Application of thiazole carboxamide compound

Abstract

The invention belongs to the technical field of medicines, and relates to application of thiazole carboxamide compounds. The thiazole carboxamide compound is shown as a general formula (I), is a mitochondrial complex I inhibitor, and can be used for treating tumors. # imgabs0 #

Description

[0001] This application is a divisional application of the application with application number 2022110040813 filed on August 22, 2022, and invention name “Thiazolecarboxamide compounds, preparation methods and uses thereof”. Technical Field

[0002] The invention belongs to the technical field of medicines and relates to the use of thiazole carboxamide compounds. Background Art

[0003] In recent years, the incidence of cancer has increased year by year, and it has become the world's leading cause of death, seriously threatening human health. In 2018, the number of new cancer patients in the world reached 18.1 million, and the number of deaths was 9.6 million. my country is a country with a high incidence of cancer. In 2018, the number of new cases in my country was 3.804 million, accounting for more than 20% of the number of new cancer cases in the world. Among them, the incidence of malignant tumors was 278.07 / 100,000, and the mortality rate was 167.89 / 100,000. Hematological tumors are a general term for a large class of malignant tumors originating from the hematopoietic system. The main categories include leukemia, lymphoma and myeloma. According to statistics, among the ten most common malignant tumors in my country, acute leukemia and lymphoma in hematological tumors are both in the top ten, and the overall incidence has been on the rise in recent years, and there is a tendency to be younger. The demand for anticancer drugs in the global market and the Chinese market is very strong.

[0004] Mitochondria are widely present in eukaryotic cells and play an important role in the energy supply, anabolism, cell survival and migration of cancer cells. In view of the important role of mitochondria in the occurrence and development of tumors, new strategies for the development of mitochondrial targeted anti-tumor drugs based on specific targets such as mitochondrial tumor metabolites, biosynthesis, and mitochondrial function have been proposed. In mitochondria, the oxidative phosphorylation pathway couples important mitochondrial processes such as the tricarboxylic acid cycle and lipid metabolism, and is the most core pathway of mitochondria. At present, a variety of small molecule inhibitors targeting mitochondrial oxidative phosphorylation have been proven to be effective against tumors in tumor cell lines, various tumor models and patient big data, and some have entered clinical research. This type of small molecule inhibitor is mainly composed of compounds targeting the mitochondrial electron transport chain complex (referred to as mitochondrial complex). Among the five complexes that constitute the mitochondrial electron transport chain, mitochondrial complex I is the starting complex for electron transfer in the respiratory chain, and most of the ATP in mitochondria is generated by electron transfer through mitochondrial complex I. The development of small molecule inhibitors targeting mitochondrial complex I can effectively inhibit mitochondrial oxidative phosphorylation and provide a new strategy for mitochondrial targeted tumor treatment.

[0005] The mitochondrial oxidative phosphorylation pathway is an important mechanism of drug resistance in hematological tumors. As the first small molecule inhibitor targeting BTK, ibrutinib has a significant effect on hematological cancers. Since its launch in 2013, the drug has been approved for the treatment of a variety of different hematological cancers, such as mantle cell lymphoma and chronic lymphocytic leukemia. However, with the use of ibrutinib, some patients have developed resistance to it, and the current standard treatment regimen cannot meet the treatment needs of such patients. Taking mantle cell lymphoma as an example, the one-year survival rate of ibrutinib-resistant patients is only 22%. Further studies have found that mantle cell lymphoma cells resistant to ibrutinib will bypass BTK and tend to mitochondrial oxidative phosphorylation and glutamine metabolism, thereby escaping ibrutinib treatment. This phenomenon makes inhibiting mitochondrial oxidative phosphorylation and / or glutamine metabolism a new idea for treating resistant hematological tumors. IACS-010759 is an oxidative phosphorylation inhibitor targeting mitochondrial complex I that has entered the clinical stage. It has a significant inhibitory effect on blood tumor cells such as mantle cell lymphoma that are resistant to ibrutinib in vitro, and also has a significant inhibitory effect on mouse disease models constructed using these tumor cells. Small molecule inhibitors targeting mitochondrial complex I will be the research and development direction of the next generation of anti-blood tumor drugs. Summary of the invention

[0006] The emergence of small molecule inhibitors targeting mitochondrial complex I has provided a new direction for the treatment of hematological malignancies and drug-resistant hematological malignancies and the development of anti-tumor drugs.

[0007] The present invention proposes a class of mitochondrial complex I inhibitors with a novel skeleton, which have excellent activity in inhibiting the activity of mitochondrial complex I, inhibiting the proliferation of drug-resistant and non-resistant blood tumors, and inhibiting the proliferation of solid tumors, and can be used as potential broad-spectrum anti-tumor drugs.

[0008] Therefore, an object of the present invention is to provide a thiazole carboxamide compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[0009] Another object of the present invention is to provide a method for preparing the thiazole carboxamide compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[0010] Another object of the present invention is to provide the use of the thiazole carboxamide compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[0011] The present invention provides a thiazole carboxamide compound or a pharmaceutically acceptable salt thereof represented by the following general formula (I):

[0012]

[0013] In the general formula (I):

[0014] R 1 , R 3 , R 5 , R 9 and R 10 Each independently selected from:

[0015] (1) -H, -OH, -SH, amino, halogen, cyano, nitro, -COOH, -C 1～6 Hydrocarbon, -NH-C 1～6 Hydrocarbon, -N(C 1～6 Hydrocarbon)2, -OC 1～6 Hydrocarbon, -SC 1～6 Hydrocarbon, -C(O)-C 1～6 Hydrocarbon, -C 1～6 Alkyl-OC 1～6 Hydrocarbon, -C 1～5 Alkyl-SC 1～6 Hydrocarbon, -C(S)-C 1～6 Hydrocarbon, -SO2-C 1～6 Hydrocarbon, -C 1～6 Hydrocarbyl-NH-C 1～6 Hydrocarbon, -C 1～6 Hydrocarbyl-N(C 1～6 Hydrocarbon)2, -C(O)-NH2, -C(O)-NH-C 1～6 Hydrocarbon, -C(O)-OC 1～6 Hydrocarbon, -C(NH-C 1～6 Hydrocarbon)2, -NH-C(O)-C 1～6 Hydrocarbon, -NH-SO2-C 1～6 Hydrocarbon, -N(C 1～6 Hydrocarbon)-SO2-C 1～6 Hydrocarbon, -SO2-NH2 and -SO2-NH-C 1～6 Hydrocarbyl; said -C 1～6 The hydrocarbon group is unsubstituted or substituted with one or more of the following substituents: O, halogen, -OH, amino, -C 1～3 Alkyl-OH, methylsulfonyl, and methyl formate;

[0016] (2) -6- to 10-membered aryl, -5- to 10-membered heterocyclic group, -5- to 10-membered heteroaryl, -C 1～6 Alkyl-6- to 10-membered aryl, -C 1～6 Alkyl-5- to 10-membered heterocyclic group, -C 1～6alkyl-5- to 10-membered heteroaryl, -O-6- to 10-membered aryl, -O-5- to 10-membered heterocyclic group, -O-5- to 10-membered heteroaryl, -S-6- to 10-membered aryl, -S-5- to 10-membered heterocyclic group, -S-5- to 10-membered heteroaryl, -NH-6- to 10-membered aryl, -NH-5- to 10-membered heterocyclic group, -NH-5- to 10-membered heteroaryl, -C(O)-6- to 10-membered aryl, -C(O)-5- to 10-membered heterocyclic group, -C(O)-5- to 10-membered heteroaryl, -OC 1～6 Alkyl-6- to 10-membered aryl, -OC 1～6 Alkyl-5- to 10-membered heterocyclic group, -OC 1～6 Alkyl-5- to 10-membered heteroaryl, -C 1～6 Alkyl-OC 1～6 Alkyl-6- to 10-membered aryl, -C 1～6 Alkyl-OC 1～6 Alkyl-5- to 10-membered heterocyclic group, -C 1～6 Alkyl-OC 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 heterocyclic group, -C 1～6 Alkyl-NH-C(O)-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -C(CH2)-6- to 10-membered aryl, -N(C 1～6 Hydrocarbon)-6- to 10-membered aryl, -N(C 1～6 Hydrocarbon)-5- to 10-membered heterocyclic group, -N(C 1～6 -C(NH)-6- to 10-membered aryl, -NH-C(O)-6- to 10-membered aryl, -NH-C(O)-5- to 10-membered heterocyclic group, -NH-C(O)-5- to 10-membered heteroaryl, -C(NH3 + )-6- to 10-membered aryl and -S(O)2-6- to 10-membered aryl;

[0017] (3)R 1 With R 3 Connected to form a ring fused with a benzene ring, the ring is: a 6-10 membered aromatic ring, a 5-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring;

[0018] In the above (2) and (3), the aryl, heterocyclic, heteroaryl, aromatic ring, heterocyclic ring and heteroaromatic ring are unsubstituted or substituted with one or more of the following substituents: O, N, -OH, halogen, amino, nitro, amine, -SH, methyl formate, methyl nitro, -C 1～6 Alkyl, C 2～5 Alkynyl, -OC 1～6 Alkyl, -C1～6 Alkyl-amino or acetonitrile.

[0019] R 2 and R 7 Each independently selected from: -H, -C 1～6 Hydrocarbon, -C 1～6 Alkyl-OH, -C 1～6 Alkyl-OC 1～6 Hydrocarbyl, -C(O)-NH2, -COOH, formic acid, pyridyl (including pyridin-2-yl, pyridin-4-yl, pyridin-3-yl) and 1,3-benzodiazole-6-yl; or, R 2 or R 7 With R 5 or R 9 Connection Formation-C 2～5 Alkylene-.

[0020] R 4 Selected from: -H, -C 1～6 Hydrocarbon, -C 1～3 Alkyl-C(O)-OC 1～6 A hydrocarbon group and a 5- to 6-membered heterocyclic group; the -C 1～6 The hydrocarbon group is unsubstituted or substituted with one or more of the following substituents: -COOH or -NH + (CH3)2; the -5- to 6-membered heterocyclic group is unsubstituted or substituted by one or more of the following substituents: -C 1～3 alkyl.

[0021] R 6 and R 8 Each is independently selected from: -H, -OH, -SH, amino, halogen, cyano, nitro, -COOH, -C 1～6 Hydrocarbon, -NH-C 1～6 Hydrocarbon, -OC 1～6 Hydrocarbon, -SO2-NH2, -C(O)-OC 1～6 Hydrocarbon, -OC(O)-NH2, -NH-C(O)-OC 1～6 Hydrocarbyl, -6- to 10-membered aryl, -5- to 10-membered heterocyclic group, -5- to 10-membered heteroaryl, and -OC 1～6 Alkyl-6- to 10-membered aryl.

[0022] The C 1～6 The hydrocarbon group is selected from: C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl and C 3～6 Cycloalkyl.

[0023] The "halogen" refers to 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 or 3.

[0024] The "alkyl group" refers to a straight-chain or branched alkyl group derived from an alkane by removing a hydrogen atom, or an alkyl group substituted with a cycloalkyl group.

[0025] The "alkenyl group" refers to a straight chain, branched chain or cyclic alkenyl group containing a carbon-carbon double bond.

[0026] The "alkynyl group" refers to a straight chain, branched chain or cyclic alkynyl group containing a carbon-carbon triple bond.

[0027] The "cycloalkyl" is a completely hydrogenated non-aromatic ring consisting of a mono-, bi- or tri-ring.

[0028] The "aryl" refers to a cyclic aromatic group whose ring atoms are carbon atoms, including monocyclic aromatic groups and condensed aromatic groups. Monocyclic aromatic groups refer to all unsaturated aromatic groups, and condensed aromatic groups refer to cyclic groups of aromatic rings formed by two or more cyclic structures sharing two adjacent carbon atoms, with at least one ring being all unsaturated.

[0029] The "heterocyclic group" or "heterocycle" refers to a saturated or unsaturated non-aromatic group or ring containing 1, 2, 3 or 4 heteroatoms selected from B, N, S and O, and consisting of 1 to 3 rings.

[0030] Preferably, when the "heterocyclic group" or "heterocycle" has 5 to 8 members or 5 to 6 members, it preferably contains 1 to 2 heteroatoms selected from N and O.

[0031] The "heteroaryl" or "heteroaromatic ring" refers to an aromatic ring structure, including monocyclic heteroaryl and condensed 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.

[0032] Preferably, when the “heteroaryl” or “heteroaromatic ring” has 5 to 8 members or 5 to 6 members, it preferably contains 1 to 2 heteroatoms selected from N and O; more preferably, it contains 1 to 2 heteroatoms selected from N.

[0033] Preferably: R 1 Selected from:

[0034] (1) -H, -OH, -SH, amino, halogen, cyano, nitro, -COOH, -C 1～6 Alkyl, -NH-C 1～6 Alkyl, -N(C 1～6 Alkyl)2, -OC 1～6 Alkyl, -SC 1～6 Alkyl, -C(O)-C1～6 Alkyl, -C 1～6 Alkyl-OC 1～6 Alkyl, -C 1～5 Alkyl-SC 1～6 Alkyl, -C(S)-C 1～6 Alkyl, -SO2-C 1～6 Alkyl, -C 1～6 Alkyl-NH-C 1～6 Alkyl, -C 1～6 Alkyl-N(C 1～6 Alkyl)2, -C(O)-NH2, -C(O)-NH-C 1～6 Alkyl, -C(O)-OC 1～6 Alkyl, -C(NH-C 1～6 Alkyl)2, -NH-C(O)-C 1～6 Alkyl, -NH-SO2-C 1～6 Alkyl, -N(C 1～6 Alkyl)-SO2-C 1～6 Alkyl, -SO2-NH2 and -SO2-NH-C 1～6 Alkyl; the -C 1～6 The alkyl group is unsubstituted or substituted with one or more of the following substituents: O, halogen, -OH, amino, -C 1～3 Alkyl-OH, methylsulfonyl, and methyl formate;

[0035] (2) -6- to 10-membered aryl, -5- to 10-membered heterocyclic group, -5- to 10-membered heteroaryl, -C 1～6 Alkyl-6- to 10-membered aryl, -C 1～6 Alkyl-5- to 10-membered heterocyclic group, -C 1～6 alkyl-5- to 10-membered heteroaryl, -O-6- to 10-membered aryl, -O-5- to 10-membered heterocyclic group, -O-5- to 10-membered heteroaryl, -S-6- to 10-membered aryl, -S-5- to 10-membered heterocyclic group, -S-5- to 10-membered heteroaryl, -NH-6- to 10-membered aryl, -NH-5- to 10-membered heterocyclic group, -NH-5- to 10-membered heteroaryl, -C(O)-6- to 10-membered aryl, -C(O)-5- to 10-membered heterocyclic group, -C(O)-5- to 10-membered heteroaryl, -OC 1～6 Alkyl-6- to 10-membered aryl, -OC 1～6 Alkyl-5- to 10-membered heterocyclic group, -OC 1～6 Alkyl-5- to 10-membered heteroaryl, -C 1～6 Alkyl-OC 1～6 Alkyl-6- to 10-membered aryl, -C 1～6 Alkyl-OC 1～6 Alkyl-5- to 10-membered heterocyclic group, -C 1～6 Alkyl-OC1～6 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 heterocyclic group, -C 1～6 Alkyl-NH-C(O)-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -C(CH2)-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)-6- to 10-membered aryl, -NH-C(O)-5- to 10-membered heterocyclic group, -NH-C(O)-5- to 10-membered heteroaryl, -C(NH3 + )-6- to 10-membered aryl and -S(O)2-6- to 10-membered aryl;

[0036] (3)R 1 With R 3 Connected to form a ring fused with a benzene ring, the ring is: a 6- to 8-membered aromatic ring, a 5- to 8-membered heterocyclic ring, or a 5- to 8-membered heteroaromatic ring;

[0037] In the above (2) and (3), the aryl, heterocyclic, heteroaryl, aromatic ring, heterocyclic ring and heteroaromatic ring are unsubstituted or substituted with one or more of the following substituents: O, N, -OH, halogen, amino, nitro, amine, -SH, methyl formate, methyl nitro, -C 1～6 Alkyl, C 2～5 Alkynyl, -OC 1～6 Alkyl, -C 1～6 Alkyl-amino or acetonitrile.

[0038] More preferably, R 1 Selected from:

[0039] (1) -H, -NH-C 1～3 Alkyl, -N(C 1～3 Alkyl)2, -OC 1～3 Alkyl, -C(O)-C 1～3 Alkyl, -C 1～3 Alkyl-OC 1～3 Alkyl, -C 1～3 Alkyl-NH-C 1～3 Alkyl, -C 1～3 Alkyl-N(C 1～3 Alkyl)2, -C(O)-NH-C 1～3 Alkyl, -C(O)-OC 1～3 Alkyl, -NH-C(O)-C1～3 Alkyl and -NH-SO2-C 1～3 Alkyl; the C 1～3 Alkyl is unsubstituted or substituted with one or more of the following substituents: halogen (preferably F);

[0040] (2) -phenyl, -5- to 6-membered heterocyclic group, -5- to 6-membered heteroaryl, -C 1～3 Alkyl-phenyl, -C 1～3 Alkyl-5- to 6-membered heterocyclic group, -C 1～3 alkyl-5- to 6-membered heteroaryl, -O-phenyl, -O-5- to 6-membered heterocyclic group, -O-5- to 6-membered heteroaryl, -C 1～3 Alkyl-OC 1～3 Alkyl-5- to 6-membered heteroaryl and -NH-C(O)-5- to 6-membered heteroaryl; the -phenyl, -5- to 6-membered heterocyclic 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 -OC 1～3 alkyl;

[0041] (3)R 1 With R 3 Connected to form a ring fused with a benzene ring, the ring is: a benzene ring, a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaromatic ring;

[0042] In the above (2) and (3), the phenyl, heterocyclic group, heteroaryl group, benzene ring, heterocyclic ring and heteroaryl ring are unsubstituted or substituted with one or more of the following substituents: O, halogen, amino, nitro, -C 1～3 Alkyl or -OC 1～3 Preferably, the heterocyclic group contains 1 to 2 heteroatoms selected from N and O; and the heteroaryl group contains 1 to 2 heteroatoms selected from N and O.

[0043] Preferably, R 3 and R 10 Each independently selected from: -H, -OH, amino, halogen, nitro, -O-CF3, -C 1～6 Hydrocarbon, -NH-C 1～6 Hydrocarbon, -N(C 1～6 Hydrocarbon)2, -OC 1～6 Hydrocarbon, -C(O)-NH2, -C(O)-NH-C 1～6 Hydrocarbon, -NH-C(O)-C 1～6 hydrocarbon group, -6- to 10-membered aryl group, -5- to 10-membered heterocyclic group, -5- to 10-membered heteroaryl group, -C(O)-6- to 10-membered aryl group, -C(O)-5- to 10-membered heterocyclic group, -C(O)-5- to 10-membered heteroaryl group, 1～6 Alkyl-OC1～6 Alkyl-6- to 10-membered aryl, -C 1～6 Alkyl-OC 1～6 Alkyl-5- to 10-membered heterocyclic group and -C 1～6 Alkyl-OC 1～6 Alkyl-5- to 10-membered heteroaryl; the -C 1～6 The hydrocarbon group is unsubstituted or substituted by one or more of the following substituents: halogen; the aryl, heterocyclic group, heteroaryl group is unsubstituted or substituted by one or more of the following substituents: O, -C 1～3 Alkyl or -COOH.

[0044] More preferably, R 3 and R 10 Each is independently selected from: -H, -OH, amino, halogen, nitro, -O-CF3, -C 1～6 Alkyl, -NH-C 1～6 Alkyl, -N(C 1～6 Alkyl)2, -OC 1～6 Alkyl, -C(O)-NH2, -C(O)-NH-C 1～6 Alkyl, -NH-C(O)-C 1～6 alkyl, -6- to 10-membered aryl, -5- to 10-membered heterocyclic group, -5- to 10-membered heteroaryl, -C(O)-6- to 10-membered aryl, -C(O)-5- to 10-membered heterocyclic group, -C(O)-5- to 10-membered heteroaryl, -C 1～6 Alkyl-OC 1～6 Alkyl-6- to 10-membered aryl, -C 1～6 Alkyl-OC 1～6 Alkyl-5- to 10-membered heterocyclic group and -C 1～6 Alkyl-OC 1～6 Alkyl-5- to 10-membered heteroaryl; the -C 1～6 The alkyl group is unsubstituted or substituted by one or more of the following substituents: halogen; the aryl, heterocyclic group, heteroaryl group is unsubstituted or substituted by one or more of the following substituents: O, -C 1～3 Alkyl or -COOH.

[0045] More preferably, R 3 Selected from: -H, amino, halogen (preferably F), -O-CF3, -C 1～3 Alkyl, -OC 1～3 Alkyl, -NH-C(O)-C 1～3 alkyl, phenyl, -5- to 6-membered heterocyclic group, -5- to 6-membered heteroaryl, -C(O)-phenyl, -C(O)-5- to 6-membered heterocyclic group, -C(O)-5- to 6-membered heteroaryl, and -C 1～3 Alkyl-OC 1～3Alkyl-5- to 6-membered heteroaryl; the phenyl, heterocyclic group, heteroaryl group is unsubstituted or substituted by one or more of the following substituents: -C 1～3 Preferably, the heterocyclic group contains 1 to 2 heteroatoms selected from N and O; and the heteroaryl group contains 1 to 2 heteroatoms selected from N and O.

[0046] More preferably, R 10 Selected from: -H and -F.

[0047] Preferably, R 5 and R 9 Each is independently selected from: -H, -OH, halogen, amino, -CF3, -SH, -C 1～6 Hydrocarbon, -OC 1～6 Hydrocarbon, -C 1～3 Alkyl-5- to 6-membered heterocyclic group and -5- to 6-membered heterocyclic group.

[0048] More preferably, R 5 and R 9 Each is independently selected from: -H, -OH, halogen, amino, -CF3, -SH, -C 1～6 Alkyl, -OC 1～6 Alkyl, -C 1～3 Alkyl-5- to 6-membered heterocyclic group and -5- to 6-membered heterocyclic group.

[0049] More preferably, R 5 and R 9 Each independently selected from: -H, -OH, -F, -SH and -OC 1～3 alkyl.

[0050] More preferably, R 5 and R 9 All selected from: -H.

[0051] Preferably: R 2 and R 7 Each independently selected from: -H, -C 1～6 Alkyl, -C 1～6 Alkyl-OH, -C 1～6 Alkyl-OC 1～6 Alkyl, -C(O)-NH2, -COOH, formate, pyridyl, and 1,3-benzodiazol-6-yl; or, R 2 or R 7 With R 5 or R 9 Connection Formation-C 2～5 Alkylene-.

[0052] More preferably, R 2 and R 7Each independently selected from: -H, -C 1～6 Alkyl, -C 1～6 Alkyl-OH and -C 1～6 Alkyl-OC 1～6 Alkyl; or, R 2 or R 7 With R 5 or R 9 Connection Formation-C 2～5 Alkylene-.

[0053] More preferably, R 2 and R 7 Each independently selected from: -H, -C 1～3 Alkyl and -C 1～3 Alkyl-OC 1～3 alkyl.

[0054] More preferably, R 2 Selected from: -H, -C 1～3 Alkyl and -C 1～3 Alkyl-OC 1～3 Alkyl, R 7 Selected from: -H.

[0055] More preferably, R 2 and R 7 All selected from: -H.

[0056] Preferably, R 4 Selected from: -H, -C 1～6 Alkyl, -C 1～3 Alkyl-C(O)-OC 1～6 Alkyl and -5 to 6 membered heterocyclic group; the -C 1～6 Alkyl is unsubstituted or substituted with one or more of the following substituents: -COOH or -NH + (CH3)2; the -5- to 6-membered heterocyclic group is unsubstituted or substituted by one or more of the following substituents: -C 1～3 alkyl.

[0057] More preferably, R 4 Selected from: -H, -C 1～6 Alkyl and -6-membered heterocyclic group.

[0058] More preferably, R 4 Selected from: -H and -C 1～3 alkyl.

[0059] Further preferably selected from: -H.

[0060] Preferably, R 6 and R 8Each is independently selected from: -H, -OH, -SH, amino, halogen, cyano, nitro, -COOH, -C 1～6 Alkyl, -NH-C 1～6 Alkyl, -OC 1～6 Alkyl, -SO2-NH2, -C(O)-OC 1～6 Alkyl, -OC(O)-NH2, -NH-C(O)-OC 1～6 alkyl, -6- to 10-membered aryl, -5- to 10-membered heterocyclic group, -5- to 10-membered heteroaryl, and -OC 1～6 Alkyl-6- to 10-membered aryl.

[0061] More preferably, R 6 and R 8 Each is independently selected from: -H, -OH, -SH, amino, halogen, -C 1～6 Alkyl, -NH-C 1～3 Alkyl, -OC 1～6 Alkyl and -NH-C(O)-OC 1～3 alkyl.

[0062] More preferably, R 6 and R 8 Each is independently selected from: -H, amino, halogen, -C 1～3 Alkyl, -OC 1～3 Alkyl and -NH-C 1～3 alkyl.

[0063] Preferably: when R 1 When R is selected from a substituent other than H, 3 , R 5 , R 9 and R 10 All are H; or, when R 3 When R is selected from a substituent other than H, 1 , R 5 , R 9 and R 10 All H; further preferably, R 1 is selected from non-H substituents, R 3 , R 5 , R 9 and R 10 Both are H.

[0064] R 1 Specifically, it can be:

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077] Preferably, R 1 Specifically, it can be:

[0078]

[0079]

[0080] More preferably, R 1 Specifically, it can be:

[0081]

[0082]

[0083] More preferably, R 1 Specifically, it can be:

[0084] R 2 Specifically, it can be:

[0085]

[0086] Preferably, R 2 Specifically, it can be:

[0087]

[0088] R 3 Specifically, it can be:

[0089]

[0090]

[0091] Preferably, R 3 Specifically, it can be:

[0092]

[0093] R 4 Specifically, it can be:

[0094]

[0095] R 5 Specifically, it can be:

[0096]

[0097] R 6 Specifically, it can be:

[0098]

[0099] R 7 Specifically, it can be:

[0100]

[0101] R 8 Specifically, it can be:

[0102]

[0103] R 9 Specifically, it can be:

[0104]

[0105] R 10 Specifically, it can be:

[0106] In a specific embodiment, the thiazole carboxamide compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is the following compound or a pharmaceutically acceptable salt thereof:

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121] The present invention provides a method for preparing a thiazole carboxamide compound of general formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

[0122]

[0123] Dissolve compound B in DMF, add HBTU and N-methylmorpholine, stir, then add compound A, stir, then add the reaction system into water, extract with ethyl acetate, and apply to column chromatography to obtain compound (I);

[0124] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 The definition of is the same as above.

[0125] The present invention provides use of a thiazole carboxamide compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in preparing a mitochondrial complex I inhibitor.

[0126] The present invention provides use of a thiazole carboxamide compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in preparing a drug for treating tumors.

[0127] Preferably, the tumor includes: blood tumor (including drug-resistant blood tumor) and solid tumor.

[0128] Preferably, the tumor includes: acute promyelocytic leukemia, acute myeloid leukemia, mantle cell lymphoma and lung cancer.

[0129] In addition, the present invention provides a pharmaceutical composition, which contains a thiazole carboxamide compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0130] In addition, the present invention provides a method for treating diseases related to mitochondrial complex I, comprising administering a thiazole carboxamide compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof. Preferably, the subject is a human.

[0131] The thiazole carboxamide compounds represented by the general formula (I) provided by the present invention are small molecule inhibitors of mitochondrial complex I with a novel structure. Compounds of this structure have a wide range of inhibitory activities on the proliferation of various blood tumor cells (including drug-resistant blood tumors) and some solid tumor cells (such as lung cancer cells), and can be used as potential new drug molecules for the treatment of blood tumors, drug-resistant blood tumors and solid tumors. DETAILED DESCRIPTION

[0132] The present invention is described below by way of examples, but the present invention is not limited thereto. The experimental methods shown in the following examples are conventional methods unless otherwise specified. The reagents and materials shown are all commercially available products. The filler used for column chromatography is: 100-200 mesh ordinary silica gel; the eluent is: ethyl acetate: petroleum ether = 1:5.

[0133] Preparation Example 1 Preparation of Compound MDD01

[0134]

[0135] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.10 g (1.0 eq) of compound A1, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD01.

[0136] MS(ES-API)cacld.for C 16 H 19 N3O3S found 334[M+1] + ; 1 H NMR(400 MHz, 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=7.0 Hz,3H).

[0137] Preparation Example 2 Preparation of Compound MDD02

[0138]

[0139] Add 100 mg of compound B to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.10 g (1.0 eq) of compound A2, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD02.

[0140] MS(ES-API)cacld.for C 18 H 19 N3OS 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).

[0141] Preparation Example 3 Preparation of Compound MDD03

[0142]

[0143] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.11 g (1.0 eq) of compound A3, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD03.

[0144] MS(ES-API)cacld.for C 17 H 22 N4O2S found 347[M+1] + ; 1H 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).

[0145] Preparation Example 4 Preparation of Compound MDD04

[0146]

[0147] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.11 g (1.0 eq) of compound A4, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD04.

[0148] MS(ES-API)cacld.for C 15 H 17 F2N3O2S 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).

[0149] Preparation Example 5 Preparation of Compound MDD05

[0150]

[0151] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.11 g (1.0 eq) of compound A5, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD05.

[0152] MS(ES-API)cacld.for C 17 H 22 N4O2S found 347[M+1] + .

[0153] Preparation Example 6 Preparation of Compound MDD06

[0154]

[0155] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.11 g (1.0 eq) of compound A6, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD06.

[0156] MS(ES-API)cacld.for C 16 H 20 N2O3S 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).

[0157] Preparation Example 7 Preparation of Compound MDD07

[0158]

[0159] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.08 g (1.0 eq) of compound A7, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD07.

[0160] MS(ES-API)cacld.for C 14 H 17 N3O3S found 292[M+1] + ; 1 H NMR (400 MHz, DMSO): δ 2.42 (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 Example 8 Preparation of Compound MDD08

[0161]

[0162] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.11 g (1.0 eq) of compound A8, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD08.

[0163] MS(ES-API)cacld.for C 18 H 19 N3O2S 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).

[0164] Preparation Example 9 Preparation of Compound MDD09

[0165]

[0166] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.10 g (1.0 eq) of compound A9, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD09.

[0167] MS(ES-API)cacld.for C 17 H 22 N4OS 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).

[0168] Preparation Example 10 Preparation of Compound MDD10

[0169]

[0170] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.12 g (1.0 eq) of compound A10, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD10.

[0171] MS(ES-API)cacld.for C 17 H 19 F2N3O2S 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).

[0172] Preparation Example 11 Preparation of Compound MDD11

[0173]

[0174] Add 100 mg of compound B2 to 2 ml of DMF, add 0.29 g (1.1 eq) of HBTU and 0.21 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.11 g (1.0 eq) of compound A11, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD11.

[0175] MS(ES-API)cacld.for C 15 H 19 N3OS 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).

[0176] Preparation Example 12 Preparation of Compound MDD12

[0177]

[0178] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.13 g (1.0 eq) of compound A12, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD12.

[0179] MS(ES-API)cacld.for C 18 H 18 N4O3S found 371[M+1] + ; 1H 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).

[0180] Preparation Example 13 Preparation of Compound MDD13

[0181]

[0182] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.10 g (1.0 eq) of compound A13, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD13.

[0183] MS(ES-API)cacld.for C 16 H 19 N3O3S 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),3.3 3(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).

[0184] Preparation Example 14 Preparation of Compound MDD14

[0185]

[0186] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.12 g (1.0 eq) of compound A14, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD14.

[0187] MS(ES-API)cacld.for C 14H 18 N4O3S2 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).

[0188] Preparation Example 15 Preparation of Compound MDD15

[0189]

[0190] Add 100 mg of compound B2 to 2 ml of DMF, add 0.29 g (1.1 eq) of HBTU and 0.21 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.14 g (1.0 eq) of compound A15, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD15.

[0191] MS(ES-API)cacld.for C 19 H 18 N2OS 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,6 H),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).

[0192] Preparation of Compound MDD16 from Preparation Example 16

[0193]

[0194] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.12 g (1.0 eq) of compound A16, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD16.

[0195] MS(ES-API)cacld.for C 19 H 20 N4O2S 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).

[0196] Preparation Example 17 Preparation of Compound MDD17

[0197]

[0198] Add 100 mg of compound B3 to 2 ml of DMF, add 0.27 g (1.1 eq) of HBTU and 0.19 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.10 g (1.0 eq) of compound A17, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD17.

[0199] MS(ES-API)cacld.for C 14 H 13 N2O2S 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),7.3 0(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).

[0200] Preparation Example 18 Preparation of Compound MDD18

[0201]

[0202] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.14 g (1.0 eq) of compound A18, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD18.

[0203] MS(ES-API)cacld.for C 17 H 19 F3N4O2S 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).

[0204] Preparation Example 19 Preparation of Compound MDD19

[0205]

[0206] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.11 g (1.0 eq) of compound A19, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD19.

[0207] MS(ES-API)cacld.for C 18 H 12 N4OS found 345[M+1] + ; 1H 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).

[0208] Preparation Example 20 Preparation of Compound MDD20

[0209]

[0210] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.11 g (1.0 eq) of compound A20, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD20.

[0211] MS(ES-API)cacld.for C 17 H 19 N5OS 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).

[0212] Preparation Example 21 Preparation of Compound MDD21

[0213]

[0214] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.13 g (1.0 eq) of compound A21, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD21.

[0215] MS(ES-API)cacld.for C 16 H 18 F3N3O2S found 374[M+1] + .

[0216] Preparation Example 22 Preparation of Compound MDD22

[0217]

[0218] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.10 g (1.0 eq) of compound A22, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD22.

[0219] MS(ES-API)cacld.for C 16 H 22 N4OS 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).

[0220] Preparation Example 23 Preparation of Compound MDD23

[0221]

[0222] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.10 g (1.0 eq) of compound A23, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD23.

[0223] MS(ES-API)cacld.for C 15 H 18 N4O2S found 319[M+1] + ; 1H 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).

[0224] Preparation Example 24 Preparation of Compound MDD24

[0225]

[0226] Add 100 mg of compound B2 to 2 ml of DMF, add 0.29 g (1.1 eq) of HBTU and 0.21 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.15 g (1.0 eq) of compound A24, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD24.

[0227] MS(ES-API)cacld.for C 18 H 21 N3O2S 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).

[0228] Preparation Example 25 Preparation of Compound MDD25

[0229]

[0230] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.11 g (1.0 eq) of compound A25, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD25.

[0231] 1H 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).

[0232] Preparation of Compound MDD26 from Preparation Example 26

[0233]

[0234] Compound B2 100 mg was added to 2 ml of DMF, HBTU 0.29 g (1.1 eq), N-methylmorpholine 0.21 g (3 eq) were added, and the mixture was stirred for 10 minutes. Compound A26 0.15 g (1.0 eq) was then added, and the mixture was stirred at room temperature overnight. TLC showed that the reaction was basically complete. The reaction solution was added to 50 ml of water, extracted with ethyl acetate, and subjected to column chromatography to obtain MDD26.

[0235] MS(ES-API)cacld.for C 18 H 23 N3O2S 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=2 3.4,8.3Hz,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).

[0236] Preparation Example 27 Preparation of Compound MDD27

[0237]

[0238] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.11 g (1.0 eq) of compound A27, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD27.

[0239] MS(ES-API)cacld.for C 17 H 21 N3O3S 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),4.0 9(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).

[0240] Preparation Example 28 Preparation of Compound MDD28

[0241]

[0242] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.12 g (1.0 eq) of compound A28, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD28.

[0243] MS(ES-API)cacld.for C 18 H 22 N4O2S found 359[M+1] + ; 1H 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).

[0244] Preparation Example 29 Preparation of Compound MDD29

[0245]

[0246] Add 100 mg of compound B2 to 2 ml of DMF, add 0.29 g (1.1 eq) of HBTU and 0.21 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.12 g (1.0 eq) of compound A29, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD29.

[0247] MS(ES-API)cacld.for C 15 H 18 N2O2S found 291[M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ9.41 (s, 1H), 8.71 (d, J = 8.1 Hz, 1H), 7.31-7.25 (m, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.06 (p, J = 7.3 Hz, 1H), 3.99 (q, J = 7.0 Hz, 2H), 3.33 (s, 1H), 1.42 (d, J = 7.0 Hz, 3H), 1.31 (t, J = 7.0 Hz, 3H). Preparation Example 30 Preparation of Compound MDD30

[0248]

[0249] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.11 g (1.0 eq) of compound A30, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD30.

[0250] MS(ES-API)cacld.for C 17 H 19 N5OS 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).

[0251] Preparation Example 31 Preparation of Compound MDD31

[0252]

[0253] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.13 g (1.0 eq) of compound A31, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD31.

[0254] MS(ES-API)cacld.for C 19 H 21 N3O3S 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,1 H),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).

[0255] Preparation Example 32 Preparation of Compound MDD32

[0256]

[0257] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.10 g (1.0 eq) of compound A32, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD32.

[0258] MS(ES-API)cacld.for C 15 H 17 N3O3S 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).

[0259] Preparation Example 33 Preparation of Compound MDD33

[0260]

[0261] Add 100 mg of compound B2 to 2 ml of DMF, add 0.29 g (1.1 eq) of HBTU and 0.21 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.13 g (1.0 eq) of compound A33, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD33.

[0262] MS(ES-API)cacld.for C 15 H 15 N5OS 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).

[0263] Preparation of Example 34 Compound MDD34

[0264]

[0265] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.10 g (1.0 eq) of compound A34, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD34.

[0266] MS(ES-API)cacld.for C 17 H 22 N4OS 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).

[0267] Preparation Example 35 Preparation of Compound MDD35

[0268]

[0269] Add 100 mg of compound B2 to 2 ml of DMF, add 0.29 g (1.1 eq) of HBTU and 0.21 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.12 g (1.0 eq) of compound A35, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD35.

[0270] MS(ES-API)cacld.for C 16 H 19 N3OS found 302[M+1] + ; 1H 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).

[0271] Preparation of Compound MDD36 from Preparation Example 36

[0272]

[0273] Add 100 mg of compound B4 to 2 ml of DMF, add 0.32 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.16 g (1.0 eq) of compound A36, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD36.

[0274] MS(ES-API)cacld.for C 16 H 17 N3O2S 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,2 H),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).

[0275] Preparation Example 37 Preparation of Compound MDD37

[0276]

[0277] Add 100 mg of compound B5 to 2 ml of DMF, add 0.26 g (1.1 eq) of HBTU and 0.19 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.12 g (1.0 eq) of compound A37, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD37.

[0278] MS(ES-API)cacld.for C 17 H 21 N3O2S 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=16.1,8.1 Hz,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).

[0279] Preparation Example 38 Preparation of Compound MDD38

[0280]

[0281] Add 100 mg of compound B6 to 2 ml of DMF, add 0.26 g (1.1 eq) of HBTU and 0.19 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.11 g (1.0 eq) of compound A9, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD38.

[0282] MS(ES-API)cacld.for C 15 H 16 ClN3OS 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).

[0283] Preparation Example 39 Preparation of Compound MDD39

[0284]

[0285] Add 100 mg of compound B7 to 2 ml of DMF, add 0.29 g (1.1 eq) of HBTU and 0.21 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.13 g (1.0 eq) of compound A37, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD39.

[0286] MS(ES-API)cacld.for C 17 H 21 N3OS 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).

[0287] Preparation Example 40 Preparation of Compound MDD40

[0288]

[0289] Add 100 mg of compound B2 to 2 ml of DMF, add 0.29 g (1.1 eq) of HBTU and 0.21 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.13 g (1.0 eq) of compound A37, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD40.

[0290] MS(ES-API)cacld.for C 17 H 21 N3OS found 316[M+1] + ; 1H 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).

[0291] Preparation Example 41 Preparation of Compound MDD41

[0292]

[0293] Add 100 mg of compound B3 to 2 ml of DMF, add 0.27 g (1.1 eq) of HBTU and 0.19 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.12 g (1.0 eq) of compound A37, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD41.

[0294] MS(ES-API)cacld.for C 18 H 23 N3OS 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).

[0295] Preparation Example 42 Preparation of Compound MDD42

[0296]

[0297] Add 100 mg of compound B4 to 2 ml of DMF, add 0.32 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.14 g (1.0 eq) of compound A35, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD42.

[0298] MS(ES-API)cacld.for C 15 H 17 N3OS 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).

[0299] Preparation Example 43 Preparation of Compound MDD43

[0300]

[0301] Add 100 mg of compound B5 to 2 ml of DMF, add 0.26 g (1.1 eq) of HBTU and 0.19 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.11 g (1.0 eq) of compound A35, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD43.

[0302] MS(ES-API)cacld.for C 16 H 19 N3O2S 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).

[0303] Preparation Example 44 Preparation of Compound MDD44

[0304]

[0305] Add 100 mg of compound B7 to 2 ml of DMF, add 0.29 g (1.1 eq) of HBTU and 0.21 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.13 g (1.0 eq) of compound A25, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD44.

[0306] MS(ES-API)cacld.for C 16 H 17 N3O2S 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).

[0307] Preparation Example 45 Preparation of Compound MDD45

[0308]

[0309] Add 100 mg of compound B3 to 2 ml of DMF, add 0.27 g (1.1 eq) of HBTU and 0.19 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.11 g (1.0 eq) of compound A9, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD45.

[0310] MS(ES-API)cacld.for C 17 H 21 N3OS found 316[M+1] + ; 1H NMR (400MHz, DMSO-d6) δ8.66(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).

[0311] Preparation of Example 46 Compound MDD46

[0312]

[0313] Add 100 mg of compound B4 to 2 ml of DMF, add 0.32 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.15 g (1.0 eq) of compound A37, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD46.

[0314] MS(ES-API)cacld.for C 16 H 19 N3OS 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).

[0315] Preparation Example 47 Preparation of Compound MDD47

[0316]

[0317] Add 100 mg of compound B7 to 2 ml of DMF, add 0.29 g (1.1 eq) of HBTU and 0.21 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.12 g (1.0 eq) of compound A35, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD47.

[0318] MS(ES-API)cacld.for C 16 H 19 N3OS 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).

[0319] Preparation Example 48 Preparation of Compound MDD48

[0320]

[0321] Add 100 mg of compound B8 to 2 ml of DMF, add 0.26 g (1.1 eq) of HBTU and 0.19 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.12 g (1.0 eq) of compound A37, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD48.

[0322] MS(ES-API)cacld.for C 17 H 22 N4OS 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).

[0323] Preparation Example 49 Preparation of Compound MDD49

[0324]

[0325] Add 100 mg of compound B4 to 2 ml of DMF, add 0.32 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.15 g (1.0 eq) of compound A25, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD49.

[0326] MS(ES-API)cacld.for C 15 H 15 N3O2S 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).

[0327] Preparation of Example 50 Compound MDD50

[0328]

[0329] Add 100 mg of compound B2 to 2 ml of DMF, add 0.29 g (1.1 eq) of HBTU and 0.21 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.13 g (1.0 eq) of compound A25, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD50.

[0330] MS(ES-API)cacld.for C 16 H 17 N3O2S 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=5.8H z,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).

[0331] Preparation Example 51 Preparation of Compound MDD51

[0332]

[0333] Add 100 mg of compound B8 to 2 ml of DMF, add 0.26 g (1.1 eq) of HBTU and 0.19 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.11 g (1.0 eq) of compound A35, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD51.

[0334] MS(ES-API)cacld.for C 16 H 20 N4OS found 316[M+1] + ; 1 H NMR (400 MHz, 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 Example 52 Preparation of Compound MDD52

[0335]

[0336] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.12 g (1.0 eq) of compound A38, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD52.

[0337] 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).

[0338] Preparation of Example 53 Compound MDD53

[0339]

[0340] Add 100 mg of compound B4 to 2 ml of DMF, add 0.32 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.18 g (1.0 eq) of compound A39, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD53.

[0341] MS(ES-API)cacld.for C 17 H 12 N2O2S 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).

[0342] Preparation of Example 54 Compound MDD54

[0343]

[0344] Add 100 mg of compound B8 to 2 ml of DMF, add 0.26 g (1.1 eq) of HBTU and 0.19 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.14 g (1.0 eq) of compound A40, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD54.

[0345] MS(ES-API)cacld.for C 18 H16N3O2S 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).

[0346] Preparation Example 55 Preparation of Compound MDD55

[0347]

[0348] Add 100 mg of compound B4 to 2 ml of DMF, add 0.32 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.15 g (1.0 eq) of compound A41, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD55.

[0349] MS(ES-API)cacld.for C 17 H 14 N2O2S 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).

[0350] Preparation of Example 56 Compound MDD56

[0351]

[0352] Add 100 mg of compound B8 to 2 ml of DMF, add 0.26 g (1.1 eq) of HBTU and 0.19 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.14 g (1.0 eq) of compound A42, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD56.

[0353] MS(ES-API)cacld.for C 18 H 16 FN3O2S found 358[M+1] + ; 1H NMR (600MHz, DMSO-d6) δ9.55 (s, 1H), 9.07 (t, J = 5.9Hz, 1H), 8.91 (s, 1H), 7.39-7.3 1(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).

[0354] Preparation of Example 57 Compound MDD57

[0355]

[0356] Add 100 mg of compound B8 to 2 ml of DMF, add 0.26 g (1.1 eq) of HBTU and 0.19 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.13 g (1.0 eq) of compound A41, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD57.

[0357] MS(ES-API)cacld.for C 18 H 17 N3O2S found 340[M+1] + ; 1 H NMR(500MHz,DMSO-d6)δ7.81(t,J=6.0Hz,2H),7.40-7.29(m,12H),7.14-7.0 7(m,2H),6.99-6.93(m,8H),4.40(d,J=6.0Hz,4H),2.45(s,1H),2.39(s,6H).

[0358] Preparation Example 58 Preparation of Compound MDD58

[0359]

[0360] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.12 g (1.0 eq) of compound A41, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD58.

[0361] MS(ES-API)cacld.for C 19 H 19 N3O2S 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).

[0362] Preparation Example 59 Preparation of Compound MDD59

[0363]

[0364] Add 100 mg of compound B1 to 2 ml of DDMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.13 g (1.0 eq) of compound A43, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD59.

[0365] MS(ES-API)cacld.for C 20 H 21 N3O3S 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).

[0366] Preparation Example 60 Preparation of Compound MDD60

[0367]

[0368] Add 100 mg of compound B1 to 2 ml of DMF, add 0.22 g (1.1 eq) of HBTU and 0.24 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.14 g (1.0 eq) of compound A39, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD60.

[0369] MS(ES-API)cacld.for C 19 H 17 F2N3O2S 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).

[0370] Preparation Example 61 Preparation of Compound MDD61

[0371]

[0372] Add 100 mg of compound B2 to 2 ml of DMF, add 0.29 g (1.1 eq) of HBTU and 0.21 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.14 g (1.0 eq) of compound A41, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD61.

[0373] MS(ES-API)cacld.for C 18 H 16 N2O2S 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).

[0374] Preparation Example 62 Preparation of Compound MDD62

[0375]

[0376] Add 100 mg of compound B2 to 2 ml of DMF, add 0.29 g (1.1 eq) of HBTU and 0.21 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.16 g (1.0 eq) of compound A44, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD62.

[0377] MS(ES-API)cacld.for C 19 H 17 FN2O2S 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).

[0378] Preparation of Example 63 Compound MDD63

[0379]

[0380] Add 100 mg of compound B2 to 2 ml of DMF, add 0.29 g (1.1 eq) of HBTU and 0.21 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.16 g (1.0 eq) of compound A43, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD63.

[0381] MS(ES-API)cacld.for C 19 H 18 NO3S found 355[M+1] + ; 1H 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).

[0382] Preparation of Example 64 Compound MDD64

[0383]

[0384] Add 100 mg of compound B2 to 2 ml of DMF, add 0.29 g (1.1 eq) of HBTU and 0.21 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.16 g (1.0 eq) of compound A39, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD64.

[0385] MS(ES-API)cacld.for C 18 H 14 F2N2O2S 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).

[0386] Preparation of Example 65 Compound MDD65

[0387]

[0388] Add 100 mg of compound B3 to 2 ml of DMF, add 0.27 g (1.1 eq) of HBTU and 0.19 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.22 g (1.0 eq) of compound A41, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD65.

[0389] MS(ES-API)cacld.for C 19 H 18 N2O2S 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),7.1 1(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).

[0390] Preparation of Example 66 Compound MDD66

[0391]

[0392] Add 100 mg of compound B3 to 2 ml of DMF, add 0.27 g (1.1 eq) of HBTU and 0.19 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.15 g (1.0 eq) of compound A43, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD66.

[0393] MS(ES-API)cacld.for C 20 H 20 N2O3S 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).

[0394] Preparation of Example 67 Compound MDD67

[0395]

[0396] Add 100 mg of compound B3 to 2 ml of DMF, add 0.27 g (1.1 eq) of HBTU and 0.19 g (3 eq) of N-methylmorpholine, stir for 10 minutes, then add 0.16 g (1.0 eq) of compound A45, stir at room temperature overnight, TLC shows that the reaction is basically complete, add the reaction solution to 50 ml of water, extract with ethyl acetate, and apply to column chromatography to obtain MDD67.

[0397] MS(ES-API)cacld.for C 19 H 17 N3O4S 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).

[0398] Experimental Example 1: Detection of the inhibitory activity of the compounds of the present invention on mitochondrial complex I

[0399] Experiment: Use Complex I Activity Assay Kit (Cayman, Item No. 700930) detects the inhibitory activity of the compounds of the present invention on mitochondrial complex I. Use DMSO to prepare the compounds of the present invention into a 50mM stock solution for use, and use DMSO to dilute the compounds of the present invention into a working solution of corresponding concentrations when testing; use 155μL of ultrapure water to dissolve all NADH, and place it on ice for use after preparation; use 1mL of 0.1M NaOH to dissolve 6.5mg of KCN (prepared within three hours before the test); each 20 portions of reaction solution A contain 910μL of Complex I Activity Assay Buffer, 20μL of KCN, 50μL of FF-BSA Assay Reagent, and 20μL of Bovine Heart Mitochondria Assay Reagent; each 20 portions of reaction solution B contain 1025μL of Complex I Activity Assay Buffer, 30μL of NADH Assay Reagent, and 20μL of Ubiquinone Assay Reagent.

[0400] 1 μL of the working solution of 45 compounds of the present invention was added to a 96-well plate, and then 50 μL of reaction solution A was added to the wells, mixed by pipetting, and incubated at room temperature for 10 min; after the incubation was completed, 50 μL of reaction solution B was added to start the reaction, and after adding the reaction solution B, the 96-well plate was quickly placed in a microplate reader (Varioskan LUX, Thermo Fisher Scientific) for detection, and the absorbance was measured at 340 nm (detected every 30 seconds for 15 minutes at 25°C); each group of experiments was repeated three times, with DMSO as a negative control and the mitochondrial complex inhibitor IACS-010759 as a positive control.

[0401] The absorbance data obtained by the detection were plotted into a graph of absorbance (Y axis) and reaction time (X axis); the slope of the curve from 2 min to 12.5 min was taken to calculate the reaction rate; the reaction rate was converted into the relative inhibition rate of the compound of the present invention on complex I using the following formula; the relative inhibition rate data were plotted into the curve using Graphpad Prism 6.0 software to determine IC 50 The value of .

[0402]

[0403] Among them, ΔOD 340c OD for the control group 340 The slope, ΔOD 340t OD for the experimental group 340 The slope of .

[0404] Results: The experimental results are shown in Table 1. The compounds of the present invention all showed activity against mitochondrial complex I. Among them, 22 compounds of the present invention had IC values ​​of 50 <15 μM. IC of positive control compound IACS-010759 on mitochondrial complex I 50 It is 0.91μM.

[0405] Table 1 Inhibitory effect of the compounds of the present invention on mitochondrial complex I

[0406]

[0407] Conclusion: The compounds of the present invention have significant inhibitory activity on mitochondrial complex I, among which the inhibitory activity of the compounds MDD09, MDD52 and MDD67 of the present invention is stronger, which is equivalent to the positive control compound IACS-010759.

[0408] Experimental Example 2: Inhibition of proliferation of four types of human tumor cells by the compounds of the present invention

[0409] Experiment: The compounds of the present invention MDD09 and MDD52 were prepared with DMSO to form a 40 mg / mL stock solution, and the positive control compounds IACS-010759 and Ibrutinib were prepared with DMSO to form a 20 mg / mL and 40 mg / mL stock solution, respectively.

[0410] Human promyelocytic acute leukemia cells HL60, human myeloid leukemia mononuclear cells THP-1, human lung cancer cells H1299 and human mantle cell lymphoma cells JeKo-1 were expanded and cultured to the logarithmic growth phase, and the cell density was adjusted to 3×10 4 cells / mL, inoculated into 96-well cell culture plates, 100 μL per well, 3 replicates per concentration gradient. Compounds MDD09 and MDD52 of the present invention were configured with complete medium at 0, 2.5, 5, 10, 20 and 40 μg / mL for a total of 6 concentration gradients and acted on cells. Positive control compound Ibrutinib was configured with complete medium at 0, 2.5, 5, 10, 20 and 40 μg / mL for a total of 6 concentration gradients and acted on cells. Positive control compound IACS-010759 was configured with complete medium at 0, 1.25, 2.5, 5, 10 and 20 μg / mL for a total of 6 concentration gradients and acted on cells. After culturing for 24h, 48h and 72h, 15 μL of CCK8 was added to each well, and cultured in a 5% CO2 incubator at 37°C and incubated in the dark for 3h. The OD value of each well at the same time point at a wavelength of 492 nm was detected using an enzyme reader (Molecular Devices SpectraMaxi3), and the measured OD value was used to analyze the effect on cell proliferation.

[0411] Results: The experimental results are shown in Table 2.

[0412] Table 2 Inhibitory activity of the compounds of the present invention on proliferation of four types of human tumor cells

[0413]

[0414] Note: “-” means: the cell inhibition rate did not reach 50% during this time period.

[0415] Conclusion: The compounds of the present invention have strong inhibitory activity on the proliferation of human hematological tumor cells and solid tumor cells. Among them, the inhibitory activity of the compound MDD52 of the present invention on some tumor cells is stronger than that of the positive control drugs IACS-010759 and ibrutinib. The above results show that the compounds MDD09 and MDD52 of the present invention can be used as the lead of anti-tumor drugs.

[0416] Experimental Example 3: Inhibition of proliferation of human promyelocytic acute leukemia cells HL60 by the compounds of the present invention

[0417] Experiment: The compound of the present invention was prepared into a 40 mg / mL stock solution with DMSO. Human promyelocytic acute leukemia cells HL60 were expanded and cultured. When the cells grew to the logarithmic growth phase, the cell density was adjusted to 3×10 4 cells / mL, inoculated into 96-well cell culture plates, 100 μL per well, 3 replicates per concentration gradient. The mother solution of the compound of the present invention was diluted with complete medium to 0, 2.5, 5, 10, 20 and 40 μg / mL for a total of 6 concentration gradients and acted on the cells. After culturing for 24h, 48h and 72h, 15 μL of CCK8 was added to each well, and cultured in a 5% CO2 incubator at 37°C and incubated in the dark for 3h. The OD value of each well at the same time point at a wavelength of 492nm was detected using an ELISA instrument (Molecular Devices SpectraMax i3), and the measured OD value was used to analyze the effect on cell proliferation.

[0418] Results: The experimental results are shown in Table 3.

[0419] Table 3 Inhibitory activity of the compounds of the present invention on HL60 cell proliferation

[0420]

[0421]

[0422] Note: “-” means: the cell inhibition rate did not reach 50% during this time period.

[0423] Conclusion: The compounds of the present invention have strong inhibitory effects on the proliferation of human promyelocytic acute leukemia cells HL60, and the compounds of the present invention MDD01, MDD08 and MDD21 have stronger inhibitory effects on human promyelocytic acute leukemia cells HL60.

[0424] Experimental Example 4: Inhibition of proliferation of three types of human tumor cells by the compounds of the present invention

[0425] Experiment: The compound MDD67 of the present invention was prepared with DMSO to a stock solution of 40 mg / mL, and the positive control drug IACS-010759 and the compounds MDD58 and MDD60 of the present invention were prepared with DMSO to a stock solution of 20 mg / mL. Human promyelocytic acute leukemia cells HL60, human lung cancer cells H1299 and human mantle cell lymphoma cells Jeko-1 were expanded and cultured. When the cells grew to the logarithmic growth phase, the cell density was adjusted to 3×10 4cells / mL, inoculated into 96-well cell culture plates, 100 μL per well, 3 replicates per concentration gradient. The compound MDD67 of the present invention was configured with complete culture medium at 0, 2.5, 5, 10, 20 and 40 μg / mL for a total of 6 concentration gradients to act on the cells; the compounds MDD58, MDD60 of the present invention and the positive control drug were configured with complete culture medium at 0, 1.25, 2.5, 5, 10 and 20 μg / mL for a total of 6 concentration gradients to act on the cells. After 24h, 48h and 72h of culture, 15 μL of CCK8 was added to each well, and cultured in a 5% CO2 incubator at 37°C and incubated in the dark for 3h. The OD value of each well at the same time point at a wavelength of 492nm was detected using an ELISA instrument (Molecular Devices SpectraMax i3), and the measured OD value was used to analyze the effect on cell proliferation.

[0426] Results: The experimental results are shown in Table 4.

[0427] Table 4 Inhibitory activity of the compounds of the present invention on the proliferation of human tumor cells

[0428]

[0429] Note: “-” means: the cell inhibition rate did not reach 50% during this time period.

[0430] Conclusion: The compounds of the present invention have strong inhibitory effects on the proliferation of three tumor cells, including human promyelocytic acute leukemia cells HL60, human lung cancer cells H1299 and human mantle cell lymphoma cells Jeko-1. The compound MDD58 of the present invention has a stronger inhibitory effect on the proliferation of three tumor cells, including human promyelocytic acute leukemia cells HL60, human lung cancer cells H1299 and human mantle cell lymphoma cells Jeko-1.

[0431] Based on the above description of the invention, those skilled in the art can fully apply the present invention, and all the same principles or similar modifications should be deemed to be included in the scope of the present invention.

Claims

1. Use of a thiazole carboxamide compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a mitochondrial complex I inhibitor, 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 Hydrocarbon, -NH-C 1～6 Hydrocarbon, -N(C 1～6 Hydrocarbon)2, -OC 1～6 Hydrocarbon, -SC 1～6 Hydrocarbon, -C(O)-C 1～6 Hydrocarbon, -C 1～6 Alkyl-OC 1～6 Hydrocarbon, -C 1～5 Alkyl-SC 1～6 Hydrocarbon, -C(S)-C 1～6 Hydrocarbon, -SO2-C 1～6 Hydrocarbon, -C 1～6 Hydrocarbyl-NH-C 1～6 Hydrocarbon, -C 1～6 Hydrocarbyl-N(C 1～6 Hydrocarbon)2, -C(O)-NH2, -C(O)-NH-C 1～6 Hydrocarbon, -C(O)-OC 1～6 Hydrocarbon, -C(NH-C 1～6 Hydrocarbon)2, -NH-C(O)-C 1～6 Hydrocarbon, -NH-SO2-C 1～6 Hydrocarbon, -N(C 1～6 Hydrocarbon)-SO2-C 1～6 Hydrocarbon, -SO2-NH2 and -SO2-NH-C 1～6 Hydrocarbyl; said -C 1～6 The hydrocarbon group is unsubstituted or substituted with one or more of the following substituents: O, halogen, -OH, amino, -C 1～3 Alkyl-OH, methylsulfonyl, and methyl formate; (2) -6- to 10-membered aryl, -5- to 10-membered heterocyclic group, -5- to 10-membered heteroaryl, -C 1～6 Alkyl-6- to 10-membered aryl, -C 1～6 Alkyl-5- to 10-membered heterocyclic group, -C 1～6 alkyl-5- to 10-membered heteroaryl, -O-6- to 10-membered aryl, -O-5- to 10-membered heterocyclic group, -O-5- to 10-membered heteroaryl, -S-6- to 10-membered aryl, -S-5- to 10-membered heterocyclic group, -S-5- to 10-membered heteroaryl, -NH-6- to 10-membered aryl, -NH-5- to 10-membered heterocyclic group, -NH-5- to 10-membered heteroaryl, -C(O)-6- to 10-membered aryl, -C(O)-5- to 10-membered heterocyclic group, -C(O)-5- to 10-membered heteroaryl, -OC 1～6 Alkyl-6- to 10-membered aryl, -OC 1～6 Alkyl-5- to 10-membered heterocyclic group, -OC 1～6 Alkyl-5- to 10-membered heteroaryl, -C 1～6 Alkyl-OC 1～6 Alkyl-6- to 10-membered aryl, -C 1～6 Alkyl-OC 1～6 Alkyl-5- to 10-membered heterocyclic group, -C 1～6 Alkyl-OC 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 heterocyclic group, -C 1～6 Alkyl-NH-C(O)-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -C(CH2)-6- to 10-membered aryl, -N(C 1～6 Hydrocarbon)-6- to 10-membered aryl, -N(C 1～6 Hydrocarbon)-5- to 10-membered heterocyclic group, -N(C 1～6 -C(NH)-6- to 10-membered aryl, -NH-C(O)-6- to 10-membered aryl, -NH-C(O)-5- to 10-membered heterocyclic group, -NH-C(O)-5- to 10-membered heteroaryl, -C(NH3 + )-6- to 10-membered aryl and -S(O)2-6- to 10-membered aryl; (3)R 1 With R 3 Connected to form a ring fused with a benzene ring, the ring is: a 6-10 membered aromatic ring, a 5-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring; In the above (2) and (3), the aryl, heterocyclic, heteroaryl, aromatic ring, heterocyclic ring and heteroaromatic ring are unsubstituted or substituted with one or more of the following substituents: O, N, -OH, halogen, amino, nitro, amine, -SH, methyl formate, methyl nitro, -C 1～6 Alkyl, C 2～5 Alkynyl, -OC 1～6 Alkyl, -C 1～6 Alkyl-amino or acetonitrile; R 2 and R 7 Each independently selected from: -H, -C 1～6 Hydrocarbon, -C 1～6 Alkyl-OH, -C 1～6 Alkyl-OC 1～6 Hydrocarbyl, -C(O)-NH2, -COOH, formic acid, pyridyl and 1,3-benzodiazole-6-yl; or, R 2 or R 7 With R 5 or R 9 Connection Formation-C 2～5 Alkylene-; R 4 Selected from: -H, -C 1～6 Hydrocarbon, -C 1～3 Alkyl-C(O)-OC 1～6 A hydrocarbon group and a 5- to 6-membered heterocyclic group; the -C 1～6 The hydrocarbon group is unsubstituted or substituted with one or more of the following substituents: -COOH or -NH + (CH3)2; the -5- to 6-membered heterocyclic group is unsubstituted or substituted by one or more of the following substituents: -C 1～3 alkyl; R 6 and R 8 Each is independently selected from: -H, -OH, -SH, amino, halogen, cyano, nitro, -COOH, -C 1～6 Hydrocarbon, -NH-C 1～6 Hydrocarbon, -OC 1～6 Hydrocarbon, -SO2-NH2, -C(O)-OC 1～6 Hydrocarbon, -OC(O)-NH2, -NH-C(O)-OC 1～6 Hydrocarbyl, -6- to 10-membered aryl, -5- to 10-membered heterocyclic group, -5- to 10-membered heteroaryl, and -OC 1～6 Alkyl-6- to 10-membered aryl.

2. The use 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 Hydrocarbon, -NH-C 1～6 Hydrocarbon, -N(C 1～6 Hydrocarbon)2, -OC 1～6 Hydrocarbon, -SC 1～6 Hydrocarbon, -C(O)-C 1～6 Hydrocarbon, -C 1～6 Alkyl-OC 1～6 Hydrocarbon, -C 1～5 Alkyl-SC 1～6 Hydrocarbon, -C(S)-C 1～6 Hydrocarbon, -SO2-C 1～6 Hydrocarbon, -C 1～6 Hydrocarbyl-NH-C 1～6 Hydrocarbon, -C 1～6 Hydrocarbyl-N(C 1～6 Hydrocarbon)2, -C(O)-NH2, -C(O)-NH-C 1～6 Hydrocarbon, -C(O)-OC 1～6 Hydrocarbon, -C(NH-C 1～6 Hydrocarbon)2, -NH-C(O)-C 1～6 Hydrocarbon, -NH-SO2-C 1～6 Hydrocarbon, -N(C 1～6 Hydrocarbon)-SO2-C 1～6 Hydrocarbon, -SO2-NH2 and -SO2-NH-C 1～6 Hydrocarbyl; said -C 1～6 The hydrocarbon group is unsubstituted or substituted with one or more of the following substituents: O, halogen, -OH, amino, -C 1～3 Alkyl-OH, methylsulfonyl, and methyl formate; (2) -6- to 10-membered aryl, -5- to 10-membered heterocyclic group, -5- to 10-membered heteroaryl, -C 1～6 Alkyl-6- to 10-membered aryl, -C 1～6 Alkyl-5- to 10-membered heterocyclic group, -C 1～6 alkyl-5- to 10-membered heteroaryl, -O-6- to 10-membered aryl, -O-5- to 10-membered heterocyclic group, -O-5- to 10-membered heteroaryl, -S-6- to 10-membered aryl, -S-5- to 10-membered heterocyclic group, -S-5- to 10-membered heteroaryl, -NH-6- to 10-membered aryl, -NH-5- to 10-membered heterocyclic group, -NH-5- to 10-membered heteroaryl, -C(O)-6- to 10-membered aryl, -C(O)-5- to 10-membered heterocyclic group, -C(O)-5- to 10-membered heteroaryl, -OC 1～6 Alkyl-6- to 10-membered aryl, -OC 1～6 Alkyl-5- to 10-membered heterocyclic group, -OC 1～6 Alkyl-5- to 10-membered heteroaryl, -C 1～6 Alkyl-OC 1～6 Alkyl-6- to 10-membered aryl, -C 1～6 Alkyl-OC 1～6 Alkyl-5- to 10-membered heterocyclic group, -C 1～6 Alkyl-OC 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 heterocyclic group, -C 1～6 Alkyl-NH-C(O)-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -C(CH2)-6- to 10-membered aryl, -N(C 1～6 Hydrocarbon)-6- to 10-membered aryl, -N(C 1～6 Hydrocarbon)-5- to 10-membered heterocyclic group, -N(C 1～6 -C(NH)-6- to 10-membered aryl, -NH-C(O)-6- to 10-membered aryl, -NH-C(O)-5- to 10-membered heterocyclic group, -NH-C(O)-5- to 10-membered heteroaryl, -C(NH3 + )-6- to 10-membered aryl and -S(O)2-6- to 10-membered aryl; (3)R 1 With R 3 Connected to form a ring fused with a benzene ring, the ring is: a 6-10 membered aromatic ring, a 5-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring; In the above (2) and (3), the aryl, heterocyclic, heteroaryl, aromatic ring, heterocyclic ring and heteroaromatic ring are unsubstituted or substituted with one or more of the following substituents: O, N, -OH, halogen, amino, nitro, amine, -SH, methyl formate, methyl nitro, -C 1～6 Alkyl, C 2～5 Alkynyl, -OC 1～6 Alkyl, -C 1～6 Alkyl-amino or acetonitrile; R 3 and R 10 Each is independently selected from: -H, -OH, amino, halogen, nitro, -O-CF3, -C 1～6 Hydrocarbon, -NH-C 1～6 Hydrocarbon, -N(C 1～6 Hydrocarbon)2, -OC 1～6 Hydrocarbon, -C(O)-NH2, -C(O)-NH-C 1～6 Hydrocarbon, -NH-C(O)-C 1～6 hydrocarbon group, -6- to 10-membered aryl group, -5- to 10-membered heterocyclic group, -5- to 10-membered heteroaryl group, -C(O)-6- to 10-membered aryl group, -C(O)-5- to 10-membered heterocyclic group, -C(O)-5- to 10-membered heteroaryl group, 1～6 Alkyl-OC 1～6 Alkyl-6- to 10-membered aryl, -C 1～6 Alkyl-OC 1～6 Alkyl-5- to 10-membered heterocyclic group and -C 1～6 Alkyl-OC 1～6 Alkyl-5- to 10-membered heteroaryl; the -C 1～6 The hydrocarbon group is unsubstituted or substituted by one or more of the following substituents: halogen; the aryl, heterocyclic group, heteroaryl group is unsubstituted or substituted by one or more of the following substituents: O, -C 1～3 Alkyl or -COOH; R 5 and R 9 Each is independently selected from: -H, -OH, halogen, amino, -CF3, -SH, -C 1～6 Hydrocarbon, -OC 1～6 Hydrocarbon, -C 1～3 Alkyl-5- to 6-membered heterocyclic group and -5- to 6-membered heterocyclic group.

3. The use 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)2, -OC 1～6 Alkyl, -SC 1～6 Alkyl, -C(O)-C 1～6 Alkyl, -C 1～6 Alkyl-OC 1～6 Alkyl, -C 1～5 Alkyl-SC 1～6 Alkyl, -C(S)-C 1～6 Alkyl, -SO2-C 1～6 Alkyl, -C 1～6 Alkyl-NH-C 1～6 Alkyl, -C 1～6 Alkyl-N(C 1～6 Alkyl)2, -C(O)-NH2, -C(O)-NH-C 1～6 Alkyl, -C(O)-OC 1～6 Alkyl, -C(NH-C 1～6 Alkyl)2, -NH-C(O)-C 1～6 Alkyl, -NH-SO2-C 1～6 Alkyl, -N(C 1～6 Alkyl)-SO2-C 1～6 Alkyl, -SO2-NH2 and -SO2-NH-C 1～6 Alkyl; the -C 1～6 The alkyl group is unsubstituted or substituted with one or more of the following substituents: O, halogen, -OH, amino, -C 1～3 Alkyl-OH, methylsulfonyl, and methyl formate; (2) -6- to 10-membered aryl, -5- to 10-membered heterocyclic group, -5- to 10-membered heteroaryl, -C 1～6 Alkyl-6- to 10-membered aryl, -C 1～6 Alkyl-5- to 10-membered heterocyclic group, -C 1～6 alkyl-5- to 10-membered heteroaryl, -O-6- to 10-membered aryl, -O-5- to 10-membered heterocyclic group, -O-5- to 10-membered heteroaryl, -S-6- to 10-membered aryl, -S-5- to 10-membered heterocyclic group, -S-5- to 10-membered heteroaryl, -NH-6- to 10-membered aryl, -NH-5- to 10-membered heterocyclic group, -NH-5- to 10-membered heteroaryl, -C(O)-6- to 10-membered aryl, -C(O)-5- to 10-membered heterocyclic group, -C(O)-5- to 10-membered heteroaryl, -OC 1～6 Alkyl-6- to 10-membered aryl, -OC 1～6 Alkyl-5- to 10-membered heterocyclic group, -OC 1～6 Alkyl-5- to 10-membered heteroaryl, -C 1～6 Alkyl-OC 1～6 Alkyl-6- to 10-membered aryl, -C 1～6 Alkyl-OC 1～6 Alkyl-5- to 10-membered heterocyclic group, -C 1～6 Alkyl-OC 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 heterocyclic group, -C 1～6 Alkyl-NH-C(O)-5- to 10-membered heteroaryl, -CH(OH)-5- to 10-membered heteroaryl, -C(CH2)-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)-6- to 10-membered aryl, -NH-C(O)-5- to 10-membered heterocyclic group, -NH-C(O)-5- to 10-membered heteroaryl, -C(NH3 + )-6- to 10-membered aryl and -S(O)2-6- to 10-membered aryl; (3)R 1 With R 3 Connected to form a ring fused with a benzene ring, the ring is: a 6- to 8-membered aromatic ring, a 5- to 8-membered heterocyclic ring, or a 5- to 8-membered heteroaromatic ring; In the above (2) and (3), the aryl, heterocyclic, heteroaryl, aromatic ring, heterocyclic ring and heteroaromatic ring are unsubstituted or substituted with one or more of the following substituents: O, N, -OH, halogen, amino, nitro, amine, -SH, methyl formate, methyl nitro, -C 1～6 Alkyl, C 2～5 Alkynyl, -OC 1～6 Alkyl, -C 1～6 Alkyl-amino or acetonitrile; R 3 and R 10 Each is independently selected from: -H, -OH, amino, halogen, nitro, -O-CF3, -C 1～6 Alkyl, -NH-C 1～6 Alkyl, -N(C 1～6 Alkyl)2, -OC 1～6 Alkyl, -C(O)-NH2, -C(O)-NH-C 1～6 Alkyl, -NH-C(O)-C 1～6 alkyl, -6- to 10-membered aryl, -5- to 10-membered heterocyclic group, -5- to 10-membered heteroaryl, -C(O)-6- to 10-membered aryl, -C(O)-5- to 10-membered heterocyclic group, -C(O)-5- to 10-membered heteroaryl, -C 1～6 Alkyl-OC 1～6 Alkyl-6- to 10-membered aryl, -C 1～6 Alkyl-OC 1～6 Alkyl-5- to 10-membered heterocyclic group and -C 1～6 Alkyl-OC 1～6 Alkyl-5- to 10-membered heteroaryl; the -C 1～6 The alkyl group is unsubstituted or substituted by one or more of the following substituents: halogen; the aryl, heterocyclic group, heteroaryl group is unsubstituted or substituted by one or more of the following substituents: O, -C 1～3 Alkyl or -COOH; R 5 and R 9 Each is independently selected from: -H, -OH, halogen, amino, -CF3, -SH, -C 1～6 Alkyl, -OC 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-OC 1～6 Alkyl, -C(O)-NH2, -COOH, formate, pyridyl, and 1,3-benzodiazol-6-yl; or, R 2 or R 7 With R 5 or R 9 Connection Formation-C 2～5 Alkylene-; R 4 Selected from: -H, -C 1～6 Alkyl, -C 1～3 Alkyl-C(O)-OC 1～6 Alkyl and -5 to 6 membered heterocyclic group; the -C 1～6 Alkyl is unsubstituted or substituted with one or more of the following substituents: -COOH or -NH + (CH3)2; the -5- to 6-membered heterocyclic group is unsubstituted or substituted by one or more of the following substituents: -C 1～3 alkyl; R 6 and R 8 Each is independently selected from: -H, -OH, -SH, amino, halogen, cyano, nitro, -COOH, -C 1～6 Alkyl, -NH-C 1～6 Alkyl, -OC 1～6 Alkyl, -SO2-NH2, -C(O)-OC 1～6 Alkyl, -OC(O)-NH2, -NH-C(O)-OC 1～6 alkyl, -6- to 10-membered aryl, -5- to 10-membered heterocyclic group, -5- to 10-membered heteroaryl, and -OC 1～6 Alkyl-6- to 10-membered aryl; Preferably, in the general formula (I): R 2 and R 7 Each independently selected from: -H, -C 1～6 Alkyl, -C 1～6 Alkyl-OH and -C 1～6 Alkyl-OC 1～6 Alkyl; or, R 2 or R 7 With R 5 or R 9 Connection Formation-C 2～5 Alkylene-; or R 4 Selected from: -H, -C 1～6 Alkyl and -6-membered heterocyclic group; or R 6 and R 8 Each is independently selected from: -H, -OH, -SH, amino, halogen, -C 1～6 Alkyl, -NH-C 1～3 Alkyl, -OC 1～6 Alkyl and -NH-C(O)-OC 1～3 alkyl.

4. The use 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)2, -OC 1～3 Alkyl, -C(O)-C 1～3 Alkyl, -C 1～3 Alkyl-OC 1～3 Alkyl, -C 1～3 Alkyl-NH-C 1～3 Alkyl, -C 1～3 Alkyl-N(C 1～3 Alkyl)2, -C(O)-NH-C 1～3 Alkyl, -C(O)-OC 1～3 Alkyl, -NH-C(O)-C 1～3 Alkyl and -NH-SO2-C 1～3 Alkyl; the C 1～3 Alkyl is unsubstituted or substituted with one or more of the following substituents: halogen; (2) -phenyl, -5- to 6-membered heterocyclic group, -5- to 6-membered heteroaryl, -C 1～3 Alkyl-phenyl, -C 1～3 Alkyl-5- to 6-membered heterocyclic group, -C 1～3 alkyl-5- to 6-membered heteroaryl, -O-phenyl, -O-5- to 6-membered heterocyclic group, -O-5- to 6-membered heteroaryl, -C 1～3 Alkyl-OC 1～3 Alkyl-5- to 6-membered heteroaryl and -NH-C(O)-5- to 6-membered heteroaryl; the -phenyl, -5- to 6-membered heterocyclic 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 -OC 1～3 alkyl; (3)R 1 With R 3 Connected to form a ring fused with a benzene ring, the ring is: 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, heterocyclic group, heteroaryl group, benzene ring, heterocyclic ring and heteroaryl ring are unsubstituted or substituted with one or more of the following substituents: O, halogen, amino, nitro, -C 1～3 Alkyl or -OC 1～3 alkyl; R 2 and R 7 Each independently selected from: -H, -C 1～3 Alkyl and -C 1～3 Alkyl-OC 1～3 alkyl; R 3 Selected from: -H, amino, halogen, -O-CF3, -C 1～3 Alkyl, -OC 1～3 Alkyl, -NH-C(O)-C 1～3 alkyl, phenyl, -5- to 6-membered heterocyclic group, -5- to 6-membered heteroaryl, -C(O)-phenyl, -C(O)-5- to 6-membered heterocyclic group, -C(O)-5- to 6-membered heteroaryl, and -C 1～3 Alkyl-OC 1～3 Alkyl-5- to 6-membered heteroaryl; the phenyl, heterocyclic group, heteroaryl group is unsubstituted or substituted by one or more of the following substituents: -C 1～3 alkyl; R 4 Selected from: -H and -C 1～3 alkyl; R 5 and R 9 Each independently selected from: -H, -OH, -F, -SH and -OC 1～3 alkyl; R 6 and R 8 Each is independently selected from: -H, amino, halogen, -C 1～3 Alkyl, -OC 1～3 Alkyl and -NH-C 1～3 alkyl; R 10 Selected from: -H and -F; Preferably, in the general formula (I): R 2 Selected from: -H, -C 1～3 Alkyl and -C 1～3 Alkyl-OC 1～3 Alkyl; R 7 Selected from: -H; or R 4 Selected from: -H; or R 5 and R 9 All selected from: -H; More preferably, in the general formula (I): R 2 and R 7 All selected from: -H.

5. The use according to claim 1, wherein In the general formula (I): When R 1 When R is selected from a substituent other than H, 3 , R 5 , R 9 and R 10 All are H; or, when R 3 When R is selected from a substituent other than H, 1 , R 5 , R 9 and R 10 All are H; Preferably, in the general formula (I): R 1 is selected from non-H substituents, R 3 , R 5 , R 9 and R 10 Both are H.

6. The use according to claim 1, wherein The thiazole carboxamide compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

7. Use of the thiazolecarboxamide compounds represented by the general formula (I) in claims 1-6 or their pharmaceutically acceptable salts in the preparation of drugs for treating tumors.

8. The use according to claim 7, characterized in that The tumors include: blood tumors and solid tumors.

9. The use according to claim 7, characterized in that: The tumors include: acute promyelocytic leukemia, acute myeloid leukemia, mantle cell lymphoma and lung cancer.

10. The following thiazolecarboxamide compounds or pharmaceutically acceptable salts thereof:

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