TW202146389A - Biaryl compound capable of serving as ror[gamma] modulator - Google Patents

Abstract

The present invention relates to a compound of formula (I), and a stereisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, a pharmaceutical composition comprising the compound, a method for treating or preventing ROR[gamma]t-related diseases by using the compound, and use of the compound in the preparation of drugs for treating or preventing the ROR[gamma]t-related diseases.

Description

Biaryls as RORγ Modulators

The invention belongs to the technical field of chemical medicine, and in particular relates to biaryl compounds with RORγt inhibitory activity, pharmaceutical compositions containing the compounds, methods for preparing the compounds, and preparation of the compounds for preventing or treating RORγt and RORγt Use in medicines related to diseases.

Retinoic acid receptor-related orphan receptors (RORs), also known as NF1R, belong to a subfamily of the ligand-dependent transcription factor nuclear receptor superfamily. The RORs subfamily mainly includes three subtypes, RORα, RORβ and RORγ. RORγ contains two members: RORγ1 (also known as RORγ) and RORγ2 (also known as RORγt), in which RORγ1 is distributed in skeletal muscle, thymus, testis, pancreas, prostate, heart and liver, etc., while RORγt is only expressed in some immune systems in cells.

Littman et al. were the first to report that RORγt is essential for the differentiation of naive CD4+ T cells into Th17 cells (Cell, 2006 126, 1121–1133). During the differentiation of Thp cells stimulated by antigens into Th17 cells, the expression of RORγt is induced under the action of cytokines such as IL-6, IL-21 and TGF-β. Thp cells isolated from RORγt-deficient mice had significantly reduced ability to differentiate into Th17 cell lines. These all suggest that RORγt is a key regulator in promoting Th17 cell differentiation.

Th17 cells are a type of helper T cells that produce IL-17 and other pro-inflammatory cytokines. Th17 cells play a key role in many mouse autoimmune disease models, such as experimental allergic encephalomyelitis (EAE) and collagen-induced arthritis (CIA) animal models. In addition, IL-17 levels can be detected in some human autoimmune diseases including rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis (Psoriasis) and inflammatory bowel disease (IBD). improvement. Increased numbers of Th17 cells were found in both tissue and peripheral blood samples from patients with autoimmune disease. Therefore, Th17 cells or the cytokine IL-17 produced by them are closely related to the pathogenesis of inflammation and autoimmune diseases.

In January 2015, Cosentyx (Secukinumab/AIN457), a monoclonal antibody developed by Novartis for the treatment of psoriasis by specifically blocking IL-17, has been approved by the FDA, which is the first drug in the market for the treatment of psoriasis. A drug that acts on IL-17. Subsequently, ixekizumab, a monoclonal antibody targeting the pro-inflammatory cytokine IL-17A, was approved for the indications of psoriasis and 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 treatment of inflammatory and autoimmune diseases by affecting the IL-17 signaling pathway through RORγt inhibitors potential for disease.

Therefore, RORγt can be used as a new target for drugs for the treatment of autoimmune diseases, and it will be of great significance to find small molecule inhibitors of RORγt and use them for the treatment of RORγt-mediated diseases, such as inflammation and autoimmune diseases.

So far, a total of 4 small molecule compounds of RORγt inhibitors are in clinical phase 2, 7 small molecules of RORγt inhibitors are in clinical phase 1, and no compound has entered clinical phase 3. Therefore, there remains a great need to discover and develop new RORyt inhibitor compounds for the prevention and/or treatment of RORyt-related diseases, such as inflammatory and autoimmune diseases. In addition to having satisfactory RORγt inhibitory activity, such compounds are also expected to have high selectivity for ROR subtypes and good or even improved druggability based on structure optimization, so as to provide more drugs for patients with related diseases The choice can also provide a better treatment effect.

The present invention relates to compounds useful in the prevention or treatment of diseases associated with RORγt. In particular, it has been identified that the compounds of the present invention not only show satisfactory RORγt inhibitory activity, have the ability to regulate Th17 cell differentiation, thereby inhibiting IL-17 production, but also show good performance in in vivo pharmacokinetic experiments, indicating that with improved druggability and improved bioavailability; in addition, it shows a good safety profile with a low risk of drug interactions. Therefore, the compounds of the present invention can not only achieve the purpose of preventing or treating diseases related to RORγt, but also the prepared medicaments are expected to have improved absorption, improved curative effect at the same dose, or provide the same curative effect with a lower dose, more Long half-life and/or reduced possible side effects. Thus, the present invention also provides the use of a compound of the present invention in the manufacture of a medicament for the prevention or treatment of a disease associated with RORγt, a pharmaceutical composition comprising the compound and the prevention and/or treatment of a disease associated with RORγt by administering the compound methods related to the disease.

(I) 其中： R₁ 和R₂ 各自獨立地選自氫、鹵素、氰基、硝基、C₁ -C₆ 烷基、-O-C₁ -C₆ 烷基、-S-C₁ -C₆ 烷基、-NH-C₁ -C₆ 烷基、-N-(C₁ -C₆ 烷基)₂ 、-C₁ -C₆ 烷基-O-C₁ -C₆ 烷基、-C₁ -C₆ 烷基-S-C₁ -C₆ 烷基、-C₁ -C₆ 烷基-NH-C₁ -C₆ 烷基或-C₁ -C₆ 烷基-N(C₁ -C₆ 烷基)₂ ，其中所述C₁ -C₆ 烷基任選被鹵素或氰基取代； R₃ 選自H、-C₁ -C₆ 烷基、-C₃ -C₇ 環烷基、-4-7元雜環烷基、-NR_a R_a 或-OR_a ，其中C₁ -C₆ 烷基、C₃ -C₇ 環烷基或4-7元雜環烷基任選被獨立地選自以下的取代基取代：鹵素、氰基、硝基、任選被鹵素取代的C₃ -C₇ 環烷基、R_a 、-OR_a 、-SR_a 或-NR_a R_a ，R_a 選自H或任選被鹵素取代的C₁ -C₆ 烷基，或者連接在同一個N原子上的兩個R_a 可以與它們所連接的N原子一起形成4-7元含氮雜環烷基； R₄ 選自-C₁ -C₆ 烷基、-C₃ -C₇ 環烷基、-4-7元雜環烷基或任選被C₁ -C₆ 烷基、C₃ -C₇ 環烷基或4-7元雜環烷基取代的氨基，其中所述C₁ -C₆ 烷基、C₃ -C₇ 環烷基或4-7元雜環烷基任選被各自獨立地選自以下的取代基取代：鹵素、氰基、硝基、R_a 、-OR_a 、-SR_a 、-NR_a R_a 或任選被鹵素取代的C₃ -C₇ 環烷基，其中R_a 選自H或任選被鹵素取代的C₁ -C₆ 烷基，或者連接在同一個N原子上的兩個基團可以與它們所連接的N原子一起形成4-7元含氮雜環烷基； R₅ 和R₆ 各自獨立地選自H、鹵素、氰基或任選被鹵素或氰基取代的C₁ -C₆ 烷基； m和p各自獨立地選自0、1或2，且 n選自0或1。Accordingly, in one aspect of the present invention there is provided a compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof:

(I) wherein: R ₁ and R ₂ are each independently selected from hydrogen, halogen, cyano, nitro, C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl , -NH-C ₁ -C ₆ alkyl, -N-(C ₁ -C ₆ alkyl) ₂ , -C ₁ -C ₆ alkyl -OC ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl base-SC ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl or -C ₁ -C ₆ alkyl-N(C ₁ -C ₆ alkyl) ₂ , wherein the C ₁ -C ₆ alkyl is optionally substituted by halogen or cyano; R _{3 is} selected from H, -C ₁ -C ₆ alkyl, -C ₃ -C ₇ cycloalkyl, -4-7 membered hetero Cycloalkyl, -NR _a R _a or -OR _a , wherein C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted independently selected from Base substitution: halogen, cyano, nitro, C ₃ -C ₇ cycloalkyl optionally substituted by halogen, R _a , -OR _a , -SR _a or -NR _a R _a , R _{a is} selected from H or any Choose a C ₁ -C ₆ alkyl substituted by halogen, or two R _a connected to the same N atom can form a 4-7 membered nitrogen-containing heterocycloalkyl together with the N atom to which they are connected; R _{4 is} selected From -C ₁ -C ₆ alkyl, -C ₃ -C ₇ cycloalkyl, -4-7 membered heterocycloalkyl or optionally by C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or 4-7 membered heterocycloalkyl substituted amino, wherein said C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted independently selected from Substituent substitution: halogen, cyano, nitro, R _a , -OR _a , -SR _a , -NR _a R _a or optionally halogen-substituted C ₃ -C ₇ cycloalkyl, wherein R _{a is} selected from H or optionally halogen-substituted C ₁ -C ₆ alkyl, or two groups attached to the same N atom may together with the N atom to which they are attached form a 4-7 membered nitrogen-containing heterocycloalkyl; R ₅ and R ₆ are each independently selected from H, halogen, cyano or optionally halogen or cyano substituted C ₁ -C ₆ alkyl group; m and p are each independently selected from 0, 1 or 2, and n is selected from from 0 or 1.

In another aspect of the present invention there are provided compounds of formula (I), stereoisomers, tautomers, stable isotopic variants thereof, having RORγt inhibitory activity for use as a medicament, especially as a RORγt inhibitor, A pharmaceutically acceptable salt or solvate.

In another aspect of the present invention there is provided a compound of formula (I), its stereoisomers, tautomers, stable isotopic variants, A pharmaceutically acceptable salt or solvate.

In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention as described above and a pharmaceutically acceptable excipient. In a specific aspect, the pharmaceutical composition of the present invention is provided for preventing or treating diseases related to RORγt. In a specific aspect, the pharmaceutical composition may additionally contain 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 present invention as described above and an additional active agent.

In another aspect of the invention there is provided a method for preventing or treating a disease associated with RORγt in a mammal, particularly a human, the method comprising administering an effective amount of a compound of the invention described herein or a medicament comprising the same combination.

In another aspect of the present invention, there is provided the use of the above-mentioned compounds or pharmaceutical compositions of the present invention for preventing or treating diseases related to RORγt.

In another aspect of the present invention, there is provided the use of the above-mentioned compound or pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating diseases related to RORγt.

In additional aspects, methods for synthesizing the compounds of the present invention are provided, of which 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 upon reading the ensuing detailed description.

definition

Unless otherwise indicated, various terms used in this specification and the claimed scope have the meanings indicated below. To the extent a particular term or phrase is not specifically defined, it should not be regarded as uncertain or unclear, but rather should be properly understood in accordance with the context herein or its ordinary meaning in the art. Many of the groups defined herein are optionally substituted, and the list of substituents given in this Definitions section is exemplary only and is not intended to limit the substituents defined elsewhere in this specification and the scope of the application.

The term "alkyl" as used herein means a straight or branched chain aliphatic hydrocarbon group having the specified number of carbon atoms. Specifically, the alkyl group may have 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Examples of suitable C _1-6 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 set forth herein. Specifically, the term refers to the group -OC _1-6 alkyl. Examples of suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, 2nd-butoxy, n-pentoxy , n-hexyloxy 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 set forth herein. Specifically, the term refers to the group -SC _1-6 alkyl. Examples of suitable alkylthio groups include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tertiary butylthio, second butylthio, n-pentylthio , n-hexylthio and 1,2-dimethylbutylthio. Particular alkylthio groups have 1 to 3 carbon atoms.

As used herein, the term "halo-substituted C ₁ -C ₆ alkyl" refers to the above C ₁ -C ₆ alkyl, wherein one or more (e.g. 4 or 5) hydrogen Atoms are replaced by halogens. 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. "Halo-substituted C ₁ -C ₆ alkyl group" exemplified for example _{-CH 2 F, -CHF 2, -CF} 3, -CCl 3, -C 2 F 5, -C 2 Cl 5, -CH 2 CF 3 , -CH ₂ Cl, CH ₂ CH ₂ CF ₃ or -CF(CF ₃ ) _2, etc.

As used herein, the term "halo-substituted C ₁ -C ₆ alkoxy" refers to the above C ₁ -C ₆ alkoxy group, wherein one or more (e.g., 4 or 5 ) hydrogen atoms are replaced by halogens. 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. Examples of "halogen substituted C ₁ -C ₆ alkoxy" are eg -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OCCl ₃ , -OC ₂ F ₅ , -OC ₂ Cl ₅ , -OCH ₂ CF ₃ , -OCH ₂ Cl or -OCH ₂ CH ₂ CF _3, etc.

As used herein, the term "halo-substituted C ₁ -C ₆ alkylthio" refers to the above C ₁ -C ₆ alkoxy group, wherein one or more (e.g., 4 or 5 ) hydrogen atoms are replaced by halogens. 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. Examples of the "halogen substituted C ₁ -C ₆ alkylthio group" for example, _{-SCH 2 F, -SCHF 2, -SCF} 3, -SCCl 3, -SC 2 F 5, -SC 2 Cl 5, -SCH 2 CF ₃ , -SCH ₂ Cl or -SCH ₂ CH ₂ CF _3, etc.

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

As used herein, the term "halogen substituted C ₃ -C ₇ cycloalkyl" refers to the above C ₃ -C ₇ cycloalkyl group, wherein one or more (e.g., 4 or 5 ) hydrogen atoms are replaced by halogens. 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, 2,2,3,3-tetrafluorocyclopropyl, 2,3-difluorocyclobutyl, 2, 4-Difluorocyclobutyl, etc.

The term "heterocycloalkyl" as used herein means a monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic non-cyclic ring that includes one or more heteroatoms independently selected from O, N, and S and the specified number of ring atoms. Aromatic saturated ring structure, or its N-oxide, or its S-oxide or S-dioxide. A heterocycloalkyl group can have 4 to 12 ring members, specifically 4 to 10 ring members, and more specifically 4 to 7 ring members. Heterocycloalkyl typically contains up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2, eg a single heteroatom, eg a 4-7 membered monocyclic heterocycloalkyl having one heteroatom such as N, Namely 4-7 membered nitrogen-containing heterocycloalkyl. Examples of suitable heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl). -pyrrolidinyl), tetrahydrofuranyl (eg 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothienyl (eg 1-tetrahydrothienyl, 2-tetrahydrothienyl and 3-tetrahydrothienyl) thienyl), piperidinyl (such as 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (such as 4-tetrahydropyranyl), Tetrahydrothiopyranyl (eg 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, in which the maximum number of heteroatoms or the type of heteroatoms contained is determined by ring size, degree of unsaturation, and valence of the heteroatoms. Decide. In general, a heterocycle can have 1 to 4 heteroatoms, so 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 halogens are fluorine or chlorine. The term "halogen-substituted" groups as used herein is intended to include mono- or polyhalogenated groups in which one or more of the same or different halogens replace one or more hydrogens in the group.

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

As used herein, the term "nitro" refers to the group -NO _2.

As used herein, the term "amino" refers to the group -NH _2; As used herein, the term "optionally substituted ......" means a group may be unsubstituted or substituted by one or more (e.g. 0,1,2, 3, 4, or 5 or more, or any range derivable therein), with the substituents listed for that group, wherein the substituents may be the same or different. In one embodiment, an optionally substituted group has 1 substituent. In another embodiment, an optionally substituted group has 2 substituents. In another embodiment, an optionally substituted group has 3 substituents. In another embodiment, an optionally substituted group has 4 substituents.

Unless otherwise defined, the definition of the compounds used herein, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or 4-7 membered heterocycloalkyl optionally bearing one or more substituents, the substituents selected from H, F, Cl, Br, I, cyano, nitro, C ₁ -C ₆ alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl, tert-butyl, pentyl, neopentyl, hexyl, 1,2-dimethylbutyl, etc.), C ₃ -C ₇ cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), -OH, -OC ₁ -C ₆ alkyl (eg methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, Second butoxy, n-pentoxy, n-hexyloxy and 1,2-dimethylbutoxy, etc.), -SH, -SC ₁ -C ₆ alkyl (such as methylthio, ethylthio, n- Propylthio, isopropylthio, n-butylthio, tertiary butylthio, second butylthio, n-pentylthio, n-hexylthio and 1,2-dimethylbutylthio, etc.) or -NH ₂ , -NH-C ₁ -C ₆ alkyl (such as methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, tert-butylamino, sec-butylamino, n-pentylamino amino, n-hexylamino, 1,2-dimethylbutylamino, etc.), -N(C ₁ -C ₆ alkyl) ₂ (such as dimethylamino, methylethylamino, diethylamino, etc.) ), wherein the C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl is optionally substituted with one or more halogens (preferably F).

The term "compounds of the invention" as used herein is intended to encompass compounds of general formula (I) as defined herein or any preferred or specific embodiments thereof, their stereoisomers, tautomers, stable isotopes Variants, pharmaceutically acceptable salts or solvates, and prodrugs. Similarly, reference herein to an "intermediate", whether claimed or not in itself, is intended to encompass its free form as well as each of the aforementioned derivative forms, as the context permits.

The term "pharmaceutically acceptable" as used herein means approved by or by the appropriate agency in each country, or listed in a generally recognized pharmacopoeia for use in animals and more particularly in humans, or when administered in an appropriate amount to animals such as humans Molecular entities and compositions that do not produce adverse, allergic or other adverse reactions.

As used herein, the term "pharmaceutically acceptable salt" means a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Specifically, such salts are nontoxic and can be inorganic acid addition salts or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids, which Organic acids such as acetic acid, propionic acid, caproic 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, mandel acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butyl Glycolic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) when the acidic proton present in the parent compound is converted to a metal ion such as a base Salts formed when metal ions, alkaline earth metal ions or aluminum ions are substituted, or when complexed with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Those skilled in the art are aware of general principles and techniques for preparing pharmaceutically acceptable salts, such as those described in Berge et al., Pharm ScL, 66, 1-19. (1977).

The term "prodrug" as used herein means a compound having a cleavable group that becomes a compound of the present invention pharmaceutically active in vivo by solvolysis or under physiological conditions, including derivatives of the compound 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 amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, or anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides and acid anhydrides derived from the pendant acid groups of the compounds of the present invention are particularly suitable prodrugs. Such prodrugs of specific compounds of the invention C _1-8 alkyl, C _2-8 alkenyl, optionally substituted C _6-10 aryl group and a (C _6-10 aryl) - (C _{1- 4} alkyl) esters.

。The term "stereoisomer" as used herein refers to isomers formed due to at least one asymmetric center. In compounds with one or more (eg, 1, 2, 3, or 4) asymmetric centers, it can give rise to racemic mixtures, single enantiomers, diastereomer mixtures, and individual enantiomers Astereoisomers. Certain molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist as mixtures of two or more different structural forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, a nitroso-oxime can exist in solution in equilibrium in the following tautomeric forms:

.

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

”或“

”表示不對稱中心即掌性中心的相對構型。相應地，在本發明所提供的化合物或中間體的命名中以R和S表示關於該掌性中心的相對構型。The compounds of the present invention may possess one or more asymmetric centers and thus may be prepared as (R)- or (S)-stereoisomers, respectively, or as mixtures thereof. As used in the structural formulas or structural fragments of the compounds herein, ""

"or"

” represents the relative configuration of the asymmetric center, that is, the chiral center. Correspondingly, in the naming of the compounds or intermediates provided by the present invention, R and S represent the relative configuration of the chiral center.

The term "solvate" as used herein refers to solvent addition forms containing stoichiometric or non-stoichiometric amounts of solvent, including, for example, solvates with water, such as hydrates, or with organic solvents, such as methanol, ethanol or A solvate of acetonitrile, ie as methanolate, ethanolate or acetonitrile, respectively; or in the form of any polymorph. It should be understood that such solvates of the compounds of the present invention also include solvates of pharmaceutically acceptable salts of the compounds of the present invention.

As used herein, the term "isotopic variant" 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 that normally found in nature. Examples of isotopes that may be incorporated at one or more atoms of the compounds of the present invention include, for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, to form an isotopic variations of the compounds of the present invention, whether radioactive thereof, are intended to be encompassed within the scope of the present invention. In some embodiments, the isotope is incorporated ² H (deuterium); in other embodiments, the isotope was incorporated ³ H (tritium).

The term "RORyt-associated disease" as used herein means a disease in which RORyt contributes to the occurrence and progression of the disease, or in which inhibition of RORyt will reduce the incidence, reduce or eliminate disease symptoms. For the purposes of the present invention, "diseases associated with RORγt" are especially selected from inflammatory or autoimmune diseases, cancer, etc., including but not limited to psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spine inflammation, 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, thyroid inflammation, dry eye, uveitis, Behcet's disease, allergic dermatitis, acne, scleroderma, bronchitis, dermatomuscular allergic rhinitis, necrotizing enterocolitis (NEC, Necrotizing Enterocolitis), liver fibrosis, Non-alcoholic steatohepatitis (NASH), New coronavirus pneumonia (New coronavirus pneumonia), insulin-dependent type I diabetes, triple-negative breast cancer and prostate cancer, etc. Preferred indications of the present invention are selected from the group consisting of psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, inflammatory bowel disease, dry eye, allergic dermatitis, chronic obstructive COPD, asthma, necrotizing enterocolitis, liver fibrosis, nonalcoholic steatohepatitis (NASH), COVID-19, triple-negative breast and prostate cancer.

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

The term "therapeutically effective amount" as used herein means an amount sufficient to reduce or completely alleviate the symptoms or other deleterious effects of the disorder; reverse, completely stop or slow the progression of the disorder; or reduce the exacerbation of the disorder when administered to a subject to treat a disease. The amount at risk, the "effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

The term "prophylaxis" as used herein means administering to a subject, eg a mammal, eg a human, a subject, eg a mammal eg a human, suspected of suffering from or susceptible to a disease associated with RORγt as defined herein, in particular an inflammatory or autoimmune disease Various compounds of the present invention result in a reduced risk of developing a defined disease. The term "prevention" encompasses the use of the compounds of the present invention prior to the diagnosis or determination of any clinical and/or pathological symptoms.

The term "treating" as used herein refers to administering one or more compounds of the invention described herein to a subject, such as a mammal, such as a human, having the disease, or a symptom of the disease, for the purpose of curing, Alleviate, alleviate or affect the disease or symptoms of the disease. In a specific embodiment of the invention, the disease is a disease associated with RORγt as defined herein, especially an inflammatory or autoimmune disease.

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

The term "pharmaceutically acceptable excipient or carrier" as used herein refers to one or more compatible solid or liquid filler or gelling substances, which are pharmacologically inactive and compatible with the other ingredients of the composition, and should be acceptable for administration to warm-blooded animals such as humans for use as a carrier or vehicle for the compounds of the present invention in administration forms, examples of which include, but are not limited to, cellulose and its derivatives (such as sodium carboxymethyl cellulose, acetic acid, etc.). cellulose, etc.), gelatin, talc, solid lubricants (such as magnesium stearate), calcium sulfate, vegetable oils, polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween), Wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, etc.

Unless otherwise specified, the compounds of the invention are defined in the C _{n-n + m} or C _n -C _{n + m} to n in each case comprises n + m carbon atoms, e.g. C _1-6 include C _1, C _2, C ₃ , C ₄ , C ₅ and C ₆ also include any one range from n to n+m, eg C _1-6 includes C _1-2 , C _1-3 , C _1-4 , C _2-6 , C _3-6 and so on. Similarly, n-membered to n+m-membered in the definition of the compound of the present invention means that the number of ring atoms is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, and a 6-membered ring. , 12-membered ring, etc., also including any range of n to n+m members, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7 membered ring, 6-8 membered ring and 6-10 membered ring etc.

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

Compounds of the present invention

As used throughout this application, the terms "compounds of the invention" and "compounds of the invention" and the like, unless otherwise indicated, encompass compounds of formula (I), their stereoisomers as defined in the various embodiments herein and specific or preferred embodiments thereof Conformers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, and prodrugs. The stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates and prodrugs are as described in the definitions section above. Preferably, the compounds of the present invention are in free form of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof; most preferably a compound of formula (I) in free form 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 solid crystalline form, the compound of formula (I) may be in the form of a co-crystal with another chemical entity, and this specification includes all such co-crystals.

In the presence of a chiral center, 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 an enantiomeric excess (%ee) of >95%, >98% or >99%. Preferably, a single enantiomer is present in >99% enantiomer excess (% ee).

(I) 其中： R₁ 和R₂ 各自獨立地選自氫、鹵素、氰基、硝基、C₁ -C₆ 烷基、-O-C₁ -C₆ 烷基、-S-C₁ -C₆ 烷基、-NH-C₁ -C₆ 烷基、-N-(C₁ -C₆ 烷基)₂ 、-C₁ -C₆ 烷基-O-C₁ -C₆ 烷基、-C₁ -C₆ 烷基-S-C₁ -C₆ 烷基、-C₁ -C₆ 烷基-NH-C₁ -C₆ 烷基或-C₁ -C₆ 烷基-N(C₁ -C₆ 烷基)₂ ，其中所述C₁ -C₆ 烷基任選被鹵素或氰基取代； R₃ 選自H、-C₁ -C₆ 烷基、-C₃ -C₇ 環烷基、-4-7元雜環烷基、-NR_a R_a 或-OR_a ，其中C₁ -C₆ 烷基、C₃ -C₇ 環烷基或4-7元雜環烷基任選被獨立地選自以下的取代基取代：鹵素、氰基、硝基、任選被鹵素取代的C₃ -C₇ 環烷基、R_a 、-OR_a 、-SR_a 或-NR_a R_a ，其中R_a 選自H或任選被鹵素取代的C₁ -C₆ 烷基，或者連接在同一個N原子上的兩個R_a 可以與它們所連接的N原子一起形成4-7元含氮雜環烷基； R₄ 選自-C₁ -C₆ 烷基、-C₃ -C₇ 環烷基、-4-7元雜環烷基或任選被C₁ -C₆ 烷基、C₃ -C₇ 環烷基或4-7元雜環烷基取代的氨基，其中所述C₁ -C₆ 烷基、C₃ -C₇ 環烷基或4-7元雜環烷基任選被各自獨立地選自以下的取代基取代：鹵素、氰基、硝基、R_a 、-OR_a 、-SR_a 、-NR_a R_a 或任選被鹵素取代的C₃ -C₇ 環烷基，R_a 選自H或任選被鹵素取代的C₁ -C₆ 烷基，或者連接在同一個N原子上的兩個基團可以與它們所連接的N原子一起形成4-7元含氮雜環烷基； R₅ 和R₆ 各自獨立地選自H、鹵素、氰基或任選被鹵素或氰基取代的C₁ -C₆ 烷基； m和p各自獨立地選自0、1或2，且 n選自0或1。Specifically, in one aspect, the present invention provides compounds of formula (I), stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof:

(I) wherein: R ₁ and R ₂ are each independently selected from hydrogen, halogen, cyano, nitro, C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl , -NH-C ₁ -C ₆ alkyl, -N-(C ₁ -C ₆ alkyl) ₂ , -C ₁ -C ₆ alkyl -OC ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl base-SC ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl or -C ₁ -C ₆ alkyl-N(C ₁ -C ₆ alkyl) ₂ , wherein the C ₁ -C ₆ alkyl is optionally substituted by halogen or cyano; R _{3 is} selected from H, -C ₁ -C ₆ alkyl, -C ₃ -C ₇ cycloalkyl, -4-7 membered hetero Cycloalkyl, -NR _a R _a or -OR _a , wherein C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted independently selected from Substituted: halogen, cyano, nitro, C ₃ -C ₇ cycloalkyl optionally substituted by halogen, R _a , -OR _a , -SR _a or -NR _a R _a , wherein R _{a is} selected from H or _{C 1} -C ₆ alkyl optionally substituted by halogen, or two R _a attached to the same N atom can form 4-7 membered nitrogen-containing heterocycloalkyl together with the N atom to which they are attached; R ₄ Selected from -C ₁ -C ₆ alkyl, -C ₃ -C ₇ cycloalkyl, -4-7 membered heterocycloalkyl or optionally by C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or 4-7 membered heterocycloalkyl substituted amino, wherein said C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted each independently selected from Substituent substitution of: halogen, cyano, nitro, R _a , -OR _a , -SR _a , -NR _a R _{a or C 3} -C ₇ cycloalkyl optionally substituted by halogen, R _{a is} selected from H optionally substituted by halogen or C ₁ -C ₆ alkyl, or two groups attached to the same N atom may form a 4-7 membered nitrogen-containing heterocyclic group together with the N atom to which they are attached; R & lt ₅ and R ₆ are each independently selected from H, halogen, cyano or optionally halogen or cyano substituted C ₁ -C ₆ alkyl group; m and p are each independently selected from 0, 1 or 2, and n is selected from from 0 or 1.

In one embodiment of the compound of formula (I), n is zero.

In one embodiment of the compound of formula (I), n is one.

In embodiments of the compounds (I) of formula in, R ₁ and R ₂ are each independently H.

In embodiments of the compounds (I) of formula in, R ₁ and R ₂ are each independently halogen, e.g. F, Cl, Br or I; preferably F or Cl.

In a specific embodiment, both R ₁ and R ₂ are H. In a specific embodiment, R ₁ is H and R ₂ is halogen. In a specific embodiment, R ₁ is halogen and R ₂ is H. In a specific embodiment, both R ₁ and R ₂ are halogen, which may be the same or different.

In one embodiment of the compound of formula (I), R ₁ and R ₂ are each independently selected from C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl, -NH -C ₁ -C ₆ alkyl or -N-(C ₁ -C ₆ alkyl) ₂ , wherein the C ₁ -C ₆ alkyl is optionally substituted by halogen (preferably F). Specific examples include but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, _{tert-butyl, -CF 3, -CHF 2, -CH} 2 CF 3, -CF 2 CF ₃ , -CH ₂ CH ₂ CF ₃ , -CH(CF ₃ ) ₂ , -OCH ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ CH ₃ , -OCH ₂ CF ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH ₂ CF ₃ , -OCH(CF ₃ ) ₂ , -SCH ₃ , -SCF ₃ , -SCH ₂ CH ₃ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NH-CH ₂ CH ₃ , -N(CH ₃ )(CH ₂ CH ₃ ), -NHCF ₃ , -N(CH ₃ )(CF ₃ ), and the like.

In one embodiment of a compound of formula (I), R ₁ and R ₂ are each independently selected from -C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl-SC ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl or -C ₁ -C ₆ alkyl-N(C ₁ -C ₆ alkyl) ₂ , wherein C ₁ -C ₆ alkyl optionally substituted with halogen (preferably F) substitutions. Specific examples include, but are not limited to, _{-CH 2 OCH 3, -CH 2 CH} 2 OCH 3, -CH 2 OCH 2 CH 3, -CH 2 CH 2 OCH 2 CH 3, -CH 2 NHCH 3, -CH 2 N ( CH ₃ ) ₂ , -CH ₂ OCF ₃ , -CH ₂ CH ₂ OCF ₃ , -CH ₂ OCH ₂ CF ₃ , -CH ₂ NHCF ₃ , -CH ₂ N(CF ₃ ) ₂ and the like.

In embodiments of the compounds (I) of formula in, R ₃ is -C ₁ -C ₆ alkyl, preferably C ₁ -C ₃ alkyl optionally substituted with one or more substituents independently selected from the group of substituted : halogen, C ₃ -C ₇ cycloalkyl optionally substituted by halogen, R _a , -OR _a , -SR _a or -NR _a R _a , wherein R _{a is} independently selected from H or optionally by one or more a halogen-substituted C ₁ -C ₆ alkyl, or are connected on the same N atom may be two R _a 4-7 membered nitrogen-containing heterocyclic group formed together with the N atom to which they are attached.

In a specific embodiment, R ₃ is -C ₁ -C ₆ alkyl, preferably C ₁ -C ₃ alkyl, optionally substituted with F, Cl, Br, I, R a or -OR _a, wherein R _a It is H or optionally substituted with one or more halogen (preferably F) substituted C ₁ -C ₃ alkyl. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, Trifluoromethoxymethyl or trifluoromethoxyethyl and the like. In a more specific embodiment, R ₃ is C ₁ -C ₃ alkyl such as methyl, ethyl, propyl or isopropyl.

In a specific embodiment, R ₃ is -C ₁ -C ₆ alkyl, preferably C ₁ -C ₃ alkyl, optionally substituted with halogen substituted C ₃ -C ₇ cycloalkyl. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentyl ethyl, etc.

In a specific embodiment, R ₃ is -C ₁ -C ₆ alkyl, preferably C ₁ -C ₃ alkyl, optionally _{substituted by -NR a} R _a , wherein R _{a is} independently selected from H or optionally by with one or more halogen substituted C ₁ -C ₃ alkyl, or attached to the same N atom may be two R _a 4-7 membered nitrogen-containing heterocyclic group formed together with the N atom to which they are attached. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, dimethylaminomethyl, methylethylamino Methyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, etc.

In embodiments of the compounds (I) of formula in, R ₃ is -C ₃ -C ₇ cycloalkyl, which is optionally substituted with one or more substituents independently selected from the following groups: halogen, optionally substituted by halogen C ₃ -C ₇ cycloalkyl, R _a , -OR _a , -SR _a or -NR _a R _a , wherein R _{a is independently selected from H or C 1} -C optionally substituted with one or more halogens _{A 6- alkyl, or two R a} attached to the same N atom can be taken together with the N atom to which they are attached to form a 4-7 membered nitrogen-containing heterocycloalkyl. In a specific embodiment, R ₃ is -C ₃ -C ₅ cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl.

In specific embodiments, R ₃ is -C ₃ -C ₇ cycloalkyl, optionally substituted with one or more groups independently selected from halogen, R _a , -OR _a or -NR _a R _a , wherein R _{a is independently selected from H or C 1} -C ₆ alkyl optionally substituted with one or more halogens. Specific examples include, but are not limited to, 2,3-difluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 2,3-difluorocyclobutyl, methylcyclopropyl, or cyclobutyl , dimethylcyclopropyl or cyclobutyl, trifluoromethylcyclopropyl or cyclobutyl, hydroxycyclopropyl or cyclobutyl, trifluoromethoxycyclopropyl or cyclobutyl, methylamino ring propyl, dimethylaminocyclopropyl, trifluoromethylaminocyclopropyl, etc.

In embodiments of the compounds (I) of formula, R ₃ is 4-7-membered heterocycloalkyl, optionally substituted with one or more groups independently selected from the following groups: halogen, R _a, -OR _a , -SR _a or -NR _a R _a , wherein R _{a is independently selected from H or C 1} -C ₆ alkyl optionally substituted with one or more halogens, or two Rs attached to the same N atom _a may together with the N atom to which they are attached form a 4-7 membered nitrogen-containing heterocycloalkyl group. In a specific embodiment, R ₃ is 4-7-membered heterocycloalkyl, for example, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl , 2-pyrrolidinyl and 3-pyrrolidinyl), tetrahydrofuranyl (such as 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothienyl (such as 1-tetrahydrothienyl, 2-tetrahydrothienyl) hydrothienyl and 3-tetrahydrothienyl), piperidinyl (such as 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (such as 4 - tetrahydropyranyl), tetrahydrothiopyranyl (eg 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl, each of which is optionally replaced by one or more substituted with, for example, 1, 2 or 3 groups independently selected from F, Cl, Br, I, R _a , -OR _a or -NR _a R _a wherein R _{a is} independently selected from H or any optionally substituted with one or more halogen C ₁ -C ₃ alkyl.

In embodiments of the compounds (I) of formula in, R ₃ is -NR _a R _a, wherein R _a is independently selected from H or optionally substituted with one or more halogen C ₁ -C ₃ alkyl, or is connected _{Two R a} on the same N atom can together with the N atom to which they are attached form a 4-7 membered nitrogen-containing heterocycloalkyl group. Specific examples include, but are not limited to, _{-NH 2, -NHCH 3, -NCH 3} CH 3, -N (CH 2 CH 3) CH 3, -N (CH 2 CH 3) (CH 2 CH 3) -, - NHCF ₃ , -N(CH ₃ )CF ₃ , -N(CF ₃ )CF ₃ , -N(CH ₂ CF ₃ )CF ₃ or -N(CH ₂ CF ₃ )(CH ₂ CF ₃ )-, -NH( CH ₂ CH ₂ CH _3), azetidinyl, pyrrolidinyl, piperidinyl and the like.

In embodiments of the compounds (I) of formula, R _{4 is} selected from -C ₁ -C ₆ alkyl, preferably C ₁ -C ₃ alkyl optionally substituted with one or more substituents independently selected from the group substituents: halogen, optionally halogen-substituted C ₃ -C _{7 cycloalkyl, R a, -OR a, -SR} a , or -NR _a R _a, wherein R _a is independently selected from H or optionally substituted with one or a plurality of halogen-substituted C ₁ -C ₆ alkyl, or are connected on the same N atom may be two R _a 4-7 membered nitrogen-containing heterocyclic group formed together with the N atom to which they are attached.

In a particular embodiment, R ₄ is -C ₁ -C ₆ alkyl, preferably C ₁ -C ₃ alkyl, optionally substituted with F, Cl, Br, I, R a or -OR _a, wherein R _a It is H or optionally substituted with one or more halogen (preferably F) substituted C ₁ -C ₃ alkyl. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, Trifluoromethoxymethyl or trifluoromethoxyethyl and the like. In a more specific embodiment, R ₄ is C ₁ -C ₃ alkyl, such as methyl, ethyl, propyl or isopropyl.

In a specific embodiment, R ₄ is -C ₁ -C ₆ alkyl, preferably C ₁ -C ₃ alkyl, optionally substituted with halogen substituted C ₃ -C ₇ cycloalkyl. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentyl ethyl, etc.

In a specific embodiment, R ₄ is -C ₁ -C ₆ alkyl, preferably C ₁ -C ₃ alkyl, optionally _{substituted by -NR a} R _a , wherein R _{a is} independently selected from H or optionally by with one or more halogen substituted C ₁ -C ₃ alkyl, or attached to the same N atom may be two R _a 4-7 membered nitrogen-containing heterocyclic group formed together with the N atom to which they are attached. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, dimethylaminomethyl, methylethylamino Methyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, etc.

In embodiments of the compounds (I) of formula in, R ₄ is -C ₃ -C ₇ cycloalkyl, which is optionally substituted with one or more substituents independently selected from the following groups: halogen, optionally substituted by halogen C ₃ -C ₇ cycloalkyl, R _a , -OR _a , -SR _a or -NR _a R _a , wherein R _{a is independently selected from H or C 1} -C optionally substituted with one or more halogens _{A 6- alkyl, or two R a} attached to the same N atom can be taken together with the N atom to which they are attached to form a 4-7 membered nitrogen-containing heterocycloalkyl. In specific embodiments, R ₄ is -C ₃ -C ₅ cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl.

In specific embodiments, R ₄ is -C ₃ -C ₇ cycloalkyl, optionally substituted with one or more groups independently selected from halogen, R _a , -OR _a or -NR _a R _a , wherein R _{a is independently selected from H or C 1} -C ₆ alkyl optionally substituted with one or more halogens. Specific examples include, but are not limited to, 2,3-difluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 2,3-difluorocyclobutyl, methylcyclopropyl, or cyclobutyl , dimethylcyclopropyl or cyclobutyl, trifluoromethylcyclopropyl or cyclobutyl, hydroxycyclopropyl or cyclobutyl, trifluoromethoxycyclopropyl or cyclobutyl, methylamino ring propyl, dimethylaminocyclopropyl, trifluoromethylaminocyclopropyl, etc.

In embodiments of the compounds (I) of formula, R _{4 is} 4-7 membered heterocycloalkyl, optionally substituted with one or more groups independently selected from the following groups: halogen, R _a, -OR _a , -SR _a or -NR _a R _a , wherein R _{a is independently selected from H or C 1} -C ₆ alkyl optionally substituted with one or more halogens, or two Rs attached to the same N atom _a may together with the N atom to which they are attached form a 4-7 membered nitrogen-containing heterocycloalkyl group. In specific embodiments, R ₄ is a 4-7 membered heterocycloalkyl, for example, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl , 2-pyrrolidinyl and 3-pyrrolidinyl), tetrahydrofuranyl (such as 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothienyl (such as 1-tetrahydrothienyl, 2-tetrahydrothienyl) hydrothienyl and 3-tetrahydrothienyl), piperidinyl (such as 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (such as 4 - tetrahydropyranyl), tetrahydrothiopyranyl (eg 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl, each of which is optionally replaced by one or more one, e.g. 1, 2 or 3 substituents independently selected from F, Cl, Br, I, R a, -OR _a substituted with -NR _a R _a or a group, wherein R _a is independently selected from H or any optionally substituted with one or more halogen C ₁ -C ₃ alkyl.

In embodiments of the compounds (I) of formula, R _{4 is} optionally substituted C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or 4-7 membered heterocycloalkyl group. In a specific embodiment, the substituted amino C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or 4-7 membered heterocycloalkyl having each of the above embodiments as R C _{4 l} - Each specific embodiment or specific example as defined by C ₆ alkyl, C ₃ -C _{7 cycloalkyl or 4-7 membered heterocycloalkyl.} In the most specific embodiment, R _{4 is amino substituted with C 1} -C ₆ alkyl optionally substituted by halogen, specific examples include but are not limited to -NH ₂ , -NHCH ₃ , -NCH ₃ CH ₃ , -N(CH ₂ CH ₃ )CH ₃ , -N(CH ₂ CH ₃ )(CH ₂ CH ₃ )-, -NHCF ₃ , -N(CH ₃ )CF ₃ , -N(CF ₃ )CF ₃ , - N(CH ₂ CF ₃ )CF ₃ or -N(CH ₂ CF ₃ )(CH ₂ CF ₃ )-, -NH(CH ₂ CH ₂ CH ₃ ), azetidine, pyrrolidinyl, piperidinyl Wait.

In embodiments of the compounds (I) of formula in, R ₅ and R ₆ are each independently selected from halogen, e.g. F, Cl, Br, I.

In embodiments of the compounds (I) of formula in, R ₅ and R ₆ are each independently selected from halogen, optionally substituted C ₁ -C ₆ alkyl. In specific embodiments, R ₅ and R ₆ are each independently selected from C ₁ -C ₃ alkyl substituted with at least three halogens. In a more specific embodiment, R ₅ and R ₆ are each independently selected from C ₁ -C ₃ alkyl substituted by three fluorines, specific examples include but are not limited to trifluoromethyl, trifluoroethyl, pentafluoromethyl Fluoroethyl etc. In a most specific embodiment, R ₅ and R ₆ are -CF _3.

In one embodiment of the compound of formula (I), m and p are both zero. In specific embodiments, m is 0 and p is 1. In another specific embodiment, m is 0 and p is 2. In another specific embodiment, m is 1 and p is 0. In another specific embodiment, m is 1 and p is 1. In another specific embodiment, m is 1 and p is 2. In another specific embodiment, m is 2 and p is 0. In another specific embodiment, m is 2 and p is 1. In another specific embodiment, m is 2 and p is 2.

It should be noted that the compound of formula (I) of the present invention covers each of the above independent embodiments or each specific embodiment, and also covers the embodiment formed by any combination or sub-combination of each of the above-mentioned embodiments or specific embodiments, and also covers the above Any preferred or exemplified combination constitutes an embodiment.

(I) 其中： R₁ 和R₂ 各自獨立地選自氫、鹵素或C₁ -C₆ 烷基，其中所述C₁ -C₆ 烷基任選被鹵素取代； R₃ 選自H、-C₁ -C₆ 烷基、-C₃ -C₇ 環烷基或-NR_a R_a ，其中C₁ -C₆ 烷基或C₃ -C₇ 環烷基任選被獨立地選自以下的取代基取代：鹵素、任選被鹵素取代的C₃ -C₇ 環烷基、R_a 、-OR_a 、-SR_a 或-NR_a R_a ； R₄ 選自-C₁ -C₆ 烷基或-NR_a R_a ，其中所述C₁ -C₆ 烷基任選被各自獨立地選自以下的取代基取代：R_a 、鹵素或-NR_a R_a ： R_a 選自H或任選被鹵素取代的C₁ -C₆ 烷基，或者連接在同一個N原子上的兩個R_a 可以與它們所連接的N原子一起形成4-7元含氮雜環烷基； R₅ 和R₆ 各自獨立地選自鹵素或任選被鹵素取代的C₁ -C₆ 烷基； m和p各自獨立地選自0、1或2，且 n選自0或1。Preferably, the present invention provides compounds of formula (I), stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof:

(I) wherein: R ₁ and R ₂ are each independently selected from hydrogen, halogen or C ₁ -C ₆ alkyl group, wherein said C ₁ -C ₆ alkyl group is optionally substituted with halogen; R _{3 is} selected from H, - C ₁ -C ₆ alkyl, -C ₃ -C ₇ cycloalkyl or -NR _a R _a , wherein C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl is optionally independently selected from the following Substituent substitution: halogen, C ₃ -C ₇ cycloalkyl optionally substituted by halogen, R _a , -OR _a , -SR _a or -NR _a R _a ; R _{4 is} selected from -C ₁ -C ₆ alkyl or -NR _a R _a , wherein the C ₁ -C ₆ alkyl is optionally substituted with a substituent each independently selected from R _a , halogen or -NR _a R _a : R _{a is} selected from H or optionally _{C 1} -C ₆ alkyl substituted by halogen, or two R _a attached to the same N atom can form 4-7 membered nitrogen-containing heterocycloalkyl together with the N atom to which they are attached; R ₅ and R ₆ are each independently selected from halogen or optionally halogen-substituted C ₁ -C ₆ alkyl group; m and p are each independently selected from 0, 1 or 2, and n is selected from 0 or 1.

In one embodiment of the above preferred compounds of formula (I), R ₁ and R ₂ are each independently selected from hydrogen or halogen, eg, F, Cl, Br, I. In a specific embodiment, both R ₁ and R ₂ are H. In a specific embodiment, R ₁ is H and R ₂ is halogen. In a specific embodiment, R ₁ is halogen and R ₂ is H. In a specific embodiment, both R ₁ and R ₂ are halogen, which may be the same or different.

In one embodiment of the above preferred compounds of formula (I), R ₃ is -C ₁ -C ₃ alkyl, optionally substituted with substituents independently selected from H, halogen or optionally halogen substituted C ₃ -C ₇ cycloalkyl. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, trifluoromethyl, trifluoroethyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl base, cyclopentylmethyl, cyclopentylethyl, etc.

In a more specific embodiment, R ₃ is -C ₁ -C ₃ alkyl, such as methyl, ethyl, propyl or isopropyl.

In a more specific embodiment, R ₃ is -C ₁ -C ₃ alkyl, substituted with -NR _a R _a , wherein R _{a is} selected from H or C ₁ -C ₃ alkyl optionally substituted with halogen, or Two R _a attached to the same N atom can form a 4-7 membered nitrogen-containing heterocycloalkyl together with the N atom to which they are attached. Specific examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, dimethylaminomethyl, methylethylaminomethyl, azetidinemethyl, pyrrolidinylmethyl base, piperidinylmethyl, etc.

In one embodiment of the above preferred compounds of formula (I), R ₃ is -C ₃ -C ₇ cycloalkyl, optionally substituted with a group independently selected from halogen, R _a or -NR _a R _a , wherein R _{a is independently selected from H or C 1} -C ₃ alkyl optionally substituted with one or more halogens. Specific examples include, but are not limited to, 2,3-difluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 2,3-difluorocyclobutyl, methylcyclopropyl, or cyclobutyl , dimethylcyclopropyl or cyclobutyl, trifluoromethylcyclopropyl or cyclobutyl, methylaminocyclopropyl, dimethylaminocyclopropyl, trifluoromethylaminocyclopropyl and the like.

In a more specific embodiment, R ₃ is -C ₃ -C ₅ cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl.

In one embodiment of the above preferred compounds of formula (I), R ₃ is -NR _a R _a , wherein R _{a is independently selected from H or C 1} -C ₃ alkyl optionally substituted with one or more halogens, _{Alternatively two R a} attached to the same N atom may together with the N atom to which they are attached form a 4-7 membered nitrogen-containing heterocycloalkyl group. Specific examples include, but are not limited to, _{-NH 2, -NHCH 3, -NCH 3} CH 3, -N (CH 2 CH 3) CH 3, -N (CH 2 CH 3) (CH 2 CH 3) -, - NHCF ₃ , -N(CH ₃ )CF ₃ , -N(CF ₃ )CF ₃ , -N(CH ₂ CF ₃ )CF ₃ or -N(CH ₂ CF ₃ )(CH ₂ CF ₃ )-, -NH( CH ₂ CH ₂ CH _3), azetidinyl, pyrrolidinyl, piperidinyl and the like.

In the embodiment above preferred embodiment a compound of formula (I), R _{4 is} -C ₁ -C ₃ alkyl is optionally substituted with halo. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, and the like.

In a more specific embodiment, R ₄ is -C ₁ -C ₃ alkyl, such as methyl, ethyl, propyl or isopropyl.

In a more specific embodiment, R ₄ is -C ₁ -C ₃ alkyl, substituted with -NR _a R _a , wherein R _{a is} selected from H or C ₁ -C ₃ alkyl optionally substituted with halogen, or Two R _a attached to the same N atom can form, together with the N atom to which they are attached, a 4-7 membered nitrogen-containing heterocycloalkyl group. Specific examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, dimethylaminomethyl, methylethylaminomethyl, azetidinemethyl, pyrrolidinylmethyl base, piperidinylmethyl, etc.

In one embodiment of the above preferred compounds of formula (I), R ₄ is -NR _a R _a , wherein R _{a is} selected from H or C ₁ -C ₃ alkyl optionally substituted with halogen, or attached to the same N The two R _a on the atom can together with the N atom to which they are attached form a 4-7 membered nitrogen-containing heterocycloalkyl group. Specific examples include, but are not limited to, _{-NH 2, -NHCH 3, -NCH 3} CH 3, -N (CH 2 CH 3) CH 3, -N (CH 2 CH 3) (CH 2 CH 3) -, - NHCF ₃ , -N(CH ₃ )CF ₃ , -N(CF ₃ )CF ₃ , -N(CH ₂ CF ₃ )CF ₃ or -N(CH ₂ CF ₃ )(CH ₂ CF ₃ )-, -NH( CH ₂ CH ₂ CH _3), azetidinyl, pyrrolidinyl, piperidinyl and the like.

In the embodiment above preferred embodiment a compound of formula (I), R ₅ is and R ₆ are each independently selected from halo substituted C ₁ -C ₃ alkyl. In a more specific embodiment, R ₅ and R ₆ are each independently selected from C ₁ -C ₃ alkyl substituted with at least three halogens. In a more specific embodiment, R ₅ and R _{6 are each independently C 1} -C ₃ alkyl substituted with at least three Fs. Specific examples include, but are not limited to, trifluoromethyl, trifluoroethyl, pentafluoroethyl, and the like. In a most specific embodiment, R ₅ and R ₆ are -CF _3.

It should be noted that the above-mentioned preferred compound of formula (I) covers each independent embodiment or each specific embodiment, and also covers an embodiment formed by any combination or sub-combination of each of the above-mentioned embodiments or specific embodiments.

。Preferred embodiments of the compounds of the present invention include the following compounds, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates,

.

The beneficial effects of the present invention

The present invention provides a class of biaryl compounds with the structure of general formula (I). It is found through research that such compounds can effectively inhibit the RORγt protein receptor, thereby regulating the differentiation of Th17 cells, inhibiting the production of IL-17, and can be used as a Immunomodulators are used in the treatment of diseases related to Th17 cell differentiation.

The compounds of the present invention have the following beneficial effects: have high inhibitory activity on the RORγt receptor; regulate the differentiation of Th17 cells, inhibit the production of IL-17; and/or have good pharmacokinetic properties, such as longer t _1/2, so that for example, increase the dosing interval, longer half-life, better patient compliance; AUC0-last data has improved, better medicine, higher bioavailability; and / Or good safety, such as membrane permeability, P450 (reduced risk of drug interaction), solubility and other excellent properties.

Compounds of the invention for use in therapy or as a medicament

In one aspect, the present invention provides compounds of the present invention for use as medicaments, particularly as RORyt inhibitors.

In another aspect, the present invention provides compounds of the present invention for use in the treatment, especially in the treatment and/or prevention of diseases associated with RORyt.

In a specific embodiment, the present invention provides the present invention for the treatment and/or prevention of diseases in which RORγt contributes to the occurrence and progression of the disease or where inhibition of RORγt will reduce the incidence of the disease, reduce or eliminate the symptoms of the disease Compounds of the invention, such as inflammatory or autoimmune diseases, cancer, etc., including but not limited to psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, systemic erythema Lupus, 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, dermatomuscular allergic rhinitis, necrotizing enterocolitis, liver fibrosis, nonalcoholic steatohepatitis (NASH), new coronavirus pneumonia, insulin Dependent type I diabetes, triple-negative breast cancer and prostate cancer, etc.

Pharmaceutical compositions and their administration

On the other hand, in order to use the compounds of the present specification for therapeutic or prophylactic purposes, the compounds of the present invention can be formulated into pharmaceutical compositions according to standard pharmaceutical practice. Meanwhile, based on the good pharmacokinetic properties, improved AUCO-last and good druggability of the compounds of the present invention, medicines with better pharmacokinetic properties and higher bioavailability can be prepared from the compounds of the present invention.

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

In a specific embodiment, the pharmaceutical composition of the present invention is provided for the prevention or treatment of a disease associated with RORγt in a mammal such as a human subject.

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

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

The choice of excipients for inclusion 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 Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004, including for example Adjuvants, diluents (eg glucose, lactose or mannitol), carriers, pH adjusters, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents , preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, perfuming agents, flavoring agents, other known additives.

The pharmaceutical compositions of the present invention can 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, wherein parenteral infusion includes 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, for example, as 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 on a range of factors, including the individual being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. In general, effective doses range from about 0.0001 to about 5000 mg per kg body weight per day, eg, about 0.01 to about 1000 mg/kg/day (single or divided administration). For a 70 kg person, this would add up to about 0.007 mg/day to about 7000 mg/day, eg, about 0.7 mg/day to about 1500 mg/day. Depending on the mode of administration, the content or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, for example 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.; accordingly, the pharmaceutical composition of the present invention will comprise 0.05 to 99% w/w (weight percent), such as 0.05 to 80% w/w, such as 0.10 to 70% w /w, eg 0.10 to 50% w/w of a compound of the invention, all weight percentages are based on the total composition. It will be understood that it may be necessary in certain circumstances to use doses above these limits.

In one 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 presented in unit dosage form, eg, in the form of a tablet, capsule, or oral liquid. Such unit dosage forms may contain 0.1 mg to 1 g, eg, 5 mg to 250 mg, of a compound of the present invention as the active ingredient.

In one 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 can be in the form of, for example, creams, lotions, ointments or transdermal patches.

In one 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. Administration by inhalation can be by oral inhalation or intranasal administration. When administered by oral inhalation, the compounds of the present invention can be effectively used in the present invention in daily doses, eg up to 500 μg, such as 0.1-50 μg, 0.1-40 μg, 0.1-30 μg, 0.1-20 μg or 0.1-10 μg of the present invention compound. Pharmaceutical compositions of the present invention for oral inhalation may be formulated as dry powders, suspensions (in liquid or gas) or solutions (in liquid), and may be in any suitable form and using any suitable inhaler known in the art Device administration includes, for example, metered dose inhalers (MDIs), dry powder inhalers (DPIs), nebulizers, and soft mist inhalers. Multi-chamber devices can be used to deliver the compounds of the present specification and one or more other active ingredients, when present.

Treatment methods and uses

Based on the beneficial effects possessed by the compounds of the present invention as described above, the compounds of the present invention can be used in methods of treating various disorders in animals, especially mammals such as humans.

Thus, in another aspect, the present invention provides a method of modulating, especially inhibiting, the activity of RORyt, the method comprising contacting a cell with a compound of the invention as previously described to modulate, especially inhibit, the activity of RORyt in the cell.

In another aspect, the present invention provides a method of preventing or treating a disease associated with RORγt (eg, a disease treatable or preventable by inhibition of RORγt), the method comprising administering to an individual in need thereof an effective amount of the present invention as previously described A compound of the invention or a pharmaceutical composition of the invention comprising the same.

In another aspect, the present invention provides the use of a compound of the present invention as previously described, or a pharmaceutical composition comprising the same, for inhibiting RORγt activity, or for treating and/or preventing a disease associated with RORγt, for example by RORγt inhibition Treatable or preventable disease.

On the other hand, the present invention also provides the use of the aforementioned compound of the present invention or the pharmaceutical composition comprising the same in the preparation of medicines, especially the use of medicines with RORγt receptor inhibitory activity.

In another aspect, the present invention provides the use of a compound of the present invention as previously described, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment or prevention of a disease associated with RORγt, such as a disease treatable or preventable by inhibition of RORγt , wherein the compound or pharmaceutical composition is optionally combined with one or more chemotherapy or immunotherapy.

drug 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 drug or therapy may have or produce the same or different pharmacological efficacy, provided that it does not result in an undesired reduction in activity, adverse interactions or side effects when used in combination with the compounds of the present invention.

Thus, in another aspect, the present invention provides pharmaceutical combinations comprising a compound of the present invention as previously described and one or more other drugs or therapies acting through the same or a different mechanism of action, or a combination of both. In a specific embodiment, the pharmaceutical combination is used to inhibit RORyt activity, or to treat and/or prevent a disease associated with RORyt.

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

Accordingly, in particular embodiments, the present invention also provides kits comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of the present invention, the remainder comprising other active agents used in combination, and each A device containing the composition. The kits of the invention are particularly suitable for administering different dosage forms, such as oral and parenteral dosage forms, or for administering different compositions at different dosage intervals.

In the pharmaceutical combinations of the present invention, suitable amounts of the compounds of the present invention and other active agents in combination can generally be determined by those skilled in the art, for example, from the dosage ranges of the compounds described in this specification and the approved or published dosage ranges of the other active compounds. Determined initially, the doses of other drugs co-administered will, of course, vary depending on factors such as the type of co-drug used, the specific drug used, the condition being treated, the general health of the patient, the judgment of the physician or veterinarian, and other factors.

For the pharmaceutical compositions and combinations of the present invention, the other active agent may be one or more of a second or additional (eg, a third) activity that does not adversely affect each other with the compound of the present invention, has an enhanced, complementary activity. ) compounds, for example these active agents may be compounds known to modulate other biologically active pathways, or may be compounds that modulate different components of the biologically active pathways involved in the compounds of the invention, or even biological targets related to the compounds of the invention overlapping compounds.

In a specific embodiment, the present invention provides a pharmaceutical combination, eg, for use as a medicament for the treatment of one of the diseases listed herein, such as psoriasis, COPD, asthma, psoriatic arthritis or ankylosing spine inflammation, comprising a compound of the present invention, and at least one active ingredient selected from the group consisting of: a) β-adrenergic receptor agonists; b) muscarinic receptor antagonists; c) joint muscarinic receptor antagonists and beta-adrenergic receptor agonists; and d) glucocorticoid receptor agonists (steroidal or non-steroidal); e) Phosphodiesterase-4 (PDE4) inhibitor.

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

Accordingly, the present invention provides a method for inhibiting RORγt activity or for treating and/or preventing a disease associated with RORγt, comprising administering to a subject in need thereof a pharmaceutical combination of the present invention. The present invention also provides the use of the pharmaceutical combination of the present invention in preparing a medicament for inhibiting RORγt activity or for treating and/or preventing RORγt-related diseases.

For the various aspects described above involving pharmaceutical compositions, methods of treatment and uses, and pharmaceutical combinations, diseases associated with RORγt (eg, diseases treatable or preventable by inhibition of RORγt) include inflammatory or autoimmune diseases, cancers, and the like, including but not limited to silver 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, Behçet's disease, atopic dermatitis, acne, scleroderma, bronchitis, dermatitis rhinitis, necrotizing enterocolitis, liver fibrosis, nonalcoholic steatohepatitis (NASH), new coronavirus pneumonia, insulin-dependent type I diabetes, triple-negative breast cancer and prostate cancer, etc. Preferred RORγt-related diseases are selected from the group consisting of psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, inflammatory bowel disease, dry eye, atopic dermatitis, chronic Obstructive pulmonary disease (COPD), asthma, necrotizing enterocolitis, liver fibrosis, nonalcoholic steatohepatitis (NASH), COVID-19, triple-negative breast cancer and prostate cancer.

For the above-mentioned compounds, pharmaceutical compositions, methods, uses, pharmaceutical combinations of the present invention, the preferred compounds of formula (I), their stereoisomers, tautomers, stable isotopic variants, pharmaceutical acceptable salts or solvates of the above; more preferably the specific compounds listed above, eg, compounds 1-13, or their pharmaceutically acceptable salts or solvates.

When dosages of a compound or drug are described herein for administration, it is to be understood that such dosages are based on the weight of the free base, excluding any derived ingredients thereof, unless the specification indicates otherwise.

Synthesis of Compounds of the Invention

In another aspect, the present invention also provides a method for the preparation of compounds of formula (I). The general synthetic schemes for synthesizing the compounds of the present invention are exemplified below. For each reaction step, appropriate reaction conditions 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 unless otherwise specified, or can be prepared by the methods below, methods analogous to those given below, or methods known in the art. If necessary, the raw materials and intermediates in the synthetic reaction scheme can be separated and purified by conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. The materials can be characterized using conventional methods including physical constants and spectral data.

其中R₁ 、R₂ 、R₃ 、R₄ 、R₅ 、R₆ 、m和p如上面對通式(I)所定義；Prot是氨基保護基，包括但不限於Boc、Cbz、Fmoc或PMB，優選Boc； 步驟1：式(I-1)化合物生成游離或鹽形式的式(I-2)化合物；該反應優選在氫溴酸(例如40%氫溴酸水溶液)的作用下進行，優選在適合的溫度進行，例如50-200℃、80-150℃，優選90-120℃；所述鹽形式例如氫溴酸鹽形式； 步驟2：游離或鹽形式的式(I-2)化合物跟式(I-3)化合物環合生成游離或鹽形式的式(I-4)化合物；該反應優選在適當的溶劑中進行，且優選在適當的溫度進行，所述溶劑可選自例如質子溶劑，例如甲醇、乙醇、丙醇等，所述溫度選自例如50-200℃、80-150℃，優選90-120℃；所述鹽形式例如氫溴酸鹽形式； 步驟3：游離或鹽形式的式(I-4)化合物與氨基保護劑生成式(I-5)化合物；其中氨基保護劑是本領域眾所周知的，包括但不限於二碳酸二第三丁酯((Boc)₂ O)、CbzCl、FmocCl或PMB-Cl，所述反應優選在適合的有機溶劑中進行，所述有機溶劑可選自四氫呋喃、醚類(例如乙醚、乙二醇單甲醚等)、N -甲基吡咯烷酮、N,N -二甲基甲醯胺、N,N -二甲基乙醯胺、二氯甲烷、1,4-二氧六環、二甲基亞碸及其任意組合，優選四氫呋喃；所述反應優選在適合的鹼存在下進行，所述的鹼可選自碳酸鈉、碳酸鉀、碳酸銫、N ,N -二異丙基乙胺、三乙胺、HOBt或吡啶，優選地，所述的鹼是三乙胺；所述反應優選在適合的溫度進行，例如0-200℃、5-100℃、10-50℃，優選室溫； 步驟4：式(I-5)化合物跟Tf試劑反應生成式(I-6)化合物；所述Tf試劑是能與羥基反應生成OTf基團的試劑，包括但不限於三氟甲磺酸酐、三氟甲磺醯氯或N -苯基雙(三氟甲磺醯)亞胺；所述反應優選在鹼存在下進行，所述的鹼可選自碳酸鈉、碳酸鉀、碳酸銫、N ,N -二異丙基乙胺、三乙胺、HOBt或吡啶；所述反應優選在有機溶劑中進行，所述有機溶劑可選自二氯甲烷、四氫呋喃、醚類(例如乙醚、乙二醇單甲醚等)、N -甲基吡咯烷酮、N,N -二甲基甲醯胺、N,N -二甲基乙醯胺、1,4-二氧六環、二甲基亞碸及其任意組合，優選二氯甲烷；所述反應優選在適合的溫度下進行，例如-50℃至200℃、-20℃至100℃、例如-10℃至50℃，例如-10℃至10℃，優選在冰浴中；所述反應優選在惰性氣體氣氛下進行，所述惰性氣體包括但不限於氮氣、氬氣或氦氣等； 步驟5：式(I-6)化合物跟式(I-7)的化合物在催化劑、如鈀催化劑的作用下通過偶聯得到式(I-8)化合物； 其中所述鈀催化劑是本領域眾所周知的用於偶聯的鈀催化劑，包括但不限於Pd₂ (dba)₃ 等；所述反應優選在適合的有機溶劑中進行，所述有機溶劑可選自四氫呋喃、醚類(例如乙醚、乙二醇單甲醚等)、N -甲基吡咯烷酮、N,N -二甲基甲醯胺、N,N -二甲基乙醯胺、二氯甲烷、1,4-二氧六環、二甲基亞碸及其任意組合，優選1,4-二氧六環；所述反應優選在膦配位基存在下進行，所述膦配位基包括但不限於4,5-雙二苯基膦-9,9-二甲基氧雜蒽；所述反應優選在適合的鹼存在下進行，所述的鹼可選自碳酸鈉、碳酸鉀、碳酸銫、N ,N -二異丙基乙胺、三乙胺、HOBt或吡啶，優選地，所述的鹼是N ,N -二異丙基乙胺；所述反應優選在適合的溫度下進行，例如50-200℃、80-150℃，優選90-120℃； 步驟6：式(I-8)化合物在氧化劑的作用下生成式(I-9)化合物；所述氧化劑選自例如H₂ O₂ 、mCPBA和過氧乙酸；所述反應優選在有機溶劑中進行，所述有機溶劑可選自二氯甲烷、四氫呋喃、醚類(例如乙醚、乙二醇單甲醚等)、N -甲基吡咯烷酮、N,N- 二甲基甲醯胺、N,N- 二甲基乙醯胺、1,4-二氧六環、二甲基亞碸及其任意組合，優選二氯甲烷；所述反應優選在適合的溫度下進行，例如-50℃至200℃、-20℃至100℃、例如-10℃至50℃，例如-10℃至10℃，優選在冰浴中； 步驟7：式(I-9)化合物水解生成式(I-10)化合物；所述反應優選在鹼存在下進行，所述的鹼可選自氫氧化鈉、氫氧化鉀、碳酸鈉、碳酸鉀或碳酸銫，所述鹼優選以水溶液形式應用；所述反應優選在有機溶劑中進行，所述有機溶劑可選自醇溶劑例如(甲醇、乙醇或丙醇)、四氫呋喃、醚類(例如乙醚、乙二醇單甲醚等)、N -甲基吡咯烷酮、N,N -二甲基甲醯胺、N,N -二甲基乙醯胺、1,4-二氧六環、二甲基亞碸及其任意組合，優選甲醇；所述反應優選在適合的溫度下進行，例如-20℃至-200℃、5-100℃、10-50℃，優選室溫； 步驟8：式(I-10)化合物在縮合劑的作用下跟式(I-11)化合物反應生成式(I-12)化合物； 其中所述縮合劑是本領域眾所周知的用於羧酸與胺偶聯的縮合劑，包括但不限於1-丙基磷酸酐(T3P)、EDC、DCC、HATU等；所述反應優選在適合的有機溶劑中進行，所述有機溶劑可選自二氯甲烷、四氫呋喃、醚類(例如乙醚、乙二醇單甲醚等)、N -甲基吡咯烷酮、N,N -二甲基甲醯胺、N,N -二甲基乙醯胺、1,4-二氧六環、二甲基亞碸及其任意組合，優選二氯甲烷；所述反應優選在適合的鹼存在下進行，所述的鹼包括但不限於碳酸鈉、碳酸鉀、碳酸銫、N ,N -二異丙基乙胺、三乙胺、HOBt或吡啶，優選地，所述的鹼是N ,N -二異丙基乙胺；所述反應優選在適合的溫度下進行，例如0-200℃、10-100℃或20-50℃，優選室溫(20-25℃)。In one embodiment, the method comprises the steps of: Scheme 1:

wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , m and p are as defined above for formula (I); Prot is an amino protecting group including but not limited to Boc, Cbz, Fmoc or PMB , preferably Boc; Step 1: The compound of formula (I-1) generates the compound of formula (I-2) in free or salt form; the reaction is preferably carried out under the action of hydrobromic acid (such as a 40% aqueous solution of hydrobromic acid), preferably At a suitable temperature, such as 50-200°C, 80-150°C, preferably 90-120°C; the salt form is, for example, the hydrobromide salt form; Step 2: The compound of formula (I-2) in free or salt form is followed by The compound of formula (I-3) is cyclized to give the compound of formula (I-4) in free or salt form; this reaction is preferably carried out in a suitable solvent, and preferably at a suitable temperature, which can be selected, for example, from protic solvents , such as methanol, ethanol, propanol, etc., the temperature is selected from, for example, 50-200°C, 80-150°C, preferably 90-120°C; the salt form is, for example, the hydrobromide salt form; Step 3: Free or salt form The compound of formula (I-4) and the amino protecting agent generate the compound of formula (I-5); wherein the amino protecting agent is well known in the art, including but not limited to di-tert-butyl dicarbonate ((Boc) ₂ O), CbzCl, FmocCl or PMB-Cl, the reaction is preferably carried out in a suitable organic solvent, the organic solvent can be selected from tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N -methylpyrrolidone, N,N -dimethylformamide, N,N -dimethylacetamide, dichloromethane, 1,4-dioxane, dimethylsulfoxide and any combination thereof, preferably tetrahydrofuran; the The reaction is preferably carried out in the presence of a suitable base, and the base can be selected from sodium carbonate, potassium carbonate, cesium carbonate, N , N -diisopropylethylamine, triethylamine, HOBt or pyridine, preferably, the The base is triethylamine; the reaction is preferably carried out at a suitable temperature, such as 0-200 ° C, 5-100 ° C, 10-50 ° C, preferably room temperature; Step 4: compound of formula (I-5) and Tf reagent The reaction generates a compound of formula (I-6); the Tf reagent is a reagent that can react with a hydroxyl group to generate an OTf group, including but not limited to trifluoromethanesulfonic anhydride, trifluoromethanesulfonic acid chloride or N -phenylbis(trifluoromethanesulfonic acid) fluoromethanesulfonic acid) imide; the reaction is preferably carried out in the presence of a base, and the base can be selected from sodium carbonate, potassium carbonate, cesium carbonate, N , N -diisopropylethylamine, triethylamine, HOBt or pyridine; the reaction is preferably carried out in an organic solvent, which can be selected from dichloromethane, tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N -methylpyrrolidone, N,N - dimethylformamide, N,N -dimethylacetamide, 1,4-dioxane, dimethylsulfoxide and any combination thereof, preferably dichloromethane; the reaction is preferably performed in a suitable temperature, such as -50°C to 200°C, -20°C to 10°C 0°C, eg -10°C to 50°C, eg -10°C to 10°C, preferably in an ice bath; the reaction is preferably carried out under an inert gas atmosphere including but not limited to nitrogen, argon or helium Step 5: The compound of formula (I-6) is coupled with the compound of formula (I-7) under the action of a catalyst, such as a palladium catalyst, to obtain a compound of formula (I-8); wherein the palladium catalyst is this Palladium catalysts well known in the art for coupling, including but not limited to Pd ₂ (dba) ₃ and the like; the reaction is preferably carried out in a suitable organic solvent, which can be selected from tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N -methylpyrrolidone, N,N -dimethylformamide, N,N -dimethylacetamide, dichloromethane, 1,4-dioxane, Dimethyl sulfoxide and any combination thereof, preferably 1,4-dioxane; the reaction is preferably carried out in the presence of phosphine ligands including but not limited to 4,5-bisdiphenyl Phosphine-9,9-dimethylxanthene; the reaction is preferably carried out in the presence of a suitable base, and the base can be selected from sodium carbonate, potassium carbonate, cesium carbonate, N , N -diisopropyl Ethylamine, triethylamine, HOBt or pyridine, preferably, the base is N , N -diisopropylethylamine; the reaction is preferably carried out at a suitable temperature, such as 50-200 ° C, 80-150 ℃, preferably 90-120 ℃; Step 6: The compound of formula (I-8) generates the compound of formula (I-9) under the action of an oxidant; the oxidant is selected from, for example, H ₂ O ₂ , mCPBA and peroxyacetic acid; The reaction is preferably carried out in an organic solvent, which can be selected from dichloromethane, tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N -methylpyrrolidone, N,N -dimethyl Formamide, N,N -dimethylacetamide, 1,4-dioxane, dimethylsulfoxide and any combination thereof, preferably dichloromethane; the reaction is preferably carried out at a suitable temperature, For example -50°C to 200°C, -20°C to 100°C, for example -10°C to 50°C, for example -10°C to 10°C, preferably in an ice bath; Step 7: The compound of formula (I-9) is hydrolyzed to form the formula (I-10) compound; the reaction is preferably carried out in the presence of a base, and the base can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, and the base is preferably applied in the form of an aqueous solution; The reaction is preferably carried out in an organic solvent, which can be selected from alcohol solvents such as (methanol, ethanol or propanol), tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N -methyl Pyrrolidone, N,N -dimethylformamide, N,N -dimethylacetamide, 1,4-dioxane, dimethylsulfoxide and any combination thereof, preferably methanol; the reaction is preferably Carry out at a suitable temperature, such as -20°C to -200°C, 5-100°C, 10-50°C, preferably room temperature; Step 8: Compound of formula (I-10) in the condensation agent react with the compound of formula (I-11) under the action to generate the compound of formula (I-12); wherein the condensing agent is a condensing agent well known in the art for coupling carboxylic acid and amine, including but not limited to 1-propyl Phosphoric anhydride (T3P), EDC, DCC, HATU, etc.; the reaction is preferably carried out in a suitable organic solvent, which can be selected from dichloromethane, tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether) etc.), N -methylpyrrolidone, N,N -dimethylformamide, N,N -dimethylacetamide, 1,4-dioxane, dimethylsulfoxide and any combination thereof, Dichloromethane is preferred; 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 , N -diisopropylethylamine, triethylamine, HOBt or pyridine, preferably, the base is N , N -diisopropylethylamine; the reaction is preferably carried out at a suitable temperature, such as 0-200°C, 10-100°C or 20-50°C, preferably Room temperature (20-25°C).

Step 9: The compound of formula (I-12) removes the amino protecting group to generate the compound of formula (I-13); the reaction is carried out, for example, under the action of an acid (such as TFA or HCl), and the reaction is preferably carried out in a suitable organic The organic solvent can be selected from dichloromethane, tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N -methylpyrrolidone, N,N -dimethylformamide, N , N -dimethylacetamide, 1,4-dioxane, dimethyl sulfoxide and any combination thereof, preferably dichloromethane; the reaction is preferably carried out at a suitable temperature, such as -50°C to 200°C, -20°C to 100°C, eg -10°C to 50°C, eg -10°C to 20°C; Step 10: Compound of formula (I-13) with formula (I-14) or its activated form (eg corresponding to The acyl chloride (formula (I-15) or acid anhydride) reacts to generate the target compound Ia; the reaction is preferably carried out in the presence of a base, and the base can be selected from sodium carbonate, potassium carbonate, cesium carbonate, N , N -dicarbonate Isopropylethylamine, triethylamine, HOBt or pyridine; the reaction is preferably carried out in an organic solvent, which can be selected from dichloromethane, tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc. ), N -methylpyrrolidone, N,N -dimethylformamide, N,N -dimethylacetamide, 1,4-dioxane, dimethylsulfoxide and any combination thereof, preferably Dichloromethane; the reaction can be carried out in the presence of, for example, a condensing agent, wherein the condensing agent is a condensing agent well known in the art for coupling carboxylic acids with amines, including but not limited to 1-propylphosphoric anhydride ( T3P), EDC, DCC, HATU; the reaction is preferably carried out at a suitable temperature, such as 0-200°C, 10-100°C or 20-50°C, preferably room temperature (20-25°C).

其中R₁ 、R₂ 、R₃ 、R₄ 、R₅ 、R₆ 、m和p如上面對通式(I)所定義；Prot是氨基保護基，包括但不限於Boc、Cbz、Fmoc或PMB，優選Boc； 步驟1：式(II-1)化合物與R₄ SH或其鹽(例如鈉鹽)反應生成式(II-2)化合物；所述反應優選在惰性氣體氣氛下進行，所述惰性氣體包括但不限於氮氣、氬氣或氦氣等； 步驟2：式(II-2)化合物與氨基保護劑反應生成式(II-3)化合物；其中氨基保護劑是本領域眾所周知的，包括但不限於二碳酸二第三丁酯((Boc)₂ O)、CbzCl、FmocCl或PMB-Cl；所述反應優選在適合的鹼存在下進行，所述的鹼可選自碳酸鈉、碳酸鉀、碳酸銫、N ,N -二異丙基乙胺、三乙胺、HOBt、吡啶或4-二甲氨基吡啶； 步驟3：式(II-3)化合物氧化劑的作用下氧化生成式(II-4)化合物；所述氧化劑選自例如H₂ O₂ 、mCPBA和過氧乙酸； 步驟4：式(II-4)化合物在還原劑的作用下還原生成式(II-5)化合物；所述還原劑例如選自DABAL-H、四氫鋁鋰或硼氫化鈉；所述反應優選在惰性氣體氣氛下進行，所述惰性氣體包括但不限於氮氣、氬氣或氦氣等； 步驟5：式(II-5)化合物與甲醇或其活化形式(例如甲醇鈉)反應生成式(II-6)化合物；所述反應優選在4-甲基苯磺酸吡啶(PPTS)存在下進行； 步驟6：式(II-6)化合物跟烷基氰矽烷(例如TMSCN)反應生成式(II-7)化合物；所述反應優選在三氟化硼乙醚存在下進行；所述反應優選在惰性氣體氣氛下進行，所述惰性氣體包括但不限於氮氣、氬氣或氦氣等； 步驟7：式(II-7)化合物脫除氨基保護基生成式(II-8)化合物；所述反應例如在酸(如TFA或者HCl)的作用下進行； 步驟8：式(II-8)化合物與R₃ COOH或其活化形式例如相應的醯氯或酸酐反應生成式(II-9)化合物；所述反應優選在鹼存在下進行，所述的鹼可選自碳酸鈉、碳酸鉀、碳酸銫、N ,N -二異丙基乙胺、三乙胺、HOBt或吡啶；所述反應可在例如縮合劑等存在下進行，其中所述縮合劑是本領域眾所周知的用於羧酸與胺偶聯的縮合劑，包括但不限於1-丙基磷酸酐(T3P)、EDC、DCC、HATU； 步驟9：式(II-9)化合物水解生成式(II-10)化合物；所述反應優選在鹼存在下進行，所述的鹼可選自氫氧化鈉、氫氧化鉀、碳酸鈉、碳酸鉀或碳酸銫； 步驟10：式(II-10)化合物在縮合劑的作用下跟式(I-11)化合物反應生成目標化合物式(I-b)化合物； 其中所述縮合劑是本領域眾所周知的用於羧酸與胺偶聯的縮合劑，包括但不限於T3P、EDC、DCC、HATU或N,N,N',N' -四甲基氯甲脒六氟磷酸鹽等；所述反應優選在適合的鹼存在下進行，所述的鹼包括但不限於碳酸鈉、碳酸鉀、碳酸銫、N ,N -二異丙基乙胺、三乙胺、N -甲基咪唑、HOBt或吡啶； 上述步驟中的反應優選在有機溶劑中進行，所述有機溶劑可選自醇溶劑例如(甲醇、乙醇或丙醇)、四氫呋喃、醚類(例如乙醚、乙二醇單甲醚等)、N -甲基吡咯烷酮、N,N -二甲基甲醯胺、N,N -二甲基乙醯胺、1,4-二氧六環、二氯甲烷、二甲基亞碸及其任意組合；對於水解反應可以使用有機溶劑與水的混合物； 上述步驟中的反應優選在適合的溫度下進行，例如-100℃至0℃、-80℃至-20℃、-50℃至200℃、-20℃至100℃、-20℃至20℃、-10℃至20℃、-10℃至50℃、0-200℃、10-100℃、20-50℃或室溫(20-25℃)。In one embodiment, the method comprises the steps of: Scheme 2:

wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , m and p are as defined above for formula (I); Prot is an amino protecting group including but not limited to Boc, Cbz, Fmoc or PMB , preferably Boc; Step 1: The compound of formula (II-1) reacts with R ₄ SH or its salt (eg, sodium salt) to form the compound of formula (II-2); the reaction is preferably carried out under an inert gas atmosphere, and the inert gas Gases include but are not limited to nitrogen, argon or helium, etc.; Step 2: The compound of formula (II-2) reacts with an amino protecting agent to form a compound of formula (II-3); wherein the amino protecting agent is well known in the art, including but not limited to: Not limited to di-tert-butyl dicarbonate ((Boc) ₂ O), CbzCl, FmocCl or PMB-Cl; the reaction is preferably carried out in the presence of a suitable base, which can be selected from sodium carbonate, potassium carbonate, Cesium carbonate, N , N -diisopropylethylamine, triethylamine, HOBt, pyridine or 4-dimethylaminopyridine; Step 3: Oxidation of the compound of formula (II-3) under the action of an oxidant to generate formula (II-4) ) compound; the oxidizing agent is selected from, for example, H ₂ O ₂ , mCPBA and peracetic acid; Step 4: The compound of formula (II-4) is reduced under the action of a reducing agent to form a compound of formula (II-5); the reducing agent For example, it is selected from DABAL-H, lithium aluminum tetrahydrogen or sodium borohydride; the reaction is preferably carried out under an inert gas atmosphere, and the inert gas includes but is not limited to nitrogen, argon or helium, etc.; Step 5: Formula (II -5) The compound is reacted with methanol or its activated form (eg, sodium methoxide) to form the compound of formula (II-6); the reaction is preferably carried out in the presence of pyridine 4-methylbenzenesulfonate (PPTS); Step 6: Formula ( II-6) The compound is reacted with an alkyl cyanosilane (such as TMSCN) to form the compound of formula (II-7); the reaction is preferably carried out in the presence of boron trifluoride ether; the reaction is preferably carried out under an inert gas atmosphere, so The inert gas includes but is not limited to nitrogen, argon or helium, etc.; Step 7: The compound of formula (II-7) removes the amino protecting group to generate the compound of formula (II-8); the reaction is, for example, in an acid (such as TFA or HCl); Step 8: The compound of formula (II-8) reacts with R ₃ COOH or its activated form such as the corresponding acyl chloride or acid anhydride to form the compound of formula (II-9); the reaction is preferably in the presence of a base Carry out, described base can be selected from sodium carbonate, potassium carbonate, cesium carbonate, N , N -diisopropylethylamine, triethylamine, HOBt or pyridine; Described reaction can be carried out in the presence of for example condensing agent etc., Wherein the condensing agent is a condensing agent well known in the art for coupling carboxylic acid and amine, including but not limited to 1-propylphosphoric anhydride (T3P), EDC, DCC, HATU; Step 9: Formula (II-9 ) compound is hydrolyzed to generate the compound of formula (II-10); the reaction is preferably carried out in the presence of a base, and the base can be selected from the group consisting of hydroxide Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate; Step 10: The compound of formula (II-10) reacts with the compound of formula (I-11) under the action of a condensing agent to generate the target compound of formula (Ib); Wherein the condensing agent is a condensing agent well known in the art for coupling carboxylic acid and amine, including but not limited to T3P, EDC, DCC, HATU or N,N,N',N' -tetramethylchloroformamidine Hexafluorophosphate, etc.; the reaction is preferably carried out in the presence of a suitable base, and the base includes but is not limited to sodium carbonate, potassium carbonate, cesium carbonate, N , N -diisopropylethylamine, triethylamine, N -methylimidazole, HOBt or pyridine; The reaction in the above steps is preferably carried out in an organic solvent, and the organic solvent can be selected from alcohol solvents such as (methanol, ethanol or propanol), tetrahydrofuran, ethers (such as diethyl ether, ethyl alcohol) glycol monomethyl ether, etc.), N -methylpyrrolidone, N,N -dimethylformamide, N,N -dimethylacetamide, 1,4-dioxane, dichloromethane, dichloromethane Methylidene and any combination thereof; for the hydrolysis reaction, a mixture of an organic solvent and water can be used; the reaction in the above steps is preferably carried out at a suitable temperature, such as -100°C to 0°C, -80°C to -20°C, -50°C to 200°C, -20°C to 100°C, -20°C to 20°C, -10°C to 20°C, -10°C to 50°C, 0-200°C, 10-100°C, 20-50°C or Room temperature (20-25°C).

The above synthetic scheme only exemplifies the preparation methods of some compounds in the present invention. The compounds of the present invention, or stereoisomers, tautomers, stable isotopic derivatives, pharmaceutically acceptable salts or solvates thereof, can be obtained by a variety of methods, including the methods given above, and given in the Examples The method or the similar method can be prepared by those of ordinary skill in the art on the basis of the above-mentioned synthetic scheme and conventional techniques in the art.

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

detailed description

The technical solutions of the present invention will be further described below with reference to specific embodiments, but the protection scope of the present invention is not limited to these embodiments. All changes or equivalent substitutions that do not depart from the concept of the present invention are included in the protection scope of the present invention.

The experimental methods without specific conditions in the following examples are generally in accordance with the conventional conditions of this type of reaction, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise specified. Unless otherwise stated, ratios of liquids are by volume.

Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial sources, prepared according to methods in the prior art, or prepared according to methods similar to those disclosed in this application.

The chemical names used in this application are IUPAC names and the abbreviations used have the 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: PdCl ₂ (dtbpf): 1,1'-di-tert-butylphosphinoferrocene palladium dichloride Pd(dppf)Cl ₂ : [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride xantphos: 4,5-bisdiphenylphosphino-9,9-dimethylxanthene Pd ₂ (dba) ₃ : tris(dibenzylidene) (ylacetone)dipalladium HATU: 2-(7-azobenzotriazole) -N , N , N ', N' -tetramethylurea hexafluorophosphate DIEA: N , N -diisopropylethyl acetate Amine DMF: N,N -Dimethylformamide DMSO: dimethylsulfoxide DCM: dichloromethane 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 TCFH: N, N, N ' , N' - tetramethyl chloroformate hexafluorophosphate Ret .time: retention time

Synthesis Example

In the preparation method of the target compound provided by the present invention, silica gel (300-400 mesh) produced by Rushan Sun Desiccant Co., Ltd. is used for column chromatography; GF254 (0.25 mm) is used for thin layer chromatography; Varian is used for nuclear magnetic resonance spectroscopy (NMR) Measured by -400 nuclear magnetic resonance apparatus; liquid mass spectrometry (LC/MS) used Agilent TechnologiESI 6120 liquid mass spectrometer.

In addition, all operations involving easily oxidizable or easily hydrolyzed raw materials are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention are all commercially available raw materials, which can be used directly without further purification, and the temperatures used in the present invention are all 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 used, unless it can be determined from the context that the name of the compound is correct.

Example 1 and Example 2: R -2-Acetyl- N- (2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2- base)-[1,1'-biphenyl]-4-yl)-5-(methylsulfonyl)isoindoline-1-carboxamide or S -2-acetyl- N- (2 '-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-5- (Methylsulfonyl)isoindoline-1-carboxamide

Synthesis of Intermediate 2-(4'-Amino-2-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

依次將4-溴-3-氟苯甲酸(30.0g，137mmol)，五氟苯酚(28.2g，153mmol)和二環己基碳二亞胺(31.9g，155mmol)溶於無水四氫呋喃(900mL)中。反應混合物在室溫下攪拌過夜，TLC監測反應完全。將反應液過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE：EA=10:1)，得到目標化合物(56.0g，粗品，白色固體)。Step 1: Synthesis of perfluorophenyl 4-bromo-3-fluorobenzoate

4-Bromo-3-fluorobenzoic acid (30.0 g, 137 mmol), pentafluorophenol (28.2 g, 153 mmol) and dicyclohexylcarbodiimide (31.9 g, 155 mmol) were sequentially dissolved in dry tetrahydrofuran (900 mL). The reaction mixture was stirred at room temperature overnight and completed by TLC. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by silica gel column (PE:EA=10:1) to obtain the target compound (56.0 g, crude product, white solid).

將全氟苯基4-溴-3-氟苯甲酸酯(56.0g，145mmol)溶於甲苯(725mL)中。在冰浴下，依次將(三氟甲基)三甲基矽烷(131mL，873mmol)和1mol/L四丁基氟化銨四氫呋喃溶液(50.9mL，50.9mmol)滴加到反應液中。加完後，不撤掉冰浴，讓反應液緩慢升到室溫攪拌反應過夜，TLC監測反應完全。將反應液倒入冰的1mol/L稀鹽酸(1.5L)中，用甲基第三丁基醚(700mLx2)萃取，合併有機相，用飽和食鹽水(1.5L)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到目標化合物(60.0g，粗品，棕色油狀物)。Step 2: Synthesis of ((2-(4-Bromo-3-fluorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)trimethylsilane

Perfluorophenyl 4-bromo-3-fluorobenzoate (56.0 g, 145 mmol) was dissolved in toluene (725 mL). Under an ice bath, (trifluoromethyl)trimethylsilane (131 mL, 873 mmol) and 1 mol/L tetrabutylammonium fluoride tetrahydrofuran solution (50.9 mL, 50.9 mmol) were sequentially added dropwise to the reaction solution. After the addition, the ice bath was not removed, and the reaction solution was slowly raised to room temperature and stirred overnight for reaction. TLC monitored the completion of the reaction. The reaction solution was poured into 1 mol/L dilute hydrochloric acid (1.5 L) in ice, extracted with methyl tert-butyl ether (700 mL×2), the organic phases were combined, washed with saturated brine (1.5 L), and dried over anhydrous sodium sulfate , filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (60.0 g, crude product, brown oil).

將((2-(4-溴-3-氟苯基)-1,1,1,3,3,3-六氟丙烷-2-基)氧基)三甲基矽烷(70.0g，169mmol)溶於四氫呋喃(700mL)中，在室溫下，將6mol/L稀鹽酸(350mL)緩慢滴加到反應液中。加完後，在室溫下繼續攪拌反應過夜，LC-MS監測反應完全。將反應液倒入水(500mL)中，用甲基第三丁基醚(500mLx2)萃取，合併有機相，用飽和食鹽水(1L)洗滌，用無水硫酸鈉乾燥，將反應液過濾，濾液減壓濃縮，得到目標化合物(46.2g，粗品，黃色油狀物)。LC-MS (ESI) m/z: 338.9 [M-H]^- 。Step 3: Synthesis of 2-(4-Bromo-3-fluorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol

((2-(4-Bromo-3-fluorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)trimethylsilane (70.0 g, 169 mmol) It was dissolved in tetrahydrofuran (700 mL), and 6 mol/L dilute hydrochloric acid (350 mL) was slowly added dropwise to the reaction solution at room temperature. After the addition, the reaction was continued to stir at room temperature overnight, and the reaction was completed by LC-MS monitoring. The reaction solution was poured into water (500 mL), extracted with methyl tert-butyl ether (500 mL×2), the organic phases were combined, washed with saturated brine (1 L), and dried over anhydrous sodium sulfate, the reaction solution was filtered, and the filtrate was reduced Concentration under pressure gave the title compound (46.2 g, crude product, yellow oil). LC-MS (ESI) m/z: 338.9 [MH] ^- .

依次將2-(4-溴-3-氟苯基)-1,1,1,3,3,3-六氟丙烷-2-醇(46.2g，135mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯胺(23.7g，108mmol)，碳酸鉀(37.4g，271mmol)和Pd(dppf)Cl₂ (4.96g，6.77mmol)溶於1,4-二氧六環(500mL)和水(50mL)的混合溶劑中。在氮氣保護下，反應混合物在100℃下攪拌反應2小時，LC-MS監測反應完全。將反應液過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE：EA=10:1-6:1)得到粗品，再經二氯甲烷打漿，得到目標化合物(20.0g，產率，白色固體)。LC-MS (ESI) m/z: 395.0 [M+ ACN+ H]⁺ 。Step 4: 2-(4'-Amino-2-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3,3-hexafluoropropane-2- Synthesis of alcohols

2-(4-Bromo-3-fluorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (46.2 g, 135 mmol), 4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (23.7 g, 108 mmol), potassium carbonate (37.4 g, 271 mmol) and Pd(dppf)Cl ₂ (4.96 g, 6.77 mmol) was dissolved in a mixed solvent of 1,4-dioxane (500 mL) and water (50 mL). Under nitrogen protection, the reaction mixture was stirred at 100 °C for 2 hours, and the reaction was complete as monitored by LC-MS. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by a silica gel column (PE:EA=10:1-6:1) to obtain a crude product, which was then slurried with dichloromethane to obtain the target compound (20.0 g, yield, white solid). LC-MS (ESI) m/z: 395.0 [M + ACN + H] ⁺ .

Intermediate: Synthesis of 2-Acetyl-5-(methylsulfonyl)isoindoline-1-carboxylic acid

向5-溴異吲哚啉-1-酮(200g，943mmol)的DMF(2.00L)溶液中加入甲硫醇鈉(50%，264g，1886mmol)。氬氣保護，將反應混合物在110℃下攪拌1小時，停止反應。將反應液冷卻至室溫後倒入冰水(6.00L)中，得到黃色懸浮液。懸浮液過濾後用清水(1.50L)洗滌，得到濾渣。將濾渣溶於DCM(5.00L)中得到黃色溶液。將溶液用無水硫酸鈉乾燥、過濾，濾液減壓濃縮，所得殘留物經真空乾燥後，得到目標化合物(140g，產率82.9%，黃色固體)。LC-MS(ESI)m/z 180.1 [M+H]⁺ 。Step 1: Synthesis of 5-Methylthioisoindolin-1-one

To a solution of 5-bromoisoindolin-1-one (200 g, 943 mmol) in DMF (2.00 L) was added sodium methanethiolate (50%, 264 g, 1886 mmol). Under argon, the reaction mixture was stirred at 110°C for 1 hour to quench the reaction. The reaction solution was cooled to room temperature and poured into ice water (6.00 L) to obtain a yellow suspension. The suspension was filtered and washed with clean water (1.50 L) to obtain a filter residue. The filter residue was dissolved in DCM (5.00 L) to give a yellow solution. The solution was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was dried in vacuo to obtain the title compound (140 g, yield 82.9%, yellow solid). LC-MS (ESI) m/z 180.1 [M+H] ⁺ .

向5-甲硫基異吲哚啉-1-酮(140g，782mmol)的DMF(1.40L)溶液中加入二碳酸二第三丁酯(222g，1016mmol)、4-二甲氨基吡啶(124g，1016mmol)。將反應混合液在室溫下攪拌反應1小時，停止反應。將反應液倒入冰水(6.00L)中，得到黃色懸浮液。懸浮液在室溫下攪拌30分鐘後過濾，再用清水(1.00L)洗滌，得到濾渣。將濾渣溶於EA(3.00L)中得到黃色溶液。溶液分別用0.1N稀鹽酸(800mL×2)、清水(800mL)洗滌後，用無水硫酸鈉乾燥、過濾，濾液減壓濃縮，所得殘留物經真空乾燥後，得到目標化合物(210 g，產率96.2%，黃色固體)。LC-MS(ESI)m/z 302.1 [M+Na]⁺ 。Step 2: Synthesis of 5-(methylthio)-1-oxoisoindoline-2-carboxylic acid tert-butyl ester

To a solution of 5-methylthioisoindolin-1-one (140 g, 782 mmol) in DMF (1.40 L) was added di-tert-butyl dicarbonate (222 g, 1016 mmol), 4-dimethylaminopyridine (124 g, 1016 mmol). The reaction mixture was stirred at room temperature for 1 hour to stop the reaction. The reaction solution was poured into ice water (6.00 L) to obtain a yellow suspension. The suspension was stirred at room temperature for 30 minutes, filtered, and washed with clean water (1.00 L) to obtain a filter residue. The filter residue was dissolved in EA (3.00 L) to give a yellow solution. The solution was washed with 0.1N dilute hydrochloric acid (800mL×2) and clear water (800mL), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was vacuum-dried to obtain the target compound (210 g, yield 96.2%, yellow solid). LC-MS (ESI) m/z 302.1 [M+Na] ⁺ .

0℃下，向5-(甲硫基)-1-氧代異吲哚啉-2-甲酸第三丁酯(210g，752mmol)的DCM(2.00L)溶液中加入間氯過氧苯甲酸(85%，382g，1879mmol)。反應混合液繼續在室溫下攪拌反應2小時，停止反應。將反應液用DCM(1.50L)稀釋後，分別用氫氧化鈉溶液(1.00L×2)、清水(1.00L)洗滌、無水硫酸鈉乾燥、過濾，濾液減壓濃縮，所得殘留物經真空乾燥後，得到目標化合物(215g，產率91.9%，黃色固體)。LC-MS(ESI)m/z 334.0 [M+Na]⁺ 。Step 3: Synthesis of 5-(methylsulfonyl)-1-oxoisoindoline-2-carboxylic acid tert-butyl ester

To a solution of 3-butyl 5-(methylthio)-1-oxoisoindoline-2-carboxylate (210 g, 752 mmol) in DCM (2.00 L) at 0°C was added m-chloroperoxybenzoic acid ( 85%, 382 g, 1879 mmol). The reaction mixture was stirred at room temperature for 2 hours to stop the reaction. The reaction solution was diluted with DCM (1.50L), washed with sodium hydroxide solution (1.00L×2), clear water (1.00L), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was dried under vacuum After that, the title compound (215 g, yield 91.9%, yellow solid) was obtained. LC-MS (ESI) m/z 334.0 [M+Na] ⁺ .

-20℃和氬氣保護下，向5-(甲磺醯基)-1-氧異吲哚啉-2-甲酸第三丁酯(50.0g，161mmol)的DCM(1.00L)溶液中滴加(時間超過40分鐘)二異丁基氫化鋁的甲苯溶液(214mL，321mmol，1.50M)，滴加完成後，氬氣保護下-20℃繼續攪拌1小時。向反應液中加入飽和酒石酸鉀鈉溶液(800mL)，攪拌20分鐘後，升溫至室溫。向混合液加入DCM(1.50L)後分離有機相。水相繼續用DCM萃取(1.00L×2)。有機相合併後減壓濃縮，所得殘留物經真空乾燥後，得到目標化合物，4批次共得(33.75g，產率64.7%，粉色固體)。LC-MS(ESI)m/z 335.9 [M+Na]⁺ 。Step 4: Synthesis of 1-hydroxy-5-(methylsulfonyl)isoindoline-2-carboxylic acid tert-butyl ester

To a solution of 3-butyl 5-(methylsulfonyl)-1-oxoisoindoline-2-carboxylate (50.0 g, 161 mmol) in DCM (1.00 L) was added dropwise at -20°C under argon (over 40 minutes) a solution of diisobutylaluminum hydride in toluene (214 mL, 321 mmol, 1.50 M), after the dropwise addition was completed, stirring was continued at -20°C for 1 hour under argon protection. A saturated potassium sodium tartrate solution (800 mL) was added to the reaction solution, and after stirring for 20 minutes, the temperature was raised to room temperature. To the mixture was added DCM (1.50 L) and the organic phase was separated. The aqueous phase was further extracted with DCM (1.00 L x 2). The organic phases were combined and concentrated under reduced pressure, and the obtained residue was vacuum-dried to obtain the target compound, which was obtained in 4 batches (33.75 g, yield 64.7%, pink solid). LC-MS (ESI) m/z 335.9 [M+Na] ⁺ .

向1-羥基-5-(甲磺醯基)異吲哚啉-2-甲酸第三丁酯(15.0g，47.9mmol)的甲醇(200mL)溶液中加入4-甲基苯磺酸吡啶(1.20g，4.79mmol)。反應混合液在室溫下攪拌反應1小時，停止反應。向反應液中加入三乙胺(33.3mL)淬滅，然後減壓濃縮，所得殘留物經真空乾燥後，得到目標化合物(16.1g，粗品，紫黑色固體)。MS(ESI)m/z 349.9 [M+Na]⁺ 。Step 5: Synthesis of 1-methoxy-5-(methylsulfonyl)isoindoline-2-carboxylic acid tert-butyl ester

To a solution of tert-butyl 1-hydroxy-5-(methylsulfonyl)isoindoline-2-carboxylate (15.0 g, 47.9 mmol) in methanol (200 mL) was added pyridine 4-methylbenzenesulfonate (1.20 g g, 4.79 mmol). The reaction mixture was stirred at room temperature for 1 hour to stop the reaction. Triethylamine (33.3 mL) was added to the reaction solution to quench, and then concentrated under reduced pressure. The obtained residue was dried in vacuo to obtain the target compound (16.1 g, crude product, purple-black solid). MS (ESI) m/z 349.9 [M+Na] ⁺ .

-70℃和氬氣保護下，向1-甲氧基-5-(甲磺醯基)異吲哚啉-2-甲酸第三丁酯(16.0g，48.9mmol)的DCM(300mL)溶液中依次加入三甲基氰矽烷(9.17mL，73.3mmol)和三氟化硼乙醚(9.25mL，73.3mmol)。反應混合物在-70℃和氬氣保護下繼續攪拌1小時，停止反應。向反應液中加入飽和碳酸氫鈉(50.0mL)溶液和DCM(200mL)後升溫至室溫。有機相分離後，水相繼續用DCM(100mL×2)萃取。有機相合併後，用無水硫酸鈉乾燥、過濾，濾液減壓濃縮，所得殘留物經管柱層析分離純化(PE：EA=5/1-3/1)，得到目標化合物(7g，兩步產率 49.3%，白色固體)。LC-MS(ESI)m/z 323.0 [M+H]⁺ 。Step 6: Synthesis of 1-cyano-5-(methylsulfonyl)isoindoline-2-carboxylic acid tert-butyl ester

To a solution of 3-butyl 1-methoxy-5-(methylsulfonyl)isoindoline-2-carboxylate (16.0 g, 48.9 mmol) in DCM (300 mL) at -70°C under argon Trimethylsilyl cyanide (9.17 mL, 73.3 mmol) was added followed by boron trifluoride ether (9.25 mL, 73.3 mmol). The reaction mixture was further stirred at -70°C under argon for 1 hour to stop the reaction. Saturated sodium bicarbonate (50.0 mL) solution and DCM (200 mL) were added to the reaction solution, and the temperature was raised to room temperature. After the organic phase was separated, the aqueous phase was further extracted with DCM (100 mL x 2). After the organic phases were combined, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (PE: EA=5/1-3/1) to obtain the target compound (7 g, produced in two steps). rate 49.3%, white solid). LC-MS (ESI) m/z 323.0 [M+H] ⁺ .

將1-氰基-5-(甲磺醯基)異吲哚啉-2-甲酸第三丁酯(22.5g，322mmol)加入鹽酸甲醇(3M，225mL)，反應混合物在80℃下攪拌5小時，停止反應。將反應液減壓濃縮，所得殘留物經真空乾燥後，得到目標化合物(20.4g，粗品，黑色固體)。LC-MS(ESI)m/z 255.9 [M+H]⁺ 。Step 7: Synthesis of methyl 5-methylsulfonylisoindoline-1-carboxylate hydrochloride

1-Cyano-5-(methylsulfonyl)isoindoline-2-carboxylic acid tert-butyl ester (22.5 g, 322 mmol) was added to methanol hydrochloride (3M, 225 mL) and the reaction mixture was stirred at 80 °C for 5 hours , stop the reaction. The reaction solution was concentrated under reduced pressure, and the obtained residue was vacuum-dried to obtain the target compound (20.4 g, crude product, black solid). LC-MS (ESI) m/z 255.9 [M+H] ⁺ .

0℃和氬氣保護下，向5-甲基磺醯異吲哚啉-1-甲酸甲酯鹽酸(20.0g，68.6mmol)的DCM(250mL)溶液中依次加三乙胺(34.7g，343mmol)和滴加乙醯氯(10.8g，137mmol)。反應混合物在0℃和氬氣保護下繼續攪拌3小時，停止反應。向反應液中加入水(250mL)，有機相分離後，水相繼續用DCM(200mL×2)萃取。有機相合併後減壓濃縮，所得殘留物經管柱層析分離純化(PE：EA=1/1-0/1)，得到目標化合物(12.17g，兩步產率58.6%，白色固體)。LC-MS(ESI)m/z 298.0 [M+H]⁺ 。¹ H NMR(400 MHz, CDCl₃ )δ 7.97 – 7.85(m, 2H), 7.70 – 7.62(m, 1H), 5.78 – 5.64(m, 1H), 5.09 – 4.99(m, 1H), 4.96 – 4.83(m, 1H), 3.85 – 3.73(m, 3H), 3.07(s, 3H), 2.25, 2.10(s, 3H)。Step 8: Synthesis of Methyl 2-Acetyl-5-(Methylsulfonyl)isoindoline-1-carboxylate

To a solution of methyl 5-methylsulfoisoindoline-1-carboxylate hydrochloride (20.0 g, 68.6 mmol) in DCM (250 mL) was successively added triethylamine (34.7 g, 343 mmol) at 0°C under argon protection. ) and acetyl chloride (10.8 g, 137 mmol) was added dropwise. The reaction mixture was further stirred for 3 hours at 0°C under argon to stop the reaction. Water (250 mL) was added to the reaction solution, and after the organic phase was separated, the aqueous phase was continuously extracted with DCM (200 mL×2). The organic phases were combined and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE: EA=1/1-0/1) to obtain the target compound (12.17 g, two-step yield 58.6%, white solid). LC-MS (ESI) m/z 298.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ )δ 7.97 – 7.85(m, 2H), 7.70 – 7.62(m, 1H), 5.78 – 5.64(m, 1H), 5.09 – 4.99(m, 1H), 4.96 – 4.83 (m, 1H), 3.85 – 3.73(m, 3H), 3.07(s, 3H), 2.25, 2.10(s, 3H).

向2-乙醯基-5-(甲磺醯基)異吲哚啉-1-甲酸甲酯(11.8g，39.7mmol)的四氫呋喃/甲醇/水(V:V:V=1:1:1，120mL)溶液中加入氫氧化鈉(3.18g，79.4mmol)。反應混合物在室溫繼續攪拌2小時，停止反應。將反應液減壓濃縮，向所得殘留物中加入水(100mL)，用鹽酸(3M)調pH~4，所得溶液攪拌16小時，過濾，濾餅水洗(10.0mL×2)，經真空乾燥後，得到目標化合物(8.80g，78.2%，類白色固體)。LC-MS(ESI)m/z 284.1 [M+H]⁺ 。¹ H NMR(400 MHz, DMSO-d₆ )δ 8.05 – 7.87(m, 2H), 7.76 – 7.58(m, 1H), 5.94 , 5.53(s, 1H), 5.05 – 4.92 , 4.90 – 4.82 , 4.69 – 4.60(m, 2H), 3.24(s, 3H), 2.13 , 2.00(s, 3H)。Step 9: Synthesis of 2-Acetyl-5-(methylsulfonyl)isoindoline-1-carboxylic acid

To methyl 2-acetyl-5-(methylsulfonyl)isoindoline-1-carboxylate (11.8 g, 39.7 mmol) in tetrahydrofuran/methanol/water (V:V:V=1:1:1 , 120 mL) solution was added sodium hydroxide (3.18 g, 79.4 mmol). The reaction mixture was continued to stir at room temperature for 2 hours to stop the reaction. The reaction solution was concentrated under reduced pressure, water (100 mL) was added to the obtained residue, the pH was adjusted to 4 with hydrochloric acid (3M), the obtained solution was stirred for 16 hours, filtered, and the filter cake was washed with water (10.0 mL×2), and dried in vacuo , the title compound (8.80 g, 78.2%, off-white solid) was obtained. LC-MS (ESI) m/z 284.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ )δ 8.05 – 7.87(m, 2H), 7.76 – 7.58(m, 1H), 5.94 , 5.53(s, 1H), 5.05 – 4.92 , 4.90 – 4.82 , 4.69 – 4.60(m, 2H), 3.24(s, 3H), 2.13 , 2.00(s, 3H).

向2-乙醯基-5-(甲磺醯)異吲哚啉-1-甲酸(4.00g，14.1mmol)和2-(4'-氨基-2-氟-[1,1'-聯苯]-4-基)-1,1,1,3,3,3-六氟丙烷-2-醇(4.17g，11.8mmol)的乙腈(80.0mL)溶液中依次加入TCFH(9.90g，35.3mmol)和N -甲基咪唑(4.83g，58.8mmol)，反應液室溫攪拌2小時後，停止反應。將反應液減壓濃縮，所得殘留物再經中壓液相製備(乙腈/水=0-45%)，得到目標化合物(3.10g，產率42.5%，白色固體)。MS(ESI)m/z 619.1 [M+H]⁺ 。¹ H NMR(400 MHz, DMSO-d ₆ )δ 10.88, 10.64(s, 1H), 9.01(s, 1H), 8.05 – 8.00(m, 1H), 7.95 – 7.89(m, 1H), 7.78 – 7.67(m, 4H), 7.62 – 7.52(m, 4H), 5.94, 5.74(s, 1H), 5.05 – 4.77(m, 2H), 3.23, 3.22(s, 3H), 2.16, 2.01(s, 3H)。Step 10: Compound 2-Acetyl- N- (2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1, Synthesis of 1'-biphenyl]-4-yl)-5-(methylsulfonyl)isoindoline-1-carboxamide

To 2-acetyl-5-(methylsulfonyl)isoindoline-1-carboxylic acid (4.00 g, 14.1 mmol) and 2-(4'-amino-2-fluoro-[1,1'-biphenyl] ]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.17 g, 11.8 mmol) in acetonitrile (80.0 mL) was sequentially added TCFH (9.90 g, 35.3 mmol) ) and N -methylimidazole (4.83 g, 58.8 mmol), the reaction solution was stirred at room temperature for 2 hours, and then the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the obtained residue was prepared by medium pressure liquid phase (acetonitrile/water=0-45%) to obtain the target compound (3.10 g, yield 42.5%, white solid). MS (ESI) m/z 619.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ )δ 10.88, 10.64(s, 1H), 9.01(s, 1H), 8.05 – 8.00(m, 1H), 7.95 – 7.89(m, 1H), 7.78 – 7.67 (m, 4H), 7.62 – 7.52(m, 4H), 5.94, 5.74(s, 1H), 5.05 – 4.77(m, 2H), 3.23, 3.22(s, 3H), 2.16, 2.01(s, 3H) .

外消旋體2-乙醯基-N -(2'-氟-4'-(1,1,1,3,3,3-六氟-2-羥基丙-2-基)-[1,1'-聯苯]-4-基)-5-(甲基磺醯基)異吲哚啉-1-甲醯胺(1.29g溶於約250mL甲醇，進樣體積8.0mL)經Waters SFC 150(室溫，100bar，214nm)和250*25mm 10µm DAICELCHIRALPAK®AS-H(超臨界二氧化碳：甲醇，45:55，3.0min，70mL/min)分離，得到R -2-乙醯基-N -(2'-氟-4'-(1,1,1,3,3,3-六氟-2-羥基丙-2-基)-[1,1'-聯苯]-4-基)-5-(甲基磺醯基)異吲哚啉-1-甲醯胺或S -2-乙醯基-N -(2'-氟-4'-(1,1,1,3,3,3-六氟-2-羥基丙-2-基)-[1,1'-聯苯]-4-基)-5-(甲基磺醯基)異吲哚啉-1-甲醯胺(500mg，白色固體，Ret .time=1.276min，e.e. 99%)。LC-MS(ESI)m/z 619.2 [M+H]⁺ 。¹ H NMR(400 MHz, DMSO-d₆ )δ 10.88 , 10.65(s, 1H), 9.01(s, 1H), 8.05 – 7.99(m, 1H), 7.95 – 7.89(m, 1H), 7.81 – 7.67(m, 4H), 7.63 – 7.50(m, 4H), 5.94, 5.75(s, 1H), 5.12 – 4.99, 4.95 – 4.77(m, 2H), 3.23-3.21(m, 3H), 2.17, 2.01(s, 3H)。Step 11: R -2-Acetyl- N- (2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1 ,1'-biphenyl]-4-yl)-5-(methylsulfonyl)isoindoline-1-carboxamide or S -2-acetyl- N- (2'-fluoro-4 '-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-5-(methylsulfonyl Synthesis of Isoindoline-1-Carboxamide

Racemate 2-Acetyl- N- (2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1, 1'-Biphenyl]-4-yl)-5-(methylsulfonyl)isoindoline-1-carboxamide (1.29 g dissolved in about 250 mL methanol, injection volume 8.0 mL) was purified by Waters SFC 150 (room temperature, 100bar, 214nm) and 250*25mm 10µm DAICELCHIRALPAK® AS-H (supercritical carbon dioxide:methanol, 45:55, 3.0min, 70mL/min) were separated to give R -2-acetyl- N- ( 2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-5 -(Methylsulfonyl)isoindoline-1-carbamide or S -2-acetyl- N- (2'-fluoro-4'-(1,1,1,3,3,3 - Hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-5-(methylsulfonyl)isoindoline-1-carboxamide (500mg as a white solid, Ret .time = 1.276min, ee 99 %). LC-MS (ESI) m/z 619.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ )δ 10.88 , 10.65(s, 1H), 9.01(s, 1H), 8.05 – 7.99(m, 1H), 7.95 – 7.89(m, 1H), 7.81 – 7.67 (m, 4H), 7.63 – 7.50(m, 4H), 5.94, 5.75(s, 1H), 5.12 – 4.99, 4.95 – 4.77(m, 2H), 3.23-3.21(m, 3H), 2.17, 2.01( s, 3H).

S -2-Acetyl- N- (2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1' -Biphenyl]-4-yl)-5-(methylsulfonyl)isoindoline-1-carboxamide or R -2-acetyl- N- (2'-fluoro-4'-( 1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-5-(methylsulfonyl)iso indoline-1-acyl-amine (516mg, as a white solid, Ret .time = 2.610min, ee 98 %). LC-MS (ESI) m/z 619.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ )δ 10.88, 10.65(s, 1H), 9.01(s, 1H), 8.06 – 7.99(m, 1H), 7.95 – 7.89(m, 1H), 7.82 – 7.67 (m, 4H), 7.64 – 7.50(m, 4H), 5.94, 5.75(s, 1H), 5.11 – 4.99, 4.93 – 4.75(m, 2H), 3.23-3.21(m, 3H), 2.17, 2.01( s, 3H).

中間體2-(第三丁氧基羰基)-6-(甲基磺醯基)-1,2,3,4-四氫異喹啉-1-甲酸的合成 步驟1：3-(2-氨基乙基)苯酚氫溴酸鹽的合成

將2-(3-甲氧基苯基)乙胺(9.00g，59.5mmol)溶於40%氫溴酸水溶液(120g，595mmol)中。反應液在110℃下攪拌反應6小時，LC-MS監測反應完全。將反應液減壓濃縮，得到目標化合物(9.00g，粗品，淺棕色固體)。LC-MS(ESI)m/z : 179.1 [M+ACN+H]⁺ 。Example 3 : 2-Acetyl- N- (4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl ]-4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

Synthesis of intermediate 2-(tert-butoxycarbonyl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid Step 1: 3-(2- Synthesis of Aminoethyl) Phenol Hydrobromide

2-(3-Methoxyphenyl)ethanamine (9.00 g, 59.5 mmol) was dissolved in 40% aqueous hydrobromic acid (120 g, 595 mmol). The reaction solution was stirred at 110° C. for 6 hours, and the reaction was completed by LC-MS monitoring. The reaction solution was concentrated under reduced pressure to obtain the title compound (9.00 g, crude product, light brown solid). LC-MS (ESI) m/z : 179.1 [M+ACN+H] ⁺ .

將3-(2-氨基乙基)苯酚氫溴酸鹽(9.00g，65.6mmol)溶於乙醇(90mL)中。在室溫下，將50%乙醛酸乙酯甲苯溶液(14.7g，72.2mmol)滴加到反應液中。加完後，反應混合物在100℃下攪拌反應過夜，LC-MS監測反應完全。將反應液減壓濃縮，得到目標化合物(20.0g，粗品，棕色油狀物)。LC-MS(ESI)m/z : 222.0 [M+H]⁺ 。Step 2: Synthesis of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid ethyl ester hydrobromide

3-(2-Aminoethyl)phenol hydrobromide (9.00 g, 65.6 mmol) was dissolved in ethanol (90 mL). At room temperature, a 50% solution of ethyl glyoxylate in toluene (14.7 g, 72.2 mmol) was added dropwise to the reaction solution. After the addition was complete, the reaction mixture was stirred at 100°C overnight, and the reaction was complete as monitored by LC-MS. The reaction solution was concentrated under reduced pressure to obtain the title compound (20.0 g, crude product, brown oil). LC-MS (ESI) m/z : 222.0 [M+H] ⁺ .

將6-羥基-1,2,3,4-四氫異喹啉-1-甲酸乙酯氫溴酸鹽(20.0g，66.2mmol)溶於四氫呋喃(200mL)和水(40mL)的混合溶劑中，在室溫下，依次將三乙胺(11.0mL，79.4mmol)和二碳酸二第三丁酯(16.7mL，72.8mmol)加到反應液中。加完後，反應液在室溫下繼續攪拌反應1小時，LC-MS監測反應完全。將反應液倒入水(150mL)中，用EA(50mLx2)萃取，合併有機相，用飽和氯化銨水溶液(100mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE：EA=4:1-2:1)，得到目標化合物(12.3g，三步產率64.4%，黃色油狀物)。LC-MS(ESI)m/z : 320.1 [M-H]^- 。Step 3: Synthesis of 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylic acid 1-ethyl ester 2-tert-butyl ester

6-Hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid ethyl ester hydrobromide (20.0 g, 66.2 mmol) was dissolved in a mixed solvent of tetrahydrofuran (200 mL) and water (40 mL) , at room temperature, triethylamine (11.0 mL, 79.4 mmol) and di-tert-butyl dicarbonate (16.7 mL, 72.8 mmol) were added to the reaction solution successively. After the addition, the reaction solution was continued to stir at room temperature for 1 hour, and LC-MS monitored the completion of the reaction. The reaction solution was poured into water (150 mL), extracted with EA (50 mL×2), the organic phases were combined, washed with saturated aqueous ammonium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was filtered through silica gel Column separation and purification (PE:EA=4:1-2:1) gave the target compound (12.3 g, three-step yield 64.4%, yellow oil). LC-MS (ESI) m/z : 320.1 [MH] ^- .

將6-羥基-3,4-二氫異喹啉-1,2(1H )-二甲酸1-乙基酯2-第三丁基酯(11.0g，34.2mmol)溶於無水DCM(200mL)中，在冰浴和氮氣保護下，依次將N -苯基雙(三氟甲磺醯)亞胺(14.7g，41.1mmol)和DIEA(11.3mL，68.5mmol)加入到反應液中。加完後，撤掉冰浴，反應混合物在室溫下攪拌反應3小時，LC-MS監測反應完全。將反應液減壓濃縮，得到目標化合物(37.0g，粗品，棕色油狀物)。LC-MS(ESI)m/z : 353.9 [M- BOC+ H]⁺ 。Step 4: 6-(((Trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-1,2( 1H )-dicarboxylic acid 1-ethyl ester 2-tertiary Synthesis of Butyl Ester

6-Hydroxy-3,4-dihydroisoquinoline-1,2( 1H )-dicarboxylic acid 1-ethyl ester 2-tert-butyl ester (11.0 g, 34.2 mmol) was dissolved in dry DCM (200 mL) ), N -phenylbis(trifluoromethanesulfonyl)imide (14.7 g, 41.1 mmol) and DIEA (11.3 mL, 68.5 mmol) were added to the reaction solution in sequence under ice bath and nitrogen protection. After the addition, the ice bath was removed, and the reaction mixture was stirred at room temperature for 3 hours, and the reaction was completed by LC-MS monitoring. The reaction solution was concentrated under reduced pressure to obtain the title compound (37.0 g, crude product, brown oil). LC-MS (ESI) m/z : 353.9 [M - BOC + H] ⁺ .

依次將6-(((三氟甲基)磺醯基)氧基)-3,4-二氫異喹啉-1,2(1H )-二甲酸1-乙基酯2-第三丁基酯(10.2g，12.4mmol)、Pd₂ (dba)₃ (1.13g，1.24mmol)、xantphos(1.43g，2.47mmol)、DIEA(4.09mL，24.7mmol)、甲硫醇(11.9g，24.7mmol)和1,4-二氧六環(50mL)加入到悶罐中。向悶罐中吹氮氣，快速密封罐子，反應混合物在100℃下攪拌反應過夜，LC-MS監測反應。將反應液冷卻至室溫，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE：EA=20:1-15:1)，得到目標化合物(6.20g，粗品，黃色油狀物)。LC-MS(ESI)m/z : 252.0 [M- BOC+ H]⁺ 。Step 5: Synthesis of 6-(methylthio)-3,4-dihydroisoquinoline-1,2-( 1H )-dicarboxylate 1-ethyl ester 2-tert-butyl ester

6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-1,2( 1H )-dicarboxylate 1-ethyl ester 2-tertiary butyl base ester (10.2 g, 12.4 mmol), Pd ₂ (dba) ₃ (1.13 g, 1.24 mmol), xantphos (1.43 g, 2.47 mmol), DIEA (4.09 mL, 24.7 mmol), methanethiol (11.9 g, 24.7 mmol) mmol) and 1,4-dioxane (50 mL) were added to a stuffed jar. Nitrogen was blown into the stuffy jar, the jar was quickly sealed, and the reaction mixture was stirred at 100 °C overnight, and the reaction was monitored by LC-MS. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by silica gel column (PE:EA=20:1-15:1) to obtain the target compound (6.20 g, crude product, yellow oil) . LC-MS (ESI) m/z : 252.0 [M - BOC + H] ⁺ .

將6-(甲硫基)-3,4-二氫異喹啉-1,2-(1H )-二甲酸1-乙基酯2-第三丁基酯(6.20g，17.6mmol)溶於DCM(100mL)中。在冰浴下，將間氯過氧苯甲酸(8.95g，44.1mmol，85%含量)緩慢加到反應液中。加完後，撤掉冰浴，反應混合物在室溫下攪拌反應2小時，LC-MS監測反應完全。將反應液過濾，濾液依次用飽和碳酸氫鈉(100mL)和飽和食鹽水(100mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE：EA=10:1-2:1)，得到目標化合物(1.38g，兩步產率：29.0%，黃色油狀物)。LC-MS(ESI)m/z : 382.1 [M-H]^- 。Step 6: Synthesis of 6-(methylsulfonyl)-3,4-dihydroisoquinoline-1,2-( 1H )-dicarboxylic acid 1-ethyl ester 2-tert-butyl ester

Dissolve 6-(methylthio)-3,4-dihydroisoquinoline-1,2-( 1H )-dicarboxylic acid 1-ethyl ester 2-tert-butyl ester (6.20 g, 17.6 mmol) in DCM (100 mL). Under an ice bath, m-chloroperoxybenzoic acid (8.95 g, 44.1 mmol, 85% content) was slowly added to the reaction solution. After the addition, the ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours, and the reaction was completed by LC-MS monitoring. The reaction solution was filtered, and the filtrate was washed successively with saturated sodium bicarbonate (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by silica gel column (PE:EA=10 :1-2:1) to obtain the title compound (1.38 g, two-step yield: 29.0%, yellow oil). LC-MS (ESI) m/z : 382.1 [MH] ^- .

將6-(甲基磺醯基)-3,4-二氫異喹啉-1,2-(1H )-二甲酸1-乙基酯2-第三丁基酯(1.38g，3.60mmol)溶於甲醇(20mL)中，在室溫下，將1mol/L氫氧化鈉水溶液(10.8mL，10.8mmol)滴加到反應液中。加完後，反應液在室溫下繼續攪拌反應2小時，LC-MS監測反應完全。將反應液倒入冰水(30mL)中，用1mol/L稀鹽酸調pH到3左右，用EA(20mLx2)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到目標化合物(1.12g，產率87.6%，黃色固體)。LC-MS(ESI)m/z : 709.1 [2M- H]^- 。Step 7: Synthesis of 2-(tert-butoxycarbonyl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

6-(Methylsulfonyl)-3,4-dihydroisoquinoline-1,2-( 1H )-dicarboxylate 1-ethyl ester 2-tert-butyl ester (1.38 g, 3.60 mmol ) was dissolved in methanol (20 mL), and 1 mol/L aqueous sodium hydroxide solution (10.8 mL, 10.8 mmol) was added dropwise to the reaction solution at room temperature. After the addition, the reaction solution was stirred at room temperature for 2 hours, and LC-MS monitored the completion of the reaction. Pour the reaction solution into ice water (30 mL), adjust the pH to about 3 with 1 mol/L dilute hydrochloric acid, extract with EA (20 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target Compound (1.12 g, 87.6% yield, yellow solid). LC-MS (ESI) m/z : 709.1 [2M - H] ^- .

將溴化銅(474mg，2.12mmol)溶於乙腈(20mL)中，在氮氣保護下，冰浴下，將亞硝酸第三丁酯(0.347mL，2.89mmol)滴加到反應液中。加完後，將2-(4-氨基苯基)-1,1,1,3,3,3-六氟丙烷-2-醇(500mg，1.93mmol)溶於乙腈(5mL)中並滴加到反應液中，加完後，反應混合物在冰浴下繼續攪拌反應1小時，LC-MS監測反應完全。將反應液倒入冰水(50mL)中，用甲基第三丁基醚(20mLx2)萃取，合併有機相，用飽和食鹽水(50mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到目標化合物(630mg，粗品，棕色油狀)。LC-MS(ESI)m/z : 320.9[M- H]^- 。Synthesis of intermediate 2-(4'-amino-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol Step 1:2 Synthesis of -(4-Bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol

Copper bromide (474 mg, 2.12 mmol) was dissolved in acetonitrile (20 mL), and tert-butyl nitrite (0.347 mL, 2.89 mmol) was added dropwise to the reaction solution under nitrogen protection and ice bath. After the addition was complete, 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (500 mg, 1.93 mmol) was dissolved in acetonitrile (5 mL) and added dropwise Into the reaction solution, after the addition, the reaction mixture was further stirred for 1 hour under an ice bath, and the reaction was completed as monitored by LC-MS. The reaction solution was poured into ice water (50 mL), extracted with methyl tert-butyl ether (20 mL×2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the title compound (630 mg, crude, brown oil) was obtained. LC-MS (ESI) m/z : 320.9 [M - H] ^- .

將2-(4-溴苯基)-1,1,1,3,3,3-六氟丙烷-2-醇(630mg，1.95mmol)、4-氨基苯硼酸頻哪醇酯(427mg，1.95mmol)、碳酸鉀(539mg，3.90mmol)和PdCl₂ (dtbpf)(143mg，0.195mmol)加入到1,4-二氧六環(10mL)和水(1mL)的混合溶劑中。在氮氣保護下，反應混合物在100℃下攪拌反應2小時，LC-MS監測反應完全。將反應混合物冷卻至室溫，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE:EA=10:1-6:1)，得到目標化合物(299mg，兩步產率46.2%，淡黃色固體)。LC-MS(ESI)m/z : 334.0 [M-H]^- 。Step 2: Synthesis of 2-(4'-amino-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

2-(4-Bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (630 mg, 1.95 mmol), 4-aminophenylboronic acid pinacol ester (427 mg, 1.95 mmol), potassium carbonate (539 mg, 3.90 mmol) and PdCl ₂ (dtbpf) (143 mg, 0.195 mmol) were added to a mixed solvent of 1,4-dioxane (10 mL) and water (1 mL). Under nitrogen protection, the reaction mixture was stirred at 100 °C for 2 hours, and the reaction was complete as monitored by LC-MS. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by silica gel column (PE:EA=10:1-6:1) to obtain the target compound (299 mg, two-step yield 46.2%, pale yellow solid). LC-MS (ESI) m/z : 334.0 [MH] ^- .

將2-(第三丁氧基羰基)-6-(甲基磺醯基)-1,2,3,4-四氫異喹啉-1-甲酸(42.4mg，0.119mmol)和2-(4'-氨基-[1,1'-聯苯]-4-基)-1,1,1,3,3,3-六氟丙烷-2-醇(40.0mg，0.119mmol)溶於無水DCM(3mL)中。在室溫下，依次將HATU(68.1mg，0.179mmol)和DIEA(0.0592mL，0.358mmol)加到反應液中。加完後，反應混合物在室溫下攪拌反應過夜，LC-MS監測反應完全。將反應液倒入水(20mL)中，用DCM(15mLx2)萃取，合併有機相，依次用飽和氯化銨(20mL)，飽和碳酸氫鈉(20mL)和飽和食鹽水(20mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到目標化合物(90.0mg，粗品，棕色油狀)。LC-MS(ESI)m/z : 673.1 [M+ H]⁺ 。2-Acetyl- N- (4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4- Synthesis step 1: 1-((4'-(1,1,1 ,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)carbamoyl)-6-(methylsulfonyl)- Synthesis of 3,4-dihydroisoquinoline-2(1 H )-carboxylate tert-butyl ester

2-(Third-butoxycarbonyl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (42.4 mg, 0.119 mmol) and 2-( 4'-Amino-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (40.0 mg, 0.119 mmol) was dissolved in dry DCM (3mL). HATU (68.1 mg, 0.179 mmol) and DIEA (0.0592 mL, 0.358 mmol) were sequentially added to the reaction at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature overnight and monitored by LC-MS for completion. The reaction solution was poured into water (20 mL), extracted with DCM (15 mL×2), the organic phases were combined, washed successively with saturated ammonium chloride (20 mL), saturated sodium bicarbonate (20 mL) and saturated brine (20 mL), and washed with anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give the title compound (90.0 mg, crude, brown oil). LC-MS (ESI) m/z : 673.1 [M + H] ⁺ .

將1-((4'-(1,1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)氨基甲醯基)-6-(甲基磺醯基)-3,4-二氫異喹啉-2(1H )-甲酸第三丁酯(90.0mg)溶於DCM(2mL)中。在冰浴下，將6mol/L鹽酸二氧六環溶液(1mL)滴加到反應液中。加完後，撤掉冰浴，反應混合物在室溫下繼續攪拌反應2小時。將反應液減壓濃縮，得到目標化合物(90.0mg，粗品，棕色油狀)。LC-MS(ESI)m/z : 573.0 [M+H]⁺ 。Step 2: N- (4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)- Synthesis of 6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride

1-((4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)aminomethane Acyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(1 H )-carboxylic acid tert-butyl ester (90.0 mg) was dissolved in DCM (2 mL). Under an ice bath, a 6 mol/L hydrochloric acid dioxane solution (1 mL) was added dropwise to the reaction solution. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (90.0 mg, crude product, brown oil). LC-MS (ESI) m/z : 573.0 [M+H] ⁺ .

將N -(4'-(1,1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)-6-(甲基磺醯基)-1,2,3,4-四氫異喹啉-1-甲醯胺鹽酸鹽(90.0mg，0.157mmol)溶於無水DCM(3mL)中。在室溫下，依次將DIEA(0.078mL，0.472mmol)和乙醯氯(0.028mL，0.393mmol)滴加到反應液中。加完後，反應液在室溫下繼續攪拌反應30分鐘。LC-MS監測反應完全。將反應液直接濃縮並溶於甲醇(3mL)中，在室溫下，將1mol/L 氫氧化鈉水溶液(2mL)滴加到反應液中。加完後，在室溫下繼續攪拌反應30分鐘，LC-MS監測反應完全。將反應液倒入水(20mL)中，用EA(15mLx2)萃取，合併有機相，用飽和氯化銨(20mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE：EA=1:1-0:1)，得到粗品，再經反向柱分離純化(乙腈：水=7：3)，得到目標化合物(15.0 mg，三步產率20.5%，白色固體)。LC-MS(ESI)m/z : 615.0 [M+ H]⁺ 。¹ H NMR(400 MHz, CDCl₃ )δ 7.88 – 7.79(m, 2H), 7.72 – 7.61(m, 3H), 7.52 – 7.28(m, 6H), 6.27(s, 1H), 4.06 – 3.93(m, 1H), 3.86 – 3.74(m, 1H), 3.41 – 3.24(m, 1H), 3.10 – 2.99(m, 4H), 2.37(s, 3H)。Step 3: 2-Acetyl- N- (4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl] Synthesis of -4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

N- (4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-6- (Methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (90.0 mg, 0.157 mmol) was dissolved in dry DCM (3 mL). At room temperature, DIEA (0.078 mL, 0.472 mmol) and acetyl chloride (0.028 mL, 0.393 mmol) were sequentially added dropwise to the reaction solution. After the addition, the reaction solution was stirred at room temperature for 30 minutes. The reaction was complete as monitored by LC-MS. The reaction solution was directly concentrated and dissolved in methanol (3 mL), and 1 mol/L aqueous sodium hydroxide solution (2 mL) was added dropwise to the reaction solution at room temperature. After the addition, the reaction was continued to stir at room temperature for 30 minutes, and the reaction was completed by LC-MS monitoring. The reaction solution was poured into water (20 mL), extracted with EA (15 mL×2), the organic phases were combined, washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was passed through a silica gel column. Separation and purification (PE:EA=1:1-0:1) gave crude product, which was then separated and purified by reverse column (acetonitrile:water=7:3) to obtain the target compound (15.0 mg, three-step yield 20.5%, white solid). LC-MS (ESI) m/z : 615.0 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ )δ 7.88 – 7.79(m, 2H), 7.72 – 7.61(m, 3H), 7.52 – 7.28(m, 6H), 6.27(s, 1H), 4.06 – 3.93(m , 1H), 3.86 – 3.74(m, 1H), 3.41 – 3.24(m, 1H), 3.10 – 2.99(m, 4H), 2.37(s, 3H).

步驟1：1-((2'-氟-4'-(1,1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)氨基甲醯基)-6-(甲磺醯基)-3,4-二氫異喹啉-2(1H )-甲酸第三丁酯的合成

將2-(第三丁氧基羰基)-6-(甲基磺醯基)-1,2,3,4-四氫異喹啉-1-甲酸(50.0mg，0.141mmol)和2-(4'-氨基-2-氟-[1,1'-聯苯]-4-基)-1,1,1,3,3,3-六氟丙烷-2-醇(49.7mg，0.141mmol)溶於無水DCM(3mL)中。在室溫下，依次將HATU(80.3mg，0.211mmol)和DIEA(0.070mL，0.422mmol)加到反應液中。加完後，反應混合物在室溫下攪拌反應過夜，LC-MS監測反應完全。將反應液倒入水(20mL)中，用DCM(15mLx2)萃取，合併有機相，依次用飽和氯化銨(20mL)，飽和碳酸氫鈉(20mL)和飽和食鹽水(20mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到目標化合物(100mg，粗品，棕色油狀)。LC-MS(ESI)m/z : 691.1 [M+ H]⁺ 。Example 4: 2-Acetyl- N- (2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1, 1'-Biphenyl]-4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

Step 1: 1-((2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl] Synthesis of -4-yl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2( 1H )-carboxylic acid tert-butyl ester

2-(Third-butoxycarbonyl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (50.0 mg, 0.141 mmol) and 2-( 4'-Amino-2-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (49.7 mg, 0.141 mmol) Dissolved in dry DCM (3 mL). HATU (80.3 mg, 0.211 mmol) and DIEA (0.070 mL, 0.422 mmol) were sequentially added to the reaction at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature overnight and monitored by LC-MS for completion. The reaction solution was poured into water (20 mL), extracted with DCM (15 mL×2), the organic phases were combined, washed successively with saturated ammonium chloride (20 mL), saturated sodium bicarbonate (20 mL) and saturated brine (20 mL), and washed with anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give the title compound (100 mg, crude, brown oil). LC-MS (ESI) m/z : 691.1 [M + H] ⁺ .

將1-((2'-氟-4'-(1,1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)氨基甲醯基)-6-(甲磺醯基)-3,4-二氫異喹啉-2(1H )-甲酸第三丁酯(100mg)溶於DCM(2mL)中。在冰浴下，將6mol/L鹽酸二氧六環溶液(1mL)滴加到反應液中。加完後，撤掉冰浴，反應混合物在室溫下繼續攪拌反應2小時。將反應液減壓濃縮，得到目標化合物(100mg，粗品，棕色油狀)。LC-MS(ESI)m/z : 591.0 [M+H]⁺ 。Step 2: N- (2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- Synthesis of 4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride

1-((2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4 -yl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2( 1H )-carboxylic acid tert-butyl ester (100 mg) was dissolved in DCM (2 mL). Under an ice bath, a 6 mol/L hydrochloric acid dioxane solution (1 mL) was added dropwise to the reaction solution. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (100 mg, crude product, brown oil). LC-MS (ESI) m/z : 591.0 [M+H] ⁺ .

將N -(2'-氟-4'-(1,1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)-6-(甲基磺醯基)-1,2,3,4-四氫異喹啉-1-甲醯胺鹽酸鹽(100mg，0.169mmol)溶於無水DCM(3mL)中。在室溫下，依次將DIEA(0.084mL，0.508mmol)和乙醯氯(0.030mL，0.423mmol)滴加到反應液中。加完後，反應液在室溫下繼續攪拌反應30分鐘。LC-MS監測反應完全。將反應液直接濃縮並溶於甲醇(3mL)中，在室溫下，將1mol/L氫氧化鈉水溶液(2mL)滴加到反應液中。加完後，在室溫下繼續攪拌反應30分鐘，LC-MS監測反應完全。將反應液倒入水(20mL)中，用EA(15mLx2)萃取，合併有機相，用飽和氯化銨(20mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE：EA=1:1-0:1)，得到粗品，再經反向矽膠柱分離純化(乙腈：水=7：3)，得到目標化合物(23.0 mg，三步產率：25.8%，白色固體)。LC-MS(ESI)m/z : 633.0 [M+ H]⁺ .¹ H NMR (400 MHz, CDCl₃ ) δ 7.87 – 7.81 (m, 2H), 7.62 – 7.44 (m, 5H), 7.42 – 7.27 (m, 3H), 6.26 (s, 1H), 3.97 – 3.87 (m, 1H), 3.85 – 3.76 (m, 1H), 3.31 – 3.19 (m, 1H), 3.10 – 3.00 (m, 4H), 2.35 (s, 3H)。Step 3: 2-Acetyl- N- (2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1 Synthesis of '-biphenyl]-4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

N- (2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4- yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100 mg, 0.169 mmol) was dissolved in dry DCM (3 mL). At room temperature, DIEA (0.084 mL, 0.508 mmol) and acetyl chloride (0.030 mL, 0.423 mmol) were sequentially added dropwise to the reaction solution. After the addition, the reaction solution was stirred at room temperature for 30 minutes. The reaction was complete as monitored by LC-MS. The reaction solution was directly concentrated and dissolved in methanol (3 mL), and 1 mol/L aqueous sodium hydroxide solution (2 mL) was added dropwise to the reaction solution at room temperature. After the addition, the reaction was continued to stir at room temperature for 30 minutes, and the reaction was completed by LC-MS monitoring. The reaction solution was poured into water (20 mL), extracted with EA (15 mL×2), the organic phases were combined, washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was passed through a silica gel column. Separation and purification (PE: EA=1:1-0:1) to obtain crude product, which was separated and purified by reverse silica gel column (acetonitrile:water=7:3) to obtain the target compound (23.0 mg, three-step yield: 25.8 %, white solid). LC-MS (ESI) m/z : 633.0 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 – 7.81 (m, 2H), 7.62 – 7.44 (m, 5H), 7.42 – 7.27 (m, 3H), 6.26 (s, 1H), 3.97 – 3.87 (m, 1H), 3.85 – 3.76 (m, 1H), 3.31 – 3.19 (m, 1H), 3.10 – 3.00 (m, 4H), 2.35 (s, 3H).

外消旋體2-乙醯基-N -(2'-氟-4'-(1,1,3,3,3-六氟-2-羥基丙-2-基)-[1,1'-聯苯]-4-基)-6-(甲基磺醯基)-1,2,3,4-四氫異喹啉-1-甲醯胺(1.60g溶於約150mL甲醇，進樣體積3.0mL)經Waters SFC 150(室溫，100bar，214nm)和250*25mm 10µm Dr.maish Reprosil Chiral-OM(類似於DAICELCHIRALCEL®OD)(超臨界二氧化碳：甲醇，50:50，2.3min，70mL/min)分離，得到R-2-乙醯基-N -(2'-氟-4'-(1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)-6-(甲基磺醯基)-1,2,3,4-四氫異喹啉-1-甲醯胺或S-2-乙醯基-N -(2'-氟-4'-(1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)-6-(甲基磺醯基)-1,2,3,4-四氫異喹啉-1-甲醯胺(676mg，黃色固體，Ret .time=0.778min，e.e. 99.74%)。LC-MS(ESI)m/z 633.1 [M+H]⁺ 。¹ H NMR(400 MHz, DMSO-d ₆ )δ 10.78 , 10.73(s, 1H), 9.00(s, 1H), 7.87 – 7.80(m, 3H), 7.75 – 7.65(m, 3H), 7.61 – 7.50(m, 4H), 5.96 , 5.85(s, 1H), 4.14 – 4.06(m, 1H), 3.74 – 3.66(m, 1H), 3.30 – 3.22(m, 1H), 3.22 – 3.19(m, 3H), 3.09 – 3.00(m, 1H), 2.18 , 2.15(s, 3H)。Example 5 and Example 6: R-2-Acetyl- N- (2'-fluoro-4'-(1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) -[1,1'-biphenyl]-4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide or S-2- Acetyl- N- (2'-fluoro-4'-(1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4 -yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

Racemate 2-Acetyl- N- (2'-fluoro-4'-(1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1' -Biphenyl]-4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (1.60g dissolved in about 150mL methanol, injected Volume 3.0mL) through Waters SFC 150 (room temperature, 100bar, 214nm) and 250*25mm 10µm Dr.maish Reprosil Chiral-OM (similar to DAICELCHIRALCEL® OD) (supercritical carbon dioxide: methanol, 50:50, 2.3min, 70mL /min) to obtain R-2-acetyl- N- (2'-fluoro-4'-(1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[ 1,1'-Biphenyl]-4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carbamide or S-2-acetamide yl- N- (2'-fluoro-4'-(1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl ) -6- (methyl sulfonyl acyl) -1,2,3,4-tetrahydro-isoquinoline-1-acyl-amine (676mg, yellow solid, Ret .time = 0.778min, ee 99.74 %). LC-MS (ESI) m/z 633.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ )δ 10.78 , 10.73(s, 1H), 9.00(s, 1H), 7.87 – 7.80(m, 3H), 7.75 – 7.65(m, 3H), 7.61 – 7.50 (m, 4H), 5.96 , 5.85(s, 1H), 4.14 – 4.06(m, 1H), 3.74 – 3.66(m, 1H), 3.30 – 3.22(m, 1H), 3.22 – 3.19(m, 3H) , 3.09 – 3.00(m, 1H), 2.18 , 2.15(s, 3H).

S-2-Acetyl- N- (2'-fluoro-4'-(1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-bi Benzyl]-4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide or R-2-ethanoyl- N- (2 '-Fluoro-4'-(1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-6-(methyl sulfo acyl group) -1,2,3,4-tetrahydro-isoquinoline-1-acyl-amine (683mg, yellow solid, Ret .time = 1.107min, ee 98.58 %). ¹ H NMR (400 MHz, DMSO- d ₆ )δ 10.78 , 10.73(s, 1H), 9.00(s, 1H), 7.87 – 7.80(m, 3H), 7.75 – 7.66(m, 3H), 7.61 – 7.51 (m, 4H), 5.96 , 5.85(s, 1H), 4.14 – 4.06(m, 1H), 3.75 – 3.65(m, 1H), 3.30 – 3.22(m, 1H), 3.22 – 3.19(m, 3H) , 3.09 – 3.01(m, 1H), 2.18 , 2.15(s, 3H).

步驟1： 6-(乙硫基)-3,4-二氫異喹啉-1,2-(1H )-二甲酸1-乙基酯2-第三丁基酯的合成

依次將6-(((三氟甲基)磺醯基)氧基)-3,4-二氫異喹啉-1,2(1H )-二甲酸1-乙基酯2-第三丁基酯(3.70g，8.16mmol)、Pd₂ (dba)₃ (747mg，0.816mmol)、xantphos(944mg，1.63mmol)、DIEA(2.70mL，16.3mmol)、乙硫醇(1.22mL，16.3mmol)和1,4-二氧六環(20mL)加入到封管中。向封管中吹氮氣，快速密封管子，反應混合物在100℃下攪拌反應過夜，LC-MS監測反應完全。將反應液冷卻至室溫，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE：EA=20:1-15:1)，得到目標化合物(1.80g，粗品，黃色油狀物)。LC-MS(ESI)m/z : 266.0 [M- BOC+ H]⁺ 。Example 7: 2-acetyl-6- (ethyl-sulfo acyl) - N - (2'- fluoro-4 '- (hexafluoro -2 1,1,1,3,3,3,3- -Hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

Step 1: Synthesis of 6-(Ethylthio)-3,4-dihydroisoquinoline-1,2-( 1H )-dicarboxylic acid 1-ethyl ester 2-tert-butyl ester

6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-1,2( 1H )-dicarboxylate 1-ethyl ester 2-tertiary butyl base ester (3.70 g, 8.16 mmol), Pd ₂ (dba) ₃ (747 mg, 0.816 mmol), xantphos (944 mg, 1.63 mmol), DIEA (2.70 mL, 16.3 mmol), ethanethiol (1.22 mL, 16.3 mmol) and 1,4-dioxane (20 mL) were added to the sealed tube. Nitrogen was blown into the sealed tube, the tube was quickly sealed, and the reaction mixture was stirred at 100° C. overnight, and the reaction was completed by LC-MS monitoring. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by silica gel column (PE:EA=20:1-15:1) to obtain the target compound (1.80 g, crude product, yellow oil) . LC-MS (ESI) m/z : 266.0 [M - BOC + H] ⁺ .

將6-(乙硫基)-3,4-二氫異喹啉-1,2-(1H )-二甲酸1-乙基酯2-第三丁基酯(1.80g，4.92mmol)溶於DCM(30mL)中。在冰浴下，將85%間氯過氧苯甲酸(2.50g，12.3mmol)緩慢加到反應液中。加完後，撤掉冰浴，反應混合物在室溫下攪拌反應2小時，LC-MS監測反應完全。將反應液過濾，濾液依次用飽和碳酸氫鈉(20mL)和飽和食鹽水(20mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE：EA=15:1-5:1)，得到目標化合物(1.10g，三步產率：81.0%，黃色油狀物)。LC-MS(ESI)m/z : 396.1 [M-H]^- 。Step 2: Synthesis of 6-(ethylsulfonyl)-3,4-dihydroisoquinoline-1,2-( 1H )-dicarboxylic acid 1-ethyl ester 2-tert-butyl ester

Dissolve 6-(ethylthio)-3,4-dihydroisoquinoline-1,2-( 1H )-dicarboxylic acid 1-ethyl ester 2-tert-butyl ester (1.80 g, 4.92 mmol) in DCM (30 mL). Under an ice bath, 85% m-chloroperoxybenzoic acid (2.50 g, 12.3 mmol) was slowly added to the reaction solution. After the addition, the ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours, and the reaction was completed by LC-MS monitoring. The reaction solution was filtered, and the filtrate was washed successively with saturated sodium bicarbonate (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by silica gel column (PE:EA=15 :1-5:1) to obtain the target compound (1.10 g, three-step yield: 81.0%, yellow oil). LC-MS (ESI) m/z : 396.1 [MH] ^- .

將6-(乙基磺醯基)-3,4-二氫異喹啉-1,2-(1H )-二甲酸1-乙基酯2-第三丁基酯(460mg，1.16mmol)溶於甲醇(5mL)中，在室溫下，將1mol/L氫氧化鈉水溶液(3.47mL，3.47mmol)滴加到反應液中。加完後，反應液在室溫下繼續攪拌反應2小時，LC-MS監測反應完全。將反應液倒入冰水(20mL)中，用1mol/L稀鹽酸調pH到3左右，用EA(10mLx2)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到目標化合物(362mg，產率84.7%，黃色固體)。LC-MS(ESI)m/z : 737.1 [2M- H]^- 。Step 3: Synthesis of 2-(tert-butoxycarbonyl)-6-(ethylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

6-(Ethylsulfonyl)-3,4-dihydroisoquinoline-1,2-( 1H )-dicarboxylate 1-ethyl ester 2-tert-butyl ester (460 mg, 1.16 mmol) It was dissolved in methanol (5 mL), and 1 mol/L aqueous sodium hydroxide solution (3.47 mL, 3.47 mmol) was added dropwise to the reaction solution at room temperature. After the addition, the reaction solution was stirred at room temperature for 2 hours, and LC-MS monitored the completion of the reaction. Pour the reaction solution into ice water (20 mL), adjust the pH to about 3 with 1 mol/L dilute hydrochloric acid, extract with EA (10 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target Compound (362 mg, 84.7% yield, yellow solid). LC-MS (ESI) m/z : 737.1 [2M - H] ^- .

將2-(第三丁氧基羰基)-6-(乙基磺醯基)-1,2,3,4-四氫異喹啉-1-甲酸(50.0mg，0.135mmol)和2-(4'-氨基-2-氟-[1,1'-聯苯]-4-基)-1,1,1,3,3,3-六氟丙烷-2-醇(47.8mg，0.203mmol)溶於無水DCM(3mL)中。在室溫下，依次將HATU(77.2mg，0.203mmol)和DIEA(0.067mL，0.406mmol)加到反應液中。加完後，反應混合物在室溫下攪拌反應過夜，LC-MS監測反應完全。將反應液倒入水(20mL)中，用DCM(15mLx2)萃取，合併有機相，依次用飽和氯化銨(20mL)、飽和碳酸氫鈉(20mL)和飽和食鹽水(20mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到目標化合物(100mg，粗品，棕色油狀)。LC-MS(ESI)m/z : 705.1 [M+ H]⁺ 。Step 4: 6-(Ethylsulfonyl)-1-((2'-fluoro-4'-(1,1,1,3,3,3,3-hexafluoro-2-hydroxypropane-2- Synthesis of tert-butyl)-[1,1'-biphenyl]-4-yl)carbamoyl)-3,4-dihydroisoquinoline-2( 1H )-carboxylate

2-(Third-butoxycarbonyl)-6-(ethylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (50.0 mg, 0.135 mmol) and 2-( 4'-Amino-2-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (47.8 mg, 0.203 mmol) Dissolved in dry DCM (3 mL). HATU (77.2 mg, 0.203 mmol) and DIEA (0.067 mL, 0.406 mmol) were sequentially added to the reaction at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature overnight and monitored by LC-MS for completion. The reaction solution was poured into water (20 mL), extracted with DCM (15 mL×2), the organic phases were combined, washed successively with saturated ammonium chloride (20 mL), saturated sodium bicarbonate (20 mL) and saturated brine (20 mL), and washed with anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give the title compound (100 mg, crude, brown oil). LC-MS (ESI) m/z : 705.1 [M + H] ⁺ .

將6-(乙基磺醯基)-1-((2'-氟-4'-(1,1,1,3,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯基]-4-基)氨基甲醯基)-3,4-二氫異喹啉-2(1H )-甲酸第三丁基酯(100mg，0.142mmol)溶於DCM(2mL)中。在冰浴下，將6mol/L鹽酸二氧六環溶液(1mL)滴加到反應液中。加完後，撤掉冰浴，反應混合物在室溫下繼續攪拌反應2小時。將反應液減壓濃縮，得到目標化合物(100mg，粗品，棕色油狀)。LC-MS(ESI)m/z : 605.0 [M+H]⁺ 。Step 5: 6- (ethyl-sulfo acyl) - N - (2'- fluoro-4 '- (1,1,1,3,3,3-hexafluoro-2-hydroxy-2-yl) - Synthesis of [1,1'-biphenyl]-4-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride

6-(Ethylsulfonyl)-1-((2'-fluoro-4'-(1,1,1,3,3,3,3-hexafluoro-2-hydroxypropan-2-yl) -[1,1'-Biphenyl]-4-yl)carbamoyl)-3,4-dihydroisoquinoline-2( 1H )-carboxylic acid tert-butyl ester (100 mg, 0.142 mmol) Dissolved in DCM (2 mL). Under an ice bath, a 6 mol/L hydrochloric acid dioxane solution (1 mL) was added dropwise to the reaction solution. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (100 mg, crude product, brown oil). LC-MS (ESI) m/z : 605.0 [M+H] ⁺ .

將6-(乙基磺醯基)-N -(2'-氟-4'-(1,1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)-1,2,3,4-四氫異喹啉-1-甲醯胺鹽酸鹽(100mg，0.165mmol)溶於無水DCM(3mL)中。在室溫下，依次將DIEA(0.082mL，0.496mmol)和乙醯氯(0.024mL，0.331mmol)滴加到反應液中。加完後，反應液在室溫下繼續攪拌反應30分鐘。LC-MS監測反應完全。將反應液直接濃縮並溶於甲醇(3mL)中，在室溫下，將1mol/L 氫氧化鈉水溶液(2mL)滴加到反應液中。加完後，在室溫下繼續攪拌反應30分鐘，LC-MS監測反應完全。將反應液倒入水(20mL)中，用EA(15mLx2)萃取，合併有機相，用飽和氯化銨(20mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE：EA=1：1-0：1)得到粗品，再經反向矽膠柱分離純化(乙腈：水=7：3)得到目標化合物(25.0mg，三步產率：34.5%，白色固體)。LC-MS(ESI)m/z : 647.0 [M+ H]⁺ ;¹ H NMR(400 MHz, CDCl₃ )δ 7.83 – 7.77(m, 2H), 7.69 – 7.56(m, 1H), 7.52 – 7.40(m, 4H), 7.34 – 7.27(m, 3H), 6.27,6.21(s, 1H), 4.05 – 3.94(m, 1H), 3.87 – 3.74(m, 1H), 3.35 – 3.24(m, 1H), 3.18 – 2.99(m, 3H), 2.37, 2.31(s, 3H), 1.30(t,J = 7.3 Hz, 3H)。Step 6: 2-acetyl-6- (ethyl-sulfo acyl) - N - (2'- fluoro-4 '- (hexafluoro-2 1,1,1,3,3,3,3- Synthesis of Hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

6- (ethyl-sulfo acyl) - N - (2'- fluoro-4 '- (1,1,1,3,3,3-hexafluoro-2-hydroxy-2-yl) - [1 ,1'-biphenyl]-4-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100 mg, 0.165 mmol) was dissolved in dry DCM (3 mL). At room temperature, DIEA (0.082 mL, 0.496 mmol) and acetyl chloride (0.024 mL, 0.331 mmol) were sequentially added dropwise to the reaction solution. After the addition, the reaction solution was stirred at room temperature for 30 minutes. The reaction was complete as monitored by LC-MS. The reaction solution was directly concentrated and dissolved in methanol (3 mL), and 1 mol/L aqueous sodium hydroxide solution (2 mL) was added dropwise to the reaction solution at room temperature. After the addition, the reaction was continued to stir at room temperature for 30 minutes, and the reaction was completed by LC-MS monitoring. The reaction solution was poured into water (20 mL), extracted with EA (15 mL×2), the organic phases were combined, washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was passed through a silica gel column. The crude product was obtained by separation and purification (PE:EA=1:1-0:1), and then separated and purified by reverse silica gel column (acetonitrile:water=7:3) to obtain the target compound (25.0mg, three-step yield: 34.5%, white solid). LC-MS (ESI) m/z : 647.0 [M + H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83 – 7.77 (m, 2H), 7.69 – 7.56 (m, 1H), 7.52 – 7.40 (m, 4H), 7.34 – 7.27(m, 3H), 6.27, 6.21(s, 1H), 4.05 – 3.94(m, 1H), 3.87 – 3.74(m, 1H), 3.35 – 3.24(m, 1H) , 3.18 – 2.99(m, 3H), 2.37, 2.31(s, 3H), 1.30(t, J = 7.3 Hz, 3H).

將2-(4’-氨基-[1,1’-聯苯]-4-基)-1,1,1,3,3,3-六氟丙-2-醇(50mg，0.149mmol)、2-乙醯基-5-(甲磺醯基)異吲哚啉-1-甲酸(46.5mg，0.164mmol)和TCFH(92mg，0.328mmol)加入到乙腈(5mL)中。向反應混合物中依次加入N -甲基咪唑(73.4mg，0.894mmol)。反應混合物在室溫下攪拌反應3小時。加入EA(15mL)和水(10mL)。分出水相用EA(10mL)萃取。合併有機相用飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾。濾液減壓濃縮得到粗產品。經柱層析分離純化(C18，甲醇/水=0~100%)得到目標化合物(30mg，產率33.5%，黃色固體)。LC-MS(ESI)m/z 601.2 [M+H]⁺ 。¹ H NMR(400 MHz, DMSO-d ₆ )δ 10.87, 10.63(s, 1H), 8.79 – 8.76(m,1H), 8.05 – 8.00(m,1H), 7.95 – 7.91(m,1H), 7.83 – 7.80(m, 2H), 7.79 – 7.70(m, 7H), 5.95 – 5.93, 5.76 – 5.73(m, 1H), 5.09 – 5.03, 4.93 – 4.88, 4.85 – 4.78(m, 2H), 3.26 – 3.22(m, 3H), 2.17, 2.02(s, 3H).Example 8: 2-Acetyl- N- (4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl-2-yl)-[1,1'-bi Benzyl]-4-yl)-5-(methylsulfonyl)isoindoline-1-carboxamide

2-(4'-Amino-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (50 mg, 0.149 mmol), 2-Acetyl-5-(methylsulfonyl)isoindoline-1-carboxylic acid (46.5 mg, 0.164 mmol) and TCFH (92 mg, 0.328 mmol) were added to acetonitrile (5 mL). To the reaction mixture was sequentially added N -methylimidazole (73.4 mg, 0.894 mmol). The reaction mixture was stirred at room temperature for 3 hours. EA (15 mL) and water (10 mL) 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. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (C18, methanol/water=0~100%), the target compound (30 mg, yield 33.5%, yellow solid) was obtained. LC-MS (ESI) m/z 601.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ )δ 10.87, 10.63(s, 1H), 8.79 – 8.76(m, 1H), 8.05 – 8.00(m, 1H), 7.95 – 7.91(m, 1H), 7.83 – 7.80(m, 2H), 7.79 – 7.70(m, 7H), 5.95 – 5.93, 5.76 – 5.73(m, 1H), 5.09 – 5.03, 4.93 – 4.88, 4.85 – 4.78(m, 2H), 3.26 – 3.22 (m, 3H), 2.17, 2.02(s, 3H).

步驟1：1,1,1,3,3,3-六氟-2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯基)丙-2-醇的合成

依次將2-(4-溴苯基)-1,1,1,3,3,3-六氟丙烷-2-醇(1000mg，3.10mmol)、聯硼酸頻那醇酯(865mg，3.41mmol)、乙酸鉀(911mg，9.29mmol)和Pd(dppf)Cl₂ (227mg，0.310mmol)加入到1,4-二氧六環(10mL)中。在氮氣保護下，反應混合物在90℃下攪拌反應過夜。將反應混合物冷卻至室溫，過濾，濾液減壓濃縮，得到目標化合物(1.00g，粗品，黑色油狀)。LC-MS(ESI)m/z : 369.1 [M-H]^- 。Example 9: 2-Acetyl- N- (2-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1 '-Biphenyl]-4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

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

2-(4-Bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1000 mg, 3.10 mmol), pinacol biboronate (865 mg, 3.41 mmol) , potassium acetate (911mg, 9.29mmol) and _{Pd (dppf) Cl 2 (227mg} , 0.310mmol) was added to 1,4-dioxane (10mL). The reaction mixture was stirred at 90°C overnight under nitrogen protection. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.00 g, crude, black oil). LC-MS (ESI) m/z : 369.1 [MH] ^- .

將1,1,1,3,3,3-六氟-2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯基)丙-2-醇(500mg，1.35mmol)、4-溴-3-氟苯胺(205mg，1.08mmol)、碳酸鉀(373mg，2.70mmol)和Pd(dppf)Cl₂ (98.9mg，0.135mmol)加入到1,4-二氧六環(5mL)和水(0.5mL)的混合溶劑中。在氮氣保護下，反應混合物在100℃下攪拌反應2小時，LC-MS監測反應完全。將反應混合物冷卻至室溫，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE:EA=10:1-2:1)得到粗品，再經反相柱分離純化(乙腈：甲醇=1:1)，得到目標化合物(30.0mg，三步產率4.40%，白色固體)。LC-MS(ESI)m/z : 352.0 [M-H]^- 。Step 2: 2-(4'-Amino-2'-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3,3-hexafluoropropane-2 - Synthesis of alcohols

1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)phenyl)propan-2-ol (500 mg, 1.35 mmol), 4-bromo-3-fluoroaniline (205 mg, 1.08 mmol), potassium carbonate (373 mg, 2.70 mmol) and Pd(dppf)Cl ₂ (98.9 mg) , 0.135 mmol) was added to a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL). Under nitrogen protection, the reaction mixture was stirred at 100 °C for 2 hours, and the reaction was complete as monitored by LC-MS. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product, which was separated and purified by silica gel column (PE:EA=10:1-2:1) to obtain crude product, and then separated and purified by reversed-phase column (acetonitrile:methanol= 1:1) to obtain the title compound (30.0 mg, 4.40% yield over three steps, white solid). LC-MS (ESI) m/z : 352.0 [MH] ^- .

將2-(4'-氨基-2'-氟-[1,1'-聯苯]-4-基)-1,1,1,3,3,3,3-六氟丙烷-2-醇(30.0mg，0.085mmol)和2-(第三丁氧基羰基)-6-(甲基磺醯基)-1,2,3,4-四氫異喹啉-1-甲酸(30.2mg，0.085mmol)溶於無水DCM(3mL)中。在室溫下，依次將HATU(48.4 mg，0.127mmol)和DIEA(0.042mL，0.255mmol)加入到反應液中。加完後，反應混合物在室溫下攪拌反應2小時，LC-MS監測反應完全。將反應液倒入水(20mL)中，用DCM(15mLx2)萃取，合併有機相，依次用飽和碳酸氫鈉(20mL)和飽和氯化銨(20mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到目標化合物(80.0mg，粗品，棕色液體)。LC-MS(ESI)m/z : 689.1 [M- H]^- 。Step 3: 1-((2-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- Synthesis of 4-yl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2( 1H )-carboxylic acid tert-butyl ester

2-(4'-Amino-2'-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3,3-hexafluoropropan-2-ol (30.0 mg, 0.085 mmol) and 2-(tert-butoxycarbonyl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (30.2 mg, 0.085 mmol) was dissolved in dry DCM (3 mL). At room temperature, HATU (48.4 mg, 0.127 mmol) and DIEA (0.042 mL, 0.255 mmol) were sequentially added to the reaction. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours, and the reaction was complete as monitored by LC-MS. The reaction solution was poured into water (20 mL), extracted with DCM (15 mL×2), the organic phases were combined, washed successively with saturated sodium bicarbonate (20 mL) and saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentration under reduced pressure gave the title compound (80.0 mg, crude, brown liquid). LC-MS (ESI) m/z : 689.1 [M - H] ^- .

將1-((2-氟-4'-(1,1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)氨基甲醯基)-6-(甲基磺醯基)-3,4-二氫異喹啉-2(1H )-甲酸第三丁酯(80.0mg)溶於DCM(1mL)中。在冰浴下，將4mol/L鹽酸二氧六環溶液(1mL)滴加到反應液中。加完後，撤掉冰浴，反應混合物在室溫下繼續攪拌反應2小時，LC-MS監測反應完全。將反應液減壓濃縮，得到目標化合物(70.0mg，粗品，棕色油狀)。LC-MS(ESI)m/z : 591.0 [M+H]⁺ 。Step 4: N- (2-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4 -yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride

1-((2-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4- (yl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2( 1H )-carboxylic acid tert-butyl ester (80.0 mg) was dissolved in DCM (1 mL) . Under an ice bath, a 4 mol/L hydrochloric acid dioxane solution (1 mL) was added dropwise to the reaction solution. After the addition, the ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours, and the reaction was completed by LC-MS monitoring. The reaction solution was concentrated under reduced pressure to obtain the title compound (70.0 mg, crude product, brown oil). LC-MS (ESI) m/z : 591.0 [M+H] ⁺ .

將N -(2-氟-4'-(1,1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)-6-(甲基磺醯基)-1,2,3,4-四氫異喹啉-1-甲醯胺鹽酸鹽(70.0mg，0.119mmol)溶於無水DCM(3mL)中。在室溫下，依次將三乙胺(0.049mL，0.356mmol)和乙醯氯(0.021mL，0.296mmol)滴加到反應液中。加完後，反應液在室溫下繼續攪拌反應30分鐘，LC-MS監測反應完全。將反應液直接濃縮並溶於甲醇(3mL)中，在室溫下，將1mol/L氫氧化鈉水溶液(2mL)滴加到反應液中。加完後，在室溫下繼續攪拌反應30分鐘，LC-MS監測反應完全。將反應液倒入水(20mL)中，用EA(15mLx2)萃取，合併有機相，用飽和氯化銨(20mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE：EA=1:1-0:1)得到粗品，再經反相柱分離純化(乙腈：水=7:3)得到目標化合物(10.0mg，三步產率18.6%，白色固體)。LC-MS(ESI)m/z : 633.0 [M+ H]⁺ 。¹ H NMR(400 MHz, CDCl₃ )δ 9.51(s, 1H), 7.90 – 7.85(m, 2H), 7.80 – 7.74(m,2H), 7.62 – 7.56(m, 3H), 7.54 – 7.50(m, 1H), 7.37 – 7.33(m, 1H), 7.24 – 7.20(m, 2H), 6.23(s, 1H), 3.89 – 3.82(m, 2H), 3.27 – 3.18(m, 1H), 3.14 – 3.05(m, 5H), 2.35(s, 3H)。Step 5: 2-Acetyl- N- (2-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1' - Synthesis of -biphenyl]-4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

N- (2-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl )-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (70.0 mg, 0.119 mmol) was dissolved in dry DCM (3 mL). At room temperature, triethylamine (0.049 mL, 0.356 mmol) and acetyl chloride (0.021 mL, 0.296 mmol) were sequentially added dropwise to the reaction solution. After the addition, the reaction solution was stirred at room temperature for 30 minutes, and LC-MS monitored the completion of the reaction. The reaction solution was directly concentrated and dissolved in methanol (3 mL), and 1 mol/L aqueous sodium hydroxide solution (2 mL) was added dropwise to the reaction solution at room temperature. After the addition, the reaction was continued to stir at room temperature for 30 minutes, and the reaction was completed by LC-MS monitoring. The reaction solution was poured into water (20 mL), extracted with EA (15 mL×2), the organic phases were combined, washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was passed through a silica gel column. The crude product was obtained by separation and purification (PE:EA=1:1-0:1), which was then separated and purified by reversed-phase column (acetonitrile:water=7:3) to obtain the target compound (10.0 mg, three-step yield 18.6%, white solid) ). LC-MS (ESI) m/z : 633.0 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ )δ 9.51(s, 1H), 7.90 – 7.85(m, 2H), 7.80 – 7.74(m, 2H), 7.62 – 7.56(m, 3H), 7.54 – 7.50(m , 1H), 7.37 – 7.33(m, 1H), 7.24 – 7.20(m, 2H), 6.23(s, 1H), 3.89 – 3.82(m, 2H), 3.27 – 3.18(m, 1H), 3.14 – 3.05 (m, 5H), 2.35(s, 3H).

步驟1：2-(4'-氨基-2'-氯-[1,1'-聯苯]-4-基)-1,1,1,3,3,3,3-六氟丙烷-2-醇的合成

將1,1,1,3,3,3-六氟-2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯基)丙-2-醇(500mg，1.35mmol)、4-溴-3-氯苯胺(223mg，1.08mmol)、碳酸鉀(373mg，2.70mmol)和Pd(dppf)Cl₂ (98.9mg，0.135mmol)加入到1,4-二氧六環(5mL)和水(0.5mL)的混合溶劑中。在氮氣保護下，反應混合物在100℃下攪拌反應2小時，LC-MS監測反應完全。將反應混合物冷卻至室溫，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE:EA=10:1-2:1)得到粗品，再經反相柱分離純化(乙腈：甲醇=1:1)，得到目標化合物(310mg，三步產率43.5%，白色固體)。LC-MS(ESI)m/z : 368.0 [M-H]^- 。Example 10: 2-Acetyl- N- (2-chloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1 '-Biphenyl]-4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

Step 1: 2-(4'-Amino-2'-chloro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3,3-hexafluoropropane-2 - Synthesis of alcohols

1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)phenyl)propan-2-ol (500 mg, 1.35 mmol), 4-bromo-3-chloroaniline (223 mg, 1.08 mmol), potassium carbonate (373 mg, 2.70 mmol) and Pd(dppf)Cl ₂ (98.9 mg) , 0.135 mmol) was added to a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL). Under nitrogen protection, the reaction mixture was stirred at 100 °C for 2 hours, and the reaction was complete as monitored by LC-MS. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product, which was separated and purified by silica gel column (PE:EA=10:1-2:1) to obtain crude product, and then separated and purified by reversed-phase column (acetonitrile:methanol= 1:1) to obtain the title compound (310 mg, 43.5% yield over three steps, white solid). LC-MS (ESI) m/z : 368.0 [MH] ^- .

將2-(4'-氨基-2'-氯-[1,1'-聯苯]-4-基)-1,1,1,3,3,3,3-六氟丙烷-2-醇(83.2mg，0.225mmol)和2-(第三丁氧基羰基)-6-(甲基磺醯基)-1,2,3,4-四氫異喹啉-1-甲酸(80.0mg，0.225mmol)溶於無水DCM(3mL)中。在室溫下，依次將HATU(111mg，0.293mmol)和DIEA(0.112mL，0.675mmol)加入到反應液中。加完後，反應混合物在室溫下攪拌反應2小時，LC-MS監測反應完全。將反應液倒入水(20mL)中，用DCM(15mLx2)萃取，合併有機相，依次用飽和碳酸氫鈉(20mL)中和飽和氯化銨(20mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到目標化合物(150mg，粗品，棕色油狀)。LC-MS(ESI)m/z : 705.1 [M- H]^- 。Step 2: 1-((2-Chloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- Synthesis of 4-yl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2( 1H )-carboxylic acid tert-butyl ester

2-(4'-Amino-2'-chloro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3,3-hexafluoropropan-2-ol (83.2 mg, 0.225 mmol) and 2-(tert-butoxycarbonyl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (80.0 mg, 0.225 mmol) was dissolved in dry DCM (3 mL). HATU (111 mg, 0.293 mmol) and DIEA (0.112 mL, 0.675 mmol) were sequentially added to the reaction at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours, and the reaction was complete as monitored by LC-MS. The reaction solution was poured into water (20 mL), extracted with DCM (15 mL×2), the organic phases were combined, washed sequentially with saturated sodium bicarbonate (20 mL) and saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure to give the title compound (150 mg, crude product, brown oil). LC-MS (ESI) m/z : 705.1 [M - H] ^- .

將1-((2-氯-4'-(1,1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)氨基甲醯基)-6-(甲基磺醯基)-3,4-二氫異喹啉-2(1H )-甲酸第三丁酯(150mg)溶於DCM(1.5mL)中。在冰浴下，將4mol/L鹽酸二氧六環溶液(1.5mL)滴加到反應液中。加完後，撤掉冰浴，反應混合物在室溫下繼續攪拌反應2小時，LC-MS監測反應完全。將反應液減壓濃縮，得到目標化合物(140mg，粗品，棕色油狀)。LC-MS(ESI)m/z : 605.1 [M-H]^- 。Step 3: N- (2-Chloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4 -yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride

1-((2-Chloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4- yl) carbamoyl acyl) -6- (methyl acyl sulfo) -3,4-dihydro-isoquinoline -2 (1 H) - carboxylic acid tert-butyl ester (150 mg of) was dissolved in DCM (1.5mL) in . Under an ice bath, 4 mol/L hydrochloric acid dioxane solution (1.5 mL) was added dropwise to the reaction solution. After the addition, the ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours, and the reaction was completed by LC-MS monitoring. The reaction solution was concentrated under reduced pressure to obtain the title compound (140 mg, crude product, brown oil). LC-MS (ESI) m/z : 605.1 [MH] ^- .

將N -(2-氯-4'-(1,1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)-6-(甲基磺醯基)-1,2,3,4-四氫異喹啉-1-甲醯胺鹽酸鹽(140mg，0.231mmol)溶於無水DCM(3mL)中。在室溫下，依次將三乙胺(0.096mL，0.692mmol)和乙醯氯(0.041mL，0.577mmol)滴加到反應液中。加完後，反應液在室溫下繼續攪拌反應30分鐘，LC-MS監測反應完全。將反應液直接濃縮並溶於甲醇(3mL)中，在室溫下，將1mol/L氫氧化鈉水溶液(2mL)滴加到反應液中。加完後，在室溫下繼續攪拌反應30分鐘，LC-MS監測反應完全。將反應液倒入水(20mL)中，用EA(15mLx2)萃取，合併有機相，用飽和氯化銨(20mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE：EA=1:1-0:1)得到粗品，再經反相柱分離純化(乙腈：水=7:3)得到目標化合物(49.3mg，三步產率12.9%，白色固體)。LC-MS(ESI)m/z : 649.0 [M+ H]⁺ 。¹ H NMR(400 MHz, CDCl₃ )δ 9.38(d,J = 11.7 Hz, 1H), 7.88 – 7.83(m, 2H), 7.80 – 7.68(m, 3H), 7.53 – 7.45(m, 3H), 7.43 – 7.38(m, 1H), 7.25 – 7.23(m, 1H), 6.20(s, 1H), 3.91 – 3.79(m, 3H), 3.26 – 3.15(m, 1H), 3.11 – 3.03(m, 4H), 2.32(s, 3H)。Step 4: 2-Acetyl- N- (2-chloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1' - Synthesis of -biphenyl]-4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

N- (2-Chloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl )-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (140 mg, 0.231 mmol) was dissolved in dry DCM (3 mL). At room temperature, triethylamine (0.096 mL, 0.692 mmol) and acetyl chloride (0.041 mL, 0.577 mmol) were sequentially added dropwise to the reaction solution. After the addition, the reaction solution was continued to stir at room temperature for 30 minutes, and the reaction was completed by LC-MS monitoring. The reaction solution was directly concentrated and dissolved in methanol (3 mL), and 1 mol/L aqueous sodium hydroxide solution (2 mL) was added dropwise to the reaction solution at room temperature. After the addition, the reaction was continued to stir at room temperature for 30 minutes, and the reaction was completed by LC-MS monitoring. The reaction solution was poured into water (20 mL), extracted with EA (15 mL×2), the organic phases were combined, washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was passed through a silica gel column. The crude product was isolated and purified (PE:EA=1:1-0:1), and then separated and purified by reversed-phase column (acetonitrile:water=7:3) to obtain the target compound (49.3 mg, three-step yield 12.9%, white solid) ). LC-MS (ESI) m/z : 649.0 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ )δ 9.38(d, J = 11.7 Hz, 1H), 7.88 – 7.83(m, 2H), 7.80 – 7.68(m, 3H), 7.53 – 7.45(m, 3H), 7.43 – 7.38(m, 1H), 7.25 – 7.23(m, 1H), 6.20(s, 1H), 3.91 – 3.79(m, 3H), 3.26 – 3.15(m, 1H), 3.11 – 3.03(m, 4H) ), 2.32(s, 3H).

步驟1：1-((2'-氟-4'-(1,1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)氨基甲醯基)-6-(甲磺醯基)-3,4-二氫異喹啉-2(1H )-甲酸第三丁基酯的合成

將2-(第三丁氧基羰基)-6-(乙基磺醯基)-1,2,3,4-四氫異喹啉-1-甲酸(553mg，1.56mmol)和2-(4'-氨基-2-氟-[1,1'-聯苯]-4-基)-1,1,1,3,3,3,3-六氟丙烷-2-醇(550mg，1.56mmol)溶於無水DCM(6mL)中。在室溫下，依次將HATU(770mg，2.02mmol)和DIEA(0.772mL，4.67mmol)加入到反應液中。加完後，反應混合物在室溫下攪拌反應2小時，TLC監測反應完全。將反應液倒入水(20mL)中，用DCM(15mLx2)萃取，合併有機相，依次用飽和碳酸氫鈉(20mL)和飽和氯化銨(20mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到目標化合物(1.00g，粗品，淡棕色固體)。Example 11: N- (2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl] -4-yl)-6-(methylsulfonyl)-2-propionyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

Step 1: 1-((2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl] Synthesis of -4-yl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2( 1H )-carboxylic acid tert-butyl ester

2-(Third-butoxycarbonyl)-6-(ethylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (553 mg, 1.56 mmol) and 2-(4 '-Amino-2-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3,3-hexafluoropropan-2-ol (550 mg, 1.56 mmol) Dissolved in dry DCM (6 mL). HATU (770 mg, 2.02 mmol) and DIEA (0.772 mL, 4.67 mmol) were sequentially added to the reaction at room temperature. After the addition, the reaction mixture was stirred at room temperature for 2 hours, and the reaction was completed by TLC monitoring. The reaction solution was poured into water (20 mL), extracted with DCM (15 mL×2), the organic phases were combined, washed successively with saturated sodium bicarbonate (20 mL) and saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentration under reduced pressure gave the title compound (1.00 g, crude, light brown solid).

將1-((2'-氟-4'-(1,1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)氨基甲醯基)-6-(甲磺醯基)-3,4-二氫異喹啉-2(1H )-甲酸第三丁基酯(1.00g)溶於DCM(5mL)中。在冰浴下，將4mol/L鹽酸二氧六環溶液(5mL)滴加到反應液中。加完後，撤掉冰浴，反應混合物在室溫下繼續攪拌反應2小時，LC-MS監測反應完全。將反應液減壓濃縮，得到目標化合物(700mg，粗品，黃色固體)。LC-MS(ESI)m/z : 591.1 [M+H]⁺ 。Step 2: N- (2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- Synthesis of 4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride

1-((2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4 -yl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2( 1H )-carboxylic acid tert-butyl ester (1.00 g) was dissolved in DCM (5 mL) middle. Under an ice bath, a 4 mol/L hydrochloric acid dioxane solution (5 mL) was added dropwise to the reaction solution. After the addition, the ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours, and the reaction was completed by LC-MS monitoring. The reaction solution was concentrated under reduced pressure to obtain the title compound (700 mg, crude product, yellow solid). LC-MS (ESI) m/z : 591.1 [M+H] ⁺ .

將N -(2'-氟-4'-(1,1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)-6-(甲基磺醯基)-1,2,3,4-四氫異喹啉-1-甲醯胺鹽酸鹽(100mg，0.169mmol)溶於無水DCM(3mL)中。在室溫下，依次將三乙胺(0.071mL，0.508mmol)和丙醯氯(0.037mL，0.423mmol)滴加到反應液中。加完後，反應液在室溫下繼續攪拌反應30分鐘，LC-MS監測反應完全。將反應液直接濃縮並溶於甲醇(3mL)中，在室溫下，將1mol/L氫氧化鈉水溶液(2mL)滴加到反應液中。加完後，在室溫下繼續攪拌反應30分鐘，LC-MS監測反應完全。將反應液倒入水(20mL)中，用EA(15mLx2)萃取，合併有機相，用飽和氯化銨(20mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE：EA=1:1-0:1)得到粗品，再經反相柱分離純化(乙腈：水=7:3)得到目標化合物(31.1mg，三步產率21.6%，白色固體)。LC-MS(ESI)m/z : 647.1 [M+ H]⁺ 。¹ H NMR(400 MHz, CDCl₃ )δ 8.26 – 7.94(m, 1H), 7.90 – 7.73(m, 2H), 7.43 – 7.30(m, 4H), 7.12 – 6.76(m, 3H), 6.48(s, 1H), 4.44 – 4.22(m, 1H), 3.75 – 3.62(m, 1H), 3.60 – 3.39(m, 1H), 3.14 – 2.90(m, 5H), 2.73 – 2.58(m, 1H), 1.45(t, 3H)。Step 3: N- (2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- Synthesis of 4-yl)-6-(methylsulfonyl)-2-propionyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

N- (2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4- yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100 mg, 0.169 mmol) was dissolved in dry DCM (3 mL). At room temperature, triethylamine (0.071 mL, 0.508 mmol) and acryl chloride (0.037 mL, 0.423 mmol) were sequentially added dropwise to the reaction solution. After the addition, the reaction solution was continued to stir at room temperature for 30 minutes, and the reaction was completed by LC-MS monitoring. The reaction solution was directly concentrated and dissolved in methanol (3 mL), and 1 mol/L aqueous sodium hydroxide solution (2 mL) was added dropwise to the reaction solution at room temperature. After the addition, the reaction was continued to stir at room temperature for 30 minutes, and the reaction was completed by LC-MS monitoring. The reaction solution was poured into water (20 mL), extracted with EA (15 mL×2), the organic phases were combined, washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was passed through a silica gel column. The crude product was obtained by separation and purification (PE:EA=1:1-0:1), and then separated and purified by reversed-phase column (acetonitrile:water=7:3) to obtain the target compound (31.1 mg, three-step yield 21.6%, white solid) ). LC-MS (ESI) m/z : 647.1 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ )δ 8.26 – 7.94(m, 1H), 7.90 – 7.73(m, 2H), 7.43 – 7.30(m, 4H), 7.12 – 6.76(m, 3H), 6.48(s , 1H), 4.44 – 4.22(m, 1H), 3.75 – 3.62(m, 1H), 3.60 – 3.39(m, 1H), 3.14 – 2.90(m, 5H), 2.73 – 2.58(m, 1H), 1.45 (t, 3H).

將N -(2'-氟-4'-(1,1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)-6-(甲基磺醯基)-1,2,3,4-四氫異喹啉-1-甲醯胺鹽酸鹽(100mg，0.169mmol)溶於無水DCM(3mL)中。在室溫下，依次將三乙胺(0.071mL，0.508mmol)和環丙基甲醯氯(0.0385mL，0.423mmol)滴加到反應液中。加完後，反應液在室溫下繼續攪拌反應30分鐘，LC-MS監測反應完全。將反應液直接濃縮並溶於甲醇(3mL)中，在室溫下，將1mol/L氫氧化鈉水溶液(2mL)滴加到反應液中。加完後，在室溫下繼續攪拌反應30分鐘，LC-MS監測反應完全。將反應液倒入水(20mL)中，用EA(15mLx2)萃取，合併有機相，用飽和氯化銨(20mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE：EA=1:1-0:1)得到粗品，再經反相柱分離純化(乙腈：水=7:3)得到目標化合物(41.7mg，三步產率28.4%，白色固體)。LC-MS(ESI)m/z : 700.0 [M+ ACN+H]⁺ 。¹ H NMR(400 MHz, DMSO-d ₆ )δ 10.83,10.70(s, 1H), 7.88 – 7.78(m, 3H), 7.74 – 7.62(m, 3H), 7.60 – 7.46(m, 4H), 6.16, 5.90(s, 1H), 4.39 – 4.19(m, 1H), 4.05 – 3.83(m, 2H), 3.27 – 3.22(m, 1H), 3.18(s, 3H), 3.10 – 3.01(m, 1H), 2.15 – 2.07(m, 1H), 0.88 – 0.68(m, 4H)。Example 12: 2- (cyclopropanecarbonyl) - N - (2'- fluoro-4 '- (1,1,1,3,3,3-hexafluoro-2-hydroxy-2-yl) - [ 1,1'-Biphenyl]-4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

N- (2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4- yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100 mg, 0.169 mmol) was dissolved in dry DCM (3 mL). At room temperature, triethylamine (0.071 mL, 0.508 mmol) and cyclopropylformyl chloride (0.0385 mL, 0.423 mmol) were sequentially added dropwise to the reaction solution. After the addition, the reaction solution was continued to stir at room temperature for 30 minutes, and the reaction was completed by LC-MS monitoring. The reaction solution was directly concentrated and dissolved in methanol (3 mL), and 1 mol/L aqueous sodium hydroxide solution (2 mL) was added dropwise to the reaction solution at room temperature. After the addition, the reaction was continued to stir at room temperature for 30 minutes, and the reaction was completed by LC-MS monitoring. The reaction solution was poured into water (20 mL), extracted with EA (15 mL×2), the organic phases were combined, washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was passed through a silica gel column. The crude product was isolated and purified (PE:EA=1:1-0:1), and then separated and purified by reversed-phase column (acetonitrile:water=7:3) to obtain the target compound (41.7 mg, three-step yield 28.4%, white solid) ). LC-MS (ESI) m/z : 700.0 [M + ACN+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ )δ 10.83, 10.70(s, 1H), 7.88 – 7.78(m, 3H), 7.74 – 7.62(m, 3H), 7.60 – 7.46(m, 4H), 6.16 , 5.90(s, 1H), 4.39 – 4.19(m, 1H), 4.05 – 3.83(m, 2H), 3.27 – 3.22(m, 1H), 3.18(s, 3H), 3.10 – 3.01(m, 1H) , 2.15 – 2.07(m, 1H), 0.88 – 0.68(m, 4H).

將N -(2'-氟-4'-(1,1,1,3,3,3-六氟-2-羥基丙烷-2-基)-[1,1'-聯苯]-4-基)-6-(甲基磺醯基)-1,2,3,4-四氫異喹啉-1-甲醯胺鹽酸鹽(100mg，0.169mmol)溶於無水DCM(3mL)中。在室溫下，依次將三乙胺(0.071mL，0.508mmol)和甲胺基甲醯氯(39.6mg，0.423mmol)加到反應液中。加完後，反應液在室溫下繼續攪拌反應30分鐘，LC-MS監測反應完全。將反應液倒入水(20mL)中，用DCM(15mLx2)萃取，合併有機相，依次用飽和碳酸氫鈉(20mL)和飽和氯化銨(20mL)洗滌，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到粗品，經矽膠柱分離純化(PE：EA=1:1-0:1)得到粗品，再經反相柱分離純化(乙腈：水=7:3)，得到目標化合物(41.7mg，三步產率28.5%，白色固體)。LC-MS(ESI)m/z : 648.0 [M+ H]⁺ 。¹ H NMR(400 MHz, DMSO-d ₆ )δ 10.60(s, 1H), 7.84 – 7.75(m, 3H), 7.73 – 7.63(m, 3H), 7.58 – 7.47(m, 4H), 6.71 – 6.65(m, 1H), 5.83(s, 1H), 3.91 – 3.81(m, 1H), 3.56 – 3.48(m, 1H), 3.22 – 3.13(m, 4H), 3.02 – 2.92(m, 1H), 2.62(d,J = 4.1 Hz, 3H)。Example 13: N 1-(2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl ]-4-yl) -N 2-methyl-6-(methylsulfonyl)-3,4-dihydroisoquinoline-1,2( 1H )-dimethylamide

N- (2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4- yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100 mg, 0.169 mmol) was dissolved in dry DCM (3 mL). Triethylamine (0.071 mL, 0.508 mmol) and methylaminoformyl chloride (39.6 mg, 0.423 mmol) were sequentially added to the reaction at room temperature. After the addition, the reaction solution was continued to stir at room temperature for 30 minutes, and the reaction was completed by LC-MS monitoring. The reaction solution was poured into water (20 mL), extracted with DCM (15 mL×2), the organic phases were combined, washed successively with saturated sodium bicarbonate (20 mL) and saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentrate under reduced pressure to obtain the crude product, which was separated and purified by silica gel column (PE:EA=1:1-0:1) to obtain the crude product, and then separated and purified by reversed-phase column (acetonitrile:water=7:3) to obtain the target compound (41.7mg , three-step yield 28.5%, white solid). LC-MS (ESI) m/z : 648.0 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ )δ 10.60(s, 1H), 7.84 – 7.75(m, 3H), 7.73 – 7.63(m, 3H), 7.58 – 7.47(m, 4H), 6.71 – 6.65 (m, 1H), 5.83(s, 1H), 3.91 – 3.81(m, 1H), 3.56 – 3.48(m, 1H), 3.22 – 3.13(m, 4H), 3.02 – 2.92(m, 1H), 2.62 (d, J = 4.1 Hz, 3H).

Activity Example 1: In vitro assay of compound inhibition of RORγt luciferase reporter gene

This experiment was basically carried out according to the method described in the literature (Current Chemical Genomics, 2010, 4, 43-49).

The RORγ-LBD coding sequence was inserted into the pBIND plasmid (Promega, E1581). This expression vector and a reporter vector (pGL4.35 carrying a 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 gene vector and inhibits reporter gene expression. The inhibitory activity of the compound on RORγ was determined according to the intensity of the chemiluminescence signal.

Reagents and Consumables Materials and Reagents supplier batch number HEK293T ATCC CRL-3216 pGL4.35 Promega E1370 pBIND-RORγ Vector Pharmaron PBS (pH 7.4, 1×, sterile) Gibico 10010 Opti-MEM® I Reduced Serum Medium Gibico 11058-021 Steady-Glo™ Promega E2520 AZD-0284 MCE HY-120384

experimental method:

1. Preparation of Experimental Compounds 1.1 All compounds to be tested were diluted 3-fold with DMSO, 10 dilution gradients, and the starting concentration was 10 mM. 1.2 The positive control AZD-0284 was diluted 3-fold with DMSO, with 10 dilution gradients, and the initial concentration was 10 mM. 1.3 Prepare 1000× positive control (10 mM AZD-0284) and 1000× negative control (100% DMSO). 1.4 Seal the compound plate and shake for 5 min.

2. Experimental procedure 2.1 Cell suspension preparation and seeding a) All cells were cultured according to ATCC standard operation, and HEK293T was subjected to experiments in exponential growth phase. b) Discard the medium. c) Wash cells twice with PBS. d) Add trypsinization solution to digest cells and stop digestion with complete medium. e) Collect the cells and count them. Only when the cell viability is greater than 90% can the experiment be performed. f) Seed 6*10 ⁶ HEK293T cells into 100mm cell culture dishes. g) Place the culture dish with the seeded cells in a 37°C, 5% CO ₂ incubator overnight.

2.2 Transfection of cells a) Place Trans-IT transfection reagent to equilibrate at room temperature; b) Add 20 μL of transfection reagent and 600 μL of Opti-MEM™ medium, being careful not to touch the tube wall, blow and mix with a pipette, and let stand at room temperature c) Add 10μg plasmid to the transfection reagent (see step 2.2.b), let stand for 20 minutes at room temperature; Plasmid: add 5μg pBIND-RORγ and 5μg pGL4.35 plasmid respectively d) Mix the DNA Add the transfection reagent to a 100mm cell culture dish (see step 2.1); e) Place the culture dish at 37°C, 5% CO ₂ incubator for 5h.

2.3 Compound treatment a) Transfer 25nL of diluted compound with Echo550 to cell culture plate (6007680-50, PE); b) Inoculate cells (see step 2.2) into 384 cell culture plate (6007680-50, PE) ), 15,000 cells per well, 25 μL of 5% charcoal-adsorbed FBS medium; c) Cells were cultured overnight _{in a 37°C, 5% CO 2 incubator.}

2.4 Detection of compounds: a) Place the Steady-Glo™ detection reagent at room temperature; b) Place the 384 cell plate (see step 2.3) at room temperature; c) Add 25μL of Steady-Glo™ Detection Reagent to each well of the cell culture plate (see step 2.4b); d) Put the board on the shaker for 5 minutes in the dark; e) Chemiluminescence values were detected with Envision 2104.

RLU_cmpd :測試化合物的螢光值 R(——)L(——)U(——) _positive :陽性對照平均值 R(——)L(——)U(——) _vehicle :陰性對照平均值 用GraphPad8.0通過擬合%Inhibition和化合物濃度的log值來計算化合物的IC₅₀ 。測定結果顯示，本發明的化合物對RORγt螢光素酶報告基因有較好的抑制活性(如表1所示)。Calculation of % Inhibition:

RLU _cmpd : Fluorescence value of the test compound R(——)L(——)U(——) _positive : Average value of positive control R(——)L(——)U(——) _vehicle : Average value of negative control GraphPad8.0 value of IC ₅₀ was calculated by fitting% Inhibition compound and a log of compound concentration. The assay results show that the compounds of the present invention have good inhibitory activity on the RORγt luciferase reporter gene (as shown in Table 1).

Table 1. Determination of Inhibitory Activity of Example Compounds on RORγt Luciferase Reporter Gene Example IC ₅₀ (nM) Emax% 1 15.46 101.5 3 106 97.07 4 34.56 100.2 5 15.84 99.5 7 76.3 97.32 8 24.98 98.29 9 185.9 99.26 10 22.54 101.1 11 76.33 101.6 12 144.6 103.5 13 697.8 96.87 AZD-0284 34.81 99.79 Note: Emax% is the relative maximum inhibition rate relative to AZD-0284 at 10 μM.

Activity Example 2: Compounds Inhibition Experiment on Human PBMC Th17 Cell Differentiation

experiment material: Materials and Reagents supplier Item# batch number# hPBMC TPCS PB100C A19Z018001 RPMI1640 Gibco A10491-01 2037571 penicillin-streptomycin Gibco 15140-122 1953104 fetal bovine serum Gibco 10099-141C 2045686CP Phosphate Buffered Saline (PBS) Gibco 10010-031 2003918 DMSO Sigma D8418-1L SHBG3288V Purified NA/LE mouse anti-human CD3 BD 555336 8152611 Purified NA/LE mouse anti-human CD28 BD 555725 8152601 Recombinant human TGF-beta 1 R&D 240-B AV7117011 Recombinant human IL-6 R&D 7270-IL-025/CF DAOM0318061 Recombinant human IL-23 R&D 1290-IL-010/CF GBI6218031 Ursolic acid (UA) Sigma U6753 BCBQ8542V Quantikine® ELISA Human IL-17 Immunoassay R&D S1700 P192117

Experimental method: First, PBMC cells were recovered and plated, and then PBMC cells were stimulated with stimulating factors (anti-hCD28: 5µg/mL; rhTGF-β1: 5ng/mL; rhIL-6: 20ng/mL; rhIL-23: 10ng/mL). Differentiated to Th17, different concentrations of compounds were added at the same time, and the maximum concentration started from 3 μM. After 48 hours, the supernatant was collected for IL-17 ELISA detection. Compared with the solvent group, the inhibition rate of compounds inhibiting the secretion of IL-17 by Th17 cells was determined using Graphad8. 0 ₅₀ fit value IC.

The assay results show that the compounds of the present invention have a good ability to inhibit the differentiation and secretion of IL-17 of Th17 cells on human PBMCs (as shown in Table 2).

Table 2. Experimental results of compounds inhibiting Th17 cell differentiation and secretion of IL-17 Example IC ₅₀ (nM) Emax% 1 28.75 83.18 4 87.32 83.4 5 55.69 100.89 8 38.38 83.15 AZD-0284 28.41 78.54 Note: Emax% is the maximum inhibition rate.

Active Example 3: Metabolic Stability Experiment of Human and Mouse Liver Microsomes

According to standard methods of in vitro metabolic stability studies routine in the field, eg (Kerns, Edward H. and Di Li (2008). Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization . San Diego: Academic Press; Di, Li et al., Optimization of a Higher Throughput Microsomal Stability Screening Assay for Profiling Drug Discovery Candidates, J. Biomol. Screen. 2003 , 8(4), The method described in 453.) was similarly carried out as follows. Liver microsomal metabolic stability test of inventive compounds.

The incubation system includes 0.5 mg protein/mL microsomes, cofactors, and PBS, pre-incubated at 37° C. for 3 min, and then adding matrix (ie, the compound to be tested) to initiate the reaction. Samples were taken at 0, 1, 5, 10, 15, 20, 30, and 60 min of the start of the reaction, and an appropriate terminator was added to terminate the reaction. type product information supplier abbreviation people Cat No. 452117 Corning HLM Lot No. 38292 CD-1 mice Cat No. BQM1000 Biopredic MLM Lot No. MIC255036

Sample processing (n=3): each appropriate sample was added, vortexed and centrifuged at high speed, and the supernatant was taken, and the matrix was detected by HPLC-MS/MS. The peak area at the 0 min time point was taken as 100%. The peak area at other time points was converted into the percentage residual amount, the natural logarithm of the residual amount at each time point was plotted against the incubation time, and the slope (-k) was calculated by linear regression, and then the inherent clearance rate (CLint) = ( k* volume of incubation solution)/mass of liver microsomes, CLint (μL/min/mg) and compound half-life (T _1/2 , min) were calculated. The results are shown in Table 3.

Table 3. Experimental results of metabolic stability of human and mouse liver microsomes human liver microsomes mouse liver microsomes Example cLogP T _1/2 (min) Remaining % (T=60min) Clint (mic) (μL/min/mg) T _1/2 (min) Remaining % (T=60min) Clint (mic) (μL/min/mg) 1 2.6 > 145 122.3% < 9.6 > 145 86.3% < 9.6 4 3.14 > 145 99.3% < 9.6 136.7 76.78% 10.1 5 3.1 > 145 96.0% < 9.6 > 145 80.4% < 9.6 7 3.67 > 145 83.1% < 9.6 57.2 49.2% 24.2 8 2.39 > 145 109.2% < 9.6 139.2 73.5% 9.9 The above experimental results show that the compounds of the present invention have good metabolic stability.

Active Example 4: Compound PK Assay in Mice

The PK determination method for each compound was as follows: 6 C57BL/6 mice (sourced from Shanghai Lingchang Biotechnology Co., Ltd.) were divided into two groups, 3 mice in each group. One group was administered intravenously (IV) at a dose of 1 mg/kg in a vehicle of 5% DMSO/95% (20% Captisol); one group was administered by oral (PO) gavage at a dose of 5 mg/kg in a vehicle of 0.5 % CMC-Na/0.5% Tween 80. Blood was collected from saphenous vein of lower leg in each group at 0, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. About 40 μL of blood was collected into anticoagulant tubes containing EDTA-K2. Immediately after collection, invert the blood collection tube at least 5 times to ensure uniform mixing and place on ice. The blood collected at each time point was centrifuged at 4°C, 8000 rpm for 5 minutes to obtain plasma. Another 1.5mL centrifuge tube was marked with the compound name, animal number, and time point, and the plasma was transferred to this tube. Plasma was stored at -80°C until analysis.

The compound concentration in plasma was determined by UPLC-MS/MS method, and the pharmacokinetic parameters of the obtained data were calculated by Phoenix WinNolin 6.4 pharmacokinetic software.

The specific experimental results are as follows. The results show that the compound has better pharmacokinetic absorption and has the advantages of pharmacokinetics. _{The AUC 0-last} (ng/mL*hr) and bioavailability of the compounds of the present invention were significantly improved, indicating that they have better druggability. Table 4. In vivo PK results of the compounds of the examples compound 1 4 AZD-0284 IV dose 1mg/kg AUC _0-last (ng/mL*hr) 7518 14147 1176 Cmax(ng/mL) 1239 1165 2484 T _1/2 (hr) 14.2 23.2 7.75 Vss(L/kg) 1.81 1.01 6.29 CL_obs(mL/min/kg) 1.56 0.77 12.6 PO dose 5mg/kg AUC _0-last (ng/mL*hr) 10233 48405 2781 Cmax(ng/mL) 707 3130 264 T _1/2 (hr) > 8 14.1 3.35 F% 27.2 68.4 38

AZD-0284。The structures of the control compounds used in the above experiments are as follows:

AZD-0284.

Those skilled in the art will appreciate that the foregoing description is exemplary and explanatory in nature and is intended to illustrate the invention and preferred embodiments thereof. Through routine experimentation, the skilled artisan will appreciate that obvious modifications and changes can be made without departing from the spirit of the invention. All such modifications as come within the scope of the appended claims are intended to be included therein. Accordingly, it is intended that the invention be defined not by the above description, but by the following claims and their equivalents.

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

Claims (15)

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

(I) wherein: R ₁ and R ₂ are each independently selected from hydrogen, halogen, cyano, nitro, C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl , -NH-C ₁ -C ₆ alkyl, -N-(C ₁ -C ₆ alkyl) ₂ , -C ₁ -C ₆ alkyl -OC ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl base-SC ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl or -C ₁ -C ₆ alkyl-N(C ₁ -C ₆ alkyl) ₂ , wherein the C ₁ -C ₆ alkyl is optionally substituted by halogen or cyano; R _{3 is} selected from H, -C ₁ -C ₆ alkyl, -C ₃ -C ₇ cycloalkyl, -4-7 membered hetero Cycloalkyl, -NR _a R _a or -OR _a , wherein C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted independently selected from radical substitution: halogen, cyano, nitro, C ₃ -C ₇ cycloalkyl optionally substituted by halogen, R _a , -OR _a , -SR _a or -NR _a R _a , wherein R _{a is} selected from H or _{C 1} -C ₆ alkyl optionally substituted by halogen, or two R _a attached to the same N atom can form 4-7 membered nitrogen-containing heterocycloalkyl together with the N atom to which they are attached; R ₄ selected from -C ₁ -C ₆ alkyl, -C ₃ -C ₇ cycloalkyl, -4-7 membered heterocycloalkyl or optionally by C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or 4-7 membered heterocycloalkyl substituted amino, wherein said C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted each independently selected from Substituent substitution of: halogen, cyano, nitro, R _a , -OR _a , -SR _a , -NR _a R _{a or C 3} -C ₇ cycloalkyl optionally substituted by halogen, wherein R _{a is} selected from _{H or C 1} -C ₆ alkyl optionally substituted by halogen, or two groups attached to the same N atom may together with the N atom to which they are attached form a 4-7 membered nitrogen-containing heterocycloalkyl; R ₅ and R ₆ are each independently selected from H, halogen, cyano, or C ₁ -C ₆ alkyl optionally substituted with halogen or cyano; m and p are each independently selected from 0, 1, or 2, and n Selected from 0 or 1. The compound of claim 1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein R ₁ and R ₂ are each independently H or halogen . The compound of claim 1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein R ₁ and R ₂ are each independently C ₁ - C ₆ alkyl or -OC ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted by halogen. The compound of any one of claims 1-3, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein R ₃ is -C ₁ -C ₆ alkyl, preferably C ₁ -C ₃ alkyl. The compound of any one of claims 1-3, a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -C ₃ -C ₇ cycloalkyl, preferably cyclopropyl, cyclobutyl or cyclopentyl. The compound of any one of claims 1-3, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein R ₃ is -NR _a R _a , wherein R _{a is independently selected from H or C 1} -C ₃ alkyl optionally substituted with one or more halogens. The compound of any one of claims 1-6, a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -C ₁ -C ₆ alkyl, preferably C ₁ -C ₃ alkyl. The compound of any one of claims 1-7, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R ₅ and R ₆ each is independently selected from halogen or halogen-substituted C ₁ -C ₆ alkyl, preferably R ₅ and R ₆ are -CF _3. A compound selected from

Stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof. A compound according to any one of claims 1 to 9, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, for use as a medicament, especially with As a RORγt inhibitor, or for the treatment, especially for the treatment or prevention of diseases related to RORγt. A pharmaceutical composition, comprising the compound described in any one of claims 1 to 9, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates and pharmaceutically acceptable with excipients. A method for preventing or treating diseases related to RORγt in mammals, particularly humans, the method comprising administering an effective amount of the compound according to any one of claims 1 to 9, a stereoisomer thereof, an interactive A variant, stable isotopic variant, pharmaceutically acceptable salt or solvate or the pharmaceutical composition of claim 11. The compound of any one of claims 1 to 9, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates or the pharmaceutical composition of claim 11 Use for the prevention or treatment of RORγt-related diseases. The compound of any one of claims 1 to 9, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates or the pharmaceutical composition of claim 11 Use in the preparation of a medicament for preventing or treating diseases related to RORγt. The compound according to claim 10, the method according to claim 12, or the use according to claim 13 or 14, wherein the disease related to RORγt 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, dermatomuscular allergic rhinitis, necrotizing enterocolitis, liver fibrosis, Nonalcoholic steatohepatitis (NASH), COVID-19, insulin-dependent type 1 diabetes, triple-negative breast and prostate cancer.