Five-membered heteroaromatic ring compounds and their applications in medicine

Abstract

The present invention relates to a class of five-membered heteroaromatic ring compounds and their use in medicine. The compounds or pharmaceutical compositions can be used as inhibitors of retinoic acid-related orphan nuclear receptor gamma t (RORγt). The present invention also relates to methods for preparing the compounds and pharmaceutical compositions, as well as their use in treating or preventing RORγt-mediated inflammatory or immune diseases in mammals, particularly humans.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a class of small molecule compounds, compositions, preparation methods, and uses thereof. The compounds or compositions can be used as inhibitors of retinoic acid-related orphan nuclear receptor gamma t (RORγt) and are used to prevent or treat immune-related diseases. Background Art

[0002] Retinoic acid-related orphan nuclear receptors (RORs) are a subfamily of transcription factors within the steroid hormone nuclear receptor superfamily. The ROR family includes RORα, RORβ, and RORγ, encoded by distinct genes (RORA, RORB, and RORC). RORs contain four major domains: an N-terminal A / B domain, a DNA-binding domain, a hinge domain, and a ligand-binding domain.

[0003] Retinoid-related orphan receptor gamma t (RORγt) is one of two isoforms of the retinoic acid-related orphan receptor gamma (RORγ), also known as RORγ2. Studies have shown that RORγt is expressed exclusively in cells of the lymphoid lineage and in embryonic lymphoid tissue inducers (Sun et al., Science 288:2369-2372, 2000; Eberl et al., Nat Immunol. 5:64-73, 2004). RORγt, as a characteristic transcription factor of helper T cells (Th17), plays an important role in Th17 cell differentiation and is a key regulator of Th17 cell differentiation (Ivanov, II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. Cell 2006; 126(6): 1121-33).

[0004] Th17 cells secrete interleukin 17 (IL-17) and other proinflammatory cytokines, playing a crucial role in autoimmune diseases and the body's defense response. IL-17 is a proinflammatory cytokine involved in the development of inflammation and various autoimmune diseases, and is closely associated with a variety of autoimmune and inflammatory diseases, such as rheumatoid arthritis, psoriasis, psoriatic arthritis, spondyloarthritis, asthma, inflammatory bowel disease, systemic lupus erythematosus, and multiple sclerosis (Jetten et al., Nucl. Recept. Signal, 2009, 7:e003; Manel et al., Nat. Immunol., 2008, 9, 641-649).

[0005] The role of RORγt in the pathogenesis of autoimmune diseases or inflammation has been extensively studied and fully elucidated (Jetten et al., Adv. Dev. Biol, 2006, 16:313-355; Meier et al. Immunity, 2007, 26:643-654; Aloisi et al., Nat. Rev. Immunol., 2006, 6:205-217; Jager et al., J. Immunol., 2009, 183:7169-7177; Barnes et al., Nat. Rev. Immunol., 2008, 8:183-192). Therefore, inhibition of RORγt will effectively inhibit Th17 cell differentiation and regulate the production and secretion of IL-17 and other proinflammatory cytokines, thereby regulating the body's immune system and treating immune and inflammatory diseases related to RORγt regulation. Summary of the Invention

[0006] The following is a summary of some aspects of the present invention and is not intended to be limiting. These and other aspects are described in greater detail below. All references in this specification are incorporated herein by reference in their entirety. In the event of a discrepancy between the disclosure of this specification and a reference, the disclosure of this specification shall prevail.

[0007] The present invention provides a class of compounds with retinoic acid-related orphan receptor gamma t (RORγt) inhibitory activity, which are used to prepare drugs for preventing or treating inflammatory or autoimmune diseases mediated by RORγt, such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune eye diseases, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, Crohn's disease or Kawasaki disease. The compounds of the present invention can effectively inhibit RORγt and have excellent physicochemical and pharmacokinetic properties.

[0008] The present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds or compositions to treat the above-mentioned diseases in mammals, especially humans.

[0009] Specifically:

[0010] In one aspect, the present invention relates to a compound as represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof of the compound as represented by formula (I).

[0011]

[0012] in:

[0013] L1 is a bond, -O-, -CH2-, *-(CH2) n -O-, *-O-(CH2) n -, -NH-, -C(=O)-, *-C(=O)-NH-, *-NH-C(=O)-, *-NH-(CH2) n - or *-(CH2) n -NH-; where * indicates connection to ring A;

[0014] L2 is -O-, **-C(=O)-NH- or **-NH-C(=O-); wherein ** indicates connection to an aromatic ring;

[0015] Z1 is CR1 or N; Z2 is CR2 or N; Z3 is CR3 or N; Z4 is CR4 or N;

[0016] R1, R2, R3 and R4 are each independently H, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C1-4 Alkoxy, hydroxy substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Haloalkyl or C 1-4 haloalkoxy;

[0017] R is F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 6-10 Aryl, C 3-8 Cycloalkyl, heterocyclic group composed of 3-7 atoms or heteroaryl composed of 5-7 atoms; wherein the C 6-10 Aryl, C 3-8 Cycloalkyl, heterocyclyl consisting of 3-7 atoms and heteroaryl consisting of 5-7 atoms are each independently optionally substituted with 1, 2, 3, 4 or 5 R5;

[0018] Each R5 is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy;

[0019] Ring A is a heteroaryl group composed of 5 atoms;

[0020] Each R6 is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl, -C(=O)-N(R a R b ), C 3-8 Cycloalkyl or heterocyclic group composed of 3-8 atoms; wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl group and the heterocyclic group consisting of 3 to 8 atoms are each independently optionally substituted by 1, 2 or 3 R 6a replaced by;

[0021] Each R 6a are independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, oxo, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl or heterocyclic group consisting of 3-8 atoms;

[0022] R a and R b are independently H, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl or C 1-4 haloalkoxy;

[0023] B ring is C 6-10 Aryl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-10 atoms or heteroaryl consisting of 5-10 atoms;

[0024] Each R7 is independently deuterium, -S(=O)2-C 1-4 Alkyl, -S(=O)2-C 1-4 Alkoxy, -S(=O)2-C 1-4 Alkylamino, -S(=O)2-C 3-6 Cycloalkyl, -S(=O)-C 1-4 Alkyl, -S(=O)2H, -COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;

[0025] R8 and R9 are each independently H, deuterium, -OH, -CN, -NH2, -NO2, -COOH, C 1-4 Alkoxy, C 1-4 C substituted with halogenated alkyl or cyano 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, carboxyl substituted C 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-C(=O)-OC 1-4 Alkyl, -C 1-4 Alkylene-C(=O)-N(R c R d ),-C 1-4 Alkylene-OC(=O)-N(R c R d ),-C 1-4 Alkylene-N(R e )-C(=O)-N(R c Rd ) or -C 1-4 Alkylene-N(R c R d );

[0026] R c and R d are independently H, deuterium, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, -C(=O)H, -C(=O)-OC 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C 1-4 Alkylene-C(=O)-OC 1-4 Alkyl or -C 1-4 Alkylene-OC 1-4 alkyl;

[0027] Each R e independently H, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, -C 1-4 Alkylene-OC 1-4 Alkyl or -C 1-4 Alkylene-C 3-6 Cycloalkyl;

[0028] n is 1, 2, 3, or 4;

[0029] m is 0, 1, 2, or 3;

[0030] p is 0, 1, 2, 3 or 4.

[0031] In some embodiments, R1, R2, R3 and R4 are each independently H, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, -C(OH)(CF3)2, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2 or -OCH2CH2CF3.

[0032] In some embodiments, R is F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2 , -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, tetrazolyl, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl or tetrahydropyranyl;

[0033] Wherein, the phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, tetrazolyl, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl and tetrahydropyranyl are each independently and optionally substituted with 1, 2, 3, 4 or 5 R5.

[0034] In some embodiments, each R5 is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH 2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2 or -OCH2CH2CF3.

[0035] In some embodiments, Ring A is

[0036] In some embodiments, each R6 is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-N(R a R b ), C 3-6 Cycloalkyl or heterocyclic group composed of 3-6 atoms; wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl and heterocyclic groups consisting of 3-6 atoms are independently optionally substituted by 1, 2 or 3 R 6a replaced.

[0037] In some embodiments, each R 6a are independently and optionally deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl or heterocyclic group consisting of 3-6 atoms;

[0038] R a and R b are independently H, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl or C 1-4 Halogenated alkoxy.

[0039] In some embodiments, each R6 is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F, -OCHF2, -OCF3, -OCH 2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, -C(=O)-CH3, -C(=O)-CH2 CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)CH3, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH2CH2CH3, -C(=O)-O-CH(CH3)CH3, -C(=O)-N(R a R b ), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl or tetrahydropyranyl;

[0040] wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl and tetrahydropyranyl are each independently and optionally replaced by 1, 2 or 3 R 6a replaced.

[0041] In some embodiments, each R 6a are independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butyl oxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl or tetrahydropyranyl.

[0042] In some embodiments, R a and R b Each is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2 or -OCH2CH2CF3.

[0043] In some embodiments, Ring B is C 6-10 Aryl, C 3-6Cycloalkyl, heterocyclic group consisting of 3-7 atoms or heteroaryl consisting of 5-6 atoms.

[0044] In some embodiments, Ring B is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, tetrazolyl, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, or tetrahydropyranyl.

[0045] In some embodiments, the compound of the present invention is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (II).

[0046]

[0047] in:

[0048] Z5 is N or CH;

[0049] R 5a 、R 5b 、R 5c 、R 5d and R 5e Each is independently H, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF 2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2 or -OCH2CH2CF3;

[0050] R6, R7, R8, R9, Z1, Z2, Z3, Z4, L1, L2, A, m and p have the meanings described in the present invention; * indicates that L1 is connected to the A ring; ** indicates that L2 is connected to the aromatic ring.

[0051] In some embodiments, each R7 is independently deuterium, -S(=O)2-CH3, -S(=O)2-CH2CH3, -S(=O)2-CH2CH2CH3, -S(=O)2-CH(CH3)CH3, -S(=O)2-OCH3, -S(=O)2-OCH2CH3, -S(=O)2-OCH2CH2CH3, -S(=O)2-OCH(CH3)CH3, -S(=O)2-cyclopropyl, -S(=O)2-cyclobutyl, -S(=O)2-cyclopentyl, -S(=O)2-cyclohexyl, -S(=O)-CH3, -S(=O)-CH2CH3, -S(=O)-CH2CH2CH3, -S(=O)-CH(CH 3) CH3, -S(=O)2-NH-CH3, -S(=O)2-NH-CH2CH3, -S(=O)2-NH-CH2CH2CH3, -S(=O)2-NH-CH(CH3)CH3, -S(=O)2H, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0052] In some embodiments, R8 and R9 are each independently H, deuterium, -OH, -CN, -NH2, -NO2, -COOH, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2OH, -CH2CH2OH, -CH2CH2 CH2OH, -CH(CH3)CH2OH, -CH2(CH2)3OH, -CH2CN, -CH2CH2CN, -CH2CH2CH2CN, -CH(CH3)CH2CN, -CH2(CH2)3CN, -CH2COOH, -CH2C H2COOH, -CH2CH2CH2COOH, -CH(CH3)CH2COOH, -CH2(CH2)3COOH, -CH2OCH3, -CH2OCH2CH3, -CH2OCH2CH2CH3, -CH2OCH(CH3)2, -C H2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH(CH3)2, -CH2CH2CH2OCH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2O CH2CH2CH3, -CH2CH2CH2OCH(CH3)2, -CH2-C(=O)-OCH3, -CH2-C(=O)-OCH2CH3, -CH2-C(=O)-OCH2CH2CH3, -CH2-C(=O)-OCH(CH3 )2, -CH2CH2-C(=O)-OCH3, -CH2CH2-C(=O)-OCH2CH3, -CH2CH2-C(=O)-OCH2CH2CH3, -CH2CH2-C(=O)-OCH(CH3)2, -CH2CH2CH2- C(=O)-OCH3, -CH2CH2CH2-C(=O)-OCH2CH3, -CH2CH2CH2-C(=O)-OCH2CH2CH3, -CH2CH2CH2-C(=O)-OCH(CH3)2, -CH2-C(=O)-N(R c R d )、-CH2CH2-C(=O)-N(R c R d )、-CH2CH2CH2-C(=O)-N(R c R d )、-CH2-OC(=O)-N(R c R d)、-CH2CH2-OC(=O)-N(R c R d )、-CH2CH2CH2-OC(=O)-N(R c R d )、-CH2-N(R e )-C(=O)-N(R c R d )、-CH2CH2-N(R e )-C(=O)-N(R c R d )、-CH2CH2CH2-N(R e )-C(=O)-N(R c R d )、-CH2N(R c R d )、-CH2CH2N(R c R d ) or -CH2CH2CH2N(R d R e ); where R c 、R d and R e Has the definition as described in the present invention.

[0053] In some embodiments, R c and R dEach is independently H, deuterium, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -C(=O)H, -CH2-C(=O)-OCH3, -CH2-C(=O)-OCH2CH3, -CH2-C(=O)-OCH2CH2CH3, -CH2-C(=O)-OCH(CH3)2, -CH2CH2-C(=O)- OCH3, -CH2CH2-C(=O)-OCH2CH3, -CH2CH2-C(=O)-OCH2CH2CH3, -CH2CH2-C(=O)-OCH(CH3)2, -CH2CH 2CH2-C(=O)-OCH3, -CH2CH2CH2-C(=O)-OCH2CH3, -CH2CH2CH2-C(=O)-OCH2CH2CH3, -CH2CH2CH2-C( =O)-OCH(CH3)2, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)CH3, -C(=O)-O -CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH2CH2CH3, -C(=O)-O-CH(CH3)CH3, -CH2OCH3, -CH2OCH2CH3, - CH2OCH2CH2CH3, -CH2OCH(CH3)2, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OC H(CH3)2, -CH2CH2CH2OCH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH2CH3 or -CH2CH2CH2OCH(CH3)2.

[0054] In some embodiments, each R eare independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH 2CH2CF3, -CH2OCH3, -CH2OCH2CH3, -CH2OCH2CH2CH3, -CH2OCH(CH3)2, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH(CH3)2, -CH2CH2CH2OCH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH2CH3, -CH2CH2CH2OCH(CH3)2, cyclopropylmethylene, cyclopropylethylene, cyclopropyl-n-propylene, cyclobutylmethylene, cyclobutylethylene, cyclobutyl-n-propylene, cyclopentylmethylene, cyclopentylethylene, cyclopentyl-n-propylene, cyclohexylmethylene, cyclohexylethylene or cyclohexyl-n-propylene.

[0055] On the other hand, the present invention relates to a pharmaceutical composition comprising a compound represented by formula (I) or formula (II) of the present invention or its stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant or a combination thereof.

[0056] In some embodiments, the pharmaceutical composition further comprises other drugs for preventing or treating inflammatory syndromes, disorders or diseases, or any combination thereof.

[0057] On the other hand, the present invention relates to the use of a compound represented by formula (I) or formula (II) or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating RORγt-mediated inflammatory or autoimmune diseases in mammals, including humans.

[0058] In some embodiments, the present invention relates to the use of a compound represented by formula (I) or formula (II) or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune eye disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, Crohn's disease or Kawasaki disease.

[0059] In another aspect, the present invention relates to methods for preparing, separating and purifying the compound represented by formula (I) or formula (II).

[0060] The biological test results show that the compound provided by the present invention has good inhibitory activity against RORγt and also has good pharmacokinetic characteristics.

[0061] Any embodiment of any aspect of the present invention can be combined with other embodiments, as long as they do not conflict. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments, as long as they do not conflict.

[0062] Detailed description of the present invention

[0063] Definitions and General Terms

[0064] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0065] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0066] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0067] Unless otherwise indicated, the terms used in the present invention shall comply with the following definitions used in the present invention. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0068] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., more than one component may be contemplated for use or use in implementing the described embodiment.

[0069] As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers to, for example, a primate (e.g., human, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0070] The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0071] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0072] "Stereoisomers" are compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0073] "Chiral" refers to a molecule that is non-superimposable on its mirror image; "achiral" refers to a molecule that is superimposable on its mirror image.

[0074] "Enantiomers" refer to two non-superimposable isomers of a compound that are mirror images of each other.

[0075] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0076] Stereochemical definitions and conventions used herein generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0077] Many organic compounds exist in optically active forms, meaning they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is left-handed. A compound prefixed with (+) or d is right-handed. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0078] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0079] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, such as a racemate or a mixture of diastereoisomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0080] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0081] Any racemate of the resulting final product or intermediate can be separated into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separating the diastereomeric salts obtained. The racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed.Robert E.Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of NotreDame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G.Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0082] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as described in the specific examples, subclasses, and classes of compounds encompassed by the present invention.

[0083] In general, the term "substituted" indicates that one or more hydrogen atoms in a given structure are replaced with a specified substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with one or more substituents selected from a specified group, the substituents may be the same or different at each position.

[0084] The term "unsubstituted" means that the designated group bears no substituents.

[0085] The term "optionally substituted with" can be used interchangeably with the term "unsubstituted or substituted with," meaning that the structure is unsubstituted or substituted with one or more substituents described herein.

[0086] In addition, it should be noted that, unless otherwise explicitly stated, the description methods used in the present invention such as "each...independently is" and "...each independently is" and "...independently is" can be interchanged and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0087] In various parts of this specification, substituents of compounds disclosed herein are disclosed in terms of group types or ranges. It is specifically noted that the present invention includes every independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl as disclosed independently.

[0088] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0089] As used herein, the term "alkyl" or "alkyl group" refers to a saturated, linear or branched, monovalent hydrocarbon radical, wherein the alkyl group may be optionally substituted with one or more substituents described herein. Unless otherwise specified, an alkyl group contains 1 to 20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 3 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in another embodiment, the alkyl group contains 1 to 4 carbon atoms; and in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.

[0090] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -CH(CH3)CH2CH3), u, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1 -butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3 ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.

[0091] The term "alkylene" refers to a saturated divalent hydrocarbon radical derived by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon radical. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In one embodiment, an alkylene group contains 1-6 carbon atoms; in another embodiment, an alkylene group contains 1-4 carbon atoms; in yet another embodiment, an alkylene group contains 1-3 carbon atoms; and in yet another embodiment, an alkylene group contains 1-2 carbon atoms. Examples include methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.

[0092] The term "carboxy", whether used alone or in combination with other terms (such as "carboxyalkyl"), refers to -CO2H or -COOH.

[0093] The term "deuterium" refers to a single deuterium atom. For example, one deuterium atom replaces one hydrogen atom in a methyl group to form a mono-deuterated methyl group (-CDH2), two deuterium atoms replace two hydrogen atoms in a methyl group to form a di-deuterated methyl group (-CD2H), and three deuterium atoms replace three hydrogen atoms in a methyl group to form a tri-deuterated methyl group (-CD3).

[0094] The term "cyano-substituted alkyl" means an alkyl group substituted by one or more cyano groups, wherein the alkyl group has the meaning as described herein. Examples include, but are not limited to, cyanomethyl, cyanoethyl, and the like.

[0095] The term "hydroxy-substituted alkyl" or "hydroxy-substituted haloalkyl" means that an alkyl or haloalkyl group is substituted by one or more hydroxy groups, wherein the alkyl and haloalkyl groups have the meanings described herein, such examples include, but are not limited to, hydroxymethyl, hydroxyethyl (including 1-hydroxyethyl, 2-hydroxyethyl), -C(OH)(CF3)2, and the like.

[0096] The term "carboxy-substituted alkyl" means an alkyl group substituted with one or more carboxy groups, wherein the alkyl group has a meaning as described herein. Examples include, but are not limited to, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH(CH3)CH2COOH, -CH2(CH2)3COOH, and the like.

[0097] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; and in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents as described herein.

[0098] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentyloxy (n-pentyloxy, -OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), and the like.

[0099] The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino group is independently substituted by one or two alkyl groups; the alkyl group has the meaning described in the present invention. In some embodiments, the alkylamino group is one or two C 1-6 In some other embodiments, the alkylamino group is one or two C 1-4 An alkyl group is formed by attaching an alkyl group to a nitrogen atom. Suitable alkylamino groups may be monoalkylamino or dialkylamino groups, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, and the like.

[0100] The term "haloalkyl" or "haloalkoxy" means that an alkyl or alkoxy group is substituted by one or more halogen atoms, wherein the alkyl or alkoxy group has the meaning as described herein, and such examples include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, etc.

[0101] The term "cycloalkyl" refers to a monovalent or multivalent saturated monocyclic, bicyclic, or tricyclic hydrocarbon group containing 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 7 to 12 carbon atoms; in another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; and in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl group may independently be unsubstituted or substituted with one or more substituents described herein.

[0102] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent monocyclic, bicyclic or tricyclic ring containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms; heterocyclyl includes spiro heterocyclyl and fused heterocyclyl. Wherein, in some embodiments, the heterocyclyl is a ring system composed of 3-12 atoms, i.e., a heterocyclyl composed of 3-12 atoms; in some embodiments, the heterocyclyl is a ring system composed of 3-10 atoms, i.e., a heterocyclyl composed of 3-10 atoms; in some embodiments, the heterocyclyl is a ring system composed of 5-10 atoms, i.e., a heterocyclyl composed of 5-10 atoms; in some embodiments, the heterocyclyl is a ring system composed of 5-8 atoms, i.e., a heterocyclyl composed of 5-8 atoms; in some embodiments, the heterocyclyl is a ring system composed of 6-8 atoms, i.e., a heterocyclyl composed of 6-8 atoms; in some embodiments, the heterocyclyl is a ring system composed of 5-6 atoms, i.e., a heterocyclyl composed of 5-6 atoms; in some embodiments, A heterocyclyl group is a ring system consisting of 3-8 atoms, i.e., a 3-8-atom heterocyclyl group; in some embodiments, a heterocyclyl group is a ring system consisting of 3-7 atoms, i.e., a 3-7-atom heterocyclyl group; in some embodiments, a heterocyclyl group is a ring system consisting of 3-6 atoms, i.e., a 3-6-atom heterocyclyl group; in some embodiments, a heterocyclyl group is a ring system consisting of 3 atoms, i.e., a 3-atom heterocyclyl group; in some embodiments, a heterocyclyl group is a ring system consisting of 4 atoms, i.e., a 4-atom heterocyclyl group; in other embodiments, a heterocyclyl group is a ring system consisting of 5 atoms, i.e., a 5-atom heterocyclyl group; in other embodiments, a heterocyclyl group is a ring system consisting of 6 atoms, i.e., a 6-atom heterocyclyl group. Unless otherwise specified, a heterocyclyl group can be attached to other groups in the molecule through a carbon atom or a nitrogen atom, and a -CH2- group can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to form an S-oxide. The ring nitrogen atom can be optionally oxidized to form an N-oxide.

[0103] Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, diazepanyl, oxepanyl, thiepanyl, oxazepine Base, diazepine thiazolinone Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, 3,5-dioxopiperidinyl, and pyrimidinedione. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic group may be optionally substituted with one or more substituents described herein.

[0104] The term "aryl" refers to a monocyclic, bicyclic or tricyclic all-carbon ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". In one embodiment, an aryl group is a carbon ring system consisting of 6-10 ring atoms and containing at least one aromatic ring, i.e., C 6-10 Aryl. Examples of aryl groups include phenyl, naphthyl, and anthracenyl. The aryl groups may be independently and optionally substituted with one or more substituents described herein.

[0105] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic aromatic systems containing 5-12 ring atoms, wherein at least one ring contains one or more heteroatoms, wherein each ring contains 5-7 ring atoms, wherein at least one ring system is aromatic, and wherein the heteroaryl group has one or more points of attachment to the rest of the molecule. The heteroaryl group may be optionally substituted with one or more substituents described herein. Unless otherwise specified, the heteroaryl group may be attached to the rest of the molecule (e.g., the main structure in the general formula) at any reasonable site (which may be C in CH or N in NH). When a -CH2- group is present in a heteroaryl group, the -CH2- group may be optionally replaced by -C(=O)-. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." In some embodiments, the heteroaryl group is a 5-10 heteroaryl group consisting of 1, 2, 3, or 4 heteroatoms independently selected from O, S, P, and N; in some embodiments, the heteroaryl group is a 5-8 heteroaryl group consisting of 1, 2, 3, or 4 heteroatoms independently selected from O, S, P, and N; in some embodiments, the heteroaryl group is a 5-7 heteroaryl group consisting of 1, 2, 3, or 4 heteroatoms independently selected from O, S, P, and N; in some embodiments, the heteroaryl group is a 5-6 heteroaryl group consisting of 1, 2, 3, or 4 heteroatoms independently selected from O, S, P, and N; in some embodiments, the heteroaryl group is a 5-atom heteroaryl group consisting of 1, 2, 3, or 4 heteroatoms independently selected from O, S, P, and N; in some embodiments, the heteroaryl group is a 6-atom heteroaryl group consisting of 1, 2, 3, or 4 heteroatoms independently selected from O, S, P, and N.

[0106] Examples of heteroaryl groups include, but are not limited to, furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl), oxazolyl), oxatriazolyl (such as 1,2,3,4-oxatriazolyl), thiazolyl (such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, thiadiazolyl (such as 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl), thiatriazolyl (such as 1,2,3,4-thiatriazolyl), tetrazolyl (such as 2H-1,2,3,4-tetrazolyl, 1H-1,2,3,4-tetrazolyl), triazolyl (such as 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), thienyl (such as 2-thienyl, 3-thienyl), 1H-pyrazolyl (such as 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl), 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrrolyl (such as N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyrimidinyl (such as 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyrimidinyl (such as 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (such as 3-pyridazinyl, 4-pyridazinyl), 2-pyrazinyl, triazinyl (such as 1,3,5-triazinyl), tetrazinyl (such as 1,2,4,5-tetrazinyl, 1,2,3,5-tetrazinyl); also include the following bicyclic rings, but are by no means limited to these bicyclic rings: benzimidazolyl, benzopyrazolyl (such as ), benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0107] The term "jk atoms," where j and k are each independently any non-zero natural number and k>j, includes j, k, and any natural number in between. Typically, this describes the number of ring atoms in a molecule, where the number of ring atoms in the molecule is jk, and the atoms include carbon atoms and / or heteroatoms such as O, N, S, and P. For example, "5-10 atoms" means that the group is composed of 5, 6, 7, 8, 9, or 10 atoms.

[0108] As used herein, the term "unsaturated" means that the group contains one or more degrees of unsaturation.

[0109] The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state of N, S and P; primary, secondary, tertiary amines and quaternary ammonium salts; or the hydrogen on the nitrogen atom in the heterocyclic ring is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR" (such as NR in N-substituted pyrrolidinyl), R" represents any possible substituent on N).

[0110] The term "halogen" or "halogen atom" refers to a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br) or an iodine atom (I).

[0111] The term "cyano" or "CN" refers to a cyano group, which may be attached to other groups.

[0112] The term "nitro" or "NO2" refers to a nitro structure, which may be attached to other groups.

[0113] As described herein, a ring system formed by a substituent connected to a central ring by a single bond indicates that the substituent can be substituted at any substitutable position on the ring. For example, Formula C indicates that the substituent R' can be substituted mono- or poly-at any substitutable position on Ring C. When n1 is greater than 1, the substituents R' are independent of each other and can be the same or different. This is shown in Formulas C1 to C19.

[0114]

[0115] As described herein, a linker attached to a ring system (as shown in Formula d) means that the linker can be attached to the rest of the molecule at any available position on the ring system. Formula d also means that any available position on the ring system can be attached to the rest of the molecule, as shown in Formulas d1 through d5.

[0116]

[0117] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) or (II) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C1-C 24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present invention containing a hydroxyl group can be acylated to produce a prodrug form of the compound. Other prodrug forms include phosphate esters, such as these phosphate ester compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound. For a complete discussion of prodrugs, see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0118] "Metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays such as those described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention encompasses metabolites of the compound, including metabolites produced by contacting a compound of the invention with a mammal for a sufficient period of time.

[0119] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in S.M. Berge et al., "Describe Pharmaceutically Acceptable Salts in Detail in J. Pharmaceutical Sciences, 1977, 66: 1-19." Pharmaceutically acceptable salts formed from non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates, or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0120] As used herein, a "solvate" refers to an association formed between one or more solvent molecules and a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecule is water.

[0121] When the solvent is water, the term "hydrate" may be used. In some embodiments, one molecule of the compound of the present invention may be associated with one water molecule, such as a monohydrate; in other embodiments, one molecule of the compound of the present invention may be associated with more than one water molecule, such as a dihydrate; and in still other embodiments, one molecule of the compound of the present invention may be associated with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the non-hydrated form of the compound.

[0122] The term "nitrogen oxide" refers to when a compound contains several amine functional groups, where one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. Available oxidants such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) can be used to treat the corresponding amine to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), where, for example, an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0123] The term "carrier" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or combination thereof, which are known to those skilled in the art (e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except in the case where any conventional carrier is incompatible with the active ingredient, its use in treatment or pharmaceutical composition is encompassed.

[0124] As used herein, the term "treatment" of any disease or condition refers to all conditions that can slow down, interrupt, prevent, control or stop the progression of a disease or condition, but does not necessarily mean that all symptoms of all diseases or conditions disappear, and it also includes preventative treatment of the symptoms, especially in patients who are susceptible to such diseases or disorders. In some embodiments, it refers to improving a disease or condition (i.e., slowing down or preventing or alleviating the development of a disease or condition or at least one of its clinical symptoms). In other embodiments, "treatment" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treatment" refers to regulating a disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing parameters of the body) or both. In other embodiments, "treatment" refers to preventing or delaying the onset, occurrence or worsening of a disease or condition.

[0125] As used herein, the term "therapeutically effective amount" or "therapeutically effective dose" refers to an amount of a compound of the present invention that can elicit a biological or medical response in an individual (e.g., reducing or inhibiting enzyme or protein activity, or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease, etc.). In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount that, when administered to an individual, is effective for: (1) at least partially alleviating, inhibiting, preventing and / or improving (i) a condition or disease mediated by RORγt, or (ii) associated with RORγt activity, or (iii) characterized by abnormal activity of RORγt; or (2) reducing or inhibiting RORγt activity; or (3) reducing or inhibiting RORγt expression. In another embodiment, the term "therapeutically effective amount" refers to an amount of an effective compound of the present invention that, when administered to a cell, or an organ, or a non-cellular biological substance, or a medium, can at least partially reduce or inhibit RORγt activity; or at least partially reduce or inhibit RORγt expression.

[0126] As used herein, the terms "administration" and "administering" a compound should be understood as providing a compound of the invention or a prodrug of a compound of the invention to an individual in need thereof. It should be recognized that one skilled in the art can treat a patient currently suffering from the disorder or prophylactically treat a patient suffering from the disorder by administering an effective amount of a compound of the invention.

[0127] As used herein, the term "composition" refers to a product comprising specified ingredients in specified amounts, as well as any product produced directly or indirectly by the combination of specified ingredients in specified amounts. The meaning of this term in relation to pharmaceutical composition includes a product comprising an active ingredient (single or multiple) and an inert ingredient (single or multiple) constituting a carrier, as well as any product produced directly or indirectly by mixing, compounding or aggregating any two or more ingredients, or by decomposing one or more ingredients, or by other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical compositions of the present invention include any composition prepared by mixing a compound of the present invention with a pharmaceutically acceptable carrier.

[0128] Description of the compounds of the present invention

[0129] The present invention discloses a class of five-membered heteroaromatic ring compounds, pharmaceutically acceptable salts thereof, pharmaceutical preparations and compositions thereof, which can be used as RORγt inhibitors and have potential uses in the treatment of inflammatory or autoimmune diseases mediated by RORγt, such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune eye diseases, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, Crohn's disease or Kawasaki disease.

[0130] In one aspect, the present invention relates to a compound as represented by formula (I) or a stereoisomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound as represented by formula (I).

[0131]

[0132] Wherein, R, R6, R7, R8, R9, Z1, Z2, Z3, Z4, L1, L2, A, B, m and p have the meanings described in the present invention; * indicates that L1 is connected to the A ring; ** indicates that L2 is connected to the aromatic ring.

[0133] In some embodiments, L1 is a bond, -O-, -CH2-, *-(CH2) n -O-, *-O-(CH2) n -, -NH-, -C(=O)-, *-C(=O)-NH-, *-NH-C(=O)-, *-NH-(CH2) n - or *-(CH2) n -NH-.

[0134] In some embodiments, L2 is -O-, **-C(=O)-NH-, or **-NH-C(=O)-.

[0135] In some embodiments, Z1 is CR1 or N; Z2 is CR2 or N; Z3 is CR3 or N; Z4 is CR4 or N; wherein R1, R2, R3 and R4 have the meanings described herein.

[0136] In some embodiments, R1, R2, R3 and R4 are each independently H, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxy substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Haloalkyl or C 1-4 Halogenated alkoxy.

[0137] In some embodiments, R is F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 6-10 Aryl, C 3-8 Cycloalkyl, heterocyclic group composed of 3-7 atoms or heteroaryl composed of 5-7 atoms; wherein the C 6-10 Aryl, C 3-8 The cycloalkyl, heterocyclyl consisting of 3-7 atoms and heteroaryl consisting of 5-7 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 R5; wherein R5 has the meaning described in the present invention.

[0138] In some embodiments, each R5 is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy.

[0139] In some embodiments, Ring A is a 5-atom heteroaryl.

[0140] In some embodiments, each R6 is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6Alkyl, -C(=O)-N(R a R b ), C 3-8 Cycloalkyl or heterocyclic group composed of 3-8 atoms; wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl group and the heterocyclic group consisting of 3 to 8 atoms are each independently optionally substituted by 1, 2 or 3 R 6a replaced by; among them, R a 、R b and R 6a has the meanings described in the present invention.

[0141] In some embodiments, each R 6a are independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl or heterocyclic group consisting of 3-8 atoms.

[0142] In some embodiments, R a and R b are independently H, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl or C 1-4 Halogenated alkoxy.

[0143] In some embodiments, Ring B is C 6-10 Aryl, C 3-8 cycloalkyl, heterocyclic group consisting of 3 to 10 atoms or heteroaryl group consisting of 5 to 10 atoms.

[0144] In some embodiments, each R7 is independently deuterium, -S(=O)2-C 1-4 Alkyl, -S(=O)2-C 1-4 Alkoxy, -S(=O)2-C 1-4 Alkylamino, -S(=O)2-C 3-6 Cycloalkyl, -S(=O)-C 1-4 Alkyl, -S(=O)2H, -COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl or C 3-6 Cycloalkyl.

[0145] In some embodiments, R8 and R9 are each independently H, deuterium, -OH, -CN, -NH2, -NO2, -COOH, C1-4 Alkoxy, C 1-4 C substituted with halogenated alkyl or cyano 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, carboxyl substituted C 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-C(=O)-OC 1-4 Alkyl, -C 1-4 Alkylene-C(=O)-N(R c R d ),-C 1-4 Alkylene-OC(=O)-N(R c R d ),-C 1-4 Alkylene-N(R e )-C(=O)-N(R c R d ) or -C 1-4 Alkylene-N(R c R d ); where R c 、R d and R e has the meanings described in the present invention.

[0146] In some embodiments, R c and R d are independently H, deuterium, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, -C(=O)H, -C(=O)-OC 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C 1-4 Alkylene-C(=O)-OC 1-4 Alkyl or -C 1-4 Alkylene-OC 1-4 alkyl.

[0147] In some embodiments, each R e independently H, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, -C 1-4 Alkylene-OC 1-4 Alkyl or -C 1-4 Alkylene-C 3-6 Cycloalkyl.

[0148] In some embodiments, n is 1, 2, 3, or 4.

[0149] In some embodiments, m is 0, 1, 2, or 3.

[0150] In some embodiments, p is 0, 1, 2, 3, or 4.

[0151] In other embodiments, R1, R2, R3 and R4 are each independently H, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, -C(OH)(CF3)2, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2 or -OCH2CH2CF3.

[0152] In other embodiments, R is F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF 2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, tetrazolyl, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl or tetrahydropyranyl;

[0153] wherein phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, tetrazolyl, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, and tetrahydropyranyl are each independently optionally substituted with 1, 2, 3, 4, or 5 R5;

[0154] Wherein, R5 has the meaning described in the present invention.

[0155] In other embodiments, each R5 is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2C H2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2 or -OCH2CH2CF3.

[0156] In other embodiments, Ring A is

[0157] In other embodiments, each R6 is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-N(R a R b ), C 3-6 Cycloalkyl or heterocyclic group composed of 3-6 atoms; wherein the C 1-4 Alkyl, C 3-6 The cycloalkyl group and the heterocyclic group consisting of 3-6 atoms are each independently optionally substituted by 1, 2 or 3 R6a replaced by; among them, R a 、R b and R 6a has the meanings described in the present invention.

[0158] In other embodiments, each R 6a are independently and optionally deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl or heterocyclic group consisting of 3-6 atoms.

[0159] In other embodiments, R a and R b are independently H, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl or C 1-4 Halogenated alkoxy.

[0160] In other embodiments, each R6 is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F, -OCHF2, -OCF3, -OC H2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, -C(=O)-CH3, -C(=O)-CH 2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)CH3, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH2CH2CH3, -C(=O)-O-CH(CH3)CH3, -C(=O)-N(R a R b), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl or tetrahydropyranyl;

[0161] wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl and tetrahydropyranyl are each independently and optionally replaced by 1, 2 or 3 R 6a replaced by;

[0162] Among them, R 6a has the meanings described in the present invention.

[0163] In other embodiments, each R 6a are independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butyl oxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl or tetrahydropyranyl.

[0164] In other embodiments, R a and R bEach is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2 or -OCH2CH2CF3.

[0165] In other embodiments, Ring B is C 6-10 Aryl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-7 atoms or heteroaryl consisting of 5-6 atoms.

[0166] In yet other embodiments, Ring B is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, tetrazolyl, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, or tetrahydropyranyl.

[0167] In some embodiments, the compound is a compound of formula (II) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof of the compound of formula (II).

[0168]

[0169] in:

[0170] Z5 is N or CH;

[0171] R 5a 、R 5b 、R 5c 、R 5d and R 5eEach is independently H, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF 2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2 or -OCH2CH2CF3;

[0172] Wherein, R6, R7, R8, R9, Z1, Z2, Z3, Z4, L1, L2, A, m and p have the meanings described in the present invention; * indicates that L1 is connected to the A ring; ** indicates that L2 is connected to the aromatic ring.

[0173] In yet other embodiments, each R is independently deuterium, -S(=O)2-CH3, -S(=O)2-CH2CH3, -S(=O)2-CH2CH2CH3, -S(=O)2-CH(CH3)CH3, -S(=O)2-OCH3, -S(=O)2-OCH2CH3, -S(=O)2-OCH2CH2CH3, -S(=O)2-OCH(CH3)CH3, -S(=O)2-cyclopropyl, -S(=O)2-cyclobutyl, -S(=O)2-cyclopentyl, -S(=O)2-cyclohexyl, -S(=O)-CH3, -S(=O)-CH2CH3, -S(=O)-CH2CH2CH3, -S(=O)-CH(CH 3) CH3, -S(=O)2-NH-CH3, -S(=O)2-NH-CH2CH3, -S(=O)2-NH-CH2CH2CH3, -S(=O)2-NH-CH(CH3)CH3, -S(=O)2H, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0174] In yet other embodiments, R8 and R9 are each independently H, deuterium, -OH, -CN, -NH2, -NO2, -COOH, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2OH, -CH2CH2OH, -CH2CH2 CH2OH, -CH(CH3)CH2OH, -CH2(CH2)3OH, -CH2CN, -CH2CH2CN, -CH2CH2CH2CN, -CH(CH3)CH2CN, -CH2(CH2)3CN, -CH2COOH, -CH2C H2COOH, -CH2CH2CH2COOH, -CH(CH3)CH2COOH, -CH2(CH2)3COOH, -CH2OCH3, -CH2OCH2CH3, -CH2OCH2CH2CH3, -CH2OCH(CH3)2, -C H2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH(CH3)2, -CH2CH2CH2OCH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2O CH2CH2CH3, -CH2CH2CH2OCH(CH3)2, -CH2-C(=O)-OCH3, -CH2-C(=O)-OCH2CH3, -CH2-C(=O)-OCH2CH2CH3, -CH2-C(=O)-OCH(CH3 )2, -CH2CH2-C(=O)-OCH3, -CH2CH2-C(=O)-OCH2CH3, -CH2CH2-C(=O)-OCH2CH2CH3, -CH2CH2-C(=O)-OCH(CH3)2, -CH2CH2CH2- C(=O)-OCH3, -CH2CH2CH2-C(=O)-OCH2CH3, -CH2CH2CH2-C(=O)-OCH2CH2CH3, -CH2CH2CH2-C(=O)-OCH(CH3)2, -CH2-C(=O)-N(R c R d )、-CH2CH2-C(=O)-N(R c R d )、-CH2CH2CH2-C(=O)-N(R c R d )、-CH2-OC(=O)-N(R c R d)、-CH2CH2-OC(=O)-N(R c R d )、-CH2CH2CH2-OC(=O)-N(R c R d )、-CH2-N(R e )-C(=O)-N(R c R d )、-CH2CH2-N(R e )-C(=O)-N(R c R d )、-CH2CH2CH2-N(R e )-C(=O)-N(R c R d )、-CH2N(R c R d )、-CH2CH2N(R c R d ) or -CH2CH2CH2N(R d R e ); where R c 、R d and R e has the meanings described in the present invention.

[0175] In yet other embodiments, R c and R dEach is independently H, deuterium, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -C(=O)H, -CH2-C(=O)-OCH3, -CH2-C(=O)-OCH2CH3, -CH2-C(=O)-OCH2CH2CH3, -CH2-C(=O)-OCH(CH3)2, -CH2CH2-C(=O)- OCH3, -CH2CH2-C(=O)-OCH2CH3, -CH2CH2-C(=O)-OCH2CH2CH3, -CH2CH2-C(=O)-OCH(CH3)2, -CH2CH 2CH2-C(=O)-OCH3, -CH2CH2CH2-C(=O)-OCH2CH3, -CH2CH2CH2-C(=O)-OCH2CH2CH3, -CH2CH2CH2-C( =O)-OCH(CH3)2, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)CH3, -C(=O)-O -CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH2CH2CH3, -C(=O)-O-CH(CH3)CH3, -CH2OCH3, -CH2OCH2CH3, - CH2OCH2CH2CH3, -CH2OCH(CH3)2, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OC H(CH3)2, -CH2CH2CH2OCH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH2CH3 or -CH2CH2CH2OCH(CH3)2.

[0176] In yet other embodiments, each R eare independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH 2CH2CF3, -CH2OCH3, -CH2OCH2CH3, -CH2OCH2CH2CH3, -CH2OCH(CH3)2, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH(CH3)2, -CH2CH2CH2OCH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH2CH3, -CH2CH2CH2OCH(CH3)2, cyclopropylmethylene, cyclopropylethylene, cyclopropyl-n-propylene, cyclobutylmethylene, cyclobutylethylene, cyclobutyl-n-propylene, cyclopentylmethylene, cyclopentylethylene, cyclopentyl-n-propylene, cyclohexylmethylene, cyclohexylethylene or cyclohexyl-n-propylene.

[0177] In some embodiments, the present invention relates to one of the following compounds or its stereoisomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, but is in no way limited to these compounds:

[0178]

[0179]

[0180]

[0181]

[0182] Unless otherwise indicated, stereoisomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds represented by formula (I) or formula (II) are all within the scope of the present invention.

[0183] On the other hand, the present invention relates to a pharmaceutical composition comprising a compound represented by formula (I) or formula (II) of the present invention or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant or a combination thereof.

[0184] In some embodiments, the pharmaceutical compositions of the present invention comprise other drugs for preventing or treating inflammatory syndromes, disorders or diseases, or any combination thereof.

[0185] In one embodiment, the pharmaceutical composition of the present invention may be in liquid, solid, semisolid, gel or spray form.

[0186] On the other hand, the present invention relates to the use of a compound represented by formula (I) or formula (II) or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating RORγt-mediated inflammatory or autoimmune diseases in mammals, including humans.

[0187] In some embodiments, the present invention relates to the use of a compound represented by formula (I) or formula (II) or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune eye disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, Crohn's disease or Kawasaki disease.

[0188] In another aspect, the present invention relates to methods for preparing, separating and purifying the compound represented by formula (I) or formula (II).

[0189] In another aspect, the present invention relates to an intermediate for preparing a compound represented by formula (I) or formula (II).

[0190] The compounds disclosed herein may contain asymmetric or chiral centers and, therefore, may exist in different stereoisomeric forms. The present invention is intended to include all stereoisomeric forms of the compounds represented by Formula (I) or Formula (II), including but not limited to diastereomers, enantiomers, atropisomers, and geometric (or conformational) isomers, as well as mixtures thereof, such as racemic mixtures, as part of the present invention.

[0191] In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated and included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, the stereoisomers of the structure are unambiguous and defined.

[0192] The compounds represented by formula (I) or formula (II) may exist in different tautomeric forms, and all of these tautomeric forms are included within the scope of the present invention.

[0193] The compound shown in formula (I) or formula (II) may exist in the form of a salt. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal treated therewith. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt and can be an intermediate for preparing and / or purifying the compound shown in formula (I) or formula (II) and / or for separating the enantiomers of the compound shown in this formula (I) or formula (II).

[0194] Pharmaceutically acceptable acid addition salts can be formed by the action of the compounds disclosed herein with inorganic or organic acids, such as acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluenesulfonate, and trifluoroacetate.

[0195] Pharmaceutically acceptable base addition salts can be formed by reacting the compounds disclosed herein with inorganic or organic bases.

[0196] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0197] Organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0198] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, the basic or acidic moiety using conventional chemical methods. Generally speaking, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used where appropriate. Additional lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0199] In addition, the compounds disclosed herein, including their salts, can also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) for their crystallization. The compounds disclosed herein can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include both solvated and unsolvated forms of the compounds disclosed herein.

[0200] Any structural formula given herein is also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have structures depicted by the general formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 I.

[0201] In another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, for example, wherein a radioactive isotope is present, such as 3 H. 14 C and 18 Those compounds of F, or in which non-radioactive isotopes are present, such as 2 H and 13 C. Such isotopically enriched compounds can be used for metabolic studies (using 14 C), reaction kinetics studies (using e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution determination, or may be used in the context of radiotherapy of patients. 18 F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of formula (I) or (II) can be prepared by conventional techniques familiar to those skilled in the art or by replacing the previously used unlabeled reagent with an appropriate isotopically labeled reagent as described in the examples and preparations herein.

[0202] In addition, heavier isotopes, particularly deuterium (i.e. 2 Substitution with H or D) can provide certain therapeutic advantages resulting from greater metabolic stability. For example, this can result in an increased in vivo half-life, a reduced dosage requirement, or an improved therapeutic index. It should be understood that deuterium in the present invention is considered a substituent of the compound represented by formula (I) or (II). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. Where a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, eg D2O, acetone-d6, DMSO-d6.

[0203] Pharmaceutical compositions, formulations and administration of the compounds of the present invention

[0204] The present invention provides a pharmaceutical composition comprising a compound disclosed in the present invention, such as the compound listed in the Examples; and a pharmaceutically acceptable excipient, carrier, adjuvant, or a combination thereof.

[0205] The present invention provides methods for treating, preventing, or ameliorating diseases or conditions, comprising administering a safe and effective amount of a combination drug comprising a compound disclosed herein and one or more therapeutically active agents. The combination drug may include one or more other drugs for preventing or treating inflammatory syndromes, disorders, or diseases, including, but not limited to:

[0206] 1) TNF-α inhibitors; 2) non-selective COX-1 / COX-2 inhibitors; 3) COX-2 inhibitors; 4) other therapeutic agents used to treat inflammatory syndromes and autoimmune diseases, including glucocorticoids, methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporine, tacrolimus, penicillamine, bucillamine, actarib, mizoribine, lobenzarit, ciclesonide, hydroxychloroquine, aurothiomalate, auranofin, cyclophosphamide, BAFF / APR IL inhibitors, CTLA-4-immunoglobulin or analogs; 5) leukotriene biosynthesis inhibitors, 5-lipoxygenase inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists; 6) LTD4 receptor antagonists; 7) PDE4 inhibitors; 8) antihistamine HI receptor antagonists; 9) α1 and α2-adrenergic receptor agonists; 10) anticholinergics; 11) P-adrenergic receptor agonists; 12) insulin-like growth factor type I analogs; 13) kinase inhibitors selected from Janus kinase inhibitors (JAK1 and / or JAK2 and / or JAK3 and / or TYK2), p38 MAPK and IKK2; 14) B cell-targeted biopharmaceuticals such as rituximab; 15) selective co-stimulatory modulators such as abatacept; 16) interleukin inhibitors selected from IL-1 inhibitors such as anakinra, IL-6 inhibitors such as tocilizumab, and IL-12 / IL-23 inhibitors such as ustekinumab.

[0207] The amount of the compound in the pharmaceutical composition disclosed in the present invention refers to the amount that can effectively detect the inhibition of retinoic acid-related orphan nuclear receptor γt in a biological sample or patient. The dosage of the active ingredient in the pharmaceutical composition of the present invention can be changed, but the amount of the active ingredient must be an amount that can obtain an appropriate dosage form. The active ingredient can be administered to patients (animals and humans) in need of such treatment at a dosage that provides optimal drug efficacy. The selected dosage depends on the desired therapeutic effect, the route of administration and the duration of treatment. The dosage will vary from patient to patient, depending on the nature and severity of the disease, the patient's weight, the patient's specific diet, concomitant medications and other factors that will be recognized by those skilled in the art.

[0208] It will also be appreciated that certain compounds of the present invention may exist and be used therapeutically in free form, or, if appropriate, in the form of pharmaceutically acceptable derivatives thereof. Pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adducts or derivatives that, when administered to a patient in need thereof, provide, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.

[0209] The drugs or pharmaceutical compositions disclosed herein can be prepared and packaged in bulk form, from which a safe and effective amount of the compound represented by formula (I) or (II) can be extracted and then administered to the patient in the form of a powder or syrup. Typically, the drug is administered to the patient at a dosage level of between 0.0001 and 10 mg / kg body weight per day to obtain an effective inhibitory effect on the retinoic acid-related orphan nuclear receptor γt. Alternatively, the pharmaceutical compositions disclosed herein can be prepared and packaged as unit dosage forms, wherein each physically discrete unit contains a safe and effective amount of the compound represented by formula (I) or (II).

[0210] When the pharmaceutical compositions of the present invention contain one or more other active ingredients in addition to the compounds of the present invention, the weight ratio of the compounds of the present invention to the second active ingredient can vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used. Thus, for example, when the compounds of the present invention are mixed with another pharmaceutical agent, the weight ratio of the compounds of the present invention to the other pharmaceutical agent generally ranges from about 1000:1 to about 1:1000. Mixtures of the compounds of the present invention with other active ingredients are generally also within the above ranges, but in each case, an effective dose of each active ingredient should be used.

[0211] As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture, or vehicle that contributes to the consistency of a dosage form or pharmaceutical composition. Each excipient, when combined, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that could significantly reduce the efficacy of the disclosed compounds upon administration to a patient and interactions that could render the pharmaceutical composition unpharmaceutically acceptable. Furthermore, each excipient must be pharmaceutically acceptable, e.g., possess a sufficiently high degree of purity.

[0212] Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected. Furthermore, pharmaceutically acceptable excipients may be selected based on their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to facilitate the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to facilitate the production of a stable dosage form. Certain pharmaceutically acceptable excipients may be selected to facilitate the transport or transportation of a compound disclosed herein from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected to enhance patient compliance.

[0213] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. It will be appreciated by those skilled in the art that certain pharmaceutically acceptable excipients may serve more than one function and may provide alternative functions, depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation.

[0214] The skilled artisan has the knowledge and skill to select a suitable pharmaceutically acceptable excipient in an appropriate amount for use in the present invention. In addition, there are a large number of resources available to the skilled artisan that describe pharmaceutically acceptable excipients and are useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0215] In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, various carriers for preparing pharmaceutically acceptable compositions and known techniques for their preparation are disclosed, and the respective contents of these documents are incorporated herein by reference. Except for any conventional carriers that are incompatible with the disclosed compounds of the present invention, such as those that produce any undesirable biological effects or that interact in a harmful manner with any other ingredient in the pharmaceutically acceptable compositions, the application of the remaining carriers falls within the scope of the present invention.

[0216] The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. A description of some common methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0217] Thus, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, adjuvant, or combination thereof, the process comprising mixing the ingredients. Pharmaceutical compositions comprising a compound disclosed herein can be prepared by mixing at, for example, ambient temperature and atmospheric pressure.

[0218] The compounds disclosed herein are generally formulated into dosage forms suitable for administration to a patient via a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

[0219] In one embodiment, the compounds disclosed herein can be formulated as oral dosage forms. In another embodiment, the compounds disclosed herein can be formulated as inhalation dosage forms. In another embodiment, the compounds disclosed herein can be formulated as nasal dosage forms. In yet another embodiment, the compounds disclosed herein can be formulated as transdermal dosage forms. In yet another embodiment, the compounds disclosed herein can be formulated as topical dosage forms.

[0220] The pharmaceutical compositions provided herein can be provided as compressed tablets, tablets, chewable lozenges, fast-dissolving tablets, composite compressed tablets, enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the effects of gastric acid but dissolves or disintegrates in the intestines, thereby protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which helps mask unpleasant tastes or odors and prevents tablet oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Composite compressed tablets are compressed tablets produced through more than one compression cycle, including multilayer tablets, press-coated, or dry-coated tablets.

[0221] Tablet dosage forms can be prepared from the active ingredient in powder, crystal or granular form alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and / or colorants. Flavoring agents and sweeteners are particularly useful in forming chewable tablets and lozenges.

[0222] The pharmaceutical composition provided by the present invention can be provided in soft capsules or hard capsules, which can be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also known as dry-filled capsule (DFC), consists of two sections, one section inserted into the other, thus completely encapsulating the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by adding glycerol, sorbitol or similar polyols. The soft gelatin shells can contain preservatives to prevent microbial growth. Suitable preservatives are those as described in the present invention, including methylparaben and propylparaben, and sorbic acid. The liquid, semisolid and solid dosage forms provided by the present invention can be encapsulated in capsules. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or sustain dissolution of the active ingredient.

[0223] The pharmaceutical compositions provided herein can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is completely dispersed in another liquid in the form of small globules, which can be oil-in-water or water-in-oil. Emulsions can include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers, and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions can include pharmaceutically acceptable acetals, such as di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet-tasting hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and can also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for accurate and convenient administration.

[0224] Other useful liquid and semisolid dosage forms include, but are not limited to, those comprising the active ingredient provided herein and a secondary mono- or poly-alkylene glycol, including 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further include one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters and dithiocarbamates.

[0225] Where appropriate, dosage unit formulations for oral administration can be microencapsulated.Delayed or sustained-release compositions can also be prepared, for example, by coating or embedding particulate material in polymers, wax, or the like.

[0226] The oral pharmaceutical composition provided by the present invention can also be provided in the form of liposomes, micelles, microspheres or nanosystems. Micellar dosage forms can be prepared using the method described in US Pat. No. 6,350,458.

[0227] The pharmaceutical compositions provided herein can be provided in non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders can include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders can include organic acids and carbon dioxide sources.

[0228] Coloring and flavoring agents may be used in all of the above dosage forms.

[0229] The compounds disclosed herein can also be combined with soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene glycol polylysine substituted with palmitoyl residues. In addition, the compounds disclosed herein can be combined with a class of biodegradable polymers used in achieving controlled release of drugs, such as crosslinked or amphiphilic block copolymers of polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.

[0230] The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0231] The pharmaceutical composition provided by the present invention can be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or co-formulated with substances that supplement the intended effect.

[0232] Pharmaceutical composition provided by the invention can be administered parenterally by injection, infusion or implantation, for local or systemic administration. Parenteral administration as used in the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

[0233] Pharmaceutical composition provided by the invention can be mixed with any dosage form suitable for parenteral administration, including solution, suspension, emulsion, micelle, liposome, microsphere, nanometer system and the solid form that is suitable for making solution or suspension in liquid before injection.Such dosage form can be prepared (referring to Remington:The Science and Practice of Pharmacy, the same) according to conventional method known to those skilled in the art of pharmaceutical science.

[0234] Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous carriers, water-miscible carriers, non-aqueous carriers, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, antifreezes, cryoprotectants, thickeners, pH adjusters, and inert gases.

[0235] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose, and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of plant origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, medium-chain triglycerides of hydrogenated soybean oil and coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butylene glycol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0236] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and glucose. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants are those described herein, including bisulfites and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those described herein, including sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin ( CyDex, Lenexa, KS).

[0237] The pharmaceutical compositions provided herein can be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials, or syringes. The multiple dose parenteral formulations must contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile, as known and practiced in the art.

[0238] In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product, including lyophilized powders and hypodermic tablets, which are reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile dry insoluble product that is reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile emulsion.

[0239] The pharmaceutical composition can be formulated as a suspension, solid, semisolid, or thixotropic liquid for administration as an implanted depot. In one embodiment, the pharmaceutical composition disclosed herein is dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse through.

[0240] Suitable inner matrices include polymethyl methacrylate, polybutyl methyl acrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic acid and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0241] Suitable outer polymeric films include polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polyvinyl chloride, copolymers of chlorinated ethylene and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers.

[0242] On the other hand, the pharmaceutical compositions disclosed herein can be formulated into any dosage form suitable for inhalation administration to a patient, such as a dry powder, an aerosol, a suspension or a solution composition. In one embodiment, the pharmaceutical compositions disclosed herein can be formulated into a dosage form suitable for inhalation administration to a patient using a dry powder. In another embodiment, the pharmaceutical compositions disclosed herein can be formulated into a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions delivered to the lungs by inhalation typically comprise a finely powdered compound disclosed herein and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di- and polysaccharides. Fine powders can be prepared, for example, by micronization and grinding. Generally, size-reduced (e.g., micronized) compounds can be prepared by a D 50 values ​​(e.g., measured by laser diffraction).

[0243] Aerosols can be prepared by suspending or dissolving the compounds disclosed herein in a liquefied propellant. Suitable propellants include chlorinated hydrocarbons, hydrocarbons, and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane, and pentane. Aerosols containing the compounds disclosed herein are typically administered to patients via a metered dose inhaler (MDI). Such devices are known to those skilled in the art.

[0244] Aerosols may contain additional pharmaceutically acceptable excipients that can be used with MDIs, such as surfactants, lubricants, co-solvents, and other excipients to improve the physical stability of the formulation, improve valve characteristics, improve solubility, or improve taste.

[0245] Pharmaceutical compositions suitable for transdermal administration can be prepared as discontinuous patches intended to remain in close contact with the patient's epidermis for an extended period of time. For example, the active ingredient can be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

[0246] The pharmaceutical composition that is suitable for topical administration can be formulated into ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.For example, ointment, cream and gel can be prepared with water or oil base, and applicable thickener and / or gel and / or solvent.Such matrix can comprise, water, and / or oil such as liquid paraffin and vegetable oil (such as peanut oil or castor oil), or solvent such as polyethylene glycol.The thickener and gel that use according to matrix properties comprise soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carboxyvinyl polyol and cellulose derivative, and / or glyceryl monostearate and / or nonionic emulsifier.

[0247] Lotions may be formulated with an aqueous or oily base, and generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.

[0248] Powders for external use may be formulated in the presence of any suitable powder base such as talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base containing one or more dispersants, solubilizers, suspending agents or preservatives.

[0249] Topical formulations can be administered by application to the affected area once or more daily; occlusive dressings covering the skin are preferred. Adhesive reservoir systems allow for continuous or prolonged administration.

[0250] Uses of the compounds and pharmaceutical compositions of the present invention

[0251] The compounds or pharmaceutical compositions disclosed in the present invention can be used to prepare drugs for treating, preventing, improving, controlling or alleviating RORγt-mediated inflammatory or autoimmune diseases in mammals, including humans, and can also be used to prepare other drugs for inhibiting RORγt.

[0252] Specifically, the amount of the compound in the pharmaceutical composition of the present invention can effectively and detectably inhibit RORγt, and the compound of the present invention can be used as a drug for preventing or treating human psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune eye disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, Crohn's disease or Kawasaki disease.

[0253] The compounds or pharmaceutical compositions of the present invention can be applied to, but are in no way limited to, the prevention, treatment or alleviation of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune eye disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, Crohn's disease or Kawasaki disease in mammals, including humans, by administering an effective amount of the compounds or pharmaceutical compositions of the present invention to patients.

[0254] In addition to being beneficial for human treatment, the compounds and pharmaceutical compositions of the present invention may also be used in veterinary treatment of pets, imported species, and mammals in farm animals. Other examples of animals include horses, dogs, and cats. The compounds of the present invention include pharmaceutically acceptable derivatives thereof.

[0255] General synthetic steps

[0256] To illustrate the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to provide methods for practicing the present invention.

[0257] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in Formula (I) or Formula (II). The following reaction schemes and examples are provided to further illustrate the present invention.

[0258] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0259] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company and used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Plant, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.

[0260] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether were dried over sodium reflux. Anhydrous dichloromethane and chloroform were dried over calcium hydride reflux. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0261] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0262] The chromatographic column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0263] NMR spectra were recorded on a Bruker 400 MHz or 600 MHz NMR spectrometer using CDC13, DMSO-d6, CD3OD, or acetone-d6 as solvents (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), qd (quartet of doublets), dt (doublet of triplets), and ddd (doublet of doublets of doublets). Coupling constants, J, are expressed in Hertz (Hz).

[0264] Low-resolution mass spectrometry (MS) data were obtained using an Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 μm, 6 min, flow rate: 0.6 mL / min. Mobile phase: 5%-95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid)), electrospray ionization (ESI), and UV detection at 210 nm / 254 nm.

[0265] The purity of the compound was determined by high performance liquid chromatography (HPLC) using an Agilent 1260HPLC (column model: Agilent zorbax Eclipse Plus C18) and detected by a DAD detector. The purity of the compound was finally calculated by the area normalization method.

[0266] The following abbreviations are used throughout this invention:

[0267]

[0268] Typical synthetic steps for preparing the compounds disclosed herein are shown in the following synthetic schemes. Unless otherwise indicated, Ring A, Ring B, Z1, Z2, Z3, Z4, Z5, L1, R, R5, R6, R7, R8, R9, q, m, and p have the same meanings as those described herein.

[0269] Synthesis Scheme 1

[0270]

[0271] In the formula, PG represents an amino protecting group; LG represents a leaving group (such as bromine, -B(OH)2 or etc.); X is NH, S or O; R6 represents a cycloalkyl group.

[0272] Compound (10a) can be prepared by the following process:

[0273] Compound (1a) undergoes a substitution reaction under alkaline conditions (such as TEA, KOH, etc.) to obtain an amino-protected product (2a), compound (2a) undergoes a free radical bromination reaction under brominating reagent conditions (such as NBS, etc.) to obtain compound (3a), compound (3a) and compound (4a) undergo a cyclization reaction under heating conditions to obtain compound (5a), compound (5a) undergoes a bromination reaction in the presence of a brominating reagent (such as NBS, etc.) to obtain compound (6a), compound (6a) and compound (7a) undergo a coupling reaction under metal catalysis (such as Pd, Ni, etc.) to obtain compound (8a), and compound (8a) and compound (9a) are condensed under condensing agent conditions (such as HATU) to obtain the target compound (10a).

[0274] Synthesis Scheme 2

[0275]

[0276] In the formula, LG1, LG2 and LG3 represent leaving groups (such as bromine, -B(OH)2 or wait).

[0277] Compound (8b) can be prepared by the following process:

[0278] Compound (1b) and compound (2b) undergo a substitution reaction under alkaline conditions (such as TEA, KOH, etc.) to obtain compound (3b). Compound (3b) and compound (4b) undergo a substitution reaction under metal catalysis (such as Pd, Ni, etc.) to obtain compound (5b). Compound (5b) is reduced by catalytic hydrogenation to obtain compound (6b). Compound (6b) and compound (7b) are condensed in the presence of a condensation reagent (such as HATU) to obtain the target product (8b).

[0279] Synthesis Scheme 3

[0280]

[0281] In the formula, LG2 and LG4 represent leaving groups (such as bromine, -B(OH)2 or wait).

[0282] Compound (5c) can be prepared by the following process:

[0283] Compound (3b) and compound (1c) undergo a substitution reaction under metal catalysis (such as Pd, Ni, etc.) to obtain compound (2c). Compound (2c) undergoes a hydrolysis reaction under alkaline conditions (such as TEA, KOH, etc.) to obtain compound (3c). Compound (3c) and compound (4c) are condensed under condensation reagent conditions (such as HATU) to obtain the target product (5c).

[0284] Synthesis Scheme 4

[0285]

[0286] Compound (1d) and compound (2d) are condensed in the presence of a condensation reagent (such as HATU) to give the target product (3d).

[0287] Synthesis Scheme 5

[0288]

[0289] Compound (1e) and compound (2e) are condensed in the presence of a condensation reagent (such as HATU) to obtain the target product (3e).

[0290] The compounds, pharmaceutical compositions and applications of the present invention are further described below with reference to the examples. Example

[0291] Example 1: 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)phenyl)acetamide

[0292]

[0293] Step 1: Synthesis of diethyl 2-(4-nitrophenyl)malonate

[0294] Under ice-cooling, NaH (280 mg, 7.00 mmol) was added to a solution of 1-fluoro-4-nitrobenzene (0.80 mL, 7.50 mmol) and diethyl malonate (1.20 mL, 7.90 mmol) in DMF (20 mL). The reaction mixture was allowed to warm to room temperature and stirred for 10 h. The reaction mixture was diluted with EtOAc (60 mL) and washed sequentially with saturated NaHCO₃(aq.) (15 mL) and NaCl(aq.) (15 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 5 / 1 / 1) to obtain the desired product as a yellow oil (455 mg, 21% yield).

[0295] 1H NMR (400MHz, CDCl3) δ (ppm): 8.22 (d, J = 8.7Hz, 2H), 7.61 (d, J = 8.6Hz, 2H), 4.72 (s, 1H), 4.23 (q, J = 7.9Hz, 4H), 1.28 (t, J = 7.1Hz, 6H).

[0296] Step 2: Synthesis of 2-(4-nitrophenyl)propane-1,3-diol

[0297] BH3·Me2S (0.64 mL, 6.40 mmol, 10 mol / L) was slowly added to a solution of diethyl 2-(4-nitrophenyl)malonate (452 ​​mg, 1.61 mmol) in THF (16 mL) with stirring at room temperature. The mixture was heated in an oil bath at 70°C with stirring for 4 h. TLC indicated substantial conversion. Water was slowly added to the reaction system under low-temperature cooling to quench the reaction. The reaction solution was then diluted with DCM (60 mL), and the organic phase was washed sequentially with saturated NaHCO3 (aq.) (10 mL) and NaCl (aq.) (10 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) to afford the product as an orange-yellow solid (127 mg, 40% yield).

[0298] MS(ESI,pos.ion)m / z=198.1[M+H] + .

[0299] Step 3: Synthesis of 2-(4-nitrophenyl)malondialdehyde

[0300] DMP (1.12 g, 2.64 mmol) was added to a solution of 2-(4-nitrophenyl)propane-1,3-diol (125 mg, 0.63 mmol) in DCM (5 mL) and stirred at room temperature. Following TLC and LC-MS, the reaction mixture was filtered through celite until substantial conversion of the starting material was achieved. The filter cake was washed with DCM, and the filtrate was washed sequentially with saturated NaHCO (aq.) (15 mL) and NaCl (aq.) (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to afford the crude product as a yellow solid (120 mg, 98% yield).

[0301] MS(ESI,neg.ion)m / z=192.0[MH] - .

[0302] Step 4: Synthesis of 4-(4-nitrophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole

[0303] 4-(Trifluoromethylphenyl)hydrazine (171 mg, 0.97 mmol) and 2-(4-nitrophenyl)malondialdehyde (119 mg, 0.62 mmol) were dissolved in EtOH (3 mL), and AcOH (0.035 mL, 0.61 mmol) was added. The reaction was stirred in an oil bath at 80°C for 8 h. The reaction solution was diluted with DCM (60 mL), washed sequentially with saturated NaHCO3 (aq.) (10 mL) and NaCl (aq.) (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 5 / 1) to give the product as a yellow solid (63 mg, yield: 31%).

[0304] MS(ESI,pos.ion)m / z=334.0[M+H] + .

[0305] Step 5: Synthesis of 4-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)aniline

[0306] Pd / C (49 mg, 10%) was added to a solution of 4-(4-nitrophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole (63 mg, 0.19 mmol) in MeOH / THF (5 mL / 3 mL). The mixture was stirred at room temperature under an atmosphere of H2, and monitored by TLC and LC-MS. After the disappearance of the starting material, the mixture was filtered, and the filtrate was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 3 / 1 / 1) to afford the product as a purple solid (19 mg, 33% yield).

[0307] MS(ESI,pos.ion)m / z=304.1[M+H] + .

[0308] Step 6: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)phenyl)acetamide

[0309] 4-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)aniline (19 mg, 0.063 mmol), 2-(4-ethylsulfonylphenyl)acetic acid (13 mg, 0.057 mmol), EDCI (25 mg, 0.13 mmol), and HOBT (16 mg, 0.12 mmol) were dissolved in DCM (2 mL). TEA (0.030 mL, 0.22 mmol) was added and the mixture was stirred at room temperature. TLC and LC-MS analysis indicated complete conversion of the starting material. The reaction solution was diluted with DCM (80 mL) and washed sequentially with 1.0 M HCl (aq.) (10 mL), saturated Na2CO3 (aq.) (15 mL), and NaCl (aq.) (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 5 / 1) to give a yellow viscous solid, which was purified by slurrying with methyl tert-butyl ether to obtain the target product as a yellow solid (10 mg, yield: 31%).

[0310] MS(ESI,pos.ion)m / z=514.1[M+H] + ;

[0311] 1 H NMR (400MHz, d6-DMSO) δ (ppm): 10.33 (s, 1H), 9.09 (s, 1H), 8.27 (s, 1H), 8.11 (d, J = 8.4Hz, 2H), 7.90 (d, J = 8 .8Hz,2H),7.85(d,J=8.3Hz,2H),7.72–7.58(m,5H),3.82(s,2H),3.29–3.26(m,3H),1.10(t,J=7.3Hz,3H).

[0312] Example 2: 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)phenyl)acetamide

[0313]

[0314] Step 1: Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrazole

[0315] 1-(Bromomethyl)-4-(trifluoromethyl)benzene (4.8 mL, 31.00 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.10 g, 26.00 mmol) and Cs2CO3 (13.00 g, 39.90 mmol) in DMF (50 mL). The mixture was heated in an oil bath at 90°C and stirred for 24 h. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was dissolved in DCM (100 mL). The residue was washed sequentially with saturated NaHCO3 (aq.) (20 mL) and NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / EA (v / v) = 5 / 1) to give the product as a yellow solid (7.24 g, yield: 78%).

[0316] MS(ESI,pos.ion)m / z=353.4[M+H] + .

[0317] Step 2: Synthesis of 4-(4-nitrophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrazole

[0318] At room temperature, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrazole (1.00 g, 2.80 mmol), 1-bromo-4-nitrobenzene (572 mg, 2.83 mmol), Pd(dppf)Cl2 (219 mg, 0.30 mmol) and CsF (862 mg, 5.68 mmol) were dissolved in DMF (6 mL), the atmosphere was N2-exchanged, and then heated in an oil bath at 100 °C with stirring for about 12 h. The reaction solution was diluted with EtOAc (80 mL), washed sequentially with saturated NaHCO3 (aq.) (20 mL) and NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EA (v / v) = 5 / 1) to give the product as a yellow solid (1.00 g, yield: 100%).

[0319] MS(ESI,pos.ion)m / z=348.0[M+H] + .

[0320] Step 3: Synthesis of 4-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)aniline

[0321] Pd / C (10%, 125 mg) was added to a solution of 4-(4-nitrophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrazole (1.00 g, 2.90 mmol) in MeOH (10 mL). The mixture was exchanged for H₂ and stirred at room temperature under a hydrogen atmosphere. TLC confirmed complete conversion of the starting material. The reaction mixture was filtered, and the residue was dissolved in DCM (50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the crude product as a yellow oil (794 mg, 87% yield).

[0322] MS(ESI,pos.ion)m / z=318.4[M+H] + .

[0323] Step 4: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)phenyl)acetamide

[0324] DIPEA (0.90 mL, 5.20 mmol) was added to a solution of 4-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)aniline (791 mg, 2.49 mmol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (570 mg, 2.50 mmol), and HATU (1.43 g, 3.76 mmol) in DCM (10 mL) and stirred at room temperature. TLC confirmed complete conversion of the starting amine. The reaction mixture was diluted with DCM (60 mL) and washed sequentially with saturated Na2CO3(aq.) (20 mL) and NaHCO3(aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 5 / 1) to yield the desired product as a white solid (563 mg, 43%). Ether (5 mL) was added to the obtained solid, and the mixture was sonicated and the liquid was removed by suction. This operation was repeated and the solid was vacuumed to obtain the target compound as a white solid (500 mg).

[0325] MS(ESI,pos.ion)m / z=528.1[M+H] + ;

[0326] 1H NMR (400MHz, CDCl3) δ (ppm): 7.91 (d, J = 8.1Hz, 2H), 7.80 (s, 1H), 7.61 (d, J = 8.9Hz, 3H), 7.56 (d, J = 8.1Hz, 2H), 7.47 (d, J = 8.4Hz, 2H) ,7.41(d,J=8.5Hz,2H),7.34(d,J=7.9Hz,2H),7.21(s,1H),5.38(s,2H),3.81(s,2H),3.12(q,J=7.5Hz,2H),1.29(t,J=7.5Hz,3H);

[0327] 13 C NMR (100MHz, CDCl3) δ (ppm): 174.53, 174.35, 173.00, 167.05, 140.63, 140.36, 137.79, 137.33, 135.88, 13 0.28,128.84,127.81,126.16,126.11,125.89,125.85,123.22,120.31,77.20,55.55,50.59,44.30,7.36.

[0328] Example 3: 2-(4-(ethylsulfonyl)phenyl)-N-(4-(2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)phenyl)acetamide

[0329]

[0330] Step 1: Synthesis of benzyl N-(4-acetylphenyl)carbamate

[0331] Dissolve 1-(4-Aminophenyl)ethanone (6.07 g, 44.90 mmol) in THF (95 mL), add benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (16.97 g, 66.73 mmol), and stir in an oil bath at 70°C for 24 hours. The aqueous phase is extracted with EA (100 ml x 3). The combined organic phases are dried over anhydrous Na2SO4, filtered, and concentrated. The crude product is separated by silica gel column chromatography (DCM / EA (v / v) = 100 / 1) to obtain a white solid product (9.00 g, yield: 74.4%). MS (ESI, pos. ion) m / z = 270.2 [M+H] + .

[0332] Step 2: Synthesis of benzyl N-(4-(2-bromoacetyl)phenyl)carbamate

[0333] NBS (5.97 g, 33.32 mmol) was dissolved in THF (37 mL), and the solution was slowly added dropwise to a solution of TsOH·H₂O (4.6.0 g, 24.00 mmol) and benzyl N-(4-acetylphenyl)carbamate (6.50 g, 24.00 mmol) in THF (96 mL). The mixture was stirred at room temperature for 43 hours. EA (50 mL) was added for dissolution, and the mixture was washed with saturated Na₂CO₃ (50 mL × 2) solution, saturated NaHCO₃ (50 mL × 2) solution, and saturated NaCl (50 mL) solution. The mixture was dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude yellow solid (8.40 g, 100% yield).

[0334] MS(ESI,pos.ion)m / z=348.0[M+H] + .

[0335] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.96 (d, J = 8.7Hz, 2H), 7.52 (d, J = 8.6Hz, 2H), 7.42–7.34 (m, 5H), 6.95 (s, 1H), 5.23 (s, 2H), 4.40 (s, 2H).

[0336] Step 3: Synthesis of benzyl (4-(2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)phenyl)carbamate

[0337] 4-(Trifluoromethyl)benzimidamide hydrochloride (61 mg, 0.27 mmol) and benzyl N-(4-(2-bromoacetyl)phenyl)carbamate (70 mg, 0.20 mmol) were dissolved in DMSO (2 mL) and stirred overnight in an oil bath at 90°C. TLC and LC-MS analysis confirmed complete conversion of the starting material. The reaction mixture was diluted with EtOAc (60 mL) and washed sequentially with saturated NaHCO₃(aq.) (20 mL) and NaCl(aq.) (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 10 / 1) to afford the product as a yellow solid (91 mg, 100% yield).

[0338] MS(ESI,pos.ion)m / z=438.0[M+H] + .

[0339] Step 4: Synthesis of 4-(2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)aniline

[0340] Benzyl (4-(2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)phenyl)carbamate (92 mg, 0.21 mmol) was dissolved in HBr (aq.) (1 mL, 48 mass%) / AcOH (3 mL) and stirred in an oil bath at 60°C for 3.0 h. The reaction mixture was cooled to room temperature, and the reaction solution was removed under reduced pressure. The residue was diluted with DCM (60 mL), washed with saturated NaHCO₃ (aq.) (15 mL x 2), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to obtain the product as a yellow oily solid (35 mg, yield: 55%). MS (ESI, pos. ion) m / z = 304.1 [M+H] + .

[0341] Step 5: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)phenyl)acetamide

[0342] Dissolve 4-(2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)aniline (34 mg, 0.11 mol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (26 mg, 0.14 mmol), EDCI (33 mg, 0.17 mmol), and HOBT (25 mg, 0.19 mmol) in DCM (2 mL). Add TEA (0.050 mL, 0.36 mmol) and stir at room temperature. Monitor by TLC and LC-MS until complete conversion of the starting material is achieved. The reaction solution was diluted with DCM (80 mL) and washed sequentially with 1.0 M HCl (aq.) (10 mL), saturated Na2CO3 (aq.) (10 mL), and saturated NaCl (aq.) (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2:1) and preparative plate separation (developing solvent: DCM / MeOH (v / v) = 10 / 1) to obtain the target product as a white solid (3 mg, yield: 5%).

[0343] MS(ESI,pos.ion)m / z=514.4[M+H] + .

[0344] Example 4: 2-(4-(ethylsulfonyl)phenyl)-N-(4-(2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)phenyl)acetamide

[0345]

[0346] Step 1: Synthesis of benzyl (4-(2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)phenyl)carbamate

[0347] 4-(Trifluoromethyl)thiobenzamide (104 mg, 0.51 mmol) and benzyl N-(4-(2-bromoacetyl)phenyl)carbamate (152 mg, 0.44 mmol) were dissolved in EtOH (2 mL) and stirred in an oil bath at 90°C for 24 h. The reaction was monitored by TLC and LC-MS. The reaction solution was diluted with EtOAc (80 mL), washed with saturated NaHCO₃(aq.) (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 5 / 1 / 1) to afford the product as a yellow solid (176 mg, 89% yield).

[0348] MS(ESI,pos.ion)m / z=455.0[M+H] + .

[0349] Step 2: Synthesis of 4-(2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)aniline

[0350] Benzyl (4-(2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)phenyl)carbamate (167 mg, 0.37 mmol) was dissolved in HBr (aq.) (1 mL, 48 mass%) / AcOH (3 mL). The reaction was stirred in a 60°C oil bath for 3.0 h. TLC indicated substantial conversion of the starting material, and heating was discontinued. The reaction solution was evaporated to dryness under reduced pressure, then diluted with DCM (60 mL) and washed sequentially with saturated NaHCO (aq.) (20 mL) and NaCl (aq.) (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 5 / 1 / 1) to afford the product as a yellow solid (116 mg, 99% yield).

[0351] MS(ESI,pos.ion)m / z=321.1[M+H] + .

[0352] Step 3: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)phenyl)acetamide

[0353] 4-(2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)aniline (114 mg, 0.36 mmol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (100 mg, 0.44 mmol), EDCI (103 mg, 0.54 mmol) and HOBT (75 mg, 0.56 mmol) were dissolved in DCM (5 mL), and TEA (0.16 mL, 1.10 mmol) was added and stirred at room temperature. The reaction was monitored by TLC. After the starting material was substantially converted, the reaction solution was diluted with DCM (80 mL) and washed sequentially with 1.0 M HCl (aq.) (15 mL), saturated Na2CO3 (aq.) (25 mL), and NaCl (aq.) (15 mL). The product was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 10 / 1) to obtain the target product as a white solid (154 mg, yield: 82%).

[0354] MS(ESI,pos.ion)m / z=531.3[M+H] + ;

[0355] 1 H NMR (600MHz, d6-DMSO) δ (ppm): 10.42 (s, 1H), 8.24 (d, J = 7.9Hz, 2H), 8.19 (s, 1H), 8.02 (d, J = 8.6Hz, 2H), 7.90 (d, J = 8.0Hz, 2H ),7.86(d,J=8.2Hz,2H),7.72(d,J=8.6Hz,2H),7.63(d,J=8.2Hz,2H),3.84(s,2H),3.30–3.24(m,2H),1.10(t,J=7.3Hz,3H);

[0356] 13 C NMR(151MHz,d6-DMSO)δ(ppm):168.78,165.49,155.87,142.52,139.69,137.30,136.99,130.75,130.59,130.3 8,129.37,128.33,127.35,127.21,126.76,126.73,125.41,123.60,119.77,115.42,49.69,43.42,40.52,7.64.

[0357] Example 5: 2-(4-(ethylsulfonyl)phenyl)-N-(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide

[0358]

[0359] Step 1: Synthesis of 4-aminobenzonitrile

[0360] Pd / C (112 mg, 10%) was added to a solution of 4-nitrobenzonitrile (1.03 g, 6.95 mmol) in MeOH (10 mL). The mixture was stirred at room temperature under a H2 (balloon) atmosphere for 2.0 h. The mixture was filtered and the filtrate was concentrated to give the crude product as a yellow solid (798 mg, 97% yield).

[0361] MS(ESI,pos.ion)m / z=119.1[M+H] + .

[0362] Step 2: Synthesis of N-(4-cyanophenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0363] 4-Aminobenzonitrile (798 mg, 6.75 mmol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (1.55 g, 6.79 mmol), EDCI (1.95 g, 10.2 mmol), and HOBT (1.38 g, 10.2 mmol) were dissolved in DCM (20 mL), followed by the addition of TEA (1.40 mL, 10.0 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (40 mL) and washed sequentially with 1.0 M HCl (aq.) (20 mL), saturated NaCl (aq.) (10 mL), and saturated NaHCO₃ (aq.) (10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 5 / 1) to afford the product as a white solid (952 mg, 43% yield).

[0364] MS(ESI,pos.ion)m / z=329.2[M+H] + .

[0365] Step 3: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(N'-hydroxyaminomethylimino)phenyl)acetamide

[0366] HONH2·HCl (405 mg, 5.83 mmol) and NaOH (233 mg, 5.83 mmol) were added sequentially to a solution of N-(4-cyanophenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide (951 mg, 2.90 mmol) in EtOH (10 mL). After 20 minutes, the mixture was refluxed (oil bath at 80°C) overnight. Heating was stopped, and the reaction solution was concentrated. The crude product was isolated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 5 / 1) to afford the product as a white solid (575 mg, 55% yield).

[0367] MS(ESI,pos.ion)m / z=362.0[M+H] + .

[0368] Step 4: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide

[0369] 4-(Trifluoromethyl)benzoyl chloride (0.13 mL, 0.88 mmol) was added to a solution of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(N'-hydroxyaminomethylimino)phenyl)acetamide (154 mg, 0.43 mmol) and K2CO3 (233 mg, 1.69 mmol) in toluene (5 mL). The reaction was stirred at room temperature for 1.0 h and then heated under reflux in an oil bath (130°C) overnight. LC-MS analysis revealed the formation of the target product. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was dissolved in DCM (80 mL) and washed sequentially with saturated NaHCO3 (aq.) (20 mL) and saturated NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 5 / 1) to afford the target product as a white solid (182 mg, yield: 83%).

[0370] MS (ESI, pos.ion): 516.1 [M+H] + ;

[0371] 1 H NMR (400MHz, d6-DMSO) δ (ppm): 10.60 (s, 1H), 8.39 (d, J = 8.1Hz, 2H), 8.01-8.08 (m, 4H), 7.83- 7.86(m,4H),7.63(d,J=8.2Hz,2H),3.87(s,2H),3.28(q,J=7.4Hz,2H),1.10(t,J=7.4Hz,3H);

[0372] 13 C NMR(151MHz,d6-DMSO)δ(ppm):174.07,168.73,168.11,142.11,141.82,136.88,130.2 8,128.88,128.06,127.85,127.13,126.53,120.49,119.38,49.20,42.95,40.06,7.15.

[0373] Example 6: 2-(4-(ethylsulfonyl)phenyl)-N-(4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)phenyl)acetamide

[0374]

[0375] Step 1: Synthesis of 2-(4-(trifluoromethyl)phenyl)acetonitrile

[0376] 1-(Bromomethyl)-4-(trifluoromethyl)benzene (3.08 g, 12.90 mmol) and KF·2H2O (1.80 g, 19.10 mmol) were dissolved in ACN (30 mL). TMSCN (2.4 mL, 19.00 mmol) and NaI (1.90 g, 12.70 mmol) were added sequentially. The reaction was heated and stirred in an oil bath at 50°C for 6 h. Heating was discontinued and the solvent was removed by concentration under reduced pressure. The residue was dissolved in DCM (100 mL) and washed sequentially with saturated NaHCO3 (aq.) (15 mL) and NaCl (aq.) (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 5 / 1) to obtain the product as a colorless, transparent liquid (2.27 g, yield: 95%).

[0377] MS(ESI,pos.ion)m / z=186.0[M+H] + .

[0378] Step 2: Synthesis of 2-(4-(trifluoromethyl)phenyl)ethylthioamide

[0379] Under nitrogen, 2-(4-(trifluoromethyl)phenyl)acetonitrile (2.27 g, 12.30 mmol), P2S5 (2.41 g, 12.60 mmol), and Na2SO3 (1.58 g, 12.50 mmol) were mixed and stirred at room temperature overnight. TLC and LC-MS analysis revealed the formation of the desired product. DCM (40 mL) and H2O (20 mL) were added to the mixture, which was then filtered. The filter cake was washed with DCM (30 mL), and the filtrate was washed with saturated NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 20 / 1) to afford the product as a white solid (165 mg, yield: 6.0%).

[0380] MS(ESI,pos.ion)m / z=220.0[M+H] + .

[0381] Step 3: Synthesis of benzyl (4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)phenyl)carbamate

[0382] 2-(4-(Trifluoromethyl)phenyl)ethylthioamide (161 mg, 0.73 mmol) and benzyl N-(4-(2-bromoacetyl)phenyl)carbamate (312 mg, 0.90 mmol) were dissolved in EtOH (5 mL) and the reaction was stirred in an oil bath at 90°C for 20 h. TLC and LC-MS analysis indicated substantial conversion of the starting material. The solvent was evaporated under reduced pressure, and the residue was dissolved in DCM (80 mL), washed with saturated NaHCO₃(aq.) (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 10 / 1 / 1) to afford the product as a white solid (201 mg, 58% yield).

[0383] MS(ESI,pos.ion)m / z=469.1[M+H] + .

[0384] Step 4: Synthesis of 4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)aniline

[0385] Under nitrogen, benzyl (4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)phenyl)carbamate (200 mg, 0.43 mmol) was dissolved in HBr (aq.) (1 mL, 48 mass%) and AcOH (3 mL). The reaction was heated and stirred in a 60°C oil bath for 2.5 h. TLC indicated substantial conversion of the starting material, and heating was discontinued. The reaction solution was evaporated to dryness under reduced pressure. The residue was diluted with DCM (60 mL), washed sequentially with saturated NaHCO (aq.) (15 mL) and NaCl (aq.) (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 5 / 1 / 1) to afford the product as a yellow solid (141 mg, 99% yield).

[0386] MS(ESI,pos.ion)m / z=335.0[M+H] + .

[0387] Step 5: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)phenyl)acetamide

[0388] Under nitrogen protection, 4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)aniline (140 mg, 0.42 mmol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (119 mg, 0.52 mmol), EDCI (129 mg, 0.67 mmol) and HOBT (85 mg, 0.63 mmol) were dissolved in DCM (5 mL), and then TEA (0.12 mL, 0.86 mmol) was added to the reaction system and stirred at room temperature for 15 h. The reaction solution was diluted with DCM (60 mL) and washed sequentially with 1.0 HCl solution (15 mL), saturated NaCl (aq.) (15 mL) and NaHCO3 (aq.) (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v / v) = 10 / 1) to give the target product as a white solid (126 mg, yield: 55%).

[0389] MS(ESI,pos.ion)m / z=545.1[M+H] + ;

[0390] 1H NMR (400MHz, d6-DMSO) δ (ppm): 10.37 (s, 1H), 7.91–7.82 (m, 5H), 7.72 (d, J = 8.1Hz, 2H), 7.66 (d, J = 8.7 Hz,2H),7.62(d,J=8.1Hz,4H),4.51(s,2H),3.82(s,2H),3.27(d,J=7.4Hz,2H),1.10(t,J=7.3Hz,3H); 13 C NMR(101MHz,d6-DMSO)δ(ppm):168.39,168.23,154.01,142.95,142.09,138.85,136.89,130.2 5,129.85,129.33,127.85,126.53,125.56,125.52,119.30,113.23,49.27,42.97,38.20,7.17.

[0391] Example 7: 2-morpholino-N-(4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)phenyl)acetamide

[0392]

[0393] To a bottle containing 4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)aniline (98 mg, 0.29 mmol) was added 2-morpholinoacetic acid (200 mg, 1.38 mmol), EDCI (122 mg, 0.64 mmol), HOBT (82 mg, 0.61 mmol), and DCM (8 mL). After stirring at room temperature for 29 hours, the mixture was diluted with DCM (100 mL), washed with saturated NaHCO3 solution (50 mL), washed with saturated NaCl solution, extracted with DCM (50 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography (DCM / EA (v / v) = 5 / 1) to give a white solid (70 mg, yield: 51.76%).

[0394] MS(ESI,pos.ion)m / z=462.1[M+H] + ;

[0395] 1H NMR (400MHz, CDCl3) δ (ppm): 9.16 (s, 1H), 7.89 (d, J = 8.5Hz, 2H), 7.64 (dd, J = 12.5, 8.4Hz, 4H), 7. 51(d,J=8.0Hz,2H),7.34(s,1H),4.46(s,2H),3.88–3.77(m,4H),3.19(s,2H),2.73–2.63(m,4H).

[0396] Example 8: (2-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)phenyl)methanol

[0397]

[0398] Step 1: Synthesis of methyl 5-acetyl-2-((tetrahydro-2H-pyran-4-yl)methoxy)benzoate

[0399] In a 100 mL single-necked flask, tetrahydropyran-4-ylmethanol (1.00 g, 8.61 mmol), methyl 5-acetyl-2-hydroxybenzoate (1.81 g, 9.32 mmol), and PPh3 (3.20 g, 9.30 mmol) were added to a THF (40 mL) solution and placed at 0°C. DIAD (2.20 mL, 11.00 mmol) was then slowly added dropwise (approximately 5 min) to the mixture. After the addition was complete, the mixture was brought to room temperature (28°C) and stirred for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM (50 mL) and washed sequentially with saturated NaHCO3 (20 mL) and NaCl (20 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was separated by silica gel column chromatography (EA / PE (v / v) = 2 / 3) to give a white solid (2.00 g, yield: 79%).

[0400] MS(ESI,pos.ion)m / z=293.1[M-56+H] + .

[0401] Step 2: Synthesis of methyl 5-(2-bromoacetyl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)benzoate

[0402] In a 50 mL single-necked flask, phenyltrimethylammonium tribromide (2.50 g, 6.70 mmol) was added to a solution of methyl 5-acetyl-2-((tetrahydropyran-4-yl)methoxy)benzoate (2.00 g, 6.84 mmol) in THF (40 mL). The mixture was stirred at room temperature (27°C) for 14 h. The reaction mixture was filtered to remove the white insoluble matter, and the filtrate was concentrated under reduced pressure. The residue was diluted with EA (50 mL), washed sequentially with saturated NaHCO₃ (15 mL) and NaCl solution (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was separated by silica gel column chromatography (EA / PE (v / v) = 2 / 3) to obtain a white solid (1.58 g, yield: 62%).

[0403] MS(ESI,pos.ion)m / z=371.1[M+H] + .

[0404] Step 3: Synthesis of methyl 2-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(2-(4-trifluoromethyl)benzyl)thiazol-4-yl)benzoate

[0405] In a 50 mL single-necked flask, methyl 5-(2-bromoacetyl)-2-((tetrahydropyran-4-yl)methoxy)benzoate (201 mg, 0.54 mmol) was added to a solution of 2-(4-(trifluoromethyl)phenyl)thioacetamide (90 mg, 0.41 mmol) in EtOH (8 mL). The mixture was heated at 80°C for 16 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (EA / PE (v / v) = 1 / 3) to obtain a light yellow solid (210 mg, yield: 79%). MS (ESI, pos. ion) m / z = 492.2 [M+H] + .

[0406] Step 4: Synthesis of (2-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)phenyl)methanol

[0407] A solution of LiBH₄ in THF (0.30 mL, 0.60 mmol, 2 mol / L) was added to a solution of methyl 2-((tetrahydropyran-4-yl)methoxy)-5-(2-((4-(trifluoromethyl)phenyl)methyl)thiazol-4-yl)benzoate (130 mg, 0.26 mmol) in dry THF (4 mL) at 0°C. After 10 min, the mixture was allowed to react at room temperature (27°C) for 13 h. The reaction was quenched by the addition of saturated NH₄Cl (20 mL) and the aqueous phase was extracted with EA (30 mL × 3). The combined organic phases were washed with saturated NaCl (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was separated by silica gel column chromatography (EA / PE (v / v) = 1 / 1) to give a white powder (80 mg, 65% yield).

[0408] MS(ESI,pos.ion)m / z=464.2[M+H] + ;

[0409] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.83 (s, 1H), 7.81 (d, J = 8.5Hz, 1H), 7.61 (d, J = 8.0Hz, 2H),7.48(d,J=8.0Hz,2H),7.27(d,J=4.3Hz,1H),6.91(d,J=8.5Hz,1H),4.76(s,2H ),4.43(s,2H),4.04(dd,J=11.3,3.5Hz,2H),3.91(d,J=6.3Hz,2H),3.46(t,J=11.3 Hz,2H),2.36(s,1H),2.18–2.07(m,1H),1.77(d,J=12.3Hz,2H),1.56–1.45(m,2H);

[0410] 13 C NMR (150MHz, CDCl3) δ (ppm): 168.44, 156.58, 155.11, 141.76, 129.50, 129.35, 127.30, 126.88 ,126.67,125.67,125.00,123.20,111.57,111.16,72.65,67.54,61.77,39.40,35.12,29.72.

[0411] Example 9: N-(4-(ethylsulfonyl)benzyl)-4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzamide

[0412]

[0413] Step 1: Synthesis of methyl 4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzoate

[0414] 2-(4-(Trifluoromethyl)phenyl)ethylthioamide (0.81 g, 3.70 mmol) and methyl 4-(2-bromoacetyl)benzoate (1.21 g, 4.71 mmol) were dissolved in EtOH (20 mL) and heated in an oil bath at 90°C with stirring for 24 h. TLC and LC-MS confirmed complete conversion of the starting material. The solvent was removed by concentration under reduced pressure, and the residue was diluted with DCM (80 mL), washed with saturated NaHCO₃(aq.) (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EA (v / v / v) = 10 / 1 / 1) to afford the product as a white solid (755 mg, 54% yield).

[0415] MS(ESI,pos.ion)m / z=378.1[M+H] + .

[0416] Step 2: Synthesis of 4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzoic acid

[0417] NaOH (165 mg, 4.12 mmol) and methyl 4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzoate (755 mg, 2.00 mmol) were dissolved in EtOH (10 mL) and heated in an oil bath from room temperature to 80°C for 4 h. Heating was discontinued, and 1.0 M HCl solution was slowly added to the reaction solution until the pH reached 2-3. The solution was then extracted with DCM (50 mL x 3). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EA (v / v) = 10 / 1) to afford the product as a yellow solid (730 mg, 100% yield).

[0418] MS(ESI,pos.ion)m / z=364.1[M+H] + .

[0419] Step 3: Synthesis of N-(4-(ethylsulfonyl)benzyl)-4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzamide

[0420] Under nitrogen, 4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzoic acid (154 mg, 0.42 mmol), (4-(ethylsulfonyl)phenyl)methanamine (131 mg, 0.66 mmol), EDCI (162 mg, 0.85 mmol) and HOBT (116 mg, 0.86 mmol) were dissolved in DCM (5 mL). TEA (0.22 mL, 1.6 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction solution was diluted with DCM (60 mL), washed sequentially with saturated NaHCO (aq.) (20 mL) and NaCl (aq.) (20 mL), dried over anhydrous Na SO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EA (v / v) = 10 / 1) and preparative silica gel plate chromatography (developing solvent: DCM / EA (v / v) = 10 / 1) to give the target product as a light yellow solid (69 mg, yield: 30%).

[0421] MS(ESI,pos.ion)m / z=545.2[M+H] + ;

[0422] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.99 (d, J = 8.4Hz, 2H), 7.82-7.88 (m, 4H), 7.61 (d, J = 8.0Hz, 2H), 7.55 (d, J = 8.1Hz, 2H), 7.4 6-7.53(m,3H),6.69(t,J=5.5Hz,1H),4.77(d,J=6.0Hz,2H),4.45(s,2H),3.10(q,J=7.4Hz,2H),1.28(d,J=7.4Hz,3H);

[0423] 13 C NMR (100MHz, CDCl3) δ (ppm): 169.14, 167.27, 154.43, 145.02, 141.60, 137.67, 133.19, 130.36, 129.55 ,128.78,128.43,127.77,127.17,126.69,125.95,125.91,114.79,63.76,50.69,43.44,39.44,7.52.

[0424] Example 10: N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzamide

[0425]

[0426] Step 1: Synthesis of 2-(4-(trifluoromethyl)phenyl)acetamide

[0427] 2-(4-(Trifluoromethyl)phenyl)acetic acid (3.03 g, 14.80 mmol), HATU (11.1 g, 29.20 mmol), NH4Cl (1.60 g, 29.90 mmol), and TEA (6.0 mL, 43.00 mmol) were dissolved in DCM (30 mL) and stirred at room temperature for 6 h. A sample was taken for LC-MS analysis, indicating substantial conversion of the starting material. The reaction solution was diluted with DCM (100 mL) and then washed with saturated NH4Cl (aq.) (15 mL). The aqueous phase was extracted with DCM (15 mL x 2). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) to afford the product as a white solid (3.0 g, yield: 99%).

[0428] MS(ESI,pos.ion)m / z=204.1[M+H] + .

[0429] Step 2: Synthesis of 2-(4-(trifluoromethyl)phenyl)ethylthioamide

[0430] Under nitrogen, Lawesson's reagent (16 g, 39.56 mmol) was added to a solution of 2-(4-(trifluoromethyl)phenyl)acetamide (6.0 g, 30.00 mmol) in toluene (100 mL), and the reaction was heated and stirred in an oil bath at 80°C for 10 h. The solvent was removed by concentration under reduced pressure, and the residue was diluted with EtOAc (200 mL), then washed sequentially with saturated Na2CO3 (aq.) (30 mL) and NaHCO3 (aq.) (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EA (v / v / v) = 10 / 10 / 1) to obtain the product as a yellow solid (2.80 g, yield: 43%).

[0431] MS(ESI,pos.ion)m / z=220.1[M+H] + .

[0432] Step 3: Synthesis of 4-acetyl-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)benzamide

[0433] 4-Acetylbenzoic acid (200 mg, 1.22 mmol), (5-(ethylsulfonyl)pyridin-2-yl)methanamine (160 mg, 0.80 mmol), EDCI (310 mg, 1.62 mmol), and HOBT (216 mg, 1.60 mmol) were dissolved in DCM (10 mL). TEA (0.22 mL, 1.60 mmol) was added and stirred at room temperature for 22 h. The reaction was monitored by TLC and LC-MS, indicating substantial conversion of the starting material. The reaction solution was diluted with DCM (80 mL), washed sequentially with saturated NaHCO₃(aq.) (20 mL) and NaCl(aq.) (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / EA (v / v) = 3 / 1) to afford the product as a yellow solid (128 mg, 46% yield).

[0434] MS(ESI,pos.ion)m / z=347.2[M+H] + .

[0435] Step 4: Synthesis of 4-(2-bromoacetyl)-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)benzamide

[0436] NBS (64 mg, 0.36 mmol) was added to a solution of TsOH·H₂O (72 mg, 0.38 mmol) and 4-acetyl-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)benzamide (124 mg, 0.36 mmol) in THF (4 mL) and stirred at room temperature for 24 h. TLC and LC-MS analysis indicated that approximately half of the starting material remained. Additional NBS (65 mg, 0.36 mmol) was added, and stirring continued for 10 h. The reaction mixture was diluted with DCM (120 mL), washed sequentially with saturated Na₂CO₃(aq.) (30 mL) and NaHCO₃(aq.) (30 mL x 2), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the product as a yellow solid (152 mg, 100% yield).

[0437] MS(ESI,pos.ion)m / z=425.0[M+H] + .

[0438] Step 5: Synthesis of N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzamide

[0439] Under nitrogen, 2-(4-(trifluoromethyl)phenyl)ethylthioamide (120 mg, 0.55 mmol) and 4-(2-bromoacetyl)-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)benzamide (152 mg, 0.36 mmol) were dissolved in EtOH (5 mL) and the reaction was stirred in an oil bath at 90°C for 24 h. The solvent was removed by concentration under reduced pressure. The residue was diluted with DCM (80 mL), washed sequentially with saturated NaHCO₃(aq.) (20 mL) and NaCl(aq.) (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EA (v / v) = 1 / 1) and preparative silica gel plate chromatography (developing solvent: DCM / EA (v / v) = 1 / 1) to obtain the desired product as a light yellow solid (60 mg, yield: 31%). MS(ESI,pos.ion)m / z=546.1[M+H] + ;

[0440] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.07 (s, 1H), 8.19 (dd, J = 8.2, 2.2Hz, 1H), 8.00 (d, J = 8.4Hz, 2H), 7.93 (d, J = 8.4Hz, 2H), 7.62 (d, J = 8.2Hz, 2H) ,7.58(d,J=8.3Hz,1H),7.48-7.53(m,3H),7.43(t,1H),4.90(d,J=5.1Hz,2H),4.46(s,2H),3.17(q,J=7.5Hz,2H),1.32(d,J=7.5Hz,3H);

[0441] 13 C NMR (101MHz, CDCl3) δ (ppm): 169.15, 167.26, 162.43, 154.51, 149.06, 141.71, 137.73, 137.03, 134.12, 13 3.29,129.87,129.55,127.82,126.69,125.95,125.91,122.54,114.87,77.36,51.24,45.10,39.61,7.50.

[0442] Examples 11 and 12: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzamide / (S)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzamide

[0443]

[0444] Step 1: Synthesis of 2-(4-acetylbenzamido)-2-(4-(ethylsulfonyl)phenyl)ethyl 4-acetylbenzoate

[0445] Under nitrogen, 4-acetylbenzoic acid (189 mg, 1.05 mmol), 2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (160 mg, 0.70 mmol), EDCI (272 mg, 1.42 mmol), and HOBT (191 mg, 1.41 mmol) were dissolved in DCM (10 mL). TEA (0.20 mL, 1.40 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (80 mL), washed sequentially with saturated NaHCO₃(aq.) (20 mL) and NaCl(aq.) (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / EA (v / v) = 10 / 1) to give the product as a white solid (278 mg, yield: 76%).

[0446] MS(ESI,pos.ion)m / z=376.2[M+H] +

[0447] Step 2: Synthesis of 4-acetyl-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0448] NaOH (45 mg, 1.12 mmol) was dissolved in H₂O (2 mL), and this solution was added to a solution of 2-(4-acetylbenzamido)-2-(4-(ethylsulfonyl)phenyl)ethyl 4-acetylbenzoate (278 mg, 0.53 mmol) in EtOH (6 mL). The mixture was stirred at room temperature for 5 h. LC-MS and TLC confirmed complete conversion of the starting material. The reaction mixture was diluted with DCM (60 mL) and washed sequentially with saturated Na₂CO₃(aq.) (20 mL) and NaCl(aq.) (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the product as a white solid (200 mg, 100% yield). MS (ESI, pos. ion) m / z = 376.2 [M+H] + .

[0449] Step 3: Synthesis of 4-(2-bromoacetyl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-benzamide

[0450] NBS (124 mg, 0.70 mmol) was added to a solution of TsOH·H₂O (172 mg, 0.90 mmol) and 4-acetyl-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide (200 mg, 0.53 mmol) in THF (6 mL) and stirred at room temperature overnight. Additional NBS (140 mg, 0.79 mmol) was added, and stirring continued for 10 h. The reaction mixture was diluted with DCM (120 mL) and washed sequentially with saturated Na₂CO₃(aq.) (30 mL) and NaHCO₃(aq.) (30 mL x 2), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the product as a yellow solid (242 mg, 100% yield).

[0451] MS(ESI,pos.ion)m / z=454.0[M+H] + .

[0452] Step 4: Synthesis of N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzamide

[0453] Under nitrogen, 2-(4-(trifluoromethyl)phenyl)ethylthioamide (175 mg, 0.80 mmol) and 4-(2-bromoacetyl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-benzamide (242 mg, 0.53 mmol) were dissolved in EtOH (6 mL) and the reaction was stirred in an oil bath at 90°C for 24 h. The solvent was removed by concentration under reduced pressure, and the residue was diluted with DCM (80 mL), washed sequentially with saturated NaHCO3 (aq.) (20 mL) and NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EA (v / v) = 1 / 2) to give a light yellow solid (268 mg, yield: 88%).

[0454] The yellow solid was separated by HPLC (n-hexane / ethanol / DCM (v / v / v) = 63 / 7 / 30) to obtain Example 11 and Example 12.

[0455] Example 11: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzamide, yellow solid, 50 mg;

[0456] MS(ESI,pos.ion)m / z=575.2[M+H] + ; HPLC: 89.45%, R:S=75.57%: 24.43%.

[0457] 1 H NMR (400MHz, CDCl3) δ (ppm): 8.02 (d, J = 8.3Hz, 2H), 7.93 (d, J = 6.0Hz, 4H), 7.64 (d, J = 7.9Hz, 4H), 7.51 (d, J = 5.5Hz, 3H), 7.16 (d, J = 6 .1Hz,1H),5.37(s,1H),4.48(s,2H),4.10(dd,J=25.9,6.1Hz,2H),3.13(q,J=7.5Hz,2H),3.02-3.07(m,1H),1.31(t,J=7.5Hz,3H).

[0458] Example 12: Preparation: A yellow solid was isolated and separated, followed by silica gel column chromatography (eluent: DCM / EA (v / v) = 1 / 1) and recrystallization from methyl tert-butyl ether to obtain compound (S)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzamide as a white solid in a yield of 30 mg.

[0459] MS(ESI,pos.ion)m / z=575.2[M+H] + ; HPLC: 92.76%, S: R=92.74%: 7.26%.

[0460] 1 H NMR (400MHz, d6-DMSO) δ (ppm): 8.86 (d, J = 7.9 Hz, 1H), 8.17 (s, 1H), 8.05 (d, J = 8. 3Hz,2H),7.98(d,J=8.5Hz,2H),7.85(d,J=8.2Hz,2H),7.74(d,J=8.3Hz,2H),7.6 8(d,J=8.3Hz,2H),7.64(d,J=7.8Hz,2H),5.14-5.19(m,1H),5.06(t,J=6.8Hz,1 H),4.55(s,2H),3.79–3.67(m,2H),3.27(q,J=7.6Hz,2H),1.10(t,J=7.6Hz,3H).

[0461] Example 13: (R)-2-(4-(ethylsulfonyl)phenyl)-3-hydroxy-N-(4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)phenyl)propanamide or (R)-2-(4-(ethylsulfonyl)phenyl)-3-hydroxy-N-(4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)phenyl)propanamide

[0462] Example 14: (S)-2-(4-(ethylsulfonyl)phenyl)-3-hydroxy-N-(4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)phenyl)propanamide or (S)-2-(4-(ethylsulfonyl)phenyl)-3-hydroxy-N-(4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)phenyl)propanamide

[0463]

[0464] Step 1: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-3-hydroxypropionic acid

[0465] 2-(4-Ethylsulfonylphenyl)acetic acid (670 mg, 2.94 mmol) was dissolved in THF (32 mL) at -20°C, followed by the dropwise addition of a solution of isopropylmagnesium bromide in diethyl ether (9.5 mL, 29.00 mmol, 3.0 mol / L). The mixture was stirred at -20°C for 3 h. After continued stirring and slowly warming to room temperature for 3 hours, paraformaldehyde (800 mg, 8.70 mmol) was added and the reaction continued with stirring for 3 hours. After completion, the reaction mixture was poured into saturated aqueous ammonium chloride (15 mL) to quench the reaction. The THF was evaporated under reduced pressure, and the residue was extracted with DCM (20 mL). The organic phase was washed with saturated NaCl (aq.) (20 mL) and dried over anhydrous Na2SO4. The crude product was separated by silica gel column chromatography (PE / EA (v / v) = 5 / 1) to obtain a pale yellow foamy solid (0.59 g, 78% yield).

[0466] MS(ESI,pos.ion)m / z=259.4[M+H] + .

[0467] Step 2: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-3-hydroxy-N-(4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)phenyl)propionamide

[0468] To a bottle containing 4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)aniline (160 mg, 0.48 mmol) was added 2-(4-(ethylsulfonyl)phenyl)-3-hydroxypropanoic acid (120 mg, 0.46 mmol), EDCI (178 mg, 0.93 mmol), HOBT (126 mg, 0.93 mmol), and DCM (8 mL). The mixture was stirred at room temperature for 4 hours. TEA (98 mg, 0.97 mmol) was added, and the mixture was stirred at room temperature for 20 hours. After workup, the mixture was diluted with DCM (100 mL), washed with saturated NaCl solution (50 mL), extracted with DCM (50 mL × 3), dried over anhydrous Na2SO4, filtered, and dried by rotary evaporation. The crude product was separated by silica gel column chromatography (DCM / EA (v / v) = 3 / 1) and concentrated by rotary evaporation to give the product as a yellow solid (92 mg, yield: 34.46%).

[0469] MS(ESI,pos.ion)m / z=575.1[M+H] + ;

[0470] 1 H NMR (400MHz, d6-DMSO) δ (ppm): 10.40 (s, 1H), 7.86 (d, J = 3.1Hz, 2H), 7.84 (d, J=2.8Hz,3H),7.72(s,1H),7.70(s,1H),7.67(d,J=4.1Hz,2H),7.65(d,J=4.6 Hz,2H),7.61(s,1H),7.59(s,1H),5.18(s,1H),4.48(s,2H),4.07(dd,J=9.3 ,5.0Hz,1H),4.01–3.96(m,1H),3.24(q,J=7.3Hz,2H),1.08(t,J=7.3Hz,3H).

[0471] The obtained yellow solid was subjected to preparative chiral separation (conditions: (n-hexane / (isopropanol)=77 / 23, IC column, column temperature 30°C, maximum absorption wavelength 286 nm, run time 60 min) to give compounds (S)-2-(4-(ethylsulfonyl)phenyl)-3-hydroxy-N-(4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)phenyl)propanamide and (R)-2-(4-(ethylsulfonyl)phenyl)-3-hydroxy-N-(4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)phenyl)propanamide, respectively.

[0472] Example 15: (R)-4-(2-(4-(difluoromethoxy)benzyl)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0473]

[0474] Step 1: Synthesis of 2-(4-hydroxyphenyl)acetamide

[0475] To methyl 2-(4-hydroxyphenyl)acetate (10.30 g, 62.00 mmol), slowly add ammonia in methanol (72 mL, 504.00 mmol, 7 mol / L). Seal the tube and stir in a 60°C oil bath for 24 hours. Remove from heat. Spin dry, dissolve in 3 mL of methanol, dilute with DCM (80 mL), filter, and wash the filter cake with DCM to obtain a white solid (5.60 g, 60% yield).

[0476] MS(ESI,pos.ion)m / z=152.2[M+H] + .

[0477] Step 2: Synthesis of 2-(4-(difluoromethoxy)phenyl)acetamide

[0478] 2-(4-Hydroxyphenyl)acetamide (3.00 g, 19.85 mmol) was dissolved in acetonitrile (60 mL). A solution of KOH (22.30 g, 397.00 mmol) in H₂O (60 mL) was added at -10°C, followed by the dropwise addition of diethyl (bromodifluoromethyl)phosphonate (7 mL, 40 mmol). The mixture was stirred at room temperature for 18 hours. The acetonitrile was removed by rotary evaporation, and the mixture was diluted with DCM (100 mL). The layers were separated, extracted with EA (2 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (PE / EA (v / v) = 10 / 1) and evaporated under reduced pressure to give a white solid (850 mg, 21% yield).

[0479] MS(ESI,pos.ion)m / z=202.2[M+H] + .

[0480] Step 3: Synthesis of 2-(4-(difluoromethoxy)phenyl)thioacetamide

[0481] 2-(4-(Difluoromethoxy)phenyl)acetamide (960 mg, 4.78 mmol) was dissolved in THF (25 mL), and Lawesson's reagent (2.30 g, 5.70 mmol) was added. The mixture was stirred in an oil bath at 70°C for 20 hours, and then heating was stopped. The mixture was quenched with saturated NaHCO₃ (10 mL) solution, diluted with EA (70 mL), and washed with saturated NaHCO₃ solution (50 mL × 2) and saturated NaCl solution (50 mL). The aqueous phase was extracted with EA (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was separated by silica gel column chromatography (PE / EA (v / v) = 2 / 1) to give a white solid (366 mg, yield: 35%).

[0482] MS(ESI,pos.ion)m / z=218.0[M+H] + .

[0483] Step 4: Synthesis of 4-acetylbenzoic acid

[0484] Dissolve methyl 4-acetylbenzoate (2.00 g, 11.23 mmol) in MeOH (24 mL), add a solution of NaOH (674 mg, 16.85 mmol) in H₂O (12 mL), and stir at room temperature for 24 hours. Adjust the pH to 1 with 6.0 M hydrochloric acid, wash with saturated NaCl solution, dry over anhydrous Na₂SO₄, filter, and concentrate to obtain a white solid (1.80 g, 98% yield).

[0485] MS(ESI,pos.ion)m / z=165.2[M+H] + .

[0486] Step 5: Synthesis of (R)-4-acetyl-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0487] 4-Acetylbenzoic acid (220 mg, 1.3402 mmol) and (2R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (300 mg, 1.31 mmol) were added to a vial. EDCI (514 mg, 2.68 mmol), HOBT (370 mg, 2.74 mmol), and DCM (6 mL) were added and stirred at room temperature for 22 hours. The reaction mixture was dried by rotary evaporation, and the crude product was separated by silica gel column chromatography (DCM / EA (v / v) = 3 / 1) to obtain a white solid (420 mg, yield: 83%). MS (ESI, pos. ion) m / z = 376.0 [M+H] + .

[0488] Step 6: Synthesis of (R)-4-(2-bromoacetyl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0489] NBS (618 mg, 3.47 mmol) was dissolved in THF (12 mL), and this solution was slowly added dropwise to a solution of TsOH (230 mg, 1.34 mmol) and (R)-4-acetyl-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide (500 mg, 1.33 mmol) in THF (5 mL). The mixture was stirred at room temperature for 26 hours. The mixture was dissolved in EA (50 mL), washed with saturated NaHCO₃ (50 mL x 2) and saturated NaCl solution (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was separated by silica gel column chromatography (DCM / EA (v / v) = 3 / 1) to give a beige solid (476 mg, 78% yield).

[0490] MS(ESI,pos.ion)m / z=454.1[M+H] + .

[0491] Step 7: Synthesis of (R)-4-(2-(4-(difluoromethoxy)benzyl)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0492] (R)-4-(2-Bromoacetyl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide (80 mg, 0.18 mmol) and 2-(4-(difluoromethoxy)phenyl)thioacetamide (70 mg, 0.32 mmol) were dissolved in EtOH (6 mL) and stirred in an oil bath at 90°C for 14 hours. Heating and stirring were then stopped. The solvent was evaporated under reduced pressure, and the residue was separated by column chromatography (DCM / EA (v / v) = 3 / 1, DCM / EA (v / v) = 1 / 1) to give a white solid (53 mg, yield: 53%).

[0493] MS(ESI,pos.ion)m / z=573.2[M+H] + ;

[0494] 1H NMR (400MHz, CDCl3) δ (ppm): 8.02 (d, J = 8.4Hz, 2H), 7.93 (t, J = 7.6Hz, 4H), 7.64 (d, J = 8.4Hz, 2H), 7.51 (s, 1H), 7.39 (d, J = 8.4Hz, 2H), 7.14 (d, J = 8 .5Hz,2H),6.72(s,1H),6.53(s,1H),6.35(s,1H),5.37(s,1H),4.41(s,2 H), 4.13 (s, 1H), 4.07 (s, 1H), 3.13 (dd, J = 14.8, 7.4Hz, 2H), 1.30 (t, 3H).

[0495] Example 16: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzamide

[0496]

[0497] Step 1: Synthesis of 4-bromo-2-(4-(trifluoromethyl)phenoxy)thiazole

[0498] Under nitrogen, 2,4-dibromothiazole (1.82 g, 7.49 mmol), 4-(trifluoromethyl)phenol (1.02 g, 6.29 mmol), and K2CO3 (2.63 g, 19.10 mmol) were dissolved in DMF (20 mL) and stirred in an oil bath at 120°C for 12 h. TLC and LC-MS analysis indicated complete conversion of the starting material. The reaction mixture was diluted with EtOAc (80 mL), washed with saturated NaCl(aq.) (80 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to afford the product as a white solid (1.09 g, 53% yield).

[0499] MS(ESI,pos.ion)m / z=323.9[M+H] + .

[0500] Step 2: Synthesis of methyl 4-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate

[0501] Under nitrogen, (4-methoxycarbonylphenyl)boronic acid (1.10 g, 6.10 mmol), 4-bromo-2-(4-(trifluoromethyl)phenoxy)thiazole (1.09 g, 3.36 mmol), Pd(dppf)Cl2 (230 mg, 0.31 mmol), and Cs2CO3 (2.00 g, 6.10 mmol) were dissolved in 1,4-dioxane (10 mL) and heated in an oil bath at 100°C with stirring for 24 h. TLC confirmed complete conversion of the starting material. The reaction solution was evaporated to dryness under reduced pressure, and the residue was diluted with DCM (100 mL), washed successively with saturated NaHCO3 (aq.) (20 mL) and NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 10 / 1 / 1) to give the product as a yellow solid (1.10 g, yield: 86%).

[0502] MS(ESI,pos.ion)m / z=380.0[M+H] + .

[0503] Step 3: Synthesis of 4-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid

[0504] LiOH (143 mg, 5.96 mmol) was added to a solution of methyl 4-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (1.10 g, 2.90 mmol) in THF / H₂O (10 mL / 3 mL) and stirred in an oil bath at 60°C for 20 h. The mixture was concentrated under reduced pressure and the solvent removed. 1.0 M HCl (aq.) (20 mL) was added to the residue, and the aqueous phase was extracted with DCM (40 mL x 3). The combined organic phases were washed with saturated NaCl (aq.) (10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give the crude product as a yellow solid (1.06 g, 100% yield).

[0505] MS(ESI,pos.ion)m / z=366.4[M+H] + .

[0506] Step 4: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzamide

[0507] 4-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid (117 mg, 0.32 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (90 mg, 0.39 mmol), EDCI (130 mg, 0.68 mmol) and HOBT (90 mg, 0.67 mmol) were dissolved in DCM (4 mL), TEA (0.14 mL, 1.00 mmol) was added, and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM (80 mL) and then washed sequentially with 1.0 M HCl (aq.) (20 mL), saturated NaCl (aq.) (20 mL), and saturated Na2CO3 (aq.) (20 mL). It was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to obtain the product as a white solid (135 mg, yield: 73%). MS (ESI, pos. ion) m / z = 577.0 [M+H] + ;

[0508] 1 H NMR (400MHz, d6-DMSO) δ (ppm): 8.86 (d, J = 7.8Hz, 1H), 7.92-7.98 (m 3H),7.85-7.90(m,3H),7.84(d,J=8.3Hz,2H),7.67(d,J=7.4Hz,4H),5.16(dd,J=13.8,7.2Hz ,1H),5.06(t,J=5.4Hz,1H),3.79–3.68(m,2H),3.26(q,J=7.3Hz,2H),1.10(t,J=7.3Hz,3H);

[0509] 13 C NMR(151MHz,d6-DMSO)δ(ppm):170.98,165.80,157.66,147.77,147.57,137.12,136.21,133.60,1 28.08,128.05,127.75,127.73,127.70,125.40,120.54,111.17,64.06,55.79,49.19,40.06,7.14.

[0510] Example 17: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-((4-(trifluoromethyl)benzyl)oxy)thiazol-4-yl)benzamide

[0511]

[0512] Step 1: Synthesis of 4-bromo-2-((4-(trifluoromethyl)benzyl)oxy)thiazole

[0513] Under nitrogen, NaH (503 mg, 12.57 mmol, 60%) was added to a solution of (4-(trifluoromethyl)phenyl)methanol (1.0 g, 5.70 mmol) and 2,4-dibromothiazole (1.70 g, 7.00 mmol) in DMF (15 mL) at room temperature. The mixture was heated in an oil bath at 120°C with stirring for 24 h. TLC and LC-MS confirmed complete conversion of the starting material. The reaction mixture was diluted with EtOAc (80 mL), washed with saturated NaCl (aq.) (80 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to afford the desired product as a yellow solid (317 mg, 16% yield).

[0514] MS(ESI,pos.ion)m / z=338.0[M+H] + .

[0515] Step 2: Synthesis of methyl 4-(2-((4-(trifluoromethyl)benzyl)oxy)thiazol-4-yl)benzoate

[0516] Under nitrogen, (4-methoxycarbonylphenyl)boronic acid (340 mg, 1.89 mmol), 4-bromo-2-((4-(trifluoromethyl)benzyl)oxy)thiazole (316.6 mg, 0.94 mmol), Pd(dppf)Cl2 (72 mg, 0.098 mmol), and Cs2CO3 (612 mg, 1.88 mmol) were dissolved in 1,4-dioxane (6 mL) and heated in an oil bath at 100°C with stirring for 24 h. TLC confirmed complete conversion of the starting material. The reaction solution was evaporated to dryness under reduced pressure, and the residue was diluted with DCM (80 mL), washed successively with saturated NaHCO3 (aq.) (20 mL) and NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 5 / 1 / 1) to give the product as a yellow solid (120 mg, yield: 33%).

[0517] MS(ESI,pos.ion)m / z=394.5[M+H] + .

[0518] Step 3: Synthesis of 4-(2-((4-(trifluoromethyl)benzyl)oxy)thiazol-4-yl)benzoic acid

[0519] LiOH (23 mg, 0.96 mmol) was added to a solution of methyl 4-(2-((4-(trifluoromethyl)benzyl)oxy)thiazol-4-yl)benzoate (120 mg, 0.31 mmol) in THF / H2O ((3 mL / 1 mL)) and stirred in an oil bath at 60°C overnight for 10 h. The mixture was concentrated under reduced pressure to remove the solvent, and 1.0 M HCl (aq.) (10 mL) was added to the residue. The aqueous phase was then extracted with DCM (20 mL×3). The organic phases were combined and washed with saturated NaCl (aq.) (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product as a yellow solid (115 mg, yield: 99%).

[0520] MS(ESI,pos.ion)m / z=380.4[M+H] + .

[0521] Step 4: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-((4-(trifluoromethyl)benzyl)oxy)thiazol-4-yl)benzamide

[0522] 4-(2-((4-(trifluoromethyl)benzyl)oxy)thiazol-4-yl)benzoic acid (115 mg, 0.30 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (85 mg, 0.37 mmol), EDCI (120 mg, 0.63 mmol) and HOBT (84 mg, 0.62 mmol) were dissolved in DCM (4 mL), TEA (0.12 mL, 0.86 mmol) was added, and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM (80 mL) and then washed sequentially with 1.0 M HCl (aq.) (20 mL), saturated NaCl (aq.) (20 mL), and saturated Na2CO3 (aq.) (20 mL). It was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 2) to obtain the product as a yellow solid (99 mg, yield: 55%). MS (ESI, pos. ion) m / z = 591.1 [M+H] + ;

[0523] 1H NMR(400MHz,d6-DMSO)δ(ppm):8.88(d,J=7.8Hz,1H),7.93(d,J=8.3Hz,2H),7 .83(d,J=8.3Hz,2H),7.65(d,J=8.3Hz,4H),7.45(d,J=8.3Hz,2H),7.18(d,J= 8.1Hz,2H),6.68(s,1H),5.14(dd,J=13.6,7.3Hz,1H),5.04(t,J=5.8Hz,1H), 5.00(s,2H),3.79–3.64(m,2H),3.26(q,J=7.3Hz,2H),1.09(t,J=7.3Hz,3H).

[0524] Example 18: (R)-4-(5-cyclopropyl-2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0525]

[0526] Step 1: Synthesis of methyl 4-(5-bromo-2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzoate

[0527] NBS (980 mg, 5.51 mmol) was dissolved in DMF (5 mL), and the solution was slowly added dropwise to a solution of methyl 4-(2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzoate (1.65 g, 4.00 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 14 hours. After post-treatment, the mixture was dissolved in EA (50 mL), washed with saturated NaHCO₃ solution (50 mL x 2), washed with water (50 mL), and washed with saturated NaCl (aq.) (30 mL x 5), dried over anhydrous Na₂SO₄, and concentrated to give a pale yellow solid (1.70 g, 85% yield).

[0528] MS(ESI,pos.ion)m / z=457.9[M+H] + .

[0529] Step 2: Synthesis of methyl 4-(5-cyclopropyl-2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzoate

[0530] Methyl 4-(5-bromo-2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzoate (320 mg, 0.70 mmol), cyclopropylboronic acid (125 mg, 1.46 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride dichloromethane complex (47 mg, 0.056 mmol), and Cs2CO3 (367 mg, 1.13 mmol) in H2O (0.53 mL) were sequentially dissolved in toluene (2 mL). The atmosphere was replaced with nitrogen and the mixture was stirred at 90°C for 22 hours. LC-MS analysis confirmed the complete reaction and heating was discontinued. The product was extracted with EA (130 mL) and filtered through Celite. The filtrate was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was separated by silica gel column chromatography (PE / EA (v / v) = 5 / 1) to obtain a light yellow oily liquid (285 mg, 97% yield).

[0531] MS(ESI,pos.ion)m / z=418.0[M+H] + ;

[0532] 1 H NMR (400MHz, CDCl3) δ (ppm): 8.19 (d, J = 8.4Hz, 2H), 7.98 (d, J = 8.4Hz, 2H), 7.61 (d, J = 8.0Hz, 2H ),7.47(d,J=8.0Hz,2H),4.36(s,2H),2.19–2.09(m,1H),1.15–1.07(m,2H),0.73–0.66(m,2H).

[0533] Step 3: Synthesis of 4-(5-cyclopropyl-2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzoic acid

[0534] Methyl 4-(5-cyclopropyl-2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzoate (285 mg, 0.68 mmol) was dissolved in MeOH (4 mL), and a solution of NaOH (56 mg, 1.40 mmol) in H₂O (2 mL) was added. The mixture was stirred at room temperature. TLC indicated complete reaction. The pH was adjusted to 1 with 1M hydrochloric acid, and the mixture was dried by spin drying. The mixture was diluted with EA (120 mL), extracted, washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was separated by silica gel column chromatography (PE / DCM / EA (v / v / v) = 1 / 1) to give the product as a white solid (270 mg, 98% yield).

[0535] MS(ESI,pos.ion)m / z=404.0[M+H] + .

[0536] Step 4: Synthesis of (R)-4-(5-cyclopropyl-2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0537] 4-(5-Cyclopropyl-2-(4-(trifluoromethyl)benzyl)thiazol-4-yl)benzoic acid (170 mg, 0.42 mmol), (2R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (120 mg, 0.52 mmol), EDCI (162 mg, 0.84 mmol), and HOBT (113 mg, 0.84 mmol) were dissolved in DCM (6 mL). TEA (87 mg, 0.86 mmol) was added and stirred at room temperature for 24 hours. The mixture was diluted with DCM (100 mL), washed with saturated NaHCO₃ solution (30 mL), washed with saturated NaCl solution (30 mL), extracted with DCM, dried over anhydrous Na₂SO₄, and concentrated. The crude product was separated by silica gel column chromatography (DCM / EA (v / v) = 2 / 1) to give a white solid (150 mg, yield: 57.90%).

[0538] MS(ESI,pos.ion)m / z=615.2[M+H] + ;

[0539] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.94 (d, J = 8.4Hz, 2H), 7.90 (d, J = 8.5Hz, 2H), 7.85 (d, J = 8.3Hz, 2H), 7.6 0(d,J=8.0Hz,2H),7.55(d,J=8.2Hz,2H),7.45(d,J=8.0Hz,2H),7.32(d,J=6.8Hz,1H),5.22(dd,J=10 .7,4.7Hz,1H),4.32(s,2H),4.00(d,J=10.5Hz,1H),3.93(dd,J=10.8,4.8Hz,1H),3.08(q,J=7.4Hz, 2H), 2.09(ddd,J=13.4,8.3,5.2Hz,1H),1.27(t,J=5.9Hz,3H),1.12–1.05(m,2H),0.72–0.63(m,2H).

[0540] Example 19: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-((4-(trifluoromethyl)phenoxy)methyl)thiazol-4-yl)benzamide

[0541]

[0542] Step 1: Synthesis of methyl 4-(2-(hydroxymethyl)thiazol-4-yl)benzoate

[0543] Under nitrogen, (4-(methoxycarbonyl)phenyl)boronic acid (3.73 g, 20.70 mmol), (4-bromothiazol-2-yl)methanol (2.02 g, 10.40 mmol), Pd(dppf)Cl2 (750 mg, 1.03 mmol), and Cs2CO3 (6.84 g, 21.00 mmol) were dissolved in 1,4-dioxane (40 mL) and stirred in an oil bath at 100°C for approximately 24 h. LC-MS analysis confirmed complete conversion of the starting material. The reaction solution was evaporated to dryness under reduced pressure, and the residue was diluted with DCM (100 mL) and neutralized with 1.0 M HCl (aq.) to a pH of about 3. The mixture was filtered through Celite, and the filtrate was separated. The organic phase was washed with saturated NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 10) to give the product as a khaki solid (2.60 g, yield: 100%).

[0544] MS(ESI,pos.ion)m / z=250.4[M+H] + .

[0545] Step 2: Synthesis of methyl 4-(2-((4-(trifluoromethyl)phenoxy)methyl)thiazol-4-yl)benzoate

[0546] Under N2 protection, methyl 4-(2-(hydroxymethyl)thiazol-4-yl)benzoate (2.60 g, 10.40 mmol), 1-bromo-4-(trifluoromethyl)benzene (3.52 g, 15.61 mmol), Cs2CO3 (6.82 g, 20.90 mmol), Pd(OAc)2 (122 mg, 0.54 mmol) and t-Bu-XPhos (450 mg, 1.06 mmol) were dissolved in toluene (50 mL) and heated in an oil bath at 90°C with stirring for 24 h. The reaction mixture was diluted with DCM (120 mL), washed sequentially with H2O (50 mL) and NaCl (aq.) (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 10 / 1) to give the product as a yellow solid (845 mg, yield: 21%).

[0547] MS(ESI,pos.ion)m / z=394.0[M+H] + .

[0548] Step 3: Synthesis of 4-(2-((4-(trifluoromethyl)phenoxy)methyl)thiazol-4-yl)benzoic acid

[0549] LiOH·H₂O (204 mg, 4.86 mmol) was added to a solution of methyl 4-(2-((4-(trifluoromethyl)phenoxy)methyl)thiazol-4-yl)benzoate (845 mg, 2.15 mmol) in THF / H₂O (10 mL / 3 mL). The mixture was heated in an oil bath at 60°C with stirring overnight (10 h). TLC and LC-MS confirmed complete conversion of the starting material. The mixture was concentrated under reduced pressure, and 1.0 M HCl (aq.) was added to the residue until the pH reached 3. The mixture was then extracted with EtOAc (20 mL x 3). The organic phases were combined, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the crude product as a yellow solid (810 mg, 99% yield).

[0550] MS(ESI,pos.ion)m / z=380.0[M+H] + .

[0551] Step 4: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-((4-(trifluoromethyl)phenoxy)methyl)thiazol-4-yl)benzamide

[0552] 4-(2-((4-(trifluoromethyl)phenoxy)methyl)thiazol-4-yl)benzoic acid (125 mg, 0.33 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (94 mg, 0.41 mmol), EDCI (134 mg, 0.70 mmol) and HOBT (94 mg, 0.70 mmol) were dissolved in DCM (6 mL), TEA (0.14 mL, 1.00 mmol) was added, and the mixture was stirred at room temperature for 20 h. The reaction solution was diluted with DCM (80 mL), then washed sequentially with 1.0 M HCl (aq.) (20 mL), saturated NaCl (aq.) (20 mL), and saturated Na2CO3 (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) and separated by silica gel preparative chromatography (developing solvent: DCM / EtOAc (v / v) = 1 / 1) to give the product as a yellow solid (76 mg, yield: 39%).

[0553] MS(ESI,pos.ion)m / z=591.1[M+H] + ;

[0554] 1H NMR (400MHz, d6-DMSO) δ (ppm): 8.97 (d, J = 7.5Hz, 1H), 8.01-8.08 (m, 5H), 7.84 (d, J = 8.2Hz, 2H), 7.68 (d, J = 8.3Hz, 4H), 7.25 (d, J=8.5Hz,2H),5.53(s,2H),5.22–5.12(dd,1H),5.07(br,1H),3.81–3.66(m,2H),3.25(t,J=7.3Hz,2H),1.10(t,J=7.3Hz,3H).

[0555] Example 20: (R)-4-(5-ethyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0556]

[0557] Step 1: Synthesis of methyl 4-(5-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate

[0558] NBS (1.21 g, 6.80 mmol) was added to a solution of methyl 4-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (2.10 g, 5.54 mmol) in DMF (16 mL) and stirred at room temperature for 20 h. EtOAc (80 mL) was added to the reaction solution, which was then washed sequentially with saturated NaHCO₃(aq.) (10 mL) and saturated NaCl(aq.) (10 mL x 4), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 3 / 1 / 1) to give the product as a yellow solid (2.45 g, yield: 97%).

[0559] MS(ESI,pos.ion)m / z=457.9[M+H] + .

[0560] Step 2: Synthesis of methyl 4-(2-(4-(trifluoromethyl)phenoxy)-5-vinylthiazol-4-yl)benzoate

[0561] Under nitrogen, methyl 4-(5-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (800 mg, 1.75 mmol), potassium vinyl trifluoroborate (712 mg, 5.31 mmol), Pd(dppf)Cl2 (133 mg, 0.18 mmol), and K2CO3 (754 mg, 5.46 mmol) were dissolved in DMSO (10 mL) and stirred in an oil bath at 80°C for 24 h. Heating was discontinued. The reaction mixture was diluted with DCM (80 mL), washed sequentially with water (20 mL) and saturated NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to afford the product as a pale yellow oil (291 mg, 41% yield).

[0562] MS(ESI,pos.ion)m / z=406.1[M+H] + .

[0563] Step 3: Synthesis of methyl 4-(5-ethyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate

[0564] Pd / C (10%, 20 mg) was added to a solution of methyl 4-(2-(4-(trifluoromethyl)phenoxy)-5-vinylthiazol-4-yl)benzoate (121 mg, 0.30 mmol) in MeOH / THF (5 / 2 mL). The mixture was stirred at room temperature under a H2 atmosphere for 2 h. The mixture was filtered and the filtrate was concentrated to obtain the crude product as a pale yellow oil, which was used directly in the next reaction.

[0565] MS(ESI,pos.ion)m / z=408.2[M+H] + .

[0566] Step 4: Synthesis of 4-(5-ethyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid

[0567] LiOH·H₂O (48 mg, 1.14 mmol) was added to a solution of methyl 4-(5-ethyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (120 mg, 0.29 mmol) in THF / H₂O (3 / 1 mL) and stirred in an oil bath at 50°C for 3 h. The reaction mixture was diluted with EtOAc (60 mL) and then washed sequentially with 1.0 M HCl (aq.) (10 mL) and saturated NaCl (aq.) (10 mL). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford the crude product as a yellow solid (112 mg, 97% yield).

[0568] MS(ESI,pos.ion)m / z=394.1[M+H] + .

[0569] Step 5: Synthesis of (R)-4-(5-ethyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0570] 4-(5-Ethyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid (112 mg, 0.28 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (77 mg, 0.34 mmol), EDCI (110 mg, 0.57 mmol), and HOBT (80 mg, 0.59 mmol) were dissolved in DCM (4 mL). TEA (0.12 mL, 0.86 mmol) was then added and the mixture was stirred at room temperature for 12 h. TLC confirmed complete conversion of the starting material. The reaction solution was diluted with DCM (80 mL), then washed sequentially with 1.0 M HCl solution (20 mL), saturated NaCl (aq.) (20 mL), and saturated Na2CO3 (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2 / 1) to give the product as a white solid (82 mg, yield: 48%).

[0571] MS(ESI,pos.ion)m / z=605.2[M+H] + ;

[0572] 1 H NMR(400MHz,d6-DMSO)δ(ppm):8.86(d,J=7.8Hz,1H),7.97(d,J=8.4Hz,2H),7.88-7.83(m,4H),7.68-7.68(m,6H),5.16(dd,J=13.7,7.2Hz ,1H),5.05(t,J=5.8Hz,1H),3.80–3.67(m,2H),3.26(q,J=7.3Hz,2H),2.93(q,J=7.5Hz,2H),1.26(t,J=7.5Hz,3H),1.10(t,J=7.4Hz,3H).

[0573] Example 21: (R)-4-(5-cyclopropyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0574]

[0575] Step 1: Synthesis of methyl 4-(5-cyclopropyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate

[0576] Under nitrogen, methyl 4-(5-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (203 mg, 0.44 mmol), cyclopropylboronic acid (122 mg, 1.42 mmol), Pd(dppf)Cl2·DCM (43 mg, 0.053 mmol), and Cs2CO3 (432 mg, 1.33 mmol) were dissolved in toluene (8 mL) and stirred in an oil bath at 100°C for approximately 24 h. Heating was then discontinued. The reaction mixture was diluted with DCM (80 mL), washed sequentially with water (20 mL) and saturated NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to afford the product as a white solid (126 mg, 68% yield).

[0577] MS(ESI,pos.ion)m / z=420.0[M+H] + .

[0578] Step 2: Synthesis of 4-(5-cyclopropyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid

[0579] LiOH·H₂O (30 mg, 0.71 mmol) was added to a solution of methyl 4-(5-cyclopropyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (126 mg, 0.30 mmol) in THF / H₂O (3 / 1 mL) and stirred in an oil bath at 50°C for 3 h. The reaction solution was diluted with EtOAc (60 mL) and then washed sequentially with 1.0 M HCl (aq.) (10 mL) and saturated NaCl (aq.) (10 mL). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford the crude product as a yellow solid (97 mg, 80% yield).

[0580] MS(ESI,pos.ion)m / z=406.2[M+H] + .

[0581] Step 3: Synthesis of (R)-4-(5-cyclopropyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0582] 4-(5-Cyclopropyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid (97 mg, 0.23 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (67 mg, 0.29 mmol), EDCI (94 mg, 0.49 mmol) and HOBT (64 mg, 0.47 mmol) were dissolved in DCM (4 mL), and TEA (0.10 mL, 0.72 mmol) was added. The mixture was stirred at room temperature for 10 h. The conversion of the starting material was complete, as monitored by TLC. The reaction solution was diluted with DCM (80 mL), then washed sequentially with 1.0 M HCl solution (20 mL), saturated NaCl (aq.) (20 mL), and saturated Na2CO3 (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc / (v / v) = 2 / 1) to give the product as an off-white solid (72 mg, yield: 49%).

[0583] MS(ESI,pos.ion)m / z=617.2[M+H] + ;

[0584] 1 H NMR(400MHz,d6-DMSO)δ(ppm):8.87(d,J=7.7Hz,1H),7.98(d,J=8.5Hz,2H),7.91-7 .83(m,6H),7.68(d,J=8.3Hz,2H),7.63(d,J=8.4Hz,2H),5.19–5.13(m,1H),5.05(t ,J=5.7Hz,1H),3.75(qd,J=11.2,6.4Hz,2H),3.26(q,J=7.3Hz,2H),2.28–2.19(m,1 H),2.03–1.94(m,1H),1.10(t,J=7.3Hz,3H),0.88–0.80(m,1H),0.69–0.62(m,2H).

[0585] Example 22: (R)-4-(5-ethyl-2-((4-(trifluoromethyl)benzyl)oxy)-thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0586]

[0587] Step 1: Synthesis of methyl 4-(5-bromo-2-hydroxythiazol-4-yl)benzoate

[0588] NBS (470 mg, 2.64 mmol) was added to a solution of methyl 4-(2-hydroxythiazol-4-yl)benzoate (515 mg, 2.19 mmol) in DMF (8 mL) and stirred at room temperature for 3 h. EtOAc (80 mL) was added to the reaction solution, which was then washed sequentially with saturated NaHCO₃(aq.) (10 mL) and saturated NaCl(aq.) (10 mL x 4), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 3 / 1 / 1) to give the product as a yellow solid (505 mg, yield: 73%).

[0589] MS(ESI,pos.ion)m / z=313.8[M+H] + .

[0590] Step 2: Synthesis of methyl 4-(5-bromo-2-oxo-3-(4-(trifluoromethyl)benzyl)-2,3-dihydrothiazol-4-yl)benzoate

[0591] Under nitrogen, 1-(bromomethyl)-4-(trifluoromethyl)benzene (786 mg, 3.29 mmol) was added to a solution of methyl 4-(5-bromo-2-hydroxythiazol-4-yl)benzoate (505 mg, 1.61 mmol) and K₂CO₃ (900 mg, 6.52 mmol) in DMF (8 mL) and stirred at room temperature for 24 h. EtOAc (80 mL) was added to the reaction solution, which was then washed sequentially with H₂O (10 mL) and saturated NaCl (aq.) (10 mL x 5), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 3 / 1 / 1) to give the product as a yellow solid (316 mg, yield: 42%).

[0592] 1 H NMR (400MHz, CDCl3) δ (ppm): 8.11–8.03 (m, 2H), 7.48 (d, J = 8.1Hz, 2H), 7.22 (d, J = 8.4Hz, 2H), 7.00 (d, J = 8.0Hz, 2H), 4.83 (s, 2H), 3.96 (s, 3H).

[0593] Step 3: Synthesis of methyl 4-(2-oxo-3-(4-(trifluoromethyl)benzyl)-5-vinyl-2,3-dihydrothiazol-4-yl)benzoate

[0594] Under nitrogen protection, methyl 4-(5-bromo-2-oxo-3-(4-(trifluoromethyl)benzyl)-2,3-dihydrothiazol-4-yl)benzoate (146 mg, 0.31 mmol), potassium vinyl trifluoroborate (152 mg, 1.13 mmol), Pd(dppf)Cl2 (30 mg, 0.041 mmol) and K2CO3 (154 mg, 1.12 mmol) were dissolved in DMSO (4 mL) and heated in an oil bath at 80°C with stirring for about 24 h. The reaction mixture was cooled to room temperature and diluted with DCM (80 mL), then washed sequentially with water (20 mL) and saturated NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 5 / 1 / 1) to obtain the product as a yellow oily liquid (43 mg, yield: 33%). MS (ESI, pos. ion) m / z = 420.0 [M+H] + .

[0595] Step 4: Synthesis of methyl 4-(5-ethyl-2-oxo-3-(4-(trifluoromethyl)benzyl)-2,3-dihydrothiazol-4-yl)benzoate

[0596] Pd / C (30 mg, 10%) was added to a solution of methyl 4-(2-oxo-3-(4-(trifluoromethyl)benzyl)-5-vinyl-2,3-dihydrothiazol-4-yl)benzoate (43 mg, 0.10 mmol) in MeOH (2 mL). The mixture was stirred at room temperature under a H2 atmosphere for 2 h. The reaction mixture was filtered and the filtrate was concentrated to obtain the crude product as a pale yellow oil, which was used directly in the next reaction.

[0597] MS(ESI,pos.ion)m / z=422.1[M+H] + .

[0598] Step 5: Synthesis of 4-(5-ethyl-2-oxo-3-(4-(trifluoromethyl)benzyl)-2,3-dihydrothiazol-4-yl)benzoic acid

[0599] LiOH·H₂O (43 mg, 1.02 mmol) was added to a solution of methyl 4-(5-ethyl-2-oxo-3-(4-(trifluoromethyl)benzyl)-2,3-dihydrothiazol-4-yl)benzoate (43 mg, 0.10 mmol) in THF / H₂O (3 mL / 1 mL) and stirred in an oil bath at 50°C for 1 h. The reaction solution was diluted with EtOAc (60 mL) and then washed sequentially with 1.0 M HCl (aq.) (10 mL) and saturated NaCl (aq.) (10 mL). The organic phases were combined, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give the crude product as a yellow solid (40 mg, 96% yield).

[0600] MS(ESI,pos.ion)m / z=408.1[M+H] + .

[0601] Step 6: Synthesis of (R)-4-(5-ethyl-2-((4-(trifluoromethyl)benzyl)oxy)-thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0602] 4-(5-Ethyl-2-oxo-3-(4-(trifluoromethyl)benzyl)-2,3-dihydrothiazol-4-yl)benzoic acid (40 mg, 0.098 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (30 mg, 0.13 mmol), EDCI (44 mg, 0.23 mmol) and HOBT (34 mg, 0.25 mmol) were dissolved in DCM (4 mL), TEA (0.06 mL, 0.4 mmol) was added, and the mixture was stirred at room temperature for 12 h. The reaction solution was diluted with DCM (80 mL), then washed sequentially with 1.0 M HCl (aq.) (20 mL), saturated NaCl (aq.) (20 mL), and saturated Na2CO3 (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to give the product as a white solid (57 mg, yield: 94%).

[0603] MS(ESI,pos.ion)m / z=619.0[M+H] + ;

[0604] 1H NMR (400MHz, CDCl3) δ (ppm): 7.91 (d, J = 8.3Hz, 2H), 7.83 (d, J = 8.2Hz, 2H), 7.60 (d, J = 8.2Hz, 2H), 7. 48(d,J=8.0Hz,2H),7.17(d,J=8.2Hz,2H),7.09(d,J=7.0Hz,1H),7.03(d,J=8.0Hz,2H),5.34(dd,J= 10.7,4.1Hz,1H),4.77(s,2H),4.15–4.07(m,1H),4.03(dt,J=10.2,4.0Hz,1H),3.11(q,J=7.4Hz,2 H),2.36(q,J=7.5Hz,2H),2.03–1.98(t,J=4.8Hz,1H),1.29(t,J=7.4Hz,3H),1.10(t,J=7.5Hz,3H).

[0605] Example 23: (R)-4-(5-cyclopropyl-2-((4-(trifluoromethyl)benzyl)oxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0606]

[0607] Step 1: Synthesis of methyl 4-(5-cyclopropyl-2-oxo-3-(4-(trifluoromethyl)benzyl)-2,3-dihydrothiazol-4-yl)benzoate

[0608] Under nitrogen, methyl 4-(5-bromo-2-oxo-3-(4-(trifluoromethyl)benzyl)-2,3-dihydrothiazol-4-yl)benzoate (169 mg, 0.36 mmol), cyclopropylboronic acid (82 mg, 0.95 mmol), Pd(dppf)Cl2·DCM (30 mg, 0.037 mmol), and Cs2CO3 (312 mg, 0.96 mmol) were dissolved in toluene (4 mL) and heated in an oil bath at 100°C with stirring for approximately 24 h. The reaction mixture was cooled to room temperature. The reaction solution was diluted with DCM (80 mL), washed successively with water (20 mL) and saturated NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 5 / 1 / 1) to give the product as a yellow oil (68 mg, yield: 44%).

[0609] MS(ESI,pos.ion)m / z=434.2[M+H] + .

[0610] Step 2: Synthesis of 4-(5-cyclopropyl-2-oxo-3-(4-(trifluoromethyl)benzyl)-2,3-dihydrothiazol-4-yl)benzoic acid

[0611] LiOH·H₂O (30 mg, 0.71 mmol) was added to a solution of methyl 4-(5-cyclopropyl-2-oxo-3-(4-(trifluoromethyl)benzyl)-2,3-dihydrothiazol-4-yl)benzoate (68 mg, 0.16 mmol) in THF / H₂O (3 mL / 1 mL) and stirred in an oil bath at 50°C for 3 h. The reaction solution was diluted with EtOAc (60 mL) and then washed sequentially with 1.0 M HCl (aq.) (10 mL) and saturated NaCl (aq.) (10 mL). The organic phases were combined, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give the crude product as a yellow solid (65 mg, 99% yield).

[0612] MS(ESI,pos.ion)m / z=420.0[M+H] + .

[0613] Step 3: Synthesis of (R)-4-(5-cyclopropyl-2-oxo-3-(4-(trifluoromethyl)benzyl)-2,3-dihydrothiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0614] 4-(5-Cyclopropyl-2-oxo-3-(4-(trifluoromethyl)benzyl)-2,3-dihydrothiazol-4-yl)benzoic acid (68 mg, 0.16 mmol), (2R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (45 mg, 0.20 mmol), EDCI (74 mg, 0.39 mmol) and HOBT (54 mg, 0.40 mmol) were dissolved in DCM (4 mL), TEA (0.08 mL, 0.6 mmol) was added, and the mixture was stirred at room temperature for 12 h. The reaction solution was diluted with DCM (80 mL), then washed sequentially with 1.0 M HCl (aq.) (20 mL), saturated NaCl (aq.) (20 mL), and saturated Na2CO3 (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to give the product as a white solid (54 mg, yield: 53%).

[0615] MS(ESI,pos.ion)m / z=631.0[M+H] + ;

[0616] 1H NMR (400MHz, CDCl3) δ (ppm): 7.91 (d, J = 8.3Hz, 2H), 7.84 (d, J = 8.3Hz, 2H), 7.60 (d, J = 8.2Hz, 2H), 7. 48(d,J=8.1Hz,2H),7.28(s,2H),7.09(d,J=7.1Hz,1H),7.04(d,J=8.0Hz,2H),5.38–5.31(m,1H),4. 80(s,2H),4.16–4.07(m,1H),4.07–3.99(m,1H),3.11(q,J=7.4Hz,2H),1.99(t,J=5.6Hz,1H),1.64( ddd,J=13.2,6.5,3.3Hz,1H),1.29(t,J=7.4Hz,3H),0.79–0.73(m,2H),0.55(dt,J=6.6,5.0Hz,2H).

[0617] Example 24: (R)-6-(5-ethyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)nicotinamide

[0618]

[0619] Step 1: Synthesis of methyl 6-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinate

[0620] Under nitrogen protection, 4-bromo-2-(4-(trifluoromethyl)phenoxy)thiazole (100 mg, 0.31 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (80 mg, 0.32 mmol), methyl 6-chloronicotinate (55 mg, 0.32 mmol), Pd(dppf)Cl2 (30 mg, 0.041 mmol) and Cs2CO3 (250 mg, 0.77 mmol) were dissolved in 1,4-dioxane (2 mL) and heated in an oil bath at 80 °C for 12 h. The reaction was cooled to room temperature, water (20 mL) was added to the reaction solution, and the aqueous phase was extracted with DCM (40 mL × 3). The organic phases were combined and washed with saturated NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 10 / 1 / 1) to give the target product as a yellow solid (26 mg, yield: 22%).

[0621] MS(ESI,pos.ion)m / z=381.0[M+H] +.

[0622] Step 2: Synthesis of methyl 6-(5-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinate

[0623] NBS (102 mg, 0.57 mmol) was added to a solution of methyl 6-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinate (171 mg, 0.45 mmol) in DMF (3 mL) and stirred at room temperature for 15 h. EtOAc (80 mL) was added to the reaction solution, which was then washed sequentially with saturated NaHCO (aq.) (10 mL) and saturated NaCl (aq.) (10 mL x 4), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product as a yellow solid (206 mg, 100% yield).

[0624] MS(ESI,pos.ion)m / z=459.0[M+H] + .

[0625] Step 3: Synthesis of methyl 6-(2-(4-(trifluoromethyl)phenoxy)-5-vinylthiazol-4-yl)nicotinate

[0626] Under nitrogen, methyl 6-(5-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinate (100 mg, 0.22 mmol), potassium vinyl trifluoroborate (92 mg, 0.69 mmol), Pd(dppf)Cl2 (23 mg, 0.031 mmol), and K2CO3 (94 mg, 0.68 mmol) were dissolved in DMSO (3 mL) and heated in an 80°C oil bath with stirring for approximately 21 h. LC-MS monitoring revealed a small amount of starting material remaining. The reaction mixture was diluted with EtOAc (80 mL), washed sequentially with water (20 mL) and saturated NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to obtain the target compound as a light yellow solid (24 mg, yield: 27%). MS (ESI, pos. ion) m / z = 407.0 [M+H] + .

[0627] Step 4: Synthesis of methyl 6-(5-ethyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinate

[0628] Pd / C (23 mg, 10%) was added to a solution of methyl 6-(2-(4-(trifluoromethyl)phenoxy)-5-vinylthiazol-4-yl)nicotinate (24 mg, 0.059 mmol) in MeOH (3 mL). The mixture was stirred at room temperature under a H atmosphere for 4 h. The mixture was filtered and the filtrate was concentrated to afford the crude product as a yellow solid (19 mg, 79% yield).

[0629] MS(ESI,pos.ion)m / z=409.1[M+H] + .

[0630] Step 5: Synthesis of 6-(5-ethyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinic acid

[0631] LiOH·H₂O (34 mg, 0.81 mmol) was added to a solution of methyl 6-(5-ethyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinate (19 mg, 0.047 mmol) in THF / H₂O (3 mL / 1 mL). The mixture was heated in an oil bath at 50°C with stirring for 2 h. TLC confirmed complete conversion of the starting material. The reaction mixture was adjusted to pH 3-4 by adding 6.0 M HCl(aq.) / isopropanol solution. The mixture was concentrated under reduced pressure and filtered to afford the crude product as a yellow solid (18 mg, 98% yield).

[0632] MS(ESI,pos.ion)m / z=395.0[M+H] + .

[0633] Step 6: Synthesis of (R)-6-(5-ethyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)nicotinamide

[0634] 6-(5-ethyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinic acid (18 mg, 0.046 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (20 mg, 0.087 mmol), EDCI (46 mg, 0.24 mmol), and HOBT (34 mg, 0.25 mmol) were dissolved in DCM (3 mL). TEA (0.04 mL, 0.3 mmol) was added and the mixture was stirred at room temperature for 10 h. LC-MS monitoring indicated that the starting material was substantially converted to the desired product. Saturated NaHCO3 (aq.) (20 mL) was added to the reaction solution, and the aqueous phase was extracted with DCM (30 mL × 3). The organic phases were combined and washed with saturated NaCl (aq.) (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to obtain the target product as a yellow solid (10 mg, yield: 36%).

[0635] MS(ESI,pos.ion)m / z=606.8[M+H] + .

[0636] Example 25: (R)-6-(5-cyclopropyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)nicotinamide

[0637]

[0638] Step 1: Synthesis of methyl 6-(5-cyclopropyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinate

[0639] Under nitrogen, methyl 6-(5-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinate (103 mg, 0.22 mmol), cyclopropylboronic acid (112 mg, 1.30 mmol), Pd(dppf)Cl2·DCM (23 mg, 0.028 mmol), and Cs2CO3 (212 mg, 0.65 mmol) were dissolved in toluene (3 mL) and stirred in an oil bath at 100°C for approximately 24 h. The reaction mixture was diluted with DCM (80 mL), washed sequentially with water (20 mL) and saturated NaCl(aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to afford the product as a pale yellow solid (24 mg, 25% yield).

[0640] MS(ESI,pos.ion)m / z=421.1[M+H]+ .

[0641] Step 2: Synthesis of 6-(5-cyclopropyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinic acid

[0642] LiOH·H₂O (44 mg, 1.05 mmol) was added to a solution of methyl 6-(5-cyclopropyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinate (24 mg, 0.057 mmol) in THF / H₂O (3 mL / 1 mL). The reaction was stirred at 50°C for 1.5 h. TLC confirmed complete conversion of the starting material. 6M HCl (aq.) in isopropanol was added to the reaction mixture to adjust the pH to 3, and the mixture was concentrated under reduced pressure to afford the crude product as a yellow solid (23 mg, 99%).

[0643] MS(ESI,pos.ion)m / z=407.0[M+H] + .

[0644] Step 3: Synthesis of (R)-6-(5-cyclopropyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)nicotinamide

[0645] 6-(5-Cyclopropyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinic acid (23 mg, 0.056 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (20 mg, 0.087 mmol), EDCI (56 mg, 0.29 mmol) and HOBT (40 mg, 0.30 mmol) were dissolved in DCM (3 mL), and TEA (0.04 mL, 0.30 mmol) was added and stirred at room temperature for 3 h. Saturated NaHCO3 (aq.) (20 mL) was added to the reaction solution, and the aqueous phase was extracted with DCM (30 mL×3). The organic phases were combined and washed with saturated NaCl (aq.) (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to give the product as a yellow solid (24 mg, yield: 69%).

[0646] MS(ESI,pos.ion)m / z=618.0[M+H] + ;

[0647] 1H NMR (400MHz, d6-DMSO) δ (ppm): 9.11 (d, J = 1.6 Hz, 1H), 9.04 ( d, J = 7.8 Hz, 1H), 8.30 ( dd, J = 8.3, 2.3H z,1H),7.89(d,J=8.1Hz,2H),7.85(d,J=8.7Hz,3H),7.69(d,J=8.3Hz,2H),7.64(d,J=8.6Hz,2H), 5.17(dd,J=13.4,7.1Hz,1H),5.08(t,J=5.9Hz,1H),3.79–3.67(m,2H),3.26(q,J=7.3Hz,,2H),2. 02–1.94(m,1H),1.17(dd,J=14.0,5.7Hz,2H),1.10(t,J=7.3Hz,3H),0.68(dd,J=7.8,4.9Hz,2H).

[0648] Example 26: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinamide

[0649]

[0650] Step 1: Synthesis of 6-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinic acid

[0651] LiOH·H₂O (30 mg, 0.71 mmol) was added to a solution of methyl 6-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinate (26 mg, 0.068 mmol) in THF / H₂O (3 mL / 1 mL) and stirred in an oil bath at 50°C for 4 h. The reaction mixture was diluted with EtOAc (60 mL) and then washed sequentially with 1.0 M HCl (aq.) (10 mL) and saturated NaCl (aq.) (10 mL). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford the crude product as a yellow solid (25 mg, 99% yield).

[0652] MS(ESI,pos.ion)m / z=367.1[M+H] + .

[0653] Step 2: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinamide

[0654] 6-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinic acid (25 mg, 0.068 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (25 mg, 0.11 mmol), EDCI (34 mg, 0.18 mmol), and HOBT (24 mg, 0.18 mmol) were dissolved in DCM (4 mL). TEA (0.04 mL, 0.30 mmol) was added, and the mixture was stirred at room temperature for 12 h. TLC confirmed complete conversion of the starting material. The reaction solution was diluted with DCM (80 mL), washed successively with saturated Na2CO3 (aq.) (20 mL) and saturated NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc / MeOH (v / v / v) = 10 / 10 / 1) and silica gel thin layer chromatography (developing solvent: DCM / EtOAc / EtOH (v / v / v) = 10 / 10 / 1) to give the product as a yellow solid (20 mg, yield: 51%).

[0655] MS(ESI,pos.ion)m / z=578.0[M+H] + ;

[0656] 1 H NMR(600MHz,d6-DMSO)δ(ppm):9.07(d,J=1.7Hz,1H),8.80(d,J=7.4Hz,1H),8.25( dd,J=8.2,1.9Hz,1H),7.87(d,J=8.2Hz,1H),7.84(s,1H),7.77(d,J=8.2Hz,2H),7 .70(d,J=8.7Hz,2H),7.62(d,J=8.3Hz,1H),7.52(d,J=8.6Hz,2H),5.90(d,J=4.9H z, 1H), 3.79 (dd, J = 10.7, 5.9Hz, 2H), 3.07 (q, J = 7.3Hz, 2H), 1.16 (t, J = 7.4Hz, 3H).

[0657] Example 27: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(5-methyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzamide

[0658]

[0659] Step 1: Synthesis of 4-bromo-5-methyl-2-(4-(trifluoromethyl)phenoxy)thiazole

[0660] Under nitrogen, 2,4-dibromo-5-methylthiazole (2.43 g, 9.46 mmol), 4-(trifluoromethyl)phenol (1.03 g, 6.35 mmol), and K2CO3 (2.64 g, 19.1 mmol) were dissolved in DMF (12 mL) and stirred in an oil bath at 120°C for 24 h. EtOAc (100 mL) was added to the reaction solution, which was then washed sequentially with water (20 mL × 3) and saturated NaCl (aq.) (15 mL × 5), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to give the product as a yellow liquid (1.66 g, yield: 77%).

[0661] MS(ESI,pos.ion)m / z=337.8[M+H] + .

[0662] Step 2: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

[0663] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (500 mg, 2.00 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (554 mg, 2.20 mmol), EDCI (778 mg, 4.06 mmol), and HOBT (550 mg, 4.07 mmol) were dissolved in DCM (10 mL). TEA (0.86 mL, 6.20 mmol) was added and the mixture was stirred at room temperature for 3 h. LC-MS monitoring indicated that the starting material was substantially converted to the desired product. The reaction mixture was diluted with DCM (80 mL), then washed with saturated NaHCO₃ (aq.) (30 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to obtain the desired product as a yellow solid (643 mg, yield: 69%). MS (ESI, pos. ion) m / z = 459.9 [M+H] + .

[0664] Step 3: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(5-methyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzamide

[0665] Under nitrogen, 4-bromo-5-methyl-2-(4-(trifluoromethyl)phenoxy)thiazole (102 mg, 0.30 mmol), (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (163 mg, 0.35 mmol), Pd(dppf)Cl2 (23 mg, 0.031 mmol) and Cs2CO3 (193 mg, 0.59 mmol) were dissolved in 1,4-dioxane (4 mL). The reaction was stirred in an oil bath at 80 °C for 24 h, and then the heating was stopped. The reaction solution was removed by concentration under reduced pressure, and the residue was diluted with DCM (80 mL) and washed successively with saturated NaHCO3 (aq.) (20 mL) and NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2 / 1) and silica gel thin layer chromatography (developing solvent: DCM / EtOAc (v / v) = 2 / 1) to give the product as a yellow solid (20 mg, yield: 11%).

[0666] MS(ESI,pos.ion)m / z=591.1[M+H] + ;

[0667] 1 H NMR (400MHz, d6-DMSO) δ (ppm): 8.85 (d, J = 7.7Hz, 1H), 7.97 (d, J = 8.4Hz, 2H), 7.85 (t, J = 8.4Hz, 4H), 7.70 (d, J = 8.4Hz, 2H), 7.67 (d, J = 8.4Hz, 2H), 7. 63(d,J=8.4Hz,2H),5.19–5.13(m,1H),5.03(t,J=5.8Hz,1H),3.80–3.68 (m,2H),3.28–3.23((q,J=7.4Hz,2H),2.53(s,3H),1.10(t,J=7.4Hz,3H).

[0668] Example 28: (R)-4-(5-(difluoromethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0669]

[0670] Step 1: Synthesis of 4-bromo-2-(4-(trifluoromethyl)phenoxy)thiazole-5-carboxaldehyde

[0671] Under nitrogen, 2,4-dibromothiazole-5-carbaldehyde (12.00 g, 44.30 mmol), 4-(trifluoromethyl)phenol (4.00 g, 25.00 mmol), and K2CO3 (10.30 g, 74.60 mmol) were dissolved in DMF (50 mL) and stirred in an oil bath at 60°C for 5 h. TLC and LC-MS analysis indicated complete conversion of the starting material. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated NaCl(aq.) (20 mL x 5), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to afford the product as a yellow liquid (5.36 g, yield: 62%).

[0672] MS(ESI,pos.ion)m / z=351.9[M+H] + .

[0673] Step 2: Synthesis of methyl 4-(5-formyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate

[0674] Under nitrogen, (4-(methoxycarbonyl)phenyl)boronic acid (2.0 g, 11.0 mmol), 4-bromo-2-(4-(trifluoromethyl)phenoxy)thiazole-5-carbaldehyde (2.09 g, 5.94 mmol), Pd(dppf)Cl2 (450 mg, 0.62 mmol), and Cs2CO3 (4.0 g, 12.0 mmol) were dissolved in 1,4-dioxane (20 mL) and heated with stirring in an oil bath at 100°C for 3.5 h. TLC indicated complete conversion. The reaction solution was evaporated under reduced pressure, and DCM (100 mL) was added to the residue. The product was washed with saturated NaHCO (aq.) (20 mL) and NaCl (aq.) (20 mL) in sequence, dried over anhydrous Na SO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to give the product as a yellow solid (1.56 g, yield: 65%).

[0675] MS(ESI,pos.ion)m / z=408.0[M+H] + .

[0676] Step 3: Synthesis of methyl 4-(5-(difluoromethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate

[0677] DAST (0.20 mL, 1.50 mmol) was slowly added to a solution of methyl 4-(5-formyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (200 mg, 0.49 mmol) in DCM (3 mL) at room temperature and stirred for 6 h. LC-MS analysis revealed a small amount of starting material remaining. The reaction was quenched by the addition of saturated NaHCO₃(aq.) (20 mL). The aqueous phase was then extracted with DCM (30 mL x 3). The combined organic phases were washed with saturated NaCl(aq.) (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to afford the product as a yellow solid (144 mg, 68% yield).

[0678] MS(ESI,pos.ion)m / z=429.9[M+H] + .

[0679] Step 4: Synthesis of 4-(5-(difluoromethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid

[0680] LiOH·H₂O (34 mg, 0.81 mmol) was added to a solution of methyl 4-(5-(difluoromethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (109 mg, 0.25 mmol) in THF / H₂O (3 / 1 mL). The mixture was heated in an oil bath at 50°C with stirring for 2.5 h. Water (20 mL) was added to the reaction solution, and the pH was adjusted to 3 with 1.0 M HCl (aq.). The aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the crude product as a yellow solid (105 mg, 100% yield).

[0681] MS(ESI,pos.ion)m / z=416.1[M+H] + .

[0682] Step 5: Synthesis of (R)-4-(5-(difluoromethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0683] 4-(5-(difluoromethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid (138 mg, 0.33 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (94 mg, 0.41 mmol), EDCI (256 mg, 1.34 mmol), and HOBT (180 mg, 1.33 mmol) were dissolved in DCM (5 mL), and TEA (0.14 mL, 1.0 mmol) was added, and the mixture was stirred at room temperature. The reaction was monitored by TLC. The reaction solution was diluted with DCM (80 mL), then washed sequentially with 1.0 M HCl solution (20 mL), saturated NaCl (aq.) (20 mL), and saturated NaHCO 3 (aq.) (20 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2 / 1) to give the product as a light yellow solid (130 mg, yield: 62%).

[0684] MS(ESI,pos.ion)m / z=627.0[M+H] + ;

[0685] 1 H NMR(400MHz,d6-DMSO)δ(ppm):8.94(d,J=7.8Hz,1H),8.03(d,J=8.2Hz,2H), 7.91(d,J=8.6Hz,2H),7.85(d,J=8.2Hz,2H),7.75(d,J=8.5Hz,2H),7.67(d,J =8.0Hz,4H),7.38(t,J=53.4Hz,1H),5.17(dd,J=13.6,6.8Hz,1H),5.06(t,J =5.7Hz,1H),3.81–3.68(m,2H),3.26(q,J=7.3Hz,2H),1.10(t,J=7.3Hz,3H);

[0686] 13 C NMR(151MHz,d6-DMSO)δ(ppm):171.88,166.12,157.42,149.85,149.80,149.75,147.91,137.61,135.39,135.24,128.85 ,128.53,128.47,128.24,128.22,127.44(q),125.23,123.43,121.70,120.85(t),111.47(t),64.51,56.31,49.66,7.57.

[0687] Example 29: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(5-(hydroxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzamide

[0688]

[0689] Step 1: Synthesis of methyl 4-(5-(hydroxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate

[0690] NaBH4 (30 mg, 0.79 mmol) was added to a solution of methyl 4-(5-formyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (315 mg, 0.77 mmol) in MeOH / THF (7 / 3 mL) at -20°C and stirred for 1 h. TLC indicated complete conversion of the starting material. The reaction was quenched by the addition of saturated NaHCO3 (aq.) (20 mL). The aqueous phase was then extracted with DCM (20 mL x 3). The combined organic phases were washed with saturated NaCl (aq.) (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product as a light yellow solid (314 mg, 99% yield), which was used directly in the next reaction.

[0691] MS(ESI,pos.ion)m / z=409.9[M+H] + .

[0692] Step 2: Synthesis of 4-(5-(hydroxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid

[0693] LiOH·H₂O (69 mg, 1.64 mmol) was added to a solution of methyl 4-(5-(hydroxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (214 mg, 0.52 mmol) in THF / H₂O (3 / 1 mL). The mixture was heated in a 50°C oil bath with stirring for 2 h. TLC confirmed complete conversion of the starting material. Water (15 mL) was added to the reaction solution, followed by the dropwise addition of 1.0 M HCl (aq.) to adjust the pH to 3. The aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford the crude product as a yellow solid (206 mg, 100% yield).

[0694] MS(ESI,pos.ion)m / z=395.8[M+H] + .

[0695] Step 3: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(5-(hydroxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzamide

[0696] 4-(5-(Hydroxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid (61 mg, 0.15 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (54 mg, 0.24 mmol), EDCI (138 mg, 0.72 mmol) and HOBT (94 mg, 0.70 mmol) were dissolved in DCM (4 mL), and TEA (0.12 mL, 0.86 mmol) was added and stirred at room temperature for 10 h. The reaction mixture was diluted with DCM (80 mL) and then washed sequentially with 1.0% HCl (aq.) (10 mL), saturated NaCl (aq.) (15 mL), and saturated NaHCO 3 (aq.) (20 mL). It was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2 / 3) to obtain the product as a yellow solid (76 mg, yield: 81%). MS (ESI, pos. ion) m / z = 607.1 [M+H] + ;

[0697] 1 H NMR(400MHz,d6-DMSO)δ(ppm):8.87(d,J=7.8Hz,1H),7.97(d,J=8.2Hz,2H),7.88(d, J=8.7Hz,2H),7.84(d,J=8.3Hz,2H),7.67(d,J=8.2Hz,4H),7.64(d,J=8.8Hz,2H),5. 97(t,J=5.3Hz,1H),5.16(dd,J=13.7,7.0Hz,1H),5.06(t,J=5.8Hz,1H),4.74(d,J=5 .2Hz,2H),3.73(td,J=11.6,5.9Hz,2H),3.26(q,J=7.3Hz,2H),1.10(t,J=7.3Hz,3H).

[0698] Example 30: (R)-4-(5-acetyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0699]

[0700] Step 1: Synthesis of 1-(4-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-5-yl)ethanol

[0701] MeMgBr in Et2O (1.50 mL, 4.50 mmol) was added to a solution of 4-bromo-2-(4-(trifluoromethyl)phenoxy)thiazole-5-carbaldehyde (998 mg, 2.83 mmol) in THF (10 mL) with stirring at -60°C. The mixture was stirred at low temperature for 2 h and then allowed to warm to room temperature. The reaction mixture was quenched by the addition of saturated NaHCO3 (aq.) (20 mL). The aqueous phase was then extracted with DCM (50 mL x 3). The combined organic phases were washed with saturated NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product as a yellow oil (1.04 g, 100% yield).

[0702] MS(ESI,pos.ion)m / z=368.0[M+H] + .

[0703] Step 2: Synthesis of 1-(4-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-5-yl)ethanone

[0704] DMP (4.0 g, 9.4 mmol) was added to a solution of 1-(4-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-5-yl)ethanol (1.04 g, 2.82 mmol) in DCM (10 mL) at room temperature and stirred for 14 h. The mixture was filtered through celite and washed with DCM. The filtrate was dried over saturated NaCO (aq.) (20 mL) and anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to give the product as a yellow solid (896 mg, 87% yield).

[0705] MS(ESI,pos.ion)m / z=366.0[M+H] + .

[0706] Step 3: Synthesis of methyl 4-(5-acetyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate

[0707] Under nitrogen protection, (4-(methoxycarbonyl)phenyl)boronic acid (303 mg, 1.68 mmol), 1-(4-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-5-yl)ethanone (300 mg, 0.82 mmol), Pd(dppf)Cl2 (60 mg, 0.082 mmol) and Cs2CO3 (534 mg, 1.64 mmol) were dissolved in 1,4-dioxane (4 mL) and the reaction was heated in an oil bath at 95 °C with stirring for 12 h. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was diluted with DCM (80 mL) and washed sequentially with saturated NaHCO (aq.) (20 mL) and NaCl (aq.) (20 mL), dried over anhydrous Na SO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to obtain the product as a yellow solid (262 mg, yield: 76%). MS (ESI, pos. ion) m / z = 422.1 [M+H] + .

[0708] Step 4: Synthesis of 4-(5-(1-hydroxyethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid

[0709] NaBH4 (12 mg, 0.32 mmol) was added to a solution of methyl 4-(5-acetyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (131 mg, 0.31 mmol) in MeOH (3 mL) at -20°C and stirred for 30 min. Saturated NaHCO3 (aq.) (20 mL) was added to the reaction solution to quench the reaction. The aqueous phase was then extracted with DCM (20 mL x 3). The combined organic phases were washed with saturated NaCl (aq.) (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product as a light yellow, transparent oil.

[0710] LiOH·H₂O (44 mg, 1.05 mmol) was added to a solution of the above crude product (130 mg, 0.31 mmol) in THF / H₂O (3 / 1 mL). The mixture was heated in an oil bath at 50°C with stirring for 2.5 h. Water (20 mL) was added to the reaction solution, and the pH was adjusted to 3 with 1.0 M HCl (aq.). The aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the crude product as a yellow solid (125 mg, 99% yield).

[0711] MS(ESI,pos.ion)m / z=410.0[M+H] + .

[0712] Step 5: Synthesis of 4-(5-acetyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid

[0713] DMP (400 mg, 0.94 mmol) was added to a solution of 4-(5-(1-hydroxyethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid (125 mg, 0.31 mmol) in DCM (4 mL) at room temperature and stirred for 24 h. TLC indicated complete conversion of the starting material. The mixture was filtered through celite and washed with DCM. The filtrate was concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2 / 1) to afford the product as a white solid (107 mg, 86% yield).

[0714] MS(ESI,pos.ion)m / z=408.1[M+H] + .

[0715] Step 6: Synthesis of (R)-4-(5-acetyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0716] 4-(5-Acetyl-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid (107 mg, 0.26 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (74 mg, 0.32 mmol), EDCI (206 mg, 1.07 mmol) and HOBT (150 mg, 1.11 mmol) were dissolved in DCM (5 mL), and TEA (0.12 mL, 0.86 mmol) was added and stirred at room temperature for 5 h. The reaction mixture was diluted with DCM (80 mL) and then washed sequentially with 1.0% HCl (aq.) (10 mL), saturated NaCl (aq.) (15 mL), and saturated NaHCO 3 (aq.) (20 mL). It was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 3 / 2) to obtain the product as a pink solid (104 mg, yield: 64%). MS (ESI, pos. ion) m / z = 619.0 [M+H] + ;

[0717] 1H NMR(400MHz,d6-DMSO)δ(pm):8.95(d,J=7.8Hz,1H),7.99(d,J=8.3Hz,2H),7.91(d,J=8.7Hz,2H),7.84(d,J=8.3Hz,2H),7.72(d,J=8.3Hz,4H),7.68 (d,J=8.3Hz,2H),5.17(dd,J=13.8,7.3Hz,1H),5.07(t,J=5.8Hz,1H),3.8 1–3.66(m,2H),3.26(q,J=7.3Hz,,2H),2.15(s,3H),1.10(t,J=7.3Hz,3H).

[0718] Example 31: (R)-4-(4-((1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)carbamoyl)phenyl)-N-methoxy-N-methyl-2-(4-(trifluoromethyl)phenoxy)thiazole-5-carboxamide

[0719]

[0720] Step 1: Synthesis of 4-bromo-2-(4-(trifluoromethyl)phenoxy)thiazole-5-carboxylic acid

[0721] Potassium hydrogen persulfate (3.00 g, 4.90 mmol) was added to a solution of 4-bromo-2-(4-(trifluoromethyl)phenoxy)thiazole-5-carbaldehyde (591 mg, 1.68 mmol) in DMF (10 mL) under cooling at 0°C. The reaction was stirred at room temperature overnight (11 h). TLC and LC-MS analysis showed substantial conversion of the starting material to the desired product. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated NaCl (aq.) (20 mL x 6), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to afford the product as a yellow solid (612 mg, 99% yield).

[0722] MS(ESI,pos.ion)m / z=567.7[M+H] + .

[0723] Step 2: Synthesis of 4-bromo-N-methoxy-N-methyl-2-(4-(trifluoromethyl)phenoxy)thiazole-5-carboxamide

[0724] 4-Bromo-2-(4-(trifluoromethyl)phenoxy)thiazole-5-carboxylic acid (200 mg, 0.54 mmol), dimethylhydroxylamine hydrochloride (64 mg, 0.66 mmol), EDCI (208 mg, 1.08 mmol), and HOBT (150 mg, 1.11 mmol) were dissolved in DCM (5 mL), and TEA (0.60 mL, 4.3 mmol) was added. The mixture was stirred at room temperature for 12 h. Saturated NaHCO₃(aq.) (20 mL) was added to the reaction mixture, and the aqueous phase was extracted with DCM (20 mL x 3). The combined organic phases were washed with saturated NaCl(aq.) (10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to obtain the desired product as a yellow solid (65 mg, yield: 29%).

[0725] MS(ESI,pos.ion)m / z=411.0[M+H] + .

[0726] Step 3: Synthesis of (R)-4-(4-((1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)carbamoyl)phenyl)-N-methoxy-N-methyl-2-(4-(trifluoromethyl)phenoxy)thiazole-5-carboxamide

[0727] Under nitrogen, (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (112 mg, 0.24 mmol), 4-bromo-N-methoxy-N-methyl-2-(4-(trifluoromethyl)phenoxy)thiazole-5-carboxamide (67 mg, 0.16 mmol), Pd(dppf)Cl2 (27 mg, 0.037 mmol), and Cs2CO3 (114 mg, 0.35 mmol) were dissolved in 1,4-dioxane (4 mL). The reaction was stirred in an oil bath at 80°C for approximately 12 h. LC-MS analysis indicated complete conversion of the starting material. The reaction solution was removed by concentration under reduced pressure, and the residue was diluted with DCM (80 mL) and washed successively with saturated NaHCO3 (aq.) (20 mL) and NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) and silica gel thin layer chromatography (developing solvent: DCM / EtOAc (v / v) = 2 / 3) to give the product as a yellow solid (40 mg, yield: 37%).

[0728] MS(ESI,pos.ion)m / z=664.8[M+H] + ;

[0729] 1 H NMR (400MHz, d6-DMSO) δ (ppm): 8.87 (d, J = 7.9 Hz, 1H), 7.92 ( d, J = 4.3 Hz, 2H), 7.90 ( d,J=4.5Hz,2H),7.84(d,J=8.4Hz,2H),7.73(d,J=8.6Hz,2H),7.67(d,J=8.3Hz,2H) ,7.62(d,J=8.4Hz,2H),5.15(dd,J=13.5,7.3Hz,1H),5.06(t,J=5.8Hz,1H),3.79–3 .68(m,2H),3.64(s,3H),3.27(q,J=7.3Hz,2H),3.20(s,3H),1.09(t,J=7.3Hz,3H).

[0730] Example 32: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(5-(2-oxopyrrolidin-1-yl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzamide

[0731]

[0732] Step 1: Synthesis of methyl 4-(5-(2-oxopyrrolidin-1-yl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate

[0733] 2-Pyrrolidone (43 mg, 0.51 mmol), methyl 4-(5-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (203 mg, 0.44 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), XantPhos (20 mg, 0.035 mmol) and Cs2CO3 (216 mg, 0.66 mmol) were dissolved in toluene (2 mL), exchanged with nitrogen, and heated in an oil bath at 100°C with stirring for 24 h. H2O (30 mL) was added to the reaction solution to dissolve the solid, and the aqueous phase was extracted with DCM (40 mL×3). The organic phases were combined and dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 5 / 1 / 1) to give the product as a yellow oil (180 mg, yield: 88%).

[0734] MS(ESI,pos.ion)m / z=463.2[M+H] + .

[0735] Step 2: Synthesis of 4-(5-(2-oxopyrrolidin-1-yl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid

[0736] LiOH·H₂O (105 mg, 2.50 mmol) was added to a solution of methyl 4-(5-(2-oxopyrrolidin-1-yl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (180 mg, 0.39 mmol) in THF / H₂O (5 / 1 mL) and stirred in an oil bath at 50°C for 1 h. 30 mL of water was added to the reaction mixture, and the mixture was extracted with DCM (20 mL x 2). The aqueous phase was adjusted to pH 2-3 with 1.0 M HCl solution and then extracted with EtOAc (30 mL x 3). The organic phases were combined, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the crude product as a yellow solid (147 mg, 84% yield). MS (ESI, pos. ion) m / z = 449.0 [M+H] + .

[0737] Step 3: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(5-(2-oxopyrrolidin-1-yl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzamide

[0738] 4-(5-(2-oxopyrrolidin-1-yl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid (147 mg, 0.33 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (90 mg, 0.39 mmol), EDCI (132 mg, 0.69 mmol), and HOBT (90 mg, 0.67 mmol) were dissolved in DCM (4 mL), and TEA (0.14 mL, 1.0 mmol) was added. The mixture was stirred at room temperature for 5 h. TLC confirmed complete conversion of the starting material. The reaction solution was diluted with DCM (80 mL), washed sequentially with 1.0 M HCl solution (20 mL), saturated NaCl (aq.) (20 mL) and saturated Na2CO3 (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc / THF / (v / v / v)=5 / 5 / 1) and silica gel thin layer chromatography (developing solvent: DCM / EtOAc / THF (v / v / v)=4 / 4 / 1) to give the product as a yellow solid (20 mg, yield: 9%).

[0739] MS(ESI,pos.ion)m / z=660.3[M+H] + ;

[0740] 1 H NMR(400MHz,d6-DMSO)δ(ppm):8.88(d,J=7.6Hz,1H),7.95(d,J=8.5Hz,2H),7.89( d,J=8.6Hz,2H),7.84(d,J=8.4Hz,2H),7.67(d,J=8.0Hz,6H),5.32(t,J=4.9Hz,1H) ,5.19–5.12(m,1H),5.05(t,J=5.9Hz,1H),3.72(m,1H),3.55–3.50(m,2H),3.40(s ,2H),3.24(d,J=7.2Hz,2H),2.11–2.05(m,1H),2.00(s,1H),1.10(t,J=7.3Hz,3H).

[0741] Example 33: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-((4-(trifluoromethyl)cyclohexyl)oxy)thiazol-4-yl)benzamide

[0742]

[0743] Step 1: Synthesis of 4-bromo-2-((4-(trifluoromethyl)cyclohexyl)oxy)thiazole

[0744] Under nitrogen, NaH (304 mg, 7.60 mmol) was added to a solution of 2,4-dibromothiazole (3.0 g, 12 mmol) and 4-(trifluoromethyl)cyclohexanol (1.0 g, 5.90 mmol) in DMF (14 mL). The reaction was stirred in an 80°C oil bath for 20 h, after which heating was discontinued. The reaction solution was diluted with EtOAc (80 mL), washed with saturated NaCl (aq.) (15 mL x 6), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to afford the product as a yellow solid (286 mg, 15% yield).

[0745] MS(ESI,pos.ion)m / z=329.7[M+H] + .

[0746] Step 2: Synthesis of methyl 4-(2-((4-(trifluoromethyl)cyclohexyl)oxy)thiazol-4-yl)benzoate

[0747] Under nitrogen, (4-(methoxycarbonyl)phenyl)boronic acid (300 mg, 1.67 mmol), 4-bromo-2-((4-(trifluoromethyl)cyclohexyl)oxy)thiazole (286 mg, 0.87 mmol), Pd(dppf)Cl2 (67 mg, 0.092 mmol), and Cs2CO3 (564 mg, 1.73 mmol) were dissolved in 1,4-dioxane (4 mL). The reaction was stirred in an oil bath at 100°C for 12 h. The reaction progress was monitored by LC-MS. The reaction solution was removed by concentration under reduced pressure, and the residue was diluted with DCM (80 mL) and washed successively with saturated NaHCO3 (aq.) (20 mL) and NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to give the target product as a yellow solid (128 mg, yield: 40%).

[0748] MS(ESI,pos.ion)m / z=385.9[M+H] + .

[0749] Step 3: Synthesis of 4-(2-((4-(trifluoromethyl)cyclohexyl)oxy)thiazol-4-yl)benzoic acid

[0750] LiOH·H₂O (102 mg, 2.43 mmol) was added to a solution of methyl 4-(2-((4-(trifluoromethyl)cyclohexyl)oxy)thiazol-4-yl)benzoate (128 mg, 0.33 mmol) in THF / H₂O (3 mL / 1 mL). The reaction was stirred in an oil bath at 50°C for 4 h. Water (15 mL) was added to the reaction solution, which was then extracted with DCM (20 mL × 3). The aqueous phase was transferred to an Erlenmeyer flask and 1.0 M HCl (aq.) was added dropwise to adjust the pH to 3. The aqueous phase was extracted with EtOAc (20 mL × 3). The organic phases were combined, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the crude product as a yellow solid (114 mg, 92% yield).

[0751] MS(ESI,pos.ion)m / z=372.0[M+H] + .

[0752] Step 4: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-((4-(trifluoromethyl)cyclohexyl)oxy)thiazol-4-yl)benzamide

[0753] 4-(2-((4-(trifluoromethyl)cyclohexyl)oxy)thiazol-4-yl)benzoic acid (114 mg, 0.31 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (95 mg, 0.41 mmol), EDCI (233 mg, 1.22 mmol) and HOBT (163 mg, 1.21 mmol) were dissolved in DCM (4 mL), and TEA (0.14 mL, 1.0 mmol) was added and stirred at room temperature for 12 h. The reaction mixture was diluted with DCM (60 mL) and then washed sequentially with 1.0 M HCl (aq.) (10 mL), saturated NaCl (aq.) (20 mL), and NaHCO 3 (aq.) (20 mL). It was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2 / 1) to give a yellow solid product (18 mg, yield: 10%). MS (ESI, pos. ion) m / z = 583.8 [M+H] + ;

[0754] 1 H NMR (400MHz, d6-DMSO) δ (ppm): 8.91 (d, J=7.8Hz, 1H), 7.99 (d, J=8.4Hz, 2H), 7.84 (d, J= 8.3Hz,2H),7.71(d,J=8.4Hz,2H),7.67(d,J=8.3Hz,2H),5.16(dd,J=13.9,7.1Hz,1H),5 .05(t,J=5.9Hz,1H),4.97–4.87(m,1H),3.73(dt,J=11.0,6.0Hz,2H),3.27(q,J=7.4Hz ,,2H),2.33(s,1H),2.26(s,2H),1.97(s,2H),1.60–1.45(m,4H),1.10(t,J=7.4Hz,3H).

[0755] Example 34: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(5-(methoxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzamide

[0756]

[0757] Step 1: Synthesis of methyl 4-(5-(methoxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate

[0758] MsCl (0.12 mL, 1.60 mmol) was added to a solution of methyl 4-(5-(hydroxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (202 mg, 0.49 mmol) and KCO (205 mg, 1.49 mmol) in DCM (4 mL) at -10°C, followed by stirring at room temperature for 1 h. Anhydrous MeOH (2 mL) was added, stirred at room temperature for 1 h, and then heated in an oil bath at 50°C for 2 h. Saturated NaHCO3 (aq.) (20 mL) was added to the reaction solution to quench the reaction, and the aqueous phase was extracted with DCM (20 mL×3). The organic phases were combined and washed with saturated NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 10 / 1 / 1) to give the product as a yellow solid (206 mg, yield: 99%).

[0759] MS(ESI,pos.ion)m / z=424.0[M+H] + .

[0760] Step 2: Synthesis of 4-(5-(methoxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid

[0761] LiOH·H2O (92 mg, 2.19 mmol) was added to a solution of methyl 4-(5-(methoxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (205 mg, 0.48 mmol) in THF / H2O (6 mL / 2 mL). The reaction was stirred in a 50°C oil bath for 2 h. Additional LiOH·H2O (200 mg, 4.77 mmol) was added, and stirring continued for 2 h. Water (20 mL) was added to the reaction solution, which was then extracted with EtOAc (20 mL). The organic phase was discarded, and 1.0 M HCl solution was added dropwise to the aqueous phase to adjust the pH to 3. The aqueous phase was extracted with DCM (30 mL x 3) and concentrated under reduced pressure to afford the crude product as a yellow solid (137 mg, 69% yield).

[0762] MS(ESI,pos.ion)m / z=410.0[M+H] + .

[0763] Step 3: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(5-(methoxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzamide

[0764] 4-(5-(Methoxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid (137 mg, 0.33 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (94 mg, 0.41 mmol), EDCI (196 mg, 1.02 mmol), and HOBT (135 mg, 1.00 mmol) were dissolved in DCM (6 mL). TEA (0.24 mL, 1.70 mmol) was added and the mixture was stirred at room temperature for 10 h. LC-MS analysis indicated complete conversion of the starting material. DCM (60 mL) was added to the reaction solution, and then washed successively with saturated NaCl (aq.) (20 mL) and saturated NaHCO 3 (aq.) (20 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2 / 1) to give the product as a yellow solid (108 mg, yield: 52%).

[0765] MS(ESI,pos.ion)m / z=621.3[M+H] + ;

[0766] 1 H NMR (400MHz, d6-DMSO) δ (ppm): 8.89 (d, J = 7.9Hz, 1H), 8.00 (d, J = 8.3Hz, 2H), 7.89 (d, J = 8.6Hz, 2H), 7.85 (d, J = 8.3Hz, 2H), 7.62-7.69 (m, 6 H),5.17(dd,J=13.8,7.1Hz,1H),5.10–5.02(m,1H),4.65(s,2H),3.74(m,2H),3.37(s,3H),3.27(q,J=7.4Hz,2H),1.10(t,J=7.3Hz,3H).

[0767] Example 35: (R)-6-(5-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)nicotinamide

[0768]

[0769] Step 1: Synthesis of methyl 6-(5-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinate

[0770] NBS (35 mg, 0.20 mmol) was added to a solution of methyl 6-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinate (50 mg, 0.13 mmol) in DMF (3 mL) and stirred at room temperature for 12 h. LC-MS analysis indicated complete conversion of the starting material. EtOAc (80 mL) was added to the reaction solution, which was then washed sequentially with saturated NaHCO₃(aq.) (10 mL) and saturated NaCl(aq.) (10 mL x 4), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the crude product as a yellow solid (60 mg, 99% yield).

[0771] MS(ESI,pos.ion)m / z=459.1[M+H] + .

[0772] Step 2: Synthesis of 6-(5-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinic acid

[0773] LiOH·H₂O (62 mg, 1.48 mmol) was added to a solution of methyl 6-(5-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinate (60 mg, 0.13 mmol) in THF / H₂O (3 mL / 1 mL). The reaction was stirred in a 50°C oil bath for 1 h. LC-MS confirmed complete conversion of the starting material. The mixture was concentrated under reduced pressure, and DCM (20 mL) was added to the residue, followed by a 6.0 M HCl / isopropanol solution dropwise to adjust the pH to 3. The mixture was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to yield the crude product as a yellow solid (58 mg).

[0774] MS(ESI,pos.ion)m / z=444.7[M+H] + .

[0775] Step 3: Synthesis of (R)-6-(5-bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)nicotinamide

[0776] 6-(5-Bromo-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinic acid (58 mg, 0.13 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (35 mg, 0.15 mmol), EDCI (133 mg, 0.69 mmol) and HOBT (93 mg, 0.69 mmol) were dissolved in DCM (4 mL), and TEA (0.10 mL, 0.72 mmol) was added and stirred at room temperature for 12 h. The reaction solution was diluted with DCM (60 mL), washed sequentially with saturated NaHCO (aq.) (20 mL) and NaCl (aq.) (20 mL), dried over anhydrous Na SO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 3 / 2) and silica gel thin layer chromatography (developing solvent: DCM / EtOAc (v / v) = 2 / 1) to give the product as a yellow solid (15 mg, yield: 18%).

[0777] MS(ESI,pos.ion)m / z=656.7[M+H] + ;

[0778] 1 H NMR (400MHz, d6-DMSO) δ (ppm): 9.16 (s, 1H), 9.09 (d, J = 7.9Hz, 1H), 8.32 (d, J = 8.5Hz, 1H), 7.94 (d, J = 6.3Hz, 1H), 7.91 (d, J = 8.3Hz, 2H), 7.85 (d, J=8.2Hz,2H),7.70(m,4H),5.21–5.15(m,1H),5.08(t,J=5.6Hz,1H),3.73(dd,J=12.0,6.1Hz,2H),3.27(q,J=7.4H,2H),1.10(t,J=7.4Hz,3H).

[0779] Example 36: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6-(5-((2-fluoroethoxy)methyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinamide

[0780]

[0781] Step 1: Synthesis of methyl 6-(5-((2-fluoroethoxy)methyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinate

[0782] Under nitrogen, methyl 6-bromonicotinate (155 mg, 0.72 mmol), 4-bromo-5-((2-fluoroethoxy)methyl)-2-(4-(trifluoromethyl)phenoxy)thiazole (74 mg, 0.18 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaboryl) (145 mg, 0.57 mmol), Pd(dppf)Cl2 (26 mg, 0.036 mmol) and Cs2CO3 (243 mg, 0.75 mmol) were dissolved in 1,4-dioxane (6 mL) and the reaction was heated in an oil bath at 100 °C with stirring for 12 h. Water (40 mL) was added to the reaction solution, and the aqueous phase was extracted with DCM (40 mL × 3). The organic phases were combined and washed with saturated NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 10 / 1 / 1) to obtain the target product as a yellow solid (15 mg, yield: 18%).

[0783] MS(ESI,pos.ion)m / z=457.0[M+H] + .

[0784] Step 2: Synthesis of 6-(5-((2-fluoroethoxy)methyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinic acid

[0785] Anhydrous LiOH (32 mg, 0.76 mmol) was added to a solution of methyl 6-(5-((2-fluoroethoxy)methyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinate (15 mg, 0.033 mmol) in THF / MeOH / H₂O (1 mL / mL / 0.3 mL). The reaction was stirred in a 50°C oil bath for 2 h. Heating was discontinued. Water (20 mL) was added to the reaction solution, and 1.0 M HCl solution was added dropwise to the aqueous phase to adjust the pH to 3. The aqueous phase was concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to obtain the product as a light yellow solid (13 mg, yield: 89%).

[0786] MS(ESI,pos.ion)m / z=443.2[M+H] + .

[0787] Step 3: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6-(5-((2-fluoroethoxy)methyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinamide

[0788] 6-(5-((2-fluoroethoxy)methyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)nicotinic acid (13 mg, 0.029 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (10 mg, 0.044 mmol), EDCI (31 mg, 0.16 mmol) and HOBT (20 mg, 0.15 mmol) were dissolved in DCM (4 mL), and TEA (0.12 mL, 0.86 mmol) was added and stirred at room temperature for 21 h. DCM (60 mL) was added to the reaction solution, and then washed successively with saturated NaCl (aq.) (20 mL) and saturated NaHCO 3 (aq.) (20 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The crude product was separated successively by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2 / 1) and silica gel chromatography (developing solvent: DCM / EtOAc (v / v) = 2 / 1) to give the product as a yellow solid (2 mg, yield: 10%).

[0789] MS(ESI,pos.ion)m / z=654.3[M+H] + .

[0790] Example 37: N-(4-(ethylsulfonyl)benzyl)-4-(2-(morpholinomethyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrol-1-yl)benzamide

[0791]

[0792] Step 1: Synthesis of methyl 4-((2S)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)benzoate

[0793] To a dry, single-necked flask, add methyl 4-bromobenzoate (2.10 g, 9.77 mmol) and ((2S)-4-(4-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methanol (2.80 g, 11.4 mmol). Dissolve the mixture in toluene (33 mL). Cs2CO3 (9.20 g, 28.20 mmol), Xantphos (253 mg, 0.4241 mmol), and Pd2(dba)3 (380 mg, 0.4025 mmol) were then added. The mixture was heated to 100°C under nitrogen and stirred for 12 hours. Heating was stopped, and the reaction mixture was cooled to room temperature before being filtered. The filtrate was concentrated, and the crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to obtain the product as a yellow solid (700 mg, yield: 16.2%).

[0794] MS(ESI,pos.ion)m / z=380.0[M+H]+ .

[0795] Step 2: Synthesis of methyl 4-(2-formyl-4-(4-(trifluoromethyl)phenyl)-1H-pyrrol-1-yl)benzoate

[0796] In a dry, single-necked flask, methyl 4-((2S)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)benzoate (690 mg, 1.82 mmol) was dissolved in DCM (40 mL). DMP (1.20 g, 2.80 mmol) was slowly added and stirred at room temperature for 10 hours. The reaction was monitored by TLC. After completion, the reaction solution was filtered to remove insoluble matter. Saturated sodium bicarbonate (aq.) (40 mL) was slowly added under ice-cooling, followed by extraction with DCM (30 mL x 2). The organic phase was washed with saturated sodium chloride (aq.) (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a viscous residue. The product was separated by silica gel column chromatography (eluent: PE / EA (v / v) = 3 / 1) to obtain the product as a light yellow solid (430 mg, yield: 63.34%).

[0797] MS(ESI,pos.ion)m / z=374.1[M+H] + .

[0798] Step 3: Synthesis of methyl 4-(2-(morpholinomethyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrol-1-yl)benzoate

[0799] Morpholine (40 mg, 0.46 mmol) was added to a dry, one-necked flask and dissolved in MeOH (16 mL). Methyl 4-(2-formyl-4-(4-(trifluoromethyl)phenyl)-1H-pyrrol-1-yl)benzoate (460 mg, 1.23 mmol) was added dropwise in an ice bath. NaBH3(CN) (45 mg, 0.68 mmol) was then added. The reaction mixture was stirred at room temperature for 8 hours. TLC monitoring indicated the disappearance of the starting material. The solvent was evaporated under reduced pressure, and the mixture was dried in vacuo. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to afford the product as a pale yellow solid (330 mg, yield: 60.26%).

[0800] MS(ESI,pos.ion)m / z=445.3[M+H] + .

[0801] Step 4: Synthesis of 4-(2-(morpholinomethyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrol-1-yl)benzoic acid

[0802] Methyl 4-(2-(morpholinomethyl)-4-(4-(trifluoromethyl)phenyl)pyrrol-1-yl)benzoate (350 mg, 0.79 mmol) was added to a single-necked flask and dissolved in THF (14 mL). H₂O (15 mL) was then added, and LiOH (1.50 g, 35.00 mmol) was slowly added. The reaction mixture was stirred at room temperature for 3 h. After the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent. Concentrated HCl was slowly added dropwise in an ice bath to adjust the pH to 6. EtOAc (50 mL) was then added for extraction. The organic phase was washed with saturated NaCl (aq.) (30 mL), dried over anhydrous Na₂SO₄, and filtered. The concentrated crude product was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 5 / 1) to obtain the product as a yellow solid (220 mg, yield: 64.90%).

[0803] MS(ESI,pos.ion)m / z=435.2[M+H] + .

[0804] Step 5: Synthesis of N-(4-(ethylsulfonyl)benzyl)-4-(2-(morpholinomethyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrol-1-yl)benzamide

[0805] To a one-necked flask, (4-(ethylsulfonyl)phenyl)methanamine (55 mg, 0.28 mmol), 4-(2-(morpholinomethyl)-4-(4-(trifluoromethyl)phenyl)pyrrol-1-yl)benzoic acid (61 mg, 0.14 mmol), HATU (79 mg, 0.20 mmol), and DIPEA (0.1 mL, 0.6 mmol) dissolved in DCM (5 mL) were added sequentially. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the reaction solution was poured into DCM (20 mL), washed successively with dilute HCl (15 mL), saturated NaHCO3 (aq.) (15 mL), H2O (20 mL), saturated NaCl (aq.) (10 mL), dried over anhydrous Na2SO4, filtered, and the crude product after concentration was a yellow solid. The product was then separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 3 / 2), and then separated and purified by silica gel thin layer chromatography (developing solvent: DCM / EtOAc (v / v) = 3 / 2) to give the product as a light yellow solid (25 mg, yield: 28.84%).

[0806] MS(ESI,pos.ion)m / z=612.9[M+H] + ;

[0807] 1H NMR (400MHz, CDCl3) δ (ppm): 7.97 (d, J = 8.5 Hz, 2H), 7.86 ( d, J = 8.3 Hz, 2H), 7.80 ( d,J=8.5Hz,2H),7.63(q,J=8.5Hz,4H),7.56(d,J=8.3Hz,2H),7.27(d,J=1.9Hz,1 H),6.84(t,J=5.9Hz,1H),6.60(d,J=1.7Hz,1H),4.80(d,J=6.0Hz,2H),3.74–3.6 2(m,4H),3.39(s,2H),3.13(q,J=7.4Hz,2H),2.49(s,4H),1.30(t,J=7.4Hz,3H).

[0808] Example 38: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-(morpholinomethyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrol-1-yl)benzamide

[0809]

[0810] To a one-necked flask, (2R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (70 mg, 0.30 mmol), 4-(2-(morpholinomethyl)-4-(4-(trifluoromethyl)phenyl)pyrrol-1-yl)benzoic acid (105 mg, 0.24 mmol), HATU (0.20 g, 0.51 mmol), and DIPEA (0.3 mL, 2.00 mmol) dissolved in DCM (20 mL) were added sequentially. The reaction mixture was stirred at room temperature for 10 hours. After completion of the reaction by TLC, the reaction solution was poured into DCM (30 mL), and then washed sequentially with 0.2 mol / L HCl (25 mL), saturated NaHCO3 (aq.) (20 mL), H2O (30 mL) and saturated NaCl (aq.) (30 mL), and dried over anhydrous Na2SO4, filtered, and the concentrated crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 3 / 2), and then separated by silica gel thin layer chromatography (developing solvent: DCM / EtOAc (v / v) = 1 / 1) to give a light yellow solid (37 mg, yield: 23.63%).

[0811] MS(ESI,pos.ion)m / z=642.8[M+H] + ;

[0812] 1H NMR (400MHz, CDCl3) δ (ppm): 7.97 (d, J = 8.5Hz, 2H), 7.92 (d, J = 8.3Hz, 2H), 7.80 (d, J=8.5Hz,2H),7.67–7.59(m,6H),7.27(d,J=1.8Hz,1H),7.20(d,J=7.0Hz,1H),6.6 0(d,J=1.7Hz,1H),5.41–5.34(m,1H),4.10(ddd,J=33.4,11.3,4.2Hz,2H),3.72–3 .63(m,4H),3.40(s,2H),3.13(q,J=7.4Hz,2H),2.50(s,4H),1.32(t,J=7.4Hz,3H).

[0813] Example 39: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-(3,3,3-trifluoropropyloxy)thiazol-4-yl)benzamide

[0814]

[0815] Step 1: Synthesis of 4-bromo-2-(3,3,3-trifluoropropoxy)thiazole

[0816] Under nitrogen, NaH (336 mg, 8.40 mmol) was added to a solution of 2,4-dibromothiazole (1.02 g, 4.20 mmol) in 3,3,3-trifluoropropyl-1-ol (10 mL, 113 mmol) in a -10°C cold bath with stirring. After 10 minutes, the mixture was brought to room temperature and stirred for 24 hours. The reaction mixture was diluted with DCM (80 mL), washed with saturated NaCl (aq.) (5 mL x 5), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product as a yellow liquid (1.10 g, 95% yield).

[0817] MS(ESI,pos.ion)m / z=276.0[M+H] + .

[0818] Step 2: Synthesis of methyl 4-(2-(3,3,3-trifluoropropoxy)thiazol-4-yl)benzoate

[0819] Under nitrogen, 4-bromo-2-(3,3,3-trifluoropropoxy)thiazole (1.10 g, 3.98 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (1.12 g, 5.18 mmol), Pd(dppf)Cl2 (303 mg, 0.41 mmol), and Cs2CO3 (2.63 g, 8.07 mmol) were dissolved in 1,4-dioxane (16 mL). The reaction was heated in an oil bath at 100°C with stirring for 20 h. LC-MS analysis indicated the formation of the product. The reaction solution was removed by concentration under reduced pressure, and the residue was diluted with DCM (100 mL) and washed successively with saturated NaHCO3 (aq.) (20 mL) and NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to give the product as a yellow solid (722 mg, yield: 54.7%).

[0820] MS(ESI,pos.ion)m / z=332.0[M+H] + .

[0821] Step 3: Synthesis of 4-(2-(3,3,3-trifluoropropyloxy)thiazol-4-yl)benzoic acid

[0822] LiOH·H₂O (24 mg, 0.57 mmol) was added to a solution of methyl 4-(2-(3,3,3-trifluoropropyloxy)thiazol-4-yl)benzoate (110 mg, 0.33 mmol) in THF / H₂O (3 mL / 1 mL). The reaction was stirred in a 50°C oil bath for 1.5 h. TLC confirmed complete conversion of the starting material. Water (10 mL) was added to the residue, followed by a 1.0 M HCl solution dropwise to adjust the pH to 3. The aqueous phase was extracted with DCM (30 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford the crude product as a yellow solid (96 mg, 100% yield).

[0823] MS(ESI,pos.ion)m / z=318.2[M+H] + .

[0824] Step 4: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-(3,3,3-trifluoropropoxy)thiazol-4-yl)benzamide

[0825] 4-(2-(3,3,3-Trifluoropropoxy)thiazol-4-yl)benzoic acid (98 mg, 0.31 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (84 mg, 0.37 mmol), EDCI (302 mg, 1.58 mmol), and HOBT (203 mg, 1.50 mmol) were dissolved in DCM (4 mL), and TEA (0.22 mL, 1.60 mmol) was added. The mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with DCM (80 mL), washed sequentially with saturated NaCl (aq.) (20 mL) and NaHCO (aq.) (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2 / 1) to give the product as a white solid (125 mg, yield: 77%).

[0826] MS(ESI,pos.ion)m / z=529.2[M+H] + ;

[0827] 1 H NMR(400MHz,d6-DMSO)δ(ppm):8.84(d,J=7.9Hz,1H),7.97(s,4H),7.85(d,J=8.3Hz,2H),7.62–7.69(m,3H),5.17(dd,J=13.8,7.1H z,1H),5.05(s,1H),4.72(t,J=5.8Hz,2H),3.75(dt,J=16.7,10.9Hz,2H),3.27(q,J=7.4Hz,2H),2.92(s,2H),1.10(t,J=7.3Hz,3H);

[0828] 13 C NMR(101MHz,d6-DMSO)δ(ppm):172.77,165.81,147.53,147.10,137.10,136.51,133.34,12 7.99,127.93,127.66,125.25,108.46,64.58,64.54,64.01,55.73,49.18,32.51(q),7.06.

[0829] Example 40: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-(4,4,4-trifluorobutoxy)thiazol-4-yl)benzamide

[0830]

[0831] Step 1: Synthesis of 4-bromo-2-(4,4,4-trifluorobutoxy)thiazole

[0832] Under nitrogen, NaH (336 mg, 8.40 mmol, 60%) was added to a solution of 2,4-dibromothiazole (1.02 g, 4.20 mmol) in 4,4,4-trifluorobutanol (10 mL, 93.14 mmol) with stirring in a cold bath at -10°C. After 10 minutes, the mixture was stirred at room temperature for 20 hours. LC-MS monitoring revealed a significant formation of the target product. The reaction mixture was diluted with DCM (80 mL), washed with saturated NaCl (aq.) (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product as a yellow liquid (1.20 g, 99% yield).

[0833] MS(ESI,pos.ion)m / z=290.1[M+H] + .

[0834] Step 2: Synthesis of methyl 4-(2-(4,4,4-trifluorobutoxy)thiazol-4-yl)benzoate

[0835] Under nitrogen, (4-(methoxycarbonyl)phenyl)boronic acid (1.1 g, 6.10 mmol), 4-bromo-2-(4,4,4-trifluorobutoxy)thiazole (1.20 g, 4.14 mmol), Pd(dppf)Cl2 (308 mg, 0.42 mmol), and Cs2CO3 (2.76 g, 8.47 mmol) were dissolved in 1,4-dioxane (20 mL) and heated in an oil bath at 100°C with stirring for 12 h. The reaction mixture was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to give the product as a yellow solid (1.24 g, 87% total yield for two steps).

[0836] MS(ESI,pos.ion)m / z=346.2[M+H] + .

[0837] Step 3: Synthesis of 4-(2-(4,4,4-trifluorobutoxy)thiazol-4-yl)benzoic acid

[0838] LiOH·H2O (92 mg, 2.19 mmol) was added to a solution of methyl 4-(2-(4,4,4-trifluorobutoxy)thiazol-4-yl)benzoate (203 mg, 0.59 mmol) in THF / H2O (3 mL / 1 mL). The reaction was heated and stirred in a 50°C oil bath for 2 h. TLC indicated incomplete conversion. Additional LiOH·H2O (300 mg, 7.15 mmol) was added, and stirring was continued for 2 h, indicating complete conversion. Water (20 mL) was added to the reaction solution, which was then extracted with EtOAc (20 mL). 1.0 M HCl solution was added dropwise to the aqueous phase to adjust the pH to 3. The aqueous phase was extracted with DCM (20 mL x 3) and concentrated under reduced pressure to afford the crude product as a white solid (77 mg, 40% yield).

[0839] MS(ESI,pos.ion)m / z=332.0[M+H] + .

[0840] Step 4: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-(4,4,4-trifluorobutoxy)thiazol-4-yl)benzamide

[0841] 4-(2-(4,4,4-trifluorobutoxy)thiazol-4-yl)benzoic acid (77 mg, 0.23 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (64 mg, 0.28 mmol), EDCI (142 mg, 0.74 mmol), and HOBT (95 mg, 0.70 mmol) were dissolved in DCM (4 mL). TEA (0.16 mL, 1.10 mmol) was added and the mixture was stirred at room temperature for 10 h. LC-MS analysis indicated complete conversion of the starting material. DCM (60 mL) was added to the reaction solution, and then washed successively with saturated NaCl (aq.) (20 mL) and saturated NaHCO 3 (aq.) (20 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The crude product was separated successively by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2 / 1), silica gel thin layer chromatography (developing solvent: DCM / EtOAc (v / v) = 2 / 1), and HPLC preparative separation: H 2 O / MeCN / TFA (v / v / v) = 44% / 56% / 0.1%) to give the product as a yellow solid (50 mg, yield: 40%).

[0842] MS(ESI,pos.ion)m / z=543.3[M+H] + ;

[0843] 1H NMR (400MHz, d6-DMSO) δ (ppm): 8.83 (d, J=7.8Hz, 1H), 7.96 (s, 4H), 7.85 (d, J= 8.3Hz,2H),7.68(d,J=8.3Hz,2H),7.65(s,1H),5.17(dd,J=13.7,7.2Hz,1H),5 .05(t,J=5.8Hz,1H),4.55(t,J=6.3Hz,2H),3.81–3.68(m,2H),3.27(q,J=7.3H z,2H),2.48–2.39(m,2H),2.04(dd,J=15.1,6.8Hz,2H),1.10(t,J=7.3Hz,3H).

[0844] Example 41: (R)-4-(2-((3,3-difluorocyclobutyl)methoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0845]

[0846] Step 1: Synthesis of 4-bromo-2-((3,3-difluorocyclobutyl)methoxy)thiazole

[0847] Under nitrogen, NaH (336 mg, 8.40 mmol, 60%) was added to a solution of 2,4-dibromothiazole (1.02 g, 4.20 mmol) in (3,3-difluorocyclobutyl)methanol (10 mL, 97.70 mmol) with stirring in a -10°C cold bath. After 10 minutes, the mixture was stirred at room temperature for 20 hours. LC-MS monitoring indicated good conversion of the starting material. The reaction mixture was diluted with DCM (80 mL), then washed with saturated NaCl (aq.) (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield the crude product as a yellow liquid. The crude product was used directly in the next reaction without isolation.

[0848] MS(ESI,pos.ion)m / z=283.9[M+H] + .

[0849] Step 2: Synthesis of methyl 4-(2-((3,3-difluorocyclobutyl)methoxy)thiazol-4-yl)benzoate

[0850] Under nitrogen, (4-(methoxycarbonyl)phenyl)boronic acid (1.14 g, 6.33 mmol), 4-bromo-2-((3,3-difluorocyclobutyl)methoxy)thiazole (1.20 g, 4.22 mmol), Pd(dppf)Cl2 (320 mg, 0.44 mmol), and Cs2CO3 (2.80 g, 8.59 mmol) were dissolved in 1,4-dioxane (20 mL) and stirred in an oil bath at 100°C for 12 h. The reaction solvent was removed by concentration under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to give the product as a yellow solid (1.34 g, 94% yield).

[0851] MS(ESI,pos.ion)m / z=340.2[M+H] + .

[0852] Step 3: Synthesis of 4-(2-((3,3-difluorocyclobutyl)methoxy)thiazol-4-yl)benzoic acid

[0853] LiOH·H2O (91 mg, 2.17 mmol) was added to a solution of methyl 4-(2-((3,3-difluorocyclobutyl)methoxy)thiazol-4-yl)benzoate (203 mg, 0.60 mmol) in THF / H2O (3 mL / 1 mL). The reaction was stirred in a 50°C oil bath for 2 h. Additional LiOH·H2O (200 mg, 4.766 mmol) was added, and stirring continued for 2 h. Water (20 mL) was added to the reaction solution, which was then extracted with EtOAc (20 mL). 1.0 M HCl solution was added dropwise to the aqueous phase to adjust the pH to 3. The aqueous phase was extracted with DCM (20 mL x 3) and concentrated under reduced pressure to afford the product as a white solid (124 mg, 64% yield).

[0854] MS(ESI,pos.ion)m / z=326.1[M+H] + .

[0855] Step 4: Synthesis of (R)-4-(2-((3,3-difluorocyclobutyl)methoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0856] 4-(2-((3,3-Difluorocyclobutyl)methoxy)thiazol-4-yl)benzoic acid (124 mg, 0.38 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (105 mg, 0.46 mmol), EDCI (222 mg, 1.16 mmol) and HOBT (155 mg, 1.15 mmol) were dissolved in DCM (6 mL), and TEA (0.26 mL, 1.90 mmol) was added and stirred at room temperature for 10 h. DCM (60 mL) was added to the reaction solution, and then washed successively with saturated NaCl (aq.) (20 mL) and saturated NaHCO 3 (aq.) (20 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2 / 1) to give the product as a yellow solid (155 mg, yield: 76%).

[0857] MS(ESI,pos.ion)m / z=537.2[M+H] + ;

[0858] 1 H NMR(400MHz,d6-DMSO)δ(ppm):8.84(d,J=7.8Hz,1H),7.96(s,4H),7.85(d,J=8.3Hz,2H),7.71–7.63(m,3H),5.17(dd,J=13.7,7.1Hz,1H),5. 06(s,1H),4.56(d,J=6.2Hz,2H),3.81–3.69(m,2H),3.27(q,J=7.4Hz,2H),2.72(dt,J=19.4,11.9Hz,3H),2.56(s,2H),1.10(t,J=7.3Hz,3H).

[0859] Example 42: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(4-(4-(trifluoromethyl)benzyl)thiazol-2-yl)benzamide

[0860]

[0861] Step 1: Synthesis of methyl 4-(4-bromothiazol-2-yl)benzoate

[0862] Under nitrogen, (4-(Methoxycarbonyl)phenyl)boronic acid (890 mg, 4.95 mmol), 2,4-dibromothiazole (1.00 g, 4.10 mmol), Pd(dppf)Cl2 (302 mg, 0.41 mmol), and Cs2CO3 (2.72 g, 8.35 mmol) were dissolved in 1,4-dioxane (15 mL) and stirred in an oil bath at 100°C for approximately 17 h. The reaction mixture was evaporated to dryness under reduced pressure, then diluted with DCM (80 mL) and washed sequentially with saturated NaHCO3 (aq.) (20 mL) and NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to afford the product as a yellow solid (300 mg, 21% yield).

[0863] MS(ESI,pos.ion)m / z=298.2[M+H] + .

[0864] Step 2: Synthesis of methyl 4-(4-(4-(trifluoromethyl)benzyl)thiazol-2-yl)benzoate

[0865] Under nitrogen, methyl 4-(4-bromothiazol-2-yl)benzoate (205 mg, 0.69 mmol), 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)benzyl)-1,3,2-dioxaborolane (575 mg, 2.01 mmol), Pd(dppf)Cl2·DCM (56 mg, 0.069 mmol) and Cs2CO3 (662 mg, 2.03 mmol) were dissolved in toluene (10 mL) and the reaction was heated in an oil bath at 80°C with stirring for 8 h. The reaction solution was diluted with DCM (80 mL), washed sequentially with water (20 mL) and saturated NaCl (aq.) (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 20 / 1 / 1) to give the target product as a yellow solid (68 mg, yield: 26%).

[0866] MS(ESI,pos.ion)m / z=377.9[M+H] + .

[0867] Step 3: Synthesis of 4-(4-(4-(trifluoromethyl)benzyl)thiazol-2-yl)benzoic acid

[0868] LiOH·H₂O (24 mg, 0.57 mmol) was added to a solution of methyl 4-(4-(4-(trifluoromethyl)benzyl)thiazol-2-yl)benzoate (68 mg, 0.18 mmol) in THF / H₂O (3 mL / 1 mL). The reaction was stirred in a 50°C oil bath for 1 h. TLC confirmed complete conversion of the starting material. The mixture was concentrated under reduced pressure, and water (10 mL) was added to the residue, followed by dropwise addition of 1.0 M HCl solution to adjust the pH to 3. The aqueous phase was extracted with DCM (20 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford the crude product as a yellow solid (65 mg, 100% yield).

[0869] Step 4: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(4-(4-(trifluoromethyl)benzyl)thiazol-2-yl)benzamide

[0870] 4-(4-(4-(trifluoromethyl)benzyl)thiazol-2-yl)benzoic acid (65 mg, 0.18 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (50 mg, 0.22 mmol), EDCI (173 mg, 0.90 mmol), and HOBT (123 mg, 0.91 mmol) were dissolved in DCM (4 mL). TEA (0.12 mL, 0.86 mmol) was added and stirred at room temperature for 18 h. The reaction mixture was diluted with DCM (80 mL) and washed sequentially with saturated NaHCO₃(aq.) (20 mL) and NaCl(aq.) (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2 / 1) to give the product as a yellow solid (25 mg, 24% yield).

[0871] MS(ESI,pos.ion)m / z=575.3[M+H] + ;

[0872] 1 H NMR (400MHz, d6-DMSO) δ (ppm): 8.95 (d, J = 7.7Hz, 1H), 8.02 (s, 4H), 7.85 (d, J = 8.1Hz, 2H), 7.69 (t, J = 7.2Hz, 4H), 7.56 (d, J = 7.7Hz, 2H),7.51(s,1H),5.22–5.14(m,1H),5.07(t,J=5.7Hz,1H),4.27(s,2H),3.74(s,2H),3.26(q,J=7.3Hz,2H),1.11(t,J=7.3Hz,3H).

[0873] Example 43: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(4-((4-(trifluoromethyl)phenyl)amino)thiazol-2-yl)benzamide

[0874]

[0875] Step 1: Synthesis of methyl 4-(4-((4-(trifluoromethyl)phenyl)amino)thiazol-2-yl)benzoate

[0876] Under nitrogen, 4-(trifluoromethyl)aniline (110 mg, 0.68 mmol), methyl 4-(4-bromothiazol-2-yl)benzoate (203 mg, 0.68 mmol), Pd(dba) (32 mg, 0.035 mmol), XantPhos (30 mg, 0.052 mmol), and CsCO (336 mg, 1.03 mmol) were dissolved in toluene (4 mL) and stirred in an oil bath at 100°C for 23 h. The reaction mixture was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 10 / 1 / 1) to afford the desired product as a yellow solid (33 mg, 12% yield).

[0877] MS(ESI,pos.ion)m / z=378.8[M+H] + .

[0878] Step 2: Synthesis of 4-(4-((4-(trifluoromethyl)phenyl)amino)thiazol-2-yl)benzoic acid

[0879] LiOH·H₂O (24 mg, 0.57 mmol) was added to a solution of methyl 4-(4-((4-(trifluoromethyl)phenyl)amino)thiazol-2-yl)benzoate (33 mg, 0.087 mmol) in THF / H₂O (3 mL / 1 mL). The mixture was heated in an oil bath at 50°C and stirred for 1 h. TLC confirmed complete conversion of the starting material. Water (10 mL) was added to the reaction system, followed by the dropwise addition of 1.0 M HCl solution to adjust the pH to 3. The aqueous phase was extracted with DCM (20 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford the crude product as a yellow solid (31 mg, 97.55% yield).

[0880] MS(ESI,pos.ion)m / z=365.1[M+H] + .

[0881] Step 3: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(4-((4-(trifluoromethyl)phenyl)amino)thiazol-2-yl)benzamide

[0882] 4-(4-((4-(trifluoromethyl)phenyl)amino)thiazol-2-yl)benzoic acid (31 mg, 0.085 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (24 mg, 0.10 mmol), EDCI (82 mg, 0.44 mmol), and HOBT (63 mg, 0.47 mmol) were dissolved in DCM (4 mL), and TEA (0.06 mL, 0.40 mmol) was added. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with DCM (80 mL), washed sequentially with saturated NaHCO₃(aq.) (20 mL) and NaCl(aq.) (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to give the product as a dark yellow solid (15 mg, yield: 31%).

[0883] MS(ESI,pos.ion)m / z=576.3[M+H] + ;

[0884] 1 H NMR (400MHz, d6-DMSO) δ (ppm): 9.60 (s, 1H), 8.96 (d, J = 7.9Hz, 1H), 8.05 (s, 4H), 7.85 (d, J = 8.3Hz, 2H), 7.69 (d, J=8.2Hz,2H),7.58(d,J=8.9Hz,2H),7.45(d,J=8.5Hz,2H),6.99(s,1H),5.18(dd,J=14.1,7.3Hz,1H),5.07(br 1H), 3.77 (s, 2H), 3.27 (d, J = 7.4Hz, 2H), 1.10 (t, J = 7.3Hz, 3H).

[0885] Example 44: (R)-4-(5-(Ethoxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0886]

[0887] Step 1: Synthesis of methyl 4-(5-(ethoxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate

[0888] MsCl (0.12 mL, 1.60 mmol) was added to a solution of methyl 4-(5-(hydroxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (202 mg, 0.49 mmol) and KCO (205 mg, 1.49 mmol) in DCM (4 mL) at -10°C, followed by stirring at room temperature for 2 h. Anhydrous EtOH (2 mL) was added, and the mixture was stirred at room temperature for 20 h, followed by heating and stirring in an 80°C oil bath for 4 h. LC-MS confirmed complete conversion of the starting material. Saturated NaCl (aq.) (20 mL) and water (20 mL) were added to the reaction mixture, and the aqueous phase was extracted with DCM (40 mL x 3). The combined organic phases were dried over anhydrous NaSO, and concentrated under reduced pressure to afford the crude product as a yellow solid (213 mg, 99% yield).

[0889] MS(ESI,pos.ion)m / z=438.0[M+H] + .

[0890] Step 2: Synthesis of 4-(5-(ethoxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid

[0891] LiOH·H₂O (112 mg, 2.67 mmol) was added to a solution of methyl 4-(5-(ethoxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (213 mg, 0.49 mmol) in THF / H₂O (6 mL / 2 mL) and stirred in a 50°C oil bath for 4 h. Water (20 mL) was added to the reaction solution, and 1.0 M HCl solution was added dropwise to the aqueous phase to adjust the pH to 3. The aqueous phase was extracted with DCM (30 mL x 3) and concentrated under reduced pressure to give the crude product as a yellow solid (200 mg, 97% yield).

[0892] MS(ESI,pos.ion)m / z=424.2[M+H] + .

[0893] Step 3: Synthesis of (R)-4-(5-(ethoxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide

[0894] 4-(5-(Ethoxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid (200 mg, 0.47 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (114 mg, 0.50 mmol), EDCI (186 mg, 0.97 mmol), and HOBT (135 mg, 1.00 mmol) were dissolved in DCM (8 mL), and TEA (0.26 mL, 1.90 mmol) was added. The mixture was stirred at room temperature for 10 h. LC-MS analysis indicated complete conversion of the starting material. DCM (60 mL) was added to the reaction solution, and then washed successively with saturated NaCl (aq.) (20 mL) and saturated NaHCO 3 (aq.) (20 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The crude product was separated successively by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2 / 1) and silica gel thin layer chromatography (developing solvent: DCM / EtOAc (v / v) = 2 / 1) to give the product as a yellow solid (80 mg, yield: 27%).

[0895] MS(ESI,pos.ion)m / z=635.3[M+H] + ;

[0896] v H NMR (400MHz, d6-DMSO) δ (ppm): 8.88 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7. 88(d,J=8.8Hz,2H),7.85(d,J=8.3Hz,2H),7.62-7.69(m,6H),5.16(dd,J=13.8 ,6.7Hz,1H),5.05(t,J=5.8Hz,1H),4.69(s,2H),3.80–3.68(m,2H),3.57(q,J= 7.0Hz, 2H), 3.27 (q, J = 7.4Hz, 2H), 1.16 (t, J = 7.0Hz, 3H), 1.10 (t, J = 7.4Hz, 3H).

[0897] Example 45: (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(5-((2-fluoroethoxy)methyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzamide

[0898]

[0899] Step 1: Synthesis of methyl 4-(5-((2-hydroxyethoxy)methyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate

[0900] MsCl (0.12 mL, 1.60 mmol) was added to a solution of methyl 4-(5-(hydroxymethyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (202 mg, 0.49 mmol), DIPEA (0.42 mL, 2.44 mmol), and KCO (205 mg, 1.49 mmol) in DCM (4 mL) at -10°C and stirred at room temperature for 2 h. Anhydrous ethylene glycol (3 mL) was added, and the reaction was heated in an oil bath at 60°C with stirring for 18 h. Saturated NaCl (aq.) (20 mL) and water (20 mL) were added to the reaction solution, and the aqueous phase was extracted with DCM (40 mL x 3). The organic phases were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to afford the crude product as a yellow solid (220 mg, 98% yield).

[0901] MS(ESI,pos.ion)m / z=454.2[M+H] + .

[0902] Step 2: Synthesis of methyl 4-(5-((2-fluoroethoxy)methyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate

[0903] DAST (0.13 mL, 0.98 mmol) was slowly added to a solution of methyl 4-(5-((2-hydroxyethoxy)methyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (220 mg, 0.49 mmol) in DCM (6 mL) under a -10°C cooling bath and stirred at room temperature for 6 h. The reaction was quenched by the addition of saturated NaHCO₃(aq.) (20 mL), and the aqueous phase was extracted with DCM (30 mL x 3). The combined organic phases were washed with saturated NaCl(aq.) (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 10 / 1 / 1) to afford the product as a yellow solid (94 mg, 43% yield).

[0904] MS(ESI,pos.ion)m / z=456.2[M+H] + .

[0905] Step 3: Synthesis of 4-(5-((2-fluoroethoxy)methyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid

[0906] LiOH·H2O (52 mg, 1.24 mmol) was added to a solution of methyl 4-(5-((2-fluoroethoxy)methyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoate (93 mg, 0.20 mmol) in THF / H2O (3 mL / 1 mL). The reaction was stirred in a 50°C oil bath for 2 h. TLC indicated a significant amount of residual starting material. Additional LiOH·H2O (110 mg, 2.62 mmol) was added, and heating and stirring were continued for 5 h. TLC indicated complete conversion of the starting material. H2O (20 mL) was added to the reaction mixture, and 1.0 M HCl solution was added dropwise to the aqueous phase to adjust the pH to 3. The aqueous phase was extracted with DCM (30 mL x 3) and concentrated under reduced pressure to afford the crude product as a yellow solid (91 mg, 100% yield).

[0907] MS(ESI,pos.ion)m / z=442.0[M+H] + .

[0908] Step 4: Synthesis of (R)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(5-((2-fluoroethoxy)methyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzamide

[0909] 4-(5-((2-fluoroethoxy)methyl)-2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid (91 mg, 0.21 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (64 mg, 0.28 mmol), EDCI (122 mg, 0.64 mmol), and HOBT (85 mg, 0.63 mmol) were dissolved in DCM (4 mL), and TEA (0.15 mL, 1.1 mmol) was added. The mixture was stirred at room temperature for 10 h. TLC indicated complete conversion of the starting material. DCM (60 mL) was added to the reaction solution, and then washed successively with saturated NaCl (aq.) (20 mL) and saturated NaHCO 3 (aq.) (20 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2 / 1) to give the product as a yellow solid (101 mg, yield: 75%).

[0910] MS(ESI,pos.ion)m / z=653.2[M+H] + ;

[0911] 1H NMR(400MHz,d6-DMSO)δ(ppm):8.89(d,J=7.8Hz,1H),7.99(d,J=8.4Hz,2H),7.89 (d,J=8.6Hz,2H),7.85(d,J=8.3Hz,2H),7.68(t,J=8.1Hz,6H),5.17(dd,J=13.8, 7.1Hz,1H),5.05(t,J=5.8Hz,1H),4.76(s,2H),4.67–4.63(m,1H),4.55–4.50(m, 1H), 3.85–3.80 (m, 1H), 3.74 (s, 3H), 3.27 (q, J = 7.3Hz, 2H), 1.10 (t, J = 7.3Hz, 3H).

[0912] Example 46: (R)-N-(1-(5-(ethylsulfonyl)pyridin-2-yl)-2-hydroxyethyl)-4-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzamide

[0913]

[0914] 4-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid (59 mg, 0.16 mmol), (R)-2-amino-2-(5-(ethylsulfonyl)pyridin-2-yl)ethanol dihydrochloride (70 mg, 0.21 mmol), EDCI (96 mg, 0.50 mmol), and HOBT (66 mg, 0.49 mmol) were dissolved in DCM (6 mL), and TEA (0.16 mL, 1.10 mmol) was added. The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM (60 mL), washed with saturated NaHCO₃(aq.) (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to give the product as a yellow solid (66 mg, yield: 71%).

[0915] MS(ESI,pos.ion)m / z=578.3[M+H] + ;

[0916] 1H NMR(400MHz,d6-DMSO)δ(ppm):8.91(d,J=7.6Hz,1H),8.83(s,1H),8.16(dd,J=8.1,1.9Hz,1H),8.04(d,J=8.1Hz,1H),7.98–7.92(m,4H),7.90(d,J=8 .8Hz,2H),7.67(d,J=8.5Hz,2H),5.21(dd,J=13.7,6.7Hz,1H),5.14(t,J=5 .8Hz,1H),3.86–3.72(m,2H),3.43(q,J=7.3Hz,3H),1.13(t,J=7.4Hz,3H).

[0917] Example 47: (S)-N-(2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-4-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzamide

[0918]

[0919] 4-(2-(4-(trifluoromethyl)phenoxy)thiazol-4-yl)benzoic acid (80 mg, 0.22 mmol), (S)-3-amino-3-(4-(ethylsulfonyl)phenyl)propionitrile (57 mg, 0.24 mmol), EDCI (62 mg, 0.32 mmol), and HOBT (44 mg, 0.33 mmol) were dissolved in DCM (6 mL). TEA (44 mg, 0.43 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 5 / 1) to give a white solid (95 mg, 74% yield).

[0920] MS(ESI,pos.ion)m / z=586.0[M+H] + ;

[0921] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.87–7.79 (m, 6H), 7.66 (d, J = 8.7Hz, 2H), 7.63 (d, J = 8.2Hz, 2H), 7.43 (d, J = 8.4 Hz,2H),7.25(d,J=6.0Hz,1H),7.18(s,1H),5.54(t,J=6.6Hz,1H),3.11–3.01(m,4H),1.22(t,J=7.4Hz,3H).

[0922] Biological activity test

[0923] In vitro RORγt affinity activity assay of the compounds of the present invention

[0924] 1) Test method

[0925] (1) Prepare RORγt assay buffer and 10 mM DTT

[0926] Prepare 100 mL of 1× basic assay buffer (HEPES (pH 7.4), 100 mM NaCl, 0.01% BSA), add 154.25 mg of DTT, and mix thoroughly.

[0927] (2) Preparation of compound concentration gradients

[0928] a. Prepare standard compounds by diluting them to 2.5 mM with 100% DMSO, then diluting them 3-fold, and performing 11 serial dilutions to a final concentration of 42.34 nM;

[0929] b. Prepare experimental compounds and reference standard compounds.

[0930] (3) Prepare 1x protein solution mixture

[0931] a. Prepare the required amount of a 2x B-RORγt LBD / SA-APC protein mixture. The concentration of B-RORγt LBD is 40 nM, and the concentration of SA-APC is 20 nM. Gently invert the mixture to mix thoroughly, and incubate at room temperature for 15 minutes. Then, add 400 nM biotin, gently invert the mixture to mix thoroughly, and incubate at room temperature for 10 minutes.

[0932] b. Prepare the required amount of a 2x Biotin-SRC1 / SA-eu protein mixture. The concentration of Biotin-SRC1 is 40 nM, and the concentration of SA-eu is 20 nM. Gently invert the mixture to mix thoroughly, and incubate at room temperature for 15 minutes. Then, add 200 nM biotin, gently invert the mixture to mix thoroughly, and incubate at room temperature for 10 minutes.

[0933] c. Mix the protein mixture prepared in step a and step b in a ratio of 1:1 and incubate at room temperature for 5 minutes;

[0934] d. Add 25 μL of the mixture in step c to a 384-well plate containing the test compound;

[0935] e. Centrifuge at 1000 rpm for one minute;

[0936] f. Incubate at room temperature for 1 hour.

[0937] (4) Data collection and calculation

[0938] After incubation at room temperature for 1 hour, the fluorescence values ​​at 665 nm and 615 nm were measured using an EnVision plate reader, and the inhibition rate was calculated. Graphpad 5.0 was used to fit the inhibition rate at each concentration point of the compound to obtain the IC 50 The final IC 50 The values ​​are shown in Table 1;

[0939] Inhibition rate (%) = [(X-Min) / (Max-Min)] × 100%

[0940] X is the fluorescence ratio of the test compound at 665 nm / 615 nm; Min is the average fluorescence ratio of the DMSO blank control at 665 nm / 615 nm; Max is the average fluorescence ratio of 10 μM Bioin-SRC1 at 665 nm / 615 nm.

[0941] 2) Test results

[0942] Table 1 Evaluation of the affinity activity of the compounds of the present invention for RORγt

[0943] Example No. <![CDATA[IC 50 (nM)]]> Example No. <![CDATA[IC 50 (nM)]]> Example 2 70 Example 17 11.3 Example 4 25 Example 18 25 Example 6 17 Example 20 30.7 Example 9 12 Example 21 50.8 Example 10 26 Example 24 71 Example 11 12 Example 27 45.4 Example 12 63 Example 34 19.5 Example 13 19 Example 44 58.5 Example 15 49.2 Example 45 64 Example 16 13.1 / /

[0944] Conclusion: The experimental results show that the compounds of the present invention have good affinity activity to RORγt.

[0945] Pharmacokinetic evaluation

[0946] ICR mice were weighed after fasting for 15 hours overnight and randomly divided into groups according to body weight. The test compound was formulated in a solvent of 5% DMSO + 5% Solutol + 90% Saline. For the experimental group administered intravenously, the experimental animals were given a dose of 1 mg / kg; for the experimental group administered orally, the experimental animals were given a dose of 5 mg / kg. Then, venous blood (approximately 0.2 mL) was collected at time points of 0, 0.083 (only intravenous injection group), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours, placed in EDTAK2 anticoagulant tubes, centrifuged at 11,000 rpm for 2 minutes, and plasma was collected and stored at -20°C or -70°C until LC / MS / MS analysis. The drug concentration in plasma at each time point was determined, and the pharmacokinetic parameters were calculated based on the drug concentration-time curve.

[0947] The pharmacokinetic properties of the compounds of the present invention were tested by the above experiments. The experimental results showed that the compounds of the present invention had good pharmacokinetic characteristics in ICR mice.

[0948] Finally, it should be noted that there are other ways to implement the present invention. Accordingly, the embodiments of the present invention are provided for illustration and are not intended to limit the present invention to the present invention. Modifications may be made within the scope of the present invention, and equivalents may be added to the claims. All publications and patents cited herein are hereby incorporated by reference.

Claims

1. A compound, which is a compound represented by formula (I) or a stereoisomer of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, in: L1 is a bond, -O-, -CH2-, *-(CH2) n -O-, *-O-(CH2) n - or -NH-; where * indicates connection to ring A; L2 is **-C(=O)-NH- or **-NH-C(=O-); wherein ** indicates connection to an aromatic ring; Z1 is CR1 or N; Z2 is CR2 or N; Z3 is CR3 or N; Z4 is CR4 or N; R1, R2, R3 and R4 are each independently H, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxy substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Haloalkyl or C 1-4 haloalkoxy; R is C 6-10 Aryl; wherein the C 6-10 Aryl is independently optionally substituted with 1, 2, 3, 4 or 5 R5; Each R5 is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; Ring A is a heteroaryl group composed of 5 atoms; Each R6 is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl, -C(=O)-N(R a R b ), C 3-8 Cycloalkyl or heterocyclic group composed of 3-8 atoms; wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl group and the heterocyclic group consisting of 3 to 8 atoms are each independently optionally substituted by 1, 2 or 3 R 6a replaced by; Each R 6a are independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl or heterocyclic group consisting of 3-8 atoms; R a and R b are independently H, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl or C 1-4 haloalkoxy; B ring is C 6-10 Aryl or heteroaryl consisting of 5-10 atoms; R7 is -S(=O)2-C 1-4 alkyl; R8 and R9 are each independently H, deuterium, -OH, -CN, -NH2, -COOH, C 1-4 Alkoxy, C 1-4 Haloalkyl, hydroxy substituted C 1-4 Alkyl or carboxyl substituted C 1-4 alkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, or 3; p is 0, 1, 2, 3 or 4.

2. The compound according to claim 1, wherein R1, R2, R3 and R4 are each independently H, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2C H2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, -C(OH)(CF3)2, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2 or -OCH2CH2CF3.

3. The compound according to claim 1, wherein R is phenyl or naphthyl; wherein the phenyl and naphthyl groups are each independently optionally substituted by 1, 2, 3, 4 or 5 R5; Each R5 is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF 2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2 or -OCH2CH2CF3.

4. The compound according to claim 1, wherein Ring A is 5. The compound according to claim 1, wherein Each R6 is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-N(R a R b ), C 3-6 Cycloalkyl or heterocyclic group composed of 3-6 atoms; wherein the C 1-4 Alkyl, C 3-6 The cycloalkyl group and the heterocyclic group consisting of 3-6 atoms are each independently optionally substituted by 1, 2 or 3 R 6a replaced by; Each R 6a are independently and optionally deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl or heterocyclic group consisting of 3-6 atoms; R a and R b are independently H, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl or C 1-4 Halogenated alkoxy.

6. The compound according to claim 1, wherein Each R6 is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2 F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, -C(=O)-CH3, -C(=O)-CH2CH 3. -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)CH3, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH2CH2CH3, -C(=O)-O-CH(CH3)CH3, -C(=O)-N(R a R b ), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl or tetrahydropyranyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl and tetrahydropyranyl are each independently and optionally replaced by 1, 2 or 3 R 6a replaced by; Each R 6a are independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butyl Oxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl or tetrahydropyranyl; R a and R b Each is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2 or -OCH2CH2CF3.

7. The compound according to claim 1, wherein B ring is C 6-10 aryl or heteroaryl consisting of 5-6 atoms; or Ring B is phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl or tetrazolyl.

8. The compound according to any one of claims 1 to 7, which is a compound represented by formula (II) or a stereoisomer of the compound represented by formula (II), or a pharmaceutically acceptable salt thereof: in: Z5 is N or CH; R 5a 、R 5b 、R 5c 、R 5d and R 5e Each is independently H, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF 2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCHFCH2F, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2 or -OCH2CH2CF3.

9. The compound according to claim 1 or 8, wherein Each R7 is independently deuterium, -S(=O)2-CH3, -S(=O)2-CH2CH3, -S(=O)2-CH2CH2CH3 or -S(=O)2-CH(CH3)CH3.

10. The compound according to claim 1 or 8, wherein R8 and R9 are each independently H, deuterium, -OH, -CN, -NH2, -COOH, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH(CH3)CH2OH, -CH2(CH2)3OH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH(CH3)CH2COOH or -CH2(CH2)3COOH.

11. A compound having one of the following structures or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, and a pharmaceutically acceptable excipient.

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, and a pharmaceutically acceptable adjuvant.

15. The pharmaceutical composition according to any one of claims 12 to 14, comprising other drugs for preventing or treating inflammatory syndromes, disorders or diseases, or any combination thereof.

16. Use of the compound of any one of claims 1 to 11 or the pharmaceutical composition of any one of claims 12 to 15 in the preparation of a medicament for treating a disease, disorder or syndrome mediated by RORγt in a mammal; wherein: The disease, disorder or syndrome mediated by RORγt is psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, autoimmune eye disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis or Kawasaki disease.

17. The use according to claim 16, wherein The inflammatory bowel disease is colitis.

18. The use according to claim 17, wherein The colitis is ulcerative colitis or Crohn's disease.

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