TW201906848A - 化學化合物 - Google Patents
化學化合物 Download PDFInfo
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- TW201906848A TW201906848A TW107115513A TW107115513A TW201906848A TW 201906848 A TW201906848 A TW 201906848A TW 107115513 A TW107115513 A TW 107115513A TW 107115513 A TW107115513 A TW 107115513A TW 201906848 A TW201906848 A TW 201906848A
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- TW
- Taiwan
- Prior art keywords
- alkyl
- halogen
- heteroaryl
- alkoxy
- compound
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 255
- 150000003839 salts Chemical class 0.000 claims abstract description 118
- 238000000034 method Methods 0.000 claims abstract description 57
- 238000011282 treatment Methods 0.000 claims abstract description 41
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 305
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 258
- -1 cyano, ethynyl Chemical group 0.000 claims description 254
- 229910052736 halogen Inorganic materials 0.000 claims description 225
- 150000002367 halogens Chemical class 0.000 claims description 225
- 125000001424 substituent group Chemical group 0.000 claims description 205
- 125000003545 alkoxy group Chemical group 0.000 claims description 204
- 125000001072 heteroaryl group Chemical group 0.000 claims description 199
- 125000000623 heterocyclic group Chemical group 0.000 claims description 192
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 148
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 144
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 111
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 101
- 229910052757 nitrogen Inorganic materials 0.000 claims description 88
- 229910052799 carbon Inorganic materials 0.000 claims description 76
- 229910052739 hydrogen Inorganic materials 0.000 claims description 55
- 229910052731 fluorine Inorganic materials 0.000 claims description 38
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 37
- 239000011737 fluorine Substances 0.000 claims description 35
- 206010028980 Neoplasm Diseases 0.000 claims description 34
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 34
- 241001465754 Metazoa Species 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 230000035772 mutation Effects 0.000 claims description 22
- 201000011510 cancer Diseases 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000002619 bicyclic group Chemical group 0.000 claims description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000001963 4 membered heterocyclic group Chemical group 0.000 claims description 11
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 11
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- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 10
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 10
- 230000002265 prevention Effects 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 9
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 7
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 7
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 claims description 7
- 206010009944 Colon cancer Diseases 0.000 claims description 6
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- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 claims description 6
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- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 6
- 230000001404 mediated effect Effects 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
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- 102200006614 rs104894229 Human genes 0.000 claims 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 2
- 230000002062 proliferating effect Effects 0.000 abstract 1
- WXLCDTBTIVJDCE-UHFFFAOYSA-N 1,4-oxazepine Chemical compound O1C=CC=NC=C1 WXLCDTBTIVJDCE-UHFFFAOYSA-N 0.000 description 230
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 216
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 198
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 128
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 125
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- 239000000377 silicon dioxide Substances 0.000 description 76
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 61
- 239000000243 solution Substances 0.000 description 61
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 60
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- DCUNRLLJHAWKRZ-UHFFFAOYSA-N 5-methyl-1h-indazole Chemical compound CC1=CC=C2NN=CC2=C1 DCUNRLLJHAWKRZ-UHFFFAOYSA-N 0.000 description 38
- 102000016914 ras Proteins Human genes 0.000 description 38
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- 235000019000 fluorine Nutrition 0.000 description 35
- 108010014186 ras Proteins Proteins 0.000 description 35
- 239000012071 phase Substances 0.000 description 34
- 239000000725 suspension Substances 0.000 description 33
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 30
- 229910052794 bromium Inorganic materials 0.000 description 27
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 27
- 238000000746 purification Methods 0.000 description 27
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 26
- 101150105104 Kras gene Proteins 0.000 description 25
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 25
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 24
- 238000010828 elution Methods 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- 239000003643 water by type Substances 0.000 description 23
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 22
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 22
- 239000000047 product Substances 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 125000005843 halogen group Chemical group 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
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- 230000003247 decreasing effect Effects 0.000 description 18
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 18
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- 230000014759 maintenance of location Effects 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 17
- 238000002953 preparative HPLC Methods 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
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- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 230000002401 inhibitory effect Effects 0.000 description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
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- 229910000104 sodium hydride Inorganic materials 0.000 description 13
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- XMYQHJDBLRZMLW-UHFFFAOYSA-N methanolamine Chemical compound NCO XMYQHJDBLRZMLW-UHFFFAOYSA-N 0.000 description 11
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- HRURFOBSNYPWDM-UHFFFAOYSA-N (5-methyl-1h-indazol-4-yl)boronic acid Chemical compound CC1=CC=C2NN=CC2=C1B(O)O HRURFOBSNYPWDM-UHFFFAOYSA-N 0.000 description 9
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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| US201762504638P | 2017-05-11 | 2017-05-11 | |
| US62/504,638 | 2017-05-11 |
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| TW201906848A true TW201906848A (zh) | 2019-02-16 |
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| TW107115513A TW201906848A (zh) | 2017-05-11 | 2018-05-08 | 化學化合物 |
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| US (2) | US20200109153A1 (enExample) |
| EP (1) | EP3621968A1 (enExample) |
| JP (1) | JP2020519589A (enExample) |
| CN (1) | CN110603258A (enExample) |
| AR (1) | AR111776A1 (enExample) |
| CA (1) | CA3061650A1 (enExample) |
| TW (1) | TW201906848A (enExample) |
| WO (1) | WO2018206539A1 (enExample) |
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|---|---|---|---|---|
| TWI765448B (zh) * | 2019-12-11 | 2022-05-21 | 美商美國禮來大藥廠 | Kras g12c抑制劑 |
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- 2018-05-08 US US16/611,538 patent/US20200109153A1/en not_active Abandoned
- 2018-05-08 WO PCT/EP2018/061787 patent/WO2018206539A1/en not_active Ceased
- 2018-05-08 TW TW107115513A patent/TW201906848A/zh unknown
- 2018-05-08 CA CA3061650A patent/CA3061650A1/en not_active Abandoned
- 2018-05-08 EP EP18728518.4A patent/EP3621968A1/en not_active Withdrawn
- 2018-05-08 CN CN201880030263.3A patent/CN110603258A/zh active Pending
- 2018-05-08 JP JP2019561278A patent/JP2020519589A/ja not_active Withdrawn
-
2021
- 2021-10-05 US US17/449,974 patent/US20220127281A1/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI765448B (zh) * | 2019-12-11 | 2022-05-21 | 美商美國禮來大藥廠 | Kras g12c抑制劑 |
| US11731984B2 (en) | 2019-12-11 | 2023-08-22 | Eli Lilly And Company | KRas G12C inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2018206539A1 (en) | 2018-11-15 |
| US20220127281A1 (en) | 2022-04-28 |
| AR111776A1 (es) | 2019-08-21 |
| CN110603258A (zh) | 2019-12-20 |
| JP2020519589A (ja) | 2020-07-02 |
| EP3621968A1 (en) | 2020-03-18 |
| US20200109153A1 (en) | 2020-04-09 |
| CA3061650A1 (en) | 2018-11-15 |
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