Thiazole amine compound and application thereof

Abstract

The present application relates to a thiazole amine derivative and its use, the thiazole amine derivative has ROR gamma t regulation activity and / or DHODH regulation activity, especially inhibitory activity, for preparing the drug for preventing or treating ROR gamma t and / or DHODH related diseases.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a thiazolamine compound and its application. The thiazolamine derivative has RORγt-regulating activity and / or DHODH-regulating activity, especially inhibitory activity, and is used to prepare drugs for the prevention or treatment of RORγt and / or DHODH-related diseases. Background Technology

[0002] Retinoic acid receptor-related orphan receptors (RORs), as members of the nuclear receptor superfamily, can be divided into three subtypes: RORα (NR1F1), RORβ (NR1F2), and RORγ (NR1F3). Each ROR subtype has its own tissue distribution and regulates various physiological processes. RORα is widely distributed in adipose tissue, liver, skin, kidneys, skeletal muscle, lungs, thymus, and brain; RORβ has a more limited distribution, mainly expressed in the central nervous system; RORγ has two subtypes: RORγ1 and RORγ2 (also known as RORγt). RORγ1 is mainly expressed in the liver, skeletal muscle, adipose tissue, and kidneys, while RORγt is highly expressed only in immune tissues, such as the thymus. RORγt is a key regulator of T helper 17 (Th17) cell differentiation and the secretion of the inflammatory cytokine interleukin-17 (IL-17). Th17 cells play a crucial role in many mouse models of autoimmune diseases, such as experimental allergic encephalomyelitis (EAE) and collagen-induced arthritis (CIA). Furthermore, elevated IL-17 levels have been detected in several human autoimmune diseases, including rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis, and inflammatory bowel disease (IBD). Increased numbers of Th17 cells have been found in tissue and peripheral blood samples from patients with autoimmune diseases. Therefore, Th17 cells or their cytokine IL-17 are closely linked to inflammation and the pathogenesis of autoimmune diseases.

[0003] In January 2015, Cosentyx (Secukinumab / AIN457), a monoclonal antibody developed by Novartis that treats psoriasis by specifically blocking IL-17, was approved by the FDA. This was the first drug on the psoriasis treatment market to act on IL-17. This also highlights the importance of the IL-17 signaling pathway in inflammatory diseases and demonstrates the potential for treating inflammatory diseases by influencing the IL-17 signaling pathway through RORγt inhibitors. Therefore, RORγt can serve as a novel target for drugs treating autoimmune diseases. RORγt small molecule modulators, especially inhibitors, can be used to treat RORγt-mediated inflammation and autoimmune diseases. CN107257791A, CN108026039A, CN108026050A, CN108064224A, and CN108863850A disclose RORγt small molecule modulators and their uses.

[0004] Recent studies have found that RORγ is a key driver upstream of the androgen receptor (AR), directly regulating AR receptor expression. The RORγ gene is highly expressed in tumors of metastatic castration-resistant prostate cancer (mCRPC) patients and drives the transcription of AR receptors (including AR-V7 mutants) in tumors, closely related to aberrant tumor signaling pathways in mCRPC. RORγ inhibitors can significantly reduce AR expression in tumor cells, demonstrating inhibitory effects on tumor growth in various AR-dependent prostate cancer xenograft models and resisting resistance to hormone therapy. Therefore, RORγ is a novel target for the treatment of mCRPC and drug-resistant prostate cancer. Nature Medicine In 2016, 22(5), 488-496), the application of RORγ inhibitors in tumor treatment has been disclosed in patent (WO2017127442). RORγt and RORγ have the same sequence in the ligand-binding domain (LBD), only the N-terminal residues are different. Therefore, RORγt inhibitors also have RORγ inhibitory activity and can be used to treat mCRPC and drug-resistant prostate cancer.

[0005] Dihydroorotate dehydrogenase (DHODH) is a key rate-limiting enzyme in the de novo pyrimidine synthesis pathway. Inhibition of DHODH leads to the blockage of the de novo pyrimidine nucleotide synthesis pathway in cells, thereby affecting the excessive proliferation of immune cells and cancer cells. DHODH inhibitors have immunomodulatory activity, most pronounced on T cells, and helper T cells 1 (Th1) and Th17 cells are important contributing factors in the development of autoimmune diseases. Therefore, DHODH is considered an ideal therapeutic target for autoimmune diseases and cancer. For most organisms, pyrimidine bases can be obtained through both de novo and salvage synthesis pathways. For resting lymphocytes in the human body, the pyrimidines obtained through the salvage pathway are sufficient to meet their metabolic needs. However, the demand for pyrimidine bases by immune-activated lymphocytes and cancer cells cannot be met through the salvage pathway alone, necessitating the initiation of the de novo synthesis pathway to satisfy their physiological needs. In immune-activated lymphocytes, DHODH inhibition leads to metabolic stress, which further reduces the release of pro-inflammatory cytokines, including IL-17 (IL-17A and IL-17F) and interferon (IFN)-γ, and increases lymphocyte apoptosis. Therefore, DHODH inhibitors can inhibit DNA or RNA synthesis in immune-activated lymphocytes and tumor cells, exerting anti-tumor effects and playing a role in the treatment of autoimmune diseases; the inhibitory effect of DHODH on the release of pro-inflammatory cytokines can also be used to treat autoimmune diseases. Furthermore, pyrimidine synthesis inhibitors, represented by DHODH inhibitors, have broad-spectrum inhibitory effects against respiratory RNA viruses and participate in the host antiviral response. In virus-infected cells, rapid viral replication requires large amounts of intracellular nucleotides, and the de novo nucleotide synthesis pathway is crucial for viral replication. Compared to DNA viruses, RNA viruses require unique UMPs in their genome but do not require TMPs. UMPs are specific nucleotides produced by DHODH, meaning that RNA viruses may be more sensitive to DHODH activity. Therefore, DHODH inhibitors can suppress viral activity and limit the cytokine storm generated in the later stages of viral infection, representing a new direction in research on combating the novel coronavirus (COVID-19). Protein Cell , 2020, 11(10), 723-739).

[0006] Several DHODH inhibitors have been approved for marketing or are currently in clinical trials. Leflunomide has been approved for the treatment of rheumatoid arthritis (RA) that is refractory to methotrexate; its active metabolite, teriflunomid, has been approved for the treatment of relapsing-remitting multiple sclerosis (MS). Brequinar is currently in Phase II clinical trials for relapsed / refractory acute myeloid leukemia (AML) and for the treatment of COVID-19. Several patents disclose the use of various DHODH inhibitors for the treatment or prevention of autoimmune diseases, immune and inflammatory diseases, destructive bone diseases, malignant tumors, angiogenesis-related diseases, viral diseases, and infectious diseases. For example, W02009137081, W02009133379, W02009021696, W02009082691, W02009029473, W02009153043, US2009209557, US2009062318, US2009082374, W02008097180, W02008077639, US 2008027079, US2007299114, US2007027193, US2007224672, W02007149211, JP20070159 52. W02006044741, W02006001961, W02006051937, W02006038606, W02006022442, US2006 199856, W02005075410, US7074831, W02004056797.

[0007] RORγt is a key regulator of Th17 cells. Inhibiting RORγt prevents Th17 cell differentiation and reduces the production of pro-inflammatory cytokines IL-17 (IL-17A and IL-17F). DHODH is the rate-limiting enzyme in de novo pyrimidine synthesis. Inhibiting DHODH reduces pyrimidine nucleotide reserves, leading to lymphocyte metabolic inhibition and reducing the production of cytokines such as IL-17, IL-6, IL-1β, IFN-γ, and TNFα. Dual-target inhibition of RORγt and DHODH may produce stronger or even synergistic anti-inflammatory, anti-infective, or anti-tumor effects, thus providing greater therapeutic benefits. Furthermore, dual-target inhibition of RORγt and DHODH may reduce thymic aberrations caused by excessive RORγt inhibition and may also reduce side effects caused by excessive DHODH inhibition. Therefore, it is of great significance to find small molecule regulators (especially inhibitors) of RORγt and / or DHODH and use them for the prevention or treatment of autoimmune diseases, immune and inflammatory diseases, destructive bone diseases, hematologic cancers, malignant tumors, angiogenesis-related diseases, viral diseases and infectious diseases, as well as for the prevention or treatment of diseases related to cell ferroptosis. Summary of the Invention

[0008] Therefore, the present invention aims to provide a thiazolamine derivative and its application, wherein the thiazolamine derivative has RORγt-regulating activity and / or DHODH-regulating activity, especially inhibitory activity, for use in the preparation of a medicament for the prevention or treatment of RORγt and / or DHODH-related diseases.

[0009] In a first aspect, the present invention provides a compound as shown in formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (I) in, R1 and R2 are independently selected from H, or substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, aryl, aralkyl, heteroaryl, heterocycloyl, heteroaryl, or substituted or unsubstituted ring formed by R1 and R2 being linked together. The substituent is selected from halogen, hydroxyl, amino or substituted amino, cyano, nitro, carboxyl, acyl or substituted acyl, acyloxy or substituted acyloxy, amide or substituted amide, aryl or substituted aryl, aryloxy or substituted aryloxy, heteroaryl or substituted heteroaryl, heterocycloyl or substituted heterocycloyl, =N-OH, =NO-C1-C8 alkyl or -O-C1-C8 alkyl; R3 is selected from H, C1-C8 alkyl, halogen-substituted C1-C8 alkyl, halogen, cyano, C1-C8 alkoxy or halogen-substituted C1-C8 alkoxy; R4 is selected from H, C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, aryl, aralkyl, haloaryl, or haloaralkyl; X is selected from CH2, NH, and O; Y is selected from N and CH; X and Y are not both heteroatoms. R5 and R6 are independently selected from H, C1-C8 alkyl, or substituted or unsubstituted three- to seven-membered rings formed by R5 and R6 being linked together; the three- to seven-membered rings may or may not include N, O, or S heteroatoms, and the substituents are selected from C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, hydroxyl, amino or substituted amino, cyano, nitro, carboxyl, acyl or substituted acyl, acyloxy or substituted acyloxy, amide or substituted amide, aryl or substituted aryl, aryloxy or substituted aryloxy, heteroaryl or substituted heteroaryl, heterocyclic or substituted heterocyclic.

[0010] Preferably, R4 is H.

[0011] Preferably, when X is CH2, Y is N; or when X is O, Y is CH.

[0012] Preferably, when R5 and R6 are linked together to form a substituted or unsubstituted six-membered ring, the six-membered ring includes an N, O, or S heteroatom, and the N, O, or S heteroatom is located at the para position of Y. The substituent is linked to the N, O, or S heteroatom, and the substituent is selected from C1-C8 alkyl groups or... R7 is selected from C l -C8 alkyl, halogen-substituted C l -C8 alkyl, C3-C8 cycloalkyl, halogen-substituted C3-C8 cycloalkyl, or C3-C8 heterocycloalkyl.

[0013] Preferably, R7 is cyclopentyl or .

[0014] Preferably, the compound is selected from: .

[0015] Secondly, the present invention also provides a method for preparing the compound as described above, characterized in that it can be prepared by the following three synthetic schemes and steps: Synthesis Scheme 1: Reaction conditions: (a) tert -butyl piperazine-1-carboxylate, AcOH, NaBH(AcO)3, 0 o C to rt,overnight; (b) 4N HCl in dioxane, rt, 5h; (c) cyclopentanecarbonyl chloride,Et3N, DCM, 5h; (d) Pd2(dba)3, K3PO4, various 2-aminothiazol, t BuBrettPhos, t BuOH, 120 o C, 5 h.

[0016] 1) The aldehydes shown in Formula 1-1 undergo a reductive amination reaction with amines under the action of sodium triacetoxyborohydride to obtain the piperazine compounds protected by Boc- as shown in Formula 1-2. 2) The compound shown in Formula 1-2 is deprotected in the dioxane hydrochloride system and then reacted with acyl chloride in an alkaline environment to give the nitro compound shown in Formula 1-3; 3) The compounds shown in Formula 1-3 undergo the Buchwald reaction in the Pd2(dba)3 / K3PO4 system to obtain the target compound.

[0017] Synthesis Scheme 2: Reaction conditions: (a) NaNO2, H2SO4, H2O, 0 o C to 100 o C, 2 h; (b) tert -butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate, K2CO3, DMF, 90 °C, overnight; (c) 4 N HCl in dioxane, rt, 5 h; (d) T3P, 4,4,4-trifluoro-3-(trifluoromethyl)butanoic acid, Et3N, DCM, rt, overnight;; (e) Pd2(dba)3, K2CO3, various 2-aminothiazol, tBuBrettPhos, t BuOH, HOAc, 110 o C, 3-5 h.

[0018] 1) The amine compounds shown in Formula 2-1 undergo diazotization, hydroxylation, and nucleophilic substitution to obtain the piperazine compounds protected by Boc- as shown in Formula 2-2; 2) The compound shown in Formula 2-2 is deprotected in the dioxane hydrochloride system and then reacted with acid in the T3P / triethylamine system to give the bromobenzene compound shown in Formula 2-3; 3) The compound shown in Formula 2-3 undergoes the Buchwald reaction in the Pd2(dba)3 / K3PO4 system to obtain the target compound.

[0019] Synthesis Scheme 3: Reaction conditions: (a) Pd2(dba)3, K2CO3, 2-amino-6,7-dihydrobenzo[ d ]thiazol-4(5 H )-one, tBuBrettPhos, t BuOH, HOAc, 110 o C, 3-5 h; (b) various fattyAmineAcOH, NaBH(OAc)3, 0 o C to rt, overnight; 1) The compound shown in Formula 3-1 undergoes the Buchwald reaction in the Pd2(dba)3 / K3PO4 system to give the compound shown in Formula 2-2; 2) The aldehyde compound shown in Formula 3-2 undergoes a reductive amination reaction with an amine under the action of sodium triacetoxyborohydride to obtain the target compound.

[0020] Thirdly, the present invention also provides a pharmaceutical composition comprising the compound as described above, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0021] In a fourth aspect, the present invention also provides the use of the pharmaceutical composition described above in the preparation of a medicament for the prevention or treatment of diseases related to RORγt and / or DHODH, said diseases including autoimmune diseases, immune and inflammatory diseases, destructive bone diseases, malignant tumor diseases, angiogenesis-related diseases, viral diseases, and infectious diseases.

[0022] Preferably, the autoimmune disease is selected from multiple sclerosis, rheumatoid arthritis, psoriasis, or inflammatory bowel disease; the immune and inflammatory diseases are selected from encephalomyelitis, Crohn's disease, or asthma; the malignant tumor disease is selected from prostate cancer, triple-negative breast cancer, acute myeloid leukemia (AML), or lung cancer; and the viral and infectious diseases are selected from COVID-19 or SARS. Attached Figure Description

[0023] Figure 1 This is a graph showing the activity of compound I-29 provided by the present invention in a DSS-induced acute enteritis model. Detailed Implementation

[0024] This invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (I) in, R1 and R2 are independently selected from H, substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, aryl, aralkyl, heteroaryl, heterocycloyl, heteroaryl, or substituted or unsubstituted ring formed by connecting R1 and R2 together. The substituent is selected from halogen, hydroxyl, amino or substituted amino, cyano, nitro, carboxyl, acyl or substituted acyl, acyloxy or substituted acyloxy, amide or substituted amide, aryl or substituted aryl, aryloxy or substituted aryloxy, heteroaryl or substituted heteroaryl, heterocycloyl or substituted heterocycloyl, =N-OH, =NO-C1-C8 alkyl or -O-C1-C8 alkyl. R3 is selected from H, C1-C8 alkyl, halogen-substituted C1-C8 alkyl, halogen, cyano, C1-C8 alkoxy or halogen-substituted C1-C8 alkoxy; R4 is selected from H, C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, aryl, haloaryl or haloaryl; X is selected from CH2, NH, and O; Y is selected from N and CH; X and Y are not both heteroatoms. R5 and R6 are independently selected from H, C1-C8 alkyl, or substituted or unsubstituted three- to seven-membered rings formed by R5 and R6 being linked together; the three- to seven-membered rings may or may not include N or O heteroatoms, and when the three- to seven-membered rings include N or O heteroatoms, the N or O heteroatoms are located at the para position of Y, and the substituents are linked to the N or O heteroatoms, and the substituents are selected from C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, hydroxyl, amino or substituted amino, cyano, nitro, carboxyl, acyl or substituted acyl, acyloxy or substituted acyloxy, amide or substituted amide, aryl or substituted aryl, aryloxy or substituted aryloxy, heteroaryl or substituted heteroaryl, heterocyclic or substituted heterocyclic.

[0025] Preferably, R4 is H.

[0026] Preferably, when X is CH2, Y is N; or when X is O, Y is CH.

[0027] Preferably, when R5 and R6 are linked together to form a substituted or unsubstituted six-membered ring, the six-membered ring includes an N or O heteroatom, and the N or O heteroatom is located at the para position of Y. The substituent is linked to the N or O heteroatom, and the substituent is selected from C1-C8 alkyl groups or... R7 is selected from C l -C8 alkyl, halogen-substituted C l -C8 alkyl, C3-C8 cycloalkyl, halogen-substituted C3-C8 cycloalkyl, or C3-C8 heterocycloalkyl.

[0028] Preferably, R7 is cyclopentyl or .

[0029] The compounds provided by this invention can be synthesized using the following synthetic scheme 1, synthetic scheme 2, or synthetic scheme 3: Synthesis Scheme 1: Reaction conditions: (a) tert -butyl piperazine-1-carboxylate, AcOH, NaBH(AcO)3, 0 oC to rt,overnight; (b) 4N HCl in dioxane, rt, 5h; (c) cyclopentanecarbonyl chloride,Et3N, DCM, 5h; (d) Pd2(dba)3, K3PO4, various 2-aminothiazol, t BuBrettPhos, t BuOH, 120 o C, 5 h.

[0030] 1) The aldehydes shown in Formula 1-1 undergo a reductive amination reaction with amines under the action of sodium triacetoxyborohydride to obtain the piperazine compounds protected by Boc- as shown in Formula 1-2. 2) The compound shown in Formula 1-2 is deprotected in the dioxane hydrochloride system and then reacted with acyl chloride in an alkaline environment to give the nitro compound shown in Formula 1-3; 3) The compounds shown in Formula 1-3 undergo the Buchwald reaction in the Pd2(dba)3 / K3PO4 system to obtain the target compound.

[0031] Synthesis Scheme 2: Reaction conditions: (a) NaNO2, H2SO4, H2O, 0 o C to 100 o C, 2 h; (b) tert -butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate, K2CO3, DMF, 90 °C, overnight; (c) 4 N HCl in dioxane, rt, 5 h; (d) T3P, 4,4,4-trifluoro-3-(trifluoromethyl)butanoic acid, Et3N, DCM, rt, overnight;; (e) Pd2(dba)3, K2CO3, various 2-aminothiazol, tBuBrettPhos, t BuOH, HOAc, 110 o C, 3-5 h.

[0032] 1) The amine compounds shown in Formula 2-1 undergo diazotization, hydroxylation, and nucleophilic substitution to obtain the piperazine compounds protected by Boc- as shown in Formula 2-2; 2) The compound shown in Formula 2-2 is deprotected in the dioxane hydrochloride system and then reacted with acid in the T3P / triethylamine system to give the bromobenzene compound shown in Formula 2-3; 3) The compound shown in Formula 2-3 undergoes the Buchwald reaction in the Pd2(dba)3 / K3PO4 system to obtain the target compound.

[0033] Synthesis Scheme 3: Reaction conditions: (a) Pd2(dba)3, K2CO3, 2-amino-6,7-dihydrobenzo[ d ]thiazol-4(5 H )-one, tBuBrettPhos, t BuOH, HOAc, 110 o C, 3-5 h; (b) various fattyAmineAcOH, NaBH(OAc)3, 0 o C to rt, overnight; 1) The compound shown in Formula 3-1 undergoes the Buchwald reaction in the Pd2(dba)3 / K3PO4 system to give the compound shown in Formula 2-2; 2) The aldehyde compound shown in Formula 3-2 undergoes a reductive amination reaction with an amine under the action of sodium triacetoxyborohydride to obtain the target compound.

[0034] Unless otherwise stated, the groups and terms used in the above synthetic schemes have the same meanings as those used in compounds of general formula I.

[0035] The above synthesis schemes only illustrate some of the preparation methods of the compounds in this invention. With reference to commonly used techniques in the field and existing technologies, those skilled in the art can use similar methods to synthesize the compounds of this invention based on the above synthesis schemes.

[0036] The "compounds" described in this invention include all stereoisomers, geometric isomers, tautomers, and isotopes.

[0037] The "compound" described in this invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. Compounds containing asymmetric carbon atoms in this invention may be isolated in optically active pure form or in racemic form; the optically active pure form may be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0038] The "compound" described in this invention also includes a tautomer form; the tautomer form is derived from the exchange of a single bond with an adjacent double bond and the migration of a proton.

[0039] This invention also includes atoms of all isotopes, whether in intermediates or the final compound; isotopic atoms include those having the same number of atoms but different mass numbers, for example, hydrogen isotopes include deuterium and tritium. Furthermore, if desired, for example for specific therapeutic or diagnostic purposes, the compounds of this invention may incorporate isotopes or radioactive isotopes known in the art, such as... 3 H, 15 O、 13 C or 13 Nitrogen isotopes.

[0040] "Pharmaceutically acceptable salts" refer to salts that are pharmaceutically acceptable in maintaining the pharmacological activity of their parent compounds while improving their physicochemical or metabolic properties. These salts include acid addition salts and base addition salts, or mixtures thereof, prepared from pharmaceutically acceptable acids or bases (including organic acids, inorganic acids, organic bases, and inorganic bases). In this invention, suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or similar acids; suitable organic acids include acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, mandelic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, salicylic acid, stearic acid, mucoconic acid, or their analogues.

[0041] The compounds according to the invention can also exist in their solvated forms, such as hydrates (hemihydrates, monohydrates, dihydrates, trihydrates, etc.).

[0042] Unless otherwise specified, the terms used in this invention have the following meanings.

[0043] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0044] The term "amino" refers to -NH2.

[0045] The term "cyano" refers to -CN.

[0046] The term "nitro" refers to -NO2.

[0047] The term "hydroxyl group" refers to -OH.

[0048] The term "thiol" refers to -SH.

[0049] The term "carbonyl" refers to C=O.

[0050] The term "carboxyl group" refers to -C(=O)OH.

[0051] The term "carboxylic acid ester group" refers to -C(=O)O (alkyl) or -C(=O)O (cycloalkyl), where alkyl and cycloalkyl are as defined above.

[0052] The term "sulfonyl" refers to -S(=O)2 (alkyl) or -S(=O)2 (cycloalkyl), where alkyl and cycloalkyl are as defined above.

[0053] The term "sulfinyl" refers to -S(=O) (alkyl) or -S(=O) (cycloalkyl), where alkyl and cycloalkyl are as defined above.

[0054] The term "phosphoryl group" refers to -P(=O)(OH)2.

[0055] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms, specifically a straight-chain or branched alkyl group containing 1 to 20 carbon atoms (C1-C2). 20 Alkyl groups, preferably C1-C8 alkyl groups, more preferably C1-C6 alkyl groups, such as methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl), and hexyl (n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl). The alkyl group may be unsubstituted or substituted by one or more substituents, including but not limited to alkyl, alkoxy, alkylthio, alkylamino, halogen, amino, cyano, nitro, hydroxy, mercapto, aryl, heteroaryl, carbonyl, carboxyl, carboxylic acid ester, sulfonyl, sulfinyl, phosphoryl, etc., forming a haloalkyl group, preferably a C1-C6 haloalkyl group.

[0056] The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl; the alkenyl group may be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, alkoxy, alkylthio, alkylamino, halogen, amino, cyano, nitro, hydroxy, mercapto, aryl, heteroaryl, carbonyl, carboxyl, carboxylic acid ester, sulfonyl, sulfinyl, and phosphoryl.

[0057] The term "alkynyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, etc.; the alkynyl group may be unsubstituted or substituted by one or more substituents, including but not limited to alkyl, alkoxy, alkylthio, alkylamino, halogen, amino, cyano, nitro, hydroxy, mercapto, aryl, heteroaryl, carbonyl, carboxyl, carboxylic acid ester, sulfonyl, sulfinyl, and phosphoryl.

[0058] The term "alkoxy" refers to -O-alkyl, where the alkyl group is as defined above.

[0059] The term "cycloalkyl" refers to a cyclic hydrocarbon substituent of a saturated or partially unsaturated monocyclic or polycyclic (fused, spiro, or bridged) ring containing 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, spiro[3.4]octyl, bicyclo[3.1.1]hexyl, etc. The cycloalkyl group may be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, alkoxy, alkylthio, alkylamino, halogen, amino, cyano, nitro, hydroxy, mercapto, aryl, heteroaryl, carbonyl, carboxyl, carboxylic acid ester, sulfonyl, sulfinyl, phosphoryl, for example forming a halocycloalkyl group, preferably a C3-C8 halocycloalkyl group, more preferably a C3-C6 halocycloalkyl group.

[0060] The term "heterocyclic alkyl" refers to a monocyclic or polycyclic (fused, spiro, or bridged) cyclic hydrocarbon substituent that is saturated or partially unsaturated and contains one or more heteroatoms of N, O, or S. Heterocyclic alkyl groups contain 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; preferably, they contain 3 to 6 ring atoms, of which 1 to 2 are heteroatoms. Typically, they are 3- to 6-membered heterocyclic groups containing one or more heteroatoms of N, O, or S, such as azirropropane-1-yl, oxadienobutane-3-yl, azirrobutane-3-yl, azirrobutane-1-yl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazineyl, morpholinyl, and their derivatives. The heterocyclic alkyl group may be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, alkoxy, alkylthio, alkylamino, halogen, amino, cyano, nitro, hydroxy, mercapto, aryl, heteroaryl, carbonyl, carboxyl, carboxylic acid ester, sulfonyl, sulfinyl, phosphoryl, for example forming a halocyclic heterocyclic alkyl group, preferably a halocyclic heterocyclic alkyl group containing 3-8 ring atoms.

[0061] The term "aryl" refers to a fully carbon monocyclic or fused ring with a fully conjugated π-electron system, typically having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms. The aryl group can be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, alkoxy, alkylthio, alkylamino, halogen, amino, cyano, nitro, hydroxy, mercapto, aryl, heteroaryl, carbonyl, carboxyl, carboxylic acid ester, sulfonyl, sulfinyl, and phosphoryl groups. Examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracene.

[0062] The term "heteroaryl" refers to a monocyclic or fused ring containing 5-12 ring atoms, of which 1-4 are selected from N, O, and S, and the remaining ring atoms are C, and which has a fully conjugated π-electron system. Heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, and tetrazolyl. Heteroaryl groups can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkoxy, alkylthio, alkylamino, halogen, amino, cyano, nitro, hydroxyl, mercapto, aryl, heteroaryl, carbonyl, carboxyl, carboxylic acid ester, sulfonyl, sulfinyl, and phosphoryl groups.

[0063] The term "aralkyl" refers to -(alkyl)-(aryl), where alkyl and aryl are defined as above.

[0064] The term "heteroaryl" refers to -(alkyl)-(heteroaryl), where alkyl and heteroaryl are as defined above.

[0065] The term "chemical bond" refers to a single bond, double bond, or triple bond.

[0066] The term "heteroatom" refers to atoms other than carbon atoms.

[0067] Administration and pharmaceutical compositions Generally, the compounds of the present invention can be administered in an effective amount via any acceptable route of administration for other similar uses. For example, the compounds of the present invention can be administered orally, parenterally, transdermally, topically, rectally, or intranasally.

[0068] When used as a pharmaceutical, the compounds of the present invention are typically administered in the form of pharmaceutical compositions. These compositions are prepared using methods well known in the pharmaceutical field and contain at least one active compound. In formulating the compositions provided by the present invention, the active ingredient is typically mixed with an excipient, diluted by the excipient, or encapsulated in a container of capsules, sachets, paper, or other forms. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid substance and can serve as a carrier, transporter, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, sprays (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0069] Some typical excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, astragalus gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. Other excipients may include lubricants (such as talc, magnesium stearate, and mineral oil), wetting agents, emulsifiers and suspending agents, preservatives (such as methylparaben and propylparaben), sweeteners, and flavor enhancers. The pharmaceutical compositions of the present invention can achieve rapid, sustained, or delayed release of the active pharmaceutical ingredient after administration to a patient via specific excipient methods, which is a widely used method in the art.

[0070] The amount of the active ingredient, i.e. the compound in this invention, in the drug composition and unit dosage form can be changed or significantly adjusted according to the specific application, the activity of the specific compound, and the expected concentration.

[0071] “Treatment” means any treatment of disease in a mammal, including: (1) preventing disease, i.e. causing the symptoms of clinical disease to not develop; (2) suppressing disease, i.e. preventing the development of clinical symptoms; and (3) alleviating disease, i.e. causing the clinical symptoms to subside.

[0072] Example The technical solution of the present invention will be further described below with reference to specific embodiments; however, the scope of protection of the present invention is not limited to these embodiments. All changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention.

[0073] In the method for preparing the target compound provided by this invention, column chromatography uses silica gel (200-300 mesh) produced by Rushan Taiyang Desiccant Co., Ltd.; thin-layer chromatography uses GF254; nuclear magnetic resonance chromatography (NMR) is performed using a Varian-400 NMR spectrometer; and liquid chromatography-mass spectrometry (LC / MS) is performed using an Agilent Technologi ESI 6120 LC / MS system. Furthermore, all operations involving easily oxidized or hydrolyzed raw materials are performed under nitrogen protection. Unless otherwise stated, the raw materials used in this invention are commercially available and can be used directly without further purification.

[0074] Example 1: General synthetic method for compounds I-1 to I-26, I-33 to I-34 (Synthetic scheme 1 above) Step 1: 1-1 substituted benzaldehyde (1 equivalent), 1-tert-butyloxycarbonylpiperazine (1.1 equivalent), and acetic acid (1.1 equivalent) were dissolved in dichloromethane and reacted with stirring at room temperature for 1 hour. Then, sodium triacetoxyborohydride (3 equivalents) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was confirmed to be complete by TLC, the reaction was quenched by adding saturated NaHCO3 solution. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product 1-2.

[0075] Step 2: Crude product 1-2 was dissolved in dichloromethane, and dioxane hydrochloride solution was added. The reaction was carried out overnight at room temperature. The supernatant of the reaction solution was discarded, and the residue was concentrated under reduced pressure. The concentrated residue was dissolved in dichloromethane and triethylamine (3 equivalents), and cyclopentylformyl chloride (1.2 equivalents) was slowly added dropwise. The reaction was carried out overnight at room temperature. After the reaction was confirmed to be complete by TLC, the reaction was quenched by adding saturated NaHCO3 solution. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 1-3.

[0076] Step 3: Crude product 1-3 was dissolved in tert-butanol, and Pd2(dba)3 (0.1 equivalent) was added. t BuBrettPhos (0.3 equivalents), K3PO4 (1.4 equivalents), and the corresponding 2-aminothiazole (1 equivalent), under nitrogen atmosphere, 110 °C o After reacting overnight, the reaction was detected by TLC to be complete. The reaction solution was diluted with ethyl acetate, the organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and a reversed-phase medium-pressure preparation system to obtain compounds I-1 to I-26, I-33 to I-34.

[0077] Example 2: Preparation of Compound I-1 Cyclopentyl(4-(2-methyl-3-(thiazol-2-ylamino)benzyl)piperazin-1-yl)methyl ketone Compound I-1. 1 H NMR (400 MHz, DMSO- d 6) δ 9.19 (s, 1H), 7.63 (d, J = 7.8Hz, 1H), 7.16 – 7.09 (m, 2H), 7.02 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 3.6 Hz,1H), 3.46 (s, 2H), 3.48 – 3.40 (m, 4H), 3.00 – 2.90 (m, 1H), 2.39 – 2.28 (m,4H), 2.24 (s, 3H), 1.79 – 1.47 (m, 8H). 13 C NMR (151 MHz, DMSO- d 6) δ 173.24,166.92, 139.98, 138.69, 137.02, 129.82, 125.95, 125.38, 121.55, 107.93,60.66, 53.16, 52.60, 44.96, 41.32, 40.05, 39.99, 29.57, 25.64, 13.31. HRMS(ESI + m / z calcd for C 21 H 28 N4OS [M+H] + : 385.2057; found: 385.2060. Example 3: Preparation of compound I-2 cyclopentyl(4-(2-methyl-3-((5-methylthiazol-2-yl)amino)benzyl)piperazin-1-yl) methyl ketone Compound I-2. 1 H NMR (400 MHz, DMSO- d 6) δ 8.95 (s, 1H), 7.62 (d, J = 8.0Hz, 1H), 7.09 (d, J= 7.8 Hz, 1H), 6.98 (d, J = 7.1 Hz, 1H), 6.79 (d, J = 1.3Hz, 1H), 3.45 (brs, 6H), 2.93 (dd, J = 15.5, 7.2 Hz, 1H), 2.42 – 2.27 (m,4H), 2.27 – 2.19 (m, 6H), 1.80 – 1.43 (m, 8H). HRMS (ESI + ) m / z calcd forC 22 H 30 N4OS [M+H] + : 399.2; found: 399.2. Example 4: Preparation of compound I-3 cyclopentyl(4-(2-methyl-3-((4-methylthiazol-2-yl)amino)benzyl)piperazin-1-yl)methyl ketone Compound I-3. 1 H NMR (400 MHz, DMSO- d 6) δ 9.10 (s, 1H), 7.60 (d, J = 7.7Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.30 (d, J = 0.9Hz, 1H), 3.45 (brs, 6H), 3.05 – 2.85 (m, 1H), 2.41 – 2.27 (m, 4H), 2.24 (s,3H), 2.14 (s, 3H), 1.80 – 1.43 (m, 8H). HRMS (ESI + m / z calcd for C 22 H 30 N4OS [M+H] + : 399.2; found: 399.2. Example 5: Preparation of compound I-4 cyclopentyl(4-(3-((4,5-dimethylthiazol-2-yl)amino)-2-methylbenzyl)piperazin-1-yl) methyl ketone Compound I-4. 1 H NMR (400 MHz, DMSO- d 6) δ 8.87 (s, 1H), 7.58 (d, J = 7.8Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 7.1 Hz, 1H), 3.44 (brs, 6H), 3.02 – 2.87 (m, 1H), 2.33 (d, J = 17.3 Hz, 4H), 2.22 (s, 3H), 2.14 (s, 3H), 2.05 (s, 3H), 1.80 – 1.45 (m, 8H). HRMS (ESI + m / z calcd for C 23 H 32 N4OS [M+H] + : 412.2; found: 412.3. Example 6: Preparation of compound I-5 cyclopentyl(4-(3-((5-ethylthiazol-2-yl)amino)-2-methylbenzyl)piperazin-1-yl)methyl ketone Compound I-5. 1 H NMR (400 MHz, DMSO- d 6) δ 8.97 (s, 1H), 7.60 (d, J = 7.8Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.82 (s, 1H), 3.45 (s, 6H), 2.99 – 2.89 (m, 1H), 2.64 (tt, J = 7.5, 3.7 Hz, 2H), 2.33 (d, J = 17.3 Hz, 4H), 2.23 (s, 3H), 1.80 – 1.46 (m, 8H), 1.17 (t, J = 7.5 Hz, 3H).HRMS (ESI + m / z calcd for C 23 H32 N4OS [M+H] + : 412.2; found: 412.3. Example 7: Preparation of compound I-6 cyclopentyl(4-(3-((4-ethylthiazol-2-yl)amino)-2-methylbenzyl)piperazin-1-yl)methyl ketone Compound I-6. 1 H NMR (400 MHz, DMSO- d 6) δ 9.12 (s, 1H), 7.60 (d, J = 7.7Hz, 1H), 7.14 (dd, J = 16.6, 8.9 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.30 (s,1H), 3.47 (s, 6H), 3.00 – 2.86 (m, 1H), 2.54 – 2.45 (m, 2H), 2.35 (d, J =16.8 Hz, 4H), 2.24 (s, 3H), 1.81 – 1.45 (m, 8H), 1.16 (t, J = 7.5 Hz, 3H).HRMS (ESI + m / z calcd for C 23 H 32 N4OS [M+H] + : 412.2; found: 412.3. Example 8: Preparation of compound I-7 cyclopentyl(4-(2-methyl-3-((5-propylthiazo-2-yl)amino)benzyl)piperazin-1-yl) methyl ketone Compound I-7. 1 H NMR (400 MHz, DMSO- d 6) δ 9.00 (s, 1H), 7.64 (d, J = 7.6Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 7.00 (d, J= 7.1 Hz, 1H), 6.84 (s, 1H), 3.46 (brs, 6H), 3.01 – 2.87 (m, 1H), 2.60 (t, J = 7.2 Hz, 2H), 2.35 (d, J =16.7 Hz, 4H), 2.25 (s, 3H), 1.84 – 1.45 (m, 10H), 0.92 (t, J = 7.3 Hz, 3H).HRMS (ESI + m / z calcd for C 24 H 34 N4OS [M+H] + : 426.3; found: 426.3. Example 9: Preparation of compound I-8 cyclopentyl(4-(2-methyl-3-((4-propylthiazo-2-yl)amino)benzyl)piperazin-1-yl) methyl ketone Compound I-8. 1 H NMR (400 MHz, DMSO- d 6) δ 9.12 (s, 1H), 7.61 (d, J = 7.7Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.1 Hz, 1H), 6.30 (s, 1H), 3.46 (brs, 6H), 3.02 – 2.81 (m, 1H), 2.45 (t, J = 7.4 Hz, 2H), 2.34 (d, J =16.6 Hz, 4H), 2.24 (s, 3H), 1.78 – 1.47 (m, 10H), 0.90 (t, J = 7.4 Hz, 3H).HRMS (ESI + m / z calcd for C 24 H 34 N4OS [M+H] + : 426.3; found: 426.3. Example 10: Preparation of compound I-9 cyclopentyl(4-(3-((5-isopropylthiazo-2-yl)amino)-2-methylbenzyl)piperazin-1-yl)methyl ketone Compound I-9. 1 H NMR (400 MHz, DMSO- d 6) δ 8.97 (s, 1H), 7.59 (d, J = 7.6Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 7.1 Hz, 1H), 6.82 (d, J = 1.0Hz, 1H), 3.45 (brs, 6H), 2.98 (ddd, J = 22.1, 14.0, 7.5 Hz, 2H), 2.33 (d, J =17.1 Hz, 4H), 2.23 (s, 3H), 1.79 – 1.42 (m, 8H), 1.22 (t, J = 7.7 Hz, 6H).HRMS (ESI + m / z calcd for C 24 H 34 N4OS [M+H] + : 426.3; found: 426.3. Example 11: Preparation of compound I-10 cyclopentyl(4-(3-((4-isopropylthiazolyl-2-yl)amino)-2-methylbenzyl)piperazin-1-yl) methyl ketone Compound I-10. 1 H NMR (400 MHz, DMSO- d 6) δ 9.14 (s, 1H), 7.64 (d, J = 7.8Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.29 (d, J = 0.5Hz, 1H), 3.47 (brs, 6H), 2.94 (dd, J= 15.4, 7.4 Hz, 1H), 2.80 (dt, J = 13.7, 6.9 Hz, 1H), 2.36 (d, J = 16.6 Hz, 4H), 2.26 (s, 3H), 1.80 – 1.45 (m, 8H), 1.20 (d, J = 6.9 Hz, 6H). HRMS (ESI + m / z calcd for C 24 H 34 N4OS [M+H] + : 426.3;found: 426.3. Example 12: Preparation of compound I-11 cyclopentyl(4-(3-((4-ethyl-5-methylthiazolyl-2-yl)amino)-2-methylbenzyl)piperazin-1-yl) methyl ketone Compound I-11. 1 H NMR (400 MHz, DMSO- d 6) 1 H NMR (400 MHz, DMSO) δ 8.89 (s,1H), 7.60 (d, J = 7.9 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 7.1 Hz,1H), 3.44 (brs, 6H), 2.93 (dd, J = 15.5, 7.3 Hz, 1H), 2.41 (q, J = 7.5 Hz, 2H), 2.33 (d, J = 17.7 Hz, 4H), 2.23 (s, 3H), 2.15 (s, 3H), 1.78 – 1.46 (m,8H), 1.11 (t, J = 7.5 Hz, 3H). HRMS (ESI + m / z calcd for C 24 H 34 N4OS [M+H] + :426.3; found: 426.3. Example 13: Preparation of compound I-12 cyclopentyl(4-(3-((4-(1-hydroxyethyl)-5-methylthiazolyl-2-yl)amino)-2-methylbenzyl)piperazin-1-yl) methyl ketone Compound I-12. 1 H NMR (400 MHz, DMSO- d 6) δ 8.92 (s, 1H), 7.62 (d, J = 7.9Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 7.1 Hz, 1H), 4.73 (d, J = 4.5Hz, 1H), 4.71 – 4.64 (m, 1H), 3.45 (brs, 6H), 2.93 (dd, J = 15.5, 7.4 Hz, 1H), 2.33 (d, J = 17.5 Hz, 4H), 2.23 (s, 6H), 1.79 – 1.47 (m, 8H), 1.33 (d, J = 6.3 Hz, 3H). HRMS (ESI + m / z calcd for C 24 H 34 N4O2S [M+H] + : 443.2; found:443.2. Example 14: Preparation of compound I-13 cyclopentyl(4-(3-((5-(1-hydroxyethyl)-4-methylthiazolyl-2-yl)amino)-2-methylbenzyl)piperazin-1-yl) methyl ketone Compound I-13. 1 H NMR (400 MHz, DMSO- d 6) δ 8.95 (s, 1H), 7.54 (d, J = 7.9Hz, 1H), 7.14 – 7.09 (m, 1H), 7.02 (t, J = 6.7 Hz, 1H), 5.17 (d, J= 3.6 Hz,1H), 4.92 – 4.82 (m, 1H), 3.41 (brs, 6H), 3.00 – 2.89 (m, 1H), 2.33 (d, J =17.6 Hz, 6H), 2.23 (s, 4H), 1.80 – 1.46 (m, 8H), 1.29 (t, J = 6.5 Hz, 3H).HRMS (ESI + m / z calcd for C 24 H 34 N4O2S [M+H] + : 443.2; found: 443.2. Example 15: Preparation of compound I-14 cyclopentyl(4-(2-methyl-3-((4-phenylthiazol-2-yl)amino)benzyl)piperazin-1-yl)methyl ketone Compound I-14. 1 H NMR (400 MHz, DMSO- d 6) δ 9.36 (s, 1H), 7.89 – 7.81 (m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.28 (t, J = 7.3 Hz,1H), 7.21 (s, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 3.48(s, 2H), 3.51 – 3.40 (m, 4H), 3.03 – 2.89 (m, 1H), 2.41 – 2.30 (m, 4H), 2.29(s, 3H), 1.82 – 1.43 (m, 8H). 13 C NMR (101 MHz, DMSO- d6) δ 173.22, 166.29,149.97, 139.78, 137.13, 134.68, 130.20, 128.49, 127.37, 126.22, 125.55,125.47, 121.72, 102.56, 60.63, 53.11, 52.54, 44.95, 41.32, 30.90, 29.54,25.60, 13.43. HRMS (ESI + m / z calcd for C 27 H 32 N4OS [M+H] + : 461.2370; found:461.2367.

[0078] Example 16: Preparation of compound I-15 cyclopentyl(4-(2-methyl-3-((5-phenylthiazol-2-yl)amino)benzyl)piperazin-1-yl)methyl ketone Compound I-15. 1 H NMR (400 MHz, DMSO- d 6) δ 9.43 (s, 1H), 7.64 (d, J = 7.6Hz, 1H), 7.59 (s, 1H), 7.51 – 7.45 (m, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.23(t, J = 7.4 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.08 (d, J = 7.1 Hz, 1H), 3.48(s, 2H), 3.51 – 3.42 (m, 4H), 3.00 – 2.90 (m, 1H), 2.42 – 2.31 (m, 4H), 2.29(s, 3H), 1.80 – 1.47 (m, 8H). 13 C NMR (101 MHz, DMSO- d6) δ 173.22, 166.04,139.54, 137.17, 135.11, 132.00, 130.47, 128.95, 126.55, 126.42, 125.99,125.46, 124.92, 122.22, 60.57, 53.13, 52.58, 44.93, 41.31, 29.54, 25.60,13.32. HRMS (ESI + m / z calcd for C 27 H 32 N4OS [M+H] + : 461.2370; found: 461.2372.

[0079] Example 17: Preparation of compound I-16 cyclopentyl(4-(2-methyl-3-((4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)amino)benzyl)piperazin-1-yl) methyl ketone Compound I-16. 1 H NMR (600 MHz, DMSO- d 6) δ 8.95 (s, 1H), 7.60 (d, J = 7.8Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 3.45 (s, 2H), 3.53 – 3.37 (m, 4H), 2.99 – 2.90 (m, 1H), 2.55 – 2.52 (m, 2H), 2.48 – 2.43(m, 2H), 2.39 – 2.28 (m, 4H), 2.23 (s, 3H), 1.78 – 1.70 (m, 6H), 1.68 – 1.47 (m, 6H). 13 C NMR (151 MHz, DMSO- d6) δ 173.23, 163.31, 144.91, 140.08, 136.89,129.68, 125.68, 125.31, 121.46, 115.84, 60.67, 53.15, 52.59, 44.95, 41.32,40.05, 29.57, 26.35, 25.64, 23.11, 22.65, 22.46, 13.32. HRMS (ESI + ) m / z calcdfor C 25 H 34 N4OS [M+H] + : 439.2526; found: 439.2530.

[0080] Example 18: Compound I-17 cyclopentyl(4-(2-methyl-3-((5,6,7,8-tetrahydro-4-)) H Preparation of cycloheptyl[d]thiazolyl-2-yl)amino)benzyl)piperazin-1-yl)methyl ketone Compound I-17. 1 H NMR (400 MHz, DMSO- d 6) δ 8.83 (s, 1H), 7.58 (d, J = 7.8Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 3.44 (s, 2H), 3.50 – 3.39 (m, 4H), 3.00 – 2.89 (m, 1H), 2.70 – 2.53 (m, 4H), 2.39 – 2.27(m, 4H), 2.22 (s, 3H), 1.81 – 1.44 (m, 14H). 13 C NMR (151 MHz, DMSO- d6) δ173.24, 161.25, 149.57, 140.28, 136.91, 129.47, 125.53, 125.32, 121.06,118.96, 79.18, 60.68, 53.15, 52.58, 44.95, 41.31, 40.05, 39.99, 31.43, 30.75,29.57, 27.93, 26.31, 25.64, 25.13, 13.30. HRMS (ESI + m / z calcd for C 26 H 36 N4OS[M+H] + : 453.2683; found: 453.2693.

[0081] Example 19: Compound I-18 cyclopentyl(4-(3-((5,6-dihydro-4-)) H Preparation of cyclopentyl[d]thiazolyl-2-yl)amino)-2-methylbenzyl)piperazin-1-yl)methyl ketone Compound I-18. 1 H NMR (400 MHz, DMSO- d 6) δ 9.03 (s, 1H), 7.62 (d, J = 7.7Hz, 1H), 7.11 (t, J = 7.7 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 3.45 (s, 2H), 3.53 – 3.37 (m, 4H), 3.01 – 2.91 (m, 1H), 2.76 – 2.53 (m, 4H), 2.42 – 2.26(m, 6H), 2.24 (s, 3H), 1.80 – 1.46 (m, 8H). 13 C NMR (151 MHz, DMSO- d6) δ173.08, 169.59, 155.66, 139.63, 136.75, 129.39, 125.56, 125.16, 121.29,119.99, 79.02, 60.52, 53.00, 52.44, 44.80, 41.17, 39.90, 29.41, 27.42, 26.15,25.81, 25.48, 13.17. HRMS (ESI + m / z calcd for C 24 H 32 N4OS [M+H] + : 425.2370;found: 425.2374.

[0082] Example 20: Compound I-19 cyclopentyl(4-(3-((6,7-dihydro-4-)) H Preparation of pyrano[4,3-d]thiazolyl-2-yl)amino)-2-methylbenzyl)piperazin-1-yl)methyl ketone Compound I-19. 1 H NMR (400 MHz, DMSO- d 6) δ 9.10 (s, 1H), 7.60 (d, J = 7.8Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 4.55 (s, 2H), 3.87 (t, J = 5.4 Hz, 2H), 3.45 (s, 2H), 3.53 – 3.37 (m, 4H), 3.01 – 2.85 (m,1H), 2.59 – 2.53 (m, 2H), 2.41 – 2.27 (m, 4H), 2.24 (s, 3H), 1.81 – 1.46 (m,8H). 13 C NMR (151 MHz, DMSO- d6) δ 173.24, 164.68, 142.80, 139.83, 137.00,129.93, 125.98, 125.37, 121.74, 113.52, 79.17, 64.59, 63.18, 60.64, 53.16,52.59, 44.96, 41.32, 40.06, 29.57, 27.28, 25.64, 13.32. HRMS (ESI + ) m / z calcdfor C 24 H 32 N4O2S [M+H] + : 441.2319; found: 441.2323.

[0083] Example 21: Preparation of compound I-20 cyclopentyl(4-(3-((7-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)amino)-2-methylbenzyl)piperazin-1-yl) methyl ketone Compound I-20. 1 H NMR (400 MHz, DMSO) δ 9.16 (s, 1H), 7.54 (d, J = 7.6Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 4.29 (s, 1H), 3.47 (s, 2H), 3.51 – 3.41 (m, 4H), 3.31 – 3.26 (m, 3H), 3.02 – 2.88 (m, 1H), 2.40 – 2.29 (m, 4H), 2.25 (s, 3H), 1.90 – 1.47 (m, 12H). 13 C NMR (101 MHz, DMSO- d 6) δ 173.21, 165.61, 148.16, 139.78, 137.06, 130.52, 126.25, 125.38,122.26, 116.77, 72.24, 60.56, 55.36, 53.12, 52.55, 44.93, 41.30, 29.54,28.36, 26.48, 25.59, 18.79, 13.28. HRMS (ESI +m / z calcd for C 25 H 34 N4O2S [M+Na] + : 477.2295; found: 477.2291.

[0084] Example 22: Preparation of compound I-21 cyclopentyl(4-(3-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)amino)-2-methylbenzyl)piperazin-1-yl) methyl ketone Compound I-21. 1 H NMR (400 MHz, DMSO- d 6) δ 8.95 (s, 1H), 7.63 (d, J = 7.8Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 4.83 (d, J = 5.6Hz, 1H), 4.43 – 4.36 (m, 1H), 3.45 (s, 2H), 3.51 – 3.41 (m, 4H), 2.99 – 2.89(m, 1H), 2.61 – 2.53 (m, 1H), 2.48 – 2.40 (m, 1H), 2.39 – 2.27 (m, 4H), 2.24(s, 3H), 1.95 – 1.83 (m, 4H) (m, 1H), 1.81 – 1.44 (m, 11H). 13 C NMR (101 MHz, DMSO- d 6) δ 173.21, 163.40, 147.94, 140.08, 136.86, 129.64, 125.65, 125.28,121.52, 119.30, 63.12, 60.63, 53.12, 52.56, 44.93, 41.30, 32.13, 29.54,25.59, 22.73, 18.72, 13.28. HRMS (ESI + m / z calcd for C 25 H 34 N4O2S [M+H] +:455.2475; found: 455.2473.

[0085] Example 23: Preparation of compound I-22-cyclopentyl(4-(3-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)amino)-2-methylbenzyl)piperazin-1-yl) methyl ketone Compound I-22. 1 H NMR (400 MHz, DMSO- d 6) δ 9.03 (s, 1H), 7.59 (d, J = 7.7Hz, 1H), 7.11 (t, J = 7.7 Hz, 1H), 7.00 (d, J = 7.7 Hz, 1H), 4.08 (t, J = 3.6Hz, 1H), 3.45 (s, 2H), 3.51 – 3.41 (m, 4H), 3.37 (s, 3H), 2.99 – 2.88 (m,1H), 2.63 – 2.55 (m, 1H), 2.51 – 2.41 (m, 1H), 2.39 – 2.27 (m, 4H), 2.24 (s,3H), 1.99 – 1.89 (m, 1H), 1.86 – 1.76 (m, 1H), 1.76 – 1.44 (m, 10H). 13 C NMR (101 MHz, DMSO-) d 6) δ 173.21, 163.53, 145.45, 139.99, 136.98, 129.89, 125.83,125.32, 121.45, 120.75, 72.59, 60.61, 56.36, 53.11, 52.54, 44.93, 41.30,29.53, 28.11, 25.59, 22.59, 18.73, 13.30. Example 24: Compound I-23 2-((3-((4-(cyclopentanecarbonyl)piperazin-1-yl)methyl)-2-methylphenyl)amino)-6,7-dihydrobenzothiazole-4(5 H Preparation of ketone Compound I-23. 1H NMR (400 MHz, DMSO- d 6) δ 9.38 (s, 1H), 7.61 (d, J = 7.8Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 3.45 (s, 2H), 3.51 – 3.41 (m, 4H), 2.99 – 2.89 (m, 1H), 2.90 (t, J = 6.0 Hz, 2H), 2.45 (t, J = 6.3 Hz, 2H), 2.39 – 2.27 (m, 4H), 2.25 (s, 3H), 2.12 – 2.03 (m, 2H), 1.79– 1.45 (m, 8H). 13 C NMR (101 MHz, DMSO- d 6) δ 189.59, 173.21, 163.36, 145.67,142.86, 139.33, 137.16, 130.46, 126.53, 125.50, 122.25, 60.54, 53.12, 52.57,44.93, 41.30, 37.85, 30.91, 29.54, 25.60, 23.67, 23.19, 22.01, 13.91, 13.27.HRMS (ESI + m / z calcd for C 25 H 32 N4O2S [M+H] + : 453.2319; found: 453.2321.

[0086] Example 25: Compound I-24 2-((3-((4-(cyclopentanecarbonyl)piperazin-1-yl)methyl)-2-methylphenyl)amino)-5,6-dihydrobenzothiazole-7(4 H Preparation of ketone Compound I-24. 1 H NMR (400 MHz, DMSO- d 6) δ 10.28 (s, 1H), 7.41 (dd, J=6.9, 2.2 Hz, 1H), 7.24 – 7.16 (m, 2H), 3.48 (s, 2H), 3.51 – 3.39 (m, 4H), 2.99 – 2.89 (m, 1H), 2.74 (t, J = 6.1 Hz, 2H), 2.43 – 2.35 (m, 2H), 2.39 –2.27 (m, 4H), 2.24 (s, 3H), 2.07 – 1.98 (m, 2H), 1.80 – 1.43 (m, 8H). 13 C NMR (101 MHz, DMSO-) d 6) δ 189.74, 173.22, 172.30, 167.59, 138.37, 137.69, 132.53,128.28, 125.87, 124.19, 118.82, 60.30, 53.11, 52.55, 44.91, 41.28, 36.79,30.91, 29.54, 26.74, 25.60, 22.45, 22.01, 13.91, 13.26. HRMS (ESI + ) m / z calcdfor C 25 H 32 N4O2S [M+H] + : 453.2319; found: 453.2323.

[0087] Example 26: Preparation of compound I-25(E)-cyclopentyl(4-(3-((4-(hydroxyimino)-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)amino)-2-methylbenzyl)piperazin-1-yl) methyl ketone Compound I-25. 1 H NMR (400 MHz, DMSO- d 6) δ 10.74 (s, 1H), 9.16 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.99 (d, J= 7.8 Hz, 1H), 3.45 (s, 2H), 3.51 – 3.38 (m, 4H), 2.99 – 2.89 (m, 1H), 2.68 (t, J = 5.9 Hz, 2H), 2.60 (t, J = 6.4 Hz, 2H), 2.40 – 2.28 (m, 4H), 2.25 (s, 3H), 1.90 – 1.79 (m, 2H), 1.79 – 1.44 (m, 8H). 13 C NMR (101 MHz, DMSO- d 6) δ 173.22, 163.06,149.22, 141.25, 139.71, 136.85, 129.34, 125.88, 125.74, 125.27, 121.29,60.65, 54.86, 53.12, 52.56, 44.94, 41.31, 29.54, 25.60, 22.33, 22.12, 21.99,13.27. HRMS (ESI + m / z calcd for C 25 H 33 N5O2S [M+H] + : 468.2428; found: 468.2429.

[0088] Example 27: Preparation of compound I-26(E)-cyclopentyl(4-(3-((4-(methoxyimino)-4,5,6,7-tetrahydrobenzothiazol-2-yl)amino)-2-methylbenzyl)piperazin-1-yl)methyl ketone Compound I-26. 1 H NMR (400 MHz, DMSO- d 6) δ 9.32 (s, 1H), 7.49 (d, J = 7.7Hz, 1H), 7.15 (t, J = 7.7 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 3.82 (s, 3H), 3.46 (s, 2H), 3.51 – 3.38 (m, 4H), 3.00 – 2.87 (m, 1H), 2.66 (t, J= 6.0 Hz, 2H), 2.59 (t, J = 6.4 Hz, 2H), 2.40 – 2.28 (m, 4H), 2.25 (s, 3H), 1.89 – 1.79 (m, 2H), 1.78 – 1.45 (m, 8H). 13 C NMR (101 MHz, DMSO- d 6) δ 173.23, 164.24,150.06, 140.38, 139.74, 137.30, 131.07, 127.42, 126.68, 125.57, 122.51,61.27, 60.55, 53.14, 52.58, 44.96, 41.33, 30.92, 29.56, 25.61, 22.66, 22.29,22.03, 21.93, 13.92, 13.29. HRMS (ESI + m / z calcd for C 26 H 35 N5O2S [M+H] + :482.2584; found: 482.2583.

[0089] Example 28: General method for synthesizing compounds I-27 to I-32 (Synthetic scheme 2 above) Step 1: At room temperature, 2-methyl-3-bromo-5-chloroaniline (1.0 equivalent) was dissolved in 50% sulfuric acid. Sodium nitrite (1.0 equivalent) was added under ice bath conditions, and the reaction was carried out for 1 hour. The reaction mixture was then added dropwise to boiling 20% ​​sulfuric acid, and refluxed for half an hour. After the reaction was complete, the mixture was cooled to room temperature, extracted three times with ethyl acetate, and evaporated to dryness for the next step. The crude product was then dissolved in DMF, and ((methanesulfonyl)oxy)piperidine-1-carboxylate (2.0 equivalent) and potassium carbonate (3.0 equivalent) were added at 90°C. o C was reacted overnight. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated brine, filtered, concentrated under reduced pressure, and the residue was slurried with petroleum ether and filtered to obtain crude product 2-2.

[0090] Step 2: Crude product 2-2 was dissolved in dichloromethane, and dioxane hydrochloride solution was added. The reaction was allowed to proceed overnight at room temperature. The supernatant was discarded, and the residue was concentrated under reduced pressure. The concentrated residue was dissolved in dichloromethane and triethylamine (6 equivalents), and 4,4,4-trifluoro-3-(trifluoromethyl)butyric acid (1.2 equivalents) was slowly added dropwise. Then, T3P (2.0 equivalents) was added dropwise under ice bath conditions, and the reaction was allowed to proceed overnight at room temperature. After the reaction was confirmed to be complete by TLC, saturated NaHCO3 solution was added to quench the reaction. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 2-3.

[0091] Step 3: Crude product 2-3 was dissolved in tert-butanol, and Pd2(dba)3 (0.1 equivalent) was added. t BuBrettPhos (0.3 equivalents), K3PO4 (1.4 equivalents), and the corresponding 2-aminothiazole (1 equivalent), under nitrogen atmosphere, 110 °C o After reacting overnight, the reaction was detected by TLC to be complete. The reaction solution was diluted with ethyl acetate, the organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and reversed-phase medium-pressure preparation system to obtain compounds I-27 to I-32.

[0092] Example 29: Preparation of compound I-27 1-(4-(5-chloro-2-methyl-3-((4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)amino)phenoxy)piperidin-1-yl)-4,4,4-trifluoro-3-(trifluoromethyl)butanone Compound I-27. 1 H NMR (400 MHz, DMSO- d 6) δ 9.09 (s, 1H), 7.69 (s, 1H), 6.83 (d, J = 1.6 Hz, 1H), 4.74 – 4.64 (m, 1H), 4.44 – 4.29 (m, 1H), 3.81 –3.66 (m, 2H), 3.53 – 3.40 (m, 2H), 3.00 (d, J = 5.3 Hz, 2H), 2.60 – 2.53 (m,2H), 2.07 (s, 3H), 1.99 – 1.83c (m, 2H), 1.80 – 1.71 (m, 4H), 1.70 – 1.51 (m,2H). 13C NMR (151 MHz, DMSO- d 6) δ 165.20, 161.33, 155.63, 144.95, 141.60,130.47, 123.99 (d, J = 281.8 Hz), 117.38, 115.48, 112.33, 107.98, 72.02,43.59 (dt, J = 55.4, 27.6 Hz), 41.76, 30.71, 30.03, 26.47, 26.35, 23.02,22.61, 22.39, 10.21. HRMS (ESI + m / z calcd for C 24 H 26 ClF6N3O2S [M+H] + :570.1411; found: 570.1412.

[0093] Example 30: Compound I-28 2-((5-chloro-2-methyl-3-((1-(4,4,4-trifluoro-3-(trifluoromethyl)butyryl)piperidin-4-yl)oxy)phenyl)amino)-6,7-dihydrobenzothiazole-4(5 H Preparation of ketone Compound I-28. 1 H NMR (600 MHz, DMSO- d 6) δ 9.47 (s, 1H), 7.74 (s, 1H), 6.92 (d, J = 1.7 Hz, 1H), 4.75 – 4.69 (m, 1H), 4.41 – 4.33 (m, 1H), 3.79 –3.68 (m, 2H), 3.51 – 3.42 (m, 2H), 3.00 (d, J = 5.4 Hz, 2H), 2.94 (t, J = 5.9Hz, 2H), 2.49 – 2.45 (m, 2H), 2.13 – 2.06 (m, 5H), 1.98 – 1.86 (m, 2H), 1.70 – 1.56 (m, 2H). 13 C NMR (151 MHz, DMSO- d6) δ 189.61, 165.21, 161.41, 155.72,145.42, 144.12, 140.81, 130.63, 124.02 (d, J = 279.0 Hz), 116.27, 113.07,108.80, 72.08, 43.59 (dt, J = 56.0, 28.2 Hz), 41.77, 37.87, 30.70, 30.01,26.47, 23.65, 23.18, 10.28. HRMS (ESI + m / z calcd for C 24 H 24 ClF6N3O3S [M+H] + :584.1204; found: 584.1209.

[0094] Example 31: Preparation of compound I-29 1-(4-(5-chloro-3-((4-hydroxy-4,5,6,7-tetrahydrobenzothiazol-2-yl)amino)-2-methylphenoxy)piperidin-1-yl)-4,4,4-trifluoro-3-(trifluoromethyl)butanone Compound I-29. 1 H NMR (400 MHz, DMSO- d 6) δ 9.10 (s, 1H), 7.71 (s, 1H), 6.84 (d, J = 1.9 Hz, 1H), 4.91 (d, J = 5.8 Hz, 1H), 4.74 – 4.63 (m, 1H), 4.44(dd, J = 9.2, 4.0 Hz, 1H), 4.42 – 4.30 (m, 1H), 3.83 – 3.65 (m, 2H), 3.53 –3.40 (m, 2H), 3.00 (d, J = 5.4 Hz, 2H), 2.66 – 2.57 (m, 1H), 2.53 – 2.44 (m,1H), 2.08 (s, 3H), 1.99 – 1.83 (m, 3H), 1.81 – 1.53 (m, 5H). 13 C NMR (151 MHz, DMSO- d6) δ 165.20, 161.42, 155.62, 147.85, 141.57, 130.51, 124.00 (d, J =279.6 Hz), 115.50, 112.45, 108.01, 72.02, 63.02, 43.60 (dt, J = 56.4, 28.2Hz), 41.77, 32.19, 30.95, 30.72, 30.04, 26.47, 22.71, 22.06, 18.61, 13.96,10.24. HRMS (ESI + m / z calcd for C 24 H 26 ClF6N3O3S [M+H] + : 586.1360; found:586.1362.

[0095] Example 32: Preparation of compounds I-30 and I-31 A pair of enantiomeric compounds, I-30 and I-31, were prepared from compound I-29 by chiral HPLC. Compound I-29 possesses a chiral center, similar to the reported... (S) The structure of 6,6-dimethyl-2-phenyl-4,5,6,7-tetrahydrobenzo[d]oxazol-4-ol is similar. The absolute configurations of compounds I-30 and I-31 can be determined by optical rotation comparison. (The last sentence appears to be incomplete and possibly contains errors.) (S) 6,6-Dimethyl-2-phenyl-4,5,6,7-tetrahydrobenzo[d]oxazol-4-ol ([α-) D 20.4 Compound I-31 ([α]) with the same optical rotation direction as +22.4° (c = 1.10, CHCl3) D 20.4 +3.516° (c = 1.10, CHCl3) was determined to be (S) -Enantiomers of the configuration; while compound I-30 ([α) D 20.4 -3.455° (c = 1.10, CHCl3) is opposite to the optical rotation direction of the compounds reported above, and should be... (R) -Enantiomers of configuration. Example 33: Preparation of compound I-32 1-(4-(3-((4-amino-4,5,6,7-tetrahydrobenzothiazol-2-yl)amino)-5-chloro-2-methylphenoxy)piperidin-1-yl)-4,4,4-trifluoro-3-(trifluoromethyl)butanone Compound I-32. 1 H NMR (400 MHz, DMSO- d 6) δ 9.32 (s, 1H), 7.76 (s, 2H), 7.61 (s, 1H), 6.89 (s, 1H), 4.71 (s, 1H), 4.45 – 4.29 (m, 1H), 4.16 (s, 1H), 3.83 – 3.64 (m, 2H), 3.46 (d, J = 8.7 Hz, 2H), 3.00 (d, J = 5.2 Hz, 2H), 2.63(t, J = 10.9 Hz, 2H), 2.08 (s, 3H), 1.99 – 1.53 (m, 7H), 1.24 (s, 1H). MS(ESI + m / z calcd for C 24 H 27 ClF6N4O2S [M+H] + : 585.1; found: 585.1. Example 34: Preparation of compound I-33 2-((4-chloro-3-((4-(cyclopentylcarbonyl)piperazin-1-yl)methyl)-2-methylphenyl)amino)-6,7-dihydrobenzothiazol-4(5H)-one Compound I-33. 1 H NMR (400 MHz, DMSO- d 6) δ 9.44 (s, 1H), 7.78 (d, J = 8.7Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 3.67 (s, 2H), 3.43 (s, 4H), 2.95 (dd, J =14.0, 8.2 Hz, 3H), 2.50 – 2.45 (m, 2H), 2.41 (d, J= 17.9 Hz, 4H), 2.36 (s,3H), 2.15 – 2.05 (m, 2H), 1.82 – 1.43 (m, 8H). MS (ESI + ) m / z calcd forC 25 H 31 ClN4O2S [M+H] + : 487.2; found: 487.1. Example 35: Preparation of compound I-34 (4-(6-chloro-3-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)amino)-2-methylbenzyl)piperazin-1-yl)(cyclopentyl) methyl ketone Compound I-34. 1 H NMR (400 MHz, DMSO- d 6) δ 9.04 (s, 1H), 7.80 (d, J = 8.7Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 4.84 (d, J = 5.6 Hz, 1H), 4.41 (d, J = 5.1Hz, 1H), 3.65 (s, 2H), 3.42 (s, 4H), 3.00 – 2.89 (m, 1H), 2.59 (dt, J = 16.1, 4.5 Hz, 1H), 2.46 (d, J = 6.6 Hz, 1H), 2.39 (d, J = 18.7 Hz, 4H), 2.33 (s,3H), 1.96 – 1.43 (m, 12H). MS (ESI + m / z calcd for C 25 H 33 ClN4O2S [M+H] + : 489.2;found: 489.2. Example 36: General method for synthesizing compounds I-35 to I-43 (synthesis scheme 3 above) Step 1: 1-1 (1 equivalent) of benzaldehyde was substituted and dissolved in tert-butanol, and Pd2(dba)3 (0.1 equivalent) was added.t BuBrettPhos (0.3 equivalents), K3PO4 (1.4 equivalents), and the corresponding 2-aminothiazole (1 equivalent), under nitrogen atmosphere, 110 °C o After reacting overnight, the reaction was detected by TLC to be complete. The reaction solution was diluted with ethyl acetate, the organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain crude product 3-2.

[0096] Step 2: Crude 3-2,-tert-butyloxycarbonylpiperazine (1.1 equivalents) and acetic acid (1.1 equivalents) were dissolved in dichloromethane and reacted with stirring at room temperature for 1 hour. Then, sodium triacetoxyborohydride (3 equivalents) was added, and the reaction was allowed to proceed overnight at room temperature. After TLC detection of complete reaction, the reaction was quenched with saturated NaHCO3 solution. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography and a reversed-phase medium-pressure preparation system to obtain compounds I-35 to I-43.

[0097] Example 37: Preparation of compound I-35 1-(4-(6-chloro-3-((4-hydroxy-4,5,6,7-tetrahydrobenzothiazol-2-yl)amino)-2-methylbenzyl)piperazin-1-yl)ethane-1-one Compound I-35. 1 H NMR (400 MHz, DMSO- d 6) δ 9.04 (s, 1H), 7.80 (d, J = 8.8Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 4.85 (d, J = 5.5 Hz, 1H), 4.41 (d, J = 5.1Hz, 1H), 3.65 (s, 2H), 3.36 (d, J = 9.0 Hz, 4H), 2.59 (dt, J = 16.1, 4.7 Hz, 1H), 2.47 (d, J = 6.0 Hz, 1H), 2.44 – 2.34 (m, 4H), 1.97 (s, 3H), 1.89 (ddd, J= 14.3, 10.1, 5.8 Hz, 1H), 1.78 – 1.64 (m, 3H). MS (ESI + ) m / z calcd forC 21 H 27 ClN4O2S [M+H] + : 435.2; found: 435.2. Example 38: Preparation of compound I-36 2-((4-chloro-3-(isoindol-2-ylmethyl)-2-methylphenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol Compound I-36. 1 H NMR (400 MHz, DMSO- d 6) δ 9.04 (s, 1H), 7.82 (d, J = 8.8Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.25 – 7.14 (m, 4H), 4.85 (d, J = 5.6 Hz, 1H), 4.41 (dd, J = 9.2, 4.1 Hz, 1H), 4.0 5 (s, 2H), 3.89 (s, 4H), 2.59 (dt, J = 16.1, 4.7 Hz, 1H), 2.49 – 2.41 (m, 1H), 2.35 (s, 3H), 1.96 – 1.62 (m, 4H).MS (ESI + m / z calcd for C 23 H 24 ClN3OS [M+H] + : 425.1; found: 425.2. Example 39: Preparation of compound I-37 2-((4-chloro-2-methyl-3-(piperidin-1-ylmethyl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol Compound I-37. 1 H NMR (400 MHz, DMSO- d 6) δ 9.01 (s, 1H), 7.75 (d, J = 8.7Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 4.84 (d, J = 5.5 Hz, 1H), 4.40 (dd, J =9.2, 4.2 Hz, 1H), 3.57 (s, 2H), 2.58 (dt, J = 16.1, 4.6 Hz, 1H), 2.49 – 2.33(m, 5H), 2.31 (s, 3H), 1.88 (ddd, J = 14.4, 9.8, 5.7 Hz, 1H), 1.80 – 1.63 (m,3H), 1.49 – 1.31 (m, 6H). MS (ESI + m / z calcd for C 20 H 26 ClN3OS [M+H] + : 392.2;found: 392.2. Example 40: Preparation of compound I-38 2-((4-chloro-2-methyl-3-(pyrrolidone-1-ylmethyl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol Compound I-38. 1 H NMR (400 MHz, DMSO- d 6) δ 9.03 (s, 1H), 7.77 (d, J = 8.7Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 4.86 (d, J = 5.5 Hz, 1H), 4.41 (dd, J =9.2, 4.2 Hz, 1H), 3.55 (s, 2H), 2.57 (dt, J = 16.1, 4.6 Hz, 1H), 2.49 – 2.33(m, 5H), 2.32 (s, 3H), 1.89 (ddd, J= 14.4, 9.8, 5.7 Hz, 1H), 1.80 – 1.62 (m,3H), 1.49 – 1.31 (m, 4H). MS (ESI + m / z calcd for C 19 H 24 ClN3OS [M+H] + : 378.1;found: 378.1. Example 41: Preparation of compound I-39 2-((4-chloro-3-((dimethylamino)methyl)-2-methylphenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol Compound I-39. 1 H NMR (400 MHz, DMSO- d 6) δ 9.02 (s, 1H), 7.77 (d, J = 8.8Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 4.85 (d, J = 5.6 Hz, 1H), 4.41 (dd, J =9.2, 4.2 Hz, 1H), 3.54 (s, 2H), 2.59 (dt, J = 16.0, 4.6 Hz, 1H), 2.49 – 2.41(m, 1H), 2.30 (s, 3H), 2.17 (s, 6H), 1.95 – 1.84 (m, 1H), 1.79 – 1.72 (m,2H), 1.72 – 1.63 (m, 1H). MS (ESI + m / z calcd for C 17 H 22 ClN3OS [M+H] + : 352.1;found: 352.1. Example 42: Preparation of compound I-40 2-((4-chloro-2-methyl-3-(morpholinomethyl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol Compound I-40. 1 H NMR (400 MHz, DMSO-d 6) δ 9.03 (s, 1H), 7.78 (d, J = 8.8Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 4.84 (d, J = 5.6 Hz, 1H), 4.40 (dd, J =9.2, 4.2 Hz, 1H), 3.63 (s, 2H), 3.56 – 3.46 (m, 4H), 2.59 (dt, J = 16.0, 4.7Hz, 1H), 2.47 (d, J = 6.0 Hz, 1H), 2.44 – 2.38 (m, 4H), 2.32 (s, 3H), 1.95 –1.82 (m, 1H), 1.75 (dd, J = 9.7, 5.4 Hz, 2H), 1.72 – 1.64 (m, 1H). MS (ESI + )m / z calcd for C 19 H 24 ClN3O2S [M+H] + : 394.1; found: 394.1. Example 43: Preparation of compound I-41 2-((4-chloro-2-methyl-3-(piperazin-1-ylmethyl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol) Compound I-41. 1 H NMR (400 MHz, DMSO- d 6) δ 9.02 (brs, 2H), 7.77 (d, J =8.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 4.84 (d, J = 5.6 Hz, 1H), 4.40 (d, J =5.0 Hz, 1H), 3.61 (s, 2H), 2.58 (dt, J = 16.2, 4.7 Hz, 1H), 2.49 – 2.36 (m,5H), 2.28 (d, J= 17.9 Hz, 7H), 1.88 (dt, J = 19.3, 7.5 Hz, 1H), 1.78 – 1.64(m, 3H). MS (ESI + m / z calcd for C 19 H 25 ClN4OS [M+H] + : 393.1; found: 393.1. Example 44: Preparation of compound I-42 2-((4-chloro-2-methyl-3-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol) Compound I-42. 1 H NMR (400 MHz, DMSO- d 6) δ 9.02 (s, 1H), 7.78 (d, J = 8.8Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 4.85 (d, J = 5.6 Hz, 1H), 4.41 (d, J = 5.0Hz, 1H), 3.60 (s, 2H), 2.57 (dt, J = 16.2, 4.7 Hz, 1H), 2.50 – 2.35 (m, 5H), 2.27 (d, J = 17.9 Hz, 7H), 2.12 (s, 3H), 1.87 (m, 1H), 1.78 – 1.64 (m, 3H).MS (ESI + m / z calcd for C 20 H 27 ClN4OS [M+H] + : 407.2; found: 407.2. Example 45: Preparation of compound I-43 2-((4-chloro-3-((4-isopropylpiperazin-1-yl)methyl)-2-methylphenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol) Compound I-43.1 H NMR (400 MHz, DMSO- d 6) δ 9.02 (s, 1H), 7.76 (d, J = 8.8Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 4.84 (d, J = 5.5 Hz, 1H), 4.40 (dd, J =9.0, 4.1 Hz, 1H), 3.60 (s, 2H), 2.58 (dd, J = 11.9, 5.2 Hz, 2H), 2.49 – 2.32(m, 9H), 2.30 (s, 3H), 1.88 (ddd, J = 14.3, 10.0, 5.6 Hz, 1H), 1.75 (dd, J =9.7, 5.3 Hz, 2H), 1.71 – 1.62 (m, 1H), 0.93 (d, J = 6.5 Hz, 6H). MS (ESI + m / z calcd for C 22 H 31 ClN4OS [M+H] + : 435.2; found: 435.2. Example 46: Cellular-level assay to determine the inhibitory activity of the compound against RORγt For compounds I-1, I-11 to I-32 of the present invention, the inhibitory activity against RORγt at the cellular level was determined using RORγt GAL4. This inhibitory activity was measured using the half-maximal inhibitory concentration (IC50). 50 ) is used to represent this.

[0098] The luciferase reporter gene system is a reporter system that uses luciferin as a substrate to detect luciferase activity. The principle is to fuse the coding sequence of the luciferin reporter gene with a gene expression regulatory sequence to form a chimeric gene, which is then transcribed and expressed under the control of the regulatory sequence. The expression status of the target gene is then indicated by the degree to which the expressed luciferase breaks down the substrate.

[0099] Experimental methods: ① Cell preparation: 293T cells were passaged in 6 cm plates and cultured under DMEM + 10% FBS conditions.

[0100] ② Plasmid transfection: ROR-GAL4 and pGL4.31 were 2 μg each, and the transfection reagent was 10 μL. After diluting with 50 μL DMEM, they were mixed and incubated for 30 min, and then evenly dropped into a 6 cm plate.

[0101] ③ Cell plating: After 4.5 h, count the cells and plate them in 96-well plates, 50,000 cells per well, with 100 μL of culture medium.

[0102] ④ Cell drug administration: 20 h later, the test compound was diluted with DMEM + 15% FBS, and 100 μL of the corresponding diluted compound was added to each well.

[0103] ⑤ Fluorescence Detection: Detect the luciferase reporter gene after 24 h. Dilute the lysis buffer: 50 μL per well. Based on 96 wells, a total of 4.8 mL~5 mL of lysis buffer is needed (96 × 50 = 4.8 mL). The purchased Passive lysis buffer is a 5× solution, so 1 mL of stock solution is needed. Dilute with 4 mL of ultrapure water and gently shake in the mixing tank. Remove cells from the cell culture chamber, discard the culture medium, rinse once with pre-cooled PBS, aspirate the PBS, add 50 μL of lysis buffer to each well, shake well, and lyse on ice for 20 minutes. Prepare the kit. After 20 minutes, remove cells from ice and place them on a microplate shaker to fully resuspend the cells. Add 50 μL of lysis buffer to each 96-well white plate, add the firefly luminescent agent Dual-Glo to each well, and incubate for 10 min in the dark. Detect the activity of firefly luciferase using the chemiluminescence system of a Synergy2 microplate reader. Add 10 μL of Dual-Glo stop & Glo reagent to each well in the dark (RLA:RLAbuffer = 1:100 should be prepared fresh before use), incubate for 10 min and then take the reading.

[0104] ⑥ Data processing: Luciferase activity is calculated by dividing the luciferase activity in each sample by the René luciferase activity. The René luciferase activity is used to correct for differences in transfection efficiency. Relative luciferase activity is the sample luciferase activity divided by the DMSO blank value. The inhibition rate is calculated using the following formula: To verify the transfection efficiency of this system, we used the positive compound T0901317 for detection. The inhibition IC50 of T0901317 in this system was [value missing]. 50 The value was 0.81 μM. However, in some references, the IC50 value for the full-length RORγt luciferase reporter gene was 0.81 μM. 50 The concentration was 1.7 μM. The results showed that the compounds of this invention exhibited good inhibitory activity against the RORγ protein receptor (as shown in Table 1).

[0105] Table 1. Results of RORγ GAL4 cell activity assay for the compounds in the examples The inhibition rate is the average of at least two independent trials. Inhibition rate value: **** indicates 0.50 μM ≥ IC50 50 *** indicates 5.0 μM ≥ IC 50 > 0.50 μM; ** indicates 10.0 μM ≥ IC 50 > 5.0 μM; * indicates IC 50 > 10.0 μM The above experimental results show that, regardless of whether R1 and R2 are independently selected from alkyl or substituted alkyl, alkoxy, cycloalkyl, etc., or are connected together to form a substituted or unsubstituted ring, as long as R5 and R6 are connected together to form a substituted six-membered ring containing a nitrogen atom, and the nitrogen atom is located at the para position of Y, the substituent is connected to the nitrogen heteroatom, and the substituent is selected from... Therefore, the obtained compound exhibits excellent RORγt inhibitory activity, and most compounds show RORγ GAL4 IC 50 < 0.5 μM (****).

[0106] Example 47: In vitro assay to determine the inhibitory activity of the compound against DHODH The inhibitory activity of compounds I-1, I-11 to I-43 of the present invention against DHODH was determined by DCIP method. This inhibitory activity was expressed as the half-maximal inhibitory concentration (IC50). 50 ) is used to represent this.

[0107] Experimental method: DCIP method DCIP, or sodium 2,6-dichloroindophenol, has a specific absorbance at 600 nm. When the substrate dihydroorotic acid (DHO) is catalytically dehydrogenated by hDHODH, CoQ0 is reduced, and DCIP, acting as the final electron acceptor in the respiratory chain, is oxidized. This reduces the original amount of DCIP in the reaction system, thus lowering the absorbance at 600 nm. Therefore, the rate of change in absorbance reflects the enzyme activity and the inhibitory activity of the compound. A larger rate of change indicates a more vigorous redox reaction, stronger enzyme activity, and relatively weaker inhibitory activity of the compound.

[0108] Purified HsDHODH protein was diluted to 10 nM with an activity assay solution consisting of 50 mM HEPES pH 8.0, 150 mM KCl, and 0.1% Triton X-100. CoQ0 and DCIP were added to final concentrations of 100 μM and 120 μM, respectively. After mixing, the mixture was pipetted into a 96-well plate and incubated at room temperature for 5 min. Then, the substrate DHO was added to initiate the reaction, with a final DHO concentration of 500 μM. The absorbance at 600 nm was measured using a BioTek microplate reader, with readings every 30 s for 6 min. The initial rate of the enzymatic reaction was calculated. V 0. The inhibitor activity test involves adding different concentrations of inhibitor to the above reaction system and calculating the initial rate of the enzyme-catalyzed reaction. V i, the inhibition rate of the compound is given by formula (1- V i / V The IC50 was calculated as 0) × 100%. In calculating the IC50 of the compound, the inhibition rate was tested at least at 8 concentrations, and the IC50 value was calculated using Origin 8.0. A77 1726 was used as a positive control during the experiment, and at least three replicates were set up for each experiment. The results showed that the compound of the present invention has good inhibitory activity against DHODH (as shown in Table 2).

[0109] Table 2. Results of DHODH inhibitory activity tests on the compounds in the examples The inhibition rate is the average of at least two independent trials. Inhibition rate value: **** indicates 0.50 μM ≥ IC50 50 *** indicates 5.0 μM ≥ IC 50 > 0.50 μM; ** indicates 10.0 μM ≥ IC 50 > 5.0 μM; * indicates IC 50 > 10.0 μM The above experimental results indicate that when R1 and R2 are connected together to form a substituted or unsubstituted ring, regardless of whether R5 and R6 are independently selected from H, C1-C8 alkyl, or substituted or unsubstituted three- to seven-membered rings formed by R5 and R6 being connected together; the three- to seven-membered rings may or may not include N, O, or S heteroatoms, and the substituents are selected from C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, hydroxyl, amino or substituted amino, cyano, nitro, carboxyl, acyl or substituted acyl (… The compounds obtained all exhibited good DHODH inhibitory activity, with most compounds showing DHODH IC50. These compounds were acyloxy or substituted acyloxy groups, amide groups or substituted amide groups, aryl or substituted aryl groups, aryloxy or substituted aryloxy groups, heteroaryl or substituted heteroaryl groups, and heterocyclic or substituted heterocyclic groups. 50 < 5.0 μM (***).

[0110] Based on the results of the two experiments, some compounds provided by this invention possess dual-target inhibitory activity against RORγt and DHODH, with RORγ GAL4 IC... 50 ≤ 5.0 μM and DHODH inhibitory activity IC 50 ≤ 5.0 μM is the standard for high activity. Highly active dual-target inhibitors of RORγt and DHODH include compounds I-11, I-16, I-17, I-18, I-21, I-22, I-23, I-24, I-27, I-28, I-29, I-30 and I-31.

[0111] Example 48: In vivo determination of the effect of the compound in a DSS-induced acute enteritis model The in vivo activity of compound I-29 of the present invention was determined using an acute enteritis model induced by dextran sulfate sodium (DSS).

[0112] Extensive data have demonstrated that the etiology, clinical symptoms, pathological changes, and treatment response of DSS-induced colitis models are similar to those of human ulcerative colitis (UC). DSS is a polyanionic derivative of dextran, formed by the esterification reaction of dextran and chlorosulfonic acid, with the molecular formula (C6H7Na3O). 14 S3) n MW: varies from 36,000 to 50,000, and sulfur content is generally 17%-20%. DSS is often used to induce colitis models, although its induction mechanism is not yet clear. Current research mainly suggests that DSS increases intestinal permeability, disrupts the intestinal mucosal barrier, upregulates certain cytokines (tumor necrosis factor, interleukin, interferon, IL-10 and IL-12), activates certain pathways (NF-κB pathway and TRPV1 pathway), or is related to intestinal flora imbalance.

[0113] Acute colitis was induced in male C57BL / 6 mice by oral administration of 2.5% (wt / vol) DSS in water (days 1–5). Compound I-29 was dissolved in an aqueous solution containing 0.5% sodium carboxymethyl cellulose and administered orally from day 1 to day 10. An equal volume of solvent was given to the control group and the IBD group. The control group received normal drinking water for 10 days until sacrifice.

[0114] Following administration of drinking water containing 2.5% DSS, mice exhibited acute clinical symptoms, including decreased appetite, weight loss, diarrhea, and severe bloody stools. Compared to the IBD group, oral administration of compound I-29 dose-dependently alleviated weight loss and reduced the disease activity index (DAI) (Figure 1D). At the end of the treatment period, colon length was measured, and administration of compound I-29 significantly attenuated the shortening of colon length in the acute colitis model. Figure 1 BC). Histopathological analysis, which indirectly reflects the degree of colonic inflammation, showed severe pathological changes in the DSS-induced colitis mouse model, mainly including crypt necrosis, significant inflammatory infiltration, and mucosal damage. Figure 1 Compound I-29 significantly improved the symptoms of acute enteritis (E).

[0115] In summary, the RORγ GAL4 cell assay results show that the 2-aminothiazole derivatives of this invention can effectively inhibit RORγt activity. The DHODH inhibitory activity assay results show that the 2-aminothiazole derivatives of this invention can effectively inhibit DHODH activity. Animal activity data for compound I-29 indicate that the 2-aminothiazole derivatives of this invention can effectively alleviate autoimmune diseases, such as inflammatory bowel disease. The 2-aminothiazole derivatives of this invention can effectively inhibit RORγt activity and DHODH activity, thereby inhibiting lymphocyte proliferation, Th17 cell differentiation, and T cell expansion and activation. They can be further used as therapeutic drugs for RORγt and / or DHODH-mediated inflammation, autoimmune diseases, cancer, and viral infections.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, The compound is selected from: 。 2. A compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, The compound is selected from: 。 3. A compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, The compound is selected from: 。 4. A compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, The compound is selected from: 。 5. A compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, The compound is selected from: 。 6. A pharmaceutical composition, characterized in that, Includes the compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

7. Use of the compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of a medicament for the prevention or treatment of RORγt and / or DHODH-mediated diseases, said diseases being selected from immune and inflammatory diseases, destructive bone diseases, malignant neoplasms, angiogenesis-related diseases, and infectious diseases.

8. Use of the compound of claim 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of a medicament for the prevention or treatment of RORγt and / or DHODH-mediated diseases, said diseases being selected from immune and inflammatory diseases, destructive bone diseases, malignant neoplasms, angiogenesis-related diseases, and infectious diseases.

9. Use of the compound of claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of a medicament for the prevention or treatment of RORγt-mediated diseases selected from immune and inflammatory diseases, destructive bone diseases, malignant neoplasms, angiogenesis-related diseases, and infectious diseases.

10. Use of the compound of claim 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of a medicament for the prevention or treatment of DHODH-mediated diseases selected from immune and inflammatory diseases, destructive bone diseases, malignant neoplasms, angiogenesis-related diseases, and infectious diseases.

11. Use of the compound of claim 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of a medicament for the prevention or treatment of DHODH-mediated diseases selected from immune and inflammatory diseases, destructive bone diseases, malignant neoplasms, angiogenesis-related diseases, and infectious diseases.

12. The use according to any one of claims 7-11, characterized in that, The immune and inflammatory diseases mentioned are selected from autoimmune diseases.

13. The use according to any one of claims 7-11, characterized in that, The immune and inflammatory diseases are selected from encephalomyelitis, Crohn's disease, or asthma; the malignant tumor diseases are selected from prostate cancer, triple-negative breast cancer, acute myeloid leukemia, or lung cancer; the infectious diseases are selected from COVID-19 or SARS.

14. The use according to claim 12, characterized in that, The autoimmune diseases mentioned are selected from multiple sclerosis, rheumatoid arthritis, psoriasis, or inflammatory bowel disease.

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