JP2020519589A - Ｇ１２ｃ変異型ｒａｓタンパク質を阻害するヘテロアリール化合物 - Google Patents
Ｇ１２ｃ変異型ｒａｓタンパク質を阻害するヘテロアリール化合物 Download PDFInfo
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- JP2020519589A JP2020519589A JP2019561278A JP2019561278A JP2020519589A JP 2020519589 A JP2020519589 A JP 2020519589A JP 2019561278 A JP2019561278 A JP 2019561278A JP 2019561278 A JP2019561278 A JP 2019561278A JP 2020519589 A JP2020519589 A JP 2020519589A
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- alkyl
- hydroxy
- halo
- heteroaryl
- heterocyclyl
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- 125000001072 heteroaryl group Chemical group 0.000 title claims description 199
- 102000016914 ras Proteins Human genes 0.000 title description 40
- 108010014186 ras Proteins Proteins 0.000 title description 36
- 102200006538 rs121913530 Human genes 0.000 title description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 262
- 150000003839 salts Chemical class 0.000 claims abstract description 119
- 238000000034 method Methods 0.000 claims abstract description 50
- 238000011282 treatment Methods 0.000 claims abstract description 47
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 298
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 250
- 125000005843 halogen group Chemical group 0.000 claims description 241
- 125000000623 heterocyclic group Chemical group 0.000 claims description 213
- 125000001424 substituent group Chemical group 0.000 claims description 208
- 125000003545 alkoxy group Chemical group 0.000 claims description 192
- -1 cyano, acetylenyl Chemical group 0.000 claims description 171
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 150
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 127
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 111
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 101
- 229910052739 hydrogen Inorganic materials 0.000 claims description 54
- 229910052757 nitrogen Inorganic materials 0.000 claims description 54
- 229910052799 carbon Inorganic materials 0.000 claims description 51
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 40
- 206010028980 Neoplasm Diseases 0.000 claims description 36
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 35
- 241001465754 Metazoa Species 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 125000001153 fluoro group Chemical group F* 0.000 claims description 23
- 201000011510 cancer Diseases 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
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- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 10
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- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 claims description 8
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 7
- 206010009944 Colon cancer Diseases 0.000 claims description 6
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- 230000000996 additive effect Effects 0.000 claims description 6
- 230000001404 mediated effect Effects 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
- 241000282412 Homo Species 0.000 claims description 5
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- 208000035475 disorder Diseases 0.000 claims description 5
- 229910052727 yttrium Inorganic materials 0.000 claims description 4
- 102200006614 rs104894229 Human genes 0.000 claims 2
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- 230000008569 process Effects 0.000 abstract description 8
- 239000000543 intermediate Substances 0.000 abstract description 4
- 230000002062 proliferating effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 219
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 204
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 155
- 239000000203 mixture Substances 0.000 description 138
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 130
- 238000005160 1H NMR spectroscopy Methods 0.000 description 91
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 91
- 239000007787 solid Substances 0.000 description 81
- 239000011541 reaction mixture Substances 0.000 description 78
- 239000000377 silicon dioxide Substances 0.000 description 76
- 239000000243 solution Substances 0.000 description 75
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 64
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 57
- 235000019439 ethyl acetate Nutrition 0.000 description 57
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 55
- 239000012043 crude product Substances 0.000 description 52
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- 239000002904 solvent Substances 0.000 description 43
- 125000000753 cycloalkyl group Chemical group 0.000 description 40
- LGIBDQRYOFBMTC-UHFFFAOYSA-N dnc010031 Chemical compound C1=CC(O)=CC=C1C1C(=O)NC2=CC=CC=C2C2=C3C1=CNC3=NC=C2 LGIBDQRYOFBMTC-UHFFFAOYSA-N 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 35
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 33
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 32
- 239000012071 phase Substances 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 28
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 26
- 239000000725 suspension Substances 0.000 description 26
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- 230000002829 reductive effect Effects 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000000047 product Substances 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 22
- 101150105104 Kras gene Proteins 0.000 description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 21
- 239000002585 base Substances 0.000 description 19
- 239000003480 eluent Substances 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 19
- 238000002953 preparative HPLC Methods 0.000 description 19
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
- 230000014759 maintenance of location Effects 0.000 description 17
- 238000000746 purification Methods 0.000 description 17
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 101150073096 NRAS gene Proteins 0.000 description 14
- 239000006260 foam Substances 0.000 description 14
- 230000035772 mutation Effects 0.000 description 14
- 210000004881 tumor cell Anatomy 0.000 description 14
- 229910000104 sodium hydride Inorganic materials 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 12
- 230000003247 decreasing effect Effects 0.000 description 12
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 12
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- 125000006239 protecting group Chemical group 0.000 description 12
- 239000012312 sodium hydride Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000010828 elution Methods 0.000 description 11
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 10
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- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 10
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
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- 125000004430 oxygen atom Chemical group O* 0.000 description 9
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- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 9
- 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 8
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- BTSLADGESTVJLG-KRWDZBQOSA-N 1-[(7S)-11-chloro-16-[2-(dimethylamino)ethylamino]-12-(5-methyl-1H-indazol-4-yl)-9-oxa-2,5,15,17-tetrazatetracyclo[8.7.1.02,7.014,18]octadeca-1(17),10,12,14(18),15-pentaen-5-yl]prop-2-en-1-one Chemical compound N(C)(CCNC1=NC2=C3C(=C(C(=C2)C2=C4C(NN=C4)=CC=C2C)Cl)OC[C@H]2N(C3=N1)CCN(C2)C(=O)C=C)C BTSLADGESTVJLG-KRWDZBQOSA-N 0.000 description 4
- QIRZHOHJBWPVGZ-UHFFFAOYSA-N 10-oxa-2,4,11-triazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8,12-hexaene Chemical compound O1NC=CC=2N=CN=C3C=CC=C1C=23 QIRZHOHJBWPVGZ-UHFFFAOYSA-N 0.000 description 4
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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| US201762504638P | 2017-05-11 | 2017-05-11 | |
| US62/504,638 | 2017-05-11 | ||
| PCT/EP2018/061787 WO2018206539A1 (en) | 2017-05-11 | 2018-05-08 | Heteroaryl compounds that inhibit g12c mutant ras proteins |
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| JP2020519589A true JP2020519589A (ja) | 2020-07-02 |
| JP2020519589A5 JP2020519589A5 (https=) | 2021-06-17 |
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| US (2) | US20200109153A1 (https=) |
| EP (1) | EP3621968A1 (https=) |
| JP (1) | JP2020519589A (https=) |
| CN (1) | CN110603258A (https=) |
| AR (1) | AR111776A1 (https=) |
| CA (1) | CA3061650A1 (https=) |
| TW (1) | TW201906848A (https=) |
| WO (1) | WO2018206539A1 (https=) |
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| JP2021532061A (ja) * | 2018-05-08 | 2021-11-25 | アストラゼネカ・アクチエボラーグAstrazeneca Aktiebolag | 四環式ヘテロアリール化合物 |
| JP2024506029A (ja) * | 2021-02-09 | 2024-02-08 | ジェネンテック， インコーポレイテッド | 四環系オキサゼピン化合物及びその使用 |
| JP2024510022A (ja) * | 2021-03-17 | 2024-03-05 | ▲勁▼方医▲薬▼科技（上海）有限公司 | ピリミジン縮合環系化合物、その製造方法、及び使用 |
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| JP2024526295A (ja) * | 2021-07-02 | 2024-07-17 | シャンハイ ドーァ ノボ ファーマテック カンパニー，リミティド | Ｋｒａｓ ｇ１２ｄ阻害剤及びその使用 |
| JP2025525406A (ja) * | 2022-07-05 | 2025-08-05 | ファイザー・インク | ピリド［４，３－ｄ］ピリミジン化合物 |
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| WO2020085504A1 (ja) | 2018-10-26 | 2020-04-30 | 大鵬薬品工業株式会社 | 光照射ザンドマイヤー反応を用いたクロロアゾールカルボキシレート誘導体の製造方法 |
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| KR20220012255A (ko) * | 2019-04-28 | 2022-02-03 | 젠플리트 테라퓨틱스 (상하이) 아이엔씨. | 옥사아자퀴나졸린-7(8h)-케톤 화합물, 이의 제조 방법 및 이의 약학적 응용 |
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| CN112390818B (zh) * | 2019-08-12 | 2023-08-22 | 劲方医药科技(上海)有限公司 | 取代的杂芳环并二氢嘧啶酮衍生物，其制法与医药上的用途 |
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| US20220127281A1 (en) | 2022-04-28 |
| EP3621968A1 (en) | 2020-03-18 |
| CN110603258A (zh) | 2019-12-20 |
| TW201906848A (zh) | 2019-02-16 |
| WO2018206539A1 (en) | 2018-11-15 |
| AR111776A1 (es) | 2019-08-21 |
| CA3061650A1 (en) | 2018-11-15 |
| US20200109153A1 (en) | 2020-04-09 |
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