TWI705067B - 螺環化合物 - Google Patents

Info

Publication number

TWI705067B

TWI705067B TW105110691A TW105110691A TWI705067B TW I705067 B TWI705067 B TW I705067B TW 105110691 A TW105110691 A TW 105110691A TW 105110691 A TW105110691 A TW 105110691A TW I705067 B TWI705067 B TW I705067B

Authority

TW

Taiwan

Prior art keywords

group

unsubstituted

compound

hydrogen

pharmaceutically acceptable

Prior art date

2015-04-03

Links

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• 125000000217 alkyl group Chemical group 0.000 claims description 254
• 150000003839 salts Chemical class 0.000 claims description 139
• 125000001072 heteroaryl group Chemical group 0.000 claims description 137
• 229910052739 hydrogen Inorganic materials 0.000 claims description 125
• 239000001257 hydrogen Substances 0.000 claims description 125
• -1 bicyclo[1.1.1]pentyl group Chemical group 0.000 claims description 100
• 150000002431 hydrogen Chemical class 0.000 claims description 61
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 54
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 50
• XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 claims description 43
• 125000003277 amino group Chemical group 0.000 claims description 39
• 229910052736 halogen Inorganic materials 0.000 claims description 39
• 150000002367 halogens Chemical class 0.000 claims description 39
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 36
• 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 claims description 35
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
• 125000003342 alkenyl group Chemical group 0.000 claims description 26
• 125000002950 monocyclic group Chemical group 0.000 claims description 26
• 125000000304 alkynyl group Chemical group 0.000 claims description 25
• 230000000694 effects Effects 0.000 claims description 25
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 24
• 239000003814 drug Substances 0.000 claims description 24
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 22
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• 125000003545 alkoxy group Chemical group 0.000 claims description 13
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• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
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• 125000004414 alkyl thio group Chemical group 0.000 claims description 10
• 229910052760 oxygen Inorganic materials 0.000 claims description 10
• 229910052717 sulfur Inorganic materials 0.000 claims description 10
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• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
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• 125000001188 haloalkyl group Chemical group 0.000 claims description 8
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 8
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• 125000002252 acyl group Chemical group 0.000 claims description 6
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• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 5
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 5
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 5
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• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 5
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• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 5
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• 208000003174 Brain Neoplasms Diseases 0.000 claims description 4
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• 208000026310 Breast neoplasm Diseases 0.000 claims description 4
• 208000008839 Kidney Neoplasms Diseases 0.000 claims description 4
• 206010029260 Neuroblastoma Diseases 0.000 claims description 4
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• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
• 206010038389 Renal cancer Diseases 0.000 claims description 4
• 206010039491 Sarcoma Diseases 0.000 claims description 4
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 4
• 239000003795 chemical substances by application Substances 0.000 claims description 4
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• 201000007270 liver cancer Diseases 0.000 claims description 4
• 208000014018 liver neoplasm Diseases 0.000 claims description 4
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• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
• 201000004404 Neurofibroma Diseases 0.000 claims description 3
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• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 3
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 9
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 3
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
• GAXAFTQHTHBBPG-LHEWISCISA-N 2-methoxy-4-[5-[(5S)-7-[2-[4-[4-(1-methyl-1,2,4-triazol-3-yl)phenyl]-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-1H-indazol-3-yl]benzonitrile Chemical compound COC1=C(C=CC(=C1)C1=NNC2=C1C=C(C=C2)N1CC[C@]2(CCN(CC(=O)N3CCC(=CC3)C3=CC=C(C=C3)C3=NN(C)C=N3)C2)C1=O)C#N GAXAFTQHTHBBPG-LHEWISCISA-N 0.000 claims 1
• VGKFRMVABBXTKV-LHEWISCISA-N 2-methoxy-4-[5-[(5S)-7-[2-[4-[4-(4-methyl-5-oxo-1,3,4-oxadiazol-2-yl)phenyl]-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-1H-indazol-3-yl]benzonitrile Chemical compound COC1=C(C=CC(=C1)C1=NNC2=C1C=C(C=C2)N1CC[C@]2(CCN(CC(=O)N3CCC(=CC3)C3=CC=C(C=C3)C3=NN(C)C(=O)O3)C2)C1=O)C#N VGKFRMVABBXTKV-LHEWISCISA-N 0.000 claims 1
• IYSICUHAZQBAHA-LHEWISCISA-N 2-methoxy-5-[5-[(5S)-7-[2-[4-[4-(4-methyl-5-oxo-1,3,4-oxadiazol-2-yl)phenyl]-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-1H-indazol-3-yl]benzonitrile Chemical compound COC1=C(C=C(C=C1)C1=NNC2=C1C=C(C=C2)N1CC[C@]2(CCN(CC(=O)N3CCC(=CC3)C3=CC=C(C=C3)C3=NN(C)C(=O)O3)C2)C1=O)C#N IYSICUHAZQBAHA-LHEWISCISA-N 0.000 claims 1
• AZRIIERYKDENHS-QNGWXLTQSA-N 4-[5-[(5S)-7-[2-[4-[4-(1-methyl-1,2,4-triazol-3-yl)phenyl]-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-1H-indazol-3-yl]benzonitrile Chemical compound CN1C=NC(=N1)C1=CC=C(C=C1)C1=CCN(CC1)C(=O)CN1CC[C@]2(CCN(C2=O)C2=CC3=C(NN=C3C3=CC=C(C=C3)C#N)C=C2)C1 AZRIIERYKDENHS-QNGWXLTQSA-N 0.000 claims 1
• CFIIXPSJXDHGHV-QNGWXLTQSA-N 4-[5-[(5S)-7-[2-[4-[4-(4-methyl-5-oxo-1,3,4-oxadiazol-2-yl)phenyl]-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-1H-indazol-3-yl]benzonitrile Chemical compound CN1N=C(OC1=O)C1=CC=C(C=C1)C1=CCN(CC1)C(=O)CN1CC[C@]2(CCN(C2=O)C2=CC3=C(NN=C3C3=CC=C(C=C3)C#N)C=C2)C1 CFIIXPSJXDHGHV-QNGWXLTQSA-N 0.000 claims 1
• AMSLGMCDVAAHDF-QNGWXLTQSA-N 5-[5-[(5S)-7-[2-[4-[4-(1-methyl-1,2,4-triazol-3-yl)phenyl]-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-1H-indazol-3-yl]-2-(trifluoromethoxy)benzonitrile Chemical compound CN1C=NC(=N1)C1=CC=C(C=C1)C1=CCN(CC1)C(=O)CN1CC[C@]2(CCN(C2=O)C2=CC3=C(NN=C3C3=CC(C#N)=C(OC(F)(F)F)C=C3)C=C2)C1 AMSLGMCDVAAHDF-QNGWXLTQSA-N 0.000 claims 1
• 150000001540 azides Chemical class 0.000 claims 1
• 210000004126 nerve fiber Anatomy 0.000 claims 1
• 229910052727 yttrium Inorganic materials 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 64
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 356
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• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 245
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 156
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• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 143
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• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 117
• 238000005481 NMR spectroscopy Methods 0.000 description 116
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 99
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• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 63
• 125000003107 substituted aryl group Chemical group 0.000 description 61
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• 125000003118 aryl group Chemical group 0.000 description 57
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• NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical group [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 46
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• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
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• 241001465754 Metazoa Species 0.000 description 8
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