WO2020192570A1 - 小分子pd-1/pd-l1抑制剂、其与pd-l1抗体的药物组合物及其应用 - Google Patents

小分子pd-1/pd-l1抑制剂、其与pd-l1抗体的药物组合物及其应用 Download PDF

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WO2020192570A1
WO2020192570A1 PCT/CN2020/080362 CN2020080362W WO2020192570A1 WO 2020192570 A1 WO2020192570 A1 WO 2020192570A1 CN 2020080362 W CN2020080362 W CN 2020080362W WO 2020192570 A1 WO2020192570 A1 WO 2020192570A1
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PCT/CN2020/080362
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English (en)
French (fr)
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王玉光
王飞澜
张农
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上海再极医药科技有限公司
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Priority to CA3134171A priority Critical patent/CA3134171A1/en
Priority to AU2020246317A priority patent/AU2020246317A1/en
Priority to KR1020217034418A priority patent/KR20220004036A/ko
Priority to EP20778787.0A priority patent/EP3943083A4/en
Priority to US17/441,410 priority patent/US20220168268A1/en
Priority to JP2021556946A priority patent/JP2022527892A/ja
Priority to SG11202110388VA priority patent/SG11202110388VA/en
Publication of WO2020192570A1 publication Critical patent/WO2020192570A1/zh

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K2317/00—Immunoglobulins specific features
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    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to a small molecule PD-1/PD-L1 inhibitor, a pharmaceutical composition thereof and PD-L1 antibody, and applications thereof.
  • Human programmed death factor ligand 1 (PD-L1), also known as B7-H1, belongs to the B7 family and is widely distributed in peripheral tissues and hematopoietic cells.
  • PD-L1q full-length cDNA 870bp, encoding a type I transmembrane protein containing 290 amino acids, PD-L1 is mainly expressed in the bearing CD4 T cells, CD8 T cells, B cells, monocytes, and dendritic cells (Dendritic Cells, DCs), macrophages and other hematopoietic cells and some non-hematopoietic cells, such as endothelial cells, pancreatic islet cells, mast cells and other membrane surfaces.
  • PD-L1 is highly expressed in a variety of tumors, such as lung cancer, gastric cancer, multiple bone marrow, melanoma and breast cancer.
  • Programmed death-1 (PD-1) is the main receptor of PD-L1. It is mainly distributed in immune-related cells such as T cells, B cells and NK cells. It is used in autoimmune diseases, tumors, infections, and organs. Transplantation, allergies, immune privileges, etc. all play an important role in the immune response process.
  • PD-L1 inhibits the activation of T cells or induces apoptosis of mature T cells by interacting with its receptor programmed death factor 1, so that the immune response is inhibited.
  • cancer cells will up-regulate the expression of PD-L1 to induce apoptosis of T cells and prevent the immune system from eliminating them.
  • PD-L1 targeting antibody drugs can break the tumor immune tolerance by specifically blocking the interaction of PD-1/PD-L1, restore the killing function of tumor-specific T cells to tumor cells, and then achieve tumor clearance.
  • the indications include melanoma, urothelial cancer (bladder cancer), and metastatic non-small cell Lung cancer (stage IV); AstraZeneca's Durvalumab (devaruzumab, trade name: Imfinzi), indicated for advanced or metastatic urothelial cancer (bladder cancer); Pfizer and Merck's Avelumab (trade name) : Bavencio), the indication is rare skin cancer Merck cell carcinoma (MCC); Regeneron’s Cemiplimab (trade name: Libtayo), the indication is the treatment of metastatic or locally advanced skin squamous cell carcinoma.
  • MCC Merck cell carcinoma
  • Regeneron’s Cemiplimab trade name: Libtayo
  • PD-L1 antibody drugs under development, such as the PD-L1 antibody developed by companies such as Corning Jereh, CStone Pharmaceuticals, Hengrui Pharmaceuticals, Maibos, BeiGene, Kelun Botai and Zhaoke Pharmaceuticals.
  • the drug has already started clinical research.
  • Atezolizumab By analyzing the crystal complex of Atezolizumab, the first PD-L1 antibody approved for marketing by the FDA (Oncotarget, 2017, 8, 90215-90224), it can be found that the combination of Atezolizumab and PD-L1 involves a large number of hydrogen bonds, hydrophobic Interaction and ⁇ - ⁇ superposition or cation- ⁇ interaction. In addition, mutation studies have shown that PD-L1 has two hot residues (E58, R113). In conclusion, Atezolizumab competes with PD-1 for the same surface binding site of PD-L1.
  • WO2018006795 discloses a new small molecule PD-1/PD-L1 inhibitor that has shown anti-tumor effects in mouse tumor models.
  • the technical problem to be solved by the present invention is to provide a small molecule PD-1/PD-L1 inhibitor, a pharmaceutical composition with PD-L1 antibody, and application thereof.
  • the present invention provides an aromatic vinyl or aromatic ethyl derivative represented by the general formula (I), its pharmaceutically acceptable salt, deuterated product, metabolite, metabolic precursor or prodrug:
  • Each R 1 is the same or different, and is each independently deuterium, halogen, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
  • R 2 is substituted or unsubstituted alkyl or halogen
  • Each R 3 is the same or different and is each independently deuterium, halogen, substituted or unsubstituted alkylthio, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted Substituted alkoxy,
  • R 1a is a C 1 -C 4 alkyl group, or two adjacent R 3 and the two carbon atoms connected to them together form a 5-7 membered carbocyclic or carbocyclic ring; the carbocyclic ring Where the heteroatoms are oxygen and/or nitrogen, and the number of heteroatoms is 1-4;
  • the substituent in the substituted alkyl group, the substituted alkoxy group or the substituted alkylthio group is selected from one or more of the following groups One: halogen, C 1-4 alkyl, hydroxyl, A C 1-4 alkoxy group, a carboxy C 1-4, C 1-4 and C 1-4 ester group an amide group; when a plurality of substituents, the substituents are the same or different;
  • R a and R b are independently hydrogen, or a substituted or unsubstituted alkyl group;
  • R a or R b the substituted alkyl group in a substituent selected from the group of one or more of: halo, C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 alkoxy group, C 1 -C 4 carboxyl group, C 1 -C 4 ester group or C 1 -C 4 amide group;
  • R a1 and R b1 are independently hydrogen or C 1 -C 4
  • the substituent in the substituted hydroxy group or the substituted amino group is selected from one or more of the following groups: C 1-4 alkyl, C 1 -4 alkoxy group, C 1-4 carboxyl group, C 1-4 ester group and C 1-4 amide group;
  • n 1, 2, 3, 4 or 5, preferably 1, 2 or 3;
  • n 0, 1, 2, 3, 4 or 5, preferably 0, 1, 2 or 3;
  • aromatic vinyl or aromatic ethyl derivatives represented by the general formula (I) are not the following compounds:
  • each R 1 is independently halogen, or, substituted or unsubstituted alkyl; or two adjacent R 1 and two carbon atoms connected to it together form a 5-7 Membered carbon heterocycle.
  • each R 1 is independently halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
  • R 2 is alkyl or halogen.
  • each R 3 is independently halogen, alkylthio or alkoxy; or two adjacent R 3 and the two carbon atoms connected to them together form a 5-7 member ⁇ carbon heterocycle.
  • the substituent in the substituted alkyl group is selected from one or more of the following groups: halogen or R a and R b are independently hydrogen, or a substituted or unsubstituted alkyl group; R a or R b, the substituted alkyl group in a substituent selected from the group of one or more of: Hydroxyl group or C 1 -C 4 carboxyl group.
  • the substituent in the substituted alkyl group, the substituted alkoxy group, the substituted hydroxy group or the substituted amino group means a Or more halogen substitutions, preferably one or more F substitutions.
  • the two adjacent R 3 and the two carbon atoms connected to them together form a 5-7 membered carbocyclic ring or carbocyclic ring
  • the carbocyclic or carbocyclic heterocyclic ring may be further substituted by one or more of C 1-4 alkyl (e.g. ).
  • heteroatoms in the heteroaromatic ring are selected from N, O and S, and the number of heteroatoms is 1-4.
  • the substituents are selected from one or more of the following groups: halogen, C 1-4 alkyl, hydroxyl, A C 1-4 alkoxy group, a carboxy C 1-4, C 1-4 and C 1-4 ester group an amide group; when a plurality of substituents, the substituents are the same or different; R a and R b are independently hydrogen, or a substituted or unsubstituted alkyl group; R a or R b, the substituted alkyl group in a substituent selected from the group of one or more of: halo, C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 alkoxy group, C 1 -C 4 carboxyl group, C 1 -C 4 ester group or C 1 -C 4 amide group; R a1 and R b1 are independently hydrogen or C 1 -C 4 alkyl ;
  • the substituents in the substituted heteroaromatic ring are preferably one or more
  • the heteroatoms in the heteroaromatic ring are selected from N and O, and the number of heteroatoms is 1-3.
  • the heteroatom is a N atom and the number of heteroatoms is 1 or 2; when the heteroaromatic ring is a bicyclic heteroaryl group and the heteroatom is N, the number of heteroatoms is preferably 3;
  • the heteroaromatic ring is a bicyclic heteroaryl, the heteroatom is selected from N and O, and the number of heteroatoms is 2; the heteroatoms are not adjacent.
  • n is 0, 1, 2, 3, 4 or 5, preferably 0, 1, 2 or 3.
  • R 3 is preferably halogen, alkylthio or alkoxy; and R 3 is located at the ortho, meta or para position of the benzene ring, for example
  • n is 2, preferably, two R 3 are located at the ortho and meta positions of the benzene ring, for example Wherein, two R 3 are the same or different; or two R 3 are adjacent, and two adjacent R 3 and the two carbon atoms connected to them together form a 5-7 membered carbocyclic ring, for example
  • the ring M is a 5-7 membered carbocyclic ring.
  • Ring M is a 5-7 membered carbocyclic ring (e.g. 2,3-dihydro-1,4-dioxane Oxazole ring such as Isoxazole ring such as Pyrazole ring such as ); Ring M may be further substituted by one or more of C 1-4 alkyl groups (for example ).
  • n is 4 or 5, preferably R 3 is deuterium;
  • m is 2 or 3.
  • the two R 1 are preferably located at the ortho and meta positions of the benzene ring, for example The two R 1 are the same or different.
  • m is 3, preferably, two R 1 are adjacent, and the two adjacent R 1 and the two carbon atoms connected to them together form a 5-7 membered carbocyclic ring, for example Wherein Ring N is a 5-7 membered carbocyclic ring, such as 2,3-dihydrofuran ring
  • two R 1 are located at the ortho and meta positions of the benzene ring respectively, and the two R 1 are the same or different; the R 1 at the ortho position of the benzene ring is F, A substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkoxy group.
  • one of R 1 (preferably located at the ortho position of the benzene ring) is preferably an alkyl or halogen-substituted alkyl; the other R 1 (preferably located at the meta position of the benzene ring) is preferably Substituted alkyl; when m is 3, two R 1 are adjacent, and the two adjacent R 1 and the two carbon atoms connected to them together form a 5-7 membered carbocyclic ring, the third R 1 is Substituted alkyl; wherein, the alkyl group is preferably a C 1-4 alkyl group.
  • the halogen-substituted alkyl group is preferably a C 1 -C 4 alkyl group substituted by one or more halogens, such as trifluoromethyl. Said The substituted alkyl group is preferably Substituted C 1 -C 4 alkyl.
  • the The substituted C 1 -C 4 alkyl group is preferably Wherein, R a and R b are one of H, the other is substituted with a hydroxyl group and / or carboxyalkyl.
  • the The substituted C 1 -C 4 alkyl group is preferably Among them, the carbons marked with * are S-configuration chiral carbons, R-configuration chiral carbons or achiral carbons. among them, Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably
  • Each R 1 is independently halogen, or, substituted or unsubstituted alkyl; or two adjacent R 1 and two carbon atoms connected to it together form a 5-7 membered carbocyclic ring;
  • R 2 is alkyl or halogen
  • Each R 3 is independently deuterium, halogen, alkylthio or alkoxy; or two adjacent R 3 and the two carbon atoms connected to them together form a 5-7 membered carbocyclic ring;
  • n 0, 1, 2, 3, 4 or 5, preferably 0, 1, 2 or 3;
  • Each R 1 is independently deuterium, or, substituted or unsubstituted alkyl; or two adjacent R 1 and two carbon atoms connected to it together form a 5-7 membered carbocyclic ring;
  • the substituent in the substituted alkyl group is selected from one or more of the following groups: halogen or R a and R b are independently hydrogen, or a substituted or unsubstituted alkyl group; R a or R b, the substituted alkyl group in a substituent selected from the group of one or more of: Hydroxyl group or C 1 -C 4 carboxyl group;
  • R 2 is alkyl or halogen
  • Each R 3 is independently deuterium, halogen, alkylthio or alkoxy; or two adjacent R 3 and the two carbon atoms connected to them together form a 5-7 membered carbocyclic ring;
  • n 0, 1, 2, 3, 4 or 5, preferably 0, 1, 2 or 3.
  • R 3 is preferably halogen, alkylthio or alkoxy; and R 3 is located on the benzene ring Ortho, meta, or para, for example
  • n 2 preferably, two R 3 are located at the ortho and meta positions of the benzene ring, for example Wherein, two R 3 are the same or different; or two R 3 are adjacent, and two adjacent R 3 and the two carbon atoms connected to them together form a 5-7 membered carbocyclic ring; for example Wherein ring M is a 5- to 7-membered carbocyclic ring; when n is 3, preferably, one of R 3 is halogen, the other two R 3 are adjacent, and the adjacent two R 3 are connected to them Two carbon atoms together form a 5-7 membered carbocyclic ring, for example Wherein ring M is a 5-7 membered carbocyclic ring;
  • m are 2 or 3; when m is 2, two R 1 are preferably located at the ortho and meta positions of the benzene ring, for example R 1 located at the ortho position of the benzene ring is preferably an alkyl group or halogen substituted alkyl; R 1 located at the meta position of the benzene ring is preferably Substituted alkyl; when m is 3, two R 1 are adjacent, and the two adjacent R 1 and the two carbon atoms connected to them together form a 5-7 membered carbocyclic ring, the third R 1 is Substituted alkyl; when n is 4 or 5, R 3 is deuterium.
  • Each R 1 is independently halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
  • R 2 is substituted or unsubstituted alkyl or halogen
  • Each R 3 is independently deuterium, halogen, substituted or unsubstituted alkylthio, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy ,
  • R 1a is a C 1 -C 4 alkyl group
  • the substituent in the substituted alkyl group, the substituted alkoxy group, the substituted hydroxy group or the substituted amino group refers to substitution by one or more halogens, Preferably substituted by one or more F;
  • the substituents in the substituted alkyl group described in each R 2 and each R 3 , the substituted alkoxy group described in each R 3 and the substituted alkylthio group are selected from the following groups One or more of: halogen, C 1-4 alkyl, hydroxyl, A C 1-4 alkoxy group, a carboxy C 1-4, C 1-4 and C 1-4 ester group an amide group; when a plurality of substituents, the substituents are the same or different; R a and R b are independently hydrogen, or a substituted or unsubstituted alkyl group; R a or R b, the substituted alkyl group in a substituent selected from the group of one or more of: halo, C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 alkoxy group, C 1 -C 4 carboxyl group, C 1 -C 4 ester group or C 1 -C 4 amide group; R a1 and R b1 are independently hydrogen or
  • the substituent in the substituted hydroxy group or the substituted amino group is selected from one or more of the following groups: C 1-4 alkyl, C 1-4 alkoxy Group, C 1-4 carboxyl group, C 1-4 ester group and C 1-4 amide group;
  • n 2 or 3;
  • n 0, 1, 2, 3, 4 or 5, preferably 0, 1, 2 or 3;
  • R 1 When m is 2, two R 1 each located at the benzene ring ortho and meta positions, the same or different two R < located on the benzene ring ortho position, R 1 is F, a substituted or unsubstituted alkyl group, or Substituted or unsubstituted alkoxy;
  • the heteroatoms in the heteroaromatic ring are selected from N, O and S, and the number of heteroatoms is 1-4;
  • the substituents in the substituted heteroaromatic ring One or more selected from the following groups: halogen, C 1-4 alkyl, hydroxyl, A C 1-4 alkoxy group, a carboxy C 1-4, C 1-4 and C 1-4 ester group an amide group; when a plurality of substituents, the substituents are the same or different;
  • R a and R b are independently hydrogen, or a substituted or unsubstituted alkyl group;
  • R a or R b the substituted alkyl group in a substituent selected from the group of one or more of: halo, C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 alkoxy group, C 1
  • R 3 is halogen or alkoxy, and R 3 is located at the para position of the benzene ring, m is 2 or 3, and when m is 2, it is located at the ortho position of the benzene ring.
  • R 1 is preferably a halogen-substituted alkyl group.
  • R 3 when n is 1 and R 3 is halogen, R 3 is preferably F or Cl. When R 3 is F, R 3 is preferably in the meta position of the benzene ring.
  • R 3 is deuterium
  • aromatic vinyl or aromatic ethyl derivatives represented by the general formula (I) are preferably any of the following compounds:
  • aromatic vinyl or aromatic ethyl derivatives represented by general formula (I) are preferably aromatic vinyl or aromatic ethyl derivatives represented by general formula (II):
  • R 1, R 2, R 3, n, R a R b are as previously defined and the.
  • the present invention also provides a preparation method of the aromatic vinyl or aromatic ethyl derivatives represented by the general formula (II), which comprises the following steps: combining compound (Ia) with Carry out the reductive amination reaction shown below to obtain the compound represented by the general formula (II);
  • R 1, R 2, R 3, n, R a R b are defined as previously described and, M1 is 2, 3 or 4, preferably 0, 1 or 2.
  • the method and conditions of the reductive amination reaction can be conventional methods and conditions of such reactions in the art.
  • the acid may also be added to the reductive amination reaction.
  • the acid is preferably an inorganic acid and/or an organic acid.
  • the inorganic acid is preferably hydrochloric acid and/or sulfuric acid.
  • the organic acid is preferably glacial acetic acid.
  • the molar ratio of the acid to the compound (I-a) is preferably 0.2:1 to 5:1 (for example, 2:1).
  • the solvent is preferably an organic solvent and/or water.
  • the organic solvent may be an organic solvent commonly used in such reactions in the art, preferably one or more of alcohol solvents, chlorinated hydrocarbon solvents, ether solvents and amide solvents.
  • the alcohol solvent is preferably methanol and/or ethanol.
  • the halogenated hydrocarbon solvent is preferably dichloromethane.
  • the ether solvent is preferably 1,4-dioxane.
  • the amide solvent is preferably N,N-dimethylformamide.
  • the solvent is preferably a mixed solvent of alcohol solvent and chlorinated hydrocarbon solvent, such as a mixed solvent of methanol and dichloromethane.
  • the volume ratio of the alcohol solvent to the chlorinated hydrocarbon solvent is preferably 1:0.1 to 1:5 (for example, 1:1).
  • the amount of the solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • the volume-to-mass ratio of the solvent to the compound represented by compound (I-a) is preferably 10 mL/g-200 mL/g.
  • the reducing agent may be a reducing agent commonly used in such reductive amination reactions, preferably one or more of sodium cyanoborohydride, sodium acetate borohydride, sodium borohydride and lithium borohydride, preferably cyanoborohydride sodium.
  • the molar ratio of the reducing agent to the compound (I-a) is preferably 0.3:1 to 10:1 (for example, 5:1).
  • compound (Ia) and The molar ratio of is preferably 1:1-1:3 (preferably 1:2).
  • the temperature of the reductive amination reaction is preferably 0°C to 120°C, more preferably 0°C to 50°C, and further preferably room temperature (10°C to 30°C).
  • the progress of the reductive amination reaction can be monitored by TLC or HPLC, and the end of the reaction is generally when the compound (I-a) disappears.
  • the product can be further purified by post-treatment.
  • the method for preparing the compound (Ia) preferably includes the following steps: in a solvent, under the action of a palladium catalyst, compound (II-b) and Carry out the coupling reaction shown below to obtain compound (Ia), and that is;
  • R 1, R 2, R 3, n, R a R b are defined as previously described and, X is halogen, M1 is 2, 3 or 4, preferably 0, 1 or 2.
  • the methods and conditions of the coupling reaction can be conventional methods and conditions of such reactions in the art.
  • a base may be added to the coupling reaction.
  • the base is preferably an alkali metal carbonate, more preferably sodium carbonate, potassium carbonate or cesium carbonate.
  • the molar ratio of the base to the compound (II-b) is preferably 1:1-5:1.
  • the solvent is preferably an organic solvent and/or water.
  • the organic solvent may be an organic solvent commonly used in such reactions in the field, preferably one or more of ether solvents, aromatic hydrocarbon solvents and amide solvents.
  • the ether solvents are preferably 1,4-dioxane and ethylene glycol dimethyl ether.
  • the aromatic hydrocarbon solvent is preferably toluene.
  • the amide solvent is preferably N,N-dimethylformamide.
  • the solvent is preferably aromatic hydrocarbon solvent.
  • the volume mass ratio of the solvent to the compound (II-b) is preferably 10 mL/g to 110 mL/g.
  • the palladium catalyst may be a palladium catalyst commonly used in such coupling reactions, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, One or more of tris(dibenzylidene indeneacetone) dipalladium, palladium acetate, and tetrakis(triphenylphosphine)palladium.
  • the molar ratio of the palladium catalyst to the compound (II-b) is preferably 0.005:1 to 0.5:1, more preferably 0.01:1 to 0.10:1.
  • the coupling reaction is preferably carried out under the action of a ligand, and the ligand is preferably 2-dicyclohexylphosphorus-2',4',6'-triisopropyl Biphenyl.
  • the temperature of the coupling reaction is preferably 50°C to 150°C (for example, 80 to 90°C).
  • the progress of the coupling reaction can be monitored by TLC or HPLC, and the end of the reaction is generally when compound (II-b) disappears.
  • the product can be further purified by post-treatment.
  • the compound of the present invention can be obtained by a variety of methods well known in the art and using known raw materials, such as chemical synthesis or extraction from plants. These methods are all included in the present invention. Unless otherwise specified or a preparation method is provided, the raw materials used to prepare the compound of the present invention or its intermediates are all known in the art or commercially available.
  • the present invention also provides the aromatic vinyl or aromatic ethyl derivatives represented by the general formula (I), pharmaceutically acceptable salts, deuterated substances, metabolites, metabolic precursors or prodrugs used in the preparation of PD -1 inhibitors and/or PD-L1 inhibitors.
  • the present invention also provides the aromatic vinyl or aromatic ethyl derivatives represented by the general formula (I), its pharmaceutically acceptable salts, deuterated products, metabolites, metabolic precursors or prodrugs used in the preparation Application in drugs for preventing, relieving or treating cancer, infection, autoimmune disease or related diseases.
  • the aromatic vinyl or aromatic ethyl derivatives represented by the general formula (I) its pharmaceutically acceptable salts, deuterated products, metabolites, metabolic precursors or prodrugs used in the preparation Application in drugs for preventing, relieving or treating cancer, infection, autoimmune disease or related diseases.
  • the cancer is preferably one or more of lung cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, blood cancer and bone cancer.
  • the present invention also provides a pharmaceutical composition, which comprises a therapeutically and/or preventively effective amount of the aromatic vinyl or aromatic ethyl derivative represented by the general formula (I), its pharmaceutically acceptable salt, Deuterated products, metabolites, metabolic precursors or prodrugs, and pharmaceutically acceptable carriers and/or diluents.
  • a pharmaceutical composition which comprises a therapeutically and/or preventively effective amount of the aromatic vinyl or aromatic ethyl derivative represented by the general formula (I), its pharmaceutically acceptable salt, Deuterated products, metabolites, metabolic precursors or prodrugs, and pharmaceutically acceptable carriers and/or diluents.
  • the present invention also provides a pharmaceutical composition, which comprises:
  • the PD-L1 antibody may be one or more of Atezolizumab (atezolizumab), Durvalumab, Avelumab, Cemiplimab, KN035, CS1001, MBS2311, BGB-A333, KL-A167, SHR-1316 and STI-A1014 Kind.
  • the PD-L1 antibody is Durvalumab.
  • the small molecule PD-1/PD-L1 inhibitor is an aromatic vinyl or aromatic ethyl derivative, a pharmaceutically acceptable salt, deuterated product, metabolite, metabolic precursor, or prodrug body.
  • the molecular weight of the small molecule PD-1/PD-L1 inhibitor is less than 1500 daltons, for example, less than 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600 or 500 daltons pause.
  • the small molecule PD-1/PD-L1 inhibitor has a PD-1/PD-L1 binding experiment (for example, the PD-1/PD-L1 binding experiment in Effect Example 1 herein) IC 50 values of less than 100nM, for example less than 90nM, 80nM, 70nM, 60nM, 50nM, 40nM, 30nM, 20nM, IC 50 values of 10nM or 1nM.
  • the small molecule PD-1/PD-L1 inhibitor binds to PD-L1. In some embodiments, the small molecule PD-1/PD-L1 inhibitor binds to PD-1.
  • the small molecule PD-1/PD-L1 inhibitor is a PD-L1 inhibitor. In some embodiments, the small molecule PD-1/PD-L1 inhibitor is a PD-1 inhibitor.
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention include compounds disclosed in WO2015034820 (the entirety of which is incorporated herein by reference), such as
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2018009505 (the entirety of which is incorporated herein by reference), such as
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2018195321 (the entirety of which is incorporated herein by reference), for example
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2018119263 (the entirety of which is incorporated herein by reference), such as
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2018119221 (the entirety of which is incorporated herein by reference), such as
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2018119224 (the entirety of which is incorporated herein by reference), for example
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2018119236 (the entirety of which is incorporated herein by reference), for example
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2018119266 (the entirety of which is incorporated herein by reference), for example
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2018119286 (the entirety of which is incorporated herein by reference), such as
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include the compounds disclosed in WO2018044783 (the entirety of which is incorporated herein by reference), such as
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2018013789 (the entirety of which is incorporated herein by reference), for example
  • the small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2017222976 (the entirety of which is incorporated herein by reference), such as
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2017205464 (the entirety of which is incorporated herein by reference), for example
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2017192961 (the entirety of which is incorporated herein by reference), for example
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2017112730 (the entirety of which is incorporated herein by reference), for example
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2017106634 (the entirety of which is incorporated herein by reference), for example
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2017087777 (the entirety of which is incorporated herein by reference), for example
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2017070089 (the entirety of which is incorporated herein by reference), such as
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2018026971 (the entirety of which is incorporated herein by reference), for example
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2018005374 (the entirety of which is incorporated herein by reference), for example
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2018051254 (the entirety of which is incorporated herein by reference), for example
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds described in CN201711445262.9 (the full text of which is incorporated herein by reference), for example
  • the small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds described in CN201710064453.4 (the full text of which is incorporated herein by reference), for example
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2017202273 (the entirety of which is incorporated herein by reference), such as
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2017202275 (the entirety of which is incorporated herein by reference), for example
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in WO2017202276 (the entirety of which is incorporated herein by reference), for example
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include the compounds disclosed in WO2018006795 (the entirety of which is incorporated herein by reference).
  • Small molecule PD-1/PD-L1 inhibitors within the scope of the present invention also include compounds disclosed in CN201710539028.6 (the entirety of which is incorporated herein by reference), for example
  • the small molecule PD-1/PD-L1 inhibitor can also be an aromatic vinyl or aromatic ethyl derivative represented by the general formula (I) as described above, and its pharmaceutically acceptable Salt, deuterium, metabolite, metabolic precursor or prodrug.
  • the small molecule PD-1/PD-L1 inhibitor is compound 29 or a pharmaceutically acceptable salt thereof.
  • the PD-L1 antibody is Durvalumab
  • the small molecule PD-1/PD-L1 inhibitor is compound 29 Or a pharmaceutically acceptable salt thereof.
  • the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor may be present in a single pharmaceutical composition, or may be present in separate separate pharmaceutical compositions.
  • PD-L1 antibody and small molecule PD-1/PD-L1 inhibitor need to be administered by different routes of administration or different dosing intervals, PD-L1 antibody and small molecule PD-1/PD-L1 inhibition are preferred
  • the agents are present in separate separate pharmaceutical compositions.
  • the pharmaceutical composition may also include a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises:
  • a pharmaceutically acceptable carrier is selected from:
  • the pharmaceutical composition comprises:
  • the first pharmaceutical composition which comprises a PD-L1 antibody and a pharmaceutically acceptable carrier;
  • the second pharmaceutical composition comprises a small molecule PD-1/PD-L1 inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be made into various suitable dosage forms according to different administration modes, including dosage forms for gastrointestinal administration (for example, oral dosage forms) and parenteral administration forms (for example, injection dosage forms).
  • the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor can be in a single unit dosage form, or they can be in different unit dosage forms.
  • the route and interval of administration of PD-L1 antibody and small molecule PD-1/PD-L1 inhibitor are different, it is preferable that PD-L1 antibody and small molecule PD-1/PD-L1 inhibitor exist in different units In the dosage form.
  • the PD-L1 antibody is in an injection dosage form, such as a subcutaneous injection dosage form, an intramuscular injection dosage form, or an intravenous injection dosage form.
  • the PD-L1 antibody is in the form of subcutaneous injection.
  • the PD-L1 antibody is in an intravenous dosage form.
  • the PD-L1 antibody is Durvalumab, which is in the form of injection.
  • the PD-L1 antibody is Durvalumab, which is in the form of subcutaneous injection.
  • the PD-L1 antibody is Durvalumab, which is an intravenous injection formulation.
  • the small molecule PD-1/PD-L1 inhibitor is an oral dosage form, such as an oral solid dosage form (e.g., tablet, capsule, pill, granule) and an oral liquid dosage form (e.g., oral solution, Oral suspension or syrup).
  • an oral solid dosage form e.g., tablet, capsule, pill, granule
  • an oral liquid dosage form e.g., oral solution, Oral suspension or syrup
  • the small molecule PD-1/PD-L1 inhibitor is an oral liquid dosage form, such as an oral suspension.
  • the small molecule PD-1/PD-L1 inhibitor is compound 29, which is an oral liquid dosage form, such as an oral suspension.
  • the small molecule PD-1/PD-L1 inhibitor is compound 29, which is 10% (w/v) polyoxyethylene hydrogenated castor oil 40 (Cremophor RH40), 20% (w/v) ) Sulfobutyl ether- ⁇ -cyclodextrin (SBE- ⁇ -CD) and 70% (w/v) water of compound 29 suspension (that is, a certain amount of compound 29 is suspended in 10% (w/v) ) Polyoxyethylene hydrogenated castor oil 40, 20% sulfobutyl ether- ⁇ -cyclodextrin and 70% water in a mixed solution).
  • the PD-L1 antibody is Durvalumab
  • the small molecule PD-1/PD-L1 inhibitor is compound 29 or a pharmaceutically acceptable salt thereof
  • Durvalumab is an injection dosage form
  • Compound 29 is an oral dosage form.
  • the PD-L1 antibody is Durvalumab
  • the small molecule PD-1/PD-L1 inhibitor is compound 29 or a pharmaceutically acceptable salt thereof
  • Durvalumab is a subcutaneous injection dosage form
  • Compound 29 is an oral liquid dosage form.
  • the PD-L1 antibody is Durvalumab
  • the small molecule PD-1/PD-L1 inhibitor is compound 29
  • Durvalumab is an intravenous injection dosage form
  • Compound 29 is an oral liquid dosage form.
  • the PD-L1 antibody is Durvalumab
  • the small molecule PD-1/PD-L1 inhibitor is compound 29
  • Durvalumab is in the form of subcutaneous injection; compound 29 is compound 29 with 10% (w/v) polyoxyethylene hydrogenated castor oil 40, 20% (w/v) sulfobutyl ether- ⁇ -cyclodextrin and 70% water Suspension.
  • the pharmaceutical composition can be presented in a unit dosage form containing a predetermined amount of active ingredient per unit dose.
  • the amount of active ingredient per dose depends on the condition being treated, the route of administration, and the age, weight and condition of the patient.
  • Preferred unit dose compositions contain a single dose, daily dose or sub-dose of the active ingredient, or suitable portions thereof.
  • this pharmaceutical composition can be prepared by any method well known in the pharmaceutical art.
  • the content of the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor in the unit dosage form of the pharmaceutical composition is a therapeutically effective amount.
  • the content ratio of the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor in the unit dosage form of the pharmaceutical composition may be 1:1-1:9, such as 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8 or 1:9.
  • the present invention provides an application of the pharmaceutical composition as described herein in the preparation of a medicine for treating cancer.
  • the present invention provides a method of treating cancer, which comprises administering a therapeutically effective amount of a pharmaceutical composition as described herein to a subject in need thereof.
  • the cancer is lung cancer, gastric cancer, colorectal cancer, cervical cancer, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, liver cancer, bladder cancer, kidney cancer, bone cancer, skin cancer, melanoma, Glioma, glioblastoma, leukemia or lymphoma.
  • the cancer is lung cancer, colorectal cancer, breast cancer, melanoma, leukemia, or lymphoma.
  • the cancer is colorectal cancer.
  • the cancer is colon cancer.
  • the dosage regimen of the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor can be adjusted by those skilled in the art as needed to provide the optimal The therapeutic effect.
  • the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor can be administered simultaneously or separately (for example, sequential administration).
  • the "simultaneous administration” means that the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor can be in a single pharmaceutical composition containing the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor Simultaneous application and combined use.
  • the "separate administration” means that the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor can be administered separately in each of the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor.
  • the pharmaceutical composition is administered separately in a sequential manner, for example, the PD-L1 antibody or the small molecule PD-1/PD-L1 inhibitor is administered first and the other is administered second.
  • Such sequential administration can be close in time (e.g. simultaneously) or distant in time.
  • the PD-L1 antibody can be administered by any suitable route in the art, including oral, injection (for example, intravenous, intramuscular, subcutaneous) and the like.
  • the PD-L1 antibody is administered by injection.
  • the PD-L1 antibody is administered by intravenous injection.
  • the PD-L1 antibody is administered by subcutaneous injection.
  • the PD-L1 antibody is Durvalumab, which is administered by injection.
  • the PD-L1 antibody is Durvalumab, which is administered by intravenous injection.
  • the PD-L1 antibody is Durvalumab, which is administered by subcutaneous injection.
  • the PD-L1 antibody (such as Durvalumab) can be administered according to the weight of the subject, and a non-limiting example range can be 1.0-1000 mg/kg, such as 10-150 mg/kg, such as 5 mg/kg, 10 mg/kg, 15mg/kg, 20mg/kg, 30mg/kg, 40mg/kg, 50mg/kg, 60mg/kg, 70mg/kg, 80mg/kg, 90mg/kg, 100mg/kg, 110mg/kg, 120mg/kg or 150mg/ kg. In some embodiments, the dose of PD-L1 antibody is 20 mg/kg.
  • the above dosage can be QD (once a day), BID (twice a day), TID (three times a day), QOD (one day apart), QW (once a week), BIW (twice a week) or Q2W (once every two weeks), etc. Dosing frequently.
  • the PD-L1 antibody is administered at BIW frequency.
  • the PD-L1 antibody (for example, Durvalumab) is administered by injection (for example, intravenous injection, subcutaneous injection) according to the above-mentioned dosage and frequency.
  • the PD-L1 antibody is Durvalumab, which is administered by injection (for example, intravenous injection, subcutaneous injection) at a dose of 20 mg/kg according to the BIW frequency.
  • the PD-L1 antibody (for example, Durvalumab) can also be administered to the subject in a fixed dose, that is, a fixed or predetermined amount of dose is given to the subject.
  • the small molecule PD-1/PD-L1 inhibitor can be administered by any suitable route in the art, including oral, injection (for example, intravenous, intramuscular, subcutaneous) and the like.
  • the small molecule PD-1/PD-L1 inhibitor is administered orally.
  • the small molecule PD-1/PD-L1 inhibitor is compound 29 and is administered orally.
  • the dosage regimen of the small molecule PD-1/PD-L1 inhibitor can be adjusted as needed to provide the best therapeutic effect.
  • the small molecule PD-1/PD-L1 inhibitor (such as compound 29) can be administered according to the weight of the subject, and a non-limiting example can range from 1.0-1000 mg/kg, such as 5-180 mg/kg, for example 5mg/kg, 10mg/kg, 15mg/kg, 20mg/kg, 30mg/kg, 40mg/kg, 50mg/kg, 60mg/kg, 70mg/kg, 80mg/kg, 90mg/kg, 100mg/kg, 110mg/ kg, 120mg/kg or 150mg/kg.
  • 1.0-1000 mg/kg such as 5-180 mg/kg, for example 5mg/kg, 10mg/kg, 15mg/kg, 20mg/kg, 30mg/kg, 40mg/kg, 50mg/kg, 60mg/kg, 70mg/kg, 80mg/kg, 90mg/kg, 100mg/kg, 110mg/ kg, 120mg/kg or 150mg
  • the dose of the small molecule PD-1/PD-L1 inhibitor is 15-180 mg/kg, such as 30-120 mg/kg, such as 60-120 mg/kg.
  • the above dosage can be QD (once a day), BID (twice a day), TID (three times a day), QOD (one day apart), QW (once a week), BIW (twice a week) or Q2W (once every two weeks) Dosing frequently.
  • small molecule PD-1/PD-L1 inhibitors are administered as frequently as BID.
  • the small molecule PD-1/PD-L1 inhibitor (for example, Compound 29) is administered orally according to the above-mentioned dosage and frequency.
  • the small molecule PD-1/PD-L1 inhibitor is compound 29, which is administered orally at a dose of 60 mg/kg according to the frequency of BID.
  • the small molecule PD-1/PD-L1 inhibitor (such as compound 29) can also be administered to the subject in a fixed dose, that is, a fixed or predetermined amount of dose is given to the subject.
  • the PD-L1 antibody is Durvalumab, which is administered by injection (for example, intravenous injection, subcutaneous injection) at a dose of 20 mg/kg according to the BIW frequency; and,
  • the small molecule PD-1/PD-L1 inhibitor is compound 29, which is administered orally at a dose of 60 mg/kg according to the frequency of BID.
  • the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor are administered separately, the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor can be continuously administered according to their respective administration cycles Administration.
  • the administration cycle of the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor can start at the same time or at different times.
  • the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor can be administered continuously on the same day according to their respective dosing cycles; or, the small molecule PD-1/PD-L1 inhibitor can be administered in PD -L1 antibody is administered on the second day or on the third day or more after the start of administration, and then both are administered continuously according to their respective administration cycles.
  • the pharmaceutical composition described herein can be presented in the form of a combination kit (or called a kit of parts).
  • kit or “kit of parts” as used herein refers to a container for administering one or more pharmaceutical compositions of the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor.
  • the combination kit can include the PD-L1 antibody and the small molecule PD-L1 in a single pharmaceutical composition or a separate pharmaceutical composition. 1/PD-L1 inhibitor.
  • the combination kit will contain a separate first pharmaceutical composition containing PD-L1 antibody and a small molecule PD-1 /PD-L1 inhibitor of the second pharmaceutical composition.
  • the combination kit comprises:
  • a pharmaceutically acceptable carrier is selected from:
  • the PD-L1 antibody and the small molecule PD-1/PD-L1 inhibitor are provided in a form suitable for simultaneous administration and/or separate administration.
  • the combination kit comprises:
  • a first container comprising a first pharmaceutical composition, the first pharmaceutical composition comprising a PD-L1 antibody and a pharmaceutically acceptable carrier;
  • a second container which contains a second pharmaceutical composition, the second pharmaceutical composition comprising a small molecule PD-1/PD-L1 inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • compositions described herein can be used alone or in combination with one or more other therapeutic agents (eg, immunomodulators, other anti-tumor agents, etc.). Therefore, the pharmaceutical composition described herein may include PD-L1 antibodies, small molecule PD-1/PD-L1 inhibitors, and optionally other therapeutic agents. This combination of agents can be administered together or separately, and when administered separately, they can be administered simultaneously or sequentially in any order that is close in time and distant in time.
  • therapeutic agents eg, immunomodulators, other anti-tumor agents, etc.
  • the pharmaceutical composition described herein may include PD-L1 antibodies, small molecule PD-1/PD-L1 inhibitors, and optionally other therapeutic agents. This combination of agents can be administered together or separately, and when administered separately, they can be administered simultaneously or sequentially in any order that is close in time and distant in time.
  • composition described herein can also be used together with other treatment methods for cancer treatment (for example, chemotherapy, surgery and/or radiation therapy, etc.).
  • small molecule PD-1/PD-L1 inhibitor refers to any small molecule compound that can directly or indirectly reduce or inhibit (partially or completely) the activity of the PD-L1/PD-1 pathway, which can be expressed as " Small molecule PD-1/PD-L1 pathway inhibitor".
  • Small molecule PD-1/PD-L1 inhibitors can inhibit the interaction of PD-1, PD-L1, and/or PD-1/PD-L1.
  • small molecules should be understood as a concept opposite to biological macromolecules, that is, small molecules do not include biological macromolecular drugs (such as antibodies), which should not be understood as unclear.
  • antibody as used herein is intended to include whole molecules as well as fragments that contain an antigen binding site and can bind to an epitope.
  • PD-L1 as used herein includes isotypes, mammalian, such as human PD-L1, species homologs of human PD-L1, and analogs containing at least one common epitope with PD-L1.
  • the amino acid sequence of PD-L1, such as human PD-L1, is known in the art.
  • homologous refers to the subunit sequence identity between two polymeric molecules, for example, between two nucleic acid molecules, such as between two DNA molecules or two RNA molecules, or between two polypeptide molecules. between.
  • two molecules are occupied by the same monomer subunit at a subunit position, for example, if two DNA molecules are each occupied by adenine at a position, then they are homologous or identical at that position of.
  • the homology between two sequences is a direct function of the number of matches or homologous positions; for example, if half of the positions in the two sequences (for example, five positions in a ten subunit long polymer) are homologous , The two sequences are 50% homologous; if 90% of the positions (for example, 9 out of 10) are matched or homologous, the two sequences are 90% homologous.
  • P-L1 antibody as used herein may be polyclonal or monoclonal.
  • monoclonal antibody refers to those that exhibit binding specificity and affinity to only a single specific epitope.
  • Monoclonal antibodies can be prepared by hybridoma technology or methods that do not use hybridoma technology (such as recombinant methods).
  • the PD-L1 antibodies described herein may be humanized.
  • the term "humanized” refers to a non-human (e.g., murine) antibody form containing minimal sequences derived from non-human immunoglobulins, which may be chimeric immunoglobulins, immunoglobulin chains or fragments thereof.
  • the PD-L1 antibody described herein also includes a homology of more than 80%, preferably more than 90%, more preferably 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98 % Or more than 99% of antibody molecules.
  • treatment refers to therapeutic therapy.
  • treatment refers to: (1) alleviating one or more biological manifestations of the disease or disease, (2) interfering with (a) one or more points in the biological cascade causing or causing the disease, or (b) ) One or more biological manifestations of the disease, (3) Improve one or more symptoms, effects or side effects related to the disease, or one or more symptoms, effects or side effects related to the disease or its treatment, Or (4) to slow down the development of the disease or one or more biological manifestations of the disease.
  • the compounds of the invention are administered as a preventive measure.
  • preventing or “preventing” refers to reducing the risk of acquiring a given disease or condition.
  • the designated compound is administered to a subject as a preventive measure, such as a subject with a family history or tendency of cancer or autoimmune disease.
  • terapéuticaally effective amount refers to an amount of a compound that is sufficient to effectively treat the diseases or conditions described herein when administered to a subject.
  • the amount of the compound constituting the “therapeutically effective amount” will vary according to the compound, the condition and its severity, the age of the subject to be treated, the compound dosage form, the mode of administration, the interval of administration, etc., but can be determined by those skilled in the art as required Make sure.
  • administration refers to the subject's administration of one or more substances (for example, PD-L1 antibody and/or PD-L1 small molecule inhibitor), which can also be expressed as “administration”.
  • substances for example, PD-L1 antibody and/or PD-L1 small molecule inhibitor
  • pharmaceutical composition (pharmaceutical composition) used herein can also be expressed as “pharmaceutical combination”, and the two can be substituted for each other in this document.
  • dose refers to a single dose.
  • container refers to any container and closure suitable for storing, transporting, dispensing and/or handling pharmaceuticals.
  • pharmaceutically acceptable refers to salts, compositions, excipients and the like that are generally non-toxic, safe, and suitable for use by subjects, preferably mammalian subjects, more preferably human subjects.
  • subject or “patient” as used herein refers to any animal that is about to or has received administration of the compound or composition according to an embodiment of the present invention, mammals are preferred, and humans are preferred.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
  • subject and patient are used interchangeably herein.
  • salts include, but are not limited to: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinic acid Salt, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate , Fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate , P-toluenesulfonate and pamoate (i.e.
  • Suitable alkali salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, bismuth, and diethanolamine salts.
  • Suitable alkali salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, bismuth, and diethanolamine salts.
  • halogen as used herein is preferably F, Cl, Br or I.
  • substituted or unsubstituted alkyl group is preferably a substituted or unsubstituted C 1 -C 4 alkyl with.
  • the substituted or unsubstituted C 1 -C 4 alkyl group is preferably substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl , Substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, or, substituted or unsubstituted tert-butyl.
  • substituted or unsubstituted alkoxy is preferably a substituted or unsubstituted C 1 -C 4 alkoxy group.
  • the substituted or unsubstituted C 1 -C 4 alkoxy group is preferably substituted or unsubstituted methoxy, substituted or unsubstituted ethoxy, substituted or unsubstituted n-propoxy, substituted or unsubstituted
  • alkylthio as used herein is preferably -SR s , where R s is a C 1 -C 4 alkyl group.
  • C 1-4 alkyl as used herein is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • C 1-4 alkoxy as used herein is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
  • C 1-4 carboxyl as used herein is preferably
  • C 1-4 ester group used herein is preferably Wherein, R 2a is a C 1- C 4 alkyl group.
  • R 1b is hydrogen or C 1- C 4 alkyl.
  • heteromatic ring used herein is preferably a C 1 -C 10 heteroaromatic ring, more preferably an acridine ring, a carbazole ring, a cinnoline ring, a carboline ring, a quinoxaline ring, an imidazole ring, a pyrazole ring, a pyrrole Ring, indole ring, indoline ring, benzotriazole ring, benzimidazole ring, furan ring, thiophene ring, isothiazole ring, benzothiophene ring, dihydrobenzothiophene ring, benzofuran ring, Isobenzofuran ring, benzoxazole ring, benzofuran ring, benzopyrazole ring, quinoline ring, isazaindene ring, isoquinoline ring, oxazole ring, oxadiazole
  • 5-7 membered carbocyclic ring refers to a 5-7 membered carbocyclic ring where the heteroatom is oxygen and/or nitrogen, and the number of heteroatoms is 1-4. There are 5, 6 or 7 ring atoms in the 5-7 membered carbon heterocyclic ring.
  • the 5-7 membered carbocyclic ring includes but is not limited to: azetidine ring, piperazine ring, piperidine ring, pyrrole ring, morpholine ring, thiomorpholine ring, 1,4-dioxane ring , Pyran ring, dihydroimidazole ring, dihydroisoxazole ring, dihydroisothiazole ring, dihydrooxadiazole ring, dihydrooxazole ring, dihydropyrazine ring, dihydropyrazole ring, dihydro Pyridine ring, dihydropyrimidine ring, dihydropyrrole ring, dihydroquinoline ring, dihydrotetrazole ring, dihydrothiadiazole ring, dihydrothiazole ring, dihydrotriazole ring, dihydroazetidine ring , Imidazole ring, pyrazole ring, pyrrol
  • pharmaceutically acceptable carrier refers to any preparation or carrier medium that can deliver an active substance, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient.
  • the pharmaceutical composition can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and Suspension), etc., preferably liquid, suspension, emulsion, suppository, injection (solution and suspension), etc.
  • any excipient known and widely used in the art can be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, etc.
  • binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrant such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose, etc.
  • disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenated Oil
  • adsorption promoters such as
  • any known and widely used excipients in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc; binders , Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol; disintegrants such as agar and kelp powder.
  • carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc
  • binders Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol
  • disintegrants such as agar and kelp powder.
  • any excipients known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. .
  • the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin, etc.) to prepare an injection that is isotonic with blood.
  • any carriers commonly used in the art can also be used.
  • usual dissolving agents, buffers and analgesics can also be added.
  • the diluent may be a conventional diluent in the art.
  • the pharmaceutical composition may be in the form of oral or sterile injectable aqueous solution, and the oral or injection composition may be prepared according to any method known in the art for preparing pharmaceutical compositions.
  • the term "prodrug” refers to a derivative of a compound containing a biologically reactive functional group, such that under biological conditions (in vitro or in vivo), the biologically reactive functional group can be cleaved from the compound or otherwise reacted to provide the The compound.
  • the prodrug is inactive, or at least less active than the compound itself, so that the compound cannot exert its activity until the compound is cleaved from the biologically reactive functional group.
  • the bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound.
  • the prodrug may contain a biohydrolyzable group.
  • biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphate, biohydrolyzable ester, biohydrolyzable amide, biohydrolyzable carbonate, biohydrolyzable carbamate, and biohydrolyzable Urea.
  • stereoisomers refers to cis- and trans-isomers, R- and S-enantiomers, and diastereomers.
  • stereoisomer refers to cis- and trans-isomers, R- and S-enantiomers, and diastereomers.
  • These stereoisomers can be prepared by asymmetric synthesis methods or chiral separation methods (for example, separation, crystallization, thin layer chromatography, column chromatography, gas chromatography, high performance liquid chromatography).
  • stereoisomers can also be derived from diastereomers in which a mixture of enantiomers or racemates are reacted with a suitable chiral compound, and then obtained by crystallization or any other suitable conventional method.
  • the compound of the present invention may also include its metabolites.
  • the term "metabolite” as used herein refers to the active substance produced after the chemical structure of the drug molecule undergoes changes in the body.
  • the active substance is generally a derivative of the aforementioned drug molecule, which can also be chemically modified.
  • the compound of the present invention may also include its polymorph.
  • crystal form refers to one or more crystal structures formed by different arrangements of molecules in the lattice space during crystallization.
  • the compound of the present invention may also include its solvate.
  • solvate refers to a crystalline form of a compound, its pharmaceutically acceptable salt, crystal form, co-crystal, stereoisomer, isotopic compound, metabolite or prodrug, and it also contains one or A variety of solvent molecules incorporated into the crystal structure.
  • Solvates may include stoichiometric or non-stoichiometric amounts of solvent, and solvent molecules in the solvent may exist in an ordered or non-ordered arrangement.
  • a solvate containing a non-stoichiometric amount of solvent molecules may result from the solvate losing at least a portion (but not all) of the solvent molecules.
  • a solvate is a hydrate, meaning that the crystalline form of the compound further includes water molecules.
  • the compounds of the present invention may also include their prodrugs.
  • prodrug refers to a derivative of a compound containing a biologically reactive functional group, such that under biological conditions (in vitro or in vivo), the biologically reactive functional group can be cleaved from the compound or otherwise react to provide the compound.
  • the prodrug is inactive, or at least less active than the compound itself, so that the compound cannot exert its activity until the compound is cleaved from the biologically reactive functional group.
  • the bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound.
  • the prodrug may contain a biohydrolyzable group.
  • biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphate, biohydrolyzable ester, biohydrolyzable amide, biohydrolyzable carbonate, Biohydrolyzable carbamates and biohydrolyzable ureas.
  • the compounds of the present invention may also include isotopic derivatives thereof.
  • isotopic derivative refers to the compound containing one or more natural or unnatural abundance atomic isotopes. Atomic isotopes of unnatural abundance include but are not limited to deuterium ( 2 H or D), tritium ( 3 H or T), iodine-125 ( 125 I), phosphorus-32 ( 32 P), carbon-13 ( 13 C) Or carbon-14 ( 14 C). All isotopic variants of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • the compound codes used herein such as KN035, CS1001, MBS2311, BGB-A333, KL-A167, SHR-1316, STI-A1014, etc., are all known in the art.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is to provide a small molecule PD-1/PD-L1 inhibitor or a pharmaceutical composition with PD-L1 antibody, which can be used to treat cancer.
  • Fig. 1 is a graph showing the change in body weight of mice in each group in effect example 3.
  • Fig. 2 is a graph showing the rate of change in body weight of mice in each group in Effect Example 3.
  • Fig. 3 is a graph showing the tumor volume growth curve of each group of mice in Effect Example 3.
  • Figure 4 is a graph showing the tumor inhibition rate of each group of mice in Effect Example 3.
  • room temperature refers to 10°C-30°C
  • reflux refers to the solvent reflux temperature
  • overnight refers to 8-24 hours, preferably 12-18 hours.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the nuclear magnetic resonance spectrum is obtained by Bruker Avance-500 instrument. Deuterated dimethyl sulfoxide, deuterated chloroform and deuterated methanol are used as solvents. Tetramethyl Silane (TMS) is an internal standard.
  • TMS Tetramethyl Silane
  • the mass spectrum was obtained by a liquid chromatography-mass spectrometry (LC-MS) combined instrument Agilent Technologies 6110, using an ESI ion source.
  • the microwave reaction is carried out in the Explorer automatic microwave synthesizer produced by CEM, USA.
  • the magnetron frequency is 2450MHz and the continuous microwave output power is 300W.
  • the instrument used for HPLC preparation is Gilson 281, and the preparation column used is Shimadazu Shim-Pack, PRC-ODS, 20x250mm, 15 ⁇ m.
  • 1,4-dioxane-6-phenylboronic acid (3.60g, 20mmol) and 2,6-dibromotoluene (7.50g, 30mmol) were dissolved in 1,4-dioxane (100mL) and water ( 15 mL) was added to the mixed solution of [1,1'-bis(diphenylphosphorferrocene)] palladium dichloride dichloromethane complex (817 mg, 1 mmol) and sodium carbonate (6.38 g, 60 mmol). After the reaction system was replaced with nitrogen three times, it was heated to 80°C and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 1-c (2.70 g, yield: 44%).
  • ⁇ -(Hydroxymethyl)serine (135mg, 1mmol) was dissolved in water (3mL) and 1M sodium hydroxide (2mL) in an aqueous solution, compound 3-b (110mg, 0.3mmol) in tetrahydrofuran (3mL) and In a mixed solution of ethanol (5 mL), the mixture was stirred at room temperature for 16 hours. The reaction solution was cooled to 0°C, sodium borohydride (38 mg, 1 mmol) was added, and stirring was continued for 1 hour.
  • a homogeneous time-resolved fluorescence (Homogenouse Time-Resolved Fluorescence, HTRF) binding test is used to detect the binding ability of the compound of the present invention to PD-1/PD-L1.
  • the purchased kit contains the reagents needed for experiments such as PD-1, PD-L1, anti-tag1-Eu, Anti-tag2-XL665, Dilute Buffer and Detection Buffer.
  • the compound is configured with 100% DMSO into 10 concentrations with a concentration gradient of 3 times.
  • the internal standard Glipizide (Glipizide, molecular formula C 21 H 27 N 5 O 4 S, molecular weight 445.5 g/mol, analytical grade) was purchased from Sigma-Aldrich (USA). Methanol, acetonitrile, and formic acid (HPLC grade) were purchased from Sigma-Aldrich Company (USA), and pure water was purchased from Hangzhou Wahaha Group Co., Ltd. (Hangzhou, China). Other chemical reagents are of analytical grade.
  • WinNonlin 6.4 software USA was used to calculate the pharmacokinetic parameters of the compound according to the non-compartmental model.
  • mice pharmacokinetic results of the compound of the present invention are as follows (Table 2):
  • Antibody PD-L1 antibody Imfinzi (Durvalumab), specification 120mg/2.4mL (50mg/mL), Lot: 041E17C.
  • Manufacturer AstraZeneca, purchased from Hong Kong Mingchuang Pharmaceutical Co., Ltd., and stored at 2-8°C.
  • mice human PD-1 transgenic mice, strain: C57BL/6-hPD-1 mice, 6-8 weeks, weighing 18-21 grams, female, 120, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. .
  • Cremophor RH40 (CAS: 61788-85-0, Lot: 29761847G0, supplier: Shanghai Xietai Chemical Co., Ltd.); SBE- ⁇ -CD (CAS: 128446-35-5, Lot: R1804474, supplier: Shanghai Shaoyuan Reagent Co., Ltd.); DMEM (CAS: 11995-065, Lot: 2025378, supplier: Gibco); Penicillin double antibody (CAS: 15140-122, Lot: 1953101, supplier: Hyclone); Bovine serum (CAS: 10099-141, Lot: 1966174C, supplier: Gibco); hygromycinB (CAS: 10687010, Lot: HY069-L12, supplier: Invitrogen).
  • MC-38-hPD-Ll cells Human PD-L1 gene knocked into MC-38 cells adhered culture in vitro, the culture conditions are DMEM medium with 10% heat-inactivated fetal bovine serum, and hygromycinB (final concentration 100 ⁇ L/mL), incubated at 37°C with 5% CO 2 . Passage treatment three times a week. When the cells are in the exponential growth phase, the cells are collected and counted. 100 ⁇ L of 1 ⁇ 106 MC-38-hPD-L1 cell suspension was inoculated subcutaneously on the right dorsal side of C57BL/6-hPD-1 mice.
  • tumor-bearing mice Six days after inoculation, 60 tumor-bearing mice with transplanted tumor volume ranging from 31.49mm 3 -110.26mm 3 were selected. According to the experimental plan, the tumor-bearing mice were randomly divided into 6 groups, each with 10 mice, and the administration was started on the same day.
  • Solvent preparation Measure 800mL of sterile water into the volumetric flask, turn on the magnetic stirring to make the liquid surface have a vortex, slowly add 100g of Cremophor RH40 medicine spoon into the vortex, continue to stir until the solution is clear, then slowly add 200g The SBE- ⁇ -CD is continuously stirred until the solution is clear, and the final volume is adjusted to 1000 mL to obtain an aqueous solution containing 10% (w/v) Cremophor RH40+20% (w/v) SBE- ⁇ -CD.
  • Preparation of compound 29 suspension weigh 150.92 mg of compound 29, add 12.5 mL of 10% (w/v) Cremophor RH40 + 20% (w/v) SBE- ⁇ -CD aqueous solution (hereinafter referred to as solvent), vortex Rotate for 2 minutes to mix well, and ultrasonic for 30 minutes to obtain a suspension solution with a concentration of 12.0 mg/mL.
  • solvent 10% (w/v) Cremophor RH40 + 20% (w/v) SBE- ⁇ -CD aqueous solution (hereinafter referred to as solvent), vortex Rotate for 2 minutes to mix well, and ultrasonic for 30 minutes to obtain a suspension solution with a concentration of 12.0 mg/mL.
  • Aspirate 5.0 mL of the compound 29 suspension solution with a concentration of 12.0 mg/mL add 5.0 mL of the solvent solution, vortex for 1 minute to mix well, and sonicate for 5 minutes to obtain a suspension solution with a concentration of 6.0 mg/mL.
  • Preparation of PD-L1 antibody Pipette 0.12mL of Durvalumab stock solution (concentration: 50mg/mL), divide into 6 aliquots in 5mL sterile centrifuge tubes, each with a content of 6.0mg, and place the aliquots in a refrigerator at 4°C for later use. Before administration, take a 0.12mL stock solution with a concentration of 50mg/mL, add 2.88mL 0.9% sodium chloride solution, vortex slightly to mix the solution completely, and obtain 3mL of Durvalumab solution with a final concentration of 2mg/mL.
  • mice in the vehicle control group were weighed and recorded on an electronic balance according to their numbers.
  • the mice were given the vehicle by gavage twice a day, with a capacity of 0.1mL/10g, and each mouse took about 20 seconds.
  • Each group It takes about 5 minutes to share with 10 animals.
  • mice in the compound 29 (30mg/kg) group were weighed and recorded on an electronic balance according to their numbers.
  • the compound 29 suspension was given by gavage twice a day according to the mouse body weight, and the compound 29 was given at 30 mg/kg.
  • Medicine, the administration volume is 0.1mL/10g, it takes about 20 seconds for each mouse, and about 5 minutes for each group of 10 mice.
  • mice in the compound 29 (60mg/kg) group were weighed and recorded on an electronic balance according to their numbers.
  • the compound 29 suspension was administered by gavage twice a day according to the mouse body weight, and the compound 29 suspension was administered at 60 mg/kg.
  • Medicine, the administration volume is 0.1mL/10g, it takes about 20 seconds for each mouse, and about 5 minutes for each group of 10 mice.
  • mice in the compound 29 (120mg/kg) group were weighed and recorded on an electronic balance according to their numbers, and the compound 29 suspension was given by gavage twice a day according to the weight of the mice, and the compound 29 was given at 120 mg/kg.
  • Medicine, the administration volume is 0.1mL/10g, it takes about 20 seconds for each mouse, and about 5 minutes for each group of 10 mice.
  • mice in the combined drug (compound 29: 60mg/kg; Durvalumab: 20mg/kg) group were weighed and recorded on an electronic balance according to their numbers, and the compound was given by intragastric administration twice a day according to the weight of the mice
  • the 29 suspension is administered at 60 mg/kg with a dosage volume of 0.1 mL/10 g. It takes about 20 seconds for each mouse, and about 5 minutes for each group of 10 mice.
  • mice in the combined drug (compound 29: 60mg/kg; Durvalumab: 20mg/kg) group were weighed and recorded on an electronic balance according to their numbers, and the formulated Durvalumab was injected into the abdominal cavity according to the mouse body weight at 20 mg/kg It is administered twice a week, with a volume of 0.1mL/10g. It takes about 20 seconds for each mouse, and about 5 minutes for each group of 10 mice.
  • Figure 1 is a graph of the weight change of each group of mice, drawn from the average weight of each group of mice measured daily during the experiment.
  • Figure 2 is a graph of the relative change rate of body weight of each group of mice, drawn from the average of the daily body weight change rate of each group of mice during the experiment.
  • Figure 3 is a graph of the tumor volume growth curve of each group of mice, drawn from the average value of the tumor volume measured by each group of mice during the experiment.
  • Figure 4 is a graph of the tumor inhibition rate of each group of mice, drawn from the average value of the tumor inhibition rate calculated for each group of mice during the experiment.
  • P value is calculated based on tumor volume (compared with solvent control group).
  • the experimental results showed that, compared with the vehicle control group, the tumor inhibition rate of group 2 (PD-L1 antibody Durvalumab) was 48.17%, the maximum tumor inhibition rate of compound 29 was 51.21%, and the inhibition rate of the combination group was 51.21%. The tumor rate was 62.82%. From this, the following conclusions can be drawn: The inhibitory effect of the combination group on colon cancer (MC-38-hPD-L1) cells is significantly better than that of single component compound 29 or PD-L1 antibody, which can be significant Increase the tumor inhibition rate in mice, and has statistical significance.

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Abstract

一种小分子PD-1/PD-L1抑制剂、其与PD-L1抗体的药物组合物及其应用。其中，该小分子PD-1/PD-L1抑制剂例如通式（I）所示的芳香乙烯或芳香乙烯类衍生物，其可以用于治疗癌症。

Description

小分子PD-1/PD-L1抑制剂、其与PD-L1抗体的药物组合物及其应用
本申请要求申请日为2019/03/22的中国专利申请201910222624.0的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种小分子PD-1/PD-L1抑制剂、其与PD-L1抗体的药物组合物及其应用。
背景技术
人程序性死亡因子配体1(PD-L1)，又称B7-H1，属于B7家族成员，广泛分布于外周组织和造血细胞。PD-L1q全长cDNA 870bp，编码一段含290个氨基酸的I型过膜蛋白，PD-L1主要表达于承受的CD4T细胞、CD8T细胞、B细胞、单核细胞、树突状细胞(Dendritic Cells,DCs)、巨噬细胞等造血细胞及一些非造血细胞，如内皮细胞、胰岛细胞、肥大细胞等的膜表面。其中PD-L1在多种肿瘤中高表达，如肺癌、胃癌、多发性骨髓、黑色素瘤和乳腺癌等。程序性死亡因子1(programmed death-1,PD-1)是PD-L1的主要受体，主要分布于T细胞、B细胞和NK细胞等免疫相关细胞，在自身免疫病、肿瘤、感染、器官移植、过敏、免疫特权等等的免疫应答过程中都扮演着重要角色。
PD-L1通过与其受体程序性死亡因子1相互作用抑制T细胞的激活或诱导成熟T细胞凋亡，使得免疫反应受到抑制。肿瘤发展过程中，癌细胞会通过上调PD-L1表达，诱导T细胞的凋亡，避免免疫系统对其的清除。PD-L1靶向抗体药物能够通过特异性阻断PD-1/PD-L1的相互作用打破肿瘤免疫耐受，恢复肿瘤特异性T细胞对肿瘤细胞的杀伤功能，进而实现肿瘤的清除。目前有四个PD-L1抗体药物上市，分别是：罗氏的Atezolizumab(阿特珠单抗，商品名：Tecentriq)，适应症包括黑色素瘤、尿路上皮癌(膀胱癌)、转移性非小细胞肺癌(IV期)；阿斯利康的Durvalumab(德瓦鲁单抗，商品名：Imfinzi)，适应症为晚期或转移性尿路上皮癌(膀胱癌)；辉瑞和德国默克的Avelumab(商品名：Bavencio)，适应症为罕见皮肤癌默克細胞癌(MCC)；再生元的Cemiplimab(商品名：Libtayo)，适应症为治疗转移性或局部晚期皮肤鳞状细胞癌。同时，还有许多正在研发的PD-L1抗体药物，康宁杰瑞、基石药业、恒瑞医药、迈博斯、百济神州、科伦博泰和兆科药业等企业研发的PD-L1抗体药物已经开始了临床研究。
随着免疫治疗在很多癌症以及临床试验取得的不错疗效，很多肿瘤患者获益于PD-1/PD-L1单抗，但是研究发现，PD-1/PD-L1大分子抗体并非对所有的癌症都有较好的治 疗效果，临床试验数据显示，PD-1/PD-L1抗体单抗药物治疗肿瘤的有效率仅有10-30％之间。
最近，中国科学院微生物研究所高福团队通过结构免疫学平台，成功解析了Durvalumab抗体与人PD-L1分子的复合物结构，阐明了PD-L1靶向性肿瘤治疗抗体的作用机制(Protein&Cell,2018,9(1),135-139)。研究发现，Durvalumab的重链和轻链都参与了与PD-L1的结合，结合所导致的空间结构的折叠阻止了PD-L1与PD-1的结合。通过对首个被FDA批准上市的PD-L1抗体Atezolizumab的晶体复合体的解析(Oncotarget,2017,8,90215-90224)可以发现，Atezolizumab和PD-L1的结合涉及了大量的氢键、疏水的相互作用和π-π叠加作用或阳离子-π的相互作用。此外，突变研究显示PD-L1有二个热点残基(E58，R113)。总之，Atezolizumab与PD-1竞争PD-L1的相同表面结合位点。
前不久来自波兰雅盖隆大学的Tad A.Holak等人在杂志(J.Med.Chem.2017,60,5857-5867)上发表文章，揭示了作用于PD-1/PD-L1通路的小分子抑制剂的作用机制——诱导PD-L1的二聚化，当配体小分子和PD-L1蛋白结合后会诱导PD-L1的二聚化。肿瘤细胞的PD-L1一旦二聚化则无法和PD-1正常结合。当肿瘤细胞的PD-L1无法和T细胞的PD-1结合时，肿瘤细胞将被活化的T细胞杀死。
由于小分子药物在批量生产和质量控制等方面的优势，小分子PD-1/PD-L1抑制剂也在积极研发之中。WO2018006795公开了一种新的小分子PD-1/PD-L1抑制剂，在小鼠肿瘤模型中显示出了抗肿瘤作用。
目前还未有PD-L1抗体和小分子PD-1/PD-L1抑制剂的联合用药的公开报道，如果这一联合用药策略能提高治疗肿瘤疗效的话，将对免疫治疗肿瘤产生深远的影响。
发明内容
本发明所要解决的技术问题是提供一种小分子PD-1/PD-L1抑制剂、其与PD-L1抗体的药物组合物及其应用。
本发明提供了一种通式(I)所示的芳香乙烯或芳香乙基类衍生物、其药学上可接受的盐、氘代物、代谢产物、代谢前体或药物前体：
Figure PCTCN2020080362-appb-000001
其中：
Figure PCTCN2020080362-appb-000002
为单键或双键；
每个R 1相同或不同，各自独立地为氘、卤素、取代或未取代的羟基、取代或未取代的氨基、取代或未取代的烷基、或取代或未取代的烷氧基；
或者相邻的两个R 1和与它们相连的两个碳原子共同形成一个5-7元的碳环或碳杂环；所述碳杂环中，杂原子为氧和/或氮，杂原子数为1-4个；
R 2为取代或未取代的烷基或卤素；
每个R 3相同或不同，各自独立地为氘、卤素、取代或未取代的烷硫基、取代或未取代的羟基、取代或未取代的氨基、取代或未取代的烷基、取代或未取代的烷氧基、
Figure PCTCN2020080362-appb-000003
Figure PCTCN2020080362-appb-000004
其中，R 1a为C 1-C 4烷基，或者相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳环或碳杂环；所述碳杂环中，杂原子为氧和/或氮，杂原子数为1-4个；
每个R 1或每个R 3中，所述的取代的烷基、所述的取代的烷氧基或所述的取代的烷硫基中的取代基选自下列基团中的一个或多个：卤素、C 1-4的烷基、羟基、
Figure PCTCN2020080362-appb-000005
C 1-4的烷氧基、C 1-4的羧基、C 1-4的酯基和C 1-4酰胺基；当取代基为多个时，所述的取代基相同或不同；R a和R b独立地为氢、或、取代或未取代的烷基；R a或R b中，所述的取代的烷基中的取代基选自下列基团中的一个或多个：卤素、C 1-C 4烷基、羟基、
Figure PCTCN2020080362-appb-000006
C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基或C 1-C 4酰胺基；R a1和R b1独立地为氢或C 1-C 4的烷基；
每个R 1或每个R 3中，所述的取代的羟基或所述的取代的氨基中的取代基选自下列基团中的一个或多个：C 1-4的烷基、C 1-4的烷氧基、C 1-4的羧基、C 1-4的酯基和C 1-4酰胺基；
m为1、2、3、4或5，优选1、2或3；
n为0、1、2、3、4或5，优选0、1、2或3；
当
Figure PCTCN2020080362-appb-000007
为双键，m为2时，两个R 1分别位于苯环的邻位和间位，例如
Figure PCTCN2020080362-appb-000008
两个R 1相同或不同；
当
Figure PCTCN2020080362-appb-000009
为双键，m为3时，两个R 1相邻，且相邻的两个R 1和与它们相连的两个碳原子共同形成一个5-7元的碳杂环；
所述的通式(I)所示的芳香乙烯或芳香乙基类衍生物不为下列化合物：
Figure PCTCN2020080362-appb-000010
在本发明一优选实施方案中，每个R 1独立地为卤素、或、取代或未取代的烷基；或者相邻的两个R 1和与其相连的两个碳原子共同形成一个5-7元的碳杂环。
在本发明一优选实施方案中，每个R 1独立地为卤素、取代或未取代的烷基、或取代或未取代的烷氧基。
在本发明一优选实施方案中，R 2为烷基或卤素。
在本发明一优选实施方案中，每个R 3独立地为卤素、烷硫基或烷氧基；或相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳杂环。
在本发明一优选实施方案中，每个R 1中，所述的取代的烷基中的取代基选自下列基团中的一个或多个：卤素或
Figure PCTCN2020080362-appb-000011
R a和R b独立地为氢、或、取代或未取代的烷基；R a或R b中，所述的取代的烷基中的取代基选自下列基团中的一个或多个：羟基或C 1-C 4羧基。
在本发明一优选实施方案中，每个R 1中，所述的取代的烷基、所述取代的烷氧基、所述取代的羟基或所述取代的氨基中的取代基是指被一个或多个卤素取代，优选被一个或多个F取代。
本发明一优选实施方案中，当两个R 3相邻，且相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳环或碳杂环时，所述的碳环或碳杂环还可进一步被C 1-4的烷基中的一个或多个所取代(例如
Figure PCTCN2020080362-appb-000012
)。
本发明一优选实施方案中，
Figure PCTCN2020080362-appb-000013
还可替换为取代或未取代的杂芳环，所述的杂芳环中的杂原子选自N、O和S，杂原子数为1-4个，所述的取代的杂芳环中的取代基选自下列基团中的一个或多个：卤素、C 1-4的烷基、羟基、
Figure PCTCN2020080362-appb-000014
C 1-4的烷氧基、C 1-4的羧基、C 1-4的酯基和C 1-4酰胺基；当取代基为多个时，所述的取代基相同或不同；R a和R b独立地为氢、或、取代或未取代的烷基；R a或R b中，所述的取代的烷基中的取代基选自下列基团中的一个或多个：卤素、C 1-C 4烷基、羟基、
Figure PCTCN2020080362-appb-000015
C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基或C 1-C 4酰胺基；R a1和R b1独立地为氢或C 1-C 4的烷基；所述的取代的杂芳环中的取代基优选选自C 1-4的烷基中的一个或多个。
本发明一优选实施方案中，当
Figure PCTCN2020080362-appb-000016
替换为取代或未取代的杂芳环时，所述的杂芳环中的杂原子选自N和O，杂原子数为1-3个。进一步优选地，当杂芳环为单环时，杂原子为N原子，杂原子数为1或2；当杂芳环为双环杂芳基，杂原子为N时，杂原子数优选3个；当杂芳环为双环杂芳基，杂原子选自N和O，杂原子数为2时；杂原子不相邻。
在本发明一优选实施方案中，n为0、1、2、3、4或5，优选0、1、2或3。当n为1时，R 3优选为卤素、烷硫基或烷氧基；且R 3位于苯环的邻位、间位或对位，例如
Figure PCTCN2020080362-appb-000017
Figure PCTCN2020080362-appb-000018
当n为2时，优选地，两个R 3位于苯环的邻位和间位，例如
Figure PCTCN2020080362-appb-000019
其中，两个R 3相同或不同；或者两个R 3相邻，且相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳杂环，例如
Figure PCTCN2020080362-appb-000020
其中环M为5-7元 的碳杂环。当n为3时，优选地，其中两个R 3相邻，且相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳杂环，例如
Figure PCTCN2020080362-appb-000021
其中环M为5-7元的碳杂环(例如2,3-二氢-1,4-二氧六环
Figure PCTCN2020080362-appb-000022
噁唑环例如
Figure PCTCN2020080362-appb-000023
异噁唑环例如
Figure PCTCN2020080362-appb-000024
吡唑环例如
Figure PCTCN2020080362-appb-000025
)；环M还可进一步被C 1-4的烷基中的一个或多个所取代(例如
Figure PCTCN2020080362-appb-000026
)。当n为4或5时，优选地，R 3为氘；
在本发明一优选实施方案中，m为2或3。当m为2时，两个R 1分别优选位于苯环的邻位和间位，例如
Figure PCTCN2020080362-appb-000027
两个R 1相同或不同。当m为3时，优选地，其中两个R 1相邻，且相邻的两个R 1和与它们相连的两个碳原子共同形成一个5-7元的碳杂环，例如
Figure PCTCN2020080362-appb-000028
其中环N为5-7元的碳杂环，例如2,3-二氢呋喃环
Figure PCTCN2020080362-appb-000029
在本发明一优选实施方案中，当m为2时，两个R 1分别位于苯环的邻位和间位，两个R 1相同或不同；位于苯环的邻位的R 1为F、取代或未取代的烷基、或取代或未取代的烷氧基。
在本发明一优选实施方案中，当m为2时，其中一个R 1(优选位于苯环邻位)优选烷基或卤素取代的烷基；另一个R 1(优选位于苯环间位)优选
Figure PCTCN2020080362-appb-000030
取代的烷基；当m为3时，两个R 1相邻，且相邻的两个R 1和与它们相连的两个碳原子共同形成一个5-7元的碳杂环，第三个R 1为
Figure PCTCN2020080362-appb-000031
取代的烷基；其中，所述的烷基优选C 1-4的烷基。所述的卤素取代的烷基优选被一个或多个卤素取代的C 1-C 4的烷基，例如三氟甲基。所述的
Figure PCTCN2020080362-appb-000032
取 代的烷基优选被
Figure PCTCN2020080362-appb-000033
取代的C 1-C 4的烷基。
在本发明一优选实施方案中，所述的被
Figure PCTCN2020080362-appb-000034
取代的C 1-C 4的烷基优选
Figure PCTCN2020080362-appb-000035
Figure PCTCN2020080362-appb-000036
其中，R a和R b一个为H，另一个为被羟基和/或羧基取代的烷基。
在本发明一优选实施方案中，所述的被
Figure PCTCN2020080362-appb-000037
取代的C 1-C 4的烷基优选
Figure PCTCN2020080362-appb-000038
Figure PCTCN2020080362-appb-000039
其中，用*标注的碳为S构型手性碳、R构型手性碳或非手性碳。其中，
Figure PCTCN2020080362-appb-000040
优选为
Figure PCTCN2020080362-appb-000041
Figure PCTCN2020080362-appb-000042
优选为
Figure PCTCN2020080362-appb-000043
优选为
Figure PCTCN2020080362-appb-000044
Figure PCTCN2020080362-appb-000045
优选为
Figure PCTCN2020080362-appb-000046
在本发明一优选实施方案中，
每个R 1独立地为卤素、或、取代或未取代的烷基；或者相邻的两个R 1和与其相连的两个碳原子共同形成一个5-7元的碳杂环；
R 2为烷基或卤素；
每个R 3独立地为氘、卤素、烷硫基或烷氧基；或相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳杂环；
n为0、1、2、3、4或5，优选为0、1、2或3；
和m为2。
在本发明一优选实施方案中，
每个R 1独立地为氘、或、取代或未取代的烷基；或者相邻的两个R 1和与其相连的两个碳原子共同形成一个5-7元的碳杂环；所述的取代的烷基中的取代基选自下列基团中的一个或多个：卤素或
Figure PCTCN2020080362-appb-000047
R a和R b独立地为氢、或、取代或未取代的烷基；R a或R b中，所述的取代的烷基中的取代基选自下列基团中的一个或多个：羟基或C 1-C 4羧基；
R 2为烷基或卤素；
每个R 3独立地为氘、卤素、烷硫基或烷氧基；或相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳杂环；
n为0、1、2、3、4或5，优选0、1、2或3，当n为1时，R 3优选为卤素、烷硫基或烷氧基；且R 3位于苯环的邻位、间位或对位，例如
Figure PCTCN2020080362-appb-000048
当n为2时，优选地，两个R 3位于苯环的邻位和间位，例如
Figure PCTCN2020080362-appb-000049
其中，两个R 3相同或不同；或者两个R 3相邻，且相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳杂环；例如
Figure PCTCN2020080362-appb-000050
其中环M为5-7元的碳杂环；当n为3时，优选地，其中一个R 3为卤素，另外两个R 3相邻，且相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳杂环，例如
Figure PCTCN2020080362-appb-000051
其中环M为5-7元的碳杂环；
和m为2或3；当m为2时，两个R 1分别优选位于苯环的邻位和间位，例如
Figure PCTCN2020080362-appb-000052
位于苯环邻位的R 1优选烷基或卤素取代的烷基；位于苯环间位的R 1优选
Figure PCTCN2020080362-appb-000053
取代的烷基；当m为3时，其中两个R 1相邻，且相邻的两个R 1和与它们相连的两个碳原子共同形成一个5-7元的碳杂环，第三个R 1为
Figure PCTCN2020080362-appb-000054
取代的烷基；当n为4或5 时，R 3为氘。
在本发一优选实方案中，
每个R 1独立地为卤素、取代或未取代的烷基、或取代或未取代的烷氧基；
R 2为取代或未取代的烷基或卤素；
每个R 3独立地为氘、卤素、取代或未取代的烷硫基、取代或未取代的羟基、取代或未取代的氨基、取代或未取代的烷基、取代或未取代的烷氧基、
Figure PCTCN2020080362-appb-000055
其中，R 1a为C 1-C 4烷基；
每个R 1中，所述的取代的烷基、所述的取代的烷氧基、所述的取代的羟基或所述的取代的氨基中的取代基是指被一个或多个卤素取代，优选被一个或多个F取代；
每个R 2和每个R 3中所述的取代的烷基、每个R 3中所述的取代的烷氧基和所述的取代的烷硫基中的取代基选自下列基团中的一个或多个：卤素、C 1-4的烷基、羟基、
Figure PCTCN2020080362-appb-000056
C 1-4的烷氧基、C 1-4的羧基、C 1-4的酯基和C 1-4酰胺基；当取代基为多个时，所述的取代基相同或不同；R a和R b独立地为氢、或、取代或未取代的烷基；R a或R b中，所述的取代的烷基中的取代基选自下列基团中的一个或多个：卤素、C 1-C 4烷基、羟基、
Figure PCTCN2020080362-appb-000057
C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基或C 1-C 4酰胺基；R a1和R b1独立地为氢或C 1-C 4的烷基；
每个R 3中，所述的取代的羟基或所述的取代的氨基中的取代基选自下列基团中的一个或多个：C 1-4的烷基、C 1-4的烷氧基、C 1-4的羧基、C 1-4的酯基和C 1-4酰胺基；
m为2或3；
n为0、1、2、3、4或5，优选0、1、2或3；
当m为2时，两个R 1分别位于苯环的邻位和间位，两个R 1相同或不同；位于苯环的邻位的R 1为F、取代或未取代的烷基、或取代或未取代的烷氧基；
当
Figure PCTCN2020080362-appb-000058
为双键，m为3时，两个R 1相邻，且相邻的两个R 1和与它们相连的两个碳原子共同形成一个5-7元的碳杂环；
或所述的通式(I)所示的芳香乙烯或芳香乙基类衍生物中，
Figure PCTCN2020080362-appb-000059
替换为取 代或未取代的杂芳环，所述的杂芳环中的杂原子选自N、O和S，杂原子数为1-4个；所述的取代的杂芳环中的取代基选自下列基团中的一个或多个：卤素、C 1-4的烷基、羟基、
Figure PCTCN2020080362-appb-000060
C 1-4的烷氧基、C 1-4的羧基、C 1-4的酯基和C 1-4酰胺基；当取代基为多个时，所述的取代基相同或不同；R a和R b独立地为氢、或、取代或未取代的烷基；R a或R b中，所述的取代的烷基中的取代基选自下列基团中的一个或多个：卤素、C 1-C 4烷基、羟基、
Figure PCTCN2020080362-appb-000061
C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基或C 1-C 4酰胺基；R a1和R b1独立地为氢或C 1-C 4的烷基。
在本发明一优选实施方案中，
Figure PCTCN2020080362-appb-000062
优选
Figure PCTCN2020080362-appb-000063
Figure PCTCN2020080362-appb-000064
在本发明一优选实施方案中，
Figure PCTCN2020080362-appb-000065
优选
Figure PCTCN2020080362-appb-000066
Figure PCTCN2020080362-appb-000067
在本发明一优选实施方案中，
Figure PCTCN2020080362-appb-000068
优选
Figure PCTCN2020080362-appb-000069
Figure PCTCN2020080362-appb-000070
Figure PCTCN2020080362-appb-000071
在本发明一优选实施方案中，当n为1，R 3为卤素或烷氧基，R 3位于苯环对位时，m为2或3，当m为2时，位于苯环邻位的R 1优选卤素取代的烷基。
在本发明一优选实施方案中，当n为1，R 3为卤素时，R 3优选F或Cl。当R 3为F时，R 3优选位于苯环间位。
在本发明一优选实施方案中，当n为5，R 3为氘。
本发明一优选实施方案中，通式(I)所示的芳香乙烯或芳香乙基类衍生物、其药学上可接受的盐、代谢产物、代谢前体或药物前体中，
Figure PCTCN2020080362-appb-000072
可替换为取代或未取代的杂芳环，其他字母和基团定义均同前所述。
本发明中，所述的通式(I)所示的芳香乙烯或芳香乙基类衍生物优选下列任一化合物：
Figure PCTCN2020080362-appb-000073
Figure PCTCN2020080362-appb-000074
Figure PCTCN2020080362-appb-000075
Figure PCTCN2020080362-appb-000076
本发明一优选实施方案中，所述的通式(I)所示的芳香乙烯或芳香乙基类衍生物优选通式(II)所示的芳香乙烯或芳香乙基类衍生物：
Figure PCTCN2020080362-appb-000077
其中，R 1、R 2、R 3、n、R a和R b的定义均同前所述。
本发明还提供了所述的通式(II)所示的芳香乙烯或芳香乙基类衍生物的制备方法，其包括下列步骤：将化合物(I-a)与
Figure PCTCN2020080362-appb-000078
进行如下所示的还原胺化反应，制得通式(II)所示的化合物；
Figure PCTCN2020080362-appb-000079
上述通式化合物中，R 1、R 2、R 3、n、R a和R b的定义均同前所述，m1为0、1、2、3或4，优选0、1或2。所述的还原胺化反应的方法和条件可为本领域此类反应常规的方法和条件。
所述还原胺化反应中还可加入酸。所述酸优选无机酸和/或有机酸。所述的无机酸优选盐酸和/或硫酸。所述的有机酸优选冰醋酸。所述酸与化合物(I-a)的摩尔比优选0.2:1-5:1(例如2:1)。
所述溶剂优选有机溶剂和/或水。所述有机溶剂可为本领域此类反应常用的有机溶剂，优选醇类溶剂、氯代烃类溶剂、醚类溶剂和酰胺类溶剂中的一种或多种。所述的醇类溶剂优选甲醇和/或乙醇。所述的卤代烃类溶剂优选二氯甲烷。所述的醚类溶剂优选1,4-二氧六环。所述的酰胺类溶剂优选N,N-二甲基甲酰胺。所述的溶剂优选醇类溶剂和氯代烃类溶剂的混合溶剂，例如甲醇和二氯甲烷的混合溶剂。所述醇类溶剂和氯代烃类溶剂的混合溶剂中，所述的醇类溶剂和所述的氯代烃类溶剂的体积比优选1:0.1-1:5(例如1:1)。所述的溶剂的用量可不作具体限定，只要不影响反应的进行即可，所述的溶剂与化合物(I-a)所示的化合物的体积质量比优选10mL/g-200mL/g。
所述还原剂可为此类还原胺化反应中常用的还原剂，优选氰基硼氢化钠、醋酸硼氢化钠、硼氢化钠和硼氢化锂中的一种或多种，优选氰基硼氢化钠。所述还原剂与化合物(I-a)的摩尔比优选0.3:1-10:1(例如5:1)。
所述还原胺化反应中，化合物(I-a)和
Figure PCTCN2020080362-appb-000080
的摩尔比优选1:1-1:3(优选1:2)。
所述还原胺化反应的温度优选0℃-120℃，更优选0℃-50℃，进一步优选室温(10℃-30℃)。
所述还原胺化反应的进程可通过TLC或HPLC进行监测，一般以化合物(I-a)消失时作为反应的终点。
所述还原胺化反应结束时，可通过后处理进一步纯化产物。所述后处理的方法优选包括如下方法：重结晶、硅胶薄层层析制备板纯化(例如二氯甲烷:甲醇＝15:1)、硅胶色谱柱纯化和高效液相制备纯化(流动相：水(10mM碳酸氢铵)和乙腈；梯度：25％-55％)中的一种或多种。
所述的化合物(I-a)的制备方法优选包括下列步骤：溶剂中，在钯催化剂作用下，将化合物(II-b)和
Figure PCTCN2020080362-appb-000081
进行如下所示的偶联反应，制得化合物(I-a)，即可；
Figure PCTCN2020080362-appb-000082
其中，R 1、R 2、R 3、n、R a和R b的定义均同前所述，X为卤素，m1为0、1、2、3或4，优选0、1或2。
所述的偶联反应的方法和条件可为本领域此类反应常规的方法和条件。
在化合物(I-a)的制备方法中，所述偶联反应还可加入碱。所述碱优选碱金属的碳酸盐，更优选碳酸钠、碳酸钾或碳酸铯。所述碱与化合物(II-b)的摩尔比优选1:1-5:1。
在化合物(I-a)的制备方法中，所述溶剂优选有机溶剂和/或水。所述有机溶剂可为本领域此类反应常用的有机溶剂，优选醚类溶剂、芳烃类溶剂和酰胺类溶剂中的一种或多种。所述的醚类溶剂优选1,4-二氧六环和乙二醇二甲醚。所述的芳烃类溶剂优选甲苯。所述的酰胺类溶剂优选N,N-二甲基甲酰胺。所述的溶剂优选芳烃类溶剂。所述溶剂与所述化合物(II-b)的体积质量比优选10mL/g-110mL/g。
在化合物(I-a)制备方法中，所述钯催化剂可为此类偶联反应中常用的钯催化剂，优选[1,1’-双(二苯基膦基)二茂铁]二氯化钯、三(二亚苄基茚丙酮)二钯、醋酸钯和四(三苯基膦)钯中的一种或多种。所述钯催化剂与所述化合物(II-b)的摩尔比优选0.005:1-0.5:1，更优选0.01:1-0.10:1。
在化合物(I-a)的制备方法中，所述的偶联反应优选在配体的作用下进行，所述的配体优选2-二环己基磷-2',4',6'-三异丙基联苯。
在化合物(I-a)的制备方法中，所述偶联反应的温度优选50℃-150℃(例如80-90℃)。
在化合物(I-a)的制备方法中，所述偶联反应的进程可通过TLC或HPLC进行监测，一般以化合物(II-b)消失时作为反应的终点。
在化合物(I-a)的制备方法中，所述偶联反应结束时，可通过后处理进一步纯化产物。所述后处理的方法优选包括如下方法：重结晶、硅胶薄层层析制备板纯化、硅胶色谱柱纯化(洗脱剂＝石油醚：乙酸乙酯)和高效液相制备纯化中的一种或多种。
本领域人员应理解，在得知了本发明化合物的结构以后，可通过多种本领域熟知的方法、利用公知的原料，来获得本发明的化合物，比如化学合成或从植物中提取的方法，这些方法均包含在本发明中。除非另外说明或提供制备方法，制备本发明的化合物或其中间体所用的原料均是本领域已知或可通过商购获得的。
本发明还提供了所述的通式(I)所示的芳香乙烯或芳香乙基类衍生物、其药学上可接受的盐、氘代物、代谢产物、代谢前体或药物前体在制备PD-1抑制剂和/或PD-L1抑制剂中的应用。
本发明还提供了所述的通式(I)所示的芳香乙烯或芳香乙基类衍生物、其药学上可接受的盐、氘代物、代谢产物、代谢前体或药物前体在制备用于预防、缓解或治疗癌症、感染、自身免疫性疾病或其相关疾病的药物中的应用。
所述癌症优选肺癌、食管癌、胃癌、大肠癌、肝癌、鼻咽癌、脑肿瘤、乳腺癌、宫颈癌、血癌和骨癌中的一种或多种。
本发明还提供了一种药物组合物，其包括治疗和/或预防有效量的所述的通式(I)所示的芳香乙烯或芳香乙基类衍生物、其药学上可接受的盐、氘代物、代谢产物、代谢前体或药物前体，及药学上可接受载体和/或稀释剂。
另一方面，本发明还提供了一种药物组合物，其包含：
PD-L1抗体；和
小分子PD-1/PD-L1抑制剂或其药学上可接受的盐。
所述PD-L1抗体可以为Atezolizumab(阿特珠单抗)、Durvalumab、Avelumab、Cemiplimab、KN035、CS1001、MBS2311、BGB-A333、KL-A167、SHR-1316和STI-A1014中的一种或多种。
在一些实施方案中，所述PD-L1抗体为Durvalumab。
在一些实施方案中，所述小分子PD-1/PD-L1抑制剂为芳香乙烯或芳香乙基类衍生物、其药学上可接受的盐、氘代物、代谢产物、代谢前体或药物前体。
在一些实施方案中，所述小分子PD-1/PD-L1抑制剂的分子量小于1500道尔顿，例如小于1400、1300、1200、1100、1000、900、800、700、600或500道尔顿。
在一些实施方案中，所述小分子PD-1/PD-L1抑制剂在PD-1/PD-L1结合实验(例如本文效果实施例1中的PD-1/PD-L1结合实验)中具有小于100nM的IC 50值，例如小于90nM、80nM、70nM、60nM、50nM、40nM、30nM、20nM、10nM或1nM的IC 50值。
在一些实施方案中，所述小分子PD-1/PD-L1抑制剂与PD-L1结合。在一些实施方案中，所述小分子PD-1/PD-L1抑制剂与PD-1结合。
在一些实施方案中，所述小分子PD-1/PD-L1抑制剂为PD-L1抑制剂。在一些实施方案中，所述小分子PD-1/PD-L1抑制剂为PD-1抑制剂。
在本发明范围内的小分子PD-1/PD-L1抑制剂包括WO2015034820(其全文以引用的 方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000083
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2018009505(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000084
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2018195321(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000085
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2018119263(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000086
Figure PCTCN2020080362-appb-000087
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2018119221(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000088
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2018119224(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000089
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2018119236(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000090
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2018119266(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000091
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2018119286(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000092
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2018044783(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000093
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2018013789(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000094
Figure PCTCN2020080362-appb-000095
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2017222976(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000096
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2017205464(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000097
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2017192961(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000098
Figure PCTCN2020080362-appb-000099
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2017112730(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000100
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2017106634(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000101
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2017087777(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000102
Figure PCTCN2020080362-appb-000103
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2017070089(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000104
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2018026971(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000105
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2018005374(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000106
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2018051254(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000107
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括CN201711445262.9(其全文以引用的方式并入本文中)记载的化合物，例如
Figure PCTCN2020080362-appb-000108
Figure PCTCN2020080362-appb-000109
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括CN201710064453.4(其全文以引用的方式并入本文中)记载的化合物，例如
Figure PCTCN2020080362-appb-000110
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2017202273(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000111
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2017202275(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000112
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2017202276(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000113
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括WO2018006795(其全文以引用的方式并入本文中)公开的化合物。
在本发明范围内的小分子PD-1/PD-L1抑制剂还包括CN201710539028.6(其全文以引用的方式并入本文中)公开的化合物，例如
Figure PCTCN2020080362-appb-000114
Figure PCTCN2020080362-appb-000115
Figure PCTCN2020080362-appb-000116
在一些实施方案中，所述小分子PD-1/PD-L1抑制剂还可以为如上所述的通式(I)所示的芳香乙烯或芳香乙基类衍生物、其药学上可接受的盐、氘代物、代谢产物、代谢前体或药物前体。
在一些实施方案中，所述小分子PD-1/PD-L1抑制剂为化合物29或其药学上可接受的盐。
在一些实施方案中，所述PD-L1抗体为Durvalumab；并且，
所述小分子PD-1/PD-L1抑制剂为化合物29
Figure PCTCN2020080362-appb-000117
或其药学上可接受的盐。
所述PD-L1抗体和小分子PD-1/PD-L1抑制剂可以存在于单一药物组合物中，也可以分别存在于分开的单独药物组合物中。当PD-L1抗体和小分子PD-1/PD-L1抑制剂需要以不同的给药途径或不同的给药间隔给药时，优选PD-L1抗体和小分子PD-1/PD-L1抑制剂分别存在于分开的单独药物组合物中。
所述的药物组合物还可以包含药学上可接受的载体。
在一些实施方案中，所述药物组合物包含：
PD-L1抗体；
小分子PD-1/PD-L1抑制剂或其药学上可接受的盐；和，
药学上可接受的载体。
在一些实施方案中，所述药物组合物包含：
第一药物组合物，其包含PD-L1抗体和药学上可接受的载体；
第二药物组合物，其包含小分子PD-1/PD-L1抑制剂或其药学上可接受的盐以及药学上可接受的载体。
所述的药物组合物根据给药方式不同可制成各种合适的剂型，包括经胃肠道给药剂型(例如口服剂型)和非经胃肠道给药剂型(例如注射剂型)。其中PD-L1抗体和小分子PD-1/PD-L1抑制剂可以存在一个单独的单位剂型中，也可以分别存在于不同的单位剂型中。当PD-L1抗体和小分子PD-1/PD-L1抑制剂的给药途径、给药间隔不同时，优选PD-L1抗体和小分子PD-1/PD-L1抑制剂存在于不同的单位剂型中。
在一些实施方案中，所述PD-L1抗体为注射剂型，例如皮下注射剂型、肌肉注射剂型或静脉注射剂型。
在一些实施方案中，所述PD-L1抗体为皮下注射剂型。
在一些实施方案中，所述PD-L1抗体为静脉注射剂型。
在一些实施方案中，所述PD-L1抗体为Durvalumab，其为注射剂型。
在一些实施方案中，所述PD-L1抗体为Durvalumab，其为皮下注射剂型。
在一些实施方案中，所述PD-L1抗体为Durvalumab，其为静脉注射剂型。
在一些实施方案中，所述小分子PD-1/PD-L1抑制剂为口服剂型，例如口服固体剂型(例如片剂、胶囊剂、丸剂、颗粒剂)和口服液体剂型(例如口服溶液剂、口服混悬剂或糖浆剂)。
在一些实施方案中，所述小分子PD-1/PD-L1抑制剂为口服液体剂型，例如口服混悬剂。
在一些实施方案中，所述小分子PD-1/PD-L1抑制剂为化合物29，其为口服液体剂型，例如口服混悬剂。
在一些实施方案中，所述小分子PD-1/PD-L1抑制剂为化合物29，其为10％(w/v)聚氧乙烯氢化蓖麻油40(Cremophor RH40)、20％(w/v)磺丁基醚-β-环糊精(SBE-β-CD)和70％(w/v)水的化合物29混悬液(即将一定量的化合物29混悬于由10％(w/v)聚氧乙烯氢化蓖麻油40、20％磺丁基醚-β-环糊精和70％水形成的混合液中)。
在一些实施方案中，所述PD-L1抗体为Durvalumab；所述小分子PD-1/PD-L1抑制 剂为化合物29或其药学上可接受的盐；
其中，Durvalumab为注射剂型；化合物29为口服剂型。
在一些实施方案中，所述PD-L1抗体为Durvalumab；所述小分子PD-1/PD-L1抑制剂为化合物29或其药学上可接受的盐；
其中，Durvalumab为皮下注射剂型；化合物29为口服液体剂型。
在一些实施方案中，所述PD-L1抗体为Durvalumab；所述小分子PD-1/PD-L1抑制剂为化合物29；
其中，Durvalumab为静脉注射剂型；化合物29为口服液体剂型。
在一些实施方案中，所述PD-L1抗体为Durvalumab；所述小分子PD-1/PD-L1抑制剂为化合物29；
其中，Durvalumab为皮下注射剂型；化合物29为10％(w/v)聚氧乙烯氢化蓖麻油40、20％(w/v)磺丁基醚-β-环糊精和70％水的化合物29混悬液。
药物组合物可以每单位剂量含预定量活性成分的单位剂型呈现。如本领域技术人员已知，每剂量的活性成分的量取决于所治疗病症、施用途径以及患者的年龄、体重和状况。优选的单位剂量组合物含有活性成分的单次剂量、日剂量或亚剂量或其合适部分。此外，这种药物组合物可通过制药领域熟知的任何方法制备。
在一些实施方案中，药物组合物单位剂型中PD-L1抗体和小分子PD-1/PD-L1抑制剂的含量为治疗有效量。
所述药物组合物单位剂型中PD-L1抗体和小分子PD-1/PD-L1抑制剂的含量比例可以为1:1-1:9，例如1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8或1:9。
另一方面，本发明提供一种如本文所述的药物组合物在制备治疗癌症的药物中的应用。
另一方面，本发明提供一种治疗癌症的方法，其包括向有此需要的受试者给予治疗有效量的如本文所述的药物组合物。
在一些实施方案中，所述癌症为肺癌、胃癌、结直肠癌、宫颈癌、卵巢癌、前列腺癌、乳腺癌、胰腺癌、肝癌、膀胱癌、肾癌、骨癌、皮肤癌、黑色素瘤、神经胶质瘤、神经胶母细胞瘤、白血病或淋巴瘤。
在一些实施方案中，所述癌症为肺癌、结直肠癌、乳腺癌、黑色素瘤、白血病或淋巴瘤。
在一些实施方案中，所述癌症为结直肠癌。
在一些实施方案中，所述癌症为结肠癌。
所述PD-L1抗体和小分子PD-1/PD-L1抑制剂的给药方案(例如给药途径、给药剂量、给药间隔)可以由本领域技术人员根据需要进行调整，以提供最优的治疗效果。
所述PD-L1抗体和小分子PD-1/PD-L1抑制剂可同时给药或分开给药(例如顺序给药)。所述“同时给药”，指PD-L1抗体和小分子PD-1/PD-L1抑制剂可在含PD-L1抗体和小分子PD-1/PD-L1抑制剂的单一药物组合物中同时施用而联用。所述“分开给药”，指PD-L1抗体和小分子PD-1/PD-L1抑制剂可在包含PD-L1抗体和小分子PD-1/PD-L1抑制剂之一的各自的单独药物组合物中以顺序形式分开施用，例如PD-L1抗体或小分子PD-1/PD-L1抑制剂首先施用且另一个第二施用。这种顺序施用可在时间上接近(如同时)或时间上距离较远。
所述PD-L1抗体可以采用本领域中任何合适的途径给药，包括口服、注射(例如静脉、肌肉、皮下)等。
在一些实施方案中，所述PD-L1抗体经注射给药。
在一些实施方案中，所述PD-L1抗体经静脉注射给药。
在一些实施方案中，所述PD-L1抗体经皮下注射给药。
在一些实施方案中，所述PD-L1抗体为Durvalumab，经注射给药。
在一些实施方案中，所述PD-L1抗体为Durvalumab，经静脉注射给药。
在一些实施方案中，所述PD-L1抗体为Durvalumab，经皮下注射给药。
所述PD-L1抗体(例如Durvalumab)可根据受试者的体重来给药，非限制性实例范围可以为1.0-1000mg/kg，例如10-150mg/kg，例如5mg/kg、10mg/kg、15mg/kg、20mg/kg、30mg/kg、40mg/kg、50mg/kg、60mg/kg、70mg/kg、80mg/kg、90mg/kg、100mg/kg、110mg/kg、120mg/kg或150mg/kg。在一些实施方案中，PD-L1抗体的剂量为20mg/kg。上述剂量可以QD(一天一次)、BID(一天二次)、TID(一天三次)、QOD(间隔一天)、QW(每周一次)、BIW(每周二次)或Q2W(每两周一次)等频次给药。在一些实施方案中，所述PD-L1抗体按照BIW频次给药。在一些实施方案中，所述PD-L1抗体(例如Durvalumab)经注射(例如静脉注射、皮下注射)按照上述剂量、频次给药。在一些实施方案中，所述PD-L1抗体为Durvalumab，通过注射(例如静脉注射、皮下注射)以20mg/kg的剂量按照BIW频次给药。
所述PD-L1抗体(例如Durvalumab)也可以固定剂量施用于受试者，即给予受试者固定或预定量的剂量。
所述小分子PD-1/PD-L1抑制剂可以采用本领域中任何合适的途径给药，包括口服、注射(例如静脉、肌肉、皮下)等。
在一些实施方案中，所述小分子PD-1/PD-L1抑制剂经口服给药。
在一些实施方案中，所述小分子PD-1/PD-L1抑制剂为化合物29，经口服给药。
所述小分子PD-1/PD-L1抑制剂的给药方案可以根据需要进行调整，以提供最优的治疗效果。
所述小分子PD-1/PD-L1抑制剂(例如化合物29)可根据受试者的体重来给药，非限制性实例范围可以为1.0-1000mg/kg，例如5-180mg/kg，例如5mg/kg、10mg/kg、15mg/kg、20mg/kg、30mg/kg、40mg/kg、50mg/kg、60mg/kg、70mg/kg、80mg/kg、90mg/kg、100mg/kg、110mg/kg、120mg/kg或150mg/kg。在一些实施方案中，小分子PD-1/PD-L1抑制剂的剂量为15-180mg/kg，例如30-120mg/kg，例如60-120mg/kg。上述剂量可以QD(一天一次)、BID(一天二次)、TID(一天三次)、QOD(间隔一天)、QW(每周一次)、BIW(每周二次)或Q2W(每两周一次)的频次给药。在一些实施方案中，小分子PD-1/PD-L1抑制剂按照BID频次给药。在一些实施方案中，所述小分子PD-1/PD-L1抑制剂(例如化合物29)经口服按照上述剂量、频次给药。在一些实施方案中，所述小分子PD-1/PD-L1抑制剂为化合物29，通过口服以60mg/kg的剂量按照BID频次给药。
所述小分子PD-1/PD-L1抑制剂(例如化合物29)也可以固定剂量施用于受试者，即给予受试者固定或预定量的剂量。
在一些实施方案中，所述PD-L1抗体为Durvalumab，通过注射(例如静脉注射、皮下注射)以20mg/kg的剂量按照BIW频次给药；并且，
所述小分子PD-1/PD-L1抑制剂为化合物29，通过口服以60mg/kg的剂量按照BID频次给药。
当所述PD-L1抗体和小分子PD-1/PD-L1抑制剂分开给药时，所述PD-L1抗体和小分子PD-1/PD-L1抑制剂可以按照各自的给药周期连续给药。所述PD-L1抗体和小分子PD-1/PD-L1抑制剂的给药周期可以开始于同一时间或不同时间。例如，所述PD-L1抗体和小分子PD-1/PD-L1抑制剂可以在同一天开始按照各自的给药周期连续给药；或者，小分子PD-1/PD-L1抑制剂在PD-L1抗体开始给药后的第二日或第三日或更多日后开始给药，然后两者按照各自的给药周期连续给药。
本文所述药物组合物可以组合药盒(或称为成套药盒)的形式呈现。所用术语“组合药盒”或“成套药盒”指用于施用所述PD-L1抗体和小分子PD-1/PD-L1抑制剂的一种或多种药物组合物的容器。当所述PD-L1抗体和小分子PD-1/PD-L1抑制剂同时施用时，所述组合药盒能包含处于单一药物组合物或单独药物组合物的PD-L1抗体和小分子PD- 1/PD-L1抑制剂。当PD-L1抗体和小分子PD-1/PD-L1抑制剂不是同时施用时，所述组合药盒会包含分开的含PD-L1抗体的第一药物组合物，和含小分子PD-1/PD-L1抑制剂的第二药物组合物。
在一些实施方案中，所述组合药盒包含：
PD-L1抗体；
小分子PD-1/PD-L1抑制剂；和，
药学上可接受的载体；
其中PD-L1抗体和小分子PD-1/PD-L1抑制剂以适合同时施用和/或分开施用的形式提供。
在一些实施方案中，所述组合药盒包含：
第一容器，其包含第一药物组合物，所述第一药物组合物包含PD-L1抗体以及药学上可接受的载体；
第二容器，其包含第二药物组合物，所述第二药物组合物包含小分子PD-1/PD-L1抑制剂或其药学上可接受的盐以及药学上可接受的载体。
本文所述药物组合物可单独使用或与一种或多种其它治疗剂(例如免疫调节剂、其他抗肿瘤剂等等)联用。因此，本文所述药物组合物可以包括PD-L1抗体、小分子PD-1/PD-L1抑制剂以及可选的其它治疗剂。这种药剂组合可一起或分开施用，分开施用时，可同时或以在时间上接近和距离较远的任何顺序依序进行。
本文所述药物组合物也可与癌症治疗的其它治疗方法(例如化疗、手术和/或放射治疗等)一起使用。
本文所用术语“小分子PD-1/PD-L1抑制剂”是指任何能够直接或者间接降低或者抑制(部分或者完全)PD-L1/PD-1通路活性的小分子化合物，其可以表述为“小分子PD-1/PD-L1通路抑制剂”。小分子PD-1/PD-L1抑制剂可以抑制PD-1、PD-L1、和/或PD-1/PD-L1相互作用。其中，“小分子”应当被理解为与生物大分子相对的概念，即小分子不包括生物大分子药物(如抗体)，其不应当被理解为不清楚。
本文所用术语“抗体”意在包括完整分子以及含有抗原结合位点且能结合表位的片段。
本文所用术语“PD-L1”包括同种型，哺乳动物的，例如人PD-L1，人PD-L1的物种同源物，和包含至少一个与PD-L1的共同表位的类似物。PD-L1的氨基酸序列，例如人PD-L1，是本领域已知的。
本文所用术语“同源”是指两个聚合分子之间的亚单位序列同一性，例如，两个核酸 分子之间，如两个DNA分子或两个RNA分子之间，或两个多肽分子之间。当两个分子在一个亚单位位置上被相同的单体亚单位占据时，例如，如果两个DNA分子的每个在一个位置上都被腺嘌呤占据，那么它们在该位置是同源或同一的。两个序列之间的同源性是匹配或同源位置数量的直接函数；例如，如果两个序列中的一半位置(例如，十个亚单位长的聚合物中的五个位置)是同源的，则两个序列是50％同源；如果90％的位置(例如，10个中9个)是匹配或同源的，则两个序列是90％同源的。
本文所用术语“PD-L1抗体”可以为多克隆或单克隆的。其中术语“单克隆抗体”是指对仅对单一特定抗原表位展现结合特异性和亲和性的。单克隆抗体可以通过杂交瘤技术或不采用杂交瘤技术的方法(如重组方法)制备。
本文所述的PD-L1抗体可以为人源化的。其中术语“人源化”是指含有源自非人免疫球蛋白的最小序列的非人(例如，鼠)抗体形式，其可以是嵌合免疫球蛋白、免疫球蛋白链或其片段。
本文所述的PD-L1抗体还包括与其同源性在80％以上，优选在90％以上，更优选在91％、92％、93％、94％、95％、96％、97％、98％或99％以上的抗体分子。
本文所用术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。
在某些实施例中，本发明的化合物作为预防措施给药。如本文所用，“预防”或“正在预防”是指降低获得给定疾病或病症的风险。在实施例的优选模式中，将指定化合物作为预防措施给予受试者，例如有癌症或自身免疫性疾病家族病史或倾向的受试者。
本文所用术语“治疗有效量”是指在给予受试者时足以有效治疗本文所述的疾病或病症的化合物的量。构成“治疗有效量”的化合物的量将根据化合物、病症及其严重度、欲治疗受试者的年龄、化合物剂型、给药方式、给药间隔等而变化，但可由本领域技术人员根据需要进行确定。
本文所用术语“给药”指向受试者施用一种或多种物质(例如PD-L1抗体和/或PD-L1小分子抑制剂)，其也可以表述为“施用”。
本文所用术语“药物组合物”(pharmaceutical composition)也可以表述为“药物组合”(pharmaceutical combination)，两者在本文中可以相互替换。
除非另有说明，本文所用术语“剂量”是指单次给药的量。
本文所用术语“容器”是指适用于储存、运输、分配和/或处理药品的任何容器和封盖。
本文所用术语“药学上可接受的”，是指盐、组合物、辅料等一般无毒、安全，并且适合于受试者使用，优选哺乳动物受试者，更优选为人受试者。
本文所用术语“受试者”或“患者”是指根据本发明的实施例，即将或已经接受了该化合物或组合物给药的任何动物，哺乳动物为优，人类最优。如本文所用，术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为最优。术语“受试者”和“患者”在本文中可互换使用。
本文所用术语“药学上可接受的盐”指药学上可接受的有机或无机盐。示例性盐包括但不限于：硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、gentisinate、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲烷磺酸盐、乙烷磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1-1-亚甲基-双(2-羟基-3-萘甲酸盐))。本发明中所用化合物可与各种氨基酸形成药学上可接受的盐。合适的碱盐包括但不限于铝盐、钙盐、锂盐、镁盐、钾盐、钠盐、锌盐、铋和二乙醇胺盐。药学上可接受的盐的综述见Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
本文所用术语“卤素”优选F、Cl、Br或I。
本文所用术语“取代或未取代的烷基”优选取代或未取代的C 1-C 4的烷基。所述的取代或未取代的C 1-C 4的烷基优选取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基、或、取代或未取代的叔丁基。
本文所用术语“取代或未取代的烷氧基”优选取代或未取代的C 1-C 4的烷氧基。所述的取代或未取代的C 1-C 4的烷氧基优选取代或未取代的甲氧基、取代或未取代的乙氧基、取代或未取代的正丙氧基、取代或未取代的异丙氧基、取代或未取代的正丁氧基、取代或未取代的异丁氧基、或、取代或未取代的叔丁氧基。
本文所用术语“烷硫基”优选-S-R s，其中，R s为C 1-C 4的烷基。
本文所用术语“C 1-4的烷基”优选甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
本文所用术语“C 1-4的烷氧基”优选甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基。
本文所用术语“C 1-4的羧基”优选
Figure PCTCN2020080362-appb-000118
Figure PCTCN2020080362-appb-000119
本文所用术语“C 1-4的酯基”优选
Figure PCTCN2020080362-appb-000120
其中，R 2a为C 1-C 4烷基。
本文所用术语“C 1-4酰胺基”优选
Figure PCTCN2020080362-appb-000121
其中，R 1b为氢或C 1-C 4烷基。
本文所用术语“杂芳环”优选C 1-C 10的杂芳环，更优选吖啶环、咔唑环、噌啉环、咔啉环、喹喔啉环、咪唑环、吡唑环、吡咯环、吲哚环、二氢吲哚环、苯并三唑环、苯并咪唑环、呋喃环、噻吩环、异噻唑环、苯并噻吩环、二氢苯并噻吩环、苯并呋喃环、异苯并呋喃环、苯并噁唑环、苯并呋咱环、苯并吡唑环、喹啉环、异氮杂茚环、异喹啉环、噁唑环、噁二唑环、异噁唑环、吲哚环、吡嗪环、吡啶并吡啶环、四唑并吡啶环、咪唑并吡啶环、咪唑并吡嗪环、哒嗪环、吡啶环、萘嘧啶环、嘧啶环、四唑环、噻二唑环、噻唑环、噻吩环、三唑环、喹唑啉环、四氢喹啉环、二氢苯并咪唑环、二氢苯并呋喃环、二氢苯并噁唑环或二氢喹啉环。
本文所用术语“5-7元碳杂环”是指杂原子选自杂原子为氧和/或氮，杂原子数为1-4个的5-7元碳杂环。所述的5-7元碳杂环中环原子为5、6或7个。所述的5-7元碳杂环包括但不限于：氮杂环丁环、哌嗪环、哌啶环、吡咯环、吗啉环、硫代吗啉环、1,4-二氧六环、吡喃环、二氢咪唑环、二氢异噁唑环、二氢异噻唑环、二氢噁二唑环、二氢噁唑环、二氢吡嗪环、二氢吡唑环、二氢吡啶环、二氢嘧啶环、二氢吡咯环、二氢喹啉环、二氢四唑环、二氢噻二唑环、二氢噻唑环、二氢三唑环、二氢氮杂环丁环、咪唑环、吡唑环、吡咯环、呋喃环、噻吩环、异噻唑环、噁唑环、噁二唑环、异噁唑环、吡嗪环、哒嗪环、吡啶环、嘧啶环、四唑环、噻二唑环、噻唑环、噻吩环和三唑环；所述的5-7元的碳杂环优选为2,3-二氢-1,4-二氧六环(优选
Figure PCTCN2020080362-appb-000122
)、噁唑环(优选
Figure PCTCN2020080362-appb-000123
)、异噁唑环(优选
Figure PCTCN2020080362-appb-000124
)或吡唑环(优选
Figure PCTCN2020080362-appb-000125
)。
本文所用术语“药学上可接受的载体”是指能够递送活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质。
本发明中，根据治疗目的，可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等，优选液体、悬浮液、乳液、栓剂和针剂(溶液及悬浮液)等。
为了使片剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。例如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液，羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油；吸附促进剂，如季胺碱和十二烷基硫酸钠等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。还可以根据需要选用通常的涂渍材料制成糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。
为了使丸剂形式的药物组合物成形，可使用本领域任何已知的并广泛使用的赋形剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石粉等；粘合剂，如阿拉伯树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。
为了使栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋性剂，例如，聚乙二醇，椰子油，高级醇，高级醇的酯，明胶和半合成的甘油酯等。
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油等)，制成与血液等渗压的针剂。在制备针剂时，也可使用本领域内任何常用的载体。例如，水，乙醇，丙二醇，乙氧基化的异硬脂醇，聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可加入通常的溶解剂、缓冲剂和止痛剂等。
所述药物组合物中，所述稀释剂可为本领域中常规的稀释剂。
所述药物组合物可以是口服的形式，也可以是无菌注射水溶液形式，可按照本领域任何已知制备药用组合物的方法制备口服或注射组合物。
如本文所用，术语“药物前体”是指包含生物反应官能团的化合物的衍生物，使得在生物条件下(体外或体内)，生物反应官能团可从化合物上裂解或以其他方式发生反应以提 供所述化合物。通常，药物前体无活性，或者至少比化合物本身活性低，使得直到将所述化合物从生物反应官能团上裂解后才能发挥其活性。生物反应官能团可在生物条件下水解或氧化以提供所述化合物。例如，药物前体可包含可生物水解的基团。可生物水解的基团实例包括但不限于可生物水解的磷酸盐、可生物水解的酯、可生物水解的酰胺、可生物水解的碳酸酯、可生物水解的氨基甲酸酯和可生物水解的酰脲。
本发明的化合物可以含有一个或多个不对称中心(“立体异构体”)。如本文所用，术语“立体异构体”是指顺式-和反式-异构体、R-和S-对映体以及非对映体。这些立体异构体可以通过不对称合成法或手性分离法(例如，分离、结晶、薄层色谱法、柱色谱法、气相色谱法、高效液相色谱法)制备。这些立体异构体也可由对映体或外消旋物的混合物与适当的手性化合物反应的非对映体衍生，然后通过结晶或任何其它合适的常规方法得到。
本发明所述的化合物还可以包括其代谢物。本文所用术语“代谢物”是指药物分子在体内所经历的化学结构的变化后产生的活性物质，该活性物质一般为前述药物分子的衍生物，其还可被化学修饰。
本发明所述的化合物还可以包括其晶型(polymorph)。本文所用术语“晶型”是指在结晶时，分子在晶格空间的排列不同而形成的一种或多种晶体结构。
本发明所述的化合物还可以包括其溶剂化物。本文所用术语“溶剂化物”是指化合物、其药学上可接受的盐、晶型、共晶、立体异构体、同位素化合物、代谢物或前药的一种晶体形式，它还包含一种或多种融入晶体结构中的溶剂分子。溶剂化物可包括化学计量量或非化学计量量的溶剂，并且溶剂中的溶剂分子可能以有序或非有序排列的形式存在。含有非化学计量量溶剂分子的溶剂化物可能是溶剂化物至少丢失一部分(但并非全部)溶剂分子得到的。在一个特定实施例中，一种溶剂化物是一种水合物，意味着化合物的结晶形式进一步包括水分子。
本发明所述的化合物还可以包括其前药。本文所用术语“前药”是指包含生物反应官能团的化合物的衍生物，使得在生物条件下(体外或体内)，生物反应官能团可从化合物上裂解或以其他方式发生反应以提供所述化合物。通常，前药无活性，或者至少比化合物本身活性低，使得直到将所述化合物从生物反应官能团上裂解后才能发挥其活性。生物反应官能团可在生物条件下水解或氧化以提供所述化合物。例如，前药可包含可生物水解的基团，可生物水解的基团实例包括但不限于可生物水解的磷酸盐、可生物水解的酯、可生物水解的酰胺、可生物水解的碳酸酯、可生物水解的氨基甲酸酯和可生物水解的酰脲。有关前药的综述参见，例如，J.Rautio et al.,Nature Reviews Drug Discovery(2008)7,255-270and Prodrugs:Challenges和Rewards(V.Stella et al.ed.,Springer,2007)。
本发明的化合物还可以包括其同位素衍生物。本文所用术语“同位素衍生物”是指该化合物中含有一个或多个天然或非天然丰度的原子同位素。非天然丰度的原子同位素包括但不限于氘( 2H或D)、氚( 3H或T)、碘-125( 125I)、磷-32( 32P)、碳-13( 13C)或碳-14( 14C)。本发明的化合物的所有同位素变体，无论是否具有放射性，都包括在本发明的范围内。
如无另外说明，本文所用术语的单数形式“一”、“一个”或“一种”也包括复数意义。
本文所使用的化合物代号，例如KN035、CS1001、MBS2311、BGB-A333、KL-A167、SHR-1316、STI-A1014等，均为本领域所公知。
本文提及的所有出版物、专利申请、专利和其他参考文献都通过引用其全文并入本文中。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：提供一种小分子PD-1/PD-L1抑制剂或其与PD-L1抗体的药物组合物，其可以用于治疗癌症。
附图说明
图1为效果实施例3中各组小鼠体重变化曲线图。
图2为效果实施例3中各组小鼠体重变化率曲线图。
图3为效果实施例3中各组小鼠肿瘤体积增长曲线图。
图4为效果实施例3中各组小鼠的抑瘤率曲线图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
下述实施例中，室温是指10℃-30℃；回流是指溶剂回流温度；过夜是指8-24小时，优选12-18小时。
化合物的结构由核磁共振(NMR)或质谱(MS)来确定，核磁共振谱是通过Bruker Avance-500仪器获得，氘代二甲亚砜，氘代氯仿和氘代甲醇等为溶剂，四甲基硅烷(TMS)为内标。质谱是由液相色谱-质谱(LC-MS)联用仪Agilent Technologies 6110获得，采用ESI 离子源。
微波反应是在美国CEM公司生产的Explorer全自动微波合成仪中进行，磁控管频率为2450MHz，连续微波输出功率为300W。
高效液相制备所用的仪器是Gilson 281，所用的制备柱是Shimadazu Shim-Pack，PRC-ODS，20x250mm，15μm。
实施例1
(E)-2-(3-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基丙酸(化合物1)
合成路线：
Figure PCTCN2020080362-appb-000126
化合物1-c的合成
将1,4-二氧六环-6-苯硼酸(3.60g，20mmol)和2,6-二溴甲苯(7.50g，30mmol)溶解在1,4-二氧六环(100mL)和水(15mL)的混合溶液中，加入[1,1’-双(二苯基磷)二茂铁]二氯化钯二氯甲烷络合物(817mg，1mmol)和碳酸钠(6.38g，60mmol)。反应体系用氮气置换三次后，加热到80℃，并搅拌16小时。将反应液冷却至室温，减压浓缩，剩余物经制硅胶柱层析纯化(石油醚)得到化合物1-c(2.70g，产率：44％)。
化合物1-b的合成
将化合物1-c(915mg，3mmol)和乙烯基硼酸频哪醇酯(924mg，6mmol)溶解在甲苯(10mL)溶液中，加入二(三叔丁基膦)钯(120mg，0.24mmol)和三乙胺(2.0g，20mmol)。反应体系用氮气置换三次后，加热到80℃搅拌6小时。将反应液冷却至室温，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝10:1)得到化合物1-b(540mg，产率：48％)。
化合物1-a的合成
将化合物1-b(475mg，1.26mmol)和3-溴-4-三氟甲基苯甲醛(265.7mg，1.05mmol) 溶解在1,4-二氧六环(20mL)和水(1mL)的混合溶液中，加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(90.8mg，0.105mmol)和碳酸钠(277.8mg，2.62mmol)。反应体系用氮气置换三次后，加热到80℃搅拌16小时。将反应液冷却至室温，减压浓缩，剩余物用乙酸乙酯(50mL)溶解，接着依次用水(20mL×3)和饱和食盐水(20mL)洗，有机相用无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝10：1)得到化合物1-a(366mg，产率：80.4％)。
1H NMR(500MHz,CDCl 3)δ:10.15(s,1H),8.27(s,1H),7.86(s,2H),7.57-7.55(d,J＝7.5Hz,1H),7.52-7.49(d,J＝16.0Hz,1H),7.37-7.34(m,1H),7.29-7.27(m,1H),7.22-7.21(m,1H),6.93-6.91(d,J＝8.5Hz,1H),6.84-6.83(m,1H),6.79-6.77(m,1H),4.31(s,4H),2.35(s,3H)ppm
化合物1的合成
将化合物1-a(200mg，0.40mmol)和丝氨酸(99mg，0.94mmol)溶解在甲醇(15mL)和二氯甲烷(15mL)的混合溶液中，加入冰醋酸(0.05mL,0.94mmol)。反应液在室温下搅拌2小时后，加入氰基硼氢化钠(119mg，1.89mmol)并继续搅拌12小时。反应液减压浓缩，剩余物用乙酸乙酯(50mL)溶解，接着依次用水(20mL)和饱和食盐水(20mL)洗，有机相用无水硫酸钠干燥，减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：15％-65％(初始流动相为15％水-85％的乙腈，结束时流动相为65％水-35％乙腈，其中％是指体积百分比))纯化后得到化合物1(12mg，产率：5.8％)。LC-MS(ESI):m/z＝514[M+H] +.
1H NMR(400MHz,DMSO)δ:8.05(s,1H),7.74-7.73(d,J＝6.4Hz,1H),7.59-7.51(m,3H),7.30-7.15(m,3H),6.93-6.91(d,J＝6.8Hz,1H),6.80-6.75(m,2H),4.28(s,4H),4.09-4.06(d,J＝11.2Hz,1H),3.96-3.93(d,J＝11.2Hz,1H),3.69-3.62(m,2H),3.20-3.18(t,J＝4.0Hz,1H),2.29(s,3H)ppm
实施例2
(E)-2-(3-(2-(4’-甲氧基-2-甲基联苯-3-基)乙烯基)-4-甲基苄基氨基)-3-羟基-2-甲基丙酸(化合物2)
合成路线：
Figure PCTCN2020080362-appb-000127
Figure PCTCN2020080362-appb-000128
化合物2-c的合成
在室温条件下，往2-溴-6-氯甲苯(15.67g，76.26mmol)和乙烯基硼酸频哪醇酯(14.30g，91.51mmol)的甲苯(300mL)溶液中加入二(三叔丁基膦)钯(2.73g，5.34mmol)和三乙胺(61.74g，610.08mmol)，将反应液加热至80℃，在氮气条件下搅拌反应过夜。反应结束后，加入乙酸乙酯稀释(100mL)，用水(100mL)和饱和食盐水(100mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝10：1)得化合物2-c(10.5g，产率：49.4％)。
1H NMR(500MHz,CDCl 3)δ:7.65-7.62(d,J＝18.5Hz,1H),7.42-7.41(d,J＝7.5Hz,1H),7.31-7.30(d,J＝7.5Hz,1H),7.12-7.09(t,1H),6.06-6.02(d,J＝18.0Hz,1H),2.45(s,3H),1.32(s,12H)ppm
化合物2-b的合成
在室温条件下，往3-溴-4-甲基苯甲醛(5.0g，17.95mmol)和2-c(2.98g，14.96mmol)的1,4-二氧六环(40mL)和水(2mL)中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(1.294g，1.496mmol)和碳酸钠(3.963g，37.39mmol)，将反应液加热至80℃，在氮气条件下搅拌反应过夜。反应结束后，加入乙酸乙酯稀释(50mL)，依次用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝40：1)得到化合物2-b(3.31g，产率：81.9％)。
1H NMR(500MHz,CDCl 3)δ:10.03(s,1H),8.08(s,1H),7.72-7.70(d,J＝8.0Hz,1H),7.47-7.45(d,J＝7.5Hz,1H),7.37-7.31(m,3H),7.18-7.12(m,2H),2.50(s,6H)ppm
化合物2-a的合成
在室温条件下，往对甲氧基苯硼酸(202mg，1.329mmol)和2-b(300mg，1.108mmol)的甲苯(20mL)溶液中加入三(二亚苄基丙酮)二钯(101.6mg，0.111mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(211.7mg，0.444mmol)和磷酸钾(705.6mg，3.324mmol)，将反应液加热至90℃，在氮气条件下搅拌反应过夜。反应结束后，加入乙酸乙酯(50mL)稀释，依次用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝40：1)得到化合物2-a(334mg，产率：87.9％)。
1H NMR(500MHz,CDCl 3)δ:10.03(s,1H),8.10(s,1H),7.71-7.69(d,J＝7.5Hz,1H),7.58-7.56(d,J＝7.5Hz,1H),7.42-7.36(m,4H),7.21-7.17(m,2H),6.98-6.96(d,J＝8.5Hz,2H),3.87(s,3H),2.51(s,3H),2.33(s,3H)ppm
化合物2的合成
在室温条件下，往2-a(330mg，0.964mmol)和2-甲基丝氨酸(229.9mg，1.93mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(115.9mg，1.93mmol)，反应液在室温条件下搅拌1小时。然后，加入氰基硼氢化钠(302.9mg，4.82mmol)搅拌16小时。反应结束后，将有机溶剂旋干，残留物用乙酸乙酯(50mL)溶解后，依次用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(二氯甲烷：甲醇＝10：1)得到化合物2(85mg，产率：19.8％)。LC-MS(ESI):m/z＝444.0[M-H] +.
1H NMR(500MHz,DMSO-d6)δ:7.79(s,1H),7.67-7.65(d,J＝7.5Hz,1H),7.40-7.37(d,J＝16.5Hz,1H),7.30-7.23(m,6H),7.14-7.13(d,J＝7.5Hz,1H),7.03-7.01(d,J＝9.0Hz,2H),4.01-3.94(m,2H),3.81(s,3H),3.68-3.66(d,J＝11.5Hz,1H),3.60-3.58(d,J＝11.0Hz,1H),2.41(s,3H),2.29(s,3H),1.31(s,3H)ppm
实施例3
(E)-2-(3-(2-(3’-氟-2-甲基联苯-3-基)乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物3)
合成路线：
Figure PCTCN2020080362-appb-000129
化合物3-b的合成
在室温条件下，往3-溴-4-三氟甲基苯甲醛(4.16g，16.45mmol)和化合物2-c(5.5g，19.74mmol)的1,4-二氧六环(40mL)和水(2mL)的混合溶液中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(1.423g，1.645mmol)和碳酸钠(4.36g，41.13mmol)，将反应 液加热至80℃，在氮气条件下搅拌16小时。反应结束后，加入乙酸乙酯(50mL)稀释，依次用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝40：1)得到化合物3-b(4.16g，产率：78％)
1H NMR(500MHz,CDCl 3)δ:10.15(s,1H),8.25(s,1H),7.87(s,2H),7.47-7.40(m,2H),7.37-7.36(d,J＝7.0Hz,1H),7.32-7.29(m,1H),7.20-7.17(m,1H),2.50(s,3H)ppm
化合物3-a的合成
往化合物3-b(300mg，0.93mmol)的甲苯(20mL)溶液中加入3-氟苯硼酸(156mg，1.11mmol)，磷酸钾(590mg，2.78mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(66mg，0.132mmol)和三(二亚苄基丙酮)二钯(30mg，0.03mmol)。反应体系用氮气置换3次，将反应液加热到90℃并搅拌12小时。将反应液冷却至室温，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝100：1)得到黄色固体3-a(240mg，产率：68％)。LC-MS(ESI):m/z＝385[M+H] +.
化合物3的合成
将化合物3-a(240mg，0.625mmol)和2-甲基丝氨酸(150mg，1.25mmol)溶解在甲醇(15mL)和二氯甲烷(15mL)的混合溶液中，加入冰醋酸(0.07mL,1.25mmol)。反应液在室温下搅拌2小时后，加入氰基硼氢化钠(157mg，2.5mmol)并继续搅拌12小时。反应液减压浓缩，剩余物用乙酸乙酯(50mL)溶解，接着依次用水(20mL)和饱和食盐水(20mL)洗，有机相用无水硫酸钠干燥，减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：15％-65％(初始流动相为15％水-85％的乙腈，结束时流动相为65％水-35％乙腈，其中％是指体积百分比))纯化后得到化合物3(75mg，产率：24.5％)。LC-MS(ESI):m/z＝488[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ:8.06(s,1H),7.76-7.74(d,J＝6.4Hz,1H),7.61-7.56(m,3H),7.53-7.48(m,1H),7.36-7.32(t,J＝12.4Hz,1H),7.07-7.17(m,5H),3.99(s,2H),3.64-3.61(d,J＝8.8Hz,1H),3.57-3.55(d,J＝8.8Hz,1H),2.29(s,3H),1.27(s,3H)ppm
实施例4
(E)-2-(3-(2-(4’-甲硫基-2-甲基联苯-3-基)乙烯基)-4-甲基苄基氨基)-3-羟基-2-甲基丙酸(化合物4)
合成路线：
Figure PCTCN2020080362-appb-000130
化合物4-a的合成
在室温条件下，往对甲硫基苯硼酸(223.3mg，1.329mmol)和2-b(300mg，1.108mmol)的甲苯(20mL)溶液中加入三(二亚苄基丙酮)二钯(101.6mg，0.111mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(211.7mg，0.444mmol)和磷酸钾(705.6mg，3.324mmol)，将反应液加热至90℃，在氮气条件下搅拌反应过夜。反应结束后，加入乙酸乙酯(50mL)稀释，依次用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝40：1)得到化合物4-a(323mg，产率：81.2％)。
1H NMR(500MHz,CDCl 3)δ:10.03(s,1H),8.10(s,1H),7.71-7.69(d,J＝7.0Hz,1H),7.63-7.62(m,1H),7.59-7.58(d,J＝7.5Hz,2H),7.43-7.36(m,4H),7.33-7.32(m,2H),7.21-7.18(m,2H),2.54(,s 3H),2.51(s,3H),2.33(s,3H)ppm
化合物4的合成
在室温条件下，往4-a(323mg，0.901mmol)和2-甲基丝氨酸(214.7mg，1.802mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(108.2mg，1.802mmol)，反应液在室温条件下搅拌1小时。然后，加入氰基硼氢化钠(254.5mg，4.505mmol)搅拌16小时。反应结束后，将有机溶剂旋干，残留物用乙酸乙酯(20mL)溶解后，依次用水(20mL)和饱和食盐水(20mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(二氯甲烷：甲醇＝10：1)得到化合物4(112mg，产率：26.9％)。LC-MS(ESI):m/z＝460.0[M-H] +.
1H NMR(500MHz,CD 3OD)δ:7.78(s,1H),7.69-7.68(d,J＝7.5Hz,1H),7.39-7.33(m,3H),7.31-7.26(m,5H),7.24-7.22(d,J＝8.0Hz,1H),7.15-7.13(d,J＝7.0Hz,1H),4.00-3.92(m,2H),3.67-3.65(d,J＝11.5Hz,1H),3.59-3.57(d,J＝10.5Hz,1H),2.52(s,3H),2.41(s,3H),2.29(s,3H),1.30(s,3H)ppm
实施例5
(E)-2-(3-(2-(2-甲基联苯-3-基)乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物5)
合成路线：
Figure PCTCN2020080362-appb-000131
化合物5-a的合成
在室温条件下，往苯硼酸(135.3mg，1.11mmol)和化合物3-b(300mg，0.924mmol)的甲苯(20mL)溶液中加入三(二亚苄基丙酮)二钯(84.2mg，0.092mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(175.4mg，0.368mmol)和磷酸钾(588.4mg，2.772mmol)，将反应液加热至90℃，在氮气条件下搅拌反应过夜。反应结束后，加入乙酸乙酯(50mL)稀释，依次用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝40：1)得到化合物5-a(254mg，产率：74.9％)。
1H NMR(500MHz,CDCl 3)δ:10.15(s,1H),8.28(s,1H),7.87(s,2H),7.60-7.59(d,J＝7.5Hz,1H),7.53-7.50(d,J＝16.0Hz,1H),7.45-7.42(m,2H),7.39-7.35(m,2H),7.33-7.29(m,3H),7.25-7.23(m,1H),2.33(s,3H)ppm
化合物5的合成
在室温条件下，往5-a(254mg，0.693mmol)和2-甲基丝氨酸(165.1mg，1.386mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(83.2mg，1.386mmol)，反应液在室温条件下搅拌1小时。然后，加入氰基硼氢化钠(254.5mg，4.505mmol)搅拌16小时。反应结束后，将有机溶剂旋干，残留物用乙酸乙酯(20mL)溶解后，依次用水(20mL)和饱和食盐水(20mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(二氯甲烷：甲醇＝10：1)得到化合物5(95mg，产率：29.2％)。LC-MS(ESI):m/z＝468.0[M-H] +.
1H NMR(500MHz,CD 3OD)δ:8.17(s,1H),7.80-7.79(d,J＝8.0Hz,1H),7.68-7.62(m,2H),7.57-7.56(d,J＝7.5Hz,1H),7.46-7.43(m,2H),7.39-7.29(m,5H),7.21-7.19(d,J＝7.5Hz,1H),4.35-4.27(m,2H),4.02-4.00(d,J＝12.0Hz,1H),3.86-3.83(d,J＝12.0Hz,1H),2.34(s,3H),1.56(s,3H)ppm
实施例6
(E)-2-(3-(2-(4’-氟-2-甲基联苯-3-基)乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物6)
合成路线：
Figure PCTCN2020080362-appb-000132
化合物6-a的合成
往化合物3-b(300mg，0.93mmol)的甲苯(20mL)溶液中加入3-氟苯硼酸(156mg，1.11mmol)，磷酸钾(590mg，2.78mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(60mg，0.132mmol)和三(二亚苄基丙酮)二钯(30mg，0.03mmol)。反应体系用氮气置换3次，将反应液加热到90℃并搅拌12小时。将反应液冷却至室温，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝100：1)得到黄色固体6-a(240mg，产率：68％)。LC-MS(ESI):m/z＝385[M+H] +.
化合物6的合成
将化合物6-a(240mg，0.625mmol)和2-甲基丝氨酸(150mg，1.25mmol)溶解在甲醇(15mL)和二氯甲烷(15mL)的混合溶液中，加入冰醋酸(0.07mL,1.25mmol)。反应液在室温下搅拌2小时后，加入氰基硼氢化钠(157mg，2.5mmol)并继续搅拌12小时。反应液减压浓缩，剩余物用乙酸乙酯(50mL)溶解，接着依次用水(20mL)和饱和食盐水(20mL)洗，有机相用无水硫酸钠干燥，减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：15％-65％(初始流动相为15％水-85％的乙腈，结束时流动相为65％水-35％乙腈，其中％是指体积百分比))纯化后得到化合物6(65mg，产率：21.3％)。LC-MS(ESI):m/z＝488[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ:8.06(s,1H),7.76-7.74(d,J＝6.8Hz,1H),7.59-7.56(m,3H),7.39-7.23(m,6H),7.20-7.19(m,1H),3.99(s,2H),3.63-3.61(d,J＝8.8Hz,1H),3.56-3.54(d,J＝8.8Hz,1H),2.28(s,3H),1.27(s,3H)ppm
实施例7
(E)-2-(3-(2-(4’-氟-2-甲基联苯-3-基)乙烯基)-4-甲基苄基氨基)-3-羟基-2-甲基丙酸(化合物7)
合成路线：
Figure PCTCN2020080362-appb-000133
化合物7-a的合成
往化合物2-b(300mg,1.11mmol)的甲苯(20mL)溶液中加入对氟苯硼酸(187mg,1.33mmol)，磷酸钾(708mg,3.33mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(60mg，0.132mmol)和三(二亚苄基丙酮)二钯(30mg，0.03mmol)。反应体系用氮气置换3次，将反应液加热到90℃并搅拌12小时。将反应液冷却至室温，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝100：1)得到黄色固体7-a(340mg，产率：92％)。LC-MS(ESI):m/z＝331[M+H] +.
化合物7的合成
将化合物7-a(340mg，1.15mmol)和2-甲基丝氨酸(274mg，2.3mmol)溶解在甲醇(15mL)和二氯甲烷(15mL)的混合溶液中，加入冰醋酸(0.07mL,1.25mmol)。反应液在室温下搅拌2小时后，加入氰基硼氢化钠(290mg，4.6mmol)并继续搅拌12小时。反应液减压浓缩，剩余物用乙酸乙酯(50mL)溶解，接着依次用水(20mL)和饱和食盐水(20mL)洗，有机相用无水硫酸钠干燥，减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：15％-65％(初始流动相为15％水-85％的乙腈，结束时流动相为65％水-35％乙腈，其中％是指体积百分比))纯化后得到化合物7(35mg，产率：7％)。LC-MS(ESI):m/z＝434[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ:7.77(s,1H),7.70-7.68(d,J＝6Hz,1H),7.39-7.35(m,3H),7.31-7.23(m,6H),7.15-7.14(m,1H),3.99-3.92(m,2H),3.67-3.64(d,J＝9.2Hz,1H),3.58-3.56(d,J＝9..2Hz,1H),2.41(s,3H),2.26(s,3H),1.29(s,3H)ppm
实施例8
(E)-2-(3-(2-(2-甲基联苯-3-基)乙烯基)-4-甲基苄基氨基)-3-羟基-2-甲基丙酸(化合物8)
合成路线：
Figure PCTCN2020080362-appb-000134
化合物8-a的合成
往化合物2-b(300mg，1.108mmol)的甲苯(20mL)溶液中加入苯硼酸(162.2mg，1.33mmol)，磷酸钾(705.6mg，3.324mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(211.7mg，0.444mmol)和三(二亚苄基丙酮)二钯(101.6mg，0.111mmol)。反应体系用氮气置换3次，将反应液加热到90℃并搅拌12小时。反应结束后，加入乙酸乙酯(50mL)稀释，依次用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝40：1)得到化合物8-a(323 mg，产率：93.1％)。
1H NMR(500MHz,CDCl 3)δ:10.03(s,1H),8.10(s,1H),7.71-7.69(d,J＝8.0Hz,1H),7.60-7.59(d,J＝7.0Hz,1H),7.45-7.40(m,3H),7.38-7.36(m,2H),7.33-7.29(m,3H),7.23-7.18(m,2H),2.52(s,3H),2.32(s,3H)ppm
化合物8的合成
在室温条件下，往8-a(323mg，1.034mmol)和2-甲基丝氨酸(246.3mg，2.068mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(124.2mg，2.068mmol)，反应液在室温条件下搅拌1小时。然后，加入氰基硼氢化钠(324.9mg，5.17mmol)搅拌16小时。反应结束后，将有机溶剂旋干，残留物用乙酸乙酯(20mL)溶解后，依次用水(20mL)和饱和食盐水(20mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(二氯甲烷：甲醇＝10：1)得到化合物8(95mg，产率：22.1％)。LC-MS(ESI):m/z＝414.0[M-H] +.
1H NMR(500MHz,CD3OD)δ:7.87(s,1H),7.64-7.63(d,J＝7.5Hz,1H),7.52-7.48(d,J＝16.0Hz,1H),7.46-7.43(m,2H),7.39-7.36(m,2H),7.32-7.26(m,5H),7.16-7.15(d,J＝6.5Hz,1H),4.23-4.15(m,2H),4.00-3.98(d,J＝12.0Hz,1H),3.84-3.81(d,J＝12.0Hz,1H),3.37(s,3H),2.48(s,3H),2.32(s,3H),1.54(s,3H)ppm
实施例9
(E)-2-(3-(2-(3’-甲基-2-甲基联苯-3-基)乙烯基)-4-甲基苄基氨基)-3-羟基-2-甲基丙酸(化合物9)
合成路线：
Figure PCTCN2020080362-appb-000135
化合物9-a的合成
往化合物2-b(300mg,1.11mmol)的甲苯(20mL)溶液中加入3-氟苯硼酸(187mg,1.33mmol)，磷酸钾(708mg,3.33mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(60mg，0.132mmol)和三(二亚苄基丙酮)二钯(30mg，0.03mmol)。反应体系用氮气置换3次，将反应液加热到90℃并搅拌12小时。将反应液冷却至室温，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝100：1)得到黄色固体9-a(330mg，产率：90％)。LC-MS(ESI):m/z＝331[M+H] +.
化合物9的合成
将化合物9-a(330mg，1.0mmol)和2-甲基丝氨酸(238mg，2.0mmol)溶解在甲醇(15mL)和二氯甲烷(15mL)的混合溶液中，加入冰醋酸(0.1mL,2.3mmol)。反应液在室温下搅拌2小时后，加入氰基硼氢化钠(251mg，4.0mmol)并继续搅拌12小时。反应液减压浓缩，剩余物用乙酸乙酯(50mL)溶解，接着依次用水(20mL)和饱和食盐水(20mL)洗，有机相用无水硫酸钠干燥，减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：15％-65％(初始流动相为15％水-85％的乙腈，结束时流动相为65％水-35％乙腈，其中％是指体积百分比))纯化后得到化合物9(80mg，产率：18.4％)。LC-MS(ESI):m/z＝434[M+H] +.
11H NMR(400MHz,DMSO-d 6)δ:7.78(s,1H),7.72-7.71(d,J＝6Hz,1H),7.52-7.48(m,1H),7.39-7.36(m,1H),7.32-7.26(m,3H),7.22-7.16(m,5H),3.99-3.92(m,2H),3.67-3.65(d,J＝9.2Hz,1H),3.59-3.57(d,J＝9.2Hz,1H),2.41(s,3H),2.28(s,3H),1.29(s,3H)ppm
实施例10
(E)-2-(3-(2-(4’-氯-2-甲基联苯-3-基)乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物10)
合成路线：
Figure PCTCN2020080362-appb-000136
化合物10-a的合成
在室温条件下，往对氯苯硼酸(173.6mg，1.11mmol)和化合物3-b(300mg，0.924mmol)的甲苯(20mL)溶液中加入三(二亚苄基丙酮)二钯(84.2mg，0.092mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(175.4mg，0.368mmol)和磷酸钾(588.4mg，2.772mmol)，将反应液加热至90℃，在氮气条件下搅拌反应过夜。反应结束后，加入乙酸乙酯(50mL)稀释，依次用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝40：1)得到化合物10-a(144mg，产率：38.9％)。
化合物10的合成
在室温条件下，往10-a(144mg，0.359mmol)和2-甲基丝氨酸(85.5mg，0.718mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(43.1mg，0.718mmol)，反应液在室温条件下搅拌1小时。然后，加入氰基硼氢化钠(112.8mg，1.795mmol)搅拌16小时。反应结束后，将有机溶剂旋干，残留物用乙酸乙酯(20mL)溶解 后，依次用水(20mL)和饱和食盐水(20mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(二氯甲烷：甲醇＝10：1)得到化合物10(27mg，产率：14.9％)。LC-MS(ESI):m/z＝502.0[M-H] +.
1H NMR(500MHz,CD 3OD)δ:8.16(s,1H),7.80-7.78(d,J＝8.0Hz,1H),7.66-7.56(m,3H),7.46-7.44(m,2H),7.36-7.30(m,4H),7.20-7.18(m,1H),4.31-4.26(m,2H),4.01-3.99(d,J＝12.0Hz,1H),3.85-3.83(d,J＝12.0Hz,1H),2.33(s,3H),1.56(s,3H)ppm
实施例11
(E)-2-(3-(2-(4’-甲氧基-2-甲基联苯-3-基)乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物11)
合成路线：
Figure PCTCN2020080362-appb-000137
化合物11-a的合成
在室温条件下，往对甲氧基苯硼酸(168.7mg，1.11mmol)和化合物3-b(300mg，0.924mmol)的甲苯(20mL)溶液中加入三(二亚苄基丙酮)二钯(84.2mg，0.092mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(175.4mg，0.368mmol)和磷酸钾(588.4mg，2.772mmol)，将反应液加热至90℃，在氮气条件下搅拌反应过夜。冷却至室温后，加入乙酸乙酯(50mL)稀释，依次用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝40：1)得到化合物11-a(325mg，产率：74.9％)。
1H NMR(500MHz,CDCl 3)δ:10.15(s,1H),8.28(s,1H),7.86(s,2H),7.76-7.73(d,J＝15.5Hz,1H),7.58-7.56(d,J＝7.5Hz,1H),7.53-7.50(d,J＝16.0Hz,1H),7.44-7.41(m,2H),7.38-7.34(m,1H),7.11-7.08(d,J＝16.0Hz,1H),6.98-6.96(d,J＝7.0Hz,2H),3.87(s,3H),2.34(s,3H)ppm
化合物11的合成
在室温条件下，往11-a(325mg，0.82mmol)和2-甲基丝氨酸(195.4mg，1.64mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(98.5mg，1.64mmol)，反应液在室温条件下搅拌1小时。然后，加入氰基硼氢化钠(571.8mg，9.1mmol)搅拌16小时。反应结束后，将有机溶剂旋干，残留物用乙酸乙酯(20mL)溶解后，依次用水(20mL)和饱和食盐水(20mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩 余物经硅胶薄层层析制备板纯化(二氯甲烷：甲醇＝10：1)得到化合物11(76mg，产率：24.6％)。LC-MS(ESI):m/z＝498.0[M-H] +.
1H NMR(500MHz,CD 3OD)δ:8.16(s,1H),7.80-7.78(d,J＝7.5Hz,1H),7.68-7.62(m,2H),7.54-7.53(d,J＝7.5Hz,1H),7.34-7.32(m,2H),7.29-7.18(m,4H),7.02-7.00(m,1H),4.33-4.25(m,2H),4.01-3.99(d,J＝2.0Hz,1H),3.85-3.83(d,J＝12.5Hz,1H),3.86(s,3H),2.35(s,3H),1.55(s,3H)ppm
实施例12
(E)-2-(3-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯乙烯基)-4-氟苄基氨基)-3-羟基丙酸(化合物12)
合成路线：
Figure PCTCN2020080362-appb-000138
化合物12-a的合成
在室温条件下，往3-溴-4-氟苯甲醛(161mg，0.79mmol)和1-b(300mg，0.79mmol)的1,4-二氧六环(20mL)和水(2mL)中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(57.8mg，0.079mmol)和碳酸钠(216.2g，2.4mmol)，将反应液加热至80℃，在氮气条件下搅拌16小时。冷却至室温后，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝15：1)得到化合物12-a(140mg，产率：47％)。
化合物12的合成
在室温条件下，往12-a(140mg,0.37mmol)和丝氨酸(77.7mg,0.74mmol)的甲醇(5mL)和二氯甲烷(5mL)混合溶液中加入冰醋酸(0.04mL,0.65mmol)，反应液在室温条件下搅拌6小时。然后，加入氰基硼氢化钠(70mg,1.1mmol)搅拌18小时。减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：30％-60％(初始流动相为30％水-70％的乙腈，结束时流动相为60％水-40％乙腈，其中％是指体积百分比))纯化后得到化合物12(18mg，产率：11％)。LC-MS(ESI):m/z＝464[M-H] +.
1H NMR(400MHz,DMSO-d 6)δ:7.89(d,J＝4.8Hz,1H),7.64(d,J＝6.0Hz,1H),7.57(d,J＝12.8Hz,1H),7.40-7.37(m,1H),7.28-7.22(m,2H),7.16-7.12(m,2H),6.92(d,J＝6.4Hz,1H),6.80(d,J＝2.0Hz,1H),6.77-6.75(dd,J 1＝2.0Hz,J 2＝6.4Hz,1H),4.28(s,4H),4.04-3.93(q,2H),3.69-3.65(m,2H),3.19-3.17(m,1H),2.29(s,3H)ppm
实施例13
(E)-2-(3-(2-(2’-氟-2-甲基联苯-3-基)乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基丙酸(化合物13)
合成路线：
Figure PCTCN2020080362-appb-000139
化合物13-a的合成
在室温条件下，往2-氟苯硼酸(259mg,1.85mmol)和化合物3-b(500mg,1.54mmol)的甲苯(20mL)溶液中加入三(二亚苄基丙酮)二钯(50mg，0.05mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(100mg，0.21mmol)和磷酸钾(983mg,4.63mmol)，将反应液加热至90℃，在氮气条件下搅拌反应过夜。反应结束后，加入乙酸乙酯(50mL)稀释，依次用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝100：1)得到黄色固体13-a(250mg，产率：42％)。LC-MS(ESI):m/z＝385[M-H] +.
化合物13的合成
在室温条件下，往13-a(125mg,0.33mmol)和丝氨酸(68mg,0.65mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(0.04mL,0.65mmol)，反应液在室温条件下搅拌2小时。然后，加入氰基硼氢化钠(82mg,1.3mmol)搅拌16小时。减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：40％-70％(初始流动相为40％水-60％的乙腈，结束时流动相为70％水-30％乙腈，其中％是指体积百分比))纯化后得到化合物13(13mg，产率：8.3％)。LC-MS(ESI):m/z＝474[M-H] +.
1H NMR(400MHz,DMSO-d 6)δ:8.07(s,1H),7.75-7.74(m,1H),7.64-7.52(m,4H),7.36-7.20(m,6H),4.06-3.96(m,2H),3.68-3.64(m,2H),3.22-3.18(m,1H),2.21(s,3H)ppm
实施例14
(S,E)-2-(3-(3-(5-氟-2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯乙烯基)-4-甲基苄基氨基)-3-羟基丙酸(化合物14)
合成路线：
Figure PCTCN2020080362-appb-000140
化合物14-d的合成
将3-氟邻苯二酚(2g，15.63mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入无水碳酸钾(6.5g，46.89mmol)和1,2-二溴乙烷(14.7g，78.15mmol)。反应混合物加热到80℃搅拌24小时。冷却至室温后，将反应混合物倒入冰水(100mL)中，用石油醚(100mL×2)萃取，有机相经无水硫酸钠干燥，过滤，滤液减压浓缩得到浅棕色的油状物14-d(2.3g，产率：95.8％)。此产品无需进一步纯化。
化合物14-c的合成
将化合物14-d(2.3g，14.93mmol)溶于N,N-二甲基甲酰胺(20mL)中，冷却到0℃后，分10次加入N-溴代丁二酰亚胺(2.64g，14.93mmol)。反应混合物室温搅拌16小时后倒入冰水(200mL)中，用乙酸乙酯(200mL×2)萃取，分离有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝50：1)得到浅黄色固体14-c(2.5g，产率：73％)。
1HNMR(500MHz,CDCl 3)δ:6.96(dd，1H)，6.59(dd，1H)，4.27-4.32(m，4H)ppm
化合物14-b的合成
将化合物14-c(2.3g，10mmol)溶于无水四氢呋喃(30mL)中，冷却到-70℃，滴加2.5M的正丁基锂正己烷溶液(6mL，15mmol)。反应液搅拌1小时后滴加硼酸三异丙酯(2.7g，15mmol)，并继续搅拌1小时。反应液升到室温，加入2N盐酸(20mL)后再搅拌30分钟。乙酸乙酯(100mL)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物加入石油醚(20mL)并强力搅拌得到白色固体14-b(1.2g，产率：61％)。
1HNMR(500MHz,DMSO-d 6)δ:7.97(s，2H),6.99(m，1H),6.65(m，1H),4.27(m,4H)ppm
化合物14-a的合成
将化合物14-b(74mg，0.37mmol)溶于甲苯(5mL)中，加入2-b(100mg，0.31mmol)，三(二亚苄基茚丙酮)二钯(27mg，0.04mmol)，2-二环己基磷-2,4,6-三异丙基联苯(59mg， 0.13mmol)和无水磷酸钾(197mg，0.93mmol)。反应混合物在氮气保护下加热至105℃搅拌16小时。冷却至室温后，反应混合物减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝10：1)得到黄色固体14-a(60mg，产率：45％)。
1HNMR(500MHz,CDCl 3)δ:10.12(s，1H),8.09(d,J＝1Hz,1H),7.69(dd,J＝8Hz,J＝2Hz,1H),7.37(m,2H),7.28(m,1H),7.17(m,2H),6.78(m,1H),6.70(m,2H),4.34(m,4H),2.51(s,3H),2.28(s,3H)ppm
化合物14的合成
将化合物14-a(60mg，0.14mmol)和L-丝氨酸(29mg，0.27mmol)溶于四氢呋喃(3mL)，乙醇(3mL)和水(3mL)的混合溶液中，加入氢氧化钠(22mg，0.54mmol)，反应液在25℃条件下搅拌18小时。然后，加入硼氢化钠(20mg，0.53mmol)搅拌半小时。减压浓缩反应液，剩余物用0.5M盐酸调节至pH＝5，接着用乙酸乙酯(50mL×2)萃取，有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(二氯甲烷：甲醇＝10：1)得到化合物14(10mg，产率：14％)。LC-MS(ESI):m/z＝478[M-H] +.
1HNMR(500MHz,CDCl 3)δ:7.39(s,2H),6.89-7.11(m,6H),6.57-6.65(m,2H),4.24(s,4H),3.64-3.81(br,4H),3.17(br,2H),2.17(s,3H),2.11(s,3H)ppm
实施例15
(E)-2-(3-(2-(2’,3’-二氟-2-甲基联苯-3-基)乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基丙酸(化合物15)
合成路线：
Figure PCTCN2020080362-appb-000141
化合物15-a的合成
在室温条件下，往2,3-二氟苯硼酸(632mg,4.0mmol)和化合物3-b(648mg,2.0mmol)的甲苯(30mL)溶液中加入三(二亚苄基丙酮)二钯(183mg，0.2mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(200mg，0.42mmol)和磷酸钾(2120mg,10.0mmol)，将反应液加热至100℃，在氮气条件下搅拌反应过夜。反应结束后，加入乙酸乙酯(100mL)稀释，依次用水(100mL)和饱和食盐水(100mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝100：1)得到淡黄色固体15-a(300mg，产率：37％)。
1H NMR(400MHz,CD 3OD)δ:10.14(s,1H),8.27(s,1H),7.87(s,2H),7.65(d,J＝6.0Hz, 1H),7.50(d,J＝12.4Hz,1H),7.39-7.36(m,1H),7.33(t,J＝6.0Hz,1H),7.22-7.14(m,3H),7.03-7.01(m,1H),2.28(s,3H)ppm
化合物15的合成
在室温条件下，往15-a(120mg,0.3mmol)和丝氨酸(63mg,0.6mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(0.04mL,0.65mmol)，反应液在室温条件下搅拌2小时。然后，加入氰基硼氢化钠(56.7mg,0.9mmol)搅拌12小时。减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：40％-70％(初始流动相为40％水-60％的乙腈，结束时流动相为70％水-30％乙腈，其中％是指体积百分比))纯化后得到化合物15(26mg，产率：18％)。LC-MS(ESI):m/z＝492[M-H] +.
1H NMR(400MHz,DMSO-d 6)δ:8.04(s,1H),7.71(d,J＝6.8Hz,1H),7.66(d,J＝6.0Hz,1H),7.59(d,J＝12.8Hz,1H),7.52-7.47(m,2H),7.37(t,J＝6.0Hz,1H),7.34-7.23(m,3H),7.19-7.16(m,1H),4.00(d,J＝12.0Hz,1H),3.88(d,J＝12.0Hz,1H),3.55-3.49(m,2H),2.94(d,J＝4.8Hz,1H),2.22(s,3H)ppm
实施例16
(S,E)-2-(3-(3-(5-氟-2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基丙酸(化合物16)
合成路线：
Figure PCTCN2020080362-appb-000142
化合物16-a的合成
将化合物14-b(300mg，1.48mmol)溶于甲苯(5mL)中，加入化合物3-b(400mg，1.24mmol)，三(二亚苄基茚丙酮)二钯(100mg，0.11mmol)，2-二环己基磷-2,4,6-三异丙基联苯(100mg，0.21mmol)和无水磷酸钾(790mg，3.72mmol)。反应混合物在氮气保护下加热到105℃搅拌24小时。冷却至室温后，反应混合物减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝10：1)得到黄色固体16-a(360mg，产率：66％)。
化合物16的合成
将化合物16-a(72mg，0.16mmol)和L-丝氨酸(26mg，0.26mmol)溶于四氢呋喃(2mL)，乙醇(2mL)和水(2mL)的混合溶液中，加入氢氧化钠(22mg，0.54mmol)，反应液在25℃条件下搅拌18小时。然后，加入硼氢化钠(20mg，0.53mmol)搅拌半小时。减压浓缩反应液，剩余物用0.5M盐酸调节至pH＝5，接着用乙酸乙酯(50mL×2) 萃取，有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(二氯甲烷：甲醇＝10：1)得到化合物16(8mg，产率：10％)。LC-MS(ESI):m/z＝532[M-H] +.
1HNMR(500MHz,CD 3OD)δ:8.12(s,1H),7.76(d,J＝9Hz,1H),7.57-7.65(m,3H),7.28-7.36(m,2H),7.16(d,J＝8Hz,1H),6.76(dd,J＝9Hz,J＝1Hz,1H),6.69(m,1H),4.35(s,4H),4.31(d,J＝13Hz,1H),4.23(d,J＝13Hz,1H),3.98(m,1H),3.87(m,1H),3.52(m,1H),2.28(s,3H)ppm
实施例17
(E)-2-(3-(2-(2’-氟-2-甲基联苯-3-基)乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物17)
合成路线：
Figure PCTCN2020080362-appb-000143
化合物17的合成
在室温条件下，往13-a(100mg,0.26mmol)和2-甲基丝氨酸(62mg,0.52mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(0.03mL,0.52mmol)，反应液在室温条件下搅拌2小时。然后，加入氰基硼氢化钠(65mg,1.04mmol)搅拌16小时。减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：42％-72％(初始流动相为42％水-58％的乙腈，结束时流动相为72％水-28％乙腈，其中％是指体积百分比))纯化后得到化合物17(24mg，产率：19％)。LC-MS(ESI):m/z＝486[M-H] +.
1H NMR(400MHz,DMSO-d 6)δ:8.07(s,1H),7.77-7.51(d,J＝7.2Hz,1H),7.64-7.57(m,3H),7.49-7.45(m,1H),7.39-7.26(m,6H),3.99(s,2H),3.60-3.54(m,2H),2.22(s,3H),1.27(s,3H)ppm
实施例18
2-(3-(2-(2-甲基联苯-3-基)乙基)-4-(三氟甲基)苄基氨基)-3-羟基丙酸(化合物18)
合成路线：
Figure PCTCN2020080362-appb-000144
化合物18-b的合成
将化合物5-a(500mg,1.37mmol)溶于异丙醇(10mL)和四氢呋喃(20mL)混合溶液中，在室温下向溶液中加入10％钯-炭(150mg)，反应在氢气氛(1atm)下搅拌12小时。反应液过滤，滤液减压浓缩得到白色固体18-b(600mg)，产品无需进一步纯化，直接用于下一步。LC-MS(ESI):m/z＝371[M+1] +.
化合物18-a的合成
将化合物18-b(600mg,1.62mmol)溶于二氧六环(20mL)中，在室温下加入活性二氧化锰(2.1g,24.3mmol)。反应混合物在50℃下搅拌6小时。过滤，滤液减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝40：1)得到黄色固体18-a(300mg，产率：50％)。LC-MS(ESI):m/z＝369[M+H] +。
化合物18的合成
在室温条件下，往18-a(100mg,0.27mmol)和丝氨酸(57mg,0.54mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(0.03mL,0.54mmol)，反应液在室温条件下搅拌2小时。然后，加入氰基硼氢化钠(68mg,1.08mmol)搅拌16小时。减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：40％-70％(初始流动相为40％水-60％的乙腈，结束时流动相为70％水-30％乙腈，其中％是指体积百分比))纯化后得到化合物18(17mg，产率：13.8％)。LC-MS(ESI):m/z＝456[M-H] +.
1H NMR(400MHz,DMSO-d 6)δ:7.68-7.67(m,1H),7.58(s,1H),7.46-7.43(m,3H),7.38-7.35(m,1H),7.31-7.29(m,2H),7.22-7.19(m,2H),7.07-7.05(m,1H),4.00-3.98(d,J＝11.2Hz,1H),3.87-3.84(d,J＝11.2Hz,1H),3.62-3.67(m,2H),3.13-3.11(m,1H),2.99-2.92(m,4H),2.17(s,3H)ppm
实施例19
(E)-2-(3-(2-(2-甲基联苯-3-基)乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-羟甲基丙酸(化合物19)
合成路线：
Figure PCTCN2020080362-appb-000145
化合物19-a的合成
向500毫升反应瓶中加入丝氨酸(2.95g,28mmol)，无水硫酸铜(0.96g,6mmol)，碳酸钠(11.9g,112mmol)，37％的甲醛水溶液(20mL)以及400毫升水。混合物加热回流2小时，冷却至室温，过滤，滤液减压浓缩，剩余物加适量水溶解，以4M的盐酸调节pH＝3后，将此水溶液上Dowex-50X离子交换柱纯化(6.0cm×40cm,200～400目，氢型)。先以水淋洗，待流出液pH值由酸性转至中性后，再用250毫升水淋洗充分，然后以2M的氨水洗脱产物，并用茚三酮显色剂检测。收集对茚三酮显色的流出液，减压浓缩。剩余物加入无水乙醇(10mL)并强力搅拌，过滤，滤饼经真空干燥得到α-(羟甲基)丝氨酸(2.2g，产率：58％)。
1H NMR(500MHz,CD 3OD)δ:3.90(d,J＝14.0Hz，2H),3.76(d,J＝14.0Hz，2H)ppm
化合物19的合成
将α-(羟甲基)丝氨酸(135mg,1mmol)溶于水(3mL)和1M的氢氧化钠(2mL)的水溶液中，加入化合物3-b(110mg,0.3mmol)的四氢呋喃(3mL)和乙醇(5mL)的混合溶液中，并在室温下搅拌16小时。反应液冷却至0℃，加入硼氢化钠(38mg,1mmol)，继续搅拌1小时。减压浓缩，剩余物加水(20mL)稀释，用柠檬酸调节pH值至5，有固体析出，过滤，滤饼干燥后得到粗产物，接着用乙酸乙酯(10mL)重结晶得到白色固体19(20mg,产率：14％)。LC-MS(ESI):m/z＝486[M-H] +.
1H NMR(500MHz,CD 3OD)δ:8.18(s,1H),7.79(d,J＝8.0Hz,1H),7.63-7.69(m,2H),7.57(d,J＝8.0Hz,1H),7.44-7.47(m,2H),7.29-7.33(m,5H),7.20(d,J＝8.0Hz,1H),4.38(s,2H),4.01(d,J＝12.0Hz,2H),3.97(d,J＝12.0Hz,2H),2.34(s,3H)ppm
实施例20
(E)-2-(3-(3-(5-氟-2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物20)
合成路线：
Figure PCTCN2020080362-appb-000146
化合物20的合成
将化合物16-a(80mg，0.18mmol)和2-甲基丝氨酸(33mg，0.27mmol)溶于四氢呋喃(2mL)，乙醇(2mL)和水(2mL)的混合溶液中，加入氢氧化钠(22mg，0.54mmol)，反应液在25℃条件下搅拌18小时。然后，加入硼氢化钠(20mg，0.53mmol)搅拌半小时。减压浓缩反应液，剩余物用0.5M盐酸调节至pH＝5，接着用乙酸乙酯(50mL×2)萃取，有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(二氯甲烷：甲醇＝10：1)得到化合物20(12mg，产率：10％)。LC-MS(ESI):m/z＝546[M-H] +.
1HNMR(500MHz,CD 3OD)δ:8.17(s,1H),7.76(d,J＝9Hz,1H),7.58-7.66(m,3H),7.35-7.38(m,1H),7.29-7.33(m,1H),7.17(d,J＝8Hz,1H),6.77(dd,J 1＝9Hz,J 2＝1Hz,1H),6.69(m,1H),4.38(m,2H),4.35(s,4H),4.10(d,J＝12Hz,1H),3.90(d,J＝12Hz,1H),2.28(s,3H),1.65(s,3H)ppm
实施例21
2-(3-(2-(2-甲基联苯-3-基)乙基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物21)
合成路线：
Figure PCTCN2020080362-appb-000147
化合物21的合成
在室温条件下，往18-a(100mg,0.27mmol)和2-甲基丝氨酸(65mg,0.54mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(0.03mL,0.54mmol)，反应液在室温条件下搅拌2小时。然后，加入氰基硼氢化钠(68mg,1.08mmol)搅拌16小时。减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：40％-70％(初始流动相为40％水-60％的乙腈，结束时流动相为70％水-30％乙腈，其中％是指体积百分比))纯化后得到化合物21(27mg，产率：21.3％)。LC-MS(ESI):m/z＝ 470[M-H] +.
1H NMR(400MHz,DMSO-d 6)δ:7.69-7.68(d,J＝6.4Hz,1H),7.62(s,1H),7.49-7.43(m,3H),7.38-7.35(m,1H),7.31-7.29(m,2H),7.25-7.20(m,2H),7.07-7.05(m,1H),3.94-3.90(m,2H),3.61-3.52(m,2H),2.99-2.92(m,4H),2.17(s,3H),1.24(s,3H)ppm
实施例22
2-(3-(2-(2-甲基联苯-3-基)乙基)-4-(三氟甲基)苄基氨基)丙酸(化合物22)
合成路线：
Figure PCTCN2020080362-appb-000148
化合物22的合成
在室温条件下，往18-a(100mg,0.27mmol)和丙氨酸(44mg,0.54mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(0.03mL,0.54mmol)，反应液在室温条件下搅拌2小时。然后，加入氰基硼氢化钠(68mg,1.08mmol)搅拌16小时。减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：40％-70％(初始流动相为40％水-60％的乙腈，结束时流动相为70％水-30％乙腈，其中％是指体积百分比))纯化后得到化合物21(25mg，产率：21％)。LC-MS(ESI):m/z＝440[M-H] +.
1H NMR(400MHz,DMSO-d 6)δ:7.68-7.67(d,J＝6.4Hz,1H),7.59(s,1H),7.46-7.43(m,3H),7.38-7.35(m,1H),7.30-7.29(m,2H),7.22-7.19(m,2H),7.07-7.15(m,1H),3.98-3.95(d,J＝11.2Hz,1H),3.85-3.83(d,J＝11.2Hz,1H),3.17-3.15(m,1H),2.99-2.92(m,4H),2.17(s,3H),1.25-1.24(d,J＝5.6Hz,3H)ppm
实施例23
(E)-2-(3-(2-(2’,3’-二氟-2-甲基联苯-3-基)乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物23)
合成路线：
Figure PCTCN2020080362-appb-000149
化合物23的合成
在室温条件下，往15-a(120mg,0.3mmol)和2-甲基丝氨酸(71.4mg,0.6mmol)的甲醇(5mL)和二氯甲烷(5mL)混合溶液中加入冰醋酸(0.04mL,0.65mmol)，反应液在室温条件下搅拌2小时。然后，加入氰基硼氢化钠(56.7mg,0.9mmol)搅拌12小时。减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：42％-72％(初始流动相为42％水-68％的乙腈，结束时流动相为72％水-28％乙腈，其中％是指体积百分比))纯化后得到化合物23(26mg，产率：17％)。LC-MS(ESI):m/z＝506[M-H] +.
1H NMR(400MHz,DMSO-d 6)δ:8.19(s,1H),7.81(d,J＝6.4Hz,1H),7.68-7.64(m,3H),7.39-7.21(m,5H),7.12-7.09(m,1H),4.36(d,J＝10.0Hz,1H),4.30(d,J＝10.0Hz,1H),4.02(d,J＝9.2Hz,1H),3.85(d,J＝10.0Hz,1H),2.29(s,3H),1.57(s,3H)ppm
实施例24
(E)-2-((7-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯乙烯基)-2,3-二氢苯并呋喃-5-基)甲基氨基)-3-羟基-2-甲基丙酸(化合物24)
合成路线：
Figure PCTCN2020080362-appb-000150
化合物24-b的合成
将苯并二氢呋喃-5-甲醛(2.96g，20mmol)溶于冰乙酸(40mL)中，加入无水乙酸钠(2.1g，24mmol)。反应混合物冷却到10℃，滴加液溴(6.39g，40mmol)，然后升至室温并搅拌16小时。将冰水(100mL)加入到混合物中，用碳酸钾调节pH至9-10。用乙 酸乙酯(100mL×2)萃取，有机相经无水硫酸钠干燥，过滤，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝10：1)得到黄色固体24-b(3.8g，产率：85％)。
1HNMR(500MHz,CDCl 3)δ:9.78(s,1H),7.82(d,J＝1Hz,1H),7.66(d,J＝1Hz,1H),4.79(t,J＝9Hz,2H),3.38(d,J＝9Hz,2H)ppm
化合物24-a的合成
将化合物24-b(158mg，0.69mmol)溶于二氧六环(5mL)和水(0.5mL)中，加入化合物1-b(370mg，0.97mmol)，1,1'-双二苯基膦二茂铁二氯化钯(59mg，0.07mmol)和碳酸钠(219mg，2.07mmol)。反应混合物在氮气保护下加热到80℃搅拌16小时。冷却至室温后，加入二氯甲烷(50mL)和水(50mL)，有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝3：1)得到黄色固体16-a(180mg，产率：65％)。
1HNMR(500MHz,CDCl 3)δ:9.89(s,1H),7.84(s,1H),7.70(s,1H),7.66(d,J＝10Hz,1H),7.57(d,J＝8Hz,1H),7.24(m,1H),7.15(d,J＝7Hz,1H),7.04(d,J＝11Hz,1H),6.91(d,J＝8Hz,1H),6.83(d,J＝2Hz,1H),6.77(m,1H),4.80(t,J＝9Hz,2H),4.31(s,4H),3.31(d,J＝9Hz,2H),2.32(s,3H)ppm
化合物24的合成
将化合物24-a(180mg，0.46mmol)和2-甲基丝氨酸(54mg，0.92mmol)溶于四氢呋喃(4mL)，乙醇(4mL)和水(4mL)的混合溶液中，加入氢氧化钠(75mg，1.84mmol)，反应液在25℃条件下搅拌18小时。然后，加入硼氢化钠(70mg，1.84mmol)搅拌半小时。减压浓缩反应液，剩余物用0.5M盐酸调节至pH＝5，接着用乙酸乙酯(50mL×2)萃取，有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(二氯甲烷：甲醇＝10：1)得到化合物24(12mg，产率：6％)。LC-MS(ESI):m/z＝502[M-H] +.
1HNMR(500MHz,CD 3OD)δ:7.74(d,J＝16Hz，1H),7.56(m，1H),7.48(m,1H),7.29(m,1H),7.21(m,1H),7.08(m,1H),7.03(m,J＝11Hz,1H),6.88(m,1H),6.76(m,1H),4.78(t,J＝9Hz,2H),4.29(s,4H),4.12(m,1H),3.77(m,1H),3.62(m,1H),3.32(t,J＝9Hz,2H),2.29(s,3H),1.49(s,3H)ppm
实施例25
(E)-2-(3-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯乙烯基)-4-氟苄基氨基)-3-羟基-2-甲基丙酸(化合物25)
合成路线：
Figure PCTCN2020080362-appb-000151
化合物25的合成
在室温条件下，往12-a(186mg,0.5mmol)和2-甲基丝氨酸(119mg,1.0mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(0.04mL,0.65mmol)，反应液在室温条件下搅拌6小时。然后，加入氰基硼氢化钠(94.5mg,1.5mmol)搅拌18小时。减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：35％-65％(初始流动相为35％水-65％的乙腈，结束时流动相为65％水-35％乙腈，其中％是指体积百分比))纯化后得到化合物25(29mg，产率：12.1％)。LC-MS(ESI):m/z＝478[M-H] +.
1H NMR(400MHz,CD3OD)δ:7.98(d,J＝4.0Hz,1H),7.68(d,J＝12.8Hz,1H),7.59(d,J＝6.4Hz,1H),7.50-7.47(m,1H),7.26-7.13(m,4H),6.89(d,J＝6.4Hz,1H),6.77-6.73(m,2H),4.29(s,4H),4.26-4.18(q,2H),3.99(d,J＝10Hz,1H),3.83(d,J＝10Hz,1H),2.32(s,3H),1.55(s,3H)ppm
实施例26
(S,E)-2-(3-(3-(5-氟-2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯乙烯基)-4-甲基苄基氨基)-3-羟基-2-甲基丙酸(化合物26)
合成路线：
Figure PCTCN2020080362-appb-000152
化合物26的合成
在室温条件下，往14-a(100mg,0.26mmol)和(S)-2-甲基丝氨酸(68mg,0.52mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(0.03mL,0.52mmol)，反应液在室温条件下搅拌2小时。然后，加入氰基硼氢化钠(65mg,1.03mmol)搅拌16小时。减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：40％-70％(初始流动相为40％水-60％的乙腈，结束时流动相为70％水-30％乙腈，其中％是指体积百分比))纯化后得到化合物26(20mg，产率：15.6％)。LC-MS(ESI):m/z＝490 [M-H] +.
1H NMR(400MHz,DMSO-d 6)δ:7.78(s,1H),7.72-7.03(d,J＝6.0Hz,1H),7.38-7.35(m,1H),7.31-7.25(m,3H),7.23-7.22(m,1H),7.12-7.11(m,1H),6.81-6.79(m,1H),6.73-6.70(m,1H),4.34(s,4H),4.01-3.93(m,2H),3.67-3.65(m,1H),3.59-3.57(m,1H),2.41(s,3H),2.19(s,3H),1.29(s,3H)ppm
实施例27
(R,E)-2-(3-(2-(2-甲基联苯-3-基)乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物27)
合成路线：
Figure PCTCN2020080362-appb-000153
化合物27的合成
在室温条件下，往5-a(100mg,0.27mmol)和(R)-2-甲基丝氨酸(65mg,0.54mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(32.8mg,0.54mmol)，反应液在室温条件下搅拌1小时。然后，加入氰基硼氢化钠(85.8mg,1.36mmol)搅拌16小时。减压浓缩反应液，剩余物溶于乙酸乙酯(50mL)中，用水(20mL)和饱和食盐水(20mL)洗涤，有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(二氯甲烷：甲醇＝10：1)得到化合物27(24mg，产率：18.7％)。LC-MS(ESI):m/z＝468[M-H] +
1H NMR(500MHz,CD 3OD)δ:8.17(s,1H),7.81-7.79(d,J＝8.5Hz,1H),7.68-7.62(m,2H),7.57-7.55(d,J＝8.0Hz,1H),7.46-7.43(m,2H),7.39-7.28(m,5H),7.20-7.19(d,J＝7.0Hz,1H),4.36-4.28(q,2H),4.03-4.00(d,J＝12.5Hz,1H),3.86-3.84(d,J＝12.5Hz,1H),2.33(s,3H),1.57(s,3H)ppm
实施例28
(S,E)-2-(3-(2-(2-甲基联苯-3-基)乙烯基)-4-甲基苄基氨基)-3-羟基-2-甲基丙酸(化合物28)
合成路线：
Figure PCTCN2020080362-appb-000154
化合物28的合成
在室温条件下，往8-a(120mg,0.38mmol)和(S)-2-甲基丝氨酸(92mg,0.77mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(0.034mL,0.77mmol)，反应液在室温条件下搅拌2小时。然后，加入氰基硼氢化钠(97mg,1.53mmol)搅拌12小时。减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：40％-70％(初始流动相为40％水-60％的乙腈，结束时流动相为70％水-30％乙腈，其中％是指体积百分比))纯化后得到化合物28(50mg，产率：31.7％)。LC-MS(ESI):m/z＝414[M-H] +.
1H NMR(400MHz,DMSO-d 6)δ:7.78(s,1H),7.69-7.68(d,J＝6.0Hz,1H),7.47-7.44(m,2H),7.39-7.36(m,2H),7.33-7.22(m,6H),7.15-7.14(m,1H),4.01-3.93(m,2H),3.67-3.65(m,1H),3.59-3.58(m,1H),2.41(s,3H),2.27(s,3H),1.29(s,3H)ppm
实施例29
(S,E)-2-(3-(2-(2-甲基联苯-3-基)乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物29)
合成路线：
Figure PCTCN2020080362-appb-000155
化合物29的合成
在室温条件下，往5-a(100mg,0.27mmol)和(S)-2-甲基丝氨酸(65mg,0.54mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(32.8mg,0.54mmol)，反应液在室温条件下搅拌1小时。然后，加入氰基硼氢化钠(85.8mg,1.36mmol)搅拌16小时。减压浓缩反应液，剩余物溶于乙酸乙酯(50mL)中，用水(20mL)和饱和食盐水(20mL)洗涤，有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板 纯化(二氯甲烷：甲醇＝10：1)得到化合物29(42mg，产率：32.8％)。LC-MS(ESI):m/z＝468[M-H] +
1H NMR(500MHz,CD 3OD)δ:8.05(s,1H),7.68-7.67(d,J＝8.0Hz,1H),7.56-7.50(m,2H),7.45-7.44(d,J＝7.5Hz,1H),7.34-7.31(m,2H),7.27-7.16(m,5H),7.08-7.07(d,J＝7.0Hz,1H),4.24-4.15(q,2H),3.90-3.88(d,J＝12.0Hz,1H),3.74-3.71(d,J＝12.0Hz,1H),2.21(s,3H),1.45(s,3H)ppm
实施例30
(S,E)-2-(3-(3-(5-氟-2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯乙烯基)-4-甲基苄基氨基)-3-羟基-2-甲基丙酸(化合物30)
合成路线：
Figure PCTCN2020080362-appb-000156
化合物30的合成
在室温条件下，往14-a(100mg,0.26mmol)和(S)-2-甲基丝氨酸(69mg,0.52mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(0.03mL,0.52mmol)，反应液在室温条件下搅拌2小时。然后，加入氰基硼氢化钠(65mg,1.03mmol)搅拌12小时。减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：40％-70％(初始流动相为40％水-60％的乙腈，结束时流动相为70％水-30％乙腈，其中％是指体积百分比))纯化后得到化合物30(40mg，产率：31.3％)。LC-MS(ESI):m/z＝490[M-H] +.
1H NMR(400MHz,DMSO-d 6)δ:7.79(s,1H),7.72-7.71(d,J＝6.0Hz,1H),7.39-7.35(m,1H),7.31-7.26(m,3H),7.23-7.21(m,1H),7.13-7.11(m,1H),6.81-6.79(m,1H),6.74-6.70(m,1H),4.34(s,4H),4.00-3.93(m,2H),3.67-3.57(m,2H),2.41(s,3H),2.19(s,3H),1.29(s,3H)ppm
实施例31
(S,E)-2-(3-(2-(2-甲基联苯-3-基)乙烯基)-4-甲基苄基氨基)-3-羟基-2-甲基丙酸(化合物31)
合成路线：
Figure PCTCN2020080362-appb-000157
化合物31的合成
在室温条件下，往8-a(120mg,0.38mmol)和(S)-2-甲基丝氨酸(92mg,0.77mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(0.04mL,0.77mmol)，反应液在室温条件下搅拌2小时。然后，加入氰基硼氢化钠(97mg,1.53mmol)搅拌12小时。减压浓缩，剩余物经高效液相色谱法(流动相：水(10mM碳酸氢铵)，乙腈；梯度：40％-70％(初始流动相为40％水-60％的乙腈，结束时流动相为70％水-30％乙腈，其中％是指体积百分比))纯化后得到化合物31(50mg，产率：31.7％)。LC-MS(ESI):m/z＝414[M-H] +.
1H NMR(400MHz,DMSO-d 6)δ:7.78(s,1H),7.69-7.68(d,J＝6.0Hz,1H),7.47-7.44(m,2H),7.39-7.36(m,2H),7.33-7.22(m,6H),7.15-7.14(m,1H),4.01-3.93(m,2H),3.67-3.65(m,1H),3.59-3.58(m,1H),2.41(s,3H),2.27(s,3H),1.29(s,3H)ppm
实施例32
(E)-2-(1-(3-(2-(2-甲基联苯-3-基)乙烯基)-4-(三氟甲基)苯基)乙基氨基)乙酸(化合物32)
合成路线：
Figure PCTCN2020080362-appb-000158
化合物32-d的合成
将化合物5-a(500mg，1.37mmol)和叔丁基亚磺酰胺(248mg，2.05mmol)溶于四氢呋喃(10mL)中，加入钛酸四异丙酯(773mg，2.74mmol)。反应液加热到60℃搅拌1小时后，冷却至室温。加入饱和氯化钠溶液(20mL)，用乙酸乙酯(50mL×3)萃取，有机相经无水硫酸钠干燥，过滤，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝5:1)得到浅黄色固体32-d(610mg，产率：95％)。
化合物32-c的合成
将化合物32-d(610mg，1.3mmol)溶于无水四氢呋喃(10mL)中，冷却到0℃，滴加甲基溴化镁的乙醚溶液(3M，0.9mL，2.7mmol)，滴加完后搅拌30分钟。用饱和氯化铵溶液(20mL)淬灭反应，乙酸乙酯(50mL)萃取，有机相经无水硫酸钠干燥，过滤，减压浓缩，剩余物用甲基叔丁基醚(50mL)洗涤得到白色固体32-c(410mg，产率：65％)。产品无需进一步纯化。LC-MS(ESI):m/z＝485[M+H] +.
化合物32-b的合成
将化合物32-c(410mg，0.85mmol)溶于甲醇(5mL)中，加入4N氯化氢二氧六环溶液(5mL)，反应液加热到60℃搅拌2小时。冷却至室温后，反应液减压浓缩，剩余物用石油醚(50mL)洗涤得到白色固体32-b(320mg，产率：91％)。产品无需进一步纯化。LC-MS(ESI):m/z＝382[M+H] +.
化合物32-a的合成
将化合物32-b(180mg，0.43mmol)溶于乙腈(5mL)，加入三乙胺(1mL)和溴乙酸叔丁酯(92mg，0.48mmol)，反应液加热到80℃搅拌3小时。冷却至室温后，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝3:1)得到黄色固体32-a(60mg，产率：28％)。
化合物32的合成
将化合物32-a(60mg，0.12mmol)溶于二氯甲烷(3mL)中，加入三氟乙酸(3mL)。反应液在室温下搅拌3小时后，减压浓缩，剩余物用饱和碳酸氢钠水溶液调节pH至5-6。用乙酸乙酯(50mL)萃取，有机相经无水硫酸钠干燥，过滤，减压浓缩，剩余物经硅胶薄层层析制备板纯化(二氯甲烷：甲醇＝10:1)得到白色固体32(25mg，产率：47％)。LC-MS(ESI):m/z＝440[M+H] +.
1HNMR(500MHz,CD 3OD)δ:8.08(s,1H),7.83(d,J＝8Hz,1H),7.64(d,J＝15Hz,1H),7.57(m,2H),7.45(m,2H),7.29-7.38(m,5H),7.21(d,J＝8Hz,1H),4.60(m,1H),3.46(d,J＝16Hz,1H),3.36(d,J＝16Hz,1H),2.34(s,3H),1.73(d,J＝7Hz,1H)ppm
实施例33
(S,E)-2-(3-(2-(2-氟联苯-3-基)乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物33)
合成路线：
Figure PCTCN2020080362-appb-000159
化合物33-c的合成
在室温条件下，往1-溴-3-氯-2-氟苯(5.0g，23.87mmol)和乙烯基硼酸频哪醇酯(4.47g，28.65mmol)的甲苯(100mL)溶液中加入二(三叔丁基膦)钯(853.9mg，1.67mmol)和三乙胺(19.32g，190.9mmol)，将反应液加热至80℃，在氮气条件下搅拌反应过夜。反应结束后，加入乙酸乙酯稀释(50mL)，用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝10：1)得化合物33-c(3.45g，产率：51.1％)。
1H NMR(500MHz,CDCl 3)δ:7.56-7.52(d,J＝18.5Hz,1H),7.47-7.44(m,1H),7.34-7.30(m,1H),7.07-7.04(t,1H),6.27-6.23(d,J＝18.5Hz,1H),1.32(s,12H)ppm
化合物33-b的合成
在室温条件下，往3-溴-4-三氟甲基苯甲醛(2.57g，10.18mmol)和33-c(3.45g，12.21mmol)的1,4-二氧六环(40mL)和水(2mL)中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(880mg，1.64mmol)和碳酸钠(2.69g，25.44mmol)，将反应液加热至80℃，在氮气条件下搅拌反应过夜。反应结束后，加入乙酸乙酯稀释(50mL)，依次用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝40：1)得到化合物33-b(1.62g，产率：48.5％)。
1H NMR(500MHz,CDCl 3)δ:10.15(s,1H),8.28(s,1H),7.91-7.86(m,2H),7.58-7.55(m,1H),7.53-7.50(m,1H),7.39-7.35(m,1H),7.34-7.31(d,J＝16.5Hz,1H),7.15-7.12(m,1H)ppm
化合物33-a的合成
在室温条件下，往苯硼酸(721.8mg，5.92mmol)和33-b(300mg，1.108mmol)的甲苯(50mL)溶液中加入三(二亚苄基丙酮)二钯(226.2mg，0.24mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(470mg，0.98mmol)和磷酸钾(3.14g，14.79mmol)，将反应液加热至90℃，在氮气条件下搅拌反应过夜。反应结束后，加入乙酸乙酯(50mL)稀释，依次用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝40：1)得到化合物33-a(1.56g，产率：85.2％)。
1H NMR(500MHz,CDCl 3)δ:10.14(s,1H),8.31(s,1H),7.89-7.85(m,2H),7.64-7.56(m,4H),7.49-7.39(m,5H),7.28-7.24(m,1H)ppm
化合物33的合成
在室温条件下，往33-a(100mg，0.27mmol)和(S)-2-甲基丝氨酸(64.3mg，0.54mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(32.4mg，0.54mmol)，反应液在室温条件下搅拌1小时。然后，加入氰基硼氢化钠(84.8mg，1.35mmol)搅拌16小时。反应结束后，将有机溶剂旋干，残留物用乙酸乙酯(50mL)溶解后，依次用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(二氯甲烷：甲醇＝10：1)得到化合物33(30mg，产率：23.6％)。LC-MS(ESI):m/z＝472[M-H] +.
1H NMR(400MHz,CD 3OD)δ:8.17(s,1H),7.79-7.77(d,J＝8.0Hz,1H),7.67-7.59(m,3H),7.56-7.50(m,3H),7.48-7.37(m,4H),7.32-7.28(m,1H),4.35-4.24(m,2H),4.01-3.98(d,J＝12.4Hz,1H),3.84-3.81(d,J＝12.0Hz,1H),1.55(s,3H)ppm
实施例34
(R,E)-2-(3-(2-(2-氟联苯-3-基)乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物34)
合成路线：
Figure PCTCN2020080362-appb-000160
化合物34的合成
在室温条件下，往33-a(100mg，0.27mmol)和(R)-2-甲基丝氨酸(64.3mg，0.54mmol)的甲醇(10mL)和二氯甲烷(10mL)混合溶液中加入冰醋酸(32.4mg，0.54mmol)，反应液在室温条件下搅拌1小时。然后，加入氰基硼氢化钠(84.8mg，1.35mmol)搅拌16小时。反应结束后，将有机溶剂旋干，残留物用乙酸乙酯(50mL)溶解后，依次用水(50mL)和饱和食盐水(50mL)洗涤。所得有机相经无水硫酸钠干燥，减压浓缩，剩余物经硅胶薄层层析制备板纯化(二氯甲烷：甲醇＝10：1)得到化合物34(24mg，产率：18.9％)。LC-MS(ESI):m/z＝472[M-H] +.
1H NMR(400MHz,CD 3OD)δ:8.17(s,1H),7.79-7.77(d,J＝8.0Hz,1H),7.67-7.59(m,3H),7.56-7.50(m,3H),7.48-7.37(m,4H),7.32-7.28(m,1H),4.35-4.24(m,2H),4.01-3.98(d,J＝12.4Hz,1H),3.84-3.81(d,J＝12.0Hz,1H),1.55(s,3H)ppm
实施例35
(S,E)-2-(3-(3-苯并[d]噁唑-6-基)-2-甲基苯乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物35)
合成路线：
Figure PCTCN2020080362-appb-000161
化合物35-b的合成
向100毫升反应瓶中加入3-b(3.24g,10mmol)，联硼酸频哪醇酯(3.05g,12mmol)，三(二亚苄基丙酮)二钯(458mg,0.5mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(952mg，2.0mmol)，醋酸钾(3.00g,112mmol)以及80毫升甲苯。混合物于90℃氮气条件下搅拌16小时。冷却至室温，过滤，滤液于旋转蒸发仪上旋干。所得的剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝25：1)得到化合物35-b(3.06g，产率：82％)。1H NMR(500MHz,CD3Cl)δ:10.15(s,1H),8.28(s,1H),7.85(s,2H),7.73-7.76(m,1H),7.62(d,J＝7.5Hz,1H),7.50(d,J＝18Hz,1H),7.26-7.28(m,1H),7.23(d,J＝7.5Hz,1H),2.65(s,3H),1.37(s,12H)ppm
化合物35-a的合成
向6-溴-苯并[d]噁唑(600mg，3.0mmol)和35-b(1.00g，2.4mmol)的1,4-二氧六环(20mL)的混合物中加入水(3mL)、[1,1’-双(二苯基磷)二茂铁]二氯化钯(180mg，0.24mmol)和碳酸钠(636mg，6.0mmol)，将反应液加热至80℃，在氮气条件下搅拌16小时。减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝25：1)得到化合物35-a(700mg，产率：72％)。
化合物35的合成
向50毫升单口瓶中加入溶有(S)-2-甲基丝氨酸(119mg,1mmol)的3毫升水溶液以及2毫升1M的氢氧化钠水溶液。加毕，向此溶液中加入35-a(194mg,0.5mmol)溶于3毫升四氢呋喃的溶液，并加入5毫升甲醇使混合物为均相。室温搅拌16小时后，于冰水浴冷却下，加入硼氢化钠(38mg,1mmol)。加毕，冰水浴下继续搅拌1小时。减压旋除溶剂，残留物加水稀释，用柠檬酸调节PH值至5～6。过滤，收集固体，干燥，得到粗产物。向粗产品中加入10毫升乙酸乙酯，加热回流数分钟，冷却至室温，过滤，收集固体，干燥，得到白色固体产物化合物35(44mg,17％)。LC-MS(ESI):m/z＝511(M+H)+.
1H NMR(500MHz,CD 3OD)δ:8.54(s,1H),8.19(s,1H),7.83(d,J＝8.0Hz,1H),7.81(d,J＝8.0Hz,1H),7.69(d,J＝18.0Hz,1H),7.61-7.63(m,3H),7.33-7.41(m,3H),7.27(d,J＝7.5Hz,1H),4.36(d,J＝12.5Hz,1H),4.30(d,J＝12.5Hz,1H),4.02(d,J＝11.5Hz,1H),3.84(d,J＝11.5Hz,1H),2.36(s,3H),1.57(s,3H)ppm
实施例36
(S,E)-2-(3-(3-咪唑并[1,2-a]吡啶-6-基)-2-甲基苯乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物36)
合成路线：
Figure PCTCN2020080362-appb-000162
化合物36-a的合成
在室温条件下，往6-溴-咪唑并[1,2-a]吡啶(197mg，1.0mmol)和35-b(416mg，1.0mmol)的1,4-二氧六环(20mL)溶液中，加入水(3mL)、[1,1’-双(二苯基磷)二茂铁]二氯化钯(73mg，0.1mmol)和碳酸钠(318mg，3.0mmol)。将反应液加热至80℃，在氮气条件下搅拌16小时。减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝3：1)得到化合物36-a(280mg，产率：69％)。
化合物36的合成
搅拌下，向(S)-2-甲基丝氨酸(238mg,2.0mmol)以及36-a(203mg,0.5mmol)的30毫升甲醇悬浮液中，加入氢氧化钠(80mg,2.0mmol)溶于6毫升水的溶液。混合物变为澄清的均相体系。室温搅拌3小时，然后冷却至0℃。于0℃下加入硼氢化钠(38mg,1.0mmol)，加毕，自然升温至室温，继续搅拌2小时。减压旋除甲醇，残留物加水10毫升稀释，用柠檬酸调节PH值至7。加入10毫升乙酸乙酯，搅拌10分钟。过滤，收集固体，干燥，得到产物36(68mg,26％)。LC-MS(ESI):m/z＝510(M+H)+.
1H NMR(500MHz,CD 3OD)δ:8.45(s,1H),8.17(s,1H),7.91(m,1H),7.79(m,1H),7.62-7.68(m,5H),7.30-7.38(m,4H),4.29(d,J＝10Hz,1H),4.24(d,J＝10Hz,1H),3.97(d,J＝11Hz,1H),3.83(d,J＝11Hz,1H),2.40(s,3H),1.54(s,3H)ppm
实施例37
(S,E)-2-(3-(3-咪唑并[1,2-a]吡嗪-6-基)-2-甲基苯乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物37)
Figure PCTCN2020080362-appb-000163
化合物37-a的合成
在室温条件下，往6-溴-咪唑并[1,2-a]吡啶(198mg，1.0mmol)和35-b(416mg，1.0mmol)的1,4-二氧六环(20mL)溶液中加入水(3mL)、[1,1’-双(二苯基磷)二茂铁]二氯化钯(73mg，0.1mmol)和碳酸钠(270mg，2.5mmol)。反应混合物加热至80℃，在氮气条件下搅拌16小时。减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝6： 1)得到化合物37-a(95mg，产率：23％)。LC-MS(ESI):m/z＝408(M+H)+.
化合物37的合成
搅拌下，向(S)-2-甲基丝氨酸(119mg,1.0mmol)以及37-a(81mg,0.2mmol)的20毫升甲醇悬浮液中，加入氢氧化钠(40mg,1.0mmol)溶于5毫升水的溶液。混合物变为澄清的均相体系。室温搅拌3小时，然后冷却至0℃。于0℃下加入硼氢化钠(19mg,0.5mmol)，加毕，自然升温至室温，继续搅拌2小时。减压旋除甲醇，残留物加水10毫升稀释，用柠檬酸调节PH值至7。加入10毫升乙酸乙酯，搅拌10分钟。过滤，收集固体，干燥，得到产物37(33mg,产率：32％)。LC-MS(ESI):m/z＝511(M+H)+.
1H NMR(500MHz,CD 3OD)δ:9.10(s,1H),8.64(s,1H),8.20(s,1H),8.15(s,1H),7.91(s,1H),7.80(d,J＝8Hz,1H),7.64-7.71(m,3H),7.34-7.43(m,3H),4.37(d,J＝12Hz,1H),4.31(d,J＝12Hz,1H),4.02(d,J＝12Hz,1H),3.86(d,J＝12Hz,1H),2.43(s,3H),1.58(s,3H)ppm
实施例38
(S,E)-2-(3-(3-苯并[d]异噁唑-6-基)-2-甲基苯乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物38)
Figure PCTCN2020080362-appb-000164
化合物38-a的合成
在室温条件下，往6-溴-苯并[d]异噁唑(198mg，1.0mmol)和35-b(416mg，1.0mmol)的1,4-二氧六环(20mL)溶液中加入水(3mL)、[1,1’-双(二苯基磷)二茂铁]二氯化钯(73mg，0.1mmol)和碳酸钠(270mg，2.5mmol)。反应混合物加热至80℃，在氮气条件下搅拌16小时。减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝6：1)得到化合物37-a(86mg，产率：21％)。LC-MS(ESI):m/z＝408(M+H)+.
化合物38的合成
搅拌下，向(S)-2-甲基丝氨酸(48mg,0.4mmol)以及38-a(82mg,0.2mmol)的20毫升甲醇悬浮液中，加入氢氧化钠(20mg,0.5mmol)溶于4毫升水的溶液。混合物变为澄清 的均相体系。室温搅拌3小时，然后冷却至0℃。于0℃下加入硼氢化钠(23mg,0.6mmol)，加毕，自然升温至室温，继续搅拌2小时。减压旋除甲醇，残留物加水10毫升稀释，用柠檬酸调节PH值至5～6。加入10毫升乙酸乙酯，搅拌10分钟。过滤，收集固体，干燥，得到产物38(12mg,产率：12％)。LC-MS(ESI):m/z＝511(M+H)+.
1H NMR(500MHz,CD 3OD)δ:8.17(s,1H),7.80(d,J＝8Hz,1H),7.59-7.87(m,5H),7.31-7.37(m,2H),7.19(d,J＝7.5Hz,1H),6.89-6.91(m,2H),4.33(d,J＝12Hz,1H),4.27(d,J＝12Hz,1H),4.00(d,J＝12Hz,1H),3.84(d,J＝12Hz,1H),2.34(s,3H),1.56(s,3H)ppm
实施例39
(S,E)-3-羟基-2-甲基-2-(3-(2-甲基-3-(吡啶-2-基)-苯乙烯基)-4-(三氟甲基)苄基氨基)-丙酸(化合物39)
Figure PCTCN2020080362-appb-000165
化合物39-a的合成
将2-溴吡啶(158mg，1.00mmol)和35-b(500.0mg，1.20mmol)溶于1，4-二氧六环和水的混合液中(20mL,1,4-二氧六环和水的体积比20:1)，加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(86.5mg，0.10mmol)和碳酸钠(814.6mg，2.50mmol)，将反应液加热至80℃，在氮气条件下搅拌反应过夜。反应结束后，加入乙酸乙酯稀释，用水洗涤三次，饱和食盐水洗涤一次。所得有机相经无水硫酸钠干燥，旋干后得到粗品化合物，经制备板纯化(PE/EA＝5:1)后得到目标化合物39-a(90mg，产率：24％)。
化合物39的合成
往39-a(105mg，0.29mmol)和(S)-2-甲基丝氨酸(68mg，0.57mmol)溶于甲醇和二氯甲烷(10mL，甲醇和二氯甲烷的体积比1:1)混合溶液中，加入冰醋酸(34mg，0.57mmol)，反应液在常温条件下搅拌1小时。然后，加入氰基硼氢化钠(90mg，1.43mmol)搅拌反应过夜。反应结束后，将溶剂旋干后得到粗品化合物，经制备板纯化(DCM:MeOH ＝15:1)后得到目标化合物39(34mg，产率：25％)。LC-MS(ESI):m/z＝471.0[M+H]+.
1H NMR(500MHz,CD 3OD)δ:8.64-8.63(d,J＝5.0Hz,1H),8.19(s,1H),7.99-7.96(m,1H),7.82-7.80(d,J＝7.5Hz,1H),7.70-7.64(m,3H),7.54(d,J＝7.0Hz,1H),7.48-7.46(m,1H),7.40-7.32(m,3H),4.37(d,J＝12Hz,1H),4.29(d,J＝12Hz,1H),4.02(d,J＝12Hz,1H),3.85(d,J＝12Hz,1H),2.36(s,3H),1.57(s,3H)ppm
实施例40
(S,E)-3-羟基-2-甲基-2-(3-(2-甲基-3-(吡啶-3-基)-苯乙烯基)-4-(三氟甲基)苄基氨基)-丙酸(化合物40)
Figure PCTCN2020080362-appb-000166
化合物40-a的合成
在常温条件下，往3-溴吡啶(63.2mg，0.40mmol)和35-b(200.0mg，0.48mmol)的1，4-二氧六环和水的混合溶液(20mL,1,4-二氧六环和水的体积比20:1)中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(34.6mg，0.04mmol)和碳酸钠(106mg，1.0mmol)，将反应液加热至80℃，在氮气条件下搅拌反应过夜。反应结束后，加入乙酸乙酯稀释，用水洗涤三次，饱和食盐水洗涤一次。所得有机相经无水硫酸钠干燥，旋干后得到粗品化合物，经制备板纯化(PE/EA＝10:1～5:1)后得到目标化合物40-a(57mg，产率：39％)LC-MS(ESI):m/z＝368.0[M+H]+.
化合物40的合成
往40-a(57mg，0.155mmol)和(S)-2-甲基丝氨酸(37mg，0.31mmol)溶于甲醇和二氯甲烷的混合溶液中(10mL，甲醇和二氯甲烷的体积比1:1)，加入冰醋酸(19mg，0.31mmol)，反应液在常温条件下搅拌1小时。然后，加入氰基硼氢化钠(49mg，0.78mmol)搅拌反应过夜。反应结束后，将溶剂旋干后得到粗品化合物，经制备板纯化(DCM:MeOH＝15:1)后得到目标化合物40(19mg，产率：26％)。LC-MS(ESI):m/z＝471.0[M-H]+.
1H NMR(500MHz,CD 3OD)δ:8.58(dd,J＝2.0Hz,J＝5.5Hz,1H),8.54(s,1H),8.19(s,1H),7.86(d,J＝8.0Hz,1H),7.81(d,J＝7.5Hz,1H),7.69-7.64(m,3H),7.58-7.55(m,1H),7.39-7.36(m,2H),7.25(d,J＝12Hz,1H),4.37(d,J＝12Hz,1H),4.29(d,J＝12Hz,1H),4.03(d,J＝12Hz,1H),3.85(d,J＝12Hz,1H),2.36(s,3H),1.57(s,3H)ppm.
实施例41
(S,E)-3-羟基-2-甲基-2-(3-(2-甲基-3-(吡嗪-2-基)-苯乙烯基)-4-(三氟甲基)苄基氨基)-丙酸(化合物41)
Figure PCTCN2020080362-appb-000167
化合物41-a的合成
往2-氯吡嗪(180mg，1.57mmol)和35-b(985mg，2.37mmol)溶于1,4-二氧六环(5mL)的溶液中加入水(2mL)，无水碳酸钠(500mg，4.71mmol)和1,1'-双二苯基膦二茂铁二氯化钯(87mg，0.11mmol)，氮气保护下加热到80℃反应过夜。减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝3:1)得到浅黄色固体41-a(75mg，产率：13％)。LC-MS(ESI):m/z＝369[M+H]+.
化合物41的合成
往41-a(75mg，0.21mmol)溶于二氯甲烷(5mL)和甲醇(5mL)的混合溶液中，加入(S)-2-甲基丝氨酸(49mg，0.41mmol)和冰乙酸(1滴)。室温搅拌3小时后加入氰基硼氢化钠(20mg，0.32mmol)。室温下搅拌过夜，浓缩干后薄层层析硅胶板纯化(二氯甲烷：甲醇＝10：1)得到类白色固体41(46mg，产率：40％)。LC-MS(ESI):m/z＝572[M+H]+.
1H-NMR(500MHz,MeOD)δ:8.78(d，J＝1Hz,1H),8.73(d,J＝3Hz,1H),8.64(d,J＝3Hz,1H),8.19(s,1H),7.65-7.82(m,4H),7.37-7.43(m,3H),4.33(m,2H),4.01(d,J＝12Hz,1H),3.85(d,J＝12Hz,1H),2.42(s,3H),1.58(s,3H)ppm.
实施例42
(S,E)-3-羟基-2-甲基-2-(3-(2-甲基-3-(2-甲基-2H-吲唑-6-基)-苯乙烯基)-4-(三氟甲基)苄基氨基)-丙酸(化合物42)
Figure PCTCN2020080362-appb-000168
化合物42-a的合成
将6-溴-2-甲基-2H-吲唑(210mg，1.0mmol)和35-b(560mg，1.35mmol)溶于1,4-二氧六环(5mL),加入水(2mL)，无水碳酸钠(191mg，3.0mmol)和1,1'-双二苯基膦二茂铁二氯化钯(100mg，0.1mmol)，氮气保护下加热到80℃反应过夜。减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝10:1)得到浅黄色固体42-a(150mg，产率：36％)。LC-MS(ESI):m/z＝421[M+H]+.
化合物42的合成
往42-a(150mg，0.36mmol)溶于二氯甲烷(5mL)和甲醇(5mL)的混合溶液中，加入(S)-2-甲基丝氨酸(85mg，0.72mmol)和冰乙酸(1滴)。室温搅拌3小时后加入氰基硼氢化钠(67mg，1.08mmol)。室温下搅拌过夜，浓缩干后薄层层析硅胶板纯化(二氯甲烷：甲醇＝10：1)得到类白色固体42(56mg，产率：30％)。LC-MS(ESI):m/z＝524[M+H]+.
1H-NMR(500MHz,MeOD)δ:8.26(s，1H)，8.18(s，1H)，7.58-7.81(m，5H),7.38(s,1H),7.26-7.35(m,3H),7.06(d,J＝9Hz,1H),4.28(m,5H),3.99(d,J＝12Hz,1H),3.83(d,J＝12Hz,1H),2.37(s,3H),1.54(s,3H)ppm.
实施例43
(S,E)-3-羟基-2-甲基-2-(3-(2-甲基-3-(2-甲基苯并[d]噁唑-6-基)-苯乙烯基)-4-(三氟甲基)苄基氨基)-3-羟基-2-甲基丙酸(化合物43)
Figure PCTCN2020080362-appb-000169
化合物43-c的合成
往6-溴-2-甲基-苯并[d]-噁唑(400mg，1.89mmol)和3-b(1104mg，2.65mmol)溶于1,4-二氧六环(15mL)溶液中，加入水(3mL)，无水碳酸钠(600mg，5.66mmol)和1,1'-双二苯基膦二茂铁二氯化钯(164mg，0.21mmol)，氮气保护下加热到80℃反应过夜。减压浓缩后经硅胶柱层析纯化(石油醚：乙酸乙酯＝5:1)得到浅黄色固体43-c(510mg，产率：64％)。LC-MS(ESI):m/z＝422[M+H]+.
化合物43-b的合成
43-c(510mg，1.21mmol)溶于乙醇(10mL)中，加入硼氢化钠(92mg，2.42mmol)。室温搅拌2小时后浓缩干，残留物用乙酸乙酯(50mL)和水(50mL)分液。有机相分出后干燥，过滤，浓缩干后重新溶于二氯甲烷(20mL)。加入DMF(1滴)和氯化亚砜(3mL)，室温搅拌2小时。残留物浓缩干后得到43-b直接用于下一步反应。
化合物43-a的合成
43-b(360mg，0.82mmol)和L-2-甲基丝氨酸甲酯盐酸盐(127mg，0.82mmol)溶于乙腈(10mL)中，加入碳酸钾(339mg，2.46mmol)和碘化钠(125mg，0.82mmol)。混合物加热到85℃反应8小时，浓缩干后残留物用乙酸乙酯(50mL)和水(50mL)分液，有机相分出后，无水硫酸钠干燥，过滤，浓缩干过柱(石油醚：乙酸乙酯＝1:1)得到浅黄色油43-a(150mg，产率：34％)。LC-MS(ESI):m/z＝539[M+H]+。
化合物43的合成
往43-a(150mg，0.28mmol)溶于甲醇(2mL)和水(2mL)的混合溶液中，加入氢 氧化锂(18mg，0.42mmol)。室温搅拌过夜，浓缩干后残留物用水稀释，酸化后pH＝3～4.过滤，水洗，干燥得到浅黄色固体43(67mg，产率：46％)。LC-MS(ESI):m/z＝525[M+H]+.
1H-NMR(500MHz,MeOD)δ:8.18(s,1H),7.53-7.81(m,6H),7.25-7.38(m,4H),4.32(m,2H),4.00(m,1H),3.84(d,J＝12Hz,1H),2.69(s,3H),2.35(s,3H),1.53(s,3H)ppm.
实施例44
(S,E)-3-羟基-2-甲基-2-(3-(2-(2',3',4',5',6'-五氘代-2-甲基联苯-3-基)乙烯基)-4-(三氟甲基)苄基氨基)-丙酸(化合物44)
Figure PCTCN2020080362-appb-000170
化合物44-a的合成
向五氘代溴苯(162mg，1.0mmol)和3-b(416mg，1.0mmol)的乙二醇二甲醚(15mL)的混合物中加入[1,1’-双(二苯基磷)二茂铁]二氯化钯(73mg，0.1mmol)，磷酸钾(424mg，2.0mmol)和氟化钾(116mg，2.0mmol)，在氮气条件下将反应液加热至80℃，搅拌6小时。减压浓缩，剩余物经硅胶柱层析纯化(石油醚：乙酸乙酯＝100：1)得到化合物44-a(190mg，产率：50％)。
化合物44的合成
向50毫升单口瓶中加入溶有(S)-2-甲基丝氨酸(119mg,1mmol)的3毫升水以及2毫升1M的氢氧化钠水溶液。加毕，向此溶液中加入44-a(185mg,0.5mmol)溶于4毫升四氢呋喃的溶液，并加入10毫升甲醇调节混合物为均相。室温搅拌16小时后，于冰水浴冷却下，加入硼氢化钠(38mg,1mmol)。加毕，冰水浴下继续搅拌1小时。减压旋除溶剂，残留物加水稀释，用柠檬酸调节PH值至5～6。过滤，收集固体，干燥，得到粗产物。向粗产品中加入10毫升乙酸乙酯，加热回流数分钟，冷却至室温，过滤，收集固体，干燥，得到白色固体产物44(50mg,产率：20％)。LC-MS(ESI):m/z＝475(M+H) +；
1H NMR(500MHz,CD 3OD)δ:8.16(s,1H),7.77(d,J＝8.0Hz,1H),7.64(d,J＝18.0Hz, 1H),7.61(d,J＝8.0Hz,1H),7.54(d,J＝7.5Hz,1H),7.31～7.35(m,1H),7.28(t,J＝8.0Hz,1H),7.17(d,J＝8.0Hz,1H),J＝4.33(d,J＝13Hz,1H),4.27(d,J＝13Hz,1H),3.99(d,J＝12Hz,1H),3.82(d,J＝12Hz,1H),2.32(s,3H),1.55(s,3H)ppm.
效果实施例1
采用均相时间分辨荧光(Homogenouse Time-Resolved Fluorescence,HTRF)结合试验来检测本发明的化合物对PD-1/PD-L1的结合能力。
购买来的试剂盒(CisBio，#64CUS000C-1)中包含有PD-1、PD-L1、anti-tag1-Eu、Anti-tag2-XL665、Dilute Buffer和Detection Buffer等实验所需的试剂。
实验步骤
1.将化合物用100％DMSO配置成浓度梯度为3倍的10个浓度。
2.将化合物的DMSO溶液加入到稀释缓冲溶液(Dilute Buffer)中，混合均匀后转移到96孔板中。
3.将PD-L1用稀释缓冲溶液(Dilute Buffer)稀释，然后加入到上述96孔板中。
4.将PD-1用稀释缓冲溶液(Dilute Buffer)稀释，然后加入到上述96孔板中，并在室温下培养30分钟。
5.将一份anti-tag1-Eu和一份Anti-tag2-XL665加入到检测缓冲溶液(Detection Buffer)中，混合均匀后转移到上述96孔板中。
6.此96孔板中的混合液在室温下培养1到24小时。
7.用Envision读取HTRF数值。
实验结果
本发明化合物的生物学活性通过以上的试验进行测定，测得的结果如下(表1)：
表1 本发明部分化合物对PD-1/PD-L1结合的IC 50值
化合物 IC 50(μM) 化合物 IC 50(μM)
1 0.014 2 3.1
3 0.046 5 0.023
6 0.32 7 1.4
8 0.042 9 0.057
12 0.024 13 0.013
14 0.019 15 0.014
16 0.013 17 0.020
18 0.046 19 0.061
20 0.018 21 0.085
22 0.044 23 0.026
24 0.430 25 0.066
26 0.020 27 0.018
28 0.029 29 0.019
30 0.027 31 0.041
32 0.024 33 0.230
34 0.180 35 1.1
36 >10 37 1.3
38 >10 39 2.2
40 0.580 41 0.540
42 0.880 43 0.540
效果实施例2：小鼠药代动力学实验
分析用内标格列吡嗪(Glipizide，分子式C 21H 27N 5O 4S，分子量为445.5g/mol，分析纯)购自Sigma-Aldrich公司(美国)。甲醇，乙腈、甲酸(HPLC级)均购自Sigma-Aldrich公司(美国)，纯水购自杭州娃哈哈集团有限公司(中国杭州)。其他化学试剂均为分析纯。
CD1雄性小鼠每组6只，6-7周龄，29-31g，购自LC Laboratory Animal Co.LTD公司。试验前，动物应至少饲养3天以适应环境。整个试验中，动物需禁食过夜，期间自由饮水，存活动物给药后4小时恢复给食。
实验步骤
1.将化合物用10％DMSO+10％Solutol HS 15+80％Saline配制成0.4mg/mL浓度的溶液。
2.将上述配好的溶液以尾静脉注射的方式(化合物用量为2mg/kg)给到3只小鼠，同时以口服灌胃的方式(化合物用量为10mg/kg)给到另3只小鼠。
3.分别在给药后5、15、30分钟以及1、2、4、8和24小时的时候采集上述6只小鼠的血液每只大约30μL置于EDTA-K2抗凝管中(置于湿冰上)，并马上将其中20μL血液用60μL水稀释，然后放于-70℃冰箱长期保存直至样品分析。
4.取20μL上述溶液置于96孔深孔提样板中，加入150μL格列吡嗪内标乙腈溶液(浓度为100ng/ml)涡旋10min，58rpm离心10min。取上清液1μL进行LCMSMS分析。
5.根据药物浓度-时间数据，采用WinNonlin 6.4软件(美国)按非房室模型计算化合物的药动学参数。
实验结果
本发明化合物的小鼠药代动力学的结果如下(表2)：
表2 本发明部分化合物的小鼠药代动力学的口服生物利用度
Figure PCTCN2020080362-appb-000171
效果实施例3：PD-L1抗体Durvalumab和化合物29在hPD-1敲入小鼠结肠癌MC-38-hPD-Ll模型中，单用或二者联用的体内药效学研究
1.实验所需的材料
抗体：PD-L1抗体Imfinzi(Durvalumab)，规格120mg/2.4mL(50mg/mL)，Lot:041E17C。生产商：AstraZeneca，购自香港名创大药坊有限公司，储存于2-8℃。
实验动物：人源PD-1转基因小鼠，品系：C57BL/6-hPD-1小鼠，6-8周，体重18-21克，雌性，120只，购自江苏集萃药康生物科技有限公司。
制剂原料：Cremophor RH40(CAS:61788-85-0，Lot:29761847G0，供应商:上海协泰化工有限公司)；SBE-β-CD(CAS:128446-35-5，Lot:R1804474，供应商:上海韶远试剂有 限公司)；DMEM(CAS:11995-065，Lot:2025378，供应商：Gibco)；青链霉素双抗(CAS:15140-122,Lot:1953101，供应商：Hyclone)；胎牛血清(CAS：10099-141，Lot:1966174C,供应商：Gibco)；hygromycinB(CAS：10687010，Lot：HY069-L12，供应商：Invitrogen)。
2.肿瘤模型的建立
人源PD-L1基因敲入MC-38细胞(MC-38-hPD-Ll细胞)体外贴壁培养，培养条件为DMEM培养基中加10％热灭活胎牛血清，并加入hygromycinB(终浓度100μL/mL)，37℃ 5％CO 2培养。一周三次传代处理。当细胞呈指数生长期时，收取细胞，计数。将100μL 1×106MC-38-hPD-Ll细胞混悬液接种于C57BL/6-hPD-1小鼠右背侧皮下。接种6天后选移植瘤体积在31.49mm 3-110.26mm 3范围的60只荷瘤鼠，按实验方案把荷瘤鼠随机分为6组，每组10只，并于当天开始给药。
3.供试品配制
溶媒的配制：量取800mL的无菌用水加入容量瓶中，开启磁力搅拌，使液面有漩涡产生，将100g的Cremophor RH40用药勺缓慢加入漩涡之中，持续搅拌待溶液澄清，再缓慢加入200g的SBE-β-CD，持续搅拌至溶液澄清，最后定容至1000mL，即得含10％(w/v)Cremophor RH40+20％(w/v)SBE-β-CD的水溶液。
化合物29混悬液的配制：称取150.92mg化合物29，加入12.5mL含10％(w/v)Cremophor RH40+20％(w/v)SBE-β-CD的水溶液(以下简称溶媒)，涡旋2分钟使其充分混匀，超声30分钟，即获得浓度为12.0mg/mL的混悬溶液。吸取5.0mL浓度为12.0mg/mL的化合物29混悬溶液，加入5.0mL的溶媒溶液，涡旋1分钟使其充分混匀，超声5分钟，即获得浓度为6.0mg/mL的混悬溶液。吸取2.0mL浓度为12.0mg/mL的化合物29混悬溶液，加入6.0mL的溶媒溶液，涡旋1分钟使其充分混匀，超声5分钟，即获得浓度为3.0mg/mL的混悬溶液。化合物29的混悬液每日配制一次。
PD-L1抗体的配制：吸取0.12mL Durvalumab原液(浓度:50mg/mL)，分装6份于5mL无菌离心管中，每份含量6.0mg，分装后放置于4℃冰箱备用。给药前取一份含0.12mL,浓度50mg/mL原液，加入2.88mL 0.9％的氯化钠溶液，轻微震荡涡旋，使溶液完全混匀，获得终浓度为2mg/mL的Durvalumab溶液3mL。
4.实验步骤
1)将溶媒对照组小鼠按编号分别放在电子天平中称重并记录，按小鼠体重每天二次灌胃给溶媒，容量0.1mL/10g，每只小鼠用时约20秒，每组10只共用时约5分钟。
2)将化合物29(30mg/kg)组小鼠按编号分别放在电子天平中称重并记录，按小鼠体重每天二次灌胃给配制好的化合物29混悬液，按30mg/kg给药，给药容量 0.1mL/10g，每只小鼠用时约20秒，每组10只共用时约5分钟。
3)将化合物29(60mg/kg)组小鼠按编号分别放在电子天平中称重并记录，按小鼠体重每天二次灌胃给配制好的化合物29混悬液，按60mg/kg给药，给药容量0.1mL/10g，每只小鼠用时约20秒，每组10只共用时约5分钟。
4)将化合物29(120mg/kg)组小鼠按编号分别放在电子天平中称重并记录，按小鼠体重每天二次灌胃给配制好的化合物29混悬液，按120mg/kg给药，给药容量0.1mL/10g，每只小鼠用时约20秒，每组10只共用时约5分钟。
5)将联合用药(化合物29：60mg/kg；Durvalumab：20mg/kg)组小鼠按编号分别放在电子天平中称重并记录，按小鼠体重先每天二次灌胃给配制好的化合物29混悬液，按60mg/kg给药，给药容量0.1mL/10g，每只小鼠用时约20秒，每组10只共用时约5分钟。
6)将Durvalumab(20mg/kg)组小鼠按编号分别放在电子天平中称重并记录，按小鼠体重腹腔注射配制好的Durvalumab，按20mg/kg每周二次给药，给药容量0.1mL/10g，每只小鼠用时约20秒，每组10只共用时约5分钟。
7)将联合用药(化合物29：60mg/kg；Durvalumab：20mg/kg)组小鼠按编号分别放在电子天平中称重并记录，按小鼠体重腹腔注射配制好的Durvalumab，按20mg/kg每周二次给药，给药容量0.1mL/10g，每只小鼠用时约20秒，每组10只共用时约5分钟。
5.数据采集及实验终点
1)每周三次用数显游标卡尺测量肿瘤并计算出肿瘤体积。当瘤体积超过2,000mm 3，或动物有严重疾病，或疼痛，或不能自由取食和饮水，须处以安乐死。当对照组瘤体积平均值达到2000mm 3，实验终止。
2)每天用电子天平称取动物体重。当动物明显消瘦，体重降低大于20％时，须处以安乐死。
3)实验在化合物29给药19天后结束。
6.数据分析及结果
图1为各组小鼠体重变化曲线图，由每组小鼠在实验期间每日测得体重的平均值绘制而成。图2为各组小鼠体重相对变化率曲线图，由每组小鼠在实验期间每日体重变化率的平均值绘制而成。图3为各组小鼠肿瘤体积增长曲线图，由每组小鼠在实验期间每次测得肿瘤体积的平均值绘制而成。图4为各组小鼠的抑瘤率曲线图，由每组小鼠在实验期间每次计算所得抑瘤率的平均值绘制而成。抑瘤率计算公式为TGI(％)＝(1-(给 药组当天肿瘤体积-给药组第一天肿瘤体积)/(空白组当天肿瘤体积-空白组第一天肿瘤体积))*100％。
采用GraphPad Prism 5.0软件作图，小鼠肿瘤体积变化采用Two-way ANOVA分析，并依Bonferroni posttests法和溶媒对照组进行比较，P<0.05认为有显著性差异。实验结果如表3所示。
表3：hPD-1敲入小鼠结肠癌MC-38-hPD-Ll模型中单药或联合用药体内药效学结果
Figure PCTCN2020080362-appb-000172
注：a.Mean±SEM。
b.P值根据肿瘤体积计算(与溶剂对照组相比)。
实验结果显示：至给药19天，与溶媒对照组相比，组2(PD-L1抗体Durvalumab)的抑瘤率为48.17％，化合物29的最大抑瘤率为51.21％，联合用药组的抑瘤率为62.82％，由此可以得出以下结论：联合用药组对结肠癌(MC-38-hPD-L1)细胞的抑制效果明显优于单一组分化合物29或者PD-L1抗体，可以显著性提高小鼠肿瘤抑制率，并有统计学意义。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (21)

  1. 一种药物组合物，其包含：
    PD-L1抗体；和，
    小分子PD-1/PD-L1抑制剂或其药学上可接受的盐。
  2. 如权利要求1所述的药物组合物，其特征在于：所述PD-L1抗体为Atezolizumab、Durvalumab、Avelumab、Cemiplimab、KN035、CS1001、MBS2311、BGB-A333、KL-A167、SHR-1316和STI-A1014中的一种或多种。
  3. 如权利要求2所述的药物组合物，其特征在于：所述PD-L1抗体为Durvalumab。
  4. 如权利要求1-3中任一项所述的药物组合物，其特征在于：所述小分子PD-1/PD-L1抑制剂为芳香乙烯或芳香乙基类衍生物、其药学上可接受的盐、氘代物、代谢产物、代谢前体或药物前体；
    和/或，所述小分子PD-1/PD-L1抑制剂的分子量小于1500道尔顿；
    和/或，所述小分子PD-1/PD-L1抑制剂在PD-1/PD-L1结合实验中具有小于100nM的IC 50值；
    和/或，所述小分子PD-1/PD-L1抑制剂与PD-L1结合。
  5. 如权利要求1-4中任一项所述的药物组合物，其特征在于：所述小分子PD-1/PD-L1抑制剂为通式(I)所示的芳香乙烯或芳香乙基类衍生物、其药学上可接受的盐、氘代物、代谢产物、代谢前体或药物前体：
    Figure PCTCN2020080362-appb-100001
    其中：
    Figure PCTCN2020080362-appb-100002
    为单键或双键；
    每个R 1相同或不同，各自独立地为氘、卤素、取代或未取代的羟基、取代或未取代的氨基、取代或未取代的烷基、或取代或未取代的烷氧基；
    或者相邻的两个R 1和与它们相连的两个碳原子共同形成一个5-7元的碳环或碳杂环；所述碳杂环中，杂原子为氧和/或氮，杂原子数为1-4个；
    R 2为取代或未取代的烷基或卤素；
    每个R 3相同或不同，各自独立地为氘、卤素、取代或未取代的烷硫基、取代或未取 代的羟基、取代或未取代的氨基、取代或未取代的烷基、取代或未取代的烷氧基、
    Figure PCTCN2020080362-appb-100003
    Figure PCTCN2020080362-appb-100004
    其中，R 1a为C 1-C 4烷基，或者相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳环或碳杂环；所述碳杂环中，杂原子为氧和/或氮，杂原子数为1-4个；当两个R 3相邻，且相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳环或碳杂环时，所述的碳环或碳杂环还进一步被C 1-4的烷基中的一个或多个所取代；
    每个R 1、R 2和每个R 3中所述的取代的烷基、每个R 1和每个R 3中所述的取代的烷氧基，和每个R 3中所述的取代的烷硫基中的取代基选自下列基团中的一个或多个：卤素、C 1-4的烷基、羟基、
    Figure PCTCN2020080362-appb-100005
    C 1-4的烷氧基、C 1-4的羧基、C 1-4的酯基和C 1-4酰胺基；当取代基为多个时，所述的取代基相同或不同；R a和R b独立地为氢、或、取代或未取代的烷基；R a或R b中，所述的取代的烷基中的取代基选自下列基团中的一个或多个：卤素、C 1-C 4烷基、羟基、
    Figure PCTCN2020080362-appb-100006
    C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基或C 1-C 4酰胺基；R a1和R b1独立地为氢或C 1-C 4的烷基；
    每个R 1或每个R 3中，所述的取代的羟基或所述的取代的氨基中的取代基选自下列基团中的一个或多个：C 1-4的烷基、C 1-4的烷氧基、C 1-4的羧基、C 1-4的酯基和C 1-4酰胺基；
    m为1、2、3、4或5；
    n为0、1、2、3、4或5；当
    Figure PCTCN2020080362-appb-100007
    为双键，m为2时，两个R 1分别位于苯环的邻位和间位，两个R 1相同或不同；
    当
    Figure PCTCN2020080362-appb-100008
    为双键，m为3时，两个R 1相邻，且相邻的两个R 1和与它们相连的两个碳原子共同形成一个5-7元的碳杂环；
    或所述的通式(I)所示的芳香乙烯或芳香乙基类衍生物中，
    Figure PCTCN2020080362-appb-100009
    替换为取代或未取代的杂芳环，所述的杂芳环中的杂原子选自N、O和S，杂原子数为1-4个；所述的取代的杂芳环中的取代基选自下列基团中的一个或多个：卤素、C 1-4的烷基、羟基、
    Figure PCTCN2020080362-appb-100010
    C 1-4的烷氧基、C 1-4的羧基、C 1-4的酯基和C 1-4酰胺基；当取代基为多个时，所述的取代基相同或不同；R a和R b独立地为氢、或、取代或未取代的烷基；R a或R b中，所述的取代的烷基中的取代基选自下列基团中的一个或多个：卤素、C 1-C 4烷基、羟基、
    Figure PCTCN2020080362-appb-100011
    C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基或C 1-C 4酰胺基；R a1和R b1独立地为氢或C 1-C 4的烷基；
    所述的通式(I)所示的芳香乙烯或芳香乙基类衍生物不为下列化合物：
    Figure PCTCN2020080362-appb-100012
  6. 如权利要求5所述的药物组合物，其特征在于，
    当每个R 1、R 2和每个R 3中所述的取代的烷基、每个R 1和每个R 3中所述的取代的烷氧基、每个R 3中所述的取代的烷硫基和所述的杂芳环中的取代基选自卤素时，所述的卤素为F、Cl、Br或I；
    和/或，当每个R 1、R 2和每个R 3中所述的取代的烷基，每个R 1和每个R 3中所述的取代的烷氧基、所述的取代的羟基或所述的取代的氨基、每个R 3中所述的取代的烷硫基、所述的取代的杂芳环和取代的5-7元的碳杂环中的取代基选自C 1-4的烷基时，所述的C 1- 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
    和/或，当每个R 1、R 2和每个R 3中所述的取代的烷基、每个R 1和每个R 3中所述的取代的烷氧基、每个R 3中所述的取代的烷硫基和所述的取代的杂芳环中的取代基选自
    Figure PCTCN2020080362-appb-100013
    R a或R b为卤素时，所述的卤素为F、Cl、Br或I；
    和/或，当每个R 1、R 2和每个R 3中所述的取代的烷基、每个R 1和每个R 3中所述的取代的烷氧基、每个R 3中所述的取代的烷硫基和所述的取代的杂芳环中的取代基选自
    Figure PCTCN2020080362-appb-100014
    R a或R b为C 1-4的烷基时，所述的C 1-4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
    和/或，当每个R 1、R 2和每个R 3中所述的取代的烷基、每个R 1和每个R 3中所述的取代的烷氧基、每个R 3中所述的取代的烷硫基和所述的取代的杂芳环中的取代基选自
    Figure PCTCN2020080362-appb-100015
    R a或R b为
    Figure PCTCN2020080362-appb-100016
    R a1或R b1为C 1-C 4的烷基时，所述的C 1-4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
    和/或，当每个R 1、R 2和每个R 3中所述的取代的烷基、每个R 1和每个R 3中所述的取代的烷氧基、每个R 3中所述的取代的烷硫基和所述的取代的杂芳环中的取代基选自
    Figure PCTCN2020080362-appb-100017
    R a或R b为C 1-C 4烷氧基时，所述的C 1-4的烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基；
    和/或，当每个R 1、R 2和每个R 3中所述的取代的烷基、每个R 1和每个R 3中所述的取代的烷氧基、每个R 3中所述的取代的烷硫基和所述的取代的杂芳环中的取代基选自
    Figure PCTCN2020080362-appb-100018
    R a或R b为C 1-C 4羧基时，所述的C 1-C 4羧基为
    Figure PCTCN2020080362-appb-100019
    Figure PCTCN2020080362-appb-100020
    和/或，当每个R 1、R 2和每个R 3中所述的取代的烷基、每个R 1和每个R 3中所述的取代的烷氧基、每个R 3中所述的取代的烷硫基和所述的取代的杂芳环中的取代基选自
    Figure PCTCN2020080362-appb-100021
    R a或R b为C 1-C 4酯基时，所述的C 1-C 4酯基为
    Figure PCTCN2020080362-appb-100022
    R 2a为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
    和/或，当每个R 1、R 2和每个R 3中所述的取代的烷基、每个R 1和每个R 3中所述的取代的烷氧基、每个R 3中所述的取代的烷硫基和所述的取代的杂芳环中的取代基选自
    Figure PCTCN2020080362-appb-100023
    R a或R b为C 1-C 4酰胺基时，所述的C 1-C 4酰胺基为
    Figure PCTCN2020080362-appb-100024
    R 1b为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
    和/或，当每个R 1、R 2和每个R 3中所述的取代的烷基、每个R 1和每个R 3中所述的取代的烷氧基、所述的取代的羟基或所述的取代的氨基、每个R 3中所述的取代的烷硫基和所述的取代的杂芳环中的取代基选自C 1-C 4烷氧基时，所述的C 1-4的烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基；
    和/或，当每个R 1、R 2和每个R 3中所述的取代的烷基、每个R 1和每个R 3中所述的取代的烷氧基、所述的取代的羟基或所述的取代的氨基、每个R 3中所述的取代的烷硫基和所述的取代的杂芳环中的取代基选自C 1-4的羧基时，所述的C 1-C 4羧基为
    Figure PCTCN2020080362-appb-100025
    Figure PCTCN2020080362-appb-100026
    和/或，当每个R 1、R 2和每个R 3中所述的取代的烷基、每个R 1和每个R 3中所述的取代的烷氧基、所述的取代的羟基或所述的取代的氨基、每个R 3中所述的取代的烷硫基和所述的取代的杂芳环中的取代基选自C 1-C 4酯基时，所述的C 1-C 4酯基为
    Figure PCTCN2020080362-appb-100027
    R 2a为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
    和/或，当每个R 1、R 2和每个R 3中所述的取代的烷基、每个R 1和每个R 3中所述的取代的烷氧基、所述的取代的羟基或所述的取代的氨基、每个R 3中所述的取代的烷硫基和所述的取代的杂芳环中的取代基选自C 1-C 4酰胺基时，所述的C 1-C 4酰胺基为
    Figure PCTCN2020080362-appb-100028
    R 1b为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
  7. 如权利要求5所述的药物组合物，其特征在于，
    每个R 1、R 2和每个R 3中，所述的卤素为F、Cl、Br或I；
    和/或，每个R 1、R 2和每个R 3中，所述的取代或未取代的烷基为取代或未取代的C 1- C 4的烷基；所述的取代或未取代的C 1-C 4的烷基优选取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基、或、取代或未取代的叔丁基；
    和/或，每个R 1和每个R 3中，所述的取代或未取代的烷氧基为取代或未取代的C 1-C 4的烷氧基；所述的取代或未取代的C 1-C 4的烷氧基优选取代或未取代的甲氧基、取代或未取代的乙氧基、取代或未取代的正丙氧基、取代或未取代的异丙氧基、取代或未取代的正丁氧基、取代或未取代的异丁氧基、或、取代或未取代的叔丁氧基；
    和/或，每个R 3中，所述的取代或未取代的烷硫基为-S-R s，其中，R s为取代或未取代的C 1-C 4的烷基；所述的取代或未取代的C 1-C 4的烷基优选取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基、或、取代或未取代的叔丁基；
    和/或，每个R 3中，所述的
    Figure PCTCN2020080362-appb-100029
    中，R 1a为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
    和/或，当相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳杂环，所述的5-7元碳杂环为氮杂环丁环、哌嗪环、哌啶环、吡咯环、吗啉环、硫代吗啉环、1,4-二氧六环、吡喃环、二氢咪唑环、二氢异噁唑环、二氢异噻唑环、二氢噁二唑环、二氢噁唑环、二氢吡嗪环、二氢吡唑环、二氢吡啶环、二氢嘧啶环、二氢吡咯环、二氢喹啉环、二氢四唑环、二氢噻二唑环、二氢噻唑环、二氢三唑环、二氢氮杂环丁环、咪唑环、吡唑环、吡咯环、呋喃环、噻吩环、异噻唑环、噁唑环、噁二唑环、异噁唑环、吡嗪环、哒嗪环、吡啶环、嘧啶环、四唑环、噻二唑环、噻唑环、噻吩环或三唑环；
    和/或，当
    Figure PCTCN2020080362-appb-100030
    替换为取代或未取代的杂芳环时，所述的杂芳环为C 1-C 10的杂芳环，所述的杂芳环中的杂原子优选选自N和O，杂原子数为1-3个，所述的杂芳环进一步优选吖啶环、咔唑环、噌啉环、咔啉环、喹喔啉环、咪唑环、吡唑环、吡咯环、吲哚环、二氢吲哚环、苯并三唑环、苯并咪唑环、呋喃环、噻吩环、异噻唑环、苯并噻吩环、二氢苯并噻吩环、苯并呋喃环、异苯并呋喃环、苯并噁唑环、苯并呋咱环、苯并吡唑环、喹啉环、异氮杂茚环、异喹啉环、噁唑环、噁二唑环、异噁唑环、吲哚环、吡嗪环、吡啶并吡啶环、四唑并吡啶环、咪唑并吡啶环、咪唑并吡嗪环、哒嗪环、吡啶环、萘嘧啶环、嘧啶环、四唑环、噻二唑环、噻唑环、噻吩环、三唑环、喹唑啉环、四氢喹啉环、二氢苯 并咪唑环、二氢苯并呋喃环、二氢苯并噁唑环或二氢喹啉环。
  8. 如权利要求5-7中任一项所述的药物组合物，其特征在于，
    每个R 1独立地为卤素、或、取代或未取代的烷基；或者相邻的两个R 1和与其相连的两个碳原子共同形成一个5-7元的碳杂环；或者每个R 1独立地为卤素、取代或未取代的烷基、或取代或未取代的烷氧基；
    和/或，R 2为烷基或卤素；
    和/或，每个R 3独立地为氘、卤素、烷硫基或烷氧基；或相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳杂环；当两个R 3相邻，且相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳环或碳杂环时，所述的碳环或碳杂环还可进一步被C 1-4的烷基中的一个或多个所取代；
    和/或，n为0、1、2、3、4或5；
    和/或，m为2或3；优选m为2；
    和/或，
    Figure PCTCN2020080362-appb-100031
    还可替换为取代或未取代的杂芳环。
  9. 如权利要求8所述的药物组合物，其特征在于，
    当R 1为取代的烷基时，所述的取代的烷基中的取代基选自下列基团中的一个或多个：卤素或
    Figure PCTCN2020080362-appb-100032
    R a和R b独立地为氢、或、取代或未取代的烷基；R a或R b中，所述的取代的烷基中的取代基选自下列基团中的一个或多个：羟基或C 1-C 4羧基；
    和/或，R 1中，所述的取代的烷基、所述取代的烷氧基、所述取代的羟基或所述取代的氨基中的取代基是指被一个或多个卤素取代，优选被一个或多个F取代；
    和/或，当n为1时，R 3为卤素、烷硫基或烷氧基；且R 3位于苯环的邻位、间位或对位；
    和/或，当n为2时，两个R 3位于苯环的邻位和间位，两个R 3相同或不同；或者两个R 3相邻，且相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳杂环；当两个R 3相邻，且相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳环或碳杂环时，所述的碳环或碳杂环还可进一步被C 1-4的烷基中的一个或多个所取代；所述的5-7元的碳杂环优选2,3-二氢-1,4-二氧六环、噁唑环、异噁唑环或吡唑环；
    和/或，当n为3时，其中两个R 3相邻，且相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳杂环；当两个R 3相邻，且相邻的两个R 3和与它们相连的两个 碳原子共同形成一个5-7元的碳环或碳杂环时，所述的碳环或碳杂环还可进一步被C 1-4的烷基中的一个或多个所取代；所述的5-7元的碳杂环优选2,3-二氢-1,4-二氧六环、噁唑环、异噁唑环或吡唑环；
    和/或，当n为4或5时，R 3为氘；
    和/或，当m为2时，两个R 1分别位于苯环的邻位和间位，两个R 1相同或不同；位于苯环邻位的R 1为烷基或卤素取代的烷基；位于苯环间位的R 1为
    Figure PCTCN2020080362-appb-100033
    取代的烷基；
    和/或，当m为2时，两个R 1分别位于苯环的邻位和间位，两个R 1相同或不同；位于苯环的邻位的R 1为F、取代或未取代的烷基、或取代或未取代的烷氧基；
    和/或，当m为3时，其中两个R 1相邻，且相邻的两个R 1和与它们相连的两个碳原子共同形成一个5-7元的碳杂环，第三个R 1为
    Figure PCTCN2020080362-appb-100034
    取代的烷基；
    和/或，当
    Figure PCTCN2020080362-appb-100035
    替换为取代或未取代的杂芳环时，所述的杂芳环中的杂原子选自N和O，杂原子数为1-3个；进一步优选地，当杂芳环为单环时，杂原子为N原子，杂原子数为1或2；当杂芳环为双环杂芳基，杂原子为N时，杂原子数为3个；当杂芳环为双环杂芳基，杂原子选自N和O，杂原子数为2时；杂原子不相邻。
  10. 如权利要求9所述的药物组合物，其特征在于，
    所述的位于苯环邻位的R 1为C 1-4的烷基或被一个或多个卤素取代的C 1-C 4的烷基，例如三氟甲基；
    和/或，所述的
    Figure PCTCN2020080362-appb-100036
    取代的烷基为被
    Figure PCTCN2020080362-appb-100037
    取代的C 1-C 4的烷基；所述的被
    Figure PCTCN2020080362-appb-100038
    取代的C 1-C 4的烷基优选
    Figure PCTCN2020080362-appb-100039
    其中，R a和R b一个为H，另一个为被羟基和/或羧基取代的烷基；所述的被
    Figure PCTCN2020080362-appb-100040
    取代的C 1-C 4的烷基更优选为
    Figure PCTCN2020080362-appb-100041
    Figure PCTCN2020080362-appb-100042
    其中，用*标注的碳为S构型手性碳、R构型手性碳或非手性碳；其中，
    Figure PCTCN2020080362-appb-100043
    优选为
    Figure PCTCN2020080362-appb-100044
    Figure PCTCN2020080362-appb-100045
    优选为
    Figure PCTCN2020080362-appb-100046
    优选为
    Figure PCTCN2020080362-appb-100047
    Figure PCTCN2020080362-appb-100048
    优选为
    Figure PCTCN2020080362-appb-100049
  11. 如权利要求5-10中任一项所述的药物组合物，其特征在于，
    每个R 1独立地为H、或、取代或未取代的烷基；或者相邻的两个R 1和与其相连的两个碳原子共同形成一个5-7元的碳杂环；所述的取代的烷基中的取代基选自下列基团中的一个或多个：卤素或
    Figure PCTCN2020080362-appb-100050
    R a和R b独立地为氢、或、取代或未取代的烷基；R a或R b中，所述的取代的烷基中的取代基选自下列基团中的一个或多个：羟基或C 1-C 4羧基；
    R 2为烷基或卤素；
    每个R 3独立地为H、卤素、烷硫基或烷氧基；或相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳杂环；
    n为0、1、2、3、4或5；当n为1时，R 3为卤素、烷硫基或烷氧基；且R 3位于苯环的邻位、间位或对位；当n为2时，两个R 3位于苯环的邻位和间位，其中，两个R 3相同或不同；或者两个R 3相邻，且相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳杂环；当n为3时，其中一个R 3为卤素，另外两个R 3相邻，且相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳杂环；当两个R 3相邻，且相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳环或碳杂环时，所述的碳环或碳杂环还进一步被C 1-4的烷基中的一个或多个所取代；当n为4或5时，R 3为氘；
    m为2或3；当m为2时，两个R 1分别位于苯环的邻位和间位，位于苯环邻位的R 1 为烷基或卤素取代的烷基；位于苯环间位的R 1为
    Figure PCTCN2020080362-appb-100051
    取代的烷基；当m为3时，两个R 3相邻，且相邻的两个R 3和与它们相连的两个碳原子共同形成一个5-7元的碳杂环，第三个R 3为
    Figure PCTCN2020080362-appb-100052
    取代的烷基；
    和
    Figure PCTCN2020080362-appb-100053
    还可替换为取代或未取代的杂芳环，所述的杂芳环中的杂原子选自N和O，杂原子数为1-3个；进一步优选地，当杂芳环为单环时，杂原子为N原子，杂原子数为1或2；当杂芳环为双环杂芳基，杂原子为N时，杂原子数为3个；当杂芳环为双环杂芳基，杂原子选自N和O，杂原子数为2时；杂原子不相邻。
  12. 如权利要求5-11中任一项所述的药物组合物，其特征在于，
    Figure PCTCN2020080362-appb-100054
    为
    Figure PCTCN2020080362-appb-100055
    和/或，
    Figure PCTCN2020080362-appb-100056
    为
    Figure PCTCN2020080362-appb-100057
    Figure PCTCN2020080362-appb-100058
    Figure PCTCN2020080362-appb-100059
  13. 如权利要求5所述的药物组合物，其特征在于，
    每个R 1独立地为卤素、取代或未取代的烷基、或取代或未取代的烷氧基；
    R 2为取代或未取代的烷基或卤素；
    每个R 3独立地为氘、卤素、取代或未取代的烷硫基、取代或未取代的羟基、取代或未取代的氨基、取代或未取代的烷基、取代或未取代的烷氧基、
    Figure PCTCN2020080362-appb-100060
    其中，R 1a为C 1-C 4烷基；
    每个R 1中，所述的取代的烷基、所述的取代的烷氧基、所述的取代的羟基或所述的取代的氨基中的取代基是指被一个或多个卤素取代，优选被一个或多个F取代；
    每个R 2和每个R 3中所述的取代的烷基、每个R 3中所述的取代的烷氧基和所述的取代的烷硫基中的取代基选自下列基团中的一个或多个：卤素、C 1-4的烷基、羟基、
    Figure PCTCN2020080362-appb-100061
    C 1-4的烷氧基、C 1-4的羧基、C 1-4的酯基和C 1-4酰胺基；当取代基为多个时，所述的取代基相同或不同；R a和R b独立地为氢、或、取代或未取代的烷基；R a或R b中，所述的取代的烷基中的取代基选自下列基团中的一个或多个：卤素、C 1-C 4烷基、羟基、
    Figure PCTCN2020080362-appb-100062
    C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基或C 1-C 4酰胺基；R a1和R b1独立地为氢或C 1-C 4的烷基；
    每个R 3中，所述的取代的羟基或所述的取代的氨基中的取代基选自下列基团中的一个或多个：C 1-4的烷基、C 1-4的烷氧基、C 1-4的羧基、C 1-4的酯基和C 1-4酰胺基；
    m为2或3；
    n为0、1、2、3、4或5；
    当m为2时，两个R 1分别位于苯环的邻位和间位，两个R 1相同或不同；位于苯环的邻位的R 1为F、取代或未取代的烷基、或取代或未取代的烷氧基；
    当
    Figure PCTCN2020080362-appb-100063
    为双键，m为3时，两个R 1相邻，且相邻的两个R 1和与它们相连的两个碳原子共同形成一个5-7元的碳杂环；
    或所述的通式(I)所示的芳香乙烯或芳香乙基类衍生物中，
    Figure PCTCN2020080362-appb-100064
    替换为取代或未取代的杂芳环，所述的杂芳环中的杂原子选自N、O和S，杂原子数为1-4个；所述的取代的杂芳环中的取代基选自下列基团中的一个或多个：卤素、C 1-4的烷基、羟基、
    Figure PCTCN2020080362-appb-100065
    C 1-4的烷氧基、C 1-4的羧基、C 1-4的酯基和C 1-4酰胺基；当取代基为多个时，所述的取代基相同或不同；R a和R b独立地为氢、或、取代或未取代的烷基；R a或R b中，所述的取代的烷基中的取代基选自下列基团中的一个或多个：卤素、C 1-C 4烷基、羟基、
    Figure PCTCN2020080362-appb-100066
    C 1-C 4烷氧基、C 1-C 4羧基、C 1-C 4酯基或C 1-C 4酰胺基；R a1和R b1独立地为氢或C 1-C 4的烷基。
  14. 如权利要求5-13中任一项所述的药物组合物，其特征在于，所述的通式(I)所示的芳香乙烯或芳香乙基类衍生物为下列任一化合物：
    Figure PCTCN2020080362-appb-100067
    Figure PCTCN2020080362-appb-100068
    Figure PCTCN2020080362-appb-100069
    Figure PCTCN2020080362-appb-100070
  15. 如权利要求5-14中任一项所述的药物组合物，其特征在于，所述的通式(I)所示的芳香乙烯或芳香乙基类衍生物为通式(II)所示的芳香乙烯或芳香乙基类衍生物：
    Figure PCTCN2020080362-appb-100071
    其中，R 1、R 2、R 3、n、R a和R b的定义均同权利要求5所述，m1为0、1或2。
  16. 如权利要求5-15中任一项所述的药物组合物，其特征在于：所述的通式(I)所示的芳香乙烯或芳香乙基类衍生物为化合物29
    Figure PCTCN2020080362-appb-100072
  17. 如权利要求16所述的药物组合物，其特征在于：化合物29为口服剂型；
    和/或，PD-L1抗体为Durvalumab，其为注射剂型。
  18. 如权利要求1-4中任一项所述的药物组合物，其特征在于：所述小分子PD-1/PD-L1抑制剂为如下任一化合物或其药学上可接受的盐：
    Figure PCTCN2020080362-appb-100073
    Figure PCTCN2020080362-appb-100074
    Figure PCTCN2020080362-appb-100075
    Figure PCTCN2020080362-appb-100076
    Figure PCTCN2020080362-appb-100077
    Figure PCTCN2020080362-appb-100078
    Figure PCTCN2020080362-appb-100079
    Figure PCTCN2020080362-appb-100080
    Figure PCTCN2020080362-appb-100081
  19. 如权利要求1-18中任一项所述的药物组合物，其特征在于：所述药物组合物还包含药学上可接受的载体；
    和/或，所述PD-L1抗体和小分子PD-1/PD-L1抑制剂存在于单一药物组合物中，或者分别存在于分开的单独药物组合物中。
  20. 一种如权利要求1-19中任一项所述的药物组合物在制备治疗癌症的药物中的应用。
  21. 如权利要求20所述的应用，其特征在于：所述癌症为肺癌、胃癌、结直肠癌、宫颈癌、卵巢癌、前列腺癌、乳腺癌、胰腺癌、肝癌、膀胱癌、肾癌、骨癌、皮肤癌、黑色素瘤、神经胶质瘤、神经胶母细胞瘤、白血病或淋巴瘤，例如结直肠癌，例如结肠癌；
    和/或，PD-L1抗体和小分子PD-1/PD-L1抑制剂同时给药或分开给药；
    和/或，PD-L1抗体经注射给药；
    和/或，小分子PD-1/PD-L1抑制剂经口服给药。
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