Polθ inhibitor and pharmaceutical composition thereof and use

Abstract

The present invention relates to a heterocyclic compound for inhibiting the activity of a DNA polymerase Theta(Polθ), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt of the compound and a use thereof in preparation of a drug for treating or preventing cancer. Specifically, provided are a compound as shown in formula I or a stereoisomer form and pharmaceutically acceptable salt thereof, wherein the definition of each group is as described in the description. The compound has relatively high Polθ inhibitory activity, so that the compound can be used for treating diseases related to overexpression of Polθ.

Description

Polθ inhibitors and pharmaceutical compositions and applications thereof Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a Polθ inhibitor or its stereoisomers, tautomers, and pharmaceutically acceptable salts, as well as to a pharmaceutical composition of the compound and its use in treating cancer. Background Art

[0002] DNA damage repair pathways include base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and double-strand break (DSB) repair. Double-strand DNA damage repair pathways primarily include homologous recombination (HR), nonhomologous end joining (NHEJ), and microhomology-mediated end joining (alt-EJ or MMEJ). Homologous recombination primarily relies on homologous chromosomes to guide the repair of damaged DNA, while nonhomologous end joining directly joins the two broken DNA strands to achieve repair. BRCA1 and BRCA2, key proteins involved in homologous recombination, are important tumor suppressors. Absence of these two proteins significantly reduces the rate of homologous recombination and increases sensitivity to ionizing radiation, ultimately leading to an increased risk of breast and ovarian cancer. Furthermore, the proper functioning of the nonhomologous end joining (NHEJ) repair pathway is crucial; defects in related genes can lead to diseases such as ataxia telangiectasia and Fanconi anemia. MMEJ repair is driven by annealing of microhomology sequences flanking the DNA ends and was initially considered a backup pathway for gene repair. However, as research progressed, it was discovered that MMEJ is not a backup repair mechanism.

[0003] DNA polymerase θ (Polθ or POLQ) is a synthetically lethal target of homologous recombination (HR) defects and plays a crucial role in the DNA damage response (DDR) pathway for double-strand breaks (DSBs). When DNA end resection occurs, in the presence of BRCA2, BRCA2 not only recruits the recombinase RAD51 to the DSB to promote HR but also inhibits repair pathways such as alt-NHEJ. When homologous recombination-mediated repair is impaired (HR deficiency), as in the case of BRCA1 or BRCA2 mutations, Polθ becomes highly expressed and directs DSB repair toward alt-NHEJ, initiating the DNA repair process of microhomology-mediated end joining (MMEJ). In the context of HR deficiency, inhibition of Polθ leads to cell death through the accumulation of toxic RAD51 intermediates and inhibition of the alt-NHEJ repair pathway.

[0004] Pol θ is expressed in only a few tissue types but is highly expressed in many cancer cells. Pol θ can confer resistance to cancer therapies and promote the survival of abnormal cells lacking DNA damage repair pathways. The primary function of DNA polymerase θ (Pol θ) is to act as a reverse transcriptase. In healthy cells, Pol θ acts as an RNA-mediated DNA repair enzyme. In cancer cells, Pol θ is highly expressed and promotes cancer cell growth and drug resistance.

[0005] Researchers from Thomas Jefferson University and the University of Southern California published a research paper titled "Polθ reverse transcribes RNA and promotes RNA-templated DNA repair" in Science Advances, a subsidiary of the top international academic journal Science. The paper revealed the activity of DNA polymerase θ (Polθ) on RNA and how it promotes DNA repair and cancer cell proliferation. This not only challenges the basic law of life science, the "central dogma", but also suggests that Polθ is a promising anti-cancer drug target.

[0006] Documents such as CN114127062A, CN114667167A, WO2020160213, WO2022118210, WO2021123785, and WO2023134708 disclose DNA polymerase Theta (Polθ) inhibitors. Summary of the Invention

[0007] SUMMARY OF THE INVENTION

[0008] The inventors conducted extensive research and discovered that the compound represented by Formula I below has potent Pol θ inhibitory activity, inhibiting the proliferation of DLD1 BRCA2- / - cells and HCT116 BRCA2- / - cells. It exhibits strong activity, good selectivity, and good oral absorption in mice, overcoming the shortcomings of prior Pol θ inhibitors. The heterocyclic compounds provided by the present invention exhibit potent Pol θ inhibitory effects.

[0009] The present invention solves the above technical problems through the following technical solutions.

[0010] In one aspect, the present invention provides a compound represented by formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0011] R1, R2, R3, R4, R5, R6 and R7 are independently selected from H, deuterium, halogen, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy;

[0012] R8 is selected from H, hydroxy, C1-C6 alkoxy, NR a R b ;

[0013] R9 is phenyl, heteroaryl, heterocyclic, -O(CH2) r -cycloalkyl, -O(CH2) r -heterocycloalkyl, -O(CH2) r -heteroaryl, the phenyl, heteroaryl, heterocyclic, -O(CH2) r -cycloalkyl, -O(CH2) r -heterocycloalkyl, -O(CH2) r -heteroaryl may be optionally substituted by one or more R n replace;

[0014] R n Selected from H, halogen, cyano, NR a R b , hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkylamino, C1-C6 haloalkoxy, -(CH2) r -O-C1-C6 alkyl, -C(O)NR a R b 、-S(O)2NR a R b 、-NH(CH2) r C1-C6 haloalkyl, -NH(CH2) r OH, -(CH2) r OC1-C6 haloalkyl, C1-C6 haloalkyl;

[0015] R a 、R b Each is independently selected from absent, hydrogen, C1-C6 alkyl;

[0016] r is an integer from 0 to 3.

[0017] As a preferred technical solution, the R9 is selected from the group consisting of one or more R n Substituted phenyl, 5-6 membered heteroaryl containing 1 to 3 selected from N, O, S, 5-6 membered heterocyclic group containing 1 to 3 selected from N, O, S, -O(CH2) r -C3-C6 cycloalkyl, -O(CH2) r -C3-C6 heterocycloalkyl, -O(CH2) r -5-6 membered heteroaryl.

[0018] As a preferred technical solution, wherein R9 is selected from

[0019] As a preferred technical solution, R1 is selected from hydrogen.

[0020] As a preferred technical solution, R2 is selected from methyl.

[0021] As a preferred technical solution, R3 is selected from hydrogen.

[0022] As a preferred technical solution, R4 is selected from methoxy.

[0023] As a preferred technical solution, R5 is selected from hydrogen.

[0024] As a preferred technical solution, R7 is selected from hydrogen.

[0025] As a preferred technical solution, the compound of the present invention or its stereoisomers, tautomers, and pharmaceutically acceptable salts has the structural formula (I-1):

[0026] As a preferred technical solution, R6 is selected from halogen, amino, C1-C6 alkyl, and C1-C6 haloalkyl.

[0027] As a more preferred technical solution, R6 is selected from chlorine, methyl, difluoromethyl, and amino.

[0028] As the most preferred technical solution, R6 is selected from chlorine.

[0029] As a preferred technical solution, R8 is selected from hydrogen, hydroxyl, methoxy, amino, and aminoalkyl.

[0030] As a more preferred technical solution, R8 is selected from hydrogen, hydroxyl, methoxy, amino, and aminomethyl.

[0031] In a second aspect, the present invention further provides the following compounds or their stereoisomers, tautomers, and pharmaceutically acceptable salts, wherein the compound is selected from:

[0032] In a third aspect, the present invention further provides the above-mentioned compounds, tautomers and stereoisomers thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0033] In a fourth aspect, the present invention also provides the use of the compound, tautomers and stereoisomers thereof or pharmaceutically acceptable salts or compositions thereof in the preparation of drugs for inhibiting diseases caused by overexpression of Polθ.

[0034] As a preferred technical solution, the disease is cancer.

[0035] As a more preferred technical solution, the cancer is solid tumor, breast cancer, lung cancer, bladder cancer, esophageal cancer, prostate cancer, pancreatic cancer, or cervical cancer.

[0036] In a fifth aspect, the present invention also provides a method for preparing a drug for treating homologous recombination (HR)-deficient cancer in a patient, comprising administering a therapeutically effective amount of the compound or composition to the patient.

[0037] In a sixth aspect, the present invention also provides the use of preparing a drug for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of the compound or composition, wherein the cancer is characterized by reduced or absent BRCA gene expression, absent BRCA genes, or reduced BRCA protein function.

[0038] Without being bound by theory, it is expected that the Pol θ inhibitors of the present invention exhibit certain properties that make them particularly useful in the treatment of certain cancers. For example, in one embodiment, the Pol θ inhibitors of the present invention are moderately lethal in BRCA1 and BRCA2 deficient primary and secondary solid tumors, including breast, ovarian, prostate, and pancreatic.

[0039] In another embodiment, the Pol θ inhibitors of the present invention have moderate lethality in a variety of primary and secondary solid tumors that are HRD by mechanisms other than BRCA deficiency, such as those with promoter hypermethylation. In these tumors where no DSB repair pathways may be completely downregulated, Pol θ can also be administered together with another DDR modulator such as a PARP inhibitor, DNA-PK inhibitor, ATR inhibitor, ATM inhibitor, wee1 inhibitor or CHK1 inhibitor.

[0040] In another embodiment, Pol θ inhibitors of the invention are moderately lethal in primary and secondary breast, ovarian, prostate, and pancreatic tumors that retain BRCA1 deficiency but are resistant to PARPi treatment with or without exposure to PARPi drugs.

[0041] In another embodiment, the Polθ inhibitors of the present invention modestly increase ORR, including CRR, will delay the onset of PARPi resistance, will increase time to relapse and DFS, and will increase OS in HRD (BRCA1 / 2 deficiency and other HRD mechanisms) primary and secondary tumors (breast, ovary, prostate, and pancreas) when administered with PARPi treatment regimens.

[0042] The present invention also provides a compound represented by formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0043] Wherein, R8 and R9 are defined as described in any of the above items.

[0044] The present invention also provides any of the following intermediate compounds or their stereoisomers, tautomers, and pharmaceutically acceptable salts:

[0045] The present inventors have discovered that these compounds are highly effective Polθ inhibitors with extremely strong Polθ inhibitory activity, good selectivity, good oral absorption, and favorable pharmacokinetics. They can be used to prepare drugs for the prevention and / or treatment of indications related to Polθ inhibition, including solid tumors, breast cancer, lung cancer, bladder cancer, esophageal cancer, prostate cancer, pancreatic cancer, and cervical cancer. The present invention was completed based on the above discovery.

[0046] Detailed Description of the Invention

[0047] Various aspects and features of the present invention are further described below.

[0048] All documents cited in the present invention are incorporated herein by reference in their entirety, and if the meanings expressed in these documents are inconsistent with the present invention, the description of the present invention shall prevail. In addition, the various terms and phrases used in the present invention have the general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases herein. If the terms and phrases mentioned are inconsistent with the generally known meanings, the meanings expressed in the present invention shall prevail. The following are definitions of various terms used in the present invention, which apply to the terms used throughout the specification of this application, unless otherwise specified in the specific case.

[0049] The compounds according to the present invention may exist in tautomeric forms and the present invention then includes all tautomeric forms.

[0050] The compounds of the present invention possess asymmetric centers. Compounds of the present invention containing asymmetrically substituted atoms can be separated into optically active or racemic forms. Those skilled in the art will appreciate how to prepare optically active forms, such as by racemate resolution or synthesis from optically active starting materials. Unless otherwise indicated with respect to specific stereochemistry or isomeric forms, the present invention encompasses all chiral, diastereoisomer, and racemic forms. Methods for preparing the compounds of the present invention and intermediates thereto are also intended to be included in the present invention. All tautomers of the compounds of the present invention are also intended to be included in the present invention.

[0051] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" refers to events or circumstances where the alkyl group may be substituted as well as instances where the alkyl group is not substituted.

[0052] The term "substituted" refers to a moiety having a substituent that replaces a hydrogen on one or more carbons of the main chain. It should be understood that "substituted" or "substituted by..." includes implicit conditions, i.e., such substitution is consistent with the allowed valence of the substituted atom and the substituent, and the substitution produces a stable compound, for example, it will not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For appropriate organic compounds, the permissible substituents can be one or more and the same or different. For the purposes of the present invention, a heteroatom such as nitrogen can have a hydrogen substituent and / or any permissible substituent of an organic compound as described herein that satisfies the valence of the heteroatom. Substituents can include any substituent described herein, such as halogen, hydroxyl, alkyl, alkoxy, amino, cyano, heteroaryl, heterocyclic, etc. It will be understood by those skilled in the art that substituents may themselves be substituted, if appropriate.

[0053] As used herein, the terms "halogen," "halo," and the like refer to fluorine, chlorine, bromine, or iodine, and particularly to fluorine, chlorine, and bromine, with fluorine and chlorine being particularly preferred. The term "cyano" refers to a group in which a carbon atom is triple-bonded to a nitrogen atom. The term "alkoxy" is a customary expression and refers to an alkyl group attached to the rest of the molecule via an oxygen atom, and refers to an alkyl group containing an oxygen atom. Examples of such groups include methoxy, ethoxy, or propoxy.

[0054] As used herein, the term "alkyl" refers to an alkyl group having a specified number of carbon atoms, which is a linear or branched alkyl group, and which may include its subgroups. For example, when referring to "C1-C6 alkyl", it may also include sub-ranges of groups represented by C1-C4 alkyl, C1-C3 alkyl, C2-C6 alkyl, C2-C4 alkyl, etc., as well as specific groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.

[0055] The term "haloalkyl" refers to an alkyl group as defined above attached to the rest of the molecule via a halo linkage. For example, C 1-6 Haloalkyl refers to an alkyl group having 1 to 6 carbon atoms or 1 to 3 carbon atoms connected to the rest of the molecule via a halo linkage. Preferred haloalkyl groups include, but are not limited to, -CH2Cl, -CHCl2, -CF3, and the like.

[0056] As used herein, the term "hydroxy" or "hydroxyl," by itself or in combination with other terms, means -OH.

[0057] The terms "heterocycle", "heterocyclic" or "heterocyclyl" are used interchangeably and refer to substituted and unsubstituted 3 to 7 membered monocyclic groups, 7 to 11 membered bicyclic groups and 10 to 15 membered tricyclic groups having at least one heteroatom (O, S or N) in at least one ring, the heteroatom-containing ring preferably having 1, 2 or 3 heteroatoms selected from O, S and N. Each ring of such heteroatom-containing groups may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. Nitrogen and sulfur atoms may be optionally oxidized, and nitrogen atoms may be optionally quaternized. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or fully unsaturated. Heterocyclic groups may be attached to any available nitrogen or carbon atom. The heterocyclic radicals include heterocycloalkyl and the like.

[0058] The term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11- to 14-membered tricyclic groups having at least one heteroatom (O, S, or N) in at least one ring, the heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the heteroaryl containing heteroatoms can contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less, and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups can contain only carbon atoms and can be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. A bicyclic or tricyclic heteroaryl must include at least one fully aromatic ring, but the other one or more fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached to any available nitrogen or carbon atom of any ring. Where valence permits, if the other ring is a cycloalkyl or heterocycle, it is further optionally substituted with =0 (oxo). Examples of heteroaryl include, but are not limited to, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthracene, dibenzofuranyl, benzothiophenyl ... pyrrolopyridinyl, pyrazolopyrimidinyl, furopyridinyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotriazole, benzothiadiazolyl, benzotriazole ...

[0059] Certain compounds of formula (I) may be in the form of salts. In addition to salts, the compounds provided herein may also exist in the form of prodrugs. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert into the compounds of the present invention. Additionally, prodrugs may be converted to the compounds of the present invention by chemical or biochemical methods in vivo.

[0060] As used herein, the term "disease" refers to a physical condition of the subject that is associated with the disease described herein. For example, cancer described herein. Cancer described herein includes standard treatments such as surgery, radiation therapy, chemotherapy, and hormone therapy.

[0061] "Cancer" or "malignancy" refers to any of a variety of diseases characterized by uncontrolled abnormal proliferation of cells, the ability of affected cells to spread locally or through the bloodstream and lymphatic system to other sites in the body (i.e., metastasis), and any of a number of characteristic structural and / or molecular features. "Cancer includes mesothelioma, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis and hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumor, head and neck cancer, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, gallbladder cancer, bronchial tumor, advanced solid tumors, small cell lung cancer, etc.

[0062] The compound of the present invention or the pharmaceutical composition containing the same can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, intravenous drip, subcutaneous injection, nasal cavity, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

[0063] The dosage form can be a liquid dosage form, a solid dosage form, or a semisolid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and multiple emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, micropills, dropping pills, suppositories, films, patches, aerosols (powders), and sprays; semisolid dosage forms can be ointments, gels, pastes, and the like.

[0064] To achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known method of administration.

[0065] The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0066] Beneficial technical effects

[0067] The inventors have discovered that the compounds of the present invention have excellent Pol θ inhibitory activity, with an IC50 value lower than that of the positive control, can inhibit the proliferation of DLD1BRCA2- / - cells and HCT116 BRCA2- / - cells, and exhibit unexpectedly good oral absorption and exposure in mice, as well as good selectivity. The present invention provides a class of novel, highly active Pol θ inhibitor compounds, which have promising application prospects in preventing and / or treating indications associated with Pol θ inhibition, such as reduced or absent BRCA gene expression, absent BRCA genes, or reduced BRCA protein function. DETAILED DESCRIPTION

[0068] The following embodiments are intended to help those skilled in the art better understand the technical solutions of the present invention, but are not intended to limit the present invention in any way.

[0069] For all of the following examples, standard procedures and methods known to those skilled in the art can be used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. The structures of the compounds are determined by nuclear magnetic resonance spectroscopy (NMR) and / or mass spectroscopy (MS).

[0070] The structures of the compounds of the present invention were confirmed by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are expressed in parts per million (ppm). NMR measurements were performed using a Bruker Avance-400 NMR spectrometer. The solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0071] Liquid phase mass spectrometry LC-MS measurement The liquid phase part used ACQUITY UPLC ultra-high pressure liquid chromatography, and the mass spectrometry part used Xevo G2-S Qtof mass spectrometer.

[0072] The starting materials used in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0073] Example 1: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 1)

[0074] Step 1: Synthesis of methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate

[0075] Methyl 4-bromo-6-methylnicotinate (2 g, 8.7 mmol, 1.0 eq) was dissolved in 1,4-dioxane (25.0 mL). (2-chloro-5-methoxypyridin-4-yl)boronic acid (1.63 g, 8.7 mmol, 1.0 eq), cesium carbonate (8.478 g, 26.1 mmol, 3.0 eq), deionized water (5.0 mL), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (636.5 mg, 0.87 mmol, 0.1 eq) were added. The mixture was reacted at 80°C under nitrogen for 3 hours. After completion of the reaction, the mixture was filtered and purified by normal phase column chromatography to obtain methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (1.734 g, 68.3% yield) as a white solid. LCMS (ESI) [M+H] + :293.0. 1 H NMR (400MHz, DMSO) δ8.87(s,1H),8.22(s,1H),7.50(s,1H),7.37(s,1H),3.78(s,3H),3.68(s,3H),2.57(s,3H).

[0076] Step 2: Synthesis of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid

[0077] Methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (1.734 g, 5.9 mmol, 1.0 eq) was dissolved in anhydrous methanol (10 mL) and lithium hydroxide (0.748 g, 17.8 mmol, 3.0 eq) was added. The mixture was allowed to react at 60°C for 3 hours. After the reaction was complete, dilute hydrochloric acid was added to adjust the pH to 4. The mixture was extracted with ethyl acetate and the organic phase was concentrated to obtain 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (1.586 g, 96.0% yield) as a white solid. LCMS (ESI) [M+H] + :279.0. 1H NMR (400MHz, DMSO) δ13.08(s,1H),8.88(s,1H),8.21(s,1H),7.45(s,1H),7.31(s,1H),3.78(s,3H),2.55(s,3H).

[0078] Step 3: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0079] Dissolve 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (120 mg, 0.43 mmol, 1.0 eq) in ultra-dry N,N-dimethylformamide (10 mL). Add 6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (98.3 mg, 0.43 mmol, 1.0 eq), N-methylimidazole (107 mg, 1.3 mmol, 3.0 eq), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (168 mg, 0.65 mmol, 1.5 eq). Allow to react at room temperature for 4 hours. After the reaction is complete, the product is filtered, concentrated, and purified by preparative separation to obtain a yellow solid 2'-chloro-5'-methoxy-6-methyl-N-(6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (130.0 mg, yield 65.1%). LCMS (ESI) [M+H] + :491.1570. 1 H NMR (400MHz, DMSO) δ12.52(s,1H),8.78(s,1H),8.17(s,1H),7.52(s,1H),7.41(s,1H),7.37-7.27(m,4H),7. 22(m,J=5.5,2.6Hz,1H),3.62(s,3H),3.08-2.87(m,2H),2.81-2.65(m,3H),2.58(s,3H),2.07-1.96(m,2H).

[0080] Example 2: Synthesis of 2'-chloro-N-[6-(6-fluoro-4-methylpyridin-3-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 2)

[0081] Step 1: Synthesis of 1,4-dioxyaspirino[4.5]dec-7-en-8-yl trifluoromethanesulfonate

[0082] 1,4-Dioxyaspirino[4.5]decan-8-one (10 g, 64.0 mmol, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (100.0 mL). Lithium bis(trimethylsilyl)amide (21.45 g, 128.0 mmol, 2.0 eq) was slowly added at -78°C over a 1-hour period. Dry trifluoromethanesulfonic acid (21.7 g, 76.8 mmol, 1.2 eq) was then slowly added and allowed to react at -78°C for 6 hours. After completion, saturated ammonium chloride solution was added to quench the reaction. Water and ethyl acetate were then added for extraction. The organic phase was collected and concentrated, and purified by normal phase column chromatography to obtain 1,4-dioxyaspirino[4.5]decan-7-en-8-yl trifluoromethanesulfonate (9.0 g, 48.8% yield). LCMS (ESI) [M+H] + :289.1.

[0083] Step 2: Synthesis of 2-fluoro-4-methyl-5-(1,4-dioxyaspirino[4.5]dec-7-en-8-yl)pyridine

[0084] 1,4-Dioxyaspirin[4.5]dec-7-en-8-yl trifluoromethanesulfonate (9.29 g, 32.3 mmol, 1.0 eq) was dissolved in 1,4-dioxane (50 mL), and (6-fluoro-4-methylpyridin-3-yl)boric acid (5 g, 32.3 mmol, 1.0 eq), cesium carbonate (31.55 g, 95.7 mmol, 3.0 eq), deionized water (10 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (943.3 mg, 1.3 mmol, 0.04 eq) were added. The mixture was reacted at 80 °C for 4 hours under nitrogen protection. After the reaction was complete, the product was purified by normal phase column to obtain a white solid 2-fluoro-4-methyl-5-(1,4-dioxyaspirino[4.5]dec-7-en-8-yl)pyridine (6.1 g, yield 75.9%). LCMS (ESI) [M+H] + :250.1.

[0085] Step 3: Synthesis of 2-fluoro-4-methyl-5-(1,4-dioxyaspirino[4.5]dec-8-yl)pyridine

[0086] 2-Fluoro-4-methyl-5-(1,4-dioxyaspirino[4.5]dec-7-en-8-yl)pyridine (1.0 g, 4.02 mmol, 1.0 eq) was dissolved in methanol (10 mL), and palladium on carbon (42.6 mg, 0.40 mmol, 0.1 eq) was added. The mixture was then reacted at 60°C under a hydrogen atmosphere for 10 hours. After the reaction was complete, the mixture was filtered and the organic phase was concentrated to obtain 2-fluoro-4-methyl-5-(1,4-dioxyaspirino[4.5]dec-8-yl)pyridine (820 mg, 81.3%) as a white solid. LCMS (ESI) [M+H] + :252.1.

[0087] Step 4: Synthesis of 4-(6-fluoro-4-methylpyridin-3-yl)cyclohexane-1-one

[0088] 2-Fluoro-4-methyl-5-(1,4-dioxaspirino[4.5]dec-8-yl)pyridine (400 mg, 1.59 mmol, 1.0 eq) was dissolved in tetrahydrofuran (6 mL) and ethanol (3 mL). Hydrochloric acid (2 mL) was then added and the mixture was allowed to react at room temperature for 3 hours. After the reaction was complete, saturated aqueous sodium bicarbonate was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate, and the organic phase was concentrated to obtain 4-(6-fluoro-4-methylpyridin-3-yl)cyclohexane-1-one (320 mg, 80.2%) as a white solid. LCMS (ESI) [M+H] + :208.0. 1 HNMR (400MHz, DMSO) δ8.07(s,1H),7.01(s,1H),3.26(m,J=12.0,3.4Hz,1H),2.62(m,J=14.3,6.2H z,2H),2.44(m,J=1.6Hz,3H),2.31-2.23(m,2H),2.07-1.96(m,2H),1.93(dd,J=13.0,3.9Hz,2H).

[0089] Step 5: Synthesis of 6-(6-fluoro-4-methylpyridin-3-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0090] Dissolve 4-(6-fluoro-4-methylpyridin-3-yl)cyclohexane-1-one (120 mg, 0.58 mmol, 1.0 eq) in acetonitrile (3 mL), add azobisisobutyronitrile (94.9 mg, 0.58 mmol, 1.0 eq), and then add N-bromosuccinimide (113.4 mg, 0.64 mmol, 1.1 eq) at 0°C. The mixture is then reacted at 80°C for 2 hours. After the reaction is complete, cool to room temperature, add thiourea (66.0 mg, 0.88 mmol, 1.5 eq), and react at 80°C for 2 hours. After the reaction was complete, separation and purification were performed using a normal phase column. Impurities were first removed by rinsing with ethyl acetate, and then purified with dichloromethane and methanol (4:1) to obtain a brown solid 6-(6-fluoro-4-methylpyridin-3-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (90.0 mg, yield 59.1%). LCMS (ESI) [M+H] + :264.0. 1 HNMR (400MHz, DMSO) δ8.09 (s, 1H), 7.00 (s, 1H), 6.68 (s, 2H), 4.11 (s, 4H), 2.74 (dd, J = 15.5, 5.1Hz, 1H), 2.39 (s, 3H), 2.06-1.82 (m, 2H).

[0091] Step 6: Synthesis of 2'-chloro-N-[6-(6-fluoro-4-methylpyridin-3-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0092] 6-(6-Fluoro-4-methylpyridin-3-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (90.0 mg, 0.34 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (95.1 mg, 0.34 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (2 mL), and N-methylimidazole (84.2 mg, 1.03 mmol, 3.0 eq) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (105.8 mg, 0.41 mmol, 1.2 eq) were added, followed by reaction at room temperature for 2.0 hours. After the reaction is complete, a brown solid 2'-chloro-N-[6-(6-fluoro-4-methylpyridin-3-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (10.0 mg, yield 5.6%) is obtained. LCMS (ESI) [M+H] + :524.1249. 1H NMR (400MHz, DMSO) δ8.78(s,1H),8.17(s,1H),8.13(s,1H),7.51(s,1H),7.40(s,1H),7.02(s,1H),3. 62(s,3H),3.21(s,1H),2.97-2.78(m,2H),2.74(s,2H),2.58(s,3H),2.40(s,3H),2.15-1.92(m,2H).

[0093] Example 3: Synthesis of 2'-chloro-N-{6-[2-fluoro-4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 3)

[0094] Step 1: Synthesis of 8-[2-fluoro-4-(trifluoromethyl)phenyl]-1,4-dioxyaspirino[4.5]dec-7-ene

[0095] 1,4-Dioxyaspirino[4.5]dec-7en-8-yl trifluoromethanesulfonate (4.5 g, 15.61 mmol, 1.0 eq) and [2-fluoro-4-(trifluoromethyl)phenyl]boronic acid (3.24 g, 15.61 mmol, 1.0 eq) were dissolved in 1,4-dioxane (25 mL), followed by the addition of deionized water (8 mL), cesium carbonate (15.27 g, 46.83 mmol, 3.0 eq) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (34.20 mg, 0.468 mmol, 0.03 eq), and the reaction was carried out at 80 ° C for 2.5 hours. After the reaction was completed, the product was separated and purified by forward column to obtain a white solid 8-[2-fluoro-4-(trifluoromethyl)phenyl]-1,4-dioxaspirino[4.5]dec-7-ene (3.58 g, yield 75.9%). LCMS (ESI) [M+H] + :303.0. 1 H NMR (400MHz, DMSO) δ7.63(d,J=11.1Hz,1H),7.55(d,J=6.8Hz,2H),5.96–5.92( m, 1H), 3.93 (s, 4H), 2.53 (s, 2H), 2.40 (t, J = 3.2Hz, 2H), 1.80 (t, J = 6.4Hz, 2H).

[0096] Step 2: Synthesis of 8-[2-fluoro-4-(trifluoromethyl)phenyl]-1,4-dioxyaspirino[4.5]decane

[0097] 8-[2-Fluoro-4-(trifluoromethyl)phenyl]-1,4-dioxyaspirino[4.5]dec-7-ene (400 mg, 1.32 mmol, 1.0 eq) was dissolved in methanol (3 mL), and palladium / carbon (14.06 mg, 0.13 mmol, 0.1 eq) was added. The mixture was then reacted at room temperature for 3 hours under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered and the organic phase was concentrated to obtain a white solid crude product, 8-[2-fluoro-4-(trifluoromethyl)phenyl]-1,4-dioxyaspirino[4.5]decane (385.0 mg), which was used directly in the next reaction. LCMS (ESI) [M+H] + :305.0. 1 H NMR (400MHz, DMSO) δ7.63–7.50 (m, 3H), 3.89 (s, 4H), 2.95 (d, J = 12.6Hz, 1H), 1.81–1.64 (m, 8H).

[0098] Step 3: Synthesis of 4-[2-fluoro-4-(trifluoromethyl)phenyl]cyclohexane-1-one

[0099] 8-[2-Fluoro-4-(trifluoromethyl)phenyl]-1,4-dioxaspirin[4.5]decane (380 mg, 1.25 mmol, 1.0 eq) was dissolved in tetrahydrofuran (6 mL) and ethanol (3 mL), followed by the addition of hydrochloric acid (2 mL) and the reaction was allowed to react at room temperature for 3 hours. After the reaction was complete, saturated aqueous sodium bicarbonate solution was added to adjust the pH to neutral, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to obtain a white solid crude product, 4-[2-fluoro-4-(trifluoromethyl)phenyl]cyclohexane-1-one (424 mg), which was used directly in the next reaction. LCMS (ESI) [M+H] + :261.1. 1 H NMR (400MHz, DMSO) δ7.67–7.50(m,3H),3.43(m,J=10.9,3.7Hz,1H),2.64(m,J=14.2,6.1Hz,2 H), 2.29 (m, J = 14.8, 2.1Hz, 2H), 2.06 (m, J = 12.6, 6.2, 3.1Hz, 2H), 1.95 (m, J = 13.1, 4.4Hz, 2H).

[0100] Step 4: Synthesis of 6-[2-fluoro-4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0101] 4-[2-Fluoro-4-(trifluoromethyl)phenyl]cyclohexane-1-one (290 mg, 1.11 mmol, 1.0 eq) and azobisisobutyronitrile (182.92 mg, 1.11 mmol, 1.0 eq) were dissolved in acetonitrile (3 mL). N-bromosuccinimide (21.81 mg, 1.22 mmol, 1.1 eq) was added at 0°C and reacted at 80°C for 2 hours. After the reaction, the reaction solution was cooled to room temperature and thiourea (84.49 mg, 1.11 mmol, 1.0 eq) was added. The reaction was continued at 80°C for 1 hour. After the reaction, the product was purified by normal phase column, first rinsing with ethyl acetate to remove impurities, then eluting with a dichloromethane and methanol system. When the volume ratio of dichloromethane to methanol was 20:1, the target product eluted. Concentration gave an off-white solid 6-[2-fluoro-4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (242 mg, yield 76.82%). LCMS (ESI) [M+H] + :317.0. 1 H NMR (400MHz, DMSO) δ7.68–7.60 (m, 2H), 7.56 (dd, J = 8.1, 1.8Hz, 1H), 6.79 (s, 2H ),4.04–3.94(m,1H),2.81–2.66(m,2H),2.61–2.53(m,2H),2.03–1.94(m,2H).

[0102] Step 5: Synthesis of 2'-chloro-N-{6-[2-fluoro-4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0103] 6-[2-Fluoro-4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (113.49 mg, 0.36 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (100 mg, 0.36 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (3 mL). N-methylimidazole (88.23 mg, 1.08 mmol, 3.0 eq) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (150.7 mg, 0.54 mmol, 1.5 eq) were then added and reacted at room temperature for 2 hours. After the reaction, preparative separation and purification were performed to obtain a white solid 2'-chloro-N-{6-[2-fluoro-4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (42.7 mg, yield 20.62%). LCMS (ESI) [M+H] + :577.0884. 1 H NMR (400MHz, DMSO) δ11.92(s,1H),8.78(s,1H),8.17(s,1H),7.66(dd,J=9.3,5.9Hz,2H),7.58(d,J=8.1Hz,1H),7.52(s,1H),7.41(s,1H),3.62 (s,3H),3.39(d,J=14.2Hz,1H),2.96(dd,J=15.9,5.1Hz,1H),2.83(dd,J=16.5,10.4Hz,1H),2.78–2.68(m,2H),2.58(s,3H),2.16–2.00(m,2H).

[0104] Example 4: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-[6-(2,4,5-trifluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-[4,4'-bipyridine]-3-carboxamide (Compound 4)

[0105] Step 1: Synthesis of 8-(2,4,5-trifluorophenyl)-1,4-dioxyaspirino[4.5]dec-7-ene

[0106] 1,4-Dioxyaspirin[4.5]dec-7-en-8-yl trifluoromethanesulfonate (8.19 g, 28.4 mmol, 1.0 eq) and (2,4,5-trifluorophenyl)boronic acid (5.0 g, 28.4 mmol, 1.0 eq) were added to 1,4-dioxane (80 mL), followed by cesium carbonate (27.78 g, 85.3 mmol, 3.0 eq) and water (20 mL). Finally, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (831 mg, 1.1 mmol, 0.04 eq) was added. The mixture was stirred at 80 °C under nitrogen protection for 1.5 hours. After the reaction was completed, ethyl acetate and water were added to extract the reaction solution. The organic layer was collected and dried over anhydrous sodium sulfate. The organic layer was concentrated and purified by normal phase column chromatography to obtain a white solid 8-(2,4,5-trifluorophenyl)-1,4-dioxyaspirino[4.5]dec-7-ene (6.6 g, yield 86.0%). LCMS (ESI) [M+H] + :271. 1 H NMR (400MHz, MeOD) δ7.21 (m, J=11.4, 9.0, 7.0Hz, 1H), 7.10 (m, J=10.5, 6.8Hz, 1H), 5.84 (dd, J=5.0, 3.2Hz, 1H), 3.99 (d, J = 1.8Hz, 4H), 2.60–2.49 (m, 2H), 2.41 (q, J = 2.9Hz, 2H), 1.86 (t, J = 6.4Hz, 2H).

[0107] Step 2: Synthesis of 8-(2,4,5-trifluorophenyl)-1,4-dioxyaspirino[4.5]decane

[0108] 8-(2,4,5-trifluorophenyl)-1,4-dioxyaspirino[4.5]dec-7-ene (1.0 g, 3.7 mmol, 1.0 eq) was dissolved in anhydrous methanol (10 mL) and ultra-dry tetrahydrofuran (5 mL). Palladium on carbon (100 mg) was added and the mixture was reacted at room temperature for 16 hours under hydrogen protection. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to obtain a white solid crude product 8-(2,4,5-trifluorophenyl)-1,4-dioxyaspirino[4.5]decane (1.1 g). LCMS (ESI) [M+H] + :273. 1 H NMR (400MHz, DMSO) δ7.50–7.41(m,1H),7.41–7.33(m,1H),3.88(d,J=2.5Hz,4H),2.82(dt,J=15.1,7.6Hz,1H),1.82–1.53(m,8H).

[0109] Step 3: Synthesis of 4-(2,4,5-trifluorophenyl)cyclohexane-1-one

[0110] 8-(2,4,5-trifluorophenyl)-1,4-dioxyaspirino[4.5]decane (1.0 g, 4.39 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL) and anhydrous ethanol (5 mL). Hydrochloric acid (5 mL) was added and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (40 mL) was added to the reaction solution. Solid sodium hydroxide was then added in small amounts to adjust the pH to 8-9 under ice-cooling conditions. Ethyl acetate was added for extraction and the organic layer was collected, dried over anhydrous sodium sulfate, and concentrated to obtain a brown solid crude product, 4-(2,4,5-trifluorophenyl)cyclohexane-1-one (890 mg). LCMS (ESI) [M+H] + :229. 1 H NMR (400MHz, DMSO) δ7.51 (m, J=12.2, 10.4, 6.0Hz, 2H), 2.61 (m, J=14.2, 6.1Hz, 2H), 2. 26(m,J=14.6,2.0Hz,2H),2.05–2.00(m,1H),1.99(s,2H),1.92(m,J=12.8,4.0Hz,2H).

[0111] Step 4: Synthesis of 2-bromo-4-(2,4,5-trifluorophenyl)cyclohexan-1-one

[0112] 4-(2,4,5-trifluorophenyl)cyclohexane-1-one (880 mg, 3.86 mmol, 1.0 eq) and azobisisobutyronitrile (634 mg, 3.86 mmol, 1.0 eq) were added to carbon tetrachloride (15 mL). N-bromosuccinimide (756 mg, 4.25 mmol, 1.1 eq) was then added in small portions in an ice bath. The mixture was stirred at 80°C for 16 hours. After the reaction was complete, the reaction solution was concentrated to obtain crude 2-bromo-4-(2,4,5-trifluorophenyl)cyclohexane-1-one (1.2 g) as a yellow oil, which was used directly in the next reaction.

[0113] Step 5: Synthesis of 6-(2,4,5-trifluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0114] 2-Bromo-4-(2,4,5-trifluorophenyl)cyclohexan-1-one (1.2 g, 3.92 mmol, 1.0 eq) was dissolved in acetonitrile (10 mL), and thiourea (358 mg, 4.7 mmol, 1.2 eq) was added. The mixture was stirred at 80°C for 2 hours. After completion of the reaction, the reaction solution was directly concentrated and purified by normal phase column chromatography to obtain 6-(2,4,5-trifluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (500 mg, 45.6% yield) as a brown solid. LCMS (ESI) [M+H] + :285.

[0115] Step 6: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-[6-(2,4,5-trifluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-[4,4'-bipyridine]-3-carboxamide

[0116] Compound 6-(2,4,5-trifluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (240 mg, 0.85 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (235 mg, 0.85 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (3.5 mL), and N-methylimidazole (208 mg, 2.54 mmol, 3.0 eq) was added. Finally, tetramethylchlorouronium hexafluorophosphate (356 mg, 1.27 mmol, 1.5 eq) was added in an ice bath and the reaction was stirred at room temperature for 1.5 hours. After the reaction was completed, a white solid 2'-chloro-5'-methoxy-6-methyl-N-[6-(2,4,5-trifluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-[4,4'-bipyridine]-3-carboxamide (12.3 mg, yield 2.7%) was obtained. LCMS (ESI) [M+H] + :545.1237. 1 H NMR (400MHz, DMSO) δ12.52(s,1H),8.77(s,1H),8.17(s,1H),7.63–7.48(m,3H),7.41(s,1H),3.61(s,3H),3.25(d,J= 12.0Hz, 1H), 2.90 (dd, J=16.0, 5.2Hz, 1H), 2.84–2.78 (m, 1H), 2.75 (d, J=11.0Hz, 2H), 2.58 (s, 3H), 2.12–1.94 (m, 2H).

[0117] Example 5: Synthesis of 2'-chloro-N-(6-(4-cyano-3-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 5)

[0118] Step 1: Synthesis of 2-fluoro-4-(1,4-dioxyaspirino[4.5]dec-7-en-8-yl)benzonitrile

[0119] 1,4-Dioxyaspirino[4.5]dec-7-en-8-yl trifluoromethanesulfonate (2.0 g, 6.94 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL). (4-Cyano-3-fluorophenyl)boronic acid (1.01 g, 6.94 mol, 1.0 eq), cesium carbonate (6.79 g, 20.8 mmol, 3.0 eq), deionized water (2 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (253.8 mg, 0.35 mmol, 0.05 eq) were added. The mixture was reacted at 80°C under nitrogen for 4 hours. After completion of the reaction, the product was purified by normal phase column chromatography to obtain 2-fluoro-4-(1,4-dioxyaspirino[4.5]dec-7-en-8-yl)benzonitrile (1.516 g, 84.3% yield) as a white solid. LCMS (ESI) [M+H] + :260. 1 HNMR (400MHz, DMSO) δ7.84 (dd, J=8.2, 7.2Hz, 1H), 7.57 (dd, J=11.7, 1.7Hz, 1H), 7.47 (dd, J=8.3, 1.7Hz, 1H), 6.36 (m, J=4.0, 2.0Hz, 1H), 3.95(s,2H),2.55(m,J=6.2,1.9Hz,2H),2.41(dt,J=4.5,2.4Hz,2H),2.36(t,J=7.1Hz,1H),1.93(t,J=7.0Hz,1H),1.81(t,J=6.5Hz,2H).

[0120] Step 2: Synthesis of 2-fluoro-4-(1,4-dioxyaspirino[4.5]dec-8-yl)benzonitrile

[0121] 2-Fluoro-4-(1,4-dioxyaspirino[4.5]dec-7-en-8-yl)benzonitrile (1.0 g, 3.86 mmol, 1.0 eq) was dissolved in methanol (5 mL) and palladium on carbon (81.8 mg, 0.772 mmol, 0.2 eq) was added. The mixture was then reacted at room temperature under a hydrogen atmosphere for 8 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to obtain a crude white solid of 2-fluoro-4-(1,4-dioxyaspirino[4.5]dec-8-yl)benzonitrile (820 mg, yield 89.3%). LCMS (ESI) [M+H] + :262.

[0122] Step 3: Synthesis of 2-fluoro-4-(4-oxocyclohexyl)benzonitrile

[0123] 2-Fluoro-4-methyl-5-(1,4-dioxaspirino[4.5]dec-8-yl)pyridine (500 mg, 1.92 mmol, 1.0 eq) was dissolved in tetrahydrofuran (6 mL) and ethanol (3 mL). Hydrochloric acid (2 mL) was then added and the mixture was allowed to react at room temperature for 3 hours. After the reaction was complete, saturated aqueous sodium bicarbonate solution was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate, and the organic phase was collected and concentrated to obtain 2-fluoro-4-(4-oxocyclohexyl)benzonitrile (301 mg, 72.4% yield) as a white solid. LCMS (ESI) [M+H] + :218.

[0124] Step 4: Synthesis of 4-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-2-fluorobenzonitrile

[0125] 2-Fluoro-4-(4-oxocyclohexyl)benzonitrile (300 mg, 1.37 mmol, 1.0 eq) was dissolved in acetonitrile (10 mL), and azobisisobutyronitrile (224.6 mg, 1.37 mmol, 1.0 eq) was added. N-bromosuccinimide (268.2 mg, 1.5 mmol, 1.1 eq) was then added at 0°C, and the mixture was allowed to react at 80°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and thiourea (156.2 mg, 2.05 mmol, 1.5 eq) was added, followed by a reaction at 80°C for 2 hours. After the reaction was complete, the mixture was separated and purified using a normal phase column. The impurities were first removed by rinsing with ethyl acetate, and then purified using dichloromethane and methanol (4:1) to obtain 4-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-2-fluorobenzonitrile (215 mg, 57.5% yield) as a brown solid. LCMS (ESI) [M+H] + :274. 1HNMR (400MHz, DMSO) δ7.87(t,J=7.5Hz,1H),7.54(dd,J=11.0,1.5Hz,1H),7.39(dd,J=8.1,1.5Hz,1H),7.02 (d, J = 17.9 Hz, 2H), 3.55 (m, J = 6.1 Hz, 1H), 3.12 (d, J = 11.9 Hz, 2H), 2.69-2.51 (m, 2H), 1.95 (q, J = 8.6 Hz, 2H).

[0126] Step 5: Synthesis of 2'-chloro-N-(6-(4-cyano-3-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0127] 4-(2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-2-fluorobenzonitrile (200.0 mg, 0.73 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (204 mg, 0.73 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (3 mL), followed by the addition of N-methylimidazole (180 mg, 2.2 mmol, 3.0 eq) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (226 mg, 0.88 mmol, 1.2 eq) and the reaction was carried out at room temperature for 3.0 hours. After the reaction was complete, preparative separation and purification were performed to obtain a brown solid 2'-chloro-N-(6-(4-cyano-3-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (31.0 mg, yield 7.9%). LCMS (ESI) [M+H] + :534.0972. 1 HNMR (400MHz, DMSO) δ12.52(s,1H),8.77(s,1H),8.17(s,1H),7.89(t,J=7.5Hz,1H),7.61-7.50(m,2H),7.47-7.39(m,2H),3.61 (s,3H),3.19(d,J=6.8Hz,1H),2.95(dd,J=15.8,5.0Hz,1H),2.85–2.74(m,1H),2.72(s,2H),2.58(s,3H),2.04(q,J=8.1Hz,2H).

[0128] Example 6: Synthesis of 2'-chloro-N-(6-(3-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 6)

[0129] Step 1: Synthesis of 6-(3-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0130] 4-(3-Fluorophenyl)cyclohexane-1-one (1.0 g, 5.20 mmol, 1.0 eq) was dissolved in acetonitrile (8 mL), and 2,2'-azobisisobutyronitrile (853 mg, 5.20 mmol, 1.0 eq) was added. N-bromosuccinimide (1.02 g, 5.72 mmol, 1.1 eq) was then added in an ice-water bath, and the mixture was allowed to react at 80°C for 1.5 hours. After completion of the reaction, thiourea (396 mg, 5.20 mmol, 1.1 eq) was added, and the reaction was continued at 80°C for 1 hour. After completion of the reaction, the reaction solution was cooled, and solid precipitated. Filtering gave the crude off-white solid 6-(3-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (402 mg). LCMS (ESI) [M+H] + :249. 1 H NMR (400MHz, DMSO) δ9.23 (s, 2H), 7.37 (q, J = 7.6Hz, 1H), 7.16 (t, J = 7.3Hz, 2H), 7.06 (td, J = 8.6, 2.5 Hz,1H),6.22(s,6H),3.04(s,1H),2.84–2.75(m,1H),2.65–2.54(m,4H),1.98(s,2H),1.66(s,1H).

[0131] Step 2: Synthesis of 2'-chloro-N-[6-(3-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0132] 6-(3-Fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (107 mg, 0.43 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (120 mg, 0.43 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (3 mL), and N-methylimidazole (106 mg, 1.29 mmol, 3.0 eq) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (181.0 mg, 0.645 mmol, 1.5 eq) were added, followed by reaction at room temperature for 2.0 hours. After the reaction was complete, a yellow solid 2'-chloro-N-[6-(3-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (44.2 mg, yield 20.18%) was obtained. LCMS (ESI) [M+H] + :509.1159. 1 HNMR (400MHz, DMSO) δ12.54(s,1H),8.81(s,1H),8.18(s,1H),7.53(s,1H),7.47(s,1H),7.36(q,J=7.5Hz,1H),7.22–7.16(m,2H),7. 08–7.01(m,1H),3.62(s,3H),3.11–3.02(m,1H),2.93(dd,J=15.7,5.0Hz,1H),2.81–2.66(m,3H),2.60(s,3H),2.03(t,J=6.9Hz,2H).

[0133] Example 7: Synthesis of 2'-chloro-N-[6-(4-hydroxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 7)

[0134] Step 1: Synthesis of 4-(4-oxocyclohexyl)phenyl acetate

[0135] Dissolve 4-(4-hydroxyphenyl)cyclohexane-1-one (1.0 g, 5.26 mmol, 1.0 eq) in ultra-dry dichloromethane (50.0 mL) and slowly add acetyl chloride (412.9 mg, 5.26 mmol, 1.0 eq) dropwise. Allow to react at room temperature for 4 hours. After completion of the reaction, extract with water and ethyl acetate. The organic phases are combined and concentrated to yield crude 4-(4-oxocyclohexyl)phenyl acetate (880 mg, 72.1% yield), which is used directly in the next reaction. LCMS (ESI) [M+H] + :233.1.

[0136] Step 2: Synthesis of phenyl 4-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)acetate

[0137] 4-(4-Oxocyclohexyl)phenyl acetate (800 mg, 3.45 mmol, 1.0 eq) was dissolved in ultra-dry acetonitrile (5 mL), followed by the addition of azobisisobutyronitrile (565.8 mg, 3.45 mmol, 1.0 eq) and the reaction was allowed to proceed at 80°C for 1 hour. The reaction solution was cooled to room temperature, and thiourea (393 mg, 5.17 mmol, 1.5 eq) was added, and the reaction was continued at 80°C for 1 hour. After the reaction, the product was separated and purified using a normal phase column to obtain 4-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)phenyl acetate (230 mg, yield 23.1%) as a yellow oil. LCMS (ESI) [M+H] + :289.09.

[0138] Step 3: Synthesis of phenyl 4-[2-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridyl]-3-carboxamido)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl]acetate

[0139] 4-(2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)phenyl acetate (200 mg, 0.69 mmol, 1.0 eq) was dissolved in ultra-dry N,N-dimethylformamide (4 mL), and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (212 mg, 0.76 mmol, 1.1 eq), N-methylimidazole (172 mg, 2.09 mmol, 3.0 eq) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (214 mg, 0.83 mmol, 1.2 eq) were added in sequence and reacted at room temperature for 2.0 hours. After the reaction, the reaction solution was filtered, the filtrate was concentrated, and the product was purified by normal phase purification to obtain a brown oily product, 4-[2-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridyl]-3-carboxamido)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)phenyl acetate (90.0 mg, yield 18.4%). LCMS (ESI) [M+H] + :549.1. 1H NMR(400MHz, CDCl3)δ8.85(s,1H),8.03(s,1H),8.01(s,2H),7.24-7.20(m,2H),7.06-7.01(m, 2H),3.72(s,3H),3.06-2.97(m,2H),2.76(s,2H),2.70(s,3H),2.29(s,3H),2.08-1.77(m,2H).

[0140] Step 4: Synthesis of 2'-chloro-N-[6-(4-hydroxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0141] 4-[2-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridyl]-3-carboxamido]-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)phenyl acetate (70 mg, 0.13 mmol, 1.0 eq) was dissolved in anhydrous methanol (2 mL), followed by the addition of sodium carbonate (27 mg, 0.26 mmol, 2.0 eq) and the reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction, preparative separation and purification afforded 2'-chloro-N-[6-(4-hydroxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridyl]-3-carboxamide (17.7 mg, 27.4% yield) as a yellow solid. LCMS (ESI) [M+H] + :507.1050. 1 H NMR(400MHz, CDCl3)δ8.80(s,1H),8.18(s,1H),7.53(s,1H),7.46(s,1H),7.14-7.07(m,2H),6.74- 6.66(m,2H),3.62(s,3H),2.95-2.80(m,2H),2.69(d,J=8.3Hz,3H),2.59(s,3H),2.07-1.80(m,2H).

[0142] Example 8: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide (Compound 15)

[0143] Step 1: Synthesis of 8-[4-(trifluoromethyl)phenyl]-1,4-dioxyaspirino[4.5]dec-7-ene

[0144] 1,4-Dioxyaspirino[4.5]dec-7-en-8-yl trifluoromethanesulfonate (6.0 g, 20.81 mmol, 1.0 eq) and [4-(trifluoromethyl)phenyl]boronic acid (3.95 g, 20.81 mmol, 1.0 eq) were dissolved in ultra-dry 1,4-dioxane (10.0 mL), followed by the addition of deionized water (2.5 mL), cesium carbonate (20.34 g, 62.4 mmol, 3.0 eq) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (456.0 mg, 0.624 mmol, 0.03 eq), nitrogen was replaced, and the reaction was carried out at 80°C for 2.5 hours. After the reaction was completed, forward column purification was performed to obtain 8-[4-(trifluoromethyl)phenyl]-1,4-dioxaspirino[4.5]dec-7-ene (4.04 g, yield 68.35%) as a white solid. LCMS (ESI) [M+H] + : 285. 1 H NMR (400MHz, DMSO) δ7.65 (m, J = 8.5 Hz, 4H), 6.21–6.16 (m, 1H), 3.92 (s, 4H), 2.57 (m J = 6.7, 2.3Hz, 2H), 2.42–2.38 (m, 2H), 1.83 (t, J = 6.5Hz, 2H).

[0145] Step 2: Synthesis of 8-[4-(trifluoromethyl)phenyl]-1,4-dioxyaspirino[4.5]decane

[0146] 8-[4-(Trifluoromethyl)phenyl]-1,4-dioxyaspirino[4.5]dec-7-ene (850 mg, 2.99 mmol, 1.0 eq) was dissolved in methanol (15.0 mL), and palladium / carbon (31.8 mg, 0.299 mmol, 0.1 eq) was added. The mixture was then reacted at room temperature under a hydrogen atmosphere for 3.0 hours. After the reaction was complete, the mixture was filtered and the organic phase was concentrated to obtain 8-[4-(trifluoromethyl)phenyl]-1,4-dioxyaspirino[4.5]decane (757 mg) as a white solid, which was used directly in the next reaction. LCMS (ESI) [M+H]+: 287. 1 H NMR (400MHz, DMSO) δ7.66 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 3.90 (d, J = 2.3 Hz, 4H), 2.72 (m, J = 14.4, 9.3, 3.2 Hz, 1H), 1.85–1.59 (m, 8H).

[0147] Step 3: Synthesis of 4-[4-(trifluoromethyl)phenyl]cyclohexane-1-one

[0148] 8-(4-(Trifluoromethyl)phenyl)-1,4-dioxaspirin[4.5]decane (700 mg, 2.44 mmol, 1.0 eq) was dissolved in 1,4-dioxane hydrochloride (4.0 mL, 4 mol / L) and allowed to react at room temperature for 16 hours. After completion, saturated sodium bicarbonate solution was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate, and the organic phase was concentrated to obtain 4-[4-(trifluoromethyl)phenyl]cyclohexane-1-one (603 mg) as a colorless, transparent oil, which was used directly in the next reaction. LCMS (ESI) [M+H]+: 243. 1 H NMR (400MHz, DMSO) δ7.67(d,J=8.2Hz,2H),7.54(d,J=8.1Hz,2H),3.18(m,J=12.1,3.5Hz,1H),2.60(m,J=14. 2, 6.0Hz, 2H), 2.28 (m, J = 14.7, 4.4, 2.1Hz, 2H), 2.08 (m, J = 12.2, 5.9, 2.9Hz, 2H), 1.92 (m, J = 13.2, 4.2Hz, 2H).

[0149] Step 4: Synthesis of 6-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0150] 4-[4-(Trifluoromethyl)phenyl]cyclohexan-1-one (300 mg, 1.24 mmol, 1.0 eq) was dissolved in acetonitrile (3 mL), and azobisisobutyronitrile (305 mg, 1.86 mmol, 1.5 eq) was added. N-bromosuccinimide (243 mg, 1.36 mmol, 1.1 eq) was then added at 0°C, and the mixture was allowed to react at 80°C for 2.0 hours. After the reaction was complete, thiourea (103 mg, 1.36 mmol, 1.1 eq) was added without further treatment. The mixture was allowed to react at 80°C for 1 hour, and then purified on a normal phase column. Impurities were removed by washing with ethyl acetate, followed by elution with a carbon dichloride and methanol system. The desired product eluted at a carbon dichloride:methanol volume ratio of 20:1. The organic phase was concentrated to yield 6-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (100 mg) as a yellow solid. LCMS (ESI) [M+H] +: 299.

[0151] Step 5: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide

[0152] 6-[4-(Trifluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (70.0 mg, 0.234 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (65.3 mg, 0.234 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (3 mL). N-methylimidazole (57.6 mg, 0.702 mmol, 3.0 eq) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (98.5 mg, 0.35 mmol, 1.5 eq) were then added and reacted at room temperature for 2.0 hours. After the reaction was complete, a white solid 2'-chloro-5'-methoxy-6-methyl-N-{6-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide (22.8 mg, yield 16.89%) was obtained. LCMS (ESI) [M+H]+: 559.0953. 1 H NMR (400MHz, DMSO) δ12.52(s,1H),8.77(s,1H),8.17(s,1H),7.68(d,J=8.1Hz,2H),7.58(d,J=8.1Hz,2H),7.52(s,1H),7.41(s ,1H),3.62(s,3H),3.15(d,J=9.8Hz,1H),2.96(dd,J=16.0,5.0Hz,1H),2.84–2.70(m,3H),2.58(s,3H),2.06(t,J=6.7Hz,2H).

[0153] Example 9: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-[6-(4-methylthiophen-2-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-[4,4'-bipyridine]-3-carboxamide (Compound 16)

[0154] Step 1: Synthesis of 8-(4-methylthiophen-2-yl)-1,4-dioxyaspirino[4.5]dec-7-ene

[0155] To 1,4-dioxane (20 mL) was added 1,4-dioxyaspirino[4.5]dec-7-en-8-yl trifluoromethanesulfonate (4.06 g, 14.09 mmol, 1.0 eq) and (4-methylthiophen-2-yl)boronic acid (2.0 g, 14.09 mmol, 1.0 eq). Cesium carbonate (13.77 g, 42.26 mmol, 3.0 eq) and water (5 mL) were then added. Finally, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (514 mg, 0.7 mmol, 0.05 eq) was added. The mixture was stirred at 80°C under nitrogen for 2 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and water. The organic layer was collected and dried over anhydrous sodium sulfate. The organic layer was concentrated and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 4:1) to afford 8-(4-methylthiophen-2-yl)-1,4-dioxaspirino[4.5]dec-7-ene (1.98 g, yield 59.6%) as a yellow oil. LCMS (ESI) [M+H] + : 237. 1 H NMR (400MHz, CDCl3) δ6.76(s,1H),6.67(d,J=1.7Hz,1H),6.01(m,J=4.0,1.4Hz,1H),4.00(d,J= 1.1Hz, 4H), 2.69–2.59 (m, 2H), 2.47–2.39 (m, 2H), 2.21 (d, J = 1.2Hz, 3H), 1.90 (t, J = 6.6Hz, 2H).

[0156] Step 2: Synthesis of 8-(4-methylthiophen-2-yl)-1,4-dioxaspiro[4.5]decane

[0157] 8-(4-Methylthiophen-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene (1.00 g, 4.24 mmol, 1.0 eq) was dissolved in anhydrous methanol (10 mL) and palladium on carbon (100 mg) was added. The mixture was reacted under hydrogen at room temperature for 4 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to obtain crude 8-(4-methylthiophen-2-yl)-1,4-dioxaspiro[4.5]decane (920 mg, 91.3% yield) as a clear oil.

[0158] Step 3: Synthesis of 4-(4-methylthiophen-2-yl)cyclohexane-1-one

[0159] 8-(4-Methylthiophen-2-yl)-1,4-dioxaspiro[4.5]decane (920 mg, 3.87 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL) and anhydrous ethanol (5 mL). Hydrochloric acid (5 mL) was added and the mixture was stirred at room temperature for 30 minutes. After the reaction was complete, water (40 mL) was added to the reaction solution. Solid sodium hydroxide was then added in small portions in an ice bath to adjust the pH to 8-9. The mixture was then extracted with ethyl acetate. The organic layer was collected and dried over anhydrous sodium sulfate. The organic layer was concentrated and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 37:3) to afford 4-(4-methylthiophen-2-yl)cyclohexane-1-one (636 mg, 84.8% yield) as a yellow oil. LCMS (ESI) [M+H]+: 195. 1 H NMR (400MHz, CDCl3) δ6.73(m,J=1.2Hz,1H),6.68(t,J=1.1Hz,1H),3.27(m,J=11.2,3.6 Hz,1H),2.51–2.46(m,4H),2.40–2.31(m,2H),2.23(d,J=1.1Hz,3H),2.02–1.90(m,2H).

[0160] Step 4: Synthesis of 6-(4-methylthiophen-2-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0161] 4-(4-Methylthiophen-2-yl)cyclohexane-1-one (636 mg, 3.28 mmol, 1.0 eq) and azobisisobutyronitrile (808 mg, 4.92 mmol, 1.5 eq) were added to acetonitrile (15 mL). N-bromosuccinimide (875 mg, 4.92 mmol, 1.5 eq) was then added in small portions under an ice bath. The mixture was stirred at 80°C for 4.5 hours. After the reaction was complete, the mixture was cooled to room temperature, and thiourea (300 mg, 3.94 mmol, 1.2 eq) was added. The mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated and purified by normal phase column chromatography (dichloromethane:methanol = 9:1) to afford crude 6-(4-methylthiophen-2-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine as a brown solid (150 mg, 18.3% yield). LCMS (ESI) [M+H] +: 251.

[0162] Step 5: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-[6-(4-methylthiophen-2-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-[4,4'-bipyridine]-3-carboxamide

[0163] 6-(4-Methylthiophen-2-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (100 mg, 0.4 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (167 mg, 0.6 mmol, 1.5 eq) were dissolved in ultra-dry N,N-dimethylformamide (3 mL). N-methylimidazole (99 mg, 1.2 mmol, 3.0 eq) was added, and finally tetramethylchlorouronium hexafluorophosphate (168 mg, 0.6 mmol, 1.5 eq) was added in an ice bath. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, a white solid 2'-chloro-5'-methoxy-6-methyl-N-[6-(4-methylthiophen-2-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-[4,4'-bipyridine]-3-carboxamide (13.0 mg, yield 6.4%) was obtained. LCMS (ESI) [M+H]+: 511.0735. 1 H NMR (400MHz, DMSO) δ12.50(s,1H),8.77(s,1H),8.17(s,1H),7.52(s,1H),7.41(s,1H),6.91(t,J=1.3Hz,1H),6.78(s,1H),3.61(s,3H),3.27(d ,J=13.9Hz,1H),3.06(dd,J=15.9,5.1Hz,1H),2.80–2.65(m,3H),2.58( s,3H),2.19(d,J=11.5Hz,1H),2.16(d,J=1.1Hz,3H),1.98–1.83(m,1H).

[0164] Example 10: Synthesis of 2'-chloro-N-[6-(4-cyanophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 17)

[0165] Step 1: Synthesis of 4-(1,4-dioxyaspirino[4.5]dec-7-en-8-yl)benzonitrile

[0166] 1,4-Dioxyaspirin[4.5]dec-7-en-8-yl trifluoromethanesulfonate (3.0 g, 10.42 mmol, 1.0 eq) and (4-cyanophenyl)boronic acid (1.68 g, 11.45 mmol, 1.1 eq) were dissolved in ultra-dry 1,4-dioxane (40.0 mL). Deionized water (10 mL), cesium carbonate (10.17 g, 31.22 mmol, 3.0 eq), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (760 mg, 1.04 mmol, 0.1 eq) were added. The atmosphere was replaced with nitrogen and the reaction was carried out at 80°C for 4 hours. After completion of the reaction, forward purification was performed to obtain 4-(1,4-dioxyaspirin[4.5]dec-7-en-8-yl)benzonitrile (2.26 g, 90.0% yield) as a yellow solid. LCMS (ESI) [M+H] +: 242. 1 H NMR (400MHz, DMSO-d6) δ7.80–7.73(m,2H),7.64–7.56(m,2H),6.24(m,J=4.1,2.4Hz,1 H), 3.92 (s, 4H), 2.56 (m, J = 4.5, 2.3Hz, 2H), 2.42–2.38 (m, 2H), 1.82 (t, J = 6.5Hz, 2H).

[0167] Step 2: Synthesis of 4-(1,4-dioxyaspirino[4.5]dec-8-yl)benzonitrile

[0168] 4-(1,4-Dioxyaspirino[4.5]dec-7-en-8-yl)benzonitrile (2.2 g, 9.13 mmol, 1.0 eq) was dissolved in methanol (60.0 mL) and palladium / carbon (1.1 g, 0.5 wt %) was added. The mixture was then reacted at room temperature under a hydrogen atmosphere for 0.5 hours. After completion of the reaction, the mixture was filtered and subjected to normal phase separation to obtain 4-(1,4-Dioxyaspirino[4.5]dec-8-yl)benzonitrile (1.28 g, 58.18% yield) as a white solid. LCMS (ESI) [M+H]+: 244. 1 H NMR (400MHz, DMSO-d6) δ7.78–7.70(m,2H),7.44(d,J=8.1Hz,2H),3.88(d,J= 2.0Hz, 4H), 2.69 (t, J = 10.8Hz, 1H), 1.76 (d, J = 9.4Hz, 4H), 1.70–1.56 (m, 4H).

[0169] Step 3: Synthesis of 4-(4-oxocyclohexyl)benzonitrile

[0170] 4-(1,4-Dioxyaspirino[4,5]dec-8-yl)benzonitrile (500 mg, 2.12 mmol, 1.0 eq) was dissolved in dioxane hydrochloride and allowed to react at room temperature for 16 hours. After completion, saturated sodium bicarbonate was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate and subjected to normal phase separation to afford 4-(4-oxocyclohexyl)benzonitrile (840 mg, 82.35% yield) as a white solid. LCMS (ESI) [M+H]+: 200. 1 H NMR (400MHz, DMSO-d6) δ7.85–7.73(m,2H),7.61–7.34(m,2H),3.22–3.11(m,1H),2.58(td,J=14 .1,6.0Hz,2H),2.27(m,J=12.9,4.7,2.5Hz,2H),2.13–2.00(m,2H),1.93(m,J=12.9,4.1Hz,2H).

[0171] Step 4: Synthesis of 4-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)benzonitrile

[0172] 4-(4-Oxocyclohexyl)benzonitrile (250 mg, 1.26 mmol, 1.0 eq), N-bromosuccinimide (245 mg, 1.38 mmol, 1.1 eq), and azobisisobutyronitrile (309 mg, 1.89 mmol, 1.5 eq) were added to acetonitrile (10 mL) and allowed to react for 12 hours. After the reaction was complete, thiourea (105 mg, 1.26 mmol, 1.1 eq) was added and the mixture was allowed to react at 80°C for 2 hours. The reaction solution was filtered, and the filtrate was separated by normal phase column chromatography to obtain crude 4-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)benzonitrile (28 mg) as a yellow solid. LCMS (ESI) [M+H]+: 256.

[0173] Step 5: Synthesis of 2'-chloro-N-[6-(4-cyanophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0174] 4-(2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)benzonitrile (28 mg, 0.11 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (30 mg, 0.11 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (2 mL). N-Methylimidazole (27 mg, 0.33 mmol, 3.0 eq) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (46 mg, 0.16 mmol, 1.5 eq) were added and reacted at room temperature for 4.0 hours. After the reaction was complete, a white solid, 2'-chloro-N-[6-(4-cyanophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (9.5 mg, yield 16.96%), was obtained. LCMS (ESI) [M+H]+: 516.1180. 1 H NMR (400MHz, DMSO-d6) δ12.47(s,1H),8.77(s,1H),8.17(s,1H),7.85–7.75(m,2H),7.58–7.54(m,2H),7.52(s,1H),7.41(s,1H),3.61(s, 3H),3.22–3.08(m,1H),2.94(dd,J=15.9,5.0Hz,1H),2.83–2.76(m,1H),2.73(d,J=12.2Hz,2H),2.58(s,3H),2.04(q,J=7.2,5.6Hz,2H).

[0175] Example 11: Synthesis of 2'-chloro-5'-methoxy-N-[6-(4-methoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 19)

[0176] 2'-Chloro-N-[6-(4-hydroxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (50 mg, 0.098 mmol, 1.0 eq) and sodium carbonate (31.4 mg, 0.296 mmol, 3.0 eq) were dissolved in methanol (2.0 mL). Methyl iodide (14.0 mg, 0.098 mmol, 1.0 eq) was slowly added dropwise at 0°C and the mixture was reacted at room temperature for 1 hour. After the reaction was complete, water and ethyl acetate were added to extract the separated liquids, and the organic phases were combined and purified to obtain 2'-chloro-5'-methoxy-N-[6-(4-methoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-6-methyl-[4,4'-bipyridine]-3-carboxamide (0.9 mg, yield 1.75%). LCMS (ESI) [M+H] + :521.10. 1 H NMR (400MHz, DMSO) δ8.81(s,1H),8.18(s,1H),7.53(s,1H),7.48(s,1H),7.11(d,J=8.2Hz,2H),6.70(d,J= 8.5Hz,2H),3.62(s,3H),2.95–2.82(m,2H),2.68(dd,J=10.6,4.8Hz,3H),2.60(s,3H),2.03–1.86(m,2H).

[0177] Example 12: Synthesis of 2'-(difluoromethyl)-5'-methoxy-6-methyl-N-(6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 25)

[0178] Step 1: Synthesis of methyl 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate

[0179] 2-(Difluoromethyl)-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 1.75 mmol, 1.0 eq) and methyl 4-bromo-6-methylnicotinate (403 mg, 1.75 mmol, 1.0 eq) were dissolved in ultra-dry 1,4-dioxane (4.0 mL). Water (1.0 mL), cesium carbonate (1.71 g, 5.25 mmol, 3.0 eq) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (38.4 mg, 0.05 mmol, 0.03 eq) were then added. The atmosphere was replaced with nitrogen and the reaction was carried out at 80°C for 2.5 hours. After the reaction was completed, forward column separation and purification afforded methyl 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (601 mg, crude) as a colorless oily liquid. LCMS (ESI) [M+H]+: 309.1. 1 H NMR (400MHz, DMSO) δ8.88(s,1H),8.52(s,1H),7.63(s,1H),7.37(s,1H),7.15–6.80(m,1H),3.85(s,3H),3.66(s,3H),2.58(s,3H).

[0180] Step 2: Synthesis of 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid

[0181] Methyl 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (550 mg, 1.78 mmol, 1.0 eq) was dissolved in methanol (6 mL) and lithium hydroxide monohydrate (112.5 mg, 2.67 mmol, 1.5 eq) was added. The mixture was reacted at 60°C for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, the pH was adjusted to neutral, and the mixture was extracted three times with ethyl acetate. The organic phase was concentrated to afford the crude product 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (500 mg, 95.60% yield) as a white solid. LCMS (ESI) [M+H]+: 295.08. 1 HNMR (400MHz, DMSO) δ13.04(s,1H),8.88(s,1H),8.50(s,1H),7.58(s,1H),7.30(s,1H),7.14–6.77(m,1H),3.85(s,3H),2.56(s,3H).

[0182] Step 3: Synthesis of 2'-(difluoromethyl)-5'-methoxy-6-methyl-N-(6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0183] 2'-(Difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (32 mg, 0.108 mmol, 1.0 eq) was dissolved in ultra-dry N,N-dimethylformamide (3 mL). 6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (25 mg, 0.108 mmol, 1.0 eq), N-methylimidazole (26.6 mg, 0.324 mmol, 3.0 eq) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (45.7 mg, 0.162 mmol, 1.5 eq) were added in sequence and reacted at room temperature for 2 hours. After the reaction, a white solid 2'-(difluoromethyl)-5'-methoxy-6-methyl-N-(6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (32.8 mg, yield 59.9%) was obtained. LCMS (ESI) [M+H] + :507.1668. 1 H NMR (400MHz, DMSO-d6) δ12.54(s,1H),8.77(s,1H),8.46(s,1H),7.68(s,1H),7.41(s,1H),7.36–7.29(m,4H),7.22(m,J=8.6,5.6,2.6Hz,1H) ,7.15–6.80(m,1H),3.69(s,3H),3.02(m,J=9.8,5.1Hz,1H),2.91(dd, J=16.0,5.0Hz,1H),2.80–2.65(m,3H),2.59(s,3H),2.06–1.98(m,2H).

[0184] Example 13: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[(tetrahydrofuran-3-yl)methoxy]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide (Compound 28)

[0185] Step 1: Synthesis of 3-(bromomethyl)tetrahydrofuran

[0186] (Tetrahydrofuran-3-yl)methanol (1.00 g, 9.79 mmol, 1.0 eq) and carbon tetrabromide (3.85 g, 11.61 mmol, 1.2 eq) were added to ultra-dry dichloromethane (15 mL). Triphenylphosphine (3.85 g, 14.68 mmol, 1.5 eq) was then added under an ice bath. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, dichloromethane and water were added to extract the reaction solution. The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated to yield crude 3-(bromomethyl)tetrahydrofuran as a yellow solid.

[0187] Step 2: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[(tetrahydrofuran-3-yl)methoxy]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide

[0188] 3-(Bromomethyl)tetrahydrofuran (76 mg, 0.47 mmol, 4.0 eq) was dissolved in ultra-dry N,N-dimethylformamide (4 mL). Sodium hydroxide (47 mg, 1.16 mmol, 10.0 eq) was added under ice-cooling conditions. 2'-Chloro-N-(6-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (50 mg, 0.12 mmol, 1.0 eq) dissolved in ultra-dry N,N-dimethylformamide was added dropwise. The mixture was reacted at 100°C for 2 hours. After the reaction was complete, the reaction solution was filtered to obtain 2'-chloro-5'-methoxy-6-methyl-N-{6-[(tetrahydrofuran-3-yl)methoxy]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide (5.0 mg, 8.3% yield) as a white solid. LCMS (ESI) [M+H]+: 515.1010. 1 H NMR (400MHz, DMSO) δ9.04(s,1H),8.11(d,J=1.4Hz,1H),7.43(d,J=1.4Hz,1H),7.23( s,1H),4.99(d,J=3.8Hz,1H),4.00(s,1H),3.84–3.68(m,3H),3.65–3.59(m,1H),3.57 (d,J=1.3Hz,3H),3.51(m,J=7.8,5.7Hz,1H),2.74(dd,J=16.2,4.6Hz,1H),2.70–2.5 3(m,6H),2.40(dd,J=16.1,6.0Hz,1H),1.93–1.71(m,3H),1.55(m,J=9.3,5.9Hz,1H).

[0189] Example 14: Synthesis of 2'-chloro-N-[6-(4-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 29)

[0190] Step 1: Synthesis of 8-(4-fluorophenyl)-1,4-dioxyaspirino[4.5]decane

[0191] 1,4-Dioxyaspirino[4.5]dec-7-en-8-yl trifluoromethanesulfonate (4.0 g, 13.87 mmol, 1.0 eq) and 4-fluorophenylboronic acid (2.64 g, 13.87 mmol, 1.0 eq) were dissolved in ultra-dry 1,4-dioxane (30.0 mL). Deionized water (7.5 mL), cesium carbonate (13.56 g, 41.62 mmol, 3.0 eq), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (0.456 g, 0.624 mmol, 0.41 eq) were then added. The atmosphere was purged with nitrogen and the reaction was continued at 80°C for 2.5 hours. After completion of the reaction, forward column purification afforded 8-(4-fluorophenyl)-1,4-dioxyaspirino[4.5]decane (2.04 g, 67.46% yield) as a white solid. LCMS (ESI) [M+H] +: 235. 1 H NMR (400MHz, DMSO) δ7.48–7.41(m,2H),7.16–7.10(m,2H),6.00–5.96(m,1H),3.91(s,4H),2.52(s,2H),2.38–2.33(m,2H),1.80(t,J=6.5Hz,2H).

[0192] Step 2: Synthesis of 8-(4-fluorophenyl)-1,4-dioxyaspirino[4.5]decane

[0193] 8-(4-Fluorophenyl)-1,4-dioxyaspirino[4.5]dec-7-ene (1.0 g, 4.26 mmol, 1.0 eq) was dissolved in methanol (15.0 mL), followed by the addition of palladium / carbon (45.4 mg, 0.42 mmol, 0.1 eq). The reaction was allowed to proceed at room temperature under a hydrogen atmosphere for 3 hours. After completion of the reaction, the reaction solution was filtered, and the organic phase was concentrated to afford crude white solid 8-(4-fluorophenyl)-1,4-dioxyaspirino[4.5]decane (980 mg), which was used directly in the next reaction. LCMS (ESI) [M+H]+: 237. 1H NMR (400MHz, DMSO) δ7.28–7.22(m,2H),7.12–7.05(m,2H),3.88(d,J=2.4Hz,4H),2.58(m,J=14.5,9.5,3.1Hz,1H),1.79–1.55(m,8H).

[0194] Step 3: Synthesis of 4-(4-fluorophenyl)cyclohexane-1-one

[0195] 8-(4-Fluorophenyl)-1,4-dioxaspirino[4.5]decane (500 mg, 2.12 mmol, 1.0 eq) was dissolved in tetrahydrofuran (4 mL) and ethanol (2 mL). Concentrated hydrochloric acid (2 mL) was added and the mixture was allowed to react at room temperature for 16 hours. After the reaction was complete, saturated aqueous sodium bicarbonate was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate, and the organic phase was concentrated to obtain crude 4-(4-fluorophenyl)cyclohexane-1-one (424 mg) as a colorless, transparent oil, which was used directly in the next reaction. LCMS (ESI) [M+H]+: 193. 1 H NMR (400MHz, DMSO) δ7.38–7.29(m,2H),7.17–7.06(m,2H),3.14–3.01(m,1H),2.57(td,J=14.1,6.0Hz ,2H),2.25(m,J=14.7,4.5,2.1Hz,2H),2.04(m,J=12.1,5.8,2.7Hz,2H),1.86(m,J=13.2,4.1Hz,2H).

[0196] Step 4: Synthesis of 6-(4-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0197] 4-(4-Fluorophenyl)cyclohexane-1-one (200 mg, 1.04 mmol, 1.0 eq) was dissolved in acetonitrile (3 mL), and azobisisobutyronitrile (256 mg, 1.56 mmol, 1.5 eq) was added. N-bromosuccinimide (204 mg, 1.14 mmol, 1.1 eq) was added at 0°C, and the mixture was allowed to react at 80°C for 2 hours. After the reaction was complete, thiourea (87 mg, 1.14 mmol, 1.1 eq) was added without further treatment, and the reaction was continued at 80°C for 1 hour. A solid precipitated, which was filtered to give the crude product 6-(4-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (103 mg) as a white solid. LCMS (ESI) [M+H]+: 249. 1HNMR (400MHz, DMSO) δ9.22(s,2H),7.37–7.32(m,2H),7.18–7.12(m,2H),3.06–2.98(m,1H),2.61–2.55(m,4H),2.01–1.89(m,2H).

[0198] Step 5: Synthesis of 2'-chloro-N-[6-(4-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0199] 6-(4-Fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (89.2 mg, 0.359 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (100 mg, 0.359 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (3 mL), followed by the addition of N-methylimidazole (88.3 mg, 1.16 mmol, 3.0 eq) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (151.1 mg, 0.54 mmol, 1.5 eq), and the mixture was reacted at room temperature for 2.0 hours. After the reaction was complete, a white solid 2'-chloro-N-[6-(4-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (54.6 mg, yield 29.89%) was obtained. LCMS (ESI) [M+H] + :509.0911. 1 H NMR (400MHz, DMSO) δ8.80(s,1H),8.16(s,1H),7.49(s,1H),7.39–7.34(m,3H),7.17–7.10(m,2H),6.07(s,1H),3.62(s ,3H),3.03(dd,J=9.8,4.7Hz,1H),2.90(dd,J=15.4,4.9Hz,1H),2.76–2.65(m,3H),2.57(s,3H),1.99(q,J=8.2Hz,2H).

[0200] Example 15: Synthesis of 5'-methoxy-2',6'-dimethyl-N-(6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 24)

[0201] Step 1: Synthesis of 5'-methoxy-2',6'-dimethyl-[4,4'-bipyridine]-3-carboxylic acid

[0202] 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (200 mg, 0.72 mmol, 1.0 eq) and trimethylcyclotriboroxane (3.5 mol / L) (0.23 mL, 0.79 mmol, 1.1 eq) were dissolved in ethylene glycol dimethyl ether (3.5 mL). Potassium carbonate (300 mg, 2.16 mmol, 3.0 eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (53 mg, 0.072 mmol, 0.1 eq) were added. The mixture was reacted at 120°C in a sealed tube under nitrogen protection for 8 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was separated and purified by reverse phase column chromatography to obtain crude 5'-methoxy-2',6'-dimethyl-[4,4'-bipyridine]-3-carboxylic acid (45 mg, yield 24.2%). LCMS (ESI) [M + H] + :259.

[0203] Step 2: Synthesis of 5'-methoxy-2',6'-dimethyl-N-(6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0204] 5'-Methoxy-2',6'-dimethyl-[4,4'-bipyridine]-3-carboxylic acid (40 mg, 0.16 mmol, 1.0 eq) and 6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (36 mg, 0.16 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (2 mL), followed by the addition of N-methylimidazole (76 mg, 0.93 mmol, 6.0 eq). Finally, N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (65 mg, 0.23 mmol, 1.5 eq) was added in an ice bath and the reaction was allowed to proceed at room temperature for 16 hours. After the reaction, the product was isolated and purified to give a white solid 5'-methoxy-2',6'-dimethyl-N-(6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (11.7 mg, yield 16.0%). LCMS (ESI) [M + H] + :471.2464. 1H NMR(400MHz,DMSO)δ12.45(s,1H),8.71(s,1H),8.18(s,1H),7.36–7.29(m,5H),7.25–7.19(m,2H),3.57(s,3H),3.09–2.96(m,1H), 2.92(dd,J=17.0,4.2Hz,1H), 2.77(dd,J=14.2,4.0Hz,1H), 2.72(d,J=5.3Hz,2H), 2.57(s,3H), 2.47(s,3H), 2.02(m,J=4.9Hz,2H).

[0205] Example 16: Synthesis of 2'-chloro-N-{6-[(4,4-difluorocyclohexyl)methoxy]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 27)

[0206] Step 1: Synthesis of 1,1-difluoro-4-(iodomethyl)cyclohexane

[0207] (4,4-Difluorocyclohexyl)methanol (500 mg, 3.33 mmol, 1.0 eq) was dissolved in ultra-dry dichloromethane (10.0 mL). Imidazole (295 mg, 4.33 mmol, 1.3 eq), triphenylphosphine (1.14 g, 4.33 mmol, 1.3 eq), and iodine (1.1 g, 4.33 mmol, 1.3 eq) were added sequentially in an ice bath. The mixture was allowed to react at 0°C for 30 minutes. After completion, the reaction was quenched by the addition of saturated aqueous sodium bisulfite solution. The separated phases were extracted with ethyl acetate, and the organic phases were combined and concentrated to afford crude 1,1-difluoro-4-(iodomethane)cyclohexane as a yellow solid (3.2 g, 100.0% yield).

[0208] Step 2: Synthesis of 6-[(4,4-difluorocyclohexyl)methoxy]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0209] Dissolve tert-butyl (6-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbamate (300 mg, 1.11 mmol, 1.0 eq) in ultra-dry N,N-dimethylformamide (3 mL). Add sodium hydroxide (356 mg, 8.89 mmol, 8.0 eq) in an ice bath. Stir and react for 5 minutes. Then, slowly add 1,1-difluoro-4-(iodomethane)cyclohexane (2.3 g, 8.89 mmol, 8.0 eq) dissolved in 2 mL of ultra-dry N,N-dimethylformamide dropwise. React at 80°C for 1 hour. After completion of the reaction, saturated ammonium chloride solution was added dropwise in an ice bath to quench the reaction mixture. Ethyl acetate was then added to extract the separated liquids. The organic phases were combined, concentrated, and then dissolved in methanol. Separation and purification using a reverse-phase column gave 6-[(4,4-difluorocyclohexyl)methoxy]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (73 mg, 21.7% yield) as a transparent oil. LCMS (ESI) [M+H]+: 303.

[0210] Step 3: Synthesis of 2'-chloro-N-{6-[(4,4-difluorocyclohexyl)methoxy]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0211] 6-[(4,4-Difluorocyclohexyl)methoxy]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (70 mg, 0.23 mmol, 1.0 eq) was dissolved in ultra-dry N,N-dimethylformamide (4 mL), and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (64 mg, 0.23 mmol, 1.0 eq) and N-methylimidazole (114 mg, 1.39 mmol, 6.0 eq) were added. Then, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (98 mg, 0.35 mmol, 1.5 eq) was added under ice-cooling conditions and the reaction was carried out at room temperature for 16 hours. After the reaction, preparative separation and purification were performed to obtain 2'-chloro-N-(6-((4,4-difluorocyclohexyl)methoxy)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (4.0 mg, 3.1% yield) as a white solid. LCMS (ESI) [M+H]+: 563.1645. 1H NMR (400MHz, DMSO) δ8.86 (s, 1H), 8.13 (s, 1H), 7.46 (d, J = 6.2Hz, 2H), 7.32 (s, 1H) ),5.15(m,J=5.1,3.7Hz,1H),3.76(s,3H),3.12–3.02(m,2H),2.83(dd,J=16.3,4 .8Hz,1H),2.56(s,3H),2.39(dd,J=15.7,5.9Hz,2H),2.28–2.16(m,1H),1.99(d ,J=9.3Hz,2H),1.81(s,3H),1.74(d,J=14.8Hz,4H),1.17(m,J=13.3,7.9Hz,2H).

[0212] Example 17: Synthesis of 2'-chloro-N-{6-[4-(difluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 30)

[0213] Step 1: Synthesis of 8-[4-(difluoromethyl)phenyl]-1,4-dioxyaspirino[4.5]dec-7-ene

[0214] 1,4-Dioxyaspirino[4.5]dec-7-en-8-yl trifluoromethanesulfonate (3.0 g, 10.4 mmol, 1.0 eq) and 4-(difluoromethyl)phenylboronic acid (2.64 g, 13.87 mmol, 1.0 eq) were dissolved in ultra-dry 1,4-dioxane (16.0 mL), and deionized water (4.0 mL), cesium carbonate (10.17 g, 31.2 mmol, 3.0 eq) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (228 mg, 0.312 mmol, 0.03 eq) were added. The nitrogen atmosphere was replaced three times and the reaction was carried out at 80°C for 2.5 hours. After the reaction was complete, the product peak was purified in the forward direction (petroleum ether:ethyl acetate volume ratio of 8:1) and concentrated to afford 8-[4-(difluoromethyl)phenyl]-1,4-dioxaspirino[4.5]dec-7-ene (1.76 g, 46.21% yield) as a white solid. LCMS (ESI) [M+H]+: 267.3. 1 H NMR (400MHz, DMSO) δ7.53 (m, J=8.3Hz, 4H), 7.15–6.84 (m, 1H), 6.14–6.10 (m, 1H), 3.92(s,4H),2.56(m,J=3.7,1.9Hz,2H),2.41–2.37(m,2H),1.82(t,J=6.5Hz,2H).

[0215] Step 2: Synthesis of 8-[4-(difluoromethyl)phenyl]-1,4-dioxyaspirino[4.5]decane

[0216] 8-[4-(Difluoromethyl)phenyl]-1,4-dioxyaspirino[4.5]dec-7-ene (1.0 g, 3.76 mmol, 1.0 eq) was dissolved in methanol (15.0 mL), and palladium / carbon (40.0 mg, 0.376 mmol, 0.1 eq) was added. The mixture was then reacted at room temperature under a hydrogen atmosphere for 4 hours. After the reaction was complete, the mixture was filtered and the organic phase was concentrated to obtain 8-[4-(difluoromethyl)phenyl]-1,4-dioxyaspirino[4.5]decane (1.04 g) as a white solid, which was used in the next step without purification. LCMS (ESI) [M+H]+: 269.3. 1 H NMR (400MHz, DMSO) δ7.48(d,J=7.9Hz,2H),7.36(d,J=8.0Hz,2H),7.14–6.82(m, 1H), 3.88 (d, J = 2.3Hz, 4H), 2.64 (m, J = 14.5, 9.6, 3.4Hz, 1H), 1.78–1.58 (m, 8H).

[0217] Step 3: Synthesis of 4-[4-(difluoromethyl)phenyl]cyclohexane-1-one

[0218] 8-[4-(Difluoromethyl)phenyl]-1,4-dioxaspirino[4.5]decane (400 mg, 1.41 mmol, 1.0 eq) was dissolved in a tetrahydrofuran / ethanol solution (4 mL / 2 mL) and concentrated hydrochloric acid (1.0 mL) was added. The mixture was then reacted at 60°C for 2.0 hours. After completion of the reaction, the pH was adjusted to neutral by adding saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and purified by forward purification (petroleum ether:ethyl acetate = 2:1) to yield the product. The organic phase was concentrated to afford 4-[4-(difluoromethyl)phenyl]cyclohexane-1-one (263 mg, 83.22% yield) as a yellow, transparent oil. LCMS (ESI) [M+H]+: 225.3. 1 H NMR (400MHz, DMSO) δ7.53–7.42(m,4H),7.15–6.84(m,1H),3.13(m,J=12.1,3.5Hz,1H),2.59(m,J=14.2,6 .0Hz,2H),2.27(m,J=14.6,4.4,2.1Hz,2H),2.07(m,J=12.2,5.9,3.0Hz,2H),1.90(m,J=13.2,4.1Hz,2H).

[0219] Step 4: Synthesis of 6-[4-(difluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0220] 4-[4-(Difluoromethyl)phenyl]cyclohexan-1-one (220 mg, 0.98 mmol, 1.0 eq) was dissolved in acetonitrile (2 mL), and azobisisobutyronitrile (242 mg, 1.47 mmol, 1.5 eq) was added. N-bromosuccinimide (192 mg, 1.07 mmol, 1.1 eq) was then added at 0°C, and the mixture was allowed to react at 80°C for 2.0 hours. After the reaction was complete, thiourea (87 mg, 1.14 mmol, 1.1 eq) was added without further treatment. After 1.0 hour at 80°C, the product precipitated and was filtered to obtain 6-[4-(difluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (136 mg, 34.46% yield) as a white solid. LCMS (ESI) [M+H]+: 281. 1 H NMR (400MHz, DMSO) δ9.18 (s, 2H), 7.57–7.44 (m, 4H), 7.28–7.01 (m, 1H), 3.08 (m, J = 1 0.4, 4.1Hz, 1H), 2.80 (dd, J = 15.7, 4.9Hz, 1H), 2.66–2.55 (m, 3H), 2.04–1.91 (m, 2H).

[0221] Step 5: Synthesis of 2'-chloro-N-{6-[4-(difluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0222] 6-[4-(Difluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (60.0 mg, 0.215 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (60.6 mg, 0.215 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (2 mL), and N-methylimidazole (53 mg, 0.646 mmol, 3.0 eq) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (90.8 mg, 0.323 mmol, 1.5 eq) were added, followed by reaction at room temperature for 2 hours. After the reaction was complete, 2'-chloro-N-{6-[4-(difluoromethyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (17.4 mg, yield 14.96%) was obtained as a white solid. LCMS (ESI) [M+H]+: 541.1991. 1H NMR (400MHz, DMSO) δ12.51(s,1H),8.77(s,1H),8.17(s,1H),7.55–7.46(m,5H),7.41(s,1H),7.17–6.85(m,1H),3.62 (s,3H),3.09(d,J=10.2Hz,1H),2.94(dd,J=15.9,5.0Hz,1H),2.81–2.68(m,3H),2.58(s,3H),2.04(m,J=8.0Hz,2H).

[0223] Example 18: Synthesis of N-[6-(4-aminophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 18)

[0224] Step 1: Synthesis of tert-butyl [4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl]carbamate

[0225] 1,4-Dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (4 g, 13.9 mmol, 1.0 eq), {4-[(tert-butoxycarbonyl)amino]phenyl}boronic acid (3.62 g, 15.2 mmol, 1.1 eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.02 g, 1.39 mmol, 0.1 eq) and cesium carbonate (9.03 g, 27.8 mmol, 2.0 eq) were dissolved in 1,4-dioxane (40 mL) and water (4 mL) and reacted at 80 ° C under nitrogen protection for 5 hours. After the reaction was complete, the reaction solution was filtered, concentrated, mixed, and then separated and purified by normal phase column (ethyl acetate / petroleum ether, ethyl acetate content was 30%) to obtain a yellow solid [4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl]carbamic acid tert-butyl ester (2.13 g, yield 46%). 1 H NMR(400MHz, DMSO)δ9.36(s,1H),7.42(d,J=8.4Hz,2H),7.35–7.28(m,2H),5.94(m,J=3.9,2.0H z, 1H), 3.92 (s, 4H), 2.35 (dd, J = 4.4, 2.1Hz, 2H), 1.81 (t, J = 6.4Hz, 2H), 1.50 (d, J = 6.1Hz, 11H).

[0226] Step 2: Synthesis of tert-butyl [4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl]carbamate

[0227] Dissolve tert-butyl [4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl]carbamate (2.13 g, 6.4 mmol, 1.0 eq) and palladium on carbon (213 mg) in methanol (23 mL). The mixture was replaced with hydrogen three times and allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was filtered, stirred, and purified using a normal phase column (ethyl acetate / petroleum ether, ethyl acetate % = 20%) to obtain tert-butyl [4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl]carbamate (1.13 g, 3.4 mmol, 50% yield) as a white solid. 1 H NMR (400MHz, DMSO) δ9.23 (s, 1H), 7.36 (d, J = 8.1Hz, 2H), 7.10 (d, J = 8.5Hz, 2H), 3.89 (d, J = 2.3Hz, 4H), 1.80–1.53 (m, 9H), 1.48 (s, 9H).

[0228] Step 3: Synthesis of tert-butyl [4-(4-oxocyclohexyl)phenyl]carbamate

[0229] Tert-butyl [4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl]carbamate (1.13 g, 3.4 mmol, 1.0 eq) and p-toluenesulfonic acid hydrate (130 mg, 0.68 mmol, 0.2 eq) were dissolved in acetone (5 mL) and water (10 mL) and reacted at 60°C for 16 hours. After the reaction was complete, the mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate and water. The organic phase was dehydrated with anhydrous sodium sulfate, concentrated, and dried to afford tert-butyl [4-(4-oxocyclohexyl)phenyl]carbamate (700 mg, 2.42 mmol, 71% yield) as a yellow solid. 1 H NMR(400MHz,DMSO)δ9.26(s,1H),7.39(d,J=8.2Hz,2H),7.22–7.14(m,2H),2.99(m,J=12.0,3.4Hz,1H),2.65 –2.53(m,2H),2.27(m,J=14.6,4.4,2.1Hz,2H),2.10–1.99(m,2H),1.84(m,J=13.2,4.1Hz,2H),1.48(s,9H).

[0230] Step 4: Synthesis of tert-butyl [4-(3-bromo-4-oxocyclohexyl)phenyl]carbamate

[0231] Dissolve tert-butyl [4-(4-oxocyclohexyl)phenyl]carbamate (700 mg, 1.9 mmol, 1.0 eq) in tetrahydrofuran, add phenyltrimethylammonium tribromide (715 mg, 1.9 mmol, 1.0 eq), and react at room temperature. After completion of the reaction, extract the mixture with ethyl acetate and water. The organic phase is retained and concentrated to yield crude tert-butyl [4-(3-bromo-4-oxocyclohexyl)phenyl]carbamate (400 mg). LCMS (ESI) [M+H]+: 268.

[0232] Step 5: Synthesis of tert-butyl [4-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)phenyl]carbamate

[0233] Dissolve tert-butyl [4-(3-bromo-4-oxocyclohexyl)phenyl]carbamate (300 mg, 0.82 mmol, 1.0 eq) in acetonitrile (5 mL), add thiourea (63 mg, 0.82 mmol, 1.0 eq), and react at 35°C for 3 hours. After the reaction is complete, mix the sample and purify it using a normal phase column (dichloromethane / methanol, 10% methanol content) to obtain tert-butyl [4-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)phenyl]carbamate (150 mg, 0.43 mmol, 53% yield) as a brown solid. 1 H NMR (400MHz, DMSO) δ9.28(s,1H),8.07(s,2H),7.40(d,J=8.2Hz,2H),7.26–7.14(m,2H),3.12(m,J=7.3,3.5 Hz, 1H), 2.92 (m, J = 12.3, 3.6 Hz, 1H), 2.78–2.69 (m, 1H), 2.58–2.54 (m, 3H), 1.97–1.88 (m, 1H), 1.48 (s, 9H).

[0234] Step 6: Synthesis of tert-butyl {4-[2-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridyl]-3-carboxamido)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl]phenyl}carbamate

[0235] Tert-butyl [4-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)phenyl]carbamate (60 mg, 0.174 mmol, 1.0 eq), 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (45 mg, 0.26 mmol, 2.0 eq), N,N,N,N-tetramethylchloromethylimidazole hexafluorophosphate (73 mg, 0.26 mmol, 1.5 eq) and N-methylimidazole (43 mg, 0.52 mmol, 3.0 eq) were dissolved in N,N-dimethylformamide (2 mL) and reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated to give crude tert-butyl {4-[2-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridyl]-3-carboxamido)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl]phenyl}carbamate (70 mg) as a brown oil. LCMS (ESI) [M+H]+: 606.2424.

[0236] Step 7: Synthesis of N-[6-(4-aminophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0237] Tert-butyl {4-[2-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl]phenyl}carbamate (65 mg, 0.11 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (0.3 mL) and dichloromethane (1 mL) and allowed to react at room temperature for 3 hours. Upon completion of the reaction, N-[6-(4-aminophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (5.7 mg, 10% yield) was obtained as a white solid. LCMS (ESI) [M+H]+: 506.1417. 1 H NMR(400MHz,DMSO)δ12.45(s,1H),8.77(s,1H),8.17(s,1H),7.52(s,1H),7.41(s,1H),7.00–6.92(m,2H),6.55–6.47(m,2H) ,4.89(s,2H),3.62(s,3H),2.84(d,J=12.0Hz,2H),2.73–2.60(m,2H),2.58(s,3H),2.53(d,J=9.7Hz,1H),2.00–1.84(m,2H).

[0238] Example 19: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(6-morpholinyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 13)

[0239] Step 1: Synthesis of 6-morpholino-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0240] 4-Morpholinocyclohexan-1-one (1 g, 5.46 mmol, 1.0 eq) was dissolved in acetonitrile (10 mL), and N-bromosuccinimide (972 mg, 5.46 mmol, 1.0 eq) was added. The mixture was reacted at 80°C under nitrogen for 2 hours. The temperature was then cooled to room temperature, and thiourea (415 mg, 1.0 eq) was added. The reaction was continued at 80°C under nitrogen for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and stirred for 6 hours. The reaction solution was filtered to obtain a crude yellow solid, 6-morpholino-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (256 mg, 19.6% yield). This crude product was used directly in the next step without further purification. LCMS (ESI) [M+H]+: 240.

[0241] Step 2: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(6-morpholino-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0242] 6-Morpholinyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (256 mg, 1.07 mmol, 1.0 eq) was dissolved in acetonitrile (5 mL), and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (298 mg, 1.07 mmol, 1.0 eq), tetramethylchlorouronium hexafluorophosphate (359 mg, 1.21 mmol, 1.2 eq) and N-methylimidazole (263 mg, 3.21 mmol, 3.0 eq) were added. The reaction was carried out at room temperature under nitrogen protection for 12 hours. After the reaction was complete, preparative separation and purification were performed to obtain a white solid 2'-chloro-5'-methoxy-6-methyl-N-(6-morpholinyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (8.5 mg, yield 1.6%). LCMS (ESI) [M+H]+: 500.15. 1H NMR (400MHz, DMSO) δ12.49(s,1H),8.77(s,1H),8.18(d,J=1.6Hz,1H),7.53(d,J=1.6Hz,1H),7.42 (s,1H),3.62(d,J=1.6Hz,6H),2.89–2.63(m,5H),2.59(d,J=1.6Hz,8H),2.05(s,1H),1.70(s,1H).

[0243] Example 20: Synthesis of N-[6-(6-aminopyridin-3-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 20)

[0244] Step 1: Synthesis of tert-butyl[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate

[0245] Tert-butyl (5-bromopyridin-2-yl) carbamate (10 g, 36.6 mmol, 1.0 eq), pinacol diboron (13.96 g, 55.0 mmol, 1.5 eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2.66 g, 3.66 mmol, 0.1 eq), and potassium acetate (10.76 g, 109.8 mmol, 3.0 eq) were dissolved in 1,4-dioxane (40.0 mL) and reacted at 100°C under nitrogen for 16 hours. After completion of the reaction, the filtrate was collected, concentrated, and purified by normal phase purification to obtain the crude product, tert-butyl [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl] carbamate (5.0 g, 42.6% yield), as a yellow solid. LCMS(TOF MS ES+)m / z[M+H]+:265.13.

[0246] Step 2: Synthesis of [5-(1,4-dioxaspiro[4.5]dec-7-ene-8-yl)pyridin-2-yl]carbamate

[0247] 1,4-Dioxaspiro[4.5]decane-7-ene-8-trifluoromethanesulfonate (3.4 g, 10.6 mmol, 1.2 eq), tert-butyl[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (2.55 g, 8.85 mmol, 1.0 eq), cesium carbonate (8.6 g, 26.6 mmol, 3.0 eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (647 mg, 0.885 mmol, 0.1 eq) were dissolved in a mixed solvent of 1,4-dioxane (30 mL) and water (3 mL) and reacted at 80 ° C under nitrogen atmosphere for 3 hours. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated and purified by normal phase purification to obtain the product, tert-butyl[5-(1,4-dioxaspiro[4.5]dec-7-ene-8-yl)pyridin-2-yl]carbamate (2.25 g, 63.9% yield), as a white solid. LCMS (TOF MS ES+) m / z [M+H]+: 277.11. 1 H NMR (400MHz, DMSO) δ9.77 (s, 1H), 8.29 (d, J = 2.4Hz, 1H), 7.82–7.70 (m, 2H), 6.05–5.99 (m, 1H ),3.91(s,4H),2.53(t,J=4.8Hz,2H),2.39–2.33(m,2H),1.80(t,J=6.5Hz,2H),1.47(s,9H).

[0248] Step 3: Synthesis of [5-(1,4-dioxaspiro[4.5]n-decane-8-yl)pyridin-2-yl]decane

[0249] Tert-butyl[5-(1,4-dioxaspiro[4.5]decane-7-ene-8-yl)pyridin-2-yl]carbamate (2.2 g, 6.6 mmol, 1.0 eq) was dissolved in methanol (20.0 mL) and a palladium-carbon catalyst (220 mg) was added. The mixture was reacted at 30°C under a hydrogen atmosphere for 16 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated to afford tert-butyl[5-(1,4-dioxaspiro[4.5]decane-7-ene-8-yl)pyridin-2-yl]decane (1.3 g, 59.1% yield) as a white solid. LCMS (TOF MS ES+) m / z [M+H]+: 279.12. 1H NMR (400MHz, DMSO) δ9.61(s,1H),8.09(s,1H),7.69(d,J=8.6Hz,1H),7.58(d,J=8.7Hz,1H),3.88(d ,J=2.0Hz,4H),1.75(d,J=10.7Hz,4H),1.62(t,J=11.7Hz,4H),1.46(d,J=1.9Hz,9H),1.23(s,1H).

[0250] Step 4: Synthesis of 4-(6-aminopyridin-3-yl)cyclohexanone

[0251] Tert-butyl[5-(1,4-dioxaspiro[4,5-[1,5-decan-8-yl]pyridin-2-yl]decane (1.3 g, 3.9 mmol, 1.0 eq) and toluenesulfonic acid monohydrate (892.7 mg, 4.7 mmol, 1.2 eq) were dissolved in a mixture of acetone (5.0 mL) and water (10.0 mL) and reacted at 60°C for 1 hour. After completion of the reaction, the mixture was quenched with saturated sodium bicarbonate and extracted three times with ethyl acetate. The mixture was concentrated and purified by reverse phase chromatography to afford 4-(6-aminopyridin-3-yl)cyclohexanone (600 mg, 80.6% yield) as a yellow oil. LCMS (TOF MS ES+) m / z [M+H]+: 191.11. 1 H NMR (400MHz, DMSO) δ7.82(d,J=2.4Hz,1H),7.34(dd,J=8.5,2.5Hz,1H),6.41(d,J=8.4Hz,1H),5.81(s ,2H),2.62–2.51(m,3H),2.23(m,J=14.7,2.3Hz,2H),2.04–1.94(m,2H),1.80(m,J=13.2,4.0Hz,2H).

[0252] Step 5: Synthesis of [5-(4-oxocyclohexyl)pyridin-2-yl]carbamate

[0253] 4-(6-Aminopyridin-3-yl)cyclohexanone (400 mg, 2.094 mmol, 1.0 eq), di-tert-butyl dicarbonate (913 mg, 4.188 mmol, 2.0 eq), and 4-dimethylaminopyridine (255.5 mg, 2.094 mmol, 1.0 eq) were dissolved in tetrahydrofuran (15.0 mL) and reacted at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated and purified using a normal phase column to obtain tert-butyl [5-(4-oxocyclohexyl)pyridin-2-yl]carbamate (120 mg, 19.8% yield). LCMS (TOF MS ES+) m / z [M+H]+: 235.12. 1H NMR (400MHz, DMSO) δ9.64(s,1H),8.18(d,J=2.3Hz,1H),7.74–7.63(m,2H),3.04(t,J=12.1Hz,1H),2.57(m ,J=14.2,6.0Hz,2H),2.26(d,J=14.5Hz,2H),2.09–1.95(m,2H),1.88(m,J=13.0,4.0Hz,2H),1.46(s,9H).

[0254] Step 6: Synthesis of tert-butyl[5-(3-bromo-4-oxocyclohexyl)pyridin-2-yl]carbamate

[0255] Dissolve tert-butyl (5-(4-oxocyclohexyl)pyridin-2-yl)carbamate (80 mg, 0.275 mmol, 1.0 eq) and phenyltrimethylammonium tribromide (103.6 mg, 0.275 mmol, 1.0 eq) in tetrahydrofuran (4.0 mL) and allow to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and extracted with ethyl acetate to obtain the crude product, tert-butyl [5-(3-bromo-4-oxocyclohexyl)pyridin-2-yl]carbamate, which was directly used in the next step. LCMS (TOF MS ES+) m / z [M+H]+: 369.07.

[0256] Step 7: Synthesis of tert-butyl[5-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)pyridin-2-yl]carbamate

[0257] Dissolve tert-butyl [5-(3-bromo-4-oxocyclohexyl)pyridin-2-yl]carbamate (101 mg, 0.275 mmol, 1.0 eq) in acetonitrile (4.0 mL) and add thiourea (21 mg, 0.275 mmol, 1.0 eq). The mixture was reacted at 80°C under a nitrogen atmosphere for 1 hour. After completion of the reaction, the product was concentrated and purified by normal phase chromatography to afford tert-butyl [5-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)pyridin-2-yl]carbamate (55.0 mg, 57.8% yield) as a yellow oil. LCMS (TOF MS ES+) m / z [M+H]+: 291.08.

[0258] Step 8: Synthesis of {5-[2-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl]pyridin-2-yl}carbamate

[0259] Tert-butyl [5-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)pyridin-2-yl]carbamate (50 mg, 0.144 mmol, 1.0 eq), 2'-bromo-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (48 mg, 0.173 mmol, 1.2 eq), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (61 mg, 0.217 mmol, 1.5 eq) and N-methylimidazole (36 mg, 0.433 mmol, 3.0 eq) were dissolved in N,N-dimethylformamide (2.0 mL) and reacted at room temperature under nitrogen protection for 3 hours. After completion of the reaction, the product was quenched with sodium bicarbonate solution, extracted with ethyl acetate, and concentrated to afford crude tert-butyl {5-[2-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl]pyridin-2-yl}carbamate (71.0 mg, 97.2% yield), which was used directly in the next step. LCMS (TOF MS ES+) m / z [M+H]+: 507.13.

[0260] Step 9: Synthesis of N-[6-(6-aminopyridin-3-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0261] Tert-butyl {5-[2-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl]pyridin-2-yl}carbamate (60 mg, 0.09 mmol, 1.0 eq) was dissolved in dichloromethane (1.0 mL), trifluoroacetic acid (0.3 mL) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated and purified by preparative separation to give N-[6-(6-aminopyridin-3-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (14.4 mg, 28.9% yield) as a white solid. LCMS(TOF MS ES+)m / z[M+H]+:507.1369. 1H NMR(400MHz,DMSO)δ8.76(s,1H),8.16(s,1H),7.84(s,1H),7.51(s,1H),7.40(s,1H),7.36(d,J=8.1Hz,1H),6.41 (d,J=8.6Hz,1H),5.75(s,2H),3.61(s,3H),2.84(d,J=12.9Hz,2H),2.72–2.65(m,3H),2.57(s,3H),1.94(s,2H).

[0262] Example 21: Synthesis of 2'-chloro-N-(6-hydroxy-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 22)

[0263] Step 1: Synthesis of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-ol

[0264] 1,4-Dioxaspirino[4.5]decan-8-one (5.00 g, 32 mmol, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (50.0 mL). Phenylmagnesium bromide (1 mol / L) in tetrahydrofuran (35.22 mL, 35.22 mmol, 1.1 eq) was added dropwise in an ice bath. The reaction was allowed to react at room temperature for 1 hour. After completion, the reaction was quenched with saturated aqueous ammonium chloride in an ice bath. The mixture was extracted with ethyl acetate, and the organic phase was concentrated. Purification by normal phase column chromatography afforded 8-phenyl-1,4-dioxaspiro[4.5]decan-8-ol (1.9 g, 25.4% yield) as a white solid. 1 H NMR (400MHz, DMSO) δ7.49–7.42(m,2H),7.30(dd,J=8.4,7.0Hz,2H),7.23–7.16(m,1H),4.89(s ,1H),3.88(d,J=2.1Hz,4H),2.01–1.85(m,4H),1.64(dd,J=9.6,2.5Hz,2H),1.58–1.46(m,2H).

[0265] Step 2: Synthesis of 4-hydroxy-4-phenylcyclohexane-1-one

[0266] 8-Phenyl-1,4-dioxaspiro[4.5]decan-8-ol (500 mg, 2.14 mmol, 1.0 eq) was dissolved in tetrahydrofuran (6 mL) and ethanol (3 mL). Concentrated hydrochloric acid (3 mL) was added dropwise in an ice bath. The mixture was reacted at 0°C for 30 minutes. After completion of the reaction, saturated aqueous sodium bicarbonate solution was added in an ice bath to adjust the pH to 7-8. The mixture was extracted with ethyl acetate, and the organic phase was concentrated to obtain a crude white solid of 4-hydroxy-4-phenylcyclohexane-1-one (480 mg, 100.00% yield).

[0267] Step 3: Synthesis of 2-bromo-4-hydroxy-4-phenylcyclohexane-1-one

[0268] 4-Methoxy-4-phenylcyclohexane-1-one (200 mg, 1.05 mmol, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (3 mL). Phenyltrimethylammonium tribromide (396 mg, 1.05 mmol, 1.0 eq) dissolved in ultra-dry tetrahydrofuran (3 mL) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, water and ethyl acetate were added to the reaction mixture, and the organic phase was concentrated to afford crude 2-bromo-4-hydroxy-4-phenylcyclohexane-1-one (290 mg, 100.0% yield) as a brown oil.

[0269] Step 4: Synthesis of 2-amino-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-6-ol

[0270] 2-Bromo-4-hydroxy-4-phenylcyclohexan-1-one was dissolved in acetonitrile (4 mL), and thiourea (120 mg, 1.58 mmol, 1.5 eq) was added. The mixture was allowed to react at room temperature for 16 hours. After completion, the reaction solution was concentrated to afford crude 2-amino-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-6-ol (240 mg, 92.7% yield) as a brown oil. LCMS (ESI) [M+H]+: 247.

[0271] Step 5: Synthesis of (R)-2'-chloro-N-(6-hydroxy-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0272] 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (117 mg, 0.422 mmol, 1.0 eq) was dissolved in ultra-dry N,N-dimethylformamide (3 mL), and 2-amino-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-6-ol (108 mg, 0.422 mmol, 1.0 eq) and N-methylimidazole (208 mg, 2.53 mmol, 6.0 eq) were added. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (178 mg, 0.633 mmol, 1.5 eq) was then added under ice-cooling conditions and the reaction was carried out at room temperature for 2 hours. After the reaction, the racemic compound 2'-chloro-N-(6-hydroxy-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (37.7 mg, yield 17.7%) was obtained by preparative separation and purification. The racemate was further purified by chiral separation column to give (R)-2'-chloro-N-(6-hydroxy-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (5.6 mg) and (S)-2'-chloro-N-(6-hydroxy-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (5.6 mg). LCMS (ESI) [M+H]+: 507.1248. 1 HNMR(400MHz,DMSO)δ8.82(s,1H),8.19(s,1H),7.57–7.50(m,3H),7.47(s,1H),7.33(dd,J=8.3,6.8Hz,2H),7.27–7.20(m,1H),3.63( s,3H),3.09(d,J=16.5Hz,1H),2.79(d,J=16.5Hz,2H),2.60(s,3H),2.54(s,1H),2.21(m,J=11.9,5.7Hz,1H),1.92(d,J=12.6Hz,1H).

[0273] Example 22: Synthesis of 2'-chloro-5'-methoxy-N-(6-methoxy-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 23)

[0274] Step 1: Synthesis of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-ol

[0275] 1,4-Dioxaspirino[4.5]decan-8-one (5.00 g, 32 mmol, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (50.0 mL). Phenylmagnesium bromide (1 mol / L) in tetrahydrofuran (35.22 mL, 35.22 mmol, 1.1 eq) was added dropwise in an ice bath. The reaction was allowed to react at room temperature for 1 hour. After completion, the reaction was quenched with saturated aqueous ammonium chloride in an ice bath. The mixture was extracted with ethyl acetate, and the organic phase was concentrated. Purification by normal phase column chromatography afforded 8-phenyl-1,4-dioxaspiro[4.5]decan-8-ol (1.9 g, 25.4% yield) as a white solid. 1 H NMR (400MHz, DMSO) δ7.49–7.42(m,2H),7.30(dd,J=8.4,7.0Hz,2H),7.23–7.16(m,1H),4.89(s ,1H),3.88(d,J=2.1Hz,4H),2.01–1.85(m,4H),1.64(dd,J=9.6,2.5Hz,2H),1.58–1.46(m,2H).

[0276] Step 2: Synthesis of 8-methoxy-8-phenyl-1,4-dioxaspiro[4.5]decane

[0277] 8-Phenyl-1,4-dioxaspiro[4.5]decan-8-ol (800 mg, 3.42 mmol, 1.0 eq) was dissolved in ultra-dry N,N-dimethylformamide (6 mL). Sodium hydroxide (410 mg, 10.26 mmol, 3.0 eq) was added under ice-cooling conditions. The mixture was reacted at 0°C for 10 minutes, followed by the addition of iodomethane (728 mg, 5.13 mmol, 1.5 eq). The mixture was allowed to react at 50°C for 16 hours. After completion of the reaction, saturated aqueous ammonium chloride was added to quench the reaction mixture under ice-cooling conditions. The mixture was extracted with ethyl acetate, and the organic phase was concentrated to obtain 8-methoxy-8-phenyl-1,4-dioxaspiro[4.5]decane (458 mg, 54.0% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO) δ7.41–7.32(m,4H),7.26(m,J=8.5,5.9,2.0Hz,1H),3.88( s,4H),2.87(s,3H),2.02–1.94(m,2H),1.93–1.75(m,4H),1.63–1.50(m,2H).

[0278] Step 3: Synthesis of 4-methoxy-4-phenylcyclohexane-1-one

[0279] 8-Methoxy-8-phenyl-1,4-dioxaspiro[4.5]decane (700 mg, 2.82 mmol, 1.0 eq) was dissolved in tetrahydrofuran (6 mL) and ethanol (3 mL). Concentrated hydrochloric acid (3 mL) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, saturated aqueous sodium bicarbonate was added to adjust the pH to 7-8 in an ice bath. The mixture was extracted with ethyl acetate, and the organic phase was concentrated to afford 4-methoxy-4-phenylcyclohexane-1-one (536 mg, 93.1% yield) as a pale yellow oil.

[0280] Step 4: Synthesis of 2-bromo-4-methoxy-4-phenylcyclohexane-1-one

[0281] 4-Methoxy-4-phenylcyclohexane-1-one (180 mg, 0.88 mmol, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (3 mL). Phenyltrimethylammonium tribromide (332 mg, 0.88 mmol, 3.0 eq) dissolved in ultra-dry tetrahydrofuran (3 mL) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, water and ethyl acetate were added to the reaction mixture, and the organic phase was concentrated to afford crude 2-bromo-4-methoxy-4-phenylcyclohexane-1-one (270 mg, 100.0% yield) as a pale yellow solid.

[0282] Step 5: Synthesis of 6-methoxy-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0283] Crude 8-phenyl-1,4-dioxaspiro[4.5]decan-8-ol was dissolved in acetonitrile (5 mL) and thiourea (134 mg, 1.76 mmol, 2.0 eq) was added. The mixture was allowed to react at room temperature for 16 hours. After completion, the reaction solution was concentrated to afford crude 6-methoxy-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine as a brown solid (240 mg, 100.0% yield). LCMS (ESI) [M+H]+: 261.

[0284] Step 6: Synthesis of (R)-2'-chloro-5'-methoxy-N-(6-methoxy-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0285] 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (160 mg, 0.577 mmol, 1.5 eq) was dissolved in acetonitrile (3 mL), and 6-methoxy-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (100 mg, 0.384 mmol, 1.0 eq) and N-methylimidazole (189 mg, 2.308 mmol, 6.0 eq) were added. Then, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (162 mg, 0.577 mmol, 1.5 eq) was added under ice-cooling conditions and the reaction was carried out at room temperature for 1 hour. After the reaction, the racemic compound 2'-chloro-5'-methoxy-N-(6-methoxy-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (45.0 mg) was obtained by preparative separation and purification. The racemic compound was then separated and purified by chiral column to give (R)-2'-chloro-5'-methoxy-N-(6-methoxy-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (10.5 mg) and (S)-2'-chloro-5'-methoxy-N-(6-methoxy-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (10.5 mg). LCMS (ESI) [M+H]+: 521.1406. 1 H NMR (400MHz, DMSO) δ12.47(s,1H),8.76(s,1H),8.17(s,1H),7.51(s,1H),7.46–7.33(m,5H),7.29(t,J=7.0Hz,1H),3.62(s,3H),3.14(d,J=1 6.6Hz,1H),3.00(d,J=16.5Hz,1H),2.92(s,3H),2.68(dt,J=15.1,7.0Hz,1H),2.57(s,3H),2.41(dt,J=16.3,5.2Hz,1H),2.35–2.17(m,2H).

[0286] Example 23: Synthesis of 2'-amino-5'-methoxy-6-methyl-N-(6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 26)

[0287] Step 1: Synthesis of 2'-amino-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid

[0288] 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (255 mg, 0.92 mmol, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (5.0 mL). Under ice bath conditions, a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1 mol / L) (4.59 mL, 4.59 mmol, 5.0 eq) was added dropwise. Tris(dibenzylideneacetone)dipalladium (84 mg, 0.09 mmol, 0.1 eq) and 2-(dicyclohexylphosphino)biphenyl (64 mg, 0.18 mmol, 0.2 eq) were then added. The reaction was carried out at 65°C under nitrogen protection for 1.5 hours. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench the reaction solution, the system was concentrated, N,N-dimethylformamide (4 mL) was added, and the mixture was filtered. The filtrate was separated and purified by reverse phase column to obtain a brown solid 2'-amino-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (20 mg, yield 8.4%).

[0289] Step 2: Synthesis of 2'-amino-5'-methoxy-6-methyl-N-(6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0290] 2'-Amino-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (20 mg, 0.077 mmol, 1.0 eq) was dissolved in ultra-dry N,N-dimethylformamide (1 mL). Acetonitrile (2 mL), 6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (18 mg, 0.077 mmol, 1.0 eq) and N-methylimidazole (38 mg, 0.463 mmol, 6.0 eq) were added. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (32 mg, 0.116 mmol, 1.5 eq) was then added in an ice bath. The reaction was allowed to proceed at room temperature for 16 hours. After the reaction, preparative separation and purification were performed to obtain a white solid 2'-amino-5'-methoxy-6-methyl-N-(6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (6.6 mg, yield 18.1%). LCMS (ESI) [M+H]+: 472.1797. 1H NMR(400MHz,DMSO)δ8.68(s,1H),7.63(s,1H),7.36–7.29(m,4H),7.27(s,1H),7.24–7.18(m,1H),6.43(s,1H),5.64(s,2H ),3.44(s,3H),3.02(m,J=6.7Hz,1H),2.91(dd,J=16.1,5.3Hz,1H),2.80–2.65(m,3H),2.56(s,3H),2.02(m,J=8.4Hz,2H).

[0291] Example 24: Synthesis of 2'-chloro-N-[6-(4-cyanophenyl)-6-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 32)

[0292] Step 1: Synthesis of (4-cyanophenyl)magnesium bromide

[0293] 4-Bromobenzonitrile (10.0 g, 54.94 mmol, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (40.0 mL). Under nitrogen protection, isopropylmagnesium chloride lithium chloride complex (1.3 mol / L, 40.0 mL) was added dropwise at room temperature. The mixture was reacted at room temperature for 16 hours to obtain a brown liquid (4-cyanophenyl)magnesium bromide tetrahydrofuran solution (0.66 mol / L, 82.26 mL).

[0294] Step 2: Synthesis of 4-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)benzonitrile

[0295] 1,4-Dioxaspirino[4.5]decan-8-one (6.5 g, 41.67 mmol, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (40.0 mL). Under nitrogen, a solution of (4-cyanophenyl)magnesium bromide in tetrahydrofuran (75.0 mL, 1.2 eq) was added dropwise at 0°C. The mixture was allowed to react at room temperature for 3 hours. After completion, the reaction was quenched with saturated aqueous ammonium chloride in an ice bath. The mixture was then extracted with water and ethyl acetate. The resulting organic phase was dried over saturated brine and anhydrous sodium sulfate, filtered, and concentrated to afford crude 4-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)benzonitrile (3.1 g, 28.73% yield) as a yellow oil. 1H NMR (400MHz, DMSO) δ7.77(d,J=8.2Hz,2H),7.65(d,J=8.4Hz,2H),5.18(s,1H),3.89(d,J=1.5Hz,4H),2.5 9(dd,J=13.1,5.6Hz,2H),2.49–2.42(m,2H),2.22(dt,J=13.9,5.2Hz,2H),2.14(dd,J=13.1,5.6Hz,2H).

[0296] Step 3: Synthesis of 4-(1-hydroxy-4-oxocyclohexyl)benzonitrile

[0297] 4-(8-Hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)benzonitrile (2.74 g, 10.58 mmol, 1.0 eq) was dissolved in acetone (10.0 mL), followed by the addition of p-toluenesulfonic acid monohydrate (604 mg, 3.17 mmol, 0.3 eq) and water (20.0 mL). The mixture was allowed to react at 60°C for 2 hours. After completion, the mixture was extracted with water and ethyl acetate. The resulting organic phase was dried over saturated brine and anhydrous sodium sulfate, filtered, and concentrated to afford crude 4-(1-hydroxy-4-oxocyclohexyl)benzonitrile (1.07 g, 47.14% yield) as a brown solid. 1 H NMR (400MHz, DMSO) δ7.80(d,J=8.4Hz,2H),7.76(d,J=8.4Hz,2H),5.65(s,1H),2.75(m,J=17.7,11 .0,5.6Hz,3H),2.66–2.53(m,J=4.1,3.5Hz,1H),2.28(td,J=13.4,5.0Hz,2H),2.20–2.11(m,2H).

[0298] Step 4: Synthesis of 4-(2-amino-6-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)benzonitrile

[0299] 4-(1-Hydroxy-4-oxocyclohexyl)benzonitrile (1.07 g, 4.98 mmol, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (10.0 mL). A solution of phenyltrimethylammonium tribromide (1.87 g, 4.98 mmol, 1.0 eq) in ultra-dry tetrahydrofuran (8 mL) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 16 hours. After completion, water and ethyl acetate were added to the reaction mixture, and the organic phase was concentrated. The resulting product was dissolved in acetonitrile (20 mL), and thiourea (568 mg, 7.47 mmol, 1.5 eq) was added. The reaction was allowed to react at room temperature for 4 hours. After completion, the reaction mixture was filtered to yield 4-(2-amino-6-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)benzonitrile (210 mg, 15.56% yield) as a gray solid. LCMS (ESI) [M+H] +: 272. 1 H NMR (400MHz, DMSO) δ9.20 (s, 2H), 7.87–7.80 (m, 2H), 7.76–7.69 (m, 2H), 2.94 (dd, J = 17.3, 2.6Hz, 1H), 2.64 (d, J=16.5Hz, 2H), 2.52 (s, 1H), 2.19 (ddd, J=13.0, 10.7, 6.0Hz, 1H), 1.91–1.80 (m, 1H).

[0300] Step 5: Synthesis of 2'-chloro-N-[6-(4-cyanophenyl)-6-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0301] 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (103 mg, 0.37 mmol, 1.0 eq) and 4-(2-amino-6-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)benzonitrile (100 mg, 0.37 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (2.0 mL). N-methylimidazole (121 mg, 1.48 mmol, 4.0 eq) was added, followed by N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (155 mg, 0.55 mmol, 1.5 eq) in an ice bath. The mixture was reacted at room temperature for 16 hours. After the reaction, preparative separation and purification were performed to obtain 2'-chloro-N-[6-(4-cyanophenyl)-6-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (41 mg, yield 20.92%). LCMS (ESI) [M+H]+: 532.1210. 1H NMR (400MHz, DMSO) δ12.50(s,1H),8.77(s,1H),8.17(s,1H),7.81(d,J=8.5Hz,2H),7.73(d,J=8.4Hz,2H),7.51(s,1H),7.41(s,1H) ,5.50(s,1H),3.62(s,3H),3.12(d,J=16.4Hz,1H),2.79(d,J=16.4Hz,2H),2.58(s,4H),2.30–2.18(m,1H),1.90(d,J=12.8Hz,1H).

[0302] Example 25: Synthesis of 2'-chloro-N-{6-[4-(difluoromethoxy)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 35)

[0303] Step 1: Synthesis of 8-[4-(difluoromethoxy)phenyl]-1,4-dioxaspiro[4.5]dec-7-ene

[0304] (4-Cyano-3-methoxyphenyl)boronic acid (2.8 g, 16.0 mmol, 1.0 eq) was dissolved in 1,4-dioxane (20 mL), and then 1,4-dioxyaspirin[4.5]dec-7-en-8-yl trifluoromethanesulfonate (5.07 g, 17.6 mmol, 1.1 eq), cesium carbonate (15.6 g, 48.0 mmol, 3.0 eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (350 mg, 0.48 mmol, 0.03 eq) and deionized water (5 mL) were added in sequence. Under nitrogen protection, the reaction was carried out at 80 ° C for 4 hours. After the reaction was complete, the mixture was purified by normal phase chromatography (petroleum ether:ethyl acetate = 11:1) to give a white solid 8-[4-(difluoromethoxy)phenyl]-1,4-dioxaspiro[4.5]dec-7-ene (3.1 g, yield 68.88%). LCMS (ESI) [M + H] + :283.11. 1 H NMR (400MHz, DMSO-d6) δ7.49-7.43(m,2H),7.41-7.02(m,3H),6.00(m,J=3.9,2.0Hz,1 H), 3.91 (s, 4H), 2.57–2.50 (m, 2H), 2.36 (m, J = 4.3, 2.4Hz, 2H), 1.81 (t, J = 6.5Hz, 2H).

[0305] Step 2: Synthesis of 8-[4-(difluoromethoxy)phenyl]-1,4-dioxaspiro[4.5]decane

[0306] 8-[4-(Difluoromethoxy)phenyl]-1,4-dioxaspiro[4.5]dec-7-ene (3.1 g, 10.99 mmol, 1.0 eq) was dissolved in methanol (20 mL) and palladium on carbon (117.0 mg, 1.1 mmol, 0.1 eq) was added. The mixture was then reacted at room temperature under a hydrogen atmosphere for 8 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and purified by normal phase chromatography (petroleum ether:ethyl acetate = 21:1) to obtain 8-[4-(difluoromethoxy)phenyl]-1,4-dioxaspiro[4.5]decane (2.67 g, yield 85.5%) as a white solid. LCMS (ESI) [M + H] + :285.13. 1 H NMR (400MHz, DMSO-d6) δ7.29-7.24(m,3H),7.08(d,J=8.5Hz,2H),3.88(d,J=2.1 Hz, 4H), 2.59 (m, J = 14.4, 9.4, 3.2Hz, 1H), 1.79-1.71 (m, 4H), 1.70-1.58 (m, 4H).

[0307] Step 3: Synthesis of 4-[4-(difluoromethoxy)phenyl]cyclohexan-1-one

[0308] 8-[4-(Difluoromethoxy)phenyl]-1,4-dioxaspiro[4.5]decane (1.0 g, 3.52 mmol, 1.0 eq) was dissolved in acetone / water (6 mL / 3 mL), and p-toluenesulfonic acid monohydrate (201 mg, 1.05 mmol, 0.3 eq) was added. The mixture was then reacted at 60°C for 2 hours. After the reaction was complete, saturated aqueous sodium bicarbonate solution was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate, and the organic phase was concentrated to obtain a white solid 4-[4-(difluoromethoxy)phenyl]cyclohexan-1-one (810 mg, yield 95.88%), which was used directly in the next reaction. LCMS (ESI) [M + H] + :241.10. 1 H NMR (400MHz, DMSO-d6) δ7.36(dd,J=8.6,2.1Hz,2H),7.30-6.95(m,3H),3.07(m,J=12.1,3.4Hz,1H),2.57(m,J =14.1, 6.0Hz, 2H), 2.26 (m, J = 14.6, 2.1Hz, 2H), 2.05 (m, J = 12.4, 6.0, 2.8Hz, 2H), 1.86 (m, J = 13.2, 4.0Hz, 2H).

[0309] Step 4: Synthesis of 6-[4-(difluoromethoxy)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0310] 4-[4-(Difluoromethoxy)phenyl]cyclohexan-1-one (810 mg, 3.38 mmol, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (10 mL). Phenyltrimethylammonium tribromide (1.27 g, 3.38 mmol, 1.0 eq) was added under ice-cooling and allowed to react at room temperature for 2 hours. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. After concentration and drying, the mixture was dissolved in acetonitrile (5 mL) and thiourea (385 mg, 5.06 mmol, 1.5 eq) was added. After reacting at room temperature for 2 hours, the mixture was filtered and washed with acetonitrile (20 mL) to obtain 6-[4-(difluoromethoxy)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (251 mg, yield 25.63%) as a white solid, which was used directly in the next step. LCMS (ESI) [M + H] + :297.08.

[0311] Step 5: Synthesis of 2'-chloro-N-{6-[4-(difluoromethoxy)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0312] 6-[4-(Difluoromethoxy)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (248 mg, 0.84 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (232 mg, 0.84 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (5 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (350 mg, 1.25 mmol, 1.5 eq) and N-methylimidazole (205 mg, 2.51 mmol, 3.0 eq) were added, followed by reaction at room temperature for 5.0 hours. After the reaction was complete, the product was purified to give a white solid 2'-chloro-N-{6-[4-(difluoromethoxy)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (8.8 mg, yield 1.9%). LCMS (ESI) [M + H] + :557.1229. 1H NMR (400MHz, DMSO-d6) δ8.76(s,1H),8.16(d,J=2.1Hz,1H),7.50(d,J=2.1Hz,1H),7.39(d,J=2.4Hz,2H),7.37(d,J=2.1Hz,1H),7.18-6.96( m, 3H), 3.61 (d, J = 2.0Hz, 3H), 3.02 (d, J = 11.5Hz, 1H), 2.96-2.85 (m, 1H), 2.71 (t, J = 7.2Hz, 3H), 2.57 (d, J = 2.1Hz, 3H), 1.99 (d, J = 9.9Hz, 2H).

[0313] Example 26: Synthesis of 2'-chloro-N-[6-(4-cyano-2-methoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 41)

[0314] Step 1: Synthesis of 3-methoxy-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzonitrile

[0315] 4,4,5,5-Tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (1.5 g, 5.63 mmol, 1.0 eq) and 4-bromo-3-methoxybenzonitrile (1.19 g, 5.63 mmol, 1.0 eq) were dissolved in a mixed solution of 1,4-dioxane (20.0 mL) and water (5.0 mL). Cesium carbonate (5.49 g, 16.89 mmol, 3.0 eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (124.27 mg, 0.17 mmol, 0.03 eq) were added, and the mixture was reacted at 80°C under a nitrogen atmosphere for 2 hours. After the reaction was complete, the mixture was purified by normal phase purification (petroleum ether / ethyl acetate = 3:1) and concentrated to give a white solid 3-methoxy-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzonitrile (1.3 g, yield 85.52%). LCMS (ESI) [M + H] + :272.1. 1H NMR (400MHz, DMSO) δ7.43(d,J=1.5Hz,1H),7.36(dd,J=7.7,1.5Hz,1H),7.26(d,J=7.8Hz,1H),5.70(m,J=3.8 ,1.9Hz,1H),3.91(s,4H),3.82(s,3H),2.52–2.43(m,2H),2.34(m,J=4.2,2.3Hz,2H),1.75(t,J=6.4Hz,2H).

[0316] Step 2: Synthesis of 3-methoxy-4-(1,4-dioxaspiro[4.5]dec-8-yl)benzonitrile

[0317] 3-Methoxy-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzonitrile (1.3 g, 4.79 mmol, 1.0 eq) was dissolved in methanol (30 mL) and palladium on carbon (50.9 mg, 0.48 mmol, 0.1 eq) was added. The mixture was then reacted under a hydrogen atmosphere for 8 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and purified by normal phase chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 3-methoxy-4-(1,4-dioxaspiro[4.5]dec-8-yl)benzonitrile (220 mg, yield 16.8%) as a white solid. LCMS (ESI) [M + H] + :274.14. 1 H NMR (400MHz, DMSO) δ7.40 (d, J = 1.3 Hz, 1H), 7.36–7.34 (m, 2H), 3.87 (d, J = 1.8 Hz, 4H), 3.85 (s, 3H), 3.01–2.91 (m, 1H), 1.77–1.56 (m, 8H).

[0318] Step 3: Synthesis of 3-methoxy-4-(4-oxocyclohexyl)benzonitrile

[0319] 3-Methoxy-4-(1,4-dioxaspiro[4.5]dec-8-yl)benzonitrile (220 mg, 0.80 mmol, 1.0 eq) was dissolved in acetone / water (8 mL / 4 mL) and p-toluenesulfonic acid monohydrate (45.9 mg, 0.24 mmol, 0.3 eq) was added. The mixture was then reacted at 60°C for 2 hours. After the reaction was complete, saturated aqueous sodium bicarbonate solution was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate and the organic phase was concentrated to obtain a white solid 3-methoxy-4-(4-oxocyclohexyl)benzonitrile (165 mg), which was used directly in the next reaction. LCMS (ESI) [M + H] + :230.11. 1H NMR (400MHz, DMSO) δ7.46–7.34(m,3H),3.89(s,3H),3.45(m,J=12.1,3.4Hz,1H),2.59(m,J=14.2,6.0H z, 2H), 2.26 (m, J = 14.7, 4.4, 2.1Hz, 2H), 2.00 (m, J = 12.6, 6.0, 3.0Hz, 2H), 1.85 (m, J = 13.1, 4.1Hz, 2H).

[0320] Step 4: Synthesis of 4-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-3-methoxybenzonitrile

[0321] 3-Methoxy-4-(4-oxocyclohexyl)benzonitrile (150 mg, 0.65 mmol, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (10 mL). Phenyltrimethylammonium tribromide (245.1 mg, 0.65 mmol, 1.0 eq) was added under ice-cooling conditions. After concentration to dryness, the mixture was dissolved in acetonitrile (3 mL) and thiourea (54.6 mg, 0.72 mmol, 1.1 eq) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered and washed with acetonitrile (20 mL) to obtain a white solid crude product, 4-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-3-methoxybenzonitrile (197 mg), which was used directly in the next reaction. LCMS (ESI) [M + H] + :286.

[0322] Step 5: Synthesis of 2'-chloro-N-[6-(4-cyano-2-methoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0323] 4-(2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-3-methoxybenzonitrile (102.6 mg, 0.36 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (100 mg, 0.36 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (151.4 mg, 0.54 mmol, 1.5 eq) and N-methylimidazole (88.56 mg, 1.08 mmol, 3.0 eq) were added, followed by reaction at room temperature for 1.5 hours. After the reaction was complete, a white solid 2'-chloro-N-[6-(4-cyano-2-methoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (14.4 mg, yield 7.34%) was obtained. LCMS (ESI) [M + H]+:546.1362. 1 H NMR(400MHz,DMSO)δ12.49(s,1H),8.77(s,1H),8.17(s,1H),7.51(s,1H),7.47–7.38(m,4H),3.87(s,3H),3.62 (s,3H),3.45–3.35(m,1H),2.89(dd,J=15.6,4.9Hz,1H),2.70(m,J=9.5Hz,3H),2.58(s,3H),2.14–1.91(m,2H).

[0324] Example 27: Synthesis of 2'-chloro-N-{6-[4-(difluoromethyl)-2-methoxyphenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 42)

[0325] Step 1: Synthesis of 3-methoxy-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzaldehyde

[0326] 3-Methoxy-4-bromo-benzoyl (1.0 g, 4.67 mmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (1.24 g, 4.67 mmol, 1.0 eq) were dissolved in 1,4-dioxane (12 mL), and cesium carbonate (4.56 g, 14.01 mmol, 3.0 eq), deionized water (3 mL) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (170 mg, 0.23 mmol, 0.05 eq) were added. The mixture was reacted at 80 ° C for 4 hours under nitrogen protection. After the reaction was completed, deionized water and ethyl acetate were added for extraction, and the organic phase was concentrated to obtain a brown solid 3-methoxy-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzaldehyde (1.27 g), which was used directly in the next reaction without further purification. LCMS (ESI) [M+H] + :275.

[0327] Step 2: Synthesis of 8-[4-(difluoromethyl)-2-methoxyphenyl]-1,4-dioxaspiro[4.5]dec-7-ene

[0328] 3-Methoxy-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzaldehyde (800 mg, 2.55 mmol, 1.0 eq) was dissolved in ultra-dry dichloromethane (10 mL). Diethylaminosulfur trifluoride (617 mg, 3.83 mmol, 1.5 eq) was slowly added to the mixture under an ice bath. The mixture was then allowed to react at room temperature for 3 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the mixture. The mixture was extracted with ethyl acetate, and the organic phase was concentrated and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 90:10) to afford 8-[4-(difluoromethyl)-2-methoxyphenyl]-1,4-dioxaspiro[4.5]dec-7-ene (610 mg, 70.6% yield) as a yellow oil. LCMS (ESI) [M+H] + :297. 1 H NMR (400MHz, DMSO) δ7.21(d,J=7.6Hz,1H),7.14(s,1H),7.09(d,J=7.8Hz,1H),7.12–6.82(m,1H),5.73– 5.56(m,1H),3.92(s,4H),3.80(s,3H),2.49–2.45(m,2H),2.33(m,J=2.7Hz,2H),1.75(t,J=6.4Hz,2H).

[0329] Step 3: Synthesis of 8-[4-(difluoromethyl)-2-methoxyphenyl]-1,4-dioxaspiro[4.5]decane

[0330] 8-[4-(Difluoromethyl)-2-methoxyphenyl]-1,4-dioxaspiro[4.5]dec-7-ene (580 mg, 1.96 mmol, 1.0 eq) was dissolved in anhydrous methanol (10 mL), and palladium on carbon (58 mg, 10%) was added. The mixture was reacted under a hydrogen atmosphere at room temperature and pressure for 2 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to obtain a yellow oil, 8-[4-(difluoromethyl)-2-methoxyphenyl]-1,4-dioxaspiro[4.5]decane (582 mg, yield 99.8%), which was used directly in the next reaction. LCMS (ESI) [M+H] + :299. 1 H NMR (400MHz, DMSO) δ7.29(d,J=7.6Hz,1H),7.10(d,J=7.7Hz,2H),7.09–6.80(m ,1H),3.88(d,J=2.3Hz,4H),3.83(s,3H),3.02–2.88(m,1H),1.79–1.55(m,8H).

[0331] Step 4: Synthesis of 4-[4-(difluoromethyl)-2-methoxyphenyl]cyclohexan-1-one

[0332] 8-[4-(Difluoromethyl)-2-methoxyphenyl]-1,4-dioxaspiro[4.5]decane (530 mg, 1.78 mmol, 1.0 eq) was dissolved in a mixed solvent of acetone (5 mL) and water (5 mL). p-Toluenesulfonic acid monohydrate (101 mg, 0.53 mmol, 0.3 eq) was added and reacted at 60°C for 6 hours. After the reaction was complete, ethyl acetate was added for extraction, and the organic phase was concentrated to obtain 4-[4-(difluoromethyl)-2-methoxyphenyl]cyclohexan-1-one (380 mg, yield 84.3%) as a yellow oil. LCMS (ESI) [M+H] + :255. 1 H NMR (400MHz, DMSO) δ7.35(d,J=7.8Hz,1H),7.16(s,1H),7.11(s,1H),7.12–6.82(m,1H),3.87(s,3H),3.43(m,J=10.6,3.7Hz,1H ), 2.59(td,J=14.2,6.0Hz,2H), 2.27(m,J=14.2,4.4,2.1Hz,2H), 2.02(m,J=11.4,4.6,2.5Hz,2H), 1.85(m,J=13.1,4.1Hz,2H).

[0333] Step 5: Synthesis of 6-[4-(difluoromethyl)-2-methoxyphenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0334] 4-[4-(Difluoromethyl)-2-methoxyphenyl]cyclohexan-1-one (300 mg, 1.18 mmol, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (5 mL), and phenyltrimethylammonium tribromide (488 mg, 1.30 mmol, 1.1 eq) was added portionwise. The mixture was allowed to react at room temperature and pressure for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate, the organic phase was concentrated, and redissolved in acetonitrile (3 mL). Thiourea (89.7 mg, 1.18 mmol, 1.0 eq) was then added. The mixture was allowed to react at 60°C for 3 hours. After the reaction was complete, the mixture was allowed to cool to room temperature and filtered to afford 6-[4-(difluoromethyl)-2-methoxyphenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (135 mg, 36.9% yield) as an off-white solid. This was used directly in the next step without further purification. LCMS (ESI) [M+H] + :311.

[0335] Step 6: Synthesis of 2'-chloro-N-{6-[4-(difluoromethyl)-2-methoxyphenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0336] 6-[4-(Difluoromethyl)-2-methoxyphenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (100 mg, 0.32 mmol, 1.0 eq) was dissolved in acetonitrile (2 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (90 mg, 0.32 mmol, 1.0 eq) and N-methylimidazole (79.2 mg, 0.97 mmol, 3.0 eq) were added sequentially. The mixture was allowed to react at room temperature and pressure for 12 hours. Upon completion of the reaction, 2'-chloro-N-{6-[4-(difluoromethyl)-2-methoxyphenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (4.1 mg, 2.34% yield) was obtained as a white solid. LCMS (ESI) [M+H] + :571.14. 1H NMR (400MHz, DMSO) δ12.50(s,1H),8.76(s,1H),8.16(s,1H),7.51(s,1H),7.44–7.35(m,2H),7.17–6.82(m,3H),3.8 4(s,3H),3.62(s,3H),2.89(dd,J=15.6,4.8Hz,1H),2.76–2.63(m,3H),2.58(s,3H),2.55(s,1H),2.13–1.92(m,2H).

[0337] Example 28: Synthesis of 2'-chloro-N-[6-(4-cyano-3-methoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 43)

[0338] Step 1: Synthesis of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[0339] 4-Bromo-2-methoxybenzonitrile (5.0 g, 23.69 mmol, 1.0 eq) was dissolved in ultra-dry 1,4-dioxane (50.0 mL). Diboronic acid pinacol bis(pyrazol)diol (11.98 g, 47.39 mmol, 2.0 eq), potassium acetate (6.96 g, 71.07 mmol, 3.0 eq), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (517 mg, 0.71 mmol, 0.03 eq) were added. The mixture was reacted at 100°C under nitrogen for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and concentrated to obtain a black oily product, 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (5.8 g, yield 94.9%), which was used directly in the next reaction. LCMS (ESI) [M + H] + :260.14.

[0340] Step 2: Synthesis of 2-methoxy-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzonitrile

[0341] 2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (5.8 g, 22.39 mmol, 1.0 eq) was dissolved in 1,4-dioxane (20 mL), followed by the addition of 1,4-dioxyaspirino[4.5]dec-7-en-8-yl trifluoromethanesulfonate (6.45 g, 22.39 mmol, 1.0 eq), cesium carbonate (21.83 g, 67.17 mmol, 3.0 eq), deionized water (5 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (489.77 mg, 0.67 mmol, 0.03 eq), and the reaction was carried out at 80 ° C for 4 hours under nitrogen protection. After the reaction was complete, the mixture was purified by normal phase chromatography (petroleum ether:ethyl acetate = 7:1) to give a white oily substance, 2-methoxy-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzonitrile (4.8 g, yield 80.51%). LCMS (ESI) [M + H] + :272.12.

[0342] Step 3: Synthesis of 2-methoxy-4-(1,4-dioxaspiro[4.5]dec-8-yl)benzonitrile

[0343] 2-Methoxy-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzonitrile (4.8 g, 17.71 mmol, 1.0 eq) was dissolved in methanol (20 mL) and palladium on carbon (187.7 mg, 1.77 mmol, 0.1 eq) was added. The mixture was then reacted at room temperature under a hydrogen atmosphere for 8 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and purified by normal phase chromatography (petroleum ether:ethyl acetate = 21:4) to obtain 2-methoxy-4-(1,4-dioxaspiro[4.5]dec-8-yl)benzonitrile (3.84 g, yield 79.5%) as a white solid. LCMS (ESI) [M + H] + :274.14. 1 H NMR (400MHz, DMSO-d6) δ7.61(d,J=7.9Hz,1H),7.06(d,J=1.4Hz,1H),6.95(dd,J=7.9,1.4Hz,1H),3.91(s,3H) ,3.89(d,J=2.2Hz,4H),2.68(m,J=11.3,3.4Hz,1H),1.77(d,J=10.2Hz,4H),1.63(m,J=23.7,11.6,3.2Hz,4H).

[0344] Step 4: Synthesis of 2-methoxy-4-(4-oxocyclohexyl)benzonitrile

[0345] 2-Methoxy-4-(1,4-dioxaspiro[4.5]dec-8-yl)benzonitrile (1.0 g, 3.65 mmol, 1.0 eq) was dissolved in acetone / water (6 mL / 3 mL) and p-toluenesulfonic acid monohydrate (208 mg, 1.09 mmol, 0.3 eq) was added. The mixture was then reacted at 60°C for 2.0 hours. After the reaction was complete, saturated aqueous sodium bicarbonate solution was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate and the organic phase was concentrated to obtain a white solid 2-methoxy-4-(4-oxocyclohexyl)benzonitrile (820 mg, 98.1% yield), which was used directly in the next reaction. LCMS (ESI) [M + H] + :230.11. 1 H NMR (400MHz, DMSO-d6) δ7.64(d,J=7.9Hz,1H),7.19(d,J=1.5Hz,1H),7.04(dd,J=7.9,1.4Hz,1H),3.92(s,3H),3.15(m,J= 12.0,3.5Hz,1H),2.63-2.52(m,2H),2.28(m,J=14.6,4.4,2.1Hz,2H),2.07(m,J=12.4,6.2,3.6Hz,2H),2.00-1.89(m,2H).

[0346] Step 5: Synthesis of 4-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-2-methoxybenzonitrile

[0347] 2-Methoxy-4-(4-oxocyclohexyl)benzonitrile (800 mg, 3.51 mmol, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (10 mL). Phenyltrimethylammonium tribromide (1.32 g, 3.51 mmol, 1.0 eq) was slowly added in an ice bath. The mixture was allowed to react at room temperature for 2 hours. Water and ethyl acetate were added to extract the separated liquid. After drying and concentration, the mixture was dissolved in acetonitrile (5 mL). Thiourea (320 mg, 4.21 mmol, 1.2 eq) was added. The mixture was allowed to react at room temperature for 2 hours. The mixture was filtered and washed with acetonitrile (20 mL) to obtain 4-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-2-methoxybenzonitrile (450 mg, yield 45.0%) as a white solid. LCMS (ESI) [M + H] + :286.1. 1H NMR (400MHz, DMSO-d6) δ9.22(s,2H),7.68(d,J=8.0Hz,1H),7.22(d,J=1.4Hz,1H),7.05(dd,J=8.1,1.4Hz,1H),3.92(s,3H),3.10( m,J=10.2,5.2Hz,1H),2.81(dd,J=15.9,5.2Hz,1H),2.68(m,J=13.9,3.0Hz,1H),2.61(d,J=7.3Hz,2H),2.00(m,J=4.9,3.3Hz,2H).

[0348] Step 6: Synthesis of 2'-chloro-N-[6-(4-cyano-3-methoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0349] 4-(2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-2-methoxybenzonitrile (200.0 mg, 0.70 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (195 mg, 0.70 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (3 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (295 mg, 1.05 mmol, 1.5 eq) and N-methylimidazole (173 mg, 2.10 mmol, 3.0 eq) were added, followed by reaction at room temperature for 5 hours. After the reaction was complete, a white solid 2'-chloro-N-[6-(4-cyano-3-methoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (8.2 mg, yield 2.1%) was obtained. LCMS (ESI) [M + H] + :546.1370. 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),8.77(s,1H),8.17(s,1H),7.66(d,J=8.0Hz,1H),7.52(s,1H),7.41(s,1H),7.24(d,J=1.4Hz,1H),7.0 7(dd,J=8.1,1.4Hz,1H),3.92(s,3H),3.61(s,3H),3.12(dt,J=10.5,5.6Hz,1H),3.01–2.77(m,2H),2.73(s,2H),2.58(s,3H),2.05(s,2H).

[0350] Example 29: Synthesis of 2'-chloro-N-{6-[4-(difluoromethyl)-3-methoxyphenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 44)

[0351] Step 1: Synthesis of 3-methoxy-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzaldehyde

[0352] 2-Methoxy-4-bromo-benzoyl (1.0 g, 4.67 mmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (1.24 g, 4.67 mmol, 1.0 eq) were dissolved in 1,4-dioxane (12 mL), and cesium carbonate (4.56 g, 14.01 mmol, 3.0 eq), deionized water (3 mL) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (170 mg, 0.23 mmol, 0.05 eq) were added. The mixture was reacted at 80 ° C for 4 hours under nitrogen protection. After the reaction was complete, deionized water and ethyl acetate were added for extraction, and the organic phase was concentrated to obtain a brown solid 2-methoxy-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzaldehyde (1.26 g, yield 98.4%), which was used directly in the next reaction without further purification. LCMS (ESI) [M+H] + :275.

[0353] Step 2: Synthesis of 8-[4-(difluoromethyl)-3-methoxyphenyl]-1,4-dioxaspiro[4.5]dec-7-ene

[0354] 2-Methoxy-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzaldehyde (1.0 g, 3.19 mmol, 1.0 eq) was dissolved in ultra-dry dichloromethane (10 mL). Diethylaminosulfur trifluoride (771 mg, 4.79 mmol, 1.5 eq) was slowly added to the mixture under ice-cooling. The mixture was then allowed to react at room temperature for 6 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was concentrated and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 90:10) to afford 8-[4-(difluoromethyl)-3-methoxyphenyl]-1,4-dioxaspiro[4.5]dec-7-ene (752 mg, 69.6% yield) as a yellow oil. LCMS (ESI) [M+H] + :297. 1H NMR (400MHz, DMSO) δ7.43(d,J=8.0Hz,1H),7.14–7.06(m,2H),7.19–6.88(m,1H),6.14(td,J=3.9,2.0Hz ,1H),3.92(s,4H),3.87(s,3H),2.58(m,J=6.4,2.1Hz,2H),2.39(m,J=2.1Hz,2H),1.82(t,J=6.5Hz,2H).

[0355] Step 3: Synthesis of 8-[4-(difluoromethyl)-3-methoxyphenyl]-1,4-dioxaspiro[4.5]decane

[0356] 8-[4-(Difluoromethyl)-3-methoxyphenyl]-1,4-dioxaspiro[4.5]dec-7-ene (700 mg, 2.37 mmol, 1.0 eq) was dissolved in anhydrous methanol (10 mL), and palladium on carbon (70 mg, 10%) was added. The mixture was reacted under a hydrogen atmosphere at room temperature and pressure for 2 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to obtain a yellow oil, 8-[4-(difluoromethyl)-3-methoxyphenyl]-1,4-dioxaspiro[4.5]decane (698 mg, yield 99.0%). LCMS (ESI) [M+H] + :299. 1 H NMR (400MHz, DMSO) δ7.42(d,J=7.9Hz,1H),7.18–6.87(m,1H),6.99(s,1H),6.94(dd,J=7.8,1 .4Hz,1H),3.91(d,J=2.6Hz,4H),3.86(s,3H),2.66(m,J=11.4,3.4Hz,1H),1.85–1.56(m,8H).

[0357] Step 4: Synthesis of 4-[4-(difluoromethyl)-3-methoxyphenyl]cyclohexan-1-one

[0358] 8-[4-(Difluoromethyl)-3-methoxyphenyl]-1,4-dioxaspiro[4.5]decane (650 mg, 2.18 mmol, 1.0 eq) was dissolved in acetone (5 mL) and water (5 mL). p-Toluenesulfonic acid monohydrate (124 mg, 0.65 mmol, 0.3 eq) was added and reacted at 60°C for 16 hours. After the reaction was complete, ethyl acetate was added for extraction. The organic phase was concentrated to obtain 4-[4-(difluoromethyl)-3-methoxyphenyl]cyclohexan-1-one (463 mg, 83.5% yield) as a yellow oil. LCMS (ESI) [M+H] + :255. 1H NMR (400MHz, DMSO) δ7.44(d,J=7.9Hz,1H),7.11(d,J=1.6Hz,1H),7.19–6.89(m,1H),7.01(dd,J=7.8,1.5Hz,1H),3.87(s,3H),3.13(m, J=12.0,3.5Hz,1H),2.60(m,J=14.1,6.1Hz,2H),2.29(m,J=14.5,4.3,2.1Hz,2H),2.10(m,J=12.2,5.9,3.0Hz,2H),2.04–1.88(m,2H).

[0359] Step 5: Synthesis of 6-[4-(difluoromethyl)-3-methoxyphenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0360] 4-[4-(Difluoromethyl)-3-methoxyphenyl]cyclohexan-1-one (400 mg, 1.57 mmol, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (6 mL), and phenyltrimethylammonium tribromide (651 mg, 1.73 mmol, 1.1 eq) was added portionwise. The mixture was allowed to react at room temperature and pressure for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate, the organic phase was concentrated, and the mixture was redissolved in acetonitrile (4 mL). Thiourea (120 mg, 1.57 mmol, 1.0 eq) was then added and the mixture was allowed to react at 60°C for 4 hours. After the reaction was complete, the mixture was allowed to cool to room temperature and filtered to obtain 6-[4-(difluoromethyl)-3-methoxyphenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (185 mg) as an off-white solid. The mixture was used directly in the next step without further purification. LCMS (ESI) [M+H] + :311.

[0361] Step 6: Synthesis of 2'-chloro-N-{6-[4-(difluoromethyl)-3-methoxyphenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0362] 6-[4-(Difluoromethyl)-3-methoxyphenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (150 mg, 0.48 mmol, 1.0 eq) was dissolved in acetonitrile (3 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (135 mg, 0.48 mmol, 1.0 eq) and N-methylimidazole (119 mg, 1.46 mmol, 3.0 eq) were added sequentially. The mixture was allowed to react at room temperature and pressure for 12 hours. After the reaction was complete, 2'-chloro-N-{6-[4-(difluoromethyl)-3-methoxyphenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (8.0 mg, 3.04% yield) was obtained as a white solid. LCMS (ESI) [M+H] + :571.14. 1 H NMR (400MHz, DMSO) δ8.78(s,1H),8.17(s,1H),7.52(s,1H),7.45–7.39(m,2H),7.14(s,1H),7.04(d,J=1.7Hz,1H),7.19– 6.87(m,1H),3.85(s,3H),3.62(s,3H),3.08(s,1H),2.98–2.78(m,2H),2.74(s,2H),2.58(s,3H),2.05(t,J=6.6Hz,2H).

[0363] Example 30: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[2-(2,2,2-trifluoroethyl)amino]pyrimidin-5-yl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl-[4,4'-bipyridine]-3-carboxamide (Compound 52)

[0364] Step 1: Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine

[0365] 2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (5.00 g, 20.8 mmol, 1.0 eq), 2,2,2-trifluoroethylamine (8.43 g, 62.5 mmol, 3.0 eq), and diisopropylethylamine (26.8 g, 208.3 mmol, 10.0 eq) were added to N,N-dimethylformamide (30 mL) and reacted at 80°C for 24 hours. After completion of the reaction, the reaction solution was concentrated and extracted with ethyl acetate and water. The organic phase was concentrated to yield a crude yellow solid, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine (8.0 g). LCMS (TOF MS ES+) m / z [M+H] + :304.13.

[0366] Step 2: Synthesis of 5-(1,4-dioxyaspirino[4.5]dec-7-en-8-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine

[0367] 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine (3.0 g, 9.9 mmol, 1.0 eq), 1,4-dioxaspirino[4.5]dec-7-en-8-yl trifluoromethanesulfonate (2.85 g, 9.9 mmol, 1.0 eq), 1,1-bis(diphenylphosphino)dibenzoylmethanepalladium chloride (723 mg, 0.99 mmol, 0.1 eq) and potassium carbonate (3.41 g, 24.7 mmol, 2.5 eq) were added to 1,4-dioxane (40 mL) and water (8 mL) and reacted at 80 ° C for 2 hours. After the reaction, the reaction solution was filtered, and the filtrate was extracted with ethyl acetate and water. The product was purified by normal phase column chromatography to obtain a white solid 5-(1,4-dioxyaspirino[4.5]dec-7-en-8-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine (1.2 g, yield 38.3%). LCMS (TOF MS ES+) m / z [M+H] + :316.11. 1 H NMR (400MHz, DMSO) δ8.46 (s, 2H), 7.78 (t, J = 6.7Hz, 1H), 5.99 (m, J = 3.9, 1.9Hz, 1H), 4.15 (m, J = 9.7, 6.7Hz, 2H), 3.93 (s, 4H), 2.50 (d, J = 7.5Hz, 2H), 2.35 (dd, J = 4.1, 2.2Hz, 2H), 1.81 (t, J = 6.5Hz, 2H).

[0368] Step 3: Synthesis of 5-(1,4-dioxyaspirino[4.5]dec-8-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine

[0369] 5-(1,4-Dioxyaspirino[4.5]dec-7-en-8-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine (1.2 g, 3.8 mmol, 1.0 eq) and palladium on carbon (240 mg) were added to tetrahydrofuran (30 mL) and stirred at room temperature for 1 hour. After the reaction was complete, the mixture was filtered through celite and the filtrate was concentrated to obtain 5-(1,4-Dioxyaspirino[4.5]dec-8-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine (1.1 g, yield 91.0%) as a white solid, which was used directly in the next reaction. LCMS (TOF MS ES+) m / z [M+H] + :318.13. 1 H NMR (400MHz, DMSO) δ8.26 (s, 2H), 7.58 (t, J = 6.7Hz, 1H), 4.11 (m, J = 9.6, 6.7Hz, 2H), 3. 89(d,J=2.4Hz,4H),2.48(d,J=10.8Hz,1H),1.77(d,J=9.7Hz,4H),1.71–1.54(m,4H).

[0370] Step 4: Synthesis of 4-[2-(2,2,2-trifluoroethyl)amino]pyrimidin-5-ylcyclohexane-1-one

[0371] 5-(1,4-Dioxyaspirino[4.5]dec-8-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine (200 mg, 0.63 mmol, 1.0 eq) and p-toluenesulfonic acid monohydrate (180 mg, 0.94 mmol, 1.5 eq) were added to acetone (6 mL) and water (2 mL) and reacted at 60°C for 1 hour. After completion of the reaction, ethyl acetate and water were added for extraction. Purification by normal phase column chromatography afforded a yellow solid, 4-[2-(2,2,2-trifluoroethyl)amino]pyrimidin-5-ylcyclohexane-1-one (171 mg, 99.0% yield). LCMS (TOF MS ES+) m / z [M+H] + :274.10. 1H NMR (400MHz, DMSO) δ8.35(s,2H),7.63(t,J=6.7Hz,1H),4.12(m,J=9.6,6.6Hz,2H),2.97(m,J=12.2,3.5Hz ,1H),2.58(m,J=14.9,7.5Hz,2H),2.27(d,J=14.4Hz,2H),2.12–2.01(m,2H),1.89(m,J=13.1,4.1Hz,2H).

[0372] Step 5: Synthesis of 6-{2-[(2,2,2-trifluoroethyl)amino]pyrimidin-5-yl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0373] 4-[2-(2,2,2-trifluoroethyl)amino]pyrimidin-5-ylcyclohexane-1-one (150 mg, 0.55 mmol, 1.0 eq), elemental iodine (167 mg, 0.66 mmol, 1.2 eq), and thiourea (83 mg, 1.10 mmol, 2.0 eq) were added to ethanol (5 mL) and stirred at 100°C for 2 hours. After the reaction, sodium bicarbonate solution and sodium thiosulfate solution were added, followed by extraction with ethyl acetate and water. The product was separated and purified by normal phase column chromatography to obtain 6-{2-[(2,2,2-trifluoroethyl)amino]pyrimidin-5-yl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (172 mg, 94.9% yield) as a yellow solid. LCMS (TOF MS ES+) m / z [M+H] + :330.09.

[0374] Step 6: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[2-(2,2,2-trifluoroethyl)amino]pyrimidin-5-yl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl-[4,4'-bipyridine]-3-carboxamide

[0375] 6-{2-[(2,2,2-trifluoroethyl)amino]pyrimidin-5-yl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (150 mg, 0.45 mmol, 1.0 eq), 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (126 mg, 0.45 mmol, 1.0 eq), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (191 mg, 0.68 mmol, 1.5 eq) and N-methylimidazole (149 mg, 1.82 mmol, 4.0 eq) were added to acetonitrile (6 mL) and reacted at room temperature for 1 hour. After the reaction, the reaction solution was concentrated and purified by high performance liquid chromatography to obtain a white solid 2'-chloro-5'-methoxy-6-methyl-N-{6-[2-(2,2,2-trifluoroethyl)amino]pyrimidin-5-yl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl-[4,4'-bipyridine]-3-carboxamide (62.3 mg, yield 23.2%). LCMS (TOF MS ES+) m / z [M+H] + :590.1340. 1 H NMR (400MHz, DMSO) δ12.49(s,1H),8.77(s,1H),8.35(s,2H),8.17(s,1H),7.63(t,J=6.7Hz,1H),7.51(s,1H),7.41(s,1H),4 .11(dd,J=10.1,7.2Hz,2H),3.62(s,3H),2.92(d,J=14.3Hz,2H),2.73(q,J=15.0Hz,3H),2.58(s,3H),2.00(d,J=7.3Hz,2H).

[0376] Example 31: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[4-(2,2,2-trifluoroethyl)amino]phenyl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl-[4,4'-bipyridine]-3-carboxamide (Compound 54)

[0377] Step 1: Synthesis of 4-bromo-N-(2,2,2-trifluoroethyl)aniline

[0378] (4-Bromophenyl)boronic acid (5.00 g, 24.9 mmol, 1.0 eq), 2,2,2-trifluoroethylamine (7.39 g, 74.7 mmol, 3.0 eq), copper acetate (6.76 g, 37.3 mmol, 1.5 eq), and triethylamine (7.54 g, 74.7 mmol, 3.0 eq) were added to acetonitrile (100 mL) and reacted at room temperature for 16 hours, then at 80°C for 1 hour. After completion of the reaction, the insoluble material was removed by filtration through Celite, and the filtrate was concentrated and purified by normal phase column chromatography to obtain 4-bromo-N-(2,2,2-trifluoroethyl)aniline (4.15 g, 65.4% yield) as a colorless oil. LCMS (TOF MS ES+) m / z [M+H] + :253.97. 1 H NMR (400MHz, DMSO) δ7.30–7.20(m,2H),6.76–6.66(m,2H),6.44(t,J=7.0Hz,1H),3.93(m,J=9.7,6.9Hz,2H).

[0379] Step 2: Synthesis of 4-(1,4-dioxyaspirino[4.5]dec-7-en-8-yl)-N-(2,2,2-trifluoroethyl)aniline

[0380] 4-Bromo-N-(2,2,2-trifluoroethyl)aniline (4.15 g, 16.3 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (5.21 g, 19.6 mmol, 1.5 eq), 1,1-bis(diphenylphosphino)diborane iron palladium dichloride (1.19 g, 1.63 mmol, 0.1 eq) and potassium carbonate (5.64 g, 40.8 mmol, 2.5 eq) were added to 1,4-dioxane (60 mL) and water (12 mL) and reacted at 90 ° C for 24 hours. After the reaction, the product was filtered, and the filtrate was extracted with ethyl acetate and water. The product was purified by normal phase column chromatography to obtain a yellow solid 4-(1,4-dioxyaspirino[4.5]dec-7-en-8-yl)-N-(2,2,2-trifluoroethyl)aniline (2.1 g, yield 41.1%). LCMS (TOF MS ES+) m / z [M+H] + :314.12. 1H NMR (400MHz, DMSO) δ7.24–7.16(m,2H),6.73–6.65(m,2H),6.23(m,J=6.8Hz,1H),5.86–5.79 (m,1H),3.97–3.88(m,6H),2.50(d,J=10.3Hz,2H),2.36–2.32(m,2H),1.79(t,J=6.5Hz,2H).

[0381] Step 3: Synthesis of 4-(1,4-dioxyaspirino[4.5]dec-8-yl)-N-(2,2,2-trifluoroethyl)aniline

[0382] 4-(1,4-Dioxyaspirino[4.5]dec-7-en-8-yl)-N-(2,2,2-trifluoroethyl)aniline (2.1 g, 6.7 mmol, 1.0 eq) and palladium on carbon (210 mg) were added to tetrahydrofuran (40 mL) and stirred at room temperature for 1 hour. After the reaction, the mixture was filtered through celite and the filtrate was concentrated to obtain a yellow solid, 4-(1,4-dioxyaspirino[4.5]dec-8-yl)-N-(2,2,2-trifluoroethyl)aniline (2.1 g, yield 99.4%), which was used directly in the next reaction. LCMS (TOF MS ES+) m / z [M+H] + :316.14.

[0383] Step 4: Synthesis of 4-[4-(2,2,2-trifluoroethyl)amino]phenylcyclohexane-1-one

[0384] 4-(1,4-Dioxyaspirino[4.5]dec-8-yl)-N-(2,2,2-trifluoroethyl)aniline (2.1 g, 6.66 mmol, 1.0 eq) and p-toluenesulfonic acid monohydrate (2.53 g, 13.33 mmol, 2.0 eq) were added to acetone (30 mL) and water (10 mL) and reacted at 60°C for 1 hour. After the reaction, ethyl acetate and water were added for extraction. Purification by normal phase column chromatography afforded a purple solid, 4-[4-(2,2,2-trifluoroethyl)amino]phenylcyclohexane-1-one (3.6 g, 85.0% yield). LCMS (TOF MS ES+) m / z [M+H] + :272.11. 1H NMR (400MHz, DMSO) δ7.07–6.98(m,2H),6.70–6.62(m,2H),6.05(t,J=7.0Hz,1H),3.86(m,J=9.8,6.9Hz,2H),2.90(m,J=12.0,3. 4Hz, 1H), 2.55 (m, J = 14.1, 7.1Hz, 2H), 2.23 (m, J = 14.7, 4.5, 2.2Hz, 2H), 2.01 (m, J = 12.6, 3.0Hz, 2H), 1.79 (m, J = 13.2, 4.1Hz, 2H).

[0385] Step 5: Synthesis of 6-{4-[(2,2,2-trifluoroethyl)amino]phenyl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0386] 4-[4-(2,2,2-trifluoroethyl)amino]phenylcyclohexane-1-one (200 mg, 0.74 mmol, 1.0 eq), elemental iodine (206 mg, 0.81 mmol, 1.1 eq), and thiourea (112 mg, 1.48 mmol, 2.0 eq) were added to ethanol (40 mL) and stirred at 80°C for 16 hours. After the reaction, sodium bicarbonate solution and sodium thiosulfate solution were added, followed by extraction with ethyl acetate and water. Separation and purification by normal phase column chromatography afforded 6-{4-[(2,2,2-trifluoroethyl)amino]phenyl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (210 mg, 87.0% yield) as a yellow solid. LCMS (TOF MS ES+) m / z [M+H] + :328.10.

[0387] Step 6: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[4-(2,2,2-trifluoroethyl)amino]phenyl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl-[4,4'-bipyridine]-3-carboxamide

[0388] 6-{4-[(2,2,2-trifluoroethyl)amino]phenyl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (200 mg, 0.61 mmol, 1.0 eq), 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (170 mg, 0.61 mmol, 1.0 eq), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (257 mg, 0.91 mmol, 1.5 eq) and N-methylimidazole (200 mg, 2.44 mmol, 4.0 eq) were added to acetonitrile (10 mL) and reacted at room temperature for 1 hour. After the reaction, the reaction solution was concentrated and separated by high performance liquid chromatography to obtain a white solid 2'-chloro-5'-methoxy-6-methyl-N-{6-[4-(2,2,2-trifluoroethyl)amino]phenyl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl-[4,4'-bipyridine]-3-carboxamide (35.7 mg, yield 9.9%). LCMS (TOF MS ES+) m / z [M+H] + :588.1451. 1 H NMR (400MHz, DMSO) δ12.45(s,1H),8.77(s,1H),8.17(s,1H),7.51(s,1H),7.41(s,1H),7.07(d,J=8.2Hz,2H),6.67(d,J=8.2Hz,2H),6.07 (t,J=7.0Hz,1H),3.88(m,J=9.9,7.0Hz,2H),3.62(s,3H),2.86(d,J=13.0Hz,2H),2.69(d,J=8.7Hz,3H),2.58(s,3H),2.02–1.85(m,2H).

[0389] Example 32: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[4-(N-methylaminosulfonyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide (Compound 49)

[0390] Step 1: Synthesis of N-methyl-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzenesulfonamide

[0391] 4-Bromo-N-methylbenzenesulfonamide (8 g, 32 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (8.5 g, 32 mmol, 1.0 eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2.3 g, 3.2 mmol, 0.1 eq) and potassium carbonate (8.8 g, 64 mmol, 2.0 eq) were dissolved in 1,4-dioxane (20 mL) and water (4 mL) and reacted at 80 ° C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, the sample was stirred, and then purified by normal phase column separation (ethyl acetate / petroleum ether, ethyl acetate% = 20%) to obtain N-methyl-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzenesulfonamide (4.7 g, yield 47.9%) as a yellow solid. LCMS (ESI) [M+H]: 310.1099.

[0392] Step 2: Synthesis of N-methyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)benzenesulfonamide

[0393] N-methyl-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzenesulfonamide (2.4 g, 6.4 mmol, 1.0 eq) and palladium on carbon (480 mg) were dissolved in methanol (5 mL). The mixture was replaced with hydrogen three times and allowed to react at room temperature for 16 hours. After the reaction was complete, the mixture was filtered and the filtrate was concentrated to obtain N-methyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)benzenesulfonamide (2.4 g) as a white solid, which was used directly in the next reaction. LCMS (ESI) [M+H]: 310.127.

[0394] Step 3: Synthesis of N-methyl-4-(4-oxocyclohexyl)benzenesulfonamide

[0395] N-Methyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)benzenesulfonamide (800 g, 2.57 mmol, 1.0 eq) and p-toluenesulfonic acid hydrate (977 mg, 5.1 mmol, 2.0 eq) were dissolved in acetone (9 mL) and water (3 mL) and reacted at 60°C for 16 hours. After the reaction was complete, the mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate and water. The organic phase was dehydrated with anhydrous sodium sulfate and concentrated to yield N-methyl-4-(4-oxocyclohexyl)benzenesulfonamide (627 mg, 91% yield) as a white solid. LCMS (ESI) [M+H]: 310.127.

[0396] Step 4: Synthesis of 4-(2-amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)-N-methylbenzenesulfonamide

[0397] N-methyl-4-(4-oxocyclohexyl)benzenesulfonamide (100 mg, 0.37 mmol, 1.0 eq), thiourea (57 mg, 0.75 mmol, 2.0 eq), and iodine (114 mg, 0.56 mmol, 1.2 eq) were dissolved in ethanol (2 mL) and reacted at 80°C for 2 hours. After the reaction was complete, the mixture was concentrated and then quenched with saturated sodium bicarbonate solution and sodium thiosulfate solution. The mixture was then extracted with ethyl acetate and water to obtain crude 4-(2-amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)-N-methylbenzenesulfonamide (121 mg) as a yellow oil. 1 H NMR (400MHz, DMSO) δ7.77–7.68(m,2H),7.60–7.52(m,2H),7.42(s,1H),3.19(m,J=12.0,3.5Hz,1H),2.61(td,J=14.2 ,6.0Hz,2H),2.42(s,3H),2.30(m,J=14.7,2.1Hz,2H),2.11(m,J=12.7,6.0,3.0Hz,2H),1.94(m,J=13.1,6.1Hz,2H).

[0398] Step 5: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[4-(N-methylaminosulfonyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide

[0399] 4-(2-Amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)-N-methylbenzenesulfonamide (120 mg, 0.37 mmol, 1.0 eq), 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (103 mg, 0.37 mmol, 1.0 eq), N,N,N,N-tetramethylchloromethylimidazole hexafluorophosphate (312 mg, 1.11 mmol, 3.0 eq) and N-methylimidazole (610 mg, 3.7 mmol, 20.0 eq) were dissolved in acetonitrile (5 mL) and reacted at room temperature for 2 hours. After the reaction was completed, the reaction mixture was purified to give a yellow powder of 2'-chloro-5'-methoxy-6-methyl-N-{6-[4-(N-methylaminosulfonyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide (13.5 mg, yield 6%). 1H NMR (400MHz, DMSO) δ12.50(s,1H),8.78(s,1H),8.17(s,1H),7.72(d,J=7.9Hz,2H),7.57(d,J=8.1Hz,2H),7.52(s,1H),7.43–7.34(m ,2H),3.62(s,3H),3.15(s,1H),2.97(d,J=17.7Hz,1H),2.83–2.66(m,3H),2.58(s,3H),2.41(d,J=4.9Hz,3H),2.05(d,J=7.6Hz,2H).

[0400] Example 33: Synthesis of 2'-chloro-N-{6-[4-(N,N-dimethylsulfamoyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 50)

[0401] Step 1: Synthesis of N,N-dimethyl-4-{1,4-dioxaspiro[4.5]dec-8-yl}benzenesulfonamide

[0402] N-Methyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)benzenesulfonamide (600 mg, 1.85 mmol, 1.0 eq) was dissolved in ultra-dry N,N-dimethylformamide (7.0 mL). Sodium hydride (153.6 mg, 3.86 mmol, 2.0 eq) and iodomethane (142 mg, 2.89 mmol, 1.5 eq) were slowly added at 0°C. After complete addition, the mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the mixture was quenched with ammonium chloride solution and extracted with ethyl acetate and water. The organic phase was dried and concentrated, and separated by normal phase column chromatography to afford N,N-dimethyl-4-{1,4-dioxaspiro[4.5]dec-8-yl}benzenesulfonamide (620 mg, 98.9% yield) as a yellow solid. LCMS (ESI) [M+H]: 326.1416. 1 H NMR (400MHz, DMSO) δ7.66 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 3.91–3.87 (m, 4H), 2.77–2.55 (m, 7H), 1.84–1.52 (m, 8H).

[0403] Step 2: Synthesis of N,N-dimethyl-4-(4-oxocyclohexyl)benzenesulfonamide

[0404] N,N-Dimethyl-4-{1,4-dioxaspiro[4.5]dec-8-yl}benzenesulfonamide (600 mg, 1.85 mmol, 1.0 eq) and p-toluenesulfonic acid hydrate (527 mg, 2.77 mmol, 1.5 eq) were dissolved in acetone (9 mL) and water (3 mL) and reacted at 60°C for 2 hours. Upon completion, the mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate and water. The organic phase was dehydrated with anhydrous sodium sulfate, concentrated, and dried to afford a yellow solid, N,N-dimethyl-4-(4-oxocyclohexyl)benzenesulfonamide (530 mg), which was used directly in the next reaction. LCMS (ESI) [M+H]: 282.1233. 1 H NMR (400MHz, DMSO) δ7.72–7.65(m,2H),7.58(d,J=8.0Hz,2H),3.20(m,J=12.1,3.5Hz,1H),2.6 0(d,J=1.3Hz,8H),2.29(d,J=13.8Hz,2H),2.10(m,J=13.1,6.4,3.4Hz,2H),2.01–1.85(m,2H).

[0405] Step 3: Synthesis of 4-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-N,N-dimethylbenzenesulfonamide

[0406] N,N-Dimethyl-4-(4-oxocyclohexyl)benzenesulfonamide (150 mg, 0.534 mmol, 1.0 eq), thiourea (81.3 mg, 1.07 mmol, 2.0 eq), and iodine (163 mg, 0.641 mmol, 1.2 eq) were dissolved in ethanol (10 mL) and reacted at 90°C for 16 hours. After the reaction was complete, the mixture was concentrated and quenched with saturated sodium bicarbonate and sodium thiosulfate solutions. The mixture was then extracted with ethyl acetate and water to afford 4-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-N,N-dimethylbenzenesulfonamide (150 mg, 83.3% yield) as a yellow solid. LCMS (ESI) [M+H]: 338.1068. 1 H NMR (400MHz, DMSO) δ7.68 (d, J = 7.8 Hz, 2H), 7.58 (dd, J = 8.4, 2.2 Hz, 2H), 2.60 (d, J = 1. 6Hz, 7H), 2.50 (s, 3H), 2.33–2.24 (m, 1H), 2.10 (d, J = 11.9Hz, 1H), 2.03–1.83 (m, 2H).

[0407] Step 4: Synthesis of 2'-chloro-N-{6-[4-(N,N-dimethylsulfamoyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0408] 4-(2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-N,N-dimethylbenzenesulfonamide (135 mg, 0.40 mmol, 1.0 eq), 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (111 mg, 0.40 mmol, 1.0 eq), N,N,N,N-tetramethylchloromethylimidazole hexafluorophosphate (168 mg, 0.60 mmol, 1.5 eq) and N-methylimidazole (115 mg, 1.41 mmol, 3.5 eq) were dissolved in ultra-dry N,N-dimethylformamide (3.5 mL) and reacted at room temperature for 2 hours. After the reaction was complete, the product was purified and prepared to give 2'-chloro-N-{6-[4-(N,N-dimethylsulfamoyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (10.0 mg, 4.2% yield) as a pale yellow solid. LCMS (ESI) [M+H]: 598.1321. 1 H NMR (400MHz, DMSO) δ12.48(s,1H),8.79(s,1H),8.17(s,1H),7.70(d,J=8.1Hz,2H),7.62(d,J=8.2Hz,2H) ,7.50(s,1H),7.39(s,1H),3.62(s,3H),3.00–2.69(m,5H),2.59(d,J=11.7Hz,9H),2.07(t,J=7.4Hz,2H).

[0409] Example 34: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(6-(6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 56)

[0410] Step 1: Synthesis of 5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridin-2-amine

[0411] 4,4,5,5-Tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (5.0 g, 18.79 mmol, 1.0 eq) and 5-bromopyridin-2-amine (3.25 g, 18.79 mmol, 1.0 eq) were dissolved in a mixed solution of 1,4-dioxane (50.0 mL) and water (12.5 mL). Cesium carbonate (12.25 g, 37.58 mmol, 2.0 eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (274 mg, 0.375 mmol, 0.03 eq) were added, and the mixture was reacted at 80°C under nitrogen protection for 2 hours. After the reaction was complete, the product was extracted with ethyl acetate and purified by normal phase purification (petroleum ether / ethyl acetate = 3:1) to give 5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridin-2-amine (4.07 g, yield 93.34%) as a brown solid. LCMS (ESI) [M+H]+: 233.12.

[0412] Step 2: Synthesis of 5-(1,4-dioxyaspirino[4.5]dec-8-yl)pyridin-2-amine

[0413] 5-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)pyridin-2-amine (4.0 g, 17.2 mmol, 1.0 eq) was dissolved in methanol (30 mL), and palladium / carbon (183 mg, 1.72 mmol, 0.1 eq) was added. The mixture was then reacted at room temperature under a hydrogen atmosphere for 8 hours. Upon completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to afford crude 5-(1,4-dioxaspirino[4.5]dec-8-yl)pyridin-2-amine (4.0 g) as a yellow solid, which was used directly in the next reaction. LCMS (ESI) [M+H]+: 235.1. 1 H NMR (400MHz, DMSO) δ8.88(s,1H),7.48(s,1H),4.04(s,3H).

[0414] Step 3: Synthesis of 4-(6-aminopyridin-3-yl)cyclohexan-1-one

[0415] 5-(1,4-Dioxyaspirino[4,5]dec-8-yl)pyridin-2-amine (2.0 g, 8.6 mmol, 1.0 eq) was dissolved in a mixture of tetrahydrofuran (10.0 mL) and ethanol (5.0 mL). Concentrated hydrochloric acid (5.0 mL) was then added and allowed to react at room temperature for 2 hours. Upon completion of the reaction, the pH was adjusted to neutral and the product was purified by normal phase purification (dichloromethane / methanol = 10:1) to afford 4-(6-aminopyridin-3-yl)cyclohexan-1-one (1.31 g, 80.36% yield) as a yellow solid. LCMS (ESI) [M+H]+: 190.1.

[0416] Step 4: Synthesis of 2,2,2-trifluoro-N-[5-(4-oxocyclohexyl)pyridin-2-yl]acetamide

[0417] 4-(6-Aminopyridin-3-yl)cyclohexan-1-one (1.3 g, 6.8 mmol, 1.0 eq) was dissolved in ultra-dry dichloromethane (25 mL). Triethylamine (2.06 g, 20.41 mmol, 3.0 eq) and trifluoroacetic anhydride (2.14 g, 10.2 mmol, 1.5 eq) were added dropwise in an ice bath. The mixture was then allowed to react at room temperature for 1.5 hours. After the reaction was complete, the mixture was purified by normal phase chromatography (petroleum ether:ethyl acetate = 3:2) to give 2,2,2-trifluoro-N-[5-(4-oxocyclohexyl)pyridin-2-yl]acetamide (1.41 g, yield 72.68%) as a white solid. LCMS (ESI) [M + H] + :287.1.

[0418] Step 5: Synthesis of N-[5-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)pyridin-2-yl]-2,2,2-trifluoroacetamide

[0419] 2,2,2-Trifluoro-N-[5-(4-oxocyclohexyl)pyridin-2-yl]acetamide (400 mg, 1.39 mmol, 1.0 eq) was dissolved in tetrahydrofuran and phenyltrimethylammonium tribromide (522.5 mg, 1.39 mmol, 1.0 eq) was added. The mixture was reacted at room temperature for 2 hours. The mixture was then extracted with ethyl acetate, concentrated, and dissolved in acetonitrile. Thiourea (116.2 mg, 1.52 mmol, 1.1 eq) was added and the reaction continued at room temperature for 4 hours. After the reaction was completed, the mixture was concentrated to obtain a yellow liquid crude product, N-[5-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)pyridin-2-yl]-2,2,2-trifluoroacetamide (677 mg), which was used directly in the next reaction. LCMS (ESI) [M + H] + :343.08.

[0420] Step 6: Synthesis of 6-{6-[(2,2,2-trifluoroethyl)amino]pyridin-3-yl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0421] Sodium borohydride (200 mg, 5.28 mmol, 1.0 eq) and zinc chloride (1.44 g, 10.57 mmol, 2.0 eq) were dissolved in ultra-dry tetrahydrofuran (20 mL) and reacted at room temperature overnight to obtain a solution of System 1. N-[5-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)pyridin-2-yl]-2,2,2-trifluoroacetamide (300 mg) was weighed. , 0.876mmol, 1.0eq) was dissolved in more than dry tetrahydrofuran (10.0mL). Under ice bath conditions, the solution of system 1 was slowly added dropwise. The mixture was reacted at 80℃ for 2 hours. Methanol was added to extract the separated liquid. The mixture was concentrated to obtain a yellow liquid crude product 6-{6-[(2,2,2-trifluoroethyl)amino]pyridin-3-yl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (533mg), which was used directly in the next reaction. LCMS (ESI) [M + H] + :329.1.

[0422] Step 7: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0423] 6-{6-[(2,2,2-trifluoroethyl)amino]pyridin-3-yl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (100.0 mg, 0.304 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (84.7 mg, 0.304 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (2 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (126 mg, 0.456 mmol, 1.5 eq) and N-methylimidazole (74.8 mg, 0.912 mmol, 3.0 eq) were added and reacted at room temperature for 1.5 hours. After the reaction, 2'-chloro-5'-methoxy-6-methyl-N-(6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (16.3 mg, yield 9.10%) was prepared and purified. LCMS (ESI) [M + H]+:589.1.

[0424] Example 35: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[4-(N-ethylaminosulfonyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide (Compound 62)

[0425] Step 1: Synthesis of 4-bromo-N-ethylbenzenesulfonamide

[0426] 4-Bromobenzenesulfonyl chloride (25.5 g, 0.1 mol, 1.0 eq), ethylamine hydrochloride (9.78 g, 0.12 mol, 1.2 eq), and triethylamine (30.3 g, 0.3 mmol, 3.0 eq) were dissolved in dichloromethane and stirred at room temperature for 0.5 hour. After the reaction was complete, dichloromethane and water were added to extract the separated liquids. The organic phases were combined and concentrated to obtain 4-bromo-N-ethylbenzenesulfonamide (26.6 g) as a white solid, which was used directly in the next reaction. LCMS (ESI) [M+H]: 263.9. 1 H NMR (400MHz, DMSO-d6) δ7.84–7.79(m,2H),7.73–7.69(m,2H),7.67(t,J=5.7Hz,1H),2.78(m,J=7.2,5.6Hz,2H),0.97(t,J=7.2Hz,3H).

[0427] Step 2: Synthesis of N-ethyl-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzenesulfonamide

[0428] 4-Bromo-N-ethylbenzenesulfonamide (26.3 g, 0.1 mol, 1.0 eq), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (26.6 g, 0.1 mol, 1.0 eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.3 g, 0.01 mol, 0.1 eq), and potassium carbonate (41 g, 0.3 mol, 3.0 eq) were dissolved in 1,4-dioxane (300 mL) and water (50 mL), and the system was protected by nitrogen. The reaction was carried out at 80 ° C for 3 hours. After the reaction was complete, the reaction solution was filtered, concentrated, and stirred, then purified by normal phase column chromatography (ethyl acetate / petroleum ether, ethyl acetate % = 60%) to obtain N-ethyl-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzenesulfonamide (22.82 g, yield 70.43%) as a yellow solid. LCMS (ESI) [M+H]: 324. 1H NMR (400MHz, DMSO-d6) δ7.71(d,J=8.4Hz,2H),7.62(d,J=8.4Hz,2H),7.51(t,J=5.7Hz,1H),6.30–6.14(m,1H),3.92(s,4H ),2.80–2.71(m,2H),2.57(m,J=4.6,2.4Hz,2H),2.40(m,J=4.3,2.4Hz,2H),1.82(t,J=6.5Hz,2H),0.96(t,J=7.2Hz,3H).

[0429] Step 3: Synthesis of N-ethyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)benzenesulfonamide

[0430] N-ethyl-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzenesulfonamide (17 g, 52.63 mmol, 1.0 eq) and palladium on carbon (1.7 g) were dissolved in methanol (200 mL) and the atmosphere was replaced with hydrogen three times. The mixture was then allowed to react at room temperature for 2.5 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to afford N-ethyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)benzenesulfonamide (14.66 g, 85.73% yield) as a yellow oil. LCMS (ESI) [M+H]+: 326. 1 H NMR(400MHz, DMSO-d6)δ7.79–7.63(m,2H),7.46(dd,J=7.0,5.1Hz,3H),3.91( d,J=2.1Hz,4H),2.84–2.69(m,2H),1.82–1.56(m,9H),0.98(t,J=7.2Hz,3H).

[0431] Step 4: Synthesis of N-ethyl-4-(4-oxocyclohexyl)benzenesulfonamide

[0432] N-Ethyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)benzenesulfonamide (14.66 g, 45.11 mmol, 1.0 eq) and p-toluenesulfonic acid hydrate (8.57 mg, 45.11 mmol, 1.0 eq) were dissolved in acetone (50 mL) and water (100 mL) and reacted at 50°C for 4 hours. After the reaction was complete, the mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate and water. The organic phase was dehydrated with anhydrous sodium sulfate and concentrated to afford N-ethyl-4-(4-oxocyclohexyl)benzenesulfonamide (9.1 mg, 91% yield) as a yellow oil. LCMS (ESI) [M+H]: 282.

[0433] Step 5: Synthesis of 4-(2-amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)-N-ethylbenzenesulfonamide

[0434] N-ethyl-4-(4-oxocyclohexyl)benzenesulfonamide (9.1 g, 32.38 mmol, 1.0 eq), thiourea (4.9 g, 64.79 mmol, 2.0 eq), and iodine (12.3 g, 48.57 mmol, 1.5 eq) were dissolved in ethanol (200 mL) and reacted at 80°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated and then quenched with saturated sodium bicarbonate solution and sodium thiosulfate solution. The mixture was then extracted with ethyl acetate and water, and the organic phase was concentrated to obtain a crude yellow solid of 4-(2-amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)-N-ethylbenzenesulfonamide (5.85 g).

[0435] Step 6: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[4-(N-ethylaminosulfonyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide

[0436] 4-(2-Amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)-N-ethylbenzenesulfonamide (3 g, 8.9 mmol, 1.0 eq), 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (2.5 g, 8.9 mmol, 1.0 eq), N,N,N,N-tetramethylchloromethylimidazole hexafluorophosphate (3.7 g, 13.4 mmol, 1.5 eq), and N-methylimidazole (2.2 g, 26.7 mmol, 3.0 eq) were dissolved in acetonitrile (100 mL) and reacted at room temperature for 2 hours. After the reaction was complete, the product was separated by a forward column and purified by pure ethyl acetate. The product was then separated and purified by a reverse column. When the acetonitrile content was 90%, the product was concentrated to afford a yellow powder, 2'-chloro-5'-methoxy-6-methyl-N-{6-[4-(N-ethylaminosulfonyl)phenyl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide (1.77 g, 33.21% yield). LCMS (ESI) [M+H]: 598.1329. 1H NMR (400MHz, DMSO-d6) δ12.54(s,1H),8.78(s,1H),8.17(s,1H),7.78–7.68(m,2H),7.56(d,J=8.3Hz,2H),7.53–7.47(m,2H),7.41(s,1H),3.6 2(s,3H),3.14(m,J=10.3,4.9Hz,1H),2.96(dd,J=15.8,5.0Hz,1H),2.84–2.70(m,5H),2.58(s,3H),2.09–1.99(m,2H),0.97(t,J=7.2Hz,3H).

[0437] Example 36: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(6-(4-(2,2,2-trifluoroethyl)amino)piperidin-1-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 65)

[0438] Step 1: Synthesis of tert-butyl 4-(2,2,2-trifluoroethyl)amino)piperidine-1-carboxylate

[0439] Dissolve tert-butyl 4-chloropiperidine-1-carboxylate (5 g, 23.0 mmol, 1.0 eq) in dichloromethane (20 ml), then add 2,2,2-trifluoroethylamine (2.7 g, 27.0 mmol, 1.2 eq) and triethylamine (6.9 g, 69.0 mol, 3.0 eq). Allow to react at room temperature for 2 hours. After the reaction is complete, extract with water and ethyl acetate (100 mL x 3). The organic phase is dried and concentrated to yield tert-butyl 4-(2,2,2-trifluoroethyl)amino)piperidine-1-carboxylate (4.1 g, 63.2% yield) as a brown oil. LCMS (ESI) [M+H]+: 283.1.

[0440] Step 2: Synthesis of N-(2,2,2-trifluoroethyl)piperidin-4-amine

[0441] Dissolve tert-butyl 4-(2,2,2-trifluoroethyl)amino)piperidin-1-carboxylate (4.1 g, 14.0 mmol, 1.0 eq) in dichloromethane (20 mL). Slowly add trifluoroacetic acid (5 mL) and allow to react at room temperature for 2 hours. Upon completion, extract with water and ethyl acetate (100 mL x 3). The organic phase is concentrated and dried to afford N-(2,2,2-trifluoroethyl)piperidin-4-amine (2.1 g, 82.4% yield) as a brown oil. LCMS (ESI) [M+H]+: 183.1.

[0442] Step 3: Synthesis of tert-butyl (6-(4-(2,2,2-trifluoroethyl)amino)piperidin-1-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbamate

[0443] Dissolve N-(2,2,2-trifluoroethyl)piperidin-4-amine (2.0 g, 11.0 mmol, 1.0 eq) in methanol (20 mL), add tert-butyl (5-oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbamate (3.24 g, 12.0 mmol, 1.1 eq), sodium cyanoborohydride (2.07 g, 33.0 mmol, 3.0 eq), and acetic acid (660 g, 11.0 mmol, 1.0 eq). The mixture was reacted at 80°C for 4 hours. After completion of the reaction, the product was purified by normal phase chromatography (petroleum ether:ethyl acetate = 2:1) to afford tert-butyl (6-(4-(2,2,2-trifluoroethyl)amino)piperidin-1-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbamate (600 mg, 12.5% ​​yield) as a brown solid. LCMS (ESI) [M+H] +: 435.2.

[0444] Step 4: Synthesis of 6-(4-((2,2,2-trifluoroethyl)amino)piperidin-1-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0445] Dissolve tert-butyl (6-(4-(2,2,2-trifluoroethyl)amino)piperidin-1-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbamate (600 mg, 1.38 mmol, 1.0 eq) in dichloromethane (8 mL). Slowly add trifluoroacetic acid (1 mL) and react at room temperature for 30 minutes. After the reaction is complete, extract with water and ethyl acetate (100 mL x 3). The organic phase is concentrated and dried to yield 6-(4-((2,2,2-trifluoroethyl)amino)piperidin-1-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine as a brown oil (310 mg, 67.2% yield). LCMS (ESI) [M+H]+: 335.14.

[0446] Step 5: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(6-(4-(2,2,2-trifluoroethyl)amino)piperidin-1-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0447] 6-(4-((2,2,2-trifluoroethyl)amino)piperidin-1-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (300 mg, 0.90 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (249 mg, 0.90 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (4 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (378 mg, 1.3 mmol, 1.5 eq) and N-methylimidazole (221 mg, 2.7 mmol, 3.0 eq) were added, followed by reaction at room temperature for 5 hours. After the reaction was complete, a white solid, 2'-chloro-5'-methoxy-6-methyl-N-(6-(4-(2,2,2-trifluoroethyl)amino)piperidin-1-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (20 mg, 3.7% yield) was obtained. LCMS (ESI) [M+H]+: 595.1.

[0448] Example 37: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[(1-methylazetidin-3-yl)methoxy]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide (Compound 68)

[0449] Step 1: Synthesis of 3-(chloromethyl)-1-methylazetidine

[0450] Dissolve 3-(Chloromethyl)azetidine (3 g, 28.0 mmol, 1.0 eq) in dichloromethane (20 mL), then add iodomethane (4.8 g, 34.0 mmol, 1.2 eq) and triethylamine (8.6 g, 0.086 mol, 3.0 eq). Incubate at 50°C for 2 hours. After completion, extract with water and ethyl acetate (100 mL x 3). The organic phase is dried and concentrated to yield a brown solid, 3-(chloromethyl)-1-methylazetidine (1.8 g, 54% yield). LCMS (ESI) [M+H]+: 120.05.

[0451] Step 2: Synthesis of 6-[(1-methylazetidin-3-yl)methoxy]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0452] 3-(Chloromethyl)-1-methylazetidine (1.2 g, 10 mmol, 1.0 eq) was dissolved in anhydrous ethanol (10 mL), followed by the addition of 2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-ol (1.7 g, 10.0 mmol, 1.0 eq) and potassium carbonate (4.1 g, 30.0 mmol, 3.0 eq). The mixture was allowed to react at 80°C for 5 hours. Upon completion, the reaction was purified by reverse-phase column chromatography to afford 6-[(1-methylazetidin-3-yl)methoxy]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine as a brown oil (560 mg, 22.1% yield). LCMS (ESI) [M+H]+: 254.1.

[0453] Step 3: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[(1-methylazetidin-3-yl)methoxy]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide

[0454] 6-[(1-Methylazetidin-3-yl)methoxy]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (230 mg, 0.91 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (253 mg, 0.91 mmol, 1.0 eq) were dissolved in ultra-dry N,N-dimethylformamide (5 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (381 mg, 1.36 mmol, 1.5 eq) and N-methylimidazole (224 mg, 2.73 mmol, 3.0 eq) were added, followed by reaction at room temperature for 5 hours. After the reaction was complete, a white solid, 2'-chloro-5'-methoxy-6-methyl-N-{6-[(1-methylazetidin-3-yl)methoxy]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide (34 mg, yield 7.3%) was obtained. LCMS (ESI) [M+H]+: 514.1.

[0455] Example 38: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[5-(2,2,2-trifluoroethyl)amino]pyridin-2-yl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl-[4,4'-bipyridine]-3-carboxamide (Compound 63)

[0456] Step 1: Synthesis of 6-bromo-N-(2,2,2-trifluoroethyl)pyridin-3-amine

[0457] 2-Bromopyridine-5-boronic acid (5.00 g, 24.9 mmol, 1.0 eq), 2,2,2-trifluoroethylamine (7.39 g, 74.7 mmol, 3.0 eq), copper acetate (6.76 g, 37.3 mmol, 1.5 eq), and triethylamine (7.54 g, 74.7 mmol, 3.0 eq) were added to acetonitrile (50 mL) and reacted at 80°C for 2 hours. After completion of the reaction, the insoluble material was removed by filtration through Celite, and the filtrate was concentrated and purified by normal phase column chromatography to obtain 6-bromo-N-(2,2,2-trifluoroethyl)pyridin-3-amine (427 mg, 6.7% yield) as a yellow solid. LCMS (ESI) [M+H]+: 254.9.

[0458] Step 2: Synthesis of 6-(1,4-dioxyaspirino[4.5]dec-7-en-8-yl)-N-(2,2,2-trifluoroethyl)pyridin-3-amine

[0459] 6-Bromo-N-(2,2,2-trifluoroethyl)pyridin-3-amine (427 mg, 1.67 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (489 mg, 1.84 mmol, 1.1 eq), 1,1-bis(diphenylphosphino)diborane iron palladium dichloride (122 mg, 0.167 mmol, 0.1 eq), and potassium carbonate (577 mg, 4.18 mmol, 2.5 eq) were added to 1,4-dioxane (10 ml) and water (2 ml). The mixture was reacted at 80°C under a nitrogen atmosphere for 4 hours. After the reaction, the mixture was filtered, and the filtrate was extracted with ethyl acetate (20 mL x 2) and water (15 mL). The organic phase was concentrated and purified by normal phase column chromatography to obtain 6-(1,4-dioxyaspirino[4.5]dec-7-en-8-yl)-N-(2,2,2-trifluoroethyl)pyridin-3-amine (328 mg, 62.3% yield) as a brown oil. LCMS (ESI) [M+H]+: 315.1.

[0460] Step 3: Synthesis of 6-(1,4-dioxyaspirino[4.5]dec-8-yl)-N-(2,2,2-trifluoroethyl)pyridin-3-amine

[0461] 6-(1,4-Dioxyaspirino[4.5]dec-7-en-8-yl)-N-(2,2,2-trifluoroethyl)pyridin-3-amine (328 mg, 1.04 mmol, 1.0 eq) and palladium on carbon (66 mg) were added to tetrahydrofuran (6 ml) and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was filtered through celite and the filtrate was concentrated to obtain 6-(1,4-Dioxyaspirino[4.5]dec-8-yl)-N-(2,2,2-trifluoroethyl)pyridin-3-amine (290 mg, 87.9% yield) as a brown oil. LCMS (ESI) [M+H]+: 317.1.

[0462] Step 4: Synthesis of 4-[5-(2,2,2-trifluoroethyl)aminopyridin-2-yl]cyclohexan-1-one

[0463] 6-(1,4-Dioxyaspirin[4.5]dec-8-yl)-N-(2,2,2-trifluoroethyl)pyridin-3-amine (290 mg, 0.92 mmol, 1.0 eq) and p-toluenesulfonic acid monohydrate (174 mg, 0.92 mmol, 1.0 eq) were added to acetone (9 ml) and water (3 ml) and reacted at 60°C for 1 hour. After completion of the reaction, ethyl acetate (20 mL) and water (15 mL) were added for extraction. The organic phase was concentrated and purified by normal phase column chromatography to obtain 4-[5-(2,2,2-trifluoroethyl)aminopyridin-2-yl]cyclohexan-1-one (173 mg, 68.8% yield) as a brown oil. LCMS (ESI) [M+H]+: 273.1.

[0464] Step 5: Synthesis of 6-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0465] 4-[5-(2,2,2-trifluoroethyl)aminopyridin-2-yl]cyclohexan-1-one (173 mg, 0.63 mmol, 1.0 eq), iodine (194 mg, 0.76 mmol, 1.2 eq), and thiourea (96 mg, 1.26 mmol, 2.0 eq) were added to ethanol (5 mL) and stirred at 80°C for 16 hours. After completion of the reaction, saturated aqueous sodium bicarbonate (15 mL) and saturated aqueous sodium thiosulfate (15 mL) were added, followed by extraction with ethyl acetate (20 mL) and water (15 mL). The organic phase was concentrated to afford crude 6-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (305 mg) as a brown solid. LCMS (ESI) [M+H]+: 329.1.

[0466] Step 6: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[5-(2,2,2-trifluoroethyl)amino]pyridin-2-yl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl-[4,4'-bipyridine]-3-carboxamide

[0467] 6-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (208 mg, 0.636 mmol, 1.0 eq), 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (176 mg, 0.636 mmol, 1.0 eq), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (267 mg, 0.954 mmol, 1.5 eq) and N-methylimidazole (208 mg, 2.544 mmol, 4.0 eq) were added to acetonitrile (10 ml) and reacted at room temperature for 1 hour. After the reaction, the reaction solution was concentrated and separated by high performance liquid chromatography to give a white solid 2'-chloro-5'-methoxy-6-methyl-N-{6-[5-(2,2,2-trifluoroethyl)amino]pyridin-2-yl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl-[4,4'-bipyridine]-3-carboxamide (9.2 mg, two-step yield 2.4%). LCMS(ESI)[M+H]+:589.1381;1H NMR (400MHz, DMSO) δ12.40(s,1H),8.78(s,1H),8.17(s,1H),8.05(d,J=2.5Hz,1H),7.51(s,1H),7.40(s,1H),7.10(s,2H),6.34(t,J=6.9Hz,1 H),3.95(m,J=9.7,6.8Hz,2H),3.62(s,3H),3.05–2.96(m,1H),2.87(t,J=7.1Hz,2H),2.70(d,J=6.8Hz,2H),2.58(s,3H),2.11–1.86(m,2H).

[0468] Example 39: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[5-(N-methylsulfamoyl)pyridin-2-yl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide (Compound 64)

[0469] Step 1: Synthesis of 6-chloropyridine-3-sulfonyl chloride

[0470] (a) SOCl2 (11 mL) was added dropwise to a solution (70 mL) at 0°C. CuCl (115 mg, 1.17 mmol, 0.03 eq) was then added to the system and the reaction continued for 30 minutes. (b) 6-Chloropyridin-3-amine (5 g, 38.89 mmol, 1.0 eq) was added portionwise to concentrated HCl (40 mL) at 0°C. A solution of NaNO2 (3 g, 43.48 mol, 1.1 eq) in water (10 mL) was then added and the reaction continued for 10 minutes. Solution (b) was slowly added to solution (a) at 0°C and the reaction continued for 2 hours. Filtration and concentration afforded 6-chloropyridine-3-sulfonyl chloride (6.6 g, 80.2% yield) as a white solid. LCMS (ESI) [M+H]+: 212.04.

[0471] Step 2: Synthesis of 6-chloro-N-methylpyridine-3-sulfonamide

[0472] 6-Chloropyridine-3-sulfonyl chloride (6 g, 28.29 mol, 1.0 eq), methylamine hydrochloride (2.3 g, 0.034 mol, 1.2 eq), and triethylamine (8.6 g, 0.085 mol, 3.0 eq) were added sequentially to dichloromethane (20 ml) and allowed to react at room temperature for 2 hours. H₂O (100 mL) and ethyl acetate (100 ml x 3) were added to the system, and the mixture was extracted. The organic phase was concentrated to afford 6-chloro-N-methylpyridine-3-sulfonamide (2.5 g, 43.3% yield) as a brown oil. LCMS (ESI) [M+H]⁺: 207.00.

[0473] Step 3: Synthesis of N-methyl-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine-3-sulfonamide

[0474] 6-Chloro-N-methylpyridine-3-sulfonamide (1.0 g, 4.85 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (1.55 g, 5.82 mmol, 1.2 eq), cesium carbonate (4.72 g, 14.5 mmol, 3.0 eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (177 mg, 0.24 mmol, 0.05 eq) were added to a solution of 1,4-dioxane (10 ml) and water (2.5 ml) and reacted at 80 ° C under N2 atmosphere for 3 hours. The mixture was filtered, concentrated, and purified by normal phase column chromatography to obtain a yellow solid N-methyl-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine-3-sulfonamide (990 mg, yield 65.8%). LCMS (ESI) [M+H]+: 311.1.

[0475] Step 4: Synthesis of N-methyl-6-(1,4-dioxaspiro[4.5]dec-8-yl)pyridine-3-sulfonamide

[0476] N-Methyl-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine-3-sulfonamide (980 mg, 3.16 mmol, 1.0 eq) and palladium / carbon (67 mg, 0.63 mmol, 0.2 eq) were added to methanol (5 mL) and reacted under an H2 atmosphere for 16 h. Filtration and concentration afforded a crude yellow solid of N-methyl-6-(1,4-dioxaspiro[4.5]dec-8-yl)pyridine-3-sulfonamide (1.0 g), which was used directly in the next step. LCMS (ESI) [M+H]+: 313.11.

[0477] Step 5: Synthesis of N-methyl-6-(4-oxocyclohexyl)pyridine-3-sulfonamide

[0478] N-Methyl-6-(1,4-dioxaspiro[4.5]dec-8-yl)pyridine-3-sulfonamide (1.0 g, 3.2 mmol, 1.0 eq) and toluenesulfonic acid monohydrate (183 mg, 0.96 mmol, 0.3 eq) were added to acetone / water (6 mL / 3 mL) and reacted at 60°C for 2 hours. The pH was adjusted to neutral by adding saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (15 mL x 2). The organic phase was concentrated to obtain a brown crude solid of N-methyl-6-(4-oxocyclohexyl)pyridine-3-sulfonamide (550 mg), which was used directly in the next reaction. LCMS (ESI) [M+H]+: 269.09.

[0479] Step 6: Synthesis of 6-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-N-methylpyridine-3-sulfonamide

[0480] N-Methyl-6-(4-oxocyclohexyl)pyridine-3-sulfonamide (200 mg, 0.75 mmol, 1.0 eq) was dissolved in ethanol (5 ml). Iodine (227 mg, 0.89 mmol, 1.2 eq) and thiourea (113 mg, 1.49 mmol, 2.0 eq) were added under ice-cooling. The mixture was allowed to react at 80°C for 2 hours. After completion, the reaction was quenched by addition of saturated sodium thiosulfate solution. The organic phase was extracted with EA (25 mL x 2) and concentrated to dryness to obtain a crude brown oil, 6-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-N-methylpyridine-3-sulfonamide (60 mg), which was used directly in the next reaction. LCMS (ESI) [M+H]+: 325.07.

[0481] Step 7: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-[5-(N-methylsulfamoyl)pyridin-2-yl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide

[0482] 6-(2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-N-methylpyridine-3-sulfonamide (60 mg, 0.18 mmol, 1.0 eq) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (51 mg, 0.18 mmol, 1.0 eq) were dissolved in N,N-dimethylformamide (3 mL), and then N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (78 mg, 0.27 mmol, 1.5 eq) and N-methylimidazole (46 mg, 0.54 mmol, 3.0 eq) were added to the system and reacted at room temperature for 5 hours. After the reaction, the reaction solution was concentrated and separated by high performance liquid chromatography to give 2'-chloro-5'-methoxy-6-methyl-N-{6-[5-(N-methylsulfamoyl)pyridin-2-yl]-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl}-[4,4'-bipyridine]-3-carboxamide (11 mg, yield 10.4%) as a white solid. LCMS(ESI)[M+H]+:585.1125;1H NMR (400MHz, DMSO-d6) δ8.87(d,J=2.5Hz,1H),8.77(s,1H),8.17(s,1H),8.11(m,J=8.2,2.4Hz,1H),7.65(d,J=8.2Hz,2H),7.52(s, 1H),7.41(s,1H),3.62(s,3H),3.32–3.25(m,1H),2.99(t,J=7.9Hz,2H),2.74(s,2H),2.58(s,3H),2.46(s,3H),2.20–2.02(m,2H).

[0483] Example 40: Synthesis of N-{6-amino-6-[4-(2,2,2-trifluoroethyl)amino]phenyl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 70)

[0484] Step 1: Synthesis of 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfonamide

[0485] 1,4-Dioxaspirino[4.5]decan-8-one (16.0 g, 102.45 mmol, 1.0 eq) was dissolved in tetrahydrofuran (160 mL), and 2-methylpropane-2-sulfonamide (12.42 g, 102.45 mmol, 1.0 eq) was added, followed by tetraethyl titanate (46.73 g, 204.89 mmol, 2.0 eq). The reaction was allowed to react at 50°C for 16 hours. After completion, the reaction solution was poured into saturated sodium bicarbonate solution in an ice bath, filtered through celite, and the filtrate was extracted with ethyl acetate (150 mL x 2). The organic layer was concentrated and purified by normal phase column chromatography to obtain 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfonamide (12.36 g, 46.55% yield) as a white solid.

[0486] LCMS (ESI) [M+H] +: 260.13.

[0487] Step 2: Synthesis of N-(8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]decan-8-yl)-2-methylpropane-2-sulfonamide

[0488] A solution of 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfonamide (6.46 g, 24.93 mmol, 1.0 eq) dissolved in tetrahydrofuran (35 mL) was slowly added dropwise to (4-chlorophenyl)magnesium bromide (65 mL, 1.0 M, 2.6 eq) in an ice bath. The reaction was allowed to react at room temperature for 2 hours. After completion, the reaction solution was poured into saturated ammonium chloride solution in an ice bath and extracted with ethyl acetate (150 mL x 2). The organic layer was concentrated and purified using a normal phase column to afford N-(8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]decan-8-yl)-2-methylpropane-2-sulfonamide (2.87 g, 31.03% yield) as a white solid. LCMS (ESI) [M+H]+: 394.13.

[0489] Step 3: Synthesis of 2-methyl-N-{8-[4-(2,2,2-trifluoroethyl)amino]phenyl}-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfonamide

[0490] N-(8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]decan-8-yl)-2-methylpropane-2-sulfonamide (1.00 g, 2.7 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL), followed by the addition of sodium tert-butoxide (777 mg, 8.09 mmol, 3.0 eq) and methanesulfonic acid (2-di-tert-butylphosphino-3.6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (230 mg, 0.27 mmol, 0.1 eq). After nitrogen substitution, 2,2,2-trifluoroethanol-1-amine (1.34 g, 13.48 mmol, 5.0 eq) was added dropwise, and the reaction was carried out at 100°C for 1 hour. After the reaction was completed, the reaction solution was concentrated and purified by normal phase column separation to obtain 2-methyl-N-{8-[4-(2,2,2-trifluoroethyl)amino]phenyl}-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfonamide (850 mg, 72.65% yield) as a white solid. LCMS (ESI) [M+H]+: 457.19.

[0491] Step 4: Synthesis of 2-methyl-N-(4-oxo-1-{4-[(2,2,2-trifluoroethyl)amino]phenyl}cyclohexyl)propane-2-sulfonamide 2-Methyl-N-(8-(4-(2,2,2-trifluoroethyl)amino)phenyl)-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfonamide (800 mg, 1.84 mmol, 1.0 eq) was dissolved in acetone (9 mL), followed by addition of p-toluenesulfonic acid monohydrate (34 mg, 0.18 mmol, 0.1 eq) and water (3 mL), and the reaction was carried out at 60 °C for 3 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (50 mL) and water (50 mL). The organic layer was collected, dried, concentrated, and purified by normal phase column chromatography to obtain crude 2-methyl-N-(4-oxo-1-{4-[(2,2,2-trifluoroethyl)amino]phenyl}cyclohexyl)propane-2-sulfonamide (320 mg, 44.51% yield) as a brown oil. LCMS (ESI) [M+H]+: 413.16.

[0492] Step 5: Synthesis of 6-{4-[(2,2,2-trifluoroethyl)amino]phenyl}-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine

[0493] Crude 2-methyl-N-(4-oxo-1-(4-(2,2,2-trifluoroethyl)amino)phenyl)cyclohexyl)propane-2-sulfonamide (100 mg, 0.256 mmol, 1.0 eq) was dissolved in anhydrous ethanol (2 mL). Thiourea (39 mg, 0.513 mmol, 2.0 eq) and iodine (98 mg, 0.385 mmol, 1.5 eq) were added and reacted at 80°C for 3 hours. After completion of the reaction, the reaction solution was concentrated to afford 6-{4-[(2,2,2-trifluoroethyl)amino]phenyl}-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (130 mg, 100.00% yield) as a brown solid. LCMS (ESI) [M+H]+: 326.09.

[0494] Step 6: Synthesis of N-{6-amino-6-[4-(2,2,2-trifluoroethyl)amino]phenyl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0495] 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (81 mg, 0.29 mmol, 1.0 eq) and 6-(4-((2,2,2-trifluoroethyl)amino)phenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (100 mg, 0.29 mmol, 1.0 eq) were dissolved in acetonitrile (5 mL). N-Methylimidazole (96 mg, 1.17 mmol, 4.0 eq) was added, followed by N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (123 mg, 0.44 mmol, 1.5 eq) in an ice bath. The mixture was reacted at room temperature for 16 hours. After completion of the reaction, preparative separation and purification were performed to obtain a yellow solid, N-{6-amino-6-[4-(2,2,2-trifluoroethyl)amino]phenyl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (1.1 mg, 0.63% yield). LCMS (ESI) [M+H]+: 586.12. 1H NMR (400MHz, DMSO) δ8.78(s,1H),8.17(s,1H),7.54(s,1H),7.42(s,1H),7.34(d,J=8.5Hz,2H),6.77(s,1H),6.73(d,J=8.4Hz,2H ),6.39(t,J=6.9Hz,1H),3.94(p,J=9.4Hz,2H),3.60(s,3H),3.43(s,2H),3.42(s,2H),2.83(dd,J=16.4,7.1Hz,4H),2.58(s,3H).

[0496] Example 41: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-{6-(methylamino)-6-[4-(2,2,2-trifluoroethyl)amino]phenyl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 71)

[0497] N-{6-amino-6-[4-(2,2,2-trifluoroethyl)amino]phenyl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (75 mg, 0.124 mmol 1.0 eq), paraformaldehyde (6 mg, 0.20 mmol, 1.6 eq) and sodium cyanoborohydride (13 mg, 0.21 mmol, 1.6 eq) were dissolved in methanol (4 mL) and reacted at room temperature for 16 hours. After completion of the reaction, preparative separation and purification were performed to obtain 2'-chloro-5'-methoxy-6-methyl-N-(6-(methylamino)-6-{4-[(2,2,2-trifluoroethyl)amino]phenyl}-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (3.3 mg, 4.3% yield) as a yellow solid. LCMS (ESI) [M+H]+: 617.16. 1H NMR (400MHz, DMSO) δ8.87(d,J=6.7Hz,1H),8.21(d,J=1.9Hz,1H),7.65(d,J=12.4 Hz,1H),7.57(d,J=2.2Hz,1H),7.27(d,J=8.4Hz,2H),6.73(d,J=8.4Hz,2H),3.93( s,3H),3.75(d,J=16.2Hz,2H),3.60(s,3H),3.18(d,J=16.1Hz,1H),2.77–2.57(m ,5H),2.40(dt,J=11.9,6.0Hz,1H),2.20(t,J=5.3Hz,3H),2.10(d,J=11.5Hz,1H).

[0498] The compounds listed in Table 1 below were prepared by methods similar to those described in the Examples, with appropriate variations in reactants, reagent amounts, protection and deprotection, solvents, and reaction conditions. Characterization data for the compounds are summarized in Table 1 below.

[0499] Table 1: Structure and characterization of some compounds

[0500] Experimental Example 1: Effect of the compounds of the present invention on HCT116 BRCA2 - / -Determination of cell proliferation

[0501] Experimental purpose: The purpose of this test case is to test the effect of the compound on HCT116 BRCA2 - / - Cell proliferation effect.

[0502] Background principle: DNA polymerase theta (Polθ) is a synthetic lethal target with homologous recombination deficiency and plays an important role in the DNA damage response pathway of double-strand breaks (DSBs). When homologous recombination-mediated repair is impaired (HR deficiency), such as BRCA1 or BRCA2 mutations, Polθ is highly expressed and guides DSB repair towards alt-EJ, turning on the DNA repair process of microhomology-mediated end joining (MMEJ). In the case of HR deficiency, inhibition of Polθ leads to cell death through the accumulation of toxic RAD51 intermediates and inhibition of the alt-EJ repair pathway. Therefore, by testing the effects of compounds on HCT116 BRCA2 - / - The inhibition rate of cell proliferation can be used to screen Polθ protein inhibitors.

[0503] Specific experimental process:

[0504] Construct HCT116 BRCA2 knockout cells and screen monoclonal clones. - / - WT and WT cells were seeded into 96-well plates, with 90 μL per well (1000 cells / well) and incubated overnight at 37°C. The next day, 10 μL of compound was added at various concentrations, starting at 100 μM. Nine 10-fold dilutions were performed (final DMSO concentration was 1%), and the mixture was incubated at 37°C for 6 days. On the 6th day, the old medium was aspirated and 110 μL of medium (at a 100:10 ratio of medium to CCK8) was added. The mixture was incubated at 37°C for 1-4 hours. The absorbance was measured at 450 nM, and the IC50 value was calculated using GraphPad software. Compounds were screened by comparing the concentration to positively charged drugs.

[0505] The positive control compounds and preparation methods used in the present invention are as follows: ART558 is compound 24 in Chinese patent application CN201980101280.6, RP25 is compound 25 in PCT application WO2023050007A1, and compound A is compound 4 in WO2023233295. The structural formulas of the control compounds are as follows:

[0506] ART558: Control compound A:

[0507] Table 2: Results of the assay on the proliferation of HCT116 BRCA2- / - cells

[0508] The results showed that the compounds of the present invention can inhibit the proliferation of HCT116 BRCA2- / - cells, with IC50 values ​​reaching the nM level. The activity of some compounds is surprisingly significantly better than the positive control. This strong inhibitory effect has important therapeutic significance for the treatment of conditions or diseases related to Polθ inhibition; however, the inhibitory effect on HCT116 WT cells is weak, showing excellent selectivity.

[0509] Experimental Example 2: Determination of the effect of the compounds of the present invention on DLD1 BRCA2- / -- cell proliferation

[0510] Experimental purpose: The purpose of this test case is to test the effect of the compound on DLD1 BRCA2 - / - Cell proliferation effect.

[0511] Specific experimental process:

[0512] DLD1 BRCA2 knockout cells were constructed and single clones were screened. - / -WT and WT cells were seeded into 96-well plates, with 90 μL per well (1000 cells / well) and incubated overnight at 37°C. The next day, 10 μL of compound was added at various concentrations, starting at 100 μM. Nine 10-fold dilutions were performed (final DMSO concentration was 1%), and the mixture was incubated at 37°C for 6 days. On the 6th day, the old medium was aspirated and 110 μL of medium (at a 100:10 ratio of medium to CCK8) was added. The mixture was incubated at 37°C for 1-4 hours. The absorbance was measured at 450 nM, and the IC50 value was calculated using GraphPad software. Compounds were screened by comparing the concentration to positively charged drugs.

[0513] Table 3: Results of the assay on the proliferation of DLD1 BRCA2- / - cells

[0514] The results showed that the compounds of the present invention could inhibit the proliferation of DLD1 BRCA2- / - cells, IC 50 The value reaches nM level, and this strong inhibitory effect has important therapeutic significance for the treatment of diseases or disorders related to Polθ inhibition.

[0515] Experimental Example 3: Testing of the Effects of the Compounds of the Present Invention on the Function of Polθ Protein Polymerase

[0516] Experimental Purpose: The purpose of this test case is to test the effect of the compound on the function of Polθ protein polymerase.

[0517] Principle: Polθ consists of a C-terminal family A DNA polymerase and an N-terminal superfamily 2 (SF2) DNA helicase, separated by a long, poorly conserved central domain of unknown function. ART558 binds to an allosteric site within the Polθ polymerase catalytic domain and inhibits MMEJ in a dose-dependent manner. Therefore, compounds that inhibit Polθ polymerase function can be used to screen for Polθ inhibitors.

[0518] Specific experimental process:

[0519] POLθ-polymerase domain protein expression: The POLθ-polymerase domain sequence (residues 1819-2590) was cloned into the pET24N vector containing an N-terminal (His) 6x tag and a tobacco etch virus (TEV) protease cleavage site. The constructed vector was transformed into Escherichia coli Rosetta (DE3) and incubated at an OD of 0.6. 1 mM IPTG was added and cultured at 12°C for 16 hours. The cells were harvested, disrupted by sonication, and the supernatant was centrifuged. The protein was purified using Ni-NTA and dialyzed for determination of protein concentration and purity.

[0520] Purified POLθ-polymerase domain protein was added to assay buffer (20 mM Tris, pH 7.80, 50 mM KCl, 10 mM MgCl, 1 mM DTT, 0.01% BSA, 0.01% Tween 20) at a protein concentration of 4 nM. Test compounds (an 11-point dilution series) were then added. The enzyme and test compound inhibitor mixture were incubated at room temperature for 15 minutes. dNTPs and primers (primer: 5-GCG GCT GTC ATA AG-3; template: 5-GCT ACA TTG ACA ATG GCA TCA AAT CTC AGA TTG CGT CTT ATG ACA GCC GCG-3; primer: template ratio = 1:1.1) were added to all assay wells and incubated at room temperature in the dark for 60 minutes. The reaction was terminated by adding 16 μL of TE stop solution containing 0.5% PicoGreen dye to each well and incubated in the dark for 90 minutes. Fluorescence was read at 485 / 520 nm using a microplate reader, and IC50 was calculated using GraphPad software. Compounds were screened by comparing with the positive drug RP25.

[0521] Table 4: Test results on the function of Polθ protein polymerase

[0522] The results showed that the compound of the present invention has a very strong inhibitory effect on the polymerase function of Polθ-polymerase domain protein, IC 50 The values ​​all reached the nM level, and the inhibitory effects of some compounds were equivalent to or better than those of the positive control drug. This strong inhibitory effect has important therapeutic significance for the treatment of conditions or diseases related to Polθ inhibition.

[0523] Experimental Example 4: Pharmacokinetics of the compounds of the present invention in mice

[0524] Experimental purpose: To administer the compound of the present invention to ICR female mice by oral gavage (PO) to investigate its pharmacokinetic characteristics

[0525] Specific experimental process:

[0526] The compound of the present invention and the control compound A (preparation method refers to compound 4 in patent application WO2023233295) were administered by gavage (50 mg / kg), PO solvent: 40% PEG300 + 15% Tween 80 + 45% water, prepared on the day of administration. Blood was collected from the jugular vein 0h before administration and 0.25h, 0.5h, 1h, 2h, 4h, 7h, 24h after administration (gavage), and about 0.02mL of each sample was collected. K2-EDTA was used for anticoagulation and the samples were placed on ice after collection. Plasma sample processing: After blood sample collection, it was placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 4000g, 5 minutes, 2-8°C). Plasma samples were stored in a -80°C refrigerator before analysis. Pharmacokinetic parameters were calculated using Phoenix WinNonlin7.0 based on the blood drug concentration data at different time points. The experimental results are shown in Table 4 below:

[0527] Table 5: In vivo pharmacokinetic test results in ICR female mice

[0528] The pharmacokinetic data of the compounds of the present invention in mice showed that the oral exposure of the tested representative compounds in mice was unexpectedly good compared with the control compound A.

Claims

1. A compound represented by formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in, R1, R2, R3, R4, R5, R6 and R7 are independently selected from H, deuterium, halogen, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; R8 is selected from H, hydroxy, C1-C6 alkoxy, NR a R b ; R9 is phenyl, heteroaryl, heterocyclic, -O(CH2) r -cycloalkyl, -O(CH2) r -heterocycloalkyl, -O(CH2) r -heteroaryl, the phenyl, heteroaryl, heterocyclic, -O(CH2) r -cycloalkyl, -O(CH2) r -heterocycloalkyl, -O(CH2) r -heteroaryl may be optionally substituted by one or more R n replace; R n Selected from H, halogen, cyano, NR a R b , hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkylamino, C1-C6 haloalkoxy, -(CH2) r -O-C1-C6 alkyl, -C(O)NR a R b 、-S(O)2NR a R b 、-NH(CH2) r C1-C6 haloalkyl, -NH(CH2) r OH, -(CH2) r OC1-C6 haloalkyl, C1-C6 haloalkyl; R a 、R b Each is independently selected from absent, hydrogen, C1-C6 alkyl; r is an integer from 0 to 3.

2. The compound according to claim 1 or its stereoisomer, tautomer, pharmaceutically acceptable salt, wherein said R9 is selected from the group consisting of: n Substituted phenyl, 5-6 membered heteroaryl containing 1 to 3 selected from N, O, S, 5-6 membered heterocyclic group containing 1 to 3 selected from N, O, S, -O(CH2) r -C3-C6 cycloalkyl, -O(CH2) r -C3-C6 heterocycloalkyl, -O(CH2) r -5-6 membered heteroaryl.

3. The compound according to any one of claims 1 to 2, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R9 is selected from 4. The compound according to any one of claims 1 to 3 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from hydrogen.

5. The compound according to any one of claims 1 to 4 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from methyl.

6. The compound according to any one of claims 1 to 5 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from hydrogen.

7. The compound according to any one of claims 1 to 6 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from methoxy.

8. The compound according to any one of claims 1 to 7 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from hydrogen.

9. The compound according to any one of claims 1 to 8 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from hydrogen.

10. The compound according to any one of claims 1 to 9 or its stereoisomers, tautomers, or pharmaceutically acceptable salts, which has the structural formula (I-1):

11. The compound according to any one of claims 1 to 10 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R6 is selected from halogen, amino, C1-C6 alkyl, or C1-C6 haloalkyl, preferably selected from chlorine, methyl, difluoromethyl, or amino, and more preferably selected from chlorine.

12. The compound according to any one of claims 1 to 11 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R8 is selected from hydrogen, hydroxy, methoxy, amino, and aminoalkyl, preferably hydrogen, hydroxy, methoxy, amino, and aminomethyl.

13. A compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

15. Use of the compound defined in any one of claims 1 to 13 or the composition according to claim 14 in the preparation of a medicament for treating a disease caused by overexpression of Pol θ, preferably the disease is cancer, more preferably the cancer is a solid tumor, breast cancer, lung cancer, bladder cancer, esophageal cancer, prostate cancer, pancreatic cancer, or cervical cancer.

16. Use of a method for preparing a medicament for treating homologous recombination (HR)-deficient cancer in a patient, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 13 or a composition according to claim 14.

17. Use of a medicament for treating cancer in a patient, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 13, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or the composition according to claim 14, wherein the cancer is characterized by reduced or absent BRCA gene expression, absent BRCA genes, or reduced BRCA protein function.

18. A compound represented by formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in, R8 and R9 are as defined in any of the preceding claims.

19. A compound as shown below, and its stereoisomers, tautomers or pharmaceutically acceptable salts,

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