WO2019024908A1 - 取代五元并六元杂环类化合物、其制备方法、药物组合及其用途 - Google Patents
取代五元并六元杂环类化合物、其制备方法、药物组合及其用途 Download PDFInfo
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- WO2019024908A1 WO2019024908A1 PCT/CN2018/098457 CN2018098457W WO2019024908A1 WO 2019024908 A1 WO2019024908 A1 WO 2019024908A1 CN 2018098457 W CN2018098457 W CN 2018098457W WO 2019024908 A1 WO2019024908 A1 WO 2019024908A1
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- 0 CC(C)c1c(*)c(N)c(C=N)c(N)c1N Chemical compound CC(C)c1c(*)c(N)c(C=N)c(N)c1N 0.000 description 24
- TXIOGJHPPVXTOY-UHFFFAOYSA-N CCN1CCN(C)CC1 Chemical compound CCN1CCN(C)CC1 TXIOGJHPPVXTOY-UHFFFAOYSA-N 0.000 description 2
- JGZQBXZLEGYWIA-UHFFFAOYSA-N Cc(ccc(C(Nc1cccc(C(F)(F)F)c1)=O)c1)c1NI Chemical compound Cc(ccc(C(Nc1cccc(C(F)(F)F)c1)=O)c1)c1NI JGZQBXZLEGYWIA-UHFFFAOYSA-N 0.000 description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N CCN1CCOCC1 Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- DYBVNOUCRJYHCQ-UHFFFAOYSA-N CN1CCN(Cc2cc(C(F)(F)F)cc(N)c2)CC1 Chemical compound CN1CCN(Cc2cc(C(F)(F)F)cc(N)c2)CC1 DYBVNOUCRJYHCQ-UHFFFAOYSA-N 0.000 description 1
- WGSMMEOGVRIHPL-UHFFFAOYSA-N CS(C)c1c[o]cc1 Chemical compound CS(C)c1c[o]cc1 WGSMMEOGVRIHPL-UHFFFAOYSA-N 0.000 description 1
- NSWFPFUFXKVPGD-UHFFFAOYSA-N Cc(c(NC)c1)ccc1C(Nc1cc(C(F)(F)F)c(CN2CCN(C)CC2)cc1)=O Chemical compound Cc(c(NC)c1)ccc1C(Nc1cc(C(F)(F)F)c(CN2CCN(C)CC2)cc1)=O NSWFPFUFXKVPGD-UHFFFAOYSA-N 0.000 description 1
- QLJVBNCEMZCIPV-UHFFFAOYSA-N Cc(ccc(NC(c1cc(C(F)(F)F)ccc1)=O)c1)c1NC Chemical compound Cc(ccc(NC(c1cc(C(F)(F)F)ccc1)=O)c1)c1NC QLJVBNCEMZCIPV-UHFFFAOYSA-N 0.000 description 1
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N Cc1c[nH]cn1 Chemical compound Cc1c[nH]cn1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 1
- BLHTXORQJNCSII-UHFFFAOYSA-N Cc1c[n](C)cn1 Chemical compound Cc1c[n](C)cn1 BLHTXORQJNCSII-UHFFFAOYSA-N 0.000 description 1
- JWPQIOJOACWQIS-UHFFFAOYSA-N Cc1cc(NC(Nc2cc(Br)ccc2OC)=S)ccc1 Chemical compound Cc1cc(NC(Nc2cc(Br)ccc2OC)=S)ccc1 JWPQIOJOACWQIS-UHFFFAOYSA-N 0.000 description 1
- LFKMVWXKXUDOPI-UHFFFAOYSA-N Cc1cc(NC(Nc2cc(C(F)(F)F)ccc2)=O)ccc1 Chemical compound Cc1cc(NC(Nc2cc(C(F)(F)F)ccc2)=O)ccc1 LFKMVWXKXUDOPI-UHFFFAOYSA-N 0.000 description 1
- WLYLSLCWAKBFLN-UHFFFAOYSA-N Cc1cc(NC(Nc2cc(C(F)(F)F)ccc2)=S)ccc1 Chemical compound Cc1cc(NC(Nc2cc(C(F)(F)F)ccc2)=S)ccc1 WLYLSLCWAKBFLN-UHFFFAOYSA-N 0.000 description 1
- ZCJUQOSWLFTGFJ-UHFFFAOYSA-N Cc1cc(NC(c2cccc(C(F)(F)F)c2)=O)ccc1 Chemical compound Cc1cc(NC(c2cccc(C(F)(F)F)c2)=O)ccc1 ZCJUQOSWLFTGFJ-UHFFFAOYSA-N 0.000 description 1
- ZGNNVNCFQUJRAG-UHFFFAOYSA-N Cc1cccc(NC(c(cc2)ccc2Cl)=O)c1 Chemical compound Cc1cccc(NC(c(cc2)ccc2Cl)=O)c1 ZGNNVNCFQUJRAG-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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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
- A61K31/435—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
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P35/04—Antineoplastic agents specific for metastasis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
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- 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
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention relates to the field of medicinal chemistry, and in particular to a compound having a PIKfyve kinase selective inhibitory activity, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, a process for the preparation thereof, and a pharmaceutical composition comprising the same And the use of these compounds in the manufacture of a medicament for preventing or treating a disease associated with PIKfyve in an organism, especially in the preparation of a medicament for preventing or treating tumor growth and metastasis.
- Tumors are a serious threat to human health and life. According to data released by the World Health Organization in 2003, there were 10 million malignant tumor patients worldwide in 2000, and 6.2 million deaths due to malignant tumors, accounting for 12% to 25% of the total death toll. It is expected that by 2020, there will be 15 million new cases worldwide each year.
- the targeted therapeutic drugs imatinib, crizotinib, osimertinib, etc. have been listed, benefiting a large number of patients. These drugs selectively inhibit key protein molecules in tumor cell growth and proliferation processes, such as BCR-ABL, ALK, EGFR, etc., and therefore have the advantages of high efficacy and small side effects.
- PIKfyve is a phospholipase that can further phosphorylate phosphatidylinositol-3-phosphate to form phosphatidylinositol-3,5-diphosphate. It can perform multiple regulatory functions in the body, such as regulating the release of exosomes. Swallow route, etc.
- PIKfyve kinase activity is inhibited, cells exhibit significant vacuolation (EMBO Reports 2008, 9, 164-174).
- PIKfyve also plays an important role in promoting tumor growth and metastasis. For example, PIKfyve is involved in the invasion and migration of tumor cells (J Biol. Chem.
- PIKfyve inhibits serum protein-dependent cell proliferation (Dev. Cell 2016, 38, 536-547); inhibition of PIKfyve and cell surface nutrient transporters can kill a variety of tumor cells such as LS180, SW480, MDA-MB-231 (J. Clin. Invest. 2016, 126, 4088-4102); in non-Hodgkin's lymphoma cells, the action of small molecule inhibitors on PIKfyve effectively kills a variety of such cells and displays them on animal models.
- PIKfyve has become a new target for tumor therapy, and the development of new PIKfyve inhibitors can be used for PIKfyve-mediated cancer or other related diseases, as well as the treatment of refractory tumors, and has good application value.
- the inventors of the present invention have designed and synthesized a series of substituted five-membered and six-membered heterocyclic compounds with novel structure, high safety and high activity against the kinase PIKfyve, and studied this new type of derivative. Antitumor activity of the substance.
- the present invention provides compounds of the general formula:
- X 1 , X 2 , X 3 , X 4 , X 5 , X 6 may comprise the following combinations:
- Another object of the present invention is to provide a process for the preparation of the above compounds.
- Another object of the present invention is to provide a pharmaceutical composition comprising the above compound.
- Another object of the present invention is to provide a use of the above compound and a pharmaceutical composition comprising the above compound for the preparation of a medicament for the prevention and treatment of PIKfyve mediated cancer or other diseases, as well as refractory tumors.
- Another object of the invention is to provide a method of treating cancer comprising administering to a subject an effective amount of a compound or composition of the invention.
- V-c-19 (1 ⁇ mol / L) induced vacuolation of MDA-MB-231 cells with good time tolerance.
- V-c-19 (1 ⁇ mol/L) induced vacuolation of MDA-MB-231 cells with good concentration tolerance.
- FIG. 3 Representative compound V-c-17 inhibits PIKfyve causing lysosomal dysfunction. Under the action of V-c-17 or the control compound apilimod, immature cathepsins A and D gradually increased with good dose tolerance.
- FIG. 4 Representative compound I-a-1 is effective in inhibiting tumor growth in a xenograft model of triple negative breast cancer cells (MDA-MB-231).
- MDA-MB-231 xenograft mouse model a dose of 5 mg/kg and 20 mg/kg was administered daily and administered via the tail vein.
- the administration group was effective in inhibiting tumor volume growth in a dose-dependent manner;
- the final tumor weight of the administration group was significantly smaller than that of the control group, and was in a dose-dependent manner.
- FIG. 5 Representative compound V-c-17 is effective in inhibiting tumor growth in a heterologous metastasis model of non-Hodgkin's lymphoma cells (JeKo-1).
- JeKo-1 a heterologous metastasis model of non-Hodgkin's lymphoma cells
- a dose of 25 mg/kg once a day or twice a day was administered and administered via the tail vein.
- the administration group was effective in inhibiting tumor volume growth in a dose-dependent manner;
- the final tumor weight of the administration group was significantly smaller than that of the control group, and was in a dose-dependent manner.
- the present invention has been achieved by the following technical solutions.
- the present scheme provides a compound represented by the following formula:
- X 1 , X 2 , X 3 , X 4 , X 5 , X 6 may comprise the following combinations:
- R 1 and R 2 are selected from:
- a substituted or unsubstituted C6-C10 aryl, heteroaryl group the substituent is selected from the group consisting of: a halogen atom, a C6-C10 aryl group, a heteroaryl group, a heterocyclic group, a C1-C6 alkyl group, a C1-C6 alkane Oxyl, C1-C6 oxyalkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, nitro, cyano, amino, hydroxy, wherein said substituent is passed directly or optionally through NHCO , CONH, SO 2 NH, NHSO 2 , NHCONH, NHCSNH or CO are linked to a C6-C10 aryl or heteroaryl group;
- R 1 and R 2 are selected from the group consisting of:
- L 1 is selected from the group consisting of NHCO, CONH, SO 2 NH, NHSO 2 , NHCONH, NHCSNH,
- R 4 is selected from hydrogen, substituted or unsubstituted C6-C10 aryl, heteroaryl, heterocyclic, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxyalkyl, C1-C6 Fluorinated alkyl, C1-C6 fluoroalkoxy, nitro, cyano, amino, hydroxy C3-C7 cycloalkyl;
- L 2 is selected from the group consisting of NHCO, CONH, SO 2 NH, NHSO 2 , NHCONH, NHCSNH, CO,
- R 5 is selected from substituted or unsubstituted C6-C10 aryl, heteroaryl, heterocyclic, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxyalkyl, C1-C6 fluoro Alkyl, C1-C6 fluoroalkoxy, nitro, cyano, amino, hydroxy C3-C7 cycloalkyl;
- n 0, 1 or 2;
- One of Y 1 , Y 2 , Y 3 is selected from N;
- R 6 is selected from the group consisting of hydrogen, a halogen atom, and a C1-C6 alkyl group
- R 3 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, and the substituent is selected from the group consisting of halogen, amino, hydroxy, alkoxysilyl;
- the pharmaceutically acceptable salt is: a mineral acid salt selected from the group consisting of hydrochlorides, hydrobromides, hydroiodides, nitrates, hydrogencarbonates and carbonates, sulfates or phosphates; or organic acids a salt selected from the group consisting of formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, ascorbate, alpha-ketopentane
- the salt is a besylate or a p-toluenesulfonate or the like.
- the compound, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure:
- R 1 is selected from:
- An optionally substituted heteroaryl group preferably selected from the group consisting of:
- the substituent is a C1-C6 alkyl group, a C1-C3 alkoxy group, a C1-C3 oxyalkyl group, a C1-C3 fluoroalkane , C1-C3 fluoroalkoxy, halogen, amino, hydroxy, nitro, cyano;
- one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of hydrogen, hydrogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxyalkyl, C1-C3 fluorine-containing alkyl group, C1-C3 fluorine-containing alkoxy group, halogen, amino group, hydroxyl group, nitro group, cyano group;
- Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of the following:
- Z 3 , Z 2 or Z 4 is selected from the group consisting of hydrogen, hydrogen, chlorine, amino, hydroxyl, methyl;
- L 2 is selected from the group consisting of NHCO, CONH, SO 2 NH, NHSO 2 , NHCONH, NHCSNH; preferably L 2 is NHCO, CONH; most preferably L 2 is NHCO;
- R 5 is selected from substituted or unsubstituted C 6 -C 10 aryl, preferably substituted or unsubstituted phenyl;
- R 5 is preferably Wherein one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of the following:
- R 5 is Wherein Z 2 or Z 4 is selected from the group consisting of hydrogen, hydrogen, chlorine, amino, hydroxy, trifluoromethyl;
- R 5 is Wherein Z 2 or Z 4 is a trifluoromethyl group, and the balance is hydrogen;
- R 7 is selected from H, C 1 -C 6 alkyl; preferably R 7 is methyl;
- R 2 is selected from:
- An optionally substituted heteroaryl group preferably selected from the group consisting of:
- the substituent is a C1-C6 alkyl group, a C1-C3 alkoxy group, a C1-C3 oxyalkyl group, a C1-C3 fluoroalkane , C1-C3 fluoroalkoxy, halogen, amino, hydroxy, nitro, cyano;
- one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of hydrogen, hydrogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxyalkyl, C1-C3 fluorine-containing alkyl group, C1-C3 fluorine-containing alkoxy group, halogen, amino group, hydroxyl group, nitro group, cyano group;
- Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of the following:
- Z 3 , Z 2 or Z 4 is selected from the group consisting of hydrogen, hydrogen, chlorine, amino, hydroxy, methyl, methoxy;
- L 2 is selected from the group consisting of NHCO, CONH, SO 2 NH, NHSO 2 , NHCONH, NHCSNH, CO; preferably NHCO, CONH, NHCONH, NHCSNH, CO;
- R 5 is selected from substituted or unsubstituted C6-C10 aryl, heteroaryl, optionally substituted heterocyclic, C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy , C1-C6 fluorine-containing alkyl group, C1-C6 fluorine-containing alkoxy group, nitro group, cyano group, amino group, hydroxyl group C3-C7 cycloalkyl group;
- R 5 is selected from the group consisting of:
- R 5 is Wherein 1 or 2 of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are independently selected from the group consisting of hydrogen: hydrogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 An oxyalkyl group, a C1-C3 fluoroalkyl group, a C1-C3 fluoroalkoxy group, a halogen, an amino group, a hydroxy group, a nitro group, a cyano group, a C1-C6 alkane substituted with an optionally substituted heterocyclic group base;
- Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are independently selected from the group consisting of hydrogen: hydrogen, chlorine, fluorine, methyl, trifluoromethyl, methoxy , trifluoromethoxy,
- Z 2 or Z 4 is selected from the group consisting of hydrogen: hydrogen, trifluoromethyl, methoxy, trifluoromethoxy, methyl, chloro, fluoro; or Z 2 and Z 3 or Z 2 Z 4 is independently selected from the group consisting of trifluoromethyl, chlorine, or
- R 5 is also an amino-substituted C1-C6 alkyl group, wherein preferably a C1-C6 alkyl group is a methyl group, an ethyl group, a propyl group, more preferably a C1-C6 alkyl group is a methyl group;
- R 5 is also a substituted heteroaryl group, wherein preferably the substituted heteroaryl group is a plurality of C1-C6 alkyl-substituted pyrazolyl groups; most preferably the substituted heteroaryl group is or
- R 5 is also an optionally substituted heterocyclic group, preferably substituted by a C1-C6 alkyl group. Among them, a heterocyclic group is preferred
- R 7 is selected from
- R 7 is hydrogen, methyl, fluorine,
- R 9 is selected from H, C 1 -C 6 alkoxy; preferably R 9 is hydrogen, methoxy;
- R 7 and R 9 are non-hydrogen groups, they are not present at the same time;
- R 3 is selected from: -H, C1-C6 alkyl; preferably selected from: -H, -CH 3.
- the compound, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure:
- R 1 is selected from the group consisting of an optionally substituted heteroaryl group, preferably selected from the group consisting of:
- R 2 is selected from: among them,
- L 2 is selected from the group consisting of NHCO, CONH, SO 2 NH, NHSO 2 , NHCONH, NHCSNH; preferably L 2 is NHCO, CONH;
- R 5 is selected from substituted or unsubstituted C 6 -C 10 aryl, preferably substituted or unsubstituted phenyl;
- R 5 is preferably Wherein one or two of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are independently selected from the group consisting of hydrogen, hydrogen, halogen, amino, hydroxy, C1-C3 fluoroalkyl, and a C1-C6 alkyl group substituted with a substituted heterocyclic group;
- R 5 is wherein Z 2 or Z 4 is selected from the group consisting of hydrogen: hydrogen, trifluoromethyl; or Z 2 and Z 3 are independently selected from the group consisting of hydrogen: trifluoromethyl,
- R 7 is selected from H, C 1 -C 6 alkyl; preferably R 7 is methyl;
- R 3 is selected from: -H, C1-C6 alkyl; preferably selected from: -H, -CH 3.
- the compound, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure:
- R 1 is selected from:
- An optionally substituted heteroaryl group preferably selected from the group consisting of:
- the substituent is a C1-C6 alkyl group, a C1-C3 alkoxy group, a C1-C3 oxyalkyl group, a C1-C3 fluoroalkane , C1-C3 fluoroalkoxy, halogen, amino, hydroxy, nitro, cyano;
- one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of hydrogen, hydrogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxyalkyl, C1-C3 fluorine-containing alkyl group, C1-C3 fluorine-containing alkoxy group, halogen, amino group, hydroxyl group, nitro group, cyano group;
- Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of the following:
- Z 3 , Z 2 or Z 4 is selected from the group consisting of hydrogen, chlorine, amino, hydroxyl;
- L 1 is selected from the group consisting of NHCO, CONH, SO 2 NH, NHSO 2 , NHCONH, NHCSNH; L 1 is preferably NHCONH, NHCSNH,
- R 4 is selected from hydrogen, substituted or unsubstituted C6-C10 aryl, preferably substituted or unsubstituted phenyl;
- R 4 is preferably Wherein one or two of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are independently selected from the group consisting of hydrogen: halogen, amino, hydroxy, C1-C3 fluoroalkyl;
- R 4 is wherein Z 2 or Z 4 is selected from the group consisting of hydrogen, hydrogen, chlorine, amino, hydroxy, trifluoromethyl; or Z 2 and Z 4 are each independently selected from the group consisting of hydrogen: bromine, methoxy, Amino group, hydroxyl group;
- R 4 is Wherein Z 2 or Z 4 is a trifluoromethyl group, and the balance is hydrogen; or Z 2 and Z 4 are each independently selected from the group consisting of hydrogen: bromine, methoxy;
- L 2 is selected from the group consisting of NHCO, CONH, SO 2 NH, NHSO 2 , NHCONH, NHCSNH; preferably L 2 is NHCO, CONH; most preferably L 2 is CONH;
- R 5 is selected from substituted or unsubstituted C 6 -C 10 aryl, preferably substituted or unsubstituted phenyl;
- R 5 is preferably Wherein one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of the following:
- R 5 is Wherein Z 2 or Z 4 is selected from the group consisting of hydrogen, chlorine, amino, hydroxyl, trifluoromethyl;
- R 5 is Wherein Z 2 or Z 4 is a trifluoromethyl group, and the balance is hydrogen;
- R 7 is selected from H, C 1 -C 6 alkyl; preferably R 7 is methyl;
- R 2 is selected from:
- L 2 is selected from the group consisting of NHCO, CONH, SO 2 NH, NHSO 2 , NHCONH, NHCSNH; preferably L 2 is NHCO, CONH;
- R 5 is selected from substituted or unsubstituted C 6 -C 10 aryl, preferably substituted or unsubstituted phenyl;
- R 5 is preferably Wherein one or two of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are independently selected from the group consisting of hydrogen, hydrogen, halogen, amino, hydroxyl, C1-C3 fluorine-containing alkyl, and a C1-C6 alkyl group substituted with a substituted heterocyclic group;
- R 5 is wherein Z 2 or Z 4 is selected from the group consisting of hydrogen: hydrogen, trifluoromethyl, trifluoromethoxy, methyl, methoxy; or Z 2 and Z 3 or Z 2 and Z 4 are independently Selected from the following, the rest is hydrogen: trifluoromethyl,
- R 5 is Wherein Z 2 or Z 4 is a trifluoromethyl group, and the balance is hydrogen; or Z 2 and Z 3 or Z 2 and Z 4 are each independently selected from the following, and the balance is hydrogen: trifluoromethyl,
- R 7 is selected from H, C 1 -C 6 alkyl; preferably R 7 is methyl;
- R 3 is selected from: -H, C1-C6 alkyl; preferably selected from: -H, -CH 3.
- the compound, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure:
- R 1 is selected from the group consisting of an optionally substituted heteroaryl group, preferably selected from the group consisting of:
- R 2 is selected from: among them,
- L 2 is selected from the group consisting of NHCO, CONH, SO 2 NH, NHSO 2 , NHCONH, NHCSNH; preferably L 2 is NHCO, CONH;
- R 5 is selected from substituted or unsubstituted C 6 -C 10 aryl, preferably substituted or unsubstituted phenyl;
- R 5 is preferably Wherein 1 or 2 of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are independently selected from the group consisting of hydrogen: hydrogen, halogen, amino, hydroxy, C1-C3 fluoroalkyl, C1- a C1-fluoroalkoxy group, a C1-C6 alkyl group substituted with an optionally substituted heterocyclic group;
- R 5 is wherein Z 2 or Z 4 is selected from the group consisting of hydrogen: hydrogen, trifluoromethyl, trifluoromethoxy; or Z 2 and Z 3 are independently selected from the group consisting of hydrogen: trifluoromethyl,
- R 7 is selected from H, C 1 -C 6 alkyl; preferably R 7 is methyl;
- R 3 is selected from: -H, C1-C6 alkyl; preferably selected from: -H, -CH 3.
- the compound, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure:
- R 1 is selected from:
- An optionally substituted heteroaryl group preferably selected from the group consisting of:
- the substituent is a C1-C6 alkyl group, a C1-C3 alkoxy group, a C1-C3 oxyalkyl group, a C1-C3 fluoroalkane , C1-C3 fluoroalkoxy, halogen, amino, hydroxy, nitro, cyano, HOOC-, C1-C6 alkoxycarbonyl;
- one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of hydrogen, hydrogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 fluorine-containing alkyl, a C1-C3 fluoroalkoxy group, a halogen, an amino group, a hydroxyl group, a HOOC-, a C1-C6 alkoxy formyl group;
- Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of the following:
- Z 3 , Z 2 or Z 4 is selected from the group consisting of hydrogen, chlorine, amino, hydroxyl, HOOC-, ethoxycarbonyl (EtOOC-);
- L 1 is selected from the group consisting of NHCO, CONH, SO 2 NH, NHSO 2 , NHCONH, NHCSNH; preferably L 1 is NHCO, CONH, NHCONH, NHCSNH;
- R 4 is selected from hydrogen, substituted or unsubstituted C6-C10 aryl, preferably substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl, preferably substituted or unsubstituted pyridyl ;
- R 4 is preferably Wherein 1 or 2 of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are independently selected from the group consisting of hydrogen: hydrogen, halogen, amino, hydroxy, C1-C3 fluoroalkyl, C1- C3 alkoxy;
- R 4 is Wherein Z 2 or Z 4 or Z 3 is selected from the group consisting of hydrogen: hydrogen, chlorine, amino, trifluoromethyl; or Z 1 and Z 4 are each independently selected from the group consisting of hydrogen: bromine, methoxy ;or
- R 4 is preferably Wherein one of Z 1 , Z 2 , Z 3 , Z 4 is selected from the group consisting of hydrogen, hydrogen, halogen, amino, hydroxyl; more preferably R 4 is Wherein Z 2 is selected from the group consisting of hydrogen, hydrogen, chlorine, amino, and hydroxyl; most preferably R 4 is Wherein Z 2 is an amino group and the balance is hydrogen;
- L 2 is selected from the group consisting of NHCO, CONH, SO 2 NH, NHSO 2 , NHCONH, NHCSNH;
- L 2 is selected from the group consisting of NHCO, CONH, NHSO 2 , NHCONH, NHCSNH;
- R 5 is selected from substituted or unsubstituted C 6 -C 10 aryl, preferably substituted or unsubstituted phenyl;
- R 5 is preferably Wherein 1 or 2 of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are independently selected from the group consisting of hydrogen: hydrogen, halogen, amino, hydroxy, C1-C3 fluoroalkyl, C1- C3-alkoxy, C1-C6 amido, C1-C6 alkylsulfonylamino, C1-C3 fluoroalkoxy, nitro, cyano, C1-C6 substituted with an optionally substituted heterocyclic group An alkyl group, optionally substituted heteroaryl;
- R 5 is more preferably Wherein one or two of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are independently selected from the group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, nitrate Base, cyano, methoxy, acetamido (-NHAc), amino, methanesulfonylamino (-NHMs),
- R 5 is Wherein Z 2 or Z 4 is hydrogen or -OCF 3 , or Z 3 is hydrogen, -NO 2 , -CN or -OMe, or one of Z 2 or Z 4 , Z 3 is hydrogen, -CF 3 or - One of NHAc, or Z 1 or Z 5 , Z 2 or Z 4 , Z 3 is hydrogen, -NH 2 or -NHMs; or Z 2 and Z 4 are independently selected from -CF 3 , Or Z 2 and Z 3 are independently selected from -CF 3 , Or Z 1 and Z 4 are independently selected from -CF 3 , -OMe, -F, -Cl; the balance being hydrogen;
- R 7 is selected from
- R 7 is hydrogen, methyl, methoxy
- Preferred is an unsubstituted phenyl group or an amino group substituted with a phenyl group substituted by a phenyl group monosubstituted by a methanesulfonylamino group, a phenyl group which is disubstituted by a heterocyclic group;
- a heteroaryl-substituted amino group preferably a pyridylamino group, most preferably:
- R 2 is selected from:
- the substituent is a C1-C6 alkyl group, a C1-C3 alkoxy group, a C1-C3 oxyalkyl group, a C1-C3 fluoroalkane , C1-C3 fluoroalkoxy, halogen, amino, hydroxy, nitro, cyano, C1-C6 alkylsulfonyl;
- one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of hydrogen, hydrogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 fluorine-containing alkyl, a C1-C3 fluoroalkoxy group, a halogen, an amino group, a hydroxyl group, a nitro group, a cyano group, a C1-C3 alkylsulfonyl group;
- one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, C1-C3 alkoxy, C1-C3 alkane Sulfonyl;
- Z 3 is selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, methylsulfonyl (-Ms);
- L 2 is selected from the group consisting of NHCO, CONH, SO 2 NH, NHSO 2 , NHCONH, NHCSNH; preferably L 2 is NHCO, CONH, NHSO 2 , NHCONH, NHCSNH;
- R 5 is selected from substituted or unsubstituted C 6 -C 10 aryl, preferably substituted or unsubstituted phenyl;
- R 5 is preferably Wherein 1 or 2 of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are independently selected from the group consisting of hydrogen: hydrogen, halogen, amino, a di-C1-C3 alkyl-substituted amino group, a hydroxyl group, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 fluoroalkyl, C1-C3 fluoroalkoxy, optionally substituted heteroaryl, substituted with optionally substituted heterocyclyl C1-C6 alkyl;
- R 5 is more preferably Wherein one or two of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, amino, and a double C1-C3 alkyl group. Amino, hydroxy, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl substituted a C1-C6 alkyl group, a C1-C3 alkyl group, a C1-C3 alkoxy group optionally substituted by a C1-C6 alkyl-substituted heterocyclic group;
- R 5 is wherein Z 2 or Z 4 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl, methoxy, amino, dimethylamino, trifluoromethoxy, hydroxy; Z 2 and Z 3 or Z 2 and Z 4 are each independently selected from the following, and the remainder is hydrogen: trifluoromethyl,
- R 7 is selected from H, C 1 -C 6 alkyl; preferably R 7 is H, methyl;
- amino groups selected from the group consisting of:
- a heterocyclic group substituted with a heteroaryl group substituted with a di(C1-C6 alkyl)amino group and a C1-C6 alkyl group is preferred,
- R 3 is selected from: -H, C1-C6 alkyl; preferably selected from: -H, -CH 3.
- the compound, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure:
- R 1 is selected from the group consisting of an optionally substituted heteroaryl group, preferably selected from the group consisting of:
- R 2 is selected from:
- L 2 is selected from the group consisting of NHCO, CONH, SO 2 NH, NHSO 2 , NHCONH, NHCSNH; preferably L 2 is NHCO, CONH;
- R 5 is selected from substituted or unsubstituted C 6 -C 10 aryl, preferably substituted or unsubstituted phenyl;
- R 5 is preferably Wherein 1 or 2 of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are independently selected from the group consisting of hydrogen: hydrogen, halogen, amino, hydroxy, C1-C3 fluoroalkyl, C1- a C1 fluoroalkoxy group, an optionally substituted heteroaryl group, a C1-C6 alkyl group substituted with an optionally substituted heterocyclic group;
- R 5 is more preferably Wherein 1 or 2 of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are independently selected from the group consisting of hydrogen, fluorine, chlorine, amino, hydroxyl, trifluoromethyl, trifluoromethyl Oxygen, C1-C6 alkyl substituted a C1-C6 alkyl group optionally substituted by a C1-C6 alkyl-substituted heterocyclic group;
- R 5 is wherein Z 2 or Z 4 is selected from the group consisting of hydrogen: hydrogen, fluorine, trifluoromethyl, trifluoromethoxy; or Z 2 and Z 3 or Z 2 and Z 4 are each independently selected from the following, and the rest Is hydrogen: trifluoromethyl,
- R 7 is selected from H, C 1 -C 6 alkyl; preferably R 7 is methyl;
- R 3 is selected from the group consisting of: -H, halogen, C1-C6 alkyl, C3-C7 cycloalkyl; preferably selected from the group consisting of: -H, fluorine, chlorine, C1-C3 alkyl, C3-C7 cycloalkyl; most preferred From: -H, -Br, -CH 3 ,
- the compound, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure:
- R 1 is selected from: among them,
- L 1 is selected from NHCO, CONH; L 1 is preferably NHCO;
- R 4 is selected from hydrogen, substituted or unsubstituted C6-C10 aryl, preferably substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl, preferably substituted or unsubstituted pyridyl ;
- R 4 is preferably Wherein one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of hydrogen, hydrogen, halogen, amino, hydroxy, C1-C3 fluoroalkyl; more preferably R 4 is Wherein Z 2 or Z 4 is selected from the group consisting of hydrogen, hydrogen, chlorine, amino, hydroxy, trifluoromethyl; most preferably R 4 is Wherein Z 2 or Z 4 is trifluoromethyl and the balance is hydrogen; or
- R 4 is preferably Wherein one of Z 1 , Z 2 , Z 3 , Z 4 is selected from the group consisting of hydrogen, hydrogen, halogen, amino, hydroxyl; more preferably R 4 is Wherein Z 2 is selected from the group consisting of hydrogen, hydrogen, chlorine, amino, and hydroxyl; most preferably R 4 is Wherein Z 2 is an amino group and the balance is hydrogen;
- R 2 is selected from:
- Preferred is an amino group selected from an amino group substituted with a cyclopropyl group, a heteroaryl group optionally substituted by a C1-C6 alkyl group;
- It is preferably selected from heterocyclic groups substituted with a di(C1-C6 alkyl)amino group and a C1-C6 alkyl group.
- the compound, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure:
- R 1 is selected from the group consisting of an optionally substituted heteroaryl group, preferably selected from the group consisting of:
- R 2 is selected from: among them,
- L 2 is selected from the group consisting of NHCO, CONH, SO 2 NH, NHSO 2 , NHCONH, NHCSNH; preferably L 2 is NHCO, CONH;
- R 5 is selected from substituted or unsubstituted C 6 -C 10 aryl, preferably substituted or unsubstituted phenyl;
- R 5 is preferably Wherein one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of hydrogen, hydrogen, halogen, amino, hydroxyl, C1-C3 fluorine-containing alkyl;
- R 5 is Wherein Z 2 or Z 4 is selected from the group consisting of hydrogen: hydrogen, trifluoromethyl;
- R 7 is selected from H, C 1 -C 6 alkyl; preferably R 7 is H, methyl;
- the C1-C6 oxyalkyl group means a group in which a C1-C6 alkyl skeleton is substituted by one or more C1-C6 alkoxy groups, for example, a methoxyethyl group, a methoxy group. Ethyl ethoxymethyl and the like.
- a C1-C3 oxyalkyl group means a group formed by substituting a C1-C3 alkyl skeleton with one or more C1-C6 alkoxy groups.
- aryl or "C6-C10 aryl” refers to a C6-10 mono-, di- or poly-carbacyclic hydrocarbon having from 1 to 2, optionally further fused or linked to each other by a single bond.
- the aryl ring can be optionally further fused or attached to the aromatic and non-aromatic carbocyclic and heterocyclic rings.
- Non-limiting examples of such aryl groups are phenyl, alpha- or beta-naphthyl.
- heteroaryl refers to an aromatic heterocyclic ring, typically a 5- to 8-membered heterocyclic ring having from 1 to 3 heteroatoms selected from N, O or S; heteroaryl rings may optionally be Further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings.
- Non-limiting examples of such heteroaryl groups are, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, fluorenyl, imidazolyl, thiazolyl, isothiazolyl, thiazolyl, pyrrolyl, benzene Base-pyrrolyl, furyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzofuranyl, benzothienyl, benzo1,3-dioxolane (benzodioxan), isoindoline, benzimidazolyl, oxazolyl, quinolyl, isoquinolyl, 1,2,3-triazolyl, 1-phenyl-1, 2,3-Triazolyl, 2,3-dihydroindenyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo
- C6-C10 arylamino refers to a group of -NH- or a nitrogen-containing group attached to an "aryl” or “C6-C10 aryl” group as defined above, the group and the other of the compound Part of the attachment position is on the -NH- or nitrogen-containing group.
- heteroarylamino refers to a group of -NH- or a nitrogen-containing group attached to a “heteroaryl” group as defined above, the position of which is attached to the other moiety of the compound at - NH- or nitrogen-containing groups.
- heterocyclyl (also referred to as “heterocycloalkyl”) refers to 3-, 4-, 5-, 6- and 7-membered saturated or partially unsaturated carbocyclic rings wherein one or more carbon atoms Substituted by heteroatoms such as nitrogen, oxygen and sulfur.
- heterocyclic groups are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1,3- Dioxolane, piperidine, piperazine, morpholine, morphinolyl, tetrahydropyrrolyl, thiomorpholinyl and the like.
- heterocyclic group is one or more of "C1-C6 alkyl group", “C1-C3 alkyl group”, “C3-C6 cycloalkyl group”, etc. Replace.
- C1-C6 alkyl refers to any straight or branched chain group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutylene.
- Base tert-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl and the like.
- C1-C3 alkyl refers to any straight or branched chain group containing from 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, and the like.
- C 3 -C 7 cycloalkyl refers to a hydrocarbon of a 3-7 membered monocyclic system having a saturated ring
- the C 3 -C 7 cycloalkyl group may be a cyclopropyl group, a cyclobutyl group, Cyclopentyl, cyclohexyl, cycloheptyl.
- C 3 -C 6 cycloalkyl refers to a hydrocarbon of a 3-6 membered monocyclic system having a saturated ring
- the C 3 -C 7 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentane.
- Base cyclohexyl.
- C1-C6 fluoroalkyl refers to a group wherein a C1-C6 alkyl skeleton is substituted by one or more fluoro groups, for example, carbon tetrafluoride, monofluoromethyl, difluoroethyl, tri Fluoromethyl and the like.
- C1-C3 fluoroalkyl refers to a group in which a C1-C3 alkyl skeleton is substituted with one or more fluoro groups, for example, carbon tetrafluoride, monofluoromethyl, difluoroethyl. Base, trifluoromethyl and the like.
- alkoxy refers to any of the above alkyl groups (eg, C 1 -C 6 alkyl, C 1 -C 3 alkyl, etc.), cycloalkyl (eg, C). 3 -C 6 cycloalkyl), which is connected to the rest of the molecule through an oxygen atom (-O-).
- any group whose name is a compound name such as "fluorine-containing oxyalkyl group” shall mean a moiety conventionally derived therefrom, for example, from a fluorine group.
- a substituted oxyalkyl group is constructed wherein the alkyl group is as defined above.
- fluoroalkoxy group there is also a "fluoroalkoxy group”.
- arylamino shall mean a moiety that is conventionally derived therefrom, for example, from an amino group substituted with an aryl group, wherein the aryl group is as defined above.
- heteroarylamino can be understood.
- any term such as alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, cycloalkyloxycarbonyl, alkoxycarbonyl, etc.
- a group wherein the alkyl group, the alkoxy group, the aryl group, the C 3 -C 7 cycloalkyl group and the heterocyclic group are as defined above.
- each of the above substituents may be further substituted with one or more of the above-exemplified groups, if appropriate.
- halogen atom refers to a fluorine, chlorine, bromine or iodine atom.
- cyano refers to the -CN residue.
- nitro refers to a -NO 2 group.
- prodrug refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs undergo this reaction to become active compounds only under biological conditions, or they are active in their unreacted form. Prodrugs can generally be prepared using well-known methods, such as those described in 1 Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, ed. 5th edition).
- compositions can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid that provides a pharmaceutically acceptable anion.
- treating generally refers to obtaining the desired pharmacological and/or physiological effects.
- the effect may be prophylactic according to the prevention of the disease or its symptoms in whole or in part; and/or may be therapeutic according to the partial or complete stabilization or cure of the disease and/or side effects due to the disease.
- treatment encompasses any treatment for a patient's condition, including: (a) prevention of a disease or condition in a patient who is susceptible to an infectious disease or condition but has not yet diagnosed the disease; (b) inhibition of the symptoms of the disease, That is, to prevent its development; or (c) to alleviate the symptoms of the disease, that is, to cause the disease or symptoms to degenerate.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound according to any one of the above aspects, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof And a pharmaceutically acceptable carrier, diluent or excipient.
- a method of preparing the pharmaceutical composition comprises incorporating a suitable pharmaceutical excipient, carrier, diluent, and the like.
- the pharmaceutical preparations of the invention are prepared in a known manner, including conventional methods of mixing, dissolving or lyophilizing.
- the compounds of the present invention can be formulated into pharmaceutical compositions and administered to a patient in a variety of ways suitable for the chosen mode of administration, for example, orally or parenterally (by intravenous, intramuscular, topical or subcutaneous routes).
- the compounds of the invention may be administered systemically, for example, orally, in association with a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules and can be compressed into tablets.
- a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules and can be compressed into tablets.
- the active compound may be combined with one or more excipients and in the form of swallowable tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. use.
- Such compositions and preparations should contain at least 0.1% of active compound.
- the ratio of such compositions and formulations may of course vary and may range from about 1% to about 99% by weight of a given unit dosage form.
- the amount of active compound is such that an effective dosage level can be obtained.
- Tablets, lozenges, pills, capsules and the like may also contain: a binder such as tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, Potato starch, alginic acid, etc.; a lubricant such as magnesium stearate; and a sweetener such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as mint, wintergreen or cherry.
- a binder such as tragacanth, acacia, corn starch or gelatin
- an excipient such as dicalcium phosphate
- a disintegrating agent such as corn starch, Potato starch, alginic acid, etc.
- a lubricant such as magnesium stearate
- a sweetener such as sucrose, fructose, lactose or aspartame
- a flavoring agent such as mint, wintergreen or cherry
- any material used to prepare any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
- the active compound can be incorporated into sustained release formulations and sustained release devices.
- the active compound can also be administered intravenously or intraperitoneally by infusion or injection.
- An aqueous solution of the active compound or a salt thereof can be prepared, optionally mixed with a non-toxic surfactant.
- Dispersing agents in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof, and oils can also be prepared. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions of the active ingredient (optionally encapsulated in liposomes) containing the immediate formulation of a suitable injectable or injectable solution or dispersing agent. Or sterile powder. In all cases, the final dosage form must be sterile, liquid, and stable under the conditions of manufacture and storage.
- the liquid carrier can be a solvent or liquid dispersion medium including, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, non-toxic glycerides, and suitable mixtures thereof.
- Proper fluidity can be maintained, for example, by liposome formation, by maintaining the desired particle size in the case of a dispersing agent, or by the use of a surfactant.
- the action of preventing microorganisms can be produced by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- isotonic agents such as sugars, buffers or sodium chloride.
- Prolonged absorption of the injectable compositions can be brought about by the use of compositions that delay the absorbent (for example, aluminum monostearate and gelatin).
- Sterile injectable solutions are prepared by combining the required active compound in a suitable solvent with the various other ingredients enumerated above, followed by filter sterilization.
- the preferred preparation methods are vacuum drying and lyophilization techniques which result in a powder of the active ingredient plus any additional ingredients present in the previously sterile filtration solution. .
- Useful solid carriers include comminuted solids (e.g., talc, clay, microcrystalline cellulose, silica, alumina, etc.).
- Useful liquid carriers include water, ethanol or ethylene glycol or a water-ethanol/ethylene glycol mixture, and the compounds of the present invention may be dissolved or dispersed in an effective amount, optionally with the aid of a non-toxic surfactant.
- Adjuvants such as fragrances
- additional antimicrobial agents can be added to optimize the properties for a given use.
- Thickeners can also be used with liquid carriers to form coatable pastes, gels, ointments , soap, etc., used directly on the user's skin.
- the term "subject" can refer to a patient or other animal, particularly a mammal, for example, a mammal, such as a mammal, that receives a compound or pharmaceutical composition of the invention to treat, prevent, ameliorate, and/or alleviate the disease or condition described herein. People, dogs, monkeys, cows, horses, etc.
- the term "effective amount” or “required amount” refers to a dose that can achieve a treatment, prevention, alleviation, and/or alleviation of a disease or condition described herein in a subject.
- the therapeutic requirements of a compound or an active salt or derivative thereof depend not only on the particular salt selected, but also on the mode of administration, the nature of the disease to be treated, and the age and condition of the patient, ultimately depending on the attending physician or clinician decision.
- unit dosage form is a unit dispersion unit containing a unit dosage unit suitable for administration to humans and other mammalian bodies.
- the unit dosage form can be a capsule or tablet, or a plurality of capsules or tablets.
- the amount of unit dose of the active ingredient may vary or be adjusted between about 0.1 and about 1000 mg or more, depending on the particular treatment involved.
- milk liposomes such as milk liposomes, microspheres and nanospheres
- microparticle dispersion systems including polymeric micelles, nanoemulsions, submicroemuls Agents prepared from microcapsules, microspheres, liposomes, and niosomes (also known as nonionic surfactant vesicles).
- the present invention provides a method for preparing the compound according to any one of the above technical solutions, comprising the steps of:
- Reaction conditions (a) a metal palladium-catalyzed coupling reaction of a heteroaryl chloride with a carbon-carbon bond of a boronic acid or a boronic acid ester, or a metal palladium-catalyzed formation of a carbon-nitrogen bond between a heteroaryl chloride and an amine compound Coupling reaction, or nucleophilic substitution reaction of an amine compound on a heteroaryl chloride under basic conditions, or nucleophilic substitution reaction of an amine compound on a heteroaryl chloride under acidic conditions; (b) metal palladium catalyzed a coupling reaction of a heteroaryl chloro compound with a carbon-carbon bond of a boric acid or a boric acid ester, or a coupling reaction of a metal palladium-catalyzed heteroaryl chloro compound with a carbon-nitrogen bond of an amine compound, or an amine under acidic conditions
- heteroaryl chloride comprises the following types:
- the boric acid or boric acid ester is selected from a substituted or unsubstituted C6-C10 aryl group, a heteroaryl boronic acid or a boric acid ester; the amine compound is selected from a substituted or unsubstituted C6-C10 arylamine, a heterocyclic group.
- the metal palladium catalyst is selected from the group consisting of palladium acetate, tetrakis(triphenylphosphine)palladium, bistriphenylphosphinepalladium dichloride, 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, Tris(dibenzylideneacetone)dipalladium;
- the basic condition means the presence of any of the following: triethylamine, diisopropylethylamine, pyridine, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, carbonic acid ⁇ , lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride;
- the acidic conditions are in the presence of any of the following: acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, Camphorsulfonic acid.
- the present invention provides a stereoisomer of the compound of any one of the above aspects, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, and a medicament comprising the same Use of a composition for the manufacture of a medicament for the prevention and treatment of PIKfyve mediated cancer and other diseases.
- the compounds of the invention are synthesized using the methods described herein or other methods well known in the art.
- Thin layer chromatography was carried out on a silica gel GF254 precoated plate (Qingdao Marine Chemical Plant). Column chromatography was carried out by silica gel (300-400 mesh, Yantai Zhihuang Silica Gel Development Reagent Factory) under medium pressure or by column chromatography using a pre-packed silica gel cartridge (ISCO or Welch) using an ISCO Combiflash Rf200 rapid purification system. The ingredients were developed by UV light (: 254 nm) and by iodine vapor.
- the compounds were prepared by preparative HPLC on a Waters Symmetry C18 (19 x 50 mm, 5 ⁇ m) column or via a Waters X Terra RP 18 (30 x 150 mm, 5 ⁇ m) column using Waters preparative HPLC equipped with a 996 Waters PDA detector. 600 and Micromass mod. ZMD single quadrupole mass spectrometry (electrospray ionization, cationic mode).
- Method 1 Phase A: 0.1% TFA / MeOH 95/5 ; phase B: MeOH / H 2 O 95/5 . Gradient: 10 to 90% B for 8 min, 90% B 2 min; flow rate 20 mL/min.
- Method 2 Phase A: 0.05% NH 4 OH / MeOH 95/5; phase B: MeOH / H 2 O 95/5 . Gradient: 10 to 100% B for 8 min, maintaining 100% B 2 min. The flow rate was 20 mL/min.
- Electrospray (ESI) mass spectra were obtained on a Finnigan LCQ ion trap.
- HPLC-UV-MS analysis for evaluating compound purity was performed by combining an ion trap MS apparatus with an HPLC system SSP4000 (Thermo Separation Products) equipped with an autosampler LC Pal (CTC Analytics) and a UV6000LP diode array Detector (UV detection 215-400 nm). Device control, data acquisition and processing with Xcalibur 1.2 software (Finnigan). HPLC chromatography was carried out at room temperature and a flow rate of 1 mL/min using a Waters X Terra RP 18 column (4.6 x 50 mm; 3.5 [mu]m).
- Mobile phase A was ammonium acetate 5 mM buffer (pH 5.5 with acetic acid): acetonitrile 90:10
- mobile phase B ammonium acetate 5 mM buffer (pH 5.5 with acetic acid): acetonitrile 10:90; gradient 0 to 100% B Perform for 7 minutes and then maintain 100% B for 2 minutes before rebalancing.
- the raw materials involved are: p-trifluoromethylbenzoyl chloride (CAS: 329-15-7, Anne, Shanghai), 3-methyl-4-nitroaniline (CAS: 611-05-2, An Nai Kyrgyzstan, Shanghai), m-nitroaniline (CAS: 99-09-2, Anikei, Shanghai), p-acetamidobenzoyl chloride (CAS: 16331-48-9, An Nike, Shanghai), p-cyano Benzoyl chloride (CAS: 6068-72-0, Angic, Shanghai), p-nitrobenzoyl chloride (CAS: 122-04-3, Angie, Shanghai), m-trifluoromethylbenzenesulfonyl chloride ( CAS: 777-44-6, Anne, Shanghai).
- the raw materials involved are: m-nitrobenzoic acid (CAS: 121-92-6, Anne, Shanghai), m-bis(trifluoromethyl)aniline (CAS: 328-74-5, Anji, Shanghai) , m-methoxyaniline (CAS: 536-90-3, Angic, Shanghai), m-trifluoromethoxyaniline (CAS: 1535-73-5, Anne, Shanghai), m-toluidine (CAS) : 108-44-1, Anne, Shanghai), 3-methanesulfonamidoaniline (CAS: 37045-73-1, Suiyuan, Shanghai), m-chloroaniline (CAS: 108-42-9, An Nai Kyrgyzstan, Shanghai), 3-amino-4-chlorobenzotrifluoride (CAS: 121-50-6, Anikei, Shanghai), 2-fluoro-5-trifluoromethylaniline (CAS: 535-52-4 , Anne, Shanghai), 2-methoxy-5-trifluoromethylaniline (CAS:
- the raw materials involved are: 2-chloro-5-aminobenzotrifluoride (CAS: 320-51-4, Yifei, Shanghai), 5-bromo-2-methoxyaniline (CAS: 6358-77-6, Bi De Medicine, Shanghai), sulfur phosgene (CAS: 463-71-8, An Naiji, Shanghai);
- Phenylboronic acid (CAS: 98-80-6, Adamas, Switzerland);
- Method A Compound 1 (6 g, 32 mmol) was dissolved in 30 mL of dry N-N-dimethylformamide and stirred in ice-water bath for 10 min, and sodium hydride (1.9 g, 48 mmol) was added in portions and stirred for 15 min. Then, 2-(trimethylsilyl)ethoxymethyl chloride (6.8 mL, 38.4 mmol) was added dropwise to the reaction system, followed by stirring at room temperature until the end of the reaction (LC-MS tracking).
- Method B Compound 2a (500 mg, 1.58 mmol), arylamine compound 3 (465 mg, 1.58 mmol) tris(dibenzylideneacetone) dipalladium (72 mg, 0.08 mmol), 2-dicyclohexylphosphon-2', 4',6'-triisopropylbiphenyl (57 mg, 0.12 mmol) and potassium carbonate (654 mg, 4.74 mmol) were dispersed in tert-butanol, the system was replaced with nitrogen, and placed in an oil bath preheated to 100 °C. Stirring in the middle of the reaction until the end of the reaction (TLC tracking), the reaction was stopped. After cooling, the solid was filtered, and the filtrate was washed with MeOH. The filtrate was concentrated and purified by silica gel column chromatography to give compound 4a (540 mg, yield 60%) and 4c (77 mg) , yield 8.5%).
- Method C Compound 2b (201 mg, 1 mmol) and 3 (294 mg, 1 mmol) in tert-butanol (5 mL) were heated at 85 ° C under the action of trifluoroacetic acid (89 ⁇ L, 1.2 mmol) until the end of the reaction (LC-MS tracking). After cooling, ethyl acetate (50 mL) was added, and the mixture was washed twice with saturated NaHHHHHHHHHHHHHHHHHHHHHHHHHHHH 61%).
- Method D Compound 4a (288 mg, 0.5 mmol), 3-pyridine boronic acid (73 mg, 0.6 mmol), PdCl 2 (dppf) ⁇ CH 2 Cl 2 (41 mg, 0.05 mmol) and Na 2 CO 3 (265 mg, 2.5 mmol) Disperse in 1,4-dioxane/H 2 O (4/1 mL) in a reaction flask, replace the air with nitrogen, heat at 100 ° C until the end of the reaction (LC-MS tracking), remove insoluble matter by filtration, and concentrate the filtrate on silica gel column. Purification of the aimed product 5a (500 mg, yield 81%).
- Compound I-b-1 was synthesized from 4b by Method D; Compound I-c-1 was synthesized from 4c by Method D, Method E.
- Compound 6b was synthesized from Method 6A by Method A.
- Compound 8 was synthesized from Compound 7 and 3-pyridine boronic acid by Method D.
- Method G Compound 8 (1 mmol) was dissolved in DCM (5 mL), and then slowly dropped into mCMBA (1.5 eq.) in DCM (5 mL) at -30 ° C, incubated for 2-4 h, TLC was followed until the conversion was completed, and diluted with DCM. washed with saturated aqueous NaHCO 3, the organic phase was purified by silica gel column and concentrated to give a yellowish solid.
- Compounds III-a-1 and III-a-2 were synthesized from Method 13 by 13a, 13b and 3-pyridineboronic acid, respectively.
- Compounds IV-a-1 and IV-b-1 can be synthesized from 14a and 14b by Method C and Method D, respectively.
- Compound V-c-1 was synthesized from 16c by Method D, Method B and Method E.
- Compound 21a has a 19 by methods F, Method D synthesis, MS (ESI) m / z : 243 [M + H] +.
- Method K Compound 23a (410 mg, 2 mmol), cyclopropylamine (166 ⁇ L, 2.4 mmol) and diisopropylethylamine (0.5 mL, 3 mmol) were reacted in 2-butanol at 75 ° C, followed by TLC until the reaction was complete. After concentration, the column was purified to give the aimed product 347 mg, yield 77%.
- Compound VII-a-1 was prepared by the methods 25a and 26.
- Compound VIII-a-1 was prepared from 27a by Method C, Method D.
- vacuoles are generated in the cytoplasm, and the amount of vacuoles observed by microscopy shows that the compound inhibits the activity of PIKfyve kinase.
- Cell plating Take a single cell suspension of cells growing in log phase, count with a cell counter and dilute to a cell concentration of about 2 ⁇ 10 5 /mL, then inoculate the cells in a 12-well plate. Incubate at 37 ° C in a 5% CO 2 incubator.
- binding reaction 384 plates, 0.02mL system, DNA-labeled protein, magnetic beads attached to small molecule ligands and different concentrations of test compounds mixed in the reaction solution (0.17x PBS, 0.05% Tween 20, 6mM DTT) Shake for 1 hour at room temperature and elute with an eluent (1 x PBS, 0.05% Tween 20).
- the magnetic beads were resuspended in an eluent (1 x PBS, 0.05% Tween 20, 0.5 ⁇ M biotin-labeled small molecule ligand), and shaken for 30 minutes at room temperature to separate the eluent.
- Kd value The content of protein in the above eluate was passed through qPCR. Determination of test compound 11 3-fold dilutions, the concentration of each of the DMSO control set 3, K d value obtained by curve fitting.
- Cell plating Count the cell counts in the growth phase and inoculate them in 96-well plates (20,000 cells per well).
- IC 50 value After culture for 5 days, add 20 ⁇ L of MTS reaction solution, mix and incubate in a cell culture incubator (37 ° C; 5% CO 2 ) for 1-4 hours, and measure 490 nm with a microplate reader OD 490. The OD value at the wavelength.
- the cell growth inhibition rate is calculated by the following formula:
- the effect of a compound is calculated by measuring inhibition rate GradPad Prism 5 software in the half cell inhibitory concentration IC 50.
- the following table shows the inhibition rate of the compound of IC 50 values JeKo-1 or 10 ⁇ M of cells.
- a represents the growth inhibition rate of cells at a concentration of 10 ⁇ M of the compound.
- the Cell Titer Glo method measures the growth inhibition rate of compounds against PIKfyve-mediated tumor cells.
- Cell plating Take the cell count of the growth phase and inoculate it in a 384-well plate.
- the table below shows the inhibition rate of some compounds against Toledo and ST486 cells (3.3 10 ⁇ M).
- JeKo-1 cells were treated with V-c-17 for 24 hours and then lysed by Wstern Blot. It was found that immature cathepsin A and cathepsin D increased and had good concentration tolerance. This is similar to the treatment of the known PIKfyve inhibitor apilimod.
- Compound I-a-1 potently inhibited tumor growth in a triple negative breast cancer xenograft model with good dose tolerance ( Figure 4).
- tumor volume (length ⁇ width ⁇ width ⁇ 0.5) to 100 mm 3 is randomly divided into four groups: control group, 5 mg/kg once a day, 20 mg/kg once a day, and the initial tumor volume is recorded;
- mice were sacrificed, and the tumors grown under the skin were completely peeled off, and the weight of the tumor was recorded.
- tumor volume (length X width X height X ⁇ /4) to 100 mm 3 is randomly divided into three groups: control group, 25 mg/kg once a day Vc-17 group, 25 mg/kg twice a day Vc- Group 17 and 25 mg/kg were administered once a day in the apilimod group, and the initial tumor volume was recorded.
- mice were sacrificed, and the tumors grown under the skin were completely peeled off, and the weight of the tumor was recorded.
Abstract
Description
Cell Lines | 抑制率% |
A375 | 93.97 |
SK-MEL-28 | 64.03 |
SK-MEL-30 | 61.87 |
A549 | 65.3 |
MDA-MB-231 | 48.39 |
MDA-MB-435S | 56.23 |
MCF-7 | 44.23 |
HCT116 | 55.83 |
BGC823 | 53.95 |
HepG2 | 64.85 |
Claims (16)
- 以下通式的化合物:或该化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,其中,X 1,X 2,X 3,X 4,X 5,X 6可包含以下几种组合:R 1、R 2选自:1)取代或未被取代的C6-C10芳基、杂芳基,取代基选自:卤素原子、C6-C10芳基、杂芳基、杂环基、C1-C6烷基,C1-C6烷氧基、C1-C6含氧烷基,C1-C6含氟烷基、C1-C6含氟烷氧基、硝基、氰基、氨基、羟基,其中所述取代基直接或任选地通过NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH或CO与C6-C10芳基、杂芳基相连接;2)取代或未被取代的C6-C10芳胺基、杂芳胺基、C1-C6烷基氨基、C3-C7环烷基氨基、C1-C6含氧烷基氨基、C3-C7含氧环烷基氨基,取代基选自:卤素原子、C6-C10芳基、杂芳基、杂环基、C1-C6烷基,C1-C6烷氧基、C1-C6含氧烷基,C1-C6含氟烷基、C1-C6含氟烷氧基、硝基、氰基、氨基、羟基,其中所述取代基任选地通过NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH与C6-C10芳胺基、杂芳胺基、C1-C6烷基氨基、C3-C7环烷基氨基、C1-C6含氧烷基氨基、C3-C7含氧环烷基氨基相连接;优选R 1、R 2选自:1)取代或未被取代的苯、吡啶、呋喃、噻吩、苯并呋喃、苯并噻吩、苯并二噁茂、咪唑、吡唑、噻唑、噁唑、嘧啶、吲哚、喹啉,取代基选自卤素原子、C1-C6烷基,C1-C6烷氧基、C1-C6含氧烷基,C1-C6含氟烷基、C1-C6含氟烷氧基、硝基、氰基、氨基、羟基;L 1选自NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH,R 4选自氢、取代或未被取代的C6-C10芳基、杂芳基、杂环基、C1-C6烷基、C1-C6烷氧基、C1-C6含氧烷基,C1-C6含氟烷基、C1-C6含氟烷氧基、硝基、氰基、氨基、羟基C3-C7环烷基;L 2选自NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH、CO,R 5选自取代或未被取代的C6-C10芳基、杂芳基、杂环基、C1-C6烷基、C1-C6烷氧基、C1-C6含氧烷基,C1-C6含氟烷基、C1-C6含氟烷氧基、硝基、氰基、氨基、羟基C3-C7环烷基;n=0、1或2;Y 1、Y 2、Y 3之一选自N;R 6选自氢、卤素原子、C1-C6烷基;5)甲胺基、乙胺基、丙氨基、环丙基氨基、环丁基氨基、四氢吡咯基、哌啶基、吗啉基、4-氨基哌啶基、4-N,N-二甲基氨基哌啶基、3,5-二甲基吗啉基、N-甲基哌嗪基;R 3选自氢、卤素、取代或未被取代的烷基、环烷基,取代基选自卤素、氨基、羟基、烷硅氧基;优选,药学上可接受的盐为:无机酸盐,选自盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸氢盐和碳酸盐、硫酸盐或磷酸盐;或有机酸盐,选自甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、α-酮戊二酸盐、α-甘油磷酸盐、烷基磺酸盐或芳基磺酸盐;优选地,所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐;所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐等。
- 根据权利要求1所述的化合物及其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,其中,所述化合物为以下所示:其中,R 1选自:2)任选被取代的C6-C10芳基,在取代的情况下,其取代基为C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基,氰基;优选为 其中Z 1,Z 2,Z 3,Z 4,Z 5中的1个选自以下,其余为氢:氢、C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基,氰基;氢、氟,氯,溴,氨基,羟基、C1-C3烷基;其中,L 2选自NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH;优选L 2为NHCO、CONH;最优选L 2为NHCO;R 5选自取代或未被取代的C6-C10芳基,优选取代或未被取代的苯基;氢、卤素,氨基,羟基、C1-C3含氟烷基;R 7选自H、C1-C6烷基;优选R 7为甲基;R 2选自:2)任选被取代的C6-C10芳基,在取代的情况下,其取代基为C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基,氰基;优选为 其中Z 1,Z 2,Z 3,Z 4,Z 5中的1个选自以下,其余为氢:氢、C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基,氰基;氢、氟,氯,溴,氨基,羟基、C1-C3烷基、C1-C3烷氧基;L 2选自NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH、CO;优选NHCO、CONH、NHCONH、NHCSNH、CO;R 5选自取代或未被取代的C6-C10芳基、杂芳基、任选被取代的杂环基、C1-C6烷基、氨基取代的C1-C6烷基、C1-C6烷氧基、C1-C6含氟烷基、C1-C6含氟烷氧基、硝基、氰基、氨基、羟基C3-C7环烷基;优选R 5选自以下:当L 2为NHCO、CONH、NHCONH、NHCSNH时,R 5为 其中Z 1,Z 2,Z 3,Z 4,Z 5中的1个或2个独立地选自以下,其余为氢:氢、C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基、氰基、经任选被取代的杂环基所取代的C1-C6烷基;当L 2为NHCO时,R 5还为氨基取代的C1-C6烷基,其中优选C1-C6烷基为甲基、乙基、丙基,更优选C1-C6烷基为甲基;或者R 7选自1)H、卤素、任选被取代的杂环基;2)取代或未取代的C1-C6烷基,取代基为任选被取代的杂环基、双C1-C3烷基取代的氨基;3)双取代的氨基,取代基选自C1-C3烷基、双C1-C3烷氨基取代的C1-C3烷基;R 9选自H、C1-C6烷氧基;优选R 9为氢、甲氧基;其中,R 7和R 9都为非氢基团时,它们不同时存在;R 3选自:-H,C1-C6烷基;优选选自:-H,-CH 3。
- 根据权利要求1所述的化合物及其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,其中,所述化合物为以下所示:其中,L 2选自NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH;优选L 2为NHCO、CONH;R 5选自取代或未被取代的C6-C10芳基,优选取代或未被取代的苯基;R 7选自H、C1-C6烷基;优选R 7为甲基;R 3选自:-H,C1-C6烷基;优选选自:-H,-CH 3。
- 根据权利要求1所述的化合物及其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,其中,所述化合物为以下所示:其中,R 1选自:2)任选被取代的C6-C10芳基,在取代的情况下,其取代基为C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基、氰基;优选为 其中Z 1,Z 2,Z 3,Z 4,Z 5中的1个选自以下,其余为氢:氢、C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基、氰基;氢、氟,氯,溴,氨基,羟基;L 1选自NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH;L 1优选为NHCONH、NHCSNH,R 4选自氢、取代或未被取代的C6-C10芳基、优选取代或未被取代的苯基;L 2选自NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH;优选L 2为NHCO、CONH;最优选L 2为CONH;R 5选自取代或未被取代的C6-C10芳基,优选取代或未被取代的苯基;氢、卤素、氨基、羟基、C1-C3含氟烷基;R 7选自H、C1-C6烷基;优选R 7为甲基;R 2选自:L 2选自NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH;优选L 2为NHCO、CONH;R 5选自取代或未被取代的C6-C10芳基,优选取代或未被取代的苯基;R 7选自H、C1-C6烷基;优选R 7为甲基;R 3选自:-H,C1-C6烷基;优选选自:-H,-CH 3。
- 根据权利要求1所述的化合物及其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,其中,所述化合物为以下所示:其中,L 2选自NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH;优选L 2为NHCO、CONH;R 5选自取代或未被取代的C6-C10芳基,优选取代或未被取代的苯基;R 5优选为 其中Z 1,Z 2,Z 3,Z 4,Z 5中的1个或2个独立地选自以下,其余为氢:氢、卤素,氨基,羟基、C1-C3含氟烷基、C1-C3含氟烷氧基、经任选被取代的杂环基所取代的C1-C6烷基;R 7选自H、C1-C6烷基;优选R 7为甲基;R 3选自:-H,C1-C6烷基;优选选自:-H,-CH 3。
- 根据权利要求1所述的化合物及其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,其中,所述化合物为以下所示:其中,R 1选自:2)任选被取代的C6-C10芳基,在取代的情况下,其取代基为C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基,氰基、HOOC-、C1-C6烷氧基甲酰基;优选为 其中Z 1,Z 2,Z 3,Z 4,Z 5中的1个选自以下,其余为氢:氢、C1-C6烷基、C1-C3烷氧基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、HOOC-、C1-C6烷氧基甲酰基;氢、氟,氯,氨基,羟基、C1-C3烷基、HOOC-、乙氧基甲酰基(EtOOC-);L 1选自NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH;优选L 1为NHCO、CONH、NHCONH、NHCSNH;R 4选自氢、取代或未被取代的的C6-C10芳基、优选取代或未被取代的苯基,或取代或未被取代的的杂芳基、优选取代或未被取代的吡啶基;R 4优选为 其中Z 1,Z 2,Z 3,Z 4中的1个选自以下,其余为氢:氢、卤素,氨基,羟基;更优选R 4为 其中Z 2选自以下,其余为氢:氢、氯,氨基,羟基;最优选R 4为 其中Z 2为氨基,其余为氢;L 2选自NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH;优选L 2选自NHCO、CONH、NHSO 2、NHCONH、NHCSNH;R 5选自取代或未被取代的C6-C10芳基、优选取代或未被取代的苯基;R 5优选为 其中Z 1,Z 2,Z 3,Z 4,Z 5中的1个或2个独立地选自以下,其余为氢:氢、卤素,氨基,羟基、C1-C3含氟烷基、C1-C3烷氧基、C1-C6酰胺基、C1-C6烷基磺酰胺基、C1-C3含氟烷氧基、硝基、氰基、经任选被取代的杂环基所取代的C1-C6烷基、任选被取代的杂芳基;R 5更优选为 其中Z 1,Z 2,Z 3,Z 4,Z 5中的1个或2个独立地选自以下,其余为 氢:氢、氟、氯、三氟甲基、三氟甲氧基、硝基、氰基、甲氧基、乙酰胺基(-NHAc)、氨基、甲磺酰氨基(-NHMs)、最优选R 5为 其中,Z 2或Z 4为氢或-OCF 3,或Z 3为氢、-NO 2、-CN或-OMe,或Z 2或Z 4、Z 3中的一个为氢、-CF 3或-NHAc,或Z 1或Z 5、Z 2或Z 4、Z 3中的一个为氢、-NH 2或-NHMs;或Z 2与Z 4独立地选自-CF 3、 或Z 2与Z 3独立地选自-CF 3、 或Z 1与Z 4独立地选自-CF 3、-OMe、-F、-Cl;其余为氢;R 7选自1)H、卤素、任选被取代的杂环基;2)取代或未取代的C1-C6烷基,取代基为任选被取代的杂环基、双C1-C3烷基取代的氨基;3)双取代的氨基,取代基选自C1-C3烷基、双C1-C3烷氨基取代的C1-C3烷基;5)经任选被取代的苯基取代的氨基,优选为未取代的苯基或被以下取代的苯基取代的氨基:被甲磺酰氨基单取代的苯基,被杂环基双取代的苯基;R 2选自:1)任选被取代的杂芳基,2)任选被取代的C6-C10芳基,在取代的情况下,其取代基为C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基,氰基、C1-C6烷基磺酰基;优选为 其中Z 1,Z 2,Z 3,Z 4,Z 5中的1个选自以下,其余为氢:氢、C1-C6烷基、C1-C3烷氧基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基,氰基、C1-C3烷基磺酰基;L 2选自NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH;优选L 2为NHCO、CONH、NHSO 2、NHCONH、NHCSNH;R 5选自取代或未被取代的C6-C10芳基、优选取代或未被取代的苯基;R 5优选为 其中Z 1,Z 2,Z 3,Z 4,Z 5中的1个或2个独立地选自以下,其余为氢:氢、卤素,氨基,双C1-C3烷基取代的氨基、羟基、C1-C3烷基、C1-C3烷氧基、C1-C3含氟烷基、C1-C3含氟烷氧基、任选被取代的杂芳基、经任选被取代的杂环基所取代的C1-C6 烷基;R 5更优选为 其中Z 1,Z 2,Z 3,Z 4,Z 5中的1个或2个独立地选自以下,其余为氢:氢、氟、氯、溴、氨基、双C1-C3烷基取代的氨基、羟基、三氟甲基、三氟甲氧基、C1-C6烷基取代的 经任选被C1-C6烷基取代的杂环基所取代的C1-C6烷基、C1-C3烷基、C1-C3烷氧基;最优选R 5为 其中,Z 2或Z 4选自以下,其余为氢:氢、氟、氯、溴、三氟甲基、甲基、甲氧基、氨基、二甲氨基、三氟甲氧基、羟基;或Z 2与Z 3或Z 2与Z 4分别独立地选自以下,其余为氢:三氟甲基、R 7选自H、C1-C6烷基;优选R 7为H、甲基;4)任选经C3-C7环烷基、任选被取代的杂芳基或任选被杂芳基取代的C1-C6烷基所取代的氨基;优选选自被以下取代的氨基:C3-C6环烷基,任选经C1-C6烷基取代的杂芳基或任选经杂芳基取代的C1-C6烷基;最优选选自以下取代的氨基:5)任选被取代的杂环基,优选选自经二(C1-C6烷基)氨基、C1-C6烷基取代的杂芳基取代的杂环基,R 3选自:-H,C1-C6烷基;优选选自:-H,-CH 3。
- 根据权利要求1所述的化合物及其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,其中,所述化合物为以下所示:其中,R 2选自:L 2选自NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH;优选L 2为NHCO、CONH;R 5选自取代或未被取代的C6-C10芳基、优选取代或未被取代的苯基;R 5优选为 其中Z 1,Z 2,Z 3,Z 4,Z 5中的1个或2个独立地选自以下,其余为氢:氢、卤素,氨基,羟基、C1-C3含氟烷基、C1-C3含氟烷氧基、任选被取代的杂芳基、经任选被取代的杂环基所取代的C1-C6烷基;R 5更优选为 其中Z 1,Z 2,Z 3,Z 4,Z 5中的1个或2个独立地选自以下,其余为氢:氢、氟、氯、氨基,羟基、三氟甲基、三氟甲氧基、C1-C6烷基取代的 经任选被C1-C6烷基取代的杂环基所取代的C1-C6烷基、;R 7选自H、C1-C6烷基;优选R 7为甲基;
- 根据权利要求1所述的化合物及其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,其中,所述化合物为以下所示:其中,L 1选自NHCO、CONH;L 1优选为NHCO;R 4选自氢、取代或未被取代的的C6-C10芳基、优选取代或未被取代的苯基,或取代或未被取代的的杂芳基、优选取代或未被取代的吡啶基;R 4优选为 其中Z 1,Z 2,Z 3,Z 4,Z 5中的1个选自以下,其余为氢:氢、卤素,氨基,羟基、C1-C3含氟烷基;更优选R 4为 其中Z 2或Z 4选自以下,其余为氢:氢、氯,氨基,羟基、三氟甲基;最优选R 4为 其中Z 2或Z 4为三氟甲基,其余为氢;或R 4优选为 其中Z 1,Z 2,Z 3,Z 4中的1个选自以下,其余为氢:氢、卤素,氨基,羟基;更优选R 4为 其中Z 2选自以下,其余为氢:氢、氯,氨基,羟基;最优选R 4为 其中Z 2为氨基,其余为氢;R 2选自:1)任选被C3-C7环烷基取代的氨基、经任选被取代的杂芳基取代的氨基;优选选自被环丙基取代的氨基、经任选被C1-C6烷基取代的杂芳基取代的氨基;2)任选被取代的杂环基,优选选自经二(C1-C6烷基)氨基、C1-C6烷基取代的杂环基,
- 根据权利要求1所述的化合物及其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,其中,所述化合物为以下所示:其中,L 2选自NHCO、CONH、SO 2NH、NHSO 2、NHCONH、NHCSNH;优选L 2为NHCO、CONH;R 5选自取代或未被取代的C6-C10芳基、优选取代或未被取代的苯基;R 7选自H、C1-C6烷基;优选R 7为H、甲基;
- 药物组合物,其包含权利要求1-10中任一项的化合物或其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物以及任选的药学上可以接受的赋形剂。
- 制备权利要求1-10中任一项所述化合物的方法,包括以下步骤:反应条件:(a)金属钯催化的杂芳基氯代物与硼酸或硼酸酯的碳碳键形成偶联反应,或金属钯催化的杂芳基氯代物与胺类化合物的碳氮键形成的偶联反应,或碱性条件下胺类化合物对杂芳基氯代物的亲核取代反应,或酸性条件下胺类化合物对杂芳基氯代物的亲核取代反应;(b)金属钯催化的杂芳基氯代物与硼酸或硼酸酯的碳碳键形成偶联反应,或金属钯催化的杂芳基氯代物与胺类化合物的碳氮键形成的偶联反应,或酸性条件下胺类化合物对杂芳基氯代物的亲核取代反应;其中,所述杂芳基氯代物包含以下类型:所述硼酸或硼酸酯选自取代或未被取代的C6-C10芳基、杂芳基硼酸或硼酸酯;所述胺类化合物选自取代或未被取代的C6-C10芳胺、杂芳胺、C1-C6烷基氨、C3-C7环烷基氨、C1-C6含氧烷基氨、C3-C7含氧环烷基氨,详见前述任一项权利要求所述;所述金属钯催化剂选自醋酸钯、四(三苯基膦)钯、双三苯基磷二氯化钯、1,1'-双(二苯基膦)二茂铁]二氯化钯、三(二亚苄基丙酮)二钯;所述碱性条件指以下任意物质存在的条件下:三乙胺、二异丙基乙基胺、吡啶、碳酸氢钠、碳酸钠、碳酸钾、碳酸铯、氢氧化锂、氢氧化钠、氢氧化钾、氢化钠、氢化钾;所述酸性条件指以下任意物质存在的条件下:乙酸、三氟乙酸、盐酸、甲磺酸、对甲苯磺酸、樟脑磺酸。
- 权利要求1-10中任一项的化合物或其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物或者权利要求11所述的药物组合物在制备用于预防或治疗与生物体内PIKfyve介导的疾病的药物中的用途,尤其是在制备用于预防或治疗具有K-RAS突变、营养物质获取障碍特点的肿瘤以及非霍奇金淋巴瘤的生长与转移的药物中的用途。
- 根据权利要求13的用途,所述药物导致细胞产生空泡化,任选地,所述药物通过抑制PIKfyve导致细胞产生空泡化。
- 根据权利要求13的用途,所述PIKfyve介导的疾病是癌症,优选是乳腺癌,最优选是三阴性乳腺癌。
- 一种治疗PIKfyve介导的癌症的方法,所述方法包括向受试者施用有效量的权利要求1-10中任一项的化合物或其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物或者权利要求11所述的药物组合物,。优选地,所述癌症是三阴性乳腺癌或非霍奇金淋巴瘤。
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CN114127063A (zh) * | 2019-04-22 | 2022-03-01 | 上海仕谱生物科技有限公司 | 嘧啶并五元杂环类化合物及其作为突变型idh2抑制剂的用途 |
CN114127063B (zh) * | 2019-04-22 | 2023-12-01 | 上海仕谱生物科技有限公司 | 嘧啶并五元杂环类化合物及其作为突变型idh2抑制剂的用途 |
WO2021050900A1 (en) | 2019-09-13 | 2021-03-18 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Receptor tyrosine kinase inhibitors for treatment of protein kinase modulation-responsive disease or disorder |
WO2023055181A1 (ko) * | 2021-09-30 | 2023-04-06 | 한미약품 주식회사 | PIKfyve 키나아제 억제제 |
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Publication number | Publication date |
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CN110997669B (zh) | 2022-12-27 |
CN110997669A (zh) | 2020-04-10 |
IL272446A (en) | 2020-03-31 |
AU2018309245B2 (en) | 2021-03-04 |
US20200165246A1 (en) | 2020-05-28 |
JP2021176847A (ja) | 2021-11-11 |
EP3663293A4 (en) | 2021-04-21 |
CN115057855A (zh) | 2022-09-16 |
US11352354B2 (en) | 2022-06-07 |
CN115057855B (zh) | 2024-04-26 |
CA3071900A1 (en) | 2019-02-07 |
EP3663293A1 (en) | 2020-06-10 |
AU2018309245A1 (en) | 2020-03-19 |
TW201910329A (zh) | 2019-03-16 |
JP2020529968A (ja) | 2020-10-15 |
JP7050093B2 (ja) | 2022-04-07 |
CN109384782A (zh) | 2019-02-26 |
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