RORγt inhibitors, methods for producing same and uses thereof

Abstract

The present invention relates to the technical field of drugs, specifically to RORγt inhibitors, their preparation and use, as well as to pharmaceutical compositions containing the compounds, methods for preparing the pharmaceutical compositions, and the use of the compounds or pharmaceutical compositions in the prevention or treatment of cancer, inflammation, or autoimmune diseases mediated by RORγt in mammals, particularly humans.

Description

[Technical Field]

[0001] This application primarily claims priority from Chinese Patent Application No. 202010008803.7 filed on January 6, 2020 and Chinese Patent Application No. 202010009133.0 filed on January 6, 2020.

[0002] The present invention relates to the technical field of drugs, and specifically to small molecule compounds, compositions, and methods for producing and using the same. The compounds or compositions can be used as retinoid-related orphan receptor gamma t (RORγt) inhibitors for the prevention or treatment of cancer, inflammation, or immune-related diseases. [Background technology]

[0003] Retinoid-related orphan receptors (RORs) are a subfamily of transcription factors within the steroid hormone nuclear receptor superfamily. The ROR family includes RORα, RORβ, and RORγ, which are encoded by distinct genes (RORA, RORB, and RORC), respectively. Retinoid-related orphan receptors contain four major domains: an N-terminal A / B domain, a DNA-binding domain, a hinge domain, and a ligand-binding domain.

[0004] Retinoid-related orphan receptor gamma t (RORγt) is one of two isoforms of retinoid-related orphan receptor gamma (RORγ), and may also be referred to as RORγ2. Studies have shown that RORγt is expressed exclusively in lymphoid and fetal lymphoid tissue-derived cells (Sun et al., Science 288: 2369-2372, 2000; Eberl et al., Nat Immunol. 5: 64-73, 2004). RORγt, a hallmark transcription factor of helper T cells (Th17), plays an important role in Th17 cell differentiation and is a key modulator of Th17 cell differentiation (Ivanov, II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. Cell 2006; 126(6): 1121-33).

[0005] Th17 cells secrete interleukin 17 (IL-17) and other inflammatory cytokines, which play an important role in autoimmune diseases and host defense responses. IL-17 is a pro-inflammatory cytokine involved in the progression of inflammation and various autoimmune diseases, including 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). IL-17 is also associated with the development of inflammation-related tumors. Th17 cells are activated during disease processes and recruit other inflammatory cell types, such as neutrophils, to mediate pathology in target tissues (Korn et al., Annu. Rev. Immunol., 2009, 27:485-517).

[0006] The role of RORγt in the pathogenesis of autoimmune diseases or inflammation has been widely studied and well described (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, inhibiting RORγt can effectively inhibit the differentiation of Th17 cells, regulate the production and secretion levels of IL-17 and other inflammatory cytokines, and regulate the body's immune system, treating cancer, immune diseases and inflammatory diseases associated with RORγt regulation. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Sun et al., Science 288: 2369-2372, 2000 [Non-patent document 2] Eberl et al., Nat Immunol. 5: 64-73, 2004 [Non-patent document 3] Ivanov, II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. Cell 2006; 126(6): 1121-33 [Non-patent document 4] Jetten et al., Nucl. Recept. Signal, 2009, 7:e003 [Non-Patent Document 5] Manel et al., Nat. Immunol., 2008, 9, 641-649 [Non-patent document 6] Jetten et al., Adv. Dev.Biol, 2006, 16: 313-355 [Non-Patent Document 7] Meier et al. Immunity, 2007, 26:643-654 [Non-patent document 8] Aloisi et al., Nat. Rev. Immunol., 2006, 6:205-217 [Non-Patent Document 9] Jager et al., J. Immunol., 2009, 183:7169-7177 [Non-Patent Document 10] Barnes et al., Nat. Rev. Immunol., 2008, 8: 183-192 Summary of the Invention

[0008] The following is a summary of only some aspects of the present invention, and the present invention is not limited thereto. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. If the disclosure of this specification differs from the cited references, the disclosure of this specification shall prevail.

[0009] The present invention provides compounds having retinoid-related orphan receptor gamma t (RORγt) inhibitory activity, which can be used for the manufacture of medicaments for preventing or treating cancer, inflammation, or autoimmune diseases mediated by RORγt, such as cancer, 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, Kawasaki disease, etc. The compounds of the present invention can effectively inhibit RORγt and have excellent physicochemical and pharmacokinetic properties.

[0010] The invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds or compositions to treat such disorders in mammals, particularly humans.

[0011] in particular, In one aspect, the present invention relates to a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (I).

[0012] [ka] (In the formula, R is C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylamino group, C 3-8 Cycloalkylamino group, -C 1-6 Alkylene-C 3-8 Cycloalkyl groups, C 3-8 Cycloalkyl groups, C 1-6 Halogenated alkyl group or C 1-6 is a halogenated alkoxy group, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are each independently 1 or N, Each R 1 are independently hydrogen, deuterium, cyano group, fluorine, chlorine, bromine, iodine, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, hydroxy-substituted C 1-6 Alkyl group, -C 1-6 Alkylene-C 1-6 Alkoxy group, C 1-6 Alkoxy group, C 3-8 a cycloalkyl group or a 3- to 7-membered heterocyclic group, Ring A is a 3- to 5-membered heterocyclic group or a 7-membered heterocyclic group, and the 3- to 5-membered heterocyclic group and the 7-membered heterocyclic group independently contain 1, 2, 3, 4, or 5 R 2 optionally substituted with *, and * indicates the direction in which ring A and ring C are bonded; Each R 2 are independently an oxo group, R a , C 1-6 Alkyl group, -C 1-6 Alkylene-R a , -OR b , -C 1-6 Alkylene-OR b , -C(=O)-R a , -C 1-6 Alkylene-C(=O)-R a , -C(=O)-NR c R d or -C 1-6 Alkylene-C(=O)-NR c R d and Each R a are independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 3-8 Cycloalkyl groups, C 6-10 an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 7-membered heterocyclic group, a 5- to 12-membered spirocyclic group, a 4- to 12-membered fused ring group, a 5- to 12-membered spiroheterocyclic group, or a 4- to 12-membered fused heterocyclic group; Each R b , R c and R d are independently hydrogen, deuterium, and C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 3-8 Cycloalkyl groups, C 6-10 an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 7-membered heterocyclic group, a 5- to 12-membered spirocyclic group, a 4- to 12-membered fused ring group, a 5- to 12-membered spiroheterocyclic group, or a 4- to 12-membered fused heterocyclic group, or R c and R dform a 4- to 7-membered heterocyclic group together with the N atom to which they are bonded, and each R a , R b , R c and R d independently, 1, 2, 3, 4, 5, or 6 R g optionally replaced by Each R g are independently deuterium, fluorine, chlorine, bromine, iodine, oxo, hydroxyl group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 3-8 a cycloalkyl group or a 3- to 7-membered heterocyclic group, The B ring is C 6-10 Aryl group, C 3-8 a cycloalkyl group, a 5- to 12-membered heteroaryl group, a 3- to 7-membered heterocyclic group, a 4- to 12-membered fused heterocyclic group, a 5- to 12-membered spiro heterocyclic group, a 4- to 12-membered fused ring group, or a 5- to 12-membered spiro ring group, and the B ring is e optionally replaced by Each R e are independently deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro group, hydroxyl group, amino group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-8 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 1-6 Halogenated alkyl group or C 1-6 is a halogenated alkoxy group, 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-8 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 1-6 Halogenated alkyl groups and C 1-6 the halogenated alkoxy group is optionally substituted with 1, 2, 3, or 4 substituents independently selected from a cyano group, a nitro group, a hydroxyl group, an amino group, or a 3- to 7-membered heterocyclic group; L 1is -S(=O)2-NH-, -NH-S(=O)2-, -S(=O)-NH-, -NH-S(=O)-, -C(=O)NH- or -NHC(=O)-, L 2 is a bond or -CR 3 R 4 - and L 3 is a carbonyl group, S, -O-, -NR 5 -or-CR 6 R 7 - and R 3 is hydrogen, deuterium, hydroxy-substituted C 1-6 Alkyl group, -C 1-6 Alkylene-OC(=O)-R f , -C 1-6 Alkylene-C(=O)-OR f or -C 1-6 Alkylene-R f and R f is C 2-6 Alkyl, amino-substituted C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, -C 1-6 Alkylene-C(=O)-OR h Or -OP(=O)-(OR m )(OR n ) and R h , R m and R n are independently hydrogen, deuterium, sodium, potassium, and C 1-6 Alkyl group or C 1-6 is a halogenated alkyl group, R 4 is hydrogen, deuterium or hydroxy substituted C 1-6 is an alkyl group, R 5 are hydrogen, deuterium, and C 1-4 Alkyl group, C 1-4 Halogenated alkyl groups, C 1-4 Alkoxy group, C 3-6 a cycloalkyl group or a 3- to 6-membered heterocyclic group, Each R 6 and R 7are independently hydrogen, deuterium, and C 1-4 Alkyl group, C 1-4 Halogenated alkyl groups, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy group, C 3-6 It is a cycloalkyl group or a 3- to 6-membered heterocyclic group.

[0013] In some embodiments, R is C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Alkylamino group, C 3-6 Cycloalkylamino group, -C 1-4 Alkylene-C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyl groups, C 1-4 Halogenated alkyl group or C 1-4 It is a halogenated alkoxy group.

[0014] In some embodiments, each R 1 are independently hydrogen, deuterium, cyano group, fluorine, chlorine, bromine, iodine, C 1-4 Alkyl group, C 1-4 Halogenated alkyl groups, hydroxy-substituted C 1-4 Alkyl group, -C 1-4 Alkylene-C 1-4 Alkoxy group, C 1-4 Alkoxy group, C 3-6 It is a cycloalkyl group or a 3- to 7-membered heterocyclic group.

[0015] In some embodiments, each R 2 are independently oxo, R a , C 1-4 Alkyl group, -C 1-4 Alkylene-R a , -OR b , -C 1-4 Alkylene-OR b , -C(=O)-R a , -C 1-4 Alkylene-C(=O)-R a , -C(=O)-NR c R d or -C1-4 Alkylene-C(=O)-NR c R d is.

[0016] In some embodiments, each R a are independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl group, amino group, nitro group, cyano group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 6-10 an aryl group, a 5- to 7-membered heteroaryl group, a 3- to 7-membered heterocyclic group, a 5- to 12-membered spirocyclic group, a 4- to 12-membered fused ring group, a 5- to 12-membered spiroheterocyclic group, or a 4- to 12-membered fused heterocyclic group; Each R b , R c and R d are independently hydrogen, deuterium, and C 1-4 Alkyl group, C 1-4 Halogenated alkyl groups, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 6-10 an aryl group, a 5- to 7-membered heteroaryl group, a 3- to 7-membered heterocyclic group, a 5- to 12-membered spirocyclic group, a 4- to 12-membered fused ring group, a 5- to 12-membered spiroheterocyclic group, or a 4- to 12-membered fused heterocyclic group, or R c and R d form a 4- to 7-membered heterocyclic group together with the N atom to which they are bonded, and each R a , R b , R c and R d independently, 1, 2, 3, 4, 5, or 6 R g is optionally replaced by

[0017] In some embodiments, each R g are independently deuterium, fluorine, chlorine, bromine, iodine, oxo, hydroxyl group, amino group, nitro group, cyano group, C 1-4 Alkyl group, C 1-4 Halogenated alkyl groups, C 1-4 Alkoxy group, C 1-4 Halogenated alkoxy groups, C3-6 It is a cycloalkyl group or a 3- to 7-membered heterocyclic group.

[0018] In some embodiments, the B ring is C 6-10 Aryl group, C 3-6 a cycloalkyl group, a 5- to 7-membered heteroaryl group, a 3- to 7-membered heterocyclic group, a 4- to 12-membered fused heterocyclic group, a 5- to 12-membered spiro heterocyclic group, a 4- to 12-membered fused ring group, or a 5- to 12-membered spiro ring group, and the B ring is e is optionally replaced by

[0019] In some embodiments, each R e are independently deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro group, hydroxyl group, amino group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 1-4 Halogenated alkyl group or C 1-4 is a halogenated alkoxy group, 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 1-4 Halogenated alkyl groups and C 1-4 The halogenated alkoxy group is optionally substituted with 1, 2, 3, or 4 substituents independently selected from a cyano group, a nitro group, a hydroxyl group, an amino group, or a 3- to 7-membered heterocyclic group.

[0020] In some embodiments, R 3 is hydrogen, deuterium, hydroxy-substituted C 1-4 Alkyl group, -C 1-4 Alkylene-OC(=O)-R f , -C 1-4 Alkylene-C(=O)-OR f or -C 1-4 Alkylene-R f is.

[0021] R f is C 2-4 Alkyl, amino-substituted C1-4 Alkyl group, C 1-4 Halogenated alkyl groups, -C 1-4 Alkylene-C(=O)-OR h Or -OP(=O)-(OR m )(OR n ) and R h , R m and R n are independently hydrogen, deuterium, sodium, potassium, and C 1-4 Alkyl group or C 1-4 is a halogenated alkyl group, R 4 is hydrogen, deuterium or hydroxy substituted C 1-4 It is an alkyl group.

[0022] In another embodiment, R is methyl, ethyl, n-propyl, isopropyl, -CHF, -CHF, -CF, -CHFCHF, -CFCH, -CHCHF, -CHCF, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, ethylamino, dimethylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, -methylene-cyclopropyl, -methylene-cyclobutyl, -methylene-cyclopentyl, -methylene-cyclohexyl, -ethylene-cyclopropyl, -ethylene-cyclobutyl, -ethylene-cyclopentyl, -ethylene-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0023] In another embodiment, each R 1are independently hydrogen, deuterium, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, -CHF, -CHF, -CF, -CHFCHF, -CFCH, -CHCHF, -CHCF, methoxy, ethoxy, n-propoxy, isopropoxy, hydroxymethyl, 2-hydroxyethyl, -methylenemethoxy, -methyleneethoxy, -methylene-n-propoxy, -methyleneisopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0024] In another embodiment, the A ring is [ka] wherein * represents the direction in which ring A and ring C are bonded, and ring A is a ring having 1, 2, 3, 4, or 5 R 2 is optionally replaced by

[0025] In another embodiment, each R 2 are independently oxo, R a , methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, tert-butyl group, -CH2R a , -CH2CH2R a , -CH2CH2CH2R a , -C(CH3)2R a , -CH(CH3)CH2R a , -OR b , -CH2OR b , -CH2CH2OR b , -CH2CH2CH2OR b , -C(CH3)2OR b , -CH(CH3)CH2OR b , -C(=O)-R a , -CH2C(=O)-R a , -CH2CH2C(=O)-R a , -CH2CH2CH2C(=O)-R a , -C(CH3)2C(=O)-R a , -CH(CH3)CH2C(=O)-Ra , -C(=O)-NR c R d , -CH2C(=O)-NR c R d , -CH2CH2C(=O)-NR c R d , -CH2CH2CH2C(=O)-NR c R d , -C(CH3)2C(=O)-NR c R d or -CH(CH3)CH2C(=O)-NR c R d is.

[0026] In another embodiment, each R a are independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl group, amino group, nitro group, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, tert-butyl group, methoxy group, ethoxy group, isopropoxy group, -CH2F, -CHF2, -CF3, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CH2CH3, -CH2CH2CHF2, -CF2CH2F, -CF2CHF2, -CF2CF3, oxetanyl group, azetidinyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, piperidinyl group, piperazinyl group, oxepanyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, thiazolyl group, pyrazolyl group, imidazolyl group, furanyl group, oxazolyl group, isoxazolyl group, triazole group, thienyl group, pyrrole group, pyridyl group, pyrimidinyl group, [ka] and Each R b , R c and R dare independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CH2CH3, -CH2CH2CHF2, -CF2CH2F, -CF2CHF2, -CF2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutyloxy, sec-butoxy a silyl group, a tert-butoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, an oxetanyl group, an azetidinyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a morpholinyl group, a thiomorpholinyl group, a piperidinyl group, a piperazinyl group, an oxepanyl group, a thiazolyl group, a pyrazolyl group, an imidazolyl group, a furanyl group, an oxazolyl group, an isoxazolyl group, a triazole group, a thienyl group, a pyrrole group, a pyridyl group, a pyrimidinyl group, [ka] or R c and R d together with the N atoms to which they are attached, [ka] Forming Each of the above R a , R b , R c and R d independently, 1, 2, 3, 4, 5, or 6 R g is optionally replaced by

[0027] In another embodiment, each R gare independently deuterium, fluorine, chlorine, bromine, iodine, oxo, hydroxyl group, amino group, nitro group, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, tert-butyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, -CH2F, -CHF2, -CF3, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CH2CH3, -CH2CH2CHF2, -CF2CH2F, -CF2CHF2, -CF2C F3, -OCH2F, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CH3, -OCH2CHF2, -OCH2CF3, -OCF2CH2CH3, -OCH2CH2CHF2, -OCF2CH2F, -OCF2CHF2, -OCF2CF3, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, azetidinyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, piperidinyl group, piperazinyl group or oxepanyl group.

[0028] In another embodiment, Ring B is selected from the group consisting of a phenyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a pyridyl group, a pyrimidinyl group, a pyrrole group, a pyrazolyl group, a thiazolyl group, an imidazolyl group, a furanyl group, an oxazolyl group, an isoxazolyl group, a thienyl group, a triazole group, a tetrazolium group, a piperazinyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, an azetidinyl group, an oxetanyl group, [ka] and the B ring is selected from the group consisting of 1, 2, 3, or 4 R e is optionally replaced by

[0029] In another embodiment, each R eare independently deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro group, hydroxyl group, methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, azetidinyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, piperidinyl group, piperazinyl group, oxepanyl group, -CHF, -CHF, - CF3, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CH2CH3, -CH2CH2CHF2, -CF2CH2F, -CF2CHF2, -CF2CF3, -OCH2F, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CH3, -OCH2CHF2, -OCH2CF3, -OCF2CH2CH3, -OCH2CH2CHF2, -OCF2CH2F, -OCF2CHF2 or -OCF2CF3, and the methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, Ethoxy group, n-propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, azetidinyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, piperidinyl group, piperazinyl group, oxepanyl group, -CH2F, -CHF2, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CH2CH3, -CH2CH2CHF2, -CF2CH2F, -CF2CHF2, - OCH2F, -OCHF2, -OCHFCH2F, -OCF2CH3, -OCH2CHF2, -OCH2CF3, -OCF2CH2CH3, -OCH2CH2CHF2, -OCF2CH2F and -OCF2CHF2 are optionally substituted with 1, 2, 3 or 4 substituents independently selected from cyano, nitro, hydroxyl, amino, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, azetidinyl or oxetanyl groups. In another embodiment, R 3represents hydrogen, deuterium, hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxy-n-propyl group, 2-hydroxy-1-methylethyl group, -CH2OC(=O)R f , -CH2CH2OC(=O)R f , -CH2CH2CH2OC(=O)R f , -CH(CH3)2OC(=O)R f , -CH2C(=O)OR f , -CH2CH2C(=O)OR f , -CH2CH2CH2C(=O)OR f , -CH(CH3)2C(=O)OR f , -CH2R f , -CH2CH2R f , -CH2CH2CH2R f or -CH(CH3)2R f and R f is an ethyl group, an n-propyl group, an isopropyl group, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(NH2)CH(CH3)2, -CH2F, -CHF2, -CF3, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, -CH2C(=O)ONa, -CH2CH2C(=O)-ONa, -CH2CH2CH2C(=O)ONa, -CH(CH3)2C(=O)ONa or -OP(=O)(ONa)2, R 4 is hydrogen, deuterium, a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxyethyl group, a 3-hydroxy-n-propyl group, or a 2-hydroxy-1-methylethyl group.

[0030] In another embodiment, R 5 is hydrogen, deuterium, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, s-butyl, tert-butyl, -CHF, -CHF2, -CF3, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl or azetidinyl; Each R6 and R 7 are independently hydrogen, deuterium, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, s-butyl, tert-butyl, -CHF, -CHF2, -CF3, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, or azetidinyl.

[0031] In another aspect, the pharmaceutical composition of the present invention comprises a compound of formula (I) of the present invention or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, or a combination thereof.

[0032] The pharmaceutical composition may further contain, as other active ingredients, a drug for treating cancer, a drug for preventing or treating inflammatory syndromes, a drug for preventing or treating autoimmune diseases, or any combination thereof.

[0033] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof in the manufacture of a medicament for preventing or treating cancer, inflammation or autoimmune disease mediated by RORγt in a mammal, including a human.

[0034] In some embodiments, the present invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof in the manufacture of a medicament for preventing or treating cancer, 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.

[0035] In another aspect, the present invention relates to methods for making, isolating and purifying compounds of formula (I).

[0036] The biological test results show that the compounds according to the present invention have good inhibitory activity against RORγt and also have good pharmacokinetic properties.

[0037] Any embodiment of any aspect of the present invention may be combined with any other embodiment unless there is a contradiction, and any technical feature of any embodiment of any aspect of the present invention may be applied to the same technical feature of any other embodiment.

[0038] The foregoing outlines some aspects of the present invention, which are not intended to be limiting, and these and other aspects are described in more detail and completely below.

[0039] Detailed Description of the Invention Definitions and General Terms Some embodiments of the present invention are described in detail below, examples of which are illustrated by the accompanying structural and chemical formulae. The present invention is intended to include all alternatives, modifications, and equivalent technical solutions, all of which are included within the scope of the present invention as defined by the claims. It will be apparent to those skilled in the art that numerous methods and materials similar or equivalent to those described herein can all be applied to the practice of the present invention. The present invention is not limited to the methods and materials described herein. In the event that one or more of the referenced literature, patents, or similar materials differs or contradicts this application (including, but not limited to, defined terms, term usage, described techniques, etc.), this application controls.

[0040] It should be noted that some features of the invention are, for clarity, described in the context of separate embodiments, but may also be provided in combination in a single example. Conversely, various features of the invention may, for convenience, be described in a single embodiment, but may also be provided alone or in any suitable subcombination.

[0041] Unless otherwise specified, all scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patent documents and publications related to this invention are incorporated herein by reference in their entirety.

[0042] The following definitions as used herein apply unless otherwise specified. For purposes of the present invention, the chemical elements are defined in accordance with the CAS version of the Periodic Table of the Elements and the Handbook of Chemistry and Physics, 75th Edition, 1994. For general principles of organic chemistry, reference may also be made to 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.

[0043] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," "one," and "said," as used herein, are intended to mean "at least one" or "one or more." Thus, as used herein, these articles refer to one or more (i.e., at least one) of the object article. For example, "a component" means one or more components, i.e., one or more components may be employed or used in the embodiments.

[0044] As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. Subject also refers to, for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0045] As used herein, the term "patient" refers to a human (including adults and children) or other animal. In some embodiments, "patient" refers to a human.

[0046] The term "comprising" is an open-ended expression, ie, including the content specified in the present invention, but not excluding other content.

[0047] "Stereoisomers" means compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereoisomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, atropisomers, etc.

[0048] "Chiral" refers to a molecule that has the property of not being superimposable on its mirror image, whereas "achiral" refers to a molecule that is superimposable on its mirror image.

[0049] "Enantiomers" refer to two isomers of a compound which are non-superimposable mirror images of one another.

[0050] "Diastereoisomer" means a stereoisomer that has 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 (e.g., HPLC).

[0051] The stereochemical definitions and rules used in the present invention generally follow those in S.P. 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.

[0052] Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and l, or (+) and (-), are used to indicate the sign of rotation of plane-polarized light by the compound, with (-) or l indicating that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. Specific stereoisomers are enantiomers, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate; this situation can occur when there is no stereoselection or stereospecificity in a chemical reaction or process.

[0053] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can be present in racemic or enantiomerically enriched form, such as the (R)-, (S)-, or (R,S)-configuration. In some 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 the (R)- or (S)-configuration.

[0054] Depending on the selection of starting materials and methods, the compounds of the present invention can exist in the form of one of the possible isomers (depending on the number of asymmetric carbon atoms) or in the form of a mixture thereof, for example, in the form of a racemate or a diastereoisomeric mixture. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds contain one double bond, the substituents can be in the E- or Z-configuration, and when the compounds contain a disubstituted cycloalkyl group, the cycloalkyl group substituents can have a cis- or trans-configuration.

[0055] Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, or diastereoisomers based on differences in the physicochemical properties of the components, for example, by chromatographic and / or fractional crystallization techniques.

[0056] Any racemic final product or intermediate obtained can be resolved into its optical antipodes by methods known to those skilled in the art, for example, by separation of the diastereoisomeric salts obtained. Racemic products can also be resolved by chiral chromatography, for example, by high performance liquid chromatography using a chiral adsorbent (HPLC: chromatography column: Chiralpak AD-H (4.6 mm*250 mm, 5 μm), mobile phase: n-hexane:ethanol=40:60, isocratic elution, flow rate: 1 mL / min). In particular, enantiomers can be prepared by asymmetric synthesis, for example, as described in Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Reference may be made to Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0057] As described herein, the compounds of the present invention are compounds that may be optionally substituted with one or more substituents, such as compounds of the general formula above, or specific examples, subclasses, and compounds included in the examples.

[0058] Generally, the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent. Unless otherwise specified, a substituted group may have a substituent substituting at each substitutable position of the group. When more than one position in a given structural formula is substitutable with one or more substituents selected from a specified group, the substituents substituting at each position may be the same or different.

[0059] The term "unsubstituted" means that the specified group bears no substituents.

[0060] The term "optionally substituted with" may be used interchangeably with the term "unsubstituted or substituted with," i.e., the above structure is unsubstituted or substituted with one or more substituents according to the present invention. Substituents according to the present invention include, but are not limited to, D, oxo (=O), F, Cl, Br, I, CN, NO, OH, SH, NH, carboxyl, aldehyde, alkyl, halogenated alkyl, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, alkylenealkoxy, alkylenecycloalkyl, cycloalkylamino, carbocyclic, cycloalkyl, heterocyclic, aryl, heteroaryl, spiroheterocyclic, fused heterocyclic, spirocyclic, fused ring, and the like.

[0061] Unless otherwise clearly stated, the phrases "each *** independently," "respectively independently," and "independently" used in the present invention may be used interchangeably, and may mean that specific objects represented by the same symbol in different groups do not affect each other, or may mean that specific objects represented by the same symbol in the same group do not affect each other, and should all be understood in a broad sense.

[0062] In various parts of this specification, substituents for compounds disclosed in the present invention are disclosed according to group types or ranges. It should be noted that the present invention includes all independent subcombinations of each member within these group types and ranges. For example, the term "C 1-6 By "alkyl group" is meant in particular methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups, which are disclosed separately.

[0063] Each part of the present invention describes a linking substituent. When the structure clearly requires a linking group, the Markush variable recited for that group should be understood to be the linking group. For example, when the structure requires a linking group and an "alkyl group" or an "aryl group" is recited for the Markush group definition of the variable, the "alkyl group" or "aryl group" should be understood to represent a linking alkylene group or arylene group, respectively.

[0064] As used herein, the term "alkyl" or "alkyl group" refers to a saturated, linear or branched, monovalent hydrocarbon group, which 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, an alkyl group contains 1 to 12 carbon atoms; in another embodiment, an alkyl group contains 3 to 12 carbon atoms; in another embodiment, an alkyl group contains 1 to 6 carbon atoms; in another embodiment, an alkyl group contains 1 to 4 carbon atoms; and in yet another embodiment, an alkyl group contains 1 to 3 carbon atoms.

[0065] Examples of alkyl groups include 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), s-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C( CH3)3), n-pentyl group (-CH2CH2CH2CH2CH3), 2-pentyl group (-CH(CH3)CH2CH2CH3), 3-pentyl group (-CH(CH2CH3)2), 2-methyl-2-butyl group (-C(CH3)2CH2CH3), 3-methyl-2-butyl group (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl group (-CH2CH2CH(CH3)2), 2-methyl-1-butyl group (-CH2 CH(CH3)CH2CH3), n-hexyl group (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl group (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl group (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl group (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl group (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl group (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl group (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl group (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl group (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl group (-CH(CH3)C(CH3)3), n-heptyl group, n-octyl group, and the like.

[0066] The term "alkylene group" means a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched-chain hydrocarbon group. Unless otherwise specified, an alkylene group contains 1 to 12 carbon atoms. In one embodiment, an alkylene group contains 1 to 6 carbon atoms; in another embodiment, an alkylene group contains 1 to 4 carbon atoms; in one embodiment, an alkylene group contains 1 to 3 carbon atoms; and in another embodiment, an alkylene group contains 1 to 2 carbon atoms. Examples of such groups include methylene (-CH-), ethylene (-CHCH-), isopropylene (-CH(CH)CH-), and the like.

[0067] The term "alkoxy group" means an alkyl group attached to the rest of the molecule via an oxygen atom, where alkyl is as defined herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms, in another embodiment, the alkoxy group contains 1 to 4 carbon atoms, and in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents as described herein.

[0068] Examples of alkoxy groups include methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), n-propoxy (n-PrO, 1-propoxy, -OCH2CH2CH3), isopropoxy (i-PrO, i-propoxy, -OCH(CH3)2), n-butoxy (n-BuO, 1-butoxy, -OCH2CH2CH2CH3), isobutyloxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), tert-butoxy (t-BuO, t-butoxy, -OCH(CH3)CH2CH3), and Examples of methyl groups include, but are not limited to, methyl-2-methyl-1-butoxy groups, such as -OC(CH3)3), n-pentyloxy groups (1-pentyloxy groups, -OCH2CH2CH2CH2CH3), 2-pentyloxy groups (-OCH(CH3)CH2CH2CH3), 3-pentyloxy groups (-OCH(CH2CH3)2), 2-methyl-2-butoxy groups (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy groups (-OCH(CH3)CH(CH3)2), 3-methyl-1-butoxy groups (-OCH2CH2CH(CH3)2), and 2-methyl-1-butoxy groups (-OCH2CH(CH3)CH2CH3).

[0069] The terms "alkylamino" or "alkylamino group" can be used interchangeably herein and include "N-alkylamino group" and "N,N-dialkylamino group," in which the amino group is each independently substituted with one or two alkyl groups, said alkyl groups having the definition set forth in the present invention. In some embodiments, the alkylamino group is substituted with one or two C 1-6 In another embodiment, the alkylamino group is a lower alkylamino group in which the alkyl group is attached to a nitrogen atom. ... 1-4 and a lower alkyl group of the formula (I) attached to the nitrogen atom. Suitable alkylamino groups may be mono- or di-alkylamino groups, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, and the like.

[0070] The term "halogenated alkyl group" or "halogenated alkoxy group" means an alkyl or alkoxy group substituted with one or more halogen atoms, where alkyl or alkoxy group is as defined herein, and examples of such include, but are not limited to, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3-tetrafluoropropyl, difluoromethoxy, trifluoromethoxy, and the like.

[0071] The term "hydroxy-substituted alkyl group" or "hydroxy-substituted halogenated alkyl group" means that an alkyl group or halogenated alkyl group is substituted with one or more hydroxy groups, where alkyl group or halogenated alkyl group is as defined in the present invention, and examples thereof include, but are not limited to, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 2-hydroxy-1,1,1,3,3,3-hexafluoroisopropyl group, and the like. For example, "hydroxy-substituted C 1-6 "Alkyl group" means an alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group.

[0072] The term "amino-substituted alkyl group" means that an alkyl group is substituted with one or more amino groups, wherein alkyl group is as defined herein, examples of which include, but are not limited to, -CHNH, -CHCHNH, -CH(NH)CH(CH), and the like.

[0073] The term "cycloalkyl group" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic hydrocarbon group containing 3 to 12 carbon atoms. In one embodiment, a cycloalkyl group contains 7 to 12 carbon atoms; in another embodiment, a cycloalkyl group contains 3 to 8 carbon atoms; and in another embodiment, a cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl groups may be independently and optionally substituted with one or more substituents described herein. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0074] The term "cycloalkylamino group" includes "N-cycloalkylamino group" and "N,N-dicycloalkylamino group," in which the amino group is each independently substituted with one or two cycloalkyl groups, wherein the cycloalkyl group has the definition set forth herein. In some embodiments, the cycloalkylamino group is substituted with one or two C 3-8 In another embodiment, the cycloalkylamino group is a cycloalkylamino group having one or two C 3-6 A cycloalkylamino group is a cycloalkyl group in which the cycloalkyl group is bonded to a nitrogen atom. Suitable cycloalkylamino groups may be monocycloalkylamino groups or dicycloalkylamino groups, examples of which include, but are not limited to, N-cyclopropylamino groups, N-cyclobutylamino groups, N-cyclohexylamino groups, N,N-dicyclopropylamino groups, and the like.

[0075] The terms "cycloalkylalkyl group" or "-alkylene-cycloalkyl group" are used interchangeably herein and mean that a cycloalkyl group is linked to an alkyl group (or alkylene group) by a cycloalkyl, where cycloalkyl, alkyl group, or alkylene group is as defined herein. Examples of such include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, and the like.

[0076] The term "carbocycle" or "carbocyclic group" means a monovalent or polyvalent non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic, or tricyclic hydrocarbon group containing 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbobicyclic groups and fused carbobicyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. In one embodiment, a carbocyclic group contains 3 to 10 carbon atoms; in one embodiment, a carbocyclic group contains 3 to 8 carbon atoms; and in yet another embodiment, a carbocyclic group contains 3 to 6 carbon atoms. Examples of carbocyclic groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. The carbocyclic groups may be optionally substituted, independently, with one or more substituents according to the present invention.

[0077] The terms "heterocyclic group" 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, at least one ring atom being selected from nitrogen, sulfur, and oxygen. Polycyclic heterocyclic groups include spiroheterocyclic groups and fused heterocyclic groups. In some embodiments, heterocyclic groups contain 3 to 10 ring atoms; in other embodiments, heterocyclic groups contain 3 to 8 ring atoms; in other embodiments, heterocyclic groups contain 3 to 6 ring atoms; and in other embodiments, heterocyclic groups contain 5 to 6 ring atoms. Unless otherwise specified, heterocyclic groups may be bonded to other groups in a molecule through a carbon atom or a nitrogen atom, and -CH- groups may be optionally substituted with -C(=O)-. Sulfur atoms in the ring may be optionally oxidized to sulfur oxides. The ring nitrogen atoms may be optionally oxidized to N-oxides. Examples of heterocyclic groups include, but are not limited to, ethylene oxide, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 2-pyrrolidinyl, 3-pyrrolidinyl), pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyran, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, diazepanyl, oxepanyl, thiepanyl, oxazepine, diazepine, and thiazepine groups. Examples of heterocyclic groups in which the -CH2- group is replaced with -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone, pyridazinone, 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 groups may be optionally substituted with one or more substituents described in the present invention.

[0078] The term "spirocyclic group" means a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent bicyclic or tricyclic ring containing 5 to 12 ring atoms, the rings sharing one carbon atom, and all of the ring atoms being carbon atoms. Unless otherwise specified, a spirocyclic group may be bonded to other groups in the molecule via a carbon atom, and the -CH2- group may be optionally replaced with -C(=O)-. Examples of spirocyclic groups are: [ka] Including, but not limited to:

[0079] The terms "spiroheterocyclic group" and "spiroheterocycle" may be used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent bicyclic or tricyclic ring containing 5 to 12 ring atoms, at least one ring atom being selected from nitrogen, sulfur, and oxygen atoms, and rings sharing one carbon atom. In some embodiments, a spiroheterocyclic group is a 5- to 12-membered spiroheterocyclic group, and in other embodiments, a spiroheterocyclic group is a 7- to 12-membered spiroheterocyclic group. Unless otherwise specified, a spiroheterocyclic group may be bonded to other groups in a molecule through a carbon atom or a nitrogen atom, and a -CH2- group may be optionally substituted with -C(=O)-. A sulfur atom in the ring may be optionally oxidized to an S-oxide. A nitrogen atom in the ring may be optionally oxidized to an N-oxide. Examples of spiroheterocycles include: [ka] Including, but not limited to:

[0080] The term "fused ring group" means a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent bicyclic or tricyclic ring containing 4 to 12 ring atoms, and the rings share a ring edge (share one single bond), and all of the ring atoms are carbon atoms. Unless otherwise specified, a fused ring group may be bonded to other groups in the molecule through a carbon atom, and -CH2- groups may optionally be replaced with -C(=O)-. Examples of fused rings are: [ka] Including, but not limited to:

[0081] The terms "fused heterocyclic group," "fused heterocycle," and "fused heterocyclic group" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent bicyclic or tricyclic ring containing 4 to 12 ring atoms, at least one ring atom being selected from nitrogen, sulfur, and oxygen, and the rings share a ring edge (share a single bond). In some embodiments, the 4 to 12 ring atoms of the fused heterocyclic group contain 3 to 9 carbon atoms; in other embodiments, the 4 to 12 ring atoms of the fused heterocyclic group contain 3 to 8 carbon atoms; and in still other embodiments, the 4 to 12 ring atoms of the fused heterocyclic group contain 3 to 6 carbon atoms. Unless otherwise specified, a fused heterocyclic group may be bonded to other groups in the molecule through a carbon atom or a nitrogen atom, and the -CH- group may be optionally substituted with -C(=O)-. Sulfur atoms in the ring may be optionally oxidized to S-oxides. Nitrogen atoms in the ring may be optionally oxidized to N-oxides. Examples of fused heterocycles are: [ka] Including, but not limited to:

[0082] The term "aryl group" refers to a monocyclic, bicyclic, or tricyclic all-carbon ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, in which at least one ring is aromatic and has one or more points of attachment to the rest of the molecule. The term "aryl group" may be used interchangeably with the term "aromatic ring." In one embodiment, an aryl group is a carbocyclic ring system consisting of 6 to 10 ring atoms and containing at least one aromatic ring. Examples of aryl groups may include phenyl, naphthyl, and anthracene groups. The aryl groups may be independently optionally substituted with one or more substituents described herein.

[0083] The term "heteroaryl group" refers to monocyclic, bicyclic, and tricyclic rings containing 5 to 12 ring atoms, in which at least one ring is aromatic and at least one ring contains one or more heteroatoms, and the heteroaryl group has one or more points of attachment to other parts of the molecule. The term "heteroaryl group" may be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound." In some embodiments, a heteroaryl group is a 5- to 12-membered heteroaryl group; in other embodiments, a heteroaryl group is a 5- to 10-membered heteroaryl group; and in still other embodiments, a heteroaryl group is a 5- to 7-membered heteroaryl group, including a 5-, 6-, or 7-membered heteroaryl group. In one embodiment, a heteroaryl group is a heteroaryl group of 5 to 12 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, in one embodiment, a heteroaryl group is a heteroaryl group of 5 to 10 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, and in another embodiment, a heteroaryl group is a heteroaryl group of 5 to 6 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. The heteroaryl groups are optionally substituted with one or more substituents described herein.

[0084] Examples of heteroaryl groups include furanyl groups (e.g., 2-furanyl group, 3-furanyl group), imidazolyl groups (e.g., N-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group), isoxazolyl groups (e.g., 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group), oxazolyl groups (e.g., 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group), oxadiazolyl groups (e.g., 1,2,3-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,2 ,4-oxadiazolyl group), oxatriazolyl group (e.g., 1,2,3,4-oxatriazolyl group), thiazolyl group (e.g., 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group), isothiazolyl group, 2-thiadiazolyl group (e.g., 1,3,4-thiadiazolyl group, 1,2,3-thiadiazolyl group, 1,2,5-thiadiazolyl group), thiatriazolyl group (e.g., 1,2,3,4-thiatriazolyl group), tetrazolyl group (e.g., 2H-1,2,3,4-tetrazolyl group, 1H-1,2,3,4-tetrazolyl group, triazolyl group), triazolyl group (e.g., 2H-1,2,3-triazolyl group, 1H-1,2,4-triazolyl group, 4H-1,2,4-triazolyl group), thienyl group (e.g., 2-thienyl group, 3-thienyl group), 1H-pyrazolyl group (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl), 1,2,3-thiodiazolyl group, 1,3,4-thiodiazolyl group, 1,2,5-thiodiazolyl group, pyrrole group (e.g., N-pyrrole group, 2-pyrrole group, 3-pyrrole group), These include, but are not limited to, pyridyl groups (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl groups (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl groups (e.g., 3-pyridazinyl, 4-pyridazinyl), 2-pyrazinyl, triazinyl groups (e.g., 1,3,5-triazinyl), tetrazinyl groups (e.g., 1,2,4,5-tetrazinyl, 1,2,3,5-tetrazinyl), and further include benzimidazolyl groups, benzopyrazolyl groups (e.g., [ka] ), a benzofuranyl group, a benzothienyl group, a benzodioxazolyl group, an indolyl group (e.g., a 2-indolyl group), a purinyl group, a quinolyl group (e.g., a 2-quinolyl group, a 3-quinolyl group, a 4-quinolyl group), an isoquinolinyl group (e.g., a 1-isoquinolinyl group, a 3-isoquinolinyl group, or a 4-isoquinolinyl group), an imidazo[1,2-a]pyridyl group, a pyrazolo[1,5-a]pyridyl group, a pyrazolo[1,5-a]pyrimidinyl group, an imidazo[1,2-b]pyridazinyl group, a [1,2,4]triazolo[4,3-b]pyridazinyl group, a [1,2,4]triazolo[1,5-a]pyrimidinyl group, a [1,2,4]triazolo[1,5-a]pyridyl group, [ka] Bicycles include, but are not limited to, bicycles such as:

[0085] As used herein, the term "unsaturated" indicates that a group contains one or more degrees of unsaturation.

[0086] The term "heteroatom" refers to O, S, N, P, and Si, and includes any oxidized form of N, S, and P, primary, secondary, and tertiary amine and quaternary ammonium salt forms, or forms in which a hydrogen atom on a nitrogen atom in a heterocycle is substituted, such as N (N in a 3,4-dihydro-2H-pyrrole group), NH (e.g., NH in a pyrrolidinyl group), or NR (e.g., NR in an N-substituted pyrrolidinyl group).

[0087] The term "halogen" or "halogen atom" means a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br) or an iodine atom (I).

[0088] The terms "cyano" or "CN" refer to a cyano structure, and such a group may be bonded to another group.

[0089] The term "nitro group" or "NO2" refers to a nitro group structure, and such a group may be bonded to other groups.

[0090] The term "amino group" or "NH2" refers to an amino group structure, and such a group can be bonded to other groups.

[0091] The term "carboxyl group", whether used alone or in combination with other terms, for example, as a "carboxyl group", means -COH, and the term "carbonyl group", whether used alone or in combination with other terms, for example, as an "aminocarbonyl group" or an "acyloxy group", means -(C=O)- or -C(=O)-.

[0092] The term "j to k-membered" means that the cyclic group consists of j to k ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, and P, where j and k are each independently any natural number other than 0 and k > j, and "j to k" includes j, k, and any natural numbers therebetween. For example, "5 to 12-membered," "5 to 10-membered," or "3 to 7-membered" means that the cyclic group consists of 5 to 12 (i.e., 5, 6, 7, 8, 9, 10, 11, or 12), 5 to 10 (i.e., 5, 6, 7, 8, 9, or 10), 5 to 6 (i.e., 5 or 6), or 3 to 7 (i.e., 3, 4, 5, 6, or 7) ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, and P.

[0093] A ring system formed by attaching a substituent to a central ring via a single bond (represented by formula b) indicates that the substituent can be substituted at any substitutable position on the ring. For example, formula b indicates that the substituent R' can be mono- or polysubstituted at any substitutable position on the ring, including, but not limited to, those represented by formulas b1 to b9. [ka] As described herein, the attachment of a bond to a ring system (represented by formula c) indicates that the ring can be attached to another part of the molecule via the bond at any available position on the ring system. Formula c means that the ring can be attached to another part of the molecule at any available position on the ring, including, but not limited to, those represented by formulas c1 to c6. [ka]

[0094] As described in the present invention, when a group is bonded to another part of a molecule through two sites, unless otherwise specified, the two sites are independently bonded to other groups of the molecule, and the groups to which the two sites are bonded may be interchanged. For example, the piperidinyl group in formula e may be bonded to another part of a molecule through the E1 and E2 ends, and the E1 and E2 ends may be interchanged when the other parts of the molecule remain unchanged. [ka]

[0095] The term "protecting group" or "PG" refers to a substituent commonly used to block or protect a particular functionality during reaction with another functional group. For example, an "amino protecting group" refers to a substituent that blocks or protects the amino functionality in a compound by attaching the substituent to the amino group; suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz), and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxyl group that blocks or protects the hydroxyl functionality; suitable protecting groups include acetyl and silyl. The term "carboxyl-protecting group" refers to a substituent of a carboxyl group that blocks or protects the functionality of the carboxyl group. Common carboxyl-protecting groups include -CHCHSOPh, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, and nitroethyl. For a general description of protecting groups, see T. W. Greene, "Protective Groups in Organic Synthesis," John Wiley & Sons, New York, 1991; and P. J. Kocienski, "Protecting Groups," Thieme, Stuttgart, 2005.

[0096] The term "prodrug" as used in the present invention refers to a compound that is converted in vivo to a compound represented by formula (I). Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention may be esters, and in previous inventions, esters that can be used as prodrugs include phenyl esters, aliphatic (C1-C 24) esters, acyloxymethyl esters, carbonate esters, carbamates, and amino acid esters. For example, the compounds of the present invention contain a hydroxy group, i.e., acylation thereof provides the prodrug form of the compound. Other prodrug forms include phosphate esters, and these phosphate ester compounds are obtained, for example, by phosphorylation of the parent hydroxy group. For a complete discussion of prodrugs, the following references may be consulted: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium 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.

[0097] "Metabolite" refers to a product produced by in vivo metabolism of a specific compound or a salt thereof. Metabolic products of a compound can be identified using techniques known in the art, and their activity can be characterized by test methods as described herein. Such products can be obtained by subjecting an administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, or enzymatic cleavage, among other processes. Correspondingly, the present invention includes metabolic products of a compound, including metabolic products produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

[0098] As used herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art and are described, for example, in SM Berge et al., "Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19." Salts formed with pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with an amino group, such as hydrochloride, hydrobromide, phosphate, sulfate, and perchlorate, and organic acid salts, such as acetate, oxalate, maleate, tartrate, citrate, succinate, and malonate. Alternatively, these salts can be obtained by other methods described in textbooks and literature, such as ion exchange methods. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- Salts derived from appropriate bases include hydroxy-ethanesulfonate, 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, pentanoate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4The present invention also contemplates quaternary ammonium salts formed with any compound containing an N group. Water- or oil-soluble or dispersible products can be obtained by quaternary ammonium salt formation. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts include suitable non-toxic ammonium and quaternary ammonium salts, as well as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 and amine cations formed with counterions such as sulfonates and aromatic sulfonates.

[0099] The term "solvate" as used herein refers to an association formed between one or more solvent molecules and the 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 in which the solvent molecule is water.

[0100] When the solvent is water, the term "hydrate" can be used. In some embodiments, a single compound molecule of the present invention may combine with one water molecule to form, for example, a monohydrate; in other embodiments, a single compound molecule of the present invention may combine with two or more water molecules to form, for example, a dihydrate; and in still other embodiments, a single compound molecule of the present invention may combine with less than one water molecule to form, for example, a hemihydrate. Note that the hydrates described in the present invention retain the bioavailability of the non-hydrated form of the compound.

[0101] The term "nitrogen oxide" refers to a compound containing multiple amine functional groups, in which one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides include the N-oxides of tertiary amines or N-oxides containing nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) (see Advanced Organic Chemistry, Wiley Interscience, 4th Edition, Jerry March, pages 1977). In particular, N-oxides can be prepared by the LWDready method (Syn. Comm. 1977, 7, 509-514), for example, by reacting an amine compound with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent (e.g., dichloromethane).

[0102] The term "carrier" includes any solvent, dispersion medium, coating agent, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, drug stabilizer, binder, excipient, dispersing agent, lubricant, sweetener, flavoring agent, coloring agent, or combinations thereof, all of which are known to those skilled in the art (e.g., as described in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

[0103] The term "treatment" as used herein means treating any disease or disorder and anything that can alleviate, interrupt, inhibit, control, or halt the progression of the disease or disorder, but does not necessarily indicate the elimination of all symptoms of the disease or disorder. It also includes prophylactic treatment of such symptoms, particularly in patients predisposed to such disease or disorder. In some embodiments, it refers to ameliorating a disease or disorder (i.e., alleviating, inhibiting, or reducing the progression of the disease or at least one clinical symptom thereof). In another embodiment, "treatment" refers to alleviating or improving at least one physical parameter, including physical parameters imperceptible to the patient. In another embodiment, "treatment" refers to modulating the disease or disorder physically (e.g., stable detectable symptoms) or physiologically (e.g., stable physical parameters), or both. In another embodiment, "treatment" refers to preventing or delaying the onset, development, or worsening of a disease or disorder. The term "therapeutically effective amount" or "therapeutically effective dose," as used herein, refers to an amount of a compound of the present invention that can elicit a biological or medical response in an individual (e.g., reduction or inhibition of enzyme or protein activity, or amelioration of symptoms, reduction of a disorder, mitigation or delay of disease progression, or prevention of a disease, etc.). In a non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to an individual, is effective to (1) at least partially alleviate, inhibit, prevent, and / or ameliorate a disorder or disease that is (i) mediated by RORγt, or (ii) associated with activity of RORγt, or (iii) characterized by abnormal activity of RORγt, or (2) reduce or inhibit activity of RORγt, or (3) reduce or inhibit expression of RORγt. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that is effective when administered to a cell, or an organ, or a non-cellular biological material, or a medium, to at least partially reduce or inhibit the activity of RORγt or at least partially reduce or inhibit the expression of RORγt.

[0104] As used herein, the terms "dosing" a compound and "administration" a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to an individual in need thereof. Those skilled in the art will understand that an effective amount of a compound of the invention will be used to treat a patient currently suffering from the disorder or to prophylactically treat a patient suffering from the disorder.

[0105] The term "composition" as used herein refers to a product containing predetermined amounts of predetermined ingredients, and any product produced directly or indirectly by combining predetermined amounts of the predetermined ingredients. This term, in reference to a pharmaceutical composition, is intended to include a product containing an active ingredient(s) and an inactive ingredient(s) that constitute a carrier, as well as any product produced directly or indirectly by the mixing, complexation, or aggregation of any two or more ingredients, or by the decomposition of one or more ingredients, or by any other type of reaction or interaction of one or more ingredients. Thus, a pharmaceutical composition of the present invention includes any composition prepared by mixing a compound of the present invention with a pharmaceutically acceptable carrier. Description of the compounds of the present invention

[0106] The present invention discloses sulfonyl-substituted (hetero)aromatic ring derivatives, pharmaceutically acceptable salts thereof, pharmaceutical formulations and compositions thereof, which have potential use as RORγt inhibitors in the treatment of cancer, inflammation or autoimmune diseases mediated by RORγt, such as cancer, 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.

[0107] In one aspect, the present invention relates to a compound of formula (I), or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (I). [ka] (In the formula, A ring, B ring, L 1 , L 2 , L 3 , R, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 is as defined in the present invention, and * indicates the direction in which ring A and ring C are bonded.

[0108] In some embodiments, R is C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylamino group, C 3-8 Cycloalkylamino group, -C 1-6 Alkylene-C 3-8 Cycloalkyl groups, C 3-8 Cycloalkyl groups, C 1-6 Halogenated alkyl group or C 1-6 It is a halogenated alkoxy group.

[0109] In another embodiment, R is C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Alkylamino group, C 3-6 Cycloalkylamino group, -C 1-4 Alkylene-C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyl groups, C 1-4 Halogenated alkyl group or C 1-4 It is a halogenated alkoxy group.

[0110] In yet another embodiment, R is methyl, ethyl, n-propyl, isopropyl, -CHF, -CHF, -CF, -CHFCHF, -CFCH, -CHCHF, -CHCF, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, ethylamino, dimethylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, -methylene-cyclopropyl, -methylene-cyclobutyl, -methylene-cyclopentyl, -methylene-cyclohexyl, -ethylene-cyclopropyl, -ethylene-cyclobutyl, -ethylene-cyclopentyl, -ethylene-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0111] In some embodiments, Z 1 is CR 1 or N and R 1 is as defined in the present invention.

[0112] In some embodiments, Z 2 is CR 1 or N and R 1 is as defined in the present invention.

[0113] In some embodiments, Z 3 is CR 1 or N and R 1 is as defined in the present invention.

[0114] In some embodiments, Z 4 is CR 1 or N and R 1 is as defined in the present invention.

[0115] In some embodiments, Z 5 is CR 1 or N and R 1 is as defined in the present invention.

[0116] In some embodiments, Z 6 is CR 1 or N and R 1 is as defined in the present invention.

[0117] In some embodiments, Z 7 is CR 1 or N and R 1 is as defined in the present invention.

[0118] In some embodiments, Z 8 is CR 1 or N and R 1 is as defined in the present invention.

[0119] In some embodiments, each R 1 are independently hydrogen, deuterium, cyano group, fluorine, chlorine, bromine, iodine, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, hydroxy-substituted C 1-6 Alkyl group, -C 1-6 Alkylene-C 1-6 Alkoxy group, C 1-6 Alkoxy group, C 3-8 It is a cycloalkyl group or a 3- to 7-membered heterocyclic group.

[0120] In another embodiment, each R 1 are independently hydrogen, deuterium, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, -CHF, -CHF, -CF, -CHFCHF, -CFCH, -CHCHF, -CHCF, methoxy, ethoxy, n-propoxy, isopropoxy, hydroxymethyl, 2-hydroxyethyl, -methylenemethoxy, -methyleneethoxy, -methylene-n-propoxy, -methyleneisopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0121] In some embodiments, the A ring is a 3- to 5-membered heterocyclic group or a 7-membered heterocyclic group, and the 3- to 5-membered heterocyclic group and the 7-membered heterocyclic group independently contain 1, 2, 3, 4, or 5 R 2 optionally substituted with *, and R 2 is as defined in the present invention.

[0122] In yet another embodiment, the A ring is: [ka] and In the formula, * indicates the direction in which ring A and ring C are bonded, and ring A is a ring having 1, 2, 3, 4, or 5 R 2 optionally substituted with R 2 is as defined in the present invention.

[0123] In some embodiments, each R 2 are independently an oxo group, R a , C 1-6 Alkyl group, -C 1-6 Alkylene-R a , -OR b , -C 1-6 Alkylene-OR b , -C(=O)-R a , -C 1-6 Alkylene-C(=O)-R a , -C(=O)-NR c R d or -C 1-6 Alkylene-C(=O)-NR c R d and R a , R b , R c and R d is as defined in the present invention.

[0124] In another embodiment, each R 2 are independently oxo, R a , C 1-4 Alkyl group, -C 1-4 Alkylene-R a , -ORb , -C 1-4 Alkylene-OR b , -C(=O)-R a , -C 1-4 Alkylene-C(=O)-R a , -C(=O)-NR c R d or -C 1-4 Alkylene-C(=O)-NR c R d and R a , R b , R c and R d is as defined in the present invention.

[0125] In yet another embodiment, each R 2 are independently oxo, R a , methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, tert-butyl group, -CH2R a , -CH2CH2R a , -CH2CH2CH2R a , -C(CH3)2R a , -CH(CH3)CH2R a , -OR b , -CH2OR b , -CH2CH2OR b , -CH2CH2CH2OR b , -C(CH3)2OR b , -CH(CH3)CH2OR b , -C(=O)-R b , -CH2C(=O)-R b , -CH2CH2C(=O)-R b , -CH2CH2CH2C(=O)-R b , -C(CH3)2C(=O)-R b , -CH(CH3)CH2C(=O)-R b , -C(=O)-NR c R d , -CH2C(=O)-NR c R d , -CH2CH2C(=O)-NR c R d , -CH2CH2CH2C(=O)-NRc R d , -C(CH3)2C(=O)-NR c R d or -CH(CH3)CH2C(=O)-NR c R d and R a , R b , R c and R d is as defined in the present invention.

[0126] In some embodiments, each R a are independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 3-8 Cycloalkyl groups, C 6-10 an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 7-membered heterocyclic group, a 5- to 12-membered spirocyclic group, a 4- to 12-membered fused ring group, a 5- to 12-membered spiroheterocyclic group, or a 4- to 12-membered fused heterocyclic group; Each R b , R c and R d are independently hydrogen, deuterium, and C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 3-8 Cycloalkyl groups, C 6-10 an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 7-membered heterocyclic group, a 5- to 12-membered spirocyclic group, a 4- to 12-membered fused ring group, a 5- to 12-membered spiroheterocyclic group, or a 4- to 12-membered fused heterocyclic group, or R c and R d form a 4- to 7-membered heterocyclic group together with the N atom to which they are bonded, and each of the R a , R b , R c and R d independently, 1, 2, 3, 4, 5, or 6 R g optionally substituted with R g is as defined in the present invention.

[0127] In another embodiment, each R a are independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl group, amino group, nitro group, cyano group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 6-10 an aryl group, a 5- to 7-membered heteroaryl group, a 3- to 7-membered heterocyclic group, a 5- to 12-membered spirocyclic group, a 4- to 12-membered fused ring group, a 5- to 12-membered spiroheterocyclic group, or a 4- to 12-membered fused heterocyclic group; Each R b , R c and R d are independently hydrogen, deuterium, and C 1-4 Alkyl group, C 1-4 Halogenated alkyl groups, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 6-10 an aryl group, a 5- to 7-membered heteroaryl group, a 3- to 7-membered heterocyclic group, a 5- to 12-membered spirocyclic group, a 4- to 12-membered fused ring group, a 5- to 12-membered spiroheterocyclic group, or a 4- to 12-membered fused heterocyclic group, or R c and R d form a 4- to 7-membered heterocyclic group together with the N atom to which they are bonded, and each of the R a , R b , R c and R d independently, 1, 2, 3, 4, 5, or 6 R g optionally substituted with R g is as defined in the present invention.

[0128] In yet another embodiment, each R aare independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl group, amino group, nitro group, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, tert-butyl group, methoxy group, ethoxy group, isopropoxy group, -CH2F, -CHF2, -CF3, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CH2CH3, -CH2CH2CHF2, -CF2CH2F, -CF2CHF2, -CF2CF3, oxetanyl group, azetidinyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, piperidinyl group, piperazinyl group, oxepanyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, thiazolyl group, pyrazolyl group, imidazolyl group, furanyl group, oxazolyl group, isoxazolyl group, triazole group, thienyl group, pyrrole group, pyridyl group, pyrimidinyl group, [ka] and Each R b , R c and R dare independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CH2CH3, -CH2CH2CHF2, -CF2CH2F, -CF2CHF2, -CF2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutyloxy, sec-butoxy a silyl group, a tert-butoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, an oxetanyl group, an azetidinyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a morpholinyl group, a thiomorpholinyl group, a piperidinyl group, a piperazinyl group, an oxepanyl group, a thiazolyl group, a pyrazolyl group, an imidazolyl group, a furanyl group, an oxazolyl group, an isoxazolyl group, a triazole group, a thienyl group, a pyrrole group, a pyridyl group, a pyrimidinyl group, [ka] or R c and R d together with the N atoms to which they are attached, [ka] Forming Each of the above R a , R b , R c and R d independently, 1, 2, 3, 4, 5, or 6 R g optionally substituted with R g is as defined in the present invention.

[0129] In some embodiments, each R g are independently deuterium, fluorine, chlorine, bromine, iodine, oxo, hydroxyl group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C1-6 Halogenated alkoxy groups, C 3-8 It is a cycloalkyl group or a 3- to 7-membered heterocyclic group.

[0130] In another embodiment, each R g are independently deuterium, fluorine, chlorine, bromine, iodine, oxo, hydroxyl group, amino group, nitro group, cyano group, C 1-4 Alkyl group, C 1-4 Halogenated alkyl groups, C 1-4 Alkoxy group, C 1-4 Halogenated alkoxy groups, C 3-6 It is a cycloalkyl group or a 3- to 7-membered heterocyclic group.

[0131] In yet another embodiment, each R g are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, oxo, hydroxyl group, amino group, nitro group, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, tert-butyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, -CH2F, -CHF2, -CF3, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CH2CH3, -CH2CH2CHF2, -CF2CH2F, -CF2CHF2, -CF2 CF3, -OCH2F, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CH3, -OCH2CHF2, -OCH2CF3, -OCF2CH2CH3, -OCH2CH2CHF2, -OCF2CH2F, -OCF2CHF2, -OCF2CF3, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, azetidinyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, piperidinyl group, piperazinyl group or oxepanyl group.

[0132] In some embodiments, the B ring is C 6-10 Aryl group, C 3-8a cycloalkyl group, a 5- to 12-membered heteroaryl group, a 3- to 7-membered heterocyclic group, a 4- to 12-membered fused heterocyclic group, a 5- to 12-membered spiro heterocyclic group, a 4- to 12-membered fused ring group, or a 5- to 12-membered spiro ring group, and the ring B is e optionally substituted with R e is as defined in the present invention.

[0133] In another embodiment, the B ring is C 6-10 Aryl group, C 3-6 a cycloalkyl group, a 5- to 7-membered heteroaryl group, a 3- to 7-membered heterocyclic group, a 4- to 12-membered fused heterocyclic group, a 5- to 12-membered spiro heterocyclic group, a 4- to 12-membered fused ring group, or a 5- to 12-membered spiro ring group, and the ring B is e optionally substituted with R e is as defined in the present invention.

[0134] In yet another embodiment, Ring B is selected from the group consisting of a phenyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a pyridyl group, a pyrimidinyl group, a pyrrole group, a pyrazolyl group, a thiazolyl group, an imidazolyl group, a furanyl group, an oxazolyl group, an isoxazolyl group, a thienyl group, a triazole group, a tetrazolium group, a piperazinyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, an azetidinyl group, an oxetanyl group, [ka] and the B ring is selected from the group consisting of 1, 2, 3, or 4 R e optionally substituted with R e is as defined in the present invention.

[0135] In some embodiments, each R e are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro group, hydroxyl group, amino group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-8Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 1-6 Halogenated alkyl group or C 1-6 A halogenated alkoxy group, 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-8 Cycloalkyl groups, C 1-6 Halogenated alkyl groups and C 1-6 The halogenated alkoxy group is optionally substituted with 1, 2, 3, or 4 substituents independently selected from a cyano group, a nitro group, a hydroxyl group, an amino group, or a 3- to 7-membered heterocyclic group.

[0136] In another embodiment, each R e are independently deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro group, hydroxyl group, amino group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 1-4 Halogenated alkyl group or C 1-4 A halogenated alkoxy group, 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-4 Halogenated alkyl groups and C 1-4 The halogenated alkoxy group is optionally substituted with 1, 2, 3, or 4 substituents independently selected from a cyano group, a nitro group, a hydroxyl group, an amino group, or a 3- to 7-membered heterocyclic group.

[0137] In yet another embodiment, each R eare independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro group, hydroxyl group, methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, azetidinyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, piperidinyl group, piperazinyl group, oxepanyl group, -CH2F, -CHF2 , -CF3, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CH2CH3, -CH2CH2CHF2, -CF2CH2F, -CF2CHF2, -CF2CF3, -OCH2F, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CH3, -OCH2CHF2, -OCH2CF3, -OCF2CH2CH3, -OCH2CH2CHF2, -OCF2CH2F, -OCF2CHF2 or -OCF2CF3, and the above-mentioned methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group , ethoxy group, n-propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, azetidinyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, piperidinyl group, piperazinyl group, oxepanyl group, -CH2F, -CHF2, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CH2CH3, -CH2CH2CHF2, -CF2CH2F, -CF2CHF2, - OCH2F, -OCHF2, -OCHFCH2F, -OCF2CH3, -OCH2CHF2, -OCH2CF3, -OCF2CH2CH3, -OCH2CH2CHF2, -OCF2CH2F and -OCF2CHF2 are optionally substituted with 1, 2, 3 or 4 substituents independently selected from cyano, nitro, hydroxyl, amino, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, azetidinyl or oxetanyl groups. In some embodiments, L 1is -S(=O)2-NH-, -NH-S(=O)2-, -S(=O)-NH-, -NH-S(=O)-, -C(=O)NH- or -NHC(=O)-, and specifically, from left to right, L 1 The left end of each of the bonding groups in the formula (I) is bonded to the ring C, and for example, -S(=O)2-NH- is bonded to the ring C via the sulfur atom at the left end.

[0138] In some embodiments, L 2 is a bond or -CR 3 R 4 - and R 3 and R 4 is as defined in the present invention.

[0139] In some embodiments, L 3 -C(=O)-, -S-, -O-, -NR 5 -or-CR 6 R 7 - and R 5 , R 6 and R 7 is as defined in the present invention.

[0140] In some embodiments, R 3 is hydrogen, deuterium, hydroxy-substituted C 1-6 Alkyl group, -C 1-6 Alkylene-OC(=O)-R f , -C 1-6 Alkylene-C(=O)-OR f or -C 1-6 Alkylene-R f and R f is as defined in the present invention.

[0141] In another embodiment, R 3 is hydrogen, deuterium, hydroxy-substituted C 1-4 Alkyl group, -C 1-4 Alkylene-OC(=O)-R f , -C 1-4 Alkylene-C(=O)-OR f or -C 1-4 Alkylene-Rf and R f is as defined in the present invention.

[0142] In yet another embodiment, R 3 represents hydrogen, deuterium, hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxy-n-propyl group, 2-hydroxy-1-methylethyl group, -CH2OC(=O)R f , -CH2CH2OC(=O)R f , -CH2CH2CH2OC(=O)R f , -CH(CH3)2OC(=O)R f , -CH2C(=O)OR f , -CH2CH2C(=O)OR f , -CH2CH2CH2C(=O)OR f , -CH(CH3)2C(=O)OR f , -CH2R f , -CH2CH2R f , -CH2CH2CH2R f or -CH(CH3)2R f and R f is as defined in the present invention.

[0143] In some embodiments, R f is C 2-6 Alkyl, amino-substituted C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, -C 1-6 Alkylene-C(=O)-OR h Or -OP(=O)-(OR m )(OR n ) and R h , R m and R n are independently hydrogen, deuterium, sodium, potassium, and C 1-6 Alkyl group or C 1-6 It is a halogenated alkyl group.

[0144] In another embodiment, R f is C 2-4 Alkyl, amino-substituted C1-4 Alkyl group, C 1-4 Halogenated alkyl groups, -C 1-4 Alkylene-C(=O)-OR h Or -OP(=O)-(OR m )(OR n ) and R h , R m and R n are independently hydrogen, deuterium, sodium, potassium, and C 1-4 Alkyl group or C 1-4 It is a halogenated alkyl group.

[0145] In yet another embodiment, R f is an ethyl group, an n-propyl group, an isopropyl group, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(NH2)CH(CH3)2, -CH2F, -CHF2, -CF3, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, -CH2C(=O)ONa, -CH2CH2C(=O)-ONa, -CH2CH2CH2C(=O)ONa, -CH(CH3)2C(=O)ONa or -OP(=O)(ONa)2.

[0146] In some embodiments, R 4 is hydrogen, deuterium or hydroxy substituted C 1-6 It is an alkyl group.

[0147] In another embodiment, R 4 is hydrogen, deuterium or hydroxy substituted C 1-4 It is an alkyl group.

[0148] In yet another embodiment, R 4 is hydrogen, deuterium, a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxyethyl group, a 3-hydroxy-n-propyl group, or a 2-hydroxy-1-methylethyl group.

[0149] In some embodiments, R 5 are hydrogen, deuterium, and C 1-4 Alkyl group, C 1-4Halogenated alkyl groups, C 1-4 Alkoxy group, C 3-6 a cycloalkyl group or a 3- to 6-membered heterocyclic group, Each R 6 and R 7 are independently hydrogen, deuterium, and C 1-4 Alkyl group, C 1-4 Halogenated alkyl groups, C 1-4 Alkoxy group, C 3-6 It is a cycloalkyl group or a 3- to 6-membered heterocyclic group.

[0150] In another embodiment, R 5 is hydrogen, deuterium, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, s-butyl, tert-butyl, -CHF, -CHF2, -CF3, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl or azetidinyl; Each R 6 and R 7 are independently hydrogen, deuterium, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, s-butyl, tert-butyl, -CHF, -CHF2, -CF3, -CHFCH2F, -CF2CH3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, or azetidinyl.

[0151] In some embodiments, the present invention relates to a compound represented by Formula (II), or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of a compound represented by Formula (II).

[0152] [ka] (In the formula, A ring, B ring, L 1 , L 3 , R, Z 1 , Z 2 , Z3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , R 2 , R 3 and R 4 is as defined in the present invention.

[0153] In some embodiments, the present invention relates to one of the following compounds, or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, but is not limited to these compounds: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0154] Unless otherwise specified, all stereoisomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds represented by formula (I) or formula (II) are included within the scope of the present invention.

[0155] In some embodiments, pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, hydrochloride salts, sodium salts, potassium salts, and the like.

[0156] Studies have shown that the compounds of the present invention have high affinity for RORγ, stability in liver microsomes, and excellent pharmacokinetic properties in vivo. Specifically, some compounds of the present invention may be first metabolized to the corresponding alcohol compounds in vivo, and the corresponding alcohols have excellent pharmacokinetic properties in vivo.

[0157] In another aspect, the pharmaceutical composition of the present invention comprises a compound of formula (I) or formula (II) of the present invention or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, or a combination thereof.

[0158] In some embodiments, the drug composition further contains other drugs that prevent or treat cancer, inflammatory syndromes, or autoimmune diseases, or any combination thereof.

[0159] In one embodiment, the drug composition may be in liquid, solid, semi-solid, gel, or spray form.

[0160] In another aspect, the present invention relates to the use of a compound of formula (I) or formula (II) or a pharmaceutical composition thereof in the manufacture of a medicament for preventing or treating cancer, inflammation or autoimmune disease mediated by RORγt in a mammal, including a human.

[0161] In some embodiments, the present invention relates to use of a compound of Formula (I) or Formula (II) or a pharmaceutical composition thereof in the manufacture of a medicament for preventing or treating cancer, 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.

[0162] In another aspect, the present invention relates to methods for making, isolating and purifying compounds of formula (I) or formula (II).

[0163] In another aspect, the present invention relates to intermediates for preparing compounds of formula (I) or formula (II).

[0164] The compounds disclosed in the present invention may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. The present invention contemplates that all stereoisomeric forms, including but not limited to diastereoisomers, enantiomers, atropisomers and geometric (or conformational) isomers of the compounds of Formula (I) or Formula (II), as well as mixtures thereof, including racemic mixtures, are part of the present invention.

[0165] In a structure disclosed in this invention, when the stereochemistry of any particular chiral atom is not designated, all stereoisomers of that structure are considered to be within the scope of the present invention and are included in the present invention as compounds disclosed in this invention. When stereochemistry is designated by a solid wedge or dashed line indicating a particular configuration, stereoisomers of that structure are so specified and defined.

[0166] The compounds of formula (I) or formula (II) may exist in different tautomeric forms and all such tautomers are included within the scope of the invention.

[0167] The compound of 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 other ingredients comprising the formulation and / or the mammal being treated therewith. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, but may be an intermediate for preparing and / or purifying the compound of Formula (I) or Formula (II) and / or for separating the enantiomers of the compound of Formula (I) or Formula (II).

[0168] Pharmaceutically acceptable acid addition salts may be formed by the action of a compound disclosed herein with an inorganic or organic acid, such as acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, hydrogensulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorotheophylline, citrate, ethanedisulfonate, fumarate, glucoheptanoate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, Lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluenesulfonate and trifluoroacetate.

[0169] Pharmaceutically acceptable base addition salts may be formed by the action of compounds disclosed in the present invention with an inorganic base or an organic base.

[0170] 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 some embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly suitable salts including ammonium, potassium, sodium, calcium, and magnesium salts.

[0171] Organic bases from which salts can be derived include primary amines, secondary amines, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Some organic amines include, for example, isopropylamine, benzathine benzylpenicillin, choline cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and trometamol.

[0172] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (e.g., 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 an appropriate acid. Such reactions are generally carried out in water or an organic solvent, or a mixture of both. Generally, non-aqueous media such as ethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, as appropriate, must be used. Lists of other 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).

[0173] The compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form containing their solvents (e.g., ethanol, DMSO, etc.) for their crystallization. Because the compounds disclosed in the present invention can inherently or by design form solvates in pharmaceutically acceptable solvents (including water), the present invention is intended to encompass solvated and unsolvated forms of the compounds disclosed in the present invention.

[0174] Any structural formulas provided herein are intended to represent isotopically non-enriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure shown in the general formulas provided herein except that one or more atoms are replaced with atoms having selected atomic masses or mass numbers. Exemplary isotopes that can be incorporated into compounds of the present invention are: 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 Includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as I.

[0175] On the other hand, compounds according to the present invention include isotopically enriched compounds as defined in the present invention, for example: 3 H, 14 C and 18 Compounds in which radioactive isotopes such as F are present, or 2 H and 13 These compounds contain non-radioactive isotopes such as C. Such isotopically enriched compounds are useful for metabolic studies ( 14 C), reaction kinetic studies (e.g. 2 H or 3 H), positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or for radiation treatment of patients.18 F-enriched compounds are particularly ideal for PE or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art, or by methods described in the examples and processes of the present invention, in which suitable isotopically labeled reagents are substituted for conventionally used non-labeled reagents.

[0176] Also, heavier isotopes, especially deuterium (i.e. 2 Substitution with H or D) can provide several therapeutic advantages, and these advantages are due to increased metabolic stability, for example, increased in vivo half-life or reduced dose requirements, or improved therapeutic index. It should be understood that deuterium in the present invention is considered to be a substituent of the compounds represented by formula (I). The concentration of such heavier isotopes (particularly deuterium) can be defined by the isotopic enrichment factor. As used in the present invention, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. When 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). In the present invention, pharmaceutically acceptable solvates include those in which the crystallization solvent, such as DO, acetone-d6, or DMSO-d6, may be isotopically substituted.

[0177] Pharmaceutical Compositions, Formulations and Administration of Compounds of the Invention The pharmaceutical compositions of the present invention comprise a compound disclosed in the present invention, such as the compounds listed in the Examples, and a pharmaceutically acceptable excipient, carrier, adjuvant, or combination thereof.

[0178] The method of treating, preventing, or ameliorating a disease or disorder according to the present invention comprises administering a safe and effective amount of a combination drug containing a compound disclosed in the present invention and one or more therapeutically active agents, wherein the combination drug contains one or more other drugs that prevent or treat the inflammatory syndrome, disorder, or disease, and the other drugs include: 1) TNF-α inhibitors, 2) non-selective COX-1 / COX-2 inhibitors, 3) COX-2 inhibitors, 4) glucocorticoids, methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporine, tacrolimus, penicillamine, bucillamine, actarit, mizoribine, lobenzarit, ciclesonide, hydroxychloroquine, aurothiomalate, auranofin, cyclophosphamide, BAFF / APRIL inhibitors, CTLA-4 immunoglobulin, etc. other therapeutic agents for treating inflammatory syndromes and autoimmune diseases, 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, α1 and α2-adrenergic receptor agonists, 9) anticholinergic agents, 10) P-adrenergic receptor agonists, 11) insulin-like growth factor type I analogs, 12) Janus kinase inhibitors (JAK1 and / or JAK2 and / or JAK3 and / or TYK2), p38 13) biologic drugs that target B cells, such as rituximab; 14) selective costimulatory modulators, such as abatacept; and 15) 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.

[0179] The amount of compound in the pharmaceutical compositions disclosed herein refers to an amount capable of effectively and detectably inhibiting retinoid-related orphan receptor γt in a biological sample or patient. The dosage of the active ingredient in the compositions of the present invention may vary, but the amount of the active ingredient should be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and humans) in need of such treatment at dosages that provide optimal drug efficacy. The selected dosage will depend on the desired therapeutic effect, the route of administration, and the duration of treatment. Dosages will vary from patient to patient and will depend on the nature and severity of the disease, the patient's weight, the patient's specific diet, concomitant medications, and other factors recognized by those skilled in the art. In one embodiment, the dosage range is about 0.5 mg to 500 mg per patient per day, and in another embodiment, about 0.5 mg to 200 mg per patient per day.

[0180] It will be appreciated that some compounds of the present invention may exist in free form and be used in therapy, or, where appropriate, may exist in the form of a pharmaceutically acceptable derivative thereof, which includes pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or any other adduct or derivative that is capable of providing, directly or indirectly, a compound of the present invention or a metabolic product or residue thereof when administered to a patient in need thereof.

[0181] The drugs or drug compositions disclosed in the present invention may be manufactured and packaged in bulk form, from which a safe and effective amount of the compound of Formula (I) can be extracted and then administered to a patient in the form of a powder or syrup. Generally, effective inhibitory effects on retinoid-related orphan receptor γt are achieved by administering the drug to a patient at a dosage level of 0.0001 to 10 mg / kg body weight per day. Alternatively, the drug compositions disclosed in the present invention may be manufactured and packaged in unit dosage form, with each physically discrete unit containing a safe and effective amount of the compound of Formula (I). When manufactured in unit dosage form, the drug compositions disclosed in the present invention may generally contain an effective dose of the compound of the present invention.

[0182] When the pharmaceutical composition of the present invention contains one or more other active ingredients in addition to the compound of the present invention, the weight ratio of the compound of the present invention to the second active ingredient may vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used. Thus, for example, when the compound of the present invention is mixed with another drug, the weight ratio of the compound of the present invention to the other drug is generally in the range of about 1000:1 to about 1:1000, for example, about 200:1 to about 1:200. The mixture of the compound of the present invention with another active ingredient is also generally within the above range, but in any case, an effective dose of each active ingredient should be used.

[0183] As used herein, the term "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, mixture, or solvent associated with the consistency of a dosage form or drug composition. Each excipient must be compatible with the other components of the drug composition when mixed together to avoid interactions that significantly reduce the efficacy of the compounds disclosed herein when administered to a patient and interactions that result in a pharmaceutically unacceptable drug composition. Furthermore, each excipient must be pharmaceutically acceptable, e.g., have a sufficiently high purity.

[0184] Suitable pharmaceutically acceptable excipients vary depending on the specific dosage form selected. Furthermore, pharmaceutically acceptable excipients may be selected according to their specific function in the composition. For example, some pharmaceutically acceptable excipients may be selected to contribute to the production of a uniform dosage form. Some pharmaceutically acceptable excipients may be selected to contribute to the production of a stable dosage form. Some pharmaceutically acceptable excipients may be selected to contribute to carrying or transporting the compounds disclosed herein from one organ or part of the body to another organ or part of the body when administered to a patient. Some pharmaceutically acceptable excipients may be selected to enhance patient compliance.

[0185] Suitable pharmaceutically acceptable excipients include excipients such as diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. As one of ordinary skill in the art will recognize, some pharmaceutically acceptable excipients can serve more than one function and may serve selected functions, depending on how much of the excipient is present in the formulation and what other excipients are present in the formulation.

[0186] Those skilled in the art possess the knowledge and skill in the art to enable them to select appropriate pharmaceutically acceptable excipients in appropriate amounts for use in the present invention. Additionally, there are numerous resources available to those skilled in the art that describe pharmaceutically acceptable excipients and are useful in selecting appropriate 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).

[0187] 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, disclose various carriers for preparing pharmaceutically acceptable compositions and known techniques used in their preparation, the contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the compounds disclosed herein, such as by producing any undesirable biological effect or by interacting in a deleterious manner with any other ingredients in the pharmaceutically acceptable composition, its use is considered to be within the scope of the present invention.

[0188] The pharmaceutical compositions disclosed in the present invention are prepared using techniques and methods known to those skilled in the art. For a description of some common methods in this field, reference may be made to Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0189] Thus, in another aspect, the present invention relates to a process for producing a pharmaceutical composition, the pharmaceutical composition comprising a compound disclosed in the present invention and a pharmaceutically acceptable excipient, carrier, adjuvant, or a combination thereof, the process comprising mixing the various ingredients. The pharmaceutical composition containing the compound disclosed in the present invention can be produced, for example, by mixing at ambient temperature and atmospheric pressure.

[0190] The compounds disclosed in the present invention are generally formulated into dosage forms suitable for administration to patients via the required route, including (1) tablets, capsules, caplets, pellets, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and wafers for oral administration, (2) sterile solutions, suspensions, and reconstituted powders for parenteral administration, (3) transdermal patches for transdermal administration, (4) suppositories for rectal administration, (5) aerosols, solutions, and dry powders for inhalation, and (6) creams, ointments, lotions, solutions, pastes, sprays, foams, and gels for topical administration.

[0191] In one embodiment, the compounds disclosed in the present invention may be formulated as an oral dosage form. In another embodiment, the compounds disclosed in the present invention may be formulated as an inhalation dosage form. In another embodiment, the compounds disclosed in the present invention may be formulated as an intranasal dosage form. In yet another embodiment, the compounds disclosed in the present invention may be formulated as a transdermal dosage form. Also, in one embodiment, the compounds disclosed in the present invention may be formulated as a topical dosage form.

[0192] The pharmaceutical compositions of the present invention may be provided as compressed tablets, molded tablets, chewable lozenges, quick-dissolving tablets, multiple 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 action of stomach acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting 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 that helps mask unpleasant tastes or odors and protects the tablets from 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, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart general properties similar to those of sugar coatings. Multiple compressed tablets are compressed tablets made by two or more compression cycles, including multi-layer tablets and compressed-coated or dry-coated tablets.

[0193] Tablet dosage forms can be prepared from powdered, crystalline, or granular active ingredient, 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 and sweetening agents are particularly useful when forming chewable tablets and lozenges.

[0194] The pharmaceutical compositions of the present invention may be provided as soft or hard capsules, which may be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as a dry-filled capsule (DFC), consists of two sections, one of which fits snugly over the other, completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, spherical shell, such as a gelatin shell, which is plasticized by adding glycerol, sorbitol, or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those described in this invention and include methylparaben, propylparaben, and sorbic acid. Liquid, semisolid, and solid dosage forms of the present invention may be encapsulated. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions may be prepared as described in U.S. Pat. Nos. 4,328,245, 4,409,239, and 4,410,545. The capsules may be coated to improve or sustain dissolution of the active ingredient, as known to those skilled in the art.

[0195] The pharmaceutical compositions of the present invention may 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 dispersed in the form of small globules throughout another liquid, which may be oil-in-water or water-in-oil. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifying agent, and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may contain a pharmaceutically acceptable acetal, such as a di(lower alkyl)acetal of a lower alkyl aldehyde (e.g., acetaldehyde diethyl acetal), and a water-soluble solvent having one or more hydroxy groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened aqueous alcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, such as sucrose, and may contain a preservative. For a liquid dosage form, for example, a solution in polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be accurately and conveniently administered.

[0196] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing an active ingredient of the present invention and a dialkylated 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, and polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further contain one or more antioxidants such as butylhydroxytoluene (BHT), butylhydroxyanisole (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.

[0197] Where appropriate, dosage unit formulations for oral administration can be microencapsulated, or can be made into a prolonged or sustained release composition, for example, by coating or embedding particulate material in a polymer or wax or the like.

[0198] The oral pharmaceutical compositions of the present invention may also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micelle dosage forms may be prepared by the methods described in U.S. Pat. No. 6,350,458.

[0199] The drug compositions of the present invention may be provided as non-effervescent or effervescent granules and powders to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners, and humectants. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and a carbon dioxide source.

[0200] In all of the above dosage forms, coloring and flavoring agents may be used.

[0201] The compounds disclosed in the present invention may be conjugated to soluble polymers that serve as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or palmitoyl-substituted polyethylene oxide polylysine. Furthermore, the compounds disclosed in the present invention may be conjugated to biodegradable polymers used to achieve controlled drug release, such as polylactic acid, polyε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked hydrogels or amphiphilic block copolymers.

[0202] The pharmaceutical compositions of the present invention may be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0203] The pharmaceutical composition of the present invention may be formulated with other active ingredients that do not impair the desired therapeutic action, or may be formulated with substances that supplement the desired action.

[0204] The pharmaceutical compositions of the present invention may 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.

[0205] The pharmaceutical compositions of the present invention may be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for preparation as a solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in the art (see, again, Remington: The Science and Practice of Pharmacy).

[0206] Drug compositions intended for parenteral administration may contain one or more pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, 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, cryoprotectants, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

[0207] Suitable aqueous vehicles include, but are not limited to, water, saline, normal 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 vegetable 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-butanediol, 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.

[0208] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, amalgam, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propylparaben, and sorbic acid. Suitable isotonicity 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 as described herein and include bisulfites and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are as described herein and include sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters 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.

[0209] The pharmaceutical compositions of the present invention may be formulated for single-dose or multiple-dose administration. The single-dose formulations are packaged in ampoules, vials, or syringes. The multiple-dose parenteral formulations must contain bacteriostatic or fungistatic concentrations of antibacterial agents. All parenteral formulations must be sterile, as known and practiced in the art.

[0210] In one embodiment, the drug composition is provided as a ready-to-use sterile solution. In another embodiment, the drug composition is provided as a sterile dry soluble product, including lyophilized powders and hypodermic tablets, which are reconstituted with a vehicle before use. In yet another embodiment, the drug composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the drug composition is formulated as a sterile dry insoluble product, which is reconstituted with a vehicle before use. In another embodiment, the drug composition is formulated as a ready-to-use sterile emulsion.

[0211] The drug composition may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implant depot. In one embodiment, the drug 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 drug composition to diffuse through it.

[0212] Suitable inner matrices include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0213] Suitable outer polymeric membranes include polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, dimethylpolysiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer.

[0214] In other aspects, the drug compositions disclosed herein may be formulated in any dosage form suitable for administration to a patient via inhalation, such as a dry powder, aerosol, suspension, or solution composition. In one embodiment, the drug compositions disclosed herein may be formulated in a dosage form suitable for administration to a patient via inhalation using a dry powder. In another embodiment, the drug compositions disclosed herein may be formulated in a dosage form suitable for administration to a patient via inhalation using a nebulizer. Dry powder compositions delivered to the lung via inhalation generally contain a compound disclosed herein in fine powder form and one or more pharmaceutically acceptable excipients in fine powder form. 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 may be produced, for example, by micronization and grinding. Generally, a reduced-size (e.g., micronized) compound will have a D of about 1 to 10 microns. 50 It can be defined by a value (for example, measured by laser diffraction).

[0215] Aerosols may 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 metered-dose inhalers (MDIs). Such devices are known to those skilled in the art.

[0216] Aerosols can contain additional pharmaceutically acceptable excipients that may be used in MDIs, such as surfactants, lubricants, cosolvents, and other excipients to improve the physical stability of the formulation, improve valve performance, improve solubility, or improve taste.

[0217] Pharmaceutical compositions suitable for transdermal administration may be manufactured as discrete patches intended to remain in intimate contact with the patient's epidermis for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

[0218] Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. For example, ointments, creams, and gels may be formulated using an aqueous or oily base and appropriate thickening and / or gelling agents and / or solvents. Such bases may contain water and / or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Depending on the nature of the base, thickening agents and gelling agents used include soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carboxyvinyl polymers and cellulose derivatives, and / or glycerol monostearate, and / or non-ionic emulsifiers.

[0219] Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.

[0220] Powders for external application may be formed 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 dispersing agents, solubilizing agents, suspending agents, or preservatives.

[0221] Topical formulations may be administered by application to the affected area one or more times daily, preferably using an occlusive dressing over the skin. Continuous or chronic administration may also be achieved by adhesive reservoir systems.

[0222] Uses of the Compounds and Pharmaceutical Compositions of the Invention The compounds or pharmaceutical compositions disclosed in the present invention can be used in the manufacture of a medicament for treating, preventing, ameliorating, controlling or alleviating cancer, inflammation or autoimmune diseases mediated by RORγt in mammals, including humans, and can also be used in the manufacture of other medicaments for inhibiting RORγt.

[0223] Specifically, the amount of the compound in the composition of the present invention is such that it can effectively and detectably inhibit RORγt, and the compound of the present invention can be used as a drug for preventing or treating human cancer, 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.

[0224] Uses of the compounds or compositions of the invention may include, but are not limited to, preventing, treating, or ameliorating cancer, 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 a mammal, including a human, by administering to the patient an effective amount of a compound or composition of the invention.

[0225] In addition to being useful for human treatment, the compounds and pharmaceutical compositions of the present invention are also useful for veterinary treatment of mammals such as companion animals, exotic animals, and farm animals. Examples of other animals include horses, dogs, and cats. Here, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

[0226] General synthetic steps In order to illustrate the present invention, the following examples are given. However, it should be understood that the present invention is not limited to these examples, which merely provide a method of practicing the present invention.

[0227] In general, the compounds of the present invention can be prepared by the methods described herein, and the substituents are as defined in Formula (I) or Formula (II) unless further specified. The following reaction schemes and examples are used to further illustrate the subject matter of the present invention.

[0228] Those skilled in the art will recognize that the chemical reactions described in this invention can be adapted to produce many other compounds of this invention, and all other methods for producing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of unexemplified compounds of this invention can be successfully carried out by those skilled in the art by modifying the method, for example, by appropriately protecting interfering groups, by utilizing known reagents other than those described in this invention, or by making routine changes to the reaction conditions. It is also believed that the reactions disclosed in this invention or known reaction conditions can be applied to the production of other compounds of this invention.

[0229] In the examples described below, all temperatures are in degrees Celsius unless otherwise specified. Unless otherwise specified, reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company and used without further purification. Common reagents were purchased from Shantou Xilonghua Factory, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Plant, Wuhan Guanghua Yuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0230] Anhydrous tetrahydrofuran, dioxane, toluene, and ethyl ether are obtained by refluxing and drying over metallic sodium. Anhydrous dichloromethane and chloroform are obtained by refluxing and drying over calcium hydride. Ethyl acetate, petroleum ether, normal hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are dried over anhydrous sodium sulfate before use.

[0231] The following reactions are generally carried out in anhydrous solvents under a positive pressure of nitrogen or argon gas, or using a drying tube (unless otherwise specified), with the reaction flask fitted with an appropriate rubber stopper and the substrate introduced via syringe. All glassware is dried.

[0232] A silica gel column (300-400 mesh) is used as the chromatography column, purchased from Qingdao Haining Chemical Factory.

[0233] Nuclear magnetic resonance spectra were recorded on a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer using CDC13, DMSO-d6, CD3OD, or acetone-d6 (in ppm) as solvents, referenced to TMS (0 ppm) or chloroform (7.26 ppm). When multiplets appear, the abbreviations s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), and dt (doublet of triplets) are used. Coupling constants, J, are given in Hertz (Hz).

[0234] Low-resolution mass spectral (MS) data were collected using an Agilent 6120 quadrupole HPLC-M (column: Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 min, flow rate: 0.6 mL / min. Mobile phase: 5%-95% (ACN containing 0.1% formic acid in HO containing 0.1% formic acid) ratio) with electrospray ionization (ESI) and UV detection at 210 nm / 254 nm.

[0235] The purity of the compound was measured by high performance liquid chromatography (HPLC) using an Agilent 1260 HPLC (column model: Agilent Zorbax Eclipse Plus C18) and detected by a DAD detector, and finally calculated using the area normalization method to obtain the purity of the compound.

[0236] The following abbreviations are used throughout this specification: Ac2O Acetic anhydride / Acetic anhydride AcOH Ethanoic acid / Acetic acid AgOTf Silver trifluoromethanesulfonate Boc2O Di-tert-butyl dicarbonate CbzCl Benzyl chloroformate CDC13 Deuterated Chloroform CDI N,N'-carbonyldiimidazole DCM dichloromethane DAST Diethylaminosulfur trifluoride DIAD Diisopropyl azodicarboxylate DMF N,N-dimethylformamide DIPEA N,N-Diisopropylethylamine DMAP 4-dimethylaminopyridine DMSO dimethyl sulfoxide DMSO-d6 Deuterated Dimethyl Sulfoxide dccp·HBF4 1,3-Bis(dicyclohexylphosphino)propanebis(tetrafluoroborate) EtI Iodoethane EtOAc / EA ethyl acetate EtOH Ethanol Et3N / TEA Triethylamine EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HOBT 1-Hydroxybenzotriazole i-PrOH isopropanol KOAc Potassium Acetate t-BuOK Potassium tert-butoxide t-BuONa Sodium tert-butoxide LiOH Lithium hydroxide LiBH4 Lithium borohydride MeCN / ACN acetonitrile MeI Iodomethane MeOH methanol MeONa Sodium methoxide MsCl Methylsulfonyl chloride Pd2(dba)3 tris(dibenzylideneacetone)dipalladium Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc)2 Palladium Acetate Pd(P(o-Tol)3)2(OAc)2 Diacetoxybis(tri-o-tolylphosphine)palladium(II) PE Petroleum Ether TMSCF3 (trifluoromethyl)trimethylsilane TBSOTf tert-Butyldimethylsilyl trifluoromethanesulfonate Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride TMSCF2Br (Bromo(difluoro)methyl)trimethylsilane Pd / C Palladium / carbon TLC thin layer chromatography THF tetrahydrofuran TFA trifluoroacetic acid XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene g grams h time min minutes mmol millimole ℃ Celsius mL (ml) milliliter RT, rt, rt room temperature rpm Revolutions per minute Dess-Martin Reagent 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one Rt retention time t-Bu-XPhos 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl Lawesson's Reagent N(n-Bu)4CN Tetrabutylammonium cyanide Typical synthetic steps for preparing the compounds disclosed in the present invention are as shown in the following synthetic scheme: wherein X represents a halogen atom, PG represents an amino-protecting group, each of T1 and T2 is independently selected from a carboxyl group or an amino group, and T1 and T2 are not the same group, and n is 1 or 3. Unless otherwise specified, the B ring, R, R 2 , R 3 , R 4 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 is as defined in the present invention.

[0237] Synthesis of key intermediates: [ka] Intermediate (a) can be prepared by the following process: Compound (aa) is reacted with compound (ab) to produce compound (ac), which is then catalytically hydrogenated to give compound (ad), and the amino protecting group of compound (ad) is then removed to give intermediate compound (a).

[0238] Synthesis Scheme 1 [ka] Compound (4a) or (4a′) can be prepared by the following process: Compound (2a) is produced by a substitution reaction between compound (a) and compound (1a), and compound (4a) or (4a') is obtained by an acylation reaction between compound (2a) and compound (3a).

[0239] Synthesis Scheme 2 [ka] Compound (7b) or (7b') can be prepared by the following process: Compound (1b) is subjected to an acylation reaction with compound (1a) to produce compound (2b) or (2b'), compound (2b) or (2b') is subjected to an addition reaction with compound (3b) to produce compound (4b) or (4b'), the amino-protecting group of compound (4b) or (4b') is removed to produce compound (5b) or (5b'), and compound (5b) or (5b') is reacted with compound (6b) to produce compound (7b) or (7b').

[0240] Synthesis Scheme 3 [ka] Compound (5c) or (5c') can be prepared by the following process: Compound (2c) is produced by an addition reaction of compound (1c), compound (2c) is subjected to a substitution reaction with compound (aa) to produce compound (3c), the amino protecting group of compound (3c) is removed to produce compound (4c), and compound (4c) is subjected to a substitution reaction with compound (2b) or (2b') to produce compound (5c) or (5c').

[0241] Synthesis Scheme 4 [ka] Compound (5d) or (5d') can be prepared by the following process: Compound (1d) is reacted with compound (1c) to produce compound (2d), compound (2d) is subjected to a methylation reaction to produce compound (3d), the amino protecting group of compound (3d) is removed to produce compound (4d), and compound (4d) is subjected to a substitution reaction with compound (2b) or (2b') to produce compound (5d) or (5d').

[0242] The compounds, pharmaceutical compositions and uses thereof according to the present invention will now be further described with reference to the following examples.

[0243] Synthesis of intermediate: (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol [ka] It is produced by the method disclosed in International Patent Application No. 2017132432.

[0244] Example Example 1 2-(4-(ethylsulfonyl)phenyl)-N-(4-(3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)phenyl)acetamide [ka] Step 1: Synthesis of tert-butyl 4-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-pyrrole-1-carboxylate Under nitrogen gas protection, 1-bromo-4-(trifluoromethyl)benzene (1.00 g, 4.40 mmol), tert-butyl 3-methylenepyrrolidine-1-carboxylate (1.20 g, 6.50 mmol), Pd(P(o-Tol)3)2(OAc)2 (14 mg, 0.02 mmol), and Ag2CO3 (1.20 g, 4.40 mmol) were dissolved in DMF (10 mL), and then DIPEA (3.00 mL, 18.15 mmol) was added to prepare a 100% DMF solution. o The reaction mixture was heated to 10°C and stirred for 24 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL), washed with saturated NaHCO3 solution (15 mL × 2) and saturated NaCl solution (15 mL × 3) successively, 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 a yellow oily liquid (1.03 g, 71%).

[0245] MS (ESI, pos.ion) m / z: 272.0 [M-56+H] + . Step 2: Synthesis of tert-butyl 3-(4-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate Pd / C (132 mg, 10%) was added to a solution of tert-butyl 4-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (1.03 g, 3.15 mmol) in MeOH (20 mL) and stirred under hydrogen gas atmosphere at room temperature for 2 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 6 / 1 / 1) to give a yellow oily liquid (143 mg, 14%).

[0246] MS (ESI, pos.ion) m / z: 274.2 [M-56+H] + . Step 3: Synthesis of 3-(4-(trifluoromethyl)benzyl)pyrrolidine hydrochloride tert-Butyl 3-(4-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate (143 mg, 0.43 mmol) was dissolved in a solution of HCl in i-PrOH (4 mL, 24.00 mmol, 6 mol / L) and stirred at room temperature for 6 h. Concentration under reduced pressure gave 3-(4-(trifluoromethyl)benzyl)pyrrolidine hydrochloride.

[0247] MS (ESI, pos.ion) m / z: 230.2 [M+H] + . Step 4: Synthesis of 1-(4-nitrophenyl)-3-(4-(trifluoromethyl)benzyl)pyrrolidine Under nitrogen gas protection, 3-(4-(trifluoromethyl)benzyl)pyrrolidine hydrochloride, 1-fluoro-4-nitrobenzene (0.10 mL, 0.94 mmol), and DIPEA (0.74 mL, 4.30 mmol) were dissolved in ACN (4 mL), and the reaction mixture was heated and stirred at 80 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with DCM (50 mL), and washed successively with saturated NaHCO solution (20 mL) and saturated NaCl solution (10 mL), dried over anhydrous NaSO, 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 a yellow solid (105 mg, 69%).

[0248] MS (ESI, pos.ion) m / z: 351.2 [M+H] + . Step 5: Synthesis of 4-(3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)aniline Pd / C (20 mg, 10%) was added to a solution of 1-(4-nitrophenyl)-3-(4-(trifluoromethyl)benzyl)pyrrolidine (105 mg, 0.30 mmol) in MeOH (5 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a dark solid (75 mg, 78%).

[0249] MS (ESI, pos.ion) m / z: 321.2 [M+H] + . Step 6: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)phenyl)acetamide Under nitrogen gas protection, 4-(3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)aniline (75 mg, 0.24 mmol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (106 mg, 0.46 mmol), EDCI (89 mg, 0.46 mmol), and HOBT (64 mg, 0.47 mmol) were dissolved in DCM (4 mL), and TEA (0.14 mL, 1.01 mmol) was added and stirred at room temperature for 18 h. The reaction mixture was diluted with DCM (80 mL) and washed successively with HCl solution (20 mL, 1 mol / L), saturated NaCl solution (20 mL), and saturated NaHCO solution (20 mL), dried over anhydrous NaSO, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 6 / 1 / 1) to give a colorless solid (75 mg, 60%).

[0250] MS (ESI, pos.ion) m / z: 531.1 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.90 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.1 Hz, 4H), 7.31 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 6.98 (s, 1H), 6.45 (d, J = 8.8 Hz, 2H), 3.77 (s, 2H), 3.37 - 3.32 (m, 1H), 3.28 (s, 1H), 3.10 (q, J = 7.5 Hz, 2H), 2.98 (t, J= 8.0 Hz, 1H), 2.81 (d, J = 7.5 Hz, 2H), 2.64 - 2.56 (m, 1H), 2.15 - 2.05 (m, 1H), 2.01 (dd, J = 11.3, 5.8 Hz, 1H), 1.77 (dd, J = 10.7, 6.5 Hz, 1H), 1.30 (t, J = 7.5 Hz, 3H). Example 2 N-(4-(ethylsulfonyl)phenyl)-4-(3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of methyl 4-(3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, 3-(4-(trifluoromethyl)benzyl)pyrrolidine (400 mg, 1.75 mmol), methyl 4-bromobenzoate (750 mg, 3.49 mmol), Pd(dba) (141 mg, 0.15 mmol), XantPhos (173 mg, 0.30 mmol), and CsCO (1.11 g, 3.41 mmol) were dissolved in 1,4-dioxane (12 mL), and the reaction mixture was heated and stirred in an oil bath at 100 °C for 18 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with DCM (50 mL), washed successively with saturated NaHCO3 solution (20 mL) and saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 6 / 1) to give a white powder (400 mg, 64%).

[0251] MS (ESI, pos.ion) m / z: 364.2 [M+H] + . Step 2: Synthesis of 4-(3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (461 mg, 10.99 mmol) in HO (3 mL) was added to a solution of methyl 4-(3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzoate (200 mg, 0.55 mmol) in THF (10 mL) and MeOH (6 mL) and the mixture was reacted at 70 °C for 11 h. The reaction mixture was cooled to room temperature, and the pH of the mixture was adjusted to approximately 5 by adding HCl solution (1 mol / L) (a large amount of white solid product precipitated during the dropwise addition). The mixture was concentrated under reduced pressure and filtered to give the product as a white solid. The filtrate was extracted with EtOAc (30 mL × 2). The combined organic phases were dried over anhydrous NaSO and concentrated under reduced pressure to give the product as a white solid. The combined yield was a white solid (192 mg, 100%).

[0252] MS (ESI, pos.ion) m / z: 350.2 [M+H] + . Step 3: Synthesis of N-(4-(ethylsulfonyl)benzyl)-4-(3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzamide HATU (165 mg, 0.43 mmol), 4-(3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzoic acid (100 mg, 0.29 mmol), and (4-(ethylsulfonyl)phenyl)methanamine (88 mg, 0.44 mmol) were dissolved in DCM (5 mL), and TEA (88 mg, 0.87 mmol) was added and stirred at room temperature for 4 h. The reaction mixture was diluted with DCM (40 mL), washed sequentially with saturated NaHCO solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: EtOAc / DCM (v / v) = 1 / 4) to give a white powder (100 mg, 66%).

[0253] MS (ESI, pos.ion) m / z: 531.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.76 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 6.77 (t, J = 6.0 Hz, 1H), 6.48 (d, J = 8.8 Hz, 2H), 4.68 (d, J = 6.0 Hz, 2H), 3.48 - 3.39 (m, 2H), 3.36 - 3.30 (m, 1H), 3.10 - 3.02 (m, 3H), 2.83 (d, J = 7.5 Hz, 2H), 2.66 - 2.59 (m, 1H), 2.17 - 2.10 (m, 1H), 1.79 - 1.74 (m, 1H), 1.24 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ (ppm): 167.540, 149.99, 145.65, 144.36, 137.06, 128.96, 128.66, 128.45, 128.07, 125.46, 119.89, 110.79, 52.72, 50.62, 47.14, 43.10, 40.18, 39.36, 31.19, 7.39. Example 3 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-yl)phenyl)acetamide [ka] Step 1: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-iodophenyl)acetamide Under nitrogen gas protection, 2-(4-(ethylsulfonyl)phenyl)acetic acid (10.20 g, 44.73 mmol), 4-iodoaniline (7.50 g, 34.25 mmol), and HATU (19.80 g, 52.07 mmol) were dissolved in DCM (150 mL), and DIPEA (13 mL, 73.20 mmol) was added. The mixture was stirred at room temperature for 18 h. DCM (200 mL) was added to the reaction mixture, which was then washed with water (50 mL × 4). The organic phase was dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1) to give a white solid (14.20 g, 97%).

[0254] MS (ESI, pos.ion) m / z: 430.1 [M+H] + . Step 2: Synthesis of benzyl 3-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate Under nitrogen gas protection, 2-(4-(ethylsulfonyl)phenyl)-N-(4-iodophenyl)acetamide (500 mg, 1.17 mmol), benzyl 2,5-dihydropyrrole-1-carboxylate (0.41 g, 2.00 mmol), Pd(P(o-Tol)3)2(OAc)2 (150 mg, 0.16 mmol), Ag2CO3 (320 mg, 1.16 mmol), and DIPEA (0.20 mL, 1.00 mmol) were dissolved in DMF (40 mL). The reaction mixture was heated and stirred in an oil bath at 110 °C for 8 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a pale yellow solid (130 mg, 22%).

[0255] MS (ESI, pos.ion) m / z: 505.6 [M+H] + . Step 3: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(pyrrolidin-3-yl)phenyl)acetamide Pd / C (155 mg, 5%) was added to a solution of benzyl 3-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (120 mg, 0.24 mmol) in MeOH (50 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) to give a brown solid (80 mg, 90%).

[0256] MS (ESI, pos.ion) m / z: 373.1 [M+H] + . Step 4: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-yl)phenyl)acetamide Under ice-cooling, NaBHCN (100 mg, 1.21 mmol) was added to a solution of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(pyrrolidin-3-yl)phenyl)acetamide (100 mg, 0.27 mmol) and 4-(trifluoromethyl)benzaldehyde (0.10 mL, 0.70 mmol) in MeOH (20 mL), and the mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 15 / 1) to give a pale yellow solid (110 mg, 77%).

[0257] MS (ESI, pos.ion) m / z: 531.6 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.39 (s, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.64 (s, 4H), 7.58 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 4.19 (s, 2H), 3.82 (s, 2H), 3.64 - 3.53 (m, 2H), 3.53 - 3.33 (m, 2H), 3.22 (s, 2H), 3.09 (ddd, J = 25.8, 14.8, 7.4 Hz, 4H), 2.95 (t, J = 9.8 Hz, 1H), 2.64 (s, 2H), 2.36 (s, 1H), 2.06 (d, J = 8.6 Hz, 1H), 1.29 (d, J = 7.4 Hz, 3H). Example 4 N-(4-(ethylsulfonyl)benzyl)-4-(1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-yl)benzamide [ka] Step 1: Synthesis of 4-bromo-N-(4-(ethylsulfonyl)benzyl)benzamide Under nitrogen gas protection, 4-bromobenzoic acid (1.03 g, 5.12 mmol), (4-(ethylsulfonyl)phenyl)methanamine (1.02 g, 5.12 mmol), EDCI (1.43 g, 7.46 mmol), and HOBT (1.00 g, 7.40 mmol) were dissolved in DCM (10 mL). TEA (1.4 mL, 10 mmol) was then added to the reaction mixture and stirred at room temperature for 4 h. The reaction mixture was diluted with DCM (80 mL), washed sequentially with saturated NaHCO solution (20 mL) and saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 10 / 1) to give a yellow solid (1.42 g, 72%).

[0258] MS (ESI, pos.ion) m / z: 382.1 [M+H] + . Step 2: Synthesis of benzyl 4-(4-((4-(ethylsulfonyl)benzyl)carbamoyl)phenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate Under nitrogen gas protection, 4-bromo-N-(4-(ethylsulfonyl)benzyl)benzamide (368 mg, 0.96 mmol), benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (1.72 mL, 9.58 mmol), Pd(P(o-Tol))(OAc) (50 mg, 0.05 mmol), and AgCO (265 mg, 0.96 mmol) were dissolved in DMF (5 mL), and DIPEA (0.5 mL, 2.82 mmol) was added. The reaction mixture was heated and stirred in an oil bath at 100 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed successively with saturated NaHCO3 solution (20 mL) and saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 10 / 1) to give a yellow oily liquid (372 mg, 77%).

[0259] MS (ESI, pos.ion) m / z: 505.1 [M+H] + . Step 3: Synthesis of N-(4-(ethylsulfonyl)benzyl)-4-(pyrrolidin-3-yl)benzamide Pd / C (265 mg, 10%) was added to a solution of benzyl 4-(4-((4-(ethylsulfonyl)benzyl)carbamoyl)phenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (372 mg, 0.74 mmol) in MeOH (10 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 h. The reaction mixture was filtered, dried over anhydrous NaSO, and concentrated under reduced pressure to give a dark yellow oil (274 mg, 100%).

[0260] MS (ESI, pos.ion) m / z: 373.1 [M+H] + . Step 4: Synthesis of N-(4-(ethylsulfonyl)benzyl)-4-(1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-yl)benzamide 4-(Trifluoromethyl)benzaldehyde (145 mg, 0.83 mmol) and N-(4-(ethylsulfonyl)benzyl)-4-(pyrrolidin-3-yl)benzamide (154 mg, 0.41 mmol) were dissolved in EtOH (3 mL) and THF (3 mL). AcOH (0.02 mL, 0.40 mmol) and NaBHCN (259 mg, 4.12 mmol) were added sequentially and stirred at room temperature for 12 h. The reaction mixture was extracted with saturated NaHCO solution (20 mL) slowly and concentrated under reduced pressure to remove the organic solvent. The residue was extracted with DCM (30 mL × 3). The combined organic phases were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 10 / 1) to give a yellow solid (18 mg, 8%).

[0261] MS (ESI, pos.ion) m / z: 531.3 [M+H] + . Example 5 2-(4-(ethylsulfonyl)phenyl)-N-(4-(4-methyl-1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-yl)phenyl)acetamide [ka] Step 1: Synthesis of tert-butyl 3-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-4-methyl-2,3-dihydro-1H-pyrrole-1-carboxylate Under nitrogen gas protection, 2-(4-(ethylsulfonyl)phenyl)-N-(4-iodophenyl)acetamide (9.30 g, 21.68 mmol), tert-butyl 3-methyl-2,5-dihydropyrrole-1-carboxylate (3.01 g, 16.40 mmol), Pd(P(o-Tol))(OAc) (1.26 g, 1.34 mmol), and AgCO (7.50 g, 27.20 mmol) were dissolved in DMF (35 mL), and DIPEA (12.00 mL, 67.60 mmol) was added. The reaction mixture was heated in an oil bath at 100 °C for 14 h. The reaction mixture was cooled to room temperature, water (200 mL) was added to the reaction mixture, and then extracted with EtOAc (200 mL × 2). The organic phase was washed with water (150 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1) to give a gray oil (3.00 g, 38%).

[0262] MS (ESI, pos.ion) m / z: 485.1 [M+H] + . Step 3: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(4-methyl-2,3-dihydro-1H-pyrrol-3-yl)phenyl)acetamide tert-Butyl 3-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-4-methyl-2,3-dihydro-1H-pyrrole-1-carboxylate (3.00 g, 6.19 mmol) was dissolved in HCl in EtOAc (25 mL, 6 mol / L) and stirred at room temperature for 5 h. Saturated NaHCO3 solution (40 mL) was added to the reaction mixture, which was then concentrated under reduced pressure to remove the organic solvent. The remaining aqueous phase was extracted with EtOAc (50 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) to give a gray oil (217 mg, 9%).

[0263] MS (ESI, pos.ion) m / z: 385.3 [M+H] + . Step 4: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(4-methylpyrrolidin-3-yl)phenyl)acetamide Pd / C (612 mg, 10%) was added to a mixture of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(4-methyl-2,3-dihydro-1H-pyrrol-3-yl)phenyl)acetamide (217 mg, 0.56 mmol) in a THF / MeOH (5 mL / 5 mL) mixture and stirred under a hydrogen atmosphere at room temperature for 6 h. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give a white solid (149 mg, 68%).

[0264] MS (ESI, pos.ion) m / z: 387.3 [M+H] + . Step 5: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(4-methyl-1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-yl)phenyl)acetamide AcOH (0.01 mL, 0.50 mmol) was added to a solution of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(4-methylpyrrolidin-3-yl)phenyl)acetamide (149 mg, 0.39 mmol) and 4-(trifluoromethyl)benzaldehyde (0.10 mL, 0.70 mmol) in EtOH / THF (3 mL / 3 mL) and stirred at room temperature for 1 h. Then NaBHCN (318 mg, 5.06 mmol) was added and stirred at room temperature for 16 h. The reaction mixture was quenched by adding saturated Na2CO3 solution (20 mL) and concentrated under reduced pressure to remove the organic solvent. The aqueous phase was extracted with EtOAc (40 mL × 2). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 19) to give a white solid (83 mg, 40%).

[0265] MS (ESI, pos.ion) m / z: 545.1 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 10.21 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 7.7 Hz, 2H), 7.59 (dd, J = 17.3, 7.9 Hz, 4H), 7.51 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 3.78 (s, 2H), 3.77 - 3.73 (m, 1H), 3.69 (d, J = 11.8 Hz, 1H), 3.28 - 3.24 (m, 2H), 2.97 - 2.84 (m, 2H), 2.74 (dd, J = 14.8, 7.3 Hz, 1H), 2.65 (s, 1H), 2.29 (s, 1H), 2.19 - 2.11 (m, 1H), 1.10 (t, J = 7.3 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H). Example 6 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzamide [ka] EDCI (96 mg, 0.50 mmol), HOBT (70 mg, 0.52 mmol), DIPEA (40 mg, 0.31 mmol), 4-(3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzoic acid (100 mg, 0.29 mmol), and (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (66 mg, 0.29 mmol) were added sequentially to DCM (5 mL) and stirred at room temperature for 4 h. The reaction mixture was diluted with DCM (40 mL), washed sequentially with saturated NaHCO solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / EtOAc (v / v) = 1 / 1) to give a white powder (100 mg, 62%).

[0266] MS (ESI, pos.ion) m / z: 561.2 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.76 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.19 (s, 1H), 6.43 (d, J = 8.6 Hz, 2H), 5.18 (s, 1H), 3.87 (d, J = 12.2 Hz, 2H), 3.46 - 3.36 (m, 2H), 3.33 - 3.27 (m, 1H), 3.04 (q, J = 7.4 Hz, 3H), 2.82 (d, J = 7.6 Hz, 2H), 2.65 - 2.57 (m, 1H), 2.15 - 2.11 (m, 1H), 2.05 - 1.92 (m, 1H), 1.80 - 1.71 (m, 1H), 1.22 (t, J = 7.4 Hz, 3H). Example 7 N-(4-(ethylsulfonyl)benzyl)-4-((2S)-2-(methoxymethyl)-4-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of (S)-1-tert-butyl 2-methyl 4-methylenepyrrolidine-1,2-dicarboxylate EDCI (16.11 g, 84.04 mmol), DMAP (1.71 g, 14.00 mmol), and (S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid (10.00 g, 44.00 mmol) were dissolved in DCM / MeOH (100 mL / 28 mL) and reacted for 29 h at 35° C. The reaction mixture was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a colorless liquid (10.21 g, 96%).

[0267] MS (ESI, pos.ion) m / z: 242.2 [M+H] + . Step 2: Synthesis of (S)-1-tert-butyl 2-methyl 4-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate Under nitrogen gas protection, AgCO (6.09 g, 22.10 mmol), Pd(P(o-Tol))(OAc) (220 mg, 0.23 mmol), 1-bromo-4-(trifluoromethyl)benzene (5.00 g, 21.77 mmol), (S)-1-tert-butyl 2-methyl-4-methylenepyrrolidine-1,2-carboxylate (6.40 g, 26.50 mmol), and DIPEA (15 mL, 86.70 mmol) were dissolved in DMF (60 mL), and the reaction mixture was heated and stirred in an oil bath at 100 °C for 21 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL) and then washed successively with HO (30 mL) and saturated NaCl solution (15 mL × 3). The organic phase was dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a pale yellow oily liquid (7.5 g, 89%).

[0268] MS (ESI, pos.ion) m / z: 330.1 [M-56+H] + . Step 3: Synthesis of (2S)-1-tert-butyl 2-methyl 4-(4-(trifluoromethyl)benzyl)pyrrolidine-1,2-dicarboxylate Pd / C (1.00 g, 10%) was added to a solution of (S)-1-tert-butyl 2-methyl 4-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (7.50 g, 19.46 mmol) in MeOH (40 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 14 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a clear yellow liquid (7.50 g, 99%).

[0269] MS (ESI, pos.ion) m / z: 332.0 [M-56+H] + . Step 4: Synthesis of (2S)-tert-butyl 2-(hydroxymethyl)-4-(4-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate A solution of LiBH4 in THF (18 mL, 36.00 mmol, 2 mol / L) was added to a solution of (2S)-1-tert-butyl 2-methyl 4-(4-(trifluoromethyl)benzyl)pyrrolidine-1,2-dicarboxylate (7.00 g, 18.07 mmol) in THF (40 mL) under ice bath, and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by slowly pouring saturated NH4Cl solution (30 mL) into the reaction mixture, which released a large amount of gas. The mixture was allowed to stand and the layers were separated. The upper organic layer was separated, and the aqueous layer was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 5 / 1) to give a pale yellow oily liquid (5.51 g, 85%).

[0270] MS (ESI, pos.ion) m / z: 304.1 [M-56+H] + . Step 5: Synthesis of (2S)-tert-butyl 2-(methoxymethyl)-4-(4-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate Iodomethane (0.85 mL, 14.00 mmol) was added to a solution of (2S)-tert-butyl 2-(hydroxymethyl)-4-(4-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate (1.00 g, 2.80 mmol) and NaOH (220 mg, 5.50 mmol) in DMF (10 mL) and stirred at room temperature for 22 h. The reaction mixture was diluted with EtOAc (80 mL), washed sequentially with HO (20 mL) and saturated NaCl solution (20 mL × 3), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 5 / 1) to give a colorless liquid (900 mg, 87%).

[0271] MS (ESI, pos.ion) m / z: 318.1 [M+H] + . Step 6: Synthesis of (2S)-2-(methoxymethyl)-4-(4-(trifluoromethyl)benzyl)pyrrolidine (2S)-tert-Butyl 2-(methoxymethyl)-4-(4-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate (900 mg, 2.41 mmol) was added to a DCM / TFA (8 mL / 3 mL) solution and stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure, and the pH of the reaction mixture was adjusted to approximately 9 by slowly adding NaOH solution (4 mol / L). The mixture was extracted with DCM (20 mL x 3), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) to give a yellow solid (200 mg, 30%).

[0272] MS (ESI, pos.ion) m / z: 274.1 [M+H] + . Step 7: Synthesis of methyl 4-((2S)-2-(methoxymethyl)-4-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, (2S)-2-(methoxymethyl)-4-(4-(trifluoromethyl)benzyl)pyrrolidine (200 mg, 0.73 mmol), methyl 4-bromobenzoate (320 mg, 1.49 mmol), Pd(dba) (66 mg, 0.07 mmol), XantPhos (86 mg, 0.15 mmol), and CsCO (723 mg, 2.22 mmol) were dissolved in 1,4-dioxane (8 mL), and the reaction mixture was heated and stirred in an oil bath at 100 °C for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (50 mL) and then washed successively with saturated NaHCO3 solution (20 mL) and saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to give a yellow solid (120 mg, 40%).

[0273] MS (ESI, pos.ion) m / z: 408.2 [M+H] + . Step 8: Synthesis of 4-((2S)-2-(methoxymethyl)-4-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (250 mg, 5.96 mmol) in HO (2 mL) was added to a solution of methyl 4-((2S)-2-(methoxymethyl)-4-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzoate (120 mg, 0.29 mmol) in THF (4 mL) and MeOH (2 mL), and the reaction mixture was heated and stirred in an oil bath at 70 °C for 18 h. The reaction mixture was cooled to room temperature, and HCl solution (1 mol / L) was added to the reaction mixture until the pH reached approximately 5. The mixture was concentrated under reduced pressure, and the residue was extracted with EtOAc (20 mL × 2). The combined organic phase was dried over anhydrous NaSO and concentrated under reduced pressure to give a white solid (100 mg, 86%).

[0274] MS (ESI, pos.ion) m / z: 394.3 [M+H] + . Step 9: Synthesis of N-(4-(ethylsulfonyl)benzyl)-4-((2S)-2-(methoxymethyl)-4-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzamide HATU (119 mg, 0.31 mmol), TEA (80 mg, 0.79 mmol), 4-((2S)-2-(methoxymethyl)-4-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzoic acid (80 mg, 0.20 mmol), and (4-(ethylsulfonyl)phenyl)methanamine (62 mg, 0.31 mmol) were dissolved in DCM (6 mL) and stirred at room temperature for 8 h. The reaction mixture was diluted with DCM (40 mL), washed sequentially with saturated NaHCO solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 4 / 1) to give a white solid (55 mg, 47%).

[0275] MS (ESI, pos.ion) m / z: 575.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.78 (d, J = 8.2 Hz, 2H), 7.74 (dd, J = 8.6, 6.2 Hz, 2H), 7.59 (dd, J = 7.5, 4.5 Hz, 2H), 7.48 (d, J = 7.9 Hz, 2H), 7.34 (dd, J = 7.5, 4.5 Hz, 2H), 6.82 (d, J = 3.7 Hz, 1H), 6.60 (dd, J = 8.6, 6.2 Hz, 2H), 4.70 (d, J = 5.6 Hz, 2H), 4.08 - 3.96 (m, 1H), 3.64 (dd, J = 9.4, 2.9 Hz, 1H), 3.53 - 3.46 (m, 1H), 3.40 (dd, J = 9.4, 6.7 Hz, 1H), 3.35 (d, J = 4.8 Hz, 2H), 3.29 - 3.16 (m, 1H), 3.09 (q, J = 7.4 Hz, 2H), 2.93 - 2.84 (m, 2H), 2.56 - 2.48 (m, 1H), 2.43 - 2.33 (m, 1H), 1.82 (dd, J = 11.2, 8.0 Hz, 2H), 1.26 (t, J = 7.4 Hz, 3H). Example 8 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S)-2-(methoxymethyl)-4-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzamide [ka] EDCI (75 mg, 0.39 mmol), HOBT (56 mg, 0.39 mmol), 4-((2S)-2-(methoxymethyl)-4-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)benzoic acid (100 mg, 0.25 mmol), and (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (90 mg, 0.39 mmol) were dissolved in DCM (6 mL) and stirred at room temperature for 14 h. The reaction mixture was diluted with DCM (40 mL), washed sequentially with saturated NaHCO solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 4 / 1) to give a white solid (101 mg, 66%).

[0276] MS (ESI, pos.ion) m / z: 605.3 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.82 (d, J = 8.0 Hz, 2H), 7.70 (dd, J = 8.6, 6.3 Hz, 2H), 7.57 (dd, J = 7.8, 4.6 Hz, 2H), 7.53 (d, J = 7.2 Hz, 2H), 7.32 (dd, J = 7.8, 4.6 Hz, 2H), 7.03 (dd, J = 6.8, 3.2 Hz, 1H), 6.58 (dd, J = 8.7, 5.7 Hz, 2H), 5.22 (d, J = 4.6 Hz, 1H), 4.04 - 3.94 (m, 2H), 3.91 (dd, J = 11.3, 4.9 Hz, 1H), 3.61 (dd, J = 9.5, 3.1 Hz, 1H), 3.53 - 3.46 (m, 1H), 3.39 (dd, J = 9.5, 6.5 Hz, 1H), 3.33 (d, J = 4.4 Hz, 3H), 3.27 - 3.14 (m, 1H), 3.07 (q, J = 7.4 Hz, 2H), 2.88 - 2.80 (m, 2H), 2.54 - 2.36 (m, 1H), 2.39 - 2.31 (m, 1H), 2.22 - 2.10 (m, 1H), 1.82 - 1.75 (m, 2H), 1.25 (t, J = 7.4 Hz, 3H). Example 9 N-(4-(ethylsulfonyl)benzyl)-4-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of benzyl 3-hydroxypyrrolidine-1-carboxylate NaBH (1.00 g, 26.00 mmol) was added to a solution of benzyl 3-oxopyrrolidine-1-carboxylate (3.34 g, 15.20 mmol) in MeOH (30 mL) under ice-water bath, then the mixture was warmed to room temperature and stirred for 12 h. After completion of the reaction, the reaction mixture was quenched by adding saturated NaHCO solution (30 mL) and concentrated under reduced pressure to remove MeOH. The aqueous phase was extracted with DCM (30 mL × 3). The combined organic phase was dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 2 / 1 / 1) to give a yellow liquid (3.30 g, 98%).

[0277] MS (ESI, pos.ion) m / z: 222.1 [M+H] + . Step 2: Synthesis of benzyl 3-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate Under nitrogen gas protection, benzyl 3-hydroxypyrrolidine-1-carboxylate (1.03 g, 4.66 mmol), 1-bromo-4-(trifluoromethyl)benzene (1.53 g, 6.80 mmol), CsCO (2.98 g, 9.15 mmol), Pd(OAc) (54 mg, 0.24 mmol), and t-Bu-XPhos (199 mg, 0.47 mmol) were dissolved in toluene (20 mL), and the reaction mixture was stirred in an oil bath at 90 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with DCM (80 mL), washed successively with saturated NaHCO3 solution (20 mL) and saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 5 / 1 / 1) to give a yellow oily liquid (688 mg, 40%).

[0278] MS (ESI, pos.ion) m / z: 366.1 [M+H] + . Step 3: Synthesis of 3-(4-(trifluoromethyl)phenoxy)pyrrolidine Benzyl 3-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (688 mg, 1.88 mmol) was dissolved in MeOH (10 mL), and Pd / C (70 mg, 10%) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow-brown liquid (429 mg, 98%).

[0279] MS (ESI, pos.ion) m / z: 232.1 [M+H] + . Step 4: Synthesis of N-(4-(ethylsulfonyl)benzyl)-4-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide Under nitrogen gas protection, 3-(4-(trifluoromethyl)phenoxy)pyrrolidine (123 mg, 0.53 mmol), 4-bromo-N-(4-(ethylsulfonyl)benzyl)benzamide (302 mg, 0.79 mmol), Pd2(dba)3 (93 mg, 0.10 mmol), XantPhos (68 mg, 0.12 mmol), and t-BuONa (100 mg, 1.04 mmol) were dissolved in toluene (5 mL), and the reaction mixture was heated and stirred in an oil bath at 110 °C for 23 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (60 mL), washed successively with saturated NaHCO3 solution (10 mL) and saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 5 / 1) to give a yellow solid (120 mg, 42%).

[0280] MS (ESI, pos.ion) m / z: 533.1 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.85 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 8.7 Hz, 2H), 6.46 (t, J = 5.8 Hz, 1H), 5.14 (m, 1H), 4.73 (d, J = 6.0 Hz, 2H), 3.76 (dd, J = 11.2, 4.6 Hz, 1H), 3.56 (dd, J = 11.7, 8.2 Hz, 3H), 3.09 (q, J = 7.4 Hz, 2H), 2.44 - 2.30 (m, 2H), 1.27 (t, J = 7.4 Hz, 3H). Example 10 N-(4-(ethylsulfonyl)benzyl)-4-(3-(methyl(4-(trifluoromethyl)phenyl)amino)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of benzyl 3-((4-(trifluoromethyl)phenyl)amino)pyrrolidine-1-carboxylate 4-(Trifluoromethyl)aniline (2.05 g, 12.73 mmol), benzyl 3-oxopyrrolidine-1-carboxylate (3.32 g, 15.15 mmol), and AcOH (1.40 mL, 24.50 mmol) were dissolved in EtOH (30 mL) and stirred at room temperature for 2 h. NaBHCN (3.90 g, 62.06 mmol) was then added and the mixture was stirred at room temperature for 12 h. The reaction mixture was quenched by the addition of saturated NaHCO3 solution (30 mL) and concentrated under reduced pressure. The aqueous phase was then extracted with DCM (40 mL × 3). The organic phase was washed with saturated NaCl solution (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 a yellow solid (1.11 g, 24%).

[0281] MS (ESI, pos.ion) m / z: 365.3 [M+H] + . Step 2: Synthesis of benzyl 3-(methyl(4-(trifluoromethyl)phenyl)amino)pyrrolidine-1-carboxylate Mel (0.30 mL, 4.80 mmol) was added dropwise to a suspension of benzyl 3-((4-(trifluoromethyl)phenyl)amino)pyrrolidine-1-carboxylate (504 mg, 1.38 mmol) and NaOH (75 mg, 1.88 mmol) in ACN (8 mL), followed by stirring at room temperature for 12 h. The reaction mixture was diluted with DCM (60 mL) and washed successively with saturated NaHCO solution (20 mL) and NaCl solution (20 mL). The aqueous phase was extracted with DCM (20 mL × 2). The combined organic phase was dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 10 / 1 / 1) to give a clear yellow liquid (391 mg, 75%).

[0282] MS (ESI, pos.ion) m / z: 379.2 [M+H] + . Step 3: Synthesis of N-methyl-N-(4-(trifluoromethyl)phenyl)pyrrolidin-3-amine Benzyl 3-(methyl(4-(trifluoromethyl)phenyl)amino)pyrrolidine-1-carboxylate (198 mg, 0.52 mmol) was dissolved in MeOH (8 mL), and Pd / C (50 mg, 10%) was added. The mixture was stirred at room temperature for 12 h under a hydrogen gas atmosphere. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil (128 mg, 100%).

[0283] MS (ESI, pos.ion) m / z: 245.2 [M+H] + . Step 4: Synthesis of N-(4-(ethylsulfonyl)benzyl)-4-(3-(methyl(4-(trifluoromethyl)phenyl)amino)pyrrolidin-1-yl)benzamide Under nitrogen gas protection, N-methyl-N-(4-(trifluoromethyl)phenyl)pyrrolidin-3-amine (126 mg, 0.52 mmol), N-(4-(ethylsulfonyl)benzyl)-4-iodobenzamide (342 mg, 0.80 mmol) (see Step 1 of Example 4 for the synthesis method), Pd2(dba)3 (97 mg, 0.11 mmol), XantPhos (70 mg, 0.12 mmol), and t-BuONa (100 mg, 1.04 mmol) were dissolved in toluene (6 mL), and the reaction mixture was heated and stirred in an oil bath at 110 °C for 14 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then diluted with DCM (80 mL) and washed successively with saturated NaHCO3 solution (10 mL) and saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified twice by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 10 / 1) to give a yellow solid (141 mg, 50%).

[0284] MS (ESI, pos.ion) m / z: 546.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.84 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.58 (d, J = 8.6 Hz, 2H), 6.52 (t, J = 5.7 Hz, 1H), 4.74 (t, J = 7.0 Hz, 2H), 4.70 - 4.62 (m, 1H), 3.67 - 3.53 (m, 2H), 3.42 (dt, J = 10.5, 6.9 Hz, 2H), 3.09 (q, J = 7.4 Hz, 2H), 2.91 (s, 3H), 2.27 (ddd, J = 18.0, 13.6, 6.4 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H). Example 11 N-(4-(ethylsulfonyl)benzyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of benzyl 3-((tert-butoxycarbonyl)(4-(trifluoromethyl)phenyl)amino)pyrrolidine-1-carboxylate BocO (0.90 mL, 3.90 mmol) was slowly added to a solution of benzyl 3-((4-(trifluoromethyl)phenyl)amino)pyrrolidine-1-carboxylate (714 mg, 1.96 mmol) and DMAP (470 mg, 3.85 mmol) in DCM (6 mL) and stirred at room temperature for 5 h. The reaction mixture was then heated to reflux for 20 h. The reaction mixture was diluted with DCM (60 mL), washed successively with saturated NaHCO solution (20 mL) and saturated NaCl solution (20 mL), dried over anhydrous NaSO, 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 a colorless liquid (539 mg, 59%).

[0285] MS (ESI, pos.ion) m / z: 487.2 [M+23] + . Step 2: Synthesis of tert-butyl pyrrolidin-3-yl(4-(trifluoromethyl)phenyl)carbamate Benzyl 3-((tert-butoxycarbonyl)(4-(trifluoromethyl)phenyl)amino)pyrrolidine-1-carboxylate (485 mg, 1.33 mmol) was dissolved in MeOH (8 mL), and Pd / C (50 mg, 10%) was added. The mixture was stirred at room temperature under a hydrogen gas atmosphere for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil (300 mg, 100%).

[0286] MS (ESI, pos.ion) m / z: 331.1 [M+H] + . Step 3: Synthesis of tert-butyl (1-(4-((4-(ethylsulfonyl)benzyl)carbamoyl)phenyl)pyrrolidin-3-yl(4-(trifluoromethyl)phenyl)carbamate Under nitrogen gas protection, tert-butyl pyrrolidin-3-yl(4-(trifluoromethyl)phenyl)carbamate (132 mg, 0.45 mmol), N-(4-(ethylsulfonyl)benzyl)-4-iodobenzamide (642 mg, 1.55 mmol), Pd(dba) (93 mg, 0.10 mmol), XantPhos (68 mg, 0.12 mmol), and t-BuONa (100 mg, 1.04 mmol) were dissolved in toluene (4 mL). The reaction mixture was heated and stirred in an oil bath at 100 °C for 24 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (60 mL), washed sequentially with saturated NaHCO solution (10 mL) and saturated NaCl solution (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a yellow oil (277 mg, 97%).

[0287] MS (ESI, pos.ion) m / z: 632.2 [M+H] + . Step 4: Synthesis of N-(4-(ethylsulfonyl)benzyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrrolidin-1-yl)benzamide tert-Butyl (1-(4-((4-(ethylsulfonyl)benzyl)carbamoyl)phenyl)pyrrolidin-3-yl(4-(trifluoromethyl)phenyl)carbamate (70 mg, 0.11 mmol) was dissolved in HCl in i-PrOH (20 mL, 91.60 mmol, 4.58 mol / L) and stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM (60 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (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) = 2 / 1) to give a yellow solid (55 mg, 94%).

[0288] MS (ESI, pos.ion) m / z: 532.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.84 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 8.5 Hz, 2H), 6.56 (d, J = 8.7 Hz, 2H), 6.49 (t, J = 6.0 Hz, 1H), 4.73 (d, J = 6.1 Hz, 2H), 4.28 (m, 1H), 4.18 (br, 1H), 3.75 (dd, J = 10.1, 5.7 Hz, 1H), 3.54 (m, 1H), 3.51 - 3.42 (m, 1H), 3.30 (dd, J = 10.3, 3.3 Hz, 1H), 3.09 (q, J = 7.4 Hz, 2H), 2.45 - 2.36 (m, 1H), 2.16 - 2.05 (m, 1H), 1.27 (t, J = 7.4 Hz, 3H). Example 12 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of 4-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile Under nitrogen gas protection, K2CO3 (1.50 g, 10.90 mmol) was added to a solution of 3-(4-(trifluoromethyl)phenoxy)pyrrolidine (478 mg, 2.07 mmol) and 4-fluorobenzonitrile (750 mg, 6.19 mmol) in DMSO (10 mL), and the reaction mixture was heated and stirred in an oil bath at 120 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (80 mL), washed with saturated NaCl solution (10 mL × 3), 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 a white solid (512 mg, 75%).

[0289] MS (ESI, pos.ion) m / z: 333.1 [M+H] + . Step 2: Synthesis of 4-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid MeONa (2.87 g, 52.52 mmol) was added to a solution of 4-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile (512 mg, 1.54 mmol) in EtOH (15 mL), and the reaction mixture was heated to reflux in a 100 °C oil bath for 10 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. HO (100 mL) was added to the residue to dissolve all solids. The aqueous phase was extracted with DCM (30 mL × 3). The combined organic phases were dried over anhydrous NaSO and concentrated under reduced pressure to give the by-product amide as a yellow solid. The aqueous phase was neutralized with HCl solution (1 mol / L) until the pH was approximately 3. The aqueous phase was extracted with EtOAc (30 mL × 3). The combined organic phases were dried over anhydrous NaSO and concentrated under reduced pressure to give a yellow solid (329 mg, 61%).

[0290] MS (ESI, pos.ion) m / z: 352.1 [M+H] + . Step 3: Synthesis of N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide 4-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (123 mg, 0.35 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 (4 mL), and TEA (0.14 mL, 1.00 mmol) was added. The mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM (80 mL), washed successively with HCl solution (20 mL, 1 mol / L), saturated NaCl solution (20 mL), and saturated NaCO solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to give a pale yellow solid (122 mg, 62%).

[0291] MS (ESI, pos.ion) m / z: 563.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.86 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.1 Hz, 4H), 6.96 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 6.7 Hz, 1H), 6.56 (d, J = 8.8 Hz, 2H), 5.28 (dd, J = 10.9, 4.3 Hz, 1H), 5.14 (s, 1H), 4.09 - 3.94 (m, 2H), 3.76 (dd, J = 11.2, 4.7 Hz, 1H), 3.63 - 3.50 (m, 3H), 3.09 (q, J = 7.4 Hz, 2H), 2.49 - 2.28 (m, 3H), 1.28 (t, J = 7.4 Hz, 3H). Example 13 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((R)-3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of (R)-tert-butyl 3-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (S)-tert-Butyl 3-hydroxypyrrolidine-1-carboxylate (1.00 g, 5.34 mmol), 4-(trifluoromethyl)phenol (865 mg, 5.34 mmol), and PPh3 (2.00 g, 5.83 mmol) were added to THF (20 mL), and DIAD (1.40 mL, 7.11 mmol) was added slowly at 0 °C. After the addition, the mixture was stirred at room temperature for 21 h. The reaction mixture was concentrated under reduced pressure, and the remaining liquid was diluted with methyl tert-butyl ether (30 mL) and stirred at −20° C. to precipitate a large amount of white insoluble solid. The solid was filtered while still cold, and the filter cake was washed with cold methyl tert-butyl ether. The filtrate was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 6 / 1) to give the product as a pale yellow liquid (1.76 g, 100%).

[0292] MS (ESI, pos.ion) m / z: 276.2 [M-56+H] + . Step 2: Synthesis of (R)-3-(4-(trifluoromethyl)phenoxy)pyrrolidine A solution of HCl in methanol (2 mL, 20%) was added to a solution of (R)-tert-butyl 3-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (800 mg, 2.42 mmol) in DCM (8 mL) and stirred at room temperature for 9 h. After completion of the reaction, saturated sodium bicarbonate was added and the reaction mixture was washed, and the reaction mixture was concentrated under reduced pressure to give a pale red liquid (558 mg, 100%).

[0293] MS (ESI, pos.ion) m / z: 232.2 [M+H] + . Step 3: Synthesis of methyl (R)-4-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, (R)-3-(4-(trifluoromethyl)phenoxy)pyrrolidine (600 mg, 2.60 mmol), Pd(dba) (237 mg, 0.26 mmol), Xantphos (225 mg, 0.39 mmol), CsCO (1.70 g, 5.22 mmol), and methyl 4-iodobenzoate (840 mg, 3.91 mmol) were added in order to 1,4-dioxane (16 mL) and reacted at 100 °C for 19 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The remaining liquid was diluted with DCM (80 mL), washed successively with saturated NaHCO3 solution (30 mL) and saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 5 / 1) to give a yellow solid (800 mg, 84%).

[0294] MS (ESI, pos.ion) m / z: 366.2 [M+H] + . Step 4: Synthesis of (R)-4-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (88 mg, 2.10 mmol) in HO (2 mL) was added to a solution of (R)-methyl 4-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (300 mg, 0.82 mmol) in MeOH (7 mL) and THF (3 mL) and stirred at room temperature for 7 h. The reaction mixture was concentrated under reduced pressure, and the pH of the remaining mixture was adjusted to approximately 4 with HCl (1 mol / L). The mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with saturated NaCl (25 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 4 / 1) to give a white solid (251 mg, 87%).

[0295] MS (ESI, pos.ion) m / z: 352.1 [M+H] + . Step 5: Synthesis of N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((R)-3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide EDCI (81 mg, 0.42 mmol), HOBT (57 mg, 0.42 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (78 mg, 0.34 mmol), (R)-4-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (100 mg, 0.28 mmol), and TEA (43 mg, 0.42 mmol) were added sequentially to DCM (6 mL) and stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (40 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a white solid (133 mg, 83%).

[0296] MS (ESI, pos.ion) m / z: 563.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.85 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 6.99 - 6.92 (m, 3H), 6.55 (d, J = 8.8 Hz, 2H), 5.26 (dd, J = 10.8, 4.3 Hz, 1H), 5.13 (s, 1H), 4.05 - 3.93 (m, 2H), 3.76 (dd, J = 11.2, 4.7 Hz, 1H), 3.60 - 3.50 (m, 3H), 3.08 (q, J = 7.4 Hz, 2H), 2.62 (t, J = 5.7 Hz, 1H), 2.41 - 2.28 (m, 2H), 1.27 (t, J = 7.4 Hz, 3H). Example 14 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((S)-3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] The title compound was prepared as a white solid (125 mg, 78%) using tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate as the starting material and following the method of Steps 1 to 5 of Example 13.

[0297] MS (ESI, pos.ion) m / z: 563.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.82 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.1 Hz, 4H), 7.18 (d, J = 7.0 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.53 (d, J = 8.8 Hz, 2H), 5.22 (d, J = 5.3 Hz, 1H), 5.12 (s, 1H), 3.96 (dd, J = 11.3, 3.9 Hz, 1H), 3.88 (dd, J = 11.4, 5.2 Hz, 1H), 3.74 (dd, J = 11.2, 4.7 Hz, 1H), 3.58 - 3.48 (m, 3H), 3.07 (q, J = 7.4 Hz, 2H), 2.41 - 2.27 (m, 2H), 1.24 (t, J = 7.4 Hz, 3H). Example 15 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((R)-2-oxo-3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of (S)-2-oxopyrrolidin-3-ylmethyl sulfonate MsCl (1.00 mL, 12.92 mmol) was slowly added dropwise to a solution of (S)-3-hydroxypyrrolidin-2-one (1.03 g, 10.20 mmol) and TEA (3.00 mL, 21.58 mmol) in THF (20 mL) under ice bath, and the mixture was stirred at room temperature for 12 h. The reaction mixture was used directly in the next reaction.

[0298] Step 2: Synthesis of (R)-3-(4-(trifluoromethyl)phenoxy)pyrrolidin-2-one (S)-2-Oxopyrrolidin-3-yl methanesulfonate (1.82 g, 10.20 mmol), 4-(trifluoromethyl)phenol (1.65 g, 10.20 mmol), and K2CO3 (7.00 g, 50.65 mmol) were dissolved in DMF (20 mL), and the reaction mixture was heated and stirred in an oil bath at 80 °C for 22 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (80 mL), and washed with saturated NaHCO3 solution (20 mL × 5). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v / v) = 10 / 1) to give a yellow oil (315 mg, 13%).

[0299] MS (ESI, pos.ion) m / z: 246.2 [M+H] + . Step 3: Synthesis of methyl (R)-4-(2-oxo-3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, (R)-3-(4-(trifluoromethyl)phenoxy)pyrrolidin-2-one (315 mg, 1.28 mmol), methyl 4-bromobenzoate (198 mg, 0.92 mmol), Pd(dba) (22 mg, 0.02 mmol), XantPhos (22 mg, 0.04 mmol), and CsCO (403 mg, 1.23 mmol) were dissolved in 1,4-dioxane (6 mL). The reaction mixture was heated and stirred in an oil bath at 100 °C for 6 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 5 / 1 / 1) to give a yellow solid (335 mg, 68%).

[0300] MS (ESI, pos.ion) m / z: 380.0 [M+H] + . Step 4: Synthesis of (R)-4-(2-oxo-3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid LiOH·HO (81 mg, 1.93 mmol) was added to a solution of (R)-4-(2-oxo-3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (232 mg, 0.61 mmol) in THF / HO (10 mL / 3 mL), and the reaction mixture was heated and stirred in a 50 °C oil bath for 2 h. The reaction mixture was cooled to room temperature, and HO (20 mL) was added. HCl solution (1 mol / L) was then added dropwise to adjust the pH to approximately 3. The aqueous phase was concentrated under reduced pressure to give a yellow solid (223 mg, 100%).

[0301] MS (ESI, pos.ion) m / z: 398.3[M+Na] + . Step 5: Synthesis of N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((R)-2-oxo-3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide (R)-4-(2-oxo-3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (122 mg, 0.33 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (93 mg, 0.41 mmol), EDCI (195 mg, 1.02 mmol), and HOBT (139 mg, 1.03 mmol) were dissolved in DCM (10 mL), and TEA (0.20 mL, 1.40 mmol) was added and stirred at room temperature for 20 h. The reaction mixture was added with DCM (80 mL), washed successively with saturated NaHCO3 solution (20 mL) and saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 2) to give a yellow solid (130 mg, 68%).

[0302] MS (ESI, pos.ion) m / z: 577.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.80 (d, J = 7.7 Hz, 1H), 7.98 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.2 Hz, 4H), 7.68 (t, J = 8.2 Hz, 4H), 7.27 (d, J = 8.6 Hz, 2H), 5.46 (t, J = 8.3 Hz, 1H), 5.16 (dd, J = 13.4, 6.9 Hz, 1H), 5.06 (t, J = 5.7 Hz, 1H), 3.99 - 3.85 (m, 2H), 3.79 - 3.67 (m, 2H), 3.26 (q, J = 7.3 Hz, 2H), 2.81 - 2.72 (m, 1H), 2.21 - 2.12 (m, 1H), 1.10 (t, J = 7.3 Hz, 3H). Example 16 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((S)-2-oxo-3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] Starting from (S)-3-hydroxypyrrolidin-2-one, the title compound was prepared as a yellow solid (120 mg, 62%) by following the method of Steps 1 to 5 of Example 15.

[0303] MS (ESI, pos.ion) m / z: 577.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.81 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.2 Hz, 4H), 7.69 (t, J = 8.8 Hz, 4H), 7.28 (d, J = 8.5 Hz, 2H), 5.47 (t, J = 8.3 Hz, 1H), 5.19 - 5.13 (m, 1H), 5.06 (t, J = 5.7 Hz, 1H), 3.99 - 3.89 (m, 2H), 3.79 - 3.68 (m, 2H), 3.27 (q, J = 7.3 Hz, 2H), 2.83 - 2.73 (m, 1H), 2.22-2.12 (m, 1H), 1.10 (t, J = 7.3 Hz, 3H). Example 17 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((3S,4S)-3-fluoro-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of tert-butyl (3S,4S)-3-fluoro-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate Under nitrogen gas protection, tert-butyl (3S,4S)-3-fluoro-4-hydroxypyrrolidine-1-carboxylate (500 mg, 2.44 mmol), 1-bromo-4-(trifluoromethyl)benzene (822 mg, 3.65 mmol), Pd(OAc) (30 mg, 0.13 mmol), t-Bu-XPhos (106 mg, 0.25 mmol), and CsCO (1.58 g, 4.85 mmol) were dissolved in toluene (16 mL), and the reaction mixture was heated and stirred in an oil bath at 90 °C for 24 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (100 mL), washed successively with saturated NaHCO3 solution (30 mL) and saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a white solid (300 mg, 35%).

[0304] MS (ESI, pos.ion) m / z: 294.7 [M-56+H] + . Step 2: Synthesis of (3S,4S)-3-fluoro-4-(4-(trifluoromethyl)phenoxy)pyrrolidine A solution of HCl in methanol (2 mL, 20%) was added to a solution of tert-butyl (3S,4S)-3-fluoro-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (300 mg, 0.86 mmol) in DCM (6 mL) and stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM (60 mL), washed sequentially with saturated NaHCO solution (20 mL) and saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a pale yellow liquid (106 mg, 50%).

[0305] MS (ESI, pos.ion) m / z: 250.2 [M+H] + . Step 3: Synthesis of ethyl 4-((3S,4S)-3-fluoro-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, (3S,4S)-3-fluoro-4-(4-(trifluoromethyl)phenoxy)pyrrolidine (100 mg, 0.40 mmol), ethyl 4-iodobenzoate (166 mg, 0.60 mmol), Pd(dba) (36 mg, 0.04 mmol), XantPhos (34 mg, 0.06 mmol), and CsCO (261 mg, 0.80 mmol) were dissolved in 1,4-dioxane (6 mL), and the reaction mixture was heated and stirred in an oil bath at 100 °C for 23 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (60 mL), washed successively with saturated NaHCO3 solution (20 mL) and saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 5 / 1) to give a yellow liquid (100 mg, 63%).

[0306] MS (ESI, pos.ion) m / z: 398.1 [M+H] + . Step 4: Synthesis of 4-((3S,4S)-3-fluoro-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (86 mg, 2.05 mmol) in HO (1 mL) was added to a solution of ethyl 4-((3S,4S)-3-fluoro-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (100 mg, 0.25 mmol) in MeOH (6 mL) and the mixture was allowed to react at room temperature for 24 h. The pH of the reaction mixture was adjusted to approximately 5 with HCl (1 mol / L) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with saturated NaCl (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 2) to give a pale yellow solid (50 mg, 54%).

[0307] MS (ESI, pos.ion) m / z: 340.2 [M+H] + . Step 5: Synthesis of N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((3S,4S)-3-fluoro-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide (R)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol (37 mg, 0.16 mmol), 4-((3S,4S)-3-fluoro-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (50 mg, 0.16 mmol), EDCI (38 mg, 0.20 mmol), HOBT (27 mg, 0.20 mmol), and TEA (27 mg, 0.27 mmol) were dissolved in DCM (5 mL) and stirred at room temperature for 16 h. The reaction mixture was added with DCM (40 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (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) = 1 / 1) to give a white solid (50 mg, 64%).

[0308] MS (ESI, pos.ion) m / z: 581.3 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.85 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 6.97 (s, 1H), 6.57 (d, J = 8.7 Hz, 2H), 5.39 (d, J = 3.4 Hz, 1H), 5.30 - 5.25 (m, 1H), 5.12 (dd, J = 9.8, 4.3 Hz, 1H), 4.03 (dd, J = 11.2, 3.5 Hz, 1H), 3.96 (dd, J = 11.2, 4.9 Hz, 1H), 3.90 (dd, J = 13.0, 3.2 Hz, 1H), 3.87 - 3.76 (m, 1H), 3.78 - 3.67 (m, 1H), 3.64 (d, J = 11.3 Hz, 1H), 3.08 (q, J = 7.4 Hz, 2H), 1.27 (t, J = 7.4 Hz, 3H). Example 18 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of (2S,4R)-1-tert-butyl 2-methyl 4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1,2-dicarboxylate (2S,4S)-1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10.00 g, 40.77 mmol), 4-(trifluoromethyl)phenol (6.60 g, 40.71 mmol), and PPh3 (15.40 g, 44.87 mmol) were dissolved in THF (160 mL), and DIAD (10.50 mL, 53.30 mmol) was added slowly in an ice bath. After the addition, the mixture was stirred at room temperature for 21 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with methyl tert-butyl ether (50 mL). The temperature was controlled at −20° C. and the mixture was stirred to precipitate a large amount of white insoluble solid. The solid was filtered while still cold, and the filter cake was washed with cold methyl tert-butyl ether. The filtrate was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 6 / 1) to give a white solid (9.30 g, 58%).

[0309] MS (ESI, pos.ion) m / z: 411.9 [M+Na] + . Step 2: tert-butyl (2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate LiBH (590 mg, 27.09 mmol) was added to a solution of (2S,4R)-1-tert-butyl 2-methyl 4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1,2-dicarboxylate (7.00 g, 17.98 mmol) in THF (70 mL) under ice bath, and the mixture was stirred at room temperature for 14 h. The reaction mixture was quenched by adding saturated NH Cl (40 mL) solution, and the mixture was allowed to stand for phase separation. The upper organic layer was separated and removed, and the aqueous layer was extracted with EtOAc (30 mL × 2). The combined organic layers were dried over anhydrous Na SO and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to give a colorless oily liquid (5.90 g, 91%).

[0310] MS (ESI, pos.ion) m / z: 383.9 [M+Na] + . Step 3: Synthesis of ((2S,4R)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-2-yl)methanol (2S,4R)-tert-Butyl 2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (5.90 g, 16.33 mmol) was dissolved in DCM (40 mL) and a solution of HCl in methanol (20 mL, 20%) and stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give a brown liquid (4.30 g, 100%).

[0311] MS (ESI, pos.ion) m / z: 262.2 [M+H] + . Step 4: Synthesis of ethyl 4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, ((2S,4R)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-2-yl)methanol (500 mg, 1.91 mmol), Pd(dba) (175 mg, 0.19 mmol), XantPhos (167 mg, 0.29 mmol), CsCO (1.90 g, 5.83 mmol), and ethyl 4-iodobenzoate (686 mg, 2.48 mmol) were dissolved in 1,4-dioxane (12 mL), and the reaction mixture was heated and stirred in an oil bath at 100 °C for 10 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (60 mL), washed successively with saturated NaHCO3 solution (20 mL) and saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to give a brown solid (248 mg, 32%).

[0312] MS (ESI, pos.ion) m / z: 410.3 [M+H] + . Step 5: Synthesis of 4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (95 mg, 2.26 mmol) in HO (1 mL) was added to a solution of ethyl 4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (150 mg, 0.37 mmol) in THF (6 mL) and stirred at room temperature for 6 h. The pH of the reaction mixture was adjusted to approximately 5 with HCl solution (1 mol / L), and the aqueous phase was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with saturated NaCl solution (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a colorless liquid (100 mg, 72%).

[0313] MS (ESI, pos.ion) m / z: 382.1 [M+H] + . Step 6: Synthesis of N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide 4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (100 mg, 0.26 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (72 mg, 0.31 mmol), EDCI (75 mg, 0.39 mmol), HOBT (53 mg, 0.39 mmol), and TEA (53 mg, 0.52 mmol) were dissolved in DCM (5 mL) and reacted at room temperature for 10 h. The reaction mixture was diluted with DCM (40 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a white solid (78 mg, 50%).

[0314] MS (ESI, pos.ion) m / z: 593.4 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.75 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 7.0 Hz, 1H), 6.94 (d, J = 8.5 Hz, 2H), 6.53 (d, J = 8.5 Hz, 2H), 5.18 (s, 2H), 4.13 (d, J = 3.4 Hz, 1H), 3.91 - 3.80 (m, 4H), 3.57 (d, J = 11.1 Hz, 1H), 3.49 - 3.42 (m, 1H), 3.03 (q, J = 7.3 Hz, 2H), 2.58 - 2.49 (m, 1H), 2.36 - 2.28 (m, 1H), 1.21 (t, J = 7.4 Hz, 3H). Example 19 4-((2S)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-(4-(ethylsulfonyl)benzyl)benzamide [ka] Step 1: Synthesis of (2S)-1-tert-butyl 2-methyl 4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1,2-dicarboxylate Under nitrogen gas protection, (2S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10.03 g, 40.89 mmol), 1-bromo-4-(trifluoromethyl)benzene (13.80 g, 61.30 mmol), CsCO (27 g, 82.87 mmol), Pd(OAc) (460 mg, 2.05 mmol), and t-Bu-XPhos (1.70 g, 4.00 mmol) were dissolved in toluene (100 mL), and the reaction mixture was heated and stirred in an oil bath at 90 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with DCM (120 mL), washed successively with HO (50 mL) and saturated NaCl solution (50 mL), dried over anhydrous NaSO, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 5 / 1 / 1) to give a yellow oily liquid (4.34 g, 27%).

[0315] MS (ESI, pos.ion) m / z: 412.2 [M+Na] + . Step 2: Synthesis of tert-butyl (2S)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate LiBH (500 mg, 22.96 mmol) was added to a solution of (2S)-1-tert-butyl 2-methyl 4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1,2-dicarboxylate (4.34 g, 11.10 mmol) in THF (30 mL) and stirred at room temperature for 10 h. The reaction was quenched by the addition of saturated NaHCO solution (40 mL) and then extracted with DCM (50 mL × 3). The organic phase was washed with saturated NaCl solution (40 mL), dried over anhydrous NaSO, 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 a white solid (3.16 g, 79%).

[0316] MS (ESI, pos.ion) m / z: 384.2 [M+Na] + . Step 3: Synthesis of ((2S)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-2-yl)methanol (2S)-tert-Butyl 2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (231 mg, 0.64 mmol) was dissolved in HCl in i-PrOH (10 mL, 45.80 mmol, 4.58 mol / L) and stirred at room temperature for 10 h. The reaction mixture was concentrated under reduced pressure, and saturated Na2CO3 solution (20 mL) was added to the residue. The aqueous phase was extracted with DCM (40 mL x 3). The combined organic phase was washed with saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a pink solid (160 mg, 96%).

[0317] MS (ESI, pos.ion) m / z: 262.2 [M+H] + . Step 4: Synthesis of 4-((2S)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile Under nitrogen gas protection, ((2S)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-2-yl)methanol (160 mg, 0.61 mmol), 4-iodobenzonitrile (230 mg, 1.26 mmol), Pd(dba) (115 mg, 0.13 mmol), XantPhos (80 mg, 0.14 mmol), and CsCO (500 mg, 1.53 mmol) were dissolved in 1,4-dioxane (4 mL), and the reaction mixture was heated and stirred in an oil bath at 100 °C for 24 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DCM (80 mL), washed successively with saturated NaHCO3 solution (40 mL) and saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / DCM / EtOAc (v / v / v) = 2 / 1 / 1) to give a tan solid (198 mg, 89%).

[0318] MS (ESI, pos.ion) m / z: 363.3 [M+H] + . Step 5: Synthesis of 4-((2S)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile Under nitrogen gas protection, NaH (55 mg, 1.38 mmol, 60%) was added to a solution of 4-((2S)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile (250 mg, 0.69 mmol) in DMF (4 mL). After 30 min, EtI (0.10 mL, 1.25 mmol) was added and the mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc (60 mL), washed with saturated NaCl solution (10 mL × 5), dried over anhydrous NaSO, 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 a yellow solid (188 mg, 70%).

[0319] MS (ESI, pos.ion) m / z: 391.5 [M+H] + . Step 6: Synthesis of 4-((2S)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid MeONa (453 mg, 8.07 mmol) was added to a solution of 4-((2S)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile (188 mg, 0.48 mmol) in EtOH (5 mL), and the mixture was heated to 100 °C for 24 h. The reaction mixture was cooled to room temperature and quenched by adding HCl solution (20 mL, 1 mol / L). The aqueous phase was then extracted with EtOAc (20 mL × 3). The combined organic phase was washed with saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a dark yellow solid (195 mg, 99%).

[0320] MS (ESI, pos.ion) m / z: 410.5 [M+H] + . Step 7: Synthesis of 4-((2S)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-(4-(ethylsulfonyl)benzyl)benzamide 4-((2S)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (95 mg, 0.23 mmol), (4-(ethylsulfonyl)phenyl)methanamine (70 mg, 0.35 mmol), EDCI (90 mg, 0.47 mmol), and HOBT (63 mg, 0.47 mmol) were dissolved in DCM (3 mL), and TEA (0.10 mL, 0.72 mmol) was added. The mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM (80 mL), washed successively with HCl solution (20 mL, 1 mol / L), saturated NaCl solution (20 mL), and saturated Na2CO3 solution (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 plate chromatography (developer: DCM / EtOAc (v / v) = 5 / 1) to give a yellow solid (34 mg, 25%).

[0321] MS (ESI, pos.ion) m / z: 591.2 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.88 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 6.70 (d, J = 8.9 Hz, 2H), 6.46 (t, J = 6.1 Hz, 1H), 5.17 (t, J = 4.5 Hz, 1H), 4.76 (d, J = 6.0 Hz, 2H), 4.16 (td, J = 8.5, 4.3 Hz, 1H), 3.74 (ddd, J = 16.1, 10.4, 4.7 Hz, 3H), 3.59 - 3.43 (m, 3H), 3.12 (q, J = 7.4 Hz, 2H), 2.54 (d, J = 14.2 Hz, 1H), 2.41 (dd, J = 8.4, 5.4 Hz, 1H), 1.29 (t, J = 7.4 Hz, 3H), 1.19 (t, J = 7.0 Hz, 3H). Example 20 4-((2S)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide [ka] 4-((2S)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (95 mg, 0.23 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (65 mg, 0.28 mmol), EDCI (90 mg, 0.47 mmol), and HOBT (63 mg, 0.47 mmol) were dissolved in DCM (3 mL), and TEA (0.10 mL, 0.72 mmol) was added. The mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM (80 mL), washed successively with HCl solution (20 mL, 1 mol / L), saturated Na2CO3 solution (20 mL), and saturated NaCl solution (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 / 2) and silica gel plate chromatography (developer: DCM / EtOAc (v / v) = 1 / 1) to give a yellow solid (75 mg, 52%).

[0322] MS (ESI, pos.ion) m / z: 621.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.86 (d, J = 6.7 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 7.57 (t, J = 6.9 Hz, 4H), 6.97 (d, J = 8.6 Hz, 3H), 6.67 (d, J = 8.6 Hz, 2H), 5.30 (s, 1H), 5.14 (t, J = 4.5 Hz, 1H), 4.12 (dd, J = 8.3, 4.2 Hz, 1H), 4.02 (d, J = 15.6 Hz, 2H), 3.80 - 3.63 (m, 3H), 3.58 - 3.40 (m, 3H), 3.09 (q, J = 7.4 Hz, 2H), 2.51 (d, J = 14.2 Hz, 1H), 2.37 (td, J = 8.5, 4.4 Hz, 1H), 1.28 (t, J = 7.9 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H). Example 21 4-((2S,4R)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide [ka] Step 1: Synthesis of tert-butyl (2S,4R)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate Under nitrogen gas protection, NaH (531 mg, 13.28 mmol, 60%) was added to a solution of iodoethane (1.50 mL, 18.75 mmol) and tert-butyl (2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (600 mg, 1.66 mmol) in THF (10 mL) and stirred at room temperature for 23 h. The reaction mixture was quenched with HCl solution (1 mol / L) and the pH of the solution was adjusted to approximately 5. The mixture was diluted with EtOAc (30 mL), extracted, and the organic phase was washed with saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a yellow liquid (150 mg, 23%).

[0323] MS (ESI, pos.ion) m / z: 334.1 [M-56+H] + . Step 2: Synthesis of (2S,4R)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine A solution of HCl in methanol (2 mL, 20%) was added to a solution of tert-butyl (2S,4R)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (150 mg, 0.39 mmol) in DCM (6 mL) and stirred at room temperature for 11 h. After completion of the reaction, saturated sodium bicarbonate was added and washed, and the reaction solution was concentrated under reduced pressure to give a brown liquid (111 mg, 100%).

[0324] MS (ESI, pos.ion) m / z: 290.2 [M+H] + . Step 3: Synthesis of ethyl 4-((2S,4R)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, (2S,4R)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine (100 mg, 0.35 mmol), Pd(dba) (31 mg, 0.03 mmol), XantPhos (30 mg, 0.05 mmol), CsCO (225 mg, 0.69 mmol), and ethyl 4-iodobenzoate (89 mg, 0.41 mmol) were added sequentially to 1,4-dioxane (6 mL), and the reaction mixture was heated in an oil bath at 100 °C for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The remaining liquid was diluted with DCM (60 mL), washed successively with saturated NaHCO3 solution (20 mL) and saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 5 / 1) to give a yellow liquid (70 mg, 48%).

[0325] MS (ESI, pos.ion) m / z: 424.0 [M+H] + . Step 4: Synthesis of 4-((2S,4R)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (50 mg, 1.19 mmol) in HO (1 mL) was added to a solution of ethyl 4-((2S,4R)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (80 mg, 0.19 mmol) in MeOH (4 mL) and stirred at room temperature for 13 h. The reaction mixture was adjusted to pH 5 with HCl solution (1 mol / L) and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 4 / 1) to give a yellow solid (60 mg, 78%).

[0326] MS (ESI, pos.ion) m / z: 410.1 [M+H] + .

[0327] Step 5: Synthesis of 4-((2S,4R)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide EDCI (56 mg, 0.29 mmol), HOBT (39 mg, 0.29 mmol), TEA (30 mg, 0.30 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (40 mg, 0.17 mmol), and 4-((2S,4R)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (60 mg, 0.15 mmol) were added sequentially to DCM (4 mL) and stirred at room temperature for 18 h. The reaction mixture was diluted with DCM (40 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to give a white solid (50 mg, 55%).

[0328] MS (ESI, pos.ion) m / z: 621.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.87 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.2 Hz, 4H), 6.98 (d, J = 8.3 Hz, 3H), 6.64 (d, J = 8.7 Hz, 2H), 5.29 - 5.22 (m, 2H), 4.29 - 4.24 (m, 1H), 4.05 (dd, J = 11.1, 3.4 Hz, 1H), 3.98 (dd, J = 11.3, 4.8 Hz, 1H), 3.93 (dd, J = 10.4, 6.3 Hz, 1H), 3.61 - 3.55 (m, 2H), 3.53 - 3.44 (m, 3H), 3.10 (q, J = 7.4 Hz, 2H), 2.60 - 2.55 (m, 1H), 2.45 - 2.37 (m, 1H), 1.30 (t, J = 7.4 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H). Example 22 4-((2S,4S)-2-(ethoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide [ka] Starting from (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2.00 g, 8.15 mmol), the title compound was prepared as a white solid (60 mg, 72%) by following Steps 1 and 2 of Example 18 and Steps 1 to 5 of Example 21.

[0329] MS (ESI, pos.ion) m / z: 621.4 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.83 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H),7.03 (d, J = 6.6 Hz, 1H), 6.97 (d, J = 8.5 Hz, 2H), 6.66 (d, J = 8.7 Hz, 2H), 5.24 (d, J = 5.7 Hz, 1H), 5.14 (s, 1H), 4.16 - 4.08 (m, 1H), 4.00 (dd, J = 11.2, 3.5 Hz, 1H), 3.93 (dd, J = 11.2, 4.8 Hz, 1H), 3.76 - 3.64 (m, 3H), 3.55 - 3.40 (m, 3H), 3.07 (q, J = 7.4 Hz, 2H), 2.50 (d, J = 14.3 Hz, 1H), 2.41 - 2.31 (m, 1H), 1.27 (t, J = 7.4 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H). Example 23 N-(4-(ethylsulfonyl)benzyl)-4-((2S,4R)-2-(fluoromethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of 4-((2S,4R)-2-(fluoromethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile DAST (0.30 mL, 2.30 mmol) was slowly added to a solution of 4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile (210 mg, 0.58 mmol) ((2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate as the starting material; see Steps 1 to 4 of Example 19 for the preparation method) in DCM (5 mL) at room temperature, and the mixture was stirred at room temperature for 3 h. Saturated NaHCO3 solution (20 mL) was added to the reaction mixture, and then the aqueous phase was extracted with DCM (30 mL × 3). The combined organic phases were washed with saturated NaCl solution (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 a tan solid (171 mg, 81%).

[0330] MS (ESI, pos.ion) m / z: 365.2 [M+H] + . Step 2: Synthesis of 4-((2S,4R)-2-(fluoromethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid MeONa (822 mg, 15.22 mmol) was added to a solution of 4-((2S,4R)-2-(fluoromethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile (135 mg, 0.37 mmol) in EtOH (6 mL), and the reaction mixture was heated and stirred in an oil bath at 100 °C for 12 h. The reaction mixture was cooled to room temperature, and HO (20 mL) was added to the reaction mixture. The reaction mixture was then extracted with DCM (10 mL × 2). The aqueous phase was adjusted to pH 3 with HCl solution (1.0 mol / L), and the mixture was then extracted with EtOAc (20 mL × 3). The combined organic phases were dried over anhydrous NaSO and concentrated under reduced pressure to give a yellow solid (99 mg, 70%).

[0331] MS (ESI, pos.ion) m / z: 384.2 [M+H] + . Step 3: Synthesis of N-(4-(ethylsulfonyl)benzyl)-4-((2S,4R)-2-(fluoromethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide 4-((2S,4R)-2-(fluoromethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (43 mg, 0.11 mmol), (4-(ethylsulfonyl)phenyl)methanamine (30 mg, 0.15 mmol), EDCI (45 mg, 0.23 mmol), and HOBT (32 mg, 0.24 mmol) were dissolved in DCM (4 mL), and TEA (0.05 mL, 0.40 mmol) was added and the mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with DCM (80 mL), washed successively with HCl solution (20 mL, 1 mol / L), saturated NaCl solution (20 mL), and saturated NaCO solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 5 / 1) to give a yellow solid (51 mg, 81%).

[0332] MS (ESI, pos.ion) m / z: 565.1 [M+H] + ; 1H NMR (600 MHz, CDCl3) δ (ppm): 7.88 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 6.51 (t, J = 5.9 Hz, 1H), 5.10 (d, J = 46.8 Hz, 1H), 4.85 (m, 1H), 4.75 (d, J = 6.0 Hz, 2H), 3.95 (dd, J = 12.7, 3.5 Hz, 1H), 3.91 - 3.83 (m, 1H), 3.42 - 3.32 (m, 1H), 3.24 - 3.19 (m, 1H), 3.12 (q, J = 7.4 Hz, 2H), 2.55 (m, 1H), 2.09 - 1.99 (m, 1H), 1.30 (t, J = 7.4 Hz, 3H). Example 24 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S,4R)-2-(fluoromethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] 4-((2S,4R)-2-(fluoromethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (56 mg, 0.15 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (43 mg, 0.19 mmol), EDCI (57 mg, 0.30 mmol), and HOBT (42 mg, 0.31 mmol) were dissolved in DCM (4 mL), and TEA (0.06 mL, 0.40 mmol) was added and stirred at room temperature for 21 h. The reaction mixture was diluted with DCM (80 mL), washed successively with HCl solution (20 mL, 1 mol / L), saturated NaCO solution (20 mL), and saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to give a pink solid (55 mg, 63%).

[0333] MS (ESI, pos.ion) m / z: 595.1 [M+H] + ; 1H NMR (600 MHz, CDCl3) δ (ppm): 7.89 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 6.89 (d, 1H), 5.33 - 5.29 (m, 1H), 5.08 (d, J = 46.6 Hz, 1H), 4.85 - 4.80 (m, 1H), 4.10 - 4.05 (m, 1H), 4.03 - 3.99 (m, 1H), 3.93 (dd, J = 12.7, 3.5 Hz, 1H), 3.88 - 3.83 (m, 1H), 3.35 (ddd, J = 31.2, 13.6, 1.8 Hz, 1H), 3.20 (dd, J = 12.7, 8.3 Hz, 1H), 3.10 (q, J = 7.4 Hz, 2H), 2.56 - 2.50 (m, 1H), 2.02 (m, 1H), 1.29 (t, J = 7.4 Hz, 3H). Example 25 N-(4-(ethylsulfonyl)benzyl)-4-((2S,4R)-2-(methoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of 4-((2S,4R)-2-(methoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile Under nitrogen gas protection, NaH (50 mg, 1.25 mmol, 60%) was added to a solution of MeI (0.15 mL, 2.40 mmol) and 4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile (150 mg, 0.41 mmol) in THF (4 mL) and stirred at room temperature for 17 h. The reaction mixture was quenched by the addition of saturated NaCl solution (20 mL), extracted with EtOAc (30 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a yellow liquid (120 mg, 77%).

[0334] MS (ESI, pos.ion) m / z: 377.1 [M+H] + . Step 2: Synthesis of 4-((2S,4R)-2-(methoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid MeONa (5.70 g, 105.52 mmol) was added to a solution of 4-((2S,4R)-2-(methoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile (400 mg, 1.06 mmol) in EtOH (10 mL), and the reaction mixture was heated and stirred in an oil bath at 100 °C for 24 h. The reaction mixture was quenched by adding HO (15 mL), and the pH of the solution was adjusted to approximately 5 by adding HCl solution (1 mol / L), concentrated under reduced pressure, and the residue was diluted with saturated NaCl solution (20 mL). It was then extracted with EtOAc (60 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to give a pale yellow solid (360 mg, 85%).

[0335] MS (ESI, pos.ion) m / z: 396.3 [M+H] + . Step 3: Synthesis of N-(4-(ethylsulfonyl)benzyl)-4-((2S,4R)-2-(methoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide (4-(Ethylsulfonyl)phenyl)methanamine (90 mg, 0.45 mmol), 4-((2S,4R)-2-(methoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (100 mg, 0.25 mmol), HATU (216 mg, 0.57 mmol), and TEA (0.10 mL, 0.72 mmol) were dissolved in DCM (4 mL) and stirred at room temperature for 17 h. The reaction mixture was diluted with DCM (50 mL), washed sequentially with saturated NaHCO solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 4 / 1) to give a white solid (115 mg, 53%).

[0336] MS (ESI, pos.ion) m / z: 577.3 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.78 - 7.72 (m, 4H), 7.54 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 6.88 (t, J = 5.7 Hz, 1H), 6.60 (d, J = 8.6 Hz, 2H), 5.23 - 5.16 (m, 1H), 4.67 (d, J = 6.0 Hz, 2H), 4.26 - 4.20 (m, 1H), 3.90 (dd, J = 10.4, 6.1 Hz, 1H), 3.54 (dd, J = 9.6, 4.8 Hz, 1H), 3.47 (dd, J = 10.3, 4.4 Hz, 2H), 3.32 (s, 3H), 3.06 (q, J = 7.4 Hz, 2H), 2.56 - 2.50 (m, 1H), 2.41 - 2.33 (m, 1H), 1.23 (t, J = 7.4 Hz, 3H). Example 26 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S,4R)-2-(methoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] (R)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol (132 mg, 0.58 mmol), 4-((2S,4R)-2-(methoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (190 mg, 0.48 mmol), EDCI (138 mg, 0.72 mmol), and HOBT (97 mg, 0.72 mmol) were dissolved in DCM (4 mL) and stirred at room temperature for 17 h. The reaction mixture was diluted with DCM (50 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to give a white solid (110 mg, 38%).

[0337] MS (ESI, pos.ion) m / z: 607.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.80 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.53 (t, J = 8.4 Hz, 4H), 7.10 (d, J = 6.9 Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H), 6.59 (d, J = 8.8 Hz, 2H), 5.22 - 5.17 (m, 2H), 4.26 - 4.22 (m, 1H), 3.96 (dd, J = 11.5, 3.8 Hz, 1H), 3.89 (dd, J = 10.2, 6.0 Hz, 2H), 3.54 (dd, J = 9.6, 4.8 Hz, 1H), 3.48 (dd, J = 9.9, 3.1 Hz, 2H), 3.32 (s, 3H), 3.06 (q, J = 7.4 Hz, 2H), 2.56 - 2.50 (m, 1H), 2.41 - 2.33 (m, 1H), 1.24 (t, J = 7.4 Hz, 3H). Example 27 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S,4R)-2-(propoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of ethyl 4-((2S,4R)-2-(propoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, NaH (195 mg, 4.88 mmol, 60%) was added to a solution of 1-bromopropane (0.50 mL, 4.66 mmol) and ethyl 4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (200 mg, 0.49 mmol) in THF (6 mL) and stirred at room temperature for 17 h. The reaction mixture was quenched by adding HCl solution (1 mol / L) and the pH of the solution was adjusted to about 5. The mixture was then diluted with EtOAc (50 mL), extracted, and the organic phase was washed with saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a yellow liquid (160 mg, 72%).

[0338] MS (ESI, pos.ion) m / z: 452.3 [M+H] + . Step 2: Synthesis of 4-((2S,4R)-2-(propoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (442 mg, 10.53 mmol) in HO (3 mL) was added to a solution of ethyl 4-((2S,4R)-2-(propoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (160 mg, 0.35 mmol) in MeOH (6 mL) and stirred at room temperature for 23 h. The reaction mixture was adjusted to pH 5 by adding HCl solution (1 mol / L), followed by extraction with EtOAc (30 mL × 2). The combined organic phases were washed with saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to give a yellow solid (70 mg, 47%).

[0339] MS (ESI, pos.ion) m / z: 424.3 [M+H] + . Step 3: Synthesis of N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S,4R)-2-(propoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide (R)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol (50 mg, 0.22 mmol), 4-((2S,4R)-2-(propoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (70 mg, 0.17 mmol), HATU (95 mg, 0.25 mmol), and DIPEA (64 mg, 0.50 mmol) were dissolved in DCM (4 mL) and stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (40 mL), washed sequentially with saturated NaHCO solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to give a white solid (40 mg, 38%).

[0340] MS (ESI, pos.ion) m / z: 635.1 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.83 (d, J = 7.8 Hz, 2H), 7.73 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.3 Hz, 4H), 7.03 (d, J = 6.9 Hz, 1H), 6.96 (d, J = 8.5 Hz, 2H), 6.60 (d, J = 8.5 Hz, 2H), 5.27 - 5.20 (m, 2H), 4.25 (s, 1H), 4.01 - 3.88 (m, 3H), 3.57 (dd, J = 9.4, 4.6 Hz, 1H), 3.55 - 3.45 (m, 2H), 3.40 - 3.29 (m, 2H), 3.07 (q, J = 7.3 Hz, 2H), 2.59 - 2.52 (m, 1H), 2.42 - 2.32 (m, 1H), 1.60 - 1.51 (m, 2H), 1.26 (t, J = 7.3 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H). Example 28 4-((2S,4R)-2-(butoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide [ka] Step 1: Synthesis of ethyl 4-((2S,4R)-2-(butoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, NaH (98 mg, 2.45 mmol, 60%) was added to a solution of 1-bromobutane (0.50 mL, 4.66 mmol) and ethyl 4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (200 mg, 0.49 mmol) in THF (6 mL) and stirred at room temperature for 17 h. The reaction mixture was quenched by adding HCl solution (1 mol / L) and the pH of the solution was adjusted to approximately 5. EtOAc (50 mL) was added to dilute the mixture. The organic phase was extracted and separated. The organic phase was washed with saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a yellow liquid (160 mg, 70%).

[0341] MS (ESI, pos.ion) m / z: 466.1 [M+H] + . Step 2: Synthesis of 4-((2S,4R)-2-(butoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (442 mg, 10.53 mmol) in HO (3 mL) was added to a solution of ethyl 4-((2S,4R)-2-(butoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (160 mg, 0.34 mmol) in MeOH (6 mL) and stirred at room temperature for 23 h. The reaction mixture was adjusted to pH 5 with HCl solution (1 mol / L) and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to give a yellow solid (70 mg, 47%).

[0342] MS (ESI, pos.ion) m / z: 438.3 [M+H] + . Step 3: Synthesis of 4-((2S,4R)-2-(butoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide (R)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol (50 mg, 0.22 mmol), 4-((2S,4R)-2-(butoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (70 mg, 0.16 mmol), HATU (95 mg, 0.25 mmol), and DIPEA (64 mg, 0.50 mmol) were dissolved in DCM (4 mL) and stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (40 mL), washed sequentially with saturated NaHCO solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to give a white solid (35 mg, 34%).

[0343] MS (ESI, pos.ion) m / z: 649.2 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.83 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 7.4 Hz, 4H), 7.03 (d, J = 7.0 Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H), 6.60 (d, J = 8.8 Hz, 2H), 5.29 - 5.21 (m, 2H), 4.24 (d, J = 3.4 Hz, 1H), 4.00 (dd, J = 11.3, 3.8 Hz, 1H), 3.96 - 3.86 (m, 2H), 3.57 (dd, J = 9.7, 4.6 Hz, 1H), 3.52 (dd, J = 9.7, 4.6 Hz, 1H), 3.48 (dd, J = 10.5, 4.1 Hz, 1H), 3.44 - 3.33 (m, 2H), 3.07 (q, J = 7.4 Hz, 2H), 2.58 - 2.52 (m, 1H), 2.41 - 2.33 (m, 1H), 1.55 - 1.48 (m, 2H), 1.37 - 1.31 (m, 2H), 1.26 (t, J = 7.4 Hz, 6H), 0.90 (t, J = 7.4 Hz, 3H). Example 29 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S,4R)-2-((2-fluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of ethyl 4-((2S,4R)-2-((2-fluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, NaH (272 mg, 6.80 mmol, 60%) was added to a solution of 1-bromo-2-fluoroethane (2.00 mL, 26.77 mmol) and ethyl 4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (450 mg, 1.10 mmol) in THF (8 mL), and the mixture was stirred at room temperature for 17 h. The reaction mixture was quenched by adding HCl solution (1 mol / L) and the pH of the solution was adjusted to about 5. EtOAc (50 mL) was added to dilute the mixture. The organic layer was extracted and separated. The organic layer was washed with saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to give a yellow liquid (240 mg, 48%).

[0344] MS (ESI, pos.ion) m / z: 456.3 [M+H] + . Step 2: Synthesis of 4-((2S,4R)-2-((2-fluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (442 mg, 10.53 mmol) in HO (3 mL) was added to a solution of ethyl 4-((2S,4R)-2-((2-fluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (240 mg, 0.53 mmol) in MeOH (6 mL) and stirred at room temperature for 14 h. The reaction mixture was adjusted to pH 5 with HCl solution (1 mol / L) and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to give a yellow solid (150 mg, 67%).

[0345] MS (ESI, pos.ion) m / z: 428.1 [M+H] + . Step 3: Synthesis of N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S,4R)-2-((2-fluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide (R)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol (96 mg, 0.42 mmol), 4-((2S,4R)-2-((2-fluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (150 mg, 0.35 mmol), EDCI (100 mg, 0.52 mmol), and HOBT (71 mg, 0.53 mmol) were dissolved in DCM (4 mL) and stirred at room temperature for 17 h. The reaction mixture was diluted with DCM (40 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to give a white solid (90 mg, 40%).

[0346] MS (ESI, pos.ion) m / z: 639.1 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.84 (d, J = 7.9 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 7.59 - 7.54 (m, 4H), 7.15 (d, J = 6.5 Hz, 1H), 6.99 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 8.3 Hz, 2H), 5.30 - 5.23 (m, 2H), 4.58 (s, 1H), 4.46 (s, 1H), 4.29 (d, J = 3.6 Hz, 1H), 4.04 - 3.98 (m, 1H), 3.95 (dd, J = 9.8, 6.0 Hz, 2H), 3.75 - 3.68 (m, 2H), 3.68 - 3.61 (m, 2H), 3.50 (dd, J = 10.3, 3.7 Hz, 1H), 3.09 (q, J = 7.4 Hz, 2H), 2.63 - 2.57 (m, 1H), 2.45 - 2.37 (m, 1H), 1.27 (t, J = 7.4 Hz, 3H). Example 30 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S,4R)-2-((2,2,2-trifluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of ((2S,4R)-1-(4-cyanophenyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-2-yl)methyl methanesulfonate Under nitrogen gas protection, MsCl (0.10 mL, 1.29 mmol) was added to a solution of 4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile (200 mg, 0.55 mmol) and TEA (0.20 mL, 1.43 mmol) in DCM (6 mL) and stirred at room temperature for 24 h. The reaction mixture was quenched by the addition of saturated NaCl solution (20 mL), then diluted with DCM (30 mL), and the organic phase was extracted and separated. The organic phase was dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to give a yellow liquid (160 mg, 66%).

[0347] MS (ESI, pos.ion) m / z: 441.3 [M+H] + . Step 2: Synthesis of 4-((2S,4R)-2-((2,2,2-trifluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile CsCO (177 mg, 0.54 mmol) and 3,3,3-trifluoropropyl-1-ol (160 mg, 1.60 mmol) were added to a solution of ((2S,4R)-1-(4-cyanophenyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-2-yl)methyl methanesulfonate (60 mg, 0.14 mmol) in ACN (4 mL), and the reaction mixture was heated and stirred in an oil bath at 80 °C for 17 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a yellow solid (46 mg, 76%).

[0348] MS (ESI, pos.ion) m / z: 445.2 [M+H] + . Step 3: Synthesis of 4-((2S,4R)-2-((2,2,2-trifluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid MeONa (1.20 g, 22.21 mmol) was added to a solution of 4-((2S,4R)-2-((2,2,2-trifluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile (400 mg, 1.06 mmol) in EtOH (5 mL), and the reaction mixture was heated and stirred in an oil bath at 100 °C for 18 h. The reaction mixture was cooled to room temperature, and HCl solution (1 mol / L) was added to the reaction mixture to quench the reaction and adjust the pH of the solution to about 5. The mixture was extracted with EtOAc (30 mL × 2). The organic phase was washed with saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1) to give a pale yellow solid (80 mg, 77%).

[0349] MS (ESI, pos.ion) m / z: 464.2 [M+H] + . Step 4: Synthesis of N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S,4R)-2-((2,2,2-trifluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide (R)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol (55 mg, 0.24 mmol), 4-((2S,4R)-2-((2,2,2-trifluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (80 mg, 0.17 mmol), EDCI (49 mg, 0.26 mmol), and HOBT (35 mg, 0.26 mmol) were dissolved in DCM (4 mL) and stirred at room temperature for 13 h. The reaction mixture was diluted with DCM (50 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 1 / 1) to give a white solid (76 mg, 65%).

[0350] MS (ESI, pos.ion) m / z: 675.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.84 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.7 Hz, 2H), 7.57 (t, J = 7.4 Hz, 4H), 7.08 (d, J = 7.0 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.7 Hz, 2H), 5.32 - 5.21 (m, 2H), 4.34 - 4.27 (m, 1H), 4.01 (dd, J = 11.3, 3.8 Hz, 1H), 3.97 - 3.90 (m, 2H), 3.88 - 3.72 (m, 4H), 3.52 (dd, J = 10.3, 3.7 Hz, 1H), 3.09 (q, J = 7.4 Hz, 2H), 2.62 - 2.56 (m, 1H), 2.48 - 2.39 (m, 1H), 1.28 (t, J = 7.4 Hz, 3H). Example 31 4-((2S,4R)-2-((cyclopropylmethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide [ka] Step 1: Synthesis of 4-((2S,4R)-2-((cyclopropylmethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile Under nitrogen gas protection, NaH (100 mg, 2.50 mmol, 60%) was added to a solution of 4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile (300 mg, 0.83 mmol) and (bromomethyl)cyclopropane (0.40 mL, 4.12 mmol) in THF (8 mL) and stirred at room temperature for 20 h. The reaction mixture was then quenched by the addition of saturated NaCl solution (20 mL), extracted with EtOAc (30 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a yellow liquid (178 mg, 52%).

[0351] MS (ESI, pos.ion) m / z: 416.9 [M+H] + . Step 2: Synthesis of 4-((2S,4R)-2-((cyclopropylmethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid MeONa (2.20 g, 40.73 mmol) was added to a solution of 4-((2S,4R)-2-((cyclopropylmethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzonitrile (400 mg, 1.06 mmol) in EtOH (8 mL), and the reaction mixture was heated and stirred in an oil bath at 100 °C for 16 h. The reaction mixture was cooled to room temperature, quenched by adding HO (15 mL), adjusted to a pH of about 5 by adding HCl solution (12 mol / L), and concentrated under reduced pressure. The residue was diluted with saturated NaCl solution (20 mL) and then extracted with EtOAc (60 mL × 2). The combined organic phases were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to give a pale yellow solid (160 mg, 85%).

[0352] MS (ESI, pos.ion) m / z: 436.3 [M+H] + . Step 3: Synthesis of 4-((2S,4R)-2-((cyclopropylmethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide (R)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol (84 mg, 0.37 mmol), 4-((2S,4R)-2-((cyclopropylmethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (160 mg, 0.37 mmol), EDCI (105 mg, 0.55 mmol), and HOBT (74 mg, 0.55 mmol) were dissolved in DCM (4 mL) and stirred at room temperature for 22 h. The reaction mixture was diluted with DCM (50 mL), washed sequentially with saturated NaHCO solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 2 / 1) to give a white solid (100 mg, 42%).

[0353] MS (ESI, pos.ion) m / z: 647.0 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.82 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 6.9 Hz, 1H), 6.97 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 8.8 Hz, 2H), 5.27 - 5.20 (m, 2H), 4.28 - 4.23 (m, 1H), 3.99 (dd, J = 11.3, 3.9 Hz, 1H), 3.95 - 3.88 (m, 2H), 3.58 (d, J = 3.8 Hz, 2H), 3.48 (dd, J = 10.4, 4.1 Hz, 1H), 3.25 (d, J = 6.8 Hz, 2H), 3.07 (q, J = 7.4 Hz, 2H), 2.59 - 2.54 (m, 1H), 2.42 - 2.34 (m, 1H), 1.26 (t, J = 7.4 Hz, 3H), 1.03 - 0.96 (m, 1H), 0.53 - 0.48 (m, 2H), 0.19-0.15 (m, 2H). Example 32 4-((2S,4R)-2-((2-cyanoethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide [ka] Step 1: Synthesis of 4-((2S,4R)-2-((2-cyanoethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid Under nitrogen gas protection, NaH (60 mg, 1.50 mmol, 60%) was added to a solution of 3-bromopropionitrile (0.30 mL, 3.62 mmol) and 4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (80 mg, 0.21 mmol) in THF (6 mL) and stirred at room temperature for 24 h. The reaction mixture was quenched by adding HCl solution (1 mol / L) and the pH of the solution was adjusted to about 5. The mixture was diluted with EtOAc (30 mL), extracted, and the organic phase was washed with saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a white solid (25 mg, 27%).

[0354] MS (ESI, pos.ion) m / z: 435.1 [M+H] + . Step 2: Synthesis of 4-((2S,4R)-2-((2-cyanoethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide (R)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol (15 mg, 0.07 mmol), 4-((2S,4R)-2-((2-cyanoethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (25 mg, 0.06 mmol), EDCI (16 mg, 0.08 mmol), HOBT (11 mg, 0.08 mmol), and TEA (11 mg, 0.11 mmol) were dissolved in DCM (2 mL) and stirred at room temperature for 10 h. The reaction mixture was diluted with DCM (40 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a white solid (10 mg, 27%).

[0355] MS (ESI, pos.ion) m / z: 646.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.86 (d, J = 7.3 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.57 (d,, J = 7.3 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.5 Hz, 3H), 6.62 (d, J = 8.7 Hz, 2H), 5.31 - 5.26 (m, 2H), 4.31 (s, 1H), 4.02 (s, 1H), 3.97 (dd, J = 10.2, 6.1 Hz, 2H), 3.75 (dd, J = 9.7, 3.8 Hz, 1H), 3.66 - 3.63 (m, 2H), 3.62 - 3.56 (m, 2H), 3.51 (dd, J = 10.4, 3.7 Hz, 1H), 3.09 (q, J = 7.4 Hz, 2H), 2.63 - 2.58 (m, 1H), 2.58 - 2.54 (m, 2H), 2.46 - 2.40 (m, 1H), 1.28 (t, J = 7.4 Hz, 3H). Example 33 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S,4R)-2-((((S)-tetrahydrofuran-3-yl)oxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of 4-((2S,4R)-2-((((S)-tetrahydrofuran-3-yl)oxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid Under nitrogen gas protection, NaH (80 mg, 2.00 mmol, 60%) was added to a solution of (R)-tetrahydrofuran-3-yl methanesulfonate (420 mg, 2.53 mmol) and ethyl 4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (200 mg, 0.49 mmol) in THF (6 mL), and the mixture was stirred at room temperature for 23 h. The reaction mixture was quenched by adding HCl solution (1 mol / L) and the pH of the solution was adjusted to about 5. The mixture was diluted with saturated NaCl solution (20 mL), extracted with EtOAc (30 mL × 3), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a yellow liquid (50 mg, 23%).

[0356] MS (ESI, pos.ion) m / z: 452.1 [M+H] + . Step 2: Synthesis of N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S,4R)-2-((((S)-tetrahydrofuran-3-yl)oxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide (R)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol (30 mg, 0.13 mmol), 4-((2S,4R)-2-((((S)-tetrahydrofuran-3-yl)oxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (50 mg, 0.11 mmol), EDCI (31 mg, 0.16 mmol), HOBT (22 mg, 0.16 mmol), and TEA (22 mg, 0.22 mmol) were dissolved in DCM (4 mL) and stirred at room temperature for 9 h. The reaction mixture was diluted with DCM (40 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a white solid (25 mg, 34%).

[0357] MS (ESI, pos.ion) m / z: 663.4 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.88 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 6.9 Hz, 1H), 6.97 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 8.8 Hz, 2H), 5.29 (d, J = 6.1 Hz, 1H), 5.26 - 5.19 (m, 1H), 4.29 (d, J = 3.3 Hz, 1H), 4.07 - 4.03 (m, 2H), 3.98 (dd, J = 11.3, 4.9 Hz, 1H), 3.90 (dd, J = 10.4, 6.2 Hz, 1H), 3.84 - 3.73 (m, 4H), 3.67 (dd, J = 9.4, 4.4 Hz, 1H), 3.55 - 3.49 (m, 2H), 3.10 (t, J = 7.4 Hz, 2H), 2.59 - 2.53 (m, 1H), 2.45 - 2.37 (m, 1H), 1.99 - 1.83 (m, 2H), 1.30 (t, J = 7.4 Hz, 3H). Example 34 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S,4R)-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] Using tetrahydro-2H-pyran-4-yl methanesulfonate (600 mg, 3.33 mmol) as a starting material, the title compound was prepared as a white solid (12 mg, 28%) according to the synthesis method of Example 33.

[0358] MS (ESI, pos.ion) m / z: 667.2 [M+H] + ; 1 H NMR (600 MHz, CDCl3) δ (ppm): 7.86 (d, J = 7.5 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.57 (d, J = 7.5 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H), 6.98 (s, 1H), 6.95 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 8.6 Hz, 2H), 5.28 (s, 1H), 5.25 - 5.21 (m, 1H), 4.28 (d, J = 3.5 Hz, 1H), 4.05 - 4.01 (m, 1H), 3.99 - 3.95 (m, 2H), 3.92 - 3.86 (m, 2H), 3.84 - 3.80 (m, 1H), 3.67 - 3.62 (m, 2H), 3.58 (dd, J = 9.5, 2.2 Hz, 1H), 3.50 (dd, J = 10.4, 3.7 Hz, 1H), 3.45 - 3.38 (m, 3H), 3.39 - 3.36 (m, 1H), 3.08 (q, J = 7.3 Hz, 2H), 2.57 - 2.53 (m, 1H), 2.44 - 2.39 (m, 1H), 2.05 - 1.99 (m, 1H), 1.87 (d, J = 13.0 Hz, 1H), 1.27 (s, 3H). Example 35 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S,4R)-2-(((S)-3-methylmorpholinyl)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide [ka] Step 1: Synthesis of tert-butyl (2S,4R)-2-((S)-3-methylmorpholine-4-carbonyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-2-carboxylic acid (800 mg, 2.13 mmol), (3S)-3-methylmorpholine (323 mg, 3.20 mmol), HATU (1.22 g, 3.21 mmol), and TEA (0.90 mL, 6.46 mmol) were dissolved in DCM (16 mL) and stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 2) to give a colorless liquid (851 mg, 87%).

[0359] MS (ESI, pos.ion) m / z: 459.3 [M+H] + . Step 2: Synthesis of tert-butyl (2S,4R)-2-(((S)-3-methylmorpholinyl)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate BH3·SMe2 (0.50 mL, 5.00 mmol, 1.0 mol / L) was added dropwise to tert-butyl (2S,4R)-2-((S)-3-methylmorpholine-4-carbonyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (800 mg, 1.75 mmol) in THF (12 mL) under ice bath conditions, followed by stirring at room temperature for 17 h. The reaction mixture was quenched by the addition of MeOH (20 mL) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 3 / 1) to give a pale yellow liquid (480 mg, 62%).

[0360] MS (ESI, pos.ion) m / z: 445.1 [M+H] + . Step 3: Synthesis of (S)-3-methyl-4-(((2S,4R)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-2-yl)methyl)morpholine A solution of HCl in methanol (2 mL, 20%) was added to a solution of tert-butyl (2S,4R)-2-(((S)-3-methylmorpholinyl)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (400 mg, 0.90 mmol) in DCM (8 mL) and stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give a pale yellow liquid (310 mg, 100%).

[0361] MS (ESI, pos.ion) m / z: 345.3 [M+H] + . Step 4: Synthesis of ethyl 4-((2S,4R)-2-(((S)-3-methylmorpholinyl)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, (S)-3-methyl-4-(((2S,4R)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-2-yl)methyl)morpholine (300 mg, 0.87 mmol), Pd(dba) (79 mg, 0.09 mmol), XantPhos (75 mg, 0.13 mmol), CsCO (567 mg, 1.74 mmol), and ethyl 4-iodobenzoate (312 mg, 1.13 mmol) were dissolved in 1,4-dioxane (8 mL), and the reaction mixture was heated and stirred in an oil bath at 100 °C for 13 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (80 mL), washed successively with saturated NaHCO3 solution (20 mL) and saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a brown liquid (346 mg, 81%).

[0362] MS (ESI, pos.ion) m / z: 493.4 [M+H] + . Step 5: Synthesis of 4-((2S,4R)-2-(((S)-3-methylmorpholinyl)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (127 mg, 3.03 mmol) in HO (2 mL) was added to a solution of ethyl 4-((2S,4R)-2-(((S)-3-methylmorpholinyl)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (150 mg, 0.30 mmol) in MeOH (6 mL) and stirred at room temperature for 24 h. The reaction mixture was adjusted to pH 5 with HCl solution (1 mol / L) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with saturated NaCl solution (15 mL), dried over anhydrous NaSO, 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 brown liquid (90 mg, 64%).

[0363] MS (ESI, pos.ion) m / z: 465.1 [M+H] + . Step 6: Synthesis of N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S,4R)-2-(((S)-3-methylmorpholinyl)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzamide (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (47 mg, 0.20 mmol), 4-((2S,4R)-2-(((S)-3-methylmorpholinyl)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (80 mg, 0.17 mmol), EDCI (50 mg, 0.26 mmol), HOBT (34 mg, 0.25 mmol), and TEA (3 The reaction mixture (4 mg, 0.34 mmol) was dissolved in DCM (4 mL) and stirred at room temperature for 11 h. The reaction mixture was diluted with DCM (40 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a white solid (76 mg, 65%).

[0364] MS (ESI, pos.ion) m / z: 676.4 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.82 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 7.0 Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H), 6.60 (d, J = 8.7 Hz, 2H), 5.24 (d, J = 6.2 Hz, 1H), 5.17 - 5.10 (m, 1H), 4.25 - 4.17 (m, 1H), 3.99 (dd, J = 11.3, 3.8 Hz, 1H), 3.95 - 3.86 (m, 2H), 3.78 (d, J = 11.3 Hz, 1H), 3.74 (d, J = 6.5 Hz, 1H), 3.73 - 3.68 (m, 1H), 3.68 - 3.63 (m, 1H), 3.61 (d, J = 9.5 Hz, 1H), 3.53 (dd, J = 10.7, 3.5 Hz, 1H), 3.26 (dd, J = 10.9, 8.9 Hz, 1H), 3.07 (q, J = 7.4 Hz, 2H), 2.89 (d, J = 11.6 Hz, 1H), 2.61 (dd, J = 12.8, 9.1 Hz, 1H), 2.57 - 2.50 (m, 1H), 2.46 (dd, J = 13.2, 3.1 Hz, 1H), 2.42 - 2.37 (m, 2H), 1.25 (t, J = 7.4 Hz, 3H), 0.94 (d, J = 6.2 Hz, 3H). Example 36 4-((2R,4R)-2-(シアノメチル)-4-(4-(トリフルオロメチル)フェノキシ)ピロリジン- 1-イル)-N-((R)-1-(4-(エチルスルホニル)フェニル)-2-ヒドロキシエチル)ベンズアミド

change

[0365] MS (ESI, pos.ion) m / z: 419.2 [M+H] + . Step 2: Synthesis of 4-((2R,4R)-2-(cyanomethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (402 mg, 9.58 mmol) in HO (3 mL) was added to a solution of ethyl 4-((2R,4R)-2-(cyanomethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (150 mg, 0.36 mmol) in MeOH (6 mL) and stirred at room temperature for 21 h. The reaction mixture was adjusted to pH 5 with HCl solution (1 mol / L) and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 4 / 1) to give a colorless liquid (95 mg, 68%).

[0366] MS (ESI, pos.ion) m / z: 391.2 [M+H] + . Step 3: Synthesis of 4-((2R,4R)-2-(cyanomethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide (R)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol (68 mg, 0.30 mmol), 4-((2R,4R)-2-(cyanomethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (90 mg, 0.23 mmol), HATU (131 mg, 0.34 mmol), and DIPEA (101 mg, 0.78 mmol) were dissolved in DCM (4 mL) and stirred at room temperature for 13 h. The reaction mixture was diluted with DCM (40 mL), washed sequentially with saturated NaHCO solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a white solid (60 mg, 43%).

[0367] MS (ESI, pos.ion) m / z: 602.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.84 (d, J = 6.8 Hz, 2H), 7.77 (d, J = 7.7 Hz, 2H), 7.59 - 7.51 (m, 4H), 7.09 (s, 1H), 6.93 (d, J = 8.5 Hz, 2H), 6.60 (d, J = 7.6 Hz, 2H), 5.24 (s, 2H), 4.42 (s, 1H), 4.07 - 3.91 (m, 3H), 3.63 (d, J = 10.5 Hz, 1H), 3.08 (q, J = 7.3 Hz, 2H), 2.85 (dd, J = 17.0, 6.0 Hz, 1H), 2.70 (d, J = 16.6 Hz, 2H), 2.56 - 2.47 (m, 1H), 1.27 (t, J = 7.3 Hz, 3H). Example 37 (2S,4R)-1-(4-(((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)carbamoyl)phenyl)-N-methoxy-N-methyl-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-2-carboxamide [ka] Step 1: Synthesis of tert-butyl (2S,4R)-2-(methoxy(methyl)carbamoyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-2-carboxylic acid (1.00 g, 2.66 mmol), N-methoxymethylamine hydrochloride (312 mg, 3.20 mmol), HATU (1.52 g, 4.00 mmol), and DIPEA (1.30 mL, 7.87 mmol) were dissolved in DCM (16 mL) and stirred at room temperature for 16 h. The reaction mixture was filtered to remove white insoluble material. The filtrate was diluted with DCM (40 mL), washed sequentially with saturated NaHCO solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 2 / 1) to give a colorless liquid (912 mg, 82%).

[0368] MS (ESI, pos.ion) m / z: 441.3 [M+Na] + . Step 2: Synthesis of (2S,4R)-N-methoxy-N-methyl-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-2-carboxamide A solution of HCl in methanol (6 mL, 20%) was added to a solution of tert-butyl (2S,4R)-2-(methoxy(methyl)carbamoyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (900 mg, 2.15 mmol) in DCM (16 mL) and stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give a colorless liquid (4.30 g, 100%).

[0369] MS (ESI, pos.ion) m / z: 319.1 [M+H] + . Step 3: Synthesis of ethyl 4-((2S,4R)-2-(methoxy(methyl)carbamoyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, (2S,4R)-N-methoxy-N-methyl-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-2-carboxamide (400 mg, 1.26 mmol), Pd(dba) (175 mg, 0.13 mmol), XantPhos (109 mg, 0.19 mmol), CsCO (818 mg, 2.51 mmol), and ethyl 4-iodobenzoate (416 mg, 1.51 mmol) were dissolved in 1,4-dioxane (8 mL), and the reaction mixture was heated and stirred in an oil bath at 100 °C for 18 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (80 mL), washed successively with saturated NaHCO3 solution (20 mL) and saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to give a yellow liquid (150 mg, 26%).

[0370] MS (ESI, pos.ion) m / z: 467.3 [M+H] + . Step 4: Synthesis of 4-((2S,4R)-2-(methoxy(methyl)carbamoyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (89 mg, 2.12 mmol) in HO (2 mL) was added to a solution of ethyl 4-((2S,4R)-2-(methoxy(methyl)carbamoyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (150 mg, 0.37 mmol) in MeOH (6 mL) and stirred at room temperature for 6 h. The reaction mixture was adjusted to pH 5 with HCl solution (1 mol / L) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a white solid (30 mg, 32%).

[0371] MS (ESI, pos.ion) m / z: 439.1 [M+H] + . Step 5: Synthesis of (2S,4R)-1-(4-(((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)carbamoyl)phenyl)-N-methoxy-N-methyl-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-2-carboxamide (R)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol (10 mg, 0.34 mmol), 4-((2S,4R)-2-(methoxy(methyl)carbamoyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (15 mg, 0.03 mmol), EDCI (10 mg, 0.05 mmol), HOBT (7 mg, 0.05 mmol), and TEA (8 mg, 0.08 mmol) were dissolved in DCM (2 mL) and stirred at room temperature for 12 h. The reaction mixture was diluted with DCM (30 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a white solid (6 mg, 27%).

[0372] MS (ESI, pos.ion) m / z: 550.4 [M+H]+ ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.85 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 6.8 Hz, 1H), 6.96 (d, J = 8.5 Hz, 2H), 6.53 (d, J = 8.6 Hz, 2H), 5.20 (s, 2H), 5.04 (s, 1H), 4.05 (dd, J = 10.4, 5.4 Hz, 1H), 3.97 - 3.92 (m, 2H), 3.84 (s, 3H), 3.70 (d, J = 9.8 Hz, 1H), 3.58 - 3.52 (m, 1H), 3.23 (s, 3H), 3.08 (q, J = 7.4 Hz, 2H), 2.72 - 2.66 (m, 1H), 2.52 - 2.44 (m, 1H), 1.33 (t, J = 7.4 Hz, 3H). Example 38 4-((2R,4R)-2-((difluoromethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide [ka] Step 1: Synthesis of (2R,4R)-1-tert-butyl 2-methyl 4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1,2-dicarboxylate (2R,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2.00 g, 8.15 mmol), 4-(trifluoromethyl)phenol (1.60 g, 9.87 mmol), and PPh3 (3.10 g, 9.03 mmol) were added to THF (30 mL), and DIAD (2.00 mL, 10.16 mmol) was added slowly at 0 °C. After the addition, the mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure, and the remaining liquid was diluted with methyl tert-butyl ether (25 mL) and stirred at −20° C. to precipitate a large amount of white insoluble solid (triphenylphosphine oxide). The solid was filtered while still cold, and the filter cake was washed with cold methyl tert-butyl ether. The filtrate was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a white solid (2.50 g, 79%).

[0373] MS (ESI, pos.ion) m / z: 412.1 [M+Na] + . Step 2: Synthesis of tert-butyl (2R,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (2R,4R)-1-tert-butyl 2-methyl 4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1,2-dicarboxylate (3.00 g, 7.70 mmol) was added to a solution of (2R,4R)-1-tert-butyl 2-methyl 4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1,2-dicarboxylate in 30 mL of THF. LiBH (336 mg, 15.43 mmol) was added slowly at 0 °C, and the mixture was allowed to react at room temperature for 16 h. The reaction mixture was quenched by the addition of saturated NH Cl (30 mL). The mixture was allowed to stand for phase separation, and the upper organic layer was separated and removed. The aqueous layer was extracted with EtOAc (30 mL × 2). The combined organic layers were dried over anhydrous Na SO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to give a colorless liquid (2.50 g, 90%).

[0374] MS (ESI, pos.ion) m / z: 384.0 [M+Na] + . Step 3: Synthesis of tert-butyl (2R,4R)-2-((difluoromethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate HO (1 mL), KOAc (678 mg, 6.91 mmol), and TMSCFBr (0.50 mL, 3.22 mmol) were added sequentially to a solution of tert-butyl (2R,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (500 mg, 1.38 mmol) in DCM (1 mL) and reacted at room temperature for 17 h. The reaction mixture was diluted with DCM (30 mL), washed with saturated NaCl (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a colorless liquid (420 mg, 74%).

[0375] MS (ESI, pos.ion) m / z: 434.3 [M+Na] + . Step 4: Synthesis of (2R,4R)-2-((difluoromethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine A solution of HCl in methanol (2 mL, 20%) was added to a solution of tert-butyl (2R,4R)-2-((difluoromethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (400 mg, 0.97 mmol) in DCM (8 mL) and stirred at room temperature for 23 h. The reaction mixture was concentrated under reduced pressure, and the remaining liquid was diluted with DCM (30 mL), washed sequentially with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a colorless liquid (280 mg, 93%).

[0376] MS (ESI, pos.ion) m / z: 312.1 [M+H] + . Step 5: Synthesis of methyl 4-((2R,4R)-2-((difluoromethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, (2R,4R)-2-((difluoromethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine (280 mg, 0.90 mmol), Pd2(dba)3 (82 mg, 0.09 mmol), XantPhos (78 mg, 0.13 mmol), Cs2CO3 (300 mg, 0.92 mmol), and methyl 4-iodobenzoate (353 mg, 1.35 mmol) were added sequentially to 1,4-dioxane (6 mL), and the reaction mixture was heated in an oil bath at 100 °C for 22 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The remaining liquid was diluted with DCM (50 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a yellow liquid (300 mg, 75%).

[0377] MS (ESI, pos.ion) m / z: 446.0 [M+H] + . Step 6: Synthesis of 4-((2R,4R)-2-((difluoromethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (226 mg, 5.39 mmol) in HO (2 mL) was added to a solution of methyl 4-((2R,4R)-2-((difluoromethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (240 mg, 0.54 mmol) in MeOH (6 mL) and the mixture was allowed to react at room temperature for 17 h. The pH of the reaction mixture was adjusted to approximately 4 with HCl (1 mol / L) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with saturated NaCl (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a pale yellow solid (172 mg, 74%).

[0378] MS (ESI, pos.ion) m / z: 432.0 [M+H] + . Step 7: Synthesis of 4-((2R,4R)-2-((difluoromethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide EDCI (43 mg, 0.22 mmol), HOBT (30 mg, 0.22 mmol), (R)-2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol (44 mg, 0.19 mmol), 4-((2R,4R)-2-((difluoromethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (65 mg, 0.15 mmol), and TEA (45 mg, 0.44 mmol) were added sequentially to DCM (4 mL) and stirred at room temperature for 17 h. The reaction mixture was diluted with DCM (40 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a white solid (84 mg, 87%).

[0379] MS (ESI, pos.ion) m / z: 643.0 [M+H]+ ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.83 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.03 (d, J = 6.9 Hz, 1H), 6.97 (d, J = 8.6 Hz, 2H), 6.64 (d, J = 8.8 Hz, 2H), 6.22 (t, J = 74.3 Hz, 1H), 5.24 (dd, J = 10.7, 4.4 Hz, 1H), 5.17 (t, J = 4.5 Hz, 1H), 4.23 - 4.13 (m, 2H), 4.03 - 3.91 (m, 3H), 3.76 (d, J = 11.4 Hz, 1H), 3.70 (dd, J = 11.4, 4.7 Hz, 1H), 3.07 (q, J = 7.4 Hz, 2H), 2.51 (d, J = 14.4 Hz, 1H), 2.43 - 2.34 (m, 1H), 1.26 (t, J = 7.4 Hz, 3H). Example 39 4-((2S,4S)-2-((difluoromethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide [ka] The title compound was prepared as a white solid (55 mg, 62%) using (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate as the starting material and following the procedures of Steps 1 to 7 of Example 38.

[0380] MS (ESI, pos.ion) m / z: 643.1 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.78 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 7.6 Hz, 4H), 7.50 (s, 1H), 6.93 (d, J = 8.3 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 6.18 (t, J = 74.4 Hz, 1H), 5.18 (s, 1H), 5.13 (s, 1H), 4.20 - 4.05 (m, 2H), 3.96 - 3.86 (m, 2H), 3.85 - 3.77 (m, 1H), 3.74 - 3.62 (m, 2H), 3.05 (q, J = 7.2 Hz, 2H), 2.46 (d, J = 14.3 Hz, 1H), 2.39 - 2.30 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H). Example 40 4-((2S,4R)-2-((difluoromethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide [ka] Using (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate as the starting material, the title compound was prepared as a white solid (66 mg, 74%) according to the methods of Steps 1 to 7 of Example 38.

[0381] MS (ESI, pos.ion) m / z: 643.1 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.82 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 7.0 Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 8.8 Hz, 2H), 6.20 (t, J = 74.2 Hz, 1H), 5.23 (dd, J = 10.8, 4.5 Hz, 1H), 5.20 - 5.14 (m, 1H), 4.37 - 4.30 (m, 1H), 4.02 - 3.96 (m, 3H), 3.92 (dd, J = 10.7, 5.8 Hz, 2H), 3.54 (dd, J = 10.6, 3.5 Hz, 1H), 3.07 (q, J = 7.4 Hz, 2H), 2.57 - 2.43 (m, 2H), 1.25 (t, J = 7.4 Hz, 3H). Example 41 4-((2R,4S)-2-((difluoromethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide [ka] The title compound was prepared as a pale yellow solid (48 mg, 81%) using (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2.00 g, 8.15 mmol) as the starting material and following the procedures of Steps 1 to 7 of Example 38.

[0382] MS (ESI, pos.ion) m / z: 643.1 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.86 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 5.0 Hz, 2H), 7.57 (d, J = 4.6 Hz, 2H), 7.04 (d, J = 6.8 Hz, 1H), 6.98 (d, J = 8.6 Hz, 2H), 6.64 (d, J = 8.7 Hz, 2H), 6.23 (t, J = 74.1 Hz, 1H), 5.27 (d, J = 6.1 Hz, 1H), 5.23 - 5.17 (m, 1H), 4.37 (d, J = 4.1 Hz, 1H), 4.06 - 3.92 (m, 5H), 3.57 (dd, J = 10.6, 3.3 Hz, 1H), 3.10 (q, J = 7.4 Hz, 2H), 2.60 - 2.46 (m, 2H), 1.30 (d, J = 7.4 Hz, 3H). Example 42 4-((2S,4R)-2-((1,1-difluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide [ka] Step 1: Synthesis of benzyl (2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate CbzCl (0.35 mL, 2.49 mmol) was added to a solution of ((2S,4R)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-2-yl)methanol (500 mg, 1.91 mmol) and NaHCO (643 mg, 7.65 mmol) in THF / HO (8 mL / 3 mL) and stirred at room temperature for 16 h. The reaction mixture was diluted with saturated NaHCO (15 mL) and EtOAc (20 mL), allowed to stand, and the layers were separated. The upper organic layer was separated, and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic layers were washed with saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a colorless liquid (700 mg, 93%).

[0383] MS (ESI, pos.ion) m / z: 396.2 [M+H] + . Step 2: Synthesis of benzyl (2S,4R)-2-(acetoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate AcO (0.25 mL, 2.66 mmol) and TEA (0.50 mL, 3.60 mmol) were added sequentially to a solution of benzyl (2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate and DMAP (21 mg, 0.17 mmol) in DCM (10 mL), followed by stirring at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to give a colorless liquid (700 mg, 90%).

[0384] MS (ESI, pos.ion) m / z: 438.2 [M+H] + . Step 3: Synthesis of benzyl (2S,4R)-2-((thioacetoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate Lawesson's reagent (8.41 g, 20.79 mmol) was added to a solution of benzyl (2S,4R)-2-(acetoxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (700 mg, 1.60 mmol) in toluene (12 mL), and the reaction mixture was heated and stirred in an oil bath at 110° C. for 17 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 5 / 1) to give a yellow liquid (76 mg, 10%).

[0385] MS (ESI, pos.ion) m / z: 476.3 [M+Na] + . Step 4: Synthesis of benzyl (2S,4R)-2-((1,1-difluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate Under nitrogen gas protection, DAST (60 mg, 0.37 mmol) was slowly added to a solution of benzyl (2S,4R)-2-((thioacetoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (85 mg, 0.19 mmol) in DCM (2 mL) and stirred at room temperature for 7 h. The reaction mixture was added to DCM (20 mL), washed sequentially with saturated NaHCO solution (10 mL) and saturated NaCl solution (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a yellow liquid (56 mg, 65%).

[0386] MS (ESI, pos.ion) m / z: 482.0 [M+Na] + . Step 5: Synthesis of (2S,4R)-2-((1,1-difluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine Pd / C (20 mg, 10%) was added to a solution of benzyl (2S,4R)-2-((1,1-difluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (56 mg, 0.12 mmol) in MeOH (6 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a colorless liquid (39 mg, 98%).

[0387] MS (ESI, pos.ion) m / z: 326.2 [M+H] + . Step 6: Synthesis of methyl 4-((2S,4R)-2-((1,1-difluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, (2S,4R)-2-((1,1-difluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine (35 mg, 0.11 mmol), Pd(dba) (10 mg, 0.01 mmol), XantPhos (10 mg, 0.01 mmol), CsCO (70 mg, 0.21 mmol), and methyl 4-iodobenzoate (42 mg, 0.16 mmol) were dissolved in 1,4-dioxane (4 mL), and the reaction mixture was heated and stirred in an oil bath at 100 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (40 mL), washed successively with saturated NaHCO3 solution (20 mL) and saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a yellow solid (16 mg, 32%).

[0388] MS (ESI, pos.ion) m / z: 460.3 [M+H] + . Step 7: Synthesis of 4-((2S,4R)-2-((1,1-difluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (30 mg, 0.72 mmol) in HO (1 mL) was added to a solution of methyl 4-((2S,4R)-2-((1,1-difluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (15 mg, 0.03 mmol) in MeOH (4 mL) and stirred at room temperature for 24 h. The reaction mixture was diluted with HO (10 mL) and the pH of the solution was adjusted to approximately 4 with HCl solution (1 mol / L). The mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a white solid (9 mg, 62%).

[0389] MS (ESI, pos.ion) m / z: 446.3 [M+H] + . Step 8: Synthesis of 4-((2S,4R)-2-((1,1-difluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide (R)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol (6 mg, 0.03 mmol), 4-((2S,4R)-2-((1,1-difluoroethoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (8 mg, 0.02 mmol), EDCI (6 mg, 0.03 mmol), HOBT (5 mg, 0.04 mmol), and TEA (5 mg, 0.05 mmol) were dissolved in DCM (2 mL) and stirred at room temperature for 21 h. The reaction mixture was diluted with DCM (40 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a white solid (7 mg, 59%).

[0390] MS (ESI, pos.ion) m / z: 657.5 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.87 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.0 Hz, 4H), 6.95 (d, J = 8.4 Hz, 3H), 6.63 (d, J = 8.6 Hz, 2H), 5.30 (s, 1H), 5.16 (s, 1H), 4.31 (s, 1H), 4.07 - 3.96 (m, 3H), 3.93 - 3.84 (m, 2H), 3.57 - 3.51 (m, 1H), 3.09 (q, J = 7.5 Hz, 2H), 2.54 - 2.44 (m, 2H), 1.75 (t, J = 13.1 Hz, 3H), 1.29 (t, J = 7.5 Hz, 3H). Example 43 4-((2S,4R)-2-((1,1-difluoropropoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide [ka] Step 1: Synthesis of methyl 4-((2S,4R)-2-(((1,1-difluoroallyl)oxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, NaH (101 mg, 2.53 mmol, 60%) was added to a solution of 3-bromo-3,3-difluoropropan-1-ene (0.40 mL, 3.91 mmol) and methyl 4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (200 mg, 0.51 mmol) in THF (6 mL), and the mixture was stirred at room temperature for 14 h. The reaction mixture was quenched by adding HCl solution (1 mol / L) and the pH of the solution was adjusted to about 5. The mixture was diluted with saturated NaCl solution (20 mL), extracted with EtOAc (30 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 6 / 1) to give a pale yellow liquid (90 mg, 38%).

[0391] MS (ESI, pos.ion) m / z: 472.1 [M+H] + . Step 2: Synthesis of methyl 4-((2S,4R)-2-((1,1-difluoropropoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Pd / C (20 mg, 10%) was added to a solution of methyl 4-((2S,4R)-2-(((1,1-difluoroallyl)oxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (90 mg, 0.19 mmol) in MeOH (6 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a colorless liquid (90 mg, 100%).

[0392] MS (ESI, pos.ion) m / z: 474.1 [M+H] + . Step 3: Synthesis of 4-((2S,4R)-2-((1,1-difluoropropoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (80 mg, 1.91 mmol) in HO (2 mL) was added to a solution of methyl 4-((2S,4R)-2-((1,1-difluoropropoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (90 mg, 0.19 mmol) in MeOH (6 mL) and stirred at room temperature for 15 h. The reaction mixture was diluted with HO (6 mL), and the pH of the solution was adjusted to approximately 5 with HCl solution (1 mol / L). The mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 4 / 1) to give a white solid (75 mg, 86%).

[0393] MS (ESI, pos.ion) m / z: 460.1 [M+H] + . Step 4: Synthesis of 4-((2S,4R)-2-((1,1-difluoropropoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide (R)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol (17 mg, 0.07 mmol), 4-((2S,4R)-2-((1,1-difluoropropoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (30 mg, 0.07 mmol), EDCI (18 mg, 0.09 mmol), HOBT (13 mg, 0.10 mmol), and TEA (10 mg, 0.10 mmol) were dissolved in DCM (4 mL) and stirred at room temperature for 18 h. The reaction mixture was diluted with DCM (40 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a white solid (30 mg, 69%).

[0394] MS (ESI, pos.ion) m / z: 671.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.86 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.1 Hz, 4H), 6.95 (d, J = 8.8 Hz, 2H), 6.92 (s, 1H), 6.64 (d, J = 8.8 Hz, 2H), 5.28 (d, J = 6.3 Hz, 1H), 5.19 - 5.14 (m, 1H), 4.33 (s, 1H), 4.07 - 3.95 (m, 3H), 3.91 (dd, J = 10.5, 6.0 Hz, 2H), 3.55 (dd, J = 10.5, 3.8 Hz, 1H), 3.09 (q, J = 7.4 Hz, 2H), 2.56 - 2.38 (m, 3H), 2.04 - 1.93 (m, 2H), 1.28 (t, J = 7.4 Hz, 3H), 1.04 (t, J = 7.5 Hz, 3H). Example 44 4-((2S,4R)-2-((3,3-difluoropropoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide [ka] Step 1: Synthesis of methyl 4-((2S,4R)-2-(((3,3-difluoroallyl)oxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, NaH (75 mg, 1.88 mmol, 60%) was added to a solution of 3-bromo-3,3-difluoropropan-1-ene (0.30 mL, 2.95 mmol) and methyl 4-((2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (150 mg, 0.38 mmol) in THF (6 mL), and the mixture was stirred at room temperature for 14 h. The reaction mixture was quenched by adding HCl solution (1 mol / L) and the pH of the mixture was adjusted to about 5. The mixture was diluted with saturated NaCl solution (20 mL), extracted with EtOAc (30 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 6 / 1) to give a pale yellow liquid (25 mg, 14%).

[0395] MS (ESI, pos.ion) m / z: 472.1 [M+H] + . Step 2: Synthesis of methyl 4-((2S,4R)-2-((3,3-difluoropropoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Pd / C (10 mg, 10%) was added to a solution of methyl 4-((2S,4R)-2-(((3,3-difluoroallyl)oxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (25 mg, 0.05 mmol) in MeOH (6 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a colorless liquid (25 mg, 100%).

[0396] MS (ESI, pos.ion) m / z: 474.1 [M+H] + . Step 3: Synthesis of 4-((2S,4R)-2-((3,3-difluoropropoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (50 mg, 1.19 mmol) in HO (1 mL) was added to a solution of methyl 4-((2S,4R)-2-((3,3-difluoropropoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (25 mg, 0.05 mmol) in MeOH (4 mL) and stirred at room temperature for 24 h. HO (10 mL) was added to the reaction mixture, and the pH of the solution was adjusted to approximately 4 with HCl solution (1 mol / L). The mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: DCM / EtOAc (v / v) = 4 / 1) to give a white solid (15 mg, 62%).

[0397] MS (ESI, pos.ion) m / z: 460.1 [M+H] + . Step 4: Synthesis of 4-((2S,4R)-2-((3,3-difluoropropoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide (R)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol (11 mg, 0.05 mmol), 4-((2S,4R)-2-((3,3-difluoropropoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid (15 mg, 0.03 mmol), EDCI (12 mg, 0.06 mmol), HOBT (8 mg, 0.06 mmol), and TEA (6 mg, 0.06 mmol) were dissolved in DCM (2 mL) and stirred at room temperature for 13 h. The reaction mixture was diluted with DCM (40 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a white solid (15 mg, 69%).

[0398] MS (ESI, pos.ion) m / z: 671.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.86 (d, J = 7.8 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.1 Hz, 4H), 7.01 (s, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 8.3 Hz, 2H), 6.06 - 5.75 (m, 1H), 5.28 (s, 1H), 5.21 (s, 1H), 4.29 (s, 1H), 4.07 - 3.95 (m, 2H), 3.90 (dd, J = 10.3, 5.9 Hz, 1H), 3.62 - 3.52 (m, 4H), 3.10 (q, J = 7.3 Hz, 2H), 2.56 - 2.50 (m, 1H), 2.47 - 2.39 (m, 1H), 2.30 - 2.20 (m, 1H), 2.14 - 2.03 (m, 2H), 1.29 (t, J = 7.3 Hz, 3H). Example 45 4-((2S,4S)-2-((1,1-difluoropropoxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide [ka] Using (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate as the starting material, the title compound was prepared as a white solid (60 mg, 69%) by following the procedures of Steps 1 to 4 in Example 18 and Steps 1 to 4 in Example 43.

[0399] MS (ESI, pos.ion) m / z: 671.1 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.84 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 9.3 Hz, 2H), 7.56 (d, J = 9.3 Hz, 2H), 7.00 (d, J = 6.4 Hz, 1H), 6.98 (d, J = 8.7 Hz, 2H), 6.65 (d, J = 8.6 Hz, 2H), 5.26 (s, 1H), 5.16 (s, 1H), 4.22 - 4.14 (m, 2H), 4.02 (dd, J = 11.2, 3.5 Hz, 1H), 3.97 - 3.91 (m, 2H), 3.75 - 3.67 (m, 2H), 3.08 (q, J = 7.4 Hz, 2H), 2.49 (d, J = 14.3 Hz, 1H), 2.41 - 2.32 (m, 1H), 1.99 - 1.89 (m, 2H), 1.28 (t, J = 7.4 Hz, 3H), 1.00 (t, J = 7.5 Hz, 3H). Example 46 4-((2R,4R)-2-(2-(difluoromethoxy)ethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide [ka] Step 1: Synthesis of tert-butyl (2S,4R)-2-(((methylsulfonyl)oxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate Under nitrogen gas protection, MsCl (0.15 mL, 1.90 mmol) was added to a solution of TEA (0.40 mL, 2.87 mmol) and tert-butyl (2S,4R)-2-(hydroxymethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (345 mg, 0.95 mmol) in DCM (8 mL) and stirred at room temperature for 15 h. The reaction mixture was quenched by the addition of saturated NaCl solution (20 mL), diluted with DCM (50 mL), and the organic layer was extracted and separated. The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure to give a pale yellow liquid (419 mg, 100%).

[0400] MS (ESI, pos.ion) m / z: 462.3 [M+Na] + . Step 2: Synthesis of tert-butyl (2R,4R)-2-(cyanomethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (2S,4R)-tert-Butyl 2-(((methylsulfonyl)oxy)methyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (400 mg, 0.91 mmol) and N(n-Bu)CN (366 mg, 1.36 mmol) were added to ACN (8 mL), and the reaction mixture was heated and stirred in an oil bath at 85 °C for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a colorless liquid (230 mg, 68%).

[0401] MS (ESI, pos.ion) m / z: 315.2 [M-56+H] + . Step 3: Synthesis of methyl 2-((2S,4R)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-2-yl)acetate A solution of HCl in methanol (6 mL, 20%) was added to a solution of tert-butyl (2R,4R)-2-(cyanomethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (1.30 g, 3.51 mmol) in MeOH (4 mL), and the reaction mixture was heated and stirred in an oil bath at 80 °C for 24 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was washed with saturated NaHCO3 solution (30 mL) and extracted with EtOAc (40 mL × 2). The combined organic phases were washed with saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a brown liquid (780 mg, 73%).

[0402] MS (ESI, pos.ion) m / z: 304.3 [M+H] + . Step 4: Synthesis of 2-((2R,4R)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-2-yl)ethanol LiBH (200 mg, 9.18 mmol) was added to methyl 2-((2S,4R)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-2-yl)acetate (700 mg, 2.31 mmol) in THF (12 mL) and stirred at room temperature for 15 h. The reaction mixture was quenched by adding saturated NH Cl (15 mL) solution, allowed to stand, and the layers were separated. The upper organic layer was separated and removed, and the aqueous layer was extracted with EtOAc (15 mL × 2). The combined organic layers were washed with saturated NaCl solution (15 mL), dried over anhydrous Na SO , and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) to give a brown liquid (100 mg, 16%).

[0403] MS (ESI, pos.ion) m / z: 276.3 [M+H] + . Step 5: Synthesis of methyl 4-((2R,4R)-2-(2-hydroxyethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate Under nitrogen gas protection, 2-((2R,4R)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-2-yl)ethanol (100 mg, 0.36 mmol), Pd(dba) (33 mg, 0.04 mmol), XantPhos (31 mg, 0.05 mmol), CsCO (177 mg, 0.54 mmol), and methyl 4-iodobenzoate (123 mg, 0.47 mmol) were dissolved in 1,4-dioxane (8 mL), and the reaction mixture was heated and stirred in an oil bath at 100 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (40 mL), washed successively with saturated NaHCO3 solution (15 mL) and saturated NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to give a brown liquid (31 mg, 21%).

[0404] MS (ESI, pos.ion) m / z: 410.2 [M+H] + . Step 6: Synthesis of methyl 4-((2R,4R)-2-(2-(difluoromethoxy)ethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate TMSCFBr (0.20 mL, 1.29 mmol) was added to a solution of methyl 4-((2R,4S)-2-(2-hydroxyethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (30 mg, 0.07 mmol) and KOAc (90 mg, 0.92 mmol) in DCM / HO (1 mL / 1 mL) and stirred at room temperature for 14 h. The reaction mixture was added with DCM (20 mL), washed with saturated NaCl (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 5 / 1) to give a pale yellow liquid (19 mg, 56%).

[0405] MS (ESI, pos.ion) m / z: 460.3 [M+H] + . Step 7: Synthesis of 4-((2R,4R)-2-(2-(difluoromethoxy)ethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoic acid A solution of LiOH·HO (34 mg, 0.81 mmol) in HO (1 mL) was added to a solution of methyl 4-((2R,4R)-2-(2-(difluoromethoxy)ethyl)-4-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)benzoate (19 mg, 0.04 mmol) in MeOH (2 mL) and stirred at room temperature for 24 h. HO (10 mL) was added to the reaction mixture, and the pH of the solution was adjusted to approximately 4 with HCl solution (1 mol / L). The mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with saturated NaCl solution (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. T...

Claims

1. A compound which is a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, hydrate, solvate or pharma- ceutically acceptable salt of a compound of formula (I). 【Chemistry 1】 (In the formula, R is a C1-4 alkyl group, a C3-6 cycloalkylamino group, or a -C1-4 alkylene-C3-6 cycloalkyl group; Z １ , Z ２ , Z ３ , Z ４ , Z ５ , Z ６ , Z ７ and Z ８ are each independently １ or N, Each R １ are independently hydrogen, deuterium, cyano, fluorine, chlorine, bromine, iodine, a C1-4 alkyl group, a C1-4 halogenated alkyl group, a hydroxy-substituted C1-4 alkyl group, a -C1-4 alkylene-C1-4 alkoxy group or a C1-4 alkoxy group; The A ring is 【Chemistry 2】 wherein * represents the direction in which ring A and ring C are bonded, and ring A is optionally substituted with 1, 2, 3, 4 or 5 R 2 ; Each R ２ are independently an oxo group, R ａ , C1-4 alkyl group, -C1-4 alkylene-R ａ , -OR ｂ , —C1-4 alkylene-OR ｂ , -C(=O)-R ａ , —C1-4 alkylene-C(═O)—R ａ , -C(=O)-NR ｃ R ｄ Or -C1-4 alkylene-C(=O)-NR ｃ R ｄ and Each R ａ are independently deuterium, fluorine, chlorine, bromine, iodine, a hydroxyl group, an amino group, a nitro group, a cyano group, a C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 halogenated alkyl group, a C3-6 cycloalkyl group, a 3- to 7-membered heterocyclic group or a 5- to 12-membered spiroheterocyclic group; Each R ｂ , R ｃ and R ｄ are independently hydrogen, deuterium, a C1-4 alkyl group, a C1-4 halogenated alkyl group, a C1-4 alkoxy group, a C3-6 cycloalkyl group or a 3- to 7-membered heterocyclic group; Each of the R ａ , R ｂ , R ｃ and R ｄ independently represents 1, 2, 3, 4, 5 or 6 R ｇ optionally replaced by Each R ｇ are independently deuterium, fluorine, chlorine, bromine, iodine, oxo, hydroxyl group, amino group, nitro group, cyano group, C1-4 alkyl group, C1-4 halogenated alkyl group, C1-4 alkoxy group, C1-4 halogenated alkoxy group, C3-6 cycloalkyl group or 3- to 7-membered heterocyclic group, B ring is C ６－１０ an aryl group, a 3- to 7-membered heterocyclic group, or a 4- to 12-membered fused heterocyclic group, and the B ring is one, two, three, or four R ｅ optionally replaced by Each R ｅ are independently deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, amino, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, 3- to 7-membered heterocyclic, C1-4 halogenated alkyl or C1-4 halogenated alkoxy, wherein the C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, 3- to 7-membered heterocyclic, C1-4 halogenated alkyl and C1-4 halogenated alkoxy are optionally substituted by 1, 2, 3 or 4 substituents independently selected from a cyano, a nitro, a hydroxyl, an amino or a 3- to 7-membered heterocyclic; L １ is -C(=O)NH- or -NHC(=O)-, L ２ is -CR ３ R ４ - and L ３ is -S-, -O-, -NR ５ -or- ６ R ７ - and R ３ is hydrogen, deuterium, a hydroxy-substituted C1-4 alkyl group, -C1-4 alkylene-O-C(=O)-R ｆ Or -C1-4 alkylene-R ｆ and R ｆ represents a C2-4 alkyl group, an amino-substituted C1-4 alkyl group, a C1-4 halogenated alkyl group, -C1-4 alkylene-C(=O)-OR ｈ Or -O-P(=O)-(OR ｍ ) (OR ｎ ) and R ｈ , R ｍ and R ｎ are each independently hydrogen, deuterium, sodium, potassium, a C1-4 alkyl group, or a C1-4 halogenated alkyl group; R ４ is hydrogen, deuterium or a hydroxy-substituted C1-4 alkyl group; R ５ is hydrogen, deuterium, C １－４ Alkyl group or C １－４ is a halogenated alkyl group, Each R ６ and R ７ are independently hydrogen, deuterium, C １－４ Alkyl group or C １－４ It is a halogenated alkyl group.

2. In the formula, R is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropylamino group, a cyclobutylamino group, a cyclopentylamino group, a cyclohexylamino group, a methylene-cyclopropyl group, a methylene-cyclobutyl group, a methylene-cyclopentyl group, a methylene-cyclohexyl group, an ethylene-cyclopropyl group, an ethylene-cyclobutyl group, an ethylene-cyclopentyl group, or an ethylene-cyclohexyl group; Each R １ are independently hydrogen, deuterium, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, -CH ２ F, -CHF ２ , -CF ３ , -CHFCH ２ F, -CF ２ CH ３ , -CH ２ CHF ２ , -CH ２ CF ３ , a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a hydroxymethyl group, a 2-hydroxyethyl group, a methylenemethoxy group, a methyleneethoxy group, a methylene-n-propoxy group, or a methyleneisopropoxy group.

3. In the formula, ring B is a phenyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a pyridyl group, a pyrimidinyl group, a pyrrole group, a pyrazolyl group, a thiazolyl group, an imidazolyl group, a furanyl group, an oxazolyl group, an isoxazolyl group, a thienyl group, a triazole group, a tetrazolium group, a piperazinyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, an azetidinyl group, an oxetanyl group, 【Chemistry 3】 and the B ring is selected from the group consisting of 1, 2, 3, or 4 R ｅ optionally replaced by Each R ｅ are independently deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro group, hydroxyl group, methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, azetidinyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, piperidinyl group, piperazinyl group, oxepanyl group, -CH ２ F, -CHF ２ , -CF ３ , -CHFCH ２ F, -CF ２ CH ３ , -CH ２ CHF ２ , -CH ２ CF ３ , -CF ２ CH ２ CH ３ , -CH ２ CH ２ CHF ２ , -CF ２ CH ２ F, -CF ２ CHF ２ , -CF ２ CF ３ , -OCH ２ F, -OCHF ２ , -OCF ３ , -OCHFCH ２ F, -OCF ２ CH ３ , -OCH ２ CHF ２ , -OCH ２ CF ３ , -OCF ２ CH ２ CH ３ , -OCH ２ CH ２ CHF ２ , -OCF ２ CH ２ F, -OCF ２ CHF ２ Or -OCF ２ CF ３ and the above-mentioned methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, azetidinyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, piperidinyl group, piperazinyl group, oxepanyl group, -CH ２ F, -CHF ２ , -CHFCH ２ F, -CF ２ CH ３ , -CH ２ CHF ２ , -CH ２ CF ３ , -CF ２ CH ２ CH ３ , -CH ２ CH ２ CHF ２ , -CF ２ CH ２ F, -CF ２ CHF ２ , -OCH ２ F, -OCHF ２ , -OCHFCH ２ F, -OCF ２ CH ３ , -OCH ２ CHF ２ , -OCH ２ CF ３ , -OCF ２ CH ２ CH ３ , -OCH ２ CH ２ CHF ２ , -OCF ２ CH ２ F and -OCF ２ CHF ２ is optionally substituted with 1, 2, 3 or 4 substituents independently selected from cyano, nitro, hydroxyl, amino, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, azetidinyl or oxetanyl groups.

4. In the formula, R ３ is hydrogen, deuterium, hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxy-n-propyl group, 2-hydroxy-1-methylethyl group, -CH ２ O.C.(=O)R ｆ , -CH ２ CH ２ O.C.(=O)R ｆ , -CH ２ CH ２ CH ２ O.C.(=O)R ｆ , -CH(CH ３ ) ２ O.C.(=O)R ｆ , -CH ２ R ｆ , -CH ２ CH ２ R ｆ , -CH ２ CH ２ CH ２ R ｆ or -CH(CH ３ ) ２ R ｆ and R ｆ is an ethyl group, an n-propyl group, an isopropyl group, -CH ２ N.H. ２ , -CH ２ CH ２ N.H. ２ , -CH ２ CH ２ CH ２ N.H. ２ , -CH(NH ２ )CH(CH ３ ) ２ , -CH ２ F, -CHF ２ , -CF ３ , -CHFCH ２ F, -CF ２ CH ３ , -CH ２ CHF ２ , -CH ２ CF ３ , -CH ２ C(=O)ONa, -CH ２ CH ２ C(=O)-ONa, -CH ２ CH ２ CH ２ C(=O)ONa, -CH(CH ３ ) ２ C(=O)ONa or -O-P(=O)(ONa) ２ and R ４ is hydrogen, deuterium, a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxyethyl group, a 3-hydroxy-n-propyl group, or a 2-hydroxy-1-methylethyl group.

5. Each R ２ are independently oxo, R ａ , methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, tert-butyl group, —CH ２ R ａ , -CH ２ CH ２ R ａ , -CH ２ CH ２ CH ２ R ａ , -C(CH ３ ) ２ R ａ , -CH(CH ３ ) CH ２ R ａ , -OR ｂ , -CH ２ OR ｂ , -CH ２ CH ２ OR ｂ , -CH ２ CH ２ CH ２ OR ｂ , -C(CH ３ ) ２ OR ｂ , -CH(CH ３ ) CH ２ OR ｂ , -C(=O)-R ａ , -CH ２ C(=O)-R ａ , -CH ２ CH ２ C(=O)-R ａ , -CH ２ CH ２ CH ２ C(=O)-R ａ , -C(CH ３ ) ２ C(=O)-R ａ , -CH(CH ３ ) CH ２ C(=O)-R ａ , -C(=O)-NR ｃ R ｄ , -CH ２ C(=O)-NR ｃ R ｄ , -CH ２ CH ２ C(=O)-NR ｃ R ｄ , -CH ２ CH ２ CH ２ C(=O)-NR ｃ R ｄ , -C(CH ３ ) ２ C(=O)-NR ｃ R ｄ or -CH(CH ３ ) CH ２ C(=O)-NR ｃ R ｄ The compound according to any one of claims 1 to 4,

6. Each R ａ are independently deuterium, fluorine, chlorine, bromine, iodine, a hydroxyl group, an amino group, a nitro group, a cyano group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a s-butyl group, a tert-butyl group, a methoxy group, an ethoxy group, an isopropoxy group, -CH ２ F, -CHF ２ , -CF ３ , -CHFCH ２ F, -CF ２ CH ３ , -CH ２ CHF ２ , -CH ２ CF ３ , -CF ２ CH ２ CH ３ , -CH ２ CH ２ CHF ２ , -CF ２ CH ２ F, -CF ２ CHF ２ , -CF ２ CF ３ , an oxetanyl group, an azetidinyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a morpholinyl group, a thiomorpholinyl group, a piperidinyl group, a piperazinyl group, an oxepanyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, 【Chemistry 4】 and Each R ｂ , R ｃ and R ｄ are independently hydrogen, deuterium, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a s-butyl group, a tert-butyl group, -CH ２ F, -CHF ２ , -CF ３ , -CHFCH ２ F, -CF ２ CH ３ , -CH ２ CHF ２ , -CH ２ CF ３ , -CF ２ CH ２ CH ３ , -CH ２ CH ２ CHF ２ , -CF ２ CH ２ F, -CF ２ CHF ２ , -CF ２ CF ３ , a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an oxetanyl group, an azetidinyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a morpholinyl group, a thiomorpholinyl group, a piperidinyl group, a piperazinyl group, or an oxepanyl group, Each of the R ａ , R ｂ , R ｃ and R ｄ independently represents 1, 2, 3, 4, 5 or 6 R ｇ The compound of any one of claims 1 to 5, optionally substituted with

7. Each R ｇ are independently deuterium, fluorine, chlorine, bromine, iodine, oxo, hydroxyl group, amino group, nitro group, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, tert-butyl, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, -CH ２ F, -CHF ２ , -CF ３ , -CHFCH ２ F, -CF ２ CH ３ , -CH ２ CHF ２ , -CH ２ CF ３ , -CF ２ CH ２ CH ３ , -CH ２ CH ２ CHF ２ , -CF ２ CH ２ F, -CF ２ CHF ２ , -CF ２ CF ３ , -OCH ２ F, -OCHF ２ , -OCF ３ , -OCHFCH ２ F, -OCF ２ CH ３ , -OCH ２ CHF ２ , -OCH ２ CF ３ , -OCF ２ CH ２ CH ３ , -OCH ２ CH ２ CHF ２ , -OCF ２ CH ２ F, -OCF ２ CHF ２ , -OCF ２ CF ３ , a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an oxetanyl group, an azetidinyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a morpholinyl group, a thiomorpholinyl group, a piperidinyl group, a piperazinyl group, or an oxepanyl group.

8. R ５ represents hydrogen, deuterium, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, s-butyl, tert-butyl, -CH ２ F, -CHF ２ , -CF ３ , -CHFCH ２ F, -CF ２ CH ３ , -CH ２ CHF ２ or CH ２ CF3, Each R ６ and R ７ are independently hydrogen, deuterium, a methyl group, an ethyl group, an isopropyl group, an n-propyl group, an n-butyl group, an isobutyl group, a s-butyl group, a tert-butyl group, -CH ２ F, -CHF ２ , -CF ３ , -CHFCH ２ F, -CF ２ CH ３ , -CH ２ CHF ２ or -CH ２ The compound according to any one of claims 1 to 7, which is CF3.

9. 9. The compound of any one of claims 1 to 8, which is a compound having the structure of one of the following formulas, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, or pharmacologically acceptable salt thereof: 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, a pharma- ceutically acceptable excipient, carrier, adjuvant, or a combination thereof.

11. The pharmaceutical composition according to claim 10, further comprising as other active ingredients a drug for treating cancer, a drug for preventing or treating inflammatory syndromes, a drug for preventing or treating autoimmune diseases, or any combination thereof.

12. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11 in the manufacture of a medicament for the prevention or treatment of a disease, disorder or syndrome mediated by RORγt in a mammal.

13. The RORγt-mediated disease, disorder or syndrome is cancer, inflammation or an autoimmune disease; or The use according to claim 12, wherein the disease, disorder or syndrome mediated by RORγt is cancer, psoriasis, 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.

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