CN115716823A - Thiazole carboxamide compound and preparation method and application thereof - Google Patents
Thiazole carboxamide compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN115716823A CN115716823A CN202211004081.3A CN202211004081A CN115716823A CN 115716823 A CN115716823 A CN 115716823A CN 202211004081 A CN202211004081 A CN 202211004081A CN 115716823 A CN115716823 A CN 115716823A
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- CN
- China
- Prior art keywords
- alkyl
- membered
- hydrocarbyl
- aryl
- heteroaryl
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 105
- -1 Thiazole carboxamide compound Chemical class 0.000 title claims description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 246
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 25
- 230000002438 mitochondrial effect Effects 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 17
- QWEWLLNSJDTOKH-UHFFFAOYSA-N 1,3-thiazole-2-carboxamide Chemical class NC(=O)C1=NC=CS1 QWEWLLNSJDTOKH-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003112 inhibitor Substances 0.000 claims abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 210
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 207
- 125000000217 alkyl group Chemical group 0.000 claims description 169
- 238000006243 chemical reaction Methods 0.000 claims description 143
- 238000003756 stirring Methods 0.000 claims description 138
- 125000003118 aryl group Chemical group 0.000 claims description 115
- 125000000623 heterocyclic group Chemical group 0.000 claims description 111
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 75
- 238000004440 column chromatography Methods 0.000 claims description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 69
- 229940126062 Compound A Drugs 0.000 claims description 55
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 55
- 229910052736 halogen Inorganic materials 0.000 claims description 44
- 150000002367 halogens Chemical class 0.000 claims description 44
- 125000001424 substituent group Chemical group 0.000 claims description 42
- 125000001072 heteroaryl group Chemical group 0.000 claims description 36
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 23
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 10
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
- 201000005787 hematologic cancer Diseases 0.000 claims description 7
- 201000005202 lung cancer Diseases 0.000 claims description 7
- 208000020816 lung neoplasm Diseases 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 230000002489 hematologic effect Effects 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 claims description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 122
- 239000000243 solution Substances 0.000 description 71
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- 230000005764 inhibitory process Effects 0.000 description 16
- 230000000694 effects Effects 0.000 description 15
- 238000011068 loading method Methods 0.000 description 14
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- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
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- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 9
- 229960001507 ibrutinib Drugs 0.000 description 9
- 239000013641 positive control Substances 0.000 description 9
- HWJWNWZJUYCGKV-UHFFFAOYSA-N 5-[5-methyl-1-[[3-(4-methylsulfonylpiperidin-1-yl)phenyl]methyl]-1,2,4-triazol-3-yl]-3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazole Chemical compound CC1=NC(C=2ON=C(N=2)C=2C=CC(OC(F)(F)F)=CC=2)=NN1CC(C=1)=CC=CC=1N1CCC(S(C)(=O)=O)CC1 HWJWNWZJUYCGKV-UHFFFAOYSA-N 0.000 description 8
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- 125000006413 ring segment Chemical group 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 239000012224 working solution Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 201000011066 hemangioma Diseases 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
- 230000005787 mitochondrial ATP synthesis coupled electron transport Effects 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
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- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
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- NPCOQXAVBJJZBQ-UHFFFAOYSA-N reduced coenzyme Q9 Natural products COC1=C(O)C(C)=C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)C(O)=C1OC NPCOQXAVBJJZBQ-UHFFFAOYSA-N 0.000 description 1
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- 239000011593 sulfur Substances 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- 229940035936 ubiquinone Drugs 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
Classifications
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- 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
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
- C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
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Abstract
The invention belongs to the technical field of medicines, and relates to thiazole carboxamide compounds, a preparation method and application thereof. The thiazole carboxamide compoundsThe compound is shown as the following general formula (I), is a mitochondrial complex I inhibitor and can be used for treating tumors.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to thiazole carboxamide compounds, a preparation method and application thereof.
Background
In recent years, the incidence of cancer has increased year by year, and the cancer has become the first death disease worldwide and seriously threatens human health. In 2018, the number of newly added cancer patients reaches 1810 ten thousand, and the number of deaths is 960 ten thousand. China is a high cancer incidence country, 380.4 cases of new cases in China in 2018 account for more than 20% of new cancer cases in the world, wherein the incidence rate of malignant tumors is 278.07/10 ten thousand, and the mortality rate is 167.89/10 ten thousand. Hematological tumors are a general term for a large group of malignant tumors originating from the hematopoietic system, and the main groups include leukemia, lymphoma, myeloma, and the like. According to statistics, acute leukemia and lymphoma in hematological tumors are ranked in the first ten in ten common malignant tumors in China, and the incidence rate of the tumors is on the rise as a whole in recent years and the tumors tend to be younger. The demand for anticancer drugs is very strong in both global and chinese markets.
Mitochondria are widely present in eukaryotic cells and play an important role in energy supply, anabolism, cell survival and migration of cancer cells. In view of the important role of mitochondria in tumorigenesis and development, new strategies for developing mitochondria-targeted antitumor drugs based on specific targets such as mitochondrial tumor metabolites, biosynthesis and mitochondrial function have been proposed. In mitochondria, oxidative phosphorylation pathways are coupled with important mitochondrial processes such as tricarboxylic acid cycle and lipid metabolism, and are the most central pathways of mitochondria. Currently, a variety of small molecule inhibitors targeting mitochondrial oxidative phosphorylation have been shown to be effective against tumors in tumor cell lines, a variety of tumor models, and patient data, and have been partially studied clinically. The small molecule inhibitor mainly comprises compounds which take mitochondrial electron transport chain complexes (mitochondrial complexes for short) as targets. Of the 5 complexes constituting the mitochondrial electron transport chain, mitochondrial complex I is the initiation complex of respiratory chain electron transport, and most of ATP in mitochondria is generated by electron transport through mitochondrial complex I. The small molecule inhibitor of the targeted mitochondrial compound I can effectively inhibit the oxidative phosphorylation of mitochondria, and provides a new strategy for the mitochondrial targeted tumor treatment.
The oxidative phosphorylation pathway of mitochondria is an important mechanism for drug resistance in hematological tumors. As a first small molecule inhibitor targeting BTK, the ibrutinib has a remarkable curative effect on hematologic cancers. Since the appearance of the drug on the market in 2013, the drug has been approved for treating various blood cancers such as mantle cell lymphoma and chronic lymphocytic leukemia. However, with the use of ibrutinib, some patients have developed drug resistance to ibrutinib, and the current standard treatment scheme cannot meet the treatment requirements of such patients. Taking mantle cell lymphoma as an example, the 1-year survival rate of ibrutinib-resistant patients is only 22%. Further studies have found that the metabolism of the iburtinib-resistant mantle cell lymphoma cells bypasses BTK and tends to undergo mitochondrial oxidative phosphorylation and glutamine metabolism, thereby escaping ibutinib treatment. This phenomenon makes inhibition of mitochondrial oxidative phosphorylation and/or glutamine metabolism a new approach to the treatment of drug-resistant hematological tumors. IACS-010759 is an oxidative phosphorylation inhibitor of a targeted mitochondrial complex I which enters a clinical stage, has an obvious inhibition effect on blood tumor cells such as mantle cell lymphoma resistant to ibrutinib in vitro, and also has an obvious inhibition effect on a mouse disease model constructed by using the tumor cells. The small molecule inhibitor targeting the mitochondrial complex I will be the development direction of the next generation of anti-blood tumor drugs.
Disclosure of Invention
The appearance of the small molecule inhibitor of the targeted mitochondrial complex I provides a new direction for the treatment of hemangioma and drug-resistant hemangioma and the research and development of antitumor drugs.
The invention provides a mitochondrial complex I inhibitor with a novel framework, which has excellent activity in the aspects of inhibiting the activity of a mitochondrial complex I, inhibiting the proliferation of drug-resistant and non-drug-resistant blood tumors, inhibiting the proliferation of solid tumors and the like, and can be used as a potential broad-spectrum antitumor drug.
Therefore, an object of the present invention is to provide thiazolecarboxamide compounds represented by the following general formula (I) or pharmaceutically acceptable salts thereof.
The invention also aims to provide a preparation method of the thiazole carboxamide compound shown in the following general formula (I) or pharmaceutically acceptable salt thereof.
The invention also provides application of the thiazole carboxamide compound shown in the general formula (I) or pharmaceutically acceptable salt thereof.
The invention provides thiazole carboxamide compounds shown as the following general formula (I) or pharmaceutically acceptable salts thereof,
in the general formula (I):
R 1 、R 3 、R 5 、R 9 and R 10 Each independently selected from:
(1) -H, -OH, -SH, amino, halogen, cyano, nitro, -COOH, -C 1～6 Hydrocarbyl, -NH-C 1～6 Hydrocarbyl, -N (C) 1～6 Alkyl radical) 2 、-O-C 1～6 Hydrocarbyl, -S-C 1～6 Hydrocarbyl radicals, -C (O) -C 1～6 Hydrocarbyl, -C 1～6 alkyl-O-C 1～6 Hydrocarbyl, -C 1～5 alkyl-S-C 1～6 Hydrocarbyl radicals, -C (S) -C 1～6 Hydrocarbyl, -SO 2 -C 1～6 Hydrocarbyl radical, -C 1～6 hydrocarbyl-NH-C 1～6 Hydrocarbyl, -C 1～6 hydrocarbyl-N (C) 1～6 Alkyl radical) 2 、-C(O)-NH 2 、-C(O)-NH-C 1～6 Hydrocarbyl, -C (O) -O-C 1～6 Hydrocarbyl, -C (NH-C) 1～6 Alkyl radical) 2 、-NH-C(O)-C 1～6 Hydrocarbyl, -NH-SO 2 -C 1～6 Hydrocarbyl, -N (C) 1～6 Hydrocarbyl) -SO 2 -C 1～6 Hydrocarbyl, -SO 2 -NH 2 and-SO 2 -NH-C 1～6 A hydrocarbyl group; said-C 1～6 The hydrocarbyl group is unsubstituted or substituted with one or more of the following substituents: o, halogen, -OH, amino, -C 1～3 alkyl-OH, methanesulfonyl and methoxycarbonyl;
(2) -6-to 10-membered aryl, -5-to 10-membered heterocyclyl, -5-to 10-membered heteroaryl, -C 1～6 Alkyl-6-to 10-membered aryl, -C 1～6 Alkyl-5-to 10-membered heterocyclyl, -C 1～6 Alkyl-5-to 10-membered heteroaryl, -O-6-to 10-membered aryl, -O-5-to 10-membered heterocyclyl, -O-5-to 10-membered heteroaryl, -S-6-to 10-membered aryl, -S-5-to 10-membered heterocyclyl, -S-5-to 10-membered heteroaryl, -NH-6-to 10-membered aryl, -NH-5-to 10-membered heterocyclyl, -NH-5-to 10-membered heteroaryl, -C (O) -6-to 10-membered aryl, -C (O) -5-to 10-membered heterocyclyl, -C (O) -5-to 10-membered heteroaryl, -O-C 1～6 Alkyl-6-to 10-membered aryl, -O-C 1～6 Alkyl-5-to 10-membered heterocyclyl, -O-C 1～6 Alkyl-5-to 10-membered heteroaryl, -C 1～6 alkyl-O-C 1～6 Alkyl-6-to 10-membered aryl, -C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heterocyclyl, -C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heteroaryl, -C 1～6 alkyl-NH-C (O) -6-to 10-membered aryl, -C 1～6 alkyl-NH-C (O) -5-to 10-membered heterocyclyl-C 1～6 alkyl-NH-C (O) -5-10 membered heteroaryl, -CH (OH) -5-10 membered heteroaryl, -C (CH) 2 ) -6-to 10-membered aryl, -N (C) 1～6 Alkyl) -6-to 10-membered aryl, -N (C) 1～6 Hydrocarbyl) -5-to 10-membered heterocyclyl, -N (C) 1～6 Alkyl) -5-to 10-membered heteroaryl, -C (NH) -6-to 10-membered aryl, -NH-C (O) -5-to 10-membered heterocyclyl, -NH-C (O) -5-to 10-membered heteroaryl, -C (NH) 3 + ) -6 to 10 membered aryl and-S (O) 2 -6-to 10-membered aryl;
(3)R 1 and R 3 Linked to form a ring fused to a benzene ring, the ring being: a 6-to 10-membered aromatic ring, a 5-to 10-membered heterocycle or a 5-to 10-membered heteroaromatic ring;
in the above (2) and (3), the aryl group, the heterocyclic group, the heteroaryl group, the aromatic ring, the heterocyclic ring and the heteroaromatic ring are unsubstituted or substituted with one or more of the following substituents: o, N, -OH,Halogen, amino, nitro, amino, -SH, carbomethoxy, -C 1～6 Alkyl radical, C 2～5 Alkynyl, -O-C 1～6 Alkyl, -C 1～6 Alkyl-amino or acetonitrile groups.
R 2 And R 7 Each independently selected from: -H, -C 1～6 Hydrocarbyl, -C 1～6 alkyl-OH, -C 1～6 alkyl-O-C 1～6 Hydrocarbyl, -C (O) -NH 2 -COOH, formyl, pyridyl (including pyridin-2-yl, pyridin-4-yl, pyridin-3-yl) and 1, 3-benzoxadiazol-6-yl; or, R 2 Or R 7 And R 5 Or R 9 Formation of a connection to 2～5 Alkylene-.
R 4 Selected from: -H, -C 1～6 Hydrocarbyl, -C 1～3 alkyl-C (O) -O-C 1～6 A hydrocarbon group and a-5-to 6-membered heterocyclic group; said-C 1～6 The hydrocarbyl group is unsubstituted or substituted with one or more of the following substituents: -COOH or-NH + (CH 3 ) 2 (ii) a The-5-to 6-membered heterocyclic group is unsubstituted or substituted with one or more of the following substituents: -C 1～3 An alkyl group.
R 6 And R 8 Each independently selected from: -H, -OH, -SH, amino, halogen, cyano, nitro, -COOH, -C 1～6 Hydrocarbyl, -NH-C 1～6 Hydrocarbyl, -O-C 1～6 Hydrocarbyl, -SO 2 -NH 2 、-C(O)-O-C 1～6 Hydrocarbyl, -O-C (O) -NH 2 、-NH-C(O)-O-C 1～6 Alkyl, -6-to 10-membered aryl, -5-to 10-membered heterocyclyl, -5-to 10-membered heteroaryl, and-O-C 1～6 Alkyl-6 to 10 membered aryl.
Said C is 1～6 The hydrocarbyl group is selected from: c 1～6 Alkyl radical, C 2～6 Alkenyl radical, C 2～6 Alkynyl and C 3～6 A cycloalkyl group.
The "halogen" means fluorine, chlorine, bromine or iodine as a substituent. When a halogen atom is used as a substituent, the number of substitutions is one or more, including 1, 2, 3, or the like.
The "alkyl" refers to a straight or branched chain alkyl or cycloalkyl substituted alkyl derived from an alkane by the removal of one hydrogen atom.
The "alkenyl group" means a straight-chain or branched-chain or cyclic alkenyl group having a carbon-carbon double bond.
The "alkynyl group" refers to a straight or branched chain or cyclic alkynyl group containing a carbon-carbon triple bond.
The "cycloalkyl" is a fully hydrogenated non-aromatic ring consisting of mono-, bi-or tricyclic rings.
The "aryl" refers to a cyclic aromatic group in which the ring atoms are carbon atoms, and includes monocyclic aryl and fused ring aryl. Monocyclic aryl refers to fully unsaturated aryl groups, and fused-ring aryl refers to cyclic groups having at least one ring that is fully unsaturated aromatic, formed from two or more cyclic structures that share two adjacent carbon atoms with each other.
The "heterocyclic group" or "heterocycle" means a saturated or unsaturated non-aromatic group or ring consisting of 1 to 3 rings containing 1, 2, 3 or 4 heteroatoms selected from B, N, S and O.
Preferably, when the "heterocyclic group" or "heterocycle" is 5 to 8-membered or 5 to 6-membered, it preferably contains 1 to 2 heteroatoms selected from N and O.
The term "heteroaryl" or "heteroaromatic ring" refers to aromatic ring structures, including monocyclic heteroaryl and fused ring heteroaryl. Wherein at least one of the ring atoms is a heteroatom selected from N, S and O and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen and sulfur.
Preferably, when the "heteroaryl" or "heteroaromatic ring" is 5 to 8-membered or 5 to 6-membered, it preferably contains 1 to 2 heteroatoms selected from N and O; more preferably 1 to 2 heteroatoms selected from N.
Preferably: r is 1 Selected from:
(1) -H, -OH, -SH, amino, halogen, cyano, nitro, -COOH, -C 1～6 Alkyl, -NH-C 1～6 Alkyl, -N (C) 1～6 Alkyl radical) 2 、-O-C 1～6 Alkyl, -S-C 1～6 Alkyl, -C (O) -C 1～6 Alkyl, -C 1～6 alkyl-O-C 1～6 Alkyl, -C 1～5 alkyl-S-C 1～6 Alkyl, -C (S) -C 1～6 Alkyl, -SO 2 -C 1～6 Alkyl, -C 1～6 alkyl-NH-C 1～6 Alkyl, -C 1～6 alkyl-N (C) 1～6 Alkyl radical) 2 、-C(O)-NH 2 、-C(O)-NH-C 1～6 Alkyl, -C (O) -O-C 1～6 Alkyl, -C (NH-C) 1～6 Alkyl radical) 2 、-NH-C(O)-C 1～6 Alkyl, -NH-SO 2 -C 1～6 Alkyl, -N (C) 1～6 Alkyl) -SO 2 -C 1～6 Alkyl, -SO 2 -NH 2 and-SO 2 -NH-C 1～6 An alkyl group; said-C 1～6 Alkyl is unsubstituted or substituted with one or more of the following substituents: o, halogen, -OH, amino, -C 1～3 alkyl-OH, methanesulfonyl and methoxycarbonyl;
(2) -6-to 10-membered aryl, -5-to 10-membered heterocyclyl, -5-to 10-membered heteroaryl, -C 1～6 Alkyl-6-to 10-membered aryl, -C 1～6 Alkyl-5-to 10-membered heterocyclyl, -C 1～6 Alkyl-5-to 10-membered heteroaryl, -O-6-to 10-membered aryl, -O-5-to 10-membered heterocyclyl, -O-5-to 10-membered heteroaryl, -S-6-to 10-membered aryl, -S-5-to 10-membered heterocyclyl, -S-5-to 10-membered heteroaryl, -NH-6-to 10-membered aryl, -NH-5-to 10-membered heterocyclyl, -NH-5-to 10-membered heteroaryl, -C (O) -6-to 10-membered aryl, -C (O) -5-to 10-membered heterocyclyl, -C (O) -5-to 10-membered heteroaryl, -O-C 1～6 Alkyl-6-to 10-membered aryl, -O-C 1～6 Alkyl-5-to 10-membered heterocyclyl, -O-C 1～6 Alkyl-5-to 10-membered heteroaryl, -C 1～6 alkyl-O-C 1～6 Alkyl-6-to 10-membered aryl, -C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heterocyclyl, -C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heteroaryl, -C 1～6 alkyl-NH-C (O) -6-to 10-membered aryl, -C 1～6 alkyl-NH-C (O) -5-to 10-membered heterocyclyl-C 1～6 alkyl-NH-C (O) -5-10 membered heteroaryl, -CH (OH) -5-10 membered heteroaryl, -C (CH) 2 ) -6-to 10-membered aryl, -N (C) 1～6 Alkyl) -6-to 10-membered aryl, -N (C) 1～6 Alkyl) -5-to 10-membered heterocyclyl, -N (C) 1～6 Alkyl) -5-to 10-membered heteroaryl, -C (NH) -6-to 10-membered aryl, -NH-C (O) -6-to 10-membered aryl,-NH-C (O) -5-to 10-membered heterocyclyl, -NH-C (O) -5-to 10-membered heteroaryl, -C (NH) 3 + ) -6 to 10 membered aryl and-S (O) 2 -6-to 10-membered aryl;
(3)R 1 and R 3 Linked to form a ring fused to the benzene ring, the ring being: a 6-to 8-membered aromatic ring, a 5-to 8-membered heterocycle or a 5-to 8-membered heteroaromatic ring;
in the above (2) and (3), the aryl group, the heterocyclic group, the heteroaryl group, the aromatic ring, the heterocyclic ring and the heteroaromatic ring are unsubstituted or substituted with one or more of the following substituents: o, N, -OH, halogen, amino, nitro, amino, -SH, carbomethoxy, -C 1～6 Alkyl radical, C 2～5 Alkynyl, -O-C 1～6 Alkyl, -C 1～6 Alkyl-amino or acetonitrile groups.
Further preferably, R 1 Selected from:
(1)-H、-NH-C 1～3 alkyl, -N (C) 1～3 Alkyl radical) 2 、-O-C 1～3 Alkyl, -C (O) -C 1～3 Alkyl, -C 1～3 alkyl-O-C 1～3 Alkyl, -C 1～3 alkyl-NH-C 1～3 Alkyl, -C 1～3 alkyl-N (C) 1～3 Alkyl radical) 2 、-C(O)-NH-C 1～3 Alkyl, -C (O) -O-C 1～3 Alkyl, -NH-C (O) -C 1～3 Alkyl and-NH-SO 2 -C 1～3 An alkyl group; said C is 1～3 Alkyl is unsubstituted or substituted with one or more of the following substituents: halogen (preferably F);
(2) -phenyl, -5-to 6-membered heterocyclyl, -5-to 6-membered heteroaryl, -C 1～3 Alkyl-phenyl, -C 1～3 Alkyl-5-to 6-membered heterocyclyl, -C 1～3 Alkyl-5-6 membered heteroaryl, -O-phenyl, -O-5-6 membered heterocyclyl, -O-5-6 membered heteroaryl, -C 1～3 alkyl-O-C 1～3 Alkyl-5-to 6-membered heteroaryl and-NH-C (O) -5-to 6-membered heteroaryl; the-phenyl, -5-to 6-membered heterocyclyl or-5-to 6-membered heteroaryl is unsubstituted or substituted with one or more of the following substituents: o, -OH, halogen (preferably F), nitro, -C 1～3 Alkyl or-O-C 1～3 An alkyl group;
(3)R 1 and R 3 Connection ofForming a ring fused to the benzene ring, the ring being: a benzene ring, a 5-to 6-membered heterocyclic ring or a 5-to 6-membered heteroaromatic ring;
in the above (2) and (3), the phenyl group, the heterocyclic group, the heteroaryl group, the benzene ring, the heterocyclic ring and the heteroaromatic ring are unsubstituted or substituted with one or more of the following substituents: o, halogen, amino, nitro, -C 1～3 Alkyl or-O-C 1～3 An alkyl group. Preferably, the heterocyclic group contains 1 to 2 hetero atoms selected from N and O; the heteroaryl group contains 1 to 2 heteroatoms selected from N and O.
Preferably, R 3 And R 10 Each independently selected from: selected from the group consisting of: -H, -OH, amino, halogen, nitro, -O-CF 3 、-C 1～6 Hydrocarbyl, -NH-C 1～6 Hydrocarbyl, -N (C) 1～6 Alkyl radical) 2 、-O-C 1～6 Hydrocarbyl, -C (O) -NH 2 、-C(O)-NH-C 1～6 Hydrocarbyl, -NH-C (O) -C 1～6 Alkyl, -6-to 10-membered aryl, -5-to 10-membered heterocyclyl, -5-to 10-membered heteroaryl, -C (O) -6-to 10-membered aryl, -C (O) -5-to 10-membered heterocyclyl, -C (O) -5-to 10-membered heteroaryl, -C (O) -6-to 10-membered heteroaryl 1～6 alkyl-O-C 1～6 Alkyl-6-to 10-membered aryl, -C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heterocyclic group and-C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heteroaryl; said-C 1～6 The hydrocarbyl group is unsubstituted or substituted with one or more of the following substituents: a halogen; the aryl, heterocyclyl, heteroaryl groups are unsubstituted or substituted with one or more of the following substituents: o, -C 1～3 Alkyl or-COOH.
Further preferably, R 3 And R 10 Each independently selected from: selected from: -H, -OH, amino, halogen, nitro, -O-CF 3 、-C 1～6 Alkyl, -NH-C 1～6 Alkyl, -N (C) 1～6 Alkyl radical) 2 、-O-C 1～6 Alkyl, -C (O) -NH 2 、-C(O)-NH-C 1～6 Alkyl, -NH-C (O) -C 1～6 Alkyl, -6-to 10-membered aryl, -5-to 10-membered heterocyclyl, -5-to 10-membered heteroaryl, -C (O) -6-to 10-membered aryl, -C (O) -5-to 10-membered heterocyclyl, -C (O) -5-to 10-membered heteroaryl, -C 1～6 alkyl-O-C 1～6 alkyl-6E10-membered aryl, -C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heterocyclic group and-C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heteroaryl; said-C 1～6 Alkyl is unsubstituted or substituted with one or more of the following substituents: halogen; the aryl, heterocyclic and heteroaryl groups are unsubstituted or substituted by one or more of the following substituents: o, -C 1～3 Alkyl or-COOH.
Further preferably, R 3 Selected from: -H, amino, halogen (preferably F), -O-CF 3 、-C 1～3 Alkyl, -O-C 1～3 Alkyl, -NH-C (O) -C 1～3 Alkyl, phenyl, -5-to 6-membered heterocyclyl, -5-to 6-membered heteroaryl, -C (O) -phenyl, -C (O) -5-to 6-membered heterocyclyl, -C (O) -5-to 6-membered heteroaryl and-C 1～3 alkyl-O-C 1～3 Alkyl-5-6 membered heteroaryl; the phenyl, heterocyclyl and heteroaryl groups are unsubstituted or substituted with one or more of the following substituents: -C 1～3 An alkyl group. Preferably, said heterocyclic group contains 1 to 2 heteroatoms selected from N and O; the heteroaryl group contains 1 to 2 heteroatoms selected from N and O.
Further preferably, R 10 Selected from: -H and-F.
Preferably, R 5 And R 9 Each independently selected from: -H, -OH, halogen, amino, -CF 3 、-SH、-C 1～6 Hydrocarbyl, -O-C 1～6 Hydrocarbyl radical, -C 1～3 Alkyl-5-to 6-membered heterocyclic group and-5-to 6-membered heterocyclic group.
Further preferably, R 5 And R 9 Each independently selected from: -H, -OH, halogen, amino, -CF 3 、-SH、-C 1～6 Alkyl, -O-C 1～6 Alkyl, -C 1～3 Alkyl-5-to 6-membered heterocyclic group and-5-to 6-membered heterocyclic group.
Further preferably, R 5 And R 9 Each independently selected from: -H, -OH, -F, -SH and-O-C 1～3 An alkyl group.
Further preferably, R 5 And R 9 Are all selected from: -H.
Preferably: r 2 And R 7 Each is independentThe site is selected from: -H, -C 1～6 Alkyl, -C 1～6 alkyl-OH, -C 1～6 alkyl-O-C 1～6 Alkyl, -C (O) -NH 2 -COOH, formyl, pyridyl and 1, 3-benzoxadiazol-6-yl; or, R 2 Or R 7 And R 5 Or R 9 Formation of a connection to 2～5 Alkylene-.
Further preferably, R 2 And R 7 Each independently selected from: -H, -C 1～6 Alkyl, -C 1～6 alkyl-OH and-C 1～6 alkyl-O-C 1～6 An alkyl group; or, R 2 Or R 7 And R 5 Or R 9 Formation of a connection to 2～5 An alkylene group-.
Further preferably, R 2 And R 7 Each independently selected from: -H, -C 1～3 Alkyl and-C 1～3 alkyl-O-C 1～3 An alkyl group.
Further preferably, R 2 Selected from the group consisting of: -H, -C 1～3 Alkyl and-C 1～3 alkyl-O-C 1～3 Alkyl radical, R 7 Selected from: -H.
Further preferably, R 2 And R 7 Are all selected from: -H.
Preferably, R 4 Selected from: -H, -C 1～6 Alkyl, -C 1～3 alkyl-C (O) -O-C 1～6 Alkyl and-5 to 6 membered heterocyclyl; said-C 1～6 Alkyl is unsubstituted or substituted with one or more of the following substituents: -COOH or-NH + (CH 3 ) 2 (ii) a The-5-to 6-membered heterocyclic group is unsubstituted or substituted with one or more of the following substituents: -C 1～3 An alkyl group.
Further preferably, R 4 Selected from: -H, -C 1～6 Alkyl and-6 membered heterocyclyl.
Further preferably, R 4 Selected from the group consisting of: -H and-C 1～3 An alkyl group.
Further preferably selected from: -H.
Preferably, R 6 And R 8 Each independently selected from: -H, -OH, -SH, amino, halogen, cyano, nitro, -COOH, -C 1～6 Alkyl, -NH-C 1～6 Alkyl, -O-C 1～6 Alkyl, -SO 2 -NH 2 、-C(O)-O-C 1～6 Alkyl, -O-C (O) -NH 2 、-NH-C(O)-O-C 1～6 Alkyl, -6-to 10-membered aryl, -5-to 10-membered heterocyclyl, -5-to 10-membered heteroaryl and-O-C 1～6 Alkyl-6 to 10 membered aryl.
Further preferably, R 6 And R 8 Each independently selected from: -H, -OH, -SH, amino, halogen, -C 1～6 Alkyl, -NH-C 1～3 Alkyl, -O-C 1～6 Alkyl and-NH-C (O) -O-C 1～3 An alkyl group.
Further preferably, R 6 And R 8 Each independently selected from: -H, amino, halogen, -C 1～3 Alkyl, -O-C 1～3 Alkyl and-NH-C 1～3 An alkyl group.
Preferably: when R is 1 When selected from substituents other than H, R 3 、R 5 、R 9 And R 10 Are all H; or, when R 3 When selected from substituents other than H, R 1 、R 5 、R 9 And R 10 Are all H; further preferably, R 1 Selected from substituents other than H, R 3 、R 5 、R 9 And R 10 Are all H.
R 1 The method specifically comprises the following steps:
preferably, R 1 The method specifically comprises the following steps:
further preferably, R 1 The method specifically comprises the following steps:
further preferably, R 1 The method specifically comprises the following steps:
R 2 the method specifically comprises the following steps:
preferably, R 2 The method specifically comprises the following steps:
R 3 the method specifically comprises the following steps:
preferably, R 3 The method specifically comprises the following steps:
R 4 the method specifically comprises the following steps:
R 5 the method specifically comprises the following steps:
R 6 the method specifically comprises the following steps:
R 7 the method specifically comprises the following steps:
R 8 the method specifically comprises the following steps:
R 9 the method specifically comprises the following steps:
R 10 the method specifically comprises the following steps:
in a specific embodiment, the thiazole carboxamide compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof is the following compound or a pharmaceutically acceptable salt thereof:
the invention provides a preparation method of thiazole carboxamide compounds with general formula (I) or pharmaceutically acceptable salts thereof, which comprises the following steps:
dissolving the compound B in DMF, adding HBTU and N-methylmorpholine, stirring, adding the compound A, stirring, adding the reaction system into water, extracting with ethyl acetate, and performing column chromatography to obtain a compound (I);
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 And R 10 The definition of (c) is the same as that described above.
The invention provides an application of thiazole carboxamide compounds shown in general formula (I) or pharmaceutically acceptable salts thereof in preparing mitochondrial complex I inhibitors.
The invention provides an application of thiazole carboxamide compounds shown in a general formula (I) or pharmaceutically acceptable salts thereof in preparing medicaments for treating tumors.
Preferably, the tumor comprises: hematologic (including drug resistant hematologic) and solid tumors.
Preferably, the tumor comprises: acute promyelocytic leukemia, acute myeloid leukemia, mantle cell lymphoma, and lung cancer.
In addition, the invention provides a pharmaceutical composition which contains the thiazole carboxamide compound shown in the general formula (I) or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
In addition, the present invention provides a method for treating a disease associated with mitochondrial complex I, which comprises administering a thiazolecarboxamide compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof. Preferably, the subject is a human.
The thiazole carboxamide compounds shown in the general formula (I) provided by the invention are mitochondrion compound I small molecule inhibitors with novel structures, and the compounds with the structures have wide inhibitory activity on proliferation of various blood tumor cells (including drug-resistant blood tumors) and partial solid tumor cells (such as lung cancer cells), and can be used as potential new drug molecules for treating blood tumors, drug-resistant blood tumors and solid tumors.
Detailed Description
The present invention will be described below with reference to examples, but the present invention is not limited thereto. The experimental procedures shown in the following examples are conventional unless otherwise specified. The reagents and materials shown are all commercially available products. The column chromatography uses the following fillers: common silica gel of 100-200 meshes; the eluent is: ethyl acetate petroleum ether = 1.
Preparation of the Compound of example 1 MDD01
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.10g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain MDD01.
MS(ES-API)cacld.for C 16 H 19 N 3 O 3 S found 334[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ7.62-7.53(m,2H),6.91-6.75(m,3H),4.99-4.91(m,1H),4.20(s,4H),3.34(s,3H),2.79(d,J＝4.6Hz,3H),2.42(s,3H),1.39(d,J＝7.0Hz,3H).
Preparation example 2 preparation of the Compound MDD02
Adding 100mg of the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.10g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain MDD02.
MS(ES-API)cacld.for C 18 H 19 N 3 OS found 326[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ7.97-7.74(m,1H),7.65-7.39(m,1H),5.39-5.01(m,0H),3.32(d,J＝9.2Hz,1H),2.78(d,J＝4.6Hz,1H),2.60-2.22(m,5H),1.55(d,J＝7.0Hz,1H).
Preparation example 3 preparation of Compound MDD03
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.11g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD03.
MS(ES-API)cacld.for C 17 H 22 N 4 O 2 S found 347[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ9.82(s,1H),7.79(d,J＝6.0Hz,2H),7.56-7.49(m,3H),7.24(dd,J＝8.6,2.7Hz,3H),4.37(d,J＝4.8Hz,3H),3.33(d,J＝12.5Hz,4H),2.82(dd,J＝4.8,3.0Hz,4H),2.44(d,J＝3.0Hz,4H),2.26(td,J＝7.3,3.0Hz,3H),1.66-1.52(m,3H),0.90(td,J＝7.4,2.9Hz,4H).
Preparation example 4 preparation of the Compound MDD04
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.11g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain MDD04.
MS(ES-API)cacld.for C 15 H 17 F 2 N 3 O 2 S found 342[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ7.69(s,1H),7.56(s,1H),7.43(d,J＝8.2Hz,4H),7.19(s,1H),7.13(d,J＝8.3Hz,4H),5.09-5.01(m,2H),3.33(s,4H),2.79(s,5H),2.44(s,5H),1.43(d,J＝7.0Hz,5H).
Preparation example 5 preparation of the Compound MDD05
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 5.11 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete basic reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain the MDD05.
MS(ES-API)cacld.for C 17 H 22 N 4 O 2 S found 347[M+1] + .
Preparation of the Compound of EXAMPLE 6 preparation of MDD06
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.11g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete basic reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain MDD06.
MS(ES-API)cacld.for C 16 H 20 N 2 O 3 S found 321[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.75(d,J＝8.3Hz,1H),7.30(d,J＝8.5Hz,2H),6.88(d,J＝8.5Hz,2H),5.21-5.11(m,1H),3.99(q,J＝6.9Hz,2H),3.60(t,J＝9.4Hz,1H),3.49(dd,J＝10.0,5.4Hz,1H),3.32(d,J＝9.2Hz,3H),1.31(t,J＝6.9Hz,3H).
Preparation of the Compound of EXAMPLE 7 MDD07
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.08g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete basic reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD07.
MS(ES-API)cacld.for C 14 H 17 N 3 O 3 S found 292[M+1] + ； 1 H NMR(400MHz,DMSO):δ2.42(s,3H),2.81(s,3H),3.72(s,3H),4.35(d,2H),6.87(d,2H),7.24(d,2H),6.9(d，2H),7.78(s,2H).
Preparation of the Compound of EXAMPLE 8 MDD08
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.11g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain MDD08.
MS(ES-API)cacld.for C 18 H 19 N 3 O 2 S found 342[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ7.85-7.75(m,3H),7.72(s,1H),7.46(d,J＝8.5Hz,1H),7.29(d,J＝2.7Hz,1H),7.14(dd,J＝8.9,2.5Hz,1H),4.56(d,J＝4.7Hz,2H),3.86(s,4H),3.31(s,2H),2.82(s,3H),2.46(s,4H).
Preparation of the Compound of EXAMPLE 9 MDD09
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.10g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain the MDD09.
MS(ES-API)cacld.for C 17 H 22 N 4 OS found 331[M+1] + ； 1 H NMR(400MHz,DMSO):δ1.9(m,4H),2.42(s,3H),2.81(s,3H),3.18(m,4H),4.3(d,2H),6.4(d，2H)7.1(d,1H),7.6(m,1H),7.7(m,1H).
Preparation of the Compound of EXAMPLE 10 preparation of MDD10
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 10.12 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD10.
MS(ES-API)cacld.for C 17 H 19 F 2 N 3 O 2 S found 368[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ7.7(m,2H),7.34(d,1H),7.18(s,1H),6.98(d,1H),6.91(d,1H),5.14(d,2H),2.73-2.84(m,5H),2.38(s,3H),1.98(m,2H),1.8(m,2H),2.45(s,3H).
Preparation of the Compound of EXAMPLE 11 MDD11
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.29g (1.1 eq) of HBTU and 0.21g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.11g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain MDD11.
MS(ES-API)cacld.for C 15 H 19 N 3 OS found 290[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ9.35(d,J＝2.0Hz,1H),8.76(s,1H),7.03(dd,J＝8.5,2.3Hz,3H),6.51(d,J＝8.2Hz,3H),5.50(d,J＝6.0Hz,1H),4.26(d,J＝5.8Hz,3H),3.34(d,J＝1.8Hz,3H),2.93(q,J＝6.9,6.4Hz,3H),2.55(d,J＝2.1Hz,4H),1.52(p,J＝7.1Hz,3H),0.92(td,J＝7.5,2.2Hz,4H).
Preparation example 12 preparation of Compound MDD12
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.13g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain the MDD12.
MS(ES-API)cacld.for C 18 H 18 N 4 O 3 S found 371[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ10.16(s,1H),7.93(s,1H),7.81(s,1H),7.68(d,J＝8.1Hz,2H),7.34-7.20(m,3H),6.70(dd,J＝3.5,1.7Hz,1H),4.40(d,J＝5.0Hz,2H),3.31(s,2H),2.82(s,3H),2.45(s,3H).
Preparation of the Compound of EXAMPLE 13 MDD13 preparation
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.10g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete basic reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain the MDD13.
MS(ES-API)cacld.for C 16 H 19 N 3 O 3 S found 334[M+1] + . 1 H NMR(400MHz,DMSO-d6)δ7.97-7.91(m,1H),7.38(s,1H),3.84(d,J＝1.5Hz,2H),3.33(d,J＝1.4Hz,2H),2.84(s,2H),2.78(dd,J＝4.7,1.5Hz,2H),2.14(d,J＝1.5Hz,2H).
Preparation of the Compound of EXAMPLE 14 MDD14
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 14.12 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete basic reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain the MDD14.
MS(ES-API)cacld.for C 14 H 18 N 4 O 3 S 2 found 355[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.29(d,J＝8.1Hz,1H),7.16(d,J＝8.2Hz,1H),4.39(d,J＝5.2Hz,1H),3.34(s,2H),2.95(s,2H),2.82(d,J＝4.1Hz,2H),2.45(s,2H).
Preparation of the Compound of EXAMPLE 15 MDD15
Adding compound B2 mg, adding into DMF 2ml, adding HBTU 0.29g (1.1 eq) and N-methylmorpholine 0.21g (3 eq), stirring for 10min, adding compound A15.14 g (1.0 eq), stirring overnight at room temperature, TLC showing complete reaction, adding the reaction solution into water 50ml, extracting with ethyl acetate, and loading to column chromatography to obtain MDD15.
MS(ES-API)cacld.for C 19 H 18 N 2 OS found 323[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ9.45(s,1H),8.80(d,J＝7.9Hz,1H),7.62(t,J＝8.7Hz,6H),7.48-7.41(m,6H),7.33(t,J＝7.4Hz,1H),5.12(q,J＝7.3Hz,1H),3.28(s,5H),2.51(s,18H),1.47(d,J＝7.1Hz,4H).
Preparation of Compound of EXAMPLE 16 preparation of MDD16
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.12g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD16.
MS(ES-API)cacld.for C 19 H 20 N 4 O 2 S found 369[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ7.82-7.74(m,2H),7.40(t,J＝7.9Hz,1H),7.26(q,J＝7.9Hz,4H),6.40(d,J＝9.2Hz,1H),6.22(t,J＝6.7Hz,1H),5.06(s,2H),4.39(d,J＝5.1Hz,2H),3.33(s,3H),2.81(d,J＝3.6Hz,3H),2.44(s,3H).
Preparation of the Compound of EXAMPLE 17 preparation of MDD17
Adding compound B3 mg, adding into DMF 2ml, adding HBTU 0.27g (1.1 eq) and N-methylmorpholine 0.19g (3 eq), stirring for 10min, adding compound A17.10 g (1.0 eq), stirring overnight at room temperature, TLC showing the basic reaction is complete, adding the reaction solution into water 50ml, extracting with ethyl acetate, and loading to column chromatography to obtain MDD17.
MS(ES-API)cacld.for C 14 H 13 N 2 O 2 S found 331[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ8.86(d,J＝6.3Hz,1H),7.48(t,J＝7.9Hz,1H),7.36(d,J＝7.7Hz,1H),7.30(s,1H),7.25(d,J＝7.8Hz,1H),4.49(d,J＝6.0Hz,2H),3.27(s,3H),2.51(s,14H),2.36(s,4H).
Preparation of the Compound of EXAMPLE 18 MDD18
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.14g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain the MDD18.
MS(ES-API)cacld.for C 17 H 19 F 3 N 4 O 2 S found 401[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ9.07(t,J＝6.3Hz,1H),7.87(d,J＝8.0Hz,3H),7.35(s,2H),7.16(s,1H),4.12-4.02(m,3H),3.31(s,3H),2.87-2.76(m,9H),2.14(s,4H).
Preparation of the Compound of EXAMPLE 19 MDD19
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.11g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain MDD19.
MS(ES-API)cacld.for C 18 H 12 N 4 OS found 345[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.29-7.16(m,3H),4.41(d,J＝5.0Hz,1H),3.52(d,J＝2.6Hz,1H),3.34(s,2H),2.82(d,J＝3.7Hz,2H),2.49-2.35(m,5H),1.67(p,J＝3.2Hz,2H).
Preparation of the Compound of EXAMPLE 20 preparation of MDD20
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 20.11 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD20.
MS(ES-API)cacld.for C 17 H 19 N 5 OS found 342[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.82(s,2H),7.50(s,1H),7.42(d,J＝7.9Hz,1H),7.30(t,J＝7.6Hz,1H),7.15(d,J＝7.8Hz,1H),4.45(d,J＝5.2Hz,2H),3.86(s,3H),3.32(s,2H),2.82(d,J＝4.6Hz,3H),2.47(s,6H).
Preparation of the Compound of EXAMPLE 21 MDD21
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.13g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD21.
MS(ES-API)cacld.for C 16 H 18 F 3 N 3 O 2 S found 374[M+1] + .
Preparation of the Compound of EXAMPLE 22 MDD22
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.10g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain the MDD22.
MS(ES-API)cacld.for C 16 H 22 N 4 OS found 319[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ7.82(s,1H),7.24(q,J＝7.9Hz,3H),4.42(d,J＝5.2Hz,1H),2.82(d,J＝4.6Hz,2H),2.45(s,2H),2.11(s,4H).
Preparation of the Compound of EXAMPLE 23 MDD23
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.10g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD23.
MS(ES-API)cacld.for C 15 H 18 N 4 O 2 S found 319[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ9.9(s，1H)7.8(m，2H)7.5(s，1H)7.4(m，1H)7.2(m,1H),6.7(d 1H),4.42(s,2H),2.8(s,3H),2.47(s，3H)，2.3(s,3H).
Preparation of the Compound of EXAMPLE 24 preparation of MDD24
Adding compound B2 mg, adding into DMF 2ml, adding HBTU 0.29g (1.1 eq) and N-methylmorpholine 0.21g (3 eq), stirring for 10min, adding compound A24.15 g (1.0 eq), stirring overnight at room temperature, TLC showing basic reaction completion, adding the reaction solution into water 50ml, extracting with ethyl acetate, and loading to column chromatography to obtain MDD24.
MS(ES-API)cacld.for C 18 H 21 N 3 O 2 S found 344[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ9.41(s,1H),9.01(t,J＝5.9Hz,1H),7.41(d,J＝7.8Hz,1H),7.39(s,1H),7.30(s,1H),7.24(d,J＝5.5Hz,1H),4.47(d,J＝5.3Hz,2H),3.56(s,1H),2.56(s,3H),1.60(d,J＝6.1Hz,2H),1.53(s,1H),1.42(s,1H).
Preparation of the Compound of EXAMPLE 25 MDD25
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.11g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD25.
1 H NMR(400MHz,DMSO-d6)δ7.8(m,2)7.6(d,2H)7.3(d,2H),4.4(d,2H),3.8(t,2H),2.8(s,3H)2.4(m,5H),2.03(m,2H).
Preparation of the Compound of EXAMPLE 26 preparation of MDD26
Adding compound B2 mg, adding into DMF 2ml, adding HBTU 0.29g (1.1 eq) and N-methylmorpholine 0.21g (3 eq), stirring for 10min, adding compound A26.15 g (1.0 eq), stirring overnight at room temperature, TLC showing basic reaction completion, adding the reaction solution into water 50ml, extracting with ethyl acetate, and loading to sample column for chromatography to obtain MDD26
MS(ES-API)cacld.for C 18 H 23 N 3 O 2 S found 346[M+1] + ； 1 H NMR(600MHz,DMSO-d6)δ9.37(d,J＝4.8Hz,5H),8.87(dt,J＝12.0,6.2Hz,5H),7.24(dd,J＝23.4,8.3Hz,10H),6.96(dd,J＝19.4,8.4Hz,2H),6.91(d,J＝8.2Hz,8H),4.56(s,1H),4.40(s,2H),4.34(d,J＝6.0Hz,10H),4.29(d,J＝10.0Hz,1H),3.50-3.44(m,2H),3.15(s,2H),3.10(s,2H),2.82(s,2H),2.54(s,17H),2.17(s,1H),1.95(s,5H),1.69(s,3H),1.22(s,1H).
Preparation of the Compound of EXAMPLE 27 MDD27
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.11g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD27.
MS(ES-API)cacld.for C 17 H 21 N 3 O 3 S found 348[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ7.59(dd,J＝14.2,6.6Hz,1H),6.99(s,1H),6.92(q,J＝8.4Hz,2H),5.02-4.94(m,1H),4.09(q,J＝5.8Hz,4H),3.31(s,3H),2.79(d,J＝4.5Hz,3H),2.43(s,3H),2.07(t,J＝5.5Hz,2H),1.40(d,J＝6.9Hz,3H).
Preparation of the Compound of EXAMPLE 28 MDD28
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.12g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD28.
MS(ES-API)cacld.for C 18 H 22 N 4 O 2 S found 359[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ7.81(d,J＝5.9Hz,1H),7.29(d,J＝7.8Hz,1H),7.17(d,J＝7.7Hz,1H),4.42(d,J＝5.2Hz,1H),4.33(s,1H),3.33(s,1H),3.20(t,J＝7.0Hz,1H),2.82(d,J＝4.6Hz,2H),2.45(s,2H),2.27(t,J＝8.0Hz,1H),1.90(p,J＝7.6Hz,1H).
Preparation of the Compound of EXAMPLE 29 MDD29
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.29g (1.1 eq) of HBTU and 0.21g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.12g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD29.
MS(ES-API)cacld.for C 15 H 18 N 2 O 2 S found 291[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.71(d,J＝8.1Hz,1H),7.31-7.25(m,2H),6.87(d,J＝8.4Hz,2H),5.06(p,J＝7.3Hz,1H),3.99(q,J＝7.0Hz,2H),3.33(s,1H),1.42(d,J＝7.0Hz,3H),1.31(t,J＝7.0Hz,3H).
Preparation of the Compound of EXAMPLE 30 preparation of MDD30
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.11g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain the MDD30.
MS(ES-API)cacld.for C 17 H 19 N 5 OS found 342[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ7.80(s,2H),7.30(d,J＝7.8Hz,2H),7.25-7.12(m,4H),6.92(s,1H),5.17(d,J＝2.7Hz,2H),4.40(d,J＝5.5Hz,2H),2.81(d,J＝4.3Hz,3H),2.44(d,J＝2.7Hz,3H).
Preparation of the Compound of EXAMPLE 31 MDD31
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.13g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD31.
MS(ES-API)cacld.for C 19 H 21 N 3 O 3 S found 372[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ7.80(dt,J＝20.3,5.6Hz,2H),7.62(t,J＝1.4Hz,1H),7.32-7.26(m,2H),7.26-7.18(m,1H),7.16(d,J＝7.5Hz,1H),6.41(d,J＝1.7Hz,2H),4.43(dd,J＝11.3,6.6Hz,6H),2.89-2.78(m,3H),2.43(s,3H).
Preparation of the Compound of EXAMPLE 32 MDD32
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.10g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD32.
MS(ES-API)cacld.for C 15 H 17 N 3 O 3 S found 320[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ7.75(s,1H),6.79(d,J＝11.9Hz,5H),4.30(d,J＝5.2Hz,3H),4.20(s,7H),3.31(s,2H),2.82(d,J＝3.8Hz,5H),2.43(d,J＝4.7Hz,5H).
Preparation of the Compound of EXAMPLE 33 preparation of MDD33
Adding compound B2 mg, adding into DMF 2ml, adding HBTU 0.29g (1.1 eq) and N-methylmorpholine 0.21g (3 eq), stirring for 10min, adding compound A33.13 g (1.0 eq), stirring overnight at room temperature, TLC showing complete reaction, adding the reaction solution into water 50ml, extracting with ethyl acetate, and loading to column chromatography to obtain MDD33.
MS(ES-API)cacld.for C 15 H 15 N 5 OS found 314[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ13.6(s,1H),9.4(s,1H),9.0(t,1H),7.96(s,1H),7.8(d,1H),7.4(m,2H),4.5(d,2H),2.57(s,3H),2.39(m,3H).
Preparation of the Compound of EXAMPLE 34 MDD34
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.10g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain the MDD34.
MS(ES-API)cacld.for C 17 H 22 N 4 OS found 331[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ7.75(q,J＝5.1Hz,1H),7.61(t,J＝5.9Hz,1H),6.94(dd,J＝8.3,2.2Hz,1H),6.84(d,J＝2.2Hz,1H),6.50(d,J＝8.3Hz,1H),4.24(d,J＝5.9Hz,2H),3.14-3.08(m,2H),2.80(d,J＝5.0Hz,3H),2.77(s,3H),2.64(t,J＝6.5Hz,2H),2.39(s,3H),1.89-1.80(m,2H).
Preparation of the Compound of EXAMPLE 35 MDD35
Adding compound B2 mg, adding into DMF 2ml, adding HBTU 0.29g (1.1 eq) and N-methylmorpholine 0.21g (3 eq), stirring for 10min, adding compound A35.12 g (1.0 eq), stirring overnight at room temperature, TLC showing complete reaction, adding the reaction solution into water 50ml, extracting with ethyl acetate, and loading to column chromatography to obtain MDD35.
MS(ES-API)cacld.for C 16 H 19 N 3 OS found 302[M+1] + ； 1 H NMR(600MHz,DMSO-d6)δ9.32(s,1H),8.75(t,J＝5.9Hz,1H),7.11(d,J＝8.2Hz,2H),6.48(d,J＝8.2Hz,2H),4.28(d,J＝5.9Hz,2H),3.19-3.14(m,4H),2.53(s,3H),1.95-1.88(m,4H).
Preparation of the Compound of EXAMPLE 36 preparation of MDD36
Adding 100mg of compound B, adding into 2ml of DMF, adding 0.32g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.16g (1.0 eq) of compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain MDD36.
MS(ES-API)cacld.for C 16 H 17 N 3 O 2 S found 316[M+1] + ； 1 H NMR(600MHz,DMSO-d6)δ9.57(s,1H),8.89(s,1H),8.83(d,J＝7.9Hz,1H),7.57(d,J＝8.5Hz,2H),7.35(d,J＝8.4Hz,2H),5.10(p,J＝7.2Hz,1H),3.82-3.76(m,2H),2.46(t,J＝8.0Hz,21H),2.03(p,J＝7.7Hz,2H),1.45(d,J＝7.0Hz,3H).
Preparation of the Compound of EXAMPLE 37 preparation of MDD37
Adding compound B5 mg into DMF 2ml, adding HBTU 0.26g (1.1 eq) and N-methylmorpholine 0.19g (3 eq), stirring for 10min, adding compound A37.12 g (1.0 eq), stirring overnight at room temperature, TLC showing complete reaction, adding the reaction solution into 50ml water, extracting with ethyl acetate, and loading to column chromatography to obtain MDD37.
MS(ES-API)cacld.for C 17 H 21 N 3 O 2 S found 332[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ9.00(d,J＝12.8Hz,1H),7.11(d,J＝8.1Hz,1H),6.93(d,J＝8.1Hz,1H),6.48(dd,J＝16.1,8.1Hz,2H),4.47(s,1H),4.21(s,1H),3.95(s,3H),3.22-3.14(m,4H),2.78(s,1H),2.68(s,2H),1.92(t,J＝5.9Hz,4H).
Preparation of the Compound of EXAMPLE 38 MDD38
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.26g (1.1 eq) of HBTU and 0.19g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.11g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD38.
MS(ES-API)cacld.for C 15 H 16 ClN 3 OS found 322[M+1] + ； 1 H NMR(600MHz,DMSO-d6)δ9.36(d,J＝1.5Hz,1H),8.88(t,J＝5.8Hz,1H),7.11(d,J＝8.0Hz,2H),6.50-6.46(m,2H),4.28(d,J＝5.9Hz,2H),3.20-3.14(m,4H),1.92(q,J＝6.3,5.7Hz,4H).
Preparation of the Compound of EXAMPLE 39 MDD39
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.29g (1.1 eq) of HBTU and 0.21g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.13g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain MDD39.
MS(ES-API)cacld.for C 17 H 21 N 3 OS found 316[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ8.48(d,J＝4.8Hz,1H),7.14(d,J＝8.1Hz,1H),6.88(d,J＝8.1Hz,1H),6.49(dd,J＝15.6,8.1Hz,2H),4.52(s,1H),4.27(s,1H),3.19(t,J＝7.3Hz,4H),2.85(s,1H),2.72(s,2H),1.91(d,J＝5.7Hz,4H).
Preparation of the Compound of EXAMPLE 40 preparation of MDD40
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.29g (1.1 eq) of HBTU and 0.21g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.13g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD40.
MS(ES-API)cacld.for C 17 H 21 N 3 OS found 316[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ7.14(d,J＝8.1Hz,1H),6.89(d,J＝7.9Hz,1H),6.49(dd,J＝16.0,8.0Hz,2H),4.52(s,1H),4.27(s,1H),3.30(s,5H),3.18(d,J＝8.0Hz,4H),2.87(s,1H),2.71(s,2H),2.35(d,J＝4.6Hz,3H),1.92(q,J＝4.8,3.5Hz,4H).
Preparation of the Compound of EXAMPLE 41 MDD41
Adding compound B3 mg, adding into DMF 2ml, adding HBTU 0.27g (1.1 eq) and N-methylmorpholine 0.19g (3 eq), stirring for 10min, adding compound A37.12 g (1.0 eq), stirring overnight at room temperature, TLC showing the basic reaction is complete, adding the reaction solution into water 50ml, extracting with ethyl acetate, and loading to column chromatography to obtain MDD41.
MS(ES-API)cacld.for C 18 H 23 N 3 OS found 330[M+1] + ； 1 H NMR(600MHz,DMSO-d6)δ7.14(d,J＝8.1Hz,1H),6.82(d,J＝8.2Hz,1H),6.51(d,J＝8.2Hz,1H),6.47(d,J＝8.2Hz,1H),4.58-4.49(m,1H),3.19(q,J＝5.2,4.0Hz,3H),3.16(d,J＝6.5Hz,1H),2.89(s,1H),2.63(s,2H),2.40(d,J＝20.4Hz,3H),2.25(d,J＝2.4Hz,3H),1.92(qd,J＝6.7,3.2Hz,4H).
Preparation of the Compound of EXAMPLE 42 MDD42
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.32g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 35.14 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain MDD42.
MS(ES-API)cacld.for C 15 H 17 N 3 OS found 288[M+1] + ； 1 H NMR(600MHz,DMSO-d6)δ9.52(s,1H),8.89(d,J＝8.3Hz,2H),7.11(d,J＝8.2Hz,2H),6.48(d,J＝8.2Hz,2H),4.31(d,J＝5.9Hz,2H),3.19-3.14(m,4H),1.95-1.88(m,4H).
Preparation of the Compound of EXAMPLE 43 preparation of MDD43
Adding compound B5 mg, adding into DMF 2ml, adding HBTU 0.26g (1.1 eq) and N-methylmorpholine 0.19g (3 eq), stirring for 10min, adding compound A35.11 g (1.0 eq), stirring overnight at room temperature, TLC showing the basic reaction is complete, adding the reaction solution into water 50ml, extracting with ethyl acetate, and loading to column chromatography to obtain MDD43.
MS(ES-API)cacld.for C 16 H 19 N 3 O 2 S found 318[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ8.16(d,J＝6.3Hz,1H),7.12(dd,J＝8.6,2.1Hz,2H),6.48(dd,J＝8.6,2.1Hz,2H),4.31(d,J＝5.9Hz,2H),4.01(d,J＝2.1Hz,3H),3.32(d,J＝9.3Hz,2H),3.18(q,J＝4.3Hz,4H),1.93(h,J＝3.0,2.5Hz,4H).
Preparation of the Compound of EXAMPLE 44 preparation of MDD44
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.29g (1.1 eq) of HBTU and 0.21g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 25.13 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain MDD44.
MS(ES-API)cacld.for C 16 H 17 N 3 O 2 S found 316[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ8.92(t,J＝6.0Hz,1H),8.79(s,1H),7.60(d,J＝8.3Hz,2H),7.32(d,J＝8.3Hz,2H),4.42(d,J＝5.9Hz,2H),3.81(t,J＝7.0Hz,2H),3.33(s,2H),2.71(s,3H),2.47(d,J＝8.1Hz,11H),2.05(p,J＝7.6Hz,2H).
Preparation of the Compound of EXAMPLE 45 preparation of MDD45
Adding compound B3 mg, adding into DMF 2ml, adding HBTU 0.27g (1.1 eq) and N-methylmorpholine 0.19g (3 eq), stirring for 10min, adding compound A9.11 g (1.0 eq), stirring overnight at room temperature, TLC showing the basic reaction is complete, adding the reaction solution into water 50ml, extracting with ethyl acetate, and loading to column chromatography to obtain MDD45.
MS(ES-API)cacld.for C 17 H 21 N 3 OS found 316[M+1] + ； 1 H NMR (400mhz, dmso-d 6) δ 8.66 (t, J =6.0hz, 1h), 7.13 (d, J =8.1hz, 2h), 6.50 (d, J =8.2hz, 2h), 4.31 (d, J =5.9hz, 2h), 3.32 (d, J =9.5hz, 2h), 3.18 (d, J =6.3hz, 4h), 2.36 (s, 3H), 1.93 (q, J =3.4hz, 4h), preparation of compound MDD46 of example 46
Adding 100mg of compound B, adding into 2ml of DMF, adding 0.32g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.15g (1.0 eq) of compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain MDD46.
MS(ES-API)cacld.for C 16 H 19 N 3 OS found 302[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ9.33(s,1H),8.73(s,1H),8.66(s,1H),7.14(d,J＝8.1Hz,3H),6.95(s,2H),6.50(d,J＝8.1Hz,7H),4.51(s,3H),4.39(s,2H),3.28(s,10H),3.18(d,J＝6.1Hz,15H),2.87(d,J＝7.9Hz,11H),1.92(t,J＝4.3Hz,15H).
Preparation of the Compound of EXAMPLE 47 MDD47
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.29g (1.1 eq) of HBTU and 0.21g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 35.12 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain MDD47.
MS(ES-API)cacld.for C 16 H 19 N 3 OS found 302[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ8.76(d,J＝6.2Hz,1H),7.13(d,J＝8.1Hz,1H),6.49(d,J＝8.1Hz,1H),4.31(d,J＝5.8Hz,1H),3.19(d,J＝6.3Hz,2H),2.71(s,2H),1.93(q,J＝3.6Hz,2H).
Preparation of the Compound of EXAMPLE 48 MDD48
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.26g (1.1 eq) of HBTU and 0.19g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.12g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain the MDD48.
MS(ES-API)cacld.for C 17 H 22 N 4 OS found 330[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ6.99(s,1H),6.74(s,1H),6.47(d,J＝8.1Hz,2H),3.28(s,4H),3.16(d,J＝6.3Hz,4H),2.72(s,3H),2.10(s,3H),1.91(p,J＝3.4Hz,4H).
Preparation of the Compound of EXAMPLE 49 MDD49
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.32g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 25.15 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD49.
MS(ES-API)cacld.for C 15 H 15 N 3 O 2 S found 302[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ9.5(s,1H),9.1(t,1H),8.9(s,1H),7.6(d,2H),7.3(d,2H),4.44(d,2H),3.8(t,2H),2.48(d,2H),2.05(m,2H).
Preparation of the Compound of EXAMPLE 50 MDD50
Adding compound B2 mg, adding into DMF 2ml, adding HBTU 0.29g (1.1 eq) and N-methylmorpholine 0.21g (3 eq), stirring for 10min, adding compound A25.13 g (1.0 eq), stirring overnight at room temperature, TLC showing complete reaction, adding the reaction solution into water 50ml, extracting with ethyl acetate, and loading to column chromatography to obtain MDD50.
MS(ES-API)cacld.for C 16 H 17 N 3 O 2 S found 316[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.94(d,J＝6.4Hz,1H),7.64-7.57(m,2H),7.32(d,J＝8.2Hz,2H),4.40(d,J＝5.8Hz,2H),3.81(t,J＝7.0Hz,2H),3.34(d,J＝1.5Hz,1H),2.56(d,J＝1.5Hz,3H),2.51-2.44(m,14H),2.05(p,J＝7.6Hz,2H).
Preparation of the Compound of EXAMPLE 51 preparation of MDD51
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.26g (1.1 eq) of HBTU and 0.19g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 35.11 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain MDD51.
MS(ES-API)cacld.for C 16 H 20 N 4 OS found 316[M+1] + ； 1 H NMR(400MHz,DMSO-d6)δ7.7(m,1H),7.29(d,2H)7.14(d,2H),6.48(d,2H),4.28(d,2H),3.25(t,4H),2.35(s,3H),1.93(m,4H).
Preparation of the Compound of EXAMPLE 52 preparation of MDD52
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.12g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD52.
1 H NMR(400MHz,Chloroform-d)δ8.31-8.25(m,1H),7.31-7.23(m,3H),7.13(d,J＝8.2Hz,2H),6.99-6.87(m,4H),6.02(d,J＝5.9Hz,1H),4.55(d,J＝5.6Hz,2H),2.97(d,J＝5.1Hz,3H),2.52(s,3H),2.33(s,3H),1.26(s,1H).
Preparation of the Compound of EXAMPLE 53 MDD53
Adding 100mg of compound B into 2ml of DMF, adding 0.32g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine into the mixture, stirring the mixture for 10 minutes, then adding 39.18 g (1.0 eq) of compound A into the mixture, stirring the mixture at room temperature overnight, TLC (thin layer chromatography) shows that the reaction is basically completed, adding the reaction solution into 50ml of water, extracting the mixture by using ethyl acetate, and performing column chromatography on the mixture to obtain MDD53.
MS(ES-API)cacld.for C 17 H 12 N 2 O 2 S found 347[M+1] + ； 1 H NMR(600MHz,DMSO-d6)δ9.56(s,1H),9.10(t,J＝5.9Hz,1H),8.91(s,1H),7.40-7.30(m,2H),7.21-7.12(m,3H),7.04(ddd,J＝11.9,10.4,8.3Hz,2H),4.45(d,J＝5.9Hz,2H).
Preparation of the Compound of EXAMPLE 54 MDD54
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.26g (1.1 eq) of HBTU and 0.19g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 40.14 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain the MDD54.
MS(ES-API)cacld.for C 18 H16N 3 O 2 S found 358[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ7.82(t,J＝6.0Hz,1H),7.42-7.33(m,5H),7.06-6.99(m,2H),6.93(td,J＝8.5,2.5Hz,1H),6.84-6.79(m,1H),6.79-6.74(m,1H),4.41(d,J＝5.9Hz,2H),2.39(s,3H).
Preparation of the Compound of EXAMPLE 55 MDD55
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.32g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 41.15 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain MDD55.
MS(ES-API)cacld.for C 17 H 14 N 2 O 2 S found 311[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ7.78(t,J＝5.8Hz,4H),7.43-7.36(m,10H),7.36(s,4H),7.34(s,7H),7.20-7.13(m,4H),7.06-7.00(m,8H),6.84(dd,J＝11.3,2.4Hz,4H),6.79(dd,J＝8.5,2.5Hz,4H),4.41(d,J＝5.8Hz,8H),2.41(s,1H),2.38(s,12H).
Preparation of the Compound of EXAMPLE 56 preparation of MDD56
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.26g (1.1 eq) of HBTU and 0.19g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.14g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain MDD56.
MS(ES-API)cacld.for C 18 H 16 FN 3 O 2 S found 358[M+1] + ； 1 H NMR(600MHz,DMSO-d6)δ9.55(s,1H),9.07(t,J＝5.9Hz,1H),8.91(s,1H),7.39-7.31(m,4H),7.10(t,J＝7.4Hz,1H),6.96(dd,J＝8.3,4.4Hz,4H),4.44(d,J＝5.9Hz,2H).
Preparation of the Compound of EXAMPLE 57 MDD57
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.26g (1.1 eq) of HBTU and 0.19g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 41.13 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain MDD57.
MS(ES-API)cacld.for C 18 H 17 N 3 O 2 S found 340[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ7.81(t,J＝6.0Hz,2H),7.40-7.29(m,12H),7.14-7.07(m,2H),6.99-6.93(m,8H),4.40(d,J＝6.0Hz,4H),2.45(s,1H),2.39(s,6H).
Preparation of the Compound of EXAMPLE 58 MDD58
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 41.12 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain MDD58.
MS(ES-API)cacld.for C 19 H 19 N 3 O 2 S found 354[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ7.80(t,J＝5.9Hz,2H),7.40-7.30(m,4H),7.10(t,J＝7.4Hz,1H),6.99-6.93(m,4H),4.40(d,J＝5.9Hz,2H),2.81(d,J＝4.9Hz,3H),2.45(s,1H),2.44(s,3H).
Preparation of the Compound of EXAMPLE 59 preparation of MDD59
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.13g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain MDD59.
MS(ES-API)cacld.for C 20 H 21 N 3 O 3 S found 384[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ7.78(d,J＝5.9Hz,1H),7.27-7.20(m,1H),7.20-7.11(m,1H),7.01-6.90(m,1H),6.80-6.73(m,1H),4.36(d,J＝5.9Hz,1H),3.71(s,2H),2.80(d,J＝4.4Hz,2H),2.42(s,2H).
Preparation example 60 preparation of Compound MDD60
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.22g (1.1 eq) of HBTU and 0.24g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 39.14 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete basic reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain MDD60.
MS(ES-API)cacld.for C 19 H 17 F 2 N 3 O 2 S found 390[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ7.82(t,J＝5.7Hz,1H),7.41-7.29(m,1H),7.22-7.16(m,1H),7.16-7.11(m,1H),7.03(td,J＝9.9,9.2,7.0Hz,1H),4.41(d,J＝5.9Hz,1H),2.81(d,J＝4.8Hz,2H),2.44(s,2H).
Preparation of the Compound of EXAMPLE 61 MDD61
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.29g (1.1 eq) of HBTU and 0.21g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 41.14 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC (thin layer chromatography) for complete basic reaction, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing column chromatography on a sample to obtain MDD61.
MS(ES-API)cacld.for C 18 H 16 N 2 O 2 S found 325[M+1] + ； 1 H NMR(600MHz,DMSO-d6)δ9.39(s,3H),8.92(t,J＝6.0Hz,3H),7.46(t,J＝7.8Hz,1H),7.39-7.31(m,12H),7.16-7.08(m,5H),6.97(dd,J＝8.6,2.6Hz,12H),4.40(d,J＝5.9Hz,6H),2.55(s,9H).
Preparation of the Compound of EXAMPLE 62 MDD62
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.29g (1.1 eq) of HBTU and 0.21g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.16g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain MDD62.
MS(ES-API)cacld.for C 19 H 17 FN 2 O 2 S found 357[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ9.45(s,1H),8.78(d,J＝7.9Hz,1H),7.43-7.31(m,3H),7.22(dd,J＝8.4,2.1Hz,1H),7.16-7.06(m,2H),6.97-6.91(m,2H),5.11(p,J＝7.1Hz,1H),2.51(s,4H),1.45(d,J＝7.0Hz,3H).
Preparation of the Compound of EXAMPLE 63 MDD63
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.29g (1.1 eq) of HBTU and 0.21g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 0.16g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain MDD63.
MS(ES-API)cacld.for C 19 H 18 NO 3 S found 355[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ9.37(s,1H),8.88(t,J＝5.9Hz,1H),7.27-7.20(m,2H),7.18(ddd,J＝8.6,6.9,1.8Hz,1H),7.14(dd,J＝8.3,1.8Hz,1H),7.01-6.91(m,2H),6.81-6.74(m,2H),4.36(d,J＝5.9Hz,2H),3.71(s,3H),2.54(s,3H).
Preparation of the Compound of EXAMPLE 64 preparation of MDD64
Adding 100mg of the compound B, adding the compound B into 2ml of DMF, adding 0.29g (1.1 eq) of HBTU and 0.21g (3 eq) of N-methylmorpholine, stirring for 10 minutes, then adding 39.16 g (1.0 eq) of the compound A, stirring overnight at room temperature, TLC shows that the reaction is basically complete, adding the reaction solution into 50ml of water, extracting with ethyl acetate, and performing sample column chromatography to obtain MDD64.
MS(ES-API)cacld.for C 18 H 14 F 2 N 2 O 2 S found 361[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ9.41(s,1H),8.96(t,J＝6.0Hz,1H),7.41-7.29(m,2H),7.22-7.11(m,3H),7.04(td,J＝10.1,9.3,6.6Hz,2H),4.42(d,J＝6.0Hz,2H),2.55(s,3H).
Preparation of the Compound of EXAMPLE 65 MDD65
Adding compound B3 mg, adding into DMF 2ml, adding HBTU 0.27g (1.1 eq) and N-methylmorpholine 0.19g (3 eq), stirring for 10min, adding compound A41.22 g (1.0 eq), stirring overnight at room temperature, TLC showing the basic reaction is complete, adding the reaction solution into water 50ml, extracting with ethyl acetate, and loading to column chromatography to obtain MDD65.
MS(ES-API)cacld.for C 19 H 18 N 2 O 2 S found 339[M+1] + ； 1 H NMR(600MHz,DMSO-d6)δ8.77(t,J＝6.1Hz,1H),7.37(t,J＝7.8Hz,2H),7.34(d,J＝8.2Hz,2H),7.11(t,J＝7.4Hz,1H),6.98(dd,J＝8.2,5.9Hz,4H),4.43(d,J＝6.0Hz,2H),2.50(s,6H),2.36(s,3H).
Preparation of the Compound of EXAMPLE 66 preparation of MDD66
Adding compound B3 mg, adding into DMF 2ml, adding HBTU 0.27g (1.1 eq) and N-methylmorpholine 0.19g (3 eq), stirring for 10min, adding compound A43.15 g (1.0 eq), stirring overnight at room temperature, TLC showing the basic reaction is complete, adding the reaction solution into water 50ml, extracting with ethyl acetate, and loading to column chromatography to obtain MDD66.
MS(ES-API)cacld.for C 20 H 20 N 2 O 3 S found 369[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ8.74(t,J＝6.0Hz,1H),7.28-7.22(m,2H),7.18(ddd,J＝8.7,7.0,1.7Hz,1H),7.15(dd,J＝8.3,1.8Hz,1H),7.00(dd,J＝7.8,1.7Hz,1H),6.95(td,J＝7.9,7.4,1.7Hz,1H),6.82-6.76(m,2H),4.38(d,J＝6.0Hz,2H),3.71(s,3H),2.35(s,3H).
Preparation of the Compound of EXAMPLE 67 MDD67
Adding compound B3 mg into DMF 2ml, adding HBTU 0.27g (1.1 eq) and N-methylmorpholine 0.19g (3 eq), stirring for 10min, adding compound A45.16 g (1.0 eq), stirring overnight at room temperature, TLC showing complete reaction, adding the reaction solution into 50ml water, extracting with ethyl acetate, and loading to column chromatography to obtain MDD67.
MS(ES-API)cacld.for C 19 H 17 N 3 O 4 S found 384[M+1] + ； 1 H NMR(500MHz,DMSO-d6)δ8.27-8.21(m,1H),7.47-7.41(m,1H),7.20-7.15(m,1H),7.14-7.06(m,1H),4.48(d,J＝6.0Hz,1H),2.52(s,2H),2.37(s,2H).
Experimental example 1: detection of inhibitory Activity of Compounds of the present invention on mitochondrial Complex I
Experiment: use of
Complex I Activity Assay Kit (Cayman, item No. 700930) measures the inhibitory Activity of the compounds of the present invention against mitochondrial Complex I. Preparing a 50mM mother solution of the compound by using DMSO for later use, and performing gradient dilution on the compound by using DMSO to obtain a working solution with a corresponding concentration when the compound is to be detected; dissolving all NADH with 155 microliter of ultrapure water, and placing on ice for later use after preparation; 6.5mg of KCN (prepared within three hours prior to detection) was dissolved in 1mL of 0.1M NaOH; each 20 parts of the reaction solution A contained complete I Activity Assay Buffer 910. Mu.L, KCN 20. Mu.L, FF-BSA Assay Reagent 50. Mu.L, and Bovine Heart Mitochondria Assay Reagent 20. Mu.L; each 20 parts of the reaction solution B contained Complex I Activity Assay Buffer 1025. Mu.L, NADH Assay Reagent 30. Mu.L, and Ubiquinone Assay Reagent 20. Mu.L.
Sucking 45 working solutions of the compound of the invention with the volume of 1 mu L, adding the working solutions into a 96-well plate, adding 50 mu L of reaction solution A into the wells, blowing and uniformly mixing the reaction solution A by using a pipette, and incubating the mixture for 10min at room temperature; after incubation is completed, 50 mu L of reaction liquid B is added to start reaction, after the reaction liquid B is added, a 96-well plate is quickly placed into an enzyme-labeling instrument (Varioskan LUX, thermo Fisher Scientific) to carry out detection, and the absorbance is measured at 340nm (the detection lasts for 15 minutes every 30 seconds at 25 ℃); each set of experiments was performed in triplicate, with DMSO as negative control and the mitochondrial complex inhibitor IACS-010759 as positive control.
Drawing the detected light absorption value data into a relation graph of light absorption (Y axis) and reaction time (X axis); taking a curve slope meter from 2min to 12.5minCalculating the reaction rate; the reaction rate was converted to the relative inhibition of the compound of the invention to complex I using the following formula; relative inhibition data were plotted into curves using Graphpad Prism 6.0 software to determine IC 50 The value of (c).
Wherein, Δ OD 340c As a control group OD 340 Slope of, Δ OD 340t Is OD of the experimental group 340 The slope of (c).
As a result: the results of the experiment are shown in table 1. The compounds of the invention all show activity on mitochondrial complex I. Of these, 22 compounds of the invention were IC for mitochondrial Complex I 50 <15 μ M. IC of Positive control Compound IACS-010759 on mitochondrial Complex I 50 It was 0.91. Mu.M.
TABLE 1 inhibition of mitochondrial Complex I by Compounds of the invention
And (4) conclusion: the compound of the invention has obvious inhibitory activity on mitochondrial complex I, wherein the inhibitory activity of the compounds MDD09, MDD52 and MDD67 is stronger and is equivalent to that of a positive control compound IACS-010759.
Experimental example 2: inhibition of proliferation of 4 human tumor cells by the compounds of the invention
Experiment: compounds of the invention MDD09 and MDD52 were prepared in DMSO as 40mg/mL stock solutions, and positive control compounds IACS-010759 and Ibrutinib (Ibrutinib) were prepared in DMSO as 20mg/mL and 40mg/mL stock solutions, respectively.
Amplifying and culturing human promyelocytic acute leukemia cell HL60, human myelogenous leukemia monocyte THP-1, human lung cancer cell H1299 and human mantle cell lymphoma cell JeKo-1 to logarithmic growth phase, and adjusting cell density to 3 × 10 4 cells/mL, 100. Mu.L per well, each concentration gradient, were plated into 96-well cell culture plates3 multiple holes. The compounds of the invention, MDD09 and MDD52, were applied to the cells using a complete medium set up to 6 concentration gradients of 0, 2.5, 5, 10, 20 and 40. Mu.g/mL. The positive control compound, ibrutinib, was applied to the cells using 6 concentration gradients of 0, 2.5, 5, 10, 20 and 40 μ g/mL in complete medium. The positive control compound IACS-010759 was applied to the cells using 6 concentration gradients of 0, 1.25, 2.5, 5, 10 and 20. Mu.g/mL in complete medium. 15 μ L of CCK8 per well after 24h, 48h and 72h of incubation, 37 ℃,5% CO 2 And culturing in an incubator for 3h in a dark place. The OD value of each well at the same time point at a wavelength of 492nm was measured using a microplate reader (Molecular Devices SpectraMax i 3), and the effect of cell proliferation was analyzed using the OD value thus measured.
As a result: the results of the experiment are shown in table 2.
TABLE 2 inhibitory Activity of the Compounds of the present invention on proliferation of 4 human tumor cells
Note: "-" indicates that: the cell inhibition rate does not reach 50% in the time period.
And (4) conclusion: the compound of the invention has stronger inhibitory activity to the proliferation of human blood tumor cells and solid tumor cells. The compound MDD52 has stronger inhibitory activity on partial tumor cells than the positive control drugs IACS-010759 and ibrutinib. The results show that the compounds MDD09 and MDD52 can be used as a lead of antitumor drugs.
Experimental example 3: inhibition of proliferation of human promyelocytic acute leukemia cell HL60 by the compounds of the invention
Experiment: the compound of the present invention was prepared as a40 mg/mL stock solution in DMSO. Culturing HL60 cell of human promyelocytic acute leukemia by amplification, and adjusting cell density to 3 × 10 when the cell grows to logarithmic phase 4 cells/mL, seeded into 96-well cell culture plates, 100. Mu.L per well, 3 replicates per concentration gradient. The mother liquors of the compounds of the present invention were diluted to 0, 2.5, 5, 10, 20 and complete medium, respectivelyA total of 6 concentration gradients of 40. Mu.g/mL were applied to the cells. After 24h, 48h and 72h incubation respectively, 15. Mu.L of CCK8 was added to each well, 37 ℃,5% CO 2 Culturing in an incubator for 3h in a dark place. The OD value of each well at the same time point at a wavelength of 492nm was measured using a microplate reader (Molecular Devices SpectraMax i 3), and the effect of cell proliferation was analyzed using the OD value thus measured.
As a result: the results of the experiment are shown in table 3.
TABLE 3 inhibitory Activity of the Compounds of the present invention on HL60 cell proliferation
Note: "-" indicates: the cell inhibition rate does not reach 50% in the time period.
And (4) conclusion: the compound has strong inhibition effect on the proliferation of human promyelocytic acute leukemia cell HL 60. The compounds MDD01, MDD08 and MDD21 have stronger inhibition effect on human promyelocytic acute leukemia cell HL 60.
Experimental example 4: inhibition of proliferation of 3 human tumor cells by the compounds of the invention
Experiment: the compound of the present invention, MDD67, was prepared in DMSO as a40 mg/mL stock solution, and the positive control drug, IACS-010759, and the compounds of the present invention, MDD58 and MDD60, were prepared in DMSO as a20 mg/mL stock solution. Amplifying and culturing human promyelocytic acute leukemia cell HL60, human lung cancer cell H1299 and human mantle cell lymphoma cell Jeko-1, and adjusting the cell density to 3 × 10 when the cells grow to logarithmic phase 4 cells/mL, seeded into 96-well cell culture plates, 100. Mu.L per well, 3 replicates per concentration gradient. The compound MDD67 of the invention is acted on cells by 6 concentration gradients of 0, 2.5, 5, 10, 20 and 40 mug/mL by using complete culture medium; the compounds MDD58 and MDD60 of the invention and the positive control drugs are prepared into 0, 1.25, 2.5, 5 by using complete culture medium6 concentration gradients of 10 and 20. Mu.g/mL were applied to the cells. 15 μ L of CCK8 per well after 24h, 48h and 72h of incubation, 37 ℃,5% CO 2 And culturing in an incubator for 3h in a dark place. The OD value of each well at the same time point at a wavelength of 492nm was measured using a microplate reader (Molecular Devices SpectraMax i 3), and the effect of cell proliferation was analyzed using the OD value thus measured.
As a result: the results of the experiment are shown in table 4.
TABLE 4 inhibitory Activity of the Compounds of the present invention against human tumor cell proliferation
Note: "-" indicates: the cell inhibition rate does not reach 50% in the time period.
And (4) conclusion: the compound has strong inhibition effect on the proliferation of 3 tumor cells such as human promyelocytic acute leukemia cell HL60, human lung cancer cell H1299, human mantle cell lymphoma cell Jeko-1 and the like. And the compound MDD58 has stronger inhibition effect on the proliferation of 3 tumor cells such as human promyelocytic acute leukemia cell HL60, human lung cancer cell H1299, human mantle cell lymphoma cell Jeko-1 and the like.
Based on the above description of the summary of the invention, a person skilled in the art can apply the invention in its entirety, and all changes that are the same principle or similar are to be considered as included in the scope of the invention.
Claims (10)
1. Thiazole carboxamide compounds shown in general formula (I) or pharmaceutically acceptable salts thereof,
in the general formula (I):
R 1 、R 3 、R 5 、R 9 and R 10 Each independently selected from:
(1) -H, -OH, -SH, amino, halogen, cyanoNitro, -COOH, -C 1～6 Hydrocarbyl, -NH-C 1～6 Hydrocarbyl, -N (C) 1～6 Alkyl radical) 2 、-O-C 1～6 Hydrocarbyl, -S-C 1～6 Hydrocarbyl, -C (O) -C 1～6 Hydrocarbyl, -C 1～6 alkyl-O-C 1～6 Hydrocarbyl radical, -C 1～5 alkyl-S-C 1～6 Hydrocarbyl radicals, -C (S) -C 1～6 Hydrocarbyl, -SO 2 -C 1～6 Hydrocarbyl, -C 1～6 hydrocarbyl-NH-C 1～6 Hydrocarbyl radical, -C 1～6 hydrocarbyl-N (C) 1～6 Alkyl radical) 2 、-C(O)-NH 2 、-C(O)-NH-C 1～6 Hydrocarbyl, -C (O) -O-C 1～6 Hydrocarbyl, -C (NH-C) 1～6 Alkyl radical) 2 、-NH-C(O)-C 1～6 Hydrocarbyl, -NH-SO 2 -C 1～6 Hydrocarbyl, -N (C) 1～6 Hydrocarbyl) -SO 2 -C 1～6 Hydrocarbyl, -SO 2 -NH 2 and-SO 2 -NH-C 1～6 A hydrocarbyl group; said-C 1～6 The hydrocarbyl group is unsubstituted or substituted with one or more of the following substituents: o, halogen, -OH, amino, -C 1～3 alkyl-OH, methanesulfonyl, and methoxycarbonyl;
(2) -6-to 10-membered aryl, -5-to 10-membered heterocyclyl, -5-to 10-membered heteroaryl, -C 1～6 Alkyl-6-to 10-membered aryl, -C 1～6 Alkyl-5-to 10-membered heterocyclyl, -C 1～6 Alkyl-5-to 10-membered heteroaryl, -O-6-to 10-membered aryl, -O-5-to 10-membered heterocyclyl, -O-5-to 10-membered heteroaryl, -S-6-to 10-membered aryl, -S-5-to 10-membered heterocyclyl, -S-5-to 10-membered heteroaryl, -NH-6-to 10-membered aryl, -NH-5-to 10-membered heterocyclyl, -NH-5-to 10-membered heteroaryl, -C (O) -6-to 10-membered aryl, -C (O) -5-to 10-membered heterocyclyl, -C (O) -5-to 10-membered heteroaryl, -O-C 1～6 Alkyl-6-to 10-membered aryl, -O-C 1～6 Alkyl-5-to 10-membered heterocyclyl, -O-C 1～6 Alkyl-5-to 10-membered heteroaryl, -C 1～6 alkyl-O-C 1～6 Alkyl-6-to 10-membered aryl, -C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heterocyclyl, -C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heteroaryl, -C 1～6 alkyl-NH-C (O) -6-to 10-membered aryl, -C 1～6 alkyl-NH-C (O) -5-to 10-membered heterocyclyl-C 1～6 alkyl-NH-C (O) -5-10 membered heteroaryl, -CH (OH) -5-10 membered heteroaryl, -C (CH) 2 ) -6-to 10-membered aryl, -N (C) 1～6 Alkyl) -6-to 10-membered aryl, -N (C) 1～6 Hydrocarbyl) -5-to 10-membered heterocyclyl, -N (C) 1～6 Alkyl) -5-to 10-membered heteroaryl, -C (NH) -6-to 10-membered aryl, -NH-C (O) -5-to 10-membered heterocyclyl, -NH-C (O) -5-to 10-membered heteroaryl, -C (NH) 3 + ) -6 to 10 membered aryl and-S (O) 2 -6-to 10-membered aryl;
(3)R 1 and R 3 Linked to form a ring fused to a benzene ring, the ring being: a 6-to 10-membered aromatic ring, a 5-to 10-membered heterocyclic ring or a 5-to 10-membered heteroaromatic ring;
in the above (2) and (3), the aryl group, the heterocyclic group, the heteroaryl group, the aromatic ring, the heterocyclic ring and the heteroaromatic ring are unsubstituted or substituted with one or more of the following substituents: o, N, -OH, halogen, amino, nitro, amino, -SH, carbomethoxy, -C 1～6 Alkyl radical, C 2～5 Alkynyl, -O-C 1～6 Alkyl, -C 1～6 Alkyl-amino or acetonitrile groups;
R 2 and R 7 Each independently selected from: -H, -C 1～6 Hydrocarbyl, -C 1～6 alkyl-OH, -C 1～6 alkyl-O-C 1～6 Hydrocarbyl, -C (O) -NH 2 -COOH, formate, pyridyl and 1, 3-benzoxadiazol-6-yl; or, R 2 Or R 7 And R 5 Or R 9 Formation of a connection to 2～5 Alkylene-;
R 4 selected from: -H, -C 1～6 Hydrocarbyl radical, -C 1～3 alkyl-C (O) -O-C 1～6 A hydrocarbon group and a-5-to 6-membered heterocyclic group; said-C 1～6 The hydrocarbyl group is unsubstituted or substituted with one or more of the following substituents: -COOH or-NH + (CH 3 ) 2 (ii) a The-5-to 6-membered heterocyclic group is unsubstituted or substituted with one or more of the following substituents: -C 1～3 An alkyl group;
R 6 and R 8 Each independently selected from: -H, -OH, -SH, amino, halogen, cyano, nitro, -COOH, -C 1～6 Hydrocarbyl, -NH-C 1～6 Hydrocarbyl, -O-C 1～6 Hydrocarbyl, -SO 2 -NH 2 、-C(O)-O-C 1～6 Hydrocarbyl, -O-C (O) -NH 2 、-NH-C(O)-O-C 1～6 Alkyl, -6-to 10-membered aryl, -5-to 10-membered heterocyclyl, -5-to 10-membered heteroaryl and-O-C 1～6 Alkyl-6 to 10 membered aryl.
2. The thiazole carboxamide compound represented by the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein in the general formula (I):
R 1 selected from:
(1) -H, -OH, -SH, amino, halogen, cyano, nitro, -COOH, -C 1～6 Hydrocarbyl, -NH-C 1～6 Hydrocarbyl, -N (C) 1～6 Alkyl radical) 2 、-O-C 1～6 Hydrocarbyl, -S-C 1～6 Hydrocarbyl radicals, -C (O) -C 1～6 Hydrocarbyl radical, -C 1～6 alkyl-O-C 1～6 Hydrocarbyl radical, -C 1～5 alkyl-S-C 1～6 Hydrocarbyl radicals, -C (S) -C 1～6 Hydrocarbyl, -SO 2 -C 1～6 Hydrocarbyl radical, -C 1～6 hydrocarbyl-NH-C 1～6 Hydrocarbyl radical, -C 1～6 hydrocarbyl-N (C) 1～6 Alkyl radical) 2 、-C(O)-NH 2 、-C(O)-NH-C 1～6 Hydrocarbyl, -C (O) -O-C 1～6 Hydrocarbyl, -C (NH-C) 1～6 Alkyl radical) 2 、-NH-C(O)-C 1～6 Hydrocarbyl, -NH-SO 2 -C 1～6 Hydrocarbyl, -N (C) 1～6 Hydrocarbyl) -SO 2 -C 1～6 Hydrocarbyl, -SO 2 -NH 2 and-SO 2 -NH-C 1～6 A hydrocarbyl group; said-C 1～6 The hydrocarbyl group is unsubstituted or substituted with one or more of the following substituents: o, halogen, -OH, amino, -C 1～3 alkyl-OH, methanesulfonyl, and methoxycarbonyl;
(2) -6-to 10-membered aryl, -5-to 10-membered heterocyclyl, -5-to 10-membered heteroaryl, -C 1～6 Alkyl-6-to 10-membered aryl, -C 1～6 Alkyl-5-to 10-membered heterocyclyl, -C 1～6 Alkyl-5-to 10-membered heteroaryl, -O-6-to 10-membered aryl, -O-5-to 10-membered heterocyclyl, -O-5-to 10-membered heteroaryl, -S-6-to 10-membered aryl, -S-5-to 10-membered heterocyclyl, -S-5-to 10-membered heteroaryl, -NH-6-to 10-membered aryl, -NH-5-10-membered heterocyclyl, -NH-5-10-membered heteroaryl, -C (O) -6-10-membered aryl, -C (O) -5-10-membered heterocyclyl, -C (O) -5-10-membered heteroaryl, -O-C 1～6 Alkyl-6-to 10-membered aryl, -O-C 1～6 Alkyl-5-to 10-membered heterocyclyl, -O-C 1～6 Alkyl-5-to 10-membered heteroaryl, -C 1～6 alkyl-O-C 1～6 Alkyl-6-to 10-membered aryl, -C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heterocyclyl, -C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heteroaryl, -C 1～6 alkyl-NH-C (O) -6-to 10-membered aryl, -C 1～6 alkyl-NH-C (O) -5-to 10-membered heterocyclyl-C 1～6 alkyl-NH-C (O) -5-to 10-membered heteroaryl, -CH (OH) -5-to 10-membered heteroaryl, -C (CH) 2 ) -6-to 10-membered aryl, -N (C) 1～6 Alkyl) -6-to 10-membered aryl, -N (C) 1～6 Hydrocarbyl) -5-to 10-membered heterocyclyl, -N (C) 1～6 Alkyl) -5-to 10-membered heteroaryl, -C (NH) -6-to 10-membered aryl, -NH-C (O) -5-to 10-membered heterocyclyl, -NH-C (O) -5-to 10-membered heteroaryl, -C (NH) 3 + ) -6 to 10 membered aryl and-S (O) 2 -6-to 10-membered aryl;
(3)R 1 and R 3 Linked to form a ring fused to a benzene ring, the ring being: a 6-to 10-membered aromatic ring, a 5-to 10-membered heterocyclic ring or a 5-to 10-membered heteroaromatic ring;
in the above (2) and (3), the aryl group, the heterocyclic group, the heteroaryl group, the aromatic ring, the heterocyclic ring and the heteroaromatic ring are unsubstituted or substituted with one or more of the following substituents: o, N, -OH, halogen, amino, nitro, amino, -SH, carbomethoxy, -C 1～6 Alkyl radical, C 2～5 Alkynyl, -O-C 1～6 Alkyl, -C 1～6 Alkyl-amino or acetonitrile groups;
R 3 and R 10 Each independently selected from: selected from: -H, -OH, amino, halogen, nitro, -O-CF 3 、-C 1～6 Hydrocarbyl, -NH-C 1～6 Hydrocarbyl, -N (C) 1～6 Alkyl radical) 2 、-O-C 1～6 Hydrocarbyl, -C (O) -NH 2 、-C(O)-NH-C 1～6 Hydrocarbyl, -NH-C (O) -C 1～6 Alkyl, -6-10 membered aryl, -5-10 membered heterocyclyl, -5-10 membered heteroaryl, -C (O) -one-substituted6-to 10-membered aryl, -C (O) -5-to 10-membered heterocyclyl, -C (O) -5-to 10-membered heteroaryl, -C 1～6 alkyl-O-C 1～6 Alkyl-6-to 10-membered aryl, -C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heterocyclic group and-C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heteroaryl; said-C 1～6 The hydrocarbyl group is unsubstituted or substituted with one or more of the following substituents: a halogen; the aryl, heterocyclyl, heteroaryl groups are unsubstituted or substituted with one or more of the following substituents: o, -C 1～3 Alkyl or-COOH;
R 5 and R 9 Each independently selected from: -H, -OH, halogen, amino, -CF 3 、-SH、-C 1～6 Hydrocarbyl, -O-C 1～6 Hydrocarbyl radical, -C 1～3 Alkyl-5-to 6-membered heterocyclic group and-5-to 6-membered heterocyclic group.
3. The thiazole carboxamide compound represented by the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein in the general formula (I):
R 1 selected from:
(1) -H, -OH, -SH, amino, halogen, cyano, nitro, -COOH, -C 1～6 Alkyl, -NH-C 1～6 Alkyl, -N (C) 1～6 Alkyl radical) 2 、-O-C 1～6 Alkyl, -S-C 1～6 Alkyl, -C (O) -C 1～6 Alkyl, -C 1～6 alkyl-O-C 1～6 Alkyl, -C 1～5 alkyl-S-C 1～6 Alkyl, -C (S) -C 1～6 Alkyl, -SO 2 -C 1～6 Alkyl, -C 1～6 alkyl-NH-C 1～6 Alkyl, -C 1～6 alkyl-N (C) 1～6 Alkyl radical) 2 、-C(O)-NH 2 、-C(O)-NH-C 1～6 Alkyl, -C (O) -O-C 1～6 Alkyl, -C (NH-C) 1～6 Alkyl radical) 2 、-NH-C(O)-C 1～6 Alkyl, -NH-SO 2 -C 1～6 Alkyl, -N (C) 1～6 Alkyl) -SO 2 -C 1～6 Alkyl, -SO 2 -NH 2 and-SO 2 -NH-C 1～6 An alkyl group; said-C 1～6 Alkyl is unsubstituted or substituted bySubstituted with one or more of the following substituents: o, halogen, -OH, amino, -C 1～3 alkyl-OH, methanesulfonyl, and methoxycarbonyl;
(2) -6-to 10-membered aryl, -5-to 10-membered heterocyclyl, -5-to 10-membered heteroaryl, -C 1～6 Alkyl-6-to 10-membered aryl, -C 1～6 Alkyl-5-to 10-membered heterocyclyl, -C 1～6 Alkyl-5-to 10-membered heteroaryl, -O-6-to 10-membered aryl, -O-5-to 10-membered heterocyclyl, -O-5-to 10-membered heteroaryl, -S-6-to 10-membered aryl, -S-5-to 10-membered heterocyclyl, -S-5-to 10-membered heteroaryl, -NH-6-to 10-membered aryl, -NH-5-to 10-membered heterocyclyl, -NH-5-to 10-membered heteroaryl, -C (O) -6-to 10-membered aryl, -C (O) -5-to 10-membered heterocyclyl, -C (O) -5-to 10-membered heteroaryl, -O-C 1～6 Alkyl-6-to 10-membered aryl, -O-C 1～6 Alkyl-5-to 10-membered heterocyclyl, -O-C 1～6 Alkyl-5-to 10-membered heteroaryl, -C 1～6 alkyl-O-C 1～6 Alkyl-6-to 10-membered aryl, -C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heterocyclyl, -C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heteroaryl, -C 1～6 alkyl-NH-C (O) -6-to 10-membered aryl, -C 1～6 alkyl-NH-C (O) -5-to 10-membered heterocyclyl-C 1～6 alkyl-NH-C (O) -5-10 membered heteroaryl, -CH (OH) -5-10 membered heteroaryl, -C (CH) 2 ) -6-to 10-membered aryl, -N (C) 1～6 Alkyl) -6-to 10-membered aryl, -N (C) 1～6 Alkyl) -5-to 10-membered heterocyclic group, -N (C) 1～6 Alkyl) -5-to 10-membered heteroaryl, -C (NH) -6-to 10-membered aryl, -NH-C (O) -5-to 10-membered heterocyclyl, -NH-C (O) -5-to 10-membered heteroaryl, -C (NH) 3 + ) -6 to 10 membered aryl and-S (O) 2 -6-to 10-membered aryl;
(3)R 1 and R 3 Linked to form a ring fused to a benzene ring, the ring being: a 6-to 8-membered aromatic ring, a 5-to 8-membered heterocycle or a 5-to 8-membered heteroaromatic ring;
in the above (2) and (3), the aryl group, the heterocyclic group, the heteroaryl group, the aromatic ring, the heterocyclic ring and the heteroaromatic ring are unsubstituted or substituted with one or more of the following substituents: o, N, -OH, halogen, amino, nitro, amino, -SH, carbomethoxy, -C 1～6 Alkyl radical, C 2～5 Alkynyl, -O-C 1～6 Alkyl, -C 1～6 Alkyl-amino or acetonitrile groups;
R 3 and R 10 Each independently selected from: -H, -OH, amino, halogen, nitro, -O-CF 3 、-C 1～6 Alkyl, -NH-C 1～6 Alkyl, -N (C) 1～6 Alkyl radical) 2 、-O-C 1～6 Alkyl, -C (O) -NH 2 、-C(O)-NH-C 1～6 Alkyl, -NH-C (O) -C 1～6 Alkyl, -6-to 10-membered aryl, -5-to 10-membered heterocyclyl, -5-to 10-membered heteroaryl, -C (O) -6-to 10-membered aryl, -C (O) -5-to 10-membered heterocyclyl, -C (O) -5-to 10-membered heteroaryl, -C (O) -6-to 10-membered heteroaryl 1～6 alkyl-O-C 1～6 Alkyl-6-to 10-membered aryl, -C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heterocyclic group and-C 1～6 alkyl-O-C 1～6 Alkyl-5-to 10-membered heteroaryl; said-C 1～6 Alkyl is unsubstituted or substituted with one or more of the following substituents: halogen; the aryl, heterocyclic and heteroaryl groups are unsubstituted or substituted by one or more of the following substituents: o, -C 1～3 Alkyl or-COOH;
R 5 and R 9 Each independently selected from: -H, -OH, halogen, amino, -CF 3 、-SH、-C 1～6 Alkyl, -O-C 1～6 Alkyl, -C 1～3 Alkyl-5-to 6-membered heterocyclic group and-5-to 6-membered heterocyclic group;
R 2 and R 7 Each independently selected from: -H, -C 1～6 Alkyl, -C 1～6 alkyl-OH, -C 1～6 alkyl-O-C 1～6 Alkyl, -C (O) -NH 2 -COOH, formyl, pyridyl and 1, 3-benzoxadiazol-6-yl; or, R 2 Or R 7 And R 5 Or R 9 Formation of a connection to 2～5 Alkylene-; preferably, R 2 And R 7 Each independently selected from: -H, -C 1～6 Alkyl, -C 1～6 alkyl-OH and-C 1～6 alkyl-O-C 1～6 An alkyl group; or, R 2 Or R 7 And R 5 Or R 9 Formation of a connection to 2～5 Alkylene-;
R 4 selected from: -H, -C 1～6 Alkyl, -C 1～3 alkyl-C (O) -O-C 1～6 Alkyl and-5-to 6-membered heterocyclic groups; said-C 1～6 Alkyl is unsubstituted or substituted with one or more of the following substituents: -COOH or-NH + (CH 3 ) 2 (ii) a The-5-to 6-membered heterocyclic group is unsubstituted or substituted with one or more of the following substituents: -C 1～3 An alkyl group; preferably, R 4 Selected from: -H, -C 1～6 Alkyl and-6 membered heterocyclyl;
R 6 and R 8 Each independently selected from: -H, -OH, -SH, amino, halogen, cyano, nitro, -COOH, -C 1～6 Alkyl, -NH-C 1～6 Alkyl, -O-C 1～6 Alkyl, -SO 2 -NH 2 、-C(O)-O-C 1～6 Alkyl, -O-C (O) -NH 2 、-NH-C(O)-O-C 1～6 Alkyl, -6-to 10-membered aryl, -5-to 10-membered heterocyclyl, -5-to 10-membered heteroaryl and-O-C 1～6 Alkyl-6 to 10 membered aryl; preferably, R 6 And R 8 Each independently selected from: -H, -OH, -SH, amino, halogen, -C 1～6 Alkyl, -NH-C 1～3 Alkyl, -O-C 1～6 Alkyl and-NH-C (O) -O-C 1～3 An alkyl group.
4. The thiazole carboxamide compound represented by the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein in the general formula (I):
R 1 selected from:
(1)-H、-NH-C 1～3 alkyl, -N (C) 1～3 Alkyl radical) 2 、-O-C 1～3 Alkyl, -C (O) -C 1～3 Alkyl, -C 1～3 alkyl-O-C 1～3 Alkyl, -C 1～3 alkyl-NH-C 1～3 Alkyl, -C 1～3 alkyl-N (C) 1～3 Alkyl radical) 2 、-C(O)-NH-C 1～3 Alkyl, -C (O) -O-C 1～3 Alkyl, -NH-C (O) -C 1～3 Alkyl and-NH-SO 2 -C 1～3 An alkyl group; said C is 1～3 Alkyl is unsubstituted or substituted with one or more of the following substituents: halogen;
(2) -phenyl, -5 to 6A heterocyclic radical, -a 5-to 6-membered heteroaryl group, -C 1～3 Alkyl-phenyl, -C 1～3 Alkyl-5-to 6-membered heterocyclyl, -C 1～3 Alkyl-5-6 membered heteroaryl, -O-phenyl, -O-5-6 membered heterocyclyl, -O-5-6 membered heteroaryl, -C 1～3 alkyl-O-C 1～3 Alkyl-5-to 6-membered heteroaryl and-NH-C (O) -5-to 6-membered heteroaryl; the-phenyl, -5-to 6-membered heterocyclyl or-5-to 6-membered heteroaryl is unsubstituted or substituted with one or more of the following substituents: o, -OH, halogen, nitro, -C 1～3 Alkyl or-O-C 1～3 An alkyl group;
(3)R 1 and R 3 Linked to form a ring fused to a benzene ring, the ring being: a benzene ring, a 5-to 6-membered heterocyclic ring or a 5-to 6-membered heteroaromatic ring;
in the above (2) and (3), the phenyl group, the heterocyclic group, the heteroaryl group, the benzene ring, the heterocyclic ring and the heteroaromatic ring are unsubstituted or substituted with one or more of the following substituents: o, halogen, amino, nitro, -C 1～3 Alkyl or-O-C 1～3 An alkyl group;
R 2 and R 7 Each independently selected from: -H, -C 1～3 Alkyl and-C 1～3 alkyl-O-C 1～3 An alkyl group; preferably, R 2 Selected from: -H, -C 1～3 Alkyl and-C 1～3 alkyl-O-C 1～3 Alkyl radical, R 7 Selected from: -H; more preferably, R 2 And R 7 Are all selected from: -H;
R 3 selected from: -H, amino, halogen, -O-CF 3 、-C 1～3 Alkyl, -O-C 1～3 Alkyl, -NH-C (O) -C 1～3 Alkyl, phenyl, -5-to 6-membered heterocyclyl, -5-to 6-membered heteroaryl, -C (O) -phenyl, -C (O) -5-to 6-membered heterocyclyl, -C (O) -5-to 6-membered heteroaryl and-C 1～3 alkyl-O-C 1～3 Alkyl-5-6 membered heteroaryl; the phenyl, heterocyclyl and heteroaryl groups are unsubstituted or substituted with one or more of the following substituents: -C 1～3 An alkyl group;
R 4 selected from the group consisting of: -H and-C 1～3 An alkyl group; preferably selected from: -H;
R 5 and R 9 Each independently selected from: -H, -OH, -F, -SH and-O-C 1～3 An alkyl group; preferably, R 5 And R 9 Are all selected from: -H;
R 6 and R 8 Each independently selected from: -H, amino, halogen, -C 1～3 Alkyl, -O-C 1～3 Alkyl and-NH-C 1～3 An alkyl group;
R 10 selected from: -H and-F.
5. The thiazole carboxamide compound represented by the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein in the general formula (I):
when R is 1 When selected from substituents other than H, R 3 、R 5 、R 9 And R 10 Are all H; or, when R 3 When selected from substituents other than H, R 1 、R 5 、R 9 And R 10 Are all H; preferably, R 1 Selected from substituents other than H, R 3 、R 5 、R 9 And R 10 Are all H.
6. The thiazole carboxamide compound represented by general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein the thiazole carboxamide compound represented by general formula (I) or the pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:
7. a process for the preparation of thiazolecarboxamide compounds represented by the general formula (I) or pharmaceutically acceptable salts thereof according to claim 1, comprising the steps of:
dissolving the compound B in DMF, adding HBTU and N-methylmorpholine, stirring, adding the compound A, stirring, adding the reaction system into water, extracting with ethyl acetate, and performing column chromatography to obtain a compound (I);
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 And R 10 Is as defined in claim 1.
8. Use of thiazole carboxamide compounds of the general formula (I) according to claim 1 or of pharmaceutically acceptable salts thereof for the preparation of mitochondrial complex I inhibitors.
9. Use of thiazole carboxamide compounds of the general formula (I) according to claim 1 or of pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of tumors; preferably, the tumor comprises: hematologic and solid tumors; more preferably, the tumor comprises: acute promyelocytic leukemia, acute myeloid leukemia, mantle cell lymphoma, and lung cancer.
10. A pharmaceutical composition, which comprises the thiazole carboxamide compound shown in the general formula (I) in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary material.
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| WO2005070889A1 (en) * | 2004-01-23 | 2005-08-04 | E.I. Dupont De Nemours And Company | Herbicidal amides |
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