CN113666853A

CN113666853A - Biaryl compounds useful as ROR gamma modulators

Info

Publication number: CN113666853A
Application number: CN202110526063.0A
Authority: CN
Inventors: 程耀邦; 黄亚飞; 周娟; 董志强
Original assignee: Shanghai Huiqi Biomedical Technology Co ltd
Current assignee: Lidi (Hangzhou) Pharmaceutical Technology Co.,Ltd.
Priority date: 2020-05-15
Filing date: 2021-05-14
Publication date: 2021-11-19
Anticipated expiration: 2041-05-14
Also published as: TW202146381A; CN113666853B; WO2021228215A1

Abstract

The present invention relates to compounds of formula (I), stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates thereof, pharmaceutical compositions comprising the same, methods of using the same for treating or preventing ROR γ t-related diseases, and uses thereof in the manufacture of medicaments for treating or preventing ROR γ t-related diseases。

Description

Biaryl compounds useful as ROR gamma modulators

Technical Field

The invention belongs to the technical field of chemical medicines, and particularly relates to a biaryl compound with ROR gamma t inhibitory activity, a pharmaceutical composition containing the compound, a method for preparing the compound, and application of the compound in preparing a medicine for preventing or treating ROR gamma t related diseases.

Background

Retinoic acid receptor-Related Orphan Receptors (RORs), also known as NF1R, belong to a subfamily of the nuclear receptor superfamily of ligand-dependent transcription factors. The RORs subfamily mainly includes three subtypes, ROR α, ROR β and ROR γ. ROR γ contains two members: ROR γ 1 (also called ROR γ) and ROR γ 2 (also called ROR γ t), in which ROR γ 1 is distributed in skeletal muscle, thymus, testis, pancreas, prostate, heart, liver, and the like, and ROR γ t is expressed only in some immune cells.

Littman et al first reported that ROR γ T was necessary for the initial differentiation of CD4+ T cells into Th17 cells (Cell,2006126, 1121-1133). During the differentiation process of antigen-stimulated Thp cells to Th17 cells, ROR gamma t is induced and expressed under the action of cytokines such as IL-6, IL-21 and TGF-beta. The ability of Thp cells isolated from ROR γ t-deficient mice to differentiate into the Th17 cell line was significantly reduced. These all indicate that ROR γ t is a key regulator for promoting differentiation of Th17 cells.

Th17 cells are one of the helper T cells, and produce IL-17 and other proinflammatory cytokines. Th17 cells play a key role in many mouse models of autoimmune disease, such as Experimental Allergic Encephalomyelitis (EAE) and collagen-induced arthritis (CIA) animal models. Furthermore, increased IL-17 levels are detectable in some human autoimmune diseases, including Rheumatoid Arthritis (RA), Multiple Sclerosis (MS), Psoriasis (Psoriasis) and Inflammatory Bowel Disease (IBD). The number of Th17 cells found in both tissues and peripheral blood samples from patients with autoimmune disease is increased. Therefore, the Th17 cell or the cytokine IL-17 produced by it are closely related to the pathogenesis of inflammation and autoimmune diseases.

The monoclonal antibody Cosentyx (Secukinumab/AIN457) developed by Nowa, which is used to treat psoriasis by specifically blocking IL-17, was approved by the FDA to be marketed in 1 month 2015, and is the first drug acting on IL-17 in the psoriasis-treating drug market. Subsequently, the monoclonal antibody ixekizumab, targeting the pro-inflammatory cytokine IL-17A, was approved for use in the indications psoriasis, psoriatic arthritis. The clinical success of these monoclonal antibodies demonstrates the importance of the IL-17 signaling pathway in inflammatory and autoimmune diseases and demonstrates the potential for treating inflammatory and autoimmune diseases by affecting the IL-17 signaling pathway through ROR γ t inhibitors.

Therefore, ROR gamma t can be used as a new target of drugs for treating autoimmune diseases, and the search for ROR gamma t small molecule inhibitors and the application of ROR gamma t small molecule inhibitors in treating ROR gamma t mediated diseases such as inflammation and autoimmune diseases have important significance.

To date, a total of 4 small molecules of ROR γ t inhibitors were in clinical stage 2, 7 small molecules of ROR γ t inhibitors were in clinical stage 1, and none of the compounds had entered clinical stage 3. Therefore, there is still a great need to find and develop new ROR γ t inhibitor compounds for the prevention and/or treatment of diseases associated with ROR γ t, such as inflammatory and autoimmune diseases. In addition to satisfactory ROR γ t inhibitory activity, such compounds are expected to have high selectivity for ROR subtypes and good or even improved druggability based on structural optimization, so as to provide more drug options and better therapeutic effects for patients with related diseases.

Brief description of the invention

The present invention relates to compounds useful for the prevention or treatment of diseases associated with ROR γ t. In particular, it has been identified that the compounds of the present invention not only show satisfactory ROR γ t inhibitory activity, have the ability to regulate Th17 cell differentiation, thereby inhibiting IL-17 production, but also show good performance in vivo pharmacokinetic experiments, suggesting improved druggability and improved bioavailability; in addition, the compound also shows good safety and has lower risk of drug interaction. Therefore, the compound of the present invention can not only achieve the purpose for preventing or treating diseases associated with ROR γ t, but also the prepared drug is expected to have improved absorption, enhanced therapeutic effect at the same dose, or provide the same therapeutic effect at a lower dose, longer half-life and/or reduce possible side effects. Thus, the present invention also provides the use of the compounds of the present invention for the preparation of medicaments for the prevention or treatment of diseases associated with ROR γ t, pharmaceutical compositions comprising the compounds and methods for the prevention and/or treatment of diseases associated with ROR γ t by administering the compounds.

Accordingly, in one aspect of the present invention, there is provided a compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof:

wherein:

x is selected from CH or N;

R₁selected from hydrogen, halogen, cyano, nitro, C₁-C₆Alkyl, -O-C₁-C₆Alkyl, S-C₁-C₆Alkyl, -NH-C₁-C₆Alkyl, -N- (C)₁-C₆Alkyl radical)₂、C₁-C₆alkyl-O-C₁-C₆Alkyl, -C₁-C₆alkyl-S-C₁-C₆Alkyl radical, C₁-C₆alkyl-NH-C₁-C₆Alkyl or C₁-C₆alkyl-N (C)₁-C₆Alkyl radical)₂Wherein said C is₁-C₆Alkyl radical orOptionally substituted by halogen or cyano;

R₂selected from hydrogen, halogen, cyano, nitro or C₁-C₆Alkyl radical, wherein said C₁-C₆Alkyl is optionally substituted with substituents independently selected from: -R_aor-OH, wherein R_aIs C optionally substituted by halogen₁-C₆An alkyl group;

R₃、R₄each independently selected from halogen, cyano, nitro, R_b、-OR_b、-SR_bor-NR_bR_bWherein R is_bIs H or optionally substituted C₁-C₆Alkyl, each of said substituents being independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH₂、-O-C₁-C₆Alkyl, -S-C₁-C₆Alkyl, -NH-C₁-C₆Alkyl or-N (-C)₁-C₆Alkyl radical)₂；

R₅Is selected from-OR_c、-SR_c、-NR_cR_c、-NHCOR_c、-NHSO₂R_c、-COOR_c、-CONR_cR_cor-SO₂NR_cR_cWherein R is_cIndependently at each occurrence, is selected from hydrogen, C optionally substituted with halogen₁-C₆Alkyl or C optionally substituted by halogen₃-C₇Cycloalkyl, or two R bound to the same N atom_cMay form, together with the N atom to which they are attached, a 4-7 membered nitrogen containing heterocycloalkyl group;

R₆is selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 4-7 membered heterocycloalkyl or optionally substituted by C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl or 4-7 membered heterocycloalkyl substituted-NH₂Wherein said C is₁-C₆Alkyl radical, C₃-C₇Cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted with substituents each independently selected from: hydrogen, halogen, cyano, nitro, -R_a、-OR_a、-SR_aor-NR_aR_aOr optionally substituted by halogenSubstituted by elements C₃-C₇Cycloalkyl radical, R_aIndependently at each occurrence, is selected from H or C optionally substituted with halogen₁-C₆Alkyl, wherein two groups attached to the N atom of the amino group may form a 4-7 membered ring together with the N to which they are attached; and is

n is selected from 0, 1 or 2.

In another aspect of the present invention, there is provided a compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, having ROR γ t inhibitory activity for use as a medicament, particularly as an inhibitor of ROR γ t.

In another aspect of the invention, there is provided a compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, for use in the treatment, particularly in the treatment or prevention of a disease associated with ROR γ t.

In another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention as described above and a pharmaceutically acceptable excipient. In a specific aspect, the pharmaceutical composition of the present invention is provided for the prevention or treatment of diseases associated with roryt. In a particular aspect, the pharmaceutical composition may additionally comprise additional therapeutically active ingredients suitable for use in combination with the compounds of the present invention.

In another aspect of the present invention, there is provided a pharmaceutical combination comprising a compound of the invention as described above and an additional active agent.

In another aspect of the present invention, there is provided a method for the prevention or treatment of diseases associated with roryt in a mammal, particularly a human, which comprises administering an effective amount of a compound of the present invention described herein or a pharmaceutical composition comprising the same.

In another aspect of the present invention, there is provided a use of the above-described compound or pharmaceutical composition of the present invention for preventing or treating a disease associated with roryt.

In another aspect of the present invention, there is provided a use of the above-described compound or pharmaceutical composition of the present invention for the preparation of a medicament for the prevention or treatment of a disease associated with roryt.

In further aspects, methods are provided for the synthesis of compounds of the invention, wherein representative synthetic schemes and routes are described below.

Other objects and advantages of the present invention will become apparent to those skilled in the art from a reading of the following detailed description.

Detailed Description

Definition of

Unless otherwise indicated, each term used in the specification and claims has the following meaning. Where a particular term or phrase is not specifically defined, it should not be considered uncertain or clear, but rather should be understood appropriately according to the context herein or ordinary meaning in the art. Many of the groups defined herein are optionally substituted and the list of substituents given in this definition section are exemplary only and are not intended to limit the substituents defined elsewhere in this specification and claims.

The term "alkyl" as used herein means a straight or branched chain aliphatic hydrocarbon group having the indicated number of carbon atoms. Specifically, the alkyl group can have 1 to 6,1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Suitably C_1-6Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and isohexyl. Particular alkyl groups have 1 to 3 carbon atoms.

The term "alkoxy" as used herein means the group-O-alkyl, wherein alkyl has the meaning described herein. In particular, the term refers to the group-O-C_1-6An alkyl group. Examples of suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1, 2-dimethylbutoxy. Particular alkoxy groups have 1 to 3 carbon atoms.

The term "alkylthio" as used herein means the group-S-alkyl, wherein alkyl has the meaning described herein. In particular, the term refers to the group-S-C_1-6An alkyl group. Examples of suitable alkylthio groups include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio, sec-butylthio, n-pentylthio, n-hexylthio, and 1, 2-dimethylbutylthio. Particular alkylthio groups have 1 to 3 carbon atoms.

As used herein, the term "halogen-substituted C₁-C₆Alkyl "means C as defined above₁-C₆Alkyl, wherein one or more (e.g. 1,2, 3, 4 or 5) hydrogen atoms are replaced by halogen. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. "halogen-substituted C₁-C₆Examples of alkyl radicals "are, for example, -CH₂F、-CHF₂、-CF₃、-CCl₃、-C₂F₅、-C₂Cl₅、-CH₂CF₃、-CH₂Cl、CH₂CH₂CF₃or-CF (CF)₃)₂And the like.

As used herein, the term "halogen-substituted C₁-C₆Alkoxy "means C as defined above₁-C₆Alkoxy, wherein one or more (e.g. 1,2, 3, 4 or 5) hydrogen atoms are replaced by halogen. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. "halogen-substituted C₁-C₆Examples of alkoxy "are e.g. -OCH₂F、-OCHF₂、-OCF₃、-OCCl₃、-OC₂F₅、-OC₂Cl₅、-OCH₂CF₃、-OCH₂Cl or-OCH₂CH₂CF₃And the like.

As used herein, the term "halogen-substituted C₁-C₆Alkylthio "refers to C as defined above₁-C₆Alkylthio, wherein one or more (e.g. 1,2, 3, 4 or 5) hydrogen atoms are replaced by halogen. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogenMay be the same or different and may be located on the same or different C atoms. "halogen-substituted C₁-C₆Examples of alkylthio "are e.g. -SCH₂F、-SCHF₂、-SCF₃、-SCCl₃、-SC₂F₅、-SC₂Cl₅、-SCH₂CF₃、-SCH₂Cl or-SCH₂CH₂CF₃And the like.

The term "cycloalkyl" as used herein means a monocyclic, fused polycyclic, bridged polycyclic or spiro non-aromatic saturated hydrocarbon ring structure having the indicated number of ring atoms. The cycloalkyl group can have 3 to 12 carbon atoms, specifically 3 to 10, and more specifically 3 to 7 carbon atoms, i.e., C₃-C₇A cycloalkyl group. Examples of suitable cycloalkyl groups include, but are not limited to, monocyclic C₃-C₇Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Particular cycloalkyl groups have 3 to 5 carbon atoms.

As used herein, the term "halogen-substituted C₃-C₇Cycloalkyl "means C as defined above₃-C₇Cycloalkyl, wherein one or more (e.g. 1,2, 3, 4 or 5) hydrogen atoms are replaced by halogen. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. Specific examples include, but are not limited to, 2-fluorocyclopropyl, 2, 3-difluorocyclopropyl, 2,3, 3-tetrafluorocyclopropyl, 2, 3-difluorocyclobutyl, 2, 4-difluorocyclobutyl, and the like.

The term "heterocycloalkyl" as used herein is intended to include one or more heteroatoms independently selected from O, N and S and a monocyclic, fused polycyclic, spiro, or bridged polycyclic non-aromatic saturated ring structure of the indicated number of ring atoms, or an N-oxide thereof, or an S-oxide or S-dioxide thereof. The heterocycloalkyl group can have 4 to 12 ring members, specifically 4 to 10 ring members, and more specifically 4 to 7 ring members. Heterocycloalkyl groups typically contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2, e.g. a single heteroatom, e.g. a 4-7 membered monocyclic heterocycloalkyl having one heteroatom such as N, i.e. a 4-7 membered nitrogen containing heterocycloalkyl. Examples of suitable heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl), tetrahydrothienyl (e.g., 1-tetrahydrothienyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g., 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, or azepanyl.

It will be understood by those of ordinary skill in the art of organic synthesis that stable, chemically feasible heterocycles, whether aromatic or non-aromatic, have a maximum number of heteroatoms or type of heteroatoms included that is determined by the ring size, degree of unsaturation, and the valency of the heteroatom. In general, a heterocycle may have from 1 to 4 heteroatoms, as long as the heterocycle or heteroaromatic ring is chemically feasible and stable.

The term "halo" or "halogen" as used herein means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). Particular halo groups are fluoro or chloro. The term "halogen-substituted" group as used herein is intended to include monohalogenated or polyhalogenated groups in which one or more of the same or different halogens substitute for one or more hydrogens in the group.

The term "cyano" as used herein means the group-CN.

The term "nitro" as used herein means the group-NO₂。

The term "amino" as used herein means the group-NH₂；

The term "optionally substituted with … …" as used herein means that a group may be unsubstituted or substituted with one or more substituents (e.g., 0, 1,2, 3, 4, or 5 or more, or any range derivable therein) as set forth for that group, wherein the substituents may be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 substituents. In another embodiment, the optionally substituted group has 3 substituents. In another embodiment, the optionally substituted group has 4 substituents.

Unless otherwise defined, C as used in the definition of compounds herein₁-C₆Alkyl radical, C₃-C₇Cycloalkyl or 4-7 membered heterocycloalkyl optionally carrying one or more substituents which may be selected from H, F, Cl, Br, I, cyano, nitro, C₁-C₆Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, 1, 2-dimethylbutyl, etc.), C₃-C₇Cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), -OH, -O-C₁-C₆Alkyl (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1, 2-dimethylbutoxy, etc.), -SH, -S-C₁-C₆Alkyl (e.g., methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio, s-butylthio, n-pentylthio, n-hexylthio, 1, 2-dimethylbutylthio, etc.) or-NH₂、-NH-C₁-C₆Alkyl (e.g., methylamino, ethylamino, propylamino, isopropylamino, N-butylamino, tert-butylamino, sec-butylamino, N-pentylamino, N-hexylamino, and 1, 2-dimethylbutylamino), N (C)₁-C₆Alkyl radical)₂(e.g., dimethylamino, methylethylamino, diethylamino, etc.), wherein C₁-C₆Alkyl or C₃-C₇Cycloalkyl is optionally substituted with one or more halogens (preferably F).

The term "compound of the invention" as used herein is intended to encompass a compound of general formula (I) as defined herein or any preferred or specific embodiment thereof, stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates thereof, and prodrugs. Similarly, references herein to "intermediates", whether or not they are themselves claimed, are intended to cover the free forms thereof as well as the various derivatives described above, if the context permits.

The term "pharmaceutically acceptable" as used herein means molecular entities and compositions that are approved by or can be approved by the corresponding authorities in the various countries or listed in the generally recognized pharmacopoeias for animals, and more particularly humans, or that do not produce adverse, allergic, or other untoward reactions when administered in moderate amounts to animals, such as humans.

The term "pharmaceutically acceptable salt" as used herein means a salt of a compound of the present invention which is pharmaceutically acceptable and which possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic acid addition salts or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or an acid addition salt formed with an organic acid such as acetic acid, propionic acid, hexanoic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) a salt formed when an acidic proton present in the parent compound is replaced with a metal ion such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, or the like. The general principles and techniques for preparing pharmaceutically acceptable salts are known to those skilled in the art, for example, those described in Berge et al, Pharm ScL, 66, 1-19 (1977).

The term "prodrug" as used herein means a compound of the present invention having a cleavable group and becoming pharmaceutically active in vivo by solvolysis or under physiological conditions, including derivatives of the compounds of the present invention. Prodrugs include acid derivatives well known in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or substituted or unsubstituted aminesAmide, or anhydride or mixed anhydride. Simple aliphatic or aromatic esters, amides and anhydrides derived from the pendant acid groups of the compounds of the present invention are particularly useful prodrugs. Particular such prodrugs are C of the compounds of the present invention_1-8Alkyl radical, C_2-8Alkenyl, optionally substituted C_6-10Aryl and (C)_6-10Aryl group) - (C_1-4Alkyl) esters.

The term "stereoisomer" as used herein denotes an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., 1,2, 3, or 4) asymmetric centers, they can result in racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The particular molecule may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as a mixture of two or more different structural forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, a nitroso-oxime may exist in solution in equilibrium with the following tautomeric forms:

it is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

The compounds of the invention may have one or more asymmetric centers and may thus be prepared as (R) -or (S) -stereoisomers, respectively, or as mixtures thereof. Structural formula or structural fragment of compound used in the invention

Or

Indicating the relative configuration of asymmetric centers, i.e., chiral centers. Accordingly, the relative configuration with respect to the chiral center is denoted by R and S in the nomenclature of the compounds or intermediates provided herein.

The term "solvate" as used herein refers to a form of solvent addition comprising a stoichiometric or non-stoichiometric amount of solvent, including for example solvates with water, such as hydrates, or with organic solvents, such as methanol, ethanol or acetonitrile, i.e. as methanolate, ethanolate or acetonitrilate, respectively; or in the form of any polymorph. It will be understood that such solvates of the compounds of the invention also include solvates of pharmaceutically acceptable salts of the compounds of the invention.

The term "isotopic variation" as used herein refers to a compound in which one or more atoms constituting the compound are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into one or more atoms of a compound of the invention include, for example²H、³H、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F and³⁶cl, thereby forming isotopically-varied forms of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. In some embodiments, the incorporated isotope is 2H (deuterium); in other embodiments, the incorporated isotope is 3H (tritium).

The term "disease associated with ROR γ t" as used herein means a disease in which ROR γ t contributes to the onset and progression of the disease, or inhibition of ROR γ t reduces the incidence of disease, reduces or eliminates disease symptoms. For the purposes of the present invention, a "disease associated with ROR γ t" is chosen in particular from inflammatory or autoimmune diseases, cancer and the like, including but not limited to psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, asthma, glomerulonephritis, lupus nephritis, myocarditis, thyroiditis, dry eye, uveitis, behcet's disease, allergic dermatitis, acne, scleroderma, bronchitis, cutaneous allergic rhinitis, Necrotizing Enterocolitis (NEC), hepatic fibrosis, nonalcoholic steatohepatitis (NASH), New coronaviral pneumonia (New coronavirus pneumanias), insulin-dependent type I diabetes mellitus, triple negative breast cancer, and prostate cancer, among others. Preferred indications of the invention are selected from psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, inflammatory bowel disease, dry eye, allergic dermatitis, Chronic Obstructive Pulmonary Disease (COPD), asthma, necrotizing enterocolitis, liver fibrosis, non-alcoholic steatohepatitis, neocoronavirus pneumonia, triple negative breast cancer and prostate cancer.

The term "subject" or "individual" as used herein includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) having a disease (e.g., a disease described herein) or normal individuals. "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

The term "therapeutically effective amount" as used herein means an amount sufficient to alleviate or completely alleviate the symptoms or other deleterious effects of a disorder when administered to a subject to treat a disease; reversing, completely stopping, or slowing the progression of the disorder; or an amount that reduces the risk of worsening the condition, "effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject to be treated.

The term "prevention" as used herein means the administration of one or more compounds of the invention to a subject, e.g. a mammal, e.g. a human, suspected of suffering from or susceptible to a disease associated with roryt as defined herein, in particular an inflammatory or autoimmune disease, such that the risk of suffering from the defined disease is reduced. The term "prevention" encompasses the use of a compound of the invention prior to diagnosis or determination of any clinical and/or pathological condition.

The term "treating" as used herein refers to administering one or more compounds of the invention described herein to a subject, e.g., a mammal, e.g., a human, suffering from, or having symptoms of, the disease, for the purpose of curing, alleviating, or otherwise affecting the disease or symptoms of the disease. In a particular embodiment of the invention, the disease is a disease associated with ROR γ t as defined herein, in particular an inflammatory or autoimmune disease.

The term "pharmaceutical combination" as used herein means that the compounds of the present invention can be used in combination with other active agents for the purpose of the present invention. The additional active agent may be one or more additional compounds of the invention, or may be a second or additional (e.g., third) compound that is compatible with, i.e., does not adversely affect, each other, or has complementary activity. Such active agents are suitably present in combination in an effective amount to achieve the intended purpose. The additional active agents may be co-administered with the compounds of the present invention in a single pharmaceutical composition, or separately administered in separate discrete units from the compounds of the present invention, either simultaneously or sequentially when administered separately. The sequential administration may be close in time or remote in time.

The term "pharmaceutically acceptable excipient or carrier" as used herein refers to one or more compatible solid or liquid filler or gel substances which are pharmacologically inactive, compatible with the other ingredients of the composition, and which are intended to be acceptable for administration to a warm-blooded animal such as man, and which serve as a carrier or vehicle for the compounds of the present invention in the form in which they are to be administered, examples of which include, but are not limited to, cellulose and its derivatives (e.g., sodium carboxymethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., magnesium stearate), calcium sulfate, vegetable oils, polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g., tweens), wetting agents (e.g., sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, and the like.

Unless otherwise specified, C in the definition of the compounds of the invention_n-n+mOr C_n-C_n+mIncluding n to n + m carbon atoms, e.g. C_1-6Comprising C₁、C₂、C₃、C₄、C₅And C₆Also included are any ranges of n to n + m, e.g. C_1-6Comprising C_1-2、C_1-3、C_1-4、C_2-6、C_3-6And the like. Similarly, n-to n + m-membered in the definition of the compounds of the present invention means that the number of ring atoms is n to n + m, for example, 3-to 12-membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 12-membered rings and the like, and any range of n to n + m-membered rings is also included, for example, 3-to 12-membered rings include 3-to 6-membered rings, 3-to 9-membered rings, 5-to 6-membered rings, 5-to 7-membered rings, 6-to 8-membered rings, 6-to 10-membered rings and the like.

It is to be understood that the dosages referred to when describing the compounds of the present invention, pharmaceutical compositions, pharmaceutical combinations comprising the same, and related uses and methods, are by weight of the free form, and not by any salt, hydrate, solvate or the like thereof, unless otherwise defined in the specification.

Compounds of the invention

The terms "inventive compound" and the like, as used throughout this application, unless otherwise indicated, encompass compounds of formula (I), as defined in the various embodiments herein and in the specific or preferred embodiments thereof, stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates thereof, and prodrugs. The stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates, and prodrugs are described in the definitions section above. Preferably, the compounds of the invention are free forms of the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof; most preferred is the free form of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

Certain compounds of the present invention may exist in polymorphic or amorphous forms, which also fall within the scope of the present invention. When in a solid crystalline form, the compound of formula (I) may be in the form of a co-crystal with another chemical entity, and the specification includes all such co-crystals.

Where chiral centers are present, the compounds of the present invention may exist as individual enantiomers or as mixtures of enantiomers. According to one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a single enantiomer with enantiomeric excess (% ee) > 95, > 98% or > 99%. Preferably, the single enantiomer is present in an enantiomeric excess (% ee) of > 99%.

In particular, in one aspect, the present invention provides compounds of formula (I), stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts, or solvates thereof:

wherein:

x is selected from CH or N;

R₁selected from hydrogen, halogen, cyano, nitro, C₁-C₆Alkyl, -O-C₁-C₆Alkyl, S-C₁-C₆Alkyl, -NH-C₁-C₆Alkyl, -N- (C)₁-C₆Alkyl radical)₂、C₁-C₆alkyl-O-C₁-C₆Alkyl, -C₁-C₆alkyl-S-C₁-C₆Alkyl radical, C₁-C₆alkyl-NH-C₁-C₆Alkyl or C₁-C₆alkyl-N (C)₁-C₆Alkyl radical)₂Wherein said C is₁-C₆Alkyl is optionally substituted by halogen or cyano;

R₆is selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 4-7 membered heterocycloalkyl or optionally substituted by C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl or 4-7 membered heterocycloalkyl substituted-NH₂Wherein said C is₁-C₆Alkyl radical, C₃-C₇Cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted with substituents each independently selected from: hydrogen, halogen, cyano, nitro, -R_a、-OR_a、-SR_aor-NR_aR_aOr C optionally substituted by halogen₃-C₇Cycloalkyl radical, R_aIndependently at each occurrence, is selected from H or C optionally substituted with halogen₁-C₆Alkyl, wherein two groups attached to the N atom of the amino group may form a 4-7 membered ring together with the N to which they are attached; and is

n is selected from 0, 1 or 2.

In one embodiment of the compounds of formula (I), X is CH.

In one embodiment of the compounds of formula (I), R₁Is H.

In one embodiment of the compounds of formula (I), R₁Is halogen, such as F, Cl, Br or I; f or Cl is preferred.

In one embodiment of the compounds of formula (I), R₁Is C₁-C₆Alkyl, preferably C₁-C₃Alkyl, optionally substituted by halogen (preferably F), e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CF₃、-CHF₂、-CH₂CF₃、-CF₂CF₃、-CH₂CH₂CF₃、-CH(CF₃)₂And the like.

In one embodiment of the compounds of formula (I), R₁Is selected from-O-C₁-C₆Alkyl, -S-C₁-C₆Alkyl, -NH-C₁-C₆Alkyl or-N- (C)₁-C₆Alkyl radical)₂Wherein C is₁-C₆Alkyl is optionally substituted with one or more halogen (preferably F), examples include, but are not limited to-OCH₃、-OCF₃、-OCHF₂、-OCH₂CH₃、-OCH₂CF₃、-OCH₂CH₂CH₃、-OCH₂CH₂CF₃、-OCH(CF₃)₂、-SCH₃、-SCF₃、-SCH₂CH₃、-NH₂、-NHCH₃、-N(CH₃)₂、-NH-CH₂CH₃、-N(CH₃)(CH₂CH₃)、-NHCF₃、-N(CH₃)(CF₃) And the like. In a more specific embodiment, R₁Is selected from-O-C₁-C₆Alkyl radical, wherein C₁-C₆Alkyl radicals substituted by at least three halogens, preferably F, e.g. -OCF₃、-OCH₂CF₃、-OCH₂CH₂CF₃、-CH(CF₃)₂And the like.

In one embodiment of the compounds of formula (I), R₁Is selected from-C₁-C₆alkyl-O-C₁-C₆Alkyl, -C₁-C₆alkyl-S-C₁-C₆Alkyl, -C₁-C₆alkyl-NH-C₁-C₆Alkyl or-C₁-C₆alkyl-N (C)₁-C₆Alkyl radical)₂Wherein C is₁-C₆Alkyl is optionally substituted with halogen (preferably F). Specific examples include, but are not limited to, -CH₂OCH₃、-CH₂CH₂OCH₃、-CH₂OCH₂CH₃、-CH₂CH₂OCH₂CH₃、-CH₂NHCH₃、-CH₂N(CH₃)₂、-CH₂OCF₃、-CH₂CH₂OCF₃、-CH₂OCH₂CF₃、-CH₂NHCF₃、-CH₂N(CF₃)₂And the like.

In one embodiment of the compounds of formula (I), R₂Is hydrogen.

In one embodiment of the compounds of formula (I), R₂Is halogen, such as F, Cl, Br or I; f or Cl is preferred.

In one embodiment of the compounds of formula (I), R₂Is C₁-C₆Alkyl, preferably C₁-C₃Alkyl, e.g. para to the phenyl radical, wherein said C₁-C₃C with alkyl substituted by two halogen radicals, preferably F₁-C₃Alkyl and one-OH substitution, e.g.

In a specific embodiment, R₁Is H and R₂Selected from halogen or

In one embodiment of the compounds of formula (I), R₃、R₄Each independently selected from H, halogen or C optionally substituted by halogen₁-C₆An alkyl group.

In a compound of formula (I)In the embodiment (1), R₃、R₄Each independently selected from H or halogen, preferably fluorine or chlorine, most preferably Cl, e.g. R₃Is H and R₄Is halogen, preferably F or Cl, or vice versa. In a specific embodiment, R₃And R₄And at the same time halogen, preferably fluorine or chlorine, most preferably at the same time Cl.

In one embodiment of the compounds of formula (I), R₃、R₄Each independently selected from H or C₁-C₆Alkyl, optionally substituted with halogen. In a specific embodiment, R₃Is H and R₄Is C optionally substituted by halogen, preferably F₁-C₆Alkyl, or vice versa, e.g. R₃Is H and R₄Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CF₃、-CHF₂、-CH₂CF₃、-CF₂CF₃、-CH₂CH₂CF₃or-CH (CF)₃)₂Etc., or vice versa. In a specific embodiment, R₃And R₄Is selected from C₁-C₆Alkyl, optionally substituted by halogen (preferably F), e.g. R₃And R₄While being methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CF₃、-CHF₂、-CH₂CF₃、-CF₂CF₃、-CH₂CH₂CF₃or-CH (CF)₃)₂Etc. or R₃And R₄Each independently is one of the exemplary groups described above.

In one embodiment of the compounds of formula (I), R₃、R₄Each independently selected from-OR_b、-SR_bor-NR_bR_bWherein R is_bIs H or C optionally substituted by halogen₁-C₆Alkyl radicals, e.g. OH, -SH, -OCH₃、-OCF₃、-OCHF₂、-OCH₂CH₃、-OCH₂CF₃、-OCH₂CH₂CH₃、-OCH₂CH₂CF₃、-OCH(CF₃)₂、-SCH₃、-SCF₃、-SCH₂CH₃、-NH₂、-NHCH₃、-N(CH₃)₂、-NH-CH₂CH₃、-N(CH₃)(CH₂CH₃)、-NHCF₃、-N(CH₃)(CF₃) And the like.

In one embodiment of the compounds of formula (I), R₅Is selected from-OR_cWherein R is_cSelected from hydrogen, C optionally substituted by halogen₁-C₆Alkyl or C optionally substituted by halogen₃-C₇A cycloalkyl group. In a specific embodiment, R₅is-OH. In a specific embodiment, R₅is-O-C₁-C₆Alkyl, optionally substituted by halogen, e.g. -OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)、-OCF₃、-OCHF₂、-OCH₂CF₃、-OCH₂CH₂CF₃、-OCH(CF₃) And the like. In a specific embodiment, R₅is-O-C₃-C₇Cycloalkyl, optionally substituted with halo, such as-O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, and the like. In a more specific embodiment, R₅is-O-C₁-C₃Alkyl radicals, e.g. -OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃) And the like.

In one embodiment of the compounds of formula (I), R₅Is selected from-NR_cR_c、-NHCOR_cor-NHSO₂R_cpreferably-NR_cR_cor-NHCOR_cWherein R is_cIndependently at each occurrence, is selected from hydrogen, C optionally substituted with halogen₁-C₆Alkyl or C optionally substituted by halogen₃-C₇Cycloalkyl, or two R bound to the same N atom_cMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group.

In a specific embodiment, R₅Is selected from-NR_cR_cor-NHCOR_cWherein R is_cIndependently at each occurrence, is selected from hydrogen or C optionally substituted with halogen (preferably F)₁-C₆Alkyl, specific examples include, but are not limited to-NH₂、-NHCH₃、-N(CH₃)₂、-NH-CH₂CH₃、-N(CH₃)(CH₂CH₃)、-N(CH₂CH₃)(CH₂CH₃)-、-NH(CH₂CH₂CH₃)、-NHCF₃、-N(CH₃)(CF₃)、-N(CF₃)CF₃、-N(CH₂CF₃)CF₃or-N (CH)₂CF₃)(CH₂CF₃)-、-NHCOCH₃、-NHCO-CH₂CH₃、-NHCO-CH₂CF₃. In a specific embodiment, R₅Is selected from-NR_cR_cIn which two R are bound to the same N atom_cMay form, together with the N atom to which they are attached, a 4-7 membered nitrogen containing heterocycloalkyl group, such as-azetidine, aziridine, piperidinyl and the like. In a more specific embodiment, R₅Is selected from-NH₂、-NHCH₃、-N(CH₃)₂、-NH-CH₂CH₃、-NH(CH₂CH₂CH₃)、-N(CH₃)(CH₂CH₃)、-NHCOCH₃、-NHCO-CH₂CH₃-azetidine, aziridine or piperidinyl.

In a specific embodiment, R₅Is selected from-NR_cR_cor-NHCOR_cWherein R is_cIndependently at each occurrence, is selected from hydrogen or C optionally substituted with halogen₃-C₇Cycloalkyl groups, such as-NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NHCO-cyclopropyl, -NHCO-cyclobutyl, -NHCO-cyclopentyl, and the like.

In one embodiment of the compounds of formula (I), R₅Is selected from-COOR_c、-CONR_cR_cor-SO₂NR_cR_cpreferably-COOR_cor-CONR_cR_cWherein R is_cIndependently at each occurrence, is selected from hydrogen, C optionally substituted with halogen₁-C₆Alkyl or C optionally substituted by halogen₃-C₇Cycloalkyl, or two R bound to the same N atom_cMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group.

In a specific embodiment, R₅Is selected from-COOR_cor-CONR_cR_cWherein R is_cIndependently at each occurrence, is selected from H or C optionally substituted with halogen (preferably F)₁-C₆Alkyl radicals, e.g. COOH, -COOCH₃、-COOCF₃、-COOCH₂CH₃、-COOCH₂CF₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-CON(CH₃)(CH₂CH₃)、-CONHCF₃、-CON(CF₃)₂. In a specific embodiment, R₅Is selected from-CONR_cR_cIn which two R are bound to the same N atom_cMay form, together with the N atom to which they are attached, a 4-7 membered nitrogen containing heterocycloalkyl group such as-CO-azetidine, -CO-aziridine, -CO-piperidinyl and the like.

In one embodiment of the compounds of formula (I), R₆Is selected from C₁-C₆Alkyl, preferably C₁-C₃Alkyl optionally substituted with one or more groups independently selected from: H. halogen, C₃-C₇Cycloalkyl radical, R_a、-OR_a、-SR_aor-NR_aR_aWherein R is_aIndependently selected from H or C optionally substituted with one or more halogens₁-C₆Alkyl, or two R bound to the same N atom_aMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group.

In a specific embodiment, R₆Is C₁-C₆Alkyl, preferably C₁-C₃Alkyl, optionally substituted by F, Cl, Br, I, R_aOR-OR_aIs substituted in whichR_aIs H or C optionally substituted by one or more halogen (preferably F)₁-C₃An alkyl group. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, trifluoromethoxy methyl or trifluoromethoxyethyl, and the like. In more specific embodiments, R₆Is C₁-C₃Alkyl groups such as methyl, ethyl, propyl or isopropyl.

In a specific embodiment, R₆Is C₁-C₆Alkyl, preferably C₁-C₃Alkyl, C optionally substituted by halogen₃-C₇Cycloalkyl is substituted. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl and the like.

In specific embodiments, R₆Is C₁-C₆Alkyl, preferably C₁-C₃Alkyl, optionally substituted by-NR_aR_aIs substituted in which R_aIndependently selected from H or C optionally substituted with one or more halogens₁-C₃Alkyl, or two R bound to the same N atom_aMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, dimethylaminomethyl, methylethylaminomethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl and the like.

In one embodiment of the compounds of formula (I), R₆is-C₃-C₇Cycloalkyl optionally substituted with one or more groups independently selected from: H. halogen, C optionally substituted by halogen₃-C₇Cycloalkyl radical, R_a、-OR_a、-SR_aor-NR_aR_aWherein R is_aIndependently selected from H or C optionally substituted with one or more halogens₁-C₆Alkyl radicalOr two R's bound to the same N atom_aMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. In specific embodiments, R₆is-C₃-C₅Cycloalkyl groups, such as cyclopropyl, cyclobutyl or cyclopentyl.

In a specific embodiment, R₆is-C₃-C₇Cycloalkyl optionally substituted with one or more groups independently selected from: halogen, R_a、-OR_aor-NR_aR_aWherein R is_aIndependently selected from H or C optionally substituted with one or more halogens₁-C₆An alkyl group. Specific examples include, but are not limited to, 2, 3-difluorocyclopropyl, 2,3, 3-tetrafluorocyclopropyl, 2, 3-difluorocyclobutyl, methylcyclopropyl or cyclobutyl, dimethylcyclopropyl or cyclobutyl, trifluoromethylcyclopropyl or cyclobutyl, hydroxycyclopropyl or cyclobutyl, trifluoromethoxycyclopropyl or cyclobutyl, methylaminocyclopropyl, dimethylaminocyclopropyl, trifluoromethylaminocyclopropyl, and the like.

In one embodiment of the compounds of formula (I), R₆Is a 4-7 membered heterocycloalkyl group, optionally substituted with one or more groups independently selected from: H. halogen, R_a、-OR_a、-SR_aor-NR_aR_aWherein R is_aIndependently selected from H or C optionally substituted with one or more halogens₁-C₆Alkyl, or two R bound to the same N atom_aMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. In specific embodiments, R₆Is a 4-to 7-membered heterocycloalkyl group such as azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothienyl (e.g., 1-tetrahydrothienyl, 2-tetrahydrothienyl and 3-tetrahydrothienyl), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g., 4-tetrahydrothiopyranyl), morpholinyl, oxetanyl, thiobutanyl, oxetanyl, and the like,Thiomorpholinyl, dioxanyl, piperazinyl or azepanyl, each of which is optionally substituted by one or more, e.g. 1,2 or 3, independently selected from F, Cl, Br, I, R_a、-OR_aor-NR_aR_aWherein R is_aIndependently selected from H or C optionally substituted with one or more halogens₁-C₃An alkyl group.

In one embodiment of the compounds of formula (I), R₆Is optionally substituted by C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl or 4-7 membered heterocycloalkyl substituted amino. In a particular embodiment, C substituted on the amino group₁-C₆Alkyl radical, C₃-C₇Cycloalkyl or 4-7 membered heterocycloalkyl each have the above embodiment pairs as R₆C of (A)₁-C₆Alkyl radical, C₃-C₇Each embodiment or specific example as defined for cycloalkyl or 4-7 membered heterocycloalkyl. In a most specific embodiment, R₆Is C optionally substituted by halogen₁-C₆Alkyl-substituted amino, specific examples include, but are not limited to, -NH₂、-NHCH₃、-NCH₃CH₃、-N(CH₂CH₃)CH₃、-N(CH₂CH₃)(CH₂CH₃)-、-NHCF₃、-N(CH₃)CF₃、-N(CF₃)CF₃、-N(CH₂CF₃)CF₃or-N (CH)₂CF₃)(CH₂CF₃)-、-NH(CH₂CH₂CH₃) And the like.

It is to be understood that the compounds of formula (I) of the present invention encompass each of the above independent embodiments or each specific embodiment, and also encompass embodiments comprised of any combination or subcombination of the above-described embodiments or specific embodiments, as well as embodiments comprised of any combination of any of the above preferences or exemplifications.

Preferably, the present invention provides a compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof:

wherein:

x is selected from CH;

R₁selected from hydrogen, -O-C₁-C₆Alkyl, S-C₁-C₆Alkyl, -NH-C₁-C₆Alkyl or-N- (C)₁-C₆Alkyl radical)₂Wherein said C is₁-C₆Alkyl optionally substituted with halo;

R₂selected from hydrogen, halogen or C₁-C₆Alkyl radical, wherein said C₁-C₆The alkyl group is substituted with a substituent independently selected from the group consisting of: -R_aor-OH, wherein R_aIs C substituted by halogen₁-C₆An alkyl group;

R₃、R₄each independently selected from H, halogen, cyano or C optionally substituted by halogen₁-C₆An alkyl group;

R₅is selected from-OR_c、-SR_c、-NR_cR_c、-NHCOR_c、-NHSO₂R_c、-COOR_c、-CONR_cR_cor-SO₂NR_cR_cWherein R is_cIndependently at each occurrence, is selected from hydrogen or C optionally substituted with halogen₁-C₆Alkyl, or two R bound to the same N atom_cMay form, together with the N atom to which they are attached, a 4-7 membered nitrogen containing heterocycloalkyl group;

R₆is selected from C₁-C₆Alkyl or-NR_aR_aWherein said C is₁-C₆Alkyl is optionally substituted with substituents each independently selected from: halogen, -R_aor-NR_aR_a，R_aIndependently at each occurrence, selected from H, C optionally substituted with halogen₁-C₆Alkyl or C optionally substituted by halogen₃-C₇Cycloalkyl in which two are bound to the N atom of the amino groupR is_aMay form a 4-7 membered ring together with the N to which they are attached; and is

n is selected from 0, 1 or 2.

In one embodiment of one of the preferred compounds of formula (I) above, R₁Selected from hydrogen or-O-C₁-C₆Alkyl radical, wherein said C₁-C₆Alkyl is optionally substituted with halogen. In a specific embodiment, R₁Selected from hydrogen or-O-C₁-C₆Alkyl radical, wherein said C₁-C₆Alkyl is substituted with one or more, e.g. one, two or three, halogens (preferably F). In a more specific embodiment, R₁is-O-C₁-C₆Alkyl radical, wherein said C₁-C₆Alkyl radicals substituted by at least three halogens, preferably F, e.g. -O-CF₃、-O-CH₂CF₃、-O-CH₂CH₂CF₃、-O-CF₂CF₃And the like.

In one embodiment of the above preferred compounds of formula (I), R₂Is hydrogen.

In one embodiment of the above preferred compounds of formula (I), R₂Is halogen, such as F, Cl, Br or I; f or Cl is preferred.

In one embodiment of the above preferred compounds of formula (I), R₂Is C₁-C₆Alkyl, preferably C₁-C₃Alkyl, C substituted by two halogens (preferably F)₁-C₃Alkyl and one-OH substitution, e.g.

In one embodiment of the above preferred compounds of formula (I), R₁Is H and R₂Selected from halogen or

In one embodiment of the above preferred compounds of formula (I), R₃、R₄Each independently selected from H or halogen, preferably F or Cl, most preferably Cl, e.g. R₃Is H and R₄Is halogen, preferably F or Cl, or vice versa. In a specific embodiment, R₃And R₄And at the same time halogen, preferably fluorine or chlorine, most preferably at the same time Cl.

In one embodiment of the above preferred compounds of formula (I), R₃、R₄Each independently selected from H or C₁-C₆Alkyl, optionally substituted with halogen. In a specific embodiment, R₃Is H and R₄Is C optionally substituted by halogen, preferably F₁-C₆Alkyl, or vice versa, e.g. R₃Is H and R₄Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CF₃、-CHF₂、-CH₂CF₃、-CF₂CF₃、-CH₂CH₂CF₃or-CH (CF)₃)₂Etc., or vice versa. In a specific embodiment, R₃And R₄Is selected from C₁-C₆Alkyl radicals, e.g. R₃And R₄While being methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CF₃、-CHF₂、-CH₂CF₃、-CF₂CF₃、-CH₂CH₂CF₃or-CH (CF)₃)₂Etc. or R₃And R₄Each independently is one of the exemplary groups described above.

In one embodiment of the above preferred compounds of formula (I), R₅Is selected from-OR_cWherein R is_cSelected from hydrogen or C optionally substituted by halogen₁-C₆An alkyl group. In a specific embodiment, R₅is-OH. In a specific embodiment, R₅is-O-C₁-C₆Alkyl, optionally substituted by halogen, e.g. -OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)、-OCF₃、-OCH₂CF₃、-OCH₂CH₂CF₃、-OCH(CF₃) And the like. In a more specific embodiment, R₅is-O-C₁-C₃Alkyl radicals, e.g. -OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃) And the like.

In one embodiment of the above preferred compounds of formula (I), R₅Is selected from-NR_cR_cor-NHCOR_cWherein R is_cIndependently at each occurrence, is selected from hydrogen or C optionally substituted with halogen (preferably F)₁-C₆Alkyl, specific examples include, but are not limited to-NH₂、-NHCH₃、-N(CH₃)₂、-NH-CH₂CH₃、-N(CH₃)(CH₂CH₃)、-N(CH₂CH₃)(CH₂CH₃)-、-NH(CH₂CH₂CH₃)、-NHCF₃、-N(CH₃)(CF₃)、-N(CF₃)CF₃、-N(CH₂CF₃)CF₃or-N (CH)₂CF₃)(CH₂CF₃)-、-NHCOCH₃、-NHCO-CH₂CH₃、-NHCO-CH₂CF₃. In a specific embodiment, R₅Is selected from-NR_cR_cIn which two R are bound to the same N atom_cMay form, together with the N atom to which they are attached, a 4-7 membered nitrogen containing heterocycloalkyl group, such as-azetidine, aziridine, piperidinyl and the like. In a more specific embodiment, R₅Is selected from-NH₂、-NHCH₃、-N(CH₃)₂、-NH-CH₂CH₃、-N(CH₃)(CH₂CH₃)、-NH(CH₂CH₂CH₃)、-NHCOCH₃、-NHCO-CH₂CH₃-azetidine, aziridine or piperidinyl.

In one embodiment of the above preferred compounds of formula (I), R₅Is selected from-COOR_cor-CONR_cR_cWherein R is_cIndependently at each occurrence, is selected from H or C optionally substituted with halogen (preferably F)₁-C₆Alkyl radicals, e.g. COOH, -COOCH₃、-COOCH₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-CON(CH₃)(CH₂CH₃). In a specific embodiment, R₅Is selected from-CONR_cR_cIn which two R are bound to the same N atom_cMay form, together with the N atom to which they are attached, a 4-7 membered nitrogen containing heterocycloalkyl group such as-CO-azetidine, -CO-aziridine, -CO-piperidinyl and the like.

In one embodiment of the above preferred compounds of formula (I), R₆is-C₁-C₆Alkyl, preferably-C₁-C₃Alkyl, optionally substituted with halogen. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, and the like.

In a more specific embodiment, R₆is-C₁-C₃Alkyl groups such as methyl, ethyl, propyl or isopropyl.

In one embodiment of the above preferred compounds of formula (I), R₆is-C₁-C₆Alkyl, preferably-C₁-C₃Alkyl, optionally substituted by-NR_aR_aIs substituted in which R_aSelected from H or C optionally substituted by halogen₁-C₃Alkyl, or two R bound to the same N atom_aMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. Specific examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, dimethylaminomethyl, methylethylaminomethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, and the like.

In one embodiment of the above preferred compounds of formula (I), R₆is-C₁-C₆Alkyl, preferably-C₁-C₃Alkyl, C optionally substituted by halogen₃-C₇Cycloalkyl is substituted. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethylAnd the like.

In one embodiment of the above preferred compounds of formula (I), R₆is-NR_aR_aWherein R is_aSelected from H or C optionally substituted by halogen₁-C₃Alkyl, or two R bound to the same N atom_aMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. Specific examples include, but are not limited to, -NH₂、-NHCH₃、-NCH₃CH₃、-N(CH₂CH₃)CH₃、-N(CH₂CH₃)(CH₂CH₃)-、-NHCF₃、-N(CH₃)CF₃、-N(CF₃)CF₃、-N(CH₂CF₃)CF₃or-N (CH)₂CF₃)(CH₂CF₃)-、-NH(CH₂CH₂CH₃) Azetidinyl, pyrrolidinyl, piperidinyl and the like.

It is to be understood that the preferred compounds of formula (I) described above encompass each individual embodiment or each specific embodiment, as well as embodiments that consist of any combination or subcombination of the various embodiments or specific embodiments described above.

Preferred embodiments of the compounds of the present invention include the following compounds, stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates thereof,

the invention has the advantages of

The invention provides biaryl compounds with a structure shown in a general formula (I), and researches show that the compounds can effectively inhibit ROR gamma t protein receptors, so that the differentiation of Th17 cells is regulated and controlled, the generation of IL-17 is inhibited, and the biaryl compounds can be used as immunomodulators for treating diseases related to Th17 cell differentiation.

The compound of the invention has the following beneficial effects:

has high inhibitory activity on ROR gamma t receptor;

regulating the differentiation of Th17 cells, and inhibiting the production of IL-17; and/or

Having good pharmacokinetic properties, e.g. having a longer t_1/2Thus, for example, the dosing interval can be increased, the half-life is longer, and the patient has better compliance;

the compound has improved AUC0-last data, better druggability and higher bioavailability; and/or

Good safety, excellent properties like membrane permeability, P450 (reduced risk of drug interaction), solubility, etc.

Compounds of the invention for use in therapy or as medicaments

In one aspect, the present invention provides compounds of the invention for use as medicaments, in particular as ROR γ t inhibitors.

In another aspect, the present invention provides a compound of the invention for use in the treatment, especially for use in the treatment and/or prevention of a disease associated with roryt.

In particular embodiments, the invention provides compounds of the invention for use in the treatment and/or prevention of diseases in which ROR γ t contributes to the onset and progression of the disease or in which inhibition of ROR γ t would reduce the incidence of, reduce or eliminate the symptoms of, the disease, e.g., inflammation or autoimmune disease, cancer, etc., including but not limited to psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, asthma, glomerulonephritis, lupus nephritis, myocarditis, thyroiditis, dry eye, uveitis, behcet disease, allergic dermatitis, acne, scleroderma, bronchitis, dermatomyositis, necrotizing enterocolitis, Hepatic fibrosis, nonalcoholic steatohepatitis (NASH), neocoronavirus pneumonia, insulin-dependent type I diabetes, triple negative breast cancer, prostate cancer, and the like.

Pharmaceutical compositions and their administration

In another aspect, for use of the compounds of the present specification for therapeutic or prophylactic purposes, the compounds of the present invention may be formulated as pharmaceutical compositions in accordance with standard pharmaceutical practice. Meanwhile, based on good pharmacokinetic property, improved AUC0-last and good drug forming property of the compound, the compound can be used for preparing a drug with better pharmacokinetic property and higher bioavailability.

Accordingly, the present invention provides a pharmaceutical composition comprising a compound of the invention as described above and a pharmaceutically acceptable excipient.

In a specific embodiment, said pharmaceutical composition of the invention is provided for use in the prevention or treatment of a disease associated with roryt in a mammalian, e.g. human, subject.

In a particular embodiment, the pharmaceutical composition of the invention may additionally comprise additional therapeutically active ingredients suitable for use in combination with the compounds of the invention. In another specific embodiment, the additional therapeutic agent is as defined herein for the pharmaceutical combination.

The Pharmaceutical compositions of the present invention may be formulated by techniques known to those skilled in the art, such as those disclosed in Remington's Pharmaceutical Sciences, 20 th edition. For example, the pharmaceutical compositions of the present invention described above may be prepared by mixing a compound of the present invention with one or more pharmaceutically acceptable excipients. The preparation may further comprise the step of mixing one or more other active ingredients with the compound of the present invention and one or more pharmaceutically acceptable excipients.

The choice of excipients to include in a particular composition will depend on a variety of factors, such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Ansel, Howard C., et al, Ansel's Pharmaceutical Delivery Forms and Drug Delivery systems Philadelphia, Lippincott, Williams & Wilkins,2004, including, for example, adjuvants, diluents (e.g., glucose, lactose or mannitol), carriers, pH adjusting agents, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, flavorants, flavoring agents, other known additives.

The pharmaceutical compositions of the present invention may be administered in a standard manner. For example, suitable modes of administration include oral, intravenous, rectal, parenteral, topical, transdermal, ocular, nasal, buccal or pulmonary (inhalation) administration, with parenteral infusion including intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. For these purposes, the compounds of the present invention may be formulated by methods known in the art into the form of, for example, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops, aerosols, dry powder formulations and sterile injectable aqueous or oily solutions or suspensions.

The size of a prophylactic or therapeutic dose of a compound of the invention will vary depending upon a number of factors, including the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the judgment of the prescribing physician. Generally, an effective dose is in the range of about 0.0001 to about 5000mg per kg body weight per day, e.g., about 0.01 to about 1000 mg/kg/day (single or divided administration). For a 70kg human, this may amount to about 0.007 mg/day to about 7000 mg/day, for example about 0.7 mg/day to about 1500 mg/day. Depending on the mode of administration, the amount or amount of a compound of the invention in a pharmaceutical composition may be from about 0.01mg to about 1000mg, suitably 0.1-500mg, preferably 0.5-300mg, more preferably 1-150mg, especially preferably 1-50mg, e.g. 1.5mg, 2mg, 4mg, 10mg, 25mg etc.; accordingly, the pharmaceutical composition of the invention will comprise 0.05 to 99% w/w (weight percentages), such as 0.05 to 80% w/w, such as 0.10 to 70% w/w, such as 0.10 to 50% w/w of the compound of the invention, all weight percentages being based on the total composition. It will be appreciated that it may be necessary in some cases to use dosages outside these limits.

In a specific embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, the composition being formulated for oral administration. The composition may be provided in unit dosage form, for example in the form of a tablet, capsule or oral liquid formulation. Such unit dosage forms may contain, as active ingredient, from 0.1mg to 1g, for example from 5mg to 250mg, of a compound of the invention.

In a specific embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, the composition being formulated for topical administration. Topical administration may be in the form of, for example, a cream, lotion, ointment, or transdermal patch.

In a specific embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, the composition being formulated for administration by inhalation. Inhalation administration can be by oral inhalation, or by intranasal administration. When administered by oral inhalation, the compounds of the invention may be effectively used in the present invention in a daily dose, for example up to 500. mu.g, such as 0.1 to 50. mu.g, 0.1 to 40. mu.g, 0.1 to 30. mu.g, 0.1 to 20. mu.g or 0.1 to 10. mu.g of a compound of the invention. The pharmaceutical compositions of the present invention for oral inhalation may be formulated as a dry powder, a suspension (in a liquid or gas) or a solution (in a liquid), and may be administered in any suitable form and using any suitable inhaler device known in the art, including for example Metered Dose Inhalers (MDIs), Dry Powder Inhalers (DPIs), nebulizers and soft mist inhalers. The multi-compartment device may be used to deliver a compound of the present specification and one or more other active ingredients (when present).

Methods of treatment and uses

Based on the beneficial effects described above with respect to the compounds of the present invention, the compounds of the present invention are useful in methods of treating various conditions in animals, particularly mammals such as humans.

Thus, in another aspect, the invention provides a method of modulating, particularly inhibiting, ROR γ t activity, the method comprising contacting a cell with a compound of the invention as hereinbefore described to modulate, particularly inhibit, ROR γ t activity in the cell.

In another aspect, the present invention provides a method of preventing or treating a disease associated with roryt (e.g. a disease treatable or preventable by roryt inhibition), the method comprising administering to a subject in need thereof an effective amount of a compound of the invention as hereinbefore described or a pharmaceutical composition of the invention comprising the same.

In another aspect, the invention provides the use of a compound of the invention, or a pharmaceutical composition comprising the same, as described hereinbefore, for inhibiting ROR γ t activity, or for the treatment and/or prevention of a disease associated with ROR γ t, for example a disease treatable or preventable by ROR γ t inhibition.

In another aspect, the present invention also provides the use of a compound of the invention or a pharmaceutical composition comprising the same as described above for the manufacture of a medicament, in particular a medicament having ROR γ t receptor inhibitor activity.

In another aspect, the invention provides the use of a compound of the invention, or a pharmaceutical composition comprising the same, as described hereinbefore, optionally in combination with one or more chemotherapeutics or immunotherapeutics, in the manufacture of a medicament for the treatment or prevention of a disease associated with roryt, for example a disease treatable or preventable by roryt inhibition.

Pharmaceutical combination

The compounds of the present invention may be administered as the sole active ingredient or in combination with additional drugs or therapies. The additional drugs or therapies may have or produce the same or different pharmacological effects, provided however that the use in combination with the compounds of the present invention does not result in an undesirable reduction in activity, adverse interaction or side effect.

Thus, in another aspect, the invention provides a pharmaceutical combination comprising or consisting of a compound of the invention as hereinbefore described together with one or more other drugs or therapies acting by the same or different mechanism of action. In a specific embodiment, the pharmaceutical combination is for use in inhibiting ROR γ t activity, or for use in the treatment and/or prevention of a disease associated with ROR γ t.

The compounds of the invention and the other active agents used in combination in the pharmaceutical combination of the invention may be administered simultaneously, separately or sequentially by the same or different routes of administration. The additional active agents may be co-administered in a single pharmaceutical composition with the compounds of the present invention or separately administered in separate discrete units from the compounds of the present invention, e.g., as a combination product, preferably in kit form. When administered separately, may be simultaneous or sequential, which sequential administration may be close in time or remote in time. Furthermore, the compound of the invention and the further medicament may be administered (i) prior to sending the combination product to a physician (e.g. in the case of a kit comprising a compound of the invention and a further medicament); (ii) by the physician himself (or under the direction of the physician) immediately before administration; (iii) the combination therapy is added by the patient himself, for example during sequential administration of the compound of the invention and the further drug, together.

Thus, in a particular embodiment, the invention also provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of the invention, the remainder comprising other active agents used in combination, and means for separately containing said compositions. The kit of the invention is particularly suitable for administration of different dosage forms, such as oral dosage forms and parenteral dosage forms, or for administration of different compositions at different dosage intervals.

In the pharmaceutical combinations of the present invention, the appropriate amounts of the compound of the present invention and the other active agents to be combined will generally be determined by those skilled in the art by, for example, starting from the dosage ranges for the compounds described in the specification and approved or published dosage ranges for the other active compounds, and the dosages of the other drugs co-administered will, of course, vary depending upon such factors as the type of co-drug employed, the particular drug employed, the condition being treated, the general health of the patient, the judgment of the physician or veterinarian, and the like.

For pharmaceutical compositions and combinations of the invention, the additional active agent may be one or more second or additional (e.g., third) compounds that have enhanced, complementary activity that does not adversely affect the compound of the invention, e.g., the active agent may be a compound known to modulate other pathways of biological activity, or may be a compound that modulates different components of the pathway of biological activity to which the compound of the invention relates, or even a compound that overlaps with the biological target of the compound of the invention.

In a particular embodiment, the present invention provides a pharmaceutical combination, for example for use as a medicament for the treatment of one of the diseases listed herein, such as psoriasis, COPD, asthma, psoriatic arthritis or ankylosing spondylitis, comprising a compound of the invention, and at least one active ingredient selected from:

a) a beta-adrenoceptor agonist;

b) a muscarinic receptor antagonist;

c) joint muscarinic receptor antagonists and β -adrenergic receptor agonists; and

d) glucocorticoid receptor agonists (steroidal or non-steroidal);

e) phosphodiesterase-4 (PDE4) inhibitors.

The compounds of the present invention may also be combined with other therapies including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), tumor immunotherapy, and the like.

Accordingly, the present invention provides a method for inhibiting ROR γ t activity or for the treatment and/or prevention of a disease associated with ROR γ t, comprising administering a pharmaceutical combination of the invention to a subject in need thereof. The invention also provides the application of the pharmaceutical composition in preparing a medicament for inhibiting the activity of ROR gamma t or treating and/or preventing ROR gamma t related diseases.

For the various aspects described above relating to pharmaceutical compositions, methods of treatment and uses, and pharmaceutical combinations, diseases associated with ROR γ t (e.g., diseases treatable or preventable by ROR γ t inhibition) include inflammatory or autoimmune diseases, cancer, and the like, including, but not limited to, psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, asthma, glomerulonephritis, lupus nephritis, myocarditis, thyroiditis, dry eye, uveitis, behcet's disease, allergic dermatitis, acne, scleroderma, bronchitis, dermato-muscular allergic rhinitis, necrotizing enterocolitis, hepatic fibrosis, nonalcoholic steatitis (NASH), neoviral pneumonia, neocoronary pneumonia, and the like, Insulin-dependent type I diabetes, triple negative breast cancer, prostate cancer, and the like. Preferred diseases associated with roryt are selected from psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, inflammatory bowel disease, dry eye, allergic dermatitis, Chronic Obstructive Pulmonary Disease (COPD), asthma, necrotizing enterocolitis, liver fibrosis, nonalcoholic steatohepatitis (NASH), neocoronavirus pneumonia, triple negative breast cancer and prostate cancer.

Preferred for the above-described compounds, pharmaceutical compositions, methods, uses, pharmaceutical combinations of the invention are the preferred compounds of formula (I), stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates thereof, as described above; more preferred are the specific compounds listed above, e.g., compounds 1-26, or their pharmaceutically acceptable salts or solvates.

When a dosage of a compound or drug for administration is described herein, it is understood that the dosage is based on the weight of the free base, excluding any derivative thereof, unless the specification indicates otherwise.

Synthesis of Compounds of the invention

In another aspect, the invention also provides a process for the preparation of compounds of formula (I), the general synthetic scheme for the synthesis of the compounds of the invention being illustrated below. Suitable reaction conditions for each reaction step are known to those skilled in the art or can be routinely determined. The starting materials and reagents used in the preparation of these compounds are generally commercially available or can be prepared by the methods hereinafter, by methods similar to those given hereinafter, or by methods known in the art, if not otherwise specified. If desired, the starting materials and intermediates in the synthetic reaction schemes can be isolated and purified using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. The materials may be characterized using conventional methods including physical constants and spectroscopic data.

In one embodiment, the method comprises the steps of:

synthesis scheme 1:

wherein R is₁、R₂、R₃、R₄、R₆、R_cAnd X is as defined above for formula (I), Z is Br or I; and R is_cIs not H;

step 1: the compound of formula (I-1) or formula (I-2) and the compound of formula (I-3) are subjected to coupling reaction such as Suzuki coupling reaction under the action of a catalyst such as a palladium catalyst to obtain an intermediate compound of formula (I-4);

wherein the palladium catalyst is a palladium catalyst for Suzuki coupling as is well known in the art, including but not limited to PdCl₂(dtbpf)、Pd(dppf)Cl₂Etc.; the reaction is preferably carried out in the presence of a suitable base which may be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, preferably the base is potassium carbonate;

step 2: reacting the compound shown in the formula (I-5) with paraformaldehyde under the action of sodium methoxide to generate a compound shown in the formula (I-6);

and step 3: alkylation of the compound of formula (I-6) to produce a compound of formula (I-7); the alkylation is for example in HBF₄With TMSCN or, for example, with an alkyl halide in the presence of a base; the alkali can be selected from butyl lithium, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate;

and 4, step 4: hydrolysis of a compound of formula (I-7) to give a compound of formula (I-8), preferably in the presence of a base selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate or an acid selected from hydrochloric acid, sulphuric acid or trifluoroacetic acid; and/or

And 5: the compound of the formula (I-8) and the intermediate compound of the formula (I-4) generate the compound of the formula (I-a) under the action of a condensing agent.

Wherein the condensing agent is one well known in the art for coupling carboxylic acids with amines, including but not limited to EDC, DCC, HATU, N' -tetramethylchloroformamidine hexafluorophosphate, and the like; the reaction is preferably carried out in the presence of a suitable base including, but not limited to, sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt, N-methylimidazole or pyridine.

In one embodiment, the method comprises the steps of:

synthesis scheme 2:

wherein R is₁、R₂、R₃、R₄、R₆、R_cAnd X is as defined above for formula (I).

Step 1: the compound of the formula (II-1) and the compound of the formula (II-2) generate the compound of the formula (II-3) under the action of a condensing agent.

Wherein the condensing agent is one well known in the art for coupling carboxylic acids with amines, including but not limited to EDC, DCC, HATU, N' -tetramethylchloroformamidine hexafluorophosphate, and the like; (ii) a The reaction is preferably carried out in the presence of a suitable base including, but not limited to, sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt, N-methylimidazole or pyridine;

step 2: reacting the compound of the formula (II-3) with paraformaldehyde under the action of sodium methoxide to generate a compound of a formula (I-b);

step 3 a: alkylating the compound of formula (I-b) to produce a compound of formula (I-a); the alkylation is for example in HBF₄With TMSCN or, for example, with an alkyl halide in the presence of a base; the alkali is selected from butyl lithium, sodium hydroxide, potassium hydroxide, and sodium carbonatePotassium carbonate or cesium carbonate;

and step 3 b: reacting the compound shown in the formula (I-b) with methanesulfonyl chloride to generate a compound shown in a formula (II-4); the reaction is preferably carried out in the presence of a suitable base including, but not limited to, sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt, N-methylimidazole or pyridine; and/or

And 4, step 4: the compound of formula (I-4) and HNR_cR_cNucleophilic substitution reaction to generate a compound of formula (I-c); the reaction is preferably carried out in the presence of a suitable base including, but not limited to, sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt, N-methylimidazole or pyridine.

In one embodiment, the method comprises the steps of:

synthesis scheme 3:

wherein R is₁、R₂、R₃、R₄、R₆、R_cAnd X is as defined above for formula (I),

step 1a) Compounds of formula (III-1) with R_cCOOH or an activated form thereof, such as the corresponding acid chloride or anhydride, to produce a compound of formula (I-d); the reaction is preferably carried out in the presence of a base selected from sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt or pyridine; the reaction may be carried out in the presence of condensing agents such as, for example, and the like, wherein the condensing agents are well known in the art for the coupling of carboxylic acids to amines, including but not limited to 1-propylphosphoric anhydride (T3P), EDC, DCC, HATU; or

Step 1b) Compounds of formula (III-1) with R_cSO₂Cl to generate a compound shown as a formula (I-e); the reaction is preferably carried out in the presence of a base selected from sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt or pyridine;

in one embodiment, the method comprises the steps of:

synthesis scheme 4:

step 1: hydrolysis of the compound of formula (IV-1) to give the compound of formula (IV-2), preferably in the presence of a base selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate,

step 2: reacting the compound of formula (IV-2) with the compound of formula (I-4) to obtain the compound of formula (IV-3) under the conditions described in step 1 of FIG. 2;

and step 3: hydrolysis of a compound of formula (IV-3) to give a compound of formula (I-f), preferably in the presence of an acid which may be selected from, for example, hydrochloric acid, sulphuric acid or trifluoroacetic acid;

step 4 a: optionally, a compound of formula (I-f) with R_cOH reaction to obtain a compound of formula (I-g); the reaction is preferably carried out in the presence of a base selected from sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt or pyridine; the reaction may be carried out in the presence of a condensing agent such as, for example, an alcohol, wherein the condensing agent is well known in the art for coupling carboxylic acids to alcohols, including but not limited to 1-propylphosphoric anhydride (T3P), EDC, DCC, or HATU;

and 4 b: optionally, a compound of formula (I-f) with HNR_cR_cThe reaction gives compounds of formula (I-h) under conditions as described in FIG. 2, step 1;

the reaction in the above step is preferably carried out in an organic solvent which may be selected from alcohol solvents such as (methanol, ethanol or propanol), tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, dichloromethane, dimethyl sulfoxide and any combination thereof; mixtures of organic solvents with water can be used for the hydrolysis reaction;

the reaction in the above step is preferably carried out at a suitable temperature, for example, -100 ℃ to 0 ℃, -80 ℃ to-20 ℃, -50 ℃ to 200 ℃, -20 ℃ to 100 ℃, -20 ℃ to 20 ℃, -10 ℃ to 50 ℃, 0-200 ℃, 10-100 ℃, 20-50 ℃ or room temperature (20-25 ℃). The above synthetic schemes are only illustrative of some of the methods of preparation of the compounds of the present invention. The compounds of the present invention or stereoisomers, tautomers, stable isotopic derivatives, pharmaceutically acceptable salts or solvates thereof can be prepared by a variety of methods, including those set forth above, in the examples, or by analogous methods thereto, by one of ordinary skill in the art based on the synthetic schemes described above, in conjunction with routine techniques in the art.

The compounds described in this specification are further illustrated in the following examples. These examples are given by way of illustration only and not by way of limitation.

Detailed Description

The technical solutions of the present invention are further described below with reference to specific examples, but the scope of the present invention is not limited to these examples. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.

Experimental procedures without specific conditions noted in the following examples are generally carried out according to conventional conditions for such reactions, or according to conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight. Unless otherwise specified, the ratio of liquids is by volume.

The experimental materials and reagents used in the following examples are commercially available, prepared according to methods of the prior art or prepared according to methods similar to those disclosed herein, unless otherwise specified.

Chemical names used herein are IUPAC names and abbreviations used herein have meanings commonly understood in the art unless clearly defined otherwise in the specification. The meanings of the abbreviations used in the specification are listed below:

PdCl₂(dtbpf): 1,1' -di-tert-butylphosphino ferrocene palladium dichloride

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

xanthophos 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene

Pd₂(dba)₃Tris (dibenzylideneacetone) dipalladium

HATU: 2- (7-azobenzotriazol) -N, N, N ', N', -tetramethyluronium hexafluorophosphate

TCFH N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate

DIEA: n, N-diisopropylethylamine

DMF: n, N-dimethylformamide

DMSO, DMSO: dimethyl sulfoxide

DCM: methylene dichloride

EA ethyl acetate

PE: petroleum ether

rt-room temperature

LC-MS: liquid chromatography-mass spectrometry

ESI electrospray ionization

m/z: mass to charge ratio

TLC thin layer chromatography

Time: retention time

Synthetic examples

In the preparation method of the target compound, the column chromatography adopts silica gel (300-400 meshes) produced by Ningsan Sun drying agent GmbH; thin layer chromatography using GF254(0.25 mm); nuclear magnetic resonance chromatography (NMR) was measured using a Varian-400 nuclear magnetic resonance spectrometer; LC/MS an Agilent technology ESI 6120 LC/MS instrument was used.

In addition, all operations involving easily oxidizable or hydrolyzable raw materials were carried out under nitrogen protection. Unless otherwise indicated, all starting materials used in the present invention are commercially available, can be used without further purification, and are used in the present invention at temperatures in degrees Celsius.

When the structure of the compound of the present invention is inconsistent with the name of the compound, the structural formula is generally subject to the standard unless the name of the compound can be determined to be correct by context.

Example 1: n- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) -3-methoxypropionamide

Synthesis of intermediate 2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-amine

Step 1: synthesis of 4-bromo-3, 5-dichloroaniline

N-bromosuccinimide (69.2g,389mmol) was added to a solution of 3, 5-dichloroaniline (60.0g,370mmol) in acetonitrile (1.00L) under ice-cooling, and the reaction mixture was stirred at room temperature for 1.5 hours, whereupon the reaction was stopped. The reaction mixture was concentrated under reduced pressure to give a residue, and a mixed solvent of PE/EA (200mL, volume ratio 10:1) was added thereto, and after stirring at room temperature for 10 minutes, the mixture was filtered, and the filter cake was washed with PE (150mL), and dried to obtain the objective compound (70.0g, yield 78.5%, brown solid). LC-MS (ESI) M/z 240.2[ M + H ]]⁺/242.2[M+2+H]⁺。¹H NMR(400MHz,CDCl₃)δ8.64(s,2H),6.71(s,2H)。

Step 2: synthesis of 2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-amine

To a mixed solution of 4-bromo-3, 5-dichloroaniline (49.5g,206mmol) and (2- (trifluoromethoxy) phenyl) boronic acid (46.5g,226mmol) in water (50.0mL) and 1, 4-dioxane (500mL) was added potassium carbonate (56.8g,411mmol) and PdCl₂(dtbpf) (4.03g,6.16 mmol). The reaction mixture was stirred at 60 ℃ for 16 hours under argon protection, and then the reaction was stopped. Cooling the reaction mixture to room temperature, adding water (C)300mL), the mixture was extracted with EA (300mL × 2), the organic phase was separated, washed with saturated brine (200mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (PE: EA 12:1-8:1) to give the title compound (20.5g, yield 31.0%, white solid). LC-MS (ESI) M/z 321.9[ M + H ]]⁺/323.9[M+2+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.56–7.50(m,1H),7.47–7.41(m,2H),7.35–7.30(m,1H),6.71(s,2H),5.81(s,2H)。

Intermediate: synthesis of 2- (4- (methylsulfonyl) phenyl) -3-methoxypropionic acid

Step 1: synthesis of methyl 2- (4-methylsulfonyl) phenylacetate

2- (4-Methylsulfonyl) phenylacetic acid (9.00g,42.0mmol) was dissolved in methanol (100mL) and thionyl chloride (15.0g,126mmol) was added under ice-water bath conditions. The reaction mixture was warmed to room temperature and stirred for 1 hour, and the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (PE: EA ═ 3:1-2:1) to obtain the objective compound (8.60g, yield 89.7%, yellow solid). LC-MS (ESI) M/z 229.0[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.91(d,J＝8.4Hz,2H),7.49(d,J＝8.5Hz,2H),3.73(s,2H),3.72(s,3H),3.05(s,3H)。

Step 2: synthesis of methyl 2- (4-methylsulfonyl) phenyl-3-hydroxypropionate

Methyl 2- (4-methylsulfonyl) phenylacetate (9.40g,41.2mmol) was dissolved in anhydrous DMSO (100.0mL), and paraformaldehyde (1.17g,39.2mmol) and sodium methoxide (89.0mg,1.65mmol) were sequentially added thereto, and the reaction was stopped after the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was added to ice water (300.0mL), the mixture was neutralized with a 1.0M hydrochloric acid solution, extracted with EA (400 mL. times.2), and allowed to stand for separation. The organic phase was washed with saturated brine (60.0 mL. times.3),dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (PE: EA ═ 3:1-1:1) to obtain the objective compound (6.15g, yield 57.8%, light yellow oil).¹H NMR(400MHz,DMSO-d₆)δ7.87(d,2H),7.57(d,2H),5.08(t,J＝4.9Hz,1H),3.95–3.90(m,2H),3.72–3.65(m,1H),3.61(s,3H),3.18(s,3H)。

And step 3: synthesis of methyl 2- (4- (methylsulfonyl) phenyl) -3-methoxypropionate

Methyl 2- (4- (methylsulfonyl) phenyl) -3-hydroxypropionate (6.10g,23.6mmol) was dissolved in DCM (140mL), and 50% aqueous fluoroboric acid (4.14g,23.6mmol) and trimethylsilylated diazomethane (11.8mL,23.6mmol,2.0M n-hexane solution) were added to the reaction mixture in an ice-water bath under exclusion of light. After 20 minutes, trimethylsilylated diazomethane (11.8mL,23.6mmol,2.0M n-hexane solution) was added again. After 20 minutes, trimethylsilylated diazomethane (11.8mL,23.6mmol,2.0M n-hexane solution) was added again. After 20 minutes, trimethylsilylated diazomethane (11.8mL,23.6mmol,2.0M n-hexane solution) was added again. The reaction mixture was poured into water (80.0mL), extracted with DCM (200 mL. times.3), and allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (PE: EA ═ 5:1-3:1) to obtain the objective compound (4.62g, yield 71.9%, colorless oil). LC-MS (ESI) M/z 273.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.90(d,2H),7.53(d,2H),4.00–3.92(m,2H),3.71(s,3H),3.69–3.65(m,1H),3.35(s,3H),3.04(s,3H)。

And 4, step 4: synthesis of 2- (4- (methylsulfonyl) phenyl) -3-methoxypropionic acid

Methyl 2- (4- (methylsulfonyl) phenyl) -3-methoxypropionate (3.60g,13.2mmol) was dissolved in 1.4-dioxane (40).0mL) and 6.0M hydrochloric acid (40.0 mL). The reaction mixture was stirred at 80 ℃ for 1 hour, and then the reaction was stopped. The reaction mixture was cooled to room temperature, poured into water (50.0mL), extracted with EA (200 mL. times.2), and allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was subjected to medium pressure liquid phase preparation (acetonitrile/water containing 0.05% formic acid) to give the title compound (2.00g, yield 58.8%, white solid). MS (ESI) M/z 515.0[2M-H]^-。¹H NMR(400MHz,CDCl₃)δ7.91(d,J＝8.4Hz,2H),7.56(d,J＝8.4Hz,2H),4.02–3.92(m,2H),3.74–3.68(m,1H),3.37(s,3H),3.04(s,3H)。

Synthesis of N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) -3-methoxypropionamide

2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl]-4-amine (50.0mg,0.155mmol) and 2- (4- (methylsulfonyl) phenyl) -3-methoxypropionic acid (48.0mg, 0.186mmol) were added to acetonitrile (2.0 mL). To the reaction mixture was added N-methylimidazole (26.8mg, 0.326mmol) and TCFH (52.2mg, 0.186 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was directly purified by reverse phase chromatography (C18, methanol: water 0-80%) to obtain the objective compound (40.0mg, yield 45.9%, white solid). LC-MS (ESI) M/z [ M + H ]]⁺/[M+2+H]⁺562.0/564.0。¹H NMR(500MHz,DMSO-d₆)δ10.73(s,1H),7.93(d,J＝8.3Hz,2H),7.84(s,2H),7.68(d,J＝8.4Hz,2H),7.63–7.59(m,1H),7.54–7.49(m,2H),7.41–7.37(m,1H),4.16–4.12(m,1H),4.04–3.98(m,1H),3.66–3.61(m,1H),3.30(s,3H),3.21(s,3H)。

Examples 2 and 3: rel- (S) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) -3-methoxypropionamide or rel- (R) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) -3-methoxypropionamide

Racemic N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (methylsulfonyl) phenyl) -3-methoxypropionamide (50mg in about 13mL methanol, 1.5mL injection volume) was passed through Waters SFC 150 (room temperature, 100bar,214nm) and 250. mu.25 mm 10Dr

OD)) (supercritical carbon dioxide: methanol, 80:20,6.0min,70mL/min) to obtain rel- (S) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (methylsulfonyl) phenyl) -3-methoxypropionamide or rel- (R) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl]-4-yl) -2- (4- (methylsulfonyl) phenyl) -3-methoxypropionamide (13.8mg, white solid, ret. time. 2.961min, e.e.99%). LC-MS (ESI) M/z 561.9[ M + H ]]⁺/563.9[M+2+H]⁺。¹H NMR(400MHz,CDCl₃)δ8.41(s,1H),7.96(d,J＝8.4Hz,2H),7.67(s,2H),7.59(d,J＝8.4Hz,2H),7.48–7.45(m,1H),7.39–7.35(m,2H),7.26-7.25,7.24-7.23(m,1H),4.06–4.00(m,1H),3.97–3.92(m,1H),3.82–3.78(m,1H),3.51(s,3H),3.06(s,3H)。

rel- (R) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (methylsulfonyl) phenyl) -3-methoxypropionamide or rel- (S) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl]-4-yl) -2- (4- (methylsulfonyl) phenyl) -3-methoxypropionamide (12.9mg, white solid, ret. time 3.380min, e.e.97%). LC-MS (ESI) M/z 561.8[ M + H ]]⁺/563.8[M+2+H]⁺。¹H NMR(400MHz,CDCl₃)δ8.41(s,1H),7.96(d,J＝8.4Hz,2H),7.67(s,2H),7.59(d,J＝8.4Hz,2H),7.50–7.45(m,1H),7.40–7.35(m,2H),7.26–7.25,7.24-7.23(m,1H),4.06–4.01(m,1H),3.96–3.92(m,1H),3.82–3.78(m,1H),3.51(s,3H),3.06(s,3H)。

Example 4: n- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) -3-hydroxypropionamide

Step 1: synthesis of N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) acetamide

2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl]-4-amine (150mg, 0.466mmol), 2- (4- (methylsulfonyl) phenyl) acetic acid (120mg, 0.559mmol) and HATU (213mg, 0.559mmol) were added to DCM (10 mL). DIEA (0.231mL, 1.40mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate (5.0mL) was added. After separating the organic phase, the aqueous phase was extracted with more DCM (10mL), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (silica gel, EA/PE 0-60%) gave the title compound (240mg, 99.4% yield, white solid). LC-MS (ESI) M/z 518.0[ M + H ]]⁺。

Step 2: synthesis of N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) -3-hydroxypropionamide

Mixing N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (methylsulfonyl) phenyl) acetamide (240mg, 0.463mmol) was added to anhydrous DMSO (8 mL). To the reaction mixture was added paraformaldehyde (12.5mg, 0.417mmol) and sodium methoxide (1.03mg, 0.019mmol) in this order. The reaction mixture was stirred at room temperature for 4 hours. EA (15mL) and water (20mL) were added. The organic phase was separated, the aqueous phase was extracted with EA (15mL), and the combined organic phases were washed with saturated brine (15 mL. times.3), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Warp columnPurification by chromatography (silica gel, EA/PE 0-100%) gave the title compound (149mg, 58.7% yield, white solid). LC-MS (ESI) M/z 548.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.67(s,1H),7.92(d,J＝8.5Hz,2H),7.88–7.83(m,2H),7.66(d,J＝8.5Hz,2H),7.63–7.57(m,1H),7.54–7.48(m,2H),7.41–7.37(m,1H),5.14(t,J＝5.2Hz,1H),4.13–4.06(m,1H),4.01–3.94(m,1H),3.72–3.63(m,1H),3.20(s,3H)。

Examples 5 and 6: rel- (S) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) -3-hydroxypropionamide or rel- (R) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) -3-hydroxypropionamide

Racemic N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (methylsulfonyl) phenyl) -3-hydroxypropionamide (470mg in about 120mL of methanol, injection volume 3.0mL) was purified by passing Waters SFC 150 (room temperature, 100bar,214nm) and 250 × 25mm 10 μm Dr

OD) (supercritical carbon dioxide: methanol, 70:30,3.0min,70mL/min) to obtain rel- (S) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (methylsulfonyl) phenyl) -3-hydroxypropionamide or rel- (R) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl]-4-yl) -2- (4- (methylsulfonyl) phenyl) -3-hydroxypropionamide (204mg, white solid, ret. time. 4.166min, e.e.99%). LC-MS (ESI) M/z 548.2[ M + H ]]⁺/550.2[M+2+H]⁺。¹H NMR(400MHz,CDCl₃)δ8.23(s,1H),7.89(d,J＝8.2Hz,2H),7.70(d,J＝4.6Hz,2H),7.57(d,J＝8.2Hz,2H),7.50–7.44(m,1H),7.40–7.34(m,2H),7.26–7.23(m,1H),4.23–4.15(m,1H),4.04–3.92(m,2H),3.07(s,3H)。

rel- (R) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (methylsulfonyl) phenyl) -3-hydroxypropionamide or rel- (S) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl]-4-yl) -2- (4- (methylsulfonyl) phenyl) -3-hydroxypropionamide (171mg, white solid, ret. time. 4.453min, e.e.99%). LC-MS (ESI) M/z 548.2[ M + H ]]⁺/550.2[M+2+H]⁺。¹H NMR(400MHz,CDCl₃)δ8.04(s,1H),7.99–7.89(m,2H),7.77–7.67(m,2H),7.66–7.56(m,2H),7.53–7.47(m,1H),7.44–7.36(m,2H),7.29–7.24(m,1H),4.32–4.16(m,1H),4.11–3.90(m,2H),3.10(s,3H)。

Example 7: 4- ((2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) amino) -3- (4- (methylsulfonyl) phenyl) -4-oxobutanoic acid

Step 1: synthesis of 4-tert-butyl 2- (4- (methylsulfonyl) phenyl) succinate 1-methyl ester

Methyl 2- (4- (methylsulfonyl) phenyl) acetate (900mg,3.95mmol) was added to tetrahydrofuran (10mL), cooled to 0 ℃, and NaH (166mg,4.15mmol, 60% in oil) was added and the reaction was continued at 0 ℃ for 30 minutes, then tert-butyl 2-bromoacetate (847mg/0.63mL,4.34mmol) was added to the reaction flask by syringe, the reaction was continued at 0 ℃ for 30 minutes, TLC detected that the starting material was reacted, after the reaction was completed, saturated ammonium chloride (20mL) was added to quench the reaction, EA extraction (20mLx3) was performed, silica gel column separation [ (PE: DCM ═ 2: 1): EA is 100% -65%]The desired product was obtained (920mg, yield 68.1%, colorless oil).¹H NMR(400MHz,CDCl₃)δ7.93–7.88(m,2H),7.53–7.48(m,2H),4.18–4.10(m,1H),3.69(s,3H),3.18–3.07(m,1H),3.04(s,3H),2.68–2.58(m,1H).

Step 2: synthesis of 4- (tert-butoxy) -2- (4- (methylsulfonyl) phenyl) -4-oxobutanoic acid

4-tert-butyl 2- (4- (methylsulfonyl) phenyl) succinate 1-methyl ester (810mg,2.37mmol) and lithium hydroxide (109mg,2.6mmol) were added to a tetrahydrofuran/water (10mL/2mL) solution, reacted at room temperature for 1 hour, 1N hydrochloric acid (3mL) was added, EA (10mLx3) was extracted, washed once with a saturated sodium chloride (20mL) solution, and the solvent was spin-dried under reduced pressure to give the desired product (800mg, colorless oil). LC-MS (ESI) M/z 273.1[ M-56+ H ]]⁺.

And step 3: synthesis of tert-butyl 4- ((2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) amino) -3- (4- (methylsulfonyl) phenyl) -4-oxobutyrate

2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-amine (200mg,0.62mmol), 4- (tert-butoxy) -2- (4- (methylsulfonyl) phenyl) -4-oxobutanoic acid (345mg,1.05mmol), HATU (285mg,0.75mmol) and DIEA (160mg,1.24mmol) were added to DCM (5mL) and reacted overnight at room temperature, TLC checked for completion of the starting material reaction, after which the reaction was completed, washed once with saturated sodium bicarbonate, and silica gel column separated [ (PE: DCM ═ 2: 1): EA 100% -50% ] to obtain the target product (500mg, colorless oil). And 4, step 4: synthesis of 4- ((2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) amino) -3- (4- (methylsulfonyl) phenyl) -4-oxobutanoic acid

The preparation method comprises the step of reacting 4- ((2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]Tert-butyl (4-yl) amino) -3- (4- (methylsulfonyl) phenyl) -4-oxobutyrate (500mg) was added to DCM (5mL), then trifluoroacetic acid (1mL) was added, the reaction was carried out at room temperature for 2 hours, after completion of the reaction, the solvent was directly spin-dried, then EA (20mL) was added, saturated sodium bicarbonate was washed once, the organic layer was spin-dried to obtain a crude product, and the crude product was subjected to reverse phase column separation (water: methanol is 100%, 0-30%, 70%) The expected product was obtained (270mg, 73.6% yield, white solid). LC-MS (ESI) M/z 576.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.44(s,1H),10.74(s,1H),7.97–7.89(m,2H),7.84–7.77(m,2H),7.71–7.63(m,2H),7.63–7.56(m,1H),7.54–7.47(m,2H),7.39–7.34(m,1H),4.29–4.18(m,1H),3.25,3.20(s,3H),3.18–3.09(m,1H),2.76–2.67(m,1H).

Example 8: n is a radical of¹- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -N⁴-methyl-2- (4- (methylsulfonyl) phenyl) succinamide

The preparation method comprises the step of reacting 4- ((2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) amino) -3- (4- (methylsulfonyl) phenyl) -4-oxobutanoic acid (270mg,0.47mmol), methylamine hydrochloride (53mg,0.94mmol), HATU (357mg,0.94mmol) and DIEA (243mg,1.88mmol) were added to DCM (5mL) and reacted overnight at room temperature, TLC checked for completion of the starting material reaction, after which time it was washed with saturated sodium bicarbonate, plate separated (DCM: methanol-40: 1) gave the title product (120mg, 43.3% yield, white solid). LC-MS (ESI) M/z 589.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.73(s,1H),7.95–7.88(m,3H),7.81(dd,J＝6.7,2.0Hz,2H),7.64(d,J＝8.5Hz,2H),7.62–7.56(m,1H),7.54–7.47(m,2H),7.37(dd,J＝7.9,1.7Hz,1H),4.33–4.26(m,1H),3.20(s,3H),3.05–2.96(m,1H),2.62–2.52(m,4H).

Example 9: n is a radical of¹- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (methylsulfonyl) phenyl) succinamide

The preparation method comprises the step of reacting 4- ((2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) amino) -3- (4- (methylsulfonyl) phenyl) -4-oxobutanoic acid (58mg,0.1mmol), ammonium chloride (10.6mg,0.2mmol), HATU (46mg,0.12mmol) and DIPEA (26mg,0.2mmol) were added to DCM (2mL),the reaction was carried out overnight at room temperature, the starting material was completely reacted by TLC, and after completion of the reaction, it was washed once with saturated sodium bicarbonate and separated on preparative plates (PE: EA: 1) to give the desired product (8mg, yield 13.8%, white solid). LC-MS (ESI) M/z 577.0[ M + H ]]⁺。¹H NMR(500MHz,DMSO-d₆)δ10.46(s,1H),7.91(d,J＝8.4Hz,2H),7.79(dd,J＝6.4,2.0Hz,2H),7.70–7.65(m,1H),7.65–7.57(m,3H),7.54–7.48(m,2H),7.42–7.38(m,1H),7.00(s,1H),4.21–4.14(m,1H),3.21(s,3H),3.18–3.11(m,1H),2.82–2.75(m,1H).

Example 10: n- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-hydroxypropionamide

Step 1: synthesis of N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (ethylsulfonyl) phenyl) acetamide

2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl]-4-amine (50.0mg,0.155mmol) and 2- (4- (ethylsulfonyl) phenyl) acetic acid (42.5mg, 0.186mmol) were added to DCM (5 mL). To the reaction mixture was added HATU (70.7mg, 0.186mmol) and DIEA (0.077mL, 0.465mmol) in that order. The reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate (10mL) and DCM (10mL) were added. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (silica gel, EA/PE 0-100%) gave the title compound (70.0mg, 84.8% yield, white solid). LC-MS (ESI) M/z [ M + H ]]⁺532.0。

Step 2: synthesis of N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-hydroxypropionamide

Mixing N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (ethylsulfonyl) phenyl) acetamide (70.0mg, 0.131mmol) was added to anhydrous DMSO (2 mL). To the reaction mixture were added paraformaldehyde (3.54mg, 0.118mmol) and sodium methoxide (0.27mg,0.005mmol) in this order. The reaction mixture was stirred at room temperature overnight. EA (10mL) and water (10mL) were added. The aqueous phase was separated and extracted with EA (10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (silica gel, EA/PE 0-100%) gave the title compound (40.0mg, 54.3% yield, white solid). LC-MS (ESI) M/z 562.0[ M + H ]]⁺。¹H NMR(500MHz,DMSO-d₆)δ10.68(s,1H),7.90-7.82(m,4H),7.66(d,J＝8.3Hz,2H),7.63-7.58(m,1H),7.53-7.47(m,2H),7.40-7.36(m,1H),5.14(t,J＝5.2Hz,1H),4.12-4.06(m,1H),4.00-3.95(m,1H),3.71-3.65(m,1H),3.32(s,3H),3.27(q,J＝7.3Hz,2H),1.10(t,J＝7.3Hz,3H)。

Examples 11 and 12: (R) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-hydroxypropionamide or (S) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-hydroxypropionamide

Racemic N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-hydroxypropionamide (50mg in about 12mL methanol, injection volume 4.0mL) was purified by passing Waters SFC 150 (room temperature, 100bar,214nm) and 250 × 25mm 10 μm Dr

OD) (supercritical carbon dioxide: methanol, 65:35,3.0min,70mL/min) to obtain (R) -N- (2, 6-dichloro-methane)-2'- (trifluoromethoxy) - [1,1' -biphenyl]-4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-hydroxypropionamide or (S) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl]-4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-hydroxypropionamide (19.0mg, white solid, ret. time ═ 1.925min, e.e.98%). LC-MS (ESI) M/z 561.9[ M + H ]]⁺/563.9[M+2+H]⁺，¹H NMR(400MHz,CDCl₃)δ7.96(s,1H),7.88(d,J＝8.3Hz,2H),7.71–7.67(m,2H),7.57(d,J＝8.3Hz,2H),7.51–7.45(m,1H),7.40–7.35(m,2H),7.26–7.25,7.24–7.23(m,1H),4.26–4.16(m,1H),4.06–3.97(m,1H),3.97–3.90(m,1H),3.14(q,J＝7.4Hz,2H),2.73(t,J＝6.0Hz,1H),1.31(t,J＝7.4Hz,3H)。

(S) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-hydroxypropionamide or (R) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl]-4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-hydroxypropionamide (22.3mg, white solid, ret. time. 2.453min, e.e.99%). LC-MS (ESI) M/z 561.9[ M + H ]]⁺/563.9[M+2+H]⁺，¹H NMR(400MHz,CDCl₃)δ7.92(s,1H),7.90(d,J＝8.3Hz,2H),7.70–7.66(m,2H),7.58(d,J＝8.2Hz,2H),7.50–7.45(m,1H),7.40–7.35(m,2H),7.26–7.25,7.24-7.23(m,1H),4.26–4.16(m,2H),4.06–3.98(m,1H),3.96–3.90(m,1H),3.14(q,J＝7.4Hz,2H),2.76–2.68(m,1H),1.31(t,J＝7.4Hz,3H)。

Example 13: synthesis of N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -3-hydroxy-2- (4- (N-methylsulfonylamino) phenyl) propionamide

Step 1: synthesis of methyl 2- (4- (chlorosulfonyl) phenyl) acetate

Methyl 2- (4- (benzylthio) phenyl) acetate (500mg, 1.84mmol) was addedTo a mixed solvent of acetic acid (5mL) and water (1 mL). N-chlorosuccinimide (737mg, 5.52mmol) was added portionwise to the reaction mixture at 0 ℃. The reaction mixture was warmed to room temperature, and stirred at room temperature for 1 hour. EA (10mL) and water (5mL) were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (silica gel, EA/PE 0-30%) gave the title compound (380mg, yield 83.0%, colorless oil).¹H NMR(400MHz,CDCl₃)δ8.04–7.97(m,2H),7.55(d,J＝8.5Hz,2H),3.76(s,2H),3.74(s,3H)。

Step 2: synthesis of methyl 2- (4- (N-methylsulfonylamino) phenyl) acetate

Methyl 2- (4- (chlorosulfonyl) phenyl) acetate (380mg, 1.53mmol) and methylamine hydrochloride (124mg, 1.84mmol) were added to DCM (8 mL). After the reaction mixture was cooled to 0 ℃ under argon, triethylamine (0.638mL, 4.59mmol) was added. The reaction mixture was warmed to room temperature and stirred at room temperature overnight. Water (5mL) was added. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (silica gel, EA/(DCM/PE 1:2) ═ 0-50%) gave the title compound (230mg, yield 61.8%, white solid). LC-MS (ESI) M/z 244.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.76–7.69(m,2H),7.50(d,J＝8.3Hz,2H),7.43(q,J＝5.0Hz,1H),3.82(s,2H),3.63(s,3H),2.41(d,J＝5.0Hz,3H)。

And step 3: synthesis of 2- (4- (N-methylsulfonamido) phenyl) acetic acid

Methyl 2- (4- (N-Methanesulfonamido) phenyl) acetate (230mg, 0.945mmol) was added to tetrakisTetrahydrofuran (4 mL). To the mixture was added a solution of lithium hydroxide monohydrate (79.3mg, 1.89mmol) in water (1 mL). After the reaction mixture was stirred at room temperature for 2 hours, dilute hydrochloric acid (1N, 2mL) was added. DCM (10mL) and water (5mL) were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the objective compound (156mg, yield 71.2%, colorless oil). LC-MS (ESI) M/z 230.1[ M + H ]]⁺。

And 4, step 4: synthesis of N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (N-methylsulfonylamino) phenyl) acetamide

2- (4- (N-Methanesulfonamido) phenyl) acetic acid (150mg, 0.654mmol), 2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl]-4-amine (232mg, 0.719mmol), HATU (298mg, 0.785mmol) and DIEA (0.324mL, 1.96mmol) were added sequentially to DCM (8 mL). The reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate (10mL) and DCM (10mL) were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (silica gel, EA/PE 0-50%) gave the title compound (320mg, 91.7% yield, colorless oil). LC-MS (ESI) M/z 533.0[ M + H ]]⁺。

And 5: synthesis of N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -3-hydroxy-2- (4- (N-methylsulfonylamino) phenyl) propionamide

Mixing N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (N-methylsulfonylamino) phenyl) acetamide (320mg, 0.600mmol) was added to anhydrous DMSO (3 mL). To the reaction mixture was added paraformaldehyde (16.2mg, 0.540mmol) and sodium methoxide (1.29mg, 0.024mmol) in that order. The reaction mixture was at room temperatureThe reaction was stirred for 2 hours. EA (15mL) and water (10mL) were added. The aqueous phase was separated and extracted with EA (10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (C18, methanol/water 0-100%) gave the title compound (139mg, yield 41.1%, white solid). LC-MS (ESI) M/z 563.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.69(s,1H),7.91–7.83(m,2H),7.77(d,J＝8.3Hz,2H),7.65–7.57(m,3H),7.55–7.49(m,2H),7.46(q,J＝5.0Hz,1H),7.42–7.37(m,1H),5.15(t,J＝5.2Hz,1H),4.13–4.04(m,1H),3.99–3.92(m,1H),3.69–3.63(m,1H),2.41(d,J＝5.0Hz,3H)。

Example 14: n- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -3-methoxy-2- (4- (N-methylsulfonylamino) phenyl) propanamide

Mixing N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -3-hydroxy-2- (4- (N-methylsulfonylamino) phenyl) propionamide (89mg, 0.158mmol) was added to DCM (3 mL). After the reaction mixture was cooled to 0 ℃, fluoroboric acid (28.9mg, 0.158mmol, 48% aqueous solution) and trimethylsilyl diazomethane (2N, 0.079mL, 0.158mmol) were added sequentially under the exclusion of light. After the reaction mixture was stirred at 0 ℃ for 20 minutes, trimethylsilyldiazomethane (2N, 0.079mL, 0.158mmol) was added again and the reaction mixture was stirred at 0 ℃ for an additional 20 minutes. This step was repeated two more times. Water (10mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. DCM (15mL) was added. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by preparative plate separation (silica gel, EA/PE ═ 1:1) afforded the title compound (29mg, yield 31.9%, white solid). LC-MS (ESI) m/z:577.0[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.72(s,1H),7.87–7.81(m,2H),7.77(d,J＝8.3Hz,2H),7.63(d,J＝8.3Hz,2H),7.61–7.57(m,1H),7.54–7.48(m,2H),7.46(q,J＝4.9Hz,1H),7.41–7.36(m,1H),4.14–4.07(m,1H),4.00(t,J＝9.1Hz,1H),3.65–3.57(m,1H),3.29(s,3H),2.41(d,J＝5.1Hz,3H)。

Example 15: process for preparation of 3-amino-N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) propanamide

Step 1: synthesis of methyl 2- (4-methylsulfonyl) phenylacetate

2- (4-Methylsulfonyl) phenylacetic acid (5.00g,23.3mmol) was dissolved in methanol (100mL) and thionyl chloride (8.33g,70.0mmol) was added under ice-water bath conditions. The reaction mixture was warmed to room temperature and stirred for 1 hour, and the reaction was stopped. The reaction mixture was concentrated under reduced pressure, and the resulting residue was redissolved in EA (80.0mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE: EA ═ 3:1-2:1) to obtain the objective compound (5.00g, yield 94.0%, off-white solid).

Step 2: synthesis of methyl 3- (1, 3-dioxoisoindolin-2-yl) -2- (4- (methylsulfonyl) phenyl) propionate

Methyl 2- (4- (methylsulfonyl) phenyl) acetate (2.00g,8.76mmol) was dissolved in ultra-dry tetrahydrofuran (60.0mL), lithium bistrimethylsilylamide (10.5mL,10.5mmol) was slowly added dropwise to the reaction system at-78 ℃ under nitrogen protection, after the reaction mixture was stirred at-78 ℃ for 30 minutes, 2- (bromomethyl) isoindoline-1, 3-dione (2.30g,9.58mmol) (dissolved in ultra-dry tetrahydrofuran) was slowly added dropwise to the reaction system, and after the reaction mixture was stirred at-78 ℃ for 1.5 hours, the reaction was stopped. Saturated ammonium chloride is used for reaction mixture(20.0mL) of the aqueous solution, EA (30.0 mL. times.2) of the extract, washing the organic phase with saturated brine (15.0 mL. times.2), drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain the objective compound (3.00g, crude product, gray solid). LC-MS (ESI) M/z 388.0[ M + H ]]⁺。

And step 3: synthesis of 3- (1, 3-dioxoisoindolin-2-yl) -2- (4- (methylsulfonyl) phenyl) propanoic acid

To a solution of methyl 3- (1, 3-dioxoisoindolin-2-yl) -2- (4- (methylsulfonyl) phenyl) propionate (3.00g,7.74mmol) in 1, 4-dioxane (20.0mL) was added aqueous hydrochloric acid (6.0N) (20.0 mL). After the reaction mixture was stirred at 80 ℃ for 16 hours, the reaction was stopped. After the reaction mixture was cooled to room temperature, water (20.0mL), EA (20.0 mL. times.2) was added to the mixture to extract, and the organic phase was washed with saturated brine (10.0 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the objective compound (3.13g, 95.7% yield in two steps, white solid). LC-MS (ESI) M/z 374.4[ M + H ]]⁺。

Step 4 Synthesis of N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -3- (1, 3-dioxoisoindolin-2-yl) -2- (4- (methylsulfonyl) phenyl) propionamide

At room temperature, 2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl]-4-amine (1.50g,4.66mmol) and 3- (1, 3-dioxoisoindolin-2-yl) -2- (4- (methylsulfonyl) phenyl) propanoic acid (3.13g,8.38mmol) were dissolved in acetonitrile (75.0mL) and then N-methylimidazole (1.91g,23.3mmol) and TCFH (3.92g,14.0mmol) were added in sequence and the reaction was stopped after the reaction solution was stirred for 2 hours at room temperature. Concentrating the reaction solution under reduced pressure, extracting the residue with EA (30.0mL × 2), washing with saturated saline (25.0mL × 2), drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain residue, and separating and purifying by column chromatography(PE: EA ═ 10:1-2:1) to obtain the title compound (4.00g, yield 70.4%, white solid).¹H NMR(400MHz,DMSO-d₆)δ10.78(s,1H),7.91(d,J＝8.3Hz,2H),7.87–7.81(m,4H),7.80–7.78(m,1H),7.76–7.74(m,1H),7.68(d,J＝8.3Hz,2H),7.63–7.57(m,1H),7.53–7.47(m,2H),7.39–7.35(m,1H),4.50–4.43(m,1H),4.30–4.23(m,1H),4.14–4.07(m,1H),3.18(s,3H)。

Step 5 Synthesis of 3-amino-N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) propanamide

To produce N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]To a solution of (4-yl) -3- (1, 3-dioxoisoindolin-2-yl) -2- (4- (methylsulfonyl) phenyl) propanamide (100mg,0.148mmol) in absolute ethanol (2.00mL) was added hydrazine hydrate (98% aqueous solution, 1.00mL), and the reaction mixture was stirred at 80 ℃ for 16 hours, and then the reaction was stopped. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the obtained residue was purified by preparative (acetonitrile/water containing 0.05% formic acid) to obtain the objective compound (40.8mg, yield 50.5%, white solid). LC-MS (ESI) M/z 547.0[ M + H ]]⁺/549.0[M+2+H]⁺。¹H NMR(400MHz,CD₃OD)δ7.97(d,J＝8.4Hz,2H),7.83(d,J＝2.0Hz,1H),7.76(d,J＝2.1Hz,1H),7.68(d,J＝8.4Hz,2H),7.56–7.50(m,1H),7.45–7.38(m,2H),7.30–7.27(m,1H),3.97–3.91(m,1H),3.44–3.36(m,1H),3.11(s,3H),3.05–2.98(m,1H)。

Example 16: 3-acetylamino-N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) propanamide

3-amino-N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (methylsulfonyl) phenyl) propanamide (100mg,0.183mmol) and triethylamine (46.2mg,0.457mmol) in solutionIn DCM (4.00mL), acetyl chloride (14.4mg,0.183mmol) was slowly added to the mixture under ice bath. The reaction mixture was stirred at room temperature for 1 hour, and then the reaction was stopped. The reaction mixture was poured into water (10.0mL), extracted with DCM (10.0mL × 2), washed with saturated brine (10.0mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was prepared (acetonitrile/water containing 0.05% formic acid) to give the title compound (44.3mg, yield 41.2%, yellow solid). LC-MS (ESI) M/z 588.9[ M + H ]]⁺/590.9[M+2+H]⁺。¹H NMR(400MHz,CD₃OD)δ10.37(s,CONH),8.30(t,J＝6.4Hz,CH₃CONH),7.97(d,J＝8.4Hz,2H),7.84–7.68(m,4H),7.56–7.50(m,1H),7.46–7.37(m,2H),7.31–7.26(m,1H),4.42–4.36,4.17–4.07(m,1H),4.02–3.93,3.81–3.71(m,1H),3.68–3.59,3.50–3.46(m,1H),3.11(s,3H),2.14,2.07,1.91(s,3H)。

Example 17: n- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -3- (methylamino) -2- (4- (methylsulfonyl) phenyl) propionamide formate salt

Step 1 Synthesis of 3- ((2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) amino) -2- (4- (methylsulfonyl) phenyl) -3-oxopropyl methanesulfonate

Mixing N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -3-hydroxy-2- (4- (methylsulfonyl) phenyl) propionamide (200mg,0.364mmol) and triethylamine (111mg,1.09mmol) were dissolved in DCM (4.00mL) and methanesulfonyl chloride (50.2mg,0.438mmol) was added to the mixture under ice bath. The reaction mixture was stirred at room temperature for 1 hour, and then the reaction was stopped. The reaction mixture was poured into water (10.0mL), extracted with DCM (10.0 mL. times.2), washed with saturated brine (10.0 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (200mg, two steps)Yield 87.6%, white solid). LC-MS (ESI) M/z 625.9[ M + H ]]⁺/627.9[M+2+H]⁺。

Step 2 Synthesis of N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -3- (methylamino) -2- (4- (methylsulfonyl) phenyl) propionamide formate salt

Methanesulfonic acid 3- ((2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) amino) -2- (4- (methylsulfonyl) phenyl) -3-oxopropyl ester (90.0mg,0.144mmol) and triethylamine (29.1mg,0.288mmol) were dissolved in DCM (5.00mL) and methylamine hydrochloride (11.6mg,0.172mmol) was added to the mixture at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and then the reaction was stopped. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative chromatography (acetonitrile/water containing 0.05% formic acid) to give the objective compound (20.3mg, yield 23.3%, formate salt, white solid). LC-MS (ESI) M/z 560.9[ M + H ]]⁺/562.9[M+2+H]⁺。¹H NMR(400MHz,CD₃OD)δ8.48(s,1H),8.03(d,J＝8.3Hz,2H),7.85(d,J＝2.0Hz,1H),7.77–7.69(m,3H),7.57–7.50(m,1H),7.46–7.37(m,2H),7.28(dd,J＝7.6,1.6Hz,1H),4.31–4.25(m,1H),3.77–3.69(m,1H),3.29–3.27(m,1H),3.13(s,3H),2.72(s,3H)。

Example 18: 3- (azetidin-1-yl) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) propanamide

Methanesulfonic acid 3- ((2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) amino) -2- (4- (methylsulfonyl) phenyl) -3-oxopropyl ester (110mg,0.176mmol) and triethylamine (35.5mg,0.351mmol) were dissolved in DCM (5.00mL) and azetidine (12.0mg,0.210mmol) was added slowly to the mixture while cooling on ice. The reaction mixture was stirred at room temperature for 2 hours, and then the reaction was stopped. Will be reversedThe mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative chromatography (acetonitrile/water containing 0.05% formic acid) to give the title compound (25.9mg, yield 25.1%, white solid). LC-MS (ESI) M/z 587.0[ M + H ]]⁺/589.0[M+2+H]⁺。¹H NMR(400MHz,MeOD)δ7.99(d,J＝8.3Hz,2H),7.83(d,J＝2.0Hz,1H),7.73(d,J＝2.0Hz,1H),7.71(d,J＝8.3Hz,2H),7.56–7.51(m,1H),7.46–7.38(m,2H),7.28(dd,J＝7.6,1.6Hz,1H),4.03–3.97(m,1H),3.80–3.64(m,5H),3.22–3.16(m,1H),3.12(s,3H),2.33–2.25(m,2H).

Example 19: n- (2-chloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -3-hydroxy-2- (4- (methylsulfonyl) phenyl) propanamide

Step 1 Synthesis of 2-chloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-amine

To the microwave tube were added 2- (trifluoromethoxy) phenylboronic acid (1.00g,4.86mmol), 4-bromo-3-chloroaniline (1.10g,5.33mmol), potassium carbonate (1.00g,7.23mmol), Pd (dppf) Cl₂(396mg,0.460mmol) and acetonitrile/water (8.00mL/2.00 mL). After the addition, the nitrogen gas was replaced for 3 minutes, and the reaction mixture was stirred at 90 ℃ for 6 hours, and then the reaction was stopped. The reaction mixture was concentrated, extracted with EA (30.0mL × 3), the organic phase was washed with saturated brine (30.0mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was separated and purified by column chromatography (PE: EA ═ 5:1) to give the objective compound (1.20g, yield 85.7%, black solid). LC-MS (ESI) m/z: 287.8[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.51–7.38(m,3H),7.37–7.32(m,1H),6.95(d,J＝8.3Hz,1H),6.71(d,J＝2.2Hz,1H),6.59–6.53(m,1H),5.53(s,2H)。

Step 2 Synthesis of N- (2-chloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) acetamide

To 2-chloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl]N-methylimidazole (285mg,3.48mmol) and TCFH (585mg,2.09mmol) were added to a solution of (E) -4-amine (200mg,0.695mmol) and (4- (methylsulfonyl) phenyl) acetic acid (223mg,1.04mmol) in acetonitrile (5.00mL), and the reaction mixture was stirred at room temperature for 16 hours, whereupon the reaction was stopped. The reaction mixture was concentrated under reduced pressure, extracted with EA (30.0 mL. times.3), and the organic phase was washed with saturated brine (30.0 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (PE: EA ═ 1:1-2:3) to give the title compound (150mg, yield 44.6%, grey solid). LC-MS (ESI) M/z 525.1[ M + ACN + H ]]⁺。

Step 3 Synthesis of N- (2-chloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -3-hydroxy-2- (4- (methylsulfonyl) phenyl) propanamide

To N- (2-chloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]A solution of (4-yl) -2- (4- (methylsulfonyl) phenyl) acetamide (100mg,0.207mmol) in anhydrous DMSO (2.00mL) was added paraformaldehyde (4.00mg,0.145mmol), followed by sodium methoxide (0.500mg,0.008mmol), and after addition, the reaction mixture was stirred at room temperature for 2 hours, and LC-MS showed completion of the reaction. The reaction solution was purified by high pressure liquid preparative chromatography (acetonitrile/water containing 0.05% formic acid) to give the objective compound (40.0mg, yield 37.7%, white solid). LC-MS (ESI) M/z 514.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.57(s,1H),7.99(s,J＝2.0Hz,1H),7.92(d,J＝8.4Hz,2H),7.66(d,J＝8.4Hz,2H),7.59–7.53(m,2H),7.50–7.45(m,2H),7.41–7.38(m,J＝7.8,1.7Hz,1H),7.30(d,J＝8.4Hz,1H),5.14(s,1H),4.10(t,J＝9.3Hz,1H),4.03–3.97(m,J＝8.6,5.6Hz,1H),3.70–3.63(m,J＝9.8,5.5Hz,1H),3.20(s,3H)。

Example 20: n- (2-trifluoromethyl-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -3-hydroxy-2- (4- (methylsulfonyl) phenyl) propanamide

Step 1 Synthesis of 2-trifluoromethyl-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-amine

Into a microwave tube were placed 4-bromo-3-trifluoromethylaniline (500mg,2.08mmol), 2- (trifluoromethoxy) phenylboronic acid (515mg,2.50mmol), potassium carbonate (576mg,4.17mmol), Pd (dppf) Cl in that order₂(171mg,0.208mmol) and 1, 4-dioxane/water (8.00mL/2.00 mL). After the nitrogen gas was replaced for 3 minutes, the reaction mixture was stirred at 100 ℃ for 6 hours, and then the reaction was stopped. The reaction mixture was concentrated, extracted with EA (30.0mL × 3), the organic phase was washed with saturated brine (30.0mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was separated and purified by column chromatography (PE: EA ═ 9:1 to 5:1) to give the target compound (600mg, yield 89.6%, gray solid). LC-MS (ESI) M/z 321.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.43–7.37(m,1H),7.33–7.27(m,3H),7.11–7.04(m,2H),6.93–6.87(m,1H),4.59(s,2H)。

Step 2 Synthesis of 2- (4- (methylsulfonyl) phenyl) -N- (2'- (trifluoromethoxy) -2- (trifluoromethyl) - [1,1' -biphenyl ] -4-yl) acetamide

To 2-trifluoromethyl-2 '- (trifluoromethoxy) - [1,1' -biphenyl]N-methylimidazole (255mg,3.12mmol) and TCFH (524mg,1.87mmol) were added to a solution of (E) -4-amine (200mg,0.623mmol) and (2- (4- (methylsulfonyl) phenyl) acetic acid (200mg,0.934mmol) in acetonitrile (5.00mL), and the reaction mixture was stirred at room temperature for 14 hours, whereupon the reaction was stopped. After the reaction liquid is concentrated,the mixture was extracted with EA (30.0 mL. times.3), and the organic phase was washed with saturated brine (30.0 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (PE: EA ═ 3:2-2:3) to give the title compound (180mg, yield 55.9%, grey solid). LC-MS (ESI) M/z 518.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.96–7.86(m,3H),7.80(m,1H),7.68(s,1H),7.56(d,J＝8.1Hz,2H),7.46–7.40(m,1H),7.35–7.24(m,4H),3.85,3.83(s,2H),3.07,3.06(s,3H)。

Step 3 Synthesis of N- (2-trifluoromethyl-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -3-hydroxy-2- (4- (methylsulfonyl) phenyl) propanamide

To the reaction solution of 2- (4- (methylsulfonyl) phenyl) -N- (2'- (trifluoromethoxy) -2- (trifluoromethyl) - [1,1' -biphenyl]Polyformaldehyde (4.78mg,0.159mmol) and sodium methoxide (0.430mg,0.008mmol) were added to a DMSO (2.00mL) solution of (100mg,0.199mmol) and the reaction mixture was stirred at room temperature for 2 hours, and the reaction was stopped. The reaction solution was purified by high pressure liquid phase (acetonitrile/water containing 0.05% formic acid) to obtain the objective compound (60.0mg, yield 37.7%, white solid). LC-MS (ESI) M/z 548.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.71(s,1H),8.29–8.19(m,1H),7.92(d,J＝8.3Hz,2H),7.89–7.82(m,1H),7.67(d,J＝8.3Hz,2H),7.61–7.52(m,1H),7.49–7.40(m,2H),7.40–7.27(m,2H),5.20–5.10(m,1H),4.24–3.92(m,2H),3.79–3.58(m,1H),3.20(s,3H)。

Example 21: n- (2, 6-dimethyl-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -3-hydroxy-2- (4- (methylsulfonyl) phenyl) propanamide

Step 1: synthesis of N- (2, 6-dimethyl-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) acetamide

2, 6-dimethyl-2 '- (trifluoromethoxy) - [1,1' -biphenyl]-4-amine (150mg,0.53mmol), 2- (4- (methylsulfonyl) phenyl) acetic acid (137mg,0.64mmol), HATU (243mg,0.64mmol) and DIEA (137mg,1.06mmol) were added to DCM (3mL) and reacted at room temperature for 2 hours, after which the reaction was completed and silica gel column isolated (PE: DCM ═ 1:1) to give the desired product (250mg, yield 99.2%, white solid).¹H NMR(400MHz,CDCl₃)δ7.94(d,J＝8.3Hz,2H),7.57(d,J＝8.3Hz,2H),7.44(s,1H),7.43–7.31(m,3H),7.27–7.25(m,2H),7.16–7.11(m,1H),3.81(s,2H),3.06(s,3H),1.97(s,6H).

Step 2: synthesis of N- (2, 6-dimethyl-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -3-hydroxy-2- (4- (methylsulfonyl) phenyl) propanamide

The preparation method comprises the steps of dissolving N- (2, 6-dimethyl-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (methylsulfonyl) phenyl) acetamide (100mg,0.21mmol) and paraformaldehyde (5.98mg,0.20mmol) were added to a solution of anhydrous DMSO (2mL), sodium methoxide (0.43mg,0.008mmol) was added with stirring, the reaction was carried out at room temperature for 2 hours, after completion of the reaction, water (20mL) was added, EA (20mLx3) was extracted, the organic layers were combined, washed with water 3 times, the solvent was spin-dried, and the column was reversed-phase separated (water: methanol 100% -75%) to give the desired product (26mg, 24.3% yield, white solid). LC-MS (ESI) M/z 508.0[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.19(s,1H),7.93–7.88(m,2H),7.66(d,J＝8.4Hz,2H),7.60–7.44(m,3H),7.43–7.36(m,2H),7.26(dd,J＝7.8,1.8Hz,1H),5.14,5.07(t,J＝5.2Hz,1H),4.22–4.05(m,1H),4.04–3.95(m,1H),3.70–3.63(m,1H),3.21,3.20(s,2H),1.90(s,6H).

Example 22: n- (2, 6-dichloro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] -4-yl) -3-hydroxy-2- (4- (methylsulfonyl) phenyl) propanamide

Step 1: synthesis of 2- (4-bromophenyl) -1,1,1,3,3, 3-hexafluoropropane-2-ol

Cupric bromide (517mg, 2.32mmol) was dissolved in acetonitrile (5mL), and tert-butyl nitrite (0.347mL, 2.89mmol) was added dropwise to the reaction solution under ice bath and nitrogen atmosphere. After the addition was completed, 2- (4-aminophenyl) -1,1,1,3,3, 3-hexafluoropropane-2-ol (500mg, 1.93mmol) was dissolved in acetonitrile (3mL) and added dropwise to the reaction solution, and after the addition was completed, the reaction mixture was stirred for further 1 hour under ice bath, and the completion of the reaction was monitored by LC-MS. The reaction mixture was poured into ice water (20mL), extracted with methyl tert-butyl ether (15mLx2), and the organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (694mg, crude, brown oil). LC-MS (ESI) M/z 323.0[ M-H ]]^-。

Step 2: synthesis of 1,1,1,3,3, 3-hexafluoro-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propan-2-ol

2- (4-bromophenyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (694mg, 2.15mmol), pinacol diboron (600mg, 2.36mmol), potassium acetate (633mg, 6.45mmol) and Pd (dppf) Cl₂(157mg, 0.215mmol) was added to 1, 4-dioxane (10 mL). The reaction mixture was stirred at 90 ℃ overnight under nitrogen. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (800mg, crude, white solid).

And step 3: synthesis of 2- (4 '-amino-2', 6 '-dichloro- [1,1' -biphenyl ] -4-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol

1,1,1,3,3, 3-hexafluoro-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propan-2-ol (800mg, 2.16mmol), 4-bromo-3, 5-dichloroaniline (417mg, 1.73mmol), potassium carbonate (597mg, 4.32mmol) and PdCl₂(dtbpf) (141mg, 0.216mmol) was added to a mixed solvent of 1, 4-dioxane (10mL) and water (1 mL). The reaction mixture was stirred at 100 ℃ for 2 hours under nitrogen, and LC-MS monitored the reaction was complete. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (PE: EA ═ 10:1-2:1) to give the target compound (248mg, 31.9% yield in three steps, light brown solid). LC-MS (ESI) M/z 445.0[ M + ACN + H]⁺。

And 4, step 4: synthesis of N- (2, 6-dichloro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) acetamide

2- (4 '-amino-2', 6 '-dichloro- [1,1' -biphenyl)]-4-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (82.0mg, 0.203mmol) and 2- (4- (methylsulfonyl) phenyl) acetic acid (43.5mg, 0.203mmol) were dissolved in anhydrous DCM (3 mL). HATU (116mg, 0.304mmol) and DIEA (0.101mL, 0.609mmol) were added to the reaction mixture at room temperature in that order. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water (20mL), extracted with DCM (15mLx2), the organic phases were combined, washed successively with saturated ammonium chloride (20mL) and saturated sodium bicarbonate (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column (PE: EA ═ 4:1-2:1) to give the desired compound (110.0mg, yield 90.3%, yellow solid). LC-MS (ESI) M/z 598.0[ M-H ]]^-。

And 5: synthesis of N- (2, 6-dichloro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] -4-yl) -3-hydroxy-2- (4- (methylsulfonyl) phenyl) propionamide

Mixing N- (2, 6-dichloro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropane-2-yl) - [1,1' -biphenyl ]]-4-yl) -2- (4- (methylsulfonyl) phenyl) acetamide (110mg,0.183mmol) was dissolved in anhydrous DMSO (2 mL). Paraformaldehyde (15.7mg,0.174mmol) and sodium methoxide (0.394mg,0.0073mmol) were sequentially added to the reaction solution at room temperature, and after the addition was completed, the reaction mixture was stirred at room temperature overnight. The reaction solution was poured into ice water (25mL), the mixture was neutralized with 1.0M diluted hydrochloric acid solution, extracted with EA (15mLx3), the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel separation (PE: EA ═ 4:1-0:1) to give the objective compound (16.7mg, yield 14.5%, white solid). LC-MS (ESI) M/z 629.9[ M + H ]]⁺.

¹H NMR(400MHz,CD₃OD)δ7.95(d,J＝8.4Hz,2H),7.83–7.78(m,4H),7.70(d,J＝8.4Hz,2H),7.33(d,J＝8.5Hz,2H),4.62–4.57(m,1H),4.27–4.21(m,1H),4.01–3.96(m,1H),3.83–3.76(m,1H),3.11(s,3H).

Example 23: n- (2' -fluoro-4 ' - (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] -4-yl) -3-hydroxy-2- (4- (methylsulfonyl) phenyl) propanamide

Step 1: synthesis of 2- (4-bromo-3-fluorophenyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol

2- (4-amino-3-fluorophenyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (277mg,1mmol), copper bromide (349.5mg,1.5mmol) and acetonitrile (5mL) are sequentially added into a 25mL single-neck flask, tert-butyl nitrite (155mg,1.5mmol) is slowly dripped into the reaction solution for reaction at room temperature overnight, TLC raw material reaction is completed, water (20mL) and EA (20mLx2) are added for extraction after the reaction is completed, saturated sodium chloride is washed once, and the solvent is dried under reduced pressure to obtain a target product (340mg, yield 100%, orange oily substance).

Step 2: synthesis of 2- (4 '-amino-2-fluoro- [1,1' -biphenyl ] -4-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol

2- (4-bromo-3-fluorophenyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (341mg,1mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (263mg,1.2mmol), potassium carbonate (408mg,3mmol) and Pd (dppf) Cl₂(37mg, 0.05mmol) was added to 1, 4-dioxane/water (5mL/1mL), the mixture was heated at 110 ℃ for 3 hours under nitrogen protection, TLC detected that the starting material was completely reacted, after completion of the reaction, the mixture was cooled to room temperature, water (20mL) was added, EA (20mLx2) was extracted, and the product was automatically separated by column chromatography on silica gel (PE: EA ═ 1:2) to give the present product (270mg, yield 76.5, white solid). LC-MS (ESI) M/z 354.0[ M + H ]]⁺。

And step 3: synthesis of N- (2' -fluoro-4 ' - (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] -4-yl) -2- (4- (methylsulfonyl) phenyl) acetamide

2- (4 '-amino-2-fluoro- [1,1' -biphenyl)]-4-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (60.0mg, 0.170mmol) and 2- (4- (methylsulfonyl) phenyl) acetic acid (40.0mg, 0.187mmol) were dissolved in anhydrous DCM (3 mL). HATU (96.9mg, 0.255mmol) and DIEA (0.0842mL, 0.510mmol) were added to the reaction mixture at room temperature in that order. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction was poured into water (20mL), extracted with DCM (15mLx2), the organic phases combined, and saturated ammonium chloride (20mL) and saturated carbonic acid sequentiallySodium hydrogen (20mL) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (PE: EA ═ 4:1-2:1) to give the title compound (59.0mg, yield 63.2%, yellow solid). LC-MS (ESI) M/z 548.1[ M-H ]]^-。

And 4, step 4: synthesis of N- (2' -fluoro-4 ' - (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] -4-yl) -3-hydroxy-2- (4- (methylsulfonyl) phenyl) propionamide

Mixing N- (2' -fluoro-4 ' - (1,1,1,3,3, 3-hexafluoro-2-hydroxypropane-2-yl) - [1,1' -biphenyl ]]Preparation of (4-yl) -2- (4- (methylsulfonyl) phenyl) acetamide (59.0mg,0.107mmol) was dissolved in anhydrous DMSO (2 mL). Paraformaldehyde (9.19mg,0.102mmol) and sodium methoxide (0.232mg,0.0043mmol) were sequentially added to the reaction solution at room temperature, and after the addition was completed, the reaction mixture was stirred at room temperature for reaction overnight. The reaction solution was poured into ice water (25mL), the mixture was neutralized with 1.0M diluted hydrochloric acid solution, extracted with EA (15mLx3), the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel separation (PE: EA ═ 4:1-0:1) to give the objective compound (26.2mg, yield 42.1%, white solid). LC-MS (ESI) M/z 580.0[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.39(s,1H),7.88(d,J＝8.1Hz,2H),7.71(d,J＝8.4Hz,2H),7.68–7.60(m,3H)，7.57–7.48(m,4H),5.11–5.05(m,1H),4.10–4.03(m,1H),4.00–3.95(m,1H),3.67–3.60(m,1H),3.16(s,3H).

Example 24: n- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-methoxypropionamide

Step 1: synthesis of methyl 2- (4-ethylsulfonyl) phenylacetate

2- (4-Methylsulfonyl) phenylacetic acid (25.0g,110mmol) was dissolved in methanol (150mL) and thionyl chloride (11.9mL,164mmol) was added under ice-water bath conditions. The reaction mixture was warmed to room temperature and stirred for 1 hour, and the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (PE: EA ═ 10:1 to 3:1) to obtain the objective compound (24.2g, yield 91.3%, white solid). MS (ESI) M/z 242.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.87(d,J＝8.3Hz,2H),7.49(d,J＝8.4Hz,2H),3.78–3.69(m,5H),3.11(q,J＝7.4Hz,2H),1.29(d,J＝7.4Hz,3H).

Step 2: synthesis of methyl 2- (4-ethylsulfonyl) phenyl-3-hydroxypropionate

To methyl 2- (4-ethylsulfonyl) phenylacetate (24.2g,100mmol) and paraformaldehyde (2.85g,95.0mmol) in anhydrous DMSO (250mL) was added sodium methoxide (216mg,4.00mmol), and the reaction mixture was stirred at room temperature for 16 hours, whereupon the reaction was stopped. The reaction mixture was poured into ice water (400mL), extracted with EA (600 mL. times.2), and allowed to stand for separation. The organic phase was washed with saturated brine (120mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (PE: EA ═ 3:1-1:1) to obtain the objective compound (15.9g, yield 58.5%, colorless oil).

And step 3: synthesis of methyl 2- (4- (ethylsulfonyl) phenyl) -3-methoxypropionate

Methyl 2- (4- (ethylsulfonyl) phenyl) -3-hydroxypropionate (15.8g,58.0mmol) was dissolved in DCM (140mL), and a 50% aqueous solution of fluoroboric acid (3.72mL,58.0mmol) and trimethylsilylated diazomethane (29.0mL,58.0 mmol) were added to the reaction mixture in an ice-water bath under exclusion of light,2.0M n-hexane solution). After 20 minutes, trimethylsilylated diazomethane (29.0mL,58.0mmol,2.0M n-hexane solution) was added again. After 20 minutes, trimethylsilylated diazomethane (29.0mL,58.0mmol,2.0M n-hexane solution) was added again. After 20 minutes, trimethylsilylated diazomethane (29.0mL,58.0mmol,2.0M n-hexane solution) was added again. The reaction mixture was poured into water (150mL), extracted with DCM (300 mL. times.2), and allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (PE: EA ═ 4:1-3:1) to obtain the objective compound (9.60g, yield 57.8%, colorless oil). MS (ESI) M/z 287.1[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ7.87(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),4.03–3.93(m,2H),3.72(s,3H),3.69–3.63(m,1H),3.36(s,3H),3.11(q,J＝7.4Hz,2H),1.29(t,J＝7.4Hz,3H).

And 4, step 4: synthesis of 2- (4- (ethylsulfonyl) phenyl) -3-methoxypropionic acid

To a solution of methyl 2- (4- (ethylsulfonyl) phenyl) -3-methoxypropionate (9.60g,33.5mmol) in 1.4-dioxane (100mL) was added 6.0M hydrochloric acid (100 mL). The reaction mixture was stirred at 80 ℃ for 1 hour, and then the reaction was stopped. The reaction mixture was cooled to room temperature, poured into water (80.0mL), extracted with EA (250 mL. times.2), and allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was subjected to medium pressure liquid phase preparation (acetonitrile/water containing 0.05% formic acid) to give the title compound (6.60g, yield 72.4%, pale yellow oil, which gradually solidified to a white solid after standing for 4 hours).¹H NMR(400MHz,CDCl₃)δ7.89(d,J＝8.4Hz,2H),7.55(d,J＝8.3Hz,2H),4.06–3.92(m,2H),3.77–3.62(m,1H),3.39(s,3H),3.11(q,J＝7.4Hz,2H),1.29(t,J＝7.4Hz,3H).

Step 5 Synthesis of N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-methoxypropionamide

To 2- (4- (ethylsulfonyl) phenyl) -3-methoxypropionic acid (50.7mg,0.186mmol), 2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl]To a solution of (E) -4-amine (50.0mg,0.155mmol) and N-methylimidazole (63.6mg,0.775mmol) in acetonitrile (1.00mL) was added TCFH (130mg,0.465mmol), and the reaction mixture was stirred at room temperature for 1 hour, whereupon the reaction was stopped. The reaction was directly subjected to high pressure liquid phase preparation (acetonitrile/water containing 0.05% formic acid) to give the title compound (34.1mg, yield 38.2%, white solid). LC-MS (ESI) M/z 575.9[ M + H ]]⁺/577.9[M+2+H]⁺。¹H NMR(400MHz,CDCl₃)δ8.42(s,1H),7.91(d,J＝8.3Hz,2H),7.68(s,2H),7.59(d,J＝8.3Hz,2H),7.51–7.44(m,1H),7.41–7.34(m,2H),7.26–7.25,7.24–7.23(m,1H),4.05–4.00(m,1H),3.96–3.91(m,1H),3.82–3.76(m,1H),3.50(s,3H),3.13(q,J＝7.4Hz,2H),1.30(t,J＝7.4Hz,3H)。

Example 25 and example 26: rel- (S) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-methoxypropionamide or rel- (R) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-methoxypropionamide

Racemic N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-methoxypropionamide (30mg in ca. 25mL methanol, 2.0mL injection volume) was purified by passing Waters SFC 150 (room temperature, 100bar,214nm) and 250 × 25mm 10 μm Dr

OD) (supercritical carbon dioxide: ethanol, 60:40,5.0min,70mL/min) to obtain (S) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-methoxypropionamide or (R) -N- (2, 6-dichloro-2' - (trifluoromethoxy) -, [2 ]1,1' -Biphenyl]-4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-methoxypropionamide (11.6mg, white solid, ret. time 1.644min, e.e.100%). LC-MS (ESI) M/z 575.8[ M + H ]]⁺/577.8[M+2+H]⁺。¹H NMR(400MHz,CDCl₃)δ8.40(s,1H),7.91(d,J＝8.2Hz,2H),7.68(s,2H),7.59(d,J＝8.2Hz,2H),7.50–7.45(m,1H),7.40–7.35(m,2H),7.26–7.25),7.24–7.23(m,1H),4.06–4.00(m,1H),3.97–3.91(m,1H),3.82–3.77(m,1H),3.50(s,3H),3.12(q,J＝7.4Hz,2H),1.30(t,J＝7.4Hz,3H)。

(R) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-methoxypropionamide or (S) -N- (2, 6-dichloro-2 '- (trifluoromethoxy) - [1,1' -biphenyl]-4-yl) -2- (4- (ethylsulfonyl) phenyl) -3-methoxypropionamide (9.20mg, white solid, ret. time 2.219min, e.e.98%). LC-MS (ESI) M/z 575.9[ M + H ]]⁺/577.9[M+2+H]⁺。¹H NMR(400MHz,CD₃OD)δ7.91(d,J＝8.3Hz,2H),7.80–7.78(m,1H),7.77–7.76(m,1H),7.72(d,J＝8.4Hz,1H),7.56–7.50(m,1H),7.45–7.38(m,2H),7.31–7.27(m,1H),4.12–4.05(m,1H),3.70–3.62(m,1H),3.39(s,3H),3.20(q,J＝7.4Hz,2H),1.21(t,J＝7.4Hz,3H)。

Active example 1: in vitro assay of the inhibitory Effect of Compounds on the ROR Gamma t luciferase reporter Gene

The experiment was carried out essentially as described in the literature (Current Chemical Genomics,2010,4, 43-49).

The ROR γ -LBD coding sequence was inserted into the pBIND plasmid (Promega, E1581). The expression vector and reporter vector (pGL4.35 carrying stably integrated GAL4 promoter driven luciferase reporter gene) were co-expressed in HEK293T host cells. When the inhibitor binds to the corresponding chimeric receptor, the chimeric receptor binds to the GAL4 binding site on the reporter vector and inhibits reporter expression. The inhibitory activity of the compound on ROR γ was determined from the intensity of the chemiluminescent signal.

Reagent and consumable

The experimental method comprises the following steps:

1 preparation of test Compounds

1.1 all test compounds were diluted in DMSO in 3-fold gradients, 10 dilution gradients, starting at 10 mM.

1.2 Positive control GSK993 was diluted in DMSO in 3-fold gradients, 10 dilution gradients, starting at 10 mM.

1.3 prepare 1000 × Positive control (10mM GSK993) and 1000 × negative control (100% DMSO).

1.4 the compound plate was blocked and shaken for 5 min.

2. Procedure of experiment

2.1 cell suspension preparation and plating

a) All cells were cultured according to ATCC standard procedures, and HEK293T was tested in exponential growth phase.

b) The medium was discarded.

c) Cells were washed 2 times with PBS.

d) The cells were digested by adding pancreatin digest and the digestion was stopped with complete medium.

e) Cells were collected and counted and experiments were only performed if the cell viability rate was greater than 90%.

f) Seed 6 x 10⁶HEK293T cells into 100mm cell culture dishes.

g) The well-seeded cell culture dish was placed at 37 ℃ in 5% CO₂The incubator was used for overnight culture.

2.2 transfection of cells

a) Placing the Trans-IT transfection reagent at room temperature for balancing;

b) adding 20 μ l transfection reagent into 600 μ l Opti-MEMTM culture medium, sucking and blowing with pipette tip without touching the tube wall, mixing well, standing at room temperature for 5 min;

c) add 10. mu.g plasmid to transfection reagent (see step 2.2.b), stand for 20 minutes at room temperature;

plasmid: separately, 5. mu.g of pBIND-ROR. gamma. and 5. mu.g of pGL4.35 plasmid were added

d) The transfection reagent mixed with DNA was added to a 100mm cell culture dish (see step 2.1);

e) the Petri dish was placed at 37 ℃ in 5% CO₂The incubator is used for 5 h.

2.3 treatment of the Compounds

a) Transfer 25nl of the diluted compound to a cell culture plate with Echo550 (6007680-50, PE);

b) cells (see step 2.2) were seeded into 384 cell culture plates (6007680-50, PE) at 15,000 cells per well in 25. mu.l of 5% charcoal-adsorbed FBS medium;

c) cells were incubated at 37 ℃ with 5% CO₂Overnight culture in an incubator

2.4 detection of Compounds:

a) subjecting Steady-Glo^TMPlacing the detection reagent at room temperature;

b) the 384 cell plate (see step 2.3) was left at room temperature;

c) add 25. mu.L of Steady-Glo to each well^TMDetecting the reagents on the cell culture plate (see step 2.4 b);

d) placing the plate on an oscillator and shaking for 5min in a dark place;

e) chemiluminescence values were measured using Envision 2104.

Calculation of% Inhibition:

RLU fluorescence values of test Compounds

Mean positive control

Average of negative controls

IC of compounds was calculated by fitting% Inhibition and log of compound concentration using Graphad8.0₅₀. The determination result shows that the compound of the invention has better inhibitory activity to the ROR gamma t luciferase reporter gene (shown in Table 1).

TABLE 1 determination of ROR gamma t luciferase reporter inhibitory Activity by the example Compounds

Active example 2: human PBMC Th17 cell differentiation inhibition assay

Test materials:

the experimental method comprises the following steps: firstly, PBMC cells are thawed and plated, then the PBMC cells are stimulated to differentiate to Th17 by stimulating factors (anti-hCD 28: 5 mu g/mL; rhTGF-beta 1: 5 ng/mL; rhIL-6: 20 ng/mL; rhIL-23: 10ng/Ml), compounds with different concentrations are added, the maximum concentration is started from 3 mu M, supernatants are collected after 48 hours for IL-17ELISA detection, the inhibition rate of the compounds for inhibiting the IL-17 secretion of Th17 cells is determined by comparing with a solvent group, and IC is fitted by Graphad8.0₅₀The value is obtained.

The determination result shows that the compound of the invention has better capability of inhibiting Th17 cells from differentiating and secreting IL-17 (shown in Table 2) for human PBMC.

TABLE 2 Experimental results of IL-17 secretion by inhibiting Th17 cell differentiation by compound

Examples	IC₅₀(nM)
		1	16.52
2	3.49
		4	11.41
5	6.287
		9	24.54
12	6.928
		16	91.42
19	39.96
		20	48.95
22	81.12
		23	80.05
25	9.197

Active example 3: human and mouse liver microsome metabolic stability assay

Liver Microsomal metabolic Stability assays for the compounds of the invention are similarly performed according to standard Methods of in vitro metabolic Stability studies conventional in the art, for example as described in (Kerns, Edward H.and Di Li (2008), Drug-like Properties: Concepts, Structure Design and Methods: from ADME to sensitivity Optimization, san Diego: Academic Press, Di, Li et al, Optimization of a high Throughput micro particulate Stability Screening Assay for Profiling Drug Discovery assays, J.biomol. Screen.2003,8(4), 453.).

The incubation system contained 0.5mg protein/mL microsome, cofactor, PBS, preincubated for 3min at 37 deg.C, and substrate (i.e., test compound) was added to initiate the reaction. Samples were taken at 0, 1, 5, 10, 15, 20, 30, 60min from the start of the reaction and appropriate stoppers were added to stop the reaction.

Sample treatment (n ═ 3): adding appropriate samples, vortexing, centrifuging at high speed, taking supernatant, and detecting the substrate by HPLC-MS/MS. The peak area at the time point of 0min was taken as 100%. The peak areas at other time points were converted to the residual percentages, the natural logarithm of the residual percentages at each time point was plotted against the incubation time, the slope (-k) was calculated by linear regression, and Clint (uL/min/mg) and the half-life of the compound (T1/2, min) were calculated from the intrinsic clearance (Clint) ((k) volume of incubation)/mass of liver microsomes. The results are shown in Table 3.

TABLE 3 results of the stability of liver microsome metabolism in human and mouse

The experimental results show that the compound of the invention has good metabolic stability.

Active example 4: FASSIF solubility assay for Compounds

The solubility Properties of the compounds of the invention were examined as follows, according to standard Methods of solubility determination conventional in the art, which are well known to the person skilled in the art, for example the method described in (Kerns, Edward H.and Di Li (2008), Drug-like Properties: Concepts, Structure Design and Methods: from ADME to sensitivity optimization, san Diego: Academic Press), using FaSSIF (pH6.5), which simulates intestinal fluid in the hunger state before a human meal.

The powder samples of each compound were weighed separately in volumetric flasks, 450. mu.L of a pH6.5 FaSSIF solution were added to obtain a supersaturated suspension, the samples were vortexed for at least 2 minutes, and the volumetric flasks were shaken on a shaker screen at 800 rpm for 24 hours. Then centrifuged at 4000rpm for 20 minutes. The compressed filtrate was added to a high performance liquid chromatography system and the concentration was calculated by a standard curve method, the results are shown in table 4.

The composition of the rapid simulated intestinal fluid FaSSIF is: 0.056% (w/v) lecithin, 0.161% (w/v) sodium taurocholate, 0.39% (w/v) potassium phosphate, 0.77% (w/v) potassium chloride, deionised H₂O,pH 6.5。

TABLE 4 solubility of Compounds in FaSSIF

Examples	FaSSIF pH＝6.5(μg/ml)	Examples	FaSSIF pH＝6.5(μg/ml)
				2	82.30	12	33.90
4	137.00	16	296.36
				5	23.10	25	73.20
8	32.50	GSK993	5.08

The above experimental results show that the example compounds of the present invention unexpectedly have significantly higher solubility and thus better druggability than the control.

Active example 5: CYP450 enzyme inhibitory Activity assay

The inhibitory effect of the compounds of the invention on Cytochrome P450 enzyme systems is similarly examined as follows, according to standard methods routinely used In the art for the study of Cytochrome P450 enzyme systems, for example as described In (Lin, Tong et al, In Vitro Assessment of Cytochrome P450 Inhibition: Strategies for incorporated LC/MS-Based Assay Throughput Using a One-Point IC50 Method and Multiplexing High-Performance Liquid Chromatography; J.pharm.Sci.2007,96(9), 2485.).

The following substrate stock solutions were prepared with methanol and substrate solutions at the following concentrations were further prepared with PB (phosphate buffer solution 100 mM):

stock solutions of the following standard inhibitors were prepared in DMSO at concentrations of 3mM each: α -naphthalenone (α -naphofelone), Sulfaphenazole (sulfophenazole), (+) -N-3-benzylnivanol ((+) -N-3-benzylnivanol), Quinidine (Quinidine) and Ketoconazole (Ketoconazole), and accordingly each solution was further formulated with methanol at a concentration of 300 μ M as a positive control solution so that the test final concentration was 3 μ M.

A0.253 mg/mL human liver microsome solution (Cat No.452117/Lot No.38293, Corning, final concentration: 0.2mg/mL) was prepared with PB (100 mM); and using 33mM MgCl₂A10 mM cofactor solution (NADPH, Cat No.00616/Lot No.002162-050403, Chem-impex International, final concentration: 1mM) was prepared.

Stock solutions of 10mM of each test compound were prepared in DMSO and further working solutions at concentrations of 5, 1.50, 0.500, 0.150, 0.050, 0.015, 0.005mM in 1:1DMSO: MeOH, respectively, so that the final test concentrations were 50, 15, 5, 1.5, 0.5, 0.15, 0.05. mu.M.

mu.L of substrate solution was added to each well of the plate and 20. mu.L of PB was added to the blank wells. Add 2. mu.L of test compound and positive control working solution to the reaction wells and 2. mu.L of solvent to the non-inhibitor wells and blank wells. Adding 158 μ L of human liver microsome working solution to each incubation well, preheating the plate in a water bath at 37 ℃ for about 10 minutes; add 20. mu.L of NADPH solution to each incubation well and incubate all CYP in a 37 ℃ water bath for 10 min with mixing. After 60 minutes of reaction, the reaction was stopped by adding 400. mu.L of a cold stop solution (200ng/mL of tolbutamide and labetanol in acetonitrile). The sample was centrifuged at 4000rpm for 20 minutes to precipitate the protein, and 200. mu.L of the supernatant was transferred to 100. mu.L of high performance liquid chromatography water and shaken for 10 minutes for LC/MS/MS analysis, and the amount of the metabolite produced by each probe substrate was detected. The mass spectrum detection condition is electrospray ionization (ESI) source, the selective reaction monitoring (MRM) scanning mode, the chromatographic separation condition is Thermo GLOD, C8 chromatographic column (2.1mm multiplied by 50mm,1.9 mu g), the mobile phase is gradient elution with 0.1% formic acid acetonitrile-0.1% formic acid aqueous solution, the flow rate is 0.5m L min-1, and the semi-Inhibitory Concentration (IC) is calculated by applying Graph pad Prism 5 software₅₀)。

TABLE 5 results of inhibition of CYP450 enzymes by Compounds

The above experimental results show that the compounds of the examples of the present invention unexpectedly have significantly lower CYP450 inhibitory activity (especially for CYP2C9, CYP2C19, CYP2D 6) compared to the control, indicating that they have reduced risk of drug interaction, resulting in lower toxicity and higher safety.

Active example 6: compound PK assay in mice

The PK assay for each compound was as follows: 6C 57BL/6 mice (sourced from Shanghai Ling Biotech, Inc.) were divided into two groups of 3 mice each. One group was given Intravenously (IV) at a dose of 1mg/kg, with 5% DMSO/95% (20% Captisol); one group was administered by oral (PO) gavage at a dose of 5mg/kg with vehicle of 0.5% CMC-Na/0.5% Tween 80. Each group was collected via the saphenous vein of the lower leg at 0, 0.083, 0.25, 0.5, 1,2, 4, 6, 8, 24h post-dose. Approximately 40. mu.L of blood was collected in an anticoagulation tube containing EDTA-K2. The tubes were inverted at least 5 times immediately after collection to ensure uniform mixing, and then placed on ice. Blood was collected at each time point and centrifuged at 8000rpm for 5 minutes at 4 ℃ to obtain plasma. Another 1.5mL centrifuge tube was labeled with compound name, animal number, time point and plasma was transferred to the tube. Plasma was stored at-80 ℃ until analysis.

The concentrations of the compounds in plasma were determined by the UPLC-MS/MS method, and pharmacokinetic parameters were calculated on the data obtained with Phoenix WinNolin 6.4 pharmacokinetic software.

The specific experimental results are as follows, and the results show that the compound has better drug absorption and pharmacokinetic advantages.

TABLE 6 in vivo PK results for the example Compounds

The structure of the control compound used in the above experiment is as follows:

those skilled in the art will appreciate that the foregoing description is exemplary and illustrative in nature and is intended to illustrate the present invention and its preferred embodiments. Obvious modifications and variations will be apparent to those skilled in the art without departing from the spirit of the invention. All such modifications within the scope of the appended claims are intended to be included therein. Accordingly, it is intended that the invention not be limited by the foregoing description, but be defined by the scope of the following claims and their equivalents.

All publications cited in this specification are herein incorporated by reference.

Claims

1. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof,

wherein:

x is selected from CH or N;

n is selected from 0, 1 or 2.

2. A compound according to claim 1, a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, wherein X is CH.

3. A compound according to claim 1 or 2, a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, wherein R is₁Is selected from-O-C₁-C₆Alkyl radical, wherein C₁-C₆Alkyl substituted by halogen, preferably-OCF₃、-OCHF₂、-OCH₂CF₃、-OCH₂CH₂CF₃、-CH(CF₃)₂。

4. A compound according to claim 1 or 2, a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, wherein R is₁Is hydrogen, and R₂Selected from halogen and

5. a compound according to any one of claims 1 to 4, a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, wherein R₃、R₄Each independently selected from H, halogen or C optionally substituted by halogen₁-C₆An alkyl group.

6. A compound according to any one of claims 1 to 5, a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, wherein R₅is-OR_cWherein R is_cSelected from hydrogen, C optionally substituted by halogen₁-C₆An alkyl group.

7. A compound according to any one of claims 1 to 5, a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, wherein R₅Is selected from-NR_cR_cor-NHCOR_cWherein R is_cIndependently at each occurrence, is selected from hydrogen or C optionally substituted with halogen₁-C₆Alkyl, or two R bound to the same N atom_cMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group.

8. A compound according to any one of claims 1 to 5, a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, wherein R₅Is selected from-COOR_cor-CONR_cR_cWherein R is_cIndependently at each occurrence, is selected from H or C optionally substituted with halogen₁-C₆An alkyl group.

9. A compound according to any one of claims 1 to 8, a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, wherein R₆Is selected from C₁-C₆Alkyl, preferably C₁-C₃Alkyl, optionally substituted by C₃-C₇Cycloalkyl is substituted.

10. A compound according to any one of claims 1 to 8, a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, wherein R₆Selected from optionally substituted-NH₂Said substituent being selected from C optionally substituted by halogen₁-C₆An alkyl group.

11. A compound selected from

Stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates thereof.

12. A compound according to any one of claims 1 to 11, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, for use as a medicament, particularly as an inhibitor of ROR γ t, or for use in the treatment, particularly in the treatment or prevention of a disease in which ROR γ t is involved.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, and a pharmaceutically acceptable excipient.

14. A method for the prevention or treatment of diseases related to roryt in mammals, in particular humans, which comprises administering an effective amount of a compound according to any one of claims 1 to 11, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 13.

15. Use of a compound according to any one of claims 1 to 11, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 13 for the prophylaxis or treatment of a disease associated with roryt.

16. Use of a compound according to any one of claims 1 to 11, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 13, for the preparation of a medicament for the prophylaxis or treatment of a disease associated with roryt.

17. A compound according to claim 12, a method according to claim 14 or a use according to claim 15 or 16, wherein the disease associated with roryt is selected from psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, asthma, glomerulonephritis, lupus nephritis, myocarditis, thyroiditis, dry eye, uveitis, behcet's disease, allergic dermatitis, acne, scleroderma, bronchitis, dermato-allergic rhinitis, necrotizing enterocolitis, liver fibrosis, non-alcoholic steatohepatitis (NASH), neocoronary pneumonia, insulin dependent type I diabetes, triple negative breast cancer and prostate cancer, and the like.