TH57985A - Monocyclic compound-7H-pyrolo[2,3-d]pyrimidine, its composition and uses. - Google Patents

Abstract

DC60 (03/09/42) The compound according to the formula (chemical formula) (I), where R1, R2 and R3 are as specified above, is a tyrosine kinase inhibitor such as genus kinase 3 and is useful in immunosuppressive therapy for organ transplantation, lupus, multiple sclerosis, rheumatic arthritis, psoriasis, type I diabetes and complicated forms of diabetes, cancer, asthma, hereditary allergic skin disease, thyroid autoimmune disorders, ulcerative colitis, inflammatory bowel disease, Alzheimer's disease, leukemia and other autoimmune diseases. The compound according to the formula (chemical formula) (I), where R1, R2 and R3 are as specified above, is a tyrosine kinase inhibitor such as genus kinase 3 and is useful in immunosuppressive therapy for Organ transplantation, lupus, multiple sclerosis, rheumatic arthritis, psoriasis, type 1 diabetes and complicated forms of diabetes, cancer, asthma, hereditary allergic skin diseases, thyroid autoimmune disorders, intestinal ulcers, inflammatory bowel disease, Alzheimer's disease, leukemia, and other autoimmune diseases.

Claims (10)

1. The compound according to the formula (chemical formula) (I) or its pharmaceutically recognized salt, where R1 is the formula group (chemical formula) (IV), where the dashed line is a possible double bond, m is 0,1,2 or 3, n is 0,1,2 or 3, X, B and D are each independent. The atoms A and E are each represented by CR7R8 and R6, and are selected from the following groups: 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, hydroxyl (C2-C6) alkyl, (C1-C6) asiloxy(C2-C6) alkyl, (C1-C6) alkoxy (C2-C6) alkyl, piperazinyl(C1-C6) alkyl, (C1-C6) acylamino (C1-C6) alkyl, (C6-C10) erythryl Ryl(C1-C6) alkoxy(C1-C6)alkyl, (C5-C9)heteroe. Ryl(C3-C6)alkoxy (C1-C6) alkyl, (C1-C6)alkylthio (C1-C6)alkyl, (C6-C10)erylthio(C1-C6)alkyl, (C1-C6) alkyl. Sulfinyl(C1-C6)alkyl, (C6-C10)erylsulfinyl (C1-C6) alkyl, (C1-C6) alkylsulfonyl (C1-C6) alkyl, (C6-C10)erylsulfonyl(C1-C6)alkyl, amino(C1-C60)alkyl, (C1-C6)alkylamino. (C1-C6)alkyl, ((C1-C9)alkyl)2amino(C1-C6)alkyl, R13CO(C1-C6)alkyl where R13 is R20O or R20R21N, where R20 and R21 are chosen independently from the group. It consists of hydrogen, (C1-C6) alkyl, (C6-C10) aryl (C1-C6) alkyl or (C5-C9) heteroaryl (C1-C6) alkyl or R14 (C2-C6) alkyl, where R14 is (C1-C6) acyl piperacino, (C6-C10) aryl piperacino, (C5-C9) heteroaryl piperacino, (C1-C6) alkyl piperacino, (C6-C10) aryl (C1-C6) alkyl piperacino, (C5-C9) heteroaryl (C1-C6) alkyl piperacino, morpholino, thiomorpholino, piperidino, pyrolidino. Piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C5-C9)heteroarylpiperidyl, (C6-C10)aryl(C1-C6)alkylaminoeridyl,(C5-C9)heteroaryl(C1-C6)alkylpiperidyl, (C1-C6)alkoxyacyl, (C1-C6)alkylaminoaryl, ((C1-C6)alkyl2aminoacyl(C1-C6)acylpiperidyl, R7 and R8 were selected from the group containing hydrogen, deuterium, (C1-C6)alkyl, amino, hydroxy, (C1-C6)alkoxy, (C1-C6)alkylamino, ((C1-C6)alkyl)amino, (C1-C6)acylamino, carboxy, (C1-C6)alkoxyacyl, (C1-C6)alkylaminoacyl, ((C1-C6)alkyl)2aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl(C1-C6)alkyl, (C1-C6)alkyl(trifluoromethylene), (C1-C3)alkyl(difluoromethylene)(C1-C3)alkyl,(C6-C10)aryl, (C5C9)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)aziloxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, piperazinil(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)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 or R13CO(C3-C10)cycloalkyl where R13 is R20O or R20R21N where R20 and R21 are selectively chosen. Independent of the hydrogen-containing groups, (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 is (C1-C6)acylpiperacino, (C6-C10)arylpiperacino, (C5-C9)heteroarylpiperacino, (C1-C6)alkylpiperacino, (C6-C10)aryl, (C1-C6)alkylpiperacino, (C5-C9)heteroaryl(C1-C6)alkylpiperacino, morpholino, thio. Morfolino, piperidino, pyrolidino, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10) arylpiperidyl, (C5-C9)heteroarylpiperidyl, (C6-C10)aryl(C1-C6)alkylpiperidyl,(C5-C9)heteroaryl(C1-C6)alkylpiperidyl or (C1-C6)acylpiperidyl, or the group according to the formula (chemical formula) (III), where p is 0,1,2 or 3 and Z is hydroxyl, (C1-C6)alkoxy or NR1R2, where R1 and R2 are independently chosen from the hydrogen-containing groups. (C1-C6)alkyl, piperidil, (C1-C6)alkyl piperidil, (C6-C10)yryl piperidil, (C5-C9)heteroyryl piperidil, (C6-C10)yryl (C1-C6)Alkyl Piperidil, (C5-C9)Heteroeril, (C1-C6)Alkyl Piperidil, (C1-C6)Acil Piperidil, (C6-C10)Eril, (C5-C9)Heteroeril, (C6-C10)Eril, (C1-C6)Alkyl, (C5-C9)Heteroeril, (C1-C6)Alkyl, (C6-C10)Eril, (C6-C10)Eril, (C6-C10)Eril, (C6-C10)Eril (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, R2(C1-C6)alkyl, (C1-C5)alkyl(CHR5)(C1-C6)alkyl where R5 is hydroxyl, (C1-C6)aceloxy, (C1-C6)alkoxy, piperacino, (C1-C6)acelamino, (C1-C6)alkylthio, (C6-C10)arylthio, (C1-C6)alkylsulfinyl, (C6-C10)arylsulfinyl, (C1-C8)alkylsulfoxy, (C6-C10)aryl Sulfoxyl, amino, (C1-C6) alkylamino, ((C1-C6) alkyl)2amino, (C1-C6) acyl piperacino, (C1-C6) alkiperacino, (C6-C10) eryl (C1-C6) alkyl piperacino, (C5-C9) heteroeryl (C1-C6) alkyl piperacino, morpholino, thiomorpholino Piperidino or pyrolidino, R6(C1-C6)alkyl, (C1-C5)alkyl(CHR6)(C1-C6)alkyl, where R6 is piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C6-C10)aryl(C1-C6)alkylpiperidyl, (C5-C9)heteroarylpiperidyl or (C5-C9)heteroaryl(C1-C6)alkylpiperidyl, or when n is at least 1, D and E or D and X each are CR7 R8. Adjacent R7 groups may be combined with their attached carbons to form groups according to the formula (chemical formula) (V) (VI), where the dashed line is the part that may be a double bond, a is 0, 1 or 2. m, A, B, and X are as defined above, and G, J, L, and M are each independent oxygen, S(O)d where d is 0, 1, or 2, NR6 or CR7 R8 where R6, R7, and R8 are as defined above, or where n is 1, D and E are each CR7 R8 and m is 1, A and B are each CR7 R8. Adjacent R7 groups may be combined with the carbon they are attached to form groups according to the formula (chemical formula) (XIII), where the dashed line is the part that may be a double bond, a, G, J, L, and M are as defined above, r is 0 or 1, c is 0, 1, or 2, and R, W, Y, and S are each independent oxygen, S(O)d where d is 0, 1, or 2, NR6 or CR7 R8 where R6, R7, and R8 are as defined above. R2 and R3 are chosen independently from the hydrogen-containing groups, Deuterium, amino, halo, hydroxy, nitro, carboxy, (C2-C6) alkynyl, (C2-C6) alkynyl, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy, where the alkyl or alkoxy group may be replaced by one to three groups chosen from halo, 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 or R2 and R3 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 where the groups are heteroaryl,heterocycloalkyl. And aryl may be replaced by one to three groups of halo, (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)alkyl, (C1-C6)alkoxy-CO-NH-(C1-C6)alkoxy, carboxy, carboxy(C1-C6)alkyl, carboxy(C1-C6)alkoxy, benzoyoxycarbonyl(C1-C6)alkoxy,(C1-C6)alkoxycarbonyl(C1-C6)alkoxy, (C6-C10)aryl, amino, amino(C1-C6)alkyl, (C1-C6)alkoxycarbonilamino, (C6-C10) aryl(C1-C6)alkoxycarbonilamino, (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)alkoxycarbonyl(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)arylamino-CO-NH-, (C5-C9)heteroaryl amino-CO-NH-, (C1-C6)alkylamino-CO-NH-(C1-C6)alkyl, ((C1-C6)alkyl)2amino-CO-NH-(C1-C6)alkyl, (C6-C10)arylamino-CO-NH-(C1-C6)alkyl, (C5-C9)heterocycl ... Erylamino-CO-NH-(C1-C6)alkyl, (C1-C6)alkylsulfonil, (C1-C6)alkylsulfonilamino, (C1-C6)alkyl, (C6-C10)arylsulfonil, (C6-C10)arylsulfonilamino, (C6-C10)arylsulfonilamino, (C1-C6)alkyl, (C1-C6)alkylsulfonilamino, (C1-C6)altylsulfonilamino, (C1-C6)alkyl, (C5-C9)heteroaryl or (C2-C9)heterocycloalkyl, provided that A, B, or X in formula V or VI are designated as NR6 or CR7, R8, R2, and/or R3 must be halo. The conditions are that when each R2 and R3 are independent hydrogen or (C1-C6) alkyls, R1 cannot be replaced by piperidinil; that when each R2 and R3 are hydrogen, R1 cannot be replaced by morpholinylpyrrolidinil; that when each R2 and R3 are hydrogen, R1 cannot be piperazinil; and that the groups IV, V, VI, or XIII do not contain oxygen, sulfur, or either of these two atoms in two or more adjacent positions. 2. Compounds according to claim 1, where R1 is the group according to the formula (chemical formula) (IV), where the dashed line is the part that may be a double bond, m is 0, 1, 2 or 3, n is 0, 1, 2 or 3, X, B and D each independent are oxygen, S(O)d where d is 0, 1 or 2, NR6 or CR7R8, A and E each are CR7R8 or NR6 or when n is 1, D and E each are CR7R8 and m is 1, A and B each are CR7R8. Adjacent R7 groups may be combined with the carbon to which they are attached to form groups according to the formula (chemical formula) (XIII), where the dashed line is the part that may be a double bond, a, G, J, L and M are as defined above, r is 0 or 1, c is 0, 1 or 2 and R, W, Y and S each independent are oxygen, S(O)d where d is 0, 1 or 2, NR6 or CR7R8, where R6, R7, and R8 are as defined above. 3. Compounds according to claim 1, where each R1 and R3 are independently selected from a group containing hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C10)cycloalkyl, (C3-C10)cycloalkoxy, (C2-C9)heterocycloalkyl, (C5-C9)heteroaryl, or (C6-C10)aryl. 4. Compounds according to clause 1, where such compounds are selected from the group consisting of 5-fluoro-4-piperidin-1-yl-7H-pyrolo[2,3-d]pyrimidine, 4-piperidin-1yl-5-trifluoromethyl-7H-pyrolo[2,3-d]pyrimidine, 2-{3-ethyl-4-[methyl-(7H-pyrolo[2,3-d]pyrimidine-4-yl}-amino]-cyclopentyl}-propan-2-ol, 2-{3-ethyl-4-[(2-hydroxy-ethyl-(7H-pyrolo[2,3-d]pyrimidine-4-yl)-amino]-cyclopentyl}-propan-2-ol, N,N-dimethyl-N'-[3-(4-piperidin-1-il-7H-pyrolo[2,3-d]pyrimidin-5-il)-benzyl]-ethane-1,2-diamine 2-[1-(5-totyl-7H-pyrolo[2,3-d]pyrimidin-4-il)piperidin-4-il]-ethanol 5-(3-isopropyl-phenyl)-4-piperidin-1-il-7H-pyrolo[2,3-d]pyrimidine 5-(3-methyl-3H-imidazole-4-il)-4-piperidin-1-il-7H-pyrolo[2,3-d]pyrimidine 5-(1-methyl-1H-imidazole-4-yl)-4-piperidin-1-yl-7H-pyrolo[2,3-d]pyrimidine 5-(2-methyl-pyridin-4-yl)-4-piperidin-1-yl-7H-pyrolo[2,3-d]pyrimidine 5-chloro-4-piperidin-1-yl-7H-pyrolo[2,3-d]pyrimidine 5-chloro-4-(octahydro-indole-1-yl)-7H-pyrolo[2,3-d]pyrimidine 5-ethinyl-4-piperidin-1-yl-7H-pyrolo[2,3-d]pyrimidine, 4-piperidin-1-yl-5-m-tolyl-7H-pyrolo[2,3-d]pyrimidine, and 4-(3,3-dimethyl-piperidin-1-yl)-7H-pyrolo[2,3-d]pyrimidine are pharmaceutical mixtures for (a) the treatment or prevention of selected disorders or conditions of transplant rejection, lupus, multiple sclerosis, rheumatic arthritis, psoriasis, type I diabetes and complicated forms of diabetes, cancer, asthma, hereditary allergic skin diseases, thyroid autoimmune disorders, intestinal ulcers, inflammatory bowel disease, Alzheimer's disease, leukemia, and autoimmune diseases. (b) Inhibition of protein tyrosine kinase or genus kinase 3 (JAK3) in mammals, including humans, of compounds according to claim 1 or a number of their pharmacologically recognized salts that produce an effect on such abnormality or symptoms, and a pharmacologically recognized carrier. 6. Pharmaceutical combinations for (a) the treatment or prevention of selected disorders or conditions arising from transplant rejection, lupus, multiple sclerosis, rheumatic arthritis, psoriasis, type I diabetes and complicated forms of diabetes, cancer, asthma, hereditary allergic skin diseases, thyroid autoimmune disorders, ulcerative colitis, inflammatory bowel disease, Alzheimer's disease, leukemia and other autoimmune diseases; or (b) the inhibition of tyrosine kinase or genus kinase 3 (JAK3) protein in mammals, including humans, consisting of a compound under claim I or one or more of its pharmaceutically recognized salts alone or in combination with one or more additional agents that modulate the mammalian immune system to the environment, or in combination with anti-inflammatory agents that are effective against such disorders or conditions and a pharmaceutically recognized carrier. 7. The use of the compound referred to in Patent 1 or its pharmaceutically recognized salts for the manufacture of drugs to inhibit tyrosine kinase or genus kinase 3 (JAK 3) protein in mammals, including humans. 8. The use of the compounds under claim 1 or their pharmaceutically recognized salts for the manufacture of medicines to treat or prevent selected disorders or conditions resulting from organ transplant rejection, lupus, multiple sclerosis, rheumatic arthritis, eczema, type I diabetes and complicated forms of diabetes, cancer, asthma, hereditary allergic skin diseases, thyroid autoimmune disorders, ulcerative colitis, enteritis, Alzheimer's disease, leukemia and other autoimmune diseases in mammals including humans. 9. The use of the compound referred to in claim 1 or its pharmaceutically recognized salts, alone or in combination with one or more additional substances, which modulate the immune system of mammals to the environment, or in combination with anti-inflammatory agents, for the production of drugs to inhibit tyrosine kinase or genus kinase 3 (JAK3) protein in mammals, including humans. 10. The use of the compounds under claim 1 or their pharmaceutically recognized salts, alone or in combination with one or more additional substances, which modulate the immune system of mammals to the environment, or in combination with anti-inflammatory agents, for the production of drugs to treat or prevent selected disorders or conditions resulting from transplant rejection, lupus, multiple sclerosis, rheumatic arthritis, psoriasis, diabetes I and complicated forms of diabetes, cancer, asthma, hereditary atopic dermatitis, thyroid autoimmune disorders, ulcerative colitis, enteritis, Alzheimer's disease, leukemia and other autoimmune diseases in mammals including humans.