CN116903489A - Terphenyl compound, preparation method and application thereof - Google Patents
Terphenyl compound, preparation method and application thereof Download PDFInfo
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- CN116903489A CN116903489A CN202310865168.8A CN202310865168A CN116903489A CN 116903489 A CN116903489 A CN 116903489A CN 202310865168 A CN202310865168 A CN 202310865168A CN 116903489 A CN116903489 A CN 116903489A
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- -1 Terphenyl compound Chemical class 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 19
- 239000003054 catalyst Substances 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- 229910052763 palladium Inorganic materials 0.000 claims description 9
- 229940002612 prodrug Drugs 0.000 claims description 9
- 239000000651 prodrug Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 150000003335 secondary amines Chemical group 0.000 claims description 7
- 239000012269 PD-1/PD-L1 inhibitor Substances 0.000 claims description 6
- 229940121653 pd-1/pd-l1 inhibitor Drugs 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- DAHKMTOSYFBPOX-UHFFFAOYSA-N 1-bromo-3-iodo-2-methylbenzene Chemical compound CC1=C(Br)C=CC=C1I DAHKMTOSYFBPOX-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical group O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 abstract description 11
- 150000003384 small molecules Chemical class 0.000 abstract description 11
- 206010028980 Neoplasm Diseases 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 9
- 230000005764 inhibitory process Effects 0.000 abstract description 7
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 229940125644 antibody drug Drugs 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- VLRGXXKFHVJQOL-UHFFFAOYSA-N 3-chloropentane-2,4-dione Chemical compound CC(=O)C(Cl)C(C)=O VLRGXXKFHVJQOL-UHFFFAOYSA-N 0.000 description 3
- 108010074708 B7-H1 Antigen Proteins 0.000 description 3
- 102000008096 B7-H1 Antigen Human genes 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- UZZMGJHLDZLPGY-UHFFFAOYSA-N 1-bromo-2-methyl-3-phenylbenzene Chemical group CC1=C(Br)C=CC=C1C1=CC=CC=C1 UZZMGJHLDZLPGY-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- JEDPSOYOYVELLZ-UHFFFAOYSA-N COc1nc(OCc2cccc(c2C)-c2ccccc2)ccc1CNCCNC(C)=O Chemical compound COc1nc(OCc2cccc(c2C)-c2ccccc2)ccc1CNCCNC(C)=O JEDPSOYOYVELLZ-UHFFFAOYSA-N 0.000 description 2
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 238000003782 apoptosis assay Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000005522 programmed cell death Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- DHGPLNJITGVCSG-UHFFFAOYSA-N 4-bromo-2-chlorobenzaldehyde Chemical compound ClC1=CC(Br)=CC=C1C=O DHGPLNJITGVCSG-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 1
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 1
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 1
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 1
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- GEBLOQXLELCEEO-UHFFFAOYSA-N bis[(2-methylpropan-2-yl)oxy]-oxophosphanium Chemical compound CC(C)(C)O[P+](=O)OC(C)(C)C GEBLOQXLELCEEO-UHFFFAOYSA-N 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- DAKZISABEDGGSV-UHFFFAOYSA-N n-(2-aminoethyl)acetamide Chemical compound CC(=O)NCCN DAKZISABEDGGSV-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
Abstract
The invention relates to the technical field of medicines, in particular to a terphenyl compound, a preparation method and application thereof. Terphenyl compoundsComprising a compound of formula 1:wherein R is 1 Selected from H, R 2 Selected from halogen and C1-C6 alkyl; r is R 3 Selected from substituted secondary amine groups. The compound has good inhibition effect on PD-1/PD-1, can be used as a PD-1/PD-1 small molecule inhibitor, and then has the effect of treating tumors.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a terphenyl compound, a preparation method and application thereof.
Background
Cancer immunotherapy has progressed rapidly in recent years. Immune checkpoint inhibitors targeting Programmed cell-death receptor1 (PD-1) and Programmed cell-death ligand 1 (PD-L1) have achieved significant success in clinical applications in the tumor field. In the tumor microenvironment, the combination of PD-1 in tumor infiltrating lymphocytes and PD-L1 expressed on the surfaces of tumor cells can make tumors generate immune escape and promote the growth of the tumors. Currently, 15 antibody drugs targeting PD-1/PD-L1 are approved by the U.S. Food and Drug Administration (FDA) and by the national drug administration to the market, which includes 9 PD-1 monoclonal antibodies and 6 PD-L1 monoclonal antibodies. However, the inherent limitations of antibody drugs include poor tissue and tumor permeability, long half-life, poor oral bioavailability, expensive production costs, and immunogenicity, which severely hampers the effectiveness of immunotherapy. The small molecule inhibitor taking PD-1/PD-L1 as a target spot has been attracting more and more attention because of better pharmacokinetic characteristics and oral availability, and can be combined with antibody drugs or even directly replace the antibody drugs.
However, the development of PD-1/PD-L1 small molecule inhibitors is far behind monoclonal antibodies, and only a few small molecule inhibitors have entered clinical studies. Early due to lack of structural information of targets, reasonable design of PD-1/PD-L1 small molecule inhibitors is limited. Until 2015, hPD-1, hPD-L1 crystal complex structures were published, more and more patents directed to antibodies, cyclic peptides and small molecule inhibitors of PD-1 and PD-L1 were published, of which the most attractive is a class of 2-methyl-3-biphenyl derivatives disclosed by Bai Shi Midshurica (BMS). The Hoalk subject group researches find that the compounds can induce PD-L1 proteins to polymerize, and two PD-L1 monomers can form a cylindrical hydrophobic pocket, so that an easy patent medicine target is provided for the design of small molecular medicines. Therefore, small molecule inhibitors targeting PD-L1 are a hotspot for research. However, no small molecule inhibitors targeting PD-L1 have been approved for sale to date, which also suggests that the development of novel PD-1/PD-1 small molecule inhibitors remains a laborious task and is a clinically unmet need.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide a terphenyl compound, a preparation method and application thereof. The terphenyl compound provided by the embodiment of the invention has good inhibition effect on PD-1/PD-1, can be used as a PD-1/PD-1 small molecule inhibitor, and further has the effect of treating tumors.
The invention is realized in the following way:
in a first aspect, the present invention provides a terphenyl compound comprising a compound of formula 1:formula 1, wherein R 1 Selected from H, R 2 Selected from halogen and C1-C6 alkyl; r is R 3 Selected from substituted secondary amine groups.
In an alternative embodiment, R 2 Selected from any one of F, cl, br, I and C1-C3 alkyl.
In an alternative embodiment, R 2 Selected from any one of Cl, br, methyl and ethyl.
In an alternative embodiment, the substituted secondary amine group is selected fromWherein n represents any integer of 1 to 5, R 4 Selected from hydroxyl, acetamido, and piperazinone groups.
In an alternative embodiment, the terphenyl compound is selected from any one of the compounds represented by the following structural formulas:
in a second aspect, the present invention provides a method for preparing a terphenyl compound according to the foregoing embodiment, including: the synthesis was performed with reference to the following synthesis route:
in an alternative embodiment, the method comprises: in the step a, the molar ratio of 1-bromo-3-iodo-2-methylbenzene to phenylboronic acid is 1:1-2, the adopted catalyst is a palladium catalyst, the temperature is 80-100 ℃, and the time is 8-12 hours;
the conditions of step b include: the catalyst is palladium catalyst, the temperature is 70-90 ℃ and the time is 10-16 hours;
the conditions of step c include: the catalyst is palladium catalyst, the temperature is 80-100 ℃ and the time is 8-12 hours;
the step d comprises the following steps: the temperature is 20-30 ℃ and the time is more than 12 hours.
In a third aspect, the present invention provides a PD-1/PD-L1 inhibitor, which comprises a terphenyl compound according to the previous embodiment, a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
In a fourth aspect, the present invention provides an application of the terphenyl compound, the pharmaceutically acceptable salt, the hydrate, the solvent compound or the prodrug thereof according to the previous embodiment in preparing a PD-1/PD-L1 inhibitor.
In a fifth aspect, the present invention provides an application of the terphenyl compound, the pharmaceutically acceptable salt, the hydrate, the solvent compound or the prodrug thereof in preparing an anti-tumor drug.
The invention has the following beneficial effects: the terphenyl compound provided by the embodiment of the invention has good inhibition effect on PD-1/PD-L1, can be used as a PD-1/PD-1 small molecule inhibitor, and further has the effect of treating tumors.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The invention is trueEmbodiments provide terphenyl compounds including compounds of formula 1:formula 1, wherein R 1 Selected from H, R 2 Selected from halogen and C1-C6 alkyl; r is R 3 Selected from substituted secondary amine groups.
Specifically, R 2 Selected from any one of F, cl, br, I and C1-C3 alkyl. The C1-C6 alkyl group may be any of alkyl groups such as methyl, ethyl, n-propyl, isopropyl, tert-butyl, etc.
Substituted secondary amine groups selected fromWherein n represents any integer of 1 to 5, R 4 Selected from hydroxyl, acetamido, and piperazinone groups.
Specifically, the terphenyl compound is selected from any one of compounds shown in the following structural formulas:
further, the invention provides a preparation method of the terphenyl compound in the previous embodiment, which comprises the following steps: taking 1-bromo-3-iodo-2-methylbenzene and phenylboronic acid as starting materials, and carrying out 3-step Suzuki-Miyaura coupling reaction to obtain a key intermediate 4; intermediate 4 reacts with corresponding amine through Schiff base, and finally the target product is obtained through reduction.
The synthesis is carried out with specific reference to the following synthesis routes:
reagents and conditions in the synthetic route: (a) Phenylboronic acid, pd (PPh) 3 ) 4 Equal palladium catalyst, K 2 CO 3 Isocarbonates, organic solvents, such as toluene/water (v/v=2:1), nitrogen at 80-100 ℃,8-12h; (b) B (B) 2 Pin 2 ，PdCl 2 Palladium catalyst such as (dtbpf), CH 3 COOK, 70-90 ℃ under nitrogen, 10-16h; (c) Pd (PPh) 3 ) 4 Equal palladium catalyst, K 2 CO 3 Isocarbonates, organic solvents, such as toluene/water (V: v=2:1), nitrogen at 80-100 ℃,8-12h; (d) i-starting materials containing secondary amine groups, organic solvents, e.g. CH 2 Cl 2 /CH 3 OH (v/v=1:1), glacial acetic acid, room temperature, 2h; ii: boron-based substances such as NaCNBH 3 Overnight at normal temperature.
In a third aspect, the present invention provides a PD-1/PD-L1 inhibitor, which comprises a terphenyl compound according to the previous embodiment, a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
In a fourth aspect, the present invention provides an application of the terphenyl compound, the pharmaceutically acceptable salt, the hydrate, the solvent compound or the prodrug thereof according to the previous embodiment in preparing a PD-1/PD-L1 inhibitor.
In a fifth aspect, the present invention provides an application of the terphenyl compound, the pharmaceutically acceptable salt, the hydrate, the solvent compound or the prodrug thereof in preparing an anti-tumor drug.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
The embodiment of the invention provides a terphenyl compound, which has the following structural formula:
the embodiment also provides a synthesis method of the terphenyl compound, which comprises the following steps:
(1) Synthesis of 3-bromo-2-methyl-1, 1' -biphenyl
1-bromo-3-iodo-2-methylbenzene (1.18 g,4.0 mmol), phenylboronic acid (0.59 g,4.8 mmol) and tetrakis triphenylphosphine palladium (0.23 g,0.2 mmol) were dissolved in 30ml of a mixed solution of toluene and water (volume ratio 2:1), then potassium carbonate (1.1 g,8.0 mmol) was added to the mixture, reacted under nitrogen at 90℃for 9 hours,TLC detection reaction was complete. The reaction mixture was extracted three times with ethyl acetate (30 ml), and the organic phases were combined, washed 2 times with 5ml of water and 5ml of saturated brine, respectively, followed by anhydrous Na 2 SO 4 And (5) drying. After filtration, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.82g of a colorless liquid, yield 83.2%.
The product characterization data are as follows: 1 H NMR(400MHz，DMSO)δ7.86-7.61(m，3H)，7.48-7.37(m，4H)，7.21(t，J＝8.4Hz，1H)，2.31(s，3H)。
(2) Synthesis of 4, 5-tetramethyl-2- (2-methyl- [1,1' -biphenyl ] -3-yl) -1,3, 2-dioxaborane
3-bromo-2-methyl-1, 1 '-biphenyl (0.82 g,3.33 mmol), pinacol biborate (1.0 g,4.0 mmol) and 1,1' -bis (di-tert-butylphosphonate) ferrocene dichloropalladium (0.1 g,0.167 mmol) were dissolved in 15ml DMSO solution, followed by potassium acetate (0.962 g,9.8 mmol) and reacted at 80℃under nitrogen for 12h, TLC detection was complete. The reaction mixture was extracted three times with ethyl acetate (30 ml), and the organic phases were combined, washed twice with 5ml of water, 5ml of saturated brine, and then with anhydrous Na 2 SO 4 And (5) drying. After filtration, the solvent was removed under reduced pressure, and 0.645g of a colorless liquid was purified by silica gel column chromatography to obtain a residue, which was 66.5% in yield.
The product characterization data are as follows: 1 H NMR(400MHz，DMSO)δ7.92-7.60(m，4H)，7.49-7.45(m，3H)，7.15(dd，J＝7.4,1.7Hz，1H)，2.33(s，3H)，1.37(d，J＝8.0Hz，12H)。
(3) Synthesis of 3-chloro-2 '-methyl- [1,1':3', 1' -triphenyl ] -4-carbaldehyde
4, 5-tetramethyl-2- (2-methyl- [1,1' -biphenyl)]-3-yl) -1,3, 2-dioxaborane (0.645 g2.19 mmol), 4-bromo-2-chlorobenzaldehyde (0.41 g,1.9 mmol) and tetrakis triphenylphosphine palladium (0.11 g,0.095 mmol) were dissolved in 30ml toluene and water (volume ratio 2: 1) To the mixture was then added potassium carbonate (0.650 g,4.75 mmol) and the reaction was completed by TLC under nitrogen at 90℃for 12 h. The reaction mixture was extracted three times with ethyl acetate (30 ml), and the organic phases were combined, washed 2 times with 5ml of water and 5ml of saturated brine, respectively, followed byBy anhydrous Na 2 SO 4 And (5) drying. After filtration, the solvent was removed under reduced pressure to give a residue of 0.34g as a white solid purified by silica gel column chromatography in 58.5% yield.
The product characterization data are as follows: 1 H NMR(400MHz，DMSO)δ10.08(s，1H),8.46(d，J＝1.7Hz，1H)，7.98-7.60(m，4H),7.56-7.46(m，6H),2.31(s，3H)。
(4) Synthesis of N- (2- (((3-chloro-2 '-methyl- [1,1':3', 1' -triphenyl ] -4-yl) methyl) amino) ethyl) acetamide
3-chloro-2 '-methyl- [1,1':3', 1' -triphenyl ] -4-carbaldehyde (0.34 g,1.1 mmol), N-acetyl ethylenediamine (0.135 g,1.32 mmol) were dissolved in 10ml of a mixed solution of dichloromethane and methanol (volume ratio 1:1), followed by addition of 0.07ml of glacial acetic acid. After 2h at room temperature, sodium cyanoborohydride (0.242, 3.85 mmol) was added and the reaction was stirred overnight at room temperature, and the completion of the reaction was detected by TLC. The solvent was distilled off under reduced pressure, and the obtained residue was purified by a silica gel column to obtain 0.33g of a white solid, yield 76.6%.
The product characterization data are as follows: 1 H NMR(400MHz，DMSO)δ8.47(d，J＝1.8Hz，1H),7.71(d，J＝8.5Hz，2H)7.68-7.63(m，3H),7.52(t，J＝8.5Hz，1H)，7.49-7.45(m，3H),7.38(d，J＝8.4Hz，1H),4.06(s，2H)，3.48(t，J＝7.1Hz，2H)，2.82(t，J＝7.1Hz，2H)，2.23(s，3H)，1.86(s，3H)。
examples 2 to 6
The corresponding terphenyl compound was synthesized by the synthetic method of example 1, and the structure and characterization data of the prepared terphenyl compound were as follows:
example 2: 1 H NMR(400MHz，DMSO)δ8.21(d，J＝1.9Hz，1H),7.72(d，J＝8.5Hz，2H)7.68-7.63(m，3H),7.52(t，J＝8.5Hz，1H)，7.48-7.45(m，3H),7.36(d，J＝8..3Hz，1H),4.02(s，2H)，3.48(t，J＝7.1Hz，2H)，2.82(t，J＝7.1Hz，2H)，2.23(s，3H)，1.86(s，3H)。
example 3: 1 H NMR(400MHz，DMSO)δ8.47(d，J＝1.8Hz，1H),7.71(d，J＝8.5Hz，2H)7.64-7.61(m，3H),7.52(t，J＝8.5Hz，1H)，7.48-7.45(m，3H),7.38(d，J＝8..4Hz，1H),4.05(s，2H)，3.51(t，J＝6.7Hz，2H)，2.79(t，J＝6.7Hz，2H)，2.23(s，3H)。
example 4: 1 H NMR(400MHz，DMSO)δ8.21(d，J＝1.9Hz，1H),7.72-7.70(m，2H)7.65-7.61(m，3H),7.52(t，J＝8.5Hz，1H)，7.48-7.45(m，3H),7.36(d，J＝8.3Hz，1H),4.00(s，2H)，3.51(t，J＝6.7Hz，2H)，2.78(t，J＝6.7Hz，2H)，2.23(s，3H)。
example 5: 1 H NMR(400MHz，DMSO)δ8.47(d，J＝1.8Hz，1H),7.72-7.70(m，2H)7.65-7.61(m，3H),7.52(t，J＝8.5Hz，1H)，7.48-7.45(m，3H),7.38(d，J＝8.4Hz，1H),4.06(s，2H)，3.55(d，J＝15.8Hz，2H)，3.40-3.12(m，2H)，2.95-2.57(m，6H)，2.23(s，3H)。
example 6: 1 H NMR(400MHz，DMSO)δ8.21(d，J＝1.9Hz，1H),7.74-7.70(m，2H)7.65-7.61(m，3H),7.52(t，J＝8.5Hz，1H)，7.48-7.46(m，3H),7.36(d，J＝8.3Hz，1H),4.02(s，2H)，3.55(d，J＝15.8Hz，2H)，3.40-3.13(m，2H)，2.95-2.57(m，6H)，2.23(s，3H)。
detection example 1
Autodock Vina molecular docking experiments were performed on the following compounds, and the binding energy between the following compounds and PD-L1 proteins was examined, and the results are shown in Table 1.
TABLE 1
From Table 1, it is understood that the compounds of the examples of the present invention were modified to provide groups having reduced binding ability, which were unable to perform good binding, and thus were unable to effectively inhibit PD-1/PD-L1 binding.
Detection example 2
1. Test of Compounds for PD-1/PD-L1 inhibitory Activity
The in vivo antitumor activity of the partial compounds was tested using Homogeneous Time Resolved Fluorescence (HTRF) method. The terphenyl derivative provided by the embodiment of the invention is tested for the inhibition effect on PD-1/PD-L1 by using an HTRF PD-1/PD-L1binding assay kit kit developed by Cisbio company according to the operation of a specification.
The experimental process comprises the following steps: in 96-well plate, adding 2 μl of diluent or target compound diluted with diluent, adding 4 μl of PD-1 protein and 4 μl of PD-L1 protein, incubating at room temperature for 15min, and adding 10 μl of anti-Tag1-Eu 3+ And anti-Tag2-XL665, fluorescence signals at 665nm and 620nm were detected after incubation for 1h at room temperature. HRTR rate= (665 nm/620 nm) ×10 4 . Each compound was assayed at 8 concentrations of 3 secondary wells per concentration. Then calculate the inhibition rate and IC 50 Experimental data are shown in table 2.
Inhibitory Activity of the Compounds of Table 2 on PD-1/PD-L1
| Compounds of formula (I) | IC 50 (nM) |
| Example 1 | 7.3 |
| Example 2 | 6.8 |
| Example 3 | 15.4 |
| Example 4 | 13.1 |
| Example 5 | 4.5 |
| Example 6 | 2.5 |
| BMS202 | 24.3 |
According to Table 2, the inhibition effect of the terphenyl derivative provided by the embodiment of the invention on PD-1/PD-L1 is measured according to a standard operation procedure by adopting the HTRF technology, and the result shows that the terphenyl derivative provided by the embodiments 1-6 of the invention has an obvious inhibition effect on PD-1/PD-L1 by taking the compound BMS202 as a reference. The compounds provided by the embodiments of the present invention are useful for the treatment of immune-based disorders such as hepatitis, HIV and tumors.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A terphenyl compound characterized by comprising a compound represented by formula 1:
wherein R is 1 Selected from H, R 2 Selected from halogen and C1-C6 alkyl; r is R 3 Selected from substituted secondary amine groups.
2. The terphenyl compound of claim 1, wherein R 2 Selected from any one of F, cl, br, I and C1-C3 alkyl.
3. The terphenyl compound of claim 2, wherein R 2 Selected from any one of Cl, br, methyl and ethyl.
4. The terphenyl compound of claim 1, wherein the substituted secondary amine group is selected from the group consisting ofWherein n represents any integer of 1 to 5, R 4 Selected from hydroxyl, acetamido, and piperazinone groups.
5. The terphenyl compound according to claim 1, wherein the terphenyl compound is selected from any one of the compounds represented by the following structural formulas:
6. a method for preparing the terphenyl compound of claim 1, comprising: the synthesis was performed with reference to the following synthesis route:
7. the method of manufacturing according to claim 6, comprising: in the step a, the molar ratio of 1-bromo-3-iodo-2-methylbenzene to phenylboronic acid is 1:1-2, the adopted catalyst is a palladium catalyst, the temperature is 80-100 ℃, and the time is 8-12 hours;
the conditions of step b include: the catalyst is palladium catalyst, the temperature is 70-90 ℃ and the time is 10-16 hours;
the conditions of step c include: the catalyst is palladium catalyst, the temperature is 80-100 ℃ and the time is 8-12 hours;
the step d comprises the following steps: the temperature is 20-30 ℃ and the time is more than 12 hours.
8. A PD-1/PD-L1 inhibitor, comprising the terphenyl compound of claim 1, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
9. Use of a terphenyl compound of claim 1, a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, in the preparation of a PD-1/PD-L1 inhibitor.
10. Use of a terphenyl compound of claim 1, a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, in the preparation of an anti-neoplastic drug.
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