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HK40062607A - BIARYL COMPOUNDS USEFUL AS RORγ MODULATORS - Google Patents

BIARYL COMPOUNDS USEFUL AS RORγ MODULATORS Download PDF

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Publication number
HK40062607A
HK40062607A HK42022050302.3A HK42022050302A HK40062607A HK 40062607 A HK40062607 A HK 40062607A HK 42022050302 A HK42022050302 A HK 42022050302A HK 40062607 A HK40062607 A HK 40062607A
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Hong Kong
Prior art keywords
alkyl
compound
halogen
optionally substituted
pharmaceutically acceptable
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HK42022050302.3A
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Chinese (zh)
Inventor
Cheng Yaobang
Huang Yafei
Zhou Juan
Dong Zhiqiang
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Shanghai Litedd Co., Ltd.
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Publication of HK40062607A publication Critical patent/HK40062607A/en

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Description

Biaryl compounds useful as ROR gamma modulators
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to a biaryl compound with ROR gamma t inhibitory activity, a pharmaceutical composition containing the compound, a method for preparing the compound, and application of the compound in preparing a medicine for preventing or treating ROR gamma t related diseases.
Background
Retinoic acid receptor-Related Orphan Receptors (RORs), also known as NF1R, belong to a subfamily of the nuclear receptor superfamily of ligand-dependent transcription factors. The RORs subfamily mainly includes three subtypes, ROR α, ROR β and ROR γ. ROR γ contains two members: ROR γ 1 (also called ROR γ) and ROR γ 2 (also called ROR γ t), in which ROR γ 1 is distributed in skeletal muscle, thymus, testis, pancreas, prostate, heart, liver, and the like, and ROR γ t is expressed only in some immune cells.
Littman et al first reported that ROR γ T was necessary for the initial differentiation of CD4+ T cells into Th17 cells (Cell, 2006126, 1121-1133). During the differentiation process of antigen-stimulated Thp cells to Th17 cells, ROR gamma t is induced and expressed under the action of cytokines such as IL-6, IL-21 and TGF-beta. The ability of Thp cells isolated from ROR γ t-deficient mice to differentiate into the Th17 cell line was significantly reduced. These all indicate that ROR γ t is a key regulator for promoting differentiation of Th17 cells.
Th17 cells are one of the helper T cells, and produce IL-17 and other proinflammatory cytokines. Th17 cells play a key role in many mouse models of autoimmune disease, such as Experimental Allergic Encephalomyelitis (EAE) and collagen-induced arthritis (CIA) animal models. Furthermore, increased IL-17 levels are detectable in some human autoimmune diseases, including Rheumatoid Arthritis (RA), Multiple Sclerosis (MS), Psoriasis (Psoriasis) and Inflammatory Bowel Disease (IBD). The number of Th17 cells found in both tissues and peripheral blood samples from patients with autoimmune disease is increased. Therefore, the Th17 cell or the cytokine IL-17 produced by it are closely related to the pathogenesis of inflammation and autoimmune diseases.
The monoclonal antibody Cosentyx (Secukinumab/AIN457) developed by Nowa, which is used to treat psoriasis by specifically blocking IL-17, was approved by the FDA to be marketed in 1 month 2015, and is the first drug acting on IL-17 in the psoriasis-treating drug market. Subsequently, the monoclonal antibody ixekizumab, targeting the pro-inflammatory cytokine IL-17A, was approved for use in the indications psoriasis, psoriatic arthritis. The clinical success of these monoclonal antibodies demonstrates the importance of the IL-17 signaling pathway in inflammatory and autoimmune diseases and demonstrates the potential for treating inflammatory and autoimmune diseases by affecting the IL-17 signaling pathway through ROR γ t inhibitors.
Therefore, ROR gamma t can be used as a new target of drugs for treating autoimmune diseases, and the search for ROR gamma t small molecule inhibitors and the application of ROR gamma t small molecule inhibitors in treating ROR gamma t mediated diseases such as inflammation and autoimmune diseases have important significance.
To date, a total of 4 small molecules of ROR γ t inhibitors were in clinical stage 2, 7 small molecules of ROR γ t inhibitors were in clinical stage 1, and none of the compounds had entered clinical stage 3. Therefore, there is still a great need to find and develop new ROR γ t inhibitor compounds for the prevention and/or treatment of diseases associated with ROR γ t, such as inflammatory and autoimmune diseases. In addition to satisfactory ROR γ t inhibitory activity, such compounds are expected to have high selectivity for ROR subtypes and good or even improved druggability based on structural optimization, so as to provide more drug options and better therapeutic effects for patients with related diseases.
Brief description of the invention
The present invention relates to compounds useful for the prevention or treatment of diseases associated with ROR γ t. In particular, it has been identified that the compounds of the present invention not only show satisfactory ROR γ t inhibitory activity, have the ability to regulate Th17 cell differentiation, thereby inhibiting IL-17 production, but also show good performance in vivo pharmacokinetic experiments, suggesting improved druggability and improved bioavailability; in addition, the compound also shows good safety and has lower risk of drug interaction. Therefore, the compound of the present invention can not only achieve the purpose for preventing or treating diseases associated with ROR γ t, but also the prepared drug is expected to have improved absorption, enhanced therapeutic effect at the same dose, or provide the same therapeutic effect at a lower dose, longer half-life and/or reduce possible side effects. Thus, the present invention also provides the use of the compounds of the present invention for the preparation of medicaments for the prevention or treatment of diseases associated with ROR γ t, pharmaceutical compositions comprising the compounds and methods for the prevention and/or treatment of diseases associated with ROR γ t by administering the compounds.
Accordingly, in one aspect of the present invention, there is provided a compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof:
wherein:
R1and R2Each independently selected from hydrogen, halogen, cyano, nitro, C1-C6Alkyl, -O-C1-C6Alkyl, -S-C1-C6Alkyl, -NH-C1-C6Alkyl, -N- (C)1-C6Alkyl radical)2、-C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-S-C1-C6Alkyl, -C1-C6alkyl-NH-C1-C6Alkyl or-C1-C6alkyl-N (C)1-C6Alkyl radical)2Wherein said C is1-C6Alkyl is optionally substituted by halogen or cyano;
R3selected from H, -C1-C6Alkyl, -C3-C7Cycloalkyl, -4-7 membered heterocycloalkyl, -NRaRaOR-ORaIn which C is1-C6Alkyl radical, C3-C7Cycloalkyl radicalsOr 4-7 membered heterocycloalkyl optionally substituted with substituents independently selected from: halogen, cyano, nitro, C optionally substituted by halogen3-C7Cycloalkyl radical, Ra、-ORa、-SRaor-NRaRa，RaSelected from H or C optionally substituted by halogen1-C6Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-7 membered nitrogen containing heterocycloalkyl group;
R4is selected from-C1-C6Alkyl, -C3-C7Cycloalkyl, -4-7 membered heterocycloalkyl or optionally substituted by C1-C6Alkyl radical, C3-C7Cycloalkyl or 4-7 membered heterocycloalkyl substituted amino, wherein said C1-C6Alkyl radical, C3-C7Cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted with substituents each independently selected from: halogen, cyano, nitro, Ra、-ORa、-SRa、-NRaRaOr C optionally substituted by halogen3-C7Cycloalkyl, wherein RaSelected from H or C optionally substituted by halogen1-C6Alkyl, or two groups attached to the same N atom may form, together with the N atom to which they are attached, a 4-7 membered nitrogen containing heterocycloalkyl group;
R5and R6Each independently selected from H, halogen, cyano or C optionally substituted by halogen or cyano1-C6An alkyl group;
m and p are each independently selected from 0, 1 or 2, and
n is selected from 0 or 1.
In another aspect of the present invention, there is provided a compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, having ROR γ t inhibitory activity for use as a medicament, particularly as an inhibitor of ROR γ t.
In another aspect of the invention, there is provided a compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, for use in the treatment, particularly in the treatment or prevention of a disease associated with ROR γ t.
In another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention as described above and a pharmaceutically acceptable excipient. In a specific aspect, the pharmaceutical composition of the present invention is provided for the prevention or treatment of diseases associated with roryt. In a particular aspect, the pharmaceutical composition may additionally comprise additional therapeutically active ingredients suitable for use in combination with the compounds of the present invention.
In another aspect of the present invention, there is provided a pharmaceutical combination comprising a compound of the invention as described above and an additional active agent.
In another aspect of the present invention, there is provided a method for the prevention or treatment of diseases associated with roryt in a mammal, particularly a human, which comprises administering an effective amount of a compound of the present invention described herein or a pharmaceutical composition comprising the same.
In another aspect of the present invention, there is provided a use of the above-described compound or pharmaceutical composition of the present invention for preventing or treating a disease associated with roryt.
In another aspect of the present invention, there is provided a use of the above-described compound or pharmaceutical composition of the present invention for the preparation of a medicament for the prevention or treatment of a disease associated with roryt.
In further aspects, methods are provided for the synthesis of compounds of the invention, wherein representative synthetic schemes and routes are described below.
Other objects and advantages of the present invention will become apparent to those skilled in the art from a reading of the following detailed description.
Detailed Description
Definition of
Unless otherwise indicated, each term used in the specification and claims has the following meaning. Where a particular term or phrase is not specifically defined, it should not be considered uncertain or clear, but rather should be understood appropriately according to the context herein or ordinary meaning in the art. Many of the groups defined herein are optionally substituted and the list of substituents given in this definition section are exemplary only and are not intended to limit the substituents defined elsewhere in this specification and claims.
The term "alkyl" as used herein means a straight or branched chain aliphatic hydrocarbon group having the indicated number of carbon atoms. Specifically, the alkyl group can have 1 to 6,1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Suitably C1-6Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and isohexyl. Particular alkyl groups have 1 to 3 carbon atoms.
The term "alkoxy" as used herein means the group-O-alkyl, wherein alkyl has the meaning described herein. In particular, the term refers to the group-O-C1-6An alkyl group. Examples of suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1, 2-dimethylbutoxy. Particular alkoxy groups have 1 to 3 carbon atoms.
The term "alkylthio" as used herein means the group-S-alkyl, wherein alkyl has the meaning described herein. In particular, the term refers to the group-S-C1-6An alkyl group. Examples of suitable alkylthio groups include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio, sec-butylthio, n-pentylthio, n-hexylthio, and 1, 2-dimethylbutylthio. Particular alkylthio groups have 1 to 3 carbon atoms.
As used herein, the term "halogen-substituted C1-C6Alkyl "means C as defined above1-C6Alkyl, wherein one or more (e.g. 1,2,3,4 or 5) hydrogen atoms are replaced by halogen. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. "halogen-substituted C1-C6Examples of alkyl radicals "are, for example, -CH2F、-CHF2、-CF3、-CCl3、-C2F5、-C2Cl5、-CH2CF3、-CH2Cl、CH2CH2CF3or-CF (CF)3)2And the like.
As used herein, the term "halogen-substituted C1-C6Alkoxy "means C as defined above1-C6Alkoxy, wherein one or more (e.g. 1,2,3,4 or 5) hydrogen atoms are replaced by halogen. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. "halogen-substituted C1-C6Examples of alkoxy "are e.g. -OCH2F、-OCHF2、-OCF3、-OCCl3、-OC2F5、-OC2Cl5、-OCH2CF3、-OCH2Cl or-OCH2CH2CF3And the like.
As used herein, the term "halogen-substituted C1-C6Alkylthio "refers to C as defined above1-C6Alkylthio, wherein one or more (e.g. 1,2,3,4 or 5) hydrogen atoms are replaced by halogen. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. "halogen-substituted C1-C6Examples of alkylthio "are e.g. -SCH2F、-SCHF2、-SCF3、-SCCl3、-SC2F5、-SC2Cl5、-SCH2CF3、-SCH2Cl or-SCH2CH2CF3And the like.
The term "cycloalkyl" as used herein means a monocyclic, fused polycyclic, bridged polycyclic or spiro non-aromatic saturated hydrocarbon ring structure having the indicated number of ring atoms. The cycloalkyl group can have 3 to 12 carbon atoms, specifically 3 to 10, and more specifically 3 to 7 carbon atoms, i.e., C3-C7A cycloalkyl group. Examples of suitable cycloalkyl groups include, but are not limited to, monocyclic C3-C7Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Particular cycloalkyl groups have 3 to 5 carbon atoms.
As used herein, the term "halogen-substituted C3-C7Cycloalkyl "means C as defined above3-C7Cycloalkyl, wherein one or more (e.g. 1,2,3,4 or 5) hydrogen atoms are replaced by halogen. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. Specific examples include, but are not limited to, 2-fluorocyclopropyl, 2, 3-difluorocyclopropyl, 2,3, 3-tetrafluorocyclopropyl, 2, 3-difluorocyclobutyl, 2, 4-difluorocyclobutyl, and the like.
The term "heterocycloalkyl" as used herein is intended to include one or more heteroatoms independently selected from O, N and S and a monocyclic, fused polycyclic, spiro, or bridged polycyclic non-aromatic saturated ring structure of the indicated number of ring atoms, or an N-oxide thereof, or an S-oxide or S-dioxide thereof. The heterocycloalkyl group can have 4 to 12 ring members, specifically 4 to 10 ring members, and more specifically 4 to 7 ring members. Heterocycloalkyl groups typically contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2, e.g. a single heteroatom, e.g. a 4-7 membered monocyclic heterocycloalkyl having one heteroatom such as N, i.e. a 4-7 membered nitrogen containing heterocycloalkyl. Examples of suitable heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl), tetrahydrothienyl (e.g., 1-tetrahydrothienyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g., 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, or azepanyl.
It will be understood by those of ordinary skill in the art of organic synthesis that stable, chemically feasible heterocycles, whether aromatic or non-aromatic, have a maximum number of heteroatoms or type of heteroatoms included that is determined by the ring size, degree of unsaturation, and the valency of the heteroatom. In general, a heterocycle may have from 1 to 4 heteroatoms, as long as the heterocycle or heteroaromatic ring is chemically feasible and stable.
The term "halo" or "halogen" as used herein means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). Particular halo groups are fluoro or chloro. The term "halogen-substituted" group as used herein is intended to include monohalogenated or polyhalogenated groups in which one or more of the same or different halogens substitute for one or more hydrogens in the group.
The term "cyano" as used herein means the group-CN.
The term "nitro" as used herein means the group-NO2。
The term "amino" as used herein means the group-NH2；
The term "optionally substituted with … …" as used herein means that a group may be unsubstituted or substituted with one or more substituents (e.g., 0, 1,2,3,4, or 5 or more, or any range derivable therein) as set forth for that group, wherein the substituents may be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 substituents. In another embodiment, the optionally substituted group has 3 substituents. In another embodiment, the optionally substituted group has 4 substituents.
Unless otherwise defined, C as used in the definition of compounds herein1-C6Alkyl radical, C3-C7Cycloalkyl or 4-7 membered heterocycloalkyl optionally carrying one or more substituents which may be selected from H, F, Cl, Br, I, cyano, nitro, C1-C6Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, 1, 2-dimethylbutyl, etc.), C3-C7Cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), -OH, -O-C1-C6Alkyl (e.g. methoxy, ethoxy, n-propoxy, iso-propoxyPropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1, 2-dimethylbutoxy), SH, -S-C1-C6Alkyl (e.g., methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio, s-butylthio, n-pentylthio, n-hexylthio, 1, 2-dimethylbutylthio, etc.) or-NH2、-NH-C1-C6Alkyl (e.g., methylamino, ethylamino, propylamino, isopropylamino, N-butylamino, tert-butylamino, sec-butylamino, N-pentylamino, N-hexylamino, and 1, 2-dimethylbutylamino), N (C)1-C6Alkyl radical)2(e.g., dimethylamino, methylethylamino, diethylamino, etc.), wherein C1-C6Alkyl or C3-C7Cycloalkyl is optionally substituted with one or more halogens (preferably F).
The term "compound of the invention" as used herein is intended to encompass a compound of general formula (I) as defined herein or any preferred or specific embodiment thereof, stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates thereof, and prodrugs. Similarly, references herein to "intermediates", whether or not they are themselves claimed, are intended to cover the free forms thereof as well as the various derivatives described above, if the context permits.
The term "pharmaceutically acceptable" as used herein means molecular entities and compositions that are approved by or can be approved by the corresponding authorities in the various countries or listed in the generally recognized pharmacopoeias for animals, and more particularly humans, or that do not produce adverse, allergic, or other untoward reactions when administered in moderate amounts to animals, such as humans.
The term "pharmaceutically acceptable salt" as used herein means a salt of a compound of the present invention which is pharmaceutically acceptable and which possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic acid addition salts or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or an acid addition salt formed with an organic acid such as acetic acid, propionic acid, hexanoic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) a salt formed when an acidic proton present in the parent compound is replaced with a metal ion such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, or the like. The general principles and techniques for preparing pharmaceutically acceptable salts are known to those skilled in the art, for example, those described in Berge et al, Pharm ScL, 66, 1-19 (1977).
The term "prodrug" as used herein means a compound of the present invention having a cleavable group and becoming pharmaceutically active in vivo by solvolysis or under physiological conditions, including derivatives of the compounds of the present invention. Prodrugs include acid derivatives well known in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or 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 anhydrides derived from the pendant acid groups of the compounds of the present invention are particularly useful prodrugs. Particular such prodrugs are C of the compounds of the present invention1-8Alkyl radical, C2-8Alkenyl, optionally substituted C6-10Aryl and (C)6-10Aryl group) - (C1-4Alkyl) esters.
The term "stereoisomer" as used herein denotes an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., 1,2,3, or 4) asymmetric centers, they can result in racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The particular molecule may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as a mixture of two or more different structural forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, a nitroso-oxime may exist in solution in equilibrium with the following tautomeric forms:
it is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
The compounds of the invention may have one or more asymmetric centers and may thus be prepared as (R) -or (S) -stereoisomers, respectively, or as mixtures thereof. Structural formula or structural fragment of compound used in the inventionIndicating the relative configuration of asymmetric centers, i.e., chiral centers. Accordingly, the relative configuration with respect to the chiral center is denoted by R and S in the nomenclature of the compounds or intermediates provided herein.
The term "solvate" as used herein refers to a form of solvent addition comprising a stoichiometric or non-stoichiometric amount of solvent, including for example solvates with water, such as hydrates, or with organic solvents, such as methanol, ethanol or acetonitrile, i.e. as methanolate, ethanolate or acetonitrilate, respectively; or in the form of any polymorph. It will be understood that such solvates of the compounds of the invention also include solvates of pharmaceutically acceptable salts of the compounds of the invention.
The term "isotopic variation" as used herein means that one or more atoms making up the compound are selected to have an atomic mass or mass number different from the atomic mass or mass number usually found in natureA compound substituted by a number of atoms. Examples of isotopes that can be incorporated into one or more atoms of a compound of the invention include, for example2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F and36cl, thereby forming isotopically-varied forms of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. In some embodiments, the incorporated isotope is 2H (deuterium); in other embodiments, the incorporated isotope is 3H (tritium).
The term "disease associated with ROR γ t" as used herein means a disease in which ROR γ t contributes to the onset and progression of the disease, or inhibition of ROR γ t reduces the incidence of disease, reduces or eliminates disease symptoms. For the purposes of the present invention, a "disease associated with ROR γ t" is chosen in particular from inflammatory or autoimmune diseases, cancer and the like, including but not limited to psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, asthma, glomerulonephritis, lupus nephritis, myocarditis, thyroiditis, dry eye, uveitis, behcet's disease, allergic dermatitis, acne, scleroderma, bronchitis, cutaneous allergic rhinitis, Necrotizing Enterocolitis (NEC), hepatic fibrosis, nonalcoholic steatohepatitis (NASH), New coronaviral pneumonia (New coronavirus pneumanias), insulin-dependent type I diabetes mellitus, triple negative breast cancer, and prostate cancer, among others. Preferred indications of the invention are selected from psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, inflammatory bowel disease, dry eye, allergic dermatitis, Chronic Obstructive Pulmonary Disease (COPD), asthma, necrotizing enterocolitis, liver fibrosis, nonalcoholic steatohepatitis (NASH), neocoronavirus pneumonia, triple negative breast cancer and prostate cancer.
The term "subject" or "individual" as used herein includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) having a disease (e.g., a disease described herein) or normal individuals. "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
The term "therapeutically effective amount" as used herein means an amount sufficient to alleviate or completely alleviate the symptoms or other deleterious effects of a disorder when administered to a subject to treat a disease; reversing, completely stopping, or slowing the progression of the disorder; or an amount that reduces the risk of worsening the condition, "effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject to be treated.
The term "prevention" as used herein means the administration of one or more compounds of the invention to a subject, e.g. a mammal, e.g. a human, suspected of suffering from or susceptible to a disease associated with roryt as defined herein, in particular an inflammatory or autoimmune disease, such that the risk of suffering from the defined disease is reduced. The term "prevention" encompasses the use of a compound of the invention prior to diagnosis or determination of any clinical and/or pathological condition.
The term "treating" as used herein refers to administering one or more compounds of the invention described herein to a subject, e.g., a mammal, e.g., a human, suffering from, or having symptoms of, the disease, for the purpose of curing, alleviating, or otherwise affecting the disease or symptoms of the disease. In a particular embodiment of the invention, the disease is a disease associated with ROR γ t as defined herein, in particular an inflammatory or autoimmune disease.
The term "pharmaceutical combination" as used herein means that the compounds of the present invention can be used in combination with other active agents for the purpose of the present invention. The additional active agent may be one or more additional compounds of the invention, or may be a second or additional (e.g., third) compound that is compatible with, i.e., does not adversely affect, each other, or has complementary activity. Such active agents are suitably present in combination in an effective amount to achieve the intended purpose. The additional active agents may be co-administered with the compounds of the present invention in a single pharmaceutical composition, or separately administered in separate discrete units from the compounds of the present invention, either simultaneously or sequentially when administered separately. The sequential administration may be close in time or remote in time.
The term "pharmaceutically acceptable excipient or carrier" as used herein refers to one or more compatible solid or liquid filler or gel substances which are pharmacologically inactive, compatible with the other ingredients of the composition, and which are intended to be acceptable for administration to a warm-blooded animal such as man, and which serve as a carrier or vehicle for the compounds of the present invention in the form in which they are to be administered, examples of which include, but are not limited to, cellulose and its derivatives (e.g., sodium carboxymethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., magnesium stearate), calcium sulfate, vegetable oils, polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g., tweens), wetting agents (e.g., sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, and the like.
Unless otherwise specified, C in the definition of the compounds of the inventionn-n+mOr Cn-Cn+mIncluding n to n + m carbon atoms, e.g. C1-6Comprising C1、C2、C3、C4、C5And C6Also included are any ranges of n to n + m, e.g. C1-6Comprising C1-2、C1-3、C1-4、C2-6、C3-6And the like. Similarly, n-to n + m-membered in the definition of the compounds of the present invention means that the number of ring atoms is n to n + m, for example, 3-to 12-membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 12-membered rings and the like, and any range of n to n + m-membered rings is also included, for example, 3-to 12-membered rings include 3-to 6-membered rings, 3-to 9-membered rings, 5-to 6-membered rings, 5-to 7-membered rings, 6-to 8-membered rings, 6-to 10-membered rings and the like.
It is to be understood that the dosages referred to when describing the compounds of the present invention, pharmaceutical compositions, pharmaceutical combinations comprising the same, and related uses and methods, are by weight of the free form, and not by any salt, hydrate, solvate or the like thereof, unless otherwise defined in the specification.
Compounds of the invention
The terms "inventive compound" and the like, as used throughout this application, unless otherwise indicated, encompass compounds of formula (I), as defined in the various embodiments herein and in the specific or preferred embodiments thereof, stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates thereof, and prodrugs. The stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates, and prodrugs are described in the definitions section above. Preferably, the compounds of the invention are free forms of the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof; most preferred is the free form of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
Certain compounds of the present invention may exist in polymorphic or amorphous forms, which also fall within the scope of the present invention. When in a solid crystalline form, the compound of formula (I) may be in the form of a co-crystal with another chemical entity, and the specification includes all such co-crystals.
Where chiral centers are present, the compounds of the present invention may exist as individual enantiomers or as mixtures of enantiomers. According to one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a single enantiomer with enantiomeric excess (% ee) > 95, > 98% or > 99%. Preferably, the single enantiomer is present in an enantiomeric excess (% ee) of > 99%.
In particular, in one aspect, the present invention provides compounds of formula (I), stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts, or solvates thereof:
wherein:
R1and R2Each independently selected from hydrogen,Halogen, cyano, nitro, C1-C6Alkyl, -O-C1-C6Alkyl, -S-C1-C6Alkyl, -NH-C1-C6Alkyl, -N- (C)1-C6Alkyl radical)2、-C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-S-C1-C6Alkyl, -C1-C6alkyl-NH-C1-C6Alkyl or-C1-C6alkyl-N (C)1-C6Alkyl radical)2Wherein said C is1-C6Alkyl is optionally substituted by halogen or cyano;
R3selected from H, -C1-C6Alkyl, -C3-C7Cycloalkyl, -4-7 membered heterocycloalkyl, -NRaRaOR-ORaIn which C is1-C6Alkyl radical, C3-C7Cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted with substituents independently selected from: halogen, cyano, nitro, C optionally substituted by halogen3-C7Cycloalkyl radical, Ra、-ORa、-SRaor-NRaRaWherein R isaSelected from H or C optionally substituted by halogen1-C6Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-7 membered nitrogen containing heterocycloalkyl group;
R4is selected from-C1-C6Alkyl, -C3-C7Cycloalkyl, -4-7 membered heterocycloalkyl or optionally substituted by C1-C6Alkyl radical, C3-C7Cycloalkyl or 4-7 membered heterocycloalkyl substituted amino, wherein said C1-C6Alkyl radical, C3-C7Cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted with substituents each independently selected from: halogen, cyano, nitro, Ra、-ORa、-SRa、-NRaRaOr C optionally substituted by halogen3-C7Cycloalkyl radical, RaSelected from H or C optionally substituted by halogen1-C6Alkyl, or two groups attached to the same N atom may form, together with the N atom to which they are attached, a 4-7 membered nitrogen containing heterocycloalkyl group;
R5and R6Each independently selected from H, halogen, cyano or C optionally substituted by halogen or cyano1-C6An 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 compounds of formula (I), n is 0.
In one embodiment of the compounds of formula (I), n is 1.
In one embodiment of the compounds of formula (I), R1And R2Each independently is H.
In one embodiment of the compounds of formula (I), R1And R2Each independently is halogen, such as F, Cl, Br, or I; f or Cl is preferred.
In a specific embodiment, R1And R2Are all H. In a specific embodiment, R1Is H and R2Is halogen. In a specific embodiment, R1Is halogen and R2Is H. In a specific embodiment, R1And R2Both are halogens, which may be the same or different.
In one embodiment of the compounds of formula (I), R1And R2Each independently selected from C1-C6Alkyl, -O-C1-C6Alkyl, -S-C1-C6Alkyl, -NH-C1-C6Alkyl or-N- (C)1-C6Alkyl radical)2Wherein C is1-C6Alkyl is optionally substituted with halogen (preferably F). Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CF3、-CHF2、-CH2CF3、-CF2CF3、-CH2CH2CF3、-CH(CF3)2、-OCH3、-OCF3、-OCHF2、-OCH2CH3、-OCH2CF3、-OCH2CH2CH3、-OCH2CH2CF3、-OCH(CF3)2、-SCH3、-SCF3、-SCH2CH3、-NH2、-NHCH3、-N(CH3)2、-NH-CH2CH3、-N(CH3)(CH2CH3)、-NHCF3、-N(CH3)(CF3) And the like.
In one embodiment of the compounds of formula (I), R1And R2Each independently selected from-C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-S-C1-C6Alkyl, -C1-C6alkyl-NH-C1-C6Alkyl or-C1-C6alkyl-N (C)1-C6Alkyl radical)2Wherein C is1-C6Alkyl is optionally substituted with halogen (preferably F). Specific examples include, but are not limited to, -CH2OCH3、-CH2CH2OCH3、-CH2OCH2CH3、-CH2CH2OCH2CH3、-CH2NHCH3、-CH2N(CH3)2、-CH2OCF3、-CH2CH2OCF3、-CH2OCH2CF3、-CH2NHCF3、-CH2N(CF3)2And the like.
In one embodiment of the compounds of formula (I), R3is-C1-C6Alkyl, preferably C1-C3Alkyl optionally substituted with one or more groups independently selected from: halogen, C optionally substituted by halogen3-C7Cycloalkyl radical, Ra、-ORa、-SRaor-NRaRaWherein R isaIndependently selected from H or C optionally substituted with one or more halogens1-C6Alkyl radicals, or attached toTwo R on the same N atomaMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group.
In a specific embodiment, R3is-C1-C6Alkyl, preferably C1-C3Alkyl, optionally substituted by F, Cl, Br, I, RaOR-ORaIs substituted in which RaIs H or C optionally substituted by one or more halogen (preferably F)1-C3An alkyl group. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, trifluoromethoxy methyl or trifluoromethoxyethyl, and the like. In more specific embodiments, R3Is C1-C3Alkyl groups such as methyl, ethyl, propyl or isopropyl.
In a specific embodiment, R3is-C1-C6Alkyl, preferably C1-C3Alkyl, C optionally substituted by halogen3-C7Cycloalkyl is substituted. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl and the like.
In specific embodiments, R3is-C1-C6Alkyl, preferably C1-C3Alkyl, optionally substituted by-NRaRaIs substituted in which RaIndependently selected from H or C optionally substituted with one or more halogens1-C3Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, dimethylaminomethyl, methylethylaminomethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl and the like.
In one embodiment of the compounds of formula (I), R3is-C3-C7Cycloalkyl optionally substituted with one or more groups independently selected from: halogen, C optionally substituted by halogen3-C7Cycloalkyl radical, Ra、-ORa、-SRaor-NRaRaWherein R isaIndependently selected from H or C optionally substituted with one or more halogens1-C6Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. In specific embodiments, R3is-C3-C5Cycloalkyl groups, such as cyclopropyl, cyclobutyl or cyclopentyl.
In a specific embodiment, R3is-C3-C7Cycloalkyl optionally substituted with one or more groups independently selected from: halogen, Ra、、-ORaor-NRaRaWherein R isaIndependently selected from H or C optionally substituted with one or more halogens1-C6An alkyl group. Specific examples include, but are not limited to, 2, 3-difluorocyclopropyl, 2,3, 3-tetrafluorocyclopropyl, 2, 3-difluorocyclobutyl, methylcyclopropyl or cyclobutyl, dimethylcyclopropyl or cyclobutyl, trifluoromethylcyclopropyl or cyclobutyl, hydroxycyclopropyl or cyclobutyl, trifluoromethoxycyclopropyl or cyclobutyl, methylaminocyclopropyl, dimethylaminocyclopropyl, trifluoromethylaminocyclopropyl, and the like.
In one embodiment of the compounds of formula (I), R3Is a 4-7 membered heterocycloalkyl group, optionally substituted with one or more groups independently selected from: halogen, Ra、-ORa、-SRaor-NRaRaWherein R isaIndependently selected from H or C optionally substituted with one or more halogens1-C6Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. In specific embodiments, R3Is a 4-to 7-membered heterocycloalkyl group, e.g. azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolylAlkyl), tetrahydrofuryl (e.g. 1-tetrahydrofuryl, 2-tetrahydrofuryl and 3-tetrahydrofuryl), tetrahydrothienyl (e.g. 1-tetrahydrothienyl, 2-tetrahydrothienyl and 3-tetrahydrothienyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl, each of which is optionally substituted by one or more, e.g. 1,2 or 3, independently selected from F, Cl, Br, I, Ra、-ORaor-NRaRaWherein R isaIndependently selected from H or C optionally substituted with one or more halogens1-C3An alkyl group.
In one embodiment of the compounds of formula (I), R3is-NRaRaWherein R isaIndependently selected from H or C optionally substituted with one or more halogens1-C3Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. Specific examples include, but are not limited to, -NH2、-NHCH3、-NCH3CH3、-N(CH2CH3)CH3、-N(CH2CH3)(CH2CH3)-、-NHCF3、-N(CH3)CF3、-N(CF3)CF3、-N(CH2CF3)CF3or-N (CH)2CF3)(CH2CF3)-、-NH(CH2CH2CH3) Azetidinyl, pyrrolidinyl, piperidinyl and the like.
In one embodiment of the compounds of formula (I), R4Is selected from-C1-C6Alkyl, preferably C1-C3Alkyl optionally substituted with one or more groups independently selected from: halogen, C optionally substituted by halogen3-C7Cycloalkyl radical, Ra、-ORa、-SRaor-NRaRaWherein R isaIndependently selected from H or C optionally substituted with one or more halogens1-C6Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group.
In a specific embodiment, R4is-C1-C6Alkyl, preferably C1-C3Alkyl, optionally substituted by F, Cl, Br, I, RaOR-ORaIs substituted in which RaIs H or C optionally substituted by one or more halogen (preferably F)1-C3An alkyl group. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, trifluoromethoxy methyl or trifluoromethoxyethyl, and the like. In more specific embodiments, R4Is C1-C3Alkyl groups such as methyl, ethyl, propyl or isopropyl.
In a specific embodiment, R4is-C1-C6Alkyl, preferably C1-C3Alkyl, C optionally substituted by halogen3-C7Cycloalkyl is substituted. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl and the like.
In specific embodiments, R4is-C1-C6Alkyl, preferably C1-C3Alkyl, optionally substituted by-NRaRaIs substituted in which RaIndependently selected from H or C optionally substituted with one or more halogens1-C3Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, dimethylaminomethyl, methylethylaminomethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl and the like.
In one embodiment of the compound of formula (I)In the formula, R4is-C3-C7Cycloalkyl optionally substituted with one or more groups independently selected from: halogen, C optionally substituted by halogen3-C7Cycloalkyl radical, Ra、-ORa、-SRaor-NRaRaWherein R isaIndependently selected from H or C optionally substituted with one or more halogens1-C6Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. In specific embodiments, R4is-C3-C5Cycloalkyl groups, such as cyclopropyl, cyclobutyl or cyclopentyl.
In a specific embodiment, R4is-C3-C7Cycloalkyl optionally substituted with one or more groups independently selected from: halogen, Ra、-ORaor-NRaRaWherein R isaIndependently selected from H or C optionally substituted with one or more halogens1-C6An alkyl group. Specific examples include, but are not limited to, 2, 3-difluorocyclopropyl, 2,3, 3-tetrafluorocyclopropyl, 2, 3-difluorocyclobutyl, methylcyclopropyl or cyclobutyl, dimethylcyclopropyl or cyclobutyl, trifluoromethylcyclopropyl or cyclobutyl, hydroxycyclopropyl or cyclobutyl, trifluoromethoxycyclopropyl or cyclobutyl, methylaminocyclopropyl, dimethylaminocyclopropyl, trifluoromethylaminocyclopropyl, and the like.
In one embodiment of the compounds of formula (I), R4Is a 4-7 membered heterocycloalkyl group, optionally substituted with one or more groups independently selected from: halogen, Ra、-ORa、-SRaor-NRaRaWherein R isaIndependently selected from H or C optionally substituted with one or more halogens1-C6Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. In specific embodiments, R4Is a 4-to 7-membered heterocycloalkyl group, e.g. azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (for exampleSuch as 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), tetrahydrofuranyl (e.g. 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothienyl (e.g. 1-tetrahydrothienyl, 2-tetrahydrothienyl and 3-tetrahydrothienyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl, each of which is optionally substituted by one or more, e.g. 1,2 or 3, independently selected from F, Cl, Br, I, Ra、-ORaor-NRaRaWherein R isaIndependently selected from H or C optionally substituted with one or more halogens1-C3An alkyl group.
In one embodiment of the compounds of formula (I), R4Is optionally substituted by C1-C6Alkyl radical, C3-C7Cycloalkyl or 4-7 membered heterocycloalkyl substituted amino. In a particular embodiment, C substituted on the amino group1-C6Alkyl radical, C3-C7Cycloalkyl or 4-7 membered heterocycloalkyl each have the above embodiment pairs as R4C of (A)1-C6Alkyl radical, C3-C7Each embodiment or specific example as defined for cycloalkyl or 4-7 membered heterocycloalkyl. In a most specific embodiment, R4Is C optionally substituted by halogen1-C6Alkyl-substituted amino, specific examples include, but are not limited to, -NH2、-NHCH3、-NCH3CH3、-N(CH2CH3)CH3、-N(CH2CH3)(CH2CH3)-、-NHCF3、-N(CH3)CF3、-N(CF3)CF3、-N(CH2CF3)CF3or-N (CH)2CF3)(CH2CF3)-、-NH(CH2CH2CH3) Azetidinyl, pyrrolidinyl, piperidinyl and the like.
In one embodiment of the compounds of formula (I), R5And R6Each of which isIndependently selected from halogens, such as F, Cl, Br, I.
In one embodiment of the compounds of formula (I), R5And R6Each independently selected from C optionally substituted with halogen1-C6An alkyl group. In a specific embodiment, R5And R6Each independently selected from C substituted with at least three halogens1-C3An alkyl group. In a more specific embodiment, R5And R6Each independently selected from C substituted with three fluorine1-C3Specific examples of alkyl groups include, but are not limited to, trifluoromethyl, trifluoroethyl, pentafluoroethyl, and the like. In a most specific embodiment, R5And R6Are all-CF3。
In one embodiment of the compounds of formula (I), m and p are both 0. In a specific embodiment, 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 is to be understood that the compounds of formula (I) of the present invention encompass each of the above independent embodiments or each specific embodiment, and also encompass embodiments comprised of any combination or subcombination of the above-described embodiments or specific embodiments, as well as embodiments comprised of any combination of any of the above preferences or exemplifications.
Preferably, the present invention provides a compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof:
wherein:
R1and R2Each of which isIndependently selected from hydrogen, halogen or C1-C6Alkyl radical, wherein said C1-C6Alkyl optionally substituted with halo;
R3selected from H, -C1-C6Alkyl, -C3-C7Cycloalkyl or-NRaRaIn which C is1-C6Alkyl or C3-C7Cycloalkyl is optionally substituted with substituents independently selected from: halogen, C optionally substituted by halogen3-C7Cycloalkyl radical, Ra、-ORa、-SRaor-NRaRa；
R4Is selected from-C1-C6Alkyl or-NRaRaWherein said C is1-C6Alkyl is optionally substituted with substituents each independently selected from: raHalogen or-NRaRa：
RaSelected from H or C optionally substituted by halogen1-C6Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-7 membered nitrogen containing heterocycloalkyl group;
R5and R6Each independently selected from halogen or C optionally substituted by halogen1-C6An 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 one of the preferred compounds of formula (I) above, R1And R2Each independently selected from hydrogen or halogen, e.g. F, Cl, Br, I. In a specific embodiment, R1And R2Are all H. In a specific embodiment, R1Is H and R2Is halogen. In a specific embodiment, R1Is halogen and R2Is H. In a specific embodiment, R1And R2Both are halogens, which may be the same or different.
In one embodiment of one of the preferred compounds of formula (I) above, R3is-C1-C3Alkyl, optionally substituted with substituents independently selected from: H. halogen or C optionally substituted by halogen3-C7A cycloalkyl group. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, trifluoromethyl, trifluoroethyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, and the like.
In a more specific embodiment, R3is-C1-C3Alkyl groups such as methyl, ethyl, propyl or isopropyl.
In a more specific embodiment, R3is-C1-C3Alkyl radical, by-NRaRaIs substituted in which RaSelected from H or C optionally substituted by halogen1-C3Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. Specific examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, dimethylaminomethyl, methylethylaminomethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, and the like.
In one embodiment of the above preferred compounds of formula (I), R3is-C3-C7Cycloalkyl optionally substituted with groups independently selected from: halogen, Raor-NRaRaWherein R isaIndependently selected from H or C optionally substituted with one or more halogens1-C3An alkyl group. Specific examples include, but are not limited to, 2, 3-difluorocyclopropyl, 2,3, 3-tetrafluorocyclopropyl, 2, 3-difluorocyclobutyl, methylcyclopropyl or cyclobutyl, dimethylcyclopropyl or cyclobutyl, trifluoromethylcyclopropyl or cyclobutyl, methylaminocyclopropyl, dimethylaminocyclopropyl, trifluoromethylaminocyclopropyl, and the like.
In more specific embodiments, R3is-C3-C5Cycloalkyl groups, such as cyclopropyl, cyclobutyl or cyclopentyl.
In one embodiment of the above preferred compounds of formula (I)In, R3is-NRaRaWherein R isaIndependently selected from H or C optionally substituted with one or more halogens1-C3Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. Specific examples include, but are not limited to, -NH2、-NHCH3、-NCH3CH3、-N(CH2CH3)CH3、-N(CH2CH3)(CH2CH3)-、-NHCF3、-N(CH3)CF3、-N(CF3)CF3、-N(CH2CF3)CF3or-N (CH)2CF3)(CH2CF3)-、-NH(CH2CH2CH3) Azetidinyl, pyrrolidinyl, piperidinyl and the like.
In one embodiment of the above preferred compounds of formula (I), R4is-C1-C3Alkyl, optionally substituted with halogen. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, and the like.
In a more specific embodiment, R4is-C1-C3Alkyl groups such as methyl, ethyl, propyl or isopropyl.
In a more specific embodiment, R4is-C1-C3Alkyl radical, by-NRaRaIs substituted in which RaSelected from H or C optionally substituted by halogen1-C3Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. Specific examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, dimethylaminomethyl, methylethylaminomethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, and the like.
In one embodiment of the above preferred compounds of formula (I), R4is-NRaRaWherein R isaSelected from H or optionally substitutedHalogen substituted C1-C3Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-to 7-membered nitrogen-containing heterocycloalkyl group. Specific examples include, but are not limited to, -NH2、-NHCH3、-NCH3CH3、-N(CH2CH3)CH3、-N(CH2CH3)(CH2CH3)-、-NHCF3、-N(CH3)CF3、-N(CF3)CF3、-N(CH2CF3)CF3or-N (CH)2CF3)(CH2CF3)-、-NH(CH2CH2CH3) Azetidinyl, pyrrolidinyl, piperidinyl and the like.
In one embodiment of the above preferred compounds of formula (I), R5And R6Each independently selected from C substituted by halogen1-C3An alkyl group. In a more specific embodiment, R5And R6Each independently selected from C substituted with at least three halogens1-C3An alkyl group. In a more specific embodiment, R5And R6C independently of each other substituted by at least three F1-C3An alkyl group. Specific examples include, but are not limited to, trifluoromethyl, trifluoroethyl, pentafluoroethyl, and the like. In a most specific embodiment, R5And R6Are all-CF3。
It is to be understood that the preferred compounds of formula (I) described above encompass each individual embodiment or each specific embodiment, as well as embodiments that consist of any combination or subcombination of the various embodiments or specific embodiments described above.
Preferred embodiments of the compounds of the present invention include the following compounds, stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates thereof,
the invention has the advantages of
The invention provides biaryl compounds with a structure shown in a general formula (I), and researches show that the compounds can effectively inhibit ROR gamma t protein receptors, so that the differentiation of Th17 cells is regulated and controlled, the generation of IL-17 is inhibited, and the biaryl compounds can be used as immunomodulators for treating diseases related to Th17 cell differentiation.
The compound of the invention has the following beneficial effects:
has high inhibitory activity on ROR gamma t receptor;
regulating the differentiation of Th17 cells, and inhibiting the production of IL-17; and/or
Having good pharmacokinetic properties, e.g. having a longer t1/2Thus, for example, the dosing interval can be increased, the half-life is longer, and the patient has better compliance;
the compound has improved AUC0-last data, better druggability and higher bioavailability; and/or
Good safety, excellent properties like membrane permeability, P450 (reduced risk of drug interaction), solubility, etc.
Compounds of the invention for use in therapy or as medicaments
In one aspect, the present invention provides compounds of the invention for use as medicaments, in particular as ROR γ t inhibitors.
In another aspect, the present invention provides a compound of the invention for use in the treatment, especially for use in the treatment and/or prevention of a disease associated with roryt.
In particular embodiments, the invention provides compounds of the invention for use in the treatment and/or prevention of diseases in which ROR γ t contributes to the onset and progression of the disease or in which inhibition of ROR γ t would reduce the incidence of, reduce or eliminate the symptoms of, the disease, e.g., inflammation or autoimmune disease, cancer, etc., including but not limited to psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, asthma, glomerulonephritis, lupus nephritis, myocarditis, thyroiditis, dry eye, uveitis, behcet disease, allergic dermatitis, acne, scleroderma, bronchitis, dermatomyositis, necrotizing enterocolitis, Hepatic fibrosis, nonalcoholic steatohepatitis (NASH), neocoronavirus pneumonia, insulin-dependent type I diabetes, triple negative breast cancer, prostate cancer, and the like.
Pharmaceutical compositions and their administration
In another aspect, for use of the compounds of the present specification for therapeutic or prophylactic purposes, the compounds of the present invention may be formulated as pharmaceutical compositions in accordance with standard pharmaceutical practice. Meanwhile, based on good pharmacokinetic property, improved AUC0-last and good drug forming property of the compound, the compound can be used for preparing a drug with better pharmacokinetic property and higher bioavailability.
Accordingly, the present invention provides a pharmaceutical composition comprising a compound of the invention as described above and a pharmaceutically acceptable excipient.
In a specific embodiment, said pharmaceutical composition of the invention is provided for use in the prevention or treatment of a disease associated with roryt in a mammalian, e.g. human, subject.
In a particular embodiment, the pharmaceutical composition of the invention may additionally comprise additional therapeutically active ingredients suitable for use in combination with the compounds of the invention. In another specific embodiment, the additional therapeutic agent is as defined herein for the pharmaceutical combination.
The pharmaceutical compositions of the present invention may be formulated by techniques known to those skilled in the art, such as those disclosed in Remington's pharmaceutical Sciences, 20 th edition. For example, the pharmaceutical compositions of the present invention described above may be prepared by mixing a compound of the present invention with one or more pharmaceutically acceptable excipients. The preparation may further comprise the step of mixing one or more other active ingredients with the compound of the present invention and one or more pharmaceutically acceptable excipients.
The choice of excipients to include in a particular composition will depend on a variety of factors, such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Ansel, Howard C., et al, Ansel's Pharmaceutical Delivery Forms and Drug Delivery systems Philadelphia, Lippincott, Williams & Wilkins,2004, including, for example, adjuvants, diluents (e.g., glucose, lactose or mannitol), carriers, pH adjusting agents, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, flavorants, flavoring agents, other known additives.
The pharmaceutical compositions of the present invention may be administered in a standard manner. For example, suitable modes of administration include oral, intravenous, rectal, parenteral, topical, transdermal, ocular, nasal, buccal or pulmonary (inhalation) administration, with parenteral infusion including intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. For these purposes, the compounds of the present invention may be formulated by methods known in the art into the form of, for example, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops, aerosols, dry powder formulations and sterile injectable aqueous or oily solutions or suspensions.
The size of a prophylactic or therapeutic dose of a compound of the invention will vary depending upon a number of factors, including the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the judgment of the prescribing physician. Generally, an effective dose is in the range of about 0.0001 to about 5000mg per kg body weight per day, e.g., about 0.01 to about 1000 mg/kg/day (single or divided administration). For a 70kg human, this may amount to about 0.007 mg/day to about 7000 mg/day, for example about 0.7 mg/day to about 1500 mg/day. Depending on the mode of administration, the amount or amount of a compound of the invention in a pharmaceutical composition may be from about 0.01mg to about 1000mg, suitably 0.1-500mg, preferably 0.5-300mg, more preferably 1-150mg, especially preferably 1-50mg, e.g. 1.5mg, 2mg, 4mg, 10mg, 25mg etc.; accordingly, the pharmaceutical composition of the invention will comprise 0.05 to 99% w/w (weight percentages), such as 0.05 to 80% w/w, such as 0.10 to 70% w/w, such as 0.10 to 50% w/w of the compound of the invention, all weight percentages being based on the total composition. It will be appreciated that it may be necessary in some cases to use dosages outside these limits.
In a specific embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, the composition being formulated for oral administration. The composition may be provided in unit dosage form, for example in the form of a tablet, capsule or oral liquid formulation. Such unit dosage forms may contain, as active ingredient, from 0.1mg to 1g, for example from 5mg to 250mg, of a compound of the invention.
In a specific embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, the composition being formulated for topical administration. Topical administration may be in the form of, for example, a cream, lotion, ointment, or transdermal patch.
In a specific embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, the composition being formulated for administration by inhalation. Inhalation administration can be by oral inhalation, or by intranasal administration. When administered by oral inhalation, the compounds of the invention may be effectively used in the present invention in a daily dose, for example up to 500. mu.g, such as 0.1 to 50. mu.g, 0.1 to 40. mu.g, 0.1 to 30. mu.g, 0.1 to 20. mu.g or 0.1 to 10. mu.g of a compound of the invention. The pharmaceutical compositions of the present invention for oral inhalation may be formulated as a dry powder, a suspension (in a liquid or gas) or a solution (in a liquid), and may be administered in any suitable form and using any suitable inhaler device known in the art, including for example Metered Dose Inhalers (MDIs), Dry Powder Inhalers (DPIs), nebulizers and soft mist inhalers. The multi-compartment device may be used to deliver a compound of the present specification and one or more other active ingredients (when present).
Methods of treatment and uses
Based on the beneficial effects described above with respect to the compounds of the present invention, the compounds of the present invention are useful in methods of treating various conditions in animals, particularly mammals such as humans.
Thus, in another aspect, the invention provides a method of modulating, particularly inhibiting, ROR γ t activity, the method comprising contacting a cell with a compound of the invention as hereinbefore described to modulate, particularly inhibit, ROR γ t activity in the cell.
In another aspect, the present invention provides a method of preventing or treating a disease associated with roryt (e.g. a disease treatable or preventable by roryt inhibition), the method comprising administering to a subject in need thereof an effective amount of a compound of the invention as hereinbefore described or a pharmaceutical composition of the invention comprising the same.
In another aspect, the invention provides the use of a compound of the invention, or a pharmaceutical composition comprising the same, as described hereinbefore, for inhibiting ROR γ t activity, or for the treatment and/or prevention of a disease associated with ROR γ t, for example a disease treatable or preventable by ROR γ t inhibition.
In another aspect, the present invention also provides the use of a compound of the invention or a pharmaceutical composition comprising the same as described above for the manufacture of a medicament, in particular a medicament having ROR γ t receptor inhibitor activity.
In another aspect, the invention provides the use of a compound of the invention, or a pharmaceutical composition comprising the same, as described hereinbefore, optionally in combination with one or more chemotherapeutics or immunotherapeutics, in the manufacture of a medicament for the treatment or prevention of a disease associated with roryt, for example a disease treatable or preventable by roryt inhibition.
Pharmaceutical combination
The compounds of the present invention may be administered as the sole active ingredient or in combination with additional drugs or therapies. The additional drugs or therapies may have or produce the same or different pharmacological effects, provided however that the use in combination with the compounds of the present invention does not result in an undesirable reduction in activity, adverse interaction or side effect.
Thus, in another aspect, the invention provides a pharmaceutical combination comprising or consisting of a compound of the invention as hereinbefore described together with one or more other drugs or therapies acting by the same or different mechanism of action. In a specific embodiment, the pharmaceutical combination is for use in inhibiting ROR γ t activity, or for use in the treatment and/or prevention of a disease associated with ROR γ t.
The compounds of the invention and the other active agents used in combination in the pharmaceutical combination of the invention may be administered simultaneously, separately or sequentially by the same or different routes of administration. The additional active agents may be co-administered in a single pharmaceutical composition with the compounds of the present invention or separately administered in separate discrete units from the compounds of the present invention, e.g., as a combination product, preferably in kit form. When administered separately, may be simultaneous or sequential, which sequential administration may be close in time or remote in time. Furthermore, the compound of the invention and the further medicament may be administered (i) prior to sending the combination product to a physician (e.g. in the case of a kit comprising a compound of the invention and a further medicament); (ii) by the physician himself (or under the direction of the physician) immediately before administration; (iii) the combination therapy is added by the patient himself, for example during sequential administration of the compound of the invention and the further drug, together.
Thus, in a particular embodiment, the invention also provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of the invention, the remainder comprising other active agents used in combination, and means for separately containing said compositions. The kit of the invention is particularly suitable for administration of different dosage forms, such as oral dosage forms and parenteral dosage forms, or for administration of different compositions at different dosage intervals.
In the pharmaceutical combinations of the present invention, the appropriate amounts of the compound of the present invention and the other active agents to be combined will generally be determined by those skilled in the art by, for example, starting from the dosage ranges for the compounds described in the specification and approved or published dosage ranges for the other active compounds, and the dosages of the other drugs co-administered will, of course, vary depending upon such factors as the type of co-drug employed, the particular drug employed, the condition being treated, the general health of the patient, the judgment of the physician or veterinarian, and the like.
For pharmaceutical compositions and combinations of the invention, the additional active agent may be one or more second or additional (e.g., third) compounds that have enhanced, complementary activity that does not adversely affect the compound of the invention, e.g., the active agent may be a compound known to modulate other pathways of biological activity, or may be a compound that modulates different components of the pathway of biological activity to which the compound of the invention relates, or even a compound that overlaps with the biological target of the compound of the invention.
In a particular embodiment, the present invention provides a pharmaceutical combination, for example for use as a medicament for the treatment of one of the diseases listed herein, such as psoriasis, COPD, asthma, psoriatic arthritis or ankylosing spondylitis, comprising a compound of the invention, and at least one active ingredient selected from:
a) a beta-adrenoceptor agonist;
b) a muscarinic receptor antagonist;
c) joint muscarinic receptor antagonists and β -adrenergic receptor agonists; and
d) glucocorticoid receptor agonists (steroidal or non-steroidal);
e) phosphodiesterase-4 (PDE4) inhibitors.
The compounds of the present invention may also be combined with other therapies including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), tumor immunotherapy, and the like.
Accordingly, the present invention provides a method for inhibiting ROR γ t activity or for the treatment and/or prevention of a disease associated with ROR γ t, comprising administering a pharmaceutical combination of the invention to a subject in need thereof. The invention also provides the application of the pharmaceutical composition in preparing a medicament for inhibiting the activity of ROR gamma t or treating and/or preventing ROR gamma t related diseases.
For the various aspects described above relating to pharmaceutical compositions, methods of treatment and uses, and pharmaceutical combinations, diseases associated with ROR γ t (e.g., diseases treatable or preventable by ROR γ t inhibition) include inflammatory or autoimmune diseases, cancer, and the like, including, but not limited to, psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, asthma, glomerulonephritis, lupus nephritis, myocarditis, thyroiditis, dry eye, uveitis, behcet's disease, allergic dermatitis, acne, scleroderma, bronchitis, dermato-muscular allergic rhinitis, necrotizing enterocolitis, hepatic fibrosis, nonalcoholic steatitis (NASH), neoviral pneumonia, neocoronary pneumonia, and the like, Insulin-dependent type I diabetes, triple negative breast cancer, prostate cancer, and the like. Preferred diseases associated with roryt are selected from psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, inflammatory bowel disease, dry eye, allergic dermatitis, Chronic Obstructive Pulmonary Disease (COPD), asthma, necrotizing enterocolitis, liver fibrosis, nonalcoholic steatohepatitis (NASH), neocoronavirus pneumonia, triple negative breast cancer and prostate cancer.
Preferred for the above-described compounds, pharmaceutical compositions, methods, uses, pharmaceutical combinations of the invention are the preferred compounds of formula (I), stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates thereof, as described above; more preferred are the specific compounds listed above, e.g., compounds 1-13, or their pharmaceutically acceptable salts or solvates.
When a dosage of a compound or drug for administration is described herein, it is understood that the dosage is based on the weight of the free base, excluding any derivative thereof, unless the specification indicates otherwise.
Synthesis of Compounds of the invention
In another aspect, the invention also provides a process for the preparation of compounds of formula (I), the general synthetic scheme for the synthesis of the compounds of the invention being illustrated below. Suitable reaction conditions for each reaction step are known to those skilled in the art or can be routinely determined. The starting materials and reagents used in the preparation of these compounds are generally commercially available or can be prepared by the methods hereinafter, by methods similar to those given hereinafter, or by methods known in the art, if not otherwise specified. If desired, the starting materials and intermediates in the synthetic reaction schemes can be isolated and purified using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. The materials may be characterized using conventional methods including physical constants and spectroscopic data.
In one embodiment, the method comprises the steps of:
scheme 1:
wherein R is1、R2、R3、R4、R5、R6M 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) is formed into a compound of formula (I-2) in free or salt form; the reaction is preferably carried out under the action of hydrobromic acid (e.g. 40% aqueous hydrobromic acid), preferably at a suitable temperature, e.g. 50-200 ℃, 80-150 ℃, preferably 90-120 ℃; such salt forms as the hydrobromide salt form;
step 2: cyclizing the compound of formula (I-2) in free or salt form with the compound of formula (I-3) to form the compound of formula (I-4) in free or salt form; the reaction is preferably carried out in a suitable solvent, which may be selected, for example, from protic solvents such as methanol, ethanol, propanol, etc., and preferably at a suitable temperature, which is selected, for example, from 50 to 200 ℃, 80 to 150 ℃, preferably 90 to 120 ℃; such salt forms as the hydrobromide salt form;
and step 3: reacting a compound of formula (I-4) in free or salt form with an amino protecting agent to produce a compound of formula (I-5); wherein the amino protecting agent is well known in the art and includes, but is not limited to, di-tert-butyl dicarbonate ((Boc)2O)、CbzCl、FmocCl or PMB-Cl, preferably in a suitable organic solvent which may be selected from tetrahydrofuran, ethers (e.g. diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, dichloromethane, 1, 4-dioxane, dimethyl sulfoxide and any combination thereof, preferably tetrahydrofuran; the reaction is preferably carried out in the presence of a suitable base which may be selected from sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt or pyridine, preferably the base is triethylamine; the reaction is preferably carried out at a suitable temperature, for example, 0-200 ℃, 5-100 ℃, 10-50 ℃, preferably room temperature;
and 4, step 4: reacting the compound of formula (I-5) with Tf reagent to produce a compound of formula (I-6); the Tf reagent is a reagent that reacts with a hydroxyl group to form an OTf group, including but not limited to trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, or N-phenylbis (trifluoromethanesulfonyl) imide; the reaction is preferably carried out in the presence of a base selected from sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt or pyridine; the reaction is preferably carried out in an organic solvent which may be selected from the group consisting of dichloromethane, tetrahydrofuran, ethers (e.g., diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, dimethyl sulfoxide, and any combination thereof, preferably dichloromethane; the reaction is preferably carried out at a suitable temperature, for example-50 ℃ to 200 ℃, -20 ℃ to 100 ℃, for example-10 ℃ to 50 ℃, for example-10 ℃ to 10 ℃, 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, and the like;
and 5: coupling the compound of formula (I-6) with the compound of formula (I-7) in the presence of a catalyst, such as a palladium catalyst, to obtain the compound of formula (I-8);
wherein the palladium catalyst is a palladium catalyst for coupling as is well known in the art, including but not limited to Pd2(dba)3Etc.; the reaction is preferably carried out in a suitable organic solvent which may be selected from tetrahydrofuran, ethers(e.g., diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, methylene chloride, 1, 4-dioxane, dimethyl sulfoxide, and any combination thereof, preferably 1, 4-dioxane; the reaction is preferably carried out in the presence of a phosphine ligand including, but not limited to, 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene; the reaction is preferably carried out in the presence of a suitable base which may be selected from sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt or pyridine, preferably the base is N, N-diisopropylethylamine; the reaction is preferably carried out at a suitable temperature, for example 50-200 ℃, 80-150 ℃, preferably 90-120 ℃;
step 6: the compound of the formula (I-8) is reacted under the action of an oxidant to generate a compound of the formula (I-9); the oxidizing agent is selected from, for example, H2O2mCPBA and peracetic acid; the reaction is preferably carried out in an organic solvent which may be selected from the group consisting of dichloromethane, tetrahydrofuran, ethers (e.g., diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, dimethyl sulfoxide, and any combination thereof, preferably dichloromethane; the reaction is preferably carried out at a suitable temperature, for example-50 ℃ to 200 ℃, -20 ℃ to 100 ℃, for example-10 ℃ to 50 ℃, for example-10 ℃ to 10 ℃, preferably in an ice bath;
and 7: hydrolyzing the compound of formula (I-9) to produce a compound of formula (I-10); the reaction is preferably carried out in the presence of a base, which may be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, the base preferably being applied in the form of an aqueous solution; the reaction is preferably carried out in an organic solvent, which may be selected from alcohol solvents such as (methanol, ethanol or propanol), tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, dimethylsulfoxide and any combination thereof, preferably methanol; the reaction is preferably carried out at a suitable temperature, for example-20 ℃ to-200 ℃, 5-100 ℃, 10-50 ℃, preferably room temperature;
and 8: reacting the compound of the formula (I-10) with the compound of the formula (I-11) under the action of a condensing agent to generate a compound of the formula (I-12);
wherein the condensing agent is well known in the art for coupling carboxylic acids to amines, including but not limited to 1-propylphosphoric anhydride (T3P), EDC, DCC, HATU, and the like; the reaction is preferably carried out in a suitable organic solvent which may be selected from the group consisting of dichloromethane, tetrahydrofuran, ethers (e.g., diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, dimethyl sulfoxide, and any combination thereof, preferably dichloromethane; the reaction is preferably carried out in the presence of a suitable base including, but not limited to, sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt or pyridine, preferably the base is N, N-diisopropylethylamine; the reaction is preferably carried out at a suitable temperature, for example from 0 to 200 ℃, from 10 to 100 ℃ or from 20 to 50 ℃, preferably at room temperature (20 to 25 ℃).
And step 9: removing amino protecting group from the compound of formula (I-12) to produce a compound of formula (I-13); the reaction is carried out, for example, under the action of an acid (such as TFA or HCl), preferably in a suitable organic solvent which may be selected from the group consisting of dichloromethane, tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, and the like), N-methylpyrrolidone, N-dimethylformamide, 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 ℃ to 200 ℃, -20 ℃ to 100 ℃, for example-10 ℃ to 50 ℃, for example-10 ℃ to 20 ℃;
step 10: the reaction of a compound of formula (I-13) with a compound of formula (I-14) or an activated form thereof (e.g. the corresponding acid chloride (formula (I-15) or anhydride) to give the target compound I-a, preferably in the presence of a base selected from sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt or pyridine, preferably in an organic solvent selected from dichloromethane, tetrahydrofuran, ethers (e.g. diethyl ether, ethylene glycol monomethyl ether etc.), N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, dimethyl sulfoxide and any combination thereof, preferably dichloromethane, in the presence of a condensing agent such as those well known in the art for coupling carboxylic acids to amines, including but not limited to 1-propylphosphoric anhydride (T3P), EDC, DCC, HATU; the reaction is preferably carried out at a suitable temperature, for example from 0 to 200 ℃, from 10 to 100 ℃ or from 20 to 50 ℃, preferably at room temperature (20 to 25 ℃).
In one embodiment, the method comprises the steps of:
and (2) a flow scheme:
wherein R is1、R2、R3、R4、R5、R6M 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: a compound of the formula (II-1) with R4SH or a salt thereof (e.g., sodium salt) to produce a compound of formula (II-2); the reaction is preferably carried out under an inert gas atmosphere, including but not limited to nitrogen, argon or helium, and the like;
step 2: reacting the compound of the formula (II-2) with an amino protective agent to generate a compound of a formula (II-3); wherein the amino protecting agent is well known in the art and includes, but is not limited to, di-tert-butyl dicarbonate ((Boc)2O), CbzCl, FmocCl or PMB-Cl; the reaction is preferably carried out in the presence of a suitable base which may be selected from sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt, pyridine or 4-dimethylaminopyridine;
and step 3: oxidizing the compound of the formula (II-3) under the action of an oxidizing agent to generate a compound of a formula (II-4); the oxidizing agent is selected from, for example, H2O2mCPBA and peracetic acid;
and 4, step 4: reducing the compound of the formula (II-4) under the action of a reducing agent to generate a compound of a formula (II-5); the reducing agent is for example selected from DABAL-H, lithium aluminium hydride or sodium borohydride; the reaction is preferably carried out under an inert gas atmosphere, including but not limited to nitrogen, argon or helium, and the like;
and 5: reacting the compound of formula (II-5) with methanol or an activated form thereof (e.g., sodium methoxide) to produce a compound of formula (II-6); the reaction is preferably carried out in the presence of pyridine 4-methylbenzenesulfonate (PPTS);
step 6: reacting the compound of formula (II-6) with an alkylcyanosilane (e.g., TMSCN) to produce a compound of formula (II-7); the reaction is preferably carried out in the presence of boron trifluoride diethyl etherate; the reaction is preferably carried out under an inert gas atmosphere, including but not limited to nitrogen, argon or helium, and the like;
and 7: removing amino protecting groups from the compound of the formula (II-7) to generate a compound of a formula (II-8); the reaction is carried out, for example, under the action of an acid (such as TFA or HCl);
and 8: a compound of the formula (II-8) with R3COOH or an activated form thereof, such as the corresponding acid chloride or anhydride, to produce a compound of formula (II-9); the reaction is preferably carried out in the presence of a base selected from sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt or pyridine; the reaction may be carried out in the presence of condensing agents such as, for example, and the like, wherein the condensing agents are well known in the art for the coupling of carboxylic acids to amines, including but not limited to 1-propylphosphoric anhydride (T3P), EDC, DCC, HATU;
and step 9: hydrolyzing the compound of formula (II-9) to produce a compound of formula (II-10); the reaction is preferably carried out in the presence of a base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate;
step 10: reacting the compound of the formula (II-10) with the compound of the formula (I-11) under the action of a condensing agent to generate a target compound, namely a compound of the formula (I-b);
wherein the condensing agent is one well known in the art for coupling carboxylic acids to amines, including but not limited to T3P, EDC, DCC, HATU or N, N' -tetramethylchloroformamidine hexafluorophosphate, and the like; the reaction is preferably carried out in the presence of a suitable base including, but not limited to, sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, N-methylimidazole, HOBt, or pyridine;
the reaction in the above step is preferably carried out in an organic solvent which may be selected from alcohol solvents such as (methanol, ethanol or propanol), tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, dichloromethane, dimethyl sulfoxide and any combination thereof; mixtures of organic solvents with water can be used for the hydrolysis reaction;
the reaction in the above step is preferably carried out at a suitable temperature, for example, -100 ℃ to 0 ℃, -80 ℃ to-20 ℃, -50 ℃ to 200 ℃, -20 ℃ to 100 ℃, -20 ℃ to 20 ℃, -10 ℃ to 50 ℃, 0-200 ℃, 10-100 ℃, 20-50 ℃ or room temperature (20-25 ℃).
The above synthetic schemes are only illustrative of some of the methods of preparation of the compounds of the present invention. The compounds of the present invention or stereoisomers, tautomers, stable isotopic derivatives, pharmaceutically acceptable salts or solvates thereof can be prepared by a variety of methods, including those set forth above, in the examples, or by analogous methods thereto, by one of ordinary skill in the art based on the synthetic schemes described above, in conjunction with routine techniques in the art.
The compounds described in this specification are further illustrated in the following examples. These examples are given by way of illustration only and not by way of limitation.
Detailed Description
The technical solutions of the present invention are further described below with reference to specific examples, but the scope of the present invention is not limited to these examples. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.
Experimental procedures without specific conditions noted in the following examples are generally carried out according to conventional conditions for such reactions, or according to conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight. Unless otherwise specified, the ratio of liquids is by volume.
The experimental materials and reagents used in the following examples are commercially available, prepared according to methods of the prior art or prepared according to methods similar to those disclosed herein, unless otherwise specified.
The chemical names used herein are IUPAC names, and the abbreviations used have meanings commonly understood in the art, unless clearly defined otherwise in the specification. The meanings of the abbreviations used in the specification are listed below:
PdCl2(dtbpf): 1,1' -di-tert-butylphosphino ferrocene palladium dichloride
Pd(dppf)Cl2: [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
xanthophos 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene
Pd2(dba)3Tris (dibenzylideneacetone) dipalladium
HATU: 2- (7-azobenzotriazol) -N, N, N ', N', -tetramethyluronium hexafluorophosphate
DIEA: n, N-diisopropylethylamine
DMF: n, N-dimethylformamide
DMSO, DMSO: dimethyl sulfoxide
DCM: methylene dichloride
EA ethyl acetate
PE: petroleum ether
rt-room temperature
LC-MS: liquid chromatography-mass spectrometry
ESI electrospray ionization
m/z: mass to charge ratio
TLC thin layer chromatography
TCFH N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate
Time: retention time
Synthetic examples
In the preparation method of the target compound, the column chromatography adopts silica gel (300-400 meshes) produced by Ningsan Sun drying agent GmbH; thin layer chromatography using GF254(0.25 mm); nuclear magnetic resonance chromatography (NMR) was measured using a Varian-400 nuclear magnetic resonance spectrometer; LC/MS an Agilent technology ESI 6120 LC/MS instrument was used.
In addition, all operations involving easily oxidizable or hydrolyzable raw materials were carried out under nitrogen protection. Unless otherwise indicated, all starting materials used in the present invention are commercially available, can be used without further purification, and are used in the present invention at temperatures in degrees Celsius.
When the structure of the compound of the present invention is inconsistent with the name of the compound, the structural formula is generally subject to the standard unless the name of the compound can be determined to be correct by context.
Example 1 and example 2: 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) 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
Step 1: synthesis of perfluorophenyl 4-bromo-3-fluorobenzoic acid ester
4-bromo-3-fluorobenzoic acid (30.0g, 137mmol), pentafluorophenol (28.2g, 153mmol) and dicyclohexylcarbodiimide (31.9g, 155mmol) were dissolved in dry tetrahydrofuran (900mL) in this order. The reaction mixture was stirred at room temperature overnight and the reaction was monitored by TLC for completion. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (PE: EA ═ 10:1) to give the title compound (56.0g, crude product, white solid).
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 (56.0g, 145mmol) was dissolved in toluene (725 mL). (trifluoromethyl) trimethylsilane (131mL, 873mmol) and a 1mol/L tetrabutylammonium fluoride tetrahydrofuran solution (50.9mL, 50.9mmol) were added dropwise to the reaction solution in this order while cooling on ice. After the addition was complete, the ice bath was removed and the reaction was allowed to slowly warm to room temperature and stirred overnight, and the completion of the reaction was monitored by TLC. The reaction solution was poured into ice of 1mol/L dilute hydrochloric acid (1.5L), extracted with methyl tert-butyl ether (700mLx2), the organic phases were combined, washed with saturated brine (1.5L), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the objective compound (60.0g, crude, brown oil).
And 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 (70.0g, 169mmol) was dissolved in tetrahydrofuran (700mL), and 6mol/L dilute hydrochloric acid (350mL) was slowly added dropwise to the reaction solution at room temperature. After the addition was complete, the reaction was stirred at room temperature overnight and monitored by LC-MS for completion. The reaction solution was poured into water (500mL), extracted with methyl tert-butyl ether (500mLx2), and the organic phases were combined, washed with saturated brine (1L), dried over anhydrous sodium sulfate, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the objective compound (46.2g, crude, yellow oil). LC-MS (ESI) M/z 338.9[ M-H ]]-。
And 4, step 4: synthesis of 2- (4 '-amino-2-fluoro- [1,1' -biphenyl ] -4-yl) -1,1,1,3,3,3, 3-hexafluoropropan-2-ol
2- (4-bromo-3-fluorophenyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (46.2g,135mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline (23.7g,108mmol), potassium carbonate (37.4g,271mmol) and Pd (dppf) Cl2(4.96g,6.77mmol) was dissolved in a mixed solvent of 1, 4-dioxane (500mL) and water (50 mL). The reaction mixture was stirred at 100 ℃ for 2 hours under nitrogen, and LC-MS monitored the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by a silica gel column (PE: EA ═ 10:1-6:1) to give a crude product, which was then slurried with dichloromethane to give the target compound (20.0g, yield, white solid). LC-MS (ESI) M/z 395.0[ M + ACN + H]+。
Intermediate: synthesis of 2-acetyl-5- (methylsulfonyl) isoindoline-1-carboxylic acid
Step 1: synthesis of 5-methylthioisoindoline-1-one
To a solution of 5-bromoisoindolin-1-one (200g,943mmol) in DMF (2.00L) was added sodium thiomethoxide (50%, 264g,1886 mmol). The reaction mixture was stirred at 110 ℃ for 1 hour under argon atmosphere to stop the reaction. The reaction mixture was cooled to room temperature and poured into ice water (6.00L) to give a yellow suspension. The suspension was filtered and washed with clear water (1.50L) to give a residue. The residue was dissolved in DCM (5.00L) to give a yellow solution. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was dried under vacuum to obtain the objective compound (140g, yield 82.9%, yellow solid). LC-MS (ESI) M/z 180.1[ M + H ]]+。
Step 2: synthesis of 5- (methylthio) -1-oxoisoindoline-2-carboxylic acid tert-butyl ester
To a solution of 5-methylthioisoindolin-1-one (140g,782mmol) in DMF (1.40L) was added di-tert-butyl dicarbonate (222g,1016mmol),4-dimethylaminopyridine (124g,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 (6.00L) to obtain a yellow suspension. The suspension was stirred at room temperature for 30 minutes, filtered and washed with clear water (1.00L) to give a residue. The residue was dissolved in EA (3.00L) to give a yellow solution. The solution was washed with 0.1N dilute hydrochloric acid (800 mL. times.2) and clear water (800mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was dried under vacuum to give the objective compound (210g, yield 96.2%, yellow solid). LC-MS (ESI) M/z302.1[ M + Na ]]+。
And step 3: synthesis of 5- (methylsulfonyl) -1-oxoisoindoline-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 5- (methylthio) -1-oxoisoindoline-2-carboxylate (210g,752mmol) in DCM (2.00L) was added m-chloroperoxybenzoic acid (85%, 382g,1879mmol) at 0 deg.C. The reaction mixture was further stirred at room temperature for 2 hours to stop the reaction. The reaction mixture was diluted with DCM (1.50L), washed with sodium hydroxide solution (1.00L × 2) and clean water (1.00L), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was dried under vacuum to give the title compound (215g, yield 91.9%, yellow solid). LC-MS (ESI) M/z 334.0[ M + Na ]]+。
And 4, step 4: synthesis of 1-hydroxy-5- (methylsulfonyl) isoindoline-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 5- (methylsulfonyl) -1-oxoisoindoline-2-carboxylate (50.0g,161mmol) in DCM (1.00L) was added dropwise (over 40 min.) a toluene solution of diisobutylaluminum hydride (214mL,321mmol,1.50M) at-20 deg.C under argon, and after completion of the addition, stirring was continued for 1h at-20 deg.C under argon. Adding saturated tartaric acid into the reaction solutionThe potassium sodium acid solution (800mL) was stirred for 20 minutes and then warmed to room temperature. DCM (1.50L) was added to the mixture and the organic phase was separated. The aqueous phase was further extracted with DCM (1.00 L.times.2). The organic phases were combined and concentrated under reduced pressure, and the residue was dried under vacuum to give the title compound in4 batches (33.75g, yield 64.7%, pink solid). LC-MS (ESI) M/z 335.9[ M + Na ]]+。
And 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 (15.0g,47.9mmol) in methanol (200mL) was added pyridine 4-methylbenzenesulfonate (1.20g,4.79 mmol). The reaction mixture was stirred at room temperature for 1 hour to stop the reaction. Triethylamine (33.3mL) was added to the reaction solution to quench, then concentrated under reduced pressure, and the resulting residue was dried under vacuum to give the target compound (16.1g, crude, violet black solid). MS (ESI) M/z 349.9[ M + Na ]]+。
Step 6: synthesis of 1-cyano-5- (methylsulfonyl) isoindoline-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 1-methoxy-5- (methylsulfonyl) isoindoline-2-carboxylate (16.0g,48.9mmol) in DCM (300mL) at-70 deg.C under argon was added sequentially trimethylsilyl cyanide (9.17mL,73.3mmol) and boron trifluoride etherate (9.25mL,73.3 mmol). The reaction mixture was stirred at-70 ℃ under argon for 1 hour to stop the reaction. To the reaction mixture were added a saturated sodium bicarbonate solution (50.0mL) and DCM (200mL), and the mixture was warmed to room temperature. After separation of the organic phase, the aqueous phase was further extracted with DCM (100 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (PE: EA ═ 5/1-3/1) to obtain the objective compound (7.g, yield in two steps 49.3%,a white solid). LC-MS (ESI) M/z 323.0[ M + H ]]+。
And 7: synthesis of 5-methylsulfonyl isoindoline-1-methyl formate hydrochloride
Tert-butyl 1-cyano-5- (methylsulfonyl) isoindoline-2-carboxylate (22.5g,322mmol) was added to methanol hydrochloride (3M,225mL) and the reaction mixture was stirred at 80 ℃ for 5 hours to stop the reaction. The reaction solution was concentrated under reduced pressure, and the obtained residue was dried under vacuum to obtain the objective compound (20.4g, crude product, black solid). LC-MS (ESI) M/z 255.9[ M + H ]]+。
And 8: synthesis of methyl 2-acetyl-5- (methylsulfonyl) isoindoline-1-carboxylate
To a solution of methyl 5-methylsulfonylisoindoline-1-carboxylate hydrochloride (20.0g,68.6mmol) in DCM (250mL) at 0 deg.C under argon, was added triethylamine (34.7g,343mmol) and acetyl chloride (10.8g,137mmol) dropwise in that order. The reaction mixture was stirred at 0 ℃ under argon for 3 hours to stop the reaction. Water (250mL) was added to the reaction mixture, the organic phase was separated, and the aqueous phase was further extracted with DCM (200 mL. times.2). The organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (PE: EA ═ 1/1-0/1) to give the title compound (12.17g, 58.6% yield in two steps, white solid). LC-MS (ESI) M/z298.0[ M + H ]]+。1H NMR(400MHz,CDCl3)δ7.97–7.85(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)。
And step 9: synthesis of 2-acetyl-5- (methylsulfonyl) isoindoline-1-carboxylic acid
To a solution of methyl 2-acetyl-5- (methylsulfonyl) isoindoline-1-carboxylate (11.8g,39.7mmol) in tetrahydrofuran/methanol/water (V: V ═ 1:1,120mL) was added sodium hydroxide (3.18g,79.4 mmol). The reaction mixture was stirred at room temperature for 2 hours and stopped. The reaction mixture was concentrated under reduced pressure, water (100mL) was added to the residue, pH-4 was adjusted with hydrochloric acid (3M), the resulting solution was stirred for 16 hours, filtered, the filter cake was washed with water (10.0 mL. times.2), and dried under vacuum to give the title compound (8.80g, 78.2%, off-white solid). LC-MS (ESI) M/z 284.1[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.05–7.87(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 10: synthesis of the compound 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
To 2-acetyl-5- (methylsulfonyl) isoindoline-1-carboxylic acid (4.00g,14.1mmol) and 2- (4 '-amino-2-fluoro- [1,1' -biphenyl]To a solution of (4-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (4.17g, 11.8mmol) in acetonitrile (80.0mL) were added TCFH (9.90g, 35.3mmol) and N-methylimidazole (4.83g, 58.8mmol) in that order, and the reaction was stopped after the reaction solution was stirred for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to medium-pressure liquid phase preparation (acetonitrile/water ═ 0 to 45%) to obtain the objective compound (3.10g, yield 42.5%, white solid). MS (ESI) M/z 619.1[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ10.88,10.64(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 11: synthesis of 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) isoindoline-1-carboxamide
Racemic 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 (1.29g in about 250mL of methanol, injection volume 8.0mL) was purified by Waters SFC150 (room temperature, 100bar,214nm) and 250 x 25mm 10 μmAS-H (supercritical carbon dioxide: methanol, 45:55,3.0min,70mL/min) separation to obtain 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) isoindoline-1-carboxylic acid amide (500mg, white solid, ret. time ═ 1.276min, e.e.99%). LC-MS (ESI) M/z 619.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ10.88,10.65(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) isoindoline-1-carboxylic acid amide (516mg, white solid, ret. time. 2.610min, e.e.98%). LC-MS (ESI) M/z 619.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ10.88,10.65(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).
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: synthesis of 3- (2-aminoethyl) phenol hydrobromide
2- (3-methoxyphenyl) ethylamine (9.00g, 59.5mmol) was dissolved in 40% aqueous hydrobromic acid (120g, 595 mmol). The reaction solution was stirred at 110 ℃ for 6 hours and the completion of the reaction was monitored by LC-MS. The reaction solution was concentrated under reduced pressure to give the objective compound (9.00g, crude, light brown solid). LC-MS (ESI) M/z 179.1[ M + ACN + H]+。
Step 2 Synthesis of 6-hydroxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylic acid ethyl ester hydrobromide salt
3- (2-aminoethyl) phenol hydrobromide (9.00g, 65.6mmol) was dissolved in ethanol (90 mL). A50% ethyl glyoxylate solution in toluene (14.7g, 72.2mmol) was added dropwise to the reaction mixture at room temperature. After the addition was complete, the reaction mixture was stirred at 100 ℃ overnight and the reaction was monitored by LC-MS for completion. The reaction solution was concentrated under reduced pressure to give the objective compound (20.0g, crude, brown oil). LC-MS (ESI) M/z 222.0[ M + H ]]+。
And step 3: synthesis of 6-hydroxy-3, 4-dihydroisoquinoline-1, 2(1H) -dicarboxylic acid 1-ethyl ester 2-tert-butyl ester
Ethyl 6-hydroxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylate hydrobromide salt (20.0g, 66.2mmol) was dissolved in a mixed solvent of tetrahydrofuran (200mL) and water (40mL), and triethylamine (11.0mL,79.4mmol) and di-tert-butyl dicarbonate (16.7mL,72.8mmol) were added to the reaction mixture in this order at room temperature. After the addition, the reaction solution was stirred at room temperature for 1 hour, and the completion of the reaction was monitored by LC-MS. The reaction solution was poured into water (150mL), extracted with EA (50mL × 2), the organic phases were combined, washed with saturated aqueous ammonium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column (PE: EA ═ 4:1-2:1) to give the target compound (12.3g, yield 64.4% in three steps, yellow oily substance). LC-MS (ESI) M/z 320.1[ M-H ]]-。
And 4, step 4: synthesis of 6- (((trifluoromethyl) sulfonyl) oxy) -3, 4-dihydroisoquinoline-1, 2(1H) -dicarboxylic acid 1-ethyl ester 2-tert-butyl ester
6-hydroxy-3, 4-dihydroisoquinoline-1, 2(1H) -dicarboxylic acid 1-ethyl 2-tert-butyl ester (11.0g,34.2mmol) was dissolved in anhydrous DCM (200mL) and N-phenylbis (trifluoromethanesulfonyl) imide (14.7g,41.1mmol) and DIEA (11.3mL, 68.5mmol) were added to the reaction mixture in that order under ice bath and nitrogen protection. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 3 hours and monitored by LC-MS for completion. The reaction solution was concentrated under reduced pressure to give the objective compound (37.0g, crude, brown oil). LC-MS (ESI) M/z 353.9[ M-BOC + H ]]+。
And 5: synthesis of 6- (methylthio) -3, 4-dihydroisoquinoline-1, 2- (1H) -dicarboxylic acid 1-ethyl ester 2-tert-butyl ester
Sequentially reacting 6- (((trifluoromethyl) sulfonyl)) Oxy) -3, 4-dihydroisoquinoline-1, 2(1H) -dicarboxylic acid 1-ethyl ester 2-tert-butyl ester (10.2g, 12.4mmol), Pd2(dba)3(1.13g, 1.24mmol), xanthphos (1.43g, 2.47mmol), DIEA (4.09mL, 24.7mmol), methyl mercaptan (11.9g, 24.7mmol) and 1, 4-dioxane (50mL) were added to a closed jar. The reaction mixture was stirred overnight at 100 ℃ in a closed vessel purged with nitrogen, the vessel was rapidly sealed, 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 give a crude product, which was purified by silica gel column separation (PE: EA ═ 20:1 to 15:1) to give the target compound (6.20g, crude product, yellow oil). LC-MS (ESI) M/z 252.0[ M-BOC + H ]]+。
Step 6 Synthesis of 6- (methylsulfonyl) -3, 4-dihydroisoquinoline-1, 2- (1H) -dicarboxylic acid 1-ethyl 2-tert-butyl ester
6- (methylthio) -3, 4-dihydroisoquinoline-1, 2- (1H) -dicarboxylic acid 1-ethyl ester 2-tert-butyl ester (6.20g, 17.6mmol) is dissolved in DCM (100 mL). Under ice bath, m-chloroperoxybenzoic acid (8.95g, 44.1mmol, 85% content) was slowly added 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 and monitored by LC-MS for completion. The reaction solution was filtered, and the filtrate was washed with saturated sodium bicarbonate (100mL) and saturated brine (100mL) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by a silica gel column (PE: EA ═ 10:1-2:1) to give the objective compound (1.38g, yield in two steps: 29.0%, yellow oily substance). LC-MS (ESI) M/z 382.1[ M-H ]]-。
And 7: synthesis of 2- (tert-butoxycarbonyl) -6- (methylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid
Reacting 6- (methylsulfonyl) -3, 4-dihydroisoquinoline-1, 2- (1H) -dicarboxylic acid 1-ethyl ester 2-tert-butyl ester(1.38g, 3.60mmol) was dissolved in methanol (20mL), and a 1mol/L aqueous solution of sodium hydroxide (10.8mL, 10.8mmol) was added dropwise to the reaction mixture at room temperature. After the addition, the reaction solution was stirred at room temperature for 2 hours, and the completion of the reaction was monitored by LC-MS. The reaction solution was poured into ice water (30mL), the pH was adjusted to about 3 with 1mol/L dilute hydrochloric acid, extracted with EA (20mLx2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.12g, yield 87.6%, yellow solid). LC-MS (ESI) M/z 709.1[2M-H]-。
Synthesis of intermediate 2- (4 '-amino- [1,1' -biphenyl ] -4-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol
Step 1: synthesis of 2- (4-bromophenyl) -1,1,1,3,3, 3-hexafluoropropane-2-ol
Cupric bromide (474mg, 2.12mmol) was dissolved in acetonitrile (20mL) and tert-butyl nitrite (0.347mL, 2.89mmol) was added dropwise to the reaction under nitrogen in an ice bath. After the addition was completed, 2- (4-aminophenyl) -1,1,1,3,3, 3-hexafluoropropane-2-ol (500mg, 1.93mmol) was dissolved in acetonitrile (5mL) and added dropwise to the reaction solution, and after the addition was completed, the reaction mixture was stirred for further 1 hour under ice bath, and the completion of the reaction was monitored by LC-MS. The reaction solution was poured into ice water (50mL), extracted with methyl tert-butyl ether (20mLx2), and the organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (630mg, crude, brown oil). LC-MS (ESI) M/z 320.9[ M-H ]]-。
Step 2: synthesis of 2- (4 '-amino- [1,1' -biphenyl ] -4-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol
Reacting 2- (4-bromophenyl) -1,1,1,3,3, 3-hexafluoropropane-2-ol (630mg, 1.95mmol), 4-aminophenylboronic acid pinacol ester (427mg, 1.95mmol),Potassium carbonate (539mg, 3.90mmol) and PdCl2(dtbpf) (143mg, 0.195mmol) was added to a mixed solvent of 1, 4-dioxane (10mL) and water (1 mL). The reaction mixture was stirred at 100 ℃ for 2 hours under nitrogen, and LC-MS monitored the reaction was complete. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (PE: EA ═ 10:1-6:1) to give the title compound (299mg, yield in two steps, 46.2%, light yellow solid). LC-MS (ESI) M/z 334.0[ M-H ]]-。
Synthesis of 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
Step 1: synthesis of tert-butyl 1- ((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) -carboxylate
2- (tert-Butoxycarbonyl) -6- (methylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid (42.4mg, 0.119mmol) and 2- (4 '-amino- [1,1' -biphenyl were added]-4-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (40.0mg, 0.119mmol) was dissolved in anhydrous DCM (3 mL). HATU (68.1mg, 0.179mmol) and DIEA (0.0592mL, 0.358mmol) were added to the reaction mixture at room temperature in that order. After the addition was complete, the reaction mixture was stirred at room temperature overnight and the reaction was monitored by LC-MS for completion. The reaction was poured into water (20mL), extracted with DCM (15mLx2), and the organic phases were combined, washed successively with saturated ammonium chloride (20mL), saturated sodium bicarbonate (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (90.0mg, crude, brown oil). LC-MS (ESI) M/z 673.1[ M + H ]]+。
Step 2: synthesis of 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
1- ((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 (90.0mg) is dissolved in DCM (2 mL). 6mol/L dioxane hydrochloride solution (1mL) was added dropwise to the reaction solution in an ice bath. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for an additional 2 hours. The reaction solution was concentrated under reduced pressure to give the objective compound (90.0mg, crude, brown oil). LC-MS (ESI) M/z 573.0[ M + H ]]+。
And step 3: synthesis of 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
Mixing N- (4'- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropane-2-yl) - [1,1' -biphenyl ]]-4-yl) -6- (methylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxamide hydrochloride (90.0mg, 0.157mmol) was dissolved in anhydrous DCM (3 mL). DIEA (0.078mL, 0.472mmol) and acetyl chloride (0.028mL, 0.393mmol) were added dropwise to the reaction mixture at room temperature in that order. After the addition, the reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LC-MS for completion. The reaction mixture was directly concentrated and dissolved in methanol (3mL), and a 1mol/L aqueous solution of sodium hydroxide (2mL) was added dropwise to the reaction mixture at room temperature. After the addition was complete, the reaction was stirred at room temperature for 30 minutes and monitored by LC-MS for completion. The reaction solution was poured into water (20mL), extracted with EA (15mLx2), the organic phases were combined, washed with saturated ammonium chloride (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column (PE: EA ═ 1:1-0:1) to give a crude product, and then separated and purified by reverse column (acetonitrile: water ═ 7:3) to give the target compound (15.0mg, yield 20.5% in three steps, white solid). LC-MS (ESI) M/z 615.0[ M + H ]]+。1H NMR(400MHz,CDCl3)δ7.88–7.79(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).
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: synthesis of tert-butyl 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) -carboxylate
2- (tert-Butoxycarbonyl) -6- (methylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid (50.0mg, 0.141mmol) and 2- (4 '-amino-2-fluoro- [1,1' -biphenyl were added]-4-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (49.7mg, 0.141mmol) was dissolved in anhydrous DCM (3 mL). HATU (80.3mg, 0.211mmol) and DIEA (0.070mL, 0.422mmol) were added to the reaction mixture at room temperature in that order. After the addition was complete, the reaction mixture was stirred at room temperature overnight and the reaction was monitored by LC-MS for completion. The reaction was poured into water (20mL), extracted with DCM (15mLx2), and the organic phases were combined, washed successively with saturated ammonium chloride (20mL), saturated sodium bicarbonate (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (100mg, crude, brown oil). LC-MS (ESI) M/z 691.1[ M + H ]]+。
Step 2: synthesis of 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- (methanesulfonyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester (100mg) is dissolved in DCM (2 mL). 6mol/L dioxane hydrochloride solution (1mL) was added dropwise to the reaction solution in an ice bath. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for an additional 2 hours. The reaction solution was concentrated under reduced pressure to give the objective compound (100mg, crude, brown oil). LC-MS (ESI) M/z 591.0[ M + H ]]+。
And step 3: synthesis of 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
Mixing N- (2' -fluoro-4 ' - (1,1,1,3,3, 3-hexafluoro-2-hydroxypropane-2-yl) - [1,1' -biphenyl ]]-4-yl) -6- (methylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100mg, 0.169mmol) was dissolved in anhydrous DCM (3 mL). DIEA (0.084mL, 0.508mmol) and acetyl chloride (0.030mL, 0.423mmol) were added dropwise to the reaction mixture at room temperature in that order. After the addition, the reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LC-MS for completion. The reaction mixture was directly concentrated and dissolved in methanol (3mL), and a 1mol/L aqueous solution of sodium hydroxide (2mL) was added dropwise to the reaction mixture at room temperature. After the addition was complete, the reaction was stirred at room temperature for 30 minutes and monitored by LC-MS for completion. The reaction solution was poured into water (20mL), extracted with EA (15mLx2), the organic phases were combined, washed with saturated ammonium chloride (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column (PE: EA ═ 1:1-0:1) to give a crude product, and further separated and purified by reverse silica gel column (acetonitrile: water ═ 7:3) to give the target compound (23.0mg, yield in three steps: 25.8%, white solid). LC-MS (ESI) M/z 633.0[ M + H ]]+.1H NMR(400MHz,CDCl3)δ7.87–7.81(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).
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.
Racemic 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 in about 150mL of methanol, injection volume 3.0mL) via Waters SFC150 (room temperature, 100bar,214nm) and 250 x 25mm 10 μm DrOD) (supercritical carbon dioxide: methanol, 50:50,2.3min,70mL/min) separation to obtain R-2-acetyl-N- (2' -fluoro-4 ' - (1,1,3,3, 3-hexafluoro-2-hydroxypropane-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 (676mg, yellow solid, ret. time ═ 0.778min, e.e.99.74%). LC-MS (ESI) M/z 633.1[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ10.78,10.73(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' -biphenyl]-4-yl) -6- (methylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxamide or 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 (683mg, yellow solid, ret. time ═ 1.107min, e.e.98.58%).1H NMR(400MHz,DMSO-d6)δ10.78,10.73(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)。
Example 7: 2-acetyl-6- (ethylsulfonyl) -N- (2' -fluoro-4 ' - (1,1,1,3,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] -4-yl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxamide
Step 1: synthesis of 6- (ethylsulfanyl) -3, 4-dihydroisoquinoline-1, 2- (1H) -dicarboxylic acid 1-ethyl ester 2-tert-butyl ester
Sequentially reacting 6- (((trifluoromethyl) sulfonyl) oxy) -3, 4-dihydroisoquinoline-1, 2(1H) -dicarboxylic acid 1-ethyl ester 2-tert-butyl ester (3.70g, 8.16mmol), Pd2(dba)3(747mg, 0.816mmol), xantphos (944mg, 1.63mmol), DIEA (2.70mL, 16.3mmol), ethanethiol (1.22mL, 16.3mmol), and 1, 4-dioxane (20mL) were added to the vial. The tube was sealed quickly by blowing nitrogen into the sealed tube, the reaction mixture was stirred overnight at 100 ℃ and the reaction was monitored by LC-MS for completion. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (PE: EA ═ 20:1 to 15:1) to give the target compound (1.80g, crude product, yellow oil). LC-MS (ESI) M/z 266.0[ M-BOC + H ]]+。
Step 2: synthesis of 6- (ethylsulfonyl) -3, 4-dihydroisoquinoline-1, 2- (1H) -dicarboxylic acid 1-ethyl ester 2-tert-butyl ester
6- (ethylsulfanyl) -3, 4-dihydroisoquinoline-1, 2- (1H) -dicarboxylic acid 1-ethyl 2-tert-butyl ester (1.80g, 4.92mmol) is dissolved in DCM (30 mL). 85% m-chloroperoxybenzoic acid (2.50g, 12.3mmol) was slowly added to the reaction solution under ice bath. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours and monitored by LC-MS for completion. The reaction solution was filtered, and the filtrate was washed with saturated sodium bicarbonate (20mL) and saturated brine (20mL) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by a silica gel column (PE: EA ═ 15:1 to 5:1) to give the objective compound (1.10g, three-step yield: 81.0%, yellow oily substance). LC-MS (ESI) M/z 396.1[ M-H ]]-。
And 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) -dicarboxylic acid 1-ethyl 2-tert-butyl ester (460mg, 1.16mmol) was dissolved in methanol (5mL), and a 1mol/L aqueous solution of sodium hydroxide (3.47mL, 3.47mmol) was added dropwise to the reaction mixture at room temperature. After the addition, the reaction solution was stirred at room temperature for 2 hours, and the completion of the reaction was monitored by LC-MS. The reaction solution was poured into ice water (20mL), the pH was adjusted to about 3 with 1mol/L dilute hydrochloric acid, extracted with EA (10mLx2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the objective compound (362mg, yield 84.7%, yellow solid). LC-MS (ESI) M/z 737.1[2M-H ]]-。
And 4, step 4: synthesis of tert-butyl 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) -carboxylate
2- (tert-Butoxycarbonyl) -6- (ethylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid (50.0mg, 0.135mmol) and 2- (4 '-amino-2-fluoro- [1,1' -biphenyl]-4-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (47.8mg, 0.203mmol) was dissolved in anhydrous DCM (3 mL). HATU (77.2mg, 0.203mmol) and DIEA (0.067mL, 0.406mmol) were added to the reaction mixture at room temperature in that order. After the addition was complete, the reaction mixture was stirred at room temperature overnight and the reaction was monitored by LC-MS for completion. The reaction was poured into water (20mL), extracted with DCM (15mL x2), and the organic phases were combined, washed successively with saturated ammonium chloride (20mL), saturated sodium bicarbonate (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (100mg, crude, brown oil). LC-MS (ESI) M/z 705.1[ M + H ]]+。
And 5: synthesis of 6- (ethylsulfonyl) -N- (2' -fluoro-4 ' - (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] -4-yl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxamide hydrochloride
Mixing 6- (ethylsulfonyl) -1- ((2' -fluoro-4 ' - (1,1,1,3,3,3, 3-hexafluoro-2-hydroxypropane-2-yl) - [1,1' -biphenyl)]-4-yl) carbamoyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester (100mg, 0.142mmol) is dissolved in DCM (2 mL). 6mol/L dioxane hydrochloride solution (1mL) was added dropwise to the reaction solution in an ice bath. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for an additional 2 hours. The reaction solution was concentrated under reduced pressure to give the objective compound (100mg, crude, brown oil). LC-MS (ESI) M/z 605.0[ M + H ]]+。
Step 6: synthesis of 2-acetyl-6- (ethylsulfonyl) -N- (2' -fluoro-4 ' - (1,1,1,3,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] -4-yl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxamide
Reacting 6- (ethylsulfonyl) -N- (2' -fluoro-4 ' - (1,1,1,3,3, 3-hexafluoro-2-hydroxypropane-2-yl) - [1,1' -biphenyl]-4-yl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100mg, 0.165mmol) was dissolved in anhydrous DCM (3 mL). DIEA (0.082mL, 0.496mmol) and acetyl chloride (0.024mL, 0.331mmol) were added dropwise to the reaction mixture at room temperature in that order. After the addition, the reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LC-MS for completion. The reaction mixture was directly concentrated and dissolved in methanol (3mL), and a 1mol/L aqueous solution of sodium hydroxide (2mL) was added dropwise to the reaction mixture at room temperature. After the addition was complete, the reaction was stirred at room temperature for 30 minutes and monitored by LC-MS for completion. The reaction solution was poured into water (20mL), extracted with EA (15mLx2), the organic phases were combined, washed with saturated ammonium chloride (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column (PE: EA ═ 1:1-0:1) to give a crude product, and further separated and purified by reverse silica gel column (acetonitrile: water ═ 7:3) to give the target compound (25.0mg, yield in three steps: 34.5%, white solid). LC-MS (ESI) M/z 647.0[ M + H ]]+；1HNMR(400MHz,CDCl3)δ7.83–7.77(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＝7.3Hz,3H)。
Example 8: 2-acetyl-N- (4'- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropyl-2-yl) - [1,1' -biphenyl ] -4-yl) -5- (methylsulfonyl) isoindoline-1-carboxylic acid amide
2- (4 '-amino- [1,1' -biphenyl)]-4-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (50mg, 0.149mmol), 2-acetyl-5- (methylsulfonyl) isoindoline-1-carboxylic acid (46.5mg, 0.164mmol) and TCFH (92mg, 0.328mmol) were added to acetonitrile (5 mL). To the reaction mixture was added N-methylimidazole (73.4mg, 0.894mmol) in that order. The reaction mixture was stirred at room temperature for 3 hours. EA (15mL) and water (10mL) were added. EA (10 m) for separating the aqueous phaseL) extracting. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (C18, methanol/water 0-100%) gave the title compound (30mg, yield 33.5%, yellow solid). LC-MS (ESI) M/z 601.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ10.87,10.63(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 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: synthesis of 1,1,1,3,3, 3-hexafluoro-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propan-2-ol
2- (4-bromophenyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (1000mg, 3.10mmol), pinacol diboron (865mg, 3.41mmol), potassium acetate (911mg, 9.29mmol) and Pd (dppf) Cl were successively added2(227mg, 0.310mmol) was added to 1, 4-dioxane (10 mL). The reaction mixture was stirred at 90 ℃ overnight under nitrogen. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.00g, crude, black oil). LC-MS (ESI) M/z 369.1[ M-H ]]-。
Step 2: synthesis of 2- (4' -amino-2 ' -fluoro- [1,1' -biphenyl ] -4-yl) -1,1,1,3,3,3, 3-hexafluoropropan-2-ol
1,1,1,3,3, 3-hexafluoro-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propan-2-ol (500mg, 1.35mmol), 4-bromo-3-fluoroaniline (205mg, 1.08mmol), potassium carbonate (373mg, 2.70mmol) and Pd (dppf) Cl2(98.9mg, 0.135mmol) was added to a mixed solvent of 1, 4-dioxane (5mL) and water (0.5 mL). The reaction mixture was stirred at 100 ℃ for 2 hours under nitrogen, and LC-MS monitored the reaction was complete. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was subjected to separation and purification on a silica gel column (PE: EA ═ 10:1-2:1) to give a crude product, and then to separation and purification on a reverse phase column (acetonitrile: methanol ═ 1:1) to give the target compound (30.0mg, yield in three steps, 4.40%, white solid). LC-MS (ESI) M/z 352.0[ M-H ]]-。
And step 3: synthesis of tert-butyl 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) -carboxylate
2- (4' -amino-2 ' -fluoro- [1,1' -biphenyl)]-4-yl) -1,1,1,3,3,3, 3-hexafluoropropan-2-ol (30.0mg, 0.085mmol) and 2- (tert-butoxycarbonyl) -6- (methylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid (30.2mg, 0.085mmol) were dissolved in anhydrous DCM (3 mL). HATU (48.4mg, 0.127mmol) and DIEA (0.042mL, 0.255mmol) were added to the reaction mixture at room temperature in that order. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours and monitored by LC-MS for completion. The reaction was poured into water (20mL), extracted with DCM (15mLx2), and the organic phases combined, washed successively with saturated sodium bicarbonate (20mL) and saturated ammonium chloride (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title compound (80.0mg, crude, brown liquid). LC-MS (ESI) M/z 689.1[ M-H ]]-。
And 4, step 4: synthesis of N- (2-fluoro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] -4-yl) -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 (80.0mg) is dissolved in DCM (1 mL). A4 mol/L dioxane hydrochloride solution (1mL) was added dropwise to the reaction mixture while cooling on ice. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for an additional 2 hours and monitored by LC-MS for completion. The reaction solution was concentrated under reduced pressure to give the objective compound (70.0mg, crude, brown oil). LC-MS (ESI) M/z 591.0[ M + H ]]+。
And 5: synthesis of 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
Mixing N- (2-fluoro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropane-2-yl) - [1,1' -biphenyl ]]-4-yl) -6- (methylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxamide hydrochloride (70.0mg, 0.119mmol) was dissolved in anhydrous DCM (3 mL). Triethylamine (0.049mL, 0.356mmol) and acetyl chloride (0.021mL, 0.296mmol) were added dropwise to the reaction solution in this order at room temperature. After the addition, the reaction solution was stirred at room temperature for 30 minutes, and the completion of the reaction was monitored by LC-MS. The reaction mixture was directly concentrated and dissolved in methanol (3mL), and a 1mol/L aqueous solution of sodium hydroxide (2mL) was added dropwise to the reaction mixture at room temperature. After the addition was complete, the reaction was stirred at room temperature for 30 minutes and monitored by LC-MS for completion. Pouring the reaction solution into water (20mL), extracting with EA (15mLx2), combining organic phases, washing with saturated ammonium chloride (20mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, separating and purifying the crude product by a silica gel column (PE: EA ═ 1:1-0:1) to obtain a crude product, and separating and purifying the crude product by a reverse phase column (acetonitrile: water ═ 7:3) to obtain the target compound (1) (1: 7:3)0.0mg, 18.6% yield in three steps, white solid). LC-MS (ESI) M/z 633.0[ M + H ]]+。1H NMR(400MHz,CDCl3)δ9.51(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).
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: synthesis of 2- (4' -amino-2 ' -chloro- [1,1' -biphenyl ] -4-yl) -1,1,1,3,3,3, 3-hexafluoropropan-2-ol
1,1,1,3,3, 3-hexafluoro-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propan-2-ol (500mg, 1.35mmol), 4-bromo-3-chloroaniline (223mg, 1.08mmol), potassium carbonate (373mg, 2.70mmol) and Pd (dppf) Cl2(98.9mg, 0.135mmol) was added to a mixed solvent of 1, 4-dioxane (5mL) and water (0.5 mL). The reaction mixture was stirred at 100 ℃ for 2 hours under nitrogen, and LC-MS monitored the reaction was complete. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was subjected to separation and purification on a silica gel column (PE: EA ═ 10:1-2:1) to give a crude product, and then to separation and purification on a reverse phase column (acetonitrile: methanol ═ 1:1) to give the target compound (310mg, yield 43.5% in three steps, white solid). LC-MS (ESI) M/z 368.0[ M-H ]]-。
Step 2: synthesis of tert-butyl 1- ((2-chloro-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) -carboxylate
2- (4' -amino-2 ' -chloro- [1,1' -biphenyl)]-4-yl) -1,1,1,3,3,3, 3-hexafluoropropan-2-ol (83.2mg, 0.225mmol) and 2- (tert-butoxycarbonyl) -6- (methylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid (80.0mg, 0.225mmol) were dissolved in anhydrous DCM (3 mL). HATU (111mg, 0.293mmol) and DIEA (0.112mL, 0.675mmol) were added to the reaction mixture at room temperature in that order. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours and monitored by LC-MS for completion. The reaction was poured into water (20mL), extracted with DCM (15mLx2), the organic phases combined, washed successively with saturated sodium bicarbonate (20mL) and saturated ammonium chloride (20mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give the title compound (150mg, crude, brown oil). LC-MS (ESI) M/z 705.1[ M-H ]]-。
And step 3: synthesis of 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) -6- (methylsulfonyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester (150mg) is dissolved in DCM (1.5 mL). A4 mol/L dioxane hydrochloride solution (1.5mL) was added dropwise to the reaction solution while cooling on ice. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for an additional 2 hours and monitored by LC-MS for completion. The reaction solution was concentrated under reduced pressure to give the objective compound (140mg, crude, brown oil). LC-MS (ESI) M/z 605.1[ M-H ]]-。
And 4, step 4: synthesis of 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
Mixing N- (2-chloro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropane-2-yl) - [1,1' -biphenyl ]]-4-yl) -6- (methylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxamide hydrochloride (140mg, 0.231mmol) was dissolved in anhydrous DCM (3 mL). Triethylamine (0.096mL, 0.692mmol) and acetyl chloride (0.041mL, 0.577mmol) were added dropwise to the reaction solution in this order at room temperature. After the addition, the reaction solution was stirred at room temperature for 30 minutes, and the completion of the reaction was monitored by LC-MS. The reaction mixture was directly concentrated and dissolved in methanol (3mL), and a 1mol/L aqueous solution of sodium hydroxide (2mL) was added dropwise to the reaction mixture at room temperature. After the addition was complete, the reaction was stirred at room temperature for 30 minutes and monitored by LC-MS for completion. The reaction solution was poured into water (20mL), extracted with EA (15mLx2), the organic phases were combined, washed with saturated ammonium chloride (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column (PE: EA ═ 1:1-0:1) to give a crude product, and then separated and purified by reverse phase column (acetonitrile: water ═ 7:3) to give the target compound (49.3mg, yield in three steps 12.9%, white solid). LC-MS (ESI) M/z 649.0[ M + H ]]+。1H NMR(400MHz,CDCl3)δ9.38(d,J＝11.7Hz,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).
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: synthesis of tert-butyl 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) -carboxylate
2- (tert-Butoxycarbonyl) -6- (ethylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid (553mg, 1.56mmol) and 2- (4 '-amino-2-fluoro- [1,1' -biphenyl ] -4-yl) -1,1,1,3,3,3, 3-hexafluoropropane-2-ol (550mg, 1.56mmol) were dissolved in anhydrous DCM (6 mL). HATU (770mg, 2.02mmol) and DIEA (0.772mL, 4.67mmol) were added to the reaction mixture at room temperature in that order. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours and the completion of the reaction was monitored by TLC. The reaction was poured into water (20mL), extracted with DCM (15mL x2), the organic phases combined, washed successively with saturated sodium bicarbonate (20mL) and saturated ammonium chloride (20mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give the title compound (1.00g, crude, light brown solid).
Step 2: synthesis of 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- (methanesulfonyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester (1.00g) is dissolved in DCM (5 mL). A4 mol/L dioxane hydrochloride solution (5mL) was added dropwise to the reaction solution while cooling on ice. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for an additional 2 hours and monitored by LC-MS for completion. The reaction solution was concentrated under reduced pressure to give the objective compound (700mg, crude, yellow solid). LC-MS (ESI) M/z 591.1[ M + H ]]+。
And step 3: synthesis of N- (2' -fluoro-4 ' - (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] -4-yl) -6- (methylsulfonyl) -2-propionyl-1, 2,3, 4-tetrahydroisoquinoline-1-carboxamide
Mixing N- (2' -fluoro-4 ' - (1,1,1,3,3, 3-hexafluoro-2-hydroxypropane-2-yl) - [1,1' -biphenyl ]]-4-yl) -6- (methylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100mg, 0.169mmol) was dissolved in anhydrous DCM (3 mL). Triethylamine (0.071mL, 0.508mmol) and propionyl chloride (0.037mL, 0.423mmol) were added dropwise to the reaction solution in that order at room temperature. After the addition, the reaction solution was stirred at room temperature for 30 minutes, and the completion of the reaction was monitored by LC-MS. The reaction mixture was directly concentrated and dissolved in methanol (3mL), and a 1mol/L aqueous solution of sodium hydroxide (2mL) was added dropwise to the reaction mixture at room temperature. After the addition was complete, the reaction was stirred at room temperature for 30 minutes and monitored by LC-MS for completion. The reaction solution was poured into water (20mL), extracted with EA (15mLx2), the organic phases were combined, washed with saturated ammonium chloride (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column (PE: EA ═ 1:1-0:1) to give a crude product, and then separated and purified by reverse phase column (acetonitrile: water ═ 7:3) to give the target compound (31.1mg, 21.6% yield in three steps, white solid). LC-MS (ESI) M/z 647.1[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.26–7.94(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).
Example 12: 2- (cyclopropanecarbonyl) -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
Mixing N- (2' -fluoro-4 ' - (1,1,1,3,3, 3-hexafluoro-2-hydroxypropane-2-yl) - [1,1' -biphenyl ]]-4-yl) -6- (methylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100mg, 0.169mmol) was dissolved in anhydrous DCM (3 mL). Triethylamine (0.071mL, 0.508mmol) and cyclopropylcarbonyl chloride (0.0385mL, 0.423mmol) were added dropwise to the reaction mixture at room temperature in that order. After the addition, the reaction mixture was stirred at room temperature for 30 minutes, LC-MS monitors the reaction to be complete. The reaction mixture was directly concentrated and dissolved in methanol (3mL), and a 1mol/L aqueous solution of sodium hydroxide (2mL) was added dropwise to the reaction mixture at room temperature. After the addition was complete, the reaction was stirred at room temperature for 30 minutes and monitored by LC-MS for completion. The reaction solution was poured into water (20mL), extracted with EA (15mLx2), the organic phases were combined, washed with saturated ammonium chloride (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column (PE: EA ═ 1:1-0:1) to give a crude product, and then separated and purified by reverse phase column (acetonitrile: water ═ 7:3) to give the target compound (41.7mg, yield 28.4% in three steps, white solid). LC-MS (ESI) M/z 700.0[ M + ACN + H]+。1H NMR(400MHz,DMSO-d6)δ10.83,10.70(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 13: n is a radical of1- (2' -fluoro-4 ' - (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl]-4-yl) -N2-methyl-6- (methylsulfonyl) -3, 4-dihydroisoquinoline-1, 2(1H) -dicarboxamide
Mixing N- (2' -fluoro-4 ' - (1,1,1,3,3, 3-hexafluoro-2-hydroxypropane-2-yl) - [1,1' -biphenyl ]]-4-yl) -6- (methylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100mg, 0.169mmol) was dissolved in anhydrous DCM (3 mL). Triethylamine (0.071mL, 0.508mmol) and methylaminocarbonyl chloride (39.6mg, 0.423mmol) were added to the reaction solution in this order at room temperature. After the addition, the reaction solution was stirred at room temperature for 30 minutes, and the completion of the reaction was monitored by LC-MS. Pouring the reaction solution into water (20mL), extracting with DCM (15mLx2), combining organic phases, washing with saturated sodium bicarbonate (20mL) and saturated ammonium chloride (20mL) in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, separating and purifying by a silica gel column (PE: EA ═ 1:1-0:1) to obtain a crude product, and separating and purifying by a reverse 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 ]]+。1H NMR(400MHz,DMSO-d6)δ10.60(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＝4.1Hz,3H).
Active example 1: in vitro assay of the inhibitory Effect of Compounds on the ROR Gamma t luciferase reporter Gene
The experiment was carried out essentially as described in the literature (Current Chemical Genomics,2010,4, 43-49).
The ROR γ -LBD coding sequence was inserted into the pBIND plasmid (Promega, E1581). The expression vector and reporter vector (pGL4.35 carrying stably integrated GAL4 promoter driven luciferase reporter gene) were co-expressed in HEK293T host cells. When the inhibitor binds to the corresponding chimeric receptor, the chimeric receptor binds to the GAL4 binding site on the reporter vector and inhibits reporter expression. The inhibitory activity of the compound on ROR γ was determined from the intensity of the chemiluminescent signal.
Reagent and consumable
The experimental method comprises the following steps:
1. preparation of test Compounds
1.1 all test compounds were diluted in DMSO in 3-fold gradients, 10 dilution gradients, starting at 10 mM.
1.2 Positive control AZD-0284 was diluted in DMSO in 3-fold gradients, 10 dilution gradients, starting at 10 mM.
1.3 prepare 1000 × Positive control (10mM AZD-0284) and 1000 × negative control (100% DMSO).
1.4 the compound plate was blocked and shaken for 5 min.
2. Procedure of experiment
2.1 cell suspension preparation and plating
a) All cells were cultured according to ATCC standard procedures, and HEK293T was tested in exponential growth phase.
b) The medium was discarded.
c) Cells were washed 2 times with PBS.
d) The cells were digested by adding pancreatin digest and the digestion was stopped with complete medium.
e) Cells were collected and counted and experiments were only performed if the cell viability rate was greater than 90%.
f) Seed 6 x 106HEK293T cells into 100mm cell culture dishes.
g) The well-seeded cell culture dish was placed in a 5% CO2 incubator at 37 ℃ overnight for culture.
2.2 transfection of cells
a) Placing the Trans-IT transfection reagent at room temperature for balancing;
b) add 20. mu.l transfection reagent 600. mu.l Opti-MEMTMThe culture medium is sucked and evenly mixed by a pipette gun without touching the tube wall, and is kept stand for 5 minutes at room temperature;
c) add 10. mu.g plasmid to transfection reagent (see step 2.2.b), stand for 20 minutes at room temperature;
plasmid: separately, 5. mu.g of pBIND-ROR. gamma. and 5. mu.g of pGL4.35 plasmid were added
d) The DNA-mixed transfection reagent was added to a 100mm cell culture dish (see step 2.1);
e) the dishes were incubated for 5h at 37 ℃ in a 5% CO2 incubator.
2.3 treatment of the Compounds
a) Transfer 25nl of the diluted compound to a cell culture plate with Echo550 (6007680-50, PE);
b) cells (see step 2.2) were seeded into 384 cell culture plates (6007680-50, PE) at 15,000 cells per well in 25. mu.l of 5% charcoal-adsorbed FBS medium;
c) cells were cultured overnight at 37 ℃ in a 5% CO2 incubator
2.4 detection of Compounds:
a) subjecting Steady-GloTMPlacing the detection reagent at room temperature;
b) the 384 cell plate (see step 2.3) was left at room temperature;
c) add 25. mu.L of Steady-Gl per welloTMDetecting the reagents on the cell culture plate (see step 2.4 b);
d) placing the plate on an oscillator and shaking for 5min in a dark place;
e) chemiluminescence values were measured using Envision 2104.
Calculation of% Inhibition:
RLUcmpdfluorescence value of test compound
Mean positive control
Average of negative controls
IC of compounds was calculated by fitting% Inhibition and log of compound concentration using Graphad8.050. The determination result shows that the compound of the invention has better inhibitory activity to the ROR gamma t luciferase reporter gene (shown in Table 1).
TABLE 1 determination of ROR gamma t luciferase reporter inhibitory Activity by the example Compounds
Examples IC50(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 relative to AZD-028410. mu.M.
Active example 2: human PBMC Th17 cell differentiation inhibition assay
Test materials:
the experimental method comprises the following steps: firstly, PBMC cells are thawed and plated, then the PBMC cells are stimulated to differentiate to Th17 by stimulating factors (anti-hCD 28: 5 mu g/mL; rhTGF-beta 1: 5 ng/mL; rhIL-6: 20 ng/mL; rhIL-23: 10ng/Ml), compounds with different concentrations are added, the maximum concentration is started from 3 mu M, supernatants are collected after 48 hours for IL-17ELISA detection, the inhibition rate of the compounds for inhibiting the IL-17 secretion of Th17 cells is determined by comparing with a solvent group, and IC is fitted by Graphad8.050The value is obtained.
The determination result shows that the compound of the invention has better capability of inhibiting Th17 cells from differentiating and secreting IL-17 (shown in Table 2) for human PBMC.
TABLE 2 Experimental results of IL-17 secretion by inhibiting Th17 cell differentiation by compound
Examples IC50(nM) 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 that Emax% is the maximum inhibition.
Active example 3: human and mouse liver microsome metabolic stability assay
Liver Microsomal metabolic Stability assays for the compounds of the invention are similarly performed according to standard Methods of in vitro metabolic Stability studies conventional in the art, for example as described in (Kerns, Edward H.and Di Li (2008), Drug-like Properties: Concepts, Structure Design and Methods: from ADME to sensitivity Optimization, san Diego: Academic Press, Di, Li et al, Optimization of a high Throughput micro particulate Stability Screening Assay for Profiling Drug Discovery assays, J.biomol. Screen.2003,8(4), 453.).
The incubation system contained 0.5mg protein/mL microsome, cofactor, PBS, preincubated for 3min at 37 deg.C, and substrate (i.e., test compound) was added to initiate the reaction. Samples were taken at 0, 1, 5, 10, 15, 20, 30, 60min from the start of the reaction and appropriate stoppers were added to stop the reaction.
Sample treatment (n ═ 3): adding appropriate samples, vortexing, centrifuging at high speed, taking supernatant, and detecting the substrate by HPLC-MS/MS. The peak area at the time point of 0min was taken as 100%. The peak areas at other time points were converted to the residual percentages, the natural logarithm of the residual percentages at each time point was plotted against the incubation time, the slope (-k) was calculated by linear regression, and Clint (uL/min/mg) and the half-life of the compound (T1/2, min) were calculated from the intrinsic clearance (Clint) ((k) volume of incubation)/mass of liver microsomes. The results are shown in Table 3.
TABLE 3 results of the stability of liver microsome metabolism in human and mouse
The experimental results show that the compound of the invention has good metabolic stability.
Active example 4: compound PK assay in mice
The PK assay for each compound was as follows: 6C 57BL/6 mice (sourced from Shanghai Ling Biotech, Inc.) were divided into two groups of 3 mice each. One group was given Intravenously (IV) at a dose of 1mg/kg, with 5% DMSO/95% (20% Captisol); one group was administered by oral (PO) gavage at a dose of 5mg/kg with vehicle of 0.5% CMC-Na/0.5% Tween 80. Each group was collected via the saphenous vein of the lower leg at 0, 0.083, 0.25, 0.5, 1,2, 4, 6, 8, 24h post-dose. Approximately 40. mu.L of blood was collected in an anticoagulation tube containing EDTA-K2. The tubes were inverted at least 5 times immediately after collection to ensure uniform mixing, and then placed on ice. Blood was collected at each time point and centrifuged at 8000rpm for 5 minutes at 4 ℃ to obtain plasma. Another 1.5mL centrifuge tube was labeled with compound name, animal number, time point and plasma was transferred to the tube. Plasma was stored at-80 ℃ until analysis.
The concentrations of the compounds in plasma were determined by the UPLC-MS/MS method, and pharmacokinetic parameters were calculated on the data obtained with Phoenix WinNolin 6.4 pharmacokinetic software.
The specific experimental results are as follows, and the results show that the compound has better drug absorption and pharmacokinetic advantages. AUC of the Compounds of the invention0-last(ng/mL hr) and bioavailability were significantly improved, indicating that it has better druggability
TABLE 4 in vivo PK results for the example Compounds
The structure of the control compound used in the above experiment is as follows:
those skilled in the art will appreciate that the foregoing description is exemplary and illustrative in nature and is intended to illustrate the present invention and its preferred embodiments. Obvious modifications and variations will be apparent to those skilled in the art without departing from the spirit of the invention. All such modifications within the scope of the appended claims are intended to be included therein. Accordingly, it is intended that the invention not be limited by the foregoing description, but be defined by the scope of the following claims and their equivalents.
All publications cited in this specification are herein incorporated by reference.

Claims (15)

1. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof,
wherein:
R1and R2Each independently selected from hydrogen, halogen, cyano, nitro, C1-C6Alkyl, -O-C1-C6Alkyl, -S-C1-C6Alkyl, -NH-C1-C6Alkyl, -N- (C)1-C6Alkyl radical)2、-C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-S-C1-C6Alkyl, -C1-C6alkyl-NH-C1-C6Alkyl or-C1-C6alkyl-N (C)1-C6Alkyl radical)2Wherein said C is1-C6Alkyl is optionally substituted by halogen or cyano;
R3selected from H, -C1-C6Alkyl, -C3-C7Cycloalkyl, -4-7 membered heterocycloalkyl, -NRaRaOR-ORaIn which C is1-C6Alkyl radical, C3-C7Cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted with substituents independently selected from: halogen, cyano, nitro, C optionally substituted by halogen3-C7Cycloalkyl radical, Ra、-ORa、-SRaor-NRaRaWherein R isaSelected from H or C optionally substituted by halogen1-C6Alkyl, or two R bound to the same N atomaMay form, together with the N atom to which they are attached, a 4-7 membered nitrogen containing heterocycloalkyl group;
R4is selected from-C1-C6Alkyl, -C3-C7Cycloalkyl, -4-7 membered heterocycloalkyl or optionally substituted by C1-C6Alkyl radical, C3-C7Cycloalkyl or 4-7 membered heterocycloalkyl substituted amino, wherein said C1-C6Alkyl radical, C3-C7Cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted with substituents each independently selected from: halogen, cyano, nitro, Ra、-ORa、-SRa、-NRaRaOr optionally substituted by halogenC of (A)3-C7Cycloalkyl, wherein RaSelected from H or C optionally substituted by halogen1-C6Alkyl, or two groups attached to the same N atom may form, together with the N atom to which they are attached, a 4-7 membered nitrogen containing heterocycloalkyl group;
R5and R6Each independently selected from H, halogen, cyano or C optionally substituted by halogen or cyano1-C6An alkyl group;
m and p are each independently selected from 0, 1 or 2, and
n is selected from 0 or 1.
2. A compound according to claim 1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, wherein R is1And R2Each independently is H or halogen.
3. A compound according to claim 1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, wherein R is1And R2Each independently is C1-C6Alkyl or-O-C1-C6Alkyl radical, wherein C1-C6Alkyl is optionally substituted with halogen.
4. A compound according to any one of claims 1-3, a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, wherein R3is-C1-C6Alkyl, preferably C1-C3An alkyl group.
5. A compound according to any one of claims 1 to 3, a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, wherein R is3is-C3-C7Cycloalkyl, preferably cyclopropyl, cyclobutyl or cyclopentyl.
6. According to the rightA compound of any one of claims 1-3, a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, wherein R is3is-NRaRaWherein R isaIndependently selected from H or C optionally substituted with one or more halogens1-C3An alkyl group.
7. A compound according to any one of claims 1 to 6, a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, wherein R is4is-C1-C6Alkyl, preferably C1-C3An alkyl group.
8. A compound according to any one of claims 1 to 7, a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, wherein R5And R6Each independently selected from halogen or C substituted by halogen1-C6Alkyl, preferably R5And R6Are all-CF3。
9. A compound selected from
Stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates thereof.
10. A compound according to any one of claims 1 to 9, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, for use as a medicament, particularly as an inhibitor of ROR γ t, or for use in the treatment, particularly in the treatment or prevention of a disease in which ROR γ t is involved.
11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, and a pharmaceutically acceptable excipient.
12. A method for the prevention or treatment of diseases related to roryt in mammals, in particular humans, which comprises administering an effective amount of a compound according to any one of claims 1 to 9, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 11.
13. Use of a compound according to any one of claims 1 to 9, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 11 for the prophylaxis or treatment of a disease associated with roryt.
14. Use of a compound according to any one of claims 1 to 9, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 11, for the preparation of a medicament for the prophylaxis or treatment of a disease associated with roryt.
15. A compound according to claim 10, a method according to claim 12 or a use according to claim 13 or 14, wherein the disease associated with roryt is selected from psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, asthma, glomerulonephritis, lupus nephritis, myocarditis, thyroiditis, dry eye, uveitis, behcet's disease, allergic dermatitis, acne, scleroderma, bronchitis, dermato-allergic rhinitis, necrotizing enterocolitis, liver fibrosis, non-alcoholic steatohepatitis (NASH), neocoronary pneumonia, insulin dependent type I diabetes, triple negative breast cancer and prostate cancer.
HK42022050302.3A 2020-05-15 2022-03-18 BIARYL COMPOUNDS USEFUL AS RORγ MODULATORS HK40062607A (en)

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