WO2021047555A1 - 芳香杂环衍生物作为免疫调节剂的制备及其应用 - Google Patents
芳香杂环衍生物作为免疫调节剂的制备及其应用 Download PDFInfo
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- WO2021047555A1 WO2021047555A1 PCT/CN2020/114263 CN2020114263W WO2021047555A1 WO 2021047555 A1 WO2021047555 A1 WO 2021047555A1 CN 2020114263 W CN2020114263 W CN 2020114263W WO 2021047555 A1 WO2021047555 A1 WO 2021047555A1
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- 0 CCCCCC(C(C)C(CCC)C1(C2)C2CCCC1)[C@](C)* Chemical compound CCCCCC(C(C)C(CCC)C1(C2)C2CCCC1)[C@](C)* 0.000 description 5
- QYXNJXDJCICQFD-UHFFFAOYSA-N Cc(c(Br)ccc1)c1-c1nc(C(N(CCO)C=C2)=O)c2[o]1 Chemical compound Cc(c(Br)ccc1)c1-c1nc(C(N(CCO)C=C2)=O)c2[o]1 QYXNJXDJCICQFD-UHFFFAOYSA-N 0.000 description 1
- DVRDPWVTNSMHST-UHFFFAOYSA-N Cc(c(Br)ccc1)c1-c1nc(C(NC=C2)=O)c2[o]1 Chemical compound Cc(c(Br)ccc1)c1-c1nc(C(NC=C2)=O)c2[o]1 DVRDPWVTNSMHST-UHFFFAOYSA-N 0.000 description 1
- KJLCPPICCWTGFW-LYBHJNIJSA-N Cc(ccc(-c1nc(/C(/N(CCCC(O)=O)C=C2C#N)=N\OC)c2[o]1)c1C)c1Br Chemical compound Cc(ccc(-c1nc(/C(/N(CCCC(O)=O)C=C2C#N)=N\OC)c2[o]1)c1C)c1Br KJLCPPICCWTGFW-LYBHJNIJSA-N 0.000 description 1
- PQLJQXVUNYEADR-YPXHKHJMSA-N Cc1cc(O[C@@H]2c3cccc(-c4cccc(-c5nc(/C(/N(CCCC(O)=O)C=C6C#N)=N/OC)c6[o]5)c4C)c3CC2)ccc1CN(CC1)CC1=O Chemical compound Cc1cc(O[C@@H]2c3cccc(-c4cccc(-c5nc(/C(/N(CCCC(O)=O)C=C6C#N)=N/OC)c6[o]5)c4C)c3CC2)ccc1CN(CC1)CC1=O PQLJQXVUNYEADR-YPXHKHJMSA-N 0.000 description 1
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- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- 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
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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Definitions
- the present invention relates to the field of small molecule drugs. Specifically, the present invention provides a small molecule compound that can be used to treat diseases related to the PD-1/PD-L1 signaling pathway.
- the immune system plays a vital role in controlling and curing many diseases, such as various cancers and diseases caused by viruses.
- cancer cells can often evade or suppress the immune system through some means, thereby reproducing rapidly.
- One way is to change the activation and inhibitory molecules expressed on immune cells. Blocking suppression of immune checkpoints, like PD-1, proved to be a very effective method of suppressing cancer cells.
- PD-1 is programmed cell death protein-1, also known as CD279. It is mainly expressed in activated T cells and B cells, and its function is to inhibit cell activation. This is a normal homeostasis mechanism of the immune system. Because excessive T/B cell activation can cause autoimmune diseases, PD- 1 is a protective wall for our human body.
- PD-1 is a type I transmembrane glycoprotein composed of 268 amino acids. Its structure mainly includes the variable region of the extra-immunoglobulin, the hydrophobic transmembrane region and the intracellular region.
- the intracellular region contains two phosphorylation sites, which are located in the immunoreceptor tyrosine suppression motif and the immunoreceptor tyrosine switching motif, which also proves that PD-1 can reversely regulate T cell receptor-mediated signal.
- PD-1 has two ligands, PD-L1 and PD-L2, which are different in expression.
- PD-L1 is up-regulated and expressed in a variety of tumor cells. It binds to PD-1 on T cells, inhibits T cell proliferation and activation, makes T cells in a state of inactivation, and finally induces immune escape.
- PD-1/PD-L1 plays a reverse immunomodulatory role.
- PD-1 binds to PD-L1, it can cause the tyrosine polyphosphorylation of the tyrosine conversion motif domain of the immunoreceptor of T cells, and the phosphorylated tyrosine can bind to the phosphatase protein tyrosinase 2 and protein tyrosinase 1.
- This can block the activation of extracellular signal-regulated kinases, and also block the activation of phosphoinositide 3-kinase (PI3K) and serine-threonine protein kinase (Akt), thereby inhibiting the proliferation of T lymphocytes and the breakdown of related cytokines.
- PI3K phosphoinositide 3-kinase
- Akt serine-threonine protein kinase
- PD-1/PD-L1 signal inhibits T cell activation and proliferation, it can also secrete the cytokines interleukin 2, interferon gamma and IL-10.
- PD-1/PD-L1 signals have similar immune functions to B cells.
- the cytoplasmic region of PD-1 interacts with tyrosinase containing protein tyrosinase 2 binding sites. Cataminase acts to hinder the activation of B cells.
- Immunotherapy based on PD-1/PD-L1 is a new generation of immunotherapy that has attracted much attention.
- PD-1/PD-L1 inhibitors have strong anti-tumor activity against a variety of tumors.
- the PD-1/PD-L1 antibody inhibitors currently on the market include BMS’s Ninolumab, Merck’s Lambrolizumab and Roche’s Atezolizumab.
- BMS Ninolumab
- Merck s Lambrolizumab
- Roche Roche’s Atezolizumab.
- there are many PD-1/PD-L1 antibody inhibitors under development including CureTech’s Pidilizumab, GSK’s AMP-224 and AstraZeneca’s MEDI-4736.
- tumor immunotherapy is considered to be a new generation of revolution in cancer treatment after targeted therapy.
- the PD-1 monoclonal antibody currently on the market and under development has its own shortcomings, including only injections, not oral, unstable in the body, easy to be decomposed by proteases, easy to produce immune cross-reactions, purification is more difficult and production The cost is high. Therefore, small molecule inhibitors of PD-1/PD-L1 interaction are a better choice for tumor immunotherapy.
- the purpose of the present invention is to provide a novel small molecule inhibitor of PD-1/PD-L1 interaction.
- the first aspect of the present invention provides a compound represented by the following formula I, or an optical isomer, a cis-trans isomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof:
- n, m, p and q are each independently selected from 0, 1, 2, 3, 4 or 5;
- L 1 is selected from the following group: chemical bond, substituted or unsubstituted C1-C4 alkylene, substituted or unsubstituted C2-C4 alkenylene, substituted or unsubstituted C2-C4 alkynylene, -S-,- O-, substituted or unsubstituted -NH-, -S(O)-, -S(O) 2 -, substituted or unsubstituted -NHC(O)NH-, Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted
- M 3 , M 4 , and M 5 are each independently selected from the following group: chemical bond, CR 6 , N, NR 6 , O, S, SO, SO 2 ;
- M 6 is each independently selected from the following group: CR 6 , N; wherein, the carbon atoms of M 1 , M 2 and M 6 can each be independently replaced by deuterium;
- Y 1 , Y 2 , and Y 3 are each independently selected from the group consisting of CH, CH 2 , NH, N, NO, CF, CRa, O, S, SO or SO 2 ;
- Each L 1a is each independently a group selected from the group consisting of: chemical bond, substituted or unsubstituted C 1 -C 7 alkylene, substituted or unsubstituted C2-C4 alkenylene, substituted or unsubstituted C2- C4 alkynylene, -S-, -O-, substituted or unsubstituted -NH-, -S(O)-, -S(O) 2 -,
- L 2a is selected from the following group: substituted or unsubstituted C6-C12 arylene, substituted or unsubstituted 5-12 membered heteroarylene having 1-3 heteroatoms, substituted or unsubstituted C3-C8 arylene Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclylene with 1-3 heteroatoms;
- L 3a is selected from the following group: H, substituted or unsubstituted C1-C10 alkyl, C1-C10 aryl, -CN, hydroxyl, amino, carboxyl, -CO-NH-SO 2 -R g , -NH-SO 2 -R g , -SO 2 -NH-CO-R g , -OR g , -N(R g ) 2 -CO 2 R g , -CON(R g ) 2 , -CONHCOR g , NR g -CO- N(R g ) 2 , -NR g -SO 2 -N(R g ) 2 ;
- r is 1, 2, 3, 4, 5, 6;
- s are 0, 1, 2 respectively;
- Rd, Re and Rg are each independently selected from the following group: H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 6- C 10 aryl;
- substituted or unsubstituted 5-12 membered heteroaryl substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 Membered C5-C12 ring group, wherein the 5-12 membered heteroaryl group and 5-12 membered heterocyclic group have 1-4 heteroatoms selected from B, P, N, O, S, wherein, as P, N, O of ring atoms can be oxo and one or more ring carbon atoms can be replaced with carbonyl groups;
- Rb, Rc and Rd are each independently selected from the following group: H, substituted or unsubstituted C 1 -C 8 alkyl; or said Rb and Rc and adjacent N atoms together form a substituted or unsubstituted 5-10 membered heterocyclic group with 1-3 heteroatoms selected from N, S and O, or said Rb and Rc together with
- R 3 is none, H, substituted or unsubstituted C1-C10 alkyl, Wherein, w is 0,1,2,3,4,5,6; each L 4 is independently selected from the following group: substituted or unsubstituted C1-C4 alkylene, -S-, -O- , NR f , -S(O)-, -S(O) 2 -; preferably substituted or unsubstituted C1-C4 alkylene; wherein the substituted or unsubstituted C1-C4 alkylene is on the carbon atom
- the hydrogens of can be independently replaced by deuterium, provided that the structure formed by each L 4 is chemically stable; wherein Rb, Rc, and Rd are each independently selected from the following group: H, substituted or unsubstituted C 1- C 8 alkyl; or said Rb and Rc together with adjacent N atoms form a substituted or unsubstituted 5-10 membered heterocyclic group with
- any one of the heteroatoms is selected from the group consisting of B, P, N, S, and O.
- n, m, p and q are each independently selected from 0, 1, 2, 3 or 4;
- L 1 is selected from the following group: chemical bond, substituted or unsubstituted C1-C4 alkylene, substituted or unsubstituted C2-C4 alkenylene, substituted or unsubstituted C2-C4 alkynylene, -S-,- O-, substituted or unsubstituted -NH-, -S(O)-, -S(O) 2 -, substituted or unsubstituted -NHC(O)NH-, Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted
- M 3 , M 4 , and M 5 are each independently selected from the following group: chemical bond, CR 6 , N, NR 6 , O, S, SO, SO 2 ;
- M 6 is each independently selected from the following group: CR 6 , N;
- Y 1 , Y 2 , and Y 3 are each independently selected from the group consisting of CH, CH 2 , NH, N, NO, CF, CRa, O, S, SO or SO 2 ;
- Each L 1a is each independently a group selected from the group consisting of: chemical bond, substituted or unsubstituted C 1 -C 7 alkylene, substituted or unsubstituted C2-C4 alkenylene, substituted or unsubstituted C2- C4 alkynylene, -S-, -O-, substituted or unsubstituted -NH-, -S(O)-, -S(O) 2 -,
- L 2a is selected from the following group: substituted or unsubstituted C6-C12 arylene, substituted or unsubstituted 5-12 membered heteroarylene having 1-3 heteroatoms, substituted or unsubstituted C3-C8 arylene Cycloalkyl, substituted or unsubstituted 5-10 membered heterocyclylene with 1-3 heteroatoms;
- L 3a is selected from the following group: H, substituted or unsubstituted C1-C10 alkyl, C1-C10 aryl, -CN, hydroxyl, amino, carboxyl, -CO-NH-SO 2 -R g , -NH-SO 2 -R g , -SO 2 -NH-CO-R g ;
- r is 1, 2, 3, 4, 5, 6;
- s are 0, 1, 2 respectively;
- Rd, Re and Rg are each independently selected from the following group: H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 6- C 10 aryl;
- substituted or unsubstituted 5-12 membered heteroaryl substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 Membered C5-C12 ring group, wherein the 5-12 membered heteroaryl group and 5-12 membered heterocyclic group have 1-4 heteroatoms selected from B, P, N, O, S, wherein, as P, N, O of ring atoms can be oxo and one or more ring carbon atoms can be replaced with carbonyl groups;
- substituted or unsubstituted C1-C6 amino substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkylene), carboxyl, substituted or unsubstituted C6-C10 Aryl, substituted or unsubstituted 5-12 membered heteroaryl with 1-3 heteroatoms, substituted or unsubstituted 5-12 membered heterocyclic with 1-4 heteroatoms, substituted or unsubstituted Substituted or unsubstituted Or -(L 1a ) r -(L 2a ) s -(L 3a ) s -;
- R 3 is wherein, Rb, Rc and Rd are each independently selected from the following group: H, substituted or unsubstituted C 1 -C 8 alkyl; or said Rb and Rc and adjacent N atoms together form a substituted or unsubstituted 5-10 membered heterocyclic group with 1-3 heteroatoms selected from N, S and O;
- substituted refers to being substituted by one or more (for example, 2, 3, 4, etc.) substituents selected from the following group: halogen: including but not limited to -F, Cl, Br, -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 F, -CHF 2 , -CF 3 , oxo, -CN, hydroxyl, amino, C1-C6 alkylamino, carboxyl, -NHAc, A group selected from the group that is unsubstituted or substituted by one or more substituents selected from the group: C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C3-C8 cycloalkyl , Halogenated C6-C10 aryl groups, 5-10 membered heteroaryl groups with 1-3 heteroatoms selected from N, S and O, and those with 1-3 heteroatoms selected from N, S and O
- any one of the heteroatoms is selected from the group consisting of B, P, N, S, and O.
- the ring It has a substituent as shown in the following formula IV:
- each L 4 is independently selected from the following group: substituted or unsubstituted C1-C4 alkylene, -S-, -O-, -NRa-, -S(O)-, -S(O ) 2 -; preferably a substituted or unsubstituted C1-C4 alkylene group, wherein the hydrogen on the carbon atom of the substituted or unsubstituted C1-C4 alkylene group can each be independently replaced by deuterium; the prerequisite is that each The structure formed by L 4 is chemically stable;
- substituted or unsubstituted C5-C10 cycloalkyl substituted or unsubstituted 3-10 membered heterocyclic group having 1-3 heteroatoms selected from B, P, N, S and O;
- the It is a 3-8 membered nitrogen-containing heterocyclic group or substituted or unsubstituted 4-10 membered cyclic amide, wherein the 3-8 membered nitrogen-containing heterocyclic group substituted or unsubstituted 4-10 membered cyclic amide group is the ring-forming carbon
- the hydrogen on the atom can be replaced by deuterium independently;
- Each R 5 is independently selected from the following group: substituted or unsubstituted C1-C6 alkyl, -CN, hydroxyl, amino, carboxyl, -OR g , -N(R g ) 2 , -CO-NH-SO 2 -R g , -NH-SO 2 -R g , -SO 2 -NH-CO-R g, -CO 2 R g , -CON(R g ) 2 , CONHCOR g , NR g -CO-N(R g ) 2 , -NR g -SO2-N(R g ) 2 ;
- the definitions of R f and R g are as described above, wherein the hydrogen on the carbon atoms of R f and R g can be replaced by deuterium independently; Wherein, the substituent is selected from the following group: halogen, hydroxyl, carboxy, cyano, C1-C6 alkoxy.
- the compound of formula I has a structure shown in the following formula:
- the bonding position of the ring may be N or C (substituents on the ring are not shown).
- the compound has the structure shown in the following formulas Id-1, Id-2 and Id-3:
- the compound has a structure shown in the following formula:
- R 5 is selected from the following group: -(L 1a ) r -(L 2a ) s -(L 3a ) s ; wherein,
- Each L 1a is each independently a group selected from the group consisting of: chemical bond, substituted or unsubstituted C 1 -C 7 alkylene, substituted or unsubstituted C2-C4 alkenylene, substituted or unsubstituted C2- C4 alkynylene, -S-, -O-, substituted or unsubstituted -NH-, -S(O)-, -S(O) 2 -,
- L 2a is selected from the following group: substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3-10 membered heterocyclylene having 1-3 heteroatoms; preferably, the heterocyclylene
- the cyclic group contains at least one N atom as a ring-forming atom;
- L 3a is selected from the following group: H, substituted or unsubstituted C1-C10 alkyl, C1-C10 aryl, -CN, hydroxyl, amino, carboxyl, -CO-NH-SO 2 -R g , -NH-SO 2 -R g , -SO 2 -NH-CO-R g ;
- r is 1, 2, 3, 4, 5, 6;
- s are 0, 1, 2 respectively;
- the compound of formula I is selected from formula Id-1, Id-2 and Id-3:
- each group is as described in claim 1, and the hydrogen on the carbon atom of R f , R 2 , R 2 'and R 1 group (if any) and H 1 ⁇ H 15 can each be Independently replaced by deuterium.
- the compound is selected from the following group:
- the second aspect of the present invention provides a method for preparing the compound of formula I according to the first aspect of the present invention, the method comprising steps selected from synthetic schemes 1, 2 or 3:
- the target product I is obtained through a Suzuki coupling reaction catalyzed by a suitable palladium catalyst.
- the intermediate 1 is prepared by the following method:
- the intermediate 2 is prepared by the following method:
- the third aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising (1) the compound according to the first aspect of the present invention or its stereoisomer or tautomer, or its pharmaceutically acceptable Salt, hydrate or solvate; (2) pharmaceutically acceptable carrier.
- the fourth aspect of the present invention provides a compound as described in the first aspect of the present invention or a stereoisomer or tautomer, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or such as
- the use of the pharmaceutical composition according to the third aspect of the present invention is used to prepare a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression of PD-1/PD-L1.
- the fifth aspect of the present invention provides a PD-1/PD-L1 inhibitor, the inhibitor comprising the compound described in the first aspect of the present invention, or its stereoisomer or tautomer, or Its pharmaceutically acceptable salt, hydrate or solvate.
- the pharmaceutical composition is used to treat diseases selected from the group consisting of cancer, infectious diseases, and autoimmune diseases.
- the cancer is selected from the group consisting of pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, and esophagus Cancer, melanoma, neuroendocrine cancer, central nervous system cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer or colon cancer, skin cancer, lung cancer, urinary system tumor, blood tumor, glial Tumors, digestive system tumors, reproductive system tumors, lymphomas, nervous system tumors, brain tumors, head and neck cancers.
- the cancer is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), bone marrow Dysplastic syndrome (MDS), myelodysplastic disease (MPD), chronic myelogenous leukemia (CML), multiple myeloma (MM), non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), Follicular lymphoma, Waldestrom macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, or diffuse large B-cell lymphoma (DLBCL).
- ALL acute lymphocytic leukemia
- AML acute myeloid leukemia
- CLL chronic lymphocytic leukemia
- SLL small lymphocytic lymphoma
- MDS bone marrow Dysplastic syndrome
- MDS myelodysplastic
- the infectious disease is selected from bacterial infection and viral infection.
- the autoimmune disease is selected from organ-specific autoimmune disease and systemic autoimmune disease.
- the organ-specific autoimmune diseases include chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Pulmonary hemorrhage nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosis, acute idiopathic polyneuritis.
- systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, self Immune hemolytic anemia.
- the pharmaceutical composition is also used to improve T cell function in patients with chronic hepatitis B (CHB).
- CHB chronic hepatitis B
- the inhibitor further includes at least one therapeutic agent selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, or ipilimumab.
- the sixth aspect of the present invention provides a method for inhibiting the interaction of PD-1/PD-L1 in vitro, which comprises the steps of: comparing the compound according to the first aspect of the present invention, or its stereoisomers or tautomers The construct, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is contacted with the PD-L1 protein.
- alkyl includes straight-chain or branched alkyl groups.
- C 1 -C 8 alkyl means a straight or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Wait.
- alkenyl includes linear or branched alkenyl.
- C 2 -C 6 alkenyl refers to a linear or branched alkenyl having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 -Butenyl, or similar groups.
- alkynyl includes straight-chain or branched alkynyl groups.
- C 2 -C 6 alkynyl refers to a linear or branched alkynyl group having 2-6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
- C 3 -C 10 cycloalkyl refers to a cycloalkyl having 3-10 carbon atoms. It may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It may also be in the form of a double ring, such as a bridged ring or a spiro ring.
- C 1 -C 8 alkylamino group refers to an amine group substituted by a C 1 -C 8 alkyl group, which may be mono- or di-substituted; for example, methylamino, ethylamino, Propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, two Tert-butylamino and so on.
- C 1 -C 8 alkoxy refers to a linear or branched alkoxy group having 1-8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propoxy, butoxy, isobutoxy, tert-butoxy, etc.
- the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S, and O" refers to those having 3-10 atoms and wherein 1-3 atoms are A saturated or partially saturated cyclic group of heteroatoms selected from the group consisting of N, S, and O. It may be in the form of a single ring or a double ring, such as a bridged ring or a spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.
- C 6 -C 10 aryl group refers to an aryl group having 6-10 carbon atoms, for example, a phenyl group or a naphthyl group and the like.
- the term "5-10 membered heteroaryl group having 1-3 heteroatoms selected from the group consisting of N, S, and O" refers to those having 5-10 atoms and wherein 1-3 atoms are selected from The following groups are cyclic aromatic groups with heteroatoms of N, S and O. It may be a monocyclic ring or a condensed ring form.
- pyridyl pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc.
- the groups of the present invention can be substituted by substituents selected from the group consisting of halogen, nitrile, nitro, hydroxyl, and amino. , C 1 -C 6 alkyl-amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1- C 6 alkyl, halo C 2 -C 6 alkenyl, halo C 2 -C 6 alkynyl, halo C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl , C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl, C 2 -C
- halogen or halogen atom refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "Halogenated” refers to substitution by an atom selected from F, Cl, Br, and I.
- the structural formula described in the present invention is intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, containing asymmetry The R and S configuration of the center, the (Z) and (E) isomers of the double bond, etc. Therefore, a single stereochemical isomer of the compound of the present invention or a mixture of its enantiomers, diastereomers or geometric isomers (or conformational isomers) all belong to the scope of the present invention.
- the structural formula described in the present invention is intended to include all possible deuterated derivatives (that is, one or more hydrogen atoms in the molecule are replaced by D).
- tautomers means that structural isomers with different energies can exceed the low energy barrier to convert into each other.
- proton tautomers ie, proton transfer
- Valence tautomers include interconversion through the recombination of some bond-forming electrons.
- solvate refers to a complex in which the compound of the present invention coordinates with solvent molecules to form a specific ratio.
- hydrate refers to a complex formed by coordination of the compound of the present invention with water.
- the compound of the present invention refers to the compound represented by formula I, and also includes various crystal forms, pharmaceutically acceptable salts, hydrates or solvates of the compound of formula I.
- Preferred compounds of the present invention include compounds 1-360 (including various R configuration and/or S configuration stereoisomers of each compound, and/or E-/Z- cis-trans isomers).
- the pharmaceutically acceptable salts include salts formed by combining with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions, or organic bases that can provide physiologically acceptable cations, and ammonium salts.
- the inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid;
- the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, lycic acid, maleic acid Tartaric acid, fumaric acid, citric acid or lactic acid;
- the alkali metal ion is selected from lithium ion, sodium ion, and potassium ion;
- the alkaline earth metal ion is selected from calcium ion and magnesium ion;
- the organic base of the accepted cation is selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.
- the preparation of the compound of the general formula I of the present invention can be obtained by the following synthetic route.
- the target product I is obtained by the Suzuki coupling reaction catalyzed by a suitable palladium catalyst;
- the compounds of Formula I can exist in the form of solvates or unsolvates, and different solvates may be obtained by crystallization with different solvents.
- the compound of the present invention has excellent PD-1/PD-L1 interaction inhibitory activity
- the pharmaceutical composition in which the compound of the present invention is the main active ingredient can be used to prevent and/or treat (stabilize, reduce or cure) diseases related to PD-1/PD-L1 interaction (for example, cancer, infectious diseases, autoimmune diseases) .
- the pharmaceutical composition of the present invention includes a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier.
- the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
- the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per agent, and more preferably, contains 10-200 mg of the compound of the present invention per agent.
- the "one dose" is a capsule or tablet.
- “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
- pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
- Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
- vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
- polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
- emulsifiers such as emulsifiers
- wetting agents such as sodium lauryl sulfate
- the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous).
- Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
- the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
- Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into a microcapsule form with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
- the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
- composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
- the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
- suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
- composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
- the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as other anticancer agents).
- the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds.
- One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used for the prevention and/or treatment of PD simultaneously, separately or sequentially with the compound of the present invention -1/PD-L1 interaction related diseases.
- a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
- the administered dose is usually 1 to 2000 mg, preferably 20 to 500 mg.
- the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are all within the skill range of a skilled physician.
- the compound of the present invention has a high inhibitory activity on PD-1/PD-L1 interaction, has a strong binding ability with PD-L1 protein, and has the ability to relieve PD-L1 from inhibiting IFN ⁇ .
- the compound of the present invention has better solubility; it has very low toxicity to normal cells, so it can be applied to treatment subjects in a larger dose range.
- the compounds of the present invention have better solubility, and therefore have good druggability. Compared with the existing compounds, the compounds of the present invention perform well in in vivo experiments. In addition, compared with the existing compounds, the compounds of the present invention can be easily prepared into pharmaceutically acceptable salts, thus contributing to the further formation of preparations.
- the proton nuclear magnetic resonance spectrum was analyzed by Bruker AV-400 (400MHz) nuclear magnetic instrument.
- the mass spectrometry data is analyzed by Finnigan LCQ Advantage, among other needs, and all reactions are performed under anhydrous and oxygen-free conditions under the protection of dry argon.
- the solid organometallic compounds are stored in an argon-protected dry box.
- Tetrahydrofuran and ether are obtained by distillation, and sodium metal and benzophenone are added to them during distillation.
- Dichloromethane, pentane and hexane are treated with calcium hydride.
- the special raw materials and intermediates involved in the present invention are customized and processed by Tianjin Changsen Pharmaceutical Co., Ltd., and all other chemical reagents are from Shanghai Chemical Reagent Company, Aldrich, and Acros. Wait for reagent suppliers to buy. If the intermediates or products required for the reaction during the synthesis process are not enough for the next step, the synthesis is repeated many times until the number is sufficient.
- the raw materials and reagents involved in the present invention can all be purchased commercially or through customized processing.
- the compounds of the present invention may contain one or more asymmetric centers, so the series of compounds may be in the form of racemic or single enantiomer.
- the compound prepared by the present invention is a heterocyclic compound with a purity higher than 95%, and the structural characterization of each final product is determined by MS or/and proton nuclear magnetic resonance ( 1 H NMR) analysis.
- MS or/and proton nuclear magnetic resonance ( 1 H NMR) analysis The following examples illustrate the synthesis of various compounds and intermediates of the present invention.
- Step 1-2
- Step 2-1
- Step 2-2
- Step 3-2
- the starting material 20 (600 mg, 1.13 mmol) was dissolved in THF/H 2 O (1:1, 50 mL), lithium hydroxide (142 mg) was added, the reaction was carried out at room temperature for 0.5 hours, and the reaction was monitored by TLC. After the reaction is complete, add 20ml of water, adjust the acid with TFA, extract with DCM (20ml x 3), dry, and concentrate to obtain 450mg of yellow solid. MS-APCI: 532[M+H] + .
- Steps 3-5
- the raw material 25 (830 mg, 1.49 mmol) was dissolved in 20 mL THF/H2O (1:1), lithium hydroxide (125 mg) was added, and the reaction was carried out at room temperature for 0.5 hours. The TLC spot plate reaction was complete. The THF was spin-dried, and TFA was added to adjust the acid. The solid precipitated, filtered, and the solid dried 740 mg yellow solid. MS-APCI:546[M+H] + .
- Step 4-5
- Step 5-2
- Step 6-2
- the starting material 30 (200 mg, 0.378 mmol) was dissolved in 10 mL THF/H2O (2:1), sodium hydroxide (45 mg, 1.135 mmol) was added, and the reaction was carried out at room temperature overnight. The reaction was monitored by TLC. After the reaction was completed, TFA (0.08 mL, 1.135 mmol) was added to the solution to adjust the solution to neutrality, the THF was spin-dried, and water was added to stir to wash. The solid precipitated, filtered, and the solid dried 195 mg of pale yellow solid. MS-APCI:514[M+H] + .
- Step 6-3
- the raw material 42 (135mg, 0.268mmol), Zn(CN) 2 (16mg, 0.137mmol), Xantphos-PdCl2 (20mg, 0.0268mmol), Cs 2 CO 3 (131mg, 0.402mmol) were mixed in a 50mL three-necked flask, N 2 Replace 3 times, inject 10mL DMF, stir at 90°C for 2h, LC-MS detects that the reaction is complete. Filter, concentrate the filtrate to dryness, mix the sample, and column chromatography to obtain 4.5 g of light yellow solid. MS-APCI:402[M+H] + .
- the raw material 104 (230 mg, 0.436 mmol) was dissolved in 10 mL THF/H2O (2:1), LiOH (21 mg, 0.872 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was completed, TFA (0.08 mL, 1.135 mmol) was added to the solution to adjust the solution to neutrality, the THF was spin-dried, water was added to stir and the solid was separated out, filtered, and the solid was dried with 200 mg of light yellow solid. MS-APCI:513[M+H] + .
- LW1005-124 895 LW1005-125 897 LW1005-126 911 LW1005-127 880 LW1005-128 894 LW1005-129 777 LW1005-130 797 LW1005-131 900 LW1005-132 914 LW1005-133 896 LW1005-134 910 LW1005-135 793 LW1005-136 813 LW1005-137 916 LW1005-138 930 LW1005-139 696 LW1005-140 680 LW1005-141 717 LW1005-142 701 LW1005-143 697 LW1005-144 681 LW1005-145 752 LW1005-146 736 LW1005-147 732 LW1005-148 716
- Example A PD-1/PD-L1 homogeneous time-resolved fluorescence (HTRF) binding assay
- the measurement was carried out in a standard black 384-well polystyrene plate with a final volume of 20 ⁇ L. First, the inhibitor was serially diluted with DMSO and then added to the wells of the plate, and then other reaction components were added. The final concentration of DMSO in the determination is 1%. The measurement was performed in a PBS buffer (pH 7.4) containing 0.05% Tween-20 and 0.1% BSA at 25°C. Recombinant human PD-L1 protein (19-238) with His tag at the C-terminus was purchased from AcroBiosystems (PD1-H5229).
- Recombinant human PD-1 protein (25-167) with an Fc tag at the C-terminus was also purchased from AcroBiosystems (PD1-H5257).
- the PD-L1 and PD-1 proteins were diluted in the assay buffer, and then 0.1 ⁇ l of the solution was extracted and added to the plate wells. The plate was centrifuged and the protein and inhibitor were pre-incubated for 40 minutes. After incubation, add 0.1 ⁇ l HTRF detection buffer containing europium blocking labeled anti-human IgG (PerkinElmer-AD0212) Fc exclusive and anti-His -Allophycocyanin (APC, PerkinElmer-AD0059H) conjugated antibody.
- APC PerkinElmer-AD0059H
- Example A The data of the example compounds obtained using the PD-1/PD-L1 homogeneous time-resolved fluorescence (HTRF) combination assay described in Example A shows that most of the tested compounds of the present invention have IC 50 less than 10 nm, and some compounds (About 25%) even less than 1 nM, the activity test data of some preferred compounds are provided in Table 1.
- HTRF time-resolved fluorescence
Abstract
本发明提供了一种芳香杂环衍生物作为免疫调节剂的制备及其应用，具体地，本发明提供了一种如下式I所示的化合物，或其光学异构体、水合物、溶剂合物，或其药学上可接受的盐；其中，各基团的定义如说明书中所述。所述的式I化合物可以用于治疗与PD-1/PD-L1信号通路有关的疾病。
Description
本发明涉及小分子药物领域，具体地，本发明提供了一种可以用于治疗与PD-1/PD-L1信号通路有关的疾病的小分子化合物。
发明背景
免疫系统对控制及根治很多疾病起着至关重要的作用，像各种癌症、病毒引起的疾病等。但癌症细胞经常能通过一些途径躲避或抑制免疫系统，从而快速繁殖。其中一个方式就是改变免疫细胞上表达的激活和抑制分子。阻断抑制免疫检查点，像PD-1，证明是一个非常有效的抑制癌细胞的方法。
PD-1是程序性细胞死亡蛋白-1，也称之为CD279。它主要在激活的T细胞和B细胞中表达，功能是抑制细胞的激活，这是免疫系统的一种正常的自稳机制，因为过度的T/B细胞激活会引起自身免疫病，所以PD-1是我们人体的一道保护墙。PD-1是由268个氨基酸组成的I型跨膜糖蛋白，它的结构主要包括外免疫球蛋白可变区、疏水跨膜区以及胞内区。胞内区包含两个磷酸化位点，分别位于免疫受体酷氨酸抑制基序和免疫受体酷氨酸转换基序，这也证明PD-1能够反向调节T细胞受体介导的信号。PD-1有两个配体，PD-L1和PD-L2，它们在表达方式上不同。PD-L1在多种肿瘤细胞中均有上调表达，它与T细胞上的PD-1结合，抑制T细胞增殖和活化，使T细胞处于失活状态，最终诱导免疫逃逸。
PD-1/PD-L1发挥着反向免疫调节作用。当PD-1与PD-L1结合后，可致使T细胞的免疫受体酷氨酸转换基序结构域的酪氨酸多磷酸化，磷酸化的酪氨酸可结合磷酸酶蛋白酪氨酸酶2和蛋白酪氨酸酶1。这样即可阻碍细胞外信号调节激酶的活化，还可阻断磷脂肌醇3-激酶(PI3K)和丝氨酸-苏氨蛋白激酶(Akt)的激活，从而抑制T淋巴细胞增殖和相关细胞因子的分沁。PD-1/PD-L1信号抑制T细胞活化和增殖的同时，还可使细胞因子白细胞介素2、干扰素γ和IL-10的分泌。此外，PD-1/PD-L1信号对B细胞也有类似的免疫功能，当PD-1与B细胞抗原受体结合后，PD-1细胞质区与含有蛋白酪氨酸酶2结合位点的酪氨酸酶发生作用，从而阻碍B细胞的活化。
基于PD-1/PD-L1的免疫疗法是新一代备受关注的免疫疗法。最近几年，一系列令人惊喜的研究结果证实PD-1/PD-L1抑制剂对多种肿瘤具有强大的抗肿瘤活性。目前已经上市的PD-1/PD-L1抗体抑制剂有BMS的Ninolumab、Merck的Lambrolizumab以及Roche的Atezolizumab。除此之外还有很多在研的PD-1/PD-L1抗体抑制剂，包括Cure Tech的Pidilizumab、GSK的AMP-224和AstraZeneca的MEDI-4736。
虽然肿瘤免疫治疗被认为是靶向治疗后癌症治疗的新一代革命。但是目前上市和在研的PD-1单抗药有其自身的缺陷，包括只能注射给药，不能口服，在体内不稳定，易被蛋白酶分解，易产生免疫交叉反应，纯化比较困难且生产成本高等。所以PD-1/PD-L1相互作用的小分子抑制剂是肿瘤免疫治疗的更好选择。
综上所述，本领域迫切需要开发新型PD-1/PD-L1相互作用的小分子抑制剂。
发明内容
本发明的目的是提供一种新型PD-1/PD-L1相互作用的小分子抑制剂。
本发明的第一方面，提供了一种如下式I所示的化合物，或其光学异构体、顺反异构体、水合物、溶剂合物，或其药学上可接受的盐：
其中，n、m、p和q各自独立地选自0、1、2、3、4或5；
L
1选自下组：化学键、取代或未取代的C1-C4亚烷基、取代或未取代的C2-C4亚烯基、取代或未取代的C2-C4亚炔基、-S-、-O-、取代或未取代的-NH-、-S(O)-、-S(O)
2-、取代或未取代的-NHC(O)NH-、
取代或未取代的
取代或未取代的
取代或未取代的
M
1、M
2各自独立地选自下组：C(R
6)
2、NR
6、O、S、SO、SO
2；其中，R
6选自下组：H，氯、溴、氟、碘、氰基、羟基、硝基、NRf、取代或未取代的C
1-C
6烷基、取代或未取代的C
3-C
8环烷基，取代或未取代的C
6-C
10芳基、取代或未取代的C
6-C
10杂芳基、-C(＝O)-NRdRe、-C(＝O)-取代或未取代的C
1-C
6烷氧基、-C(＝O)-取代或未取代的C
1-C
6烷基、-C(＝O)-取代或未取代的C
3-C
10环烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、-C(＝O)-取代或未取代的C
2-C
6烯基、-C(＝O)-取代或未取代的C
2-C
6炔基；
M
3、M
4、M
5各自独立地选自下组：化学键、CR
6、N、NR
6、O、S、SO、SO
2；
M
6各自独立地选自下组：CR
6、N；其中，M
1、M
2和M
6的碳原子均可各自独立地被氘替换；
且所述的
为芳香环；
其中，
Z
1选自下组：O、S、NRf、N-O-Rf；其中，所述的Rf选自下组：H、取代或未取代的C
1-C
6烷基、取代或未取代的C
3-C
8环烷基，取代或未取代的C
6-C
10芳基、取代或未取代的C
6-C
10杂芳基、氰基、-C(＝O)-NRdRe、-C(＝O)-取代或未取代的C
1-C
6烷氧基、-C(＝O)-取代或未取代的C
1-C
6烷基、-C(＝O)-取代或未取代的C
3-C
10环烷基、-C(＝O)-取代或未取代的C
2-C
6烯基、-C(＝O)-取代或未取代的C
2-C
6炔基；
Z
2、Z
3、Z
4各自独立地选自下组：N、CH
2、N-O、SO、SO
2、C(＝O)、NRa、CRa；其中，所述的Ra选自下组：H、氯，溴，氟，碘，氰基，羟基，硝基，-CHF
2、-OCF
3、-OCHF
2、磺酰氨基、NRf，取代或未取代的C
1-C
6烷基、取代或未取代的C
3-C
8环烷基，取代或未取代的C
6-C
10芳基、取代或未取代的C
6-C
10杂芳基、-C(＝O)-NRdRe、-C(＝O)-取代或未取代的C
1-C
6烷氧基、-C(＝O)-取代或未取代的C
1-C
6烷基、-C(＝O)-取代或未取代的C
3-C
10环烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、-C(＝O)-取代或未取代的C
2-C
6烯基、-C(＝O)-取代或未取代的C
2-C
6炔基；
Y
1、Y
2、Y
3各自独立地选自下组：CH、CH
2、NH、N、N-O、CF、CRa、O、S、SO或SO
2；
且
为芳香性或非芳香性片段；
R为H、取代或未取代的C
1-C
6烷基、取代或未取代的C
6-C
10芳基、氰基、-C(＝O)-NRdRe、-C(＝O)-取代或未取代的C
1-C
6烷氧基、-C(＝O)-取代或未取代的C
1-C
6烷基、-C(＝O)-取代或未取代的C
3-C
10环烷基、-C(＝O)-取代或未取代的C
2-C
6烯基、-C(＝O)-取代或未取代的C
2-C
6炔基，取代或未取代的C1-C10烷基、
或-(L
1a)
r-(L
2a)
s-(L
3a)
s-，其中，
各个L
1a各自独立地为选自下组的基团；化学键、取代或未取代的C
1-C
7亚烷基、取代或未取代的C2-C4亚烯基、取代或未取代的C2-C4亚炔基、-S-、-O-、取代或未取代的-NH-、-S(O)-、-S(O)
2-、
L
2a选自下组：取代或未取代的C6-C12亚芳基、取代或未取代的具有1-3个杂原子的5-12元亚杂芳基、取代或未取代的C3-C8亚环烷基、取代或未取代的具有1-3个杂原子的3-10元亚杂环基；
L
3a选自下组：H、取代或未取代的C1-C10烷基、C1-C10芳基、-CN、羟基、氨基、羧基、-CO-NH-SO
2-R
g、-NH-SO
2-R
g、-SO
2-NH-CO-R
g、-OR
g、-N(R
g)
2-CO
2R
g、-CON(R
g)
2、-CONHCOR
g、NR
g-CO-N(R
g)
2、-NR
g-SO
2-N(R
g)
2；
r为1、2、3、4、5、6；
s分别为0、1、2；
Rd、Re和Rg各自独立地选自下组：H、取代或未取代的C
1-C
6烷基、取代或未取代的C
3-C
10环烷基、取代或未取代的C
6-C
10芳基；
R
1、R
2、R
2'和R
4各自独立地选自下组：H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、氧代(即＝O)、＝NRf、-CN、羟基、NRdRe(例如氨基)、取代或未取代的C1-C6胺基、取代或未取代的-(C1-C6亚烷基)-NH-(C1-C6亚烷基)、羧基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个杂原子的5-12元杂芳基、取代或未取代的具有1-4个杂原子的5-12元杂环基，取代或未取代的
取代或未取代的
取代或未取代的
其中，Rb、Rc和R
d各自独立地选自下组：H、取代或未取代的C
1-C
8烷基；或所述的Rb和Rc与相邻的N原子共同构成取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基，，或所述的Rb和Rc与相邻的N原子共同构成取代或未取代的4-10元环酰胺，所述取代基包括但不限于：羟基、羧基、巯基、氨基、F、C，其中，Rb、Rc和Rd的碳原子上的氢均可各自独立地被氘替换；或-(L
1a)
r-(L
2a)
s-(L
3a)
s-；
R
3为无、H、取代或未取代的C1-C10烷基、
其中，w为0,1,2,3,4,5,6；所述的各个L
4独立地选自下组：取代或未取代的C1-C4亚烷基、-S-、-O-、NR
f、-S(O)-、-S(O)
2-；优选为取代或未取代的C1-C4亚烷基；其中，取代或未取代的C1-C4亚烷基上碳原子上的氢均可各自独立地被氘替换，前提条件是各个L
4共同形成的结构是化学稳定的；其中，Rb、Rc和R
d各自独立地选自下组：H、取代或未取代的C
1-C
8烷基；或所述的Rb和Rc与相邻的N原子共同构成取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素(包括-F、-Cl、-Br、-I)、-CH
2Cl、-CHCl
2、-CCl
3、-CH
2F、-CHF
2、-CF
3、氧代(＝O)、 -CN、羟基、氨基、C1-C6烷胺基、羧基、-NHAc、
未取代或被一个或多个选自下组的取代基取代的选自下组的基团：C1-C6烷基、C1-C6烷氧基、C6-C10芳基、C3-C8环烷基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-10元杂环基；所述的取代基选自下组：卤素、羟基、羧基、氰基、C1-C6烷氧基、C1-C6烷胺基；
上述各式中，任一所述杂原子选自下组：B、P、N、S和O。
一种如下式I所示的化合物，或其光学异构体、顺反异构体、水合物、溶剂合物，或其药学上可接受的盐：
其中，n、m、p和q各自独立地选自0、1、2、3或4；
L
1选自下组：化学键、取代或未取代的C1-C4亚烷基、取代或未取代的C2-C4亚烯基、取代或未取代的C2-C4亚炔基、-S-、-O-、取代或未取代的-NH-、-S(O)-、-S(O)
2-、取代或未取代的-NHC(O)NH-、
取代或未取代的
取代或未取代的
取代或未取代的
M
1、M
2各自独立地选自下组：C(R
6)
2、NR
6、O、S、SO、SO
2；其中，R
6选自下组：H，氯、溴、氟、碘、氰基、羟基、硝基、NRf、取代或未取代的C
1-C
6烷基、取代或未取代的C
3-C
8环烷基，取代或未取代的C
6-C
10芳基、取代或未取代的C
6-C
10杂芳基、-C(＝O)-NRdRe、-C(＝O)-取代或未取代的C
1-C
6烷氧基、-C(＝O)-取代或未取代的C
1-C
6烷基、-C(＝O)-取代或未取代的C
3-C
10环烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、-C(＝O)-取代或未取代的C
2-C
6烯基、-C(＝O)-取代或未取代的C
2-C
6炔基；
M
3、M
4、M
5各自独立地选自下组：化学键、CR
6、N、NR
6、O、S、SO、SO
2；
M
6各自独立地选自下组：CR
6、N；
且所述的
为芳香环；
其中，
Z
1选自下组：O、S、NRf、N-O-Rf；其中，所述的Rf选自下组：H、取代或未取代的C
1-C
6烷基、取代或未取代的C
3-C
8环烷基，取代或未取代的C
6-C
10芳基、取代或未取代的C
6-C
10杂芳基、氰基、-C(＝O)-NRdRe、-C(＝O)-取代或未取代的C
1-C
6烷氧基、-C(＝O)-取代或未取代的C
1-C
6烷基、-C(＝O)-取代或未取代的C
3-C
10环烷基、-C(＝O)-取代或未取代的C
2-C
6烯基、-C(＝O)-取代或未取代的C
2-C
6炔基；
Z
2、Z
3、Z
4各自独立地选自下组：N、CH
2、N-O、SO、SO
2、C(＝O)、NRa、CRa；其中，所述的Ra选自下组：H、氯，溴，氟，碘，氰基，羟基，硝基，NRf，取代或未取代的C
1-C
6烷基、取代或未取代的C
3-C
8环烷基，取代或未取代的C
6-C
10芳基、取代或未取代的C
6-C
10杂芳基、-C(＝O)-NRdRe、-C(＝O)-取代或未取代的C
1-C
6烷氧基、-C(＝O)-取代或未取代的C
1-C
6烷基、-C(＝O)-取代或未取代的C
3-C
10环烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、-C(＝O)-取代或未取代的C
2-C
6烯基、-C(＝O)-取代或未取代的C
2-C
6炔基；
Y
1、Y
2、Y
3各自独立地选自下组：CH、CH
2、NH、N、N-O、CF、CRa、O、S、SO或SO
2；
且
为芳香性或非芳香性片段；
R为H、取代或未取代的C
1-C
6烷基、取代或未取代的C
6-C
10芳基、氰基、-C(＝O)-NRdRe、-C(＝O)-取代或未取代的C
1-C
6烷氧基、-C(＝O)-取代或未取代的C
1-C
6烷基、-C(＝O)-取代或未取代的C
3-C
10环烷基、-C(＝O)-取代或未取代的C
2-C
6烯基、-C(＝O)-取代或未取代的C
2-C
6炔基，或-(L
1a)
r-(L
2a)
s-(L
3a)
s-，其中，
各个L
1a各自独立地为选自下组的基团；化学键、取代或未取代的C
1-C
7亚烷基、取代或未取代的C2-C4亚烯基、取代或未取代的C2-C4亚炔基、-S-、-O-、取代或未取代的-NH-、-S(O)-、-S(O)
2-、
L
2a选自下组：取代或未取代的C6-C12亚芳基、取代或未取代的具有1-3个杂原子的5-12元亚杂芳基、取代或未取代的C3-C8亚环烷基、取代或未取代的具有1-3个杂原子的5-10元亚杂环基；
L
3a选自下组：H、取代或未取代的C1-C10烷基、C1-C10芳基、-CN、羟基、氨基、羧基、-CO-NH-SO
2-R
g、-NH-SO
2-R
g、-SO
2-NH-CO-R
g；
r为1、2、3、4、5、6；
s分别为0、1、2；
Rd、Re和Rg各自独立地选自下组：H、取代或未取代的C
1-C
6烷基、取代或未取代的 C
3-C
10环烷基、取代或未取代的C
6-C
10芳基；
R
1、R
2、R
2'和R
4各自独立地选自下组：H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、氧代(即＝O)、＝NRf、-CN、羟基、NRdRe(例如氨基)、取代或未取代的C1-C6胺基、取代或未取代的-(C1-C6亚烷基)-NH-(C1-C6亚烷基)、羧基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个杂原子的5-12元杂芳基、取代或未取代的具有1-4个杂原子的5-12元杂环基，取代或未取代的
取代或未取代的
或-(L
1a)
r-(L
2a)
s-(L
3a)
s-；
R
3为
其中，Rb、Rc和R
d各自独立地选自下组：H、取代或未取代的C
1-C
8烷基；或所述的Rb和Rc与相邻的N原子共同构成取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素：包括但不限于-F、Cl、Br、-CH
2Cl、-CHCl
2、-CCl
3、-CH
2F、-CHF
2、-CF
3、氧代、-CN、羟基、氨基、C1-C6烷胺基、羧基、-NHAc、未取代或被一个或多个选自下组的取代基取代的选自下组的基团：C1-C6烷基、C1-C6烷氧基、C6-C10芳基、C3-C8环烷基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-10元杂环基；所述的取代基选自下组：卤素、羟基、羧基、氰基、C1-C6烷氧基、C1-C6烷胺基；
上述各式中，任一所述杂原子选自下组：B、P、N、S和O。
在另一优选例中，所述的环
具有如下式IV所示的取代基：
其中，所述的各个L
4独立地选自下组：取代或未取代的C1-C4亚烷基、-S-、-O-、-NRa-、-S(O)-、-S(O)
2-；优选为取代或未取代的C1-C4亚烷基，其中，取代或未取代的C1-C4亚烷基上碳原子上的氢均可各自独立地被氘替换；前提条件是各个L
4共同形成的结构是化学稳定的；
各个R
5各自独立地选自下组：取代或未取代的C1-C6烷基、-CN、羟基、氨基、羧基、、-OR
g、-N(R
g)
2、-CO-NH-SO
2-R
g、-NH-SO
2-R
g、-SO
2-NH-CO-R
g、-CO
2R
g、-CON(R
g)
2、CONHCOR
g、NR
g-CO-N(R
g)
2、-NR
g-SO2-N(R
g)
2；R
f和R
g的定义如前所述，其中R
f和R
g的碳原子上的氢均可各自独立地被氘替换；其中，所述的取代基选自下组：卤素、羟基、羧基、氰基、C1-C6烷氧基。
在另一优选例中，R
1、R
2、R
2'和R
4各自独立地选自下组：H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、氧代(即＝O)、＝NRf、-CN、羟基、NRdRe(例如氨基)、取代或未取代的C1-C6胺基、取代或未取代的-(C1-C6亚烷基)-NH-(C1-C6亚烷基)、羧基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个杂原子的5-12元杂芳基、取代或未取代的具有1-4个杂原子的5-12元杂环基，取代或未取代的
取代或未取代的
取代或未取代的
或-(L
1a)
r-(L
2a)
s-(L
3a)
s-。
在另一优选例中，所述的式I化合物具有如下式所示的结构：
在另一优选例中，所述的
为如下式所示的结构：
在另一优选例中，所述的化合物具有如下式Id-1、Id-2和Id-3所示的结构：
在另一优选例中，所述的化合物具有如下式所示的结构：
其中，
R
5选自下组：-(L
1a)
r-(L
2a)
s-(L
3a)
s；其中，
各个L
1a各自独立地为选自下组的基团；化学键、取代或未取代的C
1-C
7亚烷基、取代或未取代的C2-C4亚烯基、取代或未取代的C2-C4亚炔基、-S-、-O-、取代或未取代的-NH-、-S(O)-、-S(O)
2-、
L
2a选自下组：取代或未取代的C3-C8亚环烷基、取代或未取代的具有1-3个杂原子的3-10元亚杂环基；优选地，所述的亚杂环基至少含有一个N原子作为成环原子；
L
3a选自下组：H、取代或未取代的C1-C10烷基、C1-C10芳基、-CN、羟基、氨基、羧基、-CO-NH-SO
2-R
g、-NH-SO
2-R
g、-SO
2-NH-CO-R
g；
r为1、2、3、4、5、6；
s分别为0、1、2；
其余各基团的定义如上文中所述。
在另一优选例中，所述的式I化合物选自式Id-1，Id-2和Id-3：
其中，各个基团的定义如权利要求1中所述，且R
f、R
2、R
2’和R
1基团上的碳原子上的氢(如存在)和H
1～H
15均可各自独立被氘替换。
在另一优选例中，所述的化合物选自下组：
本发明的第二方面，提供了一种如权本发明第一方面所述的式I化合物的制备方法，所述的方法包括选自合成方案1、2或3所示的步骤：
(a)以中间体1和2为原料，通过合适的钯催化剂催化的Suzuki偶联反应得到目标产物I。
在另一优选例中，所述的中间体1通过如下方法制备：
(a)以化合物1-1为原料，在手性辅剂(如R/S-CBS)和还原剂(如硼烷)的作用下，形成手性醇1-2；
(b)以1-2(或1-5)和1-3为原料，在钯催化剂和配体的条件下，发生偶联反应(如Suzuki,Buchwald等)，得到中间体1-4(或1-6)；
(c)以化合物1-1和R/S-叔丁基磺酰亚胺为原料，在Lwesis酸(如四钛酸乙酯)和还原试剂(如四氢锂铝，硼氢化钠等)的作用下，形成保护的手性氨基化合物，而后在酸性条件下脱除保护基，得到手性氨基化合物1-5；
(d)以1-4(或1-6)和联硼酸频哪酯为原料，在钯催化剂和配体的条件下，发生Suzuki偶联反应，得到中间体1。
在另一优选例中，所述的中间体2通过如下方法制备：
(a)以化合物2-1和2-2为原料，在脱水剂(如浓硫酸，PPA等)的作用下，形成中间体2-3；
(b)以2-3(或2-4)和2-5为原料，在碱性条件下(有机碱或无机碱)，发生亲和取代反应，形成中间体2-8(或2-6)；
(c)以2-6和2-7为原料，在钯催化剂和配体的条件下，发生Suzuki偶联反应，得到中间体2-8；
(d)以化合物2-8为原料，在碘化试剂(如单质碘，NIS等)的作用下，发生取代反应，形成中间体2-9；
(e)以化合物2-9为原料，在氯化试剂(如三氯氧磷，二氯亚砜等)的作用下形成活泼氯代物，而后在氨基化合物的作用下，发生亲和加成消除反应，形成中间体2-10；
(f)以化合物2-10和2-11为原料，在催化剂和配体的条件下，发生偶联反应，形成中间体2。
本发明的第三方面，提供了一种药物组合物，其包含(1)如本发明第一方面所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物；(2)药学上可接受的载体。
本发明的第四方面，提供了一种如本发明第一方面所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物或如本发明第三方面所述的药物组合物的用途，其用于制备预防和/或治疗与PD-1/PD-L1的活性或表达量相关的疾病的药物组合物。
本发明的第五方面，提供了一种PD-1/PD-L1抑制剂，所述抑制剂包含本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
在另一优选例中，所述的药物组合物被用于治疗选自下组的疾病：癌症、感染性疾病、自身免疫性疾病。
在另一优选例中，所述的癌症选自下组：胰腺癌，膀胱癌，结肠直肠癌，乳腺癌，前列腺癌，肾癌，肝细胞癌，肺癌，卵巢癌，宫颈癌，胃癌，食道癌，黑色素瘤，神经内分泌癌，中枢神经系统癌，脑癌，骨癌，软组织肉瘤，非小细胞肺癌癌症，小细胞肺癌或结肠癌、皮肤癌、肺癌、泌尿系肿瘤、血液肿瘤、胶质瘤、消化系统肿瘤、生殖系统肿瘤、淋巴瘤、神经系统肿瘤、脑瘤、头颈癌。
在另一优选例中，所述癌症选自下组：急性淋巴细胞白血病(ALL)，急性髓性白血病(AML)，慢性淋巴细胞白血病(CLL)，小淋巴细胞性淋巴瘤(SLL)，骨髓增生异常综合征(MDS)，骨髓增生性疾病(MPD)，慢性粒细胞白血病(CML)，多发性骨髓瘤(MM)，非霍奇金淋巴瘤(NHL)，套细胞淋巴瘤(MCL)，滤泡性淋巴瘤，Waldestrom巨球蛋白血症(WM)，T细胞淋巴瘤，B细胞淋巴瘤或弥漫性大B细胞淋巴瘤(DLBCL)。
在另一优选例中，所述的感染性疾病选自细菌感染、病毒感染。
在另一优选例中，所述的自身免疫性疾病选自器官特异性自身免疫病、系统性自身免疫病。
在另一优选例中，所述的器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合症、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎。
在另一优选例中，所述的系统性自身免疫病包括类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血。
在另一优选例中，所述的药物组合物还用于改善慢性乙型肝炎(CHB)患者T细胞功能。
在另一优选例中，所述的抑制剂还包括至少一种选自下组的治疗剂：纳武单抗，派姆单抗，atezolizumab，或伊匹单抗。
本发明的第六方面，提供了一种体外抑制PD-1/PD-L1相互作用的方法，其包括步骤：将本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物与PD-L1蛋白接触。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
本发明人经过广泛而深入的研究，发现了一类具有优异的抑制效果的PD-1/PD-L1相互作用抑制剂。在此基础上，发明人完成了本发明。
定义
如本文所用，术语“烷基”包括直链或支链的烷基。例如C
1-C
8烷基表示具有1-8个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用，术语“烯基”包括直链或支链的烯基。例如C
2-C
6烯基指具有2-6个碳原子的直链或支链的烯基，例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用，术语“炔基”包括直链或支链的炔基。例如C
2-C
6炔基是指具有2-6个碳原子的直链或支链的炔基，例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用，术语“C
3-C
10环烷基”指具有3-10个碳原子的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环或螺环形式。
如本文所用，术语“C
1-C
8烷胺基”是指被C
1-C
8烷基所取代的胺基，可以是单取代或双取代的；例如，甲胺基、乙胺基、丙胺基、异丙胺基、丁胺基、异丁胺基、叔丁胺基、二 甲胺基、二乙胺基、二丙胺基、二异丙胺基、二丁胺基、二异丁胺基、二叔丁胺基等。
如本文所用，术语“C
1-C
8烷氧基”是指具有1-8个碳原子的直链或支链的烷氧基；例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基”是指具有3-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环，也可以是双环形式，例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用，术语“C
6-C
10芳基”是指具有6-10个碳原子的芳基，例如，苯基或萘基等类似基团。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
本发明所述的基团除非特别说明是“取代的或未取代的”，否则本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C
1-C
6烷基-胺基、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基、卤代C
1-C
6烷基、卤代C
2-C
6烯基、卤代C
2-C
6炔基、卤代C
1-C
6烷氧基、烯丙基、苄基、C
6-C
12芳基、C
1-C
6烷氧基-C
1-C
6烷基、C
1-C
6烷氧基-羰基、苯氧羰基、C
2-C
6炔基-羰基、C
2-C
6烯基-羰基、C
3-C
6环烷基-羰基、C
1-C
6烷基-磺酰基等。
如本文所用，“卤素”或“卤原子”指F、Cl、Br、和I。更佳地，卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
除非特别说明，本发明所描述的结构式意在包括所有可能的氘代衍生物(即，分子中的一个或多个氢原子被D取代)。
如本文所用，术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用，术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
如本文所用，术语“水合物”是指本发明化合物与水进行配位形成的配合物。
应理解，在本文中，各个基团的定义意在形成化学稳定的结构。
活性成分
如本文所用，“本发明化合物”指式I所示的化合物，并且还包括及式I化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
优选的本发明化合物包括化合物1-360(包括各化合物的各类R构型和/或S构型的立体异构体，和/或E-/Z-的顺反异构体)。
在另一优选例中，所述的药用盐包括与无机酸、有机酸、碱金属离子、碱土金属 离子或能提供生理上可接受的阳离子的有机碱结合形成的盐以及铵盐。
在另一优选例中，所述的无机酸选自盐酸、氢溴酸、磷酸或硫酸；所述的有机酸选自甲磺酸、对甲苯磺酸、三氟乙酸、枸杞酸、马来酸酒石酸、富马酸、柠檬酸或乳酸；所述的碱金属离子选自锂离子、钠离子、钾离子；所述的碱土金属离子选自钙离子、镁离子；所述的能提供生理上可接受的阳离子的有机碱选自甲胺、二甲胺、三甲胺、哌啶、吗啉或三(2-羟乙基)胺。
在本发明范围内的所有这些盐都可采用常规方法制备。在所述的通式I化合物及其溶剂化物和其盐的制备过程中，不同的结晶条件可能出现多晶或共晶。
式I化合物的制备
为了制备本发明通式I所述的化合物，依据通式I的结构，本发明制备通式I化合物可以通过以下合成路线获得。
(a)以中间体1和2为原料，通过合适的钯催化剂催化的Suzuki偶联反应得到目标产物I；
其中，中间体1的制备方法(参考WO 2018195321、WO2018005374和WO2019023575)如下：
以化合物1-1为原料，在手性辅剂(如R/S-CBS)和还原剂(如硼烷)的作用下，形成手性醇1-2；
(b)以1-2(或1-5)和1-3为原料，在合适的钯催化剂和配体的条件下，发生偶联反应(如Suzuki,Buchwald等)，得到中间体1-4(或1-6)；
(c)以化合物1-1和R/S-叔丁基磺酰亚胺为原料，在Lwesis酸(如四钛酸乙酯)和还原试剂(如四氢锂铝，硼氢化钠等)的作用下，形成保护的手性氨基化合物，而后在酸性条件下脱除保护基，得到手性氨基化合物1-5；
(d)以1-4(或1-6)和联硼酸频哪酯为原料，在合适的钯催化剂和配体的条件下，发生Suzuki偶联反应，得到中间体1；
中间体2的制备方法如下：
(a)以化合物2-1和2-2为原料，在脱水剂(如浓硫酸，PPA等)的作用下，形成中间体2-3；
(b)以2-3(或2-4)和2-5为原料，在碱性条件下(有机碱或无机碱)，发生亲和取代反应，形成中间体2-8(或2-6)；
(c)以2-6和2-7为原料，在合适的钯催化剂和配体的条件下，发生Suzuki偶联反应，得到中间体2-8；
(d)以化合物2-8为原料，在碘化试剂(如单质碘，NIS等)的作用下，发生取代反应，形成中间体2-9；
(e)以化合物2-9为原料，在氯化试剂(如三氯氧磷，二氯亚砜等)的作用下形成活泼氯代物，而后在氨基化合物的作用下，发生亲和加成消除反应，形成中间体2-10；
(f)以化合物2-10和2-11为原料，在合适的催化剂和配体的条件下，发生偶联反应，形成中间体2；
另外，上述反应中的起始原料及中间体容易得到，各步反应可依据已报道的文献或对本领域熟练技术人员来说可以用有机合成中的常规方法很容易合成。通式I所述化合物可以溶剂化物或非溶剂化物的形式存在，利用不同的溶剂进行结晶可能得到不同的溶剂化物。
药物组合物和施用方法
由于本发明化合物具有优异的PD-1/PD-L1相互作用的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)PD-1/PD-L1相互作用相关疾病(例如，癌症、感染性疾病、自身免疫性疾病)。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各 组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物(例如其他抗癌制剂)联合给药。
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的化合物。该其他药学上可接受的化合物中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗PD-1/PD-L1相互作用相关疾病。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状 况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
(1)本发明化合物对PD-1/PD-L1相互作用具有很高的抑制活性，与PD-L1蛋白具有很强的结合能力，并具有解除PD-L1抑制IFNγ的能力。
(2)本发明的化合物具有更好的溶解性较好；对正常细胞的毒性非常低，因而可以在较大的剂量范围内应用于治疗对象。
(3)相较于现有技术的化合物，本发明的化合物具有更好的溶解性，因此具有良好的成药性，相较于现有化合物而言，本发明化合物在体内实验之中表现出良好的生物利用度，除此之外，相较于现有化合物，本发明的化合物极易制成药学上可接受的盐，因而有助于进一步形成制剂。
(4)体内药效研究表明，本发明化合物无论从肿瘤体积还是重量上，都可显著的抑制皮下肿瘤的生长，并可明显增加小鼠血液中、脾脏中各淋巴细胞数量。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
通用材料及测试方法：
实施例中涉及到的仪器及原料说明如下:
核磁共振氢谱是Bruker AV-400(400MHz)核磁仪分析得到。
化学位移以四甲基硅烷为内标来记录，以ppm为单位来表示(CDC1
3:δ7.26ppm)。记录的数据信息如下:化学位移及其裂分和偶合常数(s:单重峰；d:双重峰；t：三重峰；q：四重峰；br：宽峰；m：多重峰)。
质谱数据除其他需要，都采用菲尼根高级LCQ公司(Finnigan LCQ Advantage)的液质联用仪进行分析，所有反应都在干燥氩气保护的无水无氧条件下进行操作。固体金属有机化合物在氩气保护干燥箱中进行储藏。
四氢呋喃和乙醚是经过蒸馏得到，蒸馏时在其中加入金属钠和二苯甲酮。二氯甲烷，戊烷和己烷是用氢化钙来处理。
本发明中涉及的特殊原料和中间体由天津长森药业有限公司等订制加工提供，其他所有化学试剂从上海化学试剂公司、阿尔得里奇公司(Aldrich)、阿克罗公司(Acros)等试剂供应商购买。如合成过程中反应所需的中间体或产物不够下一步试验，则重复多次合成至足够数量为止。
本发明所涉及的原料和试剂除特殊说明外均可市售或订制加工购买得到。
本发明中化合物可含有一个或多个不对称中心，因此该系列化合物可为消旋或者单一对映体形式。本发明所制备的化合物是纯度高于95％的杂环化合物，每个最终产物的结构表征分别由MS或/和氢谱核磁共振(
1H NMR)分析确定。以下通过实施例说明本发明各类化合物和中间体的合成。
实施例1 化合物LW1005-001的合成
步骤1-1：
将化合物1(5.0g,23.6mmol,WO2012158550.),2(4.4g,25.9mmol),Xantphos-PdCl2(892mg,1.18mmol)和Cs
2CO
3(15.4g,47.2mmol)加入到dioxane(100mL)中，N2保护，95度反应2小时。TLC点板反应完全。反应液过滤，滤液旋干，柱层析(EA:HEP＝1:30)，得到4.8g淡黄色固体。MS-APCI:348[M+H]
+.
步骤1-2：
将化合物3(4.8g,13.8mmol),4(2.5g,20.7mmol,溶于1.5mL AcOH)加入到DCM中，而后加入2.8g TEA，室温搅拌1h后加入NaBH(OAc)
3(4.4g,20.7mmol)。30分钟后TLC点板反应完全。反应液用饱和NaHCO3洗，DCM萃取，干燥DCM，旋干，过柱(MeOH:DCM＝1:20)纯化，得到5.1g产物，淡黄色油状粘稠物。MS-APCI:419[M+H]
+.
步骤1-3：
将化合物5(5.1g,12.2mmol),Bpin
2(3.4g,13.4mmol)，Pd(dppf)Cl
2.DCM(498 mg,0.61mmol),KOAc(2.4g,24.4mmol)加入到dioxane(100mL)中，N
2气保护,90度反应2.5小时。LC-MS检测反应完全。反应液过滤，水洗，DCM萃取，干燥，旋干，过柱(DCM:MeOH＝30:1)，得到产物5.2g灰色固体。MS-APCI:467[M+H]
+.
步骤1-4：
将化合物7(51g,Journal of Medicinal Chemistry,2019,62,276-287)，2-甲基-3-溴苯甲酸(95.56g)依次加入PPA(500g)中，140℃下机械搅拌反应6小时。反应完全后，往反应瓶内倒入冰水，稀释后倒出打浆30min，过滤。滤得固体加入500ml水，机械搅拌下加入氢氧化钠固体，水相调至pH＝6-8，过滤。滤饼固体55℃烘干，得到灰白色固体产品80g。MS-APCI:305[M+H]
+.
步骤1-5：
将原料8(20g),碳酸铯(42g)加入到300ml DMF中,加入溴乙醇(16g)，50℃加热搅拌16小时.TLC检测反应完成。反应液过滤浓缩，用水打浆，过滤，烘干得灰白色固体19g。MS-APCI:349[M+H]
+.
步骤1-6：
将原料9(15g)悬浮于DCM(300mL)中,而后依次加入Et
3N(13g)和BzCl(12g)，室温搅拌，反应一小时后，TLC显示反应完全，加入200ml水，萃取，分液，干燥，浓缩，打浆，得18g白色固体。MS-APCI:453[M+H]
+.
步骤1-7：
将原料10(18g)和NIS(10.7g)依次加入MeCN(230mL)中，滴加5ml滴TFA,油浴55℃搅拌1.5小时。TLC检测反应完成后，冷却，过滤,烘干得13.8g黄色固体。MS-APCI:579[M+H]
+.
步骤1-8：
将原料11(1.0g)加入POCl
3(10mL)中，100℃反应1小时，浓缩干，往残留液中加入甲胺水溶液，冰浴下搅拌，出现绿色固体，过滤，干燥得960mg固体。MS- APCI:592[M+H]
+.
步骤1-9：
将原料12(960mg)和K
2CO
3(770mg)依次加到MeOH(20mL)，55℃搅拌，TLC监测，至反应完毕，过滤，烘干得900mg绿色固体。MS-APCI:488[M+H]
+.
步骤1-10：
将原料13(48mg)，ZnCN
2(22mg),Pd
2(dba)
3(11mg)，dppf(15mg)混合于50mL单口瓶中，N
2保护，加入5mLDMF，95℃下搅拌16小时,TLC检测反应完成。反应液过滤，滤液水洗，EA萃取。过柱，得到28mg绿色固体。MS-APCI:387[M+H]
+.
步骤1-11：
将化合物14(100mg),6(139mg)，Pd(dppf)Cl
2(15mg),Na
2CO
3(53mg)置于反应瓶，N
2脱气保护,3mL dioxane/0.6mL水注入反应瓶中，90度反应2小时。TLC检测反应。反应完全后，反应液水洗，EA萃取，干燥，旋干，过柱，得150mg白色固体。MS-APCI:647[M+H]
+.
1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),9.75-9.61(m,2H),9.02(s,1H),8.17(d,J＝7.7Hz,1H),7.83(d,J＝8.1Hz,1H),7.67–7.45(m,3H),7.39(t,J＝7.5Hz,1H),7.25(d,J＝7.4Hz,1H),6.58(d,J＝6.5Hz,1H),6.52(t,J＝7.0Hz,1H),5.54-5.40(m,1H),5.32-5.15(m,1H),4.53-4.38(m,3H),4.36-4.31(m,1H),4.28-4.22(m,1H),4.01(s,3H),3.81(s,2H),3.61(s,3H),3.24(s,3H),3.10-3.02(m,1H),2.90-2.80(m,1H),2.74-2.58(m,2H),2.46(s,3H),2.15-2.06(m,1H),2.02-1.92(m,1H),1.87-1.78(m,1H).
实施例2 化合物LW1005-002的合成
步骤2-1：
将化合物11(1.0g,1.73mmol)加入到POCl
3(15ml)中，90℃反应1小时，浓缩干，待用。将NH
2OMe/HCl(10g)用6mL水溶解，加入NaOH(4.79g)搅拌10分钟，过滤，滤液用冰浴冷却后倒入1反应后的残留物中，冰浴下搅拌，出现固体，滤出干燥得粗品1g固体。MS-APCI:608[M+H]
+.
步骤2-2：
将化合物15(3g,4.9mmol)溶于MeOH/THF(30mL/30mL)，加入5N甲醇钠溶液(2.5mL,12.3mmol),室温搅拌，TLC点板监测。反应完毕后，加水淬灭，旋干溶剂，固体出现，过滤，固体烘干，得2.7g淡黄色固体。MS-APCI:504[M+H]
+.
步骤2-3：
将原料16(7.8g,15.5mmol)，Zn(CN)
2(1.09g,9.28mmol),Xantphos-PdCl2(1.17g,1.55mmol)，Cs
2CO
3(7.56g,23.2mmol)混合于250mL三口瓶中，N
2置换3次，注入150mLDMF，90℃下搅拌2h,LCMS检测反应完成。过滤，滤液浓缩干，固体用(DCM/MeOH＝100mL/2mL)打浆，得4.5g淡黄色固体。MS-APCI:403[M+H]
+.
步骤2-4：
4(100mg,0.25mmol),5(139mg,0.3mmol)，Pd(dppf)
2Cl
2(20mg,0.025mmol),Na
2CO
3(53mg,0.5mmol)置于反应瓶，N
2脱气保护,3mL dioxane/0.6mL水注入反应瓶中，90度反应2小时。TLC点板反应完全。反应液水洗，EA萃取，干燥，旋干，过柱(DCM:MeOH＝10:1)，得到粗品180mg,制备分离，得到29.5mg淡黄色固体。MS-APCI:663[M+H]
+.
1H NMR(400MHz,DMSO-d6)δ9.95(m,1H),8.25(s,1H),7.95(dd,J＝7.8,1.4Hz,1H),7.83(d,J＝8.1Hz,1H),7.53–7.45(m,2H),7.39(dt,J＝14.8,7.4Hz,2H),7.23(d,J＝7.4Hz,1H),6.57(d,J＝7.3Hz,1H),6.52(t,J＝8.8Hz,1H),5.49(d,J＝33.1Hz,1H),4.98(s,1H),4.44(d,J＝25.2Hz,1H),4.30(d,J＝31.6Hz,1H),4.06-3.94(m,5H),3.80-3.69(m,5H),3.63-3.50(m,1H),3.24(s,1H),2.87-2.80(m,1H),2.76–2.54(m,3H),2.38(d,J＝14.2Hz,3H),2.15-2.06(m,1H),2.03-1.92(m,1H),1.90–1.77(m,1H).
实施例3 化合物LW1005-003的合成
步骤3-1：
将原料8(5.0g,16mmol)和碳酸铯(10.0g,32mmol)混合于DMF(100mL)中,加入3-溴丙酸甲酯(8.0g,48mmol)，55℃下搅拌6小时，水洗,过滤，柱层析纯化得5.2g黄褐色固体。MS-APCI:391[M+H]
+.
步骤3-2：
将原料18(5.0g,54.6mmol)和NIS(4.3g,19.2mmol)依次加入MeCN(100mL)中，而后往反应液中滴加2mL TFA,于油浴55℃下搅拌2小时。反应完全后，冷却，过滤，用正庚烷(15mL x 3)淋洗,，烘干得5g白色固体。MS-APCI:517[M+H]
+.
步骤3-3：
以化合物19(1.0g,1.94mmol)，O-甲基羟胺盐酸盐(5g，60mmol)和NaOH(2.4g，60mmol)为反应物，按照步骤2-1的合成方法，得到1.1g黄色固体。MS-APCI:546[M+H]
+.
步骤3-4：
将原料20(600mg,1.13mmol)溶于THF/H
2O(1:1,50mL)中，加入氢氧化锂(142mg)，室温反应反应0.5小时，TLC监测反应。反应完全后，加水20ml，TFA调酸，DCM(20ml x 3)萃取，干燥，浓缩，得450mg黄色固体。MS-APCI:532[M+H]
+.
步骤3-5：
以化合物21(120mg,0.23mmol),Zn(CN)
2(26mg,0.23mmol),Xantphos-PdCl
2(17mg,0.023mmol)，Cs
2CO
3(150mg,0.46mmol)为反应物，按照步骤2-3的合成方法，得80mg黄色固体。MS-APCI:431[M+H]
+.
步骤3-6：
以化合物22(120mg,0.28mmol)，6(156mg,0.33mmol),Pd(dppf)
2Cl
2(23mg,0.028mmol)，Na
2CO3(59mg,0.56mmol)为反应物，按照步骤2-4的合成方法，得到5mg淡黄色固体。MS-APCI:691[M+H]
+.
1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),7.90(d,J＝7.9Hz,1H),7.57(d,J＝7.9Hz,1H),7.45(d,J＝7.5Hz,2H),7.35(dt,J＝19.6,7.7Hz,2H),7.17(d,J＝7.5Hz,1H),6.48(d,J＝7.1Hz,1H),6.36(t,J＝8.6Hz,1H),4.66(s,1H),4.16(s,1H),4.07(t,J＝6.8Hz,2H),3.90(s,3H),3.74(s,3H),3.50-3.45(m,2H),2.73(t,J＝6.9Hz,2H),2.65-2.50(m,3H),2.42-2.37(m,1H),2.36-2.32(m,3H),2.23-2.27(m,1H),2.08–2.00(m,1H),1.96-1.91(m,1H),1.50(dd,J＝9.9,5.7Hz,1H).
实施例4 化合物LW1005-004的合成
步骤4-1:
以化合物8(5.0g,16mmol)，4-溴丁酸甲酯(3.56g,21.4mmol)和碳酸铯(10.7g, 32mmol)为反应物，按照步骤3-1的合成方法，得5.7g灰色固体。MS-APCI:405[M+H]
+.
步骤4-2:
以化合物23(5.7g,14.1mmol)和NIS(6.35g,28.2mmol)为反应物，按照3-2的合成方法，得4.9g淡粉色固体。MS-APCI:531[M+H]
+.
步骤4-3:
以化合物24(1.0g,1.88mmol),O-甲基羟胺盐酸盐(5g，60mmol)和NaOH(2.4g，60mmol)为反应物，按照步骤2-1的合成方法，得到1.1g黄色固体。MS-APCI:560[M+H]
+.
步骤4-4:
将原料25(830mg,1.49mmol)溶于20mL THF/H2O(1:1)中，加入氢氧化锂(125mg)，室温反应0.5小时，TLC点板反应完全。旋干THF，加TFA调酸，固体析出，过滤，固体干燥740mg黄色固体。MS-APCI:546[M+H]
+.
步骤4-5:
将26(400mg,0.73mmol),Zn(CN)2(52mg,0.44mmol),Xantphos-PdCl2(56mg,0.074mmol)，Cs2CO3(358mg,1.1mmol)混合于50mL两口瓶中，加入10mL NMP,N2置换3次，85℃下搅拌1小时。LCMS检测反应完成。加水，TFA调酸，EA萃取，干燥，浓缩，柱层析得黄色固体120mg。MS-APCI:445[M+H]
+.
步骤4-6:
以化合物27(120mg,0.27mmol)，6(139mg,0.3mmol),Pd(dppf)
2Cl
2(23mg,0.028mmol)，Na
2CO3(86mg,0.81mmol)为反应物，按照步骤2-4的合成方法，得到40mg淡黄色固体。MS-APCI:704[M+H]
+.
1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),7.91(d,J＝7.8Hz,1H),7.57(d,J＝7.9Hz,1H),7.45(t,J＝6.6Hz,2H),7.35(dt,J ＝18.8,7.6Hz,2H),7.17(d,J＝7.4Hz,1H),6.48(d,J＝7.4Hz,1H),6.36(t,J＝8.6Hz,1H),4.65(s,1H),4.16(s,1H),3.95-3.91(m,1H),3.90(s,3H),3.74(s,3H),3.50-3.40(m,4H),2.83–2.71(m,1H),2.68-2.63(m,2H),2.60-2.53(m,2H),2.44-2.38(m,1H),2.35(d,J＝14.9Hz,3H),2.30-2.23(m,2H),2.08-2.02(m,1H),2.00–1.91(m,3H),1.54-1.43(m,1H).
实施例5 化合物LW1005-005的合成
步骤5-1:
以化合物3(4.8g,13.8mmol),(R)-3-吡咯烷羧酸(2.4g,20.7mmol,溶于1.5mL AcOH)和NaBH(OAc)
3(4.4g,20.7mmol)为反应物。按照步骤1-2的合成方法，得到5g淡黄色油状粘稠物。MS-APCI:447[M+H]
+.
步骤5-2:
以化合物17(650mg,1.62mmol),Bpin2(452mg,1.78mmol)，Pd(dppf)Cl2.DCM(132mg,0.162mmol),KOAc(317.5mg,3.24mmol)为反应物，按照1-3的合成方法，得到500mg白色固体。MS-APCI:451[M+H]
+.
步骤5-3:
以化合物28(89mg,0.2mmol)，29(99mg,0.22mmol),Pd(dppf)
2Cl
2(17mg,0.02mmol)和Na
2CO
3(53mg,0.5mmol)为反应物，按照2-4的合成方法，得到13mg黄色固体。MS-APCI:691[M+H]
+.
1H NMR(400MHz,DMSO-d6)δ8.21(s,1H),7.91(d,J＝9.2Hz,1H),7.57(d,J＝8.0Hz,1H),7.45(t,J＝7.0Hz,2H),7.35(dt,J＝19.7,7.5Hz,2H),7.17(d,J＝7.3Hz,1H),6.48(s,1H),6.36(t,J＝8.7Hz,1H),4.94(s,1H),4.32(s, 1H),3.95(d,J＝5.4Hz,1H),3.90(s,3H),3.73(s,1H),3.70(s,3H),3.51-3.45(m,4H),2.91-2.85(m,1H),2.70-2.64(m,2H),2.62–2.55(m,2H),2.35(dd,J＝15.0,5.9Hz,3H),2.05–2.00(m,1H),1.97-1.88(m,3H),1.43-1.35(m,1H).
实施例6 化合物LW1005-006的合成
步骤6-1:
将化合物17(2.6g，6.45mmol)溶于DCM(120mL)中，而后一次性往上述溶液中加入Dess-Martin Reagent(8.2g，19.34mmol)，室温搅拌30分钟，TLC监测反应。反应完全后，加水淬灭反应，而后依次用饱和碳酸氢纳，10％硫代硫酸钠溶液和饱和食盐水洗涤反应液，有机层用无水硫酸钠干燥，过滤，有机层倾入250mL的单口瓶中。往上述溶液中依次加入4-羧酸哌啶甲酯(1.85g，12.9mmol)，乙酸(1滴)和醋酸硼氢化钠(4.1g，19.35mmol)，室温搅拌2小时，TLC监测反应。反应完全后，加水淬灭反应，而后依次用饱和碳酸氢纳和饱和食盐水洗涤反应液，有机层用无水硫酸钠干燥，柱层析，得1.02g淡黄色固体。MS-APCI:528[M+H]
+.
步骤6-2:
将原料30(200mg,0.378mmol)溶于10mL THF/H2O(2:1)中，加入氢氧化钠(45mg，1.135mmol)，室温反应过夜，TLC监测反应。反应完全后，往其中加TFA(0.08mL,1.135mmol)调节溶液至中性，旋干THF，加水搅洗，固体析出，过滤，固体干燥195mg淡黄色固体。MS-APCI:514[M+H]
+.
步骤6-3:
以化合物31(80mg,0.155mmol)，6(90mg,0.2mmol),Pd(dppf)
2Cl
2(17mg,0.02mmol)和Na
2CO
3(53mg,0.5mmol)为反应物，按照2-4的合成方法，得到23mg黄色固体。MS-APCI:774[M+H]
+.
1H NMR(400MHz,DMSO-d6)δ8.23(d,J＝2.7Hz,1H),7.91(d,J＝7.1Hz,1H),7.62–7.52(m,1H),7.44(d,J＝6.7Hz,2H),7.40–7.27(m,2H),7.17(dd,J＝7.4,2.7Hz,1H),6.48(d,J＝7.2Hz,1H),6.40–6.27(m,1H),4.64(s,1H),4.16(s,1H),3.96(d,J＝7.2Hz,2H),3.90(s,3H),3.73(s,3H),3.45(dd,J＝10.1,2.5Hz,2H),2.82(d,J＝10.7Hz,2H),2.68-2.53(m,6H),2.42–2.31(m,3H),2.30-2.27(m,1H),2.20-2.13(m,2H),2.08-2.02(m,3H),1.98-1.90(m,2H),1.80–1.70(m,2H),1.54–1.40(m,3H).
实施例7 化合物LW1005-007的合成
步骤7-1：
将32(9.1g,1.0eq；EP2848622)、Cs2CO3(41.56g,3.0eq)加入反应瓶，加入DMF溶解，滴加2-溴乙醇(6.03mL,2.0eq)，50℃搅拌18h。LC-MS监测，反应结束。旋干DMF，加100mL水打浆1h。抽滤，滤饼用50mL水、100mL正庚烷洗涤。得咖啡色固体9.0g。MS-APCI:258[M+H]
+
步骤7-2：
将33(9.0g,1.0eq)、34(13.46g,1.3eq；Chem,2019,5,929-939)、Cs2CO3(22.73g,2.0eq)、Pd(PPh3)4(2.02g,0.05eq)加入反应瓶，N2保护，加入1,4-dioxane/水溶解，100℃搅拌3h。LC-MS监测，反应完成。反应液水洗，brine洗涤，干燥，浓缩，柱层 析,得固体10.1g。MS-APCI:348[M+H]
+
步骤7-3：
将35(5.0g,1.0eq)、Et3N(6mL,3.0eq)加入二氯甲烷中，RT下滴加BzCl，RT下搅拌2h。TLC监测反应完成。反应液用饱和碳酸氢钠溶液、饱和brine洗涤，干燥，浓缩，柱层析。得淡黄色至类白色固体6.4g。MS-APCI:452[M+H]
+
步骤7-4：
将36(11.0g,1.0eq)溶解在乙腈中，加入NIS，RT下滴加TFA，加毕，55℃搅拌3h，有大量固体析出。TLC监测反应完成，抽滤，滤饼用正庚烷洗涤，滤液旋干，EA/水萃取，10％Na2S2O3溶液洗涤，干燥，浓缩，与滤饼混合柱层析。得类白色固体13g。MS-APCI:578[M+H]
+
步骤7-5：
将37(1.0g)加入反应瓶，加5mL POCl3，90摄氏度搅拌1.5h。旋干，油泵抽至呈泡沫状固体。加入30％甲胺水溶液(20mL，100eq)，DCM溶解，rt下搅拌15min。TLC监测原料完全转化，分液，有机相brine洗涤，干燥，浓缩，柱层析，得咖啡色固体1.0g。MS-APCI:591[M+H]
+
步骤7-6：
将38(1.0g 1.0eq)分散在甲醇/THF中，加入K2CO3(700mg 3.0eq)固体，室温下搅拌3h。TLC显示有大量原料剩余，补加K2CO3(700mg 3.0eq)，室温下继续搅拌过夜，TLC显示原料基本完全反应。旋干，DCM/水萃取，有机相用brine洗涤，干燥，浓缩，柱层析。得咖啡色固体700mg。MS-APCI:487[M+H]
+
步骤7-7：
将39(2.7g 1.0eq)、Zn(CN)2(299.4mg 0.46eq)、Cs2CO3(2.17g 1.2eq)、Xantphos-PdCl2(418mg 0.1eq)加入反应瓶，N2保护，加入DMF溶解，90℃搅拌2h。LC-MS监 测，反应完成，旋干DMF，DCM/水萃取，有机相用brine洗涤，干燥，浓缩，柱层析。得咖啡色固体2.2g。MS-APCI:386[M+H]
+
步骤7-8：
将40(300mg 1.0eq)、5(352.5mg 1.2eq)、Na2CO3(164.6mg 2.0eq)、Pd(dppf)2Cl2(41mg,0.1eq)加入反应瓶，N2保护，加入1,4-dioxane/水溶解，90℃搅拌2h。LC-MS监测，反应完成。反应液用DCM/水萃取，有机相用卤水洗涤，干燥，浓缩，柱层析，制备得淡黄色固体30mg。MS-APCI:646[M+H]
+
实施例8 化合物LW1005-008的合成
步骤8-1：
将化合物37(1.5g,2.59mmol)加入到POCl
3(30ml)中，90℃反应2小时，浓缩干，待用。将NH
2OMe/HCl(22g)用10mL水溶解，加入NaOH(10.36g)搅拌10分钟，过滤，滤液用冰浴冷却后倒入1反应后的残留物中，冰浴下搅拌，出现固体，滤出干燥得粗品1.5g固体。MS-APCI:607[M+H]
+.
步骤24-2：
将化合物41(300mg,0.49mmol)溶于MeOH/THF(30mL/30mL)，加入K2CO3(28mg,0.98mmol),室温搅拌，TLC点板监测。反应完毕后，旋干溶剂，固体出现，过滤，固体烘干，得200mg淡黄色固体。MS-APCI:503[M+H]
+.
步骤8-3：
将原料42(135mg,0.268mmol)，Zn(CN)
2(16mg,0.137mmol),Xantphos-PdCl2(20mg,0.0268mmol)，Cs
2CO
3(131mg,0.402mmol)混合于50mL三口瓶中，N
2置换3次，注入10mLDMF，90℃下搅拌2h,LC-MS检测反应完成。过滤，滤液浓缩干，拌样，柱层析，得4.5g淡黄色固体。MS-APCI:402[M+H]
+.
步骤8-4：
将化合物43(50mg，0.124mmol)溶于DCM(120mL)中，而后一次性往上述溶液中加入Dess-Martin Reagent(158mg，0.373mmol)，室温搅拌30分钟，TLC监测反应。反应完全后，加水淬灭反应，而后依次用饱和碳酸氢纳，10％硫代硫酸钠溶液和饱和食盐水洗涤反应液，有机层用无水硫酸钠干燥，过滤，有机层倾入250mL的单口瓶中。往上述溶液中依次加入4-羧酸哌啶甲酯(0.05mL，0.373mmol)，乙酸(1滴)和醋酸硼氢化钠(79mg，0.373mmol)，室温搅拌2小时，TLC监测反应。反应完全后，加水淬灭反应，而后依次用饱和碳酸氢纳和饱和食盐水洗涤反应液，有机层用无水硫酸钠干燥，柱层析，得20mg淡黄色固体。MS-APCI:527[M+H]
+.
步骤8-5：
将原料104(230mg,0.436mmol)溶于10mL THF/H2O(2:1)中，加入LiOH(21mg，0.872mmol)，室温反应2小时，TLC监测反应。反应完全后，往其中加TFA(0.08mL,1.135mmol)调节溶液至中性，旋干THF，加水搅洗，固体析出，过滤，固体干燥200mg淡黄色固体。MS-APCI:513[M+H]
+.
步骤8-6：
将化合物105(200mg)，6(148mg),Pd(dppf)2Cl2(34mg)和Na2CO3(170mg)置于反应瓶，N2脱气保护,3mL dioxane/0.6mL水注入反应瓶中，90度反应2小时，TLC点板反应完全。反应液水洗，EA萃取，干燥，旋干，过柱(DCM:MeOH＝10:1)，得到18mg黄色固体。MS-APCI:767[M+H]
+
表1 按照LW1005-001～LW1005-008的合成方法用相应的原料制备下列化合物
| No. | LCMS | No. | LCMS | No. | LCMS |
| [M+H] + | [M+H] + | [M+H] + | |||
| LW1005-009 | 633 | LW1005-050 | 763 | LW1005-075 | 843 |
| LW1005-010 | 667 | LW1005-051 | 774 | LW1005-076 | 823 |
| LW1005-011 | 711 | LW1005-052 | 762 | LW1005-077 | 831 |
| LW1005-012 | 687 | LW1005-041 | 755 | LW1005-078 | 811 |
| LW1005-013 | 715 | LW1005-042 | 741 | LW1005-079 | 830 |
| LW1005-014 | 717 | LW1005-043 | 783 | LW1005-080 | 810 |
| LW1005-015 | 701 | LW1005-044 | 669 | LW1005-081 | 826 |
| LW1005-016 | 745 | LW1005-045 | 783 | LW1005-082 | 806 |
| LW1005-017 | 717 | LW1005-046 | 769 | LW1005-083 | 825 |
| LW1005-018 | 717 | LW1005-047 | 756 | LW1005-084 | 805 |
| LW1005-019 | 634 | LW1005-048 | 784 | LW1005-085 | 627 |
| LW1005-020 | 688 | LW1005-049 | 775 | LW1005-086 | 677 |
| LW1005-021 | 716 | LW1005-050 | 763 | LW1005-087 | 693 |
| LW1005-022 | 718 | LW1005-051 | 774 | LW1005-088 | 675 |
| LW1005-023 | 718 | LW1005-052 | 762 | LW1005-089 | 643 |
| LW1005-024 | 683 | LW1005-041 | 755 | LW1005-090 | 654 |
| LW1005-025 | 686 | LW1005-042 | 741 | LW1005-091 | 647 |
| LW1005-026 | 714 | LW1005-043 | 783 | LW1005-092 | 697 |
| LW1005-027 | 716 | LW1005-044 | 669 | LW1005-093 | 713 |
| LW1005-028 | 700 | LW1005-045 | 783 | LW1005-094 | 695 |
| LW1005-029 | 744 | LW1005-046 | 769 | LW1005-095 | 663 |
| LW1005-030 | 688 | LW1005-047 | 756 | LW1005-096 | 681 |
| LW1005-031 | 715 | LW1005-048 | 784 | LW1005-097 | 731 |
| LW1005-032 | 717 | LW1005-049 | 775 | LW1005-098 | 747 |
| LW1005-025 | 686 | LW1005-050 | 763 | LW1005-099 | 729 |
| LW1005-026 | 714 | LW1005-051 | 774 | LW1005-100 | 697 |
| LW1005-027 | 716 | LW1005-052 | 762 | LW1005-101 | 680 |
| LW1005-028 | 700 | LW1005-053 | 798 | LW1005-102 | 730 |
| LW1005-029 | 744 | LW1005-054 | 778 | LW1005-103 | 696 |
| LW1005-030 | 688 | LW1005-055 | 797 | LW1005-104 | 694 |
| LW1005-031 | 715 | LW1005-056 | 777 | LW1005-105 | 744 |
| LW1005-032 | 717 | LW1005-057 | 833 | LW1005-106 | 710 |
| LW1005-033 | 756 | LW1005-058 | 813 | LW1005-107 | 710 |
| LW1005-034 | 742 | LW1005-059 | 832 | LW1005-108 | 760 |
| LW1005-035 | 784 | LW1005-060 | 812 | LW1005-109 | 726 |
| LW1005-036 | 770 | LW1005-061 | 814 | LW1005-110 | 749 |
| LW1005-037 | 786 | LW1005-062 | 794 | LW1005-111 | 799 |
| LW1005-038 | 770 | LW1005-063 | 813 | LW1005-112 | 765 |
| LW1005-039 | 757 | LW1005-064 | 793 | LW1005-113 | 887 |
| LW1005-040 | 785 | LW1005-065 | 849 | LW1005-114 | 901 |
| LW1005-041 | 755 | LW1005-066 | 829 | LW1005-115 | 917 |
| LW1005-042 | 741 | LW1005-067 | 848 | LW1005-116 | 883 |
| LW1005-043 | 783 | LW1005-068 | 828 | LW1005-117 | 867 |
| LW1005-044 | 669 | LW1005-069 | 809 | LW1005-118 | 853 |
| LW1005-045 | 783 | LW1005-070 | 789 | LW1005-119 | 901 |
| LW1005-046 | 769 | LW1005-071 | 808 | LW1005-120 | 915 |
| LW1005-047 | 756 | LW1005-072 | 788 | LW1005-121 | 931 |
| LW1005-048 | 784 | LW1005-073 | 844 | LW1005-122 | 784 |
| LW1005-049 | 775 | LW1005-074 | 824 | LW1005-123 | 881 |
| LW1005-124 | 895 | LW1005-125 | 897 | LW1005-126 | 911 |
| LW1005-127 | 880 | LW1005-128 | 894 | LW1005-129 | 777 |
| LW1005-130 | 797 | LW1005-131 | 900 | LW1005-132 | 914 |
| LW1005-133 | 896 | LW1005-134 | 910 | LW1005-135 | 793 |
| LW1005-136 | 813 | LW1005-137 | 916 | LW1005-138 | 930 |
| LW1005-139 | 696 | LW1005-140 | 680 | LW1005-141 | 717 |
| LW1005-142 | 701 | LW1005-143 | 697 | LW1005-144 | 681 |
| LW1005-145 | 752 | LW1005-146 | 736 | LW1005-147 | 732 |
| LW1005-148 | 716 |
生物测试
实施例A：PD-1/PD-L1均相时间分辨荧光(HTRF)结合测定
测定在标准黑色384孔聚苯乙烯板中进行，终体积为20μL。首先将抑制剂用DMSO连续稀释后加入板孔中，再加入其他反应组分。测定中DMSO的最终浓度为1％。测定是在25℃下含有0.05％Tween-20和0.1％BSA的PBS缓冲液(pH7.4)中进行的。在C端带有His标记的重组人PD-L1蛋白(19-238)购自AcroBiosystems公司(PD1-H5229)。在C端带有Fc标记的重组人PD-1蛋白(25-167)也购自AcroBiosystems公司(PD1-H5257)。将PD-L1和PD-1蛋白在测定缓冲液中稀释然后提取0.1μl溶液加入到板孔中。离心平板并将蛋白质与抑制剂预孵育40分钟。孵育后加入0.1μl HTRF检测缓冲液含有铕封闭标记的抗人IgG(PerkinElmer-AD0212)Fc专属的和抗His的
-别藻蓝蛋白(APC，PerkinElmer-AD0059H)缀合的抗体。离心后，将孔板在25℃下孵育60分钟。置于PHERAstar FS读板器中读取数据(665nm/620nm比率)。测定中的最终浓度为～3nM PD1、10nM PD-L1、1nM铕抗人IgG和20nM抗-His-别藻蓝蛋白。使用GraphPad Prism 5.0软件拟合活性数据得出抑制剂的IC50值。
实施例中举例说明的化合物IC50值以下列方式表示：IC50：+＝≤10nM；++＝10～100nM；+++＝>100nM
使用实施例A中描述的PD-1/PD-L1均相时间分辨荧光(HTRF)结合测定获得的实施例化合物的数据表明，所测试的本发明化合物的IC
50大多数均小于10nm，部分化合物(约25％)甚至小于1nM，部分优选化合物的活性测试数据提供于表1中。
表1.
| 化合物编号 | IC50(nM) | 化合物编号 | IC50(nM) |
| LW1005-001 | + | LW1005-132 | + |
| LW1005-002 | + | LW1005-133 | + |
| LW1005-003 | + | LW1005-134 | + |
| LW1005-004 | + | LW1005-135 | + |
| LW1005-005 | + | LW1005-136 | + |
| LW1005-006 | ++ | LW1005-137 | + |
| LW1005-027 | + | LW1005-138 | + |
| LW1005-028 | + | LW1005-139 | + |
| LW1005-123 | + | LW1005-140 | + |
| LW1005-124 | + | LW1005-141 | + |
| LW1005-125 | + | LW1005-142 | + |
| LW1005-126 | + | LW1005-143 | + |
| LW1005-127 | + | LW1005-144 | + |
| LW1005-128 | + | LW1005-145 | + |
| LW1005-129 | + | LW1005-146 | + |
| LW1005-130 | + | LW1005-147 | + |
| LW1005-131 | + | LW1005-148 | + |
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (15)
- 一种如下式I所示的化合物，或其光学异构体、顺反异构体、水合物、溶剂合物，或其药学上可接受的盐：
其中，n、m、p和q各自独立地选自0、1、2、3、4或5；表示构象为
L 1选自下组：化学键、取代或未取代的C1-C4亚烷基、取代或未取代的C2-C4亚烯基、取代或未取代的C2-C4亚炔基、-S-、-O-、取代或未取代的-NH-、-S(O)-、-S(O) 2-、取代或未取代的-NHC(O)NH-、取代或未取代的
取代或未取代的
取代或未取代的
M 1、M 2各自独立地选自下组：C(R 6) 2、NR 6、O、S、SO、SO 2；其中，R 6选自下组：H，氯、溴、氟、碘、氰基、羟基、硝基、NR f、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 8环烷基，取代或未取代的C 6-C 10芳基、取代或未取代的C 6-C 10杂芳基、-C(＝O)-NR dR e、-C(＝O)-取代或未取代的C 1-C 6烷氧基、-C(＝O)-取代或未取代的C 1-C 6烷基、-C(＝O)-取代或未取代的C 3-C 10环烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、-C(＝O)-取代或未取代的C 2-C 6烯基、-C(＝O)-取代或未取代的C 2-C 6炔基；M 3、M 4、M 5各自独立地选自下组：化学键、CR 6、N、NR 6、O、S、SO、SO 2；M 6各自独立地选自下组：CR 6、N；其中，M 1、M 2和M 6的碳原子上的氢(如存在的情况下)均可各自独立地被氘替换；且所述的为芳香环；
为具有如下结构所示的基团：
其中，Z 1选自下组：O、S、NR f、N-O-R f；其中，所述的Rf选自下组：H、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 8环烷基，取代或未取代的C 6-C 10芳基、取代或未取代的C 6-C 10杂芳基、氰基、-C(＝O)-NR dR e、-C(＝O)-取代或未取代的C 1-C 6烷氧基、-C(＝O)-取代或未取代的C 1-C 6烷基、-C(＝O)-取代或未取代的C 3-C 10环烷基、-C(＝O)-取代或未取代的C 2-C 6烯基、-C(＝O)-取代或未取代的C 2-C 6炔基；Z 2、Z 3、Z 4各自独立地选自下组：N、CH 2、N-O、SO、SO 2、C(＝O)、NR a、CR a；其中，所述的R a选自下组：H、氯，溴，氟，碘，氰基，羟基，硝基，-CHF 2、-OCF 3、-OCHF 2、磺酰氨基、NR f，取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 8环烷基，取代或未取代的C 6-C 10芳基、取代或未取代的C 6-C 10杂芳基、-C(＝O)-NRdRe、-C(＝O)-取代或未取代的C 1-C 6烷氧基、-C(＝O)-取代或未取代的C 1-C 6烷基、-C(＝O)-取代或未取代的C 3-C 10环烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、-C(＝O)-取代或未取代的C 2-C 6烯基、-C(＝O)-取代或未取代的C 2-C 6炔基；Y 1、Y 2、Y 3各自独立地选自下组：CH、CH 2、NH、N、N-O、CF、CRa、O、S、SO或SO 2；为单键或双键；
且为芳香性或非芳香性片段；
R为H、取代或未取代的C 1-C 6烷基、取代或未取代的C 6-C 10芳基、氰基、-C(＝O)-NRdRe、-C(＝O)-取代或未取代的C 1-C 6烷氧基、-C(＝O)-取代或未取代的C 1-C 6烷基、-C(＝O)-取代或未取代的C 3-C 10环烷基、-C(＝O)-取代或未取代的C 2-C 6烯基、-C(＝O)-取代或未取代的C 2-C 6炔基，取代或未取代的C1-C10烷基、
或-(L 1a) r-(L 2a) s-(L 3a) s-，其中，
各个L 1a各自独立地为选自下组的基团；化学键、取代或未取代的C 1-C 7亚烷基、取代或未取代的C2-C4亚烯基、取代或未取代的C2-C4亚炔基、-S-、-O-、取代或未取代的-NH-、-S(O)-、-S(O) 2-、L 2a选自下组：取代或未取代的C6-C12亚芳基、取代或未取代的具有1-3个杂原子的5-12元亚杂芳基、取代或未取代的C3-C8亚环烷基、取代或未取代的具有1-3个杂原子的3-10元亚杂环基；L 3a选自下组：H、取代或未取代的C1-C10烷基、C1-C10芳基、-CN、羟基、氨基、羧基、-CO-NH-SO 2-R g、-NH-SO 2-R g、-SO 2-NH-CO-R g、-OR g、-N(R g) 2-CO 2R g、-CON(R g) 2、-CONHCOR g、NR g-CO-N(R g) 2、-NR g-SO 2-N(R g) 2；r为1、2、3、4、5、6；s分别为0、1、2；R d、R e和R g各自独立地选自下组：H、取代或未取代的C 1-C 6烷基、取代或未取代的 C 3-C 10环烷基、取代或未取代的C 6-C 10芳基；选自下组：取代或未取代的5-12元杂芳基、取代或未取代的C6-C10芳基、取代或未取代的5-12元杂环基、取代或未取代的5-12元的C5-C12环基，其中，所述5-12元杂芳基和5-12元杂环基具有1-4个选自B，P，N，O，S的杂原子，其中，作为成环原子的P，N，O可以被氧代且一个或多个成环的碳原子可以替换为羰基；
为选自下组的环形成的二价基团：
其中，所述的环的成键位置可以为N或C；
R 1、R 2、R 2'和R 4各自独立地选自下组：H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、氧代(即＝O)、＝NRf、-CN、羟基、NRdRe(例如氨基)、取代或未取代的C1-C6胺基、取代或未取代的-(C1-C6亚烷基)-NH-(C1-C6亚烷基)、羧基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个杂原子的5-12元杂芳基、取代或未取代的具有1-4个杂原子的5-12元杂环基，取代或未取代的取代或未取代的
取代或未取代的
其中，R b、R c和R d各自独立地选自下组：H、取代或未取代的C 1-C 8烷基；或所述的R b和R c与相邻的N原子共同构成取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基，或所述的Rb和Rc与相邻的N原子共同构成取代或未取代的4-10元环酰胺，所述取代基包括但不限于：羟基、羧基、巯基、氨基、F、C，其中，Rb、Rc和Rd的碳原子上的氢均可各自独立地被氘替换；或-(L 1a) r-(L 2a) s-(L 3a) s-；
R 3为无、H、取代或未取代的C1-C10烷基、
其中，w为0、1、2、3、4、5、6；所述的各个L 4独立地选自下组：取代或未取代的C1-C4亚烷基、-S-、-O-、NR f、-S(O)-、-S(O) 2-；优选为取代或未取代的C1-C4亚烷基；其中，取代或未取代的C1-C4亚烷基上碳原子上的氢均可各自独立地被氘替换，前提条件是各个L 4共同形成的结构是化学稳定的；其中，Rb、Rc和R d各自独立地选自下组：H、取代或未取代的C 1-C 8烷基；或所述的Rb和Rc与相邻的N原子共同构成取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素(包括-F、-Cl、-Br、-I)、-CH 2Cl、-CHCl 2、-CCl 3、-CH 2F、-CHF 2、-CF 3、氧代(＝O)、-CN、羟基、氨基、C1-C6烷胺基、羧基、-NHAc、
未取代或被一个或多个选自下组的取代基取代的选自下组的基团：C1-C6烷基、C1-C6烷氧基、C6-C10芳基、C3-C8环烷基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-10元杂环基；所述的取代基选自下组：卤素、羟基、羧基、氰基、C1-C6烷氧基、C1-C6烷胺基；
上述各式中，任一所述杂原子选自下组：B、P、N、S和O。 - 如权利要求1所述的化合物，或其光学异构体、水合物、溶剂合物，或其药学上可接受的盐，其特征在于，所述的环和/或
具有如下式IV所示的取代基：
其中，所述的各个L 4独立地选自下组：取代或未取代的C1-C4亚烷基、-S-、-O-、-NRa-、-S(O)-、-S(O) 2-；优选为取代或未取代的C1-C4亚烷基，其中，取代或未取代的C1-C4亚烷基上碳原子上的氢均可各自独立地被氘替换；前提条件是各个L 4共同形成的结构是化学稳定的；选自下组：取代或未取代的C5-C10环烷基、取代或未取代的具有1-3个选自B、P、N、S和O的杂原子的3-10元杂环基；优选地，所述的
为3-8元含氮杂环基或取代或未取代的4-10元环酰胺，其中，3-8元含氮杂环基取代或未取代的4-10元环酰胺基的成环碳原子上的氢均可各自独立被氘替换；；
各个R 5各自独立地选自下组：取代或未取代的C1-C6烷基、-CN、羟基、氨基、羧基、、-OR g、-N(R g) 2、-CO-NH-SO 2-R g、-NH-SO 2-R g、-SO 2-NH-CO-R g、-CO 2R g、-CON(R g) 2、CONHCOR g、NR g-CO-N(R g) 2、-NR g-SO2-N(R g) 2；R f和R g的定义如前所述，其中R f和R g的碳原子上的氢均可各自独立地被氘替换；其中，所述的取代基选自下组：卤素、羟基、羧基、氰基、C1-C6烷氧基。 - 如权利要求1所述的化合物，或其异构体、光学异构体、水合物、溶剂合物，或其药学上可接受的盐，其特征在于，所述的为如下式所示的结构：
其中，所述的环的成键位置可以为N或C。
- 如权利要求1所述的化合物，或其光学异构体、顺反异构体、水合物、溶剂合物，或其药学上可接受的盐，其特征在于，所述的化合物具有如下式所示的结构：
其中，R 5选自下组：-(L 1a) r-(L 2a) s-(L 3a) s；其中，各个L 1a各自独立地为选自下组的基团；化学键、取代或未取代的C 1-C 7亚烷基、取代或未取代的C2-C4亚烯基、取代或未取代的C2-C4亚炔基、-S-、-O-、取代或未取代的-NH-、-S(O)-、-S(O) 2-、L 2a选自下组：取代或未取代的C3-C8亚环烷基、取代或未取代的具有1-3个杂原子的3-10元亚杂环基；优选地，所述的亚杂环基至少含有一个N原子作为成环原子；L 3a选自下组：H、取代或未取代的C1-C10烷基、C1-C10芳基、-CN、羟基、氨基、羧基、-CO-NH-SO 2-R g、-NH-SO 2-R g、-SO 2-NH-CO-R g；r为1、2、3、4、5、6；s分别为0、1、2；其余各基团的定义如上文中所述。 - 如权利要求1所述的化合物，或其光学异构体、水合物、溶剂合物，或其药学上可接受的盐，其特征在于，所述的式I化合物选自式Id-1，Id-2和Id-3：
其中，各个基团的定义如权利要求1中所述，且R f、R 2、R 2’和R 1基团上的碳原子上的氢(如存在)和H 1～H 15均可各自独立被氘替换。 - 如权利要求1所述的化合物，或其光学异构体、顺反异构体、水合物、溶剂合物，或其药学上可接受的盐，其特征在于，所述的化合物选自下组：
- 一种如权利要求1所述的式I化合物的制备方法，其特征在于，所述的方法包括步骤：
(a)以中间体1和2为原料，通过合适的钯催化剂催化的Suzuki偶联反应得到目标产物I。 - 一种药物组合物，其特征在于，包含(1)如权利要求1所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物；(2)药学上可接受的载体。
- 如权利要求1所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物或如权利要求7所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗与PD-1/PD-L1的活性或表达量相关的疾病的药物组合物。
- 如权利要求9所述的用途，其特征在于，所述的药物组合物用于治疗选自下组的疾病：癌症、感染性疾病、自身免疫性疾病。
- 如权利要求9所述的用途，其特征在于，所述的癌症选自下组：胰腺癌，膀胱癌，结肠直肠癌，乳腺癌，前列腺癌，肾癌，肝细胞癌，肺癌，卵巢癌，宫颈癌，胃癌，食道癌，黑色素瘤，神经内分泌癌，中枢神经系统癌，脑癌，骨癌，软组织肉瘤，非小细胞肺癌癌症，小细胞肺癌或结肠癌、皮肤癌、肺癌、泌尿系肿瘤、血液肿瘤、胶质瘤、消化系统肿瘤、生殖系统肿瘤、淋巴瘤、神经系统肿瘤、脑瘤、头颈癌。
- 如权利要求9所述的用途，其特征在于，所述的感染性疾病选自细菌感染、病毒感染(如HBV、HCV)。
- 如权利要求9所述的用途，其特征在于，所述的自身免疫性疾病选自器官特异性自身免疫病、系统性自身免疫病。
- 如权利要求9所述的用途，其特征在于，所述的药物组合物还包括至少一种选自下组的治疗剂：纳武单抗，派姆单抗，atezolizumab，或伊匹单抗。
- 一种体外抑制PD-1/PD-L1相互作用的方法，其特征在于，包括步骤：将权利要求1-7任一所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物与PD-L1蛋白接触。
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| WO2018119266A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Benzooxazole derivatives as immunomodulators |
| WO2018119224A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Tetrahydro imidazo[4,5-c]pyridine derivatives as pd-l1 internalization inducers |
| WO2018195321A1 (en) * | 2017-04-20 | 2018-10-25 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
| WO2020014643A1 (en) * | 2018-07-13 | 2020-01-16 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
| CN111039942A (zh) * | 2018-10-12 | 2020-04-21 | 上海长森药业有限公司 | 含氮杂环类化合物，及其制备方法、药物组合物和应用 |
| WO2020086556A1 (en) * | 2018-10-24 | 2020-04-30 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
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| ES2899402T3 (es) * | 2016-12-22 | 2022-03-11 | Incyte Corp | Derivados de piridina como inmunomoduladores |
| CN112457329B (zh) * | 2019-09-09 | 2023-08-25 | 上海长森药业有限公司 | 芳香杂环衍生物作为免疫调节剂的制备及其应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018119266A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Benzooxazole derivatives as immunomodulators |
| WO2018119224A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Tetrahydro imidazo[4,5-c]pyridine derivatives as pd-l1 internalization inducers |
| WO2018195321A1 (en) * | 2017-04-20 | 2018-10-25 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
| WO2020014643A1 (en) * | 2018-07-13 | 2020-01-16 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
| CN111039942A (zh) * | 2018-10-12 | 2020-04-21 | 上海长森药业有限公司 | 含氮杂环类化合物，及其制备方法、药物组合物和应用 |
| WO2020086556A1 (en) * | 2018-10-24 | 2020-04-30 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
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