WO2018161922A1 - Compound having prmt5 inhibitory activity, preparation for compound, and applications thereof - Google Patents
Compound having prmt5 inhibitory activity, preparation for compound, and applications thereof Download PDFInfo
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- WO2018161922A1 WO2018161922A1 PCT/CN2018/078308 CN2018078308W WO2018161922A1 WO 2018161922 A1 WO2018161922 A1 WO 2018161922A1 CN 2018078308 W CN2018078308 W CN 2018078308W WO 2018161922 A1 WO2018161922 A1 WO 2018161922A1
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- 0 CC*C(*)(*)C(CC1)=C(**)CC1C(NC[C@](CN1CC2C=CC=CC2CC1)O)=O Chemical compound CC*C(*)(*)C(CC1)=C(**)CC1C(NC[C@](CN1CC2C=CC=CC2CC1)O)=O 0.000 description 2
- DUQHYFJHWKPYMW-UHFFFAOYSA-N CN(C)c(cc1)ccc1C(N(C1)Cc2c1ccc(C(NCC(CN(CC1)Cc3c1cccc3)O)=O)c2)=O Chemical compound CN(C)c(cc1)ccc1C(N(C1)Cc2c1ccc(C(NCC(CN(CC1)Cc3c1cccc3)O)=O)c2)=O DUQHYFJHWKPYMW-UHFFFAOYSA-N 0.000 description 2
- CHNSZYQYGWFUCR-UHFFFAOYSA-N OC(CNC(c1cc(CCCC2)c2[s]1)=O)CN(CC1)Cc2c1cccc2 Chemical compound OC(CNC(c1cc(CCCC2)c2[s]1)=O)CN(CC1)Cc2c1cccc2 CHNSZYQYGWFUCR-UHFFFAOYSA-N 0.000 description 2
- NFBIXPXYQKIXML-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)Cc2c1[s]c(C(NCC(CN(CC1)Cc3c1cccc3)O)=O)c2)=O Chemical compound CC(C)(C)OC(N(CC1)Cc2c1[s]c(C(NCC(CN(CC1)Cc3c1cccc3)O)=O)c2)=O NFBIXPXYQKIXML-UHFFFAOYSA-N 0.000 description 1
- NFBIXPXYQKIXML-FQEVSTJZSA-N CC(C)(C)OC(N(CC1)Cc2c1[s]c(C(NC[C@@H](CN(CC1)Cc3c1cccc3)O)=O)c2)=O Chemical compound CC(C)(C)OC(N(CC1)Cc2c1[s]c(C(NC[C@@H](CN(CC1)Cc3c1cccc3)O)=O)c2)=O NFBIXPXYQKIXML-FQEVSTJZSA-N 0.000 description 1
- RXCPAFIUEYPPBV-UHFFFAOYSA-N CCOC(c1cc(CN(CC2)c3ccccc3)c2[s]1)=O Chemical compound CCOC(c1cc(CN(CC2)c3ccccc3)c2[s]1)=O RXCPAFIUEYPPBV-UHFFFAOYSA-N 0.000 description 1
- NIBDPXQBVXGVJT-VWLOTQADSA-N CN(C)c(cc1)ccc1C(N(CC1)Cc2c1[s]c(C(NC[C@@H](CN(CC1)Cc3c1cccc3)O)=O)c2)=O Chemical compound CN(C)c(cc1)ccc1C(N(CC1)Cc2c1[s]c(C(NC[C@@H](CN(CC1)Cc3c1cccc3)O)=O)c2)=O NIBDPXQBVXGVJT-VWLOTQADSA-N 0.000 description 1
- MRZVDDYTJOHXDF-UHFFFAOYSA-N CN(C)c(cc1)ccc1C(N1Cc2cc(C(O)=O)ccc2C1)=O Chemical compound CN(C)c(cc1)ccc1C(N1Cc2cc(C(O)=O)ccc2C1)=O MRZVDDYTJOHXDF-UHFFFAOYSA-N 0.000 description 1
- SFZSRTCMIJIROH-UHFFFAOYSA-N CN(CC1)Cc2c1[nH]c(C(NCC(CN(CC1)Cc3c1cccc3)O)=O)c2 Chemical compound CN(CC1)Cc2c1[nH]c(C(NCC(CN(CC1)Cc3c1cccc3)O)=O)c2 SFZSRTCMIJIROH-UHFFFAOYSA-N 0.000 description 1
- OTCWNAAJDZRRLD-UHFFFAOYSA-N CN(CC1)Cc2c1cc(C(NCC(CN(CC1)Cc3c1cccc3)O)=O)[s]2 Chemical compound CN(CC1)Cc2c1cc(C(NCC(CN(CC1)Cc3c1cccc3)O)=O)[s]2 OTCWNAAJDZRRLD-UHFFFAOYSA-N 0.000 description 1
- YRCZGYLFWHZBPI-UHFFFAOYSA-N COc(cc1)ccc1C(N(CC1)Cc2c1[s]c(C(NCC(CN(CC1)Cc3c1cccc3)O)=O)c2)=O Chemical compound COc(cc1)ccc1C(N(CC1)Cc2c1[s]c(C(NCC(CN(CC1)Cc3c1cccc3)O)=O)c2)=O YRCZGYLFWHZBPI-UHFFFAOYSA-N 0.000 description 1
- TWGGCKBRLKSEKZ-UHFFFAOYSA-N Cc1c(C(NCC(CN(CC2)Cc3c2cccc3)O)=O)[s]c2c1CN(C)CC2 Chemical compound Cc1c(C(NCC(CN(CC2)Cc3c2cccc3)O)=O)[s]c2c1CN(C)CC2 TWGGCKBRLKSEKZ-UHFFFAOYSA-N 0.000 description 1
- POPFFXIOLPNPTC-UHFFFAOYSA-N OC(CNC(c1cc(CC(CC2)NC3CCCCC3)c2[s]1)=O)CN(CC1)Cc2c1cccc2 Chemical compound OC(CNC(c1cc(CC(CC2)NC3CCCCC3)c2[s]1)=O)CN(CC1)Cc2c1cccc2 POPFFXIOLPNPTC-UHFFFAOYSA-N 0.000 description 1
- BHBJACQYJUTQQR-UHFFFAOYSA-N OC(CNC(c1cc(CN(CC2)C(CCc3ccccc3)=O)c2[s]1)=O)CN1Cc2ccccc2CC1 Chemical compound OC(CNC(c1cc(CN(CC2)C(CCc3ccccc3)=O)c2[s]1)=O)CN1Cc2ccccc2CC1 BHBJACQYJUTQQR-UHFFFAOYSA-N 0.000 description 1
- VVFWLOBKAPJBDL-UHFFFAOYSA-N OC(CNC(c1cc(CN(CC2)C(c3cc(cccc4)c4cc3)=O)c2[s]1)=O)CN(CC1)Cc2c1cccc2 Chemical compound OC(CNC(c1cc(CN(CC2)C(c3cc(cccc4)c4cc3)=O)c2[s]1)=O)CN(CC1)Cc2c1cccc2 VVFWLOBKAPJBDL-UHFFFAOYSA-N 0.000 description 1
- PVPFXUDYBZEIQE-UHFFFAOYSA-N OC(CNC(c1cc(CNCC2)c2[s]1)=O)CN(CC1)Cc2c1cccc2 Chemical compound OC(CNC(c1cc(CNCC2)c2[s]1)=O)CN(CC1)Cc2c1cccc2 PVPFXUDYBZEIQE-UHFFFAOYSA-N 0.000 description 1
- WVNSEMQRZMRRAA-UHFFFAOYSA-N OC(CNC(c1cc(COCC2)c2[s]1)=O)CN(CC1)Cc2c1cccc2 Chemical compound OC(CNC(c1cc(COCC2)c2[s]1)=O)CN(CC1)Cc2c1cccc2 WVNSEMQRZMRRAA-UHFFFAOYSA-N 0.000 description 1
- GOHSXPUOHAZZLO-UHFFFAOYSA-N OC(CNC(c1ccc(CCNC2)c2c1)=O)CN1Cc2ccccc2CC1 Chemical compound OC(CNC(c1ccc(CCNC2)c2c1)=O)CN1Cc2ccccc2CC1 GOHSXPUOHAZZLO-UHFFFAOYSA-N 0.000 description 1
- FHACYTRKYWYOHP-JOCHJYFZSA-N O[C@H](CNC(c1cc(CN(CC2)S(c3ccccc3)(=O)=O)c2[s]1)=O)CN(CC1)Cc2c1cccc2 Chemical compound O[C@H](CNC(c1cc(CN(CC2)S(c3ccccc3)(=O)=O)c2[s]1)=O)CN(CC1)Cc2c1cccc2 FHACYTRKYWYOHP-JOCHJYFZSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
-
- 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
- C07D401/12—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 chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- the present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and in particular to a compound having PRMT5 inhibitory activity and its preparation and use.
- the arginine methylation involved in the protein arginine methyltransferase (PRMTs) family is a post-translational modification that is widely present in the nucleus and cytoplasm, with S-adenosyl-methionine as the methyl group. Methylation of the nitrogen atom of the arginine side chain of the modified protein produces S-adenosyl homocysteine and methylarginine.
- the substrate for PRMTs is a protein rich in glycine and arginine domains. A total of 10 PRMTs have been found in mammals, 8 of which are biologically active.
- type I PRMT catalyzes the formation of monomethylarginine and asymmetric dimethylarginine
- type II PRMT catalyzes the formation of MMA and symmetry.
- PRMT5 belongs to type II PRMT.
- PRMT5 can methylate different proteins involved in the regulation of physiological processes.
- PRMT5 can affect gene transcription through methylation of histones and transcription elongation factors; it can methylate the tumor suppressor gene p53 to change the activation state of p53.
- PRMT5 and its molecular chaperone protein MEP50 can form macromolecular complexes with various proteins, which can catalyze multiple substrates in cytoplasm and nucleus such as Sm protein, nucleolar protein, p53, histone H2A, H3 and H4, SPT5 and MBD2. Protein methylation, therefore, PRMT5 plays a key role in RNA processing, chromatin remodeling, and regulation of gene expression.
- PRMT5 regulates MAPK/ERK signaling pathway by methylation of RAF protein, regulates ribosome biosynthesis by methylation of ribosomal protein S10, and plays an important role in cell survival by regulating eIF4E expression and P53 translation. In embryonic stem cells, the differentiation gene is inhibited by methylating H2A in the cytosol. Recent studies have found that PRMT5 and MEP50 are important components of the Grg4 complex and are essential for their regulation of transcriptional repression. PRMT5 is capable of inhibiting the tumor suppressor function of programmed cell death protein 4 (PDCD4). The methyltransferase activity of PRMT5 can be regulated by phosphorylation of MEP50 or PRMT5 itself.
- PDCD4 programmed cell death protein 4
- Cyclin D1/CDK4 phosphorylates Thr5 on MEP50, activating methyltransferase activity of PRMT5 and prolonging the survival of tumor cells.
- the tumorigenic mutations on Jak2 (V617F, K539L) phosphorylate tyrosine at positions 297, 304 and 306 on PRMT5, which disrupts the binding of PRMT5 to MEP50 and down-regulates the methylation activity of histone substrates.
- PRMT5 is a promising target for tumor therapy.
- X is selected from the group consisting of NR 3 and CHR 3 ;
- Y is selected from the group consisting of O, NR 4 , CHR 4 ;
- Z is selected from the group consisting of NR 4 and CHR 4 ;
- Ring A is selected from the group consisting of substituted or unsubstituted 5-membered heteroaryl rings containing 1-2 heteroatoms selected from N, O, S, substituted or unsubstituted, containing 1-2 selected from N, O, a 6-membered heteroaryl ring, a substituted or unsubstituted phenyl group of a hetero atom of S; wherein, when ring A is a phenyl group, at least one of Y and Z is NR 4 ; and the substitution means is selected from the group consisting of Substituted by one or more substituents: halogen, C 1 -C 3 alkyl;
- R 1 and R 2 may be the same or different and are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl;
- R 3 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl
- R 4 is selected from the group consisting of hydrogen, R 5 , V 1 -R 5 ;
- V 1 is selected from the group consisting of CO, CS, CHR 6 , SO 2 , NH, CH 2 CO, COCH 2 , COCH 2 CH 2 , CH 2 CHR 6 , CHR 6 CH 2 , CONH, NHCO, OCO, COO, CH 2 CH 2 O, CH 2 CH 2 CHR 6 , CH 2 CH 2 CO;
- R 5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted, and 1-3 selected from N, O and S. a 4-10 membered cycloheteroalkyl group of a hetero atom, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-10 membered heterocyclic group containing 1-3 hetero atoms selected from N, O and S.
- An aryl group wherein said substitution is substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, C1-C6 alkyl, halo C1-C6 alkyl, 4-10 membered cycloheteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkane containing from 1 to 3 heteroatoms selected from N, O and S Oxyl, C1-C6 alkanoyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) (C1-C6 alkyl), -NH(C3-C8 cycloalkyl), -NH( C3-C8 cycloheteroalkyl), -CO (C1-C6 alkyl), -CONH 2 , -CONH (C1-C6 alkyl),
- R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl.
- p, X, Y, Z, R 1 , R 2 and R 4 are as defined above;
- Ring A is selected from the group consisting of substituted or unsubstituted 5-membered heteroaryl rings containing 1-2 heteroatoms selected from N, O, S, substituted or unsubstituted, containing 1-2 selected from N, O, a 6-membered heteroaryl ring, a substituted or unsubstituted phenyl group of a hetero atom of S; wherein, when ring A is a phenyl group, at least one of Y and Z is NR 4 ; and the substitution means is selected from the group consisting of Substituted by one or more substituents: halogen, C 1 -C 3 alkyl;
- V 1 is selected from the group consisting of CO, CS, CHR 6 , SO 2 , NH, CH 2 CO, COCH 2 , COCH 2 CH 2 , CH 2 CHR 6 , CHR 6 CH 2 , CONH, NHCO, OCO, COO, CH 2 CH 2 O, CH 2 CH 2 CHR 6 , CH 2 CH 2 CO;
- R 5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted, and 1-3 selected from N, O and S. a 4-10 membered cycloheteroalkyl group of a hetero atom, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-10 membered heterocyclic group containing 1-3 hetero atoms selected from N, O and S.
- An aryl group wherein said substitution is substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, C1-C4 alkyl, halo C1-C4 alkyl, 4-8 membered cycloheteroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, halogenated C1-C4 alkane containing from 1 to 3 heteroatoms selected from N, O and S An oxy group, a C1-C4 alkanoyl group, -NH(C1-C4 alkyl group), -N(C1-C4 alkyl group) (C1-C4 alkyl group), -CO(C1-C4 alkyl group), -CONH 2 , -CONH (C1-C4 alkyl), -CON (C1-C4 alkyl) (C1-C4 alkyl), -CO(
- R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl.
- the compound is a compound selected from the group consisting of the formula (II) or the formula (III):
- p, X, Y, Z, R 1 , R 2 and ring A are as defined above.
- Ring A is selected from the group consisting of substituted or unsubstituted thiophenes, furans, pyrroles, thiazoles, phenyl groups; wherein said substitution preferably means substitution by a methyl group.
- R 1 and R 2 may be the same or different and are each independently selected from the group consisting of hydrogen and methyl.
- V 1 is selected from the group consisting of CO, CHR 6 , SO 2 , NH, CH 2 CO, CH 2 CHR 6 , OCO, COO, CH 2 CH 2 CHR 6 , CH 2 CH 2 CO.
- the "5-10 membered aryl" is selected from the group consisting of phenyl, naphthyl.
- the "5-10 membered heteroaryl group” is a 5-9 membered heteroaryl group having 1-2 hetero atoms selected from N, S.
- the "halo" means that the hydrogen on the group is replaced by a halogen, preferably the halogen is selected from the group consisting of F, Cl, Br, I.
- R 5 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, allyl, 2-methoxyethyl, tert-butoxycarbonyl, cyclobutyl, cyclopentane , cyclohexane, 4-methylcyclohexyl, cycloheptyl, phenyl, p-methylphenyl, p-methoxyphenyl, p-chlorophenyl, p-fluorophenyl, p-acetylphenyl , p-aminophenyl, p-nitrophenyl, p-cyanophenyl, p-trifluoromethylphenyl, N,N-dimethylaminophenyl, pyridyl, thienyl, furyl, benzothienyl , tetrahydropyranyl, tetrahydropiperidinyl and 2-naph
- the compound of formula (I) is selected from the specific compounds listed in Table 1.
- any of p, X, Y, Z, ring A, R 1 , R 2 , R 3 , R 4 , V 1 , R 5 , R 6 As defined in the specific compounds shown in Table 1.
- a pharmaceutical composition comprising:
- the pharmaceutical composition is selected from the group consisting of an injection, a sachet, a tablet, a pill, a powder, or a granule.
- a compound of the first aspect of the invention and a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvent thereof
- a pharmaceutical composition according to the second aspect of the present invention for the preparation of a medicament for preventing and/or treating a cancer-related disease, preferably an arginine methyltransferase inhibitor, more preferably a PRMT5 inhibitor Agent.
- the cancer-related disease is selected from the group consisting of breast cancer, lung cancer, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, multiple myeloma AML, liver cancer, melanoma, head and neck cancer. , thyroid cancer, renal cell carcinoma, glioblastoma, and testicular cancer.
- an arginine methyltransferase enzyme activity inhibitor comprising an inhibitory effective amount of one or more compounds of the first aspect of the invention, and a stereo Isomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or solvates.
- a pharmaceutical composition for treating a cancer or an arginine methyltransferase enzymatic activity-related disease comprising a therapeutically effective amount of the first aspect of the invention
- One or more compounds, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, as active ingredients are included in a pharmaceutical composition.
- the condensation agent used in the condensation reaction is 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride/1-hydroxybenzotriazole.
- the deprotecting agent used in the deprotection reaction is trifluoroacetic acid.
- the compound (5) is obtained by reductive amination, nucleophilic substitution, or condensation reaction to give the compound (I).
- a method for inhibiting arginine methyltransferase in vitro comprising the steps of: the compound of the first aspect of the invention, and the stereoisomer thereof, geometric isomerism a body, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate or a solvate or a pharmaceutical composition according to the second aspect of the invention, in contact with an arginine methyltransferase, thereby inhibiting arginine A Base transferase.
- a method of preventing and/or treating a cancer-related disease comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of the compound of the first aspect of the invention, and a stereo thereof Isomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate or the pharmaceutical composition of the second aspect of the invention.
- the present inventors designed and synthesized a series of novel compounds by studying the structure and relationship between the crystal structure of PRMT5 and other PRMT5 inhibitors, and screening these compounds at the molecular and cellular levels. These compounds can significantly inhibit the activity of PRMT5 enzyme at the molecular level, and the cell level also significantly inhibits the proliferation of various cancer cells caused by PRMT5 mutation. On this basis, the inventors completed the present invention.
- halogen refers to F, Cl, Br, and I, and more preferably, the halogen atom is selected from the group consisting of F, Cl, and Br.
- C1-C6 alkyl refers to a straight or branched alkyl group comprising from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl. , tert-butyl, or the like.
- Boc refers to t-butoxycarbonyl, ie
- C1-C6 alkoxy includes a straight or branched alkoxy group of 1 to 6 carbon atoms.
- alkyl includes saturated or unsaturated, straight-chain, branched, cyclic all-alkylene groups of 1 to 6 carbon atoms or 1 to 3 carbon atoms thereof by oxygen, An alkyl group substituted with a hetero atom such as nitrogen or sulfur, and an aralkyl group bonded through one or more carbon atoms. Further, the alkyl group is unsubstituted or substituted.
- aryl includes fused or non-fused aryl groups, usually containing from 5 to 10 carbon atoms, and representative aryl groups include phenyl, naphthyl, or oxygen, nitrogen, sulfur, etc. Aromatic group of atoms.
- cycloheteroalkyl and “heterocycloalkyl” are used interchangeably and refer to a cycloalkyl group containing from 1 to 3 heteroatoms selected from N, O and S.
- the present invention provides a compound represented by the following formula (I), and a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;
- the compound is selected from the compounds listed in Table 1.
- the preparation of the pharmaceutically acceptable salt of the compound of the present invention can be carried out by direct salt formation reaction with an inorganic or organic acid using the free base of the compound.
- the inorganic or organic acid may be selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonate. Acid and p-toluenesulfonic acid and the like.
- solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
- Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
- the preparation process of the compounds of the present invention is as follows, wherein the starting materials and reagents used are commercially available unless otherwise specified.
- the invention also provides a pharmaceutical composition comprising:
- compositions may be prepared in a variety of forms depending on the route of administration.
- compositions of the present invention comprise a safe or effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
- safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
- the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 1000 mg of the compound of the invention per agent.
- the "one dose” is a capsule or tablet.
- “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
- pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
- magnesium stearate magnesium stearate
- calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
- the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
- Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
- the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
- inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
- compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
- the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
- suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
- compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
- Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
- Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
- the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
- the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable other compounds, such as anti-cancer drugs.
- the methods of treatment of the invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
- a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
- the dose to be administered is usually from 1 to 2000 mg, preferably from 50 to 1000 mg.
- specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
- the present invention has the following main advantages:
- the compound has a novel structure; compared with the prior patent, the representative compound EPZ015666, the compounds of the present invention have stronger inhibitory activity at the enzyme level and the cell level.
- Step 3 Preparation of tert-butyl-4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
- Step 6 Preparation of tert-butyl 2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-6,7-tetrahydro[ 3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (I-1)
- the 1-tert-butoxycarbonylpiperidone is replaced with cyclohexanone, and the remaining starting materials, reagents and preparation methods are the same as those in the first step of Example 1, to obtain a colorless oil of 2-chlorocyclohexane-1-enecarboxaldehyde. .
- Step 2 Preparation of ethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid ethyl ester
- Step 3 Preparation of ethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid
- Step 4 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrobenzo[b] Thiophene-2-carboxamide (I-3)
- Step 2 Preparation of ethyl-6,7-dihydro-4H-thieno[3,2-b]furan-2-carboxylic acid ethyl ester
- Step 3 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6,7-dihydro-4-hydro-thieno[3 ,2-c]pyran-2-carboxamide (I-4)
- Step 2 Preparation of ethyl 4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylate
- Step 3 Preparation of ethyl 5-methyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylate
- Step 5 N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-4,5,6,7-tetrahydrofuran[ 3,2-c]pyridine-2-carboxamide (I-5)
- Step 1 Preparation of ethyl 5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate
- Step 2 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-4,5,6,7-tetrahydro -1H-pyrrolo[3,2-c]pyridine-2-carboxamide (I-6)
- Step 1 Preparation of 3-fluoro-4-pyridinecarboxaldehyde and 3-fluoro-2-pyridinecarboxaldehyde
- Step 2 Preparation of ethyl thieno[2,3-c]pyridine-2-carboxylate and ethyl thieno[3,2-b]pyridine-2-carboxylate
- Step 3 Preparation of ethyl 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate
- Step 5 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-methyl-4,5,6,7-tetrahydro Thieno[2,3-c]pyridine-2-carboxamide (I-7)
- Step 1 Preparation of ethyl 6-methyl-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylate
- Step 3 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-methyl-4,5,6,7-tetrahydro Thieno[3,2-b]pyridine-2-carboxamide (I-8)
- Step 1 Preparation of methyl 4,5-bis(chloromethyl)thiophene-2-carboxylate
- Step 4 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-5,6-dihydro-4-hydrogen Thieno[2,3-c]pyrrole-2-carboxamide (I-9)
- Step 2 Preparation of (4-mercaptopyridin-3-yl)carbamic acid tert-butyl ester
- Step 6 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-4,5,6,7-tetrahydro Thiazolo[4,5-c]pyridine-2-carboxamide (I-10)
- Step 1 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(1-tert-butoxycarbonylpiperidin-4-yl )-4,5,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide
- Step 2 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(piperidin-4-yl)-4,5, 6,7-tetrahydro[3,2-c]pyridine-2-carboxamide
- Step 1 Preparation of ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
- Step 2 Preparation of ethyl 5-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
- Step 4 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-phenyl-4,5,6,7-tetrahydro [3,2-c]pyridine-2-carboxamide (I-24)
- Example 34 The acetyl chloride was replaced with phenyl chloroformate, and the remaining materials, reagents and preparation methods were the same as those in Example 34 to obtain a white powder.
- Step 3 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-cyclobutylaminobenzoyl)-4, 5,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-48)
- Step 1 Step 1: Preparation of tert-butyl(4-chloro-3-formylcyclohex-3-en-1-yl)carbamic acid
- the 1-tert-butoxycarbonylpiperidone is replaced by 4-N-Boc-aminocyclohexanone, and the remaining starting materials, reagents and preparation methods are the same as in Step 3 of Example 1, to obtain a colorless oil tert-butyl ( 4-Chloro-3-formylcyclohex-3-en-1-yl)carbamic acid was used without further purification.
- Step 2 Preparation of ethyl 5-((tert-butoxycarbonyl)amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-2carboxylate
- Step 3 Preparation of ethyl 5-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate
- Step 4 Preparation of ethyl 5-(cyclohexylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate
- Step 5 Preparation of 5-(cyclohexylamino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)
- Step 3 Preparation of ethyl 3,5-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
- Step 4 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,5-dimethyl-4,5,6,7 - Tetrahydro[3,2-c]pyridine-2-carboxamide (I-54)
- Step 3 Preparation of (S)-tert-butyl 2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-6,7 - tetrahydro[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester
- Step 4 Preparation of (S)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrothiophene And [3,2-c]pyridine-2-carboxamide
- Step 5 Preparation of (S)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-benzenesulfonyl-4,5,6 ,7-tetrahydro[3,2-c]pyridine-2-carboxamide
- Step 3 Preparation of (R)-tert-butyl 2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-6,7 - tetrahydro[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester
- Step 4 Preparation of (R)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrothiophene And [3,2-c]pyridine-2-carboxamide
- Step 5 Preparation of (R)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-benzenesulfonyl-4,5,6 ,7-tetrahydro[3,2-c]pyridine-2-carboxamide
- Step 1 Preparation of ethyl 5-benzyl-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
- Step 2 Preparation of ethyl 3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
- Step 2 Preparation of 5-(4-(dimethylamino)benzoyl)-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid ester
- Step 3 Preparation of 5-(4-(dimethylamino)benzoyl)-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid
- Step 4 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-chlorobenzoyl)-3-methyl -4,5,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide
- Step 4 Preparation of methyl 2-(4-(dimethylamino)benzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate
- Step 5 Preparation of 2-(4-(dimethylamino)benzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid
- Step 6 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-(dimethylamino)benzoyl) -1,2,3,4-tetrahydroisoquinoline-6-carboxamide
- Step 1 Preparation of methyl 2-(4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate
- Step 3 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-methoxybenzoyl)-1, 2,3,4-tetrahydroisoquinoline-6-carboxamide
- Step 1 Preparation of methyl 2-(4-bromobenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate
- Step 3 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-(4-bromobenzoyl)-1,2,3, 4-tetrahydroisoquinoline-6-carboxamide
- Step 1 Preparation of ((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-3,4-dihydroisoquinoline-2 ( 1H)-tert-butyl formate
- Step 2 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline-7 -formamide
- Step 3 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-(dimethylamino)benzoyl) -1,2,3,4-tetrahydroisoquinoline-7-carboxamide
- Step 3 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-(dimethylamino)benzoyl) Isoindane-5-carboxamide
- Step 2 Preparation of ethyl 5-benzyl-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
- Step 2 Preparation of ethyl 7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
- Step 3 Preparation of 5-(4-(dimethylamino)benzoyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2 -ethyl formate
- Step 4 Preparation of 5-(4-(dimethylamino)benzoyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2 -formic acid
- Step 5 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-(dimethylamino)benzoyl) -7,7-Dimethyl-4,5,6,7-pheno[3,2-c]pyridine-2-carboxamide
- the enzymatic activity of the compound was tested by a radioisotope method.
- the experimental methods are as follows: 1. Prepare 1x assay buffer (modified Tris-HCl buffer); 2. Dilute the compound to the desired concentration in a 96-well plate; 3. Prepare the protein solution, also use 1x assay buffer; Add the substrate to 1x assay buffer to prepare the substrate solution; 5. Add [3H]-SAM to 1x assay buffer to prepare [ 3 H]-SAM solution; 6. Add SAM to 1x assay buffer Prepare a cold SAM solution; 7. Pipette 10 L of protein solution into a 96-well plate containing the compound; 8. Incubate for 15 minutes at room temperature; 9. Add 10 L of substrate solution to each well; 10. To each well The reaction was initiated by the addition of 10 L of [ 3 H]-SAM solution; 11.
- EPZ015666 is as follows:
- the series of compounds having strong PRMT5 inhibitory activity values 50 between the IC 0.0085-2.7 ⁇ M, EPZ015666 positive control IC 50 value of 0.047 ⁇ M, the visible portion of the active compounds of the present invention is stronger than the Positive control compounds, such as I-55 (0.027 ⁇ M), I-76 (0.011 ⁇ M), I-80 (0.0085 ⁇ M), and the like. .
- the culture medium used for cell culture of MCL (Maver-1, Z138, Jeko-1) is RPMI 1640 + 10% fetal bovine serum, and in order to prevent bacterial contamination, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin were added to the culture solution. .
- the cells were cultured at 37 ° C under 5% CO 2 saturated humidity, and the cells used in the experiment were in the logarithmic growth phase.
- the concentration of MCL cells was adjusted to 1 ⁇ 10 5 /mL and inoculated into 24-well culture plates at a volume of 1 mL per well.
- the control group and the experimental group were established, and the control group was added with DMSO.
- the experimental group was added with PRMT5 active small molecule compound and the final concentration was 0.
- the three detection time points were 4, 8 and 12 days respectively.
- the cells were cultured at 37 ° C in a 5% CO 2 incubator at various time points, and the amount of viable cells was measured using CellTiter-Glo reagent.
- the concentration of the compound of the present invention showed significant dose- and time-dependent inhibition of proliferation after 4, 8 and 12 days of treatment of MCL cells in the range of 0-100 ⁇ mol/L, and the IC 50 was 0.02 to 22 ⁇ M. between, have strong cytostatic activity; active compound wherein the portion of the compound is significantly stronger than the positive EPZ015666, such as I-62 on the proliferation of cells 12 days Maver-1 inhibition IC 50 of 0.02 M, was stronger than EPZ015666 (IC 50 of 0.10 ⁇ M), I-39 on the proliferation of cells 12 days Jeko-1 inhibition IC 50 of 0.58 ⁇ M, significantly stronger than EPZ015666 (IC 50 of 1.04 ⁇ M).
- 1640 medium (Gibco, Life Technologies, 22400-089) containing 10% fetal bovine serum (Gibco, Life Technologies, 10099-141) and 1% antibiotic (penicillin and streptomycin, Life Technologies, 10378016) at 37 °C
- Acute mononuclear leukemia cell line MV4-11 (ATCC, CRL-9591) was cultured under 5% CO 2 saturated humidity conditions, and the cells were in logarithmic growth phase.
- the cell density of MV4-11 was adjusted to 1 ⁇ 10 5 /mL, gently pipetted and inoculated into a 24-well cell culture plate, and the volume of the medium was 1 mL per well, and placed in an incubator for 6 hours.
- a control group and an experimental group were established, and a control group was added with DMSO.
- the experimental group was added with a PRMT5 active small molecule compound to a final concentration of 0.015 to 100 ⁇ M, and the final concentration of DMSO was maintained at 0.1%.
- the three detection time points were 4, 8 and 12 days respectively.
- the cells were cultured at 37 ° C and 5% CO 2 incubator at various time points.
- the DMSO control cells were recounted, adjusted to the initial seeding density, and passaged into new culture plates to ensure that the DMSO control cells were in the right phase. Within the number of growth cycles.
- the cells were further cultured and re-added to the compound at the initial dose; while well-suspended 40 ⁇ L of the cell suspension was transferred to a 384-well plate, and 40 uL of CellTiter-Glo reagent (Promega, G7572) was added to each well to allow Mix well and react, incubate for 10 minutes at room temperature in a shaker, then let stand for 10 minutes.
- the detection was carried out at a wavelength of 400 to 700 nm using a Multilabel reader (EnVision, PerkinElmer), and the whole process was protected from light. Detection data analysis software by GraphPad Prism 5.0, 50 fit values calculated IC.
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Abstract
The present invention relates to a compound having PRMT5 inhibitory activity, a preparation for the compound, and applications thereof. Specifically, the compound of the present invention has a structure as represented by formula I, where the definitions of the groups and substituents are as presented in the description. Also disclosed are a preparation method for the compound and uses thereof in preventing and/or treating cancer-related diseases. The compound of the present invention has great protein arginine N-methyltransferase 5 inhibitory activity and thus is applicable in preparing a series of medicaments for treating diseases related to protein arginine N-methyltransferase 5 activity.
Description
本发明涉及药物化学和药物治疗学领域,具体地涉及一种具有PRMT5抑制活性的化合物及其制备和应用。The present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and in particular to a compound having PRMT5 inhibitory activity and its preparation and use.
蛋白质精氨酸甲基转移酶(PRMTs)家族参与的精氨酸甲基化是一种在细胞核和细胞质广泛存在的翻译后修饰方式,其以S-腺苷-甲硫氨酸为甲基供体,甲基化修饰蛋白精氨酸侧链的氮原子,生成S-腺苷同型半胱氨酸和甲基精氨酸。PRMTs的底物是富含甘氨酸和精氨酸结构域的蛋白质。目前在哺乳动物身上共发现10种PRMTs,其中8种具有生物学活性。根据甲基化产物的不同,可以将其分为Ⅰ型及Ⅱ型:Ⅰ型PRMT催化形成单甲基精氨酸和非对称的二甲基精氨酸,Ⅱ型PRMT催化形成MMA和对称的二甲基精氨酸。PRMT5属于Ⅱ型PRMT。The arginine methylation involved in the protein arginine methyltransferase (PRMTs) family is a post-translational modification that is widely present in the nucleus and cytoplasm, with S-adenosyl-methionine as the methyl group. Methylation of the nitrogen atom of the arginine side chain of the modified protein produces S-adenosyl homocysteine and methylarginine. The substrate for PRMTs is a protein rich in glycine and arginine domains. A total of 10 PRMTs have been found in mammals, 8 of which are biologically active. According to the different methylation products, they can be divided into type I and type II: type I PRMT catalyzes the formation of monomethylarginine and asymmetric dimethylarginine, and type II PRMT catalyzes the formation of MMA and symmetry. Dimethylarginine. PRMT5 belongs to type II PRMT.
PRMT5可甲基化不同的蛋白参与调节生理过程,例如PRMT5可以通过甲基化组蛋白和转录延长因子从而影响基因转录过程;它可以甲基化抑癌基因p53改变p53的激活状态。PRMT5与其分子伴侣蛋白MEP50能够与多种蛋白形成大分子复合物,使其能够催化Sm蛋白,核仁蛋白,p53,组蛋白H2A,H3和H4,SPT5和MBD2等细胞质和细胞核中多种底物蛋白的甲基化,因此,PRMT5在RNA加工、染色质重塑以及调控基因表达等过程中发挥关键作用。PRMT5通过甲基化RAF蛋白来调控MAPK/ERK信号通路,通过甲基化核糖体蛋白S10来调节核糖体的生物合成,通过调控eIF4E的表达和P53的翻译从而在细胞存活中起重要作用。在胚胎干细胞中,通过甲基化胞浆中的H2A来抑制分化基因。最近研究发现,PRMT5和MEP50作为Grg4复合物的重要组成,是其调控转录抑制所必不可少的。PRMT5能够抑制程序性细胞死亡蛋白4(PDCD4)的肿瘤抑制功能。PRMT5的甲基转移酶活性能够被MEP50或者PRMT5本身的磷酸化所调控。细胞周期蛋白D1/CDK4磷酸化MEP50上的Thr5,激活了PRMT5的甲基转移酶活性,延长了肿瘤细胞的生存期。相反,Jak2上的致瘤突变(V617F,K539L)磷酸化PRMT5上297,304和306位的酪氨酸,能够破坏PRMT5与MEP50的结合,下调对组蛋白底物的甲基催化活性。PRMT5 can methylate different proteins involved in the regulation of physiological processes. For example, PRMT5 can affect gene transcription through methylation of histones and transcription elongation factors; it can methylate the tumor suppressor gene p53 to change the activation state of p53. PRMT5 and its molecular chaperone protein MEP50 can form macromolecular complexes with various proteins, which can catalyze multiple substrates in cytoplasm and nucleus such as Sm protein, nucleolar protein, p53, histone H2A, H3 and H4, SPT5 and MBD2. Protein methylation, therefore, PRMT5 plays a key role in RNA processing, chromatin remodeling, and regulation of gene expression. PRMT5 regulates MAPK/ERK signaling pathway by methylation of RAF protein, regulates ribosome biosynthesis by methylation of ribosomal protein S10, and plays an important role in cell survival by regulating eIF4E expression and P53 translation. In embryonic stem cells, the differentiation gene is inhibited by methylating H2A in the cytosol. Recent studies have found that PRMT5 and MEP50 are important components of the Grg4 complex and are essential for their regulation of transcriptional repression. PRMT5 is capable of inhibiting the tumor suppressor function of programmed cell death protein 4 (PDCD4). The methyltransferase activity of PRMT5 can be regulated by phosphorylation of MEP50 or PRMT5 itself. Cyclin D1/CDK4 phosphorylates Thr5 on MEP50, activating methyltransferase activity of PRMT5 and prolonging the survival of tumor cells. In contrast, the tumorigenic mutations on Jak2 (V617F, K539L) phosphorylate tyrosine at positions 297, 304 and 306 on PRMT5, which disrupts the binding of PRMT5 to MEP50 and down-regulates the methylation activity of histone substrates.
目前已有研究发现在套细胞淋巴癌以及弥漫性大B细胞淋巴瘤中存在PRMT5的过表达,PRMT5与恶性肿瘤B细胞的增殖与存活有直接的关联。因此PRMT5是一个有前景的肿瘤治疗靶点。It has been found that overexpression of PRMT5 is present in mantle cell lymphoma and diffuse large B-cell lymphoma, and PRMT5 is directly associated with proliferation and survival of malignant B cells. Therefore PRMT5 is a promising target for tumor therapy.
综上所述,本领域迫切需要开发新型的精氨酸甲基转移酶抑制剂。In summary, there is an urgent need in the art to develop novel arginine methyltransferase inhibitors.
发明内容Summary of the invention
本发明的目的在于提供一种式I所示化合物及其制备方法和其在预防和/或治疗癌症 相关疾病方面的用途。It is an object of the present invention to provide a compound of formula I, a process for its preparation and its use in the prevention and/or treatment of cancer-related diseases.
本发明的第一方面,提供了一种如下式(I)所示的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物,According to a first aspect of the present invention, there is provided a compound represented by the following formula (I), and a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvent thereof. Compound,
其中,p为0或1;Where p is 0 or 1;
X选自下组:NR
3、CHR
3;
X is selected from the group consisting of NR 3 and CHR 3 ;
Y选自下组:O、NR
4、CHR
4;
Y is selected from the group consisting of O, NR 4 , CHR 4 ;
Z选自下组:NR
4、CHR
4;
Z is selected from the group consisting of NR 4 and CHR 4 ;
环A选自下组:取代或未取代的含1-2个选自N、O、S的杂原子的5元杂芳环、取代或未取代的含1-2个选自N、O、S的杂原子的6元杂芳环、取代或未取代的苯基;其中,当环A为苯基的时候,Y与Z至少一个为NR
4;并且,所述取代指被选自下组的1个或多个取代基取代:卤素、C
1-C
3烷基;
Ring A is selected from the group consisting of substituted or unsubstituted 5-membered heteroaryl rings containing 1-2 heteroatoms selected from N, O, S, substituted or unsubstituted, containing 1-2 selected from N, O, a 6-membered heteroaryl ring, a substituted or unsubstituted phenyl group of a hetero atom of S; wherein, when ring A is a phenyl group, at least one of Y and Z is NR 4 ; and the substitution means is selected from the group consisting of Substituted by one or more substituents: halogen, C 1 -C 3 alkyl;
R
1和R
2可相同或不同,分别独立地选自下组:氢、C
1-C
3烷基;
R 1 and R 2 may be the same or different and are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl;
R
3选自下组:氢、C
1-C
3烷基;
R 3 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl;
R
4选自下组:氢、R
5、V
1-R
5;
R 4 is selected from the group consisting of hydrogen, R 5 , V 1 -R 5 ;
V
1选自下组:CO、CS、CHR
6、SO
2、NH、CH
2CO、COCH
2、COCH
2CH
2、CH
2CHR
6、CHR
6CH
2、CONH、NHCO、OCO、COO、CH
2CH
2O、CH
2CH
2CHR
6、CH
2CH
2CO;
V 1 is selected from the group consisting of CO, CS, CHR 6 , SO 2 , NH, CH 2 CO, COCH 2 , COCH 2 CH 2 , CH 2 CHR 6 , CHR 6 CH 2 , CONH, NHCO, OCO, COO, CH 2 CH 2 O, CH 2 CH 2 CHR 6 , CH 2 CH 2 CO;
R
5选自下组:氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的含有1-3个选自N、O和S的杂原子的4-10元环杂烷基、取代或未取代的5-10元芳基、取代或未取代的含有1-3个选自N、O和S的杂原子的5-10元杂芳基,其中,所述取代指被选自下组的1个或多个取代基取代:卤素、氰基、硝基、氨基、羟基、C1-C6烷基、卤代C1-C6烷基、含有1-3个选自N、O和S的杂原子的4-10元环杂烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷酰基、-NH(C1~C6烷基)、-N(C1~C6烷基)(C1~C6烷基)、-NH(C3~C8环烷基)、-NH(C3~C8环杂烷基)、-CO(C1~C6烷基)、-CONH
2、-CONH(C1~C6烷基)、-CON(C1~C6烷基)(C1~C6烷基)、-CO(O)(C1~C6烷基)、-O(C1~C6烷基);
R 5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted, and 1-3 selected from N, O and S. a 4-10 membered cycloheteroalkyl group of a hetero atom, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-10 membered heterocyclic group containing 1-3 hetero atoms selected from N, O and S. An aryl group, wherein said substitution is substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, C1-C6 alkyl, halo C1-C6 alkyl, 4-10 membered cycloheteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkane containing from 1 to 3 heteroatoms selected from N, O and S Oxyl, C1-C6 alkanoyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) (C1-C6 alkyl), -NH(C3-C8 cycloalkyl), -NH( C3-C8 cycloheteroalkyl), -CO (C1-C6 alkyl), -CONH 2 , -CONH (C1-C6 alkyl), -CON (C1-C6 alkyl) (C1-C6 alkyl), -CO(O)(C1-C6 alkyl), -O(C1-C6 alkyl);
R
6选自下组:氢、C
1-C
3烷基。
R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl.
在另一优选例中,p、X、Y、Z、R
1、R
2和R
4如上文所定义;
In another preferred embodiment, p, X, Y, Z, R 1 , R 2 and R 4 are as defined above;
环A选自下组:取代或未取代的含1-2个选自N、O、S的杂原子的5元杂芳环、取代或未取代的含1-2个选自N、O、S的杂原子的6元杂芳环、取代或未取代的苯基;其中, 当环A为苯基的时候,Y与Z至少一个为NR
4;并且,所述取代指被选自下组的1个或多个取代基取代:卤素、C
1-C
3烷基;
Ring A is selected from the group consisting of substituted or unsubstituted 5-membered heteroaryl rings containing 1-2 heteroatoms selected from N, O, S, substituted or unsubstituted, containing 1-2 selected from N, O, a 6-membered heteroaryl ring, a substituted or unsubstituted phenyl group of a hetero atom of S; wherein, when ring A is a phenyl group, at least one of Y and Z is NR 4 ; and the substitution means is selected from the group consisting of Substituted by one or more substituents: halogen, C 1 -C 3 alkyl;
V
1选自下组:CO、CS、CHR
6、SO
2、NH、CH
2CO、COCH
2、COCH
2CH
2、CH
2CHR
6、CHR
6CH
2、CONH、NHCO、OCO、COO、CH
2CH
2O、CH
2CH
2CHR
6、CH
2CH
2CO;
V 1 is selected from the group consisting of CO, CS, CHR 6 , SO 2 , NH, CH 2 CO, COCH 2 , COCH 2 CH 2 , CH 2 CHR 6 , CHR 6 CH 2 , CONH, NHCO, OCO, COO, CH 2 CH 2 O, CH 2 CH 2 CHR 6 , CH 2 CH 2 CO;
R
5选自下组:氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的含有1-3个选自N、O和S的杂原子的4-10元环杂烷基、取代或未取代的5-10元芳基、取代或未取代的含有1-3个选自N、O和S的杂原子的5-10元杂芳基,其中,所述取代指被选自下组的1个或多个取代基取代:卤素、氰基、硝基、氨基、羟基、C1-C4烷基、卤代C1-C4烷基、含有1-3个选自N、O和S的杂原子的4-8元环杂烷基、C2-C4烯基、C2-C4炔基、C1-C4烷氧基、卤代C1-C4烷氧基、C1-C4烷酰基、-NH(C1~C4烷基)、-N(C1~C4烷基)(C1~C4烷基)、-CO(C1~C4烷基)、-CONH
2、-CONH(C1~C4烷基)、-CON(C1~C4烷基)(C1~C4烷基)、-CO(O)(C1~C4烷基)、-O(C1~C4烷基);
R 5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted, and 1-3 selected from N, O and S. a 4-10 membered cycloheteroalkyl group of a hetero atom, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-10 membered heterocyclic group containing 1-3 hetero atoms selected from N, O and S. An aryl group, wherein said substitution is substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, C1-C4 alkyl, halo C1-C4 alkyl, 4-8 membered cycloheteroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, halogenated C1-C4 alkane containing from 1 to 3 heteroatoms selected from N, O and S An oxy group, a C1-C4 alkanoyl group, -NH(C1-C4 alkyl group), -N(C1-C4 alkyl group) (C1-C4 alkyl group), -CO(C1-C4 alkyl group), -CONH 2 , -CONH (C1-C4 alkyl), -CON (C1-C4 alkyl) (C1-C4 alkyl), -CO(O) (C1-C4 alkyl), -O(C1-C4 alkyl);
R
6选自下组:氢、C
1-C
3烷基。
R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl.
在另一优选例中,所述化合物为选自通式(Ⅱ)或通式(Ⅲ)所示的化合物:In another preferred embodiment, the compound is a compound selected from the group consisting of the formula (II) or the formula (III):
其中,among them,
p、X、Y、Z、R
1、R
2和环A如上文所定义。
p, X, Y, Z, R 1 , R 2 and ring A are as defined above.
在另一优选例中,环A选自下组:取代或未取代的噻吩、呋喃、吡咯、噻唑、苯基;其中,所述取代优选指被甲基取代。In another preferred embodiment, Ring A is selected from the group consisting of substituted or unsubstituted thiophenes, furans, pyrroles, thiazoles, phenyl groups; wherein said substitution preferably means substitution by a methyl group.
在另一优选例中,R
1和R
2可相同或不同,分别独立地选自下组:氢、甲基。
In another preferred embodiment, R 1 and R 2 may be the same or different and are each independently selected from the group consisting of hydrogen and methyl.
在另一优选例中,V
1选自下组:CO、CHR
6、SO
2、NH、CH
2CO、CH
2CHR
6
、OCO、COO、CH
2CH
2CHR
6、CH
2CH
2CO。
In another preferred embodiment, V 1 is selected from the group consisting of CO, CHR 6 , SO 2 , NH, CH 2 CO, CH 2 CHR 6 , OCO, COO, CH 2 CH 2 CHR 6 , CH 2 CH 2 CO.
在另一优选例中,所述“5-10元芳基”选自下组:苯基、萘基。In another preferred embodiment, the "5-10 membered aryl" is selected from the group consisting of phenyl, naphthyl.
在另一优选例中,所述“5-10元杂芳基”为含1-2个选自N、S的杂原子的5-9元杂芳基。In another preferred embodiment, the "5-10 membered heteroaryl group" is a 5-9 membered heteroaryl group having 1-2 hetero atoms selected from N, S.
在另一优选例中,所述“卤代”指所述基团上的氢被卤素取代,优选地,所述卤素选自下组:F、Cl、Br、I。In another preferred embodiment, the "halo" means that the hydrogen on the group is replaced by a halogen, preferably the halogen is selected from the group consisting of F, Cl, Br, I.
在另一优选例中,R
5选自下组:甲基、乙基、丙基、异丙基、烯丙基、2-甲氧基乙基、叔丁氧羰基、环丁基、环戊基、环己烷基、4-甲基环己基、环庚烷基、苯基、对甲基苯基、对甲氧基苯基、对氯苯基、对氟苯基、对乙酰基苯基、对氨基苯基、对硝基苯基、对氰基苯基、对三氟甲基苯基、N,N-二甲基氨基苯基、吡啶基、噻吩基、呋喃基、 苯并噻吩基、四氢吡喃基、四氢哌啶基和2-萘基。
In another preferred embodiment, R 5 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, allyl, 2-methoxyethyl, tert-butoxycarbonyl, cyclobutyl, cyclopentane , cyclohexane, 4-methylcyclohexyl, cycloheptyl, phenyl, p-methylphenyl, p-methoxyphenyl, p-chlorophenyl, p-fluorophenyl, p-acetylphenyl , p-aminophenyl, p-nitrophenyl, p-cyanophenyl, p-trifluoromethylphenyl, N,N-dimethylaminophenyl, pyridyl, thienyl, furyl, benzothienyl , tetrahydropyranyl, tetrahydropiperidinyl and 2-naphthyl.
在另一优选例中,所述式(I)化合物选自表1所列具体化合物。In another preferred embodiment, the compound of formula (I) is selected from the specific compounds listed in Table 1.
在另一优选例中,所述式(I)化合物中,p、X、Y、Z、环A、R
1、R
2、R
3、R
4、V
1、R
5、R
6中任一如表1所示具体化合物中所定义。
In another preferred embodiment, in the compound of the formula (I), any of p, X, Y, Z, ring A, R 1 , R 2 , R 3 , R 4 , V 1 , R 5 , R 6 As defined in the specific compounds shown in Table 1.
本发明的第二方面,提供了一种药物组合物,所述药物组合物包括:In a second aspect of the invention, a pharmaceutical composition is provided, the pharmaceutical composition comprising:
(i)治疗有效量的如本发明第一方面所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物;和(i) a therapeutically effective amount of a compound according to the first aspect of the invention, and a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; with
(ii)任选的药学上可接受的载体。(ii) an optional pharmaceutically acceptable carrier.
在另一优选例中,所述的药物组合物选自下组:注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。In another preferred embodiment, the pharmaceutical composition is selected from the group consisting of an injection, a sachet, a tablet, a pill, a powder, or a granule.
本发明的第三方面,提供了一种本发明第一方面所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物或本发明第二方面所述的药物组合物在制备预防和/或治疗癌症相关疾病的药物中的用途,所述药物优选为精氨酸甲基转移酶抑制剂,更优选为PRMT5抑制剂。According to a third aspect of the invention, there is provided a compound of the first aspect of the invention, and a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvent thereof Use of the pharmaceutical composition according to the second aspect of the present invention or a pharmaceutical composition according to the second aspect of the invention for the preparation of a medicament for preventing and/or treating a cancer-related disease, preferably an arginine methyltransferase inhibitor, more preferably a PRMT5 inhibitor Agent.
在另一优选例中,所述的癌症相关疾病选自下组:乳腺癌、肺癌、膀胱癌、胃癌、胰腺癌、***癌、结肠癌、多发性骨髓瘤AML、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌和睾丸癌。In another preferred embodiment, the cancer-related disease is selected from the group consisting of breast cancer, lung cancer, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, multiple myeloma AML, liver cancer, melanoma, head and neck cancer. , thyroid cancer, renal cell carcinoma, glioblastoma, and testicular cancer.
本发明的第四方面,提供了一种精氨酸甲基转移酶酶活抑制剂,所述抑制剂含有抑制有效量的本发明第一方面所述的一种或多种化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物。According to a fourth aspect of the invention, there is provided an arginine methyltransferase enzyme activity inhibitor comprising an inhibitory effective amount of one or more compounds of the first aspect of the invention, and a stereo Isomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or solvates.
本发明的第五方面,提供了一种用于治疗癌症或精氨酸甲基转移酶酶活性相关疾病的药物组合物,所述药物组合物包括治疗有效量的本发明第一方面所述的一种或多种化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物,作为活性组分。According to a fifth aspect of the invention, a pharmaceutical composition for treating a cancer or an arginine methyltransferase enzymatic activity-related disease, the pharmaceutical composition comprising a therapeutically effective amount of the first aspect of the invention One or more compounds, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, as active ingredients.
本发明的第六方面,提供了一种式(I)化合物的制备方法,所述方法包括步骤:According to a sixth aspect of the invention, there is provided a process for the preparation of a compound of formula (I), the process comprising the steps of:
方案I:Option I:
化合物(1)与化合物(2)通过缩合反应得到化合物(I);或Compound (1) and compound (2) are subjected to a condensation reaction to obtain compound (I); or
方案II:Option II:
化合物(3)与化合物(2)通过缩合反应得到化合物(4),化合物(4)通过脱保护反应得到化合物(5),化合物(5)通过取代反应得到化合物(I);Compound (3) and compound (2) are obtained by condensation reaction to obtain compound (4), compound (4) is obtained by deprotection reaction to obtain compound (5), and compound (5) is obtained by substitution reaction to obtain compound (I);
其中,X、Y、Z、p、R
1、R
2和环A如本发明第一方面所定义。
Wherein X, Y, Z, p, R 1 , R 2 and ring A are as defined in the first aspect of the invention.
在另一优选例中,所述缩合反应采用的缩合剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐/1-羟基苯并***。In another preferred embodiment, the condensation agent used in the condensation reaction is 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride/1-hydroxybenzotriazole.
在另一优选例中,所述脱保护反应所用的脱保护剂为三氟乙酸。In another preferred embodiment, the deprotecting agent used in the deprotection reaction is trifluoroacetic acid.
在另一优选例中,所述化合物(5)通过还原胺化,或亲核取代,或缩合反应得到化合物(I)。In another preferred embodiment, the compound (5) is obtained by reductive amination, nucleophilic substitution, or condensation reaction to give the compound (I).
本发明的第七方面,提供了一种体外抑制精氨酸甲基转移酶的方法,所述方法包括步骤:将本发明第一方面所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物或本发明第二方面所述的药物组合物,与精氨酸甲基转移酶接触,从而抑制精氨酸甲基转移酶。According to a seventh aspect of the invention, there is provided a method for inhibiting arginine methyltransferase in vitro, the method comprising the steps of: the compound of the first aspect of the invention, and the stereoisomer thereof, geometric isomerism a body, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate or a solvate or a pharmaceutical composition according to the second aspect of the invention, in contact with an arginine methyltransferase, thereby inhibiting arginine A Base transferase.
本发明的第八方面,提供了一种预防和/或治疗癌症相关疾病的方法,所述方法包括步骤:对所需患者施用治疗有效量的本发明第一方面所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物或本发明第二方面所述的药物组合物。According to an eighth aspect of the invention, a method of preventing and/or treating a cancer-related disease, the method comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of the compound of the first aspect of the invention, and a stereo thereof Isomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate or the pharmaceutical composition of the second aspect of the invention.
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅, 在此不再一一累述。It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
本发明人经过长期而深入的研究,通过对PRMT5的晶体结构和其它PRMT5抑制剂的构效关系的研究,设计合成了一系列结构新颖的化合物,通过分子和细胞水平对这些化合物进行筛选,发现这些化合物在分子水平能够明显抑制PRMT5酶活性,细胞水平对PRMT5突变引起的各种癌细胞增殖也有显著抑制作用。在此基础上,发明人完成了本发明。After long-term and in-depth research, the present inventors designed and synthesized a series of novel compounds by studying the structure and relationship between the crystal structure of PRMT5 and other PRMT5 inhibitors, and screening these compounds at the molecular and cellular levels. These compounds can significantly inhibit the activity of PRMT5 enzyme at the molecular level, and the cell level also significantly inhibits the proliferation of various cancer cells caused by PRMT5 mutation. On this basis, the inventors completed the present invention.
术语the term
如本文所用,“卤素”指F、Cl、Br、和I,更佳地,卤原子选自F、Cl和Br。As used herein, "halogen" refers to F, Cl, Br, and I, and more preferably, the halogen atom is selected from the group consisting of F, Cl, and Br.
如本文所用,“C1-C6烷基”是指包括1-6个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、或类似基团。As used herein, "C1-C6 alkyl" refers to a straight or branched alkyl group comprising from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl. , tert-butyl, or the like.
如本文所用,“C1-C6烷氧基”包括1-6个碳原子的直链或支链的烷氧基。例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、或类似基团。As used herein, "C1-C6 alkoxy" includes a straight or branched alkoxy group of 1 to 6 carbon atoms. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, or the like.
此外,在本发明中,术语“烷基”包括饱和或不饱和、直链、支链、环状的1-6个碳原子的全碳烷基或其中的1-3个碳原子被氧、氮、硫等杂原子取代的烷基,以及通过1个或1个以上碳原子连接的芳烷基。此外,所述的烷基是未取代的或取代的。Further, in the present invention, the term "alkyl" includes saturated or unsaturated, straight-chain, branched, cyclic all-alkylene groups of 1 to 6 carbon atoms or 1 to 3 carbon atoms thereof by oxygen, An alkyl group substituted with a hetero atom such as nitrogen or sulfur, and an aralkyl group bonded through one or more carbon atoms. Further, the alkyl group is unsubstituted or substituted.
如本文所用,术语“芳基”包括稠合或非稠合的芳基,通常含有5-10个碳原子,代表性的芳基包括苯基、萘基,或含氧、氮、硫等杂原子的芳香基团。As used herein, the term "aryl" includes fused or non-fused aryl groups, usually containing from 5 to 10 carbon atoms, and representative aryl groups include phenyl, naphthyl, or oxygen, nitrogen, sulfur, etc. Aromatic group of atoms.
如本文所用,术语“环杂烷基”和“杂环烷基”可互换使用,均指包含1-3个选自N、O和S的杂原子的环烷基。As used herein, the terms "cycloheteroalkyl" and "heterocycloalkyl" are used interchangeably and refer to a cycloalkyl group containing from 1 to 3 heteroatoms selected from N, O and S.
化合物Compound
本发明提供了一种如下式(I)所示的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物,The present invention provides a compound represented by the following formula (I), and a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;
其中,p、X、Y、Z、环A、R
1、R
2、R
3、R
4、V
1、R
5、R
6如上文所定义。
Wherein p, X, Y, Z, ring A, R 1 , R 2 , R 3 , R 4 , V 1 , R 5 , R 6 are as defined above.
应理解,本发明所描述的结构式包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体),例如含有不对称中心的R、S构型)。因此,本发明的化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的保护范围。It will be understood that the structural formulae described herein include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers), such as R containing an asymmetric center, S configuration). Thus, a single stereochemical isomer of a compound of the invention, or a mixture of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof, is intended to be within the scope of the invention.
在另一优选例中,所述化合物选自表1所列化合物。In another preferred embodiment, the compound is selected from the compounds listed in Table 1.
表1Table 1
本发明化合物的药用盐的制备,可以采用化合物的游离碱,与无机或有机酸直接成盐反应进行。无机或有机酸可选自盐酸、硫酸、磷酸、硝酸、氢氟酸、氢溴酸、甲酸、乙酸、苦味酸、柠檬酸、马来酸、甲烷磺酸、三氟甲烷磺酸、乙烷磺酸和对甲苯磺酸等。The preparation of the pharmaceutically acceptable salt of the compound of the present invention can be carried out by direct salt formation reaction with an inorganic or organic acid using the free base of the compound. The inorganic or organic acid may be selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonate. Acid and p-toluenesulfonic acid and the like.
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物” 是指本发明化合物与水进行配位形成的配合物。The term "solvate" refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio. "Hydrate" means a complex formed by the coordination of a compound of the invention with water.
制备方法Preparation
下面更具体地描述本发明式I化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。The preparation of the compounds of the formula I according to the invention is described in more detail below, but these specific methods do not constitute any limitation to the invention. The compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.
典型地,本发明化合物的制备工艺流程如下,其中所用原料和试剂如无特殊说明,均可通过商业途径购买。Typically, the preparation process of the compounds of the present invention is as follows, wherein the starting materials and reagents used are commercially available unless otherwise specified.
方案I:Option I:
化合物(1)与化合物(2)通过缩合反应得到化合物(I);或Compound (1) and compound (2) are subjected to a condensation reaction to obtain compound (I); or
方案II:Option II:
化合物(3)与化合物(2)通过缩合反应得到化合物(4),化合物(4)通过脱保护反应得到化合物(5),化合物(5)通过取代反应得到化合物(I);Compound (3) and compound (2) are obtained by condensation reaction to obtain compound (4), compound (4) is obtained by deprotection reaction to obtain compound (5), and compound (5) is obtained by substitution reaction to obtain compound (I);
其中,X、Y、Z、p、R
1、R
2和环A如上文所定义。
Wherein X, Y, Z, p, R 1 , R 2 and ring A are as defined above.
药物组合物和应用Pharmaceutical compositions and applications
本发明还提供了一种药物组合物,所述药物组合物包括:The invention also provides a pharmaceutical composition comprising:
(i)治疗有效量的所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物;和(i) a therapeutically effective amount of said compound, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof;
(ii)任选的药学上可接受的载体。(ii) an optional pharmaceutically acceptable carrier.
应理解,所述药物组合物可以根据不同给药途径而制备成各种形式。It will be appreciated that the pharmaceutical compositions may be prepared in a variety of forms depending on the route of administration.
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的 盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。The pharmaceutical compositions of the present invention comprise a safe or effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. By "safe and effective amount" it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. In general, the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 1000 mg of the compound of the invention per agent. Preferably, the "one dose" is a capsule or tablet.
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
"Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By "compatibility" it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid). , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, hard Calcium citrate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。In addition to these inert diluents, the compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯 山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants. The active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
本发明化合物可以单独给药,或者与其他药学上可接受的其他化合物(如抗癌药物)联合给药。The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable other compounds, such as anti-cancer drugs.
本发明治疗方法可以单独施用,或者与其它治疗手段或者治疗药物联用。The methods of treatment of the invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选50~1000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。When a pharmaceutical composition is used, a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight, The dose to be administered is usually from 1 to 2000 mg, preferably from 50 to 1000 mg. Of course, specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
与现有技术相比,本发明具有以下主要优点:Compared with the prior art, the present invention has the following main advantages:
所述化合物结构新颖;与现有专利,文献代表性化合物EPZ015666相比,在酶水平和细胞水平,本发明化合物均具有更强的抑制活性。The compound has a novel structure; compared with the prior patent, the representative compound EPZ015666, the compounds of the present invention have stronger inhibitory activity at the enzyme level and the cell level.
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually carried out according to the conditions described in conventional conditions such as Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer. The suggested conditions. Percentages and parts are by weight unless otherwise stated.
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described may be employed in the methods of the invention. The preferred embodiments and materials described herein are for illustrative purposes only.
实施例1Example 1
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-5-叔丁氧羰基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(I-1)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiophene [3,2-c]pyridine-2-carboxamide (I-1)
步骤1:制备2-(环氧乙烷-2-基甲基)-1,2,3,4-四氢异喹啉Step 1: Preparation of 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline
将3.0克四氢异喹啉溶于40毫升乙腈中,再加入9.3克碳酸钾,室温搅拌,30分钟后加入环氧氯丙烷,保持室温搅拌,15小时后停止搅拌,反应液过滤,乙酸乙酯洗滤饼,滤液浓缩蒸干,残余物柱层析(二氯甲烷:甲醇=100:0–98:2,V/V),得到黄色液体2.71g,产率64%。Dissolve 3.0 g of tetrahydroisoquinoline in 40 ml of acetonitrile, add 9.3 g of potassium carbonate, stir at room temperature, add epichlorohydrin after 30 minutes, stir at room temperature, stop stirring after 15 hours, filter the reaction, acetic acid The cake was washed with an ester, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
1H NMR(300MHz,CDCl3)δ7.12(m,3H),7.04(m,1H),3.81(d,J=14.9Hz,1H),3.69(d,J=14.9Hz,1H),3.21(td,J=6.8,3.5Hz,1H),3.01–2.87(m,4H),2.82(dd,J=8.7,4.6Hz,2H),2.56(dd,J=4.0,2.0Hz,1H),2.45(dd,J=13.3,6.7Hz,1H).
1 H NMR (300MHz, CDCl3) δ7.12 (m, 3H), 7.04 (m, 1H), 3.81 (d, J = 14.9Hz, 1H), 3.69 (d, J = 14.9Hz, 1H), 3.21 ( Td, J=6.8, 3.5 Hz, 1H), 3.01–2.87 (m, 4H), 2.82 (dd, J=8.7, 4.6 Hz, 2H), 2.56 (dd, J=4.0, 2.0 Hz, 1H), 2.45 (dd, J=13.3, 6.7Hz, 1H).
步骤2:制备1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇Step 2: Preparation of 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol
将1克2-(环氧乙烷-2-基甲基)-1,2,3,4-四氢异喹啉溶于8毫升饱和氨的甲醇溶液中,封管加热至80℃,3小时后停止反应,反应液浓缩,柱层析(二氯甲烷:甲醇(含5%氨水)=95:5–85:15,V/V)得到微黄油状物383毫克,产率35%。1 g of 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 8 ml of saturated ammonia in methanol, and the tube was heated to 80 ° C, 3 After the lapse of time, the reaction was stopped, and the reaction mixture was concentrated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
1H NMR(300MHz,CDCl
3)δ7.10(dd,J=6.0,2.8Hz,3H),7.00(d,J=6.0Hz,1H),3.93(s,1H),3.74(d,J=15.0Hz,1H),3.59(d,J=15.0Hz,1H),2.87(s,4H),2.71(dd,J=12.9,7.5Hz,2H),2.63–2.32(m,2H).
1 H NMR (300MHz, CDCl 3 ) δ7.10 (dd, J = 6.0,2.8Hz, 3H), 7.00 (d, J = 6.0Hz, 1H), 3.93 (s, 1H), 3.74 (d, J = 15.0 Hz, 1H), 3.59 (d, J = 15.0 Hz, 1H), 2.87 (s, 4H), 2.71 (dd, J = 12.9, 7.5 Hz, 2H), 2.63 - 2.32 (m, 2H).
步骤3:制备叔丁基-4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯Step 3: Preparation of tert-butyl-4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
冰浴下,将27.5毫升三氯氧磷逐滴加入到38.5毫升N,N-二甲基甲酰胺中,保持冰浴搅拌15分钟后,将20克1-叔丁氧羰基哌啶酮溶于100毫升重蒸二氯甲烷中,再滴加到上述溶液中,氩气保护,搅拌5小时后,加入50毫升水淬灭反应,搅拌15分钟后,用二氯甲烷萃取,有机相合并用饱和食盐水洗涤两次,有机相用无水硫酸钠干燥,浓缩,柱层析(石油醚:乙酸乙酯=95:5,V/V)得黄色液体3.80克,产率16%。Under ice bath, 27.5 ml of phosphorus oxychloride was added dropwise to 38.5 ml of N,N-dimethylformamide, and after stirring for 15 minutes in an ice bath, 20 g of 1-tert-butoxycarbonylpiperidone was dissolved. 100 ml of re-distilled dichloromethane, added dropwise to the above solution, argon-protected, stirred for 5 hours, quenched by adding 50 ml of water, stirred for 15 minutes, extracted with dichloromethane, and the organic phase was combined with saturated The organic layer was washed twice with anhydrous sodium sulfate, and then evaporated and evaporated.
1H NMR(300MHz,CDCl
3)δ10.12(s,1H),4.11(s,2H),3.59(q,J=5.8Hz,2H),2.66(s,2H),1.45(s,9H).
1 H NMR (300MHz, CDCl 3 ) δ10.12 (s, 1H), 4.11 (s, 2H), 3.59 (q, J = 5.8Hz, 2H), 2.66 (s, 2H), 1.45 (s, 9H) .
步骤4:制备5-叔丁基2-乙基6,7-四氢噻吩并[3,2-c]吡啶-2,5(4H)-二甲酸酯Step 4: Preparation of 5-tert-butyl 2-ethyl 6,7-tetrahydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate
将3克叔丁基-4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯溶于20毫升二氯甲烷中,依次加入6.68毫升2-巯基乙酸乙酯和12.70毫升三乙胺,15分钟将反应液加热至40℃,5小时后停止反应,待反应液恢复室温后,加入3.4克氢氧化钾的水溶液,室 温搅拌2小时后停止,二氯甲烷,水萃取,有机相用无水硫酸钠干燥之后,浓缩,柱层析(石油醚:乙酸乙酯=95:5,V/V)得微黄色油状物2.1克,产率55%。3 g of tert-butyl-4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester was dissolved in 20 ml of dichloromethane, and 6.68 ml of 2-mercapto was added in sequence. Ethyl acetate and 12.70 ml of triethylamine, the reaction solution was heated to 40 ° C for 15 minutes, and the reaction was stopped after 5 hours. After the reaction solution was returned to room temperature, 3.4 g of an aqueous solution of potassium hydroxide was added, and the mixture was stirred at room temperature for 2 hours, and then stopped. The mixture was extracted with EtOAc (EtOAc)EtOAc.
1H NMR(300MHz,CDCl
3)δ7.45(s,1H),4.45(s,2H),4.29(q,J=7.1Hz,2H),3.69(t,J=5.4Hz,2H),2.83(t,J=5.4Hz,2H),1.50–1.39(s,9H),1.32(t,J=7.1Hz,3H).
1 H NMR (300MHz, CDCl 3 ) δ7.45 (s, 1H), 4.45 (s, 2H), 4.29 (q, J = 7.1Hz, 2H), 3.69 (t, J = 5.4Hz, 2H), 2.83 (t, J = 5.4 Hz, 2H), 1.50 - 1.39 (s, 9H), 1.32 (t, J = 7.1 Hz, 3H).
步骤5:制备5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸Step 5: Preparation of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid
将2.1克5-叔丁基2-乙基6,7-四氢噻吩并[3,2-c]吡啶-2,5(4H)-二甲酸酯溶于20毫升乙醇中加入2.70毫升5N氢氧化钠水溶液,升温至80℃,1小时后停止反应,反应液冷却之后,旋去溶剂,再加入水溶解,用3N盐酸调PH至5左右,用二氯甲烷:甲醇=10:1(V/V)萃取,有机相用无水硫酸钠干燥,浓缩得粗品1.24克,产率65%。2.1 g of 5-tert-butyl 2-ethyl 6,7-tetrahydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate was dissolved in 20 ml of ethanol and 2.70 ml of 5N was added. The aqueous sodium hydroxide solution was heated to 80 ° C, and the reaction was stopped after 1 hour. After the reaction solution was cooled, the solvent was removed, and then dissolved in water, and the pH was adjusted to about 5 with 3N hydrochloric acid, and dichloromethane: methanol = 10:1 ( After extraction with V/V), the organic layer was dried over anhydrous sodium sulfate and evaporated.
1H NMR(300MHz,DMSO)δ12.97(s,1H),7.52(s,1H),4.42(s,2H),3.62(t,J=5.6Hz,2H),2.81(t,J=5.6Hz,2H),1.42(s,9H).
1 H NMR (300MHz, DMSO) δ12.97 (s, 1H), 7.52 (s, 1H), 4.42 (s, 2H), 3.62 (t, J = 5.6Hz, 2H), 2.81 (t, J = 5.6 Hz, 2H), 1.42 (s, 9H).
步骤6:制备叔丁基2-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基甲酰基)-6,7-四氢[3,2-c]吡啶-5(4H)-羧酸叔丁酯(I-1)Step 6: Preparation of tert-butyl 2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-6,7-tetrahydro[ 3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (I-1)
将1.2克5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸,873毫克1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇,1.22克1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和857毫克1-羟基苯并***溶于15毫升N,N-二甲基甲酰胺中,氩气保护,室温搅拌4小时后,停止反应,将溶剂旋干之后柱层析(二氯甲烷:甲醇=94:6,V/V)得黄色固体700毫克,产率35%。1.2 g of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid, 873 mg of 1-amino-3-(3, 4-Dihydroisoquinoline-2(1H)-yl)propan-2-ol, 1.22 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 857 mg 1 -Hydroxybenzotriazole dissolved in 15 ml of N,N-dimethylformamide, argon-protected, stirred at room temperature for 4 hours, the reaction was stopped, and the solvent was dried and then subjected to column chromatography (dichloromethane:methanol = 94) : 6, V / V) obtained a yellow solid 700 mg, a yield of 35%.
1H NMR(300MHz,CD
3OD)δ7.21(s,1H),7.14(m,3H),7.05(d,J=8.0Hz,1H),4.36(s,2H),4.18–4.04(m,1H),3.87(s,2H),3.69(m,2H),3.45(d,J=5.9Hz,2H),2.98(s,4H),2.80(dd,J=14.1,6.4Hz,4H),1.49(s,9H).
1H NMR (300MHz, CD 3 OD) δ 7.21 (s, 1H), 7.14 (m, 3H), 7.05 (d, J = 8.0 Hz, 1H), 4.36 (s, 2H), 4.18 - 4.04 (m, 1H), 3.87 (s, 2H), 3.69 (m, 2H), 3.45 (d, J = 5.9 Hz, 2H), 2.98 (s, 4H), 2.80 (dd, J = 14.1, 6.4 Hz, 4H), 1.49(s,9H).
实施例2Example 2
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(I-2)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrothieno[3,2-c] Pyridine-2-carboxamide (I-2)
步骤:将700毫克叔丁基2-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基甲酰基)-6,7-四氢[3,2-c]吡啶-5(4H)-羧酸叔丁酯溶于10毫升二氯甲烷中,加入 2毫升三氟乙酸,氩气保护,室温搅拌2小时后停止反应,反应液用饱和碳酸氢钠溶液中和至中性,用二氯甲烷:甲醇=10:1萃取,有机相用无水硫酸钠干燥,浓缩,柱层析(二氯甲烷:甲醇(含5%氨水)=85:15,V/V)得黄色固体400毫克,产率73%。Step: 700 mg of tert-butyl 2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-6,7-tetrahydro [3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester was dissolved in 10 ml of dichloromethane, added with 2 ml of trifluoroacetic acid, argon-protected, and stirred at room temperature for 2 hours, then the reaction was stopped. The mixture was neutralized to neutrality with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane:methanol = 10:1. 85:15, V/V) gave a yellow solid 400 mg, yield 73%.
1H NMR(300MHz,CD
3OD)δ7.16(s,1H),7.11(s,3H),7.03(s,1H),4.14–4.00(m,1H),3.72(s,4H),3.44(d,J=5.8Hz,2H),3.06(d,J=5.5Hz,2H),2.89(s,2H),2.82(d,J=5.6Hz,4H),2.72–2.58(m,2H).
1 H NMR (300MHz, CD 3 OD) δ7.16 (s, 1H), 7.11 (s, 3H), 7.03 (s, 1H), 4.14-4.00 (m, 1H), 3.72 (s, 4H), 3.44 (d, J = 5.8 Hz, 2H), 3.06 (d, J = 5.5 Hz, 2H), 2.89 (s, 2H), 2.82 (d, J = 5.6 Hz, 4H), 2.72 - 2.58 (m, 2H) .
实施例3Example 3
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢苯并[b]噻吩-2-甲酰胺(I-3)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2- Formamide (I-3)
步骤1:制备2-氯环己烷-1-烯甲醛Step 1: Preparation of 2-chlorocyclohexane-1-enecarboxaldehyde
将1-叔丁氧羰基哌啶酮换成环己酮,其余所需原料、试剂及制备方法同实施例1中的步骤3,得无色油状物2-氯环己烷-1-烯甲醛。The 1-tert-butoxycarbonylpiperidone is replaced with cyclohexanone, and the remaining starting materials, reagents and preparation methods are the same as those in the first step of Example 1, to obtain a colorless oil of 2-chlorocyclohexane-1-enecarboxaldehyde. .
1H NMR(300MHz,CDCl
3)δ10.20(s,1H),2.57(dt,J=8.5,3.0Hz,2H),2.28(td,J=6.1,3.0Hz,2H),1.83–1.71(m,2H),1.71–1.60(m,2H).
1 H NMR (300MHz, CDCl 3 ) δ10.20 (s, 1H), 2.57 (dt, J = 8.5,3.0Hz, 2H), 2.28 (td, J = 6.1,3.0Hz, 2H), 1.83-1.71 ( m, 2H), 1.71–1.60 (m, 2H).
步骤2:制备乙基-4,5,6,7-四氢苯并[b]噻吩-2-羧酸乙酯Step 2: Preparation of ethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid ethyl ester
将叔丁基-4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成2-氯环己烷-1-烯甲醛,其余所需原料、试剂及制备方法同实施例1中的步骤4,得黄色油状物乙基-4,5,6,7-四氢苯并[b]噻吩-2-羧酸乙酯。Replace tert-butyl-4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 2-chlorocyclohexane-1-enecarboxaldehyde, the remaining raw materials The reagent and the preparation method were the same as those in Step 4 of Example 1, to give ethyl 4-ethyl, 4-,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate as a yellow oil.
1H NMR(300MHz,CDCl
3)δ7.45(s,1H),4.31(q,J=7.1Hz,2H),2.78(t,J=5.5Hz,2H),2.61(t,J=5.5Hz,2H),1.81(dd,J=6.9,4.4Hz,4H),1.35(t,J=7.1Hz,3H).
1H NMR (300MHz, CDCl 3) δ7.45 (s, 1H), 4.31 (q, J = 7.1Hz, 2H), 2.78 (t, J = 5.5Hz, 2H), 2.61 (t, J = 5.5Hz, 2H), 1.81 (dd, J = 6.9, 4.4 Hz, 4H), 1.35 (t, J = 7.1 Hz, 3H).
步骤3:制备乙基-4,5,6,7-四氢苯并[b]噻吩-2-羧酸Step 3: Preparation of ethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid
将4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成4,5,6,7-四氢苯并[b]噻吩-2-羧酸乙酯,其余所需原料、试剂及制备方法同实施例1中的步骤5,得4,5,6,7-四氢苯并[b]噻吩-2-羧酸。Replace 4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate Ethyl acetate, the remaining starting materials, reagents and preparation methods were the same as those in Step 5 of Example 1, to obtain 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid.
1H NMR(300MHz,DMSO)δ12.77(s,1H),7.38(s,1H),2.72(t,J=5.4Hz,2H),2.55(t,J=5.1Hz,2H),1.72(m,4H).
1 H NMR (300MHz, DMSO) δ12.77 (s, 1H), 7.38 (s, 1H), 2.72 (t, J = 5.4Hz, 2H), 2.55 (t, J = 5.1Hz, 2H), 1.72 ( m, 4H).
步骤4:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢苯并[b]噻吩-2-甲酰胺(I-3)Step 4: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrobenzo[b] Thiophene-2-carboxamide (I-3)
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成乙基-4,5,6,7-四氢苯并[b]噻吩-2-羧酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢苯并[b]噻吩-2-甲酰胺。Replace 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid with ethyl-4,5,6,7-tetra Hydrogen benzo[b]thiophene-2-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as in step 6 of Example 1, to obtain N-(3-(3,4-dihydroisoquinoline-2) 1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide.
1H NMR(300MHz,CD
3OD)δ7.22(s,1H),7.19–7.07(m,3H),7.04(d,J=6.6Hz,1H),4.19–4.05(m,1H),3.91(s,2H),3.44(d,J=5.8Hz,2H),3.02(d,J=5.0Hz,2H),2.97(d,J=5.0Hz,2H),2.89–2.76(m,2H),2.72(dd,J=10.4,5.5Hz,2H),2.50(t,J=5.4Hz,2H),1.78(m,,4H).
1 H NMR (300 MHz, CD 3 OD) δ 7.22 (s, 1H), 7.19 - 7.07 (m, 3H), 7.04 (d, J = 6.6 Hz, 1H), 4.19 - 4.05 (m, 1H), 3.91 (s, 2H), 3.44 (d, J = 5.8 Hz, 2H), 3.02 (d, J = 5.0 Hz, 2H), 2.97 (d, J = 5.0 Hz, 2H), 2.89 - 2.76 (m, 2H) , 2.72 (dd, J = 10.4, 5.5 Hz, 2H), 2.50 (t, J = 5.4 Hz, 2H), 1.78 (m,, 4H).
实施例4Example 4
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-6,7-二氢-4-氢-噻吩并[3,2-c]吡喃-2-甲酰胺(I-4)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6,7-dihydro-4-hydro-thieno[3,2-c Pyran-2-carboxamide (I-4)
步骤1:制备4-氯-5,6-二氢-2H-吡喃-3-甲醛Step 1: Preparation of 4-chloro-5,6-dihydro-2H-pyran-3-carbaldehyde
将1-叔丁氧羰基哌啶酮换成四氢吡喃酮,其余所需原料、试剂及制备方法同实施例1中的步骤3,得黄色油状物。未纯化,直接投下一步。The 1-tert-butoxycarbonylpiperidone was replaced with the tetrahydropyranone, and the remaining starting materials, reagents and preparation methods were the same as those in Step 3 of Example 1, to give a yellow oil. Without purification, directly cast the next step.
步骤2:制备乙基-6,7-二氢-4H-噻吩并[3,2-b]呋喃-2-羧酸乙酯Step 2: Preparation of ethyl-6,7-dihydro-4H-thieno[3,2-b]furan-2-carboxylic acid ethyl ester
将叔丁基-4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成4-氯-5,6-二氢-2H-吡喃-3-甲醛,其余所需原料、试剂及制备方法同实施例1中的步骤4,得无色油状物乙基-6,7-二氢-4-氢-噻吩并[3,2-b]呋喃-2-羧酸乙酯。Replace tert-butyl-4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 4-chloro-5,6-dihydro-2H-pyran- 3-formaldehyde, the remaining starting materials, reagents and preparation methods are the same as in step 4 of Example 1, to obtain a colorless oil ethyl-6,7-dihydro-4-hydro-thieno[3,2-b] Ethyl furan-2-carboxylate.
1H NMR(300MHz,CDCl
3)δ7.39(s,1H),4.64(s,2H),4.28(q,J=7.1Hz,2H),3.93(t,J=4.6Hz,2H),2.85(s,2H),1.31(t,J=7.2Hz,3H).
1 H NMR (300MHz, CDCl 3 ) δ7.39 (s, 1H), 4.64 (s, 2H), 4.28 (q, J = 7.1Hz, 2H), 3.93 (t, J = 4.6Hz, 2H), 2.85 (s, 2H), 1.31 (t, J = 7.2 Hz, 3H).
步骤3:制备乙基-6,7-二氢-4H-噻吩并[3,2-b]呋喃-2-羧酸Step 3: Preparation of ethyl-6,7-dihydro-4H-thieno[3,2-b]furan-2-carboxylic acid
将叔丁基-4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成乙基-6,7-二氢-4H- 噻吩并[3,2-b]呋喃-2-羧酸乙酯,其余所需原料、试剂及制备方法同实施例1中的步骤5,得米白色固体。Replace tert-butyl-4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with ethyl-6,7-dihydro-4H-thieno[3 , 2-b]furan-2-carboxylic acid ethyl ester, the remaining desired starting materials, reagents and preparation methods are the same as in the step 5 of Example 1, to give an off-white solid.
1H NMR(300MHz,DMSO)δ12.97(s,1H),7.44(s,1H),4.60(s,2H),3.87(t,J=5.5Hz,2H),2.84(t,J=5.4Hz,2H).
1 H NMR (300MHz, DMSO) δ12.97 (s, 1H), 7.44 (s, 1H), 4.60 (s, 2H), 3.87 (t, J = 5.5Hz, 2H), 2.84 (t, J = 5.4 Hz, 2H).
步骤3:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-6,7-二氢-4-氢-噻吩并[3,2-c]吡喃-2-甲酰胺(I-4)Step 3: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6,7-dihydro-4-hydro-thieno[3 ,2-c]pyran-2-carboxamide (I-4)
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成乙基-6,7-二氢-4H-噻吩并[3,2-b]呋喃-2-羧酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得黄色固体。Replace 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid with ethyl-6,7-dihydro-4H- Thio[3,2-b]furan-2-carboxylic acid, the remaining starting materials, reagents and preparation methods were the same as those in the step 6 of Example 1, to give a yellow solid.
1H NMR(300MHz,CD
3OD)δ7.14(s,1H),7.09(m,3H),7.01(d,J=6.9Hz,1H),4.50(s,2H),4.09(p,J=6.0Hz,1H),3.89(t,J=5.4Hz,2H),3.77(s,2H),3.46(d,J=5.9Hz,2H),2.90(s,4H),2.80(t,J=5.1Hz,2H),2.75–2.66(m,2H).
1 H NMR (300MHz, CD 3 OD) δ7.14 (s, 1H), 7.09 (m, 3H), 7.01 (d, J = 6.9Hz, 1H), 4.50 (s, 2H), 4.09 (p, J =6.0 Hz, 1H), 3.89 (t, J = 5.4 Hz, 2H), 3.77 (s, 2H), 3.46 (d, J = 5.9 Hz, 2H), 2.90 (s, 4H), 2.80 (t, J =5.1 Hz, 2H), 2.75–2.66 (m, 2H).
实施例5Example 5
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-5-甲基-4,5,6,7-四氢呋喃并[3,2-c]吡啶-2-甲酰胺(I-5)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-4,5,6,7-tetrahydrofuran[3,2 -c]pyridine-2-carboxamide (I-5)
步骤1:制备5-叔丁基2-乙基-6,7-二氢呋喃并[3,2-c]吡啶-2,5(4H)-二甲酸酯Step 1: Preparation of 5-tert-butyl 2-ethyl-6,7-dihydrofuro[3,2-c]pyridine-2,5(4H)-dicarboxylate
将1.85毫升2-羟基乙酸乙酯溶于30毫升重蒸四氢呋喃中,氩气保护,冷却到0℃,加入585毫克钠氢,保持0℃搅拌30分钟后,将800毫克叔丁基-4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯溶于20毫升重蒸四氢呋喃中,再加入到上述溶液中,加完之后,慢慢升温到66℃回流,2小时后停止加热,加水淬灭反应,乙酸乙酯萃取三次,有机相用无水硫酸钠干燥,浓缩,残余物柱层析(石油醚:乙酸乙酯=90:10,V/V)得391毫克黄色油状,收率41%。1.85 ml of 2-hydroxyethylacetate was dissolved in 30 ml of re-steamed tetrahydrofuran, argon-protected, cooled to 0 ° C, 585 mg of sodium hydrogen was added, and stirred at 0 ° C for 30 minutes, 800 mg of tert-butyl-4- Chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester was dissolved in 20 ml of re-distilled tetrahydrofuran, and added to the above solution. After the addition, the temperature was slowly raised to 66. After refluxing for 2 hours, the mixture was stirred for 2 hours. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. V) 391 mg of a yellow oil, yield 41%.
1H NMR(300MHz,CDCl3)δ7.01(s,1H),4.34(q,J=7.2Hz,4H),3.73(s,2H),2.76(s,2H),1.47(s,9H),1.35(t,J=7.2Hz,3H).
1 H NMR (300MHz, CDCl3) δ7.01 (s, 1H), 4.34 (q, J = 7.2Hz, 4H), 3.73 (s, 2H), 2.76 (s, 2H), 1.47 (s, 9H), 1.35 (t, J = 7.2 Hz, 3H).
步骤2:制备4,5,6,7-四氢呋喃并[3,2-c]吡啶-2-羧酸乙酯Step 2: Preparation of ethyl 4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylate
将345毫克5-叔丁基2-乙基-6,7-二氢呋喃并[3,2-c]吡啶-2,5(4H)-二甲酸酯溶于8毫升二氯甲烷中,加入1.5毫升三氟乙酸,室温搅拌,氩气保护,2小时后停止反应,用饱和碳酸氢钠溶液中和反应液至中性,二氯甲烷萃取,有机相无水硫酸钠干燥,浓缩,残余物柱层析(二氯甲烷:甲醇(含5%氨水)=92:8,V/V)得190毫克黄色固体,收率83%。345 mg of 5-tert-butyl 2-ethyl-6,7-dihydrofuro[3,2-c]pyridine-2,5(4H)-dicarboxylate was dissolved in 8 ml of dichloromethane. Add 1.5 ml of trifluoroacetic acid, stir at room temperature, argon gas protection, stop the reaction after 2 hours, neutralize the reaction solution to neutral with saturated sodium hydrogencarbonate solution, extract with dichloromethane, dry with organic sodium sulfate, concentrate, residue Column chromatography (dichloromethane: methanol (5% EtOAc) = EtOAc: EtOAc:
1H NMR(300MHz,CDCl
3)δ6.98(s,1H),4.34(q,J=7.1Hz,2H),3.77(s,2H),3.16(t,J=5.8Hz,2H),2.72(t,J=5.8Hz,2H),1.36(t,J=7.1Hz,3H).
1 H NMR (300MHz, CDCl 3 ) δ6.98 (s, 1H), 4.34 (q, J = 7.1Hz, 2H), 3.77 (s, 2H), 3.16 (t, J = 5.8Hz, 2H), 2.72 (t, J = 5.8 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).
步骤3:制备5-甲基-4,5,6,7-四氢呋喃并[3,2-c]吡啶-2-羧酸乙酯Step 3: Preparation of ethyl 5-methyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylate
将245毫克4,5,6,7-四氢呋喃并[3,2-c]吡啶-2-羧酸乙酯溶于8毫升二氯甲烷中,加入0.73毫升甲醛水溶液,室温搅拌,15分钟后加入628毫克氰基硼氢化钠,继续搅拌,12小时候停止,浓缩反应液,柱层析(二氯甲烷:甲醇=99:1,V/V)得到黄色固体120毫克,收率41%。245 mg of ethyl 4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylate was dissolved in 8 ml of dichloromethane, 0.73 ml of aqueous formaldehyde solution was added, stirred at room temperature, and added after 15 minutes. 628 mg of sodium cyanoborohydride, stirring was continued, and the mixture was quenched at 12 hours. The reaction mixture was concentrated and purified by chromatography (dichloromethane:methanol = 99:1, V/V)
1H NMR(300MHz,CDCl
3)δ6.99(s,1H),4.33(q,J=7.1Hz,2H),4.15(d,J=15.7Hz,1H),3.83(t,J=13.6Hz,1H),3.45–3.24(m,2H),2.98(d,J=4.7Hz,2H),2.72(s,3H),1.34(t,J=7.1Hz,3H).
1 H NMR (300 MHz, CDCl 3 ) δ 6.99 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.15 (d, J = 15.7 Hz, 1H), 3.83 (t, J = 13.6 Hz) , 1H), 3.45 - 3.24 (m, 2H), 2.98 (d, J = 4.7 Hz, 2H), 2.72 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).
步骤4:制备5-甲基-4,5,6,7-四氢呋喃并[3,2-c]吡啶-2-羧酸Step 4: Preparation of 5-methyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylic acid
将4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成5-甲基-4,5,6,7-四氢呋喃并[3,2-c]吡啶-2-羧酸乙酯,其余所需原料、试剂及制备方法同实施例1中的步骤5,得黄色固体5-甲基-4,5,6,7-四氢呋喃并[3,2-c]吡啶-2-羧酸。Replace 4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 5-methyl-4,5,6,7-tetrahydrofuran [3,2- c] ethyl pyridine-2-carboxylate, the remaining starting materials, reagents and preparation methods are the same as in step 5 of Example 1, to obtain a yellow solid 5-methyl-4,5,6,7-tetrahydrofuran [3, 2-c]pyridine-2-carboxylic acid.
步骤5:N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-5-甲基-4,5,6,7-四氢呋喃并[3,2-c]吡啶-2-甲酰胺(I-5)Step 5: N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-4,5,6,7-tetrahydrofuran[ 3,2-c]pyridine-2-carboxamide (I-5)
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成5-甲基-4,5,6,7-四氢呋喃并[3,2-c]吡啶-2-羧酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得黄色固体。Replace 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid with 5-methyl-4,5,6,7 - Tetrahydrofuro[3,2-c]pyridine-2-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as in Step 6 of Example 1, to give a yellow solid.
1H NMR(300MHz,CD
3OD)δ7.13(s,3H),7.04(s,1H),6.94(s,1H),4.15–3.99(m,2H),3.88(d,J=15.6Hz,1H),3.78(s,2H),3.54–3.40(m,2H),3.01–2.76(m,7H),2.70 (d,J=9.5Hz,5H).
1 H NMR (300MHz, CD 3 OD) δ7.13 (s, 3H), 7.04 (s, 1H), 6.94 (s, 1H), 4.15-3.99 (m, 2H), 3.88 (d, J = 15.6Hz , 1H), 3.78 (s, 2H), 3.54 - 3.40 (m, 2H), 3.01 - 2.76 (m, 7H), 2.70 (d, J = 9.5 Hz, 5H).
实施例6Example 6
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-甲基-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-甲酰胺(I-6)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-4,5,6,7-tetrahydro-1H-pyrrole And [3,2-c]pyridine-2-carboxamide (I-6)
步骤1:制备5-甲基-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-羧酸乙酯Step 1: Preparation of ethyl 5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate
将1.13克N-甲基-4-哌啶酮溶于40毫升无水甲苯中,加入1.3毫升吗菲林,80毫克对甲苯磺酸,分子筛,加热回流15小时后,冷却至室温,加入室温搅拌3小时后,反应液用20毫升水,饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,过滤,再加入1.2毫升三氟乙酸,1.5克十二羰基三铁,回流2小时,冷却至室温,过滤,滤液浓缩,残余物柱层析(二氯甲烷:甲醇(含5%氨水)=95:5,V/V),得红棕色油状物420毫克,收率20%。1.13 g of N-methyl-4-piperidone was dissolved in 40 ml of anhydrous toluene, 1.3 ml of phenanthrene, 80 mg of p-toluenesulfonic acid, molecular sieve, heated under reflux for 15 hours, cooled to room temperature, and stirred at room temperature. After 3 hours, the reaction solution was washed with 20 ml of water and saturated sodium chloride, and the organic phase was dried over anhydrous sodium sulfate, filtered, and then, then, then,,,,,,,,,,,,,,,,,,,,,,, The mixture was filtered, and the filtrate was concentrated. EtOAcjjjjjjj
1H NMR(300MHz,CDCl
3)δ8.94(s,1H),6.64(s,1H),4.28(q,J=6.9Hz,2H),3.46(s,2H),2.77(s,4H),2.49(s,3H),1.33(t,J=7.0Hz,3H).
1 H NMR (300MHz, CDCl 3 ) δ 8.94 (s, 1H), 6.64 (s, 1H), 4.28 (q, J = 6.9 Hz, 2H), 3.46 (s, 2H), 2.77 (s, 4H) , 2.49 (s, 3H), 1.33 (t, J = 7.0 Hz, 3H).
步骤2:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-甲基-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-甲酰胺(I-6)Step 2: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-4,5,6,7-tetrahydro -1H-pyrrolo[3,2-c]pyridine-2-carboxamide (I-6)
将208毫克5-甲基-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-羧酸乙酯溶于5毫升乙醇中,加入5N氢氧化钠400微升水溶液400微升,回流2小时后,用1N盐酸酸化,浓缩,直接投下一步。208 mg of ethyl 5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate was dissolved in 5 ml of ethanol, and 5N sodium hydroxide was added. 400 μl of 400 μl of aqueous solution was refluxed for 2 hours, then acidified with 1N hydrochloric acid, concentrated and taken directly to the next.
将52毫克5-甲基-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-羧酸,60毫克1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇,83毫克1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和59毫克1-羟基苯并***溶于15毫升N,N-二甲基甲酰胺中,氩气保护,室温搅拌4小时后,停止反应,将溶剂旋干之后柱层析(二氯甲烷:甲醇=94:6,V/V)得黄色固体19毫克。52 mg of 5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid, 60 mg of 1-amino-3-(3,4- Dihydroisoquinoline-2(1H)-yl)propan-2-ol, 83 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 59 mg of 1-hydroxyl The benzotriazole was dissolved in 15 ml of N,N-dimethylformamide, argon-protected, stirred at room temperature for 4 hours, the reaction was stopped, and the solvent was evaporated to dryness and then purified by column chromatography (dichloromethane:methanol=94:6 , V / V) gave a yellow solid 19 mg.
1H NMR(300MHz,CD
3OD)δ7.22–7.04(m,4H),6.51(s,1H),4.20–4.08(m,1H),4.01(s,2H),3.95(s,2H),3.50–3.38(m,2H),3.33(d,J=7.9Hz,2H),3.14(t,J =5.9Hz,2H),3.01(t,J=6.0Hz,2H),2.95(t,J=5.9Hz,2H),2.88(m,2H),2.83(s,3H).
1 H NMR (300 MHz, CD 3 OD) δ 7.22 - 7.04 (m, 4H), 6.51 (s, 1H), 4.20 - 4.08 (m, 1H), 4.01 (s, 2H), 3.95 (s, 2H) , 3.50–3.38 (m, 2H), 3.33 (d, J = 7.9 Hz, 2H), 3.14 (t, J = 5.9 Hz, 2H), 3.01 (t, J = 6.0 Hz, 2H), 2.95 (t, J = 5.9 Hz, 2H), 2.88 (m, 2H), 2.83 (s, 3H).
实施例7Example 7
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-甲酰胺(I-7)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-methyl-4,5,6,7-tetrahydrothieno[2 ,3-c]pyridine-2-carboxamide (I-7)
步骤1:制备3-氟-4-吡啶甲醛和3-氟-2-吡啶甲醛Step 1: Preparation of 3-fluoro-4-pyridinecarboxaldehyde and 3-fluoro-2-pyridinecarboxaldehyde
将15.56毫升四甲基乙二胺溶于25毫升无水四氢呋喃中,氩气保护,冷却至-78℃,将41毫升正丁基锂慢慢滴加到反应液中,30分钟滴加完毕,保持-78℃搅拌30分钟后,再加入10克3-氟吡啶,搅拌2小时后加入N,N-二甲基甲酰胺,-78℃搅拌12小时,加入饱和碳酸氢钠溶液60毫升淬灭反应,乙酸乙酯萃取,有机相合并后用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤浓缩,得10克棕色油状物3-氟-4-吡啶甲醛和3-氟-2-吡啶甲醛混合物,未分离纯化,直接投下一步。15.56 ml of tetramethylethylenediamine was dissolved in 25 ml of anhydrous tetrahydrofuran, argon-protected, cooled to -78 ° C, and 41 ml of n-butyllithium was slowly added dropwise to the reaction solution, and the addition was completed in 30 minutes. After stirring at -78 ° C for 30 minutes, 10 g of 3-fluoropyridine was further added. After stirring for 2 hours, N,N-dimethylformamide was added, and the mixture was stirred at -78 ° C for 12 hours, and then quenched with saturated sodium hydrogen carbonate solution (60 ml). The reaction was combined with ethyl acetate. EtOAc was evaporated. The formaldehyde mixture, which was not isolated and purified, was directly taken to the next step.
步骤2:制备噻吩并[2,3-c]吡啶-2-甲酸乙酯和噻吩并[3,2-b]吡啶-2-甲酸乙酯Step 2: Preparation of ethyl thieno[2,3-c]pyridine-2-carboxylate and ethyl thieno[3,2-b]pyridine-2-carboxylate
将5克3-氟-4-吡啶甲醛和3-氟-2-吡啶甲醛混合物溶于20毫升N,N-二甲基甲酰胺中,0℃下加入8.6克碳酸钾,5毫升2-巯基乙酸乙酯,15分钟后恢复至室温,搅拌24小时后停止反应,加加入100毫升水稀释反应液,用乙酸乙酯萃取,有机相合并后用饱和氯化钠水溶液洗涤3次,无水硫酸钠干燥,过滤浓缩,残余物柱层析(石油醚:乙酸乙酯=80:20,V/V)得黄色固体噻吩并[2,3-c]吡啶-2-甲酸乙酯和噻吩并[3,2-b]吡啶-2-甲酸乙酯。Mix 5 g of 3-fluoro-4-pyridinecarboxaldehyde and 3-fluoro-2-pyridinecarboxaldehyde in 20 ml of N,N-dimethylformamide, add 8.6 g of potassium carbonate at 0 ° C, 5 ml of 2-mercapto Ethyl acetate, after 15 minutes, returned to room temperature. After stirring for 24 hours, the reaction was stopped. The reaction mixture was diluted with 100 ml of water and extracted with ethyl acetate. The organic phase was combined and washed three times with saturated aqueous sodium chloride. Drying with sodium, concentrating by filtration, EtOAc EtOAc (EtOAc:EtOAc Ethyl 3,2-b]pyridine-2-carboxylate.
1H NMR(300MHz,CDCl
3)δ9.17(s,1H),8.54(d,J=5.5Hz,1H),8.03(s,1H),7.73(d,J=5.5Hz,1H),4.42(q,J=7.1Hz,2H),1.41(t,J=7.1Hz,3H).
1 H NMR (300MHz, CDCl 3 ) δ9.17 (s, 1H), 8.54 (d, J = 5.5Hz, 1H), 8.03 (s, 1H), 7.73 (d, J = 5.5Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).
1H NMR(300MHz,CDCl3)δ8.77(d,J=4.4Hz,1H),8.20(d,J=9.7Hz,2H),7.35(dd,J=8.2,4.5Hz,1H),4.44(q,J=7.2Hz,2H),1.43(t,J=7.2Hz,3H).
1 H NMR (300MHz, CDCl3) δ8.77 (d, J = 4.4Hz, 1H), 8.20 (d, J = 9.7Hz, 2H), 7.35 (dd, J = 8.2,4.5Hz, 1H), 4.44 ( q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H).
步骤3:制备6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-甲酸乙酯Step 3: Preparation of ethyl 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate
将600毫克噻吩并[2,3-c]吡啶-2-甲酸乙酯溶于12毫升乙腈中,加入碘甲烷0.54毫升,升温至40℃搅拌,氩气保护,4小时后停止反应,反应液浓缩蒸干,溶于12毫升 甲醇中,加入二***196毫克,氢气氛围下室温搅拌12小时,过滤反应液,甲醇洗涤数次,滤液浓缩,柱层析(二氯甲烷:甲醇=95:5,V/V),得423毫克,收率65%。600 mg of thieno[2,3-c]pyridine-2-carboxylic acid ethyl ester was dissolved in 12 ml of acetonitrile, 0.54 ml of methyl iodide was added, the temperature was raised to 40 ° C, stirred, argon gas was protected, and the reaction was stopped after 4 hours. The mixture was evaporated to dryness, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. 5, V / V), get 423 mg, the yield is 65%.
1H NMR(300MHz,CDCl
3)δ7.48(s,1H),4.31(q,J=7.1Hz,2H),3.64(s,2H),2.74(m,4H),2.49(s,3H),1.34(t,J=7.1Hz,3H).
1 H NMR (300MHz, CDCl 3 ) δ7.48 (s, 1H), 4.31 (q, J = 7.1Hz, 2H), 3.64 (s, 2H), 2.74 (m, 4H), 2.49 (s, 3H) , 1.34 (t, J = 7.1 Hz, 3H).
步骤4:制备6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-甲酸Step 4: Preparation of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylic acid
将4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-甲酸乙酯,其余所需原料、试剂及制备方法同实施例1中的步骤5,得6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-甲酸。Replace 4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 6-methyl-4,5,6,7-tetrahydrothiophene [2, Ethyl 3-c]pyridine-2-carboxylate, the remaining starting materials, reagents and preparation methods are the same as in step 5 of Example 1, to give 6-methyl-4,5,6,7-tetrahydrothiophene [2 , 3-c]pyridine-2-carboxylic acid.
1H NMR(300MHz,DMSO)δ7.50(s,1H),4.30(m,2H),3.31(m,2H),2.89(s,2H),2.79(s,3H).
1 H NMR (300MHz, DMSO) δ7.50 (s, 1H), 4.30 (m, 2H), 3.31 (m, 2H), 2.89 (s, 2H), 2.79 (s, 3H).
步骤5:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-甲酰胺(I-7)Step 5: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-methyl-4,5,6,7-tetrahydro Thieno[2,3-c]pyridine-2-carboxamide (I-7)
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-甲酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得黄色固体N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-甲酰胺。Replace 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid with 6-methyl-4,5,6,7 -tetrahydrothieno[2,3-c]pyridine-2-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as in step 6 of Example 1, to obtain a yellow solid N-(3-(3,4-di) Hydrogen isoquinoline-2(1H)-yl)-2-hydroxypropyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide .
1H NMR(400MHz,CD
3OD)δ7.25(s,1H),7.14(dd,J=13.6,5.5Hz,3H),7.04(d,J=7.1Hz,1H),4.15–4.04(m,1H),3.77(s,2H),3.64(s,2H),3.52–3.41(m,2H),2.91(d,J=13.4Hz,4H),2.80–2.60(m,6H),2.48(s,3H).
1 H NMR (400 MHz, CD 3 OD) δ 7.25 (s, 1H), 7.14 (dd, J = 13.6, 5.5 Hz, 3H), 7.04 (d, J = 7.1 Hz, 1H), 4.15 - 4.04 (m) , 1H), 3.77 (s, 2H), 3.64 (s, 2H), 3.52 - 3.41 (m, 2H), 2.91 (d, J = 13.4 Hz, 4H), 2.80 - 2.60 (m, 6H), 2.48 ( s, 3H).
实施例8Example 8
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4-甲基-4,5,6,7-四氢[3,2-b]吡啶-2-甲酰胺(I-8)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4-methyl-4,5,6,7-tetrahydro[3,2 -b]pyridine-2-carboxamide (I-8)
步骤1:制备6-甲基-4,5,6,7-四氢噻吩并[3,2-b]吡啶-2-甲酸乙酯Step 1: Preparation of ethyl 6-methyl-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylate
将噻吩并[2,3-c]吡啶-2-甲酸乙酯换成噻吩并[3,2-b]吡啶-2-甲酸乙酯,其余所需原料、试剂及制备方法同实施例5中的步骤3,得黄色固体6-甲基-4,5,6,7-四氢噻吩并[3,2-b] 吡啶-2-甲酸乙酯。The ethyl thieno[2,3-c]pyridine-2-carboxylate was replaced with ethyl thieno[3,2-b]pyridine-2-carboxylate, and the remaining raw materials, reagents and preparation methods were the same as in Example 5. Step 3 gave ethyl 6-methyl-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylate as a yellow solid.
1H NMR(300MHz,CDCl
3)δ7.35(s,1H),4.30(q,J=7.1Hz,2H),3.06–2.95(m,2H),2.82(s,3H),2.76(t,J=6.5Hz,2H),2.12–2.00(m,2H),1.34(t,J=7.1Hz,3H).
1 H NMR (300MHz, CDCl 3 ) δ7.35 (s, 1H), 4.30 (q, J = 7.1Hz, 2H), 3.06-2.95 (m, 2H), 2.82 (s, 3H), 2.76 (t, J = 6.5 Hz, 2H), 2.12 - 2.00 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H).
步骤2:制备6-甲基-4,5,6,7-四氢噻吩并[3,2-b]吡啶-2-甲酸Step 2: Preparation of 6-methyl-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylic acid
将4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成6-甲基-4,5,6,7-四氢噻吩并[3,2-b]吡啶-2-甲酸乙酯,其余所需原料、试剂及制备方法同实施例1中的步骤5,得6-甲基-4,5,6,7-四氢噻吩并[3,2-b]吡啶-2-甲酸。Replace 4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 6-methyl-4,5,6,7-tetrahydrothieno[3, Ethyl 2-b]pyridine-2-carboxylate, the remaining starting materials, reagents and preparation methods are the same as in step 5 of Example 1, to obtain 6-methyl-4,5,6,7-tetrahydrothiophene [3 , 2-b]pyridine-2-carboxylic acid.
步骤3:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-6-甲基-4,5,6,7-四氢噻吩并[3,2-b]吡啶-2-甲酰胺(I-8)Step 3: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-methyl-4,5,6,7-tetrahydro Thieno[3,2-b]pyridine-2-carboxamide (I-8)
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成6-甲基-4,5,6,7-四氢噻吩并[3,2-b]吡啶-2-甲酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得黄色固体。Replace 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid with 6-methyl-4,5,6,7 -tetrahydrothieno[3,2-b]pyridine-2-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as those in step 6 of Example 1, to give a yellow solid.
1H NMR(400MHz,CD
3OD)δ7.30(s,1H),7.15–7.08(m,3H),7.06–7.01(m,1H),4.13–4.04(m,1H),3.75(s,2H),3.49(dd,J=13.6,5.4Hz,1H),3.41(dd,J=13.6,5.4Hz,1H),3.01–2.95(m,2H),2.95–2.90(m,2H),2.87(ddd,J=12.2,7.1,3.5Hz,2H),2.74(s,3H),2.71(dd,J=5.7,2.9Hz,2H),2.69–2.60(m,2H),2.07–1.99(m,2H).
1 H NMR (400 MHz, CD 3 OD) δ 7.30 (s, 1H), 7.15 - 7.08 (m, 3H), 7.06 - 7.01 (m, 1H), 4.13 - 4.04 (m, 1H), 3.75 (s, 2H), 3.49 (dd, J = 13.6, 5.4 Hz, 1H), 3.41 (dd, J = 13.6, 5.4 Hz, 1H), 3.01 - 2.95 (m, 2H), 2.95 - 2.90 (m, 2H), 2.87 (ddd, J = 12.2, 7.1, 3.5 Hz, 2H), 2.74 (s, 3H), 2.71 (dd, J = 5.7, 2.9 Hz, 2H), 2.69 - 2.60 (m, 2H), 2.07 - 1.99 (m , 2H).
实施例9Example 9
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-5-甲基-5,6-二氢-4-氢噻吩并[2,3-c]吡咯-2-甲酰胺(I-9)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-5,6-dihydro-4-hydrothieno[2 ,3-c]pyrrole-2-carboxamide (I-9)
步骤1:制备4,5-双(氯甲基)噻吩-2-甲酸甲酯Step 1: Preparation of methyl 4,5-bis(chloromethyl)thiophene-2-carboxylate
将500毫克2-噻吩甲酸甲酯溶于1.33毫升氯甲基甲醚中,冷却至0℃,再慢慢滴加0.58毫升四氯化钛,滴加完毕后恢复至室温搅拌,12小时后停止,加入20毫升二氯甲烷,再将反应液倒入冰水中,二氯甲烷萃取,有机相用饱和食盐水洗一次,无水硫酸钠 干燥,过滤浓缩,蒸干溶剂,用石油醚打浆纯化,得700毫克白色固体4,5-双(氯甲基)噻吩-2-甲酸甲酯,收率83%。Dissolve 500 mg of methyl 2-thiophenecarboxylate in 1.33 ml of chloromethyl methyl ether, cool to 0 ° C, and slowly add 0.58 ml of titanium tetrachloride. After the addition is completed, return to room temperature and stir. Stop after 12 hours. 20 ml of dichloromethane was added, and the reaction solution was poured into ice water, extracted with dichloromethane, and the organic phase was washed once with brine, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated and evaporated. 700 mg of white solid 4,5-bis(chloromethyl)thiophene-2-carboxylic acid methyl ester in a yield of 83%.
1H NMR(300MHz,CDCl
3)δ7.71(s,1H),4.78(s,2H),4.59(s,2H),3.88(s,3H).
1 H NMR (300 MHz, CDCl 3 ) δ 7.71 (s, 1H), 4.78 (s, 2H), 4.59 (s, 2H), 3.88 (s, 3H).
步骤2:制备5-甲基-5,6-二氢-4H-噻吩并[2,3-B]吡咯-2-甲酸甲酯Step 2: Preparation of methyl 5-methyl-5,6-dihydro-4H-thieno[2,3-B]pyrrole-2-carboxylate
将420毫克4,5-双(氯甲基)噻吩-2-甲酸甲酯溶于25毫升乙腈中,加入108毫克甲胺盐酸盐和662毫克无水碳酸钾,室温搅拌48小时后,过滤,滤饼用甲醇洗涤数次,滤液浓缩,残余物柱层析(二氯甲烷:甲醇=95:5,V/V)得产物。420 mg of methyl 4,5-bis(chloromethyl)thiophene-2-carboxylate was dissolved in 25 ml of acetonitrile, and 108 mg of methylamine hydrochloride and 662 mg of anhydrous potassium carbonate were added thereto, and the mixture was stirred at room temperature for 48 hours, and then filtered. The filter cake was washed several times with methanol, the filtrate was concentrated, and the residue was applied tojjjjjjjj
1H NMR(300MHz,CDCl
3)δ7.52(s,1H),4.01(s,2H),3.86(s,5H),2.65(s,3H).
1 H NMR (300MHz, CDCl 3 ) δ7.52 (s, 1H), 4.01 (s, 2H), 3.86 (s, 5H), 2.65 (s, 3H).
步骤3:制备5-甲基-5,6-二氢-4H-噻吩并[2,3-B]吡咯-2-甲酸Step 3: Preparation of 5-methyl-5,6-dihydro-4H-thieno[2,3-B]pyrrole-2-carboxylic acid
将4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成5-甲基-5,6-二氢-4H-噻吩并[2,3-B]吡咯-2-甲酸甲酯,其余所需原料、试剂及制备方法同实施例1中的步骤5,得5-甲基-5,6-二氢-4-氢-噻吩并[2,3-B]吡咯-2-甲酸。Replace 4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 5-methyl-5,6-dihydro-4H-thieno[2,3 -B]methyl pyrrole-2-carboxylate, the remaining starting materials, reagents and preparation methods are the same as in step 5 of Example 1, to give 5-methyl-5,6-dihydro-4-hydro-thieno[2 , 3-B]pyrrole-2-carboxylic acid.
1H NMR(300MHz,DMSO)δ7.43(s,1H),4.44(s,2H),4.27(s,2H),2.88(s,3H).
1 H NMR (300MHz, DMSO) δ7.43 (s, 1H), 4.44 (s, 2H), 4.27 (s, 2H), 2.88 (s, 3H).
步骤4:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-5-甲基-5,6-二氢-4-氢噻吩并[2,3-c]吡咯-2-甲酰胺(I-9)Step 4: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-5,6-dihydro-4-hydrogen Thieno[2,3-c]pyrrole-2-carboxamide (I-9)
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成5-甲基-5,6-二氢-4H-噻吩并[2,3-B]吡咯-2-甲酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得黄色固体。Replacing 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid with 5-methyl-5,6-dihydro- 4H-thieno[2,3-B]pyrrole-2-carboxylic acid, the remaining starting materials, reagents and preparation methods were the same as those in the step 6 of Example 1, to obtain a yellow solid.
1H NMR(300MHz,CD
3OD)δ7.25(s,1H),7.19–7.07(m,3H),7.03(d,J=8.1Hz,1H),4.08(p,J=5.9Hz,1H),3.97(s,2H),3.76(s,4H),3.53–3.40(m,2H),2.89(dd,J=8.9,4.5Hz,4H),2.75–2.65(m,2H),2.61(s,3H).
1H NMR (300MHz, CD 3 OD) δ 7.25 (s, 1H), 7.19 - 7.07 (m, 3H), 7.03 (d, J = 8.1 Hz, 1H), 4.08 (p, J = 5.9 Hz, 1H) , 3.97 (s, 2H), 3.76 (s, 4H), 3.53 - 3.40 (m, 2H), 2.89 (dd, J = 8.9, 4.5 Hz, 4H), 2.75 - 2.65 (m, 2H), 2.61 (s , 3H).
实施例10Example 10
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-5-甲基-4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-甲酰胺(I-10)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[4 ,5-c]pyridine-2-carboxamide (I-10)
步骤1:制备N-叔丁氧羰酰胺基-3-吡啶Step 1: Preparation of N-tert-butoxycarbonylamido-3-pyridine
将2.82克3-氨基吡啶溶于30毫升无水四氢呋喃中,逐滴加入60毫升1M双三甲基硅基胺基锂的四氢呋喃溶液,氩气保护,室温搅拌20分钟后,加入7.86克二碳酸二叔丁酯,室温搅拌12小时后,加水淬灭反应,乙酸乙酯萃取,有机相用无水硫酸钠干燥,过滤浓缩,柱层析(二氯甲烷:甲醇=95:5,V/V)得3.02克黄色固体,收率52%。2.82 g of 3-aminopyridine was dissolved in 30 ml of anhydrous tetrahydrofuran, and 60 ml of a 1 M solution of lithium bis trimethylsilylamide in tetrahydrofuran was added dropwise thereto, and the mixture was stirred under argon atmosphere. After stirring at room temperature for 20 minutes, 7.86 g of dicarbonic acid was added. Di-tert-butyl ester, stirred at room temperature for 12 hours, quenched with water and ethyl acetate. EtOAc EtOAcjjjjjjjjjjjjj ) 3.02 g of a yellow solid was obtained in a yield of 52%.
1H NMR(300MHz,DMSO)δ9.55(s,1H),8.59(s,1H),8.15(d,J=4.4Hz,1H),7.86(d,J=8.0Hz,1H),7.26(dd,J=8.0,4.4Hz,1H),1.46(s,9H).
1 H NMR (300MHz, DMSO) δ9.55 (s, 1H), 8.59 (s, 1H), 8.15 (d, J = 4.4Hz, 1H), 7.86 (d, J = 8.0Hz, 1H), 7.26 ( Dd, J = 8.0, 4.4 Hz, 1H), 1.46 (s, 9H).
步骤2:制备(4-巯基吡啶-3-基)氨基甲酸叔丁酯Step 2: Preparation of (4-mercaptopyridin-3-yl)carbamic acid tert-butyl ester
将2.77克N-叔丁氧羰酰胺基-3-吡啶溶于40毫升无水四氢呋喃中,氩气保护冷却至-40℃,逐滴加入14.3毫升2.5M正丁基锂的四氢呋喃溶液,加完之后升温至0℃,搅拌2小时后,加入547克硫粉,30分钟后恢复至室温搅拌,12小时后,加水淬灭反应,用3N盐酸调PH至3-4,乙酸乙酯萃取,有机相无水硫酸钠干燥,过滤浓缩,柱层析(二氯甲烷:甲醇=95:5,V/V)得红棕色油状物1.64克,收率51%。2.77 g of N-tert-butoxycarbonylamido-3-pyridine was dissolved in 40 ml of anhydrous tetrahydrofuran, cooled to -40 ° C under argon atmosphere, and 14.3 ml of a 2.5 M solution of n-butyllithium in tetrahydrofuran was added dropwise. Then, the temperature was raised to 0 ° C, and after stirring for 2 hours, 547 g of sulfur powder was added, and after 30 minutes, it was returned to room temperature and stirred. After 12 hours, the reaction was quenched with water, and the pH was adjusted to 3-4 with 3N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate (MgSO4)
1H NMR(300MHz,DMSO)δ12.91(s,1H),8.96(s,1H),8.47(s,1H),7.62(d,J=6.4Hz,1H),7.43(d,J=6.4Hz,1H),1.48(s,9H).
1 H NMR (300 MHz, DMSO) δ 12.91 (s, 1H), 8.96 (s, 1H), 8.47 (s, 1H), 7.62 (d, J = 6.4 Hz, 1H), 7.43 (d, J = 6.4 Hz, 1H), 1.48 (s, 9H).
步骤3:制备噻唑并[4,5-c]吡啶Step 3: Preparation of thiazolo[4,5-c]pyridine
将1.64克(4-巯基吡啶-3-基)氨基甲酸叔丁酯溶于15毫升甲酸中,升温至100℃回流2小时,氩气保护,反应结束后用氢氧化钠溶液调PH至中性,二氯甲烷萃取,有机相无水硫酸钠干燥,过滤浓缩,柱层析(二氯甲烷:甲醇=95:5,V/V)得400毫克红棕色油状物噻唑并[4,5-c]吡啶,收率41%。1.64 g of (4-pyridylpyridin-3-yl)carbamic acid tert-butyl ester was dissolved in 15 ml of formic acid, heated to 100 ° C for 2 hours, argon gas protection, after the reaction was finished, the pH was adjusted to neutral with sodium hydroxide solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, then purified by column chromatography (dichloromethane:methanol=95:5, V/V) to yield 400 mg of red brown oil thiazole [4,5-c Pyridine, yield 41%.
1H NMR(300MHz,CDCl
3)δ9.45(s,1H),9.06(s,1H),8.59(d,J=5.4Hz,1H),7.93(d,J=5.4Hz,1H).
1 H NMR (300 MHz, CDCl 3 ) δ 9.45 (s, 1H), 9.06 (s, 1H), 8.59 (d, J = 5.4 Hz, 1H), 7.93 (d, J = 5.4 Hz, 1H).
步骤4:制备5-甲基-4,5,6,7-四氢噻唑并[4,5-c]吡啶Step 4: Preparation of 5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine
将390毫克噻唑并[4,5-c]吡啶溶于5毫升N,N-二甲基甲酰胺中,加入0.36毫升碘甲烷,封管加热至80℃,1小时后,反应液浓缩蒸干,在将其溶于15毫升甲醇中,冰浴下加入400毫克硼氢化钠,恢复至室温搅拌1小时后,加100毫升乙酸乙酯稀释,分别用饱和碳酸氢钠和氯化钠溶液洗涤一次,有机相无水硫酸钠干燥,过滤浓缩,柱层析(二氯甲烷:甲醇=90:10,V/V)得130毫克黄色液体5-甲基-4,5,6,7-四氢噻唑并[4,5-c]吡啶。390 mg of thiazolo[4,5-c]pyridine was dissolved in 5 ml of N,N-dimethylformamide, 0.36 ml of methyl iodide was added, and the tube was heated to 80 ° C. After 1 hour, the reaction solution was concentrated to dryness. After dissolving in 15 ml of methanol, 400 mg of sodium borohydride was added to the ice bath, and the mixture was returned to room temperature and stirred for 1 hour, then diluted with 100 ml of ethyl acetate and washed once with saturated sodium hydrogencarbonate and sodium chloride solution. The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (dichloromethane:methanol=90:10, V/V) Thiazolo[4,5-c]pyridine.
1H NMR(300MHz,CDCl
3)δ8.61(s,1H),3.74(s,2H),2.97(m,2H),2.82(t,J=5.7 Hz,2H),2.56(s,3H).
1 H NMR (300MHz, CDCl 3 ) δ8.61 (s, 1H), 3.74 (s, 2H), 2.97 (m, 2H), 2.82 (t, J = 5.7 Hz, 2H), 2.56 (s, 3H) .
步骤5:制备5-甲基-4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-羧酸Step 5: Preparation of 5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine-2-carboxylic acid
将130毫克5-甲基-4,5,6,7-四氢噻唑并[4,5-c]吡啶溶于3毫升无水四氢呋喃中,冷却至-78℃,将0.37毫升2.5M的正丁基锂的四氢呋喃溶液慢慢滴加进去,20分钟后,加入过量干冰,恢复至室温搅拌,1小时后停止反应,加入2毫升水淬灭反应,用3N盐酸中和至酸性,乙酸乙酯萃取,有机相无水硫酸钠干燥,过滤浓缩得黄色固体5-甲基-4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-羧酸。130 mg of 5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine was dissolved in 3 ml of anhydrous tetrahydrofuran, cooled to -78 ° C, and 0.37 ml of 2.5 M was positive. A solution of butyl lithium in tetrahydrofuran was slowly added dropwise. After 20 minutes, excess dry ice was added, and the mixture was stirred at room temperature. After 1 hour, the reaction was stopped. The reaction was quenched with 2 ml of water and neutralized with 3N hydrochloric acid to ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered to give a white solid, 5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine-2-carboxylic acid.
1H NMR(300MHz,DMSO)δ3.75(s,2H),3.16(s,2H),2.92(s,3H),2.55(s,2H).
1 H NMR (300MHz, DMSO) δ3.75 (s, 2H), 3.16 (s, 2H), 2.92 (s, 3H), 2.55 (s, 2H).
步骤6:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-5-甲基-4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-甲酰胺(I-10)Step 6: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-4,5,6,7-tetrahydro Thiazolo[4,5-c]pyridine-2-carboxamide (I-10)
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成5-甲基-4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-羧酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得黄色固体。Replace 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid with 5-methyl-4,5,6,7 -Tetrahydrothiazolo[4,5-c]pyridine-2-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as in the step 6 of Example 1, to give a yellow solid.
1H NMR(300MHz,CD
3OD)δ7.18–7.04(m,3H),7.00(d,J=7.1Hz,1H),4.08(p,J=5.9Hz,1H),3.74(s,2H),3.50(dd,J=5.7,3.5Hz,2H),3.45(s,2H),2.95(dd,J=13.0,7.3Hz,4H),2.84(dd,J=10.2,5.4Hz,2H),2.77(t,J=5.7Hz,2H),2.71–2.65(m,2H),2.47(s,3H).
1 H NMR (300 MHz, CD 3 OD) δ 7.18 - 7.04 (m, 3H), 7.00 (d, J = 7.1 Hz, 1H), 4.08 (p, J = 5.9 Hz, 1H), 3.74 (s, 2H) ), 3.50 (dd, J = 5.7, 3.5 Hz, 2H), 3.45 (s, 2H), 2.95 (dd, J = 13.0, 7.3 Hz, 4H), 2.84 (dd, J = 10.2, 5.4 Hz, 2H) , 2.77 (t, J = 5.7 Hz, 2H), 2.71 - 2.65 (m, 2H), 2.47 (s, 3H).
实施例11Example 11
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-甲基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-11)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-4,5,6,7-tetrahydro[3,2 -c]pyridine-2-carboxamide (I-11)
将100毫克N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺溶于4毫升甲醇中,加入0.18毫升甲醛(33%的水溶液),室温搅拌10分钟后,加入167毫克氰基硼氢化钠,5小时后,停止反应,浓缩反应液,柱层析得黄色固体。100 mg of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrothieno[3,2 -c]pyridine-2-carboxamide was dissolved in 4 ml of methanol, 0.18 ml of formaldehyde (33% in water) was added, and stirred at room temperature for 10 minutes, then 167 mg of sodium cyanoborohydride was added, and after 5 hours, the reaction was stopped and concentrated. The reaction mixture was subjected to column chromatography to give a yellow solid.
1H NMR(300MHz,CD
3OD)δ7.18(s,1H),7.13(s,3H),7.05(s,1H),4.08(s,1H),3.80(s,2H),3.45(d,J=5.2Hz,2H),3.40(s,2H),2.93(s,6H),2.79(s,2H),2.72(s,2H),2.46(s,3H).
1 H NMR (300MHz, CD 3 OD) δ7.18 (s, 1H), 7.13 (s, 3H), 7.05 (s, 1H), 4.08 (s, 1H), 3.80 (s, 2H), 3.45 (d , J = 5.2 Hz, 2H), 3.40 (s, 2H), 2.93 (s, 6H), 2.79 (s, 2H), 2.72 (s, 2H), 2.46 (s, 3H).
实施例12Example 12
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-乙基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-12)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-ethyl-4,5,6,7-tetrahydro[3,2 -c]pyridine-2-carboxamide (I-12)
将100毫克N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺,29毫克溴乙烷溶于5毫升无水乙醇中,再加入5毫克碘化钾,57毫克碳酸钠,加热回流12小时后停止反应,反应液柱层析(二氯甲烷:甲醇=90:10,V/V),得到目标产物60毫克,收率55.6%。100 mg of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrothieno[3,2 -c]pyridine-2-carboxamide, 29 mg of ethyl bromide dissolved in 5 ml of absolute ethanol, then 5 mg of potassium iodide, 57 mg of sodium carbonate, heated to reflux for 12 hours, the reaction was stopped, and the reaction liquid was subjected to column chromatography (two Methyl chloride: methanol = 90:10, V/V), 60 mg of the desired product was obtained, yield 55.6%.
1H NMR(300MHz,CD
3OD)δ7.15(s,1H),7.11(d,J=4.0Hz,3H),7.02(d,J=7.2Hz,1H),4.07(p,J=5.9Hz,1H),3.76(s,2H),3.45(d,J=5.9Hz,2H),3.42(s,2H),2.96–2.85(m,6H),2.82(d,J=5.2Hz,2H),2.67(tt,J=14.4,7.3Hz,4H),1.18(t,J=7.2Hz,3H).
1 H NMR (300MHz, CD 3 OD) δ7.15 (s, 1H), 7.11 (d, J = 4.0Hz, 3H), 7.02 (d, J = 7.2Hz, 1H), 4.07 (p, J = 5.9 Hz, 1H), 3.76 (s, 2H), 3.45 (d, J = 5.9 Hz, 2H), 3.42 (s, 2H), 2.96 - 2.85 (m, 6H), 2.82 (d, J = 5.2 Hz, 2H) ), 2.67 (tt, J = 14.4, 7.3 Hz, 4H), 1.18 (t, J = 7.2 Hz, 3H).
实施例13Example 13
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-丙基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-13)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-propyl-4,5,6,7-tetrahydro[3,2 -c]pyridine-2-carboxamide (I-13)
将甲醛换成丙醛,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色粉末。The formaldehyde was replaced with propionaldehyde, and the remaining raw materials, reagents and preparation methods were the same as those in Example 11 to obtain a yellow powder.
1H NMR(300MHz,CD
3OD)δ7.10(m,5H),4.14–3.98(m,1H),3.75(s,2H),3.45(d,J=5.8Hz,2H),3.40(s,2H),2.89(d,J=6.0Hz,6H),2.81(d,J=5.1Hz,2H),2.75–2.59(m,2H),2.58–2.43(m,2H),1.61(dd,J=15.0,7.5Hz,2H),0.96(t,J=7.2Hz,3H).
1 H NMR (300MHz, CD 3 OD) δ7.10 (m, 5H), 4.14-3.98 (m, 1H), 3.75 (s, 2H), 3.45 (d, J = 5.8Hz, 2H), 3.40 (s , 2H), 2.89 (d, J = 6.0 Hz, 6H), 2.81 (d, J = 5.1 Hz, 2H), 2.75 - 2.59 (m, 2H), 2.58 - 2.43 (m, 2H), 1.61 (dd, J=15.0, 7.5 Hz, 2H), 0.96 (t, J=7.2 Hz, 3H).
实施例14Example 14
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-异丙基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-14)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-isopropyl-4,5,6,7-tetrahydro[3, 2-c]pyridine-2-carboxamide (I-14)
将甲醛换成丙酮,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色 粉末。The formaldehyde was changed to acetone, and the remaining raw materials, reagents and preparation methods were the same as those in Example 11 to obtain a yellow powder.
1H NMR(300MHz,CD
3OD)δ7.18(s,1H),7.14(m,3H),7.07(s,1H),4.16–4.04(m,1H),3.85(s,2H),3.61(s,2H),3.45(d,J=5.8Hz,2H),3.04(dd,J=13.9,7.4Hz,1H),2.96(s,8H),2.76(t,J=6.1Hz,2H),1.19(d,J=6.5Hz,6H).
1 H NMR (300MHz, CD 3 OD) δ7.18 (s, 1H), 7.14 (m, 3H), 7.07 (s, 1H), 4.16-4.04 (m, 1H), 3.85 (s, 2H), 3.61 (s, 2H), 3.45 (d, J = 5.8 Hz, 2H), 3.04 (dd, J = 13.9, 7.4 Hz, 1H), 2.96 (s, 8H), 2.76 (t, J = 6.1 Hz, 2H) , 1.19 (d, J = 6.5 Hz, 6H).
实施例15Example 15
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-烯丙基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-15)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-allyl-4,5,6,7-tetrahydro[3, 2-c]pyridine-2-carboxamide (I-15)
将40毫克N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺,20毫克烯丙基溴溶于5毫升乙腈中,加入无水碳酸钾30毫克,升温至60℃,2小时后停止反应,过滤反应液,滤液浓缩,残余物柱层析(二氯甲烷/甲醇=92:8,V/V)得到黄色固体15毫克。40 mg of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrothiophene [3,2 -c]pyridine-2-carboxamide, 20 mg of allyl bromide was dissolved in 5 ml of acetonitrile, 30 mg of anhydrous potassium carbonate was added, and the temperature was raised to 60 ° C. After 2 hours, the reaction was stopped, the reaction solution was filtered, and the filtrate was concentrated. Column chromatography (dichloromethane / methanol = 92:8, V /V) gave
1H NMR(300MHz,CD
3OD)δ7.21–7.09(m,4H),7.06(d,J=7.3Hz,1H),5.94(td,J=17.0,6.8Hz,1H),5.29(t,J=13.3Hz,2H),4.17–4.05(m,1H),3.88(s,2H),3.45(d,J=6.0Hz,4H),3.23(d,J=6.7Hz,2H),2.98(s,4H),2.90(d,J=5.2Hz,2H),2.87–2.75(m,4H).
1 H NMR (300 MHz, CD 3 OD) δ 7.21 - 7.09 (m, 4H), 7.06 (d, J = 7.3 Hz, 1H), 5.94 (td, J = 17.0, 6.8 Hz, 1H), 5.29 (t) , J = 13.3 Hz, 2H), 4.17 - 4.05 (m, 1H), 3.88 (s, 2H), 3.45 (d, J = 6.0 Hz, 4H), 3.23 (d, J = 6.7 Hz, 2H), 2.98 (s, 4H), 2.90 (d, J = 5.2 Hz, 2H), 2.87 - 2.75 (m, 4H).
实施例16Example 16
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(2-甲氧基乙基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-16)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(2-methoxyethyl)-4,5,6,7 -tetrahydro[3,2-c]pyridine-2-carboxamide (I-16)
将40毫克N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺,40毫克2-甲氧基溴乙烷溶于5毫升乙腈中,加入无水碳酸钾30毫克,升温至80℃回流,12小时后停止反应,过滤反应液,滤液浓缩,残余物柱层析(二氯甲烷/甲醇=90:10,V/V)得到黄色固体18毫克。40 mg of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrothiophene [3,2 -c]pyridine-2-carboxamide, 40 mg of 2-methoxybromoethane dissolved in 5 ml of acetonitrile, 30 mg of anhydrous potassium carbonate was added, and the mixture was heated to reflux at 80 ° C. After 12 hours, the reaction was stopped and the reaction mixture was filtered. The filtrate was concentrated, and the residue was applied tojjjjjjjjjj
1H NMR(300MHz,CD
3OD)δ7.17(s,1H),7.17–7.07(m,3H),7.04(m,1H),4.09(p,J=6.0Hz,1H),3.81(s,2H),3.60(t,J=5.4Hz,2H),3.50(s,2H),3.44(d,J=5.9Hz,2H),3.36(s,3H),2.94(s,4H),2.88(s,4H),2.74(dt,J=12.4,5.7Hz,4H).
1 H NMR (300 MHz, CD 3 OD) δ 7.17 (s, 1H), 7.17 - 7.07 (m, 3H), 7.04 (m, 1H), 4.09 (p, J = 6.0 Hz, 1H), 3.81 (s) , 2H), 3.60 (t, J = 5.4 Hz, 2H), 3.50 (s, 2H), 3.44 (d, J = 5.9 Hz, 2H), 3.36 (s, 3H), 2.94 (s, 4H), 2.88 (s, 4H), 2.74 (dt, J = 12.4, 5.7 Hz, 4H).
实施例17Example 17
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-环丁基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-17)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-cyclobutyl-4,5,6,7-tetrahydro[3, 2-c]pyridine-2-carboxamide (I-17)
将甲醛换成环丁酮,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色粉末。The formaldehyde was replaced with cyclobutanone, and the remaining raw materials, reagents and preparation methods were the same as those in Example 11 to obtain a yellow powder.
1H NMR(300MHz,CD
3OD)δ7.09(d,J=21.1Hz,5H),4.07(s,1H),3.76(s,2H),3.46(s,2H),3.26(m,2H),2.90(m,7H),2.68(m,4H),2.14(m,2H),1.95(m,2H),1.78(m,2H).
1 H NMR (300 MHz, CD 3 OD) δ 7.09 (d, J = 21.1 Hz, 5H), 4.07 (s, 1H), 3.76 (s, 2H), 3.46 (s, 2H), 3.26 (m, 2H) ), 2.90 (m, 7H), 2.68 (m, 4H), 2.14 (m, 2H), 1.95 (m, 2H), 1.78 (m, 2H).
实施例18Example 18
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-环戊基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-18)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-cyclopentyl-4,5,6,7-tetrahydro[3, 2-c]pyridine-2-carboxamide (I-18)
将甲醛换成环戊酮,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色粉末。The formaldehyde was replaced with cyclopentanone, and the remaining raw materials, reagents and preparation methods were the same as those in Example 11 to obtain a yellow powder.
1H NMR(300MHz,CD
3OD)δ7.15(m,4H),7.06(s,1H),4.17–4.03(m,1H),3.84(s,2H),3.54(s,2H),3.45(d,J=4.7Hz,2H),2.94(d,J=10.8Hz,8H),2.90–2.79(m,1H),2.75(t,J=5.9Hz,2H),2.01(s,2H),1.76(s,2H),1.66(d,J=16.3Hz,2H),1.51(s,2H).
1 H NMR (300MHz, CD 3 OD) δ7.15 (m, 4H), 7.06 (s, 1H), 4.17-4.03 (m, 1H), 3.84 (s, 2H), 3.54 (s, 2H), 3.45 (d, J = 4.7 Hz, 2H), 2.94 (d, J = 10.8 Hz, 8H), 2.90 - 2.79 (m, 1H), 2.75 (t, J = 5.9 Hz, 2H), 2.01 (s, 2H) , 1.76 (s, 2H), 1.66 (d, J = 16.3 Hz, 2H), 1.51 (s, 2H).
实施例19Example 19
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-环己基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-19)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-cyclohexyl-4,5,6,7-tetrahydro[3,2 -c]pyridine-2-carboxamide (I-19)
将甲醛换成环己酮,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色粉末。The formaldehyde was replaced with cyclohexanone, and the remaining raw materials, reagents and preparation methods were the same as those in Example 11 to obtain a yellow powder.
1H NMR(300MHz,CD
3OD)δ7.13(m,4H),7.04(d,J=6.3Hz,1H),4.08(p,J=6.0Hz,1H),3.78(s,2H),3.59(s,2H),3.51–3.42(m,2H),3.00–2.84(m,8H),2.79–2.52(m,3H),1.92(d,J=23.3Hz,4H),1.69(d,J=11.5Hz,1H),1.45–1.12(m,5H).
1 H NMR (300MHz, CD 3 OD) δ7.13 (m, 4H), 7.04 (d, J = 6.3Hz, 1H), 4.08 (p, J = 6.0Hz, 1H), 3.78 (s, 2H), 3.59(s, 2H), 3.51–3.42 (m, 2H), 3.00–2.84 (m, 8H), 2.79–2.52 (m, 3H), 1.92 (d, J=23.3 Hz, 4H), 1.69 (d, J=11.5Hz, 1H), 1.45–1.12(m, 5H).
实施例20Example 20
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-环庚基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-20)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-cycloheptyl-4,5,6,7-tetrahydro[3, 2-c]pyridine-2-carboxamide (I-20)
将甲醛换成环庚酮,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色粉末。The formaldehyde was replaced with cycloheptanone, and the remaining raw materials, reagents and preparation methods were the same as those in Example 11 to obtain a yellow powder.
1H NMR(300MHz,CD
3OD)δ7.14(d,J=5.6Hz,4H),7.06(s,1H),4.16–4.01(m,1H),3.80(s,2H),3.58(s,2H),3.45(d,J=3.7Hz,2H),2.93(s,9H),2.72(t,J=5.8Hz,2H),1.92(s,2H),1.77(s,2H),1.60(t,J=15.7Hz,8H).
1 H NMR (300MHz, CD 3 OD) δ7.14 (d, J = 5.6Hz, 4H), 7.06 (s, 1H), 4.16-4.01 (m, 1H), 3.80 (s, 2H), 3.58 (s , 2H), 3.45 (d, J = 3.7 Hz, 2H), 2.93 (s, 9H), 2.72 (t, J = 5.8 Hz, 2H), 1.92 (s, 2H), 1.77 (s, 2H), 1.60 (t, J = 15.7 Hz, 8H).
实施例21Example 21
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-甲基环己基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-21)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-methylcyclohexyl)-4,5,6,7- Tetrahydro[3,2-c]pyridine-2-carboxamide (I-21)
将甲醛换成4-甲基环己酮,其余所需原料、试剂及制备方法同实施例11中的步骤,得白色粉末。The formaldehyde was replaced with 4-methylcyclohexanone, and the remaining materials, reagents and preparation methods were the same as those in Example 11, to obtain a white powder.
1H NMR(300MHz,CD
3OD)δ7.06(m,5H),4.13–4.00(m,1H),3.73(s,2H),3.56–3.38(m,4H),2.87(m,8H),2.75–2.57(m,2H),2.44(m,1H),1.84(m,1H),1.65(m,4H),1.57(m,4H),0.99(d,J=6.9Hz,3H).
1 H NMR (300MHz, CD 3 OD) δ7.06 (m, 5H), 4.13-4.00 (m, 1H), 3.73 (s, 2H), 3.56-3.38 (m, 4H), 2.87 (m, 8H) , 2.75–2.57 (m, 2H), 2.44 (m, 1H), 1.84 (m, 1H), 1.65 (m, 4H), 1.57 (m, 4H), 0.99 (d, J = 6.9 Hz, 3H).
实施例22Example 22
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(四氢吡喃-4-基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-22)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(tetrahydropyran-4-yl)-4,5,6, 7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-22)
将甲醛换成四氢吡喃酮,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色粉末。The formaldehyde was replaced with tetrahydropyrone, and the remaining starting materials, reagents and preparation methods were the same as those in Example 11 to obtain a yellow powder.
1H NMR(300MHz,CD
3OD)δ7.14(d,J=4.7Hz,4H),7.05(d,J=7.6Hz,1H),4.15– 3.95(m,3H),3.79(s,2H),3.54(s,2H),3.44(t,J=10.6Hz,4H),3.00–2.82(m,8H),2.79–2.62(m,3H),1.87(d,J=12.0Hz,2H),1.63(td,J=12.0,7.7Hz,2H).
1 H NMR (300MHz, CD 3 OD) δ7.14 (d, J = 4.7Hz, 4H), 7.05 (d, J = 7.6Hz, 1H), 4.15- 3.95 (m, 3H), 3.79 (s, 2H ), 3.54 (s, 2H), 3.44 (t, J = 10.6 Hz, 4H), 3.00 - 2.82 (m, 8H), 2.79 - 2.62 (m, 3H), 1.87 (d, J = 12.0 Hz, 2H) , 1.63 (td, J = 12.0, 7.7 Hz, 2H).
实施例23Example 23
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(哌啶-4-基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-23)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(piperidin-4-yl)-4,5,6,7- Tetrahydro[3,2-c]pyridine-2-carboxamide (I-23)
步骤1:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(1-叔丁氧羰基哌啶-4-基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺Step 1: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(1-tert-butoxycarbonylpiperidin-4-yl )-4,5,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide
将甲醛换成1-叔丁氧羰基-4-哌啶酮,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色粉末。The formaldehyde was replaced with 1-tert-butoxycarbonyl-4-piperidone. The remaining starting materials, reagents and preparation methods were the same as those in Example 11 to obtain a yellow powder.
步骤2:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(哌啶-4-基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺Step 2: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(piperidin-4-yl)-4,5, 6,7-tetrahydro[3,2-c]pyridine-2-carboxamide
将叔丁基2-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基甲酰基)-6,7-四氢[3,2-c]吡啶-5(4H)-羧酸叔丁酯换成N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(1-叔丁氧羰基哌啶-4-基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺,其余所需原料、试剂及制备方法同实施例2中的步骤,得微黄色固体。tert-Butyl 2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-6,7-tetrahydro[3,2 -c] pyridine-5(4H)-carboxylic acid tert-butyl ester was replaced by N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5- (1-tert-Butoxycarbonylpiperidin-4-yl)-4,5,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide, the same required starting materials, reagents and preparation methods are the same as The procedure in Example 2 gave a yellowish solid.
1H NMR(300MHz,CD
3OD)δ7.53(s,1H),7.34–7.22(m,3H),7.19(d,J=6.9Hz,1H),4.52(s,2H),4.35(m,1H),3.94(s,2H),3.73–3.59(m,2H),3.50(t,J=12.4Hz,4H),3.45–3.37(m,1H),3.26–3.08(m,6H),3.03(d,J=4.9Hz,2H),2.24(d,J=12.9Hz,2H),2.08–1.84(m,2H).
1 H NMR (300MHz, CD 3 OD) δ7.53 (s, 1H), 7.34-7.22 (m, 3H), 7.19 (d, J = 6.9Hz, 1H), 4.52 (s, 2H), 4.35 (m , 1H), 3.94 (s, 2H), 3.73–3.59 (m, 2H), 3.50 (t, J = 12.4 Hz, 4H), 3.45–3.37 (m, 1H), 3.26–3.08 (m, 6H), 3.03 (d, J = 4.9 Hz, 2H), 2.24 (d, J = 12.9 Hz, 2H), 2.08 - 1.84 (m, 2H).
实施例24Example 24
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-苯基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-24)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-phenyl-4,5,6,7-tetrahydro[3,2 -c]pyridine-2-carboxamide (I-24)
步骤1:制备4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯Step 1: Preparation of ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
将5.14克5-叔丁基2-乙基6,7-四氢噻吩并[3,2-c]吡啶-2,5(4H)-二甲酸酯溶于20毫升二氯甲烷中,加入6.13毫升三氟乙酸,室温搅拌15小时后,停止反应,反应液用饱和碳酸氢钠溶液中和,再用二氯甲烷萃取三次,有机层用无水硫酸钠干燥,过滤,浓缩,柱层析(二氯甲烷:甲醇(V/V)=10:1)得黄色固体3.30克,收率94.8%。5.14 g of 5-tert-butyl 2-ethyl 6,7-tetrahydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate was dissolved in 20 ml of dichloromethane and added 6.13 ml of trifluoroacetic acid, after stirring at room temperature for 15 hours, the reaction was stopped, the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and then extracted three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. (Dichloromethane: methanol (V/V) = 10:1) gave 3.30 g of a yellow solid, yield 94.8%.
1H NMR(300MHz,DMSO)δ7.58(s,1H),4.25(q,J=7.1Hz,2H),4.03(s,2H),3.24(d,J=5.7Hz,2H),2.97(s,2H),1.89(s,1H),1.26(t,J=7.1Hz,3H).
1 H NMR (300MHz, DMSO) δ7.58 (s, 1H), 4.25 (q, J = 7.1Hz, 2H), 4.03 (s, 2H), 3.24 (d, J = 5.7Hz, 2H), 2.97 ( s, 2H), 1.89 (s, 1H), 1.26 (t, J = 7.1 Hz, 3H).
步骤2:制备5-苯基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯Step 2: Preparation of ethyl 5-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
将180毫克4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯,348毫克碘苯,555毫克碳酸铯,40毫克2-二环己基磷-2,4,6-三异丙基联苯,40毫克三(二亚苄基丙酮)二钯混合,加入无水甲苯,除氧,氩气保护,微波加热5小时后,停止反应,反应液浓缩,柱层析(石油醚:乙酸乙酯(V/V)=90:10),得5-苯基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯100毫克,收率41%。180 mg of ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate, 348 mg of iodobenzene, 555 mg of cesium carbonate, 40 mg of 2-dicyclohexylphosphine - 2,4,6-triisopropylbiphenyl, 40 mg of tris(dibenzylideneacetone) dipalladium, add anhydrous toluene, deoxidize, argon gas protection, microwave heating for 5 hours, stop the reaction, the reaction solution Concentration, column chromatography (petroleum ether: ethyl acetate (V / V) = 90: 10) to give 5-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- Ethyl 2-carboxylate 100 mg, yield 41%.
1H NMR(300MHz,CDCl
3)δ7.55(s,1H),7.33–7.21(m,2H),6.99(d,J=8.3Hz,2H),6.88(t,J=7.3Hz,1H),4.34(t,7.2Hz,2H),4.29(s,2H),3.62(t,J=5.6Hz,2H),3.00(t,J=5.6Hz,2H),1.37(t,J=7.2Hz,3H).
1 H NMR (300 MHz, CDCl 3 ) δ 7.55 (s, 1H), 7.33 - 7.21 (m, 2H), 6.99 (d, J = 8.3 Hz, 2H), 6.88 (t, J = 7.3 Hz, 1H) , 4.34 (t, 7.2 Hz, 2H), 4.29 (s, 2H), 3.62 (t, J = 5.6 Hz, 2H), 3.00 (t, J = 5.6 Hz, 2H), 1.37 (t, J = 7.2 Hz) , 3H).
步骤3:制备5-苯基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸Step 3: Preparation of 5-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid
将4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成5-苯基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯,其余所需原料、试剂及制备方法同实施例1中的步骤5,得到5-苯基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸。Replace 4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 5-phenyl-4,5,6,7-tetrahydrothiophene [3, Ethyl 2-c]pyridine-2-carboxylate, the remaining starting materials, reagents and preparation methods are the same as those in step 5 of Example 1, to give 5-phenyl-4,5,6,7-tetrahydrothiophene [ 3,2-c]pyridine-2-carboxylic acid.
步骤4:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-苯基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-24)Step 4: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-phenyl-4,5,6,7-tetrahydro [3,2-c]pyridine-2-carboxamide (I-24)
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成5-苯基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得白色固体。Replace 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid with 5-phenyl-4,5,6,7 -tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as those in Step 6 of Example 1, to give a white solid.
1H NMR(300MHz,CD
3OD)δ7.31–7.20(m,3H),7.14(m,3H),7.07(s,1H),7.01(d,J=8.2Hz,2H),6.84(t,J=7.4Hz,1H),4.16–4.03(m,3H),3.85(s,2H),3.57(t,J=5.5Hz,2H),3.51–3.41(m,2H),2.95(m,6H),2.76(m,2H).
1 H NMR (300MHz, CD 3 OD) δ7.31-7.20 (m, 3H), 7.14 (m, 3H), 7.07 (s, 1H), 7.01 (d, J = 8.2Hz, 2H), 6.84 (t , J = 7.4 Hz, 1H), 4.16 - 4.03 (m, 3H), 3.85 (s, 2H), 3.57 (t, J = 5.5 Hz, 2H), 3.51 - 3.41 (m, 2H), 2.95 (m, 6H), 2.76 (m, 2H).
实施例25Example 25
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(环己基甲基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-25)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(cyclohexylmethyl)-4,5,6,7-tetrahydro [3,2-c]pyridine-2-carboxamide (I-25)
将甲醛换成环己烷基甲醛,其余所需原料、试剂及制备方法同实施例11中的步骤,得白色粉末。The formaldehyde was replaced with cyclohexane-based formaldehyde, and the remaining raw materials, reagents and preparation methods were the same as those in Example 11, to obtain a white powder.
1H NMR(300MHz,CD
3OD)δ7.12(d,J=4.5Hz,4H),7.04(d,J=7.1Hz,1H),4.15–4.01(m,1H),3.81(s,2H),3.47(m,2H),3.37(s,2H),2.93(s,4H),2.86(m,2H),2.81–2.67(m,4H),2.35(d,J=7.0Hz,2H),1.74(dd,J=42.5,22.7Hz,6H),1.41–1.14(m,3H),1.08–0.76(m,2H).
1 H NMR (300 MHz, CD 3 OD) δ 7.12 (d, J = 4.5 Hz, 4H), 7.04 (d, J = 7.1 Hz, 1H), 4.15 - 4.01 (m, 1H), 3.81 (s, 2H) ), 3.47 (m, 2H), 3.37 (s, 2H), 2.93 (s, 4H), 2.86 (m, 2H), 2.81 - 2.67 (m, 4H), 2.35 (d, J = 7.0 Hz, 2H) , 1.74 (dd, J = 42.5, 22.7 Hz, 6H), 1.41 - 1.14 (m, 3H), 1.08 - 0.76 (m, 2H).
实施例26Example 26
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-苄基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-26)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-benzyl-4,5,6,7-tetrahydro[3,2 -c]pyridine-2-carboxamide (I-26)
将甲醛换成苯甲醛,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色粉末。The formaldehyde was replaced with benzaldehyde, and the remaining raw materials, reagents and preparation methods were the same as those in Example 11 to obtain a yellow powder.
1H NMR(300MHz,CD
3OD)δ7.43–7.26(m,5H),7.16(s,1H),7.13(d,J=3.5Hz,3H),7.09(s,1H),4.14(m,1H),4.03(s,2H),3.74(s,2H),3.45(d,J=5.0Hz,4H),3.16(t,J =5.9Hz,2H),3.00(dd,J=12.0,5.5Hz,2H),2.96–2.78(m,6H).
1 H NMR (300MHz, CD 3 OD) δ7.43-7.26 (m, 5H), 7.16 (s, 1H), 7.13 (d, J = 3.5Hz, 3H), 7.09 (s, 1H), 4.14 (m , 1H), 4.03 (s, 2H), 3.74 (s, 2H), 3.45 (d, J = 5.0 Hz, 4H), 3.16 (t, J = 5.9 Hz, 2H), 3.00 (dd, J = 12.0, 5.5Hz, 2H), 2.96–2.78 (m, 6H).
实施例27Example 27
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(吡啶-4-基甲基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-27)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(pyridin-4-ylmethyl)-4,5,6,7 -tetrahydro[3,2-c]pyridine-2-carboxamide (I-27)
将甲醛换成4-吡啶甲醛,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色粉末。The formaldehyde was replaced with 4-pyridinecarboxaldehyde, and the remaining materials, reagents and preparation methods were the same as those in Example 11, to obtain a yellow powder.
1H NMR(300MHz,CD
3OD)δ8.51(d,J=4.3Hz,2H),7.49(d,J=4.3Hz,2H),7.07(m,5H),4.09(m,1H),3.82(s,2H),3.76(s,2H),3.45(s,2H),3.39(s,2H),2.94(m,4H),2.88(m,2H),2.78(m,4H).
1 H NMR (300 MHz, CD 3 OD) δ 8.51 (d, J = 4.3 Hz, 2H), 7.49 (d, J = 4.3 Hz, 2H), 7.07 (m, 5H), 4.09 (m, 1H), 3.82 (s, 2H), 3.76 (s, 2H), 3.45 (s, 2H), 3.39 (s, 2H), 2.94 (m, 4H), 2.88 (m, 2H), 2.78 (m, 4H).
实施例28Example 28
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-甲基苄基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-28)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-methylbenzyl)-4,5,6,7- Tetrahydro[3,2-c]pyridine-2-carboxamide (I-28)
将甲醛换成对甲基苯甲醛,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色粉末。The formaldehyde was replaced with p-methylbenzaldehyde, and the remaining raw materials, reagents and preparation methods were the same as those in Example 11, to obtain a yellow powder.
1H NMR(300MHz,CD
3OD)δ7.26(d,J=7.8Hz,2H),7.18(d,J=7.8Hz,2H),7.07(m,5H),4.09(m,1H),3.88(s,2H),3.68(s,2H),3.45(m,2H),3.38(s,2H),3.06–2.92(m,4H),2.92–2.70(m,6H),2.34(s,3H)
1 H NMR (300 MHz, CD 3 OD) δ 7.26 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 7.07 (m, 5H), 4.09 (m, 1H), 3.88 (s, 2H), 3.68 (s, 2H), 3.45 (m, 2H), 3.38 (s, 2H), 3.06 - 2.92 (m, 4H), 2.92 - 2.70 (m, 6H), 2.34 (s, 3H)
实施例29Example 29
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-甲氧基苄基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-29)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-methoxybenzyl)-4,5,6,7 -tetrahydro[3,2-c]pyridine-2-carboxamide (I-29)
将甲醛换成对甲氧基苯甲醛,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色粉末。The formaldehyde was replaced with p-methoxybenzaldehyde, and the remaining materials, reagents and preparation methods were the same as those in Example 11, to obtain a yellow powder.
1H NMR(300MHz,CD
3OD)δ7.29(d,J=8.3Hz,2H),7.05(d,J=10.3Hz,5H),6.91(d,J=8.3Hz,2H),4.15–4.00(m,1H),3.79(s,5H),3.65(s,2H),3.44(m,2H),3.34(d,J= 8.0Hz,2H),2.92(s,4H),2.86(s,2H),2.80(d,J=4.9Hz,2H),2.72(d,J=6.1Hz,2H).
1 H NMR (300MHz, CD 3 OD) δ7.29 (d, J = 8.3Hz, 2H), 7.05 (d, J = 10.3Hz, 5H), 6.91 (d, J = 8.3Hz, 2H), 4.15- 4.00 (m, 1H), 3.79 (s, 5H), 3.65 (s, 2H), 3.44 (m, 2H), 3.34 (d, J = 8.0 Hz, 2H), 2.92 (s, 4H), 2.86 (s) , 2H), 2.80 (d, J = 4.9 Hz, 2H), 2.72 (d, J = 6.1 Hz, 2H).
实施例30Example 30
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-氯苄基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-30)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-chlorobenzyl)-4,5,6,7-tetra Hydrogen [3,2-c]pyridine-2-carboxamide (I-30)
将甲醛换成对氯苯甲醛,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色粉末。The formaldehyde was replaced with p-chlorobenzaldehyde, and the remaining raw materials, reagents and preparation methods were the same as those in Example 11 to obtain a yellow powder.
1H NMR(300MHz,CD
3OD)δ7.37(s,4H),7.06(m,5H),4.07(m,1H),3.80(s,2H),3.68(s,2H),3.54–3.38(m,2H),3.35(s,2H),2.92(m,4H),2.87(m,2H),2.80(m,2H),2.73(m,2H).
1 H NMR (300MHz, CD 3 OD) δ7.37 (s, 4H), 7.06 (m, 5H), 4.07 (m, 1H), 3.80 (s, 2H), 3.68 (s, 2H), 3.54-3.38 (m, 2H), 3.35 (s, 2H), 2.92 (m, 4H), 2.87 (m, 2H), 2.80 (m, 2H), 2.73 (m, 2H).
实施例31Example 31
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-硝基苄基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-31)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-nitrobenzyl)-4,5,6,7- Tetrahydro[3,2-c]pyridine-2-carboxamide (I-31)
将甲醛换成4-硝基苯甲醛,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色粉末。The formaldehyde was changed to 4-nitrobenzaldehyde, and the remaining raw materials, reagents and preparation methods were the same as those in Example 11, to obtain a yellow powder.
1H NMR(300MHz,CD
3OD)δ8.23(d,J=8.1Hz,2H),7.65(d,J=8.1Hz,2H),7.04(m,5H),4.13–4.00(m,1H),3.82(s,2H),3.73(s,2H),3.44(t,J=5.0Hz,2H),3.38(s,2H),2.85(m,8H),2.66(d,J=5.1Hz,2H).
1 H NMR (300MHz, CD 3 OD) δ8.23 (d, J = 8.1Hz, 2H), 7.65 (d, J = 8.1Hz, 2H), 7.04 (m, 5H), 4.13-4.00 (m, 1H ), 3.82 (s, 2H), 3.73 (s, 2H), 3.44 (t, J = 5.0 Hz, 2H), 3.38 (s, 2H), 2.85 (m, 8H), 2.66 (d, J = 5.1 Hz) , 2H).
实施例32Example 32
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-氨基苄基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-32)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-aminobenzyl)-4,5,6,7-tetra Hydrogen [3,2-c]pyridine-2-carboxamide (I-32)
将128毫克N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-硝基苄基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺溶于8毫升甲醇中,加入钯碳50毫克,氢气氛围下搅拌7小时后,过滤钯碳,滤液浓缩,得100毫克。128 mg of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-nitrobenzyl)-4,5,6 7-Tetrahydro[3,2-c]pyridine-2-carboxamide was dissolved in 8 ml of methanol, and 50 mg of palladium carbon was added thereto, and the mixture was stirred under a hydrogen atmosphere for 7 hours, then palladium carbon was filtered, and the filtrate was concentrated to give 100 mg.
实施例33Example 33
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(苯并[b]噻吩-3-甲基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-33)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(benzo[b]thiophen-3-methyl)-4,5 ,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-33)
将甲醛换成3-甲醛基苯并噻吩,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色粉末。The formaldehyde was replaced with 3-formaldehyde benzothiophene, and the remaining materials, reagents and preparation methods were the same as those in Example 11, to obtain a yellow powder.
1H NMR(400MHz,CD
3OD)δ7.99(d,J=8.3Hz,1H),7.89(d,J=7.4Hz,1H),7.51(s,1H),7.42–7.30(m,2H),7.11–6.98(m,5H),4.15–4.06(m,1H),3.97(s,2H),3.89(s,2H),3.52–3.38(m,4H),3.02(d,J=5.5Hz,2H),2.96(d,J=5.6Hz,2H),2.87(m,4H),2.84–2.74(m,2H).
1 H NMR (400 MHz, CD 3 OD) δ 7.99 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.51 (s, 1H), 7.42 - 7.30 (m, 2H) ), 7.11–6.98 (m, 5H), 4.15–4.06 (m, 1H), 3.97 (s, 2H), 3.89 (s, 2H), 3.52–3.38 (m, 4H), 3.02 (d, J=5.5) Hz, 2H), 2.96 (d, J = 5.6 Hz, 2H), 2.87 (m, 4H), 2.84 - 2.74 (m, 2H).
实施例34Example 34
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-乙酰基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-34)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-acetyl-4,5,6,7-tetrahydro[3,2 -c]pyridine-2-carboxamide (I-34)
将40毫克N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺溶于4毫升无水四氢呋喃中,加入38微升三乙胺,10毫克乙酰氯,室温搅拌2小时后,加少量水淬灭反应,浓缩反应液,柱层析(二氯甲烷/甲醇=93:7,V/V)得20毫克白色粉末。40 mg of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydro[3,2-c Pyridine-2-carboxamide was dissolved in 4 ml of anhydrous tetrahydrofuran, 38 μl of triethylamine and 10 mg of acetyl chloride were added. After stirring at room temperature for 2 hours, the reaction was quenched with a small amount of water, and the reaction mixture was concentrated. Methylene chloride/methanol = 93:7, V/V) gave 20 mg of white powder.
1H NMR(300MHz,CD
3OD)δ7.20(s,1H),7.12(m,3H),7.02(m,1H),4.45(d,J=10.4Hz,2H),4.14–4.00(m,1H),3.89–3.75(m,2H),3.74(s,2H),3.46(d,J=5.2Hz,2H),2.85(m,6H),2.64(m,2H),2.17(d,J=11.5Hz,3H).
1 H NMR (300MHz, CD 3 OD) δ7.20 (s, 1H), 7.12 (m, 3H), 7.02 (m, 1H), 4.45 (d, J = 10.4Hz, 2H), 4.14-4.00 (m , 1H), 3.89 - 3.75 (m, 2H), 3.74 (s, 2H), 3.46 (d, J = 5.2 Hz, 2H), 2.85 (m, 6H), 2.64 (m, 2H), 2.17 (d, J=11.5Hz, 3H).
实施例35Example 35
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-环己烷羰基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-35)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-cyclohexanecarbonyl-4,5,6,7-tetrahydro[3 ,2-c]pyridine-2-carboxamide (I-35)
将50毫克N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺,17毫克环己基甲酸,37毫克1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和26毫克1-羟基苯并***混合溶于3毫升二氯甲烷中,氩气保护,室温搅拌4小时后停止反应,反应液浓缩之后柱层析,(二氯甲烷/甲醇=90:10,V/V)得微黄色固体。50 mg of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrothieno[3,2 -c]pyridine-2-carboxamide, 17 mg of cyclohexylcarboxylic acid, 37 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 26 mg of 1-hydroxybenzoic acid The azole mixture was dissolved in 3 ml of dichloromethane, argon-protected, and stirred at room temperature for 4 hours, then the reaction was stopped, and the reaction mixture was concentrated and then subjected to column chromatography (dichloromethane/methanol = 90:10, V/V) to obtain a yellow solid. .
1H NMR(300MHz,CD
3OD)δ7.30(d,J=13.0Hz,1H),7.18(dd,J=13.7,5.1Hz,3H),7.06(d,J=7.6Hz,1H),4.52(d,J=17.0Hz,2H),4.22–4.09(m,1H),3.98(s,2H),3.83(t,J=5.4Hz,2H),3.46(d,J=5.7Hz,2H),3.10(t,J=5.9Hz,2H),3.00(t,J=5.3Hz,2H),2.96–2.82(m,3H),2.83–2.61(m,2H),1.95–1.58(m,5H),1.56–1.23(m,5H).
1 H NMR (300 MHz, CD 3 OD) δ 7.30 (d, J = 13.0 Hz, 1H), 7.18 (dd, J = 13.7, 5.1 Hz, 3H), 7.06 (d, J = 7.6 Hz, 1H), 4.52 (d, J = 17.0 Hz, 2H), 4.22 - 4.09 (m, 1H), 3.98 (s, 2H), 3.83 (t, J = 5.4 Hz, 2H), 3.46 (d, J = 5.7 Hz, 2H) ), 3.10 (t, J = 5.9 Hz, 2H), 3.00 (t, J = 5.3 Hz, 2H), 2.96 - 2.82 (m, 3H), 2.83 - 2.61 (m, 2H), 1.95 - 1.58 (m, 5H), 1.56–1.23 (m, 5H).
实施例36Example 36
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-苯甲酰基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-36)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-benzoyl-4,5,6,7-tetrahydro[3, 2-c]pyridine-2-carboxamide (I-36)
将环己基甲酸换成苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with benzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to obtain a white powder.
1H NMR(300MHz,CD
3OD)δ7.46(m,6H),7.14(m,4H),4.69(s,1H),4.41(s,1H),4.25–3.94(m,4H),3.69(s,1H),3.46(s,2H),3.20(m,2H),2.93(m,6H).
1 H NMR (300MHz, CD 3 OD) δ7.46 (m, 6H), 7.14 (m, 4H), 4.69 (s, 1H), 4.41 (s, 1H), 4.25-3.94 (m, 4H), 3.69 (s, 1H), 3.46 (s, 2H), 3.20 (m, 2H), 2.93 (m, 6H).
实施例37Example 37
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(噻吩-2-羰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-37)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(thiophene-2-carbonyl)-4,5,6,7-tetra Hydrogen [3,2-c]pyridine-2-carboxamide (I-37)
将环己基甲酸换成2-噻吩甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 2-thiophenecarboxylic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to obtain a white powder.
1H NMR(300MHz,CD
3OD)δ7.67(d,J=5.0Hz,1H),7.46(d,J=3.6Hz,1H),7.21–7.03(m,5H),6.99(d,J=7.3Hz,1H),4.61(s,2H),4.07(m,1H),3.95(t,J=5.6Hz,2H),3.76(s,2H),3.53–3.40(m,2H),2.91(m,6H),2.79–2.59(m,2H).
1 H NMR (300MHz, CD 3 OD) δ7.67 (d, J = 5.0Hz, 1H), 7.46 (d, J = 3.6Hz, 1H), 7.21-7.03 (m, 5H), 6.99 (d, J = 7.3 Hz, 1H), 4.61 (s, 2H), 4.07 (m, 1H), 3.95 (t, J = 5.6 Hz, 2H), 3.76 (s, 2H), 3.53 - 3.40 (m, 2H), 2.91 (m, 6H), 2.79–2.59 (m, 2H).
实施例38Example 38
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(苯并[b]噻吩-3-羰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-38)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(benzo[b]thiophen-3-carbonyl)-4,5, 6,7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-38)
将环己基甲酸换成3-苯并噻吩甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 3-benzothiophenecarboxylic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to obtain a white powder.
1H NMR(300MHz,CD
3OD)δ8.01–7.91(m,1H),7.84(s,1H),7.74(s,1H),7.41(m,2H),7.01(m,5H),4.72(s,1H),4.34(s,1H),4.02(m,4H),3.69(s,1H),3.45(d,J=5.0Hz,2H),2.98(m,8H).
1 H NMR (300 MHz, CD 3 OD) δ 8.01 - 7.91 (m, 1H), 7.84 (s, 1H), 7.74 (s, 1H), 7.41 (m, 2H), 7.01 (m, 5H), 4.72 (s, 1H), 4.34 (s, 1H), 4.02 (m, 4H), 3.69 (s, 1H), 3.45 (d, J = 5.0 Hz, 2H), 2.98 (m, 8H).
实施例39Example 39
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-氟-苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-39)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-fluoro-benzoyl)-4,5,6,7 -tetrahydro[3,2-c]pyridine-2-carboxamide (I-39)
将环己基甲酸换成4-氟苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 4-fluorobenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to obtain a white powder.
1H NMR(300MHz,CD
3OD)δ7.59–7.46(m,2H),7.24(t,J=8.4Hz,3H),7.09(m,4H),4.64(s,1H),4.42(s,1H),4.12(s,1H),3.97(s,1H),3.92(s,2H),3.70(s,1H),3.47(s,2H),3.13–2.88(m,6H),2.83(s,2H).
1 H NMR (300MHz, CD 3 OD) δ7.59-7.46 (m, 2H), 7.24 (t, J = 8.4Hz, 3H), 7.09 (m, 4H), 4.64 (s, 1H), 4.42 (s , 1H), 4.12 (s, 1H), 3.97 (s, 1H), 3.92 (s, 2H), 3.70 (s, 1H), 3.47 (s, 2H), 3.13 - 2.88 (m, 6H), 2.83 ( s, 2H).
实施例40Example 40
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-硝基-苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-40)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-nitro-benzoyl)-4,5,6, 7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-40)
将环己基甲酸换成4-硝基苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 4-nitrobenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to give a white powder.
1H NMR(300MHz,CDCl
3)δ8.32(d,J=7.8Hz,2H),7.62(d,J=7.8Hz,2H),7.14(m,3H),7.02(m,2H),4.76(s,1H),4.39(s,1H),4.08(s,2H),3.93(d,J=14.4Hz,1H),3.75(m,3H),3.44(s,1H),2.97(m,4H),2.90(m,2H),2.70(m,2H).
1 H NMR (300MHz, CDCl 3 ) δ8.32 (d, J = 7.8Hz, 2H), 7.62 (d, J = 7.8Hz, 2H), 7.14 (m, 3H), 7.02 (m, 2H), 4.76 (s, 1H), 4.39 (s, 1H), 4.08 (s, 2H), 3.93 (d, J = 14.4 Hz, 1H), 3.75 (m, 3H), 3.44 (s, 1H), 2.97 (m, 4H), 2.90 (m, 2H), 2.70 (m, 2H).
实施例41Example 41
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-氰基-苯甲酰基)-4,5,6,7- 四氢[3,2-c]吡啶-2-甲酰胺(I-41)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-cyano-benzoyl)-4,5,6, 7-Tetrahydro[3,2-c]pyridine-2-carboxamide (I-41)
将环己基甲酸换成4-氰基苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 4-cyanobenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to obtain a white powder.
1H NMR(300MHz,CDCl
3)δ7.75(d,J=7.8Hz,2H),7.55(d,J=7.8Hz,2H),7.14(m,4H),7.03(m,1H),4.74(s,1H),4.38(s,1H),4.12(m,2H),3.98(d,J=14.6Hz,1H),3.82(d,J=14.6Hz,1H),3.68(m,2H),3.47–3.37(m,1H),3.08(m,1H),2.98(m,5H),2.75(m,2H).
1 H NMR (300MHz, CDCl 3 ) δ7.75 (d, J = 7.8Hz, 2H), 7.55 (d, J = 7.8Hz, 2H), 7.14 (m, 4H), 7.03 (m, 1H), 4.74 (s, 1H), 4.38 (s, 1H), 4.12 (m, 2H), 3.98 (d, J = 14.6 Hz, 1H), 3.82 (d, J = 14.6 Hz, 1H), 3.68 (m, 2H) , 3.47–3.37 (m, 1H), 3.08 (m, 1H), 2.98 (m, 5H), 2.75 (m, 2H).
实施例42Example 42
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-乙酰基苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-42)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-acetylbenzoyl)-4,5,6,7 -tetrahydro[3,2-c]pyridine-2-carboxamide (I-42)
将环己基甲酸换成4-乙酰基苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 4-acetylbenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to give a white powder.
1H NMR(300MHz,CD
3OD)δ8.11(d,J=8.0Hz,2H),7.58(m,2H),7.12(m,5H),4.68(s,1H),4.35(s,1H),4.12(m,1H),4.05(s,1H),3.90(d,J=16.8Hz,2H),3.66(s,1H),3.46(m,2H),3.02(m,6H),2.85(m,2H),2.64(s,3H).
1 H NMR (300MHz, CD 3 OD) δ8.11 (d, J = 8.0Hz, 2H), 7.58 (m, 2H), 7.12 (m, 5H), 4.68 (s, 1H), 4.35 (s, 1H ), 4.12 (m, 1H), 4.05 (s, 1H), 3.90 (d, J = 16.8 Hz, 2H), 3.66 (s, 1H), 3.46 (m, 2H), 3.02 (m, 6H), 2.85 (m, 2H), 2.64 (s, 3H).
实施例43Example 43
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-三氟甲基苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-43)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-trifluoromethylbenzoyl)-4,5,6 ,7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-43)
将环己基甲酸换成4-三氟甲基苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 4-trifluoromethylbenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to give a white powder.
1H NMR(300MHz,CD
3OD)δ7.81(s,2H),7.66(s,2H),7.33–6.83(m,5H),4.66(s,1H),4.30(s,1H),4.06(m,2H),3.81(s,2H),3.64(s,1H),3.47(s,2H),2.94(m,6H),2.73(m,2H).
1 H NMR (300MHz, CD 3 OD) δ7.81 (s, 2H), 7.66 (s, 2H), 7.33-6.83 (m, 5H), 4.66 (s, 1H), 4.30 (s, 1H), 4.06 (m, 2H), 3.81 (s, 2H), 3.64 (s, 1H), 3.47 (s, 2H), 2.94 (m, 6H), 2.73 (m, 2H).
实施例44Example 44
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(2-硝基苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-44)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(2-nitrobenzoyl)-4,5,6,7 -tetrahydro[3,2-c]pyridine-2-carboxamide (I-44)
将环己基甲酸换成2-硝基苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 2-nitrobenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to obtain a white powder.
1H NMR(400MHz,CD
3OD)δ8.29(dd,J=8.0,4.6Hz,1H),7.89(q,J=7.6Hz,1H),7.76(q,J=7.6Hz,1H),7.56(dd,J=12.5,7.6Hz,1H),7.39–6.93(m,5H),4.77(s,1H),4.70(s,1H),4.27–4.07(m,2H),3.94(m,2H),3.59(s,1H),3.48(dd,J=16.9,6.2Hz,2H),3.14–2.73(m,8H).
1 H NMR (400 MHz, CD 3 OD) δ 8.29 (dd, J = 8.0, 4.6 Hz, 1H), 7.89 (q, J = 7.6 Hz, 1H), 7.76 (q, J = 7.6 Hz, 1H), 7.56 (dd, J = 12.5, 7.6 Hz, 1H), 7.39 - 6.93 (m, 5H), 4.77 (s, 1H), 4.70 (s, 1H), 4.27 - 4.07 (m, 2H), 3.94 (m, 2H), 3.59 (s, 1H), 3.48 (dd, J = 16.9, 6.2 Hz, 2H), 3.14 - 2.73 (m, 8H).
实施例45Example 45
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(3-硝基苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-45)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(3-nitrobenzoyl)-4,5,6,7 -tetrahydro[3,2-c]pyridine-2-carboxamide (I-45)
将环己基甲酸换成3-硝基苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 3-nitrobenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to obtain a white powder.
1H NMR(300MHz,CD
3OD)δ8.37(d,J=8.2Hz,1H),8.32(s,1H),7.87(d,J=7.7Hz,1H),7.75(t,J=7.9Hz,1H),7.41–6.96(m,5H),4.70(s,1H),4.41(s,1H),4.14(s,1H),4.02(d,J=25.6Hz,3H),3.68(s,1H),3.46(s,2H),3.04(d,J=31.9Hz,8H).
1 H NMR (300MHz, CD 3 OD) δ8.37 (d, J = 8.2Hz, 1H), 8.32 (s, 1H), 7.87 (d, J = 7.7Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.41–6.96 (m, 5H), 4.70 (s, 1H), 4.41 (s, 1H), 4.14 (s, 1H), 4.02 (d, J = 25.6 Hz, 3H), 3.68 (s) , 1H), 3.46 (s, 2H), 3.04 (d, J = 31.9 Hz, 8H).
实施例46Example 46
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-苯乙酰基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-46)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-phenylacetyl-4,5,6,7-tetrahydro[3, 2-c]pyridine-2-carboxamide (I-46)
将环己基甲酸换成苯乙酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with phenylacetic acid, and the remaining materials, reagents and preparation methods were the same as those in Example 35 to obtain a white powder.
1H NMR(300MHz,CD
3OD)δ7.23(m,6H),7.14(m,3H),7.06(m,1H),4.50(d,J= 15.3Hz,2H),4.12(m,1H),3.88(m,5H),3.78(m,1H),3.45(d,J=5.5Hz,2H),3.04(m,2H),2.98(m,2H),2.84(m,3H),2.61(m,1H).
1 H NMR (300MHz, CD 3 OD) δ7.23 (m, 6H), 7.14 (m, 3H), 7.06 (m, 1H), 4.50 (d, J = 15.3Hz, 2H), 4.12 (m, 1H ), 3.88 (m, 5H), 3.78 (m, 1H), 3.45 (d, J = 5.5 Hz, 2H), 3.04 (m, 2H), 2.98 (m, 2H), 2.84 (m, 3H), 2.61 (m, 1H).
实施例47Example 47
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(苯氧基羰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-47)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(phenoxycarbonyl)-4,5,6,7-tetrahydro [3,2-c]pyridine-2-carboxamide (I-47)
将乙酰氯换成氯甲酸苯酯,其余所需原料、试剂及制备方法同实施例34中的步骤,得白色粉末。The acetyl chloride was replaced with phenyl chloroformate, and the remaining materials, reagents and preparation methods were the same as those in Example 34 to obtain a white powder.
1H NMR(300MHz,CD
3OD)δ7.38(t,J=7.6Hz,2H),7.23(m,2H),7.12(m,5H),7.03(d,J=7.7Hz,1H),4.58(s,1H),4.46(s,1H),4.20–4.02(m,1H),3.93(s,1H),3.86(s,2H),3.79(s,1H),3.46(d,J=5.5Hz,2H),3.05–2.70(m,8H).
1 H NMR (300MHz, CD 3 OD) δ7.38 (t, J = 7.6Hz, 2H), 7.23 (m, 2H), 7.12 (m, 5H), 7.03 (d, J = 7.7Hz, 1H), 4.58(s,1H), 4.46(s,1H), 4.20–4.02(m,1H),3.93(s,1H),3.86(s,2H),3.79(s,1H), 3.46(d,J= 5.5Hz, 2H), 3.05–2.70 (m, 8H).
实施例48Example 48
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-环丁氨基苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-48)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-cyclobutylaminobenzoyl)-4,5,6, 7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-48)
步骤1:制备4-(氮杂环丁烷基)苯甲酸乙酯Step 1: Preparation of ethyl 4-(azetidinyl)benzoate
将556毫克对氟苯甲酸乙酯,377毫克氮杂环丁烷,1.34克碳酸钾混合,加入8毫升二甲基亚砜,升温至150℃,两小时后停止反应,加入100毫升乙酸乙酯稀释反应液,饱和食盐水洗涤三次,有机相用无水硫酸钠干燥浓缩,柱层析,石油醚洗脱,得到630毫克4-(氮杂环丁烷基)苯甲酸乙酯,收率93%。556 mg of ethyl p-fluorobenzoate, 377 mg of azetidine, 1.34 g of potassium carbonate were mixed, 8 ml of dimethyl sulfoxide was added, and the temperature was raised to 150 ° C. After two hours, the reaction was stopped, and 100 ml of ethyl acetate was added. The reaction mixture was diluted with EtOAc (3 mL). %.
1H NMR(300MHz,CDCl
3)δ7.88(d,J=8.3Hz,2H),6.35(d,J=8.3Hz,2H),4.31(q,J=7.1Hz,2H),3.97(t,J=7.2Hz,4H),2.50–2.29(m,2H),1.35(t,J=7.1Hz,3H).
1 H NMR (300MHz, CDCl 3 ) δ7.88 (d, J = 8.3Hz, 2H), 6.35 (d, J = 8.3Hz, 2H), 4.31 (q, J = 7.1Hz, 2H), 3.97 (t , J = 7.2 Hz, 4H), 2.50 - 2.29 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H).
步骤2:制备4-(氮杂环丁烷基)苯甲酸Step 2: Preparation of 4-(azetidinyl)benzoic acid
将500毫克4-(氮杂环丁烷基)苯甲酸乙酯溶于10毫升乙醇中,加入0.73毫升5N氢氧化钠水溶液,升温至75℃,搅拌1小时后,停止反应,用6N盐酸水溶液酸化之后,过滤,滤饼用水洗涤数次之后,干燥,得黄色固体340毫克。500 mg of ethyl 4-(azetidinyl)benzoate was dissolved in 10 ml of ethanol, 0.73 ml of 5N aqueous sodium hydroxide solution was added, the temperature was raised to 75 ° C, and after stirring for 1 hour, the reaction was stopped, and 6 N hydrochloric acid aqueous solution was used. After acidification, filtration, the filter cake was washed several times with water and dried to give 340 mg of a yellow solid.
1H NMR(300MHz,DMSO)δ12.13(s,1H),7.73(d,J=8.6Hz,2H),6.38(d,J=8.6Hz,2H),3.90(t,J=7.3Hz,4H),2.34(p,J=7.3Hz,2H).
1 H NMR (300MHz, DMSO) δ12.13 (s, 1H), 7.73 (d, J = 8.6Hz, 2H), 6.38 (d, J = 8.6Hz, 2H), 3.90 (t, J = 7.3Hz, 4H), 2.34 (p, J = 7.3 Hz, 2H).
步骤3:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-环丁氨基苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-48)Step 3: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-cyclobutylaminobenzoyl)-4, 5,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-48)
将环己基甲酸换成4-(氮杂环丁烷基)苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 4-(azetidinyl)benzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to give a white powder.
1H NMR(300MHz,CD
3OD)δ7.34(d,J=8.4Hz,2H),7.08(d,J=19.0Hz,5H),6.48(d,J=8.3Hz,2H),4.53(s,2H),4.09(d,J=6.8Hz,1H),3.94(t,J=7.2Hz,4H),3.88(s,4H),3.45(s,2H),3.12–2.87(m,6H),2.80(t,J=5.9Hz,2H),2.48–2.31(m,2H).
1H NMR (300MHz, CD 3 OD) δ 7.34 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 19.0 Hz, 5H), 6.48 (d, J = 8.3 Hz, 2H), 4.53 (s) , 2H), 4.09 (d, J = 6.8 Hz, 1H), 3.94 (t, J = 7.2 Hz, 4H), 3.88 (s, 4H), 3.45 (s, 2H), 3.12 - 2.87 (m, 6H) , 2.80 (t, J = 5.9 Hz, 2H), 2.48 - 2.31 (m, 2H).
实施例49Example 49
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(呋喃2-羰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-49)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(furan-2-carbonyl)-4,5,6,7-tetrahydro [3,2-c]pyridine-2-carboxamide (I-49)
将环己基甲酸换成2-呋喃甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 2-furancarboxylic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to give a white powder.
1H NMR(300MHz,CD
3OD)δ7.73(s,1H),7.14(m,6H),6.62(s,1H),4.69(s,2H),4.14(m,1H),4.03(s,2H),3.94(s,2H),3.46(d,J=5.0Hz,2H),3.07(m,2H),2.99(m,4H),2.86(m,2H).
1 H NMR (300MHz, CD 3 OD) δ7.73 (s, 1H), 7.14 (m, 6H), 6.62 (s, 1H), 4.69 (s, 2H), 4.14 (m, 1H), 4.03 (s , 2H), 3.94 (s, 2H), 3.46 (d, J = 5.0 Hz, 2H), 3.07 (m, 2H), 2.99 (m, 4H), 2.86 (m, 2H).
实施例50Example 50
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-二甲氨基苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-50)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-dimethylaminobenzoyl)-4,5,6, 7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-50)
将环己基甲酸换成4-二甲氨基苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 4-dimethylaminobenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to obtain a white powder.
1H NMR(400MHz,CD
3OD)δ7.35(d,J=8.5Hz,2H),7.05(m,4H),6.97(d,J=7.0Hz,1H),6.75(d,J=8.5Hz,2H),4.48(s,2H),4.10–4.00(m,1H),3.81(s,2H),3.71(s,2H),3.52–3.36(m,2H),2.99(s,6H),2.85(m,6H),2.72–2.61(m,2H).
1 H NMR (400MHz, CD 3 OD) δ7.35 (d, J = 8.5Hz, 2H), 7.05 (m, 4H), 6.97 (d, J = 7.0Hz, 1H), 6.75 (d, J = 8.5 Hz, 2H), 4.48 (s, 2H), 4.10–4.00 (m, 1H), 3.81 (s, 2H), 3.71 (s, 2H), 3.52–3.36 (m, 2H), 2.99 (s, 6H) , 2.85 (m, 6H), 2.72 - 2.61 (m, 2H).
实施例51Example 51
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-甲磺酰基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-51)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methanesulfonyl-4,5,6,7-tetrahydro[3, 2-c]pyridine-2-carboxamide (I-51)
将50毫克N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺,溶于3毫升无水二氯甲烷中,冰浴下加入45微升三乙胺,18毫克甲磺酰氯,然后恢复室温搅拌12小时后,加入饱和碳酸氢钠溶液搅拌15分钟,二氯甲烷萃取,有机相用无水硫酸钠干燥,过滤浓缩,残余物柱层析(二氯甲烷/甲醇=95:5,V/V),得到30毫克白色粉末。50 mg of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrothieno[3,2 -c]pyridine-2-carboxamide, dissolved in 3 ml of anhydrous dichloromethane, and added 45 μl of triethylamine, 18 mg of methanesulfonyl chloride in an ice bath, and then stirred at room temperature for 12 hours, then added saturated hydrogen carbonate. The sodium solution was stirred for 15 minutes, extracted with methylene chloride. EtOAc (EtOAc m.
1H NMR(300MHz,CD3OD)δ7.19(s,1H),7.13(m,3H),7.03(d,J=7.3Hz,1H),4.19(s,2H),4.15–4.04(m,1H),3.83(s,2H),3.54(t,J=5.7Hz,2H),3.46(d,J=4.8Hz,2H),3.00–2.90(m,6H),2.89(s,3H),2.75(m,2H).
1 H NMR (300MHz, CD3OD) δ7.19 (s, 1H), 7.13 (m, 3H), 7.03 (d, J = 7.3Hz, 1H), 4.19 (s, 2H), 4.15-4.04 (m, 1H ), 3.83 (s, 2H), 3.54 (t, J = 5.7 Hz, 2H), 3.46 (d, J = 4.8 Hz, 2H), 3.00 - 2.90 (m, 6H), 2.89 (s, 3H), 2.75 (m, 2H).
实施例52Example 52
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-苯磺酰基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-52)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-benzenesulfonyl-4,5,6,7-tetrahydro[3, 2-c]pyridine-2-carboxamide (I-52)
将甲磺酰氯换成苯磺酰氯,其余所需原料、试剂及制备方法同实施例18中的步骤,得白色粉末。The methanesulfonyl chloride was replaced with benzenesulfonyl chloride, and the remaining starting materials, reagents and preparation methods were the same as those in Example 18 to give a white powder.
1H NMR(300MHz,CD
3OD)δ7.84(d,J=7.3Hz,2H),7.70–7.54(m,3H),7.12(d,J=12.3Hz,4H),7.04(d,J=7.4Hz,1H),4.11(s,1H),4.03(s,2H),3.87(s,2H),3.43(dd,J=13.9,6.2Hz,4H),2.98(s,4H),2.81(dd,J=14.0,7.5Hz,4H).
1 H NMR (300 MHz, CD 3 OD) δ 7.84 (d, J = 7.3 Hz, 2H), 7.70 - 7.54 (m, 3H), 7.12 (d, J = 12.3 Hz, 4H), 7.04 (d, J) = 7.4 Hz, 1H), 4.11 (s, 1H), 4.03 (s, 2H), 3.87 (s, 2H), 3.43 (dd, J = 13.9, 6.2 Hz, 4H), 2.98 (s, 4H), 2.81 (dd, J=14.0, 7.5Hz, 4H).
实施例53Example 53
5-(环己基氨基)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢苯并[b]噻吩-2-甲酰胺(I-53)5-(cyclohexylamino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrobenzene And [b]thiophene-2-carboxamide (I-53)
步骤1:步骤1:制备叔丁基(4-氯-3-甲酰基环己-3-烯-1-基)氨基甲酸Step 1: Step 1: Preparation of tert-butyl(4-chloro-3-formylcyclohex-3-en-1-yl)carbamic acid
将1-叔丁氧羰基哌啶酮换成4-N-Boc-氨基环己酮,其余所需原料、试剂及制备方法同实施例1中的步骤3,得无色油状物叔丁基(4-氯-3-甲酰基环己-3-烯-1-基)氨基甲酸,不纯化,直接投下一步。The 1-tert-butoxycarbonylpiperidone is replaced by 4-N-Boc-aminocyclohexanone, and the remaining starting materials, reagents and preparation methods are the same as in Step 3 of Example 1, to obtain a colorless oil tert-butyl ( 4-Chloro-3-formylcyclohex-3-en-1-yl)carbamic acid was used without further purification.
步骤2:制备5-((叔丁氧基羰基)氨基)-4,5,6,7-四氢苯并[b]噻吩-2羧酸乙酯Step 2: Preparation of ethyl 5-((tert-butoxycarbonyl)amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-2carboxylate
将叔丁基-4-氯-3-甲酰基-5,6-二氢吡啶-1(2氢)-羧酸叔丁酯换成叔丁基(4-氯-3-甲酰基环己-3-烯-1-基)氨基甲酸。,其余所需原料、试剂及制备方法同实施例1中的步骤4,得黄色油状物5-((叔丁氧基羰基)氨基)-4,5,6,7-四氢苯并[b]噻吩-2-羧酸乙酯。Replace tert-butyl-4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with tert-butyl (4-chloro-3-formylcyclohexane- 3-en-1-yl)carbamic acid. The remaining starting materials, reagents and preparation methods are the same as those in Step 4 of Example 1, to give a yellow oil 5-((tert-butoxycarbonyl)amino)-4,5,6,7-tetrahydrobenzo[b] ] Ethyl thiophene-2-carboxylate.
1H NMR(300MHz,CDCl
3)δ7.43(s,1H),4.59(s,1H),4.31(
q,J=6.9Hz,2H),3.99(m,1H),2.98(dd,J=16.0,5.0Hz,1H),2.88(t,J=6.3Hz,2H),2.47(dd,J=15.8,7.6Hz,1H),2.08(d,J=10.7Hz,1H),1.83(td,J=15.3,7.3Hz,1H),1.44(s,9H),1.34(t,J=7.1Hz,3H).
1 H NMR (300MHz, CDCl 3 ) δ7.43 (s, 1H), 4.59 (s, 1H), 4.31 (q, J = 6.9Hz, 2H), 3.99 (m, 1H), 2.98 (dd, J = 16.0, 5.0 Hz, 1H), 2.88 (t, J = 6.3 Hz, 2H), 2.47 (dd, J = 15.8, 7.6 Hz, 1H), 2.08 (d, J = 10.7 Hz, 1H), 1.83 (td, J = 15.3, 7.3 Hz, 1H), 1.44 (s, 9H), 1.34 (t, J = 7.1 Hz, 3H).
步骤3:制备5-氨基-4,5,6,7-四氢苯并[b]噻吩-2-羧酸乙酯Step 3: Preparation of ethyl 5-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate
将5-叔丁基2-乙基-6,7-二氢呋喃并[3,2-c]吡啶-2,5(4H)-二甲酸酯换成5-氨基-4,5,6,7-四氢苯并[b]噻吩-2-羧酸乙酯,其它原料、试剂及制备方法同实施例5中的步骤1,得5-氨基-4,5,6,7-四氢苯并[b]噻吩-2-羧酸乙酯。Replace 5-tert-butyl 2-ethyl-6,7-dihydrofuro[3,2-c]pyridine-2,5(4H)-dicarboxylate with 5-amino-4,5,6 , 7-tetrahydrobenzo[b]thiophene-2-carboxylic acid ethyl ester, other raw materials, reagents and preparation methods are the same as in step 1 of Example 5, to obtain 5-amino-4,5,6,7-tetrahydrogen Ethyl benzo[b]thiophene-2-carboxylate.
1H NMR(300MHz,CDCl
3)δ7.39(s,1H),4.26(
q,J=7.1Hz,2H),3.17(s,1H),2.97–2.68(m,3H),2.33(dd,J=15.4,8.5Hz,1H),1.98(d,J=11.9Hz,1H),1.82(s,3H),1.73–1.51(m,1H),1.36–1.23(m,3H).
1 H NMR (300MHz, CDCl 3 ) δ7.39 (s, 1H), 4.26 (q, J = 7.1Hz, 2H), 3.17 (s, 1H), 2.97-2.68 (m, 3H), 2.33 (dd, J = 15.4, 8.5 Hz, 1H), 1.98 (d, J = 11.9 Hz, 1H), 1.82 (s, 3H), 1.73 - 1.51 (m, 1H), 1.36 - 1.23 (m, 3H).
步骤4:制备5-(环己基氨基)-4,5,6,7-四氢苯并[b]噻吩-2-羧酸乙酯Step 4: Preparation of ethyl 5-(cyclohexylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate
将75毫克5-氨基-4,5,6,7-四氢苯并[b]噻吩-2-羧酸乙酯溶于5毫升二氯甲烷中,加入环己酮0.2毫升,醋酸1滴,室温搅拌30分钟后,加入350毫克三乙酰氧基硼氢化钠,室温搅拌12小时后,停止反应,加入饱和碳酸氢钠溶液,二氯甲烷萃取三次,有机相合并,用无水硫酸钠干燥,过滤,浓缩,柱层析,二氯甲烷:甲醇(V/V)=97:3,得到目标产物40毫克。75 mg of ethyl 5-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate was dissolved in 5 ml of dichloromethane, 0.2 ml of cyclohexanone and 1 drop of acetic acid were added. After stirring at room temperature for 30 minutes, 350 mg of sodium triacetoxyborohydride was added. After stirring at room temperature for 12 hours, the reaction was quenched, and the mixture was evaporated. Filtration, concentration, column chromatography, methylene chloride:methanol (V/V)=97:3
1H NMR(300MHz,CDCl
3)δ7.43(s,1H),4.30(q,J=7.1Hz,2H),3.15(s,1H),3.00–2.74(m,3H),2.67(t,J=10.3Hz,1H),2.43(dd,J=15.1,9.4Hz,1H),2.11(d,J=12.6Hz,1H),1.91(d,J=12.1Hz,2H),1.84–1.54(m,4H),1.34(t,J=7.1Hz,3H),1.29–1.03(m,6H).
1 H NMR (300MHz, CDCl 3 ) δ7.43 (s, 1H), 4.30 (q, J = 7.1Hz, 2H), 3.15 (s, 1H), 3.00-2.74 (m, 3H), 2.67 (t, J = 10.3 Hz, 1H), 2.43 (dd, J = 15.1, 9.4 Hz, 1H), 2.11 (d, J = 12.6 Hz, 1H), 1.91 (d, J = 12.1 Hz, 2H), 1.84 - 1.54 ( m, 4H), 1.34 (t, J = 7.1 Hz, 3H), 1.29 - 1.03 (m, 6H).
步骤5:制备5-(环己基氨基)-4,5,6,7-四氢苯并[b]噻吩-2-羧酸Step 5: Preparation of 5-(cyclohexylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid
将4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成5-(环己基氨基)-4,5,6,7-四氢苯并[b]噻吩-2-羧酸乙酯,其余所需原料、试剂及制备方法同实施例1中的步骤5,得4,5,6,7-四氢苯并[b]噻吩-2-羧酸。Replace 4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 5-(cyclohexylamino)-4,5,6,7-tetrahydrobenzene [b]ethyl thiophene-2-carboxylate, the remaining starting materials, reagents and preparation methods are the same as in step 5 of Example 1, to obtain 4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxylic acid.
步骤5:制备5-(环己基氨基)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)
Step 5: Preparation of 5-(cyclohexylamino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成5-(环己基氨基)-4,5,6,7-四氢苯并[b]噻吩-2-羧酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得产物。Replacing 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid with 5-(cyclohexylamino)-4,5, 6,7-Tetrahydrobenzo[b]thiophene-2-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as in Step 6 of Example 1, to obtain the product.
1H NMR(300MHz,CD
3OD)δ7.18(s,1H),7.11(s,3H),7.02(d,J=7.1Hz,1H),4.13–3.97(m,1H),3.73(s,2H),3.45(d,J=5.9Hz,2H),3.06–2.75(m,9H),2.75–2.55(m,2H),2.42(dd,J=15.3,10.1Hz,1H),2.21(d,J=9.7Hz,1H),2.05(d,J=10.5Hz,2H),1.84(d,J=13.4Hz,2H),1.73(dd,J=14.2,9.3Hz,2H),1.34(dt,J=25.2,13.6Hz,6H).
1 H NMR (300MHz, CD 3 OD) δ7.18 (s, 1H), 7.11 (s, 3H), 7.02 (d, J = 7.1Hz, 1H), 4.13-3.97 (m, 1H), 3.73 (s , 2H), 3.45 (d, J = 5.9 Hz, 2H), 3.06 - 2.75 (m, 9H), 2.75 - 2.55 (m, 2H), 2.42 (dd, J = 15.3, 10.1 Hz, 1H), 2.21 ( d, J = 9.7 Hz, 1H), 2.05 (d, J = 10.5 Hz, 2H), 1.84 (d, J = 13.4 Hz, 2H), 1.73 (dd, J = 14.2, 9.3 Hz, 2H), 1.34 ( Dt, J = 25.2, 13.6 Hz, 6H).
实施例54Example 54
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-3,5-二甲基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-54)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,5-dimethyl-4,5,6,7-tetrahydro[ 3,2-c]pyridine-2-carboxamide (I-54)
步骤1:制备4-氯-N-甲氧基-N-甲基烟酰胺Step 1: Preparation of 4-chloro-N-methoxy-N-methylnicotinamide
将3.15克4-氯烟酸,2.93克二甲羟胺盐酸盐,5.75克1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,4.05克1-羟基苯并***,5.3毫升N,N-二异丙基乙胺混合溶于50毫升N,N-二甲基甲酰胺中,室温搅拌5小时后,停止反应,将反应液倒入饱和碳酸氢钠溶液中,乙酸乙酯萃取三次,有机相合并,用饱和食盐水洗涤四次后,用无水硫酸钠干燥,过滤,浓缩,得1.72克4-氯-N-甲氧基-N-甲基烟酰胺,收率43%。3.15 g of 4-chloronicotinic acid, 2.93 g of dimethylhydroxylamine hydrochloride, 5.75 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4.05 g of 1-hydroxybenzene And triazole, 5.3 ml of N,N-diisopropylethylamine was dissolved in 50 ml of N,N-dimethylformamide, stirred at room temperature for 5 hours, the reaction was stopped, and the reaction solution was poured into saturated sodium hydrogencarbonate. The solution was extracted with EtOAc (EtOAc) EtOAc (EtOAc)EtOAc. Nicotinamide, yield 43%.
1H NMR(300MHz,CDCl
3)δ8.54(s,1H),8.52(d,J=5.4Hz,1H),7.36(d,J=5.4Hz,1H),3.46(s,3H),3.38(s,3H).
1 H NMR (300MHz, CDCl 3 ) δ8.54 (s, 1H), 8.52 (d, J = 5.4Hz, 1H), 7.36 (d, J = 5.4Hz, 1H), 3.46 (s, 3H), 3.38 (s, 3H).
步骤2:制备3-甲基噻吩并[3,2-c]吡啶-2-羧酸乙酯Step 2: Preparation of ethyl 3-methylthieno[3,2-c]pyridine-2-carboxylate
将1.3克4-氯-N-甲氧基-N-甲基烟酰胺溶于20毫升无水四氢呋喃中,氩气保护,冰浴下慢慢滴加3M甲基溴化镁的四氢呋喃溶液2.65毫升,滴加完毕之后,恢复至室温搅拌5小时,将反应液倒入饱和食盐水中,乙酸乙酯萃取两次,有机相合并,用无水硫酸钠干燥,过滤,浓缩,得到940毫克黄色液体,溶于15毫升乙腈中,加入0.66毫升2-巯基乙酸乙酯,2.1毫升三乙胺,回流12小时后,停止反应,反应液浓缩后,柱层析,石油醚:乙酸乙酯(V/V)=70:30,得到白色固体904毫克,收率62%。Dissolve 1.3 g of 4-chloro-N-methoxy-N-methylnicotinamide in 20 ml of anhydrous tetrahydrofuran, argon-protected, and slowly add 3 M methylmagnesium bromide in tetrahydrofuran solution 2.65 ml under ice bath. After the completion of the dropwise addition, the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into EtOAc EtOAc. Dissolved in 15 ml of acetonitrile, added 0.66 ml of ethyl 2-mercaptoacetate, 2.1 ml of triethylamine, refluxed for 12 hours, the reaction was stopped, the reaction mixture was concentrated, and then purified by column chromatography, petroleum ether: ethyl acetate (V/V = 70:30 gave 904 mg of a white solid, yield 62%.
1H NMR(300MHz,CDCl
3)δ9.14(s,1H),8.54(d,J=5.6Hz,1H),7.73(d,J=5.6Hz,1H),4.40(q,J=7.1Hz,2H),2.83(s,3H),1.41(t,J=7.1Hz,3H).
1 H NMR (300MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.54 (d, J = 5.6 Hz, 1H), 7.73 (d, J = 5.6 Hz, 1H), 4.40 (q, J = 7.1 Hz) , 2H), 2.83 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H).
步骤3:制备3,5-二甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯Step 3: Preparation of ethyl 3,5-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
将300毫克3-甲基噻吩并[3,2-c]吡啶-2-羧酸乙酯溶于8毫升乙腈中,加入0.25毫升碘甲烷,加热至60℃搅拌2小时,然后浓缩反应液,得到480毫克,再取400毫克溶于甲醇中,加入100毫克二氧化铂,氢气氛围下搅拌7小时,过滤不溶物,滤液浓缩,抽干,得380毫克3,5-二甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯,收率94%。300 mg of ethyl 3-methylthieno[3,2-c]pyridine-2-carboxylate was dissolved in 8 ml of acetonitrile, 0.25 ml of methyl iodide was added, and the mixture was heated to 60 ° C for 2 hours, and then the reaction mixture was concentrated. 480 mg was obtained, and 400 mg was dissolved in methanol, 100 mg of platinum dioxide was added, and the mixture was stirred under a hydrogen atmosphere for 7 hours. The insoluble material was filtered, and the filtrate was concentrated and dried to give 380 mg of 3,5-dimethyl-4. Ethyl 5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate, yield 94%.
1H NMR(300MHz,CDCl
3)δ4.30(q,J=7.1Hz,2H),4.08(s,2H),3.45(t,J=5.9Hz,2H),3.30(d,J=5.7Hz,2H),2.94(s,3H),2.39(s,3H),1.35(t,J=7.1Hz,3H).
1 H NMR (300MHz, CDCl 3 ) δ 4.30 (q, J = 7.1 Hz, 2H), 4.08 (s, 2H), 3.45 (t, J = 5.9 Hz, 2H), 3.30 (d, J = 5.7 Hz) , 2H), 2.94 (s, 3H), 2.39 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H).
步骤4:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-3,5-二甲基-4,5,6,7- 四氢[3,2-c]吡啶-2-甲酰胺(I-54)Step 4: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,5-dimethyl-4,5,6,7 - Tetrahydro[3,2-c]pyridine-2-carboxamide (I-54)
将100毫克3,5-二甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯溶于5毫升乙醇中,加入0.55毫升5摩尔每升的氢氧化钠水溶液,加热至70℃搅拌30分钟,冷却后,用盐酸酸化,再浓缩,抽干,加入40毫克毫克1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇,54毫克1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和38毫克1-羟基苯并***溶于15毫升N,N-二甲基甲酰胺中,氩气保护,室温搅拌4小时后,停止反应,将溶剂旋干之后,柱层析,得到10毫克N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-3,5-二甲基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺。100 mg of ethyl 3,5-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate was dissolved in 5 ml of ethanol, and 0.55 ml of 5 mol was added. Each liter of aqueous sodium hydroxide solution was heated to 70 ° C and stirred for 30 minutes. After cooling, it was acidified with hydrochloric acid, concentrated, and dried, and then added with 40 mg of 1-amino-3-(3,4-dihydroisoquinoline- 2(1H)-yl)propan-2-ol, 54 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 38 mg of 1-hydroxybenzotriazole In 15 ml of N,N-dimethylformamide, argon gas was added, and after stirring at room temperature for 4 hours, the reaction was stopped, and the solvent was spin-dried, followed by column chromatography to obtain 10 mg of N-(3-(3,4-di). Hydrogen isoquinoline-2(1H)-yl)-2-hydroxypropyl)-3,5-dimethyl-4,5,6,7-tetrahydro[3,2-c]pyridine-2-methyl Amide.
1H NMR(300MHz,CD
3OD)δ7.08(t,J=11.6Hz,4H),4.15–4.01(m,1H),3.80(s,2H),3.51–3.37(m,4H),2.92(s,4H),2.79(dd,J=19.6,14.9Hz,6H),2.50(s,3H),2.26(s,3H).
1 H NMR (300 MHz, CD 3 OD) δ 7.08 (t, J = 11.6 Hz, 4H), 4.15 - 4.01 (m, 1H), 3.80 (s, 2H), 3.51 - 3.37 (m, 4H), 2.92 (s, 4H), 2.79 (dd, J = 19.6, 14.9 Hz, 6H), 2.50 (s, 3H), 2.26 (s, 3H).
实施例55Example 55
(S)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-苯磺酰基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-55)(S)-N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-benzenesulfonyl-4,5,6,7-tetra Hydrogen [3,2-c]pyridine-2-carboxamide (I-55)
步骤1:制备(R)-2-(环氧乙烷-2-基甲基)-1,2,3,4-四氢异喹啉Step 1: Preparation of (R)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline
将3.0克四氢异喹啉溶于40毫升甲醇中,再加入9.3克碳酸钾,室温搅拌,30分钟后加入R-环氧氯丙烷,保持室温搅拌,15小时后停止搅拌,反应液过滤,乙酸乙酯洗滤饼,滤液浓缩蒸干,残余物柱层析(二氯甲烷:甲醇=100:0–98:2,V/V),得到黄色液体2.71g,产率64%。Dissolve 3.0 g of tetrahydroisoquinoline in 40 ml of methanol, add 9.3 g of potassium carbonate, stir at room temperature, add R-epichlorohydrin after 30 minutes, stir at room temperature, stop stirring after 15 hours, and filter the reaction solution. The cake was washed with ethyl acetate, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
1H NMR(300MHz,CDCl
3)δ7.12(m,3H),7.04(m,1H),3.81(d,J=14.9Hz,1H),3.69(d,J=14.9Hz,1H),3.21(td,J=6.8,3.5Hz,1H),3.01–2.87(m,4H),2.82(dd,J=8.7,4.6Hz,2H),2.56(dd,J=4.0,2.0Hz,1H),2.45(dd,J=13.3,6.7Hz,1H).
1 H NMR (300MHz, CDCl 3 ) δ7.12 (m, 3H), 7.04 (m, 1H), 3.81 (d, J = 14.9Hz, 1H), 3.69 (d, J = 14.9Hz, 1H), 3.21 (td, J = 6.8, 3.5 Hz, 1H), 3.01 - 2.87 (m, 4H), 2.82 (dd, J = 8.7, 4.6 Hz, 2H), 2.56 (dd, J = 4.0, 2.0 Hz, 1H), 2.45 (dd, J = 13.3, 6.7 Hz, 1H).
步骤2:制备(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇Step 2: Preparation of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol
将1克(R)-2-(环氧乙烷-2-基甲基)-1,2,3,4-四氢异喹啉溶于8毫升饱和氨的甲 醇溶液中,封管加热至80℃,3小时后停止反应,反应液浓缩,柱层析(二氯甲烷:甲醇(含5%氨水)=95:5–85:15,V/V)得到微黄油状物383毫克,产率35%。1 g of (R)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 8 ml of saturated ammonia in methanol and the tube was heated to After 80 ° C, the reaction was stopped after 3 hours, the reaction liquid was concentrated, and column chromatography (dichloromethane: methanol (containing 5% ammonia) = 95:5 - 85:15, V/V) gave 383 mg of micro-butter. The rate is 35%.
1H NMR(300MHz,CDCl
3)δ7.10(dd,J=6.0,2.8Hz,3H),7.00(d,J=6.0Hz,1H),3.93(s,1H),3.74(d,J=15.0Hz,1H),3.59(d,J=15.0Hz,1H),2.87(s,4H),2.71(dd,J=12.9,7.5Hz,2H),2.63–2.32(m,2H).
1 H NMR (300MHz, CDCl 3 ) δ7.10 (dd, J = 6.0,2.8Hz, 3H), 7.00 (d, J = 6.0Hz, 1H), 3.93 (s, 1H), 3.74 (d, J = 15.0 Hz, 1H), 3.59 (d, J = 15.0 Hz, 1H), 2.87 (s, 4H), 2.71 (dd, J = 12.9, 7.5 Hz, 2H), 2.63 - 2.32 (m, 2H).
步骤3:制备(S)-叔丁基2-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基甲酰基)-6,7-四氢[3,2-c]吡啶-5(4H)-羧酸叔丁酯Step 3: Preparation of (S)-tert-butyl 2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-6,7 - tetrahydro[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester
将1.2克5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸,873毫克(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇,1.22克1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和857毫克1-羟基苯并***溶于15毫升N,N-二甲基甲酰胺中,氩气保护,室温搅拌4小时后,停止反应,将溶剂旋干之后柱层析(二氯甲烷:甲醇=94:6,V/V)得黄色固体700毫克,产率35%。1.2 g of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid, 873 mg of (S)-1-amino-3 -(3,4-Dihydroisoquinolin-2(1H)-yl)propan-2-ol, 1.22 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride And 857 mg of 1-hydroxybenzotriazole dissolved in 15 ml of N,N-dimethylformamide, argon-protected, stirred at room temperature for 4 hours, the reaction was stopped, the solvent was spin-dried and column chromatography (dichloromethane : methanol = 94:6, V/V) yielded a yellow solid, 700 mg, yield 35%.
1H NMR(300MHz,CD
3OD)δ7.21(s,1H),7.14(m,3H),7.05(d,J=8.0Hz,1H),4.36(s,2H),4.18–4.04(m,1H),3.87(s,2H),3.69(m,2H),3.45(d,J=5.9Hz,2H),2.98(s,4H),2.80(dd,J=14.1,6.4Hz,4H),1.49(s,9H).
1 H NMR (300 MHz, CD 3 OD) δ 7.21 (s, 1H), 7.14 (m, 3H), 7.05 (d, J = 8.0 Hz, 1H), 4.36 (s, 2H), 4.18 - 4.04 (m) , 1H), 3.87 (s, 2H), 3.69 (m, 2H), 3.45 (d, J = 5.9 Hz, 2H), 2.98 (s, 4H), 2.80 (dd, J = 14.1, 6.4 Hz, 4H) , 1.49 (s, 9H).
步骤4:制备(S)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺Step 4: Preparation of (S)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrothiophene And [3,2-c]pyridine-2-carboxamide
步骤:将700毫克(S)-叔丁基2-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基甲酰基)-6,7-四氢[3,2-c]吡啶-5(4H)-羧酸叔丁酯溶于10毫升二氯甲烷中,加入2毫升三氟乙酸,氩气保护,室温搅拌2小时后停止反应,反应液用饱和碳酸氢钠溶液中和至中性,用二氯甲烷:甲醇=10:1萃取,有机相用无水硫酸钠干燥,浓缩,柱层析(二氯甲烷:甲醇(含5%氨水)=85:15,V/V)得黄色固体400毫克,产率73%。Step: 700 mg of (S)-tert-butyl 2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-6, 7-Tetrahydro[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester was dissolved in 10 ml of dichloromethane, added with 2 ml of trifluoroacetic acid, protected with argon, and stirred at room temperature for 2 hours. The reaction mixture was neutralized to neutral with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane:methanol = 10:1. % ammonia water = 85:15, V/V) yielded a yellow solid 400 mg, yield 73%.
1H NMR(300MHz,CD
3OD)δ7.16(s,1H),7.11(s,3H),7.03(s,1H),4.14–4.00(m,1H),3.72(s,4H),3.44(d,J=5.8Hz,2H),3.06(d,J=5.5Hz,2H),2.89(s,2H),2.82(d,J=5.6Hz,4H),2.72–2.58(m,2H).
1 H NMR (300MHz, CD 3 OD) δ7.16 (s, 1H), 7.11 (s, 3H), 7.03 (s, 1H), 4.14-4.00 (m, 1H), 3.72 (s, 4H), 3.44 (d, J = 5.8 Hz, 2H), 3.06 (d, J = 5.5 Hz, 2H), 2.89 (s, 2H), 2.82 (d, J = 5.6 Hz, 4H), 2.72 - 2.58 (m, 2H) .
步骤5:制备(S)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-苯磺酰基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺Step 5: Preparation of (S)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-benzenesulfonyl-4,5,6 ,7-tetrahydro[3,2-c]pyridine-2-carboxamide
将100毫克(S)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺溶于6毫升无水二氯甲烷中,加入42微升苯磺酰氯,90微升三乙胺,氩气保护,室温搅拌3小时后,停止反应,柱层析,得到42毫克。100 mg of (S)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrothiophene [3,2-c]pyridine-2-carboxamide was dissolved in 6 ml of anhydrous dichloromethane, and 42 μl of benzenesulfonyl chloride was added, 90 μl of triethylamine was argon-protected, and stirred at room temperature for 3 hours. The reaction was subjected to column chromatography to give 42 mg.
1H NMR(300MHz,CD
3OD)δ7.84(d,J=7.3Hz,2H),7.70–7.54(m,3H),7.12(d,J=12.3Hz,4H),7.04(d,J=7.4Hz,1H),4.11(s,1H),4.03(s,2H),3.87(s,2H),3.43(dd,J=13.9,6.2Hz,4H),2.98(s,4H),2.81(dd,J=14.0,7.5Hz,4H).
1 H NMR (300 MHz, CD 3 OD) δ 7.84 (d, J = 7.3 Hz, 2H), 7.70 - 7.54 (m, 3H), 7.12 (d, J = 12.3 Hz, 4H), 7.04 (d, J) = 7.4 Hz, 1H), 4.11 (s, 1H), 4.03 (s, 2H), 3.87 (s, 2H), 3.43 (dd, J = 13.9, 6.2 Hz, 4H), 2.98 (s, 4H), 2.81 (dd, J=14.0, 7.5Hz, 4H).
实施例56Example 56
(R)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-苯磺酰基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-56)(R)-N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-benzenesulfonyl-4,5,6,7-tetra Hydrogen [3,2-c]pyridine-2-carboxamide (I-56)
步骤1:制备(S)-2-(环氧乙烷-2-基甲基)-1,2,3,4-四氢异喹啉Step 1: Preparation of (S)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline
将3.0克四氢异喹啉溶于40毫升甲醇中,再加入9.3克碳酸钾,室温搅拌,30分钟后加入S-环氧氯丙烷,保持室温搅拌,15小时后停止搅拌,反应液过滤,乙酸乙酯洗滤饼,滤液浓缩蒸干,残余物柱层析(二氯甲烷:甲醇=100:0–98:2,V/V),得到黄色液体2.71g,产率64%。Dissolve 3.0 g of tetrahydroisoquinoline in 40 ml of methanol, add 9.3 g of potassium carbonate, stir at room temperature, add S-epichlorohydrin after 30 minutes, stir at room temperature, stop stirring after 15 hours, and filter the reaction solution. The cake was washed with ethyl acetate, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
1H NMR(300MHz,CDCl
3)δ7.12(m,3H),7.04(m,1H),3.81(d,J=14.9Hz,1H),3.69(d,J=14.9Hz,1H),3.21(td,J=6.8,3.5Hz,1H),3.01–2.87(m,4H),2.82(dd,J=8.7,4.6Hz,2H),2.56(dd,J=4.0,2.0Hz,1H),2.45(dd,J=13.3,6.7Hz,1H).
1 H NMR (300MHz, CDCl 3 ) δ7.12 (m, 3H), 7.04 (m, 1H), 3.81 (d, J = 14.9Hz, 1H), 3.69 (d, J = 14.9Hz, 1H), 3.21 (td, J = 6.8, 3.5 Hz, 1H), 3.01 - 2.87 (m, 4H), 2.82 (dd, J = 8.7, 4.6 Hz, 2H), 2.56 (dd, J = 4.0, 2.0 Hz, 1H), 2.45 (dd, J = 13.3, 6.7 Hz, 1H).
步骤2:制备(R)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇Step 2: Preparation of (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol
将1克(R)-2-(环氧乙烷-2-基甲基)-1,2,3,4-四氢异喹啉溶于8毫升饱和氨的甲醇溶液中,封管加热至80℃,3小时后停止反应,反应液浓缩,柱层析(二氯甲烷:甲醇(含5%氨水)=95:5–85:15,V/V)得到微黄油状物383毫克,产率35%。1 g of (R)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 8 ml of saturated ammonia in methanol and the tube was heated to After 80 ° C, the reaction was stopped after 3 hours, the reaction liquid was concentrated, and column chromatography (dichloromethane: methanol (containing 5% ammonia) = 95:5 - 85:15, V/V) gave 383 mg of micro-butter. The rate is 35%.
1H NMR(300MHz,CDCl
3)δ7.10(dd,J=6.0,2.8Hz,3H),7.00(d,J=6.0Hz,1H),3.93(s,1H),3.74(d,J=15.0Hz,1H),3.59(d,J=15.0Hz,1H),2.87(s,4H),2.71(dd,J= 12.9,7.5Hz,2H),2.63–2.32(m,2H).
1 H NMR (300MHz, CDCl 3 ) δ7.10 (dd, J = 6.0,2.8Hz, 3H), 7.00 (d, J = 6.0Hz, 1H), 3.93 (s, 1H), 3.74 (d, J = 15.0 Hz, 1H), 3.59 (d, J = 15.0 Hz, 1H), 2.87 (s, 4H), 2.71 (dd, J = 12.9, 7.5 Hz, 2H), 2.63 - 2.32 (m, 2H).
步骤3:制备(R)-叔丁基2-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基甲酰基)-6,7-四氢[3,2-c]吡啶-5(4H)-羧酸叔丁酯Step 3: Preparation of (R)-tert-butyl 2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-6,7 - tetrahydro[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester
将1.2克5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸,873毫克(R)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇,1.22克1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和857毫克1-羟基苯并***溶于15毫升N,N-二甲基甲酰胺中,氩气保护,室温搅拌4小时后,停止反应,将溶剂旋干之后柱层析(二氯甲烷:甲醇=94:6,V/V)得黄色固体700毫克,产率35%。1.2 g of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid, 873 mg of (R)-1-amino-3 -(3,4-Dihydroisoquinolin-2(1H)-yl)propan-2-ol, 1.22 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride And 857 mg of 1-hydroxybenzotriazole dissolved in 15 ml of N,N-dimethylformamide, argon-protected, stirred at room temperature for 4 hours, the reaction was stopped, the solvent was spin-dried and column chromatography (dichloromethane : methanol = 94:6, V/V) yielded a yellow solid, 700 mg, yield 35%.
1H NMR(300MHz,CD
3OD)δ7.21(s,1H),7.14(m,3H),7.05(d,J=8.0Hz,1H),4.36(s,2H),4.18–4.04(m,1H),3.87(s,2H),3.69(m,2H),3.45(d,J=5.9Hz,2H),2.98(s,4H),2.80(dd,J=14.1,6.4Hz,4H),1.49(s,9H).
1 H NMR (300 MHz, CD 3 OD) δ 7.21 (s, 1H), 7.14 (m, 3H), 7.05 (d, J = 8.0 Hz, 1H), 4.36 (s, 2H), 4.18 - 4.04 (m) , 1H), 3.87 (s, 2H), 3.69 (m, 2H), 3.45 (d, J = 5.9 Hz, 2H), 2.98 (s, 4H), 2.80 (dd, J = 14.1, 6.4 Hz, 4H) , 1.49 (s, 9H).
步骤4:制备(R)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺Step 4: Preparation of (R)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrothiophene And [3,2-c]pyridine-2-carboxamide
步骤:将700毫克(R)-叔丁基2-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基甲酰基)-6,7-四氢[3,2-c]吡啶-5(4H)-羧酸叔丁酯溶于10毫升二氯甲烷中,加入2毫升三氟乙酸,氩气保护,室温搅拌2小时后停止反应,反应液用饱和碳酸氢钠溶液中和至中性,用二氯甲烷:甲醇=10:1萃取,有机相用无水硫酸钠干燥,浓缩,柱层析(二氯甲烷:甲醇(含5%氨水)=85:15,V/V)得黄色固体400毫克,产率73%。Step: 700 mg of (R)-tert-butyl 2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-6, 7-Tetrahydro[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester was dissolved in 10 ml of dichloromethane, added with 2 ml of trifluoroacetic acid, protected with argon, and stirred at room temperature for 2 hours. The reaction mixture was neutralized to neutral with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane:methanol = 10:1. % ammonia water = 85:15, V/V) yielded a yellow solid 400 mg, yield 73%.
1H NMR(300MHz,CD
3OD)δ7.16(s,1H),7.11(s,3H),7.03(s,1H),4.14–4.00(m,1H),3.72(s,4H),3.44(d,J=5.8Hz,2H),3.06(d,J=5.5Hz,2H),2.89(s,2H),2.82(d,J=5.6Hz,4H),2.72–2.58(m,2H).
1 H NMR (300MHz, CD 3 OD) δ7.16 (s, 1H), 7.11 (s, 3H), 7.03 (s, 1H), 4.14-4.00 (m, 1H), 3.72 (s, 4H), 3.44 (d, J = 5.8 Hz, 2H), 3.06 (d, J = 5.5 Hz, 2H), 2.89 (s, 2H), 2.82 (d, J = 5.6 Hz, 4H), 2.72 - 2.58 (m, 2H) .
步骤5:制备(R)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-苯磺酰基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺Step 5: Preparation of (R)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-benzenesulfonyl-4,5,6 ,7-tetrahydro[3,2-c]pyridine-2-carboxamide
将100毫克(R)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四 氢噻吩并[3,2-c]吡啶-2-甲酰胺溶于6毫升无水二氯甲烷中,加入42微升苯磺酰氯,90微升三乙胺,氩气保护,室温搅拌3小时后,停止反应,柱层析,得到42毫克。100 mg of (R)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrothiophene [3,2-c]pyridine-2-carboxamide was dissolved in 6 ml of anhydrous dichloromethane, and 42 μl of benzenesulfonyl chloride was added, 90 μl of triethylamine was argon-protected, and stirred at room temperature for 3 hours. The reaction was subjected to column chromatography to give 42 mg.
1H NMR(300MHz,CD
3OD)δ7.84(d,J=7.3Hz,2H),7.70–7.54(m,3H),7.12(d,J=12.3Hz,4H),7.04(d,J=7.4Hz,1H),4.11(s,1H),4.03(s,2H),3.87(s,2H),3.43(dd,J=13.9,6.2Hz,4H),2.98(s,4H),2.81(dd,J=14.0,7.5Hz,4H).
1 H NMR (300 MHz, CD 3 OD) δ 7.84 (d, J = 7.3 Hz, 2H), 7.70 - 7.54 (m, 3H), 7.12 (d, J = 12.3 Hz, 4H), 7.04 (d, J) = 7.4 Hz, 1H), 4.11 (s, 1H), 4.03 (s, 2H), 3.87 (s, 2H), 3.43 (dd, J = 13.9, 6.2 Hz, 4H), 2.98 (s, 4H), 2.81 (dd, J=14.0, 7.5Hz, 4H).
实施例57Example 57
(S)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-乙酰基苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-57)(S)-N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-acetylbenzoyl)-4,5 ,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-57)
将环己基甲酸换成4-乙酰基苯甲酸,将N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺换成(S)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。Replacing cyclohexylformic acid with 4-acetylbenzoic acid, N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6 , 7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide is replaced by (S)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)- 2-hydroxypropyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, the remaining starting materials, reagents and preparation methods are the same as those in Example 35, A white powder was obtained.
1H NMR(300MHz,CD
3OD)δ8.11(d,J=8.0Hz,2H),7.58(m,2H),7.12(m,5H),4.68(s,1H),4.35(s,1H),4.12(m,1H),4.05(s,1H),3.90(d,J=16.8Hz,2H),3.66(s,1H),3.46(m,2H),3.02(m,6H),2.85(m,2H),2.64(s,3H).
1 H NMR (300MHz, CD 3 OD) δ8.11 (d, J = 8.0Hz, 2H), 7.58 (m, 2H), 7.12 (m, 5H), 4.68 (s, 1H), 4.35 (s, 1H ), 4.12 (m, 1H), 4.05 (s, 1H), 3.90 (d, J = 16.8 Hz, 2H), 3.66 (s, 1H), 3.46 (m, 2H), 3.02 (m, 6H), 2.85 (m, 2H), 2.64 (s, 3H).
实施例58Example 58
(R)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-乙酰基苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-58)(R)-N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-acetylbenzoyl)-4,5 ,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-58)
将环己基甲酸换成4-乙酰基苯甲酸,将N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺换成(R)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。Replacing cyclohexylformic acid with 4-acetylbenzoic acid, N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6 , 7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide is replaced by (R)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)- 2-hydroxypropyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, the remaining starting materials, reagents and preparation methods are the same as those in Example 35, A white powder was obtained.
1H NMR(300MHz,CD
3OD)δ8.11(d,J=8.0Hz,2H),7.58(m,2H),7.12(m,5H),4.68(s,1H),4.35(s,1H),4.12(m,1H),4.05(s,1H),3.90(d,J=16.8Hz,2H),3.66(s,1H),3.46(m,2H),3.02(m,6H),2.85(m,2H),2.64(s,3H).
1 H NMR (300MHz, CD 3 OD) δ8.11 (d, J = 8.0Hz, 2H), 7.58 (m, 2H), 7.12 (m, 5H), 4.68 (s, 1H), 4.35 (s, 1H ), 4.12 (m, 1H), 4.05 (s, 1H), 3.90 (d, J = 16.8 Hz, 2H), 3.66 (s, 1H), 3.46 (m, 2H), 3.02 (m, 6H), 2.85 (m, 2H), 2.64 (s, 3H).
实施例59Example 59
(S)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(苯乙酰基)-4,5,6,7- 四氢[3,2-c]吡啶-2-甲酰胺(I-59)(S)-N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(phenylacetyl)-4,5,6,7 - Tetrahydro[3,2-c]pyridine-2-carboxamide (I-59)
将环己基甲酸换成苯乙酸,将N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺换成(S)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。Replacing cyclohexylformic acid with phenylacetic acid, N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetra Conversion of Hydrothieno[3,2-c]pyridine-2-carboxamide to (S)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropane Base 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to give a white powder.
1H NMR(300MHz,CD
3OD)δ7.23(m,6H),7.14(m,3H),7.06(m,1H),4.50(d,J=15.3Hz,2H),4.12(m,1H),3.88(m,5H),3.78(m,1H),3.45(d,J=5.5Hz,2H),3.04(m,2H),2.98(m,2H),2.84(m,3H),2.61(m,1H).
1 H NMR (300MHz, CD 3 OD) δ7.23 (m, 6H), 7.14 (m, 3H), 7.06 (m, 1H), 4.50 (d, J = 15.3Hz, 2H), 4.12 (m, 1H ), 3.88 (m, 5H), 3.78 (m, 1H), 3.45 (d, J = 5.5 Hz, 2H), 3.04 (m, 2H), 2.98 (m, 2H), 2.84 (m, 3H), 2.61 (m, 1H).
实施例60Example 60
(R)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(苯乙酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-60)(R)-N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(phenylacetyl)-4,5,6,7 -tetrahydro[3,2-c]pyridine-2-carboxamide (I-60)
将环己基甲酸换成苯乙酸,将N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺换成(R)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。Replacing cyclohexylformic acid with phenylacetic acid, N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetra Conversion of hydrothieno[3,2-c]pyridine-2-carboxamide to (R)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropane Base 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to give a white powder.
1H NMR(300MHz,CD
3OD)δ7.23(m,6H),7.14(m,3H),7.06(m,1H),4.50(d,J=15.3Hz,2H),4.12(m,1H),3.88(m,5H),3.78(m,1H),3.45(d,J=5.5Hz,2H),3.04(m,2H),2.98(m,2H),2.84(m,3H),2.61(m,1H).
1 H NMR (300MHz, CD 3 OD) δ7.23 (m, 6H), 7.14 (m, 3H), 7.06 (m, 1H), 4.50 (d, J = 15.3Hz, 2H), 4.12 (m, 1H ), 3.88 (m, 5H), 3.78 (m, 1H), 3.45 (d, J = 5.5 Hz, 2H), 3.04 (m, 2H), 2.98 (m, 2H), 2.84 (m, 3H), 2.61 (m, 1H).
实施例61Example 61
(S)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-氟苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-61)(S)-N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-fluorobenzoyl)-4,5, 6,7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-61)
将环己基甲酸换成对氟苯乙酸,将N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺换成(S)-N-(3-(3,4-二氢异喹啉-2(1H) -基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。Replacing cyclohexylformic acid with p-fluorophenylacetic acid, N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7 -Tetrahydrothieno[3,2-c]pyridine-2-carboxamide is replaced by (S)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2- Hydroxypropyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, the remaining starting materials, reagents and preparation methods are the same as those in Example 35, giving white powder.
1H NMR(300MHz,CD
3OD)δ7.59–7.46(m,2H),7.24(t,J=8.4Hz,3H),7.09(m,4H),4.64(s,1H),4.42(s,1H),4.12(s,1H),3.97(s,1H),3.92(s,2H),3.70(s,1H),3.47(s,2H),3.13–2.88(m,6H),2.83(s,2H).
1 H NMR (300MHz, CD 3 OD) δ7.59-7.46 (m, 2H), 7.24 (t, J = 8.4Hz, 3H), 7.09 (m, 4H), 4.64 (s, 1H), 4.42 (s , 1H), 4.12 (s, 1H), 3.97 (s, 1H), 3.92 (s, 2H), 3.70 (s, 1H), 3.47 (s, 2H), 3.13 - 2.88 (m, 6H), 2.83 ( s, 2H).
实施例62Example 62
(S)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-二甲氨基苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-62)(S)-N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-dimethylaminobenzoyl)-4, 5,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-62)
将环己基甲酸换成4-二甲氨基苯甲酸,将N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺换成(S)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺,其余所需原料、试剂及制备方法同实施例35中的步骤,得(S)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-二甲氨基苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺。Replacing cyclohexylformic acid with 4-dimethylaminobenzoic acid, N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5, Conversion of 6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide to (S)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl) 2-hydroxypropyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, the remaining starting materials, reagents and preparation methods are the same as those in Example 35 (S)-N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-dimethylaminobenzoyl)- 4,5,6,7-Tetrahydro[3,2-c]pyridine-2-carboxamide.
1H NMR(400MHz,CD
3OD)δ7.35(d,J=8.5Hz,2H),7.05(m,4H),6.97(d,J=7.0Hz,1H),6.75(d,J=8.5Hz,2H),4.48(s,2H),4.10–4.00(m,1H),3.81(s,2H),3.71(s,2H),3.52–3.36(m,2H),2.99(s,6H),2.85(m,6H),2.72–2.61(m,2H).
1 H NMR (400MHz, CD 3 OD) δ7.35 (d, J = 8.5Hz, 2H), 7.05 (m, 4H), 6.97 (d, J = 7.0Hz, 1H), 6.75 (d, J = 8.5 Hz, 2H), 4.48 (s, 2H), 4.10–4.00 (m, 1H), 3.81 (s, 2H), 3.71 (s, 2H), 3.52–3.36 (m, 2H), 2.99 (s, 6H) , 2.85 (m, 6H), 2.72 - 2.61 (m, 2H).
实施例63Example 63
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-甲基苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-63)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-methylbenzoyl)-4,5,6,7 -tetrahydro[3,2-c]pyridine-2-carboxamide (I-63)
将环己基甲酸换成4-甲基苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 4-methylbenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to give a white powder.
1H NMR(300MHz,CD3OD)δ7.45–7.22(m,5H),7.01(m,4H),4.62(s,1H),4.36(s,1H),4.10(m,2H),3.78(s,2H),3.70(s,1H),3.47(d,J=5.9Hz,2H),2.92(m,6H),2.72(s,2H),2.41(s,3H).1H NMR (300MHz, CD3OD) δ 7.45 - 7.22 (m, 5H), 7.01 (m, 4H), 4.62 (s, 1H), 4.36 (s, 1H), 4.10 (m, 2H), 3.78 (s, 2H), 3.70 (s, 1H), 3.47 (d, J = 5.9 Hz, 2H), 2.92 (m, 6H), 2.72 (s, 2H), 2.41 (s, 3H).
实施例64Example 64
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-溴苯甲酰基)-4,5,6,7- 四氢[3,2-c]吡啶-2-甲酰胺(I-64)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-bromobenzoyl)-4,5,6,7- Tetrahydro[3,2-c]pyridine-2-carboxamide (I-64)
将环己基甲酸换成4-溴苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 4-bromobenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to give a white powder.
1H NMR(300MHz,CD
3OD)δ7.67(d,J=8.2Hz,2H),7.38(d,J=7.8Hz,2H),7.30–6.85(m,5H),4.62(s,1H),4.32(s,1H),4.07(m,2H),3.80(s,2H),3.67(s,1H),3.46(d,J=5.7Hz,2H),2.92(m,6H),2.73(m,2H).
1 H NMR (300MHz, CD 3 OD) δ7.67 (d, J = 8.2Hz, 2H), 7.38 (d, J = 7.8Hz, 2H), 7.30-6.85 (m, 5H), 4.62 (s, 1H ), 4.32 (s, 1H), 4.07 (m, 2H), 3.80 (s, 2H), 3.67 (s, 1H), 3.46 (d, J = 5.7 Hz, 2H), 2.92 (m, 6H), 2.73 (m, 2H).
实施例65Example 65
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-氯苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-65)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-chlorobenzoyl)-4,5,6,7- Tetrahydro[3,2-c]pyridine-2-carboxamide (I-65)
将环己基甲酸换成4-氯苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 4-chlorobenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to give a white powder.
1H NMR(300MHz,CD
3OD)δ7.53(d,J=8.5Hz,2H),7.46(d,J=8.5Hz,2H),7.35–6.78(m,5H),4.62(s,1H),4.34(s,1H),4.07(m,2H),3.77(s,2H),3.67(s,1H),3.47(d,J=5.7Hz,2H),2.91(m,6H),2.71(m,2H).
1 H NMR (300 MHz, CD 3 OD) δ 7.53 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.35 - 6.78 (m, 5H), 4.62 (s, 1H) ), 4.34 (s, 1H), 4.07 (m, 2H), 3.77 (s, 2H), 3.67 (s, 1H), 3.47 (d, J = 5.7 Hz, 2H), 2.91 (m, 6H), 2.71 (m, 2H).
实施例66Example 66
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-甲氧基苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-66)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-methoxybenzoyl)-4,5,6, 7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-66)
将环己基甲酸换成4-甲氧基苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 4-methoxybenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to give a white powder.
1H NMR(300MHz,CD
3OD)δ7.43(d,J=8.8Hz,2H),7.04(m,6H),4.52(s,2H),4.07(m,1H),3.82(m,7H),3.54–3.36(m,2H),2.92(m,6H),2.80–2.62(m,2H).
1 H NMR (300MHz, CD 3 OD) δ7.43 (d, J = 8.8Hz, 2H), 7.04 (m, 6H), 4.52 (s, 2H), 4.07 (m, 1H), 3.82 (m, 7H ), 3.54–3.36 (m, 2H), 2.92 (m, 6H), 2.80–2.62 (m, 2H).
实施例67Example 67
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(3-氟苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-67)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(3-fluorobenzoyl)-4,5,6,7- Tetrahydro[3,2-c]pyridine-2-carboxamide (I-67)
将环己基甲酸换成3-氟苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 3-fluorobenzoic acid, and the remaining materials, reagents and preparation methods were the same as those in Example 35 to obtain a white powder.
1H NMR(300MHz,CD
3OD)δ7.51(dd,J=13.6,7.8Hz,1H),7.34–7.17(m,4H),6.99(m,4H),4.60(s,1H),4.30(s,1H),4.02(m,2H),3.72(s,2H),3.63(s,1H),3.46(d,J=5.7Hz,2H),2.85(m,6H),2.67(m,2H).
1 H NMR (300 MHz, CD 3 OD) δ 7.51 (dd, J = 13.6, 7.8 Hz, 1H), 7.34 - 7.17 (m, 4H), 6.99 (m, 4H), 4.60 (s, 1H), 4.30 (s, 1H), 4.02 (m, 2H), 3.72 (s, 2H), 3.63 (s, 1H), 3.46 (d, J = 5.7 Hz, 2H), 2.85 (m, 6H), 2.67 (m, 2H).
实施例68Example 68
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(2-氟苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-68)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(2-fluorobenzoyl)-4,5,6,7- Tetrahydro[3,2-c]pyridine-2-carboxamide (I-68)
将环己基甲酸换成2-氟苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 2-fluorobenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to obtain a white powder.
1H NMR(300MHz,CD
3OD)δ7.60–7.47(m,1H),7.41(m,1H),7.34–7.19(m,3H),7.19–7.06(m,2H),7.05–6.85(m,2H),4.65(s,1H),4.22(s,1H),4.07(m,2H),3.76(m,2H),3.59(t,J=5.4Hz,1H),3.53–3.37(m,2H),2.99–2.79(m,6H),2.77–2.62(m,2H).
1 H NMR (300 MHz, CD 3 OD) δ 7.60 - 7.47 (m, 1H), 7.41 (m, 1H), 7.34 - 7.19 (m, 3H), 7.19 - 7.06 (m, 2H), 7.05 - 6.85 ( m, 2H), 4.65 (s, 1H), 4.22 (s, 1H), 4.07 (m, 2H), 3.76 (m, 2H), 3.59 (t, J = 5.4 Hz, 1H), 3.53 - 3.37 (m , 2H), 2.99–2.79 (m, 6H), 2.77–2.62 (m, 2H).
实施例69Example 69
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(3,4-二氟苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-69)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(3,4-difluorobenzoyl)-4,5,6 ,7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-69)
将环己基甲酸换成3,4-二氟苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 3,4-difluorobenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to obtain a white powder.
1H NMR(300MHz,CD
3OD)δ7.51–7.35(m,2H),7.34–6.93(m,6H),4.63(s,1H),4.40(s,1H),4.10(m,1H),3.99(s,1H),3.88(m,2H),3.68(s,1H),3.45(d,J=5.1Hz,2H),2.98(m,6H),2.80(m,2H).
1 H NMR (300 MHz, CD 3 OD) δ 7.51 - 7.35 (m, 2H), 7.34 - 6.93 (m, 6H), 4.63 (s, 1H), 4.40 (s, 1H), 4.10 (m, 1H) , 3.99 (s, 1H), 3.88 (m, 2H), 3.68 (s, 1H), 3.45 (d, J = 5.1 Hz, 2H), 2.98 (m, 6H), 2.80 (m, 2H).
实施例70Example 70
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-叔丁基苯甲酰基)-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-70)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-tert-butylbenzoyl)-4,5,6, 7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-70)
将环己基甲酸换成4-叔丁基苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 4-tert-butylbenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to give a white powder.
1H NMR(300MHz,CD
3OD)δ7.55(d,J=7.8Hz,2H),7.40(d,J=7.8Hz,2H),7.35–6.80(m,5H),4.64(s,1H),4.37(s,1H),4.11(s,1H),4.04–3.95(m,1H),3.88(s,2H),3.70(s,1H),3.47(d,J=5.7Hz,2H),2.93(m,6H),2.80(m,2H),1.36(s,9H).
1 H NMR (300 MHz, CD 3 OD) δ 7.55 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.35 - 6.80 (m, 5H), 4.64 (s, 1H) ), 4.37 (s, 1H), 4.11 (s, 1H), 4.04 - 3.95 (m, 1H), 3.88 (s, 2H), 3.70 (s, 1H), 3.47 (d, J = 5.7 Hz, 2H) , 2.93 (m, 6H), 2.80 (m, 2H), 1.36 (s, 9H).
实施例71Example 71
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-氯苯甲酰基)-3-甲基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-71)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-chlorobenzoyl)-3-methyl-4,5 ,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-71)
步骤1:制备5-苄基-3-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯Step 1: Preparation of ethyl 5-benzyl-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
将1.16克3-甲基噻吩并[3,2-c]吡啶-2-羧酸乙酯溶于15毫升乙腈中,滴加溴苄0.74毫升,室温搅拌5小时后,停止反应,过滤反应液,滤饼用乙腈洗两次,收集滤饼,再将其溶解于20毫升乙醇中,加入二氧化铂300毫克,氢气氛围下,搅拌8小时,过滤反应液,滤液浓缩之后柱层析(二氯甲烷:甲醇=95:5,V/V)得5-苄基-3-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯1.5克,84%。1.16 g of ethyl 3-methylthieno[3,2-c]pyridine-2-carboxylate was dissolved in 15 ml of acetonitrile, and 0.74 ml of benzyl bromide was added dropwise. After stirring at room temperature for 5 hours, the reaction was stopped and the reaction mixture was filtered. The filter cake was washed twice with acetonitrile, the filter cake was collected, dissolved in 20 ml of ethanol, 300 mg of platinum dioxide was added, and the mixture was stirred for 8 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated and then subjected to column chromatography. Methyl chloride:methanol = 95:5, V/V) 5-benzyl-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid The ester was 1.5 g, 84%.
1H NMR(300MHz,CD
3OD)δ7.34(m,5H),4.26(q,J=7.1Hz,2H),3.75(s,2H),3.45(s,2H),2.91–2.83(m,2H),2.79(t,J=5.2Hz,2H),2.31(s,3H),1.32(t,J=7.1Hz,3H).
1 H NMR (300 MHz, CD 3 OD) δ 7.34 (m, 5H), 4.26 (q, J = 7.1 Hz, 2H), 3.75 (s, 2H), 3.45 (s, 2H), 2.91 - 2.83 (m) , 2H), 2.79 (t, J = 5.2 Hz, 2H), 2.31 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H).
步骤2:制备3-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯Step 2: Preparation of ethyl 3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
将330毫克将660毫克5-苄基-7,7-二甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯溶于10毫升二氯甲烷中,加入290毫克碳酸钾,293微升氯甲酸1-氯乙酯,氩气保护,室温搅拌6小时后,加入二氯甲烷稀释反应液,饱和食盐水洗一次,有机相干燥,过滤,浓缩,再将其溶解到10毫升乙醇中,加热回流2小时后停止反应,浓缩反应液,柱层析得到310毫克产物,收率65%。330 mg of 660 mg of ethyl 5-benzyl-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate in 10 ml Dichloromethane, 290 mg of potassium carbonate, 293 μl of 1-chloroethyl chloroformate, argon-protected, stirred at room temperature for 6 hours, diluted with dichloromethane, washed once with saturated brine, dried and filtered After concentrating, it was dissolved in 10 ml of ethanol, and the reaction was stopped after heating under reflux for 2 hours. The reaction mixture was concentrated and purified by column chromatography to yield product (yield: 65%).
1H NMR(300MHz,CD
3OD)δ4.31(q,J=7.1Hz,2H),4.22(s,2H),3.55(t,J=6.2Hz,2H),3.16(t,J=6.1Hz,2H),2.43(s,3H),1.34(t,J=7.1Hz,3H).
1 H NMR (300 MHz, CD 3 OD) δ 4.31 (q, J = 7.1 Hz, 2H), 4.22 (s, 2H), 3.55 (t, J = 6.2 Hz, 2H), 3.16 (t, J = 6.1 Hz, 2H), 2.43 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).
步骤2:制备5-(4-(二甲基氨基)苯甲酰基)-3-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酸乙酯Step 2: Preparation of 5-(4-(dimethylamino)benzoyl)-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid ester
将环己基甲酸换成4-二甲氨基苯甲酸,将N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺换成3-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯,其余所需原料、试剂及制备方法同实施例35中的步骤,得5-(4-(二甲基氨基)苯甲酰基)-3-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酸乙酯。Replacing cyclohexylformic acid with 4-dimethylaminobenzoic acid, N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5, 6,7-Tetrahydrothieno[3,2-c]pyridine-2-carboxamide was replaced by 3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2 - ethyl carboxylate, the remaining starting materials, reagents and preparation methods are the same as those in Example 35 to give 5-(4-(dimethylamino)benzoyl)-3-methyl-4,5,6 , 7-Tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid ethyl ester.
1H NMR(300MHz,CD
3OD)δ7.39(d,J=8.9Hz,2H),6.78(d,J=8.9Hz,2H),4.59(s,2H),4.28(q,J=7.1Hz,2H),3.88(s,2H),3.02(s,6H),2.95(t,J=5.5Hz,2H),2.37(s,3H), 1.34(t,J=7.1Hz,3H).
1 H NMR (300 MHz, CD 3 OD) δ 7.39 (d, J = 8.9 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H), 4.59 (s, 2H), 4.28 (q, J = 7.1) Hz, 2H), 3.88 (s, 2H), 3.02 (s, 6H), 2.95 (t, J = 5.5 Hz, 2H), 2.37 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).
步骤3:制备5-(4-(二甲基氨基)苯甲酰基)-3-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酸Step 3: Preparation of 5-(4-(dimethylamino)benzoyl)-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid
将4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成5-(4-(二甲基氨基)苯甲酰基)-3-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酸乙酯,其余所需原料、试剂及制备方法同实施例1中的步骤5,得5-(4-(二甲基氨基)苯甲酰基)-3-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酸。Replace 4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 5-(4-(dimethylamino)benzoyl)-3-methyl -4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid ethyl ester, the remaining required starting materials, reagents and preparation methods are the same as in step 5 of Example 1, to obtain 5- ( 4-(Dimethylamino)benzoyl)-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid.
1H NMR(300MHz,DMSO)δ12.82(s,1H),7.35(d,J=8.8Hz,2H),6.73(d,J=8.8Hz,2H),4.49(s,2H),3.74(m,2H),2.96(s,6H),2.89(m,2H),2.32(s,3H).
1 H NMR (300MHz, DMSO) δ12.82 (s, 1H), 7.35 (d, J = 8.8Hz, 2H), 6.73 (d, J = 8.8Hz, 2H), 4.49 (s, 2H), 3.74 ( m, 2H), 2.96 (s, 6H), 2.89 (m, 2H), 2.32 (s, 3H).
步骤4:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-氯苯甲酰基)-3-甲基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺Step 4: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-chlorobenzoyl)-3-methyl -4,5,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成5-(4-(二甲基氨基)苯甲酰基)-3-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得白色固体。Replacing 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid with 5-(4-(dimethylamino)benzene Formyl)-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as those in Example 1. 6, a white solid.
1H NMR(300MHz,CD
3OD)δ7.39(d,J=8.8Hz,2H),7.05(m,4H),6.79(d,J=8.8Hz,2H),4.53(s,2H),4.12–4.00(m,1H),3.86(s,2H),3.73(s,2H),3.46(t,J=5.6Hz,2H),3.02(s,6H),2.87(m,6H),2.68(dd,J=6.1,3.0Hz,2H),2.23(s,3H).
1 H NMR (300MHz, CD 3 OD) δ7.39 (d, J = 8.8Hz, 2H), 7.05 (m, 4H), 6.79 (d, J = 8.8Hz, 2H), 4.53 (s, 2H), 4.12–4.00 (m, 1H), 3.86 (s, 2H), 3.73 (s, 2H), 3.46 (t, J = 5.6 Hz, 2H), 3.02 (s, 6H), 2.87 (m, 6H), 2.68 (dd, J = 6.1, 3.0 Hz, 2H), 2.23 (s, 3H).
实施例72Example 72
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-氨基甲酰基苯甲酰基)-3-甲基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-72)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-carbamoylbenzoyl)-3-methyl-4 ,5,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-72)
将环己基甲酸换成4-氨基甲酰基苯甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 4-carbamoylbenzoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to give a white powder.
1H NMR(300MHz,CD
3OD)δ7.99(d,J=8.0Hz,2H),7.54(d,J=6.8Hz,2H),7.10(m 5H),4.64(s,1H),4.33(s,1H),4.19–3.96(m,2H),3.84(m,2H),3.61(m,1H),3.47(d,J=5.0Hz,2H),2.85(m,8H).
1 H NMR (300 MHz, CD 3 OD) δ 7.99 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 6.8 Hz, 2H), 7.10 (m 5H), 4.64 (s, 1H), 4.33 (s, 1H), 4.19–3.96 (m, 2H), 3.84 (m, 2H), 3.61 (m, 1H), 3.47 (d, J = 5.0 Hz, 2H), 2.85 (m, 8H).
实施例73Example 73
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-氟苯乙酰基)-3-甲基-4,5,6,7-四氢[3,2-c]吡啶-2-甲酰胺(I-73)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-fluorophenylacetyl)-3-methyl-4,5 ,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-73)
将环己基甲酸换成4-氟苯乙酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 4-fluorophenylacetic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to obtain a white powder.
1H NMR(300MHz,CD
3OD)δ7.33–7.18(m,3H),7.17–6.95(m,6H),4.50(d,J=7.6Hz,2H),4.14–4.03(m,1H),3.92–3.76(m,6H),3.45(d,J=6.0Hz,2H),2.93(s,4H),2.80(m,1H),2.76–2.65(m,3H).
1 H NMR (300 MHz, CD 3 OD) δ 7.33 - 7.18 (m, 3H), 7.17 - 6.95 (m, 6H), 4.50 (d, J = 7.6 Hz, 2H), 4.14 - 4.03 (m, 1H) , 3.92–3.76 (m, 6H), 3.45 (d, J=6.0 Hz, 2H), 2.93 (s, 4H), 2.80 (m, 1H), 2.76–2.65 (m, 3H).
实施例74Example 74
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-2-(4-(二甲基氨基)苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酰胺(I-74)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-(dimethylamino)benzoyl)-1,2 ,3,4-tetrahydroisoquinoline-6-carboxamide (I-74)
步骤1:制备6-氰基异喹啉Step 1: Preparation of 6-cyanoisoquinoline
将5.0克6-溴异喹啉溶于80毫升N,N-二甲基甲酰胺中,加入1.69克氰化锌,氩气保护,最后加入1.39克四三苯基膦钯。反应液升温至90℃搅拌,15小时后,停止反应,乙酸乙酯萃取三次,有机相合并再用饱和食盐水洗四次,有机相用无水硫酸钠干燥之后,过滤,浓缩,柱层析(石油醚:乙酸乙酯)=70:30,V/V)得白色固体2.79克,产率84%。5.0 g of 6-bromoisoquinoline was dissolved in 80 ml of N,N-dimethylformamide, 1.69 g of zinc cyanide was added, protected with argon, and finally 1.39 g of tetrakistriphenylphosphine palladium was added. The reaction mixture was heated to 90 ° C and stirred. After 15 hours, the reaction was quenched, ethyl acetate was extracted three times, and the organic phase was combined and washed four times with brine, dried over anhydrous sodium sulfate. Petroleum ether: ethyl acetate) = 70:30, V/V) gave a white solid, 2.79 g, yield 84%.
1H NMR(300MHz,CDCl
3)δ9.36(s,1H),8.69(d,J=5.7Hz,1H),8.24(s,1H),8.10(d,J=8.6Hz,1H),7.74(dd,J=12.6,7.1Hz,2H).
1 H NMR (300 MHz, CDCl 3 ) δ 9.36 (s, 1H), 8.69 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.74 (dd, J=12.6, 7.1Hz, 2H).
步骤2:制备异喹啉6-羧酸甲酯Step 2: Preparation of isoquinoline 6-carboxylate
将2.76克6-氰基异喹啉溶于40毫升乙醇中,加入5N氢氧化钠水溶液8.6毫升,回流12小时后,浓缩反应液,再将其溶于100毫升甲醇中,加入浓硫酸2.0毫升,反应液回流4小时后停止反应,将反应浓缩,再加入乙酸乙酯,水分层,水相用乙酸乙酯萃取三次,有机相用无水硫酸钠干燥之后,过滤,浓缩得白色固体2.62克,产率81%2.76 g of 6-cyanoisoquinoline was dissolved in 40 ml of ethanol, and 8.6 ml of 5N aqueous sodium hydroxide solution was added thereto. After refluxing for 12 hours, the reaction mixture was concentrated, dissolved in 100 ml of methanol, and concentrated hydrochloric acid (2.0 ml) was added. After the reaction mixture was refluxed for 4 hours, the reaction was quenched, the reaction was concentrated, ethyl acetate was evaporated, and then aqueous layer was evaporated. Gram, yield 81%
1H NMR(300MHz,DMSO)δ9.44(s,1H),8.67(s,1H),8.62(d,J=5.7Hz,1H),8.25(d,J=8.5Hz,1H),8.16–8.10(m,1H),8.05(d,J=5.7Hz,1H),3.94(s,3H).
1 H NMR (300MHz, DMSO) δ9.44 (s, 1H), 8.67 (s, 1H), 8.62 (d, J = 5.7Hz, 1H), 8.25 (d, J = 8.5Hz, 1H), 8.16- 8.10 (m, 1H), 8.05 (d, J = 5.7 Hz, 1H), 3.94 (s, 3H).
步骤3:制备甲基1,2,3,4-四氢异喹啉-6-羧酸乙酯Step 3: Preparation of methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate
将2.2克异喹啉6-羧酸甲酯溶于30毫升甲醇中,加入220毫克二氧化铂,2.2毫升乙酸,氢气氛围下搅拌8小时,反应液直接浓缩中压层析,(二氯甲烷:甲醇)=90:10,V/V)得灰色固体2.2克,产率95%。2.2 g of methyl isoquinoline 6-carboxylate was dissolved in 30 ml of methanol, 220 mg of platinum dioxide was added, 2.2 ml of acetic acid was stirred under a hydrogen atmosphere for 8 hours, and the reaction solution was directly concentrated and subjected to medium pressure chromatography (dichloromethane). :Methanol) = 90:10, V/V) gave a gray solid, 2.2 g, yield 95%.
1H NMR(300MHz,DMSO)δ7.68(d,J=4.7Hz,2H),7.18–7.11(m,1H),3.87(s,2H),3.82(s,3H),2.93(t,J=5.8Hz,2H),2.73(t,J=5.8Hz,2H).
1 H NMR (300MHz, DMSO) δ7.68 (d, J = 4.7Hz, 2H), 7.18-7.11 (m, 1H), 3.87 (s, 2H), 3.82 (s, 3H), 2.93 (t, J = 5.8 Hz, 2H), 2.73 (t, J = 5.8 Hz, 2H).
步骤4:制备2-(4-(二甲基氨基)苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸甲酯Step 4: Preparation of methyl 2-(4-(dimethylamino)benzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate
将环己基甲酸换成4-二甲氨基苯甲酸,将N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺换成甲基1,2,3,4-四氢异喹啉-6-羧酸乙酯,其余所需原料、试剂及制备方法同实施例35中的步骤,得2-(4-(二甲基氨基)苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸甲酯Replacing cyclohexylformic acid with 4-dimethylaminobenzoic acid, N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5, 6,7-Tetrahydrothieno[3,2-c]pyridine-2-carboxamide is exchanged for methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid ethyl ester, the remaining raw materials , reagent and preparation method were the same as those in Example 35 to obtain methyl 2-(4-(dimethylamino)benzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate.
1H NMR(300MHz,CD
3OD)δ7.82(m,2H),7.38(d,J=8.8Hz,2H),7.22(s,1H),6.77(d,J=8.8Hz,2H),4.83(s,2H),3.88(s,3H),3.85(m,2H),3.04–2.94(m,8H).
1 H NMR (300MHz, CD 3 OD) δ7.82 (m, 2H), 7.38 (d, J = 8.8Hz, 2H), 7.22 (s, 1H), 6.77 (d, J = 8.8Hz, 2H), 4.83 (s, 2H), 3.88 (s, 3H), 3.85 (m, 2H), 3.04 - 2.94 (m, 8H).
步骤5:制备2-(4-(二甲基氨基)苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸Step 5: Preparation of 2-(4-(dimethylamino)benzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid
将4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成2-(4-(二甲基氨基)苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸甲酯,乙醇换成甲醇其余所需原料、试剂及制备方法同实施例1中的步骤5,得2-(4-(二甲基氨基)苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸。Replacing 4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 2-(4-(dimethylamino)benzoyl)-1,2, Methyl 3,4-tetrahydroisoquinoline-6-carboxylate, the remaining starting materials, reagents and preparation methods for the conversion of ethanol to methanol are the same as in the step 5 of Example 1, to obtain 2-(4-(dimethylamino). Benzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid.
1H NMR(300MHz,CD
3OD)δ7.84(m,2H),7.39(d,J=8.9Hz,2H),7.22(s,1H),6.78(d,J=8.9Hz,2H),4.84(s,2H),3.86(s,2H),3.05–2.95(m,8H).
1 H NMR (300MHz, CD 3 OD) δ7.84 (m, 2H), 7.39 (d, J = 8.9Hz, 2H), 7.22 (s, 1H), 6.78 (d, J = 8.9Hz, 2H), 4.84(s, 2H), 3.86(s, 2H), 3.05–2.95 (m, 8H).
步骤6:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-2-(4-(二甲基氨基)苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酰胺Step 6: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-(dimethylamino)benzoyl) -1,2,3,4-tetrahydroisoquinoline-6-carboxamide
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成2-(4-(二甲基氨基)苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得白色固体。Conversion of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid to 2-(4-(dimethylamino)benzene Formyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid, the remaining starting materials, reagents and preparation methods were the same as those in Step 6 of Example 1, to give a white solid.
1H NMR(300MHz,CD
3OD)δ7.58(m,2H),7.35(d,J=8.9Hz,2H),7.16–7.04(m,4H),7.04–6.97(m,1H),6.74(d,J=8.9Hz,2H),4.74(s,2H),4.19–4.07(m,1H),3.83(s,2H),3.76(s,2H),3.49(d,J=6.0Hz,2H),2.98(s,6H),2.95–2.87(m,4H),2.86–2.69(m,4H).
1 H NMR (300MHz, CD 3 OD) δ7.58 (m, 2H), 7.35 (d, J = 8.9Hz, 2H), 7.16-7.04 (m, 4H), 7.04-6.97 (m, 1H), 6.74 (d, J = 8.9 Hz, 2H), 4.74 (s, 2H), 4.19 - 4.07 (m, 1H), 3.83 (s, 2H), 3.76 (s, 2H), 3.49 (d, J = 6.0 Hz, 2H), 2.98 (s, 6H), 2.95–2.87 (m, 4H), 2.86–2.69 (m, 4H).
实施例75Example 75
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酰胺(I-75)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-methoxybenzoyl)-1,2,3, 4-tetrahydroisoquinoline-6-carboxamide (I-75)
步骤1:制备2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸甲酯Step 1: Preparation of methyl 2-(4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate
将环己基甲酸换成4-甲氧基苯甲酸,将N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺换成甲基1,2,3,4-四氢异喹啉-6-羧酸乙酯,其余所需原料、试剂及制备方法同实施例35中的步骤,得2-(4-甲氧基苯甲酰 基)-1,2,3,4-四氢异喹啉-6-甲酸甲酯。Replacing cyclohexylic acid with 4-methoxybenzoic acid, N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5, 6,7-Tetrahydrothieno[3,2-c]pyridine-2-carboxamide is exchanged for methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid ethyl ester, the remaining raw materials The reagents and preparation methods were the same as those in Example 35 to give methyl 2-(4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-carboxylate.
1H NMR(300MHz,DMSO)δ7.75(m,2H),7.43(d,J=8.7Hz,2H),7.29(s,1H),7.00(d,J=8.7Hz,2H),4.75(s,2H),3.88(s,3H),3.80(s,3H),3.68(m,2H),2.92(t,J=5.6Hz,2H).
1 H NMR (300MHz, DMSO) δ7.75 (m, 2H), 7.43 (d, J = 8.7Hz, 2H), 7.29 (s, 1H), 7.00 (d, J = 8.7Hz, 2H), 4.75 ( s, 2H), 3.88 (s, 3H), 3.80 (s, 3H), 3.68 (m, 2H), 2.92 (t, J = 5.6 Hz, 2H).
步骤2:制备2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸Step 2: Preparation of 2-(4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid
将4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸甲酯,乙醇换成甲醇其余所需原料、试剂及制备方法同实施例1中的步骤5,得2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸。Replace 4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 2-(4-methoxybenzoyl)-1,2,3,4 - tetrahydroisoquinoline-6-carboxylic acid methyl ester, ethanol to methanol, the remaining starting materials, reagents and preparation methods are the same as in step 5 of Example 1, to obtain 2-(4-methoxybenzoyl)-1 , 2,3,4-tetrahydroisoquinoline-6-carboxylic acid.
1H NMR(300MHz,DMSO)δ7.75(m,2H),7.43(d,J=8.7Hz,2H),7.29(s,1H),7.00(d,J=8.7Hz,2H),4.75(s,2H),3.80(s,3H),3.68(m,2H),2.92(t,J=5.6Hz,2H).
1 H NMR (300MHz, DMSO) δ7.75 (m, 2H), 7.43 (d, J = 8.7Hz, 2H), 7.29 (s, 1H), 7.00 (d, J = 8.7Hz, 2H), 4.75 ( s, 2H), 3.80 (s, 3H), 3.68 (m, 2H), 2.92 (t, J = 5.6 Hz, 2H).
步骤3:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酰胺Step 3: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-methoxybenzoyl)-1, 2,3,4-tetrahydroisoquinoline-6-carboxamide
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得白色固体。Conversion of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid to 2-(4-methoxybenzoyl) -1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid, the remaining starting materials, reagents and preparation methods were the same as those in step 6 of Example 1, to give a white solid.
1H NMR(300MHz,CDCl
3)δ7.61(s,1H),7.58(d,J=7.9Hz,1H),7.44(d,J=8.7Hz,2H),7.14(m,4H),7.01(d,J=5.7Hz,1H),6.94(d,J=8.7Hz,2H),6.84(s,1H),4.80(s,2H),4.04(m,1H),3.83(m,5H),3.80–3.69(m,2H),3.63(d,J=15.0Hz,1H),3.50–3.39(m,1H),2.93(m,5H),2.75(d,J=9.5Hz,1H),2.67–2.49(m,2H).
1 H NMR (300MHz, CDCl 3 ) δ7.61 (s, 1H), 7.58 (d, J = 7.9Hz, 1H), 7.44 (d, J = 8.7Hz, 2H), 7.14 (m, 4H), 7.01 (d, J = 5.7 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 6.84 (s, 1H), 4.80 (s, 2H), 4.04 (m, 1H), 3.83 (m, 5H) , 3.80–3.69 (m, 2H), 3.63 (d, J = 15.0 Hz, 1H), 3.50–3.39 (m, 1H), 2.93 (m, 5H), 2.75 (d, J = 9.5 Hz, 1H), 2.67–2.49 (m, 2H).
实施例76Example 76
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-2-(4-溴苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酰胺(I-76)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-bromobenzoyl)-1,2,3,4- Tetrahydroisoquinoline-6-carboxamide (I-76)
步骤1:制备2-(4-溴苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸甲酯Step 1: Preparation of methyl 2-(4-bromobenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate
将环己基甲酸换成4-溴苯甲酸,将N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺换成甲基1,2,3,4-四氢异喹啉-6-羧酸乙酯,其余所需原料、试剂及制备方法同实施例35中的步骤,得2-(4-溴苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸甲酯。Replacing cyclohexyl formate with 4-bromobenzoic acid, N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6, 7-Tetrahydrothieno[3,2-c]pyridine-2-carboxamide is exchanged for methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid ethyl ester, the remaining raw materials, reagents The preparation was carried out in the same manner as in Example 35 to give methyl 2-(4-bromobenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-carboxylate.
步骤2:制备2-(4-溴苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸Step 2: Preparation of 2-(4-bromobenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid
将4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成2-(4-溴苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸甲酯,乙醇换成甲醇其余所需原料、试剂及制备方法同实施例1中的步骤5,得2-(4-溴苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸。Replace 4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 2-(4-bromobenzoyl)-1,2,3,4-tetra Hydrogen isoquinoline-6-formic acid methyl ester, ethanol to methanol, other necessary raw materials, reagents and preparation method are the same as step 5 in Example 1, to obtain 2-(4-bromobenzoyl)-1,2,3 , 4-tetrahydroisoquinoline-6-carboxylic acid.
1H NMR(300MHz,DMSO)δ7.78(m,2H),7.66(d,J=8.2Hz,2H),7.40(m,2H),7.22–7.09(m,1H),4.80(s,1H),4.60(s,1H),3.83(s,1H),3.54(s,1H),2.90(s,2H).
1 H NMR (300MHz, DMSO) δ7.78 (m, 2H), 7.66 (d, J = 8.2Hz, 2H), 7.40 (m, 2H), 7.22-7.09 (m, 1H), 4.80 (s, 1H ), 4.60 (s, 1H), 3.83 (s, 1H), 3.54 (s, 1H), 2.90 (s, 2H).
步骤3:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-(4-溴苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酰胺Step 3: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-(4-bromobenzoyl)-1,2,3, 4-tetrahydroisoquinoline-6-carboxamide
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成2-(4-溴苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得白色固体。Conversion of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid to 2-(4-bromobenzoyl)-1 2,3,4-tetrahydroisoquinoline-6-carboxylic acid, the remaining starting materials, reagents and preparation methods were the same as those in the step 6 of Example 1, to give a white solid.
1H NMR(300MHz,CDCl
3)δ7.69–7.51(m,4H),7.33(d,J=8.2Hz,2H),7.22–7.08(m,3H),7.00(d,J=5.9Hz,1H),6.88(s,1H),4.89(s,1H),4.59(s,1H),4.03(m,2H),3.83(d,J=14.9Hz,1H),3.79–3.70(m,1H),3.62(d,J=14.8Hz,2H),3.52–3.38(m,1H),2.94(m,5H),2.81–2.68(m,1H),2.67–2.49(m,2H).
1 H NMR (300MHz, CDCl 3 ) δ 7.69 - 7.51 (m, 4H), 7.33 (d, J = 8.2 Hz, 2H), 7.22 - 7.08 (m, 3H), 7.00 (d, J = 5.9 Hz, 1H), 6.88 (s, 1H), 4.89 (s, 1H), 4.59 (s, 1H), 4.03 (m, 2H), 3.83 (d, J = 14.9 Hz, 1H), 3.79 - 3.70 (m, 1H) ), 3.62 (d, J = 14.8 Hz, 2H), 3.52 - 3.38 (m, 1H), 2.94 (m, 5H), 2.81 - 2.68 (m, 1H), 2.67 - 2.49 (m, 2H).
实施例77Example 77
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-2-(4-(二甲基氨基)苯甲 酰基)-1,2,3,4-四氢异喹啉-7-甲酰胺(I-77)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-(dimethylamino)benzoyl)-1,2 ,3,4-tetrahydroisoquinoline-7-carboxamide (I-77)
步骤1:制备((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基甲酰基)-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯Step 1: Preparation of ((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-3,4-dihydroisoquinoline-2 ( 1H)-tert-butyl formate
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成2-(叔丁氧基羰基)-1,2,3,4-四氢异喹啉-7-甲酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得白色固体。Replacing 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid with 2-(tert-butoxycarbonyl)-1, 2,3,4-tetrahydroisoquinoline-7-carboxylic acid, the remaining starting materials, reagents and preparation methods were the same as those in Step 6 of Example 1, to give a white solid.
1H NMR(300MHz,CD
3OD)δ7.57(d,J=6.7Hz,2H),7.16(d,J=8.6Hz,1H),7.09(m,3H),7.00(d,J=5.8Hz,1H),4.52(s,2H),4.09(m,1H),3.73(s,2H),3.62(t,J=5.9Hz,2H),3.57–3.40(m,2H),2.85(m,6H),2.74–2.57(m,2H),1.49(s,9H).
1 H NMR (300MHz, CD 3 OD) δ7.57 (d, J = 6.7Hz, 2H), 7.16 (d, J = 8.6Hz, 1H), 7.09 (m, 3H), 7.00 (d, J = 5.8 Hz, 1H), 4.52 (s, 2H), 4.09 (m, 1H), 3.73 (s, 2H), 3.62 (t, J = 5.9 Hz, 2H), 3.57 - 3.40 (m, 2H), 2.85 (m) , 6H), 2.74–2.57 (m, 2H), 1.49 (s, 9H).
步骤2:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-1,2,3,4-四氢异喹啉-7-甲酰胺Step 2: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline-7 -formamide
将叔丁基2-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基甲酰基)-6,7-四氢[3,2-c]吡啶-5(4H)-羧酸叔丁酯换成((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基甲酰基)-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例2中的步骤,得微黄色固体。tert-Butyl 2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-6,7-tetrahydro[3,2 -c] Pyridine-5(4H)-carboxylic acid tert-butyl ester was replaced by ((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl) -3,4-Dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester, the remaining starting materials, reagents and preparation methods were the same as those in Example 2 to give a pale yellow solid.
1H NMR(300MHz,CD
3OD)δ7.54(d,J=8.7Hz,1H),7.47(s,1H),7.11(m,4H),7.03(m,1H),4.15–4.04(m,1H),3.89(s,2H),3.74(s,2H),3.49(d,J=5.1Hz,2H),3.08(t,J=6.0Hz,2H),2.96–2.78(m,6H),2.67(t,J=5.8Hz,2H).
1 H NMR (300MHz, CD 3 OD) δ7.54 (d, J = 8.7Hz, 1H), 7.47 (s, 1H), 7.11 (m, 4H), 7.03 (m, 1H), 4.15-4.04 (m , 1H), 3.89 (s, 2H), 3.74 (s, 2H), 3.49 (d, J = 5.1 Hz, 2H), 3.08 (t, J = 6.0 Hz, 2H), 2.96 - 2.78 (m, 6H) , 2.67 (t, J = 5.8 Hz, 2H).
步骤3:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-2-(4-(二甲基氨基)苯甲酰基)-1,2,3,4-四氢异喹啉-7-甲酰胺Step 3: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-(dimethylamino)benzoyl) -1,2,3,4-tetrahydroisoquinoline-7-carboxamide
将环己基甲酸换成4-二甲氨基苯甲酸,将N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺换成N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-1,2,3,4-四氢异喹啉-7-甲酰胺,其余所需原料、试剂及制备方法同实施例35中的步骤,得产物。Replacing cyclohexylformic acid with 4-dimethylaminobenzoic acid, N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5, 6,7-Tetrahydrothieno[3,2-c]pyridine-2-carboxamide to N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxyl Propyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to give the product.
1H NMR(300MHz,CD
3OD)δ7.61(s,1H),7.54(s,1H),7.37(d,J=7.5Hz,2H),7.22(d,J=8.3Hz,1H),7.09(m,4H),6.76(d,J=7.5Hz,2H),4.75(s,2H),4.16(m,1H),3.95(s,2H),3.83(s,2H),3.48(s,2H),3.04(m,12H),2.86(s,2H).
1 H NMR (300MHz, CD 3 OD) δ7.61 (s, 1H), 7.54 (s, 1H), 7.37 (d, J = 7.5Hz, 2H), 7.22 (d, J = 8.3Hz, 1H), 7.09 (m, 4H), 6.76 (d, J = 7.5 Hz, 2H), 4.75 (s, 2H), 4.16 (m, 1H), 3.95 (s, 2H), 3.83 (s, 2H), 3.48 (s) , 2H), 3.04 (m, 12H), 2.86 (s, 2H).
实施例78Example 78
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-2-(4-(二甲基氨基)苯甲酰基)异二氢吲哚-5-甲酰胺(I-78)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-(dimethylamino)benzoyl)isoindoline哚-5-carboxamide (I-78)
步骤1:2-(4-(二甲基氨基)苯甲酰基)异吲哚啉-5-甲酸甲酯Step 1: Methyl 2-(4-(dimethylamino)benzoyl)isoindoline-5-carboxylate
将环己基甲酸换成4-二甲氨基苯甲酸,将N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺换成甲基异二氢吲哚-5-羧酸乙酯,其余所需原料、试剂及制备方法同实施例35中的步骤,得产物。Replacing cyclohexylformic acid with 4-dimethylaminobenzoic acid, N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5, 6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide is exchanged for methyl isoindoline-5-carboxylic acid ethyl ester, the remaining raw materials, reagents and preparation methods are the same as the examples The step in 35 gives the product.
1H NMR(300MHz,CD
3OD)δ7.97(s,2H),7.56(d,J=8.8Hz,2H),7.49–7.33(m,1H),6.79(d,J=8.9Hz,2H),4.99(s,4H),3.89(s,3H),3.01(d,J=9.9Hz,6H).
1 H NMR (300 MHz, CD 3 OD) δ 7.97 (s, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.49 - 7.33 (m, 1H), 6.79 (d, J = 8.9 Hz, 2H) ), 4.99 (s, 4H), 3.89 (s, 3H), 3.01 (d, J = 9.9 Hz, 6H).
步骤2:制备2-(4-(二甲基氨基)苯甲酰基)异吲哚啉-5-羧酸Step 2: Preparation of 2-(4-(dimethylamino)benzoyl)isoindoline-5-carboxylic acid
将4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成2-(4-(二甲基氨基)苯甲酰基)异吲哚啉-5-甲酸甲酯酸,乙醇换成甲醇其余所需原料、试剂及制备方法同实施例1中的步骤5,得2-(4-(二甲基氨基)苯甲酰基)异吲哚啉-5-羧酸。Replace 4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 2-(4-(dimethylamino)benzoyl)isoindoline- 5-methyl formate acid, ethanol to methanol, the remaining raw materials, reagents and preparation methods are the same as in step 5 of Example 1, to obtain 2-(4-(dimethylamino)benzoyl)isoindoline- 5-carboxylic acid.
步骤3:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-2-(4-(二甲基氨基)苯甲酰基)异二氢吲哚-5-甲酰胺Step 3: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-(dimethylamino)benzoyl) Isoindane-5-carboxamide
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成2-(4-(二甲基氨基)苯甲酰基)异吲哚啉-5-羧酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得产物。Conversion of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid to 2-(4-(dimethylamino)benzene Formyl)isoindoline-5-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as in step 6 of Example 1, to obtain the product.
1H NMR(300MHz,CD
3OD)δ7.71(s,2H),7.52(d,J=8.8Hz,2H),7.25(m,1H),7.06(m,4H),6.76(d,J=6.8Hz,2H),4.86(s,2H),4.81(s,1H),4.71(s,1H),4.12(s,1H),3.81(d,J=5.1Hz,2H),3.50(t,J=4.7Hz,2H),3.00(s,6H),2.91(m,4H),2.76(t,J=6.5Hz,2H).
1 H NMR (300MHz, CD 3 OD) δ7.71 (s, 2H), 7.52 (d, J = 8.8Hz, 2H), 7.25 (m, 1H), 7.06 (m, 4H), 6.76 (d, J = 6.8 Hz, 2H), 4.86 (s, 2H), 4.81 (s, 1H), 4.71 (s, 1H), 4.12 (s, 1H), 3.81 (d, J = 5.1 Hz, 2H), 3.50 (t , J = 4.7 Hz, 2H), 3.00 (s, 6H), 2.91 (m, 4H), 2.76 (t, J = 6.5 Hz, 2H).
实施例79Example 79
制备(S)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酰胺(I-79)Preparation of (S)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-methoxybenzoyl)-1 ,2,3,4-tetrahydroisoquinoline-6-carboxamide (I-79)
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成2-(4-甲氧基苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸,1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇换成(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇,其余所需原料、试剂及制备方法同实施例1中的步骤6,得白色固体。Conversion of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid to 2-(4-methoxybenzoyl) -1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid, 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (S)-1-Amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol, the remaining starting materials, reagents and preparation methods are the same as those in Example 1. 6, a white solid.
1H NMR(300MHz,CDCl
3)δ7.61(s,1H),7.58(d,J=7.9Hz,1H),7.44(d,J=8.7Hz,2H),7.14(m,4H),7.01(d,J=5.7Hz,1H),6.94(d,J=8.7Hz,2H),6.84(s,1H),4.80(s,2H),4.04(m,1H),3.83(m,5H),3.80–3.69(m,2H),3.63(d,J=15.0Hz,1H),3.50–3.39(m,1H),2.93(m,5H),2.75(d,J=9.5Hz,1H),2.67–2.49(m,2H).
1 H NMR (300MHz, CDCl 3 ) δ7.61 (s, 1H), 7.58 (d, J = 7.9Hz, 1H), 7.44 (d, J = 8.7Hz, 2H), 7.14 (m, 4H), 7.01 (d, J = 5.7 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 6.84 (s, 1H), 4.80 (s, 2H), 4.04 (m, 1H), 3.83 (m, 5H) , 3.80–3.69 (m, 2H), 3.63 (d, J = 15.0 Hz, 1H), 3.50–3.39 (m, 1H), 2.93 (m, 5H), 2.75 (d, J = 9.5 Hz, 1H), 2.67–2.49 (m, 2H).
实施例80Example 80
(S)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-(4-溴苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酰胺(I-80)(S)-N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-(4-bromobenzoyl)-1,2,3, 4-tetrahydroisoquinoline-6-carboxamide (I-80)
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成2-(4-溴苯甲酰基)-1,2,3,4-四氢异喹啉-6-甲酸,1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇换成(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇,其余所需原料、试剂及制备方法同实施例1中的步骤6,得白色固体。Conversion of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid to 2-(4-bromobenzoyl)-1 , 2,3,4-tetrahydroisoquinoline-6-carboxylic acid, 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol exchanged (S --1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol, the remaining starting materials, reagents and preparation methods are the same as step 6 in Example 1, A white solid was obtained.
1H NMR(300MHz,CDCl
3)δ7.69–7.51(m,4H),7.33(d,J=8.2Hz,2H),7.22–7.08(m,3H),7.00(d,J=5.9Hz,1H),6.88(s,1H),4.89(s,1H),4.59(s,1H),4.03(m,2H),3.83(d,J=14.9Hz,1H),3.79–3.70(m,1H),3.62(d,J=14.8Hz,2H),3.52–3.38(m,1H),2.94(m,5H),2.81–2.68(m,1H),2.67–2.49(m,2H).
1 H NMR (300MHz, CDCl 3 ) δ 7.69 - 7.51 (m, 4H), 7.33 (d, J = 8.2 Hz, 2H), 7.22 - 7.08 (m, 3H), 7.00 (d, J = 5.9 Hz, 1H), 6.88 (s, 1H), 4.89 (s, 1H), 4.59 (s, 1H), 4.03 (m, 2H), 3.83 (d, J = 14.9 Hz, 1H), 3.79 - 3.70 (m, 1H) ), 3.62 (d, J = 14.8 Hz, 2H), 3.52 - 3.38 (m, 1H), 2.94 (m, 5H), 2.81 - 2.68 (m, 1H), 2.67 - 2.49 (m, 2H).
实施例81Example 81
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-(二甲基氨基)苯甲酰基)-7,7-二甲基-4,5,6,7-吩并〔3,2-c]吡啶-2-甲酰胺(I-81)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-(dimethylamino)benzoyl)-7,7 -Dimethyl-4,5,6,7-pheno[3,2-c]pyridine-2-carboxamide (I-81)
步骤1:制备1-苄基-4-氯-5,5-二甲基-1,2,5,6-四氢吡啶-3-甲醛Step 1: Preparation of 1-benzyl-4-chloro-5,5-dimethyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde
将1-叔丁氧羰基哌啶酮换成1-苄基-3,3-二甲基-4-酮,其余所需原料、试剂及制备方法同实施例1中的步骤3,得1-苄基-4-氯-5,5-二甲基-1,2,5,6-四氢吡啶-3-甲醛。The 1-tert-butoxycarbonylpiperidone is replaced by 1-benzyl-3,3-dimethyl-4-ketone, and the remaining raw materials, reagents and preparation methods are the same as those in the first step in Example 1. Benzyl-4-chloro-5,5-dimethyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde.
步骤2:制备5-苄基-7,7-二甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯Step 2: Preparation of ethyl 5-benzyl-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
将叔丁基-4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成1-苄基-4-氯-5,5-二甲基-1,2,5,6-四氢吡啶-3-甲醛,其余所需原料、试剂及制备方法同实施例1中的步骤4,得5-苄基-7,7-二甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯。Replace tert-butyl-4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 1-benzyl-4-chloro-5,5-dimethyl -1,2,5,6-tetrahydropyridine-3-carbaldehyde, the remaining starting materials, reagents and preparation methods are the same as in step 4 of Example 1, to give 5-benzyl-7,7-dimethyl-4 , 5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid ethyl ester.
1H NMR(300MHz,CDCl
3)δ7.33(m Hz,6H),4.30(q,J=7.1Hz,2H),3.69(s,2H), 3.50(s,2H),2.46(s,2H),1.40–1.28(m,9H).
1 H NMR (300MHz, CDCl 3 ) δ 7.33 (m Hz, 6H), 4.30 (q, J = 7.1 Hz, 2H), 3.69 (s, 2H), 3.50 (s, 2H), 2.46 (s, 2H) ), 1.40–1.28 (m, 9H).
步骤2:制备7,7-二甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯Step 2: Preparation of ethyl 7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
将330毫克5-苄基-7,7-二甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯溶于10毫升二氯甲烷中,加入138毫克碳酸钾,162微升氯甲酸1-氯乙酯,氩气保护,室温搅拌6小时后,加入二氯甲烷稀释反应液,饱和食盐水洗一次,有机相干燥,过滤,浓缩,再将其溶解到10毫升乙醇中,加热回流2小时后停止反应,浓缩反应液,柱层析得到191毫克产物,收率80%。330 mg of ethyl 5-benzyl-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate in 10 ml of dichloromethane Add 138 mg of potassium carbonate, 162 μl of 1-chloroethyl chloroformate, argon-protected, stir at room temperature for 6 hours, dilute the reaction solution with dichloromethane, wash once with saturated brine, dry with organic Further, it was dissolved in 10 ml of ethanol, and the reaction was stopped by heating under reflux for 2 hours. The reaction mixture was concentrated and purified by column chromatography to yield 191 mg of product.
1H NMR(300MHz,CD
3OD)δ7.43(s,1H),4.29(q,J=7.1Hz,2H),3.82(s,2H),2.84(s,2H),1.39–1.30(m,9H).
1 H NMR (300 MHz, CD 3 OD) δ 7.43 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.82 (s, 2H), 2.84 (s, 2H), 1.39 - 1.30 (m) , 9H).
步骤3:制备5-(4-(二甲基氨基)苯甲酰基)-7,7-二甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酸乙酯Step 3: Preparation of 5-(4-(dimethylamino)benzoyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2 -ethyl formate
将环己基甲酸换成4-二甲氨基苯甲酸,将N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺换成7,7-二甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸乙酯,其余所需原料、试剂及制备方法同实施例35中的步骤,得5-(4-(二甲基氨基)苯甲酰基)-7,7-二甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酸乙酯。Replacing cyclohexylformic acid with 4-dimethylaminobenzoic acid, N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5, 6,7-Tetrahydrothieno[3,2-c]pyridine-2-carboxamide was replaced by 7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c] Ethyl pyridine-2-carboxylate, the remaining starting materials, reagents and preparation methods are the same as those in Example 35 to give 5-(4-(dimethylamino)benzoyl)-7,7-dimethyl -4,5,6,7-Ethyltetrahydrothieno[3,2-c]pyridine-2-carboxylate.
1H NMR(300MHz,CD
3OD)δ7.46(s,1H),7.35(d,J=8.9Hz,2H),6.77(d,J=8.9Hz,2H),4.72(s,2H),4.29(q,J=7.1Hz,2H),3.74(s,2H),3.01(s,6H),1.39–1.26(m,9H).
1 H NMR (300MHz, CD 3 OD) δ7.46 (s, 1H), 7.35 (d, J = 8.9Hz, 2H), 6.77 (d, J = 8.9Hz, 2H), 4.72 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 3.74 (s, 2H), 3.01 (s, 6H), 1.39 - 1.26 (m, 9H).
步骤4:制备5-(4-(二甲基氨基)苯甲酰基)-7,7-二甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酸Step 4: Preparation of 5-(4-(dimethylamino)benzoyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2 -formic acid
将4-氯-3-甲酰基-5,6-二氢吡啶-1(2H)-羧酸叔丁酯换成5-(4-(二甲基氨基)苯甲酰基)-7,7-二甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酸乙酯,其余所需原料、试剂及制备方法同实施例1中的步骤5,得5-(4-(二甲基氨基)苯甲酰基)-7,7-二甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酸。Replace 4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester with 5-(4-(dimethylamino)benzoyl)-7,7- Ethyl dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate, the remaining starting materials, reagents and preparation methods are the same as those in step 5 of Example 1. 5-(4-(Dimethylamino)benzoyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid.
1H NMR(300MHz,CD
3OD)δ7.43(s,1H),7.35(d,J=8.9Hz,2H),6.78(d,J=8.9Hz,2H),4.72(s,2H),3.74(s,2H),3.02(s,6H),1.31(s,6H).
1 H NMR (300MHz, CD 3 OD) δ7.43 (s, 1H), 7.35 (d, J = 8.9Hz, 2H), 6.78 (d, J = 8.9Hz, 2H), 4.72 (s, 2H), 3.74 (s, 2H), 3.02 (s, 6H), 1.31 (s, 6H).
步骤5:制备N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(4-(二甲基氨基)苯甲酰基)-7,7-二甲基-4,5,6,7-吩并〔3,2-c]吡啶-2-甲酰胺Step 5: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-(dimethylamino)benzoyl) -7,7-Dimethyl-4,5,6,7-pheno[3,2-c]pyridine-2-carboxamide
将5-(叔丁氧基羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-羧酸换成5-(4-(二甲基氨基)苯甲酰基)-7,7-二甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酸,其余所需原料、试剂及制备方法同实施例1中的步骤6,得产物。Replacing 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid with 5-(4-(dimethylamino)benzene Formyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid, the remaining raw materials, reagents and preparation methods are the same as in the first embodiment In step 6, the product is obtained.
1H NMR(300MHz,CD
3OD)δ7.33(d,J=8.7Hz,2H),7.03(m,5H),6.77(d,J=8.7Hz,2H),4.53(s,2H),4.16–3.97(m,1H),3.75(m,2H),3.67(s,2H),3.45(m,2H),2.98(s,6H),2.90(s,4H),2.79–2.63(m,2H),1.26(s,6H).
1 H NMR (300MHz, CD 3 OD) δ7.33 (d, J = 8.7Hz, 2H), 7.03 (m, 5H), 6.77 (d, J = 8.7Hz, 2H), 4.53 (s, 2H), 4.16–3.97 (m, 1H), 3.75 (m, 2H), 3.67 (s, 2H), 3.45 (m, 2H), 2.98 (s, 6H), 2.90 (s, 4H), 2.79–2.63 (m, 2H), 1.26 (s, 6H).
实施例82Example 82
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(1-苯基乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(I-82)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(1-phenylethyl)-4,5,6,7- Tetrahydrothieno[3,2-c]pyridine-2-carboxamide (I-82)
将甲醛换成苯乙酮,其余所需原料、试剂及制备方法同实施例11中的步骤,得黄色粉末。The formaldehyde was changed to acetophenone, and the remaining raw materials, reagents and preparation methods were the same as those in Example 11, to obtain a yellow powder.
1H NMR(300MHz,CD
3OD)δ7.42–7.20(m,5H),7.16–6.98(m,5H),4.06(m,1H),3.79(s,2H),3.62(q,J=6.7Hz,1H),3.51(m,1H),3.47–3.36(m,2H),3.28(d,J=5.9Hz,1H),2.92(s,4H),2.81(d,J=8.4Hz,3H),2.77–2.63(m,3H),1.46(d,J=6.7Hz,3H).
1 H NMR (300 MHz, CD 3 OD) δ 7.42 - 7.20 (m, 5H), 7.16 - 6.98 (m, 5H), 4.06 (m, 1H), 3.79 (s, 2H), 3.62 (q, J = 6.7 Hz, 1H), 3.51 (m, 1H), 3.47 - 3.36 (m, 2H), 3.28 (d, J = 5.9 Hz, 1H), 2.92 (s, 4H), 2.81 (d, J = 8.4 Hz, 3H), 2.77–2.63 (m, 3H), 1.46 (d, J = 6.7 Hz, 3H).
实施例83Example 83
N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-5-(3-苯基丙酰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(I-83)N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(3-phenylpropanoyl)-4,5,6,7- Tetrahydrothieno[3,2-c]pyridine-2-carboxamide (I-83)
将环己基甲酸换成苯丙酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with phenylpropionic acid, and the remaining materials, reagents and preparation methods were the same as those in Example 35 to obtain a white powder.
1H NMR(300MHz,CD
3OD)δ7.48–6.86(m,10H),4.49(s,1H),4.26(s,1H),4.10(m,1H),3.91–3.77(m,3H),3.70(m,1H),3.47(t,J=7.2Hz,2H),2.94(m,6H),2.76(m,6H).
1 H NMR (300 MHz, CD 3 OD) δ 7.48–6.86 (m, 10H), 4.49 (s, 1H), 4.26 (s, 1H), 4.10 (m, 1H), 3.91–3.77 (m, 3H) , 3.70 (m, 1H), 3.47 (t, J = 7.2 Hz, 2H), 2.94 (m, 6H), 2.76 (m, 6H).
实施例84Example 84
5-(2-萘甲酰基)-N-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(I-84)5-(2-naphthoyl)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetra Hydrothieno[3,2-c]pyridine-2-carboxamide (I-84)
将环己基甲酸换成2-萘甲酸,其余所需原料、试剂及制备方法同实施例35中的步骤,得白色粉末。The cyclohexylic acid was replaced with 2-naphthoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 35 to obtain a white powder.
1H NMR(300MHz,CD
3OD)δ7.98(m,4H),7.58(m,3H),7.43–6.85(m,5H),4.76(s,1H),4.45(s,1H),4.11(m,4H),3.76(s,1H),3.46(s,2H),2.97(s,8H).
1 H NMR (300MHz, CD 3 OD) δ7.98 (m, 4H), 7.58 (m, 3H), 7.43-6.85 (m, 5H), 4.76 (s, 1H), 4.45 (s, 1H), 4.11 (m, 4H), 3.76 (s, 1H), 3.46 (s, 2H), 2.97 (s, 8H).
生物实验部分Biological experiment
实施例85Example 85
化合物分子水平对PRMT5酶活的影响Effect of compound molecular level on PRMT5 enzyme activity
1、试验方法1. Test method
采用放射性同位素的方法测试化合物的酶活抑制活性。The enzymatic activity of the compound was tested by a radioisotope method.
实验方法如下:1.准备1x实验缓冲液(改进的Tris-HCl缓冲液);2.在96孔板中稀释化合物到所需的浓度;3.准备蛋白溶液,也用1x实验缓冲液;4.将底物加到1x实验缓冲液中制备底物溶液;5.将[3H]-SAM加入到1x实验缓冲液中制备[
3H]-SAM溶液;6.将SAM加入到1x实验缓冲液中制备冷的SAM溶液;7.移取10L蛋白溶液到含有化合物的96孔板中;8.室温孵育15分钟;9.向每个孔中加入10L底物溶液;10.向每个孔中加入10L[
3H]-SAM溶液引发反应;11.室温孵育240分钟。12.向每个孔中加入10L冷的SAM溶液终止反应;13.转移40L反应混合溶液到GF/B板上,用三蒸水真空洗涤3次;14.在MicroBeta液体闪烁/发光计数仪上读取数据;15.根据公式%Inh=(最大信号–化合物信号)/(最大信号–最小信号)×100计算抑制率,最大信号是从酶和底物反应得到,最小信号是从底物得到。数据处理后用GraphPad Prism5.0 作图。使用SAH、EPZ015666做阳性对照。
The experimental methods are as follows: 1. Prepare 1x assay buffer (modified Tris-HCl buffer); 2. Dilute the compound to the desired concentration in a 96-well plate; 3. Prepare the protein solution, also use 1x assay buffer; Add the substrate to 1x assay buffer to prepare the substrate solution; 5. Add [3H]-SAM to 1x assay buffer to prepare [ 3 H]-SAM solution; 6. Add SAM to 1x assay buffer Prepare a cold SAM solution; 7. Pipette 10 L of protein solution into a 96-well plate containing the compound; 8. Incubate for 15 minutes at room temperature; 9. Add 10 L of substrate solution to each well; 10. To each well The reaction was initiated by the addition of 10 L of [ 3 H]-SAM solution; 11. Incubate for 240 minutes at room temperature. 12. Add 10 L of cold SAM solution to each well to terminate the reaction; 13. Transfer 40 L of the reaction mixture to the GF/B plate and vacuum wash three times with three distilled water; 14. On the MicroBeta liquid scintillation/luminescence counter Read the data; 15. Calculate the inhibition rate according to the formula %Inh=(maximum signal-compound signal)/(maximum signal-minimum signal)×100, the maximum signal is obtained from the reaction of the enzyme and the substrate, and the minimum signal is obtained from the substrate. . Data was processed and plotted with GraphPad Prism 5.0. SAH and EPZ015666 were used as positive controls.
2.实验结果2. Experimental results
表2.化合物对PRMT5酶活抑制活性Table 2. Compounds inhibiting PRMT5 activity
如表2所示,该系列化合物具有较强的PRMT5酶抑制活性,IC
50值在0.0085-2.7μM之间,阳性对照EPZ015666的IC
50值为0.047μM,可见本发明部分化合物的活性要强于该阳性对照化合物,如I-55(0.027μM),I-76(0.011μM),I-80(0.0085μM)等。.
As shown in Table 2, the series of compounds having strong PRMT5 inhibitory activity values 50, between the IC 0.0085-2.7μM, EPZ015666 positive control IC 50 value of 0.047μM, the visible portion of the active compounds of the present invention is stronger than the Positive control compounds, such as I-55 (0.027 μM), I-76 (0.011 μM), I-80 (0.0085 μM), and the like. .
实施例86Example 86
化合物对细胞增殖的影响Effect of compounds on cell proliferation
1.试验方法Test method
MCL(Maver-1、Z138、Jeko-1)细胞培养所用的培养液是RPMI 1640+10%的胎牛血清,同时为了防止细菌污染,培养液加入了100U/mL青霉素和100μg/mL链霉素。于37℃、5%CO2饱和湿度条件下培养,实验用的细胞均处于对数生长期。调整MCL细胞浓度为1×10
5/mL并接种于24孔培养板,每孔体积1mL,设立对照组和实验组,对照组加DMSO,实验组加入PRMT5活性小分子化合物并使最终浓度达到0-100μM。3个检测时间点分别是4、8和12天。细胞置于37℃和5%CO2培养箱培养到各个时间点时,用CellTiter-Glo试剂检测活细胞量。
The culture medium used for cell culture of MCL (Maver-1, Z138, Jeko-1) is RPMI 1640 + 10% fetal bovine serum, and in order to prevent bacterial contamination, 100 U/mL penicillin and 100 μg/mL streptomycin were added to the culture solution. . The cells were cultured at 37 ° C under 5% CO 2 saturated humidity, and the cells used in the experiment were in the logarithmic growth phase. The concentration of MCL cells was adjusted to 1×10 5 /mL and inoculated into 24-well culture plates at a volume of 1 mL per well. The control group and the experimental group were established, and the control group was added with DMSO. The experimental group was added with PRMT5 active small molecule compound and the final concentration was 0. -100 μM. The three detection time points were 4, 8 and 12 days respectively. The cells were cultured at 37 ° C in a 5% CO 2 incubator at various time points, and the amount of viable cells was measured using CellTiter-Glo reagent.
2.实验结果2. Experimental results
如表3所示,本发明化合物浓度在0-100μmol/L范围内作用于MCL细胞4、8和12天后,显示出明显的剂量和时间依赖性的增殖抑制作用,且IC
50在0.02~22μM之间,具有强的细胞抑制活性;其中部分化合物的活性明显强于阳性化合物EPZ015666,如I-62对Maver-1细胞12天的增殖抑制IC
50为0.02μM,明显强于EPZ015666(IC
50为0.10μM),I-39对Jeko-1细胞12天的增殖抑制IC
50为0.58μM,明显强于EPZ015666(IC
50为1.04μM)。
As shown in Table 3, the concentration of the compound of the present invention showed significant dose- and time-dependent inhibition of proliferation after 4, 8 and 12 days of treatment of MCL cells in the range of 0-100 μmol/L, and the IC 50 was 0.02 to 22 μM. between, have strong cytostatic activity; active compound wherein the portion of the compound is significantly stronger than the positive EPZ015666, such as I-62 on the proliferation of cells 12 days Maver-1 inhibition IC 50 of 0.02 M, was stronger than EPZ015666 (IC 50 of 0.10μM), I-39 on the proliferation of cells 12 days Jeko-1 inhibition IC 50 of 0.58μM, significantly stronger than EPZ015666 (IC 50 of 1.04μM).
表3.化合物对三株MCL细胞的增殖抑制活性Table 3. Proliferation inhibitory activity of compounds on three MCL cells
实施例87Example 87
化合物对MV4-11细胞增殖的影响Effect of compounds on proliferation of MV4-11 cells
1.试验方法Test method
用含10%胎牛血清(Gibco,Life Technologies,10099-141)及1%抗生素(盘尼西林和链霉素,Life Technologies,10378016)的1640培养基(Gibco,Life Technologies,22400-089)于37℃,5%CO
2饱和湿度条件下培养急性单核白血病细胞MV4-11(ATCC,CRL-9591),使细胞处于对数生长期。调整MV4-11细胞密度为1×10
5/mL,轻缓均匀吹打并接种于24孔细胞培养板中,每孔培养基体积1mL,放在培养箱中静置孵育6小时。设立对照组和实验组,对照组加DMSO,实验组加入PRMT5活性小分子化合物并使最终浓度达到0.015~100μM,并保持DMSO的终浓度为0.1%。3个检测时间点分别是4、8和12天。细胞置于37℃和5%CO
2培养箱培养到各个时间点时,将DMSO对照组细胞重新计数,调整为起始铺种的密度,传代于新培养板中,确保DMSO对照组细胞处于对数生长周期范围内。继续培养细胞,并按照初次给药浓度重新加入化合物处理;同时将充分混悬的40μL细胞悬液转移至384孔板中,每孔加入40uL的CellTiter-Glo试剂(Promega,G7572),为使其充分混匀并反应,室温环境下摇床孵育10分钟,随 后静置10分钟。用Multilabel reader(EnVision,PerkinElmer)在400~700nm波长下进行检测,全程避光处理。检测数据通过GraphPad Prism 5.0软件分析,拟合计算得到IC
50值。
1640 medium (Gibco, Life Technologies, 22400-089) containing 10% fetal bovine serum (Gibco, Life Technologies, 10099-141) and 1% antibiotic (penicillin and streptomycin, Life Technologies, 10378016) at 37 °C Acute mononuclear leukemia cell line MV4-11 (ATCC, CRL-9591) was cultured under 5% CO 2 saturated humidity conditions, and the cells were in logarithmic growth phase. The cell density of MV4-11 was adjusted to 1×10 5 /mL, gently pipetted and inoculated into a 24-well cell culture plate, and the volume of the medium was 1 mL per well, and placed in an incubator for 6 hours. A control group and an experimental group were established, and a control group was added with DMSO. The experimental group was added with a PRMT5 active small molecule compound to a final concentration of 0.015 to 100 μM, and the final concentration of DMSO was maintained at 0.1%. The three detection time points were 4, 8 and 12 days respectively. The cells were cultured at 37 ° C and 5% CO 2 incubator at various time points. The DMSO control cells were recounted, adjusted to the initial seeding density, and passaged into new culture plates to ensure that the DMSO control cells were in the right phase. Within the number of growth cycles. The cells were further cultured and re-added to the compound at the initial dose; while well-suspended 40 μL of the cell suspension was transferred to a 384-well plate, and 40 uL of CellTiter-Glo reagent (Promega, G7572) was added to each well to allow Mix well and react, incubate for 10 minutes at room temperature in a shaker, then let stand for 10 minutes. The detection was carried out at a wavelength of 400 to 700 nm using a Multilabel reader (EnVision, PerkinElmer), and the whole process was protected from light. Detection data analysis software by GraphPad Prism 5.0, 50 fit values calculated IC.
2.实验结果2. Experimental results
如表4所示,本发明化合物浓度在0.015-100μmol/L范围内作用于MV4-11细胞12天后,显示出明显增殖抑制作用,且IC
50在0.018~0.20μM之间;其中部分化合物的活性明显强于阳性化合物EPZ015666,如I-79对MV4-11细胞12天的增殖抑制IC
50为0.023μM,I-80对MV4-11细胞12天的增殖抑制IC
50为0.018μM,明显强于EPZ015666(IC
50为0.10μM)。
As shown in Table 4, after the compound of the present invention was applied to MV4-11 cells in the range of 0.015-100 μmol/L for 12 days, it showed significant proliferation inhibition, and the IC 50 was between 0.018 and 0.20 μM; much stronger than positive compound EPZ015666, such as I-79 on the proliferation of MV4-11 cells 12 days inhibition IC 50 of 0.023μM, proliferation of I-80 for 12 days pair of MV4-11 cells inhibition IC 50 of 0.018μM, significantly stronger than EPZ015666 (IC 50 was 0.10 μM).
表4.化合物对MV4-11细胞增殖抑制活性Table 4. Compounds inhibit proliferation of MV4-11 cells
实施例中的化合物Compound in the examples | GI 50(μM) GI 50 (μM) | 实施例中的化合物Compound in the examples | GI 50(μM) GI 50 (μM) |
I-36I-36 | 0.1540.154 | I-67I-67 | 0.1660.166 |
I-37I-37 | 0.1680.168 | I-68I-68 | 0.1240.124 |
I-39I-39 | 0.1260.126 | I-69I-69 | 0.0650.065 |
I-40I-40 | 0.1410.141 | I-70I-70 | 0.1830.183 |
I-41I-41 | 0.1340.134 | I-71I-71 | 0.1010.101 |
I-42I-42 | 0.0890.089 | I-74I-74 | 0.0360.036 |
I-43I-43 | 0.1340.134 | I-75I-75 | 0.0320.032 |
I-46I-46 | 0.1470.147 | I-76I-76 | 0.0340.034 |
I-49I-49 | 0.1590.159 | I-78I-78 | 0.0920.092 |
I-50I-50 | 0.1430.143 | I-79I-79 | 0.0230.023 |
I-52I-52 | 0.2080.208 | I-80I-80 | 0.0180.018 |
I-63I-63 | 0.1100.110 | I-82I-82 | 0.1720.172 |
I-64I-64 | 0.0660.066 | I-83I-83 | 0.1840.184 |
I-65I-65 | 0.1620.162 | I-84I-84 | 0.1770.177 |
I-66I-66 | 0.0850.085 | EPZ015666EPZ015666 | 0.1060.106 |
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.
Claims (10)
- 一种如下式(I)所示的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物,a compound represented by the following formula (I), and a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;其中,p为0或1;Where p is 0 or 1;X选自下组:NR 3、CHR 3; X is selected from the group consisting of NR 3 and CHR 3 ;Y选自下组:O、NR 4、CHR 4; Y is selected from the group consisting of O, NR 4 , CHR 4 ;Z选自下组:NR 4、CHR 4; Z is selected from the group consisting of NR 4 and CHR 4 ;环A选自下组:取代或未取代的含1-2个选自N、O、S的杂原子的5元杂芳环、取代或未取代的含1-2个选自N、O、S的杂原子的6元杂芳环、取代或未取代的苯基;其中,当环A为苯基的时候,Y与Z至少一个为NR 4;并且,所述取代指被选自下组的1个或多个取代基取代:卤素、C 1-C 3烷基; Ring A is selected from the group consisting of substituted or unsubstituted 5-membered heteroaryl rings containing 1-2 heteroatoms selected from N, O, S, substituted or unsubstituted, containing 1-2 selected from N, O, a 6-membered heteroaryl ring, a substituted or unsubstituted phenyl group of a hetero atom of S; wherein, when ring A is a phenyl group, at least one of Y and Z is NR 4 ; and the substitution means is selected from the group consisting of Substituted by one or more substituents: halogen, C 1 -C 3 alkyl;R 1和R 2可相同或不同,分别独立地选自下组:氢、C 1-C 3烷基; R 1 and R 2 may be the same or different and are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl;R 3选自下组:氢、C 1-C 3烷基; R 3 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl;R 4选自下组:氢、R 5、V 1-R 5; R 4 is selected from the group consisting of hydrogen, R 5 , V 1 -R 5 ;V 1选自下组:CO、CS、CHR 6、SO 2、NH、CH 2CO、COCH 2、COCH 2CH 2、CH 2CHR 6、CHR 6CH 2、CONH、NHCO、OCO、COO、CH 2CH 2O、CH 2CH 2CHR 6、CH 2CH 2CO; V 1 is selected from the group consisting of CO, CS, CHR 6 , SO 2 , NH, CH 2 CO, COCH 2 , COCH 2 CH 2 , CH 2 CHR 6 , CHR 6 CH 2 , CONH, NHCO, OCO, COO, CH 2 CH 2 O, CH 2 CH 2 CHR 6 , CH 2 CH 2 CO;R 5选自下组:氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的含有1-3个选自N、O和S的杂原子的4-10元环杂烷基、取代或未取代的5-10元芳基、取代或未取代的含有1-3个选自N、O和S的杂原子的5-10元杂芳基,其中,所述取代指被选自下组的1个或多个取代基取代:卤素、氰基、硝基、氨基、羟基、C1-C6烷基、卤代C1-C6烷基、含有1-3个选自N、O和S的杂原子的4-10元环杂烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷酰基、-NH(C1~C6烷基)、-N(C1~C6烷基)(C1~C6烷基)、-NH(C3~C8环烷基)、-NH(C3~C8环杂烷基)、-CO(C1~C6烷基)、-CONH 2、-CONH(C1~C6烷基)、-CON(C1~C6烷基)(C1~C6烷基)、-CO(O)(C1~C6烷基)、-O(C1~C6烷基); R 5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted, and 1-3 selected from N, O and S. a 4-10 membered cycloheteroalkyl group of a hetero atom, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-10 membered heterocyclic group containing 1-3 hetero atoms selected from N, O and S. An aryl group, wherein said substitution is substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, C1-C6 alkyl, halo C1-C6 alkyl, 4-10 membered cycloheteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkane containing from 1 to 3 heteroatoms selected from N, O and S Oxyl, C1-C6 alkanoyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) (C1-C6 alkyl), -NH(C3-C8 cycloalkyl), -NH( C3-C8 cycloheteroalkyl), -CO (C1-C6 alkyl), -CONH 2 , -CONH (C1-C6 alkyl), -CON (C1-C6 alkyl) (C1-C6 alkyl), -CO(O)(C1-C6 alkyl), -O(C1-C6 alkyl);R 6选自下组:氢、C 1-C 3烷基。 R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl.
- 如权利要求1所述的式(I)化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物,其特征在于,A compound of the formula (I) according to claim 1, and a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, characterized in thatp、X、Y、Z、R 1、R 2和R 4如权利要求1所定义; p, X, Y, Z, R 1 , R 2 and R 4 are as defined in claim 1;环A选自下组:取代或未取代的含1-2个选自N、O、S的杂原子的5元杂芳环、取代 或未取代的含1-2个选自N、O、S的杂原子的6元杂芳环、取代或未取代的苯基;其中,当环A为苯基的时候,Y与Z至少一个为NR 4;并且,所述取代指被选自下组的1个或多个取代基取代:卤素、C 1-C 3烷基; Ring A is selected from the group consisting of substituted or unsubstituted 5-membered heteroaryl rings containing 1-2 heteroatoms selected from N, O, S, substituted or unsubstituted, containing 1-2 selected from N, O, a 6-membered heteroaryl ring, a substituted or unsubstituted phenyl group of a hetero atom of S; wherein, when ring A is a phenyl group, at least one of Y and Z is NR 4 ; and the substitution means is selected from the group consisting of Substituted by one or more substituents: halogen, C 1 -C 3 alkyl;V 1选自下组:CO、CS、CHR 6、SO 2、NH、CH 2CO、COCH 2、COCH 2CH 2、CH 2CHR 6、CHR 6CH 2、CONH、NHCO、OCO、COO、CH 2CH 2O、CH 2CH 2CHR 6、CH 2CH 2CO; V 1 is selected from the group consisting of CO, CS, CHR 6 , SO 2 , NH, CH 2 CO, COCH 2 , COCH 2 CH 2 , CH 2 CHR 6 , CHR 6 CH 2 , CONH, NHCO, OCO, COO, CH 2 CH 2 O, CH 2 CH 2 CHR 6 , CH 2 CH 2 CO;R 5选自下组:氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的含有1-3个选自N、O和S的杂原子的4-10元环杂烷基、取代或未取代的5-10元芳基、取代或未取代的含有1-3个选自N、O和S的杂原子的5-10元杂芳基,其中,所述取代指被选自下组的1个或多个取代基取代:卤素、氰基、硝基、氨基、羟基、C1-C4烷基、卤代C1-C4烷基、含有1-3个选自N、O和S的杂原子的4-8元环杂烷基、C2-C4烯基、C2-C4炔基、C1-C4烷氧基、卤代C1-C4烷氧基、C1-C4烷酰基、-NH(C1~C4烷基)、-N(C1~C4烷基)(C1~C4烷基)、-CO(C1~C4烷基)、-CONH 2、-CONH(C1~C4烷基)、-CON(C1~C4烷基)(C1~C4烷基)、-CO(O)(C1~C4烷基)、-O(C1~C4烷基); R 5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted, and 1-3 selected from N, O and S. a 4-10 membered cycloheteroalkyl group of a hetero atom, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-10 membered heterocyclic group containing 1-3 hetero atoms selected from N, O and S. An aryl group, wherein said substitution is substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, C1-C4 alkyl, halo C1-C4 alkyl, 4-8 membered cycloheteroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, halogenated C1-C4 alkane containing from 1 to 3 heteroatoms selected from N, O and S An oxy group, a C1-C4 alkanoyl group, -NH(C1-C4 alkyl group), -N(C1-C4 alkyl group) (C1-C4 alkyl group), -CO(C1-C4 alkyl group), -CONH 2 , -CONH (C1-C4 alkyl), -CON (C1-C4 alkyl) (C1-C4 alkyl), -CO(O) (C1-C4 alkyl), -O(C1-C4 alkyl);R 6选自下组:氢、C 1-C 3烷基。 R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl.
- 如权利要求1~2中任一项所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物,其特征在于,所述化合物为选自通式(Ⅱ)或通式(Ⅲ)所示的化合物:A compound according to any one of claims 1 to 2, and a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, characterized in that The compound is a compound selected from the group consisting of the formula (II) or the formula (III):其中,among them,p、X、Y、Z、R 1、R 2和环A如权利要求2所定义。 p, X, Y, Z, R 1 , R 2 and ring A are as defined in claim 2.
- 如权利要求1-3中任一项所述的式(I)化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物,其特征在于,所述的式(I)化合物选自下组:A compound of formula (I) according to any one of claims 1 to 3, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof , characterized in that the compound of formula (I) is selected from the group consisting of:
- 一种药物组合物,其特征在于,所述药物组合物包括:A pharmaceutical composition, characterized in that the pharmaceutical composition comprises:(i)治疗有效量的如权利要求1-4中任一项所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物;和(i) a therapeutically effective amount of a compound according to any one of claims 1 to 4, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or Solvate; and(ii)任选的药学上可接受的载体。(ii) an optional pharmaceutically acceptable carrier.
- 一种权利要求1-4中任一项所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物或权利要求5所述的药物组合物在制备预防和/或治疗癌症相关疾病的药物中的用途,所述药物优选为精氨酸甲基转移酶抑制剂,更优选为PRMT5抑制剂。A compound according to any one of claims 1 to 4, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof or claims Use of the pharmaceutical composition according to 5 for the preparation of a medicament for preventing and/or treating a cancer-related disease, which is preferably an arginine methyltransferase inhibitor, more preferably a PRMT5 inhibitor.
- 一种精氨酸甲基转移酶酶活抑制剂,其特征在于,所述抑制剂含有抑制有效量的如权利要求1-4任一所述的一种或多种化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物。An arginine methyltransferase enzyme activity inhibitor, comprising: an inhibitory effective amount of one or more compounds according to any one of claims 1-4, and stereoisomers thereof Body, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate.
- 一种用于治疗癌症或精氨酸甲基转移酶酶活性相关疾病的药物组合物,其特征在于,所述药物组合物包括治疗有效量的如权利要求1-4中任一所述的一种或多种化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物,作为活性组分。A pharmaceutical composition for treating a cancer or a disease associated with arginine methyltransferase activity, characterized in that the pharmaceutical composition comprises a therapeutically effective amount of one according to any one of claims 1-4 One or more compounds, and their stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or solvates, as active ingredients.
- 一种式(I)化合物的制备方法,其特征在于,所述方法包括步骤:A method for preparing a compound of formula (I), characterized in that the method comprises the steps of:方案I:Option I:化合物(1)与化合物(2)通过缩合反应得到化合物(I);或Compound (1) and compound (2) are subjected to a condensation reaction to obtain compound (I); or方案II:Option II:化合物(3)与化合物(2)通过缩合反应得到化合物(4),化合物(4)通过脱保护反应得到化合物(5),化合物(5)通过取代反应得到化合物(I);Compound (3) and compound (2) are obtained by condensation reaction to obtain compound (4), compound (4) is obtained by deprotection reaction to obtain compound (5), and compound (5) is obtained by substitution reaction to obtain compound (I);其中,X、Y、Z、p、R 1、R 2和环A如权利要求1所定义。 Wherein X, Y, Z, p, R 1 , R 2 and ring A are as defined in claim 1.
- 一种体外抑制精氨酸甲基转移酶的方法,其特征在于,所述方法包括步骤:将权利要求1所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物或溶剂合物或权利要求5所述的药物组合物,与精氨酸甲基转移酶接触,从而抑制精氨酸甲基转移酶。A method for inhibiting arginine methyltransferase in vitro, the method comprising the steps of: the compound of claim 1, and stereoisomers, geometric isomers, tautomers thereof A pharmaceutically acceptable salt, prodrug, hydrate or solvate or the pharmaceutical composition according to claim 5, which is contacted with arginine methyltransferase to inhibit arginine methyltransferase.
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112125886A (en) * | 2019-06-24 | 2020-12-25 | 南京圣和药物研发有限公司 | Tricyclic compound serving as PRMT5 inhibitor and application thereof |
CN112778275A (en) * | 2019-11-11 | 2021-05-11 | 石药集团中奇制药技术(石家庄)有限公司 | Adamantyl PRMT5 inhibitor and application thereof |
CN113045543A (en) * | 2019-12-26 | 2021-06-29 | 石药集团中奇制药技术(石家庄)有限公司 | PRMT5 inhibitor and application thereof |
WO2022048631A1 (en) * | 2020-09-04 | 2022-03-10 | 上海翊石医药科技有限公司 | Compound having antitumor activity and use thereof |
Families Citing this family (9)
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WO2020182018A1 (en) * | 2019-03-12 | 2020-09-17 | 四川科伦博泰生物医药股份有限公司 | Nitrogen heterocyclic compound, preparation method therefor and use thereof |
CN110698377A (en) * | 2019-10-25 | 2020-01-17 | 西安工程大学 | Fluorescent small molecular probe based on single benzene ring and synthetic method thereof |
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WO2022063094A1 (en) * | 2020-09-22 | 2022-03-31 | 南京明德新药研发有限公司 | Tetrahydroisoquinoline derivative and use thereof |
EP4339193A1 (en) | 2021-05-13 | 2024-03-20 | Innovstone Therapeutics Limited | Compound having anti-tumor activity and use thereof |
CN115124534B (en) * | 2021-11-23 | 2023-09-15 | 中山大学 | Non-nucleotide PRMT5 small molecule inhibitor, preparation method and application |
TW202406908A (en) * | 2022-08-09 | 2024-02-16 | 大陸商上海湃隆生物科技有限公司 | Novel prmt5 inhibitor and use thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014100719A2 (en) * | 2012-12-21 | 2014-06-26 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
WO2014100730A1 (en) * | 2012-12-21 | 2014-06-26 | Epizyme, Inc. | Prmt5 inhibitors containing a dihydro- or tetrahydroisoquinoline and uses thereof |
WO2015200680A2 (en) * | 2014-06-25 | 2015-12-30 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
-
2018
- 2018-03-07 CN CN201810186215.5A patent/CN108570059B/en active Active
- 2018-03-07 WO PCT/CN2018/078308 patent/WO2018161922A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014100719A2 (en) * | 2012-12-21 | 2014-06-26 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
WO2014100730A1 (en) * | 2012-12-21 | 2014-06-26 | Epizyme, Inc. | Prmt5 inhibitors containing a dihydro- or tetrahydroisoquinoline and uses thereof |
WO2015200680A2 (en) * | 2014-06-25 | 2015-12-30 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112125886A (en) * | 2019-06-24 | 2020-12-25 | 南京圣和药物研发有限公司 | Tricyclic compound serving as PRMT5 inhibitor and application thereof |
WO2020259478A1 (en) * | 2019-06-24 | 2020-12-30 | 南京圣和药物研发有限公司 | Tricyclic compound as prmt5 inhibitor and application thereof |
CN112125886B (en) * | 2019-06-24 | 2023-06-23 | 南京圣和药物研发有限公司 | Tricyclic compounds as PRMT5 inhibitors and application thereof |
CN112778275A (en) * | 2019-11-11 | 2021-05-11 | 石药集团中奇制药技术(石家庄)有限公司 | Adamantyl PRMT5 inhibitor and application thereof |
CN112778275B (en) * | 2019-11-11 | 2023-05-12 | 石药集团中奇制药技术(石家庄)有限公司 | Adamantyl PRMT5 inhibitor and application thereof |
CN113045543A (en) * | 2019-12-26 | 2021-06-29 | 石药集团中奇制药技术(石家庄)有限公司 | PRMT5 inhibitor and application thereof |
CN113045543B (en) * | 2019-12-26 | 2023-05-12 | 石药集团中奇制药技术(石家庄)有限公司 | PRMT5 inhibitor and application thereof |
WO2022048631A1 (en) * | 2020-09-04 | 2022-03-10 | 上海翊石医药科技有限公司 | Compound having antitumor activity and use thereof |
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