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

• US 9,795,607 B2
• Filed: 07/21/2016
• Issued: 10/24/2017
• Est. Priority Date: 01/16/2013
• Status: Active Grant

• Current Assignee: Signal Pharmaceuticals, LLC (Bristol-Myers Squibb Company)
• Original Assignee: Signal Pharmaceuticals, LLC (Bristol-Myers Squibb Company)
• 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
• Primary Examiner(s): Moore, Susanna
• Application Number:
  US15/215,728
• Publication Number:
  US 20160324861A1
• Time in Patent Office: 460 Days
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Provided herein are Pyrrolopyrimidine Compounds having the following structure:

• • wherein R¹, R², R³, 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.

Claims

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):

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

3. The method of claim 1, wherein R¹ is substituted or unsubstituted alkyl.

4. The method of claim 1, wherein R¹ 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 R¹ 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 —

NR₂, wherein each R is independently —

H or substituted or unsubstituted (C_1-4)alkyl.

7. The method of claim 1, wherein R¹ is substituted or unsubstituted C_3-8 cycloalkyl.

8. The method of claim 1, wherein R¹ 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 R¹ is substituted or unsubstituted non-aromatic heterocyclyl.

11. The method of claim 1, wherein R¹ is substituted or unsubstituted oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or piperidinyl.

12. The method of claim 1, wherein R¹ is substituted or unsubstituted C_1-8 alkyl,

13. The method of claim 1, wherein R² is substituted phenyl.

14. The method of claim 13, wherein R² is phenyl, substituted with one or more substituted or unsubstituted C_1-6 alkyl, halogen, —

CN, —

OR⁵, —

C(═

O)NR⁵₂, —

C(═

O)(substituted or unsubstituted heterocyclyl), —

C(═

O)(substituted or unsubstituted heterocyclylalkyl), —

NHC(═

O)R⁵, —

SO₂NR⁵₂, or substituted or unsubstituted heteroaryl, wherein each R⁵ 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 R² is phenyl, substituted with one or more —

(C_1-3 alkyl), —

(C_1-3 alkyl)NR₂, —

CF₃, —

Cl, —

F, —

CN, —

OCH₃, —

OCF₃, —

C(═

O)NR₂, —

C(═

O)NR(substituted or unsubstituted cycloalkyl), —

C(═

O)NR(CH₂)_0-2CR₂(CH₂)_0-2OR, —

C(═

O)NR(CH₂)_0-2CR₂(CH₂)_0-2NR₂, —

C(═

O)NR(CH₂)_0-2CR₂(CH₂)_0-2C(═

O)NR₂, —

C(═

O)N(substituted or unsubstituted cycloalkyl)(CH₂)_0-2OR, —

C(═

O)NR(CH₂)_0-3(substituted or unsubstituted heterocyclyl), —

C(═

O)(CH₂)_0-3(substituted or unsubstituted heterocyclyl), —

C(═

NR)NR₂, —

NRC(═

O)R, —

SO₂NR₂, —

SO₂R, 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 —

CH₃.

17. The method of claim 13, wherein R² is phenyl, substituted with one or more —

CH₃, —

CH₂CH₃, —

CH₂CH₂CH₃, —

CH(CH₃)₂, —

CH₂NH₂, —

CF₃, —

Cl, —

F, —

CN, —

OCH₃, —

OCF₃, —

C(═

O)NH₂, —

C(═

O)NHCH₃, —

C(═

O)N(CH₃)₂, —

C(═

O)NHC(CH₃)₃, —

C(═

O)NHCH₂CH₂F, —

C(═

O)NHCH₂CHF₂, —

C(═

O)NHCH₂CF₃, —

C(═

O)NHCH₂CF₂CH₃, —

C(═

O)NHCH₂CN, —

C(═

O)N(CH₃)CH₂CN, —

C(═

O)NHCH₂CH₂CN, —

C(═

O)N(CH₃)CH₂CH₂CN, —

C(═

O)NH-cyclobutyl, —

C(═

O)NH-(hydroxy-cyclobutyl), —

C(═

O)NH-cyclopentyl, —

C(═

O)NH-(hydroxy-cyclopentyl), —

C(═

O)NHCH₂CH₂OH, —

C(═

O)NHCH₂CH₂OCH₃, —

C(═

O)N(CH₃)CH₂CH₂OH, —

C(═

O)N(CH₃)CH₂CH₂OCH₃, —

C(═

O)NHCH₂CH₂CH₂OH, —

C(═

O)N(CH₃)CH₂CH₂CH₂OH, —

C(═

O)N(CH₃)CH₂CH₂CH₂OCH₃, —

C(═

O)NHCH₂CH(CH₃)OH, —

C(═

O)NHCH₂C(CH₃)₂OH, —

C(═

O)NHCH(CH₃)CH₂OH, —

C(═

O)NHC(CH₃)₂CH₂OH, —

C(═

O)NHCH₂CH₂NH₂, —

C(═

O)NHCH₂CH₂NH(CH₃), —

C(═

O)NHCH₂CH₂N(CH₃)₂, —

C(═

O)NHCH₂C(═

O)NH₂, —

C(═

O)N(CH₃)CH₂C(═

O)NH₂, —

C(═

O)NHCH₂CH₂C(═

O)NH₂, —

C(═

O)N(CH₃)CH₂CH₂C(═

O)NH₂, —

C(═

O)N(cyclopropyl)CH₂CH₂OH, —

C(═

O)NH-oxetanyl, —

C(═

O)N(CH₃)-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(CH₃)-tetrahydrofuranyl, —

C(═

O)NH-tetrahydropyranyl, —

C(═

O)N(CH₃)-tetrahydropyranyl, —

C(═

O)NHCH₂-oxetanyl, —

C(═

O)N(CH₃)CH₂-oxetanyl, —

C(═

O)NHCH₂-(methyl-oxetanyl), —

C(═

O)N(CH₃)CH₂-(methyl-oxetanyl), —

C(═

O)NHCH₂-tetrahydrofuranyl, —

C(═

O)NHCH₂-tetrahydropyranyl, —

C(═

O)NHCH₂-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)NH₂, —

NHC(═

O)CH₃, —

SO₂NHCH₃, —

SO₂CH₃, or substituted or unsubstituted pyrazolyl.

18. The method of claim 13, wherein R² is phenyl, substituted with one or more —

CH₃, —

CH₂CH₃, —

CH₂CH₂CH₃, —

CH(CH₃)₂, —

CH₂NH₂, —

CF₃, —

Cl, —

F, —

CN, —

OCH₃, —

OCF₃, —

C(═

O)NH₂, —

C(═

O)NHCH₃, —

C(═

O)N(CH₃)₂, —

C(═

O)NHC(CH₃)₃, —

C(═

O)NHCH₂CH₂F, —

C(═

O)NHCH₂CF₂CH₃, —

C(═

O)N(CH₃)CH₂CN, —

C(═

O)N(CH₃)CH₂CH₂CN, —

C(═

O)NH-(3-hydroxy-cyclobutyl), —

C(═

O)NH-cyclopentyl, —

C(═

O)NH-(2-hydroxycyclopentyl), —

C(═

O)NHCH₂CH₂OH, —

C(═

O)NHCH₂CH₂OCH₃, —

C(═

O)N(CH₃)CH₂CH₂OH, —

C(═

O)N(CH₃)CH₂CH₂OCH₃, —

C(═

O)NHCH₂CH₂CH₂OH, —

C(═

O)N(CH₃)CH₂CH₂CH₂OH, —

C(═

O)NHCH₂CH(CH₃)OH, —

C(═

O)NHCH₂C(CH₃)₂OH, —

C(═

O)NHCH(CH₃)CH₂OH, —

C(═

O)NHC(CH₃)₂CH₂OH, —

C(═

O)NHCH₂CH₂NH₂, —

C(═

O)NHCH₂CH₂NH(CH₃), —

C(═

O)NHCH₂CH₂N(CH₃)₂, —

C(═

O)N(CH₃)CH₂C(═

O)NH₂, —

C(═

O)N(CH₃)CH₂CH₂C(═

O)NH₂, —

C(═

O)N(cyclopropyl)CH₂CH₂OH, —

C(═

O)NH-oxetanyl, —

C(═

O)N(CH₃)-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(CH₃)-tetrahydropyranyl, —

C(═

O)NHCH₂-oxetanyl, —

C(═

O)N(CH₃)CH₂-(3-methyl-oxetanyl), —

C(═

O)NHCH₂-tetrahydrofuranyl, —

C(═

O)NHCH₂-tetrahydropyranyl, —

C(═

O)NHCH₂-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)NH₂, —

NHC(═

O)CH₃, —

SO₂NHCH₃, —

SO₂CH₃, or substituted or unsubstituted pyrazolyl.

19. The method of claim 1, wherein R² is substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted indazolyl or substituted or unsubstituted isoindolinone.

20. The method of claim 19, wherein R² is substituted with one or more halogen, substituted or unsubstituted (C_1-4)alkyl, —

OR, —

C(═

O)NR₂, or substituted or unsubstituted heterocyclyl, wherein each R is independently H or substituted or unsubstituted (C_1-4)alkyl.

21. The method of claim 1, wherein R³ is substituted or unsubstituted heterocyclyl.

22. The method of claim 21, wherein the heterocyclyl is substituted or unsubstituted pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, benztriazolyl, indazolyl, indolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzoxazolonyl, benzoxadiazolyl, benzimidazolyl, or quinolyl.

23. The method of claim 21, wherein the heterocyclyl is substituted with one or more substituents selected from substituted or unsubstituted (C_1-4)alkyl, halogen, —

OR, —

CN, —

NR₂, —

C(═

O)NR₂, —

NRC(═

O)R, or substituted or unsubstituted triazolyl, wherein each R is independently —

H or substituted or unsubstituted (C_1-4)alkyl.

24. The method of claim 21, wherein the heterocyclyl is substituted with one or more substituents selected from —

CH₃, —

CH(CH₃)₂, —

F, —

Cl, —

OH, —

OCH₃, —

OCH₂CH₃, —

CN, —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

C(═

O)NH(CH₃), —

NHC(═

O)CH₃, or substituted or unsubstituted triazolyl.

25. The method of claim 1, wherein R³ is substituted or unsubstituted aryl.

26. The method of claim 1, wherein R³ is substituted or unsubstituted phenyl.

27. The method of claim 26, wherein the phenyl is substituted with one or more substituents selected from substituted or unsubstituted C_1-4 alkyl, halogen, —

CN, —

OR, —

NR₂, —

NRSO₂R′

, —

NR(C═

O)NR₂, —

NR(C═

O)R′

, —

COOR, —

(C═

O)NR₂, —

C(═

N)NR₂, —

SO₂R′

, or substituted or unsubstituted heteroaryl, wherein each R is independently —

H or substituted or unsubstituted (C_1-4)alkyl, and R′

is C_1-3 alkyl.

28. The method of claim 26, wherein the phenyl is substituted with one or more substituents selected from —

CH₃, —

CH₂OH, —

CH(OH)CH₃, —

C(CH₃)₂OH, —

CN, —

F, —

Cl, —

OH, —

OCH₃, —

NH₂, —

N(CH₃)₂, —

NHSO₂CH₃, —

NH(C═

O)NH₂, —

NH(C═

O)CH₃, —

COOCH₃, —

(C═

O)NHCH₃, —

C(═

NH)NH₂, —

SO₂CH₃, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazolyl, or substituted or unsubstituted imidazolyl.

29. The method of claim 1, wherein the compound is

30. The method of claim 1, wherein the compound at a concentration of 10 μ

M inhibits triple negative breast cancer cell proliferation by at least about 50%.

31. The method of claim 29, wherein the compound at a concentration of 10 μ

M inhibits triple negative breast cancer cell proliferation by at least about 50%.

32. The method of claim 1, wherein the breast cancer is triple negative breast cancer.

33. The method of claim 29, wherein the breast cancer is triple negative breast cancer.