WO2022247770A1 - 一种含氮杂环化合物、其制备方法及应用 - Google Patents
一种含氮杂环化合物、其制备方法及应用 Download PDFInfo
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- WO2022247770A1 WO2022247770A1 PCT/CN2022/094364 CN2022094364W WO2022247770A1 WO 2022247770 A1 WO2022247770 A1 WO 2022247770A1 CN 2022094364 W CN2022094364 W CN 2022094364W WO 2022247770 A1 WO2022247770 A1 WO 2022247770A1
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- Prior art keywords
- alkyl
- heteroatoms
- substituted
- independently
- membered
- Prior art date
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- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- OQJBFFCUFALWQL-UHFFFAOYSA-N n-(piperidine-1-carbonylimino)piperidine-1-carboxamide Chemical compound C1CCCCN1C(=O)N=NC(=O)N1CCCCC1 OQJBFFCUFALWQL-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- ZOUWOGOTHLRRLS-UHFFFAOYSA-N palladium;phosphane Chemical compound P.[Pd] ZOUWOGOTHLRRLS-UHFFFAOYSA-N 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- NARVIWMVBMUEOG-UHFFFAOYSA-N prop-1-en-2-ol Chemical compound CC(O)=C NARVIWMVBMUEOG-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Substances [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- NXQKSXLFSAEQCZ-SFHVURJKSA-N sotorasib Chemical compound FC1=CC2=C(N(C(N=C2N2[C@H](CN(CC2)C(C=C)=O)C)=O)C=2C(=NC=CC=2C)C(C)C)N=C1C1=C(C=CC=C1O)F NXQKSXLFSAEQCZ-SFHVURJKSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- SIMIIXFMGJYGLR-UHFFFAOYSA-N tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC11CC(=O)C1 SIMIIXFMGJYGLR-UHFFFAOYSA-N 0.000 description 1
- UXZBTEIHIQFMIT-UHFFFAOYSA-N tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC21CCC(=O)CC2 UXZBTEIHIQFMIT-UHFFFAOYSA-N 0.000 description 1
- PDAFIZPRSXHMCO-UHFFFAOYSA-N tert-butyl n-(1-hydroxypropan-2-yl)carbamate Chemical compound OCC(C)NC(=O)OC(C)(C)C PDAFIZPRSXHMCO-UHFFFAOYSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
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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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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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- 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
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/84—Nitrogen atoms
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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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
- C07D498/02—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 two hetero rings
- C07D498/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
Description
Claims (18)
- 一种如式I所示的含氮杂环化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物:m为0、1或2;R 2为-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、被一个或多个R 2-1取代的C 1-6烷基、卤素、-OR 2a、-C(=O)R 2b、-NR 2c1R 2c2、-C(=O)OR 2d、-C(=O)NR 2e1R 2e2、C 3-10环烷基、被一个或多个R 2-2取代的C 3-10环烷基、“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”、被一个或多个R 2-3取代的“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”、C 6-20芳基、被一个或多个R 2-4取代的C 6-20芳基、“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”、或、被一个或多个R 2-5取代的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”;当取代基为多个时,相同或不同;R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为卤素、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基-O-、-C(=O)R 31、-NR 32R 33、-C(=O)OR 34、或、-C(=O)NR 35R 36;R 2a、R 2b、R 2c1、R 2c2、R 2d、R 2e1和R 2e2独立地为氢或C 1-6烷基;R 31、R 32、R 33、R 34、R 35和R 36独立地为氢或C 1-6烷基;n为0、1、2、3、4、5或6;R 4独立地为C 1-6烷基、被一个或多个R 4-1取代的C 1-6烷基、C 1-6烷基-O-、O=、-C(=O)OR 4a或-C(=O)NR 4bR 4c;或者,当n为2、3、4、5或6时,任选的两个R 4相连,独立地与其所连接的环中的原子一起形成3~8元的碳环或“含1~3个杂原子,杂原子为O、S和N中的一种或多种的3~8元杂环”;R 4-1独立地为卤素、氰基、羟基、C 1-6烷基-O-、-NR 4iR 4j、-C(=O)OR 4d或-C(=O)NR 4eR 4f;R 4a、R 4b、R 4c、R 4d、R 4e、R 4f、R 4i和R 4j独立地为氢或C 1-6烷基;p为0或1;为苯基、“含1~3个杂原子,杂原子选自O、S和N的5~7元杂环烯基”、“含1~3个 杂原子,杂原子为O、S和N中的一种或多种的5~7元杂芳基”或5~7元环烯基;其中,D 1为C、CH或N;D 2为 其中Z 1和Z 2独立地为连接键、CH、CH 2、O、S、N或NH;r为0、1、2、3、4、5或6;R 5独立地为卤素或C 1-6烷基;X 1和X 2独立地为CR b或N,且X 1和X 2不同时为CR b;L 1为连接键、-C(=O)-或C 1-6亚烷基;R 1为C 6-20芳基、C 8-11的苯并环烯基、“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”、被一个或多个R 1-1取代的C 6-20芳基、或、被一个或多个R 1-2取代的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”;当取代基为多个时,相同或不同;R b、R 1-1和R 1-2独立地为卤素、-OR c、氰基、-C(=O)R 11、-NR 12R 13、-C(=O)OR 14、-C(=O)NR 15R 16、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”、C 6-20芳基、“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”、被一个或多个R 1-1-1取代的C 1-6烷基、被一个或多个R 1-1-2取代的C 1-6烷基-O-、被一个或多个R 1-1-3取代的C 3-10环烷基、被一个或多个R 1-1-4取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”、被一个或多个R 1-1-5取代的C 6-20芳基、或、被一个或多个R 1-1-6取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”;当取代基为多个时,相同或不同;或,当R 1-1或R 1-2为多个时,任选的两个R 1-1或R 1-2相连,独立地与其所连接的环中的原子一起形成3~8元的环烯烃;R c、R 12和R 13独立地为氢、C 1-6烷基、C(=O)R c1、-C(=O)OR c2、-C(=O)NR c3R c4或-SO 2R c5;R c1、R c2、R c3、R c4和R c5独立地为氢、C 1-6烷基、C 3-10环烷基、“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”、C 6-20芳基、“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”、被一个或多个R 4-1-1取代的C 1-6烷基、被一个或多个R 4-1-2取代的C 3-10环烷基、被一个或多个R 4-1-3取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”、被一个或多个R 4-1-4取代的C 6-20芳基、或、被一个或多个R 4-1-5取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”;当取代基为多个时,相同或不同;R 1-1-1、R 1-1-2、R 1-1-3、R 1-1-4、R 1-1-5、R 1-1-6、R 4-1-1、R 4-1-2、R 4-1-3、R 4-1-4和R 4-1-5独立地为氰基、卤素、羟基、C 1-6烷基-O-、C 1-6烷基、-C(=O)R 21、-NR 22R 23、-C(=O)OR 24、或、-C(=O)NR 25R 26;R 11、R 21、R 22、R 23、R 14、R 24、R 15、R 25、R 16和R 26独立地为氢或C 1-6烷基;L 2为连接键、C 1-6亚烷基、-C(=O)-、-O(R L-1) n1-、-S(R L-2) n2-或-NR L-3(R L-4) n3-;R L-1、R L-2和R L-4独立地为C 1-6亚烷基;R L-3为氢或C 1-6烷基;n1、n2和n3独立地为0或1;R 3为C 3-12环烷基、被一个或多个R 3-1取代的C 3-12环烷基、“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”、被一个或多个R 3-2取代的“含1~3个杂原子,杂原子为O、S 和N中的一种或多种的4~12元杂环烷基”、C 1-6烷基、被一个或多个R 3-3取代的C 1-6烷基、-OR d、-SR d1、-NR e1R e2、或、-C(=O)NR e3R e4;当取代基为多个时,相同或不同;R 3-1、R 3-2和R 3-3独立地为C 1-6烷基、被一个或多个R 3-1-1取代的C 1-6烷基、羟基、C 1-6烷基-O-、卤素、O=、-NR e5R e6或-C(=O)NR e7R e8;R d、R d1、R e1、R e2、R e3和R e4独立地为氢、C 1-6烷基、C 3-10环烷基、“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”、或、被一个或多个R 3-1-2取代的C 1-6烷基;R 3-1-1和R 3-1-2独立地为氘、氰基、卤素、羟基、C 1-6烷基-O-、-C(=O)R e9、-NR e10R e11、-C(=O)OR e12、或、-C(=O)NR e13R e14;R e5、R e6、R e7、R e8、R e9、R e10、R e11、R e12、R e13和R e14独立地为氢或C 1-6烷基。
- 如权利要求1所述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物,其特征在于,m为0或1;和/或,R 2为-CN、C 1-6烷基、被一个或多个R 2-1取代的C 1-6烷基、卤素、-NR 2c1R 2c2、-C(=O)NR 2e1R 2e2、C 3-10环烷基、C 6-20芳基或“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”;和/或,R 2-1为羟基;和/或,R 2c1、R 2c2、R 2e1和R 2e2独立地为氢;和/或,n为0或1;和/或,R 4独立地为C 1-6烷基、被一个或多个R 4-1取代的C 1-6烷基、或C 1-6烷基-O-;和/或,R 4-1独立地为氰基;和/或,D 1为C或N;和/或,D 2中,Z 1和Z 2中任意一个为CH、CH 2、O、S或N,另一个为连接键;和/或,r为0或1;和/或,R 5独立地为卤素;和/或,X 1和X 2独立地为N;和/或,L 1为连接键或-C(=O)-;和/或,R 1为被一个或多个R 1-1取代的C 6-20芳基、C 8-11的苯并环烯基、含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基,或、被一个或多个R 1-2取代的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”;和/或,R 1-1独立地为卤素、-NR 12R 13、C 1-6烷基、-OR c、被一个或多个R 1-1-2取代的C 1-6烷基-O-、C 2-6炔基、C 3-10环烷基、或被一个或多个R 1-1-1取代的C 1-6烷基;或,当R 1-1为多个时,任选的两个R 1-1相连,独立地与其所连接的环中的原子一起形成3~8元的环烯烃;和/或,R c为氢、C 1-6烷基、C(=O)R c1、-C(=O)OR c2或-C(=O)NR c3R c4;和/或,R 12和R 13独立地为氢、C(=O)R c1、-C(=O)OR c2或-SO 2R c5;和/或,R 1-1-1独立地为卤素;和/或,R 1-1-2独立地为C 1-6烷基-O-;和/或,R 1-2独立地为C 1-6烷基;和/或,R c中,R c1独立地为C 1-6烷基、被一个或多个R 4-1-1取代的C 1-6烷基或被一个或多个R 4-1-4取代的C 6-20芳基;R 4-1-1为-NR 22R 23,R 22、R 23独立地为氢;R 4-1-4独立地为-NR 22R 23或C 1-6烷基,R 22、R 23独立地为氢;和/或,R c中,R c2为C 1-6烷基;和/或,R c中,R c3和R c4独立地为氢、C 1-6烷基或被一个或多个R 4-1-4取代的C 6-20芳基,R 4-1-4独立地为C 1-6烷基;和/或,R 12和R 13中,R c1、R c2和R c5独立地为C 1-6烷基;和/或,L 2为连接键或-O(R L-1) n1-;和/或,R L-1独立地为C 1-6亚烷基;和/或,n1为0或1;和/或,R 3为被一个或多个R 3-1取代的C 3-12环烷基、“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”、被一个或多个R 3-2取代的“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”、C 1-6烷基或-NR e1R e2;和/或,R 3-1独立地为-NR e5R e6,或,被一个或多个R 3-1-1取代的C 1-6烷基;R 3-1-1为-NR e10R e11;R e5、R e6、R e10和R e11独立地为C 1-6烷基;和/或,R 3-2独立地为C 1-6烷基、被一个或多个R 3-1-1取代的C 1-6烷基、卤素、-NR e5R e6或O=;R 3-1-1独立地为氘或卤素;R e5和R e6独立地为C 1-6烷基;和/或,R e1和R e2独立地为C 1-6烷基;
- 如权利要求1所述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其立体异构体、其 互变异构体或其同位素化合物,其特征在于,和/或,当 为 时,R 2为-CN、C 1-6烷基、卤素、-C(=O)NR 2e1R 2e2、C 3-10环烷基、C 6-20芳基或“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”;当 为 时,R 2为-CN、C 1-6烷基、被一个或多个R 2-1取代的C 1-6烷基、卤素、-NR 2c1R 2c2、C 3-10环烷基或C 6-20芳基;和/或,D 1为C,D 2中,Z 1和Z 2中任意一个为CH或N,另一个为连接键;或者D 1为CH,D 2中,Z 1和Z 2中任意一个为O或CH 2,,另一个为连接键;或者D 1为N,D 2中,Z 1和Z 2中任意一个为CH 2,另一个为连接键;和/或, 中,当L 2为连接键时,R 3为“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”;或者,当L 2为-O(R L-1) n1-时,R 3为被一个或多个R 3-1取代的C 3-12环烷基、被一个或多个R 3-2取代的“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”、C 1-6烷基或-NR e1R e2;和/或,当R 3为被一个或多个R 3-2取代的“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”时,R 3-2为C 1-6烷基;
- 如权利要求1-3中任一项所述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物,其特征在于,当R 2为C 1-6烷基或被一个或多个R 2-1取代的C 1-6烷基时,所述C 1-6烷基和所述的被一个或多个R 2-1取代的C 1-6烷基中的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,例如甲基;和/或,当R 2为C 2-6烯基时,所述C 2-6烯基为乙烯基、丙烯基或烯丙基;和/或,当R 2为C 2-6炔基时,所述C 2-6炔基为C 2-3炔基,例如乙炔基、丙炔基或炔丙基;和/或,当R 2为卤素时,所述卤素为氟、氯、溴或碘,例如溴;和/或,当R 2为C 3-10环烷基或被一个或多个R 2-2取代的C 3-10环烷基时,所述C 3-10环烷基和所述的被一个或多个R 2-2取代的C 3-10环烷基中的C 3-10环烷基为环己基、环戊基、环丁基或环丙基,又例如环丙基;和/或,当R 2为“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”或被一个或多个R 2-3取代的“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”时,所述的“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”和所述的被一个或多个R 2-3取代的“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”中的“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”为“含1个杂原子,杂原子为O和/或N的4~6元杂环烷基”;和/或,当R 2为C 6-20芳基或被一个或多个R 2-4取代的C 6-20芳基时,所述C 6-20芳基和所述的被一个或多个R 2-4取代的C 6-20芳基中的C 6-20芳基为C 6-10芳基,例如苯基或萘基,又例如苯基;和/或,当R 2为“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”或被一个或多个R 2-5取代的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”时,所述的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”和所述的被一个或多个R 2-5取代的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”中的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”为“含1杂原子,杂原子为O、S和N中的一种的5~6元杂芳基”,例如吡啶基,又例如和/或,当R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为卤素时,所述卤素为氟、氯、溴或碘;和/或,当R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为C 1-6烷基时,所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,例如甲基;和/或,当R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为C 2-6烯基时,所述C 2-6烯基为乙烯基、丙烯基或烯丙基;和/或,当R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为C 2-6炔基时,所述C 2-6炔基为乙炔基、丙炔基或炔丙基;和/或,当R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为C 1-6烷基-O-时,所述C 1-6烷基-O-中的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,例如甲基;和/或,当R 2a、R 2b、R 2c1、R 2c2、R 2d、R 2e1和R 2e2独立地为C 1-6烷基时,所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,例如甲基;和/或,当R 31、R 32、R 33、R 34、R 35和R 36独立地为C 1-6烷基时,所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,例如甲基;和/或,当R 4为C 1-6烷基或被一个或多个R 4-1取代的C 1-6烷基,所述C 1-6烷基和所述的被一个或多个R 4-1取代的C 1-6烷基中的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,例如甲基;和/或,当R 4为C 1-6烷基-O-时,所述C 1-6烷基-O-中的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,例如甲基;和/或,当n为2、3、4、5或6,任选的两个R 4相连,独立地与其所连接的环中的原子一起形成3~8元的碳环时,所述3~8元的碳环为3~6元的碳环,所述碳环可为单环或桥环的环烷基;和/或,当n为2、3、4、5或6,任选的两个R 4相连,独立地与其所连接的环中的原子一起形成“含1~3个杂原子,杂原子为O、S和N中的一种或多种的3~8元杂环”时,所述“含1~3个杂原子,杂原子为O、S和N中的一种或多种的3~8元杂环”为“含1个杂原子,杂原子为O、S和N中的一种的3~6元杂环”;和/或,当R 4-1独立地为卤素时,所述卤素为氟、氯、溴或碘;和/或,当R 4-1独立地为C 1-6烷基-O-时,所述C 1-6烷基-O-中的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当R 4a、R 4b、R 4c、R 4d、R 4e、R 4f、R 4i和R 4j独立地为C 1-6烷基时,所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当 为“含1~3个杂原子,杂原子为O、S和N的5~7元杂环烯基”时,所述“含1~3个杂原子,杂原子为O、S和N中的一种或多种的5~7元杂环烯基”为“含1~2个杂原子,杂原子为O和/或N的6元杂环烯基”,例如“含1个杂原子,杂原子为O和/或N的6元杂环烯基”,又例如 例如和/或,当 为“含1~3个杂原子,杂原子为O、S和N中的一种或多种的5~7元杂芳基”时,所述“含1~3个杂原子,杂原子为O、S和N中的一种或多种的5~7元杂芳基”为“含1~2个杂原子,杂原子为O、S和N中的一种或多种的6元杂芳基”,例如“含1个杂原子,杂原子为N的6元杂芳基”,又例如吡啶基,再例如和/或,当R 5独立地为卤素时,所述卤素为氟、氯、溴或碘,例如氟;和/或,当R 5独立地为C 1-6烷基时,所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当L 1为C 1-6亚烷基时,所述C 1-6亚烷基为-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH(CH 3)CH 2-、-CH 2CH 2CH 2CH 2-、-CH(CH 3)CH 2CH 2-、-CH 2CH(CH 3)CH 2-或-C(CH 3) 2CH 2-;和/或,当R 1为C 6-20芳基或被一个或多个R 1-1取代的C 6-20芳基时,所述C 6-20芳基和所述的被一个或多个R 1-1取代的C 6-20芳基中的C 6-20芳基为C 6-10芳基,例如苯基或萘基;和/或,当R 1为C 8-11的苯并环烯基时,所述的C 8-11的苯并环烯基为苯并环丁烯基、苯并环戊烯基或苯并环己烯基;和/或,当R 1为“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”或被一个或多个R 1-2取代的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”时,所述“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”和所述的被一个或多个R 1-2取代的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”中的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”为“含1~2个杂原子,杂原子为O、S和N中的一种或多种的5~9元杂芳基”,例如,“含1个杂原子,杂原子为N的5~9元杂芳基”,又例如喹啉基,再例如 例如“含2个杂原子,杂原子为N的9元杂芳基”,又例如吲唑基,再例如和/或,当R b、R 1-1和R 1-2独立地为卤素时,所述卤素为氟、氯、溴或碘,例如氟或氯;和/或,当R b、R 1-1和R 1-2独立地为C 1-6烷基或被一个或多个R 1-1-1取代的C 1-6烷基时,所述C 1-6烷基和所述的被一个或多个R 1-1-1取代的C 1-6烷基中的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当R b、R 1-1和R 1-2独立地为被一个或多个R 1-1-1取代的C 1-6烷基时,所述的多个为2个或3个;和/或,当R b、R 1-1和R 1-2独立地为C 2-6烯基时,所述C 2-6烯基为乙烯基、丙烯基或烯丙基;和/或,当R b、R 1-1和R 1-2独立地为C 2-6炔基时,所述C 2-6炔基为乙炔基、丙炔基或炔丙基;和/或,当R b、R 1-1和R 1-2独立地为被一个或多个R 1-1-2取代的C 1-6烷基-O-时,所述的被一个或多个R 1-1-2取代的C 1-6烷基-O-中的C 1-6烷基-O-中的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,例如甲基;和/或,当R b、R 1-1和R 1-2独立地为C 3-10环烷基或被一个或多个R 1-1-3取代的C 3-10环烷基时,所述C 3-10环烷基和所述的被一个或多个R 1-1-3取代的C 3-10环烷基中的C 3-10环烷基为环己基、环戊基、环丁基或环丙基,例如环丙基;和/或,当R b、R 1-1和R 1-2独立地为“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”或被一个或多个R 1-1-4取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”时,所述“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”和所述的被一个或多个R 1-1-4取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”中的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”为“含1个杂原子,杂原子为O和/或N的5~6元杂环烷基”;和/或,当R b、R 1-1和R 1-2独立地为C 6-20芳基或被一个或多个R 1-1-5取代的C 6-20芳基时,所述C 6- 20芳基和被一个或多个R 1-1-5取代的C 6-20芳基中的C 6-20芳基为C 6-10芳基,例如苯基或萘基;和/或,当R b、R 1-1和R 1-2独立地为“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”或被一个或多个R 1-1-6取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”时,所述“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”和所述的被一个或多个R 1-1-6取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”中的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”为“含1个杂原子,杂原子为O和/或N的5~6元杂芳基”;和/或,当任选的两个R 1-1或R 1-2相连,独立地与其所连接的环中的原子一起形成3~8元的环烯烃时,所述的3~8元的环烯烃为环丁烯、环戊烯或环己烯;和/或,当R c、R 12和R 13独立地为C 1-6烷基时,所述的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当R c1、R c2、R c3、R c4和R c5独立地为C 1-6烷基或被一个或多个R 4-1-1取代的C 1-6烷基时,所述的C 1-6烷基和被一个或多个R 4-1-1取代的C 1-6烷基中的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当R c1、R c2、R c3、R c4和R c5独立地为C 3-10环烷基或被一个或多个R 4-1-2取代的C 3-10环烷基时,所述的C 3-10环烷基和被一个或多个R 4-1-2取代的C 3-10环烷基中的C 3-10环烷基为环己基、环戊基、环丁基或环丙基;和/或,当R c1、R c2、R c3、R c4和R c5独立地为C 6-20芳基或被一个或多个R 4-1-4取代的C 6-20芳基时,所述C 6-20芳基和所述的被一个或多个R 4-1-4取代的C 6-20芳基中的C 6-20芳基为C 6-10芳基,例如苯基或萘基;和/或,当R 1-1-1、R 1-1-2、R 1-1-3、R 1-1-4、R 1-1-5、R 1-1-6、R 4-1-1、R 4-1-2、R 4-1-3、R 4-1-4和R 4-1-5独立地为卤素时,所述卤素为氟、氯、溴或碘,例如氟;和/或,当R 1-1-1、R 1-1-2、R 1-1-3、R 1-1-4、R 1-1-5、R 1-1-6、R 4-1-1、R 4-1-2、R 4-1-3、R 4-1-4和R 4-1-5独立地为C 1-6烷基-O-时,所述C 1-6烷基-O-中的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当R 1-1-1、R 1-1-2、R 1-1-3、R 1-1-4、R 1-1-5、R 1-1-6、R 4-1-1、R 4-1-2、R 4-1-3、R 4-1-4和R 4-1-5独立地为C 1-6烷基时,所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当R 11、R 21、R 22、R 23、R 14、R 24、R 15、R 25、R 16和R 26独立地为C 1-6烷基时,所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当L 2为C 1-6亚烷基时,所述C 1-6亚烷基为-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH(CH 3)CH 2-、-CH 2CH 2CH 2CH 2-、-CH(CH 3)CH 2CH 2-、-CH 2CH(CH 3)CH 2-或-C(CH 3) 2CH 2-;和/或,当R L-1、R L-2或R L-4独立地为C 1-6亚烷基时,所述C 1-6亚烷基为-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH(CH 3)CH 2-、-CH 2CH 2CH 2CH 2-、-CH(CH 3)CH 2CH 2-、-CH 2CH(CH 3)CH 2-或-C(CH 3) 2CH 2-,例如-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-或-CH(CH 3)CH 2-;和/或,当R L-3为C 1-6烷基时,所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当R 3为C 3-12环烷基或被一个或多个R 3-1取代的C 3-12环烷基时,所述C 3-12环烷基和所述的被一个或多个R 3-1取代的C 3-12环烷基中的C 3-12环烷基为C 3-10环烷基;例如环丙基;和/或,当R 3为C 3-12环烷基或被一个或多个R 3-1取代的C 3-12环烷基时,所述C 3-12环烷基和所述的被一个或多个R 3-1取代的C 3-12环烷基中的C 3-12环烷基为单环、桥环或螺环;和/或,当R 3为“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”时,所述“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”为“含1~2个杂原子,杂原子为O和/或N的5~8元杂环烷基”;和/或,当R 3为“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”时,所述“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”为单环烷基、螺环烷基或桥环烷基;例如氮杂环丁基、吡咯烷基、四氢呋喃基、六氢-1H-吡咯嗪基、7-氮杂螺环[3.5]壬烷基、3-氮杂螺环[5.5]十一烷基、吗啡基或哌啶基,又例如和/或,当R 3为被一个或多个R 3-2取代的“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”时,所述被一个或多个R 3-2取代的“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”中的“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”为“含1~2个杂原子,杂原子为O和/或N中的一种或多种的5~11元杂环烷基”;和/或,当R 3为被一个或多个R 3-2取代的“含1~3个杂原子,杂原子为O、S和N中的一种或多种 的4~12元杂环烷基”时,所述“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”为单环、螺环或桥环;所述被一个或多个R 3-2取代的“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”例如和/或,当R 3为C 1-6烷基或被一个或多个R 3-3取代的C 1-6烷基,所述C 1-6烷基和所述的被一个或多个R 3-3取代的C 1-6烷基中的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,例如甲基;和/或,当R 3-1、R 3-2和R 3-3独立地为C 1-6烷基或被一个或多个R 3-1-1取代的C 1-6烷基时,所述C 1- 6烷基和所述的被一个或多个R 3-1-1取代的C 1-6烷基中的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,例如甲基;和/或,当R 3-1、R 3-2和R 3-3独立地为C 1-6烷基-O-时,所述C 1-6烷基-O-中的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当R 3-1、R 3-2和R 3-3独立地为卤素时,所述卤素为氟、氯、溴或碘,例如氟;和/或,当R d、R d1、R e1、R e2、R e3和R e4独立地为C 1-6烷基或被一个或多个R 3-1-2取代的C 1-6烷基时,所述C 1-6烷基和所述的被一个或多个R 3-1-2取代的C 1-6烷基中的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,例如甲基;和/或,当R d、R d1、R e1、R e2、R e3和R e4独立地为C 3-10环烷基时,所述C 3-10环烷基为环己基、环戊基、环丁基或环丙基,例如为环丙基;和/或,当R d、R d1、R e1、R e2、R e3和R e4独立地为“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”时,所述“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”为“含1~2个杂原子,杂原子为O和/或N的4~6元杂环烷基”;和/或,当R 3-1-1和R 3-1-2独立地为卤素时,所述卤素为氟、氯、溴或碘;和/或,当R 3-1-1和R 3-1-2独立地为C 1-6烷基-O-时,所述C 1-6烷基-O-中的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当R e5、R e6、R e7、R e8、R e9、R e10、R e11、R e12、R e13和R e14独立地为C 1-6烷基时,所述的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基。
- 如权利要求1所述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物,其特征在于,如前所述的如式I所示的含氮杂环化合物,其结构为如下所示:m为0或1;R 2为-CN、C 1-6烷基、卤素、C 3-10环烷基或C 6-20芳基;n为0或1;R 4为C 1-6烷基、或、被一个或多个R 4-1取代的C 1-6烷基;R 4-1独立地为卤素;p为0或1;r为0或1;R 5为卤素或C 1-2烷基;R 1为C 6-20芳基、“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”、被一个或多个R 1-1取代的C 6-20芳基、或、被一个或多个R 1-2取代的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”;当取代基为多个时,相同或不同;R 1-1和R 1-2独立地为卤素、-OR c、C 1-6烷基、-NR 12R 13、或、被一个或多个R 1-1-2取代的C 1-6烷基-O-;当取代基为多个时,相同或不同;R 1-1-2为C 1-6烷基-O-;R c为氢、C 1-6烷基、C(=O)R c1、-C(=O)OR c2、或、-C(=O)NR c3R c4;R c1为C 1-6烷基、-NH 2取代的C 1-6烷基、C 6-20芳基、或、被一个或多个R 4-1-4取代的C 6-20芳基;R c3和R c4独立地为C 6-20芳基、或、被一个或多个R 4-1-4取代的C 6-20芳基;R 4-1-4为卤素、C 1-6烷基或-NH 2;R c2为C 1-6烷基;R 12和R 13独立地为氢、C 1-6烷基、C(=O)R c1、或、-SO 2R c5;R c1和R c5独立地为C 1-6烷基;L 2为-O(R L-1) n1;R L-1为C 1-6亚烷基;n1为0或1;R 3为“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”、被一个或多个R 3-2取代的“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”、或、-NR e1R e2;当取代基为多个时,相同或不同;R 3-2独立地为C 1-6烷基、被一个或多个R 3-1-1取代的C 1-6烷基、或、卤素;R 3-1-1独立地为氘或卤素;R e1和R e2独立地为氢或C 1-6烷基。
- 如权利要求8所述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物,其特征在于,如前所述的如式I所示的含氮杂环化合物,其结构为如下所示:m为0或1;R 2为-CN、C 1-3烷基或卤素;R 4为C 1-6烷基;R 1为萘基、喹啉基、被一个或多个R 1-1取代的萘基、或、被一个或多个R 1-2取代的喹啉基;当取代基为多个时,相同或不同;R 1-1和R 1-2独立地为卤素、-OR c、C 1-6烷基、-NR 12R 13、或、被一个或多个R 1-1-2取代的C 1-6烷基-O-;当取代基为多个时,相同或不同;R 1-1-2为C 1-6烷基-O-;R c为氢、C 1-6烷基、C(=O)R c1、-C(=O)OR c2、或、-C(=O)NR c3R c4;R c1为C 1-6烷基、-NH 2取代的C 1-6烷基、C 6-20芳基、或、被一个或多个R 4-1-4取代的C 6-20芳基;R c3和R c4独立地为C 6-20芳基、或、被一个或多个R 4-1-4取代的C 6-20芳基;R 4-1-4独立地为卤素、C 1-6烷基或-NH 2;R c2为C 1-6烷基;R 12和R 13独立地为氢、C 1-6烷基、C(=O)R c1、或、-SO 2R c5;R c1和R c5独立地为C 1-6烷基;L 2为-O(R L-1) n1;R L-1为C 1-6亚烷基;n1为1;R 3为被R 3-2取代的“含1个杂原子,杂原子为N的5~6元杂环烷基”、或、-NR e1R e2;R 3-2为C 1-2烷基或,被一个或多个R 3-1-1取代的C 1-6烷基;R 3-1-1独立地为氘;R e1和R e2独立地为氢或C 1-6烷基。
- 如权利要求8所述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物,其特征在于,如前所述的如式I所示的含氮杂环化合物,其结构为如下所示:m为0或1;R 2为-CN、C 1-3烷基或卤素;R 4为C 1-6烷基;R 1为萘基、喹啉基、被一个或多个R 1-1取代的萘基、或、被一个或多个R 1-2取代的喹啉基;当取代基为多个时,相同或不同;R 1-1和R 1-2独立地为卤素、-OR c、C 1-6烷基、-NR 12R 13、或、被一个或多个R 1-1-2取代的C 1-6烷基-O-;当取代基为多个时,相同或不同;R 1-1-2为C 1-6烷基-O-;R c为氢、C 1-6烷基、C(=O)R c1、-C(=O)OR c2、或-C(=O)NR c3R c4;R c1为C 1-6烷基、-NH 2取代的C 1- 6烷基、C 6-20芳基、或、被一个或多个R 4-1-4取代的C 6-20芳基;R c3和R c4独立地为C 6-20芳基、或、被一个或多个R 4-1-4取代的C 6-20芳基;R 4-1-4为卤素、C 1-6烷基或-NH 2;R c2为C 1-6烷基;R 12和R 13独立地为氢、C 1-6烷基、C(=O)R c1、或、-SO 2R c5;R c1和R c5独立地为C 1-6烷基;L 2为-O(R L-1) n1;R L-1为C 1-6亚烷基;n1为1;R 3为被R 3-2取代的“含1个杂原子,杂原子为N的5~6元杂环烷基”、或、-NR e1R e2;R 3-2为C 1-2烷基;R e1和R e2独立地为氢或C 1-6烷基。
- 一种如权利要求1-11任一项中所述的如式I所示的含氮杂环化合物的制备方法,其特征在于,其为下述任一路线:路线一其中,R 1、R 2、R 3、R 4、R 5、A 1、A 2、D 1、D 2、L 1、L 2、X 1、X 2、m、n、p和r的定义均同权利要求1-11中任一项所述,Q 1为离去基团,例如OTf、Cl;所述的路线一的步骤如下所述:化合物A1的羟基转换成离去基团得到A2,A2通过亲核取代方式转化为A3,A3氧化为A4或A4’,再通过亲核取代方式转化为化合物I;路线二,其中,R 1、R 2、R 3、R 4、R 5、A 1、A 2、D 1、D 2、L 1、L 2、X 1、X 2、m、n、p和r的定义均同权利要求1-11中任一项所述,Q 2为离去基团,例如OTf、Cl;所述的路线二的步骤如下所述:化合物A1 用Me保护,B1氧化得到B2或B2’,B2或B2’通过亲核取代方式转化成B3,B3脱甲基保护转化为B4,B4中的羟基转换成离去基团得到B5,B5通过亲核取代方式转化成化合物I;路线三,其中,R 1、R 2、R 3、R 4、R 5、A 1、A 2、D 1、D 2、L 1、L 2、X 1、X 2、m、n、p和r的定义均同权利要求1-11中任一项所述,Q 2独立地为离去基团,例如OTf、Cl;PG为H或氨基保护基,所述氨基保护基例如THP、Boc或Cbz;所述的路线三的步骤如下所述:化合物C1用Me保护,C2氧化得到C3或C3’,C3或C3’通过亲核取代方式转化成C4,C4脱除保护基得到C5,C5通过亲核取代、偶联方式转化为B3,B3脱甲基保护转化为B4,B4中的羟基转换成离去基团得到B5,B5通过亲核取代方式转化成化合物I;路线四,其中,R 1、R 2、R 3、R 4、R 5、A 1、A 2、D 1、D 2、L 1、L 2、X 1、X 2、m、n、p和r的定义均同权利要求1-11中任一项所述,Q 1独立地为离去基团,例如OTf、Cl;PG为H或氨基保护基,所述氨基保护基例如THP、Boc或Cbz;所述的路线四的步骤如下所述:化合物C1中的羟基转换成离去基团得到F1,F1通过亲核取代方式转化为F2,F2氧化得到F3或F3’,F3或F3’通过亲核取代方式转化为F4,F4脱除保护基得到F5,F5通过亲核取代、偶联方式转化为化合物I;路线五,其中,R 1、R 2、R 3、R 4、R 5、A 1、A 2、D 1、D 2、L 1、L 2、X 1、X 2、m、n、p和r的定义均同权利要求1-11中任一项所述,X 3、X 4、X 5独立地为离去基团,例如OTf、Cl或Br;所述的路线五的步骤如下所述:化合物G1通过亲核取代方式转化为G2,G2通过亲核取代方式转化为G3,G3通过亲核取代、偶联方式转化为化合物I;路线六,其中,R 1、R 2、R 3、R 4、R 5、A 1、A 2、D 1、D 2、L 1、L 2、X 1、X 2、m、n、p和r的定义均同权利要求1-11中任一项所述,Q 2为离去基团,例如OTf、Cl;所述的路线六的步骤如下所述:化合物H1通过亲核取代方式转化成H2,H2脱除保护基得到H3,H3通过亲核取代、偶联方式转化为H4,H4脱除苄基保护转化为B4,B4中的羟基转换成离去基团得到B5,B5通过亲核取代方式转化成化合物I。
- 一种药物组合物,其特征在于,其包含物质A和药用辅料;所述的物质A为治疗有效量的如权利要求1-11中任一项所述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物。
- 一种物质A在制备RAS抑制剂中的应用,其特征在于,所述的物质A为如权利要求1-11中任一项所述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物;所述的RAS为野生型RAS和突变型RAS;所述的突变型RAS例如KRAS突变、HRAS突变或NRAS突变;其中,所述KRAS突变可为G12、G13、Q61突变,例如KRAS G12C、KRAS G12D、KRAS G12S、KRAS G12A、KRAS G12V或KRAS G13D,又例如KRAS G12C、KRAS G12D或KRAS G12V;所述HRAS突变可为G12、G13、Q61突变,例如HRAS G12C、HRAS G12D、HRAS G12S、HRAS G12A、HRAS G12V或HRAS G13D;所述NRAS突变可为G12、G13、Q61突变,例如NRAS G12C、NRAS G12D、NRAS G12S、NRAS G12A、NRAS G12V或NRAS G13D;所述的RAS再例如为KRAS G12C。
- 一种物质A在制备药物中的应用,其特征在于,所述的药物用于治疗或预防RAS相关的疾病;所述的物质A为如权利要求1-11中任一项所述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物;所述的RAS包括野生型RAS和突变型RAS;所述的RAS突变例如KRAS突变、HRAS突变或NRAS突变,其中,所述KRAS突变例如KRAS G12C、KRAS G12D、KRAS G12S、KRAS G12A、KRAS G12V或KRAS G13D,又例如KRAS G12C、KRAS G12D或KRAS G12V;所述HRAS突变可为G12、G13、Q61突变,例如HRAS G12C、HRAS G12D、HRAS G12S、HRAS G12A、HRAS G12V或HRAS G13D;所述NRAS突变可为G12、G13、Q61突变,例如NRAS G12C、NRAS G12D、NRAS G12S、NRAS G12A、NRAS G12V或NRAS G13D;所述的RAS再例如为KRAS G12C;和/或,所述的RAS相关的疾病例如癌症,所述的癌症例如结肠癌、阑尾癌、胰腺癌、MYH相关的息肉病、血液癌、乳腺癌、子宫内膜癌、胆囊癌、胆管癌、前列腺癌、肺癌、脑癌、卵巢癌、子宫颈癌、睾丸癌、肾癌、头或颈癌、骨癌、皮肤癌、直肠癌、肝癌、食道癌、胃癌、甲状腺癌、膀胱癌、淋巴瘤、白血病和黑色素瘤中的一种或多种。
- 一种物质A在制备药物中的应用,其特征在于,所述的药物用于治疗或预防癌症;所述的物质A为如权利要求1-11中任一项所述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物;较佳地,所述癌症的定义同权利要求16中的癌症所述。
- 如权利要求1所述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物,其特征在于,其为方案一、方案二或方案三:方案一:一种如式I所示的含氮杂环化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物:m为0、1或2;R 2为-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、被一个或多个R 2-1取代的C 1-6烷基、卤素、-OR 2a、-C(=O)R 2b、-NR 2c1R 2c2、-C(=O)OR 2d、-C(=O)NR 2e1R 2e2、C 3-10环烷基、被一个或多个R 2-2取代的C 3-10环烷基、“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”、被一个或多个R 2-3取代的“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”、C 6-20芳基、被一个或多个R 2-4取代的C 6-20芳基、“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”、或、被一个或多个 R 2-5取代的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”;当取代基为多个时,相同或不同;R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为卤素、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基-O-、-C(=O)R 31、-NR 32R 33、-C(=O)OR 34、或、-C(=O)NR 35R 36;R 2a、R 2b、R 2c1、R 2c2、R 2d、R 2e1和R 2e2独立地为氢或C 1-6烷基;R 31、R 32、R 33、R 34、R 35和R 36独立地为氢或C 1-6烷基;n为0、1、2、3、4、5或6;R 4独立地为C 1-6烷基、被一个或多个R 4-1取代的C 1-6烷基、C 1-6烷基-O-、O=、-C(=O)OR 4a或-C(=O)NR 4bR 4c;或者,当n为2、3、4、5或6时,任选的两个R 4相连,独立地与其所连接的环中的原子一起形成3~8元的碳环或“含1~3个杂原子,杂原子为O、S和N中的一种或多种的3~8元杂环”;R 4-1独立地为卤素、氰基、羟基、C 1-6烷基-O-、-NR 4iR 4j、-C(=O)OR 4d或-C(=O)NR 4eR 4f;R 4a、R 4b、R 4c、R 4d、R 4e、R 4f、R 4i和R 4j独立地为氢或C 1-6烷基;为苯基、“含1~3个杂原子,杂原子为O和/或N的5~7元杂环烯基”、“含1~3个杂原子,杂原子为O、S和N中的一种或多种的5~7元杂芳基”或5~7元环烯基;其中,D 1为C、CH或N;D 2为 其中Z 1和Z 2独立地为连接键、CH、CH 2、O、S、N或NH;r为0、1、2、3、4、5或6;R 5独立地为卤素或C 1-6烷基;X 1和X 2独立地为CR b或N,且X 1和X 2不同时为CR b;L 1为连接键、-C(=O)-或C 1-6亚烷基;R 1为C 6-20芳基、“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”、被一个或多个R 1-1取代的C 6-20芳基、或、被一个或多个R 1-2取代的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”;当取代基为多个时,相同或不同;R b、R 1-1和R 1-2独立地为卤素、羟基、氰基、-C(=O)R 11、-NR 12R 13、-C(=O)OR 14、-C(=O)NR 15R 16、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基-O-、C 3-10环烷基、“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”、C 6-20芳基、“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”、被一个或多个R 1-1-1取代的C 1-6烷基、被一个或多个R 1-1-2取代的C 1-6烷基-O-、被一个或多个R 1-1-3取代的C 3-10环烷基、被一个或多个R 1-1-4取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”、被一个或多个R 1-1-5取代的C 6-20芳基、或、被一个或多个R 1-1-6取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”;当取代基为多个时,相同或不同;R 1-1-1、R 1-1-2、R 1-1-3、R 1-1-4、R 1-1-5和R 1-1-6独立地为氰基、卤素、羟基、C 1-6烷基-O-、C 1-6烷基、-C(=O)R 21、-NR 22R 23、-C(=O)OR 24、或、-C(=O)NR 25R 26;R 11、R 21、R 12、R 22、R 13、R 23、R 14、R 24、R 15、R 25、R 16和R 26独立地为氢或C 1-6烷基;L 2为连接键、C 1-6亚烷基、-C(=O)-、-O(R L-1) n1-、-S(R L-2) n2-或-NR L-3(R L-4) n3-;R L-1、R L-2和R L-4独 立地为C 1-6亚烷基;R L-3为氢或C 1-6烷基;n1、n2和n3独立地为0或1;R 3为C 3-12环烷基、被一个或多个R 3-1取代的C 3-12环烷基、“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”、被一个或多个R 3-2取代的“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”、C 1-6烷基、被一个或多个R 3-3取代的C 1-6烷基、-OR d、-SR d1、-NR e1R e2、或、-C(=O)NR e3R e4;当取代基为多个时,相同或不同;R 3-1、R 3-2和R 3-3独立地为C 1-6烷基、被一个或多个R 3-1-1取代的C 1-6烷基、羟基、C 1-6烷基-O-、卤素、O=、-NR e5R e6或-C(=O)NR e7R e8;R d、R d1、R e1、R e2、R e3和R e4独立地为氢、C 1-6烷基、C 3-10环烷基、“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”、或、被一个或多个R 3-1-2取代的C 1-6烷基;R 3-1-1和R 3-1-2独立地为氰基、卤素、羟基、C 1-6烷基-O-、-C(=O)R e9、-NR e10R e11、-C(=O)OR e12、或、-C(=O)NR e13R e14;R e5、R e6、R e7、R e8、R e9、R e10、R e11、R e12、R e13和R e14独立地为氢或C 1-6烷基;方案二:一种如式I所示的含氮杂环化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物:m为0、1或2;R 2为-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、被一个或多个R 2-1取代的C 1-6烷基、卤素、-OR 2a、-C(=O)R 2b、-NR 2c1R 2c2、-C(=O)OR 2d、-C(=O)NR 2e1R 2e2、C 3-10环烷基、被一个或多个R 2-2取代的C 3-10环烷基、“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”、被一个或多个R 2-3取代的“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”、C 6-20芳基、被一个或多个R 2-4取代的C 6-20芳基、“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”、或、被一个或多个R 2-5取代的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”;当取代基为多个时,相同或不同;R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为卤素、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基-O-、-C(=O)R 31、-NR 32R 33、-C(=O)OR 34、或、-C(=O)NR 35R 36;R 2a、R 2b、R 2c1、R 2c2、R 2d、R 2e1和R 2e2独立地为氢或C 1-6烷基;R 31、R 32、R 33、R 34、R 35和R 36独立地为氢或C 1-6烷基;n为0、1、2、3、4、5或6;R 4独立地为C 1-6烷基、被一个或多个R 4-1取代的C 1-6烷基、C 1-6烷基-O-、O=、-C(=O)OR 4a或-C(=O)NR 4bR 4c;或者,当n为2、3、4、5或6时,任选的两个R 4相连,独立地与其所连接的环中的原子一起形成3~8元的碳环或“含1~3个杂原子,杂原子为O、S和N中的一种或多种的3~8元杂环”;R 4-1独立地为卤素、氰基、羟基、C 1-6烷基-O-、-NR 4iR 4j、-C(=O)OR 4d或-C(=O)NR 4eR 4f;R 4a、R 4b、R 4c、R 4d、R 4e、R 4f、R 4i和R 4j独立地为氢或C 1-6烷基;为苯基、“含1~3个杂原子,杂原子选自O、S和N的5~7元杂环烯基”、“含1~3个杂原子,杂原子为O、S和N中的一种或多种的5~7元杂芳基”或5~7元环烯基;其中,D 1为C、CH或N;D 2为 其中Z 1和Z 2独立地为连接键、CH、CH 2、O、S、N或NH;r为0、1、2、3、4、5或6;R 5独立地为卤素或C 1-6烷基;X 1和X 2独立地为CR b或N,且X 1和X 2不同时为CR b;L 1为连接键、-C(=O)-或C 1-6亚烷基;R 1为C 6-20芳基、“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”、被一个或多个R 1-1取代的C 6-20芳基、或、被一个或多个R 1-2取代的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”;当取代基为多个时,相同或不同;R b、R 1-1和R 1-2独立地为卤素、羟基、氰基、-C(=O)R 11、-NR 12R 13、-C(=O)OR 14、-C(=O)NR 15R 16、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基-O-、C 3-10环烷基、“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”、C 6-20芳基、“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”、被一个或多个R 1-1-1取代的C 1-6烷基、被一个或多个R 1-1-2取代的C 1-6烷基-O-、被一个或多个R 1-1-3取代的C 3-10环烷基、被一个或多个R 1-1-4取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”、被一个或多个R 1-1-5取代的C 6-20芳基、或、被一个或多个R 1-1-6取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”;当取代基为多个时,相同或不同;R 1-1-1、R 1-1-2、R 1-1-3、R 1-1-4、R 1-1-5和R 1-1-6独立地为氰基、卤素、羟基、C 1-6烷基-O-、C 1-6烷基、-C(=O)R 21、-NR 22R 23、-C(=O)OR 24、或、-C(=O)NR 25R 26;R 11、R 21、R 12、R 22、R 13、R 23、R 14、R 24、R 15、R 25、R 16和R 26独立地为氢或C 1-6烷基;L 2为连接键、C 1-6亚烷基、-C(=O)-、-O(R L-1) n1-、-S(R L-2) n2-或-NR L-3(R L-4) n3-;R L-1、R L-2和R L-4独立地为C 1-6亚烷基;R L-3为氢或C 1-6烷基;n1、n2和n3独立地为0或1;R 3为C 3-12环烷基、被一个或多个R 3-1取代的C 3-12环烷基、“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”、被一个或多个R 3-2取代的“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”、C 1-6烷基、被一个或多个R 3-3取代的C 1-6烷基、-OR d、-SR d1、-NR e1R e2、或、-C(=O)NR e3R e4;当取代基为多个时,相同或不同;R 3-1、R 3-2和R 3-3独立地为C 1-6烷基、被一个或多个R 3-1-1取代的C 1-6烷基、羟基、C 1-6烷基-O-、卤素、O=、-NR e5R e6或-C(=O)NR e7R e8;R d、R d1、R e1、R e2、R e3和R e4独立地为氢、C 1-6烷基、C 3-10环烷基、“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”、或、被一个或多个R 3-1-2取代的C 1-6烷基;R 3-1-1和R 3-1-2独立地为氘、氰基、卤素、羟基、C 1-6烷基-O-、-C(=O)R e9、-NR e10R e11、-C(=O)OR e12、或、-C(=O)NR e13R e14;R e5、R e6、R e7、R e8、R e9、R e10、R e11、R e12、R e13和R e14独立地为氢或C 1-6烷基;方案三:一种如式I所示的含氮杂环化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物:m为0、1或2;R 2为-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、被一个或多个R 2-1取代的C 1-6烷基、卤素、-OR 2a、-C(=O)R 2b、-NR 2c1R 2c2、-C(=O)OR 2d、-C(=O)NR 2e1R 2e2、C 3-10环烷基、被一个或多个R 2-2取代的C 3-10环烷基、“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”、被一个或多个R 2-3取代的“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”、C 6-20芳基、被一个或多个R 2-4取代的C 6-20芳基、“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”、或、被一个或多个R 2-5取代的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”;当取代基为多个时,相同或不同;R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为卤素、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基-O-、-C(=O)R 31、-NR 32R 33、-C(=O)OR 34、或、-C(=O)NR 35R 36;R 2a、R 2b、R 2c1、R 2c2、R 2d、R 2e1和R 2e2独立地为氢或C 1-6烷基;R 31、R 32、R 33、R 34、R 35和R 36独立地为氢或C 1-6烷基;n为0、1、2、3、4、5或6;R 4独立地为C 1-6烷基、被一个或多个R 4-1取代的C 1-6烷基、C 1-6烷基-O-、O=、-C(=O)OR 4a或-C(=O)NR 4bR 4c;或者,当n为2、3、4、5或6时,任选的两个R 4相连,独立地与其所连接的环中的原子一起形成3~8元的碳环或“含1~3个杂原子,杂原子为O、S和N中的一种或多种的3~8元杂环”;R 4-1独立地为卤素、氰基、羟基、C 1-6烷基-O-、-NR 4iR 4j、-C(=O)OR 4d或-C(=O)NR 4eR 4f;R 4a、R 4b、R 4c、R 4d、R 4e、R 4f、R 4i和R 4j独立地为氢或C 1-6烷基;为苯基、“含1~3个杂原子,杂原子选自O、S和N的5~7元杂环烯基”、“含1~3个杂原子,杂原子为O、S和N中的一种或多种的5~7元杂芳基”或5~7元环烯基;其中,D 1为C、CH或N;D 2为 其中Z 1和Z 2独立地为连接键、CH、CH 2、O、S、N或NH;r为0、1、2、3、4、5或6;R 5独立地为卤素或C 1-6烷基;X 1和X 2独立地为CR b或N,且X 1和X 2不同时为CR b;L 1为连接键、-C(=O)-或C 1-6亚烷基;R 1为C 6-20芳基、C 8-11的苯并环烯基、“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”、被一个或多个R 1-1取代的C 6-20芳基、或、被一个或多个R 1-2取代的“含1~4个杂原子,杂原子为O、S和N中的一种或多种的5~12元杂芳基”;当取代基为多个时,相同或不同;R b、R 1-1和R 1-2独立地为卤素、-OR c、氰基、-C(=O)R 11、-NR 12R 13、-C(=O)OR 14、-C(=O)NR 15R 16、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”、C 6-20芳基、“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”、被一个或多个R 1-1-1取代的C 1-6烷基、被一个或多个R 1-1-2取代的C 1-6烷基-O-、被一个或多个R 1-1-3取代的C 3-10环烷基、被一个或多个R 1-1-4取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”、被一个或多个R 1-1-5取代的C 6-20芳基、或、被一个或多个R 1-1-6取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”;当取代基为多个时,相同或不同;或,当R 1-1或R 1-2为多个时,任选的两个R 1-1或R 1-2相连,独立地与其所连接的环中的原子一起形成3~8元的环烯烃;R c、R 12和R 13独立地为氢、C 1-6烷基、C(=O)R c1、-C(=O)OR c2、或-C(=O)NR c3R c4;R c1、R c2、R c3和R c4独立地为氢、C 1-6烷基、C 3-10环烷基、“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”、C 6-20芳基、“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”、被一个或多个R 4-1-1取代的C 1-6烷基、被一个或多个R 4-1-2取代的C 3-10环烷基、被一个或多个R 4-1-3取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂环烷基”、被一个或多个R 4-1-4取代的C 6-20芳基、或、被一个或多个R 4-1-5取代的“含1个或2个杂原子,杂原子为O和/或N的5~7元杂芳基”;当取代基为多个时,相同或不同;R 1-1-1、R 1-1-2、R 1-1-3、R 1-1-4、R 1-1-5、R 1-1-6、R 4-1-1、R 4-1-2、R 4-1-3、R 4-1-4和R 4-1-5独立地为氰基、卤素、羟基、C 1-6烷基-O-、C 1-6烷基、-C(=O)R 21、-NR 22R 23、-C(=O)OR 24、或、-C(=O)NR 25R 26;R 11、R 21、R 22、R 23、R 14、R 24、R 15、R 25、R 16和R 26独立地为氢或C 1-6烷基;L 2为连接键、C 1-6亚烷基、-C(=O)-、-O(R L-1) n1-、-S(R L-2) n2-或-NR L-3(R L-4) n3-;R L-1、R L-2和R L-4独立地为C 1-6亚烷基;R L-3为氢或C 1-6烷基;n1、n2和n3独立地为0或1;R 3为C 3-12环烷基、被一个或多个R 3-1取代的C 3-12环烷基、“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”、被一个或多个R 3-2取代的“含1~3个杂原子,杂原子为O、S和N中的一种或多种的4~12元杂环烷基”、C 1-6烷基、被一个或多个R 3-3取代的C 1-6烷基、-OR d、-SR d1、-NR e1R e2、或、-C(=O)NR e3R e4;当取代基为多个时,相同或不同;R 3-1、R 3-2和R 3-3独立地为C 1-6烷基、被一个或多个R 3-1-1取代的C 1-6烷基、羟基、C 1-6烷基-O-、卤素、O=、-NR e5R e6或-C(=O)NR e7R e8;R d、R d1、R e1、R e2、R e3和R e4独立地为氢、C 1-6烷基、C 3-10环烷基、“含1~3个杂原子,杂原子为O和/或N的4~10元杂环烷基”、或、被一个或多个R 3-1-2取代的C 1-6烷基;R 3-1-1和R 3-1-2独立地为氘、氰基、卤素、羟基、C 1-6烷基-O-、-C(=O)R e9、-NR e10R e11、-C(=O)OR e12、或、-C(=O)NR e13R e14;R e5、R e6、R e7、R e8、R e9、R e10、R e11、R e12、R e13和R e14独立地为氢或C 1-6烷基。
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