WO2023050104A1 - 二氢吲哚衍生物、及其制法和药物组合物与用途 - Google Patents
二氢吲哚衍生物、及其制法和药物组合物与用途 Download PDFInfo
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- WO2023050104A1 WO2023050104A1 PCT/CN2021/121488 CN2021121488W WO2023050104A1 WO 2023050104 A1 WO2023050104 A1 WO 2023050104A1 CN 2021121488 W CN2021121488 W CN 2021121488W WO 2023050104 A1 WO2023050104 A1 WO 2023050104A1
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- substitution
- bromine
- chlorine
- fluorine
- hydrogen
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
Definitions
- the invention discloses a class of indoline derivatives, its preparation method, pharmaceutical composition and application. Specifically, it relates to indoline derivatives represented by general formula I, their pharmaceutically acceptable salts, their stereoisomers and their preparation methods, compositions containing one or more of these compounds, and such compounds in Use in the treatment of diseases related to the PD-1/PD-L1 signaling pathway, such as cancer, infectious diseases, and autoimmune diseases.
- the tumor microenvironment can protect tumor cells from being recognized and killed by the body's immune system, and the immune escape of tumor cells plays a very important role in the occurrence and development of tumors.
- Science magazine listed tumor immunotherapy as the top ten breakthroughs, once again making immunotherapy the "focus" in the field of tumor treatment.
- the activation or inhibition of immune cells in the body is regulated by positive and negative signals, among which programmed death 1 (PD-1)/PD-1 ligand (PD-1 ligand, PD-L1) It is a negative immune regulatory signal, which inhibits the immune activity of tumor-specific CD8+ T cells and mediates immune escape.
- the ability of tumor cells to evade the immune system is achieved through the binding of the programmed death ligand (PD-L1) produced on its surface to the PD-1 protein of T cells.
- the tumor microenvironment in the body will induce infiltrating T cells to highly express PD-1 molecules, and tumor cells will highly express PD-1 ligands PD-L1 and PD-L2, resulting in continuous activation of the PD-1 pathway in the tumor microenvironment.
- T cell function is inhibited from finding tumors so that it cannot send the immune system the treatments it needs to attack the tumor and kill tumor cells.
- PD-1 antibody is an antibody protein against PD-1 or PD-L1, which prevents the combination of the first two proteins, blocks this pathway, partially restores the function of T cells, and enables these cells to continue to kill tumor cells.
- PD1/PDL1-based immunotherapy is a new generation of immunotherapy that is currently attracting attention. It aims to use the body's own immune system to resist tumors and induce apoptosis by blocking the PD-1/PD-L1 signaling pathway. tumor potential. Recently, a series of surprising research results have confirmed that PD1/PD-L1 inhibitory antibodies have strong anti-tumor activity against a variety of tumors, which is particularly eye-catching. September 4, 2014 Merck's (pembrolizumab) became the first FDA-approved PD-1 monoclonal antibody for the treatment of patients with advanced or unresectable melanoma who have not responded to other drug treatments.
- tumor immunotherapy is considered to be a revolution in cancer treatment after targeted therapy.
- monoclonal antibody therapy has its own defects: it is easily decomposed by protease, so it is unstable in the body and cannot be taken orally; it is easy to produce immune cross-reaction; the product quality is not easy to control, and the production technology requirements are high; High cost; inconvenient to use, only injection or drip. Therefore, small molecule inhibitors of PD1/PD-L1 interaction are a better choice for tumor immunotherapy.
- the technical problem to be solved by the present invention is to provide a kind of indoline derivative with the general structure formula I that inhibits PD1/PD-L1 interaction, and its stereoisomer and pharmaceutically acceptable salt thereof, its preparation method, medicine Composition and its use in preparing medicines for preventing or treating diseases related to PD1/PD-L1 signaling pathway.
- the present invention provides the following technical solutions:
- the first aspect of the technical solution of the present invention is to provide a class of indoline derivatives as shown in general formula I, stereoisomers thereof and pharmaceutically acceptable salts thereof,
- R1 is selected from:
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n is independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3, 3-position triple substitution;
- Y is selected from: C1-5 alkyl, C3-7 cycloalkane alkyl, pyridyl methylene, substituted C1-5 alkyl, substituted benzyl, substituted pyridyl methylene, and the substituents are independently selected from cyano Base, methylsulfonyl, acetylamino, carbamoyl, dimethylcarbamoyl, fluorine, chlorine, bromine, trifluoromethyl, C1-5 alkyl, C1-5 alkoxy;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n is independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- Y is selected from: C1-5 alkyl, C3-7 cycloalkane alkyl, pyridyl methylene, substituted C1-5 alkyl, substituted benzyl, substituted pyridyl methylene, and the substituents are independently selected from cyano Base, methylsulfonyl, acetylamino, carbamoyl, dimethylcarbamoyl, fluorine, chlorine, bromine, trifluoromethyl, C1-5 alkyl, C1-5 alkoxy;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n is independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- Z is selected from hydrogen, cyano, methanesulfonyl, acetamido, carbamoyl, dimethylcarbamoyl, fluorine, chlorine, bromine, trifluoromethyl, C1-5 alkyl, C1-5 alkoxy;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n is independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- Z is selected from hydrogen, cyano, methanesulfonyl, acetamido, carbamoyl, dimethylcarbamoyl, fluorine, chlorine, bromine, trifluoromethyl, C1-5 alkyl, C1-5 alkoxy;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n is independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- C is selected from amino, dimethylamino, cyclopropylamino, cyclobutylamino, hydroxyl, hydroxylamine, hydroxyethylamino;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n is independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- D is selected from hydrogen, cyclopropyl, methyl, isopropyl, hydroxymethyl;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n is independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- Y is selected from: C1-5 alkyl, C3-7 cycloalkane alkyl, pyridyl methylene, substituted C1-5 alkyl, substituted benzyl, substituted pyridyl methylene, and the substituents are independently selected from cyano Base, methylsulfonyl, acetylamino, carbamoyl, dimethylcarbamoyl, fluorine, chlorine, bromine, trifluoromethyl, C1-5 alkyl, C1-5 alkoxy;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n is independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- Z is selected from hydrogen, cyano, methanesulfonyl, acetamido, carbamoyl, dimethylcarbamoyl, fluorine, chlorine, bromine, trifluoromethyl, C1-5 alkyl, C1-5 alkoxy;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes mono-substituted, double-substituted , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n is independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- Z is selected from hydrogen, cyano, methanesulfonyl, acetamido, carbamoyl, dimethylcarbamoyl, fluorine, chlorine, bromine, trifluoromethyl, C1-5 alkyl, C1-5 alkoxy;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n are each independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multi-substitution includes 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- C is selected from amino, dimethylamino, cyclopropylamino, cyclobutylamino, hydroxyl, hydroxylamine, hydroxyethylamino;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n are each independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- D is selected from hydrogen, cyclopropyl, methyl, isopropyl, hydroxymethyl;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n are each independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- Y is selected from: C1-5 alkyl, C3-7 cycloalkane alkyl, pyridyl methylene, substituted C1-5 alkyl, substituted benzyl, substituted pyridyl methylene, and the substituents are independently selected from cyano Base, methylsulfonyl, acetylamino, carbamoyl, dimethylcarbamoyl, fluorine, chlorine, bromine, trifluoromethyl, C1-5 alkyl, C1-5 alkoxy;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n are each independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- Z is selected from hydrogen, cyano, methanesulfonyl, acetamido, carbamoyl, dimethylcarbamoyl, fluorine, chlorine, bromine, trifluoromethyl, C1-5 alkyl, C1-5 alkoxy;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n are each independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- Z is selected from hydrogen, cyano, methanesulfonyl, acetamido, carbamoyl, dimethylcarbamoyl, fluorine, chlorine, bromine, trifluoromethyl, C1-5 alkyl, C1-5 alkoxy;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n are each independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- C is selected from amino, dimethylamino, cyclopropylamino, cyclobutylamino, hydroxyl, hydroxylamine, hydroxyethylamino;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n are each independently selected from: 0, 1, 2, 3, 4, 5;
- n is selected from: 0, 1, 2, 3, 4, 5, 6;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- D is selected from hydrogen, cyclopropyl, methyl, isopropyl, hydroxymethyl;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n is independently selected from: 0, 1, 2, 3, 4, 5;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- Y is selected from: C1-5 alkyl, C3-7 cycloalkane alkyl, pyridyl methylene, substituted C1-5 alkyl, substituted benzyl, substituted pyridyl methylene, and the substituents are independently selected from cyano Base, methylsulfonyl, acetylamino, carbamoyl, dimethylcarbamoyl, fluorine, chlorine, bromine, trifluoromethyl, C1-5 alkyl, C1-5 alkoxy;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n is independently selected from: 0, 1, 2, 3, 4, 5;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- Z is selected from hydrogen, cyano, methanesulfonyl, acetamido, carbamoyl, dimethylcarbamoyl, fluorine, chlorine, bromine, trifluoromethyl, C1-5 alkyl, C1-5 alkoxy;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n is independently selected from: 0, 1, 2, 3, 4, 5;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- Z is selected from hydrogen, cyano, methanesulfonyl, acetamido, carbamoyl, dimethylcarbamoyl, fluorine, chlorine, bromine, trifluoromethyl, C1-5 alkyl, C1-5 alkoxy;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n is independently selected from: 0, 1, 2, 3, 4, 5;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- C is selected from amino, dimethylamino, cyclopropylamino, cyclobutylamino, hydroxyl, hydroxylamine, hydroxyethylamino;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- A is arbitrarily selected from:
- B is each independently selected from: H, OH, O:, CH 3 , CH 3 CH 2 , HOOC, CH 3 OOC, CH 3 CH 2 OOC, CH 2 COOH, CH 2 OH, F, Cl,
- n is independently selected from: 0, 1, 2, 3, 4, 5;
- R2 is selected from hydrogen, methyl, fluorine, chlorine, bromine;
- R3 is selected from hydrogen, methyl, fluorine, chlorine, bromine, cyano
- X is selected from hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, vinyl, trifluoromethyl, methoxy;
- X includes mono-substitution or multi-substitution, wherein mono-substitution includes 1-position mono-substitution, 2-position mono-substitution , 3-position single substitution, multiple substitutions include 1, 2-position double substitution, 1, 3-position double substitution, 2, 3-position double substitution, 1, 2, 3-position triple substitution;
- D is selected from hydrogen, cyclopropyl, methyl, isopropyl, hydroxymethyl;
- R4 is selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclic-1-yl, the substituents are independently selected from hydrogen, fluorine, chlorine, bromine , iodine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidine, urea amino, guanidino, sulfonylamino, sulfamo Acyl, methylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, each of the substituents independently includes single substitution, double substitution , three substitutions, four substitutions.
- indoline derivatives and their stereoisomers and pharmaceutically acceptable salts thereof are selected from but not limited to the following compounds:
- the above-mentioned indoline derivatives and their stereoisomers and pharmaceutically acceptable salts thereof are characterized in that, the pharmaceutically acceptable salts include combinations with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions or energy Salts formed by combining organic bases and ammonium salts that provide physiologically acceptable cations.
- inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid;
- organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, wolfberry acid, maleic tartaric acid, fumaric acid, Citric acid or lactic acid;
- alkali metal ion is selected from lithium ion, sodium ion, potassium ion;
- Described alkaline earth metal ion is selected from calcium ion, magnesium ion;
- Described can provide the organic base of physiologically acceptable cation selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.
- R1, R2, R3, R4, Y, and X are the same as those described in any one of claims 1-22.
- the starting materials and intermediates in the above reactions are easy to obtain, and each step of the reaction can be easily synthesized according to the reported literature or by a person skilled in the art using conventional methods in organic synthesis.
- the compound of general formula I can exist in the form of solvate or non-solvate, and different solvates may be obtained by crystallization with different solvents.
- the pharmaceutically acceptable salts described in general formula I include different acid addition salts, such as the acid addition salts of the following inorganic acids or organic acids: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, Trifluoroacetic acid, Lycic acid, Maleic acid, Tartaric acid, Fumaric acid, Citric acid, Lactic acid.
- Pharmaceutically acceptable salts described in general formula I also include different alkali metal salts (lithium, sodium, potassium salts), alkaline earth metal salts (calcium, magnesium salts) and ammonium salts, and organic compounds that can provide physiologically acceptable cations.
- Salts of bases such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine and tris(2-hydroxyethyl)amine. All such salts within the scope of this invention may be prepared by conventional methods. During the preparation process of the compound of general formula I and its solvates and salts thereof, polycrystals or co-crystals may appear under different crystallization conditions.
- the third aspect of the technical solution of the present invention is to provide a pharmaceutical composition, which contains the indoline derivatives and stereoisomers thereof as described in the first aspect of the present invention as active ingredients.
- Pharmaceutically acceptable salts and pharmaceutically acceptable carriers or excipients are provided.
- the present invention also relates to pharmaceutical compositions containing the compound of the present invention as an active ingredient.
- the pharmaceutical composition can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be prepared by combining the compounds of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
- the content of the compound of the present invention in its pharmaceutical composition is usually 0.1-95% by weight.
- the compound of the present invention or the pharmaceutical composition containing it can be administered in the form of a unit dosage, and the route of administration can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.
- the dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
- Liquid dosage forms can be solutions (including true solutions and colloid solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including aqueous injections, powder injections and infusion solutions), eye drops Agents, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.
- the compound of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.
- Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
- wetting agents can be water, ethanol, iso Propanol, etc.
- binders can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, arabic mucilage, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hypromellose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.
- disintegrants can be dry starch, microcrystalline cellulose, low-substi
- Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.
- the active ingredient compound of the present invention can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule.
- the active ingredient compound of the present invention can also be made into granules or pellets with diluents, binders, and disintegrants, and then placed in hard capsules or soft capsules.
- Various diluents, binders, wetting agents, disintegrants, and glidants used in the preparation of tablets of the compound of the present invention can also be used in the preparation of capsules of the compound of the present invention.
- water, ethanol, isopropanol, propylene glycol or their mixtures can be used as solvent and an appropriate amount of commonly used solubilizers, cosolvents, pH regulators and osmotic pressure regulators in this field can be added.
- the solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.
- the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.
- the osmotic pressure regulator can be Sodium chloride, mannitol, glucose, phosphate, acetate, etc.
- mannitol, glucose, etc. can also be added as proppants.
- coloring agents can also be added to the pharmaceutical preparations, if necessary.
- the medicine or pharmaceutical composition of the present invention can be administered by any known administration method.
- the dosage of the pharmaceutical composition of the compound of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, individual conditions of the patient or animal, administration route and dosage form, etc.
- the suitable daily dosage range of the compound of the present invention is 0.001-150 mg/Kg body weight, preferably 0.01-100 mg/Kg body weight.
- the above-mentioned dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the doctor and the dosage regimen including the use of other therapeutic means.
- the compound or composition of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs.
- the compound of the present invention has a synergistic effect with other therapeutic drugs, its dose should be adjusted according to the actual situation.
- the fourth aspect of the technical solution of the present invention is to provide indoline derivatives and their stereoisomers and their pharmaceutically acceptable salts in the preparation of drugs for the prevention and/or treatment of diseases related to the PD-1/PD-L1 signaling pathway in the application.
- the disease related to PD-1/PD-L1 signaling pathway is selected from cancer, infectious disease and autoimmune disease.
- the cancer is selected from skin cancer, lung cancer, urological tumor, blood tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, brain tumor, head and neck cancer.
- the infectious disease is selected from bacterial infection and viral infection.
- the autoimmune disease is selected from organ-specific autoimmune diseases and systemic autoimmune diseases, wherein the organ-specific autoimmune diseases include chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, Myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhage nephritic syndrome, primary biliary cirrhosis, multiple sclerosis, acute idiopathic polyneuritis, the system Sexual autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.
- organ-specific autoimmune diseases include chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, Myasthenia gravis, ulcerative colitis, pernicious anemia with
- the compound of the present invention has a high inhibitory activity on the PD-1/PD-L1 interaction, which is higher than that of the reported compounds; it has a strong binding ability to the PD-L1 protein, even stronger than the PD-L1 antibody; and has Release the ability of PD-L1 to inhibit IFN ⁇ , and the in vivo pharmacodynamic studies show that the compound of the present invention can significantly inhibit the growth of subcutaneous tumors in terms of tumor volume and weight, and can significantly increase the number of lymphocytes in the blood and spleen of mice. quantity.
- Measuring instrument Vaariaan Mercury 300 nuclear magnetic resonance instrument for nuclear magnetic resonance spectroscopy. Mass spectrometry uses ZAD-2F and VG300 mass spectrometers.
- Example 1 N-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-(3-(1-(3-(4-fluoropiperidin-1-yl) )Propyl)indoline-4-yl)-2-methylbenzyloxy)benzyl)-L-serine
- (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid instead of L-serine, the operation is the same as in Example 1 to obtain (2R,4R)-N-(5-chloro-2-((5-cyanopyridine- 3-yl)methoxy)-4-(3-(1-(3-(4-fluoropiperidin-1-yl)propyl)indoline-4-yl)-2-methylbenzyloxy )benzyl)-4-hydroxypyrrolidine-2-carboxylic acid as white solid.
- Example 36 N-(5-chloro-2-((pyridin-3-yl)methoxy)-4-(3-(1-(3-(4-hydroxy-4-carboxypiperidine-1- Base) propyl) indoline-4-yl) -2-bromobenzyloxy) benzyl) -L-serine
- the PD-1 protein is tagged with HIS, and the ligand PD-L1 of PD-1 is tagged with hFc.
- Eu-labeled anti-hFc antibody and XL665-labeled anti-HIS antibody are used to bind the two tagged proteins respectively, and laser After excitation, the energy can be transferred from the donor Eu to the acceptor XL665, making XL665 emit light, and after adding an inhibitor (compound or antibody), the combination of PD-1 and PD-L1 is blocked, making the distance between Eu and XL665 longer , energy cannot be transferred, XL665 will not emit light.
- A means that the IC 50 value is between 10 -9 and 10 -12 M
- B means that the IC 50 value is between 10 -6 and 10 -8 M
- C means that the IC 50 value is greater than 10 -6 M .
- Example compound IC 50 (M) Example IC 50 (M) 1 A 28 A 2 A 29 A 3 A 30 A 4 A 31 A 5 A 32 A 6 A 33 A 7 A 34 A 8 A 35 A 9 A 36 A 10 A 37 A 11 A 38 A 12 A 39 A 13 A 40 B 14 A 41 A 15 A 42 B 16 A 43 B 17 A 44 A 18 A 45 B 19 A 46 B 20 A 47 A twenty one A 48 B twenty two A 49 B twenty three A 50 B twenty four A 51 B,4.1 ⁇ 10-8 25 A 52 A 26 A 53 B 27 A 54 B,3.1 ⁇ 10-8
- Cisbio HTRF detection results showed that the compounds in the examples could significantly inhibit the interaction between PD-1 and PD-L1 at the molecular level, and the IC 50 of individual compounds was ⁇ 10 -11 mol/L.
- the expression level of IFN ⁇ can reflect the proliferative activity of T lymphocytes.
- PBMC human mononuclear cells
- the specific operation is as follows. Use the human lymphocyte separation medium (article number DKW-KLSH-0100) of Daktronics to extract PBMCs in human whole blood, and inoculate PBMCs into 96-well plates, and the number of inoculations per well is 3 ⁇ 10 5 . Add human PD-L1 protein (final concentration 5 ⁇ g/ml), anti-CD3/anti-CD28 antibody (final concentration 1 ⁇ g/ml) and example compounds diluted in equal proportions. After 72 hours, the expression of IFN ⁇ in the supernatant was detected using the IFN ⁇ detection kit from Cisbio. The experimental results show that the compound of the example can partially relieve the inhibitory effect of PD-L1 on IFN ⁇ at 10 nM.
- the method of subcutaneous tumor transplantation is as follows: the cultured specific tumor cells were digested and centrifuged to collect the cells, washed twice with sterile normal saline and counted, the cell concentration was adjusted to 5 ⁇ 10 6 /ml with normal saline, and 0.2ml of the cell suspension Inoculated into the right axilla of C57BL/6 or Bablc mice. The next day after inoculation, the animals were divided into random groups, 6-7 animals in each group, and administered after weighing. The compound to be tested was administered once a day, and the tumor volume of the mice was monitored. After the tumor volume reached a certain size, the mice were weighed.
- mice were sacrificed by dislocation of the neck after taking blood from the orbit, and the tumor tissue, thymus tissue and spleen tissue were stripped and weighed respectively. Finally, the tumor inhibition rate was calculated, and the intensity of the anti-tumor effect was evaluated by the tumor inhibition rate.
- the B16F10 lung metastasis model method is as follows: the cultured B16F10 tumor cells were digested and centrifuged, washed twice with sterile normal saline and counted, the cell concentration was adjusted to 2.5 ⁇ 10 6 /ml with normal saline, and 0.2ml of cells were injected into In C57BL/6 mice, tumor cells will accumulate in the lungs of the mice. On the second day after inoculation, the animals were randomly divided into groups, 6-7 animals in each group, administered after weighing, and the compound to be tested was administered once a day. After 3 weeks, the mice were weighed, and the animals were sacrificed. The lung tissues of the mice were stripped and weighed. Weight, the number of lung tumors was counted after being fixed with package solution. Finally, the tumor inhibition rate of the compound was calculated, and the antitumor effect intensity was evaluated by the tumor inhibition rate.
- the method of Lewis lung cancer pleural effusion model is as follows: homogenate the subcutaneous Lewis transplanted tumor in mice, wash it twice with sterile normal saline and count, adjust the cell concentration to 2.5 ⁇ 10 5 /ml with normal saline, inject 0.2ml of cells into into the chest cavity of C57BL/6 mice. The next day after inoculation, the animals were divided into random groups, 6-7 in each group, administered after weighing, and the compound to be tested was administered once a day, and the animals were killed when the weight of the mice in the control group suddenly dropped, and the pleural effusion was extracted with a syringe , record the volume of effusion.
- the total number of sampled cells in tumor tissue was 1 ⁇ 10 5
- the total number of sampled cells in blood and spleen tissues was 1 ⁇ 10 4 cells.
- the ratio of each type of T cells to the total number of injected cells was analyzed after a gate on the flow cytometry instrument.
- the compounds of the examples can significantly inhibit the growth of subcutaneous tumors in terms of tumor volume and weight.
- the compound of the example can increase the proportion of each lymphocyte in tumor infiltration, and the compound of the example can increase the proportion of each lymphocyte in the spleen.
- the compounds of the examples can significantly inhibit the number of lung metastases.
- the compounds of the examples can increase the number of lymphocytes in the blood of mice.
- the compounds of the examples have certain anti-tumor effects.
- the compound of the example after being administered in combination with cyclophosphamide, can increase the tumor inhibition rate of cyclophosphamide.
- the compounds of the examples have certain anti-tumor effects.
- the compounds of the examples can reduce the incidence of pleural effusion.
- the compounds of the examples have significant anti-tumor effects.
- Combined administration of cyclophosphamide CTX has a good synergistic effect.
- SPR Surface-plasmon resonance
- the total reflection of light from an optically denser medium to an optically rarer medium will form an evanescent wave and enter the optically rarer medium.
- This resonance is called surface plasmon resonance, which causes surface plasmon resonance.
- the angle of incidence is called the SPR angle.
- SPR biosensors provide a sensitive, label-free detection technique for real-time monitoring of molecular interactions.
- the sensor detects changes in the SPR angle, which in turn is related to the refractive index of the metal surface.
- the refractive index of the chip surface changes, which causes the change of the SPR angle.
- This is the basic principle of the SPR biosensor to detect the interaction between molecules in real time. During the interaction analysis, the change of SPR angle is recorded on the sensorgram in real time.
- the PD-L1 protein was captured on the Fc4 channel of the NTA chip by the capture method; the binding buffer system was PBS-P+, pH 7.4, 0.01% DMSO. A series of prepared concentrations of compounds and PD-L1 antibodies were flowed over the surface of the chip for interaction determination.
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Abstract
本发明属于医药技术领域,具体公开了一类二氢吲哚衍生物、及其制法和药物组合物与用途。具体而言,涉及通式(I)所示的二氢吲哚衍生物,其可药用盐,其立体异构体及其制备方法,含有一个或多个这化合物的组合物,和该类化合物在制备治疗与PD-1/PD-L1信号通路有关的疾病如癌症、感染性疾病、自身免疫性疾病药物方面的用途。
Description
本发明公开了一类二氢吲哚衍生物、及其制法和药物组合物与用途。具体而言,涉及通式I所示的二氢吲哚衍生物,其可药用盐,其立体异构体及其制备方法,含有一个或多个这化合物的组合物,和该类化合物在治疗与PD-1/PD-L1信号通路有关的疾病如癌症、感染性疾病、自身免疫性疾病方面的用途。
随着对肿瘤免疫研究的深入,人们发现肿瘤微环境可以保护肿瘤细胞不被机体免疫系统识别和杀伤,肿瘤细胞的免疫逃逸在肿瘤发生、发展中扮演了非常重要的角色。2013年Science杂志将肿瘤免疫治疗列为十大突破之首,再次让免疫治疗成为肿瘤治疗领域的“焦点”。机体免疫细胞的激活或抑制是通过正性信号和负性信号来调节,其中程序性死亡分子1(programmed death 1,PD-1)/PD-1配体(PD-1 ligand,PD-L1)便是负性免疫调节信号,抑制了肿瘤特异性CD8+T细胞的免疫活性,介导了免疫逃逸。
肿瘤细胞所具有的逃避免疫系统的能力,是通过在其表面产生的程序性死亡配体(PD-L1)结合到T细胞的PD-1蛋白上实现的。机体内的肿瘤微环境会诱导浸润的T细胞高表达PD-1分子,肿瘤细胞会高表达PD-1的配体PD-L1和PD-L2,导致肿瘤微环境中PD-1通路持续激活,T细胞功能被抑制而不能发现肿瘤以至于不能向免疫系统发出需要攻击肿瘤和杀伤肿瘤细胞的治疗。PD-1抗体是针对PD-1或者PD-L1的一种抗体蛋白,使得前两种蛋白不能发生结合,阻断这一通路,部分恢复T细胞的功能,使这些细胞能够继续杀伤肿瘤细胞。
基于PD1/PDL1的免疫疗法是当前备受瞩目的新一代免疫疗法,旨在利用人体自身的免疫系统抵御肿瘤,通过阻断PD-1/PD-L1信号通路诱导凋亡,具有治疗多种类型肿瘤潜力。最近,一系列令人惊喜的研究结果证实PDl/PD-Ll抑制性抗体对多种肿瘤具有强大的抗瘤活性,格外引人注目。2014年9月4日美国默克的
(pembrolizumab)成为FDA批准的首例PD-1单抗用于治疗对其它药物 治疗无效的晚期或无法切除的黑色素瘤患者。目前,默沙东正在30多种不同类型的癌症中调查Keytruda的潜力,包括各类血液癌症、肺癌、乳腺癌、膀胱癌、胃癌、头颈部癌症。2014年12月22日,制药巨头百时美施贵宝公司不负重望,率先发力,获得美国食品药品监督管理局(FDA)加速批准,其研发的抗癌免疫疗法药物nivolumab以Opdivo的商品名上市,用于治疗对其它药物没有应答的不可切除的或转移性黑色素瘤患者,是继默沙东Keytruda之后第二个在美国上市的PD-1抑制剂。FDA于2015年3月4日批准了nivolumab用于治疗在经铂为基础化疗期间或化疗后发生疾病进展的转移性鳞性非小细胞肺癌。根据默沙东公布的Keytruda(pembrolizumab)治疗实体瘤的一项Ib期KEYNOTE-028研究数据,Keytruda治疗在25例胸膜间皮瘤(pleuralmesothelioma,PM)患者中取得了28%的总缓解率(ORR),并有48%的患者病情稳定,疾病控制率达到了76%。对当前任何已获批药物均无治疗反应的晚期霍奇金淋巴瘤(HL)患者,接受默沙东Keytruda和百时美Opdvio治疗后,能够达到完全缓解。在2015AACR年会上,约翰霍普金斯基梅尔癌症中心(Kimmel Cancer Center)的肿瘤内科学副教授Leisha A.Emens,MD,PhD做出的报道指出,罗氏的MPDL3280A这一具有抗PD-L1作用的单克隆抗体,在晚期三阴性乳腺癌中表现出了持久的疗效。
虽然肿瘤免疫治疗被认为是靶向治疗后癌症治疗的革命。但是,单抗治疗药物有其本身的缺陷:易被蛋白酶分解,因而在体内不稳定,不能口服;易产生免疫交叉反应;产品质量不易控制,制作技术要求高;大量制备和纯化比较困难,生产成本高;使用不方便,只能注射或点滴。所以,PDl/PD-Ll相互作用小分子抑制剂是肿瘤免疫治疗的更佳选择。
发明内容
本发明解决的技术问题是提供一种具有抑制PDl/PD-Ll相互作用的结构通式I的二氢吲哚衍生物,以及其立体异构体及其可药用盐,其制备方法、药物组合物和其在制备预防或治疗与PDl/PD-Ll信号通路有关疾病药物中的用途。
为解决本发明的技术问题,本发明提供如下技术方案:
本发明技术方案的第一方面是提供一类如通式I所示的二氢吲哚衍生物及其立体异构体以及其可药用盐,
式中
其中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代、1、3位双取代、2、3位双取代、1、2、3、位三取代;
Y选自:C1-5烷基、C3-7环烷烷基、吡啶亚甲基、取代的C1-5烷基、取代的苄基、取代吡啶亚甲基,取代基各自独立的选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂 环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
Y选自:C1-5烷基、C3-7环烷烷基、吡啶亚甲基、取代的C1-5烷基、取代的苄基、取代吡啶亚甲基,取代基各自独立的选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA1)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA2)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA3)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
C选自氨基、二甲胺基、环丙氨基、环丁胺基、羟基、羟胺基、羟乙氨基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA4)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
D选自氢、环丙基、甲基、异丙基、羟甲基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IB)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
Y选自:C1-5烷基、C3-7环烷烷基、吡啶亚甲基、取代的C1-5烷基、取代的苄基、取代吡啶亚甲基,取代基各自独立的选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IB1)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、 噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IB2)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IB3)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;,
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、 3位双取代,2、3位双取代,1、2、3位三取代;
C选自氨基、二甲胺基、环丙氨基、环丁胺基、羟基、羟胺基、羟乙氨基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IB4)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;,
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
D选自氢、环丙基、甲基、异丙基、羟甲基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IC)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;,
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
Y选自:C1-5烷基、C3-7环烷烷基、吡啶亚甲基、取代的C1-5烷基、取代的苄基、取代吡啶亚甲基,取代基各自独立的选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IC1)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;,
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IC2)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;,
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IC3)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;,
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
C选自氨基、二甲胺基、环丙氨基、环丁胺基、羟基、羟胺基、羟乙氨基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IC4)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;,
n任选自:0、1、2、3、4、5、6;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
D选自氢、环丙基、甲基、异丙基、羟甲基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(ID)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
Y选自:C1-5烷基、C3-7环烷烷基、吡啶亚甲基、取代的C1-5烷基、取代的苄基、取代吡啶亚甲基,取代基各自独立的选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、 磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(ID1)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(ID2)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取 代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(ID3)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
C选自氨基、二甲胺基、环丙氨基、环丁胺基、羟基、羟胺基、羟乙氨基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(ID4)所示:
式中
其中B各自独立的选自:H、OH、O:、CH
3、CH
3CH
2、HOOC、CH
3OOC、CH
3CH
2OOC、CH
2COOH、CH
2OH、F、Cl,
其中m各自独立的选自:0、1、2、3、4、5;;
R2选自氢、甲基、氟、氯、溴;
R3选自氢、甲基、氟、氯、溴、氰基;
X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;
D选自氢、环丙基、甲基、异丙基、羟甲基;
R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述R4选自
最优选的二氢吲哚衍生物及其立体异构体以及其可药用盐,所述的化合物选自但不限于下列化合物:
N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
N-(5-甲基-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
N-(5-甲基-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
(S)-2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)-3-羟基-2-甲基丙酸
(R,R)-N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-4-羟基脯氨酸
N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-乙氧甲酰基-3-羟甲基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-乙氧甲酰基-3-羟甲基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
N-(5-甲基-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-甲氧甲酰基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
N-(5-甲基-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
(2S)-2-(4-(2-溴-3-(1-(3-(2-羟基-7-氮杂螺[3.5]壬烷-7-基)丙基)吲哚啉-4-基)苄氧基)-5-氯-2-((吡啶-3-基)甲氧基)苄胺基)-3-羟基丁酸
(2S)-2-(4-(2-溴-3-(1-(3-(6-氧代-2,5,7-三氮螺[3.4]辛烷-2-基)丙基)吲哚啉-4-基)苄氧基)-5-氯-2-((吡啶-3-基)甲氧基)苄胺基)-3-羟基丁酸
(S)-2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-氟吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄胺基)-3-羟基-2-甲基丙酸
2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)-丙-1,3-二醇
N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺
N-(2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺
N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(3-氟氮杂环丁烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺
以上所述的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的药用盐包括与无机酸、有机酸、碱金属离子、碱土金属离子或能提供生理上可接受的阳离子的有机碱结合形成的盐以及铵盐。
进一步所述的无机酸选自盐酸、氢溴酸、磷酸或硫酸;所述的有机酸选自甲磺酸、对甲苯磺酸、三氟乙酸、枸杞酸、马来酸酒石酸、富马酸、柠檬酸或乳酸;所述 的碱金属离子选自锂离子,钠离子,钾离子;所述的碱土金属离子选自钙离子,镁离子;所述的能提供生理上可接受的阳离子的有机碱选自甲胺、二甲胺、三甲胺、哌啶、吗啉或三(2-羟乙基)胺。
本发明技术方案的第二方面是提供了第一方面所述化合物的制备方法:
为了制备本发明通式I所述的化合物,依据通式I的结构,本发明制备通式I化合物将分为以下两步:
为了制备本发明通式I所述的化合物,依据通式I的结构,本发明制备通式I化合物大体分为两步:
(a)以含硼酯的苄氧基取代的苯甲醛衍生物1为原料,在钯催化剂条件下与溴代吲哚啉衍生物2偶联反应得到含醛基的中间体化合物3;
(b)以含醛基的中间体化合物3为原料,与含氨基或亚氨基的HR
4缩合及还原得到目标化合物I;
所述的R1、R2、R3、R4、Y、X的定义同权利要求1-22任一项所述。
另外,上述反应中的起始原料及中间体容易得到,各步反应可依据已报道的文献或对本领域熟练技术人员来说可以用有机合成中的常规方法很容易合成。通式I所述化合物可以溶剂化物或非溶剂化物的形式存在,利用不同的溶剂进行结晶可能得到不同的溶剂化物。通式I所述药学上可接受的盐包括不同酸加成盐,如下列无机酸或有机酸的酸加成盐:盐酸,氢溴酸,磷酸,硫酸,甲磺酸,对甲苯磺酸,三氟乙酸,枸杞酸,马来酸,酒石酸,富马酸,柠檬酸,乳酸。通式I所述药学上可接受的盐还包括不同碱金属盐(锂,钠,钾盐),碱土金属盐(钙,镁盐)及铵盐,和能提供生理上可接受的阳离子的有机碱的盐,如甲胺,二甲胺,三甲胺,哌啶,吗啉及三(2-羟乙基)胺的盐。在本发明范围内的所有这些盐都可采用常规方法制备。在所述的通式I化合物及其溶剂化物和其盐的制备过程中,不同结晶条件可能出现多晶或共晶。
本发明技术方案的第三方面是提供了一种药物组合物,所述的药物组合物包 含作为有效成分的本发明第一方面所述的二氢吲哚衍生物及其立体异构体以及其可药用盐和药学上可接受的载体或赋形剂。
本发明还涉及以本发明化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量%。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片, 或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明化合物与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。一般来讲,本发明化合物的每天的合适剂量范围为0.001-150mg/Kg体重,优选为0.01-100mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
本发明技术方案的第四方面是提供了二氢吲哚衍生物及其立体异构体以及其可药用盐在制备预防和/或治疗与PD-1/PD-L1信号通路有关疾病的药物中的应用。所述的与PD-1/PD-L1信号通路有关的疾病选自癌症、感染性疾病、自身免疫性疾病。所述的癌症选自皮肤癌、肺癌、泌尿系肿瘤、血液肿瘤、乳腺癌、胶质瘤、消化系统肿瘤、生殖系统肿瘤、淋巴瘤、神经系统肿瘤、脑瘤、头颈癌。所述的感染性疾病选自细菌感染、病毒感染。所述的自身免疫性疾病选自器官特异性自 身免疫病、系统性自身免疫病,其中,所述的器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎,所述的系统性自身免疫病包括类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血。
有益技术效果:
本发明化合物对PD-1/PD-L1相互作用具有很高的抑制活性,高于已报道的化合物;与PD-L1蛋白具有很强的结合能力,甚至强于PD-L1的抗体;并具有解除PD-L1抑制IFNγ的能力,体内药效研究表明,本发明化合物无论从肿瘤体积还是重量上,都可显著的抑制皮下肿瘤的生长,并可明显增加小鼠血液中、脾脏中各淋巴细胞数量。
以下将结合实施例对发明作进一步说明,但并不限制本发明的范围。
测定仪器:核磁共振光谱用Vaariaan Mercury 300型核磁共振仪。质谱用ZAD-2F和VG300质谱仪。
实施例1:N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
2-甲基-3-羟甲基苯硼酸频哪醇酯:
称取2-甲基-3-溴苄醇(19.5g,97.5mmol),联硼酸频哪醇酯(29.7g,117mmol),加入250毫升的无水二氧六环,搅拌,然后加入醋酸钾(24.0g,244mmol),双三苯基膦二氯化钯(3.4g,4.87mmol),氩气保护,升温至100℃,回流8h,停止反应,浓缩,加入300ml乙酸乙酯,硅藻土过滤,加入水200ml萃取三次(3*200ml),饱和食盐水洗涤,无水硫酸钠干燥。通过硅胶柱层析(洗脱剂:PE:EA=5:1),得 到淡黄色油状物22.1g,收率:91.32%。
核磁:
1H NMR(400MHz,DMSO-d
6)δ7.47(dd,J=7.4,1.5Hz,1H,-ArH),7.42(dd,J=7.7,1.5Hz,1H,-ArH),7.11(t,J=7.5Hz,1H,-ArH),5.01(s,1H,-OH),4.45(s,2H,-CH2-),2.36(s,3H,-CH3),1.26(s,12H,4*-CH3).
2-甲基-3-溴甲基苯硼酸频哪醇酯:
称取2-甲基-3-羟甲基苯硼酸频哪醇酯(500mg,2.0mmol),溶于20ml二氯甲烷中,氩气保护,冰浴条件下,加入三溴化磷0.182ml,加毕,移至室温反应3h,缓慢加入2ml无水甲醇淬灭反应,加入二氯甲烷和饱和碳酸氢钠溶液萃取*2,二氯甲烷相用饱和食盐水洗涤,无水硫酸钠干燥,浓缩蒸干,得到淡黄色油状物622mg,收率100%。
1H NMR(400MHz,DMSO-d
6)δ7.59(dd,J=7.5,1.4Hz,1H,-ArH),7.49(dd,J=7.6,1.4Hz,1H,-ArH),7.17(t,J=7.5Hz,1H,-ArH),4.73(s,2H,-CH2-),2.53(s,3H,-CH3),1.31(s,12H,4*-CH3).
5-氯-2-羟基-4-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苄氧基)苯甲醛
称取5-氯-2,4-二羟基苯甲醛(356mg,2.06mmol),溶于30ml色谱乙腈中,加入碳酸氢钠(518mg,6.17mmol),室温搅拌40min后,加入2-甲基-3-溴甲基苯硼酸频哪醇酯(640mg,2.06mmol)的乙腈溶液,加入碳酸钠(218mg,2.06mmol),升温至65℃,反应过夜12h,停止反应,将反应液浓缩至少量,加入水和乙酸乙酯萃取*3,乙酸乙酯相经饱和食盐水洗涤,无水硫酸钠干燥,浓缩后,通过硅胶柱层析(PE:EA=10:1),得到产物中间体5(414mg),收率:50.0%。
1H NMR(400MHz,DMSO-d
6)δ11.13(s,1H,-OH),10.03(s,1H,-CHO),7.70(s,1H,-ArH),7.64(d,J=7.4Hz,1H,-ArH),7.55(d,J=7.3Hz,1H,-ArH),7.24(t,J=7.5Hz,1H,-ArH),6.82(s,1H,-ArH),5.26(s,2H,-CH2-),2.51(s,3H,-CH3),1.34(s,12H,4*-CH3).
5-氯-2-(5-氰基吡啶-3-甲氧基)-4-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苄氧基)苯甲醛
称取5-氯-2-羟基-4-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苄氧基)苯甲醛(2.0g,4.975mmol)溶于30ml无水DMF中,加入碳酸铯(3.58g,10.94mmol)室温搅拌20min后,加入5-氯甲基烟腈盐酸盐(1.14g,5.97mmol),升温至65℃,3h后TLC检测,反应完全,停止反应,加入水和乙酸乙酯萃取*3,乙酸乙酯相经 饱和食盐水洗涤,无水硫酸钠干燥,浓缩蒸干后,加入无水甲醇析出固体,抽滤,得到白色固体1.82g,收率:70.52%。
1H NMR(400MHz,DMSO-d
6)δ10.23(s,1H,-CHO),9.07–9.01(m,2H,-ArH),8.54(t,J=2.0Hz,1H,-ArH),7.73(s,1H,-ArH),7.65(dd,J=7.5,1.4Hz,1H,-ArH),7.57(dd,J=7.5,1.3Hz,1H,-ArH),7.26–7.21(m,2H,-ArH),5.49(s,2H,-CH2-),5.36(s,2H,-CH2-),2.53(s,3H,-CH3),1.32(s,12H,4*-CH3).
4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉
称取1-(3-氯丙基)-4-氟哌啶(184mg,1.02mmol)溶于10ml DMF中,加入4-溴二氢吲哚(200mg,1.01mmol),DIPEA(382mg,3.03mmol),碘化钾(8mg,0.048mmol),90℃,8h,停止反应,加入水和乙酸乙酯萃取*3,乙酸乙酯相经饱和食盐水洗涤,无水硫酸钠干燥,浓缩后,通过硅胶柱层析(DCM:MeOH=40:1-10:1),得到棕色油状物中间体8(192mg),收率:55.82%。
1H NMR(500MHz,Chloroform-d)δ6.89(t,J=7.7Hz,1H,-ArH),6.72(d,J=7.8Hz,1H,-ArH),6.38–6.31(m,1H,-ArH),4.67(d,J=48.4Hz,1H,-CHF-),3.46–3.36(m,2H,-CH2-),3.09(t,J=6.7Hz,2H,-CH2-),2.97(t,J=8.8Hz,2H,-CH2-),2.58(brs,2H,-CH2-),2.43–2.38(m,2H,-CH2-),1.98–1.91(m,2H,-CH2-),1.87(brs,4H,2*-CH2-),1.80–1.70(m,2H,-CH2-).
5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苯甲醛
称取4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉(131mg,0.386mmol),5-氯-2-(5-氰基吡啶-3-甲氧基)-4-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苄氧基)苯甲醛(200mg,0.386mmol),碳酸钾(160mg,1.16mmol)于100ml的圆底烧瓶中,加入二氧六环/水(20ml/2ml),鼓吹氩气排除溶液中的氧气,加入X-Phos-Pa-G2(cas:1310584-14-5;15mg,0.0193mmol),氩气保护,升温至回流,反应8h后,TLC检测,反应完全,降至室温,硅藻土过滤,浓缩,加入水和乙酸乙酯萃取*3,乙酸乙酯相经饱和食盐水洗涤,无水硫酸钠干燥,浓缩后,通过硅胶柱层析(DCM:MeOH=60:1—20:1),得到棕色油状物中间体9(121mg),收率:48.01%。
1H NMR(500MHz,DMSO-d
6)δ10.26(s,1H,-CHO),8.90(brs,2H,-ArH),8.10(s,1H,-ArH),7.89(s,1H,-ArH),7.42(d,J=6.9Hz,1H,-ArH),7.25–7.20(m,2H,-ArH),7.11(t,J=7.5Hz,1H,-ArH),6.67(s,1H,-ArH),6.50(s,1H,-ArH),6.48(s,1H,-ArH),5.24(s,2H,-CH2-),5.23(s,2H,-CH2-),4.69(d,J=48.6Hz,1H,-CH-),3.40–3.25(m,2H,-CH2-),3.22–3.07(m,2H,-CH2-),2.77–2.54(m,4H,2*-CH2-),2.53–2.36(m,4H,2*-CH2-),2.20(s,3H,-CH3),2.00– 1.87(m,4H,2*-CH2-),1.85–1.79(m,2H,-CH2-).
N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
称取5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苯甲醛(65mg,0.1mmol)溶于3ml无水DMF中,加入L-丝氨酸(105mg,1.0mmol),HOAc(36mg,0.6mmol),室温搅拌30min后,加入氰基硼氢化钠(63mg,1.0mmol),室温反应18h后,经过TLC检测,原料反应完全,加入碳酸氢钠饱和溶液淬灭反应,然后加入适量水和乙酸乙酯萃取*3,有机相合并,用饱和食盐水洗涤,有机相加入无水硫酸钠干燥,浓缩,通过反相硅胶柱层析(C18,乙腈:水=0:100—100:0,梯度洗脱20min),得到淡黄色固体18mg,收率:24.32%。
1H NMR(500MHz,Methanol-d
4)δ8.93(s,1H,-ArH),8.86(s,1H,-ArH),8.38(s,1H,-ArH),7.45(s,1H,-ArH),7.42–7.33(m,1H,-ArH),7.23–7.14(m,1H,-ArH),7.12–7.07(m,1H,-ArH),7.07–7.02(m,1H,-ArH),6.99(s,1H,-ArH),6.49(d,J=5.8Hz,1H,-ArH),6.42(d,J=5.4Hz,1H,-ArH),5.32(s,2H,-CH2-),5.23(s,2H,-CH2-),4.65(d,J=47.1Hz,1H,-CHF-),4.32–4.10(m,2H,-CH2-),3.98–3.71(m,2H,-CH2-),3.46(brs,1H,-CH-),3.33–3.28(m,2H,-CH2-),3.16–3.05(m,2H,-CH2-),2.76–2.41(m,8H,4*-CH2-),2.13(s,3H,-CH3),1.99–1.72(m,6H,3*-CH2-).质谱数据:[M-H]
-:740.2813
实施例2、(S)-2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)-3-羟基-2-甲基丙酸
用(S)-3-羟基-2-甲基丙酸代替L-丝氨酸,操作同实施例1,得到(S)-2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)-3-羟基-2-甲基丙酸白色固体。
1H NMR(500MHz,Methanol-d
4)δ8.98(s,1H,-ArH),8.90(s,1H,-ArH),8.43(s,1H,-ArH),7.56(s,1H,-ArH),7.43(d,J=6.9Hz,1H,-ArH),7.25–7.19(m,1H,-ArH),7.16–7.07(m,2H, -ArH),7.04(s,1H,-ArH),6.54(d,J=7.6Hz,1H,-ArH),6.47(d,J=7.1Hz,1H,-ArH),5.37(s,2H,-CH2-),5.29(s,2H,-CH2-),4.69(d,J=49.2Hz,1H,-CHF-),4.20(s,2H,-CH2-),3.92(d,J=11.8Hz,1H,-CH2-(a)),3.73(d,J=11.9Hz,1H,-CH2-(b)),3.29(d,J=9.6Hz,2H,-CH2-),3.21–3.12(m,2H,-CH2-),2.76–2.58(m,4H,2*-CH2-),2.58–2.44(m,4H,2*-CH2-),2.19(s,3H,-CH3),2.03–1.79(m,6H,3*-CH2-),1.44(s,3H,-CH3).
质谱数据:[M-H]
-:754.29620。
实施例3、N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-高丝氨酸
用L-高丝氨酸代替L-丝氨酸,操作同实施例1,得到N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-高丝氨酸白色固体。
1H NMR(500MHz,DMSO-d
6)δ9.01(brs,2H,-ArH),8.50(s,1H,-ArH),7.45(brs,1H,-ArH),7.31(s,1H,-ArH),7.24(s,1H,-ArH),7.16–7.01(m,3H,-ArH),6.48(d,J=6.0Hz,1H,-ArH),6.44–6.32(m,1H,-ArH),5.30(s,2H,-CH2-),5.23(s,2H,-CH2-),4.67(d,J=49.6Hz,1H,-CHF-),3.57(s,2H,-CH2-),3.28–3.24(m,2H,-CH2-),3.09(s,2H,-CH2-),2.77–2.56(m,3H,-CH2-and–CH-),2.41–2.21(m,4H,2*-CH2-),2.14(s,3H,-CH3),1.93–1.78(m,2H,-CH2-),1.76–1.54(m,10H,5*-CH2-).
质谱数据:[M-H]
-:754.2979。
实施例4、(2R,4R)-N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-4-羟基吡咯烷-2-甲酸
用(2R,4R)-4-羟基吡咯烷-2-甲酸代替L-丝氨酸,操作同实施例1,得到(2R,4R)-N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-4-羟基吡咯烷-2-甲酸白色固体。
1H NMR(400MHz,Methanol-d
4)δ8.95(s,1H,-ArH),8.87(s,1H,-ArH),8.40(s,1H,-ArH),7.51(s,1H,-ArH),7.40(d,J=7.7Hz,1H,-ArH),7.25–7.16(m,1H,-ArH),7.13–6.97(m,3H,-ArH),6.50(d,J=7.8Hz,1H,-ArH),6.43(d,J=7.3Hz,1H,-ArH),5.40–5.30(m,2H,-CH2-),5.24(s,2H,-CH2-),4.65(d,J=47.8Hz,1H,-CHF-),4.55–4.44(m,2H,-CH2-),4.37(d,J=15.9Hz,1H,-CH2-(a)),4.19–4.08(m,1H,-CH2-(b)),3.56(d,J=17.4Hz,1H,-CH-),3.25–3.23(m,2H,-CH2-),3.18(d,J=12.9Hz,1H,-CH-),3.11(t,J=6.7Hz,2H,-CH2-),2.73–2.42(m,8H,4*-CH2-),2.42–2.30(m,1H,-CH2-(a)),2.14(s,3H,-CH3),2.10–2.04(m,1H,-CH2-(b)),2.00–1.76(m,6H,3*-CH2-).
质谱数据:[M-H]
-:766.29559。
实施例5、(R)-N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-哌啶-2-甲酸
用(R)-哌啶-2-甲酸代替L-丝氨酸,操作同实施例1,得到(R)-N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-哌啶-2-甲酸白色固体。
1H NMR(400MHz,Methanol-d
4)δ8.92(s,1H,-ArH),8.88(s,1H,-ArH),8.34(s,1H,-ArH),7.61(s,1H,-ArH),7.39(d,J=7.3Hz,1H,-ArH),7.19(t,J=7.7Hz,1H,-ArH),7.13–7.03(m,2H,-ArH),6.99(d,J=7.7Hz,1H, -ArH),6.50(d,J=7.9Hz,1H,-ArH),6.43(d,J=7.6Hz,1H,-ArH),5.31(s,2H,-CH2-),5.26(s,2H,-CH2-),4.66(d,J=51.5Hz,1H,-CHF-),4.40–4.13(m,2H,-CH2-),3.41(s,1H,-CH-),3.11(t,J=7.0Hz,2H,-CH2-),2.84–2.40(m,10H,5*-CH2-),2.14(s,3H,-CH3),2.01–1.39(m,14H,7*-CH2-).
质谱数据:[M-H]
-:764.31635。
实施例6、N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,操作同实施例1,得到N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸白色固体。
1H NMR(400MHz,Methanol-d
4)δ9.01(d,J=1.6Hz,1H,-ArH),8.89(d,J=1.6Hz,1H,-ArH),8.44(s,1H,-ArH),7.51(s,1H,-ArH),7.43(d,J=7.3Hz,1H,-ArH),7.21(t,J=7.6Hz,1H,-ArH),7.12(s,1H,-ArH),7.10(s,1H,-ArH),7.08–7.06(m,1H,-ArH),6.58(d,J=7.7Hz,1H,-ArH),6.48(d,J=7.5Hz,1H,-ArH),5.40(s,2H,-CH2-),5.29(s,2H,-CH2-),4.35–4.20(m,2H,-CH2-),4.06–3.92(m,2H,-CH2-),3.90–3.82(m,1H,-CH-),3.59–3.54(m,1H,-CH-),3.46–3.37(m,2H,-CH2-),3.29–3.15(m,8H,4*-CH2-),2.75–2.53(m,2H,-CH2-),2.16(s,3H,-CH3),2.13–2.10(m,2H,-CH2-),2.10–2.07(m,2H,-CH2-),1.92–1.79(m,2H,-CH2-).
质谱数据:[M-H]
-:738.28119.
实施例7、N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2-氯-3-溴苄醇代替2-甲基-3-溴苄醇,操作同实施例1,得到N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:758.23559.
实施例8、N-(5-甲基-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2-氯-3-溴苄醇代替2-甲基-3-溴苄醇,用5-甲基-2,4-二羟基苯甲醛代替5-氯-2,4-二羟基苯甲醛,操作同实施例1,得到N-(5-甲基-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:738.28138.
实施例9、N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2,3-二溴苄醇代替2-甲基-3-溴苄醇,操作同实施例1,得到N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:802.18532.
实施例10、N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2,3-二溴苄醇代替2-甲基-3-溴苄醇,操作同实施例1,得到N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:788.16432.
实施例11、N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2-氯-3-溴苄醇代替2-甲基-3-溴苄醇,操作同实施例1,得到N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:744.21456.
实施例12、N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,操作同实施例1,得到N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:724.27126.
实施例13、N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2-氯-3-溴苄醇代替2-甲基-3-溴苄醇,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,操作同实施例1,得到N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:719.23116.
实施例14、N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,操作同实施例1,得到N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:699.27456.
实施例15、N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2,3-二溴苄醇代替2-甲基-3-溴苄醇,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,操作同实施例1,得到N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:763.16982.
实施例16、N-(5-甲基-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,用5-甲基-2,4-二羟基苯甲醛代替5-氯-2,4-二羟基苯甲醛,操作同实施例1,得到N-(5-甲基-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:679.33257.
实施例17、N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,操作同实施例1,得到N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:713.29216.
实施例18、N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2-氯-3-溴苄醇代替2-甲基-3-溴苄醇,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,操作同实施例1,得到N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:733.23659.
实施例19、N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2,3-二溴苄醇代替2-甲基-3-溴苄醇,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,操作同实施例1,得到N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:777.18243.
实施例20、N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟基-3-甲氧甲酰基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2,3-二溴苄醇代替2-甲基-3-溴苄醇,操作同实施例1,酯水解后得到N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基) 丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:832.15245.
实施例21、N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟基-3-甲氧甲酰基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2-氯-3-溴苄醇代替2-甲基-3-溴苄醇,操作同实施例1,酯水解后得到N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:788.20385.
实施例22、N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟基-3-甲氧甲酰基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,操作同实施例1,酯水解后得到N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:768.26654.
实施例23、N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟基-3-甲氧甲酰基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2-氯-3-溴苄醇代替2-甲基-3-溴苄醇,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,操作同实施例1,酯水解后得到N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:763.21234.
实施例24、N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-乙氧甲酰基-3-羟甲基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟甲基-3-乙氧甲酰基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2-氯-3-溴苄醇代替2-甲基-3-溴苄醇,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,操作同实施例1,得到N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-乙氧甲酰基-3-羟甲基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:805.25332.
实施例25、N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-乙氧甲酰基-3-羟甲基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟甲基-3-乙氧甲酰基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2-氯-3-溴苄醇代替2-甲基-3-溴苄醇,操作同实施例1,得到N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-乙氧甲酰基-3-羟甲基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:830.25445.
实施例26、N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟基-3-甲氧甲酰基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,操作同实施例1,酯水解后得到N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:743.26238.
实施例27、N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟基-3-甲氧甲酰基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2,3-二溴苄醇代替2-甲基-3-溴苄醇,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,操作同实施例1,酯水解后得到N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:807.16453.
实施例28、N-(5-甲基-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟基-3-甲氧甲酰基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用5-甲基-2,4-二羟基苯甲醛代替5-氯-2,4-二羟基苯甲醛,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,操作同实施例1,酯水解后得到N-(5-甲基-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:723.32223.
实施例29、N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-甲氧甲酰基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(3-羟基-3-甲氧甲酰基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,操作同实施例1,得到N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-甲氧甲酰基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:757.28621.
实施例30、N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(4-羟基-4-甲氧甲酰基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,操作同实施例1,酯水解后得到N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:782.27235.
实施例31、N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(4-羟基-4-甲氧甲酰基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2-氯-3-溴苄醇代替2-甲基-3-溴苄醇,操作同实施例1,酯水解后得到N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:802.22336.
实施例32、N-(5-甲基-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(4-羟基-4-甲氧甲酰基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2-氯-3-溴苄醇代替2-甲基-3-溴苄醇,用5-甲基-2,4-二羟基苯甲醛代替5-氯-2,4-二羟基苯甲醛,操作同实施例1,酯水解后得到N-(5-甲基-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:782.27345
实施例33、N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(4-羟基-4-甲氧甲酰基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2,3-二溴苄醇代替2-甲基-3-溴苄醇,操作同实施例1,酯水解后得到N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:846.17227.
实施例34、N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(4-羟基-4-甲氧甲酰基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,操作同实施例1,酯水解后得到N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:757.28157.
实施例35、N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(4-羟基-4-甲氧甲酰基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2-氯-3-溴苄醇代替2-甲基-3-溴苄醇,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,操作同实施例1,酯水解后得到N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:777.22237.
实施例36、N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸
用4-溴-1-(3-(4-羟基-4-甲氧甲酰基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2,3-二溴苄醇代替2-甲基-3-溴苄醇,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,操作同实施例1,酯水解后得到N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸白色固体。质谱数据:[M-H]
-:821.17532.
实施例37、(2S)-2-(4-(2-溴-3-(1-(3-(2-羟基-7-氮杂螺[3.5]壬烷-7-基)丙基)吲哚啉-4-基)苄氧基)-5-氯-2-((吡啶-3-基)甲氧基)苄胺基)-3-羟基丁酸
用4-溴-1-(3-(2-羟基-7-氮杂螺[3.5]壬烷-7-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2,3-二溴苄醇代替2-甲基-3-溴苄醇,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,用(2S)-3-羟基丁氨酸代替L-丝氨酸,操作同实施例1,得到(2S)-2-(4-(2-溴-3-(1-(3-(2-羟基-7-氮杂螺[3.5]壬烷-7-基)丙基)吲哚啉-4-基)苄氧基)-5-氯-2-((吡啶-3-基)甲氧基)苄胺基)-3-羟基丁酸白色固体。质谱数据:[M-H]
-:831.23258.
实施例38、(2S)-2-(4-(2-溴-3-(1-(3-(6-氧代-2,5,7-三氮螺[3.4]辛烷-2-基)丙基)吲哚啉-4-基)苄氧基)-5-氯-2-((吡啶-3-基)甲氧基)苄胺基)-3-羟基丁酸
用4-溴-1-(3-(6-氧代-2,5,7-三氮螺[3.4]辛烷-2-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2,3-二溴苄醇代替2-甲基-3-溴苄醇,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,用(2S)-3-羟基丁氨酸代替L-丝氨酸,操作同实施例1,得到(2S)-2-(4-(2-溴-3-(1-(3-(6-氧代-2,5,7-三氮螺[3.4]辛烷-2-基)丙基)吲哚啉-4-基)苄氧基)-5-氯-2-((吡啶-3-基)甲氧基)苄胺基)-3-羟基丁酸白色固体。质谱数据:[M-H]
-:817.19321.
实施例39、(S)-2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-氟吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄胺基)-3-羟基-2-甲基丙酸
用4-溴-1-(3-(3-氟吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2-氯-3-溴苄醇代替2-甲基-3-溴苄醇,用(S)-3-羟基-2-甲基丙氨酸代替L-丝氨酸,操作同实施例1,得到(S)-2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-氟吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄胺基)-3-羟基-2-甲基丙酸白色固体。质谱数据:[M-H]
-:760.22478
实施例40、N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺
用4-溴-1-(3-(吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用间氰基苄氯代替5-氯甲基烟腈盐酸盐,用N-(2-氨乙基)乙酰胺代替L-丝氨酸,操作同实施例1,得到N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺白色固体。
1H NMR(400MHz,Methanol-d
4) δ7.92(s,1H,-ArH),7.84(d,J=7.8Hz,1H,-ArH),7.75–7.69(m,1H,-ArH),7.64–7.56(m,1H,-ArH),7.54–7.47(m,2H,-ArH),7.45–7.36(m,1H,-ArH),7.28–7.26(m,1H,-ArH),7.25–7.23(m,1H,-ArH),7.14–6.88(m,2H,-ArH),6.07(d,J=3.2Hz,1H,-ArH),5.34(s,2H,-CH2-),5.32–5.20(m,2H,-CH2-),4.37(t,J=6.7Hz,1H,活泼氢),4.28–4.20(m,2H,-CH2-),3.76–3.55(m,2H,-CH2-),3.45(t,J=5.7Hz,2H,-CH2-),3.37–3.31(m,2H,-CH2-),3.29–2.95(m,6H,3*-CH2-),2.40–1.96(m,13H,-CH3and 5*-CH2-),1.94(s,3H,-CH3).
质谱数据:[M+H]
+:706.3472。
实施例41、N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺
用4-溴-1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用间氰基苄氯代替5-氯甲基烟腈盐酸盐,用N-(2-氨乙基)乙酰胺代替L-丝氨酸,操作同实施例1,得到N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺白色固体。
1H NMR(400MHz,Methanol-d
4)δ7.98–7.91(m,1H,-ArH),7.88–7.82(m,1H,-ArH),7.75–7.69(m,1H,-ArH),7.65–7.57(m,1H,-ArH),7.52(d,J=3.2Hz,1H,-ArH),7.45–7.36(m,1H,-ArH),7.31–7.17(m,3H,-ArH),7.14–7.07(m,1H,-ArH),7.01(d,J=1.5Hz,1H,-ArH),6.63–6.45(m,1H,-ArH),5.39–5.22(m,4H,2*-CH2-),4.61–4.47(m,1H,活泼氢),4.37(t,J=6.7Hz,1H,-CH-),4.23(s,2H,-CH2-),3.87–3.31(m,8H,4*-CH2-),3.30–3.09(m,6H,3*-CH2-),2.40–1.95(m,9H,3*-CH2-and,-CH3),1.94(s,3H,-CH3).
质谱数据:[M+H]
+:722.34277.
实施例42、N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(3-氟吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺
用4-溴-1-(3-(3-氟吡咯烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用间氰基苄氯代替5-氯甲基烟腈盐酸盐,用N-(2-氨乙基)乙酰胺代替L-丝氨酸,操作同实施例1,得到N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(3-氟吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺白色固体。
1H NMR(400MHz,Methanol-d
4)δ7.83(s,1H,-ArH),7.76(d,J=7.8Hz,1H,-ArH),7.69(d,J=7.7Hz,1H,-ArH),7.57(t,J=7.7Hz,1H,-ArH),7.44–7.35(m,1H,-ArH),7.31(s,1H,-ArH),7.25–7.15(m,1H,-ArH),7.13–7.02(m,2H,-ArH),6.86(s,1H,-ArH),6.51(d,J=7.8Hz,1H,-ArH),6.43(d,J=7.5Hz,1H,-ArH),,5.29–5.06(m,5H,2*-CH2-and–CHF-),3.73(s,2H,-CH2-),3.30–3.22(m,4H,2*-CH2-),3.12(t,J=7.0Hz,2H,-CH2-),3.03–2.83(m,2H,-CH2-),2.73–2.51(m,6H,3*-CH2-),2.48–2.18(m,2H,-CH2-),2.15(s,3H,-CH3),2.08–1.92(m,2H,-CH2-),1.88(s,3H,-CH3),1.87–1.78(m,2H,-CH2-).
质谱数据:[M+H]
+:724.34021.
实施例43、N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(3-羟基氮杂环丁烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺
用4-溴-1-(3-(3-羟基氮杂环丁烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用间氰基苄氯代替5-氯甲基烟腈盐酸盐,用N-(2-氨乙基)乙酰胺代替L-丝氨酸,操作同实施例1,得到N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(3-羟基氮杂环丁烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺白色固体。
1H NMR (400MHz,Methanol-d
4)δ7.85(s,1H,-ArH),7.78(d,J=7.8Hz,1H,-ArH),7.71(d,J=7.4Hz,1H,-ArH),7.59(t,J=6.5Hz,1H,-ArH),7.44–7.36(m,1H,-ArH),7.32(s,1H,-ArH),7.27–7.16(m,2H,-ArH),7.13–7.07(m,1H,-ArH),6.88(s,1H,-ArH),6.52(d,J=7.8Hz,1H,-ArH),6.45(d,J=7.6Hz,1H,-ArH),5.25–5.16(m,4H,2*-CH2-),4.42–4.29(m,1H,-CH-),3.80–3.62(m,4H,2*-CH2-),3.33–3.29(m,8H,4*-CH2-),3.11(t,J=7.1Hz,1H,-CH2-(a)),2.98(t,J=7.4Hz,1H,-CH2-(b)),2.75–2.63(m,4H,2*-CH2-),2.16(s,3H,-CH3),1.89(s,3H,-CH3),1.77–1.62(m,2H,-CH2-).
质谱数据:[M+H]
+:708.34.
实施例44、N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(3-氟氮杂环丁烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺
用4-溴-1-(3-(3-氟氮杂环丁烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用间氰基苄氯代替5-氯甲基烟腈盐酸盐,用N-(2-氨乙基)乙酰胺代替L-丝氨酸,操作同实施例1,得到N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(3-氟氮杂环丁烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺白色固体。
1H NMR(400MHz,Chloroform-d)δ7.72(s,1H,-ArH),7.68–7.59(m,2H,-ArH),7.52(t,J=7.7Hz,1H,-ArH),7.42(d,J=6.6Hz,1H,-ArH),7.30(s,1H,-ArH),7.28–7.16(m,2H,-ArH),7.11(t,J=7.6Hz,1H,-ArH),6.59(s,1H,-ArH),6.49(t,J=6.8Hz,2H,-ArH),6.03(s,1H,活泼氢),5.25–5.16(m,1H,-CH-,),5.11(s,2H,-CH2-),5.08(s,2H,-CH2-),3.76(s,2H,-CH2-),3.73–3.62(m,2H,-CH2-),3.42–3.22(m,4H,2*-CH2-),3.21–3.01(m,4H,2*-CH2-),2.79–2.56(m,6H,3*-CH2-),2.18(s,3H,-CH3),1.95(s,3H,-CH3),1.69(p,J=7.0Hz,2H,-CH2-).
质谱数据:[M+H]
+:710.32324.
实施例45、N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(吗啉-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺
用4-溴-1-(3-(吗啉-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用间氰基苄氯代替5-氯甲基烟腈盐酸盐,用N-(2-氨乙基)乙酰胺代替L-丝氨酸,操作同实施例1,得到N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(吗啉-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺白色固体。
1H NMR(400MHz,Methanol-d
4)δ7.81(s,1H,-ArH),7.74(d,J=7.6Hz,1H,-ArH),7.67(d,J=7.6Hz,1H,-ArH),7.55(t,J=7.8Hz,1H,-ArH),7.35(d,J=7.6Hz,1H,-ArH),7.29(s,1H,-ArH),7.16(t,J=7.6Hz,1H,-ArH),7.11–7.00(m,2H,-ArH),6.84(s,1H,-ArH),6.49(d,J=7.9Hz,1H,-ArH),6.41(d,J=7.6Hz,1H,-ArH),5.17(s,2H,-CH2-),5.16(s,2H,-CH2-),3.71(s,2H,-CH2-),3.70–3.64(m,4H,2*-CH2-),3.26–3.21(m,4H,2*-CH2-),3.11(t,J=7.0Hz,2H,-CH2-),2.64(t,J=6.3Hz,2H,-CH2-),2.62–2.52(m,2H,-CH2-),2.50–2.41(m,6H,3*-CH2-),2.13(s,3H,-CH3),1.85(s,3H,-CH3),1.83–1.75(m,2H,-CH2-).
质谱数据:[M+H]
+:722.34387.
实施例46、N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(4-甲基哌嗪-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺
用4-溴-1-(3-(4-甲基哌嗪-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用间氰基苄氯代替5-氯甲基烟腈盐酸盐,用N-(2-氨乙基)乙酰 胺代替L-丝氨酸,操作同实施例1,得到N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(4-甲基哌嗪-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺白色固体。
1H NMR(400MHz,Methanol-d
4)δ7.84(s,1H,-ArH),7.77(d,J=7.8Hz,1H,-ArH),7.71–7.67(m,1H,-ArH),7.60–7.54(m,1H,-ArH),7.38(d,J=7.5Hz,1H,-ArH),7.31(s,1H,-ArH),7.22–7.18(m,1H,-ArH),7.12–7.04(m,2H,-ArH),6.87(s,1H,-ArH),6.51(d,J=7.5Hz,1H,-ArH),6.44(d,J=7.6Hz,1H,-ArH),5.19(s,2H,-CH2-),5.18(s,2H,-CH2-),3.74(s,2H,-CH2-),3.29–3.24(m,4H,2*-CH2-),3.12(t,J=7.0Hz,2H,-CH2-),2.71–2.35(m,14H,7*-CH2-),2.29(s,3H,-CH3),2.15(s,3H,-CH3),1.88(s,3H,-CH3),1.85–1.77(m,2H,-CH2-).
质谱数据:[M+H]
+:735.37634.
实施例47、N-(2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺
用4-溴-1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用N-(2-氨乙基)乙酰胺代替L-丝氨酸,操作同实施例1,得到N-(2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺白色固体。
1H NMR(400MHz,Chloroform-d)δ8.88(brs,2H,-ArH),8.07(s,1H,-ArH),7.49–7.36(m,2H,-ArH),7.33(s,1H,-ArH),7.25–7.18(m,1H,-ArH),7.15–7.07(m,1H,-ArH),6.61(s,1H,-ArH),6.56–6.42(m,2H,-ArH),6.03(s,1H,活泼氢),5.14(s,2H,-CH2-),5.12(s,2H,-CH2-),4.23(s,1H,活泼氢),3.80–3.68(m,3H,-CH2-and–CH-),3.34(brs,4H,2*-CH2-),3.23–3.08(m,2H,-CH2-),2.87–2.57(m,6H,3*-CH2-),2.52–2.40(m,2H,-CH2-),2.19(brs,5H,-CH3and-CH2-),1.97(s,3H,-CH3),1.97–1.86(m,2H,-CH2-),1.85–1.77(m,2H,-CH2-),1.67–1.57(m,2H,-CH2-).
质谱数据:[M+H]
+:737.3567
实施例48、N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(二甲胺基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺
用4-溴-1-(3-(二甲胺基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用间氰基苄氯代替5-氯甲基烟腈盐酸盐,用N-(2-氨乙基)乙酰胺代替L-丝氨酸,操作同实施例1,得到N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(二甲胺基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺白色固体。
1H NMR(400MHz,Chloroform-d)δ7.72(s,1H,-ArH),7.68–7.59(m,2H,-ArH),7.52(t,J=7.7Hz,1H,-ArH),7.42(d,J=6.0Hz,1H,-ArH),7.30(s,1H,-ArH),7.25–7.18(m,2H,-ArH),7.11(t,J=7.7Hz,1H,-ArH),6.59(s,1H,-ArH),6.50(s,1H,-ArH),6.48(s,1H,-ArH),6.03(s,1H,活泼氢),5.11(s,2H,-CH2-),5.08(s,2H,-CH2-),3.75(s,2H,-CH2-),3.38–3.26(m,4H,2*-CH2-),3.14(dq,J=14.1,6.9,6.3Hz,2H,-CH2-),2.76–2.61(m,4H,2*CH2-),2.45–2.37(m,2H,-CH2-),2.28(s,6H,2*-CH3),2.18(s,3H,-CH3),1.95(s,3H,-CH3),1.84–1.79(m,2H,-CH2-).
质谱数据:[M+H]
+:680.33575.
实施例49、N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(氮杂环丁烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺
用4-溴-1-(3-(氮杂环丁烷-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用间氰基苄氯代替5-氯甲基烟腈盐酸盐,用N-(2-氨乙基)乙酰胺代替L-丝氨酸,操作同实施例1,得到N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(氮杂环丁烷-1-基)丙 基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺白色固体。
1H NMR(400MHz,Chloroform-d)δ7.72(s,1H,-ArH),7.67–7.58(m,2H,-ArH),7.52(t,J=7.6Hz,1H,-ArH),7.42(d,J=7.0Hz,1H,-ArH),7.30(s,1H,-ArH),7.25–7.17(m,2H,-ArH),7.11(t,J=7.5Hz,1H,-ArH),6.59(s,1H,-ArH),6.52–6.43(m,2H,-ArH),5.11(s,2H,-CH2-),5.07(s,2H,-CH2-),3.75(s,2H,-CH2-),3.42–3.01(m,10H,5*-CH2-),2.79–2.70(m,2H,-CH2-),2.70–2.57(m,2H,-CH2-),2.53(t,J=7.2Hz,2H,-CH2-),2.18(s,3H,-CH3),2.13–2.04(m,2H,-CH2-),1.95(s,3H,-CH3),1.74–1.59(m,2H,-CH2-).
质谱数据:[M+H]
+:692.3334.
实施例50、N-(2-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺
用4-溴-1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用3-氯甲基吡啶代替5-氯甲基烟腈盐酸盐,用N-(2-氨乙基)乙酰胺代替L-丝氨酸,操作同实施例1,得到N-(2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺白色固体。
1H NMR(400MHz,Chloroform-d)δ8.68(s,1H,-ArH),8.61(d,J=4.0Hz,1H,-ArH),7.71(d,J=7.3Hz,1H,-ArH),7.43(d,J=7.1Hz,1H,-ArH),7.39–7.32(m,1H,-ArH),7.28(s,1H,-ArH),7.25–7.15(m,2H,-ArH),7.11(t,J=7.8Hz,1H,-ArH),6.64(s,1H,-ArH),6.53–6.46(m,2H,-ArH),6.02(s,1H,活泼氢),5.13(s,2H,-CH2-),5.07(s,2H,-CH2-),3.72(brs,3H,-CH-and-CH2-),3.31(q,J=11.3,10.4Hz,4H,2*-CH2-),3.14(q,J=7.3Hz,2H,-CH2-),2.89–2.77(m,2H,-CH2-),2.76–2.58(m,4H,2*-CH2-),2.51–2.42(m,2H,-CH2-),2.25–2.14(m,5H,-CH3and-CH2-),1.95(s,3H,-CH3),1.92(brs,2H,-CH2-),1.85–1.79(m,2H,-CH2-),1.67–1.58(m,2H,-CH2-).
质谱数据:[M+H]
+:712.36139.
实施例51、N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸甲酯
用4-溴-1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用L-丝氨酸甲酯代替L-丝氨酸,操作同实施例1,得到N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸甲酯白色固体。
1H NMR(400MHz,Methanol-d
4)δ8.95(d,J=1.7Hz,1H,-ArH),8.89(d,J=1.6Hz,1H,-ArH),8.43(s,1H,-ArH),7.43(d,J=7.3Hz,1H,-ArH),7.37(s,1H,-ArH),7.21(t,J=7.6Hz,1H,-ArH),7.13–7.07(m,2H,-ArH),6.98(s,1H,-ArH),6.57(d,J=7.8Hz,1H,-ArH),6.48(d,J=7.6Hz,1H,-ArH),5.30(s,2H,-CH2-),5.25(s,2H,-CH2-),3.94(d,J=13.1Hz,2H,-CH2-),3.82(d,J=12.9Hz,1H,-CH-),3.80–3.74(m,2H,-CH2-),3.67(s,3H,-OCH3),3.56(t,J=4.7Hz,1H,-CH-),3.49–3.38(m,2H,-CH2-),3.32–3.29(m,2H,-CH2-),3.27–3.17(m,6H,3*-CH2-),2.72–2.54(m,2H,-CH2-),2.16(s,3H,-CH3),2.09(dd,J=13.4,8.1Hz,4H,2*-CH2-),1.86(brs,2H,-CH2-).
质谱数据:[M+H]
+:754.3326
实施例52、2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)-丙-1,3-二醇
用4-溴-1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2-氨基丙-1,3-二醇代替L-丝氨酸,操作同实施例1,得到2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)-丙-1,3-二醇白色固体。
1H NMR(400MHz,Methanol-d
4)δ9.00(s,1H,-ArH),8.91(s,1H,-ArH),8.46(t,J=2.0Hz,1H,-ArH),7.55(s,1H,-ArH),7.45(d,J=7.6Hz,1H,-ArH),7.22(t,J=7.6Hz,1H,-ArH),7.14–7.07(m,3H,-ArH),6.59(d,J=7.9Hz,1H,-ArH),6.53–6.46(m,1H,-ArH),5.42(s,2H,-CH2-),5.32(s,2H,-CH2-),4.34(s,2H,-CH2-),3.82(dd,J=12.0,4.5Hz,2H,-CH2-),3.73(dd,J=12.0,6.2Hz,2H,-CH2-),3.70–3.64(m,1H,-CH-),3.30–3.18(m,8H,4*-CH2-),2.90(s,2H,-CH2-),2.75–2.66(m,1H,-CH-),2.67–2.51(m,2H,-CH2-),2.18(s,3H,-CH3),2.16–2.07(m,4H,2*-CH2-),1.88(brs,2H,-CH2-).
质谱数据:[M+H]
+:726.33923.
实施例53、(2R,4R)-N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-4-羟基脯氨酸甲酯
用4-溴-1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用(2R,4R)-4-羟基脯氨酸甲酯代替L-丝氨酸,操作同实施例1,得到(2R,4R)-N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-4-羟基脯氨酸甲酯白色固体。
1H NMR(400MHz,Chloroform-d)δ8.87(s,1H,-ArH),8.85(s,1H,-ArH),8.33(s,1H,-ArH),7.43(d,J=6.8Hz,1H,-ArH),7.35(s,1H,-ArH),7.25–7.16(m,2H,-ArH),7.11(t,J=7.6Hz,1H,-ArH),6.58(s,1H,-ArH),6.53–6.44(m,2H,-ArH),5.22–5.05(m,4H,-CH2-),4.49(s,1H,活泼氢),3.89–3.81(m,1H,-CH-),3.80–3.68(m,2H,-CH2-),3.58(s,3H,-OCH3),3.41–3.25(m,3H,-CH2-and–CH-),3.21–3.06(m,2H,-CH2-),2.84(dd,J=7.2,3.8Hz,2H,-CH2-),2.75–2.59(m,2H,-CH2-),2.54–2.46(m,3H,-CH2-and–CH-),2.36–2.20(m,4H,2*-CH2-),2.18(s, 3H,-CH3),2.14–2.01(m,2H,-CH2-),1.96(dd,J=11.5,4.7Hz,2H,-CH2-),1.92–1.80(m,2H,-CH2-),1.64(q,J=12.7,11.6Hz,2H,-CH2-).
质谱数据:[M+H]
+:780.35077.
实施例54、2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙醇
用4-溴-1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉代替4-溴-1-(3-(4-氟哌啶-1-基)丙基)吲哚啉,用2-氨基乙醇代替L-丝氨酸,操作同实施例1,得到2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙醇白色固体。
1H NMR(400MHz,Methanol-d
4)δ8.94(d,J=1.9Hz,1H,-ArH),8.89(d,J=1.6Hz,1H,-ArH),8.34(s,1H,-ArH),7.43(d,J=7.0Hz,1H,-ArH),7.33(s,1H,-ArH),7.21(t,J=7.6Hz,1H,-ArH),7.14–7.04(m,2H,-ArH),6.97(s,1H,-ArH),6.52(d,J=7.7Hz,1H,-ArH),6.45(d,J=7.4Hz,1H,-ArH),5.30(s,2H,-CH2-),5.24(s,2H,-CH2-),3.75(brs,2H,-CH2-),3.67–3.60(m,3H,-CH2-and,-CH-),3.35(s,2H,-CH2-),3.29–3.25(m,2H,-CH2-),3.12(t,J=7.1Hz,2H,-CH2-),2.91–2.82(m,2H,-CH2-),2.69(t,J=5.1Hz,2H,-CH2-),2.66–2.55(m,2H,-CH2-),2.53–2.46(m,2H,-CH2-),2.17(s,3H,-CH3),1.91–1.81(m,4H,2*-CH2-),1.63–1.55(m,2H,-CH2-).
质谱数据:[M+H]
+:696.33.
药理活性
1、体外活性评价:体外酶学水平的检测方法采用Cisbio公司PD-1/PD-L1 binding assay kit检测试剂盒。
PD-1/PD-L1小分子抑制剂的筛选原理和方法
1)原理:PD-1蛋白带HIS标签,PD-1的配体PD-L1带hFc标签,分别用Eu标记的anti-hFc抗体和XL665标记的anti-HIS抗体与两个标签蛋白结合,激光激发 后,能量能够从供体Eu上转移到受体XL665,使得XL665发光,而加入抑制剂(化合物或抗体)后,阻断PD-1与PD-L1的结合,使得Eu和XL665距离较远,能量不能转移,XL665不会发光。
2)实验方法:具体方法可参考Cisbio公司的PD-1/PD-L1试剂盒(货号64ICP01PEG)。简单叙述如下,96孔白色酶标板(Cisbio,货号66PL96100),每孔加入2μl稀释液或者用稀释液稀释的目标化合物,然后每孔再加入4μl PD-1蛋白和4μl PD-L1蛋白,常温孵育15min,再每孔加入10μl anti-Tag1-Eu3
+和anti-Tag2-XL665的混合液,室温孵育2h-6h后用Tecan Spark仪器检测665nm和620nm处的荧光信号。HTRF率=(665nm/620nm)*10
4。每个化合物检测6-10个浓度,采用Graphpad软件计算IC
50。
3)筛选结果见表1:A代表IC
50值在10
-9至10
-12M间,B代表IC
50值在10
-6至10
-8M间,C代表IC
50值大于10
-6M.
表1.实施例化合物在分子水平对PD-1与PD-L1相互作用的抑制活性评价筛选结果
实施例化合物 | IC 50(M) | 实施例 | IC 50(M) |
1 | A | 28 | A |
2 | A | 29 | A |
3 | A | 30 | A |
4 | A | 31 | A |
5 | A | 32 | A |
6 | A | 33 | A |
7 | A | 34 | A |
8 | A | 35 | A |
9 | A | 36 | A |
10 | A | 37 | A |
11 | A | 38 | A |
12 | A | 39 | A |
13 | A | 40 | B |
14 | A | 41 | A |
15 | A | 42 | B |
16 | A | 43 | B |
17 | A | 44 | A |
18 | A | 45 | B |
19 | A | 46 | B |
20 | A | 47 | A |
21 | A | 48 | B |
22 | A | 49 | B |
23 | A | 50 | B |
24 | A | 51 | B,4.1×10 -8 |
25 | A | 52 | A |
26 | A | 53 | B |
27 | A | 54 | B,3.1×10 -8 |
Cisbio HTRF检测结果表明,实施例化合物在分子水平可显著抑制PD-1与PD-L1的相互作用,个别化合物IC
50<10
-11mol/L。
2、实施例化合物解除配体PD-L1抑制IFNγ的能力
IFNγ的表达水平能够反映T淋巴细胞的增殖活性。利用提取的人PBMC(人单个核细胞),在anti-CD3/anti-CD28抗体激活T淋巴细胞的基础上,加入配体PD-L1抑制T淋巴细胞,考察待测化合物解除配体抑制作用的能力。
具体操作如下,采用达科为公司的人淋巴细胞分离液(货号DKW-KLSH-0100)提取人全血中的PBMC,将PBMC接种到96孔板中,每孔接种数为3×10
5个。分别加入人的PD-L1蛋白(终浓度5μg/ml),anti-CD3/anti-CD28抗体(终浓度1μg/ml)和等比例稀释的实施例化合物。72h后采用Cisbio公司的IFNγ检测试剂盒检测上清中IFNγ的表达量。实验结果显示,实施例化合物在10nM时就能部分解除PD-L1对IFNγ的抑制作用。
3、实施例化合物体内药效
药效学研究方法如下:
皮下移植瘤方法如下:将培养的特定肿瘤细胞消化后离心收集细胞,用无菌生理盐水清洗两遍后计数,用生理盐水调整细胞浓度为5×10
6/ml,将0.2ml细胞混悬液接种到C57BL/6或Bablc小鼠右侧腋下。接种后次日动物随机分组,每组6‐7只,称重后给药,待测化合物每天给药1次,监测小鼠肿瘤体积大小,待肿瘤体积达到一定大小后,称量小鼠体重,眼眶取血后脱颈处死小鼠,剥取肿瘤组织、胸腺组织和脾组织并分别称重。最后计算肿瘤抑制率,以肿瘤抑制率评价抗肿瘤作用强度。
B16F10肺转移模型方法如下:将培养的B16F10肿瘤细胞消化离心,用无菌生理盐水清洗两遍后计数,用生理盐水调整细胞浓度为2.5×10
6/ml,将0.2ml细胞通过尾静脉注射入到C57BL/6小鼠体内,肿瘤细胞将在小鼠肺部聚集。接种后次日动物随机分组,每组6‐7只,称重后给药,待测化合物每天给药1次,3周后称量小鼠体重,处死动物,剥取小鼠肺组织并称重,包式液固定后计数肺部肿瘤数目。最后计算化合物对肿瘤的抑制率,以肿瘤抑制率评价抗肿瘤作用强度。
Lewis肺癌胸水模型方法如下:将小鼠皮下Lewis移植瘤肿匀浆后,用无菌生 理盐水清洗两遍后计数,用生理盐水调整细胞浓度为2.5×10
5/ml,将0.2ml细胞注射入到C57BL/6小鼠胸腔内。接种后次日动物随机分组,每组6‐7只,称重后给药,待测化合物每天给药1次,待对照组小鼠体重突然下降时处死动物,用注射器抽取胸腔内的积液,记录积液体积。
在以上各模型作用机制研究中,各类型T细胞占总细胞比例的试验方法采用流式细胞术方法,具体步骤如下:先处理样品,对于血液组织,在处理小鼠时,取小鼠的眼眶血,先用红细胞裂解液去除红细胞后,然后用PBS溶液进行漂洗后收集细胞;对于小鼠的肿瘤和脾脏器官,先用匀浆器研磨组织,再加入PBS缓冲液稀释,然后用300目的筛网过滤。计数各样本的细胞数后,取1×10
6的细胞加入EP管中后进行流式抗体的染色,在冰上孵育1h后,用PBS溶液漂洗2遍。用BD公司的VERSE流式仪器进行细胞群的分析。其中,肿瘤组织总上样细胞数为1×10
5个,血液和脾脏组织总上样细胞数为1×10
4个。在流式仪器上圈门后分析各类型T细胞占总进样细胞数的比例。
(1)黑色素瘤高转移株B16F10皮下移植瘤模型
对于黑色素瘤高转移株B16F10,实施例化合物无论从肿瘤体积还是重量上,都可显著的抑制皮下肿瘤的生长。
从其作用机制分析,实施例化合物可增加肿瘤浸润的各淋巴细胞比例,实施例化合物可增加脾中各淋巴细胞比例。
(2)黑色素瘤高转移株B16F10肺转移模型
对于黑色素瘤高转移株B16F10肺转移模型,实施例化合物能显著抑制肺部转移灶数量。
从其作用机制分析,实施例化合物可增加小鼠血液中各淋巴细胞数量。
(3)小鼠乳腺癌EMT6皮下移植瘤模型
对于小鼠乳腺癌EMT6皮下移植瘤模型,实施例化合物具有一定的抗肿瘤作用。另外联合环磷酰胺给药后,实施例化合物能使环磷酰胺的抑瘤率提高。
(4)小鼠Lewis肺癌胸水模型
对于小鼠Lewis肺癌胸水模型,实施例化合物具有一定的抗肿瘤作用。实施例化合物能降低胸水发生率。
(5)小鼠结肠癌MC38皮下移植瘤模型
对于小鼠结肠癌MC38皮下移植瘤模型,实施例化合物具有显著的抗肿瘤作用。联合环磷酰胺CTX给药后,具有良好的协同作用。
4、利用Biacore设备测试实施例化合物以及PD-L1抗体与PD-L1蛋白的相互作用
(1)实验原理
表面等离子体是一种金属表面的电磁波,由自由振动的光子和电子相互作用产生。表面等离子体共振(surface-plasmon resonance,SPR)是一种发生在两种介质表面的光学现象,这种现象可以由光子或电子诱导。光从光密介质射入光疏介质发生全反射现象,会形成消逝波进入光疏介质。当全反射的消逝波与金属表面的等离子波相遇时,可能会发生共振,反射光能量下降,在反射光能量谱上出现共振峰,这种共振称为表面等离子体共振,引起表面等离子体共振的入射角称为SPR角。SPR生物传感器提供了一个灵敏的、实时监测分子将相互作用的非标记检测技术。该传感器检测的是SPR角的变化,SPR又与金属表面的折射率相关。当有分析物结合到芯片表面后,导致了芯片表面折射率的改变,从而引起SPR角度变化,这就是SPR生物传感器实时检测分子间相互作用的基本原理。在相互作用分析时,SPR角度的改变被实时记录在传感图上。
(2)实验方法:
采用捕获法将PD-L1蛋白捕获于NTA芯片Fc4通道上;结合缓冲液体系为PBS-P+,pH7.4,0.01%DMSO。将配制好的一系列浓度的化合物及PD-L1抗体流经芯片表面,进行相互作用测定。
(3)实验结果:
初步确定实施例化合物的结合蛋白为PD-L1,进一步采用Biacore实验证实,实施例化合物与PD-L1具有很强的结合能力。
Claims (30)
- 如通式I所示的二氢吲哚衍生物及其立体异构体以及其可药用盐,式中其中Z选自N、C,其中n各自独立的选自:0、1、2、3、4、5、6;其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代、1、3位双取代、2、3位双取代、1、2、3、位三取代;Y选自:C1-5烷基、C3-7环烷烷基、吡啶亚甲基、取代的C1-5烷基、取代的苄基、 取代吡啶亚甲基,取代基各自独立的选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求1的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;n任选自:0、1、2、3、4、5、6;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;Y选自:C1-5烷基、C3-7环烷烷基、吡啶亚甲基、取代的C1-5烷基、取代的苄基、取代吡啶亚甲基,取代基各自独立的选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求2的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA1)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、 CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;n任选自:0、1、2、3、4、5、6;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求2的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA2)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;n任选自:0、1、2、3、4、5、6;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求2的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA3)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;n任选自:0、1、2、3、4、5、6;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;C选自氨基、二甲胺基、环丙氨基、环丁胺基、羟基、羟胺基、羟乙氨基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求2的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA4)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;n任选自:0、1、2、3、4、5、6;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;D选自氢、环丙基、甲基、异丙基、羟甲基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求1的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IB)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;n任选自:0、1、2、3、4、5、6;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;Y选自:C1-5烷基、C3-7环烷烷基、吡啶亚甲基、取代的C1-5烷基、取代的苄基、取代吡啶亚甲基,取代基各自独立的选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求7的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IB1)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;n任选自:0、1、2、3、4、5、6;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、 噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求7的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IB2)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;n任选自:0、1、2、3、4、5、6;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求7的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IB3)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;n任选自:0、1、2、3、4、5、6;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、 3位双取代,2、3位双取代,1、2、3位三取代;C选自氨基、二甲胺基、环丙氨基、环丁胺基、羟基、羟胺基、羟乙氨基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求7的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IB4)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;n任选自:0、1、2、3、4、5、6;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;D选自氢、环丙基、甲基、异丙基、羟甲基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求1的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IC)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;n任选自:0、1、2、3、4、5、6;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;Y选自:C1-5烷基、C3-7环烷烷基、吡啶亚甲基、取代的C1-5烷基、取代的苄基、取代吡啶亚甲基,取代基各自独立的选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求12的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IC1)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;n任选自:0、1、2、3、4、5、6;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求12的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IC2)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;n任选自:0、1、2、3、4、5、6;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求12的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IC3)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;n任选自:0、1、2、3、4、5、6;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;C选自氨基、二甲胺基、环丙氨基、环丁胺基、羟基、羟胺基、羟乙氨基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求12的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IC4)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;n任选自:0、1、2、3、4、5、6;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;D选自氢、环丙基、甲基、异丙基、羟甲基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求1的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(ID)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;Y选自:C1-5烷基、C3-7环烷烷基、吡啶亚甲基、取代的C1-5烷基、取代的苄基、取代吡啶亚甲基,取代基各自独立的选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、 磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求17的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(ID1)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求17的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(ID2)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取 代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;Z选自氢、氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、三氟甲基、C1-5烷基、C1-5烷氧基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求17的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(ID3)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;C选自氨基、二甲胺基、环丙氨基、环丁胺基、羟基、羟胺基、羟乙氨基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求17的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(ID4)所示:式中其中B各自独立的选自:H、OH、O:、CH 3、CH 3CH 2、HOOC、CH 3OOC、CH 3CH 2OOC、CH 2COOH、CH 2OH、F、Cl,其中m各自独立的选自:0、1、2、3、4、5;R2选自氢、甲基、氟、氯、溴;R3选自氢、甲基、氟、氯、溴、氰基;X选自氢、氟、氯、溴、C1-4烷基、乙烯基、三氟甲基、甲氧基;X包括单取代或多取代,其中单取代包括1位单取代、2位单取代、3位单取代,多取代包括1、2位双取代,1、3位双取代,2、3位双取代,1、2、3位三取代;D选自氢、环丙基、甲基、异丙基、羟甲基;R4选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基各自独立的选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基,所述的取代基各自独立的包括单取代、双取代、三取代、四取代。
- 根据权利要求1的二氢吲哚衍生物及其立体异构体以及其可药用盐,所述的化合物选自:N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸N-(5-甲基-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸N-(5-甲基-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸(S)-2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)-3-羟基-2-甲基丙酸(R,R)-N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-氟哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-4-羟基脯氨酸N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-乙氧甲酰基-3-羟甲基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-乙氧甲酰基-3-羟甲基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸N-(5-甲基-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-羧基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-羟基-3-甲氧甲酰基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸N-(5-甲基-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄基)-L-丝氨酸N-(5-氯-2-((吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基-4-羧基哌啶-1-基)丙基)吲哚啉-4-基)-2-溴苄氧基)苄基)-L-丝氨酸(2S)-2-(4-(2-溴-3-(1-(3-(2-羟基-7-氮杂螺[3.5]壬烷-7-基)丙基)吲哚啉-4-基)苄氧基)-5-氯-2-((吡啶-3-基)甲氧基)苄胺基)-3-羟基丁酸(2S)-2-(4-(2-溴-3-(1-(3-(6-氧代-2,5,7-三氮螺[3.4]辛烷-2-基)丙基)吲哚啉-4-基)苄氧基)-5-氯-2-((吡啶-3-基)甲氧基)苄胺基)-3-羟基丁酸(S)-2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(3-氟吡咯烷-1-基)丙基)吲哚啉-4-基)-2-氯苄氧基)苄胺基)-3-羟基-2-甲基丙酸2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)-丙-1,3-二醇N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(3-羟基吡咯烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺N-(2-(5-氯-2-((5-氰吡啶-3-基)甲氧基)-4-(3-(1-(3-(4-羟基哌啶-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺N-(2-(5-氯-2-(间氰苄氧基)-4-(3-(1-(3-(3-氟氮杂环丁烷-1-基)丙基)吲哚啉-4-基)-2-甲基苄氧基)苄胺基)乙基)乙酰胺
- 根据权利要求1的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的药用盐包括与无机酸、有机酸、碱金属离子、碱土金属离子或能提供生理上可接受的阳离子的有机碱结合形成的盐以及铵盐。
- 根据权利要求24的二氢吲哚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的无机酸选自盐酸、氢溴酸、磷酸或硫酸;所述的有机酸选自甲磺酸、 对甲苯磺酸、三氟乙酸、枸杞酸、马来酸酒石酸、富马酸、柠檬酸或乳酸;所述的碱金属离子选自锂离子,钠离子,钾离子;所述的碱土金属离子选自钙离子,镁离子;所述的能提供生理上可接受的阳离子的有机碱选自甲胺、二甲胺、三甲胺、哌啶、吗啉或三(2-羟乙基)胺。
- 一种药物组合物,其特征在于,所述的药物组合物包含作为有效成分的权利要求1-23任一项所述的二氢吲哚衍生物及其立体异构体以及其可药用盐和药学上可接受的载体或赋形剂。
- 权利要求1-23任一项所述的二氢吲哚衍生物及其立体异构体以及其可药用盐在制备预防和/或治疗与PD-1/PD-L1信号通路有关疾病的药物中的应用。
- 根据权利要求28的应用,其特征在于,所述的与PD-1/PD-L1信号通路有关的疾病选自癌症、感染性疾病、自身免疫性疾病。
- 根据权利要求29的应用,其特征在于,所述的癌症选自皮肤癌、肺癌、泌尿系肿瘤、血液肿瘤、乳腺癌、胶质瘤、消化系统肿瘤、生殖系统肿瘤、淋巴瘤、神经系统肿瘤、脑瘤、头颈癌;所述的感染性疾病选自细菌感染、病毒感染;所述的自身免疫性疾病选自器官特异性自身免疫病、系统性自身免疫病,其中,所 述的器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎,所述的系统性自身免疫病包括类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血。
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