PYRROLO 2,3-d]PYRIMIDINE COMPOUNDS
Abstract
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Projected expiry passed 14 June 2019, 7.3 years ago.
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11 claims: 11 independent, 0 dependent
- 1Compound of formula or the pharmaceutically acceptable Salt thereof, wherein R1 a group of formula , wherein the dashed illustrating line optional double bonds; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; X, B and D are each independently Is oxygen, S (O)dWherein d is 0,1 or 2, NO6 or CR7R8th are; A and E are each CR7R8th are; and R6 selected from the group consisting of hydrogen, (C1-C6) Alkyl, trifluoromethyl, trifluoromethyl (C1-C6) Alkyl, (C1-C6) Alkyl (difluoromethylene), (C1-C3) Alkyl (difluoromethylene) (C1-C3) Alkyl, (C1-C6) Alkoxy (C1-C6) Acyl, (C1-C6) Alkylamino (C1-C6) Acyl, ((C1-C6) Alkyl)2amino (C1-C6) Acyl), (C6-C10) Aryl, (C5-C9) Heteroaryl, (C6-C10) Aryl (C1-C6) Alkyl, (C5-C9) Heteroaryl (C1-C6) Alkyl, (C6-C10) Aryl (C6-C10) Aryl, (C6-C10) Aryl (C6-C10) Aryl (C1-C6) Alkyl, (C3-C6) Cycloalkyl, (C3-C6) Cycloalkyl (C1-C6) Alkyl, hydroxy (C2-C6) Alkyl, (C1-C6) Acyloxy (C2-C6) Alkyl, (C1-C6) Alkoxy (C2-C6) Alkyl, piperazinyl (C1-C6) Alkyl, (C1-C6) Acylamino (C1-C6) Alkyl, (C6-C10) Aryl (C1-C6) Alkoxy (C1-C6) Alkyl, (C5-C9) Heteroaryl (C1-C6) Alkoxy (C1-C6) Alkyl, (C1-C6) Alkylthio (C1-C6) Alkyl, (C6-C10) Arylthio (C1-C6) Alkyl, (C1-C6) Alkylsulfinyl (C1-C6) Alkyl, (C6-C10) Arylsulfinyl (C1-C6) Alkyl, (C1-C6) Alkylsulfonyl (C1-C6) Alkyl, (C6-C10) Arylsulfonyl (C1-C6) Alkyl, amino (C1-C6) Alkyl, (C1-C6) Alkylamino (C1-C6) Alkyl, ((C1-C6) Alkyl)2amino (C1-C6) Alkyl, R13CO (C1-C6) Alkyl, wherein R13 For R20O or R20R21N wherein R20 and R21 are in each case independently selected from the group consisting from hydrogen, (C1-C6) Alkyl, (C6-C10) Aryl (C1-C6) Alkyl or (C5-C9) Heteroaryl (C1-C6) Alkyl; and R14(C2-C6) Alkyl, wherein R14 For (C1-C6) Acylpiperazino, (C6-C10) Arylpiperazino, (C5-C9) Heteroarylpiperazino, (C1-C6) Alkylipiperazino, (C6-C10) Aryl (C1-C6) Alkylpiperazino, (C5-C9) Heteroaryl (C1-C6) -alkylpiperazino, Morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C1-C5) Alkylpiperidyl, (C6-C10) -Arylpiperidyl, (C5-C9) Heteroarylpiperidyl, (C6-C10) Aryl (C1-C6) Alkylpiperidyl, (C5-C9) Heteroaryl (C1-C6) Alkylpiperidyl, (C1-C6) Alkoxyacyl, (C1-C5) Alkylaminoaryl, ((C1-C6) Alkyl)2aminoacyl or (C1-C6) Acylpiperidyl stands; R7 and R8th each independently selected are selected from the group consisting of hydrogen, deuterium, (C1-C6) Alkyl, amino, hydroxy, (C1-C6) Alkoxy, (C1-C6) Alkylamino, ((C1-C6) -alkyl) Amino, (C1-C6) Acylamino, (C1-C6) Acyl (C1-C6) Alkylamino, Carboxy, (C1-C6) Alkoxyacyl, (C1-C6) Alkylaminoacyl, ((C1-C6) Alkyl)2aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl (C1-C6) Alkyl, (C1-C6) Alkyl (difluoromethylene), (C1-C3) Alkyl (difluoromethylene) (C1-C3) Alkyl, (C6-C10) Aryl, (C5-C9) -heteroaryl, (C6-C10) Aryl (C1-C6) Alkyl, (C5-C9) Heteroaryl- (C1-C6) Alkyl, (C6-C10) Aryl (C6-C10) Aryl, (C6-C10) Aryl (C6-C10) Aryl (C1-C6) Alkyl, (C3-C6) Cycloalkyl, (C3- C6) Cycloalkyl (C1-C6) Alkyl, hydroxy (C1-C6) Alkyl, (C1-C6) Acyloxy (C1-C6) Alkyl, alkoxy (C1-C6) Alkyl, (C1-C6) Acylamino (C1-C6) Alkyl, piperidyl, (C1-C6) Alkylpiperidyl, (C6-C10) Aryl (C1-C6) Alkoxy (C1-C6) Alkyl, (C5-C9) heteroaryl (C1-C6) Alkoxy- (C1-C6) Alkyl, (C1-C6) Alkylthio (C1-C6) Alkyl, (C6-C10) Arylthio (C1-C6) Alkyl, (C1-C6) Alkylsulfinyl (C1-C6) Alkyl, (C6-C10) Aryl-sulfinyl (C1-C6) Alkyl, (C1-C6) Alkylsulfonyl (C1-C6) Alkyl, (C6-C10) Arylsulfonyl (C1-C6) Alkyl, amino (C1-C6) Alkyl, (C1-C6) Alkylamino (C1-C6) Alkyl, ((C1-C6) Alkyl)2amino (C1-C6) Alkyl, R13CO (C1-C6) Alkyl or R13CO (C3-C10) Cyloalkyl, where R13 for R20O or R20R21N, where R20 and R21 independently from the group consisting of hydrogen, (C1-C6) Alkyl, (C6-C10) Aryl (C1-C6) Alkyl or (C5-C9) Heteroaryl (C1-C6) Alkyl; R14, R14(C1-C6) Alkyl or R14(C3-C10) -cycloalkyl, where R14 (C1-C6) Acylpiperazino, (C6-C10) Aryl-piperazino, (C5-C9) Heteroarylpiperazino, (C1-C6) Alkylpiperazino, (C6-C10) Aryl (C1-C6) Alkylpi- perazino, (C5-C9) Heteroaryl (C1-C6) Alkylpiperazino, morpholino, thiomorpholino, Piperidino, pyrrolidino, piperidyl, (C1-C6) Alkylpiperidyl, (C6-C10) Arylpiperidyl, (C5-C9) Heteroarylpiperidyl, (C6-C10) Aryl (C1-C6) Alkylpiperidyl, (C5-C9) Heteroaryl (C1-C6) Alkyl-piperidyl or (C1-C6) Acylpiperidyl is; or a group of formulawherein p is 0, 1, 2 or 3; and Z is hydroxy, (C1-C6) alkoxy or NR1R2 is, where R1 and R2 each independently another selected are selected from the group consisting of hydrogen, (C1-C6) Alkyl, piperidyl, (C1-C6) Alkylpiperidyl, (C6-C10) Arylpiperidyl, (C5-C9) Straight-arylpiperidyl, (C6-C10) Aryl (C1-C6) Alkylpiperidyl, (C5-C9) Heteroaryl (C1-C6) Alkylpiperidyl, (C1-C6) Acylpiperidyl, (C6-C10) Aryl, (C5-C9) Heteroaryl, (C6-C10) Aryl (C1-C6) Alkyl, (C5-C9) Heteroaryl (C1-C6) Alkyl, (C6-C10) Aryl (C6-C10) Aryl, (C6-C10) Aryl (C6-C10) Aryl (C1-C6) Alkyl, (C3-C6) Cycloalkyl, (C3-C6) Cycloalkyl (C1-C5) Alkyl, R5(C1-C6) Alkyl, (C1-C6) Alkyl (CHR5) (C1-C6) Alkyl, where R5 Hydroxy, (C1-C6) Acyloxy, (C1-C6) Alkoxy, Piperazino, (C1-C6) Acylamino, (C1-C6) Alkylthio, (C6-C10) Arylthio, (C1-C6) Alkylsulphinyl, (C6-C10) Arylsulfinyl, (C1-C6) Alkylsulfoxyl, (C6-C10) Arylsulfoxyl, Amino, (C1-C6) Alkylamino, ((C1-C6) Alkyl)2amino, (C1-C6) Acylpiperazino, (C1-C6) Alkylpiperazino, (C6-C10) Aryl (C1-C6) Alkylpiperazino, (C5-C9) Heteroaryl (C1-C6) Alkylpiperazino, morpholino, thiomorpholino, Piperidino or pyrrolidino; R6(C1-Cs) Alkyl, (C1-C5) Alkyl (CHR6) (C1-C6) Alkyl, where R6 Piperidyl, (C1-C6) -Alkylpiperidyl, (C6-C10) Arylpiperidyl, (C6-C10) Aryl (C1-C6) -alkylpiperidyl, (C5-C9) Heteroarylpiperidyl or (C5-C9) Heteroaryl (C1-C6) -alkylpiperidyl is; or when n is at least 1, D and E, or D and X, respectively CR7R8th are the adjacent R7Groups together with the Carbon atoms to which they are bound, groups of the formulas form, wherein the dotted lines represent optional double bonds; a 0, 1 or 2; m, A, B and X are as defined above; and G, J, L and M are each independently are oxygen, S (O)dWherein d is 0, 1 or 2, NR6 or CR7R8thWherein R6, R7 and R8th as above are defined, are; or when n is 1, D and E are each CR7R8th and m is 1 , A and B are each CR7R8th are, the respective adjacent R7groups together with the carbon atoms to which they are attached, a group the following formula form:wherein the dashed bond represents optional double bonds;a, G, J, L and M are as are as defined above;r is 0 or 1;c is 0, 1 or 2;and R, W, Y and S are each independently oxygen, SO)dWherein d is 0, 1 or 2, NR6 or CR7R8thWherein R6, R7 or R8th as above are defined;are;R2 and R3 are each independently selected from from the group consisting of hydrogen, deuterium, amino, halo, Hydroxy, nitro, carboxy, (C2-C6) Alkenyl, (C2-C6) Alkynyl, Trifluoromethyl, trifluoromethoxy, (C1-C6) Alkyl, (C1-C6) Alkoxy, wherein the alkyl or alkoxy groups optionally substituted by one or three groups selected from Halogen, hydroxy, carboxy, amino (C1-C6) Alkylthio, (C1-C6) Alkylamino, ((C1-C6) Alkyl)2amino, (C5-C9) Heteroaryl, (C2-C9) Heterocycloalkyl, (C3-C9) cycloalkyl or (C6-C10) aryl are substituted;or R2 and R3 are each independently: (C3-C10) Cycloalkyl, (C3-C10) Cycloalkoxy, (C1-C6) Alkylamino, ((C1-C6) Alkyl)2amino, (C6-C10) Arylamino, (C1-C6) Alkylthio, (C6-C10) Arylthio, (C1-C6) Alkylsulfinyl, (C6-C10) Arylsulfinyl, (C1-C6) Alkylsulfonyl, (C6-C10) Arylsulfonyl, (C1-C6) Acyl, (C1-C6) Alkoxy-CO-NH-, (C1-C6) Alkylamino-CO-, (C5-C9) -heteroaryl, (C2-C9) Heterocycloalkyl or (C6-C10) Aryl wherein the heteroaryl, heterocycloalkyl and aryl groups are optionally substituted by one to three Halogens, (C1-C6) Alkyl, (C1-C6) Alkyl-CO-NH-, (C1-C6) Alkoxy-CO-NH-, (C1-C6) Alkyl-CO-NH- (C1-C6) Alkyl, (C1-C6) Alkoxy-CO-NH- (C1-C6) Alkyl, (C1-C6) Alkoxy-CO-NH- (C1-C6) Alkoxy, carboxy, Carboxy (C1-C6) Alkyl, carboxy (C1-C6) Alkoxy, benzyloxycarbonyl (C1-C6) Alkoxy, (C1-C6) Alkoxycarbonyl (C1-C6) Alkoxy, (C6-C10) -Rryl, Amino, amino (C1-C6) Alkyl, (C1-C6) Alkoxycarbonylamino, (C6-C10) Aryl (C1-C6) Alkoxycarbonylamino, (C1-C6) Alkylamino, ((C1-C6) Alkyl)2amino, (C1-C6) Alkylamino (C1-C6) Alkyl, ((C1-C6) Alkyl)2amino (C1-C6) Alkyl, hydroxy, (C1-C6) Alkoxy, carboxy, carboxy (C1-C6) Alkyl, (C1-C6) Alkoxycarbonyl, (C1-C6) Alkoxy-carbonyl (C1-C6) Alkyl, (C1-C6) Alkoxy-CO-NH-, (C1-C6) Alkyl-CO-NH-, cyano, (C5-C9) Heterocycloalkyl, amino-CO-NH-, (C1-C6) Alkylamino-CO-NH-, ((C1-C6) Alkyl)2amino-CO-NH-, (C6-C10) Aryl-amino-CO-NH-, (C5-C9) Heteroarylamino-CO-NH-, (C1-C6) Alkyl-amino-CO-NH- (C1-C6) Alkyl, (C1-C6) Alkyl)2amino-CO-NH- (C1-C6) Alkyl, (C6-C10) Arylamino-CO-NH- (C1-C6) Alkyl, (C5-C9) Hetero arylamino-CO-NH- (C1-C6) Alkyl, (C1-C6) Alkylsulfonyl, (C1-C6) -Sulfonylamino, (C1-C6) Alkylsulfonylamino (C1-C6) Alkyl, (C6-C10) Arylsulfonyl, (C6-C10) Arylsulfonylamino, (C6-C10) Aryl-sulfonylamino (C1-C6) Alkyl, (C1-C6) Alkylsulfonylamino, (C1-C6) Alkylsulfonylamino (C1-C6) Alkyl, (C5-C9) Heteroaryl or (C2-C9) Heterocycloalkyl;with the proviso that, when A, B or X, in the formula V or VI as NR6 or CR7R8th defined , R2 and or R3 halogen must be / have;With the proviso that when R2 and R3 j in each case independently from each other hydrogen or (C1-C6) Alkyl, R1 not may be unsubstituted piperidinyl;with the proviso that, when R2 and R3 each are hydrogen, R1 not unsubstituted Morpholinyl or pyrrolidinyl may be;with the proviso that, when R2 and R3 each are hydrogen, R1 not be piperazinyl can;and with the proviso that the groups of the formulas IV, V, VI or XIII do not two or more oxygen, sulfur or combinations thereof in adjacent Positions included. Verbindung der Formel oder das pharmazeutisch annehmbare Salz davon, wobei R1 eine Gruppe der Formel ist, worin die gestrichelte Linie fakultative Doppelbindungen darstellt;m 0, 1, 2 oder 3 ist;n 0, 1, 2 oder 3 ist;X, B und D jeweils unabhängig voneinander Sauerstoff, S(O)d, worin d 0,1 oder 2 ist, NR6 oder CR7R8 sind;A und E jeweils CR7R8 sind;und R6 ausgewählt ist aus der Gruppe, die besteht aus Wasserstoff, (C1-C6)Alkyl, Trifluormethyl, Trifluormethyl(C1-C6)alkyl, (C1-C6)Alkyl(difluormethylen), (C1-C3)Alkyl(difluormethylen)(C1-C3)alkyl, (C1-C6)Alkoxy(C1-C6)acyl, (C1-C6)Alkylamino(C1-C6)acyl, ((C1-C6)Alkyl)2amino(C1-C6) acyl), (C6-C10)Aryl, (C5-C9)Heteroaryl, (C6-C10)Aryl(C1-C6)alkyl, (C5-C9)Heteroaryl(C1-C6)alkyl, (C6-C10)Aryl(C6-C10)aryl, (C6-C10)Aryl(C6-C10)aryl(C1-C6)alkyl, (C3-C6)Cycloalkyl, (C3-C6)Cycloalkyl(C1-C6)alkyl, Hydroxy(C2-C6)alkyl, (C1-C6)-Acyloxy(C2-C6)alkyl, (C1-C6)Alkoxy(C2-C6)alkyl, Piperazinyl-(C1-C6)alkyl, (C1-C6)Acylamino(C1-C6)alkyl, (C6-C10)Aryl-(C1-C6)alkoxy(C1-C6)alkyl, (C5-C9)Heteroaryl(C1-C6)alkoxy(C1-C6)-alkyl, (C1-C6)Alkylthio(C1-C6)alkyl, (C6-C10)Arylthio(C1-C6)alkyl, (C1-C6)Alkylsulfinyl(C1-C6)alkyl, (C6-C10)Arylsulfinyl-(C1-C6)alkyl, (C1-C6)Alkylsulfonyl(C1-C6)alkyl, (C6-C10)Arylsulfonyl(C1-C6)alkyl, Amino(C1-C6)alkyl, (C1-C6)Alkylamino-(C1-C6)alkyl, ((C1-C6)Alkyl)2amino(C1-C6)alkyl, R13CO(C1-C6)-Alkyl, worin R13 für R20O oder R20R21N steht, worin R20 und R21 j eweils unabhängig ausgewählt sind aus der Gruppe bestehend aus Wasserstoff, (C1-C6)Alkyl, (C6-C10)Aryl(C1-C6)alkyl oder (C5-C9)Heteroaryl (C1-C6)alkyl;und R14(C2-C6)Alkyl, worin R14 für (C1-C6)Acylpiperazino, (C6-C10)Arylpiperazino, (C5-C9)Heteroarylpiperazino, (C1-C6)Alkylipiperazino, (C6-C10)Aryl(C1-C6)alkylpiperazino, (C5-C9)Heteroaryl(C1-C6)-alkylpiperazino, Morpholino, Thiomorpholino, Piperidino, Pyrrolidino, Piperidyl, (C1-C5)Alkylpiperidyl, (C6-C10)-Arylpiperidyl, (C5-C9)Heteroarylpiperidyl, (C6-C10)Aryl-(C1-C6)alkylpiperidyl, (C5-C9)Heteroaryl(C1-C6)alkylpiperidyl, (C1-C6)Alkoxyacyl, (C1-C5)Alkylaminoaryl, ((C1-C6)-Alkyl)2aminoacyl oder (C1-C6)Acylpiperidyl steht;R7 und R8 jeweils unabhängig ausgewählt sind aus der Gruppe, bestehend aus Wasserstoff, Deuterium, (C1-C6)Alkyl, Amino, Hydroxy, (C1-C6)Alkoxy, (C1-C6)Alkylamino, ((C1-C6)-Alkyl)amino, (C1-C6)Acylamino, (C1-C6)Acyl(C1-C6)alkylamino, Carboxy, (C1-C6)Alkoxyacyl, (C1-C6)Alkylaminoacyl, ((C1-C6)-Alkyl)2aminoacyl, Aminoacyl, Trifluormethyl, Trifluormethyl(C1-C6)alkyl, (C1-C6)Alkyl(difluormethylen), (C1-C3)-Alkyl(difluormethylen)(C1-C3)alkyl, (C6-C10)Aryl, (C5-C9)-Heteroaryl, (C6-C10)Aryl(C1-C6)alkyl, (C5-C9)Heteroaryl-(C1-C6)alkyl, (C6-C10)Aryl(C6-C10)aryl, (C6-C10)Aryl(C6-C10)-aryl(C1-C6)alkyl, (C3-C6)Cycloalkyl, (C3- C6)Cycloalkyl-(C1-C6)alkyl, Hydroxy(C1-C6)alkyl, (C1-C6)Acyloxy(C1-C6)alkyl, Alkoxy(C1-C6)alkyl, (C1-C6)Acylamino-(C1-C6)alkyl, Piperidyl, (C1-C6)Alkylpiperidyl, (C6-C10)Aryl-(C1-C6)alkoxy(C1-C6)alkyl, (C5-C9) Heteroaryl (C1-C6)alkoxy-(C1-C6)alkyl, (C1-C6)Alkylthio(C1-C6)alkyl, (C6-C10)Arylthio-(C1-C6)alkyl, (C1-C6)Alkylsulfinyl(C1-C6)alkyl, (C6-C10)Aryl-sulfinyl(C1-C6)alkyl, (C1-C6)Alkylsulfonyl(C1-C6)alkyl, (C6-C10)Arylsulfonyl(C1-C6)alkyl, Amino(C1-C6)alkyl, (C1-C6)-Alkylamino(C1-C6)alkyl, ((C1-C6)Alkyl)2amino(C1-C6)alkyl, R13CO(C1-C6)Alkyl oder R13CO(C3-C10)Cyloalkyl, worin R13 für R20O oder R20R21N steht, worin R20 und R21 unabhängig voneinander aus der Gruppe, bestehend aus Wasserstoff, (C1-C6)-Alkyl, (C6-C10)Aryl(C1-C6)alkyl oder (C5-C9)Heteroaryl(C1-C6)-alkyl ausgewählt sind;R14, R14(C1-C6)Alkyl oder R14(C3-C10)-Cycloalkyl, worin R14 (C1-C6)Acylpiperazino, (C6-C10)Aryl-piperazino, (C5-C9)Heteroarylpiperazino, (C1-C6)Alkylpiperazino, (C6-C10)Aryl(C1-C6)alkylpi- perazino, (C5-C9)Heteroaryl(C1-C6)alkylpiperazino, Morpholino, Thiomorpholino, Piperidino, Pyrrolidino, Piperidyl, (C1-C6)Alkylpiperidyl, (C6-C10)Arylpiperidyl, (C5-C9)Heteroarylpiperidyl, (C6-C10)-Aryl(C1-C6)alkylpiperidyl, (C5-C9)Heteroaryl(C1-C6)alkyl-piperidyl oder (C1-C6)Acylpiperidyl ist;oder einer Gruppe der Formel worin p 0, 1, 2 oder 3 ist;und Z Hydroxy, (C1-C6)Alkoxy oder NR1R2 ist, worin R1 und R2 jeweils unabhängig voneinander ausgewählt sind aus der Gruppe, bestehend aus Wasserstoff, (C1-C6)Alkyl, Piperidyl, (C1-C6)Alkylpiperidyl, (C6-C10)Arylpiperidyl, (C5-C9)Hetero-arylpiperidyl, (C6-C10)Aryl(C1-C6)alkylpiperidyl, (C5-C9)-Heteroaryl(C1-C6)alkylpiperidyl, (C1-C6)Acylpiperidyl, (C6-C10)Aryl, (C5-C9)Heteroaryl, (C6-C10)Aryl(C1-C6)alkyl, (C5-C9)Heteroaryl(C1-C6)alkyl, (C6-C10)Aryl(C6-C10)aryl, (C6-C10)Aryl(C6-C10)aryl(C1-C6)alkyl, (C3-C6)Cycloalkyl, (C3-C6)Cycloalkyl(C1-C5)alkyl, R5(C1-C6)Alkyl, (C1-C6)Alkyl(CHR5)(C1-C6)alkyl, worin R5 Hydroxy, (C1-C6)Acyloxy, (C1-C6)-Alkoxy, Piperazino, (C1-C6)Acylamino, (C1-C6)Alkylthio, (C6-C10)Arylthio, (C1-C6)Alkylsulfinyl, (C6-C10)Arylsulfinyl, (C1-C6)Alkylsulfoxyl, (C6-C10)Arylsulfoxyl, Amino, (C1-C6)-Alkylamino, ((C1-C6)Alkyl)2amino, (C1-C6)Acylpiperazino, (C1-C6)Alkylpiperazino, (C6-C10)Aryl(C1-C6)alkylpiperazino, (C5-C9)Heteroaryl(C1-C6)alkylpiperazino, Morpholino, Thiomorpholino, Piperidino oder Pyrrolidino ist;R6(C1-Cs)Alkyl, (C1-C5)Alkyl-(CHR6)(C1-C6)alkyl, worin R6 Piperidyl, (C1-C6)-Alkylpiperidyl, (C6-C10)Arylpiperidyl, (C6-C10)Aryl(C1-C6)-alkylpiperidyl, (C5-C9)Heteroarylpiperidyl oder (C5-C9)Heteroaryl(C1-C6)-alkylpiperidyl ist;oder wenn n mindestens 1 ist, D und E oder D und X jeweils CR7R8 sind, die benachbarten R7-Gruppen zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, Gruppen der Formeln bilden, wobei die gestrichelten Linien fakultative Doppelbindungen darstellen;a 0, 1 oder 2 ist;m, A, B und X wie oben definiert sind;und G, J, L und M jeweils unabhängig voneinander Sauerstoff, S(O)d, worin d 0, 1 oder 2 ist, NR6 oder CR7R8, worin R6, R7 und R8 wie oben definiert sind, sind;oder wenn n 1 ist, D und E jeweils CR7R8 sind und m 1 ist, A und B jeweils CR7R8 sind, die jeweiligen benachbarten R7-Gruppen zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, eine Gruppe der folgenden Formel bilden: worin die gestrichelte Bindung fakultative Doppelbindungen darstellt;a, G, J, L und M wie oben definiert sind;r 0 oder 1 ist;c 0, 1 oder 2 ist;und R, W, Y und S jeweils unabhängig voneinander Sauerstoff, S(O)d, worin d 0, 1 oder 2 ist, NR6 oder CR7R8, worin R6, R7 oder R8 wie oben definiert sind;sind;R2 und R3 jeweils unabhängig voneinander ausgewählt sind aus der Gruppe, bestehend aus Wasserstoff, Deuterium, Amino, Halogen, Hydroxy, Nitro, Carboxy, (C2-C6)Alkenyl, (C2-C6)Alkinyl, Trifluormethyl, Trifluormethoxy, (C1-C6)-Alkyl, (C1-C6)Alkoxy, worin die Alkyl- oder Alkoxygruppen gegebenenfalls durch eine oder drei Gruppen, ausgewählt aus Halogen, Hydroxy, Carboxy, Amino(C1-C6)alkylthio, (C1-C6)Alkylamino, ((C1-C6)Alkyl)2amino, (C5-C9)Heteroaryl, (C2-C9)Heterocycloalkyl, (C3-C9)Cycloalkyl oder (C6-C10)Aryl substituiert sind;oder R2 und R3 jeweils unabhängig voneinander sind: (C3-C10)Cycloalkyl, (C3-C10)Cycloalkoxy, (C1-C6)Alkylamino, ((C1-C6)Alkyl)2amino, (C6-C10)Arylamino, (C1-C6)Alkylthio, (C6-C10)Arylthio, (C1-C6)Alkylsulfinyl, (C6-C10)Arylsulfinyl, (C1-C6)Alkylsulfonyl, (C6-C10)Arylsulfonyl, (C1-C6)-Acyl, (C1-C6)Alkoxy-CO-NH-, (C1-C6)Alkylamino-CO-, (C5-C9)-Heteroaryl, (C2-C9)Heterocycloalkyl oder (C6-C10)Aryl, wobei die Heteroaryl-, Heterocycloalkyl- und Arylgruppen gegebenenfalls substituiert sind durch ein bis drei Halogene, (C1-C6)Alkyl, (C1-C6)Alkyl-CO-NH-, (C1-C6)Alkoxy-CO-NH-, (C1-C6)Alkyl-CO-NH-(C1-C6)alkyl, (C1-C6)Alkoxy-CO-NH-(C1-C6)-alkyl, (C1-C6)Alkoxy-CO-NH-(C1-C6)alkoxy, Carboxy, Carboxy(C1-C6)alkyl, Carboxy(C1-C6)alkoxy, Benzyloxycarbonyl-(C1-C6)Alkoxy, (C1-C6)Alkoxycarbonyl(C1-C6)alkoxy, (C6-C10)-Rryl, Amino, Amino(C1-C6)alkyl, (C1-C6)Alkoxycarbonylamino, (C6-C10)Aryl(C1-C6)alkoxycarbonylamino, (C1-C6)Alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)Alkylamino(C1-C6)alkyl, ((C1-C6)-Alkyl)2amino(C1-C6)alkyl, Hydroxy, (C1-C6)Alkoxy, Carboxy, Carboxy(C1-C6)alkyl, (C1-C6)Alkoxycarbonyl, (C1-C6)Alkoxy-carbonyl(C1-C6)alkyl, (C1-C6)Alkoxy-CO-NH-, (C1-C6)Alkyl-CO-NH-, Cyano, (C5-C9)Heterocycloalkyl, Amino-CO-NH-, (C1-C6)-Alkylamino-CO-NH-, ((C1-C6)Alkyl)2amino-CO-NH-, (C6-C10)Aryl-amino-CO-NH-, (C5-C9)Heteroarylamino-CO-NH-, (C1-C6)Alkyl-amino-CO-NH-(C1-C6)alkyl, (C1-C6)Alkyl)2amino-CO-NH-(C1-C6)-alkyl, (C6-C10)Arylamino-CO-NH-(C1-C6)alkyl, (C5-C9)Hetero-arylamino-CO-NH-(C1-C6)alkyl, (C1-C6)Alkylsulfonyl, (C1-C6)-Sulfonylamino, (C1-C6)Alkylsulfonylamino(C1-C6)alkyl, (C6-C10)Arylsulfonyl, (C6-C10)Arylsulfonylamino, (C6-C10)Aryl-sulfonylamino(C1-C6)alkyl, (C1-C6)Alkylsulfonylamino, (C1-C6)Alkylsulfonylamino(C1-C6)alkyl, (C5-C9) Heteroaryl oder (C2-C9)Heterocycloalkyl;mit der Maßgabe, dass, wenn A, B oder X in der Formel V oder VI als NR6 oder CR7R8 definiert ist, R2 und/oder R3 Halogen sein muss/müssen;mit der Maßgabe, dass, wenn R2 und R3 j eweils unabhängig voneinander Wasserstoff oder (C1-C6)Alkyl sind, R1 nicht unsubstituiertes Piperidinyl sein kann;mit der Maßgabe, dass, wenn R2 und R3 jeweils Wasserstoff sind, R1 nicht unsubstituiertes Morpholinyl oder Pyrrolidinyl sein kann;mit der Maßgabe, dass, wenn R2 und R3 jeweils Wasserstoff sind, R1 nicht Piperazinyl sein kann;und mit der Maßgabe, dass die Gruppen der Formeln IV, V, VI oder XIII nicht zwei oder mehr Sauerstoff, Schwefel oder Kombinationen davon in benachbarten Positionen enthalten.
- 2A compound according to claim 1, wherein R1 a Group of the formula , wherein the dashed illustrating line optional double bonds; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; X, B and D are each independently Is oxygen, S (O)dWherein d is 0, 1 or 2, NO6 or CR7R8th are; A and E are each independently CR7R8th or NR6 are; or when n is 1, D and E are each CR7R8th and m 1, A and B are each CR7R8th are, the respective adjacent R7groups together with the carbon atoms to which they are attached, a group the following formula can make:wherein the dashed bond represents optional double bonds;a, G, J, L and M are as are as defined above;r is 0 or 1;c is 0, 1 or 2;and R, W, Y and S are each independently oxygen, S (O)dWherein d is 0, 1 or 2, NR6 or CR7R8thWherein R6, R7 and R8th are as defined above, is. Verbindung nach Anspruch 1, wobei R1 eine Gruppe der Formel ist, worin die gestrichelte Linie fakultative Doppelbindungen darstellt;m 0, 1, 2 oder 3 ist;n 0, 1, 2 oder 3 ist;X, B und D jeweils unabhängig voneinander Sauerstoff, S(O)d, worin d 0, 1 oder 2 ist, NR6 oder CR7R8 sind;A und E jeweils unabhängig voneinander CR7R8 oder NR6 sind;oder wenn n 1 ist, D und E jeweils CR7R8 sind und m 1 ist, A und B jeweils CR7R8 sind, die jeweiligen benachbarten R7-Gruppen zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, eine Gruppe der folgenden Formel bilden können: worin die gestrichelte Bindung fakultative Doppelbindungen darstellt;a, G, J, L und M wie oben definiert sind;r 0 oder 1 ist;c 0, 1 oder 2 ist;und R, W, Y und S jeweils unabhängig Sauerstoff, S(O)d, worin d 0, 1 oder 2 ist, NR6 oder CR7R8, worin R6, R7 und R8 wie oben definiert sind, sind.
- 3A compound according to claim 1 or claim 2, wherein R2 and R3 each independently from the group consisting of hydrogen, (C1-C6) Alkyl, (C1-C6) Alkoxy, (C3-C10) Cycloalkyl, (C3-C10) Cycloalkoxy, (C2-C9) Heterocycloalkyl, (C5-C9) heteroaryl or (C6-C10) aryl selected are. Verbindung nach Anspruch 1 oder Anspruch 2, wobei R2 und R3 jeweils unabhängig voneinander aus der Gruppe, bestehend aus Wasserstoff, (C1-C6)Alkyl, (C1-C6)Alkoxy, (C3-C10)Cycloalkyl, (C3-C10)Cycloalkoxy, (C2-C9)Heterocycloalkyl, (C5-C9)Heteroaryl oder (C6-C10)Aryl ausgewählt sind.
- 4A compound according to any one of claims 1 to 3, wherein the compound is from the group consisting of:5-fluoro-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine;4-piperidin-1-yl-5-trifluoromethyl-7H-pyrrolo [2,3-d] pyrimidine;N, N-dimethyl-N '- [3- (4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -benzyl] -ethane-1,2-diamine;2- [1- (5-m-tolyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-yl] ethanol;5- (3-isopropylphenyl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine;5- (3-methyl-3H-imidazol-4-yl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine;5- (1-methyl-1H-imidazol-4-yl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine;5- (2-methylpyridin-4-yl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine;5-chloro-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine;5-Ethynyl-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine;4-piperidin-1-yl-5-m-tolyl-7H-pyrrolo [2,3-d] pyrimidine;and 4- (3,3-dimethyl-piperidin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine is selected. Verbindung nach einem der Ansprüche 1 bis 3, wobei die Verbindung aus der Gruppe, bestehend aus: 5-Fluor-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidin;4-Piperidin-1-yl-5-trifluormethyl-7H-pyrrolo[2,3-d]pyrimidin;N,N-Dimethyl-N'-[3-(4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzyl]ethan-1,2-diamin;2-[1-(5-m-Tolyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]ethanol;5-(3-Isopropylphenyl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidin;5-(3-Methyl-3H-imidazol-4-yl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidin;5-(1-Methyl-1H-imidazol-4-yl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidin;5-(2-Methylpyridin-4-yl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidin;5-Chlor-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidin;5-Ethinyl-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidin;4-Piperidin-1-yl-5-m-tolyl-7H-pyrrolo[2,3-d]pyrimidin;und 4-(3,3-Dimethylpiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin ausgewählt ist.
- 6A pharmaceutical composition for (a) treating or prevention a fault or a condition selected, from Organtransplantatabstossung, lupus, multiple sclerosis, rheumatoid Arthritis, psoriasis, Type I diabetes and complications resulting from diabetes, cancer, asthma, atopic dermatitis, autoimmune Shield gland disorders, Ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) the inhibition of protein tyrosine or Janus kinase 3 (JAK3) in a mammal, including a People to an amount of a compound according to any one of claims 1 4 or a pharmaceutically acceptable salt thereof, that in such disturbances or states is effective, and a pharmaceutically acceptable carrier. Pharmazeutische Zusammensetzung zur (a) Behandlung oder Prävention einer Störung oder eines Zustandes, ausgewählt aus Organtransplantatabstossung, Lupus, multipler Sklerose, rheumatoider Arthritis, Psoriasis, Typ I-Diabetes und Komplikationen, die aus Diabetes resultieren, Krebs, Asthma, atopischer Dermatitis, Autoimmun-Schild-drüsen-Störungen, Colitis ulcerosa, Crohn-Krankheit, Alzheimer-Krankheit, Leukämie und anderen Autoimmunkrankheiten, oder (b) Inhibierung von Proteintyrosinkinasen oder Janus-Kinase 3 (JAK3) in einem Säuger, einschließlich eines Menschen, die eine Menge einer Verbindung nach einem der Ansprüche 1 bis 4 oder eines pharmazeutisch annehmbaren Salzes davon, die bei solchen Störungen oder Zuständen wirksam ist, und einen pharmazeutisch annehmbaren Träger umfasst.
- 7A pharmaceutical composition for (a) treating or prevention a fault or a condition selected, from Organtransplantatabstossung, lupus, multiple sclerosis, rheumatoid Arthritis, psoriasis, Type I diabetes and complications resulting from diabetes, cancer, asthma, atopic dermatitis, autoimmune Shield gland disorders, Ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) the inhibition of protein tyrosine or Janus kinase 3 (JAK3) in a mammal, including a People to an amount of a compound according to any one of claims 1 4 or a pharmaceutically acceptable salt alone or in combination with one or more additional Agents, the mammalian immune system a modulate, or with means to relieve the inflammation, which in such disorders or states is efficacious, and a pharmaceutically acceptable carrier. Pharmazeutische Zusammensetzung zur (a) Behandlung oder Prävention einer Störung oder eines Zustandes, ausgewählt aus Organtransplantatabstossung, Lupus, multipler Sklerose, rheumatoider Arthritis, Psoriasis, Typ I-Diabetes und Komplikationen, die aus Diabetes resultieren, Krebs, Asthma, atopischer Dermatitis, Autoimmun-Schild-drüsen-Störungen, Colitis ulcerosa, Crohn-Krankheit, Alzheimer-Krankheit, Leukämie und anderen Autoimmunkrankheiten, oder (b) Inhibierung von Proteintyrosinkinasen oder Janus-Kinase 3 (JAK3) in einem Säuger, einschließlich eines Menschen, die eine Menge einer Verbindung nach einem der Ansprüche 1 bis 4 oder eines pharmazeutisch annehmbaren Salzes allein oder in Kombination mit einem oder mehreren zusätzlichen Agentien, die ein Säugerimmunsystem modulieren, oder mit Mitteln gegen Entzündungen, die bei solchen Störungen oder Zuständen wirk sam ist, und einen pharmazeutisch annehmbaren Träger umfasst.
- 8Use of an effective amount of a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable salt thereof for the manufacture a medicament for the inhibition of protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including of a human. Verwendung einer wirksamen Menge einer Verbindung nach einem der Ansprüche 1 bis 4 und eines pharmazeutisch annehmbaren Salzes davon zur Herstellung eines Medikaments für die Inhibierung von Proteintyrosinkinasen oder Janus-Kinase 3 (JAK3) in einem Säuger, einschließlich eines Menschen.
- 9Use of an effective amount of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof for the manufacture a medicament for the treatment or prevention a fault or a condition selected, from Organtransplantatabstossung, lupus, multiple sclerosis, rheumatoid Arthritis, psoriasis, Type I diabetes and complications from resulting diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, Ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in a mammal, including a human. Verwendung einer wirksamen Menge einer Verbindung nach einem der Ansprüche 1 bis 4 oder eines pharmazeutisch annehmbaren Salzes davon zur Herstellung eines Medikaments für die Behandlung oder Prävention einer Störung oder eines Zustandes, ausgewählt aus Organtransplantatabstossung, Lupus, multipler Sklerose, rheumatoider Arthritis, Psoriasis, Typ I-Diabetes und Komplikationen, die aus Diabetes resultieren, Krebs, Asthma, atopischer Dermatitis, Autoimmun-Schilddrüsen-Störungen, Colitis ulcerosa, Crohn-Krankheit, Alzheimer-Krankheit, Leukämie und anderen Autoimmunkrankheiten, in einem Säuger, einschließlich eines Menschen.
- 10Use of an effective amount of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional agents which an mammalian immune system modulate, or with means to relieve the inflammation, for producing a Protein tyrosine kinases medicament for inhibiting or Janus kinase 3 (JAK3) in a mammal, including of a human. Verwendung einer wirksamen Menge einer Verbindung nach einem der Ansprüche 1 bis 4 oder eines pharmazeutisch annehmbaren Salzes davon, allein oder in Kombination mit einem oder mehreren zusätzlichen Agentien, die ein Säugerimmunsystem modulieren, oder mit Mitteln gegen Entzündungen, zur Herstellung eines Medikaments zur Inhibierung von Proteintyrosinkinasen oder Janus-Kinase 3 (JAK3) in einem Säuger, einschließlich eines Menschen.
- 11Use of an effective amount of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional agents which an mammalian immune system ignitions modulate, or with means for producing an opposite Ent medicament for the treatment or prevention a fault or a condition selected, from Organtransplantatabstossung, lupus, multiple sclerosis, rheumatoid Arthritis, psoriasis, Type I diabetes and complications from resulting diabetes, cancer, asthma, atopic dermatitis, autoimmune Shield gland disorders, Ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in a mammal, including a People. Verwendung einer wirksamen Menge einer Verbindung nach einem der Ansprüche 1 bis 4 oder eines pharmazeutisch annehmbaren Salzes davon, allein oder in Kombination mit einem oder mehreren zusätzlichen Agentien, die ein Säugerimmunsystem modulieren, oder mit Mitteln gegen Ent zündungen zur Herstellung eines Medikaments für die Behandlung oder Prävention einer Störung oder eines Zustandes, ausgewählt aus Organtransplantatabstossung, Lupus, multipler Sklerose, rheumatoider Arthritis, Psoriasis, Typ I-Diabetes und Komplikationen, die aus Diabetes resultieren, Krebs, Asthma, atopischer Dermatitis, Autoimmun-Schild-drüsen-Störungen, Colitis ulcerosa, Crohn-Krankheit, Alzheimer-Krankheit, Leukämie und anderen Autoimmunkrankheiten in einem Säuger, einschließlich eines Menschen.
Independent claims11
283 paragraphs in 98 sections, as filed
background the invention
The This invention relates to pyrrolo [2,3-d] pyrimidine compounds, which Inhibitors of protein tyrosine kinases such as the enzyme Janus Kinase 3, (hereinafter also referred to as JAK3) and as such the therapeutic usefulness or utility as immunosuppressive agents for organ transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, Autoimmune thyroid disorders, Ulcerative colitis, Crohn's Disease, Alzheimer's disease, leukemia and other indications are, where immunosuppression would be desirable.
These Invention also relates to the use of such compounds for Manufacture of a medicament for the treatment of the above indications in mammals, especially humans, and for useful pharmaceutical compositions.
JAK3 is a member of the Janus family of Proteinthyrosinkinasen. Although the other members of this family mainly through all Tissue are expressed, is the JAK3 expression on hematopoietic Cells restricted. This is in accordance with its essential function in the signal transmission through the receptors for IL-2, IL-4, IL-7, IL-9 and IL-15 by non-covalent connection of JAK3 with the gamma chain which is these multi-chain receptors in common. XSCID patient populations are greatly reduced JAK3 protein levels been identified or with genetic defects to the common Gamma chain, suggesting that immunosuppression by the Block the signal transmission through the JAK3 pathway originates. Animal studies suggest that JAK3 not only play a critical role in B and T lymphocyte maturation plays, but that is required in the form of constitutive JAK3, to the T-cells function to maintain. The modulation of the immune activity through this new mechanism in the treatment of proliferative T-cell disorders, as transplant rejection and autoimmune diseases, useful prove.
The WO-A-97/27199 describes Pyrrolopyrimidinverbindungen, the inhibitors are of protein kinases and have, for example, anti-tumor activity. WO-A-96/40142 and WO-A-98/23613 describe heterocyclic ring linked to pyrimidine derivatives, the useful in the treatment of hyperproliferative diseases, such as Cancer and acne in mammals are.
Summary the invention
The This invention relates to a compound of formula <img img-content="cf" img-format="tif" he="26" wi="39" file="00020001.tif" />or the pharmaceutically acceptable Salt thereof, wherein R<sup>1</sup> a group of formula <img img-content="cf" img-format="tif" he="36" wi="55" file="00020002.tif" /> , wherein the dashed illustrating line optional double bonds; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; <?page 3?>X, B and D are each independently Is oxygen, S (O)<sub>d</sub>Wherein d is 0, 1 or 2, NO<sup>6</sup> or CR<sup>7</sup>R<sup>8th</sup> are; A and E are each CR<sup>7</sup>R<sup>8th</sup> are; and R<sup>6</sup> selected from the group consisting of hydrogen, (C<sub>1</sub>-C<sub>6</sub>) Alkyl, trifluoromethyl, trifluoromethyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkyl (difluoromethylene), (C<sub>1</sub>-C<sub>3</sub>) Alkyl (difluoromethylene) (C<sub>1</sub>-C<sub>3</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkoxy (C<sub>1</sub>-C<sub>6</sub>) Acyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylamino (C<sub>1</sub>-C<sub>6</sub>) Acyl, ((C<sub>1</sub>-C<sub>6</sub>) Alkyl)<sub>2</sub>amino (C<sub>1</sub>-C<sub>6</sub>) Acyl, (C<sub>6</sub>-C<sub>10</sub>) Aryl, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>6</sub>-C<sub>10</sub>) Aryl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>3</sub>-C<sub>6</sub>) Cycloalkyl, (C<sub>3</sub>-C<sub>6</sub>) Cycloalkyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, Hydroxy (C<sub>2</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Acyloxy (C<sub>2</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkoxy (C<sub>2</sub>-C<sub>6</sub>) Alkyl, piperazinyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Acylamino (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkoxy (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl (C<sub>1</sub>-C<sub>6</sub>) Alkoxy (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylthio (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>6</sub>-C<sub>10</sub>) Arylthio (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylsulfinyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>6</sub>-C<sub>10</sub>) Arylsulfinyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylsulfonyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>6</sub>-C<sub>10</sub>) Arylsulfonyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, amino (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylamino (C<sub>1</sub>-C<sub>6</sub>) Alkyl, ((C<sub>1</sub>-C<sub>6</sub>) Alkyl)<sub>2</sub>amino (C<sub>1</sub>-C<sub>6</sub>) Alkyl, R<sup>13</sup>CO (C<sub>1</sub>-C<sub>6</sub>) Alkyl wherein R<sup>13</sup> for R<sup>20</sup>O or R<sup>20</sup>R<sup>21</sup>N wherein R<sup>20</sup> and R<sup>21</sup> are each independently selected from the group consisting from hydrogen, (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkyl or (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl (C<sub>1</sub>-C<sub>6</sub>) Alkyl; and R<sup>19</sup> (C<sub>2</sub>-C<sub>6</sub>) Alkyl, wherein R<sup>19</sup> For (C<sub>1</sub>-C<sub>6</sub>) Acylpiperazino, (C<sub>6</sub>-C<sub>10</sub>) -Arylpiperazino, (C<sub>5</sub>-C<sub>9</sub>) Heteroarylpiperazino, (C<sub>1</sub>-C<sub>6</sub>) Alkylipiperazino, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperazino, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperazino, Morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperidyl, (C<sub>6</sub>-C<sub>10</sub>) Arylpiperidyl, (C<sub>5</sub>-C<sub>9</sub>) Heteroarylpiperidyl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperidyl, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperidyl, (C<sub>1</sub>- C<sub>6</sub>) Alkoxyacyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylaminoaryl, ((C<sub>1</sub>-C<sub>6</sub>) Alkyl)<sub>2</sub>aminoacyl or (C<sub>1</sub>-C<sub>6</sub>) Acylpiperidyl stands; R<sup>7</sup> and R<sup>8th</sup> each independently selected are selected from the group consisting of hydrogen, deuterium, (C<sub>1</sub>-C<sub>6</sub>) Alkyl, amino, Hydroxy, (C<sub>1</sub>-C<sub>6</sub>) Alkoxy, (C<sub>1</sub>-C<sub>6</sub>) Alkylamino, ((C<sub>1</sub>-C<sub>6</sub>) Alkyl) amino, (C<sub>1</sub>-C<sub>6</sub>) Acylamino, (C<sub>1</sub>-C<sub>6</sub>) Acyl (C<sub>1</sub>-C<sub>6</sub>) Alkylamino, Carboxy, (C<sub>1</sub>-C<sub>6</sub>) Alkoxyacyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylaminoacyl, ((C<sub>1</sub>-C<sub>6</sub>) Alkyl)<sub>2</sub>aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkyl (difluoromethylene), (C<sub>1</sub>-C<sub>3</sub>) Alkyl (difluoromethylene) (C<sub>1</sub>-C<sub>3</sub>) Alkyl, (C<sub>6</sub>-C<sub>10</sub>) Aryl, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>6</sub>-C<sub>10</sub>) Aryl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>3</sub>-C<sub>6</sub>) Cycloalkyl, (C<sub>3</sub>-C<sub>6</sub>) Cycloalkyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, hydroxy (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Acyloxy (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkoxy (C<sub>1</sub>-C<sub>6</sub>) Alkyl, piperazinyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Acylamino (C<sub>1</sub>-C<sub>6</sub>) Alkyl, piperidyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperidyl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkoxy (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl (C<sub>1</sub>-C<sub>6</sub>) Alkoxy (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylthio (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>6</sub>-C<sub>10</sub>) Arylthio (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylsulfinyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>6</sub>-C<sub>10</sub>) Arylsulfinyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylsulfonyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>6</sub>-C<sub>10</sub>) Arylsulfonyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, amino (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylamino (C<sub>1</sub>-C<sub>6</sub>) Alkyl, ((C<sub>1</sub>-C<sub>6</sub>) Alkyl)<sub>2</sub>amino (C<sub>1</sub>-C<sub>6</sub>) Alkyl, R<sup>13</sup>CO (C<sub>1</sub>-C<sub>6</sub>) Alkyl or R<sup>13</sup>CO (C<sub>3</sub>-C<sub>10</sub>) Cyloalkyl, where R<sup>13</sup> for R<sup>20</sup>O or R<sup>20</sup>R<sup>21</sup>N, where R<sup>20</sup> and R<sup>21</sup> each independently from the group consisting of hydrogen, (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkyl or (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, are selected; R<sup>14</sup>, R<sup>14</sup>(C<sub>1</sub>-C<sub>6</sub>) Alkyl or R<sup>14</sup>(C<sub>3</sub>-C<sub>10</sub>) Cycloalkyl, where R<sup>14</sup> (C<sub>1</sub>-C<sub>6</sub>) Acylpiperazino, (C<sub>6</sub>-C<sub>10</sub>) Arylpiperazino, (C<sub>5</sub>-C<sub>9</sub>) Heteroarylpiperazino, (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperazino, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperazino, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperazino, Morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperidyl, (C<sub>6</sub>-C<sub>10</sub>) Arylpiperidyl, (C<sub>5</sub>-C<sub>9</sub>) Heteroarylpiperidyl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperidyl, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl (C<sub>1</sub>-C<sub>6</sub>) alkylpiperidyl or (C<sub>1</sub>-C<sub>6</sub>) Acylpiperidyl is; or a group of formula <img img-content="cf" img-format="tif" he="14" wi="50" file="00050001.tif" />wherein p is 0, 1, 2 or 3; and Z is hydroxy, (C<sub>1</sub>-C<sub>6</sub>) alkoxy or NR<sup>1</sup>R<sup>2</sup> is, where R<sup>1</sup> and R<sup>2</sup> each independently another selected are selected from the group consisting of hydrogen, (C<sub>1</sub>-C<sub>6</sub>) Alkyl, piperidyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperidyl, (C<sub>6</sub>-C<sub>10</sub>) Arylpiperidyl, (C<sub>5</sub>-C<sub>9</sub>) Heteroarylpiperidyl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperidyl, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperidyl, (C<sub>1</sub>-C<sub>6</sub>) Acylpiperidyl, (C<sub>6</sub>-C<sub>10</sub>) Aryl, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>6</sub>-C<sub>10</sub>) Aryl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>3</sub>-C<sub>6</sub>) Cycloalkyl, (C<sub>3</sub>-C<sub>6</sub>) Cycloalkyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, R<sup>5</sup>(C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkyl (CHR<sup>5</sup>) (C<sub>1</sub>-C<sub>6</sub>) Alkyl, where R<sup>5</sup> Hydroxy, (C<sub>1</sub>-C<sub>6</sub>) Acyloxy, (C<sub>1</sub>-C<sub>6</sub>) Alkoxy, piperazino, (C<sub>1</sub>-C<sub>6</sub>) Acylamino, (C<sub>1</sub>-C<sub>6</sub>) Alkylthio, (C<sub>6</sub>-C<sub>10</sub>) Arylthio, (C<sub>1</sub>-C<sub>6</sub>) Alkylsulphinyl, (C<sub>6</sub>-C<sub>10</sub>) Arylsulfinyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylsulfoxyl, (C<sub>6</sub>-C<sub>10</sub>) Arylsulfoxyl, amino, (C<sub>1</sub>-C<sub>6</sub>) Alkylamino, ((C<sub>1</sub>-C<sub>6</sub>) Alkyl)<sub>2</sub>amino, (C<sub>1</sub>-C<sub>6</sub>) Acylpiperazino, (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperazino, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperazino, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperazino, morpholino, thiomorpholino, Piperidino or pyrrolidino; R<sup>6</sup> (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkyl (CHR<sup>6</sup>) (C<sub>1</sub>-C<sub>6</sub>) Alkyl, where R<sup>6</sup> Piperidyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperidyl, (C<sub>6</sub>-C<sub>10</sub>) Arylpiperidyl, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkylpiperidyl, (C<sub>5</sub>-C<sub>9</sub>) Heteroarylpiperidyl or (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl (C<sub>1</sub>-C<sub>6</sub>) Is alkylpiperidyl; or when n is at least Is 1, D and E, or D and X are each CR<sup>7</sup>R<sup>8th</sup> are, the adjacent R<sup>7</sup>-Groups together with the carbon atoms to which they are attached groups the formulas <?page 4?><img img-content="cf" img-format="tif" he="57" wi="142" file="00060001.tif" />form, wherein the dotted lines represent optional double bonds; a 0, 1 or 2; m, A, B and X are as defined above; and G, J, L and M are each independently are oxygen, S (O)<sub>d</sub>Wherein d is 0, 1 or 2, NR<sup>6</sup> or CR<sup>7</sup>R<sup>8th</sup>Wherein R<sup>6</sup>, R<sup>7</sup> and R<sup>8th</sup> as above are defined, are; or when n is 1, D and E are each CR<sup>7</sup>R<sup>8th</sup> and m is 1 , A and B are each CR<sup>7</sup>R<sup>8th</sup> are, the respective adjacent R<sup>7</sup>groups together with the carbon atoms to which they are attached, a group form the following formula <img img-content="cf" img-format="tif" he="32" wi="75" file="00060002.tif" />wherein the dashed bond represents optional double bonds; a, G, J, L and M are as are as defined above; r is 0 or 1; c is 0, 1 or 2; and R, W, Y and S are each independently oxygen, SO)<sub>d</sub>Wherein d is 0, 1 or 2, NR<sup>6</sup> or CR<sup>7</sup>R<sup>8th</sup>Wherein R<sup>6</sup>, R<sup>7</sup> or R<sup>8th</sup> as above are defined; are; R<sup>2</sup> and R<sup>3</sup> are each independently selected from from the group consisting of hydrogen, deuterium, amino, halo, Hydroxy, nitro, carboxy, (C<sub>2</sub>-C<sub>6</sub>) Alkenyl, (C<sub>2</sub>-C<sub>6</sub>) Alkynyl, trifluoromethyl, trifluoromethoxy, (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkoxy wherein the alkyl or alkoxy groups optionally substituted by one to three Groups selected from halogen, hydroxy, carboxy, amino (C<sub>1</sub>-C<sub>6</sub>) Alkylthio, (C<sub>1</sub>-C<sub>6</sub>) Alkylamino, ((C<sub>1</sub>-C<sub>6</sub>) Alkyl)<sub>2</sub>amino, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl, (C<sub>2</sub>-C<sub>9</sub>) Heterocycloalkyl, (C<sub>3</sub>-C<sub>9</sub>) cycloalkyl or (C<sub>6</sub>-C<sub>10</sub>) aryl are substituted; or R<sup>2</sup> and R<sup>3</sup> are each independently: (C<sub>3</sub>-C<sub>10</sub>) Cycloalkyl, (C<sub>3</sub>-C<sub>10</sub>) Cycloalkoxy, (C<sub>1</sub>-C<sub>6</sub>) Alkylamino, ((C<sub>1</sub>-C<sub>6</sub>) Alkyl)<sub>2</sub>amino, (C<sub>6</sub>-C<sub>10</sub>) Arylamino, (C<sub>1</sub>-C<sub>6</sub>) Alkylthio, (C<sub>6</sub>-C<sub>10</sub>) Arylthio, (C<sub>1</sub>-C<sub>6</sub>) Alkylsulfinyl, (C<sub>6</sub>-C<sub>10</sub>) Arylsulfinyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylsulfonyl, (C<sub>6</sub>-C<sub>10</sub>) Arylsulfonyl, (C<sub>1</sub>-C<sub>6</sub>) Acyl, (C<sub>1</sub>-C<sub>6</sub>) Alkoxy-CO-NH-, (C<sub>1</sub>-C<sub>6</sub>) Alkylamino-CO-, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl, (C<sub>2</sub>-C<sub>9</sub>) heterocycloalkyl or (C<sub>6</sub>-C<sub>10</sub>) Aryl, wherein the heteroaryl, heterocycloalkyl and aryl optionally are substituted by one to three halogens, (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkyl-CO-NH-, (C<sub>1</sub>-C<sub>6</sub>) Alkoxy-CO-NH-, (C<sub>1</sub>-C<sub>6</sub>) Alkyl-CO-NH- (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkoxy-CO-NH- (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkoxy-CO-NH- (C<sub>1</sub>-C<sub>6</sub>) Alkoxy, carboxy, carboxy (C<sub>1</sub>-C<sub>6</sub>) Alkyl, carboxy (C<sub>1</sub>-C<sub>6</sub>) Alkoxy, Benzyloxycarbonyl (C<sub>1</sub>-C<sub>6</sub>) Alkoxy, (C<sub>1</sub>-C<sub>6</sub>) Alkoxycarbonyl (C<sub>1</sub>-C<sub>6</sub>) Alkoxy, (C<sub>6</sub>-C<sub>10</sub>) Aryl, amino, Amino (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkoxycarbonylamino, (C<sub>6</sub>-C<sub>10</sub>) Aryl (C<sub>1</sub>-C<sub>6</sub>) Alkoxycarbonylamino, (C<sub>1</sub>-C<sub>6</sub>) Alkylamino, ((C<sub>1</sub>-C<sub>6</sub>) Alkyl)<sub>2</sub>amino, (C<sub>1</sub>-C<sub>6</sub>) Alkylamino (C<sub>1</sub>-C<sub>6</sub>) Alkyl, ((C<sub>1</sub>-C<sub>6</sub>) Alkyl)<sub>2</sub>amino (C<sub>1</sub>-C<sub>6</sub>) Alkyl, hydroxy, (C<sub>1</sub>-C<sub>6</sub>) Alkoxy, carboxy, carboxy (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkoxycarbonyl, (C<sub>1</sub>-C<sub>6</sub>) Alkoxycarbonyl (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkoxy-CO-NH-, (C<sub>1</sub>-C<sub>6</sub>) Alkyl-CO-NH-, cyano, (C<sub>5</sub>-C<sub>9</sub>) Heterocycloalkyl, amino-CO-NH-, (C<sub>1</sub>-C<sub>6</sub>) Alkylamino-CO-NH-, ((C<sub>1</sub>-C<sub>6</sub>) Alkyl)<sub>2</sub>amino-CO-NH-, (C<sub>6</sub>-C<sub>10</sub>) Arylamino-CO-NH-, (C<sub>5</sub>-C<sub>9</sub>) Heteroarylamino-CO-NH-, (C<sub>1</sub>-C<sub>6</sub>) Alkylamino-CO-NH- (C<sub>1</sub>-C<sub>6</sub>) Alkyl, ((C<sub>1</sub>-C<sub>6</sub>) Alkyl)<sub>2</sub>amino-CO-NH- (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>6</sub>-C<sub>10</sub>) Arylamino-CO-NH- (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>5</sub>-C<sub>9</sub>) Heteroarylamino-CO-NH- (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylsulfonyl, (C<sub>1</sub>-C<sub>6</sub>) Sulfonylamino, (C<sub>1</sub>-C<sub>6</sub>) Alkylsulfonylamino (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>6</sub>- C<sub>10</sub>) Arylsulfonyl, (C<sub>6</sub>-C<sub>10</sub>) Arylsulfonylamino, (C<sub>6</sub>-C<sub>10</sub>) Arylsulfonylamino (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkylsulfonylamino, (C<sub>1</sub>-C<sub>6</sub>) Alkylsulfonylamino (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>5</sub>-C<sub>9</sub>) Heteroaryl or (C<sub>2</sub>-C<sub>9</sub>) Heterocycloalkyl; with the proviso that, when A, B or X, in the formula V or VI as NR<sup>6</sup> or CR<sup>7</sup>R<sup>8th</sup> defined , R<sup>2</sup> and or <?page 5?>R<sup>3</sup> halogen must be / have; With the proviso that when R<sup>2</sup> and R<sup>3</sup> each independently from each other hydrogen or (C<sub>1</sub>-C<sub>6</sub>) Alkyl, R<sup>1</sup> not may be unsubstituted piperidinyl; with the proviso that, when R<sup>2</sup> and R<sup>3</sup> each are hydrogen, R<sup>1</sup> not unsubstituted Morpholinyl or pyrrolidinyl may be; with the proviso that, when R<sup>2</sup> and R<sup>3</sup> each are hydrogen, R<sup>1</sup> not be piperazinyl can; and with the proviso, that the groups of the formulas IV, V, VI or XIII do not two or more oxygen, sulfur or combinations thereof in adjacent Positions included.
The This invention also relates to pharmaceutically acceptable acid addition salts the compounds of the formula I. The acids which are used to the pharmaceutically acceptable acid addition salts of the mentioned inventive basic produce compounds are those which form non-toxic acid addition salts form, ie, salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, Phosphate, acid phosphate, Acetate, lactate, citrate, acid citrate, Tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, Benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ie, 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)] - salts.
The Invention also relates to base addition salts of formula I. The chemical bases that may be used as reagents to the pharmaceutically acceptable base salts of those compounds of prepare Formula I which by their nature are sour, are those form non-toxic base salts with such compounds. Such non-toxic base salts include those derived from such pharmacologically acceptable cations such as alkali metal cations (for Example potassium and sodium) and alkaline earth metal cations (for example, are calcium and magnesium) derived, ammonium or water-soluble amine addition salts, such as N-methylglucamine (meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines, but are not limited thereto.
Of the Term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent Hydrocarbon radicals having straight, branched or cyclic groups or combinations thereof.
Of the Term "alkoxy" includes as used herein, O-alkyl groups wherein "alkyl" is as defined above is.
Of the Term "halogen" includes, as used herein, unless otherwise stated, fluoro, Chlorine, bromine or iodine.
The compounds of the invention can Double bonds. If those double bonds are present, can Compounds of the invention exist in cis and trans configurations and as mixtures thereof.
So far otherwise indicated, mentioned here Alkyl and alkenyl and alkyl radicals of other groups referred to herein be linear or branched (eg, alkoxy), and they can also cyclic (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or Cyclohep tyl) or be linear or branched and cyclic Radicals contain. Unless otherwise indicated, halogen includes fluorine, Chlorine, bromine and iodine.
(C<sub>3</sub>-C<sub>10</sub>) cycloalkyl refers when it is used herein refers to cycloalkyl groups, the zero to two of unsaturation included, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, Cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, Bicyclo [3.2.1] octane, norbornanyl etc.
(C<sub>2</sub>-C<sub>9</sub>) heterocycloalkyl refers when it is used herein refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, Tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, Methylendioxyl, Chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, Isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, Thio morpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-1-yl, Tetrahydroazepinyl, piperazinyl, chromanyl, etc. The skilled artisan will know that the link said (C<sub>2</sub>-C<sub>9</sub>) Heterocycloalkyl rings over a Carbon atom or a sp<sup>3</sup>hybridised Nitrogen hetero atom.
(C<sub>2</sub>-C<sub>9</sub>) Heteroaryl refers when it is used herein refers to furyl, thienyl, thiazolyl, Pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, Tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-Oxadiazo<?page 6?>lyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, Pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo [3,4-b] pyridinyl, cinnolinyl, pteridinyl, Purinyl, 6,7-dihydro-5H- [1] pyridinyl, benzo [b] thiophenyl, 5,6,7,8-tetrahydroquinoline-3-yl, Benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, Benzimidazolyl, thianaphthenyl, Isothianaphthenyl, benzofuranyl, isobenzofuranyl, Isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, Phthalazinyl, quinoxalinyl, quinazolinyl, etc. It is understood benzoxazinyl for skilled in the art that the link the C<sub>2</sub>-C<sub>9</sub>) Heterocycloalkyl rings over a Carbon atom or a sp<sup>3</sup>hybridised Nitrogen hetero atom.
(C<sub>6</sub>-C<sub>10</sub>) Aryl refers when it is used herein refers to phenyl or naphthyl.
compounds of formula (I) can in pharmaceutically acceptable form either alone or in compound with one or more additional Means the mammalian immune system a administered modulate, or together with anti-inflammatory agents will. These agents include Cyclosporin A (eg Sandimmune<sup>®</sup> or Neoral<sup>®</sup>) Rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate (For example Cellcept<sup>®</sup>), Azathioprine (e.g. Imuran<sup>®</sup>) Daclizumab (Zenapax for example<sup>®</sup>), OKT3 (For example, Orthoclone<sup>®</sup>), AtGam, aspirin, acetaminophen, Ibuprofen, naproxen, piroxicam, and antiinflammatory steroids (E.g. prednisolone or dexamethasone) a. These agents have the Part of the same or separate dosage forms over the same or a different route of administration and with the same or a different frequency of administration according to conventional pharmaceutical practice can be administered.
The compounds of the invention conclude all Configurational isomers (e.g., cis and trans isomers) and all optical isomers of the compounds of formula I (for example enantiomers and diastereoisomers) as well as racemic, diastereomeric and other mixtures Such isomers. The invention also includes all rotamers of compounds the formula I and mixtures scelemische a.
Preferred Compounds of formula I include those wherein R<sup>1</sup> a group of formula <img img-content="cf" img-format="tif" he="37" wi="55" file="00120001.tif" />, wherein the dashed illustrating line optional double bonds; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; X, B and D are each independently Is oxygen, S (O)<sub>d</sub>Wherein d is 0, 1 or 2, NO<sup>6</sup> or CR<sup>7</sup>R<sup>8th</sup> are; A and E are each independently CR<sup>7</sup>R<sup>8th</sup> or NR<sup>6</sup> are; or when n is 1, D and E are each CR<sup>7</sup>R<sup>8th</sup> and m 1, A and B are each CR<sup>7</sup>R<sup>8th</sup> are, the respective adjacent R<sup>7</sup>groups together with the carbon atoms to which they are attached, a group the following formula can make: <img img-content="cf" img-format="tif" he="32" wi="76" file="00120002.tif" />wherein the dashed bond represents optional double bonds; a, G, J, L and M are as are as defined above; r is 0 or 1; c is 0, 1 or 2; and R, W, Y and S are each independently oxygen, S (O)<sub>d</sub>Wherein d is 0, 1 or 2, NR<sup>6</sup> or CR<sup>7</sup>R<sup>8th</sup>Wherein R<sup>6</sup>, R<sup>7</sup> and R<sup>8th</sup> are as defined above, is.
<?page 7?>
More preferred compounds of formula I include those wherein R<sup>2</sup> and R<sup>3</sup> each independently from the group consisting of hydrogen, (C<sub>1</sub>-C<sub>6</sub>) Alkyl, (C<sub>1</sub>-C<sub>6</sub>) Alkoxy, (C<sub>3</sub>-C<sub>10</sub>) Cycloalkyl, (C<sub>3</sub>-C<sub>10</sub>) Cycloalkoxy, (C<sub>2</sub>-C<sub>9</sub>) Heterocycloalkyl, (C<sub>5</sub>-C<sub>9</sub>) heteroaryl or (C<sub>6</sub>-C<sub>10</sub>) aryl selected are.
Specific preferred compounds of formula I include the following: 5-Fluoro-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 4-piperidin-1-yl-5-trifluoromethyl-7H-pyrrolo [2,3-d] pyrimidine; N, N-dimethyl-N '- [3- (4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -benzyl] -ethane-1,2-diamine; 2- [1- (5-m-tolyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-yl] ethanol; 5- (3-isopropylphenyl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 5- (3-methyl-3H-imidazol-4-yl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 5- (1-methyl-1H-imidazol-4-yl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 5- (2-methylpyridin-4-yl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 5-chloro-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 5-Ethynyl-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 4-piperidin-1-yl-5-m-tolyl-7H-pyrrolo [2,3-d] pyrimidine; and 4- (3,3-dimethyl-piperidin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine.
The The present invention relates to a pharmaceutical composition for (a) treating or preventing a fault or a condition selected, repulsion of organ transplant, Lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications resulting from diabetes, cancer, Asthma, atopic dermatitis, autoimmune thyroid disorders, Ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) the inhibition of protein tyrosine or Janus kinase 3 (JAK3) in a mammal, including a Human, comprising an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or such disorders states is effective, and a pharmaceutically acceptable carrier.
The The present invention relates to a pharmaceutical composition for (a) treating or preventing a fault or a condition selected, from organ transplant rejection, Lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications resulting from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) the inhibition of protein tyrosine or Janus kinase 3 (JAK3) in a mammal, including a Human, comprising an amount of a compound of formula I, or a pharmaceutically acceptable salt, alone or in combination with T cell immunosuppressive agents or agents with anti-inflammatory, the case of such disorders or states are effective, and a pharmaceutically acceptable carrier.
The This invention also relates to the use of an effective Amount of a compound of formula I or a pharmaceutically acceptable Salt thereof for the manufacture of a medicament for the inhibition of protein tyrosine or Janus kinase 3 (JAK3) in a mammal, including a People.
The This invention also relates to the use of an effective Amount of a compound of formula I or a pharmaceutically acceptable Salt thereof for the manufacture of a medicament for the treatment or prevention of a fault or a condition selected, from Organtransplantatabstossung, lupus, multiple sclerosis, rheumatoid Arthritis, psoriasis, Type I diabetes and complications from diabetes result, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, Ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases, one in a mammal, including People.
The This invention also relates to the use of an effective Amount of a compound of formula I or a pharmaceutically acceptable Salt thereof, alone or in combination with T-cell immunosuppressant Resources or funds to relieve the inflammation, for producing a Protein tyrosine kinases medicament for inhibiting or Janus kinase 3 (JAK3) in a mammal, including of a human.
The This invention also relates to the use of an effective Amount of a compound of formula I or a pharmaceutically acceptable Salt thereof, alone or in combination with T-cell immunosuppressant Resources or funds to relieve the inflammation of making a medicament for the treatment or prevention a fault or a condition selected, from Organtransplantatabstossung, <?page 8?>Lupus, multiple sclerosis, rheumatoid Arthritis, psoriasis, Type I diabetes and complications resulting from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, Ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in a mammal, including of a human.
Detailed Description of the Invention
The following reaction schemes illustrate the preparation of compounds of the invention. So far otherwise indicated, R<sup>1</sup>, R<sup>2</sup>, R<sup>3</sup> and R<sup>9</sup> in the following reaction schemes and in the following discussion as defined above.
SCHEMA 1 <img img-content="cf" img-format="tif" he="135" wi="41" file="00160001.tif" />
<?page 9?>
SCHEMA 2 <img img-content="cf" img-format="tif" he="176" wi="48" file="00170001.tif" />
<?page 10?>
SCHEMA 3 <img img-content="cf" img-format="tif" he="144" wi="55" file="00180001.tif" />
<?page 11?>
SCHEMA 4 <img img-content="cf" img-format="tif" he="175" wi="60" file="00190001.tif" />
In Reaction 1 of Scheme 1, the 4-Chlorpyrrolo [2,3-d] pyrimidine compound of formula XVII to the corresponding compound of formula XVI, wherein R Benzenesulfonyl or benzyl, by treating XVII with Benzenesulfonyl chloride, benzyl chloride or benzyl in the presence a base such as sodium hydride or potassium carbonate, and a polar aprotic solvent, such as dimethylformamide or tetrahydrofuran, converted. The reaction mixture at a temperature between about 0 ° C to about 70 ° C, preferably about 30 ° C, for a Time period between about one hour and about three hours, preferably about two hours, stirred.
In Reaction 2 of Scheme 1, the 4-Chlorpyrrolo [2,3-d] pyrimidine compound of the formula XVI to the corresponding 4-aminopyrrolo [2,3-d] pyrimidine compound of formula XV by coupling XVI with a compound of formula R<sup>1</sup>H converted. The reaction is conducted in a alcoholic solvent, such as tert-butanol, methanol or ethanol, or other high-boiling organic solvents, such as dimethylformamide, 1,4-dioxane or 1,2-dichloroethane, at a Temperature between about 60 ° C to about 120 ° C, preferably about 80 ° C performed. Typical reaction times are between about two hours to about 48 hours, preferably about 16 hours.
<?page 12?>
In Reaction 3 of Scheme 1, the protecting group of the compound of formula XV, wherein R is benzenesulfonyl , to afford the corresponding compound of formula I cleaved by XV with an alkali base such as sodium or potassium hydroxide, in an alcoholic solvent such as methanol or Ethanol, or mixed solvents, such as alcohol / tetrahydrofuran or alcohol / water is treated. The reaction is at room temperature over a period between about 15 minutes to about one hour, preferably 30 minutes. The Removal of the protecting group of the compound of formula XV, wherein R is benzyl, is by treating XV with sodium in ammonia at a temperature of about -78 ° C over a Period between about 15 minutes to about one hour.
In Reaction 1 of Scheme 2, the 4-Chlorpyrrolo [2,3-d] pyrimidine compound of formula XXI, wherein R is hydrogen or benzenesulfonate, is to of 4-chloro-5-halopyrrolo [2,3-d] pyrimidine compound of formula XX, wherein Y is Chlorine, bromine or iodine, by reacting XXI with N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide converted. The reaction mixture is in chloroform a time period between about one hour to about three hours, preferably heated for about one hour under reflux. Alternatively, In reaction 1 of Scheme 2, 4-Chlorpyrrolo [2,3-d] pyrimidine of formula XXI, wherein R hydrogen is, to the corresponding 4-chloro-5-Nitropyrrolo [2,3-d] pyrimidine of formula XX, wherein Y is nitro, by reacting XXI with nitric acid in sulfuric acid at a temperature between about -10 ° C to about 10 ° C, preferably about 0 ° C, over a Period between about five Minutes to about 15 minutes, preferably about 10 minutes, converted. The compound of formula XXI, wherein Y is nitro, is added to the corresponding 4-chloro-5-aminopyrrolo [2,3-d] pyrimidine of formula XX, wherein Y is amino is, by reacting XXI under a variety of conditions, which are known in the art such as palladium hydrogenolysis or tin (IV) chloride and hydrochloric acid, converted.
In Reaction 2 of Scheme 2, the 4-chloro-5-halopyrrolo [2,3-d] pyrimidine compound of formula XX, wherein R Is hydrogen to the corresponding compound of formula XIX, where R<sup>2</sup> (C<sub>1</sub>-C<sub>6</sub>) Alkyl or benzyl, by treating of XX with N-butyllithium, at a temperature of about -78 ° C and reacting the Dianionzwischenstufe which has been so prepared, with an alkyl halide or benzylhalide at a temperature between about -78 ° C to room temperature, preferably room temperature, converted. Alternatively, the so Dianion produced or formed with molecular oxygen Formation of the corresponding 4-chloro-5-hydroxypyrrolo [2,3-d] pyrimidine compound of formula XIX, wherein R<sup>2</sup> Is hydroxy, is reacted. The compound of formula XX, wherein Y is bromine or iodine and R Benzenesulfonate means is added to the compound of formula XIX, where R<sup>2</sup> (C<sub>6</sub>-C<sub>12</sub>) Aryl or vinyl, by treating of XX with N-butyllithium, at a temperature of about -78 ° C and subsequent addition of converted from zinc chloride at a temperature of about -78 ° C. The thus prepared corresponding Organozinkzwischenstufe is then reacted with Aryl iodide or vinyl iodide in the presence of a catalytic amount Palladium implemented. The reaction mixture is at a temperature between about 50 ° C to about 80 ° C, preferably about 70 ° C, for a Period between about one hour to about three hours, preferably about an hour, stirring.
In Reaction 3 of Scheme 2, the compound of formula XIX to the corresponding compound of formula XVI by treating XIX with N-butyllithium, lithium diisopropylamine or sodium hydride at a Temperature of about -78 ° C in the presence of a polar aprotic solvent, such as tetrahydrofuran, converted. The anionic thus prepared Intermediate is further reacted with (a) alkylhalide or benzylhalide a at a temperature between about -78 ° C to room temperature, preferably -78 ° C, when R<sup>3</sup> For Alkyl or benzyl, is reacted, (b) an aldehyde or ketone at a temperature between about -78 ° C to room temperature, preferably -78 ° C, when R<sup>3</sup> For Alkoxy and (c) zinc chloride at a temperature between about -78 ° C to room temperature, preferably -78 ° C, and the corresponding Organozinkzwischenstufe so formed is then reacted with Aryl iodide or vinyl iodide in the presence of a catalytic amount Palladium implemented. The resulting reaction mixture is stirred at a temperature between about 50 ° C to about 80 ° C, preferably about 70 ° C, for a Period between about one hour to about three hours, preferably about an hour, stirring. Alternatively, the anion so formed with molecular oxygen converted to the corresponding 4-chloro-6-hydroxypyrrolo [2,3-d] pyrimidine compound of formula XVI, wherein R<sup>3</sup> Is hydroxy to produce.
In Reaction 1 of Scheme 3, the 4-Chlorpyrrolo [2,3-d] pyrimidine compound of the formula XXI to the corresponding compound of formula XXII in accordance with the above converted in reaction 3 of Scheme 2 described method.
In Reaction 2 of Scheme 3, the compound of formula XXII to the corresponding compound of formula XVI according to the above in reactions 1 and 2 converted from Scheme 3 described method.
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In Reaction 1 of Scheme 4, the 4-Chlorpyrrolo [2,3-d] pyrimidine compound of the formula XX to the corresponding 4-aminopyrrolo [2,3-d] pyrimidine compound of formula XXIV, according to the above converted in reaction 2-described method.
In Reaction 2 of Scheme 4, the 4-amino-5-halopyrrolo [2,3-d] pyrimidine compound of the formula XXIV, wherein R is benzenesulfonate and Z is bromine or Iodine, through to the corresponding compound of formula XXIII Reacting XXIV with (a) arylboronic acid, when R<sup>2</sup> is aryl, in an aprotic solvent, such as tetrahydrofuran or dioxane, in the presence of a catalytic Amount of palladium (0) at a temperature between about 50 ° C to about 100 ° C, preferably about 70 ° C, for a Period between about two hours to about 48 hours, preferably about 12 hours, (b) alkynes, when R<sup>2</sup> alkynyl , in the presence of a catalytic amount of copper (I) iodide and palladium (0) and a polar solvent such as dimethylformamide at room temperature a period between about one hour to about five hours preferably about three hours, and (c) alkenes or styrenes, when R<sup>2</sup> For Vinyl or styryl, in the presence of a catalytic amount Palladium in dimethylformamide, dioxane or tetrahydrofuran at a Temperature between about 80 ° C to about 100 ° C, preferably about 100 ° C, for a Period between about two hours to about 48 hours, preferably about 48 hours, converted.
In Reaction 3 of Scheme 4, the compound of formula XXIII the corresponding compound of formula XV according to the above in reaction 3 of Scheme procedures described 2 converted.
The Compounds of the invention, which are by nature basic, can create a large variety of form salts with various inorganic and organic acids. Although such salts for administering to animals must be pharmaceutically acceptable is, often in practice expedient that compound of the invention from the reaction mixture as a pharmaceutically unacceptable isolate salt and the latter simply to the free base Reconvert treatment with an alkaline reagent and the latter free base to a pharmaceutically acceptable acid addition salt to convert. The acid addition salts the basic inventive Compounds are readily prepared by treating the basic Compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous dissolution medium or in a suitable organic solvent such as methanol or Ethanol. Upon careful evaporation of the solvent is the desired solid salt obtained easily. The desired acid salt can also consist of a solution of the free base in an organic solvent by adding a appropriate mineral or organic acid can be precipitated to the solution.
The Compounds of the invention, which by their nature are acidic, can with numerous pharmacologically acceptable cations form basic salts. Examples of such salts conclude the alkali metal or alkaline earth metal salts and particularly the Sodium and potassium salts. These salts are all by conventional methods produced. The chemical bases that uses as reagents are to the pharmaceutically acceptable basic inventive produce salts are those which form non-toxic base salts with the acid of the invention Compounds form. Such non-toxic base salts include those a, which, from such pharmacologically acceptable cations as sodium Potassium, calcium and magnesium, etc. are derived. These salts can in a simple way by treating the corresponding acidic compounds with an aqueous Solution, desired the containing pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure, made will. Alternatively, They also prepared by mixing lower alkanol solutions of the acidic compounds and the desired Alkali metal alkoxide and then evaporating the resulting solution be prepared to dryness in the same manner as before. In both make preferably stoichiometric Quantities of reagents used to control the completeness of reaction and maximum Yields of the desired ensure final product.
The compositions of the invention can conventional pharmaceutically acceptable manner using one or more carriers be formulated. Thus, the active compounds of the invention for the oral, bukka le, intranasal, parenteral (for example intravenous, intramuscular or subcutaneous) or rectal administration or for administration in a be formulated by inhalation or insufflation suitable shape. The active compounds of the invention can also for the delayed Release be formulated.
For oral administration may The pharmaceutical compositions take the form of, for example, take tablets or capsules by conventional means with pharmaceutically acceptable excipients such as binding agents (eg, pregelatinized Corn starch, Polyvinylpyrrolidone or hydroxy<?page 14?>propylmethylcellulose); fillers (For example, lactose, microcrystalline cellulose or calcium phosphate); lubricants (For example, magnesium stearate, talc or silica); explosives (For example potato starch or sodium starch); prepared or wetting agents (eg sodium lauryl sulfate) will. The tablets may be coated by methods well known in the prior art methods. Liquid preparations for oral administration, in the form of, for example, solutions, syrups or suspensions, or they can be used as a dry product for the Prepared with water or other suitable vehicle before the use may be presented. Such liquid preparations may be prepared by conventional Means with pharmaceutically acceptable additives such as suspending (For example, sorbitol syrup, methyl cellulose or hydrogenated edible fats); Emulsifiers (eg, lecithin or acacia oil); non-aqueous vehicles (for example, Almond oil, oily esters or Ethyl alcohol); and preservatives (for example methyl or Propyl-p-hydroxybenzoates or sorbic acid), are prepared.
For buccal Administration the composition may take the form of tablets or Lozenges in conventional Way be formulated accept.
The inventive active compounds for the parenteral administration by injection, including Using conventional catheter techniques or infusion formulated will. formulations for injection may in unit dosage form, for example in ampoules or in multidose containers with, administered together with an added preservative will. The compositions may in the form of suspensions, solutions or emulsions in oily or aqueous can be present and vehicles Formulatory agents such as suspending, stabilizing and / or dispersing agents contain. Alternatively, the active ingredient may be in powder form for the preparation of with a suitable vehicle, eg sterile pyrogen-free Water, before use.
The inventive active compounds in the form of rectal compositions such as suppositories or Retentionsklestiren, for example, with conventional suppository bases, such as cocoa butter or other glycerides, are formulated.
For intranasal Administration or administration by inhalation, the inventive active Compounds expediently in the form of a solution or suspension from a pump spray container by the patient operated, ie pressed or is pumped, or as an aerosol spray presentation from a pressurized container or nebuliser using a suitable propellant, such as Dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, Carbon dioxide or other suitable gas administered. in the Case of under pressure the aerosol, the printing unit be determined by a valve is provided which a metered or write certain amount. The pressurized container or the nebulizer can a solution or suspension of the active compounds. capsules and Cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated, to appropriate a powder mixture of the active compound and a Powder base such as lactose or starch.
A recommended dosage of the active compounds of the invention for oral, parenteral or buccal administration is for the treatment of conditions mentioned above (for As asthma) in the average adult 0.1 1000 mg of active ingredient per unit dose which one example could be administered to four times per day.
aerosol formulations for treating the above mentioned disease states (for example, rheumatoid Arthritis) are preferably the average adult adjusted so that each metered Dose or "hub" of aerosol contains 20 .mu.g to 1000 .mu.g of the Verbindungμ invention. The daily Total dose of aerosol is within the range from 0.1 mg to 1000 mg. Administration may be several times a day, for example 2-, 3-, 4-, or carried out 8 times, wherein for example, every time 1, 2 or 3 doses are administered.
A Compound of formula (I) is a pharmaceutically acceptable in Form either alone or in combination with one or more additional Means the mammalian immune system a modulate, or with antiinflammatory agents, agents which Cyclosporin A (eg Sandimmune<sup>®</sup> or Neo ral<sup>®</sup>) Rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate (For example Cellcept<sup>®</sup>), Azathioprine (e.g. Imuran<sup>®</sup>) Daclizumab (Zenapax for example<sup>®</sup>) OKT3 (Ortho, for example, Colon<sup>®</sup>), AtGam, aspirin, Acctaminophen, Ibuprofen, naproxen, piroxicam, and antiinflammatory steroids (Eg prednisolone or Dexamethanson) include, but not limited to are administered and sol<?page 15?>che means can as a part thereof or separate dosage forms over the same or a different route of administration and with the same or a different frequency according to usual pharmaceutical practice can be administered.
FK506 (Tacrolimus) is given orally in a amount of 0.10 to 0.15 mg / kg body weight within the first 48 hours postoperatively administered every 12 hours. The dose is about the minimum area of the tacrolimus levels monitored in the serum.
cyclosporin A (an oral or intravernöse Sandimmun formulation or Neoral<sup>®</sup>a oral solution or Capsules) is given orally at a rate of 5 mg / kg body weight every 12 hours postoperatively administered within 48 hours. The dose will be on the Minimum area of cyclosporin A levels monitored in the blood.
The drugs can for the delayed formulated release to the skilled worker processes known per se will. examples for Such formulations can be found in U.S. Patents 3,538,214, 4,060,598, 4,173,626, 3,119,742 and 3,492,397.
The ability the compounds of formula I or their pharmaceutically acceptable Salts Janus kinase to inhibit 3 and hence their effectiveness to treat the information indicated by the Janus kinase 3 disturbances or states to demonstrate, is shown by the following in vitro assay tests.
Biological assay
JAK3 (JH1: GST) Enzymatic assay
Of the JAK3 kinase assay utilizes a protein with baculovirus in infected SF9 cells was expressed (from a fusion protein GST and the catalytic domain of human JAK3), which purified by affinity chromatography on Sepharose Glutadion has been. The substrate for the reaction is poly-Glutamic acid-Tyrosine (PGT (4: 1), Sigma catalog number P0275.), Which on Nunc maxi-sorption plates in an amount of 100 g / ml overnight at 37 ° C was applied. On the morning after applying the plates washed three times and JAK3 is added to the wells, the 100 ul of kinase buffer (50 mM HEPES, pH 7.3, 125 mM NaCl, 24 mM MgCl<sub>2</sub>) + 0.2 uM ATP + 1 mM Na orthovanadate) contained. The reaction takes 30 minutes from long at room temperature and the plates are washed three more times. The amount or concentration of phosphorylated tyrosine in a certain depression is by a standard ELISA assay Using an anti-phosphotyrosine antibody (ICN PY20, cat. No. 69-151-1) quantified.
DND39 / IL-4 Cellular Assay for JAK3 kinase inhibitors
Of the DND39 / IL-4 assay is designed to identify inhibitors of JAK3 kinase activity, which the best candidates for immunosuppression and / or allergies would. This assay used a B-cell line called DND39 which by the luciferase gene the germline IgE promoter stably integrated into one of the chromosomes let drift. When these cells are stimulated with IL-4, phosphorylates Kinase JAK3, which is associated with the IL-4 receptor, the signal transducer STAT6. STAT6 then binds to the germline IgE promoter and starts transcription of the Luciferase gene. The luciferase is in a lysate of these cells determined using the Promega luciferase Assayreagenssystems.
Note: The DND39 cells are cultured in RPMI 1640 supplemented with 10% by heat inactivated FCS, 2 mM L-glutamine and 100 units / ml Pen./Strep. was added. The cells are in an amount of 1 × 10<sup>5</sup> to 1 x 10<sup>6</sup> Cells / ml held. Friday at 1 × 10<sup>5</sup> divided is their number Monday about 1 x 10<sup>6</sup>, They are then midweek in relation to 1: 2 divided and stored as required 200 ml in a flask.
3 x 10<sup>5</sup> DND39 cells are cultured in 100 ul RPMI 1640 plated, with 1% by heat inactivated FCS, 2 mM L-glutamine and 100 units / ml Pen / Step in a Vee-well plate supplemented with 96 wells (Nunc) has been. The compounds are successively 1: 2 in DMSO diluted, being carried out at 4 mM to 1.9 uM starts. be on a polypropylene 96-well plate the pipette tips after each dilution changed. Subsequently 5 ul each dilution to 500 ul added to RPMI / 1% serum in a rack with 96 tubes. 125 .mu.l of the dilute solutions of the Compounds are added to the cells and for one hour at 37 ° C and 5% CO<sub>2</sub> incubated. After an hour 25 ul of 25 ng / ml <?page 16?>IL-4 added to the cells and mixed. The final concentration amounts of IL-4 2.5 ng / ml and the final concentration of the compound ranging from 20 uM to 156 nM. The cells are then overnight incubated for 16 to 18 hours. The plate is then in a tabletop centrifuge five Minutes at 2500-3000 r / min centrifuged. The culture supernatant is carefully removed by aspiration with an eightfold tip. 100 ul PBS with Calcium and magnesium are added to the pelleted cells. The cells are suspended in PBS and again on a white Packard Optiplate transferred. 100 ul Packards LucLite reagent in the wells of the Opti Plate given.
The following examples illustrate the preparation of the compounds according to the invention, but it is not limited to the details thereof. The melting points are uncorrected. The NMR data are given in "parts per million" (δ) and refer to the deuterium lock signal from the solvent of the sample (deuterochloroform, unless otherwise specified). commercial Reagents were used without further purification. THF means Tetrahydrofuran. DMF means N, N-dimethylformamide. Low-resolution mass spectra (LRMS) were recorded on either a Hewlett Packard 5989<sup>®</sup>spectrometer under Using chemical ionization (ammonium), or on a Fisons- (Or micromass) platform chemical ionization at atmospheric pressure (APCI) was added to give a 50/50 mixture of acetonitrile / water with 0.1% formic acid is used as the ionizing agent. Room or ambient temperature means 20-25 ° C.
BEISPEIL 1
Cyclohexylmethyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amine
METHOD A
Cyclohexylmethyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amine
On Mixture of 200 mg (1.30 mmol) of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (Prepared by the method of Davoll, J. Am. Chem. Soc., (1960), 82, 131), the product from Method A (589 mg / 5.21 mmol) and 3 ml tert-butanol for 24 hours in a sealed tube at 100 ° C for. The Reaction mixture was poured into water, with 1 N hydrochloric acid pH 1 acidified, twice with diethyl ether (ether) and washed with 1 N sodium hydroxide (NaOH) brought to pH fourteenth The resulting precipitate was filtered off and dried in vacuo to give 263 mg (88%) of the title compound were obtained, mp 177-180 ° C. <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>): Δ 1.11 to 1.22 (m, 1H), 1.43 to 1.63 (m, 4H), 1.73 (br d, 1H, J = 13.3 Hz), 1.83 to 1.90 (m, 4H), 3.23 (s, 3H), 4.69 (br, 1H), 6.53 (d, 1H, J = 3.5 Hz), 7.03 (d, 1H, J = 3.5 Hz), 8.30 (s, 1H), 10.6 (br, 1H), LMRS: 231 (M + 1).
The Title compounds of Examples 2-51 were prepared by a method prepared, which is the analogous to that described in Example 1st
EXAMPLE 2
9- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -2,3,4,4a, 9,9a-hexahydro-1H-carbazole
EXAMPLE 3
4- (2,6-dimethylmorpholine-4-yl) -7H-pyrrolo [2,3-d] pyrimidine
2,6-dimethylmorpholine. LRMS: 233.3.
EXAMPLE 4
4-morpholin-4-yl-7H-pyrrolo [2,3-d] pyrimidine
4-morpholine. LRMS: 205th
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EXAMPLE 5
4- (2,5-dimethylpyrrolidin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine
2.5 dimethylpyrrolidine. Mp 227-229 ° C; LRMS: 216.3.
EXAMPLE 6
4- (4-Benzyl-piperidin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine
4-benzylpiperidine. Mp 188-190 ° C; LRMS: 292.4.
EXAMPLE 7
4-Phenyl-1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-ol
4-phenylpiperidine-4-ol. Mp 201-202 ° C; LRMS: 294.4.
EXAMPLE 8
1- [1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-yl] -1,3-dihydro-benzoimidazol-2-one
Piperidin-4-yl-1,3-dihydrobenzimidazol. Mp 182-184 ° C; LRMS: 334.4.
EXAMPLE 9
1-Phenyl-8- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1,3,8-triazaspiro [4,5] decan-4-one
1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one. Mp 232-234 ° C.
EXAMPLE 10
4- (3-methylpiperidin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine
3-methylpiperidine. Mp 176-178 ° C; LRMS: 217.1.
EXAMPLE 11
4- (3,5-dimethyl-piperidin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine
3,5-dimethylpiperidine. Mp 258-260 ° C; LRMS: 231st
EXAMPLE 12
4- (2-methylpiperidin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine
2-methylpiperidine. Mp 144-146 ° C; LRMS: 217.1.
EXAMPLE 13
4- (2-ethylpiperidine-1-yl) -7H-pyrrolo [2,3-d] pyrimidine
2-ethylpiperidine. Mp 112-114 ° C; LRMS: 231st
EXAMPLE 14
[1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-2-yl] methanol
Piperidin-2-ylmethanol. Mp 135-136 ° C; LRMS: 232.9.
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EXAMPLE 15
1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidine-3-carboxylic acid diethylamide
Piperidine-3-carboxylic acid diethylamide. LRMS: 302.1.
EXAMPLE 16
2- [1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-2-yl] ethanol
Piperidin-2-ylethanol. Mp 139-140 ° C.
EXAMPLE 17
4-Azocan-1-yl-7H-pyrrolo [2,3-d] pyrimidine
Azapan. Mp 225-226 ° C; LRMS: 231.3.
EXAMPLE 18
1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-3-carboxylic acid amide
Piperidine-3-carboxamide. Mp 283-285 ° C.
EXAMPLE 19
Dimethyl- [1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrrolidin-3-yl] amine
Dimethylpyrrolidin-3-ylamine. Mp 210-212 ° C; LRMS: 232.2.
EXAMPLE 20
N-Ethyl-N- [1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrrolidin-3-yl] acetamide
N-Ethylpyrrolidin-3-ylacetamide. Mp 197-199 ° C; LRMS: 274.3.
EXAMPLE 21
4- (2-methoxymethylpyrrolidin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine
2-methoxymethylpyrrolidin. Mp 134-135 ° C; LRMS: 233.2.
EXAMPLE 22
[1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrrolidin-2-yl] methanol
Pyrrolidin-2-ylmethanol. Mp 188-189 ° C; LRMS: 219.3.
EXAMPLE 23
N- [1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrrolidin-3-yl] acetamide
Pyrrolidin-3-ylacetamide. Mp 260-261 ° C; LRMS: 246.3.
EXAMPLE 24
4- (2-propylpiperidine-1-yl) -7H-pyrrolo [2,3-d] pyrimidine
Propylpiperidine. Mp 106-107 ° C; LRMS: 245.3.
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EXAMPLE 25
4- (4-methylpiperazin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine
4-methylpiperazine. Mp 141-142 ° C.
EXAMPLE 26
4-piperazin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
Piperazine. Mp 164-166 ° C.
EXAMPLE 27
4-Azepan-1-yl-7H-pyrrolo [2,3-d] pyrimidine
Azapan. Melting point: 210 ° C; LRMS: 217.3.
EXAMPLE 28
1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrrolidin-3-ol
Pyrrolidin-3-ol. Mp 220-225 ° C; LRMS: 205.2.
EXAMPLE 29
[1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-3-yl] methanol
Piperidin-3-ylmethanol. Melting point: 161.5 to 163.5 ° C; LRMS: 234.3.
EXAMPLE 30
1 - (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidine-4-carboxylic acid ethyl ester
Piperidine-4-carboxylic acid ethyl ester. Mp 139-141 ° C; LRMS: 275.3.
EXAMPLE 31
1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-3-carboxylate
Piperidine-3-carboxylate. Melting point: 139.5 to 141.5 ° C; LRMS: 275.3.
EXAMPLE 32
2- [1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-yl] ethanol
Piperidin-4-ylethanol. Mp 129-131 ° C; LRMS: 265.3.
EXAMPLE 33
4- (4-phenyl-piperidin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine
4-phenylpiperidine. Melting point: 195 ° C; LRMS: 279th
EXAMPLE 34
4- (4-Trifluormethylpiperidin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine
4-Trifluormethylpiperidin. Melting point: 198 ° C; LRMS: 271st
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EXAMPLE 35
4- [4- (3-phenylpropyl) piperidin-1-yl] -7H-pyrrolo [2,3-d] pyrimidine
4- (3-phenylpropyl) piperidine. Melting point: 134 ° C; LRMS: 321st
EXAMPLE 36
4- (3,3-dimethyl-piperidin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine
3,3-dimethylpiperidine. Melting point: 204 ° C; LRMS: 231st
EXAMPLE 37
1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-3-carboxylic acid
Piperidine-3-carboxylic acid. Melting point: 159-160 ° C; LRMS: 307.3.
EXAMPLE 38
1-methyl-10-oxa-4-aza-tricyclo [5.2.1.0% 2,6 &] decane
1-Methyl-4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -10-oxa-4-aza-tricyclo [5.2.1] decane. Mp 251-252 ° C; LRMS: 271.3.
EXAMPLE 39
1- (5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) decahydroquinoline
Decahydroquinoline. Mp 190-192 ° C; LRMS: 291.8.
EXAMPLE 40
3- [1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-3-yl] -propionic acid ethyl ester
Piperidin-3-ylpropionsäureethylester. Mp 101-103 ° C; LRMS: 303.4.
EXAMPLE 41
3- [1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-3-yl] propionic acid
Piperidin-3-ylpropionsäure. Melting point: 217-219 ° C; LRMS: 275.3.
EXAMPLE 42
1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-3-ol
Piperidin-3-ol. Mp 152-154 ° C; LRMS: 219.3.
EXAMPLE 43
3- [1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-3-yl] propionamide
Piperidin-3-yl-propionamide. Mp 212-214 ° C; LRMS: 274.3.
EXAMPLE 44
4- (2,6-dimethyl-piperidin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine
2,6-dimethylpiperidine. LRMS: 231st
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EXAMPLE 45
2- [1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-3-yl] propan-2-ol
Piperidin-3-ylpropan-2-ol: Melting point: 182.8 to 183.6 ° C; LMRS: 261st
EXAMPLE 46
2- [1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-yl] propan-2-ol
Piperidin-4-yl-propan-2-ol. Melting point: 170.1 to 171.3 ° C; LRMS: 261st
EXAMPLE 47
4-Methyl-1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-ol
4-methylpiperidine-4-ol. Melting point: 163.8 to 165.1 ° C; LRMS: 233.1.
EXAMPLE 48
3-Methyl-8- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol
3-methyl-8-azabicyclo [3.2.1] octan-3-ol. Melting point: 142.1 to 143.8 ° C; LRMS: 259.1.
EXAMPLE 49
2- [1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrrolidin-2-yl] propan-2-ol
Pyrrolidin-2-yl-propan-2-ol. Melting point: 173 ° C (Dec.); LRMS: 247.1.
EXAMPLE 50
3-Methyl-1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrrolidin-3-ol
3-methylpyrrolidin-3-ol. LRMS: 219th
EXAMPLE 51
4-pyrazol-1-yl-7H-pyrrolo [2,3-d] pyrimidine
Pyrazole. LRMS: 186.2.
EXAMPLE 52
Cyclohexylmethyl (6-phenyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amine
Cyclohexylmethylamine.
METHOD B
7-Benzenesulfonyl-4-chloro-7H-pyrrolo [2,3-d] pyrimidine
In a dried with a flame flask under nitrogen 780 mg of 60% sodium hydride (19.5 mmol) in 30 ml of mineral oil Dimethylformamide (DMF) was added and the resulting mixture on 0 ° C cooled. A solution of 2.0 g (13.0 mmol) of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine in 10 ml DMF was added slowly over a period of 5 minutes was added. The reaction mixture was stirred for 10 minutes, after which the formation of hydrogen (H<sub>2</sub>) Ceased. benzenesulfonyl (1.7 ml / 13.0 mmol) was added to the reaction mixture to room temperature heated and stirred one hour. Water was added, the resulting precipitate was filtered off and dried in vacuo to give 3.4 g (89%) of the title compound were obtained as a crystalline solid, mp 163-167 ° C.
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METHOD C
7-Benzenesulfonyl-4-chloro-6-phenyl-7H-pyrrolo [2,3-d] pyrimidine
In a dried with a flame flask under nitrogen 0.53 ml (3.79 mmol) of diisopropylamine in 5 ml of tetrahydrofuran (THF) disbanded and the solution cooled to -78 ° C. n-butyllithium (3.75 mmol as a 2.5 M solution in hexane) was added and the resulting mixture to 0 ° C under continuous Stirring over a Period of 10 minutes cooled. The reaction mixture was again cooled to -78 ° C and was added to this mixture a solution of 1.0 g (3.40 mmol) of the product from Method B in 10 mL of THF over a Period of 10 minutes added. The reaction mixture was added a stirred hour at -78 ° C, whereafter 8.2 ml (4.10 mmol) of a 0.5 M solution Zinc chloride in THF was added. Subsequently, the reaction mixture was warmed to room temperature and stirred one hour. iodobenzene (0.46 ml / 4.11 mmol) and a suspension of 197 mg of tetrakis (triphenylphosphine) palladium in 2 ml THF was added. The resulting mixture was reflux stirred for three hours, cooled to room temperature and partitioned between dichloromethane and water. The aqueous phase was acidified with 1 N HCl and extracted twice with dichloromethane. The dichloromethane layers were combined with 1 N HCl and brine, over magnesium sulfate (MgSO<sub>4</sub>) Dried, filtered and concentrated in vacuo to whereby the title compound was obtained. LRMS: 370, 372 (M + 2).
METHOD D
4-chloro-6-phenyl-7H-pyrrolo [2,3-d] pyrimidine
The Product from Method C was dissolved in 10 ml of THF and this solution was added 5.0 mL of methanol and 1.0 g NaOH. The reaction mixture was stirred for 15 minutes, concentrated in vacuo and partitioned between a saturated aqueous ammonium chloride (NH<sub>4</sub>Cl) solution and ethyl acetate. The resulting aqueous layer was washed twice extracted with ethyl acetate. The ethyl acetate layers were combined, with brine dried over MgSO<sub>4</sub> dried, filtered and in vacuo concentrated. The crude product was purified by silica gel chromatography (1: 5 ethyl acetate / hexane) to give 0.59 g (76%) of the title compound as a pale yellow solid, melting point: 145 ° C (dec.). LRMS: 230, 232 (M + 2).
METHOD e
Cyclohexylmethyl amine (6-phenyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl)
The Product from Method D (50 mg / 0.218 mmol) was treated with 0.12 ml of N-methylcyclohexylamine (0.920 mmol) were reacted as described in Method. The reaction mixture was concentrated in vacuo, methanol was added and the resulting Precipitation filtered to give 7 mg (10%) of the title compound as a yellow Solids were obtained. <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) Δ 1.18 to 1.25 (m, 1H), 1.47 to 1.66 (M, 4H), 1.75-1.90 (M, 5H), 3.30 (s, 3H), 4.74 (br, 1H), 6.79 (s, 1H), 7.32 to 7.36 (m, 1H), 7.47 to 7.51 (M, 2H), 7.77 (d, 2H, J = 7.9 Hz), 8.33 (s, 1H). LMRS: 307 (M + 1).
The Title compounds of Examples 53-58 were using a method prepared, which is the analogous to that described in Example 52nd
EXAMPLE 53
1- (6-phenyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) decahydroquinoline
Decahydroquinoline. LRMS: 333.4.
EXAMPLE 54
4- (2-ethylpiperidine-1-yl) -6-phenyl-7H-pyrrolo [2,3-d] pyrimidine
2-ethylpiperidine. LRMS: 307.4.
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EXAMPLE 55
4- (3,3-dimethylpiperidin-1-yl) -6-phenyl-78-pyrrolo [2,3-d] pyrimidine
3,3-dimethylpiperidine. LRMS: 307.4.
EXAMPLE 56
6-Phenyl-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
Piperidine. LRMS: 279.4.
EXAMPLE 57
4-piperidin-1-yl-6-thiophen-3-yl-7H-pyrrolo [2,3-d] pyrimidine
Piperidine. LRMS: 285.4.
EXAMPLE 58
4-piperidin-1-yl-6-thiophen-2-yl-7H-pyrrolo [2,3-d] pyrimidine
Piperidine. LRMS: 285.4.
EXAMPLE 59
Cyclohexylmethyl amine (6-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl)
Cyclohexylmethylamine.
METHOD F
7-Benzenesulfonyl-4-chloro-6-methyl-7H-pyrrolo [2,3-d] pyrimidine
In a dried with a flame flask under N<sub>2</sub> 0.57 ml (4.07 mmol) of diisopropylamine and submitted 5.0 ml of dry THF. The solution was cooled to -78 ° C and 1.63 ml (4.08 mmol) of a 2.5 M solution of n-butyl lithium in Hexane added. The resulting mixture was warmed to 0 ° C and 10 stirred minutes. After cooling the mixture to -78 ° C again, a solution of 1.0 g (3.40 mmol) of the crude product from Method C in 10 ml of dry THF a period of 10 minutes added. The resulting mixture was stirred for one hour and then 0.28 ml (4.50 mmol) iodomethane were added. The reaction mixture was stirred for two hours, with a saturated NH<sub>4</sub>Cl solution quenched and warmed to room temperature. The mixture for 5 minutes stirred, diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with brine, MgSO<sub>4</sub> dried, filtered and evaporated in vacuo, whereby the title compound was obtained. LRMS: 308, 310 (M + 2).
METHOD G
4-chloro-6-methyl-7H-pyrrolo [2,3-d] pyrimidine
The Product from Method F was deprotected as described in Method E. The Crude product was purified by trituration with hexane and dichloromethane, whereby 250 mg (44%) of the title compound as a yellow solid were. Melting point: 205 ° C (Dec.), LRMS 168, 170 (M + 2).
METHOD H
Cyclohexylmethyl amine (6-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl)
The Product from Method G (50 mg / 0.298 mmol) was treated with 100 mg (0.883 mmol) N-methylcyclohexylamine described reacted as in method A. The reaction mixture was aufgear as in Method A<?page 24?>processed with the Except that ethyl acetate was used instead of ether. The Title compound (42 mg, 58% yield) as a white solid receive. Melting point 221 ° C (Dec.). <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) Δ: 1.15-1.25 (m, 1H), 1.43 to 1.62 (M, 4H), 1.73 (br s, 1H, J = 13.7 Hz), 1.82 to 1.90 (m, 4H), 2.41 (d, 3H, J = 0.8 Hz), 3.21 (s, 3H) 4.63 (br s, 1H), 6.20 (s, 1H), 8.22 (s, 1H), 10.1 (br s, 1H). LRMS: 245 (M + 1).
The Title compound of Example 60 was prepared by a method is the analogous to that described in Example 59th
EXAMPLE 60
6-methyl-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
Piperidine. LRMS: 217.3.
EXAMPLE 61
5-chloro-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
METHOD I
4,5-dichloro-7H-pyrrolo [2,3-d] pyrimidine
4-chloro-7H-pyrrolo [2,3-d] pyrimidine (154 mg, 1.0 mmol) were dissolved in 6.0 ml of dry dichloromethane in a suspended with a flame dried flask and this mixture was added N-chlorosuccinimide (147 mg, 1.1 mmol) added in one portion. The resulting Mixture was stirred at room temperature for 18 hours, after the solvent was removed under reduced pressure. The residue was triturated with water and isolated by filtration to give 137 mg (72%) of the title compound was obtained as a gray solid, mp 224-227 ° C (dec). LRMS: 188 (M + 1).
METHOD J
5-chloro-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
The Product of Method I was (57 mg, 0.3 mmol) in 3.0 mL of tert-butanol suspended and this solution was charged with piperidine (90 uL, 0.9 mmol) and the resulting system for one hour refluxed. The reaction mixture was cooled to room temperature and treated with water (4.0 mL). The solution was washed with 1N HCl pH 1, then washed with ether. The aqueous Phase was separated and adjusted with 2 N NaOH to pH 12th Subsequently, the solution with 2 × 15 extracted ml dichloromethane and the combined organic phases with water and then Saline and dried over MgSO<sub>4</sub> dried. Evaporation of the solvent afforded 45 mg of a yellow solid which was purified by silica gel (3: 1 ethyl acetate / hexane) to give 23 mg (32%) of Title compound as a pale yellow solid. melting point 170-172 ° C. <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) Δ 1.67 to 1.74 (m, 6H), from 3.65 to 3.67 (M, 4H), 7.10 (s, 1H), 8.31 (s, 1H). LRMS: 237 (M + 1).
The Title compounds of Examples 62-63 were prepared by a method prepared, which is the analogous to that described in Example 61st
EXAMPLE 62
5-chloro-4- (octahydroindol-1-yl) -7H-pyrrolo [2,3-d] pyrimidine
Octahydroindole. Melting point: 193 ° C; LRMS: 277.8.
EXAMPLE 63
1- (5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) decahydroquinoline
Decahydroquinoline. Mp 190-192 ° C; LRMS: 291.8.
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EXAMPLE 64
5-Phenyl-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
METHOD K
5-bromo-4-chloro-7H-pyrrolo [2,3-d] pyrimidine
To a stirred solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (30 g / 0.02 mol) dissolved, in 75 ml of chloroform, 3.5 g (0.02 mol) of N-bromosuccinamide were added and the resultant mixture for one hour under reflux heated. After cooling to room temperature, the precipitate was separated by filtration and dried under reduced pressure to give 4.1 g (89%) of Title compound he was holding. <sup>1</sup>H NMR (400 MHz) (CDCl<sub>3</sub>) Δ: 7.93 (d, 1H, J = 2.8 Hz). 8.60 (s, 1H).
METHOD L
7-Benzenesulfonyl-5-bromo-4-chloro-7H-pyrrolo [2,3-d] pyrimidine
To a slurry of the product from Method K (4.1 g / 0.018 mol) in DMF (15 ml), the was cooled to 0 ° C was 1.0 g (0.025 mol) were added 60% sodium hydride in mineral oil and the resulting mixture stirred for 15 minutes at 0 ° C. benzenesulfonyl (3.2 g / 0.018 mol) was added, the reaction mixture to room temperature heated stirred for two hours. subsequently Water was added (15 ml) and the resulting solid by separated filtration, and then dried in vacuo to give 5.9 g (89%) of the title compound.
METHOD M
7-Benzenesulfonyl-5-bromo-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
On Mixture of 2.0 g (5.37 mmol) of the product from Method L and 1.1 g (13.4 mmol) in 10 ml Pipieridin tert-butanol was two hours stirring at 60 ° C kept. After cooling to room temperature the reaction mixture was partitioned between dichloromethane distributed (25 mL) and water (25 ml). The dichloromethane phase was dried over sodium sulfate (N / A<sub>2</sub>SO<sub>4</sub>dried) and concentrated in vacuo to dryness to give 2.2 g (97%) of Title compound were obtained. <sup>1</sup>H NMR (400 MHz) (CDCl<sub>3</sub>) Δ: 1.63 to 1.72 (m, 6H), 3.54 to 3.57 (m, 4H), 7.53 (t, 2H, J = 2.0 Hz), 7.60 (s, 1H), 7.61 (t, 1H, J = 2.0 Hz), 8.17 to 8.20 (M, 2H), 8.43 (s, 1H). LRMS: 422.7, 420.7 (M + 1).
METHOD N
5-Phenyl-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
To a stirred solution of the product from Method M (100 mg / 0.237 mmol) in 1.0 ml of dioxane 32 mg (0.261 mmol) of phenylboronic acid and 75 mg (0.356 mmol) given of tribasic potassium phosphate and then 7 mg (0.006 mmol) of tetrakis (triphenylphosphine) palladium. The resulting mixture was degassed with nitrogen and stirred at 100 ° C for 48 hours. After cooling down to room temperature, 1.0 ml of methanol, and then 50 mg of NaOH and the new mixture for one hour at room temperature touched. The resulting mixture was then partitioned between dichloromethane distributed and water, the dichloromethane layer over MgSO<sub>4</sub> dried and concentrated in vacuo to dryness. The crude product was purified by Silica gel chromatography (2: 1 ethyl acetate / hexane) to give 13 mg (20%) of the title compound. <sup>1</sup>H NMR (400 MHz) (CDCl<sub>3</sub>) Δ: 1.33 to 1.34 (m, 4H), 1.43 to 1.44 (m, 2H), 3.26 to 3.28 (M, 4H), 7.12 (s, 1H), 7.27 (t, 1H, J = 7.2 Hz), 7.38 (t, 2H, J = 8.0 Hz), 7.45 (d, 2H, J = 0.8 Hz), 8.42 (s, 1H). LRMS: 279.2 (M + 1).
The Title compounds of Examples 65-77 were prepared by a method prepared, which is the analogous to that described in Example 64th
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EXAMPLE 65
5- (3-chloro-4-fluorophenyl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
Piperidine. LRMS: 331.8.
EXAMPLE 66
5- (4-fluorophenyl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
Piperidine. LRMS: 297th
EXAMPLE 67
5- (4-chlorophenyl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
Piperidine. LRMS: 313th
EXAMPLE 68
5- (3,5-Bis-trifluoromethyl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
Piperidine. LRMS: 415.4.
EXAMPLE 69
4-piperidin-1-yl-5-o-tolyl-7H-pyrrolo [2,3-d] pyrimidine
Piperidine. LRMS: 293.4.
EXAMPLE 70
4-piperidin-1-yl-5-p-tolyl-7H-pyrrolo [2,3-d] pyrimidine
Piperidine. LRMS: 293.4.
EXAMPLE 71
5- (4-methoxyphenyl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
Piperidine. LRMS: 309.4.
EXAMPLE 72
4-piperidin-1-yl-5- (3-trifluoromethylphenyl) -7H-pyrrolo [2,3-d] pyrimidine
Piperidine. LRMS: 347.4.
EXAMPLE 73
5- (3-chlorophenyl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
Piperidine. LRMS: 427.8.
EXAMPLE 74
3- (4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) benzoate
Piperidine. LRMS: 465.4.
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EXAMPLE 75
2- [3- (4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenyl] propan-2-ol
Piperidine. LRMS: 451.4.
EXAMPLE 76
4- (2-methylpiperidin-1-yl) -5-m-tolyl-7H-pyrrolo [2,3-d] pyrimidine
2-methylpiperidine. LRMS: 307.2.
EXAMPLE 77
4-Azepan-1-yl-5-m-tolyl-7H-pyrrolo [2,3-d] pyrimidine
Azepane. LRMS: 307.2.
EXAMPLE 78
METHOD O
4-piperidin-1-yl-78-pyrrolo [2,3-d] pyrimidine-5-carbonitrile
To a stirred solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine-5-carbonitrile (54 mg / 0.3 mmol) (prepared by the method of Townsend, et al., J. Am. Chem. Soc., 1969, 91, 2102), which was suspended in 3.0 mL tert-Butanol was, piperidine (59 ul / 0.60 mmol). The resulting mixture was subsequently 2.5 Hours under reflux cooked and after cooling transferred to room temperature in a separatory funnel and extracted with ether (20 mL). The solution was charged with 2 × 10 extracted ml 1 N HCl, the combined aqueous layers to pH 7 with 2 N potassium hydroxide (KOH) solution adjusted, whereby a precipitate was formed, which by collected filtration, washed with water and concentrated under reduced Pressure was dried to obtain 29 mg (42%) of the title compound were obtained as a colorless solid. Mp 209-211 ° C;<sup>1</sup>H NMR (400 MHz) (acetone-d6) δ: 1.72 to 1.74 (m, 6H), from 3.72 to 3.79 (M, 4H), 8.12 (s, 1H), 8.29 (s, 1H). LRMS: 228 (M + 1).
EXAMPLE 79
5-Ethynyl-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
METHOD P
4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine
To a stirred solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (30 g / 0.02 mol) dissolved, in 80 ml of chloroform, 4.5 g (0.02 mol) of N-iodosuccinimide were added and the resultant mixture for one hour under reflux heated. After cooling to room temperature, the precipitate was separated by filtration and dried under reduced pressure to give 4.6 g (82%) of Title compound were obtained.
METHOD Q
7-Benzenesulfonyl-4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine
The Title compound was prepared as previously described in Method L, by placing the product was used in Method O to give 5.4 g (80%) of material were obtained. LRMS: 419.6 (M + 1), 279.7.
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METHOD R
7-Benzenesulfonyl-5-iodo-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
The Title compound was prepared by the method described in Method M produced, which product was used in Method O to prepare the title compound. LRMS: 469 (M + 1), 329.1.
METHOD S
7-Benzenesulfonyl-4-piperidin-1-yl-5-triethylsilanylethinyl-7H-pyrrolo [2,3-d] pyrimidine
In a dried with a flame flask under nitrogen 211 mg (0.5 mmol) of the product from Method R, 19 mg (0.1 mmol) of copper (I) iodide and 58 mg (0.05 mmol) of tetrakis (triphenylphosphine) palladium presented. This mixture was then with 0.14 ml (1.0 mmol) of triethylamine and 0.27 ml (1.5 mmol) Triethylsilylacetylen as a solution added in 1.5 ml of dry DMF. The resulting mixture was three stirred hours at room temperature and then added 5.0 ml added water and the mixture extracted with ethyl acetate. Of the was ethyl acetate over MgSO<sub>4</sub> dried and concentrated in vacuo. The resulting crude product was then purified by silica gel (7: 1 hexane / ethyl acetate) to give 194 mg (89%) of the title compound were obtained. LRMS: 481 (M + 1), 341st
METHOD T
5-Ethynyl-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine
A stirred solution of the product from Method S (194 mg / 0.40 mmol) dissolved in 2.0 ml dry THF was treated dropwise with 0.4 ml (0.4 mmol) of 1 M solution Tetrabutylammonium fluoride in THF. The resulting mixture was stirred for 10 minutes at room temperature, then in a methanol solution (3.0 mL) containing 1 g of KOH, transferred, the new mixture 15 stirred for minutes at room temperature and concentrated in vacuo. The residue was partitioned between water and ethyl acetate, the ethyl with water and brine dried over MgSO<sub>4</sub> dried and concentrated in vacuo to dryness concentrated. The crude product was purified by silica gel chromatography (2: 1 ethyl acetate / hexane) to give 72 mg (64%) of the title compound as white crystalline solid were obtained. Mp 179-181 ° C.<sup>1</sup>H NMR (400 MHz) (CDCl<sub>3</sub>) Δ: 1.72 (br s, 6H), 3.20 (s, 1H), 3.82 to 3.83 (M, 4H), 7.47 (s, 1H), 8.35 (s, 1H). LRMS: 227 (M + 1).
Contents98
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| UA63013C2 | Ukraine | C2 | |
| KR100415791B1 | Republic of Korea | B1 | |
| JP3497823B2 | Japan | B2 | |
| UA64792C2 | Ukraine | C2 | |
| US2004058922A1 | United States of America | A1 | |
| EP1087970B1 | European Patent Office (EPO) | B1 | |
| NZ518444A | New Zealand | A | |
| AT265458T | Austria | T | |
| ATE265458T1 | Austria | T1 | |
| DE69916833D1 | Germany | D1 | |
| PT1087970E | Portugal | E | |
| OA11571A | African Intellectual Property Organization (OAPI) | A | |
| OA11572A | African Intellectual Property Organization (OAPI) | A | |
| EP1087971B1 | European Patent Office (EPO) | B1 | |
| AT270673T | Austria | T | |
| ATE270673T1 | Austria | T1 | |
| DK1087970T3 | Denmark | T3 | |
| DE69918552D1 | Germany | D1 | |
| AU2003234874B2 | Australia | B2 | |
| KR100452054B1 | Republic of Korea | B1 | |
| DK1087971T3 | Denmark | T3 |
1 legal event, as the office reported them to INPADOC
Events
| Event | Code | |
|---|---|---|
| No opposition during term of oppositionOpposition8364 | 8364 |
Numbers
- Publication
- 69918552
- Publication, DOCDB
- 69918552
- Publication, EPODOC
- DE69918552T
- Application
- 69918552
- Application, DOCDB
- 69918552
- Application, EPODOC
- DE19996018552T
Titles2
- German
- PYRROLO(2,3-D)PYRIMIDIN-VERBINDUNGEN
- English
- Pyrrolo (2,3-D) pyrimidine compounds
Classification
- CPC, 16
- C07D487/04
- A61P1/04
- A61P11/06
- A61P17/04
- A61P19/02
- A61P25/00
- A61P25/18
- A61P25/28
- A61P29/00
- A61P35/00
- A61P35/02
- A61P37/00
- A61P37/06
- A61P5/14
- A61P5/16
- A61P3/10
- IPC, 18
- A61K31 505
- A61K31 519
- A61K31 5377
- A61K31 55
- A61P1 04
- A61P3 10
- A61P5 14
- A61P11 06
- A61P17 04
- A61P19 02
- A61P25 00
- A61P25 28
- A61P29 00
- A61P35 00
- A61P35 02
- A61P37 06
- C07D487 04
- C07D519 00