WO2021228216A1 - COMPOSÉ BIARYLE CAPABLE DE SERVIR DE MODULATEUR DE RORγ - Google Patents

COMPOSÉ BIARYLE CAPABLE DE SERVIR DE MODULATEUR DE RORγ Download PDF

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WO2021228216A1
WO2021228216A1 PCT/CN2021/093788 CN2021093788W WO2021228216A1 WO 2021228216 A1 WO2021228216 A1 WO 2021228216A1 CN 2021093788 W CN2021093788 W CN 2021093788W WO 2021228216 A1 WO2021228216 A1 WO 2021228216A1
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alkyl
compound
halogen
pharmaceutically acceptable
reaction
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Chinese (zh)
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程耀邦
黄亚飞
周娟
董志强
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上海辉启生物医药科技有限公司
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Definitions

  • the present invention belongs to the technical field of chemical medicine, and specifically relates to biaryl compounds with ROR ⁇ t inhibitory activity, pharmaceutical compositions containing the compounds, methods for preparing the compounds, and preparation of the compounds for prevention or treatment and ROR ⁇ t Use in medicine for related diseases.
  • RORs Retinoic acid receptor-related orphan receptors
  • NF1R nuclear receptor superfamily of ligand-dependent transcription factors.
  • the RORs subfamily mainly includes three subtypes: ROR ⁇ , ROR ⁇ and ROR ⁇ .
  • ROR ⁇ contains two members: ROR ⁇ 1 (also called ROR ⁇ ) and ROR ⁇ 2 (also called ROR ⁇ t).
  • ROR ⁇ 1 is distributed in skeletal muscle, thymus, testis, pancreas, prostate, heart and liver, etc., while ROR ⁇ t is only expressed in certain immune systems. In the cell.
  • Th17 cells are a type of helper T cells that produce IL-17 and other pro-inflammatory cytokines. Th17 cells play a key role in many mouse autoimmune disease models, such as experimental allergic encephalomyelitis (EAE) and collagen-induced arthritis (CIA) animal models. In addition, IL-17 levels can be detected in some human autoimmune diseases including rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis (Psoriasis) and inflammatory bowel disease (IBD) The improvement. The number of Th17 cells found in tissues and peripheral blood samples of patients with autoimmune diseases increased. Therefore, Th17 cells or the cytokine IL-17 produced by Th17 cells are closely related to the pathogenesis of inflammation and autoimmune diseases.
  • RA rheumatoid arthritis
  • MS multiple sclerosis
  • Psoriasis psoriasis
  • IBD inflammatory bowel disease
  • Cosentyx (Secukinumab/AIN457), a monoclonal antibody developed by Novartis to specifically block IL-17 to treat psoriasis, has been approved by the FDA for marketing. This is the first drug in the psoriasis treatment market. A drug that acts on IL-17. Subsequently, the monoclonal antibody ixekizumab, which targets the pro-inflammatory cytokine IL-17A, was approved for indications of psoriasis and psoriatic arthritis. The clinical success of these monoclonal antibodies proves the importance of the IL-17 signaling pathway in inflammatory and autoimmune diseases, and demonstrates that ROR ⁇ t inhibitors can affect the IL-17 signaling pathway to treat inflammatory and autoimmune diseases. The potential for disease.
  • ROR ⁇ t can be used as a new target of drugs for the treatment of autoimmune diseases. It will be of great significance to find ROR ⁇ t small molecule inhibitors and use them in the treatment of ROR ⁇ t-mediated diseases, such as inflammation and autoimmune diseases.
  • ROR ⁇ t inhibitors for the prevention and/or treatment of ROR ⁇ t-related diseases, such as inflammation and autoimmune diseases.
  • ROR ⁇ t-related diseases such as inflammation and autoimmune diseases.
  • 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 medications for patients with related diseases. The choice can also provide a better treatment effect.
  • the present invention relates to compounds that can be used to prevent or treat diseases related to ROR ⁇ t.
  • the compound of the present invention not only shows satisfactory ROR ⁇ t inhibitory activity, has the ability to regulate Th17 cell differentiation, thereby inhibiting the production of IL-17, but also shows good performance in in vivo pharmacokinetic experiments, which indicates With improved druggability and improved bioavailability; in addition, it also shows good safety and has a lower risk of drug interactions.
  • the compound of the present invention can not only achieve the purpose of preventing or treating diseases related to ROR ⁇ t, but also the prepared drug is expected to have improved absorption, improved curative effect at the same dose, or provide the same curative effect at a lower dose, and more Long half-life and/or reduced possible side effects. Therefore, the present invention also provides the use of the compound of the present invention in the preparation of a medicament for the prevention or treatment of diseases related to ROR ⁇ t, a pharmaceutical composition containing the compound, and the prevention and/or treatment of ROR ⁇ t by administering the compound. Methods of related diseases.
  • a compound of formula (I), its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates are provided:
  • R 1 and R 2 are each independently selected from hydrogen, halogen, cyano, nitro, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, -SC 1 -C 6 alkyl, -NH-C 1 -C 6 alkyl, -N-(C 1 -C 6 alkyl) 2 , -C 1 -C 6 alkyl -OC 1 -C 6 alkyl, -C 1 -C 6 alkyl -SC 1- C 6 alkyl, -C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl or -C 1 -C 6 alkyl-N(C 1 -C 6 alkyl) 2 , wherein the C 1 -C 6 alkyl is optionally substituted by halogen or cyano;
  • R 3 is selected from H, -C 1 -C 6 alkyl, -C 3 -C 7 cycloalkyl, -4-7 membered heterocycloalkyl, -NR a R a or -OR a, wherein C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or 4-7 membered heterocycloalkyl are optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C 3 optionally substituted by halogen -C 7 -cycloalkyl, R a, -OR a, -SR a , or -NR a R a, R a is selected from H or an optionally halogen-substituted C 1 -C 6 alkyl, or connected to the same N two R a on the nitrogen atom may form a 4-7 membered heterocyclic group together with the N atom to which they are attached;
  • R 4 is selected from -C 1 -C 6 alkyl, -C 3 -C 7 cycloalkyl, -4-7 membered heterocycloalkyl or optionally C 1 -C 6 alkyl, C 3 -C 7 ring Alkyl or 4-7 membered heterocycloalkyl substituted amino, wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or 4-7 membered heterocycloalkyl are optionally selected independently of each other from the following substituents: halogen, cyano, nitro, R a, -OR a, -SR a, -NR a R a optionally substituted with halogen or C 3 -C 7 cycloalkyl group, wherein R a Two groups selected from H or C 1 -C 6 alkyl optionally substituted by halogen, or two groups attached to the same N atom can form 4-7 membered nitrogen-containing heterocycloalkanes together with the N
  • R 5 and R 6 are each independently selected from H, halogen, cyano or C 1 -C 6 alkyl optionally substituted by halogen or cyano;
  • n and p are each independently selected from 0, 1, or 2 and
  • n is selected from 0 or 1.
  • a compound of formula (I), its stereoisomers, tautomers, and stable isotopic variants which have ROR ⁇ t inhibitory activity and are used as drugs, especially as ROR ⁇ t inhibitors.
  • a pharmaceutically acceptable salt or solvate A pharmaceutically acceptable salt or solvate.
  • a pharmaceutical composition comprising the above-mentioned compound of the present invention and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the present invention is provided for preventing or treating diseases related to ROR ⁇ t.
  • the pharmaceutical composition may additionally contain additional therapeutically active ingredients suitable for use in combination with the compounds of the present invention.
  • a pharmaceutical combination comprising the above-mentioned compound of the present invention and another active agent.
  • a method for preventing or treating diseases related to ROR ⁇ t in a mammal, especially a human comprising administering an effective amount of the compound of the present invention described herein or a drug containing the same combination.
  • alkyl as used herein means a straight or branched chain aliphatic hydrocarbon group having the specified number of carbon atoms. Specifically, the alkyl group may have 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
  • suitable C 1-6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isoamyl Base, neopentyl, n-hexyl and isohexyl. Certain alkyl groups have 1 to 3 carbon atoms.
  • alkoxy refers to the group -O-alkyl, where alkyl has the meaning described herein. Specifically, the term refers to the group -OC 1-6 alkyl.
  • suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyl Oxy and 1,2-dimethylbutoxy.
  • Specific alkoxy groups have 1 to 3 carbon atoms.
  • alkylthio refers to the group -S-alkyl, where alkyl has the meaning described herein. Specifically, the term refers to the group -SC 1-6 alkyl.
  • suitable alkylthio groups include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, sec-butylthio, n-pentylthio, n-hexyl Sulfuryl and 1,2-dimethylbutylsulfanyl.
  • Specific alkylthio groups have 1 to 3 carbon atoms.
  • halogen-substituted C 1 -C 6 alkyl refers to the above-mentioned C 1 -C 6 alkyl, in which one or more (for example, 1, 2, 3, 4, or 5) hydrogen The atoms are replaced by halogens.
  • the halogens may be the same or different, and may be located on the same or different C atoms.
  • halogen-substituted C 1 -C 6 alkyl are, for example, -CH 2 F, -CHF 2 , -CF 3 , -CCl 3 , -C 2 F 5 , -C 2 Cl 5 , -CH 2 CF 3 , -CH 2 Cl, CH 2 CH 2 CF 3 or -CF(CF 3 ) 2 and so on.
  • halogen-substituted C 1 -C 6 alkoxy refers to the above-mentioned C 1 -C 6 alkoxy, wherein one or more (e.g., 1, 2, 3, 4 or 5 ) The hydrogen atom is replaced by a halogen.
  • the halogens may be the same or different, and may be located on the same or different C atoms.
  • halogen substituted C 1 -C 6 alkoxy group examples include, for example, -OCH 2 F, -OCHF 2 , -OCF 3 , -OCCl 3 , -OC 2 F 5 , -OC 2 Cl 5 , -OCH 2 CF 3. -OCH 2 Cl or -OCH 2 CH 2 CF 3 and so on.
  • halogen-substituted C 1 -C 6 alkylthio refers to the C 1 -C 6 alkylthio group described above, of which one or more (e.g., 1, 2, 3, 4 or 5 ) The hydrogen atom is replaced by a halogen.
  • the halogens may be the same or different, and may be located on the same or different C atoms.
  • halogen substituted C 1 -C 6 alkylthio group examples include, for example, -SCH 2 F, -SCHF 2 , -SCF 3 , -SCCl 3 , -SC 2 F 5 , -SC 2 Cl 5 , -SCH 2 CF 3. -SCH 2 Cl or -SCH 2 CH 2 CF 3 and so on.
  • cycloalkyl as used herein means a monocyclic, fused polycyclic, bridged polycyclic or spirocyclic non-aromatic saturated hydrocarbon ring structure having the specified number of ring atoms.
  • the cycloalkyl group may have 3 to 12 carbon atoms, specifically 3 to 10, and more specifically 3 to 7 carbon atoms, that is, C 3 -C 7 cycloalkyl.
  • suitable cycloalkyl groups include, but are not limited to, monocyclic C 3 -C 7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Specific cycloalkyl groups have 3 to 5 carbon atoms.
  • halogen-substituted C 3 -C 7 cycloalkyl refers to the above-mentioned C 3 -C 7 cycloalkyl, of which one or more (e.g. 1, 2, 3, 4 or 5 ) The hydrogen atom is replaced by a halogen.
  • the halogens may be the same or different, and may be located on the same or different C atoms.
  • Specific examples include, but are not limited to, 2-fluorocyclopropyl, 2,3-difluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 2,3-difluorocyclobutyl, 2, 4-Difluorocyclobutyl and so on.
  • heterocycloalkyl means a monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic heteroatom including one or more heteroatoms independently selected from O, N, and S and a specified number of ring atoms.
  • the heterocycloalkyl group may have 4 to 12 ring members, specifically 4 to 10 ring members, and more specifically 4 to 7 ring members.
  • the heterocycloalkyl group usually contains up to 4 heteroatoms, more usually up to 3 heteroatoms, more usually up to 2, such as a single heteroatom, such as a 4-7 membered monocyclic heterocycloalkyl group having one heteroatom such as N, That is, 4-7 membered nitrogen-containing heterocycloalkyl.
  • 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.
  • Tetrahydropyranyl Tetrahydrothiopyranyl (for example 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, or azepanyl.
  • heterocyclic ring can have 1 to 4 heteroatoms, as long as the heterocyclic ring or heteroaromatic ring is chemically feasible and stable.
  • halo or halogen as used herein means fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
  • the specific halogen is fluorine or chlorine.
  • halogen substituted group as used herein is intended to include monohalogenated or polyhalogenated groups in which one or more identical or different halogens replace one or more hydrogens in the group.
  • cyano as used herein means the group -CN.
  • nitro as used herein means the group -NO 2 .
  • amino as used herein means the group -NH 2 ;
  • the term "optionally substituted by” means that the group may be unsubstituted or be substituted by one or more (e.g. 0, 1, 2, 3, 4 or 5 or more, or any of which can be derived Range) Substituting the listed substituents for this group, wherein the substituents may be the same or different.
  • the optionally substituted group has 1 substituent.
  • the optionally substituted group has 2 substituents.
  • the optionally substituted group has 3 substituents.
  • the optionally substituted group has 4 substituents.
  • the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, or 4-7 membered heterocycloalkyl used in the definition of compounds herein optionally carries one or more substituents.
  • halogens preferably F
  • pharmaceutically acceptable means approved by or can be approved by the corresponding agency of each country, or listed in the generally recognized pharmacopoeia for animals and more specifically humans, or when administered to animals such as humans in appropriate amounts Molecular entities and compositions that do not produce adverse, allergic or other adverse reactions.
  • pharmaceutically acceptable salt means a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound.
  • such salts are non-toxic, and can be inorganic acid addition salts, organic acid addition salts, and base addition salts.
  • such salts include: (1) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids, Organic acids such as acetic acid, propionic acid, caproic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid Acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butyl Acetic acid, lauryl sulfuric acid, gluconic acid, glutacetate
  • prodrug means a compound that has a cleavable group and becomes a compound of the present invention that has pharmacological activity in the body through solvolysis or under physiological conditions, including derivatives of the compound of the present invention.
  • Prodrugs include acid derivatives well known in the art, such as esters prepared by reacting a parent acid with a suitable alcohol, or amides prepared by reacting a parent acid compound with a substituted or unsubstituted amine, or anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acid groups pendant to the compounds of the present invention are particularly useful prodrugs. Specific such prodrugs are C 1-8 alkyl, C 2-8 alkenyl, optionally substituted C 6-10 aryl and (C 6-10 aryl)-(C 1- 4 alkyl) esters.
  • stereoisomer as used herein means an isomer formed due to at least one asymmetric center. In compounds with one or more (for example, 1, 2, 3, or 4) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and Individual diastereomers. Specific molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present 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-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. For example, nitroso-oximes can exist in equilibrium in the following tautomeric forms in solution:
  • the compounds of the present invention may have one or more asymmetric centers, and therefore may be prepared in the form of (R)- or (S)-stereoisomers respectively or in the form of mixtures thereof.
  • R and S represent the relative configuration of the chiral center.
  • solvate refers to a solvent addition form containing stoichiometric or non-stoichiometric solvents, including, for example, solvates with water, such as hydrates, or with organic solvents, such as methanol, ethanol, or Solvates of acetonitrile, namely as methanolate, ethanolate or acetonitrile respectively; or in the form of any polymorph. It should be understood that such solvates of the compounds of the present invention also include solvates of pharmaceutically acceptable salts of the compounds of the present invention.
  • isotopic variant refers to a compound in which one or more of the atoms constituting the compound is replaced by an atom having an atomic mass or mass number that is different from the atomic mass or mass number commonly found in nature.
  • isotopes that can be incorporated into one or more atoms of the compounds of the present invention include, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, thereby forming isotopic variants of the compounds of the present invention, whether they are radioactive or not, are intended to be encompassed within the scope of the present invention.
  • the incorporated isotope is 2H (deuterium); in other embodiments, the incorporated isotope is 3H (tritium).
  • disease related to ROR ⁇ t means that ROR ⁇ t promotes the occurrence and development of the disease, or inhibiting ROR ⁇ t will reduce the incidence of the disease and reduce or eliminate the disease symptoms.
  • "disease related to ROR ⁇ t” is especially selected from inflammation or autoimmune diseases, cancer, etc., including but not limited to psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spine Inflammation, multiple sclerosis, systemic lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, asthma, glomerulonephritis, lupus nephritis, myocarditis, thyroid Inflammation, dry eye, uveitis, Behcet's disease, allergic dermatitis, acne, scleroderma, bronchitis, derm
  • the preferred indications of the present invention are selected from psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, inflammatory bowel disease, dry eye, allergic dermatitis, chronic obstruction COPD, asthma, necrotizing enterocolitis, liver fibrosis, non-alcoholic steatohepatitis (NASH), new coronavirus pneumonia, triple negative breast cancer and prostate cancer.
  • subject or “individual” as used herein includes human or non-human animals.
  • exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as those described herein.
  • non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).
  • terapéuticaally effective amount means that when administered to a subject to treat a disease, it is sufficient to reduce or completely alleviate the symptoms or other harmful effects of the disorder; reverse, completely stop or slow the progression of the disorder; or reduce the deterioration of the disorder
  • the amount of risk, the "effective amount” may vary depending on the compound, the disease and its severity, and the age and weight of the subject to be treated.
  • prevention means to administer a subject suspected of suffering from or susceptible to ROR ⁇ t-related diseases as defined herein, especially inflammation or autoimmune diseases, such as mammals, such as humans. Or multiple compounds of the present invention, which reduce the risk of suffering from the defined disease.
  • prevention encompasses the use of the compounds of the present invention prior to the diagnosis or determination of any clinical and/or pathological symptoms.
  • treatment refers to the administration of one or more of the compounds of the invention described herein to a subject suffering from the disease or having symptoms of the disease, such as a mammal, such as a human, for Cure, alleviate, alleviate or affect the disease or the symptoms of the disease.
  • the disease is a disease related to ROR ⁇ t as defined herein, especially inflammation or an autoimmune disease.
  • pharmaceutical combination means that the compound of the present invention can be combined with other active agents to achieve the purpose of the present invention.
  • the other active agent may be one or more additional compounds of the present invention, or may be a second or additional (e.g., third ) Compound. Such active agents are suitably present in combination in an effective amount to achieve the intended purpose.
  • the other active agent may be co-administered with the compound of the present invention in a single pharmaceutical composition, or administered separately from the compound of the present invention in separate discrete units, and when administered separately, they may be administered simultaneously or sequentially. The sequential administration may be close or distant in time.
  • pharmaceutically acceptable excipient or carrier refers to one or more compatible solid or liquid fillers or gel substances, which are pharmacologically inactive and are compatible with other ingredients in the composition. It should be acceptable for administration to warm-blooded animals such as humans, and used as a carrier or medium for the compound of the present invention in the administration form. Examples include, but are not limited to, cellulose and its derivatives (such as carboxymethyl cellulose).
  • solid lubricants such as magnesium stearate
  • calcium sulfate such as calcium sulfate
  • vegetable oils such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween Class
  • wetting agents such as sodium lauryl sulfate
  • coloring agents such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen, etc.
  • stabilizers
  • C n-n+m or C n -C n+m in the definition of the compound of the present invention includes various cases of n to n+m carbon atoms, for example, C 1-6 includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 , and also include any range from n to n+m, for example, C 1-6 includes C 1-2 , C 1-3 , C 1-4 , and C 2- 6. C 3-6 etc.
  • n-membered to n+m-membered in the definition of the compound of the present invention means that the number of ring atoms is from n to n+m.
  • a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, and a 6-membered ring.
  • Rings, 12-membered rings, etc. also include any range from n to n+m.
  • 3-12-membered rings include 3-6-membered rings, 3-9-membered rings, 5-6-membered rings, and 5-7-membered rings , 6-7 membered ring, 6-8 membered ring and 6-10 membered ring, etc.
  • the compound of the present invention is the free form of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof; most preferably, 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, and they also fall within the scope of the present invention.
  • the compound of formula (I) may be in the form of a co-crystal with another chemical entity, and this specification includes all such co-crystals.
  • the compounds of the present invention may exist as individual enantiomers or as a mixture of enantiomers.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof which is a single enantiomer with an enantiomeric excess (%ee) >95, >98% or >99%.
  • a single enantiomer is present in an enantiomeric excess (%ee) of >99%.
  • the present invention provides a compound of formula (I), its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates:
  • R 1 and R 2 are each independently selected from hydrogen, halogen, cyano, nitro, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, -SC 1 -C 6 alkyl, -NH-C 1 -C 6 alkyl, -N-(C 1 -C 6 alkyl) 2 , -C 1 -C 6 alkyl -OC 1 -C 6 alkyl, -C 1 -C 6 alkyl -SC 1- C 6 alkyl, -C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl or -C 1 -C 6 alkyl-N(C 1 -C 6 alkyl) 2 , wherein the C 1 -C 6 alkyl is optionally substituted by halogen or cyano;
  • R 3 is selected from H, -C 1 -C 6 alkyl, -C 3 -C 7 cycloalkyl, -4-7 membered heterocycloalkyl, -NR a R a or -OR a, wherein C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or 4-7 membered heterocycloalkyl are optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C 3 optionally substituted by halogen -C 7 -cycloalkyl, R a, -OR a, -SR a , or -NR a R a, wherein R a is selected from H or optionally halogen-substituted C 1 -C 6 alkyl, or connected to the same two R a may be formed on the N-atom together with the N atom to which they are attached, 4-7 membered nitrogen-containing heterocyclic group;
  • R 4 is selected from -C 1 -C 6 alkyl, -C 3 -C 7 cycloalkyl, -4-7 membered heterocycloalkyl or optionally C 1 -C 6 alkyl, C 3 -C 7 ring Alkyl or 4-7 membered heterocycloalkyl substituted amino, wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or 4-7 membered heterocycloalkyl are optionally selected independently of each other Substitution from the following substituents: halogen, cyano, nitro, R a , -OR a , -SR a , -NR a R a or C 3 -C 7 cycloalkyl optionally substituted by halogen, R a is selected A C 1 -C 6 alkyl group optionally substituted by H or halogen, or two groups attached to the same N atom can form a 4-7 membered nitrogen-containing heterocycloalkyl group
  • R 5 and R 6 are each independently selected from H, halogen, cyano or C 1 -C 6 alkyl optionally substituted by halogen or cyano;
  • n and p are each independently selected from 0, 1, or 2 and
  • n is selected from 0 or 1.
  • n is zero.
  • n 1
  • R 1 and R 2 are each independently H.
  • R 1 and R 2 are each independently halogen, such as F, Cl, Br or I; preferably F or Cl.
  • both R 1 and R 2 are H. In a specific embodiment, R 1 is H and R 2 is halogen. In a specific embodiment, R 1 is halogen and R 2 is H. In a specific embodiment, R 1 and R 2 are both halogen, and the two may be the same or different.
  • R 1 and R 2 are each independently selected from C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, -SC 1 -C 6 alkyl,- NH-C 1 -C 6 alkyl or -N-(C 1 -C 6 alkyl) 2 , wherein the C 1 -C 6 alkyl group is optionally substituted by halogen (preferably F).
  • R 1 and R 2 are each independently selected from -C 1 -C 6 alkyl-OC 1 -C 6 alkyl, -C 1 -C 6 alkyl-SC 1- C 6 alkyl, -C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl or -C 1 -C 6 alkyl-N(C 1 -C 6 alkyl) 2 , where C The 1- C 6 alkyl group is optionally substituted by halogen (preferably F).
  • Specific examples include but are not limited to -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 NHCH 3 , -CH 2 N( CH 3 ) 2 , -CH 2 OCF 3 , -CH 2 CH 2 OCF 3 , -CH 2 OCH 2 CF 3 , -CH 2 NHCF 3 , -CH 2 N(CF 3 ) 2 and so on.
  • R 3 is -C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, which is optionally selected by one or more groups independently selected from substituents: halogen, optionally halogen-substituted C 3 -C 7 cycloalkyl, R a, -OR a, -SR a , or -NR a R a, wherein R a is independently selected from H or optionally substituted with one or a plurality of halogen-substituted C 1 -C 6 alkyl, or are connected on the same N atom may be two R a 4-7 membered nitrogen-containing heterocyclic group formed together with the N atom to which they are attached.
  • R 3 is -C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, optionally substituted with F, Cl, Br, I, R a , or - substituted with OR a, wherein R a It is H or C 1 -C 3 alkyl optionally substituted with one or more halogens (preferably F).
  • R a It is H or C 1 -C 3 alkyl optionally substituted with one or more halogens (preferably F).
  • Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, Trifluoromethoxymethyl or trifluoromethoxyethyl, etc.
  • R 3 is C 1 -C 3 alkyl, such as methyl, ethyl, propyl or isopropyl.
  • R 3 is -C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, optionally substituted by C 3 -C 7 cycloalkyl optionally substituted by halogen.
  • Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentyl Ethyl and so on.
  • R 3 is -C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, optionally substituted with -NR a R a, wherein R a is independently selected from H or optionally with one or more halogen substituted C 1 -C 3 alkyl, or attached to the same N atom may be two R a 4-7 membered nitrogen-containing heterocyclic group formed together with the N atom to which they are attached.
  • Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, dimethylaminomethyl, methylethylamino Methyl, azetidinyl methyl, pyrrolidinyl methyl, piperidinyl methyl, etc.
  • R 3 is -C 3 -C 7 cycloalkyl, which is optionally substituted with one or more groups independently selected from: halogen, optionally halogen substituted C 3 -C 7 cycloalkyl, R a, -OR a, -SR a , or -NR a R a, wherein R a is independently selected from H or optionally substituted with one or more halogen C 1 - C 6 alkyl, or are connected on the same N atom may be two R a 4-7 membered nitrogen-containing heterocyclic group formed together with the N atom to which they are attached.
  • R 3 is -C 3 -C 5 cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl.
  • R 3 is -C 3 -C 7 cycloalkyl, optionally substituted with one or more groups independently selected from the following groups: halogen, R a ,, - OR a or -NR a R a, wherein R a is independently selected from H or optionally substituted with one or more halogen C 1 -C 6 alkyl.
  • Specific examples include, but are not limited to, 2,3-difluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 2,3-difluorocyclobutyl, methylcyclopropyl or cyclobutyl , Dimethylcyclopropyl or cyclobutyl, trifluoromethylcyclopropyl or cyclobutyl, hydroxycyclopropyl or cyclobutyl, trifluoromethoxycyclopropyl or cyclobutyl, methylamino ring Propyl, dimethylaminocyclopropyl, trifluoromethylaminocyclopropyl, etc.
  • R 3 is 4-7-membered heterocycloalkyl, optionally substituted with one or more substituents independently selected from the following radicals: halogen, R a, -OR a, -SR a, or -NR a R a, wherein R a is independently selected from H or optionally substituted with one or more halogen C 1 -C 6 alkyl, or are connected on the same two N atoms R a may form a 4-7 membered nitrogen-containing heterocyclic group together with the N atom to which they are attached.
  • R 3 is 4-7 membered heterocycloalkyl, such as azetidinyl, oxetanyl, thietane, 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-tetrahydrofuranyl) Hydrothienyl and 3-tetrahydrothienyl), piperidinyl (e.g.
  • substituents independently selected from F, Cl, Br, I, R a, -OR a substituted with -NR a R a or a group, wherein R a is independently selected from H or any Select C 1 -C 3 alkyl substituted with one or more halogens.
  • R 3 is -NR a R a, wherein R a is independently selected from H or optionally substituted with one or more halogen C 1 -C 3 alkyl, or attached to the same N atom may be two R a 4-7 membered nitrogen-containing heterocyclic group formed together with the N atom to which they are attached.
  • Specific examples include but are not limited to -NH 2 , -NHCH 3 , -NCH 3 CH 3 , -N(CH 2 CH 3 )CH 3 , -N(CH 2 CH 3 )(CH 2 CH 3 )-, -NHCF 3 , -N(CH 3 )CF 3 , -N(CF 3 )CF 3 , -N(CH 2 CF 3 )CF 3 or -N(CH 2 CF 3 )(CH 2 CF 3 )-, -NH( CH 2 CH 2 CH 3 ), azetidinyl, pyrrolidinyl, piperidinyl, etc.
  • R 4 is selected from -C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, which is optionally selected by one or more groups independently selected from group: halogen, optionally halogen-substituted C 3 -C 7 cycloalkyl, R a, -OR a, -SR a , or -NR a R a, wherein R a is independently selected from H or optionally substituted with one or more halogen substituted C 1 -C 6 alkyl, or are connected on the same N atom may be two R a 4-7 membered nitrogen-containing heterocyclic group formed together with the N atom to which they are attached.
  • R 4 is -C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, optionally substituted with F, Cl, Br, I, R a or -OR a, wherein R a It is H or C 1 -C 3 alkyl optionally substituted with one or more halogens (preferably F).
  • halogens preferably F.
  • Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, Trifluoromethoxymethyl or trifluoromethoxyethyl, etc.
  • R 4 is C 1 -C 3 alkyl, such as methyl, ethyl, propyl, or isopropyl.
  • R 4 is -C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, optionally substituted by C 3 -C 7 cycloalkyl optionally substituted by halogen.
  • Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentyl Ethyl and so on.
  • R 4 is -C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, optionally substituted with -NR a R a, wherein R a is independently selected from H or optionally with one or more halogen substituted C 1 -C 3 alkyl, or attached to the same N atom may be two R a 4-7 membered nitrogen-containing heterocyclic group formed together with the N atom to which they are attached.
  • Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, dimethylaminomethyl, methylethylamino Methyl, azetidinyl methyl, pyrrolidinyl methyl, piperidinyl methyl, etc.
  • R 4 is -C 3 -C 7 cycloalkyl, which is optionally substituted with one or more groups independently selected from: halogen, optionally halogen substituted C 3 -C 7 cycloalkyl, R a, -OR a, -SR a , or -NR a R a, wherein R a is independently selected from H or optionally substituted with one or more halogen C 1 - C 6 alkyl, or are connected on the same N atom may be two R a 4-7 membered nitrogen-containing heterocyclic group formed together with the N atom to which they are attached.
  • R 4 is -C 3 -C 5 cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl.
  • R 4 is -C 3 -C 7 cycloalkyl, optionally substituted with one or more substituents independently selected from the following radicals: halogen, R a, -OR a or -NR a R a, wherein R a is independently selected from H or optionally substituted with one or more halogen C 1 -C 6 alkyl.
  • Specific examples include, but are not limited to, 2,3-difluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 2,3-difluorocyclobutyl, methylcyclopropyl or cyclobutyl , Dimethylcyclopropyl or cyclobutyl, trifluoromethylcyclopropyl or cyclobutyl, hydroxycyclopropyl or cyclobutyl, trifluoromethoxycyclopropyl or cyclobutyl, methylamino ring Propyl, dimethylaminocyclopropyl, trifluoromethylaminocyclopropyl, etc.
  • R 4 is 4-7 membered heterocycloalkyl, optionally substituted with one or more substituents independently selected from the following radicals: halogen, R a, -OR a, -SR a, or -NR a R a, wherein R a is independently selected from H or optionally substituted with one or more halogen C 1 -C 6 alkyl, or are connected on the same two N atoms R a may form a 4-7 membered nitrogen-containing heterocyclic group together with the N atom to which they are attached.
  • R 4 is 4-7 membered heterocycloalkyl, such as azetidinyl, oxetanyl, thietane, 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-tetrahydrofuranyl) Hydrothienyl and 3-tetrahydrothienyl), piperidinyl (e.g.
  • substituents independently selected from F, Cl, Br, I, R a, -OR a substituted with -NR a R a or a group, wherein R a is independently selected from H or any Select C 1 -C 3 alkyl substituted with one or more halogens.
  • R 4 is an amino group optionally substituted with C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, or 4-7 membered heterocycloalkyl.
  • the substituted amino C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or 4-7 membered heterocycloalkyl having each of the above embodiments as R C 4 l -
  • R 4 is an amino group substituted with a C 1 -C 6 alkyl group optionally substituted by halogen.
  • Specific examples include, but are not limited to, -NH 2 , -NHCH 3 , -NCH 3 CH 3 , -N(CH 2 CH 3 )CH 3 , -N(CH 2 CH 3 )(CH 2 CH 3 )-, -NHCF 3 , -N(CH 3 )CF 3 , -N(CF 3 )CF 3 ,- N(CH 2 CF 3 )CF 3 or -N(CH 2 CF 3 )(CH 2 CF 3 )-, -NH(CH 2 CH 2 CH 3 ), azetidinyl, pyrrolidinyl, piperidinyl Wait.
  • R 5 and R 6 are each independently selected from halogens, such as F, Cl, Br, I.
  • R 5 and R 6 are each independently selected from C 1 -C 6 alkyl optionally substituted with halogen. In a specific embodiment, R 5 and R 6 are each independently selected from C 1 -C 3 alkyl substituted with at least three halogens. In a more specific embodiment, R 5 and R 6 are each independently selected from C 1 -C 3 alkyl substituted by three fluorines. Specific examples include, but are not limited to, trifluoromethyl, trifluoroethyl, penta Fluoroethyl and so on. In the most specific embodiment, both R 5 and R 6 are -CF 3 .
  • both m and p are zero.
  • m is 0 and p is 1.
  • m is 0 and p is 2.
  • m is 1 and p is 0.
  • m is 1 and p is 1.
  • m is 1 and p is 2.
  • m is 2 and p is 0.
  • m is 2 and p is 1.
  • m is 2 and p is 2.
  • the present invention provides a compound of formula (I), its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate:
  • R 1 and R 2 are each independently selected from hydrogen, halogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted by halogen;
  • R 3 is selected from H, -C 1 -C 6 alkyl, -C 3 -C 7 cycloalkyl or -NR a R a, wherein C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl optionally independently selected from the following substituents: halogen, optionally halogen-substituted C 3 -C 7 cycloalkyl, R a, -OR a, -SR a , or -NR a R a;
  • R 4 is selected from -C 1 -C 6 alkyl or -NR a R a, wherein said C 1 -C 6 alkyl is optionally independently substituted with substituents selected from: R a, halogen or -NR a R a :
  • R a is selected from H or an optionally halogen-substituted C 1 -C 6 alkyl, or are connected on the same N atom may form two R a 4-7 membered nitrogen-containing together with the N atom to which they are attached, Cycloalkyl
  • R 5 and R 6 are each independently selected from halogen or C 1 -C 6 alkyl optionally substituted by halogen;
  • n and p are each independently selected from 0, 1, or 2 and
  • n is selected from 0 or 1.
  • R 1 and R 2 are each independently selected from hydrogen or halogen, such as F, Cl, Br, I. In a specific embodiment, both R 1 and R 2 are H. In a specific embodiment, R 1 is H and R 2 is halogen. In a specific embodiment, R 1 is halogen and R 2 is H. In a specific embodiment, R 1 and R 2 are both halogen, and the two may be the same or different.
  • R 3 is -C 1 -C 3 alkyl, optionally substituted with a substituent independently selected from: H, halogen or optionally substituted by halogen ⁇ C 3 -C 7 cycloalkyl.
  • substituents independently selected from: H, halogen or optionally substituted by halogen ⁇ C 3 -C 7 cycloalkyl.
  • Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, trifluoromethyl, trifluoroethyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl Group, cyclopentylmethyl, cyclopentylethyl, etc.
  • R 3 is -C 1 -C 3 alkyl, such as methyl, ethyl, propyl or isopropyl.
  • R 3 is -C 1 -C 3 alkyl, substituted -NR a R a, wherein R a is selected from H or optionally halogen-substituted C 1 -C 3 alkyl, or attached to the same N atom may be two R a 4-7 membered nitrogen-containing heterocyclic group formed together with the N atom to which they are attached.
  • Specific examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, dimethylaminomethyl, methylethylaminomethyl, azetidinylmethyl, pyrrolidinylmethyl , Piperidinyl methyl, etc.
  • a compound of formula (I) is, R 3 is -C 3 -C 7 cycloalkyl, which is optionally substituted independently selected from the following groups: halogen, R a, or -NR a R a, wherein R a is independently selected from H or optionally substituted with one or more halogen C 1 -C 3 alkyl.
  • Specific examples include, but are not limited to, 2,3-difluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 2,3-difluorocyclobutyl, methylcyclopropyl or cyclobutyl , Dimethylcyclopropyl or cyclobutyl, trifluoromethylcyclopropyl or cyclobutyl, methylaminocyclopropyl, dimethylaminocyclopropyl, trifluoromethylaminocyclopropyl, etc.
  • R 3 is -C 3 -C 5 cycloalkyl, such as cyclopropyl, cyclobutyl, or cyclopentyl.
  • a compound of formula (I) is, R 3 is -NR a R a, wherein R a is independently selected from H or optionally substituted with one or more halogen C 1 -C 3 alkyl or connected to the same N atom may be two R a 4-7 membered nitrogen-containing heterocyclic group formed together with the N atom to which they are attached.
  • Specific examples include but are not limited to -NH 2 , -NHCH 3 , -NCH 3 CH 3 , -N(CH 2 CH 3 )CH 3 , -N(CH 2 CH 3 )(CH 2 CH 3 )-, -NHCF 3 , -N(CH 3 )CF 3 , -N(CF 3 )CF 3 , -N(CH 2 CF 3 )CF 3 or -N(CH 2 CF 3 )(CH 2 CF 3 )-, -NH( CH 2 CH 2 CH 3 ), azetidinyl, pyrrolidinyl, piperidinyl, etc.
  • R 4 is -C 1 -C 3 alkyl, optionally substituted by halogen.
  • halogen include, but are not limited to, methyl, ethyl, propyl or isopropyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, and the like.
  • R 4 is -C 1 -C 3 alkyl, such as methyl, ethyl, propyl or isopropyl.
  • R 4 is -C 1 -C 3 alkyl, substituted -NR a R a, wherein R a is selected from H or optionally halogen-substituted C 1 -C 3 alkyl, or attached to the same N atom may be two R a 4-7 membered nitrogen-containing heterocyclic group formed together with the N atom to which they are attached.
  • Specific examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, dimethylaminomethyl, methylethylaminomethyl, azetidinylmethyl, pyrrolidinylmethyl , Piperidinyl methyl, etc.
  • R 4 is is -NR a R a, wherein R a is selected from H or an optionally halogen-substituted C 1 -C 3 alkyl, or connected to the same the two R a N atom may form a 4-7 membered nitrogen-containing heterocyclic group together with the N atom to which they are attached.
  • Specific examples include but are not limited to -NH 2 , -NHCH 3 , -NCH 3 CH 3 , -N(CH 2 CH 3 )CH 3 , -N(CH 2 CH 3 )(CH 2 CH 3 )-, -NHCF 3 , -N(CH 3 )CF 3 , -N(CF 3 )CF 3 , -N(CH 2 CF 3 )CF 3 or -N(CH 2 CF 3 )(CH 2 CF 3 )-, -NH( CH 2 CH 2 CH 3 ), azetidinyl, pyrrolidinyl, piperidinyl, etc.
  • R 5 and R 6 are each independently selected from C 1 -C 3 alkyl substituted by halogen. In a more specific embodiment, R 5 and R 6 are each independently selected from C 1 -C 3 alkyl substituted with at least three halogens. In a more specific embodiment, R 5 and R 6 are each independently C 1 -C 3 alkyl substituted with at least three F. Specific examples include, but are not limited to, trifluoromethyl, trifluoroethyl, pentafluoroethyl, and the like. In the most specific embodiment, both R 5 and R 6 are -CF 3 .
  • Preferred embodiments of the compounds of the present invention include the following compounds, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates,
  • the present invention provides a class of biaryl compounds with the structure of general formula (I). It has been found through research that this class of compounds can effectively inhibit the ROR ⁇ t protein receptor, thereby regulating the differentiation of Th17 cells and inhibiting the production of IL-17. As an immunomodulator for the treatment of diseases related to Th17 cell differentiation.
  • the invention provides compounds of the invention for use as drugs, especially as ROR ⁇ t inhibitors.
  • the present invention provides compounds of the present invention for the treatment, especially for the treatment and/or prevention of diseases related to ROR ⁇ t.
  • the present invention provides the present invention for treating and/or preventing ROR ⁇ t to promote the occurrence and development of the disease or inhibiting ROR ⁇ t will reduce the incidence of the disease, reduce or eliminate the disease symptoms of the disease.
  • Compounds, the diseases such as inflammation or autoimmune diseases, 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's disease, allergic dermatitis, acne, scleroderma, bronchitis, dermatomuscular allergic rhinitis, nec
  • the compound of the present invention can be formulated into a pharmaceutical composition according to standard pharmaceutical practice.
  • drugs with better pharmacokinetic properties and higher bioavailability can be prepared from the compound of the present invention.
  • the present invention provides a pharmaceutical composition comprising the above-mentioned compound of the present invention and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the present invention is provided for use in the prevention or treatment of diseases related to ROR ⁇ t in mammals such as human subjects.
  • the pharmaceutical composition of the present invention may additionally contain additional therapeutically active ingredients suitable for use in combination with the compound of the present invention.
  • the additional therapeutic agent is as defined herein for the drug combination.
  • the pharmaceutical composition of the present invention can be formulated by techniques known to those skilled in the art, such as the technique disclosed in Remington's Pharmaceutical Sciences 20th Edition.
  • the above-mentioned pharmaceutical composition of the present invention can be prepared by mixing the compound of the present invention with one or more pharmaceutically acceptable excipients.
  • the preparation may further include the step of mixing one or more other active ingredients with the compound of the present invention and one or more pharmaceutically acceptable excipients.
  • excipients included in a particular composition will depend on various factors, such as the mode of administration and the form of the provided composition. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described in, for example, Ansel, Howard C., etc., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.
  • Diluents such as glucose, lactose or mannitol
  • carriers pH adjusters, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives Agents, antioxidants, sunscreens, glidants, processing aids, coloring agents, flavoring agents, flavoring agents, and other known additives.
  • the pharmaceutical composition of the present invention can be administered in a standard manner.
  • suitable modes of administration include oral, intravenous, rectal, parenteral, topical, transdermal, ocular, nasal, buccal, or pulmonary (inhalation) administration, where parenteral infusion includes intramuscular, intravenous, intraarterial, and peritoneal Intra or subcutaneous administration.
  • the compounds of the present invention can be formulated into tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, etc., by methods known in the art. Ointments, creams, drops, aerosols, dry powder preparations and sterile injectable aqueous or oily solutions or suspensions.
  • the size of the preventive or therapeutic dose of the compound of the present invention will vary according to a series of factors, including the individual being treated, the severity of the disorder or condition, the rate of administration, the treatment of the compound, and the judgment of the prescribing physician.
  • the effective dose is about 0.0001 to about 5000 mg per kg body weight per day, for example, about 0.01 to about 1000 mg/kg/day (single or divided administration). For a 70 kg person, this would add up to about 0.007 mg/day to about 7000 mg/day, for example, about 0.7 mg/day to about 1500 mg/day.
  • the content or amount of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, For example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.; correspondingly, the pharmaceutical composition of the present invention will contain 0.05 to 99% w/w (weight percentage), such as 0.05 to 80% w/w, such as 0.10 to 70% w/w, for example 0.10 to 50% w/w of the compound of the invention, all weight percentages are based on the total composition. It should be understood that it may be necessary in some cases to use dosages that exceed these limits.
  • the present invention provides a pharmaceutical composition
  • 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 preparation.
  • Such a unit dosage form may contain 0.1 mg to 1 g, for example 5 mg to 250 mg, of the compound of the present invention as an active ingredient.
  • the present invention provides a pharmaceutical composition
  • 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 application may be in the form of, for example, a cream, lotion, ointment, or transdermal patch.
  • 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 inhalation administration.
  • the inhalation administration can be by oral inhalation or intranasal administration.
  • the compound of the present invention can be effectively used in the present invention in a daily dose, for example, up to 500 ⁇ g, such as 0.1-50 ⁇ g, 0.1-40 ⁇ g, 0.1-30 ⁇ g, 0.1-20 ⁇ g, or 0.1-10 ⁇ g of the present invention Compound.
  • the pharmaceutical composition of the present invention for oral inhalation can be formulated as a dry powder, suspension (in liquid or gas) or solution (in liquid), and can be in any suitable form and using any suitable inhaler device known in the art Administration includes, for example, metered-dose inhalers (MDI), dry powder inhalers (DPI), nebulizers, and soft mist inhalers. Multi-chamber devices can be used to deliver the compounds of the specification and one or more other active ingredients (when present).
  • MDI metered-dose inhalers
  • DPI dry powder inhalers
  • nebulizers nebulizers
  • soft mist inhalers soft mist inhalers.
  • Multi-chamber devices can be used to deliver the compounds of the specification and one or more other active ingredients (when present).
  • the compounds of the present invention can be used in methods for treating various diseases in animals, especially mammals such as humans.
  • the present invention provides a method of modulating, especially inhibiting ROR ⁇ t activity, which method comprises contacting a cell with a compound of the present invention as described above to modulate, especially inhibiting, the activity of ROR ⁇ t in the cell.
  • the present invention provides a method for preventing or treating diseases related to ROR ⁇ t (for example, diseases treatable or preventable by ROR ⁇ t inhibition), the method comprising administering to an individual in need thereof an effective amount of the above-mentioned present
  • diseases related to ROR ⁇ t for example, diseases treatable or preventable by ROR ⁇ t inhibition
  • the present invention provides the use of the compound of the present invention or a pharmaceutical composition containing the same as described above, for inhibiting ROR ⁇ t activity, or for treating and/or preventing diseases related to ROR ⁇ t, for example, by inhibiting ROR ⁇ t Treatable or preventable diseases.
  • the present invention also provides the use of the compound of the present invention or the pharmaceutical composition containing it in the preparation of medicines, especially the use of medicines with ROR ⁇ t receptor inhibitor activity.
  • the present invention provides the use of the compound of the present invention as described above or a pharmaceutical composition containing the same in the preparation of a medicament for the treatment or prevention of diseases related to ROR ⁇ t, for example, diseases that can be treated or prevented by ROR ⁇ t inhibition , wherein the compound or pharmaceutical composition is optionally combined with one or more chemotherapy or immunotherapy.
  • the compound of the present invention can be administered as the sole active ingredient, or can be administered in combination with another drug or therapy.
  • the additional drugs or therapies may have or produce the same or different pharmacological effects, provided that when used in combination with the compounds of the present invention, they do not cause undesirable activity reduction, adverse interactions, or side effects.
  • the present invention provides a drug combination comprising the compound of the present invention as described above and one or more other drugs or therapies that function through the same or different mechanisms of action, or a combination of both.
  • the drug combination is used to inhibit ROR ⁇ t activity, or to treat and/or prevent diseases related to ROR ⁇ t.
  • the compound of the present invention in the pharmaceutical combination of the present invention and other active agents used in the combination can be administered simultaneously, separately or sequentially through the same or different administration routes.
  • the other active agent may be co-administered with the compound of the present invention in a single pharmaceutical composition, or administered separately from the compound of the present invention in separate discrete units, such as a combination product, preferably in the form of a kit.
  • they are administered separately they can be carried out simultaneously or sequentially, and the successive administrations can be close or distant in time.
  • the compound of the present invention and the additional drug can be (i) before sending the combined product to the physician (for example, in the case of a kit containing the compound of the present invention and the additional drug); (ii) immediately before administration The physician himself (or under the guidance of the physician); (iii) the patient himself, for example, during the sequential administration of the compound of the present invention and another drug, are added to the combination therapy together.
  • the present invention also provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains the compound of the present invention, and the rest contains other active agents used in combination, And a device containing the composition respectively.
  • the kit of the present invention is particularly suitable for administering different dosage forms, such as oral dosage forms and parenteral dosage forms, or for administering different compositions at different dosage intervals.
  • the appropriate dosage of the compound of the present invention and other active agents in the combination can usually be determined by those skilled in the art, for example, from the dosage range of the compound described in this specification and the approved or published dosage range of other active compounds.
  • the doses of other co-administered drugs will of course vary according to factors such as the type of co-administered drugs, the specific drugs used, the disease to be treated, the patient's general health status, and the judgment of the physician or veterinarian.
  • the other active agent may be one or more second or additional (e.g. Three) compounds.
  • these active agents may be compounds known to modulate other biologically active pathways, or may be compounds that modulate different components in the biologically active pathways involved in the compounds of the present invention, or even biologically related to the compounds of the present invention. Compounds with overlapping targets.
  • the present invention provides a drug combination, for example as a drug for the treatment of one of the diseases listed herein, such as psoriasis, COPD, asthma, psoriatic arthritis or compulsive spine Inflammation, which contains the compound of the present invention, and at least one active ingredient selected from:
  • Glucocorticoid receptor agonists (steroidal or non-steroidal);
  • PDE4 Phosphodiesterase-4
  • the compounds of the present invention can also be combined with other therapies, including but not limited to surgery, radiation therapy, transplantation (for example, stem cell transplantation, bone marrow transplantation), tumor immunotherapy and the like.
  • other therapies including but not limited to surgery, radiation therapy, transplantation (for example, stem cell transplantation, bone marrow transplantation), tumor immunotherapy and the like.
  • the present invention provides a method for inhibiting ROR ⁇ t activity or for treating and/or preventing diseases related to ROR ⁇ t, including administering the pharmaceutical combination of the present invention to a subject in need.
  • the present invention also provides the use of the pharmaceutical combination of the present invention in the preparation of drugs for inhibiting ROR ⁇ t activity or for treating and/or preventing diseases related to ROR ⁇ t.
  • diseases related to ROR ⁇ t include inflammation or autoimmune diseases, cancer, etc., including but not limited to silver.
  • Preferred diseases associated with ROR ⁇ t are selected from the group consisting of psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, inflammatory bowel disease, dry eye, allergic dermatitis, chronic Obstructive pulmonary disease (COPD), asthma, necrotizing enterocolitis, liver fibrosis, non-alcoholic steatohepatitis (NASH), new coronavirus pneumonia, triple negative breast cancer and prostate cancer.
  • COPD chronic Obstructive pulmonary disease
  • NASH non-alcoholic steatohepatitis
  • compositions, methods, uses, and pharmaceutical combinations of the present invention the preferred compounds of formula (I), their stereoisomers, tautomers, stable isotopic variants, Pharmaceutically acceptable salts or solvates; more preferred are the specific compounds listed above, such as compounds 1-13, or their pharmaceutically acceptable salts or solvates.
  • the administered dose of a compound or drug is described herein, it should be understood that the dose is based on the weight of the free base and does not include any derived components thereof, unless the instructions indicate otherwise.
  • the present invention also provides a method for preparing the compound of formula (I).
  • the following exemplifies a general synthetic scheme for synthesizing the compound of the present invention.
  • appropriate reaction conditions are known to those skilled in the art or can be routinely determined.
  • the raw materials and reagents used in the preparation of these compounds are generally commercially available, or can be prepared by the following methods, methods similar to those given below, or methods known in the art.
  • the raw materials and intermediates in the synthesis reaction process can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like.
  • the material can be characterized by conventional methods including physical constants and spectral data.
  • the method includes the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m and p are as defined above for general formula (I);
  • Prot is an amino protecting group, including but not limited to Boc, Cbz, Fmoc or PMB , Preferably Boc;
  • Step 1 The compound of formula (I-1) generates the compound of formula (I-2) in free or salt form; this reaction is preferably carried out under the action of hydrobromic acid (for example, 40% hydrobromic acid in water), preferably at a suitable temperature Carry out, for example, 50-200°C, 80-150°C, preferably 90-120°C; the salt form is, for example, the hydrobromide salt form;
  • hydrobromic acid for example, 40% hydrobromic acid in water
  • Step 2 The compound of formula (I-2) in free or salt form is cyclized with the compound of formula (I-3) to form the compound of formula (I-4) in free or salt form; this reaction is preferably carried out in a suitable solvent, and It is preferably carried out at a suitable temperature, the solvent can be selected from, for example, protic solvents, such as methanol, ethanol, propanol, etc., and the temperature is selected from, for example, 50-200°C, 80-150°C, preferably 90-120°C; Salt form such as hydrobromide salt form;
  • Step 3 The compound of formula (I-4) in free or salt form and the amino protecting agent to produce the compound of formula (I-5); wherein the amino protecting agent is well known in the art, including but not limited to di-tert-butyl dicarbonate (( Boc) 2 O), CbzCl, FmocCl or PMB-Cl, the reaction is preferably carried out in a suitable organic solvent, the organic solvent may be selected from tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, 1,4-dioxane, dimethylsulfoxide and any combination thereof, preferably Tetrahydrofuran; the reaction is preferably carried out in the presence of a suitable base, the base may be selected from sodium carbonate, potassium carbonate, cesium carbonate, N,N-diisopropylethy
  • Step 4 The compound of formula (I-5) reacts with the Tf reagent to produce the compound of formula (I-6);
  • the Tf reagent is a reagent that can react with a hydroxyl group to generate an OTf group, including but not limited to trifluoromethanesulfonic anhydride, trifluoromethanesulfonic anhydride, Fluoromethanesulfonyl chloride or N-phenylbis(trifluoromethanesulfonyl)imide;
  • the reaction is preferably carried out in the presence of a base, and the base can be selected from sodium carbonate, potassium carbonate, cesium carbonate, N,N- Diisopropylethylamine, triethylamine, HOBt or pyridine;
  • the reaction is preferably carried out in an organic solvent, the organic solvent may be selected from dichloromethane, tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl
  • Step 5 The compound of formula (I-6) and the compound of formula (I-7) are coupled under the action of a catalyst, such as a palladium catalyst, to obtain a compound of formula (I-8);
  • a catalyst such as a palladium catalyst
  • the palladium catalyst is a well-known palladium catalyst for coupling in the art, including but not limited to Pd 2 (dba) 3, etc.; the reaction is preferably carried out in a suitable organic solvent, and the organic solvent may be selected from tetrahydrofuran , Ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N,N-dimethylformamide, N,N dimethylacetamide, dichloromethane, 1,4-bis Oxane, dimethyl sulfoxide and any combination thereof, preferably 1,4-dioxane; the reaction is preferably carried out in the presence of a phosphine ligand, the phosphine ligand including but not limited to 4,5-bis Diphenylphosphine-9,9-dimethylxanthene; the reaction is preferably carried out in the presence of a suitable base, which can be selected from sodium carbonate, potassium carbonate, cesium carbon
  • Step 6 The compound of formula (I-8) generates the compound of formula (I-9) under the action of an oxidizing agent;
  • the oxidizing agent is selected from, for example, H 2 O 2 , mCPBA and peroxyacetic acid;
  • the reaction is preferably carried out in an organic solvent
  • the organic solvent can be selected from dichloromethane, tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N,N-dimethylformamide, N,N-di Methyl acetamide, 1,4-dioxane, dimethyl sulfoxide and any combination thereof, preferably dichloromethane;
  • the reaction is preferably carried out at a suitable temperature, for example -50°C to 200°C, -20 °C to 100 °C, for example -10 °C to 50 °C, for example -10 °C to 10 °C, preferably in an
  • Step 7 The compound of formula (I-9) is hydrolyzed to produce the compound of formula (I-10); the reaction is preferably carried out in the presence of a base, and the base can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate Or cesium carbonate, the base is preferably used in the form of an aqueous solution; the reaction is preferably carried out in an organic solvent, the organic solvent can 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,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, dimethylsulfoxide and Any combination thereof, preferably methanol; the reaction is preferably carried out at a suitable temperature, such as -20°C to -200°C, 5-100°C, 10-50°C,
  • Step 8 The compound of formula (I-10) reacts with the compound of formula (I-11) under the action of a condensing agent to produce a compound of formula (I-12);
  • the condensing agent is a condensing agent for coupling carboxylic acid and amine well known in the art, including but not limited to 1-propyl phosphoric anhydride (T3P), EDC, DCC, HATU, etc.; the reaction is preferably in a suitable In an organic solvent, the organic solvent can be selected from dichloromethane, tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N,N-dimethylformamide, N , N-dimethylacetamide, 1,4-dioxane, dimethylsulfoxide and any combination thereof, preferably dichloromethane; the reaction is preferably carried out in the presence of a suitable base, and the base includes But not limited to sodium carbonate, potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, triethylamine, HOBt or pyridine,
  • Step 9 The amino protecting group of the compound of formula (I-12) is removed to produce the compound of formula (I-13); the reaction is carried out under the action of an acid (such as TFA or HCl), and the reaction is preferably carried out in a suitable organic In a solvent, the organic solvent can be selected from dichloromethane, tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N,N-dimethylformamide, N, N-dimethylacetamide, 1,4-dioxane, dimethylsulfoxide and any combination thereof, preferably dichloromethane; the reaction is preferably carried out at a suitable temperature, for example -50°C to 200°C , -20°C to 100°C, such as -10°C to 50°C, such as -10°C to 20°C; Step 10: Formula (I-13) compound and formula (I-14) or its activated form (such as the corresponding
  • the method includes the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m and p are as defined above for general formula (I);
  • Prot is an amino protecting group, including but not limited to Boc, Cbz, Fmoc or PMB , Preferably Boc;
  • Step 1 The compound of formula (II-1) is reacted with R 4 SH or its salt (such as sodium salt) to produce the compound of formula (II-2); the reaction is preferably carried out under an inert gas atmosphere, and the inert gas includes but not Limited to nitrogen, argon or helium, etc.;
  • Step 2 The compound of formula (II-2) is reacted with an amino protecting agent to produce a compound of formula (II-3); wherein the amino protecting agent is well known in the art, including but not limited to di-tert-butyl dicarbonate ((Boc) 2 O ), CbzCl, FmocCl or PMB-Cl; the reaction is preferably carried out in the presence of a suitable base, and the base can be selected from sodium carbonate, potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, three Ethylamine, HOBt, pyridine or 4-dimethylaminopyridine;
  • the amino protecting agent is well known in the art, including but not limited to di-tert-butyl dicarbonate ((Boc) 2 O ), CbzCl, FmocCl or PMB-Cl; the reaction is preferably carried out in the presence of a suitable base, and the base can be selected from sodium carbonate, potassium carbon
  • Step 3 The compound of formula (II-3) is oxidized to produce the compound of formula (II-4) under the action of an oxidizing agent;
  • the oxidizing agent is selected from, for example, H 2 O 2 , mCPBA and peroxyacetic acid;
  • Step 4 The compound of formula (II-4) is reduced under the action of a reducing agent to produce a compound of formula (II-5);
  • the reducing agent is, for example, selected from DABAL-H, lithium aluminum tetrahydrogen or sodium borohydride;
  • the reaction is preferably It is carried out under an inert gas atmosphere, and the inert gas includes but is not limited to nitrogen, argon or helium, etc.;
  • Step 5 The compound of formula (II-5) is reacted with methanol or its activated form (such as sodium methoxide) to produce the compound of formula (II-6); the reaction is preferably carried out in the presence of 4-methylbenzenesulfonic acid pyridine (PPTS) ;
  • PPTS 4-methylbenzenesulfonic acid pyridine
  • Step 6 The compound of formula (II-6) is reacted with alkyl cyanosilane (such as TMSCN) to produce the compound of formula (II-7); the reaction is preferably carried out in the presence of boron trifluoride ether; the reaction is preferably in an inert gas In an atmosphere, the inert gas includes, but is not limited to, nitrogen, argon, or helium, etc.;
  • Step 7 The amino protecting group of the compound of formula (II-7) is removed to produce the compound of formula (II-8); the reaction is carried out, for example, under the action of an acid (such as TFA or HCl);
  • Step 8 The compound of formula (II-8) is reacted with R 3 COOH or its activated form such as the corresponding acid chloride or acid anhydride to produce the compound of formula (II-9); the reaction is preferably carried out in the presence of a base, and the base may be optional From sodium carbonate, potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, triethylamine, HOBt or pyridine; the reaction can be carried out in the presence of a condensing agent such as the like, wherein the condensing agent is in the art Well-known condensing agents for the coupling of carboxylic acids and amines, including but not limited to 1-propyl phosphoric anhydride (T3P), EDC, DCC, HATU;
  • Step 9 The compound of formula (II-9) is hydrolyzed to produce the compound of formula (II-10); the reaction is preferably carried out in the presence of a base, and the base can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate Or cesium carbonate;
  • Step 10 The compound of formula (II-10) reacts with the compound of formula (I-11) under the action of a condensing agent to produce the target compound of formula (I-b);
  • the condensing agent is a condensing agent for coupling carboxylic acid and amine well known in the art, including but not limited to T3P, EDC, DCC, HATU or N,N,N',N'-tetramethylchloroformamidine Hexafluorophosphate, etc.; the reaction is preferably carried out in the presence of a suitable base, including but not limited to sodium carbonate, potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, triethylamine, N-methylimidazole, HOBt or pyridine;
  • a suitable base including but not limited to sodium carbonate, potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, triethylamine, N-methylimidazole, HOBt or pyridine;
  • the reaction in the above steps is preferably carried out in an organic solvent
  • the organic solvent can 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,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, dichloromethane, dimethylsulfoxide and any combination thereof; for hydrolysis reaction A mixture of organic solvent and water can be used;
  • alcohol solvents such as (methanol, ethanol or propanol)
  • ethers such as diethyl ether, ethylene glycol monomethyl ether, etc.
  • N- Methylpyrrolidone N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, dichloromethane, dimethylsulfoxide and any combination thereof
  • the reaction in the above steps is preferably carried out at a suitable temperature, such as -100°C to 0°C, -80°C to -20°C, -50°C to 200°C, -20°C to 100°C, -20°C to 20°C, -10°C to 20°C, -10°C to 50°C, 0-200°C, 10-100°C, 20-50°C or room temperature (20-25°C).
  • a suitable temperature such as -100°C to 0°C, -80°C to -20°C, -50°C to 200°C, -20°C to 100°C, -20°C to 20°C, -10°C to 20°C, -10°C to 50°C, 0-200°C, 10-100°C, 20-50°C or room temperature (20-25°C).
  • the above synthesis scheme only lists the preparation methods of some of the compounds of the present invention.
  • the compound of the present invention or its stereoisomers, tautomers, stable isotope derivatives, pharmaceutically acceptable salts or solvates can be passed through a variety of methods, including the methods and examples given above
  • the given method or a similar method is prepared by a person of ordinary skill in the art on the basis of the above-mentioned synthesis scheme and combined with conventional techniques in the field.
  • experimental materials and reagents used in the following examples can be obtained from commercial channels, prepared according to the method of the prior art, or prepared according to a method similar to that disclosed in the present application unless otherwise specified.
  • PdCl 2 (dtbpf) 1,1'-Di-tert-butylphosphinoferrocene palladium dichloride
  • xantphos 4,5-bisdiphenylphosphine-9,9-dimethylxanthene
  • HATU 2-(7-Azobenzotriazole)-N,N,N’,N’,-Tetramethylurea hexafluorophosphate
  • PE Petroleum ether
  • column chromatography uses silica gel (300-400 mesh) produced by Rushan Sun Desiccant Co., Ltd.; thin layer chromatography uses GF254 (0.25 mm); nuclear magnetic resonance chromatography (NMR) uses Varian- 400 NMR measurement; liquid-mass spectrometry (LC/MS) uses Agilent TechnologiESI 6120 liquid-mass spectrometry.
  • Example 1 and Example 2 R-2-acetyl-N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-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-hydroxyprop-2-yl)-[1,1'-biphenyl]-4-yl)-5-(methylsulfon Acyl) isoindoline-1-carboxamide
  • Step 2 Synthesis of ((2-(4-bromo-3-fluorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)trimethylsilane
  • Step 2 Synthesis of tert-butyl 5-(methylthio)-1-oxoisoindoline-2-carboxylate
  • Step 3 Synthesis of tert-butyl 5-(methylsulfonyl)-1-oxoisoindoline-2-carboxylate
  • Step 4 Synthesis of tert-butyl 1-hydroxy-5-(methylsulfonyl)isoindoline-2-carboxylate
  • Step 5 Synthesis of tert-butyl 1-methoxy-5-(methylsulfonyl)isoindoline-2-carboxylate
  • Step 6 Synthesis of tert-butyl 1-cyano-5-(methylsulfonyl)isoindoline-2-carboxylate
  • Step 7 Synthesis of methyl 5-methylsulfonylisoindoline-1-carboxylate hydrochloride
  • Step 8 Synthesis of methyl 2-acetyl-5-(methylsulfonyl)isoindoline-1-carboxylate
  • Step 10 Compound 2-acetyl-N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)-[1,1 Synthesis of'-Biphenyl]-4-yl)-5-(methylsulfonyl)isoindoline-1-carboxamide
  • Step 11 R-2-acetyl-N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-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)isoindole Synthesis of morpholin-1-carboxamide
  • Racemate 2-acetyl-N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)-[1,1 '-Biphenyl]-4-yl)-5-(methylsulfonyl)isoindoline-1-carboxamide (1.29g dissolved in about 250mL methanol, injection volume 8.0mL) was tested by Waters SFC 150 (room temperature, 100bar,214nm) and 250*25mm 10 ⁇ m (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
  • Step 2 Synthesis of ethyl 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylate hydrobromide
  • Step 3 Synthesis of 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylic acid 1-ethyl ester 2-tert-butyl ester
  • Step 4 6-(((Trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylic acid 1-ethyl ester 2-tert-butyl ester Synthesis
  • Step 5 Synthesis of 6-(methylthio)-3,4-dihydroisoquinoline-1,2-(1H)-dicarboxylic acid 1-ethyl ester 2-tert-butyl ester
  • Step 6 Synthesis of 6-(methylsulfonyl)-3,4-dihydroisoquinoline-1,2-(1H)-dicarboxylic acid 1-ethyl ester 2-tert-butyl ester
  • Step 7 Synthesis of 2-(tert-butoxycarbonyl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid
  • Step 2 Synthesis of 2-(4'-amino-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropane-2-ol
  • Step 1 1-((4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl) Synthesis of tert-butyl carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
  • reaction mixture was stirred overnight at room temperature, and the reaction was complete as monitored by LC-MS.
  • the reaction solution was poured into water (20mL), extracted with DCM (15mLx2), the organic phases were combined, and washed with saturated ammonium chloride (20mL), saturated sodium bicarbonate (20mL) and saturated brine (20mL) successively, and It was dried with sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (90.0 mg, crude product, brown oil).
  • LC-MS(ESI) m/z: 673.1 [M+H] + .
  • Step 2 N-(4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)- Synthesis of 6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride
  • Step 3 2-Acetyl-N-(4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- Synthesis of 4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
  • LC-MS monitored the reaction to be complete.
  • the reaction solution was directly concentrated and dissolved in methanol (3 mL), and a 1 mol/L sodium hydroxide aqueous solution (2 mL) was added dropwise to the reaction solution at room temperature. After the addition, the reaction was continued to be stirred at room temperature for 30 minutes, and the reaction was completed as monitored by LC-MS.
  • the reaction solution was poured into water (20mL), extracted with EA (15mLx2), the organic phases were combined, washed with saturated ammonium chloride (20mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • Step 1 1-((2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl] Synthesis of -4-yl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester
  • Step 2 N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- Synthesis of 4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride
  • Step 3 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
  • N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4- Yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100 mg, 0.169 mmol) was dissolved in anhydrous DCM (3 mL). At room temperature, DIEA (0.084 mL, 0.508 mmol) and acetyl chloride (0.030 mL, 0.423 mmol) were sequentially added dropwise to the reaction solution. After the addition, the reaction solution was stirred and reacted for 30 minutes at room temperature.
  • LC-MS monitored the reaction to be complete.
  • the reaction solution was directly concentrated and dissolved in methanol (3 mL), and a 1 mol/L sodium hydroxide aqueous solution (2 mL) was added dropwise to the reaction solution at room temperature. After the addition, the reaction was continued to be stirred at room temperature for 30 minutes, and the reaction was completed as monitored by LC-MS.
  • the reaction solution was poured into water (20mL), extracted with EA (15mLx2), the organic phases were combined, washed with saturated ammonium chloride (20mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • 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
  • Example 7 2-Acetyl-6-(ethylsulfonyl)-N-(2'-fluoro-4'-(1,1,1,3,3,3,3-hexafluoro-2-hydroxyl) Propan-2-yl)-[1,1'-biphenyl]-4-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
  • Step 1 Synthesis of 6-(ethylthio)-3,4-dihydroisoquinoline-1,2-(1H)-dicarboxylic acid 1-ethyl ester 2-tert-butyl ester
  • Step 2 Synthesis of 6-(ethylsulfonyl)-3,4-dihydroisoquinoline-1,2-(1H)-dicarboxylic acid 1-ethyl ester 2-tert-butyl ester
  • Step 3 Synthesis of 2-(tert-butoxycarbonyl)-6-(ethylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid
  • Step 4 6-(Ethylsulfonyl)-1-((2'-fluoro-4'-(1,1,1,3,3,3,3-hexafluoro-2-hydroxypropan-2-yl )-[1,1'-Biphenyl]-4-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester
  • reaction mixture was stirred overnight at room temperature, and the reaction was complete as monitored by LC-MS.
  • the reaction solution was poured into water (20mL), extracted with DCM (15mL ⁇ 2), the organic phases were combined, and washed with saturated ammonium chloride (20mL), saturated sodium bicarbonate (20mL) and saturated brine (20mL) in turn, It was dried with sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (100 mg, crude product, brown oil).
  • Step 5 6-(Ethylsulfonyl)-N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[ Synthesis of 1,1'-biphenyl]-4-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride
  • Step 6 2-Acetyl-6-(ethylsulfonyl)-N-(2'-fluoro-4'-(1,1,1,3,3,3,3-hexafluoro-2-hydroxypropane) -2-yl)-[1,1'-biphenyl]-4-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
  • LC-MS monitored the reaction to be complete.
  • the reaction solution was directly concentrated and dissolved in methanol (3 mL), and a 1 mol/L sodium hydroxide aqueous solution (2 mL) was added dropwise to the reaction solution at room temperature. After the addition, the reaction was continued to be stirred at room temperature for 30 minutes, and the reaction was completed as monitored by LC-MS.
  • the reaction solution was poured into water (20mL), extracted with EA (15mLx2), the organic phases were combined, washed with saturated ammonium chloride (20mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • 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-carboxamide
  • Step 1 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- Synthesis of 2-yl)phenyl)propan-2-ol
  • Step 3 1-((2-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- Synthesis of 4-yl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester
  • reaction mixture was stirred at room temperature for 2 hours, and the reaction was completed as monitored by LC-MS.
  • the reaction solution was poured into water (20mL), extracted with DCM (15mL ⁇ 2), the organic phases were combined, washed with saturated sodium bicarbonate (20mL) and saturated ammonium chloride (20mL), dried with anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure to obtain the target compound (80.0 mg, crude product, brown liquid).
  • LC-MS(ESI) m/z: 689.1 [MH] - .
  • Step 4 N-(2-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4 -Yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride
  • Step 5 2-Acetyl-N-(2-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'- Synthesis of biphenyl)-4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
  • N-(2-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl )-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (70.0 mg, 0.119 mmol) was dissolved in anhydrous DCM (3 mL). At room temperature, triethylamine (0.049 mL, 0.356 mmol) and acetyl chloride (0.021 mL, 0.296 mmol) were sequentially added dropwise to the reaction solution.
  • reaction solution was stirred and reacted at room temperature for 30 minutes, and the reaction was completed as monitored by LC-MS.
  • the reaction solution was directly concentrated and dissolved in methanol (3 mL), and a 1 mol/L sodium hydroxide aqueous solution (2 mL) was added dropwise to the reaction solution at room temperature. After the addition, the reaction was continued to be stirred at room temperature for 30 minutes, and the reaction was completed as monitored by LC-MS.
  • the reaction solution was poured into water (20mL), extracted with EA (15mLx2), the organic phases were combined, washed with saturated ammonium chloride (20mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • Example 10 2-Acetyl-N-(2-chloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1' -Biphenyl)-4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
  • Step 1 2-(4'-Amino-2'-chloro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3,3-hexafluoropropane-2 -Synthesis of alcohol
  • Step 2 1-((2-Chloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- Synthesis of 4-yl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester
  • reaction mixture was stirred at room temperature for 2 hours, and the reaction was completed as monitored by LC-MS.
  • the reaction solution was poured into water (20mL), extracted with DCM (15mLx2), the organic phases were combined, washed with saturated sodium bicarbonate (20mL) and saturated ammonium chloride (20mL), dried with anhydrous sodium sulfate, and filtered The filtrate was concentrated under reduced pressure to obtain the target compound (150 mg, crude product, brown oil).
  • Step 3 N-(2-Chloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4 -Yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride
  • Step 4 2-Acetyl-N-(2-chloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'- Synthesis of biphenyl)-4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
  • N-(2-chloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl )-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (140 mg, 0.231 mmol) was dissolved in anhydrous DCM (3 mL). At room temperature, triethylamine (0.096 mL, 0.692 mmol) and acetyl chloride (0.041 mL, 0.577 mmol) were sequentially added dropwise to the reaction solution.
  • reaction solution was stirred and reacted at room temperature for 30 minutes, and the reaction was completed as monitored by LC-MS.
  • the reaction solution was directly concentrated and dissolved in methanol (3 mL), and a 1 mol/L sodium hydroxide aqueous solution (2 mL) was added dropwise to the reaction solution at room temperature. After the addition, the reaction was continued to be stirred at room temperature for 30 minutes, and the reaction was completed as monitored by LC-MS.
  • the reaction solution was poured into water (20mL), extracted with EA (15mLx2), the organic phases were combined, washed with saturated ammonium chloride (20mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • Example 11 N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl] -4-yl)-6-(methylsulfonyl)-2-propionyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
  • Step 1 1-((2'-Fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl] Synthesis of -4-yl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester
  • reaction mixture was stirred at room temperature for 2 hours, and TLC monitored the reaction to be complete.
  • the reaction solution was poured into water (20mL), extracted with DCM (15mLx2), the organic phases were combined, washed with saturated sodium bicarbonate (20mL) and saturated ammonium chloride (20mL), dried with anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure to obtain the target compound (1.00 g, crude product, light brown solid).
  • Step 2 N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- Synthesis of 4-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride
  • Step 3 N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- Synthesis of 4-yl)-6-(methylsulfonyl)-2-propionyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
  • N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4- Yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100 mg, 0.169 mmol) was dissolved in anhydrous DCM (3 mL). At room temperature, triethylamine (0.071 mL, 0.508 mmol) and propionyl chloride (0.037 mL, 0.423 mmol) were sequentially added dropwise to the reaction solution.
  • reaction solution was stirred and reacted at room temperature for 30 minutes, and the reaction was completed as monitored by LC-MS.
  • the reaction solution was directly concentrated and dissolved in methanol (3 mL), and a 1 mol/L sodium hydroxide aqueous solution (2 mL) was added dropwise to the reaction solution at room temperature. After the addition, the reaction was continued to be stirred at room temperature for 30 minutes, and the reaction was completed as monitored by LC-MS.
  • the reaction solution was poured into water (20mL), extracted with EA (15mLx2), the organic phases were combined, washed with saturated ammonium chloride (20mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • 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
  • N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4- Yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100 mg, 0.169 mmol) was dissolved in anhydrous DCM (3 mL). At room temperature, triethylamine (0.071 mL, 0.508 mmol) and cyclopropylformyl chloride (0.0385 mL, 0.423 mmol) were sequentially added dropwise to the reaction solution.
  • reaction solution was stirred and reacted at room temperature for 30 minutes, and the reaction was completed as monitored by LC-MS.
  • the reaction solution was directly concentrated and dissolved in methanol (3 mL), and a 1 mol/L sodium hydroxide aqueous solution (2 mL) was added dropwise to the reaction solution at room temperature. After the addition, the reaction was continued to be stirred at room temperature for 30 minutes, and the reaction was completed as monitored by LC-MS.
  • the reaction solution was poured into water (20mL), extracted with EA (15mLx2), the organic phases were combined, washed with saturated ammonium chloride (20mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • Example 13 N 1 -(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl ]-4-yl)-N 2 -methyl-6-(methylsulfonyl)-3,4-dihydroisoquinoline-1,2(1H)-dimethylamide
  • N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4- Yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100 mg, 0.169 mmol) was dissolved in anhydrous DCM (3 mL). At room temperature, triethylamine (0.071 mL, 0.508 mmol) and methylcarbamoyl chloride (39.6 mg, 0.423 mmol) were sequentially added to the reaction solution.
  • reaction solution was stirred and reacted at room temperature for 30 minutes, and the reaction was completed as monitored by LC-MS.
  • the ROR ⁇ -LBD coding sequence was inserted into the pBIND plasmid (Promega, E1581).
  • the expression vector and the reporter vector (pGL4.35 carrying the luciferase reporter gene driven by the stably integrated GAL4 promoter) are co-expressed in HEK293T host cells.
  • the inhibitor binds to the corresponding chimeric receptor
  • the chimeric receptor binds to the GAL4 binding site on the reporter gene carrier and inhibits reporter gene expression. According to the strength of the chemiluminescence signal, the inhibitory activity of the compound on ROR ⁇ was judged.
  • test compounds were diluted with DMSO in a 3-fold gradient, 10 dilution gradients, and the starting concentration was 10 mM.
  • the positive control AZD-0284 was diluted with DMSO in a 3-fold gradient, 10 dilution gradients, and the initial concentration was 10mM.
  • step 2.2 Inoculate the cells (see step 2.2) into a 384 cell culture plate (6007680-50, PE), 15,000 cells per well, 25 ⁇ l FBS medium containing 5% carbon adsorption;
  • Example IC 50 (nM) Emax% 1 15.46 101.5 3 106 97.07 4 34.56 100.2 5 15.84 99.5 7 76.3 97.32 8 24.98 98.29 9 185.9 99.26 10 22.54 101.1 11 76.33 101.6 12 144.6 103.5 13 697.8 96.87 AZD-0284 34.81 99.79
  • Emax% is the relative maximum inhibition rate relative to AZD-0284 at 10 ⁇ M.
  • Activity Example 2 The compound inhibits the differentiation of human PBMC Th17 cells
  • mice first resuscitate PBMC cells and plate them, and then stimulate PBMC cells with stimulating factors (anti-hCD28: 5 ⁇ g/mL; rhTGF- ⁇ 1: 5ng/mL; rhIL-6: 20ng/mL; rhIL-23: 10ng/Ml)
  • stimulating factors anti-hCD28: 5 ⁇ g/mL
  • rhTGF- ⁇ 1 5ng/mL
  • rhIL-6 20ng/mL
  • rhIL-23 10ng/Ml
  • the maximum concentration starts from 3 ⁇ M.
  • the supernatant is collected for IL-17 ELISA.
  • the inhibitory rate of the compound to inhibit the secretion of IL-17 from Th17 cells is determined by Graphad8.0 Fit the IC 50 value.
  • the assay results show that the compound of the present invention has a better ability to inhibit the differentiation and secretion of IL-17 from Th17 cells to human PBMC (as shown in Table 2).
  • Emax% is the maximum inhibition rate.
  • the incubation system contains 0.5 mg protein/mL microsomes, cofactors, and PBS, pre-incubated at 37°C for 3 minutes, and the substrate (ie, test compound) is added to initiate the reaction. Samples were taken at 0, 1, 5, 10, 15, 20, 30, 60 min at the beginning of the reaction, and appropriate terminator was added to terminate the reaction.
  • Sample processing add appropriate samples to each, vortex and centrifuge at high speed, take the supernatant, and use HPLC-MS/MS to detect the substrate.
  • the peak area at the time of 0 min is regarded as 100%.
  • the results are shown in Table 3.
  • the PK determination method of each compound is as follows: 6 C57BL/6 mice (from Shanghai Lingchang Biotechnology Co., Ltd.) were divided into two groups, 3 mice in each group. One group was administered intravenously (IV) with a dose of 1 mg/kg and the vehicle was 5% DMSO/95% (20% Captisol); one group was administered by oral (PO) intragastric administration with a dose of 5 mg/kg and the vehicle It is 0.5% CMC-Na/0.5% Tween 80. Blood was collected from the saphenous vein of the calf in each group at 0, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. Collect about 40 ⁇ L of blood into an anticoagulation tube containing EDTA-K2.
  • the blood collected at each time point was centrifuged at 4°C and 8000 rpm for 5 minutes to obtain plasma.
  • Another 1.5 mL centrifuge tube is labeled with the compound name, animal number, and time point, and the plasma is transferred to the tube.
  • the plasma was stored at -80°C until analysis.
  • the UPLC-MS/MS method was used to determine the concentration of the compound in the plasma, and the Phoenix WinNolin 6.4 pharmacokinetic software was used to calculate the pharmacokinetic parameters of the obtained data.
  • the specific experimental results are as follows, and the results show that the compound has better pharmacokinetic absorption and has pharmacokinetic advantages.
  • the AUC 0-last (ng/mL*hr) and bioavailability of the compound of the present invention are significantly improved, showing that it has better druggability

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Abstract

La présente invention concerne un composé de formule (I), et un stéréisomère, un tautomère, une variante isotopique stable, un solvate ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique comprenant ce composé, un procédé de traitement ou de prévention de maladies liées au RORγt à l'aide du composé, et l'utilisation du composé dans la préparation de médicaments pour le traitement ou la prévention des maladies liées au RORγt.
PCT/CN2021/093788 2020-05-15 2021-05-14 COMPOSÉ BIARYLE CAPABLE DE SERVIR DE MODULATEUR DE RORγ WO2021228216A1 (fr)

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WO2023232870A1 (fr) 2022-05-31 2023-12-07 Immunic Ag Modulateurs de rorg/rorgt pour le traitement d'infections virales de type covid-19

Citations (4)

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