CA3210320A1 - Synthesis of a bruton's tyrosine kinase inhibitor - Google Patents
Synthesis of a bruton's tyrosine kinase inhibitorInfo
- Publication number
- CA3210320A1 CA3210320A1 CA3210320A CA3210320A CA3210320A1 CA 3210320 A1 CA3210320 A1 CA 3210320A1 CA 3210320 A CA3210320 A CA 3210320A CA 3210320 A CA3210320 A CA 3210320A CA 3210320 A1 CA3210320 A1 CA 3210320A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- formula
- ibrutinib
- amino
- pyrazolo
- Prior art date
- 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.)
- Pending
Links
- 238000003786 synthesis reaction Methods 0.000 title abstract description 9
- 230000015572 biosynthetic process Effects 0.000 title abstract description 7
- 229940125814 BTK kinase inhibitor Drugs 0.000 title abstract description 4
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims abstract description 62
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims description 389
- 238000000034 method Methods 0.000 claims description 284
- 230000008569 process Effects 0.000 claims description 272
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 claims description 186
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 claims description 185
- 229960001507 ibrutinib Drugs 0.000 claims description 185
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 102
- 238000002360 preparation method Methods 0.000 claims description 93
- 229910052736 halogen Inorganic materials 0.000 claims description 82
- 150000002367 halogens Chemical class 0.000 claims description 82
- 239000002904 solvent Substances 0.000 claims description 76
- 238000006243 chemical reaction Methods 0.000 claims description 44
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 35
- 238000003379 elimination reaction Methods 0.000 claims description 32
- 125000006239 protecting group Chemical group 0.000 claims description 32
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 30
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical group CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 20
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical group [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 19
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 17
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- 230000010933 acylation Effects 0.000 claims description 15
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- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 12
- 239000000654 additive Substances 0.000 claims description 11
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 10
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- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
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- 238000009833 condensation Methods 0.000 claims description 5
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- 159000000021 acetate salts Chemical class 0.000 claims description 4
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- 230000003197 catalytic effect Effects 0.000 claims description 4
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 3
- UYCAUPASBSROMS-AWQJXPNKSA-M sodium;2,2,2-trifluoroacetate Chemical group [Na+].[O-][13C](=O)[13C](F)(F)F UYCAUPASBSROMS-AWQJXPNKSA-M 0.000 claims description 3
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical group C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
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- 238000005406 washing Methods 0.000 claims 1
- 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 59
- -1 -B(0R5)2 Chemical class 0.000 description 50
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 35
- 239000002253 acid Substances 0.000 description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 31
- 239000000203 mixture Substances 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 25
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 239000012141 concentrate Substances 0.000 description 15
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- 239000010949 copper Substances 0.000 description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- 229910052802 copper Inorganic materials 0.000 description 12
- 229910052759 nickel Inorganic materials 0.000 description 12
- 229910052763 palladium Inorganic materials 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 229910052719 titanium Inorganic materials 0.000 description 12
- 239000010936 titanium Substances 0.000 description 12
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 11
- 235000015165 citric acid Nutrition 0.000 description 11
- 230000008878 coupling Effects 0.000 description 11
- 238000010168 coupling process Methods 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 11
- 229910000029 sodium carbonate Inorganic materials 0.000 description 11
- 235000017550 sodium carbonate Nutrition 0.000 description 11
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 10
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 10
- 150000007529 inorganic bases Chemical class 0.000 description 10
- UYCAUPASBSROMS-UHFFFAOYSA-M sodium;2,2,2-trifluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)F UYCAUPASBSROMS-UHFFFAOYSA-M 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical class CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 9
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 125000002947 alkylene group Chemical group 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 8
- 235000021317 phosphate Nutrition 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical class COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
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- 238000004611 spectroscopical analysis Methods 0.000 description 4
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- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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| US201562103507P | 2015-01-14 | 2015-01-14 | |
| US62/103,507 | 2015-01-14 | ||
| CA2971460A CA2971460C (en) | 2015-01-14 | 2016-01-14 | Synthesis of a bruton's tyrosine kinase inhibitor |
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| CA2971460A Division CA2971460C (en) | 2015-01-14 | 2016-01-14 | Synthesis of a bruton's tyrosine kinase inhibitor |
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| CA3210320A1 true CA3210320A1 (en) | 2016-07-21 |
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| CA3210320A Pending CA3210320A1 (en) | 2015-01-14 | 2016-01-14 | Synthesis of a bruton's tyrosine kinase inhibitor |
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| CA2971460A Active CA2971460C (en) | 2015-01-14 | 2016-01-14 | Synthesis of a bruton's tyrosine kinase inhibitor |
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| EP (1) | EP3245208A4 (enExample) |
| JP (2) | JP2018502077A (enExample) |
| KR (1) | KR20170102887A (enExample) |
| CN (2) | CN113816962A (enExample) |
| AU (2) | AU2016206693A1 (enExample) |
| BR (1) | BR112017015206B1 (enExample) |
| CA (2) | CA2971460C (enExample) |
| HK (1) | HK1246293A1 (enExample) |
| IL (4) | IL322449A (enExample) |
| MA (1) | MA41350A (enExample) |
| MX (2) | MX394327B (enExample) |
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| ZA (1) | ZA201704338B (enExample) |
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| CN107207519B (zh) * | 2015-02-12 | 2019-11-08 | 正大天晴药业集团股份有限公司 | 伊布替尼的制备方法 |
| EP3424505A4 (en) | 2016-03-04 | 2019-10-16 | Taiho Pharmaceutical Co., Ltd. | PREPARATION AND COMPOSITION FOR THE TREATMENT OF MALIGNANT TUMORS |
| US11883404B2 (en) | 2016-03-04 | 2024-01-30 | Taiho Pharmaceuticals Co., Ltd. | Preparation and composition for treatment of malignant tumors |
| CN109206426B (zh) * | 2017-07-06 | 2021-10-08 | 上海复星星泰医药科技有限公司 | 吡唑并嘧啶类化合物的制备方法 |
| EP3661939B1 (en) | 2017-08-01 | 2021-07-21 | Boehringer Ingelheim International GmbH | Intermediate compounds and methods |
| CN107814804A (zh) * | 2017-10-27 | 2018-03-20 | 广州科锐特生物科技有限公司 | 依鲁替尼的制备方法 |
| TWI790364B (zh) | 2018-03-19 | 2023-01-21 | 日商大鵬藥品工業股份有限公司 | 包含烷基硫酸鈉之醫藥組合物 |
| MX2020011527A (es) | 2018-05-03 | 2021-02-26 | Juno Therapeutics Inc | Terapia de combinación de una terapia de células t-receptor de antígeno quimérico (car) y un inhibidor de cinasa. |
| JP6944496B2 (ja) | 2018-10-22 | 2021-10-06 | ファイザー・インク | ピロロ［２，３−ｄ］ピリミジントシル酸塩、その結晶形態、ならびにその製造方法および中間体 |
| WO2020095452A1 (ja) | 2018-11-09 | 2020-05-14 | 大鵬薬品工業株式会社 | ジメトキシベンゼン化合物の製造方法 |
| CN109988175A (zh) * | 2019-04-28 | 2019-07-09 | 梯尔希（南京）药物研发有限公司 | 一种依鲁替尼-d5的制备方法 |
| MX2021014245A (es) | 2019-05-21 | 2022-01-06 | Janssen Pharmaceutica Nv | Procedimientos y productos intermedios para preparar un inhibidor de btk. |
| JP7658916B2 (ja) * | 2019-05-21 | 2025-04-08 | ヤンセン ファーマシューティカ エヌ．ベー． | Ｂｔｋ阻害剤を調製するためのプロセス及び中間体 |
| US20240092785A1 (en) | 2021-01-21 | 2024-03-21 | Synthon B.V. | Process for making ibrutinib |
| CN114853662B (zh) * | 2021-02-05 | 2024-01-12 | 四川青木制药有限公司 | 手性肼基哌啶衍生物的制备方法 |
| US20250302954A1 (en) | 2022-05-11 | 2025-10-02 | Celgene Corporation | Methods to overcome drug resistance by re-sensitizing cancer cells to treatment with a prior therapy via treatment with a t cell therapy |
| WO2023242384A1 (en) | 2022-06-17 | 2023-12-21 | Krka, D.D., Novo Mesto | Crystalline form of ibrutinib |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4550214A (en) * | 1981-01-05 | 1985-10-29 | Polaroid Corporation | Blocked vinyl biphenyl compounds |
| US4874822A (en) * | 1988-04-07 | 1989-10-17 | Minnesota Mining And Manufacturing Company | Process for the acrylamidoacylation of alcohols |
| KR101164258B1 (ko) * | 2003-12-23 | 2012-07-11 | 아스텍스 테라퓨틱스 리미티드 | 단백질 키나아제 조절제로서의 피라졸 유도체 |
| NZ601278A (en) * | 2006-09-22 | 2013-09-27 | Pharmacyclics Inc | Inhibitors of Bruton's tyrosine kinase |
| CN103319488A (zh) * | 2007-03-28 | 2013-09-25 | 环状药物公司 | 布鲁顿氏酪氨酸激酶抑制剂 |
| US7741330B1 (en) * | 2009-10-12 | 2010-06-22 | Pharmacyclics, Inc. | Pyrazolo-pyrimidine inhibitors of Bruton's tyrosine kinase |
| EA201590296A1 (ru) * | 2012-07-30 | 2015-07-30 | Консерт Фармасьютикалс Инк. | Дейтерированный ибрутиниб |
| CN103121999A (zh) * | 2012-08-29 | 2013-05-29 | 苏州迪飞医药科技有限公司 | 一种酪氨酸激酶抑制剂pci-32765的合成方法 |
| US9156847B2 (en) * | 2013-03-15 | 2015-10-13 | Janssen Pharmaceutica Nv | Processes and intermediates for preparing a medicament |
| US8957080B2 (en) * | 2013-04-09 | 2015-02-17 | Principia Biopharma Inc. | Tyrosine kinase inhibitors |
| CN103626774B (zh) * | 2013-11-20 | 2015-11-04 | 苏州明锐医药科技有限公司 | 伊鲁替尼的制备方法 |
| CN105471823B (zh) * | 2014-09-03 | 2018-10-26 | 阿里巴巴集团控股有限公司 | 一种敏感信息处理方法、装置、服务器及安全判定系统 |
| WO2016115869A1 (zh) * | 2015-01-21 | 2016-07-28 | 中国科学院合肥物质科学研究院 | Flt3激酶的新型抑制剂及其用途 |
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