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WO2021047547A1 - 新型三环芳香杂环化合物，及其制备方法、药物组合物和应用 - Google Patents

新型三环芳香杂环化合物，及其制备方法、药物组合物和应用 Download PDF

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WO2021047547A1
WO2021047547A1 PCT/CN2020/114253 CN2020114253W WO2021047547A1 WO 2021047547 A1 WO2021047547 A1 WO 2021047547A1 CN 2020114253 W CN2020114253 W CN 2020114253W WO 2021047547 A1 WO2021047547 A1 WO 2021047547A1
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group
compound
cancer
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PCT/CN2020/114253
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English (en)
French (fr)
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王喆
白海云
李德亮
潜安然
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上海长森药业有限公司
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Priority to MX2022002839A priority Critical patent/MX2022002839A/es
Priority to AU2020346936A priority patent/AU2020346936B2/en
Priority to CA3153702A priority patent/CA3153702A1/en
Priority to EP20862539.2A priority patent/EP4029865A4/en
Priority to JP2022515642A priority patent/JP2022547201A/ja
Priority to KR1020227011833A priority patent/KR20220062053A/ko
Priority to US17/641,162 priority patent/US20220372031A1/en
Priority to CN202080063269.8A priority patent/CN114364676B/zh
Publication of WO2021047547A1 publication Critical patent/WO2021047547A1/zh

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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • 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
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to the field of small molecule drugs. Specifically, the present invention provides a small molecule compound that can be used to treat diseases related to the PD-1/PD-L1 signaling pathway.
  • the immune system plays a vital role in controlling and curing many diseases, such as various cancers and diseases caused by viruses.
  • cancer cells can often evade or suppress the immune system through some means, thereby reproducing rapidly.
  • One way is to change the activation and inhibitory molecules expressed on immune cells. Blocking suppression of immune checkpoints, like PD-1, proved to be a very effective method of suppressing cancer cells.
  • PD-1 is programmed cell death protein-1, also known as CD279. It is mainly expressed in activated T cells and B cells, and its function is to inhibit cell activation. This is a normal homeostasis mechanism of the immune system. Because excessive T/B cell activation can cause autoimmune diseases, PD- 1 is a protective wall for our human body.
  • PD-1 is a type I transmembrane glycoprotein composed of 268 amino acids. Its structure mainly includes the variable region of the extra-immunoglobulin, the hydrophobic transmembrane region and the intracellular region.
  • the intracellular region contains two phosphorylation sites, which are located in the immunoreceptor tyrosine suppression motif and the immunoreceptor tyrosine switching motif, which also proves that PD-1 can reversely regulate T cell receptor-mediated signal.
  • PD-1 has two ligands, PD-L1 and PD-L2, which are different in expression.
  • PD-L1 is up-regulated and expressed in a variety of tumor cells. It binds to PD-1 on T cells, inhibits T cell proliferation and activation, makes T cells in a state of inactivation, and finally induces immune escape.
  • PD-1/PD-L1 plays a reverse immunomodulatory role.
  • PD-1 binds to PD-L1, it can cause the tyrosine polyphosphorylation of the tyrosine conversion motif domain of the immunoreceptor of T cells, and the phosphorylated tyrosine can bind to the phosphatase protein tyrosinase 2 and protein tyrosinase 1.
  • This can block the activation of extracellular signal-regulated kinases, and also block the activation of phosphoinositide 3-kinase (PI3K) and serine-threonine protein kinase (Akt), thereby inhibiting the proliferation of T lymphocytes and the breakdown of related cytokines.
  • PI3K phosphoinositide 3-kinase
  • Akt serine-threonine protein kinase
  • PD-1/PD-L1 signal inhibits T cell activation and proliferation, it can also secrete the cytokines interleukin 2, interferon gamma and IL-10.
  • PD-1/PD-L1 signals have similar immune functions to B cells.
  • the cytoplasmic region of PD-1 interacts with tyrosinase containing protein tyrosinase 2 binding sites. Cataminase acts to hinder the activation of B cells.
  • Immunotherapy based on PD-1/PD-L1 is a new generation of immunotherapy that has attracted much attention.
  • PD-1/PD-L1 inhibitors have strong anti-tumor activity against a variety of tumors.
  • the PD-1/PD-L1 antibody modulators currently on the market include BMS’s Ninolumab, Merck’s Lambrolizumab and Roche’s Atezolizumab.
  • BMS Ninolumab
  • Merck s Lambrolizumab
  • Roche Roche’s Atezolizumab.
  • there are many PD-1/PD-L1 antibody modulators under development including CureTech’s Pidilizumab, GSK’s AMP-224 and AstraZeneca’s MEDI-4736.
  • tumor immunotherapy is considered to be a new generation of revolution in cancer treatment after targeted therapy.
  • the PD-1 monoclonal antibody currently on the market and under development has its own shortcomings, including only injections, not oral, unstable in the body, easy to be decomposed by proteases, easy to produce immune cross-reactions, purification is more difficult and production The cost is high. Therefore, the small molecule modulator of PD-1/PD-L1 interaction is a better choice for tumor immunotherapy.
  • the purpose of the present invention is to provide a novel small molecule modulator of PD-1/PD-L1 interaction.
  • n 0, 1, 2, 3, 4 or 5;
  • n, p, q and t, v, u are each independently selected from 0, 1, 2, 3, 4;
  • X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently selected from the following group: N, O, S, SO, SO 2 , C(R) 2 , CHR, NR;
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are each independently selected from the following group: N, CH, C;
  • the hydrogen on the carbon atoms of X 3 , X 4 , X 5 , X 7 , X 8 , and X 9 can be independently replaced by deuterium;
  • Each is independently selected from the following group: substituted or unsubstituted C6-C10 arylene group, or substituted or unsubstituted 5-12 membered (preferably 5-7 membered) heteroarylene group having 1-3 heteroatoms, Substituted or unsubstituted 5-12 membered heterocyclylene, substituted or unsubstituted 5-12 membered C3-C12 (preferably C5-C12) cycloalkylene;
  • substituted or unsubstituted 5-12 membered heteroaryl substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heterocyclic group, substituted or unsubstituted 5-12
  • L 1 is selected from the following group: chemical bond, substituted or unsubstituted C1-C4 alkylene, substituted or unsubstituted C2-C4 alkenylene, substituted or unsubstituted C2-C4 alkynylene, -S-,- O-, substituted or unsubstituted -NH-, -S(O)-, -S(O) 2 -, substituted or unsubstituted -NHC(O)NH-, Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted
  • Rb and Rc are each independently selected from the following group: H, substituted or substituted C 1 -C 8 alkyl; or said Rb and Rc and the adjacent N atom together form a substituted or unsubstituted one with 1-
  • Each L 1a is each independently a group selected from the group consisting of: chemical bond, substituted or unsubstituted C 1 -C 7 alkylene, substituted or unsubstituted C2-C4 alkenylene, substituted or unsubstituted C2- C4 alkynylene, -S-, -O-, substituted or unsubstituted -NH-, -S(O)-, or -S(O) 2 -;
  • L 2a is selected from the following group: substituted or unsubstituted C6-C12 arylene, substituted or unsubstituted 5-12 membered heteroarylene having 1-3 heteroatoms, substituted or unsubstituted C3-C8 arylene Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclylene with 1-3 heteroatoms;
  • L 3a is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, C1-C10 aryl, -CN, hydroxyl, amino, carboxyl, -CO-NH-SO 2 -R g , -NH-SO 2- R g , -SO 2 -NH-CO-R g , -OR g , -N(R g ) 2 -CO 2 R g , -CON(R g ) 2 , -CONHCOR g , NR g -CO-N( R g ) 2 , -NR g -SO 2 -N(R g ) 2 ;
  • r is 1, 2, 3, 4, 5, 6;
  • s are 0, 1, 2 respectively;
  • R d, R e and R g are each independently selected from the group: H, a substituted or unsubstituted C 1 -C 6 alkyl group, a substituted or unsubstituted C 3 -C 10 cycloalkyl group, a substituted or unsubstituted C 6 -C 10 aryl group; or 4-10 R e and R d together form a substituted or unsubstituted 1-3 hetero atoms selected from N, S and O (preferably 5-10) membered heterocyclic ring base;
  • any one of the heteroatoms is selected from the group consisting of B, P, N, S, and O.
  • B is a group selected from the group consisting of substituted or unsubstituted C6-C10 aryl groups, or substituted or unsubstituted C6-C10 aryl groups, or substituted or unsubstituted ones with 1-3 heteroatoms 5-12 membered (preferably 5-7 membered) heteroaryl group, substituted or unsubstituted 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 membered C3-C12 (preferably C5-C12) ring alkyl.
  • the compound of formula I has a structure shown in the following formula:
  • the present invention provides a compound represented by the following formula I, or an optical isomer, hydrate, solvate, or a pharmaceutically acceptable salt thereof:
  • n 0, 1, 2 or 3;
  • n, p, q, and t are each independently selected from 0, 1, 2, 3, or 4;
  • X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently selected from the following group: N, O, S, SO, SO 2 , C(R) 2 , NR;
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are each independently selected from the following group: N, CH, C;
  • Each is independently selected from the following group: substituted or unsubstituted C6-C10 arylene group, or substituted or unsubstituted 5-12 membered (preferably 5-7 membered) heteroarylene group having 1-3 heteroatoms, Substituted or unsubstituted 5-12 membered heterocyclylene, substituted or unsubstituted 5-12 membered C5-C12 cycloalkylene;
  • substituted or unsubstituted 5-12 membered heteroaryl substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 A membered C5-C12 ring group, wherein the heterocyclic group has 1 to 3 heteroatoms;
  • L 1 is selected from the following group: chemical bond, substituted or unsubstituted C1-C4 alkylene, substituted or unsubstituted C2-C4 alkenylene, substituted or unsubstituted C2-C4 alkynylene, -S-,- O-, substituted or unsubstituted -NH-, -S(O)-, -S(O) 2 -, substituted or unsubstituted -NHC(O)NH-, Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted
  • substituted or unsubstituted C1-C6 amine group substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkylene), carboxyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heteroaryl group with 1-3 heteroatoms, substituted or unsubstituted 3-12 membered heterocyclic group with 1-4 heteroatoms, substituted or unsubstituted Substituted or unsubstituted Or -(L 1a ) r -(L 2a ) s -(L 3a ) s -;
  • Each L 1a is each independently a group selected from the group consisting of: chemical bond, substituted or unsubstituted C 1 -C 7 alkylene, substituted or unsubstituted C2-C4 alkenylene, substituted or unsubstituted C2- C4 alkynylene, -S-, -O-, substituted or unsubstituted -NH-, -S(O)-, or -S(O) 2 -;
  • L 2a is selected from the following group: substituted or unsubstituted C6-C12 arylene, substituted or unsubstituted 5-12 membered heteroarylene having 1-3 heteroatoms, substituted or unsubstituted C3-C8 arylene Cycloalkyl, substituted or unsubstituted 5-10 membered heterocyclylene with 1-3 heteroatoms;
  • L 3a is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, C1-C10 aryl, -CN, hydroxyl, amino, carboxyl, -CO-NH-SO 2 -R g , -NH-SO 2- R g , -SO 2 -NH-CO-R g ;
  • r is 1, 2, 3, 4, 5, 6;
  • s are 0, 1, 2 respectively;
  • Rd, Re and Rg are each independently selected from the following group: H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 6- C 10 aryl; or Rd and Re together form a substituted or unsubstituted 5-10 membered heterocyclic group with 1-3 heteroatoms selected from N, S and O;
  • substituted refers to being substituted by one or more (for example, 2, 3, 4, etc.) substituents selected from the following group: halogen: including but not limited to -F, Cl, Br, -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 F, -CHF 2 , -CF 3 , oxo, -CN, hydroxyl, amino, C1-C6 alkylamino, carboxyl, -NHAc, A group selected from the group that is unsubstituted or substituted by one or more substituents selected from the group: C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C3-C8 cycloalkyl , Halogenated C6-C10 aryl groups, 5-10 membered heteroaryl groups with 1-3 heteroatoms selected from N, S and O, and those with 1-3 heteroatoms selected from N, S and O
  • any one of the heteroatoms is selected from the group consisting of B, P, N, S, and O.
  • the Each independently is a divalent group formed by a ring selected from the following group: Wherein, the bonding position of the ring may be N or C (substituents on the ring are not shown).
  • the R 2 and R 3 are each independently selected from the following group: methyl, -F, Cl, Br, -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 F , -CHF 2 , -CF 3 , -CN, hydroxyl, amino.
  • the The bonding position of can be o, p, m position
  • an H connected to N or C is replaced by a bond.
  • X 6 , X 7 , X 8 , X 9 , X 10 and X 11 are each independently selected from the following group: N, CR;
  • the bonding position of the ring may be N or C (substituents on the ring are not shown).
  • said R 6 is R 1 ; or wherein, Rb and Rc are each independently selected from the following group: H, substituted or unsubstituted C 1 -C 8 alkyl; or said Rb and Rc and the adjacent N atom together form a substituted or unsubstituted one having 1 -3 3-10 membered heterocyclic groups selected from N, S and O heteroatoms.
  • the ring It has a substituent as shown in the following formula IV:
  • w 0,1,2,3,4,5,6;
  • each L 4 is independently selected from the following group: substituted or unsubstituted C1-C4 alkylene, -S-, -O-, NR f , -S(O)-, -S(O) 2- ;
  • it is a substituted or unsubstituted C1-C4 alkylene group, wherein the hydrogen on the carbon atom of the substituted or unsubstituted C1-C4 alkylene group can be independently replaced by deuterium; the prerequisite is that each L 4 is common
  • the formed structure is chemically stable;
  • substituted or unsubstituted C3-C10 cycloalkyl substituted or unsubstituted 3-10 membered heterocyclic group having 1-3 heteroatoms selected from B, P, N, S and O;
  • the It is a substituted or unsubstituted 3-8 membered nitrogen-containing heterocyclic group, or a substituted or unsubstituted 4-10 membered cyclic amide, wherein the 3-8 membered nitrogen-containing heterocyclic group is substituted or unsubstituted 4-10 membered
  • the hydrogens on the ring-forming carbon atoms of the cyclic amide group can be independently replaced by deuterium;
  • Each R 7 is independently selected from the following group: substituted or unsubstituted C1-C6 alkyl, -CN, hydroxyl, amino, carboxyl, -OR g , -N(R g ) 2 , -CO-NH-SO 2 -R g , -NH-SO 2 -R g , -SO 2 -NH-CO-R g, -CO 2 R g , -CON(R g ) 2 , CONHCOR g , NR g -CO-N(R g ) 2 , -NR g -SO 2 -N(R g ) 2 ;
  • the definitions of R f and R g are as described above, wherein the hydrogen on the carbon atom of Rf and Rg can be replaced by deuterium independently, wherein, The substituent is selected from the following group: halogen, hydroxy, carboxy, cyano, C1-C6 alkoxy.
  • At least one R 4 is a group selected from the following group: NRdRe; said Rd and Re are each independently selected from the following group: H, substituted or unsubstituted C 1 -C 6 alkyl , Substituted or unsubstituted C 3 -C 10 cycloalkyl, -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -OC(O)OR 8 , -C 0-8 -NR 8 R 9 , -C 0-8 -N(R 8 )C(O)R 9 , -C 0-8 -C(O)NR 8 R 9 , substituted or unsubstituted C 6 -C 10 aryl group; or Rd and Re together form a substituted or unsubstituted 3-10 membered cycloalkyl group, or a 3-membered group having 1-3 substituted or unsubstituted
  • the substituents described here are carboxyl, hydroxyl, R 10 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, preferably, R 10 is methyl, isopropyl, cyclopropyl and 1-methyl Cyclopropyl, in which the hydrogen on the carbon atoms of Rd, Re and R 10 can each be independently replaced by deuterium.
  • the ring It has a substituent as shown in the following formula IV:
  • each L 4 is independently selected from the following group: substituted or unsubstituted C1-C4 alkylene, -S-, -O-, -NRa-, -NR f , -S(O)-, -S(O) 2 -; preferably a substituted or unsubstituted C1-C4 alkylene group, provided that the structure formed by each L 4 is chemically stable;
  • substituted or unsubstituted C5-C10 cycloalkyl substituted or unsubstituted 3-10 membered heterocyclic group having 1-3 heteroatoms selected from B, P, N, S and O;
  • the Is a 3-8 membered nitrogen-containing heterocyclic group;
  • Each R 7 is independently selected from the following group: substituted or unsubstituted C1-C6 alkyl, -CN, hydroxyl, amino, carboxyl, -OR g , -N(R g ) 2 , -CO-NH-SO 2 -R g , -NH-SO 2 -R g , -SO 2 -NH-CO-R g, -CO 2 R g , -CON(R g ) 2 , CONHCOR g , NR g -CO-N(R g ) 2 , -NR g -SO 2 -N(R g ) 2 ; wherein, the substituent is selected from the group consisting of halogen, hydroxyl, carboxyl, cyano, and C1-C6 alkoxy.
  • At least one R 4 is a group selected from the following group: NRdRe; said Rd and Re are each independently selected from the following group: H, substituted or unsubstituted C 1 -C 6 alkyl , Substituted or unsubstituted C 3 -C 10 cycloalkyl, -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -OC(O)OR 8 , -C 0-8 -NR 8 R 9 , -C 0-8 -N(R 8 )C(O)R 9 , -C 0-8 -C(O)NR 8 R 9 , substituted or unsubstituted C 6 -C 10 aryl group; or Rd and Re together form a substituted or unsubstituted 3-10 membered cycloalkyl group, or a 3-membered group having 1-3 substituted or unsubstituted
  • the substituents described here are carboxyl, hydroxyl, R 10 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, preferably, R 10 is methyl, isopropyl, cyclopropyl and 1-methyl Cyclopropyl, in which the hydrogen on the carbon atoms of Rd, Re and R 10 can each be independently replaced by deuterium.
  • the compound of formula I has a structure shown in the following formula:
  • At least one of said R 4 is selected from the following group: NRdRe; each of said Rd and Re is independently selected from the following group: H, substituted or unsubstituted C 1 -C 6 alkyl, Substituted or unsubstituted C 3 -C 10 cycloalkyl, -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -OC(O)OR 8 ,- C 0-8 -NR 8 R 9 ,-C 0-8 -N(R 8 )C(O)R 9 ,-C 0-8 -C(O)NR 8 R 9 , substituted or unsubstituted C 6 -C 10 aryl; or Rd and Re together form a substituted or unsubstituted 5-10 membered heterocyclic group with 1-3 heteroatoms selected from N, S and O; preferably, the substituent is carboxyl.
  • the Is a structure selected from the following group:
  • the compound is selected from the following compounds;
  • the second aspect of the present invention provides a method for preparing the compound of formula I as described in the first aspect of the present invention, characterized in that the method comprises steps selected from synthetic schemes 1, 2 or 3:
  • the target product I-1 is obtained by Sonogashira coupling reaction catalyzed by a palladium catalyst;
  • the preparation method of Intermediate II-2 is as follows:
  • the preparation method of Intermediate III is as follows:
  • the third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (1) the compound according to the first aspect of the present invention or its stereoisomer or tautomer, or a pharmaceutically acceptable salt thereof , Hydrate or solvate; (2) pharmaceutically acceptable carrier.
  • the fourth aspect of the present invention provides a compound as described in the first aspect of the present invention or a stereoisomer or tautomer, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or
  • the use of the pharmaceutical composition according to the third aspect of the present invention is characterized in that it is used for the preparation of prevention and/or treatment of diseases related to the activity or expression of PD-1/PD-L1 (HBV, HCV, solid tumors, Hematoma, etc.) of the pharmaceutical composition.
  • PD-1/PD-L1 HBV, HCV, solid tumors, Hematoma, etc.
  • the fifth aspect of the present invention provides a PD-1/PD-L1 modulator, the modulator comprising the compound described in the first aspect of the present invention, or its stereoisomers or tautomers, or Its pharmaceutically acceptable salt, hydrate or solvate.
  • the pharmaceutical composition is used to treat diseases selected from the group consisting of cancer, infectious diseases, and autoimmune diseases.
  • the cancer is selected from the group consisting of pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, and esophagus Cancer, melanoma, neuroendocrine cancer, central nervous system cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer or colon cancer, skin cancer, lung cancer, urinary system tumor, blood tumor, glial Tumors, digestive system tumors, reproductive system tumors, lymphomas, nervous system tumors, brain tumors, head and neck cancers.
  • the cancer is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), bone marrow Dysplastic syndrome (MDS), myelodysplastic disease (MPD), chronic myelogenous leukemia (CML), multiple myeloma (MM), non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), Follicular lymphoma, Waldestrom macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, or diffuse large B-cell lymphoma (DLBCL).
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • MDS bone marrow Dysplastic syndrome
  • MDS myelodysplastic
  • the infectious disease is selected from bacterial infection and viral infection.
  • the autoimmune disease is selected from organ-specific autoimmune disease and systemic autoimmune disease.
  • the organ-specific autoimmune diseases include chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Pulmonary hemorrhage nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosis, acute idiopathic polyneuritis.
  • systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, self Immune hemolytic anemia.
  • the pharmaceutical composition is also used to improve T cell function in patients with chronic hepatitis B (CHB).
  • CHB chronic hepatitis B
  • the inhibitor further includes at least one therapeutic agent selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, or ipilimumab.
  • the sixth aspect of the present invention provides a method for regulating the interaction of PD-1/PD-L1 in vivo, which is characterized in that it comprises the step of combining the compound described in the first aspect of the present invention, or its stereoisomer or The tautomer, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is contacted with the PD-L1 protein.
  • alkyl includes straight-chain or branched alkyl groups.
  • C 1 -C 8 alkyl means a straight or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Wait.
  • alkenyl includes linear or branched alkenyl.
  • C 2 -C 6 alkenyl refers to a linear or branched alkenyl having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 -Butenyl, or similar groups.
  • alkynyl includes straight-chain or branched alkynyl groups.
  • C 2 -C 6 alkynyl refers to a linear or branched alkynyl group having 2-6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
  • C 3 -C 10 cycloalkyl refers to a cycloalkyl having 3-10 carbon atoms. It may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It may also be in the form of a double ring, such as a bridged ring or a spiro ring.
  • C 1 -C 8 alkylamino group refers to an amine group substituted by a C 1 -C 8 alkyl group, which may be mono- or di-substituted; for example, methylamino, ethylamino, Propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, two Tert-butylamino and so on.
  • C 1 -C 8 alkoxy refers to a linear or branched alkoxy group having 1-8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propoxy, butoxy, isobutoxy, tert-butoxy, etc.
  • the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S, and O" refers to those having 3-10 atoms and wherein 1-3 atoms are A saturated or partially saturated cyclic group of heteroatoms selected from the group consisting of N, S, and O. It may be in the form of a single ring or a double ring, such as a bridged ring or a spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.
  • C 6 -C 10 aryl group refers to an aryl group having 6-10 carbon atoms, for example, a phenyl group or a naphthyl group and the like.
  • the term "5-10 membered heteroaryl group having 1-3 heteroatoms selected from the group consisting of N, S, and O" refers to those having 5-10 atoms and wherein 1-3 atoms are selected from The following groups are cyclic aromatic groups with heteroatoms of N, S and O. It may be a monocyclic ring or a condensed ring form.
  • pyridyl pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc.
  • the groups of the present invention can be substituted by substituents selected from the group consisting of halogen, nitrile, nitro, hydroxyl, and amino. , C 1 -C 6 alkyl-amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1- C 6 alkyl, halo C 2 -C 6 alkenyl, halo C 2 -C 6 alkynyl, halo C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl , C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl, C 2 -C
  • halogen or halogen atom refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "Halogenated” refers to substitution by an atom selected from F, Cl, Br, and I.
  • the structural formula described in the present invention is intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, containing asymmetry The R and S configuration of the center, the (Z) and (E) isomers of the double bond, etc. Therefore, a single stereochemical isomer of the compound of the present invention or a mixture of its enantiomers, diastereomers or geometric isomers (or conformational isomers) belongs to the scope of the present invention.
  • the structural formula described in the present invention is intended to include all possible deuterated derivatives (that is, one or more hydrogen atoms in the molecule are replaced by D).
  • tautomers means that structural isomers with different energies can exceed the low energy barrier to convert into each other.
  • proton tautomers ie, proton transfer
  • Valence tautomers include interconversion through the recombination of some bond-forming electrons.
  • solvate refers to a complex in which the compound of the present invention coordinates with solvent molecules to form a specific ratio.
  • hydrate refers to a complex formed by coordination of the compound of the present invention with water.
  • the compound of the present invention refers to the compound represented by formula I, and also includes various crystal forms, pharmaceutically acceptable salts, hydrates or solvates of the compound of formula I.
  • Preferred compounds of the present invention include compounds 1-360 (including various R configuration and/or S configuration stereoisomers of each compound, and/or E-/Z- cis-trans isomers).
  • the pharmaceutically acceptable salts include salts formed by combining with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions, or organic bases that can provide physiologically acceptable cations, and ammonium salts.
  • the inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid;
  • the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, lycic acid, maleic acid Tartaric acid, fumaric acid, citric acid or lactic acid;
  • the alkali metal ion is selected from lithium ion, sodium ion, and potassium ion;
  • the alkaline earth metal ion is selected from calcium ion and magnesium ion;
  • the organic base of the accepted cation is selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.
  • the starting materials and intermediates in the preparation method of the present invention are easily available, and each step of the reaction can be easily synthesized according to the reported literature or by conventional methods in organic synthesis for those skilled in the art.
  • the compounds of Formula I can exist in the form of solvates or unsolvates, and different solvates may be obtained by crystallization with different solvents.
  • the compound of the present invention has excellent PD-1/PD-L1 interaction modulating activity
  • the pharmaceutical composition in which the compound of the present invention is the main active ingredient can be used to prevent and/or treat (stabilize, reduce or cure) diseases related to PD-1/PD-L1 interaction (for example, cancer, infectious diseases, autoimmune diseases) .
  • the pharmaceutical composition of the present invention includes a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per agent, and more preferably, contains 10-200 mg of the compound of the present invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • wetting agents such as sodium lauryl sulfate
  • coloring agents such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen, sorbitol, etc.
  • antioxidants
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into a microcapsule form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as other anticancer agents).
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds.
  • One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used for the prevention and/or treatment of PD simultaneously, separately or sequentially with the compound of the present invention -1/PD-L1 interaction related diseases.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the administered dose is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • the compound of the present invention has high regulatory activity on the interaction of PD-1/PD-L1, has a strong binding ability with PD-L1 protein, and has the ability to relieve PD-L1 from inhibiting IFN ⁇ .
  • the compound of the present invention has better solubility; it has very low toxicity to normal cells, so it can be applied to treatment subjects in a larger dose range.
  • the compounds of the present invention have better solubility, and therefore have good druggability. Compared with the existing compounds, the compounds of the present invention perform well in in vivo experiments. In addition, compared with the existing compounds, the compounds of the present invention can be easily prepared into pharmaceutically acceptable salts, thus contributing to the further formation of preparations.
  • the proton nuclear magnetic resonance spectrum was analyzed by Bruker AV-400 (400MHz) nuclear magnetic instrument.
  • the mass spectrometry data is analyzed by Finnigan LCQ Advantage, among other needs, and all reactions are performed under anhydrous and oxygen-free conditions under the protection of dry argon.
  • the solid organometallic compounds are stored in an argon-protected dry box.
  • Tetrahydrofuran and ether are obtained by distillation, and sodium metal and benzophenone are added to them during distillation.
  • Dichloromethane, pentane and hexane are treated with calcium hydride.
  • the special raw materials and intermediates involved in the present invention are customized and processed by Tianjin Changsen Pharmaceutical Co., Ltd., and all other chemical reagents are from Shanghai Chemical Reagent Company, Aldrich, and Acros. Wait for reagent suppliers to buy. If the intermediates or products required for the reaction during the synthesis process are not enough for the next step, the synthesis is repeated many times until the number is sufficient.
  • the raw materials and reagents involved in the present invention can all be purchased commercially or through customized processing.
  • the compounds of the present invention may contain one or more asymmetric centers, so the series of compounds may be in the form of racemic or single enantiomer.
  • the compound prepared by the present invention is a heterocyclic compound with a purity higher than 95%, and the structural characterization of each final product is determined by MS or/and proton nuclear magnetic resonance ( 1 H NMR) analysis.
  • MS or/and proton nuclear magnetic resonance ( 1 H NMR) analysis The following examples illustrate the synthesis of various compounds and intermediates of the present invention.
  • Step 1-2
  • the alkyne raw material 1-15 (1.1 g) was added to THF (15 ml), replaced with nitrogen 3 times, 1 ml of 1M TBAF was added, and the reaction was carried out at room temperature; TLC tracking; post-processing: spin dry THF, add 5 ml of water, and ethyl acetate Ester extraction 2 times, saturated brine wash 2 times, mix sample, pass the column: (DCM-MeOH 100,50:1,10:1,5:1) wash off the product, concentrate to obtain 1.0 g of yellow solid, yield: 83 %. MS-APCI:449[M+H] + .
  • Step 2-1
  • Step 2-2
  • Step 3-2
  • Steps 3-5
  • the raw material 3-11 (51g, 0.34mol) was dissolved in 500ml of methanol, 300ml of water was added, sodium bicarbonate (28.9g, 0.34mmol) was added, the methanol solution of NIS was added at about 0°C, and the reaction was completed overnight.
  • Post-treatment Concentrate to dryness, add 500ml of water, 3M hydrochloric acid to adjust the pH to 3, filter the solid, ethyl acetate/ethanol beating, filter and dry to obtain 146g gray solid.
  • Step 4-5
  • step 2-6 Using compound 4-6 (200 mg, 0.416 mmol) and 1-14 (230 mg, 0.5 mmol, WO2018119286) as raw materials, according to the synthesis method of step 2-6, 180 mg of white solid was prepared.
  • step 4-3 Using compound 4-2 (10 g, 45.8 mmol) and 5-1 (11.6 g, 45.8 mmol, WO2017059135) as raw materials, according to the synthesis method of step 4-3, 15 g of off-white solid was obtained.
  • Step 5-2
  • Step 6-2
  • Step 6-3
  • Compound 6-3 (3.5 g) was dissolved in TFA (10 mL), and then stirred at room temperature for 1 hour. Suspend TFA to azeotrope once with toluene. Add saturated sodium bicarbonate solution and concentrated hydrochloric acid to the residual liquid, adjust the pH to 2–3, a large amount of solids appear, filter, and dry to obtain 2g of light brown solids.
  • Step 6-3
  • Step 6-2
  • Step 6-3
  • Step 6-3
  • reaction solution was cooled to -70 degrees, and then THF (20 mL) and NaBH4 (3.9 g, 103.2 mmol) were added to it, and the mixture was stirred at the temperature for 1 hour. Then, it was slowly raised to room temperature and stirred for 1 hour, and the reaction was detected by TLC. After the reaction is complete, a saturated aqueous ammonium chloride solution is added thereto. Then extract with ethyl acetate, dry with anhydrous sodium sulfate, and column chromatography to obtain 5 g of dark gray solid.
  • step 8-4 Using compound 11-5 (20mg, 0.035mmol) and 5-5 (15mg) as raw materials, according to the synthesis method of step 8-4, 20mg of pale yellow solid was prepared.
  • step 8-4 Using compound 12-1 (200 mg) and 5-5 (280 mg) as raw materials, according to the synthesis method of step 8-4, 52 mg of pale yellow solid was prepared.
  • step 8-4 Using compound 13-1 (50 mg) and 5-5 (52 mg) as raw materials, according to the synthesis method of step 8-4, 70 mg of pale yellow solid was prepared.
  • step 8-3 Using compound 14-7 (350 mg) as a raw material, according to the synthesis method of step 8-3, 300 mg of a pale yellow solid was obtained.
  • step 8-3 Using compound 15-1 (200 mg) as a raw material, according to the synthesis method of step 8-3, 150 mg of a pale yellow solid was obtained.
  • step 8-4 Using compound 15-1 (100 mg, WO2019191707) and 7-2 (120 mg) as raw materials, according to the synthesis method of step 8-4, 21 mg of pale yellow solid was prepared. MS(APCI):736[M+H] + .
  • step 8-3 Using compound 16-1 (200 mg) as a raw material, according to the synthesis method of step 8-3, 100 mg of a pale yellow solid was obtained.
  • step 8-4 Using compound 16-1 (50 mg, WO2019191707) and 7-2 (56 mg) as raw materials, according to the synthesis method of step 8-4, 25 mg of pale yellow solid was prepared. MS(APCI): 771[M+H] + .
  • Step 280-1
  • Step 280-2
  • Step 280-3
  • Step 280-4
  • Example A PD-1/PD-L1 homogeneous time-resolved fluorescence (HTRF) binding assay
  • the measurement was carried out in a standard black 384-well polystyrene plate with a final volume of 20 ⁇ L. First, the inhibitor was serially diluted with DMSO and then added to the wells of the plate, and then other reaction components were added. The final concentration of DMSO in the determination is 1%. The measurement was performed in a PBS buffer (pH 7.4) containing 0.05% Tween-20 and 0.1% BSA at 25°C. Recombinant human PD-L1 protein (19-238) with His tag at the C-terminus was purchased from AcroBiosystems (PD1-H5229).
  • Recombinant human PD-1 protein (25-167) with an Fc tag at the C-terminus was also purchased from AcroBiosystems (PD1-H5257).
  • the PD-L1 and PD-1 proteins were diluted in the assay buffer, and then 0.1 ⁇ l of the solution was extracted and added to the plate wells. The plate was centrifuged and the protein and inhibitor were pre-incubated for 40 minutes. After incubation, add 0.1 ⁇ l HTRF detection buffer containing europium blocking labeled anti-human IgG (PerkinElmer-AD0212) Fc exclusive and anti-His -Allophycocyanin (APC, PerkinElmer-AD0059H) conjugated antibody.
  • APC PerkinElmer-AD0059H
  • IC50 values of the compounds exemplified in the examples are expressed in the following manner: IC50: +: ⁇ 10 nM; ++: 10 nM to 100 nM; +++: >100 nM.
  • the data obtained using the PD-1/PD-L1 homogeneous time-resolved fluorescence (HTRF) combination assay described in Example A shows that the IC50 of the tested compounds of the invention is mostly less than 10nm, and some compounds About 25%) or even less than 1 nM.
  • the activity test data of some preferred compounds are provided in Table 1.
  • Compound IC 50 Compound IC 50 Compound IC 50 001 + 035 + 015 + 002 + 036 + 016 + 003 + 037 + 243 + 004 + 038 + 244 + 005 + 039 + 245 + 006 + 040 + 246 + 007 + 041 + 247 + 008 + 042 + 248 + 009 + 043 ++ 249 + 010 + 081 + 250 + 011 + 082 + 251 + 012 + 083 + 252 + 013 + 084 + 253 + 017 + 086 + 254 +

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Abstract

本发明提供了一种新型三环芳香杂环化合物，及其制备方法、药物组合物和应用，具体地，本发明提供了一种如下式I所示的化合物，或其光学异构体、水合物、溶剂合物，或其药学上可接受的盐；其中，各基团的定义如说明书中所述。所述的式I化合物可以用于治疗与PD-1/PD-L1信号通路有关的疾病。

Description

新型三环芳香杂环化合物，及其制备方法、药物组合物和应用 技术领域
本发明涉及小分子药物领域，具体地，本发明提供了一种可以用于治疗与PD-1/PD-L1信号通路有关的疾病的小分子化合物。
发明背景
免疫系统对控制及根治很多疾病起着至关重要的作用，像各种癌症、病毒引起的疾病等。但癌症细胞经常能通过一些途径躲避或抑制免疫系统，从而快速繁殖。其中一个方式就是改变免疫细胞上表达的激活和抑制分子。阻断抑制免疫检查点，像PD-1，证明是一个非常有效的抑制癌细胞的方法。
PD-1是程序性细胞死亡蛋白-1，也称之为CD279。它主要在激活的T细胞和B细胞中表达，功能是抑制细胞的激活，这是免疫系统的一种正常的自稳机制，因为过度的T/B细胞激活会引起自身免疫病，所以PD-1是我们人体的一道保护墙。PD-1是由268个氨基酸组成的I型跨膜糖蛋白，它的结构主要包括外免疫球蛋白可变区、疏水跨膜区以及胞内区。胞内区包含两个磷酸化位点，分别位于免疫受体酷氨酸抑制基序和免疫受体酷氨酸转换基序，这也证明PD-1能够反向调节T细胞受体介导的信号。PD-1有两个配体，PD-L1和PD-L2，它们在表达方式上不同。PD-L1在多种肿瘤细胞中均有上调表达，它与T细胞上的PD-1结合，抑制T细胞增殖和活化，使T细胞处于失活状态，最终诱导免疫逃逸。
PD-1/PD-L1发挥着反向免疫调节作用。当PD-1与PD-L1结合后，可致使T细胞的免疫受体酷氨酸转换基序结构域的酪氨酸多磷酸化，磷酸化的酪氨酸可结合磷酸酶蛋白酪氨酸酶2和蛋白酪氨酸酶1。这样即可阻碍细胞外信号调节激酶的活化，还可阻断磷脂肌醇3-激酶(PI3K)和丝氨酸-苏氨蛋白激酶(Akt)的激活，从而抑制T淋巴细胞增殖和相关细胞因子的分沁。PD-1/PD-L1信号抑制T细胞活化和增殖的同时，还可使细胞因子白细胞介素2、干扰素γ和IL-10的分泌。此外，PD-1/PD-L1信号对B细胞也有类似的免疫功能，当PD-1与B细胞抗原受体结合后，PD-1细胞质区与含有蛋白酪氨酸酶2结合位点的酪氨酸酶发生作用，从而阻碍B细胞的活化。
基于PD-1/PD-L1的免疫疗法是新一代备受关注的免疫疗法。最近几年，一系列令人惊喜的研究结果证实PD-1/PD-L1抑制剂对多种肿瘤具有强大的抗肿瘤活性。目前已经上市的PD-1/PD-L1抗体调节剂有BMS的Ninolumab、Merck的Lambrolizumab以及Roche的Atezolizumab。除此之外还有很多在研的PD-1/PD-L1抗体调节剂，包括Cure Tech的Pidilizumab、GSK的AMP-224和AstraZeneca的MEDI-4736。
虽然肿瘤免疫治疗被认为是靶向治疗后癌症治疗的新一代革命。但是目前上市和在研的PD-1单抗药有其自身的缺陷，包括只能注射给药，不能口服，在体内不稳定，易被蛋白酶分解，易产生免疫交叉反应，纯化比较困难且生产成本高等。所以PD-1/PD-L1相互作用的小分子调节剂是肿瘤免疫治疗的更好选择。
综上所述，本领域迫切需要开发新型PD-1/PD-L1相互作用的小分子调节剂。
发明内容
本发明的目的是提供一种新型PD-1/PD-L1相互作用的小分子调节剂。
本发明的第一方面，一种如下式I所示的化合物，或其光学异构体、水合物、溶剂合物，或其药学上可接受的盐：
Figure PCTCN2020114253-appb-000001
其中，n为0、1、2、3、4或5；
m、p、q和t，v，u各自独立地选自0、1、2、3，4；
X 1、X 2、X 3、X 4、X 5和X 6各自独立地选自下组：N、O、S、SO、SO 2、C(R) 2、CHR、NR；
Y 1、Y 2、Y 3、Y 4、Y 5和Y 6各自独立地选自下组：N、CH、C；
其中，X 3、X 4、X 5、X 7、X 8、X 9的碳原子上的氢(如存在的情况下)均可各自独立的被氘替换；
Figure PCTCN2020114253-appb-000002
各自独立地选自下组：取代或未取代的C6-C10亚芳基、或取代或未取代的具有1-3个杂原子的5-12元(优选5-7元)亚杂芳基、取代或未取代的5-12元亚杂环基、取代或未取代的5-12元的C3-C12(优选为C5-C12)亚环烷基；
Figure PCTCN2020114253-appb-000003
选自下组：取代或未取代的5-12元杂芳基、取代或未取代的C6-C10芳基、取代或未取代的5-12元杂环基、取代或未取代的5-12元的C3-C12(优选为C5-C12)环基，其中，所述的杂环基具有1-3个杂原子；
L 1选自下组：化学键、取代或未取代的C1-C4亚烷基、取代或未取代的C2-C4亚烯基、取代或未取代的C2-C4亚炔基、-S-、-O-、取代或未取代的-NH-、-S(O)-、-S(O) 2-、取代或未取代的-NHC(O)NH-、
Figure PCTCN2020114253-appb-000004
取代或未取代的
Figure PCTCN2020114253-appb-000005
取代或未取代的
Figure PCTCN2020114253-appb-000006
取代或未取代的
Figure PCTCN2020114253-appb-000007
且
Figure PCTCN2020114253-appb-000008
表示单键或双键；
R、R 1、R 2、R 3、R 4和R 5各自独立地选自下组：H、-CN、三氟甲基、-CHF 2、-OCF 3、-OCHF 2、磺酰氨基、硝基、羟基、卤素、-S-R 8、-S(O)-R 8、-S(O) 2-R 8、取代或未取代的C1-C10烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、氧代(即＝O)、＝NR f、-CN、羟基(此处两个取代基建议保留)、NR dR e(例如氨基)、取代或未取代的C1-C6胺基、取代或未取代的-(C1-C6亚烷基)-NH-(C1-C6亚烷基)、羧基、取代或未取代的C6-C10芳基、取 代或未取代的具有1-3个杂原子的5-12元杂芳基、取代或未取代的具有1-4个杂原子的3-12元杂环基，其中，取代或未取代的C1-C10烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、氧代(即＝O)、＝NR f、羟基、NR dR e(例如氨基)、取代或未取代的C1-C6胺基、取代或未取代的-(C1-C6亚烷基)-NH-(C1-C6亚烷基)、羧基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个杂原子的5-12元杂芳基、取代或未取代的具有1-4个杂原子的3-12元杂环基的碳原子上的氢均可各自独立的被氘去掉；取代或未取代的
Figure PCTCN2020114253-appb-000009
取代或未取代的
Figure PCTCN2020114253-appb-000010
取代或未取代的
Figure PCTCN2020114253-appb-000011
Figure PCTCN2020114253-appb-000012
(请修改此处结构式)改动、
Figure PCTCN2020114253-appb-000013
其中，Rb和Rc各自独立地选自下组：H、取代或取代的C 1-C 8烷基；或所述的Rb和Rc与相邻的N原子共同构成取代或未取代的具有1-3个选自N、S和O的杂原子的3-10元杂环基，或所述的Rb和Rc与相邻的N原子共同构成取代或未取代的4-10元环，所述取代基包括但不限于：羟基、羧基、巯基、氨基、F、C，其中，Rb、Rc和Rd的碳原子上的氢均可各自独立地被氘替换；或-(L 1a) r-(L 2a) s-(L 3a) s-；-C 0-8-O-R 8,-C 0-8-C(O)OR 8,-C 0-8-OC(O)OR 8,-C 0-8-NR 8R 9,-C 0-8-N(R 8)C(O)R 9,-C 0-8-C(O)NR 8R 9；
R 8和R 9各自独立地选自下组：H、羟基，取代或未取代的C1-C10烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧、取代或未取代的C3-C8环烷基、氧代(即＝O)、＝NRf、-CN、羟基、NR dR e(例如氨基)、取代或未取代的C1-C6胺基、取代或未取代的-(C1-C6亚烷基)-NH-(C1-C6亚烷基)、羧基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个杂原子的5-12元杂芳基、取代或未取代的具有1-4个杂原子的3-12元杂环基，取代或未取代的
Figure PCTCN2020114253-appb-000014
取代或未取代的
Figure PCTCN2020114253-appb-000015
取代或未取代的
Figure PCTCN2020114253-appb-000016
或-(L 1a) r-(L 2a) s-(L 3a) s-；
各个L 1a各自独立地为选自下组的基团；化学键、取代或未取代的C 1-C 7亚烷基、取代或未取代的C2-C4亚烯基、取代或未取代的C2-C4亚炔基、-S-、-O-、取代或未取代的-NH-、-S(O)-、或-S(O) 2-；
L 2a选自下组：取代或未取代的C6-C12亚芳基、取代或未取代的具有1-3个杂原子的5-12元亚杂芳基、取代或未取代的C3-C8亚环烷基、取代或未取代的具有1-3个杂原子的3-10元亚杂环基；
L 3a选自下组：取代或未取代的C1-C10烷基、C1-C10芳基、-CN、羟基、氨基、羧基、-CO-NH-SO 2-R g、-NH-SO 2-R g、-SO 2-NH-CO-R g、-OR g、-N(R g) 2-CO 2R g、-CON(R g) 2、-CONHCOR g、NR g-CO-N(R g) 2、-NR g-SO 2-N(R g) 2；
r为1、2、3、4、5、6；
s分别为0、1、2；
R d、R e和R g各自独立地选自下组：H、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 6-C 10芳基；或R d和R e共同形成取代或未取代的具有1-3个选自N、S和O的杂原子的4-10(优选为5-10)元杂环基；
所述的R f选自下组：H、取代或未取代的C 1-C 6烷基、取代或未取代的C 6-C 10芳基、取代或未取代的5-10元杂芳基、氰基、-C(＝O)-NR dR e、-C(＝O)-取代或未取代的C 1-C 6烷氧基、-C(＝O)-取代或未取代的C 1-C 6烷基、-C(＝O)-取代或未取代的C 3-C 10环烷基、-C(＝O)-取代或未取代的C 2-C 6烯基、-C(＝O)-取代或未取代的C 2-C 6炔基；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素(包括-F、-Cl、-Br、-I)、-CH 2Cl、-CHCl 2、-CCl 3、-CH 2F、-CHF 2、-CF 3、氧代(＝O)、-CN、羟基、氨基、C1-C6烷胺基、羧基、-NHAc、
Figure PCTCN2020114253-appb-000017
Figure PCTCN2020114253-appb-000018
未取代或被一个或多个取代基取代的选自下组的基团：C1-C6烷基、C1-C6烷氧基、C6-C10芳基、C3-C8环烷基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-10元杂环基；所述的取代基选自下组：卤素、羟基、羧基、氧基、氰基、C1-C6烷氧基、C1-C6烷胺基；
上述各式中，任一所述杂原子选自下组：B、P、N、S和O。
在另一优选例中，当A和L1均为无时，B为选自下组的基团：取代或未取代的C6-C10芳基、或取代或未取代的具有1-3个杂原子的5-12元(优选5-7元)杂芳基、取代或未取代的5-12元杂环基、取代或未取代的5-12元的C3-C12(优选为C5-C12)环烷基。
在另一优选例中，所述的式I化合物具有如下式所示的结构：
Figure PCTCN2020114253-appb-000019
在另一优选例中，本发明提供了一种如下式I所示的化合物，或其光学异构体、水合物、溶剂合物，或其药学上可接受的盐：
Figure PCTCN2020114253-appb-000020
其中，n为0、1、2或3；
m、p、q和t各自独立地选自0、1、2、3或4；
X 1,X 2,X 3,X 4,X 5和X 6各自独立地选自下组：N、O、S、SO、SO 2、C(R) 2、NR；
Y 1,Y 2,Y 3,Y 4,Y 5和Y 6各自独立地选自下组：N、CH、C；
Figure PCTCN2020114253-appb-000021
各自独立地选自下组：取代或未取代的C6-C10亚芳基、或取代或未 取代的具有1-3个杂原子的5-12元(优选5-7元)亚杂芳基、取代或未取代的5-12元亚杂环基、取代或未取代的5-12元的C5-C12亚环烷基；
Figure PCTCN2020114253-appb-000022
选自下组：取代或未取代的5-12元杂芳基、取代或未取代的C6-C10芳基、取代或未取代的5-12元杂环基、取代或未取代的5-12元的C5-C12环基，其中，所述的杂环基具有1-3个杂原子；
L 1选自下组：化学键、取代或未取代的C1-C4亚烷基、取代或未取代的C2-C4亚烯基、取代或未取代的C2-C4亚炔基、-S-、-O-、取代或未取代的-NH-、-S(O)-、-S(O) 2-、取代或未取代的-NHC(O)NH-、
Figure PCTCN2020114253-appb-000023
取代或未取代的
Figure PCTCN2020114253-appb-000024
取代或未取代的
Figure PCTCN2020114253-appb-000025
取代或未取代的
Figure PCTCN2020114253-appb-000026
R、R 1、R 2、R 3、R 4和R 5各自独立地选自下组：H、-CN、三氟甲基、磺酰氨基、硝基、羟基、卤素、-S-R 8、-S(O)-R 8、-S(O) 2-R 8、取代或未取代的C1-C10烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、氧代(即＝O)、＝NRf、-CN、羟基、NRdRe(例如氨基)、取代或未取代的C1-C6胺基、取代或未取代的-(C1-C6亚烷基)-NH-(C1-C6烷基)、羧基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个杂原子的5-12元杂芳基、取代或未取代的具有1-4个杂原子的3-12元杂环基，取代或未取代的
Figure PCTCN2020114253-appb-000027
取代或未取代的
Figure PCTCN2020114253-appb-000028
或-(L 1a) r-(L 2a) s-(L 3a) s-；-C 0-8-O-R 8,-C 0-8-C(O)OR 8,-C 0-8-OC(O)OR 8,-C 0-8-NR 8R 9,-C 0-8-N(R 8)C(O)R 9,-C 0-8-C(O)NR 8R 9；
R 8和R 9各自独立地选自下组：H、羟基，取代或未取代的C1-C10烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、氧代(即＝O)、＝NRf、-CN、羟基、NRdRe(例如氨基)、取代或未取代的C1-C6胺基、取代或未取代的-(C1-C6亚烷基)-NH-(C1-C6亚烷基)、羧基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个杂原子的5-12元杂芳基、取代或未取代的具有1-4个杂原子的3-12元杂环基，取代或未取代的
Figure PCTCN2020114253-appb-000029
取代或未取代的
Figure PCTCN2020114253-appb-000030
或-(L 1a) r-(L 2a) s-(L 3a) s-；
各个L 1a各自独立地为选自下组的基团；化学键、取代或未取代的C 1-C 7亚烷基、取代或未取代的C2-C4亚烯基、取代或未取代的C2-C4亚炔基、-S-、-O-、取代或未取代的-NH-、-S(O)-、或-S(O) 2-；
L 2a选自下组：取代或未取代的C6-C12亚芳基、取代或未取代的具有1-3个杂原子的5-12元亚杂芳基、取代或未取代的C3-C8亚环烷基、取代或未取代的具有1-3个杂原子的5-10元亚杂环基；
L 3a选自下组：取代或未取代的C1-C10烷基、C1-C10芳基、-CN、羟基、氨基、羧 基、-CO-NH-SO 2-R g、-NH-SO 2-R g、-SO 2-NH-CO-R g；
r为1、2、3、4、5、6；
s分别为0、1、2；
Rd、Re和Rg各自独立地选自下组：H、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 6-C 10芳基；或Rd和Re共同形成取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；
所述的Rf选自下组：H、取代或未取代的C 1-C 6烷基、取代或未取代的C 6-C 10芳基、取代或未取代的C 6-C 10杂芳基、氰基、-C(＝O)-NRdRe、-C(＝O)-取代或未取代的C 1-C 6烷氧基、-C(＝O)-取代或未取代的C 1-C 6烷基、-C(＝O)-取代或未取代的C 3-C 10环烷基、-C(＝O)-取代或未取代的C 2-C 6烯基、-C(＝O)-取代或未取代的C 2-C 6炔基；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素：包括但不限于-F、Cl、Br、-CH 2Cl、-CHCl 2、-CCl 3、-CH 2F、-CHF 2、-CF 3、氧代、-CN、羟基、氨基、C1-C6烷胺基、羧基、-NHAc、未取代或被一个或多个选自下组的取代基取代的选自下组的基团：C1-C6烷基、C1-C6烷氧基、C6-C10芳基、C3-C8环烷基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-10元杂环基；所述的取代基选自下组：卤素、羟基、羧基、氰基、C1-C6烷氧基、C1-C6烷胺基；
上述各式中，任一所述杂原子选自下组：B、P、N、S和O。
在另一优选例中，所述的
Figure PCTCN2020114253-appb-000031
各自独立地为选自下组的环形成的二价基团：
Figure PCTCN2020114253-appb-000032
Figure PCTCN2020114253-appb-000033
其中，所述的环的成键位置可以为N或C(环上的取代基未示出)。
在另一优选例中，所述的R 2和R 3各自独立地选自下组：甲基、-F、Cl、Br、-CH 2Cl、-CHCl 2、-CCl 3、-CH 2F、-CHF 2、-CF 3、-CN、羟基、氨基。
在另一优选例中，所述的
Figure PCTCN2020114253-appb-000034
的成键位置可以是o、p、m位
在另一优选例中，所述的
Figure PCTCN2020114253-appb-000035
的在一个成键位置处，一个与N或C相连的H被键所取代。
在另一优选例中，所述的
Figure PCTCN2020114253-appb-000036
为如下所示的结构：
Figure PCTCN2020114253-appb-000037
在另一优选例中，所述的
Figure PCTCN2020114253-appb-000038
具有如下式所示的结构：
Figure PCTCN2020114253-appb-000039
其中，
X 6、X 7、X 8、X 9、X 10和X 11各自独立地选自下组：N、CR；
R 6选自下组：H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、氧代(即＝O)、＝NRf、-CN、羟基、NRdRe(例如氨基)、取代或未取代的C1-C6胺基、取代或未取代的-(C1-C6亚烷基)-NH-(C1-C6亚烷基)、羧基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个杂原子的5-12元杂芳基、取代或未取代的具有1-4个杂原子的5-12元杂环基，取代或未取代的
Figure PCTCN2020114253-appb-000040
取代或未取代的
Figure PCTCN2020114253-appb-000041
取代或未取代的
Figure PCTCN2020114253-appb-000042
或-(L 1a) r-(L 2a) s-(L 3a) s-,-C 0-8-O-R 8,-C 0-8-C(O)OR 8,-C 0-8-OC(O)OR 8,-C 0-8-NR 8R 9,-C 0-8-N(R 8)C(O)R 9,-C 0-8-C(O)NR 8R 9。
在另一优选例中，所述的
Figure PCTCN2020114253-appb-000043
具有如下式所示的结构：
Figure PCTCN2020114253-appb-000044
Figure PCTCN2020114253-appb-000045
Figure PCTCN2020114253-appb-000046
其中，所述的环的成键位置可以为N或C(环上的取代基未示出)。
在另一优选例中，所述的R 6为R 1；或为
Figure PCTCN2020114253-appb-000047
其中，Rb和Rc各自独立地选自下组：H、取代或未取代的C 1-C 8烷基；或所述的Rb和Rc与相邻的N原子共同构成取代或未取代的具有1-3个选自N、S和O的杂原子的3-10元杂环基。
在另一优选例中，所述的环
Figure PCTCN2020114253-appb-000048
具有如下式IV所示的取代基：
Figure PCTCN2020114253-appb-000049
其中，w为0,1,2,3,4,5,6；
所述的各个L 4独立地选自下组：取代或未取代的C1-C4亚烷基、-S-、-O-、NR f、-S(O)-、-S(O) 2-；优选为取代或未取代的C1-C4亚烷基，其中，取代或未取代的C1-C4亚烷基上碳原子上的氢均可各自独立地被氘替换；前提条件是各个L 4共同形成的结构是化学稳定的；
Figure PCTCN2020114253-appb-000050
选自下组：取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自B、P、N、S和O的杂原子的3-10元杂环基；优选地，所述的
Figure PCTCN2020114253-appb-000051
为或取代或未取代的 3-8元含氮杂环基，或取代或未取代的4-10元环酰胺，其中，3-8元含氮杂环基取代或未取代的4-10元环酰胺基的成环碳原子上的氢均可各自独立被氘替换；
各个R 7各自独立地选自下组：取代或未取代的C1-C6烷基、-CN、羟基、氨基、羧基、-OR g、-N(R g) 2、-CO-NH-SO 2-R g、-NH-SO 2-R g、-SO 2-NH-CO-R g、-CO 2R g、-CON(R g) 2、CONHCOR g、NR g-CO-N(R g) 2、-NR g-SO 2-N(R g) 2；R f和R g的定义如前所述，其中Rf和Rg的碳原子上的氢均可各自独立地被氘替换，其中，所述的取代基选自下组：卤素、羟基、羧基、氰基、C1-C6烷氧基。
在另一优选例中，至少一个R 4为选自下组的基团：NRdRe；所述的Rd和Re各自独立地选自下组：H、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 10环烷基、-C 0-8-O-R 8、-C 0-8-C(O)OR 8、-C 0-8-OC(O)OR 8、-C 0-8-NR 8R 9、-C 0-8-N(R 8)C(O)R 9、-C 0-8-C(O)NR 8R 9、取代或未取代的C 6-C 10芳基；或Rd和Re共同形成取代或未取代的3-10元环烷基，或具有1-3个选自N、S和O的取代或未取代的杂原子的3-10元杂环基。在另一优选例中，此处所述的取代基为羧基、羟基、
Figure PCTCN2020114253-appb-000052
R 10为取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 10环烷基，优选地，R 10为甲基、异丙基、环丙基和1-甲基环丙基，其中Rd、Re和R 10的碳原子上的氢均可各自独立被氘替换。
在另一优选例中，所述的环
Figure PCTCN2020114253-appb-000053
具有如下式IV所示的取代基：
Figure PCTCN2020114253-appb-000054
其中，所述的各个L 4独立地选自下组：取代或未取代的C1-C4亚烷基、-S-、-O-、-NRa-、-NR f、-S(O)-、-S(O) 2-；优选为取代或未取代的C1-C4亚烷基，前提条件是各个L 4共同形成的结构是化学稳定的；
Figure PCTCN2020114253-appb-000055
选自下组：取代或未取代的C5-C10环烷基、取代或未取代的具有1-3个选自B、P、N、S和O的杂原子的3-10元杂环基；优选地，所述的
Figure PCTCN2020114253-appb-000056
为3-8元含氮杂环基；
各个R 7各自独立地选自下组：取代或未取代的C1-C6烷基、-CN、羟基、氨基、羧基、-OR g、-N(R g) 2、-CO-NH-SO 2-R g、-NH-SO 2-R g、-SO 2-NH-CO-R g、-CO 2R g、-CON(R g) 2、CONHCOR g、NR g-CO-N(R g) 2、-NR g-SO 2-N(R g) 2；其中，所述的取代基选自下组：卤素、羟基、羧基、氰基、C1-C6烷氧基。
在另一优选例中，至少一个R 4为选自下组的基团：NRdRe；所述的Rd和Re各自独立地选自下组：H、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 10环烷基、-C 0-8-O-R 8、-C 0-8-C(O)OR 8、-C 0-8-OC(O)OR 8、-C 0-8-NR 8R 9、-C 0-8-N(R 8)C(O)R 9、-C 0-8-C(O)NR 8R 9、取代或未取代的C 6-C 10芳基；或Rd和Re共同形成取代或未取代的3-10元环烷基，或具有1-3个选自N、S和O的取代或未取代的杂原子的3-10元杂环基。在另一优选例中，此处所述的取代基为羧基、羟基、
Figure PCTCN2020114253-appb-000057
R 10为取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 10环烷基，优选地，R 10为甲基、异丙基、环丙基和 1-甲基环丙基，其中Rd、Re和R 10的碳原子上的氢均可各自独立被氘替换。
在另一优选例中，所述的式I化合物具有如下式所示的结构：
Figure PCTCN2020114253-appb-000058
在另一优选例中，至少一个所述的R 4选自下组：NRdRe；所述的Rd和Re各自独立地选自下组：H、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 10环烷基、-C 0-8-O-R 8,-C 0-8-C(O)OR 8,-C 0-8-OC(O)OR 8,-C 0-8-NR 8R 9,-C 0-8-N(R 8)C(O)R 9,-C 0-8-C(O)NR 8R 9、取代或未取代的C 6-C 10芳基；或Rd和Re共同形成取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；优选地，所述的取代基为羧基。
在另一优选例中，所述的
Figure PCTCN2020114253-appb-000059
为选自下组的结构：
Figure PCTCN2020114253-appb-000060
在另一优选例中，所述的化合物选自下列化合物；
Figure PCTCN2020114253-appb-000061
Figure PCTCN2020114253-appb-000062
Figure PCTCN2020114253-appb-000063
Figure PCTCN2020114253-appb-000064
Figure PCTCN2020114253-appb-000065
Figure PCTCN2020114253-appb-000066
Figure PCTCN2020114253-appb-000067
Figure PCTCN2020114253-appb-000068
Figure PCTCN2020114253-appb-000069
Figure PCTCN2020114253-appb-000070
Figure PCTCN2020114253-appb-000071
Figure PCTCN2020114253-appb-000072
Figure PCTCN2020114253-appb-000073
Figure PCTCN2020114253-appb-000074
Figure PCTCN2020114253-appb-000075
Figure PCTCN2020114253-appb-000076
Figure PCTCN2020114253-appb-000077
Figure PCTCN2020114253-appb-000078
Figure PCTCN2020114253-appb-000079
Figure PCTCN2020114253-appb-000080
Figure PCTCN2020114253-appb-000081
Figure PCTCN2020114253-appb-000082
Figure PCTCN2020114253-appb-000083
Figure PCTCN2020114253-appb-000084
Figure PCTCN2020114253-appb-000085
Figure PCTCN2020114253-appb-000086
本发明的第二方面，提供了一种如本发明第一方面所述的式I化合物的制备方法，其特征在于，所述的方法包括选自合成方案1，2或3所示的步骤：
合成方案1：
Figure PCTCN2020114253-appb-000087
(a)以中间体II和III为原料，通过钯催化剂催化的Sonogashira偶联反应得到目标产物I-1；
优选地，中间体II-2的制备方法如下：
Figure PCTCN2020114253-appb-000088
(a)以II-1为原料，在路易斯酸催化下，发生卤代反应，得到中间体II-2；
优选地，中间体III的制备方法如下：
Figure PCTCN2020114253-appb-000089
(a)以化合物III-1和III-2为原料，在钯催化剂和配体的条件下，发生偶联反应(如Suzuki,Buchwald等)，得到中间体III-3；
(b)以III-3为原料，使用合适的试剂，移除硅基保护基，得到中间体III；
合成方案2：
Figure PCTCN2020114253-appb-000090
(a)以化合物II-1为原料，与硝化剂反应(如浓硫酸/NaNO 3，浓硫酸/发烟硝酸等)，形成中间体IV-1；
(b)以IV-1为原料，在还原条件下(Pd-C/H 2；锌粉/氯化铵；铁粉/醋酸等)，发生还原反应，形成中间体IV-2；
(c)以IV-2和IV-3为原料，在碱性条件下，发生亲和取代反应得到酰胺中间体；而后在合适的脱水试剂(如PPh 3/DDQ)，发生环化反应，得到中间体IV-4；
(d)以IV-4和IV-5为原料，在催化剂和配体的条件下，发生偶联反应，形成中间体I-2；
合成方案3：
Figure PCTCN2020114253-appb-000091
(a)以V-1和V-2为原料，在催化剂和配体的条件下，发生偶联反应，形成中间体V-3；
(d)以IV-4和合适的硼源(如B 2Pin 2)为原料，在催化剂和配体的条件下，发生偶联反应，形成中间体V-4；
(d)以V-4和IV-4为原料，在催化剂和配体的条件下，发生偶联反应，形成目标产物I-3；
上述X 1–X 12、R 1–R 9、t、m、n的定义如前所述。
本发明的第三方面，提供了一种药物组合物，包含(1)如本发明第一方面所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物；(2)药学上 可接受的载体。
本发明的第四方面，提供了一种如本发明第以方面所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物或如本发明第三方面所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗与PD-1/PD-L1的活性或表达量相关的疾病(HBV、HCV、实体瘤、血液瘤等)的药物组合物。
本发明的第五方面，提供了一种PD-1/PD-L1调节剂，所述调节剂包含本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
在另一优选例中，所述的药物组合物被用于治疗选自下组的疾病：癌症、感染性疾病、自身免疫性疾病。
在另一优选例中，所述的癌症选自下组：胰腺癌，膀胱癌，结肠直肠癌，乳腺癌，前列腺癌，肾癌，肝细胞癌，肺癌，卵巢癌，宫颈癌，胃癌，食道癌，黑色素瘤，神经内分泌癌，中枢神经系统癌，脑癌，骨癌，软组织肉瘤，非小细胞肺癌癌症，小细胞肺癌或结肠癌、皮肤癌、肺癌、泌尿系肿瘤、血液肿瘤、胶质瘤、消化系统肿瘤、生殖系统肿瘤、淋巴瘤、神经系统肿瘤、脑瘤、头颈癌。
在另一优选例中，所述癌症选自下组：急性淋巴细胞白血病(ALL)，急性髓性白血病(AML)，慢性淋巴细胞白血病(CLL)，小淋巴细胞性淋巴瘤(SLL)，骨髓增生异常综合征(MDS)，骨髓增生性疾病(MPD)，慢性粒细胞白血病(CML)，多发性骨髓瘤(MM)，非霍奇金淋巴瘤(NHL)，套细胞淋巴瘤(MCL)，滤泡性淋巴瘤，Waldestrom巨球蛋白血症(WM)，T细胞淋巴瘤，B细胞淋巴瘤或弥漫性大B细胞淋巴瘤(DLBCL)。
在另一优选例中，所述的感染性疾病选自细菌感染、病毒感染。
在另一优选例中，所述的自身免疫性疾病选自器官特异性自身免疫病、系统性自身免疫病。
在另一优选例中，所述的器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合症、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎。
在另一优选例中，所述的系统性自身免疫病包括类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血。
在另一优选例中，所述的药物组合物还用于改善慢性乙型肝炎(CHB)患者T细胞功能。
在另一优选例中，所述的抑制剂还包括至少一种选自下组的治疗剂：纳武单抗，派姆单抗，atezolizumab，或伊匹单抗。
本发明的第六方面，提供了一种体内调节PD-1/PD-L1相互作用的方法，其特征在于，包括步骤：将本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物与PD-L1蛋白接触。
具体实施方式
本发明人经过广泛而深入的研究，发现了一类具有优异的调节效果的PD-1/PD-L1相互作用调节剂。在此基础上，发明人完成了本发明。
定义
如本文所用，术语“烷基”包括直链或支链的烷基。例如C 1-C 8烷基表示具有1-8个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用，术语“烯基”包括直链或支链的烯基。例如C 2-C 6烯基指具有2-6个碳原子的直链或支链的烯基，例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用，术语“炔基”包括直链或支链的炔基。例如C 2-C 6炔基是指具有2-6个碳原子的直链或支链的炔基，例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用，术语“C 3-C 10环烷基”指具有3-10个碳原子的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环或螺环形式。
如本文所用，术语“C 1-C 8烷胺基”是指被C 1-C 8烷基所取代的胺基，可以是单取代或双取代的；例如，甲胺基、乙胺基、丙胺基、异丙胺基、丁胺基、异丁胺基、叔丁胺基、二甲胺基、二乙胺基、二丙胺基、二异丙胺基、二丁胺基、二异丁胺基、二叔丁胺基等。
如本文所用，术语“C 1-C 8烷氧基”是指具有1-8个碳原子的直链或支链的烷氧基；例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基”是指具有3-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环，也可以是双环形式，例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用，术语“C 6-C 10芳基”是指具有6-10个碳原子的芳基，例如，苯基或萘基等类似基团。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
本发明所述的基团除非特别说明是“取代的或未取代的”，否则本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C 1-C 6烷基-胺基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 2-C 6烯基、卤代C 2-C 6炔基、卤代C 1-C 6烷氧基、烯丙基、苄基、C 6-C 12芳基、C 1-C 6烷氧基-C 1-C 6烷基、C 1-C 6烷氧基-羰基、苯氧羰基、C 2-C 6炔基-羰基、C 2-C 6烯基-羰基、C 3-C 6环烷基-羰基、C 1-C 6烷基-磺酰基等。
如本文所用，“卤素”或“卤原子”指F、Cl、Br、和I。更佳地，卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构 体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
除非特别说明，本发明所描述的结构式意在包括所有可能的氘代衍生物(即，分子中的一个或多个氢原子被D取代)。
如本文所用，术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用，术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
如本文所用，术语“水合物”是指本发明化合物与水进行配位形成的配合物。
活性成分
如本文所用，“本发明化合物”指式I所示的化合物，并且还包括及式I化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
优选的本发明化合物包括化合物1-360(包括各化合物的各类R构型和/或S构型的立体异构体，和/或E-/Z-的顺反异构体)。
在另一优选例中，所述的药用盐包括与无机酸、有机酸、碱金属离子、碱土金属离子或能提供生理上可接受的阳离子的有机碱结合形成的盐以及铵盐。
在另一优选例中，所述的无机酸选自盐酸、氢溴酸、磷酸或硫酸；所述的有机酸选自甲磺酸、对甲苯磺酸、三氟乙酸、枸杞酸、马来酸酒石酸、富马酸、柠檬酸或乳酸；所述的碱金属离子选自锂离子、钠离子、钾离子；所述的碱土金属离子选自钙离子、镁离子；所述的能提供生理上可接受的阳离子的有机碱选自甲胺、二甲胺、三甲胺、哌啶、吗啉或三(2-羟乙基)胺。
在本发明范围内的所有这些盐都可采用常规方法制备。在所述的通式I化合物及其溶剂化物和其盐的制备过程中，不同的结晶条件可能出现多晶或共晶。
本发明制备方法中的起始原料及中间体容易得到，各步反应可依据已报道的文献或对本领域熟练技术人员来说可以用有机合成中的常规方法很容易合成。通式I所述化合物可以溶剂化物或非溶剂化物的形式存在，利用不同的溶剂进行结晶可能得到不同的溶剂化物。
药物组合物和施用方法
由于本发明化合物具有优异的PD-1/PD-L1相互作用的调节活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)PD-1/PD-L1相互作用相关疾病(例如，癌症、感染性疾病、自身免疫性疾病)。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们 适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2020114253-appb-000092
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物(例如其他抗癌制剂)联合给药。
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的化合物。该其他药学上可接受的化合物中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗PD-1/PD-L1相互作 用相关疾病。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
(1)本发明化合物对PD-1/PD-L1相互作用具有很高的调节活性，与PD-L1蛋白具有很强的结合能力，并具有解除PD-L1抑制IFNγ的能力。
(2)本发明的化合物具有更好的溶解性较好；对正常细胞的毒性非常低，因而可以在较大的剂量范围内应用于治疗对象。
(3)相较于现有技术的化合物，本发明的化合物具有更好的溶解性，因此具有良好的成药性，相较于现有化合物而言，本发明化合物在体内实验之中表现出良好的生物利用度，除此之外，相较于现有化合物，本发明的化合物极易制成药学上可接受的盐，因而有助于进一步形成制剂。
(4)体内药效研究表明，本发明化合物无论从肿瘤体积还是重量上，都可显著的抑制皮下肿瘤的生长，并可明显增加小鼠血液中、脾脏中各淋巴细胞数量。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
通用材料及测试方法：
实施例中涉及到的仪器及原料说明如下:
核磁共振氢谱是Bruker AV-400(400MHz)核磁仪分析得到。
化学位移以四甲基硅烷为内标来记录，以ppm为单位来表示(CDC1 3:δ7.26ppm)。记录的数据信息如下:化学位移及其裂分和偶合常数(s:单重峰；d:双重峰；t：三重峰；q：四重峰；br：宽峰；m：多重峰)。
质谱数据除其他需要，都采用菲尼根高级LCQ公司(Finnigan LCQ Advantage)的液质联用仪进行分析，所有反应都在干燥氩气保护的无水无氧条件下进行操作。固体金属有机化合物在氩气保护干燥箱中进行储藏。
四氢呋喃和乙醚是经过蒸馏得到，蒸馏时在其中加入金属钠和二苯甲酮。二氯甲烷，戊烷和己烷是用氢化钙来处理。
本发明中涉及的特殊原料和中间体由天津长森药业有限公司等订制加工提供，其他所有化学试剂从上海化学试剂公司、阿尔得里奇公司(Aldrich)、阿克罗公司(Acros)等试剂供应商购买。如合成过程中反应所需的中间体或产物不够下一步试验，则重复多次合成至足够数量为止。
本发明所涉及的原料和试剂除特殊说明外均可市售或订制加工购买得到。
本发明中化合物可含有一个或多个不对称中心，因此该系列化合物可为消旋或者单一对映体形式。本发明所制备的化合物是纯度高于95％的杂环化合物，每个最终产物的结构表征分别由MS或/和氢谱核磁共振( 1H NMR)分析确定。以下通过实施例说明本发明各类化合物和中间体的合成。
实施例1化合物001的合成
步骤1-1：
Figure PCTCN2020114253-appb-000093
1.3克1-1溶于DCM-3M H 2SO 4(1:1)200ML中，冰浴，5度下0.71g硝酸钠加入到反应体系中，氮气保护,室温反应过夜。TLC点板显示1-1消失，LCMS分析得知产物生成。柱层析纯化得产物1-2 600mg，MS-APCI:208[M+H] +and 1-3 300mg，MS-APCI:208[M+H] +.
步骤1-2：
Figure PCTCN2020114253-appb-000094
将4.5克化合物1-2溶于200毫升DCM(于500毫升单口烧瓶中)，加入6.3克NIS，氩气保护。室温反应过夜。TLC点板1-2反应完全。反应液加2M HCl 100mL，分液，干燥。旋干过柱(Hep-DCM 1：1，then DCM)纯化得到6g产物，淡黄色固体。MS-APCI:334[M+H] +.
步骤1-3：
Figure PCTCN2020114253-appb-000095
在50毫升三口瓶中加入945毫克化合物1-4,636毫克化合物1-5,25毫克CuI和25毫克Pd(PPh 3) 2Cl 2，氩气保护，加入20毫升DMF和1.2毫升DIPEA，55℃反应3小时。TLC点板原料消失。反应液加入到300毫升冰水中，乙酸乙酯300毫升萃取两次，2M NaOH洗涤一次，干燥旋干。过柱(DCM-MeOH 10:1)纯化，得到220mg浅黄色固体。MS-APCI:654[M+H] +.
步骤1-4：
Figure PCTCN2020114253-appb-000096
将215毫克化合物1-6,248毫克methyl azetidine-3-carboxylate hydrochloride,125毫克Na(CN)BH 3溶于10毫升THF中，氩气保护，加入167毫克三乙胺，70℃反应24小时。反应液加入到100毫升冰水中，EA 100毫升萃取两次，干燥。过柱(DCM-MeOH 100,50:1,10:1,5:1)纯化，得到53mg浅黄色固体1-7，MS-APCI:753[M+H] +.
步骤1-5：
Figure PCTCN2020114253-appb-000097
将53毫克原料1-7溶于5毫升MeOH，加入2毫升2M NaOH，26度反应5小时。反应液40度旋干，残留固体加入50毫升水，2M HCl调节PH值为7，虑出固体，水洗，THF洗，干燥，进一步制备纯化得黄色固体5毫克。MS-APCI:739[M+H] +
1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),9.00(s,1H),8.46(s,1H),8.34(d,J＝8.0Hz,1H),8.08(d,J＝8.0Hz,1H),7.77(d,J＝8.0Hz,1H),7.44(t,J＝8.0Hz,1H),7.35–7.25(m,3H),7.19(d,J＝8.0Hz,1H),6.91(d,J＝8.0Hz,1H),6.52(m,1H),4.75(brs,1H),4.20(brs,1H),3.84-3.74(m,2H),3.37-2.83(m,3H),2.66-2.28(m,2H),2.21(s,3H),2.18-2.06(m,1H),2.06(s,3H),1.96-1.58(m,5H)，1.43(m,1H).
步骤1-6：
Figure PCTCN2020114253-appb-000098
取氨基原料1-9(30克)溶于乙腈-Water(1:1)400毫升中，氮气保护，体系清澈，冰浴，在内温0～5度下加入对甲苯磺酸水合物(901克)，搅拌10分钟，体系呈粉色浑浊，内温0～5度下滴加NaNO 2水溶液(22克，45毫升)。反应30分钟，体系清澈；避光，0～5度下滴加碘化钾水溶液(67克，60毫升)，自然升至室温下反应；TLC跟踪；后处理：冰浴下加入饱和亚硫酸钠淬灭，HEP萃取，饱和食盐水洗1次，拌样，过柱：HEP冲下产品，浓缩得黄棕色液体46.9克，收率：98.1％。MS-APCI:296[M+H] +.
步骤1-7：
Figure PCTCN2020114253-appb-000099
取碘原料1-10(1克)，CuI(0.03克),Pd(Ph 3P) 2Cl 2(0.12克)加入50毫升反应瓶中，氮气置换3次，加入无水DMF(20毫升)，体系呈红褐色清澈；加入三乙胺(1.7克)，体系呈棕黄色清澈；氮气置换3次，避光，加入炔原料1-11(0.52克)，室温下反应；TLC跟踪；后处理：冰浴下加入饱和氯化铵淬灭，MTBE萃取2次，饱和食盐水洗5次，拌样，过柱：HEP冲下产品，浓缩得黄棕色液体1.03克，收率：95％。MS-APCI:309[M+H] +.
步骤1-8：
Figure PCTCN2020114253-appb-000100
取溴原料1-12(1.1克)，硼酸酯原料1-14(1g,WO2018119286),Pd(dppf)Cl 2(0.12克)和碳酸钠(0.62克)加入50毫升反应瓶中，氮气置换3次，加入1,4-二氧六环(8毫升)和水2毫升，90度下反应；TLC跟踪；后处理：冰浴下加入饱和氯化铵淬灭，MTBE萃取2次，饱和食盐水洗5次，拌样，过柱：(HEP-DCM 100,50:1,10:1,5:1)冲下产品，浓缩得黄色固体0.5克，收率：41％。MS-APCI:563[M+H] +
步骤1-10：
Figure PCTCN2020114253-appb-000101
炔原料1-15(1.1克)加入到THF(15毫升)中，氮气置换3次，加入1M TBAF 1毫升，室温下反应；TLC跟踪；后处理：旋干THF，加入水5毫升，乙酸乙酯萃取2次，饱和食盐水洗2次，拌样，过柱：(DCM-MeOH 100,50:1,10:1,5:1)冲下产品，浓缩得黄色固体1.0克，收率：83％。MS-APCI:449[M+H] +.
实施例2化合物002的合成
Figure PCTCN2020114253-appb-000102
步骤2-1：
取1-1(1.1g)，碳酸氢钠(0.57g)加入100mL三口瓶，加入甲醇(25mL)和水(5mL)溶解，冰浴降温至5℃。缓慢加入NIS(1.52g)，全部加入后自然升温，过夜反应。TLC检测原料反应完全。旋干甲醇，加入1M盐酸调节至pH<3，大量白色固体析出。过滤，滤饼固体加入到0.5M盐酸(100mL)中搅拌30分钟，再次过滤,所得滤饼固体用EA溶解，柱层析，得淡黄/白色固体产物,0.7g.MS-APCI:289[M+H] +
步骤2-2：
100mL两口瓶中，将2-1(1.5g)溶于DMF(20mL)，加入Zn(CN) 2(1.3g)，Pd(PPh 3) 4(1.2g)，N 2保护，105度反应1h，TLC点板原料反应完全。冷却后反应液加EA/HEP稀释，过滤。滤液饱和NaCl洗，EA萃取。过柱纯化，得到纯品0.9g，黄色固体。MS-APCI:188[M+H] +
步骤2-3：
25mL两口瓶中，将2-2(1.5g)悬浮于DCM(20mL)中，室温下加入NIS(2.0g)，反应10分钟，TLC点板原料消失。反应液加饱和NaHCO 3，水相调pH＝2,DCM萃取3次，DCM层用10％Na 2S 2O 3洗，干燥，旋干得到1.9g产物，棕色固体。MS-APCI:314[M+H] +
步骤2-4：
15mL反应管中，将2-3(1.6g),2-4(1.3g,WO2018195321)，Pd(PPh 3) 2Cl 2(350mg)，CuI(50mg)，DIPEA(3g,6.5mmol)溶于DMF(8mL)，N2保护，85度反应2h。TLC检测原料消失。反应完全后，往反应液加水/DCM萃取。干燥，旋干。剩余物用EA/HEP(20mL,1:1)打浆。所得固体过柱纯化，纯DCM洗脱，得到800mg产物，黄色固体。MS-APCI:355[M+H] +
步骤2-5：
15mL反应管中，将2-5(150mg),1-7(135mg)，NaBH 3CN(39mg)，TEA(83mg)加入到THF(5mL)中，70度反应5h。TLC检测1-6消失。反应液旋干，加水EA萃取。干燥EA，旋干，过柱纯化,得到纯品1-8(120mg),黄色固体。MS-APCI:454[M+H] +
步骤2-6：
将化合物2-6(100mg),1-14(100mg，WO2018119286)，Pd(dppf)Cl 2/DCM(16.7mg),Na 2CO 3(57.2mg)置于反应瓶，N 2脱气保护,3mL dioxane/0.6mL水注入反应瓶中，90度反应1小时。TLC点板反应完成。反应液加2mL水，EA萃取。干燥EA，旋干，过柱纯化，得到产物80mg,黄色固体。MS-APCI:733[M+H] +
步骤2-7：
将2-7(80mg)溶于2mL THF，加入2mL水，加热LiOH(7.8mg),室温反应1h。TLC检测反应完成。反应液40度旋干，加2M HCl调节PH值为7，虑出固体，水洗，干燥，进一步制备纯化得黄色固体50mg。MS-APCI:719[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.84(d,J＝2.0Hz,1H),8.43(d,J＝8.1Hz,1H),8.16(d,J＝1.9Hz,1H),8.04(d,J＝5.8Hz,1H),7.84(s,1H),7.81(dd,J＝7.9,1.3Hz,1H),7.46(t,J＝7.7Hz,1H),7.32(t,J＝7.9Hz,1H),7.29(d,J＝1.3Hz,1H),7.26(dd,J＝7.6,1.3Hz,1H),7.16(d,J＝5.8Hz,1H),6.90(d,J＝7.5Hz,1H),4.69(s,1H),4.20(s,1H),3.88–3.71(m,2H),3.50–3.39(m,11H),3.19–2.79(m,3H),2.76–2.58(m,2H),2.40–2.28(m,1H),2.22(s,3H),2.08(s,3H),2.00(dq,J＝14.1,7.4Hz,1H),1.87(d,J＝12.8Hz,1H),1.71(s,1H),1.57(t,J＝13.0Hz,2H).
实施例3化合物003的合成
Figure PCTCN2020114253-appb-000103
步骤3-1：
将化合物3-1(40g,230.7mmol),3-2(58.5g,230.7mmol,WO2012031004)，Pd(dppf)Cl 2/DCM(10.2g,0.05eq)，Na 2CO 3(53g,2eq)依次加入到dioxane/H 2O(300mL,5:1)中，脱气3次，N 2保护，80度反应1小时，TLC显示反应完成。反应液过滤，滤液旋干。加EA溶解，往EA中加入500mL饱和食盐水。分液。干燥EA层，旋干。所得固体用EA/HEP(200mL,1:3)打浆，过滤，得到40g黄色固体。
步骤3-2：
3-3(66g,249mmol)溶于500mL THF，冷至0度，滴加甲醇钠溶液(50mL,5N in MeOH)。滴完后0度反应30分钟。0度下，往反应液中滴加4N HCl/MeOH至pH＝7。旋走THF。剩余物用1L DCM溶解，加入2L水洗，分液。干燥DCM层。旋干。所得固体用EA/HEP(200mL,1:3)打浆，过滤，得到60g黄色固体。
步骤3-3：
3L反应瓶，机械搅拌，CuBr(45.4g,316.5mmol)加入到HBr(500mL)中，冷至0度备用。而后将化合物3-4(55g,211mmol)悬浮在HBr(500mL)中，冷至0度，滴加NaNO 2(17.5g,253mmol)(溶于50mL水中)水溶液。产生棕色烟雾。滴加完后，搅拌30分钟。将化合物3-4的HBr溶液一次性倒入到CuBr的HBr溶液中，反应液黑色，产生大量气泡。继续搅拌1h后，TLC监控SM1消失，产物点生成。反应液中加入2L水，再加入2L EtOAc，搅拌，固体溶解，分液。EA层干燥，旋干，过柱纯化(EA:DCM:HEP＝1:1:4)，得到产物45g，黄色固体。
步骤3-4：
化合物3-5(15g)悬浮于HCl/MeOH(250mL,4N)中(闷罐反应瓶)，60度加热反应过夜。反应液变澄清。TLC检测5反应完全。反应液冷至室温后，黄色固体析出。将反应液旋干，剩余固体中加入饱和碳酸氢钠(300mL)，加EA(200mL x 3)萃取。干燥EA层，旋干。所得固体用EA/HEP(240mL,1:5)打浆。过滤，滤饼固体旋干，得到产物12g，黄色固体。
步骤3-5：
化合物3-6(31g,86.7mmol)溶于无水THF(300mL)，冷至0度，分批加入LiBH 4(2.1g,95.4mmol)，0度下反应1h。TLC检测反应完成。反应液过滤。滤饼用DCM冲洗。滤液旋干。所得固体中加300mL水,EA(200mL X 3)萃取。干燥EA层，旋干，所得固体用EA/HEP(240mL,1:5)打浆。过滤，滤饼固体旋干，得到产物24g，黄色固体。
步骤3-6：
将化合物3-7(32g,97.5mmol)溶于dioxane(500mL)，加入MnO 2(51g,585.4mmol)，N 2脱气保护，95度下反应5h。TLC检测反应完成。反应液过滤，滤液旋干。所得固体用EA/HEP(180mL,1:5)打浆。过滤，滤饼固体旋干，得到产物24g，黄色固体。
步骤3-7：
将化合物3-8(22g,67.5mmol),R-3-羟基吡咯烷盐酸盐(16.6g,135mmol)，TEA(20.5g,202.5mmol)加入到DCM(300mL)中，室温反应1小时后加入NaBH(OAc) 3(21.5g,101.25mmol)，继续反应1小时。TLC检测反应完成。后处理：反应液加水(300mL),分液，DCM层用饱和食盐水洗。分液，干燥DCM，旋干，过柱纯化(DCM:MeOH＝40:1),得到15.3g产品，棕色油状物。
步骤3-8：
化合物3-9(2.0g,5mmol),Bpin2(6.37g,25.1mmol),Pd(PPh 3) 2Cl 2(352mg,0.5mmol),KOAc(984.6mg,10mmol)加入到dioxane(40mL)中,脱气3次，N2保护，90度反应过夜。反应完全后，过滤。滤液旋干。加30mL DCM溶解后加入50g硅胶拌样。过硅胶柱纯化，洗脱梯度：EA＝100％(500mL),EA:MeOH＝40:1(2050mL)。得到产物900mg棕色油状物。
步骤3-9：
将原料3-11(51g,0.34mol)溶于500ml甲醇中，加入300ml水，加入碳酸氢钠(28.9g,0.34mmol),0℃左右加入NIS的甲醇溶液，加完反应过夜。后处理：浓缩干加入500ml水，3M盐酸调节PH至3，滤出固体，乙酸乙酯/乙醇打浆，滤出干燥得灰色固体146g。
步骤3-10：
将原料3-12(61g,230mmol)、ZnCN2(27g,230mmol),Pd(PPh3)4(12.8g,11mmol)，混合于1000mL三口瓶中，加入1000mL DMF，N2置换3次，90℃下搅拌3h。TLC点板显示原料少量剩余，LCMS显示原料反应完全。
步骤3-11：
25mL两口瓶中，将3-13(15g)悬浮于DCM(20mL)中，室温下加入NIS(20g)，反应10分钟，TLC点板原料消失。反应液加饱和NaHCO 3，水相调pH＝2,DCM萃取3次，DCM层用10％Na 2S 2O 3洗，干燥，旋干得到19g产物，棕色固体。
步骤3-12：
15mL反应管中，将3-14(16g),2-4(1.3g,WO2018195321)，Pd(PPh 3) 2Cl 2(3.5g)，CuI(500mg)，DIPEA(30g,65mmol)溶于DMF(100mL)，N2保护，85度反应2h。TLC检测原料消失。反应完全后，往反应液加水/DCM萃取。干燥，旋干。剩余物用EA/HEP(20mL,1:1)打浆。所得固体过柱纯化，纯DCM洗脱，得到8g黄色固体。
步骤3-13：
15mL反应管中，将3-15(150mg),3-16(135mg)，NaBH 3CN(39mg)，TEA(83mg)加入到THF(5mL)中，70度反应5h。TLC检测1-6消失。反应液旋干，加水EA萃取。干燥EA，旋干，过柱纯化,得到100mg黄色固体。
步骤3-14：
以化合物3-17(200mg)和3-10(180mg)为原料，按照步骤2-6的合成方法，得到产物120mg黄色固体
步骤3-15：
以化合物3-18(120mg)为原料，按照步骤2-7的合成方法，得到产物40mg黄色固体。MS(APCI):684. 1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),7.87(d,J＝3.9Hz,1H),7.80(d,J＝8.0Hz,1H),7.50(d,J＝7.6Hz,1H),7.45(t,J＝7.6Hz,1H),7.40(t,J＝7.7Hz,1H),7.31(s,1H),7.27(d,J＝7.6Hz,1H),7.24(d,J＝7.4Hz,1H),5.29(t,J＝5.0Hz,1H),4.65(d,J＝4.6Hz,1H),4.29(d,J＝7.0Hz,1H),4.15(s,1H),3.99(q,J＝7.1Hz,2H),3.92(s,3H),3.71(d,J＝4.3Hz,2H),2.79(t,J＝6.8Hz,1H),2.68–2.60(m,4H),2.40(dd,J＝9.7,4.0Hz,1H),2.30(q,J＝1.9Hz,2H),2.21(s,3H),2.04(s,3H),1.96(d,J＝7.0Hz,2H).
实施例4化合物004的合成
Figure PCTCN2020114253-appb-000104
步骤4-1：
于250ml单口瓶中加入醋酸酐(75ml)，浓硝酸(5ml)，分批加入原料3-13(5.0g,28.9mmol)，水浴下搅拌，20min后，有沉淀形成，TLC点板监测，反应完毕，滤出沉淀，抽干，打浆，拉干得白色固体4.5g。
步骤4-2：
于500ml单口瓶中加入THF(200ml)，原料4-1(5.0g，23mmol)和TFA(0.2mL)，Pt/C,H2置换3次，在室温下搅拌，反应1小时后，TLC点板监测，原料反应完毕，滤出Pt/C,滤液直接用于下一步。
步骤4-3：
上述滤液4-2(10.0g,45.8mmol)的THF溶液中加入180mmol Et3N,将3-6(10.74g,46mmol,Organic Letters,2019,21,5971-5976)用15ml DCM溶解，缓慢加入其中，室温下反应1hour，出现大量浑浊，滤出固体，乙酸乙酯打浆纯化得18g灰白色固体。
步骤4-4：
室温下将PPh3(9.7g,37mmol)溶于甲苯，缓慢加入DDQ(8.4g,37mmol)搅拌均匀，此时体系悬浊，加入原料4-4(7.1g,18.5mmol),于110℃下反应1hour，TLC点板，产物主要，倒出清液，浓缩干，EA打浆，得白色固体3.7g.
步骤4-5：
以化合物4-5(1g,2.72mmol)和3-16(902mg,5.45mmol)为原料，按照步骤3-13的合成方法，制得白色固体0.8g。
步骤4-6：
以化合物4-6(200mg,0.416mmol)和1-14(230mg,0.5mmol,WO2018119286)为原料，按照步骤2-6的合成方法，制得白色固体180mg。
步骤4-7：
以化合物4-7(120mg)为原料，按照步骤2-7的合成方法，得到产物38mg黄色固体。MS(APCI):720. 1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.83(d,J＝2.0Hz, 1H),8.45(d,J＝8.2Hz,1H),8.15(d,J＝1.9Hz,1H),8.12(d,J＝7.9Hz,1H),8.04(d,J＝5.8Hz,1H),7.98(d,J＝9.9Hz,1H),7.52(t,J＝7.7Hz,1H),7.41(d,J＝7.5Hz,1H),7.33(t,J＝7.9Hz,1H),7.15(d,J＝5.8Hz,1H),6.89(d,J＝7.5Hz,1H),4.38–4.26(m,1H),4.24–4.14(m,1H),3.78(q,J＝13.7Hz,2H),3.24–3.15(m,2H),3.08–2.99(m,2H),2.93–2.76(m,2H),2.76–2.64(m,2H),2.63–2.54(m,3H),2.44(s,3H),2.35(dd,J＝9.7,3.6Hz,1H),2.25–2.16(m,2H),2.10–2.05(m,3H),2.00(dt,J＝13.5,7.3Hz,1H),1.95–1.87(m,2H),1.59–1.50(m,1H).
实施例5化合物005的合成
Figure PCTCN2020114253-appb-000105
步骤5-1：
以化合物4-2(10g,45.8mmol)和5-1(11.6g,45.8mmol,WO2017059135)为原料，按照步骤4-3的合成方法，得到灰白色固体15g。
步骤5-2：
以化合物5-2(2g)为原料，按照步骤4-4的合成方法，制备得到灰白色固体1.1g。MS(APCI):387[M+H] +
步骤5-3：
以化合物5-3(1g,2.58mmol)和化合物3-16(0.85g,5.16mmol)为原料，按照步骤3-13的合成方法，制备得到灰白色固体0.9g。MS(APCI):500[M+H] +
步骤5-4：
以化合物5-4(200mg)和5-5(200mg,WO2018119286)为原料，按照步骤2-6的合成方法，制得白色固体210mg。
步骤5-5：
以化合物5-6(120mg)为原料，按照步骤2-7的合成方法，得到产物51mg黄色固体。MS(APCI):760. 1H NMR(400MHz,DMSO-d 6)δ9.89(s,1H),9.15(d,J＝8.4Hz,1H),8.91(s,1H),8.28–8.15(m,2H),8.07(d,J＝11.0Hz,1H),7.71(d,J＝7.2Hz,2H),7.60–7.49(m,2H),7.34(d,J＝5.8Hz,1H),7.09(d,J＝7.5Hz,1H),5.31(s,1H),4.73(s,2H),4.35(dt,J＝20.7,5.9Hz,2H),4.20(s,1H),3.93(s,1H),3.89–3.72(m,2H),2.87(dd,J＝17.0,9.6Hz,2H),2.75–2.55(m,2H),2.40–2.29(m,2H),2.16–1.85(m,4H),1.56(s,2H),1.22(s,4H),0.84(t,J＝6.8Hz,1H).
实施例6化合物006的合成
Figure PCTCN2020114253-appb-000106
步骤6-1：
以化合物4-5(10g,0.0272mol)和6-1(9.3g,0.0544mol,WO2018136935)为原料，按照步骤3-13的合成方法，制得白色固体8g。
步骤6-2：
将化合物6-2(8g)进行手性柱拆分，得到化合物6-3(3.5g)。
步骤6-3：
将化合物6-3(3.5g)溶于TFA(10mL)中，而后室温搅拌1小时。悬干TFA，甲苯共沸一次。往残留液中加入饱和碳酸氢钠溶液和浓盐酸，调节PH至2–3，出现大量固体，过滤，烘干，得淡棕色固体2g。
步骤6-3：
以化合物6-4(200mg,0.416mmol)和1-14(230mg,0.5mmol,WO2018119286)为原料，按照步骤2-6的合成方法，制得白色固体32mg。MS(APCI):720. 1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.86(s,1H),8.47(d,J＝8.2Hz,1H),8.18(s,1H),8.15(d,J＝7.8Hz,1H),8.06(d,J＝5.8Hz,1H),8.02(s,1H),7.55(s,1H),7.43(d,J＝7.6Hz,1H),7.35(s,1H),7.18(d,J＝5.8Hz,1H),6.92(d,J＝7.5Hz,1H),4.32(d,J＝5.8Hz,1H),4.22(tt,J＝6.9,3.4Hz,1H),3.81(q,J＝13.7Hz,3H),3.07(q,J＝9.3,8.0Hz,3H),2.89(s,2H),2.83(d,J＝8.8Hz,2H),2.74(dd,J＝10.0,6.3Hz,2H),2.63(dq,J＝15.1,7.5Hz,3H),2.46(s,3H),2.37(dd,J＝9.7,3.6Hz,2H),2.24(q,J＝6.8Hz,2H),2.09(s,3H),2.01(dt,J＝13.7,6.8Hz,2H),1.92(d,J＝7.8Hz,2H),1.57(d,J＝3.7Hz,2H)
实施例7化合物007的合成
Figure PCTCN2020114253-appb-000107
步骤6-2：
将化合物6-2(8g)进行手性柱拆分，得到化合物7-1(4g)。
步骤6-3：
将化合物7-1(4g)溶于TFA(10mL)中，而后室温搅拌1小时。悬干TFA，甲苯共沸一次。往残留液中加入饱和碳酸氢钠溶液和浓盐酸，调节PH至2–3，出现大量固体，过滤，烘干，得淡棕色固体3.2g。
步骤6-3：
以化合物7-2(200mg,0.416mmol)和1-14(230mg,0.5mmol,WO2018119286)为原料，按照步骤2-6的合成方法，制得白色固体30mg。MS(APCI):720.1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.86(d,J＝2.0Hz,1H),8.46(d,J＝8.1Hz,1H),8.18(s,1H),8.15(d,J＝7.9Hz,1H),8.06(d,J＝5.8Hz,1H),8.01(s,1H),7.55(t,J＝7.7Hz,1H),7.43(d,J＝7.4Hz,1H),7.35(t,J＝7.9Hz,1H),7.18(d,J＝5.8Hz,1H),6.92(d,J＝7.5Hz,1H),4.36(t,J＝6.0Hz,1H),4.21(dt,J＝6.9,3.4Hz,1H),3.81(q,J＝13.8Hz,2H),3.12–3.01(m,3H),2.89(p,J＝7.5Hz,2H),2.79(s,1H),2.75(d,J＝6.1Hz,1H),2.72(dd,J＝6.3,3.4Hz,1H),2.62(dt,J＝12.3,7.5Hz,4H),2.46(s,3H),2.37(dd,J＝9.7,3.6Hz,1H),2.22(t,J＝7.2Hz,2H),2.08(s,2H),2.00(dd,J＝11.0,4.9Hz,2H),1.94(dd,J＝8.9,6.0Hz,2H),1.57(qd,J＝8.2,3.8Hz,2H)。
实施例8化合物008的合成
Figure PCTCN2020114253-appb-000108
步骤8-1：
将化合物8-1(1.9g，6.41mmol,WO2016207226)，8-2(1.1g，6.41mmol,WO2018006795)，碳酸钠(1.36g，12.82mmol)和四三苯基膦钯(222mg，0.19mmol)依次加入装有dioxane/H2O(4:1,25mL)的单口瓶中，氮气保护，于油浴80度下搅拌3小时，LC-MS检测反应。原料剩余约10％后，将反应冷却，过滤，悬干，DCM/H2O萃取，无水硫酸钠干燥，柱层析(纯PE过柱)，得淡黄色固体650mg。ESI(APCI):306[M+H] +.
步骤8-2：
将化合物8-3(200mg，0.653mmol)，R-3-羟基吡咯烷盐酸盐(121mg，0.98mmol)和三乙胺(0.09mL，0.653mmol)依次加入装有DCM(10mL)的单口瓶中，室温搅拌2小时后，往反应液中加入NaBH(OAc)3(415mg，1.96mmol)，室温搅拌过夜，TLC检测反应。反应完全后，加水淬灭，卤水洗涤，无水硫酸钠干燥，柱层析，得200mg油状物。ESI(APCI):377[M+H] +.
步骤8-3：
将化合物8-5(1g，2.72mmol)，B2Pin2(1.04g，4.08mmol)，KOAc(668mg，6.81mmol)，X-phos(258mg，0.544mmol)和Pd(dppf)2Cl2(221mg，0.272mmol)依次加入装有DMAc(20mL)的单口瓶中，氮气保护，于油浴90度下搅拌3.5小时，LC-MS检测反应。反应完全后，悬干溶剂，DCM/H2O萃取，无水硫酸钠干燥，柱层析，得黄色固体1g。ESI(APCI):415[M+H] +.
步骤8-4：
将化合物8-4(200mg，0.53mmol)，8-6(240mg，0.58mmol)，碳酸钠(168mg，1.59mmol)和Pd(dppf)2Cl2(44mg)依次加入装有dioxane/H2O(4:1,5mL)的单口瓶中，于油浴100度下搅拌3小时，LC-MS监测反应。反应完全后，过滤，悬干溶剂，DCM/H2O萃取，无水硫酸钠干燥，柱层析，得油状物120mg。ESI(APCI):585[M+H] +.
步骤8-5：
将化合物8-7(120mg，0.205mmol)，3-16(51mg，0.308mmol)，三乙胺(0.03 mL,0.205mmol)和NaBH3CN(126mg，0.616mmol)依次加入装有THF(5mL)的单口瓶中，于油浴70度搅拌过夜，LC-MS监测反应，反应完全后，加水淬灭，悬干溶剂，DCM/H2O萃取，无水硫酸钠干燥，柱层析，得油状物70mg。ESI(APCI):698[M+H] +.
步骤8-6：
将化合物8-8(70mg，0.1mmol)和LiOH(5mg，0.2mmol)依次加入装有THF/MeOH/H2O(2:1:1,4mL)的单口瓶中，室温搅拌1小时，TLC监测反应。反应完全后，加TFA调节PH至中性，用反相柱制备得10mg白色固体。ESI(APCI):684[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ8.13(d,J＝7.9Hz,1H),7.99(d,J＝9.6Hz,1H),7.74(d,J＝7.5Hz,1H),7.52(t,J＝7.7Hz,1H),7.48–7.40(m,2H),7.36(t,J＝7.5Hz,1H),7.18(d,J＝7.7Hz,1H),7.14(d,J＝7.4Hz,1H),4.68(br,1H),4.40–4.26(m,1H)，4.22–4.15(m,1H)，3.86(s,3H),3.67–3.48(m,2H),3.28–3.14(m,2H),3.09–2.98(m,1H),2.93–2.74(m,4H),2.74–2.51(m,3H),2.44(s,3H),2.44–2.34(m,3H),2.25–2.17(m,2H),2.02(s,3H),2.00–1.85(m,3H),1.58–1.51(m,1H).
实施例9化合物009的合成
Figure PCTCN2020114253-appb-000109
步骤9-1：
将化合物6-2(1g)溶于TFA(5mL)中，而后室温搅拌1小时。悬干TFA，甲苯共沸一次。往残留液中加入饱和碳酸氢钠溶液和浓盐酸，调节PH至2–3，出现大量固体，过滤，烘干，得淡棕色固体0.5g。
步骤9-2：
将化合物9-1(0.5g，1.07mmol)，环丙基磺酰胺(260mg,2.14mmol)，DMAP(261mg,2.14mmol)和EDCI(410mg,2.14mmol)一次加入装有DCM(15mL)的单口瓶中，室温搅拌过夜，TLC检测反应。反应安全后，用饱和食盐水和0.5M稀盐酸水溶液洗涤，而后无水硫酸钠干燥有机层，柱层析，得淡黄色固体0.3g。
步骤9-3：
以化合物9-2(200mg)和1-14(240mg)为原料，按照步骤8-4的合成方法，制得淡黄色固体60mg。ESI(APCI):823[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ9.30(s,1H),8.86(d,J＝2.0Hz,1H),8.42(d,J＝8.1Hz,1H),8.20(d,J＝1.9Hz,1H),8.15–8.09(m,1H),8.04(t,J＝6.0Hz,2H),7.53(t,J＝7.7Hz,1H),7.41(d,J＝7.5Hz,1H), 7.33(t,J＝7.9Hz,1H),7.16(d,J＝5.8Hz,1H),6.91(d,J＝7.5Hz,1H),4.42(d,J＝6.3Hz,1H),4.23(tt,J＝6.5,3.1Hz,1H),4.01–3.84(m,2H),3.30–3.17(m,3H),3.06(dt,J＝16.6,6.8Hz,2H),2.98–2.75(m,5H),2.74–2.54(m,4H),2.44(s,3H),2.31–2.19(m,3H),2.07(s,3H),2.05–1.85(m,4H),1.64–1.55(m,1H).
实施例10化合物010的合成(222)
Figure PCTCN2020114253-appb-000110
步骤10-1：
将004(30mg，0.0471mmol)，NH4HCO3(7mg，0.0834mmol)和Boc2O(18mg，0.0834mmol)依次加入装有THF/Pyridine(6:1,3.5mL)的单口瓶中，于室温搅拌1小时，LC-MS检测反应。反应完全后，加入TFA调节PH至7-8，而后反相柱制备得淡黄色固体10mg。ESI(APCI):719[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ9.35(s,1H),8.97(s,1H),8.39(s,1H),8.32(d,J＝8.2Hz,1H),8.16(d,J＝7.9Hz,1H),8.08(d,J＝5.7Hz,1H),7.58–7.47(m,2H),7.43(d,J＝7.5Hz,1H),7.35(t,J＝7.8Hz,1H),7.17(d,J＝5.8Hz,1H),6.94(d,J＝7.5Hz,1H),5.40–5.26(m,1H),4.57–4.32(m,2H),3.20–2.89(m,7H),2.46(s,3H),2.31–2.21(m,1H),2.19–2.08(m,2H),2.06(s,3H),2.01–1.89(m,2H),1.85–1.75(m,1H).
实施例11化合物011的合成
Figure PCTCN2020114253-appb-000111
步骤11-1：
将化合物5-3(5g,12.9mmol),S-叔丁基亚磺酰胺(4.69g,38.7mmol)和四钛酸乙酯(11.77g,51.60mmol)依次加入甲苯(50mL)中，氮气保护，升至70度加热搅拌过夜，TLC检测反应。反应完全后，冷却至室温，直接用于下一步。
步骤11-2：
将上述反应液冷却至-70度，而后往其中加入THF(20mL)和NaBH4(3.9g,103.2mmol)，并保温搅拌1小时。而后慢慢升至室温搅拌1小时，TLC检测反应。反应完全后，往其中加入饱和氯化铵水溶液。而后乙酸乙酯萃取，无水硫酸钠干燥，柱层析，得黑灰色固体5g。
步骤11-3：
将化合物11-2(1g,2.03mmol)溶于DCM(5mL)中,冰浴下搅拌。而后往溶液中加入氯化氢的dioxane溶液(3M,1mL)，加毕升至室温搅拌1小时，TLC检测反应。反应完全后，过滤，用乙酸乙酯淋洗固体，烘干，得黑灰色固体788mg。
步骤11-4：
将化合物11-3(300mg,0.77mmol)，碳酸钾(213mg)加入DMF(5mL)中，而后往反应液中加入3-溴丙酸甲酯(129mg)，而后每隔1小时加入3-溴丙酸甲酯(129mg)，共加3次，LC-MS检测反应，直至产物不再增加。用DCM和水萃取，无水硫酸钠干燥，柱层析，得产物和原料的混合物100mg。
步骤11-5：
将上述混合物溶于THF(30mL)中，而后加入Boc2O(413mg)。氮气保护，升至60度加热搅拌。TLC检测反应，上一步的的原料和产物上Boc可以在TLC上分开。而后用DCM/H2O萃取，无水硫酸钠干燥，得目标产物20mg灰色固体。
步骤11-6：
以化合物11-5(20mg,0.035mmol)和5-5(15mg)为原料，按照步骤8-4的合成方法，制得淡黄色固体20mg。
步骤11-7：
向15mL Schlenk管中加入11-6(93mg)，DCM(2mL)，滴加HCl-Dioxane(0.4mL)N2保护下室温，搅拌反应(黄色浑浊)。1h LC-MS检测反应完全。直接油泵拉干得83mg，黄色固体。
步骤11-8：
以化合物11-7(83mg)为原料，按照步骤8-6的合成方法，制得34mg淡黄色固体。ESI(APCI):734[M+H] +. 1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),9.12–9.00(m,2H),8.53(s,1H),8.39(s,1H),8.31–8.19(m,2H),7.73(q,J＝7.0,6.4Hz,2H),7.56(t,J＝8.0Hz,1H),7.38(d,J＝5.8Hz,1H),7.11(d,J＝7.7Hz,1H),5.00(s,1H),4.61(s,1H),4.43(d,J＝27.4Hz,1H),3.30–3.14(m,2H),2.71–2.58(m,3H),2.39(dd,J＝9.4,4.3Hz,0H),2.07–1.75(m,2H).
实施例12化合物012的合成
Figure PCTCN2020114253-appb-000112
步骤12-1：
将化合物11-3(1g,2.35mmol)溶于THF(30mL)中,而后加入碳酸钾(975mg,7.06mmol)和溴乙酸乙酯(393mg,2.35mmol)，于60度加热搅拌过夜，LC-MS检测反应。反应完全后，用DCM/H2O萃取，无水硫酸钠干燥，柱层析，得600mg灰棕色固体。
步骤12-2：
以化合物12-1(200mg)和5-5(280mg)为原料，按照步骤8-4的合成方法，制得淡黄色固体52mg。
步骤12-3：
以化合物11-7(52mg)为原料，按照步骤8-6的合成方法，制得21mg淡黄色固体。ESI(APCI):720[M+H] +. 1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),9.12–8.98(m,2H),8.54(d,J＝2.0Hz,1H),8.41(s,1H),8.29–8.17(m,2H),7.79–7.68(m,2H),7.56(t,J＝8.0Hz,1H),7.38(d,J＝5.8Hz,1H),7.12(dd,J＝7.6,1.5Hz,1H),5.01(dd,J＝8.1,3.5Hz,1H),4.62(s,1H),3.96(d,J＝6.2Hz,2H),3.29(s,2H),2.69–2.52(m,1H),2.47(s,2H),1.90(d,J＝55.7Hz,2H).
实施例13化合物013的合成
Figure PCTCN2020114253-appb-000113
步骤13-1：
向100mL圆底烧瓶中加入12-1(150mg，0.3159mmol)，MeI(54mg，0.3791mmol)，K2CO3(87mg,0.6318mmol)，THF(30mL)，N2保护下室温搅拌反应过夜(深黄色澄清)，LC-MS检测反应。反应完全后，旋干THF，DCM(20mL*2)萃取，柱层析，得灰色固体76mg。
步骤13-2：
以化合物13-1(50mg)和5-5(52mg)为原料，按照步骤8-4的合成方法，制得淡黄色固体70mg。
步骤13-3：
以化合物13-2(62mg)为原料，按照步骤8-6的合成方法，制得20.5mg淡黄色固体。ESI(APCI):734[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ9.89(s,1H),9.19–8.92(m,2H),8.54(s,1H),8.37(s,1H),8.33–8.12(m,2H),7.88–7.63(m,2H),7.56(t,J＝8.0Hz,1H),7.38(d,J＝5.9Hz,1H),7.13(dd,J＝7.6,1.5Hz,1H),5.47(s,2H),5.12(s,1H),4.64(d,J＝17.9Hz,2H),4.43(d,J＝26.4Hz,1H),3.28(s,2H),3.25–3.15(m,2H),2.68(s,2H),2.08–1.90(m,2H),1.83(s,2H).
实施例14化合物014的合成
Figure PCTCN2020114253-appb-000114
步骤14-1：
将化合物14-1(5g,0.0231mol,WO2019148036),乙烯基硼酸频哪酯(7.7mL,0.0463mmol),磷酸钾(14.7g,0.0693mol)，Pd(OAc) 2(0.52g,0.0023mol)和SPhos(1.89g,0.0046mol)依次加入装有1,4-dioxane/H2O(4:1，50mL)的单口瓶中，氮气保护，于油浴85℃下搅拌过夜，TLC检测反应。当原料消失后，将反应液悬干，柱层析，得淡黄色固体2.4g。
步骤14-2：
将化合物14-2(1.4g,9mmol)悬浮于原甲酸三乙酯(20mL)中，于油浴145℃下回流6小时，TLC检测反应。当原料消失后，将反应液冷却，加入正庚烷搅洗10分钟，过滤，重复以上操作2次，过滤，烘干得淡黄色固体1.35g。
步骤14-3：
将化合物14-3(1.25g，7.22mmol)和DIPEA(1.4g,10.83mmol)加入甲苯(75mL)中，升至100度搅拌，而后加入三氯氧磷(1.1g，7.22mmol)，将反应液于油浴100℃下搅拌1.5小时，TLC检测反应。当原料消失后，将反应液慢慢倒入冰块中(50g) 搅拌20分钟，过滤，分液，用卤水洗涤2次，有机层无硫酸酸钠干燥，悬干，得灰绿色固体820mg。
步骤14-4：
将化合物14-4(820mg，4.44mmol)，3-溴-2-甲基苯胺(908mg,4.88mmol)和TsOH.H2O(844mg,4.44mmol)加入异丙醇(20mL)中，升至85度回流搅拌过夜，TLC检测反应。当原料消失后，悬干溶剂，DCM/H2O萃取，合并有机层，有机层用饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥有机层，柱层析，得黄色固体600mg。
步骤14-5：
将化合物14-5(600mg,1.76mmol)，NMO(412mg,3.52mmol),K 2OsO 4 .2H 2O(65mg,0.176mmol)和NaIO4(2.63g,12.31mmol)溶于THF/H2O(10mL/5mL)中，于室温下搅拌3小时，TLC检测反应。当原料消失后，过滤，乙酸乙酯淋洗固体。取滤液，用10％的硫代硫酸钠和卤水洗涤，无水硫酸钠干燥，浓缩，得淡黄色油状物600mg，直接用于下一步反应。
步骤14-6：
将化合物14-6(600mg,1.75mmol)，(R)-3-羟基吡咯盐酸盐(949mg)和DIPEA(678mg,5.24mmol)溶于DCM(20mL)中，于室温下搅拌1小时。然后将NaBH(OAc) 3(741mg,3.5mmol)加入上述反应液中，室温搅拌过夜。当原料消失后，滴加饱和碳酸氢钠溶液淬灭反应，乙酸乙酯/水萃取，合并有机层，无水硫酸钠干燥，柱层析，得淡黄色固体350mg。
步骤14-7：
以化合物14-7(350mg)为原料，按照步骤8-3的合成方法，得淡黄色固体300mg。
步骤14-8：
以化合物14-8(200mg)和7-2(180mg)为原料，按照步骤8-4的合成方法，得淡黄色固体300mg。MS(APCI):721[M+H] +
实施例15化合物015的合成
Figure PCTCN2020114253-appb-000115
步骤15-1：
以化合物15-1(200mg)为原料，按照步骤8-3的合成方法，得淡黄色固体150 mg。
步骤15-2：
以化合物15-1(100mg,WO2019191707)和7-2(120mg)为原料，按照步骤8-4的合成方法，制得淡黄色固体21mg。MS(APCI):736[M+H] +.
实施例16化合物016的合成
Figure PCTCN2020114253-appb-000116
步骤16-1：
以化合物16-1(200mg)为原料，按照步骤8-3的合成方法，得淡黄色固体100mg。
步骤16-2:
以化合物16-1(50mg,WO2019191707)和7-2(56mg)为原料，按照步骤8-4的合成方法，制得淡黄色固体25mg。MS(APCI):771[M+H] +.
按照化合物001-016的合成方法，以相应的原料和试剂合成了下列表中的化合物：
Figure PCTCN2020114253-appb-000117
Figure PCTCN2020114253-appb-000118
Figure PCTCN2020114253-appb-000119
实施例280化合物280的合成
Figure PCTCN2020114253-appb-000120
步骤280-1：
以化合物1-3(2.4g)为原料，按照步骤1-2的合成方法，得到淡黄色固体3.1g。MS-APCI:334[M+H] +.
步骤280-2：
以化合物280-1(500mg)为原料，按照步骤1-3的合成方法，得到淡黄色固体200mg。MS-APCI:654[M+H] +.
步骤280-3：
以化合物280-2(200mg)为原料，按照步骤1-4的合成方法，得到淡黄色固体60mg。MS-APCI:753[M+H] +.
步骤280-4：
以化合物280-3(60mg)为原料，按照步骤1-5的合成方法，得到淡黄色固体16mg。MS-APCI:654[M+H] +.
1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),9.00(s,1H),8.46(s,1H),8.34(d,J＝8.0Hz,1H),8.08(d,J＝8.0Hz,1H),7.77(d,J＝8.0Hz,1H),7.44(t,J＝8.0Hz,1H),7.35–7.25(m,3H),7.19(d,J＝8.0Hz,1H),6.91(d,J＝8.0Hz,1H),6.52(m,1H),4.49-4.39(m,3H),3.37-2.83(m,3H),2.66-2.28(m,2H),2.21(s,3H),2.18-2.06(m,1H),2.06(s,3H),1.96-1.58(m,5H)，1.43(m,1H).
实施例281化合物280的合成
Figure PCTCN2020114253-appb-000121
步骤281-1：
以化合物3-12(5g)为原料，按照步骤4-1的合成方法，得到淡黄色固体3g。MS-APCI:320[M+H] +.
步骤281-2：
以化合物280-1(1g)为原料，按照步骤1-3的合成方法，得到淡黄色固体400mg。MS-APCI:640[M+H] +.
步骤281-3：
以化合物280-2(400mg)为原料，按照步骤1-4的合成方法，得到淡黄色固体10mg。MS-APCI:739[M+H] +.
步骤281-4：
以化合物280-3(100mg)为原料，按照步骤1-5的合成方法，得到淡黄色固体36mg。MS-APCI:725[M+H]
生物测试
实施例A：PD-1/PD-L1均相时间分辨荧光(HTRF)结合测定
测定在标准黑色384孔聚苯乙烯板中进行，终体积为20μL。首先将抑制剂用DMSO连续稀释后加入板孔中，再加入其他反应组分。测定中DMSO的最终浓度为1％。测定是在25℃下含有0.05％Tween-20和0.1％BSA的PBS缓冲液(pH7.4)中进行的。在C端带有His标记的重组人PD-L1蛋白(19-238)购自AcroBiosystems公司(PD1-H5229)。在C端带有Fc标记的重组人PD-1蛋白(25-167)也购自AcroBiosystems公司(PD1-H5257)。将PD-L1和PD-1蛋白在测定缓冲液中稀释然后提取0.1μl溶液加入到板孔中。离心平板并将蛋白质与抑制剂预孵育40分钟。孵育后加入0.1μl HTRF检测缓冲液含有铕封闭标记的抗人IgG(PerkinElmer-AD0212)Fc专属的和抗His的
Figure PCTCN2020114253-appb-000122
-别藻蓝蛋白(APC，PerkinElmer-AD0059H)缀合的抗体。离心后，将孔板在25℃下孵育60分钟。置于PHERAstar FS读板器中读取数据(665nm/620nm比率)。测定中的最终浓度为～3nM PD1、10nM PD-L1、1nM铕抗人IgG和20nM抗-His-别藻蓝蛋白。使用GraphPad Prism5.0软件拟合活性数据得出抑制剂的IC50值。
实施例中举例说明的化合物IC50值以下列方式表示：IC50：+：≤10nM；++：10nM～100nM；+++：>100nM。
使用实施例A中描述的PD-1/PD-L1均相时间分辨荧光(HTRF)结合测定获得的实施例化合物的数据表明，所测试的本发明化合物的IC50绝大部分小于10nm，部分化合物(约25％)甚至小于1nM，部分优选化合物的活性测试数据提供于表1中。
化合物 IC 50 化合物 IC 50 化合物 IC 50
001 + 035 + 015 +
002 + 036 + 016 +
003 + 037 + 243 +
004 + 038 + 244 +
005 + 039 + 245 +
006 + 040 + 246 +
007 + 041 + 247 +
008 + 042 + 248 +
009 + 043 ++ 249 +
010 + 081 + 250 +
011 + 082 + 251 +
012 + 083 + 252 +
013 + 084 + 253 +
017 + 086 + 254 +
018 + 087 + 255 +
019 + 088 + 256 +
020 + 162 + 257 +
021 + 175 + 258 +
022 + 182 + 259 +
023 + 231 + 260 +
024 + 232 + 261 +
025 + 233 + 262 +
026 + 234 + 263 +
027 + 235 + 264 +
028 + 236 + 265 +
029 + 237 + 266 +
030 + 238 + 267 +
031 + 239 + 268 +
032 + 240 + 271 +
033 + 241 + 274 +
034 + 242 + 280 +++
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 一种如下式I所示的化合物，或其光学异构体、水合物、溶剂合物，或其药学上可接受的盐：
    Figure PCTCN2020114253-appb-100001
    其中，n为0、1、2、3、4或5；
    m、p、q和t，v，u各自独立地选自0、1、2、3，4；
    X 1、X 2、X 3、X 4、X 5和X 6各自独立地选自下组：N、O、S、SO、SO 2、C(R) 2、CHR、NR；
    Y 1、Y 2、Y 3、Y 4、Y 5和Y 6各自独立地选自下组：N、CH、C；
    其中，X 3、X 4、X 5的碳原子上的氢(如存在的情况下)均可各自独立的被氘替换；
    Figure PCTCN2020114253-appb-100002
    各自独立地选自下组：取代或未取代的C6-C10亚芳基、或取代或未取代的具有1-3个杂原子的5-12元(优选5-7元)亚杂芳基、取代或未取代的5-12元亚杂环基、取代或未取代的5-12元的C3-C12(优选为C5-C12)亚环烷基；
    Figure PCTCN2020114253-appb-100003
    选自下组：取代或未取代的5-12元杂芳基、取代或未取代的C6-C10芳基、取代或未取代的5-12元杂环基、取代或未取代的5-12元的C3-C12(优选为C5-C12)环基，其中，所述的杂环基具有1-3个杂原子；
    L 1选自下组：化学键、取代或未取代的C1-C4亚烷基、取代或未取代的C2-C4亚烯基、取代或未取代的C2-C4亚炔基、-S-、-O-、取代或未取代的-NH-、-S(O)-、-S(O) 2-、取代或未取代的-NHC(O)NH-、
    Figure PCTCN2020114253-appb-100004
    取代或未取代的
    Figure PCTCN2020114253-appb-100005
    取代或未取代的
    Figure PCTCN2020114253-appb-100006
    取代或未取代的
    Figure PCTCN2020114253-appb-100007
    且
    Figure PCTCN2020114253-appb-100008
    表示单键或双键；
    R、R 1、R 2、R 3、R 4和R 5各自独立地选自下组：H、-CN、三氟甲基、-CHF 2、-OCF 3、-OCHF 2、磺酰氨基、硝基、羟基、卤素、-S-R 8、-S(O)-R 8、-S(O) 2-R 8、取代或未取代的C1-C10烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、氧代(即＝O)、＝NR f、-CN、羟基、NR dR e(例如氨基)、取代或未取代的C1-C6胺基、取代或未取代的-(C1-C6亚烷基)-NH-(C1-C6亚烷基)、羧基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个杂原子的5-12元杂芳基、取代或未取代的具有1-4个杂原子的3-12元杂环基，其中，取代或未取代的C1-C10烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、氧代(即＝O)、＝NR f、羟 基、NR dR e(例如氨基)、取代或未取代的C1-C6胺基、取代或未取代的-(C1-C6亚烷基)-NH-(C1-C6亚烷基)、羧基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个杂原子的5-12元杂芳基、取代或未取代的具有1-4个杂原子的3-12元杂环基的碳原子上的氢均可各自独立的被氘替换；取代或未取代的
    Figure PCTCN2020114253-appb-100009
    取代或未取代的
    Figure PCTCN2020114253-appb-100010
    取代或未取代的
    Figure PCTCN2020114253-appb-100011
    其中，Rb和Rc各自独立地选自下组：H、取代或取代的C 1-C 8烷基；或所述的Rb和Rc与相邻的N原子共同构成取代或未取代的具有1-3个选自N、S和O的杂原子的3-10元杂环基，或所述的Rb和Rc与相邻的N原子共同构成取代或未取代的4-10元内酰胺，所述取代基包括但不限于：羟基、羧基、巯基、氨基、F、Cl，其中，Rb、Rc和Rd的碳原子上的氢均可各自独立地被氘替换；或-(L 1a) r-(L 2a) s-(L 3a) s-；-C 0-8-O-R 8,-C 0-8-C(O)OR 8,-C 0-8-OC(O)OR 8,-C 0-8-NR 8R 9,-C 0-8-N(R 8)C(O)R 9,-C 0-8-C(O)NR 8R 9；
    R 8和R 9各自独立地选自下组：H、羟基，取代或未取代的C1-C10烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧、取代或未取代的C3-C8环烷基、氧代(即＝O)、＝NRf、-CN、羟基、NR dR e(例如氨基)、取代或未取代的C1-C6胺基、取代或未取代的-(C1-C6亚烷基)-NH-(C1-C6亚烷基)、羧基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个杂原子的5-12元杂芳基、取代或未取代的具有1-4个杂原子的3-12元杂环基，取代或未取代的
    Figure PCTCN2020114253-appb-100012
    取代或未取代的
    Figure PCTCN2020114253-appb-100013
    取代或未取代的
    Figure PCTCN2020114253-appb-100014
    或-(L 1a) r-(L 2a) s-(L 3a) s-；
    各个L 1a各自独立地为选自下组的基团；化学键、取代或未取代的C 1-C 7亚烷基、取代或未取代的C2-C4亚烯基、取代或未取代的C2-C4亚炔基、-S-、-O-、取代或未取代的-NH-、-S(O)-、或-S(O) 2-；
    L 2a选自下组：取代或未取代的C6-C12亚芳基、取代或未取代的具有1-3个杂原子的5-12元亚杂芳基、取代或未取代的C3-C8亚环烷基、取代或未取代的具有1-3个杂原子的3-10元亚杂环基；
    L 3a选自下组：取代或未取代的C1-C10烷基、C1-C10芳基、-CN、羟基、氨基、羧基、-CO-NH-SO 2-R g、-NH-SO 2-R g、-SO 2-NH-CO-R g、-OR g、-N(R g) 2-CO 2R g、-CON(R g) 2、-CONHCOR g、NR g-CO-N(R g) 2、-NR g-SO 2-N(R g) 2；
    r为1、2、3、4、5、6；
    s分别为0、1、2；
    R d、R e和R g各自独立地选自下组：H、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 6-C 10芳基；或R d和R e共同形成取代或未取代的具有1-3个选自N、S和O的杂原子的4-10(优选为5-10)元杂环基；
    所述的R f选自下组：H、取代或未取代的C 1-C 6烷基、取代或未取代的C 6-C 10芳基、取代或未取代的5-10元杂芳基、氰基、-C(＝O)-NR dR e、-C(＝O)-取代或未取代的C 1-C 6烷 氧基、-C(＝O)-取代或未取代的C 1-C 6烷基、-C(＝O)-取代或未取代的C 3-C 10环烷基、-C(＝O)-取代或未取代的C 2-C 6烯基、-C(＝O)-取代或未取代的C 2-C 6炔基；
    除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素(包括-F、-Cl、-Br、-I)、-CH 2Cl、-CHCl 2、-CCl 3、-CH 2F、-CHF 2、-CF 3、氧代(＝O)、-CN、羟基、氨基、C1-C6烷胺基、羧基、-NHAc、
    Figure PCTCN2020114253-appb-100015
    Figure PCTCN2020114253-appb-100016
    未取代或被一个或多个取代基取代的选自下组的基团：C1-C6烷基、C1-C6烷氧基、C6-C10芳基、C3-C8环烷基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-10元杂环基；所述的取代基选自下组：卤素、羟基、羧基、氧基、氰基、C1-C6烷氧基、C1-C6烷胺基；
    上述各式中，任一所述杂原子选自下组：B、P、N、S和O。
  2. 如权利要求1所述的化合物，或其异构体、光学异构体、水合物、溶剂合物，或其药学上可接受的盐，其特征在于，所述的
    Figure PCTCN2020114253-appb-100017
    各自独立地为选自下组的环形成的二价基团：
    Figure PCTCN2020114253-appb-100018
    Figure PCTCN2020114253-appb-100019
    其中，所述的环的成键位置可以为N或C；更佳地，所述的
    Figure PCTCN2020114253-appb-100020
    各自独立地为
    Figure PCTCN2020114253-appb-100021
  3. 如权利要求1所述的化合物，其特征在于，所述的
    Figure PCTCN2020114253-appb-100022
    具有如下式所示的结构：
    Figure PCTCN2020114253-appb-100023
    其中，
    X 6、X 7、X 8、X 9、X 10和X 11各自独立地选自下组：N、CR；
    R 6选自下组：H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、氧代(即＝O)、＝NR f、-CN、羟基、NR dR e(例如氨基)、取代或未取代的C1-C6胺基、取代或未取代的-(C1-C6亚烷基)-NH-(C1-C6亚烷基)、羧基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个杂原子的5-12元杂芳基、取代或未取代的具有1-4个杂原子的5-12元杂环基，取代或未取代的
    Figure PCTCN2020114253-appb-100024
    取代或未取代的
    Figure PCTCN2020114253-appb-100025
    取代或未取代的
    Figure PCTCN2020114253-appb-100026
    或-(L 1a) r-(L 2a) s-(L 3a) s-,-C 0-8-O-R 8,-C 0-8-C(O)OR 8,-C 0- 8-OC(O)OR 8,-C 0-8-NR 8R 9,-C 0-8-N(R 8)C(O)R 9,-C 0-8-C(O)NR 8R 9。
  4. 如权利要求1所述的化合物，或其光学异构体、水合物、溶剂合物，或其药学上可接受的盐，其特征在于，所述的
    Figure PCTCN2020114253-appb-100027
    具有如下式所示的结构：
    Figure PCTCN2020114253-appb-100028
    Figure PCTCN2020114253-appb-100029
    Figure PCTCN2020114253-appb-100030
    其中，所述的环的成键位置可以为N或C。
  5. 如权利要求1所述的化合物，或其光学异构体、水合物、溶剂合物，或其药学上可接受的盐，其特征在于，所述的环
    Figure PCTCN2020114253-appb-100031
    具有如下式IV所示的取代基：
    Figure PCTCN2020114253-appb-100032
    其中，w为0、1、2、3、4、5或6；
    所述的各个L 4独立地选自下组：取代或未取代的C1-C4亚烷基、-S-、-O-、NR f、-S(O)-、-S(O) 2-；优选为取代或未取代的C1-C4亚烷基，其中，取代或未取代的C1-C4亚烷基上碳原子上的氢均可各自独立地被氘替换；前提条件是各个L 4共同形成的结构是化学稳定的；
    Figure PCTCN2020114253-appb-100033
    选自下组：取代或未取代的C3-C10(优选C5-C10)环烷基、取代或未取代的具有1-3个选自B、P、N、S和O的杂原子的3-10元杂环基；优选地，所述的
    Figure PCTCN2020114253-appb-100034
    为或取代或未取代的3-8元含氮杂环基，或取代或未取代的4-10元环酰胺，其中，3-8元含氮杂环基取代或未取代的4-10元环酰胺基的成环碳原子上的氢均可各自独立被氘替换；
    各个R 7各自独立地选自下组：取代或未取代的C1-C6烷基、-CN、羟基、氨基、羧基、-OR g、-N(R g) 2、-CO-NH-SO 2-R g、-NH-SO 2-R g、-SO 2-NH-CO-R g、-CO 2R g、-CON(R g) 2、CONHCOR g、NR g-CO-N(R g) 2、-NR g-SO 2-N(R g) 2；R f和R g的定义如前所述，其中Rf和Rg的碳原子上的氢均可各自独立地被氘替换，其中，所述的取代基选自下组：卤素、羟基、羧基、氰基、C1-C6烷氧基。
  6. 如权利要求1所述的化合物，其特征在于，所述的
    Figure PCTCN2020114253-appb-100035
    为选自下组的结构：
    Figure PCTCN2020114253-appb-100036
  7. 如权利要求1所述的化合物，或其光学异构体、水合物、溶剂合物，或其药学 上可接受的盐，其特征在于，所述的化合物选自下列化合物；
    Figure PCTCN2020114253-appb-100037
    Figure PCTCN2020114253-appb-100038
    Figure PCTCN2020114253-appb-100039
    Figure PCTCN2020114253-appb-100040
    Figure PCTCN2020114253-appb-100041
    Figure PCTCN2020114253-appb-100042
    Figure PCTCN2020114253-appb-100043
    Figure PCTCN2020114253-appb-100044
    Figure PCTCN2020114253-appb-100045
    Figure PCTCN2020114253-appb-100046
    Figure PCTCN2020114253-appb-100047
    Figure PCTCN2020114253-appb-100048
    Figure PCTCN2020114253-appb-100049
    Figure PCTCN2020114253-appb-100050
    Figure PCTCN2020114253-appb-100051
    Figure PCTCN2020114253-appb-100052
    Figure PCTCN2020114253-appb-100053
    Figure PCTCN2020114253-appb-100054
    Figure PCTCN2020114253-appb-100055
    Figure PCTCN2020114253-appb-100056
    Figure PCTCN2020114253-appb-100057
    Figure PCTCN2020114253-appb-100058
    Figure PCTCN2020114253-appb-100059
    Figure PCTCN2020114253-appb-100060
    Figure PCTCN2020114253-appb-100061
    Figure PCTCN2020114253-appb-100062
  8. 一种如权利要求1所述的式I化合物的制备方法，其特征在于，所述的方法包括选自合成方案1、2或3所示的步骤：
    合成方案1：
    Figure PCTCN2020114253-appb-100063
    (a)以中间体II和III为原料，通过钯催化剂催化的Sonogashira偶联反应得到目标产物I-1；
    优选地，中间体II-2的制备方法如下：
    Figure PCTCN2020114253-appb-100064
    (a)以II-1为原料，在路易斯酸催化下，发生卤代反应，得到中间体II-2；
    优选地，中间体III的制备方法如下：
    Figure PCTCN2020114253-appb-100065
    (a)以化合物III-1和III-2为原料，在钯催化剂和配体的条件下，发生偶联反应(如Suzuki,Buchwald等)，得到中间体III-3；
    (b)以III-3为原料，使用合适的试剂，移除硅基保护基，得到中间体III；
    合成方案2：
    Figure PCTCN2020114253-appb-100066
    (a)以化合物II-1为原料，与硝化剂反应(如浓硫酸/NaNO 3，浓硫酸/发烟硝酸等)，形成中间体IV-1；
    (b)以IV-1为原料，在还原条件下(Pd-C/H 2；锌粉/氯化铵；铁粉/醋酸等)，发生还原反应，形成中间体IV-2；
    (c)以IV-2和IV-3为原料，在碱性条件下，发生亲和取代反应得到酰胺中间体；而后在合适的脱水试剂(如PPh 3/DDQ)，发生环化反应，得到中间体IV-4；
    (d)以IV-4和IV-5为原料，在催化剂和配体的条件下，发生偶联反应，形成中间体I-2；
    合成方案3：
    Figure PCTCN2020114253-appb-100067
    (a)以V-1和V-2为原料，在催化剂和配体的条件下，发生偶联反应，形成中间体V-3；
    (d)以IV-4和合适的硼源(如B 2Pin 2)为原料，在催化剂和配体的条件下，发生偶联反应，形成中间体V-4；
    (d)以V-4和IV-4为原料，在催化剂和配体的条件下，发生偶联反应，形成目标产物I-3；
    上述各式中，X 1-X 12、R 1-R 9、t、m、n的定义如前所述。
  9. 一种药物组合物，其特征在于，包含(1)如权利要求1所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物；(2)药学上可接受的载体。
  10. 如权利要求1所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物或如权利要求7所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗与PD-1/PD-L1的活性或表达量相关的疾病的药物组合物。
  11. 如权利要求10所述的用途，其特征在于，所述的药物组合物用于治疗选自下组的疾病：癌症、感染性疾病、自身免疫性疾病。
  12. 如权利要求10所述的用途，其特征在于，所述的癌症选自下组：胰腺癌，膀胱癌，结肠直肠癌，乳腺癌，前列腺癌，肾癌，肝细胞癌，肺癌，卵巢癌，宫颈癌，胃癌，食道癌，黑色素瘤，神经内分泌癌，中枢神经系统癌，脑癌，骨癌，软组织肉瘤，非小细胞肺癌癌症，小细胞肺癌或结肠癌、皮肤癌、肺癌、泌尿系肿瘤、血液肿瘤、胶质瘤、消化系统肿瘤、生殖系统肿瘤、淋巴瘤、神经系统肿瘤、脑瘤、头颈癌。
  13. 如权利要求10所述的用途，其特征在于，所述的感染性疾病选自细菌感染、病毒感染。
  14. 如权利要求10所述的用途，其特征在于，所述的自身免疫性疾病选自器官特异性自身免疫病、系统性自身免疫病。
  15. 如权利要求10所述的用途，其特征在于，所述的药物组合物还包括至少一种选自下组的治疗剂：纳武单抗，派姆单抗，atezolizumab，或伊匹单抗。
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