PH12015500939B1 - N-pyrrolidinyl, n`-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors - Google Patents

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Publication number

PH12015500939B1

PH12015500939B1 PH12015500939A PH12015500939A PH12015500939B1 PH 12015500939 B1 PH12015500939 B1 PH 12015500939B1 PH 12015500939 A PH12015500939 A PH 12015500939A PH 12015500939 A PH12015500939 A PH 12015500939A PH 12015500939 B1 PH12015500939 B1 PH 12015500939B1

Authority

PH

Philippines

Prior art keywords

alkyl

methyl

phenyl

methoxyethyl

formula

Prior art date

2012-11-13

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• 101150111783 NTRK1 gene Proteins 0.000 title claims abstract description 57
• -1 N-pyrrolidinyl Chemical group 0.000 title claims description 119
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 title claims description 81
• 229940043355 kinase inhibitor Drugs 0.000 title abstract description 5
• 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 5
• ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 title description 8
• UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 title description 8
• CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 title description 4
• SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 title description 4
• QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical class NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 title description 3
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• 208000035473 Communicable disease Diseases 0.000 claims abstract description 11
• 125000000217 alkyl group Chemical group 0.000 claims description 428
• 238000002360 preparation method Methods 0.000 claims description 130
• 125000003545 alkoxy group Chemical group 0.000 claims description 103
• 238000000034 method Methods 0.000 claims description 78
• 229910052736 halogen Inorganic materials 0.000 claims description 68
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• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 55
• 239000004202 carbamide Substances 0.000 claims description 49
• 239000003814 drug Substances 0.000 claims description 49
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 47
• 125000001424 substituent group Chemical group 0.000 claims description 45
• 125000001153 fluoro group Chemical group F* 0.000 claims description 41
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 40
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• 229910052760 oxygen Inorganic materials 0.000 claims description 25
• 125000005842 heteroatom Chemical group 0.000 claims description 20
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
• 229910052717 sulfur Inorganic materials 0.000 claims description 18
• 229910052739 hydrogen Inorganic materials 0.000 claims description 17
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
• PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 claims description 16
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• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 14
• 230000008878 coupling Effects 0.000 claims description 14
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• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 11
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
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• MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 claims description 3
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• SIISYXWWQBUDOP-UHFFFAOYSA-N bis(1h-imidazol-2-yl)methanethione Chemical compound N=1C=CNC=1C(=S)C1=NC=CN1 SIISYXWWQBUDOP-UHFFFAOYSA-N 0.000 claims description 2
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 2
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• IUKLNTHZUWBZRJ-NZQKXSOJSA-N 1-(5-acetyl-4-methyl-2-phenylpyrazol-3-yl)-3-[(3s,4r)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl]urea Chemical compound N([C@@H]1CN(C[C@H]1C=1C=C(F)C(F)=CC=1)CCOC)C(=O)NC1=C(C)C(C(C)=O)=NN1C1=CC=CC=C1 IUKLNTHZUWBZRJ-NZQKXSOJSA-N 0.000 claims 1
• CERDWPHMJKWGLA-RPLLCQBOSA-N 1-[(3s,4r)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl]-3-[4-methyl-5-(2-methylpyridin-3-yl)-2-phenylpyrazol-3-yl]urea Chemical compound N([C@@H]1CN(C[C@H]1C=1C=C(F)C(F)=CC=1)CCOC)C(=O)NC1=C(C)C(C=2C(=NC=CC=2)C)=NN1C1=CC=CC=C1 CERDWPHMJKWGLA-RPLLCQBOSA-N 0.000 claims 1
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• JJHKOIBJUOTVJS-JYFHCDHNSA-N 1-[(3s,4r)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl]-3-[5-(2-ethoxypyrimidin-5-yl)-4-methyl-2-phenylpyrazol-3-yl]urea Chemical compound C1=NC(OCC)=NC=C1C1=NN(C=2C=CC=CC=2)C(NC(=O)N[C@H]2[C@@H](CN(CCOC)C2)C=2C=C(F)C(F)=CC=2)=C1C JJHKOIBJUOTVJS-JYFHCDHNSA-N 0.000 claims 1
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