Substituted pyrrolopyrimidine compounds, compositions thereof, and methods of treatment therewith
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.
1. 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 compound of claim 1 , wherein L is O.
3. The compound of claim 1 , wherein R 1 is substituted or unsubstituted alkyl.
4. The compound 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 compound of claim 1 , wherein R 1 is substituted or unsubstituted methyl, ethyl, isopropyl, sec-butyl, t-butyl, or 2,2-dimethylpropyl.
6. The compound 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 compound of claim 1 , wherein R 1 is substituted or unsubstituted C 3-8 cycloalkyl.
8. The compound of claim 1 , wherein R 1 is substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
9. The compound 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 compound of claim 1 , wherein R 1 is substituted or unsubstituted non-aromatic heterocyclyl.
11. The compound of claim 1 , wherein R 1 is substituted or unsubstituted oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or piperidinyl.
12. The compound 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 compound of claim 1 , wherein R 2 is substituted phenyl.
14. The compound 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 compound 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 , —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 compound of claim 15 , wherein each R is independently —H or —CH 3 .
17. The compound 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 compound 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)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.
19. The compound of claim 1 , wherein R 2 is substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted indazolyl or substituted or unsubstituted isoindolinone.
20. The compound of claim 19 , wherein R 2 is substituted with one or more halogen, substituted or unsubstituted (C 1-4 )alkyl, —OR, —C(═O)NR 2 , or substituted or unsubstituted heterocyclyl, wherein each R is independently —H or substituted or unsubstituted (C 1-4 )alkyl.
21. The compound of claim 1 , wherein R 3 is substituted or unsubstituted heterocyclyl.
22. The compound 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 compound 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, —NR 2 , —C(═O)NR 2 , —NRC(═O)R, or substituted or unsubstituted triazolyl, wherein each R is independently —H or substituted or unsubstituted (C 1-4 )alkyl.
24. The compound of claim 21 , wherein the heterocyclyl is substituted with one or more substituents selected from —CH 3 , —CH(CH 3 ) 2 , —F, —Cl, —OH, —OCH 3 , —OCH 2 CH 3 , —CN, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)NH(CH 3 ), —NHC(═O)CH 3 , or substituted or unsubstituted triazolyl.
25. The compound of claim 1 , wherein R 3 is substituted or unsubstituted aryl.
26. The compound of claim 1 , wherein R 3 is substituted or unsubstituted phenyl.
27. The compound 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, —NR 2 , —NRSO 2 R′, —NR(C═O)NR 2 , —NR(C═O)R′, —COOR, —(C═O)NR 2 , —C(═N)NR 2 , —SO 2 R′, 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 compound of claim 26 , wherein the phenyl is substituted with one or more substituents selected from —CH 3 , —CH 2 OH, —CH(OH)CH 3 , —C(CH 3 ) 2 OH, —CN, —F, —Cl, —OH, —OCH 3 , —NH 2 , —N(CH 3 ) 2 , —NHSO 2 CH 3 , —NH(C═O)NH 2 , —NH(C═O)CH 3 , —COOCH 3 , —(C═O)NHCH 3 , —C(═NH)NH 2 , —SO 2 CH 3 , substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazolyl, or substituted or unsubstituted imidazolyl.
29. A compound, wherein the compound is
or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or isotopologue thereof.
30. The compound of claim 1 or claim 29 , wherein the compound at a concentration of 10 μM inhibits triple negative breast cancer cell proliferation by at least about 50%.
31. A pharmaceutical composition comprising an effective amount of a compound of claim 1 or claim 29 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or isotopologue thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.
32. A method for the treatment of breast cancer, the methods comprising administering to a subject in need thereof an effective amount of a compound of claim 1 or claim 29 .