CN113072521A

CN113072521A - ROR gamma t inhibitor and application thereof in medicine

Info

Publication number: CN113072521A
Application number: CN202011615479.1A
Authority: CN
Inventors: 刘兵; 潘伟; 张英俊; 何为; 王峰; 李旭珂; 许娟
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2020-01-06
Filing date: 2020-12-31
Publication date: 2021-07-06
Anticipated expiration: 2040-12-31
Also published as: CN113072521B

Abstract

The invention relates to a ROR gamma t inhibitor compound which is a compound shown as a formula (I). The compounds, or pharmaceutical compositions comprising the compounds, are useful for modulating retinoic acid-related orphan receptor gamma t (ROR γ t). The invention also relates to a method for preparing the compounds and/or pharmaceutical compositions, and application of the compounds and/or pharmaceutical compositions in preparing medicines for treating or preventing inflammatory or autoimmune diseases mediated by ROR gamma t in mammals, particularly human beings.

Description

ROR gamma t inhibitor and application thereof in medicine

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a small molecular compound, a composition, a preparation method and application thereof, wherein the compound or the composition can be used as an inhibitor of retinoic acid-related orphan receptor gamma t (ROR gamma t) and is used for preventing or treating diseases related to immunity.

Background

Retinoic acid-related nocosomal receptors are a subfamily of transcription factors in the steroid hormone nuclear receptor superfamily. The family of retinoic acid-related orphan nuclear receptors includes ROR α, ROR β, and ROR γ, each encoded by a distinct gene (RORA, RORB, and RORC). Retinoic acid-related orphan nuclear receptors contain four major domains: an N-terminal A/B domain, a DNA binding domain, a hinge domain, and a ligand binding domain.

Retinoic acid-related orphan receptor gamma t (ROR γ t) is one of two isoforms of retinoic acid-related orphan receptor gamma (ROR γ), and may also be referred to as ROR γ 2. It has been shown that ROR γ t is expressed only in lymphoid lineage and embryonic lymphoid tissue inducer cells (Sun et al, Science 288:2369-2372, 2000; Eberl et al, Nat Immunol.5:64-73,2004). ROR gamma T, a characteristic transcription factor of helper T cells (Th17), plays an important role in Th17 cell differentiation, and is a key regulator of Th17 cell differentiation (Ivanov, II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. cell 2006; 126(6): 1121-33).

Th17 can secrete interleukin 17 (IL-17) and other proinflammatory cytokines, and has important significance in autoimmune diseases and body defense response. IL-17 is a proinflammatory cytokine for inflammatory progression and various autoimmune diseases, and is closely associated with a variety of autoimmune and inflammatory diseases, such as rheumatoid arthritis, psoriasis, psoriatic arthritis, spondyloarthritis, asthma, inflammatory bowel disease, systemic lupus erythematosus, and multiple sclerosis, among others (Jetten et al, Nucl. Recept. Signal,2009,7: e 003; Manel et al, Nat. Immunol.,2008,9, 641-649).

The role ROR γ t plays in the pathogenesis of autoimmune diseases or inflammation has been extensively studied and fully elucidated (Jetten et al, adv. Dev. biol., 2006,16: 313-supplement 355; Meier et al Immunity,2007,26: 643-654; Aloisi et al, Nat. Rev. Immunol.,2006,6: 205-supplement 217; Jager et al., J. Immunol.,2009,183: 7169-supplement 7177; Barnes et al, Nat. Rev. Immunol.,2008,8: 183-supplement 192). Therefore, inhibition of ROR γ t will effectively inhibit cell differentiation of Th17, regulate the production and secretion levels of IL-17 and other proinflammatory cytokines, thereby modulating the body's immune system, treating immune and inflammatory diseases associated with ROR γ t regulation.

Summary of The Invention

The following is a summary of some aspects of the invention only and is not intended to be limiting. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.

The invention provides a compound with retinoic acid-related orphan receptor gamma t (ROR gamma t) inhibitory activity, which is used for preparing a medicament for preventing or treating ROR gamma t-mediated inflammation or autoimmune diseases, such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ophthalmopathy, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, Crohn's disease or Kawasaki disease and the like; the compound can well inhibit ROR gamma t, and has excellent physicochemical property and pharmacokinetic property.

The invention also provides processes for the preparation of these compounds, pharmaceutical compositions containing these compounds and methods of using these compounds or compositions in the treatment of the above-mentioned diseases in mammals, especially humans.

Specifically, the method comprises the following steps:

in one aspect, the invention relates to a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (I),

wherein:

r is C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_3-6Cycloalkylamino, -C_1-4alkylene-C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical, C_1-4Haloalkyl or C_1-4A haloalkoxy group;

Z¹、Z²、Z³、Z⁴、Z⁵、Z⁶、Z⁷and Z⁸Each independently is CR¹Or N;

each R¹Independently hydrogen, deuterium, cyano, fluoro, chloro, bromo, iodo, C_1-6Alkyl radical, C_1-6Haloalkyl, hydroxy-substituted C_1-6Alkyl, -C_1-6alkylene-C_1-6Alkoxy radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

ring A is a 6-membered heterocyclic ring, said 6-membered heterocyclic ring optionally substituted with 1,2,3 or 4R²Substitution;

each R²Independently is fluorine, chlorine, bromine, iodine, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_6-10Aryl radical, C_3-8Cycloalkyl, -C_0-6alkylene-OR^a、-C_0-4Alkylene- (C (═ O))_m-R^b、-C_0-4Alkylene- (O)_n-(C(＝O))_m-NR^cR^d5-10 membered heteroaryl, -C_0-4Alkylene- (3-7 membered heterocyclyl), -C_0-4Alkylene- (5-12 membered spiroheterocyclyl) or-C_0-4Alkylene- (4-12 membered fused heterocyclyl); the R is²Optionally substituted by 1,2 or 3R^fSubstitution;

or, optionally, two attached to the same carbon atomR²Together with the carbon atom to which they are attached form C_3-6Cycloalkyl or a 4-6 membered heterocyclic ring;

each R^aIndependently of one another is hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_6-10Aryl radical, C_3-8Cycloalkyl, 5-10 membered heteroaryl, 3-7 membered heterocyclyl, 5-12 membered spiroheterocyclyl or 4-12 membered fused heterocyclyl; each R^b、R^cAnd R^dIndependently hydrogen, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_6-10Aryl radical, C_3-8Cycloalkyl, 4-12 membered fused ring group, 5-12 membered spiro ring group, 5-10 membered heteroaryl, 3-7 membered heterocyclyl, 5-12 membered spiro heterocyclyl or 4-12 membered fused heterocyclyl; or R^c、R^dAnd the N atom to which they are attached together form a 4-7 membered heterocyclic ring; each of said R^a、R^b、R^cAnd R^dIndependently optionally substituted by 1,2,3,4, 5 or 6R^gSubstitution;

each R^fAnd R^gIndependently fluorine, chlorine, bromine, iodine, oxo, hydroxyl, amino, nitro, cyano, C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_1-6Haloalkyl, C_6-10Aryl radical, C_3-8Cycloalkyl, 4-12 membered fused carbocyclic group, 5-12 membered spiro carbocyclic group, 5-10 membered heteroaryl, 3-12 membered heterocyclic group, 5-12 membered spiro heterocyclic group, 4-12 membered fused heterocyclic group, C_1-6Alkoxy radical, C_1-6Alkylamino or C_1-6A haloalkoxy group;

ring B is C_6-10Aryl, 4-12 membered fused heterocyclic group, 4-12 membered fused carbocyclic group, 5-12 membered spiro carbocyclic group or C_3-8Cycloalkyl, wherein said B ring is optionally substituted with 1,2,3 or 4R^eSubstitution;

each R^eIndependently is deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl, 3-8 membered heterocyclyl, hydroxy-substituted C_1-4Alkyl, hydroxy substituted C_1-4Haloalkyl, C_1-4Haloalkyl or C_1-4A haloalkoxy group;

or, any two adjacent R^eAnd together with the atom to which they are attached form C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

wherein, said C_1-4Alkoxy is optionally substituted by 1-3-6 membered heterocyclyl or C_3-8Cycloalkyl substitution;

L¹is-S (═ O)₂-NH-、-NH-S(＝O)₂-, -S (═ O) -NH-, -NH-S (═ O) -, -C (═ O) NH-or-NHC (═ O) -;

L²is-CR³R⁴；

L³Is carbonyl, -S-, -O-, -NR⁵-or-CR⁶R⁷-；

R³Is hydrogen, hydroxy-substituted C_1-6Alkyl or cyano-substituted C_1-6An alkyl group;

R⁴is hydrogen, hydroxy-substituted C_1-6Alkyl or cyano-substituted C_1-6An alkyl group;

R⁵is hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl or 3-6 membered heterocyclyl;

each R⁶And R⁷Independently of one another is hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_3-8Cycloalkyl or 3-6 membered heterocyclyl;

each m and n is independently 0 or 1.

In some embodiments, R is methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1, 2-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, ethylamino, dimethylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylenecyclohexyl, ethylenecyclopropyl, ethylenecyclobutyl, ethylenecyclopentyl, ethylenecyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, each R is¹Independently of each other hydrogen, deuteriumCyano, fluoro, chloro, bromo, iodo, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, 1, 2-difluoroethyl, 1-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethylene, ethoxymethylene, n-propoxymethyl, isopropoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, R³Is hydrogen, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, cyanomethyl, cyanoethyl or cyano-n-propyl; r⁴Is hydrogen, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, cyanomethyl, cyanoethyl or cyano-n-propyl.

In some embodiments, the B ring is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Said B ring being optionally substituted with 1,2,3 or 4R^eAnd (4) substitution.

In some embodiments, each R is^eIndependently deuterium, fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxy-n-propyl, 2-hydroxy-1, 1,1,3,3, 3-hexafluoroisopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1, 2-difluoroethyl, methoxy, ethoxy, n-propoxy, t-butoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or 1, 2-difluoroethoxy; wherein said methoxy, ethoxy, n-propoxy, t-butoxy are optionally substituted with 1 substituent selected from the group consisting of oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl.

In some embodiments, R⁵Is hydrogen, methyl, ethyl, isopropyl, n-propyl, isobutyl, tert-butyl, n-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1, 2-difluoroethyl, 2-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl or azetidinyl;

each R⁶And R⁷Independently hydrogen, methyl, ethyl, isopropyl, n-propyl, isobutyl, tert-butyl, n-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1, 2-difluoroethyl, 1-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1, 2-difluoroethoxy, 2-difluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl or piperazinyl.

In some embodiments, ring a is

Wherein said A ring is optionally substituted with 1,2,3 or 4R²And (4) substitution.

In some embodiments, each R is²Independently fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, phenyl, C_3-6Cycloalkyl, -C_0-4alkylene-OR^a、-C_0-4Alkylene- (C (═ O))_m-R^b、-C_0-4Alkylene- (O)_n-(C(＝O))_m-NR^cR^d5-6 membered heteroaryl, -C_0-4Alkylene- (3-7 membered heterocyclyl), -C_0-4Alkylene- (5-12 membered spiroheterocyclyl) or-C_0-4Alkylene- (4-12 membered fused heterocyclyl); wherein, R is²Optionally substituted by 1,2 or 3R^fSubstitution; or, optionally, two R's attached to the same carbon atom²And with itThe carbon atoms to which they are attached together form C_3-6Cycloalkyl or a 4-6 membered heterocyclic ring.

In some embodiments, each R is^aIndependently of one another is hydrogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_6-10Aryl radical, C_3-6Cycloalkyl, 5-7 membered heteroaryl, or 3-7 membered heterocyclyl; each R^b、R^cAnd R^dIndependently hydrogen, hydroxy, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_6-10Aryl radical, C_3-6Cycloalkyl, 3-7 membered heterocyclyl or 5-12 membered spiroheterocyclyl; or R^c、R^dAnd the N atom to which they are attached together form a 4-7 membered heterocyclic ring;

wherein each R is^a、R^b、R^cAnd R^dIndependently optionally substituted by 1,2,3,4, 5 or 6R^gAnd (4) substitution.

In some embodiments, each R is²Independently fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 1-difluoroethyl, 1, 2-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OR^a、-CH₂-OR^a、-CH₂CH₂-OR^a、-CH₂(CH₂)₂-OR^a、-CH₂CH(CH₃)-OR^a、-C(CH₃)₂CH₂-OR^a、-CH₂(CH₂)₃-OR^a、-CH(CH₃)CH(CH₃)-OR^a、-CH₂C(CH₃)₂-OR^a、-(C＝O)_m-R^b、-CH₂-(C(＝O))_m-R^b、-CH₂CH₂-(C(＝O))_m-R^b、-CH₂(CH₂)₂-(C(＝O))_m-R^b、-CH₂CH(CH₃)-(C(＝O))_m-R^b、-C(CH₃)₂CH₂-(C(＝O))_m-R^b、-CH₂(CH₂)₃-(C(＝O))_m-R^b、-CH(CH₃)CH(CH₃)-(C(＝O))_m-R^b、-CH₂C(CH₃)₂-(C(＝O))_m-R^b、-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂CH₂-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂(CH₂)₂-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂CH(CH₃)-(O)_n-(C(＝O))_m-NR^cR^d、-C(CH₃)₂CH₂-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂(CH₂)₃-(O)_n-(C(＝O))_m-NR^cR^d、-CH(CH₃)CH(CH₃)-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂C(CH₃)₂-(O)_n-(C(＝O))_m-NR^cR^dOxazolyl, thiazolyl, thienyl, imidazolyl, pyridazinyl, pyridyl,

Wherein, R is²Optionally substituted by 1,2 or 3R^fSubstitution;

or, optionally, two R's attached to the same carbon atom²And together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazoleAlkyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl.

In some embodiments, each R is^aIndependently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 2, 2-difluoroethyl, 1, 2-difluoroethyl, 2,2, 2-trifluoroethyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, 2-difluoroethyl, trifluoromethyl, and mixtures thereof,

Phenyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, oxepanyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; each R^b、R^cAnd R^dIndependently hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 2, 2-difluoroethyl, 1, 2-difluoroethyl, 2,2, 2-trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, oxacycloheptanyl,

Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R^cAnd R^dTogether with the N atom to which they are attached form a 4-7 membered heterocyclic ring;

In some embodiments, each R is^fAnd R^gIndependently fluorine, chlorine, bromine, iodine, oxo, hydroxy, amino, nitroRadical, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH₂OH, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 1-difluoroethyl, 1, 2-difluoroethyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxa-ethyl, 1, 2-difluoroethyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl, oxiranyl, oxa-cyclobutyl, tetrahydrofuranyl, trifluoromethyl,

cyclopropyl, cyclobutyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) of the present invention or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant or combination thereof.

In some embodiments, the pharmaceutical composition of the present invention comprises other drugs or any combination thereof for preventing or treating inflammatory syndromes or autoimmune diseases.

In another aspect, the invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof in the manufacture of a medicament for the prevention or treatment of an inflammatory or autoimmune disease mediated by roryt in a mammal.

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 the prevention or treatment of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ocular disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, crohn's disease, or kawasaki disease.

In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).

Biological test results show that the compound provided by the invention has good inhibitory activity on ROR gamma t and good pharmacokinetic characteristics.

Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

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

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 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.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of 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.

Many organic compounds exist in an optically active form, 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 a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

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

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be isolated by chiral chromatography, e.g., high performance liquid chromatography using a chiral adsorbent (HPLC: column: Chiralpak AD-H (4.6 mm. times.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, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)^nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, a substituted group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.

The term "unsubstituted" means that the specified group bears no substituent.

The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with … …", i.e., the structure is unsubstituted or substituted with one or more substituents as described herein. Substituents described herein include, but are not limited to, D, oxo (═ O), F, Cl, Br, I, N₃、CN、NO₂、OH、SH、NH₂Carboxyl, aldehyde, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, carbocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -alkylene-cycloalkyl, cycloalkylamino, -alkylene-alkoxy, and the like.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C_1-6Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon radical, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 3 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms. In yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t)-Bu、-C(CH₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl, n-octyl, and the like.

The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms; in another embodiment, the alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 2 carbon atoms. Examples of this include methylene (-CH)₂-, ethylene (-CH)₂CH₂-, isopropylidene (-CH (CH)₃)CH₂-) and the like.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 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; 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 described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) 1-pentyloxy (n-pentyloxy, -OCH)₂CH₂CH₂CH₂CH₃) 2-pentyloxy (-OCH (CH)₃)CH₂CH₂CH₃) 3-pentyloxy (-OCH (CH))₂CH₃)₂) 2-methyl-2-butoxy (-OC (CH))₃)₂CH₂CH₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH₃)₂) 3-methyl-l-butoxy (-OCH)₂CH₂CH(CH₃)₂) 2-methyl-l-butoxy (-OCH)₂CH(CH₃)CH₂CH₃) And so on.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are each independently replaced by one or moreTwo alkyl groups; the alkyl group has the meaning described in the present invention. In some of these embodiments, the alkylamino group is one or two C_1-6The alkyl group is attached to a lower alkylamino group formed on the nitrogen atom. In still other embodiments, the alkylamino group is one or two C_1-4To the nitrogen atom to form an alkylamino group. In other embodiments, the alkylamino group is one or two C_1-3To the nitrogen atom to form an alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N-dimethylamino (dimethylamino), N-diethylamino (diethylamino), and the like.

The terms "haloalkyl", "haloalkoxy" or "haloalkylamino" denote alkyl, alkoxy or alkylamino groups substituted with one or more halogen atoms, wherein alkyl, alkoxy or alkylamino groups have the meaning as described herein, examples of which include, but are not limited to, difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 2,2,3, 3-tetrafluoropropyl, difluoromethoxy, trifluoromethoxy, trifluoromethylamino and the like.

The term "hydroxy-substituted haloalkyl" means a haloalkyl group substituted with one or more hydroxy groups, wherein the haloalkyl group has the meaning as described herein, and such examples include, but are not limited to, 2-hydroxy-1, 1,1,3,3, 3-hexafluoroisopropyl, and the like.

The term "hydroxy-substituted alkyl" means that the alkyl group is substituted with one or more hydroxy groups, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and the like. Such as "hydroxy-substituted C_1-4Alkyl "means an alkyl group having 1 to 4 carbon atoms substituted with one or more hydroxyl groups.

The term "alkoxyalkyl" or "alkoxy-alkylene" means that the alkoxy group is attached to the rest of the molecule through an alkyl group, wherein the alkoxy, alkyl, and alkylene groups have the meaning as described herein. Examples include, but are not limited to, methoxymethyl, ethoxymethyl, isopropoxymethyl, 1-methoxyethyl, 2-methoxyethyl, and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic hydrocarbon radical containing from 3 to 12 carbon atoms. In one embodiment, cycloalkyl groups contain 7 to 12 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.

The term "cycloalkylamino" includes "N-cycloalkylamino" and "N, N-bicycloalkylamino", wherein the amino groups are each independently substituted with one or two cycloalkyl groups; the cycloalkyl radicals have the meanings described in the present invention. Wherein some embodiments are cycloalkylamino is one or two C_3-8Cycloalkyl groups are attached to nitrogen atoms to form cycloalkylamino groups. In other embodiments, the cycloalkylamino group is one or two C_3-6Is attached to the nitrogen atom to form a cycloalkylamino group. Suitable cycloalkylamino groups can be monocycloalkylamino or dicycloalkylamino, and examples include, but are not limited to, N-cyclopropylamino, N-cyclobutylamino, N-cyclohexylamino, N-dicyclopropylamino, and the like.

The terms "cycloalkylalkyl" and "cycloalkyl-alkylene" are used interchangeably and both mean that the cycloalkyl group is attached to the rest of the molecule through an alkyl group, wherein cycloalkyl and alkyl groups have the meaning as described herein. Examples include, but are not limited to, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, cyclopropylethylene, cyclobutylethylene, cyclopentylethylene, cyclohexylethylene, and the like.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent, monocyclic ring containing 3 to 12 ring atoms, up toAt least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Wherein, in some embodiments, the 3-12 ring atoms of the heterocyclyl group contain 2-9 carbon atoms; in still other embodiments, the 3-12 ring atoms of the heterocyclyl group contain 2-8 carbon atoms; in still other embodiments, the 3-12 ring atoms of the heterocyclyl group contain 2-6 carbon atoms; in still other embodiments, the 3-12 ring atoms of the heterocyclyl group contain 2-5 carbon atoms. Unless otherwise indicated, a heterocyclyl group may be attached to other groups in the molecule through a carbon atom, may be attached to other groups in the molecule through a nitrogen atom, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, diazepanyl, oxepanyl, thiepanyl, oxazepanyl, thiazepanyl, oxazepanyl, and pyrrolidinyl

Radical diaza

Radical, sulfur nitrogen hetero

And (4) a base. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione. Examples of sulfur atoms in heterocyclic groups that are oxidized include, but are not limited to, sulfolane, 1-dioxoA thiomorpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.

The term "spirocarbocyclyl" refers to a saturated or partially unsaturated, non-aromatic, mono-or polyvalent, bicyclic or tricyclic ring containing 5 to 12 ring atoms, wherein the ring shares a carbon atom with the ring, and wherein the ring atoms are all carbon atoms. Unless otherwise indicated, the spiro group may be attached to other groups in the molecule through a carbon atom, and-CH₂-the group may optionally be replaced by-C (═ O) -. Examples of spiro rings include, but are not limited to:

the terms "spiroheterocyclyl" and "spiroheterocycle" are 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, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms, and the ring shares a carbon atom with the ring. Wherein, in some embodiments, the 5-12 ring atoms of the spiroheterocyclyl group contain 4-9 carbon atoms; in yet other embodiments, the 5-12 ring atoms of the spiroheterocyclyl group contain 4-8 carbon atoms; in still other embodiments, the 5-12 ring atoms of the spiroheterocyclyl group contain 4-6 carbon atoms. Unless otherwise indicated, spiroheterocyclyl groups may be attached to other groups in the molecule through a carbon atom, or through a nitrogen atom, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of spiroheterocycles include, but are not limited to:

the term "fused carbocyclic group" refers to a saturated or partially unsaturated, non-aromatic, mono-or polyvalent, bicyclic or tricyclic ring containing from 4 to 12 ring atoms, and ringsHave a common ring edge, wherein the ring atoms are all carbon atoms. Unless otherwise indicated, fused ring groups may be attached to other groups in the molecule through a carbon atom, and-CH₂-the group may optionally be replaced by-C (═ O) -. Examples of fused rings include, but are not limited to:

the terms "fused heterocyclyl" and "fused heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent, bicyclic or tricyclic ring containing from 4 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms, and the ring shares a ring side with the ring. Wherein, in some embodiments, the fused heterocyclic group contains 3 to 9 carbon atoms in 4 to 12 ring atoms; in still other embodiments, the fused heterocyclic group contains 3 to 8 carbon atoms in 4 to 12 ring atoms; in still other embodiments, the fused heterocyclic group contains 3-6 carbon atoms in 4-12 ring atoms. Unless otherwise indicated, fused heterocyclic groups may be attached to other groups in the molecule through a carbon atom, may also be attached to other groups in the molecule through a nitrogen atom, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of fused heterocycles include, but are not limited to:

the term "unsaturated" as used herein means that the group contains one or more unsaturations.

The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR 'in N-substituted pyrrolidinyl, R' being a substituent as described herein).

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

The term "cyano" or "CN" denotes a cyano structure, which group may be attached to another group.

The term "nitro" or "NO₂"denotes a nitro structure, which may be linked to other groups.

The term "amino" or "NH₂"denotes an amino structure, which may be linked to other groups.

The term "aryl" denotes a monocyclic, bicyclic or tricyclic all carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring is aromatic and has one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". In one embodiment, aryl is a carbocyclic ring system consisting of 6 to 10 ring atoms and containing at least one aromatic ring therein. Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group may independently be optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes a monocyclic, bicyclic or tricyclic ring containing 5 to 12 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms and has one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". Wherein, in some embodiments, the 5-12 ring atoms of the heteroaryl group contain 1-9 carbon atoms; in still other embodiments, the heteroaryl group contains 1 to 7 carbon atoms in 5 to 12 ring atoms; in still other embodiments, the heteroaryl group contains 1 to 5 carbon atoms in 5 to 12 ring atoms; the heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, heteroaryl is a heteroaryl consisting of 5 to 12 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S and N; in one embodiment, heteroaryl is a heteroaryl consisting of 5 to 10 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S and N; in another embodiment, heteroaryl is a heteroaryl consisting of 5 to 6 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S and N.

Examples of heteroaryl groups include, but are not limited to, furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), oxadiazolyl (e.g., 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl), oxadiazolyl (e.g., 1,2,3, 4-oxadiazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, 2-thiadiazolyl (e.g., 1,3, 4-thiadiazolyl, 1,2, 3-thiadiazolyl, 1,2, 5-thiadiazolyl), thiatriazolyl (e.g., 1,2,3, 4-thiatriazolyl), tetrazolyl (e.g., 2H-1,2,3, 4-tetrazolyl, 1H-1,2,3, 4-tetrazolyl), triazolyl (e.g., 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), 1H-pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl), 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), 2-pyrazinyl, triazinyl (e.g., 1,3, 5-triazine), tetrazinyl (e.g., 1,2,4, 5-tetrazine, 1,2,3, 5-tetrazine); the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.

The term "carboxy", whether used alone or in combination with other terms, such as "carboxy", denotes-CO₂H; the term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or "acyloxy", denotes- (C ═ O) -.

The term "j-k membered" means that the cyclic group consists of j-k ring atoms including carbon atoms and/or heteroatoms such as O, N, S, P; j and k are each independently any non-zero natural number, and k is greater than j; the term "j-k" includes j, k and any natural number therebetween. For example, "3-6 membered", "3-7 membered", "5-10 membered", "5-12 membered", "4-12 membered" or "5-6 membered" means that the cyclic group consists of 3-6 (i.e., 3,4,5 or 6), 3-7 (i.e., 3,4,5,6 or 7), 5-10 (i.e., 5,6, 7, 8,9 or 10), 5-12 (i.e., 5,6, 7, 8,9, 10, 11 or 12), 4-12 (i.e., 4,5,6, 7, 8,9, 10, 11 or 12) or 5-6 (i.e., 5 or 6) ring atoms including carbon atoms and/or heteroatoms such as O, N, S, P.

As described herein, the attachment of a linker to the ring system (as shown in formula c) means that the ring may be attached to the rest of the molecule at any attachable position on the ring system via said linker. Formula c represents that the ring may be attached to the rest of the molecule via any possible attachment position on the ring, including, but not limited to, as shown in formulas c 1-c 6.

The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" means that the substituent of the hydroxy group is used to blockOr protecting the functionality of a hydroxyl group, suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)₁-C₂₄) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs in Design and Clinical Applications, Nature Review Drug Discovery,2008,7, 255-.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

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

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

The term "treating" any disease or condition, as used herein, means all that can slow, halt, arrest, control or halt the progression of the disease or condition, but does not necessarily mean that all the symptoms of the disease or condition have disappeared, and also includes prophylactic treatment of the symptoms, particularly in patients susceptible to such disease or disorder. In some of these embodiments, refers to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, 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 invention that is capable of eliciting a biological or medical response (e.g., reducing or inhibiting enzyme or protein activity, or ameliorating symptoms, alleviating a disorder, slowing or delaying the progression of a disease, or preventing a disease, etc.) in a subject. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount that, when administered to a subject, is effective for: (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a disorder or disease (i) mediated by roryt, or (ii) associated with roryt activity, or (iii) characterized by abnormal activity of roryt; or (2) reduces or inhibits the activity of ROR γ t; or (3) reduces or inhibits expression of ROR γ t. In another embodiment, the term "therapeutically effective amount" refers to an amount that, when administered to a cell, or organ, or non-cellular biological substance, or vehicle, at least partially reduces or inhibits ROR γ t activity; or an amount of a compound of the invention effective to at least partially reduce or inhibit ROR γ t expression.

The terms "administration" and "administering" of a compound as used herein shall be understood as providing a compound of the invention or a prodrug of a compound of the invention to a subject in need thereof. It will be appreciated that one skilled in the art can treat a patient currently suffering from such a disorder or prophylactically treat a patient suffering from such a disorder by using an effective amount of a compound of the present invention.

The term "composition" as used herein refers to a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The meaning of such terms in relation to pharmaceutical compositions includes products comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from mixing, complexation or aggregation of any two or more of the ingredients, or from decomposition of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

Description of the Compounds of the invention

The invention discloses sulfonyl ester derivatives, pharmaceutically acceptable salts thereof, pharmaceutical preparations and compositions thereof, which can be used as ROR gamma t inhibitors and have potential application in treating ROR gamma t-mediated inflammation or autoimmune diseases, such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ophthalmopathy, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, Crohn's disease or Kawasaki disease.

In one aspect, the invention relates to a compound of formula (I) or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,

wherein, ring A, ring B, and ring L¹、L²、L³、R、Z¹、Z²、Z³、Z⁴、Z⁵、Z⁶、Z⁷And Z⁸Have the meaning as described in the present invention; indicates the direction of linkage of the a ring to the right (hetero) aryl.

In some embodiments, R is C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_3-6Cycloalkylamino, -C_1-4alkylene-C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical, C_1-4Haloalkyl or C_1-4A haloalkoxy group.

In other embodiments, R is methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1, 2-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, ethylamino, dimethylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylenecyclohexyl, ethylenecyclopropyl, ethylenecyclobutyl, ethylenecyclopentyl, ethylenecyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, Z¹Is CR¹Or N, wherein R¹Have the meaning as described in the present invention.

In some embodiments, Z²Is CR¹Or N, wherein R¹Have the meaning as described in the present invention.

In some embodiments, Z³Is CR¹Or N, wherein R¹Have the meaning as described in the present invention.

In some embodiments, Z⁴Is CR¹Or N, wherein R¹Have the meaning as described in the present invention.

In some embodiments, Z⁵Is CR¹Or N, wherein R¹Have the meaning as described in the present invention.

In some embodiments, Z⁶Is CR¹Or N, wherein R¹Have the meaning as described in the present invention.

In some embodiments, Z⁷Is CR¹Or N, wherein R¹Have the meaning as described in the present invention.

In some embodiments, Z⁸Is CR¹Or N, wherein R¹Have the meaning as described in the present invention.

In some embodiments, each R is¹Independently hydrogen, deuterium, cyano, fluoro, chloro, bromo, iodo, C_1-6Alkyl radical, C_1-6Haloalkyl, hydroxy-substituted C_1-6Alkyl, -C_1-6alkylene-C_1-6Alkoxy radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl.

In other embodiments, each R is¹Independently hydrogen, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, 1, 2-difluoroethyl, 1-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethylene, ethoxymethylene, n-propoxymethylene, isopropoxymethylene, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, ring B is C_6-10Aryl, 5-12 membered heteroaryl, 3-7 membered heterocyclyl, 4-12 membered fused heterocyclyl, 5-12 membered spiroheterocyclyl, 4-12 membered fused carbocyclyl, 5-12 membered spirocarbocyclyl or C_3-8Cycloalkyl, wherein said B ring is optionally substituted with 1,2,3 or 4R^eSubstitution; r^eHave the meaning as described in the present invention.

In other embodiments, ring B is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Said B ring being optionally substituted with 1,2,3 or 4R^eSubstitution; r^eHave the meaning as described in the present invention.

In some embodiments, each R is^eIndependently is deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl, 3-8 membered heterocyclyl, hydroxy-substituted C_1-4Alkyl, hydroxy substituted C_1-4Haloalkyl, C_1-4Haloalkyl or C_1-4A haloalkoxy group; or, any two adjacent R^eAnd together with the atom to which they are attached form C_3-8Cycloalkyl or 3-8 membered heterocyclyl; wherein, said C_1-4Alkoxy is optionally substituted by 1-3-6 membered heterocyclyl or C_3-8Cycloalkyl is substituted.

In other embodiments, each R is^eIndependently deuterium, fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxy-n-propyl, 2-hydroxy-1, 1,1,3,3, 3-hexafluoroisopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1, 2-difluoroethyl, methoxy, ethoxy, n-propoxy, t-butoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or 1, 2-difluoroethoxy; wherein said methoxy, ethoxy, n-propoxy, t-butoxy are optionally substituted with 1 substituent selected from the group consisting of oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl.

In some embodiments, L is¹is-S (═ O)₂-NH-、-NH-S(＝O)₂-, -S (═ O) -NH-, -NH-S (═ O) -, -C (═ O) NH-, or-NHC (═ O) -.

In some embodiments, L is²Is CR³R⁴(ii) a Wherein R is³And R⁴Have the meaning as described in the present invention.

In some embodiments, R³Is hydrogen, hydroxy-substituted C_1-6Alkyl or cyano-substituted C_1-6An alkyl group; r⁴Is hydrogen, hydroxy-substituted C_1-6Alkyl or cyano-substituted C_1-6An alkyl group.

In other embodiments, R³Is hydrogen, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, cyanomethyl, cyanoethyl or cyano-n-propyl; r⁴Is hydrogen, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, cyanomethyl, cyanoethyl or cyano-n-propyl.

In some embodiments, L is³Is carbonyl, -S-, -O-, -NR⁵-or-CR⁶R⁷-; wherein R is⁵、R⁶And R⁷Having the inventionThe meaning is stated.

In some embodiments, R⁵Is hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl or 3-6 membered heterocyclyl; each R⁶And R⁷Independently of one another is hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy or 3-6 membered heterocyclyl.

In other embodiments, R⁵Is hydrogen, methyl, ethyl, isopropyl, n-propyl, isobutyl, tert-butyl, n-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1, 2-difluoroethyl, 1-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl or azetidinyl;

each R⁶And R⁷Independently hydrogen, methyl, ethyl, isopropyl, n-propyl, isobutyl, tert-butyl, n-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1, 2-difluoroethyl, 2-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1, 2-difluoroethoxy, 2-difluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl or piperazinyl.

In some embodiments, ring a is a 6-membered heterocyclic ring, further said 6-membered heterocyclic ring is optionally substituted with 1,2,3 or 4R²Substitution; wherein R is²Have the meaning as described in the present invention.

In other embodiments, ring A is

Further said A ring is optionally substituted with 1,2,3 or 4R²Substitution; wherein R is²Have the meaning as described in the present invention.

In some embodiments, each R is²Independently fluorine, chlorine, bromine, iodineHydroxy, oxo (═ O), amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_6-10Aryl radical, C_3-8Cycloalkyl, -C_0-6alkylene-OR^a、-C_0-4Alkylene- (C (═ O))_m-R^b、-C_0-4Alkylene- (O)_n-(C(＝O))_m-NR^cR^d5-10 membered heteroaryl, -C_0-4Alkylene- (3-7 membered heterocyclyl), -C_0-4Alkylene- (5-12 membered spiroheterocyclyl) or-C_0-4Alkylene- (4-12 membered fused heterocyclyl); the R is²Optionally substituted by 1,2 or 3R^fSubstitution; or, optionally, two R's attached to the same carbon atom²Together with the carbon atom to which they are attached form C_3-6Cycloalkyl or a 4-6 membered heterocyclic ring; wherein, the m, n and R^a、R^b、R^c、R^dAnd R^fHave the meaning as described in the present invention.

wherein each R is^a、R^b、R^cAnd R^dIndependently optionally substituted by 1,2,3,4, 5 or 6R^gSubstitution; wherein, R is^gHave the meaning as described in the present invention.

In some embodiments, each R is²Independently is fluorine, chlorine, bromine, iodine, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, phenyl, C_3-6Cycloalkyl, -C_0-4alkylene-OR^a、-C_0-4Alkylene- (C (═ O))_m-R^b、-C_0-4Alkylene- (O)_n-(C(＝O))_m-NR^cR^d5-6 membered heteroaryl, -C_0-4Alkylene- (3-7 membered heterocyclyl), -C_0-4Alkylene- (5-12 membered spiroheterocyclyl) or-C_0-4Alkylene- (4-12 membered fused heterocyclyl); wherein, R is²Optionally substituted by 1,2 or 3R^fSubstitution;

or, optionally, two R's attached to the same carbon atom²Together with the carbon atom to which they are attached form C_3-6Cycloalkyl or a 4-6 membered heterocyclic ring;

wherein, the m, n and R^a、R^b、R^c、R^dAnd R^fHave the meaning as described in the present invention.

In other embodiments, each R is²Independently fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 1-difluoroethyl, 1, 2-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OR^a、-CH₂-OR^a、-CH₂CH₂-OR^a、-CH₂(CH₂)₂-OR^a、-CH₂CH(CH₃)-OR^a、-C(CH₃)₂CH₂-OR^a、-CH₂(CH₂)₃-OR^a、-CH(CH₃)CH(CH₃)-OR^a、-CH₂C(CH₃)₂-OR^a、-(C＝O)_m-R^b、-CH₂-(C(＝O))_m-R^b、-CH₂CH₂-(C(＝O))_m-R^b、-CH₂(CH₂)₂-(C(＝O))_m-R^b、-CH₂CH(CH₃)-(C(＝O))_m-R^b、-C(CH₃)₂CH₂-(C(＝O))_m-R^b、-CH₂(CH₂)₃-(C(＝O))_m-R^b、-CH(CH₃)CH(CH₃)-(C(＝O))_m-R^b、-CH₂C(CH₃)₂-(C＝O)_m-R^b、-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂CH₂-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂(CH₂)₂-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂CH(CH₃)-(O)_n-(C(＝O))_m-NR^cR^d、-C(CH₃)₂CH₂-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂(CH₂)₃-(O)_n-(C(＝O))_m-NR^cR^d、-CH(CH₃)CH(CH₃)-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂C(CH₃)₂-(O)_n-(C(＝O))_m-NR^cR^dOxazolyl, thiazolyl, thienyl, imidazolyl, pyridazinyl, pyridyl,

Wherein, R is²Optionally substituted by 1,2 or 3R^fSubstitution;

or, optionally, two R's attached to the same carbon atom²And the carbon atom to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinylOr a piperazinyl group;

In some embodiments, each R is^aIndependently of one another is hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_6-10Aryl radical, C_3-8Cycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl, 5-12 membered spiroheterocyclyl or 4-12 membered fused heterocyclyl; each R^b、R^cAnd R^dIndependently hydrogen, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_6-10Aryl radical, C_3-8Cycloalkyl, 4-12 membered fused carbocyclic group, 5-12 membered spirocarbocyclic group, 5-10 membered heteroaryl, 3-7 membered heterocyclic group, 5-12 membered spiroheterocyclic group or 4-12 membered fused heterocyclic group; or R^c、R^dAnd the N atom to which they are attached together form a 4-7 membered heterocyclic ring;

each of said R^a、R^b、R^cAnd R^dIndependently optionally substituted by 1,2,3,4, 5 or 6R^gSubstitution; wherein, R is^gHave the meaning as described in the present invention.

In other embodiments, each R is^aIndependently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 2, 2-difluoroethyl, 1, 2-difluoroethyl, 2,2, 2-trifluoroethyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, 2-difluoroethyl, trifluoromethyl, and mixtures thereof,

Phenyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, oxepanyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; each R^b、R^cAnd R^dIndependently hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 2-difluoroethylA group, 1, 2-difluoroethyl group, 2,2, 2-trifluoroethyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a phenyl group, an oxetanyl group, a tetrahydrofuryl group, a tetrahydropyranyl group, an oxepanyl group, a phenylthio group,

Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R^c、R^dAnd the N atom to which they are attached together form a 4-7 membered heterocyclic ring;

wherein each R is^a、R^b、R^cAnd R^dIndependently optionally substituted by 1,2,3,4, 5 or 6R^gSubstitution; the R is^gHave the meaning as described in the present invention.

In some embodiments, each R is^fAnd R^gIndependently fluorine, chlorine, bromine, iodine, oxo (═ O), hydroxy, amino, nitro, cyano, C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_1-6Haloalkyl, C_6-10Aryl radical, C_3-8Cycloalkyl, 4-12 membered fused carbocyclic group, 5-12 membered spiro carbocyclic group, 5-10 membered heteroaryl, 3-12 membered heterocyclic group, 5-12 membered spiro heterocyclic group, 4-12 membered fused heterocyclic group, C_1-6Alkoxy radical, C_1-6Alkylamino or C_1-6A haloalkoxy group.

In other embodiments, each R is^fAnd R^gIndependently fluorine, chlorine, bromine, iodine, oxo, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH₂OH, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 1-difluoroethyl, 1, 2-difluoroethyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxa-ethyl, 1, 2-difluoroethyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl, oxiranyl, oxa-cyclobutyl, tetrahydrofuranyl, trifluoromethyl,

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

In some embodiments, each m and n is independently 0 or 1.

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

stereoisomers, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of formula (I) are included within the scope of the present invention unless otherwise specified.

In some embodiments, the pharmaceutical composition comprises an additional agent or any combination thereof for preventing or treating an inflammatory syndrome or an autoimmune disease.

In one embodiment, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray dosage form.

In another aspect, the invention relates to intermediates for the preparation of compounds of formula (I).

The compounds of the present disclosure may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention contemplates that all stereoisomeric forms of the compounds of formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, and mixtures thereof, such as racemic mixtures, are integral to the invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.

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

The compounds of formula (I) may be present in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salts need not be pharmaceutically acceptable salts and may be intermediates useful in the preparation and/or purification of compounds of formula (I) and/or in the isolation of enantiomers of compounds of formula (I).

Pharmaceutically acceptable acid addition salts may be formed from the disclosed compounds of the invention by the action of an inorganic or organic acid, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheyl salt, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, phosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.

Pharmaceutically acceptable base addition salts may be formed from the disclosed compounds by reaction with an inorganic or organic base.

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

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

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable Salts.

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

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g., whereinRadioisotopes, e.g.³H、¹⁴C and¹⁸those compounds of F, or in which a non-radioactive isotope is present, e.g.²H and¹³those of C. The isotopically enriched compounds can be used for metabolic studies (use)¹⁴C) Reaction kinetics study (using, for example²H or³H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.¹⁸F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.

In addition, heavier isotopes are, in particular, deuterium (i.e.,²substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is to be considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D₂O, acetone-d₆、DMSO-d₆Are solvated byA compound (I) is provided.

Pharmaceutical compositions, formulations and administration of the compounds of the invention

The present invention provides a pharmaceutical composition comprising a compound disclosed herein, for example, as set forth in the examples; and a pharmaceutically acceptable excipient, carrier, adjuvant, or combination thereof.

The present invention provides methods of treating, preventing or ameliorating a disease or condition comprising administering a safe and effective amount of a combination comprising a compound of the present disclosure and one or more therapeutically active agents. Wherein the combination comprises one or more additional agents for the prophylaxis or treatment of an inflammatory syndrome, disorder or disease, and the active therapeutic agents include, but are not limited to:

1) a TNF-alpha inhibitor; 2) non-selective COX-1/COX-2 inhibitors; 3) COX-2 inhibitors; 4) other therapeutic agents for the treatment of inflammatory syndromes and autoimmune diseases, including glucocorticoids, methotrexate, leflunomide (leflunomide), sulfasalazine, azathioprine, cyclosporine, tacrolimus (tacrolimus), penicillamine, buclizine, acrilamide, mizoribine, clobenzaprine, ciclesonide, hydroxychloroquine, aurothiomalate, auranofin, cyclophosphamide, BAFF/APRIL inhibitors, CTLA-4-immunoglobulin or the like; 5) a leukotriene biosynthesis inhibitor, a 5-lipoxygenase inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist; 6) LTD4 receptor antagonists; 7) a PDE4 inhibitor; 8) an anti-histamine HI receptor antagonist; alpha 1-and alpha 2-adrenoceptor agonists; 9) anticholinergic agents; 10) a P-adrenoceptor agonist; 11) an insulin-like growth factor type I analog; 12) kinase inhibitors are selected from Janus kinase inhibitors (JAK1 and/or JAK2 and/or JAK3 and/or TYK2), p38 MAPK and IKK 2; 13) b cell targeting biopharmaceuticals such as rituximab; 14) selective co-stimulatory modulators such as albuterol; 15) an interleukin inhibitor selected from the group consisting of an IL-1 inhibitor such as anakinra, an IL-6 inhibitor such as tollizumab and an IL-12/IL-23 inhibitor such as Ultezumab.

The amount of compound in the pharmaceutical composition disclosed herein is effective to detect inhibition of retinoic acid-related nocosomal receptor gamma t in a biological sample or patient. The dosage of the active ingredient in the composition of the present invention may vary, however, the amount of the active ingredient must 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 pharmaceutical efficacy. The selected dosage depends on the desired therapeutic effect, on the route of administration and on the duration of the treatment. The dosage will vary from patient to patient depending on the nature and severity of the disease, the weight of the patient, the particular diet of the patient, the concurrent use of drugs, and other factors that will be recognized by those skilled in the art. The dosage range is generally about 0.5mg to 1.0g per patient per day and may be administered in a single dose or in multiple doses. In one embodiment, the dosage range is from about 0.5mg to 500mg per patient per day; from about 0.5mg to 200mg per patient per day in another embodiment; and in yet another embodiment from about 5mg to 50mg per patient per day.

It will also be appreciated that certain compounds of the invention may exist in free form or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof. Pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.

The medicaments or pharmaceutical compositions disclosed herein may be prepared and packaged in bulk (bulk) form, wherein a safe and effective amount of the compound of formula (I) may be extracted and then administered to a patient in the form of a powder or syrup. Typically, the patient is administered with a dose level of between 0.0001 and 10mg/kg body weight daily to achieve effective inhibition of retinoic acid-related nociceptor γ t. Alternatively, the pharmaceutical compositions disclosed herein can be prepared and packaged in unit dosage forms, wherein each physically discrete unit contains a safe and effective amount of a compound of formula (I). When prepared in unit dosage form, the disclosed pharmaceutical compositions can generally contain, for example, from 0.5mg to 1g, or from 1mg to 700mg, or from 5mg to 100mg of the disclosed compounds.

When the pharmaceutical composition of the invention contains one or more other active ingredients in addition to the compound of the invention, the compound weight ratio of the compound of the 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 a compound of the invention is mixed with another agent, the weight ratio of the compound of the invention to the other agent typically ranges from about 1000: 1 to about 1: 1000, e.g. about 200: 1 to about 1: 200. mixtures of the compounds of the invention with other active ingredients are generally also within the above-mentioned ranges, but in each case an effective dose of each active ingredient should be used.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected to facilitate carrying or transporting the disclosed compounds from one organ or portion of the body to another organ or portion of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and which other excipients are present in the formulation.

The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and The Pharmaceutical Press).

Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the disclosed compounds, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

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

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

In one embodiment, the compounds disclosed herein may be formulated in oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhalation dosage form. In another embodiment, the compounds disclosed herein can be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated for transdermal administration. In yet another embodiment, the compounds disclosed herein may be formulated for topical administration.

The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that is resistant to the action of gastric 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, which can help to mask unpleasant tastes or odors and prevent oxidation of the tablet. 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 are endowed with the same general characteristics as sugar coatings. A tabletted tablet is a compressed tablet prepared over more than one compression cycle, including a multi-layer tablet, and a press-coated or dry-coated tablet.

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

The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent nos.4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is dispersed throughout another in the form of globules, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives. Suspensions may include a pharmaceutically acceptable suspending agent and a preservative. The aqueous alcoholic solution may comprise pharmaceutically acceptable acetals, such as di (lower alkyl) acetals of lower alkyl aldehydes, e.g. acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration.

Other useful liquid and semi-solid dosage forms include, but are not limited to, those comprising the active ingredients provided herein and a secondary mono-or poly-alkylene glycol, including: 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further include one or more antioxidants, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

Dosage unit formulations for oral administration may be microencapsulated, where appropriate. They may also be prepared as extended or sustained release compositions, for example by coating or embedding the particulate material in a polymer, wax or the like.

The oral pharmaceutical composition provided by the invention can also be provided in the form of liposome, micelle, microsphere or nano system. Micellar dosage forms can be prepared using the methods described in U.S. Pat. No.6,350,458.

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

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

The disclosed compounds may also be conjugated to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of a drug, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

The pharmaceutical compositions provided by the present invention may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.

The pharmaceutical compositions provided by the present invention may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.

The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for 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 of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).

Pharmaceutical compositions intended for parenteral administration may include 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 to inhibit microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

Suitable aqueous carriers include, but are not limited to: water, saline, normal saline or Phosphate Buffered Saline (PBS), sodium chloride injection, Ringers injection, isotonic glucose 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, hydrogenated soybean oil, and the medium chain triglycerides of 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-dimethylacetamide, and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol and glucose. Suitable buffers include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpirtinePyrrolidone. 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 alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, and sulfobutyl ether-7-beta-cyclodextrin (f: (f))

CyDex,Lenexa,KS)。

The pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials or syringes. The multi-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antimicrobial agent. All parenteral formulations must be sterile, as is known and practiced in the art.

In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical compositions are provided as sterile dried soluble products, including lyophilized powders and subcutaneous injection tablets, which are reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile, dry, insoluble product that is reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a sterile emulsion ready for use.

The pharmaceutical composition may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for depot administration for implantation. In one embodiment, the disclosed pharmaceutical compositions are dispersed in a solid internal matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows diffusion therethrough of the active ingredient in the pharmaceutical composition.

Suitable internal matrices include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of hydrophilic polymers such as esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and partially hydrolyzed polyvinyl acetate of the class of copolymers.

Suitable outer polymeric films include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polyvinyl chloride, copolymers of chlorinated ethylene and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomers polyethylene terephthalate, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxyethanol copolymers.

In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension, or solution composition. In one embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient as a dry powder. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions for delivery to the lung by inhalation typically comprise a finely powdered compound of the disclosed invention and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are 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 prepared, for example, by micronization and milling. Generally, the size-reduced (e.g., micronized) compound may pass through a D of about 1 to 10 microns₅₀Values (e.g., measured by laser diffraction).

Aerosols can be formulated by suspending or dissolving the disclosed compounds 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-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane. Aerosols comprising the compounds disclosed herein are typically administered to a patient via a Metered Dose Inhaler (MDI). Such devices are known to those skilled in the art.

The aerosol may contain additional pharmaceutically acceptable excipients that may be used by MDIs, such as surfactants, lubricants, co-solvents, and other excipients, to improve the physical stability of the formulation, to improve valve characteristics, to improve solubility, or to improve taste.

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

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 with a water or oil base, and suitable thickeners and/or gelling agents and/or solvents. Such bases may include, water, and/or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickeners and gelling agents used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifiers.

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

Powders for external use may be formed in the presence of any suitable powder base, for example talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base containing one or more dispersing agents, solubilising agents, suspending agents or preservatives.

Topical formulations may be administered by application to the affected area one or more times per day; an occlusive dressing covering the skin is preferably used. Adhesive depot systems allow for continuous or extended administration.

Use of the Compounds and pharmaceutical compositions of the invention

The compounds or pharmaceutical compositions disclosed herein can be used in the preparation of medicaments for the treatment, prevention, amelioration, control or alleviation of inflammatory or autoimmune diseases mediated by ROR γ t in mammals, including humans, as well as in the preparation of other medicaments for the inhibition of ROR γ t.

Specifically, the amount of the compound in the pharmaceutical composition of the present invention is effective to detectably inhibit ROR γ t, and the compound of the present invention can be used as a medicament for preventing or treating human psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ocular disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, crohn's disease, or kawasaki disease.

The compounds or pharmaceutical compositions of the present invention may be used, but are in no way limited to, for administration to a patient for preventing, treating or alleviating psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ocular 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, using an effective amount of a compound or pharmaceutical composition of the present invention.

In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.

General synthetic procedure

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.

NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer, CDC1₃、DMSO-d₆、CD₃OD or acetone-d₆TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), q (quatet), m (multiplet), br (broadbanding), dd (doublet of doublets), dt (doublet of triplets), ddd (triplet), qd (quartet). Coupling constant J, expressed in Hertz (Hz).

The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18,2.1X30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase: 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.

The purity of the compound was determined by High Performance Liquid Chromatography (HPLC), using Agilent 1260HPLC (column model: Agilent zorbax Eclipse Plus C18) and detected by DAD detector, and finally calculated by area normalization to obtain the purity of the compound.

The following acronyms are used throughout the invention:

Ac₂o acetic anhydride/acetic anhydride; EtOH ethanol;

AcOH acetic acid/acetic acid; et (Et)₃N, TEA triethylamine;

silver AgOTf triflate; EDCI 1-ethyl- (3-dimethylaminopropyl) carbonyldiimidate

Boc₂Di-tert-butyl O-dicarbonate; an acid salt;

CDC1₃deuterated chloroform; HOBT, HOBt 1-hydroxybenzotriazole;

CDI N, N-carbonyldiimidazole; i-PrOH isopropanol;

DCM dichloromethane; i-PrMgBr isopropyl magnesium bromide;

DMFN, N-dimethylformamide; KOAc potassium acetate;

DIPEA N, N-diisopropylethylamine; t-BuOK potassium tert-butoxide;

DMSO dimethyl sulfoxide; CH (CH)₃CN, ACN acetonitrile;

DMSO-d₆deuterated dimethyl sulfoxide; MeOH with methanol;

DMAP 4-dimethylaminopyridine; MsCl methanesulfonyl chloride;

EtOAc, EA ethyl acetate; pd₂(dba)₃Tris (dibenzylideneacetone) dipalladium;

Pd(dppf)Cl₂[1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; g, g;

Pd(P(o-Tol)₃)₂(OAc)₂diacetoxybis (tri-o-tolylphosphine) -h hours;

palladium (II); min;

PE petroleum ether; mmol millimole;

TMSCF₃(trifluoromethyl) trimethylsilane; DEG C;

Tf₂o trifluoromethanesulfonic anhydride; mL;

TBSOTf tert-butyldimethylsilyl trifluoromethanesulfonate; rpm turns per minute;

ruphos 2-dicyclohexylphosphine-2 ',6' -diisopropoxybiphenyl; aq. solution;

TMSCF₂br (bromodifluoromethyl) trimethylsilane; m mol per liter;

Pd/C palladium/carbon nM nanomolar;

TLC thin layer chromatography; micromolar at μ M;

THF tetrahydrofuran; DTT dithiothreitol;

TFA trifluoroacetic acid; μ L microliter;

TBAF tetrabutylammonium fluoride; a Selectfluor selective fluorinating agent;

xanthphos 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene; sodium STAB triacetoxyborohydride;

typical synthetic procedures for preparing the disclosed compounds of the invention are shown in the following synthetic schemes. Unless otherwise stated, ring B, R, R²、R³、R⁴、Z¹、Z²、Z³、Z⁴、Z⁵、Z⁶、Z⁷、Z⁸、R^a、R^b、R^c、R^dN and m have the meanings given in the description.

In the following scheme, X represents CH₂、NR^XOr O; wherein R is^XIs C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl, -C_0-6alkylene-OR^a、-C_0-4Alkylene- (C (═ O))_m-R^b、-C_0-4Alkylene- (O)_n-(C(＝O))_m-NR^cR^dOr 5-10 membered heteroaryl; y represents a halogen atom; PG represents an amino protecting group; PG (Picture experts group)²Represents a hydroxyl protecting group; ms represents a methanesulfonyl leaving group, T¹And T²Is carboxyl or amino, and T¹And T²Cannot be the same group.

Synthesis scheme 1

Compound (6a) can be prepared by the following procedure:

the compound (1a) and the compound (1a ') or the compound (1a ') are subjected to substitution reaction to generate a compound (2a), the compound (2a) is deprotected to generate a compound (3a), the compound (3a) and the compound (3a ') are subjected to coupling reaction to generate a compound (4a), and the compound (4a) is subjected to hydrolysis reaction to generate a compound (5 a). The compound (5a) and the compound (5a') are condensed to obtain a compound (6 a).

Synthesis scheme 2

Compound (9b) can be prepared by the following procedure:

the compound (1a) is subjected to substitution reaction to generate a compound (2b), the compound (2b) is subjected to deamination protecting group under an acidic condition (such as trifluoroacetic acid) to generate a compound (3b), the compound (3b) and the compound (3a ') are subjected to coupling reaction under the action of a coupling reagent to generate a compound (4b), the compound (4b) is subjected to oxygen atom protecting group removal to generate a compound (5b), the compound (5b) is subjected to reaction with a sulfonyl compound to generate a compound (6b), the compound (6b) is subjected to sulfonyl leaving group removal, the compound (7b) is subjected to amino substitution reaction to generate a compound (7b), the compound (7b) and the compound (1a ') are subjected to substitution or coupling reaction to generate a compound (8b), and the compound (8b) and the compound (5a ') are subjected to condensation reaction.

Synthesis scheme 3

The compound (6c) or (6 c') can be prepared by the following process:

the compound (1c) and the compound (2c) are subjected to condensation reaction to generate a compound (3c) or (3c '), the compound (3c) or (3c ') and the compound (3c ') are subjected to substitution reaction to generate a compound (4c) or (4c '), the compound (4c) or (4c ') is subjected to deamination protecting group generation to generate a compound (5c) or (5c '), and the compound (5c) or (5c ') is subjected to reaction with the compound (5c ') to generate a compound (6c) or (6c ').

Synthesis scheme 4

Compound (6d) can be prepared by the following procedure:

the compound (1d) and the compound (1d ') are subjected to substitution reaction under alkaline conditions to generate a compound (2d), the compound (2d) is subjected to deamination protection under acidic conditions (such as trifluoroacetic acid) to generate a compound (3d), the compound (3d) and the compound (3a') are subjected to coupling reaction to generate a compound (4d), the compound (4d) is hydrolyzed under alkaline conditions to generate a compound (5d), and the compound (5d ') and the compound (5a') are condensed under the action of a condensation reagent to generate a compound (6 d).

The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.

Examples

Example 12- (4- (ethylsulfonyl) phenyl) -N- (4- (1- (4- (trifluoromethyl) benzyl) piperidin-3-yl) phenyl) acetamide

The method comprises the following steps: synthesis of 3- (((trifluoromethyl) sulfonyl) oxy) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

3-Oxopiperidine-1-carboxylic acid tert-butyl ester (2.00g,10.0mmol) and DMAP (3.80g,30.8mmol) were dissolved in DCM (30mL) under nitrogen, and Tf was cooled with stirring at-10 deg.C₂O (2.60mL,13.0mmol) was slowly added dropwise to the reaction system, and after the addition, the temperature was raised to room temperature and stirred for 5 h. The reaction was then quenched with water (35mL) in an ice bath, extracted with DCM (30 mL. times.3), and the organic phases combined and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 10/1) to give a colorless transparent liquid (1.15g, 35%).

Step two: synthesis of (4- (2- (4- (ethylsulfonyl) phenyl) acetamido) phenyl) boronic acid

(4-aminophenyl) boronic acid (600mg,3.49mmol), 2- (4- (ethylsulfonyl) phenyl) acetic acid (800mg,3.50mmol), EDCI (1.10g,5.62mmol) and HOBt (600mg,4.30mmol) were dissolved in DCM (50mL) and stirred at room temperature for 7 h. The reaction was quenched by the addition of HCl solution (30mL,1mol/L) to precipitate a large amount of white solid, which was filtered to give a white solid (820mg, 67%).

MS(ESI,pos.ion)m/z＝348.1[M+H]⁺.

Step three: synthesis of tert-butyl 5- (4- (2- (4- (ethylsulfonyl) phenyl) acetamido) phenyl) -3, 4-dihydropyridine-1 (2H) -carboxylate

(4- (2- (4- (ethylsulfonyl) phenyl) acetamido) phenyl) boronic acid (210mg,0.60mmol), 3- (((trifluoromethyl) sulfonyl) oxy) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (220mg,0.66mmol), Pd (dppf) Cl under nitrogen protection₂(101mg,0.13mmol) and Cs₂CO₃(500mg,1.53mmol) was dissolved in 1, 4-dioxane (40mL) and stirred at 105 ℃ for 7 h. Subsequently, it was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a pale yellow solid (103mg, 35%).

MS(ESI,pos.ion)m/z＝485.6[M+H]⁺.

Step four: synthesis of tert-butyl 3- (4- (2- (4- (ethylsulfonyl) phenyl) acetylamino) phenyl) piperidine-1-carboxylate

Pd/C (860mg, 5%) was added to a solution of tert-butyl 5- (4- (2- (4- (ethylsulfonyl) phenyl) acetylamino) phenyl) -3, 4-dihydropyridine-1 (2H) -carboxylate (200mg,0.41mmol) in MeOH (50mL) under hydrogen atmosphere, stirred at room temperature for 4H, then filtered through celite, the filtrate was concentrated under reduced pressure, and the resulting crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 20/1) to give a yellow solid (90mg, 45%).

MS(ESI,pos.ion)m/z＝509.3[M+23]⁺.

Step five: synthesis of 2- (4- (ethylsulfonyl) phenyl) -N- (4- (piperidin-3-yl) phenyl) acetamide

Tert-butyl 3- (4- (2- (4- (ethylsulfonyl) phenyl) acetamido) phenyl) piperidine-1-carboxylate (200mg,0.41mmol) was dissolved in DCM (50mL) and TFA (5mL) and stirred at room temperature for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a pale yellow liquid (151mg, 95%).

MS(ESI,pos.ion)m/z＝387.5[M+H]⁺.

Step six: synthesis of 2- (4- (ethylsulfonyl) phenyl) -N- (4- (1- (4- (trifluoromethyl) benzyl) piperidin-3-yl) phenyl) acetamide

2- (4- (ethylsulfonyl) phenyl) -N- (4- (piperidin-3-yl) phenyl) acetamide (100mg,0.26mmol) and 4- (trifluoromethyl) benzaldehyde (0.10mL,0.70mmol) were dissolved in MeOH (20mL) and NaBH was added under an ice bath₃CN (100mg,1.29mmol), the reaction was stirred at room temperature for 5 h. The reaction was concentrated under reduced pressure to remove the organic solvent, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 15/1) to give a pale yellow solid (30mg, 21%).

MS(ESI,pos.ion)m/z＝545.6[M+H]⁺.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89(d,J＝8.1Hz,2H),7.72(d,J＝2.4Hz,1H),7.65(d,J＝7.9Hz,2H),7.60–7.54(m,4H),7.40(d,J＝8.3Hz,2H),7.08(d,J＝8.4Hz,2H),3.92(dd,J＝23.6,13.4Hz,2H),3.82(s,2H),3.14(q&m,J＝7.3Hz,4H),2.97(d,J＝8.8Hz,1H),2.40(t,J＝9.7Hz,2H),1.96–1.84(m,3H),1.56–1.46(m,1H),1.30(t,J＝7.5Hz,3H).

Example 22- (4- (ethylsulfonyl) phenyl) -N- (4- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) phenyl) acetamide

The method comprises the following steps: synthesis of 4- (4-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester

1-fluoro-4-nitrobenzene (4.00g,27.78mmol) and piperazine-1-carboxylic acid tert-butyl ester (5.40g,29.01mmol) were dissolved in DCM (100mL) under nitrogen and stirred at room temperature for 63 h. The reaction was concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 4/1) to give the product as a yellow solid (860mg, 10%).

Step two: synthesis of 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester

Pd/C (172mg, 10%) was added to a solution of tert-butyl 4- (4-nitrophenyl) piperazine-1-carboxylate (860mg,2.80mmol) in EtOH (10mL) under a hydrogen atmosphere, and the mixture was stirred at room temperature for 13 h. The reaction mixture was filtered through Celite, the filtrate was rotary-evaporated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 4/1) to give a pale yellow solid (570mg, 73%).

Step three: synthesis of tert-butyl 4- (4- (2- (4- (ethylsulfonyl) phenyl) acetamido) phenyl) piperazine-1-carboxylate

Tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (570mg,2.06mmol), 2- (4- (ethylsulfonyl) phenyl) acetic acid (720mg,3.15mmol), EDCI (830mg,4.33mmol) and HOBT (560mg,4.14mmol) were dissolved in DCM (13mL) and stirred at RT for 12 h. The reaction was diluted with DCM (90mL) and saturated NaHCO₃The solution (50mL) was washed, the aqueous phase was extracted with DCM (50 mL. times.3), the organic phases were combined and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 2/1) to give a yellow solid (596mg, 59%).

MS(ESI,pos.ion)m/z＝488.2[M+H]⁺.

Step four: synthesis of 2- (4-ethylsulfonylphenyl) -N- (4- (piperazin-1-yl) phenyl) acetamide

Tert-butyl 4- (4- (2- (4- (ethylsulfonyl) phenyl) acetamido) phenyl) piperazine-1-carboxylate (412mg,0.85mmol) was dissolved in DCM/TFA (10mL/4mL) was stirred at room temperature for 5 h. The reaction was concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with DCM (130mL) and saturated Na₂CO₃The solution (50mL) was washed, the layers were separated, the aqueous phase was extracted with DCM (30mL × 3), the organic phases were combined, concentrated under reduced pressure and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a white solid (300mg, 92%).

MS(ESI,pos.ion)m/z＝388.5[M+H]⁺.

Step five: synthesis of 2- (4- (ethylsulfonyl) phenyl) -N- (4- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) phenyl) acetamide

2- (4- (ethylsulfonyl) phenyl) -N- (4- (piperazin-1-yl) phenyl) acetamide (125mg,0.32mmol), 4- (trifluoromethyl) benzaldehyde (170mg,0.98mmol) were dissolved in DCM (10mL) under nitrogen, AcOH (19mg,0.32mmol) was added, stirring was carried out at room temperature for 1h, then NaBH was added₃CN (45mg,0.72mmol), stirred at room temperature for 19 h. Saturated NaHCO was added to the system₃The reaction was quenched with solution (10mL), and the mixture was diluted with DCM (90mL), followed by saturated NaHCO₃The solution (20mL) was washed with saturated NaCl solution (30mL) and dried over anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 20/1) to give a white solid (70mg, 40%).

MS(ESI,pos.ion)m/z＝546.1[M+H]⁺.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.86(d,J＝7.7Hz,2H),7.58(d,J＝7.8Hz,2H),7.53(d,J＝7.9Hz,2H),7.47(d,J＝7.8Hz,2H),7.34(d,J＝8.8Hz,2H),6.85(d,J＝8.8Hz,2H),3.75(s,2H),3.60(s,2H),3.15(t,J＝4.2Hz,4H),3.11(q,J＝7.6Hz,2H),2.60(t,J＝4.4Hz,4H),1.28(t,J＝7.6Hz,3H).

Example 32- (4- (ethylsulfonyl) phenyl) -N- (4- (4- (((1R,4R) -4- (trifluoromethyl) cyclohexyl) methyl) piperazin-1-yl) phenyl) acetamide

Under the protection of nitrogen, 2- (4- (ethyl)Sulfonyl) phenyl) -N- (4- (piperazin-1-yl) phenyl) acetamide (25mg,0.07mmol) and 4- (trifluoromethyl) cyclohexylformaldehyde (35mg,0.19mmol) were dissolved in DCM (5mL), AcOH (4mg,0.07mmol) was added, stirring at room temperature for 1h, then NaBH was added₃CN (23mg,0.37mmol), stirred at room temperature for 24 h. Saturated NaHCO was added to the system₃The reaction was quenched with solution (6mL), diluted with DCM (90mL), and sequentially with saturated NaHCO₃The saturated solution (20mL) and saturated NaCl solution (30mL) were washed, the aqueous phase was extracted with DCM (30 mL. times.3), the organic phases were combined and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 30/1) to give a white solid (25mg, 70%).

MS(ESI,pos.ion)m/z＝552.3[M+H]⁺.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.88(d,J＝8.1Hz,2H),7.54(d,J＝8.1Hz,2H),7.33(d,J＝8.8Hz,2H),7.20(br,1H),6.85(d,J＝8.8Hz,2H),3.77(s,2H),3.18-3.07(m,6H),2.57–2.50(m,4H),2.19(d,J＝7.0Hz,2H),2.06-1.88(m,5H),1.78-1.63(m,5H),1.31(t,J＝7.3Hz,3H).

Example 42- (4- (ethylsulfonyl) phenyl) -N- (4- (4- ((1R,4R) -4- (trifluoromethyl) cyclohexylformyl) piperazin-1-yl) phenyl) acetamide

2- (4- (ethylsulfonyl) phenyl) -N- (4- (piperazin-1-yl) phenyl) acetamide (220mg,0.57mmol), 4- (trifluoromethyl) cyclohexanecarboxylic acid (167mg,0.85mmol), EDCI (219mg,1.14mmol) and HOBT (156mg,1.15mmol) were dissolved in DCM (10mL) and stirred at room temperature for 18 h. The reaction was diluted with DCM (90mL) and saturated NaHCO₃Solution (50mL) washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 40/1) to give a white solid (250mg, 78%).

MS(ESI,pos.ion)m/z＝566.1[M+H]⁺.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.93(s,1H),7.81(d,J＝8.2Hz,2H),7.49(d,J＝8.2Hz,2H),7.37(d,J＝8.9Hz,2H),6.82(d,J＝9.0Hz,2H),3.73(s,4H),3.64(s,2H),3.08(dd,J＝14.8,7.4Hz,6H),2.51(ddd,J＝11.8,8.7,3.3Hz,1H),2.09–1.99(m,3H),1.87(d,J＝14.0Hz,2H),1.66–1.53(m,2H),1.43–1.33(m,2H),1.25(t,J＝7.4Hz,3H).

Example 5N- ((R) -1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) -4- ((S) -3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzamide

The method comprises the following steps: synthesis of tert-butyl (S) -3- (4- (trifluoromethyl) phenoxy) piperidine-1-carboxylate

NaH (403mg,10.1mmol, 60%) was added to a solution of tert-butyl (S) -3-hydroxypiperidine-1-carboxylate (1.0g,5.0mmol) and 1-bromo-4- (trifluoromethyl) benzene (2.0mL,14.0mmol) in DMF (20mL) with stirring in an ice bath under nitrogen, after 20min, the reaction was heated by an 80 ℃ oil bath and stirred for 21 h. EtOAc (100mL) is added to the reaction solution followed by saturated NH₄Cl (aq.) (30 mL. times.5) washes with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/DCM/EtOAc (v/v/v) ═ 10/1/1) to give a yellow solid (629mg, 37%).

MS(ESI,pos.ion)m/z＝290.1[M+H-56]⁺.

Step two: synthesis of (S) -3- (4- (trifluoromethyl) phenoxy) piperidine

Tert-butyl (S) -3- (4- (trifluoromethyl) phenoxy) piperidine-1-carboxylate (1.35g,3.91mmol) was dissolved in HCl in MeOH (20mL) and stirred at room temperature for 2 h. Following by TLC, the starting material was substantially converted. Adding saturated Na to the reaction solution₂CO₃(aq.) (50mL) quench the reaction, then extract the aqueous phase with DCM (40 mL. times.3), combine the organic phases and wash with saturated NaCl solution (30mL), anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow oily liquid (639mg, 67%). MS (ESI, pos.ion) M/z 246.3[ M + H ═ M + H]⁺.

Step three: synthesis of methyl (S) -4- (3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoate

Under nitrogen protection, (S) -3- (4- (trifluoromethyl) phenoxy) piperidine (200mg,0.82mmol), methyl 4-iodobenzoate (430mg,1.64mmol), Pd₂(dba)₃(40mg,0.044mmol), XantPhos (35mg,0.06mmol) and Cs₂CO₃(530mg,1.62mmol) was dissolved in 1, 4-dioxane (4mL) and the reaction was stirred in a 100 ℃ oil bath with heating for 22 h. Adding saturated NaHCO into the reaction solution₃Solution (30mL), then the aqueous phase was extracted with DCM (40 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (20mL), anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/DCM/EtOAc (v/v/v) ═ 10/1/1) to give a yellow solid (200mg, 65%). MS (ESI, pos. ion) M/z 380.1[ M + H ═ M]⁺.

Step four: synthesis of (S) -4- (3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoic acid

Reacting LiOH & H₂O (122mg,2.91mmol) was added to a solution of methyl (S) -4- (3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoate (200mg,0.53mmol) in THF/MeOH (3mL/3mL) and stirred at room temperature for 12 h. Then heated by an oil bath at 60 ℃ for 1.0h, and a large amount of raw materials still remain. Additional THF/H₂O (6mL/3mL), heated in an oil bath at 60 ℃ for 1.0h, and the starting material was completely converted. The reaction solution was diluted with DCM (60mL) and water (20mL), then 1.0M HCl solution was added dropwise to adjust the pH of the system to 2-3, the layers were separated, the aqueous layer was extracted with DCM (20mL × 2), the organic layers were combined and anhydrous Na was added₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 5/1) to give a pale yellow solid (190mg, 98%).

MS(ESI,pos.ion)m/z＝366.1[M+H]⁺.

Step five: synthesis of N- ((R) -1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) -4- ((S) -3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzamide

(S) -4- (3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoic acid (90mg,0.25mmol), (R) -2-amino-2- (5- (ethylsulfonyl) pyridin-2-yl) ethanol (90mg,0.30mmol), EDCI (98mg,0.51 mm)ol) and HOBT (70mg,0.52mmol) were dissolved in DCM (6mL) and TEA (0.18mL,1.30mmol) was added and stirred at room temperature for 12 h. The reaction was diluted with DCM (60mL) and saturated NaHCO₃The solution (20mL) was washed with NaCl solution (20mL) and anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a yellow solid (60mg, 42%).

MS(ESI,pos.ion)m/z＝578.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.79(s,1H),8.55(d,J＝7.7Hz,1H),8.11(dd,J＝8.2,1.8Hz,1H),8.03(d,J＝8.0Hz,1H),7.77(d,J＝8.8Hz,2H),7.64(d,J＝8.6Hz,2H),7.15(d,J＝8.6Hz,2H),6.96(d,J＝8.8Hz,2H),5.16(dd,J＝13.8,6.8Hz,1H),5.10(t,J＝5.8Hz,1H),4.64(ddd,J＝11.6,7.2,4.1Hz,1H),3.83–3.70(m,3H),3.52(m,2H),3.42(m,3H),3.30–3.22(m,1H),3.15(m,1H),2.09–2.15(m,1H),1.89–1.79(m,1H),1.67(s,2H),1.13(t,J＝7.4Hz,3H).

Example 6N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((R) -3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzamide

The method comprises the following steps: synthesis of tert-butyl (R) - (3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) carboxylate

NaH (400mg,10.00mmol, 60%) was added to a solution of tert-butyl (R) - (3-hydroxypiperidin-1-yl) carboxylate (1.00g,4.97mmol) and 1-bromo-4- (trifluoromethyl) benzene (2mL,14.00mmol) in DMF (20mL) with stirring in an ice bath under nitrogen, after 20min, the reaction was heated in an 80 ℃ oil bath with stirring for 21 h. The reaction was cooled to room temperature, EtOAc (100mL) was added to the reaction, and saturated NH was used₄Cl solution (30 mL. times.5) washing, anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/DCM/EtOAc (v/v) ═ 10/1/1) to give a yellow solid (700mg, 41%).

MS(ESI,pos.ion)m/z＝290.1[M+H-56]⁺.

Step two: synthesis of (R) -3- (4- (trifluoromethyl) phenoxy) piperidine

Tert-butyl (R) - (3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) carboxylate (1.35g,3.91mmol) was dissolved in a solution of HCl in methanol (20mL) and stirred at room temperature for 2 h. Adding saturated Na to the reaction solution₂CO₃The reaction was quenched with solution (50mL), the aqueous phase extracted with DCM (40 mL. times.3), the organic phases combined and washed with saturated NaCl solution (30mL) anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow oily liquid (639mg, 67%).

MS(ESI,pos.ion)m/z＝246.3[M+H]⁺.

Step three: synthesis of methyl (R) -4- (3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoate

Under nitrogen protection, (R) -3- (4- (trifluoromethyl) phenoxy) piperidine (200mg,0.82mmol), methyl 4-iodobenzoate (430mg,1.64mmol), Pd₂(dba)₃(40mg,0.04mmol), XantPhos (35mg,0.06mmol) and Cs₂CO₃(530mg,1.62mmol) was dissolved in 1, 4-dioxane (4mL) and the reaction was stirred in a 100 ℃ oil bath with heating for 22 h. The reaction solution was cooled to room temperature and saturated NaHCO was added₃Solution (30mL), extraction of the aqueous phase with DCM (40 mL. times.3), combination of the organic phases and washing with saturated NaCl solution (20mL), anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/DCM/EtOAc (v/v/v) ═ 10/1/1) to give a yellow solid (210mg, 68%).

MS(ESI,pos.ion)m/z＝380.1[M+H]⁺.

Step four: synthesis of (R) -4- (3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoic acid

Reacting LiOH & H₂O (122mg,2.91mmol) was added to a solution of methyl (R) -4- (3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoate (200mg,0.53mmol) in THF/MeOH (3mL/3mL) and the reaction was heated in a 60 ℃ oil bath and stirred for 8 h. The reaction solution is cooled to room temperature, diluted by DCM (60mL) and water (20mL), added with HCl solution (1mol/L) to adjust the pH of the system to about 3, separated, the aqueous phase is extracted by DCM (20 mL. times.2), and the organic phases are combined and extracted by anhydrousWater Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 5/1) to give a pale yellow solid (192mg, 99%).

MS(ESI,pos.ion)m/z＝366.1[M+H]⁺.

Step five: synthesis of N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((S) -3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzamide

(R) -4- (3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoic acid (192mg,0.52mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (145mg,0.63mmol), EDCI (200mg,1.04mmol) and HOBT (140mg,1.04mmol) were dissolved in DCM (10mL) and TEA (0.22mL,1.60mmol) was added and stirred at room temperature for 12 h. The reaction was diluted with DCM (60mL) and successively with saturated NaHCO₃The solution (20mL) was washed with NaCl solution (20mL) and anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a pale yellow powder (210mg, 70%).

MS(ESI,pos.ion)m/z＝577.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.49(d,J＝7.8Hz,1H),7.82(d,J＝8.3Hz,2H),7.78(d,J＝8.7Hz,2H),7.64(d,J＝7.3Hz,4H),7.16(d,J＝8.6Hz,2H),6.96(d,J＝8.9Hz,2H),5.12(dd,J＝14.0,7.0Hz,1H),5.01(t,J＝5.8Hz,1H),4.68–4.61(m,1H),3.78(dd,J＝13.3,2.6Hz,1H),3.70(qd,J＝11.4,5.4Hz,2H),3.56-3.48(m,1H),3.25(q,J＝7.3Hz,2H),3.29–3.22(m,1H),3.18–3.12(m,1H),2.14–2.06(m,1H),1.89–1.79(m,1H),1.67(t,J＝7.9Hz,2H),1.09(t,J＝7.3Hz,3H).

Example 7N- ((R) -1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) -4- ((R) -3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzamide

(R) -4- (3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoic acid (90mg,0.25mmol), (R) -2-amino-2- (5- (ethylsulfonyl) ethyl esterAcyl) pyridin-2-yl) ethanol (90mg,0.30mmol), EDCI (98mg,0.51mmol) and HOBT (70mg,0.52mmol) were dissolved in DCM (6mL) and TEA (0.18mL,1.30mmol) was added and stirred at room temperature for 12 h. The reaction was diluted with DCM (60mL) and saturated NaHCO₃The solution (20mL) was washed with NaCl solution (20mL) and anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a yellow solid (70mg, 49%).

MS(ESI,pos.ion)m/z＝578.1[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.79(s,1H),8.55(d,J＝7.6Hz,1H),8.11(dd,J＝8.1,1.7Hz,1H),8.03(d,J＝8.1Hz,1H),7.77(d,J＝8.8Hz,2H),7.64(d,J＝8.6Hz,2H),7.15(d,J＝8.6Hz,2H),6.96(d,J＝8.8Hz,2H),5.16(dd,J＝13.8,6.7Hz,1H),5.11(t,J＝5.7Hz,1H),4.69–4.59(m,1H),3.76(m,3H),3.52(d,J＝13.4Hz,1H),3.42(q,J＝7.4Hz,2H),3.31–3.21(m,1H),3.19–3.12(m,1H),2.10(d,J＝11.2Hz,1H),1.83(d,J＝10.2Hz,1H),1.73–1.60(m,2H),1.13(t,J＝7.4Hz,3H).

EXAMPLE 8(R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (2-oxo-3- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-1 (2H) -yl) benzamide

The method comprises the following steps: synthesis of tert-butyl (3- ((4- (trifluoromethyl) benzyl) amino) propyl) carbamate

(3-aminopropyl) carbamic acid tert-butyl ester (1.03g,5.91mmol) and 4- (trifluoromethyl) benzaldehyde (1.53g,8.79mmol) were dissolved in EtOH (10mL) under ice-bath, stirred at room temperature for 1.0h, NaBH added₃CN (1.12g,17.8mmol), stirring was continued at room temperature for 6 h. Adding saturated Na to the reaction solution₂CO₃The reaction was quenched with solution (30mL), the aqueous phase extracted with DCM (30Ml X3), the organic phases combined and washed with saturated NaCl solution (20mL) anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow oil (844mg, 4)3％)。

MS(ESI,pos.ion)m/z＝333.3[M+H]⁺.

Step two: synthesis of 1- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-2 (1H) -one

t-BuOK (863mg,7.71mmol) was added to a solution of tert-butyl (3- ((4- (trifluoromethyl) benzyl) amino) propyl) carbamate (844mg,2.54mmol) in THF (10mL) with stirring in an ice bath under nitrogen protection, after addition, stirred at room temperature for 30min, reacted in a 60 ℃ oil bath with heating and stirring for 27 h. The reaction was cooled to room temperature, water was added to dissolve the solid, the aqueous phase was extracted with DCM (40 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (20mL), anhydrous Na₂SO₄Drying and concentration under reduced pressure gave the crude product as a yellow solid (655mg, 99%).

MS(ESI,pos.ion)m/z＝259.3[M+H]⁺.

Step three: synthesis of methyl 4- (2-oxo-3- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-1 (2H) -yl) benzoate

Under the protection of nitrogen, 1- (4- (trifluoromethyl) benzyl) tetrahydropyrimidine-2 (1H) -one (655mg,2.54mmol), methyl 4-bromobenzoate (1.03g,4.79mmol), Pd₂(dba)₃(123mg,0.13mmol), XantPhos (116mg,0.20mmol) and Cs₂CO₃(2.51g,7.65mmol) was dissolved in 1, 4-dioxane (10mL) and the reaction was stirred in a 100 ℃ oil bath with heating for 22 h. The reaction was cooled to room temperature, concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: PE/DCM/EtOAc (v/v) ═ 2/1/1) to give the title compound as a yellow solid (487mg, 49%).

MS(ESI,pos.ion)m/z＝393.3[M+H]⁺.

Step four: synthesis of 4- (2-oxo-3- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-1 (2H) -yl) benzoic acid

Reacting LiOH & H₂O (265mg,6.32mmol) methyl 4- (2-oxo-3- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-1 (2H) -yl) benzoate (487mg,1.24mmol) in THF/H₂O (10mL/3mL) solution, the reaction was stirred by heating in a 50 ℃ oil bath for 18 h. Adding water (20mL) into the reaction solution, dropwise adding HCl solution (1mol/L) into the system, adjusting the pH of the solution to about 3, and concentrating the water phase under reduced pressure to obtain a crude product which is yellowA colored solid (464mg, 99%).

Step five: synthesis of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (2-oxo-3- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-1 (2H) -yl) benzamide

4- (2-oxo-3- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-1 (2H) -yl) benzoic acid (232mg,0.6133mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (173mg,0.75mmol), EDCI (235mg,1.23mmol) and HOBT (167mg,1.24mmol) were dissolved in DCM (12mL) and TEA (0.26mL,1.9mmol) was added and stirred at room temperature for 20H. DCM (60mL) was added to the reaction solution, followed by saturated NaCl solution (20mL) and saturated NaHCO₃Solution (20mL) washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a pale yellow solid (225mg, 62%).

MS(ESI,pos.ion)m/z＝590.4[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.74(d,J＝7.8Hz,1H),7.88(d,J＝8.6Hz,2H),7.85(d,J＝8.3Hz,2H),7.73(d,J＝8.1Hz,2H),7.67(d,J＝8.3Hz,2H),7.53(d,J＝8.0Hz,2H),7.43(d,J＝8.6Hz,2H),5.15(dd,J＝13.7,7.1Hz,1H),5.05(t,J＝5.9Hz,1H),4.63(s,2H),3.80–3.66(m,4H),3.39–3.35(m,2H),3.27(q,J＝7.3Hz,2H),2.06(dd,J＝11.6,6.0Hz,2H),1.10(t,J＝7.3Hz,3H).

Example 9N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((S) -6- (methoxymethyl) -2-oxo-3- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-1 (2H) -yl) benzamide

The method comprises the following steps: synthesis of (S) -2- ((tert-butoxyformyl) amino) -4- ((4- (trifluoromethyl) benzyl) amino) butanoic acid

(S) -4-amino-2- ((tert-butoxyformyl) amino) butyric acid (3.03g,13.90mmol) and 4- (trifluoromethyl) benzaldehyde (2.0mL,15.00mmol) were dissolved in EtOH (30mL) under ice-bath, stirred at room temperature for 6h and NaBH was added₃CN(4.32g,68.70mmol)，Stirred at room temperature for 10 h. The reaction was concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a white solid (4.0g, 77%).

MS(ESI,pos.ion)m/z＝377.3[M+H]⁺.

Step two: synthesis of (S) -4- ((tert-butoxyformyl) (4- (trifluoromethyl) benzyl) amino) -2- ((tert-butoxyformyl) amino) butanoic acid

Boc in ice bath₂O (2.40mL,10.00mmol) was added (S) -2- ((tert-butoxyformyl) amino) -4- ((4- (trifluoromethyl) benzyl) amino) butanoic acid (4.0g,11.00mmol) and NaOH (850mg,21.25mmol) in THF/H₂To a solution of O (20mL/20mL), the mixture was stirred at room temperature for 8 hours after the addition. HCl solution (1mol/L) was added to the reaction solution, the pH of the solution was adjusted to about 5, the aqueous phase was extracted with DCM (40 mL. times.3), the organic phases were combined and anhydrous Na was used₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 2/1) to give a light yellow oil (3.05g, 60%).

MS(ESI,neg.ion)m/z＝475.3[M-H]^-.

Step three: synthesis of methyl (S) -2-amino-4- ((4- (trifluoromethyl) benzyl) amino) butyrate

Under ice bath, SOCl was added₂(2.8mL,39mmol) was added to a solution of (S) -4- ((tert-butoxyformyl) (4- (trifluoromethyl) benzyl) amino) -2- ((tert-butoxyformyl) amino) butyric acid (3.05g,6.40mmol) in MeOH (30mL) and stirred at room temperature for 1h, heated in an oil bath at 80 ℃ and stirred for 3 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and saturated Na was added to the residue₂CO₃The reaction was quenched with solution (30mL), the aqueous phase extracted with DCM (40 mL. times.3), the organic phases combined and washed with saturated NaCl solution (30mL) anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a pale yellow oily liquid (1.82g, 98%).

MS(ESI,pos.ion)m/z＝291.3[M+H]⁺.

Step four: synthesis of (S) -2-oxo-1- (4- (trifluoromethyl) benzyl) hexahydropyrimidine-4-carboxylic acid methyl ester

CDI (3.00g,18.50mmol) was added to a solution of methyl (S) -2-amino-4- ((4- (trifluoromethyl) benzyl) amino) butanoate (1.82g,6.27mmol) in THF (60mL) at-10 deg.C, after 30min, stirring was carried out at room temperature for 10 h. The reaction was concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 40/1) to give a yellow transparent liquid (1.20g, 60%).

MS(ESI,pos.ion)m/z＝317.3[M+H]⁺.

Step five: synthesis of (S) -4- (hydroxymethyl) -1- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-2 (1H) -one

Reacting LiBH₄To a solution of methyl (S) -2-oxo-1- (4- (trifluoromethyl) benzyl) hexahydropyrimidine-4-carboxylate (1.20g,3.79mmol) in THF (4mL) was added a THF solution of (6.0mL,12.00mmol) and stirred at room temperature for 12 h. Adding saturated NaHCO into the reaction solution₃The reaction was quenched with solution (20mL), the aqueous phase extracted with DCM (30 mL. times.3), the organic phases combined and washed with saturated NaCl solution (20mL) anhydrous Na₂SO₄Dried and concentrated under reduced pressure and the crude product was chromatographed on silica gel (eluent: DCM/MeOH (v/v) ═ 20/1) to give a pale yellow solid (274mg, 25%).

MS(ESI,pos.ion)m/z＝289.1[M+H]⁺.

Step six: synthesis of methyl (S) - (2-oxo-1- (4- (trifluoromethyl) benzyl) hexahydropyrimidin-4-yl) methanesulfonate

MsCl (0.10mL,1.30mmol) was added to a solution of (S) -4- (hydroxymethyl) -1- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-2 (1H) -one (37mg,0.13mmol) and TEA (0.60mL,4.30mmol) in DCM (4mL) under ice-cooling and stirred at room temperature for 12H. Adding saturated NaHCO into the reaction solution₃The reaction was quenched with solution (20mL), the aqueous phase was extracted with DCM (30 mL. times.3), the organic phases were combined and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a yellow solid (47mg, 100%).

MS(ESI,pos.ion)m/z＝367.1[M+H]⁺.

Step seven: synthesis of (S) -4- (methoxymethyl) -1- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-2 (1H) -one

Will K₂CO₃(209mg,1.51mmol) was added to a solution of methyl (S) - (2-oxo-1- (4- (trifluoromethyl) benzyl) hexahydropyrimidin-4-yl) methanesulfonate (47mg,0.13mmol) in MeOH (10mL) and the reaction was heated with stirring in oil at 66 deg.CAnd (4) 12 h. The reaction was cooled to room temperature, water was added to the reaction until the solid was completely dissolved, the aqueous phase was extracted with DCM (20 mL. times.3), the organic phases were combined and anhydrous Na was used₂SO₄Dried and concentrated under reduced pressure to give a yellow solid (38mg, 98%).

MS(ESI,pos.ion)m/z＝303.1[M+H]⁺.

Step eight: synthesis of methyl (S) -4- (6- (methoxymethyl) -2-oxo-3- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-1 (2H) -yl) benzoate

Under the protection of nitrogen, (S) -4- (methoxymethyl) -1- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-2 (1H) -one (38mg,0.13mmol), methyl 4-bromobenzoate (54mg,0.25mmol), Pd₂(dba)₃(58mg,0.06mmol), XantPhos (54mg,0.09mmol) and Cs₂CO₃(132mg,0.40mmol) was dissolved in 1, 4-dioxane (4mL) and the reaction was heated in a 100 ℃ oil bath with stirring for 24 h. The reaction was cooled to room temperature, concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: PE/DCM/EtOAc (v/v) ═ 2/1/1) to give a yellow solid (38mg, 69%).

MS(ESI,pos.ion)m/z＝437.4[M+H]⁺.

Step nine: synthesis of (S) -4- (6- (methoxymethyl) -2-oxo-3- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-1 (2H) -yl) benzoic acid

Methyl (S) -4- (6- (methoxymethyl) -2-oxo-3- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-1 (2H) -yl) benzoate (38mg,0.09mmol) and LiOH. H₂O (80mg,1.91mmol) was dissolved in THF/MeOH (1mL/1mL) and stirred at room temperature for 5 h. Adding water to the reaction solution to dissolve the solid, adding HCl solution (1mol/L) dropwise to dissolve, adjusting the pH of the solution to about 4, extracting the mixed solution with DCM (20mL multiplied by 3), combining organic phases and using anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a yellow solid (36mg, 98%).

MS(ESI,pos.ion)m/z＝423.2[M+H]⁺.

Step ten: synthesis of N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((S) -6- (methoxymethyl) -2-oxo-3- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-1 (2H) -yl) benzamide

Reacting (S) -4- (6- (methoxyl group)Methyl) -2-oxo-3- (4- (trifluoromethyl) benzyl) tetrahydropyrimidin-1 (2H) -yl) benzoic acid (36mg,0.09mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (30mg,0.13mmol), EDCI (50mg,0.26mmol) and HOBT (35mg,0.26mmol) were dissolved in DCM (4mL) and TEA (0.10mL,0.72mmol) was added and stirred at room temperature for 10H. The reaction was diluted with DCM (60mL) and saturated NaHCO₃Solution (20mL) washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 20/1) to give a yellow solid (20mg, 37%).

MS(ESI,pos.ion)m/z＝634.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.78(d,J＝7.8Hz,1H),7.89(d,J＝8.5Hz,2H),7.84(d,J＝8.3Hz,2H),7.73(d,J＝8.0Hz,2H),7.67(d,J＝8.3Hz,2H),7.51(d,J＝7.9Hz,2H),7.40(d,J＝8.5Hz,2H),5.20–5.10(dd,1H),5.05(t,J＝5.7Hz,1H),4.61(dd,J＝25.2Hz,15.5Hz,2H),4.06-4.14(m,1H),3.80–3.66(m,2H),3.48–3.40(m,2H),3.31(q,J＝7.3Hz,2H),3.18(s,3H),2.22–2.13(m,1H),2.10–2.04(m,1H),2.02–1.94(m,2H),1.10(t,J＝7.3Hz,3H).

Example 10N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((S) -3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzamide

The method comprises the following steps: synthesis of tert-butyl (S) - (3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) carboxylate

NaH (403mg,10.10mmol, 60%) was added to a solution of tert-butyl (S) - (3-hydroxypiperidin-1-yl) carboxylate (1.00g,4.97mmol) and 1-bromo-4- (trifluoromethyl) benzene (2mL,14.00mmol) in DMF (20mL) with stirring in an ice bath under nitrogen, after 20min, the reaction was heated in an 80 ℃ oil bath with stirring for 21 h. The reaction was cooled to room temperature, EtOAc (100mL) was added to the reaction, and saturated NH was used₄Cl solution (30 mL. times.5) washing, anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product isolated by column chromatography on silica gel (eluent: PE/DCM/EtOAc (v/v/v)10/1/1) to give a yellow solid (629mg, 37%).

MS(ESI,pos.ion)m/z＝290.1[M+H-56]⁺.

Step two: synthesis of (S) -3- (4- (trifluoromethyl) phenoxy) piperidine

Tert-butyl (S) - (3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) carboxylate (1.35g,3.91mmol) was dissolved in HCl in MeOH (20mL) and stirred at room temperature for 2 h. Adding saturated Na to the reaction solution₂CO₃The reaction was quenched with solution (50mL), the aqueous phase extracted with DCM (40 mL. times.3), the organic phases combined and washed with saturated NaCl solution (30mL) anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow oily liquid (639mg, 67%).

MS(ESI,pos.ion)m/z＝246.3[M+H]⁺.

Under nitrogen protection, (S) -3- (4- (trifluoromethyl) phenoxy) piperidine (200mg,0.82mmol), methyl 4-iodobenzoate (430mg,1.64mmol), Pd₂(dba)₃(40mg,0.04mmol), XantPhos (35mg,0.06mmol) and Cs₂CO₃(530mg,1.62mmol) was dissolved in 1, 4-dioxane (4mL) and the reaction was stirred in a 100 ℃ oil bath with heating for 22 h. The reaction solution was cooled to room temperature and saturated NaHCO was added₃Solution (30mL), extraction of the aqueous phase with DCM (40 mL. times.3), combination of the organic phases and washing with saturated NaCl solution (20mL), anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/DCM/EtOAc (v/v/v) ═ 10/1/1) to give a yellow solid (200mg, 65%).

MS(ESI,pos.ion)m/z＝380.1[M+H]⁺.

Reacting LiOH & H₂O (122mg,2.91mmol) was added to a solution of methyl (S) -4- (3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoate (200mg,0.53mmol) in THF/MeOH (3mL/3mL) and the reaction was heated in a 60 ℃ oil bath and stirred for 8 h. The reaction solution was cooled to room temperatureDiluting with DCM (60mL) and water (20mL), adding HCl solution (1mol/L) to adjust system pH to about 3, separating, extracting water phase with DCM (20mL × 2), combining organic phases and using anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 5/1) to give a pale yellow solid (190mg, 98%).

MS(ESI,pos.ion)m/z＝366.1[M+H]⁺.

(S) -4- (3- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoic acid (190mg,0.52mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (145mg,0.63mmol), EDCI (200mg,1.04mmol) and HOBT (140mg,1.04mmol) were dissolved in DCM (10mL) and TEA (0.22mL,1.60mmol) was added and stirred at room temperature for 12 h. The reaction was diluted with DCM (60mL) and successively with saturated NaHCO₃The solution (20mL) was washed with NaCl solution (20mL) and anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a pale yellow powder (240mg, 80%).

MS(ESI,pos.ion)m/z＝577.1[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.49(d,J＝8.0Hz,1H),7.83(d,J＝8.2Hz,2H),7.78(d,J＝8.7Hz,2H),7.64(d,J＝6.2Hz,4H),7.17(d,J＝8.8Hz,2H),6.97(d,J＝8.9Hz,2H),5.15–5.07(m,1H),5.02(t,J＝5.8Hz,1H),4.69–4.61(m,1H),3.83–3.76(m,1H),3.75–3.65(m,2H),3.41-3.61(m,1H),3.47-3.43(m,1H),3.40(q,J＝7.4Hz,2H),3.26–3.22(m,1H),2.15–2.05(m,1H),1.89–1.80(m,1H),1.68(dd,J＝9.3,7.3Hz,2H),1.10(t,J＝7.3Hz,3H).

Example 11N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((2S,5S) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzamide

The method comprises the following steps: synthesis of (2S,5S) -1-tert-butyl 2-methyl 5- ((tert-butyldimethylsilyl) oxy) piperidine-1, 2-dicarboxylate

TBSOTf (6.00mL,26.00mmol) was added slowly dropwise to (2S,5S) -1-tert-butyl 2-methyl 5-hydroxypiperidine-1, 2-dicarboxylate (4.68g,18.06mmol) and TEA (5.00mL,35.97mmol) in DCM (40mL) under ice-cooling, and after addition, the mixture was stirred at room temperature for 12 h. Adding saturated NaHCO into the reaction solution₃The reaction was quenched with solution (50mL), the aqueous phase was extracted with DCM (50 mL. times.3), the organic phases were combined and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: PE/DCM/EtOAc (v/v/v) ═ 20/1/1) to give a yellow oily liquid (5.07g, 75%).

MS(ESI,pos.ion)m/z＝396.0[M+Na]⁺.

Step two: synthesis of tert-butyl (2S,5S) - (5- ((tert-butyldimethylsilyl) oxy) -2- (hydroxymethyl) piperidin-1-yl) carboxylate

At room temperature, LiBH is added₄To a solution of (2S,5S) -1-tert-butyl 2-methyl 5- ((tert-butyldimethylsilyl) oxy) piperidine-1, 2-dicarboxylate (5.07g,13.60mmol) in THF (10mL) was slowly added a THF solution of (20mL,40.00mmol,2.0mol/L) and stirred at room temperature for 5 h. Adding saturated NaHCO into the reaction liquid₃The reaction was quenched with solution (40mL), the aqueous phase was extracted with DCM (40 mL. times.3), the organic phases were combined and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 10/1) to give a yellow oily liquid (3.09g, 66%).

MS(ESI,pos.ion)m/z＝368.2[M+Na]⁺.

Step three: synthesis of (6S,8S) -6- ((tert-butyldimethylsilyl) oxy) tetrahydro-1H-oxazolo [3,4-a ] pyridin-3 (5H) -one

t-BuOK (116mg,1.03mmol) was added to a solution of tert-butyl (2S,5S) -5- ((tert-butyldimethylsilyl) oxy) -2- (hydroxymethyl) piperidine-1-carboxylate (290mg,0.84mmol) in THF (10mL) at-10 ℃ and stirred at room temperature for 12 h. Adding saturated NaHCO into the reaction liquid₃The reaction was quenched with solution (30mL), the aqueous phase extracted with DCM (30 mL. times.3), the organic phases combined and washed with saturated NaCl solution (20)mL) washing, anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a pale yellow oily liquid (210mg, 92%).

MS(ESI,pos.ion)m/z＝272.1[M+H]⁺.

Step four: synthesis of (6S,8S) -6-hydroxytetrahydro-1H-oxazolo [3,4-a ] pyridin-3 (5H) -one

A THF solution of TBAF (14mL,14.00mmol,1.0mol/L) was added to (6S,8S) -6- ((tert-butyldimethylsilyl) oxy) tetrahydro-1H-oxazole [3,4-a ]]Pyridin-3 (5H) -one (1.82g,6.71mmol) in THF (10mL) was stirred at room temperature for 5H. The reaction was concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a pale yellow solid (697mg, 66%). MS (ESI, pos.ion) M/z 158.1[ M + H ═ M + H]⁺.

Step five: synthesis of (6S,8S) -6- (4- (trifluoromethyl) phenoxy) tetrahydro-1H-oxazolo [3,4-a ] pyridin-3 (5H) -one

NaH (860mg,21.50mmol, 60%) was added to 1-fluoro-4- (trifluoromethyl) benzene (5.20mL,41.00mmol) and (6S,8S) -6-hydroxytetrahydro-1H-oxazole [3,4-a ] under nitrogen with stirring in an ice bath]Pyridin-3 (5H) -one (2.12g,13.50mmol) in DMF (50mL) was stirred at room temperature for 2H and heated in a 60 ℃ oil bath for 15H. The reaction was cooled to room temperature, EtOAc (120mL) was added to the reaction, followed by saturated NaHCO₃Solution (30mL) and saturated NH₄Cl solution (20 mL. times.5) was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a yellow solid (2.62g, 65%).

MS(ESI,pos.ion)m/z＝302.2[M+H]⁺.

Step six: synthesis of ((2S,5S) -5- (4- (trifluoromethyl) phenoxy) piperidin-2-yl) methanol

t-BuOK (4.87g,43.50mmol) was added to (6S,8S) -6- (4- (trifluoromethyl) phenoxy) tetrahydro-1H-oxazole [3,4-a ] under ice-bath]Pyridin-3 (5H) -one (2.62g,8.70mmol) of i-PrOH/THF/H₂O (20mL/10mL/1mL) solution was stirred at room temperature for 16 h. Adding saturated NaHCO into the reaction solution₃The reaction was quenched with solution (50mL), the aqueous phase extracted with DCM (50 mL. times.3), the organic phases combined and washed with saturated NaCl solution (3)0mL) of water, anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a yellow oil (2.30g, 96%).

MS(ESI,pos.ion)m/z＝276.0[M+H]⁺.

Step seven: synthesis of tert-butyl (2S,5S) - (2- (hydroxymethyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) carboxylate

Reacting Boc₂O (0.27mL,1.20mmol) was added ((2S,5S) -5- (4- (trifluoromethyl) phenoxy) piperidin-2-yl) methanol (217mg,0.79mmol) and K₂CO₃(330mg,2.39mmol) of THF/H₂O (10mL/3mL) solution, and stirred at room temperature for 12 h. Adding saturated NaHCO into the reaction solution₃The reaction was quenched with solution (40mL), the aqueous phase was extracted with DCM (40 mL. times.3), the organic phases were combined and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 5/1) to give a white solid (236mg, 80%). MS (ESI, pos.ion) M/z 398.2[ M + Na ═ M + Na]⁺.

Step eight: synthesis of tert-butyl (2S,5S) - (2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) carboxylate

KOAc (250mg,2.55mmol) was added to tert-butyl (2S,5S) - (2- (hydroxymethyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) carboxylate (236mg,0.63mmol) and TMSCF₂Br (0.50mL,3.20mmol) in DCM/H₂O (2mL/2mL) solution, and stirred at room temperature for 12 h. Supplemented TMSCF₂Br (0.50mL,3.20mmol) and stirring was continued for 6 h. DCM (80mL) was added to the reaction, followed by saturated NaHCO₃The solution (20 mL. times.2) was washed and the organic phase was Na anhydrous₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/DCM/EtOAc (v/v/v) ═ 10/1/1) to give a pale yellow solid (197mg, 74%).

MS(ESI,pos.ion)m/z＝448.1[M+Na]⁺.

Step nine: synthesis of (2S,5S) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidine

(2S,5S) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidine-1-carboxylic acid tert-butyl ester (197mg,0.46mmol) was dissolved in HCl in MeOH (10mL, 20%),stirred at room temperature for 12 h. Adding saturated Na into the reaction solution₂CO₃To the solution (40mL), the aqueous phase was extracted with DCM (30 mL. times.3), the organic phases were combined and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a pale yellow oil (150mg, 100%).

MS(ESI,pos.ion)m/z＝326.2[M+H]⁺.

Step ten: synthesis of methyl 4- ((2S,5S) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoate

Under nitrogen protection, (2S,5S) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidine (150mg,0.46mmol), methyl 4-iodobenzoate (360mg,1.37mmol), Pd₂(dba)₃(21mg,0.02mmol), XantPhos (20mg,0.04mmol) and Cs₂CO₃(323mg,0.98mmol) was dissolved in 1, 4-dioxane (5mL) and the reaction was stirred in a 100 ℃ oil bath with heating for 22 h. The reaction solution was cooled to room temperature, and saturated NaHCO was added to the reaction solution₃The reaction was quenched with solution (50mL), the aqueous phase was extracted with DCM (40 mL. times.3), the organic phases were combined and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/DCM/EtOAc (v/v/v) ═ 10/1/1) to give a yellow solid (69mg, 33%).

MS(ESI,pos.ion)m/z＝460.2[M+H]⁺.

Step eleven: synthesis of 4- ((2S,5S) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoic acid

Reacting LiOH & H₂O (134mg,3.19mmol) was added to a solution of methyl 4- ((2S,5S) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoate (69mg,0.15mmol) in THF/MeOH (1mL/1mL) and stirred at room temperature for 12 h. Supplement of LiOH. H₂O (1.20g,28.60mmol), stirring was continued at room temperature for 6 h. DCM (80mL) and water (40mL) were added to the reaction solution, HCl solution (1mol/L) was added dropwise to adjust the pH of the system to about 3, the solution was separated, the aqueous phase was extracted with DCM (40 mL. times.2), the organic phases were combined and Na anhydrous₂SO₄Dried and concentrated under reduced pressure to give a yellow solid (60mg, 90%).

MS(ESI,pos.ion)m/z＝445.9[M+H]⁺.

Step twelve: synthesis of N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((2S,5S) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzamide

4- ((2S,5S) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoic acid (60mg,0.13mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (54mg,0.24mmol), EDCI (104mg,0.54mmol) and HOBT (75mg,0.56mmol) were dissolved in DCM (6mL) and TEA (0.12mL,0.86mmol) was added and the reaction stirred at room temperature for 12 h. DCM (60mL) was added to the reaction, followed by saturated NaHCO₃The solution (40mL) was washed with saturated NaCl solution (20mL) and dried over anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a yellow solid (50mg, 57%). MS (ESI, pos. ion) M/z 657.1[ M + H ═ M]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.51(d,J＝7.8Hz,1H),7.81(t,J＝8.9Hz,4H),7.65(t,J＝7.7Hz,4H),7.20(d,J＝8.5Hz,2H),7.01(d,J＝8.9Hz,2H),6.67(t,J＝76.0Hz,1H),5.12(dd,J＝13.8,6.9Hz,1H),5.00(t,J＝5.8Hz,1H),4.68–4.57(m,1H),4.32(s,1H),4.05(dd,J＝17.4,9.8Hz,1H),3.95(dd,J＝10.2,6.2Hz,2H),3.71(qd,J＝11.4,7.0Hz,2H),3.26(q,J＝7.4Hz,2H),3.12–3.03(m,1H),2.09(d,J＝8.8Hz,1H),1.91(dd,J＝10.9,9.3Hz,2H),1.78–1.63(m,1H),1.09(t,J＝7.3Hz,3H).

Example 12N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzamide

The title compound was prepared as a yellow solid (55mg, 63%) by the method of example 11, step one to step twelve, starting with (2S,5R) -1-tert-butyl 2-methyl 5-hydroxypiperidine-1, 2-dicarboxylate.

MS(ESI,pos.ion)m/z＝657.1[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.44(d,J＝7.8Hz,1H),7.82(d,J＝8.3Hz,2H),7.74(d,J＝8.8Hz,2H),7.63(d,J＝8.4Hz,4H),7.12(d,J＝8.6Hz,2H),6.89(d,J＝9.0Hz,2H),6.68(t,J＝75.8Hz,1H),5.11(dd,J＝13.8,7.1Hz,1H),4.99(t,J＝5.8Hz,1H),4.88-4.80(s,1H),4.43-4.29(m,1H),4.09–4.01(m,1H),3.93(dd,J＝16.3,6.3Hz,2H),3.76–3.62(m,2H),3.42–3.35(m,1H),3.25(q,J＝7.3Hz,2H),2.02(dd,J＝14.7,7.7Hz,2H),1.87-1.80(m,1H),1.75-1.62(m,1H),1.08(d,J＝7.3Hz,3H).

Example 13N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((2S,5S) -2- ((trifluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzamide

The method comprises the following steps: synthesis of tert-butyl (2S,5S) - (2- ((trifluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) carboxylate

2-Fluoropyridine (0.60mL,7.00mmol) and TMSCF under nitrogen₃(1.20mL,8.12mmol) tert-butyl (2S,5S) - (2- (hydroxymethyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) carboxylate (800mg,2.13mmol), AgOTf (2.21g,8.60mmol), Selectfluor (1.13g,3.19mmol) and KF (503mg,8.67mmol) in this order were added to a solution of EtOAc (20mL) and stirred at room temperature for 72 h. The reaction was filtered through celite, the filter cake was washed with DCM (50mL), and the filtrate was saturated NaHCO₃The solution (30 mL. times.2) was washed and the organic phase was Na anhydrous₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/DCM/EtOAc (v/v/v) ═ 10/1/1) to give a yellow oil (312mg, 33%).

MS(ESI,pos.ion)m/z＝388.1[M+H-56]⁺.

Step two: synthesis of (2S,5S) -2- ((trifluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidine

Tert-butyl (2S,5S) - (2- ((trifluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) carboxylate (312mg,0.70mmol) was dissolvedIn HCl in methanol (10mL, 20%) was stirred at room temperature for 4 h. Adding saturated Na into the reaction solution₂CO₃To the solution (40mL), the aqueous phase was extracted with DCM (30 mL. times.3), the organic phases were combined and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a pale yellow oil (240mg, 99%). MS (ESI, pos. ion) M/z 344.1[ M + H ═ M]⁺.

Step three: synthesis of methyl 4- ((2S,5S) -2- ((trifluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoate

Under nitrogen protection, (2S,5S) -2- ((trifluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidine (240mg,0.70mmol), methyl 4-iodobenzoate (550mg,2.10mmol), Pd₂(dba)₃(64mg,0.07mmol), XantPhos (60mg,0.10mmol) and Cs₂CO₃(463mg,1.41mmol) was dissolved in 1, 4-dioxane (6mL) and the reaction was stirred in a 100 ℃ oil bath with heating for 70 h. The reaction solution was cooled to room temperature, and saturated NaHCO was added to the reaction solution₃The reaction was quenched with solution (50mL), the aqueous phase was extracted with DCM (40 mL. times.3), the organic phases were combined and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: PE/DCM/EtOAc (v/v/v) ═ 5/1/1) to give a yellow oily solid (157mg, 47%).

MS(ESI,pos.ion)m/z＝478.2[M+H]⁺.

Step four: synthesis of 4- ((2S,5S) -2- ((trifluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoic acid

Reacting LiOH & H₂O (1.51g,36.00mmol) methyl 4- ((2S,5S) -2- ((trifluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoate (157mg,0.33mmol) in THF/MeOH/H was added₂O (3mL/3mL/1mL) solution, and stirred at room temperature for 72 h. DCM (80mL) and water (40mL) were added to the reaction solution, HCl solution (2mol/L) was added dropwise to adjust the pH of the system to about 3, the solution was separated, the aqueous phase was extracted with DCM (40 mL. times.2), the organic phases were combined and Na anhydrous₂SO₄Dried and concentrated under reduced pressure to give a yellow solid (124mg, 81%). MS (ESI, pos.ion) M/z 464.2[ M + H ═ M + H]⁺.

Step five: synthesis of N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((2S,5S) -2- ((trifluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzamide

4- ((2S,5S) -2- ((trifluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) benzoic acid (124mg,0.27mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (75mg,0.33mmol), EDCI (106mg,0.55mmol) and HOBT (76mg,0.56mmol) were dissolved in DCM (6mL) and TEA (0.16mL,1.10mmol) was added and stirred at room temperature for 12 h. DCM (80mL) was added to the reaction, followed by saturated NaHCO₃The solution (30mL) was washed with saturated NaCl solution (20mL) and dried over anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 2/1) to give a yellow solid (68mg, 38%).

MS(ESI,pos.ion)m/z＝675.1[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.54(d,J＝7.9Hz,1H),7.81(t,J＝8.6Hz,4H),7.65(t,J＝8.3Hz,4H),7.20(d,J＝8.5Hz,2H),7.03(d,J＝8.8Hz,2H),5.12(dd,J＝13.7,6.6Hz,1H),5.02(t,J＝5.8Hz,1H),4.63(ddd,J＝11.2,8.2,3.8Hz,1H),4.43(dd,J＝18.1,7.9Hz,1H),4.36–4.28(m,1H),4.24(dd,J＝9.9,6.8Hz,1H),3.97(dd,J＝13.1,4.9Hz,1H),3.78–3.63(m,2H),3.26(q,J＝7.3Hz,2H),3.16–3.06(m,1H),2.13–2.04(m,1H),2.00-1.88(m,2H),1.78–1.66(m,1H),1.09(t,J＝7.3Hz,3H).

Example 14N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (1- (4- (trifluoromethyl) benzyl) piperidin-2-yl) benzamide

The method comprises the following steps: synthesis of methyl 4- (5- ((tert-butoxycarbonyl) amino) pentanoyl) benzoate

Methyl 4-iodobenzoate (4.60g,18.00mmol) was dissolved in THF (20mL), cooled to-50 deg.C, added i-PrMgBr (17mL,17.00mmol), stirred at-50 deg.C for 1h, added tert-butyl 2-oxopiperidine-1-carboxylate (2.90g,15.00mmol), and the temperature was slowly returned to room temperature. Reacting for 3h, slowly adding dilute hydrochloric acid untilThe pH was acidic, extracted with EtOAc (25 mL. times.2), and the organic phases were combined over anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 10/1) to give a colorless liquid (2.75g, 56%). MS (ESI, pos.ion) M/z 358[ M + Na ]]⁺.

Step two: synthesis of methyl 4- (3,4,5, 6-tetrahydropyridin-2-yl) benzoate

Methyl 4- (5- ((tert-butoxycarbonyl) amino) pentanoyl) benzoate (2.57g,7.66mmol) was dissolved in DCM (10mL) and TFA (2.85mL,38.40mmol) was added and stirred at RT for 1 h. The reaction was diluted with DCM (30mL) and successively with saturated NaHCO₃The solution (15mL) was washed with saturated NaCl solution (15mL) and anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 10/1) to give a white solid (1.63g, 98%).

MS(ESI,pos.ion)m/z:218[M+H]⁺.

Step three: synthesis of methyl 4- (piperidin-2-yl) benzoate

Methyl 4- (3,4,5, 6-tetrahydropyridin-2-yl) benzoate (2.23g,11.00mmol) was dissolved in THF (12mL) and MeOH (5mL) and NaBH was added slowly at room temperature₄(0.11g,2.90 mmol). Reaction for 2h, quench with water, extract with EtOAc (15 mL. times.2), combine the organic phases, Na anhydrous₂SO₄Dried and concentrated under reduced pressure to give a colorless liquid (2.25g, 99%).

MS(ESI,pos.ion)m/z:220[M+H]⁺.

Step four: synthesis of tert-butyl (2- (4- (methoxycarbonyl) phenyl) piperidin-1-yl) carboxylate

Methyl 4- (piperidin-2-yl) benzoate (1.69g,7.71mmol) was dissolved in DCM (5mL), to which TEA (2mL,15.00mmol) and further Boc were added₂O (1.70g,7.71mmol), stirred at room temperature for 5 h. The reaction was diluted with DCM (30mL) and successively with saturated NH₄Cl solution (15mL) and saturated NaCl solution (15mL) were washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 5/1) to give a colorless liquid (1.98g, 80.4%).

MS(ESI,pos.ion)m/z:320[M+H]⁺.

Step five: synthesis of 4- (1- (tert-butoxycarbonyl) piperidin-2-yl) benzoic acid

Tert-butyl (2- (4- (methoxycarbonyl) phenyl) piperidin-1-yl) carboxylate (1.98g,6.20mmol) was dissolved in THF (10mL) and MeOH (10mL), to which LiOH (1.48g,61.80mmol) in H was added₂O (2mL) solution, stirring at room temperature for 12h, adding HCl solution (2mol/L) to the reaction solution to adjust the pH of the solution to about 5, extracting with EtOAc (25 mL. times.2), combining the organic phases, washing with saturated NaCl (20mL) solution, and adding anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 20/1) to give a white solid (1.66g, 88%).

MS(ESI,pos.ion)m/z:306[M+H]⁺.

Step six: synthesis of tert-butyl (2- (4- (((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) amido) phenyl) piperidin-1-yl) carboxylate

After 4- (1- (tert-butoxycarbonyl) piperidin-2-yl) benzoic acid (120mg,0.39mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (112mg,0.49mmol) and HATU (181mg,0.47mmol) were dissolved in DCM (12mL), TEA (0.12mL,0.92mmol) was added and stirred at room temperature for 24 h. The reaction was diluted with DCM (30mL) and successively with saturated NaHCO₃The solution (15ml) was washed with saturated NaCl solution (15ml) and anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a white solid (120mg, 59%).

MS(ESI,pos.ion)m/z:539[M+H]⁺.

Step seven: synthesis of N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (piperidin-2-yl) benzamide

Tert-butyl (2- (4- (((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) amido) phenyl) piperidin-1-yl) carboxylate (120mg,0.23mmol) was dissolved in DCM (10mL) and TFA (0.24mL,3.20mmol) was added slowly and stirred at room temperature for 3 h. The reaction was diluted with DCM (30mL) and successively with saturated NaHCO₃The solution (15ml) was washed with saturated NaCl solution (15ml) and anhydrous Na₂SO₄Drying and decompressingConcentrate to give a colorless liquid (94mg, 97%).

MS(ESI,pos.ion)m/z:417[M+H]⁺.

Step eight: synthesis of N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (1- (4- (trifluoromethyl) benzyl) piperidin-2-yl) benzamide

N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (piperidin-2-yl) benzamide (97mg,0.23mmol) was dissolved in MeOH (10mL), 4-trifluorobenzaldehyde (48mg,0.28mmol) was added, and NaBH was added₃CN (15mg,0.24mmol), stirred at room temperature for 12 h. The reaction was diluted with DCM (30mL) and successively with saturated NaHCO₃The solution (15ml) was washed with saturated NaCl solution (15ml) and anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a white solid (22mg, 16%).

MS(ESI,pos.ion)m/z:575[M+H]⁺.

¹H NMR(600MHz,CDCl₃)δ(ppm):7.87(dd,J＝8.4,2.0Hz,2H),7.82(d,J＝8.3Hz,2H),7.61–7.51(m,6H),7.40(d,J＝7.6Hz,2H),7.16(d,J＝6.7Hz,1H),5.32–5.28(m,1H),4.06(dt,J＝11.2,3.6Hz,1H),3.98(dd,J＝11.3,4.7Hz,1H),3.72(d,J＝14.2Hz,1H),3.24(d,J＝9.1Hz,1H),3.10(q,J＝7.4Hz,2H),2.95(d,J＝13.9Hz,2H),2.01(t,J＝11.3Hz,1H),1.82(dd,J＝26.3,12.9Hz,3H),1.69–1.57(m,3H),1.29(d,J＝7.1Hz,3H).

Example 15N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((2S) -2- ((difluoromethoxy) methyl) -5- ((4- (trifluoromethyl) phenyl) (methyl) amino) piperidin-1-yl) benzamide

The method comprises the following steps: synthesis of (2S) -1-tert-butyl 2-methyl 5- ((4- (trifluoromethyl) phenyl) amino) piperidine-1, 2-dicarboxylate

4- (trifluoromethyl) aniline (1.03g,6.39mmol), (S) -1-tert-butyl 2-methyl 5-oxopiperidine-1, 2-dicarboxylate (1.83g,7.11mmol) and AcOH (0.70mL,12mmol) were dissolved in toluene (20mL), reacted in an 80 ℃ oil bath and heated with stirring for 5h, concentrated under reduced pressureAnd (4) liquid. Reacting NaBH₃CN (4.0g,64mmol) was added to a solution of AcOH (0.40mL,7.0mmol) and the above concentrate in EtOH (20mL) and stirred at room temperature for 3 h. Then, the reaction solution was added with saturated Na₂CO₃To the solution (50mL), the aqueous phase was extracted with DCM (50 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (30mL), anhydrous Na₂SO₄Dried and concentrated under reduced pressure and the crude product was chromatographed on silica gel (eluent: PE/DCM/EtOAc (v/v/v) ═ 5/1/1) to give a yellow oil (1.55g, 62%).

MS(ESI,pos.ion)m/z＝403.1[M+H]⁺.

Step two: (2S,5R) - (2- (hydroxymethyl) -5- ((4- (trifluoromethyl) phenyl) amino) piperidin-1-yl) carboxylic acid tert-butyl ester

At room temperature, LiBH is added₄To a suspension of (2S) -1-tert-butyl 2-methyl 5- ((4- (trifluoromethyl) phenyl) amino) piperidine-1, 2-dicarboxylate (1.0g,2.50mmol) in THF (4mL) was added dropwise a THF solution (7.5mL,7.50mmol,1.0M) and stirred for 5 h. Following by TLC, conversion of starting material was complete. Adding saturated NaHCO into the reaction liquid₃To the solution (40mL) and then extracted with DCM (30 mL. times.3), the organic phases were combined and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 5/1) to give a yellow solid (294mg, 32%).

MS(ESI,pos.ion)m/z＝319.2[M-56+H]⁺.

Step three: synthesis of tert-butyl (2S,5R) - (2- (hydroxymethyl) -5- (methyl- (4- (trifluoromethyl) phenyl) amino) piperidin-1-yl) carboxylate

Tert-butyl (2S,5R) - (2- (hydroxymethyl) -5- ((4- (trifluoromethyl) phenyl) amino) piperidin-1-yl) carboxylate (222mg,0.59mmol), formaldehyde (120mg,4.00mmol) and AcOH (0.10mL,1.70mmol) were dissolved in toluene (8mL) and the reaction was heated in an 80 ℃ oil bath with stirring for 6 h. Concentrating under reduced pressure to obtain crude product. Reacting NaBH₃CN (360mg,5.73mmol) was added to the above crude product and AcOH (0.10mL,1.70mmol) in EtOH (5mL) and stirred at room temperature for 9 h. Adding saturated Na to the reaction solution₂CO₃The reaction was quenched with solution (40mL), then the aqueous phase was extracted with DCM (40 mL. times.3), the organic phases were combined and Na anhydrous₂SO₄The mixture is dried and then is dried,concentrated under reduced pressure and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 5/1) to give a yellow oil (66mg, 32%).

MS(ESI,pos.ion)m/z＝389.1[M+H]⁺.

Step four: synthesis of tert-butyl (2S,5R) -2- ((difluoromethoxy) methyl) -5- (methyl- (4- (trifluoromethyl) phenyl) amino) piperidin-1-yl) carboxylate

KOAc (70mg,0.71mmol) was added to tert-butyl (2S,5R) - (2- (hydroxymethyl) -5- (methyl- (4- (trifluoromethyl) phenyl) amino) piperidin-1-yl) carboxylate (66mg,0.17mmol) and TMSCF₂Br (0.30mL,1.90mmol) in DCM/H₂O (1mL/1mL) solution was stirred at room temperature for 22 h. DCM (80mL) was added to the reaction, followed by saturated NaHCO₃The solution (20 mL. times.2) was washed and the organic phase was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: PE/DCM/EtOAc (v/v/v) ═ 5/1/1) to give a yellow oily liquid (30mg, 40%).

MS(ESI,pos.ion)m/z＝439.1[M+H]⁺.

Step five: synthesis of (3R,6S) -6- ((difluoromethoxy) methyl) -N-methyl-N- (4- (trifluoromethyl) phenyl) piperidin-3-amine

Tert-butyl (2S,5R) -2- ((difluoromethoxy) methyl) -5- (methyl- (4- (trifluoromethyl) phenyl) amino) piperidin-1-yl) carboxylate (30mg,0.068mmol) was dissolved in HCl in MeOH (5mL, 30%) and stirred at room temperature for 3 h. Following by TLC, the starting material was substantially converted. Adding saturated Na to the reaction solution₂CO₃(aq.) (20mL), then the aqueous phase was extracted with DCM (20 mL. times.3), the organic phases were combined and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a pale yellow oily solid (23mg, 99%).

Step six: synthesis of methyl 4- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (methyl- (4- (trifluoromethyl) phenyl) amino) piperidin-1-yl) benzoate

Under nitrogen protection, (3R,6S) -6- ((difluoromethoxy) methyl) -N-methyl-N- (4- (trifluoromethyl) phenyl) piperidin-3-amine (23mg,0.068mmol), methyl 4-iodobenzoate (60mg,0.23mmol), Pd₂(dba)₃(12mg,0.013mmol), XantPhos (10mg,0.017mmol) andCs₂CO₃(100mg,0.30mmol) was dissolved in 1, 4-dioxane (3mL) and the reaction was heated in a 100 ℃ oil bath with stirring for 24 h. Adding saturated NaHCO into the reaction solution₃(aq.) (30mL) quench the reaction, then extract the aqueous phase with DCM (30 mL. times.3), combine the organic phases and dry Na₂SO₄Dried and concentrated under reduced pressure and the crude product was chromatographed on silica gel (eluent: PE/DCM/EtOAc (v/v/v) ═ 10/1/1) to give the product as a yellow solid (15mg, 47%).

MS(ESI,pos.ion)m/z＝473.2[M+H]⁺.

Step seven: synthesis of 4- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (methyl- (4- (trifluoromethyl) phenyl) amino) piperidin-1-yl) benzoic acid

Reacting LiOH & H₂O (104mg,2.48mmol) methyl 4- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (methyl- (4- (trifluoromethyl) phenyl) amino) piperidin-1-yl) benzoate (15mg,0.032mmol) in THF/MeOH/H was added₂O (1mL/1mL/0.2mL) solution was stirred at room temperature for 36 h. Supplement of LiOH. H₂O (500mg,11.92mmol), stirring was continued at room temperature for 5h, leaving a small amount of starting material. The reaction mixture was diluted with DCM (60mL) and water (20mL), and 1.0M HCl solution was added dropwise to the mixture to adjust the pH of the mixture to 2-3, the mixture was separated, the aqueous phase was extracted with DCM (20mL × 2), and the organic phases were combined and extracted with anhydrous Na₂SO₄Drying and concentration under reduced pressure gave the crude product as a pale yellow solid (14mg, 96%).

MS(ESI,pos.ion)m/z＝459.1[M+H]⁺.

Step eight: synthesis of N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (methyl- (4- (trifluoromethyl) phenyl) amino) piperidin-1-yl) benzamide

4- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (methyl- (4- (trifluoromethyl) phenyl) amino) piperidin-1-yl) benzoic acid (14mg,0.030mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (23mg,0.10mmol), EDCI (34mg,0.18mmol) and HOBT (23mg,0.17mmol) were dissolved in DCM (4mL) and TEA (0.10mL,0.72mmol) was added and the reaction stirred at room temperature. The reaction was followed by TLC. The reaction was diluted with DCM (60mL) and then saturated NaHCO₃Solution (20mL) and NaCl solution (20mL)Polyester, anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product chromatographed on silica gel plate (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a yellow solid (6mg, 29%).

MS(ESI,pos.ion)m/z＝669.9[M+H]⁺.

Example 16N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((S) -4- (4- (difluoromethoxy) benzyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) benzamide

The method comprises the following steps: synthesis of (S) -4-benzyl 2- (hydroxymethyl) piperazine-1, 4-dicarboxylic acid-1-tert-butyl ester

(S) -4-benzyl-1-tert-butyl-2-methylpiperazine-1, 2, 4-tricarboxylate (5.1g,13.00mmol) was dissolved in THF (15mL) and LiBH was added slowly in portions in an ice bath₄(700mg,32.14mmol) and stirred at room temperature for 24 h. Adding saturated NaHCO into the reaction solution₃Solution (100mL) and the reaction was quenched. Concentrated under reduced pressure to remove THF, extracted with DCM (120 mL. times.2), anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give a colorless oil (4.6g, 97%).

MS(ESI,pos.ion)m/z＝373.2[M+Na]⁺.

Step two: synthesis of (S) -4-benzyl 2-tert-butyl ((difluoromethoxy) methyl) piperazine-1, 4-dicarboxylate

(S) -4-benzyl 2- (hydroxymethyl) piperazine-1, 4-dicarboxylic acid 1-tert-butyl ester (4.6g,13.00mmol) was dissolved in DCM/H₂O (18mL/18mL) and KOAc (7.70g,78.00mmol) was added and (bromo (difluoro) methyl) -trimethyl-silane (8.2mL,53.00mmol) was slowly added dropwise under ice-bath and stirred at room temperature for 18 h. Adding saturated NaHCO into the reaction solution₃The reaction was quenched with solution (60mL), extracted with DCM (80 mL. times.2), anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 6/1) to give a colorless oil (3.59g, 68%). MS (ESI, pos. ion) M/z 423.3[ M + Na ]]⁺.

Step three: synthesis of benzyl (S) -3- ((difluoromethoxy) methyl) piperazine-1-carboxylate

(S) -4-benzyl 2-tert-butyl ((difluoromethoxy) methyl) piperazine-1, 4-dicarboxylate (2.10g,5.20mmol) was dissolved in EtOAc (5mL), HCl in EtOAc (6mL,18mmol,3mol/L) was added under ice bath and stirred at room temperature for 24 h. Distilling under reduced pressure to remove part of solvent, adding saturated NaHCO₃(50mL), adjusting the pH of the system to about 8, extracting with DCM (80 mL. times.2), and separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a yellow oil (1.45g, 92%).

MS(ESI,pos.ion)m/z＝301.2[M+H]⁺.

Step four: synthesis of benzyl (S) -3- ((difluoromethoxy) methyl) -4- (4- (methoxycarbonyl) phenyl) piperazine-1-carboxylate

Under nitrogen protection, (S) -benzyl 3- ((difluoromethoxy) methyl) piperazine-1-carboxylate (550mg,1.83mmol), methyl 4-iodobenzoate (665mg,2.54mmol), Pd₂(dba)₃(158mg,0.17mmol)，Ruphos(197mg,0.42mmol)，Cs₂CO₃(1.06g,3.25mmol) was dissolved in toluene (10mL) and the reaction was heated at 110 ℃ for 19 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (778mg, 98%).

MS(ESI,pos.ion)m/z＝435.1[M+H]⁺.

Step five: synthesis of methyl (S) -4- (2- ((difluoromethoxy) methyl) piperazin-1-yl) benzoate

Benzyl (S) -3- ((difluoromethoxy) methyl) -4- (4- (methoxycarbonyl) phenyl) piperazine-1-carboxylate (778mg,1.79mmol), Pd/C (1.06g,0.99mmol,10 mass%) was dissolved in MeOH/THF (5mL/5mL) under a hydrogen atmosphere and stirred at room temperature for 12 h. Celite was filtered and concentrated under reduced pressure to give a yellow oil (455mg, 85%).

MS(ESI,pos.ion)m/z＝301.2[M+H]⁺.

Step six: synthesis of methyl (S) -4- (4- (4- (difluoromethoxy) benzyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) benzoate

Reacting (S) -4- (2- ((difluoromethoxy) methyl) piperazine-1-yl) benzoic acid methyl ester (53mg,1.78mmol), 4- (difluoromethoxy) benzaldehyde (0.47mL,3.60mmol) was dissolved in EtOH/THF (6mL/6mL) and AcOH (0.5mL,9.00mmol), STAB (1.9g,9.00mmol) was added and reacted at 60 ℃ for 14 h. Adding saturated NaHCO into the reaction solution₃Solution (50mL), adjusting system pH to about 8, EtOAc (80mL × 2) extraction, organic layer anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (612mg, 76%).

MS(ESI,pos.ion)m/z＝457.1[M+H]⁺.

Step seven: synthesis of (S) -4- (4- (4- (difluoromethoxy) benzyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) benzoic acid

Methyl (S) -4- (4- (4- (difluoromethoxy) benzyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) benzoate (612mg,1.34mmol), lioh₂O (610mg,14.54mmol) was dissolved in THF/MeOH/H2O (6mL/3mL/3mL) and reacted at room temperature for 17H. To the reaction mixture was added 1.0M HCl solution (8mL), the pH of the system was adjusted to about 4, EtOAc (20 mL. times.2) was used for extraction, and the organic layer was Na anhydrous₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a white solid (160mg, 27%).

MS(ESI,pos.ion)m/z＝443.0[M+H]⁺.

Step eight: synthesis of N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((S) -4- (4- (difluoromethoxy) benzyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) benzamide

(S) -4- (4- (4- (difluoromethoxy) benzyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) benzoic acid (160mg,0.36mmol), (2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (126mg,0.47mmol), EDCI (236mg,1.23mmol), HOBT (158mg,1.17mmol) was dissolved in DCM (5mL) and DIPEA (0.5mL,3.00mmol) was added and stirred at room temperature for 24 h. DCM (50mL), saturated NaHCO was added to the reaction₃Washing (20 mL. times.2), washing with saturated NaCl (20mL), anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a white solid(204mg,86％)。

MS(ESI,pos.ion)m/z＝654.1[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.51(d,J＝7.2Hz,1H),7.82(t,J＝8.7Hz,4H),7.65(d,J＝7.7Hz,2H),7.40(d,J＝7.4Hz,2H),7.22(s,1H),7.15(d,J＝7.8Hz,2H),6.95(d,J＝8.1Hz,2H),6.61(t,J＝75.8Hz,1H),5.13(d,J＝6.3Hz,1H),5.02(t,J＝4.8Hz,1H),4.21(dd,J＝16.9,7.7Hz,2H),3.75(s,3H),3.59(d,J＝12.7Hz,2H),3.48(d,J＝13.3Hz,1H),3.26(dd,J＝14.0,6.8Hz,2H),3.06(t,J＝10.7Hz,1H),2.92(dd,J＝19.2,11.3Hz,2H),2.25–2.12(m,2H),1.10(t,J＝7.0Hz,3H).

Example 17N- (4- (ethylsulfonyl) benzyl) - (S) -4- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzamide

The method comprises the following steps: synthesis of methyl (S) -4- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoate

Methyl (S) -4- (2- ((difluoromethoxy) methyl) piperazin-1-yl) benzoate (203mg,0.68mmol), 4- (trifluoromethyl) benzaldehyde (0.12mL,0.88mmol) were dissolved in EtOH/THF (3mL/3mL) and AcOH (0.08mL,1.00mmol), STAB (299mg,1.41mmol) were added and reacted at room temperature for 18 h. STAB (2eq 300mg) was added and the reaction was carried out at 60 ℃ for 15 h. Adding saturated NaHCO into the reaction solution₃Solution (30mL), adjusting system pH to about 8, EtOAc (50mL × 2) extraction, organic layer anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (133mg, 43%).

MS(ESI,pos.ion)m/z＝459.3[M+H]⁺.

Step two: synthesis of (S) -4- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoic acid

Methyl (S) -4- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoate (133mg,0.29mmol), LiOH.H₂O (162mg,3.86mmol) was dissolved in THF/MeOH/H2O (2mL/1mL/0.7mL) and reacted at room temperature for 22H. To the reaction mixture was added 1.0M HCl solution (5mL), the pH of the system was adjusted to about 4, EtOAc (20 mL. times.2) was used for extraction, and the organic layer was Na anhydrous₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a white solid (62mg, 48%).

MS(ESI,pos.ion)m/z＝445.2[M+H]⁺.

Step three: synthesis of N- (4- (ethylsulfonyl) benzyl) - (S) -4- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzamide

(S) -4- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoic acid (106mg,0.24mmol), (4- (ethylsulfonyl) phenyl) methylamine (78mg,0.39mmol), EDCI (99mg,0.52mmol), HOBT (72mg,0.53mmol) was dissolved in DCM (5mL) and DIPEA (0.2mL,1.00mmol) was added and stirred at room temperature for 12 h. DCM (50mL), saturated NaHCO was added to the reaction₃Washing (20 mL. times.2), washing with saturated NaCl (20mL), anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/3) to give a white solid (52mg, 35%).

MS(ESI,pos.ion)m/z＝626.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.89(t,J＝5.5Hz,1H),7.82(dd,J＝14.2,8.3Hz,4H),7.70(d,J＝7.9Hz,2H),7.62–7.53(m,4H),6.96(d,J＝8.6Hz,2H),6.62(t,J＝75.8Hz,1H),4.56(d,J＝5.4Hz,2H),4.30–4.18(m,2H),3.74(dd,J＝24.8,9.4Hz,2H),3.65–3.54(m,2H),3.26(dd,J＝14.5,7.2Hz,2H),3.09(t,J＝10.8Hz,1H),2.93(t,J＝9.8Hz,2H),2.23(t,J＝13.6Hz,2H),1.09(t,J＝7.3Hz,3H).

Example 18N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) - (R) -4- (4- (cyclopentylcarbonyl) piperazin-1-yl) benzamide

The method comprises the following steps: synthesis of tert-butyl 4- (4- (methoxycarbonyl) phenyl) piperazine-1-carboxylate

Piperazine-1-carboxylic acid tert-butyl ester (8.20g,44.00mmol), methyl 4-iodobenzoate (16.90g,64.50mmol), Pd under nitrogen protection₂(dba)₃(3.88g,4.24mmol)，Ruphos(4.20g,9.00mmol)，Cs₂CO₃(27.90g,85.60mmol) was dissolved in toluene (80mL) and the reaction was heated at 110 ℃ for 19 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow solid (10g, 71%).

MS(ESI,pos.ion)m/z＝321.1[M+H]⁺.

Step two: synthesis of methyl 4- (piperazin-1-yl) benzoate

Tert-butyl 4- (4- (methoxycarbonyl) phenyl) piperazine-1-carboxylate (3g,9.36mmol) was dissolved in DCM (8mL), and 1, 4-dioxane (16mL,48.00mmol,3mol/L) as HCl was added under ice bath and stirred at room temperature for 13 h. Distilling under reduced pressure to remove part of organic solvent, precipitating solid, filtering, washing filter cake with DCM (10 mL. times.2), adding saturated NaHCO into filter cake₃(120mL), adjusting the pH of the system to about 8, extracting with DCM (150 mL. times.2), and separating the organic layer with anhydrous Na₂SO₄Drying and concentration under reduced pressure gave a brown solid (1.9g, 92%).

MS(ESI,pos.ion)m/z＝221.2[M+H]⁺.

Step three: synthesis of methyl 4- (4- (cyclopentylcarbonyl) piperazin-1-yl) benzoate

Methyl 4- (piperazin-1-yl) benzoate (1.05g,4.77mmol), cyclopentanecarboxylic acid (0.68mL,6.30mmol), EDCI (1.88g,9.81mmol), HOAT (1.35g,9.92mmol) were dissolved in DCM (15mL) and DIPEA (4mL,24.20mmol) was added and reacted at room temperature for 12 h. DCM (50mL) and saturated NH were added to the reaction solution₄Cl solution (30 mL. times.2) washing, saturated NaHCO₃The solution (30 mL. times.2) was washed, and the organic layer was Na anhydrous₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give a white solid (1.5g, 99%).

MS(ESI,pos.ion)m/z＝317.1[M+H]⁺.

Step four: synthesis of 4- (4- (cyclopentylcarbonyl) piperazin-1-yl) benzoic acid

Methyl 4- (4- (cyclopentylcarbonyl) piperazin-1-yl) benzoate (1.50g,4.70mmol), LiOH₂O (2.06g,49.10mmol) was dissolved in THF/MeOH/H2O (8mL/4mL/4mL) and reacted at room temperature for 20H. After concentration under reduced pressure, 1.0M HCl solution (25mL) was added to the reaction mixture to adjust the pH of the system to about 4, whereby a white solid precipitated, which was filtered off with suction and dried to obtain a white solid (1.4g, 98%).

MS(ESI,pos.ion)m/z＝303.2[M+H]⁺.

Step five: synthesis of N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) - (R) -4- (4- (cyclopentylcarbonyl) piperazin-1-yl) benzamide

4- (4- (Cyclopentylcarbonyl) piperazin-1-yl) benzoic acid (205mg,0.68mmol), (2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (188mg,0.82mmol), EDCI (257mg,1.34mmol), HOBT (185mg,1.37mmol) was dissolved in DCM (8mL) and DIPEA (0.8mL,5.00mmol) was added and stirred at room temperature for 17 h. DCM (50mL), saturated NaHCO was added to the reaction₃Washing (20 mL. times.2), washing with saturated NaCl (20mL), anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 15/1) to give a white solid (324mg, 93%).

MS(ESI,pos.ion)m/z＝514.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.54(d,J＝7.7Hz,1H),7.84(d,J＝7.9Hz,4H),7.66(d,J＝7.9Hz,2H),7.00(d,J＝8.8Hz,2H),5.14(d,J＝6.6Hz,1H),5.03(t,J＝5.4Hz,1H),3.79–3.69(m,2H),3.64(d,J＝15.3Hz,4H),3.26(dd,J＝14.5,7.1Hz,6H),3.08–2.98(m,1H),1.78(d,J＝7.7Hz,2H),1.65(ddd,J＝27.9,13.5,6.7Hz,4H),1.53(dd,J＝9.0,5.4Hz,2H),1.10(t,J＝7.3Hz,3H).

Example 19N- (4- (ethylsulfonyl) benzyl) -4- (4- (cyclopentylcarbonyl) piperazin-1-yl) benzamide

4- (4- (cyclopentylcarbonyl) piperazin-1-yl) benzeneFormic acid (204mg,0.67mmol), (4- (ethylsulfonyl) phenyl) methylamine (267mg,1.34mmol), EDCI (267mg,1.39mmol), HOBT (230mg,1.70mmol) was dissolved in DCM (8mL) and DIPEA (0.88mL,5.30mmol) was added and stirred at room temperature for 17 h. DCM (50mL), saturated NaHCO was added to the reaction₃Washing (20 mL. times.2), washing with saturated NaCl (20mL), anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/5) to give a white solid (101mg, 31%).

MS(ESI,pos.ion)m/z＝484.1[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.90(t,J＝5.8Hz,1H),7.83(t,J＝9.5Hz,4H),7.56(d,J＝8.1Hz,2H),7.00(d,J＝8.8Hz,2H),4.56(d,J＝5.7Hz,2H),3.63(d,J＝17.5Hz,4H),3.29(s,2H),3.25(t,J＝7.1Hz,4H),3.08–2.99(m,1H),1.78(d,J＝7.7Hz,2H),1.73–1.59(m,4H),1.55(dd,J＝9.6,6.0Hz,2H),1.09(t,J＝7.3Hz,3H).

Example 20(R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzamide

The method comprises the following steps: synthesis of methyl 4- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoate

Methyl 4- (piperazin-1-yl) benzoate (1.04g,4.72mmol), 4- (trifluoromethyl) benzaldehyde (0.8mL,6.00mmol) were dissolved in THF/EtOH (6mL/6mL) and AcOH (1.3mL,23.00mmol), STAB (4.80g,23.00mmol), 60 ℃ reacted for 18 h. Adding saturated NaHCO into the reaction solution₃Solution (60mL), adjusting system pH to about 8, EtOAc (100mL × 2) extraction, organic layer anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a brown solid (1.6g, 90%).

MS(ESI,pos.ion)m/z＝379.3[M+H]⁺.

Step two: synthesis of 4- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoic acid

Methyl 4- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoate (1.60g,4.20mmol), LiOH₂O (1.82g,43.40mmol) was dissolved in THF/MeOH/H2O (8mL/4mL/4mL) and reacted at room temperature for 48H. After concentration under reduced pressure, 1.0M HCl solution (20mL) was added to the reaction mixture to adjust the pH of the system to about 4, whereupon a brown solid precipitated, which was filtered off with suction and dried to give a brown solid (1.45g, 94%).

MS(ESI,pos.ion)m/z＝365.4[M+H]⁺.

Step three: synthesis of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzamide

4- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoic acid (200mg,0.55mmol), (2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (154mg,0.67mmol), EDCI (221mg,1.15mmol), HOBT (152mg,1.12mmol) was dissolved in DCM (8mL) and DIPEA (0.7mL,4.00mmol) was added and stirred at room temperature for 17 h. DCM (50mL), saturated NaHCO was added to the reaction₃Washing (20 mL. times.2), washing with saturated NaCl (20mL), anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 15/1) to give a white solid (247mg, 78%).

MS(ESI,pos.ion)m/z＝576.7[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.50(d,J＝7.6Hz,1H),7.82(dd,J＝12.4,8.5Hz,4H),7.72(d,J＝7.9Hz,2H),7.65(d,J＝8.2Hz,2H),7.59(d,J＝7.9Hz,2H),6.97(d,J＝8.8Hz,2H),5.13(dd,J＝13.7,6.8Hz,1H),5.02(t,J＝5.8Hz,1H),3.78–3.68(m,2H),3.64(s,2H),3.26(dd,J＝12.8,5.4Hz,6H),2.53(s,4H),1.10(t,J＝7.3Hz,3H).

Example 21N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((R) -2-methyl-4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzamide

The method comprises the following steps: synthesis of (R) -4- (4- (methoxycarbonyl) phenyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester

Under the protection of nitrogen, (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.10g,5.50mmol), 4-iodobenzoic acid methyl ester (2.21g,8.43mmol), Pd₂(dba)₃(546mg,0.60mmol)，Ruphos(475mg,1.02mmol)，Cs₂CO₃(3.34g,10.30mmol) was dissolved in toluene (20mL) and the reaction was heated at 110 ℃ for 17 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give a yellow solid (1.8g, 98%).

MS(ESI,pos.ion)m/z＝335.2[M+H]⁺.

Step two: synthesis of methyl (R) -4- (2-methylpiperazin-1-yl) benzoate

Tert-butyl (R) -4- (4- (methoxycarbonyl) phenyl) -3-methylpiperazine-1-carboxylate (1.80g,5.40mmol) was dissolved in DCM (5mL), HCl 1, 4-dioxane (12mL,48.00mmol,4mol/L) was added under ice bath, and stirring was carried out at room temperature for 20 h. Concentrating under reduced pressure, removing part of organic solvent, and adding saturated NaHCO₃(80mL), adjusting the pH of the system to about 8, extracting with DCM (100 mL. times.2), and separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a brown oil (1.3g, 100%). MS (ESI, pos.ion) M/z 235.2[ M + H ═ M]⁺.

Step three: synthesis of methyl (R) -4- (2-methyl-4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoate

Methyl (R) -4- (2-methylpiperazin-1-yl) benzoate (520mg,2.22mmol), 4- (trifluoromethyl) benzaldehyde (0.4mL,3.00mmol) were dissolved in THF/EtOH (6mL/6mL) and AcOH (0.6mL,10.00mmol), STAB (2.3g,11.00mmol) were added and reacted at 60 ℃ for 19 h. Adding saturated NaHCO into the reaction solution₃Solution (40mL), adjusting system pH to about 8, EtOAc (60mL × 2) extraction, organic layer anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give a yellow solid (735mg, 84%).

MS(ESI,pos.ion)m/z＝393.2[M+H]⁺.

Step four: synthesis of (R) -4- (2-methyl-4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoic acid

Methyl (R) -4- (2-methyl-4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoate (735mg,1.87mmol), LiOH₂O (935mg,22.28mmol) was dissolved in THF/MeOH/H2O (4mL/2mL/2mL) and reacted at room temperature for 48H. Concentrating under reduced pressure, adding 1.0M HCl solution (20mL), adjusting pH to about 4, extracting with EtOAc (50 mL. times.2), and collecting organic layer containing anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a white solid (700mg, 99%).

MS(ESI,pos.ion)m/z＝379.3[M+H]⁺.

Step five: synthesis of N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((R) -2-methyl-4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzamide

(R) -4- (2-methyl-4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoic acid (250mg,0.66mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (196mg,0.85mmol), EDCI (308mg,1.61mmol), HOBT (192mg,1.42mmol) was dissolved in DCM (8mL) and DIPEA (0.55mL,3.30mmol) was added and stirred at room temperature for 21 h. DCM (50mL) and saturated NH were added to the reaction solution₄Cl (20 mL. times.2) wash, saturated NaCl (20mL) wash, anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 15/1) to give a white solid (335mg, 86%).

MS(ESI,pos.ion)m/z＝590.3[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.48(d,J＝7.0Hz,1H),7.89–7.77(m,4H),7.72(d,J＝7.1Hz,2H),7.65(d,J＝7.6Hz,2H),7.60(d,J＝6.6Hz,2H),6.91(d,J＝7.8Hz,2H),5.13(d,J＝6.0Hz,1H),5.02(s,1H),4.18(s,1H),3.78–3.64(m,3H),3.53(dd,J＝22.1,13.0Hz,2H),3.26(d,J＝7.0Hz,2H),3.05(d,J＝10.3Hz,1H),2.90(d,J＝8.7Hz,1H),2.70(d,J＝9.8Hz,1H),2.31(d,J＝8.9Hz,1H),2.19(s,1H),1.10(s,6H).

Example 22N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (2, 6-dimethyl-4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzamide

The method comprises the following steps: synthesis of tert-butyl 4- (4- (methoxycarbonyl) phenyl) -3, 5-dimethylpiperazine-1-carboxylate

Under the protection of nitrogen, 3, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.02g,4.76mmol), 4-iodobenzoic acid methyl ester (1.95g,7.44), Pd₂(dba)₃(433mg,0.47mmol)，Ruphos(451mg,0.97mmol)，Cs₂CO₃(3.10g,9.50mmol) was dissolved in toluene (20mL) and the reaction was heated at 110 ℃ for 22 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give a yellow oil (400mg, 24%).

MS(ESI,pos.ion)m/z＝349.2[M+H]⁺.

Step two: synthesis of methyl 4- (2, 6-dimethylpiperazin-1-yl) benzoate

Tert-butyl 4- (4- (methoxycarbonyl) phenyl) -3, 5-dimethylpiperazine-1-carboxylate (400mg,1.15mmol) was dissolved in DCM (5mL), HCl 1, 4-dioxane (10mL,40.00mmol,4mol/L) was added under ice bath, and stirring was carried out at room temperature for 20 h. Concentrating under reduced pressure, removing part of organic solvent, and adding saturated NaHCO₃(40mL), adjusting the pH of the system to about 8, extracting with DCM (60 mL. times.2), and separating the organic layer with anhydrous Na₂SO₄Dried, concentrated under reduced pressure and the crude product was isolated by column chromatography over silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a brown oil (210mg, 74%). MS (ESI, pos.ion) M/z 249.1[ M + H ═ M]⁺.

Step three: synthesis of methyl 4- (2, 6-dimethyl-4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoate

Methyl 4- (2, 6-dimethylpiperazin-1-yl) benzoate (210mg,0.85mmol), 4- (trifluoromethyl) benzaldehyde (0.15mL,1.10mmol) were dissolved in THF/EtOH (3mL/3mL) and AcOH (0.25mL,4.4mmol), STAB (1.02g,4.81mmol) were added and reacted at 60 ℃ for 18 h. Adding saturated NaHCO into the reaction solution₃Solution (30mL), adjusting system pH to about 8, EtOAc (50mL × 2) extraction, organic layer anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give a yellow solid (221mg, 64%).

MS(ESI,pos.ion)m/z＝407.1[M+H]⁺.

Step four: synthesis of 4- (2, 6-dimethyl-4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoic acid

Methyl 4- (2, 6-dimethyl-4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoate (221mg,0.54mmol), lioh₂O (284mg,6.77mmol) was dissolved in THF/MeOH/H2O (2mL/1mL/1mL) and reacted at room temperature for 21H. Concentrating under reduced pressure, adding 1.0M HCl solution (10mL), adjusting pH to about 4, extracting with EtOAc (30 mL. times.2), and collecting organic layer as anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow solid (210mg, 98%).

MS(ESI,pos.ion)m/z＝393.2[M+H]⁺.

Step five: synthesis of N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (2, 6-dimethyl-4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzamide

4- (2, 6-dimethyl-4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoic acid (210mg,0.54mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (150mg,0.65mmol), EDCI (287mg,1.50mmol), HOBT (148mg,1.10mmol) was dissolved in DCM (8mL) and DIPEA (0.45mL,2.70mmol) was added and stirred at room temperature for 48 h. DCM (50mL) and saturated NH were added to the reaction solution₄Cl (20 mL. times.2) wash, saturated NaCl (20mL) wash, anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 15/1) to give a yellow solid (101mg, 31%).

MS(ESI,pos.ion)m/z＝604.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.48(d,J＝7.6Hz,1H),7.82(t,J＝8.5Hz,4H),7.73(d,J＝7.7Hz,2H),7.64(t,J＝6.9Hz,4H),6.88(d,J＝8.5Hz,2H),5.13(dd,J＝13.1,6.4Hz,1H),5.02(t,J＝5.6Hz,1H),3.93(s,2H),3.80–3.68(m,2H),3.64(s,2H),3.26(dd,J＝14.5,7.2Hz,2H),2.63(d,J＝10.4Hz,2H),2.35(d,J＝8.3Hz,2H),1.11(dd,J＝17.9,6.6Hz,9H).

Example 23N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzamide

(S) -4- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) benzoic acid (114mg,0.26mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (75mg,0.33mmol), EDCI (115mg,0.60mmol), HOBT (73mg,0.54mmol) was dissolved in DCM (5mL) and DIPEA (0.21mL,1.30mmol) was added and stirred at room temperature for 12 h. DCM (50mL), saturated NaHCO was added to the reaction₃Washing (20 mL. times.2), washing with saturated NaCl (20mL), anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 15/1) to give a white solid (126mg, 75%).

MS(ESI,pos.ion)m/z＝656.1[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.52(d,J＝7.7Hz,1H),7.83(t,J＝7.8Hz,4H),7.70(d,J＝8.0Hz,2H),7.65(d,J＝8.2Hz,2H),7.59(d,J＝7.9Hz,2H),6.96(d,J＝8.8Hz,2H),6.62(t,J＝75.8Hz,1H),5.14(dd,J＝13.3,6.7Hz,1H),5.03(t,J＝5.6Hz,1H),4.31–4.18(m,2H),3.74(dd,J＝21.7,10.1Hz,4H),3.58(d,J＝13.5Hz,2H),3.26(q,J＝7.4Hz,2H),3.09(t,J＝10.9Hz,1H),2.93(t,J＝10.2Hz,2H),2.24(dd,J＝17.7,10.3Hz,2H),1.10(t,J＝7.3Hz,3H).

EXAMPLE 24(R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (8- (4- (trifluoromethyl) benzyl) -2-oxa-5, 8-diazaspiro [3.5] non-5-yl) benzamide

The method comprises the following steps: synthesis of tert-butyl 5- (4- (methoxycarbonyl) phenyl) -2-oxa-5, 8-diazaspiro [3.5] nonane-8-carboxylate

Under the protection of nitrogen, 2-oxa-6, 9-diazaspiro [3.5]]Nonane-6-carboxylic acid tert-butyl ester (613mg,2.69mmol), methyl 4-iodobenzoate (1.1g,4.20mmol), Pd₂(dba)₃(250mg,0.27mmol)，Ruphos(249mg,0.53mmol)，Cs₂CO₃(1.7g,5.20mmol) in toluene (8mL) and heated at 110 ℃ for 19 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (430mg, 44%).

MS(ESI,pos.ion)m/z:307.1[M+H-56]⁺.

Step two: synthesis of methyl 4- (2- (chloromethyl) -2- (hydroxymethyl) piperazin-1-yl) benzoate

Reacting 5- (4- (methoxycarbonyl) phenyl) -2-oxa-5, 8-diazaspiro [3.5]Tert-butyl nonane-8-carboxylate (430mg,1.19mmol) was dissolved in DCM (2mL), HCl 1, 4-dioxane (5mL,20.00mmol,4mol/L) was added under ice-bath, and stirred at room temperature for 16 h. Distilling under reduced pressure to remove part of organic solvent, adding saturated NaHCO₃(20mL), adjust the system pH to about 8, extract with DCM (30 mL. times.2), and extract the organic layer with anhydrous Na₂SO₄Dried, concentrated under reduced pressure and the crude product was isolated by column chromatography over silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow oil (223mg, 63%).

MS(ESI,pos.ion)m/z＝299.3[M+H]⁺.

Step three: synthesis of methyl 4- (8- (4- (trifluoromethyl) benzyl) -2-oxa-5, 8-diazaspiro [3.5] nonan-5-yl) benzoate

Methyl 4- (2- (chloromethyl) -2- (hydroxymethyl) piperazin-1-yl) benzoate (223mg,0.75mmol), 1- (bromomethyl) -4- (trifluoromethyl) benzene (244mg,1.02mmol), K₂CO₃(458mg,3.31mmol) in CH₃CN (5mL) at 90 ℃ for 6 h. Concentrated under reduced pressure, and then saturated NaHCO was added to the residue₃Solution (20mL), DCM (30 mL. times.2) extraction, anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give a yellow oil (123mg, 39%).

MS(ESI,pos.ion)m/z＝421.9[M+H]⁺.

Step four: synthesis of 4- (8- (4- (trifluoromethyl) benzyl) -2-oxa-5, 8-diazaspiro [3.5] nonan-5-yl) benzoic acid

Reacting 4- (8- (4- (trifluoromethyl) benzyl) -2-oxa-5, 8-diazaspiro [3.5]]Nonan-5-yl) benzoic acid methyl ester (123mg,0.29mmol), LiOH₂O (135mg,3.22mmol) was dissolved in THF/MeOH/H2O (1.5mL/0.8mL/0.8mL) and reacted at room temperature. Concentrating under reduced pressure, adding 1.0M HCl solution (6mL), adjusting pH to about 4, extracting with EtOAc (30 mL. times.2), and collecting organic layer as anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow solid (51mg, 43%).

MS(ESI,pos.ion)m/z＝407.8[M+H]⁺.

Step five: synthesis of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (8- (4- (trifluoromethyl) benzyl) -2-oxa-5, 8-diazaspiro [3.5] non-5-yl) benzamide

Reacting 4- (8- (4- (trifluoromethyl) benzyl) -2-oxa-5, 8-diazaspiro [3.5]]Nonan-5-yl) benzoic acid (51mg,0.16mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (37mg,0.16mmol), EDCI (56mg,0.29mmol), HOBT (37mg,0.27mmol) was dissolved in DCM (5mL) and DIPEA (0.12mL,0.73mmol) was added and stirred at room temperature for 7 h. DCM (50mL) and saturated NH were added to the reaction solution₄Cl (20 mL. times.2) wash, saturated NaCl (20mL) wash, anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 12/1) to give a yellow solid (18mg, 23%).

MS(ESI,pos.ion)m/z＝618.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.44(d,J＝7.6Hz,1H),7.83(d,J＝8.2Hz,2H),7.78(d,J＝8.7Hz,2H),7.66(dd,J＝12.2,8.3Hz,4H),7.56(d,J＝7.9Hz,2H),6.86(d,J＝8.8Hz,2H),5.12(dd,J＝13.3,6.9Hz,1H),5.00(t,J＝5.6Hz,1H),3.87(t,J＝7.5Hz,3H),3.81–3.66(m,5H),3.61(d,J＝15.5Hz,1H),3.29–3.22(m,2H),2.89(d,J＝4.5Hz,1H),2.79(s,2H),2.56(dd,J＝15.5,10.0Hz,2H),1.10(t,J＝7.3Hz,3H).

Biological activity assay

Fluorescence Resonance Energy Transfer (FRET) assay

1. Test method

(1) ROR gamma t experiment buffer and 10mM DTT are prepared

100mL of 1 Xbasic assay buffer (HEPES (pH 7.4), 100mM NaCl, 0.01% BSA) was prepared, and 154.25mg of DTT was added and mixed well.

(2) Formulation of gradient concentrations of Compounds

a. Standard compounds were prepared, diluted to 2.5mM with 100% DMSO, 3-fold diluted, 11-step dilutions to a final concentration of 42.34 nM;

b. experimental compounds were prepared with reference to standard compounds.

(3) Preparation of 1x protein solution mixture

a. The required amount of 2x B-ROR γ t LBD/SA-APC protein mixture was formulated. The concentration of B-ROR γ t LBD was 40nM and the concentration of SA-APC was 20nM, mixed by gentle inversion and incubated for 15 min at room temperature. Adding 400nM biotin, mixing by gentle inversion, and incubating at room temperature for 10 min;

b. the required amount of 2X Biotin-SRC1/SA-eu protein mixture was formulated. Bioin-SRC1 was 40nM and SA-eu was 20nM, mixed by gentle inversion and incubated for 15 min at room temperature. Adding 200nM biotin, mixing by gentle inversion, and incubating at room temperature for 10 min;

c.1:1, mixing the protein mixture prepared in the step a and the step b uniformly, and incubating for 5 minutes at room temperature;

d. adding 25 μ L of the mixture of step c to a 384 well plate containing the test compound;

e.1000rpm for one minute;

f. incubate at room temperature for 1 hour.

(4) Data collection and computation

After 1 hour of incubation at room temperature, the fluorescence values at 665nm and 615nm were measured with an EnVision plate reader, respectively, and the inhibition was calculated to obtain the IC₅₀The values are shown in Table 1;

the inhibition ratio (%) [ (X-Min)/(Max-Min) ]. times.100%

X is the value of "665/615" for the test compound; min is the average of "665/615" for DMSO blank; max is the average of "665/615" for 10 μ M SRC.

2. Results of the experiment

Table 1: evaluation of inhibitory Activity of Compounds of the present invention on ROR γ t at molecular level

And (4) conclusion: the compound has good inhibitory activity on ROR gamma t.

Pharmacokinetic evaluation

ICR mice were fasted overnight for 15 hours and then weighed, and randomly grouped according to body weight, and the test compound was formulated with 5% DMSO + 5% Solutol + 90% Saline as the vehicle. For the test group administered intravenously, the test animals were given a dose of 1 mg/kg; for the orally administered test group, the test animals were given a dose of 5 mg/kg. Then, venous blood (approximately 0.2mL) was taken at time points of 0, 0.083 (intravenous only), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours and placed in EDTA-K₂In an anticoagulation tube, centrifuge at 11,000rpm for 2 minutes, collect plasma, and store at-20 ℃ or-70 ℃ until LC/MS/MS analysis. The drug concentration in plasma was measured at each time point and pharmacokinetic parameters were calculated from the drug concentration-time curve.

The pharmacokinetic properties of the compounds of the invention were tested by the above assay. The experimental result shows that the compound has good pharmacokinetic characteristics in an ICR mouse.

Finally, it should be noted that there are other ways of implementing the invention. Accordingly, the embodiments of the present invention will be described by way of illustration, but not limitation to the description of the present invention, and modifications made within the scope of the present invention or equivalents added to the claims are possible. All publications or patents cited herein are incorporated by reference.

Claims

1. A compound which is a compound represented by formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt of a compound represented by formula (I), or a prodrug thereof,

wherein:

each R²Independently fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_6-10Aryl radical, C_3-8Cycloalkyl, -C_0-6alkylene-OR^a、-C_0-4Alkylene- (C (═ O))_m-R^b、-C_0-4Alkylene- (O)_n-(C(＝O))_m-NR^cR^d、5-10 membered heteroaryl, -C_0-4Alkylene- (3-7 membered heterocyclyl), -C_0-4Alkylene- (5-12 membered spiroheterocyclyl) or-C_0-4Alkylene- (4-12 membered fused heterocyclyl); the R is²Optionally substituted by 1,2 or 3R^fSubstitution;

each R^aIndependently of one another is hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_6-10Aryl radical, C_3-8Cycloalkyl, 5-10 membered heteroaryl, 3-7 membered heterocyclyl, 5-12 membered spiroheterocyclyl or 4-12 membered fused heterocyclyl; each R^b、R^cAnd R^dIndependently hydrogen, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_6-10Aryl radical, C_3-8Cycloalkyl, 4-12 membered fused carbocyclic group, 5-12 membered spirocarbocyclic group, 5-10 membered heteroaryl, 3-7 membered heterocyclic group, 5-12 membered spiroheterocyclic group or 4-12 membered fused heterocyclic group; or R^c、R^dAnd the N atom to which they are attached together form a 4-7 membered heterocyclic ring; each of said R^a、R^b、R^cAnd R^dIndependently optionally substituted by 1,2,3,4, 5 or 6R^gSubstitution;

each R^eIndependently of the other is deuteriumFluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl, 3-8 membered heterocyclyl, hydroxy-substituted C_1-4Alkyl, hydroxy substituted C_1-4Haloalkyl, C_1-4Haloalkyl or C_1-4A haloalkoxy group; or, any two adjacent R^eAnd together with the atom to which they are attached form C_3-8Cycloalkyl or 3-8 membered heterocyclyl; wherein, said C_1-4Alkoxy is optionally substituted by 1-3-6 membered heterocyclyl or C_3-8Cycloalkyl substitution;

L²is-CR³R⁴-；

L³Is carbonyl, -S-, -O-, -NR⁵-or-CR⁶R⁷-；

each m and n is independently 0 or 1.

2. The compound of claim 1, wherein R is methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1, 2-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, ethylamino, dimethylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylenecyclohexyl, ethylenecyclopropyl, ethylenecyclobutyl, ethylenecyclopentyl, ethylenecyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

each R¹Independently hydrogen, deuterium, cyano, fluoro, chloro, bromo, iodo, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, 1, 2-difluoroethyl, 1-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethylene, ethoxymethylene, n-propoxymethylene, isopropoxymethylene, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

R³is hydrogen, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, cyanomethyl, cyanoethyl or cyano-n-propyl; r⁴Is hydrogen, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, cyanomethyl, cyanoethyl or cyano-n-propyl;

R⁵is hydrogen, methyl, ethyl, isopropyl, n-propyl, isobutyl, tert-butyl, n-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1, 2-difluoroethyl, 1-difluoroethyl, cyclopropyl, cyclobutyl or azetidinyl;

3. The compound of any one of claims 1-2, wherein B ring is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Said B ring being optionally substituted with 1,2,3 or 4R^eSubstitution;

each R^eIndependently deuterium, fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxy-n-propyl, 2-hydroxy-1, 1,1,3,3, 3-hexafluoroisopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1, 2-difluoroethyl, methoxy, ethoxy, n-propoxy, t-butoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or 1, 2-difluoroethoxy; wherein said methoxy, ethoxy, n-propoxy, t-butoxy are optionally substituted with 1 substituent selected from the group consisting of oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl.

4. A compound according to any one of claims 1 to 3, wherein the a ring is

5. The compound according to any one of claims 1-4, wherein each R²Independently fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, phenyl, C_3-6Cycloalkyl, -C_0-4alkylene-OR^a、-C_0-4Alkylene- (C (═ O))_m-R^b、-C_0-4Alkylene- (O)_n-(C(＝O))_m-NR^cR^d5-6 membered heteroaryl, -C_0-4Alkylene- (3-7 membered heterocyclyl), -C_0-4Alkylene- (5-12 membered spiroheterocyclyl) or-C_0-4Alkylene- (4-12 membered fused heterocyclyl); wherein, R is²Optionally substituted by 1,2 or 3R^fSubstitution;

or, optionally, two R's attached to the same carbon atom²Together with the carbon atom to which they are attached form C_3-6Cycloalkyl or a 4-6 membered heterocyclic ring.

6. The compound according to any one of claims 1-5, each R^aIndependently of one another is hydrogen, C_1-4Alkyl radical, C_1-4Haloalkyl, phenyl, C_3-6Cycloalkyl, 5-7 membered heteroaryl, or 3-7 membered heterocyclyl; each R^b、R^cAnd R^dIndependently hydrogen, hydroxy, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, phenyl, C_3-6Cycloalkyl, 3-7 membered heterocyclyl or 5-12 membered spiroheterocyclyl; or R^c、R^dAnd the N atom to which they are attached together form a 4-7 membered heterocyclic ring;

7. The compound of any one of claims 1-6, wherein each R²Independently fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 1-difluoroethyl, 1, 2-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OR^a、-CH₂-OR^a、-CH₂CH₂-OR^a、-CH₂(CH₂)₂-OR^a、-CH₂CH(CH₃)-OR^a、-C(CH₃)₂CH₂-OR^a、-CH₂(CH₂)₃-OR^a、-CH(CH₃)CH(CH₃)-OR^a、-CH₂C(CH₃)₂-OR^a、-(C(＝O))_m-R^b、-CH₂-(C(＝O))_m-R^b、-CH₂CH₂-((＝O))_m-R^b、-CH₂(CH₂)₂-(C(＝O))_m-R^b、-CH₂CH(CH₃)-(C(＝O))_m-R^b、-C(CH₃)₂CH₂-(C(＝O))_m-R^b、-CH₂(CH₂)₃-(C(＝O))_m-R^b、-CH(CH₃)CH(CH₃)-(C(＝O))_m-R^b、-CH₂C(CH₃)₂-(C(＝O))_m-R^b、-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂-(O)_n-(C＝O)_m-NR^cR^d、-CH₂CH₂-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂(CH₂)₂-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂CH(CH₃)-(O)_n-(C(＝O))_m-NR^cR^d、-C(CH₃)₂CH₂-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂(CH₂)₃-(O)_n-(C(＝O))_m-NR^cR^d、-CH(CH₃)CH(CH₃)-(O)_n-(C(＝O))_m-NR^cR^d、-CH₂C(CH₃)₂-(O)_n-(C(＝O))_m-NR^cR^dOxazolyl, thiazolyl, thienyl, imidazolyl, pyridazinyl, pyridyl,

Wherein, R is²Optionally substituted by 1,2 or 3R^fSubstitution;

or, optionally, two R's attached to the same carbon atom²And the carbon atoms to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl group.

8. The compound according to any one of claims 1-7, each R^aIndependently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 2, 2-difluoroethyl, 1, 2-difluoroethyl, 2,2, 2-trifluoroethyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, 2-difluoroethyl, trifluoromethyl, and mixtures thereof,

wherein each R is^a、R^b、R^cAnd R^dIndependently optionally substituted with 1,2,3,4, 5 or 6R^gAnd (4) substitution.

9. The compound of any one of claims 1-8, wherein each R^fAnd R^gIndependently fluorine, chlorine, bromine, iodine, oxo, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH₂OH, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 1-difluoroethyl, 1, 2-difluoroethyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxa-ethyl, 1, 2-difluoroethyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl, oxiranyl, oxa-cyclobutyl, tetrahydrofuranyl, trifluoromethyl,

10. A compound having the structure of one of:

or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof.

11. A pharmaceutical composition comprising a compound of any one of claims 1-10, and a pharmaceutically acceptable excipient, carrier, adjuvant, or combination thereof.

12. Use of a compound of any one of claims 1-10 or a pharmaceutical composition of claim 11 for the manufacture of a medicament for preventing or treating a disease, disorder or syndrome mediated by roryt in a mammal.

13. The use according to claim 12, wherein the disease, disorder or syndrome mediated by roryt is psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ocular disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, crohn's disease or kawasaki disease.