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WO2020088357A1 - 联苯类化合物、其中间体、制备方法、药物组合物及应用 - Google Patents

联苯类化合物、其中间体、制备方法、药物组合物及应用 Download PDF

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WO2020088357A1
WO2020088357A1 PCT/CN2019/113209 CN2019113209W WO2020088357A1 WO 2020088357 A1 WO2020088357 A1 WO 2020088357A1 CN 2019113209 W CN2019113209 W CN 2019113209W WO 2020088357 A1 WO2020088357 A1 WO 2020088357A1
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substituted
group
alkyl
alkoxy
ring
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French (fr)
Inventor
王玉光
张农
吴添智
何敏
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Shanghai Maxinovel Pharmaceuticals Co Ltd
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Shanghai Maxinovel Pharmaceuticals Co Ltd
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Priority to AU2019373702A priority Critical patent/AU2019373702A1/en
Priority to EP19878365.6A priority patent/EP3875458A4/en
Priority to US17/288,946 priority patent/US20210387941A1/en
Priority to SG11202105850YA priority patent/SG11202105850YA/en
Priority to JP2021524391A priority patent/JP2022513592A/ja
Priority to KR1020217016692A priority patent/KR20210089195A/ko
Publication of WO2020088357A1 publication Critical patent/WO2020088357A1/zh
Anticipated expiration legal-status Critical
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Definitions

  • the present disclosure relates to a biphenyl compound, its intermediate, preparation method, pharmaceutical composition and application.
  • PD-1 (programmed death 1) programmed death receptor 1 is an important immunosuppressive molecule. It is a member of the CD28 superfamily and was originally cloned from the apoptotic mouse T cell hybridoma 2B4.11. Immunomodulation with PD-1 as a target has important significance in fighting tumors, anti-infections, anti-autoimmune diseases and organ transplantation survival. Its ligand PD-L1 can also be used as a target, and the corresponding antibody can also play the same role.
  • PD-1 / PD-L1 plays a negative immunomodulatory role.
  • PD-1 and PD-L1 on the cell surface can cause Tyr phosphorylation of the immunoreceptor tyrosine-based motif (Immunoreceptor Tyrosine-based Swith motifs, ITSM) domain in the cytoplasmic region of T cells
  • Immunoreceptor Tyrosine-based Swith motifs, ITSM immunoreceptor tyrosine-based Swith motifs, ITSM domain
  • Phosphorylated Tyr recruits phosphatase protein tyrosinase 2 and protein tyrosinase 1, which not only blocks the activation of extracellular signal-regulated kinases, but also blocks phosphatidylinositol 3-kinase (PI3K) and Activation of serine-threonine protein kinase (Akt) ultimately inhibits T lymphocyte proliferation and secretion of related cytokines.
  • PI3K phosphatid
  • PD-1 / PD-L1 signal can inhibit T cell activation and proliferation, and at the same time, the secretion of cytokines interleukin 2 (IL2), interferon gamma and IL-10 is also reduced (Eur. J. Immunol., 2002 , 32 (3), 634-643.).
  • the PD-1 / PD-L1 signal is also similar to T cells in the immune function of B cells.
  • PD-1 cytoplasmic region binds to protein tyrosinase 2 The tyrosinase at the site acts and eventually blocks the activation of B cells.
  • the role of immunonegative regulator PD-1 / PD-L1 in tumor immune escape has attracted more and more attention.
  • a large number of studies have confirmed that the PD-L1 on the surface of tumor cells in the tumor microenvironment is increased, and at the same time, it binds to PD-1 on activated T cells to transmit negative regulatory signals, resulting in tumor antigen-specific T cell apoptosis or immune incompetence. Thereby suppressing the immune response, and thereby promoting the escape of tumor cells.
  • PD-1 / PD-L1 antibody inhibitors currently on the market include Nivolumab of BMS (2014), Lambrolizumab of Merck (2014) and Atezolizumab of Roche (2016).
  • PD-1 / PD-L1 antibody inhibitors under study include Pidilizumab of Cure Tech, AMP-224 of GSK and AstraZeneca MEDI-4736. These are all biological macromolecules, and the small molecule PD-1 / PD-L1 inhibitors are still in the early stage of development.
  • the PD-L1 small molecule inhibitor AC-170 of Curis peptides (WO2012168944, WO2015033299, WO2015033301, WO2015036927, WO2015044900) Just entered the clinical phase I, BMS benzyl phenyl ether class of small molecule PD-1 / PD-L1 inhibitors (WO2015034820, WO2015160641, WO2017066227, WO2018009505, WO2018044963, WO2018118848) are still in the preclinical research stage, Incyte is also doing A series of small molecule PD-1 / PD-L1 inhibitors (WO2017070089, WO2017087777, WO2017106634, WO2017112730, WO2017192961, WO2017205464, WO2017222976, WO2018013789, WO2018044783, WO2018119221, WO2018119224, WO2018119263, WO2018219266, WO2018119286)
  • small molecular compounds can pass through cell membranes and act on intracellular targets, so they have a wide range of applications.
  • small molecules often have good bioavailability and compliance after chemical modification, effectively avoiding the decomposition and inactivation of enzymes in the digestive intestine.
  • the research on small molecules is quite mature at various levels such as production process, dosage form design and administration methods.
  • the purpose of the present disclosure is to provide a biphenyl compound completely different from the prior art, its intermediate, preparation method, pharmaceutical composition and application.
  • the biphenyl compounds of the present disclosure have a significant inhibitory effect on PD-1 and / or PD-L1, and can effectively alleviate or treat cancer and other related diseases.
  • the present disclosure provides a biphenyl compound represented by general formula I, a pharmaceutically acceptable salt thereof, a tautomer, a racemate, a racemate, a stereoisomer or a prodrug:
  • Ring A and Ring B are independently aromatic or heteroaromatic rings
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, deuterium, halogen, cyano, or substituted or unsubstituted alkyl;
  • R 1 and R 2 are independently deuterium, halogen, cyano or substituted or unsubstituted alkyl
  • Each R 3 and each R 4 are independently hydrogen, deuterium, hydroxyl, -SR 11 , -NR 12 R 13 , halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -CONH 2 , -COR 14 , -COOR 15 or -OCOR 16 ;
  • R 11 , R 12 and R 13 are independently hydrogen, C 1 -C 4 alkyl, substituted C 1 -C 4 alkyl or -COR a , R a is hydrogen, hydroxy, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
  • R 14 , R 15 and R 16 are independently hydrogen, C 1 -C 4 alkyl or substituted C 1 -C 4 alkyl;
  • substitution in the substituted C 1 -C 4 alkyl refers to C 6 -C 14 aryl, substituted C 6 -C One or more of 14 aryl, C 1 -C 10 heteroaryl and substituted C 1 -C 10 heteroaryl;
  • the substituted alkyl group, the substituted alkyl group described in each R 3 and each R 4 or the substituent in the substituted alkoxy group is selected from halogen, cyano, C 1 -C 4 alkyl , Hydroxyl, C 6 -C 14 aryl, substituted C 6 -C 14 aryl, C 1 -C 10 heteroaryl, substituted C 1 -C 10 heteroaryl, C 1 -C 4 alkoxy, C 1- One or more of C 4 carboxyl group, C 1 -C 4 ester group and C 1 -C 4 amide group; Wherein R 17 and R 18 are independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 6 -C 14 aryl, substituted or unsubstit
  • the substituents in the C 1 -C 4 alkoxy group and the substituted 5-7 membered carbon heterocycle are selected from halogen, cyano, C 1 -C 4 alkyl, substituted C 1 -C 4 alkyl, C 6 -C 14 aryl, substituted C 6 -C 14 aryl, C 1 -C 10 heteroaryl, substituted C 1 -C 10 heteroaryl, hydroxy, One or more of C 1 -C 4 alkoxy, C 1 -C 4 carboxy, C 1 -C 4 ester and C 1 -C 4 amide;
  • R 17 and R 18 when the substituted C 1 -C 4 alkyl group, the substituted C 6 -C 14 aryl group, the substituted C 3 -C 6 cycloalkyl group, the When the substituted C 1 -C 4 alkoxy group and the substituent in the substituted 5-7 membered carbon heterocycle is a substituted C 1 -C 4 alkyl group, in the substituent, the substituted C 1
  • the substituents in the -C 4 alkyl group are selected from halogen, cyano, C 1 -C 4 alkyl, C 6 -C 14 aryl, substituted C 6 -C 14 aryl, C 1 -C 10 heteroaryl , Substituted C 1 -C 10 heteroaryl, hydroxyl, One or more of C 1 -C 4 alkoxy, C 1 -C 4 carboxy, C 1 -C 4 ester and C 1 -C 4 amide; Wherein R a1 and R b1 are independently hydrogen, C
  • C 1 -C 10 heteroaryl refers to heteroatom selected from N, O and S, the number of hetero atoms from 1 to 4 C 1 -C 10 heteroaryl;
  • the substituents in all the substituted C 6 -C 14 aryl groups and substituted C 1 -C 10 heteroaryl groups are selected from cyano, halogen, hydroxy, C 1 -C 4 alkyl and C 1 -C 4 alkoxy One or more of the base;
  • substituents are the same or different;
  • n 1, 2 or 3;
  • n 1, 2 or 3.
  • aromatic rings refer to any stable monocyclic or bicyclic carbocyclic ring of up to 7 atoms in each ring, at least one of which is an aromatic ring. All terms aromatic rings are preferably C 6 -C 20 aromatic rings, more preferably C 6 -C 14 aromatic rings, most preferably C 6 -C 10 aromatic rings. Examples of aromatic rings include but are not limited to benzene, naphthalene, tetrahydronaphthalene, indan, biphenyl, phenanthrene, anthracene or acenaphthene.
  • heteroaromatic rings refer to stable monocyclic or bicyclic rings of up to 7 atoms in each ring, where at least one ring is an aromatic ring and contains 1-4 selected from O, N, and S Heteroatom.
  • heteromatic ring preferably refers to a C 1 -C 10 heteroaromatic ring in which hetero atoms are selected from O, N, and S, and the number of hetero atoms is 1, 2, 3, or 4, more preferably a hetero atom is selected From O, N and S, the number of hetero atoms is 1, 2, 3 or 4 C 1 -C 8 heteroaromatic rings, more preferably the hetero atoms are selected from O, N and S, the number of hetero atoms is 1, 2, 3 or 4 C 1 -C 6 heteroaromatic rings.
  • heteroaromatic rings include but are not limited to: acridine, carbazole, cinnoline, carboline, quinoxaline, imidazole, pyrazole, pyrrole, indole, indoline, benztriazole, benzimidazole Furan, thiophene, isothiazole, benzothiophene, dihydrobenzothiophene, benzofuran, isobenzofuran, benzoxazole, benzofuran, benzopyrazole, quinoline, isazaindene, Quinoline, oxazole, oxadiazole, isoxazole, indole, pyrazine, pyridopyridine, tetrazopyridine, pyridazine, pyridine, naphthyridine, pyrimidine, pyrrole, tetrazole, thiadiazole, thiazole, Thiophene, triazole,
  • cycloalkyl are preferably C 3 -C 20 cycloalkyl, more preferably C 3 -C 10 cycloalkyl, and most preferably C 3 -C 6 cycloalkyl.
  • cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecane and cyclododecyl and cyclohexenyl.
  • heterocycloalkyl refer to C 2 -C 10 non-aromatic rings with heteroatoms selected from O, N, and S, and having 1, 2, 3, or 4 heteroatoms.
  • the heterocyclic alkyl group preferably has a hetero atom selected from O, N, and S, and the C 2 -C 8 heterocyclic alkyl group has 1, 2, 3, or 4 hetero atoms, and further preferably has a hetero atom selected from O , N and S, C 2 -C 6 heterocycloalkyl having 1, 2, 3 or 4 heteroatoms.
  • heterocycloalkyl examples include, but are not limited to: tetrahydropyranyl, azetidine, 1,4-dioxanyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, sulfur Dimorpholinyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyridine Azinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydro Thienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl
  • aryl are preferably C 6 -C 20 aryl, more preferably C 6 -C 14 aryl, and most preferably C 6 -C 10 aryl.
  • aryl groups include, but are not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, and acenaphthyl.
  • heteroaryl are preferably heteroatoms selected from O, N, and S, C 1 -C 10 heteroaryl groups having 1, 2, 3, or 4 heteroatoms, and more preferably heteroatoms are selected from O, N, and S, C 1 -C 8 heteroaryl groups with 1, 2, 3, or 4 heteroatoms, more preferably hetero atoms are selected from O, N, and S, with 1, 2 heteroatoms , 3 or 4 C 1 -C 6 heteroaryl groups.
  • heteroaryl groups include, but are not limited to, benzimidazolyl, benzofuranyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, carbazole , Carboline, cinnoline, furanyl, imidazolyl, indoline, indolyl, indazolyl, isobenzofuranyl, isazaindenyl, isoquinolinyl, isothiazolyl , Isoxazolyl, naphthyrimidinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxobutyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine Pyridinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, qui
  • halogen are preferably fluorine, chlorine, bromine or iodine.
  • alkyl includes branched and straight-chain saturated aliphatic hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 8 carbon atoms.
  • alkyl groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl , 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and their various isomers.
  • the alkyl group is preferably a C 1 -C 4 alkyl group, and more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a tert-butyl group.
  • alkoxy means a cyclic or acyclic alkyl group having the number of carbon atoms connected by an oxygen bridge.
  • alkoxy includes the above definitions of alkyl and cycloalkyl.
  • the alkoxy group in the present disclosure is preferably a C 1 -C 4 alkoxy group, and more preferably a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, or a tert-butoxy group.
  • 5-7 membered carbon heterocycles refer to heteroatoms selected from O, N and S, the number of heteroatoms is 1, 2, 3 or 4, the number of carbon atoms is 1, 2, 3, 4, 5 or 6 5-7 membered carbon heterocycles. There are 5, 6 or 7 ring atoms in the 5-7 membered carbon heterocycle.
  • the 5-7 membered carbon heterocycle includes but is not limited to: azetidine, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrogen Imidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridine , Dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrotriazolyl and dihydroazetidinyl .
  • L 2 is absent.
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen or deuterium.
  • R 1 is halogen, such as F, Cl, Br or I.
  • R 1 is cyano
  • R 1 is alkyl, preferably C 1 -C 4 alkyl, more preferably methyl.
  • R 1 is substituted alkyl.
  • the substituent in the substituted alkyl group is preferably halogen or hydroxyl.
  • R 1 is preferably an alkyl group substituted with halogen.
  • the alkyl group substituted with halogen is preferably a C 1 -C 4 alkyl group substituted with one or more of F, Cl, Br and I, and more preferably -CH 2 F, -CHF 2 or -CF 3 .
  • R 2 is deuterium
  • R 2 is halogen, such as F, Cl, Br or I.
  • R 2 is cyano
  • R 2 is alkyl, preferably C 1 -C 4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • R 2 is substituted alkyl, preferably substituted C 1 -C 4 alkyl.
  • the substituent in the substituted alkyl group is preferably halogen, cyano group, C 1 -C 4 alkyl group, hydroxyl group, C 1 -C 4 alkoxy group, C 1 -C 4 carboxyl group, C 1 -C 4 ester group
  • One or more of the C 1 -C 4 amide groups, when there are multiple substituents, the substituents are the same or different.
  • the halogen-substituted alkyl group is preferably a C 1 -C 4 alkyl group substituted with one or more of F, Cl, Br and I, more preferably -CH 2 F, -CHF 2 or -CF 3 .
  • R 2 is in the 1-position of the benzene ring.
  • R 3 and R 4 are preferably independently deuterium, halogen, cyano, -SR 11 , -NR 12 R 13 , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy .
  • R 3 and R 4 are preferably independently deuterium, halogen, cyano, —SR 11 , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
  • R 3 and R 4 are preferably -SR 11 , and R 11 is a substituted C 1 -C 4 alkyl group.
  • R 3 and R 4 are preferably halogen.
  • R 3 and R 4 are preferably substituted or unsubstituted alkyl.
  • the substituents in the substituted alkyl are preferably halogen, cyano, hydroxyl, C 6 -C 14 aryl, substituted C 6 -C 14 aryl, C 1 -C 10 heteroaryl, substituted C 1 -C 10 heteroaryl, C 1 -C 4 alkoxy, and C 1- One or more substitutions in the C 4 carboxyl group. When there are multiple substituents, the substituents are the same or different.
  • R 3 and R 4 are preferably substituted alkyl.
  • the substituent in the substituted alkyl group is preferably halogen, One or more of substituted C 6 -C 14 aryl and substituted C 1 -C 10 heteroaryl. When there are multiple substituents, the substituents are the same or different.
  • R 3 and R 4 are preferably alkyl substituted with halogen.
  • the alkyl group substituted with halogen is preferably a C 1 -C 4 alkyl group substituted with one or more of F, Cl, Br and I, preferably -CF 3 .
  • R 3 and R 4 are preferably Substituted alkyl.
  • the substituted alkyl group is preferably replaced by Substituted C 1 -C 4 alkyl.
  • Quilt The substituted C 1 -C 4 alkyl group is preferably Among them, one of R 17 and R 18 is H, and the other is an alkyl group substituted with a hydroxyl group and / or a carboxyl group.
  • one of R 17 and R 18 is H, and the other is an alkyl group substituted with one or more of C 1 -C 4 alkoxy, hydroxy, and carboxy.
  • R 3 or R 4 is preferably an alkyl group substituted with a substituted C 6 -C 14 aryl group, more preferably
  • R 3 or R 4 is preferably an alkyl group substituted with a substituted C 1 -C 10 heteroaryl group, more preferably
  • R 3 when R 3 is substituted or unsubstituted alkyl (being Substituted alkyl), R 3 is located in the meta or para position on the ring A atom connected to L 1 .
  • R 4 when R 4 is substituted or unsubstituted alkyl (for example, Substituted alkyl), R 4 is located in the meta or para position on the ring B atom connected to L 2 .
  • ring A when R 3 is substituted or unsubstituted alkyl (for example, Substituted alkyl), ring A may also have 0, 1, or 2 substituents. When there is one more substituent, the substituent is located on a substituted or unsubstituted alkyl group (for example, Para-, meta-, or ortho of substituted alkyl).
  • ring B when R 4 is substituted or unsubstituted alkyl (for example, Substituted alkyl), ring B may also have 0, 1, or 2 substituents. When there is one more substituent, the substituent is located on a substituted or unsubstituted alkyl group (for example, Para-, meta-, or ortho of substituted alkyl).
  • R 3 and R 4 are substituted or unsubstituted alkoxy.
  • the substituent in the substituted alkoxy group is preferably halogen, cyano, hydroxyl, One or more of C 6 -C 14 aryl, substituted C 6 -C 14 aryl, C 1 -C 10 heteroaryl, and substituted C 1 -C 10 heteroaryl. When there are multiple substituents, the substituents are the same or different.
  • R 3 and R 4 are substituted or unsubstituted alkoxy.
  • the substituent in the substituted alkoxy group is preferably halogen, cyano, hydroxyl, One of C 6 -C 14 aryl, substituted C 6 -C 14 aryl, C 1 -C 10 heteroaryl, substituted C 1 -C 10 heteroaryl and C 1 -C 4 alkoxy or Multiple replacements. When there are multiple substituents, the substituents are the same or different.
  • R 3 and R 4 are substituted alkoxy groups, and the substituents in the substituted alkoxy groups are preferably C 1 -C 10 heteroaryl and substituted C 1 -C 10 hetero One or more substituents in the aryl group, when there are multiple substituents, the substituents are the same or different.
  • the substituted alkoxy group is preferably
  • R 3 and R 4 are preferably substituted alkoxy groups, and the substituents in the substituted alkoxy groups are preferably substituted with C 1 -C 4 alkoxy groups.
  • the substituted alkoxy group is preferably
  • R 3 when R 3 is a substituted or unsubstituted alkoxy group, R 3 is located in the ortho or meta position on the ring A atom connected to L 1 .
  • R 4 when R 4 is a substituted or unsubstituted alkoxy group, R 4 is located in the ortho or meta position on the ring B atom connected to L 2 .
  • R 1 and R 2 are the same as described above.
  • M 1 and N 1 are Substituted alkyl, or one of M 1 and N 1 is Substituted alkyl, the other is substituted alkoxy; where M 1 and N 1 are The definitions of substituted alkyl groups and substituted alkoxy groups are the same as the corresponding groups in R 3 or R 4 above; the definitions of R 17 , R 18 , R 3 and R 4 are the same as described above, n1 and m1 is independently 0, 1, or 2.
  • M 1 and N 1 are Or one of M 1 and N 1 is The other is an alkoxy group substituted with one or more of C 1 -C 4 alkoxy, C 1 -C 10 heteroaryl and substituted C 1 -C 10 heteroaryl; R 3 and R 4 are preferred Hydrogen, halogen, alkyl, alkyl substituted with halogen, alkoxy or substituted alkoxy, the substituent in the substituted alkoxy is preferably C 1 -C 4 alkoxy, C 1- One or more of C 10 heteroaryl and substituted C 1 -C 10 heteroaryl are substituted; R 17 and R 18 are as defined above.
  • M 1 and N 1 are Or one of M 1 and N 1 is The other is alkoxy substituted by C 1 -C 4 alkoxy; R 3 and R 4 are preferably halogen, alkyl, alkyl substituted by halogen, alkoxy or substituted by C 1 -C 4 alkoxy Alkoxy; R 17 and R 18 are as defined above.
  • N 1 , R 17 and R 18 are the same as described above.
  • M 1 , R 17 and R 18 are the same as described above.
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen or deuterium
  • R 1 is halogen, or substituted or unsubstituted alkyl
  • R 2 is halogen, or substituted or unsubstituted alkyl
  • R 3 and R 4 are independently deuterium, halogen, cyano, —SR 11 , —NR 12 R 13 , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen or deuterium
  • R 1 is halogen, or substituted or unsubstituted alkyl
  • R 2 is halogen, or substituted or unsubstituted alkyl
  • R 3 and R 4 are independently halogen, —SR 11 , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R 11 is substituted C 1 -C 4 alkyl; the substituted The substituents in the alkyl group are halogen, cyano, hydroxyl, C 6 -C 14 aryl, substituted C 6 -C 14 aryl, C 1 -C 10 heteroaryl, substituted C 1 -C 10 heteroaryl, C 1 -C 4 alkoxy, and C 1- One or more substitutions in the C 4 carboxyl group; the substituents in the substituted alkoxy group are halogen, cyano, hydroxyl, One or more of C 6 -C 14 aryl, substituted C 6 -C 14 aryl, C 1 -C 10 heteroaryl and substituted C 1 -C 10 heteroaryl; when the substituent is multiple In this case, the substituents are the same or different.
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen or deuterium;
  • R 1 is halogen, substituted or unsubstituted alkyl
  • R 2 is halogen or alkyl
  • R 3 and R 4 are independently halogen, —SR 11 , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
  • R 11 is substituted C 1 -C 4 alkyl; the substituted
  • the substituents in the alkyl group are halogen, One or more of substituted C 6 -C 14 aryl and substituted C 1 -C 10 heteroaryl; the substituent in the substituted alkoxy is preferably C 1 -C 4 alkoxy , C 1 -C 10 heteroaryl and substituted heteroaryl C 1 -C 10 aryl group substituted with one or more; and when a plurality of substituents, said substituents are the same or different.
  • R 5 and R 6 are independently hydrogen or deuterium
  • R 1 is halogen, alkyl (preferably C 1 -C 4 alkyl, more preferably methyl), or alkyl substituted with halogen,
  • R 2 is halogen or alkyl (preferably C 1 -C 4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl),
  • R 3 and R 4 are independently halogen, —SR 11 , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R 11 is substituted C 1 -C 4 alkyl; the substituted The substituent in the alkyl group is preferably halogen, One or more substitutions in the substituted C 6 -C 14 aryl group and the substituted C 1 -C 10 heteroaryl group (further R 3 and R 4 are defined as follows: (1) R 3 and R 4 are preferably -SR 11 , R 11 is a substituted C 1 -C 4 alkyl group; (2) R 3 and R 4 are preferably alkyl groups substituted by halogen; the halogen-substituted alkyl groups are preferably substituted by F, Cl, Br and I One or more substituted C 1 -C 4 alkyl groups, preferably -CF 3 ; (3) R 3 and R 4 are preferably Substituted alkyl The substituted alkyl group is
  • the biphenyl compound represented by the general formula I described in this disclosure is preferably selected from any of the following compounds:
  • the biphenyl compound represented by the general formula I is preferably a biphenyl compound represented by the general formula I-A or II:
  • ring A, ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , M 1 , N 1 , R 17 and R 18 are the same as mentioned above, n1 is 0, 1 Or 2, m1 is 0, 1 or 2.
  • the And in ring B It can be the same or different.
  • the present disclosure also provides a method for preparing the biphenyl compound represented by the general formula I-A or II,
  • the method includes the following steps: the compound represented by the general formula II-F is carried out as follows The deprotection reaction shown to produce the biphenyl compound represented by the general formula
  • n1 is 0, 1 or 2
  • m1 is 0, 1 or 2
  • R IIF is a group containing an amino or carboxyl protecting group corresponding to M 1
  • R IIF1 is the same as N 1
  • R IIF is the same as M 1
  • R IIF1 is a protecting group containing an amino or carboxy group corresponding to N 1 Group
  • R IIF is a group corresponding to M 1 that contains an amino or carboxyl protecting group
  • R IIF1 is a group corresponding to N 1 that contains an amino or carboxyl protecting group
  • the preparation method of the biphenyl compound represented by the general formula II adopts any one of the following methods:
  • Method one includes the following steps: the compound represented by the general formula II-A and the compound II-A1 are reacted as shown below to prepare the biphenyl compound represented by the general formula II,
  • Ring A, Ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 17 and R 18 are all as defined above, n1 is 0, 1 or 2, m1 is 0, 1 Or 2; in this method, in ring A and ring B the same;
  • Method two includes the following steps: the compound represented by the general formula II-B and the compound II-B1 are subjected to the reaction shown below to prepare the biphenyl compound represented by the general formula II,
  • Ring A, Ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 17 and R 18 are all as defined above, n1 is 0, 1 or 2, m1 is 0, 1 Or 2, M is halogen; in this method, the ring A and ring B the same;
  • Method three includes the following steps: the compound represented by general formula II-C and the compound II-C1 are reacted as shown below to prepare the biphenyl compound represented by general formula II,
  • Ring A, Ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 17 and R 18 are all as defined above, n1 is 0, 1 or 2, m1 is 0, 1 Or 2; one of R IIC and R IIC1 is The other is In this method, in ring A and ring B Same or different;
  • Method 4 includes the following steps: the compound represented by the general formula II-D and the compound II-D1 are reacted as shown below to prepare the biphenyl compound represented by the general formula II,
  • Ring A, Ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 17 and R 18 are all as defined above, n1 is 0, 1 or 2, m1 is 0, 1 Or 2, one of R IID and R IID1 is The other is halogen.
  • the ring A and ring B Same or different;
  • Method 5 includes the following steps: the compound represented by general formula II-E is subjected to the deprotection reaction as shown below to prepare the biphenyl compound represented by general formula II, and the compound represented by general formula II R 17 or R 18 contains carboxyl groups;
  • ring A, ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 17 and R 18 are the same as described above, n1 is 0, 1 or 2, m1 is 0, 1 or 2, R IIE and R IIE1 are Each R 17 'and each R 18' are the same or different, and at least a carboxy protecting group, free carboxyl protecting group R 17 'and R 18' each corresponding to general formula II, R 17 and R 18 The same; in this method, the ring A and ring B Same or different.
  • the present disclosure also provides compounds represented by the general formulas II-A, II-B, II-C, II-D, II-E, and II-F:
  • Ring A, Ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , M 1 , N 1 , R 17 and R 18 are all as defined above, n1 is 0, 1 or 2 , M1 is 0, 1 or 2; M is halogen, one of R IIC and R IIC1 is The other is One of R IID and R IID1 is The other is halogen, R IIE and R IIE1 are Each R 17 'is the same as or different from each R 18' , and at least one has a carboxyl protecting group, and R 17 ' and R 18' without a carboxyl protecting group are the same as the corresponding R 17 and R 18 in Formula II The same; R IIF is a group corresponding to M 1 that contains an amino or carboxyl protecting group, and R IIF1 is the same as N 1 ; or, R IIF and M 1 are the same, R IIF1 is a corresponding to N 1 that contains an amino or carboxyl protecting group Group; or R
  • the present disclosure also provides the biphenyl compounds represented by the general formula I, their pharmaceutically acceptable salts, tautomers, meso, racemates, stereoisomers or prodrugs The use of the body in the preparation of PD-1 inhibitors and / or PD-L1 inhibitors.
  • the present disclosure also provides the biphenyl compounds represented by the general formula I, their pharmaceutically acceptable salts, tautomers, meso, racemates, stereoisomers, metabolites , The use of one or more of metabolic precursors and prodrugs in the preparation of a medicament for the prevention, alleviation or treatment of cancer, infection, autoimmune diseases or related diseases.
  • the cancer is preferably one or more of lung cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, blood cancer, and bone cancer.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and / or prophylactically effective amount of the biphenyl compound represented by the general formula I, its pharmaceutically acceptable salt, tautomer, and internal Racemates, racemates, stereoisomers, metabolites, metabolic precursors or prodrugs, and pharmaceutically acceptable carriers and / or diluents.
  • the pharmaceutical composition can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and Suspension), etc., preferably liquid, suspension, emulsion, suppository, injection (solution and suspension), etc.
  • any excipient known and widely used in the art may be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc .
  • binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc .
  • disintegrants such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Calcium, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceryl stearate, starch and lactose, etc .
  • disintegration inhibitors such as white sugar, glycerol tristearate, coconut oil and hydrogenation Oil
  • Adsorption accelerators such as quaternary ammoni
  • any known and widely used excipients in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc .; , Such as gum arabic powder, tragacanth powder, gelatin and ethanol; disintegrants, such as agar and kelp powder.
  • any excipients known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. .
  • the solution or suspension can be sterilized (preferably with an appropriate amount of sodium chloride, glucose or glycerin, etc.) to make an injection that is isotonic with blood.
  • any carrier commonly used in the art may also be used.
  • common dissolving agents, buffering agents and analgesics can also be added.
  • the diluent may be a conventional diluent in the art.
  • the pharmaceutical composition may be in the form of oral or sterile injectable aqueous solution, and the oral or injectable composition may be prepared according to any method known in the art for preparing pharmaceutical compositions.
  • cycloalkyl (including when used alone and included in other groups) include saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1-3 rings, which include Monocyclic alkyl, bicyclic alkyl and tricyclic alkyl.
  • alkoxy means a cyclic or acyclic alkyl group having the stated number of carbon atoms connected by an oxygen bridge.
  • alkoxy includes the above definitions of alkyl and cycloalkyl.
  • alkenyl refer to straight, branched or cyclic non-aromatic hydrocarbon groups containing the specified number of carbon atoms and at least one carbon-carbon double bond. There is preferably one carbon-carbon double bond, and up to four non-aromatic carbon-carbon double bonds may be present.
  • the alkenyl group is preferably a C 2-12 alkenyl group, and more preferably a C 2-6 alkenyl group.
  • C 2-12 alkenyl refers to alkenyl having 2-12 carbon atoms.
  • C 2-6 alkenyl refers to alkenyl having 2-6 carbon atoms, including vinyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl.
  • the straight chain, branched chain, or ring portion of the alkenyl group may contain a double bond, and if it is indicated as a substituted alkenyl group, it may be substituted.
  • alkynyl refer to straight, branched or cyclic hydrocarbon groups containing the specified number of carbon atoms and at least one carbon-carbon triple bond. There can be up to three carbon-carbon triple bonds.
  • the alkynyl group is preferably a C 2-12 alkynyl group, and more preferably a C 2-6 alkynyl group.
  • C 2-12 alkynyl refers to an alkynyl group having 2-12 carbon atoms.
  • C 2-6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms, including ethynyl, propynyl, butynyl, 3-methylbutynyl and the like.
  • carboxy means -COOH, where C 1 -C 4 carboxy means-(CH 2 ) n COOH, where n is 0, 1, 2 or 3. All terms C 1 -C 4 carboxy are preferred
  • ester groups represent -COO-, where C 1 -C 4 ester groups refer to -COOR x and R x is C 1 -C 4 alkyl.
  • amide group means "-CONR x1 R x2 " or "-NR x3 COR x4 ", R x1 , R x2 , R x3 and R x4 are independently H or C 1 -C 4 alkyl.
  • heteroaromatic rings should also be understood to include N-oxide derivatives of any nitrogen-containing heteroaromatic ring.
  • the heteroaryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or contains no heteroatoms, it is understood that the connection is made through the aromatic ring or through the ring-containing heteroatoms, respectively.
  • therapeutically effective amount refers to an amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a subject.
  • amount of the compound constituting the "therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the subject to be treated, it can be determined by those skilled in the art in a conventional manner.
  • salt pharmaceutical composition, composition, excipient, etc.
  • pharmaceutically acceptable it means that the salt, pharmaceutical composition, composition, excipient, etc. are generally non-toxic, safe, and suitable for the subject
  • mammalian subjects are preferred, and human subjects are more preferred.
  • salts refer to pharmaceutically acceptable organic or inorganic salts of the compounds of the present disclosure.
  • Exemplary salts include, but are not limited to: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinic acid Salt, lactate, salicylate, acid citrate, tartrate, oleate, tanninate, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, dragon Bile (gentisinate), fumarate, gluconate, glucuronate, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate Salt, benzenesulfonate, p-toluenesulfonate and pamoate (ie 1- 1-methylene-bis (2-hydroxy-3-naphthoate)).
  • prodrugs refer to derivatives of compounds containing bioreactive functional groups, such that under biological conditions (in vitro or in vivo), the bioreactive functional groups can cleave from the compound or otherwise react to provide the compound.
  • prodrugs are inactive, or at least less active than the compound itself, so that the compound cannot be active until it is cleaved from the biologically reactive functional group.
  • the bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound.
  • the prodrug may contain biohydrolyzable groups.
  • biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable Acyl urea.
  • stereoisomers refer to cis- and trans-isomers, R- and S-enantiomers, and diastereomers. These stereoisomers can be prepared by asymmetric synthesis or chiral separation (eg, separation, crystallization, thin layer chromatography, column chromatography, gas chromatography, high performance liquid chromatography). These stereoisomers can also be derived from diastereomers by reacting a mixture of enantiomers or racemates with an appropriate chiral compound, and then obtained by crystallization or any other suitable conventional method.
  • mammals being preferred, and humans optimal.
  • mammals as used herein include 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 human beings being optimal.
  • treating or being treated refers to the improvement, prevention, or reversal of a disease or disorder or at least one distinguishable symptom thereof. In other embodiments, treating or being treated refers to the improvement, prevention, or reversal of at least one measurable physical parameter of the disease or condition being treated, which may not be identified in the mammal. However, in another embodiment, treatment or treatment refers to slowing the progression of the disease or condition, or is physical, such as the stabilization of distinguishable symptoms, or physiological, for example, the stabilization of physical parameters, or both Both. In other embodiments, treating or being treated refers to delaying the onset of the disease or disorder.
  • the compounds of the present disclosure can be administered as a preventive measure.
  • preventing or “preventing” refers to reducing the risk of acquiring a given disease or disorder.
  • the designated compound is administered to the subject as a preventive measure, for example, a subject with a family history or tendency of cancer or autoimmune disease.
  • the reagents and raw materials used in the present disclosure are all commercially available.
  • the positive progress effect of the present disclosure is that the biphenyl compounds of the present disclosure have a significant inhibitory effect on PD-1 and PD-L1, and can effectively alleviate or treat cancer and other related diseases.
  • room temperature means 10 ° C-30 ° C; reflux means solvent reflux temperature; overnight means 8-24 hours, preferably 12-18 hours.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the nuclear magnetic resonance spectrum is obtained by Bruker Avance-500 instrument. Deuterated dimethyl sulfoxide, deuterated chloroform and deuterated methanol are used as solvents. Tetramethyl Silane (TMS) is the internal standard.
  • Mass spectrometry is obtained by liquid chromatography-mass spectrometry (LC-MS) combined instrument Agilent Technologies 6110, using ESI ion source.
  • the microwave reaction is carried out in the Explorer automatic microwave synthesizer produced by CEM of the United States.
  • the magnetron frequency is 2450MHz, and the continuous microwave output power is 300W.
  • the instrument used for HPLC preparation is Gilson 281, and the preparation column used is Shimadazu Shim-Pack, PRC-ODS, 20x250mm, 15 ⁇ m.
  • 12-b (268 mg, 1.0 mmol), 4-f (391 mg, 1.2 mmol), 1-d (541 mg, 1.3 mmol), cesium fluoride (600 mg, 4.0 mmol), potassium phosphate ( 848 mg, 4.0 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (120 mg, 0.16 mmol) and toluene (25 mL).
  • the reaction mixture was stirred at 80 ° C for 6 hours under nitrogen protection.
  • a homogeneous time-resolved fluorescence (Homogenouse Time-Resolved Fluorescence, HTRF) binding test is used to detect the binding ability of the compounds of the present disclosure to PD-1 / PD-L1.
  • the purchased kit (CisBio, # 64CUS000C-1) contains the reagents required for experiments such as PD-1, PD-L1, anti-tag1-Eu, Anti-tag2-XL665, Dilute Buffer, and Detection Buffer.
  • Chemical compound IC 50 ( ⁇ M) Chemical compound IC 50 ( ⁇ M) 1 0.0061 2 0.0044 3 0.0032 4 0.0043 5 0.0023 6 0.0028 7 0.0026 8 0.510 9 0.0075 10 0.014 11 0.0087 12 0.0047

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Abstract

本公开提供了一种联苯类化合物、其中间体、制备方法、药物组合物及应用。本公开的联苯类化合物对PD-1和/或PD-L1具有明显抑制作用，能够有效缓解或治疗癌症等相关疾病。

Description

联苯类化合物、其中间体、制备方法、药物组合物及应用
本申请要求申请日为2018/11/2的中国专利申请201811301041.9的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开涉及一种联苯类化合物、其中间体、制备方法、药物组合物及应用。
背景技术
PD-1(programmed death 1)程序性死亡受体1，是一种重要的免疫抑制分子。其为CD28超家族成员，最初是从凋亡的小鼠T细胞杂交瘤2B4.11克隆出来。以PD-1为靶点的免疫调节对抗肿瘤、抗感染、抗自身免疫性疾病及器官移植存活等均有重要的意义。其配体PD-L1也可作为靶点，相应的抗体也可以起到相同的作用。
PD-1/PD-L1发挥着负性免疫调节作用。当细胞表面的PD-1与PD-L1耦联后，可导致T细胞胞质区的免疫受体酪氨酸转换基序(Immunoreceptor Tyrosine-based Swith motifs,ITSM)结构域的Tyr磷酸化，然后磷酸化的Tyr即可募集磷酸酶蛋白酪氨酸酶2和蛋白酪氨酸酶1，不仅可阻滞细胞外信号调节激酶的活化，还可阻断磷脂酰肌醇3-激酶(PI3K)和丝氨酸-苏氨酸蛋白激酶(Akt)的激活，最终抑制T淋巴细胞增殖和相关细胞因子的分泌。PD-1/PD-L1信号可抑制T细胞活化和增殖，与此同时，细胞因子白细胞介素2(IL2)、干扰素γ和IL-10的分泌也减少(Eur.J.Immunol.,2002,32(3),634-643.)。另外，PD-1/PD-L1信号对B细胞免疫功能也类似于T细胞，当PD-1与B细胞抗原受体发生交联后，PD-1细胞质区与含有蛋白酪氨酸酶2结合位点的酪氨酸酶发生作用，最终阻滞B细胞的活化。免疫负性调节分子PD-1/PD-L1在肿瘤免疫逃逸中的作用越来越引起人们的重视。大量研究证实，肿瘤微环境中的肿瘤细胞表面PD-L1增高，同时与活化的T细胞上的PD-1结合，传递负性调控信号，导致肿瘤抗原特异性T细胞的凋亡或免疫无能，从而抑制免疫反应，进而促使肿瘤细胞的逃逸。
目前已经上市的PD-1/PD-L1抗体抑制剂有BMS的Nivolumab(2014)、Merck的Lambrolizumab(2014)和罗氏的Atezolizumab(2016)。在研的PD-1/PD-L1抗体抑制剂有Cure Tech的Pidilizumab、GSK的AMP-224和阿斯利康MEDI-4736。以上这些都是生物大分子，而小分子PD-1/PD-L1抑制剂目前还处于前期研发阶段，Curis多肽类的PD-L1小分子抑制剂AC-170(WO2012168944,WO2015033299,WO2015033301, WO2015036927,WO2015044900)刚进入临床I期，BMS苄基苯基醚类的小分子PD-1/PD-L1抑制剂(WO2015034820,WO2015160641,WO2017066227,WO2018009505,WO2018044963,WO2018118848)还在临床前研究阶段，Incyte也做了一系列的小分子PD-1/PD-L1抑制剂(WO2017070089,WO2017087777,WO2017106634,WO2017112730,WO2017192961,WO2017205464,WO2017222976,WO2018013789,WO2018044783,WO2018119221,WO2018119224,WO2018119263,WO2018219266,WO2018119286)还处在临床前研究。相较于生物大分子，小分子化合物能够穿过细胞膜作用于细胞内靶点，所以应用范围广泛。其次，小分子经化学修饰后往往具有良好的生物利用度和依从性，有效避免消化肠道中酶类的分解失活。最后，在生产工艺、剂型设计和给药方式等多种层面，小分子的研究也颇为成熟。
目前现有技术中还未出现联苯类化合物作为小分子PD-1/PD-L1抑制剂成功上市的报道，该现状亟待解决。
发明内容
本公开的目的是为了提供一种与现有技术完全不同的联苯类化合物、其中间体、制备方法、药物组合物及应用。本公开的联苯类化合物对PD-1和/或PD-L1具有明显抑制作用，能够有效缓解或治疗癌症等相关疾病。
本公开提供了一种通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或药物前体：
Figure PCTCN2019113209-appb-000001
其中，
环A和环B独立地为芳环或杂芳环；
L 1和L 2独立地为化学键、炔基、-C(R 5)＝C(R 6)-或-CR 7R 8-CR 9R 10-、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或取代或未取代的杂芳基；
R 5、R 6、R 7、R 8、R 9和R 10分别独立地为氢、氘、卤素、氰基、或取代或未取代的烷基；
R 1和R 2独立地为氘、卤素、氰基或取代或未取代的烷基；
每个R 3和每个R 4独立地为氢、氘、羟基、-SR 11、-NR 12R 13、卤素、氰基、取代或未 取代的烷基、取代或未取代的烷氧基、-CONH 2、-COR 14、-COOR 15或-OCOR 16；R 11、R 12和R 13独立地为氢、C 1-C 4烷基、取代的C 1-C 4烷基或-COR a，R a为氢、羟基、C 1-C 4烷基或C 1-C 4烷氧基；
R 14、R 15和R 16独立地为氢、C 1-C 4烷基或取代的C 1-C 4烷基；
R 11、R 12、R 13、R 14、R 15和R 16中，所述取代的C 1-C 4烷基中的取代是指被C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳基和取代的C 1-C 10杂芳基中的一个或多个取代；
L 1和L 2中所述的取代的环烷基、所述的取代的杂环烷基、所述的取代的芳基、所述的取代的杂芳基、R 1和R 2中所述的取代的烷基、每个R 3和每个R 4中所述的取代的烷基或所述的取代的烷氧基中的取代基选自卤素、氰基、C 1-C 4烷基、羟基、
Figure PCTCN2019113209-appb-000002
C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳基、取代的C 1-C 10杂芳基、C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基和C 1-C 4酰胺基中的一个或多个；
Figure PCTCN2019113209-appb-000003
中，R 17和R 18独立地为氢、取代或未取代的C 1-C 4烷基、取代或未取代的C 6-C 14芳基、取代或未取代的C 3-C 6环烷基、或取代或未取代的C 1-C 4烷氧基；或者R 17、R 18和与它们相连接的氮原子一起形成一个取代或未取代的5-7元碳杂环；所述碳杂环中，杂原子为N，或N和O，杂原子数为1-4个；每个R 17和每个R 18相同或不同；
R 17和R 18中所述的取代的C 1-C 4烷基、所述的取代的C 6-C 14芳基、所述的取代的C 3-C 6环烷基、所述取代的C 1-C 4烷氧基和所述的取代的5-7元碳杂环中的取代基选自卤素、氰基、C 1-C 4烷基、取代的C 1-C 4烷基、C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳基、取代的C 1-C 10杂芳基、羟基、
Figure PCTCN2019113209-appb-000004
C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基和C 1-C 4酰胺基中的一个或多个；
R 17和R 18中，当所述的取代的C 1-C 4烷基、所述的取代的C 6-C 14芳基、所述的取代的C 3-C 6环烷基、所述取代的C 1-C 4烷氧基和所述的取代的5-7元碳杂环中的取代基为取代的C 1-C 4烷基时，取代基中，所述的取代的C 1-C 4烷基中的取代基选自卤素、氰基、C 1-C 4烷基、C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳基、取代的C 1-C 10杂芳基、羟基、
Figure PCTCN2019113209-appb-000005
C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基和C 1-C 4酰胺基中的一个或多个；
Figure PCTCN2019113209-appb-000006
中，R a1和R b1独立地为氢、C 1-C 4的烷基或
Figure PCTCN2019113209-appb-000007
R a11为C 1-C 4的烷基；
上述所有C 1-C 10杂芳基是指杂原子选自N、O和S，杂原子数为1-4个的C 1-C 10杂芳基；
上述所有取代的C 6-C 14芳基和取代的C 1-C 10杂芳基中的取代基选自氰基、卤素、羟基、C 1-C 4烷基和C 1-C 4烷氧基中的一个或多个；
当取代基为多个时，所述的取代基相同或不同；
m为1、2或3；
n为1、2或3。
本公开中，所有术语芳环是指任何稳定的在各环中可高达7个原子的单环或者双环碳环，其中至少一个环是芳香环。所有术语芳环优选C 6-C 20芳环，更优选C 6-C 14芳环，最优选C 6-C 10芳环。芳环的实例包括但不限于苯、萘、四氢萘、2,3-二氢化茚、联苯、菲、蒽或苊。
本公开中，所有术语杂芳环是指表示各环中可高达7个原子的稳定单环或者二环，其中至少一个环是芳香环并且含有1-4个选自O、N、和S的杂原子。本公开中“杂芳环”优选是指杂原子选自O、N和S，杂原子个数为1、2、3或4个的C 1-C 10的杂芳环，进一步优选杂原子选自O、N和S，杂原子个数为1、2、3或4个的C 1-C 8的杂芳环，更优选杂原子选自O、N和S，杂原子个数为1、2、3或4个的C 1-C 6的杂芳环。杂芳环的实例包括但不限于：吖啶、咔唑、噌啉、咔啉、喹喔啉、咪唑、吡唑、吡咯、吲哚、二氢吲哚、苯并三唑、苯并咪唑、呋喃、噻吩、异噻唑、苯并噻吩、二氢苯并噻吩、苯并呋喃、异苯并呋喃、苯并噁唑、苯并呋咱、苯并吡唑、喹啉、异氮杂茚、异喹啉、噁唑、噁二唑、异噁唑、吲哚、吡嗪、吡啶并吡啶、四唑并吡啶、哒嗪、吡啶、萘嘧啶、嘧啶、吡咯、四唑、噻二唑、噻唑、噻吩、三唑、喹唑啉、四氢喹啉、二氢苯并咪唑、二氢苯并呋喃、二氢苯并噁唑和二氢喹啉。
本公开中，所有术语环烷基优选C 3-C 20环烷基，更优选C 3-C 10环烷基，最优选C 3-C 6环烷基。环烷基的实例包括但不限于：环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸烷和环十二烷基和环己烯基。
本公开中，所有术语杂环烷基是指杂原子选自O、N和S，杂原子数为1、2、3或4个的C 2-C 10的非芳香环。本公开中，杂环烷基优选杂原子选自O、N和S，杂原子数为1、2、3或4个的C 2-C 8的杂环烷基，进一步优选杂原子选自O、N和S，杂原子数为1、2、3或4个的C 2-C 6的杂环烷基。杂环烷基的实例包括但不限于：四氢吡喃基、氮杂环 丁烷基、1,4-二噁烷基、哌嗪基、哌啶基、吡咯烷基、吗啉基、硫代吗啉基、二氢呋喃基、二氢咪唑基、二氢吲哚基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢喹啉基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、亚甲基二氧基苯甲酰基、四氢呋喃基、四氢噻吩基及其N-氧化物。
本公开中，所有术语芳基优选C 6-C 20芳基，更优选C 6-C 14芳基，最优选C 6-C 10芳基。芳基的实例包括但不限于苯基、萘基、四氢萘基、2,3-二氢化茚基、联苯基、菲基、蒽基和苊基(acenaphthyl)。
本公开中，所有术语杂芳基优选杂原子选自O、N和S，杂原子个数为1、2、3或4个的C 1-C 10的杂芳基，进一步优选杂原子选自O、N和S，杂原子个数为1、2、3或4个的C 1-C 8的杂芳基，更优选杂原子选自O、N和S，杂原子个数为1、2、3或4个的C 1-C 6的杂芳基。杂芳基的实例包括但不限于苯并咪唑基、苯并呋喃基、苯并呋咱基、苯并吡唑基、苯并三唑基、苯并噻吩基、苯并噁唑基、咔唑基、咔啉基、噌啉基、呋喃基、咪唑基、二氢吲哚基、吲哚基、吲唑基、异苯并呋喃基、异氮杂茚基、异喹啉基、异噻唑基、异噁唑基、萘嘧啶基、噁二唑基、噁唑基、噁唑啉、异噁唑啉、氧环丁基、吡喃基、吡嗪基、吡唑基、哒嗪基、吡啶并吡啶基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹喔啉基、四唑基、四唑并吡啶基、噻二唑基、噻唑基、噻吩基和三唑基。
本公开中，所有术语卤素优选氟、氯、溴或碘。
本公开中，所有术语烷基包括1-20个碳原子的支链和直链的饱和脂族烃基，优选1-10个碳原子，更优选1-8个碳原子。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基、庚基、辛基、壬基、癸基、4,4-二甲基戊基、2,2,4-三甲基戊基、十一烷基、十二烷基，及它们的各种异构体。本公开中烷基优选C 1-C 4烷基，更优选甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
本公开中，所有术语烷氧基表示通过氧桥连接的具有所述碳原子数目的环状或者非环状烷基。由此，烷氧基包含以上烷基和环烷基的定义。本公开中烷氧基优选C 1-C 4烷氧基，更优选甲氧基、乙氧基、正丙氧基、异丙氧基或叔丁氧基。
本公开中，所有术语5-7元碳杂环是指杂原子选自O、N和S，杂原子数为1、2、3或4个，碳原子数为1、2、3、4、5或6个的5-7元碳杂环。所述的5-7元碳杂环中环原子为5、6或7个。本公开中，所述的5-7元碳杂环包括但不限于：氮杂环丁烷基、哌嗪基、哌啶基、吡咯烷基、吗啉基、硫代吗啉基、二氢咪唑基、二氢吲哚基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二 氢嘧啶基、二氢吡咯基、二氢喹啉基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢三唑基和二氢氮杂环丁烷基。
在一优选实施方案中，L 1为炔基、-C(R 5)＝C(R 6)-、-CR 7R 8-CR 9R 10-、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、或取代或未取代的杂芳基，优选炔基、-C(R 5)＝C(R 6)-或-CR 7R 8-CR 9R 10-，更优选-C(R 5)＝C(R 6)-，最优选-CH＝CH-。
在一优选实施方案中，L 2为炔基、-C(R 5)＝C(R 6)-、-CR 7R 8-CR 9R 10-、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、或取代或未取代的杂芳基，优选炔基、-C(R 5)＝C(R 6)-或-CR 7R 8-CR 9R 10-，更优选-C(R 5)＝C(R 6)-，最优选-CH＝CH-。
在一优选实施方案中，L 2不存在。
在一优选实施方案中，R 5、R 6、R 7、R 8、R 9和R 10分别独立地为氢或氘。
在一优选实施方案中，R 1为卤素，例如F、Cl、Br或I。
在一优选实施方案中，R 1为氰基。
在一优选实施方案中，R 1为烷基，优选C 1-C 4烷基，更优选甲基。
在一优选实施方案中，R 1为取代的烷基。所述的取代的烷基中的取代基优选卤素或羟基。R 1优选被卤素取代的烷基。，所述的被卤素取代的烷基优选被F、Cl、Br和I中的一个或多个取代的C 1-C 4烷基，更优选-CH 2F、-CHF 2或-CF 3。
在一优选实施方案中，R 2为氘。
在一优选实施方案中，R 2为卤素，例如F、Cl、Br或I。
在一优选实施方案中，R 2为氰基。
在一优选实施方案中，R 2为烷基，优选C 1-C 4烷基，更优选甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
在一优选实施方案中，R 2为取代的烷基，优选取代的C 1-C 4烷基。所述的取代的烷基中的取代基优选卤素、氰基、C 1-C 4烷基、羟基、C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基和C 1-C 4酰胺基中的一个或多个，当取代基为多个时，所述的取代基相同或不同。所述的被卤素取代的烷基优选被F、Cl、Br和I中的一个或多个取代的C 1-C 4烷基，更优选-CH 2F、-CHF 2或-CF 3。
在一优选实施方案中，R 2在苯环1位。
在一优选实施方案中，R 3和R 4优选独立地为氘、卤素、氰基、-SR 11、-NR 12R 13、取代或未取代的烷基、或取代或未取代的烷氧基。
在一优选实施方案中，R 3和R 4优选独立地为氘、卤素、氰基、-SR 11、取代或未取代的烷基、或取代或未取代的烷氧基。
在一优选实施方案中，R 3和R 4优选-SR 11，R 11为取代的C 1-C 4烷基。
在一优选实施方案中，R 3和R 4优选卤素。
在一优选实施方案中，R 3和R 4优选取代或未取代的烷基。所述的取代的烷基中的取代基优选被卤素、氰基、羟基、
Figure PCTCN2019113209-appb-000008
C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳基、取代的C 1-C 10杂芳基、C 1-C 4烷氧基和C 1-C 4羧基中的一个或多个取代。当取代基为多个时，所述的取代基相同或不同。
在一优选实施方案中，R 3和R 4优选取代的烷基。所述的取代的烷基中的取代基优选被卤素、
Figure PCTCN2019113209-appb-000009
取代的C 6-C 14芳基和取代的C 1-C 10杂芳基中的一个或多个取代。当取代基为多个时，所述的取代基相同或不同。
在一优选实施方案中，R 3和R 4优选被卤素取代的烷基。所述的被卤素取代的烷基优选被F、Cl、Br和I中的一个或多个取代的C 1-C 4烷基，优选-CF 3。
在一优选实施方案中，R 3和R 4优选被
Figure PCTCN2019113209-appb-000010
取代的烷基。所述的被
Figure PCTCN2019113209-appb-000011
取代的烷基优选被
Figure PCTCN2019113209-appb-000012
取代的C 1-C 4的烷基。所述的被
Figure PCTCN2019113209-appb-000013
取代的C 1-C 4的烷基优选
Figure PCTCN2019113209-appb-000014
Figure PCTCN2019113209-appb-000015
其中，R 17和R 18一个为H，另一个为被羟基和/或羧基取代的烷基。
在一优选实施方式中，R 17和R 18一个为H，另一个为被C 1-C 4烷氧基、羟基和羧基中的一个或多个取代的烷基。
在一优选实施方案中，当R 3和R 4为被
Figure PCTCN2019113209-appb-000016
取代的烷基时，所述的被
Figure PCTCN2019113209-appb-000017
取代的烷基优选
Figure PCTCN2019113209-appb-000018
Figure PCTCN2019113209-appb-000019
在一优选实施方案中，R 3或R 4优选被取代的C 6-C 14芳基取代的烷基，更优选
Figure PCTCN2019113209-appb-000020
在一优选实施方案中，R 3或R 4优选被取代的C 1-C 10杂芳基取代的烷基，更优选
Figure PCTCN2019113209-appb-000021
在一优选实施方式中，当R 3为取代或未取代的烷基(被
Figure PCTCN2019113209-appb-000022
取代的烷基)时，R 3位于环A上与L 1相连的原子的间位或对位。
在一优选实施方式中，当R 4为取代或未取代的烷基(例如被
Figure PCTCN2019113209-appb-000023
取代的烷基)时，R 4位于环B上与L 2相连的原子的间位或对位。
在一优选实施方式中，当R 3为取代或未取代的烷基(例如被
Figure PCTCN2019113209-appb-000024
取代的烷基)时，环A上还可有0、1或2个取代基。当还可有1个取代基时，该取代基位于取代或未取代的烷基(例如被
Figure PCTCN2019113209-appb-000025
取代的烷基)的对位、间位或邻位。
在一优选实施方式中，当R 4为取代或未取代的烷基(例如被
Figure PCTCN2019113209-appb-000026
取代的烷基)时，环B上还可有0、1或2个取代基。当还可有1个取代基时，该取代基位于取代或未取代的烷基(例如被
Figure PCTCN2019113209-appb-000027
取代的烷基)的对位、间位或邻位。
在一优选实施方案中，R 3和R 4为取代或未取代的烷氧基。所述的取代的烷氧基中的取代基优选被卤素、氰基、羟基、
Figure PCTCN2019113209-appb-000028
C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳 基和取代的C 1-C 10杂芳基中的一个或多个取代。当取代基为多个时，所述的取代基相同或不同。
在一优选实施方案中，R 3和R 4为取代或未取代的烷氧基。所述的取代的烷氧基中的取代基优选被卤素、氰基、羟基、
Figure PCTCN2019113209-appb-000029
C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳基、取代的C 1-C 10杂芳基和C 1-C 4烷氧基中的一个或多个取代。当取代基为多个时，所述的取代基相同或不同。
在一优选实施方案中，R 3和R 4为取代的烷氧基，所述的取代的烷氧基中的取代基优选被C 1-C 10杂芳基和取代的C 1-C 10杂芳基中的一个或多个取代，当取代基为多个时，所述的取代基相同或不同。所述的取代的烷氧基优选
Figure PCTCN2019113209-appb-000030
在一优选实施方案中，R 3和R 4优选取代的烷氧基，所述的取代的烷氧基中的取代基优选被C 1-C 4烷氧基取代。所述的取代的烷氧基优选
Figure PCTCN2019113209-appb-000031
在一优选实施方式中，当R 3为取代或未取代的烷氧基时，R 3位于环A上与L 1相连的原子的邻位或间位。
在一优选实施方式中，当R 4为取代或未取代的烷氧基时，R 4位于环B上与L 2相连的原子的邻位或间位。
在一优选实施方式中，基团
Figure PCTCN2019113209-appb-000032
优选
Figure PCTCN2019113209-appb-000033
其中，R 1和R 2的定义均同前所述。
在一优选实施方式中，基团
Figure PCTCN2019113209-appb-000034
优选
Figure PCTCN2019113209-appb-000035
Figure PCTCN2019113209-appb-000036
在一优选实施方式中，
Figure PCTCN2019113209-appb-000037
独立地为
Figure PCTCN2019113209-appb-000038
Figure PCTCN2019113209-appb-000039
其中M 1和N 1为被
Figure PCTCN2019113209-appb-000040
取代的烷基，或者M 1和N 1其中一个为被
Figure PCTCN2019113209-appb-000041
取代的烷基，另一个为取代的烷氧基；其中M 1和N 1中，被
Figure PCTCN2019113209-appb-000042
取代的烷基的定义和取代的烷氧基的定义，均同前R 3或R 4中相应的基团；R 17、R 18、R 3和R 4的定义均同前所述，n1和m1独立地为0、1或2。
优选地，M 1和N 1为
Figure PCTCN2019113209-appb-000043
或者M 1和N 1其中一个为
Figure PCTCN2019113209-appb-000044
另一个为被C 1-C 4烷氧基、C 1-C 10杂芳基和取代的C 1-C 10杂芳基中的一个或多个取代的烷氧基；R 3和R 4优选氢、卤素、烷基、被卤素取代的烷基、烷氧基或取代的烷氧基，所述的取代的烷氧基中的取代基优选被C 1-C 4烷氧基、C 1-C 10杂芳基和取代的C 1-C 10杂芳基中的一个或多个取代；R 17和R 18的定义均同前所述。
更优选地，M 1和N 1为
Figure PCTCN2019113209-appb-000045
或者M 1和N 1其中一个为
Figure PCTCN2019113209-appb-000046
另一个为被C 1-C 4烷氧基取代的烷氧基；R 3和R 4优选卤素、烷基、被卤素取代的烷基、烷氧基或被C 1-C 4烷氧基取代的烷氧基；R 17和R 18的定义均同前所述。
在一优选实施方式中，
Figure PCTCN2019113209-appb-000047
优选
Figure PCTCN2019113209-appb-000048
Figure PCTCN2019113209-appb-000049
Figure PCTCN2019113209-appb-000050
其中N 1、R 17和R 18的定义均同前所述。 在一优选实施方式中，
Figure PCTCN2019113209-appb-000051
优选
Figure PCTCN2019113209-appb-000052
Figure PCTCN2019113209-appb-000053
Figure PCTCN2019113209-appb-000054
其中M 1、R 17和R 18的定义均同前所述。在一优选实施方式中，
Figure PCTCN2019113209-appb-000055
独立地优选
Figure PCTCN2019113209-appb-000056
Figure PCTCN2019113209-appb-000057
Figure PCTCN2019113209-appb-000058
Figure PCTCN2019113209-appb-000059
在一优选实施方案中，
Figure PCTCN2019113209-appb-000060
优选
Figure PCTCN2019113209-appb-000061
Figure PCTCN2019113209-appb-000062
在一优选实施方式中，
Figure PCTCN2019113209-appb-000063
优选
Figure PCTCN2019113209-appb-000064
Figure PCTCN2019113209-appb-000065
在一优选实施方式中，
Figure PCTCN2019113209-appb-000066
独立地优选
Figure PCTCN2019113209-appb-000067
Figure PCTCN2019113209-appb-000068
在一优选实施方案中，
L 1为炔基、-C(R 5)＝C(R 6)-或-CR 7R 8-CR 9R 10-，
L 2为炔基、-C(R 5)＝C(R 6)-、-CR 7R 8-CR 9R 10-或不存在，
R 5、R 6、R 7、R 8、R 9和R 10分别独立地为氢或氘，
R 1为卤素、或取代或未取代的烷基，
R 2为卤素、或取代或未取代的烷基，和
R 3和R 4独立地为氘、卤素、氰基、-SR 11、-NR 12R 13、取代或未取代的烷基、或取代或未取代的烷氧基。
在一优选实施方案中，
L 1为炔基、-C(R 5)＝C(R 6)-或-CR 7R 8-CR 9R 10-，
L 2为炔基、-C(R 5)＝C(R 6)-、-CR 7R 8-CR 9R 10-或不存在，
R 5、R 6、R 7、R 8、R 9和R 10分别独立地为氢或氘，
R 1为卤素、或取代或未取代的烷基，
R 2为卤素、或取代或未取代的烷基，和
R 3和R 4独立地为卤素、-SR 11、取代或未取代的烷基、或取代或未取代的烷氧基；R 11为取代的C 1-C 4烷基；所述的取代的烷基中的取代基为被卤素、氰基、羟基、
Figure PCTCN2019113209-appb-000069
C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳基、取代的C 1-C 10杂芳基、C 1-C 4烷氧基和C 1-C 4羧基中的一个或多个取代；所述的取代的烷氧基中的取代基为被卤素、氰基、羟基、
Figure PCTCN2019113209-appb-000070
C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳基和取代的C 1-C 10杂芳基中的一个或多个取代；当取代基为多个时，所述的取代基相同或不同。
在一优选实施方案中，
L 1为炔基、-C(R 5)＝C(R 6)-或-CR 7R 8-CR 9R 10-，
L 2为炔基、-C(R 5)＝C(R 6)-、-CR 7R 8-CR 9R 10-或不存在，
R 5、R 6、R 7、R 8、R 9和R 10分别独立地为氢或氘；
R 1为卤素、取代或未取代的烷基；
R 2为卤素或烷基，
R 3和R 4独立地为卤素、-SR 11、取代或未取代的烷基、或取代或未取代的烷氧基；R 11为取代的C 1-C 4烷基；所述的取代的烷基中的取代基为被卤素、
Figure PCTCN2019113209-appb-000071
取代的C 6-C 14芳 基和取代的C 1-C 10杂芳基中的一个或多个取代；所述的取代的烷氧基中的取代基优选被C 1-C 4烷氧基、C 1-C 10杂芳基和取代的C 1-C 10杂芳基中的一个或多个取代；当取代基为多个时，所述的取代基相同或不同。
在一优选实施方案中，
L 1为-C(R 5)＝C(R 6)-(优选-CH＝CH-)，
L 2为-C(R 5)＝C(R 6)-或不存在(优选-CH＝CH-)，
R 5和R 6独立地为氢或氘，
R 1为卤素、烷基(优选C 1-C 4烷基，更优选甲基)、或被卤素取代的烷基，
R 2为卤素或烷基(优选C 1-C 4烷基，更优选甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基)，
R 3和R 4独立地为卤素、-SR 11、取代或未取代的烷基、或取代或未取代的烷氧基；R 11为取代的C 1-C 4烷基；所述的取代的烷基中的取代基优选被卤素、
Figure PCTCN2019113209-appb-000072
取代的C 6-C 14芳基和取代的C 1-C 10杂芳基中的一个或多个取代(进一步地R 3和R 4定义如下：(1)R 3和R 4优选-SR 11，R 11为取代的C 1-C 4烷基；(2)R 3和R 4优选被卤素取代的烷基；所述的被卤素取代的烷基优选被F、Cl、Br和I中的一个或多个取代的C 1-C 4烷基，优选-CF 3；(3)R 3和R 4优选被
Figure PCTCN2019113209-appb-000073
取代的烷基；所述的被
Figure PCTCN2019113209-appb-000074
取代的烷基优选被
Figure PCTCN2019113209-appb-000075
取代的C 1-C 4的烷基；所述的被
Figure PCTCN2019113209-appb-000076
取代的C 1-C 4的烷基优选
Figure PCTCN2019113209-appb-000077
其中，R 17和R 18一个为H，另一个为被C 1-C 4烷氧基、羟基和羧基中的一个或多个取代的烷基；当R 3和R 4为被
Figure PCTCN2019113209-appb-000078
取代的烷基时，所述的被
Figure PCTCN2019113209-appb-000079
取代的烷基优选
Figure PCTCN2019113209-appb-000080
Figure PCTCN2019113209-appb-000081
Figure PCTCN2019113209-appb-000082
Figure PCTCN2019113209-appb-000083
(4)R 3和R 4优选被取代的C 6-C 14芳基取代的烷基，更优选
Figure PCTCN2019113209-appb-000084
(5)R 3和R 4优选被取代的C 1-C 10杂芳基取代的烷基，更优选
Figure PCTCN2019113209-appb-000085
(6)R 3和R 4优选取代的烷氧基，所述的取代的烷氧基中的 取代基优选被C 1-C 4烷氧基、C 1-C 10杂芳基和取代的C 1-C 10杂芳基中的一个或多个取代，所述的取代的烷氧基优选
Figure PCTCN2019113209-appb-000086
)。
本公开中所述的通式I所示的联苯类化合物优选选自下列任一化合物：
Figure PCTCN2019113209-appb-000087
Figure PCTCN2019113209-appb-000088
在一优选实施方案中，所述的通式I所示的联苯类化合物优选通式I-A或II所示的联苯类化合物：
Figure PCTCN2019113209-appb-000089
其中，环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、M 1、N 1、R 17和R 18的定义均同前所述，n1为0、1或2，m1为0、1或2。
本公开中，通式II所示的联苯类化合物中，环A中的
Figure PCTCN2019113209-appb-000090
和环B中的
Figure PCTCN2019113209-appb-000091
可相同或也可不同。
本公开还提供了一种所述的通式I-A或II所示的联苯类化合物的制备方法，
通式I-A所示的化合物中，当M 1和N 1中含有-NH-或-COOH时，其采用下列方法制 备：所述方法包括下列步骤：将通式II-F所示的化合物进行如下所示脱保护反应，制得所述的通式I-A所示的联苯类化合物，
Figure PCTCN2019113209-appb-000092
其中环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、M 1和N 1的定义均同前所述，n1为0、1或2，m1为0、1或2，R IIF为M 1对应的含有氨基或羧基保护基的基团，R IIF1与N 1相同；或者，R IIF和M 1相同，R IIF1为N 1对应的含有氨基或羧基保护基的基团；或者R IIF为M 1对应的含有氨基或羧基保护基的基团，R IIF1为N 1对应的含有氨基或羧基保护基的基团；
通式II所示的联苯类化合物的制备方法采用下列任一方法：
(1)方法一包括下列步骤：将通式II-A所示的化合物和化合物II-A1进行如下所示的反应，制得所述的通式II所示的联苯类化合物，
Figure PCTCN2019113209-appb-000093
其中化合物II-A1结构如下：
Figure PCTCN2019113209-appb-000094
或其酸式盐，
环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、R 17和R 18的定义均同前所述，n1为0、1或2，m1为0、1或2；在此方法中，环A和环B中的
Figure PCTCN2019113209-appb-000095
相同；
(2)方法二包括下列步骤：将通式II-B所示的化合物和化合物II-B1进行如下所示的反应，制得所述的通式II所示的联苯类化合物，
Figure PCTCN2019113209-appb-000096
其中化合物II-B1结构如下：
Figure PCTCN2019113209-appb-000097
或其酸式盐，
环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、R 17和R 18的定义均同前所述，n1为0、1或2，m1为0、1或2，M为卤素；在此方法中，环A和环B中的
Figure PCTCN2019113209-appb-000098
相同；
(3)方法三包括下列步骤：将通式II-C所示的化合物和化合物II-C1进行如下所示的反应，制得所述的通式II所示的联苯类化合物，
Figure PCTCN2019113209-appb-000099
其中化合物II-C1结构如下：
Figure PCTCN2019113209-appb-000100
或其酸式盐，
环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、R 17和R 18的定义均同前所述，n1为0、1或2，m1为0、1或2；R IIC和R IIC1其中一个为
Figure PCTCN2019113209-appb-000101
另一个为
Figure PCTCN2019113209-appb-000102
在此方法中，环A和环B中的
Figure PCTCN2019113209-appb-000103
相同或不同；
(4)方法四包括下列步骤：将通式II-D所示的化合物和化合物II-D1进行如下所示的反应，制得所述的通式II所示的联苯类化合物，
Figure PCTCN2019113209-appb-000104
其中化合物II-D1结构如下：
Figure PCTCN2019113209-appb-000105
或其酸式盐，
环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、R 17和R 18的定义均同前所述，n1为0、1或2，m1为0、1或2，R IID和R IID1其中一个为
Figure PCTCN2019113209-appb-000106
另一个为卤素，在此方法中，环A 和环B中的
Figure PCTCN2019113209-appb-000107
相同或不同；
(5)方法五包括下列步骤：将通式II-E所示的化合物进行如下所示脱保护反应，制得所述的通式II所示的联苯类化合物，通式II所示的化合物中R 17或R 18中含有羧基；
Figure PCTCN2019113209-appb-000108
其中环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、R 17和R 18的定义均同前所述，n1为0、1或2，m1为0、1或2，R IIE和R IIE1为
Figure PCTCN2019113209-appb-000109
每个R 17’和每个R 18’相同或不同，且至少有一个有羧基保护基，不含羧基保护基的R 17’和R 18’分别与通式II中对应的R 17和R 18相同；此方法中，环A和环B中的
Figure PCTCN2019113209-appb-000110
相同或不同。
本公开还提供了通式II-A、II-B、II-C、II-D、II-E和II-F所示的化合物：
Figure PCTCN2019113209-appb-000111
Figure PCTCN2019113209-appb-000112
环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、M 1、N 1、R 17和R 18的定义均同前所述，n1为0、1或2，m1为0、1或2；M为卤素，R IIC和R IIC1其中一个为
Figure PCTCN2019113209-appb-000113
另一个为
Figure PCTCN2019113209-appb-000114
R IID和R IID1其中一个为
Figure PCTCN2019113209-appb-000115
另一个为卤素，R IIE和R IIE1为
Figure PCTCN2019113209-appb-000116
每个R 17’和每个R 18’相同或不同，且至少有一个有羧基保护基，不含羧基保护基的R 17’和R 18’分别与通式II中对应的R 17和R 18相同；R IIF为M 1对应的含有氨基或羧基保护基的基团，R IIF1与N 1相同；或者，R IIF和M 1相同，R IIF1为N 1对应的含有氨基或羧基保护基的基团；或者R IIF为M 1对应的含有氨基或羧基保护基的基团，R IIF1为N 1对应的含有氨基或羧基保护基的基团。
本公开还提供了如下所示的化合物：
Figure PCTCN2019113209-appb-000117
Figure PCTCN2019113209-appb-000118
Figure PCTCN2019113209-appb-000119
本公开还提供了所述的通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或药物前体在制备PD-1抑制剂和/或PD-L1抑制剂中的应用。
本公开还提供了所述的通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体和药物前体中的一种或多种在制备用于预防、缓解或治疗癌症、感染、自身免疫性疾病或其相关疾病的药物中的应用。
所述癌症优选肺癌、食管癌、胃癌、大肠癌、肝癌、鼻咽癌、脑肿瘤、乳腺癌、宫颈癌、血癌和骨癌中的一种或多种。
本公开还提供了一种药物组合物，其包括治疗和/或预防有效量的所述的通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体或药物前体，及药学上可接受载体和/或稀释剂。
本公开中，根据治疗目的，可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等，优选液体、悬浮液、乳液、栓剂和针剂(溶液及悬浮液)等。
为了使片剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。例如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液，羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油；吸附促进剂，如季胺碱和十二烷基硫酸钠等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。还可以根据需要选用通常的涂渍材料制成糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。
为了使丸剂形式的药物组合物成形，可使用本领域任何已知的并广泛使用的赋形剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石粉等；粘合剂，如阿拉伯树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。
为了使栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋性剂，例如，聚乙二醇，椰子油，高级醇，高级醇的酯，明胶和半合成的甘油酯等。
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油等)，制成与血液等渗压的针剂。在制备针剂时，也可使用本领域内任何常用的载体。例如，水，乙醇，丙二醇，乙氧基化的异硬脂醇，聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可加入通常的溶解剂、缓冲剂和止痛剂等。
所述药物组合物中，所述稀释剂可为本领域中常规的稀释剂。
所述药物组合物可以是口服的形式，也可以是无菌注射水溶液形式，可按照本领域任何已知制备药用组合物的方法制备口服或注射组合物。
除非另有说明，在本公开说明书和权利要求书中出现的以下所有术语具有下述含义：
所有术语环烷基(包括单独使用及包含在其它基团中时)包含饱和或部分不饱和(包含1或2个双键)的包含1-3个环的环状碳氢基团，其包括单环烷基、双环烷基以及三 环烷基。
所有术语烷氧基表示通过氧桥连接的具有所述碳原子数目的环状或者非环状烷基。由此，烷氧基包含以上烷基和环烷基的定义。
所有术语烯基是指含有指定数目碳原子和至少一个碳碳双键的直链、支链或者环状非芳香烃基。优选存在一个碳碳双键，并且可以存在高达四个非芳香碳碳双键。烯基优选为C 2-12烯基，进一步优选为C 2-6烯基。由此，C 2-12烯基是指具有2-12个碳原子的烯基。C 2-6烯基是指具有2-6个碳原子的烯基，包括乙烯基、丙烯基、丁烯基、2-甲基丁烯基和环己烯基。烯基的直链、支链或者环部分可以含有双键，并且如果表明为取代烯基，那么可以被取代。
所有术语炔基是指含有指定数目碳原子和至少一个碳碳三键的直链、支链或者环状烃基。其中可以存在高达三个碳碳三键。炔基优选为C 2-12炔基，进一步优选为C 2-6炔基。由此，C 2-12炔基是指具有2-12个碳原子的炔基。C 2-6炔基是指具有2-6个碳原子的炔基，包括乙炔基、丙炔基、丁炔基和3-甲基丁炔基等等。
所有术语羟基表示
Figure PCTCN2019113209-appb-000120
所有术语氨基表示
Figure PCTCN2019113209-appb-000121
所有术语氰基表示-CN。
所有术语羧基表示-COOH，其中C 1-C 4羧基是指-(CH 2) nCOOH，n为0、1、2或3。所有术语C 1-C 4羧基优选
Figure PCTCN2019113209-appb-000122
Figure PCTCN2019113209-appb-000123
所有术语酯基表示-COO-，其中C 1-C 4酯基是指-COOR x，R x为C 1-C 4烷基。
所有术语酰胺基表示“-CONR x1R x2”或“-NR x3COR x4”，R x1、R x2、R x3和R x4独立地为H或C 1-C 4烷基。
所有术语杂芳环还应当理解为包括任何含氮杂芳环的N-氧化物衍生物。在其中杂芳基取代基是二环取代基并且一个环是非芳香环或者不包含杂原子的情况下，可以理解，连接分别通过芳环或者通过包含环的杂原子进行。
所有术语治疗有效量是指在给予受试者时足以有效治疗本文所述的疾病或病症的化合物的量。虽然构成“治疗有效量”的化合物的量将根据化合物、病症及其严重度、以及欲 治疗受试者的年龄而变化，但可由本领域技术人员以常规方式确定。
当提到具体盐、药物组合物、组合物、辅料等“药学上可接受的”时，是指该盐、药物组合物、组合物、辅料等一般无毒、安全，并且适合于受试者使用，优选哺乳动物受试者，更优选为人受试者。
所有术语药学上可接受的盐指本公开化合物的药学上可接受的有机或无机盐。示例性盐包括但不限于：硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐(gentisinate)、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲烷磺酸盐、乙烷磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1-1-亚甲基-双(2-羟基-3-萘甲酸盐))。
所有术语药物前体是指包含生物反应官能团的化合物的衍生物，使得在生物条件下(体外或体内)，生物反应官能团可从化合物上裂解或以其他方式发生反应以提供所述化合物。通常，药物前体无活性，或者至少比化合物本身活性低，使得直到将所述化合物从生物反应官能团上裂解后才能发挥其活性。生物反应官能团可在生物条件下水解或氧化以提供所述化合物。例如，药物前体可包含可生物水解的基团。可生物水解的基团实例包括但不限于可生物水解的磷酸盐、可生物水解的酯、可生物水解的酰胺、可生物水解的碳酸酯、可生物水解的氨基甲酸酯和可生物水解的酰脲。
本公开的化合物可以含有一个或多个不对称中心(“立体异构体”)。如本文所用，所有术语“立体异构体”是指顺式-和反式-异构体、R-和S-对映体以及非对映体。这些立体异构体可以通过不对称合成法或手性分离法(例如，分离、结晶、薄层色谱法、柱色谱法、气相色谱法、高效液相色谱法)制备。这些立体异构体也可由对映体或外消旋物的混合物与适当的手性化合物反应的非对映体衍生，然后通过结晶或任何其它合适的常规方法得到。
所有术语受试者是指根据本公开的实施例，即将或已经接受了该化合物或药物组合物给药的任何动物，哺乳动物为优，人类最优。如本文所用所有术语“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。
在某些实施例中，治疗或正在治疗是指疾病或病症或其至少一个可辨别症状的改善、预防或逆转。在另一些实施例中，治疗或正在治疗是指正在治疗的疾病或病症的至少一个可测量身体参数的改善、预防或逆转，可能并未在哺乳动物中识别所述疾病或病症。 然而在另一个实施例中，治疗或正在治疗是指减慢疾病或病症的进展，或者是身体上的，例如可辨别症状的稳定，或生理学上的，例如，身体参数的稳定，或两者兼而有之。在另一些实施例中，治疗或正在治疗是指延迟疾病或病症的发作。
在某些实施例中，本公开的化合物可作为预防措施给药。如本文所用，“预防”或“正在预防”是指降低获得给定疾病或病症的风险。在实施例的优选模式中，将指定化合物作为预防措施给予受试者，例如有癌症或自身免疫性疾病家族病史或倾向的受试者。
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，即得本公开各较佳实例。
本公开所用试剂和原料均市售可得。
本公开的积极进步效果在于：本公开的联苯类化合物对PD-1和PD-L1具有明显抑制作用，能够有效缓解或治疗癌症等相关疾病。
具体实施方式
下面通过实施例的方式进一步说明本公开，但并不因此将本公开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。
下述实施例中，室温是指10℃-30℃；回流是指溶剂回流温度；过夜是指8-24小时，优选12-18小时。
化合物的结构由核磁共振(NMR)或质谱(MS)来确定，核磁共振谱是通过Bruker Avance-500仪器获得，氘代二甲亚砜，氘代氯仿和氘代甲醇等为溶剂，四甲基硅烷(TMS)为内标。质谱是由液相色谱-质谱(LC-MS)联用仪Agilent Technologies 6110获得，采用ESI离子源。
微波反应是在美国CEM公司生产的Explorer全自动微波合成仪中进行，磁控管频率为2450MHz，连续微波输出功率为300W。
高效液相制备所用的仪器是Gilson 281，所用的制备柱是Shimadazu Shim-Pack，PRC-ODS，20x250mm，15μm。
实施例1
2-[({3-[(E)-2-(3-{3-[(E)-2-(5-{[(2-羟乙基)氨基]甲基}-2-(三氟甲基)苯基)乙烯基]-2-甲基苯基}-2-甲基苯基)乙烯基]-4-(三氟甲基)苯基}甲基)氨基]-1-乙醇1
Figure PCTCN2019113209-appb-000124
化合物1-f的合成
在室温条件下，往2-溴-6-氯甲苯(15.67g，76.26mmol)和乙烯基硼酸频哪醇酯(14.30g，91.51mmol)的甲苯(300mL)溶液中加入二(三叔丁基膦)钯(2.73g，5.34mmol)和三乙胺(61.74g，610.08mmol)，将反应液加热至80℃，在氮气条件下搅拌反应过夜。反应结束后，加入乙酸乙酯稀释(100mL)，用水(100mL)和饱和食盐水(100mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝10:1)得化合物1-f(10.5g，产率：49.4％)。
1H NMR(500MHz,CDCl 3):δ7.65-7.62(d,J＝18.5Hz,1H),7.42-7.41(d,J＝7.5Hz,1H),7.31-7.30(d,J＝7.5Hz,1H),7.12-7.09(t,1H),6.06-6.02(d,J＝18.0Hz,1H),2.45(s,3H),1.32(s,12H).
化合物1-e的合成
在室温条件下，往3-溴-4-三氟甲基苯甲醛(4.16g，16.45mmol)和化合物1-f(5.5g，19.74mmol)的1,4-二氧六环(40mL)和水(2mL)的混合溶液中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(1.423g，1.645mmol)和碳酸钠(4.36g，41.13mmol)，将反应液加热至80℃，在氮气条件下搅拌16小时。反应结束后，加入乙酸乙酯(50mL)稀释，依次用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝40:1)得到化合物1-e(4.16g，产率：78％)
1H NMR(500MHz,CDCl 3):δ10.15(s,1H),8.25(s,1H),7.87(s,2H),7.47-7.40(m,2H),7.37-7.36(d,J＝7.0Hz,1H),7.32-7.29(m,1H),7.20-7.17(m,1H),2.50(s,3H).
化合物1-d的合成
向100毫升反应瓶中加入化合物1-e(3.24g，10mmol)，联硼酸频哪醇酯(3.05g,12mmol)，三(二亚苄基丙酮)二钯(458mg，0.5mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(952mg，2.0mmol)，醋酸钾(3.0g，112mmol)以及甲苯(80mL)。混合物于90℃，氮气保护下反应16小时。冷却至室温，过滤，滤液减压浓缩，所得的剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝25:1)得到化合物1-d(3.06g，产率：82％)。
1H NMR(500MHz,CDCl 3):δ10.15(s,1H),8.28(s,1H),7.85(s,2H),7.73-7.76(m,1H),7.62(d,J＝7.5Hz,1H),7.50(d,J＝18Hz,1H),7.26-7.28(m,1H),7.23(d,J＝7.5Hz,1H),2.65(s,3H),1.37(s,12H).
化合物1-c的合成
室温下，往化合物1-d(416.24mg，1.0mmol)的四氢呋喃(20mL)溶液中加入双氧水(30％，1mL)，反应液在常温条件下搅拌16小时。反应液减压浓缩，剩余物用乙酸乙酯(20mL)溶解后，用饱和硫代硫酸钠水(20mL)洗涤两次，饱和食盐水(20mL)洗涤一次。有机相经无水硫酸钠干燥，减压浓缩，所得的剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝10:1)得化合物1-c(220mg，产率：71.9％)。
1H NMR(400MHz,CDCl 3):δ10.17(s,1H),8.29(s,1H),7.89(s,2H),7.48-7.45(d,J＝16.0Hz,1H),7.37-7.33(m,1H),7.23-7.21(d,J＝7.5Hz,1H),7.16-7.13(t,1H),6.82-6.80(d,J＝8.0Hz,1H),4.90(s,1H),2.38(s,3H).
化合物1-b的合成
室温下，往化合物1-c(529mg，1.73mmol)和苯基双(三氟甲烷磺酰)亚胺(618mg，1.73mmol)的丙酮(20mL)溶液中加入碳酸钾(358mg，2.59mmol)，反应液在常温条件下搅拌16小时。反应液减压浓缩，剩余物用乙酸乙酯(20mL)溶解后，用饱和硫代硫酸钠水溶液(20mL)洗涤两次，饱和食盐水(20mL)洗涤一次。有机相经无水硫酸钠干燥，减压浓缩，所得的剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝40:1～20:1)得化合物1-b(391mg，产率：51.7％)。
1H NMR(400MHz,CDCl 3):δ10.08(s,1H),8.18(s,1H),7.85-7.81(m,2H),7.54-7.52(d,J＝7.5Hz,1H),7.30(s,2H),7.28-7.24(m,1H),7.19-7.18(m,1H),2.39(t,3H).
化合物1-a的合成
氮气保护下，往化合物1-b(391mg，0.892mmol)和化合物1-d(445.4mg，1.070 mmol)的1,4-二氧六环(20mL)和水(1mL)混合溶液中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(77.2mg，0.0892mmol)和碳酸钠(236.4mg，2.23mmol)。反应液加热至80℃，并搅拌16小时。反应液冷却至室温，加乙酸乙酯溶液(20mL)稀释后，用水(20mL)洗涤三次，饱和食盐水(20mL)洗涤一次。有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(石油醚:乙酸乙酯＝10:1)得化合物1-a(116mg，产率：22.5％)。
1H NMR(400MHz,CDCl 3):δ10.07(s,2H),8.22(s,2H),7.80(s,4H),7.57-7.55(d,J＝7.5Hz,2H),7.46-7.43(d,J＝15.5Hz,2H),7.36-7.31(m,2H),7.26-7.21(m,2H),7.08-7.07(d,J＝7.0Hz,2H),2.11(s,6H).
化合物1的合成
室温下，往化合物1-a(100mg，0.27mmol)和氨基乙醇(64.3mg，0.54mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(32.4mg，0.54mmol)，反应液在室温下搅拌1小时。然后，加入氰基硼氢化钠(84.8mg，1.35mmol)搅拌16小时。反应液减压浓缩，剩余物用乙酸乙酯(20mL)溶解后，用水(20mL)和饱和食盐水(20mL)各洗涤一次。有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(二氯甲烷:甲醇＝10:1)得化合物1(24mg，产率：18.9％)。LC-MS(ESI):m/z＝669.0[M+H] +.
1H NMR(400MHz,CD 3OD):δ8.15(s,2H),7.84-7.83(d,J＝8.0Hz,2H),7.67-7.59(m,6H),7.41-7.33(m,4H),7.14-7.13(d,J＝6.5Hz,2H),4.41(s,4H),3.88-3.86(m,4H),3.25-3.23(m,4H),2.20(s,6H).
实施例2
(2S)-3-羟基-2-[({3-[(E)-2-(3-{3-[(E)-2-(5-{[(2-羟乙基)氨基]甲基}-2-(三氟甲基)苯基)乙烯基]-2-甲基苯基}-2-甲基苯基)乙烯基]-4-(三氟甲基)苯基}甲基)氨基]-2-甲基丙酸2
Figure PCTCN2019113209-appb-000125
Figure PCTCN2019113209-appb-000126
化合物2-e的合成
在室温下，往化合物1-b(559mg，1.275mmol)的四氢呋喃(10mL)和甲醇(10mL)混合溶液中加入硼氢化钠(96.5mg，2.551mmol)，反应液搅拌16小时。反应液减压浓缩，剩余物用乙酸乙酯(20mL)溶解后，用水(20mL)和饱和食盐水(20mL)各洗涤一次。有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝10:1)得化合物2-e(517mg，产率：92.5％)。
化合物2-d的合成
在室温下，往化合物2-e(517mg，1.174mmol)的二氯甲烷(10mL)溶液中加入氯化亚砜(698.4mg，5.87mmol)和2滴N,N-二甲基甲酰胺，反应液搅拌16小时。反应液减压浓缩，所得油状物用乙酸乙酯(20mL)溶解，经饱和碳酸氢钠水溶液(20mL)洗涤两次，饱和食盐水(20mL)洗涤一次，所得有机相经无水硫酸钠干燥，减压浓缩得化合物2-d(500mg，产率：92.9％)，直接用于下一步反应。
1H NMR(400MHz,CDCl 3):δ7.78(s,1H),7.73-7.71(d,J＝8.0Hz,1H),7.62-7.60(d,J＝8.0Hz,1H),7.47-7.45(d,J＝8.0Hz,1H),7.40-7.32(m,2H),7.29-7.25(m,2H),4.69(s,2H),2.47(m,3H).
化合物2-c的合成
往化合物2-d(500mg，1.09mmol)和(S)-2-甲基丝氨酸甲酯对甲苯磺酸盐(332.8mg，1.09mmol)的乙腈(20mL)溶液中加入碘化钠(32.7mg，0.218mmol)和碳酸钾(753.2mg，5.45mmol)，反应液加热至80℃，在氮气保护下搅拌16小时。反应液冷却至室温，加乙酸乙酯(20mL)稀释后，用水(20mL)用饱和硫代硫酸钠水溶液(20mL)洗涤两次，饱和食盐水(20mL)洗涤一次。有机相经无水硫酸钠干燥，减压浓缩，所得的剩余物经硅胶薄层层析制备板纯化(石油醚:乙酸乙酯＝5:1)得化合物2-c(471mg，产率：77.7％)。
1H NMR(400MHz,CDCl 3):δ7.74(s,1H),7.68-7.67(d,J＝8.5Hz,1H),7.61-7.60(d,J＝7.5Hz,1H),7.44-7.42(d,J＝8.0Hz,1H),7.40-7.37(m,1H),7.35-7.31(t,1H),7.28-7.24(m, 2H),3.84-3.83(d,J＝2.0Hz,2H),3.81(s,3H),3.79-3.77(d,J＝11.0Hz,1H),3.68-3.66(d,J＝11.0Hz,1H),2.47(s,3H),1.42(s,3H).
化合物2-b的合成
往化合物2-c(471mg，0.848mmol)和化合物1-d(423.3mg，1.017mmol)的1,4-二氧六环(20mL)和水(1mL)混合溶液中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(73.4mg，0.0848mmol)和碳酸钠(224.7mg，2.12mmol)，反应液在氮气保护下加热至80℃，并搅拌16小时。反应液冷却至室温，加乙酸乙酯溶液(20mL)稀释后，用水(20mL)洗涤三次，饱和食盐水(20mL)洗涤一次。有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(石油醚:乙酸乙酯＝1:1)得化合物2-b(459mg，产率：77.9％)。LC-MS(ESI):m/z＝696.0[M+H] +.
化合物2-a的合成
在室温下，往化合物2-b(459mg，0.66mmol)和氨基乙醇(80.6mg，1.32mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(79.3mg，1.32mmol)，反应液搅拌1小时后加入氰基硼氢化钠(207.4mg，3.30mmol)，搅拌16小时。反应液减压浓缩，剩余物用乙酸乙酯(20mL)溶解后，用水(20mL)和饱和食盐水(20mL)各洗涤一次。有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(二氯甲烷:甲醇＝10:1)得化合物2-a(32mg，产率：6.6％)。LC-MS(ESI):m/z＝741.0[M+H] +.
化合物2的合成
在室温下，往化合物2-a(100mg，0.27mmol)的甲醇(10mL)和水(10mL)混合溶液中加入氢氧化钠(32.4mg，0.54mmol)，并继续搅拌16小时。反应液减压浓缩，剩余物用水(20mL)稀释，用稀盐酸(1.0M)调节pH至4～5，有白色沉淀析出。过滤，滤饼用水(5mL)洗后，经真空干燥后得到化合物2(30mg，产率：98％)。LC-MS(ESI):m/z＝727.0[M+H] +.
1H NMR(400MHz,CD 3OD):δ8.20-8.16(d,J＝19.0Hz,2H),7.85-7.81(m,2H),7.69-7.59(m,6H),7.42-7.33(m,4H),7.15-7.12(m,2H),4.41(s,2H),4.39-4.30(m,2H),4.05-4.02(d,J＝12.5Hz,1H),3.88-3.85(m,3H),3.25-3.23(m,2H),2.21-2.20(d,J＝4.0Hz,6H),1.59(s,3H).
实施例3
(2S)-2-[({3-[(E)-2-(3-{3-[(E)-2-[5-({[(1S)-1-羧基-2-羟基-1-甲基乙基]氨基}甲基)-2-(三氟甲基)苯基]乙烯基]-2-甲基苯基}-2-甲基苯基)乙烯基]-4-(三氟甲基)苯基}甲基)氨基]- 3-羟基-2-甲基丙酸3
Figure PCTCN2019113209-appb-000127
化合物3-c的合成
室温下，往化合物1-a(381mg，0.659mmol)的四氢呋喃(10mL)和甲醇(10mL)的混合溶液中加入硼氢化钠(124.6mg，3.293mmol)，反应液在室温下搅拌16小时。反应液减压浓缩，剩余物用乙酸乙酯(20mL)溶解后，用水(20mL)和饱和食盐水(20mL)各洗涤一次。有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝10:1～5:1)得化合物3-c(367mg，产率：96.3％)。
化合物3-b的合成
在室温下，往化合物3-b(367mg，0.63mmol)的二氯甲烷(20mL)溶液中加入氯化亚砜(374.7mg，3.15mmol)和2滴N,N-二甲基甲酰胺，反应液搅拌16小时。反应液减压浓缩，所得油状物用乙酸乙酯(20mL)溶解，经饱和碳酸氢钠水溶液(20mL)洗涤两次，饱和食盐水(20mL)洗涤一次，所得有机相经无水硫酸钠干燥，减压浓缩得化合物3-b(333mg，产率：85.4％)，直接用于下一步反应。
化合物3-a的合成
往化合物3-b(333mg，0.538mmol)和(S)-2-甲基丝氨酸甲酯对甲苯磺酸盐(328.3mg，1.075mmol)的乙腈(20mL)溶液中加入碳酸钾(743.6mg，5.38mmol)和碘化钠(40.3mg，0.269mmol)，反应液加热至80℃，在氮气保护下搅拌16小时。反应液冷却至室温，加乙酸乙酯(20mL)稀释后，用水(20mL)用饱和硫代硫酸钠水溶液(20mL×2)洗涤，饱和食盐水(20mL)洗涤一次。有机相经无水硫酸钠干燥，减压浓缩，所得的剩余物经硅胶薄层层析制备板纯化(二氯甲烷:甲醇＝15:1)得化合物3-a(360mg，产率：82.6％)。LC-MS(ESI):m/z＝813.0[M+H] +.
化合物3的合成
在室温下，往化合物3-a(360mg，0.443mmol)的甲醇(20mL)和水(2mL)混合溶液中加入氢氧化钠(88.6mg，2.215mmol)，并继续搅拌16小时。反应液减压浓缩，剩余物用水(20mL)稀释，用稀盐酸(1.0M)调节pH至4～5，有白色沉淀析出。过滤，滤饼用水(5mL)洗后，经真空干燥后得到化合物3(264mg，产率：74.8％)。LC-MS(ESI):m/z＝785.0[M+H] +.
1H NMR(400MHz,CD 3OD):δ8.19(s,2H),7.82-7.81(d,J＝8.5Hz,2H),7.69-7.61(m,6H),7.41-7.38(m,2H),7.35-7.32(m,2H),7.14-7.13(d,J＝7.5Hz,2H),4.39-4.31(m,4H),4.06-4.03(d,J＝12.5Hz,2H),3.88-3.86(d,J＝12.5Hz,2H),2.20(s,6H),1.60(s,6H).
实施例4
2-[({3-[(E)-2-(3-{3-[(E)-2-(5-{[(2-甲氧基乙基)氨基]甲基}-2-(三氟甲基)苯基)乙烯基]-2-氯苯基}-2-甲基苯基)乙烯基]-4-(三氟甲基)苯基}甲基)氨基]-1-乙醇4
Figure PCTCN2019113209-appb-000128
化合物4-f的合成
将3-溴-4-三氟甲基苯甲醛(4.0g,15.8mmol)和乙烯硼酸酯(2.92g,18.9mmol)溶于甲苯(100mL)中，向溶液中加入二(三叔丁基磷)化钯(807mg,1.58mmol)和三乙胺(4.78g,47.4mmol)。反应液在氮气保护下于80℃搅拌5小时，薄层层析监测原料反应完全。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝50-10:1)，得到棕色粘稠物4-f(300mg，产率：58％).
化合物4-e的合成
将化合物1-溴-2-氯-3-碘苯(2.0g,8.2mmol)和化合物4-f(3.0g,9mmol)溶于二氧六环和水的混合溶液(50mL/5mL)中，向溶液中加入四(三苯基膦)钯(947mg,0.82 mmol)，碳酸钠(2.60g,24.6mmol)。反应液在氮气保护下于70℃搅拌12小时，薄层层析监测原料反应完全。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝100-10:1)，得到白色固体4-e(1.15g，产率：36％)。
化合物4-d的合成
将化合物4-e(760mg,2.0mmol)和2-甲氧基乙胺(450mg,6.0mmol)溶于二氯甲烷(30ml)和MeOH(10ml)的混合溶液中,在常温下向反应液加入冰醋酸(360mg,6.0mmo)，反应液搅拌2小时后，向反应液中加入氰基硼氢化钠(152mg,4.0mmol)，继续搅拌18个小时，薄层层析监测原料反应完全。减压浓缩，剩余物溶于二氯甲烷(80mL)中，用水(50mL)和饱和食盐水(30mL)洗涤，无水硫酸钠干燥。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝20-5:1)，得到褐色固体4-d(700mg，产率：78％)。
1H NMR(400MHz,CD 3OD)δ:7.79(s,1H),7.66-7.60(m,3H),7.49(s,1H),7.42-7.40(m,2H),7.19(t,J＝6.0Hz,1H),3.94(s,2H),3.56(t,J＝4.0Hz,2H),3.39(s,3H),2.86(t,J＝4.0Hz,2H).
化合物4-c的合成
将化合物4-d(350mg,0.78mmol)和二碳酸二叔丁酯(340mg,1.56mmol)溶于二氯甲烷(30ml)，依次加入三乙胺(315.1mg,3.12mmol)和4-二甲氨基吡啶(9.5mg,0.078mmol),反应液在常温下搅拌过夜。向反应体系加入二氯甲烷(60mL)稀释，依次用水(50ml)和饱和食盐水(40ml)洗涤，无水硫酸钠干燥。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝20-10:1)，得到黄色油状物4-c(400mg，产率：93％)。
1H NMR(400MHz,CD 3OD):δ7.69-7.60(m,4H),7.50-7.46(m,1H),7.48-7.42(m,1H),7.32-7.27(m,1H),7.19(t,J＝6.4Hz,1H),4.62(d,J＝9.2Hz,2H),3.57-3.40(m,4H),3.34(s,3H),1.54-1.39(m,9H).
化合物4-b的合成
将化合物4-c(165mg,0.3mmol)和1-d(137mg,0.33mmol)溶于二氧六环和水的混合溶液(40mL/4mL)中，向溶液中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(44mg,0.06mmol)，碳酸钠(127mg,1.2mmol)。反应液在氮气保护下于85℃下搅拌12小时。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝20-5:1)，得到黄色固体4-b(150mg，产率：66％)。
1H NMR(400MHz,CD 3OD):δ10.17(s,1H),8.31(s,1H),7.90(s,1H),7.89(s,1H),7.76-7.65(m,4H),7.60-7.34(m,6H),7.25-7.18(m,3H),4.62(d,J＝8.4Hz,2H),3.56-3.39(m,4H),3.33(s,3H),2.24(s,3H),1.45-1.39(m,9H).
化合物4-a的合成
将化合物4-b(130mg,0.17mmol)和乙醇胺(52mg,0.85mmol)溶于二氯甲烷(10mL)和甲醇(3mL)的混合溶液中,下向反应液加入1滴冰醋酸。反应混合物于室温搅拌2小时后，向反应液中加入氰基硼氢化钠(21mg,0.33mmol)，加毕，室温继续反应12小时。减压浓缩，剩余物经硅胶柱层析纯化(二氯甲烷:甲醇＝20-10:1)，得到黄色油状物4-a(130mg，产率：94％)。
化合物4的合成
将化合物4-a(130mg,0.16mmol)溶解于二氯甲烷(20mL)中，滴加三氟乙酸(1mL)保温至30℃下搅拌5小时。减压浓缩，所得剩余物经高效液相制备纯化得到白色固体4(65mg,产率：58％)。LC-MS(ESI):m/z＝703.2[M-1] +.
1H NMR(400MHz,CD 3OD):δ8.14(d,J＝4.8Hz,1H),7.87-7.74(m,4H),7.66-7.47(m,6H),7.42-7.34(m,2H),7.30(d,J＝10.6Hz,1H),7.16(d,J＝6.4Hz,1H),4.40(s,2H),4.39(s,2H),3.87-3.85(m,2H),3.71-3.69(m,2H),3.43(s,3H),3.33-3.30(m,2H),3.24-3.22(m,2H),2.23(s,3H).
实施例5
(2S)-3-羟基-2-[({3-[(E)-2-(3-{3-[(E)-2-(5-{[(2-甲氧基乙基)氨基]甲基}-2-(三氟甲基)苯基)乙烯基]-2-氯苯基}-2-甲基苯基)乙烯基]-4-(三氟甲基)苯基}甲基)氨基]-2-甲基丙酸5
Figure PCTCN2019113209-appb-000129
化合物5-a的合成
将化合物(S)-2-氨基-3-羟基-2-甲基丙酸(72mg,0.60mmol)加到甲醇(20ml)中，在室温搅拌下，慢慢滴加氢氧化钠(24mg,0.6mmol)水溶液(5mL),反应体系逐渐澄清。继续搅拌1小时后，向反应体系里滴加化合物4-b(150mg,0.2mmol)的THF(5ml) 溶液。滴加完毕后，继续搅拌过夜。向体系加入氰基硼氢化钠(25.2mg,0.4mmol)，搅拌2小时。减压浓缩，剩余物用水(3mL)洗涤，得到粗产物5-a(160mg)。直接用于下一步反应。LC-MS(ESI):m/z＝861[M+H] +.
化合物5的合成
将化合物5-a(160mg)溶解于二氯甲烷(15mL)中，滴加三氟乙酸(1mL),于30℃下搅拌5小时。TCL监测原料反应完全。减压浓缩，剩余物经高效液相制备纯化得白色固体5(31mg,产率：20％)。LC-MS(ESI):m/z＝761.2[M+H] +.
1H NMR(400MHz,CD 3OD):δ8.17(s,1H),7.97(s,1H),7.80-7.61(m,7H),7.53-7.33(m,5H),7.27(d,J＝6.0Hz,1H),7.15(d,J＝5.6Hz,1H),4.30-4.22(q,2H),3.98-3.96(m,3H),3.82(d,J＝9.6Hz,1H),3.56(t,J＝4.4Hz,2H),3.37(s,3H),2.85(t,J＝4.4Hz,2H),2.23(s,3H),1.53(s,3H).
实施例6
(2S)-3-羟基-2-[({3-[(E)-2-(3-{3-[(E)-2-(5-{[(2-羟基乙基)氨基]甲基}-2-(三氟甲基)苯基)乙烯基]-2-氯苯基}-2-甲基苯基)乙烯基]-4-(三氟甲基)苯基}甲基)氨基]-2-甲基丙酸6
Figure PCTCN2019113209-appb-000130
化合物6-d的合成
将化合物4-e(450mg,1.15mmol)和2-氨基乙醇(211mg,3.47mmol)溶于二氯甲烷(30mL)和甲醇(10mL)的混合溶液中,加入冰醋酸(0.1mL)，反应混合物于室温搅拌2小时后，加入氰基硼氢化钠(114mg,2.30mmol)，加毕，继续搅拌反应18个小时。减压浓缩，剩余物溶于二氯甲烷(50mL)，依次用水(50mL)和饱和食盐水(30mL)洗涤，无水硫酸钠干燥。减压浓缩，剩余物经硅胶柱层析纯化(甲醇:乙酸乙酯＝1-20:100)，得到白色固体6-d(430mg，产率：86％)。
1H NMR(400MHz,CD 3OD):δ7.77(s,1H),7.67-7.60(m,3H),7.52-7.38(m,3H),7.19(t,J＝6.4Hz,1H),3.95(s,2H),3.74(t,J＝4.0Hz,2H),2.88(t,J＝4.0Hz,2H).
化合物6-c的合成
将化合物6-d(430mg,1.0mmol)和二碳酸二叔丁酯(436mg,2.0mmol)溶于二氯甲烷(40mL)，依次加入三乙胺(404mg,4.0mmol)和4-N,N-二甲基吡啶(122mg,1.0mmol),反应液于室温搅拌过夜。向反应体系加入二氯甲烷(60mL)稀释，依次用水(50mL)和饱和食盐水(30mL)洗涤，无水硫酸钠干燥。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝50-15:1)，得到黄色油状物6-c(100mg，产率：18％)。LC-MS(ESI):m/z＝536.0[M+H] +.
化合物6-b的合成
将化合物6-c(100mg,0.2mmol)和1-d(100mg,0.24mmol)溶于二氧六环和水的混合溶液(20mL/2mL)中，向溶液中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(29.2mg,0.04mmol)，碳酸钠(63.6mg,0.6mmol)。反应液在85℃下搅拌10小时。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝10-2:1)，得到透明油状产物6-b(100mg，产率：66％)。LC-MS(ESI):m/z＝744.1[M+H] +.
化合物6-a的合成
将化合物(S)-2-氨基-3-羟基-2-甲基丙酸(47.6mg,0.40mmol)加到甲醇(10ml)中，在室温搅拌下，慢慢滴加氢氧化钠(16mg,0.4mmol)水溶液(3ml),反应体系逐渐澄清，继续搅拌1小时后，慢慢滴加6-b(100mg,0.13mmol)的THF(4mL)溶液。滴加完毕后，继续搅拌过夜。向体系中加入氰基硼氢化钠(12.6mg,0.2mmol)，搅拌2小时。减压浓缩，所得物用水(3mL)洗涤，得到粗产物6-a(160mg)。直接用于下一步反应。LC-MS(ESI):m/z＝861.0[M+H] +.
化合物6的合成
将化合物6-a(160mg)溶解于二氯甲烷(10mL)中，滴加三氟乙酸(1mL)，于30℃下搅拌5小时。薄层层析监测原料反应完全。减压浓缩，剩余物经高效液相制备纯化得到白色固体产物6(9mg,产率：10％)。LC-MS(ESI):m/z＝374.2[M/2+H] +.
1H NMR(400MHz,CD 3OD):δ8.17(s,1H),8.13(s,1H),7.87-7.74(m,4H),7.67-7.63(m,4H),7.55-7.34(m,4H),7.30(d,J＝6.4Hz,1H),7.1(d,J＝5.6Hz,1H),4.42-4.38(m,4H),4.10(d,J＝9.2Hz,1H),3.90(d,J＝8.8Hz,1H),3.87-3.85(m,2H),3.24-3.22(m,2H),2.23(s,3H),1.64(s,3H).
实施例7
2-[({3-[(E)-2-(3-{3-[(E)-2-(5-{[(2-羟基乙基)氨基]甲基}-2-(三氟甲基)苯基)乙烯基]-2-氯苯基}-2-甲基苯基)乙烯基]-4-(三氟甲基)苯基}甲基)氨基]-1-乙醇7
Figure PCTCN2019113209-appb-000131
化合物7-a的合成
将化合物6-b(168mg,0.2mmol)和2-氨基乙醇(35mg,0.6mmol)溶于二氯甲烷(20ml)和MeOH(5ml)的混合溶液中,向反应液加入冰醋酸(0.1mL)，于室温搅拌2小时后，加入氰基硼氢化钠(25mg,0.4mmol)，加毕，继续搅拌反应18个小时。减压浓缩，残余物溶于二氯甲烷(50mL)，依次用水(50mL)和饱和食盐水(30mL)洗涤，无水硫酸钠干燥。减压浓缩，剩余物经硅胶柱层析纯化(甲醇:乙酸乙酯＝1-20:100)，得到无色粘稠物7-a(120mg，产率：67％)。LC-MS(ESI):m/z＝789.2[M+H] +.
化合物6的合成
将化合物7-a(120mg,0.13mmol)溶解于二氯甲烷(10mL)中，滴加三氟乙酸(1mL),于30℃下搅拌5小时。减压浓缩，所得物经高效液相制备纯化得到白色固体产物7(40mg,产率：43％)。LC-MS(ESI):m/z＝689.3[M+H] +.
1H NMR(400MHz,CD 3OD):δ7.98(s,1H),7.96(s,1H),7.76(d,J＝4.2Hz,1H),7.72-7.31(m,8H),7.53-7.33(m,5H),7.27(d,J＝6.4Hz,1H),7.13(d,J 6.0Hz,1H),3.93(s,4H),3.72-3.70(m,4H),2.79-2.70(m,4H),2.22(s,3H).
实施例8
(2S)-3-羟基-2-[({3-[(E)-2-[3-(3-(E)-{2-[2-氟-5-(2-甲氧基乙氧基)苯基]乙烯基}-2-甲基苯基)-2-甲基苯基]乙烯基]-4-(三氟甲基)苯基}甲基)氨基]-2-甲基丙酸8
Figure PCTCN2019113209-appb-000132
Figure PCTCN2019113209-appb-000133
化合物8-g的合成
在常温条件下，往3-溴-4-氟苯酚(1.0g，5.24mmol)和1-溴-2-甲氧基乙烷(800mg，5.76mmol)的DMF(20mL)溶液中加入碘化钠(157mg，1.05mmol)和碳酸钾(3.62g，26.2mmol)，反应混合物于80℃条件下搅拌过夜。反应结束后，反应液用乙酸乙酯稀释，水洗(100mL)，饱和食盐水洗(100mL)。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱纯化(石油醚:乙酸乙酯＝50:1～10:1)，得到8-g(1.263g，产率：96.9％)。
1H NMR(500MHz,CDCl3):δ7.14-7.12(1H,dd,J＝.0Hz,J＝.5Hz),7.07-7.03(1H,dd,J＝.5Hz,J＝9.5Hz),6.88-6.85(1H,m),4.10-4.08(2H,m),3.76-3.75(2H,m),3.47(3H,s).
化合物8-f的合成
往8-g(1.263g，5.07mmol)和1-f(1.694g，6.08mmol)的1，4-二氧六环(20mL)和水(1mL)混合溶液中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(438mg，0.507mmol)和碳酸钠(1.344g，12.67mmol)，反应液加热至80℃，在氮气保护下搅拌反应过夜。减压浓缩，剩余物经硅胶柱纯化(PE:EA＝50:1～10:1)，得到8-f(1.20g，产率：73.9％)。
化合物8-e的合成
往8-g(1.20g，3.74mmol)和联硼酸频哪醇酯(1.14g，4.49mmol)的甲苯(20mL)溶液中加入三(二亚苄基丙酮)二钯(171mg，0.187mmol),2-二环己基磷-2',4',6'-三异丙基联苯(356.6mg，0.748mmol)和醋酸钾(1.101g，11.22mmol)，反应液加热至90℃，在氮气保护下搅拌反应过夜。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝50:1～10:1)，得到8-e(336mg，产率：21.7％)。
1H NMR(500MHz,CDCl 3):δ7.74-7.72(d,J＝.5Hz,1H),7.68-7.67(d,J＝.5Hz,1H),7.49-7.45(d,J＝6.0Hz,1H),7.25-7.20(m,2H),7.08-7.05(d,J＝16.5Hz,1H),7.02-6.99(t, J＝9.0Hz,1H),6.81-6.79(m,1H),4.17-4.14(m,2H),3.80-3.78(m,2H),3.50(s,3H),2.64(3H,s),1.39(s,12H).
化合物8-d的合成
往8-e(336mg，0.815mmol)和1-b(297mg，0.679mmol)的乙二醇二甲醚(10mL)溶液中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(58mg，0.068mmol)和氟化铯(258mg，1.70mmol)，反应液在氮气保护下于80℃搅拌过夜。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝20:1～5:1)，得到8-d(100mg，产率：25.6％)。
化合物8-c的合成
往8-d(100mg，0.174mmol)的四氢呋喃(5mL)和甲醇(5mL)混合溶液中加入硼氢化钠(13mg，0.348mmol)，反应液在在室温下搅拌过夜。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝10:1～3:1)，得到8-c(80mg，产率：80％)。
1H NMR(500MHz,CDCl 3):δ7.71(s,1H),7.59-7.52(m,3H),7.39-7.36(d,J＝16.0Hz,1H),7.32(s,2H),7.28-7.27(d,J＝8.0Hz,1H),7.22-7.17(m,2H),7.11-7.00(m,4H),6.93-6.89(t,J＝9.0H,1Hz),6.72-6.70(m,1H),4.72(s,2H),4.06-4.03(m,2H),3.69-3.67(m,2H),3.38(s,3H),2.07(s,3H),2.06(s,3H).
化合物8-b的合成
往8-c(80mg，0.139mmol)的二氯甲烷(50mL)溶液中加入氯化亚砜(82mg，0.694mmol)，反应液搅拌过夜。反应结束后，将有机溶剂旋干，剩余物用油泵抽干后，得到8-b(82mg，产率：99％)，直接用于下一步反应。
化合物8-a的合成
往8-b(82mg，0.138mmol)和(S)-2-甲基丝氨酸甲酯对甲苯磺酸盐(84mg，0.28mmol)的乙腈(10mL)溶液中加入碘化钠(10mg，0.068mmol)和K 2CO 3(191mg，1.38mmol)，反应液在氮气保护下于80℃搅拌过夜。反应结束后，旋干溶剂，残留物用乙酸乙酯溶解(100mL)，依次用饱和硫代硫酸钠水溶液(100mL×2)，饱和食盐水(100mL×1)洗涤。所得有机相经无水硫酸钠干燥，旋干后得到粗品化合物，经制备板纯化(石油醚:乙酸乙酯＝2:1)后得到目标化合物8-a(23mg，产率：24.2％)。LC-MS(ESI):m/z＝692.0[M+H] +.
化合物8的合成
往8-a(23mg，0.033mmol)的甲醇(10mL)和水(1mL)混合溶液中加入氢氧化钠(6mg，0.15mmol)，室温搅拌过夜。反应结束后，将溶剂旋干，剩余物加水稀释后，用稀盐酸(1M)调节溶液pH＝4～5，沉淀析出白色固体。过滤，干燥，得到8(20mg)。 LC-MS(ESI):m/z＝678.0[M+H] +.
1H NMR(500MHz,CD 3OD):δ8.22(1H,s),7.84-7.82(d,J＝8.5Hz,1H),7.70-7.56(m,5H),7.41-7.25(m,4H),7.17-7.03(m,4H),6.89-6.87(m,1H),4.43(s,2H),4.16-4.10(m,4H),3.77-3.76(m,2H),3.45(s,3H),2.19(s,3H),2.15(s,3H),1.69(s,3H).
实施例9
2-({[(3-(E)-2-{3-[3-(3-{[(2-羟基乙基)氨基]甲基}苯基)-2-甲基苯基]-2-甲基苯基}乙烯基)-4-(三氟甲基)苯基]甲基}氨基)-1-乙醇9
Figure PCTCN2019113209-appb-000134
化合物9-b的合成
往3-甲酰基苯硼酸(1.0g，6.67mmol)和2,6-二溴甲苯(2.5g，10.0mmol)的1,4-二氧六环(30mL)和水的(1.5mL)混合溶液中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(577mg，0.667mmol)和碳酸钠(1.768g，16.675mmol)，反应液在氮气保护下加热于80℃搅拌过夜。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝50:1～10:1)得到目标化合物9-b(1.106g，产率：60.1％)。
1H NMR(500MHz,CDCl 3):δ10.0(s,1H),7.83-7.81(m,1H),7.73(m,1H),7.55-7.47(m,3H),7.11-7.09(dd,J＝1.0Hz,J＝7.5Hz,1H),7.06-7.03(t,J＝8.0Hz,1H),2.23(s,3H).
化合物9-a的合成
往9-b(1.106g，4.02mmol)和1-d(2.00g，4.8mmol)的乙二醇二甲醚(20mL)溶液中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(348mg，0.402mmol)和氟化铯(1.527g，10.05mmol)，反应液，在氮气保护下于80℃搅拌过夜。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝10:1～3:1)得到9-a(1.69g，产率：86.7％)。
1H NMR(500MHz,CDCl 3):δ10.07(s,1H),10.01(s,1H),8.21(s,1H),7.83-7.79(m,4H),7.60-7.52(m,3H),7.46-7.43(d,J＝15.5Hz,1H),7.35-7.31(m,1H),7.27-7.23(m,2H),7.19-7.17(m,1H),7.11-7.10(m,2H),2.14(s,3H),1.87(s,3H).
化合物9的合成
在常温条件下，往9-a(100mg，0.206mmol)和乙醇胺(25mg，0.41mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(25mg，0.41mmol)，反应混合物搅拌1小时，然后加入氰基硼氢化钠(63mg，1.0mmol)，室温搅拌过夜。旋干溶剂，剩余物经高效液相制备纯化得到目标化合物9(54mg，产率：45％)。LC-MS(ESI):m/z＝575.0[M+H] +.
1H NMR(500MHz,CD 3OD):δ8.14(s,1H),7.85-7.83(d,J＝8.0Hz,1H),7.66-7.47(m,7H),7.41-7.33(m,3H),7.28-7.26(dd,J＝1.5Hz,J＝7.5Hz,1H),7.17-7.14(m,2H),4.41(s,2H),4.34(s,2H),3.88-3.84(m,4H),3.24-3.22(m,2H),3.20-3.18(m,2H),2.22(s,3H),1.96(s,3H).
实施例10
2-({[(3-(E)-2-{3-[3-(5-{[(2-羟基乙基)氨基]甲基}-2-氟-苯基)-2-甲基苯基]-2-甲基苯基}乙烯基)-4-(三氟甲基)苯基]甲基}氨基)-1-乙醇10
Figure PCTCN2019113209-appb-000135
化合物10-c的合成
往3-溴-4-氟苯甲醛(1.0g，4.93mmol)和联硼酸频哪醇酯(1.5g，5.91mmol)的甲苯(30mL)溶液中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(426mg，0.493mmol)和醋酸钾(1.452g，14.79mmol)，反应液，在氮气保护下于80℃搅拌过夜。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝50:1～10:1)，得到10-c(1.1g，产率：90.2％)。
1H NMR(500MHz,CDCl 3):δ10.00(s,1H),8.32-8.31(m,1H),8.04-8.01(m,1H),7.22- 7.19(t,J＝9.0Hz,1H),1.40(s,12H).
化合物10-b的合成
往10-c(1.11g，4.439mmol)和2,6-二溴甲苯(1.664g，6.658mmol)的1，4-二氧六环(30mL)和水的(1.5mL)混合溶液中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(384mg，0.444mmol)和碳酸钠(1.177g，11.1mmol)，反应液加热至80℃，在氮气保护下搅拌反应过夜。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝50:1～10:1)，得到目标化合物10-b(605mg，产率：46.5％)。
1H NMR(500MHz,CDCl 3):δ9.94(s,1H),7.89-7.85(m,1H),7.74-7.73(m,1H),7.58-7.56(dd,J＝2.0Hz,J＝7.5Hz,1H),7.26-7.23(t,J＝9.0Hz,1H),7.11-7.05(m,2H),2.18(s,3H).
化合物10-a的合成
往10-b(0.605g，2.064mmol)和1-d(1.031g，2.477mmol)的乙二醇二甲醚(20mL)溶液中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(178.2mg，0.206mmol)和氟化铯(784mg，5.16mmol)，反应液加热至80℃，在氮气保护下搅拌反应过夜。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝20:1～3:1)，得到目标化合物10-a(0.587g，产率：56.4％)。
1H NMR(500MHz,CDCl 3):δ10.08(s,1H),9.96(s,1H),8.21(s,1H),7.88-7.80(m,4H),7.56-7.55(d,J＝7.5Hz,1H),7.46-7.43(d,J＝16.5Hz,1H),7.35-7.31(m,1H),7.29-7.23(m,3H),7.16-7.11(m,3H),2.13(s,3H),1.82(s,3H).
化合物10的合成
往10-a(100mg，0.199mmol)和乙醇胺(24.3mg，0.398mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(23.9mg，0.398mmol)，反应混合物搅拌1小时，然后加入氰基硼氢化钠(62.5mg，0.995mmol)，搅拌过夜。反应结束后，将溶剂旋干，剩余物用高效液相制备纯化得到目标化合物10(112mg，产率：95％)。LC-MS(ESI):m/z＝593.0[M+H] +.
1H NMR(500MHz,CD 3OD):δ8.15(s,1H),7.84-7.83(d,J＝8.0Hz,1H),7.67-7.55(m,5H),7.41-7.27(m,5H),7.22-7.15(m,2H),4.41(s,2H),4.32(s,2H),3.88-3.84(m,4H),3.24-3.19(m,4H),2.22(s,3H),1.89(s,3H).
实施例11
(2S)-2-[({3-[(E)-2-(3-{3-[5-({[(1S)-1-羧基-2-羟基-1-甲基乙基]氨基}甲基)-2-氟苯基]-2-甲基苯基}-2-甲基苯基)乙烯基]-4-(三氟甲基)苯基}甲基)氨基]-3-羟基-2-甲基丙酸11
Figure PCTCN2019113209-appb-000136
化合物11的合成
将(S)-2-甲基丝氨酸(189.6mg，1.592mmol)悬浮于甲醇(5mL)中，慢慢滴加氢氧化钠(63.7mg，1.592mmol)溶于5mL水的溶液。反应液搅拌至澄清，然后加入10-a(100mg，0.199mmol)的四氢呋喃(5mL)溶液，反应搅拌过夜后，加入硼氢化钠(3mg，1.0mmol)，继续搅拌半小时。用LC/MS监测反应进程，反应结束后，将溶剂旋干，剩余物用高效液相制备纯化得到化合物11(48mg，产率：34.1％)。LC-MS(ESI):m/z＝709.0[M+H] +.
1H NMR(500MHz,CD 3OD):δ8.18(s,1H),7.85-7.83(d,J＝8.5Hz,1H),7.67-7.57(m,5H),7.42-7.29(m,5H),7.22-7.16(m,2H),4.44-4.38(dd,J＝12.5Hz,J＝4.5Hz,2H),4.37-4.31(dd,J＝13.0Hz,J＝4.5Hz,2H),4.15-4.10(t,J＝12.0Hz,2H),3.94-3.90(m,2H),2.22(s,3H),1.91(s,3H),1.68(s,3H),1.66(s,3H).
实施例12
2-[({3-[(E)-2-(3-{3-[(E)-2-(5-{[(2-羟乙基)氨基]甲基}-2-(三氟甲基)苯基)乙烯基]-2-(氟甲基)苯基}-2-甲基苯基)乙烯基]-4-(三氟甲基)苯基}甲基)氨基]-1-乙醇12
Figure PCTCN2019113209-appb-000137
化合物12-b的合成
将2,6-二溴苯甲醇(2.40g，9.06mmol)悬浮于干燥二氯甲烷(60mL)中，于-78℃慢慢滴加二乙胺基三氟化硫(1.90mg，11.8mmol)，加毕，于-78℃下继续搅拌1小时。 TLC监测反应完全。将反应液慢慢加入到饱和碳酸氢钠水溶液中(150mL)，分出有机相，水相用二氯甲烷萃取(30mL×2)。合并有机相，饱和食盐水洗(30mL)，无水硫酸钠干燥。减压浓缩，剩余物经硅胶柱层析纯化(洗脱剂：石油醚)，得到白色固体产物12-b(1.86g，产率：78％)。
化合物12-a的合成
向100毫升三口烧瓶中加入12-b(268mg，1.0mmol)，4-f(391mg，1.2mmol),1-d(541mg，1.3mmol),氟化铯(600mg，4.0mmol)，磷酸钾(848mg，4.0mmol)，[1,1’-双(二苯基磷)二茂铁]二氯化钯(120mg，0.16mmol)以及甲苯(25mL)。反应混合混合物在氮气保护于80℃下搅拌反应6小时。减压浓缩，剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝100:1～8:1)，得到浅黄色固体12-a(306mg，产率：44％)。
化合物12的合成
向12-a(150mg，0.25mmol)的二氯甲烷(10mL)溶液中，加入乙醇胺(61mg，1.0mmol)，甲醇(10mL)，冰醋酸(20mg，0.34mmol)。反应混合物搅拌1小时后，加入氰基硼氢化钠(63mg，1.0mmol)。加毕，继续搅拌16小时。减压旋除溶剂，剩余物经硅胶柱层析纯化(二氯甲烷:7N氨的甲醇溶液＝15:1)，得到类白色固体12(54mg，产率：31％)。LC-MS(ESI):m/z＝687[M+H] +.
1H NMR(400MHz,CD 3OD):δ7.98(s,1H),7.97(s,1H)，7.75(d,J＝7.6Hz,1H),7.69-7.72(m,3H),7.61-7.65(m,2H),7.52-7.57(m,2H),7.45～7.48(m,2H),7.37～7.42(m,1H),7.31～7.35(m,1H),7.22(d,J＝7.6Hz,1H),7.15(d,J＝7.2Hz,1H),5.36～5.45(m,1H),5.24～5.33(m,1H),3.93(s,2H),3.92(s,2H),3.71(d,J＝5.2Hz,4H),2.76-2.79(m,4H),2.19(s,3H).
效果实施例
采用均相时间分辨荧光(Homogenouse Time-Resolved Fluorescence,HTRF)结合试验来检测本公开的化合物对PD-1/PD-L1的结合能力。
购买来的试剂盒(CisBio，#64CUS000C-1)中包含有PD-1、PD-L1、anti-tag1-Eu、Anti-tag2-XL665、Dilute Buffer和Detection Buffer等实验所需的试剂。
实验步骤
1.将化合物用100％DMSO配置成浓度梯度为3倍的10个浓度。
2.将化合物的DMSO溶液加入到稀释缓冲溶液(Dilute Buffer)中，混合均匀后转移到96孔板中。
3.将PD-L1用稀释缓冲溶液(Dilute Buffer)稀释，然后加入到上述96孔板中。
4.将PD-1用稀释缓冲溶液(Dilute Buffer)稀释，然后加入到上述96孔板中，并在 室温下培养30分钟。
5.将一份anti-tag1-Eu和一份Anti-tag2-XL665加入到检测缓冲溶液(Detection Buffer)中，混合均匀后转移到上述96孔板中。
6.此96孔板中的混合液在室温下培养1到24小时。
7.用Envision读取HTRF数值。
实验结果
本公开化合物的生物学活性通过以上的试验进行测定，测得的结果如下(表1)：
表1本公开部分化合物对PD-1/PD-L1结合的IC 50值
化合物 IC 50(μM) 化合物 IC 50(μM)
1 0.0061 2 0.0044
3 0.0032 4 0.0043
5 0.0023 6 0.0028
7 0.0026 8 0.510
9 0.0075 10 0.014
11 0.0087 12 0.0047

Claims (16)

  1. 一种通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或药物前体：
    Figure PCTCN2019113209-appb-100001
    其中，
    环A和环B独立地为芳环或杂芳环；
    L 1为化学键、炔基、-C(R 5)＝C(R 6)-或-CR 7R 8-CR 9R 10-、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或取代或未取代的杂芳基；L 2为化学键、炔基、-C(R 5)＝C(R 6)-或-CR 7R 8-CR 9R 10-、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基或不存在；
    R 5、R 6、R 7、R 8、R 9和R 10分别独立地为氢、氘、卤素、氰基、或取代或未取代的烷基；
    R 1和R 2独立地为氘、卤素、氰基或取代或未取代的烷基；
    每个R 3和每个R 4独立地为氢、氘、羟基、-SR 11、-NR 12R 13、卤素、氰基、取代或未取代的烷基、取代或未取代的烷氧基、-CONH 2、-COR 14、-COOR 15或-OCOR 16；R 11、R 12和R 13独立地为氢、C 1-C 4烷基、取代的C 1-C 4烷基或-COR a，R a为氢、羟基、C 1-C 4烷基或C 1-C 4烷氧基；
    R 14、R 15和R 16独立地为氢、C 1-C 4烷基或取代的C 1-C 4烷基；
    R 11、R 12、R 13、R 14、R 15和R 16中，所述取代的C 1-C 4烷基中的取代是指被C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳基和取代的C 1-C 10杂芳基中的一个或多个取代；
    L 1和L 2中所述的取代的环烷基、所述的取代的杂环烷基、所述的取代的芳基、所述的取代的杂芳基、R 1和R 2中所述的取代的烷基、每个R 3和每个R 4中所述的取代的烷基或所述的取代的烷氧基中的取代基选自卤素、氰基、C 1-C 4烷基、羟基、
    Figure PCTCN2019113209-appb-100002
    C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳基、取代的C 1-C 10杂芳基、C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基和C 1-C 4酰胺基中的一个或多个；
    Figure PCTCN2019113209-appb-100003
    中，R 17和R 18独立地为氢、取代 或未取代的C 1-C 4烷基、取代或未取代的C 6-C 14芳基、取代或未取代的C 3-C 6环烷基、或取代或未取代的C 1-C 4烷氧基；或者R 17、R 18和与它们相连接的氮原子一起形成一个取代或未取代的5-7元碳杂环；所述碳杂环中，杂原子为N，或N和O，杂原子数为1-4个；每个R 17和每个R 18相同或不同；
    R 17和R 18中所述的取代的C 1-C 4烷基、所述的取代的C 6-C 14芳基、所述的取代的C 3-C 6环烷基、所述取代的C 1-C 4烷氧基和所述的取代的5-7元碳杂环中的取代基选自卤素、氰基、C 1-C 4烷基、取代的C 1-C 4烷基、C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳基、取代的C 1-C 10杂芳基、羟基、
    Figure PCTCN2019113209-appb-100004
    C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基和C 1-C 4酰胺基中的一个或多个；
    R 17和R 18中，当所述的取代的C 1-C 4烷基、所述的取代的C 6-C 14芳基、所述的取代的C 3-C 6环烷基、所述取代的C 1-C 4烷氧基和所述的取代的5-7元碳杂环中的取代基为取代的C 1-C 4烷基时，取代基中，所述的取代的C 1-C 4烷基中的取代基选自卤素、氰基、C 1-C 4烷基、C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳基、取代的C 1-C 10杂芳基、羟基、
    Figure PCTCN2019113209-appb-100005
    C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基和C 1-C 4酰胺基中的一个或多个；
    Figure PCTCN2019113209-appb-100006
    中，R a1和R b1独立地为氢、C 1-C 4的烷基或
    Figure PCTCN2019113209-appb-100007
    R a11为C 1-C 4的烷基；
    上述所有C 1-C 10杂芳基是指杂原子选自N、O和S，杂原子数为1-4个的C 1-C 10杂芳基；
    上述所有取代的C 6-C 14芳基和取代的C 1-C 10杂芳基中的取代基选自氰基、卤素、羟基、C 1-C 4烷基和C 1-C 4烷氧基中的一个或多个；
    当取代基为多个时，所述的取代基相同或不同；
    m为1、2或3；
    n为1、2或3。
  2. 如权利要求1所述的通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或药物前体，其特征在于，
    所述芳环为C 6-C 20芳环，优选C 6-C 14芳环，更优选C 6-C 10芳环，最优先苯、萘、四氢萘、2,3-二氢化茚、联苯、菲、蒽或苊；
    和/或，所述的杂芳环是指杂原子选自O、N和S，杂原子个数为1、2、3或4个的C 1-C 10的杂芳环，优选杂原子选自O、N和S，杂原子个数为1、2、3或4个的C 1-C 8的杂芳环，更优选杂原子选自O、N和S，杂原子个数为1、2、3或4个的C 1-C 6的杂芳环，最优选吖啶、咔唑、噌啉、咔啉、喹喔啉、咪唑、吡唑、吡咯、吲哚、二氢吲哚、苯并三唑、苯并咪唑、呋喃、噻吩、异噻唑、苯并噻吩、二氢苯并噻吩、苯并呋喃、异苯并呋喃、苯并噁唑、苯并呋咱、苯并吡唑、喹啉、异氮杂茚、异喹啉、噁唑、噁二唑、异噁唑、吲哚、吡嗪、吡啶并吡啶、四唑并吡啶、哒嗪、吡啶、萘嘧啶、嘧啶、吡咯、四唑、噻二唑、噻唑、噻吩、三唑、喹唑啉、四氢喹啉、二氢苯并咪唑、二氢苯并呋喃、二氢苯并噁唑或二氢喹啉；
    和/或，所述的环烷基为C 3-C 20环烷基，优选C 3-C 10环烷基，更优选C 3-C 6环烷基，最优选环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸烷和环十二烷基或环己烯基；
    和/或，所述的杂环烷基是指杂原子选自O、N和S，杂原子数为1、2、3或4个的C 2-C 10的非芳香环，优选杂原子选自O、N和S，杂原子数为1、2、3或4个的C 2-C 8的杂环烷基，进一步优选杂原子选自O、N和S，杂原子数为1、2、3或4个的C 2-C 6的杂环烷基，最优选四氢吡喃基、氮杂环丁烷基、1,4-二噁烷基、哌嗪基、哌啶基、吡咯烷基、吗啉基、硫代吗啉基、二氢呋喃基、二氢咪唑基、二氢吲哚基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢喹啉基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、亚甲基二氧基苯甲酰基、四氢呋喃基、四氢噻吩基或其N-氧化物；
    和/或，所述的芳基为C 6-C 20芳基，优选C 6-C 14芳基，更优选C 6-C 10芳基，最优选苯基、萘基、四氢萘基、2,3-二氢化茚基、联苯基、菲基、蒽基或苊基，
    和/或，所述的杂芳基是指杂原子选自O、N和S，杂原子个数为1、2、3或4个的C 1-C 10的杂芳基，进一步优选杂原子选自O、N和S，杂原子个数为1、2、3或4个的C 1-C 8的杂芳基，更优选杂原子选自O、N和S，杂原子个数为1、2、3或4个的C 1-C 6的杂芳基，最优选苯并咪唑基、苯并呋喃基、苯并呋咱基、苯并吡唑基、苯并三唑基、苯并噻吩基、苯并噁唑基、咔唑基、咔啉基、噌啉基、呋喃基、咪唑基、二氢吲哚基、吲哚基、吲唑基、异苯并呋喃基、异氮杂茚基、异喹啉基、异噻唑基、异噁唑基、萘嘧啶基、噁二唑基、噁唑基、噁唑啉、异噁唑啉、氧环丁基、吡喃基、吡嗪基、吡唑基、哒嗪基、吡啶并吡啶基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹喔啉基、四唑基、 四唑并吡啶基、噻二唑基、噻唑基、噻吩基或三唑基；
    和/或，所述的卤素为氟、氯、溴或碘；
    和/或，所述的烷基是指包括1-20个碳原子的支链和直链的饱和脂族烃基，优选1-10个碳原子，更优选1-8个碳原子，最优选甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基、庚基、辛基、壬基、癸基、4,4-二甲基戊基、2,2,4-三甲基戊基、十一烷基、十二烷基，及它们的各种异构体；
    和/或，所述的烷氧基表示通过氧桥连接的具有所述碳原子数目的环状或者非环状烷基，优选C 1-C 4烷氧基，更优选甲氧基、乙氧基、正丙氧基、异丙氧基或叔丁氧基；
    和/或，所述的5-7元碳杂环是指杂原子选自O、N和S，杂原子数为1、2、3或4个，碳原子数为1、2、3、4、5或6个的5-7元碳杂环，优选氮杂环丁烷基、哌嗪基、哌啶基、吡咯烷基、吗啉基、硫代吗啉基、二氢咪唑基、二氢吲哚基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢喹啉基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢三唑基或二氢氮杂环丁烷基。
  3. 如权利要求1或2所述的通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或药物前体，其特征在于，
    L 1为炔基、-C(R 5)＝C(R 6)-、-CR 7R 8-CR 9R 10-、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、或取代或未取代的杂芳基，优选炔基、-C(R 5)＝C(R 6)-或-CR 7R 8-CR 9R 10-，更优选-C(R 5)＝C(R 6)-，最优选-CH＝CH-；
    和/或，L 2为炔基、-C(R 5)＝C(R 6)-、-CR 7R 8-CR 9R 10-、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基或不存在，优选炔基、-C(R 5)＝C(R 6)-、-CR 7R 8-CR 9R 10-或不存在，更优选-C(R 5)＝C(R 6)-或不存在，最优选-CH＝CH-或不存在；
    和/或，R 5、R 6、R 7、R 8、R 9和R 10分别独立地为氢或氘；
    和/或，R 1为卤素、氰基、取代或未取代的烷基，所述的烷基优选C 1-C 4烷基，更优选甲基；所述的取代的烷基中的取代基优选卤素或羟基；
    和/或，R 2为氘、卤素、氰基、取代或未取代的烷基，所述的烷基优选C 1-C 4烷基，更优选甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，所述的取代的烷基中的取代基优选卤素、氰基、C 1-C 4烷基、羟基、C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基和C 1-C 4酰胺基中的一个或多个；
    和/或，R 3和R 4独立地为氘、卤素、氰基、-SR 11、-NR 12R 13、取代或未取代的烷基、 或取代或未取代的烷氧基；优选独立地为氘、卤素、氰基、-SR 11、取代或未取代的烷基、或取代或未取代的烷氧基。
  4. 如权利要求1-3中至少一项所述的通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或药物前体，其特征在于，
    R 1和R 2独立地为卤素、烷基或被卤素取代的烷基；
    或者，R 3和R 4为卤素；
    或者，R 3和R 4为取代或未取代的烷基，所述的取代的烷基中的取代基为被卤素、氰基、羟基、
    Figure PCTCN2019113209-appb-100008
    C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳基、取代的C 1-C 10杂芳基、C 1-C 4烷氧基和C 1-C 4羧基中的一个或多个取代，优选被卤素、
    Figure PCTCN2019113209-appb-100009
    取代的C 6-C 14芳基和取代的C 1-C 10杂芳基中的一个或多个取代，当取代基为多个时，所述的取代基相同或不同，
    或者，R 3和R 4为取代或未取代的烷氧基，所述的取代的烷氧基中的取代基为被卤素、氰基、羟基、
    Figure PCTCN2019113209-appb-100010
    C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳基、取代的C 1-C 10杂芳基和C 1-C 4烷氧基中的一个或多个取代，优选被C 1-C 10杂芳基、取代的C 1-C 10杂芳基和C 1-C 4烷氧基中的一个或多个取代，最优选被C 1-C 4烷氧基取代；当取代基为多个时，所述的取代基相同或不同。
  5. 如权利要求1-4中至少一项所述的通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或药物前体，其特征在于，
    R 1和R 2独立地为卤素、C 1-C 4烷基或被F、Cl、Br和I中的一个或多个取代的C 1-C 4烷基(例如-CH 2F、-CHF 2或-CF 3)；或者，R 3和R 4为被卤素取代的烷基，所述的被卤素取代的烷基优选被F、Cl、Br和I中的一个或多个取代的C 1-C 4烷基，优选-CF 3，
    或者，R 3和R 4为被
    Figure PCTCN2019113209-appb-100011
    取代的烷基，所述的被
    Figure PCTCN2019113209-appb-100012
    取代的烷基优选被
    Figure PCTCN2019113209-appb-100013
    取代的C 1-C 4的烷基，所述的被
    Figure PCTCN2019113209-appb-100014
    取代的C 1-C 4的烷基优选
    Figure PCTCN2019113209-appb-100015
    其中， R 17和R 18一个为H，另一个为被C 1-C 4烷氧基、羟基和羧基中的一个或多个取代的烷基，当R 3和R 4为被
    Figure PCTCN2019113209-appb-100016
    取代的烷基时，所述的被
    Figure PCTCN2019113209-appb-100017
    取代的烷基优选
    Figure PCTCN2019113209-appb-100018
    Figure PCTCN2019113209-appb-100019
    Figure PCTCN2019113209-appb-100020
    或者，R 3和R 4为被取代的C 6-C 14芳基取代的烷基，优选
    Figure PCTCN2019113209-appb-100021
    或者，R 3和R 4为被取代的C 1-C 10杂芳基取代的烷基，优选
    Figure PCTCN2019113209-appb-100022
    或者，当R 3为取代或未取代的烷基时，R 3位于环A上与L 1相连的原子的间位或对位；
    或者，当R 4为取代或未取代的烷基时，R 4位于环B上与L 2相连的原子的间位或对位；
    或者，当R 3为取代或未取代的烷基时，环A上还可有0、1或2个取代基，当还可有1个取代基时，该取代基位于取代或未取代的烷基的对位、间位或邻位；
    或者，当R 4为取代或未取代的烷基时，环B上还可有0、1或2个取代基，当还可有1个取代基时，该取代基位于取代或未取代的烷基的对位、间位或邻位；
    或者，R 3和R 4为取代或未取代的烷氧基，所述的取代的烷氧基中的取代基为被卤素、氰基、羟基、
    Figure PCTCN2019113209-appb-100023
    C 6-C 14芳基、取代的C 6-C 14芳基、C 1-C 10杂芳基、取代的C 1-C 10杂芳基和C 1-C 4烷氧基中的一个或多个取代；优选地，R 3和R 4为取代的烷氧基，所述的取代的烷氧基中的取代基为被C 1-C 10杂芳基、取代的C 1-C 10杂芳基和C 1-C 4烷氧基中的一个或多个取代，当取代基为多个时，所述的取代基相同或不同；所述的取代的烷氧基优选
    Figure PCTCN2019113209-appb-100024
    或者，当R 3为取代或未取代的烷氧基时，R 3位于环A上与L 1相连的原子的邻位或间位；
    或者，当R 4为取代或未取代的烷氧基时，R 4位于环B上与L 2相连的原子的邻位或 间位。
  6. 如权利要求1-5中至少一项所述的通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或药物前体，其特征在于，
    基团
    Figure PCTCN2019113209-appb-100025
    为
    Figure PCTCN2019113209-appb-100026
    其中，R 1和R 2的定义均权利要求1或2所述；基团
    Figure PCTCN2019113209-appb-100027
    优选
    Figure PCTCN2019113209-appb-100028
    Figure PCTCN2019113209-appb-100029
    或者，
    Figure PCTCN2019113209-appb-100030
    和
    Figure PCTCN2019113209-appb-100031
    独立地为
    Figure PCTCN2019113209-appb-100032
    其中M 1和N 1为被
    Figure PCTCN2019113209-appb-100033
    取代的烷基，或者M 1和N 1其中一个为被
    Figure PCTCN2019113209-appb-100034
    取代的烷基，另一个为取代的烷氧基；其中R 17、R 18、R 3和R 4的定义均同权利要求1-5任一项所述，n1和m1独立地为0、1或2；
    优选地，M 1和N 1为
    Figure PCTCN2019113209-appb-100035
    或者M 1和N 1其中一个为
    Figure PCTCN2019113209-appb-100036
    另一个为被C 1-C 4烷氧基、C 1-C 10杂芳基和取代的C 1-C 10杂芳基中的一个或多个取代的烷氧基；R 3和R 4为氢、卤素、烷基、被卤素取代的烷基、烷氧基或取代的烷氧基，所述的取代的烷氧基中的取代基优选被C 1-C 4烷氧基、C 1-C 10杂芳基和取代的C 1-C 10杂芳基中的一个或多个取代；R 17和R 18的定义均同权利要求1-5任一项所述；
    更优选地，M 1和N 1为
    Figure PCTCN2019113209-appb-100037
    或者M 1和N 1其中一个为
    Figure PCTCN2019113209-appb-100038
    另一个为被C 1-C 4烷氧基取代的烷氧基；R 3和R 4优选卤素、烷基、被卤素取代的烷基、烷氧基或被C 1-C 4烷氧基取代的烷氧基；R 17和R 18的定义均同权利要求1-5任一项所述。
  7. 如权利要求6所述的通式I所示的联苯类化合物、其药学上可接受的盐、互变异 构体、内消旋体、外消旋体、立体异构体或药物前体，其特征在于，
    Figure PCTCN2019113209-appb-100039
    为
    Figure PCTCN2019113209-appb-100040
    Figure PCTCN2019113209-appb-100041
    Figure PCTCN2019113209-appb-100042
    其中N 1、R 17和R 18同权利要求6所述；
    或者，
    Figure PCTCN2019113209-appb-100043
    为
    Figure PCTCN2019113209-appb-100044
    Figure PCTCN2019113209-appb-100045
    Figure PCTCN2019113209-appb-100046
    其中M 1、R 17和R 18的定义如权利要求6所述。
  8. 如权利要求1-7中至少一项所述的通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或药物前体，其特征在于，
    Figure PCTCN2019113209-appb-100047
    独立地为
    Figure PCTCN2019113209-appb-100048
    Figure PCTCN2019113209-appb-100049
    Figure PCTCN2019113209-appb-100050
    Figure PCTCN2019113209-appb-100051
    和/或，
    Figure PCTCN2019113209-appb-100052
    独立地为
    Figure PCTCN2019113209-appb-100053
    Figure PCTCN2019113209-appb-100054
    Figure PCTCN2019113209-appb-100055
  9. 如权利要求1-8中至少一项所述的通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或药物前体，其特征在于，所述的通式I所示的联苯类化合物选自下列任一化合物：
    Figure PCTCN2019113209-appb-100056
    Figure PCTCN2019113209-appb-100057
  10. 如权利要求1-9中至少一项所述的通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或药物前体，其特征在于，所述的通式I所示的联苯类化合物为通式I-A或II所示的联苯类化合物：
    Figure PCTCN2019113209-appb-100058
    其中，环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、M 1、N 1、R 17和R 18的定义均同权利要求1-9任一项所述，n1为0、1或2，m1为0、1或2。
  11. 一种如权利要求10所述的通式I-A或II所示的联苯类化合物的制备方法，其特征在于，
    通式I-A所示的化合物中，当M 1和N 1中含有-NH-或-COOH时，其采用下列方法制备：所述方法包括下列步骤：将通式II-F所示的化合物进行如下所示脱保护反应，制得所述的通式I-A所示的联苯类化合物，
    Figure PCTCN2019113209-appb-100059
    其中环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、M 1和N 1的定义均同权利要求10所述，n1为0、1或2，m1为0、1或2，R IIF为M 1对应的含有氨基或羧基保护基的基团，R IIF1与N 1相同；或者，R IIF和M 1相同，R IIF1为N 1对应的含有氨基或羧基保护基的基团；或者R IIF为M 1对应的含有氨基或羧基保护基的基团，R IIF1为N 1对应的含有氨基或羧基保护基的基团；
    通式II所示的联苯类化合物的制备方法采用下列任一方法：
    (1)方法一包括下列步骤：将通式II-A所示的化合物和化合物II-A1进行如下所示的反应，制得所述的通式II所示的联苯类化合物，
    Figure PCTCN2019113209-appb-100060
    其中化合物II-A1结构如下：
    Figure PCTCN2019113209-appb-100061
    或其酸式盐，
    环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、R 17和R 18的定义均同权利要求10所述，n1为0、1或2，m1为0、1或2；在此方法中，环A和环B中的
    Figure PCTCN2019113209-appb-100062
    相同；
    (2)方法二包括下列步骤：将通式II-B所示的化合物和化合物II-B1进行如下所示的反应，制得所述的通式II所示的联苯类化合物，
    Figure PCTCN2019113209-appb-100063
    其中化合物II-B1结构如下：
    Figure PCTCN2019113209-appb-100064
    或其酸式盐，
    环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、R 17和R 18的定义均同权利要求10所述，n1 为0、1或2，m1为0、1或2，M为卤素；在此方法中，环A和环B中的
    Figure PCTCN2019113209-appb-100065
    相同；
    (3)方法三包括下列步骤：将通式II-C所示的化合物和化合物II-C1进行如下所示的反应，制得所述的通式II所示的联苯类化合物，
    Figure PCTCN2019113209-appb-100066
    其中化合物II-C1结构如下：
    Figure PCTCN2019113209-appb-100067
    或其酸式盐，
    环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、R 17和R 18的定义均同权利要求10所述，n1为0、1或2，m1为0、1或2；R IIC和R IIC1其中一个为
    Figure PCTCN2019113209-appb-100068
    另一个为
    Figure PCTCN2019113209-appb-100069
    在此方法中，环A和环B中的
    Figure PCTCN2019113209-appb-100070
    相同或不同；
    (4)方法四包括下列步骤：将通式II-D所示的化合物和化合物II-D1进行如下所示的反应，制得所述的通式II所示的联苯类化合物，
    Figure PCTCN2019113209-appb-100071
    其中化合物II-D1结构如下：
    Figure PCTCN2019113209-appb-100072
    或其酸式盐，
    环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、R 17和R 18的定义均同权利要求10所述述，n1为0、1或2，m1为0、1或2，R IID和R IID1其中一个为
    Figure PCTCN2019113209-appb-100073
    另一个为卤素，在此方法中，环A和环B中的
    Figure PCTCN2019113209-appb-100074
    相同或不同；
    (5)方法五包括下列步骤：将通式II-E所示的化合物进行如下所示脱保护反应，制得所述的通式II所示的联苯类化合物，通式II所示的化合物中R 17或R 18中含有羧基；
    Figure PCTCN2019113209-appb-100075
    其中环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、R 17和R 18的定义均同权利要求10所述，n1为0、1或2，m1为0、1或2，R IIE和R IIE1为
    Figure PCTCN2019113209-appb-100076
    每个R 17’和每个R 18’相同或不同，且至少有一个有羧基保护基，不含羧基保护基的R 17’和R 18’分别与通式II中对应的R 17和R 18相同；此方法中，环A和环B中的
    Figure PCTCN2019113209-appb-100077
    相同或不同。
  12. 一种通式II-A、II-B、II-C、II-D、II-E和II-F所示的化合物：
    Figure PCTCN2019113209-appb-100078
    Figure PCTCN2019113209-appb-100079
    环A、环B、L 1、L 2、R 1、R 2、R 3、R 4、M 1、N 1、R 17和R 18的定义均同权利要求1-9中至少一项所述，n1为0、1或2，m1为0、1或2；M为卤素，R IIC和R IIC1其中一个为
    Figure PCTCN2019113209-appb-100080
    另一个为
    Figure PCTCN2019113209-appb-100081
    R IID和R IID1其中一个为
    Figure PCTCN2019113209-appb-100082
    另一个为卤素，R IIE和R IIE1为
    Figure PCTCN2019113209-appb-100083
    每个R 17’和每个R 18’相同或不同，且至少有一个有羧基保护基，不含羧基保护基的R 17’和R 18’分别与通式II中对应的R 17和R 18相同；R IIF为M 1对应的含有氨基或羧基保护基的基团，R IIF1与N 1相同；或者，R IIF和M 1相同，R IIF1为N 1对应的含有氨基或羧基保护基的基团；或者R IIF为M 1对应的含有氨基或羧基保护基的基团，R IIF1为N 1对应的含有氨基或羧基保护基的基团。
  13. 一种如下所示的化合物：
    Figure PCTCN2019113209-appb-100084
    Figure PCTCN2019113209-appb-100085
    Figure PCTCN2019113209-appb-100086
  14. 一种如权利要求1-9中至少一项所述的通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或药物前体在制备PD-1抑制剂和/或PD-L1抑制剂中的应用。
  15. 一种如权利要求1-9中至少一项所述的通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体和药物前体中的一种或多种在制备用于预防、缓解或治疗癌症、感染、自身免疫性疾病或其相关疾病的药物中的应用，所述癌症优选肺癌、食管癌、胃癌、大肠癌、肝癌、鼻咽癌、脑肿瘤、乳腺癌、宫颈癌、血癌和骨癌中的一种或多种。
  16. 一种药物组合物，其包括治疗和/或预防有效量的如权利要求1-9中至少一项所述的通式I所示的联苯类化合物、其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体或药物前体，及药学上可接受载体和/或稀释剂。
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US11718605B2 (en) 2016-07-14 2023-08-08 Incyte Corporation Heterocyclic compounds as immunomodulators
US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
US11780836B2 (en) 2020-11-06 2023-10-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
US11866451B2 (en) 2019-11-11 2024-01-09 Incyte Corporation Salts and crystalline forms of a PD-1/PD-L1 inhibitor
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
US11873309B2 (en) 2016-06-20 2024-01-16 Incyte Corporation Heterocyclic compounds as immunomodulators
US12466822B2 (en) 2016-12-22 2025-11-11 Incyte Corporation Heterocyclic compounds as immunomodulators

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Publication number Priority date Publication date Assignee Title
WO2022028557A1 (zh) * 2020-08-07 2022-02-10 上海再极医药科技有限公司 18f标记的联苯类化合物、其中间体、制备方法、药物组合物及应用
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WO2023282678A1 (ko) 2021-07-07 2023-01-12 주식회사 아델 사회적 우세성의 결여 또는 감소와 관련된 질환의 동물 모델 및 상기 질환의 예방 또는 치료용 약학 조성물
EP4626423A1 (en) * 2022-12-02 2025-10-08 Relay Therapeutics, Inc. Cdk inhibitors and methods and use thereof

Citations (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012168944A1 (en) 2011-06-08 2012-12-13 Aurigene Discovery Technologies Limited Therapeutic compounds for immunomodulation
WO2015033299A1 (en) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
WO2015034820A1 (en) 2013-09-04 2015-03-12 Bristol-Myers Squibb Company Compounds useful as immunomodulators
WO2015033301A1 (en) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators
WO2015036927A1 (en) 2013-09-10 2015-03-19 Aurigene Discovery Technologies Limited Immunomodulating peptidomimetic derivatives
WO2015044900A1 (en) 2013-09-27 2015-04-02 Aurigene Discovery Technologies Limited Therapeutic immunomodulating compounds
WO2015160641A2 (en) 2014-04-14 2015-10-22 Bristol-Myers Squibb Company Compounds useful as immunomodulators
WO2017066227A1 (en) 2015-10-15 2017-04-20 Bristol-Myers Squibb Company Compounds useful as immunomodulators
WO2017070089A1 (en) 2015-10-19 2017-04-27 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017087777A1 (en) 2015-11-19 2017-05-26 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017106634A1 (en) 2015-12-17 2017-06-22 Incyte Corporation N-phenyl-pyridine-2-carboxamide derivatives and their use as pd-1/pd-l1 protein/protein interaction modulators
WO2017112730A1 (en) 2015-12-22 2017-06-29 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017192961A1 (en) 2016-05-06 2017-11-09 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017205464A1 (en) 2016-05-26 2017-11-30 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017222976A1 (en) 2016-06-20 2017-12-28 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2018009505A1 (en) 2016-07-08 2018-01-11 Bristol-Myers Squibb Company 1,3-dihydroxy-phenyl derivatives useful as immunomodulators
CN107573332A (zh) * 2016-07-05 2018-01-12 广州再极医药科技有限公司 芳香乙炔或芳香乙烯类化合物、其中间体、制备方法、药物组合物及应用
WO2018013789A1 (en) 2016-07-14 2018-01-18 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2018044963A1 (en) 2016-09-01 2018-03-08 Bristol-Myers Squibb Company Biaryl compounds useful as immunomodulators
WO2018044783A1 (en) 2016-08-29 2018-03-08 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2018118848A1 (en) 2016-12-20 2018-06-28 Bristol-Myers Squibb Company Compounds useful as immunomodulators
WO2018119224A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Tetrahydro imidazo[4,5-c]pyridine derivatives as pd-l1 internalization inducers
WO2018119221A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Pyridine derivatives as immunomodulators
WO2018119286A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Bicyclic heteroaromatic compounds as immunomodulators
WO2018119263A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Heterocyclic compounds derivatives as pd-l1 internalization inducers
WO2018195321A1 (en) * 2017-04-20 2018-10-25 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2018219266A1 (zh) 2017-05-31 2018-12-06 深圳大学 用于制备乙肝疫苗的组合物及其制备方法和应用

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002326992A (ja) * 2001-05-02 2002-11-15 Nagase & Co Ltd ビナフチル基およびビフェニル基を含むｎ−スピロ不斉相間移動触媒
JP5430943B2 (ja) * 2006-01-25 2014-03-05 シンタ ファーマシューティカルズ コーポレーション 炎症及び免疫関連用途のための置換芳香族化合物
WO2008157844A1 (en) * 2007-06-21 2008-12-24 Forest Laboratories Holdings Limited Novel piperazine derivatives as inhibitors of stearoyl-coa desaturase
GB2548337A (en) * 2016-03-08 2017-09-20 Cambridge Display Tech Ltd Compound, composition and organic light-emitting device
EP3493804A1 (en) * 2016-08-03 2019-06-12 Arising International, Inc. Symmetric or semi-symmetric compounds useful as immunomodulators
WO2018119266A1 (en) * 2016-12-22 2018-06-28 Incyte Corporation Benzooxazole derivatives as immunomodulators
WO2018119236A1 (en) * 2016-12-22 2018-06-28 Incyte Corporation Triazolo[1,5-a]pyridine derivatives as immunomodulators
CN111712494A (zh) * 2018-02-13 2020-09-25 吉利德科学公司 Pd-1/pd-l1抑制剂

Patent Citations (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012168944A1 (en) 2011-06-08 2012-12-13 Aurigene Discovery Technologies Limited Therapeutic compounds for immunomodulation
WO2015034820A1 (en) 2013-09-04 2015-03-12 Bristol-Myers Squibb Company Compounds useful as immunomodulators
WO2015033299A1 (en) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
WO2015033301A1 (en) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators
WO2015036927A1 (en) 2013-09-10 2015-03-19 Aurigene Discovery Technologies Limited Immunomodulating peptidomimetic derivatives
WO2015044900A1 (en) 2013-09-27 2015-04-02 Aurigene Discovery Technologies Limited Therapeutic immunomodulating compounds
WO2015160641A2 (en) 2014-04-14 2015-10-22 Bristol-Myers Squibb Company Compounds useful as immunomodulators
WO2017066227A1 (en) 2015-10-15 2017-04-20 Bristol-Myers Squibb Company Compounds useful as immunomodulators
WO2017070089A1 (en) 2015-10-19 2017-04-27 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017087777A1 (en) 2015-11-19 2017-05-26 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017106634A1 (en) 2015-12-17 2017-06-22 Incyte Corporation N-phenyl-pyridine-2-carboxamide derivatives and their use as pd-1/pd-l1 protein/protein interaction modulators
WO2017112730A1 (en) 2015-12-22 2017-06-29 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017192961A1 (en) 2016-05-06 2017-11-09 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017205464A1 (en) 2016-05-26 2017-11-30 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017222976A1 (en) 2016-06-20 2017-12-28 Incyte Corporation Heterocyclic compounds as immunomodulators
CN107573332A (zh) * 2016-07-05 2018-01-12 广州再极医药科技有限公司 芳香乙炔或芳香乙烯类化合物、其中间体、制备方法、药物组合物及应用
WO2018009505A1 (en) 2016-07-08 2018-01-11 Bristol-Myers Squibb Company 1,3-dihydroxy-phenyl derivatives useful as immunomodulators
WO2018013789A1 (en) 2016-07-14 2018-01-18 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2018044783A1 (en) 2016-08-29 2018-03-08 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2018044963A1 (en) 2016-09-01 2018-03-08 Bristol-Myers Squibb Company Biaryl compounds useful as immunomodulators
WO2018118848A1 (en) 2016-12-20 2018-06-28 Bristol-Myers Squibb Company Compounds useful as immunomodulators
WO2018119224A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Tetrahydro imidazo[4,5-c]pyridine derivatives as pd-l1 internalization inducers
WO2018119221A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Pyridine derivatives as immunomodulators
WO2018119286A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Bicyclic heteroaromatic compounds as immunomodulators
WO2018119263A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Heterocyclic compounds derivatives as pd-l1 internalization inducers
WO2018195321A1 (en) * 2017-04-20 2018-10-25 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2018219266A1 (zh) 2017-05-31 2018-12-06 深圳大学 用于制备乙肝疫苗的组合物及其制备方法和应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EUR. J. IMMUNOL., vol. 32, no. 3, 2002, pages 634 - 643
See also references of EP3875458A4

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US11572366B2 (en) 2015-11-19 2023-02-07 Incyte Corporation Heterocyclic compounds as immunomodulators
US11535615B2 (en) 2015-12-22 2022-12-27 Incyte Corporation Heterocyclic compounds as immunomodulators
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US11608337B2 (en) 2016-05-06 2023-03-21 Incyte Corporation Heterocyclic compounds as immunomodulators
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US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
US11401279B2 (en) 2019-09-30 2022-08-02 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
US12247038B2 (en) 2019-09-30 2025-03-11 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
US11866451B2 (en) 2019-11-11 2024-01-09 Incyte Corporation Salts and crystalline forms of a PD-1/PD-L1 inhibitor
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US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor

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