WO2021228215A1 - 可用作RORγ调节剂的联芳基类化合物 - Google Patents

可用作RORγ调节剂的联芳基类化合物 Download PDF

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WO2021228215A1
WO2021228215A1 PCT/CN2021/093786 CN2021093786W WO2021228215A1 WO 2021228215 A1 WO2021228215 A1 WO 2021228215A1 CN 2021093786 W CN2021093786 W CN 2021093786W WO 2021228215 A1 WO2021228215 A1 WO 2021228215A1
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alkyl
halogen
compound
pharmaceutically acceptable
optionally substituted
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French (fr)
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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:
  • X is selected from CH or N;
  • R 1 is 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 halogen or Cyano substitution;
  • R 2 is selected from hydrogen, halo, cyano, nitro or C 1 -C 6 alkyl, wherein said C 1 -C 6 alkyl is optionally independently substituted with substituents selected from: -R a or - OH, wherein Ra is a C 1 -C 6 alkyl group optionally substituted by halogen;
  • R 3 and R 4 are each independently selected from halogen, cyano, nitro, R b , -OR b , -SR b or -NR b R b , wherein R b is H or optionally substituted C 1 -C 6 Alkyl, the substituents are each independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH 2 , -OC 1 -C 6 alkyl, -SC 1 -C 6 alkyl, -NH-C 1 -C 6 alkyl or -N(-C 1 -C 6 alkyl) 2 ;
  • R 5 is selected from -OR c , -SR c , -NR c R c , -NHCOR c , -NHSO 2 R c , -COOR c , -CONR c R c or -SO 2 NR c R c , where R c is in Each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl optionally substituted by halogen or C 3 -C 7 cycloalkyl optionally substituted by halogen, or two attached to the same N atom R c can form a 4-7 membered nitrogen-containing heterocycloalkyl group together with the N atom to which they are attached;
  • R 6 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 cycloalkyl or 4-7 membered heterocycloalkyl substituted -NH 2 , wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or 4-7 membered heterocycloalkyl are optionally selected from each independently the following substituents: hydrogen, halogen, cyano, nitro, -R a, -OR a, -SR a , or -NR a R a optionally substituted with halogen or C 3 -C 7 cycloalkyl, R a is independently selected from H or optionally halogen substituted at each occurrence C 1 -C 6 alkyl, wherein N together form two groups, the amino group may be N atom to which they are attached a 4-7 membere
  • n is selected from 0, 1, or 2.
  • 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, in which one or more (for example, 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 above-mentioned C 1 -C 6 alkylthio, 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) Substitution of 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.
  • Used in the structural formulas or structural fragments of the compounds in this article Indicates the relative configuration of the asymmetric center, that is, the chiral center.
  • 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, 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:
  • X is selected from CH or N;
  • R 1 is 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 halogen or Cyano substitution;
  • R 2 is selected from hydrogen, halo, cyano, nitro or C 1 -C 6 alkyl, wherein said C 1 -C 6 alkyl is optionally independently substituted with substituents selected from: -R a or - OH, wherein Ra is a C 1 -C 6 alkyl group optionally substituted by halogen;
  • R 3 and R 4 are each independently selected from halogen, cyano, nitro, R b , -OR b , -SR b or -NR b R b , wherein R b is H or optionally substituted C 1 -C 6 Alkyl, the substituents are each independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH 2 , -OC 1 -C 6 alkyl, -SC 1 -C 6 alkyl, -NH-C 1 -C 6 alkyl or -N(-C 1 -C 6 alkyl) 2 ;
  • R 5 is selected from -OR c , -SR c , -NR c R c , -NHCOR c , -NHSO 2 R c , -COOR c , -CONR c R c or -SO 2 NR c R c , where R c is in Each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl optionally substituted by halogen or C 3 -C 7 cycloalkyl optionally substituted by halogen, or two attached to the same N atom R c can form a 4-7 membered nitrogen-containing heterocycloalkyl group together with the N atom to which they are attached;
  • R 6 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 cycloalkyl or 4-7 membered heterocycloalkyl substituted -NH 2 , wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or 4-7 membered heterocycloalkyl are optionally selected from each independently the following substituents: hydrogen, halogen, cyano, nitro, -R a, -OR a, -SR a , or -NR a R a optionally substituted with halogen or C 3 -C 7 cycloalkyl, R a is independently selected from H or optionally halogen substituted at each occurrence C 1 -C 6 alkyl, wherein N together form two groups, the amino group may be N atom to which they are attached a 4-7 membere
  • n is selected from 0, 1, or 2.
  • X is CH.
  • R 1 is H.
  • R 1 is halogen, such as F, Cl, Br or I; preferably F or Cl.
  • R 1 is C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, optionally substituted by halogen (preferably F), such as methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, tert-butyl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH(CF 3 ) 2 etc.
  • halogen preferably F
  • R 1 is selected from -OC 1 -C 6 alkyl, -SC 1 -C 6 alkyl, -NH-C 1 -C 6 alkyl, or -N-( C 1 -C 6 alkyl) 2 , where the C 1 -C 6 alkyl group is optionally substituted by one or more halogens (preferably F), examples include but are not limited to -OCH 3 , -OCF 3 , -OCHF 2 , -OCH 2 CH 3 , -OCH 2 CF 3 , -OCH 2 CH 2 CH 3 , -OCH 2 CH 2 CF 3 , -OCH(CF 3 ) 2 , -SCH 3 , -SCF 3 , -SCH 2 CH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ),
  • R 1 is selected from -OC 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl group is substituted with at least three halogens (preferably F), such as -OCF 3 , -OCH 2 CF 3 , -OCH 2 CH 2 CF 3 , -CH(CF 3 ) 2 and so on.
  • halogens preferably F
  • R 1 is 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 1 -C 6 alkyl Optionally substituted by halogen (preferably F).
  • 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 2 is hydrogen
  • R 2 is halogen, such as F, Cl, Br or I; preferably F or Cl.
  • R 2 is a C 1 -C 6 alkyl group, preferably a C 1 -C 3 alkyl group, for example in the para position of the phenyl group, wherein the C 1 -C 3 Alkyl groups are substituted by two C 1 -C 3 alkyl groups substituted by halogen (preferably F) and one -OH, for example
  • halogen preferably F
  • R 1 is H and R 2 is selected from halogen or
  • R 3 and R 4 are each independently selected from H, halogen, or C 1 -C 6 alkyl optionally substituted by halogen.
  • R 3 and R 4 are each independently selected from H or halogen, preferably fluorine or chlorine, most preferably Cl, for example, R 3 is H and R 4 is halogen, preferably F or Cl, or vice versa. In a specific embodiment, R 3 and R 4 are both halogen, preferably fluorine or chlorine, and most preferably both Cl.
  • R 3 and R 4 are each independently selected from H or C 1 -C 6 alkyl, optionally substituted by halogen.
  • R 3 is H and R 4 is C 1 -C 6 alkyl optionally substituted by halogen (preferably F), or vice versa, for example R 3 is H and R 4 is methyl , Ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CH 2 CH 2 CF 3 or -CH(CF 3 ) 2, etc., or vice versa.
  • R 3 and R 4 are selected from C 1 -C 6 alkyl, optionally substituted by halogen (preferably F), for example, R 3 and R 4 are both methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, tert-butyl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CH 2 CH 2 CF 3 or -CH(CF 3 ) 2 Etc., or R 3 and R 4 are each independently one of the above-mentioned exemplary groups.
  • halogen preferably F
  • R 3 and R 4 are each independently selected from -OR b , -SR b or -NR b R b , wherein R b is H or C optionally substituted by halogen 1 -C 6 alkyl, such as -OH, -SH, -OCH 3 , -OCF 3 , -OCHF 2 , -OCH 2 CH 3 , -OCH 2 CF 3 , -OCH 2 CH 2 CH 3 , -OCH 2 CH 2 CF 3 , -OCH(CF 3 ) 2 , -SCH 3 , -SCF 3 , -SCH 2 CH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -NHCF 3 , -N(CH 3 )(CF 3 ), etc.
  • halogen 1 -C 6 alkyl such as -OH
  • R 5 is selected from -OR c , wherein R c is selected from hydrogen, C 1 -C 6 alkyl optionally substituted by halogen, or C 3 optionally substituted by halogen -C 7 cycloalkyl. In a specific embodiment, R 5 is -OH.
  • R 5 is -OC 1 -C 6 alkyl, optionally substituted by halogen, for example -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ), -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCH 2 CH 2 CF 3 , -OCH(CF 3 ), etc.
  • R 5 is -OC 3 -C 7 cycloalkyl, optionally substituted by halogen, such as -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl and the like.
  • R 5 is -OC 1 -C 3 alkyl, such as -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ), and the like.
  • R 5 is selected from -NR c R c , -NHCOR c or -NHSO 2 R c , preferably -NR c R c or -NHCOR c , wherein R c is When present, they are independently selected from hydrogen, C 1 -C 6 alkyl optionally substituted by halogen or C 3 -C 7 cycloalkyl optionally substituted by halogen, or two R c attached to the same N atom They can form a 4-7 membered nitrogen-containing heterocycloalkyl group together with the N atom to which they are attached.
  • R 5 is selected from -NR c R c or -NHCOR c , wherein each occurrence of R c is independently selected from hydrogen or C 1 -C optionally substituted by halogen (preferably F) 6 Alkyl groups, specific examples include but are not limited to -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N (CH 2 CH 3 )(CH 2 CH 3 )-, -NH(CH 2 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 )-, -NHCOCH 3 , -NHCO-CH 2 CH 3 , -NHCO-CH 2 CH 3 , -NHCO-CH 2 CF
  • R 5 is selected from -NR c R c , wherein two R c attached to the same N atom can form a 4-7 membered nitrogen-containing heterocycloalkane together with the N atom to which they are attached Group, such as -azetidine, azetidine, piperidinyl and the like.
  • R 5 is selected from -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 , -NH(CH 2 CH 2 CH 3 ), -N( CH 3 ) (CH 2 CH 3 ), -NHCOCH 3 , -NHCO-CH 2 CH 3 , -azetidine, azetidine, or piperidinyl.
  • R 5 is selected from -NR c R c or -NHCOR c , wherein each occurrence of R c is independently selected from hydrogen or C 3 -C 7 cycloalkyl optionally substituted by halogen , For example -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NHCO-cyclopropyl, -NHCO-cyclobutyl, -NHCO-cyclopentyl and the like.
  • R 5 is selected from -COOR c , -CONR c R c or -SO 2 NR c R c , preferably -COOR c or -CONR c R c , wherein R c is in Each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl optionally substituted by halogen or C 3 -C 7 cycloalkyl optionally substituted by halogen, or two attached to the same N atom R c can form a 4-7 membered nitrogen-containing heterocycloalkyl group together with the N atom to which they are attached.
  • R 5 is selected from -COOR c or -CONR c R c , wherein each occurrence of R c is independently selected from H or C 1 -C optionally substituted by halogen (preferably F) 6 Alkyl groups, such as -COOH, -COOCH 3 , -COOCF 3 , -COOCH 2 CH 3 , -COOCH 2 CF 3 , -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -CON(CH 3 ) (CH 2 CH 3 ), -CONHCF 3 , -CON(CF 3 ) 2 .
  • halogen (preferably F) 6 Alkyl groups such as -COOH, -COOCH 3 , -COOCF 3 , -COOCH 2 CH 3 , -COOCH 2 CF 3 , -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -CON(CH
  • R 5 is selected from -CONR c R c , wherein two R c connected to the same N atom can form a 4-7 membered nitrogen-containing heterocycloalkane together with the N atom to which they are connected Group, for example -CO-azetidine, -CO-azolidine, -CO-piperidinyl and the like.
  • R 6 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 substituted: H, halo, 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 the 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 6 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 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 6 is C 1 -C 3 alkyl, such as methyl, ethyl, propyl, or isopropyl.
  • R 6 is a C 1 -C 6 alkyl group, preferably a C 1 -C 3 alkyl group, optionally substituted by a C 3 -C 7 cycloalkyl group 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 6 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 substituted 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 6 is -C 3 -C 7 cycloalkyl, which is optionally substituted with one or more groups independently selected from: H, 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 halogens 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 6 is -C 3 -C 5 cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl.
  • R 6 is a -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 6 is 4-7 membered heterocycloalkyl, optionally substituted with one or more substituents independently selected from the group of substituents: H, 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 substituted C 1 -C 6 alkyl, or are connected on the same N atom two R a may form a 4-7 membered nitrogen-containing heterocyclic group together with the N atom to which they are attached.
  • R 6 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.
  • tetrahydropyranyl e.g. 4 -Tetrahydropyranyl
  • tetrahydrothiopyranyl for example 4-tetrahydrothiopyranyl
  • R 6 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 6 l -
  • R 6 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 ), etc.
  • the present invention provides a compound of formula (I), its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate:
  • X is selected from CH;
  • R 1 is selected from hydrogen, -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;
  • R 2 is selected from hydrogen, halogen, or C 1 -C 6 alkyl, wherein said C 1 -C 6 alkyl independently substituted with substituents selected from: -R a or -OH, wherein R a is halogen Substituted C 1 -C 6 alkyl;
  • R 3 and R 4 are each independently selected from H, halogen, cyano or C 1 -C 6 alkyl optionally substituted by halogen;
  • R 5 is selected from -OR c , -SR c , -NR c R c , -NHCOR c , -NHSO 2 R c , -COOR c , -CONR c R c or -SO 2 NR c R c , where R c is in Each occurrence is independently selected from hydrogen or C 1 -C 6 alkyl optionally substituted by halogen, or two R c attached to the same N atom can form 4-7 together with the N atom to which they are attached Membered nitrogen-containing heterocycloalkyl;
  • R 6 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: halogen, -R a, or -NR a R a , R a at each occurrence is independently selected from H, C 1 -C 6 alkyl optionally substituted by halogen, or C 3 -C 7 cycloalkyl optionally substituted by halogen, where it is attached to the amino group form a 4-7 membered ring two R a N N atom on which they can be connected together; and
  • n is selected from 0, 1, or 2.
  • R 1 is selected from hydrogen or -OC 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted by halogen.
  • R 1 is selected from hydrogen or -OC 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl group is substituted by one or more, such as one, two or three halogens (preferably F) replace.
  • R 1 is -OC 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is substituted with at least three halogens (preferably F), such as -O-CF 3 , -O -CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CF 2 CF 3 and so on.
  • halogens preferably F
  • R 2 is hydrogen
  • R 2 is halogen, such as F, Cl, Br or I; preferably F or Cl.
  • R 2 is C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, substituted by two halogen (preferably F) C 1 -C 3 alkyl groups and one -OH substitution, for example
  • R 1 is H and R 2 is selected from halogen or
  • R 3 and R 4 are each independently selected from H or halogen, preferably F or Cl, most preferably Cl, for example, R 3 is H and R 4 is halogen, preferably F or Cl, or vice versa. In a specific embodiment, R 3 and R 4 are both halogen, preferably fluorine or chlorine, and most preferably both Cl.
  • R 3 and R 4 are each independently selected from H or C 1 -C 6 alkyl, optionally substituted by halogen.
  • R 3 is H and R 4 is C 1 -C 6 alkyl optionally substituted by halogen (preferably F), or vice versa, for example R 3 is H and R 4 is methyl , Ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CH 2 CH 2 CF 3 or -CH(CF 3 ) 2, etc., or vice versa.
  • R 3 and R 4 are selected from C 1 -C 6 alkyl groups, for example, R 3 and R 4 are both methyl, ethyl, propyl, isopropyl, butyl, isobutyl. , Tert-butyl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CH 2 CH 2 CF 3 or -CH(CF 3 ) 2 etc., or R 3 and R 4 are independent Ground is one of the above-mentioned exemplary groups.
  • R 5 is selected from -OR c , wherein R c is selected from hydrogen or C 1 -C 6 alkyl optionally substituted by halogen.
  • R 5 is -OH.
  • R 5 is -OC 1 -C 6 alkyl, optionally substituted by halogen, for example -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ), -OCF 3 , -OCH 2 CF 3 , -OCH 2 CH 2 CF 3 , -OCH(CF 3 ), etc.
  • R 5 is -OC 1 -C 3 alkyl, such as -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ), and the like.
  • R 5 is selected from -NR c R c or -NHCOR c , wherein each occurrence of R c is independently selected from hydrogen or optionally halogen (preferably F )
  • R c is independently selected from hydrogen or optionally halogen (preferably F )
  • Substituted C 1 -C 6 alkyl specific examples include but are not limited to -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 )(CH 2 CH 3 )-, -NH(CH 2 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 )-, -NHCOCH 3 , -NHCO-
  • R 5 is selected from -NR c R c , wherein two R c attached to the same N atom can form a 4-7 membered nitrogen-containing heterocycloalkane together with the N atom to which they are attached Group, such as -azetidine, azetidine, piperidinyl and the like.
  • R 5 is selected from -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ),- NH(CH 2 CH 2 CH 3 ), -NHCOCH 3 , -NHCO-CH 2 CH 3 , -azetidine, azetidine, or piperidinyl.
  • R 5 is selected from -COOR c or -CONR c R c , wherein each occurrence of R c is independently selected from H or optionally halogenated (preferably F ) Substituted C 1 -C 6 alkyl groups, such as -COOH, -COOCH 3 , -COOCH 2 CH 3 , -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -CON(CH 3 )(CH 2 CH 3 ).
  • R 5 is selected from -CONR c R c , wherein two R c connected to the same N atom can form a 4-7 membered nitrogen-containing heterocycloalkane together with the N atom to which they are connected Group, for example -CO-azetidine, -CO-azolidine, -CO-piperidinyl and the like.
  • R 6 is -C 1 -C 6 alkyl, preferably -C 1 -C 3 alkyl, optionally substituted by halogen.
  • Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, and the like.
  • R 6 is -C 1 -C 3 alkyl, such as methyl, ethyl, propyl or isopropyl.
  • R 6 is -C 1 -C 6 alkyl, preferably -C 1 -C 3 alkyl, optionally substituted by -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 two R a N atom may form a 4-7 membered nitrogen-containing heterocycloalkyl together with the N atom to which they are attached, base.
  • Specific examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, dimethylaminomethyl, methylethylaminomethyl, azetidinylmethyl, pyrrolidinylmethyl , Piperidinyl methyl, etc.
  • R 6 is -C 1 -C 6 alkyl, preferably -C 1 -C 3 alkyl, C 3 -C optionally substituted by halogen 7 Cycloalkyl substituted.
  • Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentyl Ethyl and so on.
  • R 6 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.
  • 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. Philadelphia: Lippincott, Williams & Wilkins, 2004, including for example Adjuvants, diluents (e.g.
  • glucose, lactose or mannitol carriers, pH adjusters, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents , Preservatives, 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 1-26, 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 6 , R c and X are as defined above for general formula (I), Z is Br or I; and R c is not H;
  • Step 1 The compound of formula (I-1) or formula (I-2) and the compound of formula (I-3) are subjected to a coupling reaction such as Suzuki coupling reaction under the action of a catalyst, such as a palladium catalyst, to obtain an intermediate formula (I-4) )compound of;
  • a coupling reaction such as Suzuki coupling reaction under the action of a catalyst, such as a palladium catalyst
  • the palladium catalyst is a well-known palladium catalyst for Suzuki coupling in the art, including but not limited to PdCl 2 (dtbpf), Pd(dppf)Cl 2 etc.; the reaction is preferably carried out in the presence of a suitable base, so
  • the base can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, preferably, the base is potassium carbonate;
  • Step 2 The compound of formula (I-5) reacts with paraformaldehyde under the action of sodium methoxide to produce the compound of formula (I-6);
  • Step 3 Alkylation of the compound of formula (I-6) to produce the compound of formula (I-7); for example, the alkylation is carried out with TMSCN under the action of HBF 4 , or for example with an alkyl halide in the presence of a base
  • the base can be selected from butyl lithium, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate;
  • Step 4 The compound of formula (I-7) is hydrolyzed to obtain the compound of formula (I-8).
  • the hydrolysis is preferably carried out in the presence of a base or an acid.
  • the base may be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, Sodium carbonate, potassium carbonate or cesium carbonate
  • the acid may be selected from hydrochloric acid, sulfuric acid or trifluoroacetic acid; and/or
  • Step 5 The compound of formula (I-8) and the compound of intermediate formula (I-4) are under the action of a condensing agent to produce a compound of formula (I-a).
  • the condensing agent is a condensing agent well known in the art for the coupling of carboxylic acid and amine, including but not limited to EDC, DCC, HATU, N,N,N',N'-tetramethylchloroformamidine hexafluoro Phosphate, 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, HOBt, N-methylimidazole or pyridine.
  • a suitable base including but not limited to sodium carbonate, potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, triethylamine, HOBt, N-methylimidazole or pyridine.
  • the method includes the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 6 , R c and X are as defined above for the general formula (I).
  • Step 1 The compound of formula (II-1) and the compound of formula (II-2) are under the action of a condensing agent to produce a compound of formula (II-3).
  • the condensing agent is a condensing agent well known in the art for the coupling of carboxylic acid and amine, including but not limited to EDC, DCC, HATU, N,N,N',N'-tetramethylchloroformamidine hexafluoro Phosphate, 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, HOBt , N-methylimidazole or pyridine;
  • Step 2 The compound of formula (II-3) reacts with paraformaldehyde under the action of sodium methoxide to produce the compound of formula (I-b);
  • Step 3a The compound of formula (Ib) is alkylated to produce the compound of formula (Ia); the alkylation is carried out with TMSCN, for example, under the action of HBF 4 , or carried out with alkyl halide, for example, in the presence of a base;
  • the base can be selected from butyl lithium, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate;
  • Step 3b The compound of formula (Ib) is reacted with methanesulfonyl chloride to produce the compound of formula (II-4); the reaction is preferably carried out in the presence of a suitable base, including but not limited to sodium carbonate, potassium carbonate, and cesium carbonate , N,N-diisopropylethylamine, triethylamine, HOBt, N-methylimidazole or pyridine; and/or
  • Step 4 The compound of formula (I-4) undergoes a nucleophilic substitution reaction with HNR c R c to produce a compound of formula (Ic); the reaction is preferably carried out in the presence of a suitable base, which includes but is not limited to sodium carbonate, Potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, triethylamine, HOBt, N-methylimidazole or pyridine.
  • a suitable base which includes but is not limited to sodium carbonate, Potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, triethylamine, HOBt, N-methylimidazole or pyridine.
  • the method includes the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 6 , R c and X are as defined above for general formula (I),
  • Step 1a) The compound of formula (III-1) is reacted with R c COOH or its activated form such as the corresponding acid chloride or acid anhydride to produce the compound of formula (Id); the reaction is preferably carried out in the presence of a base, and the base may be selected from carbonic acid Sodium, 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 well known in the art Condensing agent for coupling of carboxylic acid and amine, including but not limited to 1-propyl phosphoric anhydride (T3P), EDC, DCC, HATU; or
  • Step 1b) The compound of formula (III-1) is reacted with R c SO 2 Cl to produce the compound of formula (Ie); 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 method includes the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 6 , R c and X are as defined above for general formula (I),
  • Step 1 The compound of formula (IV-1) is hydrolyzed to obtain the compound of formula (IV-2).
  • the hydrolysis is preferably carried out in the presence of a base, which may be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and sodium carbonate , Potassium carbonate or cesium carbonate,
  • Step 2 The compound of formula (IV-2) is reacted with the compound of formula (I-4) to obtain the compound of formula (IV-3).
  • reaction conditions please refer to step 1 of synthesis scheme 2;
  • Step 3 The compound of formula (IV-3) is hydrolyzed to obtain the compound of formula (I-f), and the hydrolysis is preferably carried out in the presence of an acid, which may be selected from, for example, hydrochloric acid, sulfuric acid or trifluoroacetic acid;
  • Step 4a the compound of formula (If) is reacted with R c OH to obtain the compound of formula (Ig); the reaction is preferably carried out in the presence of a base, and the base may be selected 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, where the condensing agent is well-known in the art for the coupling of carboxylic acid and alcohol Condensing agent of, including but not limited to 1-propyl phosphoric anhydride (T3P), EDC, DCC or HATU;
  • T3P 1-propyl phosphoric anhydride
  • EDC EDC
  • DCC DCC
  • HATU HATU
  • Step 4b Optionally, the compound of formula (If) is reacted with HNR c R c to obtain the compound of formula (Ih).
  • HNR c R c for the reaction conditions, please refer to Step 1 of Synthesis Scheme 2;
  • 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).
  • 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
  • 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.
  • Step 1 Synthesis of methyl 2-(4-methylsulfonyl)phenylacetate
  • Step 2 Synthesis of methyl 2-(4-methylsulfonyl)phenyl-3-hydroxypropionate
  • Methyl 2-(4-methylsulfonyl)phenylacetate (9.40g, 41.2mmol) was dissolved in anhydrous DMSO (100.0mL), and paraformaldehyde (1.17g, 39.2mmol) and sodium methoxide ( 89.0 mg, 1.65 mmol). After the reaction solution was stirred at room temperature for 16 hours, the reaction was stopped. The reaction solution was added to ice water (300.0 mL), the mixed solution was neutralized with 1.0 M hydrochloric acid solution, extracted with EA (400 mL ⁇ 2), and left to stand for layering.
  • Step 3 Synthesis of methyl 2-(4-(methylsulfonyl)phenyl)-3-methoxypropionate
  • Methyl 2-(4-(methylsulfonyl)phenyl)-3-hydroxypropionate (6.10g, 23.6mmol) was dissolved in DCM (140mL), and 50 % Fluoroboric acid aqueous solution (4.14g, 23.6mmol) and trimethylsilanated diazomethane (11.8mL, 23.6mmol, 2.0M n-hexane solution). After 20 minutes, trimethylsilylated diazomethane (11.8 mL, 23.6 mmol, 2.0 M n-hexane solution) was added again. After 20 minutes, trimethylsilylated diazomethane (11.8 mL, 23.6 mmol, 2.0 M n-hexane solution) was added again.
  • Racemate N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(4-(methylsulfonyl) Phenyl)-3-methoxypropionamide (50mg dissolved in about 13mL methanol, injection volume 1.5mL) was tested by Waters SFC 150 (room temperature, 100bar, 214nm) and 250*25mm 10Dr.maish Reprosil Chiral-AS (Similar to )) (Supercritical carbon dioxide: methanol, 80:20, 6.0min, 70mL/min) separated to obtain rel-(S)-N-(2,6-dichloro-2'-(trifluoromethoxy)-[ 1,1'-Biphenyl)-4-yl)-2-(4-(methylsulfonyl)phenyl)-3-methoxypropionamide or rel-(R)-N-(2,6-di Chloro-2'-(
  • Step 1 N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(4-(methylsulfonyl)benzene Yl) acetamide synthesis
  • Step 2 N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(4-(methylsulfonyl)benzene Yl)-3-hydroxypropionamide synthesis
  • Racemate N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(4-(methylsulfonyl) Phenyl)-3-hydroxypropionamide (470mg dissolved in about 120mL methanol, injection volume 3.0mL) was tested by Waters SFC 150 (room temperature, 100bar, 214nm) and 250*25mm 10 ⁇ m Dr.maish Reprosil Chiral-OM (Similar to ) (Supercritical carbon dioxide: methanol, 70:30, 3.0min, 70mL/min) separated to obtain rel-(S)-N-(2,6-dichloro-2'-(trifluoromethoxy)-[1 ,1'-Biphenyl)-4-yl)-2-(4-(methylsulfonyl)phenyl)-3-hydroxypropionamide or rel-(R)-N-(2,6-dichloro-2 '-(
  • Methyl 2-(4-(methylsulfonyl)phenyl)acetate (900mg, 3.95mmol) was added to tetrahydrofuran (10mL). After cooling to 0°C, NaH (166mg, 4.15mmol, 60% in oil was added) ), continue the reaction at 0°C for 30 minutes, then use a syringe to measure tert-butyl 2-bromoacetate (847mg/0.63mL, 4.34mmol) and add it to the reaction flask. Continue the reaction at 0°C for 30 minutes. TLC detects that the raw materials have reacted.
  • Step 3 4-((2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)amino)-3-(4-(methyl Synthesis of tert-butyl sulfonyl)phenyl)-4-oxobutanoate
  • Step 4 4-((2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)amino)-3-(4-(methyl Synthesis of sulfonyl)phenyl)-4-oxobutanoic acid
  • Example 8 N 1 -(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-N 4 -methyl-2-( 4-(methylsulfonyl)phenyl)succinamide
  • Step 1 N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(4-(ethylsulfonyl) Synthesis of phenyl)acetamide
  • Step 2 N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(4-(ethylsulfonyl) Synthesis of phenyl)-3-hydroxypropionamide
  • Examples 11 and 12 (R)-N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(4 -(Ethylsulfonyl)phenyl)-3-hydroxypropionamide or (S)-N-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl )-4-yl)-2-(4-(ethylsulfonyl)phenyl)-3-hydroxypropionamide
  • Racemate N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(4-(ethylsulfonyl) )Phenyl)-3-hydroxypropionamide (50mg dissolved in about 12mL methanol, injection volume 4.0mL) was tested by Waters SFC 150 (room temperature, 100bar, 214nm) and 250*25mm 10 ⁇ m Dr.maish Reprosil Chiral-OM (Similar to ) (Supercritical carbon dioxide: methanol, 65:35, 3.0min, 70mL/min) separated to obtain (R)-N-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1 '-Biphenyl)-4-yl)-2-(4-(ethylsulfonyl)phenyl)-3-hydroxypropionamide or (S)-N-(2,6-dichloro-2'
  • Step 1 Synthesis of methyl 2-(4-(chlorosulfonyl)phenyl)acetate
  • Methyl 2-(4-(benzylthio)phenyl)acetate (500 mg, 1.84 mmol) was added to a mixed solvent of acetic acid (5 mL) and water (1 mL). At 0°C, N-chlorosuccinimide (737 mg, 5.52 mmol) was added to the reaction mixture in portions. The reaction mixture was raised to room temperature, and the reaction was stirred at room temperature for 1 hour. Add EA (10 mL) and water (5 mL). The organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product.
  • Step 2 Synthesis of methyl 2-(4-(N-methylsulfonamido)phenyl)acetate
  • Step 4 N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(4-(N-methylsulfon (Amido) phenyl) acetamide synthesis
  • Step 5 N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-hydroxy-2-(4-(N -Methyl sulfonamido) phenyl) propionamide synthesis
  • N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(4-(N-methylsulfonamide) )Phenyl)acetamide (320mg, 0.600mmol) was added to anhydrous DMSO (3mL). To the reaction mixture were added paraformaldehyde (16.2 mg, 0.540 mmol) and sodium methoxide (1.29 mg, 0.024 mmol) in sequence. The reaction mixture was stirred at room temperature for 2 hours. Add EA (15 mL) and water (10 mL). The aqueous phase was separated and extracted with EA (10 mL).
  • Step 1 Synthesis of methyl 2-(4-methylsulfonyl)phenylacetate
  • Step 2 Synthesis of methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(4-(methylsulfonyl)phenyl)propionate
  • Methyl 2-(4-(methylsulfonyl)phenyl)acetate (2.00g, 8.76mmol) was dissolved in ultra-dry tetrahydrofuran (60.0mL).
  • Lithium silylamine (10.5mL, 10.5mmol) was slowly added dropwise to the reaction system, the reaction mixture was stirred at -78°C for 30 minutes, and then 2-(bromomethyl)isoindoline-1,3 -Dione (2.30g, 9.58mmol) (dissolved in ultra-dry tetrahydrofuran) was slowly added dropwise to the reaction system, and the reaction mixture was stirred at -78°C for 1.5 hours, and then the reaction was stopped.
  • Step 3 Synthesis of 3-(1,3-dioxoisoindolin-2-yl)-2-(4-(methylsulfonyl)phenyl)propionic acid
  • Step 4 N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-(1,3-dioxoiso Synthesis of indolin-2-yl)-2-(4-(methylsulfonyl)phenyl)propionamide
  • Step 5 3-Amino-N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(4-(methyl Synthesis of sulfonyl) phenyl) propionamide
  • Example 16 3-Acetylamino-N-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(4- (Methylsulfonyl)phenyl)propionamide
  • Step 1 Methanesulfonic acid 3-((2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)amino)-2-(4- Synthesis of (methylsulfonyl)phenyl)-3-oxopropyl ester
  • Step 2 N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-(methylamino)-2-(4 -(Methylsulfonyl)phenyl)propionamide formate
  • Example 18 3-(azetidine-1-yl)-N-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4 -Yl)-2-(4-(methylsulfonyl)phenyl)propionamide
  • Step 2 N-(2-Chloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(4-(methylsulfonyl)phenyl) Synthesis of acetamide
  • Step 3 N-(2-Chloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-hydroxy-2-(4-(methylsulfonyl) )Phenyl)propionamide synthesis
  • reaction solution was purified by preparative high pressure liquid chromatography (acetonitrile/water containing 0.05% formic acid) to obtain the target compound (40.0 mg, yield 37.7%, white solid).
  • LC-MS (ESI) m/z 514.2 [M+H] + .
  • Step 2 2-(4-(Methylsulfonyl)phenyl)-N-(2'-(trifluoromethoxy)-2-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) acetamide synthesis
  • Step 3 N-(2-Trifluoromethyl-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-hydroxy-2-(4-(methyl Synthesis of sulfonyl) phenyl) propionamide
  • Step 1 N-(2,6-Dimethyl-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(4-(methylsulfonyl) )Phenyl)acetamide synthesis
  • Step 2 N-(2,6-Dimethyl-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-hydroxy-2-(4-( Synthesis of methylsulfonyl)phenyl)propionamide
  • Example 22 N-(2,6-Dichloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2-yl)-[1,1'-linked Benzene)-4-yl)-3-hydroxy-2-(4-(methylsulfonyl)phenyl)propionamide
  • Step 4 N-(2,6-Dichloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl ]-4-yl)-2-(4-(methylsulfonyl)phenyl)acetamide
  • Step 5 N-(2,6-Dichloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl ]-4-yl)-3-hydroxy-2-(4-(methylsulfonyl)phenyl)propionamide
  • N-(2,6-Dichloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- 4-yl)-2-(4-(methylsulfonyl)phenyl)acetamide (110 mg, 0.183 mmol) was dissolved in anhydrous DMSO (2 mL). At room temperature, paraformaldehyde (15.7 mg, 0.174 mmol) and sodium methoxide (0.394 mg, 0.0073 mmol) were sequentially added to the reaction solution. After the addition, the reaction mixture was stirred and reacted overnight at room temperature.
  • Step 1 Synthesis of 2-(4-bromo-3-fluorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol
  • Step 2 2-(4'-amino-2-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol synthesis
  • Step 3 N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- Synthesis of 4-yl)-2-(4-(methylsulfonyl)phenyl)acetamide
  • Step 4 N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- Synthesis of 4-yl)-3-hydroxy-2-(4-(methylsulfonyl)phenyl)propionamide
  • Step 1 Synthesis of methyl 2-(4-ethylsulfonyl)phenylacetate
  • Step 2 Synthesis of 2-(4-ethylsulfonyl)phenyl-3-hydroxypropionic acid methyl ester
  • Step 3 Synthesis of methyl 2-(4-(ethylsulfonyl)phenyl)-3-methoxypropionate
  • Methyl 2-(4-(ethylsulfonyl)phenyl)-3-hydroxypropionate (15.8g, 58.0mmol) was dissolved in DCM (140mL), and 50 % Fluoroboric acid aqueous solution (3.72mL, 58.0mmol) and trimethylsilylated diazomethane (29.0mL, 58.0mmol, 2.0M n-hexane solution). After 20 minutes, trimethylsilylated diazomethane (29.0 mL, 58.0 mmol, 2.0 M n-hexane solution) was added again.
  • the resulting residue was prepared by a medium pressure liquid phase (acetonitrile/water containing 0.05% formic acid) to obtain the target compound (6.60g, yield 72.4%, light yellow oil) , And gradually solidify into a white solid after standing for 4 hours).
  • the reaction solution was directly prepared by high pressure liquid phase (acetonitrile/water containing 0.05% formic acid) to obtain the target compound (34.1 mg, yield 38.2%, white solid).
  • LC-MS(ESI) m/z: 575.9[M+H] + /577.9[M+2+H] + .
  • Example 25 and Example 26 rel-(S)-N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)- 2-(4-(ethylsulfonyl)phenyl)-3-methoxypropionamide or rel-(R)-N-(2,6-dichloro-2'-(trifluoromethoxy)- [1,1'-Biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)-3-methoxypropionamide
  • Racemate N-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(4-(ethylsulfonyl) )Phenyl)-3-methoxypropionamide (30mg dissolved in about 25mL methanol, injection volume 2.0mL) was tested by Waters SFC 150 (room temperature, 100bar, 214nm) and 250*25mm 10 ⁇ m Dr.maish Reprosil Chiral-OM ( Similar to ) (Supercritical carbon dioxide: ethanol, 60:40, 5.0min, 70mL/min) separated to obtain (S)-N-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1 '-Biphenyl)-4-yl)-2-(4-(ethylsulfonyl)phenyl)-3-methoxypropionamide or (R)-N-(2,6-dichloro-2'-(
  • 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 GSK993 was diluted with DMSO 3 times, 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) 1 34.97 2 25.02 3 306.5 4 12.81 5 18.78 6 61.59 7 391.9 8 23.5 9 34.12 10 36.08 11 66.92 12 28.21 13 28.58 14 25.95 15 297.5 16 42.28 17 613.7 18 1119 19 27.08 20 26.67 twenty one 26.31
  • 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).
  • Example IC 50 (nM) 1 16.52 2 3.49 4 11.41 5 6.287 9 24.54 12 6.928 16 91.42 19 39.96 20 48.95 twenty two 81.12 twenty three 80.05 25 9.197
  • 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.
  • composition of fast simulated intestinal fluid FaSSIF is: 0.056% (w/v) lecithin, 0.161% (w/v) sodium taurocholate, 0.39% (w/v) potassium phosphate, 0.77% (w/v) chlorination Potassium, deionized H 2 O, pH 6.5.
  • Example FaSSIF pH 6.5( ⁇ g/ml)
  • Example FaSSIF pH 6.5( ⁇ g/ml) 2 82.30 12 33.90 4 137.00 16 296.36 5 23.10 25 73.20 8 32.50 GSK993 5.08
  • reaction was terminated by adding 400 ⁇ L of cold stop solution (200 ng/mL tolbutamide and acetonitrile solution of sulfabenolidine (Labetalol)).
  • cold stop solution 200 ng/mL tolbutamide and acetonitrile solution of sulfabenolidine (Labetalol)
  • the sample was centrifuged at 4000 rpm for 20 minutes to precipitate the protein, and 200 ⁇ L of supernatant was transferred to 100 ⁇ L of high performance liquid chromatography water and shaken for 10 minutes for LC/MS/MS analysis to detect the amount of metabolite produced by each probe substrate.
  • Mass spectrometry detection conditions are electrospray ionization (ESI) source, selective reaction monitoring (MRM) scanning mode, chromatographic separation conditions are Thermo GLOD, C8 column (2.1mm ⁇ 50mm, 1.9 ⁇ g), mobile phase 0.1% formic acid acetonitrile- Gradient elution with 0.1% formic acid aqueous solution at a flow rate of 0.5 mL ⁇ min-1, using Graph pad Prism 5 software to calculate the half-inhibitory concentration (IC 50 ).
  • ESI electrospray ionization
  • MRM selective reaction monitoring
  • 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, with 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 is 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.

Abstract

本发明涉及式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物、包含其的药物组合物、使用其治疗或预防与RORγt有关的疾病的方法，以及其在制备用于治疗或预防RORγt有关的疾病的药物中的用途。

Description

可用作RORγ调节剂的联芳基类化合物
交叉引用
本申请要求2020年5月15日递交的中国专利申请202010411822.4的优先权。
技术领域
本发明属于化学医药技术领域，具体涉及具有RORγt抑制活性的联芳基类化合物、包含所述化合物的药物组合物、制备所述化合物的方法，以及所述化合物在制备用于预防或治疗与RORγt有关的疾病的药物中的用途。
背景技术
视黄酸受体相关孤儿受体(retinoic acid recetor-related orphan receptors，RORs)，又称为NF1R，属于配体依赖的转录因子核受体超家族的一个亚家族。RORs亚家族主要包括RORα、RORβ和RORγ这三个亚型。RORγ含有两个成员：RORγ1(也称RORγ)和RORγ2(也称作RORγt)，其中RORγ1分布于骨骼肌、胸腺、睾丸、胰腺、前列腺、心脏和肝脏等处，而RORγt仅表达于某些免疫细胞中。
Littman等人最早报道RORγt对于初始CD4+T细胞分化成Th17细胞是必需的(Cell,2006126,1121–1133)。经抗原刺激的Thp细胞向Th17细胞分化过程中，在IL-6、IL-21和TGF-β等细胞因子作用下诱导表达RORγt。从RORγt缺失小鼠中分离出来的Thp细胞，向Th17细胞株分化的能力明显降低。这些都表明RORγt是促进Th17细胞分化的关键调节因子。
Th17细胞是辅助性T细胞的一种，会产生IL-17及其他促炎性细胞因子。Th17细胞在许多小鼠自身免疫性疾病模型中均发挥了关键的作用，如实验性变态反应性脑脊髓炎(EAE)和胶原诱导性关节炎(CIA)动物模型。此外，在一些人类自身免疫性疾病包括类风湿性关节炎(RA)、多发性硬化(MS)、银屑病(Psoriasis)和炎症性肠病(IBD)中，均能检测到IL-17水平的提高。自身免疫性疾病患者的组织和外周血液样本中所发现的Th17细胞数量均增多。因此，Th17细胞或其产生的细胞因子IL-17与炎症及自身免疫性疾病的发病机制存在紧密联系。
2015年1月，由诺华公司开发的通过特异性阻断IL-17治疗银屑病的单克隆抗体Cosentyx(Secukinumab/AIN457)，已获FDA批准上市，这是治疗银屑病类药物市场中首个作用于IL-17的药物。随后，靶向促炎性细胞因子IL-17A的单克隆抗体ixekizumab，被批准应用于适应症银屑病、银屑病关节炎。这些单克隆抗体临床上的成功，证明了IL-17信号通路在炎性与自身免疫性疾病中的重要性，并且展示了通过RORγt抑制剂影响IL-17信号通路而治疗炎性与自身免疫性疾病的潜在可能性。
因此，RORγt可作为治疗自身免疫性疾病药物的新靶点，寻找RORγt小分子抑制剂并将其用于RORγt介导的疾病、例如炎症和自身免疫性疾病的治疗将具有重要意义。
至今为止，共有4个RORγt抑制剂的小分子化合物在临床2期，7个RORγt抑制剂的小分子在临床1期，还没有化合物进入临床3期。因此，仍然非常需要发现和开发新的RORγt 抑制剂化合物以用于预防和/或治疗与RORγt有关的疾病，例如炎症和自身免疫性疾病。这样的化合物除了应具有令人满意的RORγt抑制活性外，还期望基于结构的优化而具备对ROR亚型具有高选择性和良好的、甚至改进的成药性，以便为相关疾病患者提供更多用药选择的同时还能提供更好的治疗效果。
发明简述
本发明涉及可用于预防或治疗与RORγt有关的疾病的化合物。特别地，已经鉴定，本发明的化合物不仅显示令人满意的RORγt抑制活性，具有调控Th17细胞分化、从而抑制IL-17产生的能力，而且在体内药代动力学实验中显示良好的性能，预示着改进的成药性和改进的生物利用度；此外还显示良好的安全性，具有较低的药物相互作用风险。因此，本发明化合物不仅可实现用于预防或治疗与RORγt有关的疾病的目的，而且所制备的药物有望具有改善的吸收、在同等剂量下疗效提高、或以更低的剂量提供相同疗效、更长的半衰期和/或降低可能的副作用。由此，本发明还提供了本发明化合物在制备用于预防或治疗与RORγt有关的疾病的药物中的用途、包含所述化合物的药物组合物和通过施用所述化合物预防和/或治疗与RORγt有关的疾病的方法。
因此，在本发明的一方面，提供了式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物：
Figure PCTCN2021093786-appb-000001
其中：
X选自CH或N；
R 1选自氢、卤素、氰基、硝基、C 1-C 6烷基、-O-C 1-C 6烷基、S-C 1-C 6烷基、-NH-C 1-C 6烷基、-N-(C 1-C 6烷基) 2、C 1-C 6烷基-O-C 1-C 6烷基、-C 1-C 6烷基-S-C 1-C 6烷基、C 1-C 6烷基-NH-C 1-C 6烷基或C 1-C 6烷基-N(C 1-C 6烷基) 2，其中所述C 1-C 6烷基任选被卤素或氰基取代；
R 2选自氢、卤素、氰基、硝基或C 1-C 6烷基，其中所述C 1-C 6烷基任选被独立地选自以下的取代基取代：-R a或-OH，其中R a为任选被卤素取代的C 1-C 6烷基；
R 3、R 4各自独立地选自卤素、氰基、硝基、R b、-OR b、-SR b或-NR bR b，其中R b为H或任选取代的C 1-C 6烷基，所述取代基各自独立地选自氢、卤素、氰基、硝基、-OH、-SH、-NH 2、-O-C 1-C 6烷基、-S-C 1-C 6烷基、-NH-C 1-C 6烷基或-N(-C 1-C 6烷基) 2；
R 5选自-OR c、-SR c、-NR cR c、-NHCOR c、-NHSO 2R c、-COOR c、-CONR cR c或-SO 2NR cR c，其中R c在每次出现时独立地选自氢、任选被卤素取代的C 1-C 6烷基或任选被卤素取代的C 3- C 7环烷基，或连接在同一个N原子上的两个R c可以与它们所连接的N原子一起形成4-7元含氮杂环烷基；
R 6选自C 1-C 6烷基、C 3-C 7环烷基、4-7元杂环烷基或任选被C 1-C 6烷基、C 3-C 7环烷基或4-7元杂环烷基取代的-NH 2，其中所述C 1-C 6烷基、C 3-C 7环烷基或4-7元杂环烷基任选被各自独立地选自以下的取代基取代：氢、卤素、氰基、硝基、-R a、-OR a、-SR a或-NR aR a或任选被卤素取代的C 3-C 7环烷基，R a在每次出现时独立地选自H或任选被卤素取代的C 1-C 6烷基，其中连接在氨基N原子上的两个基团可以与它们连接的N一起形成4-7元环；且
n选自0、1或2。
在本发明的另一方面，提供了具有RORγt抑制活性、用作药物、尤其是用作RORγt抑制剂的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物。
在本发明的另一方面，提供了用于治疗、尤其是用于治疗或预防与RORγt有关的疾病的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物。
在本发明的另一方面，提供了包含上述本发明化合物和可药用赋形剂的药物组合物。在一个具体的方面，提供了所述本发明的药物组合物，用于预防或治疗与RORγt有关的疾病。在一个具体的方面，药物组合物可以另外包含适合与本发明化合物组合使用的另外的治疗活性成分。
在本发明的另一方面，提供了包含上述本发明化合物和另外的活性剂的药物组合。
在本发明的另一方面，提供了用于在哺乳动物、特别是人中预防或治疗与RORγt有关的疾病的方法，该方法包括施用有效量的本文所述的本发明化合物或包含其的药物组合物。
在本发明的另一方面，提供了上述本发明的化合物或药物组合物用于预防或治疗与RORγt有关的疾病的用途。
在本发明的另一方面，提供了上述本发明的化合物或药物组合物在制备用于预防或治疗与RORγt有关的疾病的药物中的用途。
在另外的方面，提供了用于合成本发明化合物的方法，其中代表性的合成方案和途径在下文描述。
通过阅读随后的详细描述，本发明的其它目的和优点对于本领域技术人员将变得显而易见。
发明详述
定义
除非另外指出，本说明书和权利要求书中使用的各个术语具有以下所示含义。在特定的 术语或短语没有特别定义的情况下，不应该被认为是不确定或不清楚的，而是应该按照本文上下文或者本领域的普通含义适当地理解。本文定义的许多基团都是任选被取代的，该定义部分所给出的取代基列表仅仅是示例性的，不意欲限制本说明书和权利要求书中其他部分所定义的取代基。
本文所用的术语“烷基”意指具有指定碳原子数目的直链或支链脂族烃基。具体地，烷基可以具有1至6个、1至5个、1至4个、1至3个或1至2个碳原子。适合的C 1-6烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基和异己基。特定的烷基具有1至3个碳原子。
本文所用的术语“烷氧基”意指基团-O-烷基，其中烷基具有本文所述的含义。具体地，该术语系指基团-O-C 1-6烷基。适合的烷氧基的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基及1,2-二甲基丁氧基。特定的烷氧基具有1至3个碳原子。
本文所用的术语“烷硫基”意指基团-S-烷基，其中烷基具有本文所述的含义。具体地，该术语系指基团-S-C 1-6烷基。适合的烷硫基的实例包括但不限于甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、叔丁硫基、仲丁硫基、正戊硫基、正己硫基及1,2-二甲基丁硫基。特定的烷硫基具有1至3个碳原子。
本文中所用的术语“卤素取代的C 1-C 6烷基”指上文所述的C 1-C 6烷基，其中一个或多个(例如1、2、3、4或5个)氢原子被卤素代替。本领域技术人员应当理解，当卤素取代基多于一个时，卤素可以相同也可以不同，并且可以位于相同或不同的C原子上。“卤素取代的C 1-C 6烷基”的实例有例如-CH 2F、-CHF 2、-CF 3、-CCl 3、-C 2F 5、-C 2Cl 5、-CH 2CF 3、-CH 2Cl、CH 2CH 2CF 3或-CF(CF 3) 2等。
本文中所用的术语“卤素取代的C 1-C 6烷氧基”指上文所述的C 1-C 6烷氧基，其中一个或多个(例如1、2、3、4或5个)氢原子被卤素代替。本领域技术人员应当理解，当卤素取代基多于一个时，卤素可以相同也可以不同，并且可以位于相同或不同的C原子上。“卤素取代的C 1-C 6烷氧基”的实例有例如-OCH 2F、-OCHF 2、-OCF 3、-OCCl 3、-OC 2F 5、-OC 2Cl 5、-OCH 2CF 3、-OCH 2Cl或-OCH 2CH 2CF 3等。
本文中所用的术语“卤素取代的C 1-C 6烷硫基”指上文所述的C 1-C 6烷硫基，其中一个或多个(例如1、2、3、4或5个)氢原子被卤素代替。本领域技术人员应当理解，当卤素取代基多于一个时，卤素可以相同也可以不同，并且可以位于相同或不同的C原子上。“卤素取代的C 1-C 6烷硫基”的实例有例如-SCH 2F、-SCHF 2、-SCF 3、-SCCl 3、-SC 2F 5、-SC 2Cl 5、-SCH 2CF 3、-SCH 2Cl或-SCH 2CH 2CF 3等。
本文所用的术语“环烷基”意指具有指定环原子数的单环、稠合多环、桥接多环或螺环非芳族饱和烃环结构。环烷基可具有3至12个碳原子，具体地3至10个，且更具体地3至7个碳原子，即C 3-C 7环烷基。适合的环烷基的实例包括但不限于单环C 3-C 7环烷基，如环丙 基、环丁基、环戊基、环己基和环庚基。特定的环烷基具有3至5个碳原子。
本文中所用的术语“卤素取代的C 3-C 7环烷基”指上文所述的C 3-C 7环烷基，其中一个或多个(例如1、2、3、4或5个)氢原子被卤素代替。本领域技术人员应当理解，当卤素取代基多于一个时，卤素可以相同也可以不同，并且可以位于相同或不同的C原子上。具体的实例包括但不限于2-氟环丙基、2,3-二氟环丙基、2,2,3,3-四氟环丙基、2,3-二氟环丁基、2,4-二氟环丁基等。
本文所用的术语“杂环烷基”意指包括一或多个独立地选自O、N及S的杂原子及指定环原子数的单环、稠合多环、螺环或桥接多环非芳族饱和环结构，或其N-氧化物，或其S-氧化物或S-二氧化物。杂环烷基可具有4至12个环成员，具体地4至10个环成员，且更具体地4至7个环成员。杂环烷基通常含有至多4个杂原子，更通常至多3个杂原子，更通常至多2个，例如单个杂原子，例如具有一个杂原子如N的4-7元单环杂环烷基，即4-7元含氮杂环烷基。适合的杂环烷基的实例包括但不限于氮杂环丁烷基、氧杂环丁烷基、硫杂环丁基、吡咯烷基(例如1-吡咯烷基、2-吡咯烷基及3-吡咯烷基)、四氢呋喃基(例如1-四氢呋喃基、2-四氢呋喃基及3-四氢呋喃基)、四氢噻吩基(例如1-四氢噻吩基、2-四氢噻吩基及3-四氢噻吩基)、哌啶基(例如1-哌啶基、2-哌啶基、3-哌啶基及4-哌啶基)、四氢吡喃基(例如4-四氢吡喃基)、四氢噻喃基(例如4-四氢噻喃基)、吗啉基、硫吗啉基、二噁烷基、哌嗪基或氮杂环庚烷基。
有机合成领域普通技术人员均理解，稳定的化学可行的杂环，无论芳族还是非芳族，其中最大杂原子数或所含杂原子的类型由环大小、不饱和度及杂原子的价数决定。一般而言，杂环可具有1至4个杂原子，只要杂环或杂芳环在化学可行及稳定即可。
本文所用的术语“卤代”或“卤素”意指氟(F)、氯(Cl)、溴(Br)及碘(I)。特定的卤代为氟或氯。本文所用的术语“被卤素取代的”基团旨在包括单卤代或多卤代基团，其中一个或多个相同或不同的卤素取代基团中的一个或多个氢。
本文所用的术语“氰基”意指基团-CN。
本文所用的术语“硝基”意指基团-NO 2。
本文所用的术语“氨基”意指基团-NH 2；
本文所用的术语“任选被……取代”意指基团可以是未取代的或被一个或多个(例如0、1、2、3、4或5或更多，或其中可衍生的任何范围)对该基团所列的取代基取代，其中所述取代基可以相同或不同。在一个实施方案中，任选取代的基团具有1个取代基。在另一个实施方案中，任选取代的基团具有2个取代基。在另一个实施方案中，任选取代的基团具有3个取代基。在另一个实施方案中，任选取代的基团具有4个取代基。
除非另外定义，本文化合物定义中使用的C 1-C 6烷基、C 3-C 7环烷基或4-7元杂环烷基任选地携带一个或多个取代基，所述取代基可选自H、F、Cl、Br、I、氰基、硝基、C 1-C 6烷基(例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、新戊基、己基、 1,2-二甲基丁基等)、C 3-C 7环烷基(环丙基、环丁基、环戊基、环己基、环庚基)、-OH、-O-C 1-C 6烷基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基及1,2-二甲基丁氧基等)、-SH、-S-C 1-C 6烷基(例如甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、叔丁硫基、仲丁硫基、正戊硫基、正己硫基及1,2-二甲基丁硫基等)或-NH 2、-NH-C 1-C 6烷基(例如甲基氨基、乙基氨基、丙基氨基、异丙基氨基、正丁基氨基、叔丁基氨基、仲丁基氨基、正戊基氨基、正己基氨基及1,2-二甲基丁基氨基等)、-N(C 1-C 6烷基) 2(例如二甲基氨基、甲基乙基氨基、二乙基氨基等)，其中的C 1-C 6烷基或C 3-C 7环烷基任选被一个或多个卤素(优选F)取代。
本文所用的术语“本发明的化合物”意欲涵盖如本文所定义的通式(I)的化合物或其任一优选或具体的实施方案、它们的立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，以及前药。类似地，本文中对“中间体”的称谓，无论其本身是否被请求保护，若上下文允许，则均意欲涵盖其游离形式以及上述各衍生形式。
本文所用的术语“药学可接受的”意指由各个国家的相应机构批准的或可由其批准，或列于用于动物且更具体地人类的一般公认药典中，或当向动物例如人类适量施用时不会产生不利、过敏或其它不良反应的分子实体和组合物。
本文所用的术语“药学可接受的盐”意指药学上可接受且具有母体化合物所需药理学活性的本发明化合物的盐。具体地，此类盐无毒，可为无机酸加成盐或有机酸加成盐及碱加成盐。具体地，此类盐包括：(1)与无机酸形成的酸加成盐，该无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等；或与有机酸形成的酸加成盐，该有机酸如乙酸、丙酸、己酸、乙醇酸、丙酮酸、乳酸、丙二酸、丁二酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、葡糖庚酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡萄糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸、黏康酸等；或(2)当存在于母体化合物中的酸性质子经金属离子如碱金属离子、碱土金属离子或铝离子置换时、或与有机碱如乙醇胺、二乙醇胺、三乙醇胺、N-甲基葡糖胺等配位时形成的盐。本领域技术人员了解制备药用盐的一般原理和技术，例如Berge等，Pharm ScL，66，1-19.(1977)中所述的那些。
本文所用的术语“前药”意指具有可裂解基团且通过溶剂分解或在生理条件下变成在体内具有药学活性的本发明化合物的化合物，包括本发明化合物的衍生物。前药包括本领域熟知的酸衍生物，如通过母体酸与适合醇反应制备的酯，或通过母体酸化合物与取代或未取代的胺反应制备的酰胺，或酸酐或混合酸酐。衍生自本发明化合物侧接的酸基的简单脂族或芳族酯、酰胺及酸酐为尤其适用的前药。特定的此类前药为本发明化合物的C 1-8烷基、C 2-8烯基、任选被取代的C 6-10芳基及(C 6-10芳基)-(C 1-4烷基)酯。
本文中所用的术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如1个、2个、3个或4个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定分子也可以以几何异构 体(顺式/反式)存在。类似地，本发明的化合物可以以两种或更多种处于快速平衡的不同结构形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。例如，亚硝基-肟在溶液中可以下列互变异构形式平衡存在：
Figure PCTCN2021093786-appb-000002
需要理解的是，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
本发明化合物可具有一或多个不对称中心，因此可以分别以(R)-或(S)-立体异构体形式制备或以其混合物形式制备。本文化合物结构式或结构片段中使用的
Figure PCTCN2021093786-appb-000003
表示不对称中心即手性中心的相对构型。相应地，在本发明所提供的化合物或中间体的命名中以R和S表示关于该手性中心的相对构型。
本文所用的术语“溶剂合物”是指包含化学计量的或非化学计量的溶剂的溶剂加成形式，包括例如与水的溶剂合物，例如水合物，或与有机溶剂、例如甲醇、乙醇或乙腈的溶剂合物，即分别作为甲醇化物、乙醇化物或乙腈化物；或为任何多晶型物的形式。应当理解的是，本发明化合物的这类溶剂合物还包括本发明化合物的药学可接受盐的溶剂合物。
本文所使用的术语“同位素变体”是指构成该化合物的一或多个原子被具有与自然界中通常发现的原子质量或质量数不同的原子质量或质量数的原子所取代的化合物。可以掺入本发明化合物的一个或多个原子上的同位素的实例包括例如 2H、 3H、 13C、 14C、 15N、 17O、 18O、 31P、 32P、 35S、 18F和 36Cl，从而形成本发明化合物的同位素变化形式，其无论是否具有放射性，都旨在涵盖在本发明的范围内。在一些实施方案中，所掺入的同位素是2H(氘)；在另一些实施方案中，所掺入的同位素是3H(氚)。
本文所用的术语“与RORγt有关的疾病”意指RORγt对所述疾病的发生和发展起到促进作用，或抑制RORγt将降低疾病的发生率、减少或消除疾病病状的疾病。对于本发明而言，“与RORγt有关的疾病”尤其选自炎症或自身免疫性疾病、癌症等，包括但不限于银屑病、类风湿性关节炎、银屑病性关节炎、强直性脊柱炎、多发性硬化、系统性红斑狼疮、移植物抗宿主疾病、炎症性肠病、克隆氏病、溃疡性结肠炎、慢性阻塞性肺病、哮喘、血管球性肾炎、狼疮性肾炎、心肌炎、甲状腺炎、干眼症、葡萄膜炎、白塞病、过敏性皮肤炎、粉刺、硬皮病、支气管炎、皮肌过敏性鼻炎、坏死性小肠结肠炎(NEC,Necrotizing Enterocolitis)、肝纤维化、非酒精性脂肪性肝炎(NASH)、新冠病毒肺炎(New coronavirus pneumonia)、胰岛素依赖性I型糖尿病、三阴乳腺癌和前列腺癌等。本发明优选的适应症选自银屑病、类风湿性关节炎、银屑病性关节炎、强直性脊柱炎、多发性硬化、炎症性肠病、干眼症、过敏性皮肤炎、慢性阻塞性肺病(COPD)、哮喘、坏死性小肠结肠炎、肝纤维化、非酒精性脂肪性肝炎、新冠病毒肺炎、三阴乳腺癌和前列腺癌。
本文所用的术语“受试者”或“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
本文所使用的术语“治疗有效量”意指当向受试者施用以治疗疾病时足以减轻或完全缓解病症的症状或其它有害作用；逆转、完全停止或减缓病症的进展；或降低病症恶化的风险的量，“有效量”可视化合物、疾病及其严重程度及待治疗的受试者的年龄、体重等而变化。
本文所使用的术语“预防”意指给怀疑患上或易感于如本文所定义的与RORγt有关的疾病、尤其是炎症或自身免疫疾病的受试者、例如哺乳动物、例如人施用一种或多种本发明的化合物，使得罹患所定义疾病的风险降低。术语“预防”包含在诊断或确定任何临床和/或病理症状以前使用本发明的化合物。
本文所用的术语“治疗”是指给患有所述疾病、或者具有所述疾病的症状的受试者、例如哺乳动物、例如人施用一种或多种本文所述的本发明化合物，用以治愈、缓解、减轻或影响所述疾病或所述疾病的症状。在本发明具体的实施方案中，所述疾病是本文所定义的与RORγt有关的疾病、尤其是炎症或自身免疫疾病。
本文所用的术语“药物组合”是指本发明化合物可与其它活性剂组合用于实现本发明的目的。所述其他活性剂可以是一种或多种另外的本发明化合物，或可以是与本发明化合物相容即不会相互不利影响、或具有互补活性的第二种或另外的(例如第三种)化合物。这类活性剂以达到预期目的的有效量适宜地组合存在。所述其他活性剂可以与本发明化合物在单一药物组合物中共同施用，或与本发明化合物处于不同的离散单元中分别施用，当分别施用时可以同时或相继进行。所述相继施用在时间上可以是接近或隔远的。
本文所用的术语“药学上可接受的赋形剂或载体”是指一种或多种相容性固体或液体填料或凝胶物质，其药理学上无活性，与组合物中的其它成分相容，并且应是对温血动物如人给药可接受的，用作本发明化合物在施用形式中的载体或介质，其实例包括但不限于纤维素及其衍生物(如羧甲基纤维素钠、醋酸纤维素等)、明胶、滑石、固体润滑剂(如硬脂酸镁)、硫酸钙、植物油、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温类)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂等。
除非另有规定，本发明化合物定义中的C n-n+m或C n-C n+m包括n至n+m个碳原子的各种情况，例如C 1-6包括C 1、C 2、C 3、C 4、C 5和C 6，也包括n至n+m中的任何一个范围，例如C 1-6包括C 1-2、C 1-3、C 1-4、C 2-6、C 3-6等。同理，本发明化合物定义中的n元至n+m元表示环原子数为n至n+m个，例如3-12元环包括3元环、4元环、、5元环、6元环、12元环等，也包括n至n+m元的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环和6-10元环等。
应理解，当本文描述本发明化合物、包含其的药物组合物、药物组合以及相关的用途和 方法时所涉及的剂量，是基于游离形式的重量，而非基于其任何盐、水合物或溶剂化物等，除非说明书中另外定义。
本发明化合物
本申请通篇使用的术语“发明的化合物”和“本发明的化合物”等，除非另外指出，涵盖本文各个实施方案及其具体或优选实施方式中定义的式(I)化合物、它们的立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，以及前药。所述立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物以及前药如上文定义部分所描述。优选地，本发明化合物为式(I)化合物的游离形式或其药学上可接受的盐或溶剂合物；最优选为式(I)化合物的游离形式或其药学上可接受的盐。
本发明的某些化合物可以以多晶型或无定形形式存在，它们也落入本发明的范围内。当为固体结晶形式时，式(I)化合物可以是与另一种化学实体的共晶体形式，并且本说明书包括所有这些共晶体。
在存在手性中心时，本发明的化合物可以以单独的对映异构体或对映体混合物形式存在。根据一个实施方案，提供了式(I)化合物或其药学上可接受的盐，其是对映体过量(％ee)＞95、＞98％或＞99％的单一对映体。优选地，单一对映异构体以＞99％的对映异构体过量(％ee)存在。
具体地，一方面，本发明提供式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物：
Figure PCTCN2021093786-appb-000004
其中：
X选自CH或N；
R 1选自氢、卤素、氰基、硝基、C 1-C 6烷基、-O-C 1-C 6烷基、S-C 1-C 6烷基、-NH-C 1-C 6烷基、-N-(C 1-C 6烷基) 2、C 1-C 6烷基-O-C 1-C 6烷基、-C 1-C 6烷基-S-C 1-C 6烷基、C 1-C 6烷基-NH-C 1-C 6烷基或C 1-C 6烷基-N(C 1-C 6烷基) 2，其中所述C 1-C 6烷基任选被卤素或氰基取代；
R 2选自氢、卤素、氰基、硝基或C 1-C 6烷基，其中所述C 1-C 6烷基任选被独立地选自以下的取代基取代：-R a或-OH，其中R a为任选被卤素取代的C 1-C 6烷基；
R 3、R 4各自独立地选自卤素、氰基、硝基、R b、-OR b、-SR b或-NR bR b，其中R b为H或任选取代的C 1-C 6烷基，所述取代基各自独立地选自氢、卤素、氰基、硝基、-OH、-SH、-NH 2、-O-C 1-C 6烷基、-S-C 1-C 6烷基、-NH-C 1-C 6烷基或-N(-C 1-C 6烷基) 2；
R 5选自-OR c、-SR c、-NR cR c、-NHCOR c、-NHSO 2R c、-COOR c、-CONR cR c或-SO 2NR cR c，其中R c在每次出现时独立地选自氢、任选被卤素取代的C 1-C 6烷基或任选被卤素取代的C 3-C 7环烷基，或连接在同一个N原子上的两个R c可以与它们所连接的N原子一起形成4-7元含氮杂环烷基；
R 6选自C 1-C 6烷基、C 3-C 7环烷基、4-7元杂环烷基或任选被C 1-C 6烷基、C 3-C 7环烷基或4-7元杂环烷基取代的-NH 2，其中所述C 1-C 6烷基、C 3-C 7环烷基或4-7元杂环烷基任选被各自独立地选自以下的取代基取代：氢、卤素、氰基、硝基、-R a、-OR a、-SR a或-NR aR a或任选被卤素取代的C 3-C 7环烷基，R a在每次出现时独立地选自H或任选被卤素取代的C 1-C 6烷基，其中连接在氨基N原子上的两个基团可以与它们连接的N一起形成4-7元环；且
n选自0、1或2。
在一种式(I)化合物的实施方式中，X为CH。
在一种式(I)化合物的实施方式中，R 1为H。
在一种式(I)化合物的实施方式中，R 1为卤素，例如F、Cl、Br或I；优选F或Cl。
在一种式(I)化合物的实施方式中，R 1为C 1-C 6烷基，优选C 1-C 3烷基，任选被卤素(优选F)取代，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、-CF 3、-CHF 2、-CH 2CF 3、-CF 2CF 3、-CH 2CH 2CF 3、-CH(CF 3) 2等。
在一种式(I)化合物的实施方式中，R 1选自-O-C 1-C 6烷基、-S-C 1-C 6烷基、-NH-C 1-C 6烷基或-N-(C 1-C 6烷基) 2，其中的C 1-C 6烷基任选被一个或多个卤素(优选F)取代，实例包括但不限于-OCH 3、-OCF 3、-OCHF 2、-OCH 2CH 3、-OCH 2CF 3、-OCH 2CH 2CH 3、-OCH 2CH 2CF 3、-OCH(CF 3) 2、-SCH 3、-SCF 3、-SCH 2CH 3、-NH 2、-NHCH 3、-N(CH 3) 2、-NH-CH 2CH 3、-N(CH 3)(CH 2CH 3)、-NHCF 3、-N(CH 3)(CF 3)等。在一个更具体的实施方式中，R 1选自-O-C 1-C 6烷基，其中的C 1-C 6烷基被至少三个卤素(优选F)取代，例如-OCF 3、-OCH 2CF 3、-OCH 2CH 2CF 3、-CH(CF 3) 2等。
在一种式(I)化合物的实施方式中，R 1选自-C 1-C 6烷基-O-C 1-C 6烷基、-C 1-C 6烷基-S-C 1-C 6烷基、-C 1-C 6烷基-NH-C 1-C 6烷基或-C 1-C 6烷基-N(C 1-C 6烷基) 2，其中的C 1-C 6烷基任选被卤素(优选F)取代。具体的实例包括但不限于-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-CH 2CH 2OCH 2CH 3、-CH 2NHCH 3、-CH 2N(CH 3) 2、-CH 2OCF 3、-CH 2CH 2OCF 3、-CH 2OCH 2CF 3、-CH 2NHCF 3、-CH 2N(CF 3) 2等。
在一种式(I)化合物的实施方式中，R 2为氢。
在一种式(I)化合物的实施方式中，R 2为卤素，例如F、Cl、Br或I；优选F或Cl。
在一种式(I)化合物的实施方式中，R 2为C 1-C 6烷基，优选C 1-C 3烷基，例如位于所处苯基的对位，其中所述C 1-C 3烷基被两个被卤素(优选F)取代的C 1-C 3烷基和一个-OH取代，例如
Figure PCTCN2021093786-appb-000005
在具体的实施方式中，R 1为H且R 2选自卤素或
Figure PCTCN2021093786-appb-000006
在一种式(I)化合物的实施方式中，R 3、R 4各自独立地选自H、卤素或任选被卤素取代的C 1-C 6烷基。
在一种式(I)化合物的实施方式中，R 3、R 4各自独立地选自H或卤素，优选氟或氯，最优选Cl，例如R 3为H且R 4为卤素、优选F或Cl，或反之亦然。在具体的实施方式中，R 3和R 4同时为卤素，优选氟或氯，最优选同时为Cl。
在一种式(I)化合物的实施方式中，R 3、R 4各自独立地选自H或C 1-C 6烷基，任选被卤素取代。在一个具体的实施方式中，R 3为H且R 4为任选被卤素(优选F)取代的C 1-C 6烷基，或反之亦然，例如R 3为H且R 4为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、-CF 3、-CHF 2、-CH 2CF 3、-CF 2CF 3、-CH 2CH 2CF 3或-CH(CF 3) 2等，或反之亦然。在一个具体的实施方式中，R 3和R 4选自C 1-C 6烷基，任选被卤素(优选F)取代，例如R 3和R 4同时为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、-CF 3、-CHF 2、-CH 2CF 3、-CF 2CF 3、-CH 2CH 2CF 3或-CH(CF 3) 2等，或R 3和R 4各自独立地为上述示例性基团之一。
在一种式(I)化合物的实施方式中，R 3、R 4各自独立地选自-OR b、-SR b或-NR bR b，其中R b为H或任选被卤素取代的C 1-C 6烷基，例如-OH、-SH、-OCH 3、-OCF 3、-OCHF 2、-OCH 2CH 3、-OCH 2CF 3、-OCH 2CH 2CH 3、-OCH 2CH 2CF 3、-OCH(CF 3) 2、-SCH 3、-SCF 3、-SCH 2CH 3、-NH 2、-NHCH 3、-N(CH 3) 2、-NH-CH 2CH 3、-N(CH 3)(CH 2CH 3)、-NHCF 3、-N(CH 3)(CF 3)等。
在一种式(I)化合物的实施方式中，R 5选自-OR c，其中R c选自氢、任选被卤素取代的C 1-C 6烷基或任选被卤素取代的C 3-C 7环烷基。在一个具体的实施方式中，R 5为-OH。在一个具体的实施方式中，R 5为-O-C 1-C 6烷基，任选被卤素取代，例如-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3)、-OCF 3、-OCHF 2、-OCH 2CF 3、-OCH 2CH 2CF 3、-OCH(CF 3)等。在一个具体的实施方式中，R 5为-O-C 3-C 7环烷基，任选被卤素取代，例如-O-环丙基、-O-环丁基、-O-环戊基等。在更具体的实施方式中，R 5为-O-C 1-C 3烷基，例如-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3)等。
在一种式(I)化合物的实施方式中，R 5选自-NR cR c、-NHCOR c或-NHSO 2R c，优选-NR cR c或-NHCOR c，其中R c在每次出现时独立地选自氢、任选被卤素取代的C 1-C 6烷基或任选被卤素取代的C 3-C 7环烷基，或连接在同一个N原子上的两个R c可以与它们所连接的N原子一起形成4-7元含氮杂环烷基。
在一个具体的实施方式中，R 5选自-NR cR c或-NHCOR c，其中R c在每次出现时独立地选自氢或任选被卤素(优选F)取代的C 1-C 6烷基，具体的实例包括但不限于-NH 2、-NHCH 3、-N(CH 3) 2、-NH-CH 2CH 3、-N(CH 3)(CH 2CH 3)、-N(CH 2CH 3)(CH 2CH 3)-、-NH(CH 2CH 2CH 3)、-NHCF 3、-N(CH 3)(CF 3)、-N(CF 3)CF 3、-N(CH 2CF 3)CF 3或-N(CH 2CF 3)(CH 2CF 3)-、-NHCOCH 3、-NHCO-CH 2CH 3、-NHCO-CH 2CF 3。在一个具体的实施方式中，R 5选自-NR cR c，其中连接在同一个N 原子上的两个R c可以与它们所连接的N原子一起形成4-7元含氮杂环烷基，例如-氮杂环丁烷、氮杂环戊烷、哌啶基等。在更具体的实施方式中，R 5选自-NH 2、-NHCH 3、-N(CH 3) 2、-NH-CH 2CH 3、-NH(CH 2CH 2CH 3)、-N(CH 3)(CH 2CH 3)、-NHCOCH 3、-NHCO-CH 2CH 3、-氮杂环丁烷、氮杂环戊烷或哌啶基。
在一个具体的实施方式中，R 5选自-NR cR c或-NHCOR c，其中R c在每次出现时独立地选自氢或任选被卤素取代的C 3-C 7环烷基，例如-NH-环丙基、-NH-环丁基、-NH-环戊基、-NHCO-环丙基、-NHCO-环丁基、-NHCO-环戊基等。
在一种式(I)化合物的实施方式中，R 5选自-COOR c、-CONR cR c或-SO 2NR cR c，优选-COOR c或-CONR cR c，其中R c在每次出现时独立地选自氢、任选被卤素取代的C 1-C 6烷基或任选被卤素取代的C 3-C 7环烷基，或连接在同一个N原子上的两个R c可以与它们所连接的N原子一起形成4-7元含氮杂环烷基。
在一个具体的实施方式中，R 5选自-COOR c或-CONR cR c，其中R c在每次出现时独立地选自H或任选被卤素(优选F)取代的C 1-C 6烷基，例如-COOH、-COOCH 3、-COOCF 3、-COOCH 2CH 3、-COOCH 2CF 3、-CONH 2、-CONHCH 3、-CON(CH 3) 2、-CON(CH 3)(CH 2CH 3)、-CONHCF 3、-CON(CF 3) 2。在一个具体的实施方式中，R 5选自-CONR cR c，其中连接在同一个N原子上的两个R c可以与它们所连接的N原子一起形成4-7元含氮杂环烷基，例如-CO-氮杂环丁烷、-CO-氮杂环戊烷、-CO-哌啶基等。
在一种式(I)化合物的实施方式中，R 6选自C 1-C 6烷基，优选C 1-C 3烷基，其任选被一个或多个独立地选自以下的基团取代：H、卤素、C 3-C 7环烷基、R a、-OR a、-SR a或-NR aR a，其中R a独立地选自H或任选被一个或多个卤素取代的C 1-C 6烷基，或者连接在同一个N原子上的两个R a可以与它们所连接的N原子一起形成4-7元含氮杂环烷基。
在具体的实施方式中，R 6为C 1-C 6烷基，优选C 1-C 3烷基，任选被F、Cl、Br、I、R a或-OR a取代，其中R a为H或任选被一个或多个卤素(优选F)取代的C 1-C 3烷基。具体的实例包括但不限于甲基、乙基、丙基或异丙基、三氟甲基、三氟乙基、羟基甲基、羟基乙基、甲氧基甲基、甲氧基乙基、三氟甲氧基甲基或三氟甲氧基乙基等。在更具体的实施方案中，R 6为C 1-C 3烷基，例如甲基、乙基、丙基或异丙基。
在具体的实施方式中，R 6为C 1-C 6烷基，优选C 1-C 3烷基，任选被任选被卤素取代的C 3-C 7环烷基取代。具体的实例包括但不限于甲基、乙基、丙基或异丙基、环丙基甲基、环丙基乙基、环丁基甲基、环丁基乙基、环戊基甲基、环戊基乙基等。
在具体的实施方案中，R 6为C 1-C 6烷基，优选C 1-C 3烷基，任选被-NR aR a取代，其中R a独立地选自H或任选被一个或多个卤素取代的C 1-C 3烷基，或者连接在同一个N原子上的两个R a可以与它们所连接的N原子一起形成4-7元含氮杂环烷基。具体的实例包括但不限于甲基、乙基、丙基或异丙基、氨基甲基、氨基乙基、氨基丙基、甲基氨基甲基、二甲基氨基甲基、甲基乙基氨基甲基、氮杂环丁基甲基、吡咯烷基甲基、哌啶基甲基等。
在一种式(I)化合物的实施方式中，R 6为-C 3-C 7环烷基，其任选被一个或多个独立地选自以下的基团取代：H、卤素、任选被卤素取代的C 3-C 7环烷基、R a、-OR a、-SR a或-NR aR a，其中R a独立地选自H或任选被一个或多个卤素取代的C 1-C 6烷基，或者连接在同一个N原子上的两个R a可以与它们所连接的N原子一起形成4-7元含氮杂环烷基。在具体的实施方案中，R 6为-C 3-C 5环烷基，例如环丙基、环丁基或环戊基。
在具体的实施方式中，R 6为-C 3-C 7环烷基，任选被一个或多个独立地选自以下的基团取代：卤素、R a、-OR a或-NR aR a，其中R a独立地选自H或任选被一个或多个卤素取代的C 1-C 6烷基。具体的实例包括但不限于2,3-二氟环丙基、2,2,3,3-四氟环丙基、2,3-二氟环丁基、甲基环丙基或环丁基、二甲基环丙基或环丁基、三氟甲基环丙基或环丁基、羟基环丙基或环丁基、三氟甲氧基环丙基或环丁基、甲基氨基环丙基、二甲基氨基环丙基、三氟甲基氨基环丙基等。
在一种式(I)化合物的实施方式中，R 6为4-7元杂环烷基，其任选被一个或多个独立地选自以下的基团取代：H、卤素、R a、-OR a、-SR a或-NR aR a，其中R a独立地选自H或任选被一个或多个卤素取代的C 1-C 6烷基，或者连接在同一个N原子上的两个R a可以与它们所连接的N原子一起形成4-7元含氮杂环烷基。在具体的实施方案中，R 6为4-7元杂环烷基，例如氮杂环丁烷基、氧杂环丁烷基、硫杂环丁基、吡咯烷基(例如1-吡咯烷基、2-吡咯烷基及3-吡咯烷基)、四氢呋喃基(例如1-四氢呋喃基、2-四氢呋喃基及3-四氢呋喃基)、四氢噻吩基(例如1-四氢噻吩基、2-四氢噻吩基及3-四氢噻吩基)、哌啶基(例如1-哌啶基、2-哌啶基、3-哌啶基及4-哌啶基)、四氢吡喃基(例如4-四氢吡喃基)、四氢噻喃基(例如4-四氢噻喃基)、吗啉基、硫吗啉基、二噁烷基、哌嗪基或氮杂环庚烷基，其各自任选被一个或多个、例如1个、2个或3个独立地选自F、Cl、Br、I、R a、-OR a或-NR aR a的基团取代，其中R a独立地选自H或任选被一个或多个卤素取代的C 1-C 3烷基。
在一种式(I)化合物的实施方式中，R 6为任选被C 1-C 6烷基、C 3-C 7环烷基或4-7元杂环烷基取代的氨基。在具体的实施方案中，氨基上取代的C 1-C 6烷基、C 3-C 7环烷基或4-7元杂环烷基各自具有以上实施方式中对作为R 6的C 1-C 6烷基、C 3-C 7环烷基或4-7元杂环烷基所定义的各具体实施方式或具体的实例。在最具体的实施方式中，R 6为被任选被卤素取代的C 1-C 6烷基取代的氨基，具体的实例包括但不限于-NH 2、-NHCH 3、-NCH 3CH 3、-N(CH 2CH 3)CH 3、-N(CH 2CH 3)(CH 2CH 3)-、-NHCF 3、-N(CH 3)CF 3、-N(CF 3)CF 3、-N(CH 2CF 3)CF 3或-N(CH 2CF 3)(CH 2CF 3)-、-NH(CH 2CH 2CH 3)等。
需要说明的是，本发明的式(I)化合物涵盖以上各个独立的实施方式或各个具体实施方式，还涵盖上述各个实施方式或具体实施方式的任何组合或亚组合构成的实施方式，也涵盖以上任何优选或例举的任何组合所构成的实施方式。
优选地，本发明提供式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物：
Figure PCTCN2021093786-appb-000007
其中：
X选自CH；
R 1选自氢、-O-C 1-C 6烷基、S-C 1-C 6烷基、-NH-C 1-C 6烷基或-N-(C 1-C 6烷基) 2，其中所述C 1-C 6烷基任选被卤素取代；
R 2选自氢、卤素或C 1-C 6烷基，其中所述C 1-C 6烷基被独立地选自以下的取代基取代：-R a或-OH，其中R a为被卤素取代的C 1-C 6烷基；
R 3、R 4各自独立地选自H、卤素、氰基或任选被卤素取代的C 1-C 6烷基；
R 5选自-OR c、-SR c、-NR cR c、-NHCOR c、-NHSO 2R c、-COOR c、-CONR cR c或-SO 2NR cR c，其中R c在每次出现时独立地选自氢或任选被卤素取代的C 1-C 6烷基，或连接在同一个N原子上的两个R c可以与它们所连接的N原子一起形成4-7元含氮杂环烷基；
R 6选自C 1-C 6烷基或-NR aR a，其中所述C 1-C 6烷基任选被各自独立地选自以下的取代基取代：卤素、-R a或-NR aR a，R a在每次出现时独立地选自H、任选被卤素取代的C 1-C 6烷基或任选被卤素取代的C 3-C 7环烷基，其中连接在氨基N原子上的两个R a可以与它们连接的N一起形成4-7元环；且
n选自0、1或2。
在一种上述优选式(I)化合物的具体实施方式中，R 1选自氢或-O-C 1-C 6烷基，其中所述C 1-C 6烷基任选被卤素取代。具体的实施方式中，R 1选自氢或-O-C 1-C 6烷基，其中所述C 1-C 6烷基被一个或多个、例如一个、两个或三个卤素(优选F)取代。在更具体的实施方式中，R 1为-O-C 1-C 6烷基，其中所述C 1-C 6烷基被至少三个卤素(优选F)取代，例如-O-CF 3、-O-CH 2CF 3、-O-CH 2CH 2CF 3、-O-CF 2CF 3等。
在一种上述优选式(I)化合物的实施方式中，R 2为氢。
在一种上述优选式(I)化合物的实施方式中，R 2为卤素，例如F、Cl、Br或I；优选F或Cl。
在一种上述优选式(I)化合物的实施方式中，R 2为C 1-C 6烷基，优选C 1-C 3烷基，被两个被卤素(优选F)取代的C 1-C 3烷基和一个-OH取代，例如
Figure PCTCN2021093786-appb-000008
在一种上述优选式(I)化合物的实施方式中，R 1为H且R 2选自卤素或
Figure PCTCN2021093786-appb-000009
在一种上述优选式(I)化合物的实施方式中，R 3、R 4各自独立地选自H或卤素，优选F或Cl，最优选Cl，例如R 3为H且R 4为卤素、优选F或Cl，或反之亦然。在具体的实施方式中，R 3和R 4同时为卤素，优选氟或氯，最优选同时为Cl。
在一种上述优选式(I)化合物的实施方式中，R 3、R 4各自独立地选自H或C 1-C 6烷基，任选被卤素取代。在一个具体的实施方式中，R 3为H且R 4为任选被卤素(优选F)取代的C 1-C 6烷基，或反之亦然，例如R 3为H且R 4为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、-CF 3、-CHF 2、-CH 2CF 3、-CF 2CF 3、-CH 2CH 2CF 3或-CH(CF 3) 2等，或反之亦然。在一个具体的实施方式中，R 3和R 4选自C 1-C 6烷基，例如R 3和R 4同时为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、-CF 3、-CHF 2、-CH 2CF 3、-CF 2CF 3、-CH 2CH 2CF 3或-CH(CF 3) 2等，或R 3和R 4各自独立地为上述示例性基团之一。
在一种上述优选式(I)化合物的实施方式中，R 5选自-OR c，其中R c选自氢或任选被卤素取代的C 1-C 6烷基。在一个具体的实施方式中，R 5为-OH。在一个具体的实施方式中，R 5为-O-C 1-C 6烷基，任选被卤素取代，例如-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3)、-OCF 3、-OCH 2CF 3、-OCH 2CH 2CF 3、-OCH(CF 3)等。在更具体的实施方式中，R 5为-O-C 1-C 3烷基，例如-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3)等。
在一种上述优选式(I)化合物的实施方式中，R 5选自-NR cR c或-NHCOR c，其中R c在每次出现时独立地选自氢或任选被卤素(优选F)取代的C 1-C 6烷基，具体的实例包括但不限于-NH 2、-NHCH 3、-N(CH 3) 2、-NH-CH 2CH 3、-N(CH 3)(CH 2CH 3)、-N(CH 2CH 3)(CH 2CH 3)-、-NH(CH 2CH 2CH 3)、-NHCF 3、-N(CH 3)(CF 3)、-N(CF 3)CF 3、-N(CH 2CF 3)CF 3或-N(CH 2CF 3)(CH 2CF 3)-、-NHCOCH 3、-NHCO-CH 2CH 3、-NHCO-CH 2CF 3。在一个具体的实施方式中，R 5选自-NR cR c，其中连接在同一个N原子上的两个R c可以与它们所连接的N原子一起形成4-7元含氮杂环烷基，例如-氮杂环丁烷、氮杂环戊烷、哌啶基等。在更具体的实施方式中，R 5选自-NH 2、-NHCH 3、-N(CH 3) 2、-NH-CH 2CH 3、-N(CH 3)(CH 2CH 3)、-NH(CH 2CH 2CH 3)、-NHCOCH 3、-NHCO-CH 2CH 3、-氮杂环丁烷、氮杂环戊烷或哌啶基。
在一种上述优选式(I)化合物的实施方式中，R 5选自-COOR c或-CONR cR c，其中R c在每次出现时独立地选自H或任选被卤素(优选F)取代的C 1-C 6烷基，例如-COOH、-COOCH 3、-COOCH 2CH 3、-CONH 2、-CONHCH 3、-CON(CH 3) 2、-CON(CH 3)(CH 2CH 3)。在一个具体的实施方式中，R 5选自-CONR cR c，其中连接在同一个N原子上的两个R c可以与它们所连接的N原子一起形成4-7元含氮杂环烷基，例如-CO-氮杂环丁烷、-CO-氮杂环戊烷、-CO-哌啶基等。
在一种上述优选式(I)化合物的实施方式中，R 6为-C 1-C 6烷基，优选-C 1-C 3烷基，任选被卤素取代。具体的实例包括但不限于甲基、乙基、丙基或异丙基、三氟甲基、三氟乙基、五氟乙基等。
在更具体的实施方式中，R 6为-C 1-C 3烷基，例如甲基、乙基、丙基或异丙基。
在一种上述优选式(I)化合物的实施方式中，R 6为-C 1-C 6烷基，优选-C 1-C 3烷基，任选被-NR aR a取代，其中R a选自H或任选被卤素取代的C 1-C 3烷基，或者连接在同一个N原子上的两个R a可以与它们所连接的N原子一起形成4-7元含氮杂环烷基。具体的实例包括但不限于氨基甲基、氨基乙基、氨基丙基、甲基氨基甲基、二甲基氨基甲基、甲基乙基氨基甲基、氮杂环丁基甲基、吡咯烷基甲基、哌啶基甲基等。
在一种上述优选式(I)化合物的实施方式中，R 6为-C 1-C 6烷基，优选-C 1-C 3烷基，任选被任选被卤素取代的C 3-C 7环烷基取代。具体的实例包括但不限于甲基、乙基、丙基或异丙基、环丙基甲基、环丙基乙基、环丁基甲基、环丁基乙基、环戊基甲基、环戊基乙基等。
在一种上述优选式(I)化合物的实施方式中，R 6为-NR aR a，其中R a选自H或任选被卤素取代的C 1-C 3烷基，或者连接在同一个N原子上的两个R a可以与它们所连接的N原子一起形成4-7元含氮杂环烷基。具体的实例包括但不限于-NH 2、-NHCH 3、-NCH 3CH 3、-N(CH 2CH 3)CH 3、-N(CH 2CH 3)(CH 2CH 3)-、-NHCF 3、-N(CH 3)CF 3、-N(CF 3)CF 3、-N(CH 2CF 3)CF 3或-N(CH 2CF 3)(CH 2CF 3)-、-NH(CH 2CH 2CH 3)、氮杂环丁基、吡咯烷基、哌啶基等。
需要说明的是，上述优选式(I)化合物涵盖各个独立的实施方式或各个具体实施方式，还涵盖其上述各个实施方式或具体实施方式的任何组合或亚组合构成的实施方式。
本发明化合物的优选具体实施方式包括以下化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，
Figure PCTCN2021093786-appb-000010
Figure PCTCN2021093786-appb-000011
本发明的有益效果
本发明提供了一类具有通式(I)结构的联芳基类化合物，经研究发现，该类化合物可有效抑制RORγt蛋白受体，从而调控Th17细胞的分化，抑制IL-17的产生，可作为免疫调节剂用于Th17细胞分化相关类疾病的治疗药物。
本发明的化合物具有下列有益效果：
对RORγt受体有高的抑制活性；
调控Th17细胞的分化，抑制IL-17的产生；和/或
具有良好的药物代谢动力学性质，例如具有更长的t 1/2，从而例如可以加大给药间隔，更长的半衰期，使患者具有更好的依从性；
具有改善的AUC0-last数据，具有更好的成药性，更高的生物利用度；和/或
良好的安全性，如透膜性、P450(减少的药物相互作用风险)、溶解性等优异的性质。
用于治疗或用作药物的本发明化合物
一方面，本发明提供用作药物、尤其是用作RORγt抑制剂的本发明化合物。
另一方面，本发明提供用于治疗、尤其是用于治疗和/或预防与RORγt有关疾病的本发明化合物。
在具体的实施方式中，本发明提供用于治疗和/或预防RORγt对所述疾病的发生和发展起到促进作用或抑制RORγt将降低疾病的发生率、减少或消除疾病病状的疾病的本发明化合物，所述疾病例如炎症或自身免疫性疾病、癌症等，包括但不限于银屑病、类风湿性关节炎、银屑病性关节炎、强直性脊柱炎、多发性硬化、系统性红斑狼疮、移植物抗宿主疾病、炎症性肠病、克隆氏病、溃疡性结肠炎、慢性阻塞性肺病、哮喘、血管球性肾炎、狼疮性肾炎、心肌炎、甲状腺炎、干眼症、葡萄膜炎、白塞病、过敏性皮肤炎、粉刺、硬皮病、支气管炎、皮肌过敏性鼻炎、坏死性小肠结肠炎、肝纤维化、非酒精性脂肪性肝炎(NASH)、新冠病毒肺炎、胰岛素依赖性I型糖尿病、三阴乳腺癌和前列腺癌等。
药物组合物及其施用
另一方面，为了使用本说明书的化合物用于治疗或预防目的，可以将本发明化合物根据标准药学实践配制为药物组合物。同时，基于本发明化合物良好的药物代谢动力学性质、改善的AUC0-last、良好的成药性，由本发明化合物可制备具有更好的药动学性质、更高生物利用度的药物。
因此，本发明提供一种药物组合物，其包含上述本发明化合物和药学可接受的赋形剂。
在一个具体的实施方式中，提供了所述本发明的药物组合物，用于在哺乳动物如人受试者中预防或治疗与RORγt有关的疾病。
在一个具体的实施方式中，本发明的药物组合物可以另外包含适合与本发明化合物组合使用的另外的治疗活性成分。在另一个具体的实施方式中，所述另外的治疗剂如本文对药物组合所定义。
本发明的药物组合物可以通过本领域技术人员已知的技术来配制，如在Remington’s Pharmaceutical Sciences第20版中公开的技术。例如，上述本发明的药物组合物，可以通过将本发明化合物与一种或多种药学可接受的赋形剂混合来制备。制备可进一步包括将一种或多种其它活性成分与本发明化合物和一种或多种药学可接受的赋形剂混合的步骤。
选择包含在特定组合物中的赋形剂将取决于多种因素、例如给药方式和所提供的组合物的形式。合适的药学可接受的赋形剂是本领域技术人员熟知的且描述于例如Ansel,Howard C.,等,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia:Lippincott,Williams & Wilkins,2004中，包括例如佐剂、稀释剂(例如葡萄糖、乳糖或甘露醇)、载体、pH 调节剂、缓冲剂、甜味剂、填充剂、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、加香剂、调味剂、其它已知添加剂。
本发明的药物组合物可以以标准方式施用。例如，合适的施用方式包括口服、静脉内、直肠、肠胃外、局部、经皮、眼、鼻、颊或肺(吸入)给药，其中肠胃外输注包括肌肉、静脉内、动脉内、腹膜内或皮下施用。为了这些目的，本发明的化合物可以通过本领域已知的方法配制成例如片剂、胶囊、糖浆、粉末、颗粒、水性或油性溶液或悬浮液、(脂质)乳剂、可分散粉末、栓剂、软膏、乳膏、滴剂、气溶胶、干粉制剂和无菌可注射水性或油性溶液或悬浮液的形式。
本发明化合物的预防或治疗剂量的大小将根据一系列因素而变化，包括所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约5000mg，例如约0.01至约1000mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约7000mg/日，例如约0.7mg/日至约1500mg/日。根据给药模式，本发明化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg，特别优选1-50mg，例如1.5mg、2mg、4mg、10mg、25mg等；相应地，本发明的药物组合物将包含0.05至99％w/w(重量百分比)，例如0.05至80％w/w，例如0.10至70％w/w，例如0.10至50％w/w的本发明化合物，所有重量百分比均基于总组合物。应当理解，可能有必要在某些情况下使用超出这些限制的剂量。
在一种具体实施方式中，本发明提供了一种药物组合物，其包含本发明化合物和一种或多种药学可接受的赋形剂，该组合物被配制用于口服施用。该组合物可以以单位剂型提供，例如以片剂、胶囊或口服液体制剂的形式。这样的单位剂型可以含有0.1mg至1g，例如5mg至250mg的本发明化合物作为活性成分。
在一种具体实施方式中，本发明提供了一种药物组合物，其包含本发明化合物和一种或多种药学可接受的赋形剂，该组合物被配制用于局部施用。局部施用可以是以例如乳膏剂、洗剂、软膏剂或透皮贴剂的形式。
在一种具体实施方式中，本发明提供了一种药物组合物，其包含本发明化合物和一种或多种药学可接受的赋形剂，该组合物被配制用于吸入施用。吸入施用可以通过口服吸入，也可以通过鼻内施用。当通过口服吸入施用时，本发明的化合物可以以每日剂量有效地用于本发明，例如至多500μg，如0.1-50μg、0.1-40μg、0.1-30μg、0.1-20μg或0.1-10μg的本发明化合物。口服吸入的本发明药物组合物可以配制成干粉、悬浮液(在液体或气体中)或溶液(在液体中)，且可以以任何合适的形式和使用任何本领域已知的合适的吸入器装置施用，包括例如定量吸入器(MDI)、干粉吸入器(DPI)、喷雾器和软雾吸入器。多室装置可用于递送本说明书的化合物和一种或多种其它活性成分(当存在时)。
治疗方法和用途
基于上述本发明化合物具有的有益效果，本发明化合物可用于治疗动物，特别是哺乳动物例如人的各种病症的方法中。
因此，另一方面，本发明提供了调节、尤其是抑制RORγt活性的方法，所述方法包括使细胞与如前所述的本发明化合物相接触以调节、尤其是抑制细胞中RORγt的活性。
另一方面，本发明提供了预防或治疗与RORγt相关的疾病(例如通过RORγt抑制可治疗或预防的疾病)的方法，所述方法包括向需要其的个体施用有效量的如前所述的本发明化合物或包含其的本发明药物组合物。
另一方面，本发明提供了如前所述的本发明化合物或包含其的药物组合物的用途，用于抑制RORγt活性，或者用于治疗和/或预防与RORγt相关的疾病、例如通过RORγt抑制可治疗或预防的疾病。
另一方面，本发明还提供了如前所述的本发明化合物或包含其的药物组合物在制备药物中的用途，尤其是具有RORγt受体抑制剂活性的药物中的应用。
另一方面，本发明提供如前所述的本发明化合物或包含其的药物组合物在制备用于治疗或预防与RORγt相关的疾病、例如通过RORγt抑制可治疗或预防的疾病的药物中的用途，其中所述化合物或药物组合物任选地与一种或多种化学治疗或免疫治疗联合。
药物组合
本发明的化合物可以作为唯一的活性成分施用，也可以与另外的药物或疗法组合进行施用。所述另外的药物或疗法可以具有或产生相同或不同的药理学功效，但条件是在与本发明化合物联合使用时不会导致不期望的活性降低、不良相互作用或副作用。
因此，另一方面，本发明提供药物组合，包含如前所述的本发明化合物以及一种或多种通过相同或不同作用机制发挥作用的其他药物或疗法，或由二者组成。在具体的实施方式中，该药物组合用于抑制RORγt活性，或用于治疗和/或预防与RORγt相关的疾病。
本发明的药物组合中的本发明化合物和组合使用的其他活性剂可以通过相同或不同的施用途径同时、分别或依次施用。所述其他活性剂可以与本发明化合物在单一药物组合物中共同施用，或与本发明化合物处于不同的离散单元中分别施用，例如组合产品,优选为药盒形式。当分别施用时可以同时或相继进行，所述相继施用在时间上可以是接近或隔远的。而且，本发明的化合物和另外的药物可以(i)在将组合产品发送给医师之前(例如在包含本发明的化合物和另外的药物的药盒的情形中)；(ii)在临施用前由医师自身(或在医师指导下)；(iii)由患者自身、例如在本发明的化合物和另外药物的依次施用期间，一起加入组合治疗中。
因此，在具体的实施方式中，本发明还提供了药盒，其包含两种或多种单独的药物组合物，其中至少一种包含本发明的化合物，其余的包含组合使用的其他活性剂，以及分别容纳所述组合物的装置。本发明的药盒特别适用于施用不同的剂型，如口服剂型和胃肠外剂型，或者适合于以不同的剂量间隔施用不同的组合物。
在本发明的药物组合中，本发明化合物和其他活性剂在组合时的适合用量通常可由本领域技术人员通过例如从本说明书中描述的化合物的剂量范围和其它活性化合物的批准或公布的剂量范围开始来确定，共施用的其它药物的剂量当然将根据所用的共用药物的类型、所用具体药物、待治疗的病症、患者的一般健康状况、医师或兽医的判断等因素而变化。
就本发明的药物组合物和药物组合而言，所述其他活性剂可以是一种或多种与本发明化合物不会相互不利影响、具有增强、互补活性的第二种或另外的(例如第三种)化合物，例如这些活性剂可以是已知调节其他生物活性通路的化合物，或者可以是调节本发明化合物所涉及生物活性通路中的不同组分的化合物，或甚至是与本发明化合物的生物靶点相重叠的化合物。
在一个具体的实施方式中，本发明提供了药物组合，例如用作用于治疗本文所列疾病之一的药物，所述疾病例如银屑病、COPD、哮喘、银屑病关节炎或强制性脊柱炎，其包含本发明化合物，和至少一种选自以下的活性成分：
a)β-肾上腺素受体激动剂；
b)毒蕈碱性受体拮抗剂；
c)关节毒蕈碱受体拮抗剂和β-肾上腺素受体激动剂；以及
d)糖皮质激素受体激动剂(甾族或非甾族)；
e)磷酸二酯酶-4(PDE4)抑制剂。
本发明化合物还可以与其他疗法组合，所述其他疗法包括但不限于手术、辐射治疗、移植(例如干细胞移植、骨髓移植)、肿瘤免疫疗法等。
相应地，本发明提供了用于抑制RORγt活性或用于治疗和/或预防与RORγt相关疾病的方法，包括向有需要的受试者施用本发明的药物组合。本发明还提供了所述本发明药物组合在制备用于抑制RORγt活性或用于治疗和/或预防与RORγt相关疾病的药物中的用途。
对于上述涉及药物组合物、治疗方法和用途以及药物组合的各个方面，与RORγt相关的疾病(例如通过RORγt抑制可治疗或预防的疾病)包括炎症或自身免疫疾病、癌症等，包括但不限于银屑病、类风湿性关节炎、银屑病性关节炎、强直性脊柱炎、多发性硬化、系统性红斑狼疮、移植物抗宿主疾病、炎症性肠病、克隆氏病、溃疡性结肠炎、慢性阻塞性肺病、哮喘、血管球性肾炎、狼疮性肾炎、心肌炎、甲状腺炎、干眼症、葡萄膜炎、白塞病、过敏性皮肤炎、粉刺、硬皮病、支气管炎、皮肌过敏性鼻炎、坏死性小肠结肠炎、肝纤维化、非酒精性脂肪性肝炎(NASH)、新冠病毒肺炎、胰岛素依赖性I型糖尿病、三阴乳腺癌和前列腺癌等。优选的与RORγt相关的疾病选自银屑病、类风湿性关节炎、银屑病性关节炎、强直性脊柱炎、多发性硬化、炎症性肠病、干眼症、过敏性皮肤炎、慢性阻塞性肺病(COPD)、哮喘、坏死性小肠结肠炎、肝纤维化、非酒精性脂肪性肝炎(NASH)、新冠病毒肺炎、三阴乳腺癌和前列腺癌。
对于上述本发明化合物、药物组合物、方法、用途、药物组合而言，优选上文所述优选的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物；更优选上文所列的具体化合物、例如化合物1-26，或它们药学可接受的盐或溶剂合物。
当本文描述化合物或药物的施用剂量时，应理解，该剂量基于游离碱的重量，不包括其任何衍生成份，除非说明书另外指出。
本发明化合物的合成
另一方面，本发明还提供了一种制备式(I)化合物的方法，下文举例说明了合成本发明化合物的通用合成方案。对于各反应步骤而言，适当的反应条件是本领域技术人员已知的或可以常规确定的。如果没有特别说明，在制备这些化合物中使用的原料和试剂通常可商购获得，或者可以通过下文的方法、与下文给出的方法类似的方法或本领域已知的方法制得。如果需要，合成反应流程中的原料和中间体可以采用常规技术进行分离和纯化，所述技术包括但不限于过滤、蒸馏、结晶、色谱法等。所述材料可以采用包括物理常数和波谱数据在内的常规方法表征。
在一个实施方案中，所述方法包括以下步骤：
合成方案1：
Figure PCTCN2021093786-appb-000012
其中R 1、R 2、R 3、R 4、R 6、R c和X如上面对通式(I)所定义，Z为Br或I；且R c不是H；
步骤1：式(I-1)或式(I-2)化合物与式(I-3)化合物在催化剂、如钯催化剂的作用下通过偶联反应如Suzuki偶联反应得到中间体式(I-4)的化合物；
其中所述钯催化剂是本领域众所周知的用于Suzuki偶联的钯催化剂，包括但不限于PdCl 2(dtbpf)、Pd(dppf)Cl 2等；所述反应优选在适合的碱存在下进行，所述的碱可选自氢氧化钠、氢氧化钾、碳酸钠、碳酸钾或碳酸铯，优选地，所述的碱是碳酸钾；
步骤2：式(I-5)化合物在甲醇钠作用下跟多聚甲醛反应生成式(I-6)化合物；
步骤3：式(I-6)化合物烷基化生成式(I-7)化合物；所述烷基化例如在HBF 4的作用下与TMSCN进行，或例如在碱存在下与烷基卤化物进行；所述的碱可选自丁基锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾或碳酸铯；
步骤4：式(I-7)化合物水解得到式(I-8)化合物，所述水解优选在碱或酸存在下进行，所述碱可选自氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾或碳酸铯，所述酸可选自盐酸、硫酸或三氟乙酸；和/或
步骤5：式(I-8)化合物跟中间体式(I-4)的化合物在缩合剂的作用下生成式(I-a)化合物。
其中所述缩合剂是本领域众所周知的用于羧酸与胺偶联的缩合剂，包括但不限于EDC、DCC、HATU、N,N,N',N'-四甲基氯甲脒六氟磷酸盐等；所述反应优选在适合的碱存在下进行，所述的碱包括但不限于碳酸钠、碳酸钾、碳酸铯、N,N-二异丙基乙胺、三乙胺、HOBt、N-甲基咪唑或吡啶。
在一实施方案中，所述方法包括以下步骤：
合成方案2：
Figure PCTCN2021093786-appb-000013
其中R 1、R 2、R 3、R 4、R 6、R c和X如上面对通式(I)所定义，。
步骤1：式(II-1)化合物跟式(II-2)的化合物在缩合剂的作用下生成式(II-3)化合物。
其中所述缩合剂是本领域众所周知的用于羧酸与胺偶联的缩合剂，包括但不限于EDC、DCC、HATU、N,N,N',N'-四甲基氯甲脒六氟磷酸盐等；；所述反应优选在适合的碱存在下进行，所述的碱包括但不限于碳酸钠、碳酸钾、碳酸铯、N,N-二异丙基乙胺、三乙胺、HOBt、N-甲基咪唑或吡啶；
步骤2：式(II-3)化合物在甲醇钠作用下跟多聚甲醛反应生成式(I-b)化合物；
步骤3a：式(I-b)化合物烷基化生成式(I-a)化合物；所述烷基化例如在HBF 4的作用下与TMSCN进行，或例如在碱存在下与烷基卤化物进行；所述的碱可选自丁基锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾或碳酸铯；
步骤3b：式(I-b)化合物跟甲磺酰氯反应生成式(II-4)化合物；所述反应优选在适合的碱存在下进行，所述的碱包括但不限于碳酸钠、碳酸钾、碳酸铯、N,N-二异丙基乙胺、三乙胺、HOBt、N-甲基咪唑或吡啶；和/或
步骤4：式(I-4)化合物跟HNR cR c发生亲核取代反应生成式(I-c)化合物；所述反应优选在适合的碱存在下进行，所述的碱包括但不限于碳酸钠、碳酸钾、碳酸铯、N,N-二异丙基乙胺、三乙胺、HOBt、N-甲基咪唑或吡啶。
在一实施方案中，所述方法包括以下步骤：
合成方案3：
Figure PCTCN2021093786-appb-000014
其中R 1、R 2、R 3、R 4、R 6、R c和X如上面对通式(I)所定义，
步骤1a)式(III-1)化合物与R cCOOH或其活化形式例如相应的酰氯或酸酐反应生成式(I-d)化合物；所述反应优选在碱存在下进行，所述的碱可选自碳酸钠、碳酸钾、碳酸铯、N,N-二异丙基乙胺、三乙胺、HOBt或吡啶；所述反应可在缩合剂例如等存在下进行，其中所述缩合剂是本领域众所周知的用于羧酸与胺偶联的缩合剂，包括但不限于1-丙基磷酸酐(T3P)、EDC、DCC、HATU；或
步骤1b)式(III-1)化合物与R cSO 2Cl反应生成式(I-e)化合物；所述反应优选在碱存在下进行，所述的碱可选自碳酸钠、碳酸钾、碳酸铯、N,N-二异丙基乙胺、三乙胺、HOBt或吡啶；
在一实施方案中，所述方法包括以下步骤：
合成方案4：
Figure PCTCN2021093786-appb-000015
其中R 1、R 2、R 3、R 4、R 6、R c和X如上面对通式(I)所定义，
步骤1：式(IV-1)化合物水解得到式(IV-2)化合物，所述水解优选在碱存在下进行，所述碱可选自氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾或碳酸铯，
步骤2：式(IV-2)化合物与式(I-4)化合物反应得到式(IV-3)化合物，反应条件可参见合成方案2步骤1；
步骤3：式(IV-3)化合物水解得到式(I-f)化合物，所述水解优选在酸存在下进行，所述酸可选自例如盐酸、硫酸或三氟乙酸；
步骤4a：任选地，式(I-f)化合物与R cOH反应得到式(I-g)化合物；所述反应优选在碱存在下进行，所述的碱可选自碳酸钠、碳酸钾、碳酸铯、N,N-二异丙基乙胺、三乙胺、HOBt或吡啶；所述反应可在缩合剂例如等存在下进行，其中所述缩合剂是本领域众所周知的用于羧酸与醇偶联的缩合剂，包括但不限于1-丙基磷酸酐(T3P)、EDC、DCC或HATU；
步骤4b：任选地，式(I-f)化合物与HNR cR c反应得到式(I-h)化合物，反应条件可参见合成方案2步骤1；
上述步骤中的反应优选在有机溶剂中进行，所述有机溶剂可选自醇溶剂例如(甲醇、乙醇或丙醇)、四氢呋喃、醚类(例如乙醚、乙二醇单甲醚等)、N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,4-二氧六环、二氯甲烷、二甲基亚砜及其任意组合；对于水解反应可以使用有机溶剂与水的混合物；
上述步骤中的反应优选在适合的温度下进行，例如-100℃至0℃、-80℃至-20℃、-50℃至200℃、-20℃至100℃、-20℃至20℃、-10℃至20℃、-10℃至50℃、0-200℃、10-100℃、20-50℃或室温(20-25℃)。上述合成方案只是列举了本发明中部分化合物的制备方法。本发明 的化合物或者其立体异构体、互变异构体、稳定的同位素衍生物、药学上可接受的盐或溶剂合物可以通过多种方法、包括上文给出的方法、实施例中给出的方法或与之类似的方法、由本领域普通技术人员在上述合成方案的基础上、结合本领域的常规技术而制备得到。
本说明书中描述的化合物在以下实施例中进一步举例说明。这些实施例仅作为说明给出，而非限制性的。
具体实施方式
以下结合具体实施例，对本发明的技术方案做进一步的描述，但是本发明的保护范围并不限于这些实施例。凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
下列实施例中未注明具体条件的实验方法，通常按照这类反应的常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。除非另外说明，否则液体的比为体积比。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得、依据现有技术的方法制得或根据与本申请公开的类似的方法制得。
本申请使用化学名称是IUPAC名称,本申请使用的缩写具有本领域通常理解的含义，除非说明书中另外清楚定义。在下面列出说明书中使用的缩写的含义：
PdCl 2(dtbpf)：1,1'-二叔丁基膦基二茂铁二氯化钯
Pd(dppf)Cl 2：[1,1'-双(二苯基膦基)二茂铁]二氯化钯
xantphos:4,5-双二苯基膦-9,9-二甲基氧杂蒽
Pd 2(dba) 3:三(二亚苄基丙酮)二钯
HATU：2-(7-偶氮苯并三氮唑)-N,N,N’,N’,-四甲基脲六氟磷酸盐
TCFH:N,N,N',N'-四甲基氯甲脒六氟磷酸盐
DIEA：N,N-二异丙基乙胺
DMF：N,N-二甲基甲酰胺
DMSO：二甲亚砜
DCM：二氯甲烷
EA:乙酸乙酯
PE：石油醚
rt:室温
LC-MS：液相色谱质谱联用
ESI:电喷雾离子化
m/z：质荷比
TLC:薄层色谱
Ret.time：保留时间
合成实施例
本发明提供的目标化合物制备方法中，柱层析色谱采用乳山太阳干燥剂有限公司生产的硅胶(300-400目)；薄层色谱采用GF254(0.25毫米)；核磁共振色谱(NMR)使用Varian-400核磁共振仪测定；液质联用(LC/MS)使用Agilent TechnologiESI 6120液质联用仪。
此外，凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。除非另有说明，本发明使用的原料都是市售原料、无需进一步纯化可以直接使用，本发明使用的温度均为摄氏度℃。
当本发明化合物结构与化合物名称不一致时，通常以结构式所示为准，除非通过上下文可以确定化合物名称正确。
实施例1：N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-甲氧基丙酰胺
Figure PCTCN2021093786-appb-000016
中间体2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-胺的合成
步骤1：4-溴-3,5-二氯苯胺的合成
Figure PCTCN2021093786-appb-000017
冰浴下，向3,5-二氯苯胺(60.0g,370mmol)的乙腈(1.00L)溶液中加入N-溴代丁二酰亚胺(69.2g,389mmol)，反应液在室温下搅拌1.5小时后，停止反应。将反应混合物减压浓缩得残渣，再加入PE/EA的混合溶剂(200mL,体积比＝10:1)，室温搅拌10分钟后，过滤，滤饼用PE(150mL)洗涤，干燥后得到目标化合物(70.0g，收率78.5％，棕色固体)。LC-MS(ESI)m/z:240.2[M+H] +/242.2[M+2+H] +。 1H NMR(400MHz,CDCl 3)δ8.64(s,2H),6.71(s,2H)。
步骤2：2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-胺的合成
Figure PCTCN2021093786-appb-000018
向4-溴-3,5-二氯苯胺(49.5g,206mmol)和(2-(三氟甲氧基)苯基)硼酸(46.5g,226mmol)的水(50.0mL)和1,4-二氧六环(500mL)的混合溶液中加入碳酸钾(56.8g,411mmol)和PdCl 2(dtbpf)(4.03g,6.16mmol)。氩气保护下，反应混合液在60℃下搅拌16小时后，停止反应。将反应液冷却至室温后加水(300mL)中，用EA(300mL×2)萃取，有机相分离后用饱和食盐水(200mL×2)洗涤、无水硫酸钠干燥、过滤，滤液减压浓缩，所得残留物经柱层析分离纯化(PE：EA＝12:1-8:1)得到目标化合物(20.5g，收率31.0％，白色固体)。LC-MS(ESI)m/z:321.9[M+H] +/323.9[M+2+H] +。 1H NMR(400MHz,DMSO-d 6)δ7.56–7.50(m,1H),7.47–7.41(m,2H),7.35–7.30(m,1H),6.71(s,2H),5.81(s,2H)。
中间体：2-(4-(甲磺酰基)苯基)-3-甲氧基丙酸的合成
步骤1：2-(4-甲基磺酰)苯基乙酸甲酯的合成
Figure PCTCN2021093786-appb-000019
将2-(4-甲基磺酰)苯乙酸(9.00g,42.0mmol)溶于甲醇(100mL)中，冰水浴条件下加入二氯亚砜(15.0g,126mmol)。反应液升温至室温搅拌1小时，停止反应。将反应液减压浓缩，所得残留经柱层析分离纯化(PE：EA＝3:1-2:1)得到目标化合物(8.60g,收率89.7％,黄色固体)。LC-MS(ESI)m/z:229.0[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.91(d,J＝8.4Hz,2H),7.49(d,J＝8.5Hz,2H),3.73(s,2H),3.72(s,3H),3.05(s,3H)。
步骤2：2-(4-甲基磺酰)苯基-3-羟基丙酸甲酯的合成
Figure PCTCN2021093786-appb-000020
将2-(4-甲基磺酰)苯基乙酸甲酯(9.40g,41.2mmol)溶于无水DMSO(100.0mL)中，依次加入多聚甲醛(1.17g,39.2mmol)及甲醇钠(89.0mg,1.65mmol)，反应液室温搅拌16小时后，停止反应。将反应液加入冰水中(300.0mL)中，用1.0M盐酸溶液中和混合液，EA(400mL×2)萃取，静置分层。有机相用饱和食盐水(60.0mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留经柱层析分离纯化(PE：EA＝3:1-1:1)得到目标化合物(6.15g，收率57.8％，淡黄色油状物)。 1H NMR(400MHz,DMSO-d 6)δ7.87(d,2H),7.57(d,2H),5.08(t,J＝4.9Hz,1H),3.95–3.90(m,2H),3.72–3.65(m,1H),3.61(s,3H),3.18(s,3H)。
步骤3：2-(4-(甲磺酰基)苯基)-3-甲氧基丙酸甲酯的合成
Figure PCTCN2021093786-appb-000021
将2-(4-(甲磺酰基)苯基)-3-羟基丙酸甲酯(6.10g,23.6mmol)溶于DCM(140mL)，在冰水浴避光条件下，向反应液中加入50％氟硼酸水溶液(4.14g,23.6mmol)和三甲基硅烷化重氮甲烷 (11.8mL,23.6mmol,2.0M正己烷溶液)。20分钟后，再次加入三甲基硅烷化重氮甲烷(11.8mL,23.6mmol,2.0M正己烷溶液)。20分钟后，再次加入三甲基硅烷化重氮甲烷(11.8mL,23.6mmol,2.0M正己烷溶液)。20分钟后，再次加入三甲基硅烷化重氮甲烷(11.8mL,23.6mmol,2.0M正己烷溶液)。将反应液倒入水(80.0mL)中，用DCM(200mL×3)萃取，静置分层。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留经柱层析分离纯化(PE：EA＝5:1-3:1)得到目标化合物(4.62g,收率71.9％，无色油状物)。LC-MS(ESI)m/z:273.2[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.90(d,2H),7.53(d,2H),4.00–3.92(m,2H),3.71(s,3H),3.69–3.65(m,1H),3.35(s,3H),3.04(s,3H)。
步骤4：2-(4-(甲磺酰基)苯基)-3-甲氧基丙酸的合成
Figure PCTCN2021093786-appb-000022
将2-(4-(甲磺酰基)苯基)-3-甲氧基丙酸甲酯(3.60g,13.2mmol)溶于1.4-二氧六环(40.0mL)和6.0M盐酸(40.0mL)中。反应液在80℃下搅拌1小时后，停止反应。将反应液冷却至室温，倒入水(50.0mL)中，再用EA(200mL×2)萃取，静置分层。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，所得残留物经中压液相制备(乙腈/水含0.05％甲酸)得到目标化合物(2.00g，收率58.8％，白色固体)。MS(ESI)m/z:515.0[2M-H] -。 1H NMR(400MHz,CDCl 3)δ7.91(d,J＝8.4Hz,2H),7.56(d,J＝8.4Hz,2H),4.02–3.92(m,2H),3.74–3.68(m,1H),3.37(s,3H),3.04(s,3H)。
N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-甲氧基丙酰胺的合成
Figure PCTCN2021093786-appb-000023
将2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-胺(50.0mg，0.155mmol)和2-(4-(甲磺酰基)苯基)-3-甲氧基丙酸(48.0mg，0.186mmol)加入到乙腈(2.0mL)中。向反应混合物中加入N-甲基咪唑(26.8mg，0.326mmol)和TCFH(52.2mg，0.186mmol)。反应混合物在室温下搅拌反应1.5小时。反应液直接经反相色谱法纯化(C18，甲醇：水＝0～80％)得到目标化合物(40.0mg，收率45.9％，白色固体)。LC-MS(ESI)m/z[M+H] +/[M+2+H] +562.0/564.0。 1H NMR(500MHz,DMSO-d 6)δ10.73(s,1H),7.93(d,J＝8.3Hz,2H),7.84(s,2H),7.68(d,J＝8.4Hz,2H),7.63–7.59(m,1H),7.54–7.49(m,2H),7.41–7.37(m,1H),4.16–4.12(m,1H),4.04–3.98(m,1H),3.66–3.61(m,1H),3.30(s,3H),3.21(s,3H)。
实施例2和3：rel-(S)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-甲氧基丙酰胺或rel-(R)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)- 3-甲氧基丙酰胺
Figure PCTCN2021093786-appb-000024
外消旋体N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-甲氧基丙酰胺(50mg溶于约13mL甲醇，进样体积1.5mL)经Waters SFC 150(室温,100bar,214nm)和250*25mm 10Dr.maish Reprosil Chiral-AS(Similar to
Figure PCTCN2021093786-appb-000025
))(超临界二氧化碳：甲醇，80:20,6.0min,70mL/min)分离得到rel-(S)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-甲氧基丙酰胺或rel-(R)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-甲氧基丙酰胺(13.8mg，白色固体，Ret.time＝2.961min,e.e.99％)。LC-MS(ESI)m/z 561.9[M+H] +/563.9[M+2+H] +。 1H NMR(400MHz,CDCl 3)δ8.41(s,1H),7.96(d,J＝8.4Hz,2H),7.67(s,2H),7.59(d,J＝8.4Hz,2H),7.48–7.45(m,1H),7.39–7.35(m,2H),7.26-7.25,7.24-7.23(m,1H),4.06–4.00(m,1H),3.97–3.92(m,1H),3.82–3.78(m,1H),3.51(s,3H),3.06(s,3H)。
rel-(R)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-甲氧基丙酰胺或rel-(S)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-甲氧基丙酰胺(12.9mg，白色固体，Ret.time＝3.380min,e.e.97％)。LC-MS(ESI)m/z 561.8[M+H] +/563.8[M+2+H] +。 1H NMR(400MHz,CDCl 3)δ8.41(s,1H),7.96(d,J＝8.4Hz,2H),7.67(s,2H),7.59(d,J＝8.4Hz,2H),7.50–7.45(m,1H),7.40–7.35(m,2H),7.26–7.25,7.24-7.23(m,1H),4.06–4.01(m,1H),3.96–3.92(m,1H),3.82–3.78(m,1H),3.51(s,3H),3.06(s,3H)。
实施例4：N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-羟基丙酰胺
Figure PCTCN2021093786-appb-000026
步骤1：N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)乙酰胺的合成
Figure PCTCN2021093786-appb-000027
将2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-胺(150mg，0.466mmol)、2-(4-(甲磺酰基)苯基)乙酸(120mg，0.559mmol)和HATU(213mg，0.559mmol)加入到DCM(10mL)中。向反应混合物中加入DIEA(0.231mL，1.40mmol)。反应混合物在室温下搅拌反应4小时。加入饱和碳酸氢钠水溶液(5.0mL)。分出有机相后，水相再用DCM(10mL)萃取，合并有机相并用饱和食盐水 洗，无水硫酸钠干燥，过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(硅胶，EA/PE＝0～60％)得到目标化合物(240mg，收率99.4％，白色固体)。LC-MS(ESI)m/z 518.0[M+H] +。
步骤2：N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-羟基丙酰胺的合成
Figure PCTCN2021093786-appb-000028
将N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)乙酰胺(240mg，0.463mmol)加入到无水DMSO(8mL)中。向反应混合物中依次加入多聚甲醛(12.5mg，0.417mmol)和甲醇钠(1.03mg，0.019mmol)。反应混合物在室温下搅拌反应4小时。加入EA(15mL)和水(20mL)。分出有机相，水相再用EA(15mL)萃取，合并有机相用饱和食盐水(15mL×3)洗，无水硫酸钠干燥，过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(硅胶，EA/PE＝0～100％)得到目标化合物(149mg，收率58.7％，白色固体)。LC-MS(ESI)m/z 548.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.67(s,1H),7.92(d,J＝8.5Hz,2H),7.88–7.83(m,2H),7.66(d,J＝8.5Hz,2H),7.63–7.57(m,1H),7.54–7.48(m,2H),7.41–7.37(m,1H),5.14(t,J＝5.2Hz,1H),4.13–4.06(m,1H),4.01–3.94(m,1H),3.72–3.63(m,1H),3.20(s,3H)。
实施例5和6：rel-(S)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-羟基丙酰胺或rel-(R)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-羟基丙酰胺
Figure PCTCN2021093786-appb-000029
外消旋体N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-羟基丙酰胺(470mg溶于约120mL甲醇，进样体积3.0mL)经Waters SFC 150(室温,100bar,214nm)和250*25mm 10μm Dr.maish Reprosil Chiral-OM(Similar to
Figure PCTCN2021093786-appb-000030
)(超临界二氧化碳：甲醇，70:30,3.0min,70mL/min)分离得到rel-(S)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-羟基丙酰胺或rel-(R)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-羟基丙酰胺(204mg，白色固体，Ret.time＝4.166min,e.e.99％)。LC-MS(ESI)m/z 548.2[M+H] +/550.2[M+2+H] +。 1H NMR(400MHz,CDCl 3)δ8.23(s,1H),7.89(d,J＝8.2Hz,2H),7.70(d,J＝4.6Hz,2H),7.57(d,J＝8.2Hz,2H),7.50–7.44(m,1H),7.40–7.34(m,2H),7.26–7.23(m,1H),4.23–4.15(m,1H),4.04–3.92(m,2H),3.07(s,3H)。
rel-(R)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-羟基丙酰胺或 rel-(S)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(甲磺酰基)苯基)-3-羟基丙酰胺(171mg，白色固体，Ret.time＝4.453min,e.e.99％)。LC-MS(ESI)m/z 548.2[M+H] +/550.2[M+2+H] +。 1H NMR(400MHz,CDCl 3)δ8.04(s,1H),7.99–7.89(m,2H),7.77–7.67(m,2H),7.66–7.56(m,2H),7.53–7.47(m,1H),7.44–7.36(m,2H),7.29–7.24(m,1H),4.32–4.16(m,1H),4.11–3.90(m,2H),3.10(s,3H)。
实施例7：4-((2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)氨基)-3-(4-(甲基磺酰基)苯基)-4-氧代丁酸
Figure PCTCN2021093786-appb-000031
步骤1：2-(4-(甲基磺酰基)苯基)琥珀酸4-叔丁基酯1-甲基酯的合成
Figure PCTCN2021093786-appb-000032
2-(4-(甲基磺酰基)苯基)乙酸甲酯(900mg,3.95mmol)加入到四氢呋喃(10mL)中，冷却到0℃后，加入NaH(166mg,4.15mmol,60％在油中)，0℃继续反应30分钟，然后用注射器量取2-溴乙酸叔丁酯(847mg/0.63mL,4.34mmol)加入到反应瓶中，0℃继续反应30分钟，TLC检测原料反应完，反应毕，加入饱和氯化铵(20mL)淬灭反应，EA萃取(20mLx3)，硅胶柱分离[(PE：DCM＝2:1)：EA＝100％-65％]得目标产物(920mg,产率68.1％,无色油状物)。 1H NMR(400MHz,CDCl 3)δ7.93–7.88(m,2H),7.53–7.48(m,2H),4.18–4.10(m,1H),3.69(s,3H),3.18–3.07(m,1H),3.04(s,3H),2.68–2.58(m,1H).
步骤2：4-(叔丁氧基)-2-(4-(甲基磺酰基)苯基)-4-氧代丁酸的合成
Figure PCTCN2021093786-appb-000033
把2-(4-(甲基磺酰基)苯基)琥珀酸4-叔丁基酯1-甲基酯(810mg,2.37mmol)和氢氧化锂(109mg,2.6mmol)加入到四氢呋喃/水(10mL/2mL)的溶液中，室温反应1小时，加入1N的盐酸(3mL)，EA(10mLx3)萃取，饱和氯化钠(20mL)溶液洗一遍，减压旋干溶剂得目标产物(800mg,无色油状物)。LC-MS(ESI)m/z:273.1[M-56+H] +.
步骤3：4-((2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)氨基)-3-(4-(甲基磺酰基)苯基)-4-氧代丁 酸叔丁酯的合成
Figure PCTCN2021093786-appb-000034
把2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-胺(200mg,0.62mmol)、4-(叔丁氧基)-2-(4-(甲基磺酰基)苯基)-4-氧代丁酸(345mg,1.05mmol)、HATU(285mg,0.75mmol)和DIEA(160mg,1.24mmol)加入到DCM(5mL)中，室温反应过夜，TLC检测原料反应完全，反应毕，饱和碳酸氢钠洗一遍，硅胶柱分离[(PE：DCM＝2:1)：EA＝100％-50％]得目标产物(500mg,无色油状物)。
步骤4：4-((2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)氨基)-3-(4-(甲基磺酰基)苯基)-4-氧代丁酸的合成
Figure PCTCN2021093786-appb-000035
把4-((2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)氨基)-3-(4-(甲基磺酰基)苯基)-4-氧代丁酸叔丁酯(500mg)加入到DCM(5mL)中，然后加入三氟乙酸(1mL)，室温反应2小时，反应毕，直接旋干溶剂，然后加入EA(20mL)，饱和碳酸氢钠洗一遍，有机层旋干溶剂得粗产物，粗产物反相柱分离(水：甲醇＝100％:0-30％:70％)得目标产物(270mg,产率73.6％,白色固体)。LC-MS(ESI)m/z:576.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.44(s,1H),10.74(s,1H),7.97–7.89(m,2H),7.84–7.77(m,2H),7.71–7.63(m,2H),7.63–7.56(m,1H),7.54–7.47(m,2H),7.39–7.34(m,1H),4.29–4.18(m,1H),3.25,3.20(s,3H),3.18–3.09(m,1H),2.76–2.67(m,1H).
实施例8：N 1-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-N 4-甲基-2-(4-(甲基磺酰基)苯基)琥珀酰胺
Figure PCTCN2021093786-appb-000036
把4-((2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)氨基)-3-(4-(甲基磺酰基)苯基)-4-氧代丁酸(270mg,0.47mmol)、甲胺盐酸盐(53mg,0.94mmol)、HATU(357mg,0.94mmol)和DIEA(243mg,1.88mmol)加入到DCM(5mL)中，室温反应过夜，TLC检测原料反应完全，反应毕，饱和碳酸 氢钠洗一遍，制备板分离(DCM：甲醇＝40:1)得目标产物(120mg,产率43.3％,白色固体)。LC-MS(ESI)m/z:589.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.73(s,1H),7.95–7.88(m,3H),7.81(dd,J＝6.7,2.0Hz,2H),7.64(d,J＝8.5Hz,2H),7.62–7.56(m,1H),7.54–7.47(m,2H),7.37(dd,J＝7.9,1.7Hz,1H),4.33–4.26(m,1H),3.20(s,3H),3.05–2.96(m,1H),2.62–2.52(m,4H).
实施例9：N 1-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(甲基磺酰基)苯基)琥珀酰胺
Figure PCTCN2021093786-appb-000037
把4-((2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)氨基)-3-(4-(甲基磺酰基)苯基)-4-氧代丁酸(58mg,0.1mmol)、氯化铵(10.6mg,0.2mmol)、HATU(46mg,0.12mmol)和DIPEA(26mg,0.2mmol)加入到DCM(2mL)中，室温反应过夜，TLC检测原料反应完全，反应毕，饱和碳酸氢钠洗一遍，制备板分离(PE：EA＝1:1)得目标产物(8mg,产率13.8％,白色固体)。LC-MS(ESI)m/z:577.0[M+H] +。 1H NMR(500MHz,DMSO-d 6)δ10.46(s,1H),7.91(d,J＝8.4Hz,2H),7.79(dd,J＝6.4,2.0Hz,2H),7.70–7.65(m,1H),7.65–7.57(m,3H),7.54–7.48(m,2H),7.42–7.38(m,1H),7.00(s,1H),4.21–4.14(m,1H),3.21(s,3H),3.18–3.11(m,1H),2.82–2.75(m,1H).
实施例10：N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-羟基丙酰胺
Figure PCTCN2021093786-appb-000038
步骤1：N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)乙酰胺的合成
Figure PCTCN2021093786-appb-000039
将2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-胺(50.0mg，0.155mmol)和2-(4-(乙基磺酰基)苯基)乙酸(42.5mg，0.186mmol)加入到DCM(5mL)中。向反应混合物中依次加入HATU(70.7mg，0.186mmol)和DIEA(0.077mL，0.465mmol)。反应混合物在室温下搅拌反应过夜。加入饱和碳酸氢钠水溶液(10mL)和DCM(10mL)。分出水相用DCM(10mL)萃取。合并有机相用饱和食盐水洗，无水硫酸钠干燥，过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(硅胶，EA/PE＝0～100％)得到目标化合物(70.0mg，收率84.8％，白色固体)。LC-MS(ESI)m/z:[M+H] +532.0。
步骤2：N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-羟基丙酰胺的合成
Figure PCTCN2021093786-appb-000040
将N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)乙酰胺(70.0mg，0.131mmol)加入到无水DMSO(2mL)中。向反应混合物中依次加入多聚甲醛(3.54mg，0.118mmol)和甲醇钠(0.27mg,0.005mmol)。反应混合物在室温下搅拌反应过夜。加入EA(10mL)和水(10mL)。分出水相用EA(10mL)萃取。合并有机相用饱和食盐水洗，无水硫酸钠干燥，过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(硅胶，EA/PE＝0～100％)得到目标化合物(40.0mg，收率54.3％，白色固体)。LC-MS(ESI)m/z:562.0[M+H] +。 1H NMR(500MHz,DMSO-d 6)δ10.68(s,1H),7.90-7.82(m,4H),7.66(d,J＝8.3Hz,2H),7.63-7.58(m,1H),7.53-7.47(m,2H),7.40-7.36(m,1H),5.14(t,J＝5.2Hz,1H),4.12-4.06(m,1H),4.00-3.95(m,1H),3.71-3.65(m,1H),3.32(s,3H),3.27(q,J＝7.3Hz,2H),1.10(t,J＝7.3Hz,3H)。
实施例11和12：(R)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-羟基丙酰胺或(S)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-羟基丙酰胺
Figure PCTCN2021093786-appb-000041
外消旋体N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-羟基丙酰胺(50mg溶于约12mL甲醇，进样体积4.0mL)经Waters SFC 150(室温,100bar,214nm)和250*25mm 10μm Dr.maish Reprosil Chiral-OM(Similar to
Figure PCTCN2021093786-appb-000042
)(超临界二氧化碳：甲醇，65:35,3.0min,70mL/min)分离得到(R)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-羟基丙酰胺或(S)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-羟基丙酰胺(19.0mg，白色固体，Ret.time＝1.925min,e.e.98％)。LC-MS(ESI)m/z:561.9[M+H] +/563.9[M+2+H] +， 1H NMR(400MHz,CDCl 3)δ7.96(s,1H),7.88(d,J＝8.3Hz,2H),7.71–7.67(m,2H),7.57(d,J＝8.3Hz,2H),7.51–7.45(m,1H),7.40–7.35(m,2H),7.26–7.25,7.24–7.23(m,1H),4.26–4.16(m,1H),4.06–3.97(m,1H),3.97–3.90(m,1H),3.14(q,J＝7.4Hz,2H),2.73(t,J＝6.0Hz,1H),1.31(t,J＝7.4Hz,3H)。
(S)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-羟基丙酰胺或(R)-N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-羟基丙酰胺(22.3mg，白色固体，Ret.time＝2.453min,e.e.99％)。LC-MS(ESI)m/z:561.9[M+H] +/563.9 [M+2+H] +， 1H NMR(400MHz,CDCl 3)δ7.92(s,1H),7.90(d,J＝8.3Hz,2H),7.70–7.66(m,2H),7.58(d,J＝8.2Hz,2H),7.50–7.45(m,1H),7.40–7.35(m,2H),7.26–7.25,7.24-7.23(m,1H),4.26–4.16(m,2H),4.06–3.98(m,1H),3.96–3.90(m,1H),3.14(q,J＝7.4Hz,2H),2.76–2.68(m,1H),1.31(t,J＝7.4Hz,3H)。
实施例13：N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-3-羟基-2-(4-(N-甲基磺酰胺基)苯基)丙酰胺的合成
Figure PCTCN2021093786-appb-000043
步骤1：2-(4-(氯磺酰基)苯基)乙酸甲酯的合成
Figure PCTCN2021093786-appb-000044
将2-(4-(苄硫基)苯基)乙酸甲酯(500mg，1.84mmol)加入到乙酸(5mL)和水(1mL)的混合溶剂中。在0℃下，向反应混合物中分批加入N-氯代丁二酰亚胺(737mg，5.52mmol)。将反应混合物升至室温，并在室温下搅拌反应1小时。加入EA(10mL)和水(5mL)。分出有机相用饱和食盐水洗，无水硫酸钠干燥，过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(硅胶，EA/PE＝0～30％)得到目标化合物(380mg，收率83.0％，无色油状物)。 1H NMR(400MHz,CDCl 3)δ8.04–7.97(m,2H),7.55(d,J＝8.5Hz,2H),3.76(s,2H),3.74(s,3H)。
步骤2：2-(4-(N-甲基磺酰胺基)苯基)乙酸甲酯的合成
Figure PCTCN2021093786-appb-000045
将2-(4-(氯磺酰基)苯基)乙酸甲酯(380mg，1.53mmol)和甲胺盐酸盐(124mg，1.84mmol)加入到DCM(8mL)中。在氩气保护下，将反应混合物降至0℃后，加入三乙胺(0.638mL，4.59mmol)。将反应混合物升至室温，并在室温下搅拌反应过夜。加入水(5mL)。分出水相用DCM(10mL)萃取。合并有机相用饱和食盐水洗，无水硫酸钠干燥，过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(硅胶，EA/(DCM/PE＝1:2)＝0～50％)得到目标化合物(230mg，收率61.8％，白色固体)。LC-MS(ESI)m/z 244.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ7.76–7.69(m,2H),7.50(d,J＝8.3Hz,2H),7.43(q,J＝5.0Hz,1H),3.82(s,2H),3.63(s,3H),2.41(d,J＝5.0Hz,3H)。
步骤3：2-(4-(N-甲基磺酰胺基)苯基)乙酸的合成
Figure PCTCN2021093786-appb-000046
将2-(4-(N-甲基磺酰胺基)苯基)乙酸甲酯(230mg，0.945mmol)加入到四氢呋喃(4mL)中。向混合物中加入氢氧化锂一水合物(79.3mg，1.89mmol)的水(1mL)溶液。反应混合物在室温下搅拌反应2小时后，加入稀盐酸(1N，2mL)。加入DCM(10mL)和水(5mL)。分出有机相用饱和食盐水洗，无水硫酸钠干燥，过滤。滤液减压浓缩得到目标化合物(156mg，收率71.2％，无色油状物)。LC-MS(ESI)m/z:230.1[M+H] +。
步骤4：N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(N-甲基磺酰胺基)苯基)乙酰胺的合成
Figure PCTCN2021093786-appb-000047
将2-(4-(N-甲基磺酰胺基)苯基)乙酸(150mg，0.654mmol)、2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-胺(232mg，0.719mmol)、HATU(298mg，0.785mmol)和DIEA(0.324mL，1.96mmol)依次加入到DCM(8mL)中。反应混合物在室温下搅拌反应过夜。加入饱和碳酸氢钠水溶液(10mL)和DCM(10mL)。分出有机相用饱和食盐水洗，无水硫酸钠干燥，过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(硅胶，EA/PE＝0～50％)得到目标化合物(320mg，收率91.7％，无色油状物)。LC-MS(ESI)m/z:533.0[M+H] +。
步骤5：N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-3-羟基-2-(4-(N-甲基磺酰胺基)苯基)丙酰胺的合成
Figure PCTCN2021093786-appb-000048
将N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-2-(4-(N-甲基磺酰胺基)苯基)乙酰胺(320mg，0.600mmol)加入到无水DMSO(3mL)中。向反应混合物中依次加入多聚甲醛(16.2mg，0.540mmol)和甲醇钠(1.29mg，0.024mmol)。反应混合物在室温下搅拌反应2小时。加入EA(15mL)和水(10mL)。分出水相用EA(10mL)萃取。合并有机相用饱和食盐水洗，无水硫酸钠干燥，过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(C18，甲醇/水＝0～100％)得到目标化合物(139mg，收率41.1％，白色固体)。LC-MS(ESI)m/z 563.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.69(s,1H),7.91–7.83(m,2H),7.77(d,J＝8.3Hz,2H),7.65–7.57(m,3H),7.55–7.49(m,2H),7.46(q,J＝5.0Hz,1H),7.42–7.37(m,1H),5.15(t,J＝5.2Hz,1H),4.13–4.04(m,1H),3.99–3.92(m,1H),3.69–3.63(m,1H),2.41(d,J＝5.0Hz,3H)。
实施例14：N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-3-甲氧基-2-(4-(N-甲基磺酰胺基)苯基)丙酰胺
Figure PCTCN2021093786-appb-000049
将N-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯]-4-基)-3-羟基-2-(4-(N-甲基磺酰胺基)苯基)丙酰胺(89mg，0.158mmol)加入到DCM(3mL)中。将反应混合物降至0℃后，避光下依次加入氟硼酸(28.9mg，0.158mmol，48％水溶液)和三甲基硅基重氮甲烷(2N，0.079mL，0.158mmol)。反应混合物在0℃下搅拌反应20分钟后，再次加入三甲基硅基重氮甲烷(2N，0.079mL，0.158mmol)，反应混合物继续在0℃搅拌反应20分钟。该步骤继续重复两次。向反应混合物中加入水(10mL)，在室温下搅拌10分钟。加入DCM(15mL)。分出水相用DCM(10mL)萃取。合并有机相用饱和食盐水洗，无水硫酸钠干燥，过滤。滤液减压浓缩得到粗产品。经制备板分离纯化(硅胶，EA/PE＝1:1)得到目标化合物(29mg，收率31.9％，白色固体)。LC-MS(ESI)m/z：577.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.72(s,1H),7.87–7.81(m,2H),7.77(d,J＝8.3Hz,2H),7.63(d,J＝8.3Hz,2H),7.61–7.57(m,1H),7.54–7.48(m,2H),7.46(q,J＝4.9Hz,1H),7.41–7.36(m,1H),4.14–4.07(m,1H),4.00(t,J＝9.1Hz,1H),3.65–3.57(m,1H),3.29(s,3H),2.41(d,J＝5.1Hz,3H)。
实施例15：3-氨基-N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(甲基磺酰基)苯基)丙酰胺的
Figure PCTCN2021093786-appb-000050
步骤1：2-(4-甲基磺酰)苯基乙酸甲酯的合成
Figure PCTCN2021093786-appb-000051
将2-(4-甲基磺酰)苯乙酸(5.00g,23.3mmol)溶于甲醇(100mL)中，冰水浴条件下加入二氯亚砜(8.33g,70.0mmol)。反应液升温至室温搅拌1小时，停止反应。将反应液减压浓缩，所得残留物复溶于EA(80.0mL)，经无水硫酸钠干燥、过滤、减压浓缩。所得残留物用柱层析分离纯化(PE：EA＝3:1-2:1)得到目标化合物(5.00g,收率94.0％,米白色固体)。
步骤2：3-(1,3-二氧代异吲哚啉-2-基)-2-(4-(甲基磺酰基)苯基)丙酸甲酯的合成
Figure PCTCN2021093786-appb-000052
将2-(4-(甲基磺酰基)苯基)乙酸甲酯(2.00g,8.76mmol)溶于超干四氢呋喃(60.0mL)中，氮气保护下，在-78℃下，将双三甲基硅基胺基锂(10.5mL,10.5mmol)缓慢滴加到反应体系中，反应混合物在-78℃下搅拌30分钟后，再将2-(溴甲基)异吲哚啉-1,3-二酮(2.30g,9.58mmol)(溶于超干四氢呋喃中)缓慢滴加到反应体系中，反应混合物在-78℃下搅拌1.5小时后，停止反应。反应混合物用饱和氯化铵(20.0mL)水溶液淬灭，EA(30.0mL×2)萃取，有机相用饱和食盐水(15.0mL×2)洗涤后用无水硫酸钠干燥、过滤，滤液减压浓缩得到目标化合物(3.00g，粗品，灰色固体)。LC-MS(ESI)m/z:388.0[M+H] +。
步骤3：3-(1,3-二氧代异吲哚啉-2-基)-2-(4-(甲基磺酰基)苯基)丙酸的合成
Figure PCTCN2021093786-appb-000053
向3-(1,3-二氧代异吲哚啉-2-基)-2-(4-(甲基磺酰基)苯基)丙酸甲酯(3.00g,7.74mmol)的1,4-二氧六环(20.0mL)溶液中加入盐酸水溶液(6.0N)(20.0mL)。反应混合物在80℃下搅拌16小时后，停止反应。待反应液冷却到室温，向混合液中加入水(20.0mL)，EA(20.0mL×2)萃取，有机相用饱和食盐水(10.0mL×2)洗涤后，经无水硫酸钠干燥、过滤，减压浓缩得到目标化合物(3.13g，两步收率95.7％，白色固体)。LC-MS(ESI)m/z:374.4[M+H] +。
步骤4:N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-3-(1,3-二氧代异吲哚啉-2-基)-2-(4-(甲基磺酰基)苯基)丙酰胺的合成
Figure PCTCN2021093786-appb-000054
室温下，将2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-胺(1.50g,4.66mmol)和3-(1,3-二氧代异吲哚啉-2-基)-2-(4-(甲基磺酰基)苯基)丙酸(3.13g,8.38mmol)溶于乙腈(75.0mL)中，然后再依次加入N-甲基咪唑(1.91g,23.3mmol)和TCFH(3.92g,14.0mmol)，反应液室温搅拌2小时后，停止反应。将反应液减压浓缩，所得残留物用EA(30.0mL×2)萃取，再用饱和食盐水(25.0mL×2)洗涤后，无水硫酸钠干燥、过滤及减压浓缩，所得残留物经柱层析分离纯化(PE：EA＝10:1-2:1)得到目标化合物(4.00g，收率70.4％，白色固体)。 1H NMR(400MHz,DMSO-d 6)δ10.78(s,1H),7.91(d,J＝8.3Hz,2H),7.87–7.81(m,4H),7.80–7.78(m,1H),7.76–7.74(m,1H),7.68(d,J＝8.3Hz,2H),7.63–7.57(m,1H),7.53–7.47(m,2H),7.39–7.35(m,1H),4.50–4.43(m,1H),4.30–4.23(m,1H),4.14–4.07(m,1H),3.18(s,3H)。
步骤5:3-氨基-N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(甲基磺酰基)苯基)丙酰胺的合成
Figure PCTCN2021093786-appb-000055
向N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-3-(1,3-二氧代异吲哚啉-2-基)-2-(4-(甲基磺酰基)苯基)丙酰胺(100mg,0.148mmol)的无水乙醇(2.00mL)溶液中加入水合肼(98％水溶液，1.00mL)，反应混合物在80℃下搅拌16小时后，停止反应。待反应液冷却至室温后，减压浓缩，所得残留物经制备(乙腈/水含0.05％甲酸)纯化得到目标化合物(40.8mg，收率50.5％，白色固体)。LC-MS(ESI)m/z:547.0[M+H] +/549.0[M+2+H] +。 1H NMR(400MHz,CD 3OD)δ7.97(d,J＝8.4Hz,2H),7.83(d,J＝2.0Hz,1H),7.76(d,J＝2.1Hz,1H),7.68(d,J＝8.4Hz,2H),7.56–7.50(m,1H),7.45–7.38(m,2H),7.30–7.27(m,1H),3.97–3.91(m,1H),3.44–3.36(m,1H),3.11(s,3H),3.05–2.98(m,1H)。
实施例16：3-乙酰氨基-N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(甲基磺酰基)苯基)丙酰胺
Figure PCTCN2021093786-appb-000056
将3-氨基-N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(甲基磺酰基)苯基)丙酰胺(100mg,0.183mmol)和三乙胺(46.2mg,0.457mmol)溶于DCM(4.00mL)中，在冰浴下，将乙酰氯(14.4mg,0.183mmol)缓慢加入到混合液中。反应混合液在室温下搅拌1小时后，停止反应。将反应混合物倒入水(10.0mL)中，用DCM(10.0mL×2)萃取，饱和食盐水(10.0mL×2)洗涤、无水硫酸钠干燥、过滤，滤液减压浓缩，所得残留物经制备(乙腈/水含0.05％甲酸)得到目标化合物(44.3mg，收率41.2％，黄色固体)。LC-MS(ESI)m/z:588.9[M+H] +/590.9[M+2+H] +。 1H NMR(400MHz,CD 3OD)δ10.37(s,CONH),8.30(t,J＝6.4Hz,CH 3CONH),7.97(d,J＝8.4Hz,2H),7.84–7.68(m,4H),7.56–7.50(m,1H),7.46–7.37(m,2H),7.31–7.26(m,1H),4.42–4.36,4.17–4.07(m,1H),4.02–3.93,3.81–3.71(m,1H),3.68–3.59,3.50–3.46(m,1H),3.11(s,3H),2.14,2.07,1.91(s,3H)。
实施例17：N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-3-(甲氨基)-2-(4-(甲磺酰基)苯基)丙酰胺甲酸盐
Figure PCTCN2021093786-appb-000057
步骤1:甲磺酸3-((2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)氨基)-2-(4-(甲基磺酰基)苯基)-3-氧代丙基酯的合成
Figure PCTCN2021093786-appb-000058
将N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-3-羟基-2-(4-(甲基磺酰基)苯基)丙酰胺(200mg,0.364mmol)和三乙胺(111mg,1.09mmol)溶于DCM(4.00mL)中，在冰浴下，将甲基磺酰氯(50.2mg,0.438mmol)加入到混合液中。反应混合液在室温下搅拌1小时后，停止反应。将反应混合物倒入水(10.0mL)中，用DCM(10.0mL×2)萃取，饱和食盐水(10.0mL×2)洗涤、无水硫酸钠干燥、过滤，减压浓缩得到目标化合物(200mg，两步收率87.6％，白色固体)。LC-MS(ESI)m/z:625.9[M+H] +/627.9[M+2+H] +。
步骤2:N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-3-(甲氨基)-2-(4-(甲磺酰基)苯基)丙酰胺甲酸盐的合成
Figure PCTCN2021093786-appb-000059
将甲磺酸3-((2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)氨基)-2-(4-(甲基磺酰基)苯基)-3-氧代丙基酯(90.0mg,0.144mmol)和三乙胺(29.1mg,0.288mmol)溶于DCM(5.00mL)中，在室温下，将甲胺盐酸盐(11.6mg,0.172mmol)加入到混合液中。反应混合液在室温下搅拌2小时后，停止反应。将反应混合液减压浓缩，所得残留物经制备色谱纯化(乙腈/水含0.05％甲酸)，得到目标化合物(20.3mg，收率23.3％，甲酸盐，白色固体)。LC-MS(ESI)m/z:560.9[M+H] +/562.9[M+2+H] +。 1H NMR(400MHz,CD 3OD)δ8.48(s,1H),8.03(d,J＝8.3Hz,2H),7.85(d,J＝2.0Hz,1H),7.77–7.69(m,3H),7.57–7.50(m,1H),7.46–7.37(m,2H),7.28(dd,J＝7.6,1.6Hz,1H),4.31–4.25(m,1H),3.77–3.69(m,1H),3.29–3.27(m,1H),3.13(s,3H),2.72(s,3H)。
实施例18：3-(氮杂环丁烷-1-基)-N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(甲基磺酰基)苯基)丙酰胺
Figure PCTCN2021093786-appb-000060
将甲磺酸3-((2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)氨基)-2-(4-(甲基磺酰基)苯基)-3-氧代丙基酯(110mg,0.176mmol)和三乙胺(35.5mg,0.351mmol)溶于DCM(5.00mL)中，在冰浴下，将氮杂环丁烷(12.0mg,0.210mmol)缓慢加入到混合液中。反应混合液在室温下搅拌2小时后，停止反应。将反应混合物减压浓缩，所得残留物经制备色谱纯化(乙腈/水含0.05％甲酸)得到目标化合物(25.9mg，收率25.1％，白色固体)。LC-MS(ESI)m/z:587.0[M+H] +/589.0[M+2+H] +。 1H NMR(400MHz,MeOD)δ7.99(d,J＝8.3Hz,2H),7.83(d,J＝2.0Hz,1H),7.73(d, J＝2.0Hz,1H),7.71(d,J＝8.3Hz,2H),7.56–7.51(m,1H),7.46–7.38(m,2H),7.28(dd,J＝7.6,1.6Hz,1H),4.03–3.97(m,1H),3.80–3.64(m,5H),3.22–3.16(m,1H),3.12(s,3H),2.33–2.25(m,2H).
实施例19：N-(2-氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-3-羟基-2-(4-(甲基磺酰基)苯基)丙酰胺
Figure PCTCN2021093786-appb-000061
步骤1:2-氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-胺的合成
Figure PCTCN2021093786-appb-000062
向微波管中依次加入2-(三氟甲氧基)苯硼酸(1.00g,4.86mmol)、4-溴-3-氯苯胺(1.10g,5.33mmol)、碳酸钾(1.00g,7.23mmol)、Pd(dppf)Cl 2(396mg,0.460mmol)以及乙腈/水(8.00mL/2.00mL)。加毕，置换氮气3分钟，反应混合液在90℃下搅拌6小时后，停止反应。将反应液浓缩后，用EA(30.0mL×3)萃取，有机相用饱和食盐水(30.0mL×2)洗涤、无水硫酸钠干燥、过滤，滤液减压浓缩，所得粗品经柱层析分离纯化(PE：EA＝5:1)得到目标化合物(1.20g，收率85.7％，黑色固体)。LC-MS(ESI)m/z：287.8[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ7.51–7.38(m,3H),7.37–7.32(m,1H),6.95(d,J＝8.3Hz,1H),6.71(d,J＝2.2Hz,1H),6.59–6.53(m,1H),5.53(s,2H)。
步骤2:N-(2-氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(甲基磺酰基)苯基)乙酰胺的合成
Figure PCTCN2021093786-appb-000063
向2-氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-胺(200mg,0.695mmol)、2-(4-(甲基磺酰基)苯基)乙酸(223mg,1.04mmol)的乙腈(5.00mL)溶液中加入N-甲基咪唑(285mg,3.48mmol)及TCFH(585mg,2.09mmol)，反应混合液在室温下搅拌16小时后，停止反应。将反应液减压浓缩后，用EA(30.0mL×3)萃取，有机相用饱和食盐水(30.0mL×2)洗涤、无水硫酸钠干燥、过滤，滤液减压浓缩。所得粗品经柱层析分离纯化(PE：EA＝1:1-2:3)得到目标化合物(150mg，收率44.6％，灰色固体)。LC-MS(ESI)m/z 525.1[M+ACN+H] +。
步骤3:N-(2-氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-3-羟基-2-(4-(甲基磺酰基)苯基)丙酰胺的合成
Figure PCTCN2021093786-appb-000064
向N-(2-氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(甲基磺酰基)苯基)乙酰胺(100mg,0.207mmol)的无水DMSO(2.00mL)溶液中加入多聚甲醛(4.00mg,0.145mmol)，然后加入甲醇钠(0.500mg,0.008mmol)，加毕，反应混合液在室温下搅拌2小时后，LC-MS显示反应完成。反应液经高压液相制备色谱纯化(乙腈/水含0.05％甲酸)得到目标化合物(40.0mg，收率37.7％，白色固体)。LC-MS(ESI)m/z 514.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.57(s,1H),7.99(s,J＝2.0Hz,1H),7.92(d,J＝8.4Hz,2H),7.66(d,J＝8.4Hz,2H),7.59–7.53(m,2H),7.50–7.45(m,2H),7.41–7.38(m,J＝7.8,1.7Hz,1H),7.30(d,J＝8.4Hz,1H),5.14(s,1H),4.10(t,J＝9.3Hz,1H),4.03–3.97(m,J＝8.6,5.6Hz,1H),3.70–3.63(m,J＝9.8,5.5Hz,1H),3.20(s,3H)。
实施例20：N-(2-三氟甲基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-3-羟基-2-(4-(甲基磺酰基)苯基)丙酰胺
Figure PCTCN2021093786-appb-000065
步骤1:2-三氟甲基-2'-(三氟甲氧基)-[1,1'-联苯]-4-胺的合成
Figure PCTCN2021093786-appb-000066
向微波管中依次放入4-溴-3-三氟甲基苯胺(500mg,2.08mmol)、2-(三氟甲氧基)苯硼酸(515mg,2.50mmol)、碳酸钾(576mg,4.17mmol)、Pd(dppf)Cl 2(171mg,0.208mmol)以及1,4-二氧六环/水(8.00mL/2.00mL)。置换氮气3分钟后，反应混合液在100℃下搅拌6小时后，停止反应。将反应液浓缩后，用EA(30.0mL×3)萃取，有机相用饱和食盐水(30.0mL×2)洗涤、无水硫酸钠干燥、过滤，滤液减压浓缩，所得粗品经柱层析分离纯化(PE：EA＝9:1-5:1)得到目标化合物(600mg，收率89.6％，灰色固体)。LC-MS(ESI)m/z 321.9[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.43–7.37(m,1H),7.33–7.27(m,3H),7.11–7.04(m,2H),6.93–6.87(m,1H),4.59(s,2H)。
步骤2:2-(4-(甲基磺酰基)苯基)-N-(2'-(三氟甲氧基)-2-(三氟甲基)-[1,1'-联苯]-4-基)乙酰胺的合成
Figure PCTCN2021093786-appb-000067
向2-三氟甲基-2'-(三氟甲氧基)-[1,1'-联苯]-4-胺(200mg,0.623mmol)、2-(4-(甲基磺酰基)苯基)乙酸(200mg,0.934mmol)的乙腈(5.00mL)溶液中加入N-甲基咪唑(255mg,3.12mmol)以及TCFH(524mg,1.87mmol)，反应混合液在室温下搅拌14小时后，停止反应。将反应液浓缩后，用EA(30.0mL×3)萃取，有机相用饱和食盐水(30.0mL×2)洗涤、无水硫酸钠干燥、过滤，滤液减压浓缩。所得粗品经柱层析分离纯化(PE：EA＝3:2-2:3)得到目标化合物(180mg，收率55.9％，灰色固体)。LC-MS(ESI)m/z 518.1[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.96–7.86(m,3H),7.80(m,1H),7.68(s,1H),7.56(d,J＝8.1Hz,2H),7.46–7.40(m,1H),7.35–7.24(m,4H),3.85,3.83(s,2H),3.07,3.06(s,3H)。
步骤3:N-(2-三氟甲基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-3-羟基-2-(4-(甲基磺酰基)苯基)丙酰胺的合成
Figure PCTCN2021093786-appb-000068
向2-(4-(甲基磺酰基)苯基)-N-(2'-(三氟甲氧基)-2-(三氟甲基)-[1,1'-联苯]-4-基)乙酰胺(100mg,0.199mmol)的DMSO(2.00mL)溶液中加入多聚甲醛(4.78mg,0.159mmol)，然后加入甲醇钠(0.430mg,0.008mmol)，反应混合液在室温下搅拌2小时后，停止反应。反应液经高压液相纯化(乙腈/水含0.05％甲酸)得到目标化合物(60.0mg，收率37.7％，白色固体)。LC-MS(ESI)m/z 548.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.71(s,1H),8.29–8.19(m,1H),7.92(d,J＝8.3Hz,2H),7.89–7.82(m,1H),7.67(d,J＝8.3Hz,2H),7.61–7.52(m,1H),7.49–7.40(m,2H),7.40–7.27(m,2H),5.20–5.10(m,1H),4.24–3.92(m,2H),3.79–3.58(m,1H),3.20(s,3H)。
实施例21：N-(2,6-二甲基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-3-羟基-2-(4-(甲基磺酰基)苯基)丙酰胺
Figure PCTCN2021093786-appb-000069
步骤1：N-(2,6-二甲基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(甲基磺酰基)苯基)乙酰胺的合成
Figure PCTCN2021093786-appb-000070
把2,6-二甲基-2'-(三氟甲氧基)-[1,1'-联苯]-4-胺(150mg,0.53mmol)、2-(4-(甲基磺酰基)苯基)乙酸(137mg,0.64mmol)、HATU(243mg,0.64mmol)和DIEA(137mg,1.06mmol)加入到DCM(3mL)中，室温反应2小时，反应毕，硅胶柱分离(PE：DCM＝1:1)得目标产物(250mg,产 率99.2％,白色固体)。 1H NMR(400MHz,CDCl 3)δ7.94(d,J＝8.3Hz,2H),7.57(d,J＝8.3Hz,2H),7.44(s,1H),7.43–7.31(m,3H),7.27–7.25(m,2H),7.16–7.11(m,1H),3.81(s,2H),3.06(s,3H),1.97(s,6H).
步骤2：N-(2,6-二甲基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-3-羟基-2-(4-(甲基磺酰基)苯基)丙酰胺的合成
Figure PCTCN2021093786-appb-000071
把N-(2,6-二甲基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(甲基磺酰基)苯基)乙酰胺(100mg,0.21mmol)、多聚甲醛(5.98mg,0.20mmol)加入到无水DMSO(2mL)溶液中，搅拌状态下加入甲醇钠(0.43mg,0.008mmol)，室温反应2小时，反应毕，加入水(20mL)，EA(20mLx3)萃取，合并有机层，再用水洗3次，旋干溶剂，反相柱分离(水：甲醇＝100％-75％)得目标产物(26mg,产率24.3％,白色固体)。LC-MS(ESI)m/z:508.0[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ10.19(s,1H),7.93–7.88(m,2H),7.66(d,J＝8.4Hz,2H),7.60–7.44(m,3H),7.43–7.36(m,2H),7.26(dd,J＝7.8,1.8Hz,1H),5.14,5.07(t,J＝5.2Hz,1H),4.22–4.05(m,1H),4.04–3.95(m,1H),3.70–3.63(m,1H),3.21,3.20(s,2H),1.90(s,6H).
实施例22：N-(2,6-二氯-4'-(1,1,1,3,3,3-六氟-2-羟基丙烷-2-基)-[1,1'-联苯]-4-基)-3-羟基-2-(4-(甲基磺酰基)苯基)丙酰胺
Figure PCTCN2021093786-appb-000072
步骤1：2-(4-溴苯基)-1,1,1,3,3,3-六氟丙烷-2-醇的合成
Figure PCTCN2021093786-appb-000073
将溴化铜(517mg，2.32mmol)溶于乙腈(5mL)中，在冰浴下，氮气保护下，将亚硝酸叔丁酯(0.347mL，2.89mmol)滴加到反应液中。加完后，将2-(4-氨基苯基)-1,1,1,3,3,3-六氟丙烷-2-醇(500mg，1.93mmol)溶于乙腈(3mL)中并滴加到反应液中，加完后，反应混合物在冰浴下继续搅拌反应1小时，LC-MS监测反应完全。将反应液倒入冰水(20mL)中，用甲基叔丁基醚(15mLx2)萃取，合并有机相，用饱和食盐水(50mL)洗，用无水硫酸钠干燥，过滤，滤液减压浓缩得到目标化合物(694mg，粗品，棕色油状)。LC-MS(ESI)m/z:323.0[M-H] -。
步骤2：1,1,1,3,3,3-六氟-2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯基)丙-2-醇的合成
Figure PCTCN2021093786-appb-000074
依次将2-(4-溴苯基)-1,1,1,3,3,3-六氟丙烷-2-醇(694mg，2.15mmol)、联硼酸频那醇酯(600mg，2.36mmol)、乙酸钾(633mg，6.45mmol)和Pd(dppf)Cl 2(157mg，0.215mmol)加入到1,4-二氧六环(10mL)中。在氮气保护下，反应混合物在90℃下搅拌反应过夜。将反应混合物冷却至室温，过滤，滤液减压浓缩得到目标化合物(800mg，粗品，白色固体)。
步骤3：2-(4'-氨基-2',6'-二氯-[1,1'-联苯]-4-基)-1,1,1,3,3,3-六氟丙烷-2-醇的合成
Figure PCTCN2021093786-appb-000075
将1,1,1,3,3,3-六氟-2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)苯基)丙-2-醇(800mg，2.16mmol)、4-溴-3,5-二氯苯胺(417mg，1.73mmol)、碳酸钾(597mg，4.32mmol)和PdCl 2(dtbpf)(141mg，0.216mmol)加入到1,4-二氧六环(10mL)和水(1mL)的混合溶剂中。在氮气保护下，反应混合物在100℃下搅拌反应2小时，LC-MS监测反应完全。将反应混合物冷却至室温，过滤，滤液减压浓缩得到粗品，经硅胶柱分离纯化(PE:EA＝10:1-2:1)得到目标化合物(248mg，三步收率31.9％，淡棕色固体)。LC-MS(ESI)m/z:445.0[M+ACN+H] +。
步骤4：N-(2,6-二氯-4'-(1,1,1,3,3,3-六氟-2-羟基丙烷-2-基)-[1,1'-联苯]-4-基)-2-(4-(甲基磺酰基)苯基)乙酰胺的合成
Figure PCTCN2021093786-appb-000076
将2-(4'-氨基-2',6'-二氯-[1,1'-联苯]-4-基)-1,1,1,3,3,3-六氟丙烷-2-醇(82.0mg，0.203mmol)和2-(4-(甲基磺酰基)苯基)乙酸(43.5mg，0.203mmol)溶于无水DCM(3mL)中。在室温下，依次将HATU(116mg，0.304mmol)和DIEA(0.101mL，0.609mmol)加到反应液中。加完后，反应混合物在室温下搅拌反应过夜。将反应液倒入水(20mL)中，用DCM(15mLx2)萃取，合并有机相，依次用饱和氯化铵(20mL)和饱和碳酸氢钠(20mL)洗，用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，经硅胶柱分离纯化(PE：EA＝4:1-2:1)得到目标化合物(110.0mg，收率90.3％，黄色固体)。LC-MS(ESI)m/z:598.0[M-H] -。
步骤5：N-(2,6-二氯-4'-(1,1,1,3,3,3-六氟-2-羟基丙烷-2-基)-[1,1'-联苯]-4-基)-3-羟基-2-(4-(甲基磺酰基)苯基)丙酰胺的合成
Figure PCTCN2021093786-appb-000077
将N-(2,6-二氯-4'-(1,1,1,3,3,3-六氟-2-羟基丙烷-2-基)-[1,1'-联苯]-4-基)-2-(4-(甲基磺酰基)苯基)乙酰胺(110mg,0.183mmol)溶于无水DMSO(2mL)中。在室温下，依次将多聚甲醛(15.7mg,0.174mmol)和甲醇钠(0.394mg,0.0073mmol)加入到反应液中，加完后，反应混合物在室温下搅拌反应过夜。将反应液倒入冰水(25mL)中，用1.0M稀盐酸溶液中和混合液，用EA(15mLx3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，经硅胶分离纯化(PE：EA＝4:1-0:1)得到目标化合物(16.7mg，收率14.5％，白色固体)。LC-MS(ESI)m/z:629.9[M+H] +.
1H NMR(400MHz,CD 3OD)δ7.95(d,J＝8.4Hz,2H),7.83–7.78(m,4H),7.70(d,J＝8.4Hz,2H),7.33(d,J＝8.5Hz,2H),4.62–4.57(m,1H),4.27–4.21(m,1H),4.01–3.96(m,1H),3.83–3.76(m,1H),3.11(s,3H).
实施例23：N-(2'-氟-4'-(1,1,1,3,3,3-六氟-2-羟基丙烷-2-基)-[1,1'-联苯]-4-基)-3-羟基-2-(4-(甲基磺酰基)苯基)丙酰胺
Figure PCTCN2021093786-appb-000078
步骤1：2-(4-溴-3-氟苯基)-1,1,1,3,3,3-六氟丙-2-醇的合成
Figure PCTCN2021093786-appb-000079
往25mL单口瓶中依次加入2-(4-氨基-3-氟苯基)-1,1,1,3,3,3-六氟丙-2-醇(277mg,1mmol)、溴化铜(349.5mg,1.5mmol)和乙腈(5mL)，然后取亚硝酸叔丁基酯(155mg,1.5mmol)缓慢滴加到反应液中，室温反应过夜，TLC检测原料反应完全，反应毕，加水(20mL)、EA(20mLx2)萃取，饱和氯化钠洗涤一次，减压旋干溶剂得目标产物(340mg,产率100％，橙色油状物)。
步骤2：2-(4'-氨基-2-氟-[1,1'-联苯]-4-基)-1,1,1,3,3,3-六氟丙-2-醇的合成
Figure PCTCN2021093786-appb-000080
把2-(4-溴-3-氟苯基)-1,1,1,3,3,3-六氟丙-2-醇(341mg,1mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺(263mg,1.2mmol)、碳酸钾(408mg,3mmol)和Pd(dppf)Cl 2(37mg， 0.05mmol)加入到1,4-二氧六环/水(5mL/1mL)中，氮气保护下，110℃加热反应3小时，TLC检测原料反应完全，反应毕，冷却到室温，加水(20mL)，EA(20mLx2)萃取，自动过柱机硅胶柱分离(PE：EA＝1:2)得目前产物(270mg,产率76.5,白色固体)。LC-MS(ESI)m/z:354.0[M+H] +。
步骤3：N-(2'-氟-4'-(1,1,1,3,3,3-六氟-2-羟基丙烷-2-基)-[1,1'-联苯]-4-基)-2-(4-(甲基磺酰基)苯基)乙酰胺的合成
Figure PCTCN2021093786-appb-000081
将2-(4'-氨基-2-氟-[1,1'-联苯]-4-基)-1,1,1,3,3,3-六氟丙烷-2-醇(60.0mg，0.170mmol)和2-(4-(甲基磺酰基)苯基)乙酸(40.0mg，0.187mmol)溶于无水DCM(3mL)中。在室温下，依次将HATU(96.9mg，0.255mmol)和DIEA(0.0842mL，0.510mmol)加到反应液中。加完后，反应混合物在室温下搅拌反应过夜。将反应液倒入水(20mL)中，用DCM(15mLx2)萃取，合并有机相，依次用饱和氯化铵(20mL)和饱和碳酸氢钠(20mL)洗，用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，经硅胶柱分离纯化(PE：EA＝4:1-2:1)得到目标化合物(59.0mg，收率63.2％，黄色固体)。LC-MS(ESI)m/z:548.1[M-H] -。
步骤4：N-(2'-氟-4'-(1,1,1,3,3,3-六氟-2-羟基丙烷-2-基)-[1,1'-联苯]-4-基)-3-羟基-2-(4-(甲基磺酰基)苯基)丙酰胺的合成
Figure PCTCN2021093786-appb-000082
将N-(2'-氟-4'-(1,1,1,3,3,3-六氟-2-羟基丙烷-2-基)-[1,1'-联苯]-4-基)-2-(4-(甲基磺酰基)苯基)乙酰胺的制备(59.0mg,0.107mmol)溶于无水DMSO(2mL)中。在室温下，依次将多聚甲醛(9.19mg,0.102mmol)和甲醇钠(0.232mg,0.0043mmol)加入到反应液中，加完后，反应混合物在室温下搅拌反应过夜。将反应液倒入冰水(25mL)中，用1.0M稀盐酸溶液中和混合液，用EA(15mLx3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，经硅胶分离纯化(PE：EA＝4:1-0:1)得到目标化合物(26.2mg，收率42.1％，白色固体)。LC-MS(ESI)m/z:580.0[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),7.88(d,J＝8.1Hz,2H),7.71(d,J＝8.4Hz,2H),7.68–7.60(m,3H)，7.57–7.48(m,4H),5.11–5.05(m,1H),4.10–4.03(m,1H),4.00–3.95(m,1H),3.67–3.60(m,1H),3.16(s,3H).
实施例24：N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-甲氧基丙酰胺
Figure PCTCN2021093786-appb-000083
步骤1：2-(4-乙基磺酰)苯基乙酸甲酯的合成
Figure PCTCN2021093786-appb-000084
将2-(4-甲基磺酰)苯乙酸(25.0g,110mmol)溶于甲醇(150mL)中，冰水浴条件下加入二氯亚砜(11.9mL,164mmol)。反应液升温至室温搅拌1小时，停止反应。将反应液减压浓缩，所得残留经柱层析分离纯化(PE：EA＝10:1-3:1)得到目标化合物(24.2g,收率91.3％,白色固体)。MS(ESI)m/z:242.9[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.87(d,J＝8.3Hz,2H),7.49(d,J＝8.4Hz,2H),3.78–3.69(m,5H),3.11(q,J＝7.4Hz,2H),1.29(d,J＝7.4Hz,3H).
步骤2：2-(4-乙基磺酰)苯基-3-羟基丙酸甲酯的合成
Figure PCTCN2021093786-appb-000085
向2-(4-乙基磺酰)苯基乙酸甲酯(24.2g,100mmol)及多聚甲醛(2.85g,95.0mmol)的无水DMSO(250mL)中，加入甲醇钠(216mg,4.00mmol)，反应液室温搅拌16小时后，停止反应。将反应液倾入冰水中(400mL)中，用EA(600mL×2)萃取，静置分层。有机相用饱和食盐水(120mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留经柱层析分离纯化(PE：EA＝3:1-1:1)得到目标化合物(15.9g，收率58.5％，无色油状物)。
步骤3：2-(4-(乙磺酰基)苯基)-3-甲氧基丙酸甲酯的合成
Figure PCTCN2021093786-appb-000086
将2-(4-(乙磺酰基)苯基)-3-羟基丙酸甲酯(15.8g,58.0mmol)溶于DCM(140mL)，在冰水浴避光条件下，向反应液中加入50％氟硼酸水溶液(3.72mL,58.0mmol)和三甲基硅烷化重氮甲烷(29.0mL,58.0mmol,2.0M正己烷溶液)。20分钟后，再次加入三甲基硅烷化重氮甲烷(29.0mL,58.0mmol,2.0M正己烷溶液)。20分钟后，再次加入三甲基硅烷化重氮甲烷(29.0mL,58.0mmol,2.0M正己烷溶液)。20分钟后，再次加入三甲基硅烷化重氮甲烷(29.0mL,58.0mmol,2.0M正己烷溶液)。将反应液倒入水(150mL)中，用DCM(300mL×2)萃取，静置分层。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留经柱层析分离纯化(PE：EA＝4:1-3:1)得到目标化 合物(9.60g，收率57.8％，无色油状物)。MS(ESI)m/z:287.1[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.87(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),4.03–3.93(m,2H),3.72(s,3H),3.69–3.63(m,1H),3.36(s,3H),3.11(q,J＝7.4Hz,2H),1.29(t,J＝7.4Hz,3H).
步骤4：2-(4-(乙磺酰基)苯基)-3-甲氧基丙酸的合成
Figure PCTCN2021093786-appb-000087
向2-(4-(乙磺酰基)苯基)-3-甲氧基丙酸甲酯(9.60g,33.5mmol)的1.4-二氧六环(100mL)溶液中，加入6.0M盐酸(100mL)。反应液在80℃下搅拌1小时后，停止反应。将反应液冷却至室温，倒入水(80.0mL)中，再用EA(250mL×2)萃取，静置分层。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，所得残留物经中压液相制备(乙腈/水含0.05％甲酸)得到目标化合物(6.60g，收率72.4％，淡黄色油状物，静置4小时后逐渐固化成白色固体)。 1H NMR(400MHz,CDCl 3)δ7.89(d,J＝8.4Hz,2H),7.55(d,J＝8.3Hz,2H),4.06–3.92(m,2H),3.77–3.62(m,1H),3.39(s,3H),3.11(q,J＝7.4Hz,2H),1.29(t,J＝7.4Hz,3H).
步骤5:N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-甲氧基丙酰胺的合成
Figure PCTCN2021093786-appb-000088
向2-(4-(乙磺酰基)苯基)-3-甲氧基丙酸(50.7mg,0.186mmol)、2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-胺(50.0mg,0.155mmol)及N-甲基咪唑(63.6mg,0.775mmol)的乙腈(1.00mL)溶液中，加入TCFH(130mg,0.465mmol)，反应液室温搅拌1小时后，停止反应。将反应液直接经高压液相制备(乙腈/水含0.05％甲酸)得到目标化合物(34.1mg，收率38.2％，白色固体)。LC-MS(ESI)m/z:575.9[M+H] +/577.9[M+2+H] +。 1H NMR(400MHz,CDCl 3)δ8.42(s,1H),7.91(d,J＝8.3Hz,2H),7.68(s,2H),7.59(d,J＝8.3Hz,2H),7.51–7.44(m,1H),7.41–7.34(m,2H),7.26–7.25,7.24–7.23(m,1H),4.05–4.00(m,1H),3.96–3.91(m,1H),3.82–3.76(m,1H),3.50(s,3H),3.13(q,J＝7.4Hz,2H),1.30(t,J＝7.4Hz,3H)。
实施例25和实施例26：rel-(S)-N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-甲氧基丙酰胺或rel-(R)-N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-甲氧基丙酰胺
Figure PCTCN2021093786-appb-000089
外消旋体N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-甲氧基丙酰胺(30mg溶于约25mL甲醇，进样体积2.0mL)经Waters SFC 150(室温,100bar,214nm)和250*25mm 10μm Dr.maish Reprosil Chiral-OM(Similar to
Figure PCTCN2021093786-appb-000090
)(超临界二氧化碳：乙醇，60:40,5.0min,70mL/min)分离得到(S)-N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-甲氧基丙酰胺或(R)-N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-甲氧基丙酰胺(11.6mg，白色固体，Ret.time＝1.644min,e.e.100％)。LC-MS(ESI)m/z 575.8[M+H] +/577.8[M+2+H] +。 1H NMR(400MHz,CDCl 3)δ8.40(s,1H),7.91(d,J＝8.2Hz,2H),7.68(s,2H),7.59(d,J＝8.2Hz,2H),7.50–7.45(m,1H),7.40–7.35(m,2H),7.26–7.25),7.24–7.23(m,1H),4.06–4.00(m,1H),3.97–3.91(m,1H),3.82–3.77(m,1H),3.50(s,3H),3.12(q,J＝7.4Hz,2H),1.30(t,J＝7.4Hz,3H)。
(R)-N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-甲氧基丙酰胺或(S)-N-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)-2-(4-(乙基磺酰基)苯基)-3-甲氧基丙酰胺(9.20mg，白色固体，Ret.time＝2.219min,e.e.98％)。LC-MS(ESI)m/z 575.9[M+H] +/577.9[M+2+H] +。 1H NMR(400MHz,CD 3OD)δ7.91(d,J＝8.3Hz,2H),7.80–7.78(m,1H),7.77–7.76(m,1H),7.72(d,J＝8.4Hz,1H),7.56–7.50(m,1H),7.45–7.38(m,2H),7.31–7.27(m,1H),4.12–4.05(m,1H),3.70–3.62(m,1H),3.39(s,3H),3.20(q,J＝7.4Hz,2H),1.21(t,J＝7.4Hz,3H)。
活性实施例1：体外测定化合物对RORγt荧光素酶报告基因的抑制作用
本实验基本上按照文献(Current Chemical Genomics,2010,4,43-49)所述的方法进行。
将RORγ-LBD编码序列插入到pBIND质粒(Promega,E1581)。该表达载体和报告载体(携带稳定整合的GAL4启动子驱动的荧光素酶报告基因的pGL4.35)在HEK293T宿主细胞中共表达。当抑制剂与相应的嵌合受体结合时，嵌合受体与报告基因载体上的GAL4结合位点结合并抑制报告基因表达。根据化学发光信号的强弱来判定化合物对RORγ上的抑制活性。
试剂与耗材
Figure PCTCN2021093786-appb-000091
实验方法：
1准备实验化合物
1.1所有待测化合物用DMSO进行3倍梯度稀释，10个稀释梯度，起始浓度为10mM。
1.2阳性对照GSK993用DMSO进行3倍梯度稀释，10个稀释梯度，起始浓度为10mM。
1.3准备1000×阳性对照(10mM GSK993)和1000×阴性对照(100％DMSO)。
1.4将化合物板子封闭并震荡5min。
2.实验过程
2.1细胞悬浊液制备和种板
a)所有细胞都按照ATCC标准操作培养，HEK293T在指数生长期进行实验。
b)弃去培养基。
c)用PBS清洗细胞2次。
d)加入胰酶消化液消化细胞，用完全培养基终止消化。
e)收集细胞并计数，只有在细胞活率大于90％时才可以进行实验。
f)种6*10 6HEK293T细胞到100mm细胞培养皿中。
g)将种好细胞的培养皿置于37℃，5％CO 2培养箱过夜培养。
2.2细胞转染
a)将Trans-IT转染试剂放置室温平衡；
b)加20μl转染试剂至600μl Opti-MEMTM培养基中，注意不要碰到管壁，用移液枪吹吸混匀，室温静置5分钟；
c)加入10μg质粒到转染试剂(见步骤2.2.b)中，室温静置20分钟；质粒：分别加入5μg pBIND-RORγ和5μg pGL4.35质粒
d)将混好DNA的转染试剂加到100mm细胞培养皿(见步骤2.1)中；
e)将培养皿置于37℃，5％CO 2培养箱培养5h。
2.3化合物的处理
a)将稀释好的化合物用Echo550转移25nl到细胞培养板中(6007680-50,PE)；
b)将细胞(见步骤2.2)接种到384细胞培养板中(6007680-50,PE)，每孔15,000细胞数，25μl含5％炭吸附FBS培养基；
c)细胞在37℃，5％CO 2培养箱中过夜培养
2.4化合物的检测：
a)将Steady-Glo TM检测试剂室温放置；
b)将384细胞板(见步骤2.3)室温放置；
c)每孔加入25μL Steady-Glo TM检测试剂于细胞培养板(见步骤2.4b)；
d)将板子放到振荡器上避光震荡5min；
e)用Envision 2104检测化学发光值。
％Inhibition的计算：
RLU:测试化合物的荧光值
Figure PCTCN2021093786-appb-000092
Figure PCTCN2021093786-appb-000093
阳性对照平均值
Figure PCTCN2021093786-appb-000094
阴性对照平均值
用Graphad8.0通过拟合％Inhibition和化合物浓度的log值来计算化合物的IC 50。测定结果显示，本发明的化合物对RORγt荧光素酶报告基因有较好的抑制活性(如表1所示)。
表1.实施例化合物对RORγt荧光素酶报告基因抑制活性测定
实施例 IC 50(nM)
1 34.97
2 25.02
3 306.5
4 12.81
5 18.78
6 61.59
7 391.9
8 23.5
9 34.12
10 36.08
11 66.92
12 28.21
13 28.58
14 25.95
15 297.5
16 42.28
17 613.7
18 1119
19 27.08
20 26.67
21 26.31
22 56.78
23 38.6
24 59.99
25 35.14
26 162.6
GSK993 18.77
活性实施例2：化合物对人PBMC Th17细胞分化抑制实验
试验材料：
Figure PCTCN2021093786-appb-000095
实验方法：首先将PBMC细胞复苏铺板，然后用刺激因子(anti-hCD28：5μg/mL；rhTGF-β1：5ng/mL；rhIL-6：20ng/mL；rhIL-23：10ng/Ml)刺激PBMC细胞分化至Th17，同时加入不同浓度化合物，最大浓度从3μM开始，48小时后收集上清进行IL-17ELISA检测，与溶剂组比较，测定化合物抑制Th17细胞分泌IL-17的抑制率，用Graphad8.0拟合IC 50值。
测定结果显示，本发明的化合物对人PBMC具有较好的抑制Th17细胞分化分泌IL-17的能力(如表2所示)。
表2.化合物抑制Th17细胞分化分泌IL-17实验结果
实施例 IC 50(nM)
1 16.52
2 3.49
4 11.41
5 6.287
9 24.54
12 6.928
16 91.42
19 39.96
20 48.95
22 81.12
23 80.05
25 9.197
活性实施例3：人和小鼠肝微粒体代谢稳定性实验
根据本领域常规的体外代谢稳定性研究的标准方法，例如(Kerns,Edward H.and Di Li(2008).Drug-like Properties:Concepts,Structure Design and Methods:from ADME to Toxicity Optimization.San Diego:Academic Press；Di,Li等人，Optimization of a Higher Throughput Microsomal Stability Screening Assay for Profiling Drug Discovery Candidates,J.Biomol.Screen.2003,8(4),453.)中所述的方法，类似地如下进行本发明化合物的肝微粒体代谢稳定性试验。
孵育体系包含0.5mg蛋白质/mL微粒体、辅助因子、PBS，37℃预孵育3min，加入底物(即待测化合物)启动反应。在反应开始0、1、5、10、15、20、30、60min取样，加入适当终止物终止反应。
Figure PCTCN2021093786-appb-000096
样品处理(n＝3)：各加合适样品，涡旋后高速离心，取上清液，采用HPLC-MS/MS对底物进行检测。把0min时间点峰面积作为100％。其他时间点的峰面积转换为百分剩余 量，各时间点的百分剩余量的自然对数对孵育时间作图，直线回归求算出斜率(-k)，然后按固有清除率(Clint)＝(k*孵育液体积)/肝微粒体质量，计算出Clint(uL/min/mg)及化合物半衰期(T1/2，min)。结果见表3。
表3.人和小鼠肝微粒体代谢稳定性实验结果
Figure PCTCN2021093786-appb-000097
上述实验结果表明本发明的化合物具有很好的代谢稳定性。
活性实施例4：化合物的FASSIF溶解性测定
根据本领域技术人员熟知的、本领域常规的溶解度测定标准方法，例如(Kerns,Edward H.and Di Li(2008).Drug-like Properties:Concepts,Structure Design and Methods:from ADME to Toxicity Optimization.San Diego:Academic Press)中所述的方法，以FaSSIF(pH6.5)(模拟人餐前饥饿状态下的小肠肠液)为试验系统，如下考察本发明化合物的溶解性质。
将每种化合物的样品粉末分别在容量瓶中称重，加入450μL pH值6.5FaSSIF溶液得到过饱和混悬液，对样品进行至少2分钟的涡流，在振动筛上以800转/分的速度将容量瓶摇24小时。然后4000rpm离心20分钟。将压缩后的滤液加入高效液相色谱系统中，用标准曲线法计算其浓度，结果见表4。
快速模拟肠液FaSSIF的组成是：0.056％(w/v)卵磷脂，0.161％(w/v)牛磺胆酸钠，0.39％(w/v)磷酸钾，0.77％(w/v)氯化钾，去离子化H 2O,pH 6.5。
表4.化合物在FaSSIF中的溶解度
实施例 FaSSIF pH＝6.5(μg/ml) 实施例 FaSSIF pH＝6.5(μg/ml)
2 82.30 12 33.90
4 137.00 16 296.36
5 23.10 25 73.20
8 32.50 GSK993 5.08
上述实验结果表明，与对照相比，本发明的实施例化合物出乎意料地具有显著更高的溶解性，从而具有更好的成药性。
活性实施例5：CYP450酶抑制活性测定
根据本领域常规的细胞色素P450酶系研究的标准方法，例如(Lin,Tong等人，In Vitro Assessment of Cytochrome P450 Inhibition:Strategies for Increasing LC/MS-Based Assay Throughput Using a One-Point IC50 Method and Multiplexing High-Performance Liquid Chromatography；J.Pharm.Sci.2007,96(9),2485.)中所述的方法，类似地如下考察本发明化合物对细胞色素P450酶系的抑制作用。
用甲醇制备如下底物储备溶液并用PB(磷酸盐缓冲溶液100mM)进一步配制如下浓度的底物溶液：
Figure PCTCN2021093786-appb-000098
用DMSO制备浓度各为3mM的以下标准抑制剂储备溶液：α－萘黄酮(α-Naphthoflavone)、磺胺苯吡唑(Sulfaphenazole)、(+)-N-3-苄基尼凡诺((+)-N-3-benzylnirvanol)、奎尼丁(Quinidine)和酮康唑(Ketoconazole)，并相应地进一步用甲醇配制浓度为300μM的各溶液作为阳性对照溶液，使得测试终浓度为3μM。
用PB(100mM)配制0.253mg/mL人肝微粒体溶液(Cat No.452117/Lot No.38293，Corning，终浓度:0.2mg/ml)；并用33mM MgCl 2配制10mM辅因子溶液(NADPH,Cat No.00616/Lot No.002162-050403,Chem-impex international,终浓度：1mM)。
用DMSO配制10mM的各测试化合物储备溶液，并进一步用1:1DMSO:MeOH配制浓度分别为5、1.50、0.500、0.150、0.050、0.015、0.005mM的工作溶液，使得测试终浓度为50、15、5、1.5、0.5、0.15、0.05μM。
将20μL底物溶液加至培养板的各孔，将20μL PB加至空白孔。加入2μL测试化合物和阳性对照工作溶液到反应孔中，加2μL溶剂到无抑制剂孔和空白孔中。添加158μL人肝微粒体工作液到各孵育孔中，37℃水浴预热板约10分钟；添加20μL NADPH溶液到各孵育孔中，将所有CYP在37℃水浴中混合孵育10分钟。反应60分钟后，通过添加400μL冷的终止液(200ng/mL的甲苯磺丁脲和柳胺苄心定(Labetalol)的乙腈溶液)终止反应。将样品在4000rpm离心20分钟以沉淀蛋白，转移200μL上层清液至100μL高效液相色谱水并摇动10分钟，用于LC/MS/MS分析，检测各探针底物的代谢物的生成量。质谱检测条件为电喷雾离子化(ESI)源，选择性反应监测(MRM)扫描方式，色谱分离条件为Thermo GLOD,C8色谱柱(2.1mm×50mm,1.9μg)，流动相0.1％甲酸乙腈-0.1％甲酸水溶液梯度洗脱，流速0.5m L·min-1,运用Graph pad Prism 5软件计算半抑制浓度(IC 50)。
表5.化合物对CYP450酶抑制活性结果
Figure PCTCN2021093786-appb-000099
上述实验结果表明，与对照相比，本发明的实施例化合物出乎意料地具有显著更低的CYP450抑制活性(尤其对于CYP2C9、CYP2C19、CYP2D6而言)，表明其具有减少药物相互作用的风险，从而具有更低的毒性和更高的安全性。
活性实施例6：化合物在小鼠中PK测定
每种化合物的PK测定方法如下：6只C57BL/6小鼠(来源上海灵畅生物科技有限公司)分为两组，每组3只。其中一组通过静脉(IV)给药，剂量为1mg/kg，溶媒为5％DMSO/95％(20％Captisol)；一组通过口服(PO)灌胃给药，剂量为5mg/kg，溶媒为0.5％CMC-Na/0.5％Tween 80。每一组在给药后0、0.083、0.25、0.5、1、2、4、6、8、24h分别通过小腿隐静脉采血。将约40μL血液收集到含EDTA-K2的抗凝管中。在收集完成后迅速将采血管倒置至少5次，以确保混合均匀，然后放置在冰上。采集到的各时间点血液在4℃，8000rpm离心5分钟以获得血浆。另取1.5mL离心管标记好化合物名称，动物编号，时间点，将血浆转移至该管中。血 浆保存在-80℃直至分析。
采用UPLC-MS/MS方法测定血浆中化合物浓度，用Phoenix WinNolin 6.4药代动力学软件对所得数据进行药代动力学参数计算。
具体实验结果如下，结果表明化合物药代吸收较好，具有药代动力学优势。
表6.实施例化合物体内PK结果
Figure PCTCN2021093786-appb-000100
以上实验中使用对照化合物的结构如下：
Figure PCTCN2021093786-appb-000101
GSK993。
本领域技术人员将了解，上文描述本质上为示例性及说明性的，且欲说明本发明及其优选实施方案。通过常规实验，技术人员将了解可作出明显修正及变化而不悖离本发明的精神。在随附申请专利范围内的所有此类修正欲包括于其中。因此，本发明意欲并非由上述描述而是由以下权利要求范围及其等效物定义。
本说明书中所引用的所有公开出版物以引用方式并入本文中。

Claims (17)

  1. 式(I)的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，
    Figure PCTCN2021093786-appb-100001
    其中：
    X选自CH或N；
    R 1选自氢、卤素、氰基、硝基、C 1-C 6烷基、-O-C 1-C 6烷基、S-C 1-C 6烷基、-NH-C 1-C 6烷基、-N-(C 1-C 6烷基) 2、C 1-C 6烷基-O-C 1-C 6烷基、-C 1-C 6烷基-S-C 1-C 6烷基、C 1-C 6烷基-NH-C 1-C 6烷基或C 1-C 6烷基-N(C 1-C 6烷基) 2，其中所述C 1-C 6烷基任选被卤素或氰基取代；
    R 2选自氢、卤素、氰基、硝基或C 1-C 6烷基，其中所述C 1-C 6烷基任选被独立地选自以下的取代基取代：-R a或-OH，其中R a为任选被卤素取代的C 1-C 6烷基；
    R 3、R 4各自独立地选自卤素、氰基、硝基、R b、-OR b、-SR b或-NR bR b，其中R b为H或任选取代的C 1-C 6烷基，所述取代基各自独立地选自氢、卤素、氰基、硝基、-OH、-SH、-NH 2、-O-C 1-C 6烷基、-S-C 1-C 6烷基、-NH-C 1-C 6烷基或-N(-C 1-C 6烷基) 2；
    R 5选自-OR c、-SR c、-NR cR c、-NHCOR c、-NHSO 2R c、-COOR c、-CONR cR c或-SO 2NR cR c，其中R c在每次出现时独立地选自氢、任选被卤素取代的C 1-C 6烷基或任选被卤素取代的C 3-C 7环烷基，或连接在同一个N原子上的两个R c可以与它们所连接的N原子一起形成4-7元含氮杂环烷基；
    R 6选自C 1-C 6烷基、C 3-C 7环烷基、4-7元杂环烷基或任选被C 1-C 6烷基、C 3-C 7环烷基或4-7元杂环烷基取代的-NH 2，其中所述C 1-C 6烷基、C 3-C 7环烷基或4-7元杂环烷基任选被各自独立地选自以下的取代基取代：氢、卤素、氰基、硝基、-R a、-OR a、-SR a或-NR aR a或任选被卤素取代的C 3-C 7环烷基，R a在每次出现时独立地选自H或任选被卤素取代的C 1-C 6烷基，其中连接在氨基N原子上的两个基团可以与它们连接的N一起形成4-7元环；且
    n选自0、1或2。
  2. 根据权利要求1的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中X为CH。
  3. 根据权利要求1或2的化合物、其立体异构体、互变异构体、稳定的同位素变体、药 学上可接受的盐或溶剂合物，其中R 1选自-O-C 1-C 6烷基，其中的C 1-C 6烷基被卤素取代，优选-OCF 3、-OCHF 2、-OCH 2CF 3、-OCH 2CH 2CF 3、-CH(CF 3) 2。
  4. 根据权利要求1或2的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R 1为氢，且R 2选自卤素和
    Figure PCTCN2021093786-appb-100002
  5. 根据权利要求1至4任一项的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R 3、R 4各自独立地选自H、卤素或任选被卤素取代的C 1-C 6烷基。
  6. 根据权利要求1至5任一项的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R 5为-OR c，其中R c选自氢、任选被卤素取代的C 1-C 6烷基。
  7. 根据权利要求1至5任一项的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R 5选自-NR cR c或-NHCOR c，其中R c在每次出现时独立地选自氢或任选被卤素取代的C 1-C 6烷基，或连接在同一个N原子上的两个R c可以与它们所连接的N原子一起形成4-7元含氮杂环烷基。
  8. 根据权利要求1至5任一项的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R 5选自-COOR c或-CONR cR c，其中R c在每次出现时独立地选自H或任选被卤素取代的C 1-C 6烷基。
  9. 根据权利要求1至8任一项的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R 6选自C 1-C 6烷基，优选C 1-C 3烷基，任选被C 3-C 7环烷基取代。
  10. 根据权利要求1至8任一项的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R 6选自任选被取代的-NH 2，所述取代基选自任选被卤素取代的C 1-C 6烷基。
  11. 化合物，选自
    Figure PCTCN2021093786-appb-100003
    Figure PCTCN2021093786-appb-100004
    其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物。
  12. 根据权利要求1至11任一项的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，用作药物、尤其是用作RORγt抑制剂，或用于治疗、尤其是用于治疗或预防与RORγt有关的疾病。
  13. 药物组合物，包含根据权利要求1至11任一项的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物和可药用赋形剂。
  14. 用于在哺乳动物、特别是人中预防或治疗与RORγt有关的疾病的方法，该方法包括施用有效量的根据权利要求1至11任一项的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物或根据权利要求13的药物组合物。
  15. 根据权利要求1至11任一项的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物或根据权利要求13的药物组合物用于预防或治疗与RORγt有关的疾病的用途。
  16. 根据权利要求1至11任一项的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物或根据权利要求13的药物组合物在制备用于预防或治疗与RORγt有关的疾病的药物中的用途。
  17. 根据权利要求12的化合物、根据权利要求14的方法或根据权利要求15或16的用途，其中的与RORγt有关的疾病选自银屑病、类风湿性关节炎、银屑病性关节炎、强直性脊柱炎、多发性硬化、系统性红斑狼疮、移植物抗宿主疾病、炎症性肠病、克隆氏病、溃疡性结肠炎、慢性阻塞性肺病、哮喘、血管球性肾炎、狼疮性肾炎、心肌炎、甲状腺炎、干眼症、葡萄膜炎、白塞病、过敏性皮肤炎、粉刺、硬皮病、支气管炎、皮肌过敏性鼻炎、坏死性小肠结肠炎、肝纤维化、非酒精性脂肪性肝炎(NASH)、新冠病毒肺炎、胰岛素依赖性I型糖尿病、三阴乳腺癌和前列腺癌等。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023232870A1 (en) 2022-05-31 2023-12-07 Immunic Ag Rorg/rorgt modulators for the treatment of virus infections like covid-19

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013029338A1 (en) * 2011-09-01 2013-03-07 Glaxo Group Limited Novel compounds
WO2017010399A1 (ja) * 2015-07-10 2017-01-19 塩野義製薬株式会社 ＲＯＲγｔ阻害作用を有する化合物およびそれらを含有する医薬組成物
WO2017157332A1 (zh) * 2016-03-18 2017-09-21 江苏恒瑞医药股份有限公司 芳香酰胺类衍生物、其制备方法及其在医药上的应用
CN108430973A (zh) * 2015-06-05 2018-08-21 领先制药控股公司 RORγ调节剂
CN108863850A (zh) * 2017-02-09 2018-11-23 复旦大学 联芳基类化合物及其制备方法和用途
WO2019213470A1 (en) * 2018-05-03 2019-11-07 Eternity Bioscience Inc. Benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (rorϒ) and pharmaceutical uses thereof
WO2021063362A1 (zh) * 2019-09-30 2021-04-08 上海辉启生物医药科技有限公司 磺基取代的联芳基类化合物或其盐及其制备方法和用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013171729A2 (en) * 2013-01-08 2013-11-21 Glenmark Pharmaceuticals S.A. Aryl and heteroaryl amide compounds as rorgamat modulator

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013029338A1 (en) * 2011-09-01 2013-03-07 Glaxo Group Limited Novel compounds
CN108430973A (zh) * 2015-06-05 2018-08-21 领先制药控股公司 RORγ调节剂
WO2017010399A1 (ja) * 2015-07-10 2017-01-19 塩野義製薬株式会社 ＲＯＲγｔ阻害作用を有する化合物およびそれらを含有する医薬組成物
WO2017157332A1 (zh) * 2016-03-18 2017-09-21 江苏恒瑞医药股份有限公司 芳香酰胺类衍生物、其制备方法及其在医药上的应用
CN108863850A (zh) * 2017-02-09 2018-11-23 复旦大学 联芳基类化合物及其制备方法和用途
WO2019213470A1 (en) * 2018-05-03 2019-11-07 Eternity Bioscience Inc. Benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (rorϒ) and pharmaceutical uses thereof
WO2021063362A1 (zh) * 2019-09-30 2021-04-08 上海辉启生物医药科技有限公司 磺基取代的联芳基类化合物或其盐及其制备方法和用途

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023232870A1 (en) 2022-05-31 2023-12-07 Immunic Ag Rorg/rorgt modulators for the treatment of virus infections like covid-19

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