WO2022242322A1 - 邻苯二甲酰亚胺类化合物、制备方法和应用 - Google Patents
邻苯二甲酰亚胺类化合物、制备方法和应用 Download PDFInfo
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- WO2022242322A1 WO2022242322A1 PCT/CN2022/083784 CN2022083784W WO2022242322A1 WO 2022242322 A1 WO2022242322 A1 WO 2022242322A1 CN 2022083784 W CN2022083784 W CN 2022083784W WO 2022242322 A1 WO2022242322 A1 WO 2022242322A1
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- compound
- alkyl
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- nmr
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- -1 Phthalimide compound Chemical class 0.000 title claims abstract description 102
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
- 229910052799 carbon Inorganic materials 0.000 claims description 27
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- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 16
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Chemical group 0.000 claims description 2
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- 125000003118 aryl group Chemical group 0.000 description 13
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- LYHNPONZXOVLGL-UHFFFAOYSA-N N#CC1=CC=CC(OC(C=C2C(N3C4=CC=CC(C5=CC=CC=C5)=C4F)=O)=C(CNC4CCOCC4)C=C2C3=O)=C1 Chemical compound N#CC1=CC=CC(OC(C=C2C(N3C4=CC=CC(C5=CC=CC=C5)=C4F)=O)=C(CNC4CCOCC4)C=C2C3=O)=C1 LYHNPONZXOVLGL-UHFFFAOYSA-N 0.000 description 1
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N N-methylaminoacetic acid Natural products C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 1
- 239000012269 PD-1/PD-L1 inhibitor Substances 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- KDSYNTPPPISIJB-UHFFFAOYSA-N [3-[[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxymethyl]phenyl]-(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone Chemical compound NCc1cc(OCc2cccc(c2)C(=O)N2CC(O)C(F)C2)nc(c1)C(F)(F)F KDSYNTPPPISIJB-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- GFZWHAAOIVMHOI-UHFFFAOYSA-N azetidine-3-carboxylic acid Chemical compound OC(=O)C1CNC1 GFZWHAAOIVMHOI-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 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
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 208000002409 gliosarcoma Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000004995 haloalkylthio group Chemical group 0.000 description 1
- 125000005347 halocycloalkyl group Chemical group 0.000 description 1
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XPXMKIXDFWLRAA-UHFFFAOYSA-N hydrazinide Chemical compound [NH-]N XPXMKIXDFWLRAA-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000005965 immune activity Effects 0.000 description 1
- 229940126546 immune checkpoint molecule Drugs 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000013101 initial test Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229940125645 monoclonal antibody drug Drugs 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 229940121653 pd-1/pd-l1 inhibitor Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- MYKMOIQAHCMLIR-UHFFFAOYSA-N tert-butyl 2-(methylamino)acetate Chemical compound CNCC(=O)OC(C)(C)C MYKMOIQAHCMLIR-UHFFFAOYSA-N 0.000 description 1
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- the invention relates to the field of medicinal chemistry, in particular to a phthalimide compound, a preparation method and an application.
- Immune checkpoints are a series of inhibitory signaling pathways in the immune system. Under normal circumstances, the immune system can regulate T cells through immune checkpoints to prevent their excessive activation from attacking normal somatic cells. It plays an important role in the prevention and control of autoimmune reactions, and can affect the timing and intensity of immune responses, thereby minimizing tissue damage. For normal humans, immune checkpoints can protect the body from self-injury, but by stealing this program, tumor cells can activate immune checkpoints and inhibit the immune activity of T cells, thereby achieving the purpose of immune escape and avoid being attacked by T cells. Identify and kill.
- tumor-related immune checkpoint molecules have been discovered so far, including PD-1, CTLA4, Tim3, and LAG3, among which PD-1 and CTLA4 are the most studied. If the activity of PD-1 can be temporarily inhibited, the activity of T cells can be reactivated, allowing them to re-recognize and kill tumor cells.
- PD-1/PD-L1-based immunotherapy has marketed macromolecule drugs, including Bps-Myers Squibb’s Nivolumab, Merck’s Pembrolizumab, Roche’s Atezolizumab, and AstraZeneca’s Durvaluman.
- Nivolumab and Pembrolizumab have great medicinal and market value.
- small-molecule drugs Compared with macromolecular monoclonal antibody drugs, small-molecule drugs have stronger membrane permeability, can be administered orally, and often have more Good bioavailability and pharmacokinetic parameters, low cost is an important advantage, so the rapid development of small molecule PD-1/PD-L1 inhibitors with good pharmacological activity is of great necessity.
- the present invention aims at the problems existing in the prior art, and the present invention provides a phthalimide compound, which has obvious inhibitory effect on PD-1/PD-L1 protein-protein interaction, and thus can be used in Inhibitors with PD-1/PD-L1 inhibitory activity are prepared and used as immune checkpoint inhibitors for immunotherapy of tumors.
- the invention also provides a preparation method of the phthalimide compound and its application in the preparation of medicines.
- R 1 and R 3 are H, or R 1 , R 2 or R 3 are respectively selected from: halogen, amino, C 1 -C 8 alkyl, -(CH 2 ) m CHO, -(CH 2 ) m OH, - (CH 2 ) m C(O)OH, -(CH 2 ) m C(O)NR 9 R 10 , -(CH 2 ) m NR 9 R 10 , -(CH 2 ) m C(O)C 1 - C 4 or -OR 21
- n 0, 1, 2, 3 or 4;
- R 9 is selected from: H, C 1 -C 4 alkyl or benzyl
- R is selected from any of the following:
- t 0, 1, 2, 3 or 4;
- R 11 is selected from: H, C 1 -C 4 alkyl or benzyl
- R 12 is selected from: H, C 1 -C 4 alkyl or benzyl
- R 13 is selected from: H, C 1 -C 4 alkyl or benzyl
- R 14 is selected from: H, C 1 -C 4 alkyl or benzyl
- R 15 is selected from: H, C 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl or benzyl;
- R9 and R10 together with the N atom to which they are attached form a ring selected from any of the following:
- s 0, 1 or 2;
- p 1, 2 or 3;
- Q is selected from: S, O, -NH-, -N(CH 3 )-, -N(CH(CH 3 ) 2 )-, -N((CH 2 ) 2 OH)- or -CH(R 20a ) -;
- R 20a is selected from: H, -OH, hydroxyl substituted C 1 -C 3 alkyl or carboxyl;
- R 16 is selected from: hydrogen, -OH, carboxyl, hydroxyl substituted C 1 -C 4 alkyl or -C(O)NHSO 2 R 19 ;
- R 17 is selected from: hydrogen, -OH, carboxyl, hydroxyl substituted C 1 -C 4 alkyl, -CHO or -C(O)NHSO 2 R 19 ;
- R 18 is selected from: C 1 -C 4 alkoxycarbonyl, halogen, C 1 -C 6 alkyl, carboxyl, amido, -OH, C 1 -C 4 alkyl substituted by hydroxyl, -NR a R b or benzene Oxycarbonyl, wherein the phenyl of phenoxycarbonyl is optionally replaced by halogen, -OH, -CN, -NO 2 , -NH 2 , -CF 3 , -CF 2 CF 3 , -OCF 3 , -OCF 2 CF 3.
- R a and R b are each independently selected from: H, C 1 -C 4 Alkoxycarbonyl or C 1 -C 4 alkylcarbonyl;
- R 19 is selected from: -CF 3 , cyclopropyl, C 1 -C 4 alkyl, dimethylamino or methyl-substituted imidazolyl;
- the R 21 is selected from: C 1 -C 8 alkyl, C 1 -C 4 alkoxy, X substituted C 1 -C 8 alkyl, heterocycloalkyl or -(CH) n Ar, wherein, X Selected from halogen, -OH, amino, carboxyl, amido, morpholinyl, piperidinyl, piperazinyl, tetrahydropyrrolyl or N,N-dimethylamino, n is 1-8, Ar is substituted or Unsubstituted aryl or heteroaryl; the substituted or unsubstituted aryl or heteroaryl is substituted by the following 1-3 independent substituents: C 1 -C 4 alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylsulfonyl, hydroxy-substituted C 1 -C 4 alkyl, halogen, -CN, -
- R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from: H, halogen, -CN, -NO 2 , -NH 2 , -OH, -CF 3 , -CF 2 CF 3 , -OCF 3 or -OCF 2 CF 3 , -RC , -OR C , -SR C , -S(O) RC , -S(O) 2 R C , -C (O) RC , -C(O) OH, -C(O)OR C , -OC(O)R C , -NHR C , -N(R C ) 2 , -C(O)NH 2 , -C(O)NHR C , -C(O )N(R C ) 2 , -NH(CO)R C , -NRc(CO)R C , -NH(CO)OR C , -NR C (CO)OR C ,
- R C is selected from: phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, substituted or unsubstituted C 1 -C 4 alkyl, alkenyl or alkynyl;
- each two of R 4 , R 5 , R 6 and R 7 together with the atoms to which they are attached form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted ring alkane ring, substituted or unsubstituted heterocycloalkane ring or substituted or unsubstituted heterocycloalkene ring;
- W is selected from: halogen, -CN, -NO 2 , -NH 2 , -OH, C 1 -C 8 alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, haloalkyl, haloalkane Oxy, haloalkylthio, halocycloalkyl or heterocycloalkyl;
- R 2 is -CH 2 NHCH 2 CH 3 OH
- W is C 1 -C 8 alkyl or -CN
- R 1 and R 3 are H.
- said R 1 and R 3 are H, or R 1 , R 2 or R 3 are respectively selected from: halogen, C 1 -C 4 alkyl, -(CH 2 ) m CHO, -(CH 2 ) m OH, -(CH 2 ) m C(O)OH, -(CH 2 ) m C(O)NR 9 R 10 , -(CH 2 ) m NR 9 R 10 , -(CH 2 ) m C(O) C 1 -C 4 or -OR 21 ;
- n 0, 1, 2, 3 or 4;
- R 9 is selected from: H or (C 1 -C 3 ) alkyl
- t 0, 1 or 2;
- R 11 is selected from H, C 1 -C 3 alkyl or benzyl
- R 12 is selected from H, C 1 -C 3 alkyl
- R 13 is selected from H, C 1 -C 3 alkyl
- R 15 is selected from H, C 1 -C 3 alkyl, C 1 -C 3 alkoxycarbonyl;
- R9 and R10 together with the N atom to which they are attached form a ring selected from any of the following:
- s 0, 1 or 2;
- p 1, 2 or 3;
- Q is selected from: S, O, -NH-, -NCH 3 -, -NCH(CH 3 ) 2 - or -CHR 20a -;
- R 20a is selected from: H, OH, hydroxyl substituted C 1 -C 3 alkyl or carboxyl;
- R 16 is selected from: hydrogen, -OH, carboxyl, hydroxyl substituted C 1 -C 3 alkyl or -C(O)NHSO 2 R 19 ;
- R 17 is selected from: hydrogen, -OH, carboxyl, hydroxyl substituted C 1 -C 3 alkyl or -C(O)NHSO 2 R 19 ;
- R 18 is selected from: C 1 -C 4 alkoxycarbonyl, halogen, C 1 -C 3 alkyl, carboxyl, amido, -OH, C 1 -C 4 alkyl substituted by hydroxy, NR a R b or phenoxy ylcarbonyl, wherein the phenyl of phenoxycarbonyl is optionally replaced by halogen, -OH, -CN, -NO 2 , -NH 2 , -CF 3 , -CF 2 CF 3 , -OCF 3 , -OCF 2 CF 3 , -SO 2 NH 2 , -C(O)OH, -C(O)NH 2 or -NHC(O)NH 2 are substituted, R a and R b are each independently selected from: H, C 1 -C 4 alkane Oxycarbonyl or C 1 -C 4 alkylcarbonyl;
- R 19 is selected from C 1 -C 3 alkyl
- the R 21 is selected from C 1 -C 4 alkyl, C 1 -C 3 alkoxy, X substituted C 1 -C 4 alkyl, heterocycloalkyl or -(CH) n Ar; the X is selected from From halogen, -OH, amino, carboxyl, said n is 1, Ar is substituted or unsubstituted aryl or heteroaryl, said substituted or unsubstituted aryl or heteroaryl is replaced by the following 1-3 Substituted by independent substituents: halogen, -CN, -NO 2 , -NH 2 , -OH, -CF 3 , -CF 2 CF 3 , -OCF 3 , -OCF 2 CF 3 , carboxyl, amido;
- R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from: H , halogen, -CN, -NO 2 , -NH 2 , -OH, -CF 3 , -RC , -OR C , -SR C , -S(O)R C , -S(O) 2 R C , -C(O)R C , -C(O)OH, -C(O)OR C , -OC(O)R C , -NHR C , -N(R C ) 2 , -C(O)NH 2 , -C(O)NHR C , -NH(CO)R C , -NH(CO)OR C , -NH(CO )NH 2 , -SO 2 NH 2 , -SO 2 NHR C , -NHSO 2 R C , -NR C SO 2 R C ;
- R C is selected from: phenyl, heteroaryl, substituted or unsubstituted C 1 -C 4 alkyl, alkenyl or alkynyl;
- each two of R 4 , R 5 , R 6 and R 7 together with the atoms to which they are attached form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted ring alkane ring, substituted or unsubstituted heterocycloalkane ring or substituted or unsubstituted heterocycloalkene ring;
- W is selected from: halogen, -CN or C 1 -C 4 alkyl, C 1 -C 4 haloalkyl.
- R 1 or R 3 is H, or R 1 , R 2 or R 3 is selected from the following substituents:
- the W is selected from: halogen, C 1 -C 3 alkyl, -CN, -CF 3 , -CF 2 CF 3 , -OCF 3 , -OCF 2 CF 3 ;
- R 1 is H or -(CH2) m NR 9 R 10 , m is 0, 1, 2, 3 or 4, R 9 and R 10 together with the N atoms they are connected to form a ring as shown below:
- R 18 is selected from: C 1 -C 4 alkoxycarbonyl, halogen, C 1 -C 4 alkyl, carboxyl, amido, -OH, hydroxyl substituted C 1 -C 4 alkyl;
- the R2 is selected from the following substituents:
- the R3 is selected from the following substituents:
- the R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from: H, halogen, -CN, -NO 2 , -NH 2 , -OH, -CF 3 , -R C , -OR C , -SR C , -S(O)R C , -S(O) 2 R C , -C(O)R C , -C(O)OH, -C(O)OR C , -OC(O )R C , -NHR C , -N(R C ) 2 , -C(O)NH 2 , -C(O)NHR C , -NH(CO)R C , -NH(CO)OR C , -NH (CO)NH 2 , -SO 2 NH 2 , -SO 2 NHR C , -NHSO 2 R C , -NR C SO 2 R C ;
- R C is selected from: phenyl, heteroaryl, substituted or unsubstituted C 1 -C 4 alkyl, alkenyl or alkynyl;
- each two of R 4 , R 5 , R 6 and R 7 together with the atoms to which they are attached form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted ring alkane ring, substituted or unsubstituted heterocycloalkane ring, or substituted or unsubstituted heterocycloalkene ring;
- R2 is The W is -CN, and R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are H.
- the phthalimide compounds of the present invention are as follows:
- the W is selected from: halogen, C 1 -C 3 alkyl, -CN;
- the R 1 is H
- the R2 is a first styl styl styl styl styl styl styl styl styl styl styl styl styl styl styl styl styl styl styl styl styl
- the R3 is selected from the following substituents:
- R 4 , R 5 , R 6 , R 7 are independently selected from H, phenyl or C 1 -C 4 alkyl;
- R8 is H.
- R 4 , R 5 , R 6 , and R 7 are independently selected from H and phenyl;
- the present invention further provides the preparation method of above-mentioned phthalimide compound, comprises the following steps:
- step (b) the intermediate obtained in step (a) and the substituted benzomaleic anhydride are used as a solvent to prepare a phthalimide intermediate in glacial acetic acid;
- step (c) the phthalimide intermediate obtained in step (b) is condensed with Br-R 21 or HNR 9 R 10 to generate the compound shown in formula (I); or the phthalimide intermediate obtained in step (b) After the phthalimide intermediate undergoes a redox reaction, it undergoes an ammoniation reaction with an amine compound to obtain a compound shown in formula (I).
- the 3-bromo-2-substituted aniline is preferably: 3-bromo-2-methylaniline or 3-bromo-2-cyanoaniline;
- the benzene, substituted benzene or heteroaryl ring boronic acid or boronic acid ester is preferably: phenylboronic acid;
- the substituted benzomaleic anhydride is preferably: 4-hydroxyphthalic acid
- the R 21 -Br is preferably: acetone bromide, 3-cyanobenzyl bromide, benzyl bromide, p-isopropylbenzyl bromide, 4-cyanobenzyl bromide.
- the 3-bromo-2-substituted aniline is preferably: 3-bromo-2-methylaniline or 3-bromo-2-cyanoaniline;
- the substituted benzene or heteroaromatic ring boronic acid or boronic acid ester is preferably: phenylboronic acid or benzo-1,4-dioxane-6-boronic acid;
- the substituted benzomaleic anhydride is preferably: 1,2,4-benzenetricarboxylic acid;
- the HNR 9 R 10 is preferably: ethanolamine, morpholine, N-isopropylpiperazine, N-acetylethylenediamine, L-tyrosine methyl ester or p-aminobenzoic acid methyl ester.
- intermediate 7 is prepared under the action of a reducing agent; preferably, the reducing agent is borane;
- intermediate 8 is prepared; preferably, the oxidizing agent is manganese dioxide or Dess-Martin oxidizing agent;
- the 3-bromo-2-substituted aniline is preferably: 3-bromo-2-methylaniline or 3-bromo-2-cyanoaniline;
- the substituted benzene or heteroaromatic ring boronic acid or boric acid ester is preferably: phenylboronic acid, benzo-1,4-dioxane-6-boronic acid
- the substituted benzomaleic anhydride is preferably: 1,2,4-benzenetricarboxylic acid, 5-bromo-1,2,4-benzenetricarboxylic acid;
- the amine compounds are preferably: ethanolamine, N-acetylethylenediamine, morpholine, N-isopropylpiperazine, L-serine ethyl ester hydrochloride, L-homoproline, L-proline Alcohol, L-proline, N-methyl-2-hydroxyethylamine, L-prolinamide, 3-bromo-2-methylaniline tetrahydropyran, L-serine ethyl ester hydrochloride, D- Alanine ethyl ester hydrochloride, L-alanine ethyl ester hydrochloride, N-tert-butoxycarbonyl-1,2-ethylenediamine, N-(2-aminoethyl)methanesulfonamide hydrochloride , Glycine tert-butyl ester, L-serine tert-butyl ester, L-threonine tert-butyl ester, N-acety
- the 3-bromo-2-substituted aniline is preferably: 3-bromo-2-methylaniline, 3-bromo-2-cyanoaniline, 3-bromo-2-fluoroaniline, 3-bromo-2-chloroaniline ;
- the substituted benzene or heteroaromatic ring boronic acid or boronic acid ester is preferably: phenylboronic acid, benzo-1,4-dioxane-6-boronic acid;
- the substituted benzomaleic anhydride is preferably: 4-hydroxyphthalic acid
- the R 21 -Br or R 21 -I is preferably: methyl iodide, methyl bromide, 3-cyanobenzyl bromide, 2-cyanobenzyl bromide, 4-cyanobenzyl bromide, benzyl bromide, p-iso Propylbenzyl bromide;
- the amine compounds are preferably: N-acetylethylenediamine, L-proline, L-serine tert-butyl ester, glycine tert-butyl ester, L-threonine tert-butyl ester, glycine tert-butyl ester, L -Alanine tert-butyl ester, L-homoproline, D-serine ethyl ester hydrochloride, glycine methyl ester, 4-aminotetrahydropyran, L-prolinamide, L-prolinol, (R )-3-pyrrolidinol, N-methyl-2-hydroxyethylamine, 2-methylalanine, 3-carboxycyclobutylamine, 3-hydroxyazetidine hydrochloride, N-tert-butyl Oxycarbonyl-1,2-ethylenediamine, N,N-dimethylethylenediamine, L-phenylalanine tert-but
- intermediate 13 is used as a raw material, and intermediate 14 is prepared under the action of a reducing agent; preferably, the reducing agent is borane;
- intermediate 14 (d) using intermediate 14 as a raw material, under the action of an oxidizing agent, to prepare intermediate 10;
- the oxidizing agent is manganese dioxide or Dess-Martin oxidizing agent;
- the 3-bromo-2-substituted aniline is preferably: 3-bromo-2-methylaniline or 3-bromo-2-cyanoaniline;
- the substituted benzene or heteroaromatic ring boronic acid or boronic acid ester is preferably: phenylboronic acid or benzo-1,4-dioxane-6-boronic acid;
- the substituted benzomaleic anhydride is preferably: 5-hydroxy-1,2,4-benzenetricarboxylic acid;
- the R 21 -Br or R 21 -I is preferably: methyl iodide, methyl bromide, 3-cyanobenzyl bromide, 2-cyanobenzyl bromide, 4-cyanobenzyl bromide, benzyl bromide or p-iso Propylbenzyl bromide;
- the amine compounds are preferably: ethanolamine, N-acetylethylenediamine, L-proline, L-serine tert-butyl ester, glycine tert-butyl ester, L-threonine tert-butyl ester, glycine tert-butyl ester , L-alanine tert-butyl ester, L-homoproline, D-serine ethyl ester hydrochloride, glycine methyl ester, 4-aminotetrahydropyran, L-prolineamide, L-prolinol, (R)-3-pyrrolidinol, N-methyl-2-hydroxyethylamine, 2-methylalanine, 3-carboxycyclobutylamine, 3-hydroxyazetidine hydrochloride, N- tert-butoxycarbonyl-1,2-ethylenediamine, N,N-dimethylethylenediamine, L-phenylalanine tert-but
- phthalimide compounds of the present invention their pharmaceutically acceptable salts, racemates, tautomers and stereoisomers, metabolites, metabolic precursors, prodrugs or solvates have Application of inhibitors of PD-1/PD-L1 inhibitory activity.
- the diseases treated by the inhibitors include autoimmune diseases, cancer and infectious diseases.
- the cancer is selected from lung cancer, melanoma, blood tumor, gliosarcoma, digestive system tumor, breast cancer, prostate cancer, lymphoma, nervous system tumor, urinary system tumor, skin cancer;
- the infectious disease is selected from From bacterial and viral infections;
- the autoimmune disease is selected from organ-specific and systemic autoimmune diseases.
- the phthalimide compounds of the present invention can be used as pharmaceutically acceptable salts.
- the salt can be a salt of at least one of the following acids, including inorganic acids and organic acid salts.
- the inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid
- the organic acids include formic acid, acetic acid, trichloroacetic acid, Propionic, butyric, maleic, p-toluenesulfonic, malic, malonic, cinnamic, citric, fumaric, camphoric, digluconic, aspartic, and tartaric acids.
- the present invention also provides a pharmaceutical composition for tumor immunotherapy, which contains a therapeutically effective amount of the phthalimide compound represented by the formula (I) as described in the present invention or its pharmaceutically acceptable Salts, tautomers and stereoisomers, racemates, metabolites, metabolic precursors, prodrugs or solvates of the active ingredients and pharmaceutically acceptable carriers.
- Optionally mixable carriers may vary depending on dosage form, administration form and the like. Examples of carriers include excipients, binders, disintegrants, lubricants, correctives, fragrances, colorants, sweeteners and the like.
- the pharmaceutical composition can be in the form of capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories and patches, etc.
- alkyl can be used alone or in combination, such as “alkylthio” or “haloalkyl”
- C 1 -C 8 alkyl includes straight Chain or branched chain alkyl groups such as methyl, ethyl, n-propyl, isopropyl, or different butyl groups including n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl or hexyl and their Isomers, heptane and its isomers, octane and its isomers.
- halogen which may be used alone or in a combination such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine, and, when used in a combination such as “haloalkyl”, says The alkyl group may be partially or completely substituted with halogen atoms, and the halogen atoms may be the same or different.
- haloalkyl groups include ClCHCH 3 , F 3 C, ClCH 2 , CF 3 CH 2 and CF 3 CCl 2 , others include 1,2-dichloro-n-propyl, 1-fluoro-n-butyl, perfluoro n-pentyl etc.
- Haloalkenyl “Haloalkenyl”, “haloalkynyl” and “haloalkoxy” are defined similarly to “haloalkyl”.
- haloalkynyl include HC ⁇ CCHCl , CF3C ⁇ C , CCl3C ⁇ and FCH2C ⁇ CCH2 .
- haloalkoxy include CF3O , CCl3CH2O , HCF2CH2CH2O and CF3CH2O .
- Heterocycle or “heterocycle system” means a ring or ring system in which at least one ring atom is other than carbon and contains 1 to 4 heteroatoms respectively selected from nitrogen, oxygen and sulfur, provided that each heterocycle Containing not more than 4 nitrogen, not more than 2 oxygen and not more than 2 sulfur atoms, the heterocyclic ring can be attached to any available carbon or nitrogen by substitution of hydrogen on said carbon or nitrogen atom.
- aromatic ring means a fully unsaturated carbocyclic or heterocyclic ring, wherein the polycyclic ring system is aromatic (here aromatic means that Hückel's rules are satisfied for the ring system).
- heteromatic ring means a completely aromatic ring in which at least one ring atom is other than carbon and contains 1 to 4 heteroatoms respectively selected from nitrogen, oxygen and sulfur, provided that each heterocycle contains not more than More than 4 nitrogens, no more than 2 oxygens, no more than 2 sulfurs (aromatic here refers to satisfying the Hückel rule).
- a heterocycle can be attached to any available carbon or nitrogen by substituting a hydrogen on said carbon or nitrogen.
- aromatic heterocyclic system includes fully aromatic heterocyclic rings and heterobicyclic rings in which at least one ring of the polycyclic ring system is aromatic (here aromatic means fulfilling Hückel's rule).
- heterocyclic ring system encompasses a ring system consisting of 2 fused rings in which at least one ring atom is other than carbon, as defined above, and may be aromatic or non-aromatic.
- the phthalimide compound of the present invention has a novel chemical structure, and has high inhibitory activity on PD-1/PD-L1 interaction in vitro studies, and can be used for various diseases such as cancer treatment and prevention.
- A-1, A-2 and B-3 refers to Example 1 and Example 8.
- Example 35 tert-butyl(2-((2-(2-methyl[1,1′-biphenyl]-3-yl)-1,3-dioxoisoindoline-5yl)methyl ) amino) ethyl) carbamate
- Example 36 5-(((2-aminoethyl)amino)methyl)-2-(2-methyl-[1,1′-biphenyl]-3-yl)isoindole-1,3 - dione
- Example 48 (6-methoxy-2-(2-methyl-[1,1′-biphenyl]-3-yl)-1,3-dioxoisoindoline-5-yl)methanol base)-L-serine tert-butyl ester
- Example 50 Referring to the method of Example 50, the L-serine tert-butyl ester in the example was replaced by glycine tert-butyl ester to obtain compound I-52: 1 H NMR (400MHz, DMSO) ⁇ 7.99 (s, 1H), 7.56 (s,1H),7.48(m,2H),7.43–7.34(m,6H),4.01(s,3H),3.91(s,2H),3.11(s,2H),1.98(s,3H). MS(ESI): m/z 431[M+H] + .
- Example 54 3-(((6-(((2-hydroxyethyl)amino)methyl)-2-(2-methyl[1,1′-biphenyl]-3-yl)-1, 3-Dioxoisoindoxyl-5-yl)oxy)methyl)benzonitrile
- Example 58 (6-((3-cyanophenyl)oxy)-2-(2-methyl-[1,1′-biphenyl]-3-yl)-1,3-dioxinoindol Indoline-5-yl)methyl)-glycine methyl ester
- Example 62 6-((3-cyanophenyl)oxy)-2-(2-methyl[1,1′-biphenyl]-3-yl)-5-(((tetrahydro-2H- Pyran-4-yl)amino)methyl)isoindole-1,3-dione
- Example 65 3-((6-(((2-Hydroxyethyl)(methyl)amino)methyl)-2-(2-methyl-[1,1'-biphenyl]-3-yl )-1,3-dioxoisoindolin-5-yl)oxy)methyl)benzonitrile
- Example 66 2-(((6-((3-cyanophenyl)oxy)-2-(2-methyl-[1,1′-biphenyl]-3-yl)-1,3- Dioxindolin-5-yl)methyl)amino)-2-methylpropionic acid
- Example 68 3-(((6-((3-Hydroxyazetidin-1-yl)methyl)-2-(2-methyl-[1,1′-biphenyl]-3-yl) -1,3-Dioxoisoindolin-5-yl)oxy)methyl)benzonitrile
- Example 70 3-((6-(((2-(Dimethylamino)ethyl)amino)methyl)-2-(2-methyl-[1,1′-biphenyl]-3-yl )-1,3-dioxoisoindolin-5-yl)oxy)methyl)benzonitrile
- Example 73 4-(((6-(((2-hydroxyethyl)amino)methyl)-2-(2-methyl[1,1′-biphenyl]-3-yl)-1, 3-Dioxoisoindolin-5-yl)oxy)methyl)benzonitrile
- Example 76 ((6-((3-cyanophenyl)oxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dioxoiso Indolin-5-yl)methyl)glycine tert-butyl ester
- Example 77 ((6-((3-cyanophenyl)oxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dioxoiso Indolin-5-yl)methyl)glycine
- Example 78 (6-((3-cyanophenyl)oxy)-2-(2-methyl-[1,1′-biphenyl]-3-yl)-1,3-dioxinoindol Indoline-5-yl)methyl)-L-alanine tert-butyl ester
- Example 80 (6-((3-cyanophenyl)oxy)-2-(2-methyl-[1,1′-biphenyl]-3-yl)-1,3-dioxinoindol Indoline-5-yl)methyl)-L-serine tert-butyl ester
- Example 82 (6-((3-cyanophenyl)oxy)-2-(2-methyl-[1,1′-biphenyl]-3-yl)-1,3-dioxinoindol Indoline-5-yl)methyl)-L-serine
- Example 84 (6-((3-cyanophenyl)oxy)-2-(2-methyl-[1,1′-biphenyl]-3-yl)-1,3-dioxinoindol Indoline-5-yl)methyl)-L-phenylalanine tert-butyl ester
- Example 86 (6-((3-cyanophenyl)oxy)-2-(2-methyl-[1,1′-biphenyl]-3-yl)-1,3-dioxinoindol Indoline-5-yl)methyl)-sarcosinate tert-butyl ester
- Example 88 (6-((3-cyanophenyl)oxy)-2-(2-cyano-[1,1′-biphenyl]-3-yl)-1,3-dioxoisoindol Indoline-5-yl)methyl)-L-homoproline
- Example 93 6-((3-cyanophenyl)oxy)-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2 -Methylphenyl)-5-(((tetrahydro-2H-pyran-4-yl)amino)methyl)isoindole-1,3-dione
- TR-FRET assay Time-Resolved Fluorescence Resonance Energy Transfer, time-resolved fluorescence resonance energy transfer
- Detection kits were purchased from BPS Bioscience.
- the initial test concentration of the test compound was 10uM, diluted 3 times to obtain 10 concentration gradient solutions, which were added to the 384-well plate as the experimental group, and the same amount of DMSO was added to the negative control well and positive control well, and repeated wells were detected.
- Example number IC 50 (nM) Example number IC 50 (nM) 1 1059 49 750.2
- test results show that the example compounds provided by the present invention can significantly inhibit the interaction of PD-1/PD-L1 at the molecular level.
- the compound is expected to be a candidate therapeutic compound for PD-1/PD-L1 target-related diseases.
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Abstract
本发明公开了一种邻苯二甲酰亚胺类化合物、制备方法和应用。本发明的邻苯二甲酰亚胺类化学物的结构如式(I)所示,其可药用盐,立体异构体、互变异构体、内消旋体、外消旋体、代谢产物、代谢前体、前药或溶剂化物对PD-1/PD-L1蛋白-蛋白相互作用具有明显的抑制作用,可用于治疗与PD-1/PD-L1信号通路相关的疾病如癌症、感染和身免疫类疾病等。
Description
本发明涉及药物化学领域,特别涉及一种邻苯二甲酰亚胺类化合物、制备方法和应用。
免疫检查点(immune checkpoint)是免疫***中存在的一系列抑制性信号通路,在正常情况下,免疫***可以通过免疫检查点调控T细胞,防止其过度活化进攻正常体细胞,其对于维持自身耐受、防止自身免疫性反应都有重要作用,可以影响免疫应答的时间和强度,从而使组织损伤最小化。对于正常人体而言,免疫检查点可以保护人体免受自身损伤,但是肿瘤细胞通过窃取这种程序,可以激活免疫检查点,抑制T细胞的免疫活性,从而达到免疫逃逸的目的,避免被T细胞识别和杀伤。
目前已发现的与肿瘤相关的免疫检查点分子有很多,包括PD-1、CTLA4、Tim3和LAG3等,研究较多的是PD-1和CTLA4。如果可暂时抑制PD-1的活性,则可以重新激活T细胞的活性,使其重新识别并杀伤肿瘤细胞。
目前,基于PD-1/PD-L1的免疫疗法已有上市的大分子药物,包括百事美施贵宝的Nivolumab、默沙东的Pembrolizumab、罗氏的Atezolizumab和阿斯利康的Durvaluman等。Nivolumab和Pembrolizumab两药有非常大的药用和市场价值。在研发的PD-1/PD-L1小分子抑制剂多达几十种,与大分子单克隆抗体药物相比,小分子药物有更强的透膜性,可以口服给药,并且往往具有更好的生物利用度和药代动力学参数,成本低更是一个重要优势,故快速开发具有良好药理活性的小分子PD-1/PD-L1抑制剂具有很大的必要性。
发明内容
发明目的:本发明针对现有技术存在的问题,本发明提供一种邻苯二甲酰亚胺类化合物,对PD-1/PD-L1蛋白-蛋白相互作用具有明显的抑制作用,因而可用于制备具有PD-1/PD-L1抑制活性的抑制剂,并作为免疫检查点抑制剂应用于肿瘤的免疫治疗。本发明还提供了邻苯二甲酰亚胺类化合物的制备方法及其在制备药物中的用途。
技术方案:本发明所述的一种通式如下式(I)所示的邻苯二甲酰亚胺类化合物:
R
1、R
3为H,或者R
1、R
2或R
3分别选自:卤素、氨基、C
1-C
8烷基、-(CH
2)
mCHO、-(CH
2)
mOH、-(CH
2)
mC(O)OH、-(CH
2)
mC(O)NR
9R
10、-(CH
2)
mNR
9R
10、-(CH
2)
mC(O)C
1-C
4或-OR
21
m是0、1、2、3或4;
R
9选自:H、C
1-C
4烷基或苄基;
R
10选自以下任意一种:
t是0、1、2、3或4;
R
11选自:H、C
1-C
4烷基或苄基;
R
12选自:H、C
1-C
4烷基或苄基;
R
13选自:H、C
1-C
4烷基或苄基;
R
14选自:H、C
1-C
4烷基或苄基;
R
15选自:H、C
1-C
4烷基、C
1-C
4烷氧羰基或苄基;
或者,R
9和R
10与它们所连接的N原子一起形成一个环,选自以下任意一种:
s是0、1或2;
p是1、2或3;
Q选自:S、O、-NH-、-N(CH
3)-、-N(CH(CH
3)
2)-、-N((CH
2)
2OH)-或-CH(R
20a)-;
R
20a选自:H、-OH、羟基取代的C
1-C
3烷基或羧基;
R
16选自:氢、-OH、羧基、羟基取代的C
1-C
4烷基或-C(O)NHSO
2R
19;
R
17选自:氢、-OH、羧基、羟基取代的C
1-C
4烷基、-CHO或-C(O)NHSO
2R
19;
R
18选自:C
1-C
4烷氧羰基、卤素、C
1-C
6烷基、羧基、酰胺基、-OH、羟基取代的C
1-C
4烷基、-NR
aR
b或苯氧基羰基,其中,苯氧基羰基的苯基任选被卤素、-OH、-CN、-NO
2、-NH
2、-CF
3、-CF
2CF
3、-OCF
3、-OCF
2CF
3、-SO
2NH
2、-C(O)OH、-C(O)NH
2或-NHC(O)NH
2取代,R
a和R
b各自独立地选自:H、C
1-C
4烷氧羰基或C
1-C
4烷基羰基;
R
19选自:-CF
3、环丙基、C
1-C
4烷基、二甲基氨基或甲基取代的咪唑基;
所述R
21选自:C
1-C
8烷基、C
1-C
4烷氧基、X取代的C
1-C
8烷基、杂环烷基或-(CH)
nAr, 其中,X选自卤素、-OH、氨基、羧基、酰胺基、吗啉基、哌啶基、哌嗪基、四氢吡咯基或N,N-二甲基氨基,n是1-8,Ar是取代或非取代的芳基或杂芳基;所述取代或非取代的芳基或杂芳基被下列的1-3个独立的取代基所取代:C
1-C
4烷基、C
1-C
4烷氧基、C
1-C
4烷氧羰基、C
1-C
4烷基磺酰基、羟基取代的C
1-C
4烷基、卤素、-CN、-NO
2、-NH
2、-OH、-CF
3、-CF
2CF
3、-OCF
3、-OCF
2CF
3、羧基、酰胺基、吗啉基、哌啶基、四氢吡咯基、哌嗪基、N,N-二甲基氨基、四氢吡喃基、未取代或取代的苯基;
R
4、R
5、R
6、R
7和R
8各自独立地选自:H、卤素、-CN、-NO
2、-NH
2、-OH、-CF
3、-CF
2CF
3、-OCF
3或-OCF
2CF
3、-R
C、-OR
C、-SR
C、-S(O)R
C、-S(O)
2R
C、-C(O)R
C、-C(O)OH、-C(O)OR
C、-OC(O)R
C、-NHR
C、-N(R
C)
2、-C(O)NH
2、-C(O)NHR
C、-C(O)N(R
C)
2、-NH(CO)R
C、-NRc(CO)R
C、-NH(CO)OR
C、-NR
C(CO)OR
C、-NH(CO)NH
2、-NH(CO)NHR
C、-NH(CO)N(R
C)
2、-NR
C(CO)NHR
C、-NR
C(CO)N(R
C)
2、-SO
2NH
2、-SO
2NHR
C、-SO
2N(R
C)
2、-NHSO
2R
C、-NR
CSO
2R
C、-NHSO
2NHR
C、-NHSO
2N(R
C)
2、-NR
CSO
2NHR
C、-NR
CSO
2N(R
C)
2、-C(O)NHNOH、-C(O)NHNOR
C、-C(O)NHSO
2R
C、-C(NH)NH
2、-C(NH)NHR
C、-C(NH)N(R
C)
2;
R
C选自:苯基、杂芳基、环烷基、环烯基、杂环烷基、杂环烯基、取代或非取代的C
1-C
4烷基、烯基或炔基;
或者,R
4、R
5、R
6和R
7之中每两个与它们所连接到的原子一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的杂环烷烃环或取代或非取代的杂环烯烃环;
W选自:卤素、-CN、-NO
2、-NH
2、-OH、C
1-C
8烷基、烯基、炔基、烷氧基、烷硫基、环烷基、卤代烷基、卤代烷氧基、卤代烷硫基、卤代环烷基或杂环烷基;
当R
2为-CH
2NHCH
2CH
3OH,W为C
1-C
8烷基或者为-CN,R
1、R
3为H。
优选地,所述R
1、R
3为H,或者R
1、R
2或者R
3分别选自:卤素、C
1-C
4烷基、-(CH
2)
mCHO、-(CH
2)
mOH、-(CH
2)
mC(O)OH、-(CH
2)
mC(O)NR
9R
10、-(CH
2)
mNR
9R
10、-(CH
2)
mC(O)C
1-C
4或-OR
21;
m是0、1、2、3或4;
R
9选自:H或(C
1-C
3)烷基;
t是0、1或2;
R
11选自H、C
1-C
3烷基或苄基;
R
12选自H、C
1-C
3烷基;
R
13选自H、C
1-C
3烷基;
R
15选自H、C
1-C
3烷基、C
1-C
3烷氧羰基;
或者,R
9和R
10与它们所连接的N原子一起形成一个环,选自以下任意一种:
s是0、1或2;
p是1、2或3;
Q选自:S、O、-NH-、-NCH
3-、-NCH(CH
3)
2-或-CHR
20a-;
R
20a选自:H、OH、羟基取代的C
1-C
3烷基或羧基;
R
16选自:氢、-OH、羧基、羟基取代的C
1-C
3烷基或-C(O)NHSO
2R
19;
R
17选自:氢、-OH、羧基、羟基取代的C
1-C
3烷基或-C(O)NHSO
2R
19;
R
18选自:C
1-C
4烷氧羰基、卤素、C
1-C
3烷基、羧基、酰胺基、-OH、羟基取代的C
1-C
4烷基、NR
aR
b或苯氧基羰基,其中,苯氧基羰基的苯基任选被卤素、-OH、-CN、-NO
2、-NH
2、-CF
3、-CF
2CF
3、-OCF
3、-OCF
2CF
3、-SO
2NH
2、-C(O)OH、-C(O)NH
2或-NHC(O)NH
2取代,R
a和R
b各自独立地选自:H、C
1-C
4烷氧羰基或C
1-C
4烷基羰基;
R
19选自C
1-C
3烷基;
所述R
21选自C
1-C
4烷基、C
1-C
3烷氧基、X取代的C
1-C
4烷基、杂环烷基或-(CH)
nAr;所述X选自卤素、-OH、氨基、羧基,所述n是1,Ar是取代或非取代的芳基或杂芳基,所述取代或者非取代的芳基或者杂芳基被下列的1-3个独立的取代基所取代:卤素、-CN、-NO
2、-NH
2、-OH、-CF
3、-CF
2CF
3、-OCF
3、-OCF
2CF
3、羧基、酰胺基;
R
4、R
5、R
6、R
7和R
8各自独立地选自:H、卤素、-CN、-NO
2、-NH
2、-OH、-CF
3、-R
C、-OR
C、-SR
C、-S(O)R
C、-S(O)
2R
C、-C(O)R
C、-C(O)OH、-C(O)OR
C、-OC(O)R
C、-NHR
C、-N(R
C)
2、-C(O)NH
2、-C(O)NHR
C、-NH(CO)R
C、-NH(CO)OR
C、-NH(CO)NH
2、-SO
2NH
2、-SO
2NHR
C、-NHSO
2R
C、-NR
CSO
2R
C;
R
C选自:苯基、杂芳基、取代或非取代的C
1-C
4烷基、烯基或炔基;
或者,R
4、R
5、R
6和R
7之中每两个与它们所连接到的原子一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的杂环烷烃环或取代或非取代的杂环烯烃环;
W选自:卤素、-CN或C
1-C
4烷基、C
1-C
4卤代烷基。
优选地,
所述R
1或R
3为H,或者R
1、R
2或R
3选自以下取代基:
优选地,
所述W选自:卤素、C
1-C
3烷基、-CN、-CF
3、-CF
2CF
3、-OCF
3、-OCF
2CF
3;
所述R
1为H或-(CH2)
mNR
9R
10,m是0、1、2、3或4,R
9和R
10与它们所连接的N原子一起形成如下所示的环:
R
18选自:C
1-C
4烷氧羰基、卤素、C
1-C
4烷基、羧基、酰胺基、-OH、羟基取代的C
1-C
4烷基;
所述R
2选自以下取代基:
所述R
3选自以下取代基:
所述R
4、R
5、R
6、R
7和R
8各自独立地选自:H、卤素、-CN、-NO
2、-NH
2、-OH、 -CF
3、-R
C、-OR
C、-SR
C、-S(O)R
C、-S(O)
2R
C、-C(O)R
C、-C(O)OH、-C(O)OR
C、-OC(O)R
C、-NHR
C、-N(R
C)
2、-C(O)NH
2、-C(O)NHR
C、-NH(CO)R
C、-NH(CO)OR
C、-NH(CO)NH
2、-SO
2NH
2、-SO
2NHR
C、-NHSO
2R
C、-NR
CSO
2R
C;
R
C选自:苯基、杂芳基、取代或非取代的C
1-C
4烷基、烯基或炔基;
或者,R
4、R
5、R
6和R
7之中每两个与它们所连接到的原子一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的杂环烷烃环、或取代或非取代的杂环烯烃环;
优选地,本发明所述的邻苯二甲酰亚胺类化合物如下所示:
优选地,
所述W选自:卤素、C
1-C
3烷基、-CN;
所述R
1为H;
所述R
3选自以下取代基:
所述R
4、R
5、R
6、R
7独立地选自H、苯基或C
1-C
4烷基;
或者,R
4、R
5、R
6和R
7之中每两个与它们所连接到的原子一起形成杂环烷烃环;
R
8为H。
更优选地,
所述R
4、R
5、R
6、R
7独立地选自H、苯基;
本发明所述R
4、R
5、R
6和R
7之中每两个与它们所连接到的原子一起形成1,4-二氧六环。
本发明进一步提供了上述的邻苯二甲酰亚胺类化合物的制备方法,包括以下步骤:
(a)以3-溴-2取代苯胺和苯、取代苯或杂芳环硼酸或硼酸酯为原料,通过Suzuki偶联反应得到中间体;
(b)将步骤(a)得到的中间体和取代的苯并马来酸酐,在冰醋酸为溶剂条件下制得邻苯二甲酰亚胺中间体;
(c)将步骤(b)所得的邻苯二甲酰亚胺中间体与Br-R
21或者是HNR
9R
10缩合反应生成式(I)所示化合物;或者将步骤(b)所得的邻苯二甲酰亚胺中间体经过氧化还原反应后,与胺类化合物发生氨化反应,得到式(I)所示化合物。
下面的合成路线概括并描述了本发明的式(I)化合物的制备,所有的原料都是通过这些流程中描述的方式,或有机化学领域普通技术人员熟知的方法制备的或者可商购。本 发明的全部最终衍生物都是通过这些流程中描述的方法或通过与其类似的方法制备的,本发明未详细公开的方法是有机化学领域普通技术人员熟知的。
路线一:
(a)以3-溴-2取代苯胺和苯、取代苯或杂芳环硼酸或硼酸酯为原料,通过Suzuki偶联反应得到中间体2;
(b)以中间体2和取代的苯并马来酸酐为原料,在冰醋酸为溶剂条件下制得邻苯二甲酰亚胺中间体3;
(c)以中间体3和R
21-Br在碱性环境下作用反应生成目标化合物4。
路线一中:
所述的3-溴-2取代苯胺优选为:3-溴-2-甲基苯胺或3-溴-2-氰基苯胺;
所述的苯、取代苯或杂芳环硼酸或硼酸酯优选为:苯硼酸;
所述的取代的苯并马来酸酐优选为:4-羟基邻苯二甲酸;
所述的R
21-Br优选为:溴丙酮、3-氰基苄基溴、溴化苄、对异丙基溴苄、4-氰基苄基溴。
路线二:
(a)以3-溴-2取代苯胺和苯、取代苯或杂芳环硼酸或硼酸酯为原料,通过Suzuki偶联反应得到中间体2;
(b)以中间体2和取代的苯并马来酸酐为原料,在冰醋酸为溶剂条件下制得邻苯二甲酰亚胺中间体5;
(c)以中间体5和HNR
9R
10在缩合剂催化条件下缩合生成目标化合物6。
路线二中:
所述的3-溴-2取代苯胺优选为:3-溴-2-甲基苯胺或3-溴-2-氰基苯胺;
所述的取代苯或杂芳环硼酸或硼酸酯优选为:苯硼酸或苯并-1,4-二氧六环-6-硼酸;
所述的取代的苯并马来酸酐优选为:1,2,4-苯三甲酸;
所述的HNR
9R
10优选为:乙醇胺、吗啉、N-异丙基哌嗪、N-乙酰基乙二胺、L-酪氨酸甲酯或对氨基苯甲酸甲酯。
路线三:
(a)以3-溴-2取代苯胺和苯、取代苯或杂芳环硼酸或硼酸酯为原料,通过Suzuki偶联反应得到中间体2;
(b)以中间体2和取代的苯并马来酸酐为原料,在冰醋酸为溶剂条件下制得邻苯二甲酰亚胺中间体5;
(c)以中间体5为原料,在还原剂作用下,制得中间体7;优选地,还原剂为硼烷;
(d)以中间体7为原料,在氧化剂作用下,制得中间体8;优选地,氧化剂为二氧化锰、戴斯-马丁氧化剂;
(e)以中间体8为原料,与胺类化合物发生还原氨化反应,缩制得目标化合物9。
路线三中:
所述的3-溴-2取代苯胺优选为:3-溴-2-甲基苯胺或3-溴-2-氰基苯胺;
所述的取代苯或杂芳环硼酸或硼酸酯优选为:苯硼酸、苯并-1,4-二氧六环-6-硼酸
所述的取代的苯并马来酸酐优选为:1,2,4-苯三甲酸、5-溴-1,2,4-苯三甲酸;
所述的胺类化合物优选为:乙醇胺、N-乙酰基乙二胺、吗啉、N-异丙基哌嗪、L-丝氨酸乙酯盐酸盐、L-高脯氨酸、L-脯氨醇、L-脯氨酸、N-甲基-2-羟基乙胺、L-脯氨酰胺、3-溴-2-甲基苯胺四氢吡喃、L-丝氨酸乙酯盐酸盐、D-丙氨酸乙酯盐酸盐、L-丙氨酸乙酯盐酸盐、N-叔丁氧羰基-1,2-乙二胺、N-(2-氨基乙基)甲烷磺酰胺盐酸盐、甘氨酸叔丁酯、L-丝氨酸叔丁酯、L-苏氨酸叔丁酯、N-乙酰基乙二胺。
路线四:
(a)以3-溴-2取代苯胺和苯、取代苯或杂芳环硼酸或硼酸酯为原料,通过Suzuki偶联反应得到中间体2;
(b)以中间体2和取代的苯并马来酸酐为原料,在冰醋酸为溶剂条件下制得邻苯二甲酰亚胺中间体3;
(c)以中间体4和乌洛托品反应生成中间体10;
(d)以中间体10和R
21-Br或R
21-I在碱性环境下作用反应生成目标化合物11;
(e)以中间体11为原料,与胺类化合物发生还原氨化反应,制得目标化合物12。
路线四中:
所述的3-溴-2取代苯胺优选为:3-溴-2-甲基苯胺、3-溴-2-氰基苯胺、3-溴-2-氟苯胺、3-溴-2-氯苯胺;
所述的取代苯或杂芳环硼酸或硼酸酯优选为:苯硼酸、苯并-1,4-二氧六环-6-硼酸;
所述的取代的苯并马来酸酐优选为:4-羟基邻苯二甲酸;
所述的R
21-Br或R
21-I优选为:碘甲烷、溴甲烷、3-氰基苄基溴、2-氰基苄基溴、4-氰基苄基溴、溴化苄、对异丙基苄基溴;
所述的胺类化合物优选为:N-乙酰基乙二胺、L-脯氨酸、L-丝氨酸叔丁酯、甘氨酸叔丁酯、L-苏氨酸叔丁酯、甘氨酸叔丁酯、L-丙氨酸叔丁酯、L-高脯氨酸、D-丝氨酸乙酯盐酸盐、甘氨酸甲酯、4-氨基四氢吡喃、L-脯氨酰胺、L-脯氨醇、(R)-3-吡咯烷醇、N-甲基-2-羟基乙胺、2-甲基丙氨酸、3-羧基环丁胺、3-羟基氮杂环丁烷盐酸盐、N-叔丁氧羰基-1,2-乙二胺、N,N-二甲基乙二胺、L-苯丙氨酸叔丁酯或肌氨酸叔丁酯;
路线五:
(a)以3-溴-2取代苯胺和苯、取代苯或杂芳环硼酸或硼酸酯为原料,通过Suzuki偶联反应得到中间体2;
(b)以中间体2和取代的苯并马来酸酐为原料,在冰醋酸为溶剂条件下制得邻苯二甲酰亚胺中间体13;
(c)以中间13为原料,在还原剂作用下,制得中间体14;优选地,所述的还原剂为硼烷;
(d)以中间体14为原料,在氧化剂作用下,制得中间体10;优选地,氧化剂为二氧化锰或戴斯-马丁氧化剂;
(e)以中间体10和R
21-Br或R
21-I在碱性环境下作用反应生成目标化合物11;
(f)以中间体11为原料,与胺类化合物发生还原氨化反应,制得目标化合物12。
所述的3-溴-2取代苯胺优选为:3-溴-2-甲基苯胺或3-溴-2-氰基苯胺;
所述的取代苯或杂芳环硼酸或硼酸酯优选为:苯硼酸或者苯并-1,4-二氧六环-6-硼酸;
所述的取代的苯并马来酸酐优选为:5-羟基-1,2,4-苯三甲酸;
所述的R
21-Br或R
21-I优选为:碘甲烷、溴甲烷、3-氰基苄基溴、2-氰基苄基溴、4-氰基苄基溴、溴化苄或者对异丙基苄基溴;
所述的胺类化合物优选为:乙醇胺、N-乙酰基乙二胺、L-脯氨酸、L-丝氨酸叔丁酯、甘氨酸叔丁酯、L-苏氨酸叔丁酯、甘氨酸叔丁酯、L-丙氨酸叔丁酯、L-高脯氨酸、D-丝 氨酸乙酯盐酸盐、甘氨酸甲酯、4-氨基四氢吡喃、L-脯氨酰胺、L-脯氨醇、(R)-3-吡咯烷醇、N-甲基-2-羟基乙胺、2-甲基丙氨酸、3-羧基环丁胺、3-羟基氮杂环丁烷盐酸盐、N-叔丁氧羰基-1,2-乙二胺、N,N-二甲基乙二胺、L-苯丙氨酸叔丁酯或肌氨酸叔丁酯;
还需要说明的是:以上所述的目标化合物均属于式(I)化合物所表达的通式结构。
本发明所述的邻苯二甲酰亚胺类化合物、其药学上可接受的盐、消旋体,互变及立体异构体、代谢产物、代谢前体、前药或溶剂化物在制备具有PD-1/PD-L1抑制活性的抑制剂中的应用。
所述的抑制剂治疗的疾病包括自身免疫性疾病、癌症及感染性疾病。
所述的癌症选自肺癌、黑色素瘤、血液肿瘤、神经胶质肉瘤、消化***肿瘤、乳腺癌、***癌、淋巴瘤、神经***肿瘤、泌尿系肿瘤、皮肤癌;所述的感染性疾病选自细菌及病毒感染;所述的自身免疫性疾病选自器官特异性以及***性自身免疫病。
本发明的邻苯二甲酰亚胺类化合物可作为药用盐使用。该盐可为下列酸中的至少一种的酸盐,包括无机酸及有机酸盐,所述无机酸包括:盐酸、硫酸、磷酸和甲磺酸,有机酸包括甲酸、乙酸、三氯乙酸、丙酸、丁酸、马来酸、对甲苯磺酸、苹果酸、丙二酸、肉桂酸、柠檬酸、富马酸、樟脑酸、二葡糖酸、天冬氨酸和酒石酸。
本发明还提供了一种用于肿瘤免疫治疗的药物组合物,其中含有如本发明所述的治疗有效量的式(I)所示邻苯二甲酰亚胺类化合物或其药学上可接受的盐、互变及立体异构体、消旋体、代谢产物、代谢前体、前药或溶剂化物作为活性成分和药学上可接受的载体。可任意混合的载体根据剂型、给药形式等可以改变。载体的例子包括赋形剂、粘合剂、崩解剂、润滑剂、矫味剂、香味剂、着色剂和甜味剂等。所述药物组合物可以是胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂和贴剂等制剂学上常规的制剂形式。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解,下述实例和制备例的范围并不以任何方式限制本发明的范围。
在上面的陈述中,“烷基”一词既可单独使用,也可在组合词中使用,如“烷硫基”或“卤烷基”中使用,C
1-C
8烷基它包括直链或支链烷基,如甲基,乙基,正丙基,异丙基,或不同的丁基包括正丁基、仲丁基、异丁基、叔丁基,戊基或己基及其异构体、庚烷及其异构体、辛烷及其异构体。
“卤素”一词,它可以是单独的或在组合词中如“卤烷基”,包括氟,氯,溴或碘,而且,在组合词如“卤烷基”中使用时,所说的烷基可以用卤原子部分地或完全地取代,卤原子可以是相同的或不同的。卤烷基的实例包括ClCHCH
3、F
3C,ClCH
2,CF
3CH
2和CF
3CCl
2,其余可列举的有1,2-二氯正丙基、1-氟正丁基、全氟正戊基等。
“卤烯基”,“卤炔基”和“卤烷氧基”等定义与“卤烷基”类似。卤烯基的实例包括(Cl
2)C=CHCH
2和CF
3CH
2CH=CHCH
2。“卤炔基”的实例包括HC≡CCHCl,CF
3C≡C,CCl
3C≡和FCH
2C≡CCH
2。“卤烷氧基”的实例包括CF
3O,CCl
3CH
2O,HCF
2CH
2CH
2O和CF
3CH
2O。
“杂环”或“杂环系”指的是其中至少一个环原子不是碳,并含有1~4个分别选自氮、氧和硫的杂原子的环或环系,条件是每个杂环含有不多于4个氮,不多于2个氧和不多于2个硫原子,杂环可以通过取代所说的碳或氮原子上的氢,与任一个可得的碳或氮相连。“芳系环”一词意指完全不饱和的碳环或杂环,其中多环系是芳族的(此处芳族,指的是对环系满足了Hückel规则)。“杂芳环”一词指的是完全的芳环,其中至少一个环原子不是碳,并含有1-4个分别选自氮、氧和硫的杂原子,条件是每个杂环含有不多于4个氮,不多于2个氧,不多于2个硫(此处芳族指的是满足了Hückel规则)。杂环可以通过取代所说的碳或氮上的氢而与任一个可得的碳或氮相连。“芳族杂环系”一词包括完全的 芳族杂环和杂双环,其中至少一个多环系的环是芳族的(此处芳族,指的是满足了Hückel规则)。“稠杂双环系”一词含有一个由2个稠合的环组成的环系,其中至少一个环原子不是碳,正如上面定义的,可以是芳族的或非芳族的。
有益效果:本发明的邻苯二甲酰亚胺类化合物具有新颖的化学结构,并在体外研究中对PD-1/PD-L1相互作用具有很高的抑制活性,可用于癌症等多种疾病的治疗和预防。
实施例1:2-(2-甲基-[1,1′-联苯]-3-基)-5-(2-丙酮氧基)异吲哚-1,3-二酮
合成路线:
化合物A-2的合成
取化合物A-1 3-溴-2-甲基苯胺(1.86g,10mmol),苯硼酸(1.281g,10.5mmol),碳酸钾(3.45g,25mmol)和醋酸钯(0.134g,0.6mmol),加入到100mL单口瓶中,加入水和无水乙醇各20mL,氩气保护,换气三次。室温条件下反应14h。反应完成后硅藻土过滤,滤液减压蒸除其中的乙醇后,用乙酸乙酯(25mL×3)萃取。合并三次萃取的乙酸乙酯溶液,减压浓缩,硅胶柱色谱纯化(石油醚:乙酸乙酯=5:1),得到化合物A-2(1.5g,收率82%)
1H NMR(300MHz,CDCl
3)δ7.48–7.23(m,5H),7.06(t,J=7.7Hz,1H),6.70(d,J=7.7Hz,2H),3.69(s,2H),2.05(s,3H).MS(ESI):m/z 184[M+H]
+.
化合物A-3的合成
取化合物A-2(0.915g,5mmol)和4-羟基邻苯二甲酸(1.092g,6mmol)投入到25mL冰醋酸中,120℃反应7h,冷却至室温,加入125mL水,会有大量白色固体析出。过滤取白色滤饼,加入二氯甲烷溶解后硅胶柱层析(二氯甲烷:甲醇=10:1,v/v)进一步纯化,得到化合物A-3(1.37g,收率83%)
1H NMR(300MHz,CDCl
3)δ7.82(d,J=8.2Hz,1H),7.43–7.31(m,8H),7.18(m,2H),2.06(s,3H).MS(ESI):m/z 330[M+H]
+.
化合物I-1的合成
取化合物A-3(0.329g,1mmol)加入50mL单口瓶中,加入10mLDMF溶解后,加入碳酸铯(652mg,2mmol),溴丙酮(342mg,2mmol),80℃反应2小时。降至室温后,先加入50mL水,再用乙酸乙酯(50mL×3)萃取。合并3次萃取溶液后蒸干,硅胶柱层析得到化合物I-1(154mg,收率40%)。
1H NMR(300MHz,DMSO)δ7.42(m,11H),5.15(s,2H),2.19(s,3H),1.98(s,3H).MS(ESI):m/z 386[M+H]
+.
实施例2:2-(2-氰基-[1,1′-联苯]-3-基)-5-(2-丙酮氧基)异吲哚-1,3-二酮
参照实施例1的方法,将实施例中的A-1由3-溴-2-甲基苯胺替换为3-溴-2-氰基苯胺,制得化合物I-2:
1H NMR(400MHz,DMSO)δ8.03–7.92(m,2H),7.78(m,2H),7.65–7.50(m,6H),7.46–7.40(m,1H),5.19(s,2H),2.19(s,3H).MS(ESI):m/z 397[M+H]
+.
实施例3:5-((2-氰基苄基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
参照实施例1的方法,将实施例中的溴丙酮替换为3-氰基苄基溴,制得化合物I-3:
1H NMR(400MHz,DMSO)δ8.02–7.90(m,2H),7.85(d,J=7.7Hz,2H),7.68–7.61(m,2H),7.55–7.32(m,9H),5.43(s,2H),1.98(s,3H).MS(ESI):m/z 445[M+H]
+.
实施例4:5-((2-氰基苄基)氧)-2-(2-氰基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
参照实施例1的方法,将实施例中的A-1由3-溴-2-甲基苯胺替换为3-溴-2-氰基苯胺,将溴丙酮替换为3-氰基苄基溴,制得化合物I-4:
1H NMR(300MHz,DMSO)δ8.05–7.97(m,3H),7.89–7.85(m,2H),7.82–7.76(m,2H),7.74-7.54(m,8H),5.47(s,2H).MS(ESI):m/z 456[M+H]
+.
实施例5:5-(苄氧基)-2-(2-甲基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
参照实施例1的方法,将实施例中的溴丙酮替换为溴化苄,制得化合物I-5:
1H NMR(300MHz,DMSO)δ7.92(d,J=8.3Hz,1H),7.59(d,J=2.1Hz,1H),7.53–7.31(m,14H),5.36(s,2H),1.98(s,3H).MS(ESI):m/z 420[M+H]
+.
实施例6:5-((4-异丙基苄基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
参照实施例1的方法,将实施例中的溴丙酮替换为对异丙基溴苄,制得化合物I-6:
1H NMR(300MHz,DMSO)δ7.91(d,J=8.3Hz,1H),7.58(d,J=2.3Hz,1H),7.48-7.26(m,13H),5.31(s,2H),2.90(m,1H),1.98(s,3H),1.20(d,J=6.9Hz,6H).MS(ESI):m/z 462[M+H]
+.
实施例7:5-((4-氰基苄基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
参照实施例1的方法,将实施例中的A-1由3-溴-2-甲基苯胺替换为3-溴-2-氰基苯胺,将溴丙酮替换为4-氰基苄基溴,制得化合物I-7:
1H NMR(400MHz,DMSO)δ7.99(m,2H),7.91(d,J=8.1Hz,2H),7.78(m,2H),7.70(m,3H),7.58(m,6H),5.51(s,2H).MS(ESI):m/z 456[M+H]
+.
实施例8:N-(2-羟乙基)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚-5-甲酰胺
合成路线:
化合物B-3的合成
取化合物A-2(0.915g,5mmol)和1,2,4-苯三甲酸(1.26g,6mmol)投入到25mL冰醋酸中,120℃反应7h,冷却至室温,加入125mL水,会有大量白色固体析出。过滤取白色滤饼,加入二氯甲烷溶解后硅胶柱层析(二氯甲烷:甲醇=10:1,v/v)进一步纯化,得到化合物B-3(1.52g,收率85%)
1H NMR(300MHz,DMSO)δ13.77(s,1H),8.44(dd,J=7.8,1.4Hz,1H),8.34(m,1H),8.11(dd,J=7.8,0.7Hz,1H),7.52–7.34(m,8H),2.01(s,3H).MS(ESI):m/z 358[M+H]
+.
化合物I-8的合成
取化合物B-3(0.357g,1mmol),乙醇胺(1.1mmol)和HATU(1.05mmol)加入50mL单口瓶中,5mLDMF溶解样品后逐滴加入DIPEA(3mmol),室温搅拌过夜。之后加入25mL水,以乙酸乙酯(30mL×3)萃取。合并乙酸乙酯萃取液,硅胶柱层析(二氯甲烷:甲醇=10:1,v/v)分离得到纯化的化合物I-8(180mg,收率45%)。
1H NMR(400MHz,DMSO)δ8.90(s,1H),8.53–8.27(m,2H),8.10(m,1H),7.58– 7.26(m,7H),4.79(s,1H),3.56(m,2H),3.37(m,2H),2.01(d,J=6.3Hz,3H).MS(ESI):m/z 401[M+H]
+.
实施例9:5-(吗啉-4-羰基)-2-(2-甲基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
参照实施例8的方法,将实施例中的乙醇胺替换为吗啉,制得化合物I-9:
1H NMR(400MHz,DMSO)δ8.11–7.88(m,3H),7.58–7.32(m,8H),3.80–3.52(m,6H),3.35(m,2H),2.01(s,3H).MS(ESI):m/z 427[M+H]
+.
实施例10:5-(4-异丙基哌嗪-1-羰基)-2-(2-甲基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
参照实施例8的方法,将实施例中的乙醇胺替换为N-异丙基哌嗪,制得化合物I-10:
1H NMR(400MHz,DMSO)δ8.15–8.05(m,2H),7.98(m,1H),7.54–7.35(m,8H),3.54(m,4H),3.12(m,5H),2.02(s,3H),1.23(s,6H).MS(ESI):m/z 468[M+H]
+.
实施例11:N-(2-羟乙基)-2-(2-氰基[1,1′-联苯]-3-基)-1,3-二氧异吲哚-5-甲酰胺
参照实施例8的方法,将实施例中的A-1由3-溴-2-甲基苯胺替换为3-溴-2-氰基苯胺,制得化合物I-11:
1H NMR(400MHz,DMSO)δ8.93(m,1H),8.50(s,1H),8.41(d,J=7.8Hz,1H),8.17(d,J=7.8Hz,1H),8.01(t,J=7.9Hz,1H),7.81(d,J=8.0Hz,2H),7.64(m,2H),7.57(m,3H),4.79(m,1H),3.55(m,2H),3.39(m,2H).MS(ESI):m/z 412[M+H]
+.
实施例12:5-(吗啉-4-羰基)-2-(2-氰基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
参照实施例8的方法,将实施例中的A-1由3-溴-2-甲基苯胺替换为3-溴-2-氰基苯胺,将乙醇胺替换为吗啉,制得化合物I-12:
1H NMR(400MHz,DMSO)δ8.19–8.07(m,2H),8.06–7.93(m,2H),7.80(m,2H),7.59(m,5H),3.63(m,6H),3.34(m,2H).MS(ESI):m/z 438[M+H]
+.
实施例13:N-(2-乙酰氨基乙基)-2-(2-氰基[1,1'-联苯]-3-基)-1,3-二氧异吲哚-5-甲酰胺
参照实施例12的方法,将实施例中的吗啉替换为N-乙酰基乙二胺,制得化合物I-13:
1H NMR(300MHz,DMSO)δ8.99(m,1H),8.48(s,1H),8.39(dd,J=7.8,1.1Hz,1H),8.18(d,J=7.8Hz,1H),8.01(t,J=7.9Hz,2H),7.83–7.76(m,2H),7.71–7.51(m,5H),3.36(m,2H),3.26(m,2H),1.81(s,3H).MS(ESI):m/z 453[M+H]
+.
实施例14:2-(2-甲基-[1,1'-联苯]-3-基)-1,3-二氧异吲哚-5-羰基)-L-酪氨酸甲酯
参照实施例8的方法,将实施例中的乙醇胺替换为L-酪氨酸甲酯,制得化合物I-14:
1H NMR(300MHz,DMSO)δ9.27(d,J=7.6Hz,1H),9.23(s,1H),8.42(s,1H),8.31(d,J=7.8Hz,1H),8.09(d,J=7.9Hz,1H),7.62–7.27(m,8H),7.09(dd,J=8.4,1.5Hz,2H),6.65(d,J=8.5Hz,2H),4.84–4.48(m,1H),3.65(s,3H),3.04(m,2H),2.01(s,3H).MS(ESI):m/z 535[M+H]
+.
实施例15:4-(2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚-5-羧酰胺)苯甲酸甲酯
参照实施例8的方法,将实施例中的乙醇胺替换为对氨基苯甲酸甲酯,制得化合物I-15:
1H NMR(400MHz,DMSO)δ10.93(s,1H),8.68–8.33(m,2H),8.08(m,5H),7.64–7.21(m,8H),3.85(s,3H),2.02(s,3H).MS(ESI):m/z 491[M+H]
+.
实施例16:N-(2-羟乙基)-2-(3-(2,3-二氢苯[b][1,4]二噁英-6-基)-2-甲基苯基)-1,3-二氧异吲哚-5-甲酰胺
参照实施例8的方法,将实施例中的苯硼酸替换为苯并-1,4-二氧六环-6-硼酸,制得化合物I-16:
1H NMR(400MHz,DMSO)δ8.89(t,J=5.5Hz,1H),8.43(s,1H),8.36(dd,J=7.8,1.4Hz,1H),8.08(d,J=7.8Hz,1H),7.39(m,2H),7.33(m,1H),6.94(d,J=8.2Hz,1H),6.85–6.78(m,2H),4.79(t,J=5.7Hz,1H),4.28(s,4H),3.56(m,2H),3.38(m,2H),2.01(s,3H).MS(ESI):m/z 459[M+H]
+.
实施例17:N-(2-乙酰氨基乙基)-2-(3-(2,3-二氢苯[b][1,4]二噁英-6-基)-2-甲基苯 基)-1,3-二氧异吲哚-5-甲酰胺
参照实施例16的方法,将实施例中的乙醇胺替换为N-乙酰基乙二胺,制得化合物I-17:
1H NMR(400MHz,DMSO)δ8.94(t,J=5.5Hz,1H),8.41(s,1H),8.34(dd,J=7.8,1.5Hz,1H),8.09(m,1H),8.00(d,J=5.7Hz,1H),7.39(m,2H),7.33(m,1H),6.94(d,J=8.2Hz,1H),6.87–6.78(m,2H),4.29(s,4H),3.35(m,2H),3.25(m,2H),2.00(s,3H),1.81(s,3H).MS(ESI):m/z 500[M+H]
+.
实施例18:N-(2-羟乙基)-2-(2-氰基-3-(2,3-二氢苯[b][1,4]二噁英-6-基)苯基)-1,3-二氧异吲哚-5-甲酰胺
参照实施例16的方法,将实施例中的3-溴-2-甲基苯胺替换为3-溴-2-氰基苯胺,制得化合物I-18:
1H NMR(400MHz,DMSO)δ8.93(t,J=5.5Hz,1H),8.50(s,1H),8.40(dd,J=7.8,1.5Hz,1H),8.17(d,J=7.8Hz,1H),7.95(t,J=8.0Hz,1H),7.80–7.67(m,2H),7.15(d,J=2.1Hz,1H),7.10(dd,J=8.3,2.2Hz,1H),7.04(d,J=8.3Hz,1H),4.80(t,J=5.7Hz,1H),3.55(m,2H),3.39(m,2H).MS(ESI):m/470[M+H]
+.
实施例19:N-(2-乙酰氨基乙基)-2-(2-氰基-3-(2,3-二氢苯[b][1,4]二噁英-6-基)苯基)-1,3-二氧异吲哚啉-5-甲酰胺
参照实施例17的方法,将实施例中的3-溴-2-甲基苯胺替换为3-溴-2-氰基苯胺,制得化合物I-19:
1H NMR(400MHz,DMSO)δ8.97(m,1H),8.47(s,1H),8.38(d,J=7.8Hz,1H),8.17(d,J=7.8Hz,1H),8.05–7.90(m,2H),7.75(m,2H),7.10(m,3H),4.32(s,4H),3.36(m,2H),3.25(m,2H),1.81(s,3H).MS(ESI):m/z 511[M+H]
+.
实施例20:5-(((2-羟乙基)氨基)甲基)-2-(2-甲基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
合成路线:
A-1,A-2及B-3的合成参考实施例1及实施例8。
化合物C-4的合成:
取化合物B-3(3.57g,10mmol),加入50mL四氢呋喃溶剂,完全溶解后,在冰浴条件下逐滴加入硼烷-四氢呋喃溶液25mL(1mmol/mL),完全加入后,室温反应过夜。缓慢滴加甲醇溶液,待不再产生气泡终止。溶液减压蒸干,硅胶柱层析分离纯化(石油醚:乙酸乙酯=1:1,v/v)得到化合物C-4(2.57g,收率75%)。
1H NMR(300MHz,DMSO)δ7.93(dd,J=10.9,4.2Hz,2H),7.84(dd,J=7.7,1.4Hz,1H),7.53–7.33(m,8H),4.71(s,2H),1.98(s,3H).MS(ESI):m/z 344[M+H]
+.
化合物C-5的合成:
取化合物C-4(1.715g,5mmol)放入100mL单口瓶中,加入50mL二氯甲烷溶解,之后缓慢加入戴斯-马丁氧化剂(4.24g,10mmol),室温搅拌2小时,薄层色谱检测到原料反应结束终止反应。加入饱和碳酸氢钠水溶液50mL,充分振荡后保留二氯甲烷层,弃去水层。再次用纯水(50mL×3)萃取,二氯甲烷层蒸干硅胶柱层析(石油醚:乙酸乙酯=2:1)分离得到化合物C-5(1.53g,收率90%)
1H NMR(400MHz,DMSO)δ10.24(s,1H),8.46–8.36(m,2H),8.20(d,J=7.6Hz,1H),7.50–7.31(m,8H),2.01(s,3H).MS(ESI):m/z 342[M+H]
+.
化合物I-20的合成:
取化合物C-5(0.341g,1mmol)和乙醇胺(0.183g,3mmol)放入50mL单口瓶中,加入5mL二氯甲烷完全溶解,搅拌2小时后,加入醋酸硼氢化钠(0.844g,4mmol),继续室温反应过夜。之后加入5mL饱和氯化铵溶液,搅拌10分钟后保留二氯甲烷层,弃去水层。蒸干,硅胶柱层析分离(二氯甲烷:甲醇=10:1,v/v)分离得到纯化的化合物I-20。
1H NMR(400MHz,DMSO)δ8.12–7.73(m,3H),7.52–7.33(m,8H),4.58(s,1H),3.94(s,2H),3.49(t,J=5.7Hz,2H),2.59(t,J=5.7Hz,2H),1.98(s,3H).MS(ESI):m/z 387[M+H]
+.
实施例21:N-(2-((2-(2-甲基[1,1′-联苯]-3-基)-1,3-二氧异吲哚-5-基甲基)氨基)乙基)乙酰胺
参照实施例20的方法,将实施例中的乙醇胺替换为N-乙酰基乙二胺,制得化合物 I-21:
1H NMR(400MHz,DMSO)δ7.99–7.91(m,2H),7.85(m,2H),7.50–7.34(m,8H),3.89(s,2H),3.14(m,2H),2.54(m,2H),1.98(s,3H),1.79(s,3H).MS(ESI):m/z 428[M+H]
+.
实施例22:2-(2-甲基-[1,1′-联苯]-3-基)-5-(吗啉甲基)异吲哚-1,3-二酮
参照实施例20的方法,将实施例中的乙醇胺替换为吗啉,制得化合物I-22:
1H NMR(400MHz,DMSO)δ7.92(m,3H),7.53–7.32(m,8H),3.69(m,2H),3.34(m,4H),2.42(m,4H),2.00(s,3H).MS(ESI):m/z 413[M+H]
+.
实施例23:5-(((2-羟乙基)氨基)甲基)-2-(2-氰基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
参照实施例20的方法,将实施例中的A-1由3-溴-2-甲基苯胺替换为3-溴-2-氰基苯胺,制得化合物I-23:
1H NMR(400MHz,DMSO)δ8.04(s,1H),8.02–7.96(m,2H),7.92(d,J=7.8Hz,1H),7.79(dd,J=8.0,1.0Hz,2H),7.65–7.52(m,6H),4.53(s,1H),3.95(s,2H),3.49(t,J=5.7Hz,2H),2.59(t,J=5.7Hz,2H).MS(ESI):m/z 398[M+H]
+.
实施例24:5-((4-异丙基哌嗪-1-基)甲基)-2-(2-甲基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
参照实施例20的方法,将实施例中的乙醇胺替换为N-异丙基哌嗪,制得化合物I-24:
1H NMR(400MHz,DMSO)δ7.97(m,2H),7.87(m,1H),7.48(m,2H),7.39(m,6H),3.77(s,2H),3.34(s,4H),2.95(s,4H),2.61(s,1H),1.99(s,3H),1.23(brs,6H).MS(ESI):m/z454[M+H]
+.
实施例25:(2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-丝氨酸乙酯
参照实施例20的方法,将实施例中的乙醇胺替换为L-丝氨酸乙酯盐酸盐,制得化合物I-25:
1H NMR(300MHz,DMSO)δ8.01–7.91(m,2H),7.86(m,1H),7.49(m,2H),7.45–7.29(m,6H),4.90(t,J=5.7Hz,1H),4.10(m,2H),4.04–3.96(m,1H),3.85(d,J= 15.0Hz,1H),3.62(t,J=5.5Hz,2H),3.28(s,1H),2.90–2.66(m,1H),1.99(s,3H),1.20(m,3H).MS(ESI):m/z 459[M+H]
+.
实施例26:(S)-1-((2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)哌啶-2-羧酸
参照实施例20的方法,将实施例中的乙醇胺替换为L-高脯氨酸,制得化合物I-26:
1H NMR(300MHz,DMSO)δ8.03–7.79(m,3H),7.55–7.28(m,8H),3.98(d,J=14.3Hz,1H),3.59(brd,1H),3.11(brs,1H),2.82(brs,1H),2.17(brs,1H),1.98(s,3H),1.77(m,2H),1.58–1.32(m,4H).MS(ESI):m/z 455[M+H]
+.
实施例27:(S)-5-((2-(羟甲基)吡咯烷-1-基)甲基)-2-(2-甲基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
参照实施例20的方法,将实施例中的乙醇胺替换为L-脯氨醇,制得化合物I-27:
1H NMR(400MHz,DMSO)δ7.93(m,2H),7.85(d,J=7.7Hz,1H),7.54–7.32(m,8H),4.28(dd,J=14.2,2.6Hz,1H),3.57(d,J=14.2Hz,1H),3.48(m,1H),3.39(m,1H),2.81(m,1H),2.65(m,1H),2.20(m,1H),1.99(s,3H),1.85(m,1H),1.61(m,3H).MS(ESI):m/z427[M+H]
+.
实施例28:(2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-脯氨酸
参照实施例20的方法,将实施例中的乙醇胺替换为L-脯氨酸,制得化合物I-28:
1H NMR(400MHz,DMSO)δ7.99(s,1H),7.96–7.87(m,2H),7.52–7.34(m,8H),4.20(d,J=14.0Hz,1H),3.76(d,J=13.9Hz,1H),3.30(m,1H),2.86(m,1H),2.43(m,1H),2.11(m,1H),1.99(s,3H),1.88(m,1H),1.76(m,2H).MS(ESI):m/z 441[M+H]
+.
实施例29:5-((2-羟乙基)(甲基)氨基)甲基)-2-(2-甲基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
参照实施例20的方法,将实施例中的乙醇胺替换为N-甲基-2-羟基乙胺,制得化合物I-29:
1H NMR(400MHz,DMSO)δ7.98–7.90(m,2H),7.85(m,1H),7.55–7.29(m,8H),4.51(t,J=5.4Hz,1H),3.72(s,2H),3.55(q,J=6.0Hz,2H),2.48(m,2H),2.20(s,3H),1.99(s,3H).MS(ESI):m/z 401[M+H]
+.
实施例30:(2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-脯氨酰胺
参照实施例20的方法,将实施例中的乙醇胺替换为L-脯氨酰胺,制得化合物I-30:
1H NMR(400MHz,DMSO)δ8.03(m,1H),7.94(s,2H),7.52–7.32(m,9H),7.10(m,1H),4.03(d,J=13.9Hz,1H),3.63(d,J=13.9Hz,1H),3.03(m,1H),2.91(m,1H),2.27(m,1H),2.09(m,1H),2.00(s,3H),1.74(m,3H).MS(ESI):m/z 440[M+H]
+.
实施例31:2-(2-甲基[1,1′-联苯]-3-基)-5-(((四氢-2H-吡喃-4-基)氨基)甲基)异吲哚-1,3-二酮
参照实施例20的方法,将实施例中的乙醇胺替换为3-溴-2-甲基苯胺四氢吡喃,制得化合物I-31:
1H NMR(400MHz,DMSO)δ8.00(m,1H),7.90(m,2H),7.53–7.32(m,8H),3.94(s,2H),3.83(m,2H),3.26(m,2H),2.60(m,1H),1.99(s,3H),1.79(m,2H),1.30(m,2H).MS(ESI):m/z 427[M+H]
+.
实施例32:2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-丝氨酸乙酯
参照实施例20的方法,将实施例中的乙醇胺替换为L-丝氨酸乙酯盐酸盐,制得化合物I-32:
1H NMR(400MHz,DMSO)δ8.00–7.90(m,2H),7.86(m,1H),7.52–7.34(m,8H),4.90(t,J=5.7Hz,1H),4.09(m,2H),4.04–3.98(m,1H),3.85(d,J=14.8Hz,1H),3.62(t,J=5.5Hz,2H),2.77(s,1H),1.99(s,3H),1.20(m,3H).MS(ESI):m/z 459[M+H]
+.
实施例33:2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-D-丙氨酸乙酯
参照实施例20的方法,将实施例中的乙醇胺替换为D-丙氨酸乙酯盐酸盐,制得化合物I-33:
1H NMR(400MHz,DMSO)δ7.99–7.90(m,2H),7.84(m,1H),7.51–7.34(m,8H),4.09(q,J=7.1Hz,2H),3.95(d,J=14.9Hz,1H),3.81(d,J=14.9Hz,1H),3.28(m,1H),1.98(s,3H),1.25–1.17(m,6H).MS(ESI):m/z 443[M+H]
+.
实施例34:2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-丙氨酸乙酯
参照实施例20的方法,将实施例中的乙醇胺替换为L-丙氨酸乙酯盐酸盐,制得化合物I-34:
1H NMR(400MHz,DMSO)δ7.98–7.89(m,2H),7.84(m,1H),7.50–7.34(m,8H),4.09(q,J=7.1Hz,2H),3.95(d,J=14.9Hz,1H),3.81(d,J=14.9Hz,1H),3.28(m,1H),1.98(s,3H),1.25–1.18(m,6H).MS(ESI):m/z 443[M+H]
+.
实施例35:叔丁基(2-((2-(2-甲基[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5基)甲基)氨基)乙基)氨基甲酸酯
参照实施例20的方法,将实施例中的乙醇胺替换为N-叔丁氧羰基-1,2-乙二胺,制得化合物I-35:
1H NMR(400MHz,DMSO)δ7.98–7.90(m,2H),7.85(dd,J=7.6,1.4Hz,1H),7.51–7.34(m,8H),6.80(m,1H),3.88(s,2H),3.04(m,2H),2.54(m,2H),1.98(s,3H),1.36(s,9H).MS(ESI):m/z 486[M+H]
+.
实施例36:5-(((2-氨基乙基)氨基)甲基)-2-(2-甲基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
化合物I-36的合成:
取化合物I-35(97mg,0.2mmol)溶于4mL二氯甲烷中,完全溶解后缓慢加入1mL三氟乙酸,室温搅拌过夜后蒸干溶剂,硅胶柱色谱纯化(二氯甲烷:甲醇=10:1)得到化合物I-36(69mg,收率90%)。
1H NMR(400MHz,DMSO)δ8.17(d,J=1.3Hz,1H),8.10(d,J=7.8Hz,1H),8.02(dd,J=7.8,1.3Hz,1H),7.51–7.36(m,8H),4.47(s,2H),3.27–3.11 (m,4H),1.99(s,3H).MS(ESI):m/z 386[M+H]
+.
实施例37:N-(2-((2-(2-甲基[1,1′-联苯]-3-基)-1,3-二氧异吲哚林-5-基)甲基)氨基)乙基)甲磺酰胺
参照实施例20的方法,将实施例中的乙醇胺替换为N-(2-氨基乙基)甲烷磺酰胺盐酸盐,制得化合物I-37:
1H NMR(400MHz,DMSO)δ8.00(brs,1H),7.95(d,J=7.7Hz,1H),7.87(d,J=7.7Hz,1H),7.51–7.34(m,8H),7.01(s,1H),3.95(s,2H),3.08(m,2H),2.91(s,3H),2.67(m,2H),1.98(s,3H).MS(ESI):m/z 464[M+H]
+.
实施例38:(2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)甘氨酸
化合物I-38的合成:
取化合物C-5(0.341g,1mmol)和甘氨酸叔丁酯(0.393g,3mmol)放入50mL单口瓶中,加入5mL二氯甲烷完全溶解,搅拌2小时后,加入醋酸硼氢化钠(0.844g,4mmol),继续室温反应过夜。之后加入5mL饱和氯化铵溶液,搅拌10分钟后保留二氯甲烷层,弃去水层。蒸干后再加入2mL二氯甲烷溶解,完全溶解后缓慢加入2mL三氟乙酸,室温搅拌过夜后蒸干溶剂,硅胶柱色谱纯化(二氯甲烷:甲醇=10:1)得到化合物I-38(195mg,收率48.8%)。
1H NMR(300MHz,DMSO)δ8.08(s,1H),8.04–7.90(m,2H),7.50–7.35(m,8H),4.21(s,2H),3.71(d,J=5.9Hz,2H),1.99(s,3H).MS(ESI):m/z 401[M+H]
+.
实施例39:(2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-丝氨酸
参照实施例38的方法,将实施例中的甘氨酸叔丁酯替换为L-丝氨酸叔丁酯,制得化合物I-39:
1H NMR(300MHz,DMSO)δ8.03(s,1H),7.93(m,2H),7.52–7.33(m,8H),4.19–3.94(m,2H),3.65(m,2H),3.21(m,1H),1.99(s,3H).MS(ESI):m/z 431[M+H]
+.
实施例40:(2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-苏氨酸
参照实施例38的方法,将实施例中的甘氨酸叔丁酯替换为L-苏氨酸叔丁酯,制得化合物I-40:
1H NMR(400MHz,DMSO)δ8.02(m,1H),7.96–7.88(m,2H),7.50–7.34(m,8H),4.13(m,1H),3.90(m,2H),3.02(m,1H),1.99(s,3H),1.17(d,J=6.3,3H).MS(ESI):m/z 445[M+H]
+.
实施例41:2-(3-(2,3-二氢苯并[b][1,4]二噁英-6-基)-2-甲基苯基)-5-((2-羟乙基)氨基)甲基)异吲哚-1,3-二酮
参照实施例20的方法,将实施例中的苯硼酸替换为苯并-1,4-二氧六环-6-硼酸,制得化合物I-41:
1H NMR(300MHz,DMSO)δ7.99–7.88(m,2H),7.85(dd,J=7.8,1.3Hz,1H),7.41–7.27(m,3H),6.94(d,J=8.1Hz,1H),6.86–6.75(m,2H),4.53(t,J=5.4Hz,1H),4.28(s,4H),3.92(s,2H),3.48(q,J=5.6Hz,2H),2.58(t,J=5.8Hz,2H),1.99(s,3H).MS(ESI):m/z 445[M+H]
+.
实施例42:N-(2-((2-(3-(2,3-二氢苯[b][1,4]二噁英-6-基)-2-甲基)-1,3-二氧异吲哚啉-5-基)甲基)氨基)乙基)乙酰胺
参照实施例41的方法,将实施例中的乙醇胺替换为N-乙酰基乙二胺,制得化合物I-42:
1H NMR(300MHz,DMSO)δ8.00–7.90(m,2H),7.87–7.84(m,1H),7.40–7.29(m,3H),6.94(d,J=8.1Hz,1H),6.86–6.77(m,2H),4.28(s,4H),3.90(s,2H),3.15(q,J=6.3Hz,2H),2.55(J=6.3Hz,2H),1.99(s,3H),1.79(s,3H).MS(ESI):m/z 486[M+H]
+.
实施例43:(S)-1-((6-溴-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)哌啶-2-羧酸
合成路线:
A-2的合成参考实施例1。
化合物D-3的合成
取化合物A-2(0.915g,5mmol)和5-溴-1,2,4-苯三甲酸(1.734g,6mmol)投入到25mL冰醋酸中,120℃反应7h,冷却至室温,加入125mL水,会有大量白色固体析出。过滤取白色滤饼,加入二氯甲烷溶解后硅胶柱层析(二氯甲烷:甲醇=10:1,v/v)进一步纯化,得到化合物D-3(1.74g,收率80%):
1H NMR(300MHz,DMSO)δ8.08(s,1H),7.88(s,1H),7.50–7.32(m,8H),1.97(s,3H).MS(ESI):m/z 437[M+H]
+.
化合物D-4的合成:
取化合物D-3(1.308g,3mmol),加入15mL四氢呋喃溶剂,完全溶解后,在冰浴条件下逐滴加入硼烷-四氢呋喃溶液7.5mL(1mmol/mL),完全加入后,室温反应过夜。缓慢滴加甲醇溶液,待不再产生气泡终止。溶液减压蒸干,硅胶柱层析分离纯化(石油醚:乙酸乙酯=1:1)得到化合物D-4(0.886g,收率70%):
1H NMR(300MHz,DMSO)δ8.19(s,1H),8.04(s,1H),7.57–7.20(m,8H),5.90(s,1H),4.66(d,J=4.5Hz,2H),1.99(s,3H).MS(ESI):m/z 423[M+H]
+
化合物D-5的合成:
取化合物D-4(0.844g,2mmol)放入25mL单口瓶中,加入10mL二氯甲烷溶解,之后缓慢加入戴斯-马丁氧化剂(1.696,4mmol),室温搅拌2小时,薄层色谱检测到原料反应结束终止反应。加入饱和碳酸氢钠水溶液10mL,充分振荡后保留二氯甲烷层,弃去水层。再次用纯水(10mL×3)萃取,二氯甲烷层蒸干硅胶柱层析(石油醚:乙酸乙酯=2:1)分离得到化合物D-5(0.764g,收率91%):
1H NMR(300MHz,DMSO)δ10.36(s,1H),8.44(s,1H),8.23(s,1H),7.50–7.35(m,8H),2.02(s,3H).MS(ESI):m/z 421[M+H]
+.
化合物I-43的合成:
取化合物D-5(0.42g,1mmol)和L-高脯氨酸(0.387g,3mmol)放入25mL单口瓶中,加入5mL二氯甲烷完全溶解,搅拌2小时后,加入醋酸硼氢化钠(0.844g,4mmol),继续室温反应过夜。之后加入5mL饱和氯化铵溶液,搅拌10分钟后保留二氯甲烷层,弃去水层。蒸干,硅胶柱层析分离(二氯甲烷:甲醇=10:1,v/v)分离得到纯化的化合物I-43(0.245g,收率0.46%)。
1H NMR(300MHz,DMSO)δ12.53(s,1H),8.19(s,1H),8.13(s,1H),7.56–7.33(m,8H),3.92(m,1H),3.77(m,1H),3.43(m,1H),2.89(m,1H),2.34(m,1H),2.00(s,3H),1.85(brs,2H),1.50(brs,4H).MS(ESI):m/z 534[M+H]
+.
实施例44:5-溴-2-(2-甲基-[1,1′-联苯]-3-基)-6-(吗啉甲基)异吲哚-1,3-二酮
参照实施例43的方法,将实施例中的L-高脯氨酸替换为吗啉,制得化合物I-44:
1H NMR(400MHz,DMSO)δ8.23(s,1H),8.05(s,1H),7.52–7.35(m,8H),3.73(s,2H),3.63(t,J=4.5Hz,4H),2.00(s,3H).MS(ESI):m/z 492[M+H]
+.
实施例45:5-((2-羟乙基氨基)甲基)-6-甲氧基-2-(2-甲基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
合成路线一:
A-2的合成参考实施例1。
化合物E-3的合成
取化合物A-2(1.83g,10mmol)和5-羟基-1,2,4-苯三甲酸(2.712g,12mmol)投入到25mL冰醋酸中,120℃反应7h,冷却至室温,加入125mL水,会有大量白色固体析出。过滤取白色滤饼,加入二氯甲烷溶解后硅胶柱层析(二氯甲烷:甲醇=10:1,v/v)进一步纯化,得到化合物E-3(2.312g,收率62%):
1H NMR(400MHz,DMSO)δ8.24(s,1H),7.51–7.45(m,3H),7.44–7.35(m,6H),1.99(s,3H).MS(ESI):m/z 374[M+H]
+.
化合物E-4的合成:
取化合物E-3(1.865g,5mmol),加入25mL四氢呋喃溶剂,完全溶解后,在冰浴条件下逐滴加入硼烷-四氢呋喃溶液12.5mL(1mmol/mL),完全加入后,室温反应过夜。 缓慢滴加甲醇溶液,待不再产生气泡终止。溶液减压蒸干,硅胶柱层析分离纯化(石油醚:乙酸乙酯=1:1,v/v)得到化合物E-4(1.166g,收率65%):
1H NMR(400MHz,DMSO)δ7.88(s,1H),7.52–7.45(m,2H),7.42–7.33(m,6H),7.25(s,1H),4.59(s,2H),1.97(s,3H).MS(ESI):m/z 360[M+H]
+.
化合物E-5的合成:
取化合物E-4(0.714g,2mmol)放入25mL单口瓶中,加入10mL二氯甲烷溶解,之后缓慢加入戴斯-马丁氧化剂(1.696,4mmol),室温搅拌2小时,薄层色谱检测到原料反应结束终止反应。加入饱和碳酸氢钠水溶液10mL,充分振荡后保留二氯甲烷层,弃去水层。再次用纯水(10mL×3)萃取,二氯甲烷层蒸干硅胶柱层析(石油醚:乙酸乙酯=2:1)分离得到化合物E-5(0.635g,收率89%):
1H NMR(400MHz,DMSO)δ12.34(s,1H),10.41(s,1H),8.11(s,1H),7.51–7.33(m,9H),1.98(s,3H).MS(ESI):m/z 358[M+H]
+.
化合物E-6的合成:
取化合物E-5(0.536g,1.5mmol)加入25mL单口瓶中,加入5mLDMF溶解后,加入碳酸铯(978mg,3mmol),碘甲烷(426mg,3mmol),80℃反应2小时。降至室温后,先加入25mL水,再用乙酸乙酯(25mL×3)萃取。合并3次萃取溶液后蒸干,硅胶柱层析得到化合物E-6(445mg,收率80%)。
1H NMR(400MHz,DMSO)δ10.44(s,1H),8.13(s,1H),7.86(s,1H),7.51–7.35(m,8H),4.17(s,3H),2.00(s,3H).MS(ESI):m/z 372[M+H]
+.
化合物I-45的合成:
取化合物E-6(0.371g,1mmol)和乙醇胺(0.183g,3mmol)放入25mL单口瓶中,加入5mL二氯甲烷完全溶解,搅拌2小时后,加入醋酸硼氢化钠(0.844g,4mmol),继续室温反应过夜。之后加入5mL饱和氯化铵溶液,搅拌10分钟后保留二氯甲烷层,弃去水层。蒸干,硅胶柱层析分离(二氯甲烷:甲醇=10:1,v/v)分离得到纯化的化合物I-45(0.125g,收率30%)。
1H NMR(400MHz,DMSO)δ7.99(s,1H),7.56(s,1H),7.50–7.46(m,2H),7.43–7.34(m,6H),4.02(s,3H),3.89(s,2H),3.53(t,J=5.7Hz,2H),2.68(t,J=5.7Hz,2H),1.98(s,3H).MS(ESI):m/z 417[M+H]
+.
合成路线二:
化合物A-2和A-3的合成参考实施例1。
化合物E-5的合成:
取化合物A-3(3.29g,10mmol)和乌洛托品(3.5g,25mmol),冰浴条件下,缓慢加入10mL三氟乙酸。之后升温至120℃,回流反应10h,冷却至室温后,加入50mL1N盐酸,再次升温回流2h。加入乙酸乙酯(50mL×3)萃取,合并乙酸乙酯部分,蒸干, 硅胶柱层析(石油醚:二氯甲烷:乙酸乙酯=3:1:0.1,v/v/v)得到纯化的化合物E-5(1.25g,收率35%)。
E-6,I-45的合成见实施例45合成方法一。
实施例46:N-(2-(((6-甲氧基-2-(2-甲基[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)氨基)乙基)乙酰胺
参照实施例45的方法,将实施例中的乙醇胺替换为N-乙酰基乙二胺,制得化合物I-46:
1H NMR(400MHz,DMSO)δ8.01(s,1H),7.95(m,1H),7.58(s,1H),7.50–7.46(m,2H),7.43–7.34(m,6H),4.03(s,3H),3.93(s,2H),3.22(q,J=6.3Hz,2H),2.71(t,J=6.3Hz,2H),1.98(s,3H),1.81(s,3H).MS(ESI):m/z 458[M+H]
+.
实施例47:(6-甲氧基-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-脯氨酸
参照实施例45的方法,将实施例中的乙醇胺替换为L-脯氨酸,制得化合物I-47:
1H NMR(300MHz,DMSO)δ8.02(s,1H),7.58(s,1H),7.52–7.33(m,8H),4.12–3.90(m,5H),3.44(m,1H),3.11(m,1H),2.57(m,1H),2.13(m,1H),1.98(s,3H),1.93–1.71(m,3H).MS(ESI):m/z 471[M+H]
+.
实施例48:(6-甲氧基-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-丝氨酸叔丁酯
参照实施例45的方法,将实施例中的乙醇胺替换为L-丝氨酸叔丁酯,制得化合物I-48:
1H NMR(400MHz,DMSO)δ8.00(d,J=8.2Hz,1H),7.54(d,J=1.3Hz,1H),7.51–7.45(m,2H),7.45–7.33(m,6H),4.83(m,1H),4.01(s,3H),3.93–3.70(m,2H),3.63–3.52(m,2H),3.23–3.12(m,1H),1.97(s,3H),1.38(d,J=9.1Hz,9H).MS(ESI):m/z 517[M+H]
+.
实施例49:(6-甲氧基-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-甘氨 酸叔丁酯
参照实施例45的方法,将实施例中的乙醇胺替换为甘氨酸叔丁酯,制得化合物I-49:
1H NMR(400MHz,DMSO)δ7.96(s,1H),7.55(s,1H),7.49(m,2H),7.45–7.34(m,6H),4.02(s,3H),3.83(s,2H),3.29(s,2H),1.98(s,3H),1.40(s,9H).MS(ESI):m/z 487[M+H]
+.
实施例50:(6-甲氧基-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-丝氨酸
化合物I-50的合成:
取化合物I-48(104mg,0.2mmol)溶于2mL二氯甲烷中,完全溶解后缓慢加入2mL三氟乙酸,室温搅拌过夜后蒸干溶剂,硅胶柱色谱纯化(二氯甲烷:甲醇=5:1,v/v)得到化合物I-50(78mg,收率85%)。
1H NMR(400MHz,DMSO)δ8.04(s,1H),7.57(s,1H),7.50–7.45(m,2H),7.43–7.34(m,6H),4.05–3.99(m,4H),3.91(m,1H),3.71–3.62(m,2H),3.25(m,1H),1.98(s,3H).MS(ESI):m/z 461[M+H]
+.
实施例51:(6-甲氧基-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-苏氨酸
参照实施例50的方法,将实施例中的L-丝氨酸叔丁酯替换为L-苏氨酸叔丁酯,制得化合物I-51:
1H NMR(400MHz,DMSO)δ8.07(s,1H),7.56(s,1H),7.51–7.44(m,2H),7.44–7.33(m,6H),4.01(m,4H),3.92(m,1H),3.83(m,1H),3.07(m,1H),1.99(s,3H),1.19(m,3H).MS(ESI):m/z 475[M+H]
+.
实施例52:(6-甲氧基-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-甘氨酸
参照实施例50的方法,将实施例中的L-丝氨酸叔丁酯替换为甘氨酸叔丁酯,制得化合物I-52:
1H NMR(400MHz,DMSO)δ7.99(s,1H),7.56(s,1H),7.48(m,2H),7.43–7.34(m,6H),4.01(s,3H),3.91(s,2H),3.11(s,2H),1.98(s,3H).MS(ESI):m/z 431[M+H]
+.
实施例53:(6-甲氧基-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-丙氨酸
参照实施例50的方法,将实施例中的L-丝氨酸叔丁酯替换为L-丙氨酸叔丁酯,制得化合物I-53:
1H NMR(400MHz,DMSO)δ8.01(s,1H),7.54(s,1H),7.48(m,2H),7.44–7.28(m,6H),4.01(m,4H),3.88–3.69(m,2H),1.97(s,3H),1.22(m,3H).MS(ESI):m/z 445[M+H]
+.
实施例54:3-(((6-(((2-羟乙基)氨基)甲基)-2-(2-甲基[1,1′-联苯]-3-基)-1,3-二氧异吲哚酚-5-基)氧)甲基)苯腈
参照实施例45的方法,将实施例中的碘甲烷替换为3-氰基苄基溴,制得化合物I-54:
1H NMR(400MHz,DMSO)δ8.03–7.96(m,2H),7.86(brt,J=7.5,2H),7.71–7.60(m,2H),7.48(m,2H),7.43–7.32(m,6H),5.48(s,2H),3.92(s,2H),3.51(t,J=5.7Hz,2H),2.64(t,J=5.7Hz,2H),1.98(s,3H).MS(ESI):m/z 518[M+H]
+.
实施例55:N-(2-(((6-((3-氰基苯基)氧)-2-(2-甲基[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)氨基)乙基)乙酰胺
参照实施例54的方法,将实施例中的乙醇胺替换为N-乙酰基乙二胺,制得化合物I-55:
1H NMR(400MHz,DMSO)δ8.04–7.97(m,2H),7.87(m,3H),7.67(t,J=7.8Hz, 1H),7.63(s,1H),7.51–7.33(m,8H),5.48(s,2H),3.89(s,2H),3.18(q,J=6.2Hz,2H),2.61(t,J=6.4Hz,2H),1.98(s,3H),1.80(s,3H).MS(ESI):m/z 559[M+H]
+.
实施例56:(6-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-高脯氨酸
参照实施例54的方法,将实施例中的乙醇胺替换为L-高脯氨酸,制得化合物I-56:
1H NMR(400MHz,DMSO)δ8.05(d,J=4.1Hz,1H),7.97(m,1H),7.85(m,2H),7.71–7.59(m,2H),7.52–7.33(m,8H),5.48(s,2H),3.87(t,J=14.8Hz,1H),3.73(m,1H),3.24(brs,1H),2.90(m,1H),2.28(m,1H),1.99(s,3H),1.81(m,2H),1.46(m,4H).MS(ESI):m/z586[M+H]
+.
实施例57:(6-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-D-丝氨酸乙酯
参照实施例54的方法,将实施例中的乙醇胺替换为D-丝氨酸乙酯盐酸盐,制得化合物I-57:
1H NMR(400MHz,DMSO)δ8.04(d,J=4.3Hz,1H),7.98(m,1H),7.86(m,2H),7.66(m,2H),7.52–7.34(m,8H),5.48(s,2H),4.91(m,1H),4.05(m,2H),3.99(m,1H),3.86(m,1H),3.63(m,2H),1.98(s,3H),1.15(m,3H).MS(ESI):m/z 590[M+H]
+.
实施例58:(6-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-甘氨酸甲酯
参照实施例54的方法,将实施例中的乙醇胺替换为甘氨酸甲酯,制得化合物I-58:
1H NMR(400MHz,DMSO)δ8.04–7.98(m,2H),7.86(m,2H),7.67(m,2H),7.51–7.35(m,8H),5.48(s,2H),3.97(s,2H),3.48(s,2H),3.34(s,3H),1.98(s,3H).MS(ESI):m/z 546[M+H]
+.
实施例59:3-((2-(2-甲基[1,1′-联苯]-3-基)-6-(吗啉基甲基)-1,3-二氧异吲哚啉-5-基)氧)甲基)苯腈
参照实施例54的方法,将实施例中的乙醇胺替换为4-氨基四氢吡喃,制得化合物I-59:
1H NMR(400MHz,DMSO)δ7.99(s,1H),7.93(s,1H),7.86(m,2H),7.71–7.62(m,2H),7.48(m,2H),7.44–7.32(m,6H),5.49(s,2H),3.67(brd,2H),3.62(m,4H),1.98(s,3H).MS(ESI):m/z 544[M+H]
+.
实施例60:(6-((3-氰基苯基)氧)-2-(2-甲基-[1,1'-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-脯氨酸
参照实施例54的方法,将实施例中的乙醇胺替换为L-脯氨酸,制得化合物I-60:
1H NMR(400MHz,DMSO)δ8.06(m,1H),8.02(m,1H),7.92–7.82(m,2H),7.67(m,2H),7.49(m,2H),7.45–7.31(m,6H),5.49(m,2H),4.14–3.95(m,2H),3.43(m,1H),3.08(m,1H),2.57(m,1H),2.13(m,1H),1.99(s,3H),1.91(m,1H),1.82(m,2H).MS(ESI):m/z 572[M+H]
+.
实施例61:(6-((3-氰基苯基)氧)-2-(2-甲基-[1,1'-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-脯氨酰胺
参照实施例54的方法,将实施例中的乙醇胺替换为L-脯氨酰胺,制得化合物I-61:
1H NMR(400MHz,DMSO)δ8.07(d,J=5.2Hz,1H),7.97(s,1H),7.85(m,2H),7.69–7.62(m,2H),7.48(m,2H),7.42–7.34(m,6H),7.31(m,1H),6.98(m,1H),5.49(s,2H),3.93(m,1H),3.76(m,1H),3.08(m,1H),3.00(m,1H),2.33(m,1H),2.09(m,1H),1.98(s,3H),1.76(m,3H).MS(ESI):m/z 571[M+H]
+.
实施例62:6-((3-氰基苯基)氧)-2-(2-甲基[1,1′-联苯]-3-基)-5-(((四氢-2H-吡喃-4-基)氨基)甲基)异吲哚-1,3-二酮
参照实施例54的方法,将实施例中的乙醇胺替换为4-氨基四氢吡喃,制得化合物I-62:
1H NMR(300MHz,DMSO)δ8.19(s,1H),8.06(s,1H),8.00(m,1H),7.86(m,2H),7.70–7.63(m,2H),7.50–7.34(m,8H),5.48(s,2H),3.99(s,2H),3.83(m,2H),3.26(m,2H),2.76(m,1H),1.97(s,3H),1.90–1.77(m,2H),1.44–1.29(m,2H).MS(ESI):m/z 558[M+H]
+.
实施例63:(S)-3-((6-((2-(羟甲基)吡咯啉-1-基)甲基)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)氧)甲基)苯腈
参照实施例54的方法,将实施例中的乙醇胺替换为L-脯氨醇,制得化合物I-63:
1H NMR(300MHz,DMSO)δ8.14(s,1H),8.06–7.98(m,2H),7.92–7.80(m,2H),7.70–7.61(m,2H),7.52–7.33(m,8H),5.50(s,2H),4.28(m,1H),3.81(m,1H),3.49(m,1H),3.40(m,1H),2.98(m,1H),2.87(m,1H),2.42(m,1H),1.98(s,3H),1.96–1.83(m,1H),1.68(m,3H).MS(ESI):m/z 558[M+H]
+.
实施例64:(R)-3-((6-((3-羟吡咯烷酮-1-基)甲基)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)氧)甲基)苯腈
参照实施例54的方法,将实施例中的乙醇胺替换为(R)-3-吡咯烷醇,制得化合物I-64:
1H NMR(400MHz,DMSO)δ7.97(m,1H),7.94(s,1H),7.86(m,2H),7.70–7.61(m,2H),7.54–7.32(m,8H),5.48(s,2H),4.76(d,J=4.5Hz,1H),4.24(m,1H),3.86–3.69(m,2H),2.82–2.68(m,2H),2.44(m,1H),2.04(m,1H),1.98(s,3H),1.60(m,1H).MS(ESI):m/z 544[M+H]
+.
实施例65:3-((6-(((2-羟乙基)(甲基)氨基)甲基)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)氧)甲基)苯腈
参照实施例54的方法,将实施例中的乙醇胺替换为N-甲基-2-羟基乙胺,制得化合物I-65:
1H NMR(400MHz,DMSO)δ8.07–7.97(m,2H),7.86(m,2H),7.69–7.62(m,2H),7.50–7.34(m,8H),5.48(s,2H),3.73(brs,2H),3.55(brs,2H),2.64–2.52(m,2H),2.28(s,3H),1.98(s,3H).MS(ESI):m/z 532[M+H]
+.
实施例66:2-(((6-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)氨基)-2-甲基丙酸
参照实施例54的方法,将实施例中的乙醇胺替换为2-甲基丙氨酸,制得化合物I-66:
1H NMR(500MHz,DMSO)δ8.12(s,1H),8.01(s,1H),7.87(m,2H),7.70–7.61(m,2H),7.48(t,J=7.4Hz,2H),7.43–7.32(m,6H),5.49(s,2H),3.95(s,2H),1.98(s,3H),1.29(s,6H).MS(ESI):m/z 560[M+H]
+.
实施例67:1-((6-((3-氰基苯基)氧)-2-(2-甲基-[1,1'-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)氮杂环丁烷-3-羧酸
参照实施例54的方法,将实施例中的乙醇胺替换为3-羧基环丁胺,制得化合物I-67:
1H NMR(400MHz,DMSO)δ8.00(m,1H),7.92–7.81(m,3H),7.67(t,J=7.8Hz,1H),7.62(s,1H),7.51–7.44(m,2H),7.42–7.30(m,6H),5.48(m,2H),3.77(m,2H),3.51(m,2H),3.36–3.22(m,3H),1.97(s,3H).MS(ESI):m/z 558[M+H]
+.
实施例68:3-(((6-((3-羟氮杂丁-1-基)甲基)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)氧)甲基)苯腈
参照实施例54的方法,将实施例中的乙醇胺替换为3-羟基氮杂环丁烷盐酸盐,制得化合物I-68:
1H NMR(400MHz,DMSO)δ8.01(s,1H),7.92–7.82(m,3H),7.70–7.63 (m,2H),7.51–7.45(m,2H),7.42–7.34(m,6H),5.49(s,2H),4.32(m,1H),3.86(brs,2H),3.75(brs,2H),3.32(brs,2H),3.06(brs,1H),1.98(s,3H).MS(ESI):m/z 530[M+H]
+.
实施例69:叔丁基(2-(((6-((3-氰基苯基)氧)-2-(2-甲基[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)氨基)乙基)氨基甲酸酯
参照实施例54的方法,将实施例中的乙醇胺替换为N-叔丁氧羰基-1,2-乙二胺,制得化合物I-69:
1H NMR(400MHz,DMSO)δ8.00(s,1H),7.98(m,1H),7.86(m,2H),7.66(t,J=7.8Hz,1H),7.61(s,1H),7.51–7.33(m,8H),6.80(t,J=5.7Hz,1H),5.47(s,2H),3.87(s,2H),3.06(m,2H),2.60(t,J=6.5Hz,2H),1.97(s,3H),1.36(s,9H).MS(ESI):m/z617[M+H]
+.
实施例70:3-((6-(((2-(二甲氨基)乙基)氨基)甲基)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)氧)甲基)苯腈
参照实施例54的方法,将实施例中的乙醇胺替换为N,N-二甲基乙二胺,制得化合物I-70:
1H NMR(400MHz,DMSO)δ8.04(s,1H),8.00(m,1H),7.87(m,2H),7.71–7.63(m,2H),7.51–7.34(m,8H),5.48(s,2H),2.83–2.67(m,4H),2.39(s,6H),1.98(s,3H).MS(ESI):m/z 545[M+H]
+.
实施例71:5-羟基-6-((2-羟乙基)氨基)甲基)-2-(2-甲基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
化合物I-71的合成:
取化合物E-5(0.357g,1mmol)和乙醇胺(0.183g,3mmol)放入25mL单口瓶中,加入5mL二氯甲烷完全溶解,搅拌2小时后,加入醋酸硼氢化钠(0.844g,4mmol),继续室温反应过夜。之后加入5mL饱和氯化铵溶液,搅拌10分钟后保留二氯甲烷层,弃去水层。蒸干,硅胶柱层析分离(二氯甲烷:甲醇=10:1)分离得到纯化的化合物I-71(0.097g,收率24%)。
1H NMR(400MHz,DMSO)δ7.62(s,1H),7.50–7.44(m,2H),7.41–7.27(m,6H),6.84(s,1H),4.05(s,2H),3.58(t,J=5.4Hz,2H),2.79(t,J=5.4Hz,2H),1.95(s,3H).MS(ESI):m/z 403[M+H]
+.
实施例72:2-(((6-(((2-羟乙基)氨基)甲基)-2-(2-甲基[1,1′-联苯]-3-基)-1,3-二氧异吲哚 啉-5-基)氧)甲基)苯腈
参照实施例54的方法,将实施例中的3-氰基苄基溴替换为2-氰基苄基溴,制得化合物I-72:
1H NMR(400MHz,DMSO)δ8.04(s,1H),7.96(d,J=7.7Hz,1H),7.84–7.79(m,2H),7.75(s,1H),7.62(m,1H),7.48(m,2H),7.43–7.34(m,6H),5.56(s,2H),3.94(s,2H),3.50(m,2H),2.65(s,2H),1.99(s,3H).MS(ESI):m/z 518[M+H]
+.
实施例73:4-(((6-(((2-羟乙基)氨基)甲基)-2-(2-甲基[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)氧)甲基)苯腈
参照实施例54的方法,将实施例中的3-氰基苄基溴替换为4-氰基苄基溴,制得化合物I-73:
1H NMR(400MHz,DMSO)δ8.01(s,1H),7.94–7.86(m,2H),7.71(m,2H),7.61(s,1H),7.52–7.29(m,8H),5.53(s,2H),4.57(m,1H),3.92(s,2H),3.51(m,2H),2.64(t,J=5.7Hz,2H),1.97(s,3H).MS(ESI):m/z 518[M+H]
+.
实施例74:5-(苄氧基)-6-(((2-羟乙基)氨基)甲基)-2-(2-甲基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
参照实施例54的方法,将实施例中的3-氰基苄基溴替换为溴化苄,制得化合物I-74:
1H NMR(400MHz,DMSO)δ8.00(s,1H),7.63(s,1H),7.54–7.35(m,13H),5.42(s,2H),4.56(s,1H),3.90(s,2H),3.51(m,2H),2.63(t,J=5.7Hz,2H),1.98(s,3H).MS(ESI):m/z493[M+H]
+.
实施例75:5-(((2-羟乙基)氨基)甲基)-6-((4-异丙基苄基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)异吲哚-1,3-二酮
参照实施例54的方法,将实施例中的3-氰基苄基溴替换为对异丙基苄基溴,制得化合物I-75:
1H NMR(400MHz,DMSO)δ8.06(s,1H),7.67(s,1H),7.51–7.42(m,5H),7.41–7.35(m,5H),7.32–7.29(m,2H),5.39(s,2H),4.03(s,2H),3.57(m,2H),2.90(m, 1H),2.76(t,J=5.6Hz,2H),1.98(s,3H),1.22(d,J=6.9Hz,6H).MS(ESI):m/z 535[M+H]
+.
实施例76:((6-((3-氰基苯基)氧)-2-(2-甲基-[1,1'-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)甘氨酸叔丁酯
参照实施例54的方法,将实施例中的乙醇胺替换为甘氨酸叔丁酯,制得化合物I-76:
1H NMR(400MHz,DMSO)δ8.01–7.96(m,2H),7.85(m,2H),7.67–7.61(m,2H),7.50–7.34(m,8H),5.47(s,2H),3.91(s,2H),3.29(s,2H),1.98(s,3H),1.37(s,9H).MS(ESI):m/z588[M+H]
+.
实施例77:((6-((3-氰基苯基)氧)-2-(2-甲基-[1,1'-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)甘氨酸
化合物I-77的合成:
取化合物I-76(117mg,0.2mmol)溶于2mL二氯甲烷中,完全溶解后缓慢加入2mL三氟乙酸,室温搅拌过夜后蒸干溶剂,硅胶柱色谱纯化(二氯甲烷:甲醇=5:1,v/v)得到化合物I-77(95mg,收率89%)。
1H NMR(400MHz,DMSO)δ8.13(s,1H),8.05(s,1H),7.89(m,2H),7.74(s,1H),7.67(t,J=7.8Hz,1H),7.50–7.35(m,8H),5.53(s,2H),4.44(s,2H),3.95(s,2H),1.98(s,3H).MS(ESI):m/z 532[M+H]
+.
实施例78:(6-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-丙氨酸叔丁酯
参照实施例54的方法,将实施例中的乙醇胺替换为L-丙氨酸叔丁酯,制得化合物I-78:
1H NMR(400MHz,DMSO)δ8.14(s,1H),8.02(d,J=7.4Hz,1H),7.98(m,1H),7.86(m,2H),7.69–7.62(m,2H),7.52–7.32(m,8H),5.48(s,2H),3.97–3.78(m,2H),3.25(m,1H),1.98(s,3H),1.37(d,J=6.8Hz,9H),1.22(m,3H).MS(ESI):m/z 602[M+H]
+.
实施例79:(6-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基) 甲基)-L-丙氨酸
参照实施例77的方法,将实施例中的甘氨酸叔丁酯替换为L-丙氨酸叔丁酯,制得化合物I-79:
1H NMR(300MHz,DMSO)δ8.15(s,1H),8.06(m,1H),7.95–7.84(m,2H),7.74(s,1H),7.66(t,J=7.8Hz,1H),7.54–7.32(m,8H),5.52(s,2H),4.42(s,2H),4.08(m,1H),1.98(s,3H),1.48(d,J=7.0Hz,3H).MS(ESI):m/z 546[M+H]
+.
实施例80:(6-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-丝氨酸叔丁酯
参照实施例54的方法,将实施例中的乙醇胺替换为L-丝氨酸叔丁酯,制得化合物I-80:
1H NMR(400MHz,DMSO)δ8.13(s,1H),8.04(d,J=7.7Hz,1H),7.97(m,1H),7.85(m,2H),7.68–7.60(m,2H),7.50–7.34(m,8H),5.47(s,2H),3.97(m,1H),3.84(m,1H),3.59(m,2H),3.22(m,1H),1.97(s,3H),1.35(d,J=8.7Hz,9H).MS(ESI):m/z 618[M+H]
+.
实施例81:(6-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-苏氨酸叔丁酯
参照实施例77的方法,将实施例中的甘氨酸叔丁酯替换为L-丝氨酸叔丁酯,制得化合物I-81:
1H NMR(300MHz,DMSO)δ8.09(s,1H),8.00(s,1H),7.88(m,2H),7.71–7.60(m,2H),7.52–7.34(m,8H),5.49(s,2H),4.04(m,2H),3.66(m,2H),3.22(m,1H),1.99(s,3H).MS(ESI):m/z 562[M+H]
+.
实施例82:(6-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-丝氨酸
参照实施例77的方法,将实施例中的乙醇胺替换为L-苏氨酸叔丁酯,制得化合物I-82:
1H NMR(300MHz,DMSO)δ8.10(m,1H),8.00(m,1H),7.89(m,2H),7.72–7.65(m,2H),7.54–7.48(m,2H),7.46–7.38(m,6H),5.51(s,2H),4.01(m,1H),3.85(m,2H),3.03(s,1H),2.01(s,3H),1.37(d,J=7.1Hz,9H),1.17(d,J=6.2Hz,3H).MS(ESI):m/z 632[M+H]
+.
实施例83:(6-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-苏氨酸
参照实施例77的方法,将实施例中的甘氨酸叔丁酯替换为L-苏氨酸叔丁酯,制得化合物I-83:
1H NMR(400MHz,DMSO)δ8.10(m,1H),7.99(m,1H),7.87(m,2H),7.69–7.61(m,2H),7.52–7.34(m,8H),5.48(s,2H),4.07(m,1H),3.91(m,2H),3.06(m,1H),1.99(s,3H),1.18(m,3H).MS(ESI):m/z 576[M+H]
+.
实施例84:(6-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-苯丙氨酸叔丁酯
参照实施例54的方法,将实施例中的乙醇胺替换为L-苯丙氨酸叔丁酯,制得化合物I-84:
1H NMR(400MHz,DMSO)δ7.95(m,2H),7.84(m,2H),7.68–7.60(m,2H),7.51–7.34(m,8H),7.27–7.17(m,5H),5.44(s,2H),3.95–3.74(m,2H),2.94–2.79(m,2H),1.97(s,3H),1.21(d,J=10.0Hz,9H).MS(ESI):m/z 678[M+H]
+.
实施例85:(6-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-苯丙氨酸
参照实施例77的方法,将实施例中的甘氨酸叔丁酯替换为L-苯丙氨酸叔丁酯,制得化合物I-85:
1H NMR(300MHz,DMSO)δ8.15(m,1H),8.06(m,1H),7.97–7.82(m,2H),7.75(s,1H),7.66(t,J=7.8Hz,1H),7.54–7.19(m,13H),5.53(s,2H),4.56–4.38(m,2H),4.27(m,1H),3.31(m,1H),3.09(m,1H),1.99(s,3H).MS(ESI):m/z 588[M+H]
+.
实施例86:(6-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-肌氨酸叔丁酯
参照实施例54的方法,将实施例中的乙醇胺替换为肌氨酸叔丁酯,制得化合物I-86:
1H NMR(400MHz,DMSO)δ7.99(s,2H),7.86(m,2H),7.68–7.62(m,2H),7.50–7.34(m,8H),5.47(s,2H),3.30(s,2H),2.35(s,3H),1.98(s,3H),1.41(s,9H).MS(ESI):m/z 602[M+H]
+.
实施例87:(6-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-肌氨酸
参照实施例77的方法,将实施例中的甘氨酸叔丁酯替换为肌氨酸叔丁酯,制得化合物I-87:
1H NMR(400MHz,DMSO)δ8.10(s,1H),8.02(m,1H),7.88(m,2H),7.73(s,1H),7.67(t,J=7.8Hz,1H),7.52–7.34(m,8H),5.51(s,2H),4.23(s,2H),3.73(s,2H),2.59(s,3H),1.99(s,3H).MS(ESI):m/z 546[M+H]
+.
实施例88:(6-((3-氰基苯基)氧)-2-(2-氰基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-高脯氨酸
参照实施例54的方法,将实施例中的A-1由3-溴-2-甲基苯胺替换为3-溴-2-氰基苯胺,乙醇胺替换为L-高脯氨酸,制得化合物I-88:
1H NMR(400MHz,DMSO)δ8.10(m,1H),8.02–7.94(m,2H),7.86(t,J=7.4Hz,2H),7.78(t,J=7.4Hz,2H),7.71–7.54(m,7H),5.51(s,2H),3.92–3.76(m,2H),3.15(m,1H),2.97–2.87(m,1H),2.32(m,1H),1.82(brs,2H),1.49(m,4H).MS(ESI):m/z 597[M+H]
+.
实施例89:6-((3-氰基苯基)氧)-2-(2-氟-[1,1′-联苯]-3-基)-5-(((四氢-2H-吡喃-4-基)氨基)甲基)异吲哚-1,3-二酮
参照实施例54的方法,将实施例中的A-1由3-溴-2-甲基苯胺替换为3-溴-2-氟苯胺,乙醇胺替换为4-氨基四氢吡喃,制得化合物I-89:
1H NMR(400MHz,DMSO)δ8.11(s,1H),8.02(m,1H),7.88(t,J=8.2Hz,2H),7.74–7.64(m,3H),7.61–7.43(m,7H),5.50(s,2H),4.03(s,2H),3.84(m,2H),3.28(m,2H),2.80(m,1H),1.89–1.79(m,2H),1.38(m,2H).MS(ESI):m/z 562[M+H]
+.
实施例90:(6-((3-氰基苯基)氧)-2-(2-氟-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-脯氨酸
参照实施例54的方法,将实施例中的A-1由3-溴-2-甲基苯胺替换为3-溴-2-氟苯胺,乙醇胺替换为L-脯氨酸,制得化合物I-90:
1H NMR(400MHz,DMSO)δ8.09(s,1H),8.03(s,1H),7.87(m,2H),7.75–7.37(m,10H),5.59–5.41(m,2H),4.10(m,1H),3.98(m,1H),3.43(m,1H),3.07(m,1H),2.57(m,1H),2.13(m,1H),1.86(m,3H).MS(ESI):m/z 576[M+H]
+.
实施例91:6-((3-氰基苯基)氧)-2-(2-氯-[1,1′-联苯]-3-基)-5-(((四氢-2H-吡喃-4-基)氨基)甲基)异吲哚-1,3-二酮
参照实施例54的方法,将实施例中的A-1由3-溴-2-甲基苯胺替换为3-溴-2-氯苯胺,乙醇胺替换为4-氨基四氢吡喃,制得化合物I-91:
1H NMR(400MHz,DMSO)δ8.09(s,1H),8.00(m,1H),7.90–7.83(m,2H),7.70–7.64(m,3H),7.64–7.55(m,2H),7.53–7.41(m,5H),5.49(s,2H),4.00(s,2H),3.83(m,2H),3.26(m,2H),2.78(m,1H),1.91–1.76(m,2H),1.43–1.26(m,2H).MS(ESI):m/z 579[M+H]
+.
实施例92:(6-((3-氰基苯基)氧)-2-(2-氯-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-5-基)甲基)-L-脯氨酸
参照实施例54的方法,将实施例中的A-1由3-溴-2-甲基苯胺替换为3-溴-2-氯苯胺,乙醇胺替换为L-脯氨酸,制得化合物I-92:
1H NMR(400MHz,DMSO)δ8.08(m,1H),8.02(m,1H),7.87(m,2H),7.73–7.55(m,5H),7.55–7.39(m,5H),5.55–5.40(m,2H),4.10(m,1H),3.97(m,1H),3.43(m,1H),3.07(m,1H),2.60–2.53(m,1H),2.13(m,1H),1.86(m,3H).MS(ESI):m/z 593[M+H]
+.
实施例93:6-((3-氰基苯基)氧)-2-(3-(2,3-二氢苯并[b][1,4]二噁英-6-基)-2-甲基苯基)-5-(((四氢-2H-吡喃-4-基)氨基)甲基)异吲哚-1,3-二酮
参照实施例54的方法,将实施例中的苯硼酸替换为苯并-1,4-二氧六环-6-硼酸,乙醇胺替换为4-氨基四氢吡喃,制得化合物I-93:
1H NMR(400MHz,DMSO)δ8.09(s,1H),8.02(m,1H),7.87(m,2H),7.70–7.62(m,2H),7.40–7.30(m,3H),6.94(d,J=8.2Hz,1H),6.84–6.76(m,2H),5.49(s,2H),4.28(s,4H),4.08(s,2H),3.84(m,2H),3.27(m,2H),2.89(m,1H),1.98(s,3H),1.86(m,2H),1.41(m,2H).MS(ESI):m/z 616[M+H]
+.
实施例94:5-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-4-(((四氢-2H-吡喃-4-基)氨基)甲基)异吲哚-1,3-二酮
合成路线:
化合物A-2和A-3的合成参考实施例1。
化合物F-4的合成:
取化合物A-3(16.45g,50mmol)和乌洛托品(17.5g,125mmol),冰浴条件下,缓慢加入50mL三氟乙酸。之后升温至120℃,回流反应10h,冷却至室温后,加入250mL1N盐酸,再次升温回流2h。加入乙酸乙酯(250mL×3)萃取,合并乙酸乙酯部分,蒸干,硅胶柱层析(石油醚:二氯甲烷:乙酸乙酯=3:1:0.1,v/v/v)得到纯化的化合物F-5(1.785g,收率10%)。
1H NMR(400MHz,DMSO)δ11.75(s,1H),10.82(s,1H),8.09(d,J=8.4Hz,1H),7.52–7.33(m,9H),2.02(s,3H).MS(ESI):m/z 358[M+H]
+.
化合物F-5的合成
取化合物F-4(1.428g,4mmol)加入单口瓶中,加入20mLDMF溶解后,加入碳酸铯(2.608g,8mmol),碘甲烷(1.136g,8mmol),80℃反应2小时。降至室温后,先加入100mL水,再用乙酸乙酯(100mL×3)萃取。合并3次萃取溶液后蒸干,硅胶柱层析得到化合物F-5(0544)(1.113g,收率75%)。
1H NMR(400MHz,DMSO)δ10.88(s,1H),8.22(d,J=8.5Hz,1H),8.03(s,1H),7.92–7.82(m,2H),7.69(m,2H),7.51–7.35(m,8H),5.50(s,2H),2.03(s,3H).MS(ESI):m/z 473[M+H]
+.
化合物I-94的合成:
取化合物F-5(0.472g,1mmol)和4-氨基四氢吡喃(0.303g,3mmol)放入25mL单口瓶中,加入5mL二氯甲烷完全溶解,搅拌2小时后,加入醋酸硼氢化钠(0.844g,4mmol),继续室温反应过夜。之后加入5mL饱和氯化铵溶液,搅拌10分钟后保留二氯甲烷层,弃去水层。蒸干,硅胶柱层析分离(二氯甲烷:甲醇=10:1)分离得到纯化的化合物I-94(0.289g,收率55%)。
1H NMR(400MHz,DMSO)δ8.02(m,1H),7.93–7.82(m,3H),7.66(t,J=7.8Hz,1H),7.54–7.34(m,9H),5.43(s,2H),4.22(s,2H),3.76(m,2H),3.21(m,2H),2.64(m,1H),1.99(s,3H),1.75(m,2H),1.23(m,2H).MS(ESI):m/z 558[M+H]
+.
实施例95:(5-((3-氰基苯基)氧)-2-(2-甲基-[1,1′-联苯]-3-基)-1,3-二氧异吲哚啉-4-基) 甲基)-L-脯氨酸
参照实施例94的方法,将实施例中的4-氨基四氢吡喃替换为L-脯氨酸,制得化合物I-95:
1H NMR(400MHz,DMSO)δ8.08(m,1H),8.02(m,1H),7.87(m,2H),7.73–7.55(m,5H),7.55–7.39(m,5H),5.55–5.40(m,2H),4.10(m,1H),3.97(m,1H),3.43(m,1H),3.07(m,1H),2.60–2.53(m,1H),2.13(m,1H),1.86(m,3H).MS(ESI):m/z 572[M+H]
+.
二、生物活性评价
2.1本发明的化合物对PD-1/PD-L1蛋白-蛋白相互作用的抑制活性评价
采用TR-FRET assay(Time-Resolved Fluorescence Resonance Energy Transfer,时间分辨荧光共振能量转移)的方法,对本发明所有合成的实施例化合物进行了PD-1/PD-L1蛋白-蛋白相互作用的抑制活性测试,确定各个化合物的抑制活性。检测试剂盒购买于BPS Bioscience公司。
实验材料:PD-1-Eu、PD-L1-Biotin及Dye labeled acceptor购自于BPS Bioscience公司;384孔细胞培养板购自Perkin Elmer公司。
实验步骤:
受试化合物的起始测试浓度为10uM,3倍稀释,得到10个浓度梯度溶液,加入384孔板中作为实验组,等量的DMSO加入至阴性对照孔和阳性对照孔中,复孔检测。在化合物孔和阳性对照孔分别加5μL的4倍终浓度的PD-L1-Biotin溶液(用1×modified TR-FRET assay buffer配制);在阴性对照孔中加5μL的1×modified TR-FRET assay buffer。1000rpm离心30秒,振荡混匀后室温孵育15分钟。每孔加入PD-1-Eu(含5μL的4倍终浓度的PD-1-Eu,用1×modified TR-FRET assay buffer配制)和2倍终浓度的Dye labeled acceptor混合溶液(含10μL 2倍终浓度的Dye labeled acceptor,用1×modified TR-FRET assay buffer配制)。1000rpm离心30秒,振荡混匀后室温孵育90分钟。将384孔板1000rpm离心30秒,振荡混匀后用EnVision酶标仪读取665nm和620nm的荧光强度,并计算TR-FRET ratio(665nm emission/620nm emission)。使用Graphpad prism软件计算化合物的IC
50。
本实验选用BMS公司专利WO2015034820中的化合物202(BMS-202)为阳性药。活性测试结果见表1。
表1 化合物抑制PD-1/PD-L1蛋白-蛋白相互作用的蛋白水平活性
实施例编号 | IC 50(nM) | 实施例编号 | IC 50(nM) |
1 | 1059 | 49 | 750.2 |
2 | 249.4 | 50 | 6.1 |
3 | >10000 | 51 | 9.0 |
4 | 395 | 52 | 35.9 |
5 | >10000 | 53 | 16.9 |
6 | >10000 | 54 | 45.4 |
7 | >10000 | 55 | 79.1 |
8 | 1885.0 | 56 | 117.5 |
9 | 1952.0 | 57 | 867.4 |
10 | 5128.0 | 58 | 835.8 |
11 | 3668.0 | 59 | 738.1 |
12 | 6688.0 | 60 | 52.1 |
13 | 5124.0 | 61 | 563.7 |
14 | >10000 | 62 | 45.6 |
15 | >10000 | 63 | 250.7 |
16 | 744.9 | 64 | 216.1 |
17 | 1262.0 | 65 | 150.4 |
18 | 1175.0 | 66 | 29.3 |
19 | 2462.0 | 67 | 42.4 |
20 | 342.3 | 68 | 187.4 |
21 | 590.0 | 69 | 395.4 |
22 | 2519.0 | 70 | 188.9 |
23 | 343.3 | 71 | 739.4 |
24 | 2032.0 | 72 | 170.9 |
25 | 3405.0 | 73 | 153.1 |
26 | 2113.0 | 74 | 216.4 |
27 | 2208.0 | 75 | 920.7 |
28 | 1423.0 | 76 | 1155.0 |
29 | 917.2 | 77 | 13.3 |
30 | 2765.0 | 78 | 1667.0 |
31 | 683.2 | 79 | 11.6 |
32 | 2380.0 | 80 | 607.0 |
33 | 4940.0 | 81 | 14.0 |
34 | 8794.0 | 82 | >10000 |
35 | 2400.0 | 83 | 8.9 |
36 | 912.1 | 84 | 1686.0 |
37 | 968.3 | 85 | 527.1 |
38 | 825.0 | 86 | >10000 |
39 | 156.2 | 87 | 46.6 |
40 | 698.8 | 88 | 100.0 |
41 | 212.3 | 89 | 58.7 |
42 | 789.4 | 90 | 31.6 |
43 | >10000 | 91 | 39.3 |
44 | >10000 | 92 | 22.1 |
45 | 15.6 | 93 | 50.4 |
46 | 46.2 | 94 | 1141.0 |
47 | 138.8 | 95 | 4382.0 |
48 | 296.1 |
测试结果表明,本发明提供的实施例化合物在分子水平可以显著抑制PD-1/PD-L1的相互作用。所述化合物有望成为PD-1/PD-L1靶点相关疾病的候选治疗化合物。
Claims (10)
- 一种通式如下式(I)所示的邻苯二甲酰亚胺类化合物:m是0、1、2、3或4;R 9选自:H或C 1-C 4烷基;R 10选自以下任意一种:t是0、1、2、3或4;R 11选自:H、C 1-C 4烷基或苄基;R 12选自:H或C 1-C 4烷基;R 13选自:H或C 1-C 3烷基;R 14选自:H或C 1-C 4烷基;或者,R 9和R 10与它们所连接的N原子一起形成一个环,选自以下任意一种:s是0、1或2;p是1、2或3;Q选自:S或O或-N(CH(CH 3) 2)-;R 16选自:氢;R 17选自:氢;R 18选自:羧基、酰胺基、-OH、羟基取代的C 1-C 4烷基;所述R 21选自:C 1-C 8烷基;-(CH) nAr,其中,n是1-8,Ar是未取代的苯基或者-CN或C 1-C 4烷基取代的苯基;W选自:卤素、-CN、C 1-C 8烷基;R 4、R 5、R 6、R 7各自独立地选自:H或者R 4、R 5、R 6和R 7之中每两个与它们所连接到的原子一起形成1,4-二氧六环;R 8选自为H。
- 权利要求1所述的邻苯二甲酰亚胺类化合物,其特征在于,所述W选自-CN、甲基或卤素。
- 权利要求1所述的邻苯二甲酰亚胺类化合物,其特征在于,所述W为甲基、氟、氯或溴。
- 一种如权利要求1所述的邻苯二甲酰亚胺类化合物的制备方法,其特征在于,包括以下步骤:(a)以3-溴-2取代苯胺和苯硼酸或苯并-1,4-二氧六环-6-硼酸为原料,通过Suzuki偶联反应得到中间体;(b)将步骤(a)得到的中间体和取代的苯并马来酸酐,在冰醋酸为溶剂条件下制得邻苯二甲酰亚胺中间体;(c)将步骤(b)所得的邻苯二甲酰亚胺中间体与Br-R 21或者是HNR 9R 10缩合反应生成式(I)所示化合物;或者将步骤(b)所得的邻苯二甲酰亚胺中间体经过氧化还原反应后,与胺类化合物发生氨化反应,得到式(I)所示化合物。
- 一种如权利要求1-6任一项所述的邻苯二甲酰亚胺类化合物、其药学上可接受的盐在制备具有PD-1/PD-L1抑制活性的抑制剂中的应用。
- 根据权利要求8所述的应用,其特征在于,所述的抑制剂治疗的疾病包括自身免疫性疾病、癌症及感染性疾病;所述的癌症选自肺癌、黑色素瘤、血液肿瘤、神经胶质肉瘤、消化***肿瘤、乳腺癌、***癌、淋巴瘤、神经***肿瘤、泌尿系肿瘤、皮肤癌;所述的感染性疾病选自细菌及病毒感染;所述的自身免疫性疾病选自器官特异性以及***性自身免疫病。
- 一种药用组合物,其特征在于,包含权利要求1的通式(I)化合物或其药学上可接受的盐以及药学上可接受的载体。
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