KR20090130051A - 헤지호그 경로의 억제제 - Google Patents

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Publication number

KR20090130051A

KR20090130051A KR1020097021413A KR20097021413A KR20090130051A KR 20090130051 A KR20090130051 A KR 20090130051A KR 1020097021413 A KR1020097021413 A KR 1020097021413A KR 20097021413 A KR20097021413 A KR 20097021413A KR 20090130051 A KR20090130051 A KR 20090130051A

Authority

KR

South Korea

Prior art keywords

substituted

alkyl

formula

unsubstituted

compounds

Prior art date

2007-03-14

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Ceased

Links

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• 230000037361 pathway Effects 0.000 title claims description 25
• 239000003112 inhibitor Substances 0.000 title description 2
• 241000289669 Erinaceus europaeus Species 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 823
• 150000003839 salts Chemical class 0.000 claims abstract description 98
• 239000012453 solvate Substances 0.000 claims abstract description 80
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 53
• 238000000034 method Methods 0.000 claims abstract description 38
• 201000011510 cancer Diseases 0.000 claims abstract description 35
• 238000004519 manufacturing process Methods 0.000 claims abstract description 4
• 125000000217 alkyl group Chemical group 0.000 claims description 602
• -1 Pyrido [3,2- d ] pyrimidinyl Chemical group 0.000 claims description 449
• 229910052739 hydrogen Inorganic materials 0.000 claims description 319
• 239000001257 hydrogen Substances 0.000 claims description 319
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 222
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 215
• 125000001072 heteroaryl group Chemical group 0.000 claims description 174
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 173
• 239000000543 intermediate Substances 0.000 claims description 128
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 102
• 150000002431 hydrogen Chemical class 0.000 claims description 94
• CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 93
• 125000003545 alkoxy group Chemical group 0.000 claims description 89
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 89
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 85
• 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 72
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 68
• 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 65
• 125000003282 alkyl amino group Chemical group 0.000 claims description 55
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 55
• 125000001188 haloalkyl group Chemical group 0.000 claims description 53
• 239000000203 mixture Substances 0.000 claims description 53
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 47
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 45
• 125000003884 phenylalkyl group Chemical group 0.000 claims description 41
• 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 39
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 37
• 229910052757 nitrogen Inorganic materials 0.000 claims description 36
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 34
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 33
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 32
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 31
• 201000010099 disease Diseases 0.000 claims description 30
• 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 29
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 26
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 20
• 125000005122 aminoalkylamino group Chemical group 0.000 claims description 19
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 19
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 18
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
• 150000004677 hydrates Chemical class 0.000 claims description 17
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 17
• 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 17
• 125000004432 carbon atom Chemical group C* 0.000 claims description 14
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 14
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
• 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 13
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 9
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 9
• 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 9
• 125000005059 halophenyl group Chemical group 0.000 claims description 9
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 9
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
• 108090000623 proteins and genes Proteins 0.000 claims description 8
• 239000003085 diluting agent Substances 0.000 claims description 7
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• 125000002431 aminoalkoxy group Chemical group 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 206010004146 Basal cell carcinoma Diseases 0.000 claims description 5
• 208000000172 Medulloblastoma Diseases 0.000 claims description 5
• 208000034578 Multiple myelomas Diseases 0.000 claims description 5
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 5
• 206010027191 meningioma Diseases 0.000 claims description 5
• 102000004169 proteins and genes Human genes 0.000 claims description 5
• 206010006187 Breast cancer Diseases 0.000 claims description 4
• 208000026310 Breast neoplasm Diseases 0.000 claims description 4
• 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 4
• 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 4
• 125000004689 alkyl amino carbonyl alkyl group Chemical group 0.000 claims description 4
• 208000006990 cholangiocarcinoma Diseases 0.000 claims description 4
• 201000004101 esophageal cancer Diseases 0.000 claims description 4
• 201000001441 melanoma Diseases 0.000 claims description 4
• 206010009944 Colon cancer Diseases 0.000 claims description 3
• 206010060862 Prostate cancer Diseases 0.000 claims description 3
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
• 206010041067 Small cell lung cancer Diseases 0.000 claims description 3
• 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
• 201000008275 breast carcinoma Diseases 0.000 claims description 3
• 208000029742 colonic neoplasm Diseases 0.000 claims description 3
• 206010017758 gastric cancer Diseases 0.000 claims description 3
• 208000005017 glioblastoma Diseases 0.000 claims description 3
• 230000001404 mediated effect Effects 0.000 claims description 3
• 230000002062 proliferating effect Effects 0.000 claims description 3
• 208000000587 small cell lung carcinoma Diseases 0.000 claims description 3
• 201000011549 stomach cancer Diseases 0.000 claims description 3
• 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
• 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
• WWYGEUICRXRWNI-UHFFFAOYSA-N n-[3-(morpholin-4-ylmethyl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide Chemical compound C=1C=C(NC=2N=C3C=CC=CC3=C(C=3C=CC=CC=3)N=2)C=CC=1C(=O)NC(C=1)=CC=CC=1CN1CCOCC1 WWYGEUICRXRWNI-UHFFFAOYSA-N 0.000 claims description 2
• NNUMAPVWRCYJDV-UHFFFAOYSA-N n-[3-[(dimethylamino)methyl]phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide Chemical compound CN(C)CC1=CC=CC(NC(=O)C=2C=CC(NC=3N=C4C=CC=CC4=C(C=4C=CC=CC=4)N=3)=CC=2)=C1 NNUMAPVWRCYJDV-UHFFFAOYSA-N 0.000 claims description 2
• 208000002154 non-small cell lung carcinoma 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
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 12
• 125000001475 halogen functional group Chemical group 0.000 claims 10
• 241000027355 Ferocactus setispinus Species 0.000 claims 1
• MERMDERGCWGOOJ-UHFFFAOYSA-N n-(2,6-dimethylphenyl)-4-[(4-phenyl-6,7-dihydro-5h-cyclopenta[d]pyrimidin-2-yl)amino]benzamide Chemical compound CC1=CC=CC(C)=C1NC(=O)C(C=C1)=CC=C1NC(N=C1C=2C=CC=CC=2)=NC2=C1CCC2 MERMDERGCWGOOJ-UHFFFAOYSA-N 0.000 claims 1
• YDQROWJJXAJHKS-UHFFFAOYSA-N n-[2-methyl-5-(morpholin-4-ylmethyl)phenyl]-4-[(4-phenylpyrido[2,3-d]pyrimidin-2-yl)amino]benzamide Chemical compound C1=C(NC(=O)C=2C=CC(NC=3N=C4N=CC=CC4=C(C=4C=CC=CC=4)N=3)=CC=2)C(C)=CC=C1CN1CCOCC1 YDQROWJJXAJHKS-UHFFFAOYSA-N 0.000 claims 1
• 210000004498 neuroglial cell Anatomy 0.000 claims 1
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 165
• 238000005481 NMR spectroscopy Methods 0.000 description 142
• 125000005843 halogen group Chemical group 0.000 description 102
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 59
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 58
• 239000002904 solvent Substances 0.000 description 52
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 41
• 125000003118 aryl group Chemical group 0.000 description 37
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 33
• 239000007787 solid Substances 0.000 description 33
• 239000000243 solution Substances 0.000 description 31
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
• 125000004076 pyridyl group Chemical group 0.000 description 25
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
• 238000005160 1H NMR spectroscopy Methods 0.000 description 23
• 210000004027 cell Anatomy 0.000 description 19
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
• 125000003342 alkenyl group Chemical group 0.000 description 17
• 239000011541 reaction mixture Substances 0.000 description 17
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 16
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
• 238000006243 chemical reaction Methods 0.000 description 15
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
• 125000000304 alkynyl group Chemical group 0.000 description 13
• 230000002829 reductive effect Effects 0.000 description 13
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
• 239000007821 HATU Substances 0.000 description 12
• 229910052799 carbon Inorganic materials 0.000 description 12
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
• 230000000694 effects Effects 0.000 description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
• YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical group OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 12
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• 244000060234 Gmelina philippensis Species 0.000 description 11
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• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 10
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• 229910052740 iodine Inorganic materials 0.000 description 9
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