6-phenyl-7H-pyrrolo[2,3-d]pyrimidine compounds that induce neuronal differentiation in embryonic stem cells
View Patent ↗The invention provides a novel class of compounds and compositions of Formula I: in which R 1 , R 2 and R 3 are defined herein, that are useful in the treatment or prevention of diseases or disorders associated with kinases, particularly GSK-3β, c-Abl, HER-1, HER-2, KDR, Flt-3, c-Raf-1, PDGFR-β, c-Kit, Flt-4, Flt-1, Tek, c-src, CDK1, PDK1, FGFR-1, FGFR-2, Fer, MAP3K13, EPHA7 and c-Met kinases. The invention further relates to the use of the compounds of the invention as potent inducers of neurogenesis in embryonic stem cells.
1. A compound of Formula I:
in which:
R 1 is chosen from —OR 4 , —R 5 and —NHR 6 ; wherein R 4 is chosen from C 6-10 aryl and C 5-10 heteroaryl; wherein the aryl or heteroaryl of R 4 is optionally substituted by 1 to 3 radicals selected from hydroxy, amino, C 1-6 alkyl and C 1-6 alkoxy; R 5 is chosen from C 4-8 heterocycloalkyl optionally substituted by 1 to 3 radicals independently chosen from hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy and —C(O)NR 7 R 8 ; wherein R 7 and R 8 are independently selected from hydrogen and C 1-6 alkyl; R 6 is chosen from and C 6-10 aryl
R 2 is selected from the group consisting of hydrogen and C 1-6 alkyl; and
R 3 is selected from the group consisting of hydroxy, amino and nitro; and the pharmaceutically acceptable salts thereof.
2. The compound of claim 1 in which:
R 1 is chosen from —OR 4 , —R 5 and —NHR 6 ; wherein R 4 is C 6-10 aryl optionally substituted by 1 to 3 radicals selected from hydroxy, amino, C 1-6 alkyl and C 1-6 alkoxy R 5 is chosen from C 4-8 heterocycloalkyl optionally substituted by 1 to 3 radicals independently chosen from hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy and —C(O)NH 2 ; R 6 is chosen from and C 6-10 aryl;
R 2 is selected from the group consisting of hydrogen and C 1-6 alkyl; and
R 3 is amino.
3. The compound of claim 2 in which R 1 is chosen from phenoxy optionally substituted with 1 to 3 hydroxy radicals, morpholino, piperidinyl optionally substituted with 1 to 3 radicals chosen from hydroxy and —C(O)NH 2 , phenyl-amino pyridinyl-amino and 1H-indazol-5-yl.
4. The compound of claim 1 selected from the group consisting of 3-[6-(3-amino-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-phenol, 3-(4-morpholin-4-yl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenylamine, 1-[6-(3-amino-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carboxylic acid amide, [6-(3-amino-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyridin-3-yl-amine, [6-(3-amino-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(1H-indazol-6-yl)-amine and 1-[6-(3-amino-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-ol.
5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable excipient.
6. A method for inducing neurogenesis in P19 stem cells, the method comprising contacting said cells with a compound of claim 1 effective to produce a differentiated neural cell.