WO2019120297A1 - Immunomodulateur, son procédé de préparation et son utilisation médicale - Google Patents

Immunomodulateur, son procédé de préparation et son utilisation médicale Download PDF

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WO2019120297A1
WO2019120297A1 PCT/CN2018/122818 CN2018122818W WO2019120297A1 WO 2019120297 A1 WO2019120297 A1 WO 2019120297A1 CN 2018122818 W CN2018122818 W CN 2018122818W WO 2019120297 A1 WO2019120297 A1 WO 2019120297A1
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alkyl
cancer
compound
mmol
group
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PCT/CN2018/122818
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Chinese (zh)
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彭建彪
龚超骏
茅佳荣
彭冠
林崇懒
刘力锋
张青
席宝信
关慧平
陈曦
周福生
王玮玮
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Publication of WO2019120297A1 publication Critical patent/WO2019120297A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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Definitions

  • the invention belongs to the field of medical technology.
  • the present invention relates in particular to an immunomodulator, a process for its preparation and use as a PD-1/PD-L1 inhibitor, and a pharmaceutical composition prepared therefrom.
  • PD-1 Programmed cell death-1
  • PD-L1 or PD-L2 are members of the CD28 superfamily that delivers a negative signal when interacting with its two ligands, PD-L1 or PD-L2.
  • PD-1 and its ligands are widely expressed and exert a broader range of immunomodulatory effects in T cell activation and tolerance compared to other CD28 members.
  • PD-1 and its ligands are involved in attenuating infectious and tumor immunity and promoting chronic infection and tumor progression.
  • the biological importance of PD-1 and its ligands suggests the possibility of treatment of the PD-1 pathway for a variety of human diseases (Ariel Pedoeem et al, Curr Top Microbiol Immunol. (2011); 350: 17-37). .
  • T cell activation and dysfunction are dependent on direct and regulated receptors. Based on their functional results, co-signaling molecules can be divided into co-stimulants and co-inhibitors that positively and negatively control the initiation, growth, differentiation, and functional maturation of T cell responses (Li Shi, et al, Journal of Hematology & Oncology 2013) , 6:74).
  • Therapeutic antibodies that block the programmed cell death protein-1 (PD-1) immunological checkpoint pathway prevent T cell down-regulation and promote an immune response against cancer.
  • PD-1 pathway inhibitors show strong activity at various stages of clinical trials (RD Harvey, Clinical Pharmacology & Therapeutics (2014); 96 2, 214-223).
  • Programmed death-1 is a co-receptor that is primarily expressed by T cells.
  • the binding of PD-1 to its ligand, PD-L1 or PD-L2 is critical for the physiological regulation of the immune system.
  • the primary functional role of the PD-1 signaling pathway is to inhibit autoreactive T cells, which are used to protect against autoimmune diseases.
  • elimination of the PD-1 pathway can lead to disruption of immune tolerance, which can ultimately lead to the development of pathological autoimmunity.
  • tumor cells can sometimes specify the PD-1 pathway to escape immune surveillance mechanisms. Therefore, blocking the PD-1 pathway has become an attractive target for cancer therapy.
  • Current methods include six agents that are neutralizing antibodies or fusion proteins that target PD-1 and PD-L1. More than forty clinical trials are underway to better define the role of PD-1 blockade in a variety of tumor types (Hyun-Tak Jin et al, Clinical Immunology (Amsterdam, Netherlands) (2014), 153 ( 1), 145-152).
  • the present invention provides 1,3,4-diazole and 1,3,4-thiadiazole compounds which are capable of suppressing and/or inhibiting the programmed cell death 1 (PD1) signaling pathway.
  • PD1 programmed cell death 1
  • a first aspect of the invention provides a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:
  • Z 1 is N or CR 1 ;
  • Z 2 is N or CR 2 ;
  • Z 3 is N or CR 3 ;
  • Z 4 is N or CR 4 ;
  • a 1 is N or CR 5 ;
  • a 2 is N or CR 6 ;
  • a 3 is N or CR 7 ;
  • a 4 is N or CR 8 ;
  • X is a bond, NH, O, S, S(O) or S(O) 2 ;
  • W is a C 6-10 aryl group (such as a benzene ring), a 5- to 6-membered monocyclic heteroaryl ring W 1 having 1 to 3 hetero atoms independently selected from nitrogen, oxygen or sulfur, having 1 to 5 independent
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen, hydroxy, CN, NO 2 , halogen (preferably F or Cl), -NR a0 R b0 , C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 3- 8- cycloalkoxy (preferably C 3-6 cycloalkoxy), C 2-10 alkenyl (preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl), C 2-10 alkyne a group (preferably a C 2-6 alkynyl group, more preferably a C 2-4 alkynyl group), a C 1-10 alkoxy group (preferably a C 1-6 alkoxy group, more preferably a C 1-3 alkoxy group) ), -CHO, -C(O)C 1-10 alkyl (preferably
  • R 9 and R 10 are each independently hydrogen, hydroxy, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);
  • R a is Or a C 3-8 cycloalkyl group, R b is hydrogen or a C 1-8 alkyl group; or R a , R b are bonded to an adjacent nitrogen atom to form a 5- to 6-membered saturated monoheterocyclic ring B;
  • R a1 and R b1 are each independently hydrogen, hydroxy, carboxy or C 1-8 alkyl;
  • R 0 is C 1-8 alkyl, hydroxy, carboxyl, acetamido, pyrrolidone, -(O-(CH 2 ) 2 ) m -NH 2 ;
  • alkyl, alkoxy, cycloalkyl, cycloalkoxy, alkenyl, alkynyl, aryl, W 1 , W 2 , W 3 , W 4 , W 5 , W 6 are unsubstituted or 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, halogenated C 1-8 alkyl (preferably halogenated C 1- 6 alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably F or Cl), nitro, C 6-10 aryl (preferably phenyl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 3 -8 cycloalkyl (preferably C 3-6 cycloalkyl), C 3-8 cycloalkoxy (preferably
  • X is a bond
  • the monoheterocyclic ring B is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl Carboxyl, halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably F or Cl), nitro, C 6 -10 aryl (preferably phenyl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1- 6 alkoxy, more preferably C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 3-8 cycloalkoxy (preferably C 3- 6 cycloalkoxy), C 2-10 alkenyl (preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl), C 2-10 alkenyl (
  • the monoheterocyclic ring B is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl Carboxy, C 1-8 alkyl, C 1-8 alkoxy or halogenated C 1-8 alkyl.
  • Z 1 is CR 1 ;
  • Z 2 is CR 2 ;
  • Z 3 is CR 3 ;
  • Z 4 is N.
  • a 1 is CR 5 ;
  • a 2 is CR 6 ;
  • a 3 is CR 7 ;
  • a 4 is CR 8 .
  • W is a benzene ring which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, hydroxy, hydroxymethyl, Hydroxyethyl, carboxy, halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably F or Cl), nitro , C 6-10 aryl (preferably phenyl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 3-8 cycloalkoxy (preferably C 3-6 cycloalkoxy), C 2-10 alkenyl (preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl), C 2-10 alkenyl (
  • R 1 , R 2 , and R 3 are each independently hydrogen, CN, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably Is C 1-3 alkyl) or C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); the alkyl, alkoxy is unsubstituted Or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, halo C 1-8 alkyl (preferably halogenated) C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably F or Cl), nitro, C 6-10 aryl (preferably phenyl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 al
  • R 1 , R 2 , and R 3 are each independently hydrogen, CN, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably Is C 1-3 alkyl) or C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); the alkyl, alkoxy is unsubstituted Or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, B Oxyl, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl.
  • halogen preferably F or Cl
  • C 1-10 alkyl preferably C 1-6 alkyl, more preferably Is C 1-3 al
  • R 1 is hydrogen, CN, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy);
  • R 2 , R 3 are hydrogen; the alkyl, alkoxy is unsubstituted Or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, halo C 1-3 alkyl, halogen (preferably F or Cl), C 1-3 alkoxy, C 3-6 cycloalkyl.
  • R 5 , R 6 , R 7 , R 8 are each independently hydrogen, CN, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl) More preferably, it is a C 1-3 alkyl group or a C 1-10 alkoxy group (preferably a C 1-6 alkoxy group, more preferably a C 1-3 alkoxy group); the alkyl group, alkoxy group Substituted as unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, halo C 1-8 alkyl (preferred Is a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group), a halogen (preferably F or Cl), a nitro group, a C 6-10 aryl group (preferably a phenyl group), C 1- 10 alkyl
  • the C 6-10 aryl group (preferably phenyl group) in the substituent is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano and hydroxy groups.
  • R 5 and R 7 are each independently hydrogen, CN, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1 -3 alkyl) or C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy);
  • R 6 , R 8 are hydrogen; the alkyl, alkane
  • the oxy group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, phenyl, halo C 1-3 alkyl, halogen (preferably F or Cl), C 1-3 alkoxy, C 3-6 cycloalkyl; wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, C 1 a -3 alkyl group, a halogenated C 1-3 alkyl group, a halogen (preferably F or Cl), a C 1-3 al
  • R 5 and R 7 are each independently hydrogen, CN, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1 -3 alkyl) or C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy);
  • R 6 , R 8 are hydrogen; the alkyl, alkane
  • the oxy group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, phenyl, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl; Wherein the phenyl group is unsubstituted or substituted by 1, 2 or
  • R 5 is hydrogen, CN, F, Cl or C 1-3 alkyl
  • R 7 is hydrogen, C 1-3 alkyl or C 1-3 alkoxy
  • R 6 , R 8 Is hydrogen
  • the alkyl group, alkoxy group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, halo C 1-3 alkyl, halogen (preferably Is F or Cl), C 1-3 alkoxy, phenyl, C 3-6 cycloalkyl
  • the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of Substituted: cyano, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, halogen (preferably F or Cl), C 1-3 alkoxy, C 3-6 cycloalkyl.
  • R 9 and R 10 are hydrogen.
  • the 5- to 6-membered saturated monoheterocyclic ring B formed by linking R a and R b to an adjacent nitrogen atom is selected from the group consisting of: tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine or Thiomorpholine-1,1-dioxide; said monoheterocyclic ring B is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, hydroxy, hydroxy Methyl, hydroxyethyl, carboxyl, C 1-8 alkyl, C 1-8 alkoxy or halogenated C 1-8 alkyl.
  • the 5- to 6-membered saturated monoheterocyclic ring B formed by linking R a and R b to an adjacent nitrogen atom is selected from the following structures:
  • W 1 is selected from the group consisting of: a thiophene ring, an N-alkylcyclopyrrole ring, a furan ring, a thiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring, a triazole ring, 1, 2, 3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine Ring, pyridazine ring, pyrimidine ring or pyrazine ring.
  • W 1 is selected from the group consisting of
  • the above 5- to 6-membered monocyclic heteroaryl ring is optionally substituted with 1, 2 or 3 substituents selected from the AI group.
  • the substituent of the AI group is: halogen, -O(CH 2 ) p OC 1-8 alkyl, -O(CH 2 ) p OH, -(CH 2 ) p OC 1-8 alkane a 4- to 6-membered saturated monoheterocyclic ring, a C 1-8 alkyl group (preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group), a C 3-8 cycloalkyl group (preferably C 3 ) -6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 3-8 cycloalkyl ( Preferred is a halogenated C 3-6 cycloalkyl group, a hydroxy-substituted C 1-8 alkyl group (preferably a hydroxy-substituted C 1-6 alkyl group, more preferably
  • the 4- to 6-membered saturated monocyclic ring in the AI group substituent is selected from the group consisting of azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazole Alkane, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
  • the substituent of the AI group is fluorine, chlorine, bromine, hydroxymethyl, hydroxyethyl, hydroxy, carboxy, -O(CH 2 ) p OC 1-3 alkyl, -O(CH 2 p OH, -(CH 2 ) p OC 1-3 alkyl, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, two Oxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, methyl, ethyl, n-propyl, isopropyl, ring Propyl, monochloroethyl, dichloromethyl, 1,2-dichloroethyl, monobromoethyl, monofluorine,
  • W 2 is selected from the group consisting of a benzofuran ring, a benzothiophene ring, an anthracene ring, an isoindole ring, a quinoline ring, an isoquinoline ring, an indazole ring, a benzothiazole ring, and a benzene.
  • a benzofuran ring a benzothiophene ring, an anthracene ring
  • an isoindole ring a quinoline ring
  • an isoquinoline ring an indazole ring
  • a benzothiazole ring and a benzene.
  • an imidazole ring a quinazoline ring, a quinoxaline ring, a porphyrin ring, a pyridazine ring.
  • W 3 is selected from the group consisting of azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, and Oxycyclohexyl, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
  • W 4 is selected from the group consisting of a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, a cyclohexane, a cyclohexadiene ring, a cycloheptane, and a cycloheptatriene ring.
  • W 5 is selected from the group consisting of: a tetrahydroquinoline ring, a tetrahydroisoquinoline ring, and a decahydroquinoline ring.
  • the compound of formula (I) is a compound of formula (II):
  • Z 4 is N or CR 4 ;
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen, halogen, hydroxy, cyano, C 1-8 alkyl, halo C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, C 3-8 cycloalkoxy, C 6-10 aryl, -C(O)C 1-8 Alkyl, -C(O)OC 1-8 alkyl, -CONR a0 R b0 or NR a0 R b0 ; R a0 , R b0 are each independently hydrogen or C 1-8 alkyl;
  • R w1 , R w2 , R w3 , R w4 , R w5 are each independently hydrogen, halogen, hydroxy, cyano, C 1-8 alkyl, halo C 1-8 alkyl; or R w1 , R w2 and The carbon atoms on adjacent benzene rings are bonded to form a 5- to 6-membered saturated monoheterocyclic ring A;
  • R a is Or a C 3-8 cycloalkyl group, R b is hydrogen or a C 1-8 alkyl group; or R a , R b are bonded to an adjacent nitrogen atom to form a 5- to 6-membered saturated monoheterocyclic ring B;
  • R a1 and R b1 are each independently hydrogen, hydroxy, carboxy or C 1-8 alkyl;
  • R 0 is C 1-8 alkyl, hydroxy, carboxyl, acetamido, pyrrolidone, -(O-(CH 2 ) 2 ) m -NH 2 ;
  • alkyl, alkoxy, cycloalkyl, monoheterocyclic A, monoheterocyclic B is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, Hydroxy, hydroxymethyl, hydroxyethyl, carboxy, C 1-8 alkyl, C 1-8 alkoxy or halogenated C 1-8 alkyl.
  • Z 4 is N.
  • the monoheterocyclic ring A is selected from the group consisting of: tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide , tetrahydropyran or structure Where p is 1, 2 or 3.
  • the monoheterocyclic ring B is selected from the group consisting of: tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine or thiomorpholine-1,1-dioxide.
  • R w1 , R w2 , R w3 , R w4 , R w5 are each independently hydrogen, halogen, C 1-8 alkyl.
  • R 1 is a cyano group.
  • R 6 and R 8 are each independently hydrogen.
  • R 6 , R 7 and R 8 are each independently hydrogen.
  • R 5 is hydrogen, halogen, C 1-3 alkyl, halo C 1-3 alkyl or C 1-3 alkoxy.
  • R 5 is hydrogen, fluorine, chlorine, trifluoromethyl or methoxy.
  • R 2 and R 3 are hydrogen.
  • the compound is selected from Table A.
  • the compounds of Table A include:
  • the compound is selected from Table B.
  • the compounds of Table B include:
  • a second aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first aspect of the invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; And a pharmaceutically acceptable carrier.
  • a third aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first aspect of the invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; And at least one other agent, wherein the other agent is an anticancer agent, a chemotherapeutic agent, or an antiproliferative compound.
  • a fourth aspect of the invention provides a compound according to the first aspect of the invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or as described in the second and third aspects of the invention.
  • a pharmaceutical composition for the preparation of a medicament for the treatment of cancer or an infectious disease.
  • the cancer is selected from the group consisting of bone cancer, head or neck cancer, pancreatic cancer, skin cancer, skin or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer , testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, thyroid Paracancerous adenocarcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, solid tumor of children, lymphocytic lymph Tumor, bladder cancer, renal or ureteral cancer, renal pelvic cancer
  • the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease.
  • a fifth aspect of the invention provides a method of modulating an immune response mediated by a PD-1 signaling pathway in a subject, the method comprising administering to the subject a therapeutically effective amount of the first aspect of the invention a compound or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second and third aspects of the invention.
  • a sixth aspect of the invention provides a method of inhibiting growth and/or migration of tumor cells in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the first aspect of the invention or a stereoisod thereof A construct, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second and third aspects of the invention.
  • the tumor cell is a cancer selected from the group consisting of breast cancer, colon cancer, lung cancer, melanoma, prostate cancer, and kidney cancer.
  • the tumor cell is a cancer selected from the list consisting of bone cancer, head or neck cancer, pancreatic cancer, skin cancer, skin or intraocular malignant melanoma, uterine cancer, Ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, Small bowel cancer, endocrine cancer, thyroid cancer, parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymph Cell leukemia, solid tumor of children, lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumor,
  • CNS
  • a seventh aspect of the invention provides a method of treating an infectious disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the first aspect of the invention or a stereoisomer thereof, or A pharmaceutically acceptable salt, solvate or prodrug, or a pharmaceutical composition according to the second and third aspects of the invention.
  • An eighth aspect of the invention provides a method of treating bacterial, viral and fungal infections in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the first aspect of the invention or a stereoisomer thereof Or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second and third aspects of the invention.
  • the infectious diseases include, but are not limited to, HIV, influenza, herpes, Giardia, malaria, Leishmania, pathogenic infections caused by hepatitis viruses (A, B, & C), herpes viruses (for example, VZV, HSV-I, HAV-6, HSV-II, and CMV, EB (Epstein Barr) virus, adenovirus, influenza virus, arbovirus, echovirus, rhinovirus, coxsackie virus, coronal Virus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papilloma virus, soft prion virus, poliovirus, rabies virus, JC Viral and arboviruses encephalitis virus, pathogenic infections caused by bacterial chlamydia, rickettsial bacteria, mycobacteria, staphylococcus, streptoc
  • the inventors have unexpectedly discovered such immunomodulators, particularly those having high inhibitory activity against enzymes such as PPI-HTRF, through extensive and intensive research. Therefore, this series of compounds is expected to be developed as a drug for treating tumors. On this basis, the inventors completed the present invention.
  • alkyl refers to both straight-chain and branched saturated aliphatic hydrocarbon groups, and C1-10- alkyl is alkyl having from 1 to 10 carbon atoms, preferably C1-8 alkyl, more preferably C 1-6 alkyl, more preferably C 1-3 alkyl, is similarly defined; non-limiting examples of alkyl include: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropane Base, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethyl Butyl, 1,2-dimethylbutyl, 2,2-dimethyl
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group
  • C 3-8 cycloalkyl refers to a cyclic hydrocarbon group containing from 3 to 8 carbon atoms, preferably a C 3-6 ring.
  • Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl
  • a cyclooctyl group or the like is preferably a cyclopropyl group, a cyclopentyl group or a cyclohexenyl group.
  • a hydrocarbon group For example, vinyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl, hexenyl, and the like.
  • C 2-10 alkynyl refers to a straight-chain and branched unsaturated aliphatic hydrocarbon group having a carbon-carbon triple bond having 2 to 10 (preferably 2 to 6) carbon atoms.
  • spirocyclic refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the individual rings, which may contain one or more double bonds, but none of the rings have fully conjugated ⁇ electrons. system.
  • the spiro ring is divided into a double spiro ring or a multi-spiral ring depending on the number of rings, preferably a double spiro ring. More preferably, it is preferably a 4 member/5 member, a 5 member/5 member or a 5 member/6 member double screw ring.
  • spiroheterocycle refers to a polycyclic hydrocarbon in which one atom (called a spiro atom) is shared between monocyclic rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(O) n (where n is an integer) From 0 to 2), the remaining atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spiroheterocycle is classified into a bispiral heterocyclic ring or a polyspirocyclic ring according to the number of rings, preferably a double spiro heterocyclic ring. More preferably, it is 4 yuan/5 yuan, 5 yuan/5 yuan or 5 yuan / 6 yuan double spiro heterocycle.
  • bridged ring refers to a polycyclic group that shares two or more carbon atoms.
  • the shared carbon atom is called the bridgehead carbon.
  • the two bridgehead carbons may be carbon chains or a bond. , called the bridge. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably a bicyclic or tricyclic bridged ring.
  • bridge heterocycle refers to a polycyclic group that shares two or more atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) n (where n is an integer from 0 to 2) a hetero atom, the remaining ring atoms being carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably a bicyclic or tricyclic bridge heterocycle. E.g:
  • 8- to 10-membered bicyclic refers to a bridged ring containing two rings of 8 to 10 ring atoms, which may be a saturated all-carbon bicyclic or partially unsaturated all-carbon bicyclic ring, examples of which include ( But not limited to):
  • 8- to 10-membered bicyclic heterocycle refers to a two-ring-containing bridged heterocyclic ring containing from 8 to 10 ring atoms, wherein 1, 2, 3, 4 or 5 ring carbon atoms are selected from nitrogen Substituted by a hetero atom of oxygen or sulfur.
  • bicyclic heterocycles include, but are not limited to, tetrahydroquinoline rings, tetrahydroisoquinoline rings, decahydroquinoline rings, and the like.
  • C 1-10 alkoxy refers to -O-(C 1-10 alkyl), wherein alkyl is as defined above.
  • a C 1-8 alkoxy group is preferred, a C 1-6 alkoxy group is more preferred, and a C 1-3 alkoxy group is more preferred.
  • Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentyloxy and the like.
  • C 3-8 cycloalkoxy refers to -O-(C 3-8 cycloalkyl), wherein cycloalkyl is as defined above. Preference is given to C 3-6 cycloalkoxy. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • C 6-10 aryl refers to an all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, meaning 6 to 10
  • An aryl group of a carbon atom preferably a phenyl group and a naphthyl group, more preferably a phenyl group.
  • the aryl group preferably phenyl and naphthyl, more preferably phenyl
  • the substituent is substituted by a substituent including: CN, halogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy a group (preferably a C 1-6 alkoxy group, more preferably a C 1-3 alkoxy group), a halogenated C 1-8 alkyl group (preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C) 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably a halogenated C 1-3 alkoxy group, a C 1-8 alkyl substituted amine group, an amine group, a halogenated C 1-8 alkyl group substituted amine group; preferably, the substituent is selected from the group consisting of The lower group: CN, halogen, C 1-8 alky
  • a bond refers to the attachment of two groups attached thereto through a covalent bond.
  • halogen refers to fluoro, chloro, bromo or iodo.
  • halo means that one or more (eg 1, 2, 3, 4 or 5) hydrogens in the group are replaced by a halogen.
  • halo C 1-8 alkyl refers to an alkyl group substituted with one or more (eg 1, 2, 3, 4 or 5) halo, wherein alkyl is as defined above. It is selected as a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group.
  • halogenated C 1-8 alkyl groups include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, Monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.
  • halo C 1-8 alkoxy means that the alkoxy group is substituted by one or more (eg 1, 2, 3, 4 or 5) halogens, wherein the alkoxy group is as defined above. It is preferably a halogenated C 1-6 alkoxy group, more preferably a halogenated C 1-3 alkoxy group. These include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
  • halo C 3-8 cycloalkyl refers to a cycloalkyl group substituted with one or more (eg, 1, 2, 3, 4, or 5) halo, wherein cycloalkyl is as defined above.
  • Preferred is a halogenated C 3-6 cycloalkyl group. These include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.
  • deuterated C 1-8 alkyl refers to an alkyl group substituted with one or more (eg 1, 2, 3, 4 or 5) deuterium atoms, wherein alkyl is as defined above. It is preferably a deuterated C 1-6 alkyl group, more preferably a deuterated C 1-3 alkyl group. Examples of deuterated C 1-20 alkyl groups include, but are not limited to, monodeuterated methyl, monodeuterated ethyl, dideuterated methyl, didecanoethyl, triterpene methyl, triterpenoid Base.
  • amino refers to NH 2
  • cyano refers to the CN
  • Niro refers to NO 2
  • benzyl refers to -CH 2 - phenyl
  • carbboxy Refers to -C(O)OH, -COOH or -CO 2 H
  • acetyl refers to -C(O)CH 3
  • hydroxymethyl refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CH(OH)CH 3
  • hydroxy means -OH
  • thiol means SH
  • cyclopropylene structure is: “Acetylamino” means -NH-C(O)CH 3 and "pyrrolidone” means
  • heteroaryl ring and “heteroaryl” are used interchangeably and mean having 5 to 10 ring atoms, preferably 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl.
  • the ring array shares 6, 10 or 14 ⁇ electrons; and has a group of 1 to 5 hetero atoms in addition to carbon atoms.
  • Hetero atom means nitrogen, oxygen or sulfur.
  • 3- to 7-membered saturated or partially unsaturated monocyclic refers to a saturated or partially unsaturated, all-carbon monocyclic ring containing from 3 to 7 ring atoms.
  • monocyclic rings include, but are not limited to, cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, cycloheptyl groups. Ring, cycloheptatrienyl ring, cyclooctyl ring, and the like.
  • 3 to 7 membered saturated monoheterocycle means that 1, 2 or 3 carbon atoms in a 3 to 7 membered monocyclic ring are selected from nitrogen, oxygen or S(O) t (where t is an integer 0)
  • the heteroatoms to 2) are substituted, but do not include the ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon; preferably 4 to 6 members, more preferably 5 to 6 members.
  • saturated monoheterocycles include, but are not limited to, propylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine, piperazine , dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, and the like.
  • a "5- to 6-membered monocyclic heteroaryl ring” refers to a monoheteroaryl ring containing from 5 to 6 ring atoms, including, for example, but not limited to, a thiophene ring, an N-alkylpyrrole ring, Furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5- a triazole ring, a 1,3,4-triazole ring, a tetrazole ring, an isoxazole ring, an oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, and the like.
  • 8- to 10-membered bicyclic heteroaryl ring refers to a bi-heteroaryl ring containing from 8 to 10 ring atoms, including, for example, but not limited to, benzofuran, benzothiophene, anthracene, Isoindole, quinoline, isoquinoline, carbazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, porphyrin, pyridazine.
  • 8- to 10-membered saturated or partially unsaturated bicyclic refers to a saturated all-carbon bicyclic or partially unsaturated, all-carbon bicyclic ring containing from 8 to 10 ring atoms.
  • 3 to 7 membered saturated or partially unsaturated monoheterocyclic ring means a saturated monocyclic or partially unsubstituted ring containing from 3 to 7 ring atoms and one to three carbon atoms substituted with a hetero atom selected from nitrogen, oxygen or sulfur. Saturated single ring.
  • Examples of monoheterocycles include, but are not limited to, tetrahydrofuran ring, tetrahydrothiophene ring, pyrrolidinyl ring, piperidine ring, pyrroline ring, oxazolidine ring, piperazine ring, dioxolane, morpholine ring.
  • 8 to 10 membered saturated or partially unsaturated bicyclic heterocycle means a saturated bicyclic ring having 8 to 10 ring atoms and 1 to 5 carbon atoms substituted with a hetero atom selected from nitrogen, oxygen or sulfur. Or partially unsaturated double rings.
  • the bicyclic heterocycle include, but are not limited to, a tetrahydroquinoline ring, a tetrahydroisoquinoline ring, and a decahydroquinoline ring.
  • substituted refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently substituted with each other by a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independent of each other. The ground is replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • any of the groups herein may be substituted or unsubstituted.
  • the substituent is preferably a group of 1 to 5 or less, independently selected from the group consisting of CN, halogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3) Alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferably halogen C 1- 6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkoxy (preferably halogenated) C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 alkyl substituted amine, amine, halogenated C 1-8 alkyl substituted amine, 4 Up to 6-membered saturated monoheterocyclic ring, 5-
  • the “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without any other side effects.
  • “Pharmaceutically acceptable base addition salts” including but not limited to salts of inorganic bases such as sodium, potassium, calcium and magnesium salts, and the like. These include, but are not limited to, salts of organic bases such as ammonium salts, triethylamine salts, lysine salts, arginine salts and the like.
  • solvate refers to a complex of a compound of the invention with a solvent. They either react in a solvent or precipitate out of the solvent or crystallize out. For example, a complex formed with water is referred to as a "hydrate.” Solvates of the compounds of formula (I) are within the scope of the invention.
  • the compounds of formula (I) or formula (II) of the present invention may contain one or more chiral centers and exist in different optically active forms. When the compound contains a chiral center, the compound contains the enantiomer.
  • the invention includes mixtures of the two isomers and isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When a compound of formula (I) or formula (II) contains more than one chiral center, diastereomers may be present.
  • the present invention includes resolved optically pure specific isomers as well as mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • the invention includes prodrugs of the above compounds.
  • Prodrugs include known amino protecting groups and carboxy protecting groups which are hydrolyzed under physiological conditions or released via an enzymatic reaction to give the parent compound.
  • Specific prodrug preparation methods can be referred to (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
  • a compound of the invention in general, can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like.
  • the compound of the present invention contained in these preparations may be a solid powder or granule; a solution or suspension in an aqueous or non-aqueous liquid; a water-in-oil or oil-in-water emulsion or the like.
  • the above dosage forms can be prepared from the active compound with one or more carriers or excipients via conventional pharmaceutical methods.
  • the above carriers need to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like.
  • Carriers for liquid preparations include water, physiological saline, aqueous glucose solution, ethylene glycol, polyethylene glycol, and the like.
  • the active compound can form a solution or suspension with the above carriers.
  • compositions of the present invention are formulated, quantified, and administered in a manner consistent with medical practice.
  • the "therapeutically effective amount" of a given compound will be determined by the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • terapéuticaally effective amount refers to a compound of the invention that will elicit a biological or medical response to an individual, such as reducing or inhibiting the activity of an enzyme or protein or ameliorating a condition, alleviating a condition, slowing or delaying the progression of a disease, or preventing a disease, and the like. the amount.
  • the therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, contained in the pharmaceutical composition of the present invention is preferably 0.1 mg to 5 g/kg (body weight).
  • pharmaceutically acceptable carrier means a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating or auxiliary formulation or any type of excipient that is compatible with the patient, most Preferably, it is a mammal, more preferably a human, which is suitable for delivering the active agent to a target of interest without terminating the activity of the agent.
  • patient refers to an animal, preferably a mammal, and more preferably a human.
  • mammal refers to warm-blooded vertebrate mammals including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.
  • treating refers to alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing, or alleviating one or more symptoms of the disease or condition to some extent.
  • the present invention provides a process for the preparation of a compound of formula (I-1).
  • the compounds of the present invention can be prepared by a variety of synthetic procedures, and exemplary methods of preparing such compounds can include, but are not limited to, the schemes described below.
  • the compound of the formula (I-1) of the present invention can be carried out by the following schemes and the exemplary methods described in the examples and related publications used by those skilled in the art.
  • the steps in the method can be extended or merged as needed during the specific operation.
  • a suitable reducing agent and an organic solvent Including catalytic hydrogenation methods (such as metal-catalyzed hydrogenation, metal complex catalytic reductive amination), borane reduction, reductive amination of small organic molecules, Lenckart reaction, and the like.
  • the reducing agents selected include, but are not limited to, NaBH 4 , NaBH 3 CN, NaB(OAc) 3 H, NaBH(OEh) 3 (Eh is 2-ethylhexanoyloxy), HCOONH 4 and Pd/C, etc. .
  • Step 1 Compound I-1-1-1 is reacted with potassium trifluorovinylborate in the presence of a suitable base, solvent and palladium catalyst to give compound I-1-1-2.
  • suitable bases include, but are not limited to, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, cesium carbonate, and the like.
  • Suitable palladium catalysts can be, but are not limited to, palladium acetate, Pd(dppf) 2 Cl 2 , Pd2(dba) 3 .
  • Step 2 Compound I-1-1-2 is reacted with compound I-1-1-3 at a temperature in the presence of a suitable solvent and palladium catalyst and ligand to give compound 1-1-1.
  • Suitable palladium catalysts can be, but are not limited to, palladium acetate, Pd(dppf) 2 Cl 2 , Pd2(dba) 3 .
  • the ligand used may be, but not limited to, XantPhos (4,5-bis(diphenylphosphino)-9,9-dimethyloxaxan), tris(o-methylphenyl)phosphorus.
  • a series of novel immunomodulators are provided which have high inhibitory activity against PD-1/PD-L1 and are useful as drugs for treating tumors.
  • DMB is 2,4-dimethoxybenzyl
  • THF is tetrahydrofuran
  • EA is ethyl acetate
  • PE is petroleum ether
  • Ac 2 O is acetic anhydride
  • NBS is N-bromosuccinimide.
  • DCM is dichloromethane
  • AIBN is azobisisobutyronitrile
  • Pd(dppf)Cl 2 is 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • TFA is trifluoroacetic acid
  • TBSCl Is tert-butyldimethylchlorosilane
  • NCS is N-chlorosuccinimide
  • DHP is dihydropyran
  • LiAlH 4 is lithium aluminum hydride
  • PMB is p-methoxybenzyl
  • LiHMDS is two (three Methylsilyl) lithium amide
  • Pd 2 (dba) 3 is tris(dibenzylideneacetone)dipalladium
  • RuPhos is 2-dicyclohexylphosphorin-2',6'-diisopropoxy-1,1 '-Biphenyl
  • DMAP is 4-dimethylaminopyridine
  • room temperature means about 20-25 °C.
  • Step 1 To a solution of 4-bromo-2-chloro-3-methylpyridine (2g, 10mmol) in dioxane (20ml) / water (6ml), phenylboronic acid (1.35g, 11mmol), Pd (dppf) 2 Cl 2 (366 mg, 0.5 mmol) and sodium carbonate (2.12 g, 20 mmol), and the mixture was stirred at 80 ° C overnight under nitrogen atmosphere, and LC-MS was followed until the end of the reaction. After the reaction mixture was cooled to room temperature, ethyl acetate was evaporated. MS m/z (ESI): 204.1 [M+H] + .
  • Step 2 To a solution of 1a-1 (1.82 g, 9 mmol) in dioxane (20 ml) / water (6 ml) And Pd(dppf) 2 Cl 2 (329 mg, 0.45 mmol), the mixture was stirred at 85 ° C for 4 h under nitrogen atmosphere, and LC-MS was followed until the end of the reaction. The reaction mixture was cooled to room temperature, EtOAc EtOAc (EtOAc m. [M+H] + .
  • Step 3 To a solution of compound 1a-2 (500 mg, 2.56 mmol) in triethylamine (5 ml) was added 4-bromo-3-chlorobenzaldehyde (674 mg, 3.07 mmol), palladium acetate (57 mg, 0.26 mmol) and (o-methylphenyl)phosphorus (156 mg, 0.51 mmol), the mixture was subjected to microwave reaction at 130 ° C for 1 h under nitrogen atmosphere, and LC-MS was followed until the end of the reaction. After the reaction was cooled to room temperature, the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjj ] + .
  • Step 1 To a solution of cinnamaldehyde (2.64 g, 20 mmol) and cyanoacetamide (1.85 g, 22 mmol) in EtOAc (40 mL) - MS tracks until the end of the reaction. The reaction mixture was diluted with water (400 ml), EtOAc (EtOAc, m. :197.0[M+H] + .
  • Step 2 A solution of compound 2a-1 (1.65 g, 8.42 mmol). The reaction solution was cooled to room temperature and concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate (100 ml) was added, and the mixture was evaporated. EtOAcjjjjjjjjjj /z (ESI): 215.0 [M + H] + .
  • Step 3 The preparation method of Compound 2a-3 is the same as the preparation method of Compound 1a-2.
  • Step 4 The preparation method of Compound 2a is the same as the preparation method of Compound 1a.
  • the intermediate compound is represented by the formula (II-a), and the substituents Ar 1 , R 1 , R 5 and R 7 are as shown in the following table:
  • the preparation method is referred to the preparation method of the intermediate 1a or 2a.
  • Step 1 Referring to Step 1 of the preparation method of Intermediate 1a, Compound 3b-2 was obtained. MS m/z (ESI): 266 [M+H] + .
  • Step 2 Compound 3b-2 (100 mg, 0.375 mmol), EtOAc (EtOAc, EtOAc (EtOAc) LC-MS was followed until the end of the reaction. After the reaction mixture was concentrated under reduced pressure and purified by column chromatography to give compound 3b (63mg, yield 47%), MS m / z (ESI): 360 [M + H] +.
  • the preparation method is referred to the compound 4b.
  • Step 1 CCl compound 6b-1 (1.33g, 5.1mmol) of 4 (20ml) was added NBS (910mg, 5.1mmol) and AIBN (84mg, 0.51mmol) under a nitrogen atmosphere, the mixture was stirred at 110 °C 24h, LC - MS tracks until the end of the reaction. After the reaction mixture was cooled, it was quenched with water, and ethyl acetate was evaporated. MS m/z (ESI): 341.4 [M+H] + .
  • Step 3 Refer to step 3 of the preparation method of Compound 1a. MS m/z (ESI): 496.1 [M+H]+.
  • Step 1 A solution of compound 6b-2 (500 mg, 1.5 mmol) in MeOH (20 mL) EtOAc (EtOAc) End. After the reaction mixture was cooled, it was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. MS m/z (ESI): 29.29 [M+H] + .
  • Step 2 A solution of compound 7b-1 (115 mg, 0.4 mmol) in THF (5 ml) was cooled to 0 ° C, and then argon was added LiAlH 4 (30 mg, 0.8 mmol), and the mixture was stirred at 0 ° C for 2 h, LC-MS tracking Until the end of the reaction. The reaction solution was filtered, extracted with ethyl acetate and concentrated under reduced pressure to afford crude product 7b-2.
  • Step 3 A solution of compound 7b-2 (106 mg, 0.4 mmol) in EtOAc (EtOAc)EtOAc. . The reaction mixture was filtered, and ethyl acetate was evaporated.
  • Step 1 Compound 5b (200mg, 0.81mmol) (15ml ) in DCM was cooled to 0 °C, AlCl 3 were added under nitrogen (540mg, 4.05mmol), the mixture was stirred at rt for 4h. The reaction mixture was poured into ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate
  • step 2 of compound 6b-3 the preparation method is referred to step 2 of compound 6b-3.
  • step 2 of compound 6b-3 the preparation method is referred to step 2 of compound 6b-3.
  • step 2 of compound 6b-3 the preparation method is referred to step 2 of compound 6b-3.
  • Step 1 Dissolve cinnamaldehyde (2.64 g, 20.0 mol) and 2-cyanoacetamide (1.85 g, 22.0 mmol) in 40 mL of dimethyl sulfoxide and add potassium tert-butoxide (8.96 g, 80.0 mmol) in one portion.
  • the reaction was stirred at room temperature for 16 hours. 400 mL of water and 4 M hydrochloric acid (30 mL) were added to the reaction mixture. The precipitated solid was filtered, and the filter cake was washed with water (10mL ⁇ 3) and dried in vacuo to give 2-oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile (1.65 g, light brown solid). 42.1%.
  • Step 2 2-Oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile (1.65 g, 8.42 mmol) was dissolved in 20 mL of EtOAc. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The obtained residue was purified by ethyl acetate (EtOAc) elute MS m/z (ESI): 215.0 [M+H] + .
  • Step 3 2-Chloro-4-phenylnicotinonitrile (700 mg, 3.27 mmol) was dissolved in 25 mL of 1,4-dioxane and 4 mL water, and potassium fluoroborate (1.31 g, 9.81 mmol) was added, [1 , 1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (131 mg, 0.16 mmol), sodium carbonate (1.04 g, 9.81 mmol), stirred at 85 ° C under argon atmosphere. The reaction was continued for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated, evaporated, evaporated, evaporated. -2-vinyl nicotinonitrile (650 mg, off-white solid), yield: 96.5%. MS m/z (ESI): 207.0 [M+H] + .
  • Step 4 Add to the 20 mL microwave tube: 4-phenyl-2-vinyl nicotinonitrile (150 mg, 0.73 mmol), 4-bromo-3-chlorobenzaldehyde (241 mg, 1.10 mmol), palladium acetate (16 mg, 0.07) Methyl), tris(o-methylphenyl)phosphorus (44 mg, 0.15 mmol), 2 mL of triethylamine and 6 mL of dimethylacetamide. The mixture was blown with argon for 2 minutes, covered with a microwave cover, and microwave-reacted at 150 ° C for 30 minutes. 30 mL of ethyl acetate was added, and the filtrate was concentrated under reduced pressure.
  • Step 5 (E)-2-(2-Chloro-4-formylstyryl)-4-phenylnicotinonitrile (50 mg, 0.14 mmol) and (S)-piperidine-2-carboxylic acid (36 mg 0.28 mol) was dissolved in 8 mL of methanol, sodium cyanoborohydride (18 mg, 0.28 mmol) was added, and the reaction was stirred under reflux for 4 hours.
  • Base piperidine-2-carboxylic acid (Compound P-11) (26 mg, white solid), yield: 39.1%.
  • Step 1 4-Bromo-2-chloro-3-methylpyridine (300 mg, 1.46 mmol) was dissolved in 15 mL of 1,4-dioxane and 3 mL of water, and benzo-1,4-dioxane was added. 6-boric acid (290 mg, 1.61 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (131 mg, 0.16 mmol), sodium carbonate (387 mg, 3.65) Methyl), the reaction was stirred at 85 ° C for 4 hours under argon gas protection. The reaction mixture was filtered, and the filtrate was evaporated.
  • Step 2 Dissolve 2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxol-6-yl)-3-methylpyridine (200 mg, 0.77 mmol) in 15 mL of 1,4-dioxane and 3 mL of water, potassium vinyl fluoroborate (310 mg, 2.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane The compound (32 mg, 0.04 mmol), sodium carbonate (245 mg, 2.31 mmol) was stirred under argon atmosphere for 15 hours. The reaction mixture was filtered, and the filtrate was evaporated.
  • Step 3 Add to the 20 mL microwave tube: 4-(2,3-dihydrobenzo[b][1,4]dioxol-6-yl)-3-methyl-2-vinylpyridine ( 115 mg, 0.45 mmol), 4-bromo-3-chlorobenzaldehyde (148 mg, 0.68 mmol), palladium acetate (10 mg, 0.05 mmol), tris(o-methylphenyl)phosphine (27 mg, 0.09 mmol), 1 mL triethylamine And 5 mL of dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwave-reacted at 140 ° C for 30 minutes.
  • Step 4 (E)-3-Chloro-4-(2-(4-(2,3-dihydrobenzo[b][1,4]dioxol-6-yl)-3-methyl Pyridin-2-yl)vinyl)benzaldehyde (50 mg, 0.13 mmol) and (S)-piperidine-2-carboxylic acid (34 mg, 0.26 mol) were dissolved in 8 mL of methanol and sodium cyanoborohydride (16 mg, 0.26 mmol), and the reaction was stirred under reflux for 4 hours.
  • Step 1 To a 20 mL microwave tube was added: 3-methyl-4-phenyl-2-vinylpyridine (100 mg, 0.51 mmol), 4-bromo-3-trifluoromethylbenzaldehyde (192 mg, 0.76 mmol) Palladium acetate (11 mg, 0.05 mmol), tris(o-methylphenyl)phosphorus (30 mg, 0.10 mmol), 1 mL of triethylamine and 5 mL of dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwave-reacted at 150 ° C for 30 minutes. 25 mL of ethyl acetate was added, and the filtrate was concentrated under reduced pressure.
  • Step 2 (E)-4-2-(3-Methyl-4-phenylpyridin-2-yl)vinyl)-3-(trifluoromethyl)benzaldehyde (37 mg, 0.10 mmol) and (S)
  • the piperidine-2-carboxylic acid 26 mg, 0.20 mol
  • sodium cyanoborohydride 13 mg, 0.20 mmol
  • the title product (S, E)-1-(4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)-3-(3) was obtained.
  • Step 1 To a 20 mL microwave tube was added: 3-methyl-4-phenyl-2-vinylpyridine (100 mg, 0.51 mmol), 4-bromo-5-chloro-2-methoxybenzaldehyde (165 mg, 0.66 mmol), palladium acetate (11 mg, 0.05 mmol), tris(o-methylphenyl)phosphorus (30 mg, 0.10 mmol), 1 mL triethylamine and 5 mL dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwave-reacted at 150 ° C for 45 minutes. 25 mL of ethyl acetate was added, and the filtrate was concentrated under reduced pressure.
  • Step 2 (E)-5-Chloro-2-methoxy-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzaldehyde (50 mg, 0.14 mmol)
  • (S)-Piperidine-2-carboxylic acid 36 mg, 0.28 mol was dissolved in 6 mL of methanol, sodium cyanoborohydride (18 mg, 0.28 mmol) was added, and the reaction was stirred under reflux for 4 hours.
  • Step 2 Compound 18-2 (1.4 g, 3.34 mmol) was dissolved in tetrahydrofuran (20 ml), cooled to -78 ° C with dry ice-acetone bath, and 20 ml of compound 18.1 (553 mg, 2.82 mmol) in tetrahydrofuran was slowly added dropwise. After the reaction system was naturally warmed to room temperature, it was stirred at room temperature overnight, and LC-MS was followed until the end of the reaction. The reaction was quenched with aq. EtOAc EtOAc (EtOAc) M+H] + .
  • Step 3 Compound 18-3 (350 mg, 0.92 mmol), cuprous cyanide (245 mg, 2.75 mmol), tetratriphenylphosphine palladium (35 mg), cesium carbonate (891 mg, 2.75 mmol) of dioxane (80 ml) The solution was reacted at 100 ° C overnight, and LC-MS was followed until the end of the reaction. The reaction solution was concentrated under reduced pressure, purified by column chromatography to give compound 18-4 (110mg), MS m / z (ESI): 330.0 [M + H] +.
  • Step 4 Compound 18-4 (105 mg, 0.32 mmol) was dissolved in toluene (20 ml). The system was placed in a dry ice-acetone bath and cooled to -78 ° C. DIBAL was slowly added dropwise, and the reaction was allowed to rise to room temperature. The reaction was allowed to proceed overnight at room temperature and LC-MS was followed until the end of the reaction. The reaction mixture was adjusted to pH with EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHH +H] + .
  • EtOAc EtOAc
  • EtOAc EtOAc
  • Step 1 2-Chloro-4-phenylnicotinonitrile (3.3 g, 15.4 mmol) was dissolved in 100 mL of tetrahydrofuran, and added potassium trifluoroborate (2.27 g, 17 mmol), sodium carbonate (4.9 g, 46.2 mmol) [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (902 mg, 1.23 mmol) and water 30 mL were reacted under nitrogen at 80 ° C for 20 hours. 100 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (50 mL ⁇ 3).
  • Step 2 Dissolve 4-phenyl-2-vinylnicotinonitrile (85 mg, 0.41 mmol) and 4-bromo-3-(trifluoromethyl)benzaldehyde (115 mg, 0.45 mmol) in N,N-dimethyl
  • palladium acetate 9 mg, 0.041 mmol
  • tris(o-methylphenyl)phosphine 25 mg, 0.082 mmol
  • Step 3 (E)-2-(4-Formyl-2-(trifluoromethyl)styryl)-4-phenylnicotinonitrile (20 mg, 0.053 mmol) and (S)-piperidine-2
  • the carboxylic acid 14 mg, 0.11 mmol
  • sodium cyanoborohydride 7 mg, 0.11 mmol
  • the title product (S, E)-1-1-(4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)-3-( Trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound P-19) (11 mg, white solid).
  • Step 1 2-Bromo-4-methoxy-1-(trifluoromethyl)benzene (900 mg, 3.54 mmol) and dichloromethyl methyl ether (1.21 g, 10.63 mmol) were dissolved in dichloromethane (20 mL) Titanium tetrachloride (2 g, 10.63 mmol) was added at 0 ° C and stirred at room temperature for 2 hours.
  • Step 2 Dissolve 4-bromo-2-methoxy-5-(trifluoromethyl)benzaldehyde (141 mg, 0.5 mmol) and 4-phenyl-2-vinylnicotinonitrile (103 mg, 0.5 mmol) To 3 mL of N,N-dimethylacetamide and 1 mL of triethylamine, palladium acetate (11 mg, 0.05 mmol) and tris(o-methylphenyl)phosphine (30 mg, 0.1 mmol) were added, and the reaction was carried out under nitrogen atmosphere at 160 ° C. The microwave was reacted for 30 minutes.
  • Step 1 Dissolve 4-bromo-5-chloro-2-methoxybenzaldehyde (190 mg, 0.76 mmol) and 4-phenyl-2-vinylnicotinonitrile (150 mg, 0.73 mmol) in 4.5 mL N, N -Dimethylacetamide and 1.5 mL of triethylamine, palladium acetate (16 mg, 0.073 mmol) and tris(o-methylphenyl)phosphine (44 mg, 0.15 mmol) were added, and the reaction was carried out under microwave protection at 160 ° C for microwave reaction 30 minute.
  • Step 2 (E)-2-(2-Chloro-4-formyl-5-methoxystyryl)-4-phenylnicotinonitrile (70 mg, 0.19 mmol) and (R)-2-amino 3-Hydroxypropionic acid (40 mg, 0.38 mmol) was dissolved in 10 mL of methanol, sodium cyanoborohydride (19 mg, 0.3 mmol) was added, and the reaction was stirred for 20 hours.
  • the title product (R, E)-2-(5-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)-2 was obtained by preparative chromatography.
  • -Methoxybenzylamino)-3-hydroxypropionic acid (Compound P-21) (3 mg, white solid). MS m/z (ESI): 464.1 [M+H] + .
  • Compound P-24 was prepared in the same manner as in Step 3 of Example 20 using Compound 13a as a material.
  • Step 1 4 -Bromo-5-chloro-2-methoxybenzaldehyde (500 mg, 2 mmol) was dissolved in 35 mL of dichloromethane, and then added aluminum trichloride (1.32 g, 10 mmol) at 0 ° C, stirring at room temperature 20 hours. The reaction mixture was poured into EtOAc (3 mL). The obtained residue was purified to silicagel elut elut elut elut elut elut elut Yield: 62%.
  • Step 2 Dissolve 4-bromo-5-chloro-2-hydroxybenzaldehyde (515 mg, 2.2 mmol) and bromoacetonitrile (314 mg, 2.64 mmol) in 8 mL of N,N-dimethylformamide and add potassium carbonate ( 455 mg, 3.3 mmol), stirred at room temperature for 3 hours. Water (100 mL) was added to the mixture, and the mixture was evaporated. The residue obtained was purified by silica gel column chromatography (lululululu (532 mg, yellow solid), Yield: 88.7%. MS m/z (ESI): 273.9 [M+H] + .
  • Step 3 2-(5-Bromo-4-chloro-2-formylphenoxy)acetonitrile (125 mg, 0.46 mmol) and 4-phenyl-2-vinylnicotinonitrile (90 mg, 0.44 mmol) dissolved in 1.5 To a solution of 0.5 N, N-dimethylacetamide and 0.5 mL of triethylamine, palladium acetate (10 mg, 0.044 mmol) and tris(o-methylphenyl)phosphine (27 mg, 0.088 mmol) were added. The microwave reaction was carried out for 30 minutes at °C.
  • Step 4 (E)-2-(2-Chloro-5-(cyanomethoxy)-4-formylstyryl)-4-phenylnicotinonitrile (60 mg, 0.15 mmol) and (S)- Piperidine-2-carboxylic acid (39 mg, 0.3 mmol) was dissolved in 10 mL of methanol, sodium cyanoborohydride (19 mg, 0.3 mmol) was added, and the reaction was stirred for 20 hours.
  • the title product (S, E)-1-(5-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)-2 was obtained by preparative chromatography.
  • -(Cyanomethoxy)benzyl)piperidine-2-carboxylic acid Compound P-27 (20 mg, white solid). MS m/z (ESI): 513.2 [M+H] + .
  • Step 1 4-Bromo-5-chloro-2-methoxybenzaldehyde (300 mg, 1.21 mmol) was dissolved in 10 mL of dichloromethane. After the addition was completed, the temperature was raised to room temperature, and the reaction was further stirred for 15 hours. After adding sodium sulfate decahydrate (500 mg), the mixture was stirred and the mixture was stirred at room temperature for 0.5 hr. : 82%. MS m/z (ESI): 233.1 [M+H] + .
  • Step 3 Dissolve 4-bromo-5-chloro-2-(cyclopropylmethoxy)benzaldehyde (45 mg, 0.16 mmol), 4-phenyl-2-vinylnicotinonitrile (32 mg, 0.16 mmol) in 2 mL [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (5 mg, 0.016 mmol) and 1 mL of triethylamine were added to N,N-dimethylformamide. The mixture was replaced with nitrogen three times, heated to 140 ° C, stirred in a microwave reactor for 50 minutes, and then cooled to room temperature.
  • Step 4 Dissolve (E)-2-(2-chloro-5-(cyclopropylmethoxy)-4-formylstyryl)-4-phenylnicotinonitrile (10 mg, 0.024 mmol) in 5 mL of methanol L-piperidine-2-carboxylic acid (6 mg, 0.048 mmol), sodium cyanoborohydride (3 mg, 0.048 mmol), three times with nitrogen, heated to 80 ° C, stirred for 6 hours, cooled to room temperature, reaction The liquid was concentrated under reduced pressure and the residue was purified by preparative chromatography to give the title compound (S, E)-1-(5-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl) Vinyl)-2-(cyclopropylmethoxy)benzyl)piperidine-2-carboxylic acid (Compound P-28) (1.2 mg, off-white solid), yield: 10%.
  • Step 1 Dissolve 4-bromo-5-chloro-2-hydroxybenzaldehyde (250 mg, 1.06 mmol), 3-(bromomethyl)benzonitrile (208 mg, 1.06 mmol), potassium carbonate (293 mg, 2.12 mmol) In 20 mL of acetonitrile, reflux and overnight. The reaction solution was filtered, dried, and purified by silica gel column (0-100% EA/PE) to give product 3 ((5-bromo-4-chloro-2-formylphenoxy)methyl)benzonitrile ( 200 mg, white solid), yield: 57%. MS m/z (ESI): 349.9 [M+H] + .
  • Step 2 3((5-Bromo-4-chloro-2-formylphenoxy)methyl)benzonitrile (100 mg, 0.29 mmol), 4-phenyl-2-vinylnicotinamide (59 mg, 0.29 mmol), triethylamine (0.5 mL), Pd(dppf)Cl 2 (22 mg, 0.03 mmol) was dissolved in 4 mL of N,N dimethylacetamide. The microwave was stirred at 140 ° C under argon for 1 hour. The reaction mixture was dried with EtOAc (EtOAc) (EtOAc)EtOAc.
  • Step 3 (E)-2(2-Chloro-5-(3-cyanobenzyloxy)-4-formylstyryl)-4-phenylnicotinamide (50 mg, 0.1 mmol), ( S)-Piperidine-2-carboxylic acid (40 mg, 0.31 mmol) was dissolved in 10 mL of methanol, and stirred at 60 ° C for 1 hour, and sodium cyanoborohydride (20 mg, 0.31 mmol) was added.
  • Step 1 Dissolve 5-bromo-2-(trifluoromethyl)aniline (1 g, 4.18 mmol) in 20 mL of 1,4-dioxane, followed by the addition of phenylethylboronic acid (628 mg, 4.18 mmol). Potassium (1.15 g, 8.36 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (170 mg, 0.21 mmol) and 2 mL of water, three times with nitrogen, The mixture was heated to 100 ° C, stirred for 20 hours, and then cooled to room temperature. The reaction mixture was filtered over EtOAc EtOAc. After purification, the compound 5-phenylethyl-2-(trifluoromethyl)aniline (700 mg, m. MS m/z (ESI): 266.1 [M+H] + .
  • Step 3 Dissolve 4-bromo-5-phenethyl-2-(trifluoromethyl)aniline (480 mg, 1.40 mmol) in 4 mL of N-methylpyrrolidone and add cuprous cyanide (622 mg, 6.99 mmol) The mixture was replaced with nitrogen three times, heated to 220 ° C, stirred in a microwave reactor for 40 minutes and then cooled to room temperature. The reaction mixture was poured into ethyl acetate (40 mL), EtOAc (EtOAc) 5-5-(Trifluoromethyl)phenylcarbonitrile (400 mg, yellow oil), yield: 97%. MS m/z (ESI): 29.21. [M+H] + .
  • Step 4 Dissolve 4-amino-2-phenethyl-5-(trifluoromethyl)phenylcarbonitrile (400 mg, 1.38 mmol) in 20 mL of acetonitrile and add copper bromide (457 mg, 2.07 mmol), ice The mixture was cooled to 0 ° C in a water bath, and isoamyl nitrite (242 mg, 2.07 mmol) was slowly added dropwise, and the mixture was warmed to room temperature, and the reaction was further stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc m. Phenylethyl-5-(trifluoromethyl)benzonitrile (300 mg, yellow oil), yield: 62%. MS m/z (ESI): 354.1 [M+H] + , 356.1 [M+3].
  • Step 5 Dissolve 4-bromo-2-styryl-5-(trifluoromethyl)phenyl nitrile (150 mg, 0.43 mmol) in 10 mL of dichloromethane, cool to 0 ° C in ice water, slowly add two Isobutylaluminum hydride (1.0 M, 0.64 mL, 0.64 mmol) was added, and stirring was continued at this temperature for 2 hours. Methanol (5 mL) and 36% hydrochloric acid (5 mL) were added in that order. The reaction mixture was warmed to room temperature, and the mixture was stirred for 0.5 hr. EtOAc (EtOAc) 2-Styryl-5-(trifluoromethyl)benzaldehyde (130 mg, yellow oil), yield: 86%. MS m/z (ESI): 357.1 [M+H] + .
  • Step 6 Dissolve 4-bromo-2-styryl-5-(trifluoromethyl)benzaldehyde (110 mg, 0.31 mmol) in 2 mL of N,N-dimethylacetamide, and then add 4-phenyl -2-vinyl nicotinonitrile 1 g (64 mg, 0.31 mmol), palladium acetate (7 mg, 0.031 mmol), tris(o-methylphenyl)phosphine (18 mg, 0.062 mmol) and 1 mL of triethylamine. The reaction was stirred at 150 ° C for 45 minutes in a microwave reactor, and then cooled to room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure.
  • Step 7 Dissolve 2-(4-formyl-5-phenethyl-2-(trifluoromethyl)styryl)-4-phenylnicotinonitrile (100 mg, 0.21 mmol) in 15 mL of methanol.
  • Step 1 4-Bromo-5-chloro-2-hydroxybenzaldehyde (2 g, 8.48 mmol), tert-butyldimethylhydroxyethoxysilane (1.5 g, 8.48 mmol), triphenylphosphine (4 g, 15.28 mmol) was dissolved in 20 mL of dry tetrahydrofuran and stirred at room temperature for 20 min under argon. Diisopropyl azodicarboxylate (3 g, 12.76 mmol) was added and stirred at room temperature overnight. The reaction mixture was dried with EtOAc (EtOAc) (EtOAc)EtOAc. 50% EA/PE) gave the product 4-bromo-2-(2-(tert-butyldimethylsilyloxy)ethoxy)-5-chlorobenzaldehyde (650 mg, white solid). %.
  • Step 2 4-Bromo-2-(2-(tert-butyldimethylsilyloxy)ethoxy)-5-chlorobenzaldehyde (500 mg, 1.27 mmol), 3-methyl-4-phenyl 2-vinylpyridine (248 mg, 1.27 mmol), triethylamine (0.5 mL), tris(o-methylphenyl)phosphine (78 mg, 0.25 mmol), palladium acetate (29 mg, 0.13 mmol) dissolved in 4 mL N, N In dimethylacetamide.
  • the microwave was stirred at 150 ° C under argon for 1 hour.
  • the reaction mixture was dried with EtOAc (EtOAc) (EtOAc)EtOAc.
  • Step 3 (E)-2-(2-(tert-Butyldimethylsilyloxy)ethoxy)-5-chloro-4-(2-(3-methyl-4-phenylpyridine)- 2-Based)Vinyl)benzaldehyde (200 mg, 0.51 mmol) was dissolved in 10 mL of tetrahydrofuran and 10 mL of 1M HCl solution and stirred at room temperature for 1 hour.
  • Step 4 (E)-5-Chloro-2-(2-hydroxyethoxy)-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzaldehyde ( 60 mg, 0.12 mmol), (S)-piperidine-2-carboxylic acid (48 mg, 0.36 mmol) was dissolved in 10 mL of methanol, and stirred at 60 ° C for 1 hour, and sodium cyanoborohydride (22 mg, 0.36 mmol) was added. After stirring at 60 ° C for 2 hours, it was dried to give a white solid (Compound P-33) (3 mg, 0.0006 mmol). MS m/z (ESI): 507.2 [M+H] + .
  • Step 1 Dissolve 5-bromo-2-(trifluoromethyl)aniline (10 g, 41.84 mmol) in 200 mL of 1,4-dioxane, and then add potassium trifluoroborate (6.17 g, 46.03 mmol). , potassium carbonate (11.55 g, 83.68 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (683 mg, 0.84 mmol) and 5 mL of water, nitrogen replacement After three times, the mixture was heated to 100 ° C, the reaction was stirred for 20 hours, and then cooled to room temperature.
  • Step 2 2-(Trifluoromethyl)-5-vinylaniline (1 g, 5.35 mmol) was dissolved in 2 mL of N,N-dimethylacetamide, followed by bromobenzene (1.25 g, 8.03 mmol). Palladium acetate (60 mg, 0.27 mmol), tris(o-methylphenyl)phosphine (164 mg, 0.54 mmol) and 1 mL of triethylamine, three times with nitrogen, heated to 150 ° C, stirred in a microwave reactor for 50 minutes and then cooled The reaction solution was filtered through celite, and the filtrate was evaporated to dryness.
  • Step 4 Dissolve (E)-4-bromo-5-styryl-2-(trifluoromethyl)aniline (300 mg, 0.88 mmol) in 2 mL of N-methylpyrrolidone and add cuprous cyanide (157 mg) , 1.76 mmol), three times with nitrogen, heated to 220 ° C, stirred in a microwave reactor for 40 minutes and then cooled to room temperature.
  • Step 5 Dissolve (E)-4-amino-2-styryl-5-(trifluoromethyl)phenylcarbonitrile (160 mg, 0.56 mmol) in 15 mL of acetonitrile and add copper bromide (183 mg, 0.83) (mmol), the ice water bath was cooled to 0 ° C, and isoamyl nitrite (0.11 mL, 0.83 mmol) was slowly added dropwise, and the mixture was warmed to room temperature and stirring was continued for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc m. Bromo-2-styryl-5-(trifluoromethyl)phenylcarbonitrile (200 mg, yellow solid), yield: 99%. MS m/z (ESI): 3521. [M+H] + , 354.1 [M+3].
  • Step 6 Dissolve (E)-4-bromo-2-styryl-5-(trifluoromethyl)phenylcarbonitrile (170 mg, 0.48 mmol) in 20 mL of dichloromethane and dry ice-br. °C, diisobutylaluminum hydride (1.1 M, 0.48 mL, 0.53 mmol) was slowly added dropwise, and the reaction was continued at this temperature for 0.5 hour. Methanol (5 mL) and 36% hydrochloric acid (5 mL) were added in that order. The reaction mixture was warmed to room temperature, and the reaction was further stirred for 0.5 hr, and concentrated under reduced pressure.
  • Step 7 Dissolve (E)-4-bromo-2-styryl-5-(trifluoromethyl)benzaldehyde (85 mg, 0.24 mmol) in 2 mL of N,N-dimethylacetamide and add sequentially 4-Phenyl-2-vinylnicotinonitrile (49 mg, 0.24 mmol), palladium acetate (3 mg, 0.012 mmol), tris(o-methylphenyl)phosphonate (7 mg, 0.024 mmol) and 1 mL of triethylamine After three times, the mixture was heated to 150 ° C, stirred in a microwave reactor for 50 minutes, and then cooled to room temperature.
  • Step 8 Dissolve 2-(4-formyl-5-styryl-2-(trifluoromethyl)styryl)-4-phenylnicotinonitrile (40 mg, 0.08 mmol) in 10 mL of methanol.
  • Step 1 Dissolve 4-bromo-2-chloro-3-methylpyridine (820 mg, 4 mmol) in 25 mL of 1,4-dioxane, add 2-chlorophenylboronic acid (637 mg, 4.08 mmol), sodium carbonate (848 mg, 8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (205 mg, 0.28 mmol) and 4 mL of water were reacted under nitrogen at 110 ° C for 5 hours. 30 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (30 mL ⁇ 3).
  • Step 2 Dissolve 2-chloro-4-(2-chlorophenyl)-3-methylpyridine (120 mg, 0.51 mmol) in 20 mL of 1,4-dioxane and add potassium trifluoroborate ( 74 mg, 0.56 mmol), sodium carbonate (162 mg, 1.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (29 mg, 0.04 mmol) and 4 mL of water at 80 ° C The reaction was carried out under nitrogen for 20 hours. 30 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (30 mL ⁇ 2). The obtained residue was purified (EtOAc: EtOAc:EtOAc:EtOAc) Rate: 87%. MS m/z (ESI): 230.1 [M+H] + .
  • Step 3 Dissolve 4-bromo-3-chlorobenzaldehyde (105 mg, 0.48 mmol) and 4-(2-chlorophenyl)-3-methyl-2-vinylpyridine (100 mg, 0.44 mmol) in 3 mL of N , N-dimethylacetamide and 1 mL of triethylamine, palladium acetate (10 mg, 0.044 mmol) and tris(o-methylphenyl)phosphine (27 mg, 0.088 mmol) were added, and the reaction was carried out under microwave protection at 160 ° C for microwave reaction. 30 minutes.
  • Compound P-40 was prepared from compound 28a using a similar procedure as in step 4 of Example 38.
  • Compound P-41 was prepared from compound 29a using a similar procedure as in step 4 of Example 38.
  • Compound P-43 was prepared from compound 31a using a similar method to that of step 4 in Example 38.
  • Compound P-45 was prepared from compound 32a using a similar procedure as in step 4 of Example 38.
  • Step 1 4-Methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (3.0 g, 20.0 mol) was dissolved in 80 mL of acetonitrile, and phosphorus tribromide (11.40 g, 40.0 mmol) was added. The reaction was stirred at 70 ° C for 16 hours under argon gas protection. 50 mL of water and 50 mL of saturated brine were added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL ⁇ 2). It was pulverized with isopropyl ether, filtered and dried in vacuo to give 2,4-dibromopyridine-3-carbonitrile (4.0 g, pale brown solid).
  • 1H NMR 400MHz, DMSO-d6) ⁇ 8.51 (d, 1H), 8.05 (d, 1H).
  • Step 2 Dissolve 2,4-dibromopyridine-3-carbonitrile (1.05 g, 4.0 mmol) in 30 mL of tetrahydrofuran and 7.5 mL of water and add potassium fluoroborate (590 mg, 4.40 mmol), [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (164 mg, 0.20 mmol), sodium carbonate (1.27 g, 12.0 mmol), stirred under argon at 60 ° C for 16 hours. .
  • potassium fluoroborate 590 mg, 4.40 mmol
  • [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex 164 mg, 0.20 mmol
  • sodium carbonate (1.27 g, 12.0 mmol
  • Step 3 Dissolve 2-bromo-4-vinylnicotinonitrile (460 mg, 2.20 mmol) in 20 mL of tetrahydrofuran and 5 mL of water, add phenylboronic acid (402 mg, 3.30 mmol), [1,1'-bis(diphenylphosphine) The ferrocene]palladium dichloride dichloromethane complex (90 mg, 0.11 mmol), sodium carbonate (700 mg, 6.60 mmol) was stirred under reflux with argon for 16 hours.
  • Step 4 To a 20 mL microwave tube was added: 2-phenyl-4-vinylnicotinonitrile (100 mg, 0.48 mmol), 4-bromo-3-chloro-benzaldehyde (158 mg, 0.72 mmol), palladium acetate (11 mg, 0.05 mmol), tris(o-methylphenyl)phosphorus (29 mg, 0.10 mmol), 1 mL of triethylamine and 5 mL of dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwave-reacted at 150 ° C for 30 minutes. 25 mL of ethyl acetate was added, and the filtrate was concentrated under reduced pressure.
  • Step 5 (E)-4-(2-Chloro-4-formylstyryl)-2-phenylnicotinonitrile (35 mg, 0.10 mmol) and (S)-piperidine-2-carboxylic acid (26 mg, 0.20 mol) was dissolved in 6 mL of methanol, sodium cyanoborohydride (13 mg, 0.20 mmol) was added, and the reaction was stirred under reflux for 4 hours.
  • the title product (S, E)-1-(3-chloro-4-(2-(3-cyano-2-phenylpyridin-4-yl)vinyl)benzylidene was obtained by preparative HPLC chromatography.
  • Step 1 6-Bromobenzo[d]oxazole (500 mg, 2.53 mmol) was dissolved in 20 mL of 1,4-dioxane, followed by the addition of pinacol borate (962 mg, 3.79 mmol), potassium acetate. (743 mg, 7.58 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (207 mg, 0.25 mmol), three times with nitrogen, heated to 100 ° C, After the reaction was stirred for 20 hours, the mixture was cooled to room temperature. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc.
  • EtOAc EtOAc
  • Step 2 Dissolve 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (520 mg, 2.12 mmol) in 20 mL 1
  • 2,4-dibromonicotinonitrile 552 mg, 2.12 mmol
  • potassium carbonate 585 mg, 4.24 mmol
  • [1,1'-bis(diphenylphosphine) dioxin were sequentially added.
  • Step 4 Dissolve 4-(benzo[d]oxazol-6-yl)-2-vinylnicotinonitrile (114 mg, 0.46 mmol) in 3 mL of N,N-dimethylacetamide and add 4- Bromo-5-chloro-2-methoxybenzaldehyde (172 mg, 0.69 mmol), palladium acetate (10 mg, 0.046 mmol), tris(o-methylphenyl)phosphonate (28 mg, 0.092 mmol) and 1 mL triethylamine. The mixture was replaced with nitrogen three times, heated to 150 ° C, stirred in a microwave reactor for 60 minutes, and then cooled to room temperature.
  • Step 5 (E)-4-(Benzo[d]oxazol-6-yl)-2-(2-chloro-4-formyl-5-methoxystyryl)nicotinonitrile (140 mg, 0.34 mmol) was dissolved in 20 mL of methanol, and then added L-piperidine-2-carboxylic acid (129 mg, 1.01 mmol), sodium cyanoborohydride (64 mg, 1.01 mmol), three times with nitrogen, heated to 85 ° C, stirring reaction 16 After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative chromatography to give the title compound (S, E)-1-(4-(4-(4-(benzo[d]oxazole-6) -yl)cyanopyridin-2-yl)vinyl)-5-chloro-2-methoxybenzyl)piperidine-2-carboxylic acid (Compound P-50) (11 mg, yellow solid) Yield: 6%.
  • Step 1 2,4-dibromonicotinonitrile (1.31 g, 5.0 mmol) was dissolved in 20 mL of 1,4-dioxane and 6 mL of water, and 2,6-difluorophenylboronic acid pinacol ester (1.2 g) was added. , 5.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (370 mg, 0.50 mmol), sodium carbonate (530 mg, 5.0 mmol) in argon The reaction was stirred at 100 ° C under a gas atmosphere overnight. The reaction solution was filtered, and the filtrate was evaporated, evaporated, mjjjjjjjj , light brown solid), yield: 30.3%. MS m/z (ESI): 295.1 [M+H] + .
  • Step 2 Dissolve 2-bromo-4-(2,6-difluorophenyl)nicotinonitrile (410 mg, 1.30 mmol) in 15 mL of 1,4-dioxane and 5 mL of water, and add potassium fluoroborate (200 mg). , 1.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (100 mg, 0.13 mmol), sodium carbonate (140 mg, 1.30 mmol) in argon The reaction was stirred at 100 ° C for 16 hours under gas protection. The reaction solution was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjjj 103 mg, colorless liquid), yield: 31.1%. MS m / z (ESI): 243.2 [M + H] +.
  • Step 3 Add to the 20 mL microwave tube: 4-(2,6-difluorophenyl)-2-vinylnicotinonitrile (50 mg, 0.20 mmol), 4-bromo-5-chloro-2-methoxybenzene Formaldehyde (50 mg, 0.20 mmol), palladium acetate (4.5 mg, 0.1 mmol), tris(o-methylphenyl)phosphine (6.0 mg, 0.1 mmol), 0.2 mL of triethylamine and 3 mL of dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwave-reacted at 160 ° C for 45 minutes.
  • 4-(2,6-difluorophenyl)-2-vinylnicotinonitrile 50 mg, 0.20 mmol
  • 4-bromo-5-chloro-2-methoxybenzene Formaldehyde 50 mg, 0.20 mmol
  • Step 4 (E)-2-((2-Chloro-4-formyl-5-methoxyphenyl)alkenyl)-4-(2,6-difluorophenyl)nicotinonitrile (41 mg, 0.1 Methyl) and (S)-piperidine-2-carboxylic acid (26 mg, 0.2 mol) were dissolved in 10 mL of methanol, sodium cyanoborohydride (10 mg, 0.15 mmol) was added, and the mixture was stirred under reflux for 2 hours. The title product (2S)-1-[[5-chloro-4-[(E)-2-[3-cyano-4-(2,6-difluorophenyl) was obtained.
  • Step 1 Methyl 3-hydroxycyclobutylcarboxylate (650 mg, 5.0 mol) and triethylamine (1 g, 10.0 mol) were dissolved in 15 mL of dichloromethane, and trifluoromethyl was slowly added at 0 ° C under argon atmosphere. The sulfonic anhydride (1.86 g, 6.5 mmol) was stirred at 0 ° C for 0.5 h. 50 mL of water was added to the reaction mixture, and the mixture was extracted with methylene chloride (100 mL ⁇ 2).
  • Step 2 Methyl 3-(trifluorosulfonyloxy)cyclobutylcarboxylate (650 mg, 2.4 mmol), 4-bromo-5-chloro-2-hydroxybenzaldehyde (470 mg, 2.0 mmol), 1.0 g, 6 mmol) and potassium iodide (700 mg, 4 mmol) were dissolved in 15 mL of dimethylformamide, and stirred at 130 ° C for 1 hour. 50 ml of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL ⁇ 2).
  • Step 3 Add to the 20 mL microwave tube: 4-phenyl-2-vinyl nicotinonitrile (41 mg, 0.20 mmol), 3-(5-bromo-4-chloro-2-formylphenoxy)cyclobutane Methyl formate (76 mg, 0.20 mmol), palladium acetate (4.5 mg, 0.1 mmol), tris(o-methylphenyl)phosphine (6.0 mg, 0.1 mmol), 0.2 mL of triethylamine and 3 mL of dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwaved at 160 ° C for 45 minutes.
  • Step 4 (E)-3-(4-Chloro-5-(2-(3-carbonitrile-4-phenylpyridin-2-yl)vinyl)-2-formylphenoxy)cyclobutanecarboxylic acid
  • the methyl ester (47 mg, 0.1 mmol) and (S)-piperidine-2-carboxylic acid (26 mg, 0.2 mol) were dissolved in 10 mL of methanol, sodium cyanoborohydride (10 mg, 0.15 mmol) was added, and the mixture was stirred and refluxed for 2 hours. .
  • Step 5 (S,E)-1-(5-chloro-4-(2-(3-carbonitrile-4-phenylpyridin-2-yl)vinyl)-2-(3-(methoxycarbonyl) Cyclobutoxy)phenyl)pyridine-2-carboxylic acid (70 mg, 0.12 mmol) and sodium hydroxide (10 mg, 0.24 mol) were dissolved in 5 mL of methanol and 3 mL of water, and the mixture was stirred at 40 ° C for 10 minutes.
  • Step 1 1-(Bromoethyl)benzene (280 mg, 1.5 mmol), 4-bromo-5-chloro-2-hydroxybenzaldehyde (117 mg, 0.5 mmol), potassium carbonate (200 mg, 1.5 mmol) and potassium iodide ( 160 mg, 1.0 mmol) was dissolved in 15 mL of dimethylformamide, and the reaction was stirred at 130 ° C for 1 hour. 50 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL ⁇ 2).
  • Step 2 Add to a 20 mL microwave tube: 4-phenyl-2-vinyl nicotinonitrile (70 mg, 0.35 mmol), 4-bromo-5-chloro-2-(1-phenylethoxy)benzaldehyde (290 mg) , 0.70 mmol), palladium acetate (8.0 mg, 0.07 mmol), tris(o-methylphenyl)phosphine (12.0 mg, 0.07 mmol), 0.4 mL of triethylamine and 4 mL of dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwaved at 160 ° C for 45 minutes.
  • Step 3 (E)-2-(2-Chloro-4-formyl-5-(1-phenoxy)styryl-4-phenylnicotinamide (47 mg, 0.1 mmol) and (S)-
  • the pyridine-2-carboxylic acid (26 mg, 0.2 mol) was dissolved in 10 mL of methanol, and sodium cyanoborohydride (10 mg, 0.15 mmol) was added, and the mixture was stirred under reflux for 2 hours, concentrated under reduced pressure and purified by preparative HPLC (2S) )-1-[[5-chloro-4-[(E)-2-(3-cyano-4-phenyl-2-pyridyl)ethyl]-2-(1-phenylethoxy) Phenyl]methyl]piperidine-2-carboxylic acid (Compound P-54) (6.53 mg, white solid), yield: 13.2%.
  • Step 1 2 -Methoxy-4-phenyl-3-(trifluoromethyl)pyridine (470 mg, 1.86 mol) was dissolved in 10 mL of acetonitrile, and then added to the solution of phosphorus bromide (1.07 g, 3.72 mmol) The mixture was heated to 80 ° C and stirred for 3 hours. After the reaction mixture was cooled to room temperature, it was slowly poured into ice water with stirring, and extracted with ethyl acetate (30 mL ⁇ 2). The organic phase was combined, washed with EtOAc EtOAc EtOAc m. The yield was 81.9%. The crude product was used in the next step without purification. MS m/z (ESI): 304.0 [M+H] + .
  • Step 2 Dissolve 2-bromo-4-phenyl-3-(trifluoromethyl)pyridine (460 mg, 1.52 mmol) in 15 mL of 1,4-dioxane and 1 mL of water and add potassium fluoroborate (408 mg). , 3.04 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (124 mg, 0.15 mmol), potassium carbonate (420 mg, 3.04 mmol) in argon The reaction was stirred at 80 ° C for 16 hours under gas protection. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Base-3-(trifluoromethyl)-2-vinylpyridine (175 mg, yellow oil), yield: 46.3%. MS m/z (ESI): 250.1 [M+H] + .
  • Step 3 Add to the 20 mL microwave tube: 4-phenyl-3-(trifluoromethyl)-2-vinylpyridine (125 mg, 0.5 mmol), 4-bromo-5-chloro-2-methoxybenzene Formaldehyde (187 mg, 0.75 mmol), palladium acetate (11 mg, 0.05 mmol), tris(o-methylphenyl)phosphine (15 mg, 0.05 mmol), 0.5 mL of triethylamine and 4 mL of dimethylacetamide. The mixture was blown with argon for 2 minutes, covered with a microwave cover, and microwave-reacted at 160 ° C for 45 minutes.
  • Step 4 (E)-5-Chloro-2-methoxy-4-(2-(4-phenyl-3-(trifluoromethyl)pyridin-2-yl)vinyl)benzaldehyde (42 mg 0.1 mol) and (S)-piperidine-2-carboxylic acid (26 mg, 0.2 mol) were dissolved in 3 mL of methanol, sodium cyanoborohydride (13 mg, 0.2 mmol) was added, and the reaction was stirred under reflux for 1 hour.
  • Step 1 (S,E)-1-(5-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)-2-methoxybenzyl)piperidin Pyridine-2-carboxylic acid (Compound P-44) (50 mg, 0.10 mmol), methylamine hydrochloride (69 mg, 1.02 mmol), diisopropylethylamine (79 mg, 0.61 mmol) and 2-(7- benzene oxide And triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (77 mg, 0.20 mol) was dissolved in 2 mL of N,N-dimethylformamide, and the reaction was stirred at room temperature for 10 hours.
  • Step 1 2,4-Dibromonicotinonitrile (2.60 g, 10.0 mmol) was dissolved in 45 mL of 1,4-dioxane and 15 mL of water, and pyridine-4-boronic acid (1.2 g, 10.0 mmol) was added, [1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (733 mg, 1.0 mmol), sodium carbonate (1.0 g, 10.0 mmol), stirred at 100 ° C under argon atmosphere 3 hours. The reaction solution was filtered, and the filtrate was evaporated. mjjjjjjjjjjjj Brown solid), yield: 70.3%. MS m/z (ESI): 260.1 [M+H] + .
  • Step 2 Dissolve 2-bromo-4,4'-dipyridine-3-carbonitrile (1.3 g, 5.0 mmol) in 30 mL of 1,4-dioxane and 10 mL of water, and add potassium fluoroborate (670 mg, 5.0). Ment), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (370 mg, 0.5 mmol), sodium carbonate (530 mg, 5.0 mmol), protected with argon The reaction was stirred at 100 ° C for 16 hours. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjj Brown solid), Yield: 31.1%. MS m/z (ESI): 208.2 [M+H] + .
  • Step 3 Add to the 20 mL microwave tube: 2-vinyl-4,4'-dipyridine-3-carbonitrile (40 mg, 0.20 mmol), 4-bromo-5-chloro-2-methoxybenzaldehyde (50 mg , 0.20 mmol), palladium acetate (4.5 mg, 0.1 mmol), tris(o-methylphenyl)phosphorus (6.0 mg, 0.1 mmol), 0.2 mL of triethylamine and 3 mL of dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwave-reacted at 160 ° C for 45 minutes.
  • Step 4 (E)-2-((2-Chloro-4-formyl-5-methoxyphenyl)alkenyl)-4,4'-dipyridine-3-carbonitrile (38 mg, 0.1 mmol)
  • (S)-piperidine-2-carboxylic acid (26 mg, 0.2 mol) was dissolved in 20 mL of methanol, sodium cyanoborohydride (10 mg, 0.15 mmol) was added, and the reaction was stirred under reflux for 2 hours.
  • the title product (2S)-1-[[5-chloro-4-(E)-2-(3-cyano-4-(4-pyridyl)-2-pyridine was obtained.
  • Tag1-PD-L1 protein and Tag2-PD1 protein were prepared in 1X reaction buffer at 50nM and 10nM respectively, and the final reaction concentration was Tag1-PD-L1 10nM, Tag1-PD-L1 2nM;
  • the anti-Tag1-Eu3+ antibody is disposed in the 1X concentration detection buffer at a ratio of 1:100;
  • the anti-Tag2-XL665 antibody is disposed in a 1X concentration detection buffer at a ratio of 1:25;
  • the readings of the wavelengths of 665 nm and 620 nm were read by the HTRF plate reader program. The ratio of the two wavelengths was used to judge the activity of the compound, and the IC50 of the test compound was calculated by XLFIT 5.0 (IDBS). The test results are shown in Table 1.
  • the exemplified compounds of the present invention have a good inhibitory activity against PPI-HTRF.
  • W is a substituted or unsubstituted benzene ring directly bonded to the pyridine ring
  • Z 4 is N, Z 2 , Z 3
  • CH is CR 1
  • the right side connected to the alkenyl group is a substituted or unsubstituted benzene ring
  • the activity of the compound can be several tens or even several nM.

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne un immunomodulateur, son procédé de préparation et son utilisation en tant qu'inhibiteur de PD-1/PD-L1. En particulier, la présente invention concerne un composé de formule (I) ou un sel, un stéréoisomère, un solvate ou un promédicament pharmaceutiquement acceptable de celui-ci, ainsi qu'un procédé de préparation et une utilisation associés. La définition de chaque substituant dans la formule est décrite en détail dans la description et les revendications.
PCT/CN2018/122818 2017-12-22 2018-12-21 Immunomodulateur, son procédé de préparation et son utilisation médicale WO2019120297A1 (fr)

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US11059834B2 (en) 2017-08-08 2021-07-13 Chemocentryx, Inc. Macrocyclic immunomodulators
US11135210B2 (en) 2018-02-22 2021-10-05 Chemocentryx, Inc. Indane-amines as PD-L1 antagonists
CN114057655A (zh) * 2021-12-13 2022-02-18 郑州华赞医药科技有限公司 一种二溴化合物的合成方法
US11266643B2 (en) 2019-05-15 2022-03-08 Chemocentryx, Inc. Triaryl compounds for treatment of PD-L1 diseases
US11426364B2 (en) 2016-06-27 2022-08-30 Chemocentryx, Inc. Immunomodulator compounds
US11485708B2 (en) 2019-06-20 2022-11-01 Chemocentryx, Inc. Compounds for treatment of PD-L1 diseases
US11708326B2 (en) 2017-07-28 2023-07-25 Chemocentryx, Inc. Immunomodulator compounds
US11713307B2 (en) 2019-10-16 2023-08-01 Chemocentryx, Inc. Heteroaryl-biphenyl amides for the treatment of PD-L1 diseases
US11866429B2 (en) 2019-10-16 2024-01-09 Chemocentryx, Inc. Heteroaryl-biphenyl amines for the treatment of PD-L1 diseases
US11872217B2 (en) 2019-07-10 2024-01-16 Chemocentryx, Inc. Indanes as PD-L1 inhibitors

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CN114230512A (zh) * 2020-09-09 2022-03-25 广州再极医药科技有限公司 芳香乙烯类化合物、其制备方法、中间体、药物组合物及其应用

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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

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US11793771B2 (en) 2016-06-27 2023-10-24 Chemocentryx, Inc. Immunomodulator compounds
US11426364B2 (en) 2016-06-27 2022-08-30 Chemocentryx, Inc. Immunomodulator compounds
US11708326B2 (en) 2017-07-28 2023-07-25 Chemocentryx, Inc. Immunomodulator compounds
US11691985B2 (en) 2017-08-08 2023-07-04 Chemocentryx, Inc. Macrocyclic immunomodulators
US11059834B2 (en) 2017-08-08 2021-07-13 Chemocentryx, Inc. Macrocyclic immunomodulators
US11759458B2 (en) 2018-02-22 2023-09-19 Chemocentryx, Inc. Indane-amines as PD-L1 antagonists
US11135210B2 (en) 2018-02-22 2021-10-05 Chemocentryx, Inc. Indane-amines as PD-L1 antagonists
US11266643B2 (en) 2019-05-15 2022-03-08 Chemocentryx, Inc. Triaryl compounds for treatment of PD-L1 diseases
US11485708B2 (en) 2019-06-20 2022-11-01 Chemocentryx, Inc. Compounds for treatment of PD-L1 diseases
US11872217B2 (en) 2019-07-10 2024-01-16 Chemocentryx, Inc. Indanes as PD-L1 inhibitors
US11713307B2 (en) 2019-10-16 2023-08-01 Chemocentryx, Inc. Heteroaryl-biphenyl amides for the treatment of PD-L1 diseases
US11866429B2 (en) 2019-10-16 2024-01-09 Chemocentryx, Inc. Heteroaryl-biphenyl amines for the treatment of PD-L1 diseases
CN114057655A (zh) * 2021-12-13 2022-02-18 郑州华赞医药科技有限公司 一种二溴化合物的合成方法
CN114057655B (zh) * 2021-12-13 2023-10-27 郑州华赞医药科技有限公司 一种二溴化合物的合成方法

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