —C(═O)NH-piperidyl, —C(═O)NH-tetrahydrofuranyl, —C(═O)N(CH 3 )-tetrahydrofuranyl, —C(═O)NH-tetrahydropyranyl, —C(═O)N(CH 3 )-tetrahydropyranyl, —C(═O)NHCH 2 -oxetanyl, —C(═O)N(CH 3 )CH 2 -oxetanyl, —C(═O)NHCH 2 -(methyl-oxetanyl), —C(═O)N(CH 3 )CH 2 -(methyl-oxetanyl), —C(═O)NHCH 2 -tetrahydrofuranyl, —C(═O)NHCH 2 -tetrahydropyranyl, —C(═O)NHCH 2 -dioxanyl, —C(═O)aziridinyl, —C(═O)(methyl-aziridinyl), —C(═O)(dimethyl-aziridinyl), —C(═O)(hydroxymethyl-aziridinyl), —C(═O)azetidinyl, —C(═O)pyrrolidinyl, —C(═O)(hydroxyl-pyrrolidinyl), —C(═O)(hydroxyl, methoxypyrrolidinyl), —C(═O)(dimethoxypyrrolidinyl), —C(═O)morpholinyl, —C(═O)piperazinyl, —C(═O)(methylpiperazinyl), —C(═O)(hydroxy-piperidyl), —C(═O)(fluoropiperidinyl), —(C═O)(methoxy-piperidyl), —C(═NH)NH 2 , —NHC(═O)CH 3 , —SO 2 NHCH 3 , —SO 2 CH 3 , or substituted or unsubstituted pyrazolyl.

12. The method of claim 7 , wherein R 2 is phenyl, substituted with one or more —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 NH 2 , —CF 3 , —F, —CN, —OCH 3 , —OCF 3 , —C(═O)NH 2 , —C(═O)NHCH 3 , —C(═O)N(CH 3 ) 2 , —C(═O)NC(CH 3 ) 3 , —C(═O)NHCH 2 CH 2 F, —C(═O)NHCH 2 CF 2 CH 3 , —C(═O)N(CH 3 )CH 2 CN, —C(═O)N(CH 3 )CH 2 CH 2 CN, —C(═O)NH-(3-hydroxy-cyclobutyl), —C(═O)NH-cyclopentyl, —C(═O)NH-(2-hydroxycyclopentyl), —C(═O)NHCH 2 CH 2 OH, —C(═O)NHCH 2 CH 2 OCH 3 , —C(═O)N(CH 3 )CH 2 CH 2 OH, —C(═O)N(CH 3 )CH 2 CH 2 OCH 3 , —C(═O)NHCH 2 CH 2 CH 2 OH, —C(═O)N(CH 3 )CH 2 CH 2 CH 2 OH, —C(═O)NHCH 2 CH(CH 3 )OH, —C(═O)NHCH 2 C(CH 3 ) 2 OH, —C(═O)NHCH(CH 3 )CH 2 OH, —C(═O)NHC(CH 3 ) 2 CH 2 OH, —C(═O)NHCH 2 CH 2 NH 2 , —C(═O)NHCH 2 CH 2 NH(CH 3 ), —C(═O)NHCH 2 CH 2 N(CH 3 ) 2 , —C(═O)N(CH 3 )CH 2 C(═O)NH 2 , —C(═O)N(CH 3 )CH 2 CH 2 C(═O)NH 2 , —C(═O)N(cyclopropyl)CH 2 CH 2 OH, —C(═O)NH-oxetanyl, —C(═O)N(CH 3 )-oxetanyl, —C(═O)NH-(3-methyl-oxetanyl), —C(═O)NH-(1-methylazetidinyl), —C(═O)NH-(1-acetylazetidinyl), —C(═O)NH-piperidyl, —C(═O)NH-tetrahydrofuranyl, —C(═O)NH-tetrahydropyranyl, —C(═O)N(CH 3 )-tetrahydropyranyl, —C(═O)NHCH 2 -oxetanyl, —C(═O)N(CH 3 )CH 2 -(3-methyl-oxetanyl), —C(═O)NHCH 2 -tetrahydrofuranyl, —C(═O)NHCH 2 -tetrahydropyranyl, —C(═O)NHCH 2 -dioxanyl, —C(═O)aziridinyl, —C(═O)(2-methyl-aziridinyl), —C(═O)(2,2-dimethyl-aziridinyl), —C(═O)(2-(hydroxymethyl)aziridinyl), —C(═O)azetidinyl, —C(═O)pyrrolidinyl, —C(═O)(3-hydroxy-4-methoxypyrrolidinyl), —C(═O)(3,4-dimethoxypyrrolidinyl), —C(═O)morpholinyl, —C(═O)piperazinyl, —C(═O)(4-methylpiperazinyl), —C(═O)(4-hydroxy-piperidyl), —C(═O)(4,4-difluoropiperidinyl), —(C═O)(4-methoxy-piperidyl), —C(═NH)NH 2 , —NHC(═O)CH 3 , —SO 2 NHCH 3 , —SO 2 CH 3 , or substituted or unsubstituted pyrazolyl.

13. The method of claim 1 , wherein R 3 is substituted or unsubstituted heterocyclyl.

14. The method of claim 13 , wherein the h

Assignees

• Signal Pharm Llc

Inventors

• Zhu Dan
• Boylan John
• Xu Shuichan
• Riggs Jennifer
• Shi Tao
• Wurmser Andrew
• Mikolon David
• Deyanat-Yazdi Gordafaried

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61K31/635

  having a heterocyclic ring, e.g. sulfadiazine · CPC title

• A61K31/00

  Medicinal preparations containing organic active ingredients · CPC title