WO2021136238A1 - 一种稠环化合物及其应用 - Google Patents
一种稠环化合物及其应用 Download PDFInfo
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- WO2021136238A1 WO2021136238A1 PCT/CN2020/140689 CN2020140689W WO2021136238A1 WO 2021136238 A1 WO2021136238 A1 WO 2021136238A1 CN 2020140689 W CN2020140689 W CN 2020140689W WO 2021136238 A1 WO2021136238 A1 WO 2021136238A1
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- OLOHPXUDLQJPOL-UHFFFAOYSA-N phenyl 7-[[2-(2-chlorophenyl)acetyl]amino]-5-sulfamoyl-3,4-dihydro-1H-isoquinoline-2-carboxylate Chemical compound C1CN(CC2=C1C(=CC(=C2)NC(=O)CC3=CC=CC=C3Cl)S(=O)(=O)N)C(=O)OC4=CC=CC=C4 OLOHPXUDLQJPOL-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- NARVIWMVBMUEOG-UHFFFAOYSA-N prop-1-en-2-ol Chemical compound CC(O)=C NARVIWMVBMUEOG-UHFFFAOYSA-N 0.000 description 1
- LGBWZRMZZDCIFX-UHFFFAOYSA-N propan-2-yl 7-[[2-(2-chlorophenyl)acetyl]amino]-5-sulfamoyl-3,4-dihydro-1H-isoquinoline-2-carboxylate Chemical compound CC(C)OC(=O)N1CCC2=C(C1)C=C(C=C2S(=O)(=O)N)NC(=O)CC3=CC=CC=C3Cl LGBWZRMZZDCIFX-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl 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
- 230000009467 reduction Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 229940077386 sodium benzenesulfonate Drugs 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- MZSDGDXXBZSFTG-UHFFFAOYSA-M sodium;benzenesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C1=CC=CC=C1 MZSDGDXXBZSFTG-UHFFFAOYSA-M 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005458 thianyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- WXRGABKACDFXMG-UHFFFAOYSA-N trimethylborane Chemical compound CB(C)C WXRGABKACDFXMG-UHFFFAOYSA-N 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 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
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
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- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/78—Halides of sulfonic acids
- C07C309/86—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/89—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
- C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/40—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
- C07C311/46—Y being a hydrogen or a carbon atom
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- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/63—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/36—Sulfur atoms
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
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- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
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- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/28—Cinnolines
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- 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
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- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/84—Nitrogen atoms
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- 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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- 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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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the invention relates to a fused ring compound and its application.
- ATP receptors are classified into two main families based on molecular structure, transduction mechanism and pharmacological properties, P2Y- and P2X-purin receptors.
- P2X-purine receptors are a family of ATP-gated cation channels. Several subtypes have been cloned, including: six homopolymeric receptors, P2X1; P2X2; P2X3; P2X4; P2X5; and P2X7; and three heteromeric receptors Receptors P2X2/3, P2X4/6, P2X1/5.
- the P2X4 receptor is currently the only subtype of the P2X family whose crystal structure has been solved, and its resolution is as high as And the study found that P2X4 is the P2X subtype with the strongest Ca 2+ permeability.
- Cough is the main symptom of respiratory diseases. In the respiratory clinic, 70% to 80% of patients have cough symptoms. With the increasing prevalence of COPD, IPF, etc., cough is the main symptom of most expiratory diseases, and the demand also increases. As the body's defensive nerve reflex, coughing helps to remove respiratory secretions and harmful factors, but frequent and severe coughing can seriously affect the work, life and social activities of patients.
- the indications of drugs under investigation related to P2X4 targets are mostly neuropathic pain or inflammation, and there is no information on drugs under investigation related to cough indications. And there is no P2X4 inhibitory pathway drugs on the market to treat many diseases including chronic cough. Therefore, the development of new compounds that can inhibit the activity of P2X4 is of positive significance for the treatment of diseases.
- the technical problem to be solved by the present invention is to solve the defect of insufficient P2X4 antagonists in the prior art, and to provide a new fused ring compound as a P2X4 antagonist.
- the fused ring compound of the present invention has high P2X4 antagonistic activity, good selectivity, low toxicity, and good metabolic stability.
- the present invention solves the above technical problems through the following technical solutions.
- the present invention provides a fused ring compound as shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotope compound, its crystal form, its nitrogen oxide, Its solvate or a solvate of a pharmaceutically acceptable salt thereof;
- a 6-membered heteroalkane ring with 1, 2, or 3 heteroatoms, and one or more heteroatoms selected from N, O and S "heteroatoms is 1, 2 or 3, the heteroatom is selected from one or more of N, O and S in a 6-membered heteroene ring” or "the number of heteroatoms is 1, 2, or 3, the heteroatom is selected from N, One or more of O and S 6-membered heteroaromatic ring";
- R 1-1 is halogen, hydroxyl, amino, -NHR 1-1-4 , -N(R 1-1-5 )(R 1-1-6 ), C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 1 ⁇ C 6 alkyl substituted by one or more R 1-1-1 , C 3 ⁇ C 6 cycloalkane substituted by one or more R 1-1-2 Group, or, substituted by one or more R 1-1-3 "the number of heteroatoms is 1, 2, or 3, the heteroatoms are selected from one or more of N, O and S 4 ⁇ 7-membered heterocycloalkyl";
- R 1-1-1 , R 1-1-2 , R 1-1-3 , R 1-1-4 , R 1-1-5 and R 1-1-6 are independently halogen, hydroxyl, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 1 ⁇ C 6 alkoxy or "heteroatom number is 1, 2 or 3, heteroatom is selected from N, O and S One or more of 4-7 membered heterocycloalkyl";
- n 0, 1, 2 or 3;
- R 3-1 is independently halogen, cyano, hydroxy, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 3 ⁇ C 6 cycloalkyl, and one or more R 3 -1-1 substituted C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy substituted with one or more R 3-1-2 , or C 1 ⁇ C 6 alkoxy substituted A C 1 ⁇ C 6 alkoxy group; R 3-1-1 and R 3-1-2 are independently halogen;
- R 3-2 is a C 3 -C 6 cycloalkyl group substituted by one or more R 3-2-1 , and a "heteroatom number of 1, 2" substituted by one or more R 3-2-2
- One or three heteroatoms are selected from one or more of N, O and S 5-6 membered heterocycloalkyl
- the number of heteroatoms substituted by one or more R 3-2-2 is 1, 2, or 3 heteroatoms selected from one or more of N, O and S 7-8 membered heterocycloalkyl", or, substituted by one or more R 3-2-3
- the number of heteroatoms is 1, 2, or 3, and the heteroatom is selected from one or more of N, O and S 5-6 membered heteroaryl group";
- R 3-2-1 , R 3-2-2 and R 3-2-3 are independently halogen, hydroxyl, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 1 ⁇ C 6 alkoxy, or C 1 ⁇ C 6 alkoxy substituted C 1 ⁇ C 6 alkoxy;
- n 0, 1, 2, 3 or 4;
- R 2 is oxo, halogen, cyano, isocyano, amino, C 1 ⁇ C 10 alkyl, substituted with one or more 2-1 R C 1 ⁇ C 10 alkyl group, C 2 ⁇ C 10 alkenyl group, with one or more substituents R 2-26 is C 2 ⁇ C 10 alkenyl group, C 2 ⁇ C 10 alkynyl group, with one or more substituents R 2-27 is C 2 ⁇ C 10 alkynyl group, C 3 ⁇ C 6 cycloalkyl, C 3 ⁇ C 6 cycloalkyl substituted by one or more R 2-3 , "the number of heteroatoms is 1, 2, or 3, and the heteroatoms are selected from N, O And one or more of 5 to 6 membered heterocycloalkyl in S", "3 to 3 in which the number of heteroatoms is one or two, and the heteroatom is selected from one or more of N, O and S 4-membered heterocycloalkyl", phenyl, phen
- R 2-1 independently halogen, hydroxy, cycloalkyl C 3 ⁇ C 6, and with one or more R 2-1-8 substituted cycloalkyl group of C 3 ⁇ C 6,
- number of heteroatoms is 1
- One, two or three heteroatoms are selected from one or more of N, O and S.
- 4-6 membered heterocycloalkyl "heterocycloalkyl” substituted by one or more R 2-1-7
- the number of atoms is 1, 2, or 3, and the heteroatom is selected from one or more of N, O, and S.
- R 2-1-1 , R 2-1-6 , R 2-1-7 and R 2-1-8 are independently oxo, hydroxy, amino, carboxy, halogen, -CN, C 1 ⁇ C 6 Alkyl group, C 1 ⁇ C 6 alkyl group substituted by one or more halogens , -OR 2-1-1-1 , or, -N(R 2-1-1-2 )(R 2-1- 1-3 ); R 2-1-1-1 , R 2-1-1-2 and R 2-1-1-3 are independently C 1 ⁇ C 6 alkyl groups;
- R 2-1-2 is independently C 1 ⁇ C 6 alkyl or C 3 ⁇ C 6 cycloalkyl
- R 2-1-3 and R 2-1-4 are independently hydrogen, C 1 ⁇ C 6 alkyl or C 3 ⁇ C 6 cycloalkyl;
- R 2-1-5 is independently a C 1 ⁇ C 6 alkyl group or a C 3 ⁇ C 6 cycloalkyl group;
- R 2-3 is independently a C 1 ⁇ C 6 alkyl group
- R 2-4 and R 2-5 independently halogen, hydroxy, C 1 ⁇ C 6 alkyl group, and with one or more R 2-4-3 unsubstituted C 1 ⁇ C 6 alkyl group is, -N ( R 2-4-1 )(R 2-4-2 ) or C 1 ⁇ C 6 alkoxy;
- R 2-4-1 and R 2-4-2 are independently hydrogen, C 1 ⁇ C 6 Alkyl group or C 3 ⁇ C 6 cycloalkyl group;
- R 2-4-3 is halogen;
- R 2-2 is C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, phenyl, C 1 ⁇ C 6 alkyl substituted by one or more R 2-2-2 , or , Phenyl substituted with one or more R 2-2-1 ;
- R 2-2-1 is independently halogen;
- R 2-2-2 is independently halogen;
- R 2-6 is hydrogen, C 1 ⁇ C 10 alkyl group, the 2-6-1 substituted with one or more R C 1 ⁇ C 10 alkyl group, C 3 ⁇ C 6 cycloalkyl group, C 6 ⁇ C 10 Aryl groups, C 6 ⁇ C 10 aryl groups substituted by one or more R 2-6-2 , "the number of heteroatoms is 1, 2, or 3, and the heteroatoms are selected from one of N, O and S One or more of 3-6 membered heterocycloalkyl", or, "heteroatoms number of 1, 2 or 3 substituted by one or more R 2-6-3, heteroatoms selected from N, One or more of O and S 3-6 membered heterocycloalkyl";
- R 2-6-1 is independently oxo, halo, hydroxy, amino, carboxy, -CN, C 1 ⁇ C 6 alkyl, substituted with one or more halogen C 1 ⁇ C 6 alkyl group is, C 1 ⁇ C 6 alkoxy group, C 3 ⁇ C 6 cycloalkyl group, C 6 ⁇ C 10 aryl group, substituted with one or more R 2-6-1-1 substituted C 6 ⁇ C 10 aryl group, -OR 2-6-1-2 or -N(R 2-6-1-3 )(R 2-6-1-4 );
- R 2-6-2 is independently halogen, C 1 ⁇ C 6 alkyl or C 1 ⁇ C 6 alkoxy;
- R 2-6-1-1 is independently halogen
- R 2-6-1-2 , R 2-6-1-3 and R 2-6-1-4 are independently C 1 ⁇ C 6 alkyl groups
- R 2-7 is C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl or phenyl;
- R 2-8 and R 2-9 are independently hydrogen, C 1 ⁇ C 6 alkyl group, C 6 ⁇ C 10 aryl group, or substituted with one or more substituents R 2-8-1 is C 6 ⁇ C 10 aryl base;
- R 2-8-1 is halogen or C 1 ⁇ C 6 alkoxy
- R 2-10 is independently C 1 ⁇ C 6 alkyl or oxo
- R 2-26 and R 2-27 are independently halogen or C 1 ⁇ C 6 alkyl
- R 2-11 , R 2-12 , R 2-13 , R 2-14 , R 2-15 , R 2-16 , R 2-16 , R 2-17 , R 2-18 , R 2-19 , R 2-20 , R 2-21 , R 2-22 , R 2-23 , R 2-24 and R 2-25 are independently C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 3 -C 6 cycloalkyl, "5-6 membered heterocycloalkyl with 1, 2, or 3 heteroatoms selected from one or more of N, O and S", benzene Group , phenyl substituted by one or more R 2-11-1, "heteroatom number is 1, 2 or 3, heteroatom is selected from one or more of N, O and S 5 ⁇ 6-membered heteroaromatic ring", or substituted by one or more R 2-11-2 , "the number of heteroatoms is 1, 2, or 3, the heteroatoms are selected from one of N, O and S or Various 5- to 6-membered
- R 2-11-1 and R 2-11-2 are independently halogen, cyano, hydroxy, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, or C 3 to C 6 cycloalkyl.
- R 2 is located on.
- heteroatoms is 1, 2 or 3
- the heteroatom is selected from one or more of N, O and S in a 6-membered heteroene ring” or "the number of heteroatoms is 1, 2, or 3, the heteroatom is selected from N, One or more of O and S 6-membered heteroaromatic ring";
- R 1-1 is halogen, hydroxyl, amino, -NHR 1-1-4 , -N(R 1-1-5 )(R 1-1-6 ), C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 1 ⁇ C 6 alkyl substituted by one or more R 1-1-1 , C 3 ⁇ C 6 cycloalkane substituted by one or more R 1-1-2 Group, or, substituted by one or more R 1-1-3 "the number of heteroatoms is 1, 2, or 3, the heteroatoms are selected from one or more of N, O and S 4 ⁇ 7-membered heterocycloalkyl";
- R 1-1-1 , R 1-1-2 , R 1-1-3 , R 1-1-4 , R 1-1-5 and R 1-1-6 are independently halogen, hydroxyl, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 1 ⁇ C 6 alkoxy or "heteroatom number is 1, 2 or 3, heteroatom is selected from N, O and S One or more of 4-7 membered heterocycloalkyl";
- n 0, 1, 2 or 3;
- R 3-1 is independently halogen, cyano, hydroxyl, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 3 to C 6 cycloalkyl, or, C 1 to C 6 C 1 ⁇ C 6 alkoxy substituted by alkoxy;
- R 3-2 is a C 3 -C 6 cycloalkyl group substituted by one or more R 3-2-1 , and a "heteroatom number of 1, 2" substituted by one or more R 3-2-2
- One or three heteroatoms are selected from one or more of N, O and S 5-6 membered heterocycloalkyl
- the number of heteroatoms substituted by one or more R 3-2-2 is 1, 2, or 3 heteroatoms selected from one or more of N, O and S 7-8 membered heterocycloalkyl", or, substituted by one or more R 3-2-3
- the number of heteroatoms is 1, 2, or 3, and the heteroatom is selected from one or more of N, O and S 5-6 membered heteroaryl group";
- R 3-2-1 , R 3-2-2 and R 3-2-3 are independently halogen, hydroxyl, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 1 ⁇ C 6 alkoxy, or C 1 ⁇ C 6 alkoxy substituted C 1 ⁇ C 6 alkoxy;
- n 0, 1, 2, 3 or 4;
- R 2-1 independently halogen, hydroxy, cycloalkyl C 3 ⁇ C 6, and with one or more R 2-1-8 substituted cycloalkyl group of C 3 ⁇ C 6,
- number of heteroatoms is 1
- One, two or three heteroatoms are selected from one or more of N, O and S.
- 4-6 membered heterocycloalkyl "heterocycloalkyl” substituted by one or more R 2-1-7
- the number of atoms is 1, 2, or 3, and the heteroatom is selected from one or more of N, O, and S.
- R 2-1-1 , R 2-1-6 , R 2-1-7 and R 2-1-8 are independently oxo, hydroxy, amino, carboxy, halogen, -CN, C 1 ⁇ C 6 Alkyl group, C 1 ⁇ C 6 alkyl group substituted by one or more halogens , -OR 2-1-1-1 , or, -N(R 2-1-1-2 )(R 2-1- 1-3 ); R 2-1-1-1 , R 2-1-1-2 and R 2-1-1-3 are independently C 1 ⁇ C 6 alkyl groups;
- R 2-1-2 is independently C 1 ⁇ C 6 alkyl or C 3 ⁇ C 6 cycloalkyl
- R 2-1-3 and R 2-1-4 are independently hydrogen, C 1 ⁇ C 6 alkyl or C 3 ⁇ C 6 cycloalkyl;
- R 2-1-5 is independently a C 1 ⁇ C 6 alkyl group or a C 3 ⁇ C 6 cycloalkyl group;
- R 2-3 is independently a C 1 ⁇ C 6 alkyl group
- R 2-4 and R 2-5 are independently halogen, hydroxyl, -N(R 2-4-1 )(R 2-4-2 ) or C 1 ⁇ C 6 alkoxy;
- R 2-4- 1 and R 2-4-2 are independently hydrogen, C 1 ⁇ C 6 alkyl or C 3 ⁇ C 6 cycloalkyl;
- R 2-2 is C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, phenyl, or phenyl substituted by one or more R 2-2-1 ;
- R 2-2- 1 is independently halogen;
- R 2-6 is hydrogen, C 1 ⁇ C 10 alkyl group, the 2-6-1 substituted with one or more R C 1 ⁇ C 10 alkyl group, C 3 ⁇ C 6 cycloalkyl group, C 6 ⁇ C 10 Aryl groups, C 6 ⁇ C 10 aryl groups substituted by one or more R 2-6-2 , "the number of heteroatoms is 1, 2, or 3, and the heteroatoms are selected from one of N, O and S One or more of 3-6 membered heterocycloalkyl", or, "heteroatoms number of 1, 2 or 3 substituted by one or more R 2-6-3, heteroatoms selected from N, One or more of O and S 3-6 membered heterocycloalkyl";
- R 2-6-1 is independently oxo, halo, hydroxy, amino, carboxy, -CN, C 1 ⁇ C 6 alkyl, substituted with one or more halogen C 1 ⁇ C 6 alkyl group is, C 1 ⁇ C 6 alkoxy group, C 3 ⁇ C 6 cycloalkyl group, C 6 ⁇ C 10 aryl group, substituted with one or more R 2-6-1-1 substituted C 6 ⁇ C 10 aryl group, -OR 2-6-1-2 or -N(R 2-6-1-3 )(R 2-6-1-4 );
- R 2-6-2 is independently halogen, C 1 ⁇ C 6 alkyl or C 1 ⁇ C 6 alkoxy;
- R 2-6-1-1 is independently halogen
- R 2-6-1-2 , R 2-6-1-3 and R 2-6-1-4 are independently C 1 ⁇ C 6 alkyl groups
- R 2-7 is C 1 ⁇ C 6 alkyl
- R 2-8 and R 2-9 are independently hydrogen, C 1 ⁇ C 6 alkyl group, C 6 ⁇ C 10 aryl group, or substituted with one or more substituents R 2-8-1 is C 6 ⁇ C 10 aryl base;
- R 2-8-1 is halogen or C 1 ⁇ C 6 alkoxy
- R 2-10 is independently C 1 ⁇ C 6 alkyl or oxo
- R 2-11 , R 2-12 , R 2-13 , R 2-14 , R 2-15 , R 2-16 , R 2-16 , R 2-17 , R 2-18 , R 2-19 , R 2-20 , R 2-21 , R 2-22 , R 2-23 , R 2-24 and R 2-25 are independently C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 3 -C 6 cycloalkyl, "5-6 membered heterocycloalkyl with 1, 2, or 3 heteroatoms selected from one or more of N, O and S", benzene Group , phenyl substituted by one or more R 2-11-1, "heteroatom number is 1, 2 or 3, heteroatom is selected from one or more of N, O and S 5 ⁇ 6-membered heteroaromatic ring", or substituted by one or more R 2-11-2 , "the number of heteroatoms is 1, 2, or 3, the heteroatoms are selected from one of N, O and S or Various 5- to 6-membered
- R 2-11-1 and R 2-11-2 are independently halogen, cyano, hydroxy, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, or C 3 to C 6 cycloalkyl.
- R 2 is located on.
- the above-mentioned fused ring compound represented by formula I its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, its nitrogen In the solvates of oxides, their solvates or their pharmaceutically acceptable salts, certain groups have the following definitions, and the definitions of unmentioned groups are as described in any of the above schemes (hereinafter referred to as "In certain embodiments"):
- the 6-membered heteroalkene ring when When it is "a 6-membered heteroalkene ring with 1, 2 or 3 heteroatoms selected from one or more of N, O and S", the 6-membered heteroalkene ring
- the heteroatom is selected from N, and the number of heteroatoms is one; the number of double bonds in the 6-membered heteroene ring is preferably 1 or 2; Preferably it is a double bond.
- the 6-membered heteroalkene ring when When it is "a 6-membered heteroalkene ring with 1, 2 or 3 heteroatoms, and one or more of N, O and S", the 6-membered heteroalkene ring
- the heteroatom is selected from N, and the number of heteroatoms is one; the number of double bonds in the 6-membered heteroene ring is preferably 1 or 2; Preferably it is a double bond.
- R 1-1 is a C 1 ⁇ C 6 alkyl group
- the C 1 ⁇ C 6 alkyl group is a C 1 ⁇ C 4 alkyl group, preferably methyl, ethyl, N-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, more preferably methyl.
- R 1-1 is a C 3 to C 6 cycloalkyl group
- the C 3 to C 6 cycloalkyl group is cyclopropyl, cyclobutyl or cyclopentyl.
- R 1-1 is a C 1 -C 6 alkyl group substituted with one or more R 1-1-1
- said R 1-1 is substituted with one or more R 1-1-1
- the C 1 ⁇ C 6 alkyl group in the C 1 ⁇ C 6 alkyl group is a C 1 ⁇ C 4 alkyl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Group, sec-butyl or tert-butyl.
- R 1-1-2 1-1 of as being substituted with one or more R a cycloalkyl group of C 3 ⁇ C 6 said one or more R 1-1- 2-substituted cycloalkyl ring C 3 ⁇ C 6 alkyl group in the C 3 ⁇ C 6 cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl.
- R 1-1-1 and R 1-1-2 are independently halogen
- the halogen is fluorine, chlorine, bromine or iodine.
- R 3-1 when R 3-1 is independently halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
- R 3-1 are independently C 1 ⁇ C 6 alkoxy group by one or more R 3-1-2 unsubstituted C 1 ⁇ C 6 alkoxy time, the said alkoxy group of C 1 ⁇ C 6, and with one or more R 3-1-2 unsubstituted C 1 ⁇ C 6 alkoxy group where the C 1 ⁇ C 6 alkoxy group of C 1 ⁇ C 4 alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, more preferably methoxy base.
- R 3-1-1 and R 3-1-2 are independently halogen
- the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
- the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
- the C 1 ⁇ C 10 alkyl group is a C 1 ⁇ C 4 alkyl group, preferably methyl, ethyl, or n-propyl. , Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, more preferably methyl or isopropyl.
- the C 1 to C 10 alkyl group is a C 1 to C 4 alkyl group, Preferably, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and more preferably methyl.
- R 2 is a C 2 ⁇ C 10 alkenyl, substituted 2-26 with one or more R C 2 ⁇ C 10 alkenyl group
- said C 2 ⁇ C 10 alkenyl group, and with one or more substituents R 2-26 is C 2 ⁇ C 10 alkenyl group is in C 2 ⁇ C 10 alkenyl group of C 2 ⁇ C 4 alkenyl groups such as vinyl, allyl.
- R 2 is a C 2 ⁇ C 10 alkynyl group or substituted with one or more R 2-27 is C 2 ⁇ C 10 alkynyl group
- the C 2 ⁇ C 10 alkynyl group, and with one or more substituents R 2-27 is C 2 ⁇ C 10 alkynyl group is in C 2 ⁇ C 10 alkynyl group is a C 2 ⁇ C 4 alkynyl group such as ethynyl, propynyl.
- R 2-26 and R 2-27 are independently halogen
- the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
- R 2 is C 3 ⁇ C 6 cycloalkyl
- said C 3 ⁇ C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably Cyclopropyl or cyclobutyl.
- R 2 is a "3- to 4-membered heterocycloalkyl group with one or two heteroatoms selected from one or more of N, O and S" or is When one or more R 2-10 substituted "the number of heteroatoms is 1 or 2, the heteroatom is selected from one or more of N, O and S 3 to 4 member heterocycloalkyl", the The heteroatoms in the 3- to 4-membered heterocycloalkyl group are selected from one or more of N and O, and the number of heteroatoms is preferably 1 or 2.
- the 3- to 4-membered heterocycloalkyl group is preferably
- R 2 is a 5- to 6-membered heterocycloalkyl group having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S "
- the heteroatoms in the 5- to 6-membered heterocycloalkyl group are selected from one or more of N and O, and the number of heteroatoms is preferably 1 or 2.
- the 5- to 6-membered heterocycloalkyl group Preferably
- R 2 is a 5- to 6-membered heterocycloalkyl group having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S "
- the heteroatoms in the 5- to 6-membered heterocycloalkyl group are selected from one or more of N and O, and the number of heteroatoms is preferably 1 or 2.
- the 5- to 6-membered heterocycloalkyl group Preferably
- R 2 is "a 5- to 6-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S"
- the heteroatom in the 5- to 6-membered heteroaryl group is preferably N, and the number of heteroatoms is preferably 2.
- the 5- to 6-membered heteroaryl group is preferably The 5- to 6-membered heteroaryl group is preferably
- the heteroatoms are selected from one of N, O and S or
- the heteroatom in the 5- to 6-membered heteroaryl group is preferably N, and the number of heteroatoms is preferably 1.
- the 5- to 6-membered heteroaryl group is preferably
- the heteroatoms are selected from one of N, O and S or
- R 2-1 when R 2-1 is independently halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.
- R 2-1 is independently a C 3 ⁇ C 6 cycloalkyl group
- the C 3 ⁇ C 6 cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl Or cyclohexyl, preferably cyclopropyl or cyclobutyl.
- R 2-2 is C 1 ⁇ C 6 alkyl group by one or more R 2-2-2 unsubstituted C 1 ⁇ C 6 alkyl group when, a C 1
- the alkyl group of ⁇ C 6 is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl or n-butyl, More preferably, it is a methyl group.
- R 2-2 is a C 3 ⁇ C 6 cycloalkyl group
- the C 3 ⁇ C 6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cycloalkyl.
- the hexyl group is preferably cyclopropyl or cyclobutyl.
- R 2-2-2 when R 2-2-2 is independently halogen, said halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
- R 2-4 and R 2-5 are independently halogen
- the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
- R 2-4 and R 2-5 are independently C 1 ⁇ C 6 alkyl group by one or more R 2-4-3 unsubstituted C 1 ⁇ C 6 alkyl group is when said C 1 ⁇ C 6 alkyl group and one or more R 2-4-3 unsubstituted C 1 ⁇ C 6 alkyl group in the alkyl group is preferably a C 1 ⁇ C 6 are methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl or n-butyl, more preferably methyl.
- R 2-4-3 is halogen
- the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
- R 2-6 when R 2-6 is C 1 ⁇ C 10 alkyl, said C 1 ⁇ C 10 alkyl is C 1 ⁇ C 6 alkyl, preferably methyl, ethyl, normal Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl or n-butyl, more preferably methyl, ethyl, isobutyl or isopentyl base.
- R 2-6 is a C 1 ⁇ C 10 alkyl group substituted with one or more R 2-6-1
- the C 1 ⁇ C 10 alkyl group is C 1 ⁇ C 4
- the alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and more preferably methyl or ethyl.
- R 2-6 is C 3 ⁇ C 6 cycloalkyl
- said C 3 ⁇ C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, Preferably, it is cyclopropyl, cyclobutyl or cyclopentyl.
- R 2-6 is a C 6 ⁇ C 10 aryl group
- the C 6 ⁇ C 10 aryl group is phenyl or naphthyl.
- R 2-6 is a C 6 ⁇ C 10 aryl group substituted with one or more R 2-6-2
- the C 6 ⁇ C 10 aryl group is phenyl or naphthalene
- the group is preferably a phenyl group.
- R 2-6 is a 3 to 6-membered heterocyclic ring having 1, 2, or 3 heteroatoms selected from one or more of N, O and S
- the 3- to 6-membered heterocycloalkyl is a 3- to 4-membered heterocycloalkyl; in the 3- to 4-membered heterocycloalkyl, the heteroatom is preferably N, and the number of heteroatoms is preferably 1 piece.
- the 3- to 4-membered heterocycloalkyl group is preferably
- R 2-6 when R 2-6 is substituted with one or more R 2-6-3 "the number of heteroatoms is 1, 2, or 3, the heteroatoms are selected from N, O and S One or more of 3-6 membered heterocycloalkyl", said 3-6 membered heterocycloalkyl is 3 to 4-membered heterocycloalkyl; said 3 to 4-membered heterocycloalkyl Among them, the heteroatom is preferably N, and the number of heteroatoms is preferably one.
- the 3- to 4-membered heterocycloalkyl group is preferably
- R 2-6-1 when R 2-6-1 is independently halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.
- the C 1 ⁇ C 6 alkoxy group is a C 1 ⁇ C 4 alkoxy group, preferably Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, more preferably methoxy. In certain embodiments, it is preferably ethoxy.
- R 2-6-1 is independently C 3 ⁇ C 6 cycloalkyl
- said C 3 ⁇ C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl Or cyclohexyl, preferably cyclopropyl. In certain embodiments, it is preferably cyclobutyl.
- R 2-6-1 is independently a C 6 -C 10 aryl group
- the C 6 -C 10 aryl group is phenyl or naphthyl.
- R 2-6-1 is independently C 6 ⁇ C 10 aryl substituted with one or more R 2-6-1-1 , said C 6 ⁇ C 10 aryl
- the group is phenyl or naphthyl, preferably phenyl.
- R 2-6-2 when R 2-6-2 is independently halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.
- the C 1 ⁇ C 6 alkyl group is a C 1 ⁇ C 4 alkyl group, preferably a methyl group, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, more preferably methyl.
- R 2-6-2 is independently a C 1 ⁇ C 6 alkoxy group
- the C 1 ⁇ C 6 alkoxy group is a C 1 ⁇ C 4 alkoxy group, preferably Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, more preferably methoxy.
- the C 1 to C 4 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and more preferably methyl.
- R 2-6-1-1 is independently fluorine, chlorine, bromine or iodine, preferably fluorine.
- R 2-7 is C 1 -C 4 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
- the group is more preferably a methyl group.
- R 2-7 is preferably isopropyl.
- R 2-7 is C 3 ⁇ C 6 cycloalkyl
- said C 3 ⁇ C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably It is cyclopropyl.
- R 2-8 and R 2-9 are independently C 1 ⁇ C 6 alkyl
- said C 1 ⁇ C 6 alkyl is C 1 ⁇ C 4 alkyl, preferably methyl Group, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, more preferably isopropyl. In certain embodiments, it is preferably methyl.
- R 2-8 and R 2-9 are independently C 6 ⁇ C 10 aryl
- the C 6 ⁇ C 10 aryl is phenyl or naphthyl.
- R 2-8 and R 2-9 are independently C 6 ⁇ C 10 aryl substituted with one or more R 2-8-1
- said one or more The C 6 -C 10 aryl group in the C 6 -C 10 aryl group substituted by R 2-8-1 is a phenyl group or a naphthyl group, and is preferably a phenyl group.
- R 2-8-1 when R 2-8-1 is halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.
- the C 1 ⁇ C 6 alkoxy is C 1 ⁇ C 4 alkoxy, preferably methoxy Group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group or tert-butoxy group, more preferably methoxy group.
- R 2-10 when R 2-10 is independently C 1 ⁇ C 6 alkyl, said C 1 ⁇ C 6 alkyl is C 1 ⁇ C 4 alkyl, preferably methyl, ethyl , N-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, more preferably methyl.
- It is a double bond.
- It is a phenyl group or "a 6-membered heteroaromatic ring with 1, 2, or 3 heteroatoms and heteroatoms selected from N".
- Is phenyl In some embodiments, Is phenyl.
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1-1 is C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 1 ⁇ C 6 substituted with one or more R 1-1-1 Alkyl group, C 3 to C 6 cycloalkyl group substituted by one or more R 1-1-2.
- R 1-1 is a C 1 -C 6 alkyl group.
- R 1-1-1 and R 1-1-2 are independently halogen.
- R 3 is
- n 1, 2, or 3.
- R 3-1 is independently halogen, cyano, hydroxy, C 1 -C 6 alkoxy substituted with one or more R 3-1-2.
- R 3-1 is independently halogen, cyano, or hydroxy.
- m is 0 or 1.
- R 2 is oxo, halogen, cyano, isocyano, amino, C 1 ⁇ C 10 alkyl, substituted with one or more 2-1 R C 1 ⁇ C 10 alkyl group , C 2 ⁇ C 10 alkenyl group, substituted with one or more substituents
- R 2-26 is C 2 ⁇ C 10 alkenyl group, C 2 ⁇ C 10 alkynyl, substituted 2-27 with one or more R C 2 ⁇ C 10 alkynyl, C 3 ⁇ C 6 cycloalkyl, 5-6 membered heteroatoms with 1, 2, or 3 heteroatoms selected from one or more of N, O and S Cycloalkyl", "3- to 4-membered heterocycloalkyl with one or two heteroatoms selected from one or more of N, O and S", phenyl, and one or more heteroatoms A phenyl group substituted with R 2-4 , "a 5- to 6-membered heteroaryl group with 1, 2, or 3 heteroatoms selected
- C 3 ⁇ C 6 cycloalkyl, phenyl, phenyl substituted with one or more R 2-4 , "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N, O and S One or more 3- to 4-membered heterocycloalkyl", -(C O)-R 2-2 .
- Is a benzene ring for example, R 2 is a cyano group.
- R 2 is oxo, halogen, cyano, amino, C 1 ⁇ C 10 alkyl, substituted with one or more 2-1 R C 1 ⁇ C 10 alkyl group, C 3 ⁇ C 6 cycloalkyl, "5-6 membered heterocycloalkyl with 1, 2, or 3 heteroatoms selected from one or more of N, O and S", "heteroatom The number is 1, 2, or 3, and the heteroatom is selected from one or more of N, O and S.
- heteroatoms substituted by one or more R 2-10 the number of heteroatoms is 1, 2 or 3, heteroatoms are selected from N, O and S One or more of 5-6 membered heterocycloalkyl.
- R 2 is oxo, halogen, cyano, amino, C 1 ⁇ C 10 alkyl, substituted with one or more 2-1 R C 1 ⁇ C 10 alkyl group, C 3 ⁇ C 6 cycloalkyl, "5-6 membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O and S", or, -OR 2-6 .
- R 2-1 independently halo, cycloalkyl C 3 ⁇ C 6 alkyl group, a phenyl group.
- R 2-1 is independently halogen.
- R 2-2 is C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, phenyl, C 1 ⁇ substituted with one or more R 2-2-2 C 6 alkyl group.
- R 2-4 and R 2-5 independently halogen, C 1 ⁇ C 6 alkyl group, and is 2-4-3 substituted with one or more R C 1 ⁇ C 6 alkyl in base.
- R 2-6 is hydrogen, C 1 ⁇ C 10 alkyl group, the 2-6-1 substituted with one or more R C 1 ⁇ C 10 alkyl group, C 3 ⁇ C 6 cycloalkyl group, C 6 ⁇ C 10 aryl group, substituted with one or more substituents
- R 2-6-2 is C 6 ⁇ C 10 aryl group, "number of heteroatoms is 1, 2 or 3 heteroatoms selected from N , O and S one or more of 3-6 membered heterocycloalkyl", or, substituted by one or more R 2-6-3 "heteroatom number is 1, 2 or 3 , The heteroatom is a 3- to 6-membered heterocycloalkyl group selected from one or more of N, O and S".
- R 2-6 is hydrogen, C 1 ⁇ C 10 alkyl group, the 2-6-1 substituted with one or more R C 1 ⁇ C 10 alkyl group, C 3 ⁇ C 6 cycloalkyl Group, C 6 ⁇ C 10 aryl group substituted by one or more R 2-6-2 , "the number of heteroatoms is 1, 2, or 3, and the heteroatom is selected from one of N, O and S Or a variety of 3-6 membered heterocycloalkyl" or "heteroatoms substituted by one or more R 2-6-3 , the number of heteroatoms is 1, 2, or 3, heteroatoms are selected from N, O And one or more of 3-6 membered heterocycloalkyl in S".
- R 2-6-1 is independently halogen, hydroxy, C 1 ⁇ C 6 alkoxy, C 3 ⁇ C 6 cycloalkyl, or, is substituted by one or more R 2-6- 1-1 substituted C 6 ⁇ C 10 aryl group.
- R 2-6-1 is independently halogen, C 3 ⁇ C 6 cycloalkyl, or, C 6 ⁇ C 10 aryl substituted with one or more R 2-6-1-1 base.
- R 2-7 is C 3 to C 6 cycloalkyl or phenyl.
- R 3 when R 3 is When, the R 3 is Preferably More preferred
- R 3 when R 3 is When, the R 3 is Preferably
- R 3 when R 3 is When, the R 3 is Preferably
- R 2 is oxo, methoxy, fluorine, chlorine, hydroxy, amino, -CH 2 F, difluoromethyl, trifluoromethyl, methyl, isopropyl, cyclopropyl , Cyano, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, Ethyl, dichloromethyl, Ethynyl, propynyl, Benzyl, Phenyl,
- R 2 is oxo, methoxy, fluorine, chlorine, hydroxy, amino, -CH 2 F, difluoromethyl, trifluoromethyl, methyl, isopropyl, cyclopropyl , Cyano, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy,
- R 2 is oxo, methoxy, fluorine, chlorine, hydroxy, amino, difluoromethyl, trifluoromethyl, isopropyl, cyclopropyl, cyano, ethoxy, Isopropoxy, difluoromethoxy,
- R 1-1 is a C 1 ⁇ C 6 alkyl group
- n 1, 2 or 3;
- R 3-1 is independently halogen, cyano, hydroxyl, C 1 ⁇ C 6 alkoxy substituted by one or more R 3-1-2;
- n 0, 1;
- R 2 is oxo, halogen, cyano, amino, isocyano, C 1 ⁇ C 10 alkyl, substituted with one or more 2-1 R C 1 ⁇ C 10 alkyl group, C 2 ⁇ C 10 alkenyl group, with one or more substituents R 2-26 is C 2 ⁇ C 10 alkenyl group, C 2 ⁇ C 10 alkynyl group, with one or more substituents R 2-27 is C 2 ⁇ C 10 alkynyl group, C 3 ⁇ C 6 cycloalkyl, "5-6 membered heterocycloalkyl with 1, 2, or 3 heteroatoms selected from one or more of N, O and S", " The number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O, and S.
- R 2-1 is independently halogen, C 3 ⁇ C 6 cycloalkyl or phenyl;
- R 2-2 is a C 1 ⁇ C 6 alkyl group, a C 3 ⁇ C 6 cycloalkyl group, a phenyl group or a C 1 ⁇ C 6 alkyl group substituted by one or more R 2-2-2; R 2-2-2 is independently halogen;
- R 2-4 and R 2-5 independently halogen, C 1 ⁇ C 6 alkyl group, and is 2-4-3 substituted with one or more R C 1 ⁇ C 6 alkyl group of; R 2-4- 3 is halogen;
- R 2-6 is hydrogen, C 1 ⁇ C 10 alkyl group, the 2-6-1 substituted with one or more R C 1 ⁇ C 10 alkyl group, C 3 ⁇ C 6 cycloalkyl group, C 6 ⁇ C 10 Aryl groups, C 6 ⁇ C 10 aryl groups substituted by one or more R 2-6-2 , "the number of heteroatoms is 1, 2, or 3, and the heteroatoms are selected from one of N, O and S One or more of 3-6 membered heterocycloalkyl", or, "heteroatoms number of 1, 2 or 3 substituted by one or more R 2-6-3, heteroatoms selected from N, One or more of O and S 3-6 membered heterocycloalkyl";
- R 2-6-1 is independently halogen, hydroxyl, C 1 ⁇ C 6 alkoxy, C 3 ⁇ C 6 cycloalkyl, C 6 ⁇ C substituted by one or more R 2-6-1-1 10 aryl groups;
- R 2-6-2 is independently halogen, C 1 ⁇ C 6 alkyl or C 1 ⁇ C 6 alkoxy;
- R 2-6-1-1 is independently halogen
- R 2-6-1-2 is independently a C 1 ⁇ C 6 alkyl group
- R 2-7 is C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl or phenyl;
- R 2-8 and R 2-9 are independently hydrogen, C 1 ⁇ C 6 alkyl group, C 6 ⁇ C 10 aryl group, or substituted with one or more substituents R 2-8-1 is C 6 ⁇ C 10 aryl base;
- R 2-8-1 is halogen or C 1 ⁇ C 6 alkoxy
- R 2-10 is independently C 1 ⁇ C 6 alkyl or oxo
- R 2-26 and R 2-27 are independently halogen or C 1 -C 6 alkyl.
- R 1-1 is a C 1 ⁇ C 6 alkyl group, a C 3 ⁇ C 6 cycloalkyl group, a C 1 ⁇ C 6 alkyl group substituted with one or more R 1-1-1 , one or more A C 3 ⁇ C 6 cycloalkyl substituted by R 1-1-2;
- R 1-1-1 and R 1-1-2 are independently halogen
- n 1, 2 or 3;
- R 3-1 is independently halogen, cyano, or hydroxyl
- n 0, 1;
- R 2 is oxo, halogen, cyano, amino, C 1 ⁇ C 10 alkyl group, with one or more substituents R 2-1 is C 1 ⁇ C 10 alkyl group, a cycloalkyl group of C 3 ⁇ C 6, "The number of heteroatoms is 1, 2, or 3, and the heteroatom is selected from one or more of N, O, and S.
- R 2-1 is independently halogen
- R 2-6 is hydrogen, C 1 ⁇ C 10 alkyl group, the 2-6-1 substituted with one or more R C 1 ⁇ C 10 alkyl group, C 3 ⁇ C 6 cycloalkyl group, C 6 ⁇ C 10 Aryl groups, C 6 ⁇ C 10 aryl groups substituted by one or more R 2-6-2 , "the number of heteroatoms is 1, 2, or 3, and the heteroatoms are selected from one of N, O and S One or more of 3-6 membered heterocycloalkyl", or, "heteroatoms number of 1, 2 or 3 substituted by one or more R 2-6-3, heteroatoms selected from N, One or more of O and S 3-6 membered heterocycloalkyl";
- R 2-6-1 is independently halogen, hydroxy, C 3 ⁇ C 6 cycloalkyl, C 6 ⁇ C 10 aryl substituted by one or more R 2-6-1-1;
- R 2-6-2 is independently halogen, C 1 ⁇ C 6 alkyl or C 1 ⁇ C 6 alkoxy;
- R 2-6-1-1 is independently halogen
- R 2-7 is C 1 ⁇ C 6 alkyl
- R 2-8 and R 2-9 are independently hydrogen, C 1 ⁇ C 6 alkyl group, C 6 ⁇ C 10 aryl group, or substituted with one or more substituents R 2-8-1 is C 6 ⁇ C 10 aryl base;
- R 2-8-1 is halogen or C 1 ⁇ C 6 alkoxy
- R 2-10 is independently C 1 -C 6 alkyl or oxo.
- R 1-1 is a C 1 ⁇ C 6 alkyl group
- n 1, 2 or 3;
- R 3-1 is independently halogen, cyano, or hydroxyl
- n 0, 1;
- R 2 is oxo, halogen, cyano, amino, C 1 ⁇ C 10 alkyl group, with one or more substituents R 2-1 is C 1 ⁇ C 10 alkyl group, a cycloalkyl group of C 3 ⁇ C 6, "The number of heteroatoms is 1, 2, or 3, and the heteroatom is selected from one or more of N, O, and S.
- R 2-1 is independently halogen
- R 2-6 is hydrogen, C 1 ⁇ C 10 alkyl group, the 2-6-1 substituted with one or more R C 1 ⁇ C 10 alkyl group, C 3 ⁇ C 6 cycloalkyl group, C 6 ⁇ C 10 Aryl groups, C 6 ⁇ C 10 aryl groups substituted by one or more R 2-6-2 , "the number of heteroatoms is 1, 2, or 3, and the heteroatoms are selected from one of N, O and S One or more of 3-6 membered heterocycloalkyl", or, "heteroatoms number of 1, 2 or 3 substituted by one or more R 2-6-3, heteroatoms selected from N, One or more of O and S 3-6 membered heterocycloalkyl";
- R 2-6-1 is independently halogen, hydroxyl, C 3 ⁇ C 6 cycloalkyl, C 6 ⁇ C 10 aryl substituted with one or more R 2-6-1-1;
- R 2-6-2 is independently halogen, C 1 ⁇ C 6 alkyl or C 1 ⁇ C 6 alkoxy;
- R 2-6-1-1 is independently halogen
- R 2-7 is C 1 ⁇ C 6 alkyl
- R 2-8 and R 2-9 are independently hydrogen, C 1 ⁇ C 6 alkyl group, C 6 ⁇ C 10 aryl group, or substituted with one or more substituents R 2-8-1 is C 6 ⁇ C 10 aryl base;
- R 2-8-1 is halogen or C 1 ⁇ C 6 alkoxy
- R 2-10 is independently C 1 -C 6 alkyl or oxo.
- R 2-10 is independently C 1 -C 6 alkyl or oxo.
- n 1, 2 or 3;
- R 3-1 is independently halogen, cyano, or hydroxyl
- n 0, 1;
- R 2 is oxo, halogen, cyano, amino, C 1 ⁇ C 10 alkyl group, with one or more substituents R 2-1 is C 1 ⁇ C 10 alkyl group, a cycloalkyl group of C 3 ⁇ C 6, "The number of heteroatoms is 1, 2, or 3, and the heteroatom is selected from one or more of N, O and S 5-6 membered heteroaryl group", or, -OR 2-6 ;
- R 2-1 is independently halogen
- R 2-6 is hydrogen, C 1 ⁇ C 10 alkyl group, the 2-6-1 substituted with one or more R C 1 ⁇ C 10 alkyl group, C 3 ⁇ C 6 cycloalkyl group, C 6 ⁇ C 10 Aryl groups, C 6 ⁇ C 10 aryl groups substituted by one or more R 2-6-2 , "the number of heteroatoms is 1, 2, or 3, and the heteroatoms are selected from one of N, O and S One or more of 3-6 membered heterocycloalkyl", or, "heteroatoms number of 1, 2 or 3 substituted by one or more R 2-6-3, heteroatoms selected from N, One or more of O and S 3-6 membered heterocycloalkyl";
- R 2-6-1 is independently halogen, C 3 ⁇ C 6 cycloalkyl, C 6 ⁇ C 10 aryl substituted by one or more R 2-6-1-1 ;
- R 2-6-1- 1 is independently halogen;
- R 2-6-2 is independently halogen, C 1 ⁇ C 6 alkyl or C 1 ⁇ C 6 alkoxy;
- R 2-6-1-1 is independently halogen
- R 2-10 is independently C 1 -C 6 alkyl or oxo.
- n 1, 2 or 3;
- R 3-1 is independently halogen, cyano, or hydroxyl
- n 0, 1;
- R 2 is oxo, halogen, cyano, C 1 ⁇ C 10 alkyl, or, C 1 ⁇ C 10 alkyl substituted by one or more R 2-1 , C 3 ⁇ C 6 cycloalkyl, " The number of heteroatoms is 1, 2, or 3, and the heteroatoms are selected from one or more of N, O and S. 5-6 membered heteroaryl", or, -OR 2-6 ;
- R 2-1 is independently halogen
- R 2-6 is C 1 ⁇ C 10 alkyl group, with one or more substituents R 2-6-1 is C 1 ⁇ C 10 alkyl group, C 3 ⁇ C 6 cycloalkyl, substituted with one or more R 2 -6-2 substituted C 6 ⁇ C 10 aryl group, "the number of heteroatoms is 1, 2, or 3, and the heteroatom is selected from one or more of N, O and S. Cycloalkyl" or “heteroatoms substituted by one or more R 2-6-3 " is 1, 2, or 3, and the heteroatoms are selected from one or more of N, O and S "3-6 membered heterocycloalkyl";
- R 2-6-1 is independently halogen, C 3 ⁇ C 6 cycloalkyl, C 6 ⁇ C 10 aryl substituted by one or more R 2-6-1-1 ;
- R 2-6-1- 1 is independently halogen;
- R 2-6-2 is independently halogen, C 1 ⁇ C 6 alkyl or C 1 ⁇ C 6 alkoxy;
- n 1, 2 or 3;
- R 3-1 is independently halogen, cyano, or hydroxyl
- n 0, 1;
- R 2 is chloro, cyano, C 1 ⁇ C 10 alkyl, substituted with one or more 2-1 R C 1 ⁇ C 10 alkyl group, C 3 ⁇ C 6 cycloalkyl, "number of heteroatoms is 1 One, two, or three heteroatoms are selected from one or more of N, O, and S, a 5- to 6-membered heteroaryl group", or, -OR 2-6 ;
- R 2-1 is independently halogen
- R 2-6 is C 1 ⁇ C 4 alkyl, C 1 -C 2 alkyl substituted by one or more R 2-6-1 , C 3 ⁇ C 6 cycloalkyl, substituted by one or more R 2 -6-2 substituted C 6 ⁇ C 10 aryl groups, "the number of heteroatoms is 1, 2, or 3, and the heteroatoms are selected from one or more of N, O and S. 3 to 6 membered hetero Cycloalkyl" or “heteroatoms substituted by one or more R 2-6-3 " is 1, 2, or 3, and the heteroatoms are selected from one or more of N, O and S When R 2 is chlorine, R 2 is located on Z 1 or Z 4 ;
- R 2-6-1 is independently halogen, C 3 ⁇ C 6 cycloalkyl, C 6 ⁇ C 10 aryl substituted by one or more R 2-6-1-1;
- R 2-6-2 is independently halogen, C 1 ⁇ C 6 alkyl or C 1 ⁇ C 6 alkoxy;
- a terminal connected to Z 10 represents a position of.
- the compound represented by Formula I is a compound represented by any one of the following:
- the pharmaceutically acceptable salt of the compound represented by formula I is the following compound:
- the fused ring compound represented by formula I its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotope compound, its crystal form, its nitrogen oxide, its
- the solvate or the solvate of the pharmaceutically acceptable salt thereof can be synthesized by referring to the well-known and similar methods in the chemical field, and can also be synthesized by referring to the method described in the present invention.
- the present invention also provides a method for preparing the compound represented by formula I, which is any one of the following schemes:
- the alkali can be sodium ethoxide, sodium ethoxide, ammonia or hydrazine;
- R 2 and R 3 are the same as defined above.
- the present invention also provides a compound represented by formula II, III or IV,
- n, R 2 and R 3 are the same as defined above.
- the compound represented by Formula II is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- the compound of formula III is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- the compound of formula IV is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- the present invention also provides the compounds shown below,
- the fused ring compound represented by formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound according to the present invention can be synthesized by referring to well-known and similar methods in the chemical field It can also be synthesized by referring to the method described in the present invention.
- the present invention also provides a pharmaceutical composition, which comprises substance A and at least one pharmaceutical excipient;
- the substance A is the above-mentioned fused ring compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotope compound, its crystal form, its nitroxide Solvate, its solvate, or the solvate of its pharmaceutically acceptable salt.
- the dosage of the substance A can be a therapeutically effective amount.
- the present invention also provides an application of substance A in the preparation of P2X4 receptor antagonists or drugs;
- the substance A is the above-mentioned fused ring compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotope compound, its crystal form, its nitroxide Solvate, its solvate, or the solvate of its pharmaceutically acceptable salt.
- the drugs can be used to treat or prevent urinary tract diseases, respiratory diseases, pain, autoimmune diseases, inflammation, Alzheimer's disease, Parkinson's disease, sleep disorders, epilepsy, Mental illness, arthritis, neurodegeneration, traumatic brain injury, myocardial infarction, rheumatoid arthritis, stroke, thrombosis, atherosclerosis, colon syndrome, inflammatory bowel disease, digestive tract disease, stomach Intestinal dysfunction, respiratory failure, sexual dysfunction, cardiovascular disease, heart failure, high blood pressure, urinary incontinence, cystitis, arthritis, endometriosis, blood disease, musculoskeletal and connective tissue development disorders, or, Systemic disorders.
- the urinary tract diseases are for example urinary incontinence, overactive bladder, dysuria or cystitis.
- the respiratory diseases such as respiratory disorders include idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm or cough (e.g. chronic cough).
- the pain is for example inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, pain caused by burns, migraine, cluster headache or chronic pain.
- the medicament can be used to prevent or treat diseases that are at least partially mediated by P2X4 in animals (such as humans).
- the diseases at least partly mediated by P2X4 such as urinary tract diseases, respiratory diseases, pain, autoimmune diseases, inflammation, Alzheimer's disease, Parkinson's, sleep disorders, epilepsy, mental diseases, arthritis, neurodegeneration , Traumatic brain injury, myocardial infarction, rheumatoid arthritis, stroke, thrombosis, atherosclerosis, colon syndrome, inflammatory bowel disease, digestive tract disease, gastrointestinal dysfunction, respiratory failure, sexual dysfunction , Cardiovascular diseases, heart failure, high blood pressure, urinary incontinence, cystitis, arthritis, endometriosis, blood diseases, musculoskeletal and connective tissue development disorders, or, systemic disorders.
- urinary tract diseases such as urinary tract diseases, respiratory diseases, pain, autoimmune diseases, inflammation, Alzheimer's disease, Parkinson's, sleep disorders, epilepsy, mental diseases, arthritis, neurodegeneration , Traumatic brain injury, myocardial infarction, rheumatoid arthritis, stroke, thrombosis, atherosclerosis,
- the urinary tract diseases are for example urinary incontinence, overactive bladder, dysuria or cystitis.
- the respiratory diseases such as respiratory disorders include idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm or cough (e.g. chronic cough).
- the pain is, for example, inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, pain caused by burns, migraine, cluster headache or chronic pain.
- the present invention also provides a method for treating or preventing diseases, which comprises administering a therapeutically effective amount of substance A to a patient (such as a human);
- the disease is urinary tract disease, respiratory system disease, pain, autoimmune disease, inflammation, Alzheimer's disease, Parkinson, sleep disorder, epilepsy, mental disease, arthritis, neurodegeneration, traumatic brain injury, myocardium Infarction, rheumatoid arthritis, stroke, thrombosis, atherosclerosis, colon syndrome, inflammatory bowel disease, digestive tract disease, gastrointestinal dysfunction, respiratory failure, sexual dysfunction, cardiovascular system disease, heart disease Failure, hypertension, urinary incontinence, cystitis, arthritis, endometriosis, blood disease, musculoskeletal and connective tissue development disorders, or, systemic disorders;
- the substance A is the above-mentioned fused ring compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotope compound, its crystal form, its nitroxide Solvate, its solvate, or the solvate of its pharmaceutically acceptable salt.
- the urinary tract disease is, for example, urinary incontinence, overactive bladder, dysuria, or cystitis.
- the respiratory disease such as respiratory disorders, includes idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or cough (e.g., chronic cough).
- the pain is, for example, inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, pain caused by burns, migraine, cluster headache, or chronic pain.
- the present invention also provides a method for treating or preventing diseases mediated at least in part by P2X4, which comprises administering a therapeutically effective amount of substance A to a patient (such as a human);
- the substance A is the above-mentioned fused ring compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotope compound, its crystal form, its nitroxide Solvate, its solvate, or the solvate of its pharmaceutically acceptable salt.
- the disease can be urinary tract disease, respiratory system disease, pain, autoimmune disease, inflammation, Alzheimer's disease, Parkinson, sleep disorder, epilepsy, mental disease, arthritis, neurodegeneration , Traumatic brain injury, myocardial infarction, rheumatoid arthritis, stroke, thrombosis, atherosclerosis, colon syndrome, inflammatory bowel disease, digestive tract disease, gastrointestinal dysfunction, respiratory failure, sexual dysfunction , Cardiovascular diseases, heart failure, high blood pressure, urinary incontinence, cystitis, arthritis, endometriosis, blood diseases, musculoskeletal and connective tissue development disorders, or, systemic disorders.
- the urinary tract disease is, for example, urinary incontinence, overactive bladder, dysuria, or cystitis.
- the respiratory disease such as respiratory disorders, includes idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or cough (e.g., chronic cough).
- the pain is, for example, inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, pain caused by burns, migraine, cluster headache, or chronic pain.
- pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base.
- the compound of the present invention contains a relatively acidic functional group, it can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt.
- the acid addition can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.
- a pharmaceutically acceptable acid include inorganic acids, and the inorganic acids include, but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
- the pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , Tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e.
- solvate refers to a substance formed by combining the compound of the present invention with a stoichiometric or non-stoichiometric solvent.
- the solvent molecules in the solvate can exist in an ordered or non-ordered arrangement.
- the solvents include but are not limited to: water, methanol, ethanol and the like.
- pharmaceutically acceptable salt solvate and “solvate” in the term “pharmaceutically acceptable salt” and “solvate” are as described above, and mean that the compound of the present invention is combined with 1, and relatively non-toxic, pharmaceutically acceptable 2.
- solvate of a pharmaceutically acceptable salt includes, but is not limited to, the hydrochloric acid monohydrate of the compound of the present invention.
- stereoisomer refers to the isomers caused by the same order of interconnection of atoms or atomic groups in the molecule, but different spatial arrangements, such as cis-trans isomers, optical isomers or atropisomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotation chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or salting (physical bonding, etc.).
- tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in a molecule at two positions. For example, acetone and 1-propene-2-ol can be converted into each other by the rapid movement of hydrogen atoms on oxygen and ⁇ -carbon.
- isotopic compound refers to the substitution of one or more atoms in the compound by one or more atoms having a specific atomic mass or mass number.
- isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S and 36 Cl).
- the isotopic compounds of the present invention can generally be prepared by substituting isotopically-labeled reagents for non-isotopically-labeled reagents according to the methods described herein.
- crystal form means that the ions or molecules are arranged strictly and periodically in a three-dimensional space in a certain way, and have the regularity of periodic recurrence at a certain distance; due to the above-mentioned periodic arrangement, there may be multiple Crystal form, that is, polymorphism.
- nitrogen oxide means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxide.
- N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
- the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) to form N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
- N-oxides can be prepared by the method of LWDeady (Syn.Comm.1977, 7,509-514), in which, for example, in an inert solvent such as dichloromethane, the amine compound is combined with m-chloroperoxybenzoic acid (MCPBA) reaction.
- LWDeady Syn.Comm.1977, 7,509-514
- MCPBA m-chloroperoxybenzoic acid
- any variable (such as R 1-1-1 ) appears multiple times in the definition of a compound, the definition in each position of the variable has nothing to do with the definition in other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted by 1, 2, or 3 R 1-1-1 groups, that is, the group may be substituted by up to 3 R 1-1-1 , the position R 1 The definition of -1-1 is independent of the definition of the remaining positions R 1-1-1. In addition, combinations of substituents and/or variables are only allowed if the combination results in a stable compound.
- linking substituents are described.
- the Markush variables listed for the group should be understood as the linking group.
- the group "halo -C 1 ⁇ C 6 alkyl" C 1 -C 6 alkyl group is understood to C 1 ⁇ C 6 alkylene group.
- oxo means that the two hydrogens on the methylene group are replaced by oxygen, that is, the methylene group is replaced by a carbonyl group.
- halogen refers to fluorine, chlorine, bromine or iodine.
- alkyl refers to a straight or branched chain alkyl group having the specified number of carbon atoms.
- alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and It is similar to an alkyl group.
- alkoxy refers to the group -OR X , where R X is an alkyl group as defined above.
- cycloalkyl refers to a monovalent saturated cyclic alkyl group, preferably a monovalent saturated cyclic alkyl group having 3-6 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
- alkenyl means a compound consisting of only carbon atoms and hydrogen atoms, containing at least one carbon-carbon double bond, and having no carbon-carbon triple bond, having, for example, 2-10 (preferably 2-6, more preferably 2- 4) A straight or branched hydrocarbon chain group with carbon atoms connected to the rest of the molecule through a single bond.
- the one or more carbon-carbon double bonds may be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl).
- an alkenyl group having from 2 to 4 carbon atoms ( "C 2 -C 4 alkenyl").
- Preferably there is a carbon-carbon double bond Preferably there is a carbon-carbon double bond.
- Examples of the C 2 -C 4 alkenyl group include vinyl (C 2 ; ), 1-propenyl (C 3 ; ), 2-propenyl or isopropenyl (C 3 ; ), allyl (C 3 ; ), 1-butenyl (C 4 ; ), 2-butenyl (C 4 ) (Crotonyl), 2-methylallyl (C 4 ; ), 2-methylprop-1-en-1-yl (C 4 ; ), but-3-en-1-yl (C 4 ; ), butadienyl ⁇ C 4 ; for example (E)-but-1,3-dien-1-ylbenzene ⁇ , and isomers (such as cis-trans isomers or stereoisomers).
- alkynyl refers to a straight or branched hydrocarbon group having 2 to 10 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more carbon-carbon double bonds ("C 2 -C 10 alkynyl").
- the one or more carbon-carbon triple bonds may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl).
- an alkynyl group has 2 to 4 carbon atoms (“C 2 -C 4 alkynyl”), such as ethynyl (C 2 ), prop-1-ynyl (C 3 ), prop-2-ynyl ( C 3 ), but-1-ynyl (C 4 ), but-2-ynyl ( C 4 ), but-3-ynyl ( C 4 ) or 1-methylprop-2-ynyl (C 4 ).
- C 2 -C 4 alkynyl such as ethynyl (C 2 ), prop-1-ynyl (C 3 ), prop-2-ynyl ( C 3 ), but-1-ynyl (C 4 ), but-2-ynyl ( C 4 ), but-3-ynyl ( C 4 ) or 1-methylprop-2-ynyl (C 4 ).
- heterocycloalkyl or “heteroalkane ring” refers to a saturated monocyclic group with heteroatoms, preferably saturated with 1, 2, or 3 ring heteroatoms independently selected from N, O and S Single ring.
- heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl , Piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazacycloheptanyl, oxazepanyl, etc.
- heterocycloalkenyl or “heteroene ring” refers to a monocyclic group with heteroatoms (the monocyclic group has a double bond but not aromatic), preferably containing 1, 2, or 3 A monocyclic ring of ring heteroatoms independently selected from N, O and S.
- heterocyclenyl groups are: dihydrofuranyl, dihydrothienyl, dihydropyrrolyl, dioxolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiazolyl, dihydroiso Thiazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridyl, 3,4-dihydro-2H-pyran, pyranyl, Thianyl, dihydropyridyl, dihydropyrazinyl, dihydropyrimidinyl, oxazinyl, dihydrotetrazolyl and the like.
- aryl refers to a monocyclic or polycyclic group having 6-14 ring atoms and zero heteroatoms provided in the aromatic ring system (E.g., bicyclic or tricyclic) groups of 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 shared p electrons in a cyclic array) ("C 6 -C 14 aryl ").
- aromatic ring system E.g., bicyclic or tricyclic
- 4n+2 aromatic ring systems e.g., having 6, 10, or 14 shared p electrons in a cyclic array
- Examples of the aforementioned aryl unit include phenyl, naphthyl, phenanthryl, or anthracenyl.
- heteroaryl or “heteroaromatic ring” refers to an aromatic group containing heteroatoms, preferably containing 1, 2, or 3 aromatic monocyclic rings independently selected from nitrogen, oxygen and sulfur, such as furyl, Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, Isothiazolyl, thiadiazolyl, etc.
- part refers to specific fragments or functional groups in a molecule.
- the chemical moiety is generally considered to be a chemical entity embedded or attached to a molecule.
- linking substituents are described.
- the Markush variables listed for the group should be understood as the linking group.
- the Markush group definition of the variable lists “alkyl” or “aryl” it should be understood that the “alkyl” or “aryl” respectively represents the attached Alkylene group or arylene group.
- alkylene refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon group.
- alkylene groups include methylene (-CH 2 -), ethylene ⁇ including -CH 2 CH 2 -or -CH(CH 3 )- ⁇ , isopropylene ⁇ including -CH(CH 3 )CH 2 -or -C(CH 3 ) 2 - ⁇ and so on.
- the present invention adopts traditional methods of mass spectrometry and elemental analysis, and the steps and conditions can refer to the conventional operating steps and conditions in the art.
- the present invention adopts standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.
- pharmaceutical excipients refers to excipients and additives used in the production of drugs and formulating prescriptions, and are all substances contained in pharmaceutical preparations except for active ingredients. Please refer to the Fourth Edition of the Pharmacopoeia of the People's Republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition)
- treatment refers to therapeutic therapy.
- treatment refers to: (1) alleviating one or more biological manifestations of the disease or disease, (2) interfering with (a) one or more points in the biological cascade causing or causing the disease, or (b) ) One or more biological manifestations of the disorder, (3) Improve one or more symptoms, effects or side effects related to the disorder, or one or more symptoms, effects or side effects related to the disorder or its treatment, Or (4) to slow down the development of the disease or one or more biological manifestations of the disease.
- prevention refers to a reduction in the risk of acquiring or developing a disease or disorder.
- terapéuticaally effective amount refers to an amount of a compound that is sufficient to effectively treat the diseases or conditions described herein when administered to a patient.
- the “therapeutically effective amount” will vary according to the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted by those skilled in the art as needed.
- patient refers to any animal that is about to or has received administration of the compound or composition according to an embodiment of the present invention, mammals are preferred, and humans are preferred.
- mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
- the biological activity of the compounds of the present invention can be assessed by using any conventionally known methods. Appropriate detection methods are well known in the art. For example, the P2X4 inhibitory activity, pharmacokinetic activity, and/or liver microsomal stability of the compounds of the present invention can be tested by appropriate conventional methods.
- the detection method provided by the present invention is presented only as an example and does not limit the present invention.
- the compound of the present invention has activity in at least one of the detection methods provided by the present invention.
- the reagents and raw materials used in the present invention are all commercially available.
- the positive and progressive effect of the present invention is that the fused ring compound of the present invention has high P2X4 antagonistic activity, good selectivity, low toxicity, and good metabolic stability.
- Titanium (IV) ethoxide titanium ethoxide
- Xantphos 4,5-bisdiphenylphosphine-9,9-dimethylxanthene
- TEMPO 2,2,6,6-tetramethyl-1- Piperidone
- LDA lithium diisopropylamide
- DMF N,N-dimethylformamide
- DMA N,N-dimethylacetamide
- DCM diichloromethane
- DME Ethylene glycol dimethyl ether
- PE petroleum ether
- EA ethyl acetate
- DIPEA N,N-diisopropylethylamine
- THF tetrahydrofuran
- Ac acetyl
- MeOH methanol
- Boc tert-butoxycarbonyl
- B2Pin2 pinacol biborate
- rt room temperature
- HATU 2-(7-benzotriazole oxide)-N,N,N',N'
- Overnight means 8 hours to 15 hours, such as 12 hours; room temperature means 10°C to 30°C; solvent ratio such as PE/EA means volume ratio.
- Anhydrous tetrahydrofuran, dioxane, toluene, and ether are obtained by refluxing and drying with sodium metal.
- Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride.
- Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide are dried in advance with anhydrous sodium sulfate.
- reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe.
- the glassware is dried.
- the chromatographic column is a silica gel column.
- Silica gel 300-400 mesh
- Silica gel 300-400 mesh
- NMR spectrum data are measured by BrukerAvance 400 NMR spectrometer or BrukerAvanceIIIHD600 NMR spectrometer, using CDCl 3 , DMSO-d6, CD 3 OD or Acetone-d6 as solvent (reported in ppm), using TMS (0 ppm) Or chloroform (7.25ppm) as a reference standard.
- MS mass spectrometry
- the above two spectrometers are equipped with Agilent ZorbaxSB-C18 column, the specification is 2.1 ⁇ 30mm, 5 ⁇ m.
- the injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; the HPLC peak is recorded and read by UV-Vis wavelengths at 210 nm and 254 nm.
- Step (1) (Z)-2-(2-chlorophenyl)-N-(5-(N-(((dimethylamino)methylene)sulfamoyl)-1-(4-fluorobenzene (Oxy) isoquinolin-7-yl) the preparation of acetamide
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Abstract
本发明公开了一种稠环化合物及其应用。本发明公开了一种如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物。本发明的稠环化合物具有高的P2X4拮抗活性,且具有较好的选择性,毒性较低、代谢稳定性较好。
Description
本申请要求申请日为2019/12/30的中国专利申请2019113965674的优先权。本申请引用上述中国专利申请的全文。
本发明涉及一种稠环化合物及其应用。
ATP受体基于分子结构、转导机理和药理学特性被分类成两个主要家族,P2Y-和P2X-嘌呤受体。P2X-嘌呤受体是ATP-门控的阳离子通道的家族,已克隆数种亚型,包括:六种同聚受体,P2X1;P2X2;P2X3;P2X4;P2X5;和P2X7;和三种杂聚受体P2X2/3,P2X4/6,P2X1/5。P2X4受体是目前P2X家族唯一解出晶体结构的亚型,且其分辨率高达
并且研究发现,P2X4是对Ca
2+通透性最强的P2X亚型。
咳嗽是呼吸系统疾病的主要症状表现,呼吸科门诊中,70%~80%的患者都具有咳嗽症状。随着COPD、IPF等患病率逐渐升高,而咳嗽作为大多数呼气道疾病的主要表现症状,需求也随之增大。作为机体的防御性神经反射,咳嗽有利于清除呼吸道分泌物和有害因子,但频繁剧烈的咳嗽会对患者的工作、生活和社会活动造成严重影响。
目前涉及P2X4靶点相关的在研药物的适应症多为神经性疼痛或炎症,尚无咳嗽适应症相关药物在研信息。并且尚无P2X4抑制途径治疗包括慢性咳嗽在内的众多病症的药物上市。因此,开发新的可抑制P2X4活性的化合物对于疾病的治疗具有积极意义。
发明内容
本发明所要解决的技术问题是针对现有技术中P2X4拮抗剂不足的缺陷,而提供了一种新的稠环化合物作为P2X4拮抗剂。本发明的稠环化合物具有高的P2X4拮抗活性,且具有较好的选择性,毒性较低、代谢稳定性较好。
本发明是通过下述技术方案来解决上述技术问题的。
本发明提供了一种如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物;
为苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的6元杂烷环”、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的6元杂烯环”或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的6元杂芳环”;
R
1-1为卤素、羟基、氨基、-NHR
1-1-4、-N(R
1-1-5)(R
1-1-6)、C
1~C
6的烷基、C
3~C
6的环烷基、被一个或多个R
1-1-1取代的C
1~C
6的烷基、被一个或多个R
1-1-2取代的C
3~C
6的环烷基、或、被一个或多个R
1-1-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~7元杂环烷基”;
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独立地为卤素、羟基、C
1~C
6的烷基、C
3~C
6的环烷基、C
1~C
6的烷氧基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~7元杂环烷基”;
n为0、1、2或3;
R
3-1独立地为卤素、氰基、羟基、C
1~C
6的烷基、C
1~C
6的烷氧基、C
3~C
6的环烷基、被一个或多个R
3-1-1取代的C
1~C
6的烷基、被一个或多个R
3-1-2取代的C
1~C
6的烷氧基、或、C
1~C
6的烷氧基取代的C
1~C
6的烷氧基;R
3-1-1和R
3-1-2独立地为卤素;
R
3-2为被一个或多个R
3-2-1取代的C
3~C
6的环烷基、被一个或多个R
3-2-2取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、被一个或多个R
3-2-2取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的7~8元杂环烷基”、或、被一个或多个R
3-2-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;
R
3-2-1、R
3-2-2和R
3-2-3独立地为卤素、羟基、C
1~C
6的烷基、C
3~C
6的环烷基、C
1~C
6的烷氧基、或、C
1~C
6的烷氧基取代的C
1~C
6的烷氧基;
m为0、1、2、3或4;
R
2为氧代、卤素、氰基、异氰基、氨基、C
1~C
10烷基、被一个或多个R
2-1取代的C
1~C
10烷基、C
2~C
10烯基、被一个或多个R
2-26取代的C
2~C
10烯基、C
2~C
10炔基、被一个或多个R
2-27取代的C
2~C
10炔基、C
3~C
6的环烷基、被一个或多个R
2-3取代的C
3~C
6的环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~4元杂环烷基”、苯基、被一个或多个R
2-4取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、被一个或多个R
2-5取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-(C=O)-R
2-2、-OR
2-6、-C(=O)OR
2-7、-NR
2-8R
2-9、被一个或多个R
2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、被一个或多个R
2-10取代的“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~4元杂环烷基”、-C(=O)NHR
2-11、-C(=O)NR
2-12R
2-13、-NR
2-14C(=O)R
2-15、-NR
2-16S(=O)
2R
2-17、-NR
2-18S(=O)R
2-19、-S(=O)
2NHR
2-20、-S(=O)NHR
2-21、-S(=O)
2NR
2-22R
2-23、-S(=O)
2R
2-24或-S(=O)R
2-25;
R
2-1独立地为卤素、羟基、C
3~C
6的环烷基、被一个或多个R
2-1-8取代的C
3~C
6的环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~6元杂环烷基”、被一个或多个R
2-1-7取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~6元杂环烷基”、苯基、被一个或多个R
2-1-1取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、被一个或多个R
2-1-6取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-OR
2-1-2、-N(R
2-1-3)(R
2-1-4)、或、-S(=O)
2-R
2-1-5;
R
2-1-1、R
2-1-6、R
2-1-7和R
2-1-8独立地为氧代、羟基、氨基、羧基、卤素、-CN、C
1~C
6的烷基、被一个或多个卤素取代的C
1~C
6的烷基、-OR
2-1-1-1、或、-N(R
2-1-1-2)(R
2-1-1-3);R
2-1-1-1、R
2-1-1-2和R
2-1-1-3独立地为C
1~C
6的烷基;
R
2-1-2独立地为C
1~C
6的烷基或C
3~C
6的环烷基;
R
2-1-3和R
2-1-4独立地为氢、C
1~C
6的烷基或C
3~C
6的环烷基;
R
2-1-5独立地为C
1~C
6的烷基或C
3~C
6的环烷基;
R
2-3独立地为C
1~C
6的烷基;
R
2-4和R
2-5独立地为卤素、羟基、C
1~C
6的烷基、被一个或多个R
2-4-3取代的C
1~C
6的烷基、-N(R
2-4-1)(R
2-4-2)或C
1~C
6的烷氧基;R
2-4-1和R
2-4-2独立地为氢、C
1~C
6的烷基或C
3~C
6的环烷基;R
2-4-3为卤素;
R
2-2为C
1~C
6的烷基、C
3~C
6的环烷基、苯基、被一个或多个R
2-2-2取代的C
1~C
6的烷基、或、被一个或多个R
2-2-1取代的苯基;R
2-2-1独立地为卤素;R
2-2-2独立地为卤素;
R
2-6为氢、C
1~C
10烷基、被一个或多个R
2-6-1取代的C
1~C
10烷基、C
3~C
6环烷基、C
6~C
10芳基、被一个或多个R
2-6-2取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R
2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;
R
2-6-1独立地为氧代、卤素、羟基、氨基、羧基、-CN、C
1~C
6的烷基、被一个或多个卤素取代的C
1~C
6的烷基、C
1~C
6烷氧基、C
3~C
6环烷基、C
6~C
10芳基、被一个或多个R
2-6-1-1取代的C
6~C
10芳基、-OR
2-6-1-2或-N(R
2-6-1-3)(R
2-6-1-4);
R
2-6-2独立地为卤素、C
1~C
6烷基或C
1~C
6烷氧基;
R
2-6-3独立地为-C(=O)-C
1~C
6烷基;
R
2-6-1-1独立地为卤素;
R
2-6-1-2、R
2-6-1-3和R
2-6-1-4独立地为C
1~C
6的烷基;
R
2-7为C
1~C
6烷基、C
3~C
6的环烷基或苯基;
R
2-8和R
2-9独立地为氢、C
1~C
6烷基、C
6~C
10芳基、或者被一个或多个R
2-8-1取代的C
6~C
10芳基;
R
2-8-1为卤素或C
1~C
6烷氧基;
R
2-10独立地为C
1~C
6烷基或氧代;
R
2-26和R
2-27独立地为卤素或C
1~C
6烷基;
R
2-11、R
2-12、R
2-13、R
2-14、R
2-15、R
2-16、R
2-16、R
2-17、R
2-18、R
2-19、R
2-20、R
2-21、R
2-22、R
2-23、R
2-24和R
2-25独立地为C
1~C
6烷基、C
1~C
6烷氧基、C
3~C
6环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、苯基、被一个或多个R
2-11-1取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳环”、或被一个或多个R
2-11-2取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳环”;
R
2-11-1和R
2-11-2独立地为卤素、氰基、羟基、C
1~C
6烷基、C
1~C
6烷氧基或C
3~C
6环烷基。
在某些实施方案中,所述的如式I所示的稠环化合物中,
为苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的6元杂烷环”、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的6元杂烯环”或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的6元杂芳环”;
R
1-1为卤素、羟基、氨基、-NHR
1-1-4、-N(R
1-1-5)(R
1-1-6)、C
1~C
6的烷基、C
3~C
6的环烷基、被一个或多个R
1-1-1取代的C
1~C
6的烷基、被一个或多个R
1-1-2取代的C
3~C
6的环烷基、或、被一个或多个R
1-1-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~7元杂环烷基”;
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独立地为卤素、羟基、C
1~C
6的烷基、C
3~C
6的环烷基、C
1~C
6的烷氧基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~7元杂环烷基”;
n为0、1、2或3;
R
3-1独立地为卤素、氰基、羟基、C
1~C
6的烷基、C
1~C
6的烷氧基、C
3~C
6的环烷基、或、C
1~C
6的烷氧基取代的C
1~C
6的烷氧基;
R
3-2为被一个或多个R
3-2-1取代的C
3~C
6的环烷基、被一个或多个R
3-2-2取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、被一个或多个R
3-2-2取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的7~8元杂环烷基”、或、被一个或多个R
3-2-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;
R
3-2-1、R
3-2-2和R
3-2-3独立地为卤素、羟基、C
1~C
6的烷基、C
3~C
6的环烷基、C
1~C
6的烷氧基、或、C
1~C
6的烷氧基取代的C
1~C
6的烷氧基;
m为0、1、2、3或4;
R
2为氧代、卤素、氰基、氨基、C
1~C
10烷基、被一个或多个R
2-1取代的C
1~C
10烷基、C
3~C
6的环烷基、被一个或多个R
2-3取代的C
3~C
6的环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、苯基、被一个或多个R
2-4取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、被一个或多个R
2-5取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-(C=O)-R
2-2、-OR
2-6、-C(=O)OR
2-7、-NR
2-8R
2-9、被一个或多个R
2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、-C(=O)NHR
2-11、-C(=O)NR
2-12R
2-13、-NR
2-14C(=O)R
2-15、-NR
2-16S(=O)
2R
2-17、-NR
2-18S(=O)R
2-19、-S(=O)
2NHR
2-20、-S(=O)NHR
2-21、-S(=O)
2NR
2-22R
2-23、-S(=O)
2R
2-24、-S(=O)R
2-25;
R
2-1独立地为卤素、羟基、C
3~C
6的环烷基、被一个或多个R
2-1-8取代的C
3~C
6的环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~6元杂环烷基”、被一个或多个R
2-1-7取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~6元杂环烷基”、苯基、被一个或多个R
2-1-1取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、被一个或多个R
2-1-6取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-OR
2-1-2、-N(R
2-1-3)(R
2-1-4)、或、-S(=O)
2-R
2-1-5;
R
2-1-1、R
2-1-6、R
2-1-7和R
2-1-8独立地为氧代、羟基、氨基、羧基、卤素、-CN、C
1~C
6的烷基、被一个或多个卤素取代的C
1~C
6的烷基、-OR
2-1-1-1、或、-N(R
2-1-1-2)(R
2-1-1-3);R
2-1-1-1、R
2-1-1-2和R
2-1-1-3独立地为C
1~C
6的烷基;
R
2-1-2独立地为C
1~C
6的烷基或C
3~C
6的环烷基;
R
2-1-3和R
2-1-4独立地为氢、C
1~C
6的烷基或C
3~C
6的环烷基;
R
2-1-5独立地为C
1~C
6的烷基或C
3~C
6的环烷基;
R
2-3独立地为C
1~C
6的烷基;
R
2-4和R
2-5独立地为卤素、羟基、-N(R
2-4-1)(R
2-4-2)或C
1~C
6的烷氧基;R
2-4-1和R
2-4-2独立地为氢、C
1~C
6的烷基或C
3~C
6的环烷基;
R
2-2为C
1~C
6的烷基、C
3~C
6的环烷基、苯基、或、被一个或多个R
2-2-1取代的苯基;R
2-2-1独立地为卤素;
R
2-6为氢、C
1~C
10烷基、被一个或多个R
2-6-1取代的C
1~C
10烷基、C
3~C
6环烷基、C
6~C
10芳基、被一个或多个R
2-6-2取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R
2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;
R
2-6-1独立地为氧代、卤素、羟基、氨基、羧基、-CN、C
1~C
6的烷基、被一个或多个卤素取代的 C
1~C
6的烷基、C
1~C
6烷氧基、C
3~C
6环烷基、C
6~C
10芳基、被一个或多个R
2-6-1-1取代的C
6~C
10芳基、-OR
2-6-1-2或-N(R
2-6-1-3)(R
2-6-1-4);
R
2-6-2独立地为卤素、C
1~C
6烷基或C
1~C
6烷氧基;
R
2-6-3独立地为-C(=O)-C
1~C
6烷基;
R
2-6-1-1独立地为卤素;
R
2-6-1-2、R
2-6-1-3和R
2-6-1-4独立地为C
1~C
6的烷基;
R
2-7为C
1~C
6烷基;
R
2-8和R
2-9独立地为氢、C
1~C
6烷基、C
6~C
10芳基、或者被一个或多个R
2-8-1取代的C
6~C
10芳基;
R
2-8-1为卤素或C
1~C
6烷氧基;
R
2-10独立地为C
1~C
6烷基或氧代;
R
2-11、R
2-12、R
2-13、R
2-14、R
2-15、R
2-16、R
2-16、R
2-17、R
2-18、R
2-19、R
2-20、R
2-21、R
2-22、R
2-23、R
2-24和R
2-25独立地为C
1~C
6烷基、C
1~C
6烷氧基、C
3~C
6环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、苯基、被一个或多个R
2-11-1取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳环”、或被一个或多个R
2-11-2取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳环”;
R
2-11-1和R
2-11-2独立地为卤素、氰基、羟基、C
1~C
6烷基、C
1~C
6烷氧基或C
3~C
6环烷基。
在某些实施方案中,上述的如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物里,某些基团具有如下定义,未提及的基团的定义如上任一方案所述(本段内容以下简称为“在某些实施方案中”):
在某些实施方案中,当
为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的6元杂烯环”时,所述的6元杂烯环中的杂原子选自N,杂原子数为1个;所述的6元 杂烯环中的双键个数优选为1或2;
优选为双键。所述的
优选为
在某些实施方案中,当
为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的6元杂烯环”时,所述的6元杂烯环中的杂原子选自N,杂原子数为1个;所述的6元杂烯环中的双键个数优选为1或2;
优选为双键。所述的
优选为
在某些实施方案中,当R
1-1为C
1~C
6的烷基时,所述的C
1~C
6烷基为C
1~C
4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基。
在某些实施方案中,当R
1-1为C
3~C
6的环烷基时,所述的C
3~C
6的环烷基为环丙基、环丁基或环戊基。
在某些实施方案中,当R
1-1为被一个或多个R
1-1-1取代的C
1~C
6的烷基,所述的被一个或多个R
1-1-1取代的C
1~C
6的烷基中的的C
1~C
6烷基为C
1~C
4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
在某些实施方案中,当R
1-1为被一个或多个R
1-1-2取代的C
3~C
6的环烷基时,所述的被一个或多个R
1-1-2取代的C
3~C
6的环烷基中的C
3~C
6的环烷基为环丙基、环丁基或环戊基。
在某些实施方案中,当R
1-1-1和R
1-1-2独立地为卤素时,所述的卤素为氟、氯、溴或碘。
在某些实施方案中,当R
3-1独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟或氯。
在某些实施方案中,当R
3-1独立地为C
1~C
6的烷氧基或被一个或多个R
3-1-2取代的C
1~C
6的烷氧基时,所述的C
1~C
6的烷氧基和被一个或多个R
3-1-2取代的C
1~C
6的烷氧基里的C
1~C
6的烷氧基为C
1~C
4烷氧基,优选为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基,进一步优选为甲氧基。
在某些实施方案中,当R
3-1-1和R
3-1-2独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟或氯。
在某些实施方案中,当R
2为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟或氯。
在某些实施方案中,当R
2为C
1~C
10烷基时,所述的C
1~C
10烷基为C
1~C
4烷基,优选为甲基、乙 基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基或异丙基。
在某些实施方案中,当R
2为被一个或多个R
2-1取代的C
1~C
10烷基时,所述的C
1~C
10烷基为C
1~C
4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基。
在某些实施方案中,当R
2为C
2~C
10烯基、被一个或多个R
2-26取代的C
2~C
10烯基时,所述的C
2~C
10烯基和被一个或多个R
2-26取代的C
2~C
10烯基里的为C
2~C
10烯基为C
2~C
4烯基,例如乙烯基、烯丙基。
在某些实施方案中,当R
2为C
2~C
10炔基或被一个或多个R
2-27取代的C
2~C
10炔基时,所述的C
2~C
10炔基和被一个或多个R
2-27取代的C
2~C
10炔基里的为C
2~C
10炔基为C
2~C
4炔基,例如乙炔基、丙炔基。
在某些实施方案中,当R
2-26和R
2-27独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟或氯。
在某些实施方案中,当R
2为C
3~C
6环烷基时,所述的C
3~C
6环烷基为环丙基、环丁基、环戊基或环己基,优选为环丙基或环丁基。
在某些实施方案中,当R
2为“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~4元杂环烷基”或被一个或多个R
2-10取代的“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~4元杂环烷基”时,所述3~4元杂环烷基中的杂原子选自N和O中的一种或多种,杂原子数优选为1或2;所述的3~4元杂环烷基优选为
在某些实施方案中,当R
2为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”时,所述5~6元杂环烷基中的杂原子选自N和O中的一种或多种,杂原子数优选为1或2;所述的5~6元杂环烷基优选为
在某些实施方案中,当R
2为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”时,所述5~6元杂环烷基中的杂原子选自N和O中的一种或多种,杂原子数优选为1或2;所述的5~6元杂环烷基优选为
在某些实施方案中,当R
2为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”时,所述的5~6元杂芳基中的杂原子优选为N,杂原子数优选为2。所述的5~6元杂芳基优选为
所述的5~6元杂芳基优选为
在某些实施方案中,当R
2为被一个或多个R
2-5取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”时,所述的5~6元杂芳基中的杂原子优选为N,杂原 子数优选为1。所述的5~6元杂芳基优选为
在某些实施方案中,当R
2为被一个或多个R
2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”时,所述的5~6元杂环烷基中的杂原子为N,杂原子数优选为2;所述的5~6元杂环烷基优选为
在某些实施方案中,当R
2-1独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟。
在某些实施方案中,当R
2-1独立地为C
3~C
6的环烷基时,所述的C
3~C
6的环烷基为环丙基、环丁基、环戊基或环己基,优选为环丙基或环丁基。
在某些实施方案中,当R
2-2为C
1~C
6的烷基或被一个或多个R
2-2-2取代的C
1~C
6的烷基时,所述的C
1~C
6的烷基优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基或正丁基,进一步优选为甲基。
在某些实施方案中,当R
2-2为C
3~C
6的环烷基时,所述的C
3~C
6的环烷基为环丙基、环丁基、环戊基或环己基,优选为环丙基或环丁基。
在某些实施方案中,当R
2-2-2独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟或氯。
在某些实施方案中,当R
2-4和R
2-5独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟或氯。
在某些实施方案中,当R
2-4和R
2-5独立地为C
1~C
6的烷基或被一个或多个R
2-4-3取代的C
1~C
6的烷基时,所述的C
1~C
6的烷基和被一个或多个R
2-4-3取代的C
1~C
6的烷基里的C
1~C
6的烷基优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基或正丁基,进一步优选为甲基。
在某些实施方案中,当R
2-4-3为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟或氯。
在某些实施方案中,当R
2-6为C
1~C
10烷基时,所述的C
1~C
10烷基为C
1~C
6烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基或正丁基,进一步优选为甲基、乙基、异丁基或异戊基。
在某些实施方案中,当R
2-6为被一个或多个R
2-6-1取代的C
1~C
10烷基,所述的C
1~C
10烷基为C
1~C
4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基或乙基。
在某些实施方案中,当R
2-6为C
3~C
6环烷基时,所述的C
3~C
6环烷基为环丙基、环丁基、环戊基或环己基,优选为环丙基、环丁基或环戊基。
在某些实施方案中,当R
2-6为C
6~C
10芳基时,所述的C
6~C
10芳基为苯基或萘基。
在某些实施方案中,当R
2-6为被一个或多个R
2-6-2取代的C
6~C
10芳基时,所述的C
6~C
10芳基为苯基或萘基,优选为苯基。
在某些实施方案中,当R
2-6为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”时,所述的3~6元杂环烷基为3~4元杂环烷基;所述的3~4元杂环烷基中,杂原子优选为N,杂原子数优选为1个。所述的3~4元杂环烷基优选为
在某些实施方案中,当R
2-6为被一个或多个R
2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”时,所述的3~6元杂环烷基为3~4元杂环烷基;所述的3~4元杂环烷基中,杂原子优选为N,杂原子数优选为1个。所述的3~4元杂环烷基优选为
在某些实施方案中,当R
2-6-1独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟。
在某些实施方案中,当R
2-6-1独立地为C
1~C
6烷氧基时,所述的C
1~C
6烷氧基为C
1~C
4烷氧基,优选为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基,进一步优选为甲氧基。在某些实施方案中,优选为乙氧基。
在某些实施方案中,当R
2-6-1独立地为C
3~C
6环烷基时,所述的C
3~C
6环烷基为环丙基、环丁基、环戊基或环己基,优选为环丙基。在某些实施方案中,优选为环丁基。
在某些实施方案中,当R
2-6-1独立地为C
6~C
10芳基时,所述的C
6~C
10芳基为苯基或萘基。
在某些实施方案中,当R
2-6-1独立地为被一个或多个R
2-6-1-1取代的C
6~C
10芳基时,所述的C
6~C
10芳基为苯基或萘基,优选为苯基。
在某些实施方案中,当R
2-6-2独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟。
在某些实施方案中,当R
2-6-2独立地为C
1~C
6烷基时,所述的C
1~C
6烷基为C
1~C
4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基。
在某些实施方案中,当R
2-6-2独立地为C
1~C
6烷氧基时,所述的C
1~C
6烷氧基为C
1~C
4烷氧基,优选为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基,进一步优选为甲氧基。
在某些实施方案中,R
2-6-3独立地为-C(=O)-C
1~C
4烷基,所述的-C(=O)-C
1~C
4烷基中的C
1~C
4烷基优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基。
在某些实施方案中,R
2-6-1-1独立地为氟、氯、溴或碘,优选为氟。
在某些实施方案中,R
2-7为C
1~C
4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基。在某些实施方案中,R
2-7优选为异丙基。
在某些实施方案中,R
2-7为C
3~C
6环烷基时,所述的C
3~C
6环烷基为环丙基、环丁基、环戊基或环己基,优选为环丙基。
在某些实施方案中,R
2-8和R
2-9独立地为C
1~C
6烷基时,所述的C
1~C
6烷基为C
1~C
4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为异丙基。在某些实施方案中,优选为甲基。
在某些实施方案中,当R
2-8和R
2-9独立地为C
6~C
10芳基时,所述的C
6~C
10芳基为苯基或萘基。
在某些实施方案中,当R
2-8和R
2-9独立地为被一个或多个R
2-8-1取代的C
6~C
10芳基时,所述的被一个或多个R
2-8-1取代的C
6~C
10芳基中的C
6~C
10芳基为苯基或萘基,优选为苯基。
在某些实施方案中,当R
2-8-1为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟。
在某些实施方案中,当R
2-8-1为C
1~C
6烷氧基时,所述的C
1~C
6烷氧基为C
1~C
4烷氧基,优选为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基,进一步优选为甲氧基。
在某些实施方案中,当R
2-10独立地为C
1~C
6烷基时,所述的C
1~C
6烷基为C
1~C
4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基。
在某些实施方案中,R
1-1为C
1~C
6的烷基、C
3~C
6的环烷基、被一个或多个R
1-1-1取代的C
1~C
6的烷基、被一个或多个R
1-1-2取代的C
3~C
6的环烷基。
在某些实施方案中,R
1-1为C
1~C
6的烷基。
在某些实施方案中,R
1-1-1和R
1-1-2独立地为卤素。
在某些实施方案中,n为1、2或3。
在某些实施方案中,R
3-1独立地为卤素、氰基、羟基、被一个或多个R
3-1-2取代的C
1~C
6的烷氧基。
在某些实施方案中,R
3-1独立地为卤素、氰基或羟基。
在某些实施方案中,m为0或1。
在某些实施方案中,R
2为氧代、卤素、氰基、异氰基、氨基、C
1~C
10烷基、被一个或多个R
2-1取代的C
1~C
10烷基、C
2~C
10烯基、被一个或多个R
2-26取代的C
2~C
10烯基、C
2~C
10炔基、被一个或多个R
2-27取代的C
2~C
10炔基、C
3~C
6环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~4元杂环烷基”、苯基、被一个或多个R
2-4取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、被一个或多个R
2-5取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-(C=O)-R
2-2、-OR
2-6、-C(=O)OR
2-7、-NR
2-8R
2-9、或、被一个或多个R
2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”。
R
2为氰基、异氰基、C
1~C
10烷基、被一个或多个R
2-1取代的C
1~C
10烷基、C
2~C
10烯基、被一个或多个R
2-26取代的C
2~C
10烯基、苯基、被一个或多个R
2-4取代的苯基、被一个或多个R
2-5取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-(C=O)-R
2-2或-C(=O)OR
2-7。
R
2为氧代、卤素、氰基、异氰基、氨基、C
3~C
6环烷基、苯基、被一个或多个R
2-4取代的苯基、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~4元杂环烷基”、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-(C=O)-R
2-2、或、被一个或多个R
2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”;
例如,C
3~C
6环烷基、苯基、被一个或多个R
2-4取代的苯基、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~4元杂环烷基”、-(C=O)-R
2-2。
在某些实施方案中,R
2为异氰基、苯基、被一个或多个R
2-4取代的苯基、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~4元杂环烷基”、-(C=O)-R
2-2。
在某些实施方案中,R
2为氧代、卤素、氰基、氨基、C
1~C
10烷基、被一个或多个R
2-1取代的C
1~C
10烷基、C
3~C
6环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6 元杂环烷基”、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-OR
2-6、-C(=O)OR
2-7、-NR
2-8R
2-9、或、被一个或多个R
2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”。
在某些实施方案中,R
2为氧代、卤素、氰基、氨基、C
1~C
10烷基、被一个或多个R
2-1取代的C
1~C
10烷基、C
3~C
6环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或、-OR
2-6。
在某些实施方案中,R
2-1独立地为卤素、C
3~C
6的环烷基、苯基。
在某些实施方案中,R
2-1独立地为卤素。
在某些实施方案中,R
2-2为C
1~C
6的烷基、C
3~C
6的环烷基、苯基、被一个或多个R
2-2-2取代的C
1~C
6的烷基。
在某些实施方案中,R
2-4和R
2-5独立地为卤素、C
1~C
6的烷基、被一个或多个R
2-4-3取代的C
1~C
6的烷基。
在某些实施方案中,R
2-6为氢、C
1~C
10烷基、被一个或多个R
2-6-1取代的C
1~C
10烷基、C
3~C
6环烷基、C
6~C
10芳基、被一个或多个R
2-6-2取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R
2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”。
在某些实施方案中,R
2-6为氢、C
1~C
10烷基、被一个或多个R
2-6-1取代的C
1~C
10烷基、C
3~C
6环烷基、被一个或多个R
2-6-2取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R
2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”。
在某些实施方案中,R
2-6-1独立地为卤素、羟基、C
1~C
6烷氧基、C
3~C
6环烷基、或、被一个或多个R
2-6-1-1取代的C
6~C
10芳基。
在某些实施方案中,R
2-6-1独立地为卤素、C
3~C
6环烷基、或、被一个或多个R
2-6-1-1取代的C
6~C
10芳基。
在某些实施方案中,R
2-7为C
3~C
6的环烷基或苯基。
在某些实施方案中,R
2为氧代、甲氧基、氟、氯、羟基、氨基、-CH
2F、二氟甲基、三氟甲基、甲基、异丙基、环丙基、氰基、乙氧基、异丙氧基、一氟甲氧基、二氟甲氧基、三氟甲氧基、
乙基、二氯甲基、
乙炔基、丙炔基、
苄基、
苯基、
在某些实施方案中,所述的如式I所示的稠环化合物中,
R
1-1为C
1~C
6的烷基;
n为1、2或3;
R
3-1独立地为卤素、氰基、羟基、被一个或多个R
3-1-2取代的C
1~C
6的烷氧基;
m为0、1;
R
2为氧代、卤素、氰基、氨基、异氰基、C
1~C
10烷基、被一个或多个R
2-1取代的C
1~C
10烷基、C
2~C
10烯基、被一个或多个R
2-26取代的C
2~C
10烯基、C
2~C
10炔基、被一个或多个R
2-27取代的C
2~C
10炔基、C
3~C
6的环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~4元杂环烷基”、苯基、被一个或多个R
2-4取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、被一个或多个R
2-5取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-(C=O)-R
2-2、-OR
2-6、-C(=O)OR
2-7、-NR
2-8R
2-9、被一个或多个R
2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”;
R
2-1独立地为卤素、C
3~C
6的环烷基或苯基;
R
2-2为C
1~C
6的烷基、C
3~C
6的环烷基、苯基或被一个或多个R
2-2-2取代的C
1~C
6的烷基;R
2-2-2独立地为卤素;
R
2-4和R
2-5独立地为卤素、C
1~C
6的烷基、被一个或多个R
2-4-3取代的C
1~C
6的烷基;R
2-4-3为卤素;
R
2-6为氢、C
1~C
10烷基、被一个或多个R
2-6-1取代的C
1~C
10烷基、C
3~C
6环烷基、C
6~C
10芳基、被一个或多个R
2-6-2取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R
2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;
R
2-6-1独立地为卤素、羟基、C
1~C
6烷氧基、C
3~C
6环烷基、被一个或多个R
2-6-1-1取代的C
6~C
10芳基;
R
2-6-2独立地为卤素、C
1~C
6烷基或C
1~C
6烷氧基;
R
2-6-3独立地为-C(=O)-C
1~C
6烷基;
R
2-6-1-1独立地为卤素;
R
2-6-1-2独立地为C
1~C
6的烷基;
R
2-7为C
1~C
6烷基、C
3~C
6的环烷基或苯基;
R
2-8和R
2-9独立地为氢、C
1~C
6烷基、C
6~C
10芳基、或者被一个或多个R
2-8-1取代的C
6~C
10芳基;
R
2-8-1为卤素或C
1~C
6烷氧基;
R
2-10独立地为C
1~C
6烷基或氧代;
R
2-26和R
2-27独立地为卤素或C
1~C
6烷基。
在某些实施方案中,所述的如式I所示的稠环化合物中,
R
1-1为C
1~C
6的烷基、C
3~C
6的环烷基、被一个或多个R
1-1-1取代的C
1~C
6的烷基、被一个或多个R
1-1-2取代的C
3~C
6的环烷基;
R
1-1-1和R
1-1-2独立地为卤素;
n为1、2或3;
R
3-1独立地为卤素、氰基、羟基;
m为0、1;
R
2为氧代、卤素、氰基、氨基、C
1~C
10烷基、被一个或多个R
2-1取代的C
1~C
10烷基、C
3~C
6的环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-OR
2-6、-C(=O)OR
2-7、-NR
2-8R
2-9、或、被一个或多个R
2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”;
R
2-1独立地为卤素;
R
2-6为氢、C
1~C
10烷基、被一个或多个R
2-6-1取代的C
1~C
10烷基、C
3~C
6环烷基、C
6~C
10芳基、被一个或多个R
2-6-2取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R
2-6-3取代的“杂原子数为1个、2个或3个,杂原 子选自N、O和S中的一种或多种的3~6元杂环烷基”;
R
2-6-1独立地为卤素、羟基、C
3~C
6环烷基、被一个或多个R
2-6-1-1取代的C
6~C
10芳基;
R
2-6-2独立地为卤素、C
1~C
6烷基或C
1~C
6烷氧基;
R
2-6-3独立地为-C(=O)-C
1~C
6烷基;
R
2-6-1-1独立地为卤素;
R
2-7为C
1~C
6烷基;
R
2-8和R
2-9独立地为氢、C
1~C
6烷基、C
6~C
10芳基、或者被一个或多个R
2-8-1取代的C
6~C
10芳基;
R
2-8-1为卤素或C
1~C
6烷氧基;
R
2-10独立地为C
1~C
6烷基或氧代。
在某些实施方案中,所述的如式I所示的稠环化合物中,
R
1-1为C
1~C
6的烷基;
n为1、2或3;
R
3-1独立地为卤素、氰基、羟基;
m为0、1;
R
2为氧代、卤素、氰基、氨基、C
1~C
10烷基、被一个或多个R
2-1取代的C
1~C
10烷基、C
3~C
6的环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-OR
2-6、-C(=O)OR
2-7、 -NR
2-8R
2-9、或、被一个或多个R
2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”;
R
2-1独立地为卤素;
R
2-6为氢、C
1~C
10烷基、被一个或多个R
2-6-1取代的C
1~C
10烷基、C
3~C
6环烷基、C
6~C
10芳基、被一个或多个R
2-6-2取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R
2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;
R
2-6-1独立地为卤素、羟基、C
3~C
6环烷基、被一个或多个R
2-6-1-1取代的C
6~C
10芳基;
R
2-6-2独立地为卤素、C
1~C
6烷基或C
1~C
6烷氧基;
R
2-6-3独立地为-C(=O)-C
1~C
6烷基;
R
2-6-1-1独立地为卤素;
R
2-7为C
1~C
6烷基;
R
2-8和R
2-9独立地为氢、C
1~C
6烷基、C
6~C
10芳基、或者被一个或多个R
2-8-1取代的C
6~C
10芳基;
R
2-8-1为卤素或C
1~C
6烷氧基;
R
2-10独立地为C
1~C
6烷基或氧代。在某些实施方案中,所述的如式I所示的稠环化合物中,
n为1、2或3;
R
3-1独立地为卤素、氰基、羟基;
m为0、1;
R
2为氧代、卤素、氰基、氨基、C
1~C
10烷基、被一个或多个R
2-1取代的C
1~C
10烷基、C
3~C
6的环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或、-OR
2-6;
R
2-1独立地为卤素;
R
2-6为氢、C
1~C
10烷基、被一个或多个R
2-6-1取代的C
1~C
10烷基、C
3~C
6环烷基、C
6~C
10芳基、被一个或多个R
2-6-2取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R
2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;
R
2-6-1独立地为卤素、C
3~C
6环烷基、被一个或多个R
2-6-1-1取代的C
6~C
10芳基;R
2-6-1-1独立地为卤素;
R
2-6-2独立地为卤素、C
1~C
6烷基或C
1~C
6烷氧基;
R
2-6-3独立地为-C(=O)-C
1~C
6烷基;
R
2-6-1-1独立地为卤素;
R
2-10独立地为C
1~C
6烷基或氧代。
在某些实施方案中,所述的如式I所示的稠环化合物中,
n为1、2或3;
R
3-1独立地为卤素、氰基、羟基;
m为0、1;
R
2为氧代、卤素、氰基、C
1~C
10烷基、或、被一个或多个R
2-1取代的C
1~C
10烷基、C
3~C
6环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或、-OR
2-6;
R
2-1独立地为卤素;
R
2-6为C
1~C
10烷基、被一个或多个R
2-6-1取代的C
1~C
10烷基、C
3~C
6环烷基、被一个或多个R
2-6-2取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R
2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;
R
2-6-1独立地为卤素、C
3~C
6环烷基、被一个或多个R
2-6-1-1取代的C
6~C
10芳基;R
2-6-1-1独立地为卤素;
R
2-6-2独立地为卤素、C
1~C
6烷基或C
1~C
6烷氧基;
R
2-6-3独立地为-C(=O)-C
1~C
6烷基。
在某些实施方案中,所述的如式I所示的稠环化合物中,
n为1、2或3;
R
3-1独立地为卤素、氰基、羟基;
m为0、1;
R
2为氯、氰基、C
1~C
10烷基、被一个或多个R
2-1取代的C
1~C
10烷基、C
3~C
6环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或、-OR
2-6;
R
2-1独立地为卤素;
R
2-6为C
1~C
4烷基、被一个或多个R
2-6-1取代的C
1-C
2烷基、C
3~C
6环烷基、被一个或多个R
2-6-2取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6 元杂环烷基”、或、被一个或多个R
2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;且当R
2为氯时,R
2位于Z
1或Z
4上;
R
2-6-1独立地为卤素、C
3~C
6环烷基、被一个或多个R
2-6-1-1取代的C
6~C
10芳基;
R
2-6-2独立地为卤素、C
1~C
6烷基或C
1~C
6烷氧基;
R
2-6-3独立地为-C(=O)-C
1~C
6烷基。
在某些实施方案中,所述的如式I所示的稠环化合物中,
在某些实施方案中,所述的式I所示的化合物为如下任一所示的化合物:
在某些实施方案中,所述的式I所示的化合物的药学上可接受的盐为如下的化合物:
本发明所述的如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、 其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物可参照化学领域公知的、类似的方法合成,也可参照本发明记载的方法合成。
本发明还提供了一种如式I所示的化合物的制备方法,其为以下任一方案:
方案一:溶剂中,在碱的作用下,将如式II所示的化合物进行如下所述的反应得到如式I所示的化合物即可,
其中,所述的碱可为乙醇钠、乙醇钠、氨或水肼;
方案二:溶剂中,将如式III所示的化合物和氨进行如下所述的反应得到如式I所示的化合物即可,
方案三:溶剂中,在三氟乙酸的作用下,将如式IV所示的化合物进行如下所述的反应得到如式I所示的化合物即可,
所述的如式I所示的化合物的制备条件可为本领域常规。
本发明还提供了如式II、III或IV所示的化合物,
本发明还提供了如下所示的化合物,
本发明所述的如式I所示的稠环化合物、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可参照化学领域公知的、类似的方法合成,也可参照本发明记载的方法合成。
本发明还提供了一种药物组合物,其包含物质A和至少一种药用辅料;
所述的物质A为上述的如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物。
在所述的药物组合物中,所述的物质A的剂量可为治疗有效量。
本发明还提供了一种物质A在制备P2X4受体拮抗剂或药物中的应用;
所述的物质A为上述的如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物。
在某些实施方案中,所述的药物可用于治疗或预防动物(例如人类)的泌尿道疾病、呼吸系统疾病、疼痛、自身免疫病、炎症、老年痴呆症、帕金森、睡眠障碍、癫痫、精神疾病、关节炎、神经退行性变、外伤性脑损伤、心肌梗死、类风湿性关节炎、脑卒中、血栓症、动脉粥样硬化、结肠综合症、炎性肠病、消化道疾病、胃肠功能紊乱、呼吸衰竭、性功能障碍、心血管系统疾病、心衰、高血压、尿失禁、膀胱炎、关节炎、子宫内膜异位、血液病、肌肉骨骼和结缔组织发育障碍、或、系统性障碍疾病。所述的泌尿道疾病例如尿失禁、膀胱过度活动症、排尿困难或膀胱炎。所述的呼吸系统疾病例如呼吸障碍,包括特发性肺纤维化、慢性阻塞性肺病、哮喘、支气管痉挛或咳嗽(例如慢性咳嗽)。所述的疼痛例如炎性疼痛、手术疼痛、内脏疼痛、牙痛、经前期疼痛、中枢性疼痛、由灼伤所致疼痛、偏头痛、簇性头痛或慢性疼痛。
在某些实施方案中,所述的药物可用于预防或治疗动物(例如人类)的至少部分由P2X4介导的疾病。
所述的至少部分由P2X4介导的疾病例如泌尿道疾病、呼吸系统疾病、疼痛、自身免疫病、炎症、老年痴呆症、帕金森、睡眠障碍、癫痫、精神疾病、关节炎、神经退行性变、外伤性脑损伤、心肌梗死、类风湿性关节炎、脑卒中、血栓症、动脉粥样硬化、结肠综合症、炎性肠病、消化道疾病、胃肠功能紊乱、呼吸衰竭、性功能障碍、心血管系统疾病、心衰、高血压、尿失禁、膀胱炎、关节炎、子宫内膜异位、血液病、肌肉骨骼和结缔组织发育障碍、或、系统性障碍疾病。所述的泌尿道疾病例如尿失禁、膀胱过度活动症、排尿困难或膀胱炎。所述的呼吸系统疾病例如呼吸障碍,包括特发性肺纤维化、慢性阻塞性肺病、哮喘、支气管痉挛或咳嗽(例如慢性咳嗽)。所述的疼痛例如炎性疼痛、手术疼痛、内脏疼痛、牙痛、经前期疼痛、中枢性疼痛、由灼伤所致疼痛、偏头痛、簇性头痛或慢性疼痛。
本发明还提供了一种治疗或预防疾病的方法,其包括向患者(例如人类)施用治疗有效量的物质A;
所述的疾病为泌尿道疾病、呼吸系统疾病、疼痛、自身免疫病、炎症、老年痴呆症、帕金森、睡眠障碍、癫痫、精神疾病、关节炎、神经退行性变、外伤性脑损伤、心肌梗死、类风湿性关节炎、脑卒中、血栓症、动脉粥样硬化、结肠综合症、炎性肠病、消化道疾病、胃肠功能紊乱、呼吸衰竭、性功能障碍、心血管系统疾病、心衰、高血压、尿失禁、膀胱炎、关节炎、子宫内膜异位、血液病、肌肉骨骼和结缔组织发育障碍、或、系统性障碍疾病;
所述的物质A为上述的如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物。
在某些实施方案中,所述的泌尿道疾病例如尿失禁、膀胱过度活动症、排尿困难或膀胱炎。
在某些实施方案中,所述的呼吸系统疾病例如呼吸障碍,包括特发性肺纤维化、慢性阻塞性肺病、哮喘、支气管痉挛或咳嗽(例如慢性咳嗽)。
在某些实施方案中,所述的疼痛例如炎性疼痛、手术疼痛、内脏疼痛、牙痛、经前期疼痛、中枢性疼痛、由灼伤所致疼痛、偏头痛、簇性头痛或慢性疼痛。
本发明还提供了一种治疗或预防至少部分由P2X4介导的疾病的方法,其包括向患者(例如人类)施用治疗有效量的物质A;
所述的物质A为上述的如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物。
在某一方案中,所述的疾病可为泌尿道疾病、呼吸系统疾病、疼痛、自身免疫病、炎症、老年痴呆症、帕金森、睡眠障碍、癫痫、精神疾病、关节炎、神经退行性变、外伤性脑损伤、心肌梗死、类风湿性关节炎、脑卒中、血栓症、动脉粥样硬化、结肠综合症、炎性肠病、消化道疾病、胃肠功能紊乱、呼吸衰竭、性功能障碍、心血管系统疾病、心衰、高血压、尿失禁、膀胱炎、关节炎、子宫内膜异位、血液病、肌肉骨骼和结缔组织发育障碍、或、系统性障碍疾病。
在某些实施方案中,所述的泌尿道疾病例如尿失禁、膀胱过度活动症、排尿困难或膀胱炎。
在某些实施方案中,所述的呼吸系统疾病例如呼吸障碍,包括特发性肺纤维化、慢性阻塞性肺病、哮喘、支气管痉挛或咳嗽(例如慢性咳嗽)。
在某些实施方案中,所述的疼痛例如炎性疼痛、手术疼痛、内脏疼痛、牙痛、经前期疼痛、中枢性疼痛、由灼伤所致疼痛、偏头痛、簇性头痛或慢性疼痛。
本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述,其全部内容通过引用并入本文。
除非另外说明,本发明所使用的术语具有如下定义,下文中未涉及的术语的定义如本发明所属领域技术人员的通常理解。
术语“多个”是指2个、3个、4个或5个。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于:锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸,所述无机酸包括但不限于:盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸,所述有机酸包括但不限于:乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时,可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“溶剂合物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂合物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于:水、甲醇、乙醇等。
术语“药学上可接受的盐的溶剂合物”中的“药学上可接受的盐”和“溶剂合物”如上所述,是指本发明化合物与1、与相对无毒的、药学上可接受的酸或碱制备得到的2、与化学计量或非化学计量的溶剂结合形成的物质。所述的“药学上可接受的盐的溶剂合物”包括但不限于本发明化合物的盐酸一水合物。
术语“立体异构体”是指分子中原子或原子团相互连接次序相同,但空间排列不同而引起的异构体,例如顺反异构体、旋光异构体或阻转异构体等。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集,还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。例如,丙酮和1-丙烯-2-醇可以通过氢原子在氧上和α-碳上的迅速移动而互相转变。
术语“同位素化合物”是指化合物中的一个或多个原子被一个或多个具有特定原子质量或质量数的原子取代。可以掺入本发明化合物中的同位素的实例包括但不限于氢、碳、氮、氧、氟、硫和氯的同位素(例如
2H,
3H,
13C,
14C,
15N,
18O,
17O,
18F,
35S和
36Cl)。本发明的同位素化合物通常可以根据本文所述的方法通过用同位素标记的试剂取代非同位素标记的试剂来制备。
术语“晶型”是指其中的离子或分子是按照一种确定的方式在三维空间作严格周期性排列,并具有间隔一定距离周期重复出现规律;因上述周期性排列的不同,可存在多种晶型,也即多晶型现象。
术语“氮氧化物”是指当化合物含几个胺官能团时,可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是,N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514),其中例如在惰性溶剂例如二氯甲烷中,使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。
当任意变量(例如R
1-1-1)在化合物的定义中多次出现时,该变量每一位置出现的定义与其余位置出现的定义无关,它们的含义互相独立、互不影响。因此,若某基团被1个、2个或3个R
1-1-1基团取代,也就是说,该基团可能会被最多3个R
1-1-1取代,该位置R
1-1-1的定义与其余位置R
1-1-1的定义是互相独立的。另外,取代基及/或变量的组合只有在该组合产生稳定的化合物时才被允许。
在本发明的各部分,描述了连接取代基。当该结构清楚地需要连接基团时,针对该基团所列举的马库什变量应理解为连接基团。例如,基团“卤代-C
1~C
6烷基”中的C
1-C
6烷基应当理解为C
1~C
6亚烷基。
本发明所使用的任何保护基团、氨基酸和其它化合物的缩写,除非另有说明,都以它们通常使用的、公认的缩写为准,或参照IUPAC-IUB Commissionon Biochemical Nomen clature(参见Biochem.1972,11:942-944)。
术语“氧代”是指亚甲基上的两个氢被氧取代,也即亚甲基被羰基替代。
术语“卤素”是指氟、氯、溴或碘。
术语“烷基”是指具有指定的碳原子数的直链或支链烷基。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基及其类似烷基。
术语“烷氧基”是指基团-O-R
X,其中,R
X为如上文所定义的烷基。
术语“环烷基”是指单价饱和的环状烷基,优选具有3-6个环碳原子的单价饱和的环状烷基,例如环丙基、环丁基、环戊基或环己基。
术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个碳碳双键、并且没有碳碳三键的具有例如2-10个(优选为2-6个,更优选为2-4个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。该一个或多个碳碳双键可以是内部的(例如在2-丁烯基中)或末端的(例如在1-丁烯基中)。在一些实施例中,烯基基团具有2至4个碳原子(“C
2-C
4的烯基”)。优选存在一个碳碳双键。C
2-C
4的烯基的实例包括乙烯基(C
2;
)、1-丙烯基(C
3;
)、2-丙烯基或异丙烯 基(C
3;
)、烯丙基(C
3;
)、1-丁烯基(C
4;
)、2-丁烯基(C
4
)(巴豆基)、2-甲基烯丙基(C
4;
)、2-甲基丙-1-烯-1-基(C
4;
)、丁-3-烯-1-基(C
4;
)、丁二烯基{C
4;例如(E)-丁-1,3-二烯-1-基苯
},以及异构体(例如顺反异构体或立体异构体)。
术语“炔基”是指具有2至10个碳原子、一个或多个碳碳三键以及任选地一个或多个碳碳双键的直链或支链的烃基团(“C
2-C
10炔基”)。该一个或多个碳碳三键可以是内部的(例如在2-丁炔基中)或末端的(例如在1-丁炔基中)。在一些实施例中,炔基基团具有2至4个碳原子(“C
2-C
4炔基”),例如乙炔基(C
2)、丙-1-炔基
(C
3)、丙-2-炔基(
C
3)、丁-1-炔基
(C
4)、丁-2-炔基(
C
4)、丁-3-炔基(
C
4)或1-甲基丙-2-炔基(C
4)。
术语“杂环烷基”或“杂烷环”是指具有杂原子的饱和的单环基团,优选含有1个、2个或3个独立选自N、O和S的环杂原子的饱和的单环。杂环烷基的示例为:吡咯烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢吡咯基、氮杂环丁烷基、噻唑烷基、唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、氮杂环庚烷基、二氮杂环庚烷基、氧氮杂环庚烷基等。
术语“杂环烯基”或“杂烯环”是指具有杂原子的单环基团(该单环基团具有双键、但不具有芳香性),优选含有1个、2个或3个独立选自N、O和S的环杂原子的单环。杂环烯基的示例为:二氢呋喃基、二氢噻吩基、二氢吡咯基、二氧杂环戊烯基、二氢咪唑基、二氢吡唑基、二氢噻唑基、二氢异噻唑基、二氢噁二唑基、二氢噻二唑基、二氢三唑基、二氢四唑基、四氢吡啶基、3,4-二氢-2H-吡喃、吡喃基、噻喃基、二氢吡啶基、二氢吡嗪基、二氢嘧啶基、噁嗪基、二氢四唑基等。
在本申请中,作为基团或是其它基团的一部分,术语“芳基”是指具有6-14个环原子以及提供在芳香族环系统中的零个杂原子单环的或多环的(例如,二环的或三环的)4n+2芳香族环系统(例如,在循环阵列中具有6,10,或14个共享的p电子)的基团(“C
6-C
14芳基”)。上述芳基单元的实例包括苯基、萘基、菲基、或者蒽基。
术语“杂芳基”或“杂芳环”是指含有杂原子的芳香基团,优选含有1个、2个或3个独立选自氮、氧和硫的芳族单环,例如呋喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异唑基、噁唑基、二唑基、咪唑基、吡咯基、吡唑基、三唑基、四唑基、噻唑基、异噻唑基、噻二唑基等。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时,这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产 生稳定的化合物的情况下才是被允许的。
在本发明的各部分,描述了连接取代基。当该结构清楚地需要连接基团时,针对该基团所列举的马库什变量应理解为连接基团。例如,如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”,则应该理解,该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。亚烷基基团的实例包括亚甲基(-CH
2-),亚乙基{包括-CH
2CH
2-或-CH(CH
3)-},亚异丙基{包括-CH(CH
3)CH
2-或-C(CH
3)
2-}等等。
除非另有规定,本文使用的所有技术术语和科学术语具有要求保护主题所属领域的标准含义。倘若对于某术语存在多个定义,则以本文定义为准。
应该理解,在本发明中使用的单数形式,如“一种”,包括复数指代,除非另有规定。此外,术语“包括”是开放性限定并非封闭式,即包括本发明所指明的内容,但并不排除其他方面的内容。
除非另有说明,本发明采用质谱、元素分析的传统方法,各步骤和条件可参照本领域常规的操作步骤和条件。
除非另有指明,本发明采用分析化学、有机合成化学和光学的标准命名及标准实验室步骤和技术。在某些情况下,标准技术被用于化学合成、化学分析、发光器件性能检测。
另外,需要说明的是,除非以其他方式明确指出,在本发明中所采用的描述方式“…独立地为”应做广义理解,是指所描述的各个个体之间是相互独立的,可以独立地为相同或不同的具体基团。更详细地,描述方式“…独立地为”既可以是指在不同基团中,相同符号之间所表达的具体选项之间互相不影响;也可以表示在相同的基团中,相同符号之间所表达的具体选项之间互相不影响。
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂,是除活性成分以外,包含在药物制剂中的所有物质。可参见中华人民共和国药典(2015年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009 Sixth Edition)
术语“治疗”指治疗性疗法。涉及具体病症时,治疗指:(1)缓解疾病或者病症的一种或多种生物学表现,(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现,(3)改善与病症相关的一种或多种症状、影响或副作用,或者与病症或其治疗相关的一种或多种症状、影响或副作用,或(4)减缓病症或者病症的一种或多种生物学表现发展。
术语“预防”是指获得或发生疾病或障碍的风险降低。
术语“治疗有效量”是指在给予患者时足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化,但可由本领域技术人员根据需要进行调整。
术语“患者”是指根据本发明的实施例,即将或已经接受了该化合物或组合物给药的任何动物,哺乳动物为优,人类最优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等,以人类为最优。
本发明化合物的生物活性可通过使用任何常规已知方法评定。适当的检测方法是本领域众所周知 的。例如,可以通过适当的常规方法检测本发明化合物的P2X4抑制活性、药代动力学活性和/或肝微粒体稳定性等。本发明提供的检测方法仅作为实例呈现且不限制本发明。本发明化合物在至少一种本发明提供的检测方法中具有活性。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明的稠环化合物具有高的P2X4拮抗活性,且具有较好的选择性,毒性较低、代谢稳定性较好。
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
下面简写词的使用贯穿本发明:
Titanium(IV)ethoxide(乙醇钛),Xantphos(4,5-双二苯基膦-9,9-二甲基氧杂蒽),TEMPO(2,2,6,6-四甲基-1-哌啶酮),LDA(二异丙基氨基锂),DMF(N,N-二甲基甲酰胺),DMA(N,N-二甲基乙酰胺),DCM(二氯甲烷),DME(乙二醇二甲醚),PE(石油醚),EA(乙酸乙酯),DIPEA(N,N-二异丙基乙胺),THF(四氢呋喃),Ac(乙酰基),MeOH(甲醇),Boc(叔丁氧基羰基),B2Pin2(联硼酸频那醇酯),rt(室温),HATU(2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯),reflux(回流),eq是指当量,Rf:比移值,g(克),mg(毫克),mol(摩尔),mmol(毫摩尔),h(小时),min(分钟),mL(毫升),μL(微升)。
过夜是指8小时~15小时,例如12小时;室温是指10℃~30℃;溶剂比例如PE/EA是指体积比。
下面所描述的实施例,除非其他方面表明,所有的温度定为摄氏度。除非其他方面表明,试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company,使用时都没有经过进一步纯化;一般的试剂从汕头西陇化工厂,广东光华化学试剂厂,广州化学试剂厂,天津好寓宇化学品有限公司,青岛腾龙化学试剂有限公司,和青岛海洋化工厂购买得到。
无水四氢呋喃,二氧六环,甲苯,乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯,石油醚,正己烷,N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明),反应瓶都塞上合适的橡皮塞,底物通过注射器打入。玻璃器皿均是经过干燥的。
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。核磁共振光谱数据通过BrukerAvance 400核磁共振谱仪或BrukerAvanceIIIHD600核磁共振谱仪来测定,以CDCl
3,DMSO-d6,CD
3OD或Acetone-d6为溶剂(报导以ppm为单位),用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候,将使用下面的缩写:s(singlet,单峰),d(doublet,双峰),t(triplet,三重峰),m(multiplet,多重峰),br(broadened,宽峰),dd(doublet of doublets,双二重峰),dt(doublet of triplets, 双三重峰),ddd(doublet of doublet of doublets,双双二重峰),ddt(doublet of doublet of triplets,双双三重峰),dddd(doublet of doublet of doublet of doublets,双双双二重峰)。偶合常数,用赫兹(Hz)表示。
低分辨率质谱(MS)数据通过配备G1312A二元泵和aG1316ATCC(柱温保持在30℃)的Agilent 6320系列LC-MS的光谱仪来测定的,G1329A自动采样器和G1315BDAD检测器应用于分析,ESI源应用于LC-MS光谱仪。
以上两种光谱仪都配备了Agilent ZorbaxSB-C18柱,规格为2.1×30mm,5μm。注射体积是通过样品浓度来确定;流速为0.6mL/min;HPLC的峰值是通过在210nm和254nm处的UV-Vis波长来记录读取的。
实施例1
步骤(1)7-溴-1-氯异喹啉-5-磺酰氯的制备
称取化合物1-1(5.0g,20.7mmol),加入氯磺酸(50mL),置换N
2三次后,升温至170℃,搅拌36h,取样,加水淬灭,DCM萃取,TLC显示原料约有30%剩余。将反应液缓慢滴加至冰水(200mL)中,再用DCM(200mL)萃取3次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到中间体1-2粗品,黄色油状物(5.6g)。LC-MS:[M+H]
+=339.9。
步骤(2)7-溴-1-氯异喹啉-5-磺酰胺的制备
依次将中间体1-2(5.6g,粗品)溶于THF(50mL)中溶解,再缓慢滴加到0.5M NH
3/THF(100mL)溶液中,室温搅拌1h。取样,送LCMS显示原料反应完毕。40℃浓缩拉干,再加入PE:EA=5:1 (50mL)打浆10min,过滤,滤饼拉干得中间体1-3,灰白色固体(3.2g,纯度93%)。LC-MS:[M+H]
+=322。
步骤(3)(E)-N'-(((7-溴-1-氯异喹啉-5-基)磺酰基)-N,N-二甲基甲酰胺的制备
将中间体1-3(3.2g,10mmol)溶于DMF(10mL)中,再加入DMF-DMA(1.43g,12mmol),70℃下搅拌3h。取样,LCMS显示反应完毕。降温后将反应液缓慢滴加至冰水(50mL)中,析出固体,继续拌10min后过滤,滤饼用水洗涤,再用乙腈(20mL)套蒸2次后得到中间体1-4,黄色固体(3.0g,纯度92%),LC-MS:[M+H]
+=375。
步骤(4)(E)-(1-氯-5-(N-(((二甲基氨基)亚甲基)氨磺酰基)异喹啉-7-基)氨基甲酸叔丁酯的制备
将中间体1-4(2.9g,7.73mmol)、BocNH
2(1.36g,11.6mmol)、Cs
2CO
3(3.8g,11.6mmol),加入1,4-二氧六环(30mL)搅拌溶解,再加入PdCl
2(dppf)(0.63g),Xantphos(0.45g),置换N
2三次,85℃搅拌16h。取样,加水淬灭,EA萃取,送LCMS显示原料反应完毕,降温后加入水(50mL)和DCM(100mL),搅拌后分液,水相过滤后浓缩拉干,硅胶柱纯化,45℃浓缩拉干后得到中间体1-5,黄色固体(1.2g,纯度80%),LC-MS:[M+H]
+=413。
步骤(5)(E)-N′-(((7-氨基-1-氯异喹啉-5-基)磺酰基)-N,N-二甲基甲酰胺的制备
将中间体1-5(200mg,0.5mmol)溶于DCM(5mL)中,再加入3M HCl/EA(5mL),室温搅拌3h,取样,TLC显示原料反应完毕,加入H
2O(10mL)和DCM(20mL),再用饱和NaHCO
3溶液调节pH至8~9后,分液,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤后浓缩得到中间体1-6,黄色固体(100mg)。LC-MS:[M+H]
+=313.0。
步骤(6)(E)-N-(1-氯-5-(N-(((二甲氨基)亚甲基)氨磺酰基)异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
将2-氯苯乙酸(80mg,0.05mmol)和HATU(180mg,0.05mmol)溶于DMF(5mL)中,室温搅拌1h,再加入中间体1-6(100mg,0.03mmol)和DIPEA(160mg,0.12mmol),继续搅拌12h。取样,TLC(PE:EA=1:2),显示原料:产物=1:4,向反应液中加入DCM(20mL)和H
2O(10mL),分液,有机相用盐水洗涤,无水硫酸钠干燥,过滤后40℃浓缩拉干得粗品,粗品用H
2O/CH
3CN体系经prep-HPLC制备分离,冻干后得到中间体1-8,黄色固体(40mg)。LC-MS:[M+H]
+=465.0。
步骤(7)2-(2-氯苯基)-N-(1-甲氧基-5-氨磺酰基异喹啉-7-基)乙酰胺的制备
将中间体1-8(20mg,0.043mmol)溶于DCM(0.5mL)中,再加入30质量%甲醇钠的甲醇溶液(0.1mL),室温搅拌16h,取样送LCMS显示原料反应完毕,加入DCM(10mL)稀释,过滤,滤液浓缩出得粗品。粗品用H
2O/CH
3CN体系经prep-HPLC制备分离,冻干后得到化合物1,白色固体(5.8mg,纯度97.01%)。LC-MS:[M+H]
+=406。
1H NMR(400MHz,DMSO):δ10.88(s,1H),8.86(d,J=1.3Hz,1H),8.54(d,J=2.2Hz,1H),8.06(d,J=6.2Hz,1H),7.92–7.89(m,1H),7.75(s,2H),7.48–7.44(m,2H),7.35–7.32(m,2H),4.06(s,3H),3.92(s,2H)。
实施例2
N-(1-氯-5-氨磺酰基异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
将中间体1-8(20mg,0.043mmol)溶于DCM(0.5mL)中,再加入30%甲醇钠的甲醇溶液(0.1mL),室温搅拌16h,取样送LCMS显示原料反应完毕,加入DCM(10mL)稀释,过滤,滤液浓缩出得粗品。粗品用H
2O/CH
3CN体系经prep-HPLC制备分离,冻干后得到化合物2,白色固体(3.6mg),纯度97.38%。LC-MS:[M+H]
+=409.95。
1H NMR(400MHz,DMSO):δ11.09(s,1H),9.02(s,1H),8.66(s,1H),8.38(s,2H),7.93(s,2H),7.50– 7.45(m,2H),7.37–7.32(m,2H),3.96(s,2H)。
实施例3
步骤(1)(E)-2-(2-氯苯基)-N-(5-(N-((二甲氨基)亚甲基)氨磺酰)-1-羟基异喹啉-7-基)乙酰胺的制备
将中间体1-8(70mg,0.15mmol)溶于AcOH(1mL)中,再加入HBr(0.1mL),室温搅拌16h,取样送LCMS显示原料反应完毕,过滤,滤液浓缩出得中间体3-1粗品,黄色固体(35mg)。
步骤(2)2-(2-氯苯基)-N-(1-羟基-5-氨磺酰基异喹啉-7-基)乙酰胺的制备
将中间体3-1(35mg,0.078mmol)溶于DMF(2.5mL)中,再加入7M氨的甲醇溶液(1mL),室温搅拌16h,取样送LCMS显示原料剩余5%,反应液用H
2O/CH
3CN体系经prep-HPLC制备分离,冻干后得到化合物3,灰白色固体(5.3mg,纯度98.06%)。
LC-MS:[M+H]
+=391.95。
1H NMR(400MHz,DMSO)δ11.46(d,J=4.9Hz,1H),10.74(s,1H),8.71(s,1H),8.56(d,J=1.5Hz,1H),7.64(s,2H),7.49-7.38(m,2H),7.35–7.27(m,2H),7.24–7.18(m,1H),7.08(d,J=7.3Hz,1H),3.87(s,2H)。
实施例4
步骤(1)5,7-二溴喹啉的制备
将化合物4-1(3.0g,11.96mmol)溶解于CH
3SO
3H(20mL)中,室温下加入甘油(1.32g,14.35mmol)、七水合硫酸铁(0.66g,2.39mmol)和间硝基苯磺酸钠(0.54g,2.39mmol),反应液在140℃下反应过夜。TLC显示反应完毕。反应液加水(200mL)和DCM(200mL),水相用DCM(150mL×3)萃取,合并有机相,饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液浓缩得到中间体4-3,黄色固体(2.0g)。LC-MS:[M+H]
+=286.04。
步骤(2)(5-溴喹啉-7-基)氨基甲酸叔丁酯的制备
将中间体4-3(1.0g,3.48mmol)、BocNH
2(0.5g,4.18mmol)、Cs
2CO
3(0.57g,4.18mmol)、Xant-phos(0.1g,0.17mmol)和Pd
2(dba)
3(0.09g,0.17mmol)溶解于DMF(10mL)中,反应液在85℃下搅拌反应过夜。TLC显示反应完毕。反应液加水(100mL),水相用EA(150mL×3)萃取,合并有机相,饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,浓缩得到粗品,粗品用硅胶柱层析冲出产物,得到中间体4-4,黄色固体(0.8g)。LC-MS:[M+H]
+=323.15。
步骤(3)5-溴喹啉-7-胺的制备
将中间体4-4(1.2g,3.71mmol)溶解于EA(2mL)中,再加入HCl/EA(20mL),反应液在室温反应2h。TLC显示反应完毕。反应液浓缩得到粗品,粗品用EA(2mL)洗涤得到中间体4-5,黄色固体(1.0g)。LC-MS:[M+H]
+=223.35。
步骤(4)N-(5-溴喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
将邻氯苯乙酸(0.46g,2.69mmol)、DIPEA(0.87g,6.72mmol)和HATU(1.27g,3.36mmol)溶解于DMF(5mL)中,反应液室温搅拌反应0.5h,再加入中间体4-5(0.5g,2.24mmol),反应液在室温反应过夜。TLC显示反应完毕。反应液加水(100mL),水相用EA(150mL×3)萃取,合并有机相,饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,浓缩得到粗品,粗品用硅胶柱层析得到中间体4-6,黄色固体(0.4g)。LC-MS:[M+H]
+=375.16。
步骤(5)N-(5-(苄硫基)喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
将中间体4-6(0.4g,1.06mmol)、苄硫醇(0.16g,1.28mmol)、Cs
2CO
3(0.42g,1.28mmol)、Xant-phos(0.03g,0.053mmol)和Pd
2(dba)3(0.048g,0.053mmol)溶解于DMF(10mL)中,反应液在85℃下搅拌反应过夜。TLC显示反应完毕。反应液加水(100mL),水相用EA(200mL×3)萃取,合并有机相,饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,浓缩得到粗品,粗品用硅胶柱层析得到中间体4-8,黄色固体(0.3g)。LC-MS:[M+H]
+=419.23。
步骤(6)7-(2-(2-氯苯基)乙酰胺基)喹啉-5-磺酰氯的制备
将中间体4-8(0.3g,0.72mmol)溶解于CH
3COOH(1.0mL)和水(0.3mL)中,反应液在0℃下缓慢加入NCS(0.48g,3.58mmol),反应液在0℃下继续反应4h。TLC显示反应完毕。LCMS显示原料反应完毕。反应液加水(100mL),水相用EA(150mL×3)萃取,合并有机相,饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,浓缩得到粗品,粗品用硅胶柱层析得到中间体4-9,黄色固体(0.2g)。LC-MS:[M+H]
+=395.24。
步骤(7)2-(2-氯苯基)-N-(5-氨磺酰基喹啉-7-基)乙酰胺的制备
将中间体4-9(0.2g,0.5mmol)溶解于NH
3/MeOH(20mL)中,反应液室温搅拌反应2h。TLC显示反应完毕。LCMS显示原料反应完毕。反应液直接用H
2O/MeCN体系经prep-HPLC制备分离,冻干后得到化合物4,白色固体(14.5mg,纯度99.51%)。LC-MS:[M+H]
+=375.95。
1H NMR(400MHz,DMSO)δ10.88(s,1H),8.94(d,J=4.0Hz,1H),8.90(d,J=8.6Hz,1H),8.61(s, 1H),8.44(d,J=1.6Hz,1H),7.74(s,2H),7.57(dd,J=8.6,4.2Hz,1H),7.46(s,2H),7.34(d,J=3.8Hz,2H),3.95(s,2H)。
实施例5
步骤(1)7-溴-3-氯异喹啉-5-磺酰氯的制备
将化合物5-1(4.0g,16.49mmol)溶解于HSO
3Cl(20mL)中,反应液在170℃下反应24h。TLC显示反应完毕。反应液滴加到DCM(200mL)和水(200mL)中,水相用DCM(150mL×3)萃取,合并有机相,饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液浓缩得到中间体5-2,黄色固体(3.0g)。LC-MS:[M+H]
+=340.05。
步骤(2)7-溴-3-氯异喹啉-5-磺酰胺的制备
将中间体5-2(3.0g,8.8mmol)滴加到NH
3/MeOH(30mL)中,反应液室温搅拌反应2h。TLC显示反应完毕。反应液浓缩得到中间体5-3,黄色固体(粗品3.0g)。LC-MS:[M+H]
+=320.12。
步骤(3)(E)-N′-(((7-溴-3-氯异喹啉-5-基)磺酰基)-N,N-二甲基甲酰胺的制备
将中间体5-3(3.0g,9.33mmol)溶解于DMF(5mL)中,再加入DMF-DMA(20mL),反应液在室温反应4h。TLC显示反应完毕。反应液中加入EA(200mL)和水(50mL)中加入EA(150mL×3)萃取,合并有机相,饱和食盐水(100mL×3)洗涤,无水硫酸钠干燥,过滤,浓缩得到中间体5-4,黄色固体(3.0g)。LC-MS:[M+H]
+=376.05。
步骤(4)(E)-(3-氯-5-(N-(((二甲基氨基)亚甲基)氨磺酰基)异喹啉-7-基)氨基甲酸叔丁酯的制备
将中间体5-4(2.5g,6.64mmol)、BocNH
2(0.93g,7.96mmol)、Cs
2CO
3(2.59g,7.96mmol)、Xant-phos(0.192g,0.33mmol)和Pd
2(dba)
3(0.18g,0.33mmol)溶解于DMF(30mL)中,反应液在85℃下搅拌反应过夜。TLC显示反应完毕。反应液加水(100mL),水相用EA(200mL×3)萃取,合并有机相,饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,浓缩得到粗品,粗品用硅胶柱层析得到中间体5-5,黄色固体(2.2g)。LC-MS:[M+H]
+=413.10。
步骤(5)(E)-N′-(((7-氨基-3-氯异喹啉-5-基)磺酰基)-N,N-二甲基甲酰胺的制备
将中间体5-5(2.2g,5.33mmol)溶解于EA(4mL)中,再加入HCl/EA(20mL),反应液在室温反应2h。TLC显示反应完毕。反应液浓缩得到粗品,粗品用EA(4mL)洗涤得到中间体5-6,黄色固体(1.0g)。LC-MS:[M+H]
+=313.04。
步骤(6)(E)-N-(3-氯-5-(N-(((二甲基氨基)亚甲基)氨磺酰基)异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
将邻氯苯乙酸(0.33g,1.92mmol)、DIPEA(0.62g,4.8mmol)和HATU(0.91g,2.4mmol)溶解于DMF(5mL)中,反应液室温搅拌反应0.5h,再加入中间体5-6(0.5g,1.6mmol),反应液升温至在室温反应过夜。TLC显示反应完毕。反应液加水(100mL),水相用EA(150mL×3)萃取,合并有机相,饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,浓缩得到粗品,粗品用硅胶柱层析得到中间体5-8,黄色固体(0.5g)。LC-MS:[M+H]
+=465.05。
步骤(7)N-(3-氯-5-氨磺酰基异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
将中间体5-8(0.5g,1.07mmol)溶解于NH
3/MeOH(20mL)中,反应液升温至室温反应过夜。TLC显示反应完毕。LCMS显示原料反应完毕。反应液直接用H
2O/MeCN体系经prep-HPLC制备分离,冻干后得到化合物5,白色固体(38mg,纯度99.54%)。LC-MS:[M+H]
+=409.95。
1H NMR(400MHz,DMSO)δ10.97(s,1H),9.26(s,1H),8.76(d,J=1.2Hz,1H),8.56(d,J=2.2Hz,1H),8.40(s,1H),7.91(s,2H),7.47(d,J=9.2Hz,2H),7.34(dd,J=6.6,2.4Hz,2H),3.94(s,2H)。
实施例6
步骤(1)7-溴异喹啉-5-磺酰氯的制备
7-溴异喹啉(4.0g,19.2mmol)溶于氯磺酸(60mL)中,加热至150℃,搅拌22h。反应液冷却至室温后,缓慢加入冰盐水中。保持滴加过程<-10℃,滴加完毕后,用5N的氢氧化钠溶液调至pH值9~10。过滤,用冷水洗涤,收集固体,干燥,得到中间体6-2,黄色固体(20g,纯度10%,产率34%)。LC-MS:[M+H]
+=307.9。
步骤(2)7-溴-N,N-二(4-甲氧苄基)异喹啉-5-磺酰胺的制备
将双-(4-甲氧基苄基)-胺(403mg,1.6mmol),三乙胺(396mg,3.9mmol)溶于二氯甲烷(30mL)中,室温搅拌,分批加入中间体6-2(4.0g,1.3mmol)后,室温搅拌过夜。二氯甲烷(20mL)稀释后,依次用饱和碳酸氢钠溶液(30mL),饱和食盐水(30mL)洗涤。无水硫酸钠干燥有机相,过滤浓缩,粗品硅胶柱层析纯化得到中间体6-3。白色固体(300mg,纯度75%,产率33%)。LC-MS:[M+H]
+=527.1。
步骤(3)N-(5-(N,N-二(4-甲氧苄基)氨磺酰)异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
氮气保护,将中间体6-3(80mg,0.51mmol),2-(2-氯苯基)乙酰胺(38mg,0.23mmol),碳酸铯(147mg,0.45mmol),三(二亚苄基丙酮)二钯(14mg,0.015mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(17mg,0.03mmol)加入到二氧六环(10mL)中,110℃反应16小时。恢复至室温,过滤,滤液旋干,粗品经硅胶柱层析纯化得到中间体6-5,黄色固体(120mg,纯度70%,产率91%)。LC-MS:[M+H]
+=616.1。
步骤(4)N-(5-(N,N-二(4-甲氧苄基)氨磺酰)异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
将中间体6-5(120mg,0.14mmol)溶于二氯甲烷(2mL)中,加入三氟乙酸(8mL),45℃搅拌24小时。旋干后溶于二氯甲烷(30mL),用饱和碳酸氢钠溶液调至pH值为8,分层,无水硫酸钠干燥有机相,过滤浓缩。粗品硅胶柱层析纯化得到化合物6,白色固体(20mg,产率38%)。LC-MS:[M+H]
+=375.7。
1H NMR(400MHz,d6-DMSO)δ11.01(s,1H),9.49(s,1H),8.81(d,J=1.6Hz,1H),8.62(s,1H),8.59(d,J=2.1Hz,1H),8.43(d,J=6.0Hz,1H),7.89(s,2H),7.55–7.43(m,2H),7.42–7.26(m,2H),3.96(s,2H).
实施例7
2-(2-氯苯基)-N-(3-氟-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=394.0。
实施例8
2-(2-氯苯基)-N-(1-乙氧基-5-氨磺酰基异喹啉-7-基)乙酰胺的制备
将中间体1-8(200mg,0.43mmol)溶于DCM(2mL)中,再加入10质量%乙醇钠的乙醇溶液(4mL),室温搅拌16h,取样,TLC显示原料反应完毕,加入DCM(10mL)稀释,过滤,滤液浓缩出得粗品,经prep-HPLC制备分离,冻干后得到化合物8,白色固体(4.0mg,纯度99.4%),LC-MS:[M+H]
+=420.05。
1H NMR(400MHz,DMSO)δ10.87(s,1H),8.82(d,J=1.6Hz,1H),8.59(d,J=2.2Hz,1H),8.04(d,J=6.2Hz,1H),7.89(dd,J=6.2,0.6Hz,1H),7.74(s,2H),7.50–7.44(m,2H),7.36–7.30(m,2H),4.52(q,J=7.0Hz,2H),3.92(s,2H),1.42(t,J=7.0Hz,3H)。
实施例9
2-(2-氯苯基)-N-(1-异丙氧基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=434.1。
实施例10
2-(2-氯苯基)-N-(1-环丙氧基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=432.1。
实施例11
2-(2-氯苯基)-N-(1-环丁氧基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=446.1。
实施例12
N-(1-(吖丁啶-3-氧基)-5-氨磺酰异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=447.1。
实施例13
2-(2-氯苯基)-N-(1-(环戊氧基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=460.1。
实施例14
2-(2-氯苯基)-N-(1-异丁氧基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=448.1。
实施例15
2-(2-氯苯基)-N-(1-(异戊氧基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=462.1。
实施例16
2-(2-氯苯基)-N-(1-(环丙基甲氧基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=446.1。
实施例17
2-(2-氯苯基)-N-(1-(2-环丙基乙氧基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=460.1。
实施例18
2-(2-氯苯基)-N-(4-氟-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=394.0。
实施例19
2-(2-氯苯基)-N-(5-氨磺酰-3-(三氟甲基)异喹啉-7-基)乙酰胺的制备
采用实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=444.0。
实施例20
2-(2-氯苯基)-N-(3-氰基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=401.0。
实施例21
2-(2-氯苯基)-N-(3-环丙基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=416.1。
实施例22
N-(3-(1H-咪唑-1-基)-5-氨磺酰异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
采用实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=442.1。
实施例23
2-(2-氯苯基)-N-(1-环丙基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=416.1。
实施例24
步骤(1)7-溴-1-氯-N,N-双(4-甲氧基苄基)异喹啉-5-磺酰胺的制备
将中间体1-3(20g,59mmol)溶于DCM(150mL)中,称取NH(PMB)
2(15.2g,59mmol)溶于DCM(150mL)中,再将中间体1-3溶液缓慢滴加到NH(PMB)
2溶液中,滴加完毕室温搅拌1h,取样,TLC显示原料反应完毕,将反应液浓缩拉干后加入硅胶拌样,过柱纯化后得到中间体24-1,黄色固体(32g)。LC-MS:[M+H]
+=561.0。
步骤(2)5-(N,N-双(4-甲氧基苄基)氨磺酰基)-1-氯异喹啉-7-基)氨基甲酸叔丁酯的制备
称取中间体24-1(11.5g,20.5mmol)、BocNH
2(3.6g,30.8mmol)、Cs
2CO
3(10.03g,30.8mmol),加入DMF(100mL)搅拌溶解,再加入PdCl
2(dppf)(1.5g,2.05mmol),Xantphos(1.18g,2.05mmol),置换N
2三次,85℃搅拌2h。取样,加水淬灭,EA萃取,TLC显示中间体24-1剩余约30%,降温后加入水(100mL)和EA(300mL),搅拌后分液,水相用EA(100mL)萃取3次,合并有机相,用盐水(300mL)洗涤,加入无水硫酸钠干燥,过滤,滤液浓缩拉干后过柱纯化,45℃浓缩拉干后得到中间体24-2,黄色固体(2.5g)。LC-MS:[M+H]
+=598.1。
步骤(3)叔-丁基(5-(N,N-二(4-甲氧苄基)氨磺酰)-1-(丙-1-烯-2-基)异喹啉-7-基)氨基甲酸酯的制备
将中间体24-2(240mg,0.4mmol)、异丙烯硼酸酯(100mg,0.6mmol)、Pd(PPh
3)
4(46mg,0.04mmol)、碳酸铯(388mg,1.2mmol)溶于DMF(16mL)中,N
2保护85℃下搅拌4h。TLC 显示反应完毕,反应液加水(50mL)后乙酸乙酯(30mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后过柱得到中间体24-3,浅黄色油状物(120mg,纯度95%,收率41%)。LC-MS:[M+1]
+=604。
步骤(4)叔-丁基(5-(N,N-二(4-甲氧苄基)氨磺酰)-1-异丙基异喹啉-7-基)氨基甲酸酯的制备
将中间体24-3(110mg,0.18mmol)溶于THF(7mL)后加入Pd/C(20mg),H
2保护下室温搅拌2h。LCMS显示反应完毕,反应液直接用硅藻土助滤后浓缩得到中间体24-4,浅黄色油状物(120mg,纯度92%,收率100%)。LC-MS:[M+1]
+=606。
步骤(5)7-氨基-1-异丙基-N,N-二(4-甲氧苄基)异喹啉-5-磺酰胺的制备
将中间体24-4(120mg,0.198mmol)溶于DCM(0.1mL)中,加入HCl-1,4-二氧六环(0.5mL,1.98mmol,4M)后室温反应2h。LCMS显示反应完毕,但反应有杂质生成。反应液浓缩后加水(10mL)用饱和碳酸氢钠溶液调pH=8后再用乙酸乙酯(5mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后得到中间体24-5粗品,浅黄色油状物(92mg,纯度60%,收率92%),LC-MS:[M+1]
+=506。该粗品不纯化直接用于下步反应。
步骤(6)N-(5-(N,N-二(4-甲氧苄基)氨磺酰)-1-异丙基异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
将中间体24-5(80mg,0.16mmol)、2-氯苯乙酸(41mg,0.24mmol)、HATU(100mg,0.24mmol)、 DIEA(62mg,0.48mmol)溶于DMF(5mL)中,室温下搅拌过夜。TLC显示反应完毕,反应液加水(20ml)后用乙酸乙酯(5mL)萃取两遍后合并有机相,干燥,减压浓缩后过柱纯化得到中间体24-6,黄色油状物(31mg,纯度95%,收率31%)。LC-MS:[M+1]
+=658。
步骤(7)2-(2-氯苯基)-N-(1-异丙基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
将中间体24-6(31mg,0.048mmol)溶于DCM(1mL)中,加入TFA(2mL)后55℃下搅拌2h。TLC显示反应完毕,反应液减压浓缩得到粗品。粗品经prep-HPLC制备分离,冻干后得到化合物24,白色固体(8.2mg,纯度97.91%,收率41.8%)。LC-MS:[M+1]
+=418。
1H NMR(400MHz,DMSO)δ10.90(s,1H),8.98(s,1H),8.54(d,J=1.9Hz,1H),8.47(d,J=6.0Hz,1H),8.18(m,1H),7.75(s,2H),7.52–7.41(m,2H),7.37–7.26(m,2H),3.93(s,2H),3.80(dt,J=13.5,6.6Hz,1H),1.32(d,J=6.7Hz,6H)。
实施例25
步骤(1)5-(N,N-双(4-甲氧基苄基)氨磺酰基)-1-甲基异喹啉-7-基)氨基甲酸叔丁酯的制备
称取中间体24-2(2.5g,4.2mmol),三甲基硼(1.57g,6.3mmol),Cs
2CO
3(2.73g,8.4mmol),Pd(PPh
3)
4(0.48g,0.42mmol)溶于DMF(20mL)中,置换N
2三次,85℃搅拌40h。取样,TLC显示原料:产物=1:1,降温至30℃,加入H
2O(50mL)和EA(100mL),搅拌分液,水相用EA(30 mL)萃取2次,合并有机相,再用盐水洗涤,无水硫酸钠干燥,过滤后浓缩得粗品,过柱纯化得到中间体25-1,黄色固体(0.9g)。LC-MS:[M+H]
+=578.2。
步骤(2)5-(N,N-双(4-甲氧基苄基)氨磺酰基)-1-甲酰基异喹啉-7-基)氨基甲酸叔丁酯的制备
称取中间体25-1(0.9g,1.56mmol),二氧化硒(0.52g,4.68mmol)溶于1,4-二氧六环(10mL)中,置换N
2三次,80℃搅拌1h。取样,TLC显示原料反应完毕,降温至30℃,加入H
2O(50mL)和EA(100mL),搅拌分液,水相用EA(30mL)萃取2次,合并有机相,再用盐水洗涤,无水硫酸钠干燥,过滤后浓缩得粗品,粗品得到中间体25-2,黄色固体(400mg)。LC-MS:[M+H]
+=592.2。
步骤(3)5-(N,N-双(4-甲氧基苄基)氨磺酰基)-1-(二氟甲基)异喹啉-7-基)氨基甲酸叔丁酯的制备
称取中间体25-2(400mg,0.67mmol)溶于DCM(10mL),降温至0℃,缓慢滴加DAST(0.22g,1.35mmol),滴加完毕,室温1h,取样,TLC显示原料反应完毕,向反应液中加入DCM(20mL)和H
2O(10mL),搅拌后分液,水相用DCM(10mL)萃取3次,合并有机相,用盐水洗涤,无水硫酸钠干燥,过滤,滤液45℃浓缩拉干后得中间体25-3,红色固体(370mg)。LC-MS:[M+H]
+=614.2。
步骤(4)7-氨基-1-(二氟甲基)-N,N-双(4-甲氧基苄基)异喹啉-5-磺酰胺的制备
称取中间体25-3(370mg,0.6mmol)溶于EA(10mL),再加入3M HCl/EA溶液(20mL),25℃搅拌3h,取样,TLC显示原料反应完毕,加入EA(50mL)稀释,用饱和碳酸钠溶液调节pH至8-9,分液,水相用EA(20mL)萃取3次,合并有机相,用盐水洗涤,无水硫酸钠干燥,过滤后 40℃浓缩拉干后得粗品中间体25-4,绿色固体(320mg)。LC-MS:[M+H]
+=514.1。
步骤(5)N-(5-(N,N-双(4-甲氧基苄基)氨磺酰基)-1-(二氟甲基)异喹啉-7-基)-2-(2-氯苯基)乙酰胺
将2-氯苯乙酸(0.16g,0.93mmol)和HATU(0.35g,0.93mmol)溶于DMF(20mL)中,室温搅拌1h,再加入中间体25-4(0.32g,0.62mmol)和DIPEA(0.16g,1.24mmol),40℃搅拌40h。取样,TLC显示原料反应完毕,降温至25℃,向反应液中加入EA(100mL)和H
2O(50mL),搅拌后分液,水相用EA(50mL)萃取3次,合并有机相,用盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩拉干后过柱纯化得到中间体25-5,黄色固体(290mg)。LC-MS:[M+H]
+=666.1。
步骤(6)2-(2-氯苯基)-N-(1-(二氟甲基)-5-氨磺酰基异喹啉-7-基)乙酰胺的制备
将中间体25-5(290mg,0.436mmol)溶于DCM(10mL)中,再加入TFA(20mL),40℃搅拌16h,取样,送LCMS显示原料反应完毕,向反应液中加入DCM(50mL)和H
2O(20mL),搅拌后分液,水相用DCM(20mL)萃取3次,合并有机相,用饱和碳酸钠溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩出得粗品。粗品经prep-HPLC制备分离,冻干后得到化合物25,白色固体(43mg,纯度99.53%)。
LC-MS:[M+H]
+=426。1H NMR(400MHz,DMSO)δ11.05(s,1H),9.09(s,1H),8.70(d,J=1.9Hz,1H),8.64(d,J=6.0Hz,1H),8.56(d,J=6.0Hz,1H),7.92(s,2H),7.50–7.45(m,2H),7.44(s,1H),7.34(dt,J=10.2,3.0Hz,2H),7.30(s,1H),7.17(s,1H),3.96(s,2H)。
实施例26
步骤(1)(E)-N-(1-氯-5-(N-((二甲氨基)亚甲基)氨磺酰)异喹啉-7-基)-2-(2-氯-6-氟苯基)乙酰胺的制备
中间体1-6(150mg,0.481mmol)和中间体26-1(136mg,0.721mmol)溶于DMF(3mL),在加入HOBT(77.9mg,0.577mmol),EDCI(111mg,0.577mmol),和DIEA(124mg,0.962mmol)。反应液室温搅拌过夜。反应完毕,反应液倒入水中,再用EA萃取。有机相旋干得到中间体26-2,黄色油状粗品(105mg,得率45.3%)。LC-MS:[M+H]
+=482.90。
步骤(2)2-(2-氯-6-氟苯基)-N-(1-甲氧基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
将中间体26-2(100mg,0.207mmol)溶于DCM(2mL)中,在向其中加入MeONa/MeOH(30%,186mg,1.04mmol)溶液,反应液室温搅拌3h。反应完毕。反应液倒入水中,再用EA萃取,有机相旋干,得到100mg粗品,粗品制备prep-HPLC得到化合物26。白色固体(11.8mg)。
LC-MS:[M+H]
+=423.95。
1H NMR(400MHz,DMSO-d
6)δ10.97(s,1H),8.84(s,1H),8.53(d,J=2.4Hz,1H),8.07(d,J=6.4Hz,1H),7.91(d,J=6.4Hz,1H),7.76(s,2H),7.44–7.36(m,2H),7.30-7.24(m,1H),4.06(s,3H),3.97(s,2H)。
实施例27
步骤(1)(E)-N-(1-氯-5-(N-((二甲氨基)亚甲基)氨磺酰)异喹啉-7-基)-2-(2-氯-4,5-二氟苯基)乙酰胺的制备
中间体1-6(150mg,0.481mmol)和中间体27-1(149mg,0.721mmol)溶于DMF(3mL),在加入HOBT(77.9mg,0.577mmol),EDCI(111mg,0.577mmol),和DIEA(124mg,0.962mmol)。反应液室温搅拌过夜。反应完毕,反应液倒入水中,再用EA萃取。有机相旋干得到中间体27-2,黄 色油状粗品(165mg,得率68.6%)。LC-MS:[M+H]
+=500.90。
步骤(2)2-(2-氯-4,5-二氟苯基)-N-(1-甲氧基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
将中间体27-2(160mg,0.319mmol)溶于DCM(2mL)中,在向其中加入MeONa/MeOH(30%,286mg,1.59mmol)溶液,反应液室温搅拌72h。反应完毕。反应液倒入水中,再用EA萃取,有机相旋干,得到100mg粗品,粗品制备prep-HPLC得到化合物27,白色固体(27mg)。
LC-MS:[M+H]
+=441.95。
1H NMR(400MHz,MeOD-d
4)δ8.84(d,J=2.4Hz,1H),8.63(d,J=2.0Hz,1H),8.06(d,J=6.4Hz,1H),7.98(d,J=6.4Hz,1H),7.51–7.40(m,2H),4.14(s,3H),3.96(s,2H)。
实施例28
步骤(1)7-溴-1-甲氧基-N,N-二(4-甲氧苄基)异喹啉-5-磺酰胺的制备
中间体24-1(2g,3.56mmol)溶于DCM(30mL),然后加入甲醇钠溶液(5mol/L,4.3mL,21.4mmol)。反应液室温搅拌过夜。反应完毕,反应液倒入水中,用HCl(1M)调pH=8,再用EA萃取。有机相旋干得到粗品,粗品过硅胶柱纯化得到中间体28-1,黄色固体(1.2g,收率60.5%)。 LC-MS:[M+H]
+=557.1。
步骤(2)(5-(N,N-双(4-甲氧苄基)磺酰胺)1-甲氧基异喹啉-7-基)氨基甲酸叔丁酯的制备
将中间体28-1(1g,1.78mmol)和BocNH
2(312mg,2.67mmol)溶于DMF(30mL)中,再向其中加入Pd
2(dba)
3(81.4mg,89umol),XantPhos(51.4mg,89umol)和Cs
2CO
3(1.16g,3.56mmol),反应85℃搅拌4h。反应完毕。反应液倒入水中,再用EA萃取,有机相旋干,得到粗品,粗品过硅胶柱纯化得到中间体28-2,黄色固体(1.1g,收率100%)。LC-MS:[M+H]
+=594.2。
步骤(3)7-氨基-1-羟基-N,N-二(4-甲氧苄基)异喹啉-5-磺酰胺的制备
中间体28-2(1.1g,1.84mmol)加入到HCl/EA(3M)中,室温搅拌2h,反应完毕,反应液用EA稀释,再用NaOH(1M)调节pH=6,分液,有机相旋干得到中间体28-3,黄色油状粗品(600mg,收率100%)。LC-MS:[M+H]
+=480.2。
步骤(4)N-(5-(N,N-二(4-甲氧苄基)氨磺酰)-1-羟基异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
将中间体28-3(550.0mg,1.15mmol)溶于DMF(15mL)中,加入中间体1-7(234.8mg,1.38mmol),HATU(1.72mmol),DIEA(296.5mg,2.29mmol),室温条件下,搅拌反应过夜。TLC分析(EA:PE=1:2),原料反应完全,加入水(50mL)稀释,乙酸乙酯萃取(50mL×3),合并有机相,饱和食盐水洗涤,无水Na
2SO
4干燥,旋干溶剂,柱层析分离得到中间体28-4,米黄色固体(600mg,收率82.8%)。LC-MS:[M+H]
+=632。
步骤(5)N-(5-(N,N-双(4-甲氧基苄基)氨磺酰基)-1-(二氟甲氧基)异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
将中间体28-4(500.0mg,790.98μmol)溶于MeCN(15mL)中,加入中间体28-5(241.2mg,1.58mmol)。升温至80℃,搅拌反应过夜。TLC显示原料反应完全。旋干溶剂,柱层析分离得到中间体28-6,米黄色固体(200.2mg)。LC-MS:[M+H]
+=682。
步骤(6)2-(2-氯苯基)-N-(1-(二氟甲氧基)-5-氨磺酰基异喹啉-7-基)乙酰胺的制备
将中间体28-4(490.0mg,718.33μmol)溶于DCM(8mL),加入TFA(8mL),35℃搅拌反应过夜。TLC显示原料反应完全,停止反应。旋干溶剂得粗品。粗品经prep-HPLC制备分离,冻干后得化合物28,白色固体(115.3mg,纯度99.927%)。
LC-MS:[M+H]
+=441.90。
1H NMR(400MHz,DMSO-d
6)δ11.02(s,1H),8.82(d,J=1.4Hz,1H),8.66(d,J=2.0Hz,1H),8.17(dd,J=13.5,6.2Hz,2H),8.11(s,1H),7.93(s,1H),7.87(s,2H),7.74(s,1H),7.47(dd,J=5.2,4.0Hz,2H),7.37–7.30(m,2H),3.94(s,2H)。
实施例29
2-(2-氯苯基)-N-(5-氨磺酰-1-(三氟甲基)异喹啉-7-基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=440.0。
实施例30
2-(2-氯苯基)-N-(1-苯氧基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=468.1。
实施例31
步骤(1)(Z)-2-(2-氯苯基)-N-(5-(N-(((二甲基氨基)亚甲基)氨磺酰基)-1-(4-氟苯氧基)异喹啉-7-基)乙酰胺的制备
将中间体1-8(160mg,0.35mmol),对氟苯酚(118mg,1.05mmol),碳酸钾(145mg,1.05mmol)溶于DMF中,室温搅拌过夜反应。取样点板,原料反应完全。向反应液中加水(5mL),用EA萃取三次,合并EA相,饱和食盐水洗涤,硫酸钠干燥,过滤浓缩即得中间体31-1产品(100mg)。LC-MS:[M+H]
+=541。
步骤(2)2-(2-氯苯基)-N-(1-(4-氟苯氧基)-5-氨磺酰基异喹啉-7-基)乙酰胺的制备
将中间体31-1(100mg,0.28mmol)溶入水合肼中(15mL)中,室温搅拌反应2h。取样点板显示原料反应完毕。将反应液旋干,送制备纯化处理,冻干制备液即得化合物31,白色固体(35mg)。
LC-MS:[M+H]
+=486.1。
1H NMR(400MHz,DMSO)δ:10.96(s,1H),9.04(s,1H),8.62(d,J=2.0Hz,1H),8.02(s,1H),7.97(d,J=6.0Hz,1H),7.82(s,2H),7.46(d,J=9.2Hz,2H),7.34–7.26(m,6H),3.94(s,2H)。
实施例32
2-(2-氯苯基)-N-(1-((4-氟苯甲基)氧代)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=500.1。
实施例33
N-(1-((1-乙酰基吖丁啶-3-基)氧代)-5-氨磺酰异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=489.1。
实施例34
2-(2-氯苯基)-N-(5-氨磺酰-1-(p-甲苯氧基)异喹啉-7-基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=482.1。
实施例35
2-(2-氯苯基)-N-(1-(4-甲氧基苯氧基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
采用实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=498.1。
实施例36
2-(2-氯苯基)-N-(8-氨磺酰-4-(三氟甲基)异喹啉-6-基)乙酰胺的制备
采用实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=444.0。
实施例37
步骤(1)6-溴喹啉-8-磺酰氯的制备
氮气保护,将6-溴喹啉(3.0g,14.42mmol)缓慢加入到氯磺酸(10mL)中,150℃反应3h,冷却至室温,将反应液缓慢滴加到冰(50g)中,然后用乙酸乙酯(50mL×2)萃取,合并有机相,饱和食盐水(20mL×2)洗,无水硫酸钠干燥,过滤后,减压浓缩得到中间体37-2粗品,棕色固体(1.68g),LC-MS:[M+H]
+=307.9。
步骤(2)6-溴-N,N-二(4-甲氧苄基)喹啉-8-磺酰胺的制备
氮气保护,将双-(4-甲氧基苄基)-胺(1.27g,4.94mmol)和三乙胺(2.22g,21.96mmol)溶于二氯甲烷(16mL),冰水浴,滴加中间体37-2(1.68g,5.49mmol)的二氯甲烷(4mL)溶液,滴毕后室温搅拌过夜。将反应液倒入水(30mL),二氯甲烷(30mL×2)萃取,合并有机相,饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤浓缩,粗品用硅胶柱纯化得到中间体37-3,淡黄色固体(1.30g),两步收率17%。LC-MS:[M+H]
+=528.6.
步骤(3)N-(8-(N,N-二(4-甲氧苄基)氨磺酰)喹啉-6-基)-2-(2-氯苯基)乙酰胺
将中间体37-3(1.25g,2.37mmol)和2-(2-氯苯基)乙酰胺(442mg,2.61mmol)溶于二氧六环(20mL)中,依次加入4,5-双二苯基膦-9,9-二甲基氧杂蒽(278mg,0.47mmol),三(二亚苄基丙酮)二钯(217mg,0.24mmol)和碳酸铯(1.93g,5.93mmol),氮气保护,100℃反应4h。冷却至室温,过滤,减压浓缩,粗品用硅胶柱纯化得到中间体37-4,淡黄色固体(957mg,收率63%)。LC-MS:[M+H]
+=616.1。
步骤(4)2-(2-氯苯基)-N-(8-氨磺酰喹啉-6-基)乙酰胺的制备
将中间体37-4(950mg,1.54mmol)溶于二氯甲烷(4mL),然后加入加三氟乙酸(4mL),室温反应48h。减压浓缩,然后溶于二氯甲烷(40mL),饱和碳酸氢钠溶液洗涤(20mL×2),饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤浓缩得到粗品600mg,将其中的200mg用制备色谱纯化(乙腈(0.1%氨水)-水(0.1%氨水))得到化合物37,白色固体(73mg,收率38%)。
LC-MS:[M+H]
+=376.1。
1H NMR(400MHz,DMSO)δ10.86(s,1H),8.95(dd,J=4.2,1.7Hz,1H),8.62(d,J=2.4Hz,1H),8.46(dd,J=8.5,1.9Hz,2H),7.65(dd,J=8.4,4.2Hz,1H),7.51–7.45(m,2H),7.38–7.32(m,2H),7.29(s,2H),3.94(s,2H).
实施例38
2-(2-氯苯基)-N-(2-氟-8-氨磺酰喹啉-6-基)乙酰胺的制备
采用实施例3的制备方法进行制备得到。LC-MS:[M+H]
+=394.0。
实施例39
N-(2-氨基-5-氨磺酰喹唑啉-7-基)-2-(2-氯苯基)乙酰胺的制备
采用实施例3的制备方法进行制备得到。LC-MS:[M+H]
+=392.0。
实施例40
2-(2-氯苯基)-N-(8-氨磺酰喹唑啉-6-基)乙酰胺的制备
采用实施例3的制备方法进行制备得到。LC-MS:[M+H]
+=377.0。
实施例41
2-(2-氯苯基)-N-(8-氨磺酰噌啉-6-基)乙酰胺的制备
采用实施例3的制备方法进行制备得到。LC-MS:[M+H]
+=377.0。
实施例42
步骤(1)甲基6-氰基-2-萘酸酯的制备
将称量好的中间体42-1(5g,18.86mmol)溶于DMF(100mL)中,加入CuCN(2.03g,22.63mmol),换N
2保护150℃回流反应过夜,点板监控原料反应完全。反应液降至室温,加入水(100mL)稀释,用二氯甲烷(100mL)萃取2次,有机相旋干,通过过柱纯化得到中间体42-2,黄绿色固体(3.5g)。LC-MS:[M+H]
+=212.1。
步骤(2)甲基4-溴-6-氰基-2-萘酸酯的制备
将称量好的中间体42-2(6g,28.41mmol)溶于装有DCM(200mL)中,瓶身用锡箔纸包好避光,加入TfOH(4.7g,31.247mmol)和DDH(6.5g,22.73mmol),置换N
2,室温反应过夜,点板监控原料反应完全。反应液用饱和NaHSO
3淬灭,用饱和NaHCO
3调节pH至7.0左右,分出有机相旋干,用甲醇打浆2次过滤,滤饼旋干得到中间体42-4,白色固体(6.2g)。LC-MS:[M+H]
+=290.0。
步骤(3)甲基4-(苯甲硫基)-6-氰基-2-萘酸酯的制备
将称量好的中间体42-4(6.2g,21.37mmol),苄硫醇(3.5g,27.78mmol),Pd
2(dba)
3(1.9g,2.14mmol),Xantphos(619mg,1.07mmol)和DIEA(11g,84.48mmol)依次加入到装有1,4-二氧六环(150mL)的单口瓶中,换N
2保护,105℃反应过夜,点板监控原料反应完全,反应液降至室温,加水(100mL),用EA(100mL)萃取,有机相旋干,通过过柱纯化得到中间体42-5,黄色固体(5.3g)。LC-MS:[M+H]
+=334.1。
步骤(4)甲基4-(氯磺酰)-6-氰基-2-萘酸酯的制备
将称量好的中间体42-5(4.3g,12.89mmol)溶于冰乙酸(36mL)和水(12mL)的混合液中,室温下分批加入NCS(6.9g,51.59mmol),加完室温反应2h,点板监控原料反应完全,反应液过滤,滤饼用水洗2次,旋干得到中间体42-6,淡黄色固体(3.8g)。LC-MS:[M+H]
+=310.0。
步骤(5)甲基4-(N,N-二(4-甲氧苄基)氨磺酰)-6-氰基-2-萘酸酯的制备
将称量好的双-(4-甲氧基苄基)-胺(3.8g,14.75mmol)溶于DCM(120mL)中,加入TEA(3.7g,36.87mmol),加完室温搅拌10min,加入中间体42-6(3.8g,12.29mmol),室温反应2h。点板监控原料反应完全,反应液加水(100mL),有机相用稀盐酸(0.1N)洗涤,Na
2SO
4干燥,旋干后得到中间体42-7,黄色油状液体(5.5g)。LC-MS:[M+H]
+=531.1。
步骤(6)4-(N,N-二(4-甲氧苄基)氨磺酰)-6-氰基-2-萘酰胺的制备
将称量好的中间体42-7(1.2g,2.26mmol)置于闷罐中,加入胺的甲醇溶液(7.0M,25mL),密封后70℃反应过夜,反应液降至室温,点板监控原料反应完全,直接旋干过柱得到中间体42-8,灰白色固体(530mg)。LC-MS:[M+H]
+=516.1。
步骤(7)3-氨基-7-氰基-N,N-二(4-甲氧苄基)萘-1-磺酰胺的制备
将称量好的中间体42-8(600mg,1.16mmol)和DBU(355mg,2.33mmol)溶于四氢呋喃(30mL)中,缓慢加入水(10mL),确保体系为均相(互溶无分成),降温至0℃,加入醋酸碘苯(450mg,1.39mmol),加完室温反应10min,点板监控原料反应完全。反应液加水(20mL),用EA(30mL)萃取2次,有机相旋干通过过柱纯化得到中间体42-9,黄色油状液体(500mg)。LC-MS:[M+H]
+=488.2。
步骤(8)N-(4-(N,N-二(4-甲氧苄基)氨磺酰)-6-氰基萘-2-基)-2-(2-氯苯基)乙酰胺的制备
将称量好的2-氯苯乙酸(263mg,1.54mmol),HATU(585mg,1.54mmol),DIEA(531mg,4.102mmol)溶于DMF(20mL)中,室温搅拌20min,加入中间体42-9(500mg,1.11mmol),加完室温反应过夜,点板监控原料还有一大半没反应完,只有少量产物,补加2-氯苯乙酸(263mg)和HATU(585mg)并加热至60℃反应6h,点板监控原料反应完全。反应液降温加水(20mL),用EA(20mL)萃取2次,有机相旋干过柱得到中间体42-10,黄色固体(450mg)。LC-MS:[M+H]
+=640.2。
步骤(9)2-(2-氯苯基)-N-(6-氰基-4-氨磺酰萘-2-基)乙酰胺的制备
将称量好的中间体42-10(450mg,0.72mmol)溶于DCM(15mL)中,加入TFA(15mL),40℃反应过夜,点板监控原料反应完全。反应液浓缩通过Prep-HPLC制备纯化得到化合物42。白色固体(88.2mg)。LC-MS:[M+H]
+=400.0。
LC-MS:[M+H]
+=400.00。
1H NMR(400MHz,DMSO)δ10.46(s,1H),8.53(s,1H),8.40(d,J=6.5Hz,1H),8.08(s,3H),7.80(dd,J=14.6,8.4Hz,3H),7.70(d,J=8.6Hz,2H),7.23(s,1H),7.11(d,J=5.1Hz,1H),6.97(s,1H),6.84(d,J=6.5Hz,1H),4.89(s,2H),4.57(s,2H),4.05(s,3H)。
实施例43
步骤(1)(E)-2-(2-氯苯基)-N-(5-(N-(((二甲基氨基)亚甲基)氨磺酰基)-1-氧代-1,2-二氢异喹啉-7-基)乙酰胺的制备
将中间体1-8(200.0mg,429.78μmol)溶于HOAc(15mL)中,加入KOAc(421.8mg,4.30mmol)。升温至100℃,搅拌反应3h。TLC显示原料反应完全。旋干溶剂,柱层析分离得到中间体43-1,黄色固体(200mg)。LC-MS:[M+H]
+=447。
步骤(2)2-(2-氯苯基)-N-(1-氧代-5-氨磺酰基-1,2-二氢异喹啉-7-基)乙酰胺的制备
将中间体43-1(190.0mg,425.15μmol)溶于MeOH(10mL),加入水合肼(5mL),室温条件下,搅拌反应1h。TLC显示原料反应完全,停止反应。加入水(50mL)和乙酸乙酯(50mL)稀释,分液,收集有机相,旋干溶剂得粗品。粗品经prep-HPLC制备分离,冻干后得化合物43,米黄色固体(5.0mg,纯度97.123%)。
LC-MS:[M+H]
+=391.95。
1H NMR(400MHz,DMSO)δ11.46(d,J=4.9Hz,1H),10.74(s,1H),8.71(s,1H),8.56(d,J=1.5Hz,1H),7.64(s,2H),7.49-7.38(m,2H),7.35–7.27(m,2H),7.24–7.18(m,1H),7.08(d,J=7.3Hz,1H),3.87(s,2H).
实施例44
化合物44:2-(2-氯苯基)-N-(1-氰基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例6的制备方法进行制备得到。LC-MS:[M+H]
+=400.6
实施例45
化合物45:2-(2-氯苯基)-N-(8-氨磺酰异喹啉-6-基)乙酰胺的制备
参照实施例6的制备方法进行制备得到。LC-MS:[M+H]
+=376.0
实施例46
化合物46:甲基7-(2-(2-氯苯基)乙酰氨基)-5-氨磺酰-3,4-二氢喹啉-1(2H)-羧酸酯的制备
参照实施例6的制备方法进行制备得到。LC-MS:[M+H]
+=438.1
实施例47
化合物47:2-(2-氯苯基)-N-(4-氟-8-氨磺酰异喹啉-6-基)乙酰胺的制备
参照实施例6的制备方法进行制备得到。LC-MS:[M+H]
+=394.0
实施例48
化合物48:N-(4-氯-8-氨磺酰异喹啉-6-基)-2-(2-氯苯基)乙酰胺的制备
参照实施例6的制备方法进行制备得到。LC-MS:[M+H]
+=410.0
实施例49
化合物49:N-(2-(1H-吡唑-1-基)-5-氨磺酰喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
参照实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=442.1
实施例50
化合物50:N-(3-(1H-咪唑-1-基)-8-氨磺酰异喹啉-6-基)-2-(2-氯苯基)乙酰胺的制备
参照实施例6的制备方法进行制备得到。LC-MS:[M+H]
+=442.1
实施例51
化合物51:N-(1-氨基-5-氨磺酰异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
参照实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=391.1
实施例52
化合物52:2-(2-氯苯基)-N-(1-((4-氟苯基)氨基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=485.1
实施例53
化合物53:2-(2-氯苯基)-N-(1-甲氧基-5-(S-甲基磺亚胺酰基)异喹啉-7-基)乙酰胺的制备
参照实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=404.1
实施例54
化合物54:2-(6-氯-2,3-二氟苯基)-N-(1-甲氧基-5-氨磺酰基异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体54-1的制备
将称量好的中间体28-2(600mg)溶于18mL DCM中,加入3mL TFA,加完室温反应1.5h.点板监控原料反应完全,反应液用饱和碳酸氢钠溶液淬灭,用DCM萃取,有机相饱和食盐水洗涤,硫酸钠干燥,旋干得到中间体54-1产物粗品690mg,为黄色油状液体。
步骤(2)中间体54-3的制备
将称量准确的将称量准确的中间体54-1(80mg)、中间体54-2(2-(6-氯-2,3-二氟苯基)乙酸)(40mg)、T3P(103mg)、TEA(49mg)溶于DCM中,室温搅拌反应1h。取样点板,原料反应完全。后处理,直接向反应液中加硅胶拌干过柱子(PE/EA=4:1-2:1)旋干过柱液即得产品。反应成功,得中间体54-3黄色油状液体100mg。LCMS[M+H]=682。
步骤(3)化合物54的制备
将称量准确的中间体54-3(100mg)、TFA(44.1mg)溶于DCM中,室温搅拌过夜反应。取样点板,原料反应完全,将反应液旋干,送制备纯化,冻干制备液即得产品。反应成功,得化合物54白色泡状固体12mg。LCMS[M+H]=442。
1H NMR(400MHz,dmso)δ10.99(s,1H),8.81(d,J=1.3Hz,1H),8.51(d,J=2.1Hz,1H),8.05(d,J=6.2Hz,1H),7.89(d,J=6.2Hz,1H),7.74(s,1H),7.50–7.36(m,2H),4.04(s,3H),4.00(s,2H).
实施例55
化合物55:2-(2-氯苯基)-N-(1-甲基-5-氨磺酰基异喹啉-7-基)乙酰胺)的制备
合成路线:
步骤(1)中间体55-1的制备
称取中间体1-1(10g),加入浓硫酸(10ml)溶解,再加入发烟硫酸(50ml),升温至60℃,搅拌16h,取样,加水淬灭,EA萃取,TLC(PE:EA=6:1),显示原料约有10%剩余。将反应液缓慢滴加至冰水(500mL)中,控制内温不超过10℃,滴加完毕搅拌30min后静置1h,过滤,滤饼用乙腈(200mL)套蒸3次,再用PE:EA=10:1(60mL)打浆20min,过滤后滤饼拉干得到中间体55-1灰色固体(16g)。
步骤(2)中间体55-2的制备
依次将中间体55-1(12g)溶于二氯亚砜(120ml)中,再加入DMF(1ml),70℃搅拌2h。取样,TLC(PE:EA=2:1),显示原料反应完毕。降温后40℃浓缩拉干,滤饼用DCM(200mL)套蒸3次拉干得中间体55-2,灰白色固体(13g)。
步骤(3)中间体55-3的制备
将中间体55-2(20g)溶于DCM(150ml)中,称取NH(PMB)
2(15.2g)溶于DCM(150ml)中,再将中间体55-2溶液缓慢滴加到NH(PMB)
2溶液中,滴加完毕室温搅拌1h,取样,TLC(PE:EA=2:1),显示原料反应完毕,将反应液浓缩拉干后加入硅胶拌样,过柱纯化PE:EA=5:1至2:1,纯化液弄过拉干后得到中间体55-3黄色固体(32g)。
步骤(4)中间体55-4的制备
称取中间体55-3(11.5g)、BocNH
2(3.6g)、Cs
2CO
3(10.03g),加入DMF(100ml)搅拌溶解,再加入PaCl
2(dppf)(1.5g),Xantphos(1.18g),置换N
2 3次,85℃搅拌2h。取样,加水淬灭,EA萃取,TLC(PE:EA=2:1),显示原料剩余约30%,降温后加入水(100ml)和EA(300ml),搅拌后分液,水相用EA(100ml)萃取3次,合并有机相,用Brine(300ml)洗涤,加入无水硫酸钠干燥,过滤,滤液浓缩拉干后加入硅胶拌样,PE:EA=4:1—1:1过柱纯化,45℃浓缩拉干后得到中间体55-4黄色固体2.5g。
步骤(5)中间体55-5的制备
将中间体55-4(2.5g)溶于EA(10ml)中,再加入3M HCl/EA(40ml),室温搅拌3h,取样,TLC(PE:EA=1:1)显示原料反应完毕,加入H
2O(50ml)和EA(50ml),再用饱和NaHCO
3溶液调节pH至8-9后,分液,有机相用Brine洗涤,无水硫酸钠干燥,过滤后浓缩得到中间体55-5黄色固体(1.5g)。
步骤(6)中间体55-6的制备
将中间体1-7(2-氯苯乙酸)(0.57g)和HATU(1.28g)溶于DMF(20ml)中,室温搅拌1h,再加入中间体55-5(1.4g)和DIPEA(0.76g),继续搅拌16h。取样,TLC(PE:EA=3:1),显示原料:产物=1:1,向反应液中加入EA(100ml)和H
2O(50ml),搅拌后分液,水相用EA(50ml)萃取3次,合并有机相,用Brine洗涤,无水硫酸钠干燥,过滤,滤液浓缩拉干后加入硅胶拌样,PE:EA=5:1—1:1过柱纯化,45℃浓缩拉干后得到中间体55-6黄色固体(800mg)。
步骤(7)中间体55-7的制备
称取中间体55-6(750mg),Trimethylborxine(290mg),碳酸铯(750mg)和四三苯基膦钯(130mg),再加入DMF(10ml)溶解,置换N
2 3次,85℃搅拌40h,取样,TLC(PE:EA=2:1),显示原料少量剩余,向反应液中加入EA(50ml)和H
2O(20ml),搅拌后分液,水相用EA(20ml)萃取3次,合并有机相,用Brine洗涤,无水硫酸钠干燥,过滤,滤液浓缩拉干后加入硅胶拌样,PE:EA=3:1—1:1过柱纯化,45℃浓缩拉干后得中间体55-7黄色油状物(250mg)。
步骤(8)化合物55的制备
将中间体55-7(250mg)溶于DCM(10ml)中,再加入TFA(30ml),40搅拌16h,取样,TLC(PE:EA=2:1),显示原料反应完毕,向反应液中加入DCM(50ml)和H
2O(20ml),搅拌后分液,水相用DCM(20ml)萃取3次,合并有机相,用饱和碳酸钠溶液和Brine洗涤,无水硫酸钠干燥,过滤,滤液浓缩出得粗品。粗品用H
2O/CH
3CN体系经prep-HPLC制备分离,冻干后得到化合物55白色固体(51mg),纯度96.46%,[M+H]+=390.06。
1H NMR(400MHz,DMSO)δ10.93(s,1H),8.84(s,1H),8.59(s,1H),8.40(d,J=6.1Hz,1H),8.23(d,J=5.5Hz,1H),7.79(s,2H),7.49–7.45(m,2H),7.36–7.32(m,2H),3.95(s,2H),2.87(s,3H)。
实施例56
化合物56:2-(2-氯苯基)-N-(1-(氟甲基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例24的制备方法进行制备得到。LC-MS:[M+H]
+=408.0
实施例57
化合物57:N-(5-(N,N-二(4-甲氧苄基)氨磺酰)-2-氯喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
合成路线:
步骤(1)中间体57-1的制备
将中间体4-9(500mg)加入DCM(10ml)中,加入三乙胺(260mg)后0℃下分批向该溶液中加入NH(PMB)
2(390mg),室温下搅拌1h。TLC显示反应完毕,反应液减压浓缩后过柱纯化得到中间体57-1,浅黄色固体(580mg,纯度97%,收率75.3%)。LC-MS:[M]
+=616。
步骤(2)中间体57-2的制备
将中间体57-1(200mg)加入DCM(5ml)后0℃下向该溶液中加入m-CPBA(150mg),室温下搅拌2h。TLC显示反应完毕,反应液用饱和碳酸氢钠调pH=8,DCM萃取后分离,干燥,浓缩得到中间体57-2,浅黄色油状物(200mg,纯度90%,收率100%)。LC-MS:[M]
+=632。
步骤(3)中间体57-3的制备
将中间体57-2(200mg)加入DCM(2ml)后向该溶液中加入POCl
3(100mg),50℃下搅拌4h。LCMS显示反应完毕,[M]
+=650/530,反应液用饱和碳酸氢钠调pH=8,DCM萃取后分离,干燥,浓缩得到中间体57-3,浅黄色油状物(230mg粗品),该产物不用纯化,直接用于下步反应。
步骤(4)化合物57的制备
将中间体57-3(230mg粗品)溶于DCM(5ml)中,加入TFA(10ml)后50℃下搅拌2h。TLC显示反应完毕,反应液减压浓缩得到粗品。粗品用H2O/CAN体系经prep-HPLC制备分离,冻干后得到化合物57,白色固体(51.2mg,纯度98.31%,收率39.2%)。LC-MS:[M]
+=410。
1H NMR(400MHz,DMSO)δ10.96(s,1H),8.90(d,J=9.1Hz,1H),8.47(dd,J=17.4,2.0Hz,2H),7.85(s,2H),7.65(d,J=9.0Hz,1H),7.45(dd,J=5.3,4.0Hz,2H),7.37–7.24(m,2H),3.94(s,2H).
实施例58
化合物58:2-(2-氯苯基)-N-(2-甲氧基-5-氨磺酰喹啉-7-基)乙酰胺的制备
参照实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=406.1
实施例59
化合物59:N-(3-氯-8-氨磺酰异喹啉-6-基)-2-(2-氯苯基)乙酰胺的制备
参照实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=410.0
实施例60
化合物60:2-(2-氯苯基)-N-(5-氨磺酰-1-(三氟甲氧基)异喹啉-7-基)乙酰胺的制备
参照实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=460.0
实施例61
化合物61:2-(2-氯苯基)-N-(1-(氟甲氧基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=424.1
实施例62
化合物62:2-(2-氯-6-羟基苯基)-N-(1-甲氧基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=422.1
实施例63
化合物63:2-(6-氯-3-氟-2-羟基苯基)-N-(1-甲氧基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=440.0
实施例64
化合物64:2-(2-氰基苯基)-N-(1-甲氧基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=397.1
实施例65
化合物65:2-(2-氯苯基)-N-(2-甲氧基-5-氨磺酰喹啉-7-基)乙酰胺的制备
合成路线
步骤(1)中间体65-1的制备
将中间体4-3(2.6g)溶于DCM(20ml)并搅拌5min,0℃下分批加入m-CPBA(3.1g),室温搅拌2h。TLC显示反应完成。将反应液用硫代硫酸钠溶液淬灭后,用1N NaOH调pH=10后再用二 氯甲烷(50mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤浓缩得2.5g黄色固体粗品。向该粗品加入DCM(10ml)和POCl
3(2.5g)后55℃下封管反应4h,TLC显示反应完成。将反应液用碳酸氢钠溶液淬灭后,用二氯甲烷(50mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤浓缩过柱得到中间体65-1,棕色固体(1.4g,纯度95%,收率56%)。LC-MS:[M]
+=322。
步骤(2)中间体65-2的制备
将中间体65-1(1.3g)溶于DMF(15ml)中,加入甲醇钠甲醇溶液(4ml),室温下搅拌1h。TLC显示反应完毕,反应液加水(50mL)后乙酸乙酯(30mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后过柱得到中间体65-2,黄色固体(1.0g,纯度98%,收率74%)。LC-MS:[M]
+=317。
步骤(3)中间体65-3的制备
将中间体65-2(500mg)、NH
2Boc(186mg)、Pd2(dba)3(72mg)、碳酸铯(760mg)、Xantphos(45mg)溶于DMF(40ml)中,N
2保护80℃下搅拌16h。TLC显示反应完毕,反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后过柱得到中间体65-3,黄色固体(480mg,纯度93.7%,收率83%)。LC-MS:[M]
+=355。
步骤(4)中间体65-4的制备
将中间体65-3(480mg)溶于DCM(5ml)中,加入TFA(5ml)室温下搅拌2h。TLC显示反应完毕,反应液减压浓缩得到中间体65-4,黄色油状物粗品520mg,不纯化,直接用下步反应。
步骤(5)中间体65-5制备
将中间体65-4(520mg)、中间体1-7(2-氯苯乙酸)(340g)、HATU(760mg)、DIEA(520mg)溶于DMF(5ml)中,室温下搅拌2h。TLC显示反应完毕,反应液加水(30ml)后用乙酸乙酯(10ml)萃取两遍后合并有机相,干燥,减压浓缩后过柱纯化得到中间体65-5,浅黄色固体(400mg,纯度84.5%,收率80%)。LC-MS:[M]
+=406。
步骤(6)中间体65-6的制备
将中间体65-5(400mg)、中间体4-7(苄硫醇)(150mg)、Pd2(dba)3(50mg)、碳酸铯(488mg)、Xantphos(30mg)溶于DMF(5ml)中,85℃下搅拌4h。TLC显示反应完毕,反应液加水(50ml)后用乙酸乙酯(10ml)萃取两遍后合并有机相,干燥,减压浓缩后过柱纯化得到中间体65-6,浅黄色固体(350mg,纯度92.6%,收率78%)。LC-MS:[M]
+=449。
步骤(7)中间体65-7的制备
将中间体65-6(160mg)加入HOAc/H
2O(2/0.7ml)中,分批向该浑浊液中加入NCS(236mg)室温下搅拌5h,TLC显示反应完毕,反应液加水(20ml)后用乙酸乙酯(10ml)萃取两遍后合并有机相,用饱和碳酸氢钠调pH=8后分液,减压浓缩得到中间体65-7,浅黄色固体粗品160mg,收率110%,不纯化直接用下步反应。
步骤(8)化合物65的制备
将中间体65-7(160mg)加入DCM(0.1ml)后向该溶液中加入NH3-dioxane(2.5ml),室温下搅拌过夜。TLC显示反应完毕,反应液减压浓缩得到粗品。粗品用H2O/CAN体系经prep-HPLC制备分离,冻干后得到化合物65,白色固体(55.2mg,纯度99.7%,收率32.6%)。LC-MS:[M]
+=406。
1H NMR(400MHz,DMSO)δ10.77(s,1H),8.75(d,J=9.3Hz,1H),8.42(d,J=1.9Hz,1H),8.18(d,J=2.1Hz,1H),7.71(s,2H),7.48–7.41(m,2H),7.36–7.26(m,2H),7.05(d,J=9.2Hz,1H),3.97(s,3H),3.91(s,2H).
实施例66
化合物66:2-(2-氯苯基)-N-(2-(2-羟基乙氧基)-5-氨磺酰喹啉-7-基)乙酰胺的制备
参照实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=436.1
实施例67
化合物67:2-(2-氯苯基)-N-(2-(哌啶-1-基)-5-氨磺酰喹啉-7-基)乙酰胺的制备
参照实施例4的制备方法进行制备得到。LC-MS:[M+H]
+=459.1
实施例68
化合物68:2-(2-氯苯基)-N-(2-吗啉代-5-氨磺酰喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体68-1的制备
将中间体4-6(8.2g)加入DCM(150ml)后0℃下向该溶液中加入m-CPBA(9.3g),室温下搅拌48h。TLC显示反应完毕,反应液用1M氢氧化钠调pH=10,DCM萃取后分离,干燥,浓缩过柱纯化(PE/EA=3/1~0/1)得到中间件68-1,为黄色固体(5.2g,收率62.1%)。LC-MS:[M]
+=391。
步骤(2)中间体68-2的制备
将中间体68-1(5.2g)加入DCM(100ml)后向该溶液中加入POCl
3(6.0g),55℃下搅拌16h。LCMS显示反应完毕,反应液冰水浴下用水崔灭后用饱和碳酸钠调pH=9,DCM萃取后分离,干燥,浓缩过柱纯化(PE/EA=8/1~3/1)得到中间体68-2,为黄色固体(2.9g,收率53.7%)。LC-MS:[M]
+=410。
步骤(3)中间体68-3的制备
将中间体68-2(250mg),吗啉(160mg),DIEA(390mg)溶入DMF(5ml)60℃下搅拌过夜。TLC显示反应完成,将反应液用水(50mL)稀释后,用乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后过柱得到中间体68-3,黄色固体(200mg,纯度97.1%,收率72%)。LC-MS:[M]
+=461。
步骤(4)中间体68-4的制备
将中间体68-3(200mg)、中间体4-7(苄硫醇)(80.8mg)、Pd2(dba)3(20mg)、DIEA(138mg)、Xantphos(15mg)溶于DMF(2ml)中,90℃下搅拌5h。TLC显示反应完毕,反应液加水(50ml)后用乙酸乙酯(10ml)萃取两遍后合并有机相,干燥,减压浓缩后过柱纯化得到中间体68-4,浅黄 色固体(250mg,纯度99%,收率98%)。LC-MS:[M]
+=504。
步骤(5)中间体68-5的制备
将中间体68-4(200mg)加入HOAc/H
2O(4/1.2ml)中,分批向该浑浊液中加入NCS(260mg)室温下搅拌3h,TLC显示反应完毕,反应液加水(20ml)后用乙酸乙酯(10ml)萃取两遍后合并有机相,用饱和碳酸氢钠调pH=8后分液,干燥,浓缩得到中间体68-5,为浅黄色固体粗品190mg,收率81%,不纯化直接用下步反应。
步骤(6)化合物68的制备
将中间体68-5(190mg)加入DCM(0.1ml)后向该溶液中加入NH3-dioxane(10ml),室温下搅拌过夜。TLC显示反应完毕,反应液减压浓缩得到粗品。粗品用H2O/CAN体系经prep-HPLC制备分离,冻干后得到化合物68,为白色固体(88.3mg,纯度99.58%,收率42.1%)。LC-MS:[M]
+=461。
1H NMR(400MHz,DMSO)δ10.62(s,1H),8.59(d,J=9.5Hz,1H),8.19(d,J=1.5Hz,1H),8.00(d,J=2.0Hz,1H),7.61(s,2H),7.48–7.40(m,2H),7.33–7.27(m,2H),7.23(d,J=9.6Hz,1H),3.88(s,2H),3.67(dd,J=16.7,4.8Hz,8H).
实施例69
化合物69:2-(2-氯苯基)-N-(2-(4-甲基哌嗪-1-基)-5-氨磺酰喹啉-7-基)乙酰胺的制备
合成路线
步骤(1)中间体69-1的制备
将中间体68-2(400mg),1-甲基哌嗪(489mg),DIEA(630mg),DMF(5mL)加入反应瓶中,反应在80℃下搅拌过夜。将反应液倒入水中,乙酸乙酯萃取,有机相浓缩拌样经柱层析纯化,得到中间体69-1,为黄色固体产物270mg。LC-MS:NB190114-71-02,ESI(+)m/z=475[M+1].
步骤(2)中间体69-2的制备
将中间体69-1(250mg),BnSH(327.7mg),DIEA(341mg)溶于DMF(5mL),向反应瓶加入Xantphos(31mg)和Pd
2(dba)
3,N
2置换三次后反应在100℃下搅拌36h。将反应液倒入水中,乙酸乙酯萃取,有机相浓缩拌样经柱层析纯化,得到中间体69-2,为棕色固体产物220mg。LC-MS:NB190114-76-02,ESI(+)m/z=517[M+1].
步骤(3)中间体69-3的制备
将中间体69-2(210mg)溶于AcOH(6mL)和H
2O(2mL)中,向反应瓶分批加入NCS(271mg),反应在室温下搅拌1h。将反应液未经后处理直接用于下一步反应。LC-MS:NB190114-81-01,ESI(+)m/z=493[M+1].
步骤(4)化合物69的制备
将中间体69-3的反应液(8mL)加入盛有NH3.H2O(20mL)的反应瓶中滴加完毕后,反应液倒入水中,EA萃取,有机相浓缩旋干得150mg粗品,送制备后得化合物69,为白色固体(32.6mg,纯度99.993%)。LC-MS:NB190114-82-01,ESI(+)m/z=474[M+1].
1H NMR(400MHz,dmso)δ10.69(s,1H),9.88(s,1H),8.64(d,J=9.2Hz,1H),8.30(d,J=2.0Hz,1H),8.00(d,J=2.0Hz,1H),7.68(s,2H),7.49-7.40(m,2H),7.36–7.22(m,3H),4.65(d,J=14.0Hz,2H),3.89(s,2H),3.53(d,J=11.6Hz,2H),3.25(s,2H),3.09(s,2H),2.83(s,3H).
实施例70
化合物70:2-(2-氯苯基)-N-(2-(4-甲基-3-羰基哌嗪-1-基)-5-氨磺酰喹啉-7-基)乙酰胺的制备
参照实施例4的制备方法进行制备得到。LC-MS:[M+H]
+=488.1
实施例71
化合物71:2-(2-氯苯基)-N-(2-((4-甲氧苯基)氨基)-5-氨磺酰喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体71-1的制备
将化合物4(600mg)溶于DMF(5ml)中,加入DMF-DMA(380mg)后60℃下搅拌3h。TLC显示反应完毕,反应液加水(50ml)后用乙酸乙酯(10ml)萃取两遍后合并有机相,干燥,减压浓缩后过柱纯化得到中间体71-1,为浅黄色固体(660mg,收率92%)。
步骤(2)中间体71-2的制备
将中间体71-1(560mg)溶于DCM(30ml)并搅拌5min,0℃下分批加入m-CPBA(600mg),室温搅拌过夜。TLC显示反应完成。将反应液用加水后,用1N NaOH调pH=10后再用二氯甲烷(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤浓缩得中间体71-2,浅黄色固体(600mg,收率92%)。
步骤(3)中间体71-3的制备
将中间体71-2(600mg)溶于DCM(5ml)和POCl
3(610mg)后55℃下封管反应4h,TLC显示反应完成。将反应液用碳酸氢钠溶液淬灭后,用二氯甲烷(10mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤浓缩过柱得到中间体71-3,浅黄色固体(300mg,收率48.2%)。
步骤(4)中间体71-5的制备
将中间体71-3(100mg)、中间体71-4(对甲氧基苯胺)(50mg)、Pd2(dba)3(9mg)、DIEA(77.4mg)、Xantphos(6mg)溶于DMF(4ml)中,100℃下搅拌16h。TLC显示反应完毕,反应液加水(20ml)后用乙酸乙酯(10ml)萃取两遍后合并有机相,干燥,减压浓缩后过柱纯化得到中间体71-5,黄色固体(42.6mg,收率41.8%)。
步骤(5)化合物71的制备
将中间体71-5(42mg)溶于甲醇(2ml)中,滴加水合肼溶液(12.7mg,85%)后室温下搅拌30min。TLC显示反应完毕,反应液减压浓缩得到粗品。粗品用H2O/CAN体系经prep-HPLC制备分离,冻干后得到化合物71,黄色固体(17.2mg,纯度98.86%,收率31.8%)。LC-MS:[M]
+=497。
1H NMR(400MHz,DMSO)δ10.70(s,1H),9.54(s,2H),8.56(d,J=9.3Hz,1H),8.32(s,1H),7.99(d,J=1.9Hz,1H),7.77(d,J=8.0Hz,2H),7.63(s,2H),7.50–7.40(m,2H),7.37–7.25(m,2H),7.00(d,J=9.4Hz,1H),6.93(d,J=8.9Hz,2H),3.90(s,3H),3.72(s,3H).
实施例72
化合物72:2-(2-氯苯基)-N-(2-(4-甲氧基苯氧基)-5-氨磺酰喹啉-7-基)乙酰胺的制备
参照实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=498.1
实施例73
化合物73:2-(2-氯苯基)-N-(2-(异丙基氨基)-5-氨磺酰喹啉-7-基)乙酰胺的制备
参照实施例6的制备方法进行制备得到。LC-MS:[M+H]
+=433.1
实施例74
化合物74:2-(2-氯苯基)-N-(2-(2-甲氧基乙氧基)-5-氨磺酰喹啉-7-基)乙酰胺的制备
参照实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=450.1
实施例75
化合物75:2-(2-氯苯基)-N-(3-甲氧基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=406.1
实施例76
化合物76:2-(2-氯苯基)-N-(3-(2-羟基乙氧基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=436.1
实施例77
化合物77:2-(2-氯苯基)-N-(3-(哌啶-1-基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=459.1
实施例78
化合物78:2-(2-氯苯基)-N-(3-吗啉代-5-氨磺酰基异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)化合物78的制备
先将NaH(211mg)加入吗啉(3.0ml)于80℃搅拌反应1h,冷却至室温后将中间体5-8(0.5g)加入反应体系中再升温至80℃过夜反应,取样点板,原料大部分反应完全,加水淬灭反应后用EA萃取水相3次,合并EA相层析柱分离纯化后送制备再纯化,冻干制备液得化合物78,为黄色固体粉末10mg。
1H NMR(400MHz,dmso)δ10.62(s,1H),9.01(s,1H),8.49(s,1H),8.33(d,J=2.0Hz,1H),7.62(s,2H),7.46–7.41(m,2H),7.34–7.28(m,3H),3.87(s,2H),3.79–3.71(m,4H),3.56–3.48(m,4H).
实施例79
化合物79:2-(2-氯苯基)-N-(3-(4-甲基哌嗪-1-基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=474.1
实施例80
化合物80:2-(2-氯苯基)-N-(3-(4-甲基-3-羰基哌嗪-1-基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=488.1
实施例81
化合物81:2-(2-氯苯基)-N-(3-((4-甲氧苯基)氨基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=497.1
实施例82
化合物82:2-(2-氯苯基)-N-(3-(4-甲氧基苯氧基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=498.1
实施例83
化合物83:2-(2-氯苯基)-N-(3-(异丙基氨基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=433.1
实施例84
化合物84:2-(2-氯苯基)-N-(3-(2-甲氧基乙氧基)-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例5的制备方法进行制备得到。LC-MS:[M+H]
+=450.1
实施例85
化合物85:2-(2-氯苯基)-N-(2-环丙基-5-氨磺酰喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体85-1的制备
将化合物65(2.0g)于HCl/dixoane(盐酸二氧六环)(40ml),于封口瓶中80℃反应过夜。LCMS显示反应完毕,将反应液降温至室温,过滤,滤饼以乙酸乙酯洗涤,干燥后得中间体85-1,为白色固体,1.2g,收率:62.12%。LCMS:NB190103-77-02,ESI(+)m/z=392.05[M+1]
+
步骤(2)中间体85-2的制备
将中间体85-1(600mg),溶于DMF(6ml)中,搅拌下向反应滴加DMF-DMA(548mg),加完于室温反应1h。LCMS反应完毕,反应液加水(20mL)淬灭,有固体析出,过滤,滤饼以水洗2次,干燥得中间体85-2,为白色固体535mg。LCMS:NB190103-91-01,ESI(+)m/z=447.05[M+1]
+
步骤(3)中间体85-3的制备
将中间体85-2(535mg)溶于吡啶(5ml)中。向反应滴加Tf
2O(1.7g),于室温下搅拌反应1h。 LCMS显示反应完毕。反应液用EtOAc(30ml)搅拌溶解,该有机相以1M HCl溶液洗涤2次,至体系呈弱酸性,再用饱和NaHCO3溶液洗涤一次,有机相用无水硫酸钠干燥后,过滤,滤液减压浓缩得到中间体85-3,为淡黄色固体,700mg。LCMS:NB190103-92-01,ESI(+)m/z=579.05[M+1]
+
步骤(4)中间体85-4的制备
依次将中间体85-3(150mg),环丙基硼酸(45mg),NaCO
3,(85mg),甲苯/水(10/1,3.0ml)于封口反应瓶中,N2置换,升温110℃,过夜反应。LCMS反应完毕,加水淬灭,乙酸乙酯萃取三次,合并EtOAc相,用水洗两次,饱和食盐水洗一次,用无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品80mg,直接用于下一步反应。LCMS:NB190103-93-03,ESI(+)m/z=471.05[M+1]
+
步骤(5)化合物85的制备
将中间体85-4(80mg)溶于MeOH(0.8ml)中。再加入水合肼(0.4mL)后于室温下反应1小时。LCMS显示反应完毕。反应液加水淬灭,用EtOAc(5ml)萃取三次,合并EtOAc相,用水洗两次,饱和食盐水洗一次,用无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。经perp-HPLC纯化,得到化合物85,白色固体(2.4mg,纯度99.316%)。LCMS:NB190103-97-03,ESI(+)m/z=416.10[M+1]
+
1H NMR(400MHz,dmso)δ10.77(s,1H),8.70(d,J=8.8Hz,1H),8.42(d,J=1.6Hz,1H),8.24(d,J=2.2Hz,1H),7.70(s,2H),7.47–7.41(m,3H),7.32–7.28(m,2H),3.90(s,2H),2.28–2.24(m,1H),1.05(d,J=6.4Hz,4H).
实施例86
化合物86:2-(2-氯苯基)-N-(2-乙炔基-5-氨磺酰喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体86-1的制备
依次将中间体85-3(200mg),三甲基硅基乙炔(42mg),CuI(34mg),DIEA(135mg),二(三苯基膦)二氯化钯(70.1mg),DMF(4ml)于封口瓶中,N
2置换,120℃反应2h。LCMS显示反应完毕,将反应液降温至室温,加水淬灭,用EtOAc(8ml)萃取三次,合并EtOAc相,用水洗两次,饱和食盐水洗一次,用无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。经硅胶柱纯化,得到中间体86-1,白色固体(120mg,纯度87%)。LCMS:NB190103-94-02,ESI(+)m/z=527.10[M+1]
+
步骤(2)中间体86-2的制备
将中间体86-1(120mg),溶于MeOH(2ml)中,搅拌下向反应加入K
2CO
3(94mg),加完于室温反应1h。LCMS反应完毕,反应液过滤浓缩的粗品200mg,直接用于下一步反应。LCMS:NB190103-95-01,ESI(+)m/z=455.05[M+1]
+
步骤(3)化合物86的制备
将中间体86-2(80mg)溶于MeOH(0.8ml)中。再加入甲醇钠甲醇(0.4mL)后于室温下反应1小时。LCMS显示反应完毕。反应液加水淬灭,用EtOAc(5ml)萃取三次,合并EtOAc相,用水洗两次,饱和食盐水洗一次,用无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。经perp-HPLC纯化,得到化合物86,棕色固体(2.5mg,纯度98.174%)。LCMS:NB190103-96-05,ESI(+)m/z=400.00[M+1]
+
1H NMR(400MHz,dmso)δ10.92(s,1H),8.88(d,J=8.8Hz,1H),8.51(d,J=1.6Hz,1H),8.45(d,J=2.2Hz,1H),7.81(s,2H),7.67(d,J=8.8Hz,1H),7.47–7.42(m,2H),7.34–7.29(m,2H),4.55(s,1H),3.93(s,2H).
实施例87
化合物87:2-(2-氯苯基)-N-(2-(丙-1-炔-1-基)-5-氨磺酰喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体87-2的制备
依次将中间体85-3(150mg),中间体87-1(2-丁炔酸)(54mg),DPPB(22.0mg),TBAF(168mg),PdCl
2(PPh
3)
2(18.0mg)溶于DMF(2mL)中,置换N
2四次后,升温至100℃,加热反应1小时。TLC(PE/EA=0/1)显示反应完了,关闭加热自然降温。将反应液用EA(5mL)稀释后,再 加水(10ml)水相用EA(5mL)萃取三次。合并有机相,用饱和食盐水(10mL)洗涤2次,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。经大板纯化(PE/EA=0/1),得到中间体87-2,黄色固体产物(40.0mg,纯度59%)。LC-MS:[M+H]
+=469.10。
步骤(2)化合物87的制备
将中间体87-2(1.30g)溶在THF(1ml),MeOH(1mL)中,加入水合肼,于室温25℃反应0.5小时。LCMS显示反应完毕。将反应液旋干,prep-HPLC制备分离,冻干后得到化合物87(5.50mg,纯度96.4%)黄色固体粉末。LC-MS:[M+H]+=416.05。
1H NMR(400MHz,DMSO-d)δ10.90(s,1H),8.84(d,J=8.8Hz,1H),8.49(d,J=1.6Hz,1H),8.43(d,J=2.0Hz,1H),7.81(s,2H),7.59(d,J=8.8Hz,1H),7.49–7.44(m,2H),7.36–7.32(m,2H),3.94(s,2H),2.15(s,3H).
实施例88
化合物88:2-(2-氯苯基)-N-(2-(二甲氨基)-5-氨磺酰喹啉-7-基乙酰胺的制备
合成路线
步骤(1)化合物88的制备
将化合物57(62.0mg)溶在DMSO(1.30mL),中,加入二甲胺盐酸盐(37.0mg),DIEA(58.0mg),KF(26.0mg)于温80℃反应12小时。LCMS显示反应完毕。将反应液冷却至室温用水(5mL)稀释后,过滤,滤饼回收,旋干,经prep-HPLC制备分离,冻干后得到化合物88(6.8mg,纯度99.3%)黄色粉末。LC-MS:[M+H]+=419.05。
1H NMR(400MHz,DMSO-d)δ10.62(s,1H),8.55(d,J=9.6Hz,1H),8.18(s,1H),7.95(d,J=1.6Hz,1H),7.60(s,2H),7.46(dd,J=8.8,3.6Hz,2H),7.37–7.28(m,2H),7.08(d,J=9.6Hz,1H),3.90(s,2H),3.16(s,6H).
实施例89
化合物89:-(2-氯苯基)-N-(2-(吡咯烷-1-基)-5-氨磺酰喹啉-7-基)乙酰胺的制备
合成路线:
将中间体88-1(62.0mg)溶在DMSO(1.50ml),中,加入吡咯烷(32.0mg),DIEA(58.0mg),KF(26.0mg)于80℃反应2小时。LCMS显示反应完毕。将反应液冷却至室温用水(5mL)和EA(3mL)稀释后,水相用EA(3mL)萃取三次。合并EA相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品旋干,经prep-HPLC制备分离,冻干后得到化合物89(8.30mg,纯度98.3%)浅绿色粉末。LC-MS:[M+H]+=445.10。
1H NMR(400MHz,DMSO-d)δ10.58(s,1H),8.54(d,J=9.2Hz,1H),8.16(s,1H),7.93(d,J=2.0Hz,1H),7.59(s,2H),7.48–7.41(m,2H),7.35–7.28(m,2H),6.87(d,J=9.6Hz,1H),3.89(s,2H),3.53(s,4H),1.97(d,J=5.6Hz,4H).
实施例90
化合物90:2-(2-氯苯基)-N-(1-异氰基-5-氨磺酰异喹啉-7-基)乙酰胺
合成路线:
步骤(1)中间体90-1的制备
将中间体6-3(7-溴-N,N-二(4-甲氧苄基)异喹啉-5-磺酰胺)(260mg,75%,0.37mmol)溶于二氯甲烷(10mL),室温下加入间氯过氧苯甲酸(100mg,85%,0.49mmol),室温搅拌两小时。TLC监控反应,原料消失,二氯甲烷(40mL)稀释,依次用饱和亚硫代酸钠溶液(10mL),碳酸氢钠溶液(20mL),饱和食盐水(20mL)洗涤,干燥浓缩得到粗品直接用于下一步的反应。得中间体90-1,为黄色固体,150mg,产率75%。MS[M+H]+=543.1
步骤(2)中间体90-3的制备
将中间体90-1(150mg)溶于二氯甲烷(10mL),依次加入中间体90-2(二甲氨基甲酰氯)(297mg)和三甲基氰硅烷(137mg)。加入回流6小时。二氯甲烷(40mL)稀释,饱和食盐水洗涤(30mL),无水硫酸钠干燥,过滤浓缩。粗品硅胶柱层析纯化(石油醚:乙酸乙酯2:1)得中间体90-3,为白色固体140mg,产率87%。MS[M+H]+=551.5
步骤(3)中间体90-4的制备
氮气保护,将中间体90-3(120mg),中间体6-4(2-(2-氯苯基)乙酰胺)(55mg),碳酸铯(212mg)和三(二亚苄-BASE丙酮)二钯(14mg)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(25mg)的二氧六环(10mL)溶液于90℃搅拌11小时。直接旋干,硅胶柱层析纯化得到中间体90-4,为黄色固体,共计120mg,纯度70%,产率91%。MS[M+H]+=640.6
步骤(4)化合物90的制备
中间体90-4(60mg)溶于二氯甲烷(2mL)中,加入三氟乙酸(10mL),室温搅拌24小时。减压浓缩后溶于二氯甲烷(40mL)中,依次用饱和碳酸氢钠溶液(20mL),饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤浓缩,高效液相制备色谱纯化。得到化合物90,为白色固体,共计15mg,产率38%。MS[M+H]+=400.6。
1H NMR(400MHz,d6-DMSO)δ11.23(s,1H),9.02(d,J=1.2Hz,1H),8.77(d,J=5.9Hz,1H),8.71(d,J=2.0Hz,1H),8.67(d,J=5.9Hz,1H),8.02(s,2H),7.54–7.46(m,2H),7.40–7.30(m,2H),3.99(s, 2H).
实施例91
化合物91:2-(2,6-二氯苯基)-N-(1-甲氧基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
参照实施例1的制备方法进行制备得到。LC-MS:[M+H]
+=440.0
实施例92
化合物92:2-(2,4-二氯苯基)-N-(1-甲氧基-5-氨磺酰基异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体92-2的制备
称取中间体54-1(50mg)溶于DCM(2ml)中,再加入中间体92-1(2,4-二氯苯乙酸)(24.8mg),T
3P(64.5mg)和DIPEA(40mg),室温搅拌2h,取样,TLC(PE:EA=2:1),显示原料反应完毕,向反应液中加入DCM(10ml)和H
2O(5ml),搅拌后分液,水相用DCM(5ml)萃取2次,合并有机相,用Brine洗涤,无水硫酸钠干燥,过滤后浓缩旋干得粗品中间体92-2黄色油状物(70mg)。
步骤(2)化合物92的制备
称取化合物92-2(70mg)溶于DCM(2ml)中,再滴加TFA(4ml),室温搅拌16h,取样,送LCMS NB190127-87-01显示原料剩余10%,向反应液中加入DCM(20ml)稀释,用Sat.NaHCO
3调节pH至7-8,搅拌后分液,水相用DCM(10ml)萃取2次,合并有机相,用Brine洗涤,无水硫酸钠干燥,过滤后浓缩拉干得粗品,粗品用H
2O/CH
3CN体系经prep-HPLC制备分离,冻干后得到化合物92,为白色固体(13.4mg),纯度99.05%,[M+H]+=440.00。
1H NMR(400MHz,DMSO)δ10.88(s,1H),8.84(s,1H),8.53(d,J=2.4Hz,1H),8.06(d,J=6.4Hz,1H),7.90(d,J=6.0Hz,1H),7.75(s,2H),7.64(d,J=2.0Hz,1H),7.50(d,J=8.4Hz,1H),7.44(dd,J=8.4,2.0Hz,1H),4.06(s,3H),3.92(s,2H)。
实施例93
化合物93 2-(2-氯-5-氟苯基)-N-(1-甲氧基-5-氨磺酰异喹啉-7-基)乙酰胺
合成路线:
步骤(1)中间体93-1的制备
将称量好的中间体54-1(110mg)溶于2mL DCM中,加入2-氯-5-氟苯乙酸,T
3P和TEA,加完室温反应1h.LCMS监控显示原料反应完全,反应液直接旋干拌样,通过过柱纯化(PE/EA=4/1)得到中间体93-1产物120mg,为黄色油状液体。
步骤(2)化合物93的制备
将称量好的中间体93-1(120mg),溶于10mL DCM中,加入10mL TFA,加完40度反应过夜,LCMS显示有产物生成,反应液旋干通过Prep-HPLC制备纯化得到化合物93产物22.6mg,为白色固体。LC-MS:[M+H]
+=424.05。
1H NMR(400MHz,dmso)δ10.89(s,1H),8.85(d,J=1.9Hz,1H),8.53(d,J=2.2Hz,1H),8.06(d,J=6.2Hz,1H),7.91(d,J=6.2Hz,1H),7.76(s,2H),7.52(dd,J=8.8,5.3Hz,1H),7.38(dd,J=9.4,3.1Hz,1H),7.21(td,J=8.5,3.1Hz,1H),4.06(s,3H),3.94(s,2H).
实施例94
化合物94:2-(2-氯-4-氟苯基)-N-(1-甲氧基-5-氨磺酰基异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体94-1的制备
将称量好的中间体54-1(110mg)溶于2mL DCM中,加入2-氯-4-氟苯乙酸,T
3P和TEA,加完室温反应1h。LCMS监控显示原料反应完全,反应液直接旋干拌样,通过过柱纯化(PE/EA=4/1)得到中间体94-1产物120mg,为黄色油状液体。
步骤(2)化合物94的制备
将称量好的中间体94-1(120mg),溶于10mL DCM中,加入10mL TFA,加完40度反应过夜,LCMS显示有产物生成,反应液旋干通过Prep-HPLC制备纯化得到化合物94产物22.7mg,为白色固体。LC-MS:[M+H]
+=424.00。
1H NMR(400MHz,dmso)δ10.86(s,1H),8.85(d,J=1.9Hz,1H),8.54(d,J=2.2Hz,1H),8.06(d,J=6.2Hz,1H),7.93–7.88(m,1H),7.76(s,2H),7.49(ddd,J=11.5,8.7,4.5Hz,2H),7.23(td,J=8.5,2.7Hz,1H),4.06(s,3H),3.91(s,2H)。
实施例95
化合物95:2-(5-氟-2-甲氧基苯基)-N-(1-甲氧基-5-氨磺酰基异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体95-1的制备
将称量好的中间体54-1(110mg)溶于2mL DCM中,加入5-氟-2-甲氧基苯乙酸,T
3P和TEA,加完室温反应1h.LCMS监控显示原料反应完全,反应液直接旋干拌样,通过过柱纯化(PE/EA=4/1)得到中间体95-1的产物120mg,为黄色油状液体。
步骤(2)化合物95的制备
将称量好的中间体95-1(120mg),溶于10mL DCM中,加入10mL TFA,加完40℃反应过夜,LCMS显示有产物生成,反应液旋干通过Prep-HPLC制备纯化得到化合物95的产物22.1mg,为白色固体。LC-MS:[M+H]
+=420.05。
1H NMR(400MHz,dmso)δ10.73(s,1H),8.85(d,J=1.8Hz,1H),8.54(d,J=2.2Hz,1H),8.05(d,J=6.2Hz,1H),7.90(d,J=6.2Hz,1H),7.75(s,2H),7.16–7.06(m,2H),6.99(dd,J=9.0,4.7Hz,1H),4.06(s,3H),3.75(s,3H),3.72(s,2H).
实施例96
化合物96:N-(1-甲氧基-5-氨磺酰异喹啉-7-基)-2-(2-(三氟甲氧基)苯基)乙酰胺的制备
合成路线:
步骤(1)中间体96-2的制备
依次将中间体54-1(90mg),中间体96-1(2-(2-(三氟甲氧基)苯基)乙酸)(60mg)、DIEA(47mg)溶于DCM(1ml)中,向反应加入HATU(103mg)。LCMS反应完毕,反应液加水(5mL)后乙酸乙酯(3mL)萃取三遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。经perp-TLC纯化,得到中间体96-2,白色固体(60mg,纯度95%)。LCMS:NB190103-51-02,ESI(+)m/z=696.15[M+1]
+
步骤(2)化合物96的制备
将中间体96-2(60mg)溶于DCM(0.1ml)中。再加入TFA(0.1mL)后于60℃下反应12小时。LCMS显示反应完毕。反应液用饱和NaHCO
3溶液调节体系为弱碱性,EtOAc(20ml)萃取三次,合并EtOAc相,用水洗两次,饱和食盐水洗一次,用无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。经perp-HPLC纯化,得到化合物96,白色固体(6.8mg,纯度99.807%)。LCMS:NB190103-53-03,ESI(+)m/z=456.05[M+1]
+
1H NMR(400MHz,dmso)δ10.871(s,1H),8.849(d,J=1.6Hz,1H),8.528(d,J=2.0Hz,1H),8.065(d,J=6.4Hz,1H),7.907(d,J=6.4Hz,1H),7.764(s,2H),7.529(dd,J=7.2,2.0Hz,1H),7.463-7.361(m,3H),4.061(s,3H),3.865(s,2H).
实施例97
化合物97:2-(2-氯-3-氟苯基)-N-(1-甲氧基-5-氨磺酰异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体97-2的制备
将中间体54-1(80mg),中间体97-1(2-(2-氯-3-氟苯基)乙酸)(37mg),T3P(206mg),Et3N(49mg)和DCM(2mL)加入反应瓶中,反应在室温下搅拌过夜。反应液倒入水中,DCM萃取,有机相浓缩拌样经柱层析纯化得到中间体97-2,淡黄色固体(60mg),TLC(PE/EA=2/1)确认了产物。
步骤(2)化合物97的制备
将中间体97-2(60mg)溶于DCM(2mL),向反应瓶中加入TFA(2mL),反应在50℃下搅拌2h。反应液用碳酸氢钠水溶液调pH至8左右,EA萃取,有机相浓缩旋干后送制备得到化合物97,为白色固体(10.1mg,纯度98.635%).LC-MS:NB190044-96-01,ESI(+)m/z=424[M+1]。
1H NMR(400MHz,dmso)δ10.89(s,1H),8.83(d,J=2.0Hz,1H),8.52(d,J=2.4Hz,1H),8.04(d,J=6.4Hz,1H),7.90–7.87(m,1H),7.74(s,1H),7.39–7.28(m,4H),4.04(s,3H),3.96(s,2H).
实施例98
化合物98:2-(2-氯苯基)-N-(5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体98-1的制备
将中间体6-2(1.0g)溶入氨的四氢呋喃(7mol/L,15ml)中,室温搅拌反应3h。取样点板显示原料反应完毕。向反应液中加入水,用EA萃取三次,合并EA相,EA相依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品中间体98-1,共计800mg。
步骤(2)中间体98-2的制备
将中间体98-1(800mg)溶于DMF-DMA(10ml)中,室温搅拌反应3h,得粗品650mg,直接投下一步反应。
步骤(3)中间体98-3的制备
依次将中间体98-2(600mg),NH
2Boc(310mg),碳酸铯(860mg),XantPhos(100mg),Pd(dppf)Cl
2溶入二氧六环中,置换氮气,并在氮气的保护下升温至85℃搅拌过夜反应,反应完毕后,向反应液中加水和EA,分出EA相,水相用EA萃取3遍,合并EA相,EA相分别用饱和食盐水洗涤,硫酸钠干燥后浓缩即得到产品510mg。
步骤(4)中间体98-4的制备
将中间体98-3(500mg)溶入氯化氢的乙酸乙酯溶液(20ml)中,室温下搅拌反应3h,取样点板,原料反应完全。向反应液中加入水和EA,充分摇荡后,分出EA相,水相中加入K
2CO
3调节PH至9-10,然后再向水相中加入EA萃取3遍,合并EA相,再用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到产品中间体98-4(380mg,纯度82.2%)。
步骤(5)中间体98-5的制备
依次将中间体98-4(350mg),中间体1-7(246.5mg),HATU(684mg),DIEA(490mg)溶于 DMF(5ml)中,室温过夜搅拌反应,反应完毕后,向反应中加水,然后用EA萃取3遍,合并EA相,再用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到产品中间体98-5(210mg)。
步骤(6)中间体98-6的制备
将中间体98-5(200mg)溶入甲醇中,然后在向其中加入PtO
2(50mg),置换氢气后,并在氢气的保护下50℃搅拌反应过夜。取样点板,原料反应完毕完全,将反应液过滤然后旋干即得到产品中间体98-6(160mg)。
步骤(7)化合物98的制备
将中间体98-6(75mg)溶于氨的甲醇溶液(4mol/L,0.4ml)中,室温反应过夜,反应完全,将反应液旋干送制备,将制备液冻干得化合物98(15mg),为白色固体。
实施例99
化合物99:甲基7-(2-(2-氯苯基)乙酰氨基)-5-氨磺酰-3,4-二氢异喹啉-2(1H)-羧酸酯的制备
合成路线:
步骤(1)中间体99-2的制备
将中间体98-6(75mg)溶于DCM(3ml)中,然后向其中加入DIEA(45mg),然后冰浴下向其中滴加中间体99-1(氯甲酸甲酯)(19.5mg)室温下搅拌反应半小时,取样点板原料反应完全。向其中加入水淬灭反应,用EA萃取水相3遍,合并EA相,再用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到产品中间体99-2(50mg)
步骤(2)化合物99制备
将中间体99-2(40mg)溶于氨的甲醇溶液(4mol/L,0.4ml)中,室温反应过夜,反应完全,将反应液旋干送制备,将制备液冻干得化合物99,为白色固体12mg。
1H NMR(400MHz,dmso)δ10.50(s,1H),8.0(s.1H),7.6(s.1H),7.41-7.43(m,2H),7.25-7.30(m.2H),4.5(s,2H),3.8(s,2H),3.7(s,2H),3.6-3.7(m,2H),3.1-3.2(m,2H)。
实施例100
化合物100:异丙基-7-(2-(2-氯苯基)乙酰氨基)-5-氨磺酰-3,4-二氢异喹啉-2(1H)-羧酸酯的制备
参照实施例99的制备方法进行制备得到。LC-MS:[M+H]
+=466.1
实施例101
化合物101:环丙基-7-(2-(2-氯苯基)乙酰氨基)-5-氨磺酰-3,4-二氢异喹啉-2(1H)-羧酸酯的制备
参照实施例99的制备方法进行制备得到。LC-MS:[M+H]
+=464.1
实施例102
化合物102:N-(2-乙酰基-5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
参照实施例99的制备方法进行制备得到。LC-MS:[M+H]
+=422.1
实施例103
化合物103:2-(2-氯苯基)-N-(2-环丙基-5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体103-2的制备
将中间体98-6(140mg),和中间体103-1(1-乙氧基环丙氧基)三甲基硅烷(112mg),NaBH3CN(61mg)和MeOH(2mL)加入反应瓶中,反应在60℃下搅拌过夜。反应液倒入水中,EA萃取,有机相浓缩拌样经柱层析纯化得到中间体103-2,白色固体(80mg),LC-MS:NB200027-50-02,ESI(+)m/z=475[M+1]。
步骤(2)化合物103的制备
将中间体103-2(60mg)溶于DCM(1mL),加入NaOMe(34mg)加入反应瓶中,反应在室温下下搅拌30min。反应液倒入水中,EA萃取,有机相浓缩旋干送制备得到化合物103,白色固体(5.9mg).LC-MS:NB200027-56-01,ESI(+)m/z=420[M+1]
1H NMR(400MHz,dmso)δ10.57(s,1H),9.57(s,1H),8.07(s,1H),7.76(s,1H),7.58(s,2H),7.44–7.37(m,2H),7.32–7.25(m,2H),4.68-4.42(m,2H),3.83(s,2H),3.31–3.10(m,3H),2.94(s,2H),1.12-0.71(m,4H).
实施例104
化合物104:2-(2-氯苯基)-N-(2-苯基-5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
参照实施例99的制备方法进行制备得到。LC-MS:[M+H]
+=456.1
实施例105
化合物105:苯基7-(2-(2-氯苯基)乙酰氨基)-5-氨磺酰-3,4-二氢异喹啉-2(1H)-羧酸酯的制备
参照实施例99的制备方法进行制备得到。LC-MS:[M+H]
+=500.1
实施例106
化合物106:N-(2-苯甲酰-5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
合成路线:
步骤(1)中间体106-2的制备
将称量好的中间体98-6溶于5mL DMF中,加入DIEA和苯甲酰氯,室温反应1小时,点板监控原料反应完全,反应液直接旋干通过Prep-TLC(DCM/MeOH=40/1)纯化得到产物90mg,为黄色固体.
步骤(2)化合物106的制备
将称量好的中间体106-2溶于3mL DCM中,加入甲醇钠溶液,室温反应1h,点板监控原料反应完全,反应液加水用EA萃取,有机相浓缩通过Prep-TLC(DCM/MeOH=15/1)纯化得到产物19.4mg,为白色固体。LC-MS:[M+H]+=484.10.
1H NMR(400MHz,dmso)δ10.51(s,1H),8.08(s,1H),7.75(s,1H),7.46(dd,J=16.4,7.5Hz,7H),7.31(d,J=3.8Hz,2H),4.69(d,J=76.8Hz,2H),3.84(s,2H),3.71–3.42(m,2H),3.16(s,2H).
实施例107
化合物107:2-(2-氯苯基)-N-(2-(环丁羰基)-5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体107-1的制备
依次将中间体98-6(100mg)和DIPEA(82mg)溶于DCM(5ml)中,冰水浴下再缓慢滴加中间体107-1(环丁基甲酰氯)(36mg),滴加完毕室温搅拌1h,取样,TLC(PE:EA=1:1),显示原料反应完毕。将反应液用DCM(20mL)稀释后,再加水(10mL)洗涤,搅拌10分钟后静置分离出有机相,依次用饱和氯化铵水溶液,饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品红色油状物产品中间体107-2(160mg)。
步骤(2)化合物107的制备
将中间体107-2粗品(0.16g)溶于DCM(5ml),再加入30%CH
3ONa/MeOH溶液(4mL)后于室温下反应2h。取样,TLC(PE:EA=2:1),显示原料反应完毕。反应液用H
2O/CH
3CN体系经prep-HPLC制备分离,冻干后得到白色固体化合物107(34mg,purity:99.6%)。LC-MS:[M+H]
+=462.10。
1H NMR(400MHz,DMSO)δ10.48(s,1H),8.02(d,J=32.8Hz,1H),7.77(s,1H),7.66(s,1H),7.46–7.41(m,3H),7.31(p,J=5.9Hz,2H),4.61(s,1H),4.54(s,1H),3.84(s,2H),3.64(t,J=6.0Hz,1H),3.56(t,J=5.9Hz,1H),3.47–3.41(m,1H),3.11(t,J=5.8Hz,1H),3.06(t,J=5.8Hz,1H),2.13(dt,J=17.3,8.7Hz,4H),1.96–1.87(m,1H),1.74(d,J=6.6Hz,1H)。
实施例108
化合物108:2-(2-氯苯基)-N-(2-(环丙羰基)-5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体108-2的制备
依次将中间体98-6(100mg)和DIPEA(82mg)溶于DCM(5ml)中,冰水浴下再缓慢滴加中间体108-1(环丙基甲酰氯)(32mg),滴加完毕室温搅拌1h,取样,TLC(PE:EA=1:1),显示原料反应完毕。将反应液用DCM(20mL)稀释后,再加水(10mL)洗涤,搅拌10分钟后静置分离出有机相,依次用饱和氯化铵水溶液,饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品红色油状产物中间体108-2(150mg)。
步骤(2)化合物108的制备
将中间体108-2粗品(0.16g)溶于DCM(5ml),再加入30%CH
3ONa/MeOH溶液(4mL)后 于室温下反应2h。取样,TLC(PE:EA=2:1),显示原料反应完毕。反应液用H
2O/CH
3CN体系经prep-HPLC制备分离,冻干后得到白色固体中间体108(25mg,purity:99.8%)LC-MS:[M+H]
+=448.10。
1H NMR(400MHz,DMSO)δ10.48(s,1H),8.04(d,J=20.8Hz,1H),7.80(s,1H),7.66(s,1H),7.46–7.41(m,3H),7.34–7.28(m,2H),4.92(s,1H),4.63(s,1H),3.90(s,1H),3.84(s,2H),3.67(s,1H),3.20(s,1H),3.07(s,1H),2.07(s,1H),0.75(d,J=4.4Hz,4H)。
实施例109
化合物109:2-(2-氯苯基)-N-(2-乙基-5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体109-1的制备
将中间体98-5(150mg)、乙醛(30.7mg)和二氧化铂(40mg)溶解于EtOH(5mL)中,反应液用H
2置换三次,反应液用氢气球(15Psi)在60℃搅拌反应15h。TLC(PE:EA=1:1)显示原料反应完毕。反应液降至室温,反应液过夜,滤液减压浓缩得到粗品中间体109-1(100mg),为黄色固体。
步骤(2)化合物109的制备
将中间体109-1(100mg)溶解于MeOH(2mL)中,反应液中缓慢加入NH
3/MeOH(20mL),反应液升温至50℃下反应过夜。TLC(PE:EA=1:1)显示反应完毕。LCMS显示原料反应完毕。反应液直接用H
2O/MeCN体系经prep-HPLC制备分离,冻干后得到目标产物化合物109,为白色固体(26.5mg,纯度98.823%)。LC-MS:[M+H]
+=408.10。
1H NMR(400MHz,CD
3OD)8.13(d,J=2.2Hz,1H),7.87(d,J=2.2Hz,1H),7.40(s,2H),7.31–7.26(m,2H),4.57(s,2H),4.47–4.33(m,2H),3.89(s,2H),3.36(d,J=7.2Hz,2H),3.16(s,1H),3.04(s,1H),2.68(s,1H),1.43(t,J=7.2Hz,3H)。
实施例110
化合物110:N-(2-苯甲基-5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
合成路线:
步骤(1)中间体110-1的制备
将中间体98-6(100.0mg)溶于DCM(10mL)中,加入BnBr(39.3mg)和Et
3N(34.9mg)。室温条件下,搅拌反应过夜。TLC(MeOH:DCM=1:10)显示原料反应完全。加入30mL水和30mL DCM稀释,分液,收集有机相,旋干溶剂,得到中间体110-1,为黄色固体(90.5mg)。LC-MS:[M+H]
+=525。
步骤(2)化合物110的制备
将中间体110-1(80.5mg)溶于MeOH(10mL),加入水合肼(180.6mg),室温条件下,搅拌反应1h。TLC(MeOH:DCM=1:10)显示原料反应完全,停止反应。旋干溶剂得粗品。粗品用H
2O/ACN体系经prep-HPLC制备分离,冻干后得化合物110,为米黄色固体(51.2mg,纯度95.848%)。LC-MS(NB190054-54-01):[M+H]
+=470.05。
1H NMR(NB190054-54-01):
1H NMR(400MHz,DMSO-d
6)δ10.57(s,1H),8.04(s,1H),7.77(s,1H),7.63–7.50(m,5H),7.49(s,2H),7.45–7.39(m,2H),7.34–7.28(m,2H),4.46(s,2H),4.37(s,2H),3.84(s,2H),3.77–3.60(m,1H),3.56–3.43(m,3H).
实施例111
化合物111:2-(2-氯苯基)-N-(2-(环丙基甲基)-5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体111-2的制备
依次将中间体98-6(150mg),中间体111-1(环丙甲基溴)(45.9mg),碳酸钾(145mg)溶于DMF(3ml)中,置换N
2一次后,室温下搅拌过夜。LCMS显示反应完毕,将反应液用水(10mL)稀释后,再加乙酸乙酯(3mL)搅拌10分钟后静置分离出乙酸乙酯相。水相再用乙酸乙酯(3mL)萃取一次,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到中间体111-2粗品,浅黄色油状物(180mg)。LC-MS:[M]
+=489.1。
步骤(2)化合物111的制备
将中间体111-2(180mg)溶于甲醇(2ml)中,滴加水合肼溶液(1.5ml,85%)后室温下搅拌30min。LCMS显示反应完毕,反应液减压浓缩得到粗品。粗品用H2O/CAN体系经prep-HPLC制备分离,冻干后得到化合物111,棕色固体(22.1mg,纯度98.29%,收率11.7%,三氟乙酸盐)。LC-MS:[M]
+=434。
1H NMR(400MHz,DMSO)δ10.60(s,1H),9.97(s,1H),8.06(d,J=2.1Hz,1H),7.82(d,J=1.7Hz,1H),7.59(s,2H),7.45–7.37(m,2H),7.33–7.25(m,2H),4.63(d,J=16.0Hz,1H),4.40-4.41(m,1H),3.81(d,J=24.1Hz,3H),3.42(s,3H),3.13(s,2H),1.21–1.12(m,1H),0.66(d,J=7.5Hz,2H),0.40(d,J=4.6Hz,2H).
实施例112
化合物112:2-(2-氯苯基)-N-(2-甲基-5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体112-1的制备
将中间体98-5(1.2g)溶于MeOH(20ml,化学纯)中,加入PtO
2(63mg),然后反应液在H
2中40℃搅拌72h。反应完毕,将上述反应液用硅藻土过滤,滤液浓缩得到粗品,粗品过硅胶柱纯化得到中间体112-1(580mg黄色固体)。[M+H]
+=449。
步骤(2)化合物112的制备
将中间体112-1(200mg)溶于MeOH(5ml)中,加入N
2H
4·H
2O(529mg,85%),反应液室温搅拌20min。反应完毕,反应液室温减压浓缩得到粗品,粗品通过prep-HPLC纯化得到化合物112(19mg,白色固体粉末)。LCMS:[M+H]
+=393.95
1H NMR(400MHz,DMSO-d
6)δ10.65(s,1H),10.44(br.s,1H),8.14(d,J=1.6Hz,1H),7.73(d,J=1.3Hz,1H),7.61(s,2H),7.47–7.39(m,2H),7.35–7.27(m,2H),4.46(d,J=63.2Hz,2H),3.86(s,2H),3.77-3.55(m,4H),2.94(s,3H).
实施例113
化合物113:2-(2-氯苯基)-N-(2-异丙基-5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体113-1的制备
将中间体98-5(150mg),丙酮(2mL),异丙醇(2mL),PtO
2(40mg)加入到烧瓶中,体系用H
2置换三次并用H
2保压,在50℃下搅拌过夜(14小时),LCMS显示原料已基本反应完,将反应液直接浓缩干,得到135mg黄色固体中间体113-1,直接进行下一步反应。LC-MS:[M+H]
+=477.02。
步骤(2)2-(2-氯苯基)-N-(2-异丙基-5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
将第一步得到的中间体113-1溶于1.5mL甲醇中,再向反应液中加入NH
3/CH
3OH(10mL),在室温下搅拌过夜(14小时)。LCMS显示原料已反应完毕。将反应液浓缩干直接送制备得到白色固体(6.3mg,纯度91.35%)。LC-MS:[M+H+2]+=421.94。
1H NMR(400MHz,dmso)δ10.62(s,1H),9.84(s,1H),8.08(d,J=1.4Hz,1H),7.82(d,J=1.7Hz,1H),7.62(s,2H),7.50–7.36(m,2H),7.36–7.20(m,2H),4.44(d,J=5.0Hz,2H),3.86(s,2H),3.73–3.56(m,2H),3.31–3.22(m,2H),3.18–3.08(m,1H),1.33(d,J=5.7Hz,4H),1.25(dd,J=12.9,6.4Hz,3H).
实施例114
化合物114:2-(2-氯苯基)-N-(5-氨磺酰-2-(2,2,2-三氟乙酰基)-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体114-1的制备
将中间体98-6(100mg)溶于氨甲醇溶液中(5.0ml)中,室温搅拌反应2h。取样点板,原料反应完全。将反应液直接旋干即得中间体114-1产品60mg。LC-MS:[M+H]
+=382。
步骤(2)化合物114的制备
将中间体114-1(60mg)溶入DCM中(2ml)中,然后再将等体积的三氟乙酸酐加入其中,室温搅拌反应3h。取样点板显示原料反应完毕。将反应液旋干,送制备纯化处理,冻干制备液分别得到化合物114,为白色固体产品11mg。
1H NMR(400MHz,dmso)δ10.50(s,1H),8.07(s,1H),8.03(d,J=2.1Hz,1H),7.79(s,1H),7.71(s,1H),7.45(s,2H),7.44–7.35(m,2H),7.32–7.25(m,2H),4.76(d,J=5.4Hz,2H),3.86–3.72(m,4H),3.21(d,J=6.5Hz,2H).
实施例115
化合物115:2-(2-氯苯基)-N-(2-(二氯甲基)-5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体115-1的制备
将中间体98-6(300mg)溶于甲酰胺(5mL)中,120℃搅拌反应3h,将反应液加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍合并EA相并饱和食盐水洗涤和无水硫酸钠干燥,旋干得到黄色固体90mg。LC-MS:[M+H]
+=463.10。
步骤(2)中间体115-2((E)-2-(2-氯苯基)-N-(5-(N-((二甲氨基)亚甲基)氨磺酰)-2-甲酰基-1,2,3,4-四氢异喹啉-7-基)乙酰胺)的制备
将中间体115-1(10mg)溶于DCM(0.5mL)中,加入(CO)
2Cl
2(10mg)室温搅拌反应0.5h,升温至47℃回流1.5h。冷到室温依次加入Et
3N·3HF(16mg),Et
3N(10mg),室温搅拌反应过夜,将反应液加水和DCM,充分搅拌后分出DCM相,水相用DCM萃取两遍合并DCM相并饱和食盐水洗涤和无水硫酸钠干燥,旋干得到中间体115-2,为黄色固体16mg。LC-MS:[M+H]
+=517.10。
步骤(3)化合物115的制备
将中间体115(6mg)溶于MeOH(2.0mL)中,加入NH3/MeOH(2.0mL),120℃室温搅拌反应3h,将反应液浓缩得5mg粗品,制备得到黄色固体1.1mg。LC-MS:[M+H]
+=462.00
1H NMR(400MHz,dmso)δ8.21(d,J=14.6Hz,1H),8.13(s,1H),7.81(dd,J=9.6,2.0Hz,1H),7.53(d,J=4.4Hz,2H),7.39(ddd,J=9.8,9.2,5.8Hz,2H),7.27–7.14(m,2H),7.08(s,1H),6.95(s,1H),4.67(d,J=19.6Hz,2H),3.72–3.61(m,2H),3.41(s,2H),3.23–3.13(m,2H).
实施例116
化合物116:2-(2-氯苯基)-N-(2-(5-氯吡啶-2-基)-5-氨磺酰基-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体116-2的制备
将称量好的中间体98-6(130mg)溶于6mL DMF中,加入中间体116-1 5-氯-2-氟吡啶(130mg) 和DIEA(195mg)加完140℃反应1.5h。LCMS监控显示有产物生成,反应液降至室温加水,用EA萃取,有机相饱和食盐水洗涤,硫酸钠干燥,通过Prep-TLC(DCM/MeOH=20/1)得到产物90mg,为黄色油状液体。
步骤(2)化合物116的制备
将称量好的中间体116-2(100mg)溶于5mL甲醇中,加入水合肼2mL,加完室温反应0.5h。LCMS监控显示有产物生成,反应液直接旋干通过Prep-HPLC制备纯化得到化合物116粗品19.8mg,为白色固体。LC-MS:[M+H]
+=491.05。
1H NMR(400MHz,dmso)δ10.48(s,1H),8.13(d,J=2.6Hz,1H),8.03(d,J=1.9Hz,1H),7.77(s,1H),7.63(dd,J=9.1,2.7Hz,1H),7.53–7.38(m,4H),7.31(p,J=6.3Hz,2H),6.96(d,J=9.2Hz,1H),4.71(s,2H),3.85(s,2H),3.79(t,J=5.9Hz,2H),3.18(t,J=5.7Hz,2H).
实施例117
化合物117:2-(2-氯苯基)-N-(5-氨磺酰基-2-(5-(三氟甲基)吡啶-2-基)-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线
步骤(1)中间体117-2的制备
将称量好的中间体98-6(100mg)溶于5mL dioxane中,加入中间体117-1(2-碘-5-(三氟甲基)吡啶)(76mg),t-BuXphos-Pd-G3(19mg),t-BuXphos(10mg)和K2CO3(96mg)加完N2保护110℃反应过夜。LCMS监控显示有产物生成,反应液降至室温加水,用EA萃取,有机相饱和食盐水洗涤,硫酸钠干燥,通过Prep-TLC(DCM/MeOH=10/1)得到中间体117-2粗品90mg,为黄色固体。
步骤(2)化合物117的制备
将称量好的中间体117-2(90mg)溶于5mL甲醇中,加入水合肼2mL,加完室温反应0.5h。LCMS监控显示有产物生成,反应液直接旋干通过Prep-HPLC制备纯化得到产物粗品5.8mg,为白色 固体。LC-MS:[M+H]
+=525.10。
1H NMR(400MHz,dmso)δ10.50(s,1H),8.45(s,1H),8.04(d,J=2.1Hz,1H),7.85–7.79(m,2H),7.44(dt,J=11.5,5.5Hz,4H),7.34–7.28(m,2H),7.03(d,J=9.0Hz,1H),4.83(s,2H),3.88(t,J=6.0Hz,2H),3.85(s,2H),3.22(t,J=5.9Hz,2H).
实施例118
化合物118:N-(2-(4-氯-5-氟吡啶-2-基)-5-氨磺酰基-1,2,3,4-四氢异喹啉-7-基)-2-(2-氯苯基)乙酰胺的制备
合成路线:
步骤(1)中间体118-2的制备
将称量准确的中间体98-6(150mg)、中间体118-1(2-溴-4-氯-5-氟吡啶)(147mg)、t-Buxphos-Pd-G3(28mg)、t-Buxphos(15mg)、K
2CO
3(145mg)溶于Dioxane升温至110℃搅拌反应过夜。取样点板,原料基本反应完全。后处理,向反应液中加水和EA,分出EA相,水相用EA萃取3遍,合并EA相,EA相分别用饱和食盐水洗涤,硫酸钠干燥后旋干至3ml左右爬大板纯化,刮板浸泡旋干即得产品。反应成功,得中间体118-2白色固体60mg。LCMS[M+H]=564。
步骤(2)化合物118的制备
将称量准确得中间体118-2(60mg)溶于甲醇中,再将水合肼(20mg)加入反应体系中,室温搅拌反应2h。取样点板原料反应完全。后处理,将反应液旋干送制备纯化,冻干制备液即得化合物118产品。反应成功,得白色泡状固体2mg。LCMS[M+H]=509。
1H NMR(400MHz,dmso)δ10.46(s,1H),8.22(s,1H),8.00(d,J=2.0Hz,1H),7.75(s,1H),7.42(dd,J=10.2,7.6Hz,4H),7.32–7.26(m,2H),7.18(d,J=4.7Hz,1H),4.68(s,2H),3.82(s,2H),3.77(t,J=5.8Hz,2H),3.15(t,J=5.7Hz,2H).
实施例119
化合物119:2-(2-氯苯基)-N-(2-(1,1-二氟烯丙基)-5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体119-2的制备
将中间体98-6(150mg)溶于DMF(3mL)中,加入CS
2CO
3(225mg)和中间体119-1(3-溴-3,3-二氟丙烯)(60mg),室温搅拌反应2h,将反应液加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍合并EA相并饱和食盐水洗涤和无水硫酸钠干燥,旋干得到黄色固体100mg。LC-MS:[M+H]
+=511.10
步骤(2)化合物119的制备
将中间体119-2(100mg)溶于MeOH(4mL)中,加入水合肼(2mL)室温搅拌反应2h,将反应液浓缩得40mg粗品,粗品用H2O/CAN体系经prep-HPLC制备分离,冻干后得到化合物119,白色固体(4.3mg,纯度99.714%,收率11.8%)。LC-MS:[M]
+=456。
1H NMR(400MHz,dmso)δ10.57(s,1H),10.19(s,3H),8.03(s,1H),7.79(s,1H),7.58(s,2H),7.41(ddd,J=10.7,4.9,2.4Hz,2H),7.35–7.23(m,2H),7.20(s,1H),7.07(s,1H),6.94(s,1H),4.91(d,J=24.8Hz,2H),4.57(s,2H),4.34(s,2H),3.83(s,4H).
实施例120
化合物120:2-(2-氯苯基)-N-(2-(4-氟苯基)-5-氨磺酰基-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体120-2的制备
将称量准确的中间体98-6(80mg)、中间体120-1(4-氟苯基)硼酸)(130mg)、Cu(OAc)
2、吡啶溶于CH
2Cl
2并在O
2气氛下室温搅拌反应过夜。取样点板,原料基本反应完全。后处理,向反应液中加水和EA,分出EA相,水相用EA萃取3遍,合并EA相,EA相分别用饱和食盐水洗涤,硫酸钠干燥后旋干至3ml左右爬大板纯化,刮板浸泡旋干即得产品。反应成功,得中间体120-2的白色固体60mg。LCMS[M+H]=529。
步骤(2)化合物120的制备
将称量准确得中间体120-2(60mg)溶于甲醇中,再将水合肼(20mg)加入反应体系中,室温搅拌反应2h。取样点板原料反应完全。后处理,将反应液旋干送制备纯化,冻干制备液即得产品。反应成功,得化合物120,为白色泡状固体2mg。LCMS[M+H]=474。
1H NMR(400MHz,dmso)δ10.45(s,1H),8.00(s,1H),7.74(s,1H),7.46–7.35(m,4H),7.32–7.25(m,2H),7.05(dd,J=11.1,6.6Hz,4H),4.36–4.30(m,2H),3.83(s,2H),3.46(dd,J=12.6,6.5Hz,2H),3.18(t,J=5.7Hz,2H).
实施例121
化合物121:2-(2-氯苯基)-N-(2-(5-甲基吡啶-2-基)-5-氨磺酰基-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体121-2的制备
将称量准确的中间体98-6(150mg)、中间体121-1(2-溴-5-甲基吡啶)(147mg)、t-Buxphos-Pd-G3(28mg)、t-Buxphos(15mg)、K
2CO
3(145mg)溶于Dioxane升温至110℃搅拌反应过夜。取样点板,原料基本反应完全。后处理,向反应液中加水和EA,分出EA相,水相用EA萃取3遍,合并EA相,EA相分别用饱和食盐水洗涤,硫酸钠干燥后旋干至3ml左右爬大板纯化,刮板浸泡旋干即得产品。反应成功,得中间体121-2白色固体60mg。LCMS[M+H]=526。
步骤(2)化合物121的制备
将称量准确得中间体121-2(60mg)溶于甲醇中,再将水合肼(20mg)加入反应体系中,室温搅拌反应2h。取样点板原料反应完全。后处理,将反应液旋干送制备纯化,冻干制备液即得产品。反应成功,得化合物121,为白色泡状固体2mg。LCMS[M+H]=471。
1H NMR(400MHz,dmso)δ10.44(s,1H),8.00(s,1H),7.95(s,1H),7.74(s,1H),7.38(dd,J=26.4,17.4Hz,5H),7.31(s,2H),6.84(d,J=8.6Hz,1H),4.65(s,2H),3.83(s,2H),3.75(s,2H),3.14(s,2H),2.12(s,3H).
实施例122
化合物122:2-(2-氯-4-氟苯基)-N-(2-(5-甲基吡啶-2-基)-5-氨磺酰-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
参照实施例99的制备方法进行制备得到。LC-MS:[M+H]
+=493.1
实施例123
化合物123:2-(2-氯苯基)-N-(2-(氧杂环丁-3-基)-5-氨磺酰基-1,2,3,4-四氢异喹啉-7-基)乙酰胺的制备
合成路线:
步骤(1)中间体123-2的制备
将称量准确的中间体98-6(200mg)、三乙酰氧基硼氢化钠(340mg)、醋酸(83mg)、titanium(IV)ethoxide(315mg)、中间体123-1噁丁环-3-酮(66mg)溶于1,2-二氯乙烷中,室温搅拌过夜反应。置换氮气室温搅拌反应过夜。取样点板,原料反应完全。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,干燥旋干爬大板纯化即得产品。反应成功,得黄色油状液体50mg。LCMS[M+H]=491。
步骤(2)化合物123的制备
将称量准确的中间体123-2(50mg)溶于甲醇中,在滴加几滴水合肼,室温搅拌反应1h,取样点板原料反应完全。将反应液旋干,送制备纯化,冻干制备液即得产品。反应成功,得白色泡状固体11mg。LCMS[M+H]=436。
1H NMR(400MHz,dmso)δ10.40(s,1H),7.99(s,2H),7.58(s,1H),7.44–7.38(m,2H),7.34(s,1H),7.31–7.26(m,2H),4.55(d,J=38.5Hz,6H),3.82(s,2H),3.58–3.53(m,1H),3.46(s,2H),3.11(s,2H).
生物试验
实施例A体外生物活性评价
对本发明中化合物的拮抗剂特性利用FLIPR(荧光成像读板仪)法进行测定,所述化合物是由HEK293细胞(人肾上皮细胞系,ATCC)中所表达的hP2X4(人嘌呤能P2X受体亚型4,登录号 NM_001256796.2)激活所诱导的细胞内钙升高的抑制剂。
将稳定表达hP2X4的HEK293细胞置于37℃,湿度5%的细胞培养箱中,以含有10%FBS(胎牛血清,Biosera,FB-1058/500),1%青霉素-链霉素(Gibco,15140-122),和1mg/mL G418(CABIOCHE,345810)的DMEM高糖培养基进行培养。在FLIPR实验前18-24小时,将细胞以400000cells/mL的密度接种到384孔中(10000cells/well),在细胞培养箱中温育过夜。实验当天,弃去培养基,将细胞在FLIPR缓冲液(每30mL缓冲液中含有0.3mL丙磺舒(Thermo,P36400),0.6mL 1M HEPES(Invitrogen,15630080)和29.1mL HBSS(Invitrogen,14065056))中进行洗涤。每孔加入20μL 0.5×Calcium 6荧光染料(Molecular Devices,R8190),在37℃下染料荷载温育1.5小时。随后将10μL供试化合物(以10mM的浓度溶解于DMSO中并用缓冲液进行系列稀释)或溶媒加入各孔,并使其在室温下平衡30min。然后将细胞板放入FLIPR中,进行基线荧光测量(激发波长为485nm,发射波长为525-535nm)。随后以10μL/孔加入激动剂(终浓度2.5μM的BZ-ATP(Sigma,B6396))或溶媒(超纯水),以1秒的时间间隔测量荧光值2分钟,最后对输出的荧光计数进行分析。
使用上述方法获得的IC
50示于表1中。
表1对于实施例1-43的化合物对P2X4受体所获得的IC
50
A:IC
50≤10nM,B:10<IC
50≤50nM,C:50<IC
50≤200nM,D:200<IC
50≤5000nM。
由表1数据可见,本发明的化合物具有良好的P2X4抑制活性,我们优选IC
50<500nM的化合物,更优选IC
50<100nM的化合物。
实施例B单纯柠檬酸咳嗽模型活性测试
将雄性Dunkin Hartley豚鼠(300-350g)置于动物雾化箱中,关闭雾化箱门,同时开启超声雾化器(广东粤华),以最大雾化量(约2mL/min)往雾化箱中充17.5%的柠檬酸气体,持续雾化20s,并从雾化开始时计时,持续观察动物在10min内的咳嗽表现。10min观察期间需要进行咳嗽人工计数,根据豚鼠咳嗽姿势如腹部抽动、嘴巴张开、头部下勾等以及咳嗽声音判断咳嗽次数,记录前5min咳嗽次数、10min咳嗽次数,同时记录豚鼠的咳嗽潜伏期,即从柠檬酸诱导开始至第1次咳嗽出现的时间。
咳嗽抑制率Vs溶媒表示柠檬酸激发时,给药组与溶媒组相比咳嗽次数的减少百分比(咳嗽抑制率Vs溶媒=(溶媒组咳嗽次数-各给药组咳嗽次数)/溶媒组给药后咳嗽次数×100%);咳嗽抑制率Vs基础值表示给药组给药前后自身咳嗽次数的减少百分比(咳嗽抑制率Vs基础值=(给药前咳嗽次数-给药后组咳嗽次数)/给药前咳嗽次数×100%)。
表2对于部分化合物在体内所获得的咳嗽抑制率
以化合物1为代表,开展以上实验,如表2的结果显示;与空白溶媒组或与自身给药前相比,20、60、100mg/kg的化合物1均能够显著性的减少咳嗽次数,延长咳嗽潜伏期,并与阳性化合物右美沙芬相比有优效趋势,说明化合物1具有减少咳嗽次数,提高咳嗽潜伏期的作用,且略优于阳性化合物。
实施例C体外细胞毒性测试
对本发明中化合物的体外细胞毒性测试在HepG2细胞中利用CCK-8法进行测定。收集对数期的HepG2细胞(北纳生物),调整细胞悬液浓度,以50000cells/well在96孔细胞培养板中铺板,将细胞置于5%,37℃的细胞培养箱中孵育过夜,待板中细胞融合度达到80-90%后,换液加入各浓度梯度的供试化合物或溶媒(DMSO),在5%,37℃的细胞培养箱中孵育48小时。处理结束后,弃去板内培养基,用PBS洗涤2遍,每孔加入100μL CCK-8工作液(碧云天生物技术),37℃避光孵育1.5小时,酶标仪上检测OD
450nm处各孔的吸光值,分析计算各化合物的CC
50。
使用上述方法获得的CC
50示于表3中。
表3对于部分化合物所获得的CC
50
由表3数据可见,本发明的大部分化合物都具有较好的安全性,CC
50范围均>30μM,满足一般化合物体外对细胞毒性的要求,我们优选CC
50>30μM的化合物,更优选CC
50>100μM的化合物。
实施例D体外代谢稳定性试验
对本发明中化合物的体外代谢稳定性利用各种属肝微粒体温孵法进行测定。在肝微粒体反应体系中(1mg/mL肝微粒体蛋白,25U/mL 6-磷酸葡萄糖脱氢酶,1mM NADP,6mM D-6-磷酸葡萄糖,5mM MgCl
2)加入适量供试化合物,放入37℃水浴锅温孵启动反应,于各时间点取100μL反应液加入至含400μL 0℃预冷的内标工作液(含200ng/mL地塞米松、双氯酚酸、甲苯磺丁脲、拉贝洛尔的乙腈溶液)离心管中,终止反应,4℃离心机10000g离心10min,取上清液进LC-MS进行分析检测,获得供试化合物在各种属肝微粒体中的体外代谢半衰期。
使用上述方法获得的T
1/2示于表4中。
表4对于部分化合物所获得的T
1/2
注:“/”表述未测。
由表4数据可见,本发明的化合物在人、大鼠、豚鼠中都具有较好的代谢稳定性,本发明优选在人肝微粒体中T
1/2>30min的化合物,更优选在人肝微粒体中T
1/2>90min的化合物。
虽然以上描述了本发明的具体实施方式,但是本领域的技术人员应当理解,这些仅是举例说明,在不背离本发明的原理和实质的前提下,可以对这些实施方式做出多种变更或修改。因此,本发明的保护范围由所附权利要求书限定。
Claims (14)
- 一种如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物;为苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的6元杂烷环”、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的6元杂烯环”或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的6元杂芳环”;R 1-1为卤素、羟基、氨基、-NHR 1-1-4、-N(R 1-1-5)(R 1-1-6)、C 1~C 6的烷基、C 3~C 6的环烷基、被一个或多个R 1-1-1取代的C 1~C 6的烷基、被一个或多个R 1-1-2取代的C 3~C 6的环烷基、或、被一个或多个R 1-1-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~7元杂环烷基”;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独立地为卤素、羟基、C 1~C 6的烷基、C 3~C 6的环烷基、C 1~C 6的烷氧基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~7元杂环烷基”;n为0、1、2或3;R 3-1独立地为卤素、氰基、羟基、C 1~C 6的烷基、C 1~C 6的烷氧基、C 3~C 6的环烷基、被一个或多个R 3-1-1取代的C 1~C 6的烷基、被一个或多个R 3-1-2取代的C 1~C 6的烷氧基、或、C 1~C 6的烷氧基取代的C 1~C 6的烷氧基;R 3-1-1和R 3-1-2独立地为卤素;R 3-2为被一个或多个R 3-2-1取代的C 3~C 6的环烷基、被一个或多个R 3-2-2取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、被一个或多个R 3-2-2取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的7~8元杂环烷基”、或、被一个或多个R 3-2-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;R 3-2-1、R 3-2-2和R 3-2-3独立地为卤素、羟基、C 1~C 6的烷基、C 3~C 6的环烷基、C 1~C 6的烷氧基、或、C 1~C 6的烷氧基取代的C 1~C 6的烷氧基;m为0、1、2、3或4;R 2为氧代、卤素、氰基、异氰基、氨基、C 1~C 10烷基、被一个或多个R 2-1取代的C 1~C 10烷基、C 2~C 10烯基、被一个或多个R 2-26取代的C 2~C 10烯基、C 2~C 10炔基、被一个或多个R 2-27取代的C 2~C 10炔基、C 3~C 6的环烷基、被一个或多个R 2-3取代的C 3~C 6的环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~4元杂环烷基”、苯基、被一个或多个R 2-4取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、被一个或多个R 2-5取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-(C=O)-R 2-2、-OR 2-6、-C(=O)OR 2-7、-NR 2-8R 2-9、被一个或多个R 2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、被一个或多个R 2-10取代的“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~4元杂环烷基”、-C(=O)NHR 2-11、-C(=O)NR 2-12R 2-13、-NR 2-14C(=O)R 2-15、-NR 2-16S(=O) 2R 2-17、-NR 2-18S(=O)R 2-19、-S(=O) 2NHR 2-20、-S(=O)NHR 2-21、-S(=O) 2NR 2-22R 2-23、-S(=O) 2R 2-24或-S(=O)R 2-25;R 2-1独立地为卤素、羟基、C 3~C 6的环烷基、被一个或多个R 2-1-8取代的C 3~C 6的环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~6元杂环烷基”、被一个或多个R 2-1-7取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~6元杂环烷基”、苯基、被一个或多个R 2-1-1取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、被一个或多个R 2-1-6取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-OR 2-1-2、-N(R 2-1-3)(R 2-1-4)、或、-S(=O) 2-R 2-1-5;R 2-1-1、R 2-1-6、R 2-1-7和R 2-1-8独立地为氧代、羟基、氨基、羧基、卤素、-CN、C 1~C 6的烷基、被 一个或多个卤素取代的C 1~C 6的烷基、-OR 2-1-1-1、或、-N(R 2-1-1-2)(R 2-1-1-3);R 2-1-1-1、R 2-1-1-2和R 2-1-1-3独立地为C 1~C 6的烷基;R 2-1-2独立地为C 1~C 6的烷基或C 3~C 6的环烷基;R 2-1-3和R 2-1-4独立地为氢、C 1~C 6的烷基或C 3~C 6的环烷基;R 2-1-5独立地为C 1~C 6的烷基或C 3~C 6的环烷基;R 2-3独立地为C 1~C 6的烷基;R 2-4和R 2-5独立地为卤素、羟基、C 1~C 6的烷基、被一个或多个R 2-4-3取代的C 1~C 6的烷基、-N(R 2-4-1)(R 2-4-2)或C 1~C 6的烷氧基;R 2-4-1和R 2-4-2独立地为氢、C 1~C 6的烷基或C 3~C 6的环烷基;R 2-4-3为卤素;R 2-2为C 1~C 6的烷基、C 3~C 6的环烷基、苯基、被一个或多个R 2-2-2取代的C 1~C 6的烷基、或、被一个或多个R 2-2-1取代的苯基;R 2-2-1独立地为卤素;R 2-2-2独立地为卤素;R 2-6为氢、C 1~C 10烷基、被一个或多个R 2-6-1取代的C 1~C 10烷基、C 3~C 6环烷基、C 6~C 10芳基、被一个或多个R 2-6-2取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R 2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;R 2-6-1独立地为氧代、卤素、羟基、氨基、羧基、-CN、C 1~C 6的烷基、被一个或多个卤素取代的C 1~C 6的烷基、C 1~C 6烷氧基、C 3~C 6环烷基、C 6~C 10芳基、被一个或多个R 2-6-1-1取代的C 6~C 10芳基、-OR 2-6-1-2或-N(R 2-6-1-3)(R 2-6-1-4);R 2-6-2独立地为卤素、C 1~C 6烷基或C 1~C 6烷氧基;R 2-6-3独立地为-C(=O)-C 1~C 6烷基;R 2-6-1-1独立地为卤素;R 2-6-1-2、R 2-6-1-3和R 2-6-1-4独立地为C 1~C 6的烷基;R 2-7为C 1~C 6烷基、C 3~C 6的环烷基或苯基;R 2-8和R 2-9独立地为氢、C 1~C 6烷基、C 6~C 10芳基、或者被一个或多个R 2-8-1取代的C 6~C 10芳基;R 2-8-1为卤素或C 1~C 6烷氧基;R 2-10独立地为C 1~C 6烷基或氧代;R 2-26和R 2-27独立地为卤素或C 1~C 6烷基;R 2-11、R 2-12、R 2-13、R 2-14、R 2-15、R 2-16、R 2-16、R 2-17、R 2-18、R 2-19、R 2-20、R 2-21、R 2-22、R 2-23、R 2-24和R 2-25独立地为C 1~C 6烷基、C 1~C 6烷氧基、C 3~C 6环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、苯基、被一个或多个R 2-11-1取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳环”、或被一个或多个R 2-11-2取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳环”;R 2-11-1和R 2-11-2独立地为卤素、氰基、羟基、C 1~C 6烷基、C 1~C 6烷氧基或C 3~C 6环烷基;
- 如权利要求1所述的如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物,其特征在于,为苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的6元杂烷环”、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的6元杂烯环”或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的6元杂芳环”;R 1-1为卤素、羟基、氨基、-NHR 1-1-4、-N(R 1-1-5)(R 1-1-6)、C 1~C 6的烷基、C 3~C 6的环烷基、被一个或多个R 1-1-1取代的C 1~C 6的烷基、被一个或多个R 1-1-2取代的C 3~C 6的环烷基、或、被一个或多个R 1-1-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~7元杂环烷基”;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独立地为卤素、羟基、C 1~C 6的烷基、C 3~C 6的环烷基、C 1~C 6的烷氧基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~7元杂环烷基”;n为0、1、2或3;R 3-1独立地为卤素、氰基、羟基、C 1~C 6的烷基、C 1~C 6的烷氧基、C 3~C 6的环烷基、或、C 1~C 6的烷氧基取代的C 1~C 6的烷氧基;R 3-2为被一个或多个R 3-2-1取代的C 3~C 6的环烷基、被一个或多个R 3-2-2取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、被一个或多个R 3-2-2取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的7~8元杂环烷基”、或、被一个或多个R 3-2-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;R 3-2-1、R 3-2-2和R 3-2-3独立地为卤素、羟基、C 1~C 6的烷基、C 3~C 6的环烷基、C 1~C 6的烷氧基、或、C 1~C 6的烷氧基取代的C 1~C 6的烷氧基;m为0、1、2、3或4;R 2为氧代、卤素、氰基、氨基、C 1~C 10烷基、被一个或多个R 2-1取代的C 1~C 10烷基、C 3~C 6的环烷基、被一个或多个R 2-3取代的C 3~C 6的环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、苯基、被一个或多个R 2-4取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、被一个或多个R 2-5取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-(C=O)-R 2-2、-OR 2-6、-C(=O)OR 2-7、-NR 2-8R 2-9、被一个或多个R 2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、-C(=O)NHR 2-11、-C(=O)NR 2-12R 2-13、-NR 2-14C(=O)R 2-15、-NR 2-16S(=O) 2R 2-17、-NR 2-18S(=O)R 2-19、-S(=O) 2NHR 2-20、-S(=O)NHR 2-21、-S(=O) 2NR 2-22R 2-23、-S(=O) 2R 2-24、-S(=O)R 2-25;R 2-1独立地为卤素、羟基、C 3~C 6的环烷基、被一个或多个R 2-1-8取代的C 3~C 6的环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~6元杂环烷基”、被一个或多个R 2-1-7取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的4~6元杂环烷基”、苯基、被一个或多个R 2-1-1取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、被一个或多个R 2-1-6取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-OR 2-1-2、-N(R 2-1-3)(R 2-1-4)、或、-S(=O) 2-R 2-1-5;R 2-1-1、R 2-1-6、R 2-1-7和R 2-1-8独立地为氧代、羟基、氨基、羧基、卤素、-CN、C 1~C 6的烷基、被一个或多个卤素取代的C 1~C 6的烷基、-OR 2-1-1-1、或、-N(R 2-1-1-2)(R 2-1-1-3);R 2-1-1-1、R 2-1-1-2和R 2-1-1-3独立地为C 1~C 6的烷基;R 2-1-2独立地为C 1~C 6的烷基或C 3~C 6的环烷基;R 2-1-3和R 2-1-4独立地为氢、C 1~C 6的烷基或C 3~C 6的环烷基;R 2-1-5独立地为C 1~C 6的烷基或C 3~C 6的环烷基;R 2-3独立地为C 1~C 6的烷基;R 2-4和R 2-5独立地为卤素、羟基、-N(R 2-4-1)(R 2-4-2)或C 1~C 6的烷氧基;R 2-4-1和R 2-4-2独立地为氢、C 1~C 6的烷基或C 3~C 6的环烷基;R 2-2为C 1~C 6的烷基、C 3~C 6的环烷基、苯基、或、被一个或多个R 2-2-1取代的苯基;R 2-2-1独立地为卤素;R 2-6为氢、C 1~C 10烷基、被一个或多个R 2-6-1取代的C 1~C 10烷基、C 3~C 6环烷基、C 6~C 10芳基、被一个或多个R 2-6-2取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R 2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;R 2-6-1独立地为氧代、卤素、羟基、氨基、羧基、-CN、C 1~C 6的烷基、被一个或多个卤素取代的C 1~C 6的烷基、C 1~C 6烷氧基、C 3~C 6环烷基、C 6~C 10芳基、被一个或多个R 2-6-1-1取代的C 6~C 10芳基、-OR 2-6-1-2或-N(R 2-6-1-3)(R 2-6-1-4);R 2-6-2独立地为卤素、C 1~C 6烷基或C 1~C 6烷氧基;R 2-6-3独立地为-C(=O)-C 1~C 6烷基;R 2-6-1-1独立地为卤素;R 2-6-1-2、R 2-6-1-3和R 2-6-1-4独立地为C 1~C 6的烷基;R 2-7为C 1~C 6烷基;R 2-8和R 2-9独立地为氢、C 1~C 6烷基、C 6~C 10芳基、或者被一个或多个R 2-8-1取代的C 6~C 10芳基;R 2-8-1为卤素或C 1~C 6烷氧基;R 2-10独立地为C 1~C 6烷基或氧代;R 2-11、R 2-12、R 2-13、R 2-14、R 2-15、R 2-16、R 2-16、R 2-17、R 2-18、R 2-19、R 2-20、R 2-21、R 2-22、R 2-23、R 2-24和R 2-25独立地为C 1~C 6烷基、C 1~C 6烷氧基、C 3~C 6环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、苯基、被一个或多个R 2-11-1取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳环”、或被一个或多个R 2-11-2取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳环”;R 2-11-1和R 2-11-2独立地为卤素、氰基、羟基、C 1~C 6烷基、C 1~C 6烷氧基或C 3~C 6环烷基;
- 如权利要求2所述的如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物,其特征在于,和/或,当 为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的6元杂烯环”时,所述的6元杂烯环中的杂原子选自N,杂原子数为1个;所述的6元杂烯环中的双键个数优选为1或2个; 优选为双键;所述的 优选为和/或,当R 1-1为C 1~C 6的烷基时,所述的C 1~C 6烷基为C 1~C 4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基;和/或,当R 3-1独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟或氯;和/或,当R 2为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟或氯;和/或,当R 2为C 1~C 10烷基时,所述的C 1~C 10烷基为C 1~C 4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基或异丙基;和/或,当R 2为被一个或多个R 2-1取代的C 1~C 10烷基时,所述的C 1~C 10烷基为C 1~C 4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基;和/或,当R 2为C 3~C 6环烷基时,所述的C 3~C 6环烷基为环丙基、环丁基、环戊基或环己基,优选为环丙基或环丁基;和/或,当R 2为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”时,所述5~6元杂环烷基中的杂原子选自N和O中的一种或多种,杂原子数优选为1或2;所述的5~6元杂环烷基优选为和/或,当R 2为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”时,所述的5~6元杂芳基中的杂原子优选为N,杂原子数优选为2;所述的5~6元杂芳基优选为 例如所述的5~6元杂芳基优选为和/或,当R 2为被一个或多个R 2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”时,所述的5~6元杂环烷基中的杂原子为N,杂原子数优选为2; 所述的5~6元杂环烷基优选为和/或,当R 2-1独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟;和/或,当R 2-6为C 1~C 10烷基时,所述的C 1~C 10烷基为C 1~C 6烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基或正丁基,进一步优选为甲基、乙基、异丁基或异戊基;和/或,当R 2-6为被一个或多个R 2-6-1取代的C 1~C 10烷基,所述的C 1~C 10烷基为C 1~C 4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基或乙基;和/或,当R 2-6为C 3~C 6环烷基时,所述的C 3~C 6环烷基为环丙基、环丁基、环戊基或环己基,优选为环丙基、环丁基或环戊基;和/或,当R 2-6为C 6~C 10芳基时,所述的C 6~C 10芳基为苯基或萘基;和/或,当R 2-6为被一个或多个R 2-6-2取代的C 6~C 10芳基时,所述的C 6~C 10芳基为苯基或萘基,优选为苯基;和/或,当R 2-6为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”时,所述的3~6元杂环烷基为3~4元杂环烷基;所述的3~4元杂环烷基中,杂原子优选为N,杂原子数优选为1个;所述的3~4元杂环烷基优选为和/或,当R 2-6为被一个或多个R 2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”时,所述的3~6元杂环烷基为3~4元杂环烷基;所述的3~4元杂环烷基中,杂原子优选为N,杂原子数优选为1个;所述的3~4元杂环烷基优选为和/或,当R 2-6-1独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟;和/或,当R 2-6-1独立地为C 1~C 6烷氧基时,所述的C 1~C 6烷氧基为C 1~C 4烷氧基,优选为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基,进一步优选为甲氧基;和/或,当R 2-6-1独立地为C 3~C 6环烷基时,所述的C 3~C 6环烷基为环丙基、环丁基、环戊基或环己基,优选为环丙基;和/或,当R 2-6-1独立地为C 6~C 10芳基时,所述的C 6~C 10芳基为苯基或萘基;和/或,当R 2-6-1独立地为被一个或多个R 2-6-1-1取代的C 6~C 10芳基时,所述的C 6~C 10芳基为苯基或萘基,优选为苯基;和/或,当R 2-6-2独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟;和/或,当R 2-6-2独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为C 1~C 4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基;和/或,当R 2-6-2独立地为C 1~C 6烷氧基时,所述的C 1~C 6烷氧基为C 1~C 4烷氧基,优选为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基,进一步优选为甲氧基;和/或,R 2-6-3独立地为-C(=O)-C 1~C 4烷基,所述的-C(=O)-C 1~C 4烷基中的C 1~C 4烷基优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基;和/或,R 2-6-1-1独立地为氟、氯、溴或碘,优选为氟;和/或,R 2-7为C 1~C 4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基;和/或,R 2-8和R 2-9独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为C 1~C 4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为异丙基;和/或,当R 2-8和R 2-9独立地为C 6~C 10芳基时,所述的C 6~C 10芳基为苯基或萘基;和/或,当R 2-8和R 2-9独立地为被一个或多个R 2-8-1取代的C 6~C 10芳基时,所述的被一个或多个R 2-8-1取代的C 6~C 10芳基中的C 6~C 10芳基为苯基或萘基,优选为苯基;和/或,当R 2-8-1为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟;和/或,当R 2-8-1为C 1~C 6烷氧基时,所述的C 1~C 6烷氧基为C 1~C 4烷氧基,优选为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基,进一步优选为甲氧基;和/或,当R 2-10独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为C 1~C 4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,进一步优选为甲基;和/或,当R 1-1为C 3~C 6的环烷基时,所述的C 3~C 6的环烷基为环丙基、环丁基或环戊基;和/或,当R 1-1为被一个或多个R 1-1-1取代的C 1~C 6的烷基,所述的被一个或多个R 1-1-1取代的C 1~C 6的烷基中的的C 1~C 6烷基为C 1~C 4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;和/或,当R 1-1为被一个或多个R 1-1-2取代的C 3~C 6的环烷基时,所述的被一个或多个R 1-1-2取代的C 3~C 6的环烷基中的C 3~C 6的环烷基为环丙基、环丁基或环戊基;和/或,当R 1-1-1和R 1-1-2独立地为卤素时,所述的卤素为氟、氯、溴或碘;和/或,当R 3-1独立地为C 1~C 6的烷氧基或被一个或多个R 3-1-2取代的C 1~C 6的烷氧基时,所述的C 1~C 6的烷氧基和被一个或多个R 3-1-2取代的C 1~C 6的烷氧基里的C 1~C 6的烷氧基为C 1~C 4烷氧基,优选为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基,进一步优选为甲氧基;和/或,当R 3-1-1和R 3-1-2独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟或氯;和/或,当R 2为C 2~C 10烯基、被一个或多个R 2-26取代的C 2~C 10烯基时,所述的C 2~C 10烯基和被一个或多个R 2-26取代的C 2~C 10烯基里的为C 2~C 10烯基为C 2~C 4烯基,优选为乙烯基、烯丙基;和/或,当R 2为C 2~C 10炔基或被一个或多个R 2-27取代的C 2~C 10炔基时,所述的C 2~C 10炔基和被一个或多个R 2-27取代的C 2~C 10炔基里的为C 2~C 10炔基为C 2~C 4炔基,优选为乙炔基、丙炔基;和/或,当R 2-26和R 2-27独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟或氯;和/或,当R 2为“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~4元杂环烷基”或被一个或多个R 2-10取代的“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~4元杂环烷基”时,所述3~4元杂环烷基中的杂原子选自N和O中的一种或多种,杂原子数优选为1或2个;所述的3~4元杂环烷基优选为和/或,当R 2为被一个或多个R 2-5取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”时,所述的5~6元杂芳基中的杂原子优选为N,杂原子数优选为1个;所述的5~6元杂芳基优选为和/或,当R 2-1独立地为C 3~C 6的环烷基时,所述的C 3~C 6的环烷基为环丙基、环丁基、环戊基或环己基,优选为环丙基或环丁基;和/或,当R 2-2为C 1~C 6的烷基或被一个或多个R 2-2-2取代的C 1~C 6的烷基时,所述的C 1~C 6的烷基优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基或正丁基,进一步优选为甲基;和/或,当R 2-2为C 3~C 6的环烷基时,所述的C 3~C 6的环烷基为环丙基、环丁基、环戊基或环己基,优选为环丙基或环丁基;和/或,当R 2-2-2独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟或氯;和/或,当R 2-4和R 2-5独立地为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟或氯;和/或,当R 2-4和R 2-5独立地为C 1~C 6的烷基或被一个或多个R 2-4-3取代的C 1~C 6的烷基时,所述的C 1~C 6的烷基和被一个或多个R 2-4-3取代的C 1~C 6的烷基里的C 1~C 6的烷基优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基或正丁基,进一步优选为甲基;和/或,当R 2-4-3为卤素时,所述的卤素为氟、氯、溴或碘,优选为氟或氯;和/或,R 2-7为C 3~C 6环烷基时,所述的C 3~C 6环烷基为环丙基、环丁基、环戊基或环己基,优选为环丙基;
- 如权利要求2或3所述的如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物,其特征在于,和/或,R 1-1为C 1~C 6的烷基、C 3~C 6的环烷基、被一个或多个R 1-1-1取代的C 1~C 6的烷基、被一个或多个R 1-1-2取代的C 3~C 6的环烷基;和/或,n为1、2或3;和/或,R 3-1独立地为卤素、氰基、羟基、被一个或多个R 3-1-2取代的C 1~C 6的烷氧基;例如,R 3-1独立地为卤素、氰基或羟基;和/或,m为0或1;和/或,R 2为氧代、卤素、氰基、异氰基、氨基、C 1~C 10烷基、被一个或多个R 2-1取代的C 1~C 10烷基、C 2~C 10烯基、被一个或多个R 2-26取代的C 2~C 10烯基、C 2~C 10炔基、被一个或多个R 2-27取代的C 2~C 10炔基、C 3~C 6环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~4元杂环烷基”、苯基、被一个或多个R 2-4取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、被一个或多个R 2-5取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-(C=O)-R 2-2、-OR 2-6、-C(=O)OR 2-7、-NR 2-8R 2-9、或、被一个或多个R 2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”;例如R 2为氧代、卤素、氰基、氨基、C 1~C 10烷基、被一个或多个R 2-1取代的C 1~C 10烷基、C 3~C 6环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-OR 2-6、-C(=O)OR 2-7、-NR 2-8R 2-9、或、被一个或多个R 2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”;和/或,R 2为氧代、卤素、氰基、氨基、C 1~C 10烷基、被一个或多个R 2-1取代的C 1~C 10烷基、C 3~C 6环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或、-OR 2-6;和/或,R 2-6为氢、C 1~C 10烷基、被一个或多个R 2-6-1取代的C 1~C 10烷基、C 3~C 6环烷基、C 6~C 10芳基、被一个或多个R 2-6-2取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和 S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R 2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;和/或,R 2-6-1独立地为卤素、羟基、C 1~C 6烷氧基、C 3~C 6环烷基、或、被一个或多个R 2-6-1-1取代的C 6~C 10芳基;例如R 2-6-1独立地为卤素、C 3~C 6环烷基、或、被一个或多个R 2-6-1-1取代的C 6~C 10芳基;和/或,R 1-1为C 1~C 6的烷基;和/或,R 1-1-1和R 1-1-2独立地为卤素;和/或,R 2-1独立地为卤素、C 3~C 6的环烷基、苯基;例如R 2-1独立地为卤素;和/或,R 2-1独立地为卤素;和/或,R 2-2为C 1~C 6的烷基、C 3~C 6的环烷基、苯基、被一个或多个R 2-2-2取代的C 1~C 6的烷基;和/或,R 2-4和R 2-5独立地为卤素、C 1~C 6的烷基、被一个或多个R 2-4-3取代的C 1~C 6的烷基;和/或,R 2-7为C 3~C 6的环烷基或苯基。
- 如权利要求1或2所述的如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物,其特征在于,和/或,R 2为氧代、甲氧基、氟、氯、羟基、氨基、-CH 2F、二氟甲基、三氟甲基、甲基、异丙基、环丙基、氰基、乙氧基、异丙氧基、一氟甲氧基、二氟甲氧基、三氟甲氧基、 乙基、二氯甲基、 乙炔基、丙炔基、 苄基、 苯基、 或者,R 2为氧代、甲氧基、氟、氯、羟基、氨基、-CH 2F、二氟甲基、三氟甲基、甲基、异丙基、环丙基、氰基、乙氧基、异丙氧基、一氟甲氧基、二氟甲氧基、三氟甲氧基、 或者,R 2为氧代、甲氧基、氟、氯、羟基、氨基、二氟甲基、三氟甲基、异丙基、环丙基、氰基、乙氧基、异丙氧基、二氟甲氧基、
- 如权利要求1所述的如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物,其特征在于,其为如下任一方案:方案一:R 1-1为C 1~C 6的烷基、C 3~C 6的环烷基、被一个或多个R 1-1-1取代的C 1~C 6的烷基、被一个或多个R 1-1-2取代的C 3~C 6的环烷基;R 1-1-1和R 1-1-2独立地为卤素;n为1、2或3;R 3-1独立地为卤素、氰基或羟基;m为0、1;R 2为氧代、卤素、氰基、氨基、C 1~C 10烷基、被一个或多个R 2-1取代的C 1~C 10烷基、C 3~C 6的环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-OR 2-6、-C(=O)OR 2-7、-NR 2-8R 2-9、或、被一个或多个R 2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”;R 2-1独立地为卤素;R 2-6为氢、C 1~C 10烷基、被一个或多个R 2-6-1取代的C 1~C 10烷基、C 3~C 6环烷基、C 6~C 10芳基、被一个或多个R 2-6-2取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R 2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;R 2-6-1独立地为卤素、羟基、C 3~C 6环烷基或被一个或多个R 2-6-1-1取代的C 6~C 10芳基;R 2-6-2独立地为卤素、C 1~C 6烷基或C 1~C 6烷氧基;R 2-6-3独立地为-C(=O)-C 1~C 6烷基;R 2-6-1-1独立地为卤素;R 2-7为C 1~C 6烷基;R 2-8和R 2-9独立地为氢、C 1~C 6烷基、C 6~C 10芳基、或者被一个或多个R 2-8-1取代的C 6~C 10芳基;R 2-8-1为卤素或C 1~C 6烷氧基;R 2-10独立地为C 1~C 6烷基或氧代;方案二:n为1、2或3;R 3-1独立地为卤素、氰基或羟基;m为0或1;R 2为氧代、卤素、氰基、氨基、C 1~C 10烷基、被一个或多个R 2-1取代的C 1~C 10烷基、C 3~C 6的环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或、-OR 2-6;R 2-1独立地为卤素;R 2-6为氢、C 1~C 10烷基、被一个或多个R 2-6-1取代的C 1~C 10烷基、C 3~C 6环烷基、C 6~C 10芳基、被一个或多个R 2-6-2取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R 2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;R 2-6-1独立地为卤素、C 3~C 6环烷基、被一个或多个R 2-6-1-1取代的C 6~C 10芳基;R 2-6-1-1独立地为卤素;R 2-6-2独立地为卤素、C 1~C 6烷基或C 1~C 6烷氧基;R 2-6-3独立地为-C(=O)-C 1~C 6烷基;R 2-6-1-1独立地为卤素;R 2-10独立地为C 1~C 6烷基或氧代;方案三:n为1、2或3;R 3-1独立地为卤素、氰基或羟基;m为0或1;R 2为氧代、卤素、氰基、C 1~C 10烷基、或、被一个或多个R 2-1取代的C 1~C 10烷基、C 3~C 6环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或、-OR 2-6;R 2-1独立地为卤素;R 2-6为C 1~C 10烷基、被一个或多个R 2-6-1取代的C 1~C 10烷基、C 3~C 6环烷基、被一个或多个R 2-6-2取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R 2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;R 2-6-1独立地为卤素、C 3~C 6环烷基或被一个或多个R 2-6-1-1取代的C 6~C 10芳基;R 2-6-1-1独立地为卤素;R 2-6-2独立地为卤素、C 1~C 6烷基或C 1~C 6烷氧基;R 2-6-3独立地为-C(=O)-C 1~C 6烷基;方案四:n为1、2或3;R 3-1独立地为卤素、氰基或羟基;m为0、1;R 2为氯、氰基、C 1~C 10烷基、被一个或多个R 2-1取代的C 1~C 10烷基、C 3~C 6环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或、-OR 2-6;R 2-1独立地为卤素;R 2-6为C 1~C 4烷基、被一个或多个R 2-6-1取代的C 1-C 2烷基、C 3~C 6环烷基、被一个或多个R 2-6-2取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R 2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;且当R 2为氯时,R 2位于Z 1或Z 4上;R 2-6-1独立地为卤素、C 3~C 6环烷基或被一个或多个R 2-6-1-1取代的C 6~C 10芳基;R 2-6-2独立地为卤素、C 1~C 6烷基或C 1~C 6烷氧基;R 2-6-3独立地为-C(=O)-C 1~C 6烷基;方案五:R 1-1为C 1~C 6的烷基;n为1、2或3;R 3-1独立地为卤素、氰基、羟基或被一个或多个R 3-1-2取代的C 1~C 6的烷氧基;m为0或1;R 2为氧代、卤素、氰基、氨基、异氰基、C 1~C 10烷基、被一个或多个R 2-1取代的C 1~C 10烷基、C 2~C 10烯基、被一个或多个R 2-26取代的C 2~C 10烯基、C 2~C 10炔基、被一个或多个R 2-27取代的C 2~C 10炔基、C 3~C 6的环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~4元杂环烷基”、苯基、被一个或多个R 2-4取代的苯基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、被一个或多个R 2-5取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、-(C=O)-R 2-2、-OR 2-6、-C(=O)OR 2-7、-NR 2-8R 2-9、被一个或多个R 2-10取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂环烷基”;R 2-1独立地为卤素、C 3~C 6的环烷基或苯基;R 2-2为C 1~C 6的烷基、C 3~C 6的环烷基、苯基或被一个或多个R 2-2-2取代的C 1~C 6的烷基;R 2-2-2独立地为卤素;R 2-4和R 2-5独立地为卤素、C 1~C 6的烷基、被一个或多个R 2-4-3取代的C 1~C 6的烷基;R 2-4-3为卤素;R 2-6为氢、C 1~C 10烷基、被一个或多个R 2-6-1取代的C 1~C 10烷基、C 3~C 6环烷基、C 6~C 10芳基、被一个或多个R 2-6-2取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”、或、被一个或多个R 2-6-3取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;R 2-6-1独立地为卤素、羟基、C 1~C 6烷氧基、C 3~C 6环烷基、被一个或多个R 2-6-1-1取代的C 6~C 10芳基;R 2-6-2独立地为卤素、C 1~C 6烷基或C 1~C 6烷氧基;R 2-6-3独立地为-C(=O)-C 1~C 6烷基;R 2-6-1-1独立地为卤素;R 2-6-1-2独立地为C 1~C 6的烷基;R 2-7为C 1~C 6烷基、C 3~C 6的环烷基或苯基;R 2-8和R 2-9独立地为氢、C 1~C 6烷基、C 6~C 10芳基、或者被一个或多个R 2-8-1取代的C 6~C 10芳基;R 2-8-1为卤素或C 1~C 6烷氧基;R 2-10独立地为C 1~C 6烷基或氧代;R 2-26和R 2-27独立地为卤素或C 1~C 6烷基;方案六:所述的式I所示的化合物为如下任一所示的化合物:方案七:所述的式I所示的化合物的药学上可接受的盐为如下的化合物:
- 一种药物组合物,其包含物质A和至少一种药用辅料;所述的物质A为同权利要求1~6任一项所述的如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物。
- 一种物质A在制备P2X4受体拮抗剂或药物中的应用;所述的物质A为同权利要求1~6任一项所述的如式I所示的稠环化合物、其药学上可接受的盐、 其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物。
- 如权利要求12所述的物质A在制备P2X4受体拮抗剂或药物中的应用,其特征在于,所述的药物可用于治疗或预防动物的泌尿道疾病、呼吸系统疾病、疼痛、自身免疫病、炎症、老年痴呆症、帕金森、睡眠障碍、癫痫、精神疾病、关节炎、神经退行性变、外伤性脑损伤、心肌梗死、类风湿性关节炎、脑卒中、血栓症、动脉粥样硬化、结肠综合症、炎性肠病、消化道疾病、胃肠功能紊乱、呼吸衰竭、性功能障碍、心血管系统疾病、心衰、高血压、尿失禁、膀胱炎、关节炎、子宫内膜异位、血液病、肌肉骨骼和结缔组织发育障碍、或、系统性障碍疾病;所述的泌尿道疾病例如尿失禁、膀胱过度活动症、排尿困难或膀胱炎;所述的呼吸系统疾病例如呼吸障碍,包括特发性肺纤维化、慢性阻塞性肺病、哮喘、支气管痉挛或咳嗽;所述的疼痛例如炎性疼痛、手术疼痛、内脏疼痛、牙痛、经前期疼痛、中枢性疼痛、由灼伤所致疼痛、偏头痛、簇性头痛或慢性疼痛;所述的动物例如为人类;所述的支气管痉挛或咳嗽例如慢性咳嗽;或,所述的药物可用于预防或治疗动物的至少部分由P2X4介导的疾病;所述的至少部分由P2X4介导的疾病例如泌尿道疾病、呼吸系统疾病、疼痛、自身免疫病、炎症、老年痴呆症、帕金森、睡眠障碍、癫痫、精神疾病、关节炎、神经退行性变、外伤性脑损伤、心肌梗死、类风湿性关节炎、脑卒中、血栓症、动脉粥样硬化、结肠综合症、炎性肠病、消化道疾病、胃肠功能紊乱、呼吸衰竭、性功能障碍、心血管系统疾病、心衰、高血压、尿失禁、膀胱炎、关节炎、子宫内膜异位、血液病、肌肉骨骼和结缔组织发育障碍、或、系统性障碍疾病;所述的泌尿道疾病例如尿失禁、膀胱过度活动症、排尿困难或膀胱炎;所述的呼吸系统疾病例如呼吸障碍,包括特发性肺纤维化、慢性阻塞性肺病、哮喘、支气管痉挛或咳嗽;所述的疼痛例如炎性疼痛、手术疼痛、内脏疼痛、牙痛、经前期疼痛、中枢性疼痛、由灼伤所致疼痛、偏头痛、簇性头痛或慢性疼痛;所述的动物例如人类;所述的支气管痉挛或咳嗽例如慢性咳嗽。
- 一种治疗或预防疾病的方法,其包括向患者施用治疗有效量的物质A;所述的物质A为同权利要求1~6任一项所述的如式I所示的稠环化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物;所述的疾病为泌尿道疾病、呼吸系统疾病、疼痛、自身免疫病、炎症、老年痴呆症、帕金森、睡眠障碍、癫痫、精神疾病、关节炎、神经退行性变、外伤性脑损伤、心肌梗死、类风湿性关节炎、脑卒中、血栓症、动脉粥样硬化、结肠综合症、炎性肠病、消化道疾病、胃肠功能紊乱、呼吸衰竭、性功能障碍、心血管系统疾病、心衰、高血压、尿失禁、膀胱炎、关节炎、子宫内膜异位、血液病、肌肉骨骼和结缔组织发育障碍、或、系统性障碍疾病;所述的泌尿道疾病例如尿失禁、膀胱过度活动症、排尿困难或膀胱炎;所述的呼吸系统疾病例如呼吸障碍,包括特发性肺纤维化、慢性阻塞性肺病、哮喘、支气管痉挛或咳嗽;所述的疼痛例如炎性疼痛、手术疼痛、内脏疼痛、牙痛、经前期疼痛、中枢性疼痛、由灼伤所致疼痛、偏头痛、簇性头痛 或慢性疼痛;所述的患者例如人类;所述的支气管痉挛或咳嗽例如慢性咳嗽。
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