WO2023274396A1 - 苯并氮杂环类化合物及其在药物中的应用 - Google Patents

苯并氮杂环类化合物及其在药物中的应用 Download PDF

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WO2023274396A1
WO2023274396A1 PCT/CN2022/103288 CN2022103288W WO2023274396A1 WO 2023274396 A1 WO2023274396 A1 WO 2023274396A1 CN 2022103288 W CN2022103288 W CN 2022103288W WO 2023274396 A1 WO2023274396 A1 WO 2023274396A1
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och
alkoxy
alkyl
alkylene
independently
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French (fr)
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刘兵
张英俊
何为
马超群
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广东东阳光药业有限公司
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Definitions

  • the invention belongs to the field of medicine, and discloses a class of benzazepine heterocyclic compounds with ROR ⁇ t activity, a preparation method thereof, a pharmaceutical composition containing the compound and its application in medicine.
  • RORs Retinoic acid receptor-related orphan receptors
  • RORs are members of the steroid hormone nuclear receptor superfamily. Its family includes ROR ⁇ , ROR ⁇ and ROR ⁇ , and RORs include 4 main regions, which are shared by most nuclear receptors, N-terminal A/B domain, DNA-binding domain, hinge domain and ligand-binding structure area. Each ROR gene produces its own isoform, differing only in its N-terminal A/B domains.
  • ROR ⁇ has two subtypes --- ROR ⁇ l and ROR ⁇ t.
  • ROR ⁇ 1 is expressed in various tissues, such as thymus, muscle, and kidney, while ROR ⁇ t is only expressed in some immune cells (such as Th17 cells), and acts as a transcription factor for IL-17A and IL-17F, and a master regulator of Th17 cell differentiation factor.
  • Thl7 cells are a subset of T helper cells that preferentially produce the proinflammatory cytokines IL-17A, IL-17F, IL-21 and IL-22.
  • Th17 cells and their effector molecules are related to the pathogenesis of several autoimmunities, and studies have also confirmed that Th17 cells are associated with multiple sclerosis, rheumatoid Arthritis, psoriasis, asthma, autoimmune diseases, and graft-versus-host disease are related to the pathogenesis of several autoimmune diseases and inflammatory diseases (Jetten et al., Nucl. Recept. Signal, 2009, 7: e003; Manel et al., Nat. Immunol, 2008, 9, 641-649), and it is also related to the occurrence of inflammation-related tumors.
  • Th17 cells are activated during the disease process and are responsible for recruiting other inflammatory cell types, such as neutrophils Granulocytes to mediate pathology of target tissues (Korn et al., Annu. Rev. Immunol., 2009, 27:485-517). Therefore, drugs with ROR ⁇ t regulation are expected to show therapeutic effects on various immune diseases by regulating the differentiation and activation of Th17 cells.
  • ROR ⁇ t agonists can promote the differentiation of Th17 cells and enhance the levels of pro-inflammatory cytokines, thereby increasing the cytotoxicity of lymphocytes. At the same time, ROR ⁇ t agonists suppress the production of regulatory T cells, which suppress the immune response, so the agonist can tip the balance of the immune response toward activation. ROR ⁇ t agonists can also promote the expression of a series of co-stimulatory molecules (Co-Stimulatory Molecule) such as CD226, CD27 and 4-1BB (CD137), and inhibit the co-inhibitory molecules such as PD-1, TIGIT, TIM3, CD73 and LAG3 ( Co-Inhibitory Molecule) expression, thereby promoting T cell activation. Studies have shown that in a variety of syngeneic tumor models (Syngeneic Tumor Models), ROR ⁇ t agonists can inhibit tumor growth and prolong the survival time of animals through immune responses.
  • Co-Stimulatory Molecule such as CD226, CD27 and 4-1BB
  • Lycera was the first to report the development of ROR ⁇ t small-molecule agonists.
  • 2017. Lycera announced the initiation of a clinical phase 1/2a trial to test the ROR ⁇ t agonist LYC-55716 developed by it in the treatment of patients with advanced, recurrent or refractory solid tumors. effect.
  • ROR ⁇ t agonists have received attention in anti-tumor, and it is very possible that the IL-17 family will provide good targets for tumor treatment in the future; therefore, ROR ⁇ t is considered to be the first choice for the development of anti-tumor, anti-inflammatory and autoimmune disease drugs
  • the new target will be used as a new way for the treatment of cancer and autoimmune inflammatory diseases.
  • the technical problem solved by the present invention is to provide a class of benzazeterocyclic compounds that can be used as ROR ⁇ t agonists, which are compounds shown in formula (I) or (I-A), or formula (I) or (I-A) Stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds shown, as well as pharmaceutical compositions containing such compounds and their use in application in medicine.
  • the present invention provides a compound, which is a structure shown in formula (I-A) or a stereoisomer, tautomer, nitrogen oxide, solvent compound, metabolite, pharmaceutically acceptable salt or its prodrug,
  • Q 1 and Q 2 are each independently CH or N;
  • Ring A1 is a C 6-10 arylene group, a 5-10 membered heteroarylene group, a C 3-12 carbocyclylene group or a 3-12 membered heterocyclylene group;
  • Z is CR 4 or N
  • Ring A 2 is a 5-12 membered spirocyclylene, a 5-12 member bridged cyclylene, a cyclohexylene or a cycloheptylene;
  • R 5 and R 5a are each independently H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl , C 6-10 aryl or 5-10 membered heteroaryl;
  • n, q are each independently 1, 2, 3 or 4.
  • the present invention provides a compound, which is a structure shown in formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, Metabolites, pharmaceutically acceptable salts or prodrugs thereof,
  • Ring A1 is a C 6-10 arylene group, a 5-10 membered heteroarylene group, a C 3-12 carbocyclylene group or a 3-12 membered heterocyclylene group;
  • Z is CR 4 or N
  • Ring A 2 is a 5-12 membered spirocyclylene, a 5-12 member bridged cyclylene, a cyclohexylene or a cycloheptylene;
  • R 5 and R 5a are each independently H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl , C 6-10 aryl or 5-10 membered heteroaryl;
  • n, q are each independently 1, 2, 3 or 4.
  • the compound of the present invention has the structure shown in formula (II), (III), (IV) or (V), or its stereoisomer, tautomer, nitrogen oxide , solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,
  • ring A 1 , ring A 2 , X, Y, Z, L, R 1 , R 2 , R 3 , m, n, q, R 6 , R 6a and “*” each have definition.
  • Ring A is phenylene, naphthylene, pyridylene, pyridazinylene, pyrimidinylene, imidazolyl, pyrazolylene, pyrrolylene, indolylene, Quinolinyl, pyranylene, furylylene, cyclopentylene, cyclohexylene, piperidinylene, morpholinylene, pyrrolidinylene or piperazinylene.
  • Ring A is of the following substructure:
  • Z1 is CH or N ;
  • Z 3 and Z 4 are each independently a bond, -O-, -NH-, -OCH 2 -, -CH 2 O-, -CH 2- , or -(CH 2 ) 2 -;
  • t and t1 are each independently 0 or 1;
  • Ring A is of the following substructure:
  • each of R 4 and R 5 has the definition as described in the present invention.
  • R 5 and R 5a are each independently H, D, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl , C 6-10 aryl or 5-10 membered heteroaryl;
  • each of R 5 and R 5a is independently H, D, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CF 3 , -CH 2 Cl, -CHCl 2 , -CH 2 CHCl 2 , -CH 2 OH, -CH(OH)CH 3 , -CH 2 CH 2 OH, -CH 2 CH(OH)CH 3 , - CH 2 C(CH 3 )(OH)CH 3 , cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, phenyl, pyridyl or pyrimidinyl;
  • R 01 and R 02 are each independently D, F, Cl, Br, I, OH, CN, NO 2 , -NR 4 R 5 , C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy C 1-4 alkyl, C 1-4 alkoxy, C 1-4 deuterated alkoxy C 1-4 hydroxyalkoxy, C 1-4 alkoxy C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkoxy , 3-7 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group.
  • the present invention relates to a pharmaceutical composition, which comprises a compound described in formula (I-A), (I), (II), (III), (IV) or (V) of the present invention, or Stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, optionally further comprising pharmaceutically acceptable carriers, adjuvants, vehicles or a combination of them.
  • the present invention relates to the use of the compound described in formula (I-A), (I), (II), (III), (IV) or (V) or its pharmaceutical composition in the preparation of medicine, wherein the medicine It is used for preventing, treating or alleviating diseases mediated by ROR ⁇ t in patients.
  • the diseases mediated by ROR ⁇ t according to the present invention include cancer, multiple sclerosis, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, asthma, autoimmune Immune disease, graft versus host disease, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, colitis, bacterial infection, fungal infection, chronic obstructive pulmonary disease, allergic rhinitis, allergic dermatitis, Crohn's disease Or Kawasaki disease.
  • the tumor or cancer described in the present invention is selected from non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, Pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, glioma, glioblastoma Hepatocellular carcinoma, hepatocellular carcinoma, papillary renal tumor, head and neck cancer, leukemia, lymphoma, myeloma and non-small cell lung cancer.
  • the present invention relates to methods for the preparation, isolation and purification of compounds described in formula (I-A), (I), (II), (III), (IV) or (V).
  • the articles “a”, “an” and “the” are intended to include “at least one” or “one or more” unless otherwise stated or clearly contradicted by context. Therefore, these articles used in the present invention refer to articles of one or more than one (ie at least one) object.
  • a component refers to one or more components, ie there may be more than one component contemplated to be employed or used in the practice of the described embodiment.
  • patient refers to a human (including adults and children) or other animals. In some embodiments, “patient” refers to a human.
  • Stereoisomers refer to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, etc. . Unless otherwise indicated, all stereoisomers or mixtures of stereoisomers of the formulas described herein are within the scope of the invention. In addition, unless otherwise indicated, the formulas of the compounds described herein optionally include enriched isotopes of one or more different atoms.
  • Chiral is a molecule that has the property of being nonsuperimposable to its mirror image; and "achiral” is a molecule that is superimposable to its mirror image.
  • Enantiomer refers to two non-superimposable isomers of a compound that are mirror images of each other.
  • Diastereoisomer refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.
  • optically active compounds Many organic compounds exist in optically active forms, ie they have the ability to rotate the plane of plane polarized light.
  • the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to its chiral center or centers.
  • the prefixes d and 1 or (+) and (-) are symbols used to designate rotation of plane polarized light by a compound, where (-) or 1 indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a specific stereoisomer is an enantiomer and a mixture of such isomers is called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration exist.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the present invention can be obtained as one of the possible isomers or as mixtures thereof, such as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms) ) form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have the cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereoisomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography method and/or fractional crystallization.
  • racemates of any resulting final products or intermediates can be resolved into the optical antipodes by known methods by methods familiar to those skilled in the art, e.g., by subjecting the obtained diastereomeric salts thereof to separate. Racemic products can also be separated by chiral chromatography, eg, high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers may be prepared by asymmetric synthesis, see for example Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-enol isomerization Amine isomerization.
  • Valence tautomers include interconversions by recombination of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • Another example of tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the substituents are independent of each other, that is, the one or more substituents can be different from each other, or can be The same; or "optionally forming a salt with a suitable acid” includes that the compound forms a salt with a suitable acid or does not form a salt with any acid, and can optionally be 1:1, or 1:1.5, or 1:2 , or 1:3, or 2:1, or 3:1 ratio into salt.
  • the compounds of the present invention can be independently and optionally substituted by one or more substituents, such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention a class of compounds.
  • substituents such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention a class of compounds.
  • substituents such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention a class of compounds.
  • substituents such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention a class of compounds.
  • Substituent 1 can be further independently optionally monosubstituted by substituent 2 or polysubstituted by identical or different substituents 2 where appropriate.
  • C 1-6 alkyl specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl .
  • linking substituents are described.
  • the Markush variables recited for that group are to be understood as linking groups.
  • the Markush group definition for that variable recites “alkyl” or “aryl,” it is understood that “alkyl” or “aryl” respectively represents the linking group.
  • alkyl used in the present invention includes a saturated linear or branched monovalent hydrocarbon group of 1-20 carbon atoms, wherein the alkyl group can be independently and optionally substituted by one or more substituents described in the present invention.
  • the alkyl group contains 1-10 carbon atoms; in other embodiments, the alkyl group contains 1-8 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms, other embodiments are that the alkyl group contains 1-4 carbon atoms; other embodiments are that the alkyl group contains 1-3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methylpropyl or isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu , -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-
  • alkylene denotes a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbon.
  • alkylene groups include, but are not limited to, -CH2- , -CH2CH2- , -CH ( CH3 ) CH2-, and the like.
  • alkenyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein at least one unsaturated site is a carbon-carbon sp double bond, wherein the alkenyl group can be any Optionally substituted with one or more substituents described herein, including the “cis” and “tans” positions, or the “E” and “Z” positions.
  • an alkenyl group contains 2-8 carbon atoms; in another embodiment, an alkenyl group contains 2-6 carbon atoms; in yet another embodiment, an alkenyl group contains 2 - 4 carbon atoms.
  • alkynyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, that is, a carbon-carbon sp triple bond, wherein the alkynyl group Can be optionally substituted with one or more substituents described herein.
  • alkynyl groups contain 2-8 carbon atoms; in other embodiments, alkynyl groups contain 2-6 carbon atoms; in yet other embodiments, alkynyl groups contain 2 - 4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH2C ⁇ CH), 1 -propynyl (-C ⁇ C- CH3 ), and the like .
  • haloalkyl denotes an alkyl group which may be substituted by one or more of the same or different halogen atoms. Wherein the alkyl group has the meaning as described in the present invention, examples of haloalkyl include, but are not limited to -CF 3 , -CHF 2 , -CH 2 F, -CHFCH 2 F, -CHFCHFCH 2 F, -CHCl 2 ,Wait.
  • hydroxyalkyl denotes an alkyl group substituted with one or more hydroxy groups.
  • hydroxyalkyl represents an alkyl group substituted with 1, 2, 3 or 4 hydroxy groups.
  • hydroxyalkyl represents an alkyl group substituted with one or two hydroxy groups.
  • hydroxyalkyl means C 1-6 hydroxyalkyl, that is, C 1-6 alkyl is substituted by one or more hydroxy groups, preferably, C 1-6 hydroxyalkyl means C 1-6 alkyl substituted by a hydroxyl group.
  • hydroxyalkyl represents C 1-4 hydroxyalkyl.
  • hydroxyalkyl represents C 1-3 hydroxyalkyl. Examples of hydroxyalkyl include, but are not limited to, -CH2OH , -CH(OH) CH3 , -CH2CH2OH , -CH2CH ( OH ) CH2CH2OH , and the like.
  • alkoxy denotes an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning described herein.
  • alkoxy groups contain 1-6 carbon atoms; in other embodiments, alkoxy groups contain 1-4 carbon atoms; in still other embodiments, alkoxy groups Groups contain 1-3 carbon atoms.
  • the alkoxy groups may be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), n-propoxy (n-PrO, n-propoxy oxy, 1-propoxy, -OCH 2 CH 2 CH 3 ), isopropoxy (-OCH(CH 3 ) 2 ), and the like.
  • hydroxyalkoxy denotes an alkoxy group substituted with one or more hydroxy groups, wherein the alkoxy group has the definition set forth herein.
  • hydroxyalkoxy groups contain 1-6 carbon atoms; in other embodiments, hydroxyalkoxy groups contain 1-4 carbon atoms; in still other embodiments, hydroxyalkoxy groups contain Oxy groups contain 1-3 carbon atoms.
  • Examples of hydroxyalkoxy groups include, but are not limited to, -OCH2CH2OH, -OCH2CH (OH) CH3 , -OCH2CH ( OH) CH2 ( OH), and the like.
  • alkoxyalkyl means an alkyl group substituted by an alkoxy group, wherein alkoxy group and alkyl group have the meanings as described herein.
  • alkoxyalkyl represents C 1-6 alkoxy C 1-6 alkyl; in other embodiments, alkoxyalkyl represents C 1-4 alkoxy C 1-4 Alkyl; In other embodiments, alkoxyalkyl represents C 1-4 alkoxy C 1-3 alkyl; In some embodiments, alkoxyalkyl represents C 1-3 alkoxy C 1-3 alkyl.
  • alkoxyalkyl examples include, but are not limited to, -CH2OCH3 , -CH2CH2OCH3 , -CH2OCH2CH3 , -CH2OCH ( CH3 ) CH3 , and the like.
  • alkoxyalkoxy refers to an alkoxy group substituted by an alkoxy group, wherein alkoxy group has the definition as stated in the present invention.
  • alkoxyalkoxy represents C 1-6 alkoxy C 1-6 alkoxy; in other embodiments, alkoxyalkyl represents C 1-4 alkoxy C 1 -4 alkoxy; In other embodiments, alkoxyalkyl represents C 1-4 alkoxy C 1-3 alkoxy; In some embodiments, alkoxyalkyl represents C 1-3 Alkoxy C 1-3 alkoxy.
  • alkoxyalkoxy examples include, but are not limited to, -OCH2OCH3 , -OCH2CH2OCH3 , -OCH2OCH2CH3 , -OCH2OCH ( CH3 ) CH3 , and the like .
  • halogen means F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).
  • haloalkoxy means an alkoxy group substituted with one or more halogen atoms, wherein the alkoxy group has the definition described herein.
  • haloalkoxy groups contain 1-6 carbon atoms; in other embodiments, haloalkoxy groups contain 1-4 carbon atoms; in still other embodiments, haloalkoxy groups Groups contain 1-3 carbon atoms. Examples of haloalkoxy groups include, but are not limited to, -OCF3 , -OCCl3 , -OCHF2 , -OCHCl2 , or -OCH2Cl .
  • the haloalkoxy group may be optionally substituted with one or more substituents described herein.
  • cycloalkyl refers to a monovalent or polyvalent non-aromatic saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring carbon atoms, wherein the bicyclic, tricyclic or tetracyclic ring system is fused Or bridged or spliced to form a ring.
  • a cycloalkyl group contains 3-12 ring carbon atoms; in other embodiments, a cycloalkyl group contains 3-10 ring carbon atoms; in other embodiments, a cycloalkyl group contains 3- 8 ring carbon atoms; in other embodiments, cycloalkyl contains 3-7 ring carbon atoms; in still other embodiments, cycloalkyl contains 3-6 ring carbon atoms.
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the cycloalkyl group may be optionally substituted with one or more substituents described herein.
  • cycloalkoxy means that a cycloalkyl group is attached to the rest of the molecule through an oxygen atom, wherein the cycloalkyl group has the meaning described herein.
  • cycloalkoxy groups contain 3-12 carbon atoms; in other embodiments, cycloalkoxy groups contain 3-7 carbon atoms; Oxy groups contain 3-6 carbon atoms.
  • Examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • the cycloalkoxy group may be optionally substituted with one or more substituents described herein.
  • aromatic ring means monocyclic, bicyclic, and tricyclic carbocyclic ring systems, wherein at least one ring system is aromatic, wherein each ring system contains 6-10 carbon atoms, such as aromatic rings may include benzene, naphthalene and anthracene.
  • aromatic ring is represented as "aryl”; the term “C 6-10 aryl” means that the number of carbon atoms in the aryl group is 6-10 , and the aryl group is specifically as defined above.
  • aromatic ring When an aromatic ring is used as a divalent linking group in the Markush general formula, the "aromatic ring” represents an "arylene group".
  • arylene groups include, but are not limited to: phenylene, naphthylene, etc.;
  • C 6-10 arylene group means that the number of carbon atoms in the arylene group is 6-10, and the arylene group has the above definition.
  • Aryl and arylene groups may be substituted with one or more substituents described herein.
  • heteromatic ring means monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic, And at least one ring system contains one or more heteroatoms independently selected from O, S and N, wherein each ring system contains a ring composed of 5-7 atoms.
  • heteroaryl means that when a heteroaryl ring is used as a monovalent linking group in the Markush general formula, the "heteroaryl ring” is represented as a “heteroaryl".
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • the 5-10 atom heteroaryl or 5-10 membered heteroaryl comprises 1, 2, 3 or 4 ring heteroatoms independently selected from O, S and N.
  • heteroaryl refers to a heteroaryl ring group or a 5-6 membered heteroaryl group containing 5-6 ring atoms, which contains 1, 2, 3 or 4 independently selected from O, S and N ring heteroatoms.
  • heteroaryl refers to a heteroaryl ring group containing 5 ring atoms or a 5-membered heteroaryl group comprising 1, 2, 3 or 4 rings independently selected from O, S and N heteroatoms.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl or 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • heteroaryl When heteroaryl is the linking group, then heteroaryl means linked heteroarylene.
  • heteroarylene means a divalent heteroaryl ring group formed by removing two hydrogen atoms from a ring atom of a heteroaryl ring. Examples of heteroarylene include, but are not limited to: pyridinylene, pyrazolylene , pyrimidinyl, etc.
  • the heteroaryl or heteroarylene may be independently optionally substituted with one or more substituents described herein.
  • Carbocycle means a saturated or partially unsaturated non-aromatic carbocyclic ring system in which the ring atoms are carbon atoms, including monocarbocycle, bridged carbocycle and spirocarbocycle, wherein monocarbocycle, bridged carbocycle and spirocarbocycle Carbocycle has the definition as described herein.
  • a carbocycle represents a C 3-12 carbocycle; in other embodiments, a carbocycle represents a C 3-10 membered carbocycle; in other embodiments, a carbocycle represents a C 3-7 carbocycle ; In other embodiments, the carbocycle represents a C 3-6 membered carbocycle.
  • the "carbocycle” represents a "carbocyclyl”; when a carbocycle is used as a divalent linking group in the Markush formula, the ""Carbocycle” means "carbocyclylene".
  • carbocyclylene examples include, but are not limited to: cyclopentylene, cyclohexylene, spiro[2.5]octylene, bicyclo[2.2.1]heptylene ,Wait.
  • the carbocyclyl or carbocyclylene may be optionally substituted with one or more substituents described herein.
  • heterocycle means a saturated or partially unsaturated non-aromatic heterocyclic ring system, and the system contains at least one ring carbon atom, containing 1, 2, 3 or 4 selected from O, N, S, P ring heteroatoms.
  • the heterocyclic ring may be a monocyclic or polycyclic ring system; specifically, the polycyclic ring system may be a spiro heterocyclic ring or a bridged heterocyclic ring.
  • spiroheterocycle and bridged heterocycle have the definitions as described in the present invention.
  • the heterocycle represents a 3-12 membered heterocycle; in other embodiments, the heterocycle represents a 3-7 membered heterocycle; in other embodiments, the heterocycle represents a 3-6 membered heterocycle.
  • heterocyclic ring When a heterocyclic ring is used as a monovalent linking group in the Markush general formula, the "heterocyclic ring” represents a “heterocyclic group”; when a carbocyclic ring is used as a divalent linking group in the Markush general formula, the “"Heterocycle” means “heterocyclylene”.
  • heterocyclylene include, but are not limited to: piperidinylene, morpholinylene, pyrrolidinylene, piperazinylene, 2-oxa-6- Azaspiro[3.3]heptanyl or 3-azabicyclo[3.1.1]heptanyl, etc.
  • the heterocyclyl or heterocyclylene may be substituted by one or more substituents described in the present invention.
  • heterocyclic group may be a carbon atom group or a heteroatom group.
  • heterocyclic groups include, but are not limited to, oxiranyl, pyrrolidinyl, tetrahydrofuryl (such as tetrahydrofuran-3-yl, etc.), dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl , dihydropyranyl, tetrahydrothiopyranyl, piperidinyl (such as N-piperidinyl, 2-piperidinyl, 3-piperidinyl or 4-piperidinyl, etc.), thioxanyl, nitrogen Hetetyl, oxetanyl, thietanyl, homopiperidinyl, azepanyl, oxetanyl, thiepanyl, morpholinyl (such as N-morpholinyl , 2-morpholinyl, 3-morpholinyl,
  • oxidized sulfur atoms in heterocyclic groups include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like.
  • spirocycle means a non-aromatic saturated or partially unsaturated carbocyclic or heterocyclic ring system formed by two rings sharing one carbon atom, that is, a spirocyclic ring includes a spirocarbocyclic ring and a spiroheterocyclic ring.
  • the nitrogen atom in the spiro ring can be optionally oxidized to an N-oxygen compound.
  • the spiro ring contains 5-12 ring atoms, which means a 5-12 membered spiro ring; in other embodiments, the spiro ring contains 7-12 ring carbon atoms, which means a 7-12 membered spiro ring ring.
  • spirocarbocycles include, but are not limited to: spiro[3.3]heptane, spiro[2.5]octane, spiro[4.4]nonane, spiro[3.4]octane, spiro[4.5]decane, etc.; Examples include, but are not limited to: 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2- Thia-6-azaspiro[3.3]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, 4,7-diazepine Heteraspiro[2.5]octane, 2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane, 2,7-diazaspiro[3.5]de
  • the "spiro ring” represents a “spirocyclyl”; when the spiro ring is used as a divalent linking group in the Markush general formula, the ""Spiro” stands for "spirocyclylene". Examples of spirocyclylenes include, but are not limited to: Wait.
  • bridged ring means a non-aromatic saturated or partially unsaturated bicyclic or polycyclic carbocyclic or heterocyclic ring system sharing two or more ring atoms, that is, a bridged ring includes a bridged carbocycle and a bridged heterocycle.
  • the bridging ring is a bridging carbocyclic ring
  • the bridging ring is In the case of a bridged heterocycle, the ring atoms constituting the bridged ring system contain ring carbon atoms and contain 1, 2, 3 or 4 ring heteroatoms selected from O, N, S, and P, and the -CH 2 - group in the bridged heterocycle
  • the nitrogen atom can be optionally oxidized to N-oxygen compounds.
  • a bridged ring contains 5-12 ring atoms, which means a 5-12 membered bridged ring; in other embodiments, a bridged carbocycle contains 6-12 ring carbon atoms, which means a 6-12 membered ring. Bridged carbocycles; in other embodiments, bridged carbocycles contain 6-10 ring carbon atoms, meaning 6-10 membered bridged carbocycles.
  • bridged carbocycles include, but are not limited to: bicyclo[2.2.1]heptane, 3-azabicyclo[3.1.1]heptane, bicyclo[1.1.1]pentane, 2-azaadamantane, di Cyclo[2.2.2]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[2.2.0]hexane, bicyclo[3.3.0]octane, octane Hydropyrrolo[3,4-c]pyrrole, octahydrocyclopenta[c]pyrrole, octahydro-1H-indene, and the like.
  • bridged ring When the bridged ring is used as a monovalent linking group in the Markush general formula, the "bridged ring” represents a “bridged ring group”; when the bridged ring is used as a divalent linking group in the Markush general formula, the “bridged ring”"Bridgedring” stands for "subbridged ring group”.
  • bridging cyclic groups include, but are not limited to: Wait.
  • j-k ring atoms or “j-k members” are used interchangeably here, indicating that the cyclic group is composed of j-k ring atoms, and the ring atoms include carbon atoms and/or O, N, S, P and other heteroatoms.
  • the j and k are each independently any non-zero natural number, and k>j; the "j-k” includes j, k and any natural number between them.
  • 3-8 atoms or 3-8 members means that the cyclic group consists of 3-8 (ie, 3, 4, 5, 6, 7 or 8), 3-6 (ie, 3, 4, 5 or 6), 5-10 (i.e., 5, 6, 7, 8, 9 or 10) or 5-6 (i.e., 5 or 6) ring atoms consisting of carbon atoms and/or O , N, S, P and other heteroatoms.
  • heteroaryl consisting of 5-10 ring atoms or “5-10 membered heteroaryl” means that it includes heteroaryl consisting of 5, 6, 7, 8, 9 or 10 ring atoms group, wherein 5, 6, 7, 8, 9 or 10 represent the number of ring atoms, for example, pyridyl is a heteroaryl group or a 6-membered heteroaryl group composed of 6 ring atoms.
  • heteroatom refers to O, S, N, P, and Si, including forms in any oxidation state of N, S, and P; forms of primary, secondary, and tertiary amines, and quaternary ammonium salts; or Hydrogen-substituted forms, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR' (like N-substituted pyrrolidinyl NR', R' is the substituent described in the present invention).
  • the ring system formed by drawing a bond between a substituent and a ring means that any substitutable position of the substituent on the ring can be substituted.
  • formula (a) represents that y substituents R can be substituted at any possible substituted positions on the pyridine ring.
  • y is greater than 1, each R can be independently selected from the same or different substituent groups.
  • a linker attached to a ring to form a ring system means that the linker can be attached to the rest of the molecule at any attachable position on the ring system.
  • terminal A is fixedly connected to U 1
  • terminal A' can be connected to any possible position on U 2 -U 7 .
  • either the E end or the E' end can be connected to the rest of the molecule, that is, the connection of the two ends can be mutually Change.
  • the F terminal in formula d can only be connected to the end marked with "*" in the molecule, and the F' end can only be connected to the end not marked with "*” in the molecule, That is, the connection methods at both ends are not interchangeable.
  • pharmaceutically acceptable means that it is physiologically tolerated and generally does not produce allergic or inappropriate reactions, such as gastrointestinal upset, dizziness, etc., when administered to humans.
  • pharmaceutically acceptable means approved by a federal regulatory agency or a national government or listed in the US Pharmacopoeia or other generally recognized pharmacopeia for use in animals, especially humans.
  • carrier refers to a diluent, adjuvant, excipient or base with which the compound is administered. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, MeOH, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol.
  • esters in the present invention means that the compound represented by the formula (I-A), (I), (II), (III), (IV) or (V) containing a hydroxyl group can form an ester that can be hydrolyzed in vivo.
  • esters are, for example, pharmaceutically acceptable esters which hydrolyze in the human or animal body to yield the parent alcohol.
  • the groups of in vivo hydrolyzable esters of compounds represented by formula (I-A), (I), (II), (III), (IV) or (V) containing hydroxyl groups include, but are not limited to, phosphoric acid, acetoxy Methoxy, 2,2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, benzoacetyl, alkoxycarbonyl, dialkylcarbamoyl and N-(dialkylaminoethyl base)-N-alkylcarbamoyl, etc.
  • nitrogen oxide in the present invention means that when the compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form nitrogen oxide.
  • nitrogen oxides are nitrogen oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocyclic rings.
  • the corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids such as peroxycarboxylic acids to form nitrogen oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • nitrogen oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514) by reacting an amine compound with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as DCM.
  • MCPBA m-chloroperoxybenzoic acid
  • the compound may have various geometric isomers and tautomers, and the compound shown in the formula (I-A), (I), (II), (III), (IV) or (V) includes all such class form.
  • the compound shown in the formula (I-A), (I), (II), (III), (IV) or (V) includes all such class form.
  • prodrug used in the present invention means that a compound is transformed into a compound represented by formula (IA), (I), (II), (III), (IV) or (V) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure.
  • the prodrug compound of the present invention can be an ester.
  • the ester can be used as a prodrug with phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , carbamates and amino acid esters.
  • a compound of the present invention that contains a hydroxyl group can be acylated to give a prodrug form of the compound.
  • Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups.
  • a complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.
  • the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.
  • the present invention includes isotopically labeled compounds which are equivalent to those described in formula (IA), (I), (II), (III), (IV) or (V), but with one or more atoms replaced by atomic mass or The mass number is different from the atomic mass or mass number that atoms are substituted for in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
  • the compounds of the present invention, their prodrugs and pharmaceutically acceptable salts of the compounds or the prodrugs containing the above-mentioned isotopes and/or other isotopes of other atoms all belong to the scope of the present invention.
  • isotopically-labeled compounds of the invention eg, those incorporating radioactive isotopes (eg, 3H and14C ), are useful in drug and/or substrate tissue distribution assays.
  • Compounds and prodrugs thereof shown in formulas (IA), (I), (II), (III), (IV) or (V) of the present invention labeled with isotopes can generally be prepared in this way, after carrying out the following processes and/or In the processes disclosed in Examples and Preparations, readily available isotope-labeled reagents are used instead of non-isotope-labeled reagents.
  • Metal refers to a product obtained through metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds, including metabolites produced by contacting a compound of the invention with a mammal for a substantial period of time.
  • salt forms of the compounds of the invention are useful.
  • pharmaceutically acceptable salts refers to those salt forms which are obvious to a pharmaceutical chemist, i.e., which are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism, or excretion. Other factors, more practical in nature, are also important for selection, these are: cost of raw materials, ease of crystallization, yield, stability, hygroscopicity and fluidity of the drug substance after salt formation.
  • the "pharmaceutically acceptable salt” used in the present invention refers to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as documented in S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977.
  • Non-toxic acid-formed salts include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, nitrates, etc., and organic Acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, citrate, benzoate , mandelate, methanesulfonate, ethanesulfonate, toluenesulfonate, sulfosalicylate, etc., or obtain these salts by other methods such as ion exchange methods recorded in books and literature.
  • inorganic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, nitrates, etc.
  • organic Acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate
  • salts include adipate, malate, 2-hydroxypropionic acid, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, Borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate Salt, Glucoheptonate, Glycerophosphate, Gluconate, Hemisulfate, Heptanoate, Hexanoate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobionate, Lactate , laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, Pectate, persulfate, 3-
  • the present invention also contemplates the quaternary ammonium salts of any compound containing an N group.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like.
  • Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1 -8 sulfonates and aromatic sulfonates.
  • Amine salts such as but not limited to N,N-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine , procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkaline earth metal salts such as but not limited to barium, calcium and magnesium; transition metal salts such as but not limited to zinc.
  • protecting group refers to a substituent that reacts with another functional group, usually to block or protect specific functionality.
  • amino-protecting group refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).
  • hydroxyl protecting group refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group
  • suitable protecting groups include acetyl and silyl groups.
  • Carboxyl protecting group refers to the substituent of carboxyl to block or protect the functionality of carboxyl.
  • General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane base) ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl phosphino)ethyl, nitroethyl, etc.
  • protecting groups refer to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • Room temperature in the present invention refers to a temperature from 10°C to 40°C. In some embodiments, “room temperature” refers to a temperature from 20°C to 30°C; in other embodiments, “room temperature” refers to 25°C.
  • the present invention provides a class of benzazepine heterocyclic compounds that can be used as ROR ⁇ t agonists.
  • the compounds of the present invention or pharmaceutical compositions containing the compounds can be used to prevent, treat or alleviate diseases mediated by ROR ⁇ t in patients.
  • the present invention provides a compound, which is a structure shown in formula (I-A) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite products, pharmaceutically acceptable salts or prodrugs thereof,
  • Q 1 , Q 2 , Ring A 1 , Ring A 2 , X, Y, Z, L, R 1 , R 2 , R 3 , R 6 , R 6a , m, n, q and “*” each have Definitions as described in the present invention.
  • Q1 and Q2 are each independently CH or N.
  • Q1 and Q2 are each independently CH .
  • Q1 is CH and Q2 is N.
  • Q1 is N and Q2 is CH .
  • the present invention provides a compound, which is the structure shown in formula (I), or stereoisomers, tautomers, nitrogen oxides, solvates of the structure shown in formula (I) , metabolites, pharmaceutically acceptable salts or prodrugs thereof,
  • ring A 1 , ring A 2 , X, Y, Z, L, R 1 , R 2 , R 3 , R 6 , R 6a , m, n, q and "*" each have definition.
  • Ring A is C 6-10 membered arylene, 5-10 membered heteroarylene, C 3-12 carbocyclylene, or 3-12 membered heterocyclylene.
  • Z is CR4 or N.
  • Ring A is 5-12 membered spirocyclylene, 5-12 membered bridgecyclylene, cyclohexylene, or cycloheptylene.
  • ring A is a 5-12 membered spirocyclylene or a 5-12 membered bridged cyclocyclylene.
  • Ring A is a 5-12 membered bridged cyclocyclylene.
  • R 5 and R 5a are each independently H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3 -12 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group.
  • m, n, and q are each independently 1, 2, 3, or 4.
  • the compound of the present invention has the structure shown in formula (II), or its stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or its prodrugs,
  • ring A 1 , ring A 2 , X, Y, Z, L, R 1 , R 2 , R 3 , m, n, q, R 6 , R 6a and “*” each have definition.
  • the compound of the present invention has the structure shown in formula (III), or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or its prodrugs,
  • ring A 1 , ring A 2 , X, L, R 1 , R 2 , R 3 , m, n, q, R 6 , R 6a and “*” each have the definitions as described in the present invention.
  • the compound of the present invention has the structure shown in formula (IV), or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or its prodrugs,
  • ring A 1 , ring A 2 , X, L, R 1 , R 2 , R 3 , m, n, q, R 6 , R 6a and “*” each have the definitions as described in the present invention.
  • the compound of the present invention has the structure shown in formula (V), or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or its prodrugs,
  • ring A 1 , ring A 2 , X, L, R 1 , R 2 , R 3 , m, n, q, R 6 , R 6a and “*” each have the definitions as described in the present invention.
  • the compound of the present invention has the structure shown in formula (II-1), or its stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable Accepted salts or its prodrugs,
  • ring A 1 , ring A 2 , Y, Z, L, R 1 , R 2 , m, n, R 6 , R 6a and "*" each have the definition as described in the present invention.
  • the compound of the present invention has the structure shown in formula (III-1), or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically Acceptable salts or prodrugs thereof,
  • ring A 1 , ring A 2 , L, R 1 , R 2 , m, n, R 6 , R 6a and "*" each have the definition as described in the present invention.
  • the compound of the present invention has the structure shown in formula (IV-1), or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically Acceptable salts or prodrugs thereof,
  • ring A 1 , ring A 2 , L, R 1 , R 2 , m, n, R 6 , R 6a and "*" each have the definition as described in the present invention.
  • the compound of the present invention has the structure shown in formula (V-1), or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically Acceptable salts or prodrugs thereof,
  • ring A 1 , ring A 2 , L, R 1 , R 2 , m, n, R 6 , R 6a and "*" each have the definition as described in the present invention.
  • the compound of the present invention has the structure shown in formula (X), or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or its prodrugs,
  • each of ring A 1 , X, R 1 , R 3 , m, q, R 6 , R 6a and “*” has the definition as described in the present invention.
  • Ring A is phenylene, naphthylene, pyridylene, pyridazinylene, pyrimidinylene, imidazolyl, pyrazolylene, pyrrolylene, indolylene, Quinolinyl, pyranylene, furylylene, cyclopentylene, cyclohexylene, piperidinylene, morpholinylene, pyrrolidinylene or piperazinylene.
  • Ring A is of the following substructure:
  • Z1 is CH or N ;
  • Z 3 and Z 4 are each independently a bond, -O-, -NH-, -OCH 2 -, -CH 2 O-, -CH 2- , or -(CH 2 ) 2 -;
  • t and t1 are each independently 0 or 1;
  • Ring A 2 has the following substructural formula:
  • Ring A 2 is Wherein, "*" indicates that the connection end at * is connected with L in formula (IA), (I), (II), (III), (IV) or (V).
  • a 2 the compound of the present invention has better characteristics, such as longer half-life, higher in vivo exposure and higher blood drug concentration, etc. in terms of pharmacokinetic properties.
  • each of R 4 and R 5 has the definition as described in the present invention.
  • R 5 and R 5a are each independently H, D, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 3-7 cycloalkyl, 3 -7 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group.
  • each R 5 and R 5a is independently H, D, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CF 3 , -CH 2 Cl, -CHCl 2 , -CH 2 CHCl 2 , -CH 2 OH, -CH(OH)CH 3 , -CH 2 CH 2 OH, -CH 2 CH( OH)CH 3 , -CH 2 C(CH 3 )(OH)CH 3 , cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, phenyl, pyridine base or pyrimidinyl.
  • R 01 and R 02 are each independently D, F, Cl, Br, I, OH, CN, NO 2 , -NR 4 R 5 , C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy C 1-4 alkyl, C 1-4 alkoxy, C 1-4 deuterated alkoxy C 1-4 hydroxyalkoxy, C 1-4 alkoxy C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkoxy , 3-7 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group.
  • the compound of the present invention has one of the following structures, or its stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
  • the present invention relates to a pharmaceutical composition, the pharmaceutical composition comprising the present invention formula (I-A), (I), (II), (III), (IV), (V), (II-1), Compounds represented by (III-1), (IV-1), (V-1) or (X), or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutical A pharmaceutically acceptable salt or its prodrug, optionally further comprising a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.
  • the pharmaceutical composition comprising the present invention formula (I-A), (I), (II), (III), (IV), (V), (II-1), Compounds represented by (III-1), (IV-1), (V-1) or (X), or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutical A pharmaceutically acceptable salt or its prodrug, optionally further comprising a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.
  • the present invention relates to formulas (I-A), (I), (II), (III), (IV), (V), (II-1), (III-1), (IV-1), Use of a compound represented by (V-1) or (X) or a pharmaceutical composition thereof in the preparation of a medicament, wherein the medicament is used to prevent, treat or alleviate a patient's disease mediated by ROR ⁇ t.
  • the present invention relates to formulas (I-A), (I), (II), (III), (IV), (V), (II-1), (III-1), (IV-1),
  • the compound represented by (V-1) or (X) or the pharmaceutical composition thereof is used for preventing, treating or alleviating diseases mediated by ROR ⁇ t in patients.
  • the present invention relates to a method for preventing, treating or alleviating a disease mediated by ROR ⁇ t in a patient, comprising administering to the patient a therapeutically effective amount of the formula (I-A), (I), (II), (III), A compound represented by (IV), (V), (II-1), (III-1), (IV-1), (V-1) or (X) or a pharmaceutical composition thereof.
  • the diseases mediated by ROR ⁇ t according to the present invention include cancer, multiple sclerosis, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, asthma, autoimmune Immune disease, graft versus host disease, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, colitis, bacterial infection, fungal infection, chronic obstructive pulmonary disease, allergic rhinitis, allergic dermatitis, Crohn's disease Or Kawasaki disease.
  • the tumor or cancer described in the present invention is selected from non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, Pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, glioma, glioblastoma Hepatocellular carcinoma, hepatocellular carcinoma, papillary renal tumor, head and neck cancer, leukemia, lymphoma, myeloma and non-small cell lung cancer.
  • the pharmaceutical composition of the present invention comprises any one of formula (I-A), (I), (II), (III), (IV), (V), (II-1),
  • the compounds shown in (III-1), (IV-1), (V-1) or (X) further include pharmaceutically acceptable auxiliary materials, and these auxiliary materials, for example, as used in the present invention, include any solvent, solid Excipients, diluents, binders, disintegrants, or other liquid vehicles, dispersants, flavoring or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, Solid binders or lubricants, etc., are suitable for the specific target dosage form.
  • excipients can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except to the extent that any conventional excipients are incompatible with the compounds of the present invention, such as any adverse biological effects produced or interacted in a deleterious manner with any other components of the pharmaceutically acceptable composition, their Use is also within the scope of the present invention.
  • the substances described in the present invention as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphate; Glycine; Sorbic Acid; Potassium Sorbate; Partial Glyceride Mixtures of Saturated Vegetable Fatty Acids; Water; Salts or Electrolytes such as Protamine Sulfate, Disodium Phosphate, Potassium Phosphate, Sodium Chloride, Zinc Salts; Colloidal Silicon; Tri Magnesium silicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its Derivatives such as sodium carboxymethylcellulose, hydroxypropylcellulose, ethylcellulose and cellulose a
  • the compound of the present invention When the compound of the present invention is administered to mammals such as humans in the form of medicine, it may be administered as the compound itself or may contain, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient together with a pharmaceutically acceptable
  • the carrier is administered in the form of a pharmaceutical composition.
  • “Therapeutically effective amount” or “effective amount” means that one or more compounds of the present invention treat, prevent, alleviate, ameliorate or eliminate one or more symptoms of a particular disease, disorder or syndrome, or prevent or delay the present invention. A sufficient amount to initiate the onset of one or more symptoms of the specified disease, disorder or syndrome.
  • a therapeutically effective amount of the drug reduces the number of cancer cells; inhibits (i.e., slows to some extent or stops) the infiltration of cancer cells into surrounding organs; inhibits tumor metastasis; inhibits tumor growth to some extent; and and/or provide some relief from one or more symptoms associated with cancer.
  • a therapeutically effective amount is an amount sufficient to reduce or alleviate the symptoms of infectious disease (infection symptoms caused by bacteria, viruses and fungi).
  • infectious disease infection symptoms caused by bacteria, viruses and fungi.
  • One of ordinary skill in the art will be able to study the factors involved in the present invention and determine an effective amount of a compound of the present invention without undue experimentation.
  • the regimen of administration can affect what constitutes an effective amount.
  • Compounds of the invention may be administered to an individual either before or after the onset of a disease mediated by RORyt.
  • divided doses as well as staggered doses may be administered daily or sequentially, or may be administered as a continuous infusion, or may be administered as a bolus injection.
  • the dosage of the compounds of this invention may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • the compounds of the invention are useful in the treatment of the conditions, disorders or diseases described herein, or in the preparation of pharmaceutical compositions for the treatment of these diseases.
  • the present invention relates to the use method of this kind of compound described in the present invention in the treatment of these diseases or the pharmaceutical preparation containing the compound of the present invention for the treatment of these diseases.
  • “Pharmaceutically acceptable carrier” is recognized in the art and includes a pharmaceutically acceptable material, composition or vehicle suitable for administering the compounds of the present invention to mammals.
  • the carrier includes liquid or solid fillers, diluents, excipients, solvents or encapsulating materials involved in carrying or transferring the active pharmaceutical ingredient from one organ or part of the body to another organ or part of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, Ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil , olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffer such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol;
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents can also be present in the composition , preservatives and antioxidants.
  • antioxidants examples include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium pyrosulfite, sodium sulfite, etc.; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxybenzene Monomethyl ether (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid , phosphoric acid, etc.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium pyrosulfite, sodium sulfite, etc.
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxybenzene Monomethyl ether (BHA), butylated hydroxytoluene
  • Formulations of the invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, in units of one percent, this amount will be from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.
  • Methods of preparing such formulations or compositions include the step of bringing into association a compound of the invention with the carrier, optionally, and one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations suitable for oral administration of this invention may be capsules, cachets, pills, tablets, lozenges (with a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or in Solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions, or elixirs or syrups, or pastilles (using an inert base such as gelatin and glycerin, or sucrose and gum arabic) and/or mouthwash, etc., each containing a given amount of the compound of the present invention as an active ingredient.
  • the compounds of this invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is combined with one or more pharmaceutically acceptable carriers such as sodium citrate or Dicalcium phosphate mixed with/or any of the following: fillers or bulking agents such as starches, lactose, sucrose, dextrose, mannitol, and/or silicic acid; binders such as carboxymethylcellulose, alginates gelatin, polyvinylpyrrolidone, sucrose, and/or gum arabic; humectants, such as glycerin; disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acids, and sodium carbonate; Solution retarding agents, such as paraffin; absorption enhancers, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glyceryl monostearate; adsorbents
  • pharmaceutically acceptable carriers such as sodium citrate or Dicalcium phosphate mixed with/or any of the following: fillers or bulking agents such as starches
  • the pharmaceutical composition may also comprise buffering agents.
  • Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be formulated with binder (for example, gelatin or hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or croscarmellose sodium ), surfactants or dispersants.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • Tablets and other solid dosage forms of the pharmaceutical compositions of the invention such as dragees, capsules, pills and granules may optionally be scored or coated with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. preparation. They may also be formulated to provide slow release or controlled release of the active ingredient therein, for example, with hydroxypropylmethylcellulose, other polymer matrices, liposomes and/or microspheres in various proportions to provide the desired release profile. freed. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating the sterilizing agent in the form of a sterile solid composition which can be dissolved in sterile water or some other injectable sterile vehicle immediately before use.
  • compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the gastrointestinal tract, optionally, in a delayed manner.
  • opacifying agents include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms of the compounds of this invention for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • Liquid dosage forms may contain, in addition to the active ingredient, inert diluents commonly used in the art such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate Esters, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and dehydrated Fatty acid esters of sorbitol and mixtures thereof.
  • inert diluents commonly used in the art such as water or other solvents
  • the oral compositions can also include adjuvant such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvant such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions may contain, in addition to the active compounds, adjuvants such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, soap Soil, agar and tragacanth and mixtures thereof.
  • adjuvants such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, soap Soil, agar and tragacanth and mixtures thereof.
  • Formulations of the pharmaceutical compositions of this invention for rectal or vaginal administration may be presented as suppositories, which may be prepared by combining one or more compounds of this invention with one or more suitable non-irritating excipients or Carriers (including, for example, cocoa butter, polyethylene glycol, suppository waxes, or salicylates) are mixed and are solid at room temperature but liquid at body temperature and will therefore melt and release in the rectum or vaginal cavity active compound.
  • suitable non-irritating excipients or Carriers including, for example, cocoa butter, polyethylene glycol, suppository waxes, or salicylates
  • Formulations of the present invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers known in the art to be suitable.
  • Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants that may be required.
  • Ointments, pastes, creams and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, fibers ketone derivatives, polyethylene glycols, siloxanes, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, fibers ketone derivatives, polyethylene glycols, siloxanes, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can also contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the invention to the body.
  • dosage forms can be prepared by dissolving or dispersing the compound in the appropriate vehicle.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate of flow of the active compound can be controlled by providing a rate controlling membrane or by dispersing the active compound in a polymer matrix or gel.
  • Ophthalmic preparations are also included within the scope of the present invention.
  • compositions of the present invention suitable for parenteral administration comprise one or more compounds of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions formulations or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostatic agents, rendering the formulation isotonic with the blood of the recipient Solute or suspending agent or thickening agent.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil and Injectable organic esters such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, etc.
  • vegetable oils such as olive oil
  • Injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical forms can be brought about by the inclusion of substances which delay absorption, for example, aluminum monostearate and gelatin.
  • slowing the absorption of drugs from subcutaneous or intramuscular injections is necessary in order to prolong the effect of the drugs.
  • This can be achieved by using a liquid suspension of crystalline or amorphous material that is poorly soluble in water.
  • the rate of absorption of the drug will depend upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form.
  • prolonged absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular compound employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the formulations of the invention may be administered orally, parenterally, topically or rectally. They are of course administered in a form suitable for each route of administration. For example, they are administered in the form of tablets or capsules, administered by injection, inhalation, eye lotion, ointment, suppository, etc., administered by injection, infusion or inhalation; administered by lotion or ointment Topical administration; rectal administration via suppositories. Oral and/or intravenous administration is preferred.
  • parenteral administration means administration other than enteral and topical administration, usually by injection, including without limitation intravenous, intramuscular, intraarterial, intrathecal, intrasaccular, Intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.
  • systemic administration and "peripheral administration” as used herein mean the administration of a compound, drug or other material other than directly to the central nervous system so that it enters the patient's system and thus undergoes metabolism and other similar processes , such as subcutaneous administration.
  • the compounds may be administered to humans and other animals for treatment by any suitable route of administration, including orally, nasally (e.g. as a spray), rectally, intravaginally, parenterally, intracisternally and topically (as powders, ointments in the form of drops or drops), including buccal and sublingual administration.
  • the compounds of the invention and/or the pharmaceutical compositions of the invention which may be used in suitably hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend on a variety of factors, including the activity of the particular compound of the invention employed, or its ester, salt or amide, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of treatment, Other drugs, compounds and/or materials used in combination with the particular compound used, the age, sex, weight, condition, general health and previous medical history of the patient being treated and similar factors well known in the medical art.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian could start dosages of the compounds of the invention employed in the pharmaceutical compositions at levels lower than that required to obtain the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such effective dosage will generally depend on the factors mentioned above.
  • the compounds of this invention are administered to patients at dosages of about 0.001 to about 500 mg/kg body weight/day.
  • the effective daily dose of the active compound may, if desired, be administered at appropriate intervals throughout the day as two, three, four, five, six or more sub-doses administered separately, optionally in unit dosage form.
  • the pharmaceutical composition or combination of the present invention may be in a unit dose of about 1-1000 mg of active ingredient.
  • Therapeutically effective doses of compounds, pharmaceutical compositions or combinations thereof depend on the species, body weight, age and individual condition of the individual, the disorder or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of the disorder or disease.
  • the above-mentioned dosage properties are advantageously applied in in vitro and in vivo tests to mammals, such as mice, rats, dogs, monkeys or related organs, tissues or preparations thereof.
  • the compounds of the invention can be applied in vitro in the form of solutions, eg, aqueous solutions, and in vivo, enterally, parenterally, advantageously intravenously, eg, as suspensions or aqueous solutions.
  • the term "individual” as used in the present invention means an animal. Typically, the animal is a mammal. A subject also means, for example, primates (eg, humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the individual is a primate. In other embodiments, the individual is a human.
  • primates eg, humans, male or female
  • the individual is a primate. In other embodiments, the individual is a human.
  • the compounds of the present invention may be administered alone, it is preferred to administer the compounds in the form of pharmaceutical compositions.
  • Combination therapy using one or more compounds or compositions provided by the present invention, or pharmaceutically acceptable derivatives thereof, in combination with other drug activators is used to treat the diseases and conditions described in the present invention.
  • an effective amount of a compound, or a composition comprising a compound at a therapeutically effective concentration formulated for oral, systemic delivery, including parenteral or intravenous delivery, or for topical or topical administration, to an individual exhibiting symptoms of a disease or disorder in need of treatment .
  • the amount is effective to treat, manage or alleviate one or more symptoms of the disease or disorder.
  • the compounds, isomers, prodrugs and pharmaceutically acceptable derivatives provided by the present invention can be widely used in combination therapy to treat the present invention. Discomforts and diseases described in the invention. Accordingly, the present invention contemplates the use of the compounds, isomers, prodrugs and pharmaceutically acceptable derivatives provided herein in combination with other active agents for the treatment of the diseases and/or disorders described herein.
  • the compounds or pharmaceutical compositions disclosed in the present invention can be used to prepare medicines for preventing, treating or alleviating diseases mediated by ROR ⁇ t in patients.
  • Such diseases include, but are not limited to, cancer, multiple sclerosis, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, asthma, autoimmune disease, graft-resistant Host disease, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, inflammatory bowel syndrome, colitis, bacterial infection, fungal infection, chronic obstructive pulmonary disease, allergic rhinitis, allergic dermatitis, Crohn's disease or Kawasaki disease.
  • the compound or pharmaceutical composition of the present invention can be used, but not limited to, to treat, prevent, improve, control or alleviate cancer in mammals, including humans, by administering an effective amount of the compound or pharmaceutical composition of the present invention to a patient , infectious and autoimmune diseases.
  • the compounds and pharmaceutical compositions of the present invention are also useful in the veterinary treatment of mammals in pets, imported breeds and farm animals. Examples of additional animals include horses, dogs and cats.
  • the compounds of the present invention include their pharmaceutically acceptable derivatives.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless there are further instructions, wherein the substituents are defined as formula (I-A), (I), (II), (III), (IV) , (V), (II-1), (III-1), (IV-1), (V-1) or (X) compound.
  • substituents are defined as formula (I-A), (I), (II), (III), (IV) , (V), (II-1), (III-1), (IV-1), (V-1) or (X) compound.
  • the following reaction schemes and examples serve to further illustrate the present invention.
  • Anhydrous tetrahydrofuran, anhydrous dioxane, anhydrous toluene and anhydrous ether are obtained by reflux drying with sodium metal.
  • Anhydrous dichloromethane and anhydrous chloroform were obtained by reflux drying over calcium hydride.
  • Anhydrous ethyl acetate, anhydrous petroleum ether, anhydrous n-hexane, anhydrous N,N-dimethylacetamide and anhydrous N,N-dimethylformamide were dried with anhydrous sodium sulfate before use.
  • reaction vials were fitted with suitable rubber stoppers, and the substrate was introduced by syringe. Glassware is dried.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh
  • the nuclear magnetic resonance spectrum uses CDC1 3 , DMSO-d 6 , CD 3 OD or d 6 -acetone as the solvent (in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard.
  • MS data was determined by an Agilent 6120 series LC-MS spectrometer equipped with G1311B quaternary pump and G1316A TCC (column temperature maintained at 30 ° C), and G1329B automatic sampler and G1315D DAD detector were used for analysis , the ESI source was applied to the LC-MS spectrometer.
  • the above spectrometer is equipped with an Agilent Zorbax SB-C18 column with a specification of 2.1 ⁇ 30mm and 5 ⁇ m. Injection volume was determined by sample concentration; flow rate was 0.6 mL/min; HPLC peaks were recorded and read by UV-Vis wavelengths at 210 nm and 254 nm.
  • the mobile phases were 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in Table 1:
  • Compound (IA) can be prepared by the synthesis route of the above synthesis scheme 1, wherein Hal 1 is F, Cl, Br or I, preferably F or Cl; ring A 1 , ring A 2 , X, R 1 , R 2 , R 3 , m, n and q each have the definitions described in the present invention.
  • Compound (IA-1) reacts with compound Me 3 S(O)I under suitable conditions (such as in the presence of NaH, in THF or DMSO solvent) to obtain compound (IA-2); compound (IA-2) and compound (IA-3) was reacted under suitable conditions (such as first reacting in the presence of TBAB and Cs 2 CO 3 for a period of time, then reacting in THF solvent in the presence of NaOH) to obtain compound (IA).
  • Compound (IAa) can be prepared by the synthetic route of above-mentioned synthetic scheme 2, wherein, Hal 1 is F, Cl, Br or I, is preferably F or Cl; Ra is C 1-6 alkyl, preferably methyl, Ethyl, n-propyl or isopropyl; ring A 1 , ring A 2 , X, R 1 , R 3 , m and q each have the definitions described in the present invention.
  • Compound (IA-1a) reacts with compound Me 3 S(O)I under suitable conditions (such as in the presence of NaH, in THF or DMSO solvent) to obtain compound (IA-2a); compound (IA-2a) and compound (IA-3) under suitable conditions (such as first reacting for a period of time in the presence of TBAB and Cs 2 CO 3 , then reacting in the presence of NaOH and THF solvent) to obtain compound (IAa-1) or compound (IAa) ; Compound (IAa-1) is reacted in a suitable solvent (such as a mixed solvent of ethanol and water) under basic conditions (such as in the presence of NaOH) to obtain compound (IAa).
  • suitable solvent such as a mixed solvent of ethanol and water
  • Compound (IAb) can be prepared by the synthetic route of the above-mentioned synthesis scheme 3, wherein, Hal 1 is F, Cl, Br or I, preferably F or Cl; Pg 1 is an amino protecting group, preferably Boc; Ring A 2a is A heterocyclic ring containing at least one ring N atom; each of the rings A 1 , X, R 1 , R 3 , R 5 , m and q has the definition described in the present invention.
  • suitable conditions such as in the presence of NaH, in THF or DMSO solvent
  • suitable conditions such as in the presence of NaH, in THF or DMSO solvent
  • suitable conditions such as in the presence of NaH, in T
  • Compound (IAc) can be prepared by the synthesis route of the above-mentioned synthesis scheme 4, wherein, Hal 1 is F, Cl, Br or I, preferably F or Cl; Pg 2 is a hydroxyl protecting group, preferably Ms; Ring A 2b is A heterocyclic ring containing at least one ring N atom; L 1 is a C 1-6 alkylene group, preferably -CH 2 - or -CH 2 CH 2 -; Ring A 1 , X, R 1 , R 2 , R 3 , m, n and q each have the definitions described herein.
  • Compound (IA-3) and compound (IAc-0) were reacted under suitable conditions (such as under the action of K 2 CO 3 and TBAB) for a period of time and then heated in THF solvent under the action of NaOH to obtain compound (IAc-0). -1); Compound (IAc-1) reacts to obtain compound (IAc-2) by hydroxyl protection (as under the effect of DIAPEA, reacting with MsCl in DCM solvent); Compound (IAc-2) and compound (IAc-3) Compound (IAc) can be obtained by reacting in a suitable solvent (such as acetonitrile) under basic conditions (such as K 2 CO 3 , etc.).
  • suitable solvent such as acetonitrile
  • Compound (IAd) can be prepared by the synthesis route of the above-mentioned synthesis scheme 5, wherein, Pg 2 is a hydroxyl protecting group, preferably Ms; Pg 1 is an amino protecting group, preferably Boc; ring A 2c is at least two ring N atom heterocycle; L 1 is a C 1-6 alkylene group, preferably -CH 2 - or -CH 2 CH 2 -; Ring A 1 , X, R 1 , R 3 , R 5 , m and q each have Definitions described herein.
  • Compound (IAc-2) reacts with compound (IAd-1) in a suitable solvent (such as acetonitrile) under alkaline conditions (such as K 2 CO 3 etc.) to obtain compound (IAd-2);
  • a suitable solvent such as acetonitrile
  • alkaline conditions such as K 2 CO 3 etc.
  • Compound (IAd) can be obtained by coupling reaction in a suitable solvent (such as DCM).
  • Compound (IAe) can be prepared by the synthesis route of the above synthesis scheme 6, wherein, Pg 2 is a hydroxyl protecting group, preferably Ms; L 1 is a C 1-6 alkylene group, preferably -CH 2 - or -CH 2 CH 2 -; Ring A 2b is a heterocyclic ring containing at least one ring N atom; Ring A 1 , X, R 1 , R 3 , R 5 , m and q each have the definitions described in the present invention.
  • Compound (IAc-2) reacts with compound (IAe-1) in a suitable solvent (such as acetonitrile) under alkaline conditions (such as K 2 CO 3 etc.) to obtain compound (IAe-2);
  • a suitable solvent such as acetonitrile
  • alkaline conditions such as K 2 CO 3 etc.
  • Compound (IAe) can be obtained by hydrolysis under acidic or basic conditions.
  • Compound (IAf) can be prepared by the synthesis route of the above-mentioned synthesis scheme 7, wherein, Pg 2 is a hydroxyl protecting group, preferably Ms; L 1 is a C 1-6 alkylene group, preferably -CH 2 - or -CH 2 CH 2 -; ring A 1 , ring A 2 , X, R 1 , R 2 , R 3 , m, n and q each have the definitions described in the present invention.
  • Compound (IAg) can be prepared by the synthetic route of the above-mentioned synthesis scheme 8, wherein, Pg 2 is a hydroxyl protecting group, preferably Ms; Pg 1 is an amino protecting group, preferably Boc; L 1 is C 1-6 alkylene , preferably -CH 2 - or -CH 2 CH 2 -; Ring A 2a is a heterocyclic ring containing at least one ring N atom; Ring A 1 , X, R 1 , R 3 , R 5 , m and q each have the following Definitions of Invention.
  • a suitable catalyst such as TBAB, etc.
  • a suitable solvent such as a mixed solvent of Et 2 O and water
  • Compound (IAg-2) is obtained by reaction in medium;
  • Compound (IAg-2) is deaminated under acidic conditions to obtain compound (IAg-3);
  • appropriate reagents such as EDCI, HOBT and DIPEA
  • Compound (IAh) can be prepared by the synthesis route of the above synthesis scheme 9, wherein, Pg 2 is a hydroxyl protecting group, preferably Ms; L 1 is a C 1-6 alkylene group, preferably -CH 2 - or -CH 2 CH 2 -; ring A 1 , ring A 2 , X, R 1 , R 2 , R 3 , R 4 , m, n and q each have the definitions described in the present invention.
  • Compound (IAc-2) reacts with compound (IAh-1) in a suitable solvent (such as acetonitrile) under basic conditions (such as K 2 CO 3 ) to obtain compound (IAh).
  • Compound (IAi-1) and compound (IAi-2) under suitable conditions such as EDCI, HOBT and DIPEA under the effect in DCM solvent) generation coupling reaction obtains compound (IAi-3); Compound (IAi-3) Reaction with HCHO under basic conditions (such as NaOH) and a suitable solvent (such as a mixed solvent of H 2 O and EtOH) to obtain compound (IAi-4); compound (IAi-4) and compound (IAi-5) in Compound ( IAi _ _ -6); Compound (IAi-6) reacts with compound (IAi-7) under basic conditions (such as pyridine) to obtain compound (IAi).
  • suitable conditions such as EDCI, HOBT and DIPEA under the effect in DCM solvent
  • Compound (IA) can be prepared by the synthetic route of the above synthesis scheme 11, wherein Hal 1 is F, Cl, Br or I, preferably F or Cl; Hal 2 is F, Cl, Br or I, preferably Br or Cl; Ring A 1 , Ring A 2 , X, R 1 , R 2 , R 3 , m, n and q each have the definitions described in the present invention.
  • (IA-4) reacts with (IA-3) in a suitable solvent (such as isopropanol) under the effect of DIPEA to obtain compound (IA-5); compound (IA-5) is in HCOOH, DIPEA and RuCl [(R , R-TsDpen)] (p-cymene) under the action of reaction to obtain compound (IA-6); compound (IA-6) under the action of TBAB and NaOH in a suitable solvent (such as THF) heating reaction to obtain compound (IA) .
  • a suitable solvent such as isopropanol
  • Compound (IA) can be prepared by the synthetic route of the above-mentioned synthesis scheme 12, wherein, Hal 1 is F, Cl, Br or I, preferably F or Cl; Hal 2 is F, Cl, Br or I, preferably Br or Cl; Hal 3 is F, Cl, Br or I, preferably Br or Cl; ring A 1 , ring A 2 , X, R 1 , R 2 , R 3 , m, n and q each have the definition.
  • Compound (IA-4) reacts with compound (IA-7) in a suitable solvent (such as isopropanol) under the effect of DIPEA to obtain compound (IA-8); compound (IA-8) is reacted in HCOOH, DIPEA and RuCl[ (R, R-TsDpen)] (p-cymene) under the action of the reaction to obtain compound (IA-9); compound (IA-9) and compound (IA-10) under suitable conditions (such as Pd (dppf) Cl 2 .CH 2 Cl 2 and K 2 CO 3 under the action, in the mixed solvent of 1,4-dioxane and water) coupling reaction to obtain compound (IA-6); compound (IA-6) in TBAB and NaOH Under the action of heating in a suitable solvent (such as THF), the compound (IA) can be obtained.
  • a suitable solvent such as isopropanol
  • Compound (IAa) can be prepared by the synthetic route of the above synthesis scheme 13, wherein Hal 1 is F, Cl, Br or I, preferably F or Cl; Hal 2 is F, Cl, Br or I, preferably Br or Cl; ring A 1 , ring A 2 , X, R 1 , R 3 , R 5 , m and q each have the definitions described in the present invention.
  • (IA-4a) reacts with (IA-3) in a suitable solvent (such as isopropanol) under the effect of DIPEA to obtain compound (IA-5a); compound (IA-5a) is in HCOOH, DIPEA and RuCl[(R , R-TsDpen)] (p-cymene) under the action of reaction to obtain compound (IA-6a); compound (IA-6a) under the action of TBAB and NaOH in a suitable solvent (such as THF) heating reaction to obtain compound (IAa) .
  • a suitable solvent such as isopropanol
  • Compound (IAa) can be prepared by the synthetic route of the above-mentioned synthesis scheme 14, wherein, Hal 1 is F, Cl, Br or I, preferably F or Cl; Hal 2 is F, Cl, Br or I, preferably Br or Cl; Hal 3 is F, Cl, Br or I, preferably Br or Cl; ring A 1 , ring A 2 , X, R 1 , R 3 , R 5 , m and q each have the definitions described in the present invention.
  • Compound (IA-4a) reacts with compound (IA-7) in a suitable solvent (such as isopropanol) under the action of DIPEA to obtain compound (IA-8a); compound (IA-8a) is reacted in HCOOH, DIPEA and RuCl[ (R, R-TsDpen)] (p-cymene) under the action of the reaction to obtain compound (IA-9a); compound (IA-9a) and compound (IA-10) under suitable conditions (such as Pd (dppf) Cl 2 .CH 2 Cl 2 and K 2 CO 3 , in the mixed solvent of 1,4-dioxane and water) coupling reaction to obtain compound (IA-6a); compound (IA-6a) in TBAB and NaOH Compound (IAa) can be obtained by heating in a suitable solvent (such as THF).
  • a suitable solvent such as THF
  • N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)-3-(trifluoromethyl)benzenesulfonamide ( 210mg, 0.44mmol, Wuhan Newris Medical Technology Co., Ltd.), (S)-oxirane-2-ylmethanol (350mg, 4.73mmol), K 2 CO 3 (24.0mg, 0.17mmol) and TBAB (47mg , 0.15mmol) were mixed uniformly, and reacted at 90°C for 24h.
  • THF (8 mL) and NaOH (68 mg, 1.70 mmol) were added to the reaction liquid system, and reacted at 65° C.
  • Step 1 Synthesis of methyl 6-(methoxymethylene)spiro[3.3]heptane-2-carboxylate
  • Step 2 Synthesis of methyl 6-formylspiro[3.3]heptane-2-carboxylate
  • dilute hydrochloric acid (3.1 mL, 9.3 mmol, 3M), naturally rose to room temperature and reacted for 3 hours, stopped the reaction, added tap water to dilute (30mL), extracted with ethyl acetate (25mL ⁇ 3), the organic phases were combined, and washed successively with saturated sodium bicarbonate solution (20mL) and Wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, and concentrate to give a colorless oily product as the title compound (640 mg, yield: 57%).
  • Step 3 Synthesis of methyl 6-(oxiran-2-yl)spiro[3.3]heptane-2-carboxylate
  • Step 4 6-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-bis Synthesis of Hydrogen-2H-Benzo[b][1,4]oxazin-2-yl)spiro[3.3]heptane-2-carboxylic Acid
  • Methyl 6-(oxirane-2-yl)spiro[3.3]heptane-2-carboxylate 150mg, 0.76mmol
  • N-(3'-(difluoromethoxy)-4,5 '-Difluoro-[1,1'-biphenyl]-3-yl)-3-(trifluoromethyl)benzenesulfonamide 300mg, 0.62mmol, Wuhan Newris Pharmaceutical Technology Co., Ltd.
  • Cs 2 CO 3 (41mg, 0.12mmol) and TBAB (41mg, 0.13mmol) mixture was placed in a 90°C oil bath for 24 hours, then NaOH (100mg, 2.50mmol) and THF (10mL) were added, and the reaction was continued at 60°C for 8 hours.
  • Step 1 Synthesis of methyl 4-formylbicyclo[2.2.1]heptane-1-carboxylate
  • Step 2 Synthesis of methyl 4-(oxiran-2-yl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 3 4-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-bis Synthesis of Hydrogen-2H-Benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic Acid
  • Step 1 Synthesis of ethyl 6-(methoxymethylene)spiro[2.5]octane-1-carboxylate
  • Step 2 Synthesis of ethyl 6-formylspiro[2.5]octane-1-carboxylate
  • Step 3 Synthesis of ethyl 6-(oxiran-2-yl)spiro[2.5]octane-1-carboxylate
  • Step 4 6-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-bis Synthesis of Ethyl Hydrogen-2H-Benzo[b][1,4]oxazin-2-yl)spiro[2.5]octane-1-carboxylate
  • Step 5 6-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-bis Hydrogen-2H-benzo[b][1,4]oxazin-2-yl)spiro[2.5]octane-1-carboxylic acid isomer 1 and 6-(6-(3-(difluoromethoxy Base)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine Synthesis of -2-yl)spiro[2.5]octane-1-carboxylic acid isomer 2
  • the yellow solid is 4-((R)-6-(3-( Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1, 4] Oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid (488.0 mg, yield: 32.10%).
  • Step 1 Synthesis of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate
  • tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1.55g, 7.27mmol) was dissolved in DCM (15mL), DMP (6.20g, 15.00mmol) was added under ice-cooling ), stirred at room temperature for 18h.
  • Step 2 Synthesis of tert-butyl 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate
  • Step 3 Synthesis of tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate
  • tert-butyl 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate 700 mg, 2.93 mmol was dissolved in DCM/H 2 O (6.6 mL/3.3 mL) , TFA (0.9 mL, 10.00 mmol) was added under ice-cooling, and stirred at room temperature for 5 h.
  • Step 4 Synthesis of tert-butyl 6-(oxiran-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate
  • Step 5 6-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-bis Synthesis of tert-butyl Hydrogen-2H-Benzo[b][1,4]oxazin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate
  • N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)-3-(trifluoromethyl)benzenesulfonamide 124mg, 0.26mmol
  • tert-butyl 6-(oxirane-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate 9mg, 0.38mmol
  • K 2 CO 3 (12mg , 0.087mmol)
  • TBAB 29mg, 0.090mmol
  • Step 6 6-(3-(Difluoromethoxy)-5-fluorophenyl)-2-(2-aza[3.3]hept-6-yl)-4-((3-(trifluoromethyl Synthesis of yl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine
  • Step 7 Cyclopropyl(6-(6-(3-(difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3 , Synthesis of 4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-azaspiro[3.3]hept-2-yl)methanone
  • Step 1 (R)-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4 -Synthesis of dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl methanesulfonate
  • Step 2 (S)-2-(2-Oxa-6-azaspiro[3.3]hept-6-ylmethyl)-6-(3-(difluoromethoxy)-5-fluorophenyl Synthesis of )-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine
  • Step 1 (S)-tert-butyl 6-((6-(3-(difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonate Acyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxy Synthesis of esters
  • Step 2 (S)-2-(2,6-Diazaspiro[3.3]hept-2-ylmethyl)-6-(3-(difluoromethoxy)-5-fluorophenyl)- Synthesis of 4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine
  • Step 3 (S)-Cyclopropyl(6-((6-(3-(difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl) Sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-2,6-diazaspiro[3.3]hept-2-yl ) Synthesis of methyl ketone
  • Step 1 Synthesis of methyl 2-azaspiro[3.3]heptane-6-carboxylate
  • Step 2 (S)-2-((6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)- Synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylic acid methyl ester
  • Step 3 (S)-2-((6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)- Synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylic acid
  • Step 1 (R)-6-((6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)- tert-butyl 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methoxy)-2-azaspiro[3.3]heptane-2-carboxylate synthesis
  • Step 2 (R)-2-(((2-Azaspiro[3.3]heptan-6-yl)oxy)methyl)-6-(3-(difluoromethoxy)-5-fluoro Synthesis of phenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine
  • Step 3 (R)-Cyclopropyl(6-((6-(3-(difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl) Sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methoxy)-2-azaspiro[3.3]hept-2-yl)methyl Ketone synthesis
  • Example 11 3-(((S)-6-(3-(difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl) Synthesis of -3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid
  • Step 1 Synthesis of methyl 3-azabicyclo[3.1.1]heptane-6-carboxylate hydrochloride
  • Step 2 3-(((S)-6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)- 3,4-Dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid methyl ester synthesis
  • Step 3 3-(((S)-6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)- Synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid
  • Step 1 Synthesis of methyl 3-(benzylamino)bicyclo[1.1.1]pentane-1-carboxylate
  • Methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate (502mg, 3.56mmol) and benzaldehyde (0.4mL, 4.00mmol) were dissolved in EtOH/THF (3mL/3mL) and AcOH was added (0.2mL, 3.00mmol), NaBH 3 CN (678mg, 10.79mmol), react at 60°C for 15h.
  • Step 2 Synthesis of methyl 3-(benzyl(methyl)amino)bicyclo[1.1.1]pentane-1-carboxylate
  • Step 3 Synthesis of methyl 3-(methylamino)bicyclo[1.1.1]pentane-1-carboxylate
  • Step 4 (S)-3-(((6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl) -3,4-Dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)(methyl)amino)bicyclo[1.1.1]pentane-1-carboxylate Synthesis of esters
  • Step 5 (S)-3-(((6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl) -3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)(methyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid synthesis
  • Example 14 (S)-6-(3-(difluoromethoxy)-5-fluorophenyl)-2-((6-(methylsulfonyl)-2,6-diazaspiro[ 3.3] Hept-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4] Synthesis of oxazines
  • Step 1 (S)-6-((6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)- 3,4-Dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl Synthesis of esters
  • Step 2 (S)-2-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-(3-(difluoromethoxy)-5-fluorobenzene Synthesis of yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine
  • Step 3 (S)-6-(3-(Difluoromethoxy)-5-fluorophenyl)-2-((6-(methylsulfonyl)-2,6-diazaspiro[3.3 ]hept-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxa Synthesis of oxazine
  • Example 16 4-(7-(3-(Difluoromethoxy)-5-fluorophenyl)-4-oxo-1-((3-(trifluoromethyl)phenyl)sulfonyl) Synthesis of -1,2-dihydroquinazolin-3(4H)-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 1 Synthesis of methyl 4-(2-amino-4-bromobenzamido)bicyclo[2.2.1]heptane-1-carboxylate
  • Methyl 4-(2-amino-4-bromobenzamido)bicyclo[2.2.1]heptane-1-carboxylate (600mg, 1.63mmol), aqueous formaldehyde (0.13mL, 1.70mmol, concentration 37% ) and NaOH (102mg, 2.55mmol) were dissolved in EtOH (15mL) and reacted at 60°C for 6h.
  • Step 3 4-(7-(3-(Difluoromethoxy)-5-fluorophenyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)bicyclo[ 2.2.1] Synthesis of heptane-1-carboxylic acid
  • Step 4 4-(7-(3-(Difluoromethoxy)-5-fluorophenyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)bicyclo[ 2.2.1] Synthesis of methyl heptane-1-carboxylate
  • Step 5 4-(7-(3-(Difluoromethoxy)-5-fluorophenyl)-4-oxo-1-((3-(trifluoromethyl)phenyl)sulfonyl)- Synthesis of 1,2-dihydroquinazolin-3(4H)-yl)bicyclo[2.2.1]heptane-1-carboxylate methyl ester
  • Heptane-1-carboxylic acid methyl ester (78mg, 0.17mmol) was dissolved in pyridine (3mL), and 3-(trifluoromethyl)benzenesulfonyl chloride (0.03mL, 0.20mmol) was added dropwise under ice-cooling, and then Stir for 15h.
  • Step 6 4-(7-(3-(Difluoromethoxy)-5-fluorophenyl)-4-oxo-1-((3-(trifluoromethyl)phenyl)sulfonyl)- Synthesis of 1,2-dihydroquinazolin-3(4H)-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 2 Synthesis of methyl 2,6-diazaspiro[3.3]heptane-2-carboxylate
  • Step 3 (S)-6-((6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)- 3,4-Dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid methyl ester Synthesis
  • Example 18 2-(((S)-6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl) Synthesis of -3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-2-azaadamantane-5-carboxylic acid
  • Step 1 2-(((S)-6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)- Synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-2-azadamantane-5-carboxylic acid methyl ester
  • Step 2 2-(((S)-6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)- Synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-2-azadamantane-5-carboxylic acid
  • Step 1 Synthesis of methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate
  • Trimethylsulfoxide iodide (31.59mmol, 6.95g) was dissolved in DMSO (24mL), and potassium tert-butoxide (29.75mmol, 3.34g) was slowly added. After the addition was complete, it was stirred at room temperature for 2h.
  • Step 3 4-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-bis Synthesis of Hydrogen-2H-Benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.2]octane-1-carboxylic Acid
  • Step 4 (S)-4-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3 ,4-Dihydro-2H-benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.2]octane-1-carboxylic acid
  • Step 1 Synthesis of ethyl 4-(methoxymethylene)-1-methylcyclohexane-1-carboxylate
  • Step 2 Synthesis of ethyl 4-formyl-1-methylcyclohexane-1-carboxylate
  • Step 3 Synthesis of ethyl 1-methyl-4-(oxiran-2-yl)cyclohexane-1-carboxylate
  • Step 4 4-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-bis Synthesis of Hydrogen-2H-Benzo[b][1,4]oxazin-2-yl)-1-methylcyclohexane-1-carboxylic acid
  • Step 1 Synthesis of 4-fluoro-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)benzenesulfonamide
  • Step 2 Methyl 4-(N-((4-fluorophenyl)sulfonyl)-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'- Synthesis of biphenyl]-3-yl)glycyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 3 Methyl 4-((S)-2-((4-fluoro-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl Synthesis of ]-3-yl)phenyl)sulfonamide)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 4 4-((S)-4-((4-fluorophenyl)sulfonyl)-6-(3-(difluoromethoxy)-5-fluorophenyl)-3,4-dihydro Synthesis of -2H-Benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 1 Synthesis of N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)-3-methylbenzenesulfonamide
  • Step 2 4-(N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)-N-(m-toluenesulfonyl ) glycyl) bicyclo [2.2.1] heptane 1-carboxylate methyl ester
  • Step 3 Methyl 4-((S)-2-((N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3- Synthesis of -3-methylphenyl)sulfonyl)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 4 4-((S)-6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-(m-toluenesulfonyl)-3,4-dihydro-2H-benzo Synthesis of [b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 1 3-Fluoro-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)benzenesulfonamide synthesis
  • Step 2 Methyl 4-(N-((3-fluorophenyl)sulfonyl)-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'- Synthesis of biphenyl]-3-yl)glycyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 3 Methyl 4-((S)-2-((3-fluoro-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl Synthesis of ]-3-yl)phenyl)sulfonamide)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 4 4-((S)-4-((3-fluorophenyl)sulfonyl)-6-(3-(difluoromethoxy)-5-fluorophenyl)-3,4-dihydro Synthesis of -2H-Benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 1 Synthesis of 4-chloro-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)benzenesulfonamide
  • Step 2 Methyl 4-(N-((4-chlorophenyl)sulfonyl)-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'- Synthesis of biphenyl]-3-yl)glycyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 3 Methyl 4-((S)-2-((4-chloro-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl Synthesis of ]-3-yl)phenyl)sulfonylamino)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 4 4-((S)-4-((4-Chlorophenyl)sulfonyl)-6-(3-(difluoromethoxy)-5-fluorophenyl)-3,4-dihydro Synthesis of -2H-Benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 2 Synthesis of N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)-4-methylbenzenesulfonamide
  • Step 3 4-(N-(3'-(Difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)-N-tosylglycine Synthesis of acyl)bicyclo[2.2.1]heptane-1-carboxylate methyl ester
  • N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)-4-methylbenzenesulfonamide (2g, 4.70mmol ) and methyl 4-(2-bromoacetyl)bicyclo[2.2.1]heptane-1-carboxylate (1.34g, 4.89mmol) were dissolved in isopropanol (20mL), and N,N-di Isopropylethylamine (0.82g, 6.35mmol), stirred and reacted at 50°C.
  • Step 4 Methyl 4-((S)-2-((N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3- Synthesis of (yl)-4-methylphenyl)sulfonyl)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 5 4-((S)-4-((4-methylphenyl)sulfonyl)-6-(3-(difluoromethoxy)-5-fluorophenyl)-3,4-bis Synthesis of Hydrogen-2H-Benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic Acid
  • Step 1 Methyl 4-((S)-2-((N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3- Synthesis of -3-((trimethylsilyl)ethynyl))phenyl)sulfonyl)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 2 4-((S)-6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-ethynylphenyl)sulfonyl)-3,4-di Synthesis of Hydrogen-2H-Benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic Acid
  • Step 3 4-(2-(N-(5-bromo-2-fluorophenyl)-N-((3-(trifluoromethyl)phenyl)sulfonamido)acetyl)bicyclo[2.2.1 ]Synthesis of heptane-1-methyl carboxylate
  • Step 4 4-((S)-2-((N-(5-Bromo-2-fluorophenyl)-3-(trifluoromethyl)phenyl)sulfonamide)-1-hydroxyethyl)bicyclo [2.2.1] Synthesis of heptane-1-carboxylate
  • Step 5 Methyl 4-((S)-2-((N-(3'-ethoxy-4,5'-difluoro-[1,1'-biphenyl]-3-yl)-3 Synthesis of -(trifluoromethyl)phenyl)sulfonamido)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 6 4-((S)-6-(3-Ethoxy-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-bis Synthesis of Hydrogen-2H-Benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic Acid
  • Example 29 4-((S)-6-(3-fluoro-5-(methoxy-d 3 )phenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl) Synthesis of -3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 1 Synthesis of 1-bromo-3-fluoro-5-(methoxy-d 3 )benzene
  • Step 2 2-(3-fluoro-5-(methoxy-d 3 )phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane synthesis
  • Step 3 Methyl 4-((S)-2-((N-(3',4-difluoro-5'-(methoxy-d 3 )-[1,1'-biphenyl]-3 Synthesis of -yl)-3-(trifluoromethyl)phenylsulfonamido)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 4 4-((S)-6-(3-fluoro-5-(methoxy-d 3 )phenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)- Synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 3 Methyl 4-((S)-2-((N-(3'-chloro-4-fluoro-5'-methoxy-[1,1'-biphenyl]-3-yl)- Synthesis of 3-(trifluoromethyl)phenyl)sulfonamido)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 4 4-((S)-6-(3-Chloro-5-methoxyphenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-bis Synthesis of Hydrogen-2H-Benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic Acid
  • reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL ⁇ 2), the combined organic phases were washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, concentrated under reduced pressure, and passed through silica gel column chromatography.
  • Step 1 Synthesis of 3-chloro-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)benzenesulfonamide
  • Step 2 Methyl 4-(N-((3-chlorophenyl)sulfonyl)-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'- Synthesis of biphenyl]-3-yl)glycyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 3 Methyl 4-((S)-2-((3-chloro-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl Synthesis of ]-3-yl)phenyl)sulfonamide)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • the reaction solution was cooled to room temperature, washed with water (10mL ⁇ 2), washed with HCl aqueous solution (2M, 10mL ⁇ 2), dried the organic phase with anhydrous sodium sulfate, and concentrated the filtrate under reduced pressure to remove the solvent to obtain a brown concentrated solution.
  • the concentrated solution was dissolved in ethyl acetate (10 mL), 2-mercaptonicotinic acid (0.20 g, 0.80 mmol) and activated carbon (1.07 g) were added, and the reaction was stirred at 80° C. for 1.5 h.
  • Step 4 4-((S)-4-((3-Chlorophenyl)sulfonyl)-6-(3-(difluoromethoxy)-5-fluorophenyl)-3,4-dihydro Synthesis of -2H-Benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 1 Synthesis of 4-bromo-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)benzenesulfonamide
  • Step 2 Methyl 4-(N-((4-bromophenyl)sulfonyl)-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'- Synthesis of biphenyl]-3-yl)glycyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 3 Methyl 4-((S)-2-((4-bromo-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl Synthesis of ]-3-yl)phenyl)sulfonamide)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • the reaction solution was cooled to room temperature, washed with water (10mL ⁇ 2), washed with aqueous HCl (2M, 10mL ⁇ 2), dried the organic phase over anhydrous sodium sulfate, and concentrated the filtrate under reduced pressure to remove the solvent to obtain a brown concentrated solution.
  • the concentrated solution was dissolved in ethyl acetate (10 mL), 2-mercaptonicotinic acid (0.11 g, 0.74 mmol) and activated carbon (1.00 g) were added, and the reaction was stirred at 80° C. for 5 h.
  • Step 4 4-((S)-4-((4-bromophenyl)sulfonyl)-6-(3-(difluoromethoxy)-5-fluorophenyl)-3,4-dihydro Synthesis of -2H-Benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Example 34 4-((S)-4-((4-cyclopropylphenyl)sulfonyl)-6-(3-(difluoromethoxy)-5-fluorophenyl)-3,4 -Synthesis of dihydro-2H-benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 1 Synthesis of 4-cyclopropyl-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)benzenesulfonamide
  • Step 2 Methyl 4-(N-((4-cyclopropylphenyl)sulfonyl)-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1 Synthesis of '-biphenyl]-3-yl)glycyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 3 Methyl 4-((S)-2-((4-cyclopropyl-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'- Synthesis of biphenyl]-3-yl)phenyl)sulfonamide)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • the reaction solution was cooled to room temperature, washed with water (10mL ⁇ 2), washed with aqueous HCl (2M, 10mL ⁇ 2), dried the organic phase over anhydrous sodium sulfate, and concentrated the filtrate under reduced pressure to remove the solvent to obtain a brown concentrated solution.
  • the concentrated solution was dissolved in ethyl acetate (10 mL), 2-mercaptonicotinic acid (91 mg, 0.59 mmol) and activated carbon (0.79 g) were added, and the reaction was stirred at 80° C. for 5 h.
  • Step 4 4-((S)-4-((4-cyclopropylphenyl)sulfonyl)-6-(3-(difluoromethoxy)-5-fluorophenyl)-3,4- Synthesis of Dihydro-2H-benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Example 35 4-((S)-6-(3-fluoro-5-(trifluoromethyl)phenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3 , Synthesis of 4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • 1-fluoro-3-iodo-5-(trifluoromethyl)benzene (869-1) (1.2g, 4.14mmol), bis(pinacol) diboron (1.3g, 4.97mmol), potassium acetate ( 0.8g, 8.28mmol), palladium acetate (46mg, 0.21mmol) and dicyclohexyl-[2-(2-methylphenyl)phenyl]phosphine (150mg, 0.41mmol) dissolved in N,N-dimethyl Formamide (20 mL), stirred at 80° C. for 3 h under nitrogen protection.
  • Step 3 Methyl 4-((S)-2-((N-(3',4-difluoro-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl Synthesis of )-3-(trifluoromethyl)phenyl)sulfonamido)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 4 4-((S)-6-(3-fluoro-5-(trifluoromethyl)phenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3, Synthesis of 4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 1 Synthesis of 3-bromo-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)benzenesulfonamide
  • Step 2 Methyl 4-(N-((3-bromophenyl)sulfonyl)-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'- Synthesis of biphenyl]-3-yl)glycyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 3 Methyl 4-((S)-2-((3-bromo-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl Synthesis of ]-3-yl)phenyl)sulfonamido)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (50 mL), adjusted to pH ⁇ 4 with 4M hydrochloric acid, separated the organic phase, washed the organic phase with water (50 mL ⁇ 2), dried the organic phase over anhydrous sodium sulfate, The filtrate was concentrated by rotary evaporation under reduced pressure to remove the solvent to obtain a yellow viscous liquid (45 mg, yield: 89.79%).
  • Step 4 4-((S)-4-((3-Bromophenyl)sulfonyl)-6-(3-(difluoromethoxy)-5-fluorophenyl)-3,4-dihydro Synthesis of -2H-Benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Example 37 4-((S)-4-((3-cyclopropylphenyl)sulfonyl)-6-(3-(difluoromethoxy)-5-fluorophenyl)-3,4 -Synthesis of dihydro-2H-benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 1 Synthesis of 3-cyclopropyl-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)benzenesulfonamide
  • Step 2 Methyl 4-(N-((3-cyclopropylphenyl)sulfonyl)-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1 Synthesis of '-biphenyl]-3-yl)glycyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 3 Methyl 4-((S)-2-((3-cyclopropyl-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'- Synthesis of biphenyl]-3-yl)phenyl)sulfonamido)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (50 mL), adjusted to pH ⁇ 4 with 4M hydrochloric acid, separated the organic phase, washed the organic phase with water (50 mL ⁇ 2), dried the organic phase over anhydrous sodium sulfate, The filtrate was concentrated by rotary evaporation under reduced pressure to remove the solvent to obtain a yellow viscous liquid (295 mg, yield: 99.02%).
  • Step 4 4-((S)-4-((3-cyclopropylphenyl)sulfonyl)-6-(3-(difluoromethoxy)-5-fluorophenyl)-3,4- Synthesis of Dihydro-2H-benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Example 38 4-((S)-4-((3-tert-butylphenyl)sulfonyl)-6-(3-(difluoromethoxy)-5-fluorophenyl)-3,4 -Dihydro-2H-benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 1 Synthesis of 3-tert-butyl-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)benzenesulfonamide
  • Step 2 Methyl 4-(N-((3-tert-butylphenyl)sulfonyl)-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1 Synthesis of '-biphenyl]-3-yl)glycyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 3 Methyl 4-((S)-2-((3-tert-butyl-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'- Synthesis of biphenyl]-3-yl)phenyl)sulfonamido)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (50 mL), adjusted to pH ⁇ 4 with 4M hydrochloric acid, separated the organic phase, washed the organic phase with water (50 mL ⁇ 2), dried the organic phase over anhydrous sodium sulfate, The filtrate was concentrated by rotary evaporation under reduced pressure to remove the solvent to obtain a yellow viscous liquid (46 mg, yield: 91.19%).
  • Step 4 4-((S)-4-((3-tert-Butylphenyl)sulfonyl)-6-(3-(difluoromethoxy)-5-fluorophenyl)-3,4- Synthesis of Dihydro-2H-benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Example 39 4-((S)-6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-isopropylphenyl)sulfonyl)-3,4 -Synthesis of dihydro-2H-benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 1 Synthesis of N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)-3-isopropylbenzenesulfonamide
  • Step 2 Methyl 4-(N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((3 Synthesis of -isopropylphenyl)sulfonyl)glycyl)bicyclo[2.2.1]heptane-1-carboxylate
  • N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)-3-isopropylbenzenesulfonamide 500mg, 1.10 mmol
  • methyl 4-(2-bromoacetyl)bicyclo[2.2.1]heptane-1-carboxylate 454 mg, 1.65 mmol
  • isopropanol (2 mL)
  • N,N-diiso Propylethylamine (213mg, 1.65mmol
  • Step 3 Methyl 4-((S)-2-((N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3- Synthesis of -3-isopropylphenyl)sulfonamido)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 4 4-((S)-6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-isopropylphenyl)sulfonyl)-3,4- Synthesis of Dihydro-2H-benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 1 Synthesis of 4-cyano-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'-biphenyl]-3-yl)benzenesulfonamide
  • Step 2 Methyl 4-(N-((4-cyanophenyl)sulfonyl)-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1' Synthesis of -biphenyl]-3-yl)glycyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 3 Methyl 4-((S)-2-((4-cyano-N-(3'-(difluoromethoxy)-4,5'-difluoro-[1,1'- Synthesis of phenyl]-3-yl)phenyl)sulfonamido)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 4 4-((S)-4-((4-cyanophenyl)sulfonyl)-6-(3-(difluoromethoxy)-5-fluorophenyl)-3,4-bis Synthesis of Hydrogen-2H-Benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic Acid
  • Step 1 Synthesis of 2-(3-fluoro-5-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
  • Step 2 N-(3',4-Difluoro-5'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)-3-(trifluoromethyl)benzenesulfonate Amide synthesis
  • N-(5-bromo-2-fluorophenyl)-3-(trifluoromethyl)benzenesulfonamide 1000mg, 1.93mmol
  • 2-(3-fluoro-5-(trifluoromethoxy)benzene base)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 845mg, 2.76mmol
  • potassium carbonate 1041mg, 7.53mmol
  • [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex 102 mg, 0.13 mmol
  • 1,4-dioxane 5.0 mL
  • water 1.0 mL
  • Step 3 Methyl 4-(N-(3',4-difluoro-5'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)-N-((3 Synthesis of -(trifluoromethyl)phenyl)sulfonyl)glycyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 4 Methyl 4-((S)-2-((N-(3',4-difluoro-5'-(trifluoromethoxy)-[1,1'-biphenyl]-3- Synthesis of -3-(trifluoromethyl)phenylsulfonamido)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 5 4-((S)-6-(3-fluoro-5-(trifluoromethoxy)phenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3 , Synthesis of 4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 3 Synthesis of N-(3',4-difluoro-5'-methoxy-[1,1'-biphenyl]-3-yl)-3-(trifluoromethyl)benzenesulfonamide
  • Step 4 Methyl 4-(N-(3',4-difluoro-5'-methoxy-[1,1'-biphenyl]-3-yl)-N-((3-(trifluoro Synthesis of Methyl)phenyl)sulfonyl)glycyl)bicyclo[2.2.1]heptane-1-carboxylate
  • N-(3',4-difluoro-5'-methoxy-[1,1'-biphenyl]-3-yl)-3-(trifluoromethyl)benzenesulfonamide 500mg, 1.13mmol
  • methyl 4-(2-bromoacetyl)bicyclo[2.2.1]heptane-1-carboxylate 466mg, 1.69mmol
  • isopropanol 3.0mL
  • N,N-diiso Propylethylamine (219mg, 1.69mmol
  • Step 5 Methyl 4-((S)-2-((N-(3',4-difluoro-5'-methoxy-[1,1'-biphenyl]-3-yl)-3 Synthesis of -(trifluoromethyl)phenylsulfonamido)-1-hydroxyethyl)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 6 4-((S)-6-(3-fluoro-5-methoxyphenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-bis Synthesis of Hydrogen-2H-Benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic Acid
  • Example 43 4-((S)-6-(3-fluoro-5-isopropoxyphenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4 -Synthesis of dihydro-2H-benzo[b][1,4]oxazin-2-yl)bicyclo[2.2.1]heptane-1-carboxylic acid

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Abstract

一类可作为RORγt激动剂的苯并氮杂环类化合物及其在药物中的应用，以及包含这类化合物的药物组合物及其在药物中的应用。具体地，如式(I)所示的化合物，或式(I)所示的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，以及包含这类化合物的药物组合物。该类化合物和药物组合物用于预防、治疗或减轻患者由RORγt介导的疾病。

Description

苯并氮杂环类化合物及其在药物中的应用
相关申请
本发明要求中国专利申请号为202110750163.1的优先权，该申请于2021年07月02日递交至国家知识产权局，其所有内容在此作为引用并入本文。
技术领域
本发明属于药物领域，公开了一类具有RORγt活性的苯并氮杂环类化合物及其制备方法，以及包含这类化合物的药物组合物及其在药物中的应用。
背景技术
视黄酸受体相关孤儿受体(retinoic acid receptor-related orphan receptors，RORs)是属于甾体激素核受体超家族(steroid hormone nuclear receptor super family)的一员。其家族包括RORα、RORβ和RORγ，RORs包括4个主要区域，这些区域被大多数核受体所共享，N-末端A/B结构域，DNA-binding结构域，铰链结构域和配体结合结构域。每个ROR基因产生各自的亚型，仅在其N-末端A/B结构域不同。RORγ具有两种亚型---RORγl和RORγt。RORγ1在多种组织中表达，例如胸腺、肌肉和肾脏，而RORγt仅在部分免疫细胞中表达(如Th17细胞)，并作为IL-17A和IL-17F的转录因子，以及Th17细胞分化的主要调控因子。Thl7细胞是T辅助细胞的子集，其优先产生促炎细胞因子IL-17A，IL-17F，IL-21和IL-22。Thl7细胞及其效应分子(如IL-17，IL-21，IL-22，GM-CSF和CCL20)与几种自身免疫的发病机制有关，研究也已证实Th17细胞与多发性硬化症、类风湿性关节炎、牛皮癣、哮喘、自身免疫性疾病及移植物抗宿主病等几种自身免疫病和炎性疾病的发病机理有关(Jetten et al.,Nucl.Recept.Signal,2009,7:e003；Manel et al.,Nat.Immunol,2008,9,641-649)，同时也与炎症相关性肿瘤的发生有一定关系，Th17细胞在疾病过程中被激活，并负责募集其他炎症细胞类型，例如嗜中性粒细胞，以介导靶组织的病理(Korn et al.,Annu.Rev.Immunol.,2009,27:485-517)。因此，具有RORγt调节作用的药物有望通过调节Th17细胞的分化和激活而显示出对各种免疫疾病的治疗效果。
RORγt激动剂能够促进Th17细胞的分化，增强促炎细胞因子的水平，从而提高淋巴细胞的细胞毒性。与此同时，RORγt激动剂能够抑制调节性T细胞的产生，而这些细胞会抑制免疫反应，因此激动剂能够将免疫反应的平衡推向激活的方向。RORγt激动剂还能够促进如CD226、CD27和4-1BB(CD137)等一系列共刺激分子(Co-Stimulatory Molecule)的表达，并且抑制PD-1、TIGIT、TIM3、CD73和LAG3等共抑制分子(Co-Inhibitory Molecule)的表达，从而促进T细胞激活。研究显示，在多种同源肿瘤模型(Syngeneic Tumor Models)中，RORγt激动剂能够通过免疫反应抑制肿瘤的生长并且延长动物的生存时间。
Lycera公司最早报道RORγt小分子激动剂的研发，2017年，Lycera公司宣布启动临床1/2a期试验来检验其研发的RORγt激动剂LYC-55716治疗携带晚期、复发性或难治性实体瘤患者的功效。目前，RORγt激动剂在抗肿瘤方面已经得到关注，未来IL-17家族为肿瘤治疗提供良好的靶点也是非常有可能的；因此，RORγt被认为是抗肿瘤、抗炎以及自身免疫疾病药物研发的新靶点，将可作为癌症及自身免疫炎症疾病治疗的新途径。
发明内容
本发明解决的技术问题是提供了一类可作为RORγt激动剂的苯并氮杂环类化合物，其为如式(I)或(I-A)所示的化合物，或式(I)或(I-A)所示的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，以及包含这类化合物的药物组合物及其在药物中的应用。
具体地，一方面，本发明提供一种化合物，其为如式(I-A)所示的结构或如式(I-A)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2022103288-appb-000001
其中
Q 1和Q 2各自独立地为CH或N；
环A 1为C 6-10亚芳基、5-10元亚杂芳基、C 3-12亚碳环基或3-12元亚杂环基；
X为C 6-10芳基或5-10元杂芳基，且X任选地被1、2、3或4个选自D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6氘代烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代；
Y为-O-、-C(＝O)-、-CR 4R 5-、-NR 4-、-S-、-S(＝O)-或-S(＝O) 2-；
Z为CR 4或N；
L为键、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、C 1-6亚烷基、-C 1-6亚烷基-O-*、-C 1-6亚烷基-NR 4-*、-C 1-6亚烷基-NR 4-C(＝O)-*、-C 1-6亚烷基-C(＝O)-NR 4-*、-C 1-6亚烷基-NR 4-C(＝O)-NR 5-*、-C 1-6亚烷基-C(＝O)-*、-C 1-6亚烷基-S(＝O)-*、-C 1-6亚烷基-S(＝O) 2-*、-C 1-6亚烷基-NR 4-S(＝O) 2-*或-C 1-6亚烷基-S(＝O) 2-NR 4-*，其中“*”表示与环A 2连接；其中所述的各C 1-6亚烷基独立任选地被1、2或3个选自D、F、Cl、Br、I、OH、CN、NH 2、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、氧代、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代；
环A 2为5-12元亚螺环基、5-12元亚桥环基、亚环己基或亚环庚基；
各R 2独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)ONa、--C(＝O)OR 5、-C(＝O)R 5、-C(＝O)NR 4R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-C(＝O)NR 4-S(＝O) 2R 5、氧代、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基或5-10元杂芳基；
R 1和R 3各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基或3-12元杂环基；
各R 4独立地为H、D、-C(＝O)OR 5a、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、C 1-6烷基、C 1-6卤代烷基、 C 1-6羟基烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基或5-12元杂芳基；
R 5和R 5a各自独立地为H、D、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基或5-10元杂芳基；
R 6和R 6a各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基或3-12元杂环基；和
m、n和q各自独立地为1、2、3或4。
另一方面，本发明提供一种化合物，其为如式(I)所示的结构或如式(I)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2022103288-appb-000002
其中：
环A 1为C 6-10亚芳基、5-10元亚杂芳基、C 3-12亚碳环基或3-12元亚杂环基；
X为C 6-10芳基或5-10元杂芳基，且X任选地被1、2、3或4个选自D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6氘代烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代；
Y为-O-、-C(＝O)-、-CR 4R 5-、-NR 4-、-S-、-S(＝O)-或-S(＝O) 2-；
Z为CR 4或N；
L为键、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、C 1-6亚烷基、-C 1-6亚烷基-O-*、-C 1-6亚烷基-NR 4-*、-C 1-6亚烷基-NR 4-C(＝O)-*、-C 1-6亚烷基-C(＝O)-NR 4-*、-C 1-6亚烷基-NR 4-C(＝O)-NR 5-*、-C 1-6亚烷基-C(＝O)-*、-C 1-6亚烷基-S(＝O)-*、-C 1-6亚烷基-S(＝O) 2-*、-C 1-6亚烷基-NR 4-S(＝O) 2-*或-C 1-6亚烷基-S(＝O) 2-NR 4-*；其中“*”表示“*”处的连接端与环A 2连接；其中所述的各C 1-6亚烷基独立任选地被1、2或3个选自D、F、Cl、Br、I、OH、CN、NH 2、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、氧代、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代；
环A 2为5-12元亚螺环基、5-12元亚桥环基、亚环己基或亚环庚基；
各R 2独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)ONa、--C(＝O)OR 5、-C(＝O)R 5、-C(＝O)NR 4R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-C(＝O)NR 4-S(＝O) 2R 5、氧代、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基或5-10元杂芳基；
R 1和R 3各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、 -S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基或3-12元杂环基；
各R 4独立地为H、D、-C(＝O)OR 5a、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基或5-12元杂芳基；
R 5和R 5a各自独立地为H、D、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基或5-10元杂芳基；
R 6和R 6a各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基或3-12元杂环基；和
m、n和q各自独立地为1、2、3或4。
在一些实施方案中，本发明所述的化合物具有式(II)、(III)、(IV)或(V)所示的结构，或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2022103288-appb-000003
其中，环A 1、环A 2、X、Y、Z、L、R 1、R 2、R 3、m、n、q、R 6、R 6a和“*”各自具有如本发明所述的定义。
在一些实施方案中，环A 1为亚苯基、亚萘基、亚吡啶基、亚哒嗪基、亚嘧啶基、亚咪唑基、亚吡唑基、亚吡咯基、亚吲哚基、亚喹啉基、亚吡喃基、亚呋喃基、亚环戊基、亚环己基、亚哌啶基、亚吗啉基、亚吡咯烷基或亚哌嗪基。
在一些实施方案中，X为苯基、萘基、吡啶基、哒嗪基、嘧啶基、咪唑基、吡唑基、吡咯基、吲哚基、喹啉基或呋喃基；且X任选地被1、2、3或4个选自D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基、C 1-4氘代烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基、3-7元杂环基、C 6-10芳基或5-10元杂芳基的取代基所取代；其中R 4和R 5各自具有本发明所述的定义。
在一些实施方案中，X为苯基、萘基、吡啶基、哒嗪基、嘧啶基、咪唑基、吡唑基、吡咯基、吲哚基、喹啉基或呋喃基；且X任选地被1、2、3或4个选自D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH 2CH 2CH 2CH 3、 -CH 2CH(CH 3)CH 3、-C(CH 3) 2CH 3、-CH＝CH 2、-CH＝CHCH 3、-CH 2CH＝CH 2、-C≡CH、-C≡CCH 3、-C≡CCH 2CH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 3、-CH 2C(CH 3)(OH)CH 3、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3)CH 3、-OCH 2CH 2CH 2CH 3、-OCD 3、-OCD 2CD 3、-OCH 2CH 2OH、-OCH 2CH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、-OCH 2CH 2CF 3、-OCH 2CH 2CHF 2、-OCHFCHFCH 3、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基的取代基所取代；其中R 4和R 5各自具有本发明所述的定义。
在一些实施方案中，L为键、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、C 1-4亚烷基、-C 1-4亚烷基-O-*、-C 1-4亚烷基-NR 4-*、-C 1-4亚烷基-NR 4-C(＝O)-*、-C 1-4亚烷基-C(＝O)-NR 4-*、-C 1-4亚烷基-NR 4-C(＝O)-NR 5-*、-C 1-4亚烷基-C(＝O)-*、-C 1-4亚烷基-S(＝O)-*、-C 1-4亚烷基-S(＝O) 2-*、-C 1-4亚烷基-NR 4-S(＝O) 2-*或-C 1-4亚烷基-S(＝O) 2-NR 4-*，其中“*”表示“*”处的连接端与环A 2连接；其中所述的各C 1-4亚烷基独立任选地被1、2或3个选自D、F、Cl、Br、I、OH、CN、NH 2、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基、3-7元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代；其中，R 4、R 5、R 5a、环A 2和“*”各自具有如本发明所述的定义。
在一些实施方案中，L为键、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、-CH 2-、-(CH 2) 2-、-CH 2-O-*、-(CH 2) 2-O-*、-CH 2-NR 4-*、-(CH 2) 2-NR 4-*、-CH 2-NR 4-C(＝O)-*、-CH 2-C(＝O)-NR 4-*、-CH 2-NR 4-C(＝O)-NR 5-*、-CH 2-C(＝O)-*、-CH 2-S(＝O)-*、-CH 2-S(＝O) 2-*、-CH 2-NR 4-S(＝O) 2-*或-CH 2-S(＝O) 2-NR 4-*，其中“*”表示“*”处的连接端与环A 2连接；其中所述的-CH 2-和-(CH 2) 2-各自独立任选地被1、2或3个选自D、F、Cl、Br、I、OH、CN、NH 2、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、氧代、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH＝CH 2、-CH＝CHCH 3、-CH 2CH＝CH 2、-C≡CH、-C≡CCH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-OCH 3、-OCH 2CH 3、-OCH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基的取代基所取代；其中，R 4、R 5、R 5a、环A 2和“*”各自具有如本发明所述的定义。
在一些实施方案中，环A 2为以下子结构式：
Figure PCTCN2022103288-appb-000004
其中，各环A 2子结构式中的“*”表示*处的连接端与式(I-A)、(I)、(II)、(III)或(IV)中的L连接；
Z 1为CH或N；
Z 2为-CH 2-、-NH-、-S-、-O-、-S(＝O)-或-S(＝O) 2-；
Z 3和Z 4各自独立地为键、-O-、-NH-、-OCH 2-、-CH 2O-、-CH 2-或-(CH 2) 2-；和
t和t 1各自独立地为0或1；
在一些实施方案中，环A 2为以下子结构式：
Figure PCTCN2022103288-appb-000005
Figure PCTCN2022103288-appb-000006
其中，各环A 2子结构式中的“*”表示*处的连接端与式(I-A)、(I)、(II)、(III)、(IV)或(V)中的L连接。
在一些实施方案中，各R 2独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)ONa、-C(＝O)OR 5、-C(＝O)R 5、-C(＝O)NR 4R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-C(＝O)NR 4-S(＝O) 2R 5、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；其中，R 4和R 5各自具有如本发明所述的定义。
在一些实施方案中，各R 2独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)ONa、-C(＝O)OR 5、-C(＝O)R 5、-C(＝O)NR 4R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-C(＝O)NR 4-S(＝O) 2R 5、氧代、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-C(CH 3) 3、-CH 2CH 2CH 2CH 3、-C≡CH、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 3、-CH 2C(CH 3)(OH)CH 3、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH 2CH 2CH 2CH 3、-OCH 2CH 2OH、-OCH 2CH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、-OCH 2CH 2CF 3、-OCH 2CH 2CHF 2、-OCHFCHFCH 3、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基；其中，R 4和R 5各自具有如本发明所述的定义。
在一些实施方案中，R 1和R 3各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷 氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基或3-7元杂环基；其中，R 4和R 5各自具有如本发明所述的定义。
在一些实施方案中，R 1和R 3各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH＝CH 2、-CH＝CHCH 3、-CH 2CH＝CH 2、-C≡CH、-C≡CCH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-OCH 3、-OCH 2CH 3、-OCH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基或吗啉基；其中，R 4和R 5各自具有如本发明所述的定义。
在一些实施方案中，各R 4独立地为H、D、-C(＝O)OR 5a、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-7环烷基、3-7元杂环基、C 6-10芳基或5-6元杂芳基；
R 5和R 5a各自独立地为H、D、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-7环烷基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；
R 6和R 6a各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基或3-7元杂环基；。
在一些实施方案中，各R 4独立地为H、D、-C(＝O)OR 5a、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH 2CH 2CH 2CH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 3、-CH 2C(CH 3)(OH)CH 3、环丙基、环戊基、环己基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基；
各R 5和R 5a独立地为H、D、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH 2CH 2CH 2CH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 3、-CH 2C(CH 3)(OH)CH 3、环丙基、环戊基、环己基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基；
各R 6和R 6a独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-OCH 3、-OCH 2CH 3、-OCH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基或吗啉基。
在一些实施方案中，
Figure PCTCN2022103288-appb-000007
为
Figure PCTCN2022103288-appb-000008
在一些实施方案中，X为
Figure PCTCN2022103288-appb-000009
其中，R 01和R 02各自独立地为D、F、Cl、Br、I、OH、CN、NO 2、-NR 4R 5、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基、C 1-4氘代烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷 基、C 3-7环烷氧基、3-7元杂环基、C 6-10芳基或5-10元杂芳基。
在一些实施方案中，R 01和R 02各自独立地为D、F、Cl、Br、I、OH、CN、NO 2、-NH 2、-NH(CH 3)、-N(CH 3) 2、-N(CH 2CH 3) 2、-NH(CH 2CH 3)、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH 2CH 2CH 2CH 3、-CH 2CH(CH 3)CH 3、-C(CH 3) 2CH 3、-CH＝CH 2、-CH＝CHCH 3、-CH 2CH＝CH 2、-C≡CH、-C≡CCH 3、-C≡CCH 2CH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 3、-CH 2C(CH 3)(OH)CH 3、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3)CH 3、-OCH 2CH 2CH 2CH 3、-OCD 3、-OCD 2CD 3、-OCH 2CH 2OH、-OCH 2CH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、-OCH 2CH 2CF 3、-OCH 2CH 2CHF 2、-OCHFCHFCH 3、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基。
另一方面，本发明涉及药物组合物，该药物组合物，包含本发明式(I-A)、(I)、(II)、(III)、(IV)或(V)所述的化合物，或其立体异构体，互变异构体，氮氧化物，溶剂化物，代谢产物，药学上可接受的盐或它的前药，任选地进一步包含药学上可接受的载体、辅剂、媒介物或它们的组合。
另一方面，本发明涉及式(I-A)、(I)、(II)、(III)、(IV)或(V)所述化合物或其药物组合物在制备药物中的用途，其中所述药物用于预防、治疗或减轻患者由RORγt介导的疾病。
在一些实施方案中，本发明所述的由RORγt介导的疾病包括癌症、多发性硬化症、类风湿性关节炎、风湿性关节炎、骨关节炎、强直性脊柱炎、牛皮癣，哮喘、自身免疫性疾病、移植物抗宿主病、银屑病、系统性红斑狼疮、炎性肠病、结肠炎、细菌感染、真菌感染、慢性阻塞性肺病、过敏性鼻炎、过敏性皮炎、克罗恩病或川崎病。
本发明所述的肿瘤或癌症选自非霍奇金淋巴瘤、弥漫大B细胞淋巴瘤、滤泡性淋巴瘤、滑膜肉瘤、乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、黑色素瘤、神经胶质瘤、神经胶母细胞胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
另一方面，本发明涉及式(I-A)、(I)、(II)、(III)、(IV)或(V)所述化合物的制备、分离和纯化的方法。
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。其他方面的内容将在下面作更加具体完整的描述。
本发明详细说明书
定义和一般术语
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明，应当应用本发明所使用的下列定义。出于本发明的目的，化学元素与元素周期表 CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本发明。
除非另有说明或者上下文中有明显的冲突，本发明所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本发明所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。
术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反异构体)、阻转异构体，等等。除非其他方面表明，本发明所描述的结构式的所有立体异构体或立体异构体的混合物都属于本发明的范围。另外，除非其他方面表明，本发明所描述的化合物的结构式任选包括一个或多个不同的原子的富集同位素。
“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2 nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
术语“任选”、“任选地”或“可任选地”是指随后描述的事件或情形可以但不一定出现，即，该描述包括其中所述事件或情形出现的情况以及不出现的情况。例如，“任选地被1、2、3或4个…所取代”包括该基团被1个、或2个、或3个、或4个所述的取代基所取代的情况，以及该基团不被所述取代基取代的情况。进一步地，当该基团被1个以上所述取代基取代时，所述取代基之间是相互独立的，即，所述的1个以上的取代基可以是互不相同的，也可以是相同的；或“可任选地与合适的酸成盐”包括该化合物与合适的酸成盐或者不与任何酸成盐，可以任选以1:1、或1:1.5、或1:2、或1:3、或2:1、或3:1的比例成盐。
像本发明所描述的，本发明的化合物可以独立任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”、“任选地被……所取代”或“任选地包含”这个术语与“取代或非取代的”这个术语可以交换使用。术语“独立任选地”与术语“任选独立地”可以交换使用，一般而言，术语“独立任选地”不论是否位于术语“取代的”之前，表示所给结构中的一个或多个氢原子可以被具体取代基1所取代或未取代。除非其他方面表明，一个任选的取代基团可以由一个取代基1在基团的各个可取代的合理的位置进行取代。当所给出的结构式中不止一个位置能被选自具体基团的一个或多个取代基1所取代，那么取代基可以相同或不同地在结构式中各个合理的位置取代。其中所述的取代基1可以是，但并不限于：D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-C(＝O)NR 4R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、氧代、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基或5-10元杂芳基，等。在合理的情况下，取代基1能进一步独立任选地被取代基2单取代或被相同或不同的多个取代基2多取代。其中所述的取代基2可以是，但不限于：D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-C(＝O)NR 4R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、氧代、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基或5-10 元杂芳基等。其中R 4和R 5各自具有如本发明所述的定义。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1- 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
本发明使用的术语“烷基”包括1-20个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，烷基基团含有1-10个碳原子；另外一些实施例是，烷基基团含有1-8个碳原子；另外一些实施例是，烷基基团含有1-6个碳原子，另外一些实施例是，烷基基团含有1-4个碳原子；另外一些实施例是，烷基基团含有1-3个碳原子。烷基基团更进一步的实例包括，但并不限于，甲基(Me，-CH 3)，乙基(Et，-CH 2CH 3)，正丙基(n-Pr，-CH 2CH 2CH 3)，异丙基(i-Pr，-CH(CH 3) 2)，正丁基(n-Bu，-CH 2CH 2CH 2CH 3)，2-甲基丙基或异丁基(i-Bu，-CH 2CH(CH 3) 2)，1-甲基丙基或仲丁基(s-Bu，-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu，-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，正庚基，正辛基，等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。
术语“亚烷基”表示从饱和的直链或支链烃中去掉两个氢原子所得到的饱和的二价烃基基团。亚烷基基团的实例包括但不限于：-CH 2-、-CH 2CH 2-、-CH(CH 3)CH 2-，等。
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点为碳-碳sp 2双键，其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代，其包括“cis”和“tans”的定位，或者“E”和“Z”的定位。在一实施方案中，烯基基团包含2-8个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH 2)、烯丙基(-CH 2CH＝CH 2)、丙烯基(-CH＝CH-CH 3)等等。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，炔基基团包含2-8个碳原子；在另一些实施方案中，炔基基团包含2-6个碳原子；在又一些实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、1-丙炔基(-C≡C-CH 3)等等。
术语“卤代烷基”表示烷基可以被一个或多个相同或不同卤素原子所取代的情况。其中烷基基团具有如本发明所述的含义，卤代烷基的实例包括，但并不限于-CF 3，-CHF 2，-CH 2F，-CHFCH 2F，-CHFCHFCH 2F、-CHCl 2、等。
术语“羟基烷基”表示被一个或多个羟基取代的烷基。在一些实施方案中，羟基烷基表示被1、2、3或4个羟基取代的烷基。在一些实施方案中，羟基烷基表示被一个或两个羟基取代的烷基。在一些实施方案中，羟基烷基表示C 1-6羟基烷基，即C 1-6烷基被一个或多个羟基取代，优选的，C 1-6羟基烷基表示C 1-6烷基被一个羟基取代。在一些实施方案中，羟基烷基表示C 1-4羟基烷基。在一些实施方案中，羟基烷基表示C 1-3羟基烷基。羟基烷基的实例包括但不限于，-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 2CH 2OH，等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中，烷基基团具有如本发明所述的含义。在一些实施方案中，烷氧基基团含有1-6个碳原子；在另一些实施方案中，烷氧基基团含有1-4个碳原子；在又一些实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或 多个本发明所描述的取代基所取代。烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH 3)，乙氧基(EtO、-OCH 2CH 3)，正丙氧基(n-PrO、n-丙氧基、1-丙氧基、-OCH 2CH 2CH 3)，异丙氧基(-OCH(CH 3) 2)，等等。
术语“羟基烷氧基”表示被一个或多个羟基取代的烷氧基基团，其中烷氧基基团具有如本发明所述的定义。在一些实施方案中，羟基烷氧基基团含有1-6个碳原子；在另一些实施方案中，羟基烷氧基基团含有1-4个碳原子；在又一些实施方案中，羟基烷氧基基团含有1-3个碳原子。羟基烷氧基基团的实例包括，但并不限于，-OCH 2CH 2OH、-OCH 2CH(OH)CH 3、-OCH 2CH(OH)CH 2(OH)，等。
术语“烷氧基烷基”表示被一个烷氧基取代的烷基，其中，烷氧基和烷基具有如本发明所述的定义。在一些实施方案中，烷氧基烷基表示C 1-6烷氧基C 1-6烷基；在另一些实施方案中，烷氧基烷基表示C 1-4烷氧基C 1-4烷基；在另一些实施方案中，烷氧基烷基表示C 1-4烷氧基C 1-3烷基；在一些实施方案中，烷氧基烷基表示C 1-3烷氧基C 1-3烷基。烷氧基烷基的实例包括但不限于，-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-CH 2OCH(CH 3)CH 3，等。
术语“烷氧基烷氧基”示被一个烷氧基取代的烷氧基，其中，烷氧基具有如本发明所述的定义。在一些实施方案中，烷氧基烷氧基表示C 1-6烷氧基C 1-6烷氧基；在另一些实施方案中，烷氧基烷基表示C 1-4烷氧基C 1-4烷氧基；在另一些实施方案中，烷氧基烷基表示C 1-4烷氧基C 1-3烷氧基；在一些实施方案中，烷氧基烷基表示C 1-3烷氧基C 1-3烷氧基。烷氧基烷氧基的实例包括但不限于，-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCH 2OCH(CH 3)CH 3，等。
术语“卤素”表示示F(氟)、Cl(氯)、Br(溴)或I(碘)。
术语“氧代”表示＝O。
术语“卤代烷氧基”表示被一个或多个卤素原子取代的烷氧基基团，其中烷氧基基团具有如本发明所述的定义。在一些实施方案中，卤代烷氧基基团含有1-6个碳原子；在另一些实施方案中，卤代烷氧基基团含有1-4个碳原子；在又一些实施方案中，卤代烷氧基基团含有1-3个碳原子。卤代烷氧基基团的实例包括，但并不限于，-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2或-OCH 2Cl。所述卤代烷氧基基团可以任选地被一个或多个本发明所描述的取代基所取代。
术语“环烷基”是指含有3-12个环碳原子的，单价或多价的非芳香性的饱和单环、双环或三环体系，其中，双环，三环或者四环体系以稠合或桥接或螺接的形式成环。在一些实施方案中，环烷基包含3-12个环碳原子；在另一些实施方案中，环烷基包含3-10个环碳原子；在另一些实施方案中，环烷基包含3-8个环碳原子；在另一些实施方案中，环烷基包含3-7个环碳原子；在又一些实施方案中，环烷基包含3-6个环碳原子。环烷基基团的实例包括，但并不限于，环丙基、环丁基、环戊基、环己基等。所述环烷基基团可以任选的被一个或多个本发明所描述的取代基所取代。
术语“环烷氧基”表示环烷基基团通过氧原子与分子其余部分相连，其中，环烷基基团具有如本发明所述的含义。在一些实施方案中，环烷氧基基团含有3-12个碳原子；在另一些实施方案中，环烷氧基基团含有3-7个碳原子；在又一些实施方案中，环烷氧基基团含有3-6个碳原子。环烷氧基基团的实例包括，但并不限于，环丙氧基、环戊氧基、环己氧基，等。所述环烷氧基基团可以任选地被一个或多个本发明所描述的取代基所取代。
术语“芳环”表示单环，双环，和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含6-10个碳原子，如芳环可以包括苯、萘和蒽。当芳环作为马库什通式中的一价连接基团时，该“芳环”表示为“芳基”；术语“C 6-10芳基”指芳基中碳原子数为6-10个，芳基具体如上定义。当芳环作为马库什通式中的二价连接基团时，该“芳环”代表“亚芳基”，亚芳基的实例包括但不限于：亚苯基、亚萘基，等；术语“C 6-10亚芳基”指亚芳基中碳原子数为6-10个，亚芳基具有如上定义。芳 基和亚芳基可以被一个或多个本发明所述的取代基所取代。
术语“杂芳环”表示含有5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中至少一个环体系是芳香族的，且至少一个环体系包含一个或多个独立选自O，S和N的杂原子，其中每一个环体系包含5-7个原子组成的环。
术语“杂芳基”表示当杂芳环作为马库什通式中的一价连接基团时，该“杂芳环”表示为“杂芳基”。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，5-10个原子组成的杂芳基或5-10元杂芳基包含1，2，3或4个独立选自O，S和N的环杂原子。在一些实施方案中，术语“杂芳基”表示含有5-6个环原子的杂芳环基或5-6元杂芳基，其中包含1，2，3或4个独立选自O，S和N的环杂原子。在一些实施方案中，术语“杂芳基”表示含有5个环原子的杂芳环基或5元杂芳基，其中包含1，2，3或4个独立选自O，S和N的环杂原子。杂芳基基团的实例包括，但并不限于，2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、三唑基(如2-三唑基或5-三唑基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基或4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基，等等。当杂芳基为连接基团时，则杂芳基表示连接的亚杂芳基。术语“亚杂芳基”表示杂芳环的环原子上去掉两个氢原子后形成的二价杂芳环基团，亚杂芳基的实例包括但不限于：亚吡啶基、亚吡唑基、亚嘧啶基，等。所述杂芳基或亚杂芳基可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“碳环”表示饱和或部分不饱和的非芳香性的碳环体系，其中环原子为碳原子，包括单碳环、桥碳环和螺碳环，其中单碳环、桥碳环和螺碳环具有如本发明所述的定义。碳环中-CH 2-基团可以任选地被-C(＝O)-替代。在一些实施方案中，碳环表示C 3-12碳环；在另一些实施方案中，碳环表示C 3-10元碳环；在另一些实施方案中，碳环表示C 3-7碳环；在另一些实施方案中，碳环表示C 3-6元碳环。当碳环作为马库什通式中的一价连接基团时，该“碳环”代表“碳环基”；当碳环作为马库什通式中的二价连接基团时，该“碳环”代表“亚碳环基”，亚碳环基的例子包括但不限于：亚环戊基、亚环己基、亚螺[2.5]辛烷基、亚双环[2.2.1]庚烷基，等。所述碳环基或亚碳环基可以任选被一个或多个本发明所述的取代基所取代。
术语“杂环”表示饱和或部分不饱和的非芳香性的杂环体系，且该体系中至少包含1个环碳原子，包含1、2、3或4个选自O、N、S、P的环杂原子。所述杂环可以是单环或多环体系；具体地，所述多环体系可以是螺杂环或桥杂环。其中，螺杂环和桥杂环具有如本发明所述的定义。杂环中-CH 2-基团可以任选地被-C(＝O)-替代；杂环中硫原子可以任选地被氧化成-S(＝O)-或-S(＝O) 2-；杂环中氮原子可以任选地被氧化成N-氧化合物；杂环中的磷原子可以任选地被氧化成P-氧化合物。在一些实施方案中，杂环表示3-12元杂环；在另一些实施方案中，杂环表示3-7元杂环；在另一些实施方案中，杂环表示3-6元杂环。当杂环作为马库什通式中的一价连接基团时，该“杂环”代表“杂环基”；当碳环作为马库什通式中的二价连接基团时，该“杂环”代表“亚杂环基”，亚杂环基的例子包括但不限于：亚哌啶基、亚吗啉基、亚吡咯烷基、亚哌嗪基、亚2-氧杂-6-氮杂螺[3.3]庚烷基或亚3-氮杂双环[3.1.1]庚烷基，等。所 述杂环基或亚杂环基可以被一个或多个本发明所述的取代基所取代。
“杂环基”可以是碳原子基或杂原子基。杂环基的实例包括，但并不限于，环氧乙烷基、吡咯烷基，四氢呋喃基(如四氢呋喃-3-基，等)、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢噻喃基、哌啶基(如N-哌啶基，2-哌啶基，3-哌啶基或4-哌啶基等)、噻噁烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、高哌啶基、氮杂环庚基、氧杂环庚基、硫杂环庚基、吗啉基(如N-吗啉基，2-吗啉基，3-吗啉基等)、硫代吗啉基、哌嗪基(如N-哌嗪基，2-哌嗪基，3-哌嗪基等)、1,2,3,6-四氢吡啶-1-基、氧氮杂
Figure PCTCN2022103288-appb-000010
基、二氮杂
Figure PCTCN2022103288-appb-000011
基、硫氮杂
Figure PCTCN2022103288-appb-000012
基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、咪唑烷基、1,2,3,4-四氢异喹啉基、1,2,6-噻二嗪烷1,1-二氧-2-基、六氢-2H-[1,4]二氧芑[2,3-c]吡咯基、喹嗪基、1,1-二氧化硫代吗啉基、2,3,3a,7a-四氢-1H-异吲哚基、异吲哚啉基、1,2,3,4-四氢喹啉基、二苯并呋喃基、二氢苯并异噻嗪基、二氢苯并异噁嗪基、异苯并四氢呋喃基、异苯并二氢吡喃基、异香豆素基、异二氢吲哚基、1,3,5-三噻烷基、2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基、1,2,3,4-四氢异喹啉基、1,3-苯并二噁茂基、2-氧杂-5-氮杂双环[2.2.1]庚-5-基、4-氧代吗啉基和嘧啶二酮基。杂环基中-CH 2-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基、嘧啶二酮基，等等。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、硫代吗啉基1,1-二氧化物，等等。
术语“螺环”表示表示两个环共有一个碳原子形成的非芳香性的饱和或部分不饱和的碳环或杂环体系，即螺环包括螺碳环和螺杂环。螺环中-CH 2-基团可以任选地被-C(＝O)-替代；螺环中硫原子可以任选地被氧化成-S(＝O)-或-S(＝O) 2-；螺环中氮原子可以任选地被氧化成N-氧化合物。在一些实施方案中，螺环含有5-12个环原子，即表示5-12元螺环；在另外一些实施方案中，螺环含有7-12个环碳原子，即表示7-12元螺环。螺碳环的实例包括但不限于：螺[3.3]庚烷、螺[2.5]辛烷、螺[4.4]壬烷、螺[3.4]辛烷、螺[4.5]癸烷，等；螺杂环的实例包括但不限于：2-氮杂螺[3.3]庚烷、2,6-二氮杂螺[3.3]庚烷、2-氧杂-6-氮杂螺[3.3]庚烷、2-硫杂-6-氮杂螺[3.3]庚烷2,2-二氧化物、2-硫杂-6-氮杂螺[3.3]庚烷2,2-二氧化物、4,7-二氮杂螺[2.5]辛烷、2,8-二氮杂螺[4.5]癸烷、2,7-二氮杂螺[4.5]癸烷、2,7-二氮杂螺[3.5]癸烷、2,7-二氮杂螺[4.4]壬烷、3-氮杂螺[5.5]十一烷、2,7-二氮杂螺[4.4]壬烷-1-酮，等等。当螺环作为马库什通式中的一价连接基团时，该“螺环”代表“螺环基”；当螺环作为马库什通式中的二价连接基团时，该“螺环”代表“亚螺环基”。亚螺环基的例子包括但不限于：
Figure PCTCN2022103288-appb-000013
Figure PCTCN2022103288-appb-000014
等。
术语“桥环”表示共用两个或两个以上环原子的非芳香性的饱和或部分不饱和的双环或多环碳环或杂环体系，即桥环包括桥碳环和桥杂环。当桥环为桥碳环时，组成桥环体系的所有环原子均为碳原子，桥碳环中-CH 2-基团可以任选地被-C(＝O)-替代；当桥环为桥杂环时，组成桥环体系的环原子中包含环碳原子和含有1、2、3或4个选自O、N、S、P的环杂原子，桥杂环中-CH 2-基团可以任选地被-C(＝O)-替代，硫原子可以任选地被氧化成-S(＝O)-或-S(＝O) 2-，氮原子可以任选地被氧化成N-氧化合物。在一些实施方案中，桥环含有5-12个环原子，即表示5-12元桥环；在另外一些实施方案中，桥碳环含有6-12个环碳原子，即表示6-12元桥碳环；在另外一些实施方案中，桥碳环含有6-10个环碳原子，即表示6-10元桥碳环。桥碳环的实例包括但不限于：二环[2.2.1]庚烷、3-氮杂双环[3.1.1]庚烷、双环[1.1.1]戊烷、2- 氮杂金刚烷、二环[2.2.2]辛烷、二环[3.2.1]辛烷、二环[2.2.2]辛烷、二环[2.2.0]己烷、二环[3.3.0]辛烷、八氢吡咯并[3,4-c]吡咯、八氢环戊二烯并[c]吡咯、八氢-1H-茚，等。当桥环作为马库什通式中的一价连接基团时，该“桥环”代表“桥环基”；当桥环作为马库什通式中的二价连接基团时，该“桥环”代表“亚桥环基”。亚桥环基的例子包括但不限于：
Figure PCTCN2022103288-appb-000015
Figure PCTCN2022103288-appb-000016
等。
术语“j-k个环原子组成的”或“j-k元”在此处可交换使用，表示所述环状基团由j-k个成环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子。所述j和k各自独立地为任意非零的自然数，且k>j；所述“j-k”包括j、k和两者之间的任意自然数。例如，“3-8个原子组成的或3-8元”、“3-6个原子组成的或3-6元”、“5-10个原子组成的或5-10元”或“5-6个原子组成的或5-6元”表示所述环状基团由3-8(即，3、4、5、6、7或8)、3-6(即，3、4、5或6)、5-10(即，5、6、7、8、9或10)或5-6(即，5或6)个环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子。具体来说，例如，“5-10个环原子组成的杂芳基”或“5-10元杂芳基”代表其包括5、6、7、8、9或10个环原子组成的杂芳基，其中5、6、7、8、9或10表示成环原子数目，如吡啶基是由6个环原子组成的杂芳基或6元杂芳基。
术语“杂原子”是指O、S、N、P和Si，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR’(像N-取代的吡咯烷基中的NR’，R’为本发明所述的取代基)。
像本发明所描述的，取代基画一个键连接到环上形成的环体系代表取代基在该环上任何可取代的位置都可以取代。例如，式(a)代表y个取代基R可以在吡啶环上任何可能被取代的位置上取代，当y大于1时，各R可独立地选自相同或不同的取代基团。
Figure PCTCN2022103288-appb-000017
像本发明所描述的，连接键连接到环上形成的环体系，代表连接键可以在环体系上任何可连接的位置与分子其余部分相连。例如，如式(b)所示，A端固定连接在U 1上，A’端可以任意连接在U 2-U 7上可能的位置。
Figure PCTCN2022103288-appb-000018
像本发明所描述的，例如，如式c所示，除非以其他方式明确指出，式c中既可以是E端也可以是E’端与分子的其余部分相连，即两端的连接方式可以互换。
Figure PCTCN2022103288-appb-000019
若以其他方式明确指出，例如，如式d所示，式d中F端只能与分子中标注“*”的一端相连，F’端只能与分子中未标注“*”的一端相连，即两端的连接方式不可互换。
Figure PCTCN2022103288-appb-000020
另外，需要说明的是，除非以其他方式明确指出，在本发明中通篇采用的描述方式“各…独立地 为”、“各自独立地为”、“各…独立地选自”、“各自独立地选自”和“分别独立地为”可以互换，应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。例如，式f中r1个“R”表示r1个相同的R所表达的具体选项之间互相不影响；式-C(＝O)R 5和式-S(＝O) 2R 5两个不同基团中，相同的R 5所表达的具体选项之间互不影响。
Figure PCTCN2022103288-appb-000021
当不同的符号或基团用“各…独立地为”、“各自独立地为”、“各…独立地选自”、“各自独立地选自”或“分别独立地为”进行同时定义时，都表示不同的符号或基团所表达的具体选项之间互相不影响。例如，本发明中定义“m、n和q各自独立地为1、2、3或4”表示m、n和q的取值分别可以为1、2、3或4，但m、n和q各自的具体取值互不影响；再例如，本发明定义“R 1和R 3各自独立地为H、D、F、Cl、……”表示R 1和R 3各自的具体基团互不影响。
术语“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或不适当的反应，例如肠胃不适、眩晕等。优选地，本发明所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、特别是在人体中使用的。
术语“载体”指与所述化合物一同施用的稀释剂、辅剂、赋形剂或基质。适宜的药物载体描述于E.W.Martin的“Remington′s Pharmaceutical Sciences”中。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，MeOH，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。
本发明的“酯”是指含有羟基的式(I-A)、(I)、(II)、(III)、(IV)或(V)所示化合物可形成体内可水解的酯。这样的酯是例如在人或动物体内水解产生母体醇的药学上可接受的酯。含有羟基的式(I-A)、(I)、(II)、(III)、(IV)或(V)所示化合物体内可水解的酯的基团包括，但不限于，磷酸基、乙酰氧基甲氧基、2,2-二甲基丙酰氧基甲氧基、烷酰基、苯甲酰基、苯甲乙酰基、烷氧基羰基、二烷基氨基甲酰基和N-(二烷基氨基乙基)-N-烷基氨基甲酰基，等。
本发明的“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成氮氧化物。氮氧化物的特殊实例是叔胺的氮氧化物或含氮杂环氮原子的氮氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成氮氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，氮氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂例如DCM中，将胺化合物与间-氯过氧苯甲酸(MCPBA)反应。
化合物可存在多种不同的几何异构体和互变异构体，所述式(I-A)、(I)、(II)、(III)、(IV)或(V)所示化合物包括所有此类形式。为避免疑惑，当化合物以几种几何异构体或互变异构体之一存在并且只具体描述或显示一种时，显然所有其它形式包括在式(I-A)、(I)、(II)、(III)、(IV)或(V)所示化合物中。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I-A)、(I)、(II)、(III)、(IV)或(V)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。
除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。
另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。本发明包括同位素标记的化合物，它们等同于式(I-A)、(I)、(II)、(III)、(IV)或(V)所述的化合物，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如 3H和 14C)的那些可用于药物和/或底物组织分布测定。同位素标记的本发明式(I-A)、(I)、(II)、(III)、(IV)或(V)所示化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化、还原、水解、酰氨化、脱酰氨作用、酯化、脱脂作用、酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明化合物的各种药学上可接受的盐形式都是有用的。术语“药学上可接受的盐”是指那些盐形式对于制药化学家而言是显而易见的，即它们基本上无毒并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或排泄。其他因素，在性质上更加实用，对于选择也很重要，这些是：原材料的成本、结晶的容易程度、产率、稳定性、吸湿性和原料药成盐后的流动性。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:1-19,1977.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，无机酸盐，例如盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，硝酸盐等，和有机酸盐如乙酸盐，丙酸盐，乙醇酸盐，草酸盐，马来酸盐，丙二酸盐，琥珀酸盐，富马酸盐，酒石酸盐，枸橼酸盐，苯甲酸盐，扁桃酸盐，甲磺酸盐，乙磺酸盐，甲苯磺酸盐，磺基水杨酸盐等，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。
其他药学上可接受的盐包括己二酸盐、苹果酸盐、2-羟基丙酸、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐、等等。
本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以 通过季铵化作用得到。碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。胺盐，例如但不限于N,N-二苄基乙二胺，氯普鲁卡因，胆碱，氨，二乙醇胺和其它羟烷基胺，乙二胺，N-甲基还原葡糖胺，普鲁卡因，N-苄基苯乙胺，1-对-氯苄基-2-吡咯烷-1’-基甲基-苯并咪唑，二乙胺和其它烷基胺，哌嗪和三(羟甲基)氨基甲烷；碱土金属盐，例如但不限于钡，钙和镁；过渡金属盐，例如但不限于锌。
术语“保护基团”或“PG”是指一个取代基与别的官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(BOC)，苄氧羰基(CBZ)和9-芴亚甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH 2CH 2SO 2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.
本发明中“室温”指的是温度由10℃到40℃。在一些实施例中，“室温”指的是温度由20℃到30℃；在另一些实施例中，“室温”指的是25℃。
在本说明书中，如果在化学名称和化学结构间存在任何差异，结构是占优的。
本发明所使用的任何保护基团、氨基酸和其它化合物的缩写，除非另有说明，都以它们通常使用的、公认的缩写为准，或参照IUPAC-IUB Commission on Biochemical Nomenclature(参见Biochem.1972，11：942-944)。
本发明化合物的描述
本发明提供了一类可作为RORγt激动剂的苯并氮杂环类化合物，本发明化合物或包含所述化合物的药物组合物可用于预防、治疗或减轻患者由RORγt介导的疾病。
具体地，本发明提供一种化合物，其为如式(I-A)所示的结构或如式(I-A)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2022103288-appb-000022
其中，Q 1、Q 2、环A 1、环A 2、X、Y、Z、L、R 1、R 2、R 3、R 6、R 6a、m、n、q和“*”各自具有如本发明所述的定义。
在一些实施方案中，Q 1和Q 2各自独立地为CH或N。
在一些实施方案中，Q 1和Q 2各自独立地为CH。
在一些实施方案中，Q 1为CH，Q 2为N。
在一些实施方案中，Q 1为N，Q 2为CH。
另一方面，本发明提供一种化合物，其为如式(I)所示的结构，或如式(I)所示结构的立体异构体、 互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2022103288-appb-000023
其中，环A 1、环A 2、X、Y、Z、L、R 1、R 2、R 3、R 6、R 6a、m、n、q和“*”各自具有如本发明所述的定义。
在一些实施方案中，环A 1为C 6-10亚芳基、5-10元亚杂芳基、C 3-12亚碳环基或3-12元亚杂环基。
在一些实施方案中，X为C 6-10芳基或5-10元杂芳基，且X任选地被1、2、3或4个选自D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6氘代烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代。
在一些实施方案中，Y为-O-、-C(＝O)-、-CR 4R 5-、-NR 4-、-S-、-S(＝O)-或-S(＝O) 2-。
在一些实施方案中，Z为CR 4或N。
在一些实施方案中，L为键、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、C 1-6亚烷基、-C 1-6亚烷基-O-*、-C 1-6亚烷基-NR 4-*、-C 1-6亚烷基-NR 4-C(＝O)-*、-C 1-6亚烷基-C(＝O)-NR 4-*、-C 1-6亚烷基-NR 4-C(＝O)-NR 5-*、-C 1-6亚烷基-C(＝O)-*、-C 1-6亚烷基-S(＝O)-*、-C 1-6亚烷基-S(＝O) 2-*、-C 1-6亚烷基-NR 4-S(＝O) 2-*或-C 1-6亚烷基-S(＝O) 2-NR 4-*；其中“*”表示“*”处的连接端与环A 2连接；其中所述的各C 1-6亚烷基独立任选地被1、2或3个选自D、F、Cl、Br、I、OH、CN、NH 2、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、氧代、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代。
在一些实施方案中，环A 2为5-12元亚螺环基、5-12元亚桥环基、亚环己基或亚环庚基。
在一些优选的实施方案中，环A 2为5-12元亚螺环基或5-12元亚桥环基。
在一些更优选的实施方案中，环A 2为5-12元亚桥环基。
在一些实施方案中，各R 2独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)ONa、--C(＝O)OR 5、-C(＝O)R 5、-C(＝O)NR 4R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-C(＝O)NR 4-S(＝O) 2R 5、氧代、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基或5-10元杂芳基。
在一些实施方案中，R 1和R 3各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基或3-12元杂环基。
在一些实施方案中，各R 4独立地为H、D、-C(＝O)OR 5a、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基或5-12元杂芳基。
在一些实施方案中，R 5和R 5a各自独立地为H、D、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基或5-10元杂芳基。
在一些实施方案中，R 6和R 6a各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基或3-12元杂环基。
在一些实施方案中，m、n和q各自独立地为1、2、3或4。
在一些实施方案中，本发明所述的化合物具有式(II)所示的结构，或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2022103288-appb-000024
其中，环A 1、环A 2、X、Y、Z、L、R 1、R 2、R 3、m、n、q、R 6、R 6a和“*”各自具有如本发明所述的定义。
在另一些实施方案中，本发明所述的化合物具有式(III)所示的结构，或其立体异构体，互变异构体，氮氧化物，溶剂化物，代谢产物，药学上可接受的盐或它的前药，
Figure PCTCN2022103288-appb-000025
其中，环A 1、环A 2、X、L、R 1、R 2、R 3、m、n、q、R 6、R 6a和“*”各自具有如本发明所述的定义。
在另一些实施方案中，本发明所述的化合物具有式(IV)所示的结构，或其立体异构体，互变异构体，氮氧化物，溶剂化物，代谢产物，药学上可接受的盐或它的前药，
Figure PCTCN2022103288-appb-000026
其中，环A 1、环A 2、X、L、R 1、R 2、R 3、m、n、q、R 6、R 6a和“*”各自具有如本发明所述的定义。
在另一些实施方案中，本发明所述的化合物具有式(V)所示的结构，或其立体异构体，互变异构体，氮氧化物，溶剂化物，代谢产物，药学上可接受的盐或它的前药，
Figure PCTCN2022103288-appb-000027
其中，环A 1、环A 2、X、L、R 1、R 2、R 3、m、n、q、R 6、R 6a和“*”各自具有如本发明所述的定义。
在一些实施方案中，本发明所述的化合物具有式(II-1)所示的结构，或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2022103288-appb-000028
其中，环A 1、环A 2、Y、Z、L、R 1、R 2、m、n、R 6、R 6a和“*”各自具有如本发明所述的定义。
在另一些实施方案中，本发明所述的化合物具有式(III-1)所示的结构，或其立体异构体，互变异构体，氮氧化物，溶剂化物，代谢产物，药学上可接受的盐或它的前药，
Figure PCTCN2022103288-appb-000029
其中，环A 1、环A 2、L、R 1、R 2、m、n、R 6、R 6a和“*”各自具有如本发明所述的定义。
在另一些实施方案中，本发明所述的化合物具有式(IV-1)所示的结构，或其立体异构体，互变异构体，氮氧化物，溶剂化物，代谢产物，药学上可接受的盐或它的前药，
Figure PCTCN2022103288-appb-000030
其中，环A 1、环A 2、L、R 1、R 2、m、n、R 6、R 6a和“*”各自具有如本发明所述的定义。
在另一些实施方案中，本发明所述的化合物具有式(V-1)所示的结构，或其立体异构体，互变异构体，氮氧化物，溶剂化物，代谢产物，药学上可接受的盐或它的前药，
Figure PCTCN2022103288-appb-000031
其中，环A 1、环A 2、L、R 1、R 2、m、n、R 6、R 6a和“*”各自具有如本发明所述的定义。
在另一些实施方案中，本发明所述的化合物具有式(X)所示的结构，或其立体异构体，互变异构体，氮氧化物，溶剂化物，代谢产物，药学上可接受的盐或它的前药，
Figure PCTCN2022103288-appb-000032
其中，环A 1、X、R 1、R 3、m、q、R 6、R 6a和“*”各自具有如本发明所述的定义。
在一些实施方案中，环A 1为亚苯基、亚萘基、亚吡啶基、亚哒嗪基、亚嘧啶基、亚咪唑基、亚吡唑基、亚吡咯基、亚吲哚基、亚喹啉基、亚吡喃基、亚呋喃基、亚环戊基、亚环己基、亚哌啶基、亚吗啉基、亚吡咯烷基或亚哌嗪基。
在一些实施方案中，X为苯基、萘基、吡啶基、哒嗪基、嘧啶基、咪唑基、吡唑基、吡咯基、吲哚基、喹啉基或呋喃基；且X任选地被1、2、3或4个选自D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基、C 1-4氘代烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基、3-7元杂环基、C 6-10芳基或5-10元杂芳基的取代基所取代；其中R 4和R 5各自具有本发明所述的定义。
在一些实施方案中，X为苯基、萘基、吡啶基、哒嗪基、嘧啶基、咪唑基、吡唑基、吡咯基、吲哚基、喹啉基或呋喃基；且X任选地被1、2、3或4个选自D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH 2CH 2CH 2CH 3、-CH 2CH(CH 3)CH 3、-C(CH 3) 2CH 3、-CH＝CH 2、-CH＝CHCH 3、-CH 2CH＝CH 2、-C≡CH、-C≡CCH 3、-C≡CCH 2CH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 3、-CH 2C(CH 3)(OH)CH 3、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3)CH 3、-OCH 2CH 2CH 2CH 3、-OCD 3、-OCD 2CD 3、-OCH 2CH 2OH、-OCH 2CH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、-OCH 2CH 2CF 3、-OCH 2CH 2CHF 2、-OCHFCHFCH 3、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基的取代基所取代；其中R 4和R 5各自具有本发明所述的定义。
在一些实施方案中，L为键、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、C 1-4亚烷基、-C 1-4亚烷基-O-*、-C 1-4亚烷基-NR 4-*、-C 1-4亚烷基-NR 4-C(＝O)-*、-C 1-4亚烷基-C(＝O)-NR 4-*、-C 1-4亚烷基-NR 4-C(＝O)-NR 5-*、-C 1-4亚烷基-C(＝O)-*、-C 1-4亚烷基-S(＝O)-*、-C 1-4亚烷基-S(＝O) 2-*、-C 1-4亚烷基-NR 4-S(＝O) 2-*或-C 1-4亚烷基-S(＝O) 2-NR 4-*，其中“*”表示“*”处的连接端与环A 2连接；其中所述的各C 1-4亚烷基独立任选地被1、2或3个选自D、F、Cl、Br、I、OH、CN、NH 2、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、氧代、C 1-4烷基、 C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基、3-7元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代；其中，R 4、R 5、R 5a、环A 2和“*”各自具有如本发明所述的定义。
在一些实施方案中，L为键、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、-CH 2-、-(CH 2) 2-、-CH 2-O-*、-(CH 2) 2-O-*、-CH 2-NR 4-*、-(CH 2) 2-NR 4-*、-CH 2-NR 4-C(＝O)-*、-CH 2-C(＝O)-NR 4-*、-CH 2-NR 4-C(＝O)-NR 5-*、-CH 2-C(＝O)-*、-CH 2-S(＝O)-*、-CH 2-S(＝O) 2-*、-CH 2-NR 4-S(＝O) 2-*或-CH 2-S(＝O) 2-NR 4-*，其中“*”表示“*”处的连接端与环A 2连接；其中所述的-CH 2-和-(CH 2) 2-各自独立任选地被1、2或3个选自D、F、Cl、Br、I、OH、CN、NH 2、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、氧代、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH＝CH 2、-CH＝CHCH 3、-CH 2CH＝CH 2、-C≡CH、-C≡CCH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-OCH 3、-OCH 2CH 3、-OCH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基的取代基所取代；其中，R 4、R 5、R 5a、环A 2和“*”各自具有如本发明所述的定义。
在一些实施方案中，环A 2为以下子结构式：
Figure PCTCN2022103288-appb-000033
其中，各环A 2子结构式中的“*”表示*处的连接端与式(I-A)、(I)、(II)、(III)、(IV)或(V)中的L连接；
Z 1为CH或N；
Z 2为-CH 2-、-NH-、-S-、-O-、-S(＝O)-或-S(＝O) 2-；
Z 3和Z 4各自独立地为键、-O-、-NH-、-OCH 2-、-CH 2O-、-CH 2-或-(CH 2) 2-；和
t和t 1各自独立地为0或1；
在一些实施方案中，
环A 2为以下子结构式：
Figure PCTCN2022103288-appb-000034
Figure PCTCN2022103288-appb-000035
Figure PCTCN2022103288-appb-000036
其中，各环A 2子结构式中的“*”表示*处的连接端与式(I-A)、(I)、(II)、(III)、(IV)或(V)中的L连接。
在一些优选的实施方案中，环A 2为
Figure PCTCN2022103288-appb-000037
其中，“*”表示*处的连接端与式(I-A)、(I)、(II)、(III)、(IV)或(V)中的L连接。发明人发现，当A 2为
Figure PCTCN2022103288-appb-000038
时，本发明化合物具有更优特性，例如药代动力学性质方面具有较长半衰期、较高的体内暴露量和较高的血药浓度，等。
在一些优选实施方案中，
Figure PCTCN2022103288-appb-000039
为
Figure PCTCN2022103288-appb-000040
在一些实施方案中，各R 2独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)ONa、-C(＝O)OR 5、-C(＝O)R 5、-C(＝O)NR 4R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-C(＝O)NR 4-S(＝O) 2R 5、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；其中，R 4和R 5各自具有如本发明所述的定义。
在一些实施方案中，各R 2独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)ONa、-C(＝O)OR 5、-C(＝O)R 5、-C(＝O)NR 4R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-C(＝O)NR 4-S(＝O) 2R 5、氧代、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-C(CH 3) 3、-CH 2CH 2CH 2CH 3、-C≡CH、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 3、-CH 2C(CH 3)(OH)CH 3、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH 2CH 2CH 2CH 3、-OCH 2CH 2OH、-OCH 2CH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、-OCH 2CH 2CF 3、-OCH 2CH 2CHF 2、-OCHFCHFCH 3、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基；其中，R 4和R 5各自具有如本发明所述的定义。
在一些实施方案中，R 1和R 3各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、 C 3-7环烷氧基或3-7元杂环基；其中，R 4和R 5各自具有如本发明所述的定义。
在一些实施方案中，R 1和R 3各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH＝CH 2、-CH＝CHCH 3、-CH 2CH＝CH 2、-C≡CH、-C≡CCH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-OCH 3、-OCH 2CH 3、-OCH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基或吗啉基；其中，R 4和R 5各自具有如本发明所述的定义。
在一些实施方案中，各R 4独立地为H、D、-C(＝O)OR 5a、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-7环烷基、3-7元杂环基、C 6-10芳基或5-6元杂芳基；其中，R 5a具有如本发明所述的定义。
在一些实施方案中，R 5和R 5a各自独立地为H、D、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-7环烷基、3-7元杂环基、C 6-10芳基或5-10元杂芳基。
在一些实施方案中，R 6和R 6a各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基或3-7元杂环基；其中，R 4和R 5各自具有如本发明所述的定义。
在一些实施方案中，各R 4独立地为H、D、-C(＝O)OR 5a、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH 2CH 2CH 2CH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 3、-CH 2C(CH 3)(OH)CH 3、环丙基、环戊基、环己基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基；其中，R 5a具有如本发明所述的定义。
在一些实施方案中，各R 5和R 5a独立地为H、D、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH 2CH 2CH 2CH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 3、-CH 2C(CH 3)(OH)CH 3、环丙基、环戊基、环己基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基。
在一些实施方案中，各R 6和R 6a独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-OCH 3、-OCH 2CH 3、-OCH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基或吗啉基；其中，R 4和R 5各自具有如本发明所述的定义。
在一些实施方案中，
Figure PCTCN2022103288-appb-000041
为
Figure PCTCN2022103288-appb-000042
在一些实施方案中，
Figure PCTCN2022103288-appb-000043
为
Figure PCTCN2022103288-appb-000044
在一些实施方案中，X为
Figure PCTCN2022103288-appb-000045
其中，R 01和R 02各自独立地为D、F、Cl、Br、I、OH、CN、NO 2、-NR 4R 5、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基、C 1-4氘代烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基、3-7元杂环基、C 6-10芳基或5-10元杂芳基。
在一些实施方案中，X为
Figure PCTCN2022103288-appb-000046
其中，R 01和R 02各自独立地为D、F、Cl、Br、I、OH、CN、NO 2、-NH 2、-NH(CH 3)、-N(CH 3) 2、-N(CH 2CH 3) 2、-NH(CH 2CH 3)、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH 2CH 2CH 2CH 3、-CH 2CH(CH 3)CH 3、-C(CH 3) 2CH 3、-CH＝CH 2、-CH＝CHCH 3、-CH 2CH＝CH 2、-C≡CH、-C≡CCH 3、-C≡CCH 2CH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 3、-CH 2C(CH 3)(OH)CH 3、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3)CH 3、-OCH 2CH 2CH 2CH 3、-OCD 3、-OCD 2CD 3、-OCH 2CH 2OH、-OCH 2CH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、-OCH 2CH 2CF 3、-OCH 2CH 2CHF 2、-OCHFCHFCH 3、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基。
在一些实施方案中，本发明所述化合物具有以下其中结构之一，或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2022103288-appb-000047
Figure PCTCN2022103288-appb-000048
Figure PCTCN2022103288-appb-000049
Figure PCTCN2022103288-appb-000050
另一方面，本发明涉及药物组合物，该药物组合物，包含本发明式(I-A)、(I)、(II)、(III)、(IV)、(V)、(II-1)、(III-1)、(IV-1)、(V-1)或(X)所示的化合物，或其立体异构体，互变异构体，氮氧化物，溶剂化物，代谢产物，药学上可接受的盐或它的前药，任选地进一步包含药学上可接受的载体、辅剂、媒介物或它们的组合。
另一方面，本发明涉及式(I-A)、(I)、(II)、(III)、(IV)、(V)、(II-1)、(III-1)、(IV-1)、(V-1)或(X)所示化合物或其药物组合物在制备药物中的用途，其中所述药物用于预防、治疗或减轻患者由RORγt介导的疾病。
另一方面，本发明涉及式(I-A)、(I)、(II)、(III)、(IV)、(V)、(II-1)、(III-1)、(IV-1)、(V-1)或(X)所示化合物或其药物组合物用于预防、治疗或减轻患者由RORγt介导的疾病。
另一方面，本发明涉及一种预防、治疗或减轻患者由RORγt介导的疾病的方法，包含给予患者治疗有效量的本发明式(I-A)、(I)、(II)、(III)、(IV)、(V)、(II-1)、(III-1)、(IV-1)、(V-1)或(X)所示化合物或其药物组合物。
在一些实施方案中，本发明所述的由RORγt介导的疾病包括癌症、多发性硬化症、类风湿性关节炎、风湿性关节炎、骨关节炎、强直性脊柱炎、牛皮癣，哮喘、自身免疫性疾病、移植物抗宿主病、银屑病、系统性红斑狼疮、炎性肠病、结肠炎、细菌感染、真菌感染、慢性阻塞性肺病、过敏性鼻炎、过敏性皮炎、克罗恩病或川崎病。
本发明所述的肿瘤或癌症选自非霍奇金淋巴瘤、弥漫大B细胞淋巴瘤、滤泡性淋巴瘤、滑膜肉瘤、乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、黑色素瘤、神经胶质瘤、神经胶母细胞胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
本发明的化合物的药物组合物、制剂和给药
如本发明所描述的，本发明药物组合物包含任何一种本发明的式(I-A)、(I)、(II)、(III)、(IV)、(V)、(II-1)、(III-1)、(IV-1)、(V-1)或(X)所示化合物，进一步包含药学上可接受的辅料，这些辅料，例如像 本发明所应用的，包括任何溶剂、固体赋形剂、稀释剂、粘合剂、崩解剂、或其他液体赋形剂、分散剂、矫味剂或悬浮剂、表面活性剂、等渗剂、增稠剂、乳化剂、防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。不同的辅料可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的辅料与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。
在本发明中描述的可作为药学上可接受辅料的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯-聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，羟丙基纤维素、乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇；磷酸缓冲溶液；和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁；着色剂；释放剂；包衣衣料；甜味剂；调味剂；香料；防腐剂和抗氧化剂。当本发明的化合物以药物的形式施用于哺乳动物例如人时，其可以以化合物本身的形式被给予或者可以以含有例如0.1至99.5％(更优选0.5至90％)活性成分以及药学可接受的载体的药物组合物的形式被给予。
“治疗有效量”或“有效量”是指本发明的一种或多种化合物治疗、预防、减轻、改善或消除特定疾病、病症或综合征的一个或多个症状，或阻止或延迟本文所述的特定疾病、病症或综合征的一个或多个症状的开始的足够量。在治疗癌症的情况下，治疗有效量的药物可以减少癌细胞的数量；抑制(即，减慢到一定程度或终止)癌细胞浸润入周围器官；抑制肿瘤转移；一定程度上抑制肿瘤生长；和/或一定程度上缓解与癌症相关的一个或多个症状。在感染性疾病状态的情况下，治疗有效量是足以降低或缓解感染性疾病(由细菌、病毒和真菌引起的感染症状)的量。本领域普通技术人员将能研究本发明所包含的因素和在不进行过度实验的情况下确定本发明的化合物的有效量。
施用方案可影响有效量的构成。本发明的化合物可在由RORγt介导的疾病发作之前或之后被施用于个体。此外，可以每天或相继施用多个分剂量以及错开的剂量，或者可以连续输注给药，或者可以推注给药。此外，本发明的化合物的剂量可以根据治疗或预防的情形的紧迫性按比例酌情增加或减少。
本发明的化合物可用于治疗本发明所述的状态、病症或疾病，或用于制备治疗这些疾病的药物组合物。本发明涉及本发明所述的这一类化合物在这些疾病治疗中的使用方法或用于治疗这些疾病的含有本发明的化合物的药物制剂。
“药学上可接受的载体”在本领域中是公认的，包括适于将本发明的化合物施用于哺乳动物的药学可接受的材料、组合物或载体。所述载体包括参与携带药物有效成分或将其从一个器官或机体的一部分转移到另一个器官或机体的另一部分的液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料。各载体在与制剂中的其它成分相容和对患者无害的意义上必须是“可接受的”。可用作药学可接受的载体的材料的一些实例包括：糖类，如乳糖、葡萄糖和蔗糖；淀粉类，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，如羧甲基纤维素钠、乙基纤维素和醋酸纤维素；粉状西黄蓍胶；麦芽；明胶；滑石粉；赋形剂，如可可脂和栓剂蜡类；油类，如花生油、棉子油、红花油、芝麻油、橄榄油、玉米油和豆油；二醇类，如丙二醇；多元醇类，如甘油、山梨醇、甘露醇和聚乙二醇；酯类，如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐水；林格氏溶液；乙醇；磷酸盐缓冲液；和药物制剂中所用的其它无毒的可相容的物质。
在组合物中也可以存在润湿剂、乳化剂和润滑剂如十二烷基硫酸钠和硬脂酸镁，以及着色剂、释放剂、包衣剂、甜味剂、矫味剂和芳香剂、防腐剂和抗氧化剂。
药学可接受的抗氧化剂的实例包括：水溶性抗氧化剂，如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、焦亚硫酸钠、亚硫酸钠等；油溶性抗氧化剂，如棕榈酸抗坏血酸酯、丁基化羟基苯甲醚(BHA)、丁化羟基甲苯(BHT)、卵磷脂、棓酸丙酯、α-生育酚等；和金属螯合剂，如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
本发明的制剂包括适于口服、鼻、局部、口含、舌下、直肠、阴道和/或胃肠外施用的那些。制剂可以方便地以单位剂型形式存在并且可以通过药学领域公知的任何方法来制备。可以与载体物质组合来制备单剂量形式的活性成分的量一般是产生治疗作用的化合物的量。一般而言，以百分之一为单位，该量为约1％至约99％活性成分，优选约5％至约70％，最优选约10％至约30％。
制备这些制剂或组合物的方法包括使本发明的化合物与载体、独立任选地和一种或多种辅助成分结合的步骤。一般而言，制剂是通过将本发明的化合物与液体载体或很细的固体载体或这二者均匀且紧密地结合在一起、然后如果需要的话，将该产物成型来制备的。
本发明适于口服的制剂可以是胶囊剂、扁囊剂、丸剂、片剂、锭剂(使用矫味的基质，通常为蔗糖和阿拉伯胶或西黄蓍胶)、散剂、颗粒剂、或者在水性或非水性液体中的溶液剂或混悬剂、或者水包油或油包水型液体乳剂、或者酏剂或糖浆剂、或者软锭剂(使用惰性基质，如明胶和甘油、或蔗糖和阿拉伯胶)和/或漱口剂等的形式，其各自含有既定量的本发明的化合物作为活性成分。本发明的化合物还可以以大丸剂、药糖剂或糊剂的形式施用。
在用于口服施用的本发明的固体剂型(胶囊剂、片剂、丸剂、糖衣丸、散剂、颗粒剂等)中，将活性成分与一种或多种药学可接受的载体如柠檬酸钠或磷酸二钙和/或任何下列物质混合：填充剂或增量剂，如淀粉类、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸；粘合剂，例如，羧甲基纤维素、藻酸盐类、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶；保湿剂，如甘油；崩解剂，如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、海藻酸、某些硅酸和碳酸钠；溶液阻滞剂(solution retarding agent)，如石蜡；吸收促进剂，如季铵化合物；润湿剂，例如，鲸蜡醇和甘油单硬脂酸酯；吸附剂，如高岭土和皂土；润滑剂，如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，以及其混合物；和着色剂。在胶囊剂、片剂和丸剂的情况下，药物组合物还可包含缓冲剂。类似类型的固体组合物还可在使用赋形剂如乳糖或奶糖以及高分子量聚乙二醇等的软和硬填充明胶胶囊中用作填充物。
片剂可以通过压制或模制来制备，可任选地使用一种或多种辅助成分。压制片可以用粘合剂(例如，明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如，羟乙酸淀粉钠或交联羧甲基纤维素钠)、表面活性剂或分散剂来制备。模制片可以通过将用惰性液体稀释剂润湿的粉状化合物的混合物在合适的机器中进行模制来制备。
片剂和本发明的药物组合物的其它固体剂型如糖衣丸、胶囊剂、丸剂和颗粒剂可任选地被刻痕或用包衣和壳如肠溶衣和制药领域公知的其它包衣来制备。也可以将它们用例如提供所需释放性质的各种比例的羟丙基甲基纤维素、其它聚合物基质、脂质体和/或微球进行配制以便提供其中的活性成分的缓慢释放或控制释放。可将它们例如通过用截留细菌的滤器过滤或通过在使用前即刻掺入可溶解于无菌水或一些其它可注射无菌溶媒中的无菌固体组合物形式的灭菌剂来进行灭菌。这些组合物还可任选地含有遮光剂并且可以是仅在或优先在胃肠道的某个部分中释放活性成分、任选以延迟方式释放活性成分的组合物。可使用的包埋组合物的实例包括聚合物物质和蜡类。活性成分也可以是微囊化的形式，如果适宜的话，使用一种或多种上述赋形剂。
用于口服施用的本发明的化合物的液体剂型包括药学可接受的乳剂、微乳、溶液、混悬液、糖浆剂 和酏剂。除活性成分以外，液体剂型还可含有本领域中常用的惰性稀释剂例如水或其它溶剂、增溶剂和乳化剂如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油类(特别是棉子油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和失水山梨醇的脂肪酸酯以及其混合物。
除惰性稀释剂以外，口服组合物还可包含辅剂(adjuvant)如润湿剂、乳化剂和助悬剂、甜味剂、矫味剂、着色剂、芳香剂和防腐剂。
除活性化合物以外，混悬剂还可包含助混剂，例如乙氧基化异硬脂醇、聚氧乙烯山梨醇和失水山梨醇酯、微晶纤维素、偏氢氧化铝(aluminummetahydroxide)、皂土、琼脂和西黄蓍胶以及其混合物。
用于直肠或阴道施用的本发明的药物组合物的制剂可以以栓剂的形式存在，其可以通过将一种或多种本发明的化合物与一种或多种合适的无刺激的赋形剂或载体(包括例如可可脂、聚乙二醇、栓剂蜡或水杨酸酯)混合来制备，并且其在室温下是固体，但是在体温下是液体，因此将在直肠或阴道腔中熔化并释放出活性化合物。
适于阴道施用的本发明的制剂还包括含有本领域中已知适宜的载体的阴道栓、卫生栓、乳膏剂、凝胶剂、糊剂、泡沫剂或喷雾制剂。
本发明的化合物的用于局部或透皮施用的剂型包括散剂、喷雾剂、软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、溶液剂、贴剂和吸入剂。可以将活性成分在无菌条件下与药学可接受的载体和可能需要的任何防腐剂、缓冲剂或抛射剂混合。
除本发明的活性化合物以外，软膏剂、糊剂、乳膏剂和凝胶剂还可包含赋形剂，如动物和植物脂肪、油类、蜡类、石蜡类、淀粉、西黄蓍胶、纤维素衍生物、聚乙二醇类、硅氧烷类、皂土类、硅酸、滑石粉和氧化锌、或其混合物。
除本发明的化合物以外，散剂和喷雾剂还可包含赋形剂如乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末或这些物质的混合物。喷雾剂还可包含常规抛射剂如氯氟烃类和挥发性的未被取代的烃类，如丁烷和丙烷。
透皮贴剂具有为机体提供本发明的化合物的控制传递的另外的优点。该类剂型可以通过将化合物溶解或分散于合适的溶媒中来制备。还可以使用吸收促进剂来增加通过皮肤的化合物通量。可以通过提供控速膜或将活性化合物分散于聚合物基质或凝胶中来控制该类化合物流动的速度。
在本发明的范围内还包括眼用制剂、眼用软膏剂、散剂、溶液剂等。
适于胃肠外施用的本发明的药物组合物包含一种或多种本发明的化合物以及一种或多种药学可接受的无菌的等渗的水性或非水性溶液、分散物、混悬剂或乳剂、或者可在使用前即刻被重组到无菌的可注射溶液或分散物中的无菌粉末，其可包含抗氧化剂、缓冲剂、抑菌剂、使得制剂与接受者的血液等渗的溶质或助悬剂或增稠剂。
可用于本发明的药物组合物中的合适的水性和非水性载体的实例包括水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)以及其合适的混合物、植物油类如橄榄油和可注射的有机酯类如油酸乙酯。可以例如通过使用包衣材料如卵磷脂、在分散物的情况下通过维持所需的粒度、和通过使用表面活性剂来维持合适的流动性。
这些组合物还可包含辅剂如防腐剂、润湿剂、乳化剂和分散剂。可以通过包含各种抗细菌剂和抗真菌剂例如尼泊金酯、三氯叔丁醇、苯酚、山梨酸等来确保预防微生物的作用。还可能需要在组合物中包含等渗剂如糖类、氯化钠等。此外，可以通过包含延迟吸收的物质如单硬脂酸铝和明胶来造成可注射药物形式的延长吸收。
在一些情况中，为了延长药物的作用，需要减慢来自皮下或肌内注射的药物吸收。这可以通过使用 水溶性差的结晶性或无定形物质的液体混悬液来实现。这样，药物的吸收速率将取决于其溶出速率，溶出速率又可能取决于晶体大小和晶形。或者，通过将药物溶解或混悬于油性基质中来实现胃肠外施用的药物形式的延长吸收。
可注射的储库形式是通过在可生物降解的聚合物如聚丙交酯-聚乙交酯中形成药物的微囊基质来制备的。根据药物与聚合物的比例以及所用的具体化合物的性质，可以控制药物释放速率。其它可生物降解的聚合物的实例包括聚(原酸酯)和聚(酸酐)。可注射的储库制剂也可以通过将药物包在与机体组织相容的脂质体或微乳中来制备。
本发明的制剂可以被口服、胃肠外、局部或直肠施用。它们当然是以适合于各施用途径的形式被给予。例如，它们以片剂或胶囊剂的形式被施用，通过注射剂、吸入剂、眼用洗剂、软膏剂、栓剂等被施用，通过注射、输注或吸入被施用；通过洗剂或软膏剂被局部施用；通过栓剂被直肠施用。优选的是口服和/或静脉内施用。
本发明所用的措辞“胃肠外施用”意指除肠内和局部施用以外的施用方式，通常是通过注射施用，非限制性地包括静脉内、肌内、动脉内、鞘内、囊内、眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内和胸骨内注射和输注。
本发明所用的措辞“全身施用”和“外周施用”意指化合物、药物或其它材料的除直接施用于中枢神经系统以外的施用，从而使得其进入患者的系统中并因此进行代谢和其它相似过程，例如皮下施用。
这些化合物可通过任何合适的施用途径被施用于人和其它动物来进行治疗，包括口服、鼻(例如以喷雾剂形式)、直肠、阴道内、胃肠外、脑池内和局部(以散剂、软膏剂或滴剂形式)施用，所述局部施用包括口含和舌下施用。
不管所选择的施用途径如何，用本领域技术人员已知的常规方法将可以以合适的水合形式使用的本发明的化合物和/或本发明的药物组合物配制成药学可接受的剂型。
可以改变本发明的药物组合物中活性成分的实际剂量水平以获得对特定患者、组合物和施用方式而言可有效实现所需治疗响应、对患者无毒的活性成分的量。
所选择的剂量水平将取决于多种因素，包括所用的具体的本发明的化合物或其酯、盐或酰胺的活性、施用途径、施用时间、所用的具体化合物的排泄速率、治疗的持续时间、与所用的具体化合物组合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、体重、情况、一般健康状况和既往医学史以及医学领域中公知的类似因素。
具有本领域普通技能的医师或兽医可容易地确定和开具出所需的药物组合物的有效量。例如，医师或兽医可以以低于获得所需治疗作用所需要的剂量的水平开始药物组合物中所用的本发明的化合物的剂量并逐渐增加其剂量直至实现所需的作用。
一般而言，本发明的化合物的合适的日剂量将是有效产生治疗作用的最低剂量的化合物量。该类有效剂量一般将取决于上述因素。一般而言，本发明的化合物用于患者的剂量为约0.001至约500mg/kg体重/天。
如果需要的话，活性化合物的有效日剂量可以在一天中以分开施用的二、三、四、五、六或更多个亚剂量以适宜的时间间隔施用，任选地，所述亚剂量是单位剂型。
对于约50-70kg的个体，本发明的药物组合物或组合可以为约1-1000mg活性成分的单位剂量。化合物、其药物组合物或组合的治疗有效剂量取决于个体的种类、体重、年龄和个体条件、治疗的障碍或疾病或其严重程度。具有普通技术的医师、临床医师或兽医能够容易地确定预防、治疗或抑制障碍或疾病的进程所需的每种活性成分的有效量。
上述剂量性质在体外和体内试验中应用有利的哺乳动物，例如小鼠、大鼠、狗、猴或其相关器官、 组织或制备物可进行说明。本发明化合物可以在体外以溶液剂例如水溶液剂的形式应用，并且可以在体内以肠内、非肠道、有利地以静脉内例如作为混悬剂或水溶液剂应用。
本发明所用的术语“个体”意指动物。通常，动物是哺乳动物。个体还意指例如灵长类(例如人，男性或女性)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施例中，个体是灵长类。在其它实施例中，个体是人。
虽然本发明的化合物可以单独施用，但是优选以药物组合物的形式施用所述化合物。
药物联合
使用本发明所提供的一种或多种化合物或组合物，或其药学上可接受的衍生物与其它的药物活化剂联合来组合治疗，用于治疗本发明所述的疾病和病症。
将配制用于口服、全身性传递包括肠道外或静脉内传递或用于局部或表面施用的有效量的化合物或包含治疗有效浓度的化合物的组合物给予表现出疾病或病症症状而需要治疗的个体。所述量有效地治疗、控制或缓解了该疾病或病症的一种或多种症状。
本领域普通技术人员能够理解本发明所提供的化合物、异构体、前体药物和药学上可接受的衍生物，包括药物组合物和包含这些化合物的制剂，可广泛应用于联合治疗以治疗本发明所述的不适和疾病。因此，本发明预期将本发明所提供的化合物、异构体、前体药物和药学上可接受的衍生物与其它活性药物联合使用，以用于治疗本发明所述的疾病和/或不适。
本发明化合物和药物组合物的用途
本发明所公开的化合物或药物组合物可以用于制备预防、治疗或减轻患者由RORγt介导的疾病的药物。
这类疾病包括，但绝不限于，包括癌症、多发性硬化症、类风湿性关节炎、风湿性关节炎、骨关节炎、强直性脊柱炎、牛皮癣、哮喘、自身免疫性疾病、移植物抗宿主病、银屑病、系统性红斑狼疮、炎性肠病、炎性肠综合征、结肠炎、细菌感染、真菌感染、慢性阻塞性肺病、过敏性鼻炎、过敏性皮炎、克罗恩病或川崎病。
本发明的化合物或药物组合物可以应用于，但绝不限于，使用本发明的化合物或药物组合物的有效量对患者给药来治疗、预防、改善、控制或减轻哺乳动物，包括人类的癌症、感染性疾病和自身免疫性疾病。
本发明的化合物及药物组合物除了对人类治疗有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物中的哺乳动物。另外一些动物的实例包括马、狗和猫。在此，本发明的化合物包括其药学上可接受的衍生物。
一般合成方法
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I-A)、(I)、(II)、(III)、(IV)、(V)、(II-1)、(III-1)、(IV-1)、(V-1)或(X)所示化合物。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面所描述的实施例，除非其他方面表明，所有的温度定为℃。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，除非其他方面表明，使用时都 没有经过进一步纯化。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。
无水四氢呋喃，无水二氧六环，无水甲苯，无水乙醚是经过金属钠回流干燥得到。无水二氯甲烷和无水氯仿是经过氢化钙回流干燥得到。无水乙酸乙酯，无水石油醚，无水正己烷，无水N,N-二甲基乙酰胺和无水N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。核磁共振光谱以CDC1 3、DMSO-d 6、CD 3OD或d 6-丙酮为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)，d(doublet，双峰)，t(triplet，三重峰)，q(quartet，四重峰)，m(multiplet，多重峰)，br(broadened，宽峰)，dd(doublet of doublets，双二重峰)，dt(doublet of triplets，双三重峰)，qd(doublet of quartet,双四重峰)，ddd(doublet of doublet of doublets，双双二重峰)。偶合常数J，用赫兹(Hz)表示。
低分辨率质谱(MS)数据通过配备G1311B四元泵和G1316A TCC(柱温保持在30℃)的Agilent 6120系列LC-MS的光谱仪来测定的，G1329B自动采样器和G1315D DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。
以上光谱仪配备了Agilent Zorbax SB-C18柱，规格为2.1×30mm，5μm。注射体积是通过样品浓度来确定；流速为0.6mL/min；HPLC的峰值是通过在210nm和254nm处的UV-Vis波长来记录读取的。流动相为0.1％的甲酸乙腈溶液(相A)和0.1％的甲酸超纯水溶液(相B)。梯度洗脱条件如表1所示：
表1
时间(min) A(CH 3CN，0.1％HCOOH) B(H 2O，0.1％HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
化合物纯度是通过Agilent 1100系列高效液相色谱(HPLC)来评价的，其中UV检测在210nm和254nm处，Zorbax SB-C18柱，规格为2.1×30mm，4μm，10分钟，流速为0.6mL/min，5-95％的(0.1％甲酸乙腈溶液)的(0.1％甲酸水溶液)，柱温保持在40℃。
下面简写词的使用贯穿本发明：
Figure PCTCN2022103288-appb-000051
Figure PCTCN2022103288-appb-000052
下列合成方案描述了制备本发明化合物的步骤。
合成方案1：
Figure PCTCN2022103288-appb-000053
化合物(IA)可以通过上述合成方案1的合成路线制备得到，其中，Hal 1为F、Cl、Br或I，优选为F或Cl；环A 1、环A 2、X、R 1、R 2、R 3、m、n和q各自具有本发明所述的定义。化合物(IA-1)与化合物Me 3S(O)I在合适的条件下(如NaH存在下，在THF或DMSO溶剂中)反应得到化合物(IA-2)；化合物(IA-2)与化合物(IA-3)在合适的条件下(如先在TBAB和Cs 2CO 3存在下反应一段时间，再在NaOH存在下，在THF溶剂中反应)反应得到化合物(IA)。
合成方案2：
Figure PCTCN2022103288-appb-000054
化合物(IAa)可以通过上述合成方案2的合成路线制备得到，其中，Hal 1为F、Cl、Br或I，优选为F或Cl；R a为C 1-6烷基，优选为甲基、乙基、正丙基或异丙基；环A 1、环A 2、X、R 1、R 3、m和q各自具有本发明所述的定义。化合物(IA-1a)与化合物Me 3S(O)I在合适的条件下(如NaH存在下，在THF或DMSO溶剂中)反应得到化合物(IA-2a)；化合物(IA-2a)与化合物(IA-3)在合适的条件下(如先在TBAB和Cs 2CO 3存在下反应一段时间，再在NaOH存在下和THF溶剂中反应)反应得到化合物(IAa-1)或化合物(IAa)；化合物(IAa-1)在碱性条件下(如NaOH存在下)在合适的溶剂中(如乙醇和水的混合溶剂)反应得到化合物(IAa)。
合成方案3：
Figure PCTCN2022103288-appb-000055
化合物(IAb)可以通过上述合成方案3的合成路线制备得到，其中，Hal 1为F、Cl、Br或I，优选为F或Cl；Pg 1为氨基保护基，优选为Boc；环A 2a为至少含有一个环N原子的杂环；环A 1、X、R 1、R 3、R 5、m和q各自具有本发明所述的定义。化合物(IA-1b)与化合物Me 3S(O)I在合适的条件下(如NaH存在下，在THF或DMSO溶剂中)反应得到化合物(IA-2b)；化合物(IA-2b)与化合物(IA-3)在合适的条件下(如先在TBAB和Cs 2CO 3存在下反应一段时间，再在NaOH存在下和THF溶剂中反应)反应得到化合物(IAb-1)；化合物(IAb-1)先在酸性条件下脱去氨基保护基，然后再与化合物HO-C(＝O)R 5在合适的试剂(如EDCI、HOBT和DIPEA)作用下和合适的溶剂(如DCM)中发生偶联反应得到化合物(IAb)。
合成方案4:
Figure PCTCN2022103288-appb-000056
化合物(IAc)可以通过上述合成方案4的合成路线制备得到，其中，Hal 1为F、Cl、Br或I，优选为F或Cl；Pg 2为羟基保护基，优选为Ms；环A 2b为至少含有一个环N原子的杂环；L 1为C 1-6亚烷基，优选为-CH 2-或-CH 2CH 2-；环A 1、X、R 1、R 2、R 3、m、n和q各自具有本发明所述的定义。化合物(IA-3)与化合物(IAc-0)在合适的条件下(如在K 2CO 3和TBAB作用下)加热反应一段时间后再在THF溶剂中和NaOH作用下加热反应得到化合物(IAc-1)；化合物(IAc-1)通过羟基保护(如在DIAPEA作用下，在DCM溶剂中与MsCl反应)反应得到化合物(IAc-2)；化合物(IAc-2)与化合物(IAc-3)在碱性条件下(如K 2CO 3等)在合适的溶剂中(如乙腈)反应得到化合物(IAc)。
合成方案5：
Figure PCTCN2022103288-appb-000057
化合物(IAd)可以通过上述合成方案5的合成路线制备得到，其中，Pg 2为羟基保护基，优选为Ms；Pg 1为氨基保护基，优选为Boc；环A 2c为至少含有两个环N原子的杂环；L 1为C 1-6亚烷基，优选为-CH 2-或-CH 2CH 2-；环A 1、X、R 1、R 3、R 5、m和q各自具有本发明所述的定义。化合物(IAc-2)与化合物(IAd-1)在碱性条件下(如K 2CO 3等)在合适的溶剂中(如乙腈)反应得到化合物(IAd-2)；化合物(IAd-2)在酸性条件下(如HCl)脱氨基保护基得到化合物(IAd-3)；化合物(IAd-3)与化合物HO-C(＝O)R 5在合适的试剂(如EDCI、HOBT和DIPEA)作用下和合适的溶剂(如DCM)中发生偶联反应得到化合物(IAd)。
合成方案6：
Figure PCTCN2022103288-appb-000058
化合物(IAe)可以通过上述合成方案6的合成路线制备得到，其中，Pg 2为羟基保护基，优选为Ms；L 1为C 1-6亚烷基，优选为-CH 2-或-CH 2CH 2-；环A 2b为至少含有一个环N原子的杂环；环A 1、X、R 1、R 3、R 5、m和q各自具有本发明所述的定义。化合物(IAc-2)与化合物(IAe-1)在碱性条件下(如K 2CO 3等)在合适的溶剂中(如乙腈)反应得到化合物(IAe-2)；化合物(IAe-2)在酸性或碱性条件下水解得到化合物(IAe)。
合成方案7：
Figure PCTCN2022103288-appb-000059
化合物(IAf)可以通过上述合成方案7的合成路线制备得到，其中，Pg 2为羟基保护基，优选为Ms；L 1为C 1-6亚烷基，优选为-CH 2-或-CH 2CH 2-；环A 1、环A 2、X、R 1、R 2、R 3、m、n和q各自具有本发明所述的定义。化合物(IAc-2)与化合物(IAf-1)在碱性条件下(如NaOH等)在合适的催化剂(如TBAB等)作用下和在合适的溶剂(如Et 2O和水的混合溶剂)中反应得到化合物(IAf)。
合成方案8：
Figure PCTCN2022103288-appb-000060
化合物(IAg)可以通过上述合成方案8的合成路线制备得到，其中，Pg 2为羟基保护基，优选为Ms；Pg 1为氨基保护基，优选为Boc；L 1为C 1-6亚烷基，优选为-CH 2-或-CH 2CH 2-；环A 2a为至少含有一个环N原子的杂环；环A 1、X、R 1、R 3、R 5、m和q各自具有本发明所述的定义。化合物(IAc-2)与化合物(IAg-1)在碱性条件下(如NaOH等)在合适的催化剂(如TBAB等)作用下和在合适的溶剂(如Et 2O和水的混合溶剂)中反应得到化合物(IAg-2)；化合物(IAg-2)在酸性条件下脱氨基保护基得到化合物(IAg-3)；化合物(IAg-3)与化合物HO-C(＝O)R 5在合适的试剂(如EDCI、HOBT和DIPEA)作用下和合适的溶剂(如DCM)中发生偶联反应得到化合物(IAg)。
合成方案9：
Figure PCTCN2022103288-appb-000061
化合物(IAh)可以通过上述合成方案9的合成路线制备得到，其中，Pg 2为羟基保护基，优选为Ms；L 1为C 1-6亚烷基，优选为-CH 2-或-CH 2CH 2-；环A 1、环A 2、X、R 1、R 2、R 3、R 4、m、n和q各自具有本发明所述的定义。化合物(IAc-2)与化合物(IAh-1)在碱性条件下(如K 2CO 3)在合适的溶剂(如乙腈)中反应得到化合物(IAh)。
合成方案10：
Figure PCTCN2022103288-appb-000062
化合物(IAi)可以通过上述合成方案10的合成路线制备得到，其中，Hal 2为F、Cl、Br或I，优选为Cl或Br；r为0、1、2、3或4；R a为D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6氘代烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基和5-10元杂芳基，优选为F、Cl、Br或C 1-6烷氧基，更优选为F或-OCHF 2；环A 1、环A 2、R 1、R 2、m和n各自具有本发明所述的定义。化合物(IAi-1)与化合物(IAi-2)在合适的条件下(如EDCI、HOBT和DIPEA作用下在DCM溶剂中)发生偶联反应得到化合物(IAi-3)；化合物(IAi-3)与HCHO在碱性条件下(如NaOH)和合适的溶剂(如H 2O和EtOH的混合溶剂)中反应得到化合物(IAi-4)；化合物(IAi-4)与化合物(IAi-5)在合适的偶联剂(如Pd(dppf)Cl 2.CH 2Cl 2)作用下和碱性条件下(如K 2CO 3)在合适的溶剂中(如DCM)发生偶联反应得到化合物(IAi-6)；化合物(IAi-6)与化合物(IAi-7)在碱性条件下(如吡啶)反应得到化合物(IAi)。
合成方案11：
Figure PCTCN2022103288-appb-000063
Figure PCTCN2022103288-appb-000064
化合物(IA)可以通过上述合成方案11的合成路线制备得到，其中，Hal 1为F、Cl、Br或I，优选为F或Cl；Hal 2为F、Cl、Br或I，优选为Br或Cl；环A 1、环A 2、X、R 1、R 2、R 3、m、n和q各自具有本发明所述的定义。(IA-4)与(IA-3)在DIPEA作用下在合适的溶剂(如异丙醇)中反应得到化合物(IA-5)；化合物(IA-5)在HCOOH、DIPEA和RuCl[(R,R-TsDpen)](p-cymene)作用下反应得到化合物(IA-6)；化合物(IA-6)在TBAB和NaOH作用下在合适的溶剂(如THF)中加热反应得到化合物(IA)。
合成方案12：
Figure PCTCN2022103288-appb-000065
化合物(IA)可以通过上述合成方案12的合成路线制备得到，其中，Hal 1为F、Cl、Br或I，优选为F或Cl；Hal 2为F、Cl、Br或I，优选为Br或Cl；Hal 3为F、Cl、Br或I，优选为Br或Cl；环A 1、环A 2、X、R 1、R 2、R 3、m、n和q各自具有本发明所述的定义。化合物(IA-4)与化合物(IA-7)在DIPEA作用下在合适的溶剂(如异丙醇)中反应得到化合物(IA-8)；化合物(IA-8)在HCOOH、DIPEA和RuCl[(R,R-TsDpen)](p-cymene)作用下反应得到化合物(IA-9)；化合物(IA-9)与化合物(IA-10)在合适的条件下(如Pd(dppf)Cl 2.CH 2Cl 2和K 2CO 3作用下，在1,4-二氧六环和水的混合溶剂中)偶联反应得到化合物(IA-6)；化合物(IA-6)在TBAB和NaOH作用下在合适的溶剂(如THF)中加热反应得到化合物(IA)。
合成方案13：
Figure PCTCN2022103288-appb-000066
化合物(IAa)可以通过上述合成方案13的合成路线制备得到，其中，Hal 1为F、Cl、Br或I，优选为F或Cl；Hal 2为F、Cl、Br或I，优选为Br或Cl；环A 1、环A 2、X、R 1、R 3、R 5、m和q各自具有本发明所述的定义。(IA-4a)与(IA-3)在DIPEA作用下在合适的溶剂(如异丙醇)中反应得到化合物(IA-5a)；化合物(IA-5a)在HCOOH、DIPEA和RuCl[(R,R-TsDpen)](p-cymene)作用下反应得到化合物(IA-6a)；化合物(IA-6a)在TBAB和NaOH作用下在合适的溶剂(如THF)中加热反应得到化合物(IAa)。
合成方案14
Figure PCTCN2022103288-appb-000067
化合物(IAa)可以通过上述合成方案14的合成路线制备得到，其中，Hal 1为F、Cl、Br或I，优选为F或Cl；Hal 2为F、Cl、Br或I，优选为Br或Cl；Hal 3为F、Cl、Br或I，优选为Br或Cl；环A 1、环A 2、X、R 1、R 3、R 5、m和q各自具有本发明所述的定义。化合物(IA-4a)与化合物(IA-7)在DIPEA作用下在合适的溶剂(如异丙醇)中反应得到化合物(IA-8a)；化合物(IA-8a)在HCOOH、DIPEA和RuCl[(R,R-TsDpen)](p-cymene)作用下反应得到化合物(IA-9a)；化合物(IA-9a)与化合物(IA-10)在合适的条件下(如Pd(dppf)Cl 2.CH 2Cl 2和K 2CO 3作用下，在1,4-二氧六环和水的混合溶剂中)偶联反应得到化合物(IA-6a)；化合物(IA-6a)在TBAB和NaOH作用下在合适的溶剂(如THF)中加热反应得到化合物(IAa)。
下面的实施例可以对本发明做进一步的描述，然而，这些实施例不应作为对本发明的范围的限制。
实施例
中间体1：(R)-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲醇的合成
Figure PCTCN2022103288-appb-000068
将N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺(210mg,0.44mmol,武汉纽瑞斯医药科技有限公司)、(S)-环氧乙烷-2-基甲醇(350mg,4.73mmol)、K 2CO 3(24.0mg,0.17mmol)和TBAB(47mg,0.15mmol)混合均匀，90℃反应24h。向反应液体系中加入THF(8mL)和NaOH(68mg,1.70mmol)，65℃反应24h。减压浓缩，向浓缩液中加入饱和NaHCO 3(20mL)溶液，DCM(30mL×2)萃取，有机相用无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离(淋洗剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到黄色油状物为标题化合物(50mg,产率：21.40％)。LC-MS(ESI,neg.ion)m/z:532.2[M-H] -
实施例1：6-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)螺[3.3]庚烷-2-羧酸的合成
Figure PCTCN2022103288-appb-000069
步骤1：6-(甲氧基亚甲基)螺[3.3]庚烷-2-羧酸甲酯的合成
0℃下，向NaH(1.4g,35mmol)和甲氧基甲基三苯基氯化鏻(10.0g,29.2mmol)的混合物中加入THF(30mL)，继续0℃下反应1小时，加入6-氧代螺[3.3]庚烷-2-羧酸甲酯(3.0g,18mmol)的THF(30mL)溶液，室温反应16小时后，停止反应，加入饱和氯化铵溶液(30mL)淬灭，乙酸乙酯萃取(30mL×3)，有机相合并，饱和食盐水洗(20mL)，无水硫酸钠干燥，浓缩拌样，硅胶柱层析分离(淋洗剂：石油醚/乙酸乙酯(v/v)＝5/1)纯化得到无色油状产物为标题化合物(1.3g,产率：37％)。
步骤2：6-甲酰基螺[3.3]庚烷-2-羧酸甲酯的合成
0℃下，向6-(甲氧基亚甲基)螺[3.3]庚烷-2-羧酸甲酯(1.2g,6.1mmol)的THF(20mL)溶液中加入稀盐酸(3.1mL,9.3mmol,3M)，自然升至室温反应3小时，停止反应，加入自来水稀释(30mL)，乙酸乙酯萃取(25mL×3)，有机相合并，并依次用饱和碳酸氢钠溶液洗(20mL)和饱和食盐水洗(20mL)，无水硫酸钠干燥，浓缩得到无色油状产物为标题化合物(640mg,产率：57％)。
步骤3：6-(环氧乙烷-2-基)螺[3.3]庚烷-2-羧酸甲酯的合成
室温下，向三甲基碘化鋶嗡盐(1.48g,7.25mmol)，NaH(264mg,6.60mmol)的混合物中加入DMSO(8mL)，室温反应1小时后，加入6-甲酰基螺[3.3]庚烷-2-羧酸甲酯(600mg,3.29mmol)的DMSO(8mL)溶液，继续室温搅拌12小时后，停止反应，加水稀释，乙酸乙酯萃取(20mL×3)，有机相合并，饱和 食盐水洗(20mL)，无水硫酸钠干燥，浓缩拌样，硅胶柱层析分离(淋洗剂：石油醚/乙酸乙酯(v/v)＝8/1)纯化得到无色油状产物为标题化合物(200mg,产率：30.95％)。
步骤4：6-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)螺[3.3]庚烷-2-羧酸的合成
将6-(环氧乙烷-2-基)螺[3.3]庚烷-2-羧酸甲酯(150mg,0.76mmol)、N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺(300mg,0.62mmol，武汉纽瑞斯医药科技有限公司)、Cs 2CO 3(41mg,0.12mmol)和TBAB(41mg,0.13mmol)混合物置于90℃油浴中反应24小时后，加入NaOH(100mg,2.50mmol)和THF(10mL)，继续60℃反应8小时，停止反应，加入1M稀盐酸调至pH＝7，乙酸乙酯萃取(20mL×3)，有机相合并，饱和食盐水洗(15mL)，无水硫酸钠干燥，浓缩拌样，硅胶柱层析分离(淋洗剂：石油醚/乙酸乙酯(v/v)＝1/2)纯化得到无色油状产物为标题化合物(6mg,产率：1.375％)。LC-MS(ESI,neg.ion)m/z:640.1[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.02(d,J＝7.7Hz,2H),7.89(d,J＝7.8Hz,1H),7.81(d,J＝7.3Hz,1H),7.65(t,J＝7.7Hz,1H),7.32(s,1H),7.14(d,J＝16.0Hz,2H),6.93(d,J＝8.5Hz,1H),6.86(d,J＝8.9Hz,1H),6.59(t,J＝73.3Hz,1H),4.21(d,J＝13.7Hz,1H),3.25(s,1H),3.06(dd,J＝20.3,11.5Hz,2H),2.36(d,J＝7.9Hz,1H),2.27–2.05(m,6H),1.87(dd,J＝18.1,8.6Hz,2H).
实施例2：4-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000070
步骤1：4-甲酰基双环[2.2.1]庚烷-1-羧酸甲酯的合成
0℃下，向4-(羟甲基)双环[2.2.1]庚烷-1-羧酸甲酯(500mg,2.71mmol)的CH 2Cl 2(10mL,156.0mmol)溶液中加入PCC(627mg,2.85mmol)，自然升至室温反应。加入硅藻土搅拌10分钟后，硅藻土过滤，二氯甲烷冲洗滤饼，滤液浓缩拌样后硅胶柱层析分离(淋洗剂：石油醚/乙酸乙酯(v/v)＝5/1)纯化得到无色油状产物为标题化合物(440mg,产率：88.97％)。 1H NMR(600MHz,CDCl 3)δ9.82(s,1H),3.71(s,3H),2.09–2.04(m,4H),1.85(s,2H),1.79–1.73(m,2H),1.55(t,J＝8.2Hz,2H).
步骤2：4-(环氧乙烷-2-基)双环[2.2.1]庚烷-1-羧酸甲酯的合成
向三甲基碘化亚砜(800mg,3.63mmol)，NaH(132mg,3.30mmol)的混合物中加入DMSO(6mL)，室温反应1小时后，加入4-甲酰基双环[2.2.1]庚烷-1-羧酸甲酯(300mg,1.64mmol)的DMSO溶液，继续室温搅拌，停止反应，加入饱和氯化铵溶液(20mL)淬灭，乙酸乙酯萃取(30mL×3)，有机相合并，无水硫酸钠干燥，浓缩拌样后硅胶柱层析分离(淋洗剂：石油醚/乙酸乙酯(v/v)＝3/1)纯化得到无色油状产物为标题化合物(110mg,产率：34.0％)。
步骤3：4-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将4-(环氧乙烷-2-基)双环[2.2.1]庚烷-1-羧酸甲酯(160mg,0.81mmol)，N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺(300mg,0.62mmol)，Cs 2CO 3(41mg,0.12mmol)，TBAB(41mg,0.1272mmol)混合物置于90℃油浴中反应18小时，加入NaOH(100mg,2.50mmol)和THF(5mL)，继续65℃反应6小时，停止反应，加入1M稀盐酸调至pH＝7，乙酸乙酯萃取(30mL×3)，有机相合 并，饱和食盐水洗(15mL)，无水硫酸钠干燥，浓缩拌样，硅胶柱层析分离(淋洗剂：石油醚/乙酸乙酯(v/v)＝1/1)纯化得到无色油状产物为标题化合物(75mg,产率：18.68％)。LC-MS(ESI,neg.ion)m/z:640.1[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.04(d,J＝2.0Hz,1H),8.01(s,1H),7.89(d,J＝8.0Hz,1H),7.79(d,J＝8.0Hz,1H),7.65(t,J＝8.0Hz,1H),7.33(dd,J＝8.8,2.0Hz,1H),7.20–7.11(m,2H),6.94(d,J＝8.4Hz,1H),6.90–6.83(m,1H),6.60(t,J＝73.2Hz,1H),4.36(dd,J＝14.4,2.0Hz,1H),3.35(dd,J＝10.4,2.0Hz,1H),3.21(dd,J＝14.4,10.4Hz,1H),2.14–2.01(m,2H),1.92–1.83(m,1H),1.82–1.69(m,3H),1.64–1.54(m,1H),1.54–1.43(m,2H),1.42–1.32(m,1H).
实施例3：6-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)螺[2.5]辛烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000071
步骤1：6-(甲氧基亚甲基)螺[2.5]辛烷-1-羧酸乙酯的合成
0℃条件下，向NaH(200mg,5.00mmol)和甲氧基甲基三苯基氯化鏻(1.50g,4.38mmol)的混合物中加入THF(8mL)，继续0℃下反应1小时，加入6-氧代螺[2.5]辛烷-1-羧酸乙酯(500mg,2.55mmol)的THF(8mL)溶液，室温反应24小时后，停止反应，加入饱和氯化铵溶液(20mL)淬灭，乙酸乙酯萃取(30mL×3)，有机相合并后用饱和食盐水洗(20mL)，无水硫酸钠干燥，浓缩拌样，硅胶柱层析分离(淋洗剂：石油醚/乙酸乙酯(v/v)＝5/1)纯化得到无色油状产物为标题化合物(400mg,产率：69.99％)。
步骤2：6-甲酰基螺[2.5]辛烷-1-羧酸乙酯的合成
0℃下，向6-(甲氧基亚甲基)螺[2.5]辛烷-1-羧酸乙酯(400mg,1.78mmol)的THF(8mL)溶液中加入HCl aq.(1.35mL,5.40mmol,4M)，室温反应10小时后，停止反应，加入饱和氯化铵溶液淬灭(30mL)，乙酸乙酯萃取(30mL×3)，有机相合并，饱和食盐水洗(15mL)，无水硫酸钠干燥，浓缩拌样，硅胶柱层析分离(淋洗剂：石油醚/乙酸乙酯(v/v)＝5/1)纯化得到无色油状产物为标题化合物(310mg,产率：82.67％)。 1H NMR(400MHz,CDCl 3)δ9.67(d,J＝10.6Hz,1H),4.13(ddd,J＝10.7,5.1,3.5Hz,2H),2.33(dd,J＝12.4,8.7Hz,1H),2.04–1.45(m,8H),1.32–1.24(m,3H),1.14(dd,J＝18.9,13.4Hz,2H),0.94–0.80(m,1H).
步骤3：6-(环氧乙烷-2-基)螺[2.5]辛烷-1-羧酸乙酯的合成
室温下，向三甲基碘化亚砜(690mg,3.13mmol)，NaH(115mg,2.87mmol)的混合物中加入DMSO(6mL)，室温反应1小时后，加入6-甲酰基螺[2.5]辛烷-1-羧酸乙酯(300mg,1.42mmol)的DMSO(6mL)溶液，继续室温搅拌22小时后，停止反应，加水稀释(15mL)，乙酸乙酯萃取(30mL×3)，有机相合并后用饱和碳酸氢钠溶液洗(15mL)，饱和食盐水洗(15mL)，无水硫酸钠干燥，浓缩拌样，硅胶柱层析分离(淋洗剂：石油醚/乙酸乙酯(v/v)＝4/1)纯化得到无色油状产物为标题化合物(163mg,产率：50.93％)。 1H NMR(400MHz,CDCl 3)δ4.21–4.06(m,2H),2.82–2.68(m,2H),2.59–2.50(m,1H),1.97–1.43(m,7H),1.41–1.24(m,5H),1.11(ddd,J＝14.8,10.3,7.7Hz,1H),1.04–0.94(m,1H),0.92-0.80(m,1H).
步骤4：6-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)螺[2.5]辛烷-1-羧酸乙酯的合成
将6-(环氧乙烷-2-基)螺[2.5]辛烷-1-羧酸乙酯(120mg,0.53mmol)，N-(3'-(二氟甲氧基)-4,5'-二氟 -[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺(250mg,0.52mmol)，Cs 2CO 3(34mg,0.10mmol)，TBAB(34mg,0.10mmol)混合物置于90℃油浴中反应13小时后，加入NaOH(84mg,2.1002mmol)和THF(10mL)，继续60℃反应10小时，停止反应，加入1M稀盐酸调至pH＝7，乙酸乙酯萃取(20mL×3)，有机相合并后用饱和食盐水洗(15mL)，无水硫酸钠干燥，浓缩拌样，硅胶柱层析分离(淋洗剂：石油醚/乙酸乙酯(v/v)＝3/1)纯化得到产物为标题化合物(60mg,产率：17.6％)。 1H NMR(400MHz,CDCl 3)δ8.05–7.97(m,2H),7.87(d,J＝7.4Hz,1H),7.80(t,J＝8.0Hz,1H),7.68–7.60(m,1H),7.34–7.27(m,1H),7.14(d,J＝12.7Hz,2H),6.91(dd,J＝11.2,3.5Hz,1H),6.85(d,J＝9.2Hz,1H),6.59(t,J＝73.3Hz,1H),4.46–4.32(m,1H),4.26–4.07(m,2H),3.26(dd,J＝19.1,7.3Hz,1H),3.22–3.04(m,1H),1.94–1.52(m,7H),1.52–1.42(m,1H),1.36–1.22(m,3H),1.20–0.78(m,4H).
步骤5：6-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)螺[2.5]辛烷-1-羧酸异构体1和6-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)螺[2.5]辛烷-1-羧酸异构体2的合成
向6-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)螺[2.5]辛烷-1-羧酸乙酯(60mg,0.087mmol)的EtOH(3mL)和水(2mL)溶液中加入NaOH(84mg,2.10mmol)，置于50℃油浴中加热反应11小时，停止反应，加入1M稀盐酸调至pH＝7，乙酸乙酯萃取(20mL×3)，有机相合并，饱和食盐水洗(15mL)，无水硫酸钠干燥，浓缩拌样，硅胶柱层析分离(淋洗剂：石油醚/乙酸乙酯(v/v)＝1/1)纯化得到产物6-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)螺[2.5]辛烷-1-羧酸的两种异构体，分别为异构体1(30mg,产率：52.6％)和异构体2(20mg,产率：34.7％)。异构体1:MS(ESI,neg.ion)m/z:654.1[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.02(dd,J＝5.4,2.1Hz,1H),7.98(d,J＝6.8Hz,1H),7.88(d,J＝7.7Hz,1H),7.82(t,J＝6.8Hz,1H),7.65(dt,J＝12.6,6.3Hz,1H),7.33–7.28(m,1H),7.19–7.08(m,2H),6.91(dd,J＝8.5,6.6Hz,1H),6.85(d,J＝9.1Hz,1H),6.59(t,J＝73.3Hz,1H),4.37(ddd,J＝14.2,5.8,1.9Hz,1H),3.33–3.18(m,1H),3.08(dt,J＝15.1,7.6Hz,1H),2.00–1.82(m,3H),1.82–1.59(m,3H),1.50(t,J＝6.2Hz,1H),1.22(dd,J＝13.7,8.8Hz,2H),1.03–0.82(m,3H).异构体2:MS(ESI,neg.ion)m/z:654.1[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.03(d,J＝1.9Hz,2H),7.89(d,J＝7.7Hz,1H),7.80(d,J＝4.3Hz,1H),7.65(t,J＝7.8Hz,1H),7.31(dd,J＝8.6,1.3Hz,1H),7.20–7.09(m,2H),6.93(dd,J＝8.5,2.0Hz,1H),6.86(d,J＝9.1Hz,1H),6.60(t,J＝73.3Hz,1H),4.39(d,J＝13.1Hz,1H),3.27(ddd,J＝14.5,10.3,4.5Hz,1H),3.12(dd,J＝12.2,7.9Hz,1H),1.83(ddd,J＝48.6,27.5,13.3Hz,4H),1.69–1.49(m,3H),1.19(dd,J＝27.0,15.1Hz,3H),1.04(d,J＝10.6Hz,1H),0.93–0.84(m,1H).
实施例4：4-((R)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000072
将4-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸(1.52g,2.37mmol,实施例2)采用SFC(超临界流体色谱)手性制备色谱拆分。拆分条件：15％甲醇+二氧化碳，色谱柱是IC：30mm*250mm*5mm，检测波长：210nm，取后峰减压浓缩，得到黄色固体为4-((R)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢 -2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸(488.0mg,产率：32.10％)。LC-MS(ESI,neg.ion)m/z:640.1[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.04(d,J＝2.0Hz,1H),8.01(s,1H),7.89(d,J＝8.0Hz,1H),7.79(d,J＝8.0Hz,1H),7.65(t,J＝8.0Hz,1H),7.33(dd,J＝8.8,2.0Hz,1H),7.20–7.11(m,2H),6.94(d,J＝8.4Hz,1H),6.90–6.83(m,1H),6.60(t,J＝73.2Hz,1H),4.36(dd,J＝14.4,2.0Hz,1H),3.35(dd,J＝10.4,2.0Hz,1H),3.21(dd,J＝14.4,10.4Hz,1H),2.14–2.01(m,2H),1.92–1.83(m,1H),1.82–1.69(m,3H),1.64–1.54(m,1H),1.54–1.43(m,2H),1.42–1.32(m,1H).HPLC条件:OJ柱,乙醇/正己烷(0.1％三氟乙酸)＝10/90,流速＝1mL/min,λ＝215nm,t＝10.003min,99％ee.
实施例5：4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000073
将4-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸(1.52g,2.37mmol,实施例2)采用SFC(超临界流体色谱)手性制备色谱拆分。拆分条件：15％甲醇+二氧化碳，色谱柱是IC：30mm*250mm*5mm，检测波长：210nm，取前峰减压浓缩，得到黄色固体为4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸(454.0mg，产率：29.90％)。LC-MS(ESI,neg.ion)m/z:640.1[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.04(d,J＝2.0Hz,1H),8.01(s,1H),7.89(d,J＝8.0Hz,1H),7.79(d,J＝8.0Hz,1H),7.65(t,J＝8.0Hz,1H),7.33(dd,J＝8.8,2.0Hz,1H),7.20–7.11(m,2H),6.94(d,J＝8.4Hz,1H),6.90–6.83(m,1H),6.60(t,J＝73.2Hz,1H),4.36(dd,J＝14.4,2.0Hz,1H),3.35(dd,J＝10.4,2.0Hz,1H),3.21(dd,J＝14.4,10.4Hz,1H),2.14–2.01(m,2H),1.92–1.83(m,1H),1.82–1.69(m,3H),1.64–1.54(m,1H),1.54–1.43(m,2H),1.42–1.32(m,1H).HPLC条件:OJ柱,乙醇/正己烷(0.1％三氟乙酸)＝10/90,流速＝1mL/min,λ＝215nm,t＝11.706min,99％ee.
实施例6：环丙基(6-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)-2-氮杂螺[3.3]庚-2-基)甲酮的合成
Figure PCTCN2022103288-appb-000074
步骤1：6-氧代-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成
将6-羟基-2-氮杂螺并[3.3]庚烷-2-羧酸叔丁酯(1.55g,7.27mmol)溶于DCM(15mL)中，冰浴下加入DMP(6.20g,15.00mmol)，室温搅拌18h。向反应液中加入饱和NaHCO 3(50mL)溶液，DCM(60mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝3/1)，得到白色固体为标题化合物(1.5g,产率：98.0％)。LC-MS(ESI,pos.ion)m/z:156.2[M+2H-t-Bu] +.
步骤2：6-(甲氧基亚甲基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成
冰浴下，将LDA(8mL,16.00mmol,2mol/L)加入到(甲氧基甲基)三苯基氯化磷(5.2g,15.00mmol)的THF(30mL)溶液中，20min滴加完毕，然后室温反应2h。向反应液中加入6-氧代-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(1.6g,7.60mmol)的THF(30mL)溶液，60℃反应4h。向反应液中加入饱和NaHCO 3(50mL)溶液，EtOAc(60mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝4/1)，得到黄色油状物为标题化合物(640mg,产率：35.0％)。MS(ESI,pos.ion)m/z:184.1[M+2H-t-Bu] +.
步骤3：6-甲酰基-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成
将6-(甲氧基亚甲基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(700mg,2.93mmol)溶于DCM/H 2O(6.6mL/3.3mL)中，冰浴下加入TFA(0.9mL,10.00mmol)，室温下搅拌5h。向反应液中加入饱和NaHCO 3(50mL)溶液，DCM(60mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到黄色油状物为标题化合物(598mg,产率：90.8％)。LC-MS(ESI,pos.ion)m/z:170.1[M+2H-t-Bu] +.
步骤4：6-(环氧乙烷-2-基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成
冰浴下，将NaH(92mg,2.30mmol,60mass％)加入到Me 3S(O)I(521mg,2.37mmol)的DMF(3mL)溶液中，冰浴下反应10min。然后加入6-甲酰基-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(374mg,1.66mmol)的DMF(3mL)溶液，冰浴下反应2h。缓慢升温至室温反应。向反应液中加入饱和NH 4Cl(50mL)溶液，EtOAc(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝4/1)，得到黄色油状物为标题化合物(77mg,产率：19.4％)。GC-MS(ESI,pos.ion)m/z:184.2[M+2H-t-Bu] +.
步骤5：6-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成
将N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺(124mg,0.26mmol)、6-(环氧乙烷-2-基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(91mg,0.38mmol)、K 2CO 3(12mg,0.087mmol)和TBAB(29mg,0.090mmol)混合均匀，90℃反应20h。向反应液体系中加入THF(8mL)和NaOH(42mg,1.05mmol)，65℃反应24h。减压浓缩，向反应液中加入饱和NaHCO 3(20mL)溶液，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到黄色油状物为标题化合物(146mg,产率：80.8％)。MS(ESI,pos.ion)m/z:599.1[M+2H-Boc] +.
步骤6：6-(3-(二氟甲氧基)-5-氟苯基)-2-(2-氮杂[3.3]庚-6-基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪的合成
将6-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(146mg,0.21mmol)溶于DCM(3mL)中，冰浴下加入HCl的1,4-二氧六环溶液(1mL,4.00mmol,4mol/L)，室温下搅拌30min。减压浓缩，向反应液中加入饱和NaHCO 3(20mL)溶液，调节体系pH至8左右，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，得到黄色油状物为标题化合物(120mg,产率：95.9％)。MS(ESI,pos.ion)m/z:599.1[M+H] +.
步骤7：环丙基(6-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)-2-氮杂螺[3.3]庚-2-基)甲酮的合成
将6-(3-(二氟甲氧基)-5-氟苯基)-2-(2-氮杂[3.3]庚-6-基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪(120mg,0.20mmol)，环丙甲酸(53mg,0.62mmol)，EDCI(150mg,0.78mmol)，HOBT(87mg,0.64mmol)溶于DCM(5mL)中，并加入DIPEA(0.2mL,1.00mmol)，室温搅拌17h。向反应 液中加入DCM(50mL)，饱和NH 4Cl(20mL×2)洗涤，饱和NaHCO 3(20mL)洗涤，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝15/1)，得到白色固体为标题化合物(56mg,产率：41.9％)。LC-MS(ESI,pos.ion)m/z:667.1[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.02(d,J＝12.2Hz,1H),7.98(s,1H),7.90(d,J＝7.6Hz,1H),7.84(d,J＝7.7Hz,1H),7.67(t,J＝6.8Hz,1H),7.32(d,J＝8.3Hz,1H),7.13(d,J＝15.7Hz,2H),6.95(t,J＝8.1Hz,1H),6.86(d,J＝8.9Hz,1H),6.59(t,J＝73.3Hz,1H),4.31–4.10(m,3H),4.04(s,1H),3.92(dd,J＝19.5,10.0Hz,1H),3.35(s,1H),3.12(dd,J＝24.2,13.7Hz,1H),2.35(d,J＝7.0Hz,3H),2.12(s,2H),1.42–1.35(m,1H),0.97(s,2H),0.76(d,J＝4.9Hz,2H).
实施例7：(S)-2-(2-氧杂-6-氮杂螺[3.3]庚-6-基甲基)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪的合成
Figure PCTCN2022103288-appb-000075
步骤1：(R)-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基甲磺酸酯的合成
将(R)-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲醇(125mg,0.23mmol，中间体1)溶于DCM(5mL)，冰浴下，依次加入DIPEA(0.08mL,0.50mmol)和MsCl(0.04mL,0.50mmol)，然后室温搅拌3h。向反应液中加入饱和NaHCO 3溶液(20mL)，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝3/1)，得到黄色油状物(140mg,产率：97.7％)。
步骤2：(S)-2-(2-氧杂-6-氮杂螺[3.3]庚-6-基甲基)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪的合成
将(R)-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基甲磺酸酯(151mg,0.25mmol)，6-氧杂-2-氮杂螺[3.3]庚烷草酸盐(166mg,0.58mmol)，K 2CO 3(315mg,2.28mmol)溶于CH 3CN(6mL)中，90℃反应16h。减压浓缩，然后向剩余物中加入饱和NH 4Cl溶液(20mL)，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝20/1)，得到淡黄色固体(65mg,产率：42.8％)。LC-MS(ESI,pos.ion)m/z:615.0[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.01(d,J＝7.9Hz,2H),7.86(dd,J＝21.0,7.7Hz,2H),7.65(t,J＝7.8Hz,1H),7.31(d,J＝10.4Hz,1H),7.13(d,J＝15.6Hz,2H),6.93(d,J＝8.5Hz,1H),6.86(d,J＝9.1Hz,1H),6.59(t,J＝73.3Hz,1H),4.74(s,4H),4.35(d,J＝15.9Hz,1H),3.34(ddd,J＝24.3,13.9,8.9Hz,6H),2.58(qd,J＝12.7,5.4Hz,2H).
实施例8：(S)-环丙基(6-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-2,6-二氮杂螺[3.3]庚-2-基)甲酮的合成
Figure PCTCN2022103288-appb-000076
步骤1：(S)-叔丁基6-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并 [b][1,4]恶嗪-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸酯的合成
将(R)-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基甲磺酸酯(172mg,0.28mmol,实施例7步骤1)，2,6-二氮杂螺并[3.3]庚烷-6-羧酸叔丁酯草酸盐(148mg,0.51mmol)，K 2CO 3(350mg,2.53mmol)溶于CH 3CN(6mL)中，90℃反应3h。减压浓缩，然后向剩余物中加入饱和NaHCO 3溶液(20mL)，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝15/1)，得到黄色固体(138mg,产率：68.7％)。LC-MS(ESI,pos.ion)m/z:714.1[M+H] +.
步骤2：(S)-2-(2,6-二氮杂螺[3.3]庚-2-基甲基)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪的合成
将(S)-叔丁基6-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸酯(138mg,0.19mmol)溶于DCM(3mL)中，冰浴下加入HCl的1,4-二氧六环溶液(1mL,4.00mmol,4mol/L)，室温下搅拌3h。减压浓缩，向反应液中加入饱和NaHCO 3(20mL)溶液，调节体系pH至8左右，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，得到黄色油状物(35mg,产率：29.5％)。LC-MS(ESI,pos.ion)m/z:614.0[M+H] +.
步骤3：(S)-环丙基(6-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-2,6-二氮杂螺[3.3]庚-2-基)甲酮的合成
将(S)-2-(2,6-二氮杂螺[3.3]庚-2-基甲基)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪(110mg,0.18mmol)，环丙甲酸(67mg,0.78mmol)，EDCI(118mg,0.62mmol)，HOBT(75mg,0.56mmol)溶于DCM(5mL)中，并加入DIPEA(0.15mL,0.91mmol)，室温搅拌16h。向反应液中加入DCM(50mL)，饱和NH 4Cl溶液(20mL×2)洗涤，饱和NaHCO 3溶液(20mL)洗涤，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝15/1)，得到黄色固体32mg，进一步PTLC分离，得到淡黄色固体(13mg,产率：10.6％)。LC-MS(ESI,pos.ion)m/z:682.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.00(d,J＝13.2Hz,2H),7.87(dd,J＝16.3,7.7Hz,2H),7.66(t,J＝7.8Hz,1H),7.31(d,J＝9.0Hz,1H),7.13(d,J＝15.6Hz,2H),6.93(d,J＝8.5Hz,1H),6.87(d,J＝8.9Hz,1H),6.59(t,J＝73.3Hz,1H),4.36(d,J＝7.6Hz,3H),4.05(s,2H),3.55–3.28(m,6H),2.64(s,2H),0.97(s,2H),0.89(d,J＝6.8Hz,1H),0.81–0.74(m,2H).
实施例9：(S)-2-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-2-氮杂螺[3.3]庚烷-6-羧酸的合成
Figure PCTCN2022103288-appb-000077
步骤1：2-氮杂螺并[3.3]庚烷-6-羧酸甲酯的合成
将2-叔丁基6-甲基2-氮杂螺[3.3]庚烷-2,6-二羧酸酯(122mg,0.48mmol)溶于DCM(2mL)中，冰浴下加入HCl的1,4-二氧六环溶液(2mL,8.00mmol,4mol/L)，室温下搅拌2h。减压浓缩，向反应液中加入饱和NaHCO 3(20mL)溶液，调节体系pH至8左右，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，得到黄色油状物(70mg,产率：94.4％)。LC-MS(ESI,pos.ion)m/z:156.2[M+H] +.
步骤2：(S)-2-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-2-氮杂螺[3.3]庚烷-6-羧酸甲酯的合成
将(R)-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基甲磺酸酯(120mg,0.19mmol,实施例7步骤1)，2-氮杂螺并[3.3]庚烷-6-羧酸甲酯(70mg,0.45mmol)，K 2CO 3(278mg,2.01mmol)溶于CH 3CN(6mL)中，90℃反应12h。减压浓缩，然后向剩余物中加入饱和NaHCO 3溶液(20mL)，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝20/1)，得到黄色油状物(34mg,产率：25.8％)。MS(ESI,pos.ion)m/z:671.2[M+H] +.
步骤3：(S)-2-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-2-氮杂螺[3.3]庚烷-6-羧酸的合成
(S)-2-(((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-2-氮杂螺[3.3]庚烷-6-羧酸甲酯(68mg,0.10mmol)，LiOH·H 2O(37mg,0.88mmol)溶于H 2O/MeOH/THF(1mL/1.5mL/2mL)中，室温反应7h。向反应液中加入饱和NH 4Cl溶液(20mL)，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝8/1)，得到灰白色固体(35mg,产率：52.6％)；LC-MS(ESI,pos.ion)m/z:657.2[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ8.13(d,J＝7.5Hz,1H),8.02–7.93(m,2H),7.91–7.84(m,2H),7.50(dd,J＝8.6,2.0Hz,1H),7.35(t,J＝73Hz,1H),7.30(d,J＝9.7Hz,1H),7.19(s,1H),7.10(d,J＝9.6Hz,1H),6.96(d,J＝8.6Hz,1H),4.28(d,J＝12.8Hz,1H),3.32(s,2H),3.09(ddd,J＝28.0,22.3,6.7Hz,6H),2.89–2.82(m,1H),2.26–2.14(m,4H).
实施例10：(R)-环丙基(6-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲氧基)-2-氮杂螺[3.3]庚-2-基)甲酮的合成
Figure PCTCN2022103288-appb-000078
步骤1：(R)-6-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲氧基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成
将(R)-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基甲磺酸酯(120mg,0.19mmol,实施例7步骤1)，2-羟基-6-氮杂螺并[3.3]庚烷-6-羧酸叔丁酯(90mg,0.42mmol)，TBAB(47mg,0.15mmol)溶于Et 2O(6mL)中，并加入H 2O(0.3mL)，NaOH(140mg,3.50mmol)，室温反应16h。减压浓缩，然后向剩余物中加入饱和NaHCO 3溶液(20mL)，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到黄色油状物(41mg,产率：28.7％)。LC-MS(ESI,pos.ion)m/z:751.1[M+Na] +.
步骤2：(R)-2-(((2-氮杂螺[3.3]庚烷-6-基)氧基)甲基)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪的合成
将(R)-6-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲氧基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(36mg,0.049mmol)溶于DCM(1mL)中，冰浴下加入HCl的1,4-二氧六环溶液(1mL,4.00mmol,4mol/L)，室温下搅拌4h。减压浓缩，向反应液中加入饱和NaHCO 3(10mL)溶液，调节体系pH至8左右，DCM(20mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，得到黄色油状物(30mg,产率：96.6％)。LC-MS(ESI,pos.ion)m/z:629.5[M+H] +.
步骤3：(R)-环丙基(6-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并 [b][1,4]恶嗪-2-基)甲氧基)-2-氮杂螺[3.3]庚-2-基)甲酮的合成
将(R)-2-(((2-氮杂螺[3.3]庚烷-6-基)氧基)甲基)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪(50mg,0.080mmol)、环丙甲酸(56mg,0.65mmol)、EDCI(88mg,0.46mmol)和DIPEA(0.1mL,0.60mmol)溶于DCM(5mL)中，室温反应24h。向反应液中加入DCM(30mL)，饱和NH 4Cl溶液(20mL×2)洗涤，饱和NaHCO 3溶液(20mL×2)洗涤，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝10/1)，得到黄色固体28mg。进一步制备薄层色谱分离，得到淡黄色固体(14mg,产率：25.3％)。LC-MS(ESI,pos.ion)m/z:697.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.02(d,J＝11.0Hz,2H),7.86(dd,J＝16.8,7.9Hz,2H),7.65(t,J＝7.8Hz,1H),7.31(d,J＝7.3Hz,1H),7.14(d,J＝15.8Hz,2H),6.94(d,J＝8.5Hz,1H),6.87(d,J＝9.0Hz,1H),6.59(t,J＝73.2Hz,1H),4.41(d,J＝13.8Hz,1H),4.23(s,2H),3.99(s,2H),3.94–3.87(m,1H),3.51(d,J＝10.4Hz,2H),3.44–3.34(m,2H),2.53(s,2H),2.16(s,2H),0.97(s,2H),0.90(s,1H),0.76(d,J＝4.5Hz,2H).
实施例11：3-(((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-3-氮杂双环[3.1.1]庚烷-6-羧酸的合成
Figure PCTCN2022103288-appb-000079
步骤1：3-氮杂双环[3.1.1]庚烷-6-羧酸甲酯盐酸盐的合成
将3-叔丁基6-甲基3-氮杂双环[3.1.1]庚烷-3,6-二羧酸酯(301mg,1.18mmol)溶于DCM(2mL)中，冰浴下加入HCl的1,4-二氧六环溶液(3mL,12.00mmol,4mol/L)，室温下搅拌4h。减压浓缩，得到黄色油状物(210mg,产率：92.9％)。LC-MS(ESI,pos.ion)m/z:156.1[M+H] +.
步骤2：3-(((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-3-氮杂双环[3.1.1]庚烷-6-羧酸甲酯的合成
将(R)-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基甲磺酸酯(100mg,0.16mmol,实施例7步骤1)、3-氮杂双环[3.1.1]庚烷-6-羧酸甲酯盐酸盐(210mg,1.09mmol)和K 2CO 3(236mg,1.71mmol)溶于ACN(5mL)中，80℃反应16h。减压浓缩，然后向剩余物中加入饱和NaHCO 3溶液(20mL)，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：PET/EtOAc(v/v)＝3/1)，得到无色油状物(58mg,产率：52.9％)。LC-MS(ESI,pos.ion)m/z:671.1[M+H] +.
步骤3：3-(((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-3-氮杂双环[3.1.1]庚烷-6-羧酸的合成
将3-(((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-3-氮杂双环[3.1.1]庚烷-6-羧酸甲酯(58mg,0.086mmol)溶于H 2O/MeOH/THF(0.6mL/1mL/1.5mL)中，并加入LiOH·H 2O(48mg,1.14mmol)，室温下搅拌12h。向反应液中加入饱和NH 4Cl溶液(20mL)洗涤，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝12/1)，得到白色固体(18mg,产率：31.7％)。LC-MS(ESI,pos.ion)m/z:657.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.12(s,1H),7.99–7.90(m,2H),7.87(d,J＝7.5Hz,1H),7.66(t,J＝7.9Hz,1H),7.29(d,J＝1.7Hz,1H),7.11(d,J＝15.3Hz,2H),6.95(d,J＝8.5Hz,1H),6.86(d,J＝9.2Hz,1H),6.58(t,J＝73.2Hz,1H),4.52(d,J＝14.5Hz,1H),3.76(d,J＝6.6Hz,1H),3.34(t,J＝10.0Hz, 2H),3.19(dd,J＝14.3,9.9Hz,1H),3.00(t,J＝5.4Hz,1H),2.86(dd,J＝13.0,5.8Hz,1H),2.73(d,J＝9.4Hz,3H),2.68–2.58(m,2H),1.14(d,J＝9.3Hz,2H).
实施例12：(S)-3-(((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)(甲基)氨基)双环[1.1.1]戊烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000080
步骤1：3-(苄氨基)双环[1.1.1]戊烷-1-羧酸甲酯的合成
将3-氨基双环[1.1.1]戊烷-1-羧酸甲酯(502mg,3.56mmol)和苯甲醛(0.4mL,4.00mmol)溶于EtOH/THF(3mL/3mL)中，并加入AcOH(0.2mL,3.00mmol)，NaBH 3CN(678mg,10.79mmol)，60℃反应15h。减压浓缩，饱和NaHCO 3溶液(30mL)淬灭，EtOAc(50mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝3/1)，得到黄色油状物(429mg,产率：52.2％)。LC-MS(ESI,pos.ion)m/z:232.2[M+H] +.
步骤2：3-(苄基(甲基)氨基)双环[1.1.1]戊烷-1-羧酸甲酯的合成
将3-(苄氨基)双环[1.1.1]戊烷-1-羧酸甲酯(429mg,1.86mmol)和甲醛(57mg,1.90mmol)溶于EtOH/THF(4mL/4mL)中，并加入AcOH(0.1mL,2.00mmol)，NaBH 3CN(330mg,5.25mmol)，60℃反应16h。减压浓缩，饱和NaHCO 3溶液(20mL)淬灭，EtOAc(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝5/1)，得到黄色油状物(279mg,产率：61.3％)。LC-MS(ESI,pos.ion)m/z:246.2[M+H] +.
步骤3：3-(甲基氨基)双环[1.1.1]戊烷-1-羧酸甲酯的合成
氢气氛围下，将3-(苄基(甲基)氨基)双环[1.1.1]戊烷-1-羧酸甲酯(279mg,1.14mmol)，Pd/C(790mg,0.74mmol,含量10％)溶于MeOH/THF(3mL/3mL)中，室温下搅拌22h。硅藻土过滤，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝10/1)，得到黄色油状物(86mg,产率：48.7％)。LC-MS(ESI,pos.ion)m/z:156.1[M+H] +.
步骤4：(S)-3-(((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)(甲基)氨基)双环[1.1.1]戊烷-1-羧酸甲酯的合成
将(R)-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基甲磺酸酯(155mg,0.25mmol,实施例7步骤1)，3-(甲基氨基)双环[1.1.1]戊烷-1-羧酸甲酯(86mg,0.55mmol)，K 2CO 3(226mg,1.64mmol)溶于ACN(5mL)中，90℃反应23h。减压浓缩，然后向剩余物中加入饱和NaHCO 3溶液(20mL)，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝1/1)，得到黄色油状物(80mg,产率：47.1％)。LC-MS(ESI,pos.ion)m/z:671.2[M+H] +.
步骤5：(S)-3-(((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)(甲基)氨基)双环[1.1.1]戊烷-1-羧酸的合成
将(S)-3-(((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)(甲基)氨基)双环[1.1.1]戊烷-1-羧酸甲酯(80mg,0.12mmol)溶于H 2O/MeOH/THF(0.6mL/1mL/1.5mL)中，并加入LiOH·H 2O(65mg,1.55mmol)，室温下搅拌6h。向反应液中加入饱和NH 4Cl水溶液(20mL)洗涤，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶 柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝10/1)，得到黄色固体(23mg,产率：29.4％)。LC-MS(ESI,pos.ion)m/z:657.1[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ8.15(d,J＝7.6Hz,1H),7.96(dd,J＝12.5,6.1Hz,3H),7.88(t,J＝7.8Hz,1H),7.53(dd,J＝8.5,2.0Hz,1H),7.41(s,J＝72Hz,1H),7.34(d,J＝9.4Hz,1H),7.24(s,1H),7.13(d,J＝9.7Hz,1H),6.99(d,J＝8.6Hz,1H),4.35(d,J＝11.6Hz,1H),3.51(s,4H),2.59(d,J＝13.1Hz,2H),2.11(s,2H),1.88(s,5H).
实施例13：(S)-6-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-2-硫杂-6-氮杂螺[3.3]庚烷2,2-二氧化物的合成
Figure PCTCN2022103288-appb-000081
将(R)-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基甲磺酸酯(108mg,0.18mmol,实施例7步骤1)，2-硫杂-6-氮杂螺[3.3]庚烷2,2-二氧化物盐酸盐(68mg,0.37mmol)，K 2CO 3(256mg,1.85mmol)溶于ACN(5mL)中，90℃反应22h。硅藻土过滤，滤液减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝1/2)，得到淡黄色固体(24mg,产率：20.5％)。LC-MS(ESI,pos.ion)m/z:663.1[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.02(s,1H),7.95(d,J＝1.6Hz,1H),7.87(dd,J＝14.2,7.8Hz,2H),7.67(t,J＝7.8Hz,1H),7.31(dd,J＝8.6,2.0Hz,1H),7.17–7.06(m,2H),6.89(dd,J＝19.7,8.8Hz,2H),6.59(t,J＝73.2Hz,1H),4.31(dd,J＝14.2,1.9Hz,1H),4.24(s,4H),3.62–3.35(m,6H),2.70(s,2H).
实施例14：(S)-6-(3-(二氟甲氧基)-5-氟苯基)-2-((6-(甲基磺酰基)-2,6-二氮杂螺[3.3]庚-2-基)甲基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪的合成
Figure PCTCN2022103288-appb-000082
步骤1：(S)-6-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成
将(R)-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基甲磺酸酯(610mg,0.99mmol,实施例7步骤1)、2,6-二氮杂螺并[3.3]庚烷-6-羧酸叔丁酯(807mg,4.07mmol)和K 2CO 3(619mg,4.48mmol)加入到ACN(10mL)中，90℃反应15h。硅藻土过滤，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝1/2)，得到黄色油状物(381mg,产率：53.5％)。LC-MS(ESI,pos.ion)m/z:714.2[M+H] +.
步骤2：(S)-2-((2,6-二氮杂螺[3.3]庚烷-2-基)甲基)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪的合成
将(S)-6-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(161mg,0.23mmol)溶于DCM(3mL)中，冰浴下加入TFA(0.8mL,10.00mmol)，室温下搅拌1h。向反应液中加入饱和NaHCO 3(20mL)溶液，调节体系pH至7左右，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，得到黄色固体(138mg,产率：99.7％)。LC-MS(ESI,pos.ion)m/z:614.2[M+H] +.
步骤3：(S)-6-(3-(二氟甲氧基)-5-氟苯基)-2-((6-(甲基磺酰基)-2,6-二氮杂螺[3.3]庚-2-基)甲基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪的合成
将(S)-2-((2,6-二氮杂螺[3.3]庚烷-2-基)甲基)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪(139mg,0.23mmol)和DIPEA(0.2mL,1.00mmol)溶于DCM(3mL)中，冰浴下缓慢滴加甲磺酰氯(0.02mL,0.30mmol)，室温反应10h。向反应液中加入DCM(50mL)，饱和溶液NH 4Cl(30mL×2)洗涤，饱和NaHCO 3溶液(30mL×2)洗涤，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝1/3)，得到黄色固体(55mg,产率：35.1％)。LC-MS(ESI,pos.ion)m/z:692.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.08–7.94(m,2H),7.86(dd,J＝17.0,7.7Hz,2H),7.66(t,J＝7.9Hz,1H),7.30(d,J＝8.9Hz,1H),7.13(d,J＝15.5Hz,2H),6.93(d,J＝8.5Hz,1H),6.86(d,J＝9.2Hz,1H),6.59(t,J＝73.3Hz,1H),4.33(d,J＝12.3Hz,1H),4.00(s,4H),3.49(s,1H),3.35(dd,J＝23.4,8.2Hz,5H),2.86(s,3H),2.63(s,2H).
实施例15：(S)-2-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-7-硫-2-氮杂螺[3.5]壬烷7,7-二氧化物的合成
Figure PCTCN2022103288-appb-000083
将(R)-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基甲磺酸酯(113mg,0.18mmol,实施例7步骤1)，7-硫杂-2-氮杂螺[3.5]壬烷7,7-二氧化物盐酸盐(136mg,0.64mmol)，K 2CO 3(256mg,1.85mmol)溶于ACN(5mL)中，90℃反应23h。硅藻土过滤，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝1/3)，得到淡黄色固体(85mg,产率：66.6％)。LC-MS(ESI,pos.ion)m/z:690.9[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.03(s,1H),7.98(d,J＝2.0Hz,1H),7.88(d,J＝7.7Hz,1H),7.82(d,J＝7.8Hz,1H),7.65(t,J＝7.9Hz,1H),7.31(dd,J＝8.5,2.1Hz,1H),7.13(dd,J＝8.8,6.8Hz,2H),6.92(d,J＝8.5Hz,1H),6.87(d,J＝9.1Hz,1H),6.59(t,J＝73.2Hz,1H),4.35(dd,J＝14.3,2.2Hz,1H),3.48(s,1H),3.35(dd,J＝14.3,10.0Hz,1H),3.09(dd,J＝14.2,6.9Hz,4H),2.97(d,J＝5.7Hz,4H),2.75–2.63(m,2H),2.37–2.25(m,4H).
实施例16：4-(7-(3-(二氟甲氧基)-5-氟苯基)-4-氧代-1-((3-(三氟甲基)苯基)磺酰基)-1,2-二氢喹唑啉-3(4H)-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000084
步骤1：4-(2-氨基-4-溴苯甲酰胺基)双环[2.2.1]庚烷-1-羧酸甲酯的合成
将2-氨基-4-溴-苯甲酸(1.58g,7.31mmol)、4-氨基降冰片烷-1-羧酸甲酯(1.00g,5.91mmol)、EDCI(2.30g,12.00mmol)、HOBT(1.60g,12.00mmol)和DIPEA(3.2mL,18.00mmol)溶于DCM(15mL)中，室温反应16h。向反应液中加入DCM(50mL)，饱和NH 4Cl(30mL×2)溶液洗涤，饱和NaHCO 3(30mL×2)溶液洗涤，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝4/1)，得到黄色固体(811mg,产率：37.4％)。LC-MS(ESI,pos.ion)m/z:368.1[M+H] +.
步骤2：4-(7-溴-4-氧代-1,2-二氢喹唑啉-3(4H)-基)双环[2.2.1]庚烷-1-羧酸的合成
将4-(2-氨基-4-溴苯甲酰胺基)双环[2.2.1]庚烷-1-羧酸甲酯(600mg,1.63mmol)、甲醛水溶液(0.13mL,1.70mmol，浓度37％)和NaOH(102mg,2.55mmol)溶于EtOH(15mL)中，60℃反应6h。减压浓缩，向反应液中加入HCl水溶液(1M,30mL)，DCM(50mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝10/1)，得到黄色固体(450mg,产率：75.4％)。LC-MS(ESI,pos.ion)m/z:366.9[M+H] +.
步骤3：4-(7-(3-(二氟甲氧基)-5-氟苯基)-4-氧代-1,2-二氢喹唑啉-3(4H)-基)双环[2.2.1]庚烷-1-羧酸的合成
氮气保护下，将2-(3-(二氟甲氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(220mg,0.76mmol)、4-(7-溴-4-氧代-1,2-二氢喹唑啉-3(4H)-基)双环[2.2.1]庚烷-1-羧酸(278mg,0.76mmol)、Pd(dppf)Cl 2.CH 2Cl 2(75mg,0.10mmol)和K 2CO 3(199mg,1.44mmol)溶于1,4-二氧六环(8mL)和H 2O(2mL)的混合液中，80℃反应14h。硅藻土过滤，母液减压浓缩，EtOAc(30mL)稀释，饱和NH 4Cl溶液(20mL×2)洗涤，饱和NaCl溶液(20mL)洗涤，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝10/1)，得到棕色固体(237mg,产率：69.5％)。LC-MS(ESI,pos.ion)m/z:447.2[M+1] +.
步骤4：4-(7-(3-(二氟甲氧基)-5-氟苯基)-4-氧代-1,2-二氢喹唑啉-3(4H)-基)双环[2.2.1]庚烷-1-羧酸甲酯的合成
将4-(7-(3-(二氟甲氧基)-5-氟苯基)-4-氧代-1,2-二氢喹唑啉-3(4H)-基)双环[2.2.1]庚烷-1-羧酸(237mg,0.53mmol)溶于MeOH(5mL)中，冰浴下加入SOCl 2(0.06mL,0.80mmol)，室温下搅拌3h。减压浓缩，向反应液中加入饱和NaHCO 3溶液(20mL)，调节体系pH至7左右，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝1/1)，得到黄色油状物(18mg,产率：7.4％)。LC-MS(ESI,pos.ion)m/z:461.2[M+H] +.
步骤5：4-(7-(3-(二氟甲氧基)-5-氟苯基)-4-氧代-1-((3-(三氟甲基)苯基)磺酰基)-1,2-二氢喹唑啉-3(4H)-基)双环[2.2.1]庚烷-1-羧酸甲酯的合成
将4-(7-(3-(二氟甲氧基)-5-氟苯基)-4-氧代-1,2-二氢喹唑啉-3(4H)-基)双环[2.2.1]庚烷-1-羧酸甲酯(78mg,0.17mmol)溶于吡啶(3mL)，冰浴下滴加3-(三氟甲基)苯磺酰氯(0.03mL,0.20mmol)，然后室温搅拌15h。向反应液中加入EtOAc(50mL)，HCl(1M,20mL×3)洗涤，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到无色油状物(31mg,产率：27.4％)。LC-MS(ESI,pos.ion)m/z:669.1[M+H] +.
步骤6：4-(7-(3-(二氟甲氧基)-5-氟苯基)-4-氧代-1-((3-(三氟甲基)苯基)磺酰基)-1,2-二氢喹唑啉-3(4H)-基)双环[2.2.1]庚烷-1-羧酸的合成
将4-(7-(3-(二氟甲氧基)-5-氟苯基)-4-氧代-1-((3-(三氟甲基)苯基)磺酰基)-1,2-二氢喹唑啉-3(4H)-基)双环[2.2.1]庚烷-1-羧酸甲酯(31mg,0.046mmol)溶于H 2O/MeOH/THF(0.6mL/1mL/1.5mL)中，并加入LiOH·H 2O(30mg,0.72mmol)，室温下搅拌15h。向反应液中加入饱和NH 4Cl溶液(20mL)洗涤，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝10/1)，得到淡黄色固体(25mg,产率：82.4％)。LC-MS(ESI,pos.ion)m/z:655.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.09–8.00(m,2H),7.92(s,1H),7.83(s,1H),7.62(d,J＝8.1Hz,1H),7.55(s,2H),7.25(d,J＝6.1Hz,2H),6.98(d,J＝9.0Hz,1H),6.62(t,J＝72.9Hz,1H),5.28(s,2H),2.22(s,2H),2.12(s,4H),1.81(d,J＝8.5Hz,2H),1.51(s,2H).
实施例17：(S)-6-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸甲酯的合成
Figure PCTCN2022103288-appb-000085
步骤1：2-叔丁基6-甲基2,6-二氮杂螺[3.3]庚烷-2,6-二羧酸酯的合成
将2,6-二氮杂螺并[3.3]庚烷-6-羧酸叔丁酯(1.00g,5.04mmol)和TEA(1.4mL,10.00mmol)溶于DCM(30mL)中，-10℃下缓慢滴加氯甲酸甲酯(0.4mL,5.00mmol)，-10℃下反应3h。向反应液中加入饱和NaHCO 3溶液(50mL)，淬灭反应，DCM(50mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到白色固体(500mg,产率：38.7％)。LC-MS(ESI,pos.ion)m/z:201.1[M+2H-t-Bu] +.
步骤2：2,6-二氮杂螺并[3.3]庚烷-2-羧酸甲酯的合成
将2-叔丁基6-甲基2,6-二氮杂螺[3.3]庚烷-2,6-二羧酸酯(205mg,0.80mmol)溶于DCM(3mL)中，冰浴下加入TFA(1mL,13.46mmol)，室温下搅拌2h。减压浓缩，得到黄色油状物(120mg,产率：96.1％)。LC-MS(ESI,pos.ion)m/z:157.3[M+H] +.
步骤3：(S)-6-((6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸甲酯的合成
将(R)-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基甲磺酸酯(132mg,0.22mmol,实施例7步骤1)、2,6-二氮杂螺并[3.3]庚烷-6-羧酸甲酯(120mg,0.77mmol)和K 2CO 3(355mg,2.57mmol)溶于ACN(5mL)中，90℃反应16h。硅藻土过滤，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝1/3)，得到黄色固体(49mg,产率：33.8％)。LC-MS(ESI,pos.ion)m/z:672.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.07–7.97(m,2H),7.86(dd,J＝17.5,7.8Hz,2H),7.65(t,J＝7.8Hz,1H),7.34–7.29(m,1H),7.19–7.08(m,2H),6.93(d,J＝8.5Hz,1H),6.86(d,J＝9.1Hz,1H),6.59(t,J＝73.3Hz,1H),4.39–4.31(m,1H),4.05(s,4H),3.68(s,3H),3.47(dd,J＝9.0,5.7Hz,1H),3.41–3.27(m,5H),2.61(qd,J＝12.8,5.3Hz,2H).
实施例18：2-(((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-2-氮杂金刚烷-5-羧酸的合成
Figure PCTCN2022103288-appb-000086
步骤1：2-(((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-2-氮杂金刚烷-5-羧酸甲酯的合成
将(R)-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基甲磺酸酯(160.0mg,0.26mmol,实施例7步骤1)，2-氮杂金刚烷-5-羧酸甲酯盐酸盐(120.0mg,0.52mmol)，K 2CO 3(395.0mg,2.86mmol)溶于CH 3CN(5mL)中，90℃反应40h。硅藻土过滤，滤液减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到黄色油状物(80.0mg,产率：43.02％)。LC-MS(ESI,pos.ion)m/z:711.0[M+H] +.
步骤2：2-(((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)甲基)-2-氮杂金刚烷-5-羧酸的合成
将2-(((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪 -2-基)甲基)-2-氮杂金刚烷-5-羧酸甲酯(80.0mg,0.11mmol)溶于MeOH(1.5mL)，H 2O(1mL)，THF(2mL)中，并加入LiOH·H 2O(66.0mg,1.57mmol)，室温下搅拌14h。向反应液中加入饱和NH 4Cl溶液(30mL)洗涤，DCM(30mL×2)萃取，无水Na 2SO 4干燥，减压浓缩，粗产物经硅胶柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝10/1)，得到黄色固体(20.0mg,产率：25.50％)。LC-MS(ESI,pos.ion)m/z:697.1[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.03(s,1H),7.98(s,1H),7.91–7.82(m,2H),7.65(t,J＝7.5Hz,1H),7.33(d,J＝25.9Hz,1H),7.14(d,J＝16.3Hz,2H),6.92-6.83(m,2H),6.59(t,J＝73.3Hz,1H),4.54(d,J＝14.5Hz,1H),3.52(s,1H),3.33-3.24(m,1H),3.06(d,J＝13.2Hz,1H),2.92(s,2H),2.64(s,2H),2.17(s,2H),2.01(s,4H),1.79(s,2H),1.57(d,J＝17.4Hz,2H).
实施例19：(S)-4-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.2]辛烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000087
步骤1：4-甲酰基双环[2.2.2]辛烷-1-羧酸甲酯的合成
将4-(羟甲基)双环[2.2.2]辛烷-1-甲酸甲酯(25.22mmol,5g)溶于DCM(50mL)，冰浴条件下缓慢加入TEMPO(2.52mmol,394.1mg)和1,3,5-三氯-1,3,5-三嗪烷-2,4,6-三酮(25.22mmol,5.86g)，加料完毕后，室温搅拌。反应5h后，向体系中加入水(50mL)，分液分离得到有机相，水相用DCM(50mL×3)萃取，合并有机相，有机相用无水硫酸钠干燥并减压浓缩，硅胶柱层析分离纯化(洗脱剂：石油醚/乙酸乙酯(v/v)＝15/1–10/1)得到淡黄色油状液体4-甲酰基双环[2.2.2]辛烷-1-甲酸甲酯(4.2g,产率：85％)。 1H NMR(400MHz,CDCl 3)δ9.48(s,1H),3.68(s,3H),1.92–1.82(m,6H),1.75–1.64(m,6H).
步骤2：4-(环氧乙烷-2-基)双环[2.2.2]辛烷-1-羧酸甲酯
将三甲基碘化亚砜(31.59mmol,6.95g)溶于DMSO(24mL)，缓慢加入叔丁醇钾(29.75mmol,3.34g)，加料完毕后，室温搅拌2h。向体系中加入4-甲酰基双环[2.2.2]辛烷-1-羧酸甲酯(20.38mmol,4.0g)，反应3h后，将反应液倒入冰水中(300mL)，水相用DCM(50mL×3)萃取，合并有机相，有机相用无水硫酸钠干燥并减压浓缩，硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝15/1–10/1)得到淡黄色油状液体4-(环氧乙烷-2-基)双环[2.2.2]辛烷-1-羧酸甲酯(2.1g,产率：49％)。 1H NMR(400MHz,CDCl 3)δ3.66(s,3H),2.68(dd,J＝4.1,2.9Hz,1H),2.66–2.59(m,2H),1.88–1.74(m,6H),1.452–1.44(m,6H).
步骤3：4-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.2]辛烷-1-羧酸的合成
将4-(环氧乙烷-2-基)双环[2.2.2]辛烷-1-羧酸甲酯(4.17mmol,2.0g)，N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺(5.0mmol,1.05g)，碳酸钾(0.83mmol,0.12g)和TBAB(0.83mmol,0.27g)混合，90℃搅拌12h。将反应降温至室温，加入四氢呋喃(5mL)和氢氧化钠(8.34mmol,0.33g)。继续65℃反应6小时，停止反应，加入1M稀盐酸调至pH＝7，乙酸乙酯萃取(30mL×3)，有机相合并，饱和食盐水洗(15mL)，无水硫酸钠干燥，浓缩拌样，硅胶柱层析分离纯化(淋洗剂：石油醚/乙酸乙酯(v/v)＝1/1)得到无色油状产物4-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.2]辛烷-1-羧酸(1.3g,产率：47％).LC-MS(ESI,neg.ion)m/z:654.7[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.05–7.96(m,2H),7.88(d,J＝8.1Hz,1H),7.78(d,J＝7.9Hz,1H),7.64(t,J＝7.9Hz,1H),7.32(dd,J＝8.5,2.3Hz,1H),7.19–7.10(m,2H),6.92(d,J＝8.5Hz, 1H),6.88–6.84(m,1H),6.59(t,J＝73.3Hz,1H),4.37(dd,J＝14.4,2.1Hz,1H),3.16(dd,J＝14.4,10.6Hz,1H),2.87(dd,J＝10.6,2.1Hz,1H),1.92-1.76(m,6H),1.65–1.43(m,6H).
步骤4：(S)-4-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.2]辛烷-1-羧酸
将4-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.2]辛烷-1-羧酸(1.3g,1.98mmol)采用SFC手性制备色谱拆分。拆分条件：20％甲醇+二氧化碳，色谱柱是IC：30mm*250mm*5mm，检测波长：210nm，取前峰减压浓缩，得到白色固体(S)-4-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.2]辛烷-1-羧酸(250mg,产率：19％).LC-MS(ESI,neg.ion)m/z:654.1[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.05–7.96(m,2H),7.88(d,J＝8.1Hz,1H),7.78(d,J＝7.9Hz,1H),7.64(t,J＝7.9Hz,1H),7.32(dd,J＝8.5,2.3Hz,1H),7.19–7.10(m,2H),6.92(d,J＝8.5Hz,1H),6.88–6.84(m,1H),6.59(t,J＝73.3Hz,1H),4.37(dd,J＝14.4,2.1Hz,1H),3.16(dd,J＝14.4,10.6Hz,1H),2.87(dd,J＝10.6,2.1Hz,1H),1.88–1.80(m,6H),1.65–1.43(m,6H).
HPLC条件:OJ柱,乙醇/正己烷(0.1％三氟乙酸)＝10/90,流速＝1mL/min,λ＝215nm,t＝12.268min,99％ee.
实施例20：(R)-4-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.2]辛烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000088
将4-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.2]辛烷-1-羧酸(1.3g,1.98mmol)采用SFC手性制备色谱拆分。拆分条件：20％甲醇+二氧化碳，色谱柱是IC：30mm*250mm*5mm，检测波长：210nm，取后峰减压浓缩，得到白色固体(R)-4-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.2]辛烷-1-羧酸(300mg,产率：23％).LC-MS(ESI,neg.ion)m/z:654.1[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.05–7.96(m,2H),7.88(d,J＝8.1Hz,1H),7.78(d,J＝7.9Hz,1H),7.64(t,J＝7.9Hz,1H),7.32(dd,J＝8.5,2.3Hz,1H),7.19–7.10(m,2H),6.92(d,J＝8.5Hz,1H),6.88–6.84(m,1H),6.59(t,J＝73.3Hz,1H),4.37(dd,J＝14.4,2.1Hz,1H),3.16(dd,J＝14.4,10.6Hz,1H),2.87(dd,J＝10.6,2.1Hz,1H),1.88–1.80(m,6H),1.65–1.43(m,6H).
HPLC条件:OJ柱,乙醇/正己烷(0.1％三氟乙酸)＝10/90,流速＝1mL/min,λ＝215nm,t＝10.907min,99％ee.
实施例21：4-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)-1-甲基环己烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000089
步骤1：4-(甲氧基亚甲基)-1-甲基环己烷-1-羧酸乙酯的合成
0℃下，向NaH(210mg,5.25mmol)和甲氧基甲基三苯基氯化磷(1.59g,4.64mmol)的混合物中加入THF(10mL)，继续0℃下反应1小时。加入1-甲基-4-环己酮羧酸乙酯(500mg,2.71mmol)的THF(10mL)溶液，室温反应18小时后，停止反应，加入饱和氯化铵溶液(30mL)淬灭，乙酸乙酯萃取(20mL×3)，有机相合并，饱和食盐水洗(15mL)，无水硫酸钠干燥，浓缩后拌样，硅胶柱层析(淋洗剂：石油醚/乙酸乙酯(v/v)＝5/1)纯化得到无色油状产物为目标产物(520mg,产率：90.3％)。
步骤2：4-甲酰基-1-甲基环己烷-1-羧酸乙酯的合成
0℃下，向4-(甲氧基亚甲基)-1-甲基环己烷-1-羧酸乙酯(580mg,2.73mmol)的THF(12mL)溶液中加入HCl的水溶液(2mL,4mol/L)，室温下反12小时后，停止反应，加入饱和碳酸氢钠溶液(30mL)淬灭，乙酸乙酯萃取(20mL×3)，有机相合并，饱和食盐水洗(15mL)，无水硫酸钠干燥，浓缩拌样，硅胶柱层析(淋洗剂：石油醚/乙酸乙酯(v/v)＝3/1)纯化得到无色油状产物为目标产物(430mg,产率：79.4％)。
步骤3：1-甲基-4-(环氧乙烷-2-基)环己烷-1-羧酸乙酯的合成
0℃下，向三甲基碘化亚砜(1.05g,4.77mmol)和NaH(174mg,4.35mmol)的混合物中加入DMSO(8mL)，继续0℃下反应1小时，加入4-甲酰基-1-甲基环己烷羧酸乙酯(430mg,2.17mmol)，继续室温搅拌16小时后，停止反应，乙酸乙酯稀释(30mL)，饱和氯化铵溶液洗(10mL)，饱和食盐水洗(10mL)，无水硫酸钠干燥，浓缩拌样，硅胶柱层析(淋洗剂：石油醚/乙酸乙酯(v/v)＝5/1)纯化得到无色油状产物为目标产物(170mg,产率：36.9％)。
步骤4：4-(6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)-1-甲基环己烷-1-羧酸的合成
将1-甲基-4-(环氧乙烷-2-基)环己烷-1-羧酸乙酯(170mg,0.86mmol)，N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺(320mg,0.67mmol，武汉纽瑞斯医药科技有限公司)，Cs 2CO 3(44mg,0.14mmol)和四丁基溴化铵(44mg,0.14mmol)的混合物置于90℃油浴中反应16小时后，加入NaOH(107mg,2.67mmol)和THF(5mL)，继续65℃反应16小时。停止反应，加入1M稀盐酸调至pH＝7，二氯甲烷萃取(20mL×3)，有机相合并，饱和食盐水洗(15mL)，无水硫酸钠干燥，浓缩拌样，硅胶柱层析(淋洗剂：石油醚/乙酸乙酯(v/v)＝1/1)纯化得到无色油状产物为目标产物(50mg,产率：10.34％)。LC-MS(ESI,neg.ion)m/z:642.0[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.03(d,J＝2.0Hz,2H),7.89(d,J＝7.8Hz,1H),7.81(d,J＝7.9Hz,1H),7.65(t,J＝7.8Hz,1H),7.36–7.26(m,1H),7.15(dd,J＝8.6,6.7Hz,2H),6.93(d,J＝8.5Hz,1H),6.86(d,J＝9.1Hz,1H),6.60(t,J＝73.3Hz,1H),4.40(dd,J＝14.2,1.6Hz,1H),3.26(dd,J＝14.2,10.2Hz,1H),3.18–2.99(m,1H),1.85–1.67(m,5H),1.64(d,J＝10.5Hz,1H),1.53(dd,J＝7.0,3.4Hz,1H),1.26(d,J＝13.7Hz,5H).
实施例22：4-((S)-4-((4-氟苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000090
步骤1：4-氟-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺的合成
将3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-胺(0.60g,2.21mmol)、4-氟苯磺酰氯(0.56g,2.87mmol)、吡啶(0.53g,6.69mmol)溶于丙酮(3mL)，室温下搅拌反应17h。旋除溶剂，残余物经PE(10mL)洗涤可得淡黄色固体产物(0.90g,产率：94.85％)。LC-MS(ESI,neg.ion)m/z:428.10[M-H] -.
步骤2：甲基4-(N-((4-氟苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯基]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将4-氟-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺(0.90g,2.10mmol)、4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(0.67g,2.31mmol)溶于异丙醇(5mL)，再加入N,N-二异丙基乙胺(0.41g,3.15mmol)，室温搅拌反应4h，向反应体系中加入水(5mL)，抽滤并干燥得到白色固体产物(0.90g,产率：68.73％)。LC-MS(ESI,pos.ion)m/z:624.01[M+H] +.
步骤3：甲基4-((S)-2-((4-氟-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(0.40g,8.68mmol)溶于二氯甲烷(3mL)，脱气充氮，0℃下缓慢加入N,N-二异丙基乙胺(0.56g,4.33mmol)，滴加完毕转移到室温加入甲基4-(N-((4-氟苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯基]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(0.90g,1.44mmol)、氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(18mg,0.03mmol)，在45℃下回流反应18h。将反应液降至室温，用1M HCl水溶液调pH至酸性(pH＝1-3)，分离有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂，得无色油状产物(0.89g,产率：98.79％)，可直接用于下一步反应。LC-MS(ESI,pos.ion)m/z:626.40[M+H] +.
步骤4：4-((S)-4-((4-氟苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((4-氟-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(0.89g,1.42mmol)、氢氧化钠(0.17g,4.25mmol)和四丁基溴化铵(0.05g,0.14mmol)溶于四氢呋喃(2mL)，在60℃下搅拌反应5h。反应液置于冰浴下，用1M HCl水溶液调pH至6，然后用EA(20mL×3)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(淋洗剂：PE/EA(v/v)＝3/1)得白色固体产物。(0.73g,产率：86.90％)。LC-MS(ESI,neg.ion)m/z:590.13[M-H] -； 1H NMR(400MHz,DMSO-d 6)δ12.15(s,1H),7.95(t,J＝1.9Hz,1H),7.78(dd,J＝8.8,5.2Hz,1H),7.61(d,J＝9.1Hz,2H),7.49(dd,J＝8.6,2.3Hz,2H),7.42(s,1H),7.36–7.32(m,1H),7.16–7.11(m,2H),6.98(dd,J＝9.1,2.2Hz,1H),4.21(dd,J＝13.1,7.6Hz,1H),3.83(s,2H),1.92–1.84(m,2H),1.62–1.50(m,4H),1.37(m,J＝10.7,9.6Hz,4H).
实施例23：4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-(间甲苯磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-yl)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000091
步骤步骤1：N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-3-甲基苯磺酰胺的合成
将3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-胺(1.00g,3.69mmol)、3-甲基苯磺酰氯(0.91g,4.80mmol)和吡啶(0.88g,11.07mmol)溶于丙酮(3mL)，室温下搅拌反应3h。旋除溶剂，残余物经PE(5mL)洗涤可得淡黄色固体产物(1.50g,产率：95.56％)。LC-MS:(ESI,neg.ion)m/z:424.10[M-H] -.
步骤2：4-(N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-N-(间甲苯磺酰基)甘氨酰基)双环[2.2.1]庚烷1-羧酸甲酯的合成
将3-甲基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺(1.50g,3.53mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(1.12g,3.88mmol)溶于异丙醇(15mL)，再加入N,N-二异丙基乙胺(0.68g,5.29mmol)，室温搅拌反应20h，向反应体系中加入水(5mL)，抽滤并干燥得到白色固体产物(2.04g,93.27％)。LC-MS(ESI,pos.ion)m/z:620.30[M+H] +.
步骤3：甲基4-((S)-2-((N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-3-甲基苯基)磺胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(0.89g,19.83mmol)溶于二氯甲烷(6mL)，脱气充氮，0℃下缓慢加入N,N-二异丙基乙胺(1.25g,9.69mmol)，滴加完毕转移到室温加入4-(N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-N-(间甲苯磺酰基)甘氨酰基)双环[2.2.1]庚烷1-羧酸甲酯(2.00g,3.23mmol)、氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(41mg,0.07mmol)，在45℃下回流反应13h。将反应液降至室温，用1M HCl水溶液调pH至酸性(pH＝1-3)，分离有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂，得无色油状产物(1.90g,产率：94.63％)，可直接用于下一步反应。LC-MS(ESI,pos.ion)m/z:622.35[M+H] +.
步骤4：4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-(间甲苯磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((3-甲基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(1.90g,3.06mmol)、氢氧化钠(0.61g,15.25mmol)和四丁基溴化铵(0.10g,0.31mmol)溶于四氢呋喃(5mL)，在60℃下搅拌反应19h。反应液置于冰浴下，用1M HCl水溶液调pH至酸性(pH＝1-3)，然后用EA(20mL×3)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝20/1)得白色固体产物。(1.10g,产率：61.18％)。LC-MS(ESI,neg.ion)m/z:586.4[M-H] -； 1H NMR(400MHz,DMSO-d 6)δ12.15(s,1H),7.92(d,J＝2.2Hz,1H),7.58(t,J＝8.5Hz,2H),7.54–7.47(m,2H),7.47–7.40(m,2H),7.33(dt,J＝9.9,1.9Hz,1H),7.24–7.21(m,1H),7.12(dt,J＝9.7,2.3Hz,1H),6.99(d,J＝8.6Hz,1H),4.21(d,J＝13.6Hz,1H),3.26(d,J＝6.2Hz,2H),2.37(s,3H),1.89(dd,J＝9.5,5.2Hz,2H),1.62–1.50(m,4H),1.49–1.21(m,4H).
实施例24：4-((S)-4-((3-氟苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000092
步骤1：步骤1：3-氟-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺的合成
将3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-胺(1.00g,3.69mmol)、3-氟苯磺酰氯(0.93g,4.80mmol)、吡啶(0.88g,11.07mmol)溶于丙酮(3mL)，室温下搅拌反应20h。旋除溶剂，残余物经PE(5mL)洗涤可得淡黄色固体产物(1.50g,产率：94.68％)。LC-MS(ESI,neg.ion)m/z:428.00[M-H] -.
步骤2：甲基4-(N-((3-氟苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯基]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将3-氟-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺(1.50g,3.49mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(1.11g,3.84mmol)溶于异丙醇(15mL)，再加入N,N-二异丙基乙胺(0.68g,5.24mmol)，室温搅拌反应5h，向反应体系中加入水(5mL)，抽滤并干燥得到白色固体产物(1.45g,产率：66.63％)。LC-MS(ESI,pos.ion)m/z:624.40[M+H] +.
步骤3：甲基4-((S)-2-((3-氟-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(0.64g,13.98mmol)溶于二氯甲烷(5mL)，脱气充氮，0℃下缓慢加入N,N-二异丙基乙胺(0.90g,6.99mmol)，滴加完毕转移到室温加入甲基4-(N-((3-氟苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯基]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(1.45g,2.33mmol)、氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(30mg,0.05mmol)，在45℃下回流反应11h。将反应液降至室温，用1M HCl水溶液调pH至酸性(pH＝1-3)，分离有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂，得无色油状产物(1.40g,96.25％)，可直接用于下一步反应。LC-MS(ESI,pos.ion)m/z:626.45[M+H] +.
步骤4：4-((S)-4-((3-氟苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((3-氟-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(1.40g,2.24mmol)、氢氧化钠(0.27g,6.72mmol)和四丁基溴化铵(0.07g,0.22mmol)溶于四氢呋喃(3mL)，在60℃下搅拌反应5h。反应液置于冰浴下，用1M HCl水溶液调pH至6，然后用EA(20mL×3)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(淋洗剂：DCM/MeOH(v/v)＝20/1)得白色固体产物。(0.93g,产率：70.18％)。LC-MS(ESI,neg.ion)m/z:590.05[M-H] -； 1H NMR(400MHz,DMSO-d 6)δ12.15(s,1H),7.94(dd,J＝14.9,2.2Hz,1H),7.76–7.67(m,1H),7.64–7.49(m,4H),7.34(m,2H),7.16–7.07(m,2H),7.00(dd,J＝8.6,5.3Hz,1H),4.28–4.17(m,1H),3.75–3.70(m,2H),1.94–1.80(m,2H),1.62–1.54(m,4H),1.48–1.21(m,4H).
实施例25：4-((S)-4-((4-氯苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000093
步骤1：4-氯-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺的合成
将3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-胺(2.6g,9.59mmol)溶于吡啶(10mL)中，再缓慢滴加4-氯苯磺酰氯(2.63g,12.47mmol)，在室温下搅拌反应17h。减压浓缩，除去溶剂，再加入水(30mL)，用EA(20mL×3)萃取，合并有机相，用无水硫酸钠干燥，减压浓缩，通过硅胶柱层析纯化(EA/PE(v/v)＝1/9)，得到浅黄色固体(3.89g,产率：90.99％)。LC-MS(ESI,pos.ion)m/z:446.05[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),7.74(d,J＝8.6Hz,2H),7.65(d,J＝8.6Hz,2H),7.63–7.58(m,1H),7.52(dd,J＝7.4,2.2Hz,1H),7.34–7.28(m,2H),7.58-7.21(t,1H),7.16(d,J＝15.0Hz,2H).
步骤2：甲基4-(N-((4-氯苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯基]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将4-氯-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺(2g,4.49mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(1.28g,4.65mmol,广州安岩任医药有限公司)溶于异丙醇(20mL)中，在50℃条件下，再滴加N,N-二异丙基乙胺(4.763g,36.57mmol)，在50℃条件下，搅拌反应11h。冷却至室温，减压浓缩除去溶剂，再加入水(50mL)，用乙酸乙酯萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，通过硅胶柱层析纯化(EA/PE(v/v)＝15:85)，得到白色固体(2.32g,产率：80.73％)。LC-MS(ESI,pos.ion)m/z:640.10[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ7.80–7.67(m,5H),7.57-7.20(m,1H),7.53(dd,J＝7.0,2.0Hz,1H),7.42-7.37(m,1H),7.24(d,J＝9.9Hz,1H),7.16(d,J＝8.9Hz,2H),4.81(s,2H),3.60(s,3H),1.94–1.77(m,6H),1.62–1.48(m,4H).
步骤3：甲基4-((S)-2-((4-氯-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰氨基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将无水甲酸(0.38g,8.34mmol)溶于二氯甲烷(10mL)溶剂中，冰浴条件，在氮气氛围下，缓慢滴加N,N-二异丙基乙胺(0.54g,4.17mmol)，再加入甲基4-(N-((4-氯苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯基]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(2g,2.78mmol)和氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(26.53mg,0.042mmol)，转到45℃下搅拌反应8.5h(回流)。冷却至室温，用水(100mL×2)洗涤反应液，再用稀盐酸(2M,100mL×2)洗涤反应液，无水硫酸钠干燥有机相，减压浓缩除去溶剂。再用乙酸乙酯(15mL)溶解浓缩液，加入活性炭(0.80g,66.61mmol)与2-巯基烟酸(0.086g,0.56mmol)在80℃下回流搅拌反应3h。冷却至室温，通过硅藻土过滤，用饱和碳酸氢钠溶液洗涤滤液，滤液用无水硫酸钠干燥，减压浓缩得到无色油状产物(1.9g,产率：74.31％)。LC-MS(ESI,pos.ion)m/z:642.5[M] +.
步骤4：4-((S)-4-((4-氯苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((4-氯-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰氨基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(1.50g,2.34mmol)、氢氧化钠(280.80mg,7.02mmol)和四丁基溴化铵(75.43mg,0.23mmol)溶于四氢呋喃(5mL)溶剂中，再转入到60℃下搅拌反应6h。冷却至室温。在冰浴下，调pH＝3，然后用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，减压浓缩，通过硅胶柱层析纯化(EA/PE(v/v)＝1/4)，得到白色固体(1.04g,产率：72.58％)。LC-MS(ESI,pos.ion)m/z:608.10[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.03(d,J＝1.9Hz,1H),7.59(d,J＝8.5Hz,2H),7.46(d,J＝8.5Hz,2H),7.30(dd,J＝8.5,2.0Hz,1H),7.18–7.09(m,2H),6.92(d,J＝8.5Hz,1H),6.83(d,J＝9.1Hz,1H),6.58(t,J＝73.3Hz,1H),4.29(dd,J＝14.4,1.6Hz,1H),3.39(d,J＝9.2Hz,1H),3.16(dd, J＝14.3,10.7Hz,1H),2.09(dd,J＝12.1,3.8Hz,1H),2.04–1.97(m,1H),1.87(d,J＝9.4Hz,1H),1.74(d,J＝7.2Hz,3H),1.59(t,J＝12.0Hz,1H),1.49(d,J＝9.5Hz,2H),1.37(d,J＝11.3Hz,1H).
实施例26:4-((S)-4-((4-甲基苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000094
步骤1：N-(5-溴-2-氟苯基)-4-甲基苯磺酰胺的合成
将5-溴-2-氟苯胺(100mg,0.53mmol)溶于吡啶(1mL)，再滴加对甲基苯磺酰氯(121.25mg,0.64mmol)，在室温下搅拌反应28h。减压浓缩，除去吡啶，加入水(10mL)，用EA(10mL×3)萃取，有机相用无水硫酸钠干燥，减压浓缩，通过硅胶柱层析纯化(EA/PE(v/v)＝1/9)，得到白色固体(123mg,产率：67.42％)。LC-MS(ESI,pos.ion)m/z:344.20[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),7.63(d,J＝8.2Hz,2H),7.42–7.33(m,4H),7.20–7.13(m,1H),2.36(s,3H).
步骤2：N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-4-甲基苯磺酰胺的合成
将N-(5-溴-2-氟苯基)-4-甲基苯磺酰胺(3g,10.41mmol)、2-(3-(二氟甲氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(3.58g,10.41mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.85g,1.04mmol)和碳酸钾(2.88g,20.82mmol)溶于1,4-二氧六环(24mL)，再加入水(6mL)，置换氮气，在80℃下搅拌反应4h。停止反应，冷却至室温，加入水(30mL)，用乙酸乙酯(30mL×3)萃取，有机相用无水硫酸钠干燥，减压浓缩，再通过硅胶柱层析纯化(EA/PE(v/v)＝1/9)，得到白色固体(3.2g,产率：76.26％).LC-MS(ESI,pos.ion)m/z:426.10[M] +； 1H NMR(400MHz,DMSO-d 6)δ10.23(s,1H),7.63(d,J＝8.2Hz,2H),7.58–7.21(m,1H),7.58–7.53(m,1H),7.46–7.42(m,1H),7.41–7.34(m,3H),7.33–7.19(m,2H),7.17–7.10(m,2H),2.36(s,3H).
步骤3：4-(N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-N-甲苯磺酰基甘氨酰)双环[2.2.1]庚烷-1-羧酸甲酯的合成
将N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-4-甲基苯磺酰胺(2g,4.70mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(1.34g,4.89mmol)溶于异丙醇(20mL)，再滴加N,N-二异丙基乙胺(0.82g,6.35mmol)，在50℃下搅拌反应。冷却至室温，过滤，滤饼用IPA(15mL×2)洗涤，再通过50℃减压干燥6h，得到白色固体(2.23g,产率：:76.57％)。LC-MS(ESI,pos.ion)m/z:620.20[M] +； 1H NMR(400MHz,DMSO-d 6)δ7.76–7.70(m,1H),7.60(d,J＝8.2Hz,2H),7.57-7.14(m,1H),7.45–7.34(m,4H),7.17(dd,J＝15.6,8.2Hz,2H),7.08(s,1H),4.78(s,2H),3.60(s,3H),2.42(s,3H),1.92–1.78(m,6H),1.62–1.48(m,4H).
步骤4：甲基4-((S)-2-((N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-4-甲基苯基)磺胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将无水甲酸(419.79mg,9.12mmol)溶于二氯甲烷(5mL)溶剂中，冰浴条件，在氮气氛围下，缓慢滴加N,N-二异丙基乙胺(589.33mg,4.56mmol)，再加入4-(N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-N-甲苯磺酰基甘氨酰)双环[2.2.1]庚烷-1-羧酸甲酯(2.12g,3.04mmol)和氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(29.01mg,0.046mmol)，转到45℃下搅拌反应7h(回流)。冷却至室温，用水(100mL×2)洗涤反应液，再用稀盐酸(2M,100mL×2)洗涤反应液，无水硫酸钠干燥有机相，减压浓缩除去溶剂。再用乙酸乙酯(15mL)溶解浓缩液，加入活性炭(0.85g,70.56mmol)与2-巯基烟酸(94.34mg,0.61mmol)在80℃下回流搅拌反应3h。冷却至室温，通过硅藻土过滤，用饱和碳酸氢钠溶液洗涤滤液，滤液用无水硫酸钠干燥，减压浓缩得到无色油状产物(1.88g,产率： 99.48％)。LC-MS(ESI,pos.ion)m/z:622.20[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ7.79–7.73(m,1H),7.57-7.20(m,1H),7.55(d,J＝8.2Hz,2H),7.48(d,J＝5.4Hz,1H),7.42(s,1H),7.41–7.36(m,2H),7.36–7.31(m,1H),7.16(d,J＝12.0Hz,2H),4.85(d,J＝5.4Hz,1H),3.75–3.56(m,2H),3.57(s,3H),2.41(s,3H),1.88-1.78(m,2H),1.65(t,J＝11.8Hz,1H),1.55(d,J＝9.4Hz,3H),1.45(d,J＝11.9Hz,1H),1.35(d,J＝9.2Hz,2H),1.23(s,1H).
步骤5：4-((S)-4-((4-甲基苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-4-甲基苯基)磺胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(1.50g,2.41mmol)、氢氧化钠(289.20mg,7.32mmol)和四丁基溴化铵(77.69mg,0.24mmol)溶于四氢呋喃(5mL)溶剂中，再转入到60℃下搅拌反应4h。冷却至室温。在冰浴下，调pH＝3，然后用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，减压浓缩，通过硅胶柱层析纯化(EA/PE(v/v)＝1/4)，得到白色固体(1.2.06g产率：84.46％)。LC-MS(ESI,neg.ion)m/z:586.20[M-H] +； 1H NMR(400MHz,CDCl 3)δ8.03(d,J＝1.8Hz,1H),7.54(d,J＝8.1Hz,2H),7.29(s,3H),7.18–7.10(m,2H),6.90(d,J＝8.5Hz,1H),6.82(d,J＝9.1Hz,1H),6.58(t,J＝73.3Hz,1H),4.29(d,J＝14.2Hz,1H),3.35(d,J＝10.2Hz,1H),3.13(dd,J＝14.3,10.6Hz,1H),2.42(s,3H),2.08(d,J＝11.9Hz,1H),2.02(s,1H),1.86(d,J＝9.4Hz,1H),1.72(s,3H),1.58(t,J＝11.8Hz,1H),1.46(d,J＝9.4Hz,2H),1.36(d,J＝11.4Hz,1H).
实施例27:4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-乙炔基苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000095
步骤1：甲基4-((S)-2-((N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-3-((三甲基甲硅烷基)乙炔基))苯基)磺胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲基4-((S)-2-((3-溴-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(100mg,0.15mmol，参考实施例26步骤4相似的制备过程制备得到)溶于N,N-二甲基甲酰胺(3mL)中，再加入乙炔基三甲基硅烷(29.47mg,0.30mmol)、三苯基膦二氯化钯(52.64mg,0.075mmol)、碘化亚铜(14.28mg,0.075mmol)和三乙胺(45.54mg,0.45mmol)，转到微波60℃条件下反应2h。停止反应，加入水(10mL)，用乙酸乙酯(10mL×3)萃取，分离后，有机相再用饱和NaCl溶液(30mL)洗一次，有机相用无水硫酸钠干燥，减压浓缩，再通过硅胶柱层析纯化(EA/PE(v/v)＝15/85)，得到黄色固体(64mg,产率:60.62％)。LC-MS(ESI,pos.ion)m/z:704.20[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.81(s,1H),7.71(d,J＝7.7Hz,1H),7.62(d,J＝7.9Hz,1H),7.57–7.51(m,1H),7.46(dd,J＝15.4,7.5Hz,2H),7.19(t,J＝9.2Hz,1H),7.10–7.01(m,2H),6.89(d,J＝9.1Hz,1H),6.59(t,J＝73.1Hz,1H),3.83(d,J＝8.5Hz,1H),3.67(s,3H),3.65–3.52(m,2H),2.51(s,1H),2.03–1.93(m,2H),1.71(dt,J＝20.6,9.3Hz,4H),1.58–1.45(m,2H),1.39(dd,J＝20.8,9.1Hz,2H),0.26(s,9H).
步骤2：4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-乙炔基苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-3-((三甲基甲硅烷基)乙炔基))苯基)磺胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(310mg,0.44mmol)、氢氧化钠(70.40mg,1.76mmol)和四丁基溴化铵(21.28mg,0.066mmol)溶于四氢呋喃(4mL)溶剂中，再转入到60℃下搅拌反应6h。冷却至室温。在冰浴下，调pH＝3，然后用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，减压浓缩，通过硅胶柱层析纯化(EA/PE(v/v)＝1/4)，得到白色固体(84mg,产 率：31.95％)。LC-MS(ESI,neg.ion)m/z:596.30[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.01(s,1H),7.83(s,1H),7.69(d,J＝7.4Hz,1H),7.58(d,J＝7.6Hz,1H),7.44(t,J＝7.7Hz,1H),7.29(d,J＝8.0Hz,1H),7.18–7.09(m,2H),6.92(d,J＝8.4Hz,1H),6.83(d,J＝8.7Hz,1H),6.76-6.39(m,1H),4.28(d,J＝14.1Hz,1H),3.31(d,J＝10.3Hz,1H),3.23–3.08(m,2H),2.05(s,2H),1.87(d,J＝9.1Hz,1H),1.73(s,3H),1.61(s,1H),1.47(d,J＝8.9Hz,2H),1.40–1.17(m,4H).
实施例28:4-((S)-6-(3-乙氧基-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000096
步骤1：1-溴-3-乙氧基-5-氟苯的合成
将3-溴-5-氟苯酚(1g,5.24mmol)溶于N,N-二甲酰胺(2mL)中，再加入碳酸钾(2.17g,15.72mmol)和碘乙烷(1.63g,10.48mmol)，转到80℃下搅拌反应4.5h。停止反应，向反应体系加入水(10mL)，用乙酸乙酯(5mL×2)萃取，有机相再用水(10mL)洗一次，再饱和食盐水用(10mL)洗一次，用无水硫酸钠干燥，减压浓缩，得到浅红色液体(1.02g,产率：88.86％)。GC-MS(EI,pos.ion):m/z:218.0[M] +； 1H NMR(400MHz,CDCl 3)δ6.90–6.81(m,2H),6.60–6.53(m,1H),4.01(q,J＝7.0Hz,2H),1.43(t,J＝7.0Hz,3H).
步骤2：2-(3-乙氧基-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的合成
将1-溴-3-乙氧基-5-氟苯(1g,4.57mmol)溶于N,N-二甲基甲酰胺(6mL)，再加入联硼酸频那醇酯(1.39g,5.48mmol)、醋酸钯(51mg,0.23mmol)、醋酸钾(0.67g,6.86mmol)和2-二环己基磷-2'-甲基联苯(0.17g,0.46mmol)，置换氮气，转入到80℃下搅拌反应10h。停止反应，加入水(50mL)，搅拌2min，用乙酸乙酯(30mL×3)萃取，有机相再用水(30mL)洗一次，分离后，有机相再用饱和NaCl(50mL)洗一次，有机相用无水硫酸钠干燥，减压浓缩，再通过硅胶柱层析纯化(EtOAc/PE(v/v)＝1/19)，得到浅黄色液体(0.32g,产率:26.31％)。 1H NMR(400MHz,CDCl 3)δ7.10(d,J＝1.9Hz,1H),7.07(dd,J＝8.4,2.1Hz,1H),6.69(dt,J＝10.7,2.3Hz,1H),4.05(q,J＝7.0Hz,2H),1.40(t,J＝7.0Hz,3H),1.34(s,12H).
步骤3：4-(2-(N-(5-溴-2-氟苯基)-N-((3-(三氟甲基)苯基)磺酰胺基)乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯的合成
将N-(5-溴-2-氟苯基)-3-(三氟甲基)苯-1-磺酰胺(10g,25.11mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(7.2 5g,26.37mmol)溶于异丙醇(100mL)。室温搅拌5h。停止搅拌，TLC检测反应情况，原料消耗完毕。向体系中加入水(10mL)，有大量沉淀析出，过滤得到标题化合物为白色固体(12.2g,产率：82.02％)。LC-MS(ESI,pos.ion)m/z:592.00[M+H] +.
步骤4：4-((S)-2-((N-(5-溴-2-氟苯基)-3-(三氟甲基)苯基)磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将4-(2-(N-(5-溴-2-氟苯基)-N-((3-(三氟甲基)苯基磺酰胺基)乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(12.2g,21mmol)溶于二氯甲烷(20mL)，缓慢加入甲酸(6.21mL)和氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(0.26g,0.41mmol)，向体系中缓慢滴加N,N-二异丙基乙胺(13.65mL,82mmol)，滴加完毕后45℃搅拌10h，停止加热和搅拌，冷却至室温，用水(100mL×2)洗涤反应液，再用稀盐酸(100mL×2,2M)洗涤反应液，无水硫酸钠干燥有机相，减压浓缩得到油状粗产物，用硅胶柱层析纯化(EtOAc/PE(v/v)＝1/3)得到标题化合物为无色油状物(9.6g,产率：76.9％)。LC-MS(ESI,pos.ion)m/z:594.35[M+H] +.
步骤5：甲基4-((S)-2-((N-(3'-乙氧基-4,5'-二氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基)磺酰胺基)-1-羟乙基) 双环[2.2.1]庚烷-1-羧酸酯的合成
将甲基4-((S)-2-((N-(5-溴-2-氟苯基)-3-(三氟甲基)苯基磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(0.66g,1.11mmol)、2-(3-乙氧基-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(0.35g,1.33mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(91mg,0.11mmol)和碳酸钾(0.31g,2.22mmol)，用1,4-二氧六环(4mL)溶解，再加入水(1mL)，置换氮气，在80℃温度下搅拌反应3.5h。停止反应，冷却至室温。向反应体系加入水(20mL)，用乙酸乙酯(10mL×2)萃取，合并有机相，再用饱和氯化钠水溶液(20mL)洗涤一次，有机相用无水硫酸钠干燥，减压浓缩，粗产物经过硅胶柱层析纯化，得到黄色固体(0.56g,产率:77.18％)。 1H NMR(600MHz,CDCl 3)δ7.92(d,J＝8.6Hz,2H),7.88(d,J＝7.8Hz,1H),7.67(t,J＝7.7Hz,1H),7.55–7.49(m,2H),7.14–7.09(m,1H),6.80(s,1H),6.76(d,J＝9.3Hz,1H),6.61(d,J＝10.5Hz,1H),4.08–4.04(m,2H),3.81(d,J＝8.9Hz,1H),3.69–3.61(m,4H),3.55(d,J＝13.3Hz,1H),2.33(d,J＝2.5Hz,1H),2.00–1.93(m,2H),1.81–1.76(m,1H),1.72(d,J＝9.4Hz,1H),1.66(t,J＝9.4Hz,2H),1.53–1.49(m,1H),1.44(t,J＝7.0Hz,3H),1.39–1.27(m,3H).
步骤6：4-((S)-6-(3-乙氧基-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(3'-乙氧基-4,5'-二氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(300mg,0.46mmol)、氢氧化钠(55mg,1.38mmol)和四丁基溴化铵(22mg,0.069mmol)，用四氢呋喃(2mL)溶解，转到60℃下搅拌反应6h。停止反应，冷却至室温。在冰浴下调pH值＝0.3，用乙酸乙酯(10mL×3)萃取，有机相再用饱和氯化钠水溶液(10mL)洗涤一次，有机相用无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(EtOAc/PE(v/v)＝1/3)，得到白色固体(40mg,产率:14.03％)。LC-MS(ESI,pos.ion)m/z:620.35[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.02(d,J＝17.8Hz,2H),7.81(d,J＝37.5Hz,2H),7.61(s,1H),7.31(s,1H),6.89(s,3H),6.59(s,1H),4.33(d,J＝11.2Hz,1H),4.08(s,2H),3.24(d,J＝48.0Hz,2H),2.04(s,2H),1.84(s,1H),1.72(s,3H),1.45(s,4H),1.30(d,J＝26.8Hz,3H).
实施例29:4-((S)-6-(3-氟-5-(甲氧基-d 3)苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000097
步骤1：1-溴-3-氟-5-(甲氧基-d 3)苯的合成
将3-溴-5-氟苯酚(1.05g,5.50mmol)和碳酸钾(2.28g,16.5mmol)溶于丙酮(6mL)中，在室温下搅拌15min，再缓慢加入用丙酮(4mL)溶解的氘代碘甲烷(1.61g,11mmol)，继续在室温下搅拌反应23h。停止反应，向反应体系加入水(30mL)，用乙酸乙酯(10mL×2)萃取，有机相再用饱和氯化钠水溶液(30mL)洗一次，用无水硫酸钠干燥，减压浓缩，得到黄色液体(1.05g,产率：91.77％)。 1H NMR(400MHz,CDCl 3)δ6.88–6.81(m,2H),6.59–6.51(m,1H).
步骤2：2-(3-氟-5-(甲氧基-d 3)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的合成
将1-溴-3-氟-5-(甲氧基-d 3)苯(1.59g,7.64mmol)溶于N,N-二甲基甲酰胺(6mL)，再加入联硼酸频那醇酯(2.23g,9.17mmol)、醋酸钯(86mg,0.38mmol)、醋酸钾(1.12g,11.46mmol)和2-二环己基磷-2'-甲基联苯(0.28g,0.76mmol)，置换氮气，转入到80℃下搅拌反应。停止反应，加入水(50mL)，搅拌2min，用乙酸乙酯(30mL×3)萃取，有机相再用水(30mL)洗一次，分离后，有机相再用饱和NaCl(50mL)洗一次，有机相用无水硫酸钠干燥，减压浓缩，再通过硅胶柱层析纯化(EtOAc/PE(v/v)＝5/95)，得到浅黄色液体(0.32g,产率:16.42％)。GC-MS(EI,pos.ion)m/z:255.00[M] +； 1H NMR(400MHz,CDCl 3)δ7.14–7.08(m,2H),6.75–6.69(m,1H),1.36(s,12H).
步骤3：甲基4-((S)-2-((N-(3'，4-二氟-5'-(甲氧基-d 3)-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲基4-((S)-2-((N-(5-溴-2-氟苯基)-3-(三氟甲基)苯基磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(0.60g,1.01mmol)、2-(3-氟-5-(甲氧基-d 3)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(0.31g,1.21mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(82mg,0.10mmol)和碳酸钾(0.28g,2.02mmol)用1,4-二氧六环(4mL)溶解，再加入水(1mL)，置换氮气，在80℃温度下搅拌反应4.5h。停止反应，冷却至室温。向反应体系加入水(20mL)，用乙酸乙酯(10mL×2)萃取，合并有机相，再用饱和氯化钠水溶液(20mL)洗涤一次，有机相用无水硫酸钠干燥，减压浓缩，粗产物经过硅胶柱层析纯化(EtOAc/PE(v/v)＝1/4)，得到浅黄色粘稠状液体(163mg,产率:25.11％)。LC-MS(ESI,pos.ion)m/z:643.20[M+H] +.
步骤4：4-((S)-6-(3-氟-5-(甲氧基-d 3)苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(3',4-二氟-5'-(甲氧基-d 3)-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(163mg,0.25mmol)、氢氧化钠(30mg,0.75mmol)和四丁基溴化铵(12.09mg,0.037mmol)用四氢呋喃(1mL)溶解，转到60℃下搅拌反应4.5h。停止反应，冷却至室温。在冰浴下调pH值＝0.3，用乙酸乙酯(10mL×3)萃取，有机相再用饱和氯化钠水溶液(10mL)洗涤一次，有机相用无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(EtOAc/PE(v/v)＝1/3)得到白色固体(72mg,产率:47.32％)。LC-MS(ESI,neg.ion)m/z:607.30[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.02(d,J＝20.9Hz,2H),7.85(s,1H),7.75(s,1H),7.62(s,1H),7.32(d,J＝4.9Hz,1H),6.90(s,3H),6.60(d,J＝8.0Hz,1H),4.33(d,J＝13.4Hz,1H),3.37–3.12(m,2H),1.84(s,1H),1.72(s,3H),1.51(d,J＝48.1Hz,3H),1.30(d,J＝32.0Hz,3H).
实施例30:4-((S)-6-(3-氯-5-甲氧基苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000098
步骤1：1-溴-3-氯-5-甲氧基苯的合成
将3-溴-5-氯苯酚(1g,4.82mmol)溶于N,N-二甲酰胺(5mL)中，再加入碳酸钾(2.00g,14.46mmol)和碘甲烷(1.37g,10.48mmol)，在室温下搅拌反应14h。停止反应，向反应体系加入水(20mL)，用乙酸乙酯(5mL×2)萃取，有机相再用水(20mL)洗一次，再饱和食盐水用(20mL)洗一次，用无水硫酸钠干燥，减压浓缩，得到浅红色液体(1.01g,产率:94.61％)。LC-MS(ESI,pos.ion)m/z:221.10[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.13–7.10(m,1H),6.98–6.95(m,1H),6.86–6.83(m,1H),3.80(s,3H).
步骤2：2-(3-氯-5-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的合成
将1-溴-3-氯-5-甲氧基苯(1g,4.52mmol)溶于N,N-二甲基甲酰胺(6mL)，再加入联硼酸频那醇酯(1.38g,5.42mmol)、醋酸钯(51mg,0.23mmol)、醋酸钾(0.67g,6.78mmol)和2-二环己基磷-2'-甲基联苯(0.16g,0.45mmol)，置换氮气，转入到80℃下搅拌反应5h。停止反应，加入水(50mL)，搅拌2min，用乙酸乙酯(30mL×3)萃取，有机相再用水(30mL)洗一次，分离后，有机相再用饱和NaCl(50mL)洗一次，有机相用无水硫酸钠干燥，减压浓缩，再通过硅胶柱层析纯化(EtOAc/PE(v/v)＝5/95)，得到黄色液体(0.716g,产率:58.99％)。LC-MS(ESI,pos.ion)m/z:269.20[M+H] +； 1H NMR(600MHz,CDCl 3)δ7.39(d,J＝1.1Hz,1H),7.22(d,J＝2.1Hz,1H),7.01(t,J＝2.1Hz,1H),3.84(s,3H),1.36(s,12H).
步骤3：甲基4-((S)-2-((N-(3'-氯-4-氟-5'-甲氧基-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基)磺酰胺基)-1-羟乙基) 双环[2.2.1]庚烷-1-羧酸酯的合成
将甲基4-((S)-2-((N-(5-溴-2-氟苯基)-3-(三氟甲基)苯基磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(0.50g,0.84mmol)、2-(3-甲氧基-5-氯苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(0.27g,1.01mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(69mg,0.084mmol)和碳酸钾(0.23g,1.68mmol)用1,4-二氧六环(4mL)溶解，再加入水(1mL)，置换氮气，在80℃温度下搅拌反应5h。停止反应，冷却至室温。向反应体系加入水(20mL)，用乙酸乙酯(10mL×2)萃取，合并有机相，再用饱和氯化钠水溶液(20mL)洗涤一次，有机相用无水硫酸钠干燥，减压浓缩，粗产物经过硅胶柱层析纯化(EtOAc/PE(v/v)＝1/4)，得到黄色固体(0.5144g,产率:93.34％)。LC-MS(ESI,pos.ion)m/z:657.15[M+H] +； 1H NMR.(400MHz,CDCl 3)δ7.98–7.87(m,3H),7.69(t,J＝7.8Hz,1H),7.58–7.48(m,2H),7.16–7.11(m,1H),7.05(s,1H),6.92(d,J＝1.5Hz,2H),3.87(s,3H),3.85–3.80(m,1H),3.70(s,1H),3.67(s,3H),3.65–3.54(m,2H),2.02–1.94(m,2H),1.85–1.78(m,1H),1.77–1.66(m,3H),1.55–1.44(m,2H),1.39–1.32(m,2H).
步骤4：4-((S)-6-(3-氯-5-甲氧基苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(3'-氯-4-氟-5'-甲氧基-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(510mg,0.78mmol)、氢氧化钠(93.6mg,2.34mmol)和四丁基溴化铵(37.72mg,0.12mmol)，用四氢呋喃(5mL)溶解，转到60℃下搅拌反应7h。停止反应，冷却至室温。在冰浴下用1M稀盐酸调pH＝3，用乙酸乙酯(10mL×3)萃取，有机相再用饱和氯化钠水溶液(10mL)洗涤一次，有机相用无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(EtOAc/PE(v/v)＝1/3)，得到白色固体(300mg,产率:61.83％)。LC-MS(ESI,pos.ion)m/z:622.10[M+H] +； 1HNMR(400MHz,CDCl 3)δ8.01(d,J＝14.6Hz,2H),7.85(s,1H),7.75(s,1H),7.62(s,1H),7.30(s,1H),7.14(s,1H),6.99(s,1H),6.88(s,2H),4.33(d,J＝13.5Hz,1H),3.86(s,3H),3.37–3.11(m,2H),2.05(s,1H),1.84(s,1H),1.72(s,3H),1.56(s,1H),1.45(s,2H),1.33(s,2H).
实施例31：4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)-N-(甲基磺酰基)双环[2.2.1]庚烷-1-甲酰胺的合成
Figure PCTCN2022103288-appb-000099
将4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸(1.00g,1.56mmol)溶于四氢呋喃(10mL)，冰浴下加入N,N-羰基二咪唑(0.30g,1.85mmol)，转移到50℃下搅拌反应30min，加入甲磺酰胺(0.18g,1.89mmol)，继续在50℃下搅拌反应。反应液用水(20mL)稀释，再用乙酸乙酯(20mL×2)萃取，合并有机相用饱和食盐水(20mL)洗涤，用无水硫酸钠干燥有机相，减压浓缩，通过硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到白色固体(79mg,产率：7.05％)； 1H NMR(400MHz,CDCl 3)δ8.09(s,1H),8.05–8.00(m,2H),7.90(d,J＝7.7Hz,1H),7.80(d,J＝8.0Hz,1H),7.66(t,J＝7.9Hz,1H),7.36–7.31(m,1H),7.19–7.11(m,2H),6.93(d,J＝8.5Hz,1H),6.87(d,J＝9.1Hz,1H),6.60(t,J＝73.2Hz,1H),4.41–4.30(m,1H),3.38–3.33(m,4H),3.24–3.13(m,1H),2.06–1.75(m,6H),1.51–1.25(m,4H)；LC-MS:(ESI,neg.ion)m/z:717.40[M-H] -.
实施例32:4-((S)-4-((3-氯苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000100
步骤1：3-氯-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺的合成
将3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-胺(1.50g,5.53mmol)和吡啶(2.19g,27.65mmol)溶于二氯甲烷(10mL)，室温下缓慢滴加3-氯苯磺酰氯(1.40g,6.64mmol)与二氯甲烷(10mL)的混合溶剂，滴加完毕后在室温下搅拌反应6.5h。用稀盐酸(2M,20mL)洗涤反应液，用饱和食盐水(10mL)洗涤反应液，用无水硫酸钠干燥有机相，减压浓缩，通过硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到黄色固体(2.08g,产率：84.37％)。LC-MS(ESI,pos.ion)m/z:446.05[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.81(s,1H),7.76–7.72(m,1H),7.68(d,J＝7.8Hz,1H),7.57–7.53(m,1H),7.45–7.38(m,1H),7.31–7.27(m,1H),7.12–7.03(m,3H),6.88(d,J＝9.2Hz,1H),6.84(s,1H),6.57(t,J＝73.1Hz,1H).
步骤2：甲基4-(N-((3-氯苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯基]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将3-氯-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺(2.08g,4.67mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(1.41g,4.90mmol)溶于异丙醇(20mL)中，升温至50℃缓慢加入N,N-二异丙基乙胺(0.81g,6.30mmol)，在50℃下搅拌反应6.5h，将反应悬浊液过滤后，用异丙醇(20mL)洗涤滤饼，滤饼在50℃下真空干燥3h得到白色固体产物(2.55g,产率：85.31％)。LC-MS(ESI,pos.ion)m/z:640.10[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.79–7.73(m,1H),7.70(s,1H),7.62–7.57(m,2H),7.52–7.42(m,2H),7.15–7.09(m,1H),7.06(d,J＝9.2Hz,1H),7.02(s,1H),6.87(d,J＝9.1Hz,1H),6.56(t,J＝73.1Hz,1H),4.62(s,2H),3.69(s,3H),2.08–1.90(m,4H),1.89(s,2H),1.75–1.63(m,4H).
步骤3：甲基4-((S)-2-((3-氯-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(0.55g,11.94mmol)溶于二氯甲烷(5mL)，冰浴下缓慢加入N,N-二异丙基乙胺(0.77g,5.97mmol)，滴加完毕转移到室温加入甲基4-(N-((3-氯苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯基]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(2.55g,3.98mmol)、氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(51mg,0.08mmol)，在45℃下回流反应5h。反应液冷却至室温，用水(10mL×2)洗涤反应液,用HCl水溶液(2M,10mL×2)洗涤反应液，无水硫酸钠干燥有机相，滤液减压浓缩除去溶剂得到棕色浓缩液。将浓缩液溶于乙酸乙酯(10mL)，加入2-巯基烟酸(0.20g,0.80mmol)与活性炭(1.07g)，在80℃下搅拌反应1.5h。停止加热冷却至室温，通过硅藻土过滤，滤液用饱和碳酸氢钠溶液(20mL×2)洗涤有机相，用无水硫酸钠干燥有机相，减压浓缩得到无色油状产物(2.48g,产率：97.05％)。 1H NMR(400MHz,CDCl 3)δ7.69(s,1H),7.60(t,J＝7.3Hz,2H),7.56–7.50(m,1H),7.50–7.44(m,2H),7.21–7.14(m,1H),7.06(d,J＝9.1Hz,1H),7.03(s,1H),6.88(d,J＝9.1Hz,1H),6.57(t,J＝73.0Hz,1H),3.85–3.78(m,1H),3.65(s,3H),3.62–3.53(m,2H),2.38–2.33(m,1H),1.82–1.63(m,4H),1.60(s,2H),1.57–1.30(m,4H).
步骤4：4-((S)-4-((3-氯苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((3-氯-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(2.48g,3.86mmol)、氢氧化钠(0.46g,11.58mmol)和四丁基溴化铵(0.12g,0.39mmol)溶于四氢呋喃(5mL)，在60℃下搅拌反应。用水(10mL)稀释反应液应液置于冰浴下，用HCl水溶液(2M)调节pH＝2，然后用EA(20mL×2)萃取，合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，通过柱层析纯化得到白色固体产物(2.00g,产率：85.22％)。 1H NMR(400MHz,CDCl 3)δ8.04–7.98(m,1H),7.70(s,1H),7.61–7.56(m,1H),7.53–7.48(m,1H),7.46–7.40(m,1H),7.35 –7.28(m,1H),7.15(d,J＝9.4Hz,1H),7.12(s,1H),6.93(d,J＝8.5Hz,1H),6.84(d,J＝9.1Hz,1H),6.58(t,J＝73.3Hz,1H),4.33–4.24(m,1H),3.37–3.31(m,1H),3.21–3.11(m,1H),2.14–2.05(m,2H),1.92–1.84(m,1H),1.79–1.69(m,3H),1.65–1.55(m,1H),1.54–1.44(m,2H),1.40–1.31(m,1H).
实施例33：4-((S)-4-((4-溴苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000101
步骤1：4-溴-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺的合成
将3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-胺(3.00g,11.06mmol)和吡啶(4.37g,55.30mmol)溶于二氯甲烷(10mL)，室温下缓慢滴加4-溴苯磺酰氯(3.39g,13.27mmol)与二氯甲烷(10mL)的混合溶剂，滴加完毕后在室温下搅拌反应6h。用稀盐酸(2M,20mL)洗涤反应液，用饱和食盐水(20mL)洗涤反应液，用无水硫酸钠干燥有机相，减压浓缩，通过硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝5/1)，得到黄色固体(4.27g,78.75％)。LC-MS(ESI,pos.ion)m/z:490.00[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.78–7.73(m,1H),7.70–7.57(m,4H),7.30–7.27(m,1H),7.11–7.04(m,3H),6.88(d,J＝9.1Hz,1H),6.84(s,1H),6.58(t,J＝73.0Hz,1H).
步骤2：甲基4-(N-((4-溴苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯基]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将4-溴-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺(2.00g,4.08mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(1.23g,4.28mmol)溶于异丙醇(20mL)，升温至50℃缓慢加入N,N-二异丙基乙胺(0.71g,5.51mmol)，在50℃下搅拌反应3h，将反应悬浊液过滤后，用异丙醇(20mL)洗涤滤饼，滤饼在50℃下真空干燥3h得到白色固体产物(2.53g,产率：90.59％)。LC-MS(ESI,pos.ion)m/z:684.00[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.78–7.72(m,1H),7.66–7.54(m,4H),7.51–7.43(m,1H),7.14–7.07(m,1H),7.06–7.02(m,1H),7.01(s,1H),6.87(d,J＝9.1Hz,1H),6.57(t,J＝73.1Hz,1H),4.61(s,2H),3.69(s,3H),2.09–1.90(m,4H),1.88(s,2H),1.76–1.62(m,4H).
步骤3：甲基4-((S)-2-((4-溴-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(0.51g,11.10mmol)溶于二氯甲烷(5mL)，冰浴下缓慢加入N,N-二异丙基乙胺(0.72g,5.55mmol)，滴加完毕转移到室温加入甲基4-(N-((4-溴苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯基]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(2.53g,3.70mmol)和氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(47mg,0.07mmol)，在45℃下回流反应20.5h。反应液冷却至室温，用水(10mL×2)洗涤反应液，用HCl水溶液(2M,10mL×2)洗涤反应液，无水硫酸钠干燥有机相，滤液减压浓缩除去溶剂得到棕色浓缩液。将浓缩液溶于乙酸乙酯(10mL)，加入2-巯基烟酸(0.11g,0.74mmol)与活性炭(1.00g)，在80℃下搅拌反应5h。停止加热冷却至室温，通过硅藻土过滤，滤液用饱和碳酸氢钠溶液(20mL×2)洗涤有机相，用无水硫酸钠干燥有机相，减压浓缩得到无色油状产物(1.86g,产率：73.23％)。 1H NMR(400MHz,CDCl 3)δ7.72(d,J＝7.6Hz,2H),7.65(t,J＝7.4Hz,1H),7.57–7.48(m,3H),7.41–7.36(m,1H),7.19–7.13(m,1H),7.06–7.01(m,1H),7.00(s,1H),6.89–6.85(m,1H),6.56(t,J＝73.0Hz,1H),3.84–3.78(m,1H),3.65(s,3H),3.63–3.51(m,2H),2.01–1.90(m,2H),1.84–1.60(m,4H),1.54–1.29(m,4H).
步骤四：4-((S)-4-((4-溴苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((4-溴-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(1.86g,2.71mmol)、氢氧化钠(0.33g,8.13mmol)、四丁基溴化铵(0.09g,0.27mmol)溶于四氢呋喃(5mL)，在60℃下搅拌反应。用水(10mL)稀释反应液，在冰浴下用HCl水溶液(2M)调节pH＝2，然后用EA(20mL×2)萃取，合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，通过柱层析纯化(二氯甲烷/甲醇(v/v)＝50/1)得到白色固体产物(1.50g,产率：84.83％)。 1H NMR(400MHz,CDCl 3)δ8.08–8.02(m,1H),7.69–7.65(m,2H),7.64–7.58(m,1H),7.54–7.45(m,2H),7.32–7.27(m,1H),7.19–7.13(m,1H),7.12(s,1H),6.91(d,J＝8.5Hz,1H),6.83(d,J＝9.2Hz,1H),6.58(t,J＝73.3Hz,1H),4.33–4.22(m,1H),3.31–3.22(m,1H),3.19–3.06(m,1H),2.03–1.97(m,1H),1.87–1.79(m,1H),1.78–1.65(m,3H),1.61–1.29(m,5H).
实施例34：4-((S)-4-((4-环丙基苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000102
步骤1：4-环丙基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺的合成
将4-溴-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺(2.07g,4.22mmol，实施例34步骤1)、环丙基硼酸(0.54g,6.33mmol)、醋酸钯(94mg,0.42mmol)、三环己基膦(237mg,0.84mmol)和磷酸钾(2.69g,12.66mmol)溶于甲苯(50mL)与水(5mL)的混合溶剂中，在氮气保护，100℃下搅拌反应18h。停止反应冷却至室温，用水(50mL×2)洗涤有机相，用饱和食盐水(50mL)洗涤有机相，用无水硫酸钠干燥有机相，通过柱层析纯化(石油醚/乙酸乙酯(v/v)＝5/1)得到浅黄色色固体产物(1.38g,产率：72.44％)。LC-MS(ESI,pos.ion)m/z:452.30[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.78–7.73(m,1H),7.71(d,J＝8.4Hz,2H),7.27–7.20(m,1H),7.14(d,J＝8.4Hz,2H),7.11–7.04(m,3H),6.89(d,J＝9.1Hz,1H),6.81(s,1H),6.59(t,J＝73.1Hz,1H),1.99–1.89(m,1H),1.14–1.06(m,2H),0.80–0.72(m,2H).
步骤2：甲基4-(N-((4-环丙基苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯基]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将4-环丙基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺(1.48g,3.28mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(0.99g,3.44mmol)溶于异丙醇(20mL)，升温至50℃缓慢加入N,N-二异丙基乙胺(0.57g,4.43mmol)，在50℃下搅拌反应6h，将反应悬浊液过滤后，用异丙醇(20mL)洗涤滤饼，滤饼在50℃下真空干燥3h得到白色固体产物(1.89g,产率：89.25％)。LC-MS(ESI,pos.ion)m/z:646.50[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.66–7.61(m,1H),7.59(d,J＝8.4Hz,2H),7.47–7.40(m,1H),7.15(d,J＝8.4Hz,2H),7.13–7.07(m,1H),7.01–6.95(m,2H),6.89–6.81(m,1H),6.55(t,J＝73.2Hz,1H),4.61(s,2H),3.69(s,3H),2.08–1.92(m,4H),1.88(s,2H),1.79–1.61(m,4H),1.14–1.04(m,2H),0.81–0.74(m,2H).
步骤3：甲基4-((S)-2-((4-环丙基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(0.40g,2.93mmol)溶于二氯甲烷(5mL)，冰浴下缓慢加入N,N-二异丙基乙胺(0.57g,4.40mmol)，滴加完毕转移到室温加入甲基4-(N-((4-环丙基苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯基]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(1.89g,2.93mmol)和氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(37mg,0.02mmol)，在45℃下回流反应6.5h。反应液冷却至室温，用水(10mL×2)洗涤反应液，用HCl水溶液(2M,10mL×2)洗涤反应液，无水硫酸钠 干燥有机相，滤液减压浓缩除去溶剂得到棕色浓缩液。将浓缩液溶于乙酸乙酯(10mL)，加入2-巯基烟酸(91mg,0.59mmol)与活性炭(0.79g)，在80℃下搅拌反应5h。停止加热冷却至室温，通过硅藻土过滤，滤液用饱和碳酸氢钠溶液(20mL×2)洗涤有机相，用无水硫酸钠干燥有机相，减压浓缩得到无色油状产物(1.77g,产率：93.27％)。LC-MS(ESI,pos.ion)m/z:648.15[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.57(d,J＝8.3Hz,2H),7.52–7.46(m,1H),7.33–7.27(m,1H),7.21–7.12(m,3H),7.03–6.97(m,2H),6.90–6.83(m,1H),6.56(t,J＝73.1Hz,1H),3.82–3.76(m,1H),3.65(s,3H),3.62–3.47(m,2H),2.59–2.48(m,1H),1.97–1.85(m,2H),1.83–1.69(m,2H),1.67–1.60(m,2H),1.56–1.40(m,2H),1.40–1.29(m,2H),1.14–1.08(m,2H),0.83–0.77(m,2H).
步骤4：4-((S)-4-((4-环丙基苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((4-环丙基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(1.77g,2.73mmol)、氢氧化钠(0.33g,8.19mmol)和四丁基溴化铵(0.09g,0.27mmol)溶于四氢呋喃(4mL)，在60℃下搅拌反应5h。用水(10mL)稀释反应液，在冰浴下用HCl水溶液(2M)调节pH＝2，然后用EA(20mL×2)萃取，合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，通过柱层析纯化(二氯甲烷/甲醇(v/v)＝50/1)得到白色固体产物(1.40g,产率：83.05％)。LC-MS(ESI,neg.ion)m/z:612.20[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.05–8.01(m,1H),7.52(d,J＝8.4Hz,2H),7.29–7.27(m,1H),7.16–7.08(m,4H),6.91(d,J＝8.5Hz,1H),6.82(d,J＝9.2Hz,1H),6.57(t,J＝73.4Hz,1H),4.31–4.24(m,1H),3.38–3.31(m,1H),3.16–3.07(m,1H),2.07–1.99(m,2H),1.98–1.88(m,1H),1.86(d,J＝9.5Hz,1H),1.80–1.67(m,3H),1.63–1.51(m,1H),1.51–1.40(m,2H),1.39–1.30(m,1H),1.13–1.04(m,2H),0.81–0.69(m,2H).
实施例35:4-((S)-6-(3-氟-5-(三氟甲基)苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000103
步骤一：1-氟-3-碘-5-(三氟甲基)苯的合成
将3-氟-5-(三氟甲基)苯胺(2.0g,11.17mmol)溶于1,4-二氧六环(20mL)与浓盐酸(10mL)的混合溶液中，在-10℃下缓慢滴加亚硝酸钠(930mg,13.46mmol)与水(10mL)的混合溶剂，15min内滴加完毕，在-10℃下搅拌反应1h。在-10℃下缓慢滴加碘化钾(2.4g,14.52mmol)与水(10mL)的混合溶剂，30min内滴加完毕，在-10℃下搅拌反应4h。用乙酸乙酯(20mL)稀释反应液，用饱和亚硫酸氢钠溶液(20mL×2)洗涤有机相，用饱和食盐水(20mL)洗涤有机相，用无水硫酸钠干燥，通过柱层析纯化(石油醚)得到黄色液体产物(1.20g,产率：37.05％)。 1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.64(d,J＝7.6Hz,1H),7.31(d,J＝8.3Hz,1H).
步骤2：2-(3-氟-5-(三氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的合成
将1-氟-3-碘-5-(三氟甲基)苯(869-1)(1.2g,4.14mmol)、双(频哪醇)二硼(1.3g,4.97mmol)、醋酸钾(0.8g,8.28mmol)、醋酸钯(46mg,0.21mmol)和二环己基-[2-(2-甲基苯基)苯基]膦(150mg,0.41mmol)溶于N,N-二甲基甲酰胺(20mL)，在氮气保护，80℃下搅拌反应3h。停止反应冷却至室温，加水(20mL)稀释反应液，用PE(20mL×2)萃取，合并有机相通过硅藻土过滤，用饱和食盐水(20mL)洗涤，有机相用无水硫酸钠干燥，减压浓缩通过柱层析(PE/EA(v/v)＝50/1)纯化得到黄色液体产物(0.78g,产率：64.95％)。 1H NMR(400MHz,CDCl 3)δ7.84(s,1H),7.69–7.63(m,1H),7.39(d,J＝8.5Hz,1H),1.36(s,12H).
步骤3：甲基4-((S)-2-((N-(3',4-二氟-5'-(三氟甲基)-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基)磺酰胺基)-1-羟 乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将2-(3-氟-5-(三氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(440mg,1.52mmol)、4-((S)-2-((N-(5-溴-2-氟苯基)-3-(三氟甲基)苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸甲酯(757mg,1.27mmol)、(1,1'-双(二苯基膦)二茂铁)二氯化钯二氯甲烷络合物(100mg,0.13mmol)和碳酸钾(350mg,2.54mmol)溶于1,4-二氧六环(10mL)与水(2mL)的混合溶剂中，在氮气保护，80℃下搅拌反应4h。用水(20mL)稀释反应液，乙酸乙酯(20mL×2)萃取，合并有机相用饱和食盐水(20mL×2)洗涤，有机相用无水硫酸钠干燥，减压浓缩通过柱层析纯化(PE/EA(v/v)＝5/1)得到黄色固体产物(0.74g,产率：86.22％)。LC-MS(ESI,pos.ion)m/z:678.30[M+H] +.
步骤4：4-((S)-6-(3-氟-5-(三氟甲基)苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(3',4-二氟-5'-(三氟甲基)-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(742mg,1.10mmol)、氢氧化钠(130mg,3.30mmol)和四丁基溴化铵(35m g,0.11mmol)溶于四氢呋喃(2mL)，在60℃下搅拌反应5h。用水(10mL)稀释反应液，,在冰浴下用HCl水溶液(2M)调节pH＝2，然后用乙酸乙酯(20mL×2)萃取，合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，通过柱层析纯化(二氯甲烷/甲醇(v/v)＝50/1)得到白色固体产物(560mg,产率：77.67％)。LC-MS(ESI,neg.ion)m/z:642.20[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.06–8.02(m,1H),7.99(s,1H),7.88(d,J＝7.7Hz,1H),7.77(d,J＝8.0Hz,1H),7.68–7.61(m,1H),7.59(s,1H),7.45(d,J＝9.4Hz,1H),7.37–7.32(m,1H),7.29(d,J＝8.2Hz,1H),6.94(d,J＝8.5Hz,1H),4.38–4.29(m,1H),3.37–3.30(m,1H),3.24–3.14(m,1H),1.86(d,J＝9.5Hz,1H),1.80–1.67(m,3H),1.63–1.40(m,4H),1.40–1.28(m,2H).
实施例36:4-((S)-4-((3-溴苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000104
步骤1：3-溴-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺的合成
将3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-胺(100mg,0.37mmol)、吡啶(32mg,0.41mmol)溶于丙酮(2mL)，室温下缓慢滴加3-溴苯磺酰氯(142mg,0.55mmol)，滴加完毕后在室温下搅拌反应5h。加入乙酸乙酯(50mL)和水(20mL)，用盐酸(4M)调节pH＝4，分离有机相，有机相用水洗涤(20mL×3)，用无水硫酸钠干燥，减压旋蒸浓缩溶剂得黄色固体(130mg,71.66％)。LC-MS(ESI,pos.ion)m/z:490.20[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.96(s,1H),7.75–7.68(m,3H),7.35(t,J＝8.0Hz,1H),7.30–7.26(m,1H),7.11–7.04(m,3H),6.88(d,J＝9.1Hz,1H),6.57(t,J＝73.1Hz,1H).
步骤2：甲基4-(N-((3-溴苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将3-溴-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺(100mg,0.20mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(83mg,0.30mmol)溶于异丙醇(1mL)，缓慢加入N,N-二异丙基乙胺(39mg,0.30mmol)，室温搅拌5h.反应液用乙酸乙酯(50mL)和水(20mL)稀释，用4M盐酸调整pH＝4,分离有机相，有机相用水洗涤(30mL×2),用无水硫酸钠干燥，减压旋蒸浓缩溶剂得黄色液体，硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得白色固体(91mg,产率：66.47％)。LC-MS(ESI,pos.ion)m/z:684.30[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.84(s,1H),7.78–7.72(m,2H),7.64(d,J＝8.0Hz,1H),7.51–7.45(m,1H),7.38(t,J＝7.9Hz,1H),7.15–7.08(m,1H),7.06(d,J＝9.1Hz,1H),7.02(s,1H),6.87(d,J＝9.1Hz,1H),6.57(t,J＝73.1Hz,1H),4.62(s,2H),3.69(s,3H),2.08–1.99(m,2H),1.96– 1.86(m,4H),1.76–1.63(m,4H).
步骤3：甲基4-((S)-2-((3-溴-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(10mg,0.22mmol)溶于二氯甲烷(0.5mL)，冰浴下缓慢加入N,N-二异丙基乙胺(14mg,0.11mmol)，滴加完毕转移到室温加入甲基4-(N-((3-溴苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(50mg,0.073mmol)和氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(0.93mg,1.5umol)，在45℃下回流反应5h。反应液冷却至室温，加入乙酸乙酯(100mL)和水(50mL)稀释，用4M盐酸调节pH<4，分离有机相，有机相用水(50mL×2)洗涤，无水硫酸钠干燥有机相，滤液减压旋蒸浓缩除去溶剂得黄色粘稠液体(45mg,产率：89.79％)。LC-MS(ESI,pos.ion)m/z:686.30[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.75(d,J＝8.0Hz,1H),7.64(d,J＝7.8Hz,1H),7.55–7.49(m,1H),7.47(dd,J＝7.0,1.9Hz,1H),7.39(t,J＝7.9Hz,1H),7.20–7.13(m,1H),7.06(d,J＝9.1Hz,1H),7.03(s,1H),6.87(d,J＝9.1Hz,1H),6.57(t,J＝73.1Hz,1H),3.85–3.77(m,1H),3.65(s,3H),3.62–3.54(m,2H),2.00–1.91(m,2H),1.80–1.69(m,2H),1.68–1.58(m,2H),1.56–1.42(m,2H),1.39–1.27(m,2H).
步骤4：4-((S)-4-((3-溴苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((3-溴-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(225mg,0.33mmol)、氢氧化钠(40mg,0.99mmol)和四丁基溴化铵(21mg,0.07mmol)溶于四氢呋喃(1.5mL)中，置于60℃搅拌12h.加入乙酸乙酯(100mL)和饱和食盐水(50mL),用盐酸调节pH<4，用饱和食盐水水洗涤(50mL×2)，无水硫酸钠干燥，减压旋蒸除去溶剂,剩余物硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝3/1)纯化得黄色粉末(116mg,产率：53.87％)。LC-MS(ESI,neg.ion)m/z:650.30[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.01(s,1H),7.87(s,1H),7.74(d,J＝7.7Hz,1H),7.54(d,J＝7.7Hz,1H),7.36(t,J＝7.9Hz,1H),7.30(d,J＝7.8Hz,1H),7.20–7.08(m,2H),6.93(d,J＝8.5Hz,1H),6.84(d,J＝8.9Hz,1H),6.58(t,J＝73.3Hz,1H),4.29(d,J＝14.3Hz,1H),3.33(d,J＝10.2Hz,1H),3.23–3.10(m,1H),2.15–1.99(m,2H),1.93–1.84(m,1H),1.82–1.67(m,3H),1.66–1.56(m,1H),1.56–1.43(m,2H),1.41–1.31(m,1H).
实施例37:4-((S)-4-((3-环丙基苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000105
步骤1：3-环丙基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺的合成
将3-溴-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺(500mg,1.02mmol,实施例36步骤1)、环丙基硼酸(131mg,1.53mmol)、碳酸钾(211g,1.53mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(42mg,0.05mmol)混合在甲苯(5mL)和水(1mL)中，氮气保护下80℃搅拌12h。冷却至室温，反应液中加入水(50mL)，用石油醚(100mL×3)萃取反应液，合并有机相，无水硫酸钠干燥有机相，减压浓缩得到褐色液体，硅胶柱层析(石油醚/乙酸乙酯(v/v)＝10/1)纯化得黄色液体(302mg,产率：65.59％)。LC-MS(ESI,pos.ion)m/z:452.10[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.72(dd,J＝7.4,2.1Hz,1H),7.58(d,J＝7.7Hz,1H),7.46(s,1H),7.33(t,J＝7.7Hz,1H),7.30–7.26(m,1H),7.25–7.20(m,1H),7.08–7.02(m,3H),6.92–6.84(m,2H),6.57(t,J＝73.1Hz,1H),1.94–1.86(m,1H),0.99(q,J＝6.4Hz,2H),0.62(q,J＝4.9Hz,2H).
步骤2：甲基4-(N-((3-环丙基苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)甘氨酰基)双环 [2.2.1]庚烷-1-羧酸酯的合成
将3-环丙基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺(50mg,0.11mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(45mg,0.17mmol)溶于异丙醇(1mL)，缓慢加入N,N-二异丙基乙胺(21mg,0.17mmol)，室温搅拌5h.反应液用乙酸乙酯(50mL)和水(20mL)稀释，用4M盐酸调整pH＝4,分离有机相，有机相用水洗涤(30mL×2),用无水硫酸钠干燥，减压旋蒸浓缩溶剂得黄色液体，硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得黄色固体(55mg,产率：77.44％)。LC-MS(ESI,pos.ion)m/z:646.45[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.65(dd,J＝7.2,2.3Hz,1H),7.53–7.49(m,1H),7.48–7.43(m,1H),7.42–7.34(m,2H),7.35–7.31(m,1H),7.14–7.07(m,1H),7.03–6.97(m,2H),6.85(d,J＝9.1Hz,1H),6.55(t,J＝73.2Hz,1H),4.61(s,2H),3.69(s,3H),2.04–1.98(m,2H),1.96–1.88(m,3H),1.75–1.61(m,6H),0.99(q,J＝4.9Hz,2H),0.65(q,J＝4.9Hz,2H).
步骤3：甲基4-((S)-2-((3-环丙基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(423mg,9.20mmol)溶于二氯甲烷(1.0mL)，冰浴下缓慢加入N,N-二异丙基乙胺(595mg,4.60mmol)，滴加完毕转移到室温加入4-(N-((3-环丙基苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(300mg,0.46mmol)和氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(29mg,46umol)，在45℃下回流反应5h。反应液冷却至室温，加入乙酸乙酯(100mL)和水(50mL)稀释，用4M盐酸调节pH<4，分离有机相，有机相用水(50mL×2)洗涤，无水硫酸钠干燥有机相，滤液减压旋蒸浓缩除去溶剂得黄色粘稠液体(295mg,产率：99.02％)。LC-MS(ESI,pos.ion)m/z:648.45[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.50(d,J＝7.8Hz,2H),7.40(t,J＝7.7Hz,1H),7.36–7.28(m,3H),7.17(t,J＝9.2Hz,1H),7.04–6.98(m,2H),6.86(d,J＝9.1Hz,1H),6.56(t,J＝73.1Hz,1H),3.86–3.77(m,1H),3.64(s,3H),3.56(d,J＝9.4Hz,1H),3.52(dd,J＝14.1,2.4Hz,1H),2.00–1.88(m,3H),1.84–1.70(m,2H),1.67–1.59(m,2H),1.56–1.43(m,2H),1.38–1.29(m,2H),0.99(q,J＝5.2Hz,2H),0.64(q,J＝5.1Hz,2H).
步骤4：4-((S)-4-((3-环丙基苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((3-环丙基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(300mg,0.46mmol)、氢氧化钠(55mg,1.38mmol)和四丁基溴化铵(30mg,0.09mmol)溶于四氢呋喃(1.0mL)中，置于60℃搅拌2h.加入乙酸乙酯(100mL)和饱和食盐水(50mL),用盐酸调节pH<4,用饱和食盐水水洗涤(50mL×2),无水硫酸钠干燥,减压旋蒸除去溶剂,剩余物硅胶柱层析(洗脱剂：二氯甲烷/甲醇(v/v)＝50/1)纯化得白色固体(128mg,产率：45.35％,)。LC-MS(ESI,neg.ion)m/z:612.20[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.03(s,1H),7.40(d,J＝7.0Hz,1H),7.37–7.26(m,4H),7.19–7.07(m,2H),6.90(d,J＝8.5Hz,1H),6.83(d,J＝8.8Hz,1H),6.58(t,J＝73.4Hz,1H),4.27(d,J＝14.0Hz,1H),3.23(d,J＝10.4Hz,1H),3.19–3.05(m,1H),2.13–1.96(m,2H),1.94–1.81(m,2H),1.78–1.65(m,2H),1.63–1.51(m,1H),1.50–1.41(m,2H),1.38–1.26(m,2H),1.06–0.90(m,2H),0.73–0.45(m,2H). 13C NMR(101MHz,CDCl 3)δ181.6,164.7,162.2,152.3,147.9,146.4,143.8,138.3,131.7,131.3,129.4,124.9,124.1,123.4,118.2,115.8,113.7,111.0,106.0,74.1,51.8,50.3,46.1,44.0,33.2,33.0,31.7,29.8,29.0,15.4,10.3,9.6.
实施例38:4-((S)-4-((3-叔丁基苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸
Figure PCTCN2022103288-appb-000106
步骤1：3-叔丁基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺的合成
将3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-胺(100mg,0.37mmol)和吡啶(32mg,0.41mmol)溶于丙酮(2mL)，室温下缓慢滴加3-叔丁基苯磺酰氯(90mg,0.39mmol)，滴加完毕后在室温下搅拌反应5h。加入乙酸乙酯(50mL)和水(20mL)，用盐酸(4M)调节pH＝4，分离有机相，有机相用水洗涤(20mL×3)，用无水硫酸钠干燥，减压旋蒸浓缩溶剂得黄色液体(144mg,产率：83.25％)。LC-MS(ESI,pos.ion)m/z:468.30[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.78–7.73(m,2H),7.64(d,J＝7.8Hz,1H),7.59–7.54(m,1H),7.39(t,J＝7.9Hz,1H),7.25–7.19(m,1H),7.09–7.01(m,3H),6.87(d,J＝9.2Hz,1H),6.56(t,J＝73.1Hz,1H),1.23(s,9H).
步骤2：甲基4-(N-((3-叔丁基苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将3-叔丁基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺(50mg,0.11mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(45mg,0.17mmol)溶于异丙醇(1mL)，缓慢加入N,N-二异丙基乙胺(21mg,0.17mmol)，室温搅拌12h。反应液用乙酸乙酯(50mL)和水(20mL)稀释，用4M盐酸调整pH＝4，分离有机相，有机相用水洗涤(20mL×2)，用无水硫酸钠干燥，减压旋蒸浓缩溶剂得黄色液体，硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得黄色固体(55mg,产率：75.56％)。LC-MS(ESI,pos.ion)m/z:662.45[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.72–7.66(m,1H),7.64–7.61(m,2H),7.58(d,J＝8.1Hz,1H),7.43–7.38(m,1H),7.29(t,J＝7.8Hz,1H),7.10–7.04(m,1H),7.02–6.97(m,2H),6.84(d,J＝9.1Hz,1H),6.55(t,J＝73.2Hz,1H),4.60(s,2H),3.69(s,3H),2.07–1.87(m,4H),1.78–1.62(m,6H),1.25(s,9H).
步骤3：甲基4-((S)-2-((3-叔丁基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(10mg,0.22mmol)溶于二氯甲烷(0.5mL)，冰浴下缓慢加入N,N-二异丙基乙胺(15mg,0.11mmol)，滴加完毕转移到室温加入甲基4-(N-((3-叔丁基苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(50mg,0.076mmol)和氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(0.97mg,1.5umol)，在45℃下回流反应8h。反应液冷却至室温，加入乙酸乙酯(100mL)和水(50mL)稀释，用4M盐酸调节pH<4，分离有机相，有机相用水(50mL×2)洗涤，无水硫酸钠干燥有机相，滤液减压旋蒸浓缩除去溶剂得黄色粘稠液体(46mg,产率：91.19％)。LC-MS(ESI,pos.ion)m/z:664.50[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.65(d,J＝8.0Hz,1H),7.62–7.57(m,2H),7.53–7.44(m,2H),7.42–7.37(m,1H),7.18–7.12(m,1H),7.05–6.99(m,2H),6.87(d,J＝9.1Hz,1H),6.56(t,J＝73.0Hz,1H),3.86–3.78(m,1H),3.65(s,3H),3.60–3.50(m,2H),2.03–1.92(m,3H),1.82–1.72(m,3H),1.68–1.63(m,2H),1.55–1.47(m,2H),1.25(s,9H).
步骤4：4-((S)-4-((3-叔丁基苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((3-叔丁基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(200mg,0.30mmol)、氢氧化钠(36mg,0.90mmol)和四丁基溴化铵(19mg,0.06mmol)溶于四氢呋喃(1.0mL)中，置于60℃搅拌5h.加入乙酸乙酯(50mL)和饱和食盐水(20mL),用盐酸调节pH<4,分离有机相，有机相用饱和食盐水水洗涤(20mL×2),无水硫酸钠干燥，减压旋蒸除去溶剂,剩余物硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝3/1)纯化得白色固体色(85mg,产率：45.00％)。LC-MS(ESI,neg.ion)m/z:628.10[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.08(d,J＝2.0Hz,1H),7.61(d,J＝7.8Hz,1H),7.57(s,1H),7.46(d,J＝7.8Hz,1H),7.40(t,J＝7.7Hz,1H),7.29(dd,J＝8.6,2.1Hz,1H),7.18–7.11(m,2H),6.89(d,J＝8.5Hz,1H),6.83(d,J＝9.1Hz,1H),6.58(t,J＝73.3Hz,1H),4.28(dd,J＝14.0,1.8Hz,1H),3.23–3.06(m,2H),2.08–1.97(m,2H),1.88–1.79(m,1H),1.78–1.65(m,2H),1.57–1.49(m,1H),1.48–1.28(m,4H),1.20(s,9H). 13C NMR(101MHz,CDCl 3)δ181.7,164.7,162.2,153.2,152.3,148.1,143.8,138.1,131.8,130.8,130.3,129.3,128.6,125.0,124.5,124.3,124.1,123.6,118.4,118.2,115.8,113.7,113.2,111.0,110.8,106.0,73.9,51.7,50.3,46.1,44.0,35.1,33.2,33.0,31.7,31.1,29.8,28.8.
实施例39：4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-异丙基苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000107
步骤1：N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-3-异丙基苯磺酰胺的合成
将3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-胺(500mg,1.84mmol)和吡啶(437mg,5.52mmol)溶于丙酮(2mL)，室温下缓慢滴加3-异丙基苯磺酰氯(604mg,2.76mmol)，滴加完毕后在室温下搅拌反应5h。加入乙酸乙酯(50mL)和水(20mL)，用盐酸(4M)调节pH＝4,分离有机相，有机相用水洗涤(20mL x 3),用无水硫酸钠干燥，减压旋蒸浓缩溶剂得黄色固体，用异丙醇(2mL)打浆过滤得白色固体(681mg,产率：81.62％)。LC-MS(ESI,neg.ion)m/z:454.15[M-H] -； 1H NMR(400MHz,CDCl 3)δ7.74(dd,J＝7.4,2.1Hz,1H),7.66–7.61(m,2H),7.44–7.35(m,2H),7.25–7.19(m,1H),7.08–7.00(m,3H),6.89–6.83(m,2H),6.57(t,J＝73.1Hz,1H),2.90(p,J＝6.9Hz,1H),1.17(d,J＝6.9Hz,6H).
步骤2：甲基4-(N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-N-((3-异丙基苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-3-异丙基苯磺酰胺(500mg,1.10mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(454mg,1.65mmol)溶于异丙醇(2mL)，缓慢加入N,N-二异丙基乙胺(213mg,1.65mmol)，室温搅拌5h。反应液用乙酸乙酯(50mL)和水(20mL)稀释，用4M盐酸调整pH＝4,分离有机相，有机相用水洗涤(20mL×2),用无水硫酸钠干燥，减压旋蒸浓缩溶剂得黄色固体，硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝4/1)纯化得白色固体(611mg,产率：85.76％)。LC-MS(ESI,pos.ion)m/z:648.25[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.70(dd,J＝7.2,2.3Hz,1H),7.58(d,J＝7.5Hz,1H),7.51–7.39(m,4H),7.12–7.05(m,1H),7.03–6.98(m,2H),6.84(d,J＝9.1Hz,1H),6.55(t,J＝73.2Hz,1H),4.61(s,2H),3.68(s,3H),2.92(p,J＝6.9Hz,1H),2.08–1.97(m,2H),1.96–1.85(m,4H),1.72–1.64(m,4H),1.19(d,J＝6.9Hz,6H).
步骤3：甲基4-((S)-2-((N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-3-异丙基苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(428mg,9.3mmol)溶于二氯甲烷(1mL)，冰浴下缓慢加入N,N-二异丙基乙胺(601mg,4.65mmol)，滴加完毕转移到室温加入甲基4-(N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-N-((3-异丙基苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(600mg,0.93mmol)、氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(30mg,47umol)，在45℃下回流反应12h。反应液冷却至室温，加入乙酸乙酯(100mL)和水(50mL)稀释，用4M盐酸调节pH＝4，分离有机相，有机相用水(50mL×2)洗涤，无水硫酸钠干燥有机相，滤液减压旋蒸浓缩除去溶剂得黄色液体(552mg,产率：91.36％)。LC-MS(ESI,pos.ion)m/z:650.30[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.90(d,J＝7.4Hz,1H),7.86–7.73(m,5H),7.50–7.43(m,1H),7.39–7.33(m,2H),7.18(d,J＝9.1Hz,1H),6.90(t,J＝73.1Hz,1H),4.20–4.13(m,1H),3.97(s,3H),3.93–3.84(m,2H),3.25(p,J＝6.9Hz,1H),2.33–2.23(m,2H),2.16–2.03(m,2H),2.02–1.92(m,2H),1.90–1.75(m,2H),1.72–1.61(m,2H),1.52(d,J＝6.9Hz,6H).
步骤4：4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-异丙基苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)-3-异丙基苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(500mg,0.77mmol)、氢氧化钠(92mg,2.31mmol)和四丁基溴化铵(50mg,0.15mmol)溶于四氢呋喃(1.0mL)中，置于60℃搅拌5h.加入乙酸乙酯(50mL)和饱和食盐水(20mL)，用盐酸调节pH<4，分离有机相，有机相用饱和食盐水水洗涤(20mL×2)，无水硫酸钠干燥,减压旋蒸除去溶剂，剩余物硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝3/1)纯化得黄色固体(338mg,产率：71.30％)。LC-MS(ESI,neg.ion)m/z:614.55[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.06(s,1H),7.52–7.42 (m,3H),7.40(d,J＝7.5Hz,1H),7.29(d,J＝8.3Hz,1H),7.19–7.10(m,2H),6.89(d,J＝8.5Hz,1H),6.83(d,J＝9.0Hz,1H),6.58(t,J＝73.3Hz,1H),4.28(d,J＝14.1Hz,1H),3.23(d,J＝10.3Hz,1H),3.18–3.06(m,1H),2.95–2.83(m,1H),2.07–1.97(m,2H),1.89–1.80(m,1H),1.77–1.65(m,3H),1.59–1.30(m,4H),1.15(t,J＝6.6Hz,6H).
实施例40:4-((S)-4-((4-氰基苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000108
步骤1：4-氰基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺的合成
将3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-胺(500mg,1.84mmol)和吡啶(437mg,5.52mmol)溶于丙酮(2mL)，室温下缓慢滴加4-氰基苯磺酰氯(557mg,2.76mmol)，滴加完毕后在室温下搅拌反应5h。加入乙酸乙酯(50mL)和水(20mL)，用盐酸(4M)调节pH＝4,分离有机相，有机相用水洗涤(20mL×3),用无水硫酸钠干燥，减压旋蒸浓缩溶剂得黄色固体(681mg,产率：84.81％)。LC-MS(ESI,neg.ion)m/z:435.10[M-H] -； 1H NMR(400MHz,CDCl 3)δ7.93–7.88(m,2H),7.79–7.73(m,3H),7.35–7.28(m,1H),7.18(s,1H),7.11–7.04(m,3H),6.88(d,J＝9.1Hz,1H),6.58(t,J＝73.0Hz,1H).
步骤2：甲基4-(N-((4-氰基苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将4-氰基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯磺酰胺(50mg,0.11mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(45mg,0.17mmol)溶于异丙醇(1mL)，缓慢加入N,N-二异丙基乙胺(21mg,0.17mmol)，室温搅拌5h。反应液用乙酸乙酯(50mL)和水(20mL)稀释，用4M盐酸调整pH＝4，分离有机相，有机相用水洗涤(20mL×2)，用无水硫酸钠干燥，减压旋蒸浓缩溶剂得黄色固体，硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝4/1)纯化得白色固体(52mg,产率：74.96％)。LC-MS(ESI,pos.ion)m/z:631.40[M+H] -； 1H NMR(400MHz,CDCl 3)δ7.89–7.71(m,5H),7.50(s,1H),7.15–7.02(m,2H),6.99(s,1H),6.87(d,J＝8.5Hz,1H),6.58(t,J＝72.9Hz,1H),4.62(s,2H),3.68(s,3H),2.09–1.98(m,2H),1.95–1.82(m,4H),1.75–1.62(m,4H).
步骤3：甲基4-((S)-2-((4-氰基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(11mg,0.24mmol)溶于二氯甲烷(0.5mL)，冰浴下缓慢加入N,N-二异丙基乙胺(15mg,0.12mmol)，滴加完毕转移到室温加入甲基4-(N-((4-氰基苯基)磺酰基)-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(50mg,0.08mmol)、氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(1.0mg,1.6umol)，在45℃下回流反应5h。反应液冷却至室温，加入乙酸乙酯(100mL)和水(50mL)稀释，用4M盐酸调节pH＝4，分离有机相，有机相用水(50mL×2)洗涤，无水硫酸钠干燥有机相，滤液减压旋蒸浓缩除去溶剂得黄色粘稠液体(46mg,产率：92.04％)。LC-MS(ESI,neg.ion)m/z:668.20[M-Cl] -； 1H NMR(400MHz,CDCl 3)δ7.81(s,4H),7.59–7.51(m,2H),7.15(d,J＝8.9Hz,1H),7.12–7.06(m,1H),7.04(s,1H),6.89(d,J＝9.1Hz,1H),6.58(t,J＝72.9Hz,1H),3.82(d,J＝8.9Hz,1H),3.65(s,3H),3.64–3.55(m,2H),2.02–1.89(m,2H),1.73–1.62(m,4H),1.55–1.42(m,2H),1.43–1.28(m,3H).
步骤4：4-((S)-4-((4-氰基苯基)磺酰基)-6-(3-(二氟甲氧基)-5-氟苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((4-氰基-N-(3'-(二氟甲氧基)-4,5'-二氟-[1,1'-联苯]-3-基)苯基)磺酰胺基)-1-羟乙基)双 环[2.2.1]庚烷-1-羧酸酯(100mg,0.16mmol)、氢氧化钠(29mg,0.72mmol)和四丁基溴化铵(15mg,0.48mmol)溶于四氢呋喃(1.0mL)中，置于60℃搅拌2h.加入乙酸乙酯(50mL)和饱和食盐水(20mL),用盐酸调节pH<4,分离有机相，有机相用饱和食盐水水洗涤(20mL×2),无水硫酸钠干燥,减压旋蒸除去溶剂，剩余物硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝3/1)纯化得白色固体(50mg,产率：52.21％)。LC-MS(ESI,pos.ion)m/z:555.40[M-CO 2+H] +； 1H NMR(400MHz,CDCl 3)δ7.50(d,J＝8.8Hz,2H),7.08–7.03(m,2H),7.03–6.98(m,1H),6.93(d,J＝8.8Hz,2H),6.87–6.76(m,3H),6.56(t,J＝73.2Hz,1H),4.74(dd,J＝8.1,2.5Hz,1H),3.60(dd,J＝13.9,2.6Hz,1H),3.44(dd,J＝13.9,8.3Hz,1H),2.04–1.98(m,2H),1.83–1.67(m,4H),1.66–1.47(m,4H).
实施例41:4-((S)-6-(3-氟-5-(三氟甲氧基)苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000109
步骤1：2-(3-氟-5-(三氟甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的合成
将3-氟-5-(三氟甲氧基)溴苯(500mg,1.93mmol)、联硼酸频那醇酯(1.74mg,2.90mmol)、醋酸钾(284mg,2.90mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(79mg,0.10mmol),混合在1,4-二氧六环(1.0mL)中，氮气保护下85℃搅拌6h。冷却至室温，反应液中加入水(50mL)，用石油醚(50mL×3)萃取反应液，合并有机相，无水硫酸钠干燥有机相，减压浓缩得到黄色液体，硅胶柱层析(洗脱剂：PE)纯化得黄色液体(390mg,产率：66.02％).GC-MS(EI,pos.ion)m/z:306.1[M] +； 1H NMR(400MHz,CDCl 3)δ7.47–7.40(m,2H),7.03(d,J＝9.0Hz,1H),1.34(s,12H)..
步骤2：N-(3',4-二氟-5'-(三氟甲氧基)-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺的合成
将N-(5-溴-2-氟苯基)-3-(三氟甲基)苯磺酰胺(1000mg,1.93mmol)、2-(3-氟-5-(三氟甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(845mg,2.76mmol)、碳酸钾(1041mg,7.53mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(102mg,0.13mmol),混合在1,4-二氧六环(5.0mL)和水(1.0mL)中,氮气保护下85℃搅拌2h。冷却至室温，加水(50mL),用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，减压旋蒸浓缩得到黄色液体，硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得黄色固体(845mg,产率：67.69％)。LC-MS(ESI,neg.ion)m/z:496.10[M-H] -； 1H NMR(599MHz,CDCl 3)δ8.07(s,1H),8.00(d,J＝7.9Hz,1H),7.84(d,J＝7.8Hz,1H),7.75(dd,J＝7.3,2.2Hz,1H),7.63(t,J＝7.9Hz,1H),7.33–7.28(m,1H),7.18–7.15(m,1H),7.14(s,1H),7.11–7.05(m,2H),6.97(d,J＝8.6Hz,1H).
步骤3：甲基4-(N-(3',4-二氟-5'-(三氟甲氧基)-[1,1'-联苯]-3-基)-N-((3-(三氟甲基)苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将N-(3',4-二氟-5'-(三氟甲氧基)-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺(500mg,1.01mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(417mg,1.52mmol)溶于异丙醇(2.5mL)，缓慢加入N,N-二异丙基乙胺(196mg,1.52mmol)，室温搅拌5h。过滤得得白色固体(588mg,产率：84.18％)。LC-MS(ESI,pos.ion)m/z:693.12[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.95–7.90(m,2H),7.87(d,J＝7.8Hz,1H),7.75(dd,J＝7.1,2.2Hz,1H),7.66(t,J＝8.1Hz,1H),7.53–7.47(m,1H),7.16–7.08(m,3H),6.96(d,J＝8.7Hz,1H),4.64(s,2H),3.69(s,3H),2.09–1.99(m,2H),1.96–1.86(m,4H),1.76–1.63(m,4H).
步骤4：甲基4-((S)-2-((N-(3',4-二氟-5'-(三氟甲氧基)-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(33mg,0.72mmol)溶于二氯甲烷(1.0mL)，冰浴下缓慢加入N,N-二异丙基乙胺(47mg,0.36mmol)，滴加完毕转移到室温加入甲基4-(N-(3',4-二氟-5'-(三氟甲氧基)-[1,1'-联苯]-3-基)-N-((3-(三氟 甲基)苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(50mg,0.07mmol)和氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(0.9mg,1.4umol)，在45℃下回流反应5h.反应液冷却至室温，加入乙酸乙酯(100mL)和水(50mL)稀释，用4M盐酸调节pH＝4，分离有机相，有机相用水(50mL×2)洗涤，无水硫酸钠干燥有机相，滤液减压旋蒸浓缩除去溶剂得黄色固体(46mg,产率：92.04％)。LC-MS(ESI,pos.ion)m/z:694.40[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.95–7.86(m,3H),7.67(t,J＝7.7Hz,1H),7.56–7.51(m,2H),7.18–7.11(m,3H),6.97(d,J＝8.7Hz,1H),3.87–3.81(m,1H),3.65(s,3H),3.63–3.57(m,2H),2.01–1.91(m,2H),1.83–1.62(m,4H),1.58–1.42(m,2H),1.41–1.28(m,2H).
步骤5：4-((S)-6-(3-氟-5-(三氟甲氧基)苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(3',4-二氟-5'-(三氟甲氧基)-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(500mg,0.72mmol)、氢氧化钠(86mg,2.16mmol)和四丁基溴化铵(46mg,0.14mmol)溶于四氢呋喃(2.0mL)中，置于60℃搅拌5h.加入乙酸乙酯(50mL)和饱和食盐水(20mL),用盐酸调节pH<4,分离有机相，有机相用饱和食盐水水洗涤(20mL×2),无水硫酸钠干燥,减压旋蒸除去溶剂,剩余物硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝4/1)纯化得白色固体(335mg,产率：70.54％)。LC-MS(ESI,neg.ion)m/z:658.10[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.06(d,J＝9.4Hz,2H),7.92(d,J＝7.3Hz,1H),7.83(d,J＝7.5Hz,1H),7.68(t,J＝7.7Hz,1H),7.36(d,J＝8.3Hz,1H),7.33–7.24(m,2H),7.06–6.92(m,2H),4.39(d,J＝14.1Hz,1H),3.39(d,J＝10.3Hz,1H),3.31–3.17(m,1H),2.22–2.02(m,2H),1.98–1.87(m,1H),1.87–1.72(m,3H),1.70–1.46(m,3H),1.45–1.35(m,1H).
实施例42:4-((S)-6-(3-氟-5-甲氧基苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000110
步骤1：3-氟-5-溴苯甲醚的合成
将化合物3-羟基3-氟-5-溴苯酚(100mg,0.52mmol)、碘甲烷(111mg,0.78mmol)和碳酸钾(144mg,1.04mmol)混合在N,N-二甲基甲酰胺(1mL)中，置于80℃下搅拌5h.加入水(100mL)稀释，用石油醚(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，减压旋蒸浓缩得到黄色液体(102mg,产率95.68％).GC-MS(EI,pos.ion)m/z:204.1[M] +； 1H NMR(400MHz,CDCl 3)δ7.47–7.40(m,2H),7.03(d,J＝9.0Hz,1H),1.34(s,12H)..
步骤2：2-(3-氟-5-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的合成
将3-氟-5-溴苯甲醚(2.00g,9.76mmol)、联硼酸频那醇酯(2.73g,10.74mmol)、醋酸钾(1.44g,14.64mmol)、醋酸钯(110mg,0.49mmol)和2-二环己基磷-2’-甲基联苯(Mephos)(0.36g,0.98mmol)混合在N,N-二甲基甲酰胺(10mL)中，氮气保护下85℃搅拌6h.冷却至室温，反应液中加入水(50mL)，用石油醚(50mL×3)萃取反应液，合并有机相，无水硫酸钠干燥有机相，减压浓缩得到黄色液体，硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝10/1)纯化得黄色液体(1.48g，产率：60.15％).GC-MS(EI,pos.ion)m/z:252.1[M] +； 1H NMR(400MHz,CDCl 3)δ7.13–7.06(m,2H),6.70(dt,J＝10.7,2.3Hz,1H),3.82(s,3H),1.34(s,12H).
步骤3：N-(3',4-二氟-5'-甲氧基-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺的合成
将N-(5-溴-2-氟苯基)-3-(三氟甲基)苯磺酰胺(1000mg,2.51mmol)、2-(3-氟-5-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(696mg,2.76mmol)、碳酸钾(1041mg,7.53mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(103mg,0.13mmol)混合在1,4-二氧六环(5.0mL)和水(1.0mL) 中，氮气保护下85℃搅拌12h.冷却至室温，加水(50mL)，用乙酸乙酯(50Ml×3)萃取，合并有机相，用无水硫酸钠干燥，减压旋蒸浓缩得到黄色液体，硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得白色固体(758mg,产率：68.11％)。LC-MS(ESI,pos.ion)m/z:444.00[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.05(s,1H),7.97(d,J＝7.9Hz,1H),7.83(d,J＝7.8Hz,1H),7.77(dd,J＝7.4,2.1Hz,1H),7.62(t,J＝7.9Hz,1H),7.32–7.27(m,1H),7.03(t,J＝9.2Hz,1H),6.87(s,1H),6.84–6.78(m,2H),6.63(dt,J＝10.5,1.9Hz,1H),3.86(s,3H).
步骤4：甲基4-(N-(3',4-二氟-5'-甲氧基-[1,1'-联苯]-3-基)-N-((3-(三氟甲基)苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将N-(3',4-二氟-5'-甲氧基-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺(500mg,1.13mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(466mg,1.69mmol)溶于异丙醇(3.0mL)，缓慢加入N,N-二异丙基乙胺(219mg,1.69mmol)，室温搅拌5h。用乙酸乙酯(100mL)和水(20mL)稀释,用4M盐酸调整pH＝4,分离有机相，有机相用水洗涤(50mL×3)，减压旋蒸浓缩溶剂，剩余物进行硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得黄色粘稠液体(585mg,产率：81.19％)。LC-MS(ESI,pos.ion)m/z:638.10[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.95–7.89(m,2H),7.85(d,J＝7.9Hz,1H),7.75(dd,J＝7.2,2.2Hz,1H),7.65(t,J＝7.8Hz,1H),7.52–7.45(m,1H),7.10–7.04(m,1H),6.78(s,1H),6.74(d,J＝9.3Hz,1H),6.63–6.57(m,1H),4.62(s,2H),3.83(s,3H),3.68(s,3H),2.02–1.85(m,5H),1.73–1.62(m,5H).
步骤5：甲基4-((S)-2-((N-(3',4-二氟-5'-甲氧基-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(359mg,7.80mmol)溶于二氯甲烷(1.0mL)，冰浴下缓慢加入N,N-二异丙基乙胺(504mg,3.90mmol)，滴加完毕转移到室温加入化合物甲基4-(N-(3',4-二氟-5'-甲氧基-[1,1'-联苯]-3-基)-N-((3-(三氟甲基)苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(500mg,0.78mmol)和氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(9.92mg,16umol)，在45℃下回流搅拌5h.反应液冷却至室温,加入乙酸乙酯(100mL)和水(50mL)稀释,用4M盐酸调节pH＝4，分离有机相，有机相用水(50mL×3)洗涤，无水硫酸钠干燥有机相，滤液减压旋蒸浓缩除去溶剂得黄色粘稠固体(463mg,产率：92.80％)。LC-MS(ESI,pos.ion)m/z:640.10[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.95–7.89(m,2H),7.87(d,J＝7.6Hz,1H),7.67(t,J＝8.0Hz,1H),7.56–7.48(m,2H),7.15–7.08(m,1H),6.81(s,1H),6.77(d,J＝9.3Hz,1H),6.62(d,J＝10.4Hz,1H),3.85(s,3H),3.88–3.79(m,1H),3.65(s,3H),3.69–3.62(m,1H),3.61–3.53(m,1H),2.01–1.91(m,2H),1.82–1.60(m,4H),1.55–1.30(m,4H).
步骤6：4-((S)-6-(3-氟-5-甲氧基苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(3',4-二氟-5'-甲氧基-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(200mg,0.31mmol)、氢氧化钠(37mg,0.93mmol)和四丁基溴化铵(20mg,0.06mmol)溶于四氢呋喃(1.0mL)中，置于60℃搅拌5h。加入乙酸乙酯(50mL)和饱和食盐水(20mL)，用盐酸调节pH<4，分离有机相，有机相用饱和食盐水水洗涤(20mL×2)，无水硫酸钠干燥，减压旋蒸除去溶剂，剩余物硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝1/1)纯化得白色粉末(115mg,产率：61.26％)。LC-MS(ESI,neg.ion)m/z:604.15[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.04(d,J＝2.0Hz,1H),7.99(s,1H),7.86(d,J＝7.8Hz,1H),7.76(d,J＝7.9Hz,1H),7.61(t,J＝7.8Hz,1H),7.32(dd,J＝8.5,2.1Hz,1H),6.92–6.84(m,3H),6.60(d,J＝10.5Hz,1H),4.33(d,J＝15.8Hz,1H),3.86(s,3H),3.32(d,J＝10.5Hz,1H),3.18(dd,J＝14.2,10.8Hz,1H),2.11–1.99(m,2H),1.79–1.66(m,3H),1.62–1.54(m,1H),1.51–1.42(m,2H),1.37–1.27(m,2H).
实施例43:4-((S)-6-(3-氟-5-异丙氧基苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000111
步骤1：1-溴-3-氟-5-异丙氧基苯的合成
将3-羟基3-氟-5-溴苯酚(2.00g,10.47mmol)、异丙基碘(2.67g,15.71mmol)和碳酸钾(2.89g,20.94mmol)混合在N,N-二甲基甲酰胺(10mL)中，置于80℃下搅拌12h。加入水(100mL)稀释，用石油醚(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，减压旋蒸浓缩得到黄色液体(1.58g,产率：64.79％).GC-MS(EI,pos.ion)m/z:232.0[M] +； 1H NMR(400MHz,CDCl 3)δ6.85–6.78(m,2H),6.53(dt,J＝10.8,2.1Hz,1H),4.49(p,J＝6.1Hz,1H),1.33(d,J＝6.1Hz,6H).
步骤2：3-氟-5-异丙氧基苯硼酸频那醇酯的合成
将1-溴-3-氟-5-异丙氧基苯(2.00g,8.58mmol)、联硼酸频那醇酯(2.40g,9.44mmol)，醋酸钾(1.26g,12.87mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(350mg,0.43mmol)和2-二环己基磷-2’-甲基联苯(0.36g,0.98mmol)混合在1,4-二氧六环(10mL)中，氮气保护下85℃搅拌6h.冷却至室温，反应液中加入水(50mL)，用石油醚(50mL×3)萃取反应液，合并有机相，无水硫酸钠干燥有机相，减压浓缩得到黄色液体，硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝10/1)纯化得黄色液体(1.31g,产率：54.50％).GC-MS(EI,pos.ion)m/z:280.2[M] +； 1H NMR(400MHz,CDCl 3)δ7.14–7.10(m,1H),7.05(dd,J＝8.4,1.8Hz,1H),6.72–6.66(m,1H),4.57(p,J＝6.0Hz,1H),1.36–1.30(m,18H).
步骤3：N-(3',4-二氟-5'-异丙氧基-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺的合成
将N-(5-溴-2-氟苯基)-3-(三氟甲基)苯磺酰胺(1.00g,2.51mmol),3-氟-5-异丙氧基苯硼酸频那醇酯(773mg,2.76mmol)、碳酸钾(1041mg,7.53mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(103mg,0.13mmol)混合在1,4-二氧六环(5.0mL)和水(1.0mL)中，氮气保护下80℃搅拌6h.冷却至室温，加水(100mL)，用乙酸乙酯(100mL×3)萃取，合并有机相，用无水硫酸钠干燥，减压旋蒸浓缩得到黄色液体，硅胶柱层析(洗脱剂：60-90石油醚/乙酸乙酯(v/v)＝10/1)纯化得白色固体(681mg,57.55％)。LC-MS(ESI,pos.ion)m/z:472.10[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.05(s,1H),7.97(d,J＝7.9Hz,1H),7.82(d,J＝7.8Hz,1H),7.76(dd,J＝7.5,2.1Hz,1H),7.61(t,J＝7.9Hz,1H),7.33–7.27(m,1H),7.05–6.99(m,1H),6.89(s,1H),6.81(s,1H),6.76(d,J＝9.3Hz,1H),6.63–6.58(m,1H),4.57(p,J＝6.0Hz,1H),1.37(d,J＝6.1Hz,6H).
步骤4：甲基4-(N-(3',4-二氟-5'-异丙氧基-[1,1'-联苯]-3-基)-N-((3-(三氟甲基)苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将N-(3',4-二氟-5'-异丙氧基-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺(500mg,1.06mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(437mg,1.59mmol)溶于异丙醇(3.0mL)，缓慢加入N,N-二异丙基乙胺(206mg,1.59mmol)，室温搅拌5h.用乙酸乙酯(100mL)和水(20mL)稀释,用4M盐酸调整pH＝4,分离有机相，有机相用水洗涤(50mL×3),减压旋蒸浓缩溶剂，剩余物进行硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得黄色粘稠液体(526mg,产率：74.55％)。LC-MS(ESI,pos.ion)m/z:666.10[M+H] +； 1H NMR(400MHz,Chloroform-d)δ7.96–7.89(m,2H),7.86(d,J＝7.8Hz,1H),7.74(dd,J＝7.3,2.2Hz,1H),7.65(t,J＝7.8Hz,1H),7.51–7.46(m,1H),7.10–7.03(m,1H),6.77(s,1H),6.71(d,J＝9.3Hz,1H),6.58(d,J＝10.7Hz,1H),4.62(s,2H),4.56(p,J＝6.1Hz,1H),3.68(s,3H),2.07–1.99(m,3H),1.95–1.89(m,1H),1.78–1.62(m,6H),1.36(d,J＝6.0Hz,6H).
步骤5：甲基4-((S)-2-((N-(3',4-二氟-5'-异丙氧基-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(410mg,9.00mmol)溶于二氯甲烷(1.0mL)，冰浴下缓慢加入N,N-二异丙基乙胺(580mg,4.55mmol)，滴加完毕转移到室温加入甲基4-(N-(3',4-二氟-5'-异丙氧基-[1,1'-联苯]-3-基)-N-((3-(三氟甲基) 苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(300mg,0.45mmol)和氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(5.7mg,9umol)，在45℃下回流搅拌5h。反应液冷却至室温,加入乙酸乙酯(100mL)和水(50mL)稀释,用4M盐酸调节pH＝4，分离有机相，有机相用水(50mL×3)洗涤，无水硫酸钠干燥有机相，滤液减压旋蒸浓缩除去溶剂得紫色固体(250mg,产率：83.21％)。LC-MS(ESI,pos.ion)m/z:668.45[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.96–7.90(m,2H),7.87(d,J＝7.8Hz,1H),7.67(t,J＝8.0Hz,1H),7.57–7.46(m,2H),7.16–7.08(m,1H),6.79(s,1H),6.74(d,J＝9.3Hz,1H),6.60(d,J＝10.7Hz,1H),4.57(p,J＝6.0Hz,1H),3.84–3.77(m,1H),3.70–3.61(m,1H),3.65(s,3H),3.61–3.52(m,1H),2.03–1.91(m,2H),1.83–1.65(m,4H),1.54–1.40(m,4H),1.37(d,J＝6.0Hz,7H).
步骤6：化合物4-((S)-6-(3-氟-5-异丙氧基苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(3',4-二氟-5'-异丙氧基-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(250mg,0.37mmol)、氢氧化钠(44mg,1.11mmol)和四丁基溴化铵(24mg,0.07mmol)溶于四氢呋喃(1.0mL)中，置于60℃搅拌2h.加入乙酸乙酯(50mL)和饱和食盐水(20mL)，用盐酸调节pH<4，分离有机相，有机相用饱和食盐水水洗涤(20mL×1)，无水硫酸钠干燥，减压旋蒸除去溶剂，剩余物硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝1/1)纯化得黄白色粉末(146mg,产率：62.27％)。LC-MS(ESI,neg.ion)m/z:632.15[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.04(s,1H),7.99(s,1H),7.86(d,J＝7.5Hz,1H),7.76(d,J＝7.7Hz,1H),7.61(t,J＝7.6Hz,1H),7.31(d,J＝8.0Hz,1H),6.94–6.79(m,3H),6.58(d,J＝10.2Hz,1H),4.70–4.51(m,1H),4.33(d,J＝13.9Hz,1H),3.31(d,J＝10.3Hz,1H),3.27–3.10(m,1H),2.16–1.96(m,2H),1.94–1.80(m,1H),1.82–1.67(m,3H),1.61–1.41(m,4H),1.38(d,J＝5.8Hz,6H).
实施例44:4-((S)-6-(3-环丙氧基-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000112
步骤1：1-溴-3-环丙氧基-5-氟苯的合成
将3-羟基3-氟-5-溴苯酚(3.00g,15.71mmol)、环丙基溴(2.85g,23.57mmol)和碳酸铯(10.24g,31.42mmol)混合在N-甲基吡咯烷酮(15mL)中，微波150℃下搅拌8h.加入水(100mL)稀释，用石油醚(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，减压旋蒸浓缩得到黄色液体(1.67g,产率：46.01％).GC-MS(EI,pos.ion)m/z:230.0[M] +； 1H NMR(400MHz,CDCl 3)δ7.00(s,1H),6.88–6.83(m,1H),6.73–6.68(m,1H),3.75–3.67(m,1H),0.83–0.74(m,4H).
步骤2：3-环丙氧基-5-氟苯硼酸频那醇酯的合成
将1-溴-3-环丙氧基-5-氟苯(1.00g,4.33mmol)、联硼酸频那醇酯(1.21g,4.76mmol)，醋酸钾(0.63g,6.50mmol)、醋酸钯(49mg,0.22mmol)和2-二环己基磷-2’-甲基联苯(Mephos)(156mg,0.43mmol)混合在N,N-二甲基甲酰胺(6mL)中,氮气保护下85℃搅拌12h.冷却至室温,反应液中加入水(50mL)，用石油醚(50mL×3)萃取反应液,合并有机相,无水硫酸钠干燥有机相,减压浓缩得到黄色液体,硅胶柱层析(洗脱剂：60-90石油醚/乙酸乙酯(v/v)＝10/1)纯化得黄色液体(783mg,65.02％).GC-MS(EI,pos.ion)m/z:278.1[M] +.
步骤3：N-(3'-环丙氧基-4,5'-二氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺的合成
将N-(5-溴-2-氟苯基)-3-(三氟甲基)苯磺酰胺(1.00g,2.51mmol)、3-环丙氧基-5-氟苯硼酸频那醇酯(768mg,2.76mmol)、碳酸钾(1041mg,7.53mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合 物(103mg,0.13mmol)混合在1,4-二氧六环(5.0mL)和水(1.0mL)中，氮气保护下85℃搅拌2h.冷却至室温，加水(100mL)，用乙酸乙酯(100mL×3)萃取，合并有机相，用无水硫酸钠干燥，减压旋蒸浓缩得到黄色液体，硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得黄色粘稠固体(811mg,产率：68.83％)。LC-MS(ESI,pos.ion)m/z:470.30[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.05(s,1H),7.98(d,J＝8.0Hz,1H),7.82(d,J＝7.9Hz,1H),7.77(dd,J＝7.5,2.3Hz,1H),7.61(t,J＝7.9Hz,1H),7.33–7.26(m,1H),7.06–6.97(m,2H),6.94(t,J＝1.9Hz,1H),6.86–6.78(m,2H),3.82–3.74(m,1H),0.88–0.78(m,4H).
步骤4：甲基4-(N-(3'-环丙氧基-4,5'-二氟-[1,1'-联苯]-3-基)-N-((3-(三氟甲基)苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将N-(3'-环丙氧基-4,,5'-二氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺(500mg,1.07mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(442mg,1.60mmol)溶于异丙醇(2.5mL)，缓慢加入N,N-二异丙基乙胺(207mg,1.60mmol)，室温搅拌12h。用乙酸乙酯(100mL)和水(20mL)稀释，用4M盐酸调整pH＝4,分离有机相，有机相用水洗涤(50mL×3)，减压旋蒸浓缩溶剂，剩余物进行硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得黄色固体(613mg,产率：86.33％)。LC-MS(ESI,pos.ion)m/z:664.45[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.95–7.89(m,2H),7.85(d,J＝7.8Hz,1H),7.76(dd,J＝7.2,2.3Hz,1H),7.64(t,J＝7.7Hz,1H),7.52–7.46(m,1H),7.11–7.03(m,1H),6.90(s,1H),6.82–6.73(m,2H),4.62(s,2H),3.80–3.73(m,1H),3.68(s,3H),2.05–1.99(m,2H),1.95–1.85(m,4H),1.75–1.64(m,4H),0.83–0.78(m,4H).
步骤5：甲基4-((S)-2-((N-(3'-环丙氧基-4,,5'-二氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(690mg,15.00mmol)溶于二氯甲烷(1.0mL)，冰浴下缓慢加入N,N-二异丙基乙胺(970mg,7.50mmol)，滴加完毕转移到室温加入甲基4-(N-(3'-环丙氧基-4,,5'-二氟-[1,1'-联苯]-3-基)-N-((3-(三氟甲基)苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(500mg,0.75mmol)、氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(10mg,15umol)，在45℃下回流搅拌5h。反应液冷却至室温,加入乙酸乙酯(100mL)和水(50mL)稀释，用4M盐酸调节pH＝4，分离有机相，有机相用水(50mL×3)洗涤，无水硫酸钠干燥有机相,滤液减压旋蒸浓缩除去溶剂得紫色固体(425mg,产率：85.13％)。LC-MS(ESI,pos.ion)m/z:666.45[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.95–7.90(m,2H),7.87(d,J＝7.8Hz,1H),7.67(t,J＝8.1Hz,1H),7.55–7.49(m,2H),7.15–7.08(m,1H),6.92(s,1H),6.84–6.76(m,2H),3.86–3.74(m,2H),3.65(s,3H),3.64–3.51(m,2H),2.02–1.91(m,2H),1.83–1.58(m,4H),1.39–1.22(m,4H),0.84–0.79(m,4H).
步骤6：4-((S)-6-(3-环丙氧基-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(3'-环丙氧基-4,,5'-二氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯((250mg,0.38mmol)、氢氧化钠(46mg,1.14mmol)和四丁基溴化铵(25mg,0.08mmol)溶于四氢呋喃(1.0mL)中，置于60℃搅拌5h。加入乙酸乙酯(50mL)和饱和食盐水(20mL)，用盐酸调节pH<4，分离有机相，有机相用饱和食盐水水洗涤(20mL×1)，无水硫酸钠干燥，减压旋蒸除去溶剂，剩余物硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝2/1)纯化得黄色粉末(134mg,产率：55.83％)。LC-MS(ESI,pos.ion)m/z:632.45[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.05(d,J＝1.9Hz,1H),7.99(s,1H),7.85(d,J＝7.9Hz,1H),7.76(d,J＝7.8Hz,1H),7.61(t,J＝7.8Hz,1H),7.32(dd,J＝8.5,2.0Hz,1H),7.02(s,1H),6.89(d,J＝8.5Hz,2H),6.83–6.74(m,1H),4.38–4.28(m,1H),3.83–3.76(m,1H),3.31(d,J＝9.9Hz,1H),3.18(dd,J＝14.2,10.8Hz,1H),2.11–1.99(m,2H),1.81–1.66(m,3H),1.64–1.40(m,3H),1.37–1.25(m,2H),0.82(s,4H).
实施例45:4-((S)-6-(3-环丙氧基-5-(二甲氨基)苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000113
步骤1：3-溴-5-环丙氧基-N,N-二甲基苯胺的合成
将化合物3-羟基3-氟-5-溴苯酚(5.00g,26.18mmol)、环丙基溴(4.75g,39.27mmol)和碳酸铯(17.06g,52.36mmol)混合在N,N-二甲基甲酰(25mL)中，150℃搅拌24h.加入水(100mL)稀释，用石油醚(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，减压旋蒸浓缩得到紫色液体(2.10g,产率：31.32％).GC-MS(EI,pos.ion)m/z:255.0[M] +； 1H NMR(400MHz,CDCl 3)δ6.64(s,1H),6.49(s,1H),6.24(d,J＝2.0Hz,1H),3.70(p,J＝4.5Hz,1H),2.92(s,6H),0.76(d,J＝4.6Hz,4H).
步骤2：3-环丙氧基-5-N,N-二甲氨基苯硼酸频那醇酯的合成
将3-溴-5-环丙氧基-N,N-二甲基苯胺(1.00g,3.90mmol)、联硼酸频那醇酯(1.49g,5.85mmol)、碳酸钾(1.62g,11.70mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物)(159mg,0.20mmol)混合在N,N-二甲基甲酰胺(10mL)中，氮气保护下80℃搅拌6h。冷却至室温，反应液中加入水(50mL)，用石油醚(50mL×3)萃取反应液，合并有机相，无水硫酸钠干燥有机相，减压浓缩得到黄色液体，硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝10/1)纯化得黄色固体(823mg,产率：69.60％).GC-MS(EI,pos.ion)m/z:303.2[M] +； 1H NMR(400MHz,CDCl 3)δ6.94(s,1H),6.86(s,1H),6.47(s,1H),3.80(s,1H),2.95(s,6H),1.34(s,12H),0.75(s,4H).
步骤3：N-(3'-环丙氧基-5'-(二甲氨基)-4-氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺的合成
将N-(5-溴-2-氟苯基)-3-(三氟甲基)苯磺酰胺(1.00g,2.51mmol)、3-环丙氧基-5-N,N-二甲氨基苯硼酸频那醇酯(837mg,2.76mmol)、碳酸钾(1041mg,7.53mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(103mg,0.13mmol)混合在1,4-二氧六环(5.0mL)和水(1.0mL)中，氮气保护下85℃搅拌2h.冷却至室温，加水(100mL)，用乙酸乙酯(100mL×3)萃取，合并有机相，用无水硫酸钠干燥，减压旋蒸浓缩得到黄色液体，硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得黄色固体(790mg,产率：63.65％)。LC-MS(ESI,pos.ion)m/z:495.40[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.04(s,1H),7.97(d,J＝7.9Hz,1H),7.81(d,J＝7.5Hz,2H),7.59(t,J＝7.8Hz,1H),7.34(s,1H),7.04–6.97(m,1H),6.86–6.80(m,1H),6.61(s,1H),6.44(d,J＝11.3Hz,2H),3.80(p,J＝5.7Hz,1H),3.00(s,6H),0.81(s,4H).
步骤4：甲基4-(N-(3'-环丙氧基-5'-(二甲氨基)-4-氟-[1,1'-联苯]-3-基)-N-((3-(三氟甲基)苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将N-(3'-环丙氧基-5'-(二甲氨基)-4-氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺(760mg,1.54mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(636mg,2.31mmol)溶于异丙醇(5mL)，缓慢加入N,N-二异丙基乙胺(299mg,2.31mmol)，室温搅拌5h。用乙酸乙酯(100mL)和水(20mL)稀释，用4M盐酸调整pH＝4，分离有机相，有机相用水洗涤(50mL×3)，减压旋蒸浓缩溶剂，剩余物进行硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得黄色粘稠固体(786mg,产率：74.11％)。LC-MS(ESI,pos.ion)m/z:689.20[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.97(s,1H),7.94(d,J＝7.8Hz,1H),7.83(d,J＝7.8Hz,1H),7.77(dd,J＝7.3,1.9Hz,1H),7.63(t,J＝7.8Hz,1H),7.56–7.50(m,1H),7.08–7.01(m,1H),6.56(s,1H),6.40(s,2H),4.62(s,2H),3.82–3.74(m,1H),3.68(s,3H),2.98(s,6H),2.05–1.99(m,2H),1.96–1.86(m,4H),1.73–1.64(m,4H),0.79(s,4H).
步骤5：甲基4-((S)-2-((N-(3'-环丙氧基-5'-(二甲氨基)-4-氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(672mg,14.6mmol)溶于二氯甲烷(1.0mL)，冰浴下缓慢加入N,N-二异丙基乙胺(944mg,7.30mmol)，滴加完毕转移到室温加入化合物甲基4-(N-(3'-环丙氧基-5'-(二甲氨基)-4-氟-[1,1'-联苯]-3-基)-N-((3-(三氟甲基)苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(500mg,0.73mmol)和氯 [[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(9mg,15umol)，在45℃下回流搅拌5h。反应液冷却至室温，加入乙酸乙酯(100mL)和水(50mL)稀释，用4M盐酸调节pH＝4，分离有机相，有机相用水(50mL×3)洗涤，无水硫酸钠干燥有机相，滤液减压旋蒸浓缩除去溶剂得紫色固体(438mg,产率：86.86％)。LC-MS(ESI,pos.ion)m/z:691.30[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.96(s,1H),7.92(d,J＝7.9Hz,1H),7.86(d,J＝7.7Hz,1H),7.65(t,J＝7.8Hz,1H),7.59–7.54(m,1H),7.52(d,J＝7.2Hz,1H),7.14–7.06(m,1H),6.56(s,1H),6.42(s,2H),3.84–3.75(m,2H),3.65(s,3H),3.57–3.51(m,1H),2.99(s,6H),2.02–1.90(m,2H),1.83–1.63(m,5H),1.55–1.44(m,2H),1.36–1.29(m,2H),0.82–0.76(m,4H).
步骤6：4-((S)-6-(3-环丙氧基-5-(二甲氨基)苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(3'-环丙氧基-5'-(二甲氨基)-4-氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(400mg,0.58mmol)、氢氧化钠(70mg,1.74mmol)和四丁基溴化铵(37mg,0.12mmol)溶于四氢呋喃(1.0mL)中，置于60℃搅拌5h。加入乙酸乙酯(50mL)和饱和食盐水(20mL)，用盐酸调节pH<4，分离有机相，有机相用饱和食盐水水洗涤(20mL×1)，无水硫酸钠干燥，减压旋蒸除去溶剂，剩余物硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝4/1)纯化得白色固体(213mg,产率：55.92％)。LC-MS(ESI,pos.ion)m/z:657.20[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.09(s,1H),7.98(s,1H),7.84(d,J＝7.7Hz,1H),7.77(d,J＝7.8Hz,1H),7.60(t,J＝7.8Hz,1H),7.40–7.33(m,1H),6.87(d,J＝8.5Hz,1H),6.72(s,1H),6.57(s,1H),6.42(s,1H),4.34(d,J＝14.1Hz,1H),3.84–3.78(m,1H),3.32(d,J＝10.4Hz,1H),3.19(dd,J＝14.0,10.8Hz,1H),3.01(s,6H),2.16–1.97(m,2H),1.81–1.65(m,3H),1.63–1.22(m,5H),0.87–0.75(m,4H).
实施例46：4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-8-氟-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000114
步骤1：5-溴-2,3-二氟苯胺的合成
将5-溴-1,2-二氟-3-硝基苯(1.00g,4.20mmol)和铁粉(2.35g,42.00mmol)混于乙酸(5mL)，室温下5h。加入乙酸乙酯(100mL)稀释，通过硅藻土过滤，滤液用水洗涤(50mL×3)，用无水硫酸钠干燥，减压旋蒸浓缩溶剂得黄色液体(711mg,产率：81.39％)。GC-MS(EI,pos.ion)m/z:207.0[M] +； 1H NMR(400MHz,CDCl 3)δ6.73–6.68(m,1H),6.68–6.64(m,1H),3.90(s,2H).
步骤2：N-(5-溴-2,3-二氟苯基)-3-(三氟甲基)苯磺酰胺的合成
将5-溴-2,3-二氟苯胺(1.40g,6.73mmol)和吡啶(1.60g,20.19mmol)溶于二氯甲烷(5mL)，室温下缓慢滴加3-三氟甲基苯磺酰氯(1.81g,7.40mmol)，滴加完毕后在室温下搅拌反应2h。加入乙酸乙酯(100mL)和水(50mL)，用盐酸(4M)调节pH＝4，分离有机相，有机相用水洗涤(50mL×3)，用无水硫酸钠干燥，减压旋蒸浓缩溶剂得黄色固体，硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得白色固体(2.43g,产率：86.76％)。LC-MS(ESI,neg.ion)m/z:414.10[M-H] -；8.17(s,1H),8.10(d,J＝7.9Hz,1H),7.93–7.86(m,1H),7.70(t,J＝7.9Hz,1H),7.54(d,J＝7.8Hz,1H),7.21(t,J＝7.8Hz,1H),6.82(d,J＝6.4Hz,1H).
步骤3：N-(3'-(二氟甲氧基)-4,5,5'-三氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺的合成
将N-(5-溴-2,3-二氟苯基)-3-(三氟甲基)苯磺酰胺(1.00g,2.40mmol)、2-(3-(二氟甲氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(0.86g,3.00mmol)、碳酸钾(1.00g,1.50mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(98mg,0.12mmol)混合在甲苯(5.0mL)和水(1.0mL)中，氮 气保护下90℃搅拌3h。冷却至室温，加水(50mL)，用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，减压旋蒸浓缩得到黄色液体，硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得白色固体(0.82g,产率：68.36％)。LC-MS(ESI,neg.ion)m/z:496.05[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.12(s,1H),8.05(d,J＝7.7Hz,1H),7.87(d,J＝7.6Hz,1H),7.67(t,J＝7.7Hz,1H),7.53(d,J＝5.6Hz,1H),7.34–7.27(m,1H),7.19–7.10(m,1H),7.10–7.00(m,2H),6.90(d,J＝9.1Hz,1H),6.58(t,J＝72.9Hz,1H).
步骤4：甲基4-(N-(3'-(二氟甲氧基)-4,5,5'-三氟-[1,1'-联苯]-3-基)-N-((3-(三氟甲基)苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将N-(3'-(二氟甲氧基)-4,5,5'-三氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯磺酰胺(500mg,1.01mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(417mg,1.52mmol)溶于异丙醇(5mL)，缓慢加入N,N-二异丙基乙胺(196mg,1.52mmol),室温搅拌5h.用乙酸乙酯(50mL)和水(20mL)稀释,用4M盐酸调整pH＝4,分离有机相，有机相用水洗涤(30mL×1),减压旋蒸浓缩溶剂，剩余物进行硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得黄色液体(605mg,产率：86.61％)。LC-MS(ESI,pos.ion)m/z:692.20[M+H] +； 1H NMR(400MHz,CDCl 3)δ7.97–7.91(m,2H),7.89(d,J＝7.6Hz,1H),7.68(t,J＝7.7Hz,1H),7.50(d,J＝5.7Hz,1H),7.39–7.32(m,1H),7.00(d,J＝9.0Hz,1H),6.96(s,1H),6.88(d,J＝9.1Hz,1H),6.56(t,J＝73.0Hz,1H),4.65(s,2H),3.68(s,3H),2.07–1.99(m,2H),1.96–1.86(m,4H),1.76–1.62(m,4H).
步骤5：甲基4-((S)-2-((N-(3'-(二氟甲氧基)-4,5,5'-三氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(400mg,8.70mmol)溶于二氯甲烷(1.0mL)，冰浴下缓慢加入N,N-二异丙基乙胺(562mg,4.35mmol)，滴加完毕转移到室温加入甲基4-(N-(3'-(二氟甲氧基)-4,5,5'-三氟-[1,1'-联苯]-3-基)-N-((3-(三氟甲基)苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(600mg,0.87mmol)和氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(28mg,44umol)，在45℃下回流搅拌5h.反应液冷却至室温，加入乙酸乙酯(100mL)和水(50mL)稀释，用4M盐酸调节pH＝4，分离有机相，有机相用水(50mL×3)洗涤，无水硫酸钠干燥有机相,滤液减压旋蒸浓缩除去溶剂得黄褐色固体(578mg,产率：95.79％)。LC-MS(ESI,pos.ion)m/z:711.20[M+NH 4] +； 1H NMR(400MHz,CDCl 3)δ7.98–7.87(m,3H),7.70(t,J＝8.0Hz,1H),7.43–7.35(m,1H),7.29(d,J＝4.8Hz,1H),7.03(d,J＝9.1Hz,1H),7.00(s,1H),6.89(d,J＝8.8Hz,1H),6.56(t,J＝72.9Hz,1H),3.87(d,J＝7.3Hz,1H),3.65(s,3H),3.63–3.53(m,2H),2.01–1.92(m,2H),1.81–1.61(m,4H),1.41–1.25(m,4H).
步骤6：4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-8-氟-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(3'-(二氟甲氧基)-4,5,5'-三氟-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(500mg,0.72mmol)、氢氧化钠(86mg,2.16mmol)和四丁基溴化铵(46mg,0.14mmol)溶于四氢呋喃(1.0mL)中，置于60℃搅拌5h.加入乙酸乙酯(50mL)和饱和食盐水(20mL)，用盐酸调节pH＝4,分离有机相，有机相用饱和食盐水水洗涤(20mL×1),无水硫酸钠干燥，减压旋蒸除去溶剂，剩余物硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝4/1)纯化得白色固体(302mg,产率：63.59％)。LC-MS(ESI,neg.ion)m/z:658.10[M-H] -； 1H NMR(599MHz,CDCl 3)δ8.01(s,1H),7.89(d,J＝7.1Hz,1H),7.82(s,1H),7.79(d,J＝7.4Hz,1H),7.66(t,J＝7.4Hz,1H),7.18–7.02(m,3H),6.87(d,J＝8.4Hz,1H),6.58(t,J＝73.1Hz,1H),4.39(d,J＝14.3Hz,1H),3.38(d,J＝10.1Hz,1H),3.27–3.15(m,1H),2.11–2.00(m,2H),1.79–1.70(m,3H),1.66–1.57(m,1H),1.55–1.46(m,2H),1.41–1.22(m,2H).
实施例47:4-((S)-6-(3-(二氟甲氧基)-5-甲基苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000115
步骤1：1-溴-3-二氟甲氧基-5-甲苯的合成
将3-溴-5-甲基苯酚(3.00g,16.04mmol)和碳酸钾(6.65g,48.12mmol)混于N,N-二甲基甲酰胺(15mL)搅拌均匀，加入水(3mL)和二氟氯乙酸钠(2.45g,16.04mmol)，100℃下搅拌4h后,补加二氟氯乙酸钠(1.22g,8.02mmol)，100℃搅拌12h.加入水(50mL)，用石油醚萃取(50mL×3)，合并有机相，用无水硫酸钠干燥，减压旋蒸浓缩溶剂，剩余物硅胶柱层析(洗脱剂：石油醚)纯化得无色透明液体(1.09g,产率：28.64％)。GC-MS(EI,pos.ion)m/z:235.8[M] +； 1H NMR(400MHz,CDCl 3)δ7.19(s,1H),7.10(s,1H),6.88(s,1H),6.48(t,J＝73.5Hz,1H),2.34(s,3H).
步骤2：2-(3-(二氟甲氧基)-5-甲基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的合成
将1-溴-3-二氟甲氧基-5-甲苯(1.00g,4.22mmol)、联硼酸频那醇酯(1.61g,6.33mmol)、醋酸钾(0.62g,6.33mmol)、醋酸钯(47mg,0.21mmol)和2-二环己基磷-2’-甲基联苯(154g,0.42mmol)混合在N,N-二甲基甲酰胺(5mL)中，氮气保护下85℃搅拌12h.。加入水(50mL)，用石油醚萃取(50mL×3)，合并有机相，用无水硫酸钠干燥，减压旋蒸浓缩得到黄色液体(0.86g,产率：71.98％)。GC-MS(EI,pos.ion)m/z:284.0[M] +； 1H NMR(400MHz,CDCl 3)δ7.48(s,1H),7.33(s,1H),7.03(s,1H),6.52(t,J＝74.4Hz,1H),2.36(s,3H),1.35(s,12H).
步骤3：甲基4-((S)-2-((N-(3'-(二氟甲氧基)-4-氟-5'-甲基-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将2-(3-(二氟甲氧基)-5-甲基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(298mg,1.05mmol)、甲基4-((S)-2-((N-(5-溴-2-氟苯基)-3-(三氟甲基)苯基磺酰胺)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(500mg,0.84mmol)、碳酸钾(348mg,2.52mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(69mg,0.08mmol)混合在1,4-二氧六环(4.0mL)和水(1.0mL)中，氮气保护下80℃搅拌6h。冷却至室温，加乙酸乙酯(50mL)稀释，有机相用饱和食盐水(50mL×3)洗涤，用无水硫酸钠干燥，减压旋蒸浓缩得到黄色液体，硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得白色固体(425mg,产率：75.33％)。LC-MS(ESI,pos.ion)m/z:689.20[M+H 2O] +； 1H NMR(400MHz,CDCl 3)δ7.96–7.91(m,2H),7.88(d,J＝7.8Hz,1H),7.67(t,J＝8.1Hz,1H),7.57–7.51(m,1H),7.49(dd,J＝7.1,1.9Hz,1H),7.16–7.09(m,2H),7.02(s,1H),6.95(s,1H),6.54(t,J＝73.9Hz,1H),3.81(d,J＝9.4Hz,1H),3.65(s,3H),3.69–3.60(m,1H),3.55(d,J＝12.5Hz,1H),2.42(s,3H),2.01–1.89(m,2H),1.84–1.75(m,1H),1.69–1.61(m,2H),1.56–1.43(m,2H),1.40–1.28(m,3H).
步骤4：4-((S)-6-(3-(二氟甲氧基)-5-甲基苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(3'-(二氟甲氧基)-4-氟-5'-甲基-[1,1'-联苯]-3-基)-3-(三氟甲基)苯基磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(450mg,0.67mmol)、氢氧化钠(80mg,2.01mmol)和四丁基溴化铵(43mg,0.13mmol)溶于四氢呋喃(1.0mL)中，置于60℃搅拌5h。加入乙酸乙酯(50mL)和饱和食盐水(20mL)，用盐酸调节pH＝4，分离有机相，有机相用饱和食盐水水洗涤(20mL×1)，无水硫酸钠干燥，减压旋蒸除去溶剂，剩余物硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝5/1)纯化得白色固体(245mg,产率：57.35％)。LC-MS(ESI,neg.ion)m/z:636.10[M-H] -； 1H NMR(400MHz,CDCl 3)δ8.08–7.98(m,2H),7.86(d,J＝7.7Hz,1H),7.77(d,J＝7.8Hz,1H),7.62(t,J＝7.8Hz,1H),7.32(dd,J＝8.5,1.7Hz,1H),7.24(s,1H),7.11(s,1H),6.95–6.86(m,2H),6.56(t,J＝74.1Hz,1H),4.34(d,J＝14.1Hz,1H),3.33(d,J＝10.2Hz,1H),3.19(dd,J＝14.2,10.8Hz,1H),2.43(s,3H),2.13–1.99(m,2H),1.80–1.67(m,3H),1.63–1.52(m,1H),1.52–1.41(m,2H),1.39–1.30(m,1H),1.29–1.25(m,1H).
实施例48:4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸钠的合成
Figure PCTCN2022103288-appb-000116
将4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸(963.0mg,1.50mmol)的MeOH(5mL)溶液缓慢滴加到NaOH(62.0mg,1.48mmol)的MeOH(5mL)溶液中，室温反应14h。减压浓缩，得到白色固体(982.0mg，产率98.59％)。LC-MS(ESI,neg.ion)m/z:640.0[M-H] -.
实施例49:4-((S)-7-(3-(二氟甲氧基)-5-氟苯基)-1-((3-(三氟甲基)苯基)磺酰基)-2,3-二氢-1H-吡啶[2,3-b][1,4]恶嗪-3-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000117
步骤1：N-(5-溴-2-氟吡啶-3-基)-3-(三氟甲基)苯磺酰胺的合成
将5-溴-2-氟吡啶-3-胺(3.00g,15.71mmol)和吡啶(3.72g,47.08mmol)溶于丙酮(20mL)，室温下缓慢滴加3-三氟甲基苯磺酰氯(4.23g,17.28mmol)，滴加完毕后在室温下搅拌反应6h。加入乙酸乙酯(50mL)和水(20mL)，用盐酸(4M)调节pH＝4,分离有机相，有机相用水洗涤(20mL×3),用无水硫酸钠干燥，减压旋蒸浓缩溶剂得黄色固体，硅胶柱层析(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)纯化得白色固体(4.51g,产率71.92％)。LC-MS(ESI,pos.ion)m/z:399.10[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.15(dd,J＝8.6,2.1Hz,1H),8.10(s,1H),7.99(d,J＝6.9Hz,2H),7.89(d,J＝7.8Hz,1H),7.68(t,J＝7.8Hz,1H),7.03(s,1H).
步骤2：N-(5-(3-(二氟甲氧基)-5-氟苯基)-2-氟吡啶-3-基)-3-(三氟甲基)苯磺酰胺的合成
将N-(5-溴-2-氟吡啶-3-基)-3-(三氟甲基)苯磺酰胺(800mg,2.00mmol)、2-(3-(二氟甲氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(720mg,2.50mmol)、醋酸钾(290mg,3.00mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(82mg,0.10mmol)加入在1,4-二氧六环(5.0mL)和水(1.0mL)的混合液中，氮气保护下85℃搅拌6h。冷却至室温，加水(100mL)，用乙酸乙酯(100mL×3)萃取，合并有机相，用无水硫酸钠干燥，减压旋蒸浓缩得到黄色液体，硅胶柱层析(洗脱剂：石油醚/乙酸乙酯(v/v)＝5/1)纯化得黄色固体(438mg,产率：45.59％)。LC-MS(ESI,pos.ion)m/z:481.10[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.15(d,J＝9.1Hz,1H),8.12–8.09(m,2H),8.05–7.94(m,2H),7.88(d,J＝7.9Hz,1H),7.67(t,J＝7.8Hz,1H),7.10–7.04(m,2H),6.96(d,J＝9.1Hz,1H),6.59(t,J＝72.7Hz,1H).
步骤3：甲基4-(N-(5-(3-(二氟甲氧基)-5-氟苯基)-2-氟吡啶-3-基)-N-((3-(三氟甲基)苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将N-(5-(3-(二氟甲氧基)-5-氟苯基)-2-氟吡啶-3-基)-3-(三氟甲基)苯磺酰胺(200mg,0.42mmol)和 4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(173mg,0.42mmol)溶于异丙醇(2mL)，缓慢加入N,N-二异丙基乙胺(81mg,0.63mmol)，室温搅拌5h。用乙酸乙酯(100mL)和水(20mL)稀释，用4M盐酸调整pH＝4，分离有机相，有机相用水洗涤(50mL×3)，减压旋蒸浓缩溶剂，剩余物进行硅胶柱层析(洗脱剂：石油醚/乙酸乙酯(v/v)＝5/1)纯化得黄色液体(110mg,产率：38.82％)。LC-MS(ESI,pos.ion)m/z:675.35[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.37–8.30(m,2H),7.94(s,1H),7.92–7.84(m,2H),7.68(t,J＝7.9Hz,1H),7.14–7.07(m,2H),6.95(d,J＝9.1Hz,1H),6.58(t,J＝72.8Hz,1H),4.63(s,2H),3.69(s,3H),2.09–2.05(m,2H),1.95–1.90(m,2H),1.75–1.65(m,6H).
步骤4：甲基4-((S)-2-((N-(5-(3-(二氟甲氧基)-5-氟苯基)-2-氟吡啶-3-基)-3-(三氟甲基)苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(21mg,0.45mmol)溶于二氯甲烷(1.0mL)，冰浴下缓慢加入N,N-二异丙基乙胺(29mg,0.22mmol)，滴加完毕转移到室温加入甲基4-(N-(3'-环丙氧基-5'-(二甲氨基)-4-氟-[1,1'-联苯]-3-基)-N-((3-(三氟甲基)苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(100mg,0.15mmol)和氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(2mg,3umol)，在45℃下回流搅拌5h。反应液冷却至室温，加入乙酸乙酯(100mL)和水(50mL)稀释，用4M盐酸调节pH＝4，分离有机相，有机相用水(50mL×3)洗涤，无水硫酸钠干燥有机相，滤液减压旋蒸浓缩除去溶剂得黄色液体(100mg,产率：98.53％)。LC-MS(ESI,pos.ion)m/z:677.40[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.36(s,1H),8.11(dd,J＝8.8,2.1Hz,1H),7.95–7.84(m,3H),7.69(t,J＝7.8Hz,1H),7.16–7.09(m,2H),6.95(d,J＝9.1Hz,1H),6.59(t,J＝72.7Hz,1H),3.87(d,J＝9.6Hz,1H),3.69–3.67(m,1H),3.66(s,3H),3.54(dd,J＝14.3,10.1Hz,1H),2.02–1.91(m,3H),1.79–1.62(m,6H),1.60–1.51(m,2H).
步骤5：4-((S)-7-(3-(二氟甲氧基)-5-氟苯基)-1-((3-(三氟甲基)苯基)磺酰基)-2,3-二氢-1H-吡啶[2,3-b][1,4]恶嗪-3-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(5-(3-(二氟甲氧基)-5-氟苯基)-2-氟吡啶-3-基)-3-(三氟甲基)苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(100mg,0.15mmol)、氢氧化钠(18mg,0.45mmol)和四丁基溴化铵(10mg,0.03mmol)溶于四氢呋喃(1.0mL)中，置于60℃搅拌4h.加入乙酸乙酯(50mL)和饱和食盐水(20mL)，用盐酸调节pH<4，分离有机相，有机相用饱和食盐水水洗涤(20mL×1)，无水硫酸钠干燥，减压旋蒸除去溶剂，剩余物硅胶柱层析(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)纯化得白色固体(53mg,产率：54.99％)。LC-MS(ESI,pos.ion)m/z:643.40[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.40(d,J＝2.2Hz,1H),8.27(d,J＝2.1Hz,1H),8.03(s,1H),7.91(d,J＝7.7Hz,1H),7.78(d,J＝8.0Hz,1H),7.68(t,J＝7.9Hz,1H),7.17–7.10(m,2H),6.92(d,J＝9.2Hz,1H),6.59(t,J＝72.9Hz,1H),4.30(dd,J＝14.5,1.9Hz,1H),3.54–3.48(m,1H),3.21(dd,J＝14.5,10.7Hz,1H),2.13–1.98(m,4H),1.85–1.67(m,4H),1.55–1.47(m,2H).
实施例50：4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
Figure PCTCN2022103288-appb-000118
步骤1：N-(6-溴-3-氟吡啶-2-基)-3-(三氟甲基)苯磺酰胺的合成
将6-溴-3-氟吡啶-2-胺(1.00g,5.24mmol)和吡啶(1.24g,15.72mmol)溶于二氯甲烷(10mL)，室温下缓慢滴加3-三氟甲基苯磺酰氯(1.41g,5.76mmol)，滴加完毕后在室温下搅拌反应5h。加入乙酸乙酯(100mL)和水(50mL)，用盐酸(4M)调节pH＝4,分离有机相，有机相用水洗涤(50mL x 1)，用无水硫酸钠干燥，减压旋蒸浓缩溶剂得黄色固体,硅胶柱层析(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)纯化得黄色固体(813mg,产率：38.87％)。LC-MS(ESI,pos.ion)m/z:398.90[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.53(s,1H),8.40(d,J＝7.9Hz,1H),7.88(d,J＝7.7Hz,1H),7.71(t,J＝7.9Hz,1H),7.22(t,J＝8.8Hz,1H),7.09(dd,J＝8.4,2.9Hz,1H).
步骤2：N-(6-(3-(二氟甲氧基)-5-氟苯基)-3-氟吡啶-2-基)-3-(三氟甲基)苯磺酰胺的合成
将N-(6-溴-3-氟吡啶-2-基)-3-(三氟甲基)苯磺酰胺(400mg,1.00mmol)、2-(3-(二氟甲氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(360mg,1.25mmol)、醋酸钾(147mg,1.50mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(41mg,0.50mmol)，加入1,4-二氧六环(5.0mL)和水(1.0mL)的混合溶液中，氮气保护下85℃搅拌6h。冷却至室温，加水(100mL)，用乙酸乙酯(100mL×3)萃取，合并有机相，用无水硫酸钠干燥，减压旋蒸浓缩得到黄色液体，硅胶柱层析(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)纯化得黄色固体(348mg,产率：72.45％)。LC-MS(ESI,pos.ion)m/z:481.30[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.43(s,1H),8.37(d,J＝7.9Hz,1H),7.84(d,J＝7.8Hz,1H),7.67(t,J＝7.9Hz,1H),7.45(t,J＝8.9Hz,1H),7.37–7.27(m,3H),6.91(d,J＝9.0Hz,1H),6.57(t,J＝73.1Hz,1H).
步骤3：甲基4-(N-(6-(3-(二氟甲氧基)-5-氟苯基)-3-氟吡啶-2-基)-N-((3-(三氟甲基)苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯的合成
将N-(6-(3-(二氟甲氧基)-5-氟苯基)-3-氟吡啶-2-基)-3-(三氟甲基)苯磺酰胺(400mg,0.83mmol)和4-(2-溴乙酰基)双环[2.2.1]庚烷-1-羧酸甲酯(343mg,1.24mmol)溶于异丙醇(2mL)，缓慢加入N,N-二异丙基乙胺(161mg,1.24mmol)，室温搅拌12h。用乙酸乙酯(50mL)和水(20mL)稀释，用盐酸(4M)调整pH＝4，分离有机相，有机相用水洗涤(30mL×1)，减压旋蒸浓缩溶剂，剩余物进行硅胶柱层析(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)纯化得黄色固体(369mg,产率：65.90％)。LC-MS(ESI,pos.ion)m/z:675.13[M+H] +； 1H NMR(599MHz,CDCl 3)δ8.05(d,J＝8.0Hz,1H),7.98(s,1H),7.88(d,J＝7.8Hz,1H),7.69(t,J＝7.9Hz,1H),7.65–7.60(m,2H),7.21–7.16(m,2H),6.87(d,J＝8.9Hz,1H),6.51(t,J＝73.0Hz,1H),4.80(s,2H),3.67(s,3H),2.02–1.95(m,2H),1.88–1.83(m,2H),1.72–1.64(m,3H),1.64–1.58(m,2H).
步骤4：甲基4-((S)-2-((N-(6-(3-(二氟甲氧基)-5-氟苯基)-3-氟吡啶-2-基)-3-(三氟甲基)苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯的合成
将甲酸(203mg,4.40mmol)溶于二氯甲烷(1.0mL)，冰浴下缓慢加入N,N-二异丙基乙胺(284mg,2.20mmol)，滴加完毕转移到室温加入甲基4-(N-(6-(3-(二氟甲氧基)-5-氟苯基)-3-氟吡啶-2-基)-N-((3-(三氟甲基)苯基)磺酰基)甘氨酰基)双环[2.2.1]庚烷-1-羧酸酯(300mg,0.44mmol)、氯[[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](对甲苯磺酰基)氨基)](对伞花烃)钌(II)(14mg,22umol)，在45℃下回流搅拌12h.反应液冷却至室温,加入乙酸乙酯(100mL)和水(50mL)稀释，用4M盐酸调节pH＝4，分离有机相，有机相用水(50mL×3)洗涤，无水硫酸钠干燥有机相，滤液减压旋蒸浓缩除去溶剂得黄褐色粘稠固体(266mg,产率：89.35％)。LC-MS(ESI,pos.ion)m/z:677.40[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.01(d,J＝7.8Hz,1H),7.97(s,1H),7.89(d,J＝7.7Hz,1H),7.76(dd,J＝8.5,3.0Hz,1H),7.72–7.67(m,2H),7.24–7.19(m,2H),6.90(d,J＝8.9Hz,1H),6.52(t,J＝73.0Hz,1H),3.77(d,J＝10.1Hz,1H),3.75–3.70(m, 1H),3.64(s,3H),3.60–3.52(m,1H),1.98–1.89(m,2H),1.74–1.60(m,4H),1.52–1.40(m,4H).
步骤5：4-((S)-6-(3-(二氟甲氧基)-5-氟苯基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-2-基)双环[2.2.1]庚烷-1-羧酸的合成
将甲基4-((S)-2-((N-(6-(3-(二氟甲氧基)-5-氟苯基)-3-氟吡啶-2-基)-3-(三氟甲基)苯基)磺酰胺基)-1-羟乙基)双环[2.2.1]庚烷-1-羧酸酯(250mg,0.37mmol)、氢氧化钠(44mg,1.11mmol)和四丁基溴化铵(24mg,0.07mmol)溶于四氢呋喃(1.0mL)中，置于60℃搅拌5h.加入乙酸乙酯(50mL)和饱和食盐水(20mL),用盐酸调节pH＝4，分离有机相，有机相用饱和食盐水水洗涤(20mL×1)，无水硫酸钠干燥，减压旋蒸除去溶剂，剩余物硅胶柱层析(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)纯化得黄色粉末(38mg,产率：15.98％)。LC-MS(ESI,pos.ion)m/z:643.25[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.32(d,J＝2.1Hz,1H),8.22–8.15(m,1H),7.96(s,1H),7.87(d,J＝7.5Hz,1H),7.73(d,J＝7.9Hz,1H),7.63(t,J＝7.7Hz,1H),7.11–7.03(m,2H),6.86(d,J＝9.1Hz,1H),6.57(t,J＝73.0Hz,1H),4.24(d,J＝16.3Hz,1H),3.44(d,J＝10.4Hz,1H),3.17(dd,J＝14.4,10.6Hz,1H),2.02–1.90(m,2H),1.72–1.59(m,3H),1.58–1.29(m,5H).
本发明化合物的生物活性测试
一、RORγt受体与SRC蛋白结合试验
1.实验原理：
RORγt激动剂活性筛选采用ROR-γt受体与SRC蛋白结合试验方法。实验体系中ROR-γt-LBD蛋白带GST标签(RORγt-LBD-GST)，SRC共激活蛋白带biotin标签(SRC-biotin)，同时分别用Eu标记的anti-GST抗体(Europium anti-GST)结合RORγt-LBD-GST，D2标记的Streptavidin(Streptavidin-D2)结合SRC-biotin。当化合物能有效与ROR-γt-LBD结合并引起构型的改变，增强ROR-γt-LBD与SRC蛋白结合时，由于ROR-γt-LBD与SRC距离的拉近，在激发光的激发条件下，能量能够从供体Eu转移到受体D2上，从而产生较强的TR-FRET信号。相反，当化合物无法有效促进ROR-γt-LBD招募并结合SRC时，能量则无法从供体Eu转移到受体D2上，检测到的TR-FRET信号就会很弱。根据这个实验原理，可以通过TR-FRET信号的强弱来间接判断化合物在蛋白水平对ROR-γt受体与SRC蛋白结合的激活或抑制作用，从而达到筛选有效化合物的目的。
2.实验方法
将化合物用DMSO溶解，并配成10mM的储备液备用，同时配制1×buffer(PBS含5mM DTT，50mM KF，100mM NaCl，0.01％BSA和0.01％Tween-20)备用。用1×buffer配置4×化合物终浓度稀释液(10μM)，3倍梯度稀释，每孔5μl加于384孔板中；用1×buffer配置4×ROR-γt-LBD(20nM)，4×ursolic acid(0.4μM)混合液，每孔5μl加于384孔板中；再用1×buffer准备2×SRC(100nM)，2×Europium anti-GST(1:200)和2×Streptavidin-D2(25nM)混合液，每孔10μl加于384孔板中，1000g离心1min。室温避光孵育4h，在Envision 2104酶标仪读板机上检测665nm和615nm双波长下信号强度Ratio(665nm/615nm)，计算激活率Activity(％)，并计算出E max和EC 50值。
3.实验数据
Activity(％)计算公式如下：
Activity(％)＝(Ratio cmpd-Ratio vehicle)/(Ratio positive-Ratio vehicle)*100％
Ratio cmpd：指测试化合物在665nm/615nm条件下所测数值减去背景值后的数值；
Ratio vehicle：指DMSO空白对照在665nm/615nm条件下所测数值减去背景值后的平均数值；
Ratio positive：指10μM的阳性药(LYC-55716，结构为
Figure PCTCN2022103288-appb-000119
)在665nm/615nm条件下所测数值减去背景值后的平均数值，
其中，将化合物最大激活率Activity(％)定义为E max。
根据结合率运用Graphpad 5.0拟合以下非线性拟合公式来得到化合物的EC 50：
Y＝Bottom+(Top-Bottom)/(1+10^((LogEC 50-X)*HillSlope))
Y：激活率Activity(％)；X：化合物浓度log值。
实验结果如下：
表2本发明实施例化合物的RORγt受体与SRC蛋白结合试验结果
实施例化合物 EC 50(nM) E max％ 实施例化合物 EC 50(nM) E max％
实施例1 14 103 实施例11 6 101.4
实施例2 19 107 实施例12 3 106.6
实施例3异构体1 43 103 实施例13 3 91.2
实施例3异构体2 18 115 实施例14 49 73.8
实施例5 7 118.4 实施例15 4 80.2
实施例6 14 98.1 实施例16 15 73.8
实施例8 14 95.9 实施例18 4 93
实施例9 8 107.8 实施例19 52 88.0
实施例10 56 106.6 实施例22 17 85.2
实施例23 5 92.0 实施例37 4 118
实施例24 5 93.0 实施例38 8 104.6
实施例25 19 96.3 实施例41 8 108.6
实施例26 14 96 实施例42 4 108.8
实施例27 9 102.7 实施例43 13 101.2
实施例28 2 101.7 实施例44 8 113
实施例29 3 85.59 实施例46 4 97.26
实施例31 5 94.8 实施例47 3 105.7
实施例32 4 96.4 实施例48 3 106.6
实施例33 34 80.8 实施例49 1 106.4
实施例34 18 84.2      
实施例35 5 100.8      
实施例36 9 97.7      
实验结论：本发明化合物在蛋白水平对促进RORγt受体招募并结合SRC蛋白具有有较好的激动作用。
二、HEK293T细胞中GAL4-RORγt促进荧光素酶表达实验
1、实验原理：
构建表达RORγt-LBD与GAL4-DBD的融合蛋白载体pBIND-RORγt-LBD，再将其与pGL4.31 载体共转染HEK293T细胞后，RORγt-LBD与GAL4-DBD的共表达融合蛋白会与荧光素酶表达的上游调控序列GAL4UAS结合，从而启动荧光素酶的表达。当化合物能有效激活RORγt时，荧光素酶的表达会增加，检测到的荧光信号也会相应增强。因此，通过检测荧光素酶的表达量，可以确定化合物对RORγt的激活作用。本实验主要是利用Lipo3000脂质体转染方法和单荧光素酶检测系统，检测化合物对RORγt转录活性的影响，从而达到筛选靶向RORγt激动剂的目的。
2、实验方法：
培养HEK293T细胞至80％-90％，将2μg pBIND-RORγt-LBD和5μg pGL4.31质粒按照Lipo3000脂质体转染说明书转染到10cm 2培养盘HEK293T细胞，12-24小时后分盘计数。将转染后的HEK293T细胞用含10％FCS的无酚红DMEM重悬，按20,000细胞/孔的比例接种于96孔板中，每孔90μl，同时加入熊果酸使其终浓度为1μM。加入10μl稀释好的化合物工作液(化合物起始终浓度为5μM，3倍浓度梯度稀释，设置9个浓度点)，另外预留六个孔作阴性对照孔，加入10μl含DMSO不含药液的稀释液；六个孔作阳性对照孔，加入10μl最高给药浓度的阳性对照化合物(LYC55716)。96孔板四周外围的孔不作为试验孔，培养箱孵育24小时后，吸走上清液50μl体积，加入裂解液和荧光素酶底物buffer 50μl/孔，避光反应15min，检测荧光值(RLU,resulting Luminescence)，计算各浓度下化合物对转染细胞表达荧光的激活百分率Activity(％)，并计算EC 50和E max。
Activity(％)＝(RLU cmpd-RLU vehicle)/(RLU positive-RLU vehicle)*100％
RLU cmpd：指测试化合物所测数值RLU；
RLU vehicle：指DMSO空白对照所测RLU平均数值；
RLU positive：指阳性药(LYC-55716)在5μM给药条件下所测RLU平均数值。
其中，将化合物最大激活率Activity(％)定义为E max。
根据结合率运用Graphpad 5.0拟合以下非线性拟合公式来得到化合物的EC 50：
Y＝Bottom+(Top-Bottom)/(1+10^((LogEC 50-X)*HillSlope))
Y：激活率Activity(％)；X：化合物浓度log值。
实验结果如下：
表3本发明实施例化合物激活GAL4-RORγt的实验结果
实施例化合物 EC 50(nM) E max％ 实施例化合物 EC 50(nM)E max％
实施例1 203 145 实施例11 12283.3
实施例2 116 128 实施例12 170106.4
实施例3异构体1 352 74.5 实施例13 25487.9
实施例3异构体2 314 178.3 实施例14 56266.6
实施例4 147 92.6 实施例15 29863.1
实施例5 69 138.9 实施例16 16288
实施例6 114.2 115.6 实施例18 269109
实施例7 64 85.0 实施例19 179142
实施例9 203 144.9 实施例20 493119
实施例10 198 91.5 实施例22 356130.8
实施例23 320 121.1 实施例36 307125.9
实施例24 258 123.1 实施例37 136116.3
实施例25 249 138.2 实施例38 232142.4
实施例26 307 123.7 实施例41 130 109.48
实施例27 276 114.75 实施例42 75 103.72
实施例28 81 83.51 实施例43 179 86.44
实施例29 161 85.49 实施例44 312 134.76
实施例31 137 105.9 实施例46 138 101.2
实施例32 203 98.7 实施例47 99 87.09
实施例34 186 95.9 实施例48 198 103.8
实施例35 139 102.1 实施例49 77 123.0
实验结论：本发明化合物在细胞水平对RORγt受体有较好的激动活性。
三、药代动力学评价
1.试验方法
将C57小鼠隔夜禁食15小时后称重，根据体重进行随机分组，受试化合物配制溶媒为5％DMSO+5％Kolliphor HS15+90％Saline。对于静脉注射给药的试验组，对试验动物给予2mg/kg的剂量；对于口服给药的试验组，对试验动物给予5mg/kg的剂量。然后，在时间点为0、0.083、0.25、0.5、1.0、2.0、5.0、7.0和24小时取静脉血(约0.2mL)，置于EDTAK 2抗凝管中，在11,000rpm离心2分钟，收集血浆，并于-20℃或-70℃下保存。用LC/MS/MS分析各时间点血浆中药物浓度，计算受试化合物在C57小鼠体内药代动力学参数。
本发明化合物的药代动力学性质通过以上试验测试，口服药代动力学参数见表4。
2.试验结果
表4本发明实施例化合物的口服药代动力学参数
Figure PCTCN2022103288-appb-000120
实验结论：本发明化合物在小鼠体内有较高的体内暴露量和较高的血药浓度，说明本发明化合物具有良好的药代动力学性质。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (22)

  1. 一种化合物，其为式(I-A)所示化合物或式(I-A)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
    Figure PCTCN2022103288-appb-100001
    其中：
    Q 1和Q 2各自独立地为CH或N；
    环A 1为C 6-10亚芳基、5-10元亚杂芳基、C 3-12亚碳环基或3-12元亚杂环基；
    X为C 6-10芳基或5-10元杂芳基，且X任选地被1、2、3或4个选自D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6氘代烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代；
    Y为-O-、-C(＝O)-、-CR 4R 5-、-NR 4-、-S-、-S(＝O)-或-S(＝O) 2-；
    Z为CR 4或N；
    L为键、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、C 1-6亚烷基、-C 1-6亚烷基-O-*、-C 1-6亚烷基-NR 4-*、-C 1-6亚烷基-NR 4-C(＝O)-*、-C 1-6亚烷基-C(＝O)-NR 4-*、-C 1-6亚烷基-NR 4-C(＝O)-NR 5-*、-C 1-6亚烷基-C(＝O)-*、-C 1-6亚烷基-S(＝O)-*、-C 1-6亚烷基-S(＝O) 2-*、-C 1-6亚烷基-NR 4-S(＝O) 2-*或-C 1-6亚烷基-S(＝O) 2-NR 4-*，其中“*”表示与环A 2连接；其中所述的各C 1-6亚烷基独立任选地被1、2或3个选自D、F、Cl、Br、I、OH、CN、NH 2、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、氧代、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代；
    环A 2为5-12元亚螺环基、5-12元亚桥环基、亚环己基或亚环庚基；
    各R 2独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)ONa、-C(＝O)OR 5、-C(＝O)R 5、-C(＝O)NR 4R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-C(＝O)NR 4-S(＝O) 2R 5、氧代、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基或5-10元杂芳基；
    R 1和R 3各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基或3-12元杂环基；
    各R 4独立地为H、D、-C(＝O)OR 5a、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基或5-12元杂芳基；
    R 5和R 5a各自独立地为H、D、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基或5-10元杂芳基；
    R 6和R 6a各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基或3-12元杂环基；和
    m、n和q各自独立地为1、2、3或4。
  2. 根据权利要求1所述的化合物，其为式(I)所示化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
    Figure PCTCN2022103288-appb-100002
    其中：
    环A 1为C 6-10亚芳基、5-10元亚杂芳基、C 3-12亚碳环基或3-12元亚杂环基；
    X为C 6-10芳基或5-10元杂芳基，且X任选地被1、2、3或4个选自D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6氘代烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代；
    Y为-O-、-C(＝O)-、-CR 4R 5-、-NR 4-、-S-、-S(＝O)-或-S(＝O) 2-；
    Z为CR 4或N；
    L为键、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、C 1-6亚烷基、-C 1-6亚烷基-O-*、-C 1-6亚烷基-NR 4-*、-C 1-6亚 烷基-NR 4-C(＝O)-*、-C 1-6亚烷基-C(＝O)-NR 4-*、-C 1-6亚烷基-NR 4-C(＝O)-NR 5-*、-C 1-6亚烷基-C(＝O)-*、-C 1-6亚烷基-S(＝O)-*、-C 1-6亚烷基-S(＝O) 2-*、-C 1-6亚烷基-NR 4-S(＝O) 2-*或-C 1-6亚烷基-S(＝O) 2-NR 4-*，其中“*”表示与环A 2连接；其中所述的各C 1-6亚烷基独立任选地被1、2或3个选自D、F、Cl、Br、I、OH、CN、NH 2、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、氧代、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代；
    环A 2为5-12元亚螺环基、5-12元亚桥环基、亚环己基或亚环庚基；
    各R 2独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)ONa、--C(＝O)OR 5、-C(＝O)R 5、-C(＝O)NR 4R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-C(＝O)NR 4-S(＝O) 2R 5、氧代、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、C 6-10芳基或5-10元杂芳基；
    R 1和R 3各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基或3-12元杂环基；
    各R 4独立地为H、D、-C(＝O)OR 5a、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基或5-12元杂芳基；
    R 5和R 5a各自独立地为H、D、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基或5-10元杂芳基；
    R 6和R 6a各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、C 3-12环烷氧基或3-12元杂环基；和
    m、n和q各自独立地为1、2、3或4。
  3. 根据权利要求1或2所述的化合物具有式(II)、(III)、(IV)或(V)所示的结构，或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
    Figure PCTCN2022103288-appb-100003
    Figure PCTCN2022103288-appb-100004
  4. 根据权利要求1-3任意一项所述的化合物，其中，环A 1为亚苯基、亚萘基、亚吡啶基、亚哒嗪基、亚嘧啶基、亚咪唑基、亚吡唑基、亚吡咯基、亚吲哚基、亚喹啉基、亚吡喃基、亚呋喃基、亚环戊基、亚环己基、亚哌啶基、亚吗啉基、亚吡咯烷基或亚哌嗪基。
  5. 根据权利要求1-4任意一项所述的化合物，其中，X为苯基、萘基、吡啶基、哒嗪基、嘧啶基、咪唑基、吡唑基、吡咯基、吲哚基、喹啉基或呋喃基；且X任选地被1、2、3或4个选自D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基、C 1-4氘代烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基、3-7元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代。
  6. 根据权利要求1-5任意一项所述的化合物，其中，X为苯基、萘基、吡啶基、哒嗪基、嘧啶基、咪唑基、吡唑基、吡咯基、吲哚基、喹啉基或呋喃基；且X任选地被1、2、3或4个选自D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH 2CH 2CH 2CH 3、-CH 2CH(CH 3)CH 3、-C(CH 3) 2CH 3、-CH＝CH 2、-CH＝CHCH 3、-CH 2CH＝CH 2、-C≡CH、-C≡CCH 3、-C≡CCH 2CH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 3、-CH 2C(CH 3)(OH)CH 3、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3)CH 3、-OCH 2CH 2CH 2CH 3、-OCD 3、-OCD 2CD 3、-OCH 2CH 2OH、-OCH 2CH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、-OCH 2CH 2CF 3、-OCH 2CH 2CHF 2、-OCHFCHFCH 3、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基的取代基所取代。
  7. 根据权利要求1-6任意一项所述的化合物，其中，
    L为键、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、C 1-4亚烷基、-C 1-4亚烷基-O-*、-C 1-4亚烷基-NR 4-*、-C 1-4亚烷基-NR 4-C(＝O)-*、-C 1-4亚烷基-C(＝O)-NR 4-*、-C 1-4亚烷基-NR 4-C(＝O)-NR 5-*、-C 1-4亚烷基-C(＝O)-*、-C 1-4亚烷基-S(＝O)-*、-C 1-4亚烷基-S(＝O) 2-*、-C 1-4亚烷基-NR 4-S(＝O) 2-*或-C 1-4亚烷基-S(＝O) 2-NR 4-*，其中“*”表示与环A 2连接；其中所述的各C 1-4亚烷基独立任选地被1、2或3个选自D、F、Cl、Br、I、OH、CN、NH 2、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基C 1-4烷氧基、C 1-4 卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基、3-7元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代。
  8. 根据权利要求1-7任意一项所述的化合物，其中，
    L为键、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、-CH 2-、-(CH 2) 2-、-CH 2-O-*、-(CH 2) 2-O-*、-CH 2-NR 4-*、-(CH 2) 2-NR 4-*、-CH 2-NR 4-C(＝O)-*、-CH 2-C(＝O)-NR 4-*、-CH 2-NR 4-C(＝O)-NR 5-*、-CH 2-C(＝O)-*、-CH 2-S(＝O)-*、-CH 2-S(＝O) 2-*、-CH 2-NR 4-S(＝O) 2-*或-CH 2-S(＝O) 2-NR 4-*，其中“*”表示与环A 2连接；其中所述的-CH 2-和-(CH 2) 2-各自独立任选地被1、2或3个选自D、F、Cl、Br、I、OH、CN、NH 2、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、氧代、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH＝CH 2、-CH＝CHCH 3、-CH 2CH＝CH 2、-C≡CH、-C≡CCH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-OCH 3、-OCH 2CH 3、-OCH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基的取代基所取代。
  9. 根据权利要求1-8任意一项所述的化合物，其中，
    环A 2为以下子结构式：
    Figure PCTCN2022103288-appb-100005
    其中，各环A 2子结构式中的“*”表示与L连接；
    Z 1为CH或N；
    Z 2为-CH 2-、-NH-、-S-、-O-、-S(＝O)-或-S(＝O) 2-；
    Z 3和Z 4各自独立地为键、-O-、-NH-、-OCH 2-、-CH 2O-、-CH 2-或-(CH 2) 2-；和
    t和t 1各自独立地为0或1。
  10. 根据权利要求1-9任意一项所述的化合物，其中，
    环A 2为以下子结构式：
    Figure PCTCN2022103288-appb-100006
    Figure PCTCN2022103288-appb-100007
    Figure PCTCN2022103288-appb-100008
    其中，各环A 2子结构式中的“*”表示与L连接。
  11. 根据权利要求1-10所述的化合物，其中，
    各R 2独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)ONa、--C(＝O)OR 5、-C(＝O)R 5、-C(＝O)NR 4R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-C(＝O)NR 4-S(＝O) 2R 5、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基、3-7元杂环基、C 6-10芳基或5-10元杂芳基。
  12. 根据权利要求1-11任意一项所述的化合物，其中，
    各R 2独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)ONa、-C(＝O)OR 5、-C(＝O)R 5、-C(＝O)NR 4R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-C(＝O)NR 4-S(＝O) 2R 5、氧代、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-C(CH 3) 3、-CH 2CH 2CH 2CH 3、-C≡CH、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 3、-CH 2C(CH 3)(OH)CH 3、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH 2CH 2CH 2CH 3、-OCH 2CH 2OH、-OCH 2CH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、-OCH 2CH 2CF 3、-OCH 2CH 2CHF 2、-OCHFCHFCH 3、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基。
  13. 根据权利要求1-12任意一项所述的化合物，其中，
    R 1和R 3各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基、C 1-4 羟基烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基或3-7元杂环基。
  14. 根据权利要求1-13任意一项所述的化合物，其中，
    R 1和R 3各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH＝CH 2、-CH＝CHCH 3、-CH 2CH＝CH 2、-C≡CH、-C≡CCH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-OCH 3、-OCH 2CH 3、-OCH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基或吗啉基。
  15. 根据权利要求1-14任意一项所述的化合物，其中，
    各R 4独立地为H、D、-C(＝O)OR 5a、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-7环烷基、3-7元杂环基、C 6-10芳基或5-6元杂芳基；
    R 5和R 5a各自独立地为H、D、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-7环烷基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；
    R 6和R 6a各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基或3-7元杂环基。
  16. 根据权利要求1-15任意一项所述的化合物，其中，
    各R 4独立地为H、D、-C(＝O)OR 5a、-C(＝O)R 5a、-S(＝O)R 5a、-S(＝O) 2R 5a、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH 2CH 2CH 2CH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 3、-CH 2C(CH 3)(OH)CH 3、环丙基、环戊基、环己基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基；
    R 5和R 5a各自独立地为H、D、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH 2CH 2CH 2CH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 3、-CH 2C(CH 3)(OH)CH 3、环丙基、环戊基、环己基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基；
    R 6和R 6a各自独立地为H、D、F、Cl、Br、I、OH、CN、NO 2、-C(＝O)OR 5、-C(＝O)R 5、-S(＝O)R 5、-S(＝O) 2R 5、-NR 4R 5、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-OCH 3、-OCH 2CH 3、-OCH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基或吗啉基。
  17. 根据权利要求1-16任意一项所述的化合物，其中
    Figure PCTCN2022103288-appb-100009
    为
    Figure PCTCN2022103288-appb-100010
  18. 根据权利要求1-17任意一项所述的化合物，其中X为
    Figure PCTCN2022103288-appb-100011
    其中，R 01和R 02各自独立地为D、F、Cl、Br、I、OH、CN、NO 2、-NR 4R 5、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基、C 1-4氘代烷氧基、C 1-4羟基烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7环烷基、C 3-7环烷氧基、3-7元杂环基、C 6-10芳基或5-10元杂芳基。
  19. 根据权利要求18所述的化合物，其中，R 01和R 02各自独立地为D、F、Cl、Br、I、OH、CN、NO 2、-NH 2、-NH(CH 3)、-N(CH 3) 2、-N(CH 2CH 3) 2、-NH(CH 2CH 3)、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 3、-CH 2CH 2CH 2CH 3、-CH 2CH(CH 3)CH 3、-C(CH 3) 2CH 3、-CH＝CH 2、-CH＝CHCH 3、-CH 2CH＝CH 2、-C≡CH、-C≡CCH 3、-C≡CCH 2CH 3、-CF 3、-CH 2Cl、-CHCl 2、-CH 2CHCl 2、-CH 2OH、-CH(OH)CH 3、-CH 2CH 2OH、-CH 2CH(OH)CH 3、-CH 2C(CH 3)(OH)CH 3、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3)CH 3、-OCH 2CH 2CH 2CH 3、-OCD 3、-OCD 2CD 3、-OCH 2CH 2OH、-OCH 2CH 2CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2OCH 2CH 3、-OCH 2OCH 3、-OCH 2CH 2OCH 3、-OCH 2OCH 2CH 3、-OCF 3、-OCCl 3、-OCHF 2、-OCHCl 2、-OCH 2Cl、-OCH 2CH 2CF 3、-OCH 2CH 2CHF 2、-OCHFCHFCH 3、环丙基、环戊基、环己基、环丙氧基、环戊氧基、吡咯烷基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基或嘧啶基。
  20. 根据权利要求1-19任意一项所述的化合物具有以下其中结构之一，或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
    Figure PCTCN2022103288-appb-100012
    Figure PCTCN2022103288-appb-100013
    Figure PCTCN2022103288-appb-100014
    Figure PCTCN2022103288-appb-100015
  21. 一种药物组合物，其包含权利要求1-20任意一项所述的化合物，任选地进一步包含药学上可接受的载体、辅剂、媒介物或它们的组合。
  22. 权利要求1-20任意一项所述的化合物或权利要求21所述的药物组合物在制备药物中的用途，其中所述药物用于预防、治疗或减轻患者由RORγt介导的疾病，其中所述由RORγt介导的疾病包括癌症、多发性硬化症、类风湿性关节炎、风湿性关节炎、骨关节炎、强直性脊柱炎、牛皮癣、哮喘、自身免疫性疾病、移植物抗宿主病、银屑病、系统性红斑狼疮、炎性肠病、结肠炎、细菌感染、真菌感染、慢性阻塞性肺病、过敏性鼻炎、过敏性皮炎、克罗恩病或川崎病。
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