CN112424185A - 含苯环的化合物、其制备方法及应用 - Google Patents
含苯环的化合物、其制备方法及应用 Download PDFInfo
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- CN112424185A CN112424185A CN201980047121.2A CN201980047121A CN112424185A CN 112424185 A CN112424185 A CN 112424185A CN 201980047121 A CN201980047121 A CN 201980047121A CN 112424185 A CN112424185 A CN 112424185A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 730
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 145
- 238000002360 preparation method Methods 0.000 title claims abstract description 117
- 150000003839 salts Chemical class 0.000 claims abstract description 55
- 239000002207 metabolite Substances 0.000 claims abstract description 44
- 239000000651 prodrug Substances 0.000 claims abstract description 43
- 229940002612 prodrug Drugs 0.000 claims abstract description 43
- 239000012453 solvate Substances 0.000 claims abstract description 41
- 239000003814 drug Substances 0.000 claims abstract description 23
- 239000002955 immunomodulating agent Substances 0.000 claims abstract description 10
- 229940121354 immunomodulator Drugs 0.000 claims abstract description 10
- 230000002584 immunomodulator Effects 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 436
- -1 amino, carboxyl Chemical group 0.000 claims description 335
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 184
- 125000005842 heteroatom Chemical group 0.000 claims description 182
- 229910052739 hydrogen Inorganic materials 0.000 claims description 164
- 239000001257 hydrogen Substances 0.000 claims description 164
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 163
- 229910052736 halogen Inorganic materials 0.000 claims description 136
- 150000002367 halogens Chemical class 0.000 claims description 136
- 125000004076 pyridyl group Chemical group 0.000 claims description 123
- 150000003254 radicals Chemical class 0.000 claims description 123
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 113
- 229910052757 nitrogen Inorganic materials 0.000 claims description 102
- 150000002431 hydrogen Chemical class 0.000 claims description 98
- 229910052717 sulfur Inorganic materials 0.000 claims description 92
- 229910052760 oxygen Inorganic materials 0.000 claims description 88
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 74
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 70
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 59
- 125000000623 heterocyclic group Chemical group 0.000 claims description 56
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 52
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 50
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 44
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 44
- 125000002883 imidazolyl group Chemical group 0.000 claims description 43
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 38
- 238000006467 substitution reaction Methods 0.000 claims description 35
- 206010028980 Neoplasm Diseases 0.000 claims description 34
- 125000002541 furyl group Chemical group 0.000 claims description 33
- 125000001072 heteroaryl group Chemical group 0.000 claims description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 30
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 30
- 125000000335 thiazolyl group Chemical group 0.000 claims description 30
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 29
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 29
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- 125000001544 thienyl group Chemical group 0.000 claims description 26
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 25
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 24
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 22
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 claims description 22
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 21
- 125000002619 bicyclic group Chemical group 0.000 claims description 21
- VQNDBXJTIJKJPV-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyridine Chemical class C1=CC=NC2=NNN=C21 VQNDBXJTIJKJPV-UHFFFAOYSA-N 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 19
- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 18
- 125000005605 benzo group Chemical group 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 16
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- 125000001041 indolyl group Chemical group 0.000 claims description 14
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 12
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- 125000003386 piperidinyl group Chemical group 0.000 claims description 12
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 12
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- 201000010099 disease Diseases 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 208000035473 Communicable disease Diseases 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 150000003222 pyridines Chemical class 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 239000012269 PD-1/PD-L1 inhibitor Substances 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 7
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- 229940121653 pd-1/pd-l1 inhibitor Drugs 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 6
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 230000003993 interaction Effects 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 6
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 4
- 239000011630 iodine Substances 0.000 claims 4
- 229910052740 iodine Inorganic materials 0.000 claims 4
- 102000008096 B7-H1 Antigen Human genes 0.000 claims 2
- 230000006806 disease prevention Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 26
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- 230000008901 benefit Effects 0.000 abstract description 6
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 240
- 238000006243 chemical reaction Methods 0.000 description 162
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 129
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 121
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 119
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 116
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 115
- 238000003786 synthesis reaction Methods 0.000 description 115
- 230000015572 biosynthetic process Effects 0.000 description 113
- 239000007787 solid Substances 0.000 description 105
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 101
- 239000000243 solution Substances 0.000 description 79
- 238000003756 stirring Methods 0.000 description 78
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- KLAIOABSDQUNSA-WUKNDPDISA-N 3-[(e)-octadec-2-enyl]oxolane-2,5-dione Chemical compound CCCCCCCCCCCCCCC\C=C\CC1CC(=O)OC1=O KLAIOABSDQUNSA-WUKNDPDISA-N 0.000 description 36
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 33
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Veterinary Medicine (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
一种含苯环的化合物、其制备方法及应用。具体提供了一种如式(I‑0)所示化合物、其药学上可接受的盐、其溶剂合物、其代谢产物、其立体异构体、其互变异构体或其前药。该化合物可用作免疫调节剂，其呈现活性高、药效好、药物稳定、以及可与其它免疫调节剂进行联合用药等优点。
Description
PCT国内申请，说明书已公开。
Claims (25)
- PCT国内申请，权利要求书已公开。
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810771956 | 2018-07-13 | ||
| CN201810771956X | 2018-07-13 | ||
| CN201910064991 | 2019-01-23 | ||
| CN2019100649912 | 2019-01-23 | ||
| PCT/CN2019/095734 WO2020011246A1 (zh) | 2018-07-13 | 2019-07-12 | 含苯环的化合物、其制备方法及应用 |
Publications (2)
| Publication Number | Publication Date |
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| CN112424185A true CN112424185A (zh) | 2021-02-26 |
| CN112424185B CN112424185B (zh) | 2024-05-17 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201980047121.2A Active CN112424185B (zh) | 2018-07-13 | 2019-07-12 | 含苯环的化合物、其制备方法及应用 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN112424185B (zh) |
| WO (1) | WO2020011246A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113189071A (zh) * | 2021-04-29 | 2021-07-30 | 上海交通大学 | 用于完整器官血管三维网络精准成像的试剂盒及成像方法 |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018200571A1 (en) | 2017-04-25 | 2018-11-01 | Arbutus Biopharma Corporation | Substituted 2,3-dihydro-1h-indene analogs and methods using same |
| SG11202007646UA (en) | 2018-02-13 | 2020-09-29 | Gilead Sciences Inc | Pd-1/pd-l1 inhibitors |
| TWI712412B (zh) | 2018-04-19 | 2020-12-11 | 美商基利科學股份有限公司 | Pd‐1/pd‐l1抑制劑 |
| TWI732245B (zh) | 2018-07-13 | 2021-07-01 | 美商基利科學股份有限公司 | Pd‐1/pd‐l1抑制劑 |
| CN112955435A (zh) | 2018-10-24 | 2021-06-11 | 吉利德科学公司 | Pd-1/pd-l1抑制剂 |
| CN112028870B (zh) * | 2019-06-04 | 2021-11-05 | 中国科学院上海药物研究所 | 一种具有苄氧基芳环结构的化合物，其制备方法和用途 |
| US20220305114A1 (en) * | 2019-06-18 | 2022-09-29 | Janssen Sciences Ireland Unlimited Company | Combination of hepatitis b virus (hbv) vaccines and small molecule pdl1 or pd1 inhibitor |
| KR20230030056A (ko) | 2020-05-22 | 2023-03-03 | 알리고스 테라퓨틱스 인코포레이티드 | Pd-l1을 표적화하기 위한 방법 및 조성물 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018026971A1 (en) * | 2016-08-03 | 2018-02-08 | Arising International, Llc | Symmetric or semi-symmetric compounds useful as immunomodulators |
| WO2018045142A1 (en) * | 2016-09-02 | 2018-03-08 | Polaris Pharmaceuticals, Inc. | Immune checkpoint inhibitors, compositions and methods thereof |
| WO2018044963A1 (en) * | 2016-09-01 | 2018-03-08 | Bristol-Myers Squibb Company | Biaryl compounds useful as immunomodulators |
-
2019
- 2019-07-12 CN CN201980047121.2A patent/CN112424185B/zh active Active
- 2019-07-12 WO PCT/CN2019/095734 patent/WO2020011246A1/zh active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018026971A1 (en) * | 2016-08-03 | 2018-02-08 | Arising International, Llc | Symmetric or semi-symmetric compounds useful as immunomodulators |
| WO2018044963A1 (en) * | 2016-09-01 | 2018-03-08 | Bristol-Myers Squibb Company | Biaryl compounds useful as immunomodulators |
| WO2018045142A1 (en) * | 2016-09-02 | 2018-03-08 | Polaris Pharmaceuticals, Inc. | Immune checkpoint inhibitors, compositions and methods thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113189071A (zh) * | 2021-04-29 | 2021-07-30 | 上海交通大学 | 用于完整器官血管三维网络精准成像的试剂盒及成像方法 |
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| Publication number | Publication date |
|---|---|
| CN112424185B (zh) | 2024-05-17 |
| WO2020011246A1 (zh) | 2020-01-16 |
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