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

Patent metadata

Field	Value
Publication number	US-9795607-B2
Application number	US-201615215728-A
Country	US
Kind code	B2
Filing date	Jul 21, 2016
Priority date	Jan 16, 2013
Publication date	Oct 24, 2017
Grant date	Oct 24, 2017

Abstract

Provided herein are Pyrrolopyrimidine Compounds having the following structure:

wherein R 1 , R 2 , R 3 , and L are as defined herein, compositions comprising an effective amount of a Pyrrolopyrimidine Compound, and methods for treating or preventing breast cancer, more particularly triple negative breast cancer, comprising administering an effective amount of such Pyrrolopyrimidine Compounds to a subject in need thereof.

First claim

What is claimed is:

1. A method for the treatment of breast cancer, comprising administering to a subject in need thereof 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 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 alkyl.

4. The method of claim 1 , wherein R 1 is substituted or unsubstituted methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl, or 2,2-dimethylpropyl.

5. The method of claim 1 , wherein R 1 is substituted or unsubstituted methyl, ethyl, isopropyl, sec-butyl, t-butyl, or 2,2-dimethylpropyl.

6. The method of claim 3 , wherein the alkyl is substituted with one or more —OR or —NR 2 , wherein each R is independently —H or substituted or unsubstituted (C 1-4 )alkyl.

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

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

9. The method of claim 7 , 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.

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

11. The method of claim 1 , wherein R 1 is substituted or unsubstituted oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or piperidinyl.

12. 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.

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

14. The method of claim 13 , 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 heterocyclylalkyl), —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 heterocyclylalkyl.

15. The method of claim 13 , 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.

16. The method of claim 15 , wherein each R is independently —H or —CH 3 .

17. The method of claim 13 , 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)NHC(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.

18. The method of claim 13 , 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)NHC(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)N

Assignees

• Signal Pharmaceutical Llc
• Signal Pharm Llc

Inventors

• Calabrese Andrew Antony
• Jeffy Brandon
• Robinson Dale
• Zhu Dan
• Huang Dehua
• Elsner Jan
• Boylan John
• Tehrani Lida
• Nagy Mark A
• Raheja Raj Kumar
• Erdman Paul
• Narla Rama K
• Harris Roy L
• Tran Tam Minh
• Riggs Jennifer
• Ning Yuhong
• Xu Shuichan

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title