EA018441B1 - Ингибиторы пути хеджхога - Google Patents

Info

Publication number

EA018441B1

EA018441B1 EA200970856A EA200970856A EA018441B1 EA 018441 B1 EA018441 B1 EA 018441B1 EA 200970856 A EA200970856 A EA 200970856A EA 200970856 A EA200970856 A EA 200970856A EA 018441 B1 EA018441 B1 EA 018441B1

Authority

EA

Eurasian Patent Office

Prior art keywords

amino

methyl

alkyl

benzamide

optionally substituted

Prior art date

2007-03-14

Links

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• 230000037361 pathway Effects 0.000 title claims description 21
• 239000003112 inhibitor Substances 0.000 title description 3
• 241000289669 Erinaceus europaeus Species 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 776
• 150000003839 salts Chemical class 0.000 claims abstract description 106
• 239000012453 solvate Substances 0.000 claims abstract description 83
• 238000000034 method Methods 0.000 claims abstract description 45
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 34
• 201000011510 cancer Diseases 0.000 claims abstract description 25
• 125000000217 alkyl group Chemical group 0.000 claims description 609
• -1 5,6,7,8-tetrahydroquinazolinyl Chemical group 0.000 claims description 498
• 229910052739 hydrogen Inorganic materials 0.000 claims description 337
• 239000001257 hydrogen Substances 0.000 claims description 337
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 300
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 257
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 221
• 125000001072 heteroaryl group Chemical group 0.000 claims description 202
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 196
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 180
• 150000003254 radicals Chemical class 0.000 claims description 157
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 117
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 115
• 229910052736 halogen Inorganic materials 0.000 claims description 106
• 239000000203 mixture Substances 0.000 claims description 100
• 150000002367 halogens Chemical class 0.000 claims description 96
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 87
• 125000003545 alkoxy group Chemical group 0.000 claims description 85
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 81
• 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 76
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 76
• 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 74
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 73
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 70
• 125000003282 alkyl amino group Chemical group 0.000 claims description 58
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 58
• 125000001188 haloalkyl group Chemical group 0.000 claims description 58
• 125000003118 aryl group Chemical group 0.000 claims description 53
• 125000003884 phenylalkyl group Chemical group 0.000 claims description 42
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 40
• 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 39
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 39
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 34
• 201000010099 disease Diseases 0.000 claims description 31
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 30
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 30
• 229910052757 nitrogen Inorganic materials 0.000 claims description 29
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 28
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 27
• 125000004432 carbon atom Chemical group C* 0.000 claims description 27
• 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 27
• DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 25
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 25
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 24
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 23
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 23
• 125000004260 quinazolin-2-yl group Chemical group [H]C1=NC(*)=NC2=C1C([H])=C([H])C([H])=C2[H] 0.000 claims description 22
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 22
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
• 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 18
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 15
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 14
• 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 13
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
• 125000005122 aminoalkylamino group Chemical group 0.000 claims description 12
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 12
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 229920006395 saturated elastomer Polymers 0.000 claims description 11
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 10
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 10
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 10
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 9
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 9
• 125000004429 atom Chemical group 0.000 claims description 9
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
• 125000002619 bicyclic group Chemical group 0.000 claims description 8
• 230000015572 biosynthetic process Effects 0.000 claims description 8
• 229910052799 carbon Inorganic materials 0.000 claims description 8
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 8
• 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 7
• 239000003085 diluting agent Substances 0.000 claims description 7
• GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 7
• 125000006413 ring segment Chemical group 0.000 claims description 7
• 208000034578 Multiple myelomas Diseases 0.000 claims description 6
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 6
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 6
• 125000005842 heteroatom Chemical group 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 125000002950 monocyclic group Chemical group 0.000 claims description 6
• 125000004043 oxo group Chemical group O=* 0.000 claims description 6
• 102000004169 proteins and genes Human genes 0.000 claims description 6
• 108090000623 proteins and genes Proteins 0.000 claims description 6
• 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 6
• 125000003107 substituted aryl group Chemical group 0.000 claims description 6
• 206010004146 Basal cell carcinoma Diseases 0.000 claims description 5
• 239000004215 Carbon black (E152) Substances 0.000 claims description 5
• 208000000172 Medulloblastoma Diseases 0.000 claims description 5
• 125000004702 alkoxy alkyl carbonyl group Chemical group 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 229930195733 hydrocarbon Natural products 0.000 claims description 5
• 206010027191 meningioma Diseases 0.000 claims description 5
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 4
• 208000026310 Breast neoplasm Diseases 0.000 claims description 4
• 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 4
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
• 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
• 125000004689 alkyl amino carbonyl alkyl group Chemical group 0.000 claims description 4
• 206010017758 gastric cancer Diseases 0.000 claims description 4
• 230000003993 interaction Effects 0.000 claims description 4
• 230000001404 mediated effect Effects 0.000 claims description 4
• 201000001441 melanoma Diseases 0.000 claims description 4
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
• 208000000587 small cell lung carcinoma Diseases 0.000 claims description 4
• 201000011549 stomach cancer Diseases 0.000 claims description 4
• 229910052717 sulfur Inorganic materials 0.000 claims description 4
• 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 3
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 3
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
• 206010004593 Bile duct cancer Diseases 0.000 claims description 3
• 206010009944 Colon cancer Diseases 0.000 claims description 3
• 206010033128 Ovarian cancer Diseases 0.000 claims description 3
• 206010041067 Small cell lung cancer Diseases 0.000 claims description 3
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
• 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 3
• 208000005017 glioblastoma Diseases 0.000 claims description 3
• 125000005059 halophenyl group Chemical group 0.000 claims description 3
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
• 210000004498 neuroglial cell Anatomy 0.000 claims description 3
• 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
• 230000002062 proliferating effect Effects 0.000 claims description 3
• 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
• 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 2
• 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 2
• 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 2
• 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 2
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
• 208000017897 Carcinoma of esophagus Diseases 0.000 claims description 2
• 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
• 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
• 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
• 206010060862 Prostate cancer Diseases 0.000 claims description 2
• 208000006990 cholangiocarcinoma Diseases 0.000 claims description 2
• 208000029742 colonic neoplasm Diseases 0.000 claims description 2
• 125000006317 cyclopropyl amino group Chemical group 0.000 claims description 2
• 201000004101 esophageal cancer Diseases 0.000 claims description 2
• 201000002528 pancreatic cancer Diseases 0.000 claims description 2
• 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
• 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
• 241001024304 Mino Species 0.000 claims 6
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 5
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 5
• RRWDWFMHSVCNNM-UHFFFAOYSA-N n-[2-methyl-5-(morpholin-4-ylmethyl)phenyl]benzamide Chemical compound C1=C(NC(=O)C=2C=CC=CC=2)C(C)=CC=C1CN1CCOCC1 RRWDWFMHSVCNNM-UHFFFAOYSA-N 0.000 claims 4
• 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims 2
• 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims 2
• 241000027355 Ferocactus setispinus Species 0.000 claims 2
• 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims 2
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 2
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 2
• 229910052760 oxygen Inorganic materials 0.000 claims 2
• 239000001301 oxygen Substances 0.000 claims 2
• 239000011593 sulfur Substances 0.000 claims 2
• TXBIICIGOXHJDJ-UHFFFAOYSA-N 1-[[4-methyl-3-[[4-[(4-phenylquinazolin-2-yl)amino]benzoyl]amino]phenyl]methyl]azetidine-3-carboxylic acid Chemical compound C1=C(NC(=O)C=2C=CC(NC=3N=C4C=CC=CC4=C(C=4C=CC=CC=4)N=3)=CC=2)C(C)=CC=C1CN1CC(C(O)=O)C1 TXBIICIGOXHJDJ-UHFFFAOYSA-N 0.000 claims 1
• QRGQGYNVGTXUJG-UHFFFAOYSA-N 4-[[4-(4-chlorophenyl)quinazolin-2-yl]amino]-n-[5-[(dimethylamino)methyl]-2-methylphenyl]benzamide Chemical compound CN(C)CC1=CC=C(C)C(NC(=O)C=2C=CC(NC=3N=C4C=CC=CC4=C(C=4C=CC(Cl)=CC=4)N=3)=CC=2)=C1 QRGQGYNVGTXUJG-UHFFFAOYSA-N 0.000 claims 1
• 206010006187 Breast cancer Diseases 0.000 claims 1
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• 125000005084 alkoxyalkylaminoalkyl group Chemical group 0.000 claims 1
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• KLRRGBHZCJLIEL-UHFFFAOYSA-N n-[2-methyl-5-(methylaminomethyl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide Chemical compound CNCC1=CC=C(C)C(NC(=O)C=2C=CC(NC=3N=C4C=CC=CC4=C(C=4C=CC=CC=4)N=3)=CC=2)=C1 KLRRGBHZCJLIEL-UHFFFAOYSA-N 0.000 claims 1
• VWVNEVNBFBKBAS-UHFFFAOYSA-N n-[2-methyl-5-(morpholin-4-ylmethyl)phenyl]-4-[(4-morpholin-4-ylquinazolin-2-yl)amino]benzamide Chemical compound C1=C(NC(=O)C=2C=CC(NC=3N=C4C=CC=CC4=C(N4CCOCC4)N=3)=CC=2)C(C)=CC=C1CN1CCOCC1 VWVNEVNBFBKBAS-UHFFFAOYSA-N 0.000 claims 1
• SNQWXWNQJJRRDI-UHFFFAOYSA-N n-[2-methyl-5-(morpholin-4-ylmethyl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide Chemical compound C1=C(NC(=O)C=2C=CC(NC=3N=C4C=CC=CC4=C(C=4C=CC=CC=4)N=3)=CC=2)C(C)=CC=C1CN1CCOCC1 SNQWXWNQJJRRDI-UHFFFAOYSA-N 0.000 claims 1
• KGMZVEXWCHZPGE-UHFFFAOYSA-N n-[3-(azepan-1-ylmethyl)-2-methylphenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide Chemical compound C1=CC=C(NC(=O)C=2C=CC(NC=3N=C4C=CC=CC4=C(C=4C=CC=CC=4)N=3)=CC=2)C(C)=C1CN1CCCCCC1 KGMZVEXWCHZPGE-UHFFFAOYSA-N 0.000 claims 1
• MUUQQJCYXFFKIJ-UHFFFAOYSA-N n-[5-[(cyclopentylamino)methyl]-2-methylphenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide Chemical compound C1=C(NC(=O)C=2C=CC(NC=3N=C4C=CC=CC4=C(C=4C=CC=CC=4)N=3)=CC=2)C(C)=CC=C1CNC1CCCC1 MUUQQJCYXFFKIJ-UHFFFAOYSA-N 0.000 claims 1
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• 230000008520 organization Effects 0.000 claims 1
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• 239000002904 solvent Substances 0.000 description 51
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