CN110891953A - 吡咯并三嗪类衍生物、其制备方法及其用途 - Google Patents
吡咯并三嗪类衍生物、其制备方法及其用途 Download PDFInfo
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- CN110891953A CN110891953A CN201880047124.1A CN201880047124A CN110891953A CN 110891953 A CN110891953 A CN 110891953A CN 201880047124 A CN201880047124 A CN 201880047124A CN 110891953 A CN110891953 A CN 110891953A
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- alkyl
- pharmaceutically acceptable
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000003921 pyrrolotriazines Chemical class 0.000 title abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 96
- 239000003814 drug Substances 0.000 claims abstract description 15
- 239000003112 inhibitor Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 236
- 238000006243 chemical reaction Methods 0.000 claims description 118
- 125000000217 alkyl group Chemical group 0.000 claims description 102
- 125000000623 heterocyclic group Chemical group 0.000 claims description 81
- -1 boronic acid ester Chemical class 0.000 claims description 73
- 125000003118 aryl group Chemical group 0.000 claims description 61
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 60
- 229910052736 halogen Inorganic materials 0.000 claims description 54
- 150000002367 halogens Chemical class 0.000 claims description 54
- 125000001072 heteroaryl group Chemical group 0.000 claims description 53
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 42
- 125000003545 alkoxy group Chemical group 0.000 claims description 37
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 31
- 125000002947 alkylene group Chemical group 0.000 claims description 27
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 25
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims description 22
- 238000004519 manufacturing process Methods 0.000 claims description 22
- 239000007818 Grignard reagent Substances 0.000 claims description 21
- 150000004795 grignard reagents Chemical class 0.000 claims description 21
- 230000035772 mutation Effects 0.000 claims description 21
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 20
- 201000008736 Systemic mastocytosis Diseases 0.000 claims description 18
- 125000000539 amino acid group Chemical group 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 14
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 230000001404 mediated effect Effects 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000004450 alkenylene group Chemical group 0.000 claims description 9
- 230000002378 acidificating effect Effects 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 7
- 208000007033 Dysgerminoma Diseases 0.000 claims description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- 201000010208 Seminoma Diseases 0.000 claims description 7
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 7
- 201000010881 cervical cancer Diseases 0.000 claims description 7
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 7
- 208000000516 mast-cell leukemia Diseases 0.000 claims description 7
- 201000001441 melanoma Diseases 0.000 claims description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 206010043276 Teratoma Diseases 0.000 claims description 6
- 125000004419 alkynylene group Chemical group 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 229910052701 rubidium Inorganic materials 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 239000002253 acid Chemical class 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical class OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 3
- 150000007942 carboxylates Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 5
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 21
- 229940079593 drug Drugs 0.000 abstract description 5
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 156
- 125000004432 carbon atom Chemical group C* 0.000 description 119
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 105
- 239000012074 organic phase Substances 0.000 description 84
- 239000000243 solution Substances 0.000 description 82
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 79
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 72
- 239000007787 solid Substances 0.000 description 71
- 229920006395 saturated elastomer Polymers 0.000 description 69
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 65
- 239000003480 eluent Substances 0.000 description 60
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 55
- 239000011780 sodium chloride Substances 0.000 description 52
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- 229910052786 argon Inorganic materials 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 29
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 28
- 239000005457 ice water Substances 0.000 description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- 238000012360 testing method Methods 0.000 description 21
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 20
- 229910000024 caesium carbonate Inorganic materials 0.000 description 20
- 239000012300 argon atmosphere Substances 0.000 description 19
- 239000007864 aqueous solution Substances 0.000 description 18
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- 235000019270 ammonium chloride Nutrition 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
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- 210000004027 cell Anatomy 0.000 description 13
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- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
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- 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
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- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
公开了吡咯并三嗪类衍生物、其制备方法及其在医药上的应用。具体而言，公开了式(I)的吡咯并三嗪类衍生物及其药学上可接受的盐、其制备方法以及它们作为治疗剂，特别是c‑KIT抑制剂的用途，其中式(I)中的各取代基的定义与说明书中的定义相同。
Description
PCT国内申请，说明书已公开。
Claims (30)
- PCT国内申请，权利要求书已公开。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710713815.8A CN109400610A (zh) | 2017-08-18 | 2017-08-18 | 吡咯并三嗪类衍生物、其制备方法及其在医药上的用途 |
| CN2017107138158 | 2017-08-18 | ||
| PCT/CN2018/100901 WO2019034128A1 (zh) | 2017-08-18 | 2018-08-16 | 吡咯并三嗪类衍生物、其制备方法及其用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110891953A true CN110891953A (zh) | 2020-03-17 |
| CN110891953B CN110891953B (zh) | 2022-07-12 |
Family
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710713815.8A Pending CN109400610A (zh) | 2017-08-18 | 2017-08-18 | 吡咯并三嗪类衍生物、其制备方法及其在医药上的用途 |
| CN201880047124.1A Active CN110891953B (zh) | 2017-08-18 | 2018-08-16 | 吡咯并三嗪类衍生物、其制备方法及其用途 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710713815.8A Pending CN109400610A (zh) | 2017-08-18 | 2017-08-18 | 吡咯并三嗪类衍生物、其制备方法及其在医药上的用途 |
Country Status (3)
| Country | Link |
|---|---|
| CN (2) | CN109400610A (zh) |
| TW (1) | TWI694078B (zh) |
| WO (1) | WO2019034128A1 (zh) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2923888T3 (es) | 2013-10-17 | 2022-10-03 | Blueprint Medicines Corp | Procedimiento para preparar composiciones útiles para tratar trastornos relacionados con la KIT |
| US11040979B2 (en) | 2017-03-31 | 2021-06-22 | Blueprint Medicines Corporation | Substituted pyrrolo[1,2-b]pyridazines for treating disorders related to KIT and PDGFR |
| EA202192575A1 (ru) | 2019-03-21 | 2022-01-14 | Онксео | Соединения dbait в сочетании с ингибиторами киназ для лечения рака |
| HRP20231533T1 (hr) | 2019-04-12 | 2024-03-01 | Blueprint Medicines Corporation | Kristalni oblici od (s)-1-(4-fluorofenil)-1-(2-(4-(6-(1-metil-1h-pirazol-4-il)pirolo[2,1-f][1,2,4 ]triazin-4-il)piperazinil)-pirimidin-5-il)etan-1-amina i postupci priprave |
| EP3953357B1 (en) | 2019-04-12 | 2024-04-17 | Blueprint Medicines Corporation | Pyrrolotriazine derivatives for treating kit- and pdgfra-mediated diseases |
| CN112480116B (zh) * | 2019-09-11 | 2024-03-29 | 南京正大天晴制药有限公司 | Pkb抑制剂 |
| EP4054579A1 (en) | 2019-11-08 | 2022-09-14 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Methods for the treatment of cancers that have acquired resistance to kinase inhibitors |
| CN113150012B (zh) * | 2020-01-22 | 2023-03-24 | 浙江海正药业股份有限公司 | 吡唑并[1,5-a]吡嗪类衍生物及其制备方法和用途 |
| WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
| CN117098760A (zh) | 2020-10-14 | 2023-11-21 | 缆图药品公司 | 用于治疗kit和pdgfra介导的疾病的组合物和方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015134536A1 (en) * | 2014-03-04 | 2015-09-11 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
| CN104981247A (zh) * | 2012-09-06 | 2015-10-14 | 普莱希科公司 | 用于激酶调节的化合物和方法及其适应症 |
| CN105745209A (zh) * | 2013-09-05 | 2016-07-06 | 豪夫迈·罗氏有限公司 | 三唑并吡啶化合物、组合物及其使用方法 |
-
2017
- 2017-08-18 CN CN201710713815.8A patent/CN109400610A/zh active Pending
-
2018
- 2018-08-16 WO PCT/CN2018/100901 patent/WO2019034128A1/zh active Application Filing
- 2018-08-16 CN CN201880047124.1A patent/CN110891953B/zh active Active
- 2018-08-17 TW TW107128763A patent/TWI694078B/zh active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104981247A (zh) * | 2012-09-06 | 2015-10-14 | 普莱希科公司 | 用于激酶调节的化合物和方法及其适应症 |
| CN105745209A (zh) * | 2013-09-05 | 2016-07-06 | 豪夫迈·罗氏有限公司 | 三唑并吡啶化合物、组合物及其使用方法 |
| WO2015134536A1 (en) * | 2014-03-04 | 2015-09-11 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109400610A (zh) | 2019-03-01 |
| TW201912645A (zh) | 2019-04-01 |
| CN110891953B (zh) | 2022-07-12 |
| TWI694078B (zh) | 2020-05-21 |
| WO2019034128A1 (zh) | 2019-02-21 |
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