WO2024109462A1 - 新型双环类pd-l1抑制剂及其制备方法与医药用途 - Google Patents

新型双环类pd-l1抑制剂及其制备方法与医药用途 Download PDF

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WO2024109462A1
WO2024109462A1 PCT/CN2023/127693 CN2023127693W WO2024109462A1 WO 2024109462 A1 WO2024109462 A1 WO 2024109462A1 CN 2023127693 W CN2023127693 W CN 2023127693W WO 2024109462 A1 WO2024109462 A1 WO 2024109462A1
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arh
compound
mmol
acid
pharmaceutically acceptable
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French (fr)
Inventor
徐云根
杜慧杰
朱启华
邹毅
郭维博
张强
张弛
徐永玲
夏宇
刘备备
王淑平
秦龙
郝忠言
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XI'AN XINTONG PHARMACEUTICAL RESEARCH Co Ltd
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XI'AN XINTONG PHARMACEUTICAL RESEARCH Co Ltd
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Priority to EP23893553.0A priority Critical patent/EP4556465A4/en
Priority to AU2023383986A priority patent/AU2023383986A1/en
Priority to CN202380059724.0A priority patent/CN119768390A/zh
Priority to JP2025509197A priority patent/JP2025527595A/ja
Publication of WO2024109462A1 publication Critical patent/WO2024109462A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present application belongs to the field of pharmaceutical chemistry, and specifically relates to a class of biphenyl derivatives with PD-1/PD-L1 inhibitory activity, their preparation methods, and pharmaceutical compositions containing these compounds and their use in treating tumors.
  • tumor immunotherapy has become the focus of tumor treatment. Unlike traditional treatments that directly target tumor cells, tumor immunotherapy uses the body's own immune system to kill tumor cells. Activation of the immune checkpoint pathway inhibits the activation of T cells, prevents overactivation of the human immune system, maintains the immune tolerance of the normal body, and avoids the occurrence of autoimmune diseases. Tumors cause tumor immune escape by causing themselves and some lymphocytes to overactivate the immune checkpoint pathway. Among these immune checkpoints, overactivation of PD-1/PD-L1 plays a vital role in the development of tumors.
  • Blocking the PD-1/PD-L1 interaction can reactivate the immune system and kill tumor cells, and has shown good efficacy in the treatment of clinical melanoma, colon cancer, non-small cell lung cancer and other tumors (Clinical and Translational Oncology, 2019, 21: 702-712; Lung Cancer: Targets and Therapy, 2017: 8; Hum Vaccin Immunother, 2014, 10(11): 3111-3116; Journal of Medicinal Chemistry, 2020, 63(22): 13825-13850).
  • PD-1/PD-L1-targeted mAbs have been approved by the FDA for tumor immunotherapy, and hundreds of mAbs are currently undergoing active clinical trials.
  • these monoclonal antibodies have improved the prognosis of many cancer patients, only a small number of patients can have a lasting response due to the development of intrinsic and acquired resistance.
  • the use of monoclonal antibodies can also cause serious immune-related adverse events (irAEs), and common side effects include skin inflammation, colitis, hepatitis, hypothyroidism, and hypophysitis.
  • macromolecular drugs have the disadvantages of poor tissue permeability, complex preparation, high cost, and poor patient compliance. Therefore, the development of small molecule inhibitors is expected to solve the problems of the above-mentioned monoclonal antibodies.
  • small molecule drugs Compared with monoclonal antibodies, small molecule drugs have the following obvious advantages: 1) The administration method is simple and more suitable for oral administration. The half-life of the drug can be adjusted to avoid serious adverse events related to immunotherapy; 2) They have good membrane permeability and can be directly exposed to the tumor microenvironment or cross physiological barriers; 3) They can directly act on intracellular targets that large molecules cannot reach; 4) They are easy to obtain and the choice of dosage form and dosage is more flexible; 5) The production cost is low, no refrigeration is required, and storage and transportation are convenient.
  • the present application provides a PD- Pyridoheterocyclic derivatives with 1/PD-L1 inhibitory activity, preparation methods thereof, and pharmaceutical applications as PD-1/PD-L1 protein-protein interaction inhibitors.
  • the present application discloses a pyrido-heterocyclic derivative or a pharmaceutically acceptable salt thereof as shown in the general formula (I):
  • X 1 and X 2 each represent N or CH;
  • T and V represent and -S-; wherein R 5 represents H, C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl;
  • U represents CH or N
  • n 0, 1, 2 or 3;
  • R1 and R3 each independently represent H, D, halogen, CN, C1 - C3 haloalkyl, C1 - C3 alkyl or cyclopropyl;
  • R 2 represents H, substituted C 1 -C 6 alkyl, substituted C 3 -C 7 cycloalkyl or substituted C 3 -C 7 heterocycloalkyl, the substituent is H, OH, NH 2 , COOH, amide, ester, alkoxy or aldehyde, which may be monosubstituted or polysubstituted, and the heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S;
  • R 4 represents H, halogen, CN, CF 3 , OH, NH 2 , -O(CH 2 ) p R 6 , substituted C 1 -C 6 alkyl, substituted C 3 -C 7 cycloalkyl or substituted C 3 -C 7 heterocycloalkyl, the substituents are H, OH, NH 2 , COOH, amide, ester, alkoxy, which may be monosubstituted or polysubstituted, wherein p represents 1, 2, 3 or 4, and the heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, S;
  • R 6 represents NR 7 R 8 , OR 7 or substituted C 4 -C 6 azacycloalkyl, wherein R 7 represents H or C 1 -C 3 alkyl, R 8 represents substituted C 1 ⁇ C 6 alkyl, the C 4 -C 6 azacycloalkyl is tetrahydropyrrol-1-yl, piperidin-1-ylmorpholine-1-ylpiperazine-1-yl or azetidine-1-yl, the substituent is OH, NH 2 , COOH, amide, ester, alkoxy, and may be monosubstituted or polysubstituted.
  • Ar preferably represents
  • L represents -(CH 2 ) m -, -CH 2 O-, -CF 2 O-, -CONH-, -NHCO- or -OCH 2 -, wherein m represents 0;
  • X1 and X2 each represent N or CH;
  • T and V respectively represent -CH2- , -O-, -NH- or
  • n 0 or 1
  • R 1 and R 3 each independently represent H, D, F, Cl, Br, CN, CH 3 or CF 3 ;
  • R2 represents H, wherein q represents 0 or 1, R 9 and R 10 each represent H, OH, COOH, CH 2 COOH, CH 2 NH 2 , CH 2 OH, CH 2 CH 2 OH, F, Cl, Br, CH 3 , CH 2 CH 3 ;
  • R 11 represents OH, NH 2 , NHCH 3 , CH 3 , OCH 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 ;
  • R 12 represents CONH 2 , NHCOCH 3 , OH, CH 2 OH, CH 2 CH 2 OH, COOH, COOCH 3 , COOCH 2 CH 3 , COOCH(CH 3 ) 2 ;
  • R 13 represents H, CH 3 , CH 2 CH 3 , CH 2 OH, CH 2 CH 2 OH;
  • R 4 represents H, F, Cl, Br, CN, CF 3 , OH, NH 2 or -O(CH 2 ) p R 6 , wherein p represents 2, 3 or 4, and R 6 represents OH, wherein R 9 , R 10 , R 11 , R 12 and R 13 are as defined above, R 14 represents CH 3 , CH 2 CH 3 , CH 2 CH 2 OH, formyl or acetyl, R 15 and R 16 each represent H, OH, COOH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 OH, CH 2 CH 2 OH, CONH 2 , cyclopropyl, COOCH 3 , COOCH 2 CH 3 or COOCH(CH 3 ) 2 , and W represents -CH 2 -, -O-, -NH-, r represents 0 or 1.
  • L represents -CH 2 O- and -NHCO-
  • X1 represents CH or N, X2 represents CH;
  • V represents -CH 2 -
  • n 0 or 1.
  • R 1 and R 3 each independently represent F, Cl, Br, CN, CH 3 or CF 3 .
  • R2 represents: H
  • R4 represents H, F, Cl, CN, CF3 , OH, NH2 or -O( CH2 )3R6 , wherein R6 represents OH, CONH2 , CH2OH , COOH, COOCH3 , COOCH2CH3 or
  • the compound is any one of the following compounds:
  • the pharmaceutically acceptable salt is an acid addition salt formed by the compound of general formula (I) and the following acids: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
  • acids hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
  • the compounds (I) of the present invention are divided into types I-A, I-B, I-C, I-D, I-E and I-F, and their synthesis methods are described as follows:
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • Compound IV is prepared by suzuki reaction of compound II and compound III, wherein the solvent used is selected from toluene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water or a mixed solvent consisting of any two solvents, preferably a mixed solvent of 1,4-dioxane and water; the base used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, potassium bicarbonate, sodium carbonate, potassium carbonate or triethylamine, preferably potassium carbonate; the catalyst used is selected from [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl 2 ), tetrakis(triphenylphosphine
  • Compound V is prepared from compound IV by Sandmeyer reaction, the diazotizing agent used is selected from tert-BuONO, sodium nitrite, preferably sodium nitrite; the catalyst used is selected from dibenzoyl peroxide (BPO), azobisisobutyronitrile (AIBN), concentrated hydrochloric acid or concentrated sulfuric acid, preferably hydrochloric acid; the solvent used is selected from tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water or a mixed solvent composed of any two solvents, preferably a mixed solvent of methanol and water; the reaction temperature is selected from -25 to 80°C, preferably 0 to 25°C.
  • the diazotizing agent used is selected from tert-BuONO, sodium nitrite, preferably sodium nitrite
  • the catalyst used is selected from dibenzoyl peroxide (BPO), azobisisobutyronitrile (AIBN), concentrated hydrochloric acid or concentrated
  • Compound VII is prepared from compound VI, the acid-binding agent used is selected from triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium methoxide, sodium ethoxide or potassium tert-butoxide, preferably sodium hydride; the solvent used is selected from dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, ethyl acetate, DMF or a mixed solvent of any two, preferably tetrahydrofuran or DMF.
  • the acid-binding agent used is selected from triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium methoxide, sodium ethoxide or potassium tert-butoxide, preferably sodium hydride;
  • the solvent used is selected from dichloromethane,
  • Compound IA is prepared by suzuki reaction of compound VII and compound V, the solvent used is selected from toluene, DMF, DMAc, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water or a mixed solvent composed of any two solvents, preferably a mixed solvent of 1,4-dioxane and water; the base used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, potassium bicarbonate, sodium carbonate, potassium carbonate or triethylamine, preferably potassium carbonate; the catalyst used is selected from Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 or Pd 2 (dba) 3 , preferably Pd(PPh 3 ) 4 .
  • the reaction temperature is selected from 50 to 120
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • Compound IX is prepared from compound VIII, the acid-binding agent used is selected from triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium hydride, preferably sodium hydride; the solvent used is selected from dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, ethyl acetate, DMF or a mixed solvent of any two, preferably tetrahydrofuran or DMF.
  • the acid-binding agent used is selected from triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium hydride, preferably sodium hydride
  • the solvent used is selected from dichloromethane,
  • Compound IB is prepared by suzuki reaction of compound IX and compound V, wherein the solvent used is selected from toluene, DMF, DMAc, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water or a mixed solvent consisting of any two solvents, preferably a mixed solvent of 1,4-dioxane and water; the base used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, potassium bicarbonate, sodium carbonate, potassium carbonate or triethylamine, preferably potassium carbonate; the catalyst used is selected from Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 or Pd 2 (dba) 3 , preferably Pd(PPh 3 ) 4 .
  • the solvent used is selected
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • Compound X is reacted with SOCl2 in methanol to prepare XI; the reaction temperature is selected from 50 to 120°C, preferably 60 to 100°C.
  • Compound XII is prepared by reduction of compound XI, the solvent used is selected from tetrahydrofuran, ethanol, DMF or 1,4-dioxane, preferably methanol; the reducing agent is selected from lithium aluminum tetrahydride, sodium borohydride or potassium borohydride, preferably lithium aluminum tetrahydride.
  • Compound XIV is prepared by suzuki reaction of compound XII and compound XIII, the solvent used is selected from toluene, DMF, DMAc, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water or a mixed solvent composed of any two solvents, preferably a mixed solvent of 1,4-dioxane and water; the base used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, potassium bicarbonate, sodium carbonate, potassium carbonate or triethylamine, preferably potassium carbonate; the catalyst used is selected from Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 or Pd 2 (dba) 3 , preferably Pd(PPh 3 ) 4 .
  • the reaction temperature
  • Compound IC is prepared by reacting compound IX with compound XIV, wherein the catalyst used is selected from Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 or Pd 2 (dba) 3 , preferably Pd(OAc) 2 ;
  • the ligand used is selected from triphenylphosphine, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (Xantphos) or 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • Compound XV is prepared by suzuki reaction of compound XII and compound III, the solvent used is selected from toluene, DMF, DMAc, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water or a mixed solvent composed of any two solvents, preferably a mixed solvent of 1,4-dioxane and water; the base used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, potassium bicarbonate, sodium carbonate, potassium carbonate or triethylamine, preferably potassium carbonate; the catalyst used is selected from Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 or NiCl 2 (dppf), preferably Pd(PPh 3 ) 4 .
  • the reaction temperature is selected from 50
  • Compound ID is prepared by reacting compound IX and compound XV, the catalyst used is selected from Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 or Pd 2 (dba) 3 , preferably Pd(OAc) 2 ; the ligand used is selected from t-BuXPhos, X-Phos, Xantphos or Brett-Phos, preferably t-BuXPhos; the base used is selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate or sodium carbonate, preferably cesium carbonate; the solvent used is selected from tetrahydrofuran, 1,4-dioxane, toluene or a mixed solvent of any two of them, preferably toluene.
  • the catalyst used is selected from Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(PPh 3
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • Compound XVII is prepared from compound XVI and iodomethane under alkaline conditions, the solvent used is selected from acetone, DMF, acetonitrile or tetrahydrofuran, or a mixed solvent composed of the above solvents, preferably DMF; the base used is selected from sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide, preferably sodium hydride.
  • the solvent used is selected from acetone, DMF, acetonitrile or tetrahydrofuran, or a mixed solvent composed of the above solvents, preferably DMF
  • the base used is selected from sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide,
  • the target compound XVIII is prepared by reductive amination reaction of compound XVII with an amine compound
  • the solvent used is selected from toluene, DMF, dichloromethane, dichloroethane, chloroform, methanol, 1,4-dioxane, tetrahydrofuran, ethanol, acetonitrile, acetone, or a mixed solvent composed of the above solvents, preferably a mixed solvent of dichloromethane and methanol
  • the reducing agent used is selected from sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride or hydrosulfite, preferably sodium triacetoxyborohydride.
  • the target compound XIX is prepared by reacting compound XVIII under acidic conditions, and the solvent used is selected from ethyl acetate, acetone, dichloromethane, acetonitrile, tetrahydrofuran or a mixed solvent composed of the above solvents, preferably ethyl acetate; the acid used is selected from saturated ethyl acetate hydrogen chloride solution, saturated 1,4-dioxane hydrogen chloride solution, hydrochloric acid, trifluoroacetic acid or trifluoromethanesulfonic acid, preferably saturated ethyl acetate hydrogen chloride solution.
  • the solvent used is selected from ethyl acetate, acetone, dichloromethane, acetonitrile, tetrahydrofuran or a mixed solvent composed of the above solvents, preferably ethyl acetate
  • the acid used is selected from saturated ethyl acetate hydrogen chloride solution, saturated 1,4-d
  • the target compound XX is prepared by reacting compound XIX with paraformaldehyde, and the solvent used is selected from methanol, ethanol, ethyl acetate, acetone, dichloromethane, DMF, acetonitrile, tetrahydrofuran or a mixed solvent composed of the above solvents, preferably methanol; the base used is selected from triethylamine, dimethylaminopyridine (DMAP) or N,N-diisopropylethylamine, preferably triethylamine.
  • DMAP dimethylaminopyridine
  • N,N-diisopropylethylamine preferably triethylamine.
  • Compound IE is prepared by reacting compound XX with compound XV, the catalyst used is selected from Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 or Pd 2 (dba) 3 , preferably Pd(OAc) 2 ; the ligand used is selected from t-BuXPhos, X-Phos, Xantphos or Brett-Phos, preferably t-BuXPhos; the base used is selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate or sodium carbonate, preferably cesium carbonate; the solvent used is selected from tetrahydrofuran, 1,4-dioxane, toluene or a mixed solvent of any two, preferably toluene.
  • the reaction temperature is selected from 50 to 120° C., preferably 60 to 100° C.
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • Compound XXI is prepared from compound VIII and di-tert-butyl dicarbonate under alkaline conditions, the solvent used is selected from acetone, dichloromethane, DMF, acetonitrile, tetrahydrofuran or a mixed solvent composed of the above solvents, preferably tetrahydrofuran; the base used is selected from DMAP, triethylamine, N,N-diisopropylethylamine, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate or lithium hydroxide, preferably triethylamine.
  • the solvent used is selected from acetone, dichloromethane, DMF, acetonitrile, tetrahydrofuran or a mixed solvent composed of the above solvents, preferably tetrahydrofuran
  • Compound XXII is prepared from compound XXI, and the solvent used is selected from acetone, dichloromethane, DMF, Acetonitrile, tetrahydrofuran or a mixed solvent of the above solvents, preferably DMF; the cyanide donor is selected from zinc cyanide, cuprous cyanide or potassium ferrocyanide, preferably zinc cyanide; the catalyst used is selected from Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd 2 (dba) 3 or Pd(OAc) 2 , preferably Pd(PPh 3 ) 4 .
  • the reaction temperature is selected from 50 to 150°C, preferably 80 to 120°C.
  • Compound XXIII is prepared by hydrolysis of compound XXII under alkaline conditions, the solvent used is selected from methanol, ethanol, water, acetonitrile, tetrahydrofuran, acetone, dichloromethane, DMF, acetonitrile or a mixed solvent of the above solvents, preferably a mixed solvent of ethanol and water; the base used is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably potassium hydroxide.
  • the reaction temperature is selected from 0 to 120°C, preferably 60 to 100°C.
  • Compound XXIV is prepared by reacting compound IV and XXIII, the condensing agent used is selected from carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidinophosphine (PyBOP), preferably HATU; the acid binding agent is selected from N,N-diisopropylethylamine or triethylamine, preferably N,N-diisopropylethylamine; the solvent used is selected from acetone, dichloromethane, DMF,
  • the target compound XXV is prepared by reacting compound XXIV under acidic conditions, and the solvent used is selected from ethyl acetate, acetone, dichloromethane, acetonitrile, tetrahydrofuran or a mixed solvent composed of the above solvents, preferably ethyl acetate; the acid used is selected from saturated ethyl acetate hydrogen chloride solution, saturated 1,4-dioxane hydrogen chloride solution, hydrochloric acid, trifluoroacetic acid or trifluoromethanesulfonic acid, preferably saturated ethyl acetate hydrogen chloride solution.
  • the solvent used is selected from ethyl acetate, acetone, dichloromethane, acetonitrile, tetrahydrofuran or a mixed solvent composed of the above solvents, preferably ethyl acetate
  • the acid used is selected from saturated ethyl acetate hydrogen chloride solution, saturated 1,4-d
  • Compound I-F is prepared from compound XXV, wherein the acid-binding agent used is selected from triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate or sodium hydride, preferably sodium hydride; and the solvent used is selected from dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, ethyl acetate, DMF or a mixed solvent of any two thereof, preferably tetrahydrofuran or DMF.
  • the acid-binding agent used is selected from triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate or sodium hydride, preferably sodium hydride
  • the solvent used is selected from dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, ethyl acetate, DMF or
  • the present application also discloses a pharmaceutical composition, which contains the compound of the above general formula (I) (including chiral isomers) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the compound can be added with a pharmaceutically acceptable carrier to prepare common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions, injections, and can be added with common pharmaceutical excipients such as spices, sweeteners, liquid or solid fillers or diluents.
  • the PD-1/PD-L1 protein-protein interaction inhibitors can be used to treat cancer or tumors, for example, to prepare drugs for treating non-small cell lung cancer, colon cancer, melanoma, breast cancer, liver cancer, etc. Cancer drugs.
  • HTRF time-resolved fluorescence experiments
  • novel pyrido-heterocyclic derivatives of the present application can significantly inhibit the interaction between PD-1/PD-L1, and their activity is superior to that of the known PD-1/PD-L1 inhibitor BMS-202.
  • Drugs with it as an active ingredient can be used to treat a variety of cancers or tumors related to the immune checkpoint PD-1/PD-L1.
  • FIG1 shows the body weight growth curve of rats in a continuous administration toxicity test of the compound of the present invention.
  • FIG. 2 shows the animal tumor growth curve of the compound of the present invention in the BALB/c mouse 4T1 subcutaneous transplanted tumor model.
  • the mixture was diluted with ethyl acetate (100 mL), and the insoluble matter was removed by suction filtration.
  • the organic phase was washed with water (50 mL ⁇ 2) and saturated brine (50 mL ⁇ 2), respectively, dried over anhydrous sodium sulfate, and suction filtered.
  • the solvent was removed under reduced pressure to obtain 9.22 g of a white solid powder with a yield of 98.9%. mp103.0 ⁇ 104.0°C.
  • the palladium catalyst and insoluble matter were removed by suction filtration, diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with saturated aqueous NaCl solution (10 mL ⁇ 3), and dried over anhydrous magnesium sulfate.
  • the palladium catalyst and insoluble matter were removed by suction filtration, diluted with 5 mL of water, extracted with ethyl acetate (5 mL ⁇ 3), the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. Suction filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to obtain 0.97 g of white solid powder with a yield of 91.4%. mp78-80°C.
  • HTRF Homogeneous Time-Resolved Fluorescence
  • Tag1 and Tag2 are used to label PD-L1 protein and PD-1 protein, respectively, and Eu + and XL665 bind to PD-L1 and PD-1 through antibodies to form a complex.
  • Eu + is excited by external laser light, which triggers fluorescence resonance energy transfer toward XL665, which in turn emits specifically at 665nm.
  • This specific signal is proportional to the degree of PD1/PD-L1 interaction. Therefore, compounds or antibodies that prevent PD-1/PD-L1 interaction will result in a decrease in HTRF signal.
  • PD-1/PD-L1 binding assay kits were purchased from CISBIO; 96-well plates were purchased from CISBIO.
  • Test instrument Perkin Elmer, model: EnVision.
  • Test compound Compound of formula (I). Dissolve in DMSO and dilute with diluent buffer; DMSO concentration should not exceed 0.5%.
  • Experimental process Use PD-1/PD-L1 binding assay kits. Set up negative group, positive group and drug administration group, with 2 replicates in each group. For the positive control group, add 2 ⁇ L diluent to the 96-well plate; 4 ⁇ L PD-L1 and 4 ⁇ L PD-1 diluted according to the instructions; for the negative control group, add 6 ⁇ L diluent and 4 ⁇ L PD-L1 to the 96-well plate; for the drug administration group, add 2 ⁇ L of the test (I) compound (or positive compound BMS-202), 4 ⁇ L PD-L1 and 4 ⁇ L PD-1 to the 96-well plate in sequence.
  • test (I) compound or positive compound BMS-202
  • Values represent IC50 of ⁇ 0.07 ⁇ M; A represents 0.07-1 ⁇ M; C represents >1 ⁇ M.
  • the experimental results show that the compounds of the present application have significant inhibitory activity on PD-1/PD-L1 protein-protein interactions, among which compounds I-A-9, I-B-2, I-D-13, I-D-14, I-D-18, I-D-19, I-D-21, I-D-22, I-D-26, I-D-27, I-D-28, I-D-30 and I-E-4 have better inhibitory activity than compound BMS-202 in document WO2015034820.
  • This shows that the biphenyl compounds of the present application can be used as immune checkpoint PD-1/PD-L1 inhibitors.
  • Test samples Compound I-D-18, Compound I-D-26, Compound I-D-27.
  • Animal grouping and dosage vehicle blank group, compound I-D-18 group (500 mg/kg, 1000 mg/kg, 2000 mg/kg), compound I-D-26 (500 mg/kg, 1000 mg/kg, 2000 mg/kg), compound I-D-27 (500 mg/kg, 1000 mg/kg, 2000 mg/kg);
  • Dosing frequency Administer once.
  • Test samples Compound I-D-18, Compound I-D-26, Compound I-D-27.
  • Animal grouping and dosing vehicle blank group, compound I-D-18 group (300 mg/kg), compound I-D-26 (300 mg/kg), compound I-D-27 (300 mg/kg);
  • Dosing frequency once a day for 14 days.
  • the animal body weight growth curve during the drug administration period is shown in Figure 1.
  • Example 50 Study on the pharmacodynamic effect on breast cancer tumor cell 4T1 xenograft tumor model
  • Test samples Compound I-D-24, Compound I-D-26, Compound I-D-27
  • Compound ID-18 (10 mg/kg, ig, QD ⁇ 21 days);
  • Compound I-D-26 (10 mg/kg, i.g., QD ⁇ 21 days);
  • Compound I-D-27 (10 mg/kg, i.g., QD ⁇ 21 days);
  • Dosing frequency once a day
  • V 1/2 ⁇ major diameter ⁇ minor diameter2 (mm 3 ).
  • the animal tumor growth curve of the compound of the present invention in the BALB/c mouse 4T1 subcutaneous transplanted tumor model is shown in FIG2 .
  • Preparation of adhesive solution Weigh purified water, slowly add an appropriate amount of starch while stirring, and stir and disperse evenly to prepare an adhesive - starch slurry.
  • Preparation of soft material Use a wet mixing granulator, control the stirring speed and shearing speed, slowly add starch slurry, stir, shear, and obtain the soft material.
  • Granulation The prepared soft material is granulated using a swing granulator with a 24-mesh screen to obtain wet granules.
  • Drying Add the wet granules into a fluid bed granulator to obtain dry granules.
  • Granulation The dry granules are sieved and granulated using an oscillating granulator, and the granules obtained after granulation are weighed.
  • Filling Use a filling machine to fill the total mixed granules into empty gelatin capsules, screen out qualified capsules, and obtain capsules to be packaged.

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Abstract

本发明涉及药物化学领域，公开了一类具有PD-1/PD-L1抑制活性的吡啶并杂环衍生物及其制备方法和用途。本发明还公开了含有所述具有PD-1/PD-L1抑制活性的吡啶并杂环衍生物或其药学上可接受的盐及药学上可接受的载体的组合物、及其在制备PD-1/PD-L1抑制剂中的应用。本发明的化合物可用于治疗肿瘤。

Description

新型双环类PD-L1抑制剂及其制备方法与医药用途 技术领域
本申请属于药物化学领域，具体涉及一类具有PD-1/PD-L1抑制活性的联苯类衍生物，它们的制备方法，以及含有这些化合物的药物组合物及其在治疗肿瘤中的用途。
技术背景
近几年来肿瘤免疫疗法已成为肿瘤治疗领域的焦点，与直接针对肿瘤细胞的传统治疗手段不同，肿瘤免疫疗法是利用人体自身免疫系统对肿瘤细胞进行杀伤。免疫检查点通路的活化会抑制T细胞的激活，防止人体免疫系统的过度激活，维持正常机体的免疫耐受，避免自身免疫疾病的发生。肿瘤通过使自身和一些淋巴细胞过度激活免疫检查点通路导致肿瘤免疫逃逸的发生。在这些免疫检查点当中，PD-1/PD-L1的过度激活对于肿瘤的发展起着至关重要的作用。阻断PD-1/PD-L1相互作用可以重新激活免疫系统，杀死肿瘤细胞，在临床黑色素瘤、结肠癌、非小细胞肺癌等肿瘤治疗中展示出较好的疗效(Clinical and Translational Oncology,2019,21:702-712；Lung Cancer:Targets and Therapy,2017:8；Hum VaccinImmunother,2014,10(11):3111-3116；Journal of Medicinal Chemistry,2020,63(22):13825-13850)。
迄今为止，多个PD-1/PD-L1靶向mAbs已获得FDA批准用于肿瘤免疫治疗，数百个mAbs目前正在积极开展临床试验。尽管这些单克隆抗体改善了很多癌症患者的预后，但是由于固有耐药和获得性耐药的产生，仅有少部分患者能够有持久的响应。单抗的使用还会带来严重的免疫相关不良事件(immune-relatedadverseevents,irAEs)，常见的毒副作用包括皮肤炎症、结肠炎、肝炎、甲状腺功能减退和下垂体炎等。除此之外，大分子药物还存在组织渗透性差、制备复杂、费用昂贵、病人依从性差等缺点。因此，开发小分子抑制剂有望解决上述单克隆抗体存在的问题。
与单克隆抗体相比，小分子药物具有以下明显优势：1)给药方式简单，更适合口服给药，可调整药物半衰期，避免严重的免疫治疗相关不良事件；2)具有良好的膜渗透性，能直接暴露于肿瘤微环境中或跨越生理屏障；3)能直接作用于大分子无法到达的细胞内靶标；4)易于获得且剂型和剂量的选择更加灵活；5)生产成本较低，毋须冷藏，储存运输方便。
目前还没有PD-1/PD-L1小分子抑制剂上市，因而开发阻断PD-1/PD-L1蛋白-蛋白相互作用的抑制剂具有重大的现实意义和潜在的应用前景。
发明内容
发明目的：针对上述现有技术中存在的技术问题，本申请提供了具有PD- 1/PD-L1抑制活性的吡啶并杂环衍生物，其制备方法以及作为PD-1/PD-L1蛋白-蛋白相互作用抑制剂的制药应用。
技术方案：本申请公开了一种如通式(I)所示的吡啶并杂环衍生物或其药学上可接受的盐：
其中：
Ar代表
L代表-(CH2)m-、-O-、-NH-、-CH2O-、-CF2O-、-CH2NH-、-CONH-、-HNCO-、-NHCH2-、-OCF2-、-OCH2-或-CH＝CH-，其中m代表0、1或2；
X1、X2各自代表N或CH；
T、V各自分别代表和-S-；其中R5代表H、C1-C6的烷基或C3-C7的环烷基；
U代表CH或N；
n代表0、1、2或3；
R1和R3各自分别代表H、D、卤素、CN、C1-C3的卤代烷基、C1-C3的烷基或环丙基；
R2代表H、取代的C1-C6烷基、取代的C3-C7环烷基或取代的C3-C7杂环烷基，所述的取代基为H、OH、NH2、COOH、酰胺基、酯基、烷氧基或醛基，可以是单取代或多取代，所述杂环烷基包含1～3个选自N、O、S的杂原子；
R4代表H、卤素、CN、CF3、OH、NH2、-O(CH2)pR6、取代的C1-C6烷基、取代的C3-C7环烷基或取代的C3-C7杂环烷基，所述的取代基为H、OH、NH2、COOH、酰胺基、酯基、烷氧基，可以是单取代或多取代，其中p代表1、2、3或4，所述杂环烷基包含1～3个选自N、O、S的杂原子；
R6代表NR7R8、OR7或取代的C4-C6的氮杂环烷基，其中R7代表H或C1-C3烷基，R8代表取代的C1～C6烷基，所述C4-C6氮杂环烷基为四氢吡咯-1-基、哌啶-1-基吗啉-1-基哌嗪-1-基或氮杂环丁烷-1-基，所述的取代基为OH、NH2、COOH、酰胺基、酯基、烷氧基，可以是单取代或多取代。
其中：
Ar优选代表
L代表-(CH2)m-、-CH2O-、-CF2O-、-CONH-、-NHCO-或-OCH2-，其中m代表0；
X1和X2各自代表N或CH；
T、V各自代表-CH2-、-O-、-NH-或
U代表N；
n代表0或1；
R1和R3各自分别代表H、D、F、Cl、Br、CN、CH3或CF3；
R2代表H、其中q代表0或1，R9和R10各自分别代表H、OH、COOH、CH2COOH、CH2NH2、CH2OH、CH2CH2OH、F、Cl、Br、CH3、CH2CH3；
R11代表OH、NH2、NHCH3、CH3、OCH3、OCH2CH3、OCH(CH3)2；；
R12代表CONH2、NHCOCH3、OH、CH2OH、CH2CH2OH、COOH、COOCH3、COOCH2CH3、COOCH(CH3)2；
R13代表H、CH3、CH2CH3、CH2OH、CH2CH2OH；
R4代表H、F、Cl、Br、CN、CF3、OH、NH2或-O(CH2)pR6，其中p代表2、3或4，R6代表OH、其中R9、R10、R11、R12和R13的定义同前，R14代表CH3、CH2CH3、CH2CH2OH、甲酰基或乙酰基，R15和R16各自分别代表H、OH、COOH、NH2、CH3、CH2CH3、CH2OH、CH2CH2OH、CONH2、环丙基、COOCH3、COOCH2CH3或COOCH(CH3)2，W代表-CH2-、-O-、-NH-、r代表0或1。
其中更优选：
Ar代表
L代表-CH2O-和-NHCO-；
X1代表CH或N，X2代表CH；
T代或-CH2-；
U代表N；
V代表-CH2-；
n＝0或1。
R1和R3各自分别代表F、Cl、Br、CN、CH3或CF3。
R2代表：H、
R4代表H、F、Cl、CN、CF3、OH、NH2或-O(CH2)3R6，其中R6代表OH、CONH2、CH2OH、COOH、COOCH3、COOCH2CH3或
更优选地，所述化合物为以下任一化合物：










所述药学上可接受的盐为通式(I)化合物与下列酸形成的酸加成盐：氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
含吡啶并杂环的化合物或其药学上可接受的盐在制备用于治疗肿瘤PD-L1抑制剂药物中的用途。
本发明化合物(I)分为I-A、I-B、I-C、I-D、I-E和I-F等类型，它们的合成方法分别叙述如下：
当Ar代表X1和X2各自代表CH，L代表-(CH2)m-，m＝0，T代表C＝O，U代表N，V代表CH2，n＝0，式I-A的合成路线为：
其中R1、R2、R3和R4的定义同前。
由化合物II与化合物III经suzuki反应制备化合物IV，所用溶剂选自甲苯、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMAc)、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、甲醇、乙醇、乙腈、丙酮、水或任意两种溶剂组成的混合溶剂，优选1,4-二氧六环和水的混合溶剂；所用碱选自乙醇钠、乙酸钠、乙酸钾、磷酸钾、碳酸氢钾、碳酸钠、碳酸钾或三乙胺，优选碳酸钾；所用催化剂选自[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl2)、四(三苯基膦)钯(Pd(PPh3)4)、双(三苯基磷)二氯化钯(Pd(PPh3)2Cl2)、三(二亚苄基茚丙酮)二钯(Pd2(dba)3)或醋酸钯(Pd(OAc)2)，优选Pd(PPh3)4。反应温度选自50至120℃，优选60～100℃。
由化合物IV经桑德迈尔反应制备化合物V，所用重氮化试剂选自亚硝酸叔定(t-BuONO)，亚硝酸钠，优选亚硝酸钠；所用催化剂选自过氧化二苯甲酰(BPO)、偶氮二异丁腈(AIBN)、浓盐酸或浓硫酸，优选盐酸；所用溶剂选自四氢呋喃、甲醇、乙醇、乙腈、丙酮、水或任意两种溶剂组成的混合溶剂，优选甲醇和水的混合溶剂；反应温度选自-25至80℃，优选0～25℃。
由化合物VI制备化合物VII，所用缚酸剂选自三乙胺、N,N-二异丙基乙胺、碳酸钠、碳酸钾、碳酸铯、氢化钠、甲醇钠、乙醇钠或叔丁醇钾，优选氢化钠；所用溶剂选自二氯甲烷、四氢呋喃、1,4-二氧六环、丙酮、乙酸乙酯、DMF或任意两者组成的混合溶剂，优选四氢呋喃或DMF。
由化合物VII与化合物V经suzuki反应制备化合物I-A，所用溶剂选自甲苯、DMF、DMAc、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、甲醇、乙醇、乙腈、丙酮、水或任意两种溶剂组成的混合溶剂，优选1,4-二氧六环和水的混合溶剂；所用碱选自乙醇钠、乙酸钠、乙酸钾、磷酸钾、碳酸氢钾、碳酸钠、碳酸钾或三乙胺，优选碳酸钾；所用催化剂选自Pd(PPh3)4、Pd(dppf)Cl2、Pd(PPh3)2Cl2、Pd(OAc)2或Pd2(dba)3，优选Pd(PPh3)4。反应温度选自50至120℃，优选60～100℃。
当Ar代表X1代表N，X2代表CH，L代表-(CH2)m-，m＝0，T代表CH2，U代表N，V代表CH2，n＝1，式I-B的合成路线为：
其中R1、R2、R3和R4的定义同前。
由化合物VIII制备化合物IX，所用缚酸剂选自三乙胺、N,N-二异丙基乙胺、碳酸钠、碳酸钾、碳酸铯、甲醇钠、乙醇钠、叔丁醇钾或氢化钠，优选氢化钠；所用溶剂选自二氯甲烷、四氢呋喃、1,4-二氧六环、丙酮、乙酸乙酯、DMF或任意两者组成的混合溶剂，优选四氢呋喃或DMF。
由化合物IX与化合物V经suzuki反应制备化合物I-B，所用溶剂选自甲苯、DMF、DMAc、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、甲醇、乙醇、乙腈、丙酮、水或任意两种溶剂组成的混合溶剂，优选1,4-二氧六环和水的混合溶剂；所用碱选自乙醇钠、乙酸钠、乙酸钾、磷酸钾、碳酸氢钾、碳酸钠、碳酸钾或三乙胺，优选碳酸钾；所用催化剂选自Pd(PPh3)4、Pd(dppf)Cl2、Pd(PPh3)2Cl2、Pd(OAc)2或Pd2(dba)3，优选Pd(PPh3)4。
当Ar代表X1代表N，X2代表CH，L代表-(CH2)m-，m＝0，T为CH2，U代表N，V代表CH2，n＝1，式I-C的合成路线为：

其中R1、R2、R3和R4的定义同前。
化合物X与SOCl2在甲醇中反应制备XI；反应温度选自50至120℃，优选60～100℃。
由化合物XI经还原制备化合物XII，所用溶剂选自四氢呋喃、乙醇、DMF或1,4-二氧六环，优选甲醇；所选还原剂选自四氢锂铝、硼氢化钠或硼氢化钾，优选四氢锂铝。
由化合物XII与化合物XIII经suzuki反应制备化合物XIV，所用溶剂选自甲苯、DMF、DMAc、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、甲醇、乙醇、乙腈、丙酮、水或任意两种溶剂组成的混合溶剂，优选1,4-二氧六环和水的混合溶剂；所用碱选自乙醇钠、乙酸钠、乙酸钾、磷酸钾、碳酸氢钾、碳酸钠、碳酸钾或三乙胺，优选碳酸钾；所用催化剂选自Pd(PPh3)4、Pd(dppf)Cl2、Pd(PPh3)2Cl2、Pd(OAc)2或Pd2(dba)3，优选Pd(PPh3)4。反应温度选自50至120℃，优选60～100℃。
由化合物IX和化合物XIV反应制备化合物I-C，所用催化剂选自Pd(PPh3)4、Pd(dppf)Cl2、Pd(PPh3)2Cl2、Pd(OAc)2或Pd2(dba)3，优选Pd(OAc)2；所用配体选自三苯基膦、2-二-叔丁膦基-2',4',6'-三异丙基联苯(t-BuXPhos)、2-二环己基膦-2',4',6'-三异丙基联苯(X-Phos)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)或2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三-I-丙基-11'-联苯(Brett-Phos)，优选t-BuXPhos；所用碱选自氢氧化钠、氢氧化钾、碳酸铯、碳酸钾或碳酸钠，优选碳酸铯；所用溶剂选自四氢呋喃、1,4-二氧六环、甲苯或任意两者组成的混合溶剂，优选甲苯。反应温度选自50至120℃，优选60～100℃。
当Ar代表X1代表N，X2代表CH，L代表-CH2O-，T为CH2，U代表N，V代表CH2，n＝1，式I-D的合成路线为：
其中R1、R2、R3和R4的定义同前。
由化合物XII与化合物III经suzuki反应制备化合物XV，所用溶剂选自甲苯、DMF、DMAc、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、甲醇、乙醇、乙腈、丙酮、水或任意两种溶剂组成的混合溶剂，优选1,4-二氧六环和水的混合溶剂；所用碱选自乙醇钠、乙酸钠、乙酸钾、磷酸钾、碳酸氢钾、碳酸钠、碳酸钾或三乙胺，优选碳酸钾；所用催化剂选自Pd(PPh3)4、Pd(dppf)Cl2、Pd(PPh3)2Cl2、Pd(OAc)2或NiCl2(dppf)，优选Pd(PPh3)4。反应温度选自50至120℃，优选60～100℃。
由化合物IX和化合物XV反应制备化合物I-D，所用催化剂选自Pd(PPh3)4、Pd(dppf)Cl2、Pd(PPh3)2Cl2、Pd(OAc)2或Pd2(dba)3,优选Pd(OAc)2；所用配体选自t-BuXPhos、X-Phos、Xantphos或Brett-Phos，优选t-BuXPhos；所用碱选自氢氧化钠、氢氧化钾、碳酸铯、碳酸钾或碳酸钠，优选碳酸铯；所用溶剂选自四氢呋喃、1,4-二氧六环、甲苯或任意两者组成的混合溶剂，优选甲苯。
当Ar代表X1代表N，X2代表CH，L代表-CH2O-，T代表CH2，U代表N，V代表NCH3，n＝1，式I-E的合成路线为：
其中R1、R2、R3和R4的定义同前。
由化合物XVI与碘甲烷在碱性条件下制备化合物XVII，所用溶剂选自丙酮、DMF、乙腈或四氢呋喃、或上述溶剂组成的混合溶剂，优选DMF；所用碱选自氢化钠、甲醇钠、乙醇钠、叔丁醇钾、碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、或氢氧化锂，优选氢化钠。
由化合物XVII与胺类化合物发生还原胺化反应制备目标化合物XVIII，所用溶剂选自甲苯、DMF、二氯甲烷、二氯乙烷、三氯甲烷、甲醇、1,4-二氧六环、四氢呋喃、乙醇、乙腈、丙酮、或上述溶剂组成的混合溶剂，优选二氯甲烷和甲醇的混合溶剂；所用还原剂选自三乙酰氧基硼氢化钠、氰基硼氢化钠、硼氢化钠或保险粉，优选三乙酰氧基硼氢化钠。
由化合物XVIII在酸性条件下反应制备目标化合物XIX，所用溶剂选自乙酸乙酯、丙酮、二氯甲烷、乙腈、四氢呋喃或上述溶剂组成的混合溶剂，优选乙酸乙酯；所用酸选自饱和的乙酸乙酯的氯化氢溶液、饱和的1,4-二氧六环的氯化氢溶液、盐酸、三氟乙酸或三氟甲磺酸，优选饱和的乙酸乙酯的氯化氢溶液。
由化合物XIX与多聚甲醛反应制备目标化合物XX，所用溶剂选自甲醇、乙醇、乙酸乙酯、丙酮、二氯甲烷、DMF、乙腈、四氢呋喃或上述溶剂组成的混合溶剂，优选甲醇；所用碱选自三乙胺、二甲氨基吡啶(DMAP)或N,N-二异丙基乙胺，优选三乙胺。
由化合物XX和化合物XV反应制备化合物I-E，所用催化剂选自Pd(PPh3)4、Pd(dppf)Cl2、Pd(PPh3)2Cl2、Pd(OAc)2或Pd2(dba)3,优选Pd(OAc)2；所用配体选自t-BuXPhos、X-Phos、Xantphos或Brett-Phos，优选t-BuXPhos；所用碱选自氢氧化钠、氢氧化钾、碳酸铯、碳酸钾或碳酸钠，优选碳酸铯；所用溶剂选自四氢呋喃、1,4-二氧六环、甲苯或任意两者组成的混合溶剂，优选甲苯。反应温度选自50至120℃，优选60～100℃。
当Ar代表X1代表N，X2代表CH，L代表-NHCO-，T代表CH2，U代表N，V代表CH2，n＝1，式I-F的合成路线为：
其中R1、R2、R3和R4的定义同前。
由化合物VIII与二碳酸二叔丁酯在碱性条件下制备化合物XXI，所用溶剂选自丙酮、二氯甲烷、DMF、乙腈、四氢呋喃或上述溶剂组成的混合溶剂，优选四氢呋喃；所用碱选自DMAP、三乙胺、、N,N-二异丙基乙胺、叔丁醇钾、氢化钠、甲醇钠、乙醇钠、碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾或氢氧化锂，优选三乙胺。
由化合物XXI制备化合物XXII，所用溶剂选自丙酮、二氯甲烷、DMF、 乙腈、四氢呋喃或上述溶剂组成的混合溶剂，优选DMF；氰基供体选自氰化锌、氰化亚铜或亚铁氰化钾，优选氰化锌；所用催化剂选自Pd(dppf)Cl2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd2(dba)3或Pd(OAc)2，优选Pd(PPh3)4。反应温度选自50至150℃，优选80～120℃。
由化合物XXII在碱性条件下经水解反应制备化合物XXIII，所用溶剂选自甲醇、乙醇、水、乙腈、四氢呋喃、丙酮、二氯甲烷、DMF、乙腈或上述溶剂组成的混合溶剂，优选乙醇与水的混合溶剂；所用碱选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾或氢氧化锂，优选氢氧化钾。反应温度选自0至120℃，优选60～100℃。
由化合物IV和XXIII反应制备化合物XXIV，所用缩合剂选自羰基二咪唑(CDI)、二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(PyBOP)，优选HATU；缚酸剂选自N,N-二异丙基乙胺或三乙胺，优选N,N-二异丙基乙胺；所用溶剂选自丙酮、二氯甲烷、DMF、乙腈、四氢呋喃或上述溶剂组成的混合溶剂，优选DMF；反应温度选自0至80℃，优选25～50℃。
由化合物XXIV在酸性条件下反应制备目标化合物XXV，所用溶剂选自乙酸乙酯、丙酮、二氯甲烷、乙腈、四氢呋喃或上述溶剂组成的混合溶剂，优选乙酸乙酯；所用酸选自饱和的乙酸乙酯的氯化氢溶液、饱和的1,4-二氧六环的氯化氢溶液、盐酸、三氟乙酸或三氟甲磺酸，优选饱和的乙酸乙酯的氯化氢溶液。
由化合物XXV制备化合物I-F，所用缚酸剂选自三乙胺、N,N-二异丙基乙胺、碳酸钠、碳酸钾、碳酸铯或氢化钠，优选氢化钠；所用溶剂选自二氯甲烷、四氢呋喃、1,4-二氧六环、丙酮、乙酸乙酯、DMF或任意两者组成的混合溶剂，优选四氢呋喃或DMF。
本申请还公开了一种药物组合物，其含有上述通式(I)化合物(包括手性异构体)或其药学上可接受的盐及药学上可接受的载体。所述的化合物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂、注射剂，可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本申请所述的通式(I)化合物及其水合物、溶剂合物或结晶在制备PD-1/PD-L1蛋白-蛋白相互作用抑制剂药物中的应用也在本申请的保护范围内。
进一步地，其中的PD-1/PD-L1蛋白-蛋白相互作用抑制剂可用于治疗癌症或肿瘤，例如，制备治疗非小细胞肺癌、结肠癌、黑色素瘤、乳腺癌、肝癌等 癌症的药物。
药理实验显示，在均相时间分辨荧光实验(HTRF)中，本申请的吡啶并杂环类衍生物可以对PD-1/PD-L1的相互作用产生良好的抑制作用。本申请的吡啶并杂环衍生物活性优异，因而开发PD-1/PD-L1的联苯类抑制剂具有重大的现实意义和潜在的应用前景。
有益效果：与现有技术相比，本申请具有如下显著优点：
(1)本申请的新型吡啶并杂环类衍生物可以显著抑制PD-1/PD-L1的相互作用，且活性优于已知PD-1/PD-L1抑制剂BMS-202。
(2)本申请的吡啶并杂环类衍生物的合成路线设计巧妙、简便易行，原料便宜易得，合成工艺安全、环保，易于规模化生产。
(3)适用性广，其作为活性成分的药物可用于治疗与免疫检查点PD-1/PD-L1相关的多种癌症或肿瘤。
附图说明
图1显示了本发明化合物在连续给药毒性试验中大鼠体重生长曲线。
图2显示了本发明化合物在BALB/c小鼠4T1皮下移植瘤模型中动物肿瘤生长曲线图。
具体实施方式
实施例1
2-(5-(2'-氟-2-甲基-[1,1'-联苯]-3-基)-1-氧代异吲哚啉-2-基)乙酸乙酯(I-A-1：R1＝CH3,R3＝F,R4＝H,T代表C＝O)的合成
2'-氟-2-甲基-[1,1'-联苯]-3-胺(IV-1)的合成
将3-溴-2-甲基苯胺II-1(2.50g,13.44mmol)、2-氟苯硼酸III-1(2.26g,16.15mmol)和1,4-二氧六环(25mL)依次加入三颈瓶中，将碳酸钾(5.21g,37.69mmol)溶于水(2.5mL)加入反应液中，加入Pd(PPh3)4(0.39g,0.34mmol)，氮气保护，升温至80℃反应10小时。TLC监测原料反应完全，停止加热，冷至室温。抽滤除去钯催化剂和不溶物，加水(25mL)稀释，乙酸乙酯(25mL×3)萃取，合并有机相，用饱和NaCl水溶液(25mL×3)洗涤，无水硫酸镁干燥。抽滤，减压蒸除溶剂，残留物经柱层析纯化(石油醚:乙酸乙酯＝20:1～15:1)得黄色固体粉末2.59g，收率95.6％。m.p.61.0-62.0℃.
1H NMR(300MHz,DMSO-d6)δ7.48-7.35(m,1H,ArH),7.34-7.22(m,3H,ArH),6.98(t,J＝7.7Hz,1H,ArH),6.70(dd,J＝8.0Hz,1.4Hz,1H,ArH),6.42(dd,J＝7.5Hz,1.3Hz,1H,ArH),5.00(s,2H,NH2),1.85(s,3H,CH3).
2-(2'-氟-2-甲基-[1,1'-联苯]-3-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(V-1)的合成
将化合物IV-1(2.00g,9.94mmol)溶于甲醇(20mL)和水(10mL)中，缓慢滴入盐酸(9.92mL,3mmol/mL)溶液，25℃搅拌至反应液澄清后，降温至0℃，缓慢滴加NaNO2(4.96mL,2.2mmol/mL)水溶液。滴毕，在0℃下继续搅拌30分钟后，将联硼酸频哪醇脂(7.56g,29.85mmol)溶于甲醇(20mL)中缓慢滴加至反应液中，有大量气体生成，滴毕移至室温继续搅拌2小时。TLC(石油醚:乙酸乙酯＝30:1)监测原料反应完全，用二氯甲烷(20mL×2)萃取，合并有机相，用饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥。抽滤，减压蒸除溶剂，残留物经柱层析(石油醚～石油醚:乙酸乙酯＝200:1)得黄色固体粉末1.88g，收率60.4％。m.p.94.0-95.0℃.
1H NMR(300MHz,DMSO-d6)δ7.70(dd,J＝5.4Hz,3.7Hz,1H,ArH),7.53-7.36(m,1H,ArH),7.34-7.25(m,5H,ArH),2.27(s,3H,ArCH3),1.31(s,12H,CH3).5-(2'-氟-2-甲基-[1,1'-联苯]-3-基)异吲哚-1-酮(VII)的合成
将化合物V(0.50g,2.36mmol)、VI(0.74g,2.48mmol)和1,4-二氧六环(10mL)依次加入三颈瓶中，将碳酸钾(0.92g,6.60mmol)溶于水(1.0mL)后加入反应液中，氮气保护，加入Pd(PPh3)4(0.27g,0.25mmol)。反应液升温至80℃反应12小时。TLC(石油醚:乙酸乙酯＝4:1)监测原料反应完全，停止加热，冷至室温。抽滤除去钯催化剂和不溶物，加水(10mL)稀释，用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和NaCl水溶液(10mL×3)洗涤，无水硫酸镁干燥。抽滤，减压蒸除溶剂，残留物经柱层析纯化(石油醚:乙酸乙酯＝15:1～3:1)得白色固体粉末0.40g，收率50.9％。m.p.190-192℃.
1H NMR(300MHz,DMSO-d6)δ8.63(s,1H,ArH),7.76(d,J＝7.8Hz,1H,ArH),7.60(s,1H,ArH),7.49(d,J＝7.6Hz,2H,ArH),7.44-7.26(m,6H,ArH),4.46(s,2H,CH2),2.01(s,3H,CH3).
2-(5-(2'-氟-2-甲基-[1,1'-联苯]-3-基)-1-氧代异吲哚啉-2-基)乙酸乙酯(I-A-1)的合成
向25mL茄形瓶中加入化合物VII(0.50g,1.58mmol)，用THF溶解，0℃下加入NaH(0.12g,3.16mmol)，向该混合物滴加溴乙酸乙酯(0.32g,1.89mmol)，室温反应，监测原料反应完全，加饱和氯化铵溶液淬灭反应，EA-(10mL×3)萃取，饱和食盐水(10mL×3)洗，无水硫酸钠干燥，经柱层析分离纯化得白色固体0.63g，收率98.7％。m.p.100-101℃.
1H NMR(300MHz,DMSO-d6)δ7.81(d,J＝7.8Hz,1H,ArH),7.67-7.62(m,1H,ArH),7.57-7.47(m,2H,ArH),7.43-7.30(m,6H,ArH),4.61(s,2H,NCH2),4.44(s,2H,NCH2),4.19(q,J＝7.1Hz,2H,CH 2CH3),2.03(s,3H,CH3),1.25(t,J＝7.1Hz,3H,ArCH3).
实施例2
3-(5-(2'-氟-2-甲基-[1,1'-联苯]-3-基)-1-氧代异吲哚啉-2-基)丙酸乙酯(I-A-2：
R1＝CH3,R3＝F,R4＝H,T代表C＝O)的合成
以化合物VII(0.50g,1.58mmol)和3-溴丙酸乙酯(0.34g,1.89mmol)为原料，操作同化合物I-A-1，得无色粘稠状液体0.40g，收率60.6％。
1H NMR(300MHz,DMSO-d6)δ7.77(d,J＝7.7Hz,1H,ArH),7.67-7.62(m,1H,ArH),7.54-7.46(m,2H,ArH),7.45-7.26(m,6H,ArH),4.58(s,2H,NCH2),4.10(q,J＝7.1Hz,2H,CH 2CH3),3.82(t,J＝7.0Hz,2H,NCH2 CH2),2.73(t,J＝7.0Hz,2H,COCH2),2.01(s,3H,ArCH3),1.19(t,J＝7.1Hz,3H,CH2CH 3).
实施例3
2-(5-(2'-氟-2-甲基-[1,1'-联苯]-3-基)-1-氧代异吲哚啉-2-基)丙酸乙酯(I-A-3：R1＝CH3,R3＝F,R4＝H,T代表C＝O)的合成
以化合物VII(0.50g,1.58mmol)和2-溴丙酸乙酯(0.34g,1.89mmol)为原料，操作同化合物I-A-1，得白色固体0.58g，收率88.3％。m.p.50-52℃.
1H NMR(300MHz,DMSO-d6)δ7.80(d,J＝7.8Hz,1H,ArH),7.68-7.63(m,1H,ArH),7.56-7.45(m,2H,ArH),7.34-7.21(m,6H,ArH),4.97(q,J＝7.3Hz,1H,CH3CH),4.62(d,J＝7.0Hz,2H,NCH2),4.16(q,J＝7.1Hz,2H,CH2 CH3),2.02(s,3H,ArCH3),1.56(d,J＝7.4Hz,3H,CHCH 3),1.22(t,J＝7.0Hz,3H,CH2CH 3).
实施例4
2-(5-(2'-氟-2-甲基-[1,1'-联苯]-3-基)-1-氧代异吲哚啉-2-基)乙酸(I-A-4：R1＝CH3,R3＝F,R4＝H,T代表C＝O)的合成
向10mL茄型瓶中加入化合物I-A-1(30mg,0.16mmol)，加入甲醇(2mL)溶解，加入LiOH(8mg,0.20mmol)的水(0.5mL)溶液，室温搅拌4小时。TLC监测反应完全后，减压蒸除甲醇，用2M HCl溶液调节pH到5-6，有白色固体析出，抽滤，得灰白色固体产物20mg，收率72.1％。m.p.164-166℃.
1H NMR(400MHz,DMSO-d6)δ12.95(s,1H,OH),7.82-7.74(m,1H,ArH),7.66-7.58(m,1H,ArH),7.53-7.43(m,2H,ArH),7.41-7.23(m,6H,ArH),4.58(s,2H,NCH2),4.32(s,2H,NCH2),2.00(s,3H,CH3).
HRMS(ESI):m/z[M+H]+Calcd forC23H19FNO3:376.1349；Found:376.1350.
实施例5
3-(5-(2'-氟-2-甲基-[1,1'-联苯]-3-基)-1-氧代异吲哚啉-2-基)丙酸(I-A-5：R1＝CH3,R3＝F,R4＝H,T代表C＝O)的合成
以化合物I-A-2(50mg,0.12mmol)和LiOH(10mg,0.24mmol)的水(0.5mL)溶液为原料，操作同化合物I-A-4，得黄色固体产物40mg，收率92.2％。m.p.56-58℃.
1H NMR(300MHz,DMSO-d6)δ7.77(d,J＝7.8Hz,1H,ArH),7.63(s,1H,ArH),7.50(d,J＝7.7Hz,2H,ArH),7.44-7.28(m,6H,ArH),4.58(s,2H,NCH 2),3.78(t,J＝6.9Hz,2H,NCH 2CH2),2.65(t,J＝7.0Hz,2H,COCH 2),2.01(s,3H,CH3).
HRMS(ESI):m/z[M+H]+Calcd for C24H21FNO3:390.1505；Found:390.1503.
实施例6
2-(5-(2'-氟-2-甲基-[1,1'-联苯]-3-基)-1-氧代异吲哚啉-2-基)丙酸(I-A-6：R1＝CH3,R3＝F,R4＝H,T代表C＝O)的合成
以化合物I-A-3(50mg,0.12mmol)和LiOH(10mg,0.24mmol)的水(0.5mL)溶液为原料，操作同化合物I-A-4，得白色固体产物30mg，收率64.2％。m.p.140-142℃.
1H NMR(300MHz,DMSO-d6)δ7.78(d,J＝7.8Hz,1H,ArH),7.65(s,1H,ArH),7.54-7.46(m,2H,ArH),7.42-7.29(m,6H,ArH),4.92-4.78(m,1H,CHCH3),4.72-4.52(m,2H,CH2),2.02(s,3H,ArCH3),1.51(d,J＝7.3Hz,3H,CH3).
HRMS(ESI):m/z[M+H]+Calcd for C24H21FNO3:390.1505；Found:390.1502.
实施例7
5-(2'-氟-2-甲基-[1,1'-联苯]-3-基)-2-(2-羟乙基)异吲哚-1-酮(I-A-7：R1＝CH3,R3＝F,R4＝H,T代表C＝O)的合成
向25mL茄形瓶中加入化合物I-A-1(60mg,0.12mmol)，用THF溶解，0℃下缓慢加入氢化铝锂(8mg,0.24mmol)，监测原料反应完全，加饱和氯化铵溶液淬灭反应，有白色固体析出，抽滤除去白色固体，EA洗，滤液浓缩，分离纯化得黄色固体24mg，收率56.8％。m.p.86-88℃.
1H NMR(300MHz,DMSO-d6)δ7.77(d,J＝7.8Hz,1H,ArH),7.63(s,1H,ArH),7.52-7.45(m,2H,ArH),7.40-7.25(m,6H,ArH),4.90(brs,1H,OH),4.63 (s,2H,NCH 2),3.68-3.60(m,4H,CH 2CH 2),2.01(s,3H,CH 3).
HRMS(ESI):m/z[M+H]+Calcd for C23H21FNO2:362.1556；Found:362.1556.
实施例8
2-(5-(2'-氟-2-甲基-[1,1'-联苯]-3-基)-1-氧代异吲哚啉-2-基)乙酰胺(I-A-8：R1＝CH3,R3＝F,R4＝H,T代表C＝O)的合成
向25mL三颈瓶中加入化合物I-A-2(100mg,0.27mmol)，用THF溶解，滴加少量DMF，缓慢滴加氯化亚砜(95mg,0.78mmol)，升温至55℃反应，监测原料反应完全，恢复至室温，转移至-20℃，缓慢滴加氨水，调节pH至8，监测原料反应完全，且有新点生成，加水10mL，EA(10mL×3)萃取，饱和食盐水(10mL×3)洗，无水硫酸钠干燥，经柱层析分离纯化得淡棕色固体42mg，收率42.0％。m.p.大于250℃.
1H NMR(300MHz,DMSO-d6)δ7.77(d,J＝7.8Hz,1H,ArH),7.61(d,J＝7.6Hz,1H,ArH),7.52-7.45(m,2H,ArH),7.40-7.25(m,6H,ArH),4.57(s,2H,NCH2),4.16(s,2H,NCH2CO),2.00(s,3H,CH3).
HRMS(ESI):m/z[M+H]+Calcd for C23H20FN2O2:375.1509；Found:375.1511.
实施例9
2-(5-(2'-氟-2-甲基-[1,1'-联苯]-3-基)异吲哚啉-2-基)乙烷-1-醇(I-A-9：R1＝CH3,R3＝F,R4＝H,T代表CH2)的合成
向25mL茄形瓶中加入化合物I-A-7(30mg,0.08mmol)，用THF溶解，0℃下缓慢加入1M硼烷-四氢呋喃络合物(0.46ml,0.48mmol)，加毕，68℃回流反应3h，监测原料反应完全，加饱和氯化铵溶液淬灭反应，有白色固体析出，抽滤除去白色固体，EA洗，滤液浓缩，分离纯化得棕色固体14mg，收率48.5％。m.p.80-82℃.
1H NMR(300MHz,Chloroform-d)δ7.36-7.29(m,4H,ArH),7.25-7.13(m,6H,ArH),4.25(s,4H,2NCH2),3.86-3.80(m,2H,CH2OH),3.14-3.08(m,2H,CH 2CH2OH),2.05(s,3H,CH3).
HRMS(ESI):m/z[M+H]+Calcd for C23H23FNO:348.1764；Found:348.1762.
实施例10
2-(2-(2'-氟-2-甲基-[1,1'-联苯]-3-基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-B-1：R1＝CH3,R3＝F,R4＝H)的合成
2-(2-氯-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(IX-1)
向25mL茄形瓶中加入2-氯-5,6,7,8-四氢-1,6-萘啶盐酸盐VIII(0.50g,2.43mmol)，用THF溶解，0℃下加入NaH(0.20g,4.86mmol)，向反应液中滴加溴乙酸乙酯(0.49g,2.93mmol)，室温反应，TLC监测原料反应完全，加饱和氯化铵溶液淬灭反应，用乙酸乙酯(10mL×3)萃取，饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥，抽滤，减压蒸除溶剂，残留物经柱层析分离纯化得浅棕色固体0.60g，收率97.2％。m.p.58-60℃.
1H NMR(300MHz,Chloroform-d)δ7.45-7.37(m,5H,ArH),7.28-7.22(m,4H,ArH),4.24(q,J＝7.1Hz,2H,CH 2CH3),3.82(s,2H,NCH2),3.47(s,2H,COCH2),3.09-3.05(m,2H,NCH2CH 2),3.02-2.97(m,2H,NCH 2CH2),1.31(t,J＝7.2Hz,3H,CH3).
2-(2-(2'-氟-2-甲基-[1,1'-联苯]-3-基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-B-1)的合成
将化合物IX-1(0.25g,0.98mmol)、V-1(10,0.44g,1.47mmol)和1,4-二氧六环(5mL)依次加入三颈瓶中，将碳酸钾(0.37g,2.75mmol)溶于水(0.5mL)后加入反应液中，氮气保护，加入Pd(PPh3)4(0.14g,0.10mmol)，升温至80℃反应12小时，TLC(石油醚:乙酸乙酯＝8:1)监测原料反应完全，停止加热，冷至室温。抽滤除去钯催化剂和不溶物，加水(10mL)稀释，乙酸乙酯(10mL×3)萃取，合并有机相，饱和食盐水(10mL×3)洗涤，无水硫酸镁干燥。抽滤，减压蒸除溶剂，残留物经柱层析纯化(石油醚:乙酸乙酯＝20:1～10:1)得黄色固体180mg，收率44.6％。m.p.46-48℃.
1H NMR(300MHz,Chloroform-d)δ7.46-7.37(m,5H,ArH),7.28-7.22(m,4H,ArH),4.29(q,J＝7.2Hz,2H,CH 2CH3),3.95(s,2H,NCH2),3.55(s,2H,COCH2),3.23(t,J＝5.9Hz,2H,NCH2CH 2),3.11(t,J＝5.9Hz,2H,NCH 2CH2),2.10(s,3H,ArCH3),1.36(t,J＝7.2Hz,3H,CH3).
实施例11
2-(2-(2'-氟-2-甲基-[1,1'-联苯]-3-基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸(I-B-2：R1＝CH3,R3＝F,R4＝H)的合成
向10mL茄型瓶中加入化合物I-B-1(80mg,0.20mmol)溶解于乙醇(2mL)中，加入LiOH(17mg,0.40mmol)的水(0.3mL)溶液，室温搅拌4小时。TLC监测反应完全后，减压蒸除甲醇，用2M HCl溶液调节pH到5-6，有白色固体析出，抽滤，烘干，得黄色固体产物7mg，收率9.4％。m.p.188-190℃.
1H NMR(300MHz,DMSO-d6)δ8.29(d,J＝8.0Hz,1H,ArH),7.58(d,J＝8.0Hz,1H,ArH),7.48-7.29(m,7H,ArH),4.23(s,2H,NCH2),3.74(t,J＝6.7Hz,2H, NCH2),3.26(s,2H,COCH2),3.19(t,J＝6.4Hz,2H,NCH2),2.08(s,3H,CH3).
HRMS(ESI):m/z[M+H]+Calcd for C23H22FN2O2:377.1665；Found:377.1667.
实施例12
2-(2-(2'-氟-2-甲基-[1,1'-联苯]-3-基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙烷-1-醇(I-B-3：R1＝CH3,R3＝F,R4＝H)的合成
向25mL茄形瓶中加入化合物I-B-1(100mg，0.25mmol)，用3mLTHF溶解，0℃下缓慢加入氢化铝锂(19mg，0.50mmol)，监测原料反应完全，加饱和氯化铵溶液淬灭反应，有白色固体析出，抽滤除去白色固体，EA洗，滤液浓缩，分离纯化得黄色固体50mg，收率27.9％。m.p.66-68℃.
1H NMR(300MHz,Chloroform-d)δ7.43-7.38(m,1H,ArH),7.36-7.29(m,3H,ArH),7.24-7.11(m,5H,ArH),3.79(s,2H,NCH2),3.56(t,J＝5.4Hz,2H,CH 2OH),3.13(t,J＝5.6Hz,2H,NCH2CH 2),2.98(t,J＝5.8Hz,2H,NCH 2CH2),2.80(t,J＝5.3Hz,2H,NCH 2),2.10(s,3H,CH3).
HRMS(ESI):m/z[M+H]+Calcd for C23H23FN2O:363.1873；Found:363.1872.
实施例13
2-(2-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-C-1：R1＝CH3,)的合成
3-溴-2-甲基苯甲酸甲酯(XI-1)的合成
向50mL茄形瓶中加入3-溴-2-甲基苯甲酸X-1(0.30g,1.40mmol)和甲醇5mL，冰浴条件下缓慢滴加亚硫酰氯(0.20mL,2.79mmoL),滴毕，70℃加热回流反应1h，TLC(石油醚:乙酸乙酯＝8:1)监测原料反应完全，减压浓缩得白色固体粉末0.32g，收率99.0％。m.p.31.0-33.0℃.
1H NMR(300MHz,Chloroform-d)δ7.72(d,J＝8.5Hz,1H,ArH),7.68(d,J＝8.6Hz,1H,ArH),7.09(t,J＝7.8Hz,1H,ArH),3.90(s,3H,OCH3),2.63(s,3H,CH3).
(3-溴-2-甲基苯基)甲醇(XII-1)的合成
将化合物XI-1(10.50g,46.10mmol)、无水四氢呋喃(50.00mL)加入三颈瓶中，N2保护，降至0℃，缓慢分批加入LiAlH4(3.10g,55.30mmol)，加完撤去冰浴，室温搅拌30分钟。TLC(石油醚:乙酸乙酯＝8:1)监测原料反应完全，缓慢滴加饱和NH4Cl溶液至无气泡生成，用乙酸乙酯(100mL)稀释，抽滤除去不溶物，有机相分别用水(50mL×2)和饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，抽滤，减压除去溶剂得白色固体粉末9.22g，收率为98.9％。 m.p.103.0～104.0℃.
1H NMR(300MHz,DMSO-d6)δ7.49(d,J＝8.0Hz,1H,ArH),7.39(d,J＝7.7Hz,1H,ArH),7.12(t,J＝7.7Hz,1H,ArH),5.26(br,1H,CH2OH),4.52(s,2H,CH2),2.30(s,3H,CH3).
(3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苯基)甲醇(XIV-1)的合成
将化合物XII-1(500mg,2.49mmol)、苯并-1,4-二氧六环-6-硼酸XIII-1,(537mg,2.98mmol)和1,4-二氧六环(10mL)依次加入三颈瓶中，将碳酸钾(962mg,6.96mmol)溶于水(1mL)加入反应液中，氮气保护，加入Pd(PPh3)4(144mg,0.15mmol)后，升温至80℃反应12小时。TLC(石油醚:乙酸乙酯＝8:1)监测原料反应完全，停止加热，冷至室温。抽滤除去钯催化剂和不溶物，加水(10mL)稀释，乙酸乙酯(10mL×3)萃取，合并有机相，饱和食盐水(10mL×3)洗涤，无水硫酸镁干燥。抽滤，减压蒸除溶剂，残留物经柱层析纯化(石油醚:乙酸乙酯＝20:1～15:1)得浅棕色油状物440mg，收率69.07％。
1H NMR(300MHz,DMSO-d6)δ7.38(dd,J＝7.6Hz,1.4Hz,1H,ArH),7.20(t,J＝7.6Hz,1H,ArH),7.06(dd,J＝7.6Hz,1.5Hz,1H,ArH),6.92(d,J＝8.1Hz,1H,ArH),6.78-6.70(m,2H,ArH),4.55(s,2H,CH 2OH),4.29(s,4H,OCH 2,OCH 2),2.14(s,3H,CH3).
2-(2-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-C-1)的合成
将化合物IX-1(120mg,0.47mmol)、XIV-1(145mg,0.57mmol)、t-BuXphos(40mg,0.09mmol)和甲苯(5mL)依次加入三颈瓶中，将碳酸铯(307mg,0.94mmol)加入反应液中，氮气保护，加入Pd(OAc)2(11mg,0.05mmol)，氮气保护，升温至80℃反应12小时。TLC(石油醚：乙酸乙酯＝4:1)监测原料反应完全，停止加热，冷至室温。抽滤除去钯催化剂和不溶物，加水(10mL)稀释，乙酸乙酯(10mL×3)萃取，合并有机相，饱和NaCl水溶液(10mL×3)洗涤，无水硫酸镁干燥。抽滤除去干燥剂，减压蒸除溶剂，经柱层析纯化(石油醚:乙酸乙酯＝20:1～10:1)得黄色粘稠状液体110mg，收率49.21％。
1H NMR(300MHz,Chloroform-d)δ7.42(dd,J＝6.4Hz,2.7Hz,1H,ArH),7.23-7.19(m,3H,ArH),6.90(d,J＝8.2Hz,1H,ArH),6.83(d,J＝1.8Hz,1H,ArH),6.79(dd,J＝8.2Hz,1.9Hz,1H,ArH),6.59(d,J＝8.3Hz,1H,ArH),5.37(s,2H,OCH2),4.30(s,4H,OCH 2CH 2O),4.26(q,J＝7.1Hz,2H,CH 2CH3),3.76(s,2H,NCH2),3.46(s,2H,CH 2CO),3.00(s,4H,NCH 2CH 2),2.28(s,3H,ArCH 3),1.30(t,J＝7.1Hz,3H,CH3).
实施例14
2-(2-((2'-氟-2-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-1：R1＝CH3,R3＝F,R4＝H)的合成
(2'-氟-2-甲基-[1,1'-联苯]-3-基)甲醇(XV-1)的合成
将化合物XII-1(2.00g,9.95mmol)、2-氟苯硼酸III-1(2.09g,14.92mmol)和1,4-二氧六环(45mL)依次加入三颈瓶中，将碳酸钾(3.85g,27.85mmol)溶于水(4.5mL)加入反应液中，氮气保护，加入Pd(PPh3)4(0.57g,0.50mmol)后，升温至80℃反应12小时。TLC(石油醚:乙酸乙酯＝8:1)监测原料反应完全，停止加热，冷至室温。抽滤除去钯催化剂和不溶物，加水(50mL)稀释，乙酸乙酯(50mL×3)萃取，合并有机相，饱和食盐水(50mL×3)洗涤，无水硫酸镁干燥。抽滤，减压蒸除溶剂，残留物经柱层析纯化(石油醚:乙酸乙酯＝20:1～15:1)得无色油状液体2.05g，收率95.3％。m.p.40-42℃.
1H NMR(300MHz,DMSO-d6)δ7.52-7.42(m,2H,ArH),7.35-7.25(m,4H,ArH),7.11(d,J＝7.6Hz,1H,ArH),5.20(s,1H,OH),4.58(s,2H,CH2),2.06(s,3H,CH3).
2-(2-((2'-氟-2-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-1)的合成
将化合物IX-1(0.17g,0.67mmol)、XV-1(0.17g,0.80mmol)、t-BuXphos(0.06g,0.13mmol)和甲苯(5mL)依次加入三颈瓶中，将碳酸铯(0.43g,1.33mmol)加入反应液中，氮气保护，加入Pd(OAc)2(0.01g,0.07mmol)后，升温至80℃反应12小时。TLC(石油醚:乙酸乙酯＝4:1)监测原料反应完全，停止加热，冷至室温。抽滤除去钯催化剂和不溶物，加水(10mL)稀释，乙酸乙酯(10mL×3)萃取，合并有机相，饱和食盐水(10mL×3)洗涤，无水硫酸镁干燥。抽滤，减压蒸除溶剂，残留物经柱层析纯化(石油醚:乙酸乙酯＝20:1～10:1)得无色透明状液体0.15g，收率51.8％。
1H NMR(300MHz,Chloroform-d)δ7.54(dd,J＝7.3Hz,1.7Hz,1H,ArH),7.43-7.35(m,1H,ArH),7.30-7.13(m,6H,ArH),6.64(d,J＝8.3Hz,1H,ArH),5.43(s,2H,OCH 2),4.27(q,J＝7.1Hz,2H,CH 2CH3),3.78(s,2H,NCH 2),3.49(s,2H,NCH 2),3.03(s,4H,NCH 2CH 2),2.25(s,3H,ArCH 3),1.34(t,J＝7.1Hz,3H,CH2CH 3).
实施例15
2-(2-((2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯 (I-D-2：R1＝CH3,R3＝CH3,R4＝H)的合成
(2,2'-二甲基-[1,1'-联苯]-3-基)甲醇(XV-2)的合成
以化合物XII-1(2.00g,9.95mmol)和III-2(2.03g,14.92mmol)为原料，操作同化合物XV-1，得白色固体2.00g，收率94.7％。m.p.48-50℃.
1H NMR(300MHz,DMSO-d6)δ7.43(d,J＝7.5Hz,1H,ArH),7.32-7.23(m,4H,ArH),7.08-7.03(m,1H,ArH),6.98(d,J＝7.5Hz,1H,ArH),5.17(t,J＝5.3Hz,1H,OH),4.58(s,2H,CH2),2.00(s,3H,CH3),1.94(s,3H,CH3).
2-(2-((2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-2)的合成
以化合物IX-1(120mg,0.47mmol)和XV-2(120mg,0.57mmol)为原料，操作同I-D-1，得黄色粘稠状液体67mg，收率32.9％。
1H NMR(300MHz,Chloroform-d)δ7.45(dd,J＝7.7Hz,1.5Hz,1H,ArH),7.27(s,1H,ArH),7.25-7.18(m,4H,ArH),7.13-7.08(m,2H,ArH),6.61(d,J＝8.4Hz,1H,ArH),5.38(s,2H,OCH 2),4.24(q,J＝7.1Hz,2H,CH 2CH3),3.87(s,2H,NCH 2),3.54(s,2H,COCH 2),3.11-2.86(m,4H,NCH2 CH 2),2.07(s,3H,ArCH3),2.06(s,3H,ArCH3),1.31(t,J＝7.1Hz,3H,CH2CH 3).
实施例16
2-(2-((2'-氯-2-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-3：R1＝CH3,R3＝Cl,R4＝H)的合成
(2'-氯-2-甲基-[1,1'-联苯]-3-基)甲醇(XV-3)的合成
以化合物XII-1(500mg,2.49mmol)和III-3(580mg,3.73mmol)为原料，操作同化合物XV-1，得白色固体500mg，收率86.4％。m.p.74-76℃.
1H NMR(400MHz,DMSO-d6)δ7.56-7.54(m,1H,ArH),7.46-7.39(m,3H,ArH),7.29-7.22(m,2H,ArH),7.01(dd,J＝7.6Hz,1.4Hz,1H,ArH),4.56(s,2H,CH2),1.96(s,3H,CH3).
2-(2-((2'-氯-2-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-3)的合成
以化合物IX-1(170mg,0.73mmol)和XV-3(136mg,0.88mmol)为原料，操作同化合物I-D-1，得黄色粘稠状液体150mg，收率51.8％。
1H NMR(300MHz,Chloroform-d)δ7.57-7.55(m,2H,ArH),7.28-7.20(m,3H,ArH),7.18-7.13(m,2H,ArH),7.06(dd,J＝7.6Hz,1.5Hz,1H,ArH),6.53(d,J＝8.4Hz,1H,ArH),5.38(s,2H,OCH 2),4.17(t,J＝7.1Hz,2H,OCH 2CH3),3.69(s, 2H,NCH 2),3.39(s,2H,NCH 2CO),2.93(s,4H,NCH 2CH 2),2.06(s,3H,ArCH 3),1.22(d,J＝7.1Hz,3H,CH3).
实施例17
2-(2-((2-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-4：R1＝CH3,R3＝H,R4＝H)的合成
(2-甲基-[1,1'-联苯]-3-基)甲醇(XV-4)的合成
以化合物XII-1(500mg,2.49mmol)和III-4(470mg,2.98mmol)为原料，操作同化合物XV-1，得白色固体320mg，收率64.9％。m.p.63-65℃.
1H NMR(300MHz,DMSO-d6)δ7.48-7.35(m,4H,ArH),7.30-7.21(m,3H,ArH),7.09(dd,J＝7.6Hz,1.5Hz,1H,ArH),5.16(s,1H,OH),4.56(s,2H,CH2),2.12(s,3H,CH3).
2-(2-((2-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-4)的合成
以化合物IX-1(150mg,0.59mmol)和XV-4(140mg,0.71mmol)为原料，操作同化合物I-D-1，得无色粘稠状液体115mg，收率46.9％。
1H NMR(300MHz,Chloroform-d)δ7.47-7.36(m,4H,ArH),7.35-7.29(m,3H,ArH),7.24-7.20(m,2H,ArH),6.60(d,J＝8.3Hz,1H,ArH),5.39(s,2H,OCH2),4.24(q,J＝7.1Hz,2H,CH 2CH3),3.80(s,2H,NCH2),3.49(s,2H,CH2CO),3.03(s,4H,NCH 2CH 2),2.27(s,3H,ArCH3),1.32(t,J＝7.1Hz,3H,CH3).
实施例18
2-(2-((2-氯-2'-氟-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-5：R1＝Cl,R3＝F,R4＝H)的合成
3-溴-2-氯苯甲酸甲酯(XI-2)的合成
以3-溴-2-氯苯硼酸X-2(5.00g,21.23mmol)和亚硫酰氯(3.10mL,42.47mmoL)为原料，操作同化合物XI-1，得浅棕色油状物5.29g，收率99.88％。
1H NMR(300MHz,DMSO-d6)δ8.18(dd,J＝8.0Hz,1.6Hz,1H,ArH),7.96(dd,J＝7.7Hz,1.6Hz,1H,ArH),7.61(t,J＝7.9Hz,1H,ArH),4.08(s,3H,CH3).
(3-溴-2-氯苯基)甲醇(XII-2)的合成
以化合物XI-2(5.29g,21.20mmol)为原料，经LiAlH4(0.80g,21.20mmol)还原，操作同化合物XII-1，得白色固体粉末4.60g，收率为97.9％。m.p.56-58℃.
1H NMR(300MHz,DMSO-d6)δ7.66(d,J＝7.9Hz,1H,ArH),7.56(d,J＝7.5Hz,1H,ArH),7.31(t,J＝7.7Hz,1H,ArH),5.55(t,J＝5.7Hz,1H,OH),4.58(d,J＝5.5Hz,2H,CH2).
(2-氯-2'-氟-[1,1'-联苯]-3-基)甲醇(XV-5)的合成
以化合物XV-2(0.50g,2.26mmol)和III-1(0.38g,2.71mmol)为原料，操作同化合物XV-1，得浅棕色固体0.32g，收率59.9％。m.p.44-46℃.
1H NMR(300MHz,DMSO-d6)δ7.84(d,J＝7.7Hz,1H,ArH),7.73-7.61(m,2H,ArH),7.57-7.46(m,4H,ArH),5.68(s,1H,OH),4.83(s,2H,CH2).
2-(2-((2-氯-2'-氟-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-5)的合成
以化合物IX-1(150g,0.59mmol)和XV-5(170mg,0.71mmol)为原料，操作同化合物I-D-1，得无色粘稠状液体116mg，收率43.3％。
1H NMR(300MHz,Chloroform-d)δ7.59(dd,J＝7.4Hz,1.9Hz,1H,ArH),7.44-7.27(m,4H,ArH),7.25-7.12(m,3H,ArH),6.64(d,J＝8.3Hz,1H,ArH),5.52(s,2H,OCH2),4.23(q,J＝7.1Hz,2H,CH 2CH3),3.75(s,2H,COCH2),3.45(s,2H,NCH2),2.98(s,4H,NCH 2CH 2),1.29(t,J＝7.1Hz,3H,CH3).
实施例19
2-(2-((2-氯-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-6：R1＝Cl,R3＝CH3,R4＝H)的合成
(2-氯-2'-甲基-[1,1'-联苯]-3-基)甲醇(XV-6)的合成
以化合物XII-2(0.50g,2.26mmol)和III-2(0.37g,2.71mmol)为原料，操作同化合物XV-1，得浅棕色固体0.32g，收率59.9％。m.p.44-46℃.
1H NMR(400MHz,DMSO-d6)δ7.63-7.51(m,1H,ArH),7.44-7.00(m,6H,ArH),5.40(s,1H,OH),4.65(s,2H,CH2),2.03(s,3H,CH3).
2-(2-((2-氯-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-6)的合成
以化合物IX-1(150mg,0.59mmol)和XV-6(165mg,0.71mmol)为原料，操作同化合物I-D-1，得无色粘稠状液体117mg，收率44.0％。
1H NMR(300MHz,Chloroform-d)δ7.56(dd,J＝7.7Hz,1.7Hz,1H,ArH),7.34-7.27(m,3H,ArH),7.25-7.21(m,2H,ArH),7.20-7.12(m,2H,ArH),6.67-6.65(d,J＝8.3Hz,1H,ArH),5.51(s,2H,OCH2),4.22(q,J＝7.1Hz,2H,CH 2CH3),3.78(s,2H,NCH2),3.47(s,2H,CH2CO),2.99(s,4H,NCH 2CH 2),2.12(s,3H,ArCH3),1.32-1.30(t,J＝7.1Hz,3H,CH2CH 3).
实施例20
2-(2-((2,2'-二氯-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-7：R1＝Cl,R3＝Cl,R4＝H)的合成
(2,2'-二氯-[1,1'-联苯]-3-基)甲醇(XV-7)的合成
以化合物XII-2(0.50g,2.26mmol)和III-3(0.42g,2.71mmol)为原料，操作同化合物XV-1，得浅棕色油状物0.31g，收率54.2％。
1H NMR(300MHz,DMSO-d6)δ7.88-7.82(m,1H,ArH),7.82-7.76(m,1H,ArH),7.70-7.62(m,3H,ArH),7.57-7.51(m,1H,ArH),7.47-7.41(m,1H,ArH),5.71(s,1H,OH),4.85(s,2H,CH2).
2-(2-((2,2'-二氯-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-7)的合成
以化合物IX-I(150mg,0.59mmol)和XV-7(165mg,0.71mmol)为原料，操作同化合物I-D-1，得无色粘稠状液体130mg，收率46.8％。
1H NMR(300MHz,Chloroform-d)δ7.60(dd,J＝7.6Hz,1.8Hz,1H,ArH),7.51-7.46(m,1H,ArH),7.35-7.32(m,5H,ArH),7.24-7.19(m,2H,ArH),6.64(d,J＝8.4Hz,1H,ArH),5.52(s,2H,OCH2),4.22(q,J＝7.1Hz,2H,CH 2CH3),3.76(s,2H,NCH2),3.45(s,2H,COCH2),2.98(s,4H,NCH 2CH 2),1.30(t,J＝7.1Hz,3H,CH3).
实施例21
2-(2-((2-氯-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-8：R1＝Cl,R3＝H,R4＝H)的合成
(2-氯-[1,1’-联苯]-3-基)甲醇(XV-8)的合成
以化合物XII-2(0.50g,2.26mmol)和III-4(0.41g,2.71mmol)为原料，操作同化合物XV-1，得淡黄色固体0.41g，收率83.1％。m.p.76-78℃.
1H NMR(400MHz,DMSO-d6)δ7.59(dd,J＝7.6Hz,1.7Hz,1H,ArH),7.49-7.38(m,6H,ArH),7.28(dd,J＝7.6Hz,1.8Hz,1H,ArH),5.48(s,1H,OH),4.63(s,2H,CH2).
2-(2-((2-氯-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-8)的合成
以化合物IX-1(150mg,0.59mmol)和XV-8(155mg,0.71mmol)为原料，操作同化合物I-D-1，得无色粘稠状液体187mg，收率72.7％。
1H NMR(300MHz,Chloroform-d)δ7.55(dd,J＝6.9Hz,2.5Hz,1H,ArH),7.46-7.37(m,6H,ArH),7.34-7.28(m,2H,ArH),6.65(d,J＝8.4Hz,1H,ArH),5.52(s,2H,OCH2),4.23(q,J＝7.2Hz,2H,CH 2CH3),3.81(s,2H,NCH2),3.49(s2H,COCH2),3.02(s,4H,NCH 2CH 2),1.30(t,J＝7.1Hz,3H,CH3).
实施例22
2-(2-((2,2'-二氟-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-9：R1＝F,R3＝F,R4＝H)的合成
3-溴-2-氟苯甲酸甲酯(XI-3)的合成
以3-溴-2-氯苯硼酸X-3(5.00g，21.23mmol)和亚硫酰氯(3.10mL，42.47mmoL)为原料，操作同化合物XI-1，得淡黄色固体5.30g，收率99.6％。m.p.35-36℃.
1H NMR(300MHz,DMSO-d6)δ7.94(ddd,J＝8.1Hz,6.4Hz,1.8Hz,1H,ArH),7.83(ddd,J＝8.1Hz,6.6Hz,1.7Hz,1H,ArH),7.25(td,J＝7.9Hz,1.0Hz,1H,ArH),3.83(s,3H,CH3).
(3-溴-2-氟苯基)甲醇(XII-3)的合成
以化合物XI-3(5.30g,22.74mmol)为原料，经LiAlH4(0.86g,22.74mmol)还原，操作同化合物XII-1，得淡黄色固体4.30g，收率为92.2％。m.p.34-35℃.
1H NMR(300MHz,DMSO-d6)δ7.65-7.55(m,1H,ArH),7.53-7.43(m,1H,ArH),7.17(t,J＝7.8Hz,1H,ArH),5.42(t,J＝6.0Hz,1H,OH),4.59(s,2H,CH2).(2,2'-二氟-[1,1'-联苯]-3-基)甲醇(XV-9)的合成
以化合物XII-3(0.50g,2.44mmol)和III-1(0.41g,2.93mmol)为原料，操作同化合物XV-1，得白色固体0.37g，收率68.9％。m.p.50-52℃.
1H NMR(300MHz,DMSO-d6)δ7.49-7.32(m,3H,ArH),7.28-7.18(m,4H,ArH),4.53(s,2H,CH2).
2-(2-((2,2'-二氟-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-9)的合成
以化合物IX-1(150mg,0.59mmol)和XV-9(156mg,0.71mmol)为原料，操作同化合物I-D-1，得无色粘稠状液体100mg，收率38.7％。
1H NMR(300MHz,Chloroform-d)δ7.56-7.51(m,1H,ArH),7.42-7.33(m,4H,ArH),7.22-7.13(m,3H,ArH),6.61(d,J＝8.4Hz,1H,ArH),5.48(s,2H,OCH2),4.23(q,J＝7.2Hz,2H,CH 2CH3),3.79(s,2H,NCH2),3.48(s,2H,CH2CO),3.02-2.99(m,4H,NCH 2CH 2),1.31(t,J＝7.1Hz,3H,CH3).
实施例23
2-(2-((2-氟-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-10：R1＝F,R3＝CH3,R4＝H)的合成
(2-氟-2'-甲基-[1,1'-联苯]-3-基)甲醇(XV-10)的合成
以化合物XII-3(0.50g,2.44mmol)和III-2(0.40g,2.93mmol)为原料，操作同化合物XVII-1，得无色油状物0.34g，收率63.7％。
1H NMR(300MHz,DMSO-d6)δ7.51(td,J＝7.3Hz,1.9Hz,1H,ArH),7.34-7.32(m,2H,ArH),7.31-7.24(m,2H,ArH),7.23-7.16(m,2H,ArH),4.61(s,2H,CH2),2.14(s,3H,CH3).
2-(2-((2-氟-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-10)的合成
以化合物IX-1(150mg,0.59mmol)和XV-10(153mg,0.71mmol)为原料，操作同化合物I-D-1，得无色粘稠状液体130mg，收率50.8％。
1H NMR(300MHz,Chloroform-d)δ7.54-7.48(m,1H,ArH),7.31-7.28(m,2H,ArH),7.24-7.15(m,5H,ArH),6.61(d,J＝8.3Hz,1H,ArH),5.46(s,2H,OCH2),4.23(q,J＝7.1Hz,2H,CH 2CH3),3.79(s,2H,NCH2),3.48(s,2H,CH2CO),3.00(s,4H,NCH2 CH 2),2.21(s,3H,ArCH3),1.31(t,J＝7.1Hz,3H,CH2CH 3).
实施例24
2-(2-((2'-氯-2-氟-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-11：R1＝F,R3＝Cl,R4＝H)的合成
(2'-氯-2-氟-[1,1'-联苯]-3-基)甲醇(XV-11)的合成
以化合物XII-3(0.50g,2.44mmol)和III-3(0.46g,2.93mmol)为原料，操作同化合物XV-1，得无色油状物0.34g，收率58.9％。m.p.34-35℃.
1H NMR(300MHz,DMSO-d6)δ7.62-7.51(m,2H,ArH),7.50-7.38(m,3H,ArH),7.32-7.21(m,2H,ArH),5.36(s,1H,OH),4.61(s,2H,CH2).
2-(2-((2'-氯-2-氟-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-11)的合成
以化合物IX-1(150mg,0.59mmol)和XV-11(167mg,0.71mmol)为原料，操作同化合物I-D-1，得无色粘稠状液体104mg，收率38.8％。
1H NMR(300MHz,Chloroform-d)δ7.58-7.52(m,2.0Hz,1H,ArH),7.50-7.47(m,1H,ArH),7.35-7.32(m,3H,ArH),7.25-7.16(m,3H,ArH),6.61(d,J＝ 8.4Hz,1H,ArH),5.47(s,2H,OCH2),4.23(q,J＝7.1Hz,2H,CH 2CH3),3.77(s,2H,NCH2),3.46(s,2H,CH2CO),2.99(s,4H,NCH 2CH 2),1.30(t,J＝7.1Hz,3H,CH3).
实施例25
2-(2-((2-氟-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-12：R1＝F,R3＝H,R4＝H)的合成
(2-氟-[1,1'-联苯]-3-基)甲醇(XV-12)的合成
以化合物XII-3(0.50g,2.44mmol)和III-4(0.45g,2.93mmol)为原料，操作同化合物XV-1，得白色固体0.37g，收率75.1％。m.p.84-86℃.
1H NMR(300MHz,DMSO-d6)δ7.54-7.44(m,5H,ArH),7.43-7.36(m,2H,ArH),7.27(t,J＝7.6Hz,1H,ArH),5.32(t,J＝5.7Hz,1H,OH),4.60(d,J＝5.2Hz,2H,CH2).
2-(2-((2-氟-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-D-12)的合成
以化合物IX-1(150mg,0.59mmol)和XV-12(143mg,0.71mmol)为原料，操作同化合物I-D-1，得无色粘稠状液体149mg，收率60.2％。
1H NMR(300MHz,Chloroform-d)δ7.57-7.55(m,1H,ArH),7.49-7.38(m,6H,ArH),7.23-7.16(m,2H,ArH),6.61(d,J＝8.4Hz,1H,ArH),5.47(s,2H,OCH2),4.27(q,J＝7.1Hz,2H,CH 2CH3),3.83(s,2H,NCH2),3.51(s,2H,COCH2),3.06-3.01(m,4H,NCH 2CH 2),1.32(t,J＝7.1Hz,3H,CH3).
实施例26
2-(2-((2'-氟-2-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸(I-D-13：R1＝CH3,R3＝F,R4＝H)的合成
向10mL茄型瓶中加入化合物I-D-1(60mg,0.14mmol)，加入乙醇(2mL)溶解，加入NaOH(11mg,0.28mmol)的水(0.3mL)溶液，室温搅拌4小时。TLC监测反应完全后，减压蒸除甲醇，用2M HCl溶液调节pH到5-6，有白色固体析出，抽滤，得白色固体产物30mg，产率53.5％。m.p.130-132℃.
1H NMR(300MHz,DMSO-d6)δ7.50-7.40(m,3H,ArH),7.32-7.25(m,4H,ArH),7.18-7.16(m,1H,ArH),6.66(d,J＝8.3Hz,1H,ArH),5.34(s,2H,OCH2),3.67(s,4H,NCH 2,CH2 COOH),2.92-2.79(m,4H,NCH 2CH 2),2.11(s,3H,CH3).
HRMS(ESI):m/z[M+H]+Calcd for C24H24FN2O3:407.1771；Found:407.1768.
实施例27
2-(2-((2'-氟-2-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙烷-1-醇(I-D-14：R1＝CH3,R3＝F,R4＝H)的合成
向25mL茄形瓶中加入化合物I-D-1(80mg,018mmol)，用THF溶解，0℃下缓慢加入氢化铝锂(14mg,0.37mmol)，监测原料反应完全，加饱和氯化铵溶液淬灭反应，有白色固体析出，抽滤除去白色固体，EA洗，滤液浓缩，分离纯化得黄色固体34mg，收率41.5％。m.p.72-74℃.
1H NMR(300MHz,Chloroform-d)δ7.54(d,J＝7.3Hz,1H,ArH),7.45-7.32(m,2H,ArH),7.30-7.14(m,5H,ArH),6.67(d,J＝8.3Hz,1H,ArH),5.44(s,2H,OCH 2),3.81(t,J＝5.3Hz,2H,CH 2OH),3.76(s,2H,NCH 2),3.06-2.95(m,4H,NCH 2CH 2),2.85(t,J＝5.3Hz,2H,NCH 2),2.26(s,3H,CH 3).
HRMS(ESI):m/z[M+H]+Calcd for C24H26FN2O2:393.1978；Found:393.1975.
实施例28
2-(2-((2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙烷-1-醇(I-D-15：R1＝CH3,R3＝CH3,R4＝H)的合成
以化合物I-D-2(100mg,0.23mmol)和LiAlH4(18mg,0.47mmol)为原料，操作同化合物I-D-13，得黄色固体34mg，收率41.5％。m.p.96-98℃.
1H NMR(300MHz,Chloroform-d)δ7.47(d,J＝7.6Hz,1H,ArH),7.27-7.21(m,5H,ArH),7.16-7.08(m,2H,ArH),6.61(d,J＝8.4Hz,1H,ArH),5.39(s,2H,OCH 2),3.73(t,J＝5.3Hz,2H,CH 2OH),3.64(s,2H,NCH 2),2.96-2.90(m,4H,NCH 2CH2 ),2.76(t,J＝5.3Hz,2H,NCH 2),2.09(s,3H),2.06(s,3H).
HRMS(ESI):m/z[M+H]+Calcd for C25H29N2O2:389.2229；Found:389.2230.
实施例29
2-(2-((2'-氯-2-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙烷-1-醇(I-D-16：R1＝CH3,R3＝Cl,R4＝H)的合成
以化合物I-D-3(150mg,0.37mmol)和LiAlH4(24mg,0.73mmol)为原料，操作同化合物I-D-13，得黄色固体100mg，收率66.6％。m.p.108-110℃.
1H NMR(300MHz,Chloroform-d)δ7.58-7.50(m,2H,ArH),7.40-7.32(m,3H,ArH),7.31-7.26(m,2H,ArH),7.19-7.17(m,1H,ArH),6.67(d,J＝8.4Hz,1H),ArH,5.50-5.39(m,2H,OCH 2),3.79(t,J＝5.3Hz,2H,CH 2OH),3.72(s,2H,NCH 2),3.02-2.97(m,4H,NCH 2CH2 ),2.83(t,J＝5.3Hz,2H,NCH 2),2.19(s,3H,CH3).
HRMS(ESI):m/z[M+H]+Calcd for C24H26ClN2O2:409.1683；Found:409.1687.
实施例30
2-(2-((2-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙烷-1-醇(I-D-17：R1＝CH3,R3＝H,R4＝H)的合成
以化合物I-D-4(100mg,0.26mmol)和LiAlH4(20mg,0.53mmol)为原料，操作同化合物I-D-12，得黄色固体55mg，收率55.6％。m.p.152-154℃.
1H NMR(300MHz,Chloroform-d)δ7.48-7.36(m,4H,ArH),7.35-7.28(m,3H,ArH),7.23(s,2H,ArH),6.62(d,J＝8.3Hz,1H,ArH),5.39(s,2H,OCH2),3.74(t,J＝5.3Hz,2H,CH2OH),3.66(s,2H,NCH2),3.00-2.92(m,4H,NCH 2CH2 ),2.77(t,J＝5.3Hz,2H,CH 2CH2OH),2.28(s,3H,CH3).
HRMS(ESI):m/z[M+H]+Calcd for C24H27N2O2:375.2073；Found:375.2074.
实施例31
2-(2-((2-氯-2'-氟-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙烷-1-醇(I-D-18：R1＝Cl,R3＝F,R4＝H)的合成
以化合物I-D-5(106mg,0.23mmol)和LiAlH4(18mg,0.47mmol)为原料，操作同化合物I-D-13，得黄色固体76mg，收率79.0％。m.p.116-118℃.
1H NMR(300MHz,Chloroform-d)δ7.60(dd,J＝7.5Hz,2.0Hz,1H,ArH),7.44-7.27(m,5H,ArH),7.21-7.18(m,1H,ArH),7.17-7.12(m,1H,ArH),6.66(d,J＝8.4Hz,1H,ArH),5.52(s,2H,OCH2),3.75(t,J＝5.3Hz,2H,CH2OH),3.69(s,2H,NCH2),2.99-2.93(m,4H,NCH 2CH 2),2.79(t,J＝5.3Hz,2H,CH 2CH2OH).
HRMS(ESI):m/z[M+H]+Calcd for C23H23ClFN2O2:413.1432；Found:413.1432.
实施例32
2-(2-((2-氯-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙烷-1-醇(I-D-19：R1＝Cl,R3＝CH3,R4＝H)的合成
以化合物I-D-6(60mg,0.13mmol)和LiAlH4(10mg,0.27mmol)为原料，操作同化合物I-D-13，得白色固体30mg，收率55.2％。m.p.88-90℃.
1H NMR(300MHz,Chloroform-d)δ7.56(dd,J＝7.6Hz,1.7Hz,1H,ArH),7.34-7.26(m,4H,ArH),7.24-7.21(m,1H,ArH),7.20-7.12(m,2H,ArH),6.66(d,J＝8.5Hz,1H,ArH),5.51(s,2H,OCH2),3.74(t,J＝5.3Hz,2H,CH2OH),3.68(s,2H,NCH2),2.96-2.93(m,4H,NCH 2CH 2),2.78(t,J＝5.3Hz,2H,CH 2CH2OH),2.11(s,3H,CH3).
HRMS(ESI):m/z[M+H]+Calcd for C24H26ClN2O2:409.1683；Found:409.1682.
实施例33
2-(2-((2,2'-二氯-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙烷-1-醇(I-D-20：R1＝Cl,R3＝Cl,R4＝H)的合成
以化合物I-D-7(120mg,0.26mmol)和LiAlH4(19mg,0.51mmol)为原料，操作同化合物I-D-13，得黄色固体64mg，收率58.5％。m.p.110-112℃.
1H NMR(300MHz,Chloroform-d)δ7.61(dd,J＝7.7Hz,1.8Hz,1H,ArH),7.51-7.46(m,1H,ArH),7.38-7.27(m,5H,ArH),7.25-7.20(m,1H,ArH),6.66(d,J＝8.4Hz,1H,ArH),5.52(s,2H,OCH2),3.75(t,J＝5.3Hz,2H,CH 2OH),3.69(s,2H,NCH2),2.99-2.93(m,4H,NCH 2CH 2),2.79(t,J＝5.3Hz,2H,CH 2CH2OH).
HRMS(ESI):m/z[M+H]+Calcd for C23H23Cl2N2O2:429.1137；Found:429.1141.
实施例34
2-(2-((2-氯-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙烷-1-醇(I-D-21：R1＝Cl,R3＝H,R4＝H)的合成
以化合物I-D-8(187mg,0.43mmol)和LiAlH4(27mg,0.46mmol)为原料，操作同化合物I-D-13，得白色固体80mg，收率47.3％。m.p.148-150℃.
1H NMR(300MHz,Chloroform-d)δ7.39(dd,J＝6.9Hz,2.5Hz,1H,ArH),7.26-7.21(m,2H,ArH),7.17-7.06(m,5H,ArH),6.48(d,J＝8.5Hz,1H,ArH),5.35(s,2H,OCH2),3.55(t,J＝5.3Hz,2H,CH2OH),3.47(s,2H,NCH2),2.80-2.70(m,4H,NCH 2CH2 ),2.58(t,J＝5.3Hz,2H,CH 2CH2OH).
HRMS(ESI):m/z[M+H]+Calcd for C23H24ClN2O2:395.1526；Found:395.1522.
实施例35
2-(2-((2,2'-二氟-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙烷-1-醇(I-D-22：R1＝F,R3＝F,R4＝H)的合成
以化合物I-D-9(100mg,0.23mmol)和LiAlH4(17mg,0.46mmol)为原料，操作同化合物I-D-13，得棕色固体60mg，收率66.4％。m.p.60-62℃.
1H NMR(300MHz,Chloroform-d)δ7.57-7.52(m,1H,ArH),7.43-7.32(m,3H,ArH),7.25-7.13(m,4H,ArH),6.62(d,J＝8.3Hz,1H,ArH),5.48(s,2H,OCH2),3.74(t,J＝5.3Hz,2H,CH2OH),3.66(s,2H,NCH2),2.95-2.92(m,4H,NCH 2CH 2),2.77(t,J＝5.3Hz,2H,CH 2CH2OH).
HRMS(ESI):m/z[M+H]+Calcd for C23H23F2N2O2:397.1728；Found:397.1730.
实施例36
2-(2-((2-氟-2'-甲基-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙烷-1-醇(I-D-23：R1＝F,R3＝CH3,R4＝H)的合成
以化合物I-D-10(130mg,0.30mmol)和LiAlH4(23mg,0.59mmol)为原料，操作同化合物I-D-13，得类白色固体90mg，收率76.7％。m.p.62-64℃.
1H NMR(300MHz,Chloroform-d)δ7.56-7.48(m,1H,ArH),7.31-7.29(m,3H,ArH),7.25-7.18(m,4H,ArH),6.62(d,J＝8.3Hz,1H,ArH),5.47(s,2H,OCH2),3.73(t,J＝5.3Hz,2H,CH2OH),3.66(s,2H,NCH2),2.98-2.89(m,4H,NCH 2CH 2),2.77(t,J＝5.3Hz,2H,CH 2CH2OH),2.21(d,J＝1.4Hz,3H,CH3).
HRMS(ESI):m/z[M+H]+Calcd for C24H26FN2O2:393.1978；Found:393.1981.
实施例37
2-(2-((2'-氯-2-氟-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙烷-1-醇(I-D-24：R1＝F,R3＝Cl,R4＝H)的合成
以化合物I-D-11(104mg,0.23mmol)和LiAlH4(17mg,0.46mmol)为原料，操作同化合物I-D-13，得淡黄色固体60mg，收率74.0％。m.p.68-70℃.
1H NMR(300MHz,Chloroform-d)δ7.59-7.54(m,1H,ArH),7.51-7.47(m,1H,ArH),7.38-7.30(m,3H,ArH),7.26-7.18(m,3H,ArH),6.62(d,J＝8.3Hz,1H,ArH),5.48(s,2H,OCH2),3.74(t,J＝5.3Hz,2H,CH2OH),3.68(s,2H,NCH2),2.97-2.92(m,4H,NCH 2CH 2),2.78(t,J＝5.3Hz,2H,CH 2CH2OH).
HRMS(ESI):m/z[M+H]+Calcd for C23H23ClFN2O2:413.1432；Found:413.1430.
实施例38
2-(2-((2-氟-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙烷-1-醇(I-D-25：R1＝F,R3＝H,R4＝H)的合成
以化合物I-D-11(149mg,0.35mmol)和LiAlH4(17mg,0.46mmol)为原料，操作同化合物I-D-13，得类白色固体70mg，收率52.3％。m.p.72-74℃.
1H NMR(300MHz,Chloroform-d)δ7.57-7.36(m,7H,ArH),7.25-7.17(m,2H,ArH),6.62(d,J＝8.4Hz,1H,ArH),5.48(s,2H,OCH2),3.74(t,J＝5.3Hz,2H,CH2OH),3.68(s,J＝2.9Hz,2H,NCH2),2.99-2.90(m,4H,NCH 2CH 2),2.77(t,J＝5.3Hz,2H,CH 2CH2OH).
HRMS(ESI):m/z[M+H]+Calcd for C23H24FN2O2:379.1822；Found:379.1822.
实施例39
2-(2-((2-氯-2'-氟-[1,1'-联苯]-3-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸(I-D- 26：R1＝Cl,R3＝F,R4＝H)的合成
向10mL茄型瓶中加入化合物I-D-5(400mg,0.88mmol)，加入乙醇(3mL)溶解，加入NaOH(69mg,1.76mmol)的水(0.2mL)溶液，室温搅拌4小时。TLC监测反应完全后，减压蒸除甲醇，用2M HCl溶液调节pH到5-6，有白色固体析出，抽滤，得白色固体产物262mg，产率69.8％。m.p.101-108℃.
1H NMR(300MHz,Chloroform-d)δ7.59-7.52(m,1H,ArH),7.41-7.27(m,4H,ArH),7.22-7.01(m,3H,ArH),6.64(d,J＝8.4Hz,1H,ArH),5.46(s,2H,OCH2),4.18(s,2H,NCH2),3.59(s,2H,COCH2),3.38-3.05(m,4H,NCH 2CH2 ).
HRMS(ESI):m/z[M+H]+Calcd for C23H21ClFN2O3:427.1225Found:427.1223.
在制备I-D-26中，得到一副产物，经过结构鉴定为I-D-27，m/z：369.10(M+H).1H-NMR(400MHz,DMSO-d6)δ:7.66(dd,1H,J＝7.6&1.6Hz),7.53～7.47(m,1H),7.48～7.44(t,1H,J＝15.2&7.6Hz),7.41～7.30(m,5H),6.71(d,1H,J＝8.4Hz),5.44(s,2H),3.78(s,2H),3.01～2.98(t,1H,J＝10.4&5.2Hz),2.70～2.67(t,1H,J＝10.4&5.2Hz)
实施例40
2-(7-((2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-1-甲基-1,4-二氢吡啶[2,3-d]嘧啶-3(2H)-基)乙酸甲酯(I-E-1：R1＝CH3,R3＝CH3,R4＝H)的合成
(6-氯-3-甲酰吡啶-2-基)(甲基)氨基甲酸叔丁酯(XVII)的合成
向25mL茄型瓶中加入化合物XVI(100mg,0.39mmol)，用DMF(10mL)溶解，将CH3I(49μL,0.78mmol)缓慢滴入反应液中，降温至0℃，分批加入60％的NaH(18mg,0.469mmol)，加毕，继续在冰浴搅拌30分钟，室温反应过夜。TLC(石油醚:乙酸乙酯＝15:1)监测原料几乎完全，用饱和氯化铵淬灭，乙酸乙酯萃取(10mL×2)，合并有机相，饱和食盐水洗涤(10mL×2)，无水硫酸钠干燥，减压浓缩得粗品，经柱层析纯化得无色液体0.09g，收率85.2％.
1H NMR(300MHz,Chloroform-d)δ9.90(s,1H,CHO),8.13(d,J＝8.1Hz,1H,ArH),7.29(d,J＝8.1Hz,1H,ArH),3.44(s,3H,NCH3),1.43(s,9H,CH3).
((2-((叔丁氧羰基)(甲基)氨基)-6-氯吡啶-3-基)甲基)甘氨酸甲酯(XVIII-1)的合成
向25mL茄型瓶中加入化合物XVII(0.70g,2.73mmol)，甘氨酸甲酯盐酸盐(0.69g,5.47mmol)和二氯甲烷(10mL)，室温搅拌1小时后，0℃下分批加入三乙酰氧基硼氢化钠(1.16g,5.47mmol)，加毕，室温反应4小时，TLC监测原料反应完全后，滴加饱和碳酸钠调节pH至7，加水(5mL)，二氯甲烷(10mL×3) 萃取，合并有机相，饱和食盐水洗涤(10mL×3)，无水硫酸钠干燥，减压浓缩得油状粗品，经柱层析分离得无色液体0.35g，收率37.4％。
1H NMR(300MHz,Chloroform-d)δ7.95(d,J＝8.0Hz,1H,ArH),7.29(d,J＝8.2Hz,1H,ArH),4.86(br,1H,NH)3.78(s,3H,OCH3),3.75(s,2H,ArCH2),3.42(s,2H,CH2CO),3.28(s,3H,NCH3),1.46(s,9H,CH3).
((6-氯-2-(甲氨基)吡啶-3-基)甲基)甘氨酸甲酯(XIX-1)的合成
向50mL茄型瓶中加入化合物XVIII-1(0.67g,1.95mmol)，用乙酸乙酯(5mL)溶解，加入乙酸乙酯的氯化氢溶液，室温反应12小时，有白色固体析出，抽滤得白色固体0.34g，收率71.6％。m.p.110-112℃.
1H NMR(300MHz,DMSO-d6)δ9.67(s,2H，NH·HCl),7.58(d,J＝7.7Hz,1H,ArH),6.60(d,J＝7.6Hz,1H,ArH),4.11(s,2H,ArCH2),4.03(s,2H,CH2CO),3.72(s,3H,OCH3),2.79(s,3H,NHCH 3).
2-(7-氯-1-甲基-1,4-二氢吡啶[2,3-d]嘧啶-3(2H)-基)乙酸甲酯(XX-1)的合成
向25mL茄型瓶中加入化合物XIX-1(0.25g,0.90mmol)，用甲醇(5mL)溶解，氮气保护，加入三乙胺(249μl,1.80mmol)，搅拌10分钟，加入多聚甲醛(0.03g,1.08mmol)，室温反应8小时。TLC监测原料反应完全后，减压浓缩除去有机溶剂，加水，二氯甲烷萃取(10mL×3)，合并有机相，饱和食盐水洗涤(10mL×3)，无水硫酸钠干燥，减压浓缩得油状粗品，经柱层析分离得无色液体0.20g，收率87.4％。
1H NMR(300MHz,Chloroform-d)δ7.01(d,J＝7.5Hz,1H,ArH),6.50(d,J＝7.5Hz,1H,ArH),4.28(s,2H,NCH2N),3.97(s,2H,ArCH2),3.75(s,3H,OCH3),3.43(s,2H,CH2CO),3.05(s,3H,NCH3)
2-(7-((2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-1-甲基-1,4-二氢吡啶[2,3-d]嘧啶-3(2H)-基)乙酸甲酯(I-E-1)的合成
将化合物XX-1(170mg,0.67mmol)、XV-2(173mg,0.80mmol)、t-BuXphos(57mg,0.13mmol)和甲苯(5mL)依次加入三颈瓶中，随后加入碳酸铯(430mg,1.33mmol)，氮气保护下，加入Pd(OAc)2(15mg,0.07mmol)，升温至80℃反应12小时。TLC(石油醚:乙酸乙酯＝4:1)监测原料反应完全，停止加热，冷至室温。抽滤除去钯催化剂和不溶物，加水(10mL)稀释，乙酸乙酯(10mL×3)萃取，合并有机相，饱和食盐水(10mL×3)洗涤，无水硫酸镁干燥。抽滤，减压蒸除溶剂，残留物经柱层析纯化(石油醚:乙酸乙酯＝20:1～10:1)得无色透明状液体150mg，收率51.79％。
1H NMR(400MHz,Chloroform-d)δ(ppm):7.56-7.35(m,2H,ArH),7.29(d,J＝1.8Hz,1H,ArH),7.27-7.20(m,2H,ArH),7.12-7.08(m,3H,ArH),5.98- 5.96(m,1H,ArH),5.50-5.32(s,2H,OCH2),3.79(s,3H,CH3),4.13(s,2H,NCH2N),3.69(q,J＝4.1Hz,2H,NCH2),3.42(dd,J＝3.1Hz,2.6Hz,2H,COCH2),3.03(q,J＝3.8Hz,2.7Hz,3H,ArCH3),2.60(s,3H,NCH3),2.11(s,3H,ArCH3).
实施例41
(R)-2-(7-((3'-(3-(3-羟基吡咯烷-1-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-1-甲基-1,4-二氢吡啶[2,3-d]嘧啶-3(2H)-基)乙酸甲酯(I-E-2：R1＝CH3,R3＝CH3,)的合成
向50mL封管中加入化合物XV-2(0.43g,0.64mmol)，XX-1(0.25g,0.93mmol)，Cs2CO3(0.61g,1.56mmol)，加入Pd(OAc)2(0.02g,0.09mmol)，t-BuXPhos(0.08g,0.19mmol)和甲苯(10mL),充入N2保护，80℃回流36小时。TLC监测原料大部分反应完后，用硅藻土抽滤，液体减压浓缩得粗品，经柱层析分离得淡黄色油状物110mg，纯化得淡黄色油状物90mg，收率16.8％。
1H NMR(300MHz,Chloroform-d)δ7.50(d,J＝7.5Hz,1H,ArH),7.30-7.21(m,2H,ArH),7.15-7.09(m,2H,ArH),6.90(d,J＝7.9Hz,1H,ArH),6.81(d,J＝7.5Hz,1H,ArH),6.12(d,J＝7.9Hz,1H,ArH),5.44(s,2H,OCH2),4.45(s,1H,OH),4.31(s,2H,NCH2N),4.19-4.08(m,2H,OCH2),4.02(s,2H,NCH2),3.82(s,3H,OCH3),3.54(s,2H,COCH2),3.11(s,3H,NCH3),2.93-2.90(m,1H,1/2CH 2),2.86-2.81(m,2H,CH2),2.71-2.64(m,1H,1/2CH 2),2.50-2.43(m,1H,1/2CH 2),2.34-2.24(m,3H,1/2CH2,CH2),2.15(s,3H,ArCH3),1.99(s,3H,ArCH3),2.00-1.83(m,2H,CH2).
实施例42
2-(7-((2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-1-甲基-1,4-二氢吡啶[2,3-d]嘧啶-3(2H)-基)乙酸(I-E-3：R1＝CH3,R3＝CH3,R4＝H)的合成
向10mL茄型瓶中加入化合物I-E-1(0.20g,0.46mmol)，加入甲醇(2mL)溶解，加入2M LiOH(1mL)，室温搅拌4小时。TLC监测反应完全后，减压蒸除甲醇，用1M HCl溶液调节pH到5-6，有白色固体析出，抽滤，粗品用二氯甲烷打浆三次，得白色固体产物70mg，产率36.5％。m.p.132-134℃.
1H NMR(400MHz,Chloroform-d)δ7.59-7.38(m,2H,ArH),7.32(d,J＝1.8Hz,1H,ArH),7.30-7.23(m,2H,ArH),7.15-7.12(m,3H,ArH),6.01-5.97(m,1H,ArH),5.53(s,2H,OCH2),4.16(s,2H,NCH2N),3.72(q,J＝4.1Hz,2H,NCH2), 3.45(dd,J＝3.1Hz,2.6Hz,2H,COCH2),3.06(s,3H,ArCH3),2.63(s,3H,NCH3),2.14(s,3H,ArCH3).
HRMS(ESI):m/z[M+H]+Calcd forC25H28N3O3:418.2030；Found:418.2132.
实施例43
(R)-2-(7-((3'-(3-(3-羟基吡咯烷-1-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-1-甲基-1,4-二氢吡啶[2,3-d]嘧啶-3(2H)-基)乙酸(I-E-4：R1＝CH3,R3＝CH3,)的合成
以化合物I-E-2(90mg,0.16mmol)和2M LiOH(1mL)为原料，操作同I-E-3，得灰白色固体产物80mg，产率54.7％。m.p.162-164℃.
1H NMR(300MHz,DMSO-d6)δ7.43(d,J＝7.5Hz,1H,ArH),7.26(d,J＝8.1Hz,1H,ArH),7.2(d,J＝8.5Hz,1H,ArH),7.15(d,J＝7.8Hz,1H,ArH),7.04(d,J＝7.5Hz,1H,ArH),6.97(d,J＝8.2Hz,1H,ArH),6.69(d,J＝7.6Hz,1H,ArH),6.01(d,J＝7.8Hz,1H,ArH),5.36(s,2H,OCH2),4.25(s,1H,OH),4.16(s,2H,NCH2N),4.-0-4.13(m,3H,OCH 2CH2,CH),3.82(s,2H,ArCH2N),3.32(s,4H,CHCH 2N,NCH 2),2.97(s,3H,NCH3),2.90-2.79(m,1H,1/2NCH 2CH2),2.79-2.68(m,3H,1/2NCH 2CH2,NCH2CH 2),2.67-2.58(m,1H,1/2CH2CH 2CH),2.02(s,3H,ArCH3),1.85(s,3H,ArCH3),1.99-1.91(m,2H,CH2),1.70-1.65(m,1H,1/2CH2CH 2CH).
HRMS(ESI):m/z[M+H]+Calcd for C32H41N4O5:561.3077；Found:561.3079.
实施例44
2-(2-((2-氯-2'-氟-[1,1'-联苯]-3-基)氨甲酰)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-F-1：R1＝Cl,R3＝F,R4＝H)的合成
2-氯-7,8-二氢-1,6-萘啶-6(5H)-乙酸叔丁酯(XXI)的合成
向25mL茄形瓶中加入2-氯-5,6,7,8-四氢-1,6-萘啶盐酸盐VIII(250mg,1.22mmol)，用5mL DCM溶解，滴加三乙胺(508μl,3.66mmol)，加入(Bco)2O(399mg,1.83mmol)，监测原料反应完全，加5mL水稀释，饱和食盐水洗涤，无水硫酸钠干燥。抽滤，减压蒸除溶剂，粗品经纯化得白色固体320mg，收率97.7％。m.p.66-68℃.
1H NMR(300MHz,Chloroform-d)δ7.39(d,J＝8.1Hz,1H,ArH),7.18(d,J＝8.1Hz,1H,ArH),4.57(s,2H,NCH2),3.74(t,J＝5.9Hz,2H,NCH 2CH2),2.99(t,J＝6.0Hz,2H,NCH2CH 2),1.50(s,9H,CH3).
2-氰基-7,8-二氢-1,6-萘啶-6(5H)-乙酸叔丁酯(XXII)的合成
将化合物XXI(500mg,1.86mmol)，氰化锌(240mg,2.05mmol)加入三颈瓶中，用5mLDMF溶解，氮气保护，加入Pd(PPh3)4(215mg,0.19m)ol)，升温至120℃反应10小时，TLC(石油醚:乙酸乙酯＝2:1)监测原料反应完全，停止加热，冷却至室温。抽滤除去钯催化剂和不溶物，加5mL水稀释，乙酸乙酯(5mL×3)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥。抽滤，减压蒸除溶剂，残留物经柱层析纯化(石油醚:乙酸乙酯＝20:1～5:1)得白色固体300mg，收率62.2％。m.p.112-114℃.
1H NMR(300MHz,Chloroform-d)δ7.54(s,2H,ArH),4.66(s,2H,NCH2),3.77(t,J＝6.0Hz,2H,NCH 2CH2),3.04(t,J＝6.0Hz,2H,NCH2CH 2),1.49(s,9H,CH3).
6-(2-(叔丁氧基)-2-氧代乙基)-5,6,7,8-四氢-1,6-萘啶-2-甲酸(XXIII)的合成
将化合物XXII(1.00g,3.86mol)溶于甲醇中，加入KOH(1.08g,19.28mol)水溶液，升温至80℃反应12小时，TLC(二氯甲烷:甲烷＝10:1)监测原料反应完全，停止反应，冷却至室温。用稀盐酸调pH至中性，加5mL水稀释，乙酸乙酯(5mL×3)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥。抽滤，减压蒸除溶剂，残留物经柱层析分离(二氯甲烷:甲醇＝25:1～5:1)得白色固体630mg，收率58.7％。m.p.162-164℃.
1H NMR(300MHz,Chloroform-d)δ8.05(s,1H,ArH),7.66(s,1H,ArH),4.69(s,2H,NCH2),3.78(s,2H,NCH 2CH2),3.06(s,2H,NCH2CH 2),1.50(s,9H,CH3).
2-氯-2'-氟-[1,1'-联苯]-3-胺(IV-2)的合成
将3-溴-2-氯苯胺II-2(1.00g,4.80mmol)、2-氟苯硼酸III-1(1.02g,7.30mmol)和20mL1,4-二氧六环依次加入三颈瓶中，将碳酸钾(1.87g,13.6mmol)溶于水加入反应液中，氮气保护，加入Pd(PPh3)4(0.28g,0.20mmol)，升温至80℃反应10小时。TLC(石油醚:乙酸乙酯＝15:1)监测原料反应完全，停止加热，冷至室温。抽滤除去钯催化剂和不溶物，加5mL水稀释，乙酸乙酯(5mL×3)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥。抽滤，减压蒸除溶剂，残留物经柱层析纯化得白色固体粉末0.97g，收率91.4％。m.p.78-80℃.
1H NMR(300MHz,DMSO-d6)δ7.43-7.40(m,1H,ArH),7.32-7.22(m,3H,ArH),7.08(dd,J＝8.1Hz,7.4Hz,1H,ArH),6.85(dd,J＝8.1Hz,1.6Hz,1H,ArH),6.50(dd,J＝7.4Hz,1.6Hz,1H,ArH),5.48(s,2H,NH).
2-((2-氯-2'-氟-[1,1'-联苯]-3-基)氨甲酰)-7,8-二氢-1,6-萘啶-6(5H)-)甲酸叔丁酯(XXIV)的合成
将化合物XXIII(500mg,1.80mmol)、IV-2(397mg,1.80mmol)用二氯甲烷溶解，加入HATU(820mg,2.16mmol)和DIPEA(697mg,5.39mmol)，室温反应12小时。TLC(二氯甲烷:甲醇＝25:1)监测原料反应完全，停止反应。加5mL水稀释，乙酸乙酯(5mL×3)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥。抽滤，减压蒸除溶剂，残留物经柱层析分离纯化得白色固体580mg，收率67.1％。m.p.134-136℃.
1H NMR(300MHz,Chloroform-d)δ10.86(s,1H,NH),8.70(dd,J＝8.3Hz,1.6Hz,1H,ArH),8.13(d,J＝7.9Hz,1H,ArH),7.63(d,J＝8.0Hz,1H,ArH),7.45-7.37(m,2H,ArH),7.30-7.34(m,1H,ArH),7.24-7.20(m,1H,ArH),7.19-7.13(m,1H,ArH),7.11(dd,J＝7.6Hz,1.6Hz,1H,ArH),4.68(s,2H,NCH2),3.79(t,J＝5.9Hz,2H,NCH 2CH2),3.07(t,J＝6.0Hz,2H,NCH2CH 2),1.51(s,9H,CH3).
N-(2-氯-2'-氟-[1,1'-联苯]-3-基)-5,6,7,8-四氢-1,6-萘啶-2-甲酰胺(XXV)的合成
将化合物XXIV(580mg,1.21mmol)用甲醇溶解，缓慢滴加氯化氢的1,4-二氧六环溶液，TLC(二氯甲烷:甲醇＝15:1)监测原料反应完全，减压蒸除溶剂，得淡黄色固体616mg，收率99.9％。m.p.大于250℃.
1H NMR(400MHz,DMSO-d6)δ10.72(s,1H,NH),8.45(m,1H,ArH),8.11(d,J＝8.0Hz,1H,ArH),8.00(d,J＝8.0Hz,1H,ArH),7.50-7.55(m,2H,ArH),7.43-7.33(m,3H,ArH),7.25(dd,J＝7.6Hz,1.6Hz,1H,ArH),4.44(s,2H,NCH2),3.54(s,2H,NCH 2CH2),3.24(t,J＝6.2Hz,2H,NCH2CH 2).
2-(2-((2-氯-2'-氟-[1,1'-联苯]-3-基)氨甲酰)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸乙酯(I-F-1)的合成将化合物XXV(250mg,0.66mmol)用THF溶解，冰浴条件下缓慢加入60％NaH(31.5mg,1.31mmol)，滴毕，转移至室温反应30分钟，向反应液中缓慢滴加溴乙酸乙酯(87μl,0.79mmol)。TLC(二氯甲烷:甲醇＝25:1)监测原料反应完全，停止反应。用饱和NH4Cl溶液淬灭反应，加5mL水稀释，乙酸乙酯(5mL×3)萃取，，无水硫酸钠干燥，抽滤，减压蒸除溶剂，残留物经柱层析分离得淡黄色固体126mg，收率41.11％。m.p.158-160℃.
1H NMR(400MHz,Chloroform-d)δ10.86(s,1H,NH),8.70(d,J＝8.2Hz,1H,ArH),8.08(d,J＝7.9Hz,1H,ArH),7.55(d,J＝7.9Hz,1H,ArH),7.44-7.36(m,2H,ArH),7.34-7.29(m,1.7Hz,1H,ArH),7.23-7.15(m,2H,ArH),7.14-7.09(m, 1H,ArH),4.28(q,J＝7.1Hz,2H,CH3CH 2),3.99(s,2H,NCH2),3.53(s,2H,COCH2),3.22-3.07(m,4H,NCH 2CH 2),1.31(t,J＝7.1Hz,3H,CH3).
实施例45
N-(2-氯-2'-氟-[1,1'-联苯]-3-基)-6-(2-羟乙基)-5,6,7,8-四氢-1,6-萘啶-2-甲酰胺(I-F-2：R1＝Cl,R3＝F,R4＝H)的合成
将化合物I-F-1(60mg,0.13mmol)溶于THF中，冰浴条件下加入LiAlH4(10mg,0.26mmol)后，转移至室温反应。TLC(二氯甲烷:甲醇＝25:1)监测原料反应完全，停止反应。用饱和NH4Cl溶液淬灭反应，加5mL水稀释，乙酸乙酯(5mL×3)萃取，无水硫酸钠干燥，抽滤，减压蒸除溶剂，残留物经柱层析分离得白色固体36mg，收率54.6％。m.p.88-90℃.
1H NMR(300MHz,Chloroform-d)δ10.85(s,1H,NH),8.70(d,J＝8.4Hz,1H,ArH),8.09(d,J＝7.9Hz,1H,ArH),7.57(d,J＝7.9Hz,1H,ArH),7.40(t,J＝7.7Hz,2H,ArH),7.35-7.28(m,1H,ArH),7.23-7.09(m,2H,ArH),3.88(s,2H,NCH2),3.79(t,J＝5.3Hz,2H,CH 2OH),3.16(t,J＝5.4Hz,2H,NCH2CH 2),3.04(t,J＝5.7Hz,2H,NCH 2CH2),2.84(t,J＝5.3Hz,2H,CH 2CH2OH).
HRMS(ESI):m/z[M+H]+Calcd for C23H22ClFN3O2:426.1385；Found:426.1382.
实施例46
2-(2-((2-氯-2'-氟-[1,1'-联苯]-3-基)氨甲酰)-7,8-二氢-1,6-萘啶-6(5H)-基)乙酸(I-F-3：R1＝Cl,R3＝F,R4＝H)的合成
将化合物I-F-1(60mg,0.13mmol)溶于乙醇中，加入NaOH(10mg,0.26mmol)水溶液，室温搅拌。TLC(二氯甲烷:甲醇＝5:1)监测原料反应完全，停止反应。加5mL水稀释，乙酸乙酯(5mL×3)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥。抽滤，减压蒸除溶剂，残留物经柱层析纯化得白色固体42mg。收率74.5％。m.p.224-226℃.
1H NMR(300MHz,DMSO-d6)δ10.75(s,1H,NH),8.49(d,J＝8.2Hz,1H,ArH),8.01-7.90(m,1H,ArH),7.81-7.69(m,1H,ArH),7.54-7.45(m,2H,ArH),7.40-7.28(m,3H,ArH),7.24-7.13(m,1H,ArH),3.84(s,2H,NCH2),3.14(s,2H,COCH2),3.03-2.88(m,4H,NCH 2CH2 ).
HRMS(ESI):m/z[M+H]+Calcd for C23H20ClFN3O3:440.1177；Found:440.1172.
实施例47
本申请的化合物对PD-1/PD-L1蛋白-蛋白相互作用的抑制活性评价
实验目的：使用PD-1/PD-L1 binding assay kit检测试剂盒(CISBIO公司)，检测式(I)化合物抑制剂PD-1/PD-L1相互作用的活性。
实验原理：HTRF(均相时间分辨荧光，Homogeneous Time-Resolved Fluorescence)是一种用来检测纯液相体系中待测物的技术。其主要利用两种荧光基团的能量转移，这两种荧光基团分为能量供体铕(Eu+)和能量受体。当供体被外来激发(例如闪光灯或激光)，若与受体在足够近的距离之内，可以将能量共振转移到受体上，受体被激发出特定的波长。利用HTRF技术，该测定法能够以高通量形式对化合物和抗体阻滞剂进行简单、快速的表征。通过使用标记有Eu+(铕)(HTRF能量供体)的抗Tag1和标记有XL665(HTRF能量受体)的抗Tag2，可以检测PD-L1与PD-1之间的相互作用。使用Tag1和Tag2分别标记PD-L1蛋白和PD-1蛋白，Eu+和XL665通过抗体分别结合到PD-L1和PD-1形成复合物。当PD-L1和PD-1相互靠近结合时，Eu+被外来激光激发后会触发朝向XL665的荧光共振能量转移，后者又在665nm处特异性发射。该特定信号与PD1/PD-L1相互作用的程度成正比。因此，阻止PD-1/PD-L1相互作用的化合物或抗体将导致HTRF信号降低。
实验材料：试剂盒购买自CISBIO公司的PD-1/PD-L1 binding assay kits；96孔板：购买自CISBIO公司。
测试仪器：Perkin Elmer，型号：EnVision。
受试化合物：式(I)中的化合物。使用DMSO溶解，diluent buffer稀释；DMSO浓度不超过0.5％。
实验过程：使用PD-1/PD-L1 binding assay kits。设置阴性组、阳性组和给药组，每组2个复孔。阳性对照组，向96孔板中加入2μL diluent；按照说明书稀释后的4μL PD-L1和4μL PD-1；阴性对照组，向96孔板中加入6μL diluent和4μL PD-L1；给药组将2μL受试(I)式化合物(或者阳性化合物BMS-202)、4μL PD-L1和4μL PD-1依次加入到96孔板中。使用封板膜封板，1000rpm离心1分钟，室温孵育15分钟。而后将Buffer稀释后的Anti-Tag-Eu3+和Anti-tag-XL665等体积混合均匀，然后每孔中加入10μL混合液，封板1000rpm离心1分钟，室温孵育2小时。移除封板膜，使用EnVision读取数据665nm和615nm的荧光强度，并计算ratio＝Signal 665nm/Signal 620nm*104。使用Graphpad计算化合物的IC50。本实验选用BMS公司的WO2015034820专利中的BMS-202为阳性药，活性数据参见表1。
数值表示<0.07μM的IC50；B表示0.07-1μM；C表示>1μM。
表1化合物在蛋白水平对hPD-1/hPD-L1的阻断作用
实验结果表明，本申请的化合物具有显著的PD-1/PD-L1蛋白-蛋白相互作用的抑制活性，其中，化合物I-A-9、I-B-2、I-D-13、I-D-14、I-D-18、I-D-19、I-D-21、I-D-22、I-D-26、I-D-27、I-D-28、I-D-30和I-E-4的抑制活性优于文献WO2015034820中的化合物BMS-202。这显示本申请的联苯类化合物可用于免疫检查点PD-1/PD-L1抑制剂。
实施例48化合物的急性毒性试验
供试样品：化合物I-D-18，化合物I-D-26，化合物I-D-27。
动物种属及数量：SD大鼠；每组6只(雌雄各半)；
给药方式：口服灌胃；
动物分组和给药剂量：溶媒空白组，化合物I-D-18组(500mg/kg，1000mg/kg，2000mg/kg)，化合物I-D-26(500mg/kg，1000mg/kg，2000mg/kg)，化合物I-D-27(500mg/kg，1000mg/kg，2000mg/kg)；
给药频率：给药1次。
试验过程：
给药当天药后笼旁观察(D1)：观察频率和时间：各组动物给药后笼旁观察急性毒性反应4小时，对出现明显异常表现的动物，进行详细临床观察。观察死亡、发病、呼吸、分泌物、粪便以及饮食、饮水情况等，并记录给药期间 大鼠体重变化。详细临床观察内容包括但不限于行为活动、皮肤、被毛、眼、耳、鼻、腹部、外生殖器、肛门、四肢、足、呼吸。观察期结束后对各组动物进行安乐死处理，所有动物均进行解剖及大体观察。
实验结果：化合物I-D-18，化合物I-D-26，化合物I-D-27，以500、1000、2000mg/kg的剂量单次灌胃给予SD大鼠，各组动物均未见死亡或濒死，各剂量组动物大体观察未见与供试品相关的改变。在本试验条件下，化合物I-D-24，化合物I-D-26，化合物I-D-27，最大耐受剂量(MTD)分别大于或者等于2000mg/kg。
实施例49化合物的14天重复给药安全性试验
供试样品：化合物I-D-18，化合物I-D-26，化合物I-D-27。
动物种属及数量：SD大鼠；每组6只(雌雄各半)；
给药方式：口服灌胃；
动物分组和给药剂量：溶媒空白组，化合物I-D-18组(300mg/kg)，化合物I-D-26(300mg/kg)，化合物I-D-27(300mg/kg)；
给药频率：每天1次，给药14天。
试验过程：
给药后进行笼旁观察急性毒性反应4小时，对出现明显异常表现的动物，进行详细临床观察。一般临床观察包括试验期间每天2次(上午和下午各观察1次)。观察死亡、发病、呼吸、分泌物、粪便以及饮食、饮水情况等，并记录给药期间大鼠体重变化。详细临床观察内容包括但不限于行为活动、皮肤、被毛、眼、耳、鼻、腹部、外生殖器、肛门、四肢、足、呼吸。给药结束后对各组动物进行安乐死处理，所有动物均进行解剖及大体观察。
给药期间动物体重生长曲线参见图1。
实验结果：化合物I-D-18，化合物I-D-26，化合物I-D-27，在给药周期(14天)内，所有剂量组动物进水进食正常，活动正常，体重正常，无明显异常表现。
实施例50对乳腺癌肿瘤细胞4T1异种移植瘤模型的药效学作用的研究
模型建立和给药方案：
动物种属及数量：Balb/c Nude；每组6只；
供试样品：化合物I-D-24，化合物I-D-26，化合物I-D-27
试验组别：空白溶剂对照组；
化合物I-D-18(10mg/kg，i.g.，QD×21天)；
化合物I-D-26(10mg/kg，i.g.，QD×21天)；
化合物I-D-27(10mg/kg，i.g.，QD×21天)；
动物模型建立：体外培养并收集对数生长期的乳腺癌肿瘤细胞4T1，以0.1mL的2×106个细胞/只数量皮下接种于裸鼠的右侧背部皮下，待瘤体积生长至50～70mm3时对荷瘤裸鼠进行随机分组。随后，对每组动物进行给药，并将首次给药当天定义为试验第1天；
给药频率：每天1次；
一般状态观察：观察时间与频率：每天1次；观察指标或内容：包括但不限于动物给药局部、外观体征、一般行为活动、精神状态、死亡等情况及其它异常表现。试验结束后对动物实施安乐死。
肿瘤体积计算：V＝1/2×长径×短径2(mm3)。
实验结果：
下表中，“+”表示抑瘤率<20％；“++”表示抑瘤率20％～60％；“+++”表示抑瘤率>60％。
化合物肿瘤抑瘤率：
本发明化合物在BALB/c小鼠4T1皮下移植瘤模型中动物肿瘤生长曲线见图2。
以上数据表明，化合物I-D-18，化合物I-D-26，化合物I-D-27具有显著的抑制肿瘤的药效，在给药试验周期中，实验动物进水进食正常，活动正常，体重正常，并没有展现出毒性表现。
本发明化合物的有效性和安全性显著优于BMS-202，提示本发明化合物具有更好的治疗优势和潜在应用价值。
实施例51化合物I-D-18的胶囊制剂产品初步研究
配方组成：

胶囊制备方法：
混合：将已称好的化合物I-D-18，淀粉，羧甲淀粉钠加入湿法混合制粒机中进行混合。
粘合剂溶液配制：称取纯化水，在搅拌状态下，缓缓加入适量淀粉，搅拌分散均匀制备得到黏合剂——淀粉浆。
制软材：采用湿法混合制粒机，控制搅拌转速和剪切转速，缓缓加入淀粉浆，搅拌，剪切，制得软材。
制粒：将制得的软材采用摇摆式制粒机24目筛制粒，得湿颗粒。
干燥：将湿颗粒加入流化床制粒机中，得干燥颗粒。
整粒：将干燥颗粒采用摇摆式制粒机筛整粒，得整粒后的颗粒，称量。
混合：将整粒后的颗粒加入万相混合机中，待混合结束，再加入硬脂酸镁，总混得总混颗粒。
充填：采用充填机，将总混颗粒充填至明胶空心胶囊，筛选出合格胶囊，得待包装胶囊。
得到外观整洁的胶囊样品。

Claims (15)

  1. 通式I所示的化合物、其水合物、溶剂合物或药学上可接受的盐：
    其中：
    Ar代表
    L代表-(CH2)m-、-O-、-NH-、-CH2O-、-CF2O-、-CH2NH-、-CONH-、-HNCO-、-NHCH2-、-OCF2-、-OCH2-或-CH＝CH-，其中m代表0、1或2；
    X1、X2各自代表N或CH；
    T、V各自分别代表和-S-；其中R5代表H、C1-C6的烷基或C3-C7的环烷基；
    U代表CH或N；
    n代表0、1、2或3；
    R1和R3各自分别代表H、D、卤素、CN、C1-C3的卤代烷基、C1-C3的烷基或环丙基；
    R2代表H、取代的C1-C6烷基、取代的C3-C7环烷基或取代的C3-C7杂环烷基，所述的取代基为H、OH、NH2、COOH、酰胺基、酯基、烷氧基或醛基，可以是单取代或多取代，所述杂环烷基包含1～3个选自N、O、S的杂原子；
    R4代表H、卤素、CN、CF3、OH、NH2、-O(CH2)pR6、取代的C1-C6烷基、取代的C3-C7环烷基或取代的C3-C7杂环烷基，所述的取代基为H、OH、NH2、COOH、酰胺基、酯基、烷氧基，可以是单取代或多取代，其中p代表1、2、3或4，所述杂环烷基包含1～3个选自N、O、S的杂原子；
    R6代表NR7R8、OR7或取代的C4-C6的氮杂环烷基，其中R7代表H或C1-C3烷基，R8代表取代的C1～C6烷基，所述C4-C6氮杂环烷基为四氢吡咯-1-基、哌啶-1-基吗啉-1-基哌嗪-1-基或氮杂环丁烷-1-基，所述的取代基为OH、NH2、COOH、酰胺基、酯基、烷氧基，可以是单取代或多取代。
  2. 根据权利要求1所述的化合物、其水合物、溶剂合物或药学上可接受的盐，其特征在于，其中：
    Ar代表
    L代表-(CH2)m-、-CH2O-、-CF2O-、-CONH-、-NHCO-或-OCH2-，其中m代表0；
    X1和X2各自代表N或CH；
    T、V各自代表-CH2-、-O-、-NH-或
    U代表N；
    n代表0或1；
    R1和R3各自分别代表H、D、F、Cl、Br、CN、CH3或CF3；
    R2代表H、其中q代表0或1，R9和R10各自分别代表H、OH、COOH、CH2COOH、CH2NH2、CH2OH、CH2CH2OH、F、Cl、Br、CH3、CH2CH3；
    R11代表OH、NH2、NHCH3、CH3、OCH3、OCH2CH3、OCH(CH3)2；；
    R12代表CONH2、NHCOCH3、OH、CH2OH、CH2CH2OH、COOH、COOCH3、COOCH2CH3、COOCH(CH3)2；
    R13代表H、CH3、CH2CH3、CH2OH、CH2CH2OH；
    R4代表H、F、Cl、Br、CN、CF3、OH、NH2或-O(CH2)pR6，其中p代表2、3或4，R6代表OH、其中R9、R10、R11、R12和R13的定义同前，R14代表CH3、CH2CH3、CH2CH2OH、甲酰基或乙酰基，R15和R16各自分别代表H、OH、COOH、NH2、CH3、CH2CH3、CH2OH、CH2CH2OH、CONH2、环丙基、COOCH3、COOCH2CH3或COOCH(CH3)2，W代表-CH2-、-O-、-NH-、 r代表0或1。
  3. 根据权利要求1和2所述的化合物、其水合物、溶剂合物或药学上可接受的盐，其特征在于，其中Ar代表
    L代表-CH2O-或-NHCO-；
    X1代表CH或N；
    X2代表CH；
    T代表或-CH2-；
    U代表N；
    V代表-CH2-或
    n＝0或1；
    R1和R3各自分别代表H、F、Cl、Br、CN、CH3或CF3；
    R2代表H、其中q代表0或1；
    R9和R10各自分别代表H、OH、COOH、CH2COOH、CH2OH、CH3或CH2CH3；
    R11代表OH、NH2、NHCH3、OCH3或OCH2CH3；
    R12代表CONH2、NHCOCH3、OH、CH2OH、COOH、COOCH3、COOCH2CH3；
    R13代表H、CH3、CH2CH3、CH2OH或CH2CH2OH；
    R4代表H、F、Cl、Br、CN、CF3、OH、NH2或-O(CH2)pR6，其中p代表2、3或4，R6代表OH、COOH、CH2OH、NH2、NHCH3、CONH2、NHCOCH3、COOCH3、COOCH2CH3或其中R15和R16各自分别代表H、OH、CH3、CH2OH、CONH2、COOCH3或COOCH2CH3；
    W代表CH2、O、NH或N-CH3；
    r代表0或1。
  4. 根据权利要求1～3之一所述的化合物、其水合物、溶剂合物或药学上可接受的盐，其特征在于，Ar代表
    L代表-CH2O-和-NHCO-；
    X1代表CH或N，X2代表CH；
    T代或-CH2-；
    U代表N；
    V代表-CH2-；
    n＝0或1。
  5. 根据权利要求1～4之一所述的化合物、其水合物、溶剂合物或药学上可接受的盐，其特征在于，R1和R3各自分别代表F、Cl、Br、CN、CH3或CF3。
  6. 根据权利要求1～5之一所述的化合物、其水合物、溶剂合物或药学上可接受的盐，其特征在于，其中R2代表：H、
  7. 根据权利要求1～6之一所述的化合物、其水合物、溶剂合物或药学上可接受的盐，其特征在于，R4代表H、F、Cl、CN、CF3、OH、NH2或-O(CH2)3R6，其中R6代表OH、CONH2、CH2OH、COOH、COOCH3、COOCH2CH3或
  8. 选自以下任一式的化合物、其水合物、溶剂合物或药学上可接受的盐：



  9. 根据权利要求8所述的化合物、其水合物、溶剂合物或药学上可接受的盐，其特征在于，所述化合物为I-A-9、I-B-2、I-D-13、I-D-14、I-D-18、I-D-19、I-D-21、I-D-22、I-D-26、I-D-27、I-D-28、I-D-30或I-E-4。
  10. 根据权利要求1～9中任一项所述的化合物、其水合物、溶剂合物或药学上可接受的盐，其特征在于，药学上可接受的盐为权利要求1的通式I化合物与下列酸形成的酸加成盐：氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
  11. 根据权利要求1所述的化合物的制备方法，包括如下步骤：
    当Ar代表X1和X2各自代表CH，L代表-(CH2)m-，m＝0，T代表C＝O，U代表N，V代表CH2，n＝0时，式I-A的合成路线为：
    当Ar代表X1代表N，X2代表CH，L代表-(CH2)m-，m＝0，T代表CH2，U代表N，V代表CH2，n＝1时，式I-B的合成路线为：
    当Ar代表X1代表N，X2代表CH，L代表-(CH2)m-，m＝0，T为CH2，U代表N，V代表CH2，n＝1时，式I-C的合成路线为：
    当Ar代表X1代表N，X2代表CH，L代表-CH2O-，T为CH2，U代表N，V代表CH2，n＝1时，式I-D的合成路线为：
    当Ar代表X1代表N，X2代表CH，L代表-CH2O-，T代表CH2，U代表N，V代表NCH3，n＝1时，式I-E的合成路线为：
    或者，
    当Ar代表X1代表N，X2代表CH，L代表-HNCO-，T代表CH2，U代表N，V代表CH2，n＝1时，式I-F的合成路线为：

  12. 一种药物组合物，其特征在于，包含权利要求1～10中任一项所述的化合物、其水合物、溶剂合物或药学上可接受的盐及药学上可接受的载体。
  13. 权利要求1～10中任一项的化合物、其水合物、溶剂合物或药学上可接受的盐在制备PD-1/PD-L1抑制剂药物中的用途。
  14. 权利要求1～10中任一项的化合物、其水合物、溶剂合物或药学上可接受的盐在制备抗肿瘤药物中的用途。
  15. 治疗肿瘤的方法，其包括向有需要的患者施用治疗有效量的权利要求1～10中任一项的化合物、其水合物、溶剂合物或药学上可接受的盐。
PCT/CN2023/127693 2022-11-22 2023-10-30 新型双环类pd-l1抑制剂及其制备方法与医药用途 Ceased WO2024109462A1 (zh)

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