CN114539235A - Biphenyl compound, preparation method and application thereof - Google Patents
Biphenyl compound, preparation method and application thereof Download PDFInfo
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- CN114539235A CN114539235A CN202111362140.XA CN202111362140A CN114539235A CN 114539235 A CN114539235 A CN 114539235A CN 202111362140 A CN202111362140 A CN 202111362140A CN 114539235 A CN114539235 A CN 114539235A
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- substituted
- methyl
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- -1 Biphenyl compound Chemical class 0.000 title claims abstract description 105
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title abstract description 19
- 239000004305 biphenyl Substances 0.000 title abstract description 16
- 235000010290 biphenyl Nutrition 0.000 title abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 176
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 102000008096 B7-H1 Antigen Human genes 0.000 claims abstract description 18
- 108010074708 B7-H1 Antigen Proteins 0.000 claims abstract description 18
- 230000003287 optical effect Effects 0.000 claims abstract description 15
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 7
- 230000002924 anti-infective effect Effects 0.000 claims abstract description 4
- 239000003112 inhibitor Substances 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 166
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 55
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 150000002431 hydrogen Chemical group 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 239000000651 prodrug Substances 0.000 claims description 15
- 229940002612 prodrug Drugs 0.000 claims description 15
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 229910052805 deuterium Inorganic materials 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 239000002207 metabolite Substances 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- 230000002503 metabolic effect Effects 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000002243 precursor Substances 0.000 claims description 9
- 239000012453 solvate Substances 0.000 claims description 9
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 8
- 125000004185 ester group Chemical group 0.000 claims description 7
- 150000001721 carbon Chemical group 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 125000004442 acylamino group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 3
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 claims description 3
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 3
- 230000019491 signal transduction Effects 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 230000000118 anti-neoplastic effect Effects 0.000 claims 1
- 229940034982 antineoplastic agent Drugs 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 20
- 230000000694 effects Effects 0.000 abstract description 14
- 238000002474 experimental method Methods 0.000 abstract description 11
- 230000000259 anti-tumor effect Effects 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 230000000903 blocking effect Effects 0.000 abstract description 3
- 239000012271 PD-L1 inhibitor Substances 0.000 abstract description 2
- 229940121656 pd-l1 inhibitor Drugs 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 description 178
- 238000005160 1H NMR spectroscopy Methods 0.000 description 104
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 104
- 230000015572 biosynthetic process Effects 0.000 description 103
- 238000003786 synthesis reaction Methods 0.000 description 103
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 description 68
- JAEIBKXSIXOLOL-UHFFFAOYSA-N pyrrolidin-1-ium-3-carboxylate Chemical compound OC(=O)C1CCNC1 JAEIBKXSIXOLOL-UHFFFAOYSA-N 0.000 description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 49
- 238000006243 chemical reaction Methods 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 206010028980 Neoplasm Diseases 0.000 description 23
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 20
- 125000005605 benzo group Chemical group 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 18
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 description 10
- 108700008625 Reporter Genes Proteins 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000004576 sand Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 7
- 210000001744 T-lymphocyte Anatomy 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- 229940126657 Compound 17 Drugs 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
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- 241000699670 Mus sp. Species 0.000 description 4
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- 238000003556 assay Methods 0.000 description 4
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- GFZWHAAOIVMHOI-UHFFFAOYSA-N azetidine-3-carboxylic acid Chemical compound OC(=O)C1CNC1 GFZWHAAOIVMHOI-UHFFFAOYSA-N 0.000 description 4
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- 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 description 3
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- 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
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Abstract
The invention discloses biphenyl compounds serving as PD-L1 inhibitors, pharmaceutically acceptable salts, racemates, optical isomers or solvent compounds thereof, and a preparation method and application thereof, wherein the biphenyl compounds are shown as a general formula I:
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to biphenyl compounds serving as PD-L1 inhibitors, a preparation method and application thereof, in particular to compounds shown in a general formula I or isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, a preparation method of the compounds, pharmaceutical compositions containing the compounds, and application of the compounds or the compositions in treating cancers or infectious diseases.
Background
Malignant tumors are a serious health and life threatening disease. At present, the tumor treatment modes include surgery, radiotherapy, chemotherapy, targeted therapy and the like. The tumor immunotherapy refers to a therapeutic method for enhancing the anti-tumor immune effect by stimulating the immune system of the body, thereby inhibiting and killing tumor cells. The research of immunotherapy has been in the history of nearly one hundred years, and along with comprehensive development and cross infiltration of oncology, immunology and molecular biology, immunotherapy achieves multiple achievements and brings new hopes for tumor therapy.
Programmed Cell Death-1 (PD-1) and its ligand PD-Ll (B7. H1) belong to the CD28/B7 superfamily. PD-1 is mainly expressed on the membrane surface of T Cells, B Cells and natural Killer Cells (NK Cells), and PD-L1 is mainly expressed on the membrane surface of mature CD4T Cells, CD8T Cells, B Cells, monocytes, Dendritic Cells (DCs), macrophages and other hematopoietic Cells and some non-hematopoietic Cells, such as endothelial Cells, pancreatic islet Cells, mast Cells and the like. Wherein PD-L1 is highly expressed in various tumors, such as lung cancer, gastric cancer, multiple myeloma, melanoma, breast cancer and the like. The expression of PD-L1 on the surface of the tumor cell interacts with the ligand on the surface of the T cell, can induce the apoptosis of the T cell or reduce the reactivity of the T cell, thereby inhibiting the tumor immune response and leading the tumor cell to escape from immune attack. Therefore, the antagonist for blocking the PD1/PD-L1 signal channel can promote the activation of T cells, reverse the tumor immune microenvironment and enhance the endogenous anti-tumor immune effect. The targeted PD-1/PD-L1 inhibitor has wide application prospect in the field of tumor immunotherapy. Currently, anti-PD-1/PD-L1 antibody therapy has been shown to have a superior effect clinically, however, biological macromolecules also have some disadvantages, such as immunogenicity and limitations on the route of administration. Therefore, there is still a need to develop targeted PD-1/PD-L1 inhibitors with better efficacy. The inventor of the invention finds that a small molecule drug can specifically regulate and/or modulate the transduction of PD-L1 and related protein kinase, thereby being used for treating diseases related to PD-1/PD-L1.
Disclosure of Invention
The invention aims to provide a compound shown as a general formula I or a pharmaceutically acceptable salt, racemate, optical isomer, metabolite, metabolic precursor, prodrug or solvent compound thereof,
R1independently hydrogen, deuterium, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R2independently hydrogen, deuterium, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R3independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R4independently of each otherIs hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R5independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R6independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R7independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl;
m is 1 or 2;
n is 1 or 2;
X1independently an oxygen atom, a sulfur atom, a nitrogen atom;
X2independently carbon atom, nitrogen atom;
X3independently an oxygen atom, a carbon atom, a nitrogen atom;
X4independently carbon atom, nitrogen atom;
each R1Wherein the substituent of the substituted alkyl or the substituted alkoxy is selected from halogen, C1-C4 alkyl, hydroxyl, carboxyl, amino, or amino, or amino, or amino, amino,
Benzyl, benzyl with cyano substituent, C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 amido; the substituent of the substituted hydroxyl or the substituted amino is selected from C1-C4 alkyl, benzyl of cyano substituent, C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 amido; when the number of the substituents is plural, the substituents may be the same or different;
the above-mentioned
In, R8And R9Independently hydrogen, substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl or aminoalkyl groups; or R5、R6Together with the nitrogen atom to which they are attached form a 5-7 membered substituted or unsubstituted carbon heterocyclic ring;in the carbon heterocycle, the heteroatom is nitrogen, nitrogen or oxygen, and the number of the heteroatoms is 1-4;
R8or R9Wherein the substituent of the substituted alkyl is selected from the group consisting of halogen, C1-C4 alkyl, hydroxy, and a,
C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 acylamino; r5、R6And the nitrogen atom to which they are attached, together form a 5-7 membered substituted carbon heterocyclic ring;
the substituent in the substituted carbon heterocycle is selected from halogen, C1-C4 alkyl, hydroxyl,
C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 acylamino; when the number of the substituents is plural, the substituents may be the same or different;
In R3, the group is more preferably cyano; the group in R5 is preferably halogen, the halogen is more preferably chlorine atom; the group in R6 is preferably a substituted or unsubstituted alkoxy group, and the substituted or unsubstituted alkoxy group is more preferably a methoxy group; in R7, the group is more preferably methyl.
Wherein R is1Selected from:
wherein R is2Selected from:
typical compounds of the invention include, but are not limited to:
the biphenyl compound comprises pharmaceutically acceptable salts, racemates, optical isomers or solvent compounds of the biphenyl compound, and the biphenyl compound can be applied to preparation of immune checkpoint inhibitors.
The biphenyl compound comprises pharmaceutically acceptable salts, racemates, optical isomers or solvent compounds of the biphenyl compound, and the application of the biphenyl compound in preparation of inhibitors of the inhibitory activity of PD-L/PD-L1 signal pathways.
The biphenyl compound comprises pharmaceutically acceptable salts, racemates, optical isomers or solvent compounds thereof, and application of the biphenyl compound in preparation of antitumor drugs.
The biphenyl compound comprises pharmaceutically acceptable salts, racemates, optical isomers or solvent compounds of the biphenyl compound, and the application of the biphenyl compound in preparing anti-infective medicaments.
A pharmaceutical composition comprises the biphenyl compound or pharmaceutically acceptable salts, racemates, optical isomers or solvent compounds thereof as an active ingredient and a pharmaceutically acceptable carrier.
The pharmaceutical composition is capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository or patch.
The term "immune checkpoint inhibitor" refers to a substance that inhibits the activity of co-inhibitory receptors, blocks negative regulatory signals, restores T cell activity, and thereby enhances the immune response.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid and the like. Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt. Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.
The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
The term "metabolite" refers to a pharmaceutically active product produced by the in vivo metabolism of a compound of formula I or a salt thereof. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by a method comprising contacting a compound of the invention with a mammal for a period of time sufficient to obtain a metabolite thereof.
In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the present invention. For example, compounds containing a carboxyl group may form physiologically hydrolyzable esters that act as prodrugs by hydrolyzing in vivo to give the compounds of formula I themselves. The prodrugs are preferably administered orally, since hydrolysis in many cases takes place mainly under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood.
In the present invention, the tumor includes, but is not limited to, non-small cell lung cancer, liver cancer, stomach cancer, leukemia, melanoma, colon cancer, glioma, kidney cancer, ovarian cancer, pancreatic cancer, breast cancer, prostate cancer, multiple myeloma or cervical cancer.
In the present invention, the infectious disease includes, but is not limited to, hepatitis b, aids or tuberculosis.
The invention has the positive effects that: the biphenyl compound has an obvious effect on blocking a PD1/PD-L1 signal path, and can effectively relieve and treat related diseases such as cancer and the like.
Drawings
Fig. 1 shows the results of in vivo efficacy evaluation of compound JLPD 059.
The specific implementation mode is as follows:
the invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1: synthesis of intermediate 9:
the synthetic route is as follows:
the method comprises the following steps: synthesis of Compound 2
Weighing compound 1(14.8g,100mmol), dissolving in DCM, adding imidazole (7.48g,110mmol) and TBSCl (16.6g,110mmol) at 0 ℃, slowly raising to room temperature, and reacting for 6 h. After the reaction was completed, water quenching was added to quench the reaction, DCM was extracted, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated to dryness to give compound 2(25.98g, 99%).1H NMR(300MHz,Chloroform-d) δ7.71(dd,J＝7.4,2.1Hz,1H),7.25(t,J＝7.5Hz,1H),7.16(dd,J＝7.6,2.1Hz,1H),3.12(t,J＝8.1Hz,2H), 2.70(t,J＝8.1Hz,2H),0.98(s,9H),0.21(s,6H).MS(ESI,m/z):263.4[M+1]+.
Step two: synthesis of Compound 3
A toluene solution of R-methyl CBS-oxazolylborane (1.5mL,1.5mmol) and BH3-SMe2To a two-necked flask was added a solution of THF (25mL,50mmol), stirred at room temperature for 1h, and a solution of compound 2(2.62g,10mmol) in DCM was added slowly and reacted for 2 h. After the reaction was completed, methanol was added to quench the reaction, DCM was extracted, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated to dryness to give compound 3(2.51 g, 95%).1H NMR(300MHz,Chloroform-d)δ7.17(t,J＝7.4Hz,1H),7.09(ddd,J＝7.6,2.2,1.0Hz,1H),6.87 (dd,J＝7.3,2.1Hz,1H),4.94(td,J＝7.0,1.0Hz,1H),2.73(qt,J＝17.6,7.1Hz,2H),2.47–2.29(m,1H),2.02 (dq,J＝13.1,7.1Hz,1H),0.98(s,9H),0.21(s,6H).MS(ESI,m/z):265.4[M+1]+.
Step three: synthesis of Compound 5
Compound 3(2.64g,10mmol) and compound 4(4.29g,25mmol) were weighed out and dissolved in dry toluene, Pd (dppf) Cl was added2(731mg,1.0mmol), cesium carbonate (8.15g,25mmol), under argon, and warm to 40 ℃ for 15 h. After the reaction was completed, the reaction solution was filtered by suction, the filtrate was concentrated, and sand was prepared and purified by column chromatography (PE: EA 150:1) to obtain compound 26(3.24g, 81%).1H NMR(300MHz,Chloroform-d) δ9.83(s,1H),7.57(d,J＝8.0Hz,1H),7.19(t,J＝7.4Hz,1H),7.08(ddd,J＝7.6,2.2,1.1Hz,1H),6.90(dd,J＝ 7.3,2.1Hz,1H),6.41(d,J＝8.1Hz,1H),5.28(td,J＝6.9,1.0Hz,1H),3.96(s,3H),2.86–2.63(m,2H),2.54– 2.37(m,1H),2.22(dq,J＝13.1,7.1Hz,1H),0.98(s,9H),0.21(s,6H).MS(ESI,m/z):400.6[M+1]+.
Step four: synthesis of Compound 6
Compound 5(4.00g,10mmol) was weighed out and dissolved in a mixture of DMF (15mL) and DCM (15mL), and Palou' Chlor 2-chloro-1, 3-bis (methoxycarbonyl) guanidine (2.52g,12mmol), trifluoroacetic acid (74uL,1.0mmol) and argon protected were added and reacted at room temperature for 12 h. Adding Na2CO3Saturated solution(20mL)Na2S2O3The saturated solution (10mL) was extracted with DCM (100mL), washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, made into sand, and purified by column chromatography (PE: EA ═ 50:1) to give compound 6(3.52 g, 81%).1H NMR(300MHz,Chloroform-d)δ10.06(s,1H),8.15(s,1H),7.19(t,J＝7.4Hz,1H),7.12(ddd,J＝ 7.5,2.2,1.0Hz,1H),6.90(dd,J＝7.3,2.2Hz,1H),5.21(td,J＝6.9,1.0Hz,1H),4.03(s,3H),2.90–2.62(m,2H), 2.61–2.43(m,1H),2.23–2.04(m,1H),0.98(s,9H),0.21(s,6H).MS(ESI,m/z):435.0[M+1]+.
Step five: synthesis of Compound 7
Compound 6(4.34g,10mmol) was weighed and dissolved in tetrahydrofuran, tetrabutylammonium fluoride (3.92g,15mmol) was added and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction solution was spin-dried, EA (150mL) was added and dissolved, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, made into sand, and purified by column chromatography (DCM: MeOH ═ 50:1) to obtain compound 7(3.17g, 99%).1H NMR(300MHz, Chloroform-d)δ10.06(s,1H),8.15(s,1H),7.07(t,J＝7.5Hz,1H),6.84(ddd,J＝7.4,2.0,1.0Hz,1H),6.68(dd, J＝7.5,2.0Hz,1H),5.22(td,J＝6.9,1.0Hz,1H),4.03(s,3H),2.90–2.62(m,2H),2.59–2.42(m,1H),2.15(dq, J＝13.2,7.1Hz,1H).MS(ESI,m/z):320.7[M+1]+.
Step six: synthesis of Compound 8
Weighing compound 7(3.20g,10mmol), dissolving in dichloromethane, adding pyridine (2.01mL,25mmol), triethylamine (2.78mL,20 mmol), DMAP (122mg,1.0mmol), and under the protection of argon, slowly adding trifluoromethanesulfonic anhydride (2.02mL,12mmol) at-20 deg.C, and reacting for 30 min. The temperature is increased to room temperature, and the reaction is carried out for 6 h. Dichloromethane (100mL) was added to dissolve, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, and the mixture was granulated and purified by column chromatography (PE: EA 60:1) to obtain compound 8(4.07g, 90%).1H NMR(300MHz, Chloroform-d)δ10.07(s,1H),8.17(s,1H),7.49(dd,J＝7.5,2.0Hz,1H),7.24(t,J＝7.5Hz,1H),7.09(ddd,J＝ 7.6,2.0,0.9Hz,1H),5.22(td,J＝7.0,1.0Hz,1H),4.00(s,3H),2.87–2.67(m,2H),2.61–2.45(m,1H),2.19(dq, J＝13.2,7.1Hz,1H).MS(ESI,m/z):452.8[M+1]+.
Step seven: synthesis of Compound 9
Compound 8(4.52g,10mmol) and bis-pinacol boronate (3.05g,12mmol) were weighed out and dissolved in dioxane (60mL) and Pd (dppf) Cl was added2(731mg,1.0mmol), anhydrous potassium acetate (4.17g,25mmol), under argon, and heated to 85 ℃ for 4 h. After the reaction was completed, the reaction mixture was spin-dried, EA (150mL) was added and dissolved, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, made into sand, and purified by column chromatography (PE: EA ═ 30:1) to obtain compound 9(3.87g, 90%).1H NMR(400MHz,Chloroform-d)δ9.98 (s,1H),7.94(d,J＝0.62Hz,1H),7.26(d,J＝7.37Hz,2H),7.11(dd,J＝7.88,7.06Hz,1H),5.11(t,J＝7.00Hz, 1H),3.96(s,3H),3.20–3.01(m,2H),2.48(qd,J＝7.14,2.70Hz,2H),1.24(d,J＝20.13Hz,12H).MS(ESI, m/z):430.2[M+1]+.
Example 2: synthesis of compound intermediate 16:
the synthetic route is as follows:
the method comprises the following steps: synthesis of Compound 11
Weighing compound 10(17.72g,100mmol), dissolving in glacial acetic acid (50mL), slowly adding a mixed solution of fuming nitric acid (9.09mL,200mmol) and acetic anhydride (20mL) acetic acid (50mL) by using a constant-pressure dropping funnel under ice bath conditions, dropwise adding for about 30min, slowly raising the temperature to room temperature after dropwise adding, and reacting for 3 h. After the reaction was completed, water quenching was added to quench the reaction, DCM was extracted, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated to dryness to give compound 11(21.99g, 99%).1H NMR(400MHz,Chloroform-d)δ8.50(d,J＝ 1.46Hz,1H),8.21(d,J＝1.46Hz,1H),3.92(s,3H).MS(ESI,m/z):223.0[M+1]+.
Step two: synthesis of Compound 12
Weighing compound 11(11.11g,50mmol), adding into a two-necked flask, adding tetrahydrofuran (100mL) and zinc powder (19.62g,300mmol), and under the protection of inert gas and ice bath conditionsDilute hydrochloric acid (150mL,600mmol) was slowly added to the reaction system via a constant pressure dropping funnel and allowed to react for 15 min. After the reaction was completed, most of tetrahydrofuran was evaporated to dryness, extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to give compound 12(8.17g, 85%).1H NMR(400MHz,Chloroform-d)δ7.84(d,J＝1.46Hz, 1H),7.50(d,J＝1.46Hz,1H),3.91(s,3H).MS(ESI,m/z):193.1[M+1]+.
Step three: synthesis of Compound 14
Compound 12(1.92g,10mmol) and compound 13(2.09g,10.5mmol) were weighed and dissolved in absolute ethanol, reacted at room temperature for 3h, ethanol was evaporated under reduced pressure, absolute dichloromethane was added, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (2.50g,11mmol) was slowly added, reacted for 1h, dichloromethane was extracted, water-washed, saturated brine was washed, dried over anhydrous sodium sulfate, filtered, solvent was spin-dried, sand was made, and column chromatography purification (PE: EA ═ 50:1) gave compound 14(2.41g, 65%).1H NMR(400MHz,Chloroform-d)δ8.59(d,J＝1.46Hz,1H),8.23(d,J＝1.46 Hz,1H),7.94(dd,J＝7.47,1.45Hz,1H),7.53(dd,J＝7.47,1.45Hz,1H),7.31(t,J＝7.47Hz,1H),3.92(s,3H), 2.47(s,3H).MS(ESI,m/z):371.0[M+1]+.
Step four: synthesis of Compound 15
Compound 14(3.71g,10mmol) was weighed out and dissolved in tetrahydrofuran (40mL), and lithium borohydride (436mg,20 mmol) was added under ice bath conditions for reaction for 4 h. After the reaction was completed, ice water was added to quench the reaction, dichloromethane was used for extraction, washing with water, washing with saturated brine, drying with anhydrous sodium sulfate, filtration, evaporation of the solvent to dryness, sand preparation, and purification by column chromatography (PE: EA ═ 20:1) gave compound 15(2.54g, 74%).1H NMR(400MHz, Chloroform-d)δ7.91(dd,J＝7.47,1.66Hz,1H),7.60(d,J＝1.42Hz,1H),7.56(d,J＝1.45Hz,1H),7.53(dd,J＝7.46,1.44Hz,1H),7.31(t,J＝7.47Hz,1H),4.79(s,2H),2.46(s,3H).MS(ESI,m/z):343.0[M+1]+.
Step five: synthesis of Compound 16
Compound 15(3.43g,10mmol) was weighed out and dissolved in dichloromethane (40mL), followed by addition of dessimutan oxidant (6.36g,15mmol) and reaction at room temperature for 1 h. When the reaction is complete, the reaction is carried out,the reaction mixture was dried by spinning, extracted with dichloromethane, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, and the mixture was granulated and purified by column chromatography (DCM: MeOH ═ 30:1) to obtain compound 16(3.38g, 99%).1H NMR(400MHz, Chloroform-d)δ9.91(d,J＝0.95Hz,1H),8.27(d,J＝1.70Hz,1H),8.20(d,J＝1.46Hz,1H),7.92(dd,J＝7.47, 1.45Hz,1H),7.52(dd,J＝7.47,1.45Hz,1H),7.31(t,J＝7.47Hz,1H),2.46(s,3H).MS(ESI,m/z):341.0 [M+1]+.
Example 3: synthesis of compound JLPD001 (S) -2- (3- (1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- ((2-hydroxyethyl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile
The synthesis method comprises the following steps:
the method comprises the following steps: synthesis of Compound 17
Compound 9(430mg,1.0mmol), ethanolamine (180uL,3.0mmol) were weighed out and dissolved in 5mL DCM and 5mL MeOH, and acetic acid (57uL,1.0mmol) was added and reacted at room temperature. After the reaction was carried out for 3h, NaBH was added3CN (189mg,3.0mmol), and reacted at room temperature for 12 h. After completion of the reaction, the reaction solution was filtered with suction, the filtrate was concentrated, and then, sand was prepared and purified by column chromatography (DCM: MeOH 8:1) to obtain compound 17(365mg, 77%).1H NMR(300MHz,Chloroform-d)δ7.90(d,J＝2.1Hz,1H),7.58(dd,J＝6.1,3.3Hz, 1H),7.45–7.32(m,2H),7.24–7.06(m,2H),6.93(d,J＝7.5Hz,1H),5.24(t,J＝7.0Hz,1H),4.41–4.06(m, 4H),4.00(s,3H),3.96–3.80(m,2H),3.51–3.31(m,2H),3.18–2.97(m,3H),2.89(dt,J＝17.6,7.0Hz,1H), 2.67–2.48(m,1H),2.04-2.15(m,1H).MS(ESI,m/z):475.2[M+1]+.
Step two: synthesis of Compound 18
Compound 16(341mg,1.0mmol), ethanolamine (180uL,3.0mmol) were weighed out and dissolved in 5mL DCM and 5mL MeOH, and acetic acid (57uL,1.0mmol) was added and reacted at room temperature. After the reaction was carried out for 3 hours, NaBH was added3CN (189mg,3.0mmol), reaction at room temperature 12h. After completion of the reaction, the reaction solution was filtered with suction, the filtrate was concentrated, and purified by column chromatography (DCM: MeOH: 8:1) to give compound 17(274mg, 71%).1H NMR(300MHz,Chloroform-d)δ7.90(d,J＝2.1Hz,1H),7.58(dd,J＝6.1,3.3Hz, 1H),7.45–7.32(m,2H),7.24–7.06(m,2H),6.93(d,J＝7.5Hz,1H),5.24(t,J＝7.0Hz,1H),4.41–4.06(m, 4H),4.00(s,3H),3.96–3.80(m,2H),3.51–3.31(m,2H),3.18–2.97(m,3H),2.89(dt,J＝17.6,7.0Hz,1H), 2.67–2.48(m,1H),2.04-2.15(m,1H).MS(ESI,m/z):386.0[M+1]+.
Step three: synthesis of Compound JLPD001
Compound 17(475mg,1.0mmol) and compound 18(386mg,1.0mmol) are weighed out and dissolved in a mixed solution of dioxane (20mL) and water (4mL), Pd (dppf) Cl is added2(73mg,0.1mmol), potassium carbonate (652mg,2.0mmol), under argon, and heated to 85 ℃ for 4 h. After the reaction was completed, the reaction solution was dried, EA (100mL) was added to dissolve, filtered, the solvent was evaporated to dryness, and sand was prepared and purified by column chromatography (DCM: MeOH ═ 8:1) to obtain compound JLPD001(406mg, 62%).1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝ 7.2,1.8Hz,1H),7.74(s,1H),7.62(d,J＝1.5Hz,1H),7.58(d,J＝1.5Hz,1H),7.51–7.37(m,3H),7.31–7.20 (m,2H),5.13(t,J＝7.0Hz,1H),4.28–4.09(m,2H),4.06–3.92(m,2H),3.91(s,3H),3.81–3.62(m,4H),3.17 –2.85(m,6H),2.79(s,3H),2.49(q,J＝7.1Hz,2H).MS(ESI,m/z):654.2[M+1]+.
Example 4: synthesis of the Compound JLPD002 (S) -1- ((2- (3- ((S) -1- ((5- ((S) -3-carboxypyrrolidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.66 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.51–7.37(m,3H),7.31–7.21(m,2H),5.13(t,J＝6.9 Hz,1H),3.95–3.80(m,5H),3.72–3.56(m,2H),3.16–2.75(m,12H),2.74(s,3H),2.49(q,J＝7.1Hz,2H), 1.99–1.77(m,4H).MS(ESI,m/z):762.3[M+1]+.
Example 5: synthesis of Compound JLPD003 2- (3- ((S) -1- ((3-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- (((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.62(d,J＝1.5Hz,1H),7.57(d,J＝1.5Hz,1H),7.51–7.36(m,3H),7.30–7.21(m,2H),5.13(t,J＝6.9 Hz,1H),4.12(s,2H),4.05–3.89(m,5H),3.77(dp,J＝7.8,7.0Hz,2H),3.17–2.98(m,2H),2.95–2.83(m,2H), 2.83–2.71(m,5H),2.49(q,J＝7.1Hz,2H),2.39–2.19(m,4H),1.99–1.85(m,2H),1.81–1.65(m,2H).MS (ESI,m/z):760.3[M+1]+.
Example 6: synthesis of compound JLPD004 (S) -N- (2- ((2- (3- (1- ((5- ((2-acetamidoethyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) amino) ethyl) acetamide
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.63(d,J＝1.4Hz,1H),7.57(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.29–7.21(m,2H),5.13(t,J＝7.0 Hz,1H),4.26–4.05(m,2H),4.05–3.85(m,4H),3.49–3.26(m,4H),3.17–2.88(m,6H),2.74(s,3H),2.49(q, J＝7.1Hz,2H),1.94(d,J＝0.4Hz,6H).MS(ESI,m/z):736.2[M+1]+.
Example 7: synthesis of compound JLPD005 (S) -2- (3- (1- ((3-chloro-5- ((2- (dimethylamino) ethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- ((2- (dimethylamino) ethyl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.63(d,J＝1.4Hz,1H),7.57(d,J＝1.5Hz,1H),7.50–7.36(m,3H),7.31–7.21(m,2H),5.13(t,J＝7.0 Hz,1H),4.25–4.08(m,2H),4.05–3.87(m,5H),3.15–2.97(m,2H),2.97–2.69(m,11H),2.49(q,J＝7.1Hz, 2H),2.40(d,J＝0.7Hz,12H).MS(ESI,m/z):708.3[M+1]+.
Example 8: synthesis of compound JLPD006 2- (3- ((S) -1- ((3-chloro-5- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- ((S) -3-hydroxypyrrolidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.66 (s,1H),7.61(d,J＝1.5Hz,1H),7.54(d,J＝1.5Hz,1H),7.52–7.37(m,3H),7.30–7.20(m,2H),5.12(t,J＝7.0 Hz,1H),4.18(p,J＝7.0Hz,2H),3.95–3.77(m,5H),3.72–3.51(m,2H),3.15–2.96(m,2H),2.94–2.63(m, 11H),2.49(q,J＝7.1Hz,2H),1.96–1.62(m,4H).MS(ESI,m/z):706.3[M+1]+.
Example 9: synthesis of compound JLPD007 2- (3- ((S) -1- ((3-chloro-5- ((R) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- ((R) -3-hydroxypyrrolidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.66 (s,1H),7.61(d,J＝1.4Hz,1H),7.54(d,J＝1.5Hz,1H),7.51–7.36(m,3H),7.32–7.19(m,2H),5.12(t,J＝7.0 Hz,1H),4.18(p,J＝7.0Hz,2H),3.94–3.79(m,5H),3.71–3.53(m,2H),3.39–3.25(m,2H),3.16–2.97(m, 2H),2.94–2.76(m,6H),2.74(s,3H),2.49(q,J＝7.1Hz,2H),1.88–1.71(m,2H),1.68–1.55(m,2H).MS(ESI, m/z):706.3[M+1]+.
Example 10: synthesis of compound JLPD008 (R) -1- ((2- (3- ((S) -1- ((5- ((R) -3-carboxypyrrolidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Synthesis method JLPD001 was used as a synthesis method.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.66 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.29–7.21(m,2H),5.21–5.04(m, 1H),3.94–3.79(m,5H),3.73–3.53(m,2H),3.21–2.86(m,10H),2.85–2.69(m,5H),2.49(q,J＝7.1Hz,2H), 2.00–1.71(m,4H).MS(ESI,m/z):762.3[M+1]+.
Example 11: synthesis of compound JLPD009 2- (3- ((S) -1- ((3-chloro-5- (((R) -2, 3-dihydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- (((R) -2, 3-dihydroxypropyl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.62(d,J＝1.5Hz,1H),7.57(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.31–7.22(m,2H),5.13(t,J＝7.0 Hz,1H),4.16(d,J＝1.7Hz,2H),4.05–3.88(m,5H),3.76(h,J＝7.0Hz,2H),3.64–3.47(m,4H),3.15–2.97 (m,4H),2.91(ddd,J＝12.4,7.0,3.2Hz,2H),2.74(s,3H),2.49(q,J＝7.1Hz,2H).MS(ESI,m/z):714.3[M+1]+.
Example 12: synthesis of compound JLPD010 (S) -4- ((2- (3- ((S) -1- ((5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ7.85(s,1H),7.56(dd,J＝6.0,3.6 Hz,1H),7.47–7.32(m,2H),7.16–7.03(m,2H),7.00–6.89(m,1H),5.28–5.18(m,1H),4.33–4.07(m,4H), 4.00(s,3H),3.69(d,J＝12.4Hz,1H),3.28–3.13(m,2H),3.07(dd,J＝9.3,6.8Hz,1H),2.95(q,J＝7.2Hz,2H), 2.79(p,J＝6.9Hz,1H),2.72–2.48(m,2H),2.40–2.03(m,3H),2.01–1.82(m,1H).MS(ESI,m/z):537.2 [M+1]+.
Example 13: synthesis of compound JLPD011 (S) -1- ((2- (3- (1- ((5- ((3-carboxyazetidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) azetidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.62(d,J＝1.5Hz,1H),7.58(d,J＝1.5Hz,1H),7.51–7.36(m,3H),7.31–7.22(m,2H),5.18–5.08(m, 1H),4.22–4.06(m,4H),4.06–3.87(m,5H),3.17–2.90(m,6H),2.74(s,3H),2.55–2.34(m,6H).MS(ESI, m/z):734.2[M+1]+.
Example 14: synthesis of compound JLPD012 (S) -2- (3- (1- ((3-chloro-5- ((3-hydroxyazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- (3-hydroxyazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.70 (s,1H),7.61(d,J＝1.4Hz,1H),7.53(d,J＝1.5Hz,1H),7.51–7.37(m,3H),7.29–7.22(m,2H),5.12(t,J＝7.0 Hz,1H),4.10–3.78(m,7H),3.74–3.54(m,2H),3.24–2.98(m,10H),2.74(s,3H),2.49(q,J＝7.1Hz,2H).MS (ESI,m/z):678.2[M+1]+.
Example 15: synthesis of compound JLPD013 methyl (R) -1- ((5-chloro-6- ((S) -4- (3- (7-cyano-5- ((R) -3- (methoxycarbonyl) pyrrolidin-1-yl) methyl) benzo [ d ] oxazol-2-yl) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) pyrrolidine-3-carboxylate
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.20,1.81Hz,1H), 7.66(s,1H),7.62(d,J＝1.54Hz,1H),7.56(d,J＝1.54Hz,1H),7.52–7.36(m,3H),7.31–7.21(m,2H),5.18– 5.07(m,1H),3.96–3.79(m,5H),3.73–3.54(m,7H),3.18–2.77(m,12H),2.74(s,3H),2.49(q,J＝7.07Hz, 2H),2.01–1.70(m,4H).MS(ESI,m/z):790.3[M+1]+.
Example 16: synthesis of Compound JLPD014 (S) -2- ((2- (3- ((S) -1- ((5- (((S) -2-carboxy-1-hydroxypropyl-2-yl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) amino) -3-hydroxy-2-methylpropionic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.79 (s,1H),7.64(d,J＝1.5Hz,1H),7.58(d,J＝1.4Hz,1H),7.51–7.36(m,3H),7.30–7.21(m,2H),5.13(t,J＝7.0 Hz,1H),4.26(d,J＝1.3Hz,2H),4.02(s,2H),3.97–3.81(m,7H),3.20–2.98(m,2H),2.74(s,3H),2.49(q,J＝ 7.1Hz,2H),1.50(d,J＝1.0Hz,6H).MS(ESI,m/z):770.3[M+1]+.
Example 17: synthesis of compound JLPD015 (S) -1- ((2- (3- ((S) -1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.62(d,J＝1.4Hz,1H),7.55(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.32–7.22(m,2H),5.13(t,J＝7.0 Hz,1H),4.28–4.08(m,2H),3.91(s,3H),3.81–3.56(m,4H),3.17–2.70(m,12H),2.49(q,J＝7.1Hz,2H), 1.90–1.74(m,2H).MS(ESI,m/z):708.3[M+1]+.
Example 18: synthesis of compound JLPD016 (S) -1- ((2- (3- ((S) -1- ((3-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.51–7.36(m,3H),7.29–7.21(m,2H),5.13(t,J＝7.0 Hz,1H),4.12(q,J＝12.4Hz,2H),3.90(s,3H),3.83–3.55(m,3H),3.16–2.70(m,12H),2.49(q,J＝7.1Hz, 2H),2.38–2.20(m,2H),2.00–1.66(m,4H).MS(ESI,m/z):760.3[M+1]+.
Example 19: synthesis of compound JLPD017: (S) -1- ((2- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.31–7.21(m,2H),5.18–5.08(m, 1H),4.22–4.03(m,3H),3.91(s,3H),3.73–3.56(m,2H),3.16–2.87(m,7H),2.87–2.71(m,5H),2.54–2.37 (m,4H),1.88–1.76(m,2H).MS(ESI,m/z):766.3[M+1]+.
Example 20: synthesis of compound JLPD018 (S) -1- ((2- (3- ((S) -1- ((3-chloro-5- (((R) -2, 3-dihydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.36(m,3H),7.34–7.21(m,2H),5.13(t,J＝7.0 Hz,1H),4.16(d,J＝1.9Hz,2H),3.91(s,3H),3.83–3.47(m,5H),3.15–2.76(m,9H),2.74(s,3H),2.49(q,J＝ 7.1Hz,2H),1.89–1.77(m,2H).MS(ESI,m/z):738.3[M+1]+.
Example 21: synthesis of compound JLPD019 (S) -1- ((2- (3- ((S) -1- ((5- ((2-acetamidoethyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.51–7.37(m,3H),7.30–7.19(m,2H),5.17–5.07(m, 1H),4.22–4.08(m,2H),3.90(s,3H),3.76–3.55(m,2H),3.50–3.30(m,2H),3.15–2.88(m,7H),2.88–2.76 (m,2H),2.74(s,3H),2.49(q,J＝7.1Hz,2H),1.94(s,3H),1.89–1.79(m,2H).MS(ESI,m/z):745.3[M+1]+.
Example 22: synthesis of compound JLPD020 (S) -1- ((2- (3- ((S) -1- ((3-chloro-5- ((2- (dimethylamino) ethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Synthesis method JLPD001 was used as a synthesis method.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.52–7.36(m,3H),7.32–7.20(m,2H),5.19–5.07(m, 1H),4.25–4.07(m,2H),3.91(s,3H),3.77–3.55(m,2H),3.16–2.70(m,14H),2.49(q,J＝7.1Hz,2H),2.40(s, 5H),1.88–1.76(m,2H).MS(ESI,m/z):735.3[M+1]+.
Example 23: synthesis of compound JLPD021 (S) -1- ((2- (3- ((S) -1- ((3-chloro-5- ((S) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.66 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.31–7.21(m,2H),5.17–5.08(m, 1H),4.18(p,J＝7.0Hz,1H),3.95–3.78(m,5H),3.72–3.56(m,2H),3.15–2.62(m,14H),2.49(q,J＝7.1Hz, 2H),1.93–1.65(m,4H).MS(ESI,m/z):734.3[M+1]+.
Example 24: synthesis of compound JLPD022 (S) -1- ((2- (3- ((S) -1- ((3-chloro-5- ((R) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.66 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.51–7.37(m,3H),7.32–7.20(m,2H),5.17–5.09(m, 1H),4.18(p,J＝7.0Hz,1H),3.94–3.79(m,5H),3.72–3.55(m,2H),3.35–3.24(m,1H),3.15–2.76(m,10H), 2.74(s,3H),2.49(q,J＝7.1Hz,2H),1.91–1.72(m,3H),1.69–1.53(m,1H).MS(ESI,m/z):734.3[M+1]+.
Example 25: synthesis of compound JLPD023 (S) -1- ((2- (3- ((S) -1- ((5- ((3-carboxyazetidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.66 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.51–7.36(m,3H),7.32–7.23(m,2H),5.13(t,J＝7.0 Hz,1H),3.89(d,J＝9.7Hz,5H),3.72–3.53(m,2H),3.46–3.25(m,4H),3.15–2.76(m,8H),2.74(s,3H),2.49 (q,J＝7.1Hz,2H),1.89–1.77(m,2H).MS(ESI,m/z):748.2[M+1]+.
Example 26: synthesis of compound JLPD024 (S) -1- ((2- (3- ((S) -1- ((3-chloro-5- ((3-hydroxyazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.70 (s,1H),7.62(d,J＝1.6Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.36(m,3H),7.30–7.22(m,2H),5.13(t,J＝7.0 Hz,1H),4.03(p,J＝7.0Hz,1H),3.95–3.78(m,5H),3.74–3.52(m,2H),3.21–3.03(m,6H),3.03–2.88(m, 3H),2.88–2.75(m,2H),2.74(s,3H),2.49(q,J＝7.1Hz,2H),1.89–1.77(m,2H).MS(ESI,m/z):720.3[M+1]+.
Example 27: synthesis of compound JLPD025 (S) -1- ((2- (3- ((S) -1- ((5- (((R) -2-carboxy-1-hydroxypropyl-2-yl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.79 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.51–7.36(m,3H),7.33–7.21(m,2H),5.20–5.09(m, 1H),4.26(d,J＝1.2Hz,2H),3.95–3.80(m,5H),3.74–3.56(m,2H),3.15–2.87(m,5H),2.87–2.76(m,2H), 2.74(s,3H),2.49(q,J＝7.1Hz,2H),1.89–1.75(m,2H),1.50(s,3H).MS(ESI,m/z):766.3[M+1]+.
Example 28: synthesis of compound JLPD026 (S) -1- ((2- (3- ((S) -1- ((5- (((S) -2-carboxy-1-hydroxypropyl-2-yl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.79 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.51–7.37(m,3H),7.31–7.20(m,2H),5.13(t,J＝6.9 Hz,1H),4.26(d,J＝1.2Hz,2H),3.98–3.81(m,5H),3.74–3.56(m,2H),3.17–2.88(m,5H),2.88–2.75(m, 2H),2.74(s,3H),2.49(q,J＝7.1Hz,2H),1.90–1.75(m,2H),1.50(s,3H).MS(ESI,m/z):766.3[M+1]+.
Example 29: synthesis of JLPD027 (S) -1- ((2- (3- ((S) -1- ((5- (((R) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.30–7.21(m,2H),5.18–5.07(m, 1H),4.24–4.03(m,3H),3.91(s,3H),3.76–3.55(m,2H),3.15–2.86(m,7H),2.86–2.75(m,2H),2.74(s,3H), 2.54–2.37(m,4H),1.89–1.74(m,2H).MS(ESI,m/z):766.3[M+1]+.
Example 30: synthesis of compound JLPD028 (S) -1- ((2- (3- ((S) -1- ((5- ((carboxymethyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.78 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.30–7.21(m,2H),5.13(t,J＝7.0 Hz,1H),4.23(q,J＝12.4Hz,2H),3.91(s,3H),3.75–3.44(m,4H),3.15–2.88(m,5H),2.88–2.76(m,2H), 2.74(s,3H),2.49(q,J＝7.1Hz,2H),1.87–1.79(m,2H).MS(ESI,m/z):722.2[M+1]+.
Example 31: synthesis of compound JLPD029 (S) -1- ((2- (3- ((S) -1- ((3-chloro-5- ((ethylamino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.61(d,J＝1.4Hz,1H),7.55(d,J＝1.5Hz,1H),7.51–7.38(m,3H),7.33–7.19(m,2H),5.12(t,J＝7.0 Hz,1H),4.19–4.02(m,2H),3.91(s,3H),3.73–3.56(m,2H),3.15–2.87(m,5H),2.87–2.60(m,7H),2.49(q, J＝7.1Hz,2H),1.89–1.72(m,2H),1.19(t,J＝8.0Hz,3H).MS(ESI,m/z):692.3[M+1]+.
Example 32: synthesis of compound JLPD030 (S) -1- ((2- (3- ((S) -1- ((5- ((2-carboxyprop-2-yl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.77 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.51–7.36(m,3H),7.31–7.21(m,2H),5.13(t,J＝7.0 Hz,1H),4.32–4.13(m,2H),3.91(s,3H),3.77–3.53(m,2H),3.15–2.88(m,5H),2.87–2.75(m,2H),2.74(s, 3H),2.49(q,J＝7.1Hz,2H),1.89–1.77(m,2H),1.55(s,3H),1.50(s,3H).MS(ESI,m/z):750.3[M+1]+.
Example 33: synthesis of compound JLPD031 (S) -1- ((2- (3- ((S) -1- ((3-chloro-5- (((1S, 2R) -2-hydroxycyclopentyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.62(d,J＝1.6Hz,1H),7.56(d,J＝1.5Hz,1H),7.51–7.36(m,3H),7.33–7.22(m,2H),5.13(t,J＝7.0 Hz,1H),4.09(d,J＝0.9Hz,2H),3.91(s,4H),3.74–3.56(m,2H),3.21–2.88(m,6H),2.88–2.76(m,2H),2.74 (s,3H),2.49(q,J＝7.1Hz,2H),1.88–1.56(m,7H).MS(ESI,m/z):748.3[M+1]+.
Example 34: synthesis of the Compound JLPD032 (S) -1- ((2- (3- ((S) -1- ((5- ((1-carboxycyclobutyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Synthesis method JLPD001 was used as a synthesis method.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.79 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.51–7.36(m,3H),7.30–7.21(m,2H),5.13(t,J＝6.9 Hz,1H),4.23(q,J＝12.4Hz,2H),3.91(s,3H),3.76–3.54(m,2H),3.15–2.88(m,5H),2.88–2.75(m,2H), 2.74(s,3H),2.49(q,J＝7.1Hz,2H),2.23(qt,J＝12.4,7.1Hz,4H),1.92–1.76(m,2H),1.75–1.64(m,2H).MS (ESI,m/z):762.3[M+1]+.
Example 35: synthesis of compound JLPD033 (S) -1- ((2- (3- ((S) -1- ((5- ((R) -3-carboxypyrrolidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.66 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.36(m,3H),7.29–7.21(m,2H),5.13(t,J＝6.9 Hz,1H),3.95–3.80(m,5H),3.72–3.56(m,2H),3.19–2.87(m,9H),2.87–2.72(m,6H),2.49(q,J＝7.1Hz, 2H),1.98–1.77(m,4H).MS(ESI,m/z):762.3[M+1]+.
Example 36: synthesis of compound JLPD034 (S) -1- ((6- ((S) -4- (3- (5- ((S) -3-carboxypyrrolidin-1-yl) methyl) -7-cyanobenzo [ d ] oxazol-2-yl) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.66 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.30–7.19(m,2H),5.13(t,J＝6.9 Hz,1H),3.97–3.82(m,5H),3.74–3.55(m,2H),3.17–2.88(m,7H),2.88–2.71(m,6H),2.67–2.55(m,1H), 2.49(q,J＝7.1Hz,2H),2.06–1.90(m,2H),1.90–1.73(m,2H),1.23(s,3H).MS(ESI,m/z):776.3[M+1]+.
Example 37: synthesis of compound JLPD035 (R) -1- ((6- ((S) -4- (3- (5- ((S) -3-carboxypyrrolidin-1-yl) methyl) -7-cyanobenzo [ d ] oxazol-2-yl) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.66 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.29–7.22(m,2H),5.13(t,J＝6.9 Hz,1H),3.97–3.82(m,5H),3.75–3.54(m,2H),3.15–2.88(m,7H),2.88–2.75(m,3H),2.74(s,3H),2.64– 2.44(m,3H),2.06–1.89(m,2H),1.88–1.73(m,2H),1.23(s,3H).MS(ESI,m/z):776.3[M+1]+.
Example 38: synthesis of compound JLPD036 (R) -1- ((6- ((S) -4- (3- (5- ((S) -3-carboxypyrrolidin-1-yl) methyl) -7-cyanobenzo [ d ] oxazol-2-yl) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) piperidine-3-carboxylic acid
Synthesis method JLPD001 was used as a synthesis method.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.20,1.81Hz,1H), 7.66(s,1H),7.62(d,J＝1.54Hz,1H),7.56(d,J＝1.54Hz,1H),7.50–7.36(m,3H),7.30–7.22(m,2H),5.13(t, J＝6.94Hz,1H),3.95–3.80(m,5H),3.72–3.56(m,2H),3.23–2.88(m,7H),2.87–2.63(m,7H),2.52(dq,J＝ 19.43,7.00Hz,3H),1.89–1.57(m,6H).MS(ESI,m/z):776.3[M+1]+.
Example 39: synthesis of compound JLPD037 (S) -1- ((6- ((S) -4- (3- (5- ((S) -3-carboxypyrrolidin-1-yl) methyl) -7-cyanobenzo [ d ] oxazol-2-yl) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) piperidine-2-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.73 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.36(m,3H),7.30–7.22(m,2H),5.13(t,J＝6.9 Hz,1H),3.98–3.80(m,5H),3.72–3.55(m,2H),3.17–2.76(m,10H),2.74(s,3H),2.49(q,J＝7.1Hz,2H), 1.90–1.45(m,8H).MS(ESI,m/z):776.3[M+1]+.
Example 40: synthesis of compound JLPD038 (2S, 4S) -1- ((6- ((S) -4- (3- (5- ((S) -3-carboxypyrrolidin-1-yl) methyl) -7-cyanobenzo [ d ] oxazol-2-yl) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) -4-hydroxypyrrolidine-2-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.62(d,J＝1.6Hz,1H),7.56(d,J＝1.5Hz,1H),7.51–7.37(m,3H),7.29–7.20(m,2H),5.17–5.06(m, 1H),4.26(pd,J＝6.9,0.7Hz,1H),3.98–3.80(m,5H),3.73–3.56(m,3H),3.15–2.76(m,9H),2.74(s,3H), 2.49(q,J＝7.1Hz,2H),2.09–1.88(m,2H),1.88–1.73(m,2H).MS(ESI,m/z):778.3[M+1]+.
Example 41: synthesis of compound JLPD039 (S) -1- ((2- (3- ((S) -1- ((3-chloro-5- (((1R, 2S) -2-hydroxycyclopentyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.62(d,J＝1.6Hz,1H),7.56(d,J＝1.5Hz,1H),7.51–7.38(m,3H),7.32–7.21(m,2H),5.13(t,J＝7.0 Hz,1H),4.09(d,J＝0.9Hz,2H),3.96–3.83(m,4H),3.73–3.56(m,2H),3.21–2.87(m,6H),2.87–2.75(m, 2H),2.74(s,3H),2.49(q,J＝7.1Hz,2H),1.90–1.55(m,6H).MS(ESI,m/z):748.3[M+1]+.
Example 42: synthesis of compound JLPD040 (S) -1- ((6- ((S) -4- (3- (5- ((S) -3-carboxypyrrolidin-1-yl) methyl) -7-cyanobenzo [ d ] oxazol-2-yl) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) piperidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.66 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.32–7.21(m,2H),5.13(t,J＝6.9 Hz,1H),3.96–3.79(m,5H),3.72–3.56(m,2H),3.16–2.86(m,7H),2.86–2.66(m,7H),2.51(dq,J＝14.1,7.0 Hz,3H),1.91–1.58(m,6H).MS(ESI,m/z):776.3[M+1]+.
Example 43: synthesis of compound JLPD041 ((6- ((S) -4- (3- (5- ((S) -3-carboxypyrrolidin-1-yl) methyl) -7-cyanobenzo [ D ] oxazol-2-yl) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) -D-proline
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.73 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.35(m,3H),7.31–7.20(m,2H),5.13(t,J＝6.9 Hz,1H),4.01–3.81(m,5H),3.75–3.54(m,3H),3.15–2.89(m,7H),2.88–2.70(m,5H),2.49(q,J＝7.1Hz, 2H),1.99–1.66(m,6H).MS(ESI,m/z):762.3[M+1]+.
Example 44: synthesis of compound JLPD042 ((6- ((S) -4- (3- (5- ((S) -3-carboxypyrrolidin-1-yl) methyl) -7-cyanobenzo [ d ] oxazol-2-yl) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) -L-proline
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.73 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.51–7.36(m,3H),7.29–7.21(m,2H),5.13(t,J＝6.9 Hz,1H),3.99–3.81(m,5H),3.75–3.53(m,3H),3.11–2.88(m,7H),2.88–2.70(m,5H),2.49(q,J＝7.1Hz, 2H),2.00–1.67(m,6H).MS(ESI,m/z):762.3[M+1]+.
Example 45: synthesis of compound JLPD043 (S) -1- ((7-chloro-2- (3- ((S) -1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) benzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.00(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.56(d,J＝1.6Hz,1H),7.51–7.35(m,3H),7.33–7.22(m,3H),5.13(t,J＝7.0Hz,1H),4.28–4.09(m, 2H),3.91(s,3H),3.82–3.60(m,4H),3.11–2.88(m,7H),2.87–2.72(m,5H),2.49(q,J＝7.1Hz,2H),1.94– 1.58(m,2H).MS(ESI,m/z):717.2[M+1]+.
Example 46: synthesis of compound JLPD044 (S) -1- ((7-chloro-2- (3- ((S) -1- ((3-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) benzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.00(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.56(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.31(d,J＝1.4Hz,1H),7.28–7.21(m,2H),5.13(t,J＝7.0 Hz,1H),4.12(q,J＝12.4Hz,2H),3.90(s,3H),3.83–3.58(m,3H),3.16–2.86(m,6H),2.84–2.69(m,6H), 2.49(q,J＝7.1Hz,2H),2.39–2.16(m,2H),2.00–1.65(m,4H).MS(ESI,m/z):770.2[M+1]+.
Example 47: synthesis of JLPD045 (S) -1- ((2- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-chlorobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.00(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.56(d,J＝1.6Hz,1H),7.50–7.37(m,3H),7.31(d,J＝1.5Hz,1H),7.28–7.22(m,2H),5.13(t,J＝7.0 Hz,1H),4.21–4.02(m,3H),3.91(s,3H),3.80–3.54(m,2H),3.15–2.87(m,7H),2.87–2.76(m,2H),2.74(s, 3H),2.54–2.38(m,4H),1.90–1.73(m,2H).MS(ESI,m/z):775.2[M+1]+.
Example 48: synthesis of compound JLPD046 (S) -1- ((2- (3- ((S) -1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -6- (cyanomethoxy) benzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ7.99(dd,J＝6.5,2.5Hz,1H),7.74 (s,1H),7.50–7.40(m,3H),7.38(d,J＝0.5Hz,1H),7.32–7.22(m,2H),7.11(d,J＝0.4Hz,1H),5.13(t,J＝7.0 Hz,1H),5.01(s,2H),4.26–4.10(m,2H),3.91(s,2H),3.81–3.64(m,4H),3.17–2.83(m,8H),2.83–2.69(m, 4H),2.49(q,J＝7.1Hz,2H),1.97–1.76(m,2H).MS(ESI,m/z):738.3[M+1]+.
Example 49: synthesis of Compound JL047 (S) -1- ((2- (3- ((S) -1- ((5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -6- (cyanomethoxy) benzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ7.99(dd,J＝6.6,2.4Hz,1H),7.72 (s,1H),7.50–7.39(m,3H),7.38(d,J＝0.5Hz,1H),7.32–7.20(m,2H),7.10(d,J＝0.5Hz,1H),5.13(t,J＝7.0 Hz,1H),5.01(s,2H),4.23–4.02(m,3H),3.91(s,2H),3.74(d,J＝3.7Hz,2H),3.12–2.86(m,8H),2.84–2.72 (m,4H),2.55–2.37(m,4H),1.94–1.76(m,2H).MS(ESI,m/z):796.3[M+1]+.
Example 50: synthesis of compound JLPD048 (S) -1- ((2- (3- ((S) -1- ((3-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -6- (cyanomethoxy) benzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ7.99(dd,J＝6.6,2.4Hz,1H),7.74 (s,1H),7.52–7.39(m,3H),7.38(d,J＝0.5Hz,1H),7.29–7.20(m,2H),7.10(d,J＝0.5Hz,1H),5.13(t,J＝7.0 Hz,1H),5.01(s,2H),4.12(q,J＝12.4Hz,2H),3.90(s,2H),3.84–3.69(m,3H),3.16–2.84(m,7H),2.84–2.73 (m,5H),2.49(q,J＝7.1Hz,2H),2.38–2.19(m,2H),2.01–1.64(m,4H).MS(ESI,m/z):791.3[M+1]+.
Example 51: synthesis of compound JLPD049 (S) -1- ((2- (3- ((S) -1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) benzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.00(dd,J＝6.6,2.3Hz,1H),7.74 (s,1H),7.59(dd,J＝7.5,0.5Hz,1H),7.53–7.39(m,3H),7.39–7.31(m,2H),7.30–7.20(m,2H),5.12(t,J＝7.0Hz,1H),4.29–4.10(m,2H),3.91(s,2H),3.82–3.57(m,4H),3.20–2.87(m,7H),2.87–2.74(m,5H),2.49 (q,J＝7.1Hz,2H),1.90–1.72(m,2H).MS(ESI,m/z):683.3[M+1]+.
Example 52: synthesis of Compound JLPD050 (S) -1- ((2- (3- ((S) -1- ((3-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) benzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.00(dd,J＝6.4,2.5Hz,1H),7.74 (s,1H),7.56(dd,J＝7.5,0.5Hz,1H),7.51–7.40(m,3H),7.40–7.36(m,1H),7.33(dd,J＝7.5,1.5Hz,1H), 7.29–7.21(m,2H),5.18–5.07(m,1H),4.12(q,J＝12.4Hz,2H),3.91(s,2H),3.82–3.56(m,3H),3.18–2.82 (m,7H),2.82–2.72(m,5H),2.49(q,J＝7.1Hz,2H),2.38–2.19(m,2H),1.99–1.65(m,4H).MS(ESI,m/z): 736.3[M+1]+.
Example 53: synthesis of compound JLPD051 (S) -1- ((2- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) benzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1HNMR(300MHz,Chloroform-d)δ8.00(dd,J＝6.4, 2.5Hz,1H),7.72(s,1H),7.56(dd,J＝7.5,0.5Hz,1H),7.50–7.40(m,3H),7.40–7.36(m,1H), ＝7.5,1.5Hz,1H),7.30–7.22(m,2H),5.13(t,J＝7.0Hz,1H),4.23–4.01(m,3H), 3.91(s,3H),3.65(q,J＝12.4Hz,2H),3.15–2.86(m,8H),2.86–2.73(m,5H),2.54–2.37(m, 4H),1.90–1.76(m,2H).MS(ESI,m/z):741.3[M+1]+.
Example 54: synthesis of compound JLPD052 (S) -1- ((2- (3- ((S) -1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-methylbenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ7.99(dd,J＝6.0,3.0Hz,1H),7.74 (s,1H),7.54–7.40(m,3H),7.30–7.22(m,3H),7.21–7.16(m,1H),5.12(t,J＝7.0Hz,1H),4.25–4.09(m,2H), 3.91(s,3H),3.79–3.52(m,4H),3.15–2.86(m,7H),2.86–2.73(m,5H),2.56–2.43(m,5H),1.90–1.72(m, 2H).MS(ESI,m/z):697.3[M+1]+.
Example 55: synthesis of compound JLPD053 (S) -1- ((2- (3- ((S) -1- ((3-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-methylbenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ7.99(dd,J＝5.8,3.2Hz,1H),7.74 (s,1H),7.50–7.39(m,3H),7.32–7.21(m,3H),7.21–7.16(m,1H),5.17–5.08(m,1H),4.12(q,J＝12.4Hz, 2H),3.90(s,3H),3.76(p,J＝7.0Hz,1H),3.67–3.52(m,2H),3.14–2.86(m,6H),2.85–2.72(m,6H),2.55– 2.43(m,5H),2.37–2.18(m,2H),1.99–1.66(m,4H).MS(ESI,m/z):750.3[M+1]+.
Example 56: synthesis of compound JLPD054 (S) -1- ((2- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-methylbenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ7.99(dd,J＝5.8,3.2Hz,1H),7.72 (s,1H),7.50–7.41(m,3H),7.31–7.22(m,3H),7.21–7.17(m,1H),5.18–5.06(m,1H),4.16(d,J＝2.1Hz, 2H),4.09(p,J＝7.0Hz,1H),3.91(s,3H),3.69–3.53(m,2H),3.14–2.88(m,7H),2.87–2.74(m,5H),2.54– 2.38(m,7H),1.91–1.75(m,2H).MS(ESI,m/z):755.3[M+1]+.
Example 57: synthesis of compound JLPD055 (S) -1- ((2- (3- ((S) -1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-fluoroph-olo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ7.99(dd,J＝7.3,1.8Hz,1H),7.74 (s,1H),7.51–7.37(m,3H),7.31–7.19(m,4H),5.12(t,J＝7.0Hz,1H),4.28–4.08(m,2H),3.91(s,3H),3.81– 3.56(m,4H),3.15–2.85(m,7H),2.84–2.72(m,5H),2.49(q,J＝7.1Hz,2H),1.89–1.74(m,2H).MS(ESI, m/z):701.2[M+1]+.
Example 58: synthesis of compound JLPD056 (S) -1- ((2- (3- ((S) -1- ((3-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-fluoroph-olo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.00(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.51–7.36(m,3H),7.31–7.24(m,3H),7.22(d,J＝1.4Hz,1H),5.17–5.08(m,1H),4.12(q,J＝12.4 Hz,2H),3.90(s,3H),3.76(p,J＝7.0Hz,1H),3.71–3.57(m,2H),3.15–2.84(m,6H),2.84–2.72(m,6H),2.49 (q,J＝7.1Hz,2H),2.36–2.20(m,2H),1.99–1.66(m,4H).MS(ESI,m/z):754.3[M+1]+.
Example 59: synthesis of compound JLPD057 (S) -1- ((2- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-fluoroph-olo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.00(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.51–7.36(m,3H),7.32–7.23(m,3H),7.22(d,J＝1.4Hz,1H),5.19–5.07(m,1H),4.16(d,J＝2.1Hz, 2H),4.09(p,J＝7.0Hz,1H),3.91(s,3H),3.74–3.53(m,2H),3.14–2.85(m,7H),2.83–2.71(m,5H),2.54– 2.38(m,4H),1.88–1.76(m,2H).MS(ESI,m/z):759.3[M+1]+.
Example 60: synthesis of compound JLPD058 (S) -1- ((2- (2-chloro-3- ((S) -1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ7.83(dd,J＝7.1,1.9Hz,1H),7.74 (s,1H),7.61–7.56(m,2H),7.56–7.45(m,2H),7.41–7.25(m,3H),5.13(td,J＝7.0,0.6Hz,1H),4.28–4.10 (m,2H),3.91(s,3H),3.82–3.55(m,4H),3.17–2.88(m,7H),2.87–2.73(m,2H),2.49(q,J＝7.1Hz,2H),1.90 –1.76(m,2H).MS(ESI,m/z):728.2[M+1]+.
Example 61: synthesis of compound JLPD059 (S) -1- ((2- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ7.83(dd,J＝7.1,1.9Hz,1H),7.74 (s,1H),7.61–7.56(m,2H),7.56–7.46(m,2H),7.38–7.31(m,2H),7.31–7.24(m,1H),5.13(td,J＝7.0,0.6 Hz,1H),4.12(q,J＝12.4Hz,2H),3.90(s,3H),3.82–3.56(m,3H),3.17–2.87(m,6H),2.84–2.72(m,3H), 2.49(q,J＝7.1Hz,2H),2.38–2.18(m,2H),1.99–1.72(m,4H).MS(ESI,m/z):781.2[M+1]+.
Example 62: synthesis of compound JLPD060 (S) -1- ((2- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorophenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ7.83(dd,J＝7.1,1.9Hz,1H),7.72 (s,1H),7.62–7.56(m,2H),7.56–7.46(m,2H),7.38–7.31(m,2H),7.31–7.24(m,1H),5.13(td,J＝7.0,0.6 Hz,1H),4.25–4.02(m,3H),3.91(s,3H),3.74–3.56(m,2H),3.17–2.87(m,7H),2.87–2.73(m,2H),2.54– 2.37(m,4H),1.88–1.73(m,2H).MS(ESI,m/z):786.2[M+1]+.
Example 63: synthesis of compound JLPD061 (S) -1- ((2- (2-chloro-3- ((S) -1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -7-cyanobenzo [ d ] thiazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.13(d,J＝1.4Hz,1H),7.78(d,J ＝1.4Hz,1H),7.74(s,1H),7.69(dd,J＝6.9,2.1Hz,1H),7.56–7.44(m,2H),7.37–7.24(m,3H),5.13(t,J＝7.0 Hz,1H),4.28–4.09(m,2H),3.91(s,3H),3.82–3.55(m,4H),3.10–2.89(m,7H),2.86–2.74(m,2H),2.49(q, J＝7.1Hz,2H),1.89–1.75(m,2H).MS(ESI,m/z):744.2[M+1]+.
Example 64: synthesis of Compound JLPD062 (S) -1- ((2- (3- ((S) -1- ((3-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] thiazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.11(d,J＝1.5Hz,1H),7.76(d,J ＝1.5Hz,1H),7.74(s,1H),7.54(dd,J＝7.5,1.8Hz,1H),7.48(t,J＝7.4Hz,1H),7.41–7.30(m,2H),7.29–7.21 (m,2H),5.17–5.08(m,1H),4.12(q,J＝12.4Hz,2H),3.90(s,3H),3.83–3.53(m,3H),3.16–3.02(m,2H), 2.99–2.75(m,7H),2.70(s,3H),2.49(q,J＝7.1Hz,2H),2.36–2.18(m,2H),1.99–1.64(m,4H).MS(ESI, m/z):777.3[M+1]+.
Example 65: synthesis of JLPD063 (S) -1- ((2- (3- ((S) -1- ((5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] thiazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.11(d,J＝1.5Hz,1H),7.78(d,J ＝1.4Hz,1H),7.72(s,1H),7.54(dd,J＝7.5,1.8Hz,1H),7.48(t,J＝7.4Hz,1H),7.43–7.30(m,2H),7.29–7.18 (m,2H),5.17–5.04(m,1H),4.25–4.03(m,3H),3.91(s,3H),3.77–3.48(m,2H),3.16–3.02(m,3H),3.01– 2.88(m,4H),2.87–2.73(m,2H),2.70(s,3H),2.55–2.38(m,4H),1.92–1.72(m,2H).MS(ESI,m/z):782.3 [M+1]+.
Example 66: synthesis of compound JLPD064 (S) -1- ((2- (3- ((S) -1- ((6- (benzyloxy) -3-chloro-5- ((2-hydroxyethyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Synthesis method JLPD001 was used as a synthesis method.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.75 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.37(m,5H),7.37–7.29(m,3H),7.28–7.21(m, 2H),5.34–5.18(m,2H),5.13(t,J＝7.0Hz,1H),4.24–4.07(m,2H),3.81–3.56(m,4H),3.16–2.88(m,7H), 2.88–2.76(m,2H),2.74(s,3H),2.49(q,J＝7.1Hz,2H),1.88–1.74(m,2H).MS(ESI,m/z):784.3[M+1]+.
Example 67: synthesis of compound JLPD065 (S) -1- ((2- (3- ((S) -1- ((6- (benzyloxy) -3-chloro-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.03–7.95(m,1H),7.75(s,1H), 7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.38(m,5H),7.38–7.22(m,5H),5.35–5.18(m,2H), 5.13(td,J＝7.0,0.5Hz,1H),4.25–4.05(m,2H),3.84–3.52(m,3H),3.11–2.78(m,9H),2.74(s,3H),2.49(q,J ＝7.1Hz,2H),2.38–2.19(m,2H),2.04–1.67(m,4H).MS(ESI,m/z):837.3[M+1]+.
Example 68: synthesis of compound JLPD066 (S) -1- ((2- (3- ((S) -1- ((6- (benzyloxy) -5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloropyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.03–7.95(m,1H),7.75(s,1H), 7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.51–7.39(m,5H),7.38–7.23(m,5H),5.32–5.19(m,2H), 5.13(td,J＝7.0,0.5Hz,1H),4.26–4.02(m,3H),3.72–3.54(m,2H),3.10–2.90(m,7H),2.87–2.76(m,2H), 2.74(s,3H),2.55–2.38(m,4H),1.91–1.73(m,2H).MS(ESI,m/z):842.3[M+1]+.
Example 69: synthesis of compound JLPD067 (S) -1- ((2- (3- ((S) -1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6- ((5- (methylsulfonyl) pyridin-3-yl) methoxy) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.71(d,J＝1.6Hz,1H),8.64(d,J ＝1.4Hz,1H),8.21(t,J＝1.5Hz,1H),8.05–7.93(m,1H),7.73(s,1H),7.60(d,J＝1.4Hz,1H),7.57(d,J＝1.5 Hz,1H),7.50–7.39(m,3H),7.33–7.20(m,2H),5.38–5.21(m,2H),5.13(td,J＝7.0,0.5Hz,1H),4.28–4.09 (m,2H),3.82–3.55(m,4H),3.24(s,3H),3.12–2.90(m,7H),2.84–2.77(m,2H),2.74(s,3H),2.49(q,J＝7.1 Hz,2H),1.89–1.73(m,2H).MS(ESI,m/z):863.3[M+1]+.
Example 70: synthesis of compound JLPD068 (S) -1- ((2- (3- ((S) -1- ((3-chloro-6- ((5- (methylsulfonyl) pyridin-3-yl) methoxy) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.71(d,J＝1.6Hz,1H),8.64(d,J ＝1.4Hz,1H),8.21(t,J＝1.5Hz,1H),8.03–7.93(m,1H),7.73(s,1H),7.60(d,J＝1.4Hz,1H),7.57(d,J＝1.5 Hz,1H),7.50–7.39(m,3H),7.33–7.21(m,2H),5.36–5.23(m,2H),5.13(td,J＝7.0,0.5Hz,1H),4.19–4.03 (m,2H),3.76(p,J＝7.0Hz,1H),3.71–3.55(m,2H),3.24(s,3H),3.13–2.79(m,9H),2.74(s,3H),2.49(q,J＝ 7.1Hz,2H),2.35–2.20(m,2H),1.93–1.73(m,4H).MS(ESI,m/z):916.3[M+1]+.
Example 71: synthesis of compound JLPD069 (S) -1- ((2- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6- ((5- (methylsulfonyl) pyridin-3-yl) methoxy) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.71(d,J＝1.5Hz,1H),8.64(d,J ＝1.4Hz,1H),8.21(t,J＝1.5Hz,1H),8.02–7.93(m,1H),7.70(s,1H),7.60(d,J＝1.4Hz,1H),7.57(d,J＝1.5 Hz,1H),7.50–7.40(m,3H),7.33–7.23(m,2H),5.38–5.23(m,2H),5.13(td,J＝7.0,0.5Hz,1H),4.23–4.02 (m,3H),3.71–3.55(m,2H),3.24(s,3H),3.15–2.91(m,7H),2.86–2.77(m,2H),2.74(s,3H),2.54–2.37(m, 4H),1.87–1.74(m,2H).MS(ESI,m/z):921.3[M+1]+.
Example 72: synthesis of compound JLPD070 (S) -1- ((2- (3- ((S) -1- ((3-chloro-6- ((5-cyanopyridin-3-yl) methoxy) -5- ((2-hydroxyethyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.80–8.75(m,1H),8.70(d,J＝ 1.6Hz,1H),8.11(t,J＝1.5Hz,1H),8.01(dd,J＝7.2,1.8Hz,1H),7.74(s,1H),7.62(d,J＝1.5Hz,1H),7.56(d, J＝1.5Hz,1H),7.51–7.37(m,3H),7.33–7.19(m,2H),5.33–5.19(m,2H),5.17–5.10(m,1H),4.27–4.07(m, 2H),3.80–3.55(m,4H),3.17–2.89(m,7H),2.85–2.77(m,2H),2.74(s,3H),2.49(q,J＝7.1Hz,2H),1.88– 1.74(m,2H).MS(ESI,m/z):810.3[M+1]+.
Example 73: synthesis of compound JLPD071 (S) -1- ((2- (3- ((S) -1- ((3-chloro-6- ((5-cyanopyridin-3-yl) methoxy) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.80–8.76(m,1H),8.72–8.69(m, 1H),8.13(t,J＝1.5Hz,1H),8.02–7.94(m,1H),7.73(s,1H),7.60(d,J＝1.4Hz,1H),7.57(d,J＝1.5Hz,1H), 7.51–7.39(m,3H),7.34–7.21(m,2H),5.32–5.17(m,2H),5.13(td,J＝7.0,0.5Hz,1H),4.21–4.05(m,2H), 3.83–3.54(m,3H),3.14–2.85(m,6H),2.85–2.75(m,3H),2.74(s,3H),2.49(q,J＝7.1Hz,2H),2.37–2.20 (m,2H),1.96–1.71(m,4H).MS(ESI,m/z):863.3[M+1]+.
Example 74: synthesis of compound JLPD072 (S) -1- ((2- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6- ((5-cyanopyridin-3-yl) methoxy) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.78(d,J＝1.61Hz,1H),8.74– 8.67(m,1H),8.13(t,J＝1.48Hz,1H),8.04–7.94(m,1H),7.70(s,1H),7.60(d,J＝1.44Hz,1H),7.57(d,J＝ 1.54Hz,1H),7.51–7.39(m,3H),7.34–7.22(m,2H),5.31–5.19(m,2H),5.13(td,J＝7.02,0.50Hz,1H),4.21 –4.02(m,3H),3.73–3.55(m,2H),3.12–2.91(m,7H),2.87–2.77(m,2H),2.74(s,3H),2.54–2.36(m,4H), 1.90–1.73(m,2H).MS(ESI,m/z):868.3[M+1]+.
Example 75: synthesis of Compound JL073 (S) -1- ((2- (3- ((S) -1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6- (2- (methylamino) -2-oxoethoxy) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Synthesis method JLPD001 was used as a synthesis method.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.78 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.29–7.21(m,2H),5.19–5.09(m, 1H),4.71(q,J＝12.4Hz,2H),4.26–4.07(m,2H),3.82–3.56(m,4H),3.15–2.88(m,7H),2.87–2.76(m,2H), 2.75(d,J＝3.6Hz,6H),2.49(q,J＝7.1Hz,2H),1.91–1.74(m,2H).MS(ESI,m/z):765.3[M+1]+.
Example 76: synthesis of compound JLPD074 (S) -1- ((2- (3- ((S) -1- ((3-chloro-6- (2- (methylamino) -2-oxoethoxy) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.78 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.31–7.22(m,2H),5.13(t,J＝7.0 Hz,1H),4.71(q,J＝12.4Hz,2H),4.12(q,J＝12.4Hz,2H),3.82–3.56(m,3H),3.14–2.87(m,6H),2.87–2.76 (m,3H),2.74(d,J＝1.3Hz,6H),2.49(q,J＝7.1Hz,2H),2.34–2.19(m,2H),2.00–1.66(m,4H).MS(ESI, m/z):818.3[M+1]+.
Example 77: synthesis of compound JLPD075 (S) -1- ((2- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6- (2- (methylamino) -2-oxoethoxy) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ7.99(t,J＝4.5Hz,1H),7.78(s, 1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.51–7.38(m,3H),7.33–7.23(m,2H),5.16–5.07(m, 1H),4.71(q,J＝12.4Hz,2H),4.21–4.01(m,3H),3.74–3.53(m,2H),3.12–2.90(m,7H),2.87–2.77(m,2H), 2.74(d,J＝1.3Hz,6H),2.55–2.34(m,4H),1.91–1.71(m,2H).MS(ESI,m/z):823.3[M+1]+.
Example 78: synthesis of compound JLPD076 (R) -1- ((2- (3- ((S) -1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.60(d,J＝1.4Hz,1H),7.55(d,J＝1.5Hz,1H),7.51–7.37(m,3H),7.29–7.22(m,2H),5.16–5.07(m, 1H),4.27–4.08(m,2H),3.91(s,3H),3.81–3.55(m,4H),3.14–2.88(m,6H),2.82–2.71(m,4H),2.63–2.42 (m,3H),2.03–1.80(m,2H),1.27(s,3H).MS(ESI,m/z):722.3[M+1]+.
Example 79: synthesis of compound JLPD077 (R) -1- ((2- (3- ((S) -1- ((3-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.60(d,J＝1.4Hz,1H),7.55(d,J＝1.5Hz,1H),7.50–7.36(m,3H),7.31–7.22(m,2H),5.13(t,J＝7.0 Hz,1H),4.12(q,J＝12.4Hz,2H),3.90(s,3H),3.83–3.56(m,3H),3.14–2.96(m,4H),2.94–2.84(m,1H), 2.83–2.69(m,5H),2.64–2.44(m,3H),2.38–2.19(m,2H),2.05–1.82(m,3H),1.81–1.66(m,1H),1.26(s, 3H).MS(ESI,m/z):775.3[M+1]+.
Example 80: synthesis of compound JLPD078 (R) -1- ((2- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.60(d,J＝1.4Hz,1H),7.55(d,J＝1.5Hz,1H),7.50–7.36(m,3H),7.31–7.21(m,2H),5.18–5.05(m, 1H),4.23–4.03(m,3H),3.91(s,3H),3.64(q,J＝12.4Hz,2H),3.15–2.91(m,6H),2.82–2.70(m,4H),2.62– 2.38(m,5H),2.02–1.81(m,2H),1.26(s,3H).MS(ESI,m/z):780.3[M+1]+.
Example 81: synthesis of compound JLPD079 (R) -1- ((2- (3- ((S) -1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.62(d,J＝1.4Hz,1H),7.55(d,J＝1.5Hz,1H),7.50–7.36(m,3H),7.32–7.22(m,2H),5.13(t,J＝7.0 Hz,1H),4.26–4.10(m,2H),3.91(s,3H),3.80–3.56(m,4H),3.14–2.85(m,8H),2.85–2.71(m,4H),2.49(q, J＝7.1Hz,2H),1.96–1.71(m,2H).MS(ESI,m/z):708.3[M+1]+.
Example 82: synthesis of compound JLPD080 (R) -1- ((2- (3- ((S) -1- ((3-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.49–7.36(m,3H),7.29–7.21(m,2H),5.16–5.09(m, 1H),4.12(q,J＝12.4Hz,2H),3.90(s,3H),3.83–3.54(m,3H),3.13–3.01(m,2H),3.00–2.85(m,5H),2.85– 2.72(m,5H),2.49(q,J＝7.1Hz,2H),2.36–2.20(m,2H),1.95–1.69(m,4H).MS(ESI,m/z):761.3[M+1]+.
Example 83: synthesis of JLPD081 (R) -1- ((2- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.62(d,J＝1.5Hz,1H),7.56(d,J＝1.5Hz,1H),7.52–7.36(m,3H),7.32–7.21(m,2H),5.19–5.09(m, 1H),4.20–4.01(m,3H),3.91(s,3H),3.73–3.57(m,2H),3.16–3.00(m,3H),3.00–2.85(m,5H),2.85–2.69 (m,4H),2.55–2.39(m,4H),1.93–1.71(m,2H).MS(ESI,m/z):766.3[M+1]+.
Example 84: synthesis of compound JLPD082 (S) -1- ((2- (3- (1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) piperidine-4-carboxylic acid
Synthesis method with reference to JLPD001A synthetic method.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.62(d,J＝1.6Hz,1H),7.53(d,J＝1.5Hz,1H),7.51–7.35(m,3H),7.30–7.21(m,2H),5.18–5.05(m, 1H),4.29–4.10(m,2H),3.91(s,3H),3.81–3.63(m,2H),3.61(s,2H),3.14–2.89(m,4H),2.87–2.76(m,4H), 2.74(s,3H),2.51(dq,J＝13.1,7.0Hz,3H),1.95–1.78(m,4H).MS(ESI,m/z):722.3[M+1]+.
Example 85: synthesis of compound JLPD083 1- ((2- (3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) piperidine-4-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.62(d,J＝1.6Hz,1H),7.53(d,J＝1.5Hz,1H),7.49–7.36(m,3H),7.29–7.22(m,2H),5.13(t,J＝7.0 Hz,1H),4.12(q,J＝12.4Hz,2H),3.90(s,3H),3.76(p,J＝7.0Hz,1H),3.61(s,2H),3.15–2.98(m,2H),2.89– 2.72(m,9H),2.50(qd,J＝7.0,6.0Hz,3H),2.36–2.19(m,2H),1.98–1.67(m,6H).MS(ESI,m/z):775.3 [M+1]+.
Example 86: synthesis of compound JLPD084 1- ((2- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) piperidine-4-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.62(d,J＝1.6Hz,1H),7.53(d,J＝1.5Hz,1H),7.50–7.36(m,3H),7.32–7.21(m,2H),5.17–5.07(m, 1H),4.23–4.02(m,3H),3.91(s,3H),3.61(s,2H),3.15–2.91(m,4H),2.88–2.70(m,7H),2.59–2.38(m,5H), 1.94–1.78(m,4H).MS(ESI,m/z):780.3[M+1]+.
Example 87: synthesis of compound JLPD085 (S) -1- ((2- (3- (1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) azetidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.60(d,J＝1.4Hz,1H),7.54(d,J＝1.4Hz,1H),7.52–7.37(m,3H),7.29–7.22(m,2H),5.12(t,J＝7.0 Hz,1H),4.26–4.08(m,2H),3.91(s,3H),3.79–3.58(m,4H),3.37(dd,J＝7.0,1.0Hz,4H),3.14–2.86(m,5H), 2.74(s,3H),2.49(q,J＝7.1Hz,2H).MS(ESI,m/z):694.2[M+1]+.
Example 88: synthesis of compound JLPD086 1- ((2- (3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) azetidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.60(d,J＝1.4Hz,1H),7.55(d,J＝1.5Hz,1H),7.51–7.37(m,3H),7.33–7.21(m,2H),5.13(t,J＝7.0 Hz,1H),4.12(q,J＝12.4Hz,2H),3.90(s,3H),3.82–3.62(m,3H),3.37(dd,J＝7.0,1.0Hz,4H),3.16–2.97(m, 2H),2.97–2.85(m,2H),2.83–2.72(m,4H),2.49(q,J＝7.1Hz,2H),2.38–2.19(m,2H),1.97–1.86(m,1H), 1.80–1.66(m,1H).MS(ESI,m/z):747.3[M+1]+.
Example 89: synthesis of compound JLPD087 1- ((2- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) azetidine-3-carboxylic acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.60(d,J＝1.4Hz,1H),7.55(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.32–7.22(m,2H),5.16–5.09(m, 1H),4.22–4.01(m,3H),3.91(s,3H),3.69(q,J＝12.4Hz,2H),3.37(dd,J＝7.0,1.0Hz,4H),3.16–3.01(m, 3H),3.00–2.86(m,2H),2.74(s,3H),2.62–2.36(m,4H).MS(ESI,m/z):752.2[M+1]+.
Example 90: synthesis of compound JLPD088:2- (3- ((S) -1- ((3-chloro-5- ((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- ((R) -3-hydroxypyrrolidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.61(d,J＝1.4Hz,1H),7.54(d,J＝1.4Hz,1H),7.53–7.35(m,3H),7.30–7.20(m,2H),5.12(t,J＝7.0 Hz,1H),4.28–4.09(m,3H),3.91(s,3H),3.79–3.50(m,4H),3.40–3.27(m,1H),3.15–2.78(m,7H),2.74(s, 3H),2.49(q,J＝7.1Hz,2H),1.87–1.69(m,1H),1.70–1.50(m,1H).MS(ESI,m/z):680.3[M+1]+.
Example 91: synthesis of compound JLPD089:2- (3- ((S) -1- ((3-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- ((R) -3-hydroxypyrrolidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.74 (s,1H),7.61(d,J＝1.5Hz,1H),7.55(d,J＝1.5Hz,1H),7.50–7.36(m,3H),7.29–7.21(m,2H),5.13(t,J＝7.0 Hz,1H),4.25–4.03(m,3H),3.91(s,3H),3.76(p,J＝7.0Hz,1H),3.70–3.51(m,2H),3.42–3.28(m,1H),3.15 –2.98(m,2H),2.95–2.80(m,5H),2.74(s,3H),2.49(q,J＝7.1Hz,2H),2.37–2.18(m,2H),1.98–1.86(m, 1H),1.85–1.68(m,2H),1.62(dq,J＝12.6,7.2Hz,1H).MS(ESI,m/z):733.3[M+1]+.
Example 92: synthesis of compound JLPD090 (S) -4- ((5-chloro-6- (((S) -4- (3- (7-cyano-5- ((R) -3-hydroxypyrrolidin-1-yl) methyl) benzo [ d ] oxazol-2-yl) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis method is referred to the synthesis method of JLPD 001.1H NMR(300MHz,Chloroform-d)δ8.01(dd,J＝7.2,1.8Hz,1H),7.72 (s,1H),7.61(d,J＝1.5Hz,1H),7.55(d,J＝1.5Hz,1H),7.50–7.37(m,3H),7.30–7.23(m,2H),5.13(t,J＝7.0 Hz,1H),4.25–4.01(m,4H),3.91(s,3H),3.72–3.53(m,2H),3.38–3.29(m,1H),3.15–2.90(m,4H),2.91– 2.77(m,3H),2.74(s,3H),2.55–2.38(m,4H),1.79(dq,J＝12.5,7.1Hz,1H),1.62(dq,J＝12.5,7.2Hz,1H). MS(ESI,m/z):738.3[M+1]+.
Experimental example 1 determination of inhibitory Activity of PD1/PD-L1
(I) Experimental Equipment and reagent
(II) procedure of experiment
1.1 × modified TR-FRET assay buffer is prepared.
2. Preparation of compound concentration gradient: test compound concentrations were 10000nM starting, 3-fold dilution, 10 concentration points, single well assay. The solution was diluted to 100-fold final concentration in 384-well plates and then 200nL was transferred to 384 reaction plates with Echo550 for use. 200nL of 100% DMSO was added to each of the negative and positive control wells.
3. PD-L1-Biotin solution was prepared at 4-fold final concentration using a 1 Xmodified TR-FRET assay buffer.
4. Add 5. mu.L of PD-L1-Biotin solution with 4 times final concentration to the compound well and the positive control well, respectively; mu.L of 1 × modified TR-FRET assay buffer was added to the negative control wells.
5.1000rpm for 30 seconds, and after shaking and mixing, incubating at room temperature for 15 minutes.
6. A mixed solution of PD-1-Eu of 4 times final concentration and Dye labeled acceptor of 2 times final concentration was prepared using 1 Xmodified TR-FRET assay buffer.
7. mu.L of a mixed solution of PD-1-Eu and Dye labeled receptor (containing 5. mu.L of PD-1-Eu at 4-fold final concentration and 10. mu.L of Dye labeled receptor at 2-fold final concentration) was added.
8.1000rpm for 30 seconds, and after shaking and mixing, incubating at room temperature for 90 minutes.
9. The 384 well plate was centrifuged at 1000rpm for 30 seconds, after shaking and mixing, fluorescence intensities at 665nm and 620nm were read by EnVision, and TR-FRET ratio (665nm emission/620nm emission) was calculated.
(III) data analysis
Calculating the formula:
wherein: ratiosampleIs the ratio of sample wells; ratio (R)min: negative control well ratio mean, representing the reading of wells without the PD-1/PD-L1 interaction; ratio (R)max: positive control wells are averaged, representing readings from wells without compound inhibition.
Fitting a dose-response curve:
the log values of the concentrations were taken as the X-axis and the percent inhibition as the Y-axis, and the quantitative effect curves were fitted using the analytical software GraphPad Prism 5 log (inhibition) vs. response-Variable slope to obtain the IC50 values of each compound for enzyme activity.
(IV) results of the experiment
The results of the PD1/PD-L1 inhibitory activity assay are shown in Table 1:
table 1: PD1/PD-L1 inhibitory activity determination experiment result
EXAMPLE 2 Jurkat reporter Gene cell Activity assay
The effect of the compounds of the examples of the present invention on the interaction of PD-1/PD-L1 protein expressed on the cell surface and the resulting effect on T cell function was determined by the Jurkat reporter gene cell activity assay. Briefly, a plasmid of a reporter gene of NF-kB-Luc and a plasmid of human PD-1 are transfected into Jurkat cells, a stable cell strain which stably expresses both PD-1 and NF-kB-Luc reporter genes is established, the surface expression level of PD-1 is identified by adopting flow cytometry, and the expression level of the reporter gene is identified by using OKT-3 and the response of the reporter gene after Raiji cell stimulation. In addition, the expression plasmid of human PD-Ll is transfected into Raji cells to obtain a cell strain which stably expresses PD-Ll. The enhancement of the T cell activation signaling pathway by the inhibition of the compound on the PD-1/PD-L1 interaction is then reflected by the readout of the reporter gene response by co-culturing Jurkat/NF-kB-Luc/PD-L cells and Raji-PD-Ll cells and stimulating with OKT-3. IC in the experimental result of the determination of the inhibitory activity of the selected PD1/PD-L150Compounds of less than 1.50nM were tested for Jurkat reporter cell activity. The specific experimental method is as follows:
1. to a white 96-well plate 30. mu.L of the test compound at different dilution concentrations was added, followed by 10. mu.L of O K T3 (Biolegend,317329) (OKT3 final concentration l.0. mu.g/mL);
2. add 20. mu.L of Raji-PD-Ll cell suspension to each well, 5X 10 per well4cells, incubate for 20 minutes in incubator;
3. add 20. mu.L of Jurkat/NF-. kappa.B-Luc/PD-1 cell suspension to each well at 5X 10 per well4cells, mix well, and detect Bright-glo (Promega, E2625) after 6 h;
4. comparing readings obtained from each well after compound treatment with readings obtained from DMSO-treated wells to obtain the fold activation of compound action;
5. determination of EC for Compounds of examples of the invention by nonlinear regression analysis of fold activation at different Compound concentrations5OThe value is obtained. The specific experimental results are shown in table 2:
TABLE 2 Jurkat reporter Gene cell Activity test results
Experimental example 3 in vivo pharmacokinetic study of the Compound
The experiment was performed in male SD rats, the animal source being from zhejiang vitamin tonglihua laboratory animals ltd. The compound JLPD059 was selected as the experimental drug.
The experimental process comprises the following steps: rats were weighed before dosing and the dose was calculated from body weight. Administration was by intravenous injection (dose: 2mg/kg) or oral gavage (dose: 10 mg/kg). Before intravenous injection administration, blood is collected 1min, 2min, 5min, 10min, 30min, 1h, 2h, 5h, 8h, 12h, 16h and 24h after administration. Before the oral administration of the gavage, blood is collected for 1min, 2min, 5min, 10min, 30min, 1h, 2h, 5h, 8h, 12h, 16h and 24h after the administration. The blood is collected through the orbit, and about 0.30mL, K is collected from each sample2EDTA anticoagulation, and placing on ice after collection. Collecting blood sample, and placing on iceAnd plasma was centrifuged within 1 hour (centrifugation conditions: 8000g, 10 minutes, 2-8 ℃ C.). Plasma samples were stored in a-80 ℃ freezer prior to analysis. The test plasma is analyzed by an HPLC-MS instrument, the accuracy of the quality control sample in the day is evaluated while the sample is analyzed, and the accuracy of the quality control sample exceeding 66.7 percent is required to be between 80 and 120 percent. Pharmacokinetic parameters were calculated from the plasma concentration data at different time points using Phoenix winnonlin7.0, and the experimental results are shown in table 3.
Table 3 compound JLPD059 pharmacokinetic parameters in rats
The experimental result shows that the compound JLPD059 can be orally absorbed and has better pharmacokinetic property. The other compounds of the invention can also be absorbed orally and have better pharmacokinetic properties.
Experimental example 4 evaluation of in vivo drug efficacy of Compound
To verify the in vivo efficacy of the compounds of the present invention, the compound JLPD059 was selected for this experiment using a model of subcutaneous tumor implantation of mouse melanoma high-metastatic cells (B16F 10). The experiment was divided into vehicle control group, positive drug group (BMS-202,80mg/kg), compound JLPD059(10mg/kg) and compound JLPD059(30 mg/kg).
Animals: female C57BL/6 mice (purchased from Beijing Wintolite laboratory animals technology Co., Ltd.) weighing 18-22g, were 8 weeks old and were started after 1 week of acclimatization.
The specific operation is as follows: B16F10 cells in logarithmic growth phase were trypsinized and centrifuged to collect cells, resuspended 2 times in PBS and adjusted to 2 x 10 cell density in PBS6Each mouse was inoculated subcutaneously with 100. mu.L of cell suspension per mouse. The mice are randomly grouped after 6 hours of inoculation, 8 mice in a blank control group and 10 mice in the other three groups are respectively weighed and then administered; the compound is ground into suspension with 0.5% sodium carboxymethylcellulose water solution, administered once daily, tumor volume is measured with vernier caliper daily, and administered for 14 daysThe mice were sacrificed by cervical dislocation and tumor tissue was dissected and weighed.
Formula for calculation of tumor volume: v is 0.5a × b2And a and b represent the major and minor diameters of the tumor, respectively.
Formula for calculating relative tumor proliferation rate T/C (%): T/C ═ TRTV/CRTV × 100% (TRTV: treatment group RTV; CRTV: solvent control group RTV). From the measurements, the Relative Tumor Volume (RTV) was calculated, where Vo is the tumor volume at the beginning of the experiment and Vt is the tumor volume at each measurement.
Formula for calculating tumor growth inhibition rate TGI (%): TGI ═ 1- (average tumor volume at the end of a certain group of administrations-average tumor volume at the beginning of the group of administrations)/(average tumor volume at the end of the vehicle control group treatment-average tumor volume at the beginning of the vehicle control group treatment) ] × 100%.
The results of the experiment are shown in FIG. 1. The experimental result shows that the compound JLPD059 has obvious in-vivo anti-tumor effect. The tumor growth inhibition rate of the 10mg/kg group is 48.38%, and the tumor growth inhibition rate of the 30mg/kg group is 63.16%, which indicates that the compound JLPD059 can effectively inhibit the tumor growth. Other compounds of the invention also have similar anti-tumor efficacy.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (9)
1. A compound shown as a general formula I or a pharmaceutically acceptable salt, racemate, optical isomer, metabolite, metabolic precursor, prodrug or solvate thereof, wherein the structure is shown as follows:
R1independently is hydrogen, deuterium, substituted orUnsubstituted hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R2independently hydrogen, deuterium, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R3independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R4independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R5independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R6independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R7independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl;
m is 1 or 2;
n is 1 or 2;
X1independently an oxygen atom, a sulfur atom, a nitrogen atom;
X2independently carbon atom, nitrogen atom;
X3independently an oxygen atom, a carbon atom, a nitrogen atom;
X4independently a carbon atom, a nitrogen atom;
each R1Wherein the substituent of the substituted alkyl or the substituted alkoxy is selected from halogen, C1-C4 alkyl, hydroxyl, carboxyl, amino, or amino, or amino, or amino, amino,
Benzyl, benzyl with cyano substituent, C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 amido; the substituent of the substituted hydroxyl or the substituted amino is selected from C1-C4 alkyl, benzyl of cyano substituent, C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester or C1-C4 amide; when the number of the substituents is plural, the substituents may be the same or different;
the above-mentioned
In, R8And R9Independently hydrogen, substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl or aminoalkyl groups; or R5、R6Together with the nitrogen atom to which they are attached form a 5-7 membered substituted or unsubstituted carbon heterocyclic ring; in the carbon heterocycle, the heteroatom is nitrogen, nitrogen or oxygen, and the number of the heteroatoms is 1-4;
R8or R9Wherein the substituent of the substituted alkyl is selected from the group consisting of halogen, C1-C4 alkyl, hydroxy, and a,
C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 acylamino; r is5、R6And the nitrogen atom to which they are attached, together form a 5-7 membered substituted carbon heterocyclic ring;
the substituent in the substituted carbon heterocycle is selected from halogen, C1-C4 alkyl, hydroxyl,
C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 acylamino; when a plurality of substituents are present, the substituents may be the same or different;
2. A compound according to claim 1 of the general formula I or a pharmaceutically acceptable salt, racemate, optical isomer, metabolite, metabolic precursor, prodrug or solvate thereof, wherein:
in R3, the group is more preferably cyano; the group in R5 is preferably halogen, the halogen is more preferably chlorine atom; the group in R6 is preferably a substituted or unsubstituted alkoxy group, and the substituted or unsubstituted alkoxy group is more preferably a methoxy group; in R7, the group is more preferably methyl.
3. A compound according to claim 1 of the general formula I or a pharmaceutically acceptable salt, racemate, optical isomer, metabolite, metabolic precursor, prodrug or solvate thereof, wherein:
wherein R is1Selected from:
wherein R is2Selected from:
4. a compound according to claim 1 of the general formula I or a pharmaceutically acceptable salt, racemate, optical isomer, metabolite, metabolic precursor, prodrug or solvate thereof, wherein: wherein the compound shown in the formula I is at least one of the following compounds:
5. a pharmaceutical composition comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, racemate, optical isomer, metabolite, metabolic precursor, prodrug or solvate thereof, and a pharmaceutically acceptable adjuvant.
6. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, racemate, optical isomer, metabolite, metabolic precursor, prodrug or solvate thereof, or a pharmaceutical composition according to claim 5, in the manufacture of a medicament for use as an immune checkpoint inhibitor.
7. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, racemate, optical isomer, metabolite, metabolic precursor, prodrug or solvate thereof, or a pharmaceutical composition according to claim 5, for the preparation of an inhibitor of the inhibitory activity of the PD-L/PD-L1 signaling pathway.
8. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, racemate, optical isomer, metabolite, metabolic precursor, prodrug or solvate thereof, or a pharmaceutical composition according to claim 5, in the manufacture of an anti-neoplastic or anti-infective medicament.
9. A pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is in the form of any one of capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories, or patches.
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| CN116283896A (en) * | 2022-09-07 | 2023-06-23 | 广东晨康生物科技有限公司 | Biphenyl compound with PD-L1 inhibition activity and application thereof |
Citations (3)
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|---|---|---|---|---|
| CN110799509A (en) * | 2017-04-20 | 2020-02-14 | 吉利德科学公司 | PD-1/PD-L1 inhibitors |
| CN113121464A (en) * | 2021-04-21 | 2021-07-16 | 中国药科大学 | Five-membered heterocyclic substituted biphenyl compound and preparation method and application thereof |
| CN113637013A (en) * | 2020-05-11 | 2021-11-12 | 上海长森药业有限公司 | Preparation and application of biaryl ring linked aromatic heterocyclic derivative as immunomodulator |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110799509A (en) * | 2017-04-20 | 2020-02-14 | 吉利德科学公司 | PD-1/PD-L1 inhibitors |
| CN113637013A (en) * | 2020-05-11 | 2021-11-12 | 上海长森药业有限公司 | Preparation and application of biaryl ring linked aromatic heterocyclic derivative as immunomodulator |
| CN113121464A (en) * | 2021-04-21 | 2021-07-16 | 中国药科大学 | Five-membered heterocyclic substituted biphenyl compound and preparation method and application thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116283896A (en) * | 2022-09-07 | 2023-06-23 | 广东晨康生物科技有限公司 | Biphenyl compound with PD-L1 inhibition activity and application thereof |
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