CN114276328B - Compound as small molecule immunosuppressant, preparation method and application thereof - Google Patents
Compound as small molecule immunosuppressant, preparation method and application thereof Download PDFInfo
- Publication number
- CN114276328B CN114276328B CN202011041992.4A CN202011041992A CN114276328B CN 114276328 B CN114276328 B CN 114276328B CN 202011041992 A CN202011041992 A CN 202011041992A CN 114276328 B CN114276328 B CN 114276328B
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- CN
- China
- Prior art keywords
- methyl
- methoxy
- biphenyl
- dimethoxypyrimidin
- morpholinopropoxy
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 106
- 238000002360 preparation method Methods 0.000 title abstract description 63
- 150000003384 small molecules Chemical class 0.000 title abstract description 7
- 229960003444 immunosuppressant agent Drugs 0.000 title abstract description 4
- 230000001861 immunosuppressant effect Effects 0.000 title abstract description 4
- 239000003018 immunosuppressive agent Substances 0.000 title abstract description 4
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 8
- 208000026278 immune system disease Diseases 0.000 claims abstract description 7
- 102000008096 B7-H1 Antigen Human genes 0.000 claims abstract description 6
- 108010074708 B7-H1 Antigen Proteins 0.000 claims abstract description 6
- 230000019491 signal transduction Effects 0.000 claims abstract description 6
- 238000011282 treatment Methods 0.000 claims abstract description 6
- -1 (S) -1- ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) piperidine-2-carboxylic acid Chemical compound 0.000 claims description 232
- 238000006243 chemical reaction Methods 0.000 claims description 137
- 229960002429 proline Drugs 0.000 claims description 89
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 67
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 59
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 56
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- UENGBOCGGKLVJJ-UHFFFAOYSA-N 2-chloro-1-(2,4-difluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CCl)C(F)=C1 UENGBOCGGKLVJJ-UHFFFAOYSA-N 0.000 claims description 46
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 45
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 42
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 28
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 24
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 238000006268 reductive amination reaction Methods 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 19
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 16
- 206010028980 Neoplasm Diseases 0.000 claims description 15
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 229960003767 alanine Drugs 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- 235000011056 potassium acetate Nutrition 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 201000004624 Dermatitis Diseases 0.000 claims description 2
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- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
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- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 claims description 2
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- 206010028417 myasthenia gravis Diseases 0.000 claims description 2
- 206010061311 nervous system neoplasm Diseases 0.000 claims description 2
- 208000028466 reproductive system neoplasm Diseases 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 239000007972 injectable composition Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 16
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- 230000000155 isotopic effect Effects 0.000 abstract description 7
- 239000000651 prodrug Substances 0.000 abstract description 6
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- 229940079593 drug Drugs 0.000 abstract description 5
- 239000002207 metabolite Substances 0.000 abstract description 5
- 230000001613 neoplastic effect Effects 0.000 abstract description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 abstract description 2
- 230000000857 drug effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 120
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 77
- 239000012074 organic phase Substances 0.000 description 49
- 235000010290 biphenyl Nutrition 0.000 description 41
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 40
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 36
- 238000003756 stirring Methods 0.000 description 34
- 229910052757 nitrogen Inorganic materials 0.000 description 33
- 238000005481 NMR spectroscopy Methods 0.000 description 28
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 25
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 24
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 23
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 21
- 239000012043 crude product Substances 0.000 description 19
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 18
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- 125000001424 substituent group Chemical group 0.000 description 8
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
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- 239000007858 starting material Substances 0.000 description 6
- 125000000586 2-(4-morpholinyl)ethoxy group Chemical group [H]C([H])(O*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 5
- PBEKEFWBLFBSGQ-UHFFFAOYSA-N 2-chloro-4,6-dimethoxypyrimidine Chemical compound COC1=CC(OC)=NC(Cl)=N1 PBEKEFWBLFBSGQ-UHFFFAOYSA-N 0.000 description 5
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- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
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- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
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- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
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- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
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- 229910052794 bromium Inorganic materials 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
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- 229940098779 methanesulfonic acid Drugs 0.000 description 1
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- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
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- 102000020233 phosphotransferase Human genes 0.000 description 1
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- 125000004193 piperazinyl group Chemical group 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
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- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
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- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a compound serving as a small molecule immunosuppressant, a preparation method and application thereof. The invention specifically discloses a compound shown in a formula I or pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof. The compound of the present invention is a pyrimidine ring-containing compound that acts on the PD-1/PD-L1 signaling pathway and is relevant to the treatment of neoplastic diseases and other immune disorders. The compound of the invention can improve the drug effect and reduce the side effect of the drug. The invention also provides a preparation method of the compound and application of the compound in treating diseases related to PD-1/PD-L1 signal paths.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound for treating diseases related to PD-1/PD-L1 signal paths. The invention also relates to a preparation method of the compound and application thereof in treating cancers or immune diseases.
Background
Programmed death receptor 1 (Programmed Cell Death Protein, PD-1), a type I transmembrane protein consisting of 268 amino acids, is an immune co-suppressor molecule that is specifically expressed only on T cells. In normal organisms, PD-1 acts as a negative regulator of T cell proliferation, playing an important role in maintaining immune tolerance in the body. The programmed death receptor 1 ligand (PD-L1) is also a type I transmembrane protein, highly selectively expressed in tumor cells. When T cell receptor is activated, PD-1 and PD-L1 are combined, and are expressed in tumor infiltration lymphocytes in effector stage, so that the activity of the T lymphocytes is inhibited. When a tumor occurs, the PD-1/PD-L1 signaling pathway can inhibit the immune response of T cells so as to promote the occurrence of tumor immune escape. Studies show that blocking the PD-1/PD-L1 signal pathway can enhance the effect T lymphocytes to reach tumor sites, reduce the inhibition of regulatory T lymphocytes at the tumor sites and enhance the endogenous tumor immune effect of organisms, so that PD-1/PD-L1 has become an important drug target for tumor immunotherapy.
Several drugs have been marketed for the monoclonal PD-1/PD-L1 inhibitors, but no small molecule inhibitors have been marketed at present. Compared with the monoclonal antibody, the small molecular medicine has the advantages of flexible administration mode (oral administration), short half-life, stable property, high exposure, low price, no side effect related to immune rejection reaction and the like, so the development of the small molecular immunosuppressant is urgent.
Disclosure of Invention
The invention provides a novel pyrimidine ring-containing compound used as a PD-1/PD-L1 inhibitor, which has a structure shown in a formula I. The compounds of the present invention and pharmaceutically acceptable salts, prodrugs, isotopic derivatives, and solvates thereof, and pharmaceutical compositions containing the compounds, are useful in treating neoplastic diseases associated with inhibition of PD-1/PD-L1 signaling pathway.
The compounds of the present invention have the structure shown in formula I:
wherein X is selected from Br, cl and F;
y is selected from methyl, ethyl, isopropyl, cyclopropyl, cl, F and H;
R 1 and R is 2 Independently selected from H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituents selected from C1-C6 alkyl, C1-C6 alkoxy;
R 1 And R is 2 Optionally together with the nitrogen atom to which they are attached form a substituted or unsubstituted 4-7 membered heterocyclic group;
n＝1、2、3；
R 3 selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 6-10 membered cycloalkyl, substituted or unsubstituted 6-10 membered heterocycloalkyl, substituted or unsubstituted 5-7 membered heteroaryl;
R 4 and R is R 5 Independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted 3-6 membered cycloalkyl, and amide groups;
R 4 and R is 5 Optionally together with the nitrogen atom to which they are attached form a substituted or unsubstituted 4-7 membered heterocyclic ringA base;
R 1 、R 2 、R 1 and R is 2 4-7 membered heterocyclic ring, together with the nitrogen atom to which it is attached, R 4 、R 5 、R 4 And R is 5 4-7 membered heterocyclic ring which is formed together with the nitrogen atom to which it is attached, wherein the substituent of the 4-7 membered heterocyclic ring formed is at least one of 1-4C 1-C6 alkyl groups, 3-6 cycloalkyl groups, 3-6 heterocycloalkyl groups, hydroxyl groups, carboxyl groups, amino groups, nitrile groups, halogen groups, trifluoromethyl groups, and nitro groups; the 3-6 membered heterocycloalkyl or heteroaryl contains 1-3 heteroatoms selected from N, O, S.
In the compound disclosed by the invention, the substituent group of the biphenyl in the molecular structure of the compound can increase the conjugated system of the whole molecule, has a certain steric hindrance effect and can increase the directionality of the molecule, so that the compound can be better embedded with dimers formed by two PD-L1. Meanwhile, the substituent groups led out from the left side structure of the molecule can increase the solubility and the membrane permeability of the whole molecule, thereby increasing the drug property of the molecule. When the compound disclosed by the invention is embedded with the PD-L1 dimer, the PD-L1 can not be combined with the PD-1 any more, so that the PD-L1 can be identified and killed by T cells, and then the high expression of the PD-L1 in tumor cells is inhibited, and the purpose of treating tumor diseases is achieved.
More specifically, in the compounds of the invention, Y is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cl, F, H, these groups being smaller in volume or shorter in chain length. Mainly considering the course of the study, the inventors found that when Y selects larger or longer groups, the activity decreases significantly. The main reason is that the activity of the compounds of the invention on PD-L1 is related to Y and X in the molecule. The angle formed by the two benzene rings of a biphenyl group is related to the groups X and Y. When two benzene rings of biphenyl groups in the compound form an included angle smaller than 45 degrees, the compound has higher activity, and when Y is too large or too long, the included angle exceeds 45 degrees, instead, the directivity is reduced, and the activity of the compound is reduced.
In the above compound of formula I, the value of n is preferably not more than 3. The carbon chain n is not suitable for too long or too short, and the value of n is preferably 3. The presence of this side chain is on the one hand related to physicochemical properties such as solubility, fat-solubility etc. When n is less than or equal to 3, the compound can be made to have good physicochemical properties. When N is more than 3, the side chain is too long, resulting in a decrease in solubility and lipid solubility of the compound. On the other hand, the presence of this side chain is related to the ability of the compound to bind to the target. If the carbon chain is too long, the compound will not make effective contact with the target.
In the compound shown in the formula I, R 1 4-7 membered heterocyclic ring which may be independently co-formed with the nitrogen atom to which it is attached, R 2 Or 4-7 membered heterocyclic ring which may be formed separately from the nitrogen atom to which it is attached. Further, R is 1 And R is 2 A 4-7 membered heterocyclic ring which may be simultaneously co-formed with the attached nitrogen atom.
In addition, R 1 And R is 2 Nor should the volume be too large. R is R 1 And R is 2 Excessive volume or excessive chain length results in included angles exceeding 45 degrees, resulting in reduced activity of the compound.
Similarly, R 4 、R 5 、R 4 And R is 5 4-7 membered heterocyclic ring R, together with the nitrogen atom to which it is attached 4 、R 5 、R 4 And R is 5 A 4-7 membered heterocyclic ring which is co-formed with the nitrogen atom to which it is attached.
In the compounds of the invention of the formula I, the radicals R 1 、R 2 、R 4 、R 5 Cyclization can limit the conformation of the molecule, moderately increase rigidity, and is beneficial for increasing the directionality of the molecule. The chain substituent has larger activity, good flexibility and stronger fat solubility, but the directivity is reduced, and the metabolic site is increased. R is R 1 、R 2 、R 4 、R 5 In combination with other groups of formula I, different molecules of the compound can be specifically designed.
The compound according to the invention or a pharmaceutically acceptable salt, prodrug, metabolite, isotopic derivative, solvate thereof,
Wherein R is 1 And R is 2 Each is preferably selected from methyl, ethyl, isopropyl, cyclopropyl, phenyl, pyridinyl;
alternatively, R 1 And R is R 2 A 4-7 membered heterocyclic group together with the nitrogen atom to which it is attached, wherein R 1 And R is 2 The 4-7 membered heterocyclic group which is co-formed with the nitrogen atom to which it is attached is preferably selected from the group consisting of:
R 3 preferably selected from one of hydrogen, pyridyl, nitrile group substituted phenyl.
In the above 4-7 membered heterocyclic group, for 4-hydroxypiperidine, the polarity and solubility of the compound molecule are increased due to the presence of the hydroxyl group.
For containing R as described herein 1 And R is R 2 The compound of the group, the small molecular compound forms dimerization with two molecules of PD-L1, the small molecular compound is embedded in the middle of the dimer, so that the embedding of the compound and the PD-L1 is stronger, the activity of the compound is improved, and meanwhile, R 1 And R is R 2 Chain or cyclic substituents formed, especially at R 1 Or R is 2 The compound has better ability to form hydrogen bonds with amino acids on targets under the condition of shorter chain length or non-aromatic cyclic group formation, thereby being beneficial to improving the activity of the compound and improving the patentability of the molecule.
The compound according to the invention or a pharmaceutically acceptable salt, prodrug, metabolite, isotopic derivative, solvate thereof,
Wherein R is 4 And R is 5 Identical or different, R 4 And R is 5 Together with the attached nitrogen atom form a substituted or unsubstituted 4-7 membered heterocyclic group; wherein R is 4 And R is 5 The 4-to 7-membered heterocyclic group which constitutes a substituent(s) together with the nitrogen atom to which it is attached is preferably selected from 1-piperidyl, 1-pyrrolidinyl, 4-methyl-1-piperidyl, 1-cyclobutylamino and 1-cyclopentylamino.
Preferably, R 4 And R is 5 Independently selected from amide groups, wherein the amide groups are selected from-R 6 -C(＝O)-NH-R 7 or-R 6 -NH-C(＝O)R 7 ，R 6 And R is 7 Each independently is a C1-C5 alkyl group.
R 4 Or R is 5 Preferably with a shorter chain length or with cyclic groups. These groups have a better ability to form hydrogen bonds with amino acids on the target, helping to increase the activity of the compound.
The compound is selected from any one of the following compounds:
(S) -1- ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) piperidine-2-carboxylic acid
((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-serine
(2S, 4R) -1- ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -4-hydroxypyrrole-2-carboxylic acid
((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-alanine
(S) -1- ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) piperidine-2-carboxylic acid
((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-serine
(2S, 4R) -1- ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -4-hydroxypyrrole-2-carboxylic acid
((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-alanine
((2- ((2-bromo-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-bromo-3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2' -methyl- [1,1' -biphen yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-chloro-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-chloro-3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2' -methyl- [1,1' -biphen yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-fluoro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-fluoro-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-fluoro-3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2' -methyl- [1,1' -biphen yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-chloro-2 ' -methyl-3 ' - (2-morpholinoethoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-chloro-2 ' -methyl-3 ' - (3-piperidin-1-yl) propoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-chloro-2 ' -methyl-3 ' - (3-piperidin-1-yl) ethoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-chloro-3 '- (3-piperidinepropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxy pyrimidin-5-yl) methyl) -L-proline
((2- ((2, 2' -dichloro-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy-4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-chloro-3 ' - (3- (dimethylamino) propoxy) -2' -methyl- [1,1' -biphen-yl ] -3-yl) methoxy-4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-chloro-2 ' -ethyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-chloro-2 ' -isopropyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-chloro-2 ' -cyclopropyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4- ((3-cyanobenzyl) oxy) -6-methoxypyrimidin-5-yl) methyl) -L-proline
((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4-methoxy-6- (pyridin-3-ylmethoxy) pyrimidin-5-yl) methyl) -L-proline
(2S, 4R) -1- ((2- ((2-bromo- [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -4-hydroxypyrrole-2-carboxylic acid
((2- ((2-chloro-2 ' -butyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The present invention also provides a process for preparing a compound of formula I, wherein the process comprises the following reaction scheme:
the method comprises the following steps:
(1) Dissolving SM1 and SM2 in a solvent 1, adding an alkaline reagent, and reacting at a temperature ranging from room temperature to 70 ℃ to obtain a compound C01;
(2) Dissolving a compound C01 in a solvent 2, adding an alkaline reagent and a palladium metal catalyst, and reacting at a temperature range of 70-120 ℃ to obtain a compound C02;
(3) Dissolving a compound C02 and SM3 in a solvent 3, adding an alkaline reagent and a palladium metal catalyst, and reacting at a temperature range of 70-120 ℃ to obtain a compound C03;
(4) C03 and SM4 are dissolved in a solvent 4 to carry out reductive amination reaction, and the compound of the formula I is obtained.
Preferably, in step (1), the solvent 1 is selected from one or more of tetrahydrofuran, DMSO, DMF, acetonitrile; the alkaline reagent is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide and sodium tert-butoxide;
preferably, in step (2), the solvent 2 is selected from one or more of 1, 4-dioxane, toluene, benzene; the alkaline reagent is selected from one or more of potassium acetate, cesium carbonate, potassium carbonate and sodium carbonate; the palladium metal catalyst is selected from Pd (PPh) 3 ) 4 、Pd(dppf)Cl 2 Palladium acetate, pd 2 (dba) 3 One or more of the following;
preferably, in step (3), the solvent 3 is selected from one or more of 1, 4-dioxane, toluene and water; the alkaline reagent is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide and sodium tert-butoxide; the palladium metal catalyst is selected from Pd (PPh) 3 ) 4 、Pd(dppf)Cl 2 Palladium acetate, pd 2 (dba) 3 One or more of the following;
preferably, in step (4), the solvent 4 is selected from one or more of tetrahydrofuran, DMSO, DMF, acetonitrile, methanol, dichloromethane; the reducing agent for the reductive amination reaction is selected from NaBH 3 CN, sodium triacetoxyborohydride, sodium borohydride.
The invention also provides a pharmaceutical composition comprising the compound or a pharmaceutically salt of the compound or a solvate of the compound, and a pharmaceutically acceptable carrier.
In order to adapt to different administration modes, the pharmaceutical composition of the invention can be prepared into various dosage forms. Preferably, the pharmaceutical composition of the present invention is in the form of an oral preparation or an injection.
The compound of the invention is a PD-1/PD-L1 signal path inhibitor, and can be applied to treatment of diseases related to PD-1/PD-L1 signal paths after being prepared into various preparations, wherein the diseases can be malignant tumors or cancers, and can also be immune diseases.
Alternatively, the cancer is selected from skin cancer, lung cancer, hematological tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, head and neck cancer; the immune disease is selected from diabetes, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus and dermatitis.
Accordingly, the present invention also provides a method of treating cancer or an immune disorder, the method comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition of the present invention.
Within the meaning of the present invention, the terms used are defined as follows:
"halogen" means F, cl, br, I.
"C1-C6 alkyl" refers to an alkyl chain having 1 to 6 carbon atoms, which may be straight or branched. For example: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the like.
"C1-C8 alkoxy" means an alkyl chain having 1 to 8 carbon atoms, which may be straight or branched, wherein at least one carbon atom is replaced by an oxygen atom.
"6-10 membered aryl" means aryl having 6-10 carbon atoms, e.g., phenyl, naphthyl. The hydrogen atom on a carbon atom in the ring may be substituted with a specified substituent.
"3-6 membered cycloalkyl", "6-10 membered cycloalkyl" means a saturated carbocyclic ring having 3 to 6 and 6 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, respectively, the hydrogen atom on the carbon atom in the ring being optionally substituted by a specified substituent.
"6-10 membered heteroaryl" refers to an aryl group having 6-10 atoms, wherein 1-3 carbon atoms in the ring may be replaced by N, O, S. Such as quinolinyl, isoquinolinyl, pyridinyl, benzofuranyl, and the like.
"4-7 membered heterocyclic ring" means a heterocyclic ring having 4 to 7 atoms, such as a tetrahydropyrrole ring, piperidine ring, piperazine ring, and the like.
"3-6 membered heterocycloalkyl" means that the carbocycle having 3 to 6 carbon atoms contains at least one N, O, S heteroatom of N, O, S heteroatoms forming a heterocyclic group.
"prodrug" refers to a derivative that is converted to a compound of the present invention by an enzymatic oxidation, reduction, hydrolysis, or other reaction in vivo under physiological conditions.
"metabolite" means all molecules derived from the compounds of the invention produced in a cell or organism, preferably a human.
"isotopic derivative" means a compound comprising one or more isotopic atoms in non-natural proportions in the structure constituting the compound of the present invention. Such as deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N).
"solvate" means a form of a solvent complex formed by the physical association of a compound of the invention with a solvent molecule. The physical bonding comprises hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, tetrahydrofuran, ethyl acetate, acetonitrile, and the like. The compounds of formula I may be prepared in crystalline form and may be in solvate form (including hydrate form).
Pharmaceutically acceptable salts of the compounds of formula I contain one or more basic or acidic groups, in particular pharmaceutically usable salts thereof. Such as alkali metal salts, alkaline earth metal salts, ammonium salts. More precisely, it may be a sodium salt, potassium salt, calcium salt, magnesium salt or an organic amine such as ethylamine, ethanolamine, triethylamine or an amino acid salt. The compounds of the present invention may form protonated compounds of formula I with inorganic or organic acids, examples of which include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, lactic acid, malic acid, maleic acid, tartaric acid, and the like, as well as other acids known to those skilled in the art.
"pharmaceutical composition" when used as a medicament means a composition of a compound of formula I according to the invention, and salts, isotopic derivatives, metabolites, prodrugs, solvates and other biologically active substances, with or without, and which can be used for the treatment or prophylaxis of diseases associated with the PD1/PDL-1 signalling pathway, such as solid tumors, hematological tumors and the like.
Drawings
FIG. 1 is a general structure of a compound of formula I according to the present invention.
Detailed Description
The present invention will be described in detail with reference to the following examples.
Example 1
(S) -1- ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) piperidine-2-carboxylic acid
The structural formula of the compound is as follows:
the synthetic route is as follows:
the synthesis method comprises the following steps:
preparation of 4- (3- (3-bromo-2-methylphenoxy) propyl) morpholine:
to the reaction flask was added 3-bromo-2-methylphenol (1.61 g,1 eq), 4- (3-chloropropyl) morpholine (1.55 g,1.1 eq), acetonitrile (40 mL), potassium carbonate (3.56 g,3 eq). The temperature was raised to 70℃and the reaction was stirred for two hours. LCMS indicated completion of the reaction, stopped the reaction, quenched the system with water (150 mL), extracted with ethyl acetate (60 mL x 3), combined the organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and crude silica gel column chromatographed to give 4- (3- (3-bromo-2-methylphenoxy) propyl) morpholine (2.06 g, yield: 76%). MS [. Sup.M+1 ] +:314.1.
Preparation of 4- (3- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) morpholine:
4- (3- (3-bromo-2-methylphenoxy) propyl) morpholine (2.06 g,1 eq), pinacol biborate (3.33 g,2 eq), potassium acetate (1.29 g,2 eq), pd (dppf) Cl were added to the reaction flask 2 (0.24 g,0.05 eq) and 1, 4-dioxane (50 mL). The temperature was raised to 90℃under nitrogen protection, and the reaction was stirred for two hours LCMS to characterize the reaction was completeThe reaction was quenched by the addition of water (350 mL), extracted with ethyl acetate (100 mL. Times.3), the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and the crude product was chromatographed on silica gel to give 4- (3- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) morpholine (1.28 g, yield: 54%). MS [. Sup.M+1 ]]+:362.2.
Preparation of methyl 2-bromo-3-iodobenzoate:
to the reaction flask were added methyl 3-amino-2-bromobenzoate (25.1 g,1 eq), acetonitrile (250 mL) and water (400 mL), and concentrated hydrochloric acid (40 mL) was added to the above system with stirring. After stirring at room temperature for 10min, the temperature was lowered to 0℃and a solution of sodium nitrite (15.1 g,2 eq) in water (200 mL) was added dropwise with stirring. After stirring at 0℃for 30min, an aqueous potassium iodide solution (21.8 g,1.2eq,200mL of water) was added dropwise to the system, and the mixture was stirred at room temperature for 3 hours. LCMS indicated the reaction was complete. Ethyl acetate (300 ml x 3) and the organic phases were combined and washed once with saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated, and crude product was chromatographed on silica gel to give methyl 2-bromo-3-iodobenzoate (34 g, yield: 92%).
Preparation of methyl-2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-carboxylic acid ester:
4- (3- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) morpholine (2.56 g,1.2 eq), methyl 2-bromo-3-iodobenzoate (2.01 g,1 eq), potassium carbonate (2.44 g,3 eq), pd (dppf) Cl 2 (0.22 g,0.05 eq), toluene (100 mL), water (10 mL) and methanol (10 mL). Heating to 90 ℃ under the protection of nitrogen, stirring and reacting for 16 hours, LCMS characterizing the reaction to be complete, stopping the reaction, adding water (700 mL) to quench the system, extracting ethyl acetate (200 mL of 3), combining organic phases and washing the organic phases with saturated saline once, drying with anhydrous sodium sulfate, suction filtering, concentrating, and obtaining methyl-2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl by crude silica gel column chromatography]3-Formate (0.93 g, yield: 36%). MS [. Sup.M+1 ]]+:448.1/450.1.
Preparation of (2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methanol:
into a reaction flask was charged methyl-2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenolBase group]3-Formate (0.93 g,1 eq), freshly distilled tetrahydrofuran (50 mL), and LiAlH was added in portions at 5 ℃ 4 (0.16 g,2 eq) stirred at room temperature for 30min, TLC characterised by complete reaction, slow dropwise addition of the reaction system to saturated aqueous NH4Cl solution for quenching the reaction, extraction with ethyl acetate (100 mL. 3), combining the organic phases and washing once with saturated brine, drying over anhydrous sodium sulphate, suction filtration and concentration to give 2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ]-3-yl) methanol (0.74 g, yield: 85%) of crude product. The crude product is directly used for the next reaction without any purification treatment. MS [. Sup.M+1 ]]+:420.1/422.1.
Preparation of 2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethylpyrimidine-5-carbaldehyde:
to the reaction flask was added 2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methanol (0.74, 1 eq), 2-chloro-4, 6-dimethoxypyrimidine (0.54 g,1.5 eq), acetonitrile (50 mL), potassium carbonate (0.73 g,3 eq). The temperature was raised to 70℃and the reaction was stirred for two hours. LCMS indicated completion of the reaction, stopped the reaction, quenched the system with water (400 mL), extracted with ethyl acetate (150 mL x 3), combined the organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and the crude silica gel column chromatographed to give 2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethylpyrimidine-5-carbaldehyde (0.76 g, yield: 74%). MS [ M+1] +:586.2/588.2
Preparation of (S) -1- ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) piperidine-2-carboxylic acid:
2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethylpyrimidine-5-carbaldehyde (86.8 mg,1 eq) and L-2-piperidineic acid (57.3 mg,3 eq) were dissolved in a mixed solvent of DMF (5 mL) and methanol (2 mL), 1 drop of acetic acid was added dropwise with stirring, and after reacting at room temperature for 30min, sodium cyanoborohydride (27.9 mg,3 eq) was added to the system. Stirring overnight at room temperature, LCMS indicated that the reaction was complete, stopping the reaction, adding water (50 mL) to quench the system, extracting with ethyl acetate (20 mL. 3), combining the organic phases and washing once with saturated brine, drying over anhydrous sodium sulfate, suction filtration, concentrating, and purifying the crude product by preparative liquid phase to give (S) -1- ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) piperidine-2-carboxylic acid (29.0 mg, yield: 28%). MS [. Sup.M+1 ] +:699.2/701.2.
1H NMR(400MHz,d 6 -DMSO)δ7.58(m,1H),7.47(t,J＝7.6Hz,1H),7.27–7.18(m,2H),6.99(d,J＝8.0Hz,1H),6.70(d,J＝7.2Hz,1H),5.59–5.46,2H),4.18–3.99(m,2H),3.85(s,6H),3.69–3.62(m,2H),3.61–3.48(m,5H),2.96–2.82(m,2H),2.50–2.43(m,2H),2.40–2.30(m,4H),2.20–2.10(m,1H),1.96–1.80(m,5H),1.68–1.60(m,2H),1.49–1.34(m,3H)。
Example 2
((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The structural formula of the compound is as follows:
the synthesis method comprises the following steps:
preparation of ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline:
with reference to the synthetic method of reductive amination in example 1, 2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenylyl)]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde and L-proline to synthesize (2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl)]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :685.2/687.2.
1 H NMR(400MHz,d 6 -DMSO)δ7.61(m,1H),7.47(t,J＝7.6Hz,1H),7.26–7.14(m,2H),6.98(d,J＝8.0Hz,1H),6.68(d,J＝7.4Hz,1H),5.56–5.42(m,2H),4.12–4.00(m,2H),3.94–3.75(m,8H),3.60–3.54(m,4H),3.25–3.07(m,4H),2.49–2.43(m,2H),2.42–2.30(m,4H),2.09–2.00(m,1H),1.95–1.87(m,2H),1.87(s,3H),1.83–1.75(m,1H),1.74–1.55(m,1H)。
Example 3
((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-serine
The structural formula of the compound is as follows:
the synthesis method comprises the following steps:
preparation of ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-serine:
with reference to the synthetic method of reductive amination in example 1, 2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenylyl) ]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde and L-serine were synthesized as ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl)]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-serine. MS [. Sup.M+1 ]] + :631.2.
1 H NMR(400MHz,d 6 -DMSO)δ7.61(m,1H),7.48(t,J＝7.6Hz,1H),7.28–7.17(m,2H),6.99(d,J＝8.2Hz,1H),6.71(d,J＝7.4Hz,1H),5.61–5.43(m,2H),4.18–3.99(m,2H),3.85(s,6H),3.75–3.61(m,2H),3.69–3.62(m,2H),3.61–3.48(m,4H),2.94–2.82(m,1H),2.51–2.43(m,2H),2.42–2.31(m,4H),1.96–1.80(m,5H)。
Example 4
(2S, 4R) -1- ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -4-hydroxypyrrole-2-carboxylic acid
The structural formula of the compound is as follows:
the synthesis method comprises the following steps:
preparation of (2 s,4 r) -1- ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -4-hydroxypyrrole-2-carboxylic acid:
with reference to the synthetic method of reductive amination in example 1, 2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenylyl)]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde and (2S, 4R) -4-hydroxypyrrole-2-carboxylic acid to synthesize (2S, 4R) -1- ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenol)]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -4-hydroxypyrrole-2-carboxylic acid. MS [. Sup.M+1 ]] + :657.3。
1 H NMR(400MHz,d 6 -DMSO)δ7.56(d,J＝6.6Hz,1H),7.47(t,J＝7.6Hz,1H),7.26–7.14(m,2H),6.98(d,J＝8.2Hz,1H),6.68(d,J＝7.6Hz,1H),5.59–5.37(m,2H),4.20–3.99(m,4H),3.88(s,6H),3.73(s,2H),3.61–3.50(m,4H),3.27–3.15(m,2H),2.47–2.42(m,2H),2.39–2.30(m,4H),2.02–1.77(m,7H)。
Example 5
((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-alanine
The structural formula of the compound is as follows:
the synthesis method comprises the following steps:
preparation of ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-alanine:
with reference to the synthetic method of reductive amination in example 1, 2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenylyl)]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde and L-alanine were synthesized as ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl)]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-alanine. MS [. Sup.M+1 ]] + :614.2.
1 H NMR(400MHz,d 6 -DMSO)δ7.59(m,1H),7.49(t,J＝7.6Hz,1H),7.29–7.17(m,2H),7.01(d,J＝8.2Hz,1H),6.72(d,J＝7.4Hz,1H),5.60–5.43(m,2H),4.17–3.98(m,2H),3.86(s,6H),3.69–3.62(m,2H),3.61–3.34(m,5H),2.51–2.43(m,2H),2.42–2.31(m,4H),1.94–1.82(m,5H),1.24(d,J＝6.6HZ,3H)。
Example 6
(S) -1- ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) piperidine-2-carboxylic acid
The structural formula of the compound is as follows:
the synthetic route is as follows:
the synthesis method comprises the following steps:
preparation of 2-chloro-4, 6-dimethoxypyrimidine-5-carbaldehyde:
phosphorus oxychloride (229.2 g,15 eq) was added dropwise to a reaction flask containing DMF (109.2 g,15 eq) in an ice-water bath, stirred for 30min in an ice-water bath, and the mixture was added dropwise to the reaction systemA solution of 2-chloro-4, 6-dimethoxypyrimidine (17.4 g,1 eq) in DMF (200 mL) was added, the temperature was raised to 50℃and the reaction was stirred for two hours. LCMS indicated complete reaction and stopped the reaction. The reaction system was added dropwise to an ice-water bath under stirring, adjusted to neutrality (ph=7) with sodium bicarbonate, filtered with suction, washed twice with water, and the dried crude product was purified by silica gel column chromatography to give preparation of 2-chloro-4, 6-dimethoxypyrimidine-5-carbaldehyde (11.4 g, yield 56%). MS [. Sup.M+1 ] ] + :203.1.
Preparation of 2- ((3-bromo-2-chlorobenzyl) oxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde:
to the reaction flask was added 3-bromo-2-chlorobenzyl alcohol (2.6 g,1 eq), 2-chloro-4, 6-dimethoxypyrimidine (3.6 g,1.5 eq), acetonitrile (100 mL), potassium carbonate (4.8 g,3 eq). The temperature was raised to 70℃and the reaction was stirred for two hours. LCMS indicated completion of the reaction, stopped the reaction, quenched the system with water (700 mL), extracted with ethyl acetate (200 mL x 3), combined the organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and crude silica gel column chromatographed to give 2- ((3-bromo-2-chlorobenzyl) oxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (3.4 g, yield: 75%). MS [. Sup.M+1 ] +:389.0.
Preparation of 2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde:
to the reaction flask was added 4- (3- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) morpholine (1.28 g,1.1 eq), 2- ((3-bromo-2-chlorobenzyl) oxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (1.24 g,1 eq), potassium carbonate (1.32 g,3 eq), pd (dppf) Cl 2 (0.12 g,0.05 eq), toluene (50 mL), water (5 mL) and methanol (5 mL). Heating to 90 ℃ under the protection of nitrogen, stirring and reacting for 16 hours, LCMS (liquid Crystal ms) characterizing the reaction to be complete, stopping the reaction, adding water (350 mL) to quench the system, extracting ethyl acetate (100 mL of 3), combining organic phases and washing the organic phases with saturated common salt once, drying with anhydrous sodium sulfate, suction filtering, concentrating, and obtaining 2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl) by crude silica gel column chromatography ]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (0.78 g, yield: 45%). MS [. Sup.M+1 ]]+:542.2.
Preparation of (S) -1- ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) piperidine-2-carboxylic acid:
2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (80.2 mg,1 eq) and L-2-pipecolic acid (57.3 mg,3 eq) were dissolved in a mixed solvent of DMF (5 mL) and methanol (2 mL), 1 drop of acetic acid was added dropwise with stirring, and after reaction at room temperature for 30min, sodium cyanoborohydride (27.9 mg,3 eq) was added to the system. After stirring overnight at room temperature, LCMS indicated that the reaction was complete, the reaction was stopped, the system was quenched with water (50 mL), ethyl acetate (20 mL. 3) was extracted, the organic phases were combined and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and the crude product was purified by preparative liquid phase to give (S) -1- ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) piperidine-2-carboxylic acid (32 mg, yield: 30%). MS: [ M+1] +:655.2.
1 H NMR(400MHz,d 6 -DMSO)δ7.60(dd,J＝7.6,1.3Hz,1H),7.43(t,J＝7.6Hz,1H),7.18-7.27(m,2H),6.99(d,J＝8.2Hz,1H),6.70(d,J＝7.4Hz,1H),5.59–5.46(m,2H),4.11–3.99(m,2H),3.85(s,6H),3.69–3.62(m,2H),3.61–3.48(m,5H),2.96–2.82(m,2H),2.50–2.43(m,2H),2.40–2.30(m,4H),2.20–2.10(m,1H),1.96–1.82(m,5H),1.68–1.60(m,2H),1.49–1.34(m,3H)。
Example 7
((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The structural formula of the compound is as follows:
the synthesis method comprises the following steps:
preparation of ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline:
with reference to the synthetic method of reductive amination in example 6, 2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl) was synthesized]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde and L-proline to synthesize (2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl)]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :641.2.
1 H NMR(400MHz,d 6 -DMSO)δ7.60(d,J＝7.2Hz,1H),7.44(t,J＝7.6Hz,1H),7.31–7.18(m,2H),6.99(d,J＝8.0Hz,1H),6.70(d,J＝7.2Hz,1H),5.52(s,2H),4.10–4.00(m,2H),3.95–3.78(m,8H),3.60–3.50(m,4H),3.20–3.05(m,4H),2.50–2.43(m,2H),2.40–2.30(m,4H),2.04–1.96(m,1H),1.97–1.75(m,6H),1.73–1.55(m,1H)。
Example 8
((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-serine
The structural formula of the compound is as follows:
the synthesis method comprises the following steps:
preparation of ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-serine:
with reference to the synthetic method of reductive amination in example 6, 2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl) was synthesized]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde and L-serine were synthesized as ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl) ]-3-yl) methoxy) -4, 6-dimethoxy-azotemic acidPyridin-5-yl) methyl) -L-serine. MS [. Sup.M+1 ]] + :631.2.
1 H NMR(400MHz,d 6 -DMSO)δ7.60(dd,J＝7.6,1.3Hz,1H),7.44(t,J＝7.6Hz,1H),7.28–7.17(m,2H),6.99(d,J＝8.2Hz,1H),6.70(d,J＝7.4Hz,1H),5.59-5.47(m,2H),4.12–3.99(m,2H),3.85(s,6H),3.72–3.64(m,2H),3.61–3.47(m,2H),3.61–3.48(m,4H),2.94–2.82(m,1H),2.51–2.43(m,2H),2.42–2.31(m,4H),1.96–1.80(m,5H)。
Example 9
(2S, 4R) -1- ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -4-hydroxypyrrole-2-carboxylic acid
The structural formula of the compound is as follows:
the synthesis method comprises the following steps:
preparation of (2 s,4 r) -1- ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -4-hydroxypyrrole-2-carboxylic acid:
with reference to the synthetic method of reductive amination in example 6, 2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl) was synthesized]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde and (2S, 4R) -4-hydroxypyrrole-2-carboxylic acid to synthesize (2S, 4R) -1- ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenol)]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -4-hydroxypyrrole-2-carboxylic acid. MS [. Sup.M+1 ]] + :657.3.
1 H NMR(400MHz,d 6 -DMSO)δ7.60(d,J＝7.6Hz,1H),7.43(t,J＝7.6Hz,1H),7.29–7.16(m,2H),6.98(d,J＝8.2Hz,1H),6.70(d,J＝7.6Hz,1H),5.55–5.45(m,2H),4.17–3.99(m,3H),3.87(s,6H),3.75–3.65(m,2H),3.60–3.51(m,4H),3.24–3.10(m,2H),2.46(t,J＝7.1Hz,2H),2.40–2.26(m,5H),1.97–1.70(m,7H)。
Example 10
((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-alanine
The structural formula of the compound is as follows:
the synthesis method comprises the following steps:
preparation of ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-alanine:
With reference to the synthetic method of reductive amination in example 6, 2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl) was synthesized]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde and L-alanine to synthesize ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl)]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-alanine. MS [. Sup.M+1 ]] + :614.2.
1 H NMR(400MHz,d 6 -DMSO)δ7.60(d,J＝7.6Hz,1H),7.43(t,J＝7.6Hz,1H),7.29–7.17(m,2H),6.99(d,J＝8.2Hz,1H),6.70(d,J＝7.4Hz,1H),5.55–5.43(m,2H),4.17–3.98(m,2H),3.89(s,6H),3.69–3.62(m,2H),3.61–3.34(m,5H),2.51–2.43(m,2H),2.42–2.31(m,4H),1.94–1.82(m,5H),1.20(d,J＝6.6HZ,3H)。
Example 11
((2- ((2-bromo-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The structural formula of the compound is as follows:
the synthesis method comprises the following steps:
preparation of 1- (3- (3-bromo-2-methylphenoxy) propyl) -4-methylpiperazine:
to the reaction flask was added 3-bromo-2-methylphenol (2.82 g,1 eq), 1- (3-chloropropoxy) -4-methylpiperazine (2.91 g,1.1 eq), acetonitrile (60 mL), potassium carbonate (6.24 g,3 eq). The temperature was raised to 70℃and the reaction was stirred for two hours. LCMS indicated completion of the reaction, stopped the reaction, quenched the system with water (250 mL), extracted with ethyl acetate (100 mL x 3), combined the organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and the crude silica gel column chromatographed to give 1- (3- (3-bromo-2-methylphenoxy) propyl) -4-methylpiperazine (3.69 g, yield: 76%). MS [. Sup.M+1 ] +:327.1/329.1.
Preparation of 1-methyl-4- (3- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) piperazine:
1- (3- (3-bromo-2-methylphenoxy) propyl) -4-methylpiperazine (3.69 g,1 eq), pinacol biborate (5.73 g,2 eq), potassium acetate (2.22 g,2 eq), pd (dppf) Cl were added to the reaction flask 2 (0.42 g,0.05 eq) and 1, 4-dioxane (150 mL). The reaction was stirred for two hours with nitrogen protection at 90 ℃ and stirred for characterization of complete reaction, quenched by water (850 mL), extracted with ethyl acetate (200 mL x 3), combined organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated and crude silica gel column chromatographed to give 1-methyl-4- (3- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) piperazine (2.25 g, yield: 53%). MS [. Sup.M+1 ]]+:374.3/376.3.
Preparation of methyl-2-bromo-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propyl) - [1,1' -biphenyl ] -3-carboxylic acid ester:
1-methyl-4- (3- (2-methyl-3- (4, 5-tetramethyl)) was added to the reaction flask-1,3, 2-dioxaborane-2-yl) phenoxy) propyl piperazine (0.75 g,1.2 eq), methyl 2-bromo-3-iodobenzoate (0.56 g,1 eq), potassium carbonate (0.68 g,3 eq), pd (dppf) Cl 2 (0.06 g,0.05 eq), toluene (50 mL), water (5 mL) and methanol (5 mL). Heating to 90 ℃ under nitrogen protection, stirring and reacting for 16 hours, LCMS characterizing complete reaction, stopping reaction, adding water (400 mL) to quench the system, extracting ethyl acetate (100 mL. 3), combining organic phases and washing with saturated saline once, drying with anhydrous sodium sulfate, suction filtering, concentrating, obtaining methyl-2-bromo-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propyl) - [1,1' -biphenyl by crude silica gel column chromatography ]3-Formate (0.41 g, yield: 54%). MS [. Sup.M+1 ]]+:461.1/463.1
Preparation of (2-bromo-2 ' -methyl-3 ' - (3- (4-methylpiperidin-1-yl) propyl) - [1,1' -biphen-yl ] -3-yl) methanol:
to the reaction flask was added methyl-2-bromo-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propyl) - [1,1' -biphenyl]3-Formate (0.41 g,1 eq), freshly distilled tetrahydrofuran (50 mL), and LiAlH was added in portions at 5 ℃ 4 (67.4 mg,2 eq) stirred at room temperature for 30min, TLC indicated that the reaction was complete, the reaction system was slowly added dropwise to saturated NH 4 Quenching the reaction in Cl aqueous solution, extracting with ethyl acetate (100 mL. Times.3), combining the organic phases, washing with saturated saline once, drying with anhydrous sodium sulfate, suction filtering, concentrating, and subjecting the crude product to silica gel column chromatography to obtain (2-bromo-2 ' -methyl-3 ' - (3- (4-methylpiperidin-1-yl) propyl) - [1,1' -biphenyl)]-3-yl) methanol (0.25 g, yield: 65%). MS [. Sup.M+1 ]]+:433.1/435.1.
Preparation of 2- ((2-bromo-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propyl) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde:
to the reaction flask was added (2-bromo-2 ' -methyl-3 ' - (3- (4-methylpiperidin-1-yl) propyl) - [1,1' -biphenyl ] -3-yl) methanol (0.25 g,1 eq), 2-chloro-4, 6-dimethoxypyrimidine (0.17 g,1.5 eq), acetonitrile (30 mL), potassium carbonate (0.24 g,3 eq). The temperature was raised to 70℃and the reaction was stirred for two hours. LCMS indicated completion of the reaction, stopped the reaction, quenched the system with water (200 mL), extracted with ethyl acetate (50 mL x 3), combined the organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and the crude silica gel was chromatographed to give 2- ((2-bromo-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propyl) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (287.3 mg, yield: 83%). MS [ M+1] +:599.2/602.2
Preparation of ((2- ((2-bromo-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline:
2- ((2-bromo-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propyl) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (60.1 mg,1 eq) and L-proline (34.5 mg,3 eq) were dissolved in a mixed solvent of DMF (5 mL) and methanol (2 mL), 1 drop of acetic acid was added dropwise with stirring, and after reaction at room temperature for 30 minutes, sodium cyanoborohydride (20.9 mg,3 eq) was added to the system. Stirring overnight at room temperature, LCMS indicated the reaction was complete, stopped, quenched with water (50 mL), extracted with ethyl acetate (20 mL x 3), combined organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and the crude product purified by preparative liquid phase to give (2- ((2-bromo-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline (23.4 mg, yield: 33%). MS [. Sup.M+1 ] +:698.2/700.2.
1 H NMR(400MHz,d 6 -DMSO)δ7.66(d,J＝7.2Hz,1H),7.48(t,J＝7.6Hz,1H),7.31–7.22(m,2H),7.01(d,J＝8.0Hz,1H),6.68(d,J＝7.2Hz,1H),5.58(s,2H),4.10–4.03(m,2H),3.95(s,6H),3.37–3.33(m,2H),3.23–3.17(m,1H),2.74–2.63(m,1H),2.47–2.24(m,9H),2.17(s,3H),2.12–2.05(m,1H),1.97(s,3H),1.90–1.64(m,6H)。
Example 12
((2- ((2-bromo-3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2' -methyl- [1,1' -biphen yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The structural formula of the compound is as follows:
the synthesis method comprises the following steps:
with reference to the synthetic method of example 11, ((2- ((2-bromo-3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2' -methyl- [1,1' -biphenyl) is synthesized starting from tert-butyldimethylsilyl-protected 1- (3-chloropropyl) piperidin-4-ol]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :699.2/701.2.
1 H NMR(400MHz,d 6 -DMSO)δ7.62(d,J＝7.2Hz,1H),7.48(t,J＝7.6Hz,1H),7.15-7.26(m,2H),6.99(d,J＝8.0Hz,1H),6.70(d,J＝7.4Hz,1H),5.59-5.43(m,2H),4.12–4.06(m,2H),3.95(s,6H),3.68–3.57(m,2H),3.25–3.18(m,1H),2.72–2.64(m,1H),2.47–2.27(m,8H),2.09–2.04(m,1H),1.95(s,3H),1.84–1.64(m,9H)。
Example 13
((2- ((2-chloro-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The structural formula of the compound is as follows:
the synthesis method comprises the following steps:
preparation of 2- ((2-chloro-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propyl) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-methoxypyrimidine-5-carbaldehyde:
1-methyl-4- (3- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) piperazine (0.75 g,1.2 eq), 2- ((3-bromo-2-chlorobenzyl) oxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (0.65 g,1 eq), potassium carbonate (0.68 g,3 eq), pd (dppf)Cl 2 (0.06 g,0.05 eq), toluene (50 mL), water (5 mL) and methanol (5 mL). Heating to 90 ℃ under nitrogen protection, stirring for 16 hours, performing LCMS to characterize the reaction to be complete, stopping the reaction, adding water (400 mL) to quench the system, extracting ethyl acetate (100 mL of 3), combining organic phases, washing the organic phases with saturated saline once, drying the organic phases with anhydrous sodium sulfate, performing suction filtration, concentrating the organic phases, and performing silica gel column chromatography on the crude product to obtain 2- ((2-chloro-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propyl) - [1,1' -biphenyl) ]-3-yl) methoxy) -4, 6-methoxypyrimidine-5-carbaldehyde (0.57 g, yield: 51%). MS [. Sup.M+1 ]]+:555.2/557.2。
Preparation of ((2- ((2-chloro-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline:
2- ((2-chloro-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propyl) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-methoxypyrimidine-5-carbaldehyde (55.5 mg,1 eq) and L-proline (34.5 mg,3 eq) were dissolved in a mixed solvent of DMF (5 mL) and methanol (2 mL), 1 drop of acetic acid was added dropwise with stirring, and after reaction at room temperature for 30 minutes, sodium cyanoborohydride (20.9 mg,3 eq) was added to the system. Stirring overnight at room temperature, LCMS indicated the reaction was complete, quenched the reaction by adding water (50 mL), extracted with ethyl acetate (20 mL x 3), combined organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and the crude product purified by preparative liquid phase to give (2- ((2-bromo-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline (20.9 mg, yield: 32%). MS [. Sup.M+1 ] +:654.3/656.3.
1 H NMR(400MHz,d 6 -DMSO)δ7.61(d,J＝7.2Hz,1H),7.44(t,J＝7.6Hz,1H),7.28–7.20(m,2H),6.98(d,J＝8.0Hz,1H),6.70(d,J＝7.2Hz,1H),5.53(s,2H),4.08–4.03(m,2H),3.91(s,6H),3.33–3.31(m,2H),3.23–3.19(m,1H),2.70–2.63(m,1H),2.47–2.27(m,9H),2.14(s,3H),2.09–2.04(m,1H),1.91–1.64(m,9H)。
Example 14
((2- ((2-chloro-3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2' -methyl- [1,1' -biphen yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The synthesis method comprises the following steps:
preparation of 2- ((3 ' - (3- (4- ((tert-butyldimethylsilyl) oxy) piperidin-1-yl) propyl) -2-chloro-2 ' -methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde:
into a reaction flask was charged 4- ((tert-butyldimethyl) oxy) -1- (3- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) piperidine (1.07 g,1.3 eq), 2- ((3-bromo-2-chlorobenzyl) oxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (0.65 g,1 eq), potassium carbonate (0.68 g,3 eq), pd (dppf) Cl 2 (0.06 g,0.05 eq), toluene (50 mL), water (5 mL) and methanol (5 mL). Heating to 90 ℃ under nitrogen protection, stirring for 16 hours, performing LCMS to characterize the reaction to be complete, stopping the reaction, adding water (400 mL) to quench the system, extracting ethyl acetate (100 mL of 3), combining organic phases, washing the organic phases with saturated saline once, drying the organic phases with anhydrous sodium sulfate, suction filtering, concentrating, and performing crude silica gel column chromatography to obtain 2- ((3 ' - (3- (4- ((tert-butyldimethylsilyloxy) piperidin-1-yl) propyl) -2-chloro-2 ' -methyl- [1,1' -biphenol) phenyl]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (0.51 g, yield: 45%). MS [. Sup.M+1 ]]+:670.3.
Preparation of (S) -1- ((2- ((3 ' - (3- (4- ((tert-butyldimethylsilyl) oxy) piperidin-1-yl) propyl) -2-chloro-2 ' -methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) pyrrolidinyl-2-carboxylic acid:
2- ((3 ' - (3- (4- ((tert-butyldimethylsilyloxy) piperidin-1-yl) propyl) -2-chloro-2 ' -methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (67.0 mg,1 eq) and L-proline (34.5 mg,3 eq) were dissolved in a mixed solvent of DMF (5 mL) and methanol (2 mL), 1 drop of acetic acid was added dropwise with stirring, and after 30 minutes of reaction at room temperature, sodium cyanoborohydride (20.9 mg,3 eq) was added to the system. Stirring overnight at room temperature, LCMS indicated that the reaction was complete, the reaction was stopped, the system was quenched with water (50 mL), ethyl acetate (20 mL. 3) was extracted, the organic phases were combined and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated, and the crude product was purified by preparative liquid phase to give (S) -1- ((2- ((3 ' - (3- (4- ((tert-butyldimethylsilyloxy) oxy) piperidin-1-yl) propyl) -2-chloro-2 ' -methyl- [1,1' -bipyridyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) pyrrolidinyl-2-carboxylic acid (34.5 mg, yield: 35%). MS [. Sup.M+1 ] +:769.4.
Preparation of ((2- ((2-chloro-3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2' -methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline:
(S) -1- ((2- ((3 ' - (3- (4- ((tert-butyldimethylsilyl) oxy) piperidin-1-yl) propyl) -2-chloro-2 ' -methyl- [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) pyrrolidinyl-2-carboxylic acid (34.5 mg,1 eq) was dissolved in ultra-dry tetrahydrofuran (2 mL), and a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (TBAF, 1Min THF,0.13mL,3eq) was added dropwise to the system with stirring at room temperature. After stirring at room temperature for 2 hours, LCMS indicated complete reaction, stopped reaction, quenched with water (50 mL), extracted with ethyl acetate (20 mL x 3), combined organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and the crude product purified by preparative liquid phase to give ((2- ((2-chloro-3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2' -methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline (10.5 mg, yield: 35%). MS [. Sup.M+1 ] +:655.3.
1 H NMR(400MHz,d 6 -DMSO)δ7.61(d,J＝7.2Hz,1H),7.43(t,J＝7.6Hz,1H),7.27-7.16(m,2H),6.98(d,J＝8.0Hz,1H),6.68(d,J＝7.4Hz,1H),5.56-5.41(m,2H),4.09–4.03(m,2H),3.91(s,6H),3.68–3.57(m,2H),3.25–3.17(m,1H),2.72–2.64(m,1H),2.47–2.27(m,8H),2.09–2.04(m,1H),1.95(s,3H),1.84–1.64(m,9H)。
Example 15
((2- ((2-fluoro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The synthetic route is as follows:
((2- ((2-fluoro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
Preparation of 2- ((3-bromo-2-fluorobenzyl) oxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde:
to the reaction flask was added 3-bromo-2-fluorobenzyl alcohol (2.4 g,1 eq), 2-chloro-4, 6-dimethoxypyrimidine (3.6 g,1.5 eq), acetonitrile (100 mL), potassium carbonate (4.8 g,3 eq). The temperature was raised to 70℃and the reaction was stirred for two hours. LCMS indicated completion of the reaction, stopped the reaction, quenched the system with water (700 mL), extracted with ethyl acetate (200 mL x 3), combined the organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and crude silica gel column chromatographed to give 2- ((3-bromo-2-fluorobenzyl) oxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (3.0 g, yield: 70%). MS [. Sup.M+1 ] +:371.0/373.0.
Preparation of 2- ((2-fluoro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde:
4- (3- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) morpholine (1.28 g,1.1 eq), 2- ((3-bromo-2-fluorobenzyl) oxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (1.18 g,1 eq), potassium carbonate (1.32 g,3 eq), pd (dppf) Cl 2 (0.12 g,0.05 eq), toluene (50 mL), water (5 mL) and methanol (5 mL). Heating to 90 ℃ under the protection of nitrogen, stirring and reacting for 16 hours, LCMS (liquid Crystal ms) characterizing complete reaction, stopping reaction, adding water (350 mL) to quench the system, extracting ethyl acetate (100 mL x 3), combining organic phases and washing with saturated saline once, drying with anhydrous sodium sulfate, suction filtering, concentrating, and performing crude silica gel column chromatography to obtain 2- ((2-fluoro-2 '-methyl-3')(3-morpholinopropoxy) - [1,1' -biphenylyl ]]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (0.69 g, yield: 41%). MS [. Sup.M+1 ]]+:526.2.
Preparation of ((2- ((2-fluoro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline:
2- ((2-fluoro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (52.5 mg,1 eq) and L-proline (34.5 mg,3 eq) were dissolved in a mixed solvent of DMF (5 mL) and methanol (2 mL), 1 drop of acetic acid was added dropwise with stirring, and after reaction at room temperature for 30min, sodium cyanoborohydride (20.9 mg,3 eq) was added to the system. Stirring overnight at room temperature, LCMS indicated the reaction was complete, quenched the reaction by adding water (50 mL), extracted with ethyl acetate (20 mL x 3), combined organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and the crude product purified by preparative liquid phase to give (2- ((2-bromo-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline (26.8 mg, yield: 43%). MS [. Sup.M+1 ] +:625.3.
1 H NMR(400MHz,d 6 -DMSO)δ7.68(d,J＝7.2Hz,1H),7.43(t,J＝7.6Hz,1H),7.33–7.18(m,2H),7.01(d,J＝8.0Hz,1H),6.68(d,J＝7.2Hz,1H),5.59–5.52(m,2H),4.12–4.02(m,2H),3.95–3.78(m,8H),3.61–3.51(m,4H),3.23–3.05(m,4H),2.52–2.43(m,2H),2.40–2.20(m,4H),2.04–1.94(m,1H),1.97–1.63(m,7H)。
Example 16
((2- ((2-fluoro-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The synthetic route is as follows:
the synthetic method of reference example 15 was followed by reacting 1-methyl-4- (3- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) piperazine with 2- ((3-bromo-2-fluorobenzyl) oxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde to give 2- ((2-chloro-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propyl) - [1,1' -biphenyl ]]-3-yl) methoxy) -4, 6-methoxypyrimidine-5-carbaldehyde, then subjecting the aldehyde to reductive amination with L-proline to give ((2- ((2-fluoro-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propoxy) - [1,1' -biphenyl)]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :638.3.
1 H NMR(400MHz,d 6 -DMSO)δ7.65(d,J＝7.2Hz,1H),7.43(t,J＝7.6Hz,1H),7.28–7.21(m,2H),6.99(d,J＝8.0Hz,1H),6.69(d,J＝7.2Hz,1H),5.56–5.49(m,2H),4.08–4.03(m,2H),3.95(s,6H),3.30–3.28(m,2H),3.24–3.19(m,1H),2.74–2.63(m,1H),2.46–2.27(m,9H),2.15(s,3H),2.10–2.04(m,1H),1.91–1.64(m,9H)。
Example 17
((2- ((2-fluoro-3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2' -methyl- [1,1' -biphen yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The synthetic route is as follows:
with reference to the synthetic method of example 14, 4- ((tert-butyldimethylsilyl) oxy) -1- (3- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) piperidine was reacted with 2- ((3-bromo-2-fluorobenzyl) oxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde to give 2- ((3 ' - (3- (4- ((tert-butyldimethylsilyl) oxy) piperidin-1-yl) propyl) -2-fluoro-2 ' -methyl- [1,1' -biphenyl) ]-3-yl) methoxyThe method comprises the steps of (S) -1- ((2- ((3 ' - (3- (4- ((tert-butyldimethylsilyl) oxy) piperidin-1-yl) propyl) -2-fluoro-2 ' -methyl- [1,1' -biphenyl) by reductive amination of 4, 6-dimethoxy pyrimidine-5-carbaldehyde and L-proline]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl-methyl-pyrrolidinyl-2-carboxylic acid and finally removing the TBS protecting group by TBAF to give ((2- ((2-fluoro-3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2' -methyl- [1,1' -biphenyl)]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :639.3.
1 H NMR(400MHz,d 6 -DMSO)δ7.66(d,J＝7.2Hz,1H),7.47(t,J＝7.6Hz,1H),7.26-7.17(m,2H),7.01(d,J＝8.0Hz,1H),6.70(d,J＝7.4Hz,1H),5.55-5.48(m,2H),4.12–4.04(m,2H),3.95(s,6H),3.71–3.57(m,2H),3.25–3.14(m,1H),2.73–2.64(m,1H),2.48–2.26(m,8H),2.10–2.04(m,1H),1.95(s,3H),1.84–1.65(m,9H)。
Example 18:
((2- ((2-chloro-2 ' -methyl-3 ' - (2-morpholinoethoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The synthetic route is as follows:
preparation of 4- (2- (3-bromo-2-methylphenoxy) ethyl) morpholine:
to the reaction flask was added 3-bromo-2-methylphenol (1.87 g,1 eq), 4- (2-chloroethyl) morpholine (1.64 g,1.1 eq), acetonitrile (50 mL), potassium carbonate (4.14 g,3 eq). The temperature was raised to 70℃and the reaction was stirred for two hours. LCMS indicated completion of the reaction, stopped the reaction, quenched the system with water (150 mL), extracted with ethyl acetate (60 mL x 3), combined the organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and crude silica gel column chromatographed to give 4- (2- (3-bromo-2-methylphenoxy) ethyl) morpholine (2.16 g, yield: 72%). MS [. Sup.M+1 ] +:300.1.
Preparation of 4- (2- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) ethyl) morpholine:
4- (2- (3-bromo-2-methylphenoxy) ethyl) morpholine (2.16 g,1 eq), pinacol biborate (3.65 g,2 eq), potassium acetate (1.41 g,2 eq), pd (dppf) Cl were added to the reaction flask 2 (0.26 g,0.05 eq) and 1, 4-dioxane (60 mL). The reaction was stirred for two hours with nitrogen protection at 90 ℃ and stirred for characterization of complete reaction, quenched system with water (350 mL), extracted with ethyl acetate (100 mL x 3), combined organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated and crude silica gel column chromatographed to give 4- (2- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) ethyl) morpholine (1.27 g, yield: 51%). MS [. Sup.M+1 ]]+:348.2.
Preparation of 2- ((2-chloro-2 ' -methyl-3 ' - (2-morpholinoethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde:
to the reaction flask was added 4- (2- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) ethyl) morpholine (1.27 g,1.1 eq), 2- ((3-bromo-2-chlorobenzyl) oxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (1.29 g,1 eq), potassium carbonate (1.39 g,3 eq), pd (dppf) Cl 2 (0.12 g,0.05 eq), toluene (50 mL), water (5 mL) and methanol (5 mL). Heating to 90 ℃ under the protection of nitrogen, stirring and reacting for 16 hours, LCMS (liquid Crystal ms) characterizing complete reaction, stopping reaction, adding water (350 mL) to quench the system, extracting ethyl acetate (100 mL of 3), combining organic phases and washing the organic phases with saturated saline once, drying with anhydrous sodium sulfate, suction filtering, concentrating, and performing silica gel column chromatography on the crude product to obtain 2- ((2-chloro-2 ' -methyl-3 ' - (2-morpholinoethoxy) - [1,1' -biphenyl)]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (0.93 g, yield: 53%). MS [. Sup.M+1 ]]+:528.2.
Preparation of ((2- ((2-chloro-2 ' -methyl-3 ' - (2-morpholinoethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline:
with reference to the synthetic method of reductive amination in example 6, 2- ((2-chloro-2 ' -methyl-3 ' - (2-morpholinoethoxy) - [1,1' -biphenyl) was synthesized]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde and L-proline to synthesize ((2- ((2-chloro-2 ' -methyl-3 ' - (2-morpholinoethoxy) - [1,1' -biphenyl)]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :627.2.
1 H NMR(400MHz,d 6 -DMSO)δ7.61(dd,J＝7.6,1.5Hz,1H),7.44(t,J＝7.6Hz,1H),7.28–7.18(m,2H),7.02(d,J＝8.1Hz,1H),6.71(d,J＝7.4Hz,1H),5.61–5.46(m,2H),4.21–4.02(m,2H),3.95–3.81(m,8H),3.63–3.56(m,4H),3.27(dd,J＝9.1,5.3Hz,1H),3.19–3.10(m,1H),2.75(t,J＝5.7Hz,2H),2.66–2.57(m,1H),2.52–2.47(m,3H),2.12–2.00(m,1H),1.87(s,3H),1.84–1.55(m,4H)。
Example 19:
((2- ((2-chloro-2 ' -methyl-3 ' - (3-piperidin-1-yl) propoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The synthetic route is as follows:
preparation of 1- (3- (3-bromo-2-methylphenoxy) propyl) piperidine:
to the reaction flask was added 3-bromo-2-methylphenol (1.87 g,1 eq), 1- (3-chloropropyl) piperidine (1.78 g,1.1 eq), acetonitrile (50 mL), potassium carbonate (4.14 g,3 eq). The temperature was raised to 70℃and the reaction was stirred for two hours. LCMS indicated completion of the reaction, stopped the reaction, quenched the system with water (150 mL), extracted with ethyl acetate (60 mL x 3), combined the organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and crude silica gel column chromatographed to give 1- (3- (3-bromo-2-methylphenoxy) propyl) piperidine (2.15 g, yield: 69%). MS [. Sup.M+1 ] +:312.1.
Preparation of 1- (3- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) piperidine:
1- (3- (3-bromo-2-methylphenoxy) propyl) piperidine (2.15 g,1 eq), pinacol biborate (3.51 g,2 eq), potassium acetate (1.35 g,2 eq), pd (dppf) Cl 2 (0.26 g,0.05 eq) and 1, 4-dioxane (60 mL). The reaction was stirred for two hours with nitrogen protection at 90 ℃ to characterize the reaction completion by LCMS, stopped, quenched with water (350 mL), extracted with ethyl acetate (100 mL x 3), combined organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated and column chromatographed on crude silica gel to give 1- (3- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) piperidine (1.21 g, yield: 49%). MS [. Sup.M+1 ] ]+:360.2.
Preparation of 2- ((2-chloro-2 ' -methyl-3 ' - (3- (piperidin-1-yl) propyl) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde:
1- (3- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) piperidine (1.21 g,1.2 eq), 2- ((3-bromo-2-chlorobenzyl) oxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (1.09 g,1 eq), potassium carbonate (1.16 g,3 eq), pd (dppf) Cl 2 (0.11 g,0.05 eq), toluene (50 mL), water (5 mL) and methanol (5 mL). Heating to 90 ℃ under nitrogen protection, stirring and reacting for 16 hours, LCMS characterizing complete reaction, stopping reaction, adding water (350 mL) to quench the system, extracting ethyl acetate (100 mL. Times.3), combining organic phases and washing with saturated saline once, drying with anhydrous sodium sulfate, suction filtering, concentrating, and performing silica gel column chromatography on the crude product to obtain 2- ((2-chloro-2 ' -methyl-3 ' - (3- (piperidin-1-yl) propyl) - [1,1' -biphenol)]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (0.81 g, yield: 53%). MS [. Sup.M+1 ]]+:540.2.
Preparation of ((2- ((2-chloro-2 ' -methyl-3 ' - (3-piperidin-1-yl) propoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline:
with reference to the synthetic method of reductive amination in example 6, 2- ((2-chloro-2 ' -methyl-3 ' - (3- (piperidin-1-yl) propyl) - [1,1' -biphenyl) was synthesized ]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde and L-proline are synthesized to ((2- ((2-chloro-2 ' -methyl-3 ' - (3-piperidin-1-yl) propoxy) - [1,1' -biphenyl)]-3-yl) methoxy group-4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :639.2.
1 H NMR(400MHz,d 6 -DMSO)δ7.61(d,J＝7.2Hz,1H),7.43(t,J＝7.6Hz,1H),7.30–7.18(m,2H),6.98(d,J＝8.0Hz,1H),6.68(d,J＝7.3Hz,1H),5.55(s,2H),4.11–4.03(m,2H),3.95–3.79(m,8H),3.21–3.05(m,4H),2.46–2.39(m,2H),2.35–2.28(m,4H),2.04–1.96(m,1H),1.97–1.45(m,13H)。
Example 20:
((2- ((2-chloro-2 ' -methyl-3 ' - (2- (piperidin-1-yl) ethoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The synthetic route is as follows:
with reference to the synthesis of example 19, using 1- (2-chloroethyl) piperidine as a starting material, (2- ((2-chloro-2 ' -methyl-3 ' - (2- (piperidin-1-yl) ethoxy) - [1,1' -biphenyl) was synthesized according to the synthesis of example 19]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :624.3.
1 H NMR(400MHz,d 6 -DMSO)δ7.61(d,J＝7.2Hz,1H),7.43(t,J＝7.6Hz,1H),7.30–7.18(m,2H),6.98(d,J＝8.0Hz,1H),6.68(d,J＝7.3Hz,1H),5.55(s,2H),4.11–4.03(m,2H),3.95–3.79(m,8H),3.32–3.15(m,4H),2.48–2.39(m,2H),2.38–2.28(m,4H),2.04–1.96(m,1H),1.97–1.45(m,11H)。
Example 21:
((2- ((2-chloro-3 '- (3-piperidinepropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxy pyrimidin-5-yl) methyl) -L-proline
The synthetic route is as follows:
with reference to the synthesis of example 19, 3-bromo-phenol was used as starting material and ((2- ((2-chloro-3 '- (3-piperidylpropoxy) - [1,1' -biphenyl) was synthesized according to the synthesis of example 19]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ] ] + :627.3.
1 H-NMR(400MHz,d 6 -DMSO)δ7.62(dd,J＝7.6,1.8Hz,1H),7.45(t,J＝7.6Hz,1H),7.42–7.33(m,2H),7.00–6.91(m,3H),5.54(s,2H),4.05(t,J＝6.4Hz,2H),3.91(s,6H),3.87(s,2H),3.59–3.51(m,4H),3.33–3.25(m,2H),3.23–3.14(m,2H),2.64(dd,J＝17.2,9.8Hz,1H),2.42(t,J＝7.1Hz,2H),2.39–2.31(m,4H),2.14–2.00(m,1H),1.96–1.51(m,3H)。
Example 22:
((2- ((2-chloro-3 ' - (3- (dimethylamino) propoxy) -2' -methyl- [1,1' -biphen-yl ] -3-yl) methoxy-4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The synthetic route is as follows:
with reference to the synthesis of example 19, using 3-chloro-N, N-dimethylpropyl-1-amine as starting material, ((2- ((2-chloro-3 ' - (3- (dimethylamino) propoxy) -2' -methyl- [1,1' -biphenyl) was synthesized according to the synthesis of example 19]-3-yl) methoxy-4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :599.2.
1 H NMR(400MHz,d 6 -DMSO)δ7.60(d,J＝7.2Hz,1H),7.43(t,J＝7.6Hz,1H),7.29–7.18(m,2H),6.99(d,J＝8.0Hz,1H),6.70(d,J＝7.2Hz,1H),5.55(s,2H),4.11–4.03(m,2H),3.95(s,6H),3.91–3.79(m,2H),3.21–3.05(m,4H),2.46–2.39(m,4H),2.35–2.28(m,4H),2.04–1.96(m,1H),1.95–1.45(m,7H)。
Example 23:
((2- ((2, 2' -dichloro-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy-4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The synthetic route is as follows:
preparation of 4- (3- (3-bromo-2-chlorophenoxy) propyl) piperidine:
to the reaction flask was added 3-bromo-2-chlorophenol (2.07 g,1 eq), 1- (3-chloropropyl) piperidine (1.78 g,1.1 eq), acetonitrile (50 mL), potassium carbonate (4.14 g,3 eq). The temperature was raised to 70℃and the reaction was stirred for two hours. LCMS indicated completion of the reaction, stopped the reaction, quenched the system with water (150 mL), extracted with ethyl acetate (60 mL x 3), combined the organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and crude silica gel column chromatographed to give 4- (3- (3-bromo-2-chlorophenoxy) propyl) piperidine (2.31 g, yield: 69%). MS [. Sup.M+1 ] +:334.0.
Preparation of 4- (3- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) piperidine:
into a reaction flask was charged 4- (3- (3-bromo-2-chlorophenoxy) propyl) piperidine (2.31 g,1 eq), pinacol biborate (3.51 g,2 eq), potassium acetate (1.35 g,2 eq), pd (dppf) Cl 2 (0.26 g,0.05 eq) and 1, 4-dioxane (60 mL). Heating to 90deg.C under nitrogen protection, stirring for two hr, LCMS characterization, stopping the reaction, adding water (350 mL), quenching, extracting with ethyl acetate (100 mL×3), mixing the organic phases, and washing with saturated salineOnce, dry over anhydrous sodium sulfate, suction filtration, concentration, crude silica gel column chromatography gave 4- (3- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) piperidine (1.29 g, yield: 49%). MS [. Sup.M+1 ]]+:382.2.
Preparation of 2- ((2, 2' -chloro-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde:
to the reaction flask was added 4- (3- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) piperidine (1.29 g,1.2 eq), 2- ((3-bromo-2-chlorobenzyl) oxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (1.09 g,1 eq), potassium carbonate (1.16 g,3 eq), pd (dppf) Cl 2 (0.11 g,0.05 eq), toluene (50 mL), water (5 mL) and methanol (5 mL). Heating to 90 ℃ under the protection of nitrogen, stirring and reacting for 16 hours, LCMS (liquid Crystal ms) characterizing complete reaction, stopping reaction, adding water (350 mL) to quench the system, extracting ethyl acetate (100 mL of 3), combining organic phases and washing the organic phases with saturated saline once, drying with anhydrous sodium sulfate, suction filtering, concentrating, and performing silica gel column chromatography on the crude product to obtain 2- ((2, 2' -chloro-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl) ]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (1.00 g, yield: 53%). MS [. Sup.M+1 ]]+:562.2.
Preparation of ((2- ((2, 2' -dichloro-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy-4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline:
with reference to the synthetic method of reductive amination in example 6, 2- ((2, 2' -chloro-3 ' - (3-morpholinopropoxy) - [1,1' -biphenylyl) is reacted]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde and L-proline to synthesize ((2- ((2, 2' -dichloro-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl)]-3-yl) methoxy-4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :661.2.
1 H NMR(400MHz,d 6 -DMSO)δ7.63(dd,J＝7.6,1.4Hz,1H),7.46(t,J＝7.6Hz,1H),7.37(t,J＝8.0Hz,1H),7.30(dd,J＝7.6,1.5Hz,1H),7.23–7.19(m,1H),6.88(dd,J＝7.6,1.1Hz,1H),5.60–5.47(m,2H),4.22–4.09(m,2H),3.88(s,6H),3.80(d,J＝13.0Hz,1H),3.63(d,J＝12.8Hz,1H),3.60–3.50(m,4H),3.02–2.94(m,2H),2.46(t,J＝7.1Hz,2H),2.42–2.30(m,5H),2.01–1.86(m,3H),1.81–1.67(m,1H),1.66–1.56(m,2H)。
Example 24:
((2- ((2-chloro-2 ' -ethyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The synthetic route is as follows:
preparation of 4- (3- (3-bromo-2-ethylphenoxy) propyl) morpholine:
to the reaction flask was added 3-bromo-2-ethylphenol (2.01 g,1 eq), 1- (3-chloropropyl) piperidine (1.78 g,1.1 eq), acetonitrile (50 mL), potassium carbonate (4.14 g,3 eq). The temperature was raised to 70℃and the reaction was stirred for two hours. LCMS indicated completion of the reaction, stopped the reaction, quenched the system with water (150 mL), extracted with ethyl acetate (60 mL x 3), combined the organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and crude silica gel column chromatographed to give 4- (3- (3-bromo-2-ethylphenoxy) propyl) morpholine (2.36 g, yield: 72%). MS [. Sup.M+1 ] +:328.1.
Preparation of 4- (3- (2-ethyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) morpholine:
4- (3- (3-bromo-2-ethylphenoxy) propyl) morpholine (2.36 g,1 eq), pinacol biborate (3.65 g,2 eq), potassium acetate (1.41 g,2 eq), pd (dppf) Cl were added to the reaction flask 2 (0.26 g,0.05 eq) and 1, 4-dioxane (60 mL). The reaction was stirred for two hours with nitrogen protection at 90 ℃ and stirred for characterization of complete reaction, quenched by water (350 mL), extracted with ethyl acetate (100 mL x 3), combined organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated and column chromatographed on crude silica gel to give 4- (3- (2-ethyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) morpholine (1.43 g, 53% yield). MS [. M + ]1]+:376.2.
Preparation of 2- ((2-chloro-2 ' -ethyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde:
4- (3- (2-Ethyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) morpholine (1.43 g,1.2 eq), 2- ((3-bromo-2-chlorobenzyl) oxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (1.23 g,1 eq), potassium carbonate (1.31 g,3 eq), pd (dppf) Cl 2 (0.12 g,0.05 eq), toluene (50 mL), water (5 mL) and methanol (5 mL). Heating to 90 ℃ under the protection of nitrogen, stirring and reacting for 16 hours, LCMS (liquid Crystal ms) characterizing the reaction to be complete, stopping the reaction, adding water (350 mL) to quench the system, extracting ethyl acetate (100 mL of 3), combining organic phases and washing the organic phases with saturated saline once, drying with anhydrous sodium sulfate, suction filtering, concentrating, and obtaining 2- ((2-chloro-2 ' -ethyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl) by crude silica gel column chromatography]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde (0.87 g, yield: 49%). MS [. Sup.M+1 ]]+:556.2.
Preparation of ((2- ((2-chloro-2 ' -ethyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline:
with reference to the reductive amination synthesis of example 6, 2- ((2-chloro-2 ' -ethyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenylyl) was synthesized]-3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde and L-proline to synthesize ((2- ((2-chloro-2 ' -ethyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl)]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :655.3.
1 H NMR(400MHz,d 6 -DMSO)δ7.61(d,J＝7.2Hz,1H),7.43(t,J＝7.6Hz,1H),7.28–7.18(m,2H),6.98(d,J＝8.0Hz,1H),6.68(d,J＝7.2Hz,1H),5.52(s,2H),4.12–4.02(m,2H),3.95(s,6H),3.91–3.78(m,2H),3.61–3.50(m,4H),3.23–3.08(m,4H),2.51–2.43(m,2H),2.40–2.30(m,4H),2.04–1.97(m,3H),1.95–1.55(m,4H),1.35–1.25(m,3H)。
Example 25:
((2- ((2-chloro-2 ' -isopropyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The synthetic route is as follows:
with reference to the synthesis of example 23, 3-bromo-2-isopropyl-phenol was used as starting material, and ((2- ((2-chloro-2 ' -isopropyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl) was synthesized according to the synthesis of example 23]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :669.3.
1 H NMR(400MHz,d 6 -DMSO)δ7.60(d,J＝7.2Hz,1H),7.44(t,J＝7.6Hz,1H),7.30–7.17(m,2H),6.99(d,J＝7.6Hz,1H),6.70(d,J＝7.2Hz,1H),5.60–5.49(m,2H),4.10–4.02(m,2H),3.95(s,6H),3.91–3.78(m,2H),3.61–3.50(m,4H),3.23–3.08(m,4H),2.51–2.43(m,2H),2.40–2.30(m,4H),2.04–1.97(m,2H),1.95–1.55(m,4H),1.35–1.24(m,6H)。
Example 26:
((2- ((2-chloro-2 ' -cyclopropyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The synthetic route is as follows:
with reference to the synthesis of example 23, 3-bromo-2-cyclopropyl-phenol was used as starting material, and ((2- ((2-chloro-2 ' -cyclopropyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl) was synthesized according to the synthesis of example 23]-3-yl)Methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :667.3.
1 H NMR(400MHz,d 6 -DMSO)δ7.60(d,J＝7.2Hz,1H),7.44(t,J＝7.6Hz,1H),7.30–7.17(m,2H),6.99(d,J＝7.6Hz,1H),6.70(d,J＝7.2Hz,1H),5.60–5.49(m,2H),4.10–4.02(m,2H),3.95–3.78(m,8H),3.60–3.50(m,4H),3.23–3.08(m,4H),2.51–2.43(m,2H),2.40–2.30(m,4H),2.04–1.97(m,1H),1.95–1.55(m,5H),1.24–0.99(m,4H)。
Example 27:
((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4- ((3-cyanobenzyl) oxy) -6-methoxypyrimidin-5-yl) methyl) -L-proline
The synthetic route is as follows:
preparation of 3- (((2-chloro-6-methoxypyrimidin-4-yl) oxy) methyl) benzonitrile:
sodium hydrogen (1.21 g,1.5eq,60% purity) was added to a solution of 3-hydroxymethylbenzonitrile (2.66 g,1 eq) in DMF (50 mL) with stirring at 0deg.C. After stirring at 0 ℃ for 0.5 hours, a DMF solution of 2, 4-dichloro-6-methoxypyrimidine (3.58 g,1 eq) was added dropwise to the reaction system, the reaction was warmed to room temperature under nitrogen protection, LCMS was stirred for two hours to characterize the reaction to completion, the reaction was stopped, the system was quenched with water (500 mL), ethyl acetate (200 mL x 3) was extracted, the organic phases were combined and washed once with saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated, and crude silica gel column chromatography afforded 3- (((2-chloro-6-methoxypyrimidin-4-yl) oxy) methyl) benzonitrile (2.97 g, yield: 54%). MS [. Sup.M+1 ] +:276.0.
Preparation of 3- (((2- ((3-bromo-2-chlorobenzyloxy) oxy) -6-methoxypyrimidin-4-yl) oxy) methyl) benzonitrile:
to the reaction flask was added 3- (((2-chloro-6-methoxypyrimidin-4-yl) oxy) methyl) benzonitrile (2.97 g,1 eq), 3-bromo-2-chlorobenzyl alcohol (2.62 g,1.1 eq), acetonitrile (50 mL), potassium carbonate (4.46 g,3 eq). The temperature was raised to 70℃and the reaction was stirred for two hours. LCMS indicated completion of the reaction, stopped the reaction, quenched the system with water (250 mL), extracted with ethyl acetate (90 mL x 3), combined the organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and the crude silica gel column chromatographed to give 3- (((2- ((3-bromo-2-chlorobenzyloxy) oxy) -6-methoxypyrimidin-4-yl) oxy) methyl) benzonitrile (1.78 g, yield: 36%). MS [. Sup.M+1 ] +:460.0.
Preparation of 3- (((2- ((3-bromo-2-chlorobenzyloxy) oxy) -5-formyl-6-methoxypyrimidin-4-yl) oxy) methyl) benzonitrile:
phosphorus oxychloride (8.89 g,15 eq) was added dropwise to a reaction flask containing DMF (4.23 g,15 eq) in an ice-water bath, stirred for 30min in an ice-water bath, a solution of 3- (((2- ((3-bromo-2-chlorobenzyloxy) oxy) -6-methoxypyrimidin-4-yl) oxy) methyl) benzonitrile (1.78 g,1 eq) in DMF (20 mL) was added dropwise to the reaction system, and the reaction was stirred for two hours at 50 ℃. LCMS indicated complete reaction and stopped the reaction. The reaction was added dropwise to an ice-water bath under stirring, neutralized with sodium bicarbonate (ph=7), filtered with suction, washed twice with water, and the dried crude product was purified by silica gel column chromatography to give 3- (((2- ((3-bromo-2-chlorobenzyloxy) oxy) -5-formyl-6-methoxypyrimidin-4-yl) oxy) methyl) benzonitrile (0.87 g, yield 46%). MS [. Sup.M+1 ] ] + :488.0.
Preparation of 3- (((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -5-formyl-6-methoxypyrimidin-4-yl) oxy) methyl) benzonitrile:
to the reaction flask was added 4- (3- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy) propyl) piperidine (0.96 g,1.5 eq), 3- (((2- ((3-bromo-2-chlorobenzyloxy) oxy) -5-formyl-6-methoxypyrimidin-4-yl) oxy) methyl) benzonitrile (0.87 g,1 eq), potassium carbonate (0.74 g,3 eq), pd (dppf) Cl 2 (0.13 g,0.1 eq), toluene (50 mL), water (5 mL) and methanol (5 mL). Heating to 90deg.C under nitrogen protection, stirring for 16 hr, LCMS characterization, stopping reaction, adding water (350 mL), quenching system, extracting with ethyl acetate (100 mL×3), mixing organic phases, and adding saturated saltWashing with water once, drying with anhydrous sodium sulfate, suction filtering, concentrating, and subjecting the crude product to silica gel column chromatography to obtain 3- (((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl) group)]-3-yl) methoxy) -5-formyl-6-methoxypyrimidin-4-yl) methyl benzonitrile (0.57 g, yield: 50%). MS [. Sup.M+1 ]]+:643.2.
Preparation of ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4- ((3-cyanobenzyl) oxy) -6-methoxypyrimidin-5-yl) methyl) -L-proline:
With reference to the reductive amination synthesis of example 6, 3- (((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl) is synthesized]-3-yl-methoxy) -5-formyl-6-methoxypyrimidin-4-yl) oxy) methyl) benzonitrile and L-proline to synthesize ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl)]-3-yl) methoxy) -4- ((3-cyanobenzyl) oxy) -6-methoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :743.3.
1 H NMR(400MHz,d 6 -DMSO)δ8.19(s,1H),8.03–7.99(m,1H),7.69–7.60(m,2H),7.53–7.43(m,2H),7.32–7.20(m,2H),7.00(d,J＝8.0Hz,1H),6.68(d,J＝7.2Hz,1H),5.60–5.40(m,4H),4.08–4.00(m,2H),3.95–3.78(m,5H),3.60–3.50(m,4H),3.20–3.05(m,4H),2.50–2.43(m,2H),2.40–2.30(m,4H),2.04–1.96(m,1H),1.97–1.75(m,6H),1.73–1.65(m,1H)。
Example 28:
((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4-methoxy-6- (pyridin-3-ylmethoxy) pyrimidin-5-yl) methyl) -L-proline
The synthetic route is as follows:
with reference to the synthesis method of example 26, 3-hydroxymethylpyridine was used asStarting material synthesis ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl)]-3-yl) methoxy) -4-methoxy-6- (pyridin-3-ylmethoxy) pyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :718.3.
1 H NMR(400MHz,d 6 -DMSO)δ8.78(d,J＝1.6Hz,1H),8.58(dd,J＝4.8,1.6Hz,1H),7.98(d,J＝8.0Hz,1H),7.69–7.60(m,2H),7.48–7.43(m,1H),7.32–7.20(m,2H),7.00(d,J＝8.0Hz,1H),6.68(d,J＝7.2Hz,1H),5.60–5.40(m,4H),4.12–4.04(m,2H),4.01–3.78(m,5H),3.60–3.50(m,4H),3.20–3.05(m,4H),2.50–2.43(m,2H),2.40–2.30(m,4H),2.04–1.96(m,1H),1.97–1.55(m,7H)。
Example 29
(2S, 4R) -1- ((2- ((2-bromo- [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -4-hydroxypyrrole-2-carboxylic acid
The synthetic route is as follows:
preparation of (2 s,4 r) -1- ((2- ((2-bromo- [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -4-hydroxypyrrole-2-carboxylic acid:
2- ((2-bromo- [1,1 '-biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidine-5-carbaldehyde was reacted with L-hydroxyproline to synthesize (2 s,4 r) -1- ((2- ((2-bromo- [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -4-hydroxypyrrole-2-carboxylic acid.
MS:[M+1] + :544.1/546.1。
1 H NMR(400MHz,d 6 -DMSO)δ7.60(dd,J＝7.6,1.6Hz,1H),7.54-7.31(m,7H),5.53(s,2H),4.94(s,1H),4.22-4.11(m,1H),3.96-3.74(m,8H),3.37(t,J＝8.0Hz,2H),3.28-3.24(m,1H),1.91-1.80(m,2H)。
Example 30:
((2- ((2-chloro-2 ' -butyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline
The synthetic route is as follows:
with reference to the synthesis of example 23, 3-bromo-2-butyl-phenol was used as starting material, and ((2- ((2-chloro-2 ' -butyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl) was synthesized according to the synthesis of example 23]-3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline. MS [. Sup.M+1 ]] + :683.3.
1 H NMR(400MHz,d 6 -DMSO)δ7.61(d,J＝7.2Hz,1H),7.45(t,J＝7.6Hz,1H),7.31–7.18(m,2H),7.00(d,J＝7.6Hz,1H),6.71(d,J＝7.2Hz,1H),5.62–5.50(m,2H),4.12–4.05(m,2H),3.96(s,6H),3.92–3.80(m,2H),3.61–3.50(m,4H),3.24–3.11(m,4H),2.61–2.47(m,3H),2.40–2.30(m,4H),2.07–1.55(m,8H),1.37–1.24(m,2H),0.91–0.85(m,3H)。
Detecting the inhibitory effect of a compound on the binding of PD-1/PD-L1 proteins to each other
In vitro kinase level was measured using the PD1/PD-L1 binding assay kits assay kit from Cisbio.
Screening principle and method of PD-1/PD-L1 small molecule inhibitor:
1) Principle of: PD-L1 protein has Tag1 (Tag 1 is a common Tag of purified protein), PD-1 protein has Tag2 (Tag 2 is a common Tag of purified protein), and anti-Tag1 antibody marked by Eu and anti-Tag2 antibody marked by XL665 are respectively combined with the two Tag proteins. When excited by a laser, energy is transferred from the donor Eu to the acceptor XL665, causing the XL665 to emit light. After addition of the inhibitor, the binding of PD-1 and PD-L1 is blocked, so that Eu is far away from XL665, which will affect the fluorescence energy transfer, and the signal will be reduced. The blocking of the binding of the inhibitor to PD-L1 and PD-1 is judged by the change in the intensity of the signal.
2) The method comprises the following steps: specific experimental protocols can be found in the PD1/PD-L1 binding kit instructions 62ICP01PEG and 64ICP01PEH from Cisbio. The simple description is as follows: taking a new 384-well ELISA plate, adding 2 mu L of diluent or target compounds with different concentrations diluted by the diluent into each well, then adding 4 mu L of PD-1 protein and 4 mu L of PD-L1 protein, and incubating for 15min at normal temperature. To each well, 10. Mu.L of a mixture of anti-Tag1-Eu and anti-Tag2-XL665 was added, and after incubation at room temperature for 2 hours, fluorescence signals of 620nM and 665nM were detected with an ELISA reader. The calculation formula of the signal proportion is as follows: (665 nM signal value)/(620 nM signal value). Times.10 4 . Each compound adopts 8-10 concentration gradients, three compound holes are arranged at each concentration, and the obtained result is subjected to nonlinear fitting by GraphPad Prism software to obtain the IC50 value of the compound.
TABLE 1 IC50 values for the compounds of the invention
Note that: letter A represents an IC50 of less than 10nM;
letter B represents an IC50 between 10-100 nM;
letter C represents an IC50 of greater than 100nM.
The results in Table 1 show that the compounds of the present invention are effective in inhibiting the binding of PD-1/PD-L1 at various concentrations and are therefore useful in the treatment of diseases resulting from the binding of PD-1/PD-L1.
The invention provides a novel PD-1/PD-L1 small molecule inhibitor, and a pharmaceutical activity test result shows that the compound has excellent activity and is hopeful to become the novel PD-1/PD-L1 small molecule inhibitor.
In addition, fromAs can be seen in Table 1, relative to R 1 And R is R 2 Compounds of the invention which are long-chain groups, the compounds of the invention being based on R 1 And R is R 2 Forms a cyclic structure (or is a short chain structure) together with the nitrogen atom, limits partial conformation, has better directionality, has stronger binding force with PD-L1, and shows higher activity.
Claims (7)
1. A compound, characterized in that it is selected from any one of the following compounds:
(S) -1- ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) piperidine-2-carboxylic acid;
((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline;
((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-serine;
(2 s,4 r) -1- ((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -4-hydroxypyrrole-2-carboxylic acid;
((2- ((2-bromo-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-alanine;
(S) -1- ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) piperidine-2-carboxylic acid;
((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline;
((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-serine;
(2 s,4 r) -1- ((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -4-hydroxypyrrole-2-carboxylic acid;
((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-alanine;
((2- ((2-chloro-2 ' -methyl-3 ' - (3- (4-methylpiperazin-1-yl) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline;
((2- ((2-chloro-3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2' -methyl- [1,1' -biphen yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline;
((2- ((2-chloro-2 ' -methyl-3 ' - (3-piperidin-1-yl) propoxy) - [1,1' -biphen-yl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline;
((2- ((2, 2' -dichloro-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy-4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline;
((2- ((2-chloro-2 ' -ethyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline;
((2- ((2-chloro-2 ' -isopropyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline;
((2- ((2-chloro-2 ' -cyclopropyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4, 6-dimethoxypyrimidin-5-yl) methyl) -L-proline;
((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4- ((3-cyanobenzyl) oxy) -6-methoxypyrimidin-5-yl) methyl) -L-proline;
((2- ((2-chloro-2 ' -methyl-3 ' - (3-morpholinopropoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -4-methoxy-6- (pyridin-3-ylmethoxy) pyrimidin-5-yl) methyl) -L-proline.
2. A method of preparing the compound of claim 1, wherein the compound is the compound of claim 1; the method comprises the following reaction routes:
the method comprises the following steps:
(1) Dissolving SM1 and SM2 in a solvent 1, adding an alkaline reagent, and reacting at a temperature ranging from room temperature to 70 ℃ to obtain a compound C01;
(2) Dissolving a compound C01 and pinacol diboronate in a solvent 2, adding an alkaline reagent and a palladium metal catalyst, and reacting at a temperature range of 70-120 ℃ to obtain a compound C02;
(3) Dissolving a compound C02 and SM3 in a solvent 3, adding an alkaline reagent and palladium metal, and reacting the catalyst at a temperature of between 70 and 120 ℃ to obtain a compound C03;
(4) C03 and SM4 are dissolved in a solvent 4 to carry out reductive amination reaction to obtain a compound of the formula I;
in step (1), the solvent 1 is selected from one or more of tetrahydrofuran, DMSO, DMF, acetonitrile; the alkaline reagent is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide and sodium tert-butoxide;
in the step (2), the solvent 2 is selected from one or more of 1, 4-dioxane, toluene and benzene; the alkaline reagent is selected from one or more of potassium acetate, cesium carbonate, potassium carbonate and sodium carbonate; the palladium metal catalyst is selected from Pd (PPh) 3 ) 4 、Pd(dppf)Cl 2 Palladium acetate, pd 2 (dba) 3 One or more of the following;
in step (3), the solvent 3 is selected from one or more of 1, 4-dioxane, toluene, methanol, and water; the alkaline reagent is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide and sodium tert-butoxide; the palladium metal catalyst is selected from Pd (PPh) 3 ) 4 、Pd(dppf)Cl 2 Palladium acetate, pd 2 (dba) 3 One or more of the following;
in step (4), the solvent 4 is selected from tetrahydrofuran, DMSO, DMF, acetonitrileOne or more of methanol, dichloromethane; the reducing agent for the reductive amination reaction is selected from NaBH 3 CN, sodium triacetoxyborohydride, sodium borohydride.
3. A pharmaceutical composition comprising the compound or a pharmaceutically salt of the compound of claim 1 as an active ingredient, and a pharmaceutically acceptable carrier.
4. A pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is in the form of an oral formulation or an injectable formulation.
5. Use of a compound or a pharmaceutically salt of a compound as claimed in claim 1 or a pharmaceutical composition as claimed in claim 3 in the manufacture of a medicament for the treatment of a disease associated with the PD-1/PD-L1 signaling pathway.
6. The use according to claim 5, wherein the disease is cancer or an immune disease.
7. The use of claim 6, wherein the cancer is selected from skin cancer, lung cancer, hematological tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, head and neck cancer; the immune disease is selected from myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus and dermatitis.
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| CN108368090A (en) * | 2015-10-15 | 2018-08-03 | 百时美施贵宝公司 | Compounds as Immunomodulators |
| CN108698995A (en) * | 2016-01-08 | 2018-10-23 | 格罗宁根大学 | The inhibitor of PD-1/PD-L1 albumen/protein-interacting |
| WO2019174533A1 (en) * | 2018-03-13 | 2019-09-19 | 广东东阳光药业有限公司 | Small molecule pd-1/pd-l1 inhibitor and use thereof in drugs |
| WO2019191624A1 (en) * | 2018-03-29 | 2019-10-03 | Arbutus Biopharma, Inc. | Substituted 1,1'-biphenyl compounds, analogues thereof, and methods using same |
| CN111386265A (en) * | 2017-11-06 | 2020-07-07 | 朱比连特普罗德尔有限责任公司 | Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation |
| WO2020156323A1 (en) * | 2019-01-31 | 2020-08-06 | Betta Pharmaceuticals Co., Ltd | Immunomodulators, compositions and methods thereof |
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| CN108368090A (en) * | 2015-10-15 | 2018-08-03 | 百时美施贵宝公司 | Compounds as Immunomodulators |
| CN108698995A (en) * | 2016-01-08 | 2018-10-23 | 格罗宁根大学 | The inhibitor of PD-1/PD-L1 albumen/protein-interacting |
| CN111386265A (en) * | 2017-11-06 | 2020-07-07 | 朱比连特普罗德尔有限责任公司 | Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation |
| WO2019174533A1 (en) * | 2018-03-13 | 2019-09-19 | 广东东阳光药业有限公司 | Small molecule pd-1/pd-l1 inhibitor and use thereof in drugs |
| WO2019191624A1 (en) * | 2018-03-29 | 2019-10-03 | Arbutus Biopharma, Inc. | Substituted 1,1'-biphenyl compounds, analogues thereof, and methods using same |
| WO2020156323A1 (en) * | 2019-01-31 | 2020-08-06 | Betta Pharmaceuticals Co., Ltd | Immunomodulators, compositions and methods thereof |
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