2-aminothiazole compound derivative and use thereof

Abstract

Provided in the present invention are a 2-aminothiazole compound derivative and the use thereof. The compound has a chemical structure of general formula (I) as shown in the following formula. The compound derivative provided in the present invention has an inhibitory activity against dihydroorotate dehydrogenase (DHODH), and is expected to be used in the preparation of a drug for preventing and / or treating diseases related to DHODH.

Description

A 2-aminothiazole compound derivative and its application Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and specifically relates to 2-aminothiazole derivatives and their use as dihydroorotate dehydrogenase (DHODH) inhibitors. These compounds exhibit DHODH inhibitory activity and are promising for the preparation of drugs for preventing and / or treating DHODH-related diseases. Background Art

[0002] Dihydroorotate dehydrogenase (DHODH) is an iron-containing, flavin-dependent enzyme located in the inner mitochondrial membrane. It is a key, rate-limiting enzyme in catalyzing pyrimidine synthesis and participates in the fourth step of the de novo pyrimidine biosynthesis pathway. Pyrimidine bases are essential for cell growth, proliferation, and metabolism, serving as key precursors in the biosynthesis of DNA (thymine and cytosine), RNA (uracil and cytosine), glycoproteins, and some phospholipids.

[0003] Most organisms use two pathways to synthesize pyrimidines: the salvage pathway and the de novo pathway. A cell's need for pyrimidine nucleotides depends on the cell type and its developmental stage. In quiescent or fully differentiated cells, cells primarily obtain pyrimidine nucleotides through the salvage pathway. In activated lymphocytes or other rapidly proliferating cells (such as cancer cells), the pyrimidines produced by the salvage pathway are insufficient to meet their metabolic needs, and cells primarily synthesize pyrimidine nucleotides through the de novo pathway. Inhibiting DHODH blocks pyrimidine nucleotide synthesis in cells, thereby inhibiting DNA and RNA synthesis in immune-activated lymphocytes and tumor cells, ultimately affecting the excessive proliferation of immune cells and cancer cells. Therefore, DHODH is an attractive drug target for immunology, cancer, infectious diseases, and viral diseases.

[0004] DHODH inhibitors have been shown to have clear efficacy in a variety of autoimmune diseases, hematological cancers, solid tumors, infectious diseases, and antiviral treatments. Currently, two DHODH inhibitors have been approved for marketing in the United States: leflunomide (approved for rheumatoid arthritis and psoriatic arthritis) and teriflunomide (approved for multiple sclerosis). Other autoimmune diseases that can be treated with DHODH inhibitors include alopecia areata, dry eye, uveitis, inflammatory bowel disease, colitis, systemic lupus erythematosus, lupus nephritis, psoriasis, transplant rejection, and glomerular diseases. Preclinical studies have shown that DHODH inhibitors can also be used to treat hematological cancers (such as lymphoma, acute myeloid leukemia, chronic myelomonocytic leukemia and myelodysplastic syndrome, etc.), for the treatment of solid tumors (such as neuroblastoma, glioma, melanoma, colon cancer, breast cancer, lung cancer and prostate cancer, etc.), for the treatment of infectious diseases (such as malarial infection, invasive fungal infection, Aspergillus infection, etc.) and for antiviral treatment (such as COVID-19, etc.). Brequinar is in Phase II clinical trials for relapsed / refractory acute myeloid leukemia (AML) and against the new coronavirus (COVID-19). Various DHODH inhibitors have been disclosed for the treatment or prevention of autoimmune diseases, immune and inflammatory diseases, destructive bone diseases, malignant tumor diseases, angiogenesis-related diseases, viral diseases and infectious diseases. For example, WO2009137081, WO2009133379, WO2009021696, WO2009082691, WO2009029473, WO2009153043, US2009209557, US2009062318, US2009082374, WO2008097180, WO2008077639, US2008027079, US2007299114, and US2008097180. 07027193, US2007224672, WO2007149211, JP2007015952, WO2006044741, WO2006001961, WO2006051937, WO2006038606, WO2006022442, US2006199856, WO2005075410, US7074831, WO2004056797, WO2004056747. Summary of the Invention

[0005] The present invention aims to provide a class of 2-aminothiazole compound derivatives as DHODH inhibitors, which have DHODH inhibitory activity and are expected to be used in the preparation of drugs for preventing or treating diseases related to DHODH.

[0006] In the first aspect, the present invention provides a compound of the following general chemical structure (I) or a pharmaceutically acceptable salt thereof:

[0007] Wherein, R1 is selected from hydroxyl, carboxyl, alkoxy, -C(=O)-NH-O-alkyl, -(C=O)NH2, -(C=O)NH-alkyl, thiol, amino, -NH-alkyl, -NH(C=O)-alkyl, -NH(C=O)NH2, -NH(C=O)NH-alkyl, -CH2OH, -O(C=O)NH-alkyl, -NH(C=O)O-alkyl; R2 is selected from hydrogen, alkoxy or alkyl; or R1 and R2 are combined and form a double bond through =O, =S, =N-CN, =N-OH, =NO-alkyl, =N-alkyl, =N-aryl and other groups; or R1 and R2 are both alkoxy and are connected to each other to form a five- to seven-membered cyclic ketal structure.

[0008] X is CH or N.

[0009] R3 is C 1-6 Alkyl, C 3-8 Cycloalkyl, three to eight-membered heterocycloalkyl; wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, three to eight membered heterocycloalkyl having 0-3 substituents selected from the following groups: halogen, hydroxyl, C 1-6 Alkoxy, halogen or hydroxy substituted C 1-6 Alkoxy, C 3-8 Cycloalkyl, halogen or hydroxy substituted C 3-8 cycloalkyl, three- to eight-membered heterocycloalkyl, and three- to eight-membered heterocycloalkyl substituted with halogen or hydroxy.

[0010] A is alkynyl, alkenyl, C 3-8 Cycloalkyl, three to eight-membered heterocycloalkyl containing 1-2 heteroatoms, C 5-8 Cycloalkenyl, five- to eight-membered heterocycloalkenyl containing one heteroatom, aromatic ring or aromatic heterocycle.

[0011] n is 0, 1, 2 or 3.

[0012] R4 is hydrogen, halogen, cyano, hydroxy, amino, alkyl, halogen, hydroxy or amino substituted alkyl, alkoxy, halogen, hydroxy or amino substituted alkoxy, cycloalkyl, halogen, hydroxy or amino substituted cycloalkyl, heterocycloalkyl, halogen, hydroxy or amino substituted heterocycloalkyl, -alkylene-(hetero)cycloalkyl, halogen, hydroxy or amino substituted -alkylene-(hetero)cycloalkyl, -O-R5, -NH-R5, -CONH2, -COOH, -CO-NHOH, -SO2NH2, -CO-R5, -CONH-R5, -COO-R5, -SO2NH- R5, -SO2NHCONH-R5, -SO2-R5, -SO-R5, -NHCO-R5, -NHSO2-R5, -NHCONH-R5, -alkylene-O-R5, -alkylene-NH-R5, -alkylene-CONH2, -alkylene-COOH, -alkylene-CO-R5, -alkylene-CONH-R5, -alkylene-COO-R5, -alkylene-NHCO-R5, -alkylene-NHSO2-R5, -alkylene-NHCONH-R5; or wherein two R4 are connected and form a bridged ring or spiro ring with A. R5 is selected from unsubstituted or halogen-substituted alkyl, cycloalkyl, -alkylene-cycloalkyl, heterocycloalkyl, -alkylene-heterocycloalkyl.

[0013] In a preferred embodiment, A-(R4) n for U and V are both C or one of them is N, and R4 and n are the same as defined above.

[0014] In another preferred example, A-(R4) n for m1 and m2 are independently 0, 1 or 2 and 1≤m1+m2≤4, Y is C or N, Z is selected from C, O, and N, and R4 and n are the same as defined above.

[0015] In another preferred example, A-(R4) n for R4 is as defined above.

[0016] Preferably, the present invention provides a compound of the following chemical structure (II) or a pharmaceutically acceptable salt thereof:

[0017] R1, R2, R4, and n are as defined above, c is 0, 1, or 2; a is 0, 1, or 2; b is 1, 2, or 3; and R6 and R7 are independently hydrogen or halogen.

[0018] Preferably, A-(R4) n Selected from

[0019] Preferably, the present application provides the following compounds or pharmaceutically acceptable salts thereof:

[0020] In a second aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0021] In a third aspect, the present invention provides a use of the above-mentioned compound in the preparation of a medicament for preventing and / or treating diseases associated with DHODH, such as autoimmune diseases, immune and inflammatory diseases, destructive bone diseases, hematological cancers, malignant tumors, angiogenesis-related diseases, viral diseases and infectious diseases.

[0022] The autoimmune disease is selected from multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, alopecia areata, dry eye, systemic lupus erythematosus, lupus nephritis, etc.; the immune and inflammatory diseases are selected from neuralgia, encephalomyelitis, uveitis, colitis, transplant rejection, glomerular disease, clonal disease and asthma; the hematological cancer is selected from myeloma, lymphoma, leukemia (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), chronic bone marrow disease, myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, chronic osteoporosis, etc. Myeloproliferative diseases, monoclonal immunoglobulinemia of undetermined significance, myelodysplastic syndrome, plasma exchange amyloidosis and plasmacytoma; the malignant tumor diseases are selected from lung cancer, breast cancer, head and neck cancer, glioma, prostate cancer, colon cancer, rectal cancer, pancreatic cancer, ovarian cancer, cervical cancer, testicular cancer, bladder cancer, gastric cancer, skin cancer, thyroid cancer, kidney cancer, esophageal cancer, liver cancer, squamous cell carcinoma, basal cell carcinoma and adenocarcinoma; the viral infection diseases include diseases caused by influenza virus, coronavirus and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figures 1A-1D show the in vivo efficacy of compound I-10 in a mouse xenograft colon adenocarcinoma (RKO) model ("I-10" refers to the compound I-10-treated group, and "Vehicle" refers to the vehicle control group); Figure 1A shows the relative tumor volume changes in mice within four weeks of compound I-10 administration; Figure 1B shows the weight changes in mice in the treated and control groups within four weeks of administration; Figure 1C shows the statistical graph of mouse tumor weights after dissection; and Figure 1D shows the tumor size of each mouse after dissection after the end of administration. Figures 2A-2C show the in vivo efficacy of compounds I-15 and I-56 in the DSS-induced acute colitis model in mice ("Ctrl" refers to the control group, "DSS" refers to the dextran sulfate sodium group, "Prednisolone" refers to the prednisolone treatment group, "I-15" refers to the compound I-15 treatment group, and "I-56" refers to the compound I-56 treatment group); Figure 2A: Statistical graph of colon length of the control group, DSS group, prednisolone-treated group, I-15-treated group, and I-56-treated group; Figure 2B: Statistical graph of the weight of mice in each group; Figure 2C: Representative graph of colon length after dissection of mice in each group after the end of drug administration. DETAILED DESCRIPTION

[0024] The present invention is further described below with reference to the accompanying drawings and the following embodiments. It should be understood that the accompanying drawings and the following embodiments are only used to illustrate the present invention, rather than to limit the present invention.

[0025] As mentioned above, the present invention provides a compound having the following chemical structure (I) or a pharmaceutically acceptable salt thereof:

[0026] The definitions of the groups are as described above.

[0027] The compounds can be prepared by the following synthetic schemes. Unless otherwise specified, the groups in the synthetic schemes are defined as above.

[0028] Synthesis scheme 1:

[0029] The reaction is divided into 5-6 steps: first, 2-bromo-6-nitrophenol (X=CH) or 4-bromo-2-nitropyridine-3-ol (X=N) is used as a nucleophilic reagent to perform nucleophilic substitution on different bromo derivatives (R3Br), followed by Suzuki coupling (when R4 is an alkenyl, aryl or heteroaryl group), Buchwald coupling (when R4 is a heterocycloalkyl group connected by a heteroatom), or Sonogashira coupling (when R4 is an alkynyl group) to obtain intermediate 1-3, which is then subjected to reduction, bromine substitution, and Buchwald coupling to obtain intermediate 1-6 or a keto-type target compound. The carbonyl group is further reduced to a secondary alcohol, or reacted with methylmagnesium bromide to form a tertiary alcohol, or reacted with a diol to form a ketal, or reacted with hydroxylamine hydrochloride to form an oxime, or reductively aminated to form an amine, or the ester group is hydrolyzed or transesterified to obtain the target compound (I).

[0030] Reaction conditions: a) different bromo derivatives (R3Br) are reacted with potassium carbonate and N,N-dimethylformamide at about 90°C to obtain compounds represented by formula 1-2 through nucleophilic substitution reaction; b) the compound of formula 1-2 is reacted with substituted boronic acid in tetrakis(triphenylphosphine)palladium, potassium carbonate, toluene / ethanol at about 90°C (A is aryl, heteroaryl, cycloalkenyl or oxygen-containing heterocycloalkenyl), or the compound of formula 1-2 is reacted with a saturated ring substituted with a heteroatom in Pd2(dba)3, BINAP, sodium tert-butoxide, toluene at about 90°C (A is a nitrogen-containing heterocyclic alkyl), or the compound of formula 1-2 is reacted with a substituted terminal alkyne in Pd(PPh3)2Cl2, CuI, triethylamine / tetrahydrofuran at about 80°C to obtain a compound of formula 1-3 (A is an alkynyl group); c) the compound of formula 1-3 is reduced in hydrogen, platinum dioxide, and methanol at about 30°C to obtain a compound of formula 1-4; d) the compound of formula 1-4 is reacted in tert-butyl nitrite, copper bromide, and dichloromethane at 0°C-25°C to obtain a compound of formula 1-5; e) the compound of formula 1-5 is reacted with different 2-aminothiazole derivatives, 2- di-tert-butylphosphine-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl is reacted in tris(dibenzylideneacetone)dipalladium, potassium carbonate, tert-butanol, and acetic acid at about 110° C. for 5-8 hours, or in different 2-aminothiazole derivatives, tris(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, sodium carbonate, and toluene at about 120° C. for 12-15 hours to obtain a compound of formula 1-6 or a ketone target compound; f) the compound of formula 1-6 is reacted in the methanol of sodium borohydride The reaction is carried out in an alcohol solution at room temperature for 1 hour to reduce the secondary alcohol, or with methylmagnesium bromide in tetrahydrofuran at room temperature for 2 hours to add the tertiary alcohol, or with diol under p-toluenesulfonic acid catalysis and stirring at 150°C overnight to obtain a ketal, or with hydroxylamine hydrochloride, sodium acetate and ethanol at 80°C overnight to obtain an oxime, or with ammonium acetate, sodium cyanoborohydride and methanol at 80°C to reduce and aminize the amine; or with lithium hydroxide, ethanol / water at room temperature to obtain an acid, or with methoxyamine hydrochloride in EDCI, DMAP and DCM at room temperature to obtain the target product.

[0031] In addition to Synthesis Scheme 1, the compound can also be obtained through Synthesis Scheme 2:

[0032] The reaction is divided into 3-4 steps: 1-chloro-2-fluoro-3-iodobenzene (X=CH) or 2-chloro-3-fluoro-4-iodopyridine (X=N) is used as the starting material, and is first subjected to nucleophilic substitution with different alcohol derivatives (R3OH), followed by Suzuki coupling (when A is a cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl), Buchwald coupling (when A is a nitrogen-containing heterocycloalkyl group connected through a nitrogen atom), or Sonogashira coupling (when A is an alkynyl group) to obtain intermediate 2-3, which is then subjected to Buchwald coupling to obtain intermediate 2-4 or a keto-type target compound. The carbonyl group is further reduced to a secondary alcohol, or reacted with methylmagnesium bromide to form a tertiary alcohol, or reacted with a diol to form a ketal, or reacted with hydroxylamine hydrochloride to form an oxime, or reductively aminated to form an amine, or the ester group is hydrolyzed or subjected to transesterification to obtain the target compound (I).

[0033] Reaction conditions: a) the compound of formula 2-1 reacts with different alcohol derivatives (R3OH) in sodium hydride and tetrahydrofuran at about 0°C to obtain the compound of formula 2-2; b) the compound of formula 2-2 reacts with substituted boric acid pinacol ester in Pd(dppf)Cl2, potassium carbonate, 1,4-dioxane / water at about 70°C, or reacts with a heteroatom-substituted saturated ring in Pd2(dba)3, BINAP, sodium tert-butoxide, toluene at about 90°C, or reacts with a substituted terminal alkyne in Pd(PPh3)2Cl2, CuI, triethylamine at room temperature to obtain the compound of formula 2-3; c) the compound of formula 2-3 reacts with different 2-aminothiazole derivatives, 2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl in tris(dibenzylideneacetone)dipalladium, potassium carbonate, tert-butanol, acetic acid at about 110°C. d) the compound of formula 2-4 is reacted in sodium borohydride and methanol at room temperature for 1 hour for reduction to obtain a secondary alcohol, or reacted with methylmagnesium bromide in tetrahydrofuran at room temperature for 2 hours to obtain a tertiary alcohol, or reacted with a diol at 150°C with stirring overnight under p-toluenesulfonic acid to obtain a ketal, or reacted with hydroxylamine hydrochloride, sodium acetate and ethanol at 80°C overnight to obtain an oxime, or reacted with ammonium acetate, sodium cyanoborohydride and methanol at 80°C for reductive amination to obtain an amine; or reacted in lithium hydroxide, ethanol / water at room temperature to obtain an acid, or reacted with methoxyamine hydrochloride in EDCI, DMAP and DCM at room temperature to obtain the target product.

[0034] In addition to synthesis schemes 1 and 2, the compound can also be obtained through synthesis scheme 3:

[0035] The reaction is divided into 5-6 steps: 1-chloro-2-fluoro-3-nitrobenzene (X=CH) or 2-chloro-3-fluoro-4-nitropyridine (X=N) is used as the starting material, and is first subjected to nucleophilic substitution with different alcohol derivatives (R3OH), followed by reduction, iodination, Suzuki coupling (when A is an alkenyl, aryl or heteroaryl group), Buchwald coupling (when A is a heterocycloalkyl group connected through a heteroatom), or Sonogashira coupling (when A is an alkynyl group) to obtain intermediate 3-5, which is then subjected to Buchwald coupling to obtain intermediate 3-6 or a keto-type target compound. The carbonyl group is further reduced to a secondary alcohol, or reacted with methylmagnesium bromide to form a tertiary alcohol, or reacted with a diol to form a ketal, or reacted with hydroxylamine hydrochloride to form an oxime, or reductively aminated to form an amine, or the ester group is hydrolyzed or subjected to transesterification to obtain the target compound (I).

[0036] Reaction conditions: a) the compound of formula 3-1 reacts with a substituted alcohol derivative in potassium carbonate and N,N-dimethylformamide at 50-90°C to obtain a compound of formula 3-2; b) the compound of formula 3-2 reacts with hydrogen, platinum dioxide, and methanol at about 30°C to obtain a compound of formula 3-3; c) the compound of formula 3-3 reacts with tert-butyl nitrite, cuprous iodide, and acetonitrile at about 80°C to obtain a compound of formula 3-4; d) the compound of formula 3-4 reacts with a substituted boric acid pinacol ester in the presence of Pd(dppf )Cl2, potassium carbonate, 1,4-dioxane / water at about 70°C, or with a saturated ring substituted with a heteroatom in Pd2(dba)3, BINAP, sodium tert-butoxide, toluene at about 90°C, or with a substituted terminal alkyne in Pd(PPh3)2Cl2, CuI, triethylamine at room temperature to obtain a compound of formula 3-5; e) the compound of formula 3-5 is reacted with different 2-aminothiazole derivatives, 2-di-tert-butylphosphine-2′,4′,6′-triisopropyl-3,6 -dimethoxy-1,1′-biphenyl is reacted in tris(dibenzylideneacetone)dipalladium, potassium carbonate, tert-butanol, and acetic acid at about 110°C for 5-8 hours, or with different 2-aminothiazole derivatives in tris(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, sodium carbonate, and toluene at about 120°C for 12-15 hours to obtain a compound of formula 3-6; f) the compound of formula 3-6 is reduced in sodium borohydride and methanol at room temperature for 1 hour to obtain a secondary The alcohol can be reacted with methylmagnesium bromide in tetrahydrofuran at room temperature for 2 hours to obtain a tertiary alcohol, or reacted with a diol under p-toluenesulfonic acid catalysis and stirred at 150°C overnight to obtain a ketal, or reacted with hydroxylamine hydrochloride, sodium acetate, and ethanol at 80°C overnight to obtain an oxime, or reacted with ammonium acetate, sodium cyanoborohydride, and methanol at 80°C for reductive amination to obtain an amine; or reacted in lithium hydroxide, ethanol / water at room temperature to obtain an acid, or reacted with methoxyamine hydrochloride in EDCI, DMAP, and DCM at room temperature to obtain the target product.

[0037] The above synthesis schemes only list the preparation methods of some compounds in the present invention. With reference to the commonly used technical means in this field and the prior art, those skilled in the art can use similar methods to synthesize the compounds of the present invention based on the above synthesis schemes.

[0038] The “compounds” described in the present invention include all stereoisomers, geometric isomers, tautomers and isotopes.

[0039] The "compounds" of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. Compounds of the present invention containing asymmetric carbon atoms may be isolated in optically pure or racemic forms; optically pure forms may be resolved from racemic mixtures or synthesized using chiral starting materials or reagents.

[0040] The “compounds” described in the present invention also include tautomeric forms; tautomeric forms are derived from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0041] The present invention also includes all isotopes of atoms, whether in intermediates or final compounds; isotopes include atoms having the same atomic number but different mass numbers, for example, isotopes of hydrogen include deuterium and tritium. In addition, if necessary, for example for a specific therapeutic or diagnostic treatment, the compounds of the present invention can be introduced with isotopes or radioisotopes known in the art, such as 3 H. 15 O. 13 C or 13 N isotope.

[0042] In the present invention, unless otherwise specified, the terms used have the following meanings.

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

[0044] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms, such as C1-C 20 Alkyl, preferably C 1- C6 alkyl, such as methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylhexyl, etc.

[0045] The term "alkylene" refers to a straight-chain or branched divalent saturated hydrocarbon group, including but not limited to methylene, ethylene, propylene, and the like.

[0046] The term "alkoxy" refers to an -O-alkyl group.

[0047] The term "cycloalkyl" refers to a saturated monocyclic, fused, spirocyclic or bridged ring composed entirely of carbon, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.4]octyl, bicyclo[3.1.1]hexyl, and the like.

[0048] The term "cycloalkenyl" refers to an unsaturated monocyclic, fused, spirocyclic or bridged ring composed entirely of carbon, including but not limited to cyclopentenyl, cyclohexenyl and the like.

[0049] The term "heterocycloalkyl" refers to a saturated monocyclic, fused, spirocyclic or bridged ring containing one or more heteroatoms of N, O or S. It includes, but is not limited to, oxetanyl, oxolanyl, oxhexanyl, piperazino, N-methylpiperazinyl, homopiperazinyl, N-methylhomopiperazinyl, morpholinyl, 2-methylmorpholinyl, piperidino, pyrrolidinyl, homomorpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, and the like.

[0050] The term "heterocycloalkenyl" refers to an unsaturated monocyclic, fused, spirocyclic or bridged ring containing one or more heteroatoms such as N, O or S, such as oxolyl and oxahenyl.

[0051] The term "aryl" refers to an all-carbon monocyclic or fused ring having a completely conjugated π electron system, typically having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms. Aryl includes, but is not limited to, phenyl, naphthyl, and anthracenyl.

[0052] The term "heteroaryl" refers to a monocyclic or condensed ring of 5-12 ring atoms, containing 1-4 ring atoms selected from N, O, and S, and the remaining ring atoms are C, and has a completely conjugated π-electron system, including but not limited to pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, triazolyl, etc.

[0053] "Pharmaceutically acceptable salts" refer to pharmaceutically acceptable salts that maintain the pharmacological activity of the parent compound while improving the physicochemical properties or metabolic properties. Such salts include acid addition salts and base addition salts prepared from pharmaceutically acceptable acids or bases (including organic acids, inorganic acids, organic bases, inorganic bases), or mixtures thereof. In the present 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, muconic acid, or their analogs. If the compound of the invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared with pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. These salts may be selected from aluminum salts, ammonium salts, lithium salts, magnesium salts, sodium salts, and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine, betaine, and caffeine.

[0054] The compounds according to the present invention may also exist in the form of their solvates, such as hydrates (hemihydrate, monohydrate, dihydrate, trihydrate, etc.).

[0055] The "pharmaceutical composition" of the present invention refers to a preparation of one or more compounds of the present invention or their salts and a carrier generally accepted in the art for delivering biologically active compounds to an organism (e.g., a human). The purpose of a pharmaceutical composition is to facilitate administration and delivery to an organism.

[0056] The term "pharmaceutically acceptable carrier" refers to a substance that is co-administered with an active ingredient and facilitates the administration of the active ingredient, including but not limited to any glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the State Food and Drug Administration for use in humans or animals (e.g., livestock). Examples include but are not limited to calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0057] The pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0058] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, making sugar-coated pills, grinding, emulsifying, freeze-drying, etc.

[0059] The routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration. The preferred route of administration is oral administration.

[0060] For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with a pharmaceutically acceptable carrier well known in the art. These carriers enable the compounds of the present invention to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to a patient. For example, a pharmaceutical composition for oral administration can be prepared as follows: the active ingredient is combined with one or more solid carriers, the resulting mixture is granulated if necessary, and a small amount of excipients is added if necessary to form a mixture or granules to form a tablet or tablet core. The tablet core can be combined with an optional enteric coating material to form a coated formulation that is more conducive to absorption by an organism (e.g., a human).

[0061] Some typical excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, sterilized water, syrup and methylcellulose. In addition, lubricants (such as talc, magnesium stearate and mineral oil), wetting agents, emulsifying and suspending agents, preservatives (such as methyl parahydroxybenzoate and propyl parahydroxybenzoate), sweeteners and flavor enhancers can also be included. Pharmaceutical composition of the present invention can reach the quick, continuous or delayed release of active pharmaceutical ingredient after patient is administered by concrete excipient mode, which is also the method widely used in this area.

[0062] The amount of the active ingredient, ie, the compound of the present invention, in the pharmaceutical composition and unit dosage form can be varied or significantly adjusted depending on the specific application, the activity of the particular compound, and the desired concentration.

[0063] "Treatment" means any treatment of a disease in a mammal, including: (1) preventing the disease, i.e., causing clinical symptoms of the disease not to develop; (2) inhibiting the disease, i.e., preventing the development of clinical symptoms; (3) alleviating the disease, i.e., causing the regression of clinical symptoms.

[0064] In addition to standard methods known in the literature or exemplified in the experimental procedures, the compounds of the present invention may be prepared using reactions such as those shown in the following schemes. Therefore, the following illustrative schemes are provided for illustrative purposes and are not intended to limit the compounds listed or any particular substituents. The number of substituents shown in the schemes does not necessarily need to correspond to the number used in the claims, and for clarity, the definition of a single substituent attached to the patent formula allows for compounds with multiple substituents.

[0065] The present invention will be further described in detail below with reference to specific examples. It should also be understood that the following examples are only used to further illustrate the present invention and are not to be construed as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention all fall within the scope of protection of the present invention. The specific process parameters and the like in the following examples are only examples within a suitable range, that is, those skilled in the art can make selections within a suitable range through the description herein, and are not to be limited to the specific numerical values ​​exemplified below.

[0066] In the method for preparing the target compound provided by the present invention, column chromatography uses silica gel (300-400 mesh) produced by Rushan Sun Desiccant Co., Ltd.; thin-layer chromatography uses GF254 (0.25 mm); nuclear magnetic resonance chromatography (NMR) uses a Varian-400 nuclear magnetic resonance spectrometer; and liquid chromatography-mass spectrometry (LC / MS) uses an Agilent Technologies 6120 liquid chromatography-mass spectrometer. In addition, all operations involving easily oxidized or hydrolyzed raw materials are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention are commercially available raw materials and can be used directly without further purification, but it should be understood that they can be purified before use.

[0067] Example 1: Preparation of Compound I-1: 2-((2-ethoxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0068] Step 1: Preparation of 1-bromo-2-ethoxy-3-nitrobenzene

[0069] 2-Bromo-6-nitrophenol (2.18 g, 10.0 mmol) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (2.07 g, 15.0 mmol) was added. The mixture was stirred at room temperature for 1 hour. Ethyl iodide (0.96 mL, 12 mmol) was then added, and the mixture was heated to 90°C and allowed to react overnight. After completion of the reaction as monitored by TLC, the organic phase was diluted with ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 1.97 g of a brown oil (80% yield). LC-MS (ESI): m / z 246.0 [M+H].+ .

[0070] Step 2: Preparation of 2-ethoxy-3-nitro-1,1'-biphenyl

[0071] 1-Bromo-2-ethoxy-3-nitrobenzene (1.97 g, 8.01 mmol), phenylboronic acid (1.07 g, 8.81 mmol), potassium carbonate (1.66 g, 12.01 mmol), and tetrakistriphenylphosphine palladium (92.5 mg, 80.1 μmol) were dissolved in a mixed solvent of toluene (8 mL) and ethanol (2 mL). The nitrogen atmosphere in the reaction vessel was replaced three times using a double-row tube, and the reaction mixture was then placed at 90°C for 5 hours. After completion of the reaction, as determined by TLC, the reaction solution was cooled to room temperature, dried, and purified by silica gel column chromatography to obtain 1.63 g of a white oil with a yield of 83.7%. LC-MS (ESI): m / z 244.1 [M+H]. + .

[0072] Step 3: Preparation of 2-ethoxy-[1,1'-biphenyl]-3-amine

[0073] 2-Ethoxy-3-nitro-1,1'-biphenyl (1.63 g, 6.70 mmol) was dissolved in 15 mL of methanol, and platinum dioxide (76.1 mg, 0.335 mmol) was added. The mixture was then reacted under a hydrogen atmosphere for 5 hours. After completion of the reaction, the catalyst was filtered off with celite and dried to obtain 1.36 g of a black oil (95.2% yield). LC-MS (ESI): m / z 214.1 [M+H] + .

[0074] Step 4: Preparation of 3-bromo-2-ethoxy-1,1'-biphenyl

[0075] Under ice-cooling, tert-butyl nitrite (1.02 mL, 7.65 mmol) and cuprous bromide (1.37 g, 9.56 mmol) were dissolved in anhydrous acetonitrile (5 mL) and stirred for 10 minutes. Subsequently, a solution of 2-ethoxy-[1,1'-biphenyl]-3-amine (1.36 g, 6.38 mmol) in anhydrous acetonitrile (10 mL) was added dropwise under ice-cooling. After the addition was complete, the mixture was stirred for 10 minutes, and then the system was placed at 65°C for 1 hour. After the reaction was completed as monitored by TLC, 1N hydrochloric acid (40 mL) was added to quench the reaction, and the mixture was extracted with ether, dried, and spin-dried. Silica gel column chromatography gave 1.06 g of a colorless oil with a yield of 60.0%. LC-MS (ESI): m / z 277.1 [M+H] + .

[0076] Step 5: Preparation of 2-((2-ethoxy-[1,1'-biphenyl]-3-yl)amino)-6,7-dihydrobenzo[d]thiazol-4(5H)-one

[0077] A stir bar was placed in a 20 mL microwave tube and oven-dried. Potassium carbonate (436 mg, 3.15 mmol), Pd2(dba)3 (309 mg, 0.338 mmol), t-BuBrettPhos (720 mg, 1.49 mmol), 2-amino-5,6-dihydrobenzo[d]thiazol-7(4H)-one (398 mg, 2.36 mmol), and 3-bromo-2-ethoxy-1,1'-biphenyl (624 mg, 2.25 mmol) were then added. The microwave tube was sealed, evacuated, and backfilled with argon three times. Tert-butyl alcohol (15 mL) and acetic acid (216 mg, 1.35 mmol) were added to the microwave tube, which was then left to react at 110°C overnight. After TLC monitoring, the reaction solution was cooled, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. Silica gel column chromatography afforded 525 mg of a white solid (yield: 64.0%). LC-MS (ESI): m / z 365.1 [M+H] + .

[0078] Step 6: Preparation of 2-((2-ethoxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0079] 2-((2-Ethoxy-[1,1'-biphenyl]-3-yl)amino)-6,7-dihydrobenzo[d]thiazol-4(5H)-one (525 mg, 1.44 mmol) was dissolved in methanol (20 mL). Sodium borohydride (273 mg, 7.20 mmol) was added under ice-cooling, and the mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, as monitored by TLC, the reaction was quenched with water. The reaction solution was evaporated to dryness and purified by silica gel column chromatography using a reverse phase preparative system to afford 237 mg of a white solid (44.9% yield, mp 155.1–157.4°C). 1H NMR(600MHz,DMSO-d6)δ9.34(s,1H),8.43(d,J=7.7Hz,1H),7.59–7.54(m,2H),7.46(t,J=7.7 Hz,2H),7.37(t,J=7.4Hz,1H),7.14(t,J=7.9Hz,1H),6.92(dd,J=7.6,1.6Hz,1H),4.95(d,J= 5.0Hz,1H),4.49(d,J=3.8Hz,1H),3.50(q,J=7.0Hz,2H),2.63(dt,J=16.1,4.7Hz,1H),2.53– 2.47(m,1H),1.96–1.88(m,1H),1.82–1.76(m,2H),1.75–1.68(m,1H),1.00(t,J=7.0Hz,3H). 13 CNMR(151MHz,DMSO-d6)δ161.37,148.32,144.79,138.74,135.81,134.73,129.19,128.74,127. 69,124.61,123.26,121.05,118.56,68.78,63.66,40.54,32.66,23.15,19.24,15.43.HRMS(ESI + )m / z C 21 H 23 N2O2S[M+H] + Calculated value: 367.1475; measured value: 367.1472.

[0080] Example 2: Preparation of Compound I-2: 2-((2-methoxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0081] Referring to the synthetic route of Compound I-1 in Example 1, iodomethane was used as the starting material in Step 1. Silica gel column chromatography and reverse phase preparative system were used to obtain 53 mg of a white solid with a yield of 26% and an mp of 184.3–186.7°C. 1H NMR(600MHz,DMSO-d6)δ9.50(s,1H),8.55–8.47(m,1H),7.59–7.53(m,2H),7.49–7.44 (m,2H),7.37(ddd,J=8.6,2.4,1.2Hz,1H),7.14(t,J=7.9Hz,1H),6.91(dd,J=7.6,1.6 Hz,1H),4.96(d,J=5.2Hz,1H),4.50(d,J=4.2Hz,1H),3.31(s,3H),2.63(dt,J=16.1,4 .7Hz,1H),2.54–2.47(m,1H),1.97–1.87(m,1H),1.82–1.75(m,2H),1.75–1.67(m,1H). 13 C NMR(151MHz,DMSO-d6)δ160.80,147.82,145.42,138.04,134.90,133.87,128.66,128.37,1 27.21,124.22,122.62,120.59,117.92,63.19,60.14,40.06,32.18,22.66,18.77.HRMS(ESI + )m / z C 20 H 21 N2O2S[M+H] + Calculated value: 353.1318; measured value: 353.1315.

[0082] Example 3: Preparation of Compound I-3: 2-((2-isopropoxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0083] Referring to the synthetic route of Compound I-1 in Example 1, using isopropyl bromide as the starting material in Step 1, 84 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 42% and an mp of 145.1–147.5°C. 1H NMR (600MHz, DMSO-d6) δ9.21(s,1H),8.42(dd,J=8.2,1.0Hz,1H),7.56(dd,J=8.1,1.1Hz,2H),7.46(d d,J=10.6,4.8Hz,2H),7.38–7.34(m,1H),7.14(t,J=7.9Hz,1H),6.92(dd,J=7.6,1.6Hz,1H),4.96(d, J=5.6Hz,1H),4.49(dd,J=9.4,4.3Hz,1H),3.60(hept,J=6.1Hz,1H),2.63(dt,J=16.1,4.7Hz,1H),2. 53–2.46(m,1H),1.95–1.87(m,1H),1.82–1.74(m,2H),1.74–1.68(m,1H),0.97(dd,J=6.1,1.2Hz,6H). 13 C NMR (151MHz, DMSO-d6) δ160.76,147.86,143.07,138.64,135.90,134.31,128.63,128.30,127. 18,123.91,122.98,120.53,117.86,75.35,63.18,40.05,32.17,22.66,21.35,18.75.HRMS(ESI + )m / z C 22 H 25 N2O2S[M+H] + Calculated value: 381.1631; measured value: 381.1631.

[0084] Example 4: Preparation of Compound I-4: 2-((2-((1,1,1-trifluoromethylpropane-2-yl)oxy)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0085] Step 1: Preparation of 1-bromo-3-nitro-2-((1,1,1-trifluoropropan-2-yl)oxy)benzene

[0086] 2-Fluoro-3-bromonitrobenzene (1.00 g, 4.55 mmol) was dissolved in DMF (30 mL). Solid potassium carbonate (1.88 g, 13.6 mmol) and 1,1,1-trifluoropropane-2-ol (0.780 g, 6.82 mmol) were added sequentially at room temperature. The mixture was stirred for 0.5 h, then heated to 90°C and allowed to react for 10 h. After completion of the reaction, the reaction mixture was returned to room temperature and extracted with ethyl acetate until the aqueous phase showed no product. The organic phases were combined, washed twice with water, three times with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated, and column chromatography afforded 1.15 g of a colorless oil (80.6% yield).

[0087] Step 2-Step 6: Preparation of 2-((2-((1,1,1-trifluoromethylpropan-2-yl)oxy)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0088] Refer to steps 2 to 6 of the synthetic route for compound I-1 in Example 1. Silica gel column chromatography and reverse phase preparative chromatography yielded 86 mg of a white solid (yield 62.9%), mp 129.2–131.3°C. 1 H NMR (400MHz, DMSO-d6) δ9.20 (d, J = 34.1Hz, 1H), 8.37–8.24 (m, 1H), 7.53–7. 31(m,6H),7.25–6.97(m,1H),4.97(dd,J=5.6,2.5Hz,1H),4.50–4.48(m,1H) ,4.13–4.01(m,1H),2.66–2.60(m,1H),2.54–2.47(m,1H),1.96–1.89(m,1H ),1.81–1.77(m,2H),1.74–1.69(m,1H),1.08–0.93(m,3H).LC-MS(ESI):m / z 435.2[M+H] + .

[0089] Example 5: Preparation of Compound I-5: 2-((2-(((R)-1,1,1-trifluoromethylpropane-2-yl)oxy)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0090] Following the synthetic route of Compound I-4 in Example 4, (2S)-1,1,1-trifluoropropane-2-ol was used as the starting material in Step 1. Silica gel column chromatography and reverse-phase preparative chromatography yielded 35 mg of a white solid in a 50.5% yield, mp 147.4–148.6°C. 1H NMR(400MHz, DMSO-d6)δ9.17(s,1H),8.26(d,J=7.7Hz,1H),7.53–7.47(m,4H),7.43–7.39(m, 1H),7.23(t,J=7.9Hz,1H),6.99(dd,J=7.7,1.6Hz,1H),4.98(d,J=5.6Hz,1H),4.49(q,J=4.4H z,1H),4.05(p,J=6.7Hz,1H),2.64(dt,J=16.1,4.6Hz,1H),2.55–2.48(m,1H),1.96–1.88(m, 1H),1.81–1.77(m,2H),1.75–1.69(m,1H),1.07(d,J=6.4Hz,3H).LC-MS(ESI):m / z435.2[M+H] + .

[0091] Example 6: Preparation of Compound I-6: 2-((2-(cyclopropylmethoxy)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0092] Referring to the synthetic route of Compound I-1 in Example 1, (bromomethyl)cyclopropane was used as the starting material. Silica gel column chromatography and reverse phase preparative chromatography gave 64 mg of a white solid with a yield of 43% and an mp of 140.5-143.7°C. 1 H NMR (600MHz, DMSO-d6) δ9.31 (s, 1H), 8.41 (d, J = 8.0Hz, 1H), 7.54 (d, J = 7.3Hz, 2H), 7.45 (t, J = 7.6Hz, 2H),7.37(t,J=7.3Hz,1H),7.14(t,J=7.9Hz,1H),6.91(d,J=7.5Hz,1H),4.96(d,J=5.2Hz,1H),4.55– 4.44(m,1H),3.25(d,J=7.1Hz,2H),2.63(dt,J=15.7,4.3Hz,1H),2.53–2.46(m,1H),1.97–1.87(m,1 H),1.83–1.75(m,2H),1.74–1.65(m,1H),1.03–0.91(m,1H),0.33–0.22(m,2H),-0.13–-0.21(m,2H). 13C NMR(151MHz,DMSO-d6)δ160.87,147.90,144.20,138.19,135.32,134.40,128.89,128.22,127.16, 124.17,122.76,120.53,118.04,77.14,63.17,40.05,32.17,22.67,18.76,10.29,2.91.HRMS(ESI + )m / z C 23 H 25 N2O2S[M+H] + Calculated value: 393.1631; measured value: 393.1629.

[0093] Example 7: Preparation of Compound I-7: 2-((2-cyclobutyloxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0094] Referring to the synthetic route of Compound I-1 in Example 1, cyclobromobutane was used as the starting material in Step 1. Silica gel column chromatography and reverse phase preparative chromatography gave 53 mg of a white solid with a yield of 38% and an mp of 165.2–167.5°C. 1 H NMR(600MHz,DMSO-d6)δ9.30(s,1H),8.38(d,J=7.8Hz,1H),7.56–7.51(m,2H),7.45(t,J=7.7Hz,2H), 7.36(t,J=7.4Hz,1H),7.14(t,J=7.9Hz,1H),6.93(dd,J=7.6,1.6Hz,1H),4.95(d,J=5.6Hz,1H),4.48( dd,J=9.3,4.3Hz,1H),3.93(p,J=7.3Hz,1H),2.63(dt,J=16.1,4.7Hz,1H),2.53–2.46(m,1H),1.97–1. 87(m,3H),1.83–1.76(m,2H),1.75–1.67(m,3H),1.40(q,J=10.3Hz,1H),1.12(qt,J=10.5,7.8Hz,1H). 13C NMR(151MHz,DMSO-d6)δ160.84,147.87,143.21,138.48,135.38,134.38,128.90,128.22,127.15, 124.12,122.82,120.56,118.17,75.82,63.17,40.05,32.16,30.23,22.67,18.74,11.66.HRMS(ESI + )m / z C 23 H 25 N2O2S[M+H] + Calculated value: 393.1631; measured value: 393.1631.

[0095] Example 8: Preparation of Compound I-8: 2-((2-(oxetane-3-oxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0096] Following the synthetic route for Compound I-1 in Example 1, 3-bromobutylene oxide was used as the starting material in Step 1. Silica gel column chromatography and reverse-phase preparative chromatography yielded 126 mg of a white solid (71.2% yield, mp 120.7–121.6°C). 1 H NMR(400MHz,DMSO-d6)δ7.90(ddd,J=15.0,7.9,1.8Hz,1H),7.59–7.57(m,2H),7.44–7.40(m,2H) ,7.36–7.32(m,1H),7.08–6.98(m,2H),5.08–5.04(m,2H),4.52(q,J=4.5Hz,1H),4.34(ddd,J=29 .1,13.0,2.8Hz,1H),4.22–4.15(m,1H),3.69–3.53(m,3H),2.67(dt,J=16.2,4.7Hz,1H),2.58–2 .54(m,1H),1.99–1.88(m,1H),1.83–1.77(m,2H),1.75–1.70(m,1H).LC-MS(ESI):m / z394.8[M+H] + .

[0097] Example 9: Preparation of Compound I-9: 2-((2-(3,3-difluorocyclobutyloxy)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0098] Following the synthetic route of Compound I-4 in Example 4, 3,3-difluorocyclobutanol was used as the starting material in Step 1. Silica gel column chromatography and reverse-phase preparative chromatography yielded 260 mg of a white solid (71.7% yield, mp 137.7–139.1°C). 1 H NMR (400MHz, DMSO-d6) δ9.46 (s, 0.32H), 8.49 (dd, J=8.9, 4.0Hz, 1H), 7.57–7.48 (m, 4H), 7.47–7.41(m,1H),7.39–7.33(m,1H),7.22(t,J=7.9Hz,0.50H),6.97(dd,J=7.5,1.6Hz,0 .50H),5.01(s,0.28H),4.52(t,J=4.0Hz,1H),4.02–3.90(m,1H),2.71–2.61(m,4H),2.5 4–2.42(m,2H),1.99–1.91(m,1H),1.84–1.80(m,2H),1.77–1.72(m,1H).LC-MS(ESI):m / z 429.2[M+H] + .

[0099] Example 10: Preparation of Compound I-10: 2-((2-(cyclobutylmethoxy)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0100] Referring to the synthetic route of Compound I-1 in Example 1, (bromomethyl)cyclobutane was used as the raw material in Step 1. Silica gel column chromatography and reverse phase preparative chromatography gave 64 mg of a white solid with a yield of 43% and mp of 164.1–166.5°C. 1 H NMR(600MHz,DMSO-d6)δ9.18(s,1H),8.34(d,J=7.9Hz,1H),7.55–7.50(m,2H),7.45(t,J=7.7H z,2H),7.37(dt,J=8.5,1.1Hz,1H),7.14(t,J=7.9Hz,1H),6.92(dd,J=7.6,1.6Hz,1H),4.96(d, J=5.6Hz,1H),4.48(dd,J=9.3,4.3Hz,1H),3.42(d,J=7.0Hz,2H),2.63(dt,J=16.1,4.7Hz,1H), 2.53–2.43(m,2H),1.95–1.87(m,1H),1.79–1.66(m,6H),1.59–1.52(m,1H),1.40–1.33(m,1H). 13C NMR(151MHz,DMSO-d6)δ160.92,147.90,144.67,138.13,135.04,134.45,128.94,128.24,127.18,124 .11,123.03,120.52,118.40,76.91,63.16,40.05,34.14,32.16,24.30,22.68,18.75,17.75.HRMS(ESI + )m / z C 24 H 27 N2O2S[M+H] + Calculated value: 407.1788; measured value: 407.1785.

[0101] Example 11: Preparation of Compound I-11: 2-((2-(cyclopentyloxy)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0102] Referring to the synthetic route of Compound I-1 in Example 1, bromocyclopentane was used as the starting material in Step 1. Silica gel column chromatography and reverse phase preparative chromatography gave 53 mg of a white solid with a yield of 38% and an mp of 150.3–152.5°C. 1 H NMR (600MHz, DMSO-d6) δ9.10 (s, 1H), 8.27 (d, J = 7.5Hz, 1H), 7.54 (dd, J = 8.1, 1.1Hz, 2H), 7.45 (t, J = 7. 7Hz,2H),7.38–7.33(m,1H),7.14(t,J=7.9Hz,1H),6.96(dd,J=7.6,1.6Hz,1H),4.95(d,J=5.6Hz,1H), 4.48(dd,J=9.4,4.3Hz,1H),4.05(s,1H),2.62(dt,J=16.0,4.7Hz,1H),2.53–2.46(m,1H),1.95–1.87( m,1H),1.81–1.75(m,2H),1.73–1.68(m,1H),1.63–1.56(m,2H),1.50–1.43(m,2H),1.31–1.25(m,4H). 13C NMR(151MHz,DMSO-d6)δ160.94,147.96,143.94,138.61,135.46,134.76,128.89,128.27,127.13, 123.90,123.32,120.42,118.74,84.63,63.16,40.06,32.15,31.63,22.78,22.69,18.73.HRMS(ESI + )m / z C 24 H 27 N2O2S[M+H] + Calculated value: 407.1788; measured value: 407.1784.

[0103] Example 12: Preparation of Compound I-12: 2-((2-(cyclopentylmethoxy)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0104] Referring to the synthetic route of Compound I-1 in Example 1, (bromomethyl)cyclopentane was used as the raw material in Step 1. Silica gel column chromatography and reverse phase preparative chromatography gave 64 mg of a white solid with a yield of 43% and an mp of 156.3–158.6°C. 1 H NMR (600MHz, DMSO-d6) δ9.15 (s, 1H), 8.32 (d, J = 7.9Hz, 1H), 7.53–7.49 (m, 2H), 7.47–7.42 (m, 2H), 7.37 (ddd, J=8.6,2.4,1.2Hz,1H),7.14(t,J=7.9Hz,1H),6.92(dd,J=7.6,1.6Hz,1H),4.96(d,J=5.6Hz,1H),4.48(dd,J= 9.3,4.3Hz,1H),3.30–3.24(m,2H),2.63(dt,J=16.1,4.7Hz,1H),2.53–2.47(m,1H),2.17–2.08(m,1H),1.95 –1.87(m,1H),1.81–1.75(m,2H),1.74–1.67(m,1H),1.50–1.42(m,2H),1.34–1.27(m,4H),0.98–0.90(m,2H). 13C NMR(151MHz,DMSO-d6)δ160.98,147.91,145.02,138.16,134.88,134.59,128.98,128.18,127.17,124 .05,123.17,120.54,118.58,76.81,63.15,40.06,38.66,32.16,28.70,24.67,22.69,18.75.HRMS(ESI + )m / zC 25 H 29 N2O2S[M+H] + Calculated value: 421.1944; measured value: 421.1945.

[0105] Example 13: Preparation of Compound I-13: 2-((2-(cyclohexyloxy)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0106] Step 1: Preparation of 1-bromo-2-(cyclohexyloxy)-3-nitrobenzene

[0107] Cyclohexanol (928 mg, 9.27 mmol), 2-bromo-6-nitrophenol (2.02 g, 9.27 mmol) and triphenylphosphine (2.92 g, 11.1 mmol) were placed in a pre-dried three-necked flask. The air in the container was replaced with nitrogen three times, and then dry tetrahydrofuran (100 mL) was added to the flask. Under an ice bath, diisopropyl azodicarboxylate (2.26 g, 11.2 mmol) was slowly added dropwise, and the temperature was then naturally raised overnight. After the reaction was completed, the solvent was spin-dried and column chromatography was performed to obtain 2.12 g of a colorless oil in a yield of 76.2%. LC-MS (ESI): m / z 300.1 [M+H] + .

[0108] Step 2-Step 6: Preparation of 2-((2-(cyclohexyloxy)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0109] The subsequent steps were similar to steps 2 to 6 of the synthesis route of compound I-1 in Example 1. Silica gel column chromatography and reverse phase preparative system gave 64 mg of a white solid with a yield of 42% and mp of 186.3-188.9°C. 1H NMR(600MHz,DMSO-d6)δ9.17(s,1H),8.38(d,J=7.4Hz,1H),7.58–7.51(m,2H),7.45(t,J=7.7Hz,2H),7.39 –7.33(m,1H),7.13(t,J=7.9Hz,1H),6.91(dd,J=7.6,1.6Hz,1H),4.96(d,J=5.5Hz,1H),4.48(dd,J=8.6,4 .0Hz,1H),3.31–3.24(m,1H),2.62(dt,J=16.0,4.7Hz,1H),2.53–2.46(m,1H),1.96–1.86(m,1H),1.82–1. 75(m,2H),1.74–1.67(m,1H),1.57–1.47(m,4H),1.37–1.28(m,3H),1.00–0.92(m,1H),0.84–0.75(m,2H). 13 C NMR (151MHz, DMSO-d6) δ160.72,147.88,143.21,138.65,135.77,134.50,128.74,128.24,127.16,123.83 ,123.02,120.51,117.87,81.47,63.17,54.90,40.05,32.17,31.38,24.88,23.75,22.67,18.74.HRMS(ESI + )m / zC 25 H 29 N2O2S[M+H] + Calculated value: 421.1944; measured value: 421.1940.

[0110] Example 14: Preparation of Compound I-14: 2-((2-(cyclohexylmethoxy)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0111] Referring to the synthetic route of Compound I-1 in Example 1, (bromomethyl)cyclohexane was used as the raw material in Step 1. Silica gel column chromatography and reverse phase preparative chromatography gave 34 mg of a white solid with a yield of 35% and an mp of 154.4–156.9°C. 1H NMR(600MHz,DMSO-d6)δ9.10(s,1H),8.29(d,J=7.6Hz,1H),7.53–7.48(m,2H),7.44(t,J=7.6Hz,2H),7 .37(t,J=7.3Hz,1H),7.14(t,J=7.9Hz,1H),6.92(dd,J=7.6,1.6Hz,1H),4.96(d,J=5.6Hz,1H),4.48(dd ,J=9.3,4.3Hz,1H),3.21(d,J=6.1Hz,2H),2.63(dt,J=16.1,4.7Hz,1H),2.53–2.46(m,1H),1.95–1.87 (m,1H),1.81–1.75(m,2H),1.74–1.68(m,1H),1.55–1.48(m,6H),1.07–0.96(m,3H),0.67–0.58(m,2H). 13 C NMR(151MHz,DMSO-d6)δ161.04,147.93,145.36,138.07,134.84,134.65,129.03,128.13,127.16,124.06 ,123.23,120.53,118.73,78.28,63.15,40.06,37.14,32.16,29.11,25.90,25.18,22.70,18.75.HRMS(ESI + )m / z C 26 H 31 N2O2S[M+H] + Calculated value: 435.2101; measured value: 435.2099.

[0112] Example 15: Preparation of Compound I-15: 2-((3-cyclobutyloxy-4-phenylpyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0113] Step 1: Preparation of 4-bromo-2-nitropyridin-3-ol

[0114] Commercially available 4-bromo-2-hydroxypyridine (2.00 g, 11.5 mmol) was dissolved in sulfuric acid (20 mL). Fuming nitric acid (1.68 mL, 34.5 mmol) was slowly added dropwise to the reaction mixture in an ice bath. After addition, the mixture was stirred at room temperature for 0.5 h and heated in a 90°C oil bath for 15 h. The reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature and poured into ice water. The mixture was extracted three times with EA. The organic phases were combined, washed with saturated sodium bicarbonate, water, saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by column chromatography (PE:EA = 4:1) to obtain 1.40 g of the yellow nitrated product in a yield of 55.6%.

[0115] Step 2: Preparation of 4-bromo-3-cyclobutoxy-2-nitropyridine

[0116] 4-Bromo-2-nitropyridine-3-ol (1.40 g, 6.39 mmol) was dissolved in DMF (20 mL), and solid potassium carbonate (2.65 g, 19.2 mmol) was added. The mixture was stirred at room temperature for 0.5 h. Cyclobutyl bromide (1.29 g, 9.59 mmol) was slowly added dropwise to the mixture. The temperature was raised to 90°C and heated overnight. After completion of the reaction, the reaction solution was cooled to room temperature and extracted three times with ethyl acetate. The organic phases were combined, washed three times with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by column chromatography (PE:EA = 10:1) to obtain 530 mg of a yellow oil with a yield of 30.4%.

[0117] Step 3: Preparation of 3-cyclobutoxy-2-nitro-4-phenylpyridine

[0118] 4-Bromo-3-cyclobutoxy-2-nitropyridine (530 mg, 1.94 mmol) was dissolved in a mixed solvent of toluene (8 mL) and ethanol (2 mL). Phenylboronic acid (355 mg, 2.91 mmol), Pd(PPh3)4 (112 mg, 97.0 μL), and solid potassium carbonate (805 mg, 5.82 mmol) were added, respectively. The nitrogen atmosphere was replaced three times, and the mixture was heated in a 90°C oil bath for 6 h. The mixture was then cooled to room temperature and extracted with EA three times. The organic phases were combined, washed three times with water, washed once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by column chromatography (PE:EA = 10:1) to give 490 mg of a white solid with a yield of 93.4%.

[0119] Step 4: Preparation of 3-cyclobutoxy-4-phenylpyridin-2-amine

[0120] The compound 3-cyclobutyloxy-2-nitro-4-phenylpyridine (490 mg, 1.81 mmol) was dissolved in methanol (15 mL), and 5% by mass of platinum dioxide was added. The reaction was allowed to react at room temperature under a hydrogen atmosphere for 1 h. After the reaction was completed, the reaction was monitored by TLC, and the mixture was filtered. The filter cake was washed three times with methanol. The filtrate was dried and purified by column chromatography (PE:EA=5:1) to obtain 410 mg of a white solid with a yield of 94.1%.

[0121] Step 5: Preparation of 2-bromo-3-cyclobutoxy-4-phenylpyridine

[0122] The compound 3-cyclobutoxy-4-phenylpyridin-2-amine (410 mg, 1.71 mmol) and copper bromide (190 mg, 0.853 mmol) were dissolved in dichloromethane (10 mL). After cooling to 0°C, tert-butyl nitrite (271 μL, 2.05 mmol) was slowly added dropwise to the reaction solution. Stirring was continued in an ice bath for 0.5 h, and the mixture was transferred to room temperature. The reaction was monitored by TLC. After 16 h, the reaction was complete. The reaction was quenched with 1N dilute hydrochloric acid, extracted three times with dichloromethane, and the organic phases were combined, washed with saturated sodium bicarbonate, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, column chromatography (PE:EA=20:1) was performed to obtain 330 mg of a yellow solid with a yield of 63.6%.

[0123] Step 6: Preparation of 2-((3-cyclobutoxy-4-phenylpyridin-2-yl)amino)-6,7-dihydrobenzo[d]thiazol-4(5H)-one

[0124] The compound 2-bromo-3-cyclobutoxy-4-phenylpyridine (330 mg, 1.08 mmol), 2-amino-6,7-dihydro-5H-benzothiazol-4-one (201 mg, 1.19 mmol), catalyst Pd2(dba)3 (149 mg, 0.163 mmol), ligand XantPhos (144 mg, 0.249 mmol) and anhydrous sodium carbonate (161 mg, 1.52 mmol) were dissolved in anhydrous toluene (10 mL) and replaced with nitrogen three times. The mixture was stirred in an oil bath at 120°C for 15 h. After the reaction, the reaction solution was returned to room temperature, extracted with EA, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA=4:1–2:1) to give 110 mg of a light yellow solid with a yield of 25.9%.

[0125] Step 7: Preparation of 2-((3-cyclobutoxy-4-phenylpyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0126] The compound obtained in the previous step (110 mg, 0.281 mmol) was dissolved in methanol (10 mL). Sodium borohydride (31.9 mg, 0.843 mmol) was slowly added under ice-cooling. The reaction was stirred at room temperature for 1 h before completion. Water was added dropwise under ice-cooling to quench the reaction. The mixture was then extracted three times with EA. The combined organic phases were washed with water, saturated sodium chloride, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and separated by column chromatography (DCM:CH3OH = 150:1–100:1) to afford 42 mg of a white solid (38.0% yield, mp 179.5–181.7°C). 1 H NMR (400MHz, DMSO-d6) δ10.11(s,0.22H),8.10(d,J=5.1Hz,1H),7.64(d,J=7.4Hz,2H),7. 54(t,J=7.4Hz,2H),7.51–7.47(m,1H),6.98(d,J=5.2Hz,1H),4.96(d,J=5.9Hz,0.22H),4 .55(t,J=4.0Hz,1H),4.06(p,J=7.6Hz,1H),2.77–2.71(m,1H),2.63–2.57(m,1H),2.08–1 .93(m,3H),1.86–1.75(m,5H),1.50(q,J=10.2Hz,1H),1.24–1.17(m,1H).LC-MS(ESI):m / z 394.2[M+H] + .

[0127] In addition, compound I-15 can also be synthesized by scheme 2, that is, first refer to the preparation of compound I-42 in Example 42 to obtain compound I-42, and then use compound I-42 as a raw material and refer to the above step 7 to obtain compound I-15.

[0128] Example 16: Preparation of Compound I-16: 2-((3'-cyclobutyloxy-[3,4'-bipyridyl)-2'-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0129] Referring to the synthetic route of Compound I-15 in Example 15, 3-pyridineboronic acid was used as the starting material in Step 3. Silica gel column chromatography and reverse phase preparative system were used to obtain 16 mg of a white solid with a yield of 56.9% and mp: 179.3–180.7°C. 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),8.83(d,J=2.2Hz,1H),8.68(dd,J=4.8,1.6Hz,1H),8.14 (d,J=5.2Hz,1H),8.07(dt,J=7.9,2.0Hz,1H),7.58(dd,J=7.9,4.8Hz,1H),7.06(d,J=5.2Hz,1H ),4.55(t,J=4.2Hz,1H),4.09(p,J=7.5Hz,1H),2.72(dt,J=16.2,4.8Hz,1H),2.62–2.55(m,1H ),2.00–1.93(m,3H),1.85–1.73(m,5H),1.52–1.43(m,1H),1.22–1.16(m,1H).LC-MS(ESI):m / z 395.1[M+H] + .

[0130] Example 17: Preparation of Compound I-17: 2-((3-cyclobutyloxy-[4,4'-bipyridyl)-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0131] Referring to the synthetic route of Compound I-15 in Example 15, 4-pyridineboronic acid was used as the raw material in Step 3. Silica gel column chromatography and reverse phase preparative system were used to obtain 80 mg of a white solid with a yield of 64.2% and mp of 227.4-228.5°C. 1 H NMR (400MHz, DMSO-d6) δ8.81–8.79(m,2H),8.19(d,J=5.1Hz,1H),7.86–7.75(m,2 H),7.09(d,J=5.2Hz,1H),4.58(t,J=4.1Hz,1H),4.14(p,J=7.5Hz,1H),2.77–2.70 (m,1H),2.64–2.56(m,1H),2.07–2.01(m,2H),1.99–1.94(m,1H),1.90–1.83(m,4 H),1.80–1.76(m,1H),1.52(q,J=10.2Hz,1H),1.31–1.20(m,3H).LC-MS(ESI):m / z 395.1[M+H] + .

[0132] Example 18: Preparation of Compound I-18: 2-((3-(3,3-difluorocyclobutyloxy)-4-phenylpyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0133] Step 1: Preparation of 2-chloro-3-(3,3-difluorocyclobutyloxy)-4-nitropyridine

[0134] Commercially available 2-chloro-3-fluoro-4-nitropyridine (5.00 g, 19.4 mmol) was dissolved in DMF (50 mL). Anhydrous potassium carbonate (19.0 g, 58.3 mmol) and 3,3-difluorocyclobutanol (3.15 g, 29.1 mmol) were added sequentially to the solution at room temperature. The mixture was heated in a 50°C oil bath for 5 h. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and extracted three times with EA. The organic phases were combined, washed with saturated sodium bicarbonate, water, saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by column chromatography (PE:EA = 25:1–20:1) to obtain 3.80 g of a white solid with a yield of 77.0%.

[0135] Step 2: Preparation of 2-chloro-3-(3,3-difluorocyclobutyloxy)pyridin-4-amine

[0136] 2-Chloro-3-(3,3-difluorocyclobutyloxy)-4-nitropyridine (3.80 g, 15.0 mmol) was dissolved in methanol (100 mL), and 5% by mass of platinum dioxide (0.19 g, 0.84 mmol) was added. The mixture was reacted at room temperature for 1 h under a hydrogen atmosphere. After the reaction was completed, the reaction was monitored by TLC and filtered. The filter cake was washed three times with methanol. The filtrate was dried under reduced pressure and then column chromatography (PE:EA=2:1) ​​was performed to obtain 3.4 g of a colorless oily liquid with a yield of 97.9%.

[0137] Step 3: Preparation of 2-chloro-3-(3,3-difluorocyclobutyloxy)-4-iodopyridine

[0138] 2-Chloro-3-(3,3-difluorocyclobutyloxy)pyridin-4-amine (3.40 g, 14.5 mmol) and cuprous iodide (3.31 g, 17.4 mmol) obtained in the above step were dissolved in acetonitrile (30 mL). Tert-butyl nitrite (2.97 mL, 21.7 mmol) was slowly added dropwise to the reaction solution at room temperature. The temperature was raised to 80°C. After 2 h, the starting material disappeared completely. The reaction solution was cooled to room temperature and quenched with pre-prepared 1N dilute hydrochloric acid. The reaction was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate, water, saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the product was purified by column chromatography (PE:EA = 20:1–10:1) to obtain 2.6 g of a light yellow solid with a yield of 51.9%.

[0139] Step 4: Preparation of 2-chloro-3-(3,3-difluorocyclobutyloxy)-4-phenylpyridine

[0140] 2-Chloro-3-(3,3-difluorocyclobutyloxy)-4-iodopyridine (200 mg, 0.579 mmol) was dissolved in a mixture of 1,4-dioxane (8 mL) and water (2 mL) (4:1, 10 mL). Phenylboronic acid pinacol ester (130 mg, 0.637 mmol), Pd(dppf)Cl2 (21.2 mg, 0.0289 mmol), and solid potassium carbonate (240 mg, 1.74 mmol) were added to the mixture. The mixture was heated in an oil bath at 70°C under nitrogen for 9 h. The reaction solution was cooled to room temperature and extracted three times with EA. The organic phases were combined, washed three times with water, once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the product was purified by column chromatography (PE:EA = 20:1) to afford 148 mg of a white solid (86.5% yield).

[0141] Step 5: Preparation of 2-((3-(3,3-difluorocyclobutyloxy)-4-phenylpyridin-2-yl)amino)-6,7-dihydrobenzothiazol[d]thiazol-4(5H)-one

[0142] 2-Chloro-3-(3,3-difluorocyclobutyloxy)-4-phenylpyridine (148 mg, 0.500 mmol), 2-amino-6,7-dihydro-5H-benzothiazol-4-one (92.6 mg, 0.551 mmol), Pd2(dba)3 (68.8 mg, 75.1 μmol), XantPhos (66.6 mg, 0.115 mmol), and Na2CO3 (74.3 mg, 0.701 mmol) were dissolved in toluene (10 mL). The atmosphere was replaced with nitrogen three times and stirred in an oil bath at 120°C overnight. After completion of the reaction, the mixture was monitored by TLC. The mixture was extracted with EA, washed with water, saturated brine, and dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure and then purified by column chromatography (PE:EA=4:1) to give 155 mg of a light yellow compound in a yield of 78.1%.

[0143] Step 6: Preparation of 2-((3-(3,3-difluorocyclobutyloxy)-4-phenylpyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0144] The compound obtained in the above step (155 mg, 0.391 mmol) was dissolved in methanol (10 mL). Sodium borohydride (41.2 mg, 1.17 mmol) was added portionwise under ice-cooling. The reaction was stirred at room temperature for 1 h. Water (0.5 mL) was added dropwise under ice-cooling to quench the reaction. The mixture was then extracted three times with EA, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, column chromatography (DCM:CH3OH = 150:1) afforded 96 mg of a white solid (61.6% yield). mp 217.3–219.1°C. 1 H NMR (400MHz, DMSO-d6) δ10.80 (s, 0.35H), 8.13 (d, J = 5.1Hz, 1H), 7.64–7.62 (m, 2H),7.58–7.54(m,2H),7.53–7.51(m,1H),6.97(d,J=5.1Hz,1H),4.94(s,0.30H ),4.56(t,J=4.0Hz,1H),4.09–4.07(m,1H),2.88–2.72(m,3H),2.62–2.57(m,3H ),2.03–1.93(m,1H),1.85(q,J=4.3Hz,2H),1.80–1.74(m,1H).LC-MS(ESI):m / z 430.2[M+H] + .

[0145] Example 19: Compound I-19: Preparation of (-)-2-((3-(3,3-difluorocyclobutyloxy)-4-phenylpyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0146] Compound I-18 was separated by chiral column (conditions: CHIRALPAK AD-H column (ADHOCE-VD097), 0.46 cm ID × 25 cm L, Hexane / ETOH / DEA = 70 / 30 / 0.1 (V / V / V)) to obtain white solid I-19. The optical rotation is [α] D 20 -5.13°(c=0.10,CHCl3).

[0147] Example 20: Compound I-20: Preparation of (+)-2-((3-(3,3-difluorocyclobutyloxy)-4-phenylpyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0148] Compound I-18 was separated by chiral column (conditions: CHIRALPAK AD-H column (ADHOCE-VD097), 0.46 cm ID × 25 cm L, Hexane / ETOH / DEA = 70 / 30 / 0.1 (V / V / V)) to give a white solid I-20. The optical rotation is [α] D 20 +5.57°(c=0.10,CHCl3).

[0149] Example 21: Preparation of Compound I-21: 2-((3'-(3,3-difluorocyclobutyloxy)-[3,4'-bipyridyl]-2'-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0150] Refer to the synthetic route of Compound I-18 in Example 18. 3-Pyridineboronic acid pinacol ester was used as the starting material in Step 4. Silica gel column chromatography and reverse phase preparative chromatography yielded 45 mg of a white solid (47.2% yield). mp 210.9–212.1°C. 1 HNMR(400MHz,DMSO-d6)δ10.91(s,0.32H),8.82(d,J=2.4Hz,1H),8.71(dd,J=4.9,1.6Hz,1H) ,8.18(d,J=5.1Hz,1H),8.06(dt,J=8.0,1.9Hz,1H),7.59(dd,J=7.9,4.8Hz,1H),7.04(d,J=5. 1Hz,1H),4.96(s,0.31H),4.56(t,J=4.0Hz,1H),4.16(s,1H),2.85–2.70(m,3H),2.68–2.59( m,3H),2.01–1.92(m,1H),1.85(q,J=6.7,2H),1.81–1.74(m,1H).LC-MS(ESI):m / z431.2[M+H] + .

[0151] Example 22: Preparation of Compound I-22: 2-((2-cyclobutyloxy-2'-trifluoromethyl-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0152] Step 1: Preparation of 1,3-dibromo-2-cyclobutoxybenzene

[0153] To a solution of 2,6-dibromophenol (4.00 g, 15.9 mmol) in DMF (40 mL) was added solid potassium carbonate (6.58 g, 47.6 mmol). The mixture was stirred at room temperature for 1 h. Cyclobutyl bromide (2.24 mL, 23.8 mmol) was slowly added dropwise. The reaction flask was transferred to a 90°C oil bath and allowed to react overnight. After completion of the reaction, the mixture was cooled to room temperature and extracted three times with EA. The organic phases were combined, washed three times with water, once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the product was purified by column chromatography (PE:EA = 100:1) to obtain 4.6 g of the product as a colorless oil with a yield of 94.7%.

[0154] Step 2: Preparation of 3-bromo-2-cyclobutyloxy-2'-trifluoromethyl-1,1'-biphenyl

[0155] 1,3-Dibromo-2-cyclobutoxybenzene (1.00 g, 3.27 mmol) was dissolved in a mixture of toluene (16 mL) and ethanol (4 mL). 2-Trifluoromethylphenylboronic acid (683 mg, 3.59 mmol), solid potassium carbonate (903 mg, 6.54 mmol), and catalyst Pd(PPh3)4 (189 mg, 0.163 mmol) were added, respectively. The atmosphere was purged with nitrogen three times and heated in an oil bath at 90°C for 6 h. The mixture was then cooled to room temperature and extracted three times with EA. The organic phases were combined, washed three times with water, once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, column chromatography (PE-PE:EA = 50:1) afforded 940 mg of a pale yellow oily liquid (77.5% yield).

[0156] Step 3: Preparation of 2-((2-cyclobutoxy-2'-trifluoromethyl-[1,1'-biphenyl]-3-yl)amino)-6,7-dihydrobenzo[d]thiazol-4(5H)-one

[0157] A 20 mL microwave tube was preheated in an oven at 100°C, and then 3-bromo-2-cyclobutoxy-2'-trifluoromethyl-1,1'-biphenyl (940 mg, 2.53 mmol), 2-amino-6,7-dihydro-5H-benzothiazol-4-one (447 mg, 2.66 mmol), Pd2(dba)3 (348 mg, 0.380 mmol), t-BuBrettPhos (810 mg, 1.67 mmol) and K2CO3 (490 mg, 3.55 mmol) were added in sequence. The microwave tube was sealed, evacuated and backfilled with nitrogen. Tert-butanol (5 mL) and glacial acetic acid (0.05 mL) were added to the tube using a syringe, and the mixture was stirred at 110°C overnight. After completion of the reaction monitored by TLC, the mixture was extracted with EA, washed three times with water, washed with saturated brine, concentrated under reduced pressure, and subjected to column chromatography (PE:EA = 2:1–1:1) to obtain 783 mg of a light yellow solid product with a yield of 67.4%.

[0158] Step 4: Preparation of 2-((2-cyclobutoxy-2'-trifluoromethyl-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0159] The compound obtained in step 3 (783 mg, 1.71 mmol) was dissolved in anhydrous methanol (15 mL). Sodium borohydride (194 mg, 5.13 mmol) was added under ice-cooling. The reaction was stirred at room temperature for 1 h. Water was added dropwise to the reaction mixture under ice-cooling to quench the reaction. The mixture was then extracted three times with EA, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, column chromatography (DCM:CH3OH = 100:1–80:1) was performed using a reverse preparative system to obtain 210 mg of a white solid with a yield of 31.3% and an mp of 145.1–147.3°C. 1 H NMR(400MHz, DMSO-d6)δ9.26(d,J=37.7Hz,1H),8.40–8.34(m,1H),7.86–7.83(m,1H),7.76(dt,J =22.0,7.6Hz,1H),7.64(q,J=7.4Hz,1H),7.44(d,J=7.6Hz,1H),7.12(t,J=7.9Hz,1H),6.79(d,J =7.5Hz,1H),4.99–4.95(m,1H),4.51–4.47(m,1H),3.95(dt,J=29.6,7.6Hz,1H),2.66–2.60(m,1 H),2.54–2.47(m,1H),2.02–1.53(m,8H),1.46–1.37(m,1H),1.20–1.10(m,1H).LC-MS(ESI):m / z 461.2[M+H]+ .

[0160] Example 23: Preparation of Compound I-23: 2-((2-cyclobutyloxy-3'-trifluoromethyl-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0161] Referring to the synthetic route of Compound I-22 in Example 22, 3-trifluoromethylphenylboronic acid was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 159 mg of a white solid with a yield of 45.2% and an mp of 128.7–130.2°C. 1 HNMR(400MHz, DMSO-d6)δ9.38(s,1H),8.46(dd,J=8.2,1.6Hz,1H),7.91–7.90(m,1H),7.87–7.84(m, 1H),7.76–7.70(m,2H),7.20(t,J=7.9Hz,1H),7.03(dd,J=7.7,1.6Hz,1H),4.97(d,J=5.5Hz,1H),4. 50(q,J=4.5Hz,1H),3.98–3.90(m,1H),2.64(dt,J=16.1,4.7Hz,1H),2.55–2.47(m,1H),1.97–1.87( m,3H),1.81–1.77(m,2H),1.76–1.70(m,3H),1.45–1.37(m,1H),1.21–1.10(m,1H).LC-MS(ESI):m / z 461.3[M+H] + .

[0162] Example 24: Preparation of Compound I-24: 2-((2-cyclobutyloxy-4'-trifluoromethyl-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0163] Referring to the synthetic route of Compound I-22 in Example 22, 4-trifluoromethylphenylboronic acid was used as the raw material in Step 2. 18 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 42.0%. 1H NMR(400MHz, CDCl3) δ7.94(d,J=8.1Hz,1H),7.70–7.66(m,4H),7.19(td,J=7.9,0.8Hz,1H),6.98(d,J=7.9Hz,1H),4.82–4.80(m,1H) ,3.96–3.88(m,1H),2.77–2.70(m,1H),2.66–2.60(m,1H),2.08–2.02(m,2H),1.95–1.81(m,6H),0.95–0.85(m,2H).LC-MS(ESI):m / z 461.3[M+H] + .

[0164] Example 25: Preparation of Compound I-25: 2-((2-cyclobutyloxy-3'-fluoro-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0165] Referring to the synthetic route of Compound I-22 of Example 22, 3-fluorophenylboronic acid was used as the raw material in Step 2. Silica gel column chromatography and reverse phase preparative system were used to obtain 135 mg of a white solid with a yield of 47.3% and an mp of 131.6–133.0°C. 1 H NMR (400MHz, DMSO-d6) δ9.35 (s, 1H), 8.43 (dd, J = 8.2, 1.6Hz, 1H), 7.53–7.48 (m, 1H), 7.40–7. 34(m,2H),7.24–7.19(m,1H),7.17(t,J=8.0Hz,1H),6.98(dd,J=7.7,1.6Hz,1H),4.97(s,1H), 4.50(t,J=3.9Hz,1H),3.98(p,J=7.5Hz,1H),2.64(dt,J=16.1,4.7Hz,1H),2.55–2.41(m,1H) ,1.98–1.89(m,3H),1.81–1.70(m,5H),1.47–1.40(m,1H),1.21–1.12(m,1H).LC-MS(ESI):m / z 411.2[M+H] + .

[0166] Example 26: Preparation of Compound I-26: 2-((3'-chloro-2-cyclobutyloxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0167] Referring to the synthetic route of Compound I-22 of Example 22, 3-chlorophenylboronic acid was used as the raw material in Step 2. Silica gel column chromatography and reverse phase preparative system were used to obtain 129 mg of a white solid with a yield of 48.8% and an mp of 109.5–112.4°C. 1 H NMR(400MHz, DMSO-d6)δ9.38(s,0.43H),8.45(d,J=8.3Hz,1H),7.62(t,J=1.6Hz,1H),7.55–7.51 (m,2H),7.46(dt,J=7.1,2.1Hz,1H),7.19(t,J=7.9Hz,1H),7.00(dd,J=7.8,1.6Hz,1H),5.01(s,0 .38H),4.52(t,J=4.2Hz,1H),3.98(p,J=7.5Hz,1H),2.66(dt,J=16.1,4.7Hz,1H),2.57–2.49(m, 1H),2.01–1.92(m,3H),1.83–1.71(m,5H),1.50–1.42(m,1H),1.23–1.15(m,1H).LC-MS(ESI):m / z 427.1[M+H] + .

[0168] Example 27: Preparation of Compound I-27: 2'-cyclobutyloxy-3'-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-[1,1'-biphenyl]-3-carbonitrile

[0169] Referring to the synthetic route of Compound I-22 of Example 22, 3-cyanophenylboronic acid was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 23 mg of a white solid with a yield of 44.8% and an mp of 92.7–94.5°C. 1H NMR(400MHz, DMSO-d6)δ9.40(s,0.24H),8.49(d,J=7.9Hz,1H),8.00(t,J=1.6Hz,1H),7.93–7.87( m,2H),7.70(t,J=7.8Hz,1H),7.22(t,J=7.9Hz,1H),7.03(dd,J=7.6,1.6Hz,1H),5.01(d,J=5.6Hz ,0.26H),4.51(t,J=4.1Hz,1H),3.97(p,J=7.6Hz,1H),2.67(dt,J=16.2,4.8Hz,1H),2.57–2.49(s ,1H),1.99–1.89(m,3H),1.83–1.71(m,5H),1.48–1.41(m,1H),1.22–1.14(m,1H).LC-MS(ESI):m / z 418.2[M+H] + .

[0170] Example 28: Preparation of Compound I-28: 2-((2-cyclobutyloxy-3'-difluoromethyl-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0171] Referring to the synthetic route of Compound I-22 in Example 22, 3-difluoromethylphenylboronic acid was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 218 mg of a white solid with a yield of 67.8% and an mp of 116.1–117.5°C. 1 H NMR(400MHz, DMSO-d6)δ9.39(s,0.33H),8.46(dd,J=8.6,3.8Hz,1H),7.79(s,1H),7.74(d,J =7.5Hz,1H),7.66–7.59(m,2H),7.20(t,J=7.9Hz,1H),7.02–6.99(m,1H),5.01(s,0.28H),4. 51(t,J=4.0Hz,1H),3.95(p,J=7.5Hz,1H),2.66(dt,J=16.1,4.9Hz,1H),2.57–2.49(m,1H), 2.00–1.90(m,3H),1.83–1.71(m,5H),1.48–1.39(m,1H),1.22–1.12(m,1H).LC-MS(ESI):m / z 443.2[M+H] + .

[0172] Example 29: Preparation of Compound I-29: 2-((2-cyclobutyloxy-3'-difluoromethoxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0173] Referring to the synthetic route of Compound I-22 of Example 22, 3-difluoromethoxyphenylboronic acid was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 218 mg of a white solid with a yield of 61.0% and an mp of 124.0–125.3°C. 1 H NMR(400MHz,DMSO-d6)δ9.40(s,0.38H),8.49–8.46(m,1H),7.56–7.52(m,1H),7.45(d,J=7.7Hz,1H) ,7.39(t,J=1.9Hz,1H),7.23–7.21(m,1H),7.20–7.15(m,1H),7.00(dd,J=7.7,1.6Hz,1H),5.01(d,J= 5.5Hz,0.36H),4.51(t,J=4.0Hz,1H),3.99(p,J=7.6Hz,1H),2.66(dt,J=16.1,4.8Hz,1H),2.57–2.49 (m,1H),2.00–1.91(m,3H),1.83–1.71(m,5H),1.50–1.42(m,1H),1.22–1.14(m,1H).LC-MS(ESI):m / z 459.2[M+H] + .

[0174] Example 30: Preparation of Compound I-30: 2-((2-cyclobutyloxy-3'-trifluoromethoxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0175] Referring to the synthetic route of Compound I-22 of Example 22, 3-trifluoromethoxyphenylboronic acid was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 190 mg of a white solid with a yield of 61.6% and an mp of 111.4–113.1°C. 1H NMR (400MHz, DMSO-d6) δ9.39(s,1H),8.46(dd,J=8.1,1.6Hz,1H),7.62(t,J=7.8Hz,1H),7.57(d,J=7 .9Hz,1H),7.54–7.53(m,1H),7.40–7.37(m,1H),7.18(t,J=7.9Hz,1H),6.99(dd,J=7.7,1.6Hz,1H), 4.97(s,1H),4.50(t,J=4.1Hz,1H),3.97(p,J=7.6Hz,1H),2.64(dt,J=16.0,4.6Hz,1H),2.55–2.47( m,1H),1.96–1.68(m,3H),1.80–1.71(m,5H),1.46–1.37(m,1H),1.22–1.12(m,1H).LC-MS(ESI):m / z 477.2[M+H] + .

[0176] Example 31: Preparation of Compound I-31: 2-((3-cyclobutyloxy-4-(3-difluoromethylphenyl)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0177] Referring to the synthetic route of Compound I-15 in Example 15, 3-difluoromethylphenylboronic acid was used as the raw material in Step 3. Silica gel column chromatography and reverse phase preparative system were used to obtain 85 mg of a white solid with a yield of 49.8% and an mp of 187.8–189.1°C. 1 H NMR (400MHz, DMSO-d6) δ10.21 (s, 0.29H), 8.13 (d, J = 5.1Hz, 1H), 7.87 (s, 1H), 7.82 (t, J=4.6Hz,1H),7.70(d,J=4.6Hz,2H),7.30–7.02(m,2H),4.97(d,J=6.0Hz,0.30H),4.5 6(t,J=4.1Hz,1H),4.05(p,J=7.5Hz,1H),2.76–2.71(m,1H),2.63–2.57(m,1H),2.05– 1.93(m,3H),1.86–1.75(m,5H),1.53–1.45(m,1H),1.28–1.16(m,1H).LC-MS(ESI):m / z 444.2[M+H] + .

[0178] Example 32: Preparation of Compound I-32: 2-((3-cyclobutyloxy-4-(4-difluoromethylphenyl)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0179] Referring to the synthetic route of Compound I-15 in Example 15, 4-difluoromethylphenylboronic acid was used as the raw material in Step 3. Silica gel column chromatography and reverse phase preparative system were used to obtain 57 mg of a white solid with a yield of 32.4% and an mp of 199.6-201.8°C. 1 H NMR (400MHz, DMSO-d6) δ10.24 (s, 0.29H), 8.13 (d, J = 5.2Hz, 1H), 7.79 (d, J = 8.1Hz, 2H),7.74(d,J=8.2Hz,2H),7.30–7.01(m,2H),4.98(s,0.20H),4.56(t,J=4.1Hz,1H ),4.07(p,J=7.5Hz,1H),2.74(dt,J=16.2,4.8Hz,1H),2.63–2.55(m,1H),2.07–1.9 2(m,3H),1.87–1.74(m,5H),1.54–1.45(m,1H),1.30–1.15(m,2H).LC-MS(ESI):m / z 444.2[M+H] + .

[0180] Example 33: Preparation of Compound I-33: 4-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)benzeneacetonitrile

[0181] Referring to the synthetic route of Compound I-15 in Example 15, 4-cyanophenylboronic acid was used as the raw material in Step 3. Silica gel column chromatography and reverse phase preparative system were used to obtain 13 mg of a white solid with a yield of 61.0% and mp of 195.8-197.0°C. 1 H NMR (400MHz, CDCl3) δ8.41(d,J=5.2Hz,1H),8.02(q,J=8.1Hz,4H),7.13(d,J=5.3Hz,1H),5.14(s,1H),4.28 –4.22(m,1H),3.07–2.92(m,2H),2.36–2.25(m,6H),2.19–2.12(m,3H),1.89–1.84(m,1H).LC-MS(ESI):m / z 419.4[M+H] + .

[0182] Example 34: Preparation of Compound I-34: 2-((3-cyclobutyloxy-4-(4-fluorophenyl)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0183] Referring to the synthetic route of Compound I-15 in Example 15, 4-fluorophenylboronic acid was used as the raw material in Step 3. Silica gel column chromatography and reverse phase preparative system were used to obtain 50 mg of a white solid with a yield of 62.1% and mp of 220.1-221.6°C. 1 H NMR (400MHz, DMSO-d6) δ10.18 (s, 0.21H), 8.10 (d, J = 5.1Hz, 1H), 7.72–7.66 (m ,2H),7.39(t,J=8.8Hz,2H),6.99(d,J=5.2Hz,1H),4.55(t,J=4.1Hz,1H),4.0 7(q,J=7.4Hz,1H),2.77–2.70(m,1H),2.52–2.48(m,1H),2.08–1.93(m,3H),1 .88–1.74(m,5H),1.51(q,J=10.4Hz,1H),1.24–1.21(m,1H).LC-MS(ESI):m / z 412.2[M+H] + .

[0184] Example 35: Preparation of Compound I-35: 2-((3'-(3,3-difluorocyclobutyloxy)-6-methyl-[3,4'-bipyridyl]-2'-yl)amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0185] Referring to the synthetic route of Compound I-18 in Example 18, 2-methylpyridine-5-boronic acid pinacol ester was used as the starting material in Step 4. Silica gel column chromatography and reverse phase preparative system afforded 124 mg of a white solid with a yield of 59.9% and an mp of 247.5–248.8°C. 1H NMR (400MHz, DMSO-d6) δ10.87(s,0.29H),8.70(d,J=2.3Hz,1H),8.15(d,J=5.2H z,1H),7.96(dd,J=8.2,2.3Hz,1H),7.45(d,J=8.1Hz,1H),7.02(d,J=5.2Hz,1H) ,4.95(s,0.27H),4.56(t,J=4.0Hz,1H),4.16(s,1H),2.87–2.65(m,6H),2.59(s ,3H),2.02–1.92(m,1H),1.87–1.83(m,2H),1.78–1.74(m,1H).LC-MS(ESI):m / z 445.3[M+H] + .

[0186] Example 36: Preparation of Compound I-36: 2-((3-(3,3-difluorocyclobutyloxy)-2'-methyl-[4,4'-bipyridyl]-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0187] Referring to the synthetic route of Compound I-18 in Example 18, 2-methylpyridine-4-boronic acid pinacol ester was used as the starting material in Step 4. Silica gel column chromatography and reverse phase preparative system afforded 30 mg of a white solid with a yield of 45.9% and mp of 239.9–241.1°C. 1 H NMR (400MHz, DMSO-d6) δ10.95(s,0.32H),8.61(d,J=5.2Hz,1H),8.17(d,J=5.1Hz,1 H),7.51(s,1H),7.44(d,J=5.4Hz,1H),7.00(d,J=5.2Hz,1H),4.96(s,0.31H),4.56( t,J=3.9Hz,1H),4.15(d,J=10.7Hz,1H),2.91–2.78(m,2H),2.75–2.62(m,4H),2.58( s,3H),2.01–1.92(m,1H),1.85(q,J=5.7Hz,2H),1.79–1.74(m,1H).LC-MS(ESI):m / z 445.2[M+H] + .

[0188] Example 37: Compound I-37: Preparation of 2-((3-(3,3-difluorocyclobutyloxy)-4-(4-fluorophenyl)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0189] Referring to the synthetic route of Compound I-18 in Example 18, 4-fluorophenylboronic acid pinacol ester was used as the raw material in Step 4. Silica gel column chromatography and reverse phase preparative system gave 81 mg of a white solid with a yield of 58.1% and mp of 247.9–248.8°C. 1 H NMR (400MHz, DMSO-d6) δ10.83 (s, 0.32H), 8.13 (d, J = 5.1Hz, 1H), 7.84–7.5 8(m,2H),7.40(t,J=8.8Hz,2H),6.97(d,J=5.2Hz,1H),4.94(s,0.25H),4.5 6(t,J=3.9Hz,1H),4.13–4.10(m,1H),2.88–2.70(m,3H),2.66–2.57(m,3H) ,2.01–1.92(m,1H),1.87–1.83(m,2H),1.80–1.73(m,1H).LC-MS(ESI):m / z 448.2[M+H] + .

[0190] Example 38: Preparation of Compound I-38: 2-((3-(3,3-difluorocyclobutyloxy)-4-(3-fluorophenyl)pyridinyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0191] Referring to the synthetic route of Compound I-18 in Example 18, 3-fluorophenylboronic acid pinacol ester was used as the raw material in Step 4. Silica gel column chromatography and reverse phase preparative system gave 94 mg of a white solid with a yield of 74.9% and an mp of 187.3–188.9°C. 1 H NMR (400MHz, DMSO-d6) δ10.83 (s, 0.37H), 8.11 (d, J = 5.2Hz, 1H), 7.60–7.54 (m, 1H ),7.45–7.42(m,2H),7.33(td,J=8.6,2.6Hz,1H),6.96(d,J=5.1Hz,1H),4.91(s, 0.35H),4.53(t,J=3.9Hz,1H),4.12–4.10(m,1H),2.84–2.66(m,3H),2.64–2.53( m,3H),1.99–1.89(m,1H),1.83–1.80(m,2H),1.76–1.71(m,1H).LC-MS(ESI):m / z 448.2[M+H] + .

[0192] Example 39: Compound I-39: Preparation of 2-((3-(3,3-difluorocyclobutyloxy)-4-(3-difluoromethylphenyl)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0193] Referring to the synthetic route of Compound I-18 in Example 18, 3-difluoromethylphenylboronic acid pinacol ester was used as the starting material in Step 4. Silica gel column chromatography and reverse phase preparative system afforded 128 mg of a white solid with a yield of 55.2% and an mp of 202.5–203.7°C. 1 H NMR (400MHz, DMSO-d6) δ10.85 (s, 0.32H), 8.12 (d, J = 5.2Hz, 1H), 7.81 (s, 1H), 7.77(t,J=4.4Hz,1H),7.69(d,J=4.7Hz,2H),7.27–6.98(m,2H),4.91(s,0.27H ),4.53(t,J=4.0Hz,1H),4.07–4.05(m,1H),2.83–2.67(m,3H),2.59–2.55(m, 3H),1.97–1.89(m,1H),1.83–1.80(m,2H),1.77–1.70(m,1H).LC-MS(ESI):m / z 480.2[M+H] + .

[0194] Example 40: Compound I-40: Preparation of 3-(3-(3,3-difluorocyclobutyloxy)-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)benzeneacetonitrile

[0195] Referring to the synthetic route of Compound I-18 in Example 18, 3-cyanophenylboronic acid pinacol ester was used as the starting material in Step 4. Silica gel column chromatography and reverse phase preparative system afforded 110 mg of a white solid with a yield of 59.8% and an mp of 234.9–236°C. 1H NMR (400MHz, DMSO-d6) δ10.89 (s, 0.32H), 8.13 (d, J = 5.1Hz, 1H), 8.05 (t, J = 1. 6Hz,1H),7.99–7.89(m,2H),7.73(t,J=7.8Hz,1H),7.00(d,J=5.1Hz,1H),4.91 (s,0.27H),4.53–4.51(m,1H),4.10(s,1H),2.78–2.66(m,3H),2.63–2.55(m, 3H),1.97–1.88(m,1H),1.83–1.79(m,2H),1.76–1.70(m,1H).LC-MS(ESI):m / z 455.2[M+H] + .

[0196] Example 41: Compound I-41: Preparation of 2-((2-cyclobutyloxy-3',4',5'-trifluoro-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0197] Referring to the synthetic route of Compound I-22 in Example 22, 3,4,5-trifluorophenylboronic acid was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 34 mg of a white solid with a yield of 31.4% and an mp of 140.6–142.3°C. 1 H NMR (400MHz, CDCl3) δ7.93(dt,J=8.2,1.1Hz,1H),7.23–7.21(m,2H),7.19(t,J=8.1Hz,1H),6.92(dt,J=7.8,1.2Hz,1H),4.80(t,J=4.5Hz,1H),3.9 9–3.94(m,1H),2.77–2.70(m,1H),2.66–2.60(m,1H),2.11–2.03(m,2H), 1.99–1.91(m,6H),1.88–1.84(m,1H),1.63–1.54(m,1H).LC-MS(ESI):m / z 447.1[M+H] + .

[0198] Example 42: Preparation of Compound I-42: 2-((3-cyclobutyloxy-4-phenylpyridin-2-yl)amino)-6,7-dihydrobenzo[d]thiazol-4(5H)-one

[0199] Step 1: Preparation of 2-chloro-3-cyclobutoxy-4-iodopyridine

[0200] Cyclobutanol (2.10 g, 29.1 mmol) was dissolved in tetrahydrofuran. Sodium hydride (1.55 g, 38.9 mmol) was added portionwise under ice-cooling. After stirring for 0.5 hour, 2-chloro-3-fluoro-4-iodopyridine (5.00 g, 19.4 mmol) was added. The reaction was stirred for 1 hour before completion. Extraction was performed three times with ethyl acetate. The combined organic phases were washed with water, saturated sodium chloride, and dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure and separated by column chromatography (PE:EA = 100:1–80:1) to obtain 4.66 g of a colorless liquid in a 77.6% yield. LC-MS (ESI): m / z 308.9 [M+H] + .

[0201] Step 2: Preparation of 2-chloro-3-cyclobutoxy-4-phenylpyridine

[0202] 2-Chloro-3-cyclobutoxy-4-iodopyridine (500 mg, 1.62 mmol) was dissolved in a mixture of 1,4-dioxane (12 mL) and water (3 mL) (4:1, 15 mL). Phenylboronic acid pinacol ester (363 mg, 1.78 mmol), Pd(dppf)Cl2 (59.1 mg, 80.7 μmol), and solid potassium carbonate (670 mg, 4.85 mmol) were added to the mixture. The mixture was heated in an oil bath at 70°C under nitrogen for 9 h. The reaction solution was cooled to room temperature and extracted three times with EA. The organic phases were combined, washed three times with water, once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the product was purified by column chromatography (PE:EA = 20:1) to give 360 ​​mg of a white solid in an 85.8% yield.

[0203] Step 3: Preparation of 2-((3-cyclobutyloxy-4-phenylpyridin-2-yl)amino)-6,7-dihydrobenzo[d]thiazol-4(5H)-one

[0204] Step 3: Referring to Step 6 in the synthetic route of Compound I-15 of Example 15, 56 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 48.1%. 1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.11(d,J=5.2Hz,1H),7.64–7.62(m ,2H),7.55–7.46(m,3H),7.02(d,J=5.3Hz,1H),4.05(p,J=7.7Hz,1H),3.04 (t,J=5.9Hz,2H),2.56–2.54(m,2H),2.23–2.12(m,2H),2.07–1.98(m,2H) ,1.81–1.74(m,2H),1.51–1.43(m,1H),1.21–1.14(m,1H).LC-MS(ESI):m / z 392.1[M+H] + .

[0205] In addition, compound I-42 can also be synthesized through Scheme 1, referring to steps 1 to 6 in the synthesis route of compound I-15 in Example 15 to obtain compound I-42.

[0206] Example 43: Preparation of Compound I-43: 2-((2-cyclobutyloxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazole-4-carboxylic acid

[0207] Step 1-Step 3: Preparation of ethyl 2-((2-cyclobutyloxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazole-4-carboxylate

[0208] Refer to Example 22, Steps 1 to 3 of the synthetic route for Compound I-22. In Step 3, ethyl 2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-4-carboxylate was used as the starting material. Silica gel column chromatography yielded 498 mg of a white solid, with a yield of 49%. LC-MS (ESI): m / z 449.5 [M+H] + .

[0209] Step 4: Preparation of 2-((2-cyclobutyloxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazole-4-carboxylic acid

[0210] The intermediate obtained in the above step (498 mg, 1.11 mmol) was dissolved in a mixture of ethanol (10 mL) and water (10 mL). Lithium hydroxide monohydrate (233 mg, 5.55 mmol) was added at room temperature. After 5 h of reaction, TLC confirmed the reaction was complete. The ethanol was removed by vacuum drying, and the remaining reaction solution was extracted three times with ethyl acetate. The combined organic phases were washed with water, once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the product was purified by column chromatography (PE:EA = 2:1–1:1) using a reverse preparative system to afford 147 mg of a white solid in a 31.5% yield. mp: 142.1–143.2°C. 1 H NMR (400MHz, DMSO-d6) δ11.87(d,J=356.9Hz,1H),8.82(d,J=440.7Hz,1H),7.5 3(d,J=7.5Hz,2H),7.42(dt,J=32.9,7.3Hz,4H),7.24–6.91(m,2H),4.07–3.94 (m,1H),3.58–3.56(m,1H),2.68–2.57(m,1H),2.49–2.41(m,1H),2.01–1.89(m ,3H),1.78–1.72(m,5H),1.42–1.35(m,1H),1.23–1.05(m,1H).LC-MS(ESI):m / z 420.9[M+H] + .

[0211] Example 44: Preparation of Compound I-44: 2-((2-cyclobutyloxy-[1,1'-biphenyl]-3-yl)amino)-N-methoxy-4,5,6,7-tetrahydrobenzo[d]thiazole-4-carboxamide

[0212] To a solution of compound I-43 (100 mg, 0.238 mmol) in dichloromethane (6 mL) were added EDCI (91.2 mg, 0.476 mmol) and DMAP (58.1 mg, 0.476 mmol). The mixture was stirred at room temperature for 0.5 h. Methoxyamine hydrochloride (29.8 mg, 0.356 mmol) was then added and the reaction continued at room temperature for 2 h. After completion of the reaction, the mixture was extracted with dichloromethane. The combined organic phases were washed with water, once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by column chromatography (PE:EA = 4:1–2:1) to afford 34 mg of a white solid (31.8% yield, mp 100.4–102.5°C). 1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),9.40(s,1H),8.36(dd,J=8.1,1.6Hz,1H),7.55–7.5 2(m,2H),7.46(t,J=7.6Hz,2H),7.39–7.35(m,1H),7.07(t,J=7.9Hz,1H),6.93(dd,J=7.6 ,1.6Hz,1H),3.97–3.90(m,1H),3.67(s,3H),3.28(t,J=6.8Hz,1H),2.63–2.59(m,2H),2. 04–1.87(m,5H),1.76–1.67(m,3H),1.46–1.37(m,1H),1.20–1.09(m,1H).LC-MS(ESI):m / z 449.8[M+H] + .

[0213] Example 45: Preparation of Compound I-45: 2-((2-cyclobutyloxy-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0214] Referring to the synthetic route of Compound I-22 in Example 22, cyclohexene 1-boronic acid pinacol ester was used as the raw material in Step 2. Silica gel column chromatography and reverse phase preparative system were used to obtain 140 mg of a white solid with a yield of 36.4% and an mp of 147.1–149.6°C. 1 H NMR (400MHz, DMSO-d6) δ9.21 (s, 0.31H), 8.26–8.24 (m, 1H), 7.02 (t, J = 7.9Hz, 1H), 6.74 (d, J = 7.5Hz, 1 H),5.82(t,J=3.8Hz,1H),4.98(s,0.24H),4.48(t,J=4.1Hz,1H),4.33(p,J=7.5Hz,1H),2.64(dt,J=16 .0,4.6Hz,1H),2.53–2.49(m,1H),2.36–2.33(m,2H),2.25–2.17(m,4H),2.12–2.05(m,2H),1.99–1.8 8(m,1H),1.82–1.78(m,2H),1.75–1.71(m,3H),1.69–1.61(m,3H),1.42–1.35(m,1H).LC-MS(ESI):m / z 396.9[M+H] + .

[0215] Example 46: Preparation of Compound I-46: 2-((2-cyclobutyloxy-3-(2,5-dihydrofuran-3-yl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0216] Referring to the synthetic route of Compound I-22 of Example 22, 2,5-dihydrofuran-3-pinacol borate was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 120 mg of a white solid with a yield of 61.5% and an mp of 127.1–127.9°C. 1 H NMR(400MHz, DMSO-d6)δ9.36(s,0.36H),8.36(dd,J=8.4,4.1Hz,1H),7.09(t,J=8.0Hz,1H),6.90(dd,J=7.8,1.5Hz,1H ),6.50(t,J=2.1Hz,1H),4.99(d,J=5.5Hz,0.36H),4.93–4.90(m,2H),4.78–4.75(td,J=4.8,2.0Hz,2H),4.49(t,J=4. 0Hz,1H),4.35(p,J=7.7Hz,1H),2.65(dt,J=16.1,4.7Hz,1H),2.53–2.48(m,1H),2.29–2.19(m,2H),2.13–2.06(m,2H) ,1.99–1.88(m,1H),1.82–1.78(m,2H),1.76–1.71(m,1H),1.62(q,J=10.1Hz,1H),1.44–1.32(m,1H).LC-MS(ESI):m / z 385.2[M+H] + .

[0217] Example 47: Preparation of Compound I-47: 2-((2-cyclobutyloxy-3-(3,6-dihydro-2H-pyran-4-yl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0218] Referring to the synthetic route of Compound I-22 in Example 22, 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 78 mg of a white solid with a yield of 50.7% and an mp of 119.8–122.4°C. 1H NMR (400MHz, DMSO-d6) δ9.25 (s, 0.30H), 8.32 (dd, J=8.4, 1.7Hz, 1H), 7.06 (t, J=7.9Hz, 1H), 6.80 (dd, J=7.7, 1.6Hz, 1H),5.95(t,J=2.5Hz,1H),4.98(d,J=5.5Hz,0.31H),4.49(t,J=4.0Hz,1H),4.34(p,J=7.6Hz,1H),4.24(q,J=2.7Hz ,2H),3.84(t,J=5.4Hz,2H),2.65(dt,J=16.1,4.6Hz,1H),2.48–2.44(m,2H),2.25–2.18(m,2H),2.13–2.06(m,2H), 1.96–1.91(m,1H),1.82–1.78(m,2H),1.76–1.70(m,1H),1.64(q,J=10.2Hz,1H),1.45–1.29(m,2H).LC-MS(ESI):m / z 399.2[M+H] + .

[0219] Example 48: Preparation of Compound I-48: 2-((3-(3,3-difluorocyclobutyloxy)-4-(3,6-dihydro-2H-pyran-4-yl)pyridinyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0220] Referring to the synthetic route of Compound I-18 in Example 18, 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 70 mg of a white solid with a yield of 71.1% and an mp of 212.7–214.4°C. 1 H NMR(400MHz, DMSO-d6)δ10.70(s,0.31H),8.03(d,J=5.2Hz,1H),6.82(d,J=5.2Hz,1H),6.1 8–6.17(m,1H),4.92(s,0.24H),4.55(t,J=4.0Hz,2H),4.26(q,J=2.9Hz,2H),3.85(t,J=5. 4Hz,2H),3.12–3.00(m,2H),2.96–2.86(m,2H),2.75–2.69(m,1H),2.61–2.55(m,1H),2.46 –2.43(m,2H),2.00–1.91(m,1H),1.84(q,J=4.4Hz,2H),1.78–1.74(m,1H).LC-MS(ESI):m / z 436.2[M+H]+ .

[0221] Example 49: Preparation of Compound I-49: 2-((2-cyclobutoxy-3-(cyclopropylethynyl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0222] Step 1: Preparation of 1-bromo-2-cyclobutoxy-3-iodobenzene

[0223] Referring to Example 32, in step 1 of the synthesis of compound I-32, 2-bromo-6-iodophenol was used as the starting material to obtain 2.0 g of a colorless oil with a yield of 84.7%.

[0224] Step 2: Preparation of 1-bromo-2-cyclobutoxy-3-(cyclopropylethynyl)benzene

[0225] 1-Bromo-2-cyclobutoxy-3-iodobenzene (500 mg, 1.42 mmol), cyclopropylacetylene (103 mg, 1.56 mmol), Pd(PPh3)2Cl2 (47.6 mg, 70.9 μmol), and CuI (13.5 mg, 70.9 μmol) were dissolved in triethylamine (10 mL). The atmosphere was replaced with nitrogen three times and allowed to react at room temperature for 2 h. The mixture was then extracted three times with ethyl acetate. The organic phases were combined, washed with water, saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the product was purified by column chromatography (PE) to give 230 mg of the product as a colorless oil in a yield of 55.8%.

[0226] Step 3-Step 4: Preparation of 2-((2-cyclobutoxy-3-(cyclopropylethynyl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0227] The subsequent steps were similar to Step 3 and Step 4 in the synthetic route of Compound I-22 of Example 22. Silica gel column chromatography and reverse phase preparative system gave 98 mg of a white solid with a yield of 46.5% and mp of 162.3-164.1°C. 1H NMR (400MHz, DMSO-d6) δ9.30 (s, 0.29H), 8.40–8.37 (m, 1H), 7.01 (t, J = 7.9Hz, 1H), 6.93 (dd, J = 7. 6,1.6Hz,1H),4.98(s,0.24H),4.71(p,J=7.5Hz,1H),4.49(s,1H),2.71–2.62(m,1H),2.51–2.48( m,1H),2.34–2.24(m,2H),2.19–2.12(m,2H),1.97–1.88(m,1H),1.82–1.78(m,2H),1.75–1.71(m, 1H),1.70–1.58(m,2H),1.50–1.40(m,1H),0.97–0.93(m,2H),0.78–0.74(m,2H).LC-MS(ESI):m / z 381.2[M+H] + .

[0228] Example 50: Preparation of Compound I-50: 2-((2-cyclobutoxy-3-(3-hydroxy-3-methylbutyl-1-yn-1-yl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0229] Referring to the synthetic route of Compound I-49 of Example 49, 2-methyl-3-butyn-2-ol was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 160 mg of a white solid with a yield of 69.2% and an mp of 145.7–146.6°C. 1 H NMR(400MHz,DMSO-d6)δ9.33(s,0.41H),8.45–8.42(m,1H),7.05(t,J=8.0Hz,1H),6.94(dd,J=7.7,1 .6Hz,1H),5.52(s,0.42H),4.99(s,0.38H),4.81(p,J=7.5Hz,1H),4.49(t,J=4.0Hz,1H),2.66(dt,J =16.1,4.6Hz,1H),2.56–2.49(m,1H),2.37–2.25(m,2H),2.21–2.14(m,2H),1.97–1.89(m,1H),1.82 –1.78(m,2H),1.76–1.73(m,1H),1.71–1.64(m,1H),1.52(s,6H),1.47–1.40(m,1H).LC-MS(ESI):m / z 399.2[M+H] + .

[0230] Example 51: Preparation of Compound I-51: 2-((2-cyclobutoxy-3-(oxocyclobutane-3-ethynyl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0231] Referring to the synthetic route of Compound I-49 of Example 49, 3-ethynyloxetane was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 209 mg of a white solid with a yield of 65.0% and an mp of 112.9–114.5°C. 1 H NMR(400MHz, DMSO-d6)δ9.36(s,0.43H),8.48–8.44(m,1H),7.06(t,J=7.9Hz,1H),7.00(dd,J=7.7,1.7Hz,1H),4.9 9(d,J=5.4Hz,0.45H), 4.87(dd,J=8.5,5.4Hz,2H), 4.76(p,J=7.5Hz,1H), 4.66(dd,J=7.1,5.4Hz,2H), 4.49(t,J=4. 2Hz,1H),4.26–4.18(m,1H),3.38(d,J=7.7Hz,2H),2.66(dt,J=16.2,4.7Hz,1H),2.56–2.49(m,1H),2.37–2.27(m,2 H),2.21–2.14(m,2H),1.99–1.89(m,1H),1.82–1.78(m,2H),1.76–1.65(m,2H),1.51–1.39(m,1H).LC-MS(ESI):m / z 397.2[M+H] + .

[0232] Example 52: Preparation of Compound I-52: 2-((2-cyclobutoxy-3-((3-oxocyclobutane-3-yl)ethynyl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0233] Referring to the synthetic route of Example 49, Compound I-49, 3-ethynyloxetane-3-ol was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 230 mg of a white solid with a yield of 64.3% and an mp of 74.7–76.6°C. 1H NMR (400MHz, DMSO-d6) δ9.41 (s, 0.41H), 8.48 (dd, J=8.4, 3.6Hz, 1H), 7.09 (t, J=7.9Hz, 1H), 7.03(dd,J=7.7,1.7Hz,1H),6.68(s,0.39H),4.83–4.73(m,3H),4.67(d,J=6.3Hz,2H),4.50( t,J=4.0Hz,1H),2.71–2.63(m,1H),2.53–2.49(m,1H),2.37–2.27(m,2H),2.23–2.15(m,2H), 1.99–1.89(m,1H),1.82–1.78(m,2H),1.76–1.66(m,2H),1.50–1.39(m,1H).LC-MS(ESI):m / z 413.2[M+H] + .

[0234] Example 53: Preparation of Compound I-53: 2-((3-cyclobutoxy-4-(3-hydroxy-3-methylbutyl-1-yn-1-yl)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0235] Step 1: Preparation of 4-(3-cyclobutoxy-2-nitropyridin-4-yl)-2-methylbutyl-3-yn-2-ol

[0236] At room temperature, the intermediate 4-bromo-3-cyclobutoxy-2-nitropyridine (420 mg, 1.54 mmol), 2-methyl-3-butyn-2-ol (194 mg, 2.31 mmol), Pd(PPh3)2Cl2 (54 mg, 0.077 mmol), and CuI (15 mg, 0.077 mmol) were added to a mixed solvent of DMF (8 mL) and Et3N (8 mL). After addition, the atmosphere was replaced with nitrogen three times, the temperature was raised to 80°C, and stirring was stopped after the reaction for 1 hour. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated sodium bicarbonate, water, saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, column chromatography (PE:EA = 5:1) was performed to obtain 400 mg of a yellow solid with a yield of 94.1%.

[0237] Step 2-Step 5: Preparation of 2-((3-cyclobutoxy-4-(3-hydroxy-3-methylbutyl-1-yn-1-yl)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0238] The subsequent steps were carried out according to Steps 4 to 7 in the synthesis route of Compound I-15 of Example 15. 80 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 45.2%. 1 H NMR (400MHz, DMSO-d6) δ10.73(s,0.32H),7.95(d,J=5.2Hz,1H),6.86(d,J=5.2Hz,1H),5.12 –5.05(m,1H),4.92(s,0.28H),4.54(t,J=4.0Hz,1H),3.17–3.12(m,2H),3.02–2.92(m,2H), 2.71(dt,J=16.0,4.7Hz,1H),2.60–2.55(m,1H),1.99–1.91(m,1H),1.84(q,J=4.1Hz,2H),1 .79–1.73(m,1H),1.72–1.66(m,1H),1.04–0.99(m,2H),0.87–0.81(m,2H).LC-MS(ESI):m / z 400.5[M+H] + .

[0239] In addition, compound I-53 can also be synthesized by scheme 2, that is, first refer to the preparation of compound I-54 in Example 54 to obtain compound I-54, and then use compound I-54 as a raw material and refer to step 7 in the synthesis route of compound I-15 in Example 15 to obtain compound I-53.

[0240] Example 54: Preparation of Compound I-54: 2-((3-cyclobutoxy-4-(3-hydroxy-3-methylbutyl-1-yn-1-yl)pyridin-2-yl)amino)-6,7-dihydrobenzo[d]thiazol-4(5H)-one (Scheme 2)

[0241] Step 1: Preparation of 2-chloro-3-cyclobutoxy-4-iodopyridine

[0242] Cyclobutanol (2.10 g, 29.1 mmol) was dissolved in tetrahydrofuran. Sodium hydride (1.55 g, 38.9 mmol) was added portionwise under ice-cooling. After stirring for 0.5 hour, 2-chloro-3-fluoro-4-iodopyridine (5.00 g, 19.4 mmol) was added. The reaction was stirred for 1 hour before completion. Extraction was performed three times with ethyl acetate. The combined organic phases were washed with water, saturated sodium chloride, and dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure and separated by column chromatography (PE:EA = 100:1–80:1) to obtain 4.66 g of a colorless liquid in a 77.6% yield. LC-MS (ESI): m / z 308.9 [M+H] + .

[0243] Step 2: Preparation of 2-chloro-3-cyclobutoxy-4-phenylpyridine

[0244] 2-Chloro-3-cyclobutoxy-4-iodopyridine (2.6 g, 8.4 mmol) was dissolved in triethylamine (35 mL), and 2-methyl-3-butyn-2-ol (848 mg, 10.1 mmol), Pd(PPh3)2Cl2 (295 mg, 0.420 mmol), and cuprous iodide (80 mg, 0.42 mmol) were added, respectively. The mixture was reacted under nitrogen at room temperature for 4 h, then extracted three times with EA. The organic phases were combined, washed three times with water, once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by column chromatography (PE:EA = 8:1) to give 1.9 g of a yellow solid with a yield of 85.1%.

[0245] Step 3: Preparation of 2-((3-cyclobutoxy-4-(3-hydroxy-3-methylbutyl-1-yn-1-yl)pyridin-2-yl)amino)-6,7-dihydrobenzo[d]thiazol-4(5H)-one

[0246] Step 3: Referring to Step 6 in the synthetic route of Compound I-15 of Example 15, 55 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 43.6%. 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),7.95(d,J=5.1Hz,1H),6.89(d,J=5.1Hz,1H),5.64(s,1H),5.07(p,J=7.4Hz,1H),3.01(t,J=6.0Hz,2H),2. 54–2.52(m,2H),2.41–2.30(m,2H),2.24–2.19(m,2H),2.13(p,J=6.9Hz, 2H),1.79–1.65(m,1H),1.51(s,6H),1.48–1.41(m,1H).LC-MS(ESI):m / z 398.5[M+H] + .

[0247] In addition, compound I-54 can also be synthesized through Scheme 1, referring to steps 1 to 4 in the synthetic route of compound I-53 in Example 53, to obtain compound I-54.

[0248] Example 55: Compound I-55: Preparation of 2-((4-(cyclopropylethynyl)-3-(3,3-difluorocyclobutyloxy)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0249] Step 1: Preparation of 2-chloro-4-(cyclopropylacetylene)-3-(3,3-difluorocyclobutyloxy)pyridine

[0250] 2-Chloro-3-(3,3-difluorocyclobutyloxy)-4-iodopyridine (200 mg, 0.579 mmol) was dissolved in triethylamine (10 mL), followed by the addition of cyclopropylacetylene (57 mg, 0.87 mmol), Pd(PPh3)2Cl2 (20 mg, 0.029 mmol), and CuI (5.5 mg, 0.029 mmol). The atmosphere was replaced with nitrogen three times and allowed to react at room temperature for 2 h. The mixture was then extracted three times with ethyl acetate. The organic phases were combined, washed with water, saturated sodium chloride, and dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure and purified by column chromatography (PE:EA = 100:1) to afford 130 mg of the product as a pale yellow oil in a yield of 79.2%.

[0251] Step 2-Step 3: Preparation of 2-((4-(cyclopropylethynyl)-3-(3,3-difluorocyclobutyloxy)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0252] The subsequent steps were carried out according to Steps 5 and 6 in the synthesis route of Compound I-18 in Example 18. Silica gel column chromatography and reverse phase preparative chromatography gave 95 mg of a white solid with a yield of 49.7% and mp of 202.9-203.7°C. 1 H NMR (400MHz, DMSO-d6) δ10.73(s,0.32H),7.95(d,J=5.2Hz,1H),6.86(d,J=5.2Hz,1H),5.12 –5.05(m,1H),4.92(s,0.28H),4.54(t,J=4.0Hz,1H),3.17–3.12(m,2H),3.02–2.92(m,2H), 2.71(dt,J=16.0,4.7Hz,1H),2.60–2.55(m,1H),1.99–1.91(m,1H),1.84(q,J=4.1Hz,2H),1 .79–1.73(m,1H),1.72–1.66(m,1H),1.04–0.99(m,2H),0.87–0.81(m,2H).LC-MS(ESI):m / z 418.2[M+H] + .

[0253] Example 56: Compound I-56: Preparation of 2-((3-(3,3-difluorocyclobutyloxy)-4-(3-hydroxy-3-methylbutyl-1-yn-1-yl)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0254] Referring to the synthetic route of Example 55, Compound I-55, 2-methyl-3-butyn-2-ol was used as the starting material in Step 1. Silica gel column chromatography and reverse phase preparative chromatography afforded 30 mg of a white solid with a yield of 51.5% and an mp of 192.6–194.5°C. 1 H NMR(400MHz, DMSO-d6)δ10.80(s,0.40H),7.98(d,J=5.2Hz,1H),6.86(d,J=5.2Hz,1H), 5.72(s,0.45H),5.20–5.17(m,1H),4.93(d,J=6.2Hz,0.44H),4.54(t,J=4.3Hz,1H),3. 23–3.11(m,2H),3.05–2.95(m,2H),2.72(dt,J=16.2,4.8Hz,1H),2.61–2.57(m,1H),1. 99–1.92(m,1H),1.84(q,J=5.1Hz,2H),1.78–1.72(m,1H),1.53(s,6H).LC-MS(ESI):m / z 436.4[M+H] + .

[0255] Example 57: Preparation of Compound I-57: 2-((2-cyclobutyloxy-3-(piperidin-1-yl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0256] Step 1: Preparation of 1-(3-bromo-2-cyclobutyloxyphenyl)piperidine

[0257] To a 50 mL eggplant-shaped flask, 1,3-dibromo-2-cyclobutyloxybenzene (500 mg, 1.63 mmol) was added and dissolved in toluene (15 mL). Piperidine (153 mg, 1.80 mmol), Pd(dba) (74.8 mg, 98.1 μmol), BINAP (153 mg, 0.245 mmol), and t-BuONa (314 mg, 3.27 mmol) were then added. The atmosphere was purged with nitrogen three times and heated in an oil bath at 90°C for 12 h. The mixture was then cooled to room temperature and extracted three times with ethyl acetate. The combined organic phases were washed with water, once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by column chromatography (PE:EA = 50:1–20:1) to afford 281 mg of a colorless oil in a 55.4% yield.

[0258] Step 2-3: Preparation of 2-((2-cyclobutyloxy-3-(piperidin-1-yl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0259] The subsequent steps were similar to Step 3 and Step 4 in the synthesis route of Compound I-22 of Example 22. Silica gel column chromatography and reverse phase preparative system gave 145 mg of a white solid with a yield of 47.6% and mp of 132.7-134.8°C. 1 H NMR (400MHz, DMSO-d6) δ9.07(s,1H),7.95(dd,J=8.2,1.4Hz,1H),6.94(t,J=8.1Hz,1H),6.57(dd,J =8.0,1.5Hz,1H),4.94–4.92(m,1H),4.82–4.74(m,1H),4.47–4.46(m,1H),2.95(t,J=5.2Hz,4H),2 .62(dt,J=16.1,4.7Hz,1H),2.52–2.45(m,1H),2.29–2.18(m,2H),2.13–2.06(m,2H),1.97–1.87(m ,1H),1.80–1.76(m,2H),1.73–1.61(m,6H),1.56–1.52(m,2H),1.47–1.37(m,1H).LC-MS(ESI):m / z 400.3[M+H] + .

[0260] Example 58: Preparation of Compound I-58: 2-((2-cyclobutyloxy-3-morpholinophenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0261] Referring to the synthetic route of Compound I-57 of Example 57, morpholine was used as the starting material in Step 1. Silica gel column chromatography and reverse phase preparative chromatography afforded 170 mg of a white solid with a yield of 40.3% and an mp of 149.1–150.0°C. 1H NMR (400MHz, DMSO-d6) δ9.13(s,1H),8.01(dd,J=8.3,1.4Hz,1H),6.97(t,J=8.1Hz,1H),6.57(dd,J =8.2,1.5Hz,1H),4.94(s,1H),4.75(p,J=7.6Hz,1H),4.47(t,J=3.9Hz,1H),3.76(t,J=4.5Hz,4H), 3.01–2.99(m,4H),2.62(dt,J=16.1,4.7Hz,1H),2.49–2.45(m,1H),2.30–2.20(m,2H),2.15–2.07( m,2H),1.97–1.86(m,1H),1.80–1.75(m,2H),1.73–1.61(m,2H),1.48–1.36(m,1H).LC-MS(ESI):m / z 402.2[M+H] + .

[0262] Example 59: Compound I-59: Preparation of 2-((3-(3,3-difluorocyclobutyloxy)-4-morpholinopyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0263] Step 1: Preparation of 4-(2-chloro-3-(3,3-difluorocyclobutyloxy)pyridin-4-yl)morpholine

[0264] To a 50 mL eggplant-shaped flask, 2-chloro-3-(3,3-difluorocyclobutyloxy)-4-iodopyridine (350 mg, 1.01 mmol) was added and dissolved in 1,4-dioxane (15 mL). Morpholine (106 mg, 1.22 mmol), Pd(dba) (92.8 mg, 0.101 mmol), XantPhos (117 mg, 0.203 mmol), and CsCO (462 mg, 1.42 mmol) were then added. The atmosphere was purged with nitrogen three times and the mixture was heated in an oil bath at 100°C for 12 h. The mixture was then cooled to room temperature and extracted three times with ethyl acetate. The combined organic phases were washed with water, once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by column chromatography (PE:EA = 50:1–20:1) to afford 113 mg of a colorless oil in a 36.6% yield.

[0265] Step 2-Step 3: Preparation of 2-((3-(3,3-difluorocyclobutyloxy)-4-morpholinopyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0266] The subsequent steps were carried out according to Steps 5 and 6 in the synthesis route of Compound I-18 in Example 18. Silica gel column chromatography and reverse phase preparative chromatography gave 15 mg of a white solid with a yield of 64.9% and mp of 225.1-227.2°C. 1 H NMR (400MHz, DMSO-d6) δ10.45(s,1H),7.91(d,J=5.7Hz,1H),6.61(d,J=5.7Hz,1 H),4.95–4.89(m,1H),4.53(t,J=4.0Hz,1H),3.79–3.77(m,4H),3.20–3.18(m,4H ),3.13–3.01(m,2H),2.95–2.85(m,2H),2.74–2.67(m,1H),2.60–2.49(m,1H),1 .99–1.91(m,1H),1.83(q,J=5.1,4.7Hz,2H),1.77–1.72(m,1H).LC-MS(ESI):m / z 439.2[M+H] + .

[0267] Example 60: Preparation of Compound I-60: 2-((2-cyclobutyloxy-3-(4-methylpiperazin-1-yl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0268] Referring to the synthetic route of Compound I-57 of Example 57, N-methylpiperazine was used as the starting material in Step 1. Silica gel column chromatography and reverse phase preparative chromatography afforded 120 mg of a white solid with a yield of 50.8% and an mp of 135.4–137.0°C. 1 H NMR (400MHz, DMSO-d6) δ9.09(s,1H),7.98(dd,J=8.3,1.4Hz,1H),6.95(t,J=8.1Hz,1H),6.56( dd,J=8.2,1.5Hz,1H),4.93(d,J=5.6Hz,1H),4.74(p,J=7.5Hz,1H),4.47(q,J=4.3Hz,1H),3.0 1(s,4H),2.62(dt,J=16.1,4.7Hz,1H),2.49–2.47(m,3H),2.29–2.18(m,5H),2.13–2.04(m,2H ),1.97–1.86(m,1H),1.80–1.76(m,2H),1.73–1.61(m,2H),1.47–1.37(m,1H).LC-MS(ESI):m / z 415.3[M+H] + .

[0269] Example 61: Preparation of Compound I-61: 2-((2-cyclobutyloxy-3-(2-methylmorpholino)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0270] Referring to the synthetic route of Compound I-57 of Example 57, 2-methylmorpholine was used as the starting material in Step 1. Silica gel column chromatography and reverse phase preparative chromatography afforded 184 mg of a white solid with a yield of 47.2% and an mp of 96.8–98.9°C. 1 H NMR(400MHz, DMSO-d6)δ9.12(s,1H),8.00(dd,J=8.1,1.4Hz,1H),6.97(t,J=8.2Hz,1H),6.56(dd,J=8.1,1.5Hz,1H) ,4.94(s,1H),4.74(p,J=7.6Hz,1H),4.47(t,J=3.9Hz,1H),3.90–3.87(m,1H),3.73–3.66(m,2H),3.36–3.34(m,1H) ,3.29–3.28(m,1H),2.66–2.59(m,2H),2.49–2.47(m,1H),2.38–2.32(m,1H),2.27–2.20(m,2H),2.13–2.08(m,2H), 1.94–1.88(m,1H),1.80–1.76(m,2H),1.73–1.62(m,2H),1.47–1.35(m,1H),1.13(d,J=6.3Hz,3H).LC-MS(ESI):m / z 416.3[M+H] + .

[0271] Example 62: Preparation of Compound I-62: 2-((3-(2-oxo-5-azabicyclo[2.2.1]heptane-5-yl)-2-cyclobutyloxyphenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0272] Referring to the synthetic route of Compound I-57 of Example 57, 2-oxa-5-azabicyclo[2.2.1]heptane was used as the starting material in Step 1. Silica gel column chromatography and reverse phase preparative chromatography afforded 215 mg of a white solid (50.1% yield, mp 186.8–188.1°C). 1H NMR (400MHz, DMSO-d6) δ9.16 (s, 0.37H), 7.81–7.79 (m, 1H), 6.90 (t, J = 8.2Hz, 1H), 6.42 (d, J = 8.1Hz, 1H), 5.01–4.90 (m, 0. 30H),4.57(s,1H),4.50–4.46(m,2H),4.40(p,J=7.7Hz,1H),3.85(d,J=7.5Hz,1H),3.75(d,J=7.4Hz,1H),3.62(dd,J=9.3, 3.8Hz,1H),2.93(dd,J=10.1,4.0Hz,1H),2.64(dt,J=16.1,4.7Hz,1H),2.51–2.47(m,1H),2.31–2.23(m,1H),2.21–2.09(m ,2H),2.03–1.97(m,1H),1.92–1.78(m,5H),1.75–1.70(m,1H),1.63(q,J=10.2Hz,1H),1.44–1.34(m,1H).LC-MS(ESI):m / z 414.3[M+H] + .

[0273] Example 63: Preparation of Compound I-63: 2-((2-cyclobutyloxy-3-(pyrazolin-1-yl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0274] Referring to the synthetic route of Compound I-57 of Example 57, tetrahydropyrrole was used as the starting material in Step 1. Silica gel column chromatography and reverse phase preparative chromatography afforded 146 mg of a white solid with a yield of 44.0% and an mp of 164.6–165.8°C. 1H NMR (400MHz, DMSO-d6) δ9.15 (s, 0.34H), 7.80–7.77 (m, 1H), 6.91 (t, J = 8.2Hz, 1H), 6.44 (dd, J = 8.3, 1.5Hz,1H),4.97(s,0.25H),4.48(t,J=4.1Hz,1H),4.42(p,J=7.7Hz,1H),3.25–3.19(m,4H),2.64( dt,J=16.1,4.7Hz,1H),2.51–2.47(m,1H),2.27–2.17(m,2H),2.10–2.03(m,2H),1.95–1.88(m,5H) ,1.82–1.78(m,2H),1.75–1.71(m,1H),1.63(q,J=10.1Hz,1H),1.45–1.33(m,1H).LC-MS(ESI):m / z 386.2[M+H] + .

[0275] Example 64: Preparation of Compound I-64: 2-((2-cyclobutyloxy-3-(1,4-oxazol-4-yl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0276] Referring to the synthetic route of Compound I-57 of Example 57, homomorpholine hydrochloride was used as the starting material in Step 1. Silica gel column chromatography and reverse phase preparative system afforded 30 mg of a white solid with a yield of 33.5% and an mp of 138.4–139.9°C. 1 H NMR (400MHz, DMSO-d6) δ9.11(s,1H),7.90(dd,J=7.9,1.4Hz,1H),6.92(t,J=8.1Hz,1H),6.62(dd,J=8.0, 1.5Hz,1H),4.93(d,J=5.6Hz,1H),4.64(p,J=7.5Hz,1H),4.47(q,J=4.5Hz,1H),3.78–3.72(m,4H),3.34–3 .31(m,4H),2.62(dt,J=16.1,4.7Hz,1H),2.50–2.46(m,1H),2.25–2.17(m,2H),2.11–2.04(m,2H),1.97– 1.88(m,3H),1.80–1.76(m,2H),1.74–1.68(m,1H),1.66–1.60(m,1H),1.46–1.36(m,1H).LC-MS(ESI):m / z 416.3[M+H] + .

[0277] Example 65: Compound I-65: Preparation of 2-((2-cyclobutyloxy-3'-methoxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0278] Referring to the synthetic route of Compound I-22 in Example 22, 3-methoxyphenylboronic acid was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 34 mg of a white solid with a yield of 64.8% and an mp of 170.1–176.3°C. 1 H NMR(600MHz,DMSO-d6)δ9.29(s,1H),8.39(t,J=6.8Hz,1H),7.36(t,J=7.9Hz,1H),7 .17–7.08(m,3H),6.97–6.90(m,2H),4.95(s,1H),4.49(t,J=4.2Hz,1H),3.97(p,J= 7.5Hz,1H),3.80(s,3H),2.63(dt,J=16.1,4.8Hz,1H),2.50–2.44(m,1H),2.01–1.8 8(m,3H),1.82–1.65(m,5H),1.50–1.37(m,1H),1.21–1.09(m,1H).LC-MS(ESI):m / z 423.7[M+H] + .

[0279] Example 66: Preparation of Compound I-66: 2-((2-cyclobutyloxy-4'-methoxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0280] Referring to the synthetic route of Compound I-22 in Example 22, 4-methoxyphenylboronic acid was used as the raw material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 210 mg of a white solid with a yield of 69.1% and an mp of 166.7–173.0°C. 1H NMR (400MHz, DMSO-d6) δ9.26 (s, 1H), 8.32 (d, J = 8.2Hz, 1H), 7.46 (d, J = 8.7Hz, 2H), 7.10 (td, J=8.0,2.5Hz,1H),7.00(dd,J=8.7,2.6Hz,2H),6.89(dd,J=7.8,2.3Hz,1H),5.03–4.90(m,1 H),4.47(s,1H),3.94(p,J=8.3Hz,1H),3.79(s,3H),2.69–2.57(m,1H),2.49–2.43(m,1H),2 .02–1.83(m,3H),1.82–1.65(m,5H),1.47–1.32(m,1H),1.19–1.06(m,1H).LC-MS(ESI):m / z 423.7[M+H] + .

[0281] Example 67: Compound I-67: Preparation of 2'-cyclobutyloxy-N-ethyl-3'-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-[1,1'-biphenyl]-3-carboxamide

[0282] Referring to the synthetic route of Compound I-22 in Example 22, 3-(N-ethylcarboxamido)phenylboronic acid was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 21 mg of a white solid with a yield of 70.7% and an mp of 170.0–177.0°C. 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.55(s,1H),8.43(d,J=8.1Hz,1H),8.02(s,1H),7.83(d,J=7.8Hz ,1H),7.69(d,J=7.7Hz,1H),7.53(t,J=7.8Hz,1H),7.18(t,J=8.1Hz,1H),7.00(d,J=7.7Hz,1H),4.97(s ,1H),4.49(s,1H),3.97–3.89(m,1H),3.31–3.20(m,2H),2.74–2.57(m,1H),2.43–2.26(m,1H),1.97–1. 87(m,3H),1.82–1.77(m,2H),1.75–1.68(m,3H),1.49–1.37(m,1H),1.21–1.06(m,4H).LC-MS(ESI):m / z 464.0[M+H] + .

[0283] Example 68: Compound I-68: Preparation of 2'-cyclobutyloxy-N-ethyl-3'-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-[1,1'-biphenyl]-4-carboxamide

[0284] Referring to the synthetic route of Compound I-22 in Example 22, 4-(N-ethylcarboxamido)phenylboronic acid was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography afforded 17 mg of a white solid with a yield of 16.0% and an mp of 175.3–181.1°C. 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.58(s,1H),8.41(d,J=8.4Hz,1H),7.93(d,J=7.9Hz,2H),7 .62(d,J=8.8Hz,2H),7.16(t,J=8.1Hz,1H),6.97(d,J=7.7Hz,1H),5.01–4.95(m,1H),4.49(s,1H ),3.99–3.91(m,1H),3.32–3.28(m,2H),2.68–2.59(m,1H),2.58–2.52(m,1H),1.97–1.86(m,3H) ,1.84–1.66(m,5H),1.45–1.38(m,1H),1.37–1.33(m,1H),1.15(t,J=7.1Hz,3H).LC-MS(ESI):m / z 464.1[M+H] + .

[0285] Example 69: Compound I-69: Preparation of N-(1-(2-cyclobutyloxy-3-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)phenyl)piperidin-4-yl)propanamide

[0286] Step 1: Preparation of tert-butyl (1-(3-bromo-2-cyclobutyloxyphenyl)piperidin-4-yl)carbamate

[0287] tert-Butyl piperidin-4-ylcarbamate (687 mg, 3.27 mmol) and 1,3-dibromo-2-cyclobutyloxybenzene (1.00 g, 3.27 mmol) were dissolved in toluene (20 mL). 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (1.02 g, 1.63 mmol), cesium carbonate (1.60 g, 4.90 mmol), and tris(dibenzylideneacetone)dipalladium (23.9 mg, 32.7 μmol) were added. The system was refluxed at 120°C under nitrogen for at least 14 hours. After TLC confirmed the completion of the reaction, the reaction solution was diluted with ethyl acetate (150 mL) and washed three times with saturated brine. The organic solvent was then dried and the powder was purified by silica gel column chromatography (PE:EA = 60:1) to obtain 0.15 g of a light yellow viscous solid with a yield of 15.1%. LC-MS (ESI): m / z 425.3 [M+H] + .

[0288] Step 2: Preparation of tert-butyl (1-(2-cyclobutoxy-3-((4-oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)phenyl)piperidin-4-yl)carbamate

[0289] To tert-butyl (1-(3-bromo-2-cyclobutyloxyphenyl)piperidin-4-yl)carbamate (150 mg, 0.353 mmol), 2-amino-6,7-dihydrobenzo[d]thiazol-4(5H)-one (62.2 mg, 0.370 mmol), and 2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl (113 mg, 0.233 mmol) was added tert-butyl alcohol (10 mL). The mixture was heated briefly to dissolve the above substances. Tris(dibenzylideneacetone)dipalladium (48.4 mg, 0.052 mmol), potassium carbonate (68.2 mg, 0.494 mmol), and glacial acetic acid (0.02 mL) were then added. The mixture was refluxed at 110°C for 12 h under nitrogen protection. After TLC confirmed the completion of the reaction, dichloromethane (140 mL) was added and sonicated for 2 minutes. Insoluble matter was filtered, and the filtrate was spin-dried and purified by silica gel column chromatography (PE:EA = 1:1) to obtain a pale yellow colloidal solid containing impurities. The solid was rinsed with petroleum ether and then methanol to remove the color-dispersing impurities, yielding 0.11 g of a white to pale yellow solid in a 46% yield. LC-MS (ESI): m / z 513.4 [M+H] + .

[0290] Step 3: Preparation of 2-((3-(4-aminopiperidin-1-yl)-2-cyclobutyloxyphenyl)amino)-6,7-dihydro[d]thiazol-4(5H)-one

[0291] The intermediate obtained in the previous step (108 mg, 0.211 mmol) was dissolved in dichloromethane (10 mL), and 30% ethanolic hydrochloric acid solution (3 mL) was slowly added under ice-cooling. The mixture was reacted at room temperature for 1 h. After completion of the reaction, the mixture was spin-dried to obtain 130 mg of a solid hydrochloride salt, as monitored by TLC.

[0292] Step 4: Preparation of N-(1-(2-cyclobutyloxy-3-((4-oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)phenyl)piperidin-4-yl)propanamide

[0293] 2-(3-(4-aminopiperidin-1-yl)-2-cyclobutyloxyphenyl)amino)-6,7-dihydrobenzo[d]thiazol-4(5H)-one hydrochloride (100 mg, 0.223 mmol) was weighed and dissolved in dichloromethane (8 mL). Triethylamine (120 mg, 1.21 mmol) was added portionwise until the solid was completely dissolved. Propionic acid (89.0 mg, 1.21 mmol) and HATU (129 mg, 0.340 mmol) were added and stirred at room temperature for 2 h. After the reaction, water was added and the organic layer was washed three times with water. The organic phase was spin-dried and purified by silica gel column chromatography (DCM:CH3OH = 70:1) to obtain 57 mg of a light yellow solid in a 49% yield. LC-MS (ESI): m / z 469.7 [M+H] + .

[0294] Step 5: Preparation of N-(1-(2-cyclobutyloxy-3-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)phenyl)piperidin-4-yl)propanamide:

[0295] Step 5: Refer to step 4 of the synthesis of compound I-22 in Example 22, and after reverse phase purification, 30 mg of a white to yellowish solid was obtained with a yield of 52.6% and mp 201.1-207.1°C. 1H NMR (600MHz, DMSO-d6) δ9.06(s,1H),7.97–7.88(m,1H),7.76(d,J=7.8Hz,1H),6.94(t,J=8.2Hz,1H),6.59(d,J=8.1H z,1H),4.74(p,J=7.6Hz,1H),4.46(t,J=4.2Hz,1H),3.71–3.61(m,1H),3.45–3.36(m,3H),2.69–2.58(m,3H),2.49–2 .42(m,1H),2.28–2.20(m,2H),2.16–2.03(m,4H),1.96–1.87(m,1H),1.84(dd,J=12.6,3.9Hz,2H),1.77(dt,J=6.1,4 .2Hz,2H),1.74–1.63(m,2H),1.55(qd,J=11.8,3.9Hz,2H),1.46–1.35(m,1H),1.00(t,J=7.6Hz,3H).LC-MS(ESI):m / z 471.0[M+H] + .

[0296] Example 70: Compound I-70: Preparation of 1-(4-(2-cyclobutyloxy-3-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)phenyl)piperazin-1-yl)propan-1-one

[0297] Refer to Example 69 for the synthetic route of compound I-69, using tert-butyl piperazine-1-carboxylate as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative system gave 18 mg of a white solid with a yield of 26% and mp of 205.4–212.2°C. 1 H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.22–7.89(m,1H),7.13–6.90(m,1H),6.74–6.47(m,1H) ),4.96(s,1H),4.87–4.66(m,1H),4.59–4.36(m,1H),3.64(s,4H),3.12–2.89(m,4H),2.75– 2.60(m,1H),2.45–2.34(m,2H),2.34–2.23(m,2H),2.20–2.09(m,2H),2.00–1.88(m,1H), 1.86–1.61(m,4H),1.53–1.35(m,2H),1.11–0.98(m,3H).LC-MS(ESI):m / z 457.0[M+H] + .

[0298] Example 71: Compound I-71: Preparation of methyl 2-(4-(2-cyclobutyloxy-3-(4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)phenyl)piperazin-1-yl)acetate

[0299] Refer to steps 1–2 and 5 of the synthetic route for compound I-69 in Example 69. In step 1, ethyl 2-(piperazin-1-yl)acetate was used as the starting material. Silica gel column chromatography and reverse phase preparative chromatography afforded 15 mg of a white solid in a 30% yield, mp 209.4–213.9°C. 1 H NMR (400MHz, DMSO-d6) δ9.10(s,1H),7.98(dd,J=8.3,1.4Hz,1H),6.95(t,J=8.2Hz,1H),6.57(d d,J=8.2,1.5Hz,1H),4.93(d,J=5.6Hz,1H),4.72(p,J=7.5Hz,1H),4.46(q,J=4.5Hz,1H),3.64( s,2H),3.31(s,2H),3.07–2.93(m,4H),2.74–2.65(m,4H),2.66–2.57(m,1H),2.50–2.41(m,1H) ,2.31–2.15(m,2H),2.15–2.03(m,2H),1.97–1.84(m,1H),1.82–1.58(m,4H),1.47–1.35(m,1H).

[0300] Example 72: Compound I-72: Preparation of 2'-cyclobutyloxy-3'-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-[1,1'-biphenyl]-4-carbonitrile

[0301] Referring to the synthetic route of Compound I-22 in Example 22, 4-cyanophenylboronic acid was used as the raw material in Step 2. Silica gel column chromatography and reverse phase preparative system were performed to obtain 54 mg of a white solid with a yield of 93.1%. 1H NMR(400MHz, DMSO-d6)δ9.35(s,1H),8.44(dd,J=8.3,1.6Hz,1H),7.93(d,J=8.4Hz,2H),7.7 5(d,J=8.4Hz,2H),7.20(t,J=8.0Hz,1H),7.00(dd,J=7.7,1.6Hz,1H),5.00(d,J=5.5Hz,1H) ,4.53–4.48(m,1H),3.96(p,J=7.5Hz,1H),2.64(dt,J=16.2,4.7Hz,1H),2.51–2.47(m,1H), 1.98–1.85(m,3H),1.83–1.69(m,5H),1.47–1.38(m,1H),1.20–1.12(m,1H).LC-MS(ESI):m / z 418.0[M+H] + .

[0302] Example 73: Compound I-73: Preparation of 2'-cyclobutyloxy-3'-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-[1,1'-biphenyl]-4-carboxylic acid

[0303] Step 1-4: Synthesis of methyl 2'-cyclobutyloxy-3'-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-[1,1'-biphenyl]-4-carboxylate

[0304] Referring to the synthetic route of Compound I-22 in Example 22, 4-methoxycarbonylphenylboronic acid was used as the raw material in Step 2. Silica gel column chromatography afforded 257 mg of an off-white solid with a yield of 63.1%.

[0305] Step 5: Synthesis of 2'-cyclobutyloxy-3'-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-[1,1'-biphenyl]-4-carboxylic acid

[0306] Methyl 2'-cyclobutyloxy-3'-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-[1,1'-biphenyl]-4-carboxylate (50 mg, 0.11 mmol) was dissolved in 14 mL of a 6:1 mixture of ethanol and water by sonication. Lithium hydroxide monohydrate (23.3 mg, 55 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction as monitored by TLC, the ethanol was evaporated, the pH was adjusted to 4 with dilute hydrochloric acid, and the crude product was collected by filtration. The crude product was purified by reverse phase preparative system to afford 39 mg of a white solid in an 81.3% yield. 1H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.43(dd,J=8.2,1.6Hz,1H),8.03(d,J=8.3Hz,2H),7. 67(d,J=8.3Hz,2H),7.19(t,J=7.9Hz,1H),6.99(dd,J=7.7,1.6Hz,1H),4.97(s,1H),4.51( t,J=4.2Hz,1H),3.96(p,J=7.5Hz,1H),2.65(dt,J=16.1,4.8Hz,1H),2.52–2.44(m,1H),1. 99–1.88(m,3H),1.84–1.71(m,5H),1.50–1.37(m,1H),1.21–1.10(m,1H).LC-MS(ESI):m / z 436.9[M+H] + .

[0307] Example 74: Compound I-74: Preparation of 2-((2-cyclobutyloxy-3-(pyridin-4-yl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0308] Referring to the synthetic route of Compound I-22 in Example 22, pyridine-4-boronic acid was used as the raw material in Step 2. 30 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 98.1%. 1 H NMR (400MHz, DMSO-d6) δ9.38 (s, 1H), 8.69–8.61 (m, 2H), 8.47 (d, J = 7.9Hz, 1H), 7.62–7 .55(m,2H),7.21(t,J=8.0Hz,1H),7.03(dd,J=7.7,1.6Hz,1H),5.00(d,J=5.6Hz,1H), 4.54–4.44(m,1H),4.00(p,J=7.6Hz,1H),2.72–2.58(m,1H),2.51–2.47(m,1H),2.03– 1.86(m,3H),1.86–1.67(m,5H),1.48–1.38(m,1H),1.22–1.11(m,1H).LC-MS(ESI):m / z 394.6[M+H] + .

[0309] Example 75: Compound I-75: Preparation of 2-((2-cyclobutyloxy-3-(6-methoxypyridin-3-yl)phenyl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0310] Referring to the synthetic route of Compound I-22 in Example 22, 2-methoxy-5-pyridineboronic acid was used as the raw material in Step 2. Silica gel column chromatography and reverse phase preparative system were used to obtain 16 mg of a white solid with a yield of 88.1%. 1 H NMR (400MHz, DMSO-d6) δ9.32(s,1H),8.40(dd,J=8.3,1.6Hz,1H),8.33(d,J=2.4Hz,1H),7.89(dd,J= 8.5,2.5Hz,1H),7.16(t,J=7.9Hz,1H),6.97(dd,J=7.7,1.6Hz,1H),6.92(d,J=8.6Hz,1H),4.98(s,1 H),4.55–4.46(m,1H),4.00(p,J=7.5Hz,1H),3.92(s,3H),2.64(dt,J=16.1,4.8Hz,1H),2.51–2.46( m,1H),2.00–1.88(m,3H),1.83–1.67(m,5H),1.51–1.39(m,1H),1.23–1.11(m,1H).LC-MS(ESI):m / z 424.3[M+H] + .

[0311] Example 76: Compound I-76: Preparation of 2-((2-cyclobutyloxy-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0312] Referring to the synthetic route of Compound I-22 in Example 22, 4-trifluoromethoxyphenylboronic acid was used as the raw material in Step 2. Silica gel column chromatography and reverse phase preparative system were used to obtain 23 mg of a white solid with a yield of 93.8%. 1 H NMR (400MHz, DMSO-d6) δ9.30(s,1H),8.39(dd,J=8.3,1.6Hz,1H),7.66(d,J=8.7Hz,2H),7. 45(d,J=8.2Hz,2H),7.17(t,J=7.9Hz,1H),6.97(dd,J=7.7,1.6Hz,1H),4.56–4.44(m,1H),4 .24–4.14(m,1H),3.95(p,J=7.6Hz,1H),2.64(dt,J=16.3,4.8Hz,1H),2.57–2.41(m,1H),2 .00–1.85(m,3H),1.84–1.67(m,5H),1.47–1.36(m,1H),1.20–1.15(m,1H).LC-MS(ESI):m / z 477.2[M+H]+ .

[0313] Example 77: Compound I-77: Preparation of 2-((2-cyclobutyloxy-4'-hydroxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0314] Step 1-4: Synthesis of 2-((4'-(benzyloxy)-2-cyclobutyloxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0315] Referring to the synthetic route of Compound I-22 in Example 22, 4-benzyloxyphenylboronic acid was used as the raw material in Step 2. Silica gel column chromatography afforded 101 mg of a white solid with a yield of 50.5%.

[0316] Step 5: Synthesis of 2-((2-cyclobutoxy-4'-hydroxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0317] To 2-((4'-(benzyloxy)-2-cyclobutyloxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol (50 mg, 0.10 mmol) was added 5 mL of trifluoroacetic acid and refluxed for 4 hours. After completion of the reaction, as monitored by TLC, the solvent was evaporated and the product was purified by silica gel column chromatography using a reverse phase preparative system to obtain 24 mg of a white solid in a 59% yield. 1 H NMR (400MHz, DMSO-d6) δ9.49 (s, 1H), 9.23 (s, 1H), 8.30 (dd, J = 8.2, 1.6Hz, 1H), 7.36 (d, J = 8.5Hz, 2H),7.10(t,J=7.9Hz,1H),6.89(dd,J=7.7,1.6Hz,1H),6.84(d,J=8.6Hz,2H),4.96(s,1H),4.49 (t,J=4.3Hz,1H),3.97(p,J=7.5Hz,1H),2.64(dt,J=16.0,4.7Hz,1H),2.51–2.37(m,1H),2.03–1 .88(m,3H),1.83–1.68(m,5H),1.49–1.41(m,1H),1.23–1.10(m,1H).LC-MS(ESI):m / z409.3[M+H] + .

[0318] Example 78: Preparation of Compound I-78: 2-((4'-amino-2-cyclobutyloxy-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0319] Refer to Example 77 for the synthetic route of Compound I-77. Step 2 used 4-(N-BOC-amino)phenylboronic acid as the starting material. Step 5 used 5 mL of dichloromethane and 5 mL of trifluoroacetic acid. The reaction was carried out at room temperature for 2 h. Silica gel column chromatography using a reverse phase preparative system afforded 45 mg of a white solid in a 56.3% yield. 1 H NMR(400MHz, DMSO-d6)δ9.19(s,1H),8.24(dd,J=8.2,1.6Hz,1H),7.24(d,J=8.5Hz,2H),7.07(t ,J=7.9Hz,1H),6.86(dd,J=7.7,1.6Hz,1H),6.63(d,J=8.4Hz,2H),5.18(s,2H),4.95(d,J=5.5H z,1H),4.55–4.46(m,1H),4.01(p,J=7.5Hz,1H),2.64(dt,J=16.2,4.7Hz,1H),2.51–2.44(m,1H ),2.05–1.91(m,3H),1.83–1.72(m,5H),1.52–1.41(m,1H),1.23–1.12(m,1H).LC-MS(ESI):m / z 408.3[M+H] + .

[0320] Example 79: Compound I-79: Preparation of 2-((2-cyclobutyloxy-4'-(ethylamino)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0321] Referring to the synthetic route of Compound I-78 in Example 78, (4-N-BOC-N-ethylamino)phenylboronic acid was used as the starting material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography gave 65 mg of a white solid with a yield of 81.3%. 1H NMR (400MHz, DMSO-d6) δ9.22(s,1H),8.26(d,J=8.2Hz,1H),7.31(d,J=8.2Hz,2H),7.07(t,J =7.9Hz,1H),6.87(d,J=7.7Hz,1H),6.62(d,J=8.1Hz,2H),5.67(t,J=5.3Hz,1H),4.96(d,J= 5.5Hz,1H),4.53–4.44(m,1H),4.01(p,J=7.7Hz,1H),3.15–3.01(m,2H),2.71–2.55(m,2H), 2.06–1.88(m,3H),1.85–1.67(m,5H),1.53–1.42(m,1H),1.23–1.08(m,4H).LC-MS(ESI):m / z 436.1[M+H] + .

[0322] Example 80: Preparation of Compound I-80: 2-((2-cyclobutyloxy-4'-(ethylamino)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0323] Step 1-2: Synthesis of tert-butyl (3'-bromo-2'-cyclobutyloxy-[1,1'-biphenyl]-4-yl)carbamate

[0324] Synthesis steps: Refer to steps 1-2 of the synthesis of compound I-22 in Example 22, wherein 4-(N-BOC-amino)phenylboronic acid is used as the starting material in step 2. Silica gel column chromatography afforded 157 mg of a transparent oily liquid with a yield of 68.1%.

[0325] Step 3: Synthesis of 3'-bromo-2'-cyclobutyloxy-[1,1'-biphenyl]-4-amine

[0326] To tert-butyl (3'-bromo-2'-cyclobutyloxy-[1,1'-biphenyl]-4-yl)carbamate (150 mg, 0.36 mmol), 5 mL of dichloromethane and 5 mL of trifluoroacetic acid were added and the reaction was stirred at room temperature for 3 hours. After completion of the reaction, as monitored by TLC, the mixture was concentrated under reduced pressure, extracted with saturated sodium bicarbonate solution and dichloromethane, and washed three times with saturated sodium bicarbonate solution. The organic phase was collected, dried, and purified by silica gel column chromatography to obtain 107 mg of the product as a yellow oil in a 91% yield.

[0327] Step 4: Synthesis of N-(3'-bromo-2'-cyclobutyloxy-[1,1'-biphenyl]-4-yl)propionamide

[0328] 3'-Bromo-2'-cyclobutyloxy-[1,1'-biphenyl]-4-amine (100 mg, 0.31 mmol) was dissolved in 8 mL of dichloromethane. A solution of propionyl chloride (145 mg, 1.57 mmol) in dichloromethane (2 mL) was slowly added dropwise in an ice bath. The mixture was allowed to react at room temperature for 1 h. After completion of the reaction, the solvent was evaporated and the product was separated by silica gel column chromatography to obtain 97 mg of a white solid in 82% yield.

[0329] Step 5-6: Synthesis of 2-((2-cyclobutoxy-4'-(ethylamino)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0330] Refer to step 3-4 of the synthetic route of compound I-22 in Example 22. Silica gel column chromatography and reverse phase preparative system were used to obtain 22 mg of a white solid with a yield of 44.5%. 1 H NMR (400MHz, DMSO-d6) δ9.97(s,1H),9.27(s,1H),8.35(d,J=8.4Hz,1H),7.69(d,J=8.2Hz,2 H),7.49(d,J=8.2Hz,2H),7.14(t,J=7.9Hz,1H),6.93(dd,J=7.8,1.6Hz,1H),4.97(d,J=5.3 Hz,1H),4.57–4.42(m,1H),3.98(p,J=7.5Hz,1H),2.72–2.56(m,2H),2.37(q,J=7.5Hz,2H), 2.01–1.90(m,3H),1.85–1.71(m,5H),1.50–1.38(m,1H),1.18–1.09(m,4H).LC-MS(ESI):m / z 464.4[M+H] + .

[0331] Example 81: Compound I-81: Preparation of 1-(2'-cyclobutyloxy-3'-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-[1,1'-biphenyl]-4-yl)-3-ethylurea

[0332] Step 1-3: Synthesis of 3'-bromo-2'-cyclobutyloxy-[1,1'-biphenyl]-4-amine

[0333] Synthesis steps: Refer to the synthesis steps 1-3 of compound I-22 in Example 22, and 110 mg of yellow oily liquid can be obtained by reverse phase preparation and purification, with a yield of 93%.

[0334] Step 4: Synthesis of 1-(3'-bromo-2'-cyclobutyloxy-[1,1'-biphenyl]-4-yl)-3-ethylurea

[0335] 3'-Bromo-2'-cyclobutyloxy-[1,1'-biphenyl]-4-amine (100 mg, 0.31 mmol) was dissolved in 8 mL of dichloromethane. A solution of ethyl isocyanate (112 mg, 1.57 mmol) in dichloromethane (2 mL) was slowly added dropwise in an ice bath. The mixture was allowed to react at room temperature for 1 h. After completion of the reaction, the solvent was evaporated and the product was separated by silica gel column chromatography to obtain 87 mg of a white solid in a 71.3% yield.

[0336] Step 5-6: Synthesis of 2-((2-cyclobutoxy-4'-(ethylamino)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0337] The subsequent steps were carried out according to Step 3-Step 4 in the synthesis route of Compound I-22 of Example 22. 19 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 37.2%. 1 H NMR (400MHz, DMSO-d6) δ9.25(s,1H),8.54(s,1H),8.32(dd,J=8.2,1.6Hz,1H),7.48(d,J=8.7Hz,2H),7.41(d,J =8.8Hz,2H),7.11(t,J=8.0Hz,1H),6.91(dd,J=7.7,1.6Hz,1H),6.17(t,J=5.6Hz,1H),4.96(d,J=5.3Hz,1H),4 .53–4.46(m,1H),3.98(p,J=7.6Hz,1H),3.14(qd,J=7.2,5.5Hz,2H),2.74–2.61(m,1H),2.51–2.47(m,1H),2.0 2–1.89(m,3H),1.83–1.67(m,5H),1.53–1.40(m,1H),1.21–1.12(m,1H),1.08(t,J=7.2Hz,3H).LC-MS(ESI):m / z 479.1[M+H] + .

[0338] Example 82: Compound I-82: Preparation of 2'-cyclobutyloxy-3'-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-[1,1'-biphenyl]-4-carboxamide

[0339] Referring to the synthetic route of Compound I-22 in Example 22, 4-carbamoylphenylboronic acid was used as the raw material in Step 2. 17 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 33.1%. 1 H NMR(400MHz, DMSO-d6)δ9.30(s,1H),8.39(d,J=8.2Hz,1H),8.05(s,1H),7.95(d,J=7.9 Hz,2H),7.62(d,J=7.9Hz,2H),7.40(s,1H),7.17(t,J=7.9Hz,1H),6.98(d,J=7.7Hz,1H ),5.00(d,J=5.5Hz,1H),4.55–4.45(m,1H),4.00–3.91(m,1H),2.69–2.56(m,2H),1.98 –1.86(m,3H),1.81–1.64(m,5H),1.48–1.35(m,1H),1.21–1.02(m,1H).LC-MS(ESI):m / z 436.1[M+H] + .

[0340] Example 83: Preparation of Compound I-83: ​​2'-cyclobutyloxy-N-cyclopropyl-3'-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-[1,1'-biphenyl]-4-carboxamide

[0341] Referring to the synthetic route of Compound I-22 in Example 22, 4-(cyclopropylcarbamoyl)phenylboronic acid was used as the raw material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography gave 25 mg of a white solid with a yield of 43.1%. 1H NMR (400MHz, DMSO-d6) δ9.33(s,1H),8.50(d,J=4.2Hz,1H),8.42(dd,J=8.2,1.6Hz,1H),7.91(d,J=8.3Hz,2 H),7.62(d,J=8.3Hz,2H),7.17(t,J=8.0Hz,1H),6.97(dd,J=7.7,1.7Hz,1H),4.96(s,1H),4.51(t,J=4.1Hz, 1H),3.96(p,J=7.5Hz,1H),2.96–2.86(m,1H),2.72–2.59(m,1H),2.51–2.45(m,1H),1.98–1.86(m,3H),1.8 3–1.68(m,5H),1.49–1.34(m,1H),1.21–1.06(m,1H),0.76–0.69(m,2H),0.64–0.58(m,2H).LC-MS(ESI):m / z 476.0[M+H] + .

[0342] Example 84: Compound I-84: Preparation of 2'-cyclobutyloxy-3'-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-N,N-dimethyl-[1,1'-biphenyl]-4-carboxamide

[0343] Referring to the synthetic route of Compound I-22 in Example 22, 4-(N,N-dimethylcarbamoyl)phenylboronic acid was used as the raw material in Step 2. 19 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 38.1%. 1 H NMR(400MHz, DMSO-d6)δ9.30(s,1H),8.38(dd,J=8.2,1.6Hz,1H),7.60(d,J=8.2Hz,2H),7.49( d,J=8.2Hz,2H),7.17(t,J=7.9Hz,1H),6.98(dd,J=7.7,1.6Hz,1H),5.00(d,J=5.5Hz,1H),4.5 5–4.45(m,1H),3.97(p,J=7.4Hz,1H),3.09–2.90(m,6H),2.72–2.60(m,1H),2.51–2.45(m,1H) ,2.00–1.87(m,3H),1.84–1.67(m,5H),1.48–1.36(m,1H),1.22–1.09(m,1H).LC-MS(ESI):m / z 464.5[M+H] + .

[0344] Example 85: Compound I-85: Preparation of methyl 2-(2'-cyclobutyloxy-3'-(4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-[1,1'-biphenyl]-4-yl)acetate

[0345] Referring to the synthetic route of Compound I-22 in Example 22, 4-boronate-phenylacetic acid methyl ester was used as the raw material in Step 2. Silica gel column chromatography and reverse phase preparative system were used to obtain 10 mg of a white solid with a yield of 50%. 1 H NMR (400MHz, DMSO-d6) δ9.28(s,1H),8.37(dd,J=8.1,1.6Hz,1H),7.50(d,J=8.2Hz,2H),7.35( d,J=8.1Hz,2H),7.15(t,J=7.9Hz,1H),6.94(dd,J=7.7,1.6Hz,1H),4.96(s,1H),4.50(s,1H),3 .95(p,J=7.5Hz,1H),3.76(s,2H),3.65(s,3H),2.65(dt,J=16.1,4.8Hz,1H),2.50–2.46(m,1H ),1.99–1.89(m,3H),1.86–1.68(m,5H),1.47–1.35(m,1H),1.17–1.15(m,1H).LC-MS(ESI):m / z 465.3[M+H] + .

[0346] Example 86: Compound I-86: Preparation of 2-((2-cyclobutyloxy-4'-(ethylsulfonyl)-[1,1'-biphenyl]-3-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0347] Referring to the synthetic route of Compound I-22 in Example 22, 4-ethylsulfonylphenylboronic acid was used as the starting material in Step 2. 47 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 94%. 1H NMR (400MHz, DMSO-d6) δ9.38 (s, 1H), 8.46 (d, J = 8.1Hz, 1H), 7.97 (d, J = 8.3Hz, 2H), 7.8 3(d,J=8.2Hz,2H),7.22(t,J=7.9Hz,1H),7.03(dd,J=7.8,1.6Hz,1H),4.96(s,1H),4.5 1(t,J=4.1Hz,1H),3.96(p,J=7.6Hz,1H),3.34–3.26(m,2H),2.75–2.53(m,2H),1.99– 1.84(m,3H),1.83–1.68(m,5H),1.48–1.37(m,1H),1.19–1.09(m,4H).LC-MS(ESI):m / z 485.1[M+H] + .

[0348] Example 87: Compound I-87: Preparation of 2-((3-cyclobutyloxy-4-(4-(methylsulfonyl)phenyl)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0349] Referring to the synthetic route of Compound I-15 in Example 15, 4-(methylsulfonyl)phenylboronic acid was used as the raw material in Step 3. 47 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 94%. 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),8.15(d,J=5.2Hz,1H),8.08(d,J=8.4Hz,2H), 7.90(d,J=8.4Hz,2H),7.04(d,J=5.2Hz,1H),4.56(t,J=4.2Hz,1H),4.20–3.94(m,1 H),3.79–3.52(m,1H),3.31(s,3H),2.78–2.68(m,1H),2.65–2.56(m,1H),2.07–1.9 1(m,3H),1.91–1.69(m,5H),1.58–1.43(m,1H),1.25–1.14(m,1H).LC-MS(ESI):m / z 472.0[M+H] + .

[0350] Example 88: Preparation of Compound I-88: 2-((3-cyclobutyloxy-4-(4-methoxyphenyl)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0351] Referring to the synthetic route of Compound I-15 in Example 15, 4-methoxyphenylboronic acid was used as the raw material in Step 3. Silica gel column chromatography and reverse phase preparative system were used to obtain 20 mg of a white solid with a yield of 40.1%. 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),8.08(d,J=5.3Hz,1H),7.61(d,J=8.7Hz, 2H),7.09(d,J=8.8Hz,2H),7.01(d,J=5.3Hz,1H),4.63–4.53(m,1H),4.10(p,J =7.5Hz,1H),3.84(s,3H),2.78–2.67(m,1H),2.65–2.58(m,1H),2.12–1.92(m, 3H),1.91–1.68(m,5H),1.60–1.43(m,1H),1.24–1.13(m,1H).LC-MS(ESI):m / z 424.1[M+H] + .

[0352] Example 89: Compound I-89: Preparation of 2-((3-cyclobutyloxy-4-(3-methoxyphenyl)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0353] Referring to the synthetic route of Compound I-15 in Example 15, 3-methoxyphenylboronic acid was used as the raw material in Step 3. 35 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 70%. 1 H NMR (400MHz, DMSO-d6) δ10.05(s,1H),8.07(d,J=5.2Hz,1H),7.44(t,J=7.9Hz,1H),7.23–7.1 6(m,2H),7.05(dd,J=8.6,2.6Hz,1H),6.97(d,J=5.2Hz,1H),4.94(d,J=6.0Hz,1H),4.59–4.5 0(m,1H),4.07(p,J=7.7Hz,1H),3.83(s,3H),2.72(dt,J=15.9,4.6Hz,1H),2.64–2.57(m,1H) ,2.12–1.91(m,3H),1.88–1.70(m,5H),1.59–1.44(m,1H),1.25–1.16(m,1H).LC-MS(ESI):m / z 424.1[M+H] + .

[0354] Example 90: Compound I-90: Preparation of 2-((3-cyclobutyloxy-4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0355] Referring to the synthetic route of Compound I-15 in Example 15, 4-trifluoromethoxyphenylboronic acid was used as the raw material in Step 3. 4 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 80%. 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.10(d,J=5.2Hz,1H),7.77(d,J=8.7Hz,2 H),7.53(d,J=8.2Hz,2H),6.99(d,J=5.2Hz,1H),4.92(d,J=6.1Hz,1H),4.57–4. 50(m,1H),4.13–3.98(m,1H),2.79–2.66(m,1H),2.65–2.56(m,1H),2.06–1.91( m,3H),1.86–1.71(m,5H),1.56–1.44(m,1H),1.23–1.17(m,1H).LC-MS(ESI):m / z 478.0[M+H] + .

[0356] Example 91: Compound I-91: Preparation of 2-((3-cyclobutyloxy-4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0357] Referring to the synthetic route of Compound I-15 in Example 15, 3-trifluoromethoxyphenylboronic acid was used as the raw material in Step 3. Silica gel column chromatography and reverse phase preparative system were used to obtain 23 mg of a white solid with a yield of 46%. 1 H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.11(d,J=5.2Hz,1H),7.72–7.62(m,3H ),7.55–7.45(m,1H),7.01(d,J=5.2Hz,1H),4.97–4.91(m,1H),4.54(d,J=5.5H z,1H),4.16–4.03(m,1H),2.77–2.68(m,1H),2.64–2.56(m,1H),2.03–1.93(m, 4H),1.86–1.76(m,5H),1.51–1.43(m,1H),1.24–1.13(m,1H).LC-MS(ESI):m / z 478.0[M+H] +.

[0358] Example 92: Compound I-92: Preparation of 2-((3'-cyclobutyloxy-6-methoxy-[3,4'-bipyridyl]-2'-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0359] Referring to the synthetic route of Compound I-15 in Example 15, 2-methoxy-5-pyridineboronic acid was used as the raw material in Step 3. Silica gel column chromatography and reverse phase preparative system were used to obtain 20 mg of a white solid with a yield of 40.1%. 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),8.47(d,J=2.5Hz,1H),8.15(d,J=5.2Hz,1H),8. 01(dd,J=8.6,2.5Hz,1H),7.13(d,J=5.2Hz,1H),7.00(d,J=8.7Hz,1H),4.68–4.54(m, 1H),4.13(d,J=7.6Hz,2H),3.95(s,3H),2.78–2.66(m,1H),2.66–2.56(m,1H),2.10–1 .96(m,3H),1.94–1.71(m,5H),1.59–1.44(m,1H),1.39–1.26(m,1H).LC-MS(ESI):m / z 425.1[M+H] + .

[0360] Example 93: Preparation of Compound I-93: 2-((3-cyclobutyloxy-2'-methoxy-[4,4'-bipyridyl]-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0361] Referring to the synthetic route of Compound I-15 in Example 15, 2-methoxypyridine-4-boronic acid was used as the raw material in Step 3. Silica gel column chromatography and reverse phase preparative system were used to obtain 22 mg of a white solid with a yield of 44.1%. 1H NMR (400MHz, DMSO-d6) δ10.22(s,1H),8.30(d,J=5.3Hz,1H),8.11(d,J=5.2Hz,1H),7.23 (dd,J=5.3,1.4Hz,1H),7.04(s,1H),6.99(d,J=5.2Hz,1H),4.93(d,J=6.0Hz,1H),4.60– 4.51(m,1H),4.19–4.06(m,1H),3.93(s,3H),2.80–2.66(m,1H),2.63–2.56(m,1H),2.10 –1.93(m,3H),1.92–1.69(m,5H),1.58–1.43(m,1H),1.23–1.13(m,1H).LC-MS(ESI):m / z 425.1[M+H] + .

[0362] Example 94: Compound I-94: Preparation of 4-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)benzamide

[0363] Referring to the synthetic route of Compound I-15 in Example 15, 4-carbamoylphenylboronic acid was used as the raw material in Step 3. 12 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 24%. 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),8.11(t,J=4.2Hz,2H),8.02(d,J=8.1Hz,2H),7.7 1(d,J=8.1Hz,2H),7.49(s,1H),6.99(d,J=5.1Hz,1H),4.99–4.90(m,1H),4.55(d,J=4. 6Hz,1H),4.06(t,J=7.6Hz,1H),2.72(dt,J=16.4,4.5Hz,1H),2.63–2.57(m,1H),2.08– 1.93(m,3H),1.87–1.72(m,5H),1.55–1.43(m,1H),1.22–1.12(m,1H).LC-MS(ESI):m / z 437.1[M+H] + .

[0364] Example 95: Compound I-95: Preparation of 4-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)-N-ethylbenzamide

[0365] Referring to the synthetic route of Compound I-15 in Example 15, 4-(N-ethylcarbamoyl)phenylboronic acid was used as the starting material in Step 3. 11 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 22%. 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.61(t,J=5.6Hz,1H),8.14(d,J=5.2Hz,1H),7.99(d,J=8 .3Hz,2H),7.73(d,J=8.2Hz,2H),7.07(d,J=5.1Hz,1H),5.35(d,J=4.7Hz,1H),4.58(t,J=4.3Hz ,1H),4.09(d,J=7.8Hz,1H),3.44–3.26(m,2H),2.76–2.69(m,1H),2.66–2.59(m,1H),2.07–1.9 2(m,3H),1.90–1.70(m,5H),1.55–1.43(m,1H),1.23–1.12(m,4H).LC-MS(ESI):m / z465.1[M+H] + .

[0366] Example 96: Compound I-96: Preparation of 4-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)-N-cyclopropylbenzamide

[0367] Referring to the synthetic route of Compound I-15 in Example 15, 4-(N-cyclopropylcarbamoyl)phenylboronic acid pinacol ester was used as the raw material in Step 3. 31 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 62%. 1H NMR (400MHz, DMSO-d6) δ10.14(s,1H),8.58(d,J=4.3Hz,1H),8.10(d,J=5.2Hz,1H),7.96(d,J=8.3Hz ,2H),7.71(d,J=8.4Hz,2H),6.98(d,J=5.2Hz,1H),4.93(d,J=6.1Hz,1H),4.59–4.51(m,1H),4.11–4 .00(m,1H),2.94–2.84(m,1H),2.78–2.64(m,1H),2.64–2.52(m,1H),2.04–1.97(m,3H),1.88–1.70( m,5H),1.52–1.45(m,1H),1.23–1.12(m,1H),0.77–0.69(m,2H),0.66–0.58(m,2H).LC-MS(ESI):m / z 477.1[M+H] + .

[0368] Example 97: Compound I-97: Preparation of N-(4-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)phenyl)propanamide

[0369] Referring to the synthetic route of Compound I-15 in Example 15, 4-propionylaminophenylboronic acid pinacol ester was used as the raw material in Step 3. 44 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 89%. 1 H NMR (400MHz, DMSO-d6) δ10.27–9.78(m,2H),8.05(d,J=5.2Hz,1H),7.75(d,J=8.7Hz,2H),7.5 9(d,J=8.7Hz,2H),6.94(d,J=5.2Hz,1H),4.92(d,J=5.9Hz,1H),4.59–4.48(m,1H),4.08(p,J= 7.5Hz,1H),2.77–2.68(m,1H),2.62–2.55(m,1H),2.38(q,J=7.5Hz,2H),2.10–1.93(m,3H),1. 87–1.71(m,5H),1.57–1.45(m,1H),1.22–1.16(m,1H),1.12(t,J=7.5Hz,3H).LC-MS(ESI):m / z 465.1[M+H] + .

[0370] Example 98: Preparation of Compound I-98: N-(3-cyclobutyloxy-4-phenylpyridin-2-yl)-4-methoxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0371] Referring to the synthetic route of Compound I-15 in Example 15, 4-cyclopentanecarboxamidophenylboronic acid pinacol ester was used as the raw material in Step 3. Silica gel column chromatography and reverse phase preparative system were used to obtain 28 mg of a white solid with a yield of 68%. 1 H NMR (400MHz, DMSO-d6) δ10.07(s,1H),9.99(s,1H),8.03(d,J=5.2Hz,1H),7.74(d,J=8.4Hz,2H),7.57( d,J=8.4Hz,2H),6.92(d,J=5.2Hz,1H),4.91(d,J=6.0Hz,1H),4.52(q,J=4.3Hz,1H),4.12–4.02(m,1H), 2.86–2.76(m,1H),2.73–2.64(m,1H),2.60–2.53(m,1H),2.06–1.96(m,2H),1.96–1.84(m,3H),1.83–1 .77(m,4H),1.77–1.64(m,5H),1.60–1.52(m,2H),1.51–1.42m,1H),1.22–1.13(m,1H).LC-MS(ESI):m / z 505.3[M+H] + .

[0372] Example 99: Compound I-99: Preparation of 1-(4-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)phenyl)-3-ethylurea

[0373] Referring to the synthetic route of Compound I-15 in Example 15, 4-(3-ethylureido)phenylboronic acid pinacol ester was used as the raw material in Step 3. 49 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 98%. 1H NMR (400MHz, DMSO-d6) δ9.95 (s, 1H), 8.65 (s, 1H), 8.03 (d, J = 5.2Hz, 1H), 7.53 (s, 4H), 6.93 (d ,J=5.2Hz,1H),6.20(t,J=5.6Hz,1H),4.91(d,J=6.0Hz,1H),4.61–4.50(m,1H),4.18–3.96(m, 1H),3.21–3.09(m,2H),2.72(dt,J=16.6,5.0Hz,1H),2.63–2.55(m,1H),2.13–1.93(m,3H),1. 93–1.70(m,5H),1.57–1.46(m,1H),1.28–1.17(m,1H),1.08(t,J=7.2Hz,3H).LC-MS(ESI):m / z 480.1[M+H] + .

[0374] Example 100: Compound I-100: Preparation of methyl 2-(4-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)phenyl)acetate

[0375] Referring to the synthetic route of Compound I-15 in Example 15, methyl 4-boronate phenylacetate was used as the raw material in Step 3. 15 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 30%. 1 H NMR (400MHz, DMSO-d6) δ10.06(s,1H),8.08(d,J=5.2Hz,1H),7.59(d,J=8.2Hz,2H),7.4 2(d,J=8.0Hz,2H),6.97(d,J=5.2Hz,1H),4.93(s,1H),4.60–4.51(m,1H),4.06(p,J=7.5 Hz,1H),3.79(s,2H),3.66(s,3H),2.72(dt,J=16.2,4.8Hz,1H),2.63–2.54(m,1H),2.10 –1.89(m,3H),1.91–1.70(m,5H),1.61–1.44(m,1H),1.28–1.18(m,1H).LC-MS(ESI):m / z 466.0[M+H] + .

[0376] Example 101: Compound I-101: Preparation of 2-(4-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)phenyl)acetic acid

[0377] Step 1-7: Synthesis of methyl 2-(4-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)phenyl)acetate

[0378] Referring to the synthetic route of compound I-100 in Example 100, 100 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 37%.

[0379] Step 8: Synthesis of 2-(4-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)phenyl)acetic acid

[0380] According to the fifth step of compound I-73 of Example 73, 78 mg of white powder solid was obtained by reverse phase preparative purification with a yield of 91%. 1 H NMR (400MHz, DMSO-d6) δ12.39(s,1H),10.03(s,1H),8.07(d,J=5.1Hz,1H),7.59(d,J=8 .2Hz,2H),7.41(d,J=8.2Hz,2H),6.96(d,J=5.2Hz,1H),4.92(d,J=6.0Hz,1H),4.58–4.5 1(m,1H),4.07(p,J=7.5Hz,1H),3.68(s,2H),2.77–2.67(m,1H),2.64–2.55(m,1H),2.12 –1.90(m,3H),1.90–1.68(m,5H),1.56–1.44(m,1H),1.22–1.13(m,1H).LC-MS(ESI):m / z 452.0[M+H] + .

[0381] Example 102: Compound I-102: Preparation of 2-(4-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)phenyl)acetamide

[0382] Step 1-8: Synthesis of 2-(4-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)phenyl)acetic acid

[0383] According to the synthetic route of compound I-101 in Example 101, 150 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 30%.

[0384] Step 9: Synthesis of 2-(4-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)phenyl)acetamide

[0385] 2-(4-(3-cyclobutoxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)phenyl)acetic acid (50 mg, 0.11 mmol) was dissolved in 8 mL of dichloromethane. HATU (51 mg, 0.13 mmol) was added with stirring, and the mixture was stirred at room temperature for 20 min. A solution of ammonia in dioxane (2.77 mL, 0.2 M / L) was then slowly added dropwise. After completion of the reaction, as monitored by TLC, the solvent was evaporated, and the product was purified by silica gel column chromatography and reverse phase preparative chromatography to obtain 12 mg of a white solid in a 24% yield. 1 H NMR(400MHz, DMSO-d6)δ10.72(s,1H),8.15(d,J=5.2Hz,1H),7.66–7.53(m,3H),7.4 3(d,J=8.2Hz,2H),7.11(d,J=5.2Hz,1H),6.96(s,1H),4.90(s,1H),4.66–4.60(m,1H ),4.11(p,J=7.5Hz,1H),3.48(s,2H),2.81–2.70(m,1H),2.69–2.57(m,1H),2.13–1. 90(m,4H),1.89–1.70(m,4H),1.60–1.46(m,1H),1.31–1.17(m,1H).LC-MS(ESI):m / z 451.1[M+H] + .

[0386] Example 103: Compound I-103: Preparation of 2-(4-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)phenyl)-N-cyclopropylacetamide

[0387] Referring to the synthetic route of Compound I-102 in Example 102, cyclopropylamine was used as the raw material in Step 8. 10 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 97%. 1H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.21(d,J=4.3Hz,1H),8.11(d,J=5.2Hz,1H),7.58(d,J=7.9Hz ,2H),7.39(d,J=7.9Hz,2H),7.04(d,J=5.2Hz,1H),4.73–4.45(m,1H),4.17–4.02(m,1H),3.89–3.74( m,1H),3.45(s,2H),2.79–2.68(m,1H),2.67–2.59(m,2H),2.12–1.93(m,3H),1.93–1.69(m,5H),1.5 8–1.44(m,1H),1.24–1.15(m,1H),0.67–0.60(m,2H),0.47–0.35(m,2H).LC-MS(ESI):m / z491.1[M+H] + .

[0388] Example 104: Preparation of Compound I-104: 2-(4-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)phenyl)-N-(cyclopropylmethyl)acetamide

[0389] Referring to the synthetic route of Compound I-102 in Example 102, cyclopropylmethylamine was used as the starting material in Step 8. 8 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 96%. 1 H NMR (400MHz, DMSO-d6) δ10.03(s,1H),8.20(t,J=5.6Hz,1H),8.07(d,J=5.2Hz,1H),7.57(d,J=8.2Hz,2H),7 .41(d,J=8.2Hz,2H),6.95(d,J=5.2Hz,1H),4.93(d,J=6.0Hz,1H),4.57–4.51(m,1H),4.12–4.01(m,1H),3.5 0(s,2H),3.03–2.94(m,2H),2.78–2.68(m,1H),2.63–2.57(m,1H),2.07–1.95(m,3H),1.86–1.72(m,5H),1.5 2–1.45(m,1H),1.22–1.17(m,1H),0.94–0.86(m,1H),0.44–0.38(m,2H),0.20–0.14(m,2H).LC-MS(ESI):m / z 505.2[M+H] + .

[0390] Example 105: Compound I-105: Preparation of 3-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)benzamide

[0391] Referring to the synthetic route of Compound I-15 in Example 15, 3-carbamoylphenylboronic acid was used as the starting material in Step 3. 6 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 45%. 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),8.26–8.05(m,3H),7.96(d,J=7.8Hz,1H),7.79(d ,J=7.7Hz,1H),7.61(t,J=7.7Hz,1H),7.49(s,1H),7.04(d,J=5.2Hz,1H),4.95(s,1H),4 .56(d,J=4.1Hz,1H),4.05(p,J=7.6Hz,1H),2.77–2.67(m,1H),2.64–2.57(m,1H),2.06 –1.92(m,3H),1.88–1.67(m,5H),1.55–1.43(m,1H),1.20–1.10(m,1H).LC-MS(ESI):m / z 437.1[M+H] + .

[0392] Example 106: Compound I-106: Preparation of 3-(3-cyclobutyloxy-2-((4-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)pyridin-4-yl)-N-ethylbenzamide

[0393] Referring to the synthetic route of Compound I-15 in Example 15, 3-(N-ethylcarbamoyl)phenylboronic acid was used as the starting material in Step 3. 7 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 97%. 1H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.61(t,J=5.5Hz,1H),8.14–8.07(m,2H),7.93(d,J=7.8H z,1H),7.78(d,J=8.0Hz,1H),7.61(t,J=7.7Hz,1H),7.03(d,J=5.1Hz,1H),4.93(d,J=6.0Hz,1H ),4.60–4.49(m,1H),4.10–3.98(m,1H),3.36–3.17(m,2H),2.74–2.68(m,1H),2.60–2.57(m,1H ),2.07–1.91(m,3H),1.88–1.70(m,5H),1.53–1.42(m,1H),1.23–1.12(m,4H).LC-MS(ESI):m / z 465.1[M+H] + .

[0394] Example 107: Compound I-107: Preparation of 2-((3-cyclobutyloxy-4-(3-cyanophenyl)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0395] Referring to the synthetic route of Compound I-15 in Example 15, 3-cyanophenylboronic acid was used as the raw material in Step 3. 35 mg of a white solid was obtained by silica gel column chromatography and reverse phase preparative system with a yield of 39.8%. 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),8.10(d,J=5.1Hz,1H),8.07(s,1H),7.95(t,J=8.0H z,2H),7.73(t,J=7.8Hz,1H),7.01(d,J=5.2Hz,1H),4.91(d,J=6.0Hz,1H),4.56–4.49(m, 1H),4.13–3.99(m,1H),2.74–2.66(m,1H),2.60-2.54(m,1H),2.01–1.89(m,3H),1.86–1. 78(m,4H),1.77–1.71(m,1H),1.47(d,J=10.2Hz,1H),1.22–1.12(m,1H).LC-MS(ESI):m / z 419.1[M+H] + .

[0396] Example 108: Compound I-108: Preparation of 2-((3-cyclobutyloxy-4-(3-fluorophenyl)pyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0397] Referring to the synthetic route of Compound I-15 in Example 15, 3-fluorophenylboronic acid was used as the raw material in Step 3. Silica gel column chromatography and reverse phase preparative system were used to obtain 28 mg of a white solid with a yield of 28.9%. 1 H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.07(d,J=5.2Hz,1H),7.59–7.51(m,1H),7.49–7 .41(m,2H),7.35–7.26(m,1H),6.97(d,J=5.2Hz,1H),4.91(d,J=6.0Hz,1H),4.55–4.47( m,1H),4.13–4.00(m,1H),2.74–2.65(m,1H),2.60–2.54(m,1H),2.03-1.90(m,3H),1.86 –1.77(m,4H),1.76–1.69(m,1H),1.52–1.43(m,1H),1.37-1.25(m,1H).LC-MS(ESI):m / z 412.1[M+H] + .

[0398] Example 109: Preparation of Compound I-109: 2-((3-cyclobutyloxy-4-phenylpyridin-2-yl)amino)-4-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0399] To a solution of compound I-15 (100 mg, 0.255 mmol) in tetrahydrofuran (10 mL) was added a 3M solution of methylmagnesium bromide in tetrahydrofuran (0.426 mL, 1.28 mmol) under ice. After complete addition, the mixture was stirred on ice for 15 minutes, and then allowed to react at room temperature for 2 hours. After completion of the reaction as monitored by TLC, saturated ammonium chloride solution was added to quench the reaction. The organic phase was diluted with dichloromethane and washed three times with saturated brine. After concentration under reduced pressure, the product was purified by column chromatography (PE:EA = 2:1–1:1) to afford 73 mg of a white solid in a 70.1% yield. 1H NMR (400MHz, DMSO-d6) δ10.04(s,1H),8.05(d,J=5.2Hz,1H),7.61(d,J=5.6Hz,2H),7.5 1(t,J=7.2Hz,2H),7.46(d,J=7.2Hz,1H),6.93(d,J=5.2Hz,1H),4.65(s,1H),4.10–3.94 (m,1H),2.74–2.64(m,1H),2.63–2.52(m,1H),2.02–1.93(m,3H),1.84–1.72(m,4H),1. 71–1.66(m,1H),1.46(s,3H),1.34(d,J=6.4Hz,1H),1.19–1.15(m,1H).LC-MS(ESI):m / z 408.1[M+H] + .

[0400] Example 110: Compound I-110: Preparation of N-(3-cyclobutyloxy-4-phenylpyridin-2-yl)-6,7-dihydro-5H-spiro[benzo[d]thiazole-4,2'-[1,3]dioxanoxy]-2-amine

[0401] To a solution of compound I-42 (100 mg, 0.255 mmol) in toluene (10 mL) was added ethylene glycol (71.4 μL, 1.28 mmol) and p-toluenesulfonic acid (4.4 mg, 0.026 mmol), and the mixture was stirred at 150°C overnight. After completion of the reaction, the pH of the solution was adjusted to 7-8 with dilute hydrochloric acid, and the organic phase was diluted with dichloromethane and washed three times with saturated brine. After concentration under reduced pressure, the product was purified by column chromatography (PE:EA = 2:1–1:1) to afford 38 mg of a white solid in a 34.2% yield. 1 H NMR (400MHz, DMSO-d6) δ10.80 (s, 1H), 8.10 (d, J = 5.2Hz, 1H), 7.65–7.58 (m, 2H), 7.5 4–7.49(m,2H),7.49–7.43(m,1H),7.01(d,J=5.2Hz,1H),4.03(p,J=7.5Hz,1H),3.02 (t,J=6.0Hz,2H),2.55–2.51(m,4H),2.49–2.48(m,2H),2.19–2.09(m,2H),2.07–1. 95(m,2H),1.82–1.70(m,2H),1.51–1.39(m,1H),1.21–1.10(m,1H).LC-MS(ESI):m / z 436.1[M+H] + .

[0402] Example 111: Preparation of Compound I-111: 2-((3-cyclobutyloxy-4-phenylpyridin-2-yl)amino)-6,7-dihydrobenzo[d]thiazol-4(5H)-one oxime

[0403] To a solution of compound I-42 (100 mg, 0.255 mmol) in ethanol (10 mL) were added hydroxylamine hydrochloride (71 mg, 1.02 mmol) and sodium acetate (63 mg, 0.255 mmol), and the mixture was stirred at 80°C overnight. After completion of the reaction, monitored by TLC, the ethanol was removed by vacuum drying. The remaining reaction solution was extracted three times with ethyl acetate, and the organic phase was washed three times with saturated brine. After concentration under reduced pressure, the product was purified by column chromatography (DCM:MeOH = 200:1–100:1) to afford 86 mg of a white solid in an 82.8% yield. 1 H NMR (400MHz, DMSO-d6) δ10.71 (s, 1H), 10.30 (s, 1H), 8.07 (d, J = 5.1Hz, 1H), 7. 63–7.59(m,2H),7.52–7.45(m,3H),6.97(d,J=5.2Hz,1H),4.08–3.99(m,1H),2 .78(t,J=6.0Hz,2H),2.65(t,J=6.0Hz,2H),2.03–1.96(m,2H),1.90–1.84(m, 2H),1.81–1.74(m,2H),1.49–1.41(m,1H),1.19–1.13(m,1H).LC-MS(ESI):m / z 407.2[M+H] + .

[0404] Example 112: Compound I-112: Preparation of N2-(3-cyclobutyloxy-4-phenylpyridin-2-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,4-diamine

[0405] To a solution of compound I-42 (120 mg, 0.307 mmol) in methanol (12 mL) was added ammonium acetate (473 mg, 6.13 mmol). Sodium cyanoborohydride (193 mg, 3.07 mmol) was added portionwise under ice-cooling. The temperature was raised to 80°C and stirred for 2 h. Following completion of the reaction, monitored by TLC, the methanol was removed from the air under reduced pressure and the remaining reaction solution was extracted three times with dichloromethane. The organic phase was washed three times with saturated brine. After concentration under reduced pressure, the product was purified by column chromatography (DCM:MeOH = 200:1–100:1) to afford 68 mg of a white solid in a 56.5% yield. 1H NMR (400MHz, DMSO-d6) δ8.09(d,J=5.2Hz,1H),7.61(d,J=7.2Hz,2H),7.55–7.44(m,3H),6.98(d,J=5.2Hz,1H),4.10–3.99(m,2H),2.68(q,J=5 .6Hz,2H),2.10–2.01(m,1H),2.00–1.90(m,3H),1.86–1.75(m,3H),1.74–1.68(m,1H),1.53–1.44(m,1H),1.22–1.12(m,1H).LC-MS(ESI):m / z 393.1[M+H] + .

[0406] Example 113: Preparation of Compound I-113: (2-((3-cyclobutyloxy-4-phenylpyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methanol

[0407] Step 1: Preparation of (2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methanol

[0408] Ethyl 2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-4-carboxylate (300 mg, 1.33 mmol) was dissolved in tetrahydrofuran (15 mL). Lithium aluminum hydride (2.5 M, 1.59 mL, 3.98 mmol) was slowly added under nitrogen in an ice bath. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, as monitored by TLC, the reaction was quenched with sodium hydroxide solution. The organic phase was diluted with ethyl acetate and washed three times with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 240 mg of a yellow oil in a 98.3% yield. LC-MS (ESI): m / z 185.1 [M+H]. + .

[0409] Step 2: Preparation of (2-((3-cyclobutyloxy-4-phenylpyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methanol

[0410] Referring to the synthetic route of Compound I-15 in Example 15, (2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methanol was used as the starting material in Step 6. Silica gel column chromatography and reverse phase preparative chromatography gave 36 mg of a white solid with a yield of 36.9%. 1H NMR (400MHz, DMSO-d6)10.02(s,1H),8.05(d,J=5.2Hz,1H),7.64–7.57(m,2H),7.50(t,J=8.3 ,6.4Hz,2H),7.48–7.44(m,1H),6.93(d,J=5.2Hz,1H),4.70–4.64(m,1H),4.09–3.98(m,1H),3 .85–3.79(m,1H),3.46–3.38(m,1H),2.78–2.70(m,1H),2.65–2.60(m,2H),2.04–1.94(m,2H) ,1.88–1.81(m,2H),1.79–1.68(m,4H),1.50–1.43(m,1H),1.21–1.12(m,1H).LC-MS(ESI):m / z 408.1[M+H] + .

[0411] Comparative Example 1: Preparation of Compound II-1: 2-((2-cyclobutyloxy-3-(piperidin-1-methyl)phenyl)amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0412] Step 1: Preparation of 3-bromo-2-cyclobutoxybenzaldehyde

[0413] Commercially available 3-bromo-2-hydroxybenzaldehyde (3.00 g, 14.9 mmol) was dissolved in DMF (30 mL), followed by the addition of solid potassium carbonate (6.19 g, 44.0 mmol). The mixture was stirred at room temperature for 1 h. Cyclobutyl bromide (3.02 g, 22.4 mmol) was slowly added dropwise to the mixture, and the temperature was raised to 90°C for 8 h. The reaction solution was cooled to room temperature and extracted three times with ethyl acetate. The organic phases were combined, washed three times with water, once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, column chromatography (PE:EA = 50:1) afforded 3.42 g of the product as a colorless oil with a yield of 89.8%.

[0414] Step 2: 1-(3-Bromo-2-cyclobutyloxybenzyl)piperidine

[0415] 3-Bromo-2-cyclobutoxybenzaldehyde (1.00 g, 3.92 mmol) was added to dichloromethane (25 mL), followed by the dropwise addition of piperidine (367 mg, 4.31 mmol) and glacial acetic acid (0.22 mL, 4.3 mmol). The mixture was stirred at room temperature for 4 h. The starting material disappeared after TLC monitoring. Sodium triacetoxyborohydride (1.25 g, 5.88 mmol) was added to the reaction system and stirring continued at room temperature. After completion of the reaction, a small amount of water was added dropwise to quench the reaction. The mixture was extracted three times with dichloromethane. The organic phases were combined, washed three times with water, once with saturated sodium chloride, and dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure and purified by column chromatography (PE:EA = 50:1) to afford 0.42 g of the product as a colorless oil in a 33.0% yield.

[0416] Step 3-Step 4: Preparation of 2-((2-cyclobutoxy-3-(piperidin-1-methyl)phenyl)amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0417] The subsequent steps were carried out according to Steps 3 and 4 in the synthetic route of Compound I-22 of Example 22. Silica gel column chromatography and reverse phase preparative chromatography gave 16 mg of a white solid with a yield of 45.5% and mp of 117.8–119.0°C. LC-MS (ESI): m / z 414.2 [M+H] + .

[0418] Comparative Example 2: Preparation of Compound II-2: 2-((2-cyclobutoxy-3-(morpholinomethyl)phenyl)amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0419] Referring to the synthetic route of Compound II-1 in Comparative Example 1, morpholine was used as the raw material in Step 2. Silica gel column chromatography and reverse phase preparative chromatography gave 40 mg of a white solid with a yield of 40.6% and an mp of 126.3–127.9°C. 1H NMR (400MHz, DMSO-d6) δ9.09(s,1H),8.14(dd,J=7.8,1.9Hz,1H),7.04(t,J=7.8Hz,1H),6.99(dd,J=7.7,1.9H z,1H),4.93(d,J=5.5Hz,1H),4.46(q,J=4.4Hz,1H),4.37(p,J=7.6Hz,1H),3.58(t,J=4.5Hz,4H),3.47(s,2H) ,2.62(dt,J=16.1,4.7Hz,1H),2.49–2.45(m,1H),2.40–2.38(m,4H),2.29–2.21(m,2H),2.17–2.10(m,2H),1. 97–1.86(m,1H),1.79–1.76(m,2H),1.73–1.68(m,1H),1.65–1.58(m,1H),1.43–1.32(m,1H).LC-MS(ESI):m / z 416.3[M+H] + .

[0420] Comparative Example 3: Preparation of Compound II-3: 2-((3-cyclobutyloxypyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0421] Step 1: Preparation of 2-bromo-3-cyclobutoxypyridine

[0422] Referring to step 1 of the synthetic route of compound I-1 in Example 1, 2-bromopyridin-3-ol (500 mg, 2.87 mmol) and cyclobutanol (775 mg, 5.75 mmol) were used as raw materials to obtain 0.625 g of a colorless oil with a yield of 95.4%.

[0423] Step 2-Step 3: Preparation of 2-((3-cyclobutyloxypyridin-2-yl)amino)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol

[0424] The subsequent steps were carried out according to Steps 6 and 7 in the synthesis route of Compound I-15 of Example 15. Silica gel column chromatography and reverse phase preparative chromatography gave 90 mg of a white solid with a yield of 59.6% and mp of 195.2-197.1°C. 1H NMR (400MHz, DMSO-d6) δ9.82 (s, 1H), 7.83 (dd, J=5.0, 1.4Hz, 1H), 7.13 (dd, J=8.0, 1.4Hz, 1H),6.86(dd,J=7.9,5.0Hz,1H),4.89(s,1H),4.81(p,J=7.1Hz,1H),4.52(t,J=4.0Hz,1H) ,2.70(dt,J=16.2,4.8Hz,1H),2.60–2.54(m,1H),2.48–2.40(m,2H),2.26–2.16(m,2H),1. 99–1.90(m,1H),1.84–1.79(m,3H),1.76–1.72(m,1H),1.70–1.62(m,1H).LC-MS(ESI):m / z 318.3[M+H] + .

[0425] Example 114: In vitro assay for the inhibitory activity of compounds on DHODH

[0426] The inhibitory activity of compounds I-1 to I-113 of the present invention and comparative compounds II-1 to II-3 on DHODH was determined by the DCIP method. The inhibitory activity was measured using the half-maximal inhibitory concentration (IC 50 ) to indicate.

[0427] Experimental method: DCIP method

[0428] DCIP, or sodium 2,6-dichloroindophenol, has a specific absorbance at 600nm. When the substrate dihydroorotic acid (DHO) is dehydrogenated by hDHODH, CoQ0 is reduced while DCIP is oxidized, replacing the respiratory chain as the final electron acceptor. This reduces the amount of DCIP in the reaction system, resulting in a decrease in the absorbance at 600nm. Therefore, the rate of change in absorbance can reflect the activity of the enzyme and the inhibitory activity of the compound. A greater rate of change indicates a more intense redox reaction, stronger enzyme activity, and relatively weaker inhibitory activity of the compound.

[0429] The purified HsDHODH protein was diluted to 10nM with an activity test solution, which was 50mM HEPES pH 8.0, 150mM KCl, and 0.1% Triton X-100. CoQ0 and DCIP were added to a final concentration of 100μM and 120μM, respectively. After mixing, the mixture was added to a 96-well plate with a pipette. After incubation at room temperature for 5 minutes, the substrate DHO was added to initiate the reaction. The final concentration of DHO was 500μM. The absorbance at 600nm was detected using a BioTek microplate reader, and the reading was performed every 30 seconds for 6 minutes. The initial velocity of the enzymatic reaction, V0, was calculated. For the activity test of the inhibitor, different concentrations of inhibitors were added to the above reaction system, and the initial velocity of the enzymatic reaction, V, was calculated. i The inhibition rate of the compound is given by the formula (1-V i / V0)×100%. 50 In the calculation of the inhibition rate, at least 8 concentrations were tested, IC 50 The values ​​were calculated using Origin 8.0. A771726 was used as a positive control during the experiment, and at least three parallels were set up for each experiment. The results showed that the compounds of the present invention had good inhibitory activity against DHODH (as shown in Table 1).

[0430] Table 1. DHODH inhibitory activity test results of the compounds of Examples and Comparative Examples

[0431] IC 50 Values ​​are the average of at least two independent experiments

[0432] IC 50 Value: ***** indicates IC 50 ≤50nM; **** indicates 50nM <IC 50 ≤150nM; *** indicates 150nM <IC 50 ≤500nM; ** indicates 500nM <IC 50 ≤1000nM; * indicates IC 50 >1000nM.

[0433] From the above activity test results, it can be seen that the compounds of the present application have excellent DHODH inhibitory activity. Therefore, the compounds of the present application, as new DHODH inhibitors, can be used as anti-inflammatory agents, autoimmune disease therapeutic agents, immunosuppressants, anti-tumor drugs, viral infection therapeutic agents, etc.

[0434] As shown in Table 1, a comparison of the example compounds with comparative examples II-1 to II-3 reveals that substitution of -A-R4 in the general structure of the present invention significantly affects DHODH inhibitory activity. When the 3-position of the intermediate benzene ring or the 4-position of the pyridine ring (the position where the A fragment is attached) is unsubstituted (as in comparative example II-3), DHODH inhibitory activity is lost. When the 3-position of the intermediate benzene ring or the 4-position of the pyridine ring is directly connected to a rigid or cyclic structure (-A fragment), such as an alkynyl, alkenyl, (hetero)cycloalkyl, (hetero)cycloalkenyl, aromatic ring, or heteroaromatic ring, DHODH inhibitory activity is significantly enhanced. However, if the 3-position of the intermediate benzene ring or the 4-position of the pyridine ring (the position where the A fragment is attached) is not directly connected to a rigid or cyclic structure, but is connected via a methylene group (as in comparative examples II-1 and II-2, where A is a piperidine methylene group or a morpholinium methylene group), activity is significantly reduced.

[0435] Comparing compounds I-1 to I-14, for the intermediate benzene ring fragment connected to thiazolylamine, preferably when R3 on the oxygen atom is a larger alkyl group or cycloalkyl group, the DHODH inhibitory activity of the compound is particularly excellent, for example, R3 is C 3-8 Cycloalkyl substituted C 1-3 Alkyl, halogen-substituted C 3-8 Cycloalkyl substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, halogen-substituted C 3-8 Cycloalkyl.

[0436] Example 115: Pharmacokinetic evaluation in mice

[0437] The compound was administered via intravenous injection or oral gavage at a dose of 1 mg / kg for intravenous administration and 5 mg / kg for oral gavage (5% DMSO / 10% Solutol / 85% Saline). Six male Balb / c mice were divided into two groups of three mice each. Blood was collected from the eye sockets of the mice at each time point after administration, and the blood was centrifuged to obtain plasma. The plasma samples were precipitated with acetonitrile and analyzed for compound concentration using LC-MS / MS. Pharmacokinetic parameters were calculated from the plasma concentration-time curves using non-compartmental analysis.

[0438] Table 2. Pharmacokinetic parameters of Example compounds I-15 and I-56 in mice

[0439] The data in the table above show that compounds I-15 and I-56 have good pharmacokinetic properties in mice and good oral bioavailability (I-15: F = 51.8%, po; I-56: F = 59.9%, po).

[0440] Example 116: Inhibitory activity of the example compounds on tumor cells

[0441] Experimental Method: Adherent cells in the logarithmic growth phase (5000 cells / well) were seeded in a 96-well plate and incubated in an incubator for 24 hours (37°C, 5% CO2). A concentration gradient of the test compound was then added. The cells were incubated for a further 72 hours. 20 μL of MTT solution was added to each well, taking care to avoid air bubbles in the wells. The cells were incubated for another 4 hours. The absorbance at 450 nm was measured using a microplate reader, and data were analyzed using GraphPad Prism 6.

[0442] Table 3. Activity of Example Compounds in Inhibiting Human Tumor Cell Proliferation

[0443] “-” means not tested

[0444] IC 50 Value: ***** indicates IC 50 ≤20nM; **** indicates 20nM <IC 50 ≤100nM; *** indicates 100nM <IC 50 ≤500nM; ** indicates 500nM <IC 50 ≤1000nM; * indicates IC 50 >1000nM.

[0445] It can be seen from the data in the above table that the example compounds have excellent inhibitory activity against various solid tumor cells (human colon cancer HCT116-PIK3CA mutant and SW620-PIK3CA wild-type cells, human colon cancer RKO cells and human non-small cell lung cancer A549 cells), especially against HCT116-PIK3CA mutant human colon cancer.

[0446] Example 117: Evaluation of anti-tumor efficacy in mice

[0447] 5×10 6 Human colon adenocarcinoma RKO cells (Cell Bank of the Chinese Academy of Sciences, Shanghai) were inoculated subcutaneously on the left back of 4-6 week-old nude mice (Jicui Yaokang, Jiangsu). The growth of xenografts was observed and recorded after inoculation. When the xenografts grew to an average volume of approximately 150 mm 3At the same time, the tumor-bearing nude mice were randomly divided into two groups (5 mice in each group): a compound I-10 administration group and a vehicle control group. The dissolution scheme of compound I-10 was: 5% sodium carboxymethyl cellulose (Sigma), 20% (2-hydroxypropyl)-β-cyclodextrin (Sigma), and ultrasound. The administration was continued for 4 weeks (dosage: 20 mg / kg / day, administration method: oral). The volume of the xenograft tumor was recorded every four days. After the administration, the nude mice were killed, the xenograft tumor was surgically removed, and the photo was taken and the weight was recorded. The formula for calculating the tumor growth inhibition rate (TGI): TGI = [1-RTV (experimental group) / RTV (control group)] * 100%. TV: tumor volume. TV = (length × width × width) / 2; RTV: relative tumor volume; RTV = V t / V0.

[0448] As shown in Figures 1A-1D, compound I-10 exhibited a significant inhibitory effect on RKO tumors at a dose of 20 mg / kg, with a tumor inhibition rate of 66.9% after four weeks of oral administration (Figures 1A and 1D). Furthermore, tumor volume and weight were significantly reduced compared to the blank control group (Figure 1C). The body weight of mice in the treatment group remained unchanged (Figure 1B), indicating that compound I-10 exhibited no significant toxicity.

[0449] Example 118: Evaluation of drug efficacy in DSS-induced acute colitis in mice

[0450] Acute colitis was induced in male C57BL / 6 mice by administration of 2.5% dextran sulfate sodium (DSS). The mice were randomly divided into five groups (n=5 per group): a control group, a DSS group, a prednisolone-treated group (5 mg / kg), a compound I-15-treated group (30 mg / kg), and a compound I-56-treated group (30 mg / kg). All groups, except the control group, received 2.5% DSS as drinking water for 5 consecutive days; the control group received drinking water as a control. Compounds were dissolved in an aqueous solution containing 0.5% sodium carboxymethylcellulose and administered orally from day 1 to day 12 to the compound I-15 and I-56 treatment groups. The prednisolone-treated group received an oral prednisolone suspension, while the control and DSS groups received a blank formulation by gavage. All mice were sacrificed on day 12, and colon tissue was collected for subsequent experiments. Mouse body weight was assessed daily. At the end of the experiment, the colons were removed and their lengths measured; changes in colon length indirectly reflect the severity of colitis.

[0451] As shown in Figures 2A-2C, compounds I-15 and I-56 can restore the length of the colon to a certain extent at an oral dose of 30 mg / kg, which is comparable to the effect of the positive drug prednisolone, demonstrating an effective anti-colitis effect.

[0452] In summary, the compounds provided by the present invention have been found to effectively inhibit DHODH activity, thereby regulating the level of pyrimidine nucleotides and inhibiting the proliferation of immune-activated lymphocytes and tumor cells, and can be used as drugs for the treatment or prevention of autoimmune diseases and tumors.

[0453] The above specific embodiments further describe the purpose, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above is only a specific embodiment of the present invention and is not limited to the scope of protection of the present invention. Without departing from the purpose of the basic characteristics of the present invention, the present invention can be embodied in various forms. Therefore, the embodiments of the present invention are used for illustration rather than limitation. Since the scope of the present invention is defined by the claims rather than the specification, and all changes that fall within the scope defined by the claims or the equivalent range of the scope defined by the claims should be understood to be included in the claims. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A compound of the following general chemical formula (I) or a pharmaceutically acceptable salt thereof: in, R1 is selected from hydroxy, carboxyl, alkoxy, -C(═O)-NH-O-alkyl, -(C═O)NH2, -(C═O)NH-alkyl, thiol, amino, -NH-alkyl, -NH(C═O)-alkyl, -NH(C═O)NH2, -NH(C═O)NH-alkyl, -CH2OH, -O(C═O)NH-alkyl, -NH(C═O)O-alkyl; R2 is selected from hydrogen, alkoxy or alkyl; or R1 and R2 are combined and form a double bond through =O, =S, =N-CN, =N-OH, =N-O-alkyl, =N-alkyl or =N-aryl; or R1 and R2 are both alkoxy and are linked to each other to form a five- to seven-membered cyclic ketal structure; X is CH or N; R3 is C 1-6 Alkyl, C 3-8 Cycloalkyl, three to eight-membered heterocycloalkyl; wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, three to eight membered heterocycloalkyl having 0-3 substituents selected from the following groups: halogen, hydroxyl, C 1-6 Alkoxy, halogen or hydroxy substituted C 1-6 Alkoxy, C 3-8 Cycloalkyl, halogen or hydroxy substituted C 3-8 Cycloalkyl, three- to eight-membered heterocycloalkyl, three- to eight-membered heterocycloalkyl substituted with halogen or hydroxy; A is alkynyl, alkenyl, C 3-8 Cycloalkyl, three to eight-membered heterocycloalkyl containing 1-2 heteroatoms, C 5-8 Cycloalkenyl, five- to eight-membered heterocycloalkenyl containing one heteroatom, aromatic ring or aromatic heterocycle; n is 0, 1, 2, or 3; R4 is hydrogen, halogen, cyano, hydroxy, amino, alkyl, halogen, hydroxy or amino substituted alkyl, alkoxy, halogen, hydroxy or amino substituted alkoxy, cycloalkyl, halogen, hydroxy or amino substituted cycloalkyl, heterocycloalkyl, halogen, hydroxy or amino substituted heterocycloalkyl, -alkylene-(hetero)cycloalkyl, halogen, hydroxy or amino substituted -alkylene-(hetero)cycloalkyl, -O-R5, -NH-R5, -CONH2, -COOH, -CO-NHOH, -SO2NH2, -CO-R5, -CONH-R5, -COO-R5, -SO2NH-R5, -SO2NHCONH-R5, -SO2- R5, -SO-R5, -NHCO-R5, -NHSO2-R5, -NHCONH-R5, -alkylene-O-R5, -alkylene-NH-R5, -alkylene-CONH2, -alkylene-COOH, -alkylene-CO-R5, -alkylene-CONH-R5, -alkylene-COO-R5, -alkylene-NHCO-R5, -alkylene-NHSO2-R5, -alkylene-NHCONH-R5; or wherein two R4 are connected and form a bridged ring or spiro ring with A; R5 is selected from unsubstituted or halogen-substituted alkyl, cycloalkyl, -alkylene-cycloalkyl, heterocycloalkyl, -alkylene-heterocycloalkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that A-(R4) n for Both U and V are C or one of them is N.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that A-(R4) n for m1 and m2 are independently 0, 1 or 2 and 1≤m1+m2≤4, Y is C or N, and Z is selected from C, O, and N.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that A-(R4) n for 5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that: The compound of the general chemical formula (I) is the compound of the general chemical formula (II): wherein c is 0, 1 or 2; a is 0, 1 or 2; b is 1, 2 or 3; and R6 and R7 are independently hydrogen or halogen.

6. The compound according to claim 1 or 5 or a pharmaceutically acceptable salt thereof, characterized in that A-(R4) n Selected from 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound is selected from the following compounds:

8. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating diseases associated with DHODH.

10. The use according to claim 9, characterized in that The disease is, for example, selected from the group consisting of autoimmune diseases, immune and inflammatory diseases, destructive bone diseases, hematological cancers, malignant tumor diseases, angiogenesis-related diseases, viral diseases and infectious diseases.

Images