[go: up one dir, main page]

WO2021136339A1 - 具有双环结构的酰胺类化合物及其在药物中的应用 - Google Patents

具有双环结构的酰胺类化合物及其在药物中的应用 Download PDF

Info

Publication number
WO2021136339A1
WO2021136339A1 PCT/CN2020/141222 CN2020141222W WO2021136339A1 WO 2021136339 A1 WO2021136339 A1 WO 2021136339A1 CN 2020141222 W CN2020141222 W CN 2020141222W WO 2021136339 A1 WO2021136339 A1 WO 2021136339A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
compound
phenyl
atoms
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2020/141222
Other languages
English (en)
French (fr)
Inventor
刘兵
张英俊
黄九忠
肖粤
李少燕
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sunshine Lake Pharma Co Ltd
Original Assignee
Sunshine Lake Pharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sunshine Lake Pharma Co Ltd filed Critical Sunshine Lake Pharma Co Ltd
Publication of WO2021136339A1 publication Critical patent/WO2021136339A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicine, and discloses a kind of amide compound with ROR ⁇ t activity and a bicyclic structure and a preparation method thereof, as well as a pharmaceutical composition containing such compound and its application in medicine.
  • Retinoic acid receptor-related orphan receptors are members of the steroid hormone nuclear receptor super family. Its family includes ROR ⁇ , ROR ⁇ and ROR ⁇ , ROR ⁇ t, RORs includes 4 main regions, these regions are shared by most nuclear receptors, N-terminal A/B domain, DNA-binding domain, hinge domain and ligand Binding domain. Each ROR gene produces its own subtype, which differs only in its N-terminal A/B domain. ROR ⁇ has two subtypes-ROR ⁇ l and ROR ⁇ t.
  • ROR ⁇ 1 is expressed in a variety of tissues, such as thymus, muscle, and kidney, while ROR ⁇ t is only expressed in some immune cells (such as Th17 cells), and is used as a transcription factor for IL-17A and IL-17F, as well as the main source of Th17 cell differentiation. Regulatory factors. Th17 cells are a subset of T helper cells, which preferentially produce the pro-inflammatory cytokines IL-17A, IL-17F, IL-21 and IL-22. Th17 cells and their effector molecules (such as IL-17, IL-21, IL-22, GM-CSF and CCL20) are related to several autoimmune pathogenesis.
  • Th17 cells are associated with multiple sclerosis and rheumatoid
  • autoimmune diseases such as arthritis, psoriasis, asthma, autoimmune diseases and graft-versus-host disease are related to the pathogenesis of inflammatory diseases (Jetten et al., Nucl. Recept. Signal, 2009, 7: e003; Manel et al.,Nat.Immunol,2008,9,641-649), 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 the 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, enhance the levels of pro-inflammatory cytokines, and thereby increase the cytotoxicity of lymphocytes. At the same time, ROR ⁇ t agonists can inhibit the production of regulatory T cells, and these cells inhibit the immune response, so agonists can push the balance of immune response to the direction of 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 co-suppressive 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 through immune responses and prolong the survival time of animals.
  • Co-Stimulatory Molecule such as CD22
  • Lycera was the first company to report the development of ROR ⁇ t small molecule agonists.
  • 2017. announced the launch of a phase 1/2a clinical trial to test its ROR ⁇ t agonist LYC-55716 for the treatment of patients with advanced, relapsed, or refractory solid tumors The effect of.
  • ROR ⁇ t agonists have received attention in anti-tumor.
  • the technical problem solved by the present invention is to provide a class of amide compounds with bicyclic structure with ROR ⁇ t activity, which are compounds represented by formula (I), or stereoisomers of compounds represented by formula (I), Geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs, and pharmaceutical compositions containing such compounds and their applications in medicine,
  • One aspect of the present invention provides a compound, which is a structure as shown in formula (I) or a stereoisomer, geometric isomer, tautomer, and nitrogen oxide of a structure as shown in formula (I), Solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
  • A, B, C, L, R 1 , R 2 , R 3 , R 4 , m and n have the meanings described in the present invention.
  • the ring A of the present invention is * Means connecting to L; ** means connecting to a carbonyl group; wherein X 1 , X 2 and X 3 are each independently selected from CH 2 , NH, S(O) t or O; X 4 , X 5 , X 6 and X 7 are each independently selected from CH or N; wherein t has the meaning described in the present invention.
  • the ring A of the present invention is preferably * Means connecting to L; ** means connecting to a carbonyl group; wherein X 1 , X 2 and X 3 are each independently selected from CH 2 , NH or O; X 4 , X 5 , X 6 and X 7 are each independently selected from CH or N.
  • the ring B described in the present invention is a C 6-10 aryl group or a heteroaryl group consisting of 5-6 atoms.
  • the ring B of the present invention is preferably phenyl, naphthyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl , Tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1,3,5-triazinyl.
  • the ring C described in the present invention is a C 3-6 cycloalkyl group, a heterocyclic group composed of 3-6 atoms, a C 6-10 aryl group, or a heteroaryl group composed of 5-6 atoms. ; Wherein ring C is independently unsubstituted or substituted by 1, 2, 3 or 4 R y ; wherein said R y has the meaning described in the present invention.
  • the ring C of the present invention is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuran Group, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, dioxanyl, morpholinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, phenyl, naphthyl, pyrrolyl, pyridine Group, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl Or 1,3,5-trifluoride,
  • the ring C of the present invention is preferably phenyl, pyrid-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidine -5-yl or pyridazin-3-yl; wherein each ring C is independently unsubstituted or substituted with 1, 2, 3 or 4 R y ; wherein said R y has the meaning described in the present invention.
  • each R y described in the present invention is independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkane Group, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, heterocyclic group composed of 3-6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-10 atoms; wherein each R y is independently unsubstituted or is 1, 2, 3 Or substituted by 4 R d ; wherein the R d has the meaning described in the present invention.
  • each R y described in the present invention is independently preferably selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-4 alkyl, C 1- 4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, ring Propyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, Dioxanyl, morpholinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, phenyl, naphthyl, pyrrol
  • each R y described in the present invention is independently preferably selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, methylamino, ethylamino, methyl Thio, ethylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, nitrogen Etanyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl
  • the L described in the present invention is selected from bond, -NR x -, -O-, *-(CH 2 ) r -C(O)-(CH 2 ) r -, *-(CH 2 ) r -S(O) t -(CH 2 ) r -or C 1-6 alkylene; * means connecting to ring A; wherein said R x , r and t have the meanings described in the present invention.
  • L in the present invention is preferably selected from bond, -NR x -, -O-, -C(O)-, *-C(O)-CH 2 -, *-CH 2- C(O)-, -S(O) 2 -, *-S(O) 2 -CH 2 -, *-CH 2 -S(O) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -or -CH 2 CH 2 CH 2 CH 2 -; * means connecting with ring A.
  • the R x of the present invention is selected from H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkylene, 3-6 atom heterocyclic group, 3-6 atom heterocyclic group-C 1-6 alkylene , C 6-10 aryl, C 6-10 aryl-C 1-6 alkylene, 5-10 heteroaryl or 5-10 heteroaryl-C 1-6 alkyl.
  • each R 3 described in the present invention is independently selected from H, -NO 2 or C 3-6 cycloalkyl.
  • each R a is independently selected from H, deuterium, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-3 alkylene, 3-10 heterocyclic group, (3-10 heterocyclic group)-C 1 -3 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-3 alkylene, 5-10 heteroaryl or (5-10 heteroaryl ) -C 1-3 alkylene.
  • each R b described in the present invention is independently selected from H, deuterium, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-3 alkylene, 3-10 heterocyclic group, (3-10 heterocyclic group)-C 1 -3 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-3 alkylene, 5-10 heteroaryl or (5-10 heteroaryl ) -C 1-3 alkylene.
  • each t described in the present invention is independently 0, 1, or 2.
  • each r described in the present invention is independently 0, 1, 2, 3, or 4.
  • n in the present invention is 0, 1, 2, 3 or 4.
  • n in the present invention is 0, 1, 2, 3, or 4.
  • the compound of the present invention is not any of the following compounds:
  • the compound of the present invention has a structure as shown in formula (II) or a stereoisomer, geometric isomer, tautomer, and nitroxide with a structure as shown in formula (II).
  • Z 1 is CH or N; s is 0, 1 , 2 , 3 or 4; R 1, R 2, R 3 , R 4 , R y , A, L and m have the meanings described in the present invention.
  • the compound described in the present invention is a structure represented by formula (III) or formula (IV) or a stereoisomer of a structure represented by formula (III) or formula (IV), geometric isomers Forms, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs,
  • Z 1 is CH or N; s is 0, 1, 2, 3 or 4; R e , R 3 , R 4 , R y , A, L and m have the meanings described in the present invention.
  • the compound of the present invention is one of the following compounds or the stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites of one of the following compounds, Pharmaceutically acceptable salt or its prodrug:
  • the present invention relates to a pharmaceutical composition, which comprises the compound of formula (I), formula (II), formula (III) or formula (IV) of the present invention, or its stereoisomers, geometric Isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, optionally further comprising pharmaceutically acceptable carriers, adjuvants, vehicles or Their combination.
  • the present invention relates to the use of a compound of formula (I), formula (II), formula (III) or formula (IV) or a pharmaceutical composition thereof in the preparation of a medicine, wherein the medicine is used for prevention and treatment Or alleviate the patient's disease mediated by ROR ⁇ t.
  • the ROR ⁇ t-mediated diseases of the present invention include cancer, multiple sclerosis, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, asthma, autologous Immune disease, graft versus host disease, autoimmune eye disease, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, inflammatory bowel syndrome, colitis, bacterial infection, fungal infection, rigidity Spondylitis, asthma, chronic obstructive pulmonary disease, allergic rhinitis, allergic dermatitis, Crohn’s disease or Kawasaki disease.
  • the tumor or cancer of 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, solid tumor, glioma, nerve Glioblastoma, hepatocellular carcinoma, mastoid nephroma, head and neck tumors, leukemia, lymphoma, myeloma and non-small cell lung cancer.
  • the present invention relates to methods for the preparation, separation and purification of compounds contained in formula (I), formula (II), formula (III) or formula (IV).
  • subject used in the present invention refers to an animal. Typically the animal is a mammal.
  • the subject also refers to primates (such as humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like.
  • the subject is a primate. In other embodiments, the subject is a human.
  • patient used in the present invention refers to humans (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 arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis/trans) isomers, atropisomers, etc. .
  • Chiral refers to a molecule that can not overlap with its mirror image; and “achiral” refers to a molecule that can overlap with its mirror image.
  • Enantiomers refer to two isomers of a compound that cannot overlap but are mirror images of each other.
  • Diastereoisomers are stereoisomers with a pair or multiple chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers.
  • the prefixes d and l or (+) and (-) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (-) or l 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 a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (for example, carbon, etc.) of the compound disclosed in the present invention may exist in a racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration form 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 used as one of the possible isomers or their mixtures, such as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms).
  • 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 have an E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may have a cis or trans configuration.
  • Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physical and chemical properties of the components, for example, by chromatography Method and/or fractional crystallization method.
  • racemate of any final product or intermediate obtained can be resolved into optical enantiomers by a method familiar to those skilled in the art using known methods, for example, by performing diastereomeric salts of the obtained diastereomers. Separate.
  • the racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed.
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • keto-enol tautomerism include interconversion through the recombination of some bond-forming electrons.
  • keto-enol tautomerism are the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • the substituents are independent of each other, that is, the one or more substituents may be different from each other or the same
  • Or "optionally forming a salt with a suitable acid” includes the compound forming a salt with a suitable acid or not forming a salt with any acid, and may 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 optionally substituted with one or more substituents, such as the compounds of the general formula above, or as specific examples, subclasses, and subclasses in the examples.
  • substituents such as the compounds of the general formula above, or as specific examples, subclasses, and subclasses in the examples.
  • a class of compounds can be used interchangeably.
  • substituents such as the compounds of the general formula above, or as specific examples, subclasses, and subclasses in the examples.
  • substituents such as the compounds of the general formula above, or as specific examples, subclasses, and subclasses in the examples.
  • a class of compounds such as the compounds of the general formula above, or as specific examples, subclasses, and subclasses in the examples.
  • substituents such as the compounds of the general formula above, or as specific examples, subclasses, and subclasses in the examples.
  • a class of compounds such as the compounds of the general formula above, or as specific examples,
  • an optional substituent group can be substituted by a substituent 1 at each reasonable substitutable position of the group.
  • substituents 1 selected from specific groups then the substituents can be substituted at each reasonable position in the structural formula with the same or different substitutions.
  • Substituent 1 can be further independently optionally monosubstituted by Substituent 2 or polysubstituted by multiple substituents 2 which are the same or different.
  • C 1 - 6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition of the variable lists “alkyl” or “aryl” it should be understood that the “alkyl” or “aryl” respectively represents the attached Alkylene group or arylene group.
  • alkyl used in the present invention includes saturated linear or branched monovalent hydrocarbon groups of 1-20 carbon atoms, wherein the alkyl group may be independently optionally substituted with 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.
  • the alkyl group contains 1-4 carbon atoms; in other embodiments, 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-
  • alkenyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp 2 double bond, wherein the alkenyl group Groups can be optionally substituted with one or more substituents described in the present invention, including the positioning of "cis” and “tans", or the positioning of "E” and "Z".
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms.
  • alkynyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted by one or more substituents described in the present invention.
  • the alkynyl group contains 2-8 carbon atoms; in other embodiments, the alkynyl group contains 2-6 carbon atoms; in still other embodiments, the alkynyl group contains 2 -4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), etc. .
  • haloalkyl refers to the situation where the alkyl group may be substituted by one or more halogen atoms which may be the same or different. Where the alkyl group has the meaning as described in the present invention, such examples include, but are not limited to, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 3,3 ,3-Trifluoropropyl and so on. The haloalkyl group may be substituted by one or more substituents described in the present invention.
  • amino refers to a group having the formula -NH 2.
  • alkylamino or “alkylamino” includes “N-alkylamino” and "N,N-dialkylamino", in which the hydrogen on the amino group is independently replaced by one or two alkyl groups. Substituted;
  • the alkyl group has the meaning described in the present invention.
  • the alkylamino group is a lower alkylamino group formed by connecting one or two C 1-6 alkyl groups to a nitrogen atom.
  • the alkylamino group is an alkylamino group formed by connecting one or two C 1-4 lower alkyl groups to a nitrogen atom.
  • Suitable alkylamino groups can be monoalkylamino or dialkylamino.
  • Examples of such include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N- Diethylamino, N-methyl N-ethylamino and so on.
  • alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention.
  • the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; in still other embodiments, the alkoxy group The group contains 1-3 carbon atoms.
  • the alkoxy group may be optionally substituted with one or more substituents described in the present invention.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), n-propoxy (n-PrO, n-propyl Oxy, 1-propoxy, -OCH 2 CH 2 CH 3 ), isopropoxy (-OCH(CH 3 ) 2 ) and so on.
  • the alkanoyl group may be optionally substituted with one or more substituents described in the present invention.
  • cycloalkyl refers to a monovalent or multivalent 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 bridging or screwing into a ring.
  • the cycloalkyl group contains 3-10 ring carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 ring carbon atoms; in still other embodiments, the cycloalkyl group contains 3- 6 ring carbon atoms.
  • 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 in the present invention.
  • aryl can refer to monocyclic, bicyclic, and tricyclic carbocyclic ring systems, where at least one ring system is aromatic, and each ring system contains 6-10 carbon atoms.
  • aryl can be used interchangeably with the term “aromatic ring”.
  • the aromatic ring can include phenyl, naphthyl and anthracenyl.
  • the aryl group may be substituted by one or more substituents described in the present invention.
  • C 6-10 aryl group means that the number of carbon atoms in the aryl group is 6-10, and the aryl group has the same definition as above.
  • heteroaryl and “heteroaromatic ring” are used interchangeably herein, and they all refer to a monocyclic, bicyclic, tricyclic or polycyclic ring system, in which a bicyclic heteroaromatic ring, a tricyclic heteroaromatic ring or a tetracyclic heterocyclic ring is used interchangeably.
  • the aromatic ring system forms a ring in a condensed form.
  • the heteroaromatic ring system as a whole is aromatic, and one or more atoms on the ring are independently optionally substituted by heteroatoms (heteroatoms are selected from N, O, P, S, where S or P are independently optional Ground is replaced by one or more oxygen atoms to obtain groups like SO, SO 2 , PO, PO 2 ).
  • the heteroaromatic ring system can be connected to the main structure at any heteroatom or carbon atom to form a stable compound.
  • the heteroaromatic system group can be a monocyclic ring composed of 3-6 atoms, a bicyclic ring composed of 7-10 atoms, or a tricyclic ring composed of 10-15 atoms.
  • a bicyclic ring with 7-10 atoms can be a bicyclic ring [4,5], [5,5], [5,6] or [6,6] system
  • a tricyclic ring with 10-15 atoms can be a tricyclic ring [5,5,6], [5,7,6] or [6,5,6] system.
  • the term "heteroaryl group composed of 5-6 atoms” refers to a heteroaryl group with 5-6 atoms, and at least one heteroatom selected from N, O, S or P. The heteroaryl group has the above definition.
  • the heteroaromatic system includes the following examples, but is not limited to these examples: furanyl (such as furan-2-yl, furan-3-yl, etc.), imidazolyl (Such as N-imidazolyl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, etc.), isoxazolyl (such as isoxazol-3-yl, isoxazol-4-yl, iso Oxazol-5-yl, etc.), oxazolyl (such as oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, etc.), 4-methylisoxazol-5-yl, pyrrole Group (such as N-pyrrolyl, pyrrol-2-yl, pyrrol-3-yl, etc.), pyridyl (such as pyridin-2-yl,
  • heterocyclyl refers to a monocyclic, bicyclic, tricyclic or tetracyclic ring system, in which bicyclic, tricyclic
  • the ring or tetracyclic system forms a ring in the form of fused or bridged or spiro connection, wherein one or more carbon atoms on the ring are independently and optionally substituted by heteroatoms, and the heteroatoms are selected from nitrogen atom (N), oxygen Atom (O), sulfur atom (S), or phosphorus atom (P).
  • N nitrogen atom
  • O oxygen Atom
  • S sulfur atom
  • P phosphorus atom
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • the phosphorus atom of the ring may optionally be oxidized to form a P-oxygen compound.
  • the heterocyclic ring may be fully saturated or contain one or more degrees of unsaturation, but is not aromatic as a whole. For example, in some embodiments, in a bicyclic heterocyclic group, one of the rings is aromatic, and the other ring as a whole is not aromatic.
  • the heterocyclic ring system can be connected to the main structure at any heteroatom or carbon atom to form a stable compound.
  • One or more hydrogen atoms on the ring are independently optionally substituted with one or more substituents described in the present invention.
  • the "heterocyclyl”, “heterocyclic”, “heterocyclic” or “heterocycloalkyl” group is a 3-6 membered monocyclic ring (2-5 carbon atoms and selected from N , O, P, S 1-3 heteroatoms, when the ring is a three-membered ring, there is only one heteroatom), or a bicyclic ring composed of 5-12 atoms (4-11 carbon atoms and optional 1-3 heteroatoms from N, O, P, S).
  • the term "5-12 membered heterocycloalkyl” means that the number of atoms contained in the ring system of the heterocycloalkyl group is 5-12, wherein the heterocyclic group has the above definition.
  • heterocyclic group may be a carbon atom group or a heteroatom group.
  • Heterocyclic group also includes groups formed by condensing a heterocyclic group with a saturated or partially unsaturated ring or heterocyclic ring.
  • heterocycles include, but are not limited to, oxiranyl, pyrrolidinyl, tetrahydrofuranyl (such as tetrahydrofuran-3-yl, etc.), dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, di Hydropyranyl, tetrahydrothiopyranyl, piperidinyl (such as N-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, etc.), Thioxanyl, nitrogen heterocycle Butyl, oxetanyl, thietanyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, morpholinyl (such as N-morpholinyl, 2 -Morpholinyl, 3-morpholinyl, etc.), thiomorpholinyl, piperazinyl (such as N-piperazinyl
  • Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like.
  • cycloalkyl-C 1-6 alkyl "heterocyclyl-C 1-6 alkyl”, “aryl-C 1-6 alkyl”, “heteroaryl-C 1-6 alkyl””Means that cycloalkyl, heterocyclyl, aryl and heteroaryl are connected to the rest of the molecule through -C 1-6 alkyl, wherein -C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl groups all have the meaning as described in the present invention.
  • cycloalkyl-C 1-6 alkyl "heterocyclyl-C 1-6 alkyl”, “aryl-C 1-6 alkyl”, “heteroaryl-C 1-6 alkyl”
  • the "radical” group is optionally substituted with one or more substituents described in this invention.
  • k-atoms or "k-membered” are used interchangeably herein, where k is an integer, typically describing the number of ring atoms in a molecule, and the number of ring atoms in the molecule is k.
  • a 5-12 membered heteroaryl group means a heteroaryl group composed of 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms.
  • piperidinyl is a heterocyclic group composed of 6 ring atoms or a 6-membered heterocyclic group
  • pyridyl is a heteroaryl group composed of 6 ring atoms or a 6-membered heteroaryl group.
  • heteroatom refers to O, S, N, P and Si, including any oxidation state of N, S and P; primary, secondary, tertiary amine and quaternary ammonium salt forms; or on the nitrogen atom in the heterocyclic ring
  • the form in which hydrogen is substituted for example, N (like the N in 3,4-dihydro-2H-pyrrolyl), NH (like the NH in the pyrrolidinyl group) or NR (like the N-substituted pyrrolidinyl group NR).
  • the ring system formed by attaching a substituent to the ring by drawing a bond means that the substituent can be substituted at any substitutable position on the ring.
  • formula (a) represents that y substituents R can be substituted at any position on the pyridine ring that may be substituted. When y is greater than 1, each R can be independently selected from the same or different substituents.
  • the link system formed by connecting the link to the ring means that the link can be connected to the rest of the molecule at any linkable position on the ring system.
  • end A is fixedly connected to U 1
  • end A' can be connected to any possible position on U 2 -U 7.
  • connection points on the ring Ar in formula c that can be connected to the rest of the molecule, for example, as shown in formula c, unless expressly indicated in other ways, formula c can be either E-terminal or The E'end is connected to the rest of the molecule, that is, the connection modes of the two ends can be interchanged.
  • the F terminal in formula d can only be connected to the end marked "*" in the molecule, and the F'end can only be connected to the end marked "**” in the molecule. That is, the connection methods at both ends are not interchangeable.
  • pharmaceutically acceptable means that it is physiologically tolerable when administered to humans and generally does not produce allergies or similar inappropriate reactions, such as gastrointestinal discomfort, dizziness, and the like.
  • pharmaceutically acceptable refers to those approved by a federal regulatory agency or a national government or listed in the US Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, especially in humans.
  • carrier refers to a diluent, adjuvant, excipient or base with which the compound is administered. Suitable drug carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, MeOH, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • esters in the present invention means that the compound represented by formula (I)-formula (IV) containing a hydroxyl group can form a hydrolyzable ester in vivo.
  • esters are, for example, pharmaceutically acceptable esters that are hydrolyzed in the human or animal body to produce the parent alcohol.
  • hydrolyzable ester groups of the compounds represented by formula (I)-formula (IV) containing hydroxyl include, but are not limited to, phosphoric acid groups, acetoxymethoxy, and 2,2-dimethylpropionyloxy Methoxy, alkanoyl, benzoyl, benzylacetyl, alkoxycarbonyl, dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl, etc.
  • nitrogen oxide in the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form nitrogen oxides.
  • nitrogen oxides are nitrogen oxides of tertiary amines or nitrogen oxides of nitrogen-containing heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) 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), in which, for example, an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as DCM.
  • MCPBA m-chloroperoxybenzoic acid
  • prodrug used in the present invention represents the conversion of a compound into a compound represented by formula (I) to formula (IV) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissue.
  • the prodrug compounds of the present invention can be esters.
  • esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, that is, it can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters.
  • these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group.
  • prodrugs please refer to the following documents: T. Higuchiand 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. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
  • the structural formulas of the compounds described in the present invention include enriched isotopes of one or more different atoms.
  • the present invention includes isotopically-labeled compounds, which are equivalent to the compounds described in formula (I)-formula (IV), but one or more atoms are replaced by an atom whose atomic mass or mass number is different from the common atomic mass or mass number in nature. instead.
  • isotopes that can be introduced into the compounds of the present invention 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, and 18 respectively.
  • Isotope-labeled compounds represented by formula (I)-formula (IV) of the present invention and their prodrugs can generally be prepared in this way. When performing the processes disclosed in the following procedures and/or examples and preparation examples, use readily available Isotope-labeled reagents replace non-isotope-labeled reagents.
  • Metal refers to the product obtained by the metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, amidating, deamidating, esterifying, degreasing, enzymatic cleavage, etc. of the administered compound.
  • the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
  • pharmaceutically acceptable salts refers to those salt forms that are obvious to pharmaceutical chemists, that is, they are basically non-toxic and can provide the required pharmacokinetic properties, palatability, absorption, distribution, metabolism Or excretion. Other factors, which are more practical in nature, are also important for selection. These are: the cost of raw materials, the ease of crystallization, yield, stability, hygroscopicity, and the fluidity of the resulting raw material.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known to us in the field, as described in the literature: S.M. Berge et al., describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977.
  • Non-toxic acid salts include, but are not limited to, inorganic acid salts, such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, nitrate, etc., and organic Acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, citrate, benzoate , Mandelate, methanesulfonate, ethanesulfonate, tosylate, sulfosalicylate, etc., or by other methods described in books and literature such as ion exchange to obtain these salts.
  • inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, nitrate, etc.
  • organic Acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, citrate, be
  • salts include adipate, malate, 2-hydroxypropionic acid, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, Borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate Salt, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate , Laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, Pectinate, persulf
  • the present invention also intends to contemplate any quaternary ammonium salts formed by compounds containing N groups.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, aluminum salt and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, 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-methyl reduced glucosamine , Procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidine-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.
  • 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 when a substituent reacts with another functional group, it is usually used to block or protect a particular functionality.
  • amino protecting group refers to a substituent connected to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, and tert-butoxycarbonyl. (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenemethyleneoxycarbonyl (Fmoc).
  • hydroxyl protecting group refers to a substituent of a hydroxyl group used to block or protect the functionality of the hydroxyl group.
  • Suitable protecting groups include acetyl and silyl groups.
  • Carboxyl protecting group refers to the substituent of the carboxyl group used to block or protect the functionality of the carboxyl group.
  • General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) Phosphonyl) ethyl, nitroethyl, etc.
  • protecting groups refer to the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • room temperature 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 pharmaceutical composition of the present invention includes any one of the compounds represented by formula (I), formula (II), formula (III) or formula (IV) of the present invention, and further includes pharmaceutically acceptable excipients
  • excipients such as those used in the present invention, include any solvents, solid excipients, diluents, binders, disintegrating agents, or other liquid excipients, dispersing agents, flavoring or suspending agents, surface Active agents, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for specific target dosage forms.
  • Different excipients can be applied to the preparation of pharmaceutically acceptable compositions and their well-known preparation methods. Except for any conventional excipients that are incompatible with the compounds of the present invention, such as any adverse biological effects or interactions with any other components of the pharmaceutically acceptable composition in a harmful manner, their The use is also within the scope of the present invention.
  • the substances described in the present invention that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum proteins; buffer substances such as phosphate; Glycine; Sorbic acid; Potassium sorbate; Partial glyceride mixture of saturated plant fatty acids; Water; Salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt; colloidal silicon; three Magnesium silicate; polyvinylpyrrolidone; polyacrylate; wax; polyethylene-polyoxypropylene-blocking polymer; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and other Derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt;
  • the compound of the present invention When the compound of the present invention is administered to a mammal such as a human in the form of a medicine, it may be administered in the form of the compound itself or may contain, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient and 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, reduce, ameliorate or eliminate one or more symptoms of a particular disease, disorder or syndrome, or prevent or delay the symptoms described herein. A sufficient amount for the onset of one or more symptoms of the specified disease, disorder or syndrome.
  • a therapeutically effective amount of drugs can reduce the number of cancer cells; inhibit (ie, slow to a certain extent or stop) the infiltration of cancer cells into surrounding organs; inhibit tumor metastasis; inhibit tumor growth to a certain extent; and / Or to a certain extent alleviate one or more symptoms related to cancer.
  • a therapeutically effective amount is an amount sufficient to reduce or alleviate infectious diseases (infectious symptoms caused by bacteria, viruses, and fungi).
  • the regimen of administration can affect what constitutes an effective amount.
  • the compounds of the present invention can be administered to an individual before or after the onset of the disease mediated by ROR ⁇ t.
  • multiple divided doses and staggered doses can be administered daily or sequentially, or can be administered by continuous infusion, or can be administered by bolus injection.
  • the dose of the compound of the present invention can be increased or decreased in proportion to the urgency of the situation for treatment or prevention.
  • the compounds of the present invention can be used to treat the conditions, disorders or diseases described herein, or to prepare pharmaceutical compositions for the treatment of these diseases.
  • the present invention relates to a method of using the compound of the present invention in the treatment of these diseases or a pharmaceutical preparation containing the compound of the present invention for the treatment of these diseases.
  • “Pharmaceutically acceptable carriers” are recognized in the art and include pharmaceutically acceptable materials, compositions or carriers suitable for administering the compound of the present invention to mammals.
  • the carrier includes liquid or solid fillers, diluents, excipients, solvents or encapsulating materials that participate in carrying active ingredients of drugs or transferring them from one organ or part of the body to another organ or another part of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients in the formulation and not harmful 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 carboxymethyl cellulose, 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 Agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer
  • wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate may also be present in the composition, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents and fragrances. , Preservatives and antioxidants.
  • antioxidants examples include: water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxybenzene Methyl ether (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, ⁇ -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 metabisulfite, sodium sulfite, etc.
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxybenzene Methyl ether (BHA), butylated hydroxyto
  • the formulations of the present invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteral administration.
  • the formulation can conveniently be presented in unit dosage form and can be prepared by any method well known in the pharmaceutical art.
  • the amount of active ingredient that can be combined with a carrier material to prepare a single dosage form is generally the amount of the compound that produces a therapeutic effect. Generally speaking, in units of one percent, the amount is about 1% to about 99% of the active ingredient, preferably about 5% to about 70%, and most preferably about 10 to about 30%.
  • the method of preparing these preparations or compositions includes the step of combining the compound of the present invention with a carrier, independently and optionally, and one or more accessory ingredients.
  • a carrier independently and optionally, and one or more accessory ingredients.
  • the formulation is prepared by uniformly and tightly combining the compound of the present invention with a liquid carrier or a very fine solid carrier or both, and then, if necessary, shaping the product.
  • the preparations of the present invention suitable for oral administration can be capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, Or 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 In the form of sucrose and gum arabic) and/or mouthwash, each of which contains a predetermined amount of the compound of the present invention as an active ingredient.
  • the compound of the present invention can also be administered in the form of a bolus, electuary or paste.
  • the active ingredient is combined with one or more pharmaceutically acceptable carriers such as sodium citrate or Mixture of dicalcium phosphate and/or any of the following substances: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; binders, such as carboxymethyl cellulose, alginate , Gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; humectants, such as glycerin; disintegrating agents, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicic acid and sodium carbonate; solution blocking Solution retarding agents, such as paraffin; absorption enhancers, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glycerol monostearate;
  • the pharmaceutical composition may also comprise buffering agents. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.
  • Tablets can be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be made with binders (for example, gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, and disintegrants (for example, sodium starch glycolate or croscarmellose sodium). ), surfactant or dispersant.
  • Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.
  • Tablets and other solid dosage forms of the pharmaceutical composition of the present invention such as dragees, capsules, pills and granules can optionally be scored or coated with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. preparation. They can also be formulated with, for example, hydroxypropyl methylcellulose, other polymer matrices, liposomes and/or microspheres in various proportions that provide the desired release properties in order to provide slow release or control of the active ingredients therein. freed. They can be sterilized, for example, by filtering with a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable vehicle immediately before use.
  • compositions may also optionally contain sunscreens and may be compositions that release the active ingredient only or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner.
  • sunscreens examples include polymer substances and waxes.
  • the active ingredient may also be in microencapsulated form, using one or more of the above-mentioned excipients, if appropriate.
  • Liquid dosage forms of the compounds of the present invention for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage form may also contain 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 water loss Fatty acid esters of sorbitol and mixtures thereof.
  • inert diluents commonly used in the art such as water or other solvents, solubilizers and
  • the oral composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, fragrances, and preservatives.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, fragrances, and preservatives.
  • the suspension may also contain adjuvants, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, soap Soil, agar, tragacanth and their mixtures.
  • adjuvants such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, soap Soil, agar, tragacanth and their mixtures.
  • the formulation of the pharmaceutical composition of the present invention for rectal or vaginal administration may be in the form of suppositories, which may be prepared by combining one or more compounds of the present invention with one or more suitable non-irritating excipients or
  • the carrier including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate
  • the carrier is prepared by mixing, and it is solid at room temperature, but liquid at body temperature, so it will melt and release in the rectum or vagina The active compound.
  • compositions of the present invention suitable for vaginal administration also include vaginal suppositories, tampons, creams, gels, pastes, foams or spray formulations containing suitable carriers known in the art.
  • Dosage forms for topical or transdermal administration of the compound of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants.
  • the active ingredient can be mixed with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants that may be required under sterile conditions.
  • ointments, pastes, creams and gels may also contain excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, and fibers. Element derivatives, polyethylene glycols, siloxanes, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances.
  • Sprays may also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.
  • Transdermal patches have the additional advantage of providing the body with controlled delivery of the compounds of the invention.
  • dosage forms can be prepared by dissolving or dispersing the compound in a suitable solvent.
  • Absorption enhancers can also be used to increase the flux of the compound through the skin.
  • the flow rate of such compounds can be controlled by providing a rate-controlling membrane or dispersing the active compound in a polymer matrix or gel.
  • the scope of the present invention also includes ophthalmic preparations, ophthalmic ointments, powders, solutions and the like.
  • the pharmaceutical composition of the present invention suitable for parenteral administration comprises one or more compounds of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions Preparation or emulsion, or a sterile powder that can be reconstituted into a sterile injectable solution or dispersion immediately before use, which may contain antioxidants, buffers, bacteriostatic agents, and make the preparation isotonic with the recipient’s blood
  • the solute or suspending agent or thickening agent may contain antioxidants, buffers, bacteriostatic agents
  • 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.
  • the proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • the preventive effect of microorganisms can be ensured by including various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It may also be necessary to include isotonic agents such as sugars, sodium chloride, etc. in the composition.
  • prolonged absorption of the injectable pharmaceutical form can be caused by the inclusion of substances that delay absorption, such as aluminum monostearate and gelatin.
  • the absorption rate of the drug will depend on its dissolution rate, which in turn may depend on the crystal size and crystal shape.
  • the prolonged absorption of the drug form administered parenterally can be achieved by dissolving or suspending the drug in an oily base.
  • the injectable depot form is prepared by forming a microencapsulated matrix of the drug in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the specific compound used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.
  • the formulations of the present invention can be administered orally, parenterally, topically or rectally. They are of course administered in a form suitable for each administration route. For example, they are administered in the form of tablets or capsules, by injections, inhalants, ophthalmic lotions, ointments, suppositories, etc., by injection, infusion or inhalation; by lotions or ointments. Topical administration; administered rectally via suppositories. It is preferably administered orally and/or intravenously.
  • parenteral administration means administration methods other than enteral and topical administration, usually by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intrasaccular, orbital Intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspine and intrasternal injections and infusions.
  • systemic administration and “peripheral administration” mean the administration of a compound, drug or other material other than direct administration to the central nervous system, so that it enters the patient's system and thus undergoes metabolism and other similar processes.
  • peripheral administration mean the administration of a compound, drug or other material other than direct administration to the central nervous system, so that it enters the patient's system and thus undergoes metabolism and other similar processes.
  • subcutaneous administration for example, subcutaneous administration.
  • These compounds can be administered to humans and other animals for treatment by any suitable route of administration, including oral, nasal (e.g., in the form of spray), rectum, intravaginal, parenteral, intracisternal, and topical (in powder, ointment). Or drops) administration, the topical administration includes buccal and sublingual administration.
  • the compound of the present invention and/or the pharmaceutical composition of the present invention which can be used in a suitable hydrated form, is formulated into a pharmaceutically acceptable dosage form by conventional methods known to those skilled in the art.
  • the actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be changed to obtain an amount of the active ingredient that can effectively achieve the desired therapeutic response for a specific patient, composition, and mode of administration, and is non-toxic to the patient.
  • the dosage level selected will depend on a variety of factors, including the activity of the specific compound of the invention or its ester, salt or amide used, route of administration, time of administration, excretion rate of the specific compound used, duration of treatment, Other drugs, compounds and/or materials used in combination with the specific compound used, the age, sex, weight, condition, general health and past medical history of the patient being treated, and similar factors well known in the medical field.
  • a physician or veterinarian with ordinary skills in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian can start the dose of the compound of the present invention used in the pharmaceutical composition at a level lower than the dose required to obtain the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.
  • a suitable daily dose of the compound of the present invention will be the amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such effective doses will generally depend on the above-mentioned factors. Generally, the dose of the compound of the present invention for patients is about 0.001 to about 500 mg/kg body weight/day.
  • the effective daily dose of the active compound may be administered in two, three, four, five, six or more sub-doses administered separately throughout the day at appropriate time intervals, optionally, the sub-doses are unit Dosage form.
  • the pharmaceutical composition or combination of the present invention can be a unit dose of about 1-1000 mg of the active ingredient.
  • the therapeutically effective dose of the compound, its pharmaceutical composition or combination depends on the type, weight, age and condition of the individual, the disorder or disease to be treated or its severity. A physician, clinician or veterinarian with ordinary skills can easily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progress of the disorder or disease.
  • the above-mentioned dosage properties can be explained by using favorable mammals such as mice, rats, dogs, monkeys or related organs, tissues or preparations in in vitro and in vivo experiments.
  • the compound of the present invention can be applied in the form of a solution, such as an aqueous solution, in vitro, and can be applied in the intestine, parenterally, advantageously intravenously, for example, as a suspension or an aqueous solution.
  • the dosage in vitro can range from about 10-3 molar to 10-9 molar concentrations.
  • the therapeutically effective amount in the body can be in the range of about 0.1-500 mg/kg or about 1-100 mg/kg depending on the route of administration.
  • the term "individual” as used herein means an animal. Generally, animals are mammals. Individual also means, for example, primates (e.g., human, 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 e.g., human, male or female
  • the individual is a primate. In other embodiments, the individual is a human.
  • the compound of the present invention can be administered alone, it is preferable to administer the compound in the form of a pharmaceutical composition.
  • One or more compounds or compositions provided by the present invention, or a pharmaceutically acceptable derivative thereof, are used in combination with other drug activators for combined therapy for the treatment of the diseases and conditions described herein.
  • An effective amount of a compound or a composition containing a therapeutically effective concentration of a compound formulated for oral, systemic delivery, including parenteral or intravenous delivery, or for local or topical administration, is administered to an individual who exhibits symptoms of a disease or disorder and requires treatment .
  • the amount is effective to treat, control or alleviate one or more symptoms of the disease or condition.
  • 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.
  • the compounds or pharmaceutical compositions disclosed in the present invention can be used to prepare drugs for preventing, treating or alleviating diseases mediated by ROR ⁇ t in patients, mammals, including humans, and diseases mediated by ROR ⁇ t.
  • Such diseases include, but are by no means limited to, including cancer, multiple sclerosis, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, asthma, autoimmune diseases, graft resistance Host disease, autoimmune eye disease, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, inflammatory bowel syndrome, colitis, bacterial infection, fungal infection, ankylosing spondylitis, asthma, chronic Obstructive lung disease, allergic rhinitis, allergic dermatitis, Crohn's disease or Kawasaki disease.
  • the compound or composition of the present invention can be applied, but not limited to, the effective amount of the compound or composition of the present invention is administered to patients to treat, prevent, ameliorate, control or alleviate cancers and infections in mammals, including humans. Sexual diseases and autoimmune diseases.
  • the compound and pharmaceutical composition of the present invention can also be applied to veterinary treatment of pets, introduced species of animals, and mammals in farm animals. Other examples of animals include horses, dogs, and cats.
  • the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, the definitions of the substituents are the compounds represented by formulas (I)-(IV). The following reaction schemes and examples are used to further illustrate the content of the present invention.
  • Anhydrous tetrahydrofuran, anhydrous dioxane, anhydrous toluene, and anhydrous ether are obtained by refluxing and drying with sodium metal.
  • Anhydrous dichloromethane and anhydrous chloroform are obtained by refluxing and drying with calcium hydride.
  • Anhydrous ethyl acetate, anhydrous petroleum ether, anhydrous n-hexane, anhydrous N,N-dimethylacetamide and anhydrous N,N-dimethylformamide are dried with anhydrous sodium sulfate in advance.
  • reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe.
  • the glassware is all dried.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh
  • NMR spectroscopy uses CDC1 3 , d 6 -DMSO, CD 3 OD or d 6 -acetone as solvents (in ppm), and uses TMS (0 ppm) or chloroform (7.25 ppm) as reference standards.
  • MS mass spectrometry
  • the above spectrometer is equipped with Agilent Zorbax SB-C18 column, the specification is 2.1 ⁇ 30mm, 5 ⁇ m.
  • the injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; the HPLC peak is recorded and read by UV-Vis wavelengths at 210 nm and 254 nm.
  • the mobile phases are 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure aqueous solution (phase B).
  • the gradient elution conditions are shown in Table 1:
  • the purification of the compound was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC), with UV detection at 210nm and 254nm, Zorbax SB-C18 column, specification 2.1 ⁇ 30mm, 4 ⁇ m, 10 minutes, flow rate 0.6mL/min , 5-95% (0.1% formic acid acetonitrile solution) (0.1% formic acid aqueous solution), the column temperature is maintained at 40°C.
  • HPLC high performance liquid chromatography
  • X represents a leaving group, and the leaving group includes, but is not limited to, a halogen atom, a methylsulfonyloxy group, a p-toluenesulfonyloxy group, etc.;
  • Compound (f) can be obtained by the synthetic method of Synthetic Scheme 1: Compound (a) and compound (b) undergo nucleophilic reaction to obtain compound (c), compound (c) hydrolyzes the ester group to obtain compound (d), and compound (d) Condensation reaction with compound (e) gives the final product.
  • Step 1 Synthesis of (S)-3-((tert-butoxycarbonyl)amino)-3-(4-ethylsulfonylphenyl)propionic acid
  • Step 2 Synthesis of tert-butyl (S)-(3-amino-1-(4-(ethylsulfonyl)phenyl)-3-oxopropyl)carbamate
  • dichloromethane 300mL was added to dissolve and washed with dilute hydrochloric acid (0.5mol/L, 100mL ⁇ 2). It was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was slurried with dichloromethane (20 mL) overnight and filtered to obtain 12.5 g of white solid, yield: 89%.
  • Step 3 Synthesis of tert-butyl (S)-(2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)carbamate
  • Step 1 Synthesis of methyl 3-(2-ethoxy-2-oxoethoxy)-4-nitrobenzoate
  • Step 2 Synthesis of methyl 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate
  • Step 3 Synthesis of methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate
  • Step 4 Synthesis of 4-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid methyl ester
  • Step 5 Synthesis of 4-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid
  • Step 6 (S)-N-(2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-4-(4-(trifluoromethyl)benzyl)-3, Synthesis of 4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide
  • Step 1 Synthesis of 4-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid methyl ester
  • Step 2 Synthesis of 4-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid
  • Step 3 (S)-N-(2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-4-(4-(trifluoromethyl)phenyl)-3, Synthesis of 4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide
  • Step 1 Synthesis of 4-(2-ethoxy-2-oxoethoxy)-3-nitrobenzoic acid methyl ester
  • Step 2 Synthesis of methyl 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate
  • Step 3 Synthesis of methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate
  • Step 4 Synthesis of 4-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester
  • Step 5 Synthesis of 4-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid
  • Step 6 (S)-N-(2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-4-(4-(trifluoromethyl)benzyl)-3, Synthesis of 4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide
  • Step 1 Synthesis of 4-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester
  • Step 2 Synthesis of 4-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid
  • Step 3 (S)-N-(2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-4-(4-(trifluoromethyl)phenyl)-3, Synthesis of 4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide
  • Step 2 Synthesis of (7-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(4-(trifluoromethyl)phenyl)methanone
  • dichloromethane (4mL) was added to dissolve, and the temperature was lowered to 0°C again, and the reactants were slowly added dropwise to 7-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (300mg, 1.40mmol) and diisopropylethylamine (750 ⁇ L, 4.29mmol) in dichloromethane ( 10mL) in the solution, return to room temperature after dripping, and stir overnight.
  • Step 3 Synthesis of 4-(4-(trifluoromethyl)benzoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid
  • Step 4 (S)-N-(2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-4-(4-(trifluoromethyl)benzoyl)-3 Synthesis of ,4-Dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide
  • Step 1 Synthesis of 7-bromo-4-((4-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine
  • Step 2 Synthesis of 4-((4-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid
  • Step 3 (S)-N-(2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl )-3,4-Dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide
  • Step 2 Synthesis of 7-bromo-4-(4-(trifluoromethyl)phenethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine
  • Step 3 Synthesis of 4-(4-(trifluoromethyl)phenethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid
  • Step 4 (S)-N-(2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-4-(4-(trifluoromethyl)phenethyl)-3 Synthesis of ,4-Dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide
  • Step 1 Synthesis of 4-(2-cyano-5-cyclopropylphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid methyl ester
  • Step 2 Synthesis of 4-(2-cyano-5-cyclopropylphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid
  • Step 3 (S)-N-(2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-4-(2-cyano-5-cyclopropylphenyl)-3 Synthesis of ,4-Dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide
  • Step 3 4-(2,6-Dicyclopropylpyridin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid methyl ester synthesis
  • Step 4 Synthesis of 4-(2,6-dicyclopropylpyridin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid
  • Step 5 (S)-N-(2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-4-(2,6-dicyclopropylpyridin-4-yl)- 3,4-Dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide
  • Step 2 Synthesis of 4-(3,5-dicyclopropylphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid
  • Step 3 (S)-N-(2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-4-(3,5-dicyclopropylphenyl)-3,4 Synthesis of -Dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide
  • Step 1 4-(2-(4-(Trifluoromethyl)phenyl)acetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid Synthesis of methyl ester
  • Step 3 (S)-N-(2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-4-(2-(4-(trifluoromethyl)phenyl) Acetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide
  • Step 1 Synthesis of 7-bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine
  • Step 2 Synthesis of 4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid
  • Step 3 (S)-N-(2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl )-3,4-Dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide
  • Step 1 Synthesis of methyl 3-((3-methyl-2-buten-1-yl)oxy)-4-nitrobenzoate
  • Step 2 Synthesis of 3-(prop-2-ylidene)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid methyl ester
  • Step 3 Synthesis of 3-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid methyl ester
  • Step 6 N-((S)-2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-3-isopropyl-4-(4-(trifluoromethyl)benzene Yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide
  • Step 3 N-((S)-2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-3-isopropyl-4-(4-(trifluoromethyl)benzene Yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide
  • Step 1 Synthesis of 4-(3,5-dicyclopropylphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid
  • Step 2 (S)-3-(4-(3,5-dicyclopropylphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-methan Synthesis of Methyl Amido)-3-(4-(ethylsulfonyl)phenyl)propionate
  • Step 3 (S)-3-(4-(3,5-Dicyclopropylphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-methan Synthesis of Amido)-3-(4-(ethylsulfonyl)phenyl)propionic acid
  • Step 1 (S)-3-(4-(2,6-Dicyclopropylpyridin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine- Synthesis of Methyl 7-formylamino)-3-(4-(ethylsulfonyl)phenyl)propionate
  • Step 2 (S)-3-(4-(2,6-Dicyclopropylpyridin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine- Synthesis of 7-formylamino)-3-(4-(ethylsulfonyl)phenyl)propionic acid
  • Step 1 Synthesis of methyl indoline-5-carboxylate
  • Step 3 (S)-N-(2-cyano-1-(4-(ethylsulfonyl)phenyl)ethyl)-1-(3,5-dicyclopropylphenyl)indoline Synthesis of -5-formamide
  • Step 1 Synthesis of 1-(3,5-dicyclopropylphenyl)-1H-indole-5-carboxylic acid methyl ester
  • Step 1 Synthesis of 1-tert-butyl 6-methyl 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1,6-dicarboxylate
  • Step 2 Synthesis of 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-carboxylic acid methyl ester
  • Step 3 Synthesis of 1-(3,5-dicyclopropylphenyl)-2,3-dihydro-1H-pyridine[2,3-b][1,4]oxazine-6-carboxylic acid
  • Step 4 (R)-1-(3,5-Dicyclopropylphenyl)-N-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-2,3 Synthesis of -Dihydro-1H-pyridine[2,3-b][1,4]oxazine-6-carboxamide
  • the 1-(3,5-dicyclopropylphenyl)-2,3-dihydro-1H-pyridine[2,3-b][1,4]oxazine-6-carboxylic acid (58mg, 0.17mmol ), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62mg, 0.34mmol), 1-hydroxybenzotriazole (50mg, 0.37mmol) and (R)- 2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol (80mg, 0.35mmol) was added to a single-neck flask with a stir bar, and then dichloromethane (6mL) and triethylamine ( 73 ⁇ L, 0.52mmol).
  • the ROR ⁇ t agonist activity screening adopts the ROR- ⁇ t protein receptor binding test method.
  • the ROR- ⁇ t-LBD protein has a GST tag (RORgt-LBD-GST), and the SRC co-activator protein has a biotin tag (SRC-biotin).
  • they are respectively bound with Eu-labeled anti-GST antibody (Europium anti-GST) RORgt-LBD-GST, D2 labeled Streptavidin (Streptavidin-D2) combined with SRC-biotin.
  • the compound When the compound can effectively bind to ROR- ⁇ t-LBD and cause a configuration change, thereby enhancing the recruitment of SRC, due to the closer distance between ROR- ⁇ t-LBD and SRC, under the excitation condition of the excitation light, the energy can be reduced from The donor Eu is transferred to the acceptor D2, thereby generating a strong TR-FRET signal.
  • the strength of the TR-FRET signal can be used to indirectly determine the compound's activation effect on ROR- ⁇ t, so as to achieve the purpose of screening effective compounds.
  • the compound was dissolved in DMSO and prepared into a 10 mM stock solution for later use, and 1 ⁇ buffer (PBS containing 5 mM DTT, 50 mM KF, 100 mM NaCl, 0.01% BSA and 0.01% Tween-20) was prepared for use at the same time.
  • 1 ⁇ buffer PBS containing 5 mM DTT, 50 mM KF, 100 mM NaCl, 0.01% BSA and 0.01% Tween-20
  • E max is the maximum binding rate of the test compound. The following is the calculation formula of the binding rate:
  • X refers to the value of the test compound under the conditions of 665/615 minus the background value
  • Min refers to the average value of the DMSO blank control under the conditions of 665/615 minus the background value
  • Max refers to 10uM The average value of the positive drug under the 665/615 condition after subtracting the background value.
  • the compound of the present invention has good binding activity to ROR ⁇ t protein receptor.
  • HEK293T cells Cultivate HEK293T cells to 80%-90%, and transfect 2 ⁇ g pBIND-ROR ⁇ t-LBD and 5 ⁇ g pGL4.31 plasmid into 10cm2 culture plate HEK293T cells according to Lipo3000 liposome transfection instructions. After 12-24 hours, they are divided into plates and counted.
  • the transfected HEK293T cells were resuspended in phenol red-free DMEM containing 10% FCS and seeded in a 96-well plate at a ratio of 20,000 cells/well, 90 ⁇ l per well, and ursolic acid was added to make the final concentration 1 ⁇ M.
  • the compound of the present invention has good agonistic activity on ROR ⁇ t protein receptor.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Dermatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一类具有RORγt活性的具有双环结构的酰胺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。具体的，提供了如式(I)所示的化合物，或式(I)所示的化合物的立体异构体，几何异构体，互变异构体，氮氧化物，溶剂化物，代谢产物，盐或前药，以及包含这类化合物的药物组合物及它们在药物中的应用。

Description

具有双环结构的酰胺类化合物及其在药物中的应用 技术领域
本发明属于药物领域，公开了一类具有RORγt活性的具有双环结构的酰胺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。
发明背景
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，RORγt，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)表达，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，业内有大量研究，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具有RORγt活性的具有双环结构的酰胺类化合物，其为如式(I)所示的化合物，或式(I)所示的化合物的立体异构体，几何异构体，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，
本发明一方面提供一种化合物，其为如式(I)所示的结构或如式(I)所示结构的立体异构体，几何异构体，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 PCTCN2020141222-appb-000001
其中，A、B、C、L、R 1、R 2、R 3、R 4、m和n具有本发明所述的含义。
在一些实施方案中，本发明所述的环A为
Figure PCTCN2020141222-appb-000002
*表示与L连接；**表示与羰基连接；其中X 1、X 2和X 3各自独立地选自CH 2、NH、S(O) t或O；X 4、X 5、X 6和X 7各自独立地选自CH或N；其中t具有本发明所述的含义。
在一些实施方案中，本发明所述的环A优选地为
Figure PCTCN2020141222-appb-000003
Figure PCTCN2020141222-appb-000004
*表示与L连接；**表示与羰基连接；其中X 1、X 2和X 3各自独立地选自CH 2、NH或O；X 4、X 5、X 6和X 7各自独立地选自CH或N。
在一些实施方案中，本发明所述的环B为C 6-10芳基或5-6个原子组成的杂芳基。
在一些实施方案中，本发明所述的环B优选地为苯基、萘基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基或1,3,5-三嗪基。
在一些实施方案中，本发明所述的环C为C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基；其中环C独立地未被取代或被1、2、3或4个R y所取代；其中所述R y具有本发明所述的含义。
在一些实施方案中，本发明所述的环C优选地为环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、四氢噻吩基、四氢吡喃基、二氧六环基、吗啉基、哌啶基、哌嗪基、六氢嘧啶基、苯基、萘基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基或1,3,5-三嗪基；其中各环C独 立地未被取代或被1、2、3或4个R y所取代；其中所述R y具有本发明所述的含义。
在一些实施方案中，本发明所述的环C优选地为苯基、吡啶-2-基、吡啶-3-基、吡啶-4-基、嘧啶-2-基，嘧啶-4-基，嘧啶-5-基或哒嗪-3-基；其中各环C独立地未被取代或被1、2、3或4个R y所取代；其中所述R y具有本发明所述的含义。
在一些实施方案中，本发明所述的各R y独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；其中各R y独立地未被取代或被1、2、3或4个R d所取代；其中所述R d具有本发明所述的含义。
在一些实施方案中，本发明所述的各R y独立地优选地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、C 2-4烯基、C 2-4炔基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、四氢噻吩基、四氢吡喃基、二氧六环基、吗啉基、哌啶基、哌嗪基、六氢嘧啶基、苯基、萘基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基或1,3,5-三嗪基；其中各R y独立地未被取代或被1、2、3或4个R d所取代；其中所述R d具有本发明所述的含义。
在一些实施方案中，本发明所述的各R y独立地优选地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、三氟甲基、甲氨基、乙氨基、甲硫基、乙硫基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、四氢噻吩基、四氢吡喃基、二氧六环基、吗啉基、哌啶基、哌嗪基、六氢嘧啶基、苯基、萘基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基或1,3,5-三嗪基；其中各R y独立地未被取代或被1、2、3或4个R d所取代；其中所述R d具有本发明所述的含义。
在一些实施方案中，本发明所述的各R d独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-S(＝O) 2R a、-S(＝O) 2NR aR b、C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；其中R a和R b具有本发明所述的含义。
在一些实施方案中，本发明所述的各R d独立地优选地选自氘、F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-S(＝O) 2R a、-S(＝O) 2NR aR b、C 1-4卤代烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、C 2-4烯基、C 2-4炔基、C 3-10环烷基、3-10个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；其中R a和R b具有本发明所述的含义。
在一些实施方案中，本发明所述的各R d独立地优选地选自氘、F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-S(＝O) 2R a、-S(＝O) 2NR aR b、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、三氟甲基、二氟甲基、一氟甲基、三氟甲氧基、二氟甲氧基、一氟甲氧基、甲氨基、乙氨基、甲硫基、乙硫基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、氮杂环戊基、苯基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻唑烷基、吡唑烷基、恶唑烷基、咪唑烷基、异恶唑烷基、哌啶基、哌嗪基、吗啉基、吡咯基、呋喃基、噻吩基、噻唑基、吡唑基、吡啶基或嘧啶基；其中R a和R b具有本发明所述的含义。
在一些实施方案中，本发明所述的L选自键、-NR x-、-O-、*-(CH 2) r-C(O)-(CH 2) r-、*-(CH 2) r-S(O) t-(CH 2) r-或C 1-6亚烷基；*表示与环A连接；其中所述R x、r和t具有本发明所述的含义。
在一些实施方案中，本发明所述的L优选地选自键、-NR x-、-O-、-C(O)-、*-C(O)-CH 2-、*-CH 2-C(O)-、-S(O) 2-、*-S(O) 2-CH 2-、*-CH 2-S(O) 2-、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-或-CH 2CH 2CH 2CH 2-；*表示与环A连接。
在一些实施方案中，本发明所述的R x选自H、氘、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6环烷基-C 1-6亚烷基、3-6个原子组成的杂环基、3-6个原子组成的杂环基-C 1-6亚烷基、C 6-10芳基、C 6-10芳基-C 1-6亚烷基、5-10个原子组成的杂芳基或5-10个原子组成的杂芳基-C 1-6亚烷基。
在一些实施方案中，本发明所述的各R 4独立地选自H、氘、F、Cl、Br、I、-CN、-OH、-NR aR b、-C(＝O)OR f、-C(＝O)R f、-C(＝O)NR aR b、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基或C 1-6烷氨基；其中各R 4独立地未被取代或被1、2、3或4个R c所取代；其中所述R a、R b、R f和R c具有本发明所述的含义。
在一些实施方案中，本发明所述的各R 4独立地优选地选自H、氘、F、Cl、Br、I、-CN、-OH、-NH 2、-NHCH 3、N’N-二甲基氨基、-C(＝O)OH、-C(＝O)OCH 3、-C(＝O)OCH 2CH 3、-C(＝O)H、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟甲基、二氟甲基、一氟甲基、2,2,2-三氟乙基、1,1-二氟乙基、2,2-二氟乙基、1-氟乙基、2-氟乙基、甲氧基、乙氧基、丙氧基、甲硫基、乙硫基、甲氨基、乙氨基、N’N-二甲基氨基、C 1-4卤代烷氧基、C 2-4烯基或C 2-4炔基；其中各R 4独立地未被取代或被1、2、3或4个R c所取代；其中所述R c具有本发明所述的含义。
在一些实施方案中，本发明所述的各R c独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OR f、-C(＝O)NR aR b、-S(＝O) 2R f、-S(＝O) 2NR aR b、C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；其中所述R a、R b和R f具有本发明所述的含义。
在一些实施方案中，本发明所述的各R c独立地优选地选自氘、F、Cl、Br、I、-CN、-NO 2、-OH、-SH、 -NH 2、-C(＝O)OH、-C(＝O)OCH 3、-C(＝O)OCH 2CH 3、-C(＝O)H、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-S(＝O) 2CH 3、-S(＝O) 2CH 2CH 3、-S(＝O) 2NH 2、C 1-4卤代烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、C 2-4烯基、C 2-4炔基、C 3-10环烷基、3-10个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基。
在一些实施方案中，本发明所述的R 1选自H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、-S(＝O) 2-C 1-3烷基、-C(＝O)-C 1-3烷基、-C(＝O)O-C 1-3烷基、-C(＝O)NH-C 1-3烷基、C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 2-6烯基、C 2-6炔基、氰基取代的C 1-6烷基、羧基取代的C 1-6烷基、羟基取代的C 1-6烷基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基，其中各R 1独立地未被取代或被1、2、3或4个R e所取代；其中所述R e具有本发明所述的含义。
在一些实施方案中，本发明所述的R 1优选地选自H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、-CH 2OH、-CH 2CN、-CH 2COOH、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟甲基、二氟甲基、一氟甲基、2,2,2-三氟乙基、1,1-二氟乙基、2,2-二氟乙基、1-氟乙基、2-氟乙基、甲氧基、乙氧基、丙氧基、甲硫基、乙硫基、甲氨基、乙氨基、N’N-二甲基氨基、C 1-4卤代烷氧基、环丙基、环丁基、环戊基、环氧乙烷基、氧杂环丁基或四氢呋喃基，其中各R 1独立地未被取代或被1、2、3或4个R e所取代；其中所述R e具有本发明所述的含义。
在一些实施方案中，本发明所述的R 2选自F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、-S(＝O) 2-C 1-3烷基、-C(＝O)-C 1-3烷基、-C(＝O)O-C 1-3烷基、-C(＝O)NH-C 1-3烷基、C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 2-6烯基、C 2-6炔基、氰基取代的C 1-6烷基、羧基取代的C 1-6烷基、羟基取代的C 1-6烷基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基，其中各R 2独立地未被取代或被1、2、3或4个R e所取代；其中所述R e具有本发明所述的含义。
在一些实施方案中，本发明所述的R 2优选地选自F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、-CH 2OH、-CH 2CN、-CH 2COOH、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟甲基、二氟甲基、一氟甲基、2,2,2-三氟乙基、1,1-二氟乙基、2,2-二氟乙基、1-氟乙基、2-氟乙基、甲氧基、乙氧基、丙氧基、甲硫基、乙硫基、甲氨基、乙氨基、N’N-二甲基氨基、C 1-4卤代烷氧基、环丙基、环丁基、环戊基、环氧乙烷基、氧杂环丁基或四氢呋喃基，其中各R 2独立地未被取代或被1、2、3或4个R e所取代；其中所述R e具有本发明所述的含义。
在一些实施方案中，本发明所述的各R 3独立地选自H、-NO 2或C 3-6环烷基。
在一些实施方案中，本发明所述的各R 3独立地选自氘、F、Cl、Br、I、-CN、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、-S(＝O) 2-C 1-3烷基、-S(＝O)-C 1-3烷基、-C(＝O)-C 1-3烷基、-C(＝O)O-C 1-3烷基、 -C(＝O)NH-C 1-3烷基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 2-6烯基、C 2-6炔基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基，其中各R 3独立地未被取代或被1、2、3或4个R e所取代；其中所述R e具有本发明所述的含义。
在一些实施方案中，本发明所述的各R 3独立地优选地选自氘、F、Cl、Br、I、-CN、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、-S(＝O) 2-CH 3、-S(＝O)-CH 3、-S(＝O) 2-CH 2CH 3或-S(＝O) 2-CH 2CH 2CH 3；其中各R 3独立地未被取代或被1、2、3或4个R e所取代；其中所述R e具有本发明所述的含义。
在一些实施方案中，本发明所述的各R e独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OR a、-S(＝O) 2R a、-C(＝O)NR aR b、-S(＝O) 2NR aR b、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；其中所述R a和R b具有本发明所述的含义。
在一些实施方案中，本发明所述的各R e独立地优选地选自氘、F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)OCH 3、-S(＝O) 2CH 3、-S(＝O) 2CH 2CH 3、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、C 1-4烷硫基、C 2-4烯基、C 2-4炔基、C 3-10环烷基、3-10个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基。
在一些实施方案中，本发明所述的各R a独立地选自H、氘、C 1-6卤代烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10环烷基-C 1-3亚烷基、3-10个原子组成的杂环基、(3-10个原子组成的杂环基)-C 1-3亚烷基、C 6-10芳基、C 6-10芳基-C 1-3亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-3亚烷基。
在一些实施方案中，本发明所述的各R b独立地选自H、氘、C 1-6卤代烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10环烷基-C 1-3亚烷基、3-10个原子组成的杂环基、(3-10个原子组成的杂环基)-C 1-3亚烷基、C 6-10芳基、C 6-10芳基-C 1-3亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-3亚烷基。
各R f独立地选自H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-6卤代烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10环烷基C 1-3烷基、3-10个原子组成的杂环基、(3-10个原子组成的杂环基)-C 1-3亚烷基、C 6-10芳基、C 6-10芳基-C 1-3亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-3亚烷基。
在一些实施方案中，本发明所述的各t独立地为0、1或2。
在一些实施方案中，本发明所述的各r独立地为0、1、2、3或4。
在一些实施方案中，本发明所述的n为0、1、2、3或4。
在一些实施方案中，本发明所述的m为0、1、2、3或4。
在一些实施方案中，本发明所述的化合物不为以下任一化合物：
Figure PCTCN2020141222-appb-000005
在一些实施方案中，本发明所述的化合物为如式(II)所示的结构或如式(II)所示结构的立体异构体，几何异构体，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 PCTCN2020141222-appb-000006
其中，Z 1为CH或N；s为0、1、2、3或4；R 1、R 2、R 3、R 4、R y、A、L和m具有本发明所述的含义。
在一些实施方案中，本发明所述的化合物为如式(III)或式(IV)所示的结构或如式(III)或式(IV)所示结构的立体异构体，几何异构体，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 PCTCN2020141222-appb-000007
其中，Z 1为CH或N；s为0、1、2、3或4；R e、R 3、R 4、R y、A、L和m具有本发明所述的含义。
在一些实施方案中，本发明化合物为以下其中之一的化合物或以下其中之一的化合物的立体异构体，几何异构体，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 PCTCN2020141222-appb-000008
Figure PCTCN2020141222-appb-000009
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)、式(II)、式(III)或式(IV)所述的化合物，或其立体异构体，几何异构体，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。
一方面，本发明涉及式(I)、式(II)、式(III)或式(IV)所述的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、自身免疫性眼病、银屑病、系统性红斑狼疮、多发性硬化症、炎性肠病、炎性肠综合征、结肠炎、细菌感染、真菌感染、强直性脊柱炎、哮喘、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、实体瘤、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)、式(II)、式(III)或式(IV)所包含的化合物的制备、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。其他的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，应当应用本文所使用的下列定义。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文。
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文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“受试对象”是指动物。典型地所述动物是哺乳动物。受试对象，例如也指灵长类动物(例如人类，男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中，所述受试对象是灵长类动物。在其他实施方案中，所述受试对象是人。
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。
“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”对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  ofAsymmetric 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，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只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：氢，氘，氧代，氟，氯，溴，碘，羟基，氨基，羧基，烷基，烷基-S(＝O) z-，卤代烷基，羟基烷基，氨基烷基，醛基，氨基酰基，烷氧基，烷氨基，烷硫基，烷酰基、卤代烷氧基，氰基，芳基，杂芳基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基烷氧基，烷基-(C＝O)-，苄基，环烷基，烷氨基-C(＝O)-，CN-烷基-C(＝O)-，烷基-O-C(＝O)-烷基，酯基，羟基烷基酰基，或烷氧基烷基等。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：氢，氧代，氟，氯，溴，碘，羟基，氨基， 羧基，烷基，烷基-S(＝O) z-，卤代烷基，羟基烷基，氨基烷基，醛基，氨基酰基，烷氧基，烷氨基，烷硫基，卤代烷氧基，氰基，芳基，杂芳基，烯基，炔基，环烷基、杂环基，巯基，硝基，芳氧基，羟基烷氧基，烷基-(C＝O)-，苄基，烷氨基-C(＝O)-，CN-烷基-C(＝O)-，烷基-O-C(＝O)-烷基，酯基，羟基烷基酰基，或烷氧基烷基等。其中，z为0，1，或2。
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“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，即有一个碳-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，这样的实例包括，但并不限于三氟甲基，二氟甲基，一氟甲基，2,2-二氟乙基，3,3,3-三氟丙基等。卤代烷基可以被一个或多个本发明所述的取代基所取代。
术语“氨基”是指具有式-NH 2的基团。
术语“羧基”，无论是单独使用还是和其他术语连用，表示-C(＝O)OH；术语“羰基”，无论是单独使用还是和其他术语连用，表示-(C＝O)-。
术语“烷氨基”或者“烷基氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团上的氢分别独立地被一个或两个烷基基团所取代；所述烷基具有本发明所描述的含义。其中一些实施例是，烷氨基是一个或两个C 1-6烷基连接到氮原子上形成的较低级的烷氨基基团。另外一些实施例是，烷氨基是一个或两个C 1-4的较低级的烷基连接到氮原子上形成的烷氨基基团。合适的烷氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，N-甲氨基、N-乙氨基、N,N-二甲氨基、N,N-二乙基氨基、N-甲基N-乙基氨基等等。
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“烷酰基”、“烷基酰基”或“烷基甲酰基”表示烷基基团通过羰基(-C(＝O)-)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。所述烷酰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。烷酰基基团的实例包括，但并不限于，乙酰基(-C(＝O)CH 3)，丙酰基(-C(＝O)CH 2CH 3)，丁酰基(-C(＝O)CH 2CH 2CH 3)等等；其中，特别的，甲酰基(-C(＝O)H)也包括在烷酰基范围内。
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3-10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“芳基”可以是单环，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。术语“芳基”可以和术语“芳香环”交换使用，如芳香环可以包括苯基，萘基和蒽基。芳基可以被一个或多个本发明所述的取代基所取代。术语“C 6-10芳基”指芳基中碳原子数为6-10个，芳基具有如上定义。
术语“杂芳基”，“杂芳环”在此处可交换使用，都是指单环，双环，三环或者多环体系，其中，双环杂芳环，三环杂芳环或者四环杂芳环体系以稠合的形式成环。其中，杂芳环体系整体是芳香性的，环上一个 或多个原子独立地任选地被杂原子所取代(杂原子选自N、O、P、S、在此S或P独立任选地被一个或多个氧原子所取代得到像SO、SO 2、PO、PO 2的基团)。杂芳环体系可以在任何杂原子或者碳原子上连接到主结构上从而形成稳定的化合物。杂芳体系基团可以是3-6个原子组成的单环，或7-10个原子组成的双环，或10-15个原子组成的三环。具有7-10个原子的双环可以是二环[4,5]，[5,5]，[5,6]或[6,6]体系，具有10-15个原子的三环可以是三环[5,5,6]、[5,7,6]或[6,5,6]体系。术语“5-6个原子组成的杂芳基”指杂芳基中原子数为5-6个，其中至少有一个选自N、O、S或P的杂原子，杂芳基具有如上定义。
另外一些实施例是，杂芳体系(包含杂芳基，杂芳环)包括以下例子，但并不限于这些例子：呋喃基(如呋喃-2-基、呋喃-3-基等)，咪唑基(如N-咪唑基、咪唑-2-基、咪唑-4-基、咪唑-5-基等)，异噁唑基(如异噁唑-3-基、异噁唑-4-基、异噁唑-5-基等)，噁唑基(如噁唑-2-基，噁唑-4-基，噁唑-5-基等)，4-甲基异噁唑-5-基，吡咯基(如N-吡咯基，吡咯-2-基，吡咯-3-基等)，吡啶基(如吡啶-2-基，吡啶-3-基，吡啶-4-基等)，嘧啶基(嘧啶-2-基，嘧啶-4-基，嘧啶-5-基等)，哒嗪基(如哒嗪-3-基)，噻唑基(如噻唑-2-基，噻唑-4-基，噻唑-5-基等)，四唑基(如四唑-5-基等)，三唑基(如1,2,3-三唑-2-基等)，噻吩基(如噻吩-2-基，噻吩-3-基等)，吡唑基(如吡唑-2-基)，异噻唑基，噁二唑基(如1,2,3-噁二唑基等)，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，1,3,4-噻二唑-2-基，吡嗪基(如吡嗪-2-基等)，1,3,5-三嗪基，苯并[d]噻唑-2-基，咪唑并[1,5-a]吡啶-6-基，苯并咪唑基，苯并恶唑基，二苯并呋喃基，咪唑并吡啶基，吲唑基，吲哚嗪基，吲哚基，异喹啉基，异噻唑烷基，异噻唑基，萘啶基，噁唑烷二酮基，噁唑烷基，噁唑并吡啶基，噁唑基，茶嵌二氮苯基，菲啶基，菲绕啉基，吩砒嗪基，吩嗪基，吩噻嗪基，吩噁嗪基，酞嗪基，蝶啶基，吡啶并吡啶基，喹唑啉基，喹噁啉基，硫代苯基，三嗪基，2H-吡咯并[3,4-c]吡啶基，咪唑并[2',1':2,3]噻唑并[4,5-b]吡嗪基，咪唑并[2',1':2,3]噻唑并[5,4-b]吡啶基，咪唑并[2',1':2,3]噻唑并[4,5-c]吡啶基，1H-苯并[f]咪唑并[4,5-b][1,4]硫氮杂
Figure PCTCN2020141222-appb-000010
基等。杂芳基可以被一个或多个本发明所述的取代基所取代。
术语“杂环基”，“杂环”，“杂环的”或“杂环烷基”在此处可交换使用，都是指单环，双环，三环或者四环体系，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，其中环上一个或多个碳原子独立任选地被杂原子所取代，所述杂原子选自氮原子(N)、氧原子(O)、硫原子(S)或磷原子(P)。且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。环的磷原子可以任选地被氧化成P-氧化合物。所述杂环可以是完全饱和的或包含一个或多个不饱和度，但整体不具有芳香性。例如一些实施例中，双环的杂环基，其中一个环具有芳香性，另一个环整体不具有芳香性。杂环体系可以在任何杂原子或者碳原子上连接到主结构上从而形成稳定的化合物。一个或多个环上的氢原子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，“杂环基”，“杂环”，“杂环的”或“杂环烷基”基团是3-6元的单环(2-5个碳原子和选自N，O，P，S的1-3个杂原子，当所述的环为三元环时，其中只有一个杂原子)，或5-12个原子组成的双环(4-11个碳原子和选自N，O，P，S的1-3个杂原子)。术语“5-12元杂环烷基”指杂环烷基中的环体系中含有的原子数为5-12个，其 中杂环基具有如上定义。
“杂环基”可以是碳原子基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和环或杂环稠合所形成的基团。杂环的实例包括，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，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 PCTCN2020141222-appb-000011
基，二氮杂
Figure PCTCN2020141222-appb-000012
基，硫氮杂
Figure PCTCN2020141222-appb-000013
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，异苯并四氢噻嗯基，异苯并噻嗯基，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“环烷基-C 1-6烷基”、“杂环基-C 1-6烷基”、“芳基-C 1-6烷基”、“杂芳基-C 1-6烷基”表示环烷基、杂环基、芳基和杂芳基通过-C 1-6烷基与分子其余部分相连，其中-C 1-6烷基、环烷基、杂环基、芳基和杂芳基基团均具有如本发明所述的含义。所述“环烷基-C 1-6烷基”、“杂环基-C 1-6烷基”、“芳基-C 1-6烷基”、“杂芳基-C 1-6烷基”基团任选地被一个或多个本发明所描述的取代基所取代。
术语“k个原子组成的”或“k元”在此处可交换使用，其中k是整数，典型地描述分子中成环原子的数目，在所述分子中成环原子的数目是k。例如，5-12元杂芳基表示5、6、7、8、9、10、11或12个环原子组成的杂芳基。再例如，哌啶基是6个环原子组成的杂环基或6元杂环基，而吡啶基是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)。
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 PCTCN2020141222-appb-000014
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 PCTCN2020141222-appb-000015
像本发明所描述的，式c中环Ar上有两个连接点可与分子其余部分相连，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 PCTCN2020141222-appb-000016
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’端只能与分子中标注“**”的一端相连，即两端的连接方式不可互换。
Figure PCTCN2020141222-appb-000017
另外，需要说明的是，除非以其他方式明确指出，在本文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”表示相同或不同的基团，且相互之间不影响；“r1”和“r2”表示相同或不同的取值，且相互之间不影响。
Figure PCTCN2020141222-appb-000018
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相似不适当的反应，例如肠胃不适、眩晕等。优选地，本文所用的术语“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)-式(IV)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)-式(IV)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几何异构体和互变异构体，所述式(I)、式(II)、式(III)或式(IV)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)、式(II)、式(III)或式(IV)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)-式(IV)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.Higuchiand V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.SymposiumSeries,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Designand 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)-式(IV)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)-式(IV)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、产率、稳定性、吸湿性和结果原料药的流动性。
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)、式(II)、式(III)或式(IV)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文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文所述的状态、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。
适于口服施用的本发明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，需要减慢得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。
本文所用的措辞“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。
本文所用的措辞“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。体外剂量范围可以是约10-3摩尔至10-9摩尔浓度之间。体内治疗有效量范围可以取决于施用途径，为约0.1-500mg/kg或约1-100mg/kg之间。
本文所用的术语“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，用于治疗本文所述的疾病和病症。
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/不适。
本发明化合物和组合物的用途
本发明所公开的化合物或药物组合物可以用于制备用于预防、治疗或减轻患者由RORγt介导的疾病，哺乳动物，包括人类与RORγt介导有关的疾病的药物。
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、自身免疫性眼病、银屑病、系统性红斑狼疮、多发性硬化症、炎性肠病、炎性肠综合征、结肠炎、细菌感染、真菌感染、强直性脊柱炎、哮喘、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。
本发明的化合物或组合物可以应用于，但绝不限于，使用本发明的化合物或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)-(IV)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、d 6-DMSO、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)，m(multiplet，多重峰)，br(broadened，宽峰)，dd(doublet of doublets，四重峰)，dt(doublet of triplets，双三重峰)。偶合常数，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
化合物纯化是通过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 PCTCN2020141222-appb-000019
Figure PCTCN2020141222-appb-000020
下列合成方案描述了制备本发明公开化合物的步骤，除非另外说明，其中各X 1、X 2、X 3X 4、X 5、环B、环C、R 1、R 2、R 3、R y、L、r和n具有如本发明所述的含义。
合成方案一
Figure PCTCN2020141222-appb-000021
在式中，X表示离去基团，所述的离去基团包括但不限于卤素原子、甲磺酰基氧基、对甲基苯磺酰基氧基等；
化合物(f)可以通过合成方案一的合成方法得到：化合物(a)与化合物(b)发生亲核反应得到化合物(c)，化合物(c)水解酯基得到化合物(d)，化合物(d)再与化合物(e)进行缩合反应，得到最终产物。
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。
中间体1的合成：(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇
Figure PCTCN2020141222-appb-000022
采用专利申请WO2017132432中公开的方法制备。
中间体2的合成：(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐
Figure PCTCN2020141222-appb-000023
步骤一：(S)-3-((叔丁氧羰基)氨基)-3-(4-乙基磺酰基苯基)丙酸的合成
室温下，将LiOH(10g,459.10mmol)溶于水(50mL)，再加入(S)-3-((叔丁氧羰基)氨基)-3-(4-乙基磺酰基苯基)丙酸甲酯(18.00g,41.91mmol)的甲醇(50mL)溶液中，室温下反应16h。反应液减压浓缩，向剩余水相中加入浓盐酸(12mol/L)调节pH至5，用EtOAc(100mL×2)萃取，用饱和食盐水(80mL)洗涤，无水硫酸钠干燥，减压浓缩，得到白色固体14g，产率：93％。
MS(ESI,pos.ion)m/z:302.1[M-56+H] +.
步骤二：(S)-(3-氨基-1-(4-(乙基磺酰基)苯基)-3-氧代丙基)氨基甲酸叔丁酯的合成
将氯化铵(6.28g,117.41mmol)、HATU(20.00g,52.60mmol)、三乙胺(16.3mL,117.27mmol)依次加入(S)-3-((叔丁氧羰基)氨基)-3-(4-乙基磺酰基苯基)丙酸(14g,39.17mmol)的二氯甲烷(160mL)溶液中，室温下反应16h。反应液减压浓缩后，加入甲醇(100mL)溶解，过滤除去不溶物，滤液减压浓缩后，再加入二氯甲烷(300mL)溶解，用稀盐酸洗涤(0.5mol/L,100mL×2)，无水硫酸钠干燥，减压浓缩，粗产物用二氯甲烷(20mL)打浆过夜，过滤，得到白色固体12.5g，产率：89％。
MS(ESI,pos.ion)m/z:301.1[M-56+H] +.
步骤三：(S)-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)氨基甲酸叔丁酯的合成
氮气保护，-10℃下，将三氟乙酸酐(33mL,237.4mmol)缓慢滴加至(S)-(3-氨基-1-(4-(乙基磺酰基)苯基)-3-氧代丙基)氨基甲酸叔丁酯(48g,134.70mmol)和吡啶(40.00mL,497.00mmol)的THF(600mL)溶液中(耗时约30min)，滴加完毕后搅拌1h，然后移入室温继续反应12h。向反应液中加入饱和碳酸氢钠水溶液(200mL)淬灭反应，减压浓缩至有白色固体析出，过滤并用水洗涤滤饼，滤饼用二氯甲烷(100mL)溶解，再用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，减压浓缩，得到白色固体产物43.0g，产率：94％。MS(ESI,pos.ion)m/z:361.1[M+Na] +.
步骤四：(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐的合成
0℃下，将盐酸二氧六环溶液(100mL,4mol/L)滴加到(S)-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)氨基甲酸叔丁酯(45.00g,133.00mmol)的二氯甲烷(300mL)溶液中，加毕，移置室温下反应过夜，过滤得到白色固体34.2g，产率：94％。
MS(ESI,pos.ion)m/z:239.1[M+H] +；
1H NMR(400MHz,CD 3OD)δ(ppm):8.09(d,J＝8.4Hz,2H),7.87(d,J＝8.3Hz,2H),4.96(t,J＝7.0Hz,1H),3.37(d,J＝6.9Hz,2H),3.29(q,J＝7.4Hz,2H),1.25(t,J＝7.4Hz,3H)。
中间体3的合成：(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙酸甲酯盐酸盐
Figure PCTCN2020141222-appb-000024
室温下，向(S)-3-((叔丁氧羰基)氨基)-3-(4-(乙基磺酰基)苯基)丙酸甲酯(467mg,1.26mmol)的二氯甲烷(6mL,93.61mmol)溶液中加入盐酸二氧六环溶液(1mL,4M)，室温反应24小时，直接浓缩得到白色固体产物398mg，产率：99％。
MS(ESI,pos.ion)m/z:272.1[M+H] +
实施例1
(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000025
步骤一：3-(2-乙氧基-2-氧代乙氧基)-4-硝基苯甲酸甲酯的合成
向3-羟基-4-硝基-苯甲酸甲酯(5.0g,25mmol)与碳酸钾(7.1g,51mmol)的混合物中加入丙酮(210mL)，然后加入2-溴乙酸乙酯(3.2mL,30mmol)，回流反应12小时后停止反应。加水稀释(60mL)，乙酸乙酯萃取(50mL×3)，有机相合并，饱和食盐水洗涤(30mL)，无水硫酸钠干燥，柱层析(淋洗剂：PE/EtOAc(v/v)＝3/1)得到淡黄色固体产物5.8g，产率：81％。
MS(ESI,pos.ion)m/z:284.20[M+H] +
1H NMR(400MHz,CDCl 3)δ7.78(d,J＝8.4Hz,1H),7.66(dd,J＝8.4,1.1Hz,1H),7.59(s,1H),4.79(s,2H),4.20(q,J＝7.1Hz,2H),3.88(s,3H),1.22(t,J＝7.1Hz,3H).
步骤二：3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸甲酯的合成
向3-(2-乙氧基-2-氧代乙氧基)-4-硝基苯甲酸甲酯(5.6g,20mmol)和Pd/C(560mg)的混合物中加入四氢呋喃(32mL)和甲醇(90mL)，置换氢气后，室温搅拌24小时。硅藻土过滤后浓缩反应液，得到白色固体粗产物，然后加入醋酸(50mL)，100℃加热反应1小时后，浓缩醋酸，石油醚打浆过滤得到灰白色固体产物4g，产率：97.8％。
MS(ESI,pos.ion)m/z:209.10[M+H] +
1H NMR(400MHz,DMSO-d 6)δ11.06(s,1H),7.58(dd,J＝8.2,1.5Hz,1H),6.98(d,J＝8.2Hz,1H),4.64(s,2H),3.81(s,3H).
步骤三：3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸甲酯的合成
在0℃下，向3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸甲酯(4.15g,20.0mmol)中加入无水四氢呋喃(80mL)，氮气保护下加入三氟化硼乙醚(3.3mL,42mmol)，加完后恢复室温搅拌30分钟，再降温至0℃，缓慢加入硼氢化钠(1.6g,42mmol)，加完后恢复室温继续反应5h后。加入稀盐酸淬灭(20mL,1.0M)，加入饱和碳酸氢钠溶液中和至pH＝7左右，乙酸乙酯萃取(50mL×3)，有机层合并，饱和食盐水洗涤(30mL)，无水硫酸钠干燥，硅胶拌样、柱层析(淋洗剂：PE/EtOAc(v/v)＝3/1)得到目标产物3.2g，产率：83％。
MS(ESI,pos.ion)m/z:194.2[M+H] +
步骤四：4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸甲酯的合成
向3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸甲酯(300mg,1.55mmol)，4-(三氟甲基)苄溴(570mg,2.34mmol)，碳酸钾(429mg,3.10mmol)的混合物中加入N,N-二甲基甲酰胺(5mL)，氮气保护，100℃反应16小时。加水稀释，乙酸乙酯萃取(20mL×3)，有机相合并后用饱和食盐水洗涤(15mL)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝5/1)得到淡黄色固体产物490mg，产率：89.83％。
MS(ESI,pos.ion)m/z:352.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.62(d,J＝8.1Hz,2H),7.47–7.37(m,4H),6.86(d,J＝8.2Hz,1H),4.56(s,2H),4.38–4.30(m,2H),3.84(s,3H),3.41–3.33(m,2H).
13C NMR(101MHz,CDCl 3)δ167.11,148.20,141.76,134.90,129.76(q,J＝32.5Hz),127.53,125.72(q,J＝3.8Hz),124.13(q,J＝272.0Hz),123.47,120.63,116.31,113.64,64.83,54.51,51.77,46.75.
步骤五：4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸的合成
向4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸甲酯(490mg,1.40mmol)的甲醇(12mL,297mmol)溶液中加入氢氧化钠(223mg,5.58mmol)的水(3mL)溶液，65℃加热反应10小时。稀盐酸(1M)调节pH＝5-6，二氯甲烷萃取(20mL×3)，无水硫酸钠干燥，浓缩得到淡黄色固体产物450mg，产率：95.6％。
MS(ESI,pos.ion)m/z:338.1[M+H] +
步骤六：(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺的合成
向4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸(34mg,0.10mmol)的二氯甲烷(2mL)溶液中依次加入HATU(58mg,0.15mmol)，(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(30mg,0.11mmol)和三乙胺(55μL,0.40mmol)，室温搅拌16小时。停止反应，加入饱和氯化铵溶液淬灭(20mL)，二氯甲烷萃取(20mL×3)，有机相合并后，用饱和食盐水洗涤(15mL)，无水硫酸干燥，硅胶拌样，柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到白色固体产物37mg，产率：59.1％，纯度：89.74％。
MS(ESI,pos.ion)m/z:558.2[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.93(d,J＝8.1Hz,1H),7.87(d,J＝8.3Hz,2H),7.69(dd,J＝16.1,8.1Hz,4H),7.54(d,J＝7.9Hz,2H),7.20(d,J＝8.2Hz,1H),7.14(s,1H),6.83(d,J＝8.2Hz,1H),5.43(dd,J＝14.9,8.3Hz,1H),4.63(s,2H),4.30(s,2H),3.44(s,2H),3.27(dd,J＝14.7,7.3Hz,1H),3.14–3.10(m,1H),2.69(s,2H),1.08(t,J＝7.3Hz,3H).
实施例2
(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000026
步骤一：4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸甲酯的合成
向3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸甲酯(150mg,0.77mmol)，Pd(OAc) 2(17mg,0.08mmol)，(R)-(+)-1,1’-联萘-2,2’-双二苯膦(50mg,0.08mmol)，碳酸铯(1.3g,4.0mmol)的混合物中加入甲苯(5mL)，4-三氟甲基碘苯(320mg,1.17mmol)，氮气保护，95℃反应12小时。反应完毕，过滤，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝4/1)得到白色固体产物259mg，产率：98.90％。
MS(ESI,pos.ion)m/z:338.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.79(d,J＝1.9Hz,1H),7.61(d,J＝8.5Hz,2H),7.58(dd,J＝8.5,2.0Hz,1H),7.30(d,J＝8.5Hz,2H),6.96(d,J＝8.5Hz,1H),4.39–4.32(m,2H),3.85(s,3H),3.81–3.75(m,2H).
步骤二：4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸的合成
向4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸甲酯(259mg,0.77mmol)的甲醇(5mL)溶液中加入氢氧化钠溶液(1mL,4M)，65℃加热反应12小时。停止反应，稀盐酸(1M)中和至pH＝5-6之间，二氯甲烷萃取(30mL×3)，有机相合并，饱和食盐水洗涤(20mL)，无水硫酸钠干燥，浓缩得到淡黄色固体产物230mg，产率：92.65％。
MS(ESI,pos.ion)m/z:324.1[M+H] +
步骤三：(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺的合成
向4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸(100mg,0.31mmol)的二氯甲烷(5mL)溶液中依次加入HATU(180mg,0.47mmol)，(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(85mg,0.31mmol)和三乙胺(180μL,1.29mmol)，室温搅拌24小时。停止反应，加入饱和氯化铵溶液(15mL)淬灭，二氯甲烷萃取(25mL×3)，有机相合并，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到白色固体产物110mg，产率：63.41％，纯度：96.92％。
MS(ESI,pos.ion)m/z:544.15[M+H] +
1H NMR(400MHz,CDCl 3)δ7.89(d,J＝8.3Hz,2H),7.64(dd,J＝8.4,3.2Hz,4H),7.42(d,J＝1.7Hz,1H),7.34(d,J＝8.3Hz,2H),7.30–7.26(m,1H),7.00(t,J＝9.6Hz,2H),5.60(dd,J＝13.2,6.3Hz,1H),4.34(s,2H),3.79(s,2H),3.13(d,J＝7.2Hz,4H),1.29(t,J＝7.3Hz,3H).
实施例3
(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺
Figure PCTCN2020141222-appb-000027
步骤一：4-(2-乙氧基-2-氧代乙氧基)-3-硝基苯甲酸甲酯的合成
室温下，向4-羟基-3-硝基-苯甲酸甲酯(5.0g,25mmol)与碳酸钠(4.0g,37.74mmol)的混合物中加入丙酮(210mL)，然后加入2-溴乙酸甲酯(4.2g,27mmol)，60℃下回流反应20小时。加水稀释，乙酸乙酯萃取(20mL×2)，有机相合并，饱和食盐水洗涤(15mL)，无水硫酸钠干燥，硅胶拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝10/1)得到淡黄色固体2.5g，产率：37％。
MS(ESI,pos.ion)m/z:270.1[M+H] +
1H NMR(400MHz,CDCl 3)δ8.46(d,J＝2.1Hz,1H),8.14(dd,J＝8.8,2.1Hz,1H),7.01(d,J＝8.8Hz,1H),4.85(s,2H),3.90(s,3H),3.78(s,3H).
步骤二：3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸甲酯的合成
向4-(2-乙氧基-2-氧代乙氧基)-3-硝基苯甲酸甲酯(2.5g,9.3mmol)和Pd/C(250mg)的混合物中加入四氢呋喃(40mL)和甲醇(16mL)，氢气置换后，室温搅拌12小时。TLC检测原料消失，过滤浓缩，得到白色固体粗产物，加入醋酸(20mL)溶解，115℃加热反应1小时，浓缩溶剂，得到棕色固体，石油醚打浆过滤得到棕色粉末产物1.6g，产率：84％。
MS(ESI,pos.ion)m/z:208.05[M+H] +
1H NMR(400MHz,DMSO-d 6)δ10.88(s,1H),7.54(dd,J＝11.2,2.8Hz,2H),7.03(d,J＝8.3Hz,1H),4.68(s,2H),3.82(s,3H).
步骤三：3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸甲酯的合成
向3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸甲酯(900mg,4.34mmol)中加入无水四氢呋喃(20mL)，然后在氮气保护下加入三氟化硼乙醚(720μL,9.21mmol)，室温搅拌30分钟后，慢慢加入硼氢化钠(340mg,8.99mmol)，继续室温反应过夜，乙酸乙酯稀释(30mL)，稀盐酸(1.0M)淬灭，加入饱和碳酸氢钠溶液中和至中性后，乙酸乙酯萃取(20mL×2)，有机层合并，食盐水洗涤(15mL)，无水硫酸钠干燥，硅胶拌样，柱层析(淋洗剂：PE/EtOAc(v/v)＝3/1)得到目标产物630mg，产率：75.1％。
MS(ESI,pos.ion)m/z:194.2[M+H] +
步骤四：4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸甲酯的合成
室温下，向3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸甲酯(300mg,1.55mmol)，4-(三氟甲基)苄基溴(570mg,2.34mmol)，碳酸钾(429mg,3.10mmol)的混合物中加入N,N-二甲基甲酰胺(5mL)，氮气保护，100℃反应过夜。冷却至室温后加水稀释(35mL)，乙酸乙酯萃取(20mL×2)，有机相合并后用饱和食盐水洗涤(25mL)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝5/1)得到淡黄色固体产物490mg，产率：89.8％。
MS(ESI,pos.ion)m/z:352.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.62(d,J＝8.1Hz,2H),7.47–7.37(m,4H),6.86(d,J＝8.2Hz,1H),4.56(s,2H),4.38–4.30(m,2H),3.84(s,3H),3.41–3.33(m,2H).
步骤五：4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸的合成
向4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸甲酯(490mg,1.40mmol)的甲醇(12mL)溶液中加入氢氧化钠溶液(2M,2mL)，65℃加热反应5小时。停止反应后冷却至室温，稀盐酸(1M)调pH＝5-6，二氯甲烷萃取(25mL×2)，无水硫酸钠干燥，浓缩得到淡黄色固体产物450mg，产率：95.65％。
MS(ESI,pos.ion)m/z:338.1[M+H] +
步骤六：(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺的合成
向4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸(34mg,0.10mmol)的二氯甲烷(2mL)溶液中依次加入HATU(58mg,0.15254mmol)，(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(30mg,0.11mmol)和三乙胺(55μL,0.40mmol)，室温搅拌24小时，停止反应，加入饱和氯化铵溶液(30mL)淬灭，二氯甲烷萃取(25mL×3)，有机相合并后，用饱和食盐水洗涤(20mL)，无水硫酸干燥，硅胶拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到白色固体产物37mg，产率：59.07％，纯度：89.74％。
MS(ESI,pos.ion)m/z:588.2[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.93(d,J＝8.1Hz,1H),7.87(d,J＝8.3Hz,2H),7.69(dd,J＝16.1,8.1Hz,4H),7.54(d,J＝7.9Hz,2H),7.20(d,J＝8.2Hz,1H),7.14(s,1H),6.83(d,J＝8.2Hz,1H),5.43(dd,J＝14.9,8.3Hz,1H),4.63(s,2H),4.30(s,2H),3.44(s,2H),3.27(dd,J＝14.7,7.3Hz,1H),3.14–3.10(m,1H),2.69(s,2H),1.08(t,J＝7.3Hz,3H).
实施例4
(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺
Figure PCTCN2020141222-appb-000028
步骤一：4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸甲酯的合成
向3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸甲酯(390mg,2.01mmol)，Pd(OAc) 2(40mg,0.18mmol)，(R)-(+)-1,1’-联萘-2,2’-双二苯膦(120mg,0.18mmol)，碳酸铯(3.1g,9.5mmol)的混合物中加入甲苯(16mL)，1-碘-4-(三氟甲基)苯(780mg,2.86mmol)，氮气保护，95℃反应12小时。停止反应后冷却至室温，硅藻土过滤，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝4/1)得到白色固体产物590mg，产率：86.65％。
MS(ESI,pos.ion)m/z:338.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.79(d,J＝1.9Hz,1H),7.61(d,J＝8.5Hz,2H),7.58(dd,J＝8.5,2.0Hz,1H),7.30(d,J＝8.5Hz,2H),6.96(d,J＝8.5Hz,1H),4.39–4.32(m,2H),3.85(s,3H),3.81–3.75(m,2H).
步骤二：4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸的合成
向4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸甲酯(590mg,1.75mmol)的甲醇(15mL)溶液中加入氢氧化钠溶液(2mL,2M)，65℃反应10小时。停止反应后冷却至室温，稀盐酸(1M)调pH＝5-6，二氯甲烷萃取(25mL×3)，干燥，浓缩得到淡黄色固体产物520mg，产率：91.95％。
MS(ESI,pos.ion)m/z:324.1[M+H] +
步骤三：(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺的合成
向4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸(32mg,0.10mmol)，(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(30mg,0.11mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(28mg,0.14mmol)，1-羟基苯并三唑(20mg,0.14mmol)的混合物中加入N,N-二甲基甲酰胺(1.5mL)，三乙胺(55μL,0.40mmol)室温搅拌24小时后，停止反应，加入饱和氯化铵溶液(20mL)稀释，二氯甲烷萃取(25mL×3)，有机相合并，饱和食盐水洗涤(15mL)，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到白色固体产物16mg，产率：28.69％，纯度：96.47％。
MS(ESI,pos.ion)m/z:544.15[M+H] +
1H NMR(400MHz,CDCl 3)δ7.91(d,J＝8.2Hz,2H),7.67–7.58(m,4H),7.31(d,J＝8.3Hz,2H),7.26–7.20(m,1H),6.95(d,J＝8.4Hz,1H),6.71(d,J＝7.3Hz,1H),5.53(dd,J＝12.7,6.3Hz,1H),4.45–4.27(m,2H),3.87–3.71(m,2H),3.22–2.95(m,4H),1.31–1.27(m,3H).
13C NMR(101MHz,CDCl 3)δ166.65,149.08,148.80,144.37,138.96,131.09,129.14,127.49,126.93(dd,J＝7.5,3.7Hz),125.69,124.63(dd,J＝152.0,119.3Hz),121.81,119.81,117.48,117.43,116.50,64.72,50.59,49.65,47.59,24.04,7.32.
实施例5
(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-(4-(三氟甲基)苯甲酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000029
步骤一：7-溴-3,4-二氢-2H-苯并[b][1,4]噁嗪的合成
向2-氨基-5-溴-苯酚(500mg,2.66mmol)、碳酸钾(1.85g,13.4mmol)的混合物中加入N,N-二甲基甲酰胺(8mL)，1,2-二溴乙烷(350μL,4.02mmol)，125℃加热反应12小时后，停止反应后冷却至室温，加入饱和氯化铵(25mL)稀释，乙酸乙酯萃取(20mL×3)，有机相合并用饱和食盐水洗涤(20mL)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝2/1)得到棕色固体产物180mg，产率：31.6％。
MS(ESI,pos.ion)m/z:214.0[M+H] +
1H NMR(400MHz,CDCl 3)δ6.93(d,J＝1.7Hz,1H),6.86(dd,J＝8.4,1.6Hz,1H),6.46(d,J＝8.4Hz,1H),4.27–4.20(m,2H),3.78(s,1H),3.46–3.37(m,2H).
13C NMR(101MHz,CDCl 3)δ144.80,132.90,123.97,119.66,116.49,109.66,65.18,40.71.
步骤二：(7-溴-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)(4-(三氟甲基)苯基)甲酮的合成
在0℃下，向4-(三氟甲基)苯甲酸(540mg,2.84mmol)的二氯甲烷(10mL)溶液中依次加入草酰氯(550μL,7.10mmol)，N,N-二甲基甲酰胺(16μL)，然后恢复至室温，搅拌1小时，浓缩旋干，减压蒸去溶剂和草酰氯后，加入二氯甲烷(4mL)溶解，再次降温至0℃，将反应物缓慢滴加至7-溴-3,4-二氢-2H-苯并[b][1,4]噁嗪(300mg,1.40mmol)和二异丙基乙基胺(750μL,4.29mmol)的二氯甲烷(10mL)溶液中，滴加完后恢复至室温，搅拌过夜。向反应液中加入饱和氯化铵溶液(20mL)稀释，二氯甲烷萃取(20mL×3)，有机相合并，用饱和食盐水洗涤(20mL)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝4/1)得到棕色固体产物290mg，产率：53.58％。
MS(ESI,pos.ion)m/z:386.1[M+H] +
1H NMR(400MHz,CDCl 3)δ7.66(dd,J＝23.1,8.2Hz,4H),7.12(s,1H),6.84(d,J＝6.1Hz,2H),4.46–4.34(m,2H),4.01(s,2H).
步骤三：4-(4-(三氟甲基)苯甲酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸的合成
室温下，向Pd(OAc) 2(8mg,0.035mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(21mg,0.035mmol)的混合物中依次加入甲酸(190μL,5.04mmol)，(7-溴-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)(4-(三氟甲基)苯基)甲酮(270mg,0.70mmol)的N,N-二甲基甲酰胺(5mL)溶液，二环己基碳二亚胺(30mg,0.14mmol)和三乙胺(200μL,1.43mmol)的N,N-二甲基甲酰胺溶液(5mL)，100℃加热反应36小时。停止反应后冷却至室温，浓缩溶剂，加入饱和氯化铵稀释(20mL)，二氯甲烷萃取(20mL×3)，有机相合并，饱和氯化铵溶液洗涤(15mL)，饱和食盐水洗涤(15mL)，无水硫酸钠干燥，浓缩柱层析(淋洗剂：PE/EtOAc(v/v)＝4/1) 得到淡黄色固体产物230mg，产率：93.65％。
MS(ESI,pos.ion)m/z:352.1[M+H] +
1H NMR(400MHz,DMSO-d 6)δ12.89(s,1H),7.96(s,1H),7.85(d,J＝8.3Hz,2H),7.80(d,J＝8.2Hz,2H),7.43(d,J＝1.7Hz,1H),7.35(d,J＝8.1Hz,1H),4.42–4.31(m,2H),3.93–3.83(m,2H).
步骤四：(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-(4-(三氟甲基)苯甲酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺的合成
向4-(4-(三氟甲基)苯甲酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸(110mg,0.31mmol),(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(95mg,0.34mmol)，1-羟基苯并三唑(86mg,0.63mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(122mg,0.63mmol)的混合物中加入二氯甲烷(8mL,124.8mmol)，三乙胺(180μL,1.29mmol)，室温搅拌24小时后，停止反应，加入二氯甲烷稀释(25mL)，饱和氯化铵溶液洗涤(15mL×2)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到目标产物93mg，产率：51.96％，纯度：96.07％。
MS(ESI,pos.ion)m/z:572.10[M+H] +
1H NMR(400MHz,DMSO-d 6)δ9.17(d,J＝8.1Hz,1H),7.90(d,J＝8.2Hz,2H),7.86(d,J＝8.2Hz,2H),7.80(d,J＝7.9Hz,2H),7.72(d,J＝8.2Hz,2H),7.51(s,1H),7.30(d,J＝7.1Hz,2H),5.50(dd,J＝15.0,8.2Hz,1H),4.40(s,2H),3.89(s,2H),3.28(t,J＝7.2Hz,2H),3.15(dd,J＝7.4,4.1Hz,2H),1.10(t,J＝7.3Hz,3H).
实施例6
(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-((4-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000030
步骤一：7-溴-4-((4-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪的合成
向7-溴-3,4-二氢-2H-苯并[b][1,4]噁嗪(300mg,1.40mmol)的二氯甲烷(8mL,124.8mmol)溶液中依次加入二异丙基乙基胺(750μL,4.29mmol)，3-(三氟甲基)苯磺酰氯(350μL,2.18mmol)和4-二甲氨基吡啶(35mg,0.28mmol)，室温搅拌18小时后，直接加入硅胶拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝5/1)得到棕色油状产物530mg，产率：89.57％。
1H NMR(400MHz,CDCl 3)δ7.83–7.70(m,5H),7.10(dd,J＝8.9,2.2Hz,1H),7.02(d,J＝2.2Hz,1H),3.97–3.87(m,2H),3.81–3.70(m,2H).
步骤二：4-((4-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸的合成
室温下，向Pd(OAc) 2(6mg,0.026mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(15mg,0.025mmol)的混合物中依次加入甲酸(155mg,3.39mmol)，7-溴-4-((4-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪(200mg,0.47mmol)的N,N-二甲基甲酰胺(5mL,63.9mmol)溶液，二环己基碳二亚胺(20mg,0.10mmol)和三乙胺(96mg,0.95mmol)的N,N-二甲基甲酰胺溶液(3mL)，100℃加热反应。24小时后停止反应，冷却至室温后加入饱和氯化铵稀释(25mL)，二氯甲烷萃取(20mL×3)，有机相合并，依次用饱和氯化铵溶液(20mL×2)和饱和食盐水(15mL)洗涤，无水硫酸钠干燥，浓缩柱层析(淋洗剂：PE/EtOAc(v/v)＝1/1)得到棕色固体166mg，产率：90.48％。
MS(ESI,pos.ion)m/z:388.1[M+H] +
1H NMR(400MHz,DMSO-d 6)δ12.95(s,1H),8.13(d,J＝8.4Hz,1H),8.06(d,J＝7.9Hz,1H),8.02(s,1H),7.85(dd,J＝18.4,8.3Hz,2H),7.53(dd,J＝8.6,1.8Hz,1H),7.33(d,J＝1.7Hz,1H),4.12–4.00(m,2H),3.92–3.80(m,2H).
步骤三：(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-((4-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺的合成
向4-((4-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸(110mg,0.28mmol)，(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(88mg,0.32mmol)，1-羟基苯并三唑(80mg,0.58mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(110mg,0.57mmol)的混合物中加入二氯甲烷(8mL,124.8mmol)，三乙胺(160μL,1.15mmol)，室温搅拌20小时后，停止反应，加入二氯甲烷稀释(25mL)，饱和氯化铵溶液洗涤(20mL×2)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到目标产物83mg，产率：48.10％，纯度：92.79％。
MS(ESI,pos.ion)m/z:608.10[M+H] +
1H NMR(400MHz,CDCl 3)δ7.89(t,J＝11.1Hz,3H),7.82(d,J＝8.3Hz,2H),7.76(d,J＝8.3Hz,2H),7.65(d,J＝8.2Hz,2H),7.41(d,J＝8.7Hz,1H),7.36(s,1H),7.25(d,J＝7.7Hz,1H),5.60(dd,J＝13.3,6.4Hz,1H),3.93(d,J＝4.3Hz,2H),3.85(d,J＝4.1Hz,2H),3.28–2.89(m,4H),1.27(t,J＝7.4Hz,3H).
13C NMR(101MHz,CDCl 3)δ166.17,146.49,144.47,141.81,138.67,135.30,130.97,129.00,127.68,126.99,126.72,123.62,127.40–118.50,119.80,117.34,116.70,63.23,50.60,49.80,44.45,23.87,7.29.
实施例7
(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-(4-(三氟甲基)苯乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000031
步骤一：2-(4-(三氟甲基)苯基)乙醛的合成
室温下，向2-(4-(三氟甲基)苯基)乙醇(570mg,2.99mmol)的二氯甲烷(12mL,187.2mmol)溶液中加入Dess-Martin氧化剂(1.9g,4.50mmol)，室温搅拌5小时。反应停止，饱和碳酸氢钠溶液洗涤(15mL×2)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝3/1)得到目标产物350mg，产率：62.06％。
1H NMR(400MHz,CDCl 3)δ9.81(d,J＝1.9Hz,1H),7.65(d,J＝8.0Hz,2H),7.36(d,J＝8.0Hz,2H),3.81(s,2H).
步骤二：7-溴-4-(4-(三氟甲基)苯乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪的合成
室温下，向7-溴-3,4-二氢-2H-苯并[b][1,4]噁嗪(200mg,0.93mmol)的甲醇(2mL)溶液中依次加入2-(4-(三氟甲基)苯基)乙醛(243mg,1.29mmol)的甲醇(8mL)溶液、氰基硼氢化钠(90mg,1.43mmol)和醋酸(0.7mL)，室温搅拌14小时。停止反应，加入饱和碳酸氢钠溶液(20mL)淬灭，乙酸乙酯萃取(25mL×3)，有机相合并，饱和食盐水洗涤(15mL)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝3/1)得到棕色油状物320mg，产率：88.68％。
MS(ESI,pos.ion)m/z:386.1[M+H] +
1H NMR(400MHz,CDCl 3)δ7.59(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),7.01–6.94(m,2H),6.56(d,J＝8.3Hz,1H),4.21–4.07(m,2H),3.52(t,J＝7.4Hz,2H),3.28–3.19(m,2H),2.95(t,J＝7.4Hz,2H).
步骤三：4-(4-(三氟甲基)苯乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸的合成
在室温，氮气保护下，向Pd(OAc) 2(10mg,0.04mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(24mg,0.04mmol)的混合物中依次加入无水甲酸(268mg,5.82mmol)和7-溴-4-(4-(三氟甲基)苯乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪(320mg,0.83mmol)的N,N-二甲基甲酰胺(8mL,102mmol)溶液，二环己基碳二亚胺(34mg,0.16mmol)和三乙胺(240μL,1.72mmol)的N,N-二甲基甲酰胺溶液(3mL)，100℃加热反应18小时。停止反应，冷却至室温，将溶剂浓缩，加入饱和氯化铵稀释(30mL)，二氯甲烷萃取(25mL×3)，有机相合并，饱和氯化铵溶液洗涤(15mL)，饱和食盐水洗涤(15mL)，无水硫酸钠干燥，浓缩、拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到淡黄色固体110mg，产率：37.79％。
MS(ESI,pos.ion)m/z:352.1[M+H] +
1H NMR(400MHz,DMSO-d 6)δ12.16(s,1H),7.67(d,J＝7.9Hz,2H),7.54(d,J＝8.0Hz,2H),7.41(d,J＝7.1Hz,1H),7.18(d,J＝1.5Hz,1H),6.81(d,J＝8.5Hz,1H),4.20–4.04(m,2H),3.62(t,J＝7.3Hz,2H),3.40(s,2H),2.95(t,J＝7.4Hz,2H).
步骤四：(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-(4-(三氟甲基)苯乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺的合成
向4-(4-(三氟甲基)苯乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸(110mg,0.31mmol)、(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(95mg,0.34mmol)、1-羟基苯并三唑(86mg,0.63mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(122mg,0.63mmol)的混合物中加入二氯甲烷(8mL)，三乙胺(180μL,1.29mmol)，室温搅拌24小时。停止反应，加入饱和氯化铵溶液洗涤(15mL×2)，饱和食盐水洗涤(15mL)，无水硫酸钠干燥，浓缩、拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到白色固体产物75mg，产率：40.13％，纯度：95.77％。
MS(ESI,pos.ion)m/z:572.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.91(d,J＝8.2Hz,2H),7.65(d,J＝8.2Hz,2H),7.58(d,J＝7.9Hz,2H),7.41(dd,J＝8.4,1.6Hz,1H),7.33(d,J＝7.9Hz,2H),7.29(d,J＝2.3Hz,1H),6.87(d,J＝7.7Hz,1H),6.67(d,J＝8.5Hz,1H),5.60(dd,J＝13.0,6.2Hz,1H),4.20–4.04(m,2H),3.60(t,J＝7.2Hz,2H),3.33–3.21(m,2H),3.20–3.03(m,4H),2.98(t,J＝7.1Hz,2H),1.29(t,J＝7.4Hz,3H).
实施例8
(S)-N-(2-氰基-1-(4-(乙磺酰基)苯基)乙基)-4-(2-氰基-5-环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000032
步骤一：4-(2-氰基-5-环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯的合成
向3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(250mg,1.29mmol)，Pd(OAc) 2(29mg,0.13mmol)，(R)-(+)-1,1’-联萘-2,2’-双二苯膦(83mg,0.13mmol)，碳酸铯(2.1g,6.4mmol)的混合物中加入甲苯(10mL)，2-溴-4-环丙基-苯甲腈(300mg,1.35mmol)，氮气保护，95℃反应14小时，停止反应，冷却至室温，加入饱和氯化铵溶液(25mL)，乙酸乙酯萃取(25mL×3)，无水硫酸钠干燥，硅胶拌样柱层析，得到黄色油状产物258mg，产率：59.62％。
MS(ESI,pos.ion)m/z:335.1[M+H] +
1H NMR(600MHz,CDCl 3)δ7.62(d,J＝8.1Hz,1H),7.60(d,J＝1.8Hz,1H),7.47(dd,J＝8.5,1.8Hz,1H),7.10(d,J＝1.1Hz,1H),6.99(dd,J＝8.1,1.4Hz,1H),6.57(d,J＝8.5Hz,1H),4.41–4.35(m,2H),3.89(s,3H),3.86–3.79(m,2H),1.92(ddd,J＝13.3,8.5,5.0Hz,1H),1.16–1.09(m,2H),0.80–0.73(m,2H).
步骤二：4-(2-氰基-5-环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸的合成
向4-(2-氰基-5-环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(258mg,0.77mmol)的甲醇(2mL)和四氢呋喃(2mL)溶液中加入氢氧化钠溶液(1.5mL,2M)，室温反应24小时后，停止反应，稀盐酸(1M)调节pH至6-7，二氯甲烷萃取(25mL×3)，无水硫酸钠干燥，浓缩得到黄色固体产物238mg，产率：96.31％。
MS(ESI,pos.ion)m/z:321.2[M+H] +
步骤三：(S)-N-(2-氰基-1-(4-(乙磺酰基)苯基)乙基)-4-(2-氰基-5-环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺的合成
向4-(2-氰基-5-环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸(70mg,0.22mmol)，(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(67mg,0.24mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(85mg,0.44mmol)和1-羟基苯并三唑(60mg,0.44mmol)的混合物中加入二氯甲烷(5mL,78.01mmol)，三乙胺(95μL,0.68mmol)，室温反应30小时后，停止反应，加入二氯甲烷(25mL)稀释，饱和氯化铵(20mL)洗涤，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到白色固体产物57mg，产率：46.95％，纯度：97.31％。
MS(ESI,pos.ion)m/z:541.1[M+H] +
1H NMR(400MHz,CDCl 3)δ7.83(d,J＝8.0Hz,2H),7.63(d,J＝8.2Hz,2H),7.59(d,J＝8.1Hz,1H),7.50–7.39(m,2H),7.27(d,J＝7.8Hz,1H),7.07(s,1H),6.97(d,J＝8.0Hz,1H),6.52(d,J＝8.5Hz,1H),5.56(dd,J＝13.9,6.7Hz,1H),4.32(s,2H),3.77(d,J＝3.3Hz,2H),3.19–3.07(m,2H),3.07–2.97(m,2H),1.90(ddd,J＝13.2,8.5,5.0Hz,1H),1.25(t,J＝7.4Hz,3H),1.10(d,J＝7.7Hz,2H),0.75(d,J＝4.7Hz,2H).
13C NMR(101MHz,CDCl 3)δ166.79,152.70,148.85,145.10,144.05,138.39,135.88,134.32,128.89,127.71,124.83,124.44,123.36,121.04,117.42,116.93,116.47,115.38,106.99,64.29,50.58,49.88,49.18,24.00,15.98,10.93,7.33.
实施例9
(S)-N-(2-氰基-1-(4-(乙磺酰基)苯基)乙基)-4-(2,6-二环丙基吡啶-4-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000033
步骤一：2,6-二环丙基吡啶-4-醇的合成
向2,6-二溴-4-溴吡啶(1.0g,4.0mmol)，环丙基硼酸(710mg,8.27mmol)，磷酸钾(5.9g,28mmol)， Pd(OAc) 2(92mg,0.40mmol)和三(环己基)膦(220mg,0.78mmol)的混合物中加入甲苯(20mL)和水(2.5mL)，110℃回流反应12小时后，加入饱和氯化铵溶液(30mL)稀释，乙酸乙酯萃取(15mL×3)，有机相合并用饱和食盐水洗涤(30mL)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝10/1)得到淡黄色油状物产物320mg，产率：46％。
MS(ESI,pos.ion)m/z:176.3[M+H] +
步骤二：2,6-二环丙基吡啶-4-基三氟甲磺酸酯的合成
0℃下，向2,6-二环丙基吡啶-4-醇(320mg,1.82mmol)的二氯甲烷(8mL)溶液中加入三乙胺(390μL,2.80mmol)，然后滴加三氟甲磺酸酐(470μL,2.74mmol)，室温反应过夜后，停止反应，加入饱和氯化铵溶液(25mL)稀释，乙酸乙酯萃取(25mL×3)，有机相合并用饱和食盐水洗涤(15mL)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝4/1)得到淡黄色油状物产物318mg，产率：56.67％。
MS(ESI,pos.ion)m/z:308.2[M+H] +
步骤三：4-(2,6-二环丙基吡啶-4-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯的合成
向3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(100mg,0.52mmol)，Pd(OAc) 2(12mg,0.05mmol)，(R)-(+)-1,1’-联萘-2,2’-双二苯膦(34mg,0.05mmol)，碳酸铯(850mg,2.61mmol)的混合物中加入甲苯(6mL)，2,6-二环丙基吡啶-4-基三氟甲磺酸酯(160mg,0.67mmol)，氮气保护，100℃反应12小时。冷却至室温后加入饱和氯化铵溶液淬灭(25mL)，乙酸乙酯萃取(25mL×3)，有机相合并，无水硫酸钠干燥，浓缩柱层析(淋洗剂：PE/EtOAc(v/v)＝4/1)得到棕色油状产物23.5mg，产率：68.4％。
MS(ESI,pos.ion)m/z:352.2[M+H] +
步骤四：4-(2,6-二环丙基吡啶-4-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸的合成
向4-(2,6-二环丙基吡啶-4-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(93mg,0.26mmol)中加入甲醇(2mL)和四氢呋喃(2mL)溶解，随后加入氢氧化钠水溶液(1mL,4M)，50℃加热反应7小时后，停止反应，冷却至室温，稀盐酸(1M)调节pH至6-7，二氯甲烷萃取(25mL×3)，无水硫酸钠干燥，浓缩得到黄色固体产85mg，产率：95.20％。
MS(ESI,pos.ion)m/z:337.2[M+H] +
步骤五：(S)-N-(2-氰基-1-(4-(乙磺酰基)苯基)乙基)-4-(2,6-二环丙基吡啶-4-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
向4-(2,6-二环丙基吡啶-4-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸(85mg,0.25mmol)，(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(77mg,0.28mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(100mg,0.51mmol)和1-羟基苯并三唑(70mg,0.51mmol)的混合物中加入二氯甲烷(5mL)，三乙胺(110μL,0.79mmol)，室温反应18小时，停止反应，加入二氯甲烷稀释(25mL)，饱和氯化铵洗涤(15mL×2)，无水硫酸钠干燥，浓缩，柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到白色固体产物25mg，产率：17.35％， 纯度：97.63％。
MS(ESI,pos.ion)m/z:557.15[M+H] +
1H NMR(400MHz,MeOD)δ7.88(d,J＝8.3Hz,2H),7.63(d,J＝8.3Hz,2H),7.40(d,J＝1.9Hz,1H),7.31–7.29(m,1H),7.16(d,J＝8.6Hz,1H),6.63(s,2H),5.54(t,J＝6.7Hz,1H),4.29–4.20(m,2H),3.77–3.69(m,2H),3.14–2.96(m,4H),1.92–1.77(m,2H),1.25(d,J＝7.4Hz,4H),0.88(t,J＝6.7Hz,7H).
实施例10
(S)-N-(2-氰基-1-(4-(乙磺酰基)苯基)乙基)-4-(3,5-二环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000034
步骤一：1-氯-3,5-二环丙基苯的合成
向1,3-溴-5-氯苯(270mg,1.0mmol)，环丙基硼酸(180mg,2.1mmol)，磷酸钾(1.5g,7.1mmol)，Pd(OAc) 2(23mg,0.10mmol)和三(环己基)膦(56mg,0.20mmol)混合物中加入甲苯(10mL)和水(0.5mL)，氮气保护，100℃加热反应5小时，停止反应，冷却至室温后加入饱和氯化铵溶液淬灭(20mL)，乙酸乙酯萃取(15mL×3)，有机相合并，饱和食盐水洗涤(15mL)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/0)得到无色油状产物180mg，产率：93.54％。
1H NMR(400MHz,CDCl 3)δ6.84(s,2H),6.74(d,J＝1.1Hz,1H),1.93–1.79(m,2H),1.06–0.92(m,4H),0.72(dd,J＝7.0,4.2Hz,4H).
步骤二：4-(3,5-二环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸的合成
向3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(100mg,0.52mmol)，1-氯-3,5-二环丙基苯(100mg,0.52mmol)，叔丁醇钠(150mg,1.56mmol)，Pd 2(dba) 3(48mg,0.05mmol)和三(叔丁基)膦(10mg,0.05mmol)的混合物中加入二甲苯(8mL)，155℃反应30小时，停止反应，冷却至室温后加入饱和氯化铵溶液(25mL)淬灭，二氯甲烷萃取(15mL×3)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到淡黄色固体产物150mg，产率：86.40％。
MS(ESI,pos.ion)m/z:336.1[M+H] +
1H NMR(400MHz,CDCl 3)δ7.61(d,J＝1.8Hz,1H),7.50(dd,J＝8.6,1.8Hz,1H),6.76(s,2H),6.74(s,1H),6.68(s,1H),4.42–4.28(m,2H),3.85–3.68(m,2H),1.88(ddd,J＝13.5,8.5,5.1Hz,2H),1.08–0.93(m,4H),0.70(q,J＝4.9Hz,4H).
步骤三：(S)-N-(2-氰基-1-(4-(乙磺酰基)苯基)乙基)-4-(3,5-二环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7- 甲酰胺的合成
向4-(3,5-二环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸(85mg,0.25mmol)，(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(77mg,0.28mmol)，1-羟基苯并三唑(70mg,0.51mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(100mg,0.51mmol)的混合物中加入二氯甲烷(8mL)，三乙胺(145μL,1.04mmol)，室温搅拌24小时后，停止反应，加入二氯甲烷稀释(15mL)，饱和氯化铵溶液洗涤(15mL×2)，无水硫酸钠干燥，浓缩柱层析得到(淋洗剂：PE/EtOAc(v/v)＝1/2)白色固体产物102mg，产率：66.98％，纯度：92.48％。
MS(ESI,pos.ion)m/z:556.20[M+H] +
1H NMR(400MHz,CDCl 3)δ7.91(d,J＝8.1Hz,2H),7.65(d,J＝8.1Hz,2H),7.36(s,1H),7.23(d,J＝8.6Hz,1H),6.84(d,J＝7.6Hz,1H),6.78(d,J＝8.5Hz,1H),6.73(s,2H),6.65(s,1H),5.59(dd,J＝12.9,6.3Hz,1H),4.50–4.23(m,2H),3.73(d,J＝3.8Hz,2H),3.23–3.02(m,4H),1.93–1.80(m,2H),1.38–1.24(m,4H),0.97(q,J＝5.2Hz,4H),0.69(q,J＝5.0Hz,3H).
实施例11
(R)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000035
向4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸(76mg,0.22mmol)的二氯甲烷(4mL)溶液中依次加入HATU(130mg,0.34mmol)，(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇(60mg,0.26mmol)和三乙胺(130μL,0.93mmol)，室温搅拌22小时，停止反应，加入饱和氯化铵稀释(25mL)，二氯甲烷萃取(15mL×3)，有机相合并用饱和食盐水洗涤(15mL)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到白色固体产物80mg，产率：62.24％，纯度：96.17％。
MS(ESI,pos.ion)m/z:549.1[M+H] +
1H NMR(400MHz,CDCl 3)δ7.83(d,J＝8.1Hz,2H),7.61(d,J＝7.9Hz,2H),7.54(d,J＝8.1Hz,2H),7.38(d,J＝7.8Hz,2H),7.34(s,1H),7.31(d,J＝10.3Hz,1H),7.06(d,J＝6.7Hz,1H),6.56(d,J＝8.4Hz,1H),5.24(s,1H),4.60(s,2H),4.30(s,2H),4.05–3.88(m,2H),3.73(dd,J＝14.0,7.0Hz,2H),3.09(dd,J＝14.7,7.3Hz,2H),1.27–1.23(m,3H).
实施例12
(R)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺
Figure PCTCN2020141222-appb-000036
向4-(4-(三氟甲基)苄基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸(34mg,0.10mmol)的二氯甲烷(2mL)溶液中依次加入HATU(58mg,0.15mmol)，(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇(30mg,0.13mmol)和三乙胺(55μL,0.40mmol)，室温搅拌23小时。停止反应，加入饱和氯化铵溶液(15mL)淬灭，二氯甲烷萃取(15mL×3)，有机相合并后，用饱和食盐水洗涤(15mL)，无水硫酸干燥，硅胶拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到白色固体产物35mg，产率：57.35％，纯度：90.61％。
MS(ESI,pos.ion)m/z:549.1[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.50(d,J＝7.5Hz,1H),7.81(d,J＝8.0Hz,2H),7.71(d,J＝7.9Hz,2H),7.60(d,J＝8.0Hz,2H),7.54(d,J＝7.7Hz,2H),7.22(d,J＝8.1Hz,1H),7.17(s,1H),6.80(d,J＝8.2Hz,1H),5.07(d,J＝6.4Hz,1H),5.01(s,1H),4.64(s,2H),4.29(s,2H),3.80–3.60(m,2H),3.42(s,2H),3.25(dd,J＝14.4,7.1Hz,2H),1.09(t,J＝7.2Hz,3H).
实施例13
(R)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-4-(4-(三氟甲基)苯基)-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000037
向4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸(120mg,0.37mmol)的二氯甲烷(5mL)溶液中依次加入HATU(215mg,0.56mmol)，(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇(105mg,0.45mmol)和三乙胺(210μL,1.51mmol)，室温搅拌24小时。停止反应，加入饱和氯化铵溶液淬灭(15mL)，二氯甲烷萃取(15mL×3)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到白色固体产物150mg，产率：70.41％，纯度：93.14％。
MS(ESI,pos.ion)m/z:535.1[M+H] +
1H NMR(400MHz,CDCl 3)δ7.87(d,J＝8.3Hz,2H),7.64(d,J＝8.5Hz,2H),7.58(d,J＝8.2Hz,2H),7.43(d,J＝1.8Hz,1H),7.35(d,J＝8.4Hz,2H),7.30(d,J＝1.9Hz,1H),7.09(d,J＝6.9Hz,1H),7.04(d,J＝8.5Hz,1H),5.34–5.21(m,1H),4.40–4.28(m,2H),4.05(dd,J＝11.3,3.5Hz,1H),3.97(dd,J＝11.1,4.8Hz,1H),3.84–3.76(m,2H),3.11(q,J＝7.4Hz,2H),1.29(t,J＝7.4Hz,3H).
实施例14
(R)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-4-(4-(三氟甲基)苯基)-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺
Figure PCTCN2020141222-appb-000038
向4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸(90mg,0.28mmol)的二氯甲烷(5mL)溶液中依次加入HATU(158mg,0.41mmol)，(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇(80mg,0.35mmol)和三乙胺(120μL,0.86mmol)，室温搅拌24小时后，停止反应，加入饱和氯化铵溶液(15mL)淬灭，二氯甲烷萃取(15mL×3)，有机相合并后，用饱和食盐水洗涤(15mL)，无水硫酸干燥，硅胶拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝2/1)得到白色固体产物91mg，产率：56.96％，纯度：93.15％。
MS(ESI,pos.ion)m/z:535.10[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.63(d,J＝7.1Hz,1H),7.82(d,J＝7.5Hz,2H),7.68(d,J＝8.8Hz,3H),7.61(d,J＝7.5Hz,2H),7.54(d,J＝7.7Hz,1H),7.40(d,J＝7.7Hz,2H),6.99(d,J＝8.1Hz,1H),5.08(d,J＝5.6Hz,1H),5.02(s,1H),4.32(d,J＝26.1Hz,2H),3.81(s,2H),3.68(s,2H),3.25(d,J＝7.0Hz,2H),1.15–1.06(m,3H).
实施例15
(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-(2-(4-(三氟甲基)苯基)乙酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000039
步骤一：4-(2-(4-(三氟甲基)苯基)乙酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯的合成
室温下，向2-(4-(三氟甲基)苯基)乙酸(260mg,1.27mmol)的二氯甲烷(8mL)溶液中依次加入HATU(590mg,1.55mmol)，3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(200mg,1.03mmol)和三乙胺(580μL,4.17mmol)，室温搅拌6小时。加入饱和氯化铵淬灭(30mL)，乙酸乙酯萃取(30mL×3)，有机相合并，饱和食盐水洗涤(20mL)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝4/1)得到白色固体产物368mg，产率：93.72％。
MS(ESI,pos.ion)m/z:408.1[M+H] +
1H NMR(400MHz,CDCl 3)δ7.59(d,J＝6.9Hz,4H),7.37(d,J＝7.9Hz,2H),4.33–4.20(m,2H),4.02(s,2H),3.96(s,2H),3.91(s,3H).
步骤二：4-(2-(4-(三氟甲基)苯基)乙酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸的合成
室温下，向4-(2-(4-(三氟甲基)苯基)乙酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(38mg,0.10mmol)的四氢呋喃(2mL)溶液中依次加入一水合氢氧化锂(9mg,0.21mmol)和水(0.2mL)，室温搅拌12小时。TLC检测原料反应完全，加水稀释，用稀盐酸(1M)中和至pH＝5-6，二氯甲烷萃取(15mL×3)，浓缩拌样柱层析得到目标产物(淋洗剂：PE/EtOAc(v/v)＝1/2)为黄绿色固体10mg，产率：27.32％。
MS(ESI,pos.ion)m/z:366.1[M+H] +
步骤三：(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-(2-(4-(三氟甲基)苯基)乙酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺的合成
室温下，向4-(2-(4-(三氟甲基)苯基)乙酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸(30mg,0.08mmol)的二氯甲烷(3mL)溶液中依次加入HATU(50mg,0.13mmol)和(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(28mg,0.10mmol)，室温搅拌16小时。停止反应，加入饱和氯化铵淬灭(30mL)，二氯甲烷萃取(25mL×3)，有机相合并用饱和食盐水洗涤(15mL)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到淡黄色固体产物11mg，产率：22.87％，纯度：94.75％。
MS(ESI,pos.ion)m/z:587.1[M+H] +
1H NMR(400MHz,CDCl 3)δ7.90(d,J＝8.1Hz,2H),7.63(dd,J＝14.6,8.1Hz,4H),7.38(dd,J＝15.9,7.6Hz,4H),7.23(d,J＝7.1Hz,1H),5.59(dd,J＝12.9,6.3Hz,1H),4.26(s,2H),4.01(s,2H),3.94(s,2H),3.67(d,J＝5.5Hz,1H),3.17–3.04(m,4H),1.31(s,3H).
实施例16
(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000040
步骤一：7-溴-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪的合成
向7-溴-3,4-二氢-2H-苯并[b][1,4]噁嗪(300mg,1.40mmol)的二氯甲烷(8mL)溶液中依次加入N,N-二异丙基乙胺(750μL,4.29mmol)、3-(三氟甲基)苯磺酰氯(350μL,2.18mmol)和4-二甲氨基吡啶(35mg,0.28mmol)，室温搅拌过夜。直接加入硅胶拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝5/1)得到棕色油状产物 530mg，产率：89.57％。
1H NMR(400MHz,CDCl 3)δ7.97(s,1H),7.87(d,J＝7.9Hz,1H),7.79(d,J＝7.9Hz,1H),7.72(d,J＝8.9Hz,1H),7.65(t,J＝7.9Hz,1H),7.10(dd,J＝8.9,2.2Hz,1H),7.00(d,J＝2.2Hz,1H),3.96–3.87(m,2H),3.82–3.68(m,2H).
步骤二：4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸的合成
室温下，向Pd(OAc) 2(6mg,0.026mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(15mg,0.03mmol)的混合物中依次加入无水甲酸(155mg,3.37mmol)、7-溴-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪(200mg,0.47mmol)的N,N-二甲基甲酰胺(5mL)溶液，二环己基碳二亚胺(20mg,0.10mmol)和三乙胺(96mg,0.95mmol)的N,N-二甲基甲酰胺(5mL)溶液，100℃加热反应16小时。停止反应，加入饱和氯化铵稀释(20mL)，二氯甲烷萃取(30mL×3)，有机相合并，饱和氯化铵溶液洗涤(20mL)，饱和食盐水洗涤(20mL)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/1)得到棕色固体166mg，产率：90.48％。
MS(ESI,pos.ion)m/z:388.1[M+H] +
1H NMR(400MHz,DMSO-d 6)δ12.95(s,1H),8.13(d,J＝8.4Hz,1H),8.06(d,J＝7.9Hz,1H),8.02(s,1H),7.85(dd,J＝18.4,8.3Hz,2H),7.53(dd,J＝8.6,1.8Hz,1H),7.33(d,J＝1.7Hz,1H),4.12–4.00(m,2H),3.92–3.80(m,2H).
步骤三：(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺的合成
向4-((3-(三氟甲基)苯基)磺酰基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸(20mg,0.05mmol)的二氯甲烷(4mL)溶液中依次加入HATU(30mg,0.08mmol)、(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(16mg,0.06mmol)和三乙胺(39μL,0.28mmol)，室温搅拌过夜。停止反应，加入饱和氯化铵(20mL)稀释，二氯甲烷萃取(30mL×2)，有机相合并后用饱和食盐水洗涤(20mL)，无水硫酸钠干燥，浓缩、拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到白色固体20mg，产率：61.30％，纯度：96.17％。
MS(ESI,pos.ion)m/z:608.1[M+H] +
1H NMR(400MHz,CDCl 3)δ7.98(s,1H),7.83(dd,J＝17.3,8.4Hz,5H),7.72–7.58(m,4H),7.41(d,J＝8.6Hz,1H),7.36(s,1H),5.59(dd,J＝13.7,6.6Hz,1H),3.97–3.77(m,4H),3.10(q,J＝7.3Hz,4H),1.26(t,J＝7.3Hz,3H).
实施例17
N-((S)-2-氰基-1-(4-(乙磺酰基)苯基)乙基)-3-异丙基-4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000041
步骤一：3-((3-甲基-2-丁烯-1-基)氧基)-4-硝基苯甲酸甲酯的合成
向3-羟基-4-硝基-苯甲酸甲酯(1g,5.07mmol)与碳酸钾(1.4g,10mmol)的混合物中加入丙酮(40mL,540mmol)，然后加入1-溴-3-甲基-2-丁烯(700μL,6.06mmol)，回流反应7小时，停止反应。冷却至室温后加水稀释(35mL)，乙酸乙酯萃取(30mL×3)，有机相合并，饱和食盐水洗涤(25mL)，无水硫酸钠干燥，浓缩得到黄色固体，石油醚打浆后过滤得到淡黄色固体产物1.12g，产率：83.2％。
MS(ESI,pos.ion)m/z:266.0[M+H] +
1H NMR(400MHz,CDCl 3)δ7.81(d,J＝8.3Hz,1H),7.76(s,1H),7.67(d,J＝8.3Hz,1H),5.48(t,J＝6.6Hz,1H),4.74(d,J＝6.7Hz,2H),3.98(s,3H),1.80(d,J＝5.1Hz,6H).
步骤二：3-(丙-2-亚基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯的合成
向3-((3-甲基-2-丁烯-1-基)氧基)-4-硝基苯甲酸甲酯(450mg,1.70mmol)中加入亚磷酸三乙酯(1.78mL,10.2mmol)，160℃封管反应6小时后，停止反应。冷却至室温后加水稀释(25mL)，乙酸乙酯萃取(20mL×3)，有机相合并，饱和食盐水洗涤(15mL)，无水硫酸钠干燥，浓缩得到棕色固体产230mg，产率：58.12％。
MS(ESI,pos.ion)m/z:234.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.53(dd,J＝8.3,1.5Hz,1H),7.50(s,1H),6.61(d,J＝8.2Hz,1H),5.07(d,J＝19.1Hz,2H),4.28(d,J＝11.7Hz,2H),3.94(dt,J＝9.8,8.0Hz,2H),3.87(s,3H),1.84(s,3H).
步骤三：3-异丙基-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯的合成
向3-(丙-2-亚基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(150mg,0.64mmol)，Pd/C(19mg)中加入甲醇(6mL)，氢气氛围下，室温反应24小时后，停止反应，硅藻土过滤，浓缩得到无色油状产物150mg，产率：99.15％。
MS(ESI,pos.ion)m/z:236.1[M+H] +
步骤四：3-异丙基-4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯的合成
向3-异丙基-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(90mg,0.38mmol)，Pd(OAc) 2(9mg,0.04mmol)，(R)-(+)-1,1’-联萘-2,2’-双二苯膦(25mg,0.04mmol)，碳酸铯(625mg,1.92mmol)，4-(三氟甲基)碘苯(136mg,0.50mmol)的混合物中加入甲苯(6mL)，氮气保护，100℃反应24小时，冷却至室温后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，浓缩柱层析(淋洗 剂：PE/EtOAc(v/v)＝4/1)，得到棕色油状产物40mg，产率：27.56％。
MS(ESI,pos.ion)m/z:380.2[M+H] +
步骤五：3-异丙基-4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸的合成
向3-异丙基-4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(43mg,0.11mmol)的中加入甲醇(1mL)，四氢呋喃(1mL)和氢氧化钠溶液(1mL，2M)，50℃反应4小时后，冷却至室温后用稀盐酸(1M)调至pH＝5-6，二氯甲烷萃取(20mL×3)，无水硫酸钠干燥，浓缩得到粗产物38mg，产率：91.76％。
MS(ESI,pos.ion)m/z:366.1[M+H] +
步骤六：N-((S)-2-氰基-1-(4-(乙磺酰基)苯基)乙基)-3-异丙基-4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺的合成
向3-异丙基-4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸(38mg,0.10mmol)，(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(32mg,0.12mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(41mg,0.21mmol)和1-羟基苯并三唑(29mg,0.21mmol)的混合物中加入二氯甲烷(4mL,62.40mmol)，三乙胺(45μL,0.32mmol)，室温反应24小时后，停止反应，加入二氯甲烷稀释(20mL)，饱和氯化铵溶液洗涤(15mL)，饱和食盐水洗涤(15mL)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到淡黄色目标产物25mg，产率：39.15％，纯度：95.38％。
MS(ESI,pos.ion)m/z:586.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.90(d,J＝8.2Hz,2H),7.66(d,J＝8.2Hz,2H),7.56(d,J＝8.5Hz,2H),7.45(s,1H),7.33(d,J＝8.5Hz,1H),7.27(d,J＝6.7Hz,2H),7.10(d,J＝8.5Hz,1H),6.97(d,J＝7.1Hz,1H),5.62(dd,J＝13.2,6.3Hz,1H),4.48(d,J＝11.0Hz,1H),3.97(dd,J＝11.0,2.0Hz,1H),3.43(d,J＝9.7Hz,1H),3.24–3.02(m,4H),1.91(td,J＝13.6,6.8Hz,1H),1.31–1.27(m,3H),1.15(d,J＝6.8Hz,3H),1.08(d,J＝6.6Hz,3H).
实施例18
N-((S)-2-氰基-1-(4-(乙磺酰基)苯基)乙基)-3-异丙基-4-(3-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000042
步骤一：3-异丙基-4-(3-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯的合成
向3-异丙基-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(90mg,0.38mmol)，Pd(OAc) 2(9mg,0.04mmol)， (R)-(+)-1,1’-联萘-2,2’-双二苯膦(25mg,0.04mmol)，碳酸铯(625mg,1.91mmol)，3-(三氟甲基)碘苯(136mg,0.50mmol)的混合物中加入甲苯(6mL)，氮气保护，100℃反应22小时，冷却至室温后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，浓缩柱层析(淋洗剂：PE/EtOAc(v/v)＝4/1)得到棕色油状产物31mg，产率：21.36％。
MS(ESI,pos.ion)m/z:380.2[M+H] +
步骤二：3-异丙基-4-(3-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸的合成
向3-异丙基-4-(3-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(38mg,0.10mmol)的中加入甲醇(1mL)，四氢呋喃(1mL)和氢氧化钠溶液(1mL)，50℃反应4小时，冷却至室温后用稀盐酸(1M)调至pH＝5-6，二氯甲烷萃取(20mL×3)，无水硫酸钠干燥，浓缩得到粗产物31mg，产率：84.70％。
MS(ESI,pos.ion)m/z:366.3[M+H] +
步骤三：N-((S)-2-氰基-1-(4-(乙磺酰基)苯基)乙基)-3-异丙基-4-(4-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺的合成
向3-异丙基-4-(3-(三氟甲基)苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸(38mg,0.10mmol)，(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(32mg,0.11mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(41mg,0.21mmol)和1-羟基苯并三唑(29mg,0.21mmol)的混合物中加入二氯甲烷(4mL)，三乙胺(45μL,0.32mmol)，室温反应24后，停止反应，加入二氯甲烷稀释(20mL)，饱和氯化铵溶液洗涤(15mL)，饱和食盐水洗涤(15mL)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)，得到淡黄色固体产物16mg，产率：23.39％，纯度：89.03％。
MS(ESI,pos.ion)m/z:586.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.91(d,J＝8.3Hz,2H),7.67(d,J＝8.2Hz,2H),7.45(dd,J＝8.0,6.3Hz,3H),7.34(dd,J＝16.6,9.6Hz,2H),7.09–6.91(m,2H),5.62(dd,J＝12.9,6.1Hz,1H),4.75(s,1H),4.47(d,J＝11.0Hz,1H),3.98(dd,J＝11.0,2.0Hz,1H),3.39(d,J＝9.2Hz,1H),3.23–3.04(m,4H),1.92(dd,J＝14.9,7.0Hz,1H),1.29(s,3H),1.15(d,J＝6.8Hz,3H),1.07(d,J＝6.6Hz,3H).
实施例19
(R)-4-(3,5-二环丙基苯基)-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000043
向4-(3,5-二环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸(60mg,0.18mmol)，(R)-2-氨基-2-(4-(乙 基磺酰基)苯基)乙醇(53mg,0.23mmol)，1-羟基苯并三唑(50mg,0.36mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(70mg,0.36mmol)的混合物中加入二氯甲烷(8mL)，三乙胺(100μL,0.72mmol)，室温搅拌36小时后，停止反应，二氯甲烷稀释(25mL)，饱和氯化铵溶液洗涤(15mL)，无水硫酸钠干燥，浓缩拌样，柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到白色固体产物64mg，产率：61.52％，纯度：94.01％。
MS(ESI,pos.ion)m/z:547.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.88(d,J＝7.8Hz,2H),7.58(d,J＝8.1Hz,2H),7.37(d,J＝1.6Hz,1H),7.24(d,J＝8.5Hz,1H),6.97(t,J＝6.3Hz,1H),6.81(d,J＝8.5Hz,1H),6.74(s,2H),6.64(s,1H),5.28(s,1H),4.33(d,J＝3.9Hz,2H),4.09–3.90(m,2H),3.74(d,J＝4.0Hz,2H),3.11(q,J＝7.4Hz,2H),1.87(ddd,J＝13.4,8.5,5.1Hz,2H),1.31–1.27(m,3H),1.03–0.92(m,4H),0.75–0.63(m,4H).
实施例20
(R)-4-(2,6-二环丙基吡啶-4-基)-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰胺
Figure PCTCN2020141222-appb-000044
向4-(2,6-二环丙基-4-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸(60mg,0.18mmol)，(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇(45mg,0.20mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(70mg,0.36mmol)和1-羟基苯并三唑(50mg,0.37mmol)的混合物中加入二氯甲烷(5mL,78.01mmol)，三乙胺(75μL,0.538mmol)，室温反应36小时后，停止反应，加入二氯甲烷稀释(25mL)，饱和氯化铵溶液洗涤(15mL)，无水硫酸钠干燥，浓缩拌样，柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到白色固体产物52mg，产率：52.30％。
MS(ESI,pos.ion)m/z:548.3[M+H] +
1H NMR(600MHz,CDCl 3)δ7.77(t,J＝7.0Hz,3H),7.55(d,J＝7.7Hz,2H),7.48(s,1H),7.39(d,J＝8.5Hz,1H),7.17(t,J＝8.4Hz,1H),6.65(s,2H),5.21(d,J＝4.6Hz,1H),4.24(s,2H),3.98–3.88(m,2H),3.83(s,1H),3.76–3.67(m,2H),3.06(q,J＝7.3Hz,2H),1.92(dt,J＝12.9,6.6Hz,2H),1.25–1.19(m,4H),0.93(dd,J＝20.8,4.9Hz,7H).
实施例21
(R)-1-(2,6-二环丙基吡啶-4-基)-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-2,3-二氢-1H-吡啶并[2,3-b][1,4]噁嗪-6-甲酰胺
Figure PCTCN2020141222-appb-000045
向1-(2,6-二环丙基吡啶-4-基)-2,3-二氢-1H-吡啶并[2,3-b][1,4]噁嗪-6-甲酸(67mg,0.19mmol)，(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇(53mg,0.23mmol)，1-羟基苯并三唑(55mg,0.40mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(78mg,0.40mmol)的混合物中加入二氯甲烷(8mL)，三乙胺(110μL,0.79mmol)，室温搅拌30小时后，停止反应，二氯甲烷稀释(25mL)，饱和氯化铵溶液洗涤(15mL)，无水硫酸钠干燥，浓缩拌样，柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到白色固体产物11mg，产率：9.34％，纯度：88.41％。
MS(ESI,pos.ion)m/z:549.2[M+H] +
1H NMR(400MHz,CDCl 3)δ8.40(d,J＝7.6Hz,1H),7.90(d,J＝8.2Hz,2H),7.74(d,J＝8.2Hz,1H),7.63(d,J＝8.2Hz,2H),7.58(d,J＝8.2Hz,1H),6.74(s,2H),5.31(dd,J＝12.1,5.1Hz,1H),4.58–4.48(m,2H),4.05(t,J＝5.1Hz,2H),3.85–3.78(m,2H),3.11(q,J＝7.4Hz,2H),1.93–1.87(m,2H),1.32–1.30(m,3H),1.04–0.99(m,4H),0.93–0.90(m,4H).
实施例22
(S)-3-(4-(3,5-二环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-甲酰胺基)-3-(4-(乙基磺酰基)苯基)丙酸
Figure PCTCN2020141222-appb-000046
步骤一：4-(3,5-二环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-羧酸的合成
将Pd 2(dba) 3(200mg,0.21mmol)、叔丁醇钠(600mg,6.24mmol)、三叔丁基磷(43.0mg,0.21mmol)依次加入3,4-二氢-2H-1,4-苯并恶嗪-7-羧酸甲酯(400mg,2.07mmol)与1-氯-3,5-二环丙基-苯(400mg,2.08mmol)的二甲苯(12mL)溶液中，在氮气保护下，155℃下反应12小时。反应停止后冷却至室温，加入饱和氯化钠水溶液(30mL)淬灭。用二氯甲烷(20mL×3)萃取，合并有机相后，用无水硫酸钠干燥过滤。有机相减压浓缩，粗产物由硅胶柱层析分离(淋洗剂：PE/EtOAc(v/v)＝2/1)得到白色固体产物226mg，产率：33％。
MS(ESI,pos.ion)m/z:336.2[M+H] +
步骤二：(S)-3-(4-(3,5-二环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-甲酰胺基)-3-(4-(乙基磺酰基)苯基)丙 酸甲酯的合成
向(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙酸甲酯盐酸盐(61.0mg,0.20mmol)、4-(3,5-二环丙基苯基)-2,3-二氢-1,4-苯并恶嗪-7-羧酸(60.0mg,0.18mmol)的二氯甲烷(6.0mL)溶液中加入HATU(143mg,0.36mmol)与三乙胺(80μL,0.57mmol)室温下搅拌2小时。停止反应后，加入二氯甲烷(20mL)稀释。经饱和氯化铵溶液(10mL)淬灭洗涤，无水硫酸钠干燥。有机相减压浓缩，粗产物由硅胶柱层析分离(淋洗剂：PE/EtOAc(v/v)＝1/2)得到淡黄色固体105mg，产率：99％。
MS(ESI,pos.ion)m/z:589.3[M+H] +
步骤三：(S)-3-(4-(3,5-二环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-甲酰胺基)-3-(4-(乙基磺酰基)苯基)丙酸的合成
将碳酸钾(215mg,1.56mmol)加入(S)-3-(4-(3,5-二环丙基苯基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-甲酰胺基)-3-(4-(乙基磺酰基)甲酯苯基)丙酸甲酯(115mg,0.20mmol)的甲醇(6mL)溶液中，室温搅拌12小时。停止反应后，向反应液中加入二氯甲烷(100mL)稀释，硅藻土过滤。滤液减压浓缩后，粗产物由硅胶柱层析分离(淋洗剂：DCM/MeOH(v/v)＝10/1)得到淡棕色白色固体产物100mg，产率：89％，纯度85.47％。
MS(ESI,pos.ion)m/z:573.1[M+H] +
1H NMR(400MHz,DMSO-d 6)δ9.13(s,1H),7.80(d,J＝8.1Hz,2H),7.62(d,J＝8.1Hz,2H),7.34(s,1H),7.24(d,J＝8.3Hz,1H),6.75–6.67(m,3H),6.59(s,1H),5.38(d,J＝6.5Hz,1H),4.26(s,2H),3.68(s,2H),3.25(d,J＝7.4Hz,3H),2.89(s,1H),2.73(s,1H),1.86(ddd,J＝13.4,8.5,5.2Hz,2H),1.09(t,J＝7.3Hz,3H),0.91(dt,J＝5.8,4.2Hz,4H),0.66(d,J＝4.6Hz,4H).
实施例23
(S)-3-(4-(2,6-二环丙基吡啶-4-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰氨基)-3-(4-(乙基磺酰基)苯基)丙酸
Figure PCTCN2020141222-appb-000047
步骤一：(S)-3-(4-(2,6-二环丙基吡啶-4-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰氨基)-3-(4-(乙基磺酰基)苯基)丙酸甲酯的合成
向4-(2,6-二环丙基吡啶-4-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酸(60mg,0.18mmol)，(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙酸甲酯盐酸盐(61mg,0.19mmol)，HATU(136mg,0.35mmol)的二氯甲烷(6mL,93.61mmol)溶液中加入三乙胺(80μL,0.57mmol)，室温搅拌12小时，停止反应，加入饱和氯化铵溶液淬灭(25mL)，二氯甲烷萃取(25mL×3)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v) ＝1/2)得到淡黄色油状产物100mg，产率：95.08％。
MS(ESI,pos.ion)m/z:590.2[M+H] +
步骤二：(S)-3-(4-(2,6-二环丙基吡啶-4-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰氨基)-3-(4-(乙基磺酰基)苯基)丙酸的合成
向(S)-3-(4-(2,6-二环丙基吡啶-4-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲酰氨基)-3-(4-(乙基磺酰基)苯基)丙酸甲酯(100mg,0.17mmol)的甲醇(5mL)溶液中加入碳酸钾(118mg,0.85mmol)，室温搅拌48小时。加入二氯甲烷稀释(20mL)，硅藻土过滤，硅胶浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/2)得到产物85mg，产率：83.00％，纯度：95.33％.
MS(ESI,pos.ion)m/z:576.4[M+H] +
1H NMR(400MHz,DMSO-d 6)δ9.06(s,1H),7.83(d,J＝8.2Hz,2H),7.66(d,J＝8.3Hz,2H),7.43(d,J＝1.5Hz,1H),7.37(d,J＝8.5Hz,1H),7.22(d,J＝8.5Hz,1H),6.87(s,2H),5.44(dd,J＝14.3,7.4Hz,1H),4.25(s,2H),3.79(s,2H),3.26(dd,J＝14.8,7.4Hz,2H),2.88–2.74(m,2H),1.95–1.89(m,2H),1.09(t,J＝7.3Hz,3H),0.83(d,J＝7.8Hz,8H).
实施例24
(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-1-(3,5-二环丙基苯基)吲哚啉-5-甲酰胺
Figure PCTCN2020141222-appb-000048
步骤一：吲哚啉-5-甲酸甲酯的合成
0℃下，向1H-吲哚-5-甲酸甲酯(500mg,2.85mmol)的醋酸(6mL)溶液中加入氰基硼氢化钠(540mg,8.59mmol)，自然升至室温反应过夜，停止反应，加入饱和碳酸氢钠溶液淬灭(30mL)，乙酸乙酯萃取(30mL×3)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝3/1)得到淡黄色固体产物250mg，产率：49.43％。
MS(ESI,pos.ion)m/z:178.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.77(d,J＝4.1Hz,2H),6.56(d,J＝8.6Hz,1H),3.87(s,3H),3.67(t,J＝8.5Hz,2H),3.08(t,J＝8.5Hz,2H).
步骤二：1-(3,5-二环丙基苯基)吲哚啉-5-甲酸的合成
向吲哚啉-5-甲酸甲酯(240mg,1.35mmol)，1-氯-3,5-环丙基苯(274mg,1.42mmol)，叔丁醇钠(390mg,4.06mmol)，Pd 2(dba) 3(125mg,0.13mmol)和三(叔丁基)膦(28mg,0.14mmol)的混合物中加入二甲苯(10 mL)，氮气保护，155℃反应12小时后，停止反应，冷却至室温后加入饱和氯化铵溶液淬灭(30mL)，二氯甲烷萃取(30mL×3)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/1)得到淡黄色固体产物40mg，产率：9.25％。
MS(ESI,pos.ion)m/z:320.1[M+H] +
步骤三：(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-1-(3,5-二环丙基苯基)吲哚啉-5-甲酰胺的合成
向1-(3,5-二环丙基苯基)吲哚啉-5-甲酸(36mg,0.11mmol)，(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(33mg,0.12mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(44mg,0.23mmol)，1-羟基苯并三唑(31mg,0.22mmol)的混合物中加入二氯甲烷(4mL)和三乙胺(50μL,0.36mmol)，室温反应12h。停止反应，加入饱和氯化铵溶液淬灭(25mL)，二氯甲烷萃取(30mL×3)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/1)得到淡黄色固体产物23mg，产率：34.52％，纯度：91.29％。
MS(ESI,pos.ion)m/z:540.0[M+H] +
1H NMR(400MHz,CDCl 3)δ7.92(d,J＝8.3Hz,2H),7.67(d,J＝8.3Hz,2H),7.63(s,1H),7.58(d,J＝8.4Hz,1H),6.97(d,J＝8.4Hz,1H),6.80(d,J＝7.7Hz,1H),6.75(s,2H),6.52(s,1H),5.62(dd,J＝13.0,6.2Hz,1H),4.02(t,J＝8.6Hz,2H),3.28–2.98(m,6H),1.93–1.80(m,2H),1.31(d,J＝7.4Hz,3H),1.02–0.93(m,4H),0.79–0.64(m,4H).
实施例25
(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-1-(3,5-二环丙基苯基)-1H-吲哚-5-甲酰胺
Figure PCTCN2020141222-appb-000049
步骤一：1-(3,5-二环丙基苯基)-1H-吲哚-5-甲酸甲酯的合成
将1H-吲哚-5-甲酸甲酯(200mg,1.14mmol)，1-氯-3,5-二环丙基苯(241mg,1.25mmol)，Pd 2(dba) 3(54mg,0.05mmol)，2-二环己膦基-2'-(N,N-二甲胺)-联苯(70mg,0.17mmol)和叔丁醇钠(165mg,1.72mmol)，二甲苯(8mL)依次加入封管中，氮气保护，130℃加热反应12小时后，停止反应，冷却至室温后加入饱和氯化铵溶液(15mL)淬灭，乙酸乙酯萃取(25mL×3)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝5/1)得到产物269mg，产率：71.10％。
MS(ESI,pos.ion)m/z:332.1[M+H] +
步骤二：1-(3,5-二环丙基苯基)-1H-吲哚-5-甲酸的合成
向1-(3,5-二环丙基苯基)-1H-吲哚-5-甲酸甲酯(269mg,0.81mmol)中加入甲醇(2mL)和四氢呋喃 (2mL)，氢氧化钠(0.6mL,2mmol)，55℃加热反应12小时，停止反应，冷却至室温后加入饱和氯化铵溶液(8mL)淬灭，稀盐酸(1M)调节pH至7左右，二氯甲烷萃取(30mL×3)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝3/1)得到淡黄色固体产物110mg，产率：42.70％。
MS(ESI,pos.ion)m/z:318.2[M+H] +
步骤三：(S)-N-(2-氰基-1-(4-(乙基磺酰基)苯基)乙基)-1-(3,5-二环丙基苯基)-1H-吲哚-5-甲酰胺的合成
向1-(3,5-二环丙基苯基)-1H-吲哚-5-甲酸(50mg,0.15mmol)，(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙腈盐酸盐(46mg,0.16mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(61mg,0.31mmol)，1-羟基苯并三唑(43mg,0.31mmol)的二氯甲烷(5mL)溶液中加入三乙胺(70μL,0.50mmol)，室温反应24小时，停止反应，加入饱和氯化铵溶液淬灭(15mL)，二氯甲烷萃取(20mL×3)，无水硫酸钠干燥，浓缩拌样柱层析(淋洗剂：PE/EtOAc(v/v)＝1/1)得到淡黄色固体产物53mg，产率：59.74％，纯度：95.48％。
MS(ESI,pos.ion)m/z:538.2[M+H] +
1H NMR(400MHz,CDCl 3)δ8.21(s,1H),7.89(d,J＝8.3Hz,2H),7.71(d,J＝8.7Hz,1H),7.67(d,J＝8.3Hz,2H),7.52(d,J＝8.7Hz,1H),7.38(d,J＝3.2Hz,1H),7.28–7.20(m,1H),6.93(d,J＝1.0Hz,2H),6.85(s,1H),6.70(d,J＝3.2Hz,1H),5.65(q,J＝6.3Hz,1H),3.18–3.04(m,4H),1.94(td,J＝8.4,4.2Hz,2H),1.32–1.27(m,3H),1.08–0.97(m,4H),0.79–0.70(m,4H).
实施例26
(R)-1-(3,5-二环丙基苯基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2,3-二氢-1H-吡啶[2,3-b][1,4]恶嗪-6-羧酰胺
Figure PCTCN2020141222-appb-000050
步骤一：1-叔丁基6-甲基2,3-二氢-1H-吡啶并[2,3-b][1,4]恶嗪-1,6-二羧酸酯的合成
室温下向6-溴-2,3-二氢-1H-吡啶并[2,3-b][1,4]恶嗪-1-羧酸叔丁酯(370mg,1.17mmol)、Pd(OAc) 2(20mg,0.09mmol)、1,1'-双(二苯基膦)二茂铁(170mg,0.29mmol)的混合物中加入三乙胺(330μL,2.36mmol)和甲醇(10mL)，在一氧化碳氛围下50℃反应24小时。停止反应后冷却至室温。将反应液减压浓缩除去溶剂，加入二氯甲烷稀释(50mL)，用饱和氯化铵溶液洗涤(20mL)，无水硫酸钠干燥。过滤后将有机相减压浓缩，柱层析分离(淋洗剂：PE/EtOAc(v/v)＝3/2)，得到淡黄色色固体产物262mg，产率：76％。
MS(ESI,pos.ion)m/z:295.3[M+H] +。
步骤二：2,3-二氢-1H-吡啶并[2,3-b][1,4]恶嗪-6-羧酸甲酯的合成
向1-叔丁基6-甲基2,3-二氢-1H-吡啶并[2,3-b][1,4]恶嗪-1,6-二羧酸酯(262mg,0.89mmol)的二氯甲烷 (6mL)溶液中加入盐酸1,4-二氧六环溶液(2mL,8mmol,4M)，室温下搅拌过夜。停止反应，浓缩溶剂，加入饱和碳酸氢钠溶液中和至中性，乙酸乙酯萃取(30mL×3)，合并有机相后经无水硫酸钠干燥，过滤后减压浓缩得到棕色固体产物157mg，产率：91％。
MS(ESI,pos.ion)m/z:195.1[M+H] +
步骤三：1-(3,5-二环丙基苯基)-2,3-二氢-1H-吡啶[2,3-b][1,4]恶嗪-6-羧酸的合成
将叔丁醇钠(186mg,1.93mmol)、三叔丁基磷(15mg,0.07mmol)、Pd 2(dba) 3(62mg,0.06mmol)、1-氯-3,5-二环丙基-苯(136mg,0.70mmol)依次加入2,3-二氢-1H-吡啶并[2,3-b][1,4]恶嗪-6-羧酸甲酯(125mg,0.64mmol)的二甲苯(7mL)溶液中，在氮气保护下于155℃反应12h。反应停止后，冷却至室温。反应液用饱和氯化铵溶液(30mL)淬灭。用二氯甲烷(25mL×3)萃取，无水硫酸钠干燥过滤后。柱层析分离(淋洗剂：DCM/MeOH(v/v)＝4/1)，得到棕色固体46mg，产率：21％。
MS(ESI,pos.ion)m/z:337.1[M+H] +
步骤四：(R)-1-(3,5-二环丙基苯基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2,3-二氢-1H-吡啶[2,3-b][1,4]恶嗪-6-羧酰胺的合成
将1-(3,5-二环丙基苯基)-2,3-二氢-1H-吡啶[2,3-b][1,4]恶嗪-6-羧酸(58mg,0.17mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(62mg,0.34mmol)、1-羟基苯并三唑(50mg,0.37mmol)与(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇(80mg,0.35mmol)依次加入到带有搅拌子的单口瓶中，再加入二氯甲烷(6mL)和三乙胺(73μL,0.52mmol)。室温下搅拌12小时，反应完毕后，反应液用二氯甲烷稀释(40mL)。有机相混合后用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥。过滤后减压浓缩，通过柱层析分离(淋洗剂：PE/EtOAc(v/v)＝5/1)，得到淡黄色固体14mg，产率：15％，纯度：92.69％。
MS(ESI,pos.ion)m/z:548.6[M+H] +
1H NMR(400MHz,CDCl 3)δ8.31(d,J＝7.3Hz,1H),7.87(d,J＝8.2Hz,2H),7.61(t,J＝7.9Hz,3H),7.06(d,J＝8.2Hz,1H),6.70(s,2H),6.67(s,1H),5.28(dd,J＝11.5,5.1Hz,1H),4.56–4.46(m,2H),4.02(s,2H),3.77–3.68(m,2H),3.09(q,J＝7.3Hz,2H),2.72(s,1H),1.85(td,J＝8.5,4.3Hz,2H),1.29(d,J＝7.3Hz,3H),0.97(q,J＝6.0Hz,4H),0.67(q,J＝5.1Hz,4H).
本发明化合物的生物活性测试
RORγt蛋白受体结合试验
1.实验原理：
RORγt激动剂活性筛选采用ROR-γt蛋白受体结合试验方法。实验体系中ROR-γt-LBD蛋白带GST标签(RORgt-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RORgt-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，从而增强对SRC的招募时，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，当化合物无法有效地促进ROR-γt-LBD招募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对ROR-γt的激活作用，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，同时配置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(10uM)，3倍梯度稀释，每孔5ul加于384孔板中；用1×buffer配置4×ROR-γt-LBD(20nM)，4×ursolic acid(0.4uM)混合液，每孔5ul加于384孔板中；再用1×buffer准备2×SRC(100n M)，2×Europium anti-GST(1:200)和2×Streptavidin-D2(25nM)混合液，每孔10ul加于384孔板中，1000g离心1min。室温避光孵育4h，在Envision2104酶标仪读板机上检测665nm和615nm双波长下信号强度，并计算结合率，计算出Emax和EC 50值。
3.实验数据
根据在Envision 2104酶标仪读板机上检测665nm和615nm双波长下信号强度数值，并计算结合率，计算出E max和EC 50值。E max即为测试化合物的最大结合率，以下是结合率的计算公式：
结合率(％)＝(X-min)/(max-min)*100％
X：指测试化合物在665/615条件下所测数值减去背景值后的数值；Min：指DMSO空白对照在665/615条件下所测数值减去背景值后的平均数值；Max：指10uM的阳性药在665/615条件下所测数值减去背景值后的平均数值。
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：
Z＝Bottom+(Top-Bottom)/(1+10^((LogEC 50-Y)*HillSlope))
Z：结合率(％)；Y：化合物浓度log值。
实验结果如下：
表2本发明化合物的RORγt蛋白受体结合试验结果
实施例编号 EC 50(nM) E max％ 实施例编号 EC 50(nM) E max％
8 19.1 121.1 21 6 132.1
10 29.29 158 22 5 129.9
19 2.7 127.4 23 37.7 120.3
20 5.4 126.6 26 0.3 126.6
实验结论：本发明的化合物对RORγt蛋白受体有较好的结合活性。
细胞功能活性实验评估ROR-γt激动剂体外药效
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10cm2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。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，计算各浓度下化合物对转染细胞表达荧光的激活百分率并计算EC 50和E max。
实验结果如下：
表3本发明化合物的体外药效实验结果
实施例编号 EC 50(nM) E max％ 实施例编号 EC 50(nM) E max％
8 101 57.03 21 340 107.5
19 106 82.1 26 68 73.92
20 196 100.3      
实验结论：本发明的化合物对RORγt蛋白受体有较好的激动活性。
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须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 (11)

  1. 一种化合物，其为式(I)所示化合物或式(I)所示化合物的立体异构体、几何异构体、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 PCTCN2020141222-appb-100001
    其中：
    环A为
    Figure PCTCN2020141222-appb-100002
    其中*表示与L连接；**表示与羰基连接；
    其中X 1、X 2和X 3各自独立地选自CH 2、NH、S(O) t或O；X 4、X 5、X 6和X 7各自独立地选自CH或N；
    环B选自C 6-10芳基或5-6个原子组成的杂芳基；
    各R 4独立地选自H、氘、F、Cl、Br、I、-CN、-OH、-NR aR b、-C(＝O)OR f、-C(＝O)R f、-C(＝O)NR aR b、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基或C 1-6烷氨基；其中各R 4独立地未被取代或被1、2、3或4个R c所取代；
    L选自键、-NR x-、-O-、*-(CH 2) r-C(O)-(CH 2) r-、*-(CH 2) r-S(O) t-(CH 2) r-或C 1-6亚烷基；其中*表示与环A连接；
    R x选自H、氘、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6环烷基-C 1-6亚烷基、3-6个原子组成的杂环基、3-6个原子组成的杂环基-C 1-6亚烷基、C 6-10芳基、C 6-10芳基-C 1-6亚烷基、5-10个原子组成的杂芳基或5-10个原子组成的杂芳基-C 1-6亚烷基；
    环C选自C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基；其中环C独立地未被取代或被1、2、3或4个R y所取代；
    R 1选自H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、-S(＝O) 2-C 1-3烷基、-C(＝O)-C 1-3烷基、-C(＝O)O-C 1-3烷基、-C(＝O)NH-C 1-3烷基、C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基，其中各R 1独立地未被取代或被1、2、3或4个R e所取代；
    R 2选自F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、-S(＝O) 2-C 1-3烷基、-C(＝O)-C 1-3烷基、-C(＝O)O-C 1-3烷基、-C(＝O)NH-C 1-3烷基、C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基，其中各R 2独立地未被取代或被1、2、3或4个R e所取代；
    各R 3独立地选自氘、F、Cl、Br、I、-CN、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、 -S(＝O) 2-C 1-3烷基、-C(＝O)-C 1-3烷基、-C(＝O)O-C 1-3烷基、-C(＝O)NH-C 1-3烷基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 2-6烯基、C 2-6炔基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基，其中各R 3独立地未被取代或被1、2、3或4个R e所取代；
    各R y独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；其中各R y独立地未被取代或被1、2、3或4个R d所取代；
    各R c独立地选自氘、F、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OR f、-C(＝O)NR aR b、-S(＝O) 2R f、-S(＝O) 2NR aR b、C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；
    各R d独立地选自氘、F、Cl、Br、Cl、I、-CN、-NO 2、-OH、-SH、-NH 2、S(＝O) 2R f、C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；
    各R a和R b独立地选自H、氘、C 1-6卤代烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10环烷基-C 1-3亚烷基、3-10个原子组成的杂环基、(3-10个原子组成的杂环基)-C 1-3亚烷基、C 6-10芳基、C 6-10芳基-C 1-3亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-3亚烷基；
    各R f独立地选自H、氘、-OH、-SH、-NH 2、C 1-6卤代烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10环烷基C 1-3烷基、3-10个原子组成的杂环基、(3-10个原子组成的杂环基)-C 1-3亚烷基、C 6-10芳基、C 6-10芳基-C 1-3亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-3亚烷基；
    各R e独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OR f、-S(＝O) 2R f、-C(＝O)NR aR b、-S(＝O) 2NR aR b、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；
    各t独立地为0、1或2；
    各r独立地为0、1、2、3或4；
    n为1、2、3或4；
    m为0、1、2、3或4；
    其中，所述化合物不为以下任一化合物：
    Figure PCTCN2020141222-appb-100003
    Figure PCTCN2020141222-appb-100004
  2. 根据权利要求1所述的化合物，其中：
    所述环A为
    Figure PCTCN2020141222-appb-100005
    Figure PCTCN2020141222-appb-100006
    *表示与L连接；**表示与羰基连接；
    其中X 1、X 2和X 3各自独立地选自CH 2、NH或O；X 4、X 5、X 6和X 7各自独立地选自CH或N；
    所述环B选自苯基、萘基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基或1,3,5-三嗪基；
    所述环C选自环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、四氢噻吩基、四氢吡喃基、二氧六环基、吗啉基、哌啶基、哌嗪基、六氢嘧啶基、苯基、萘基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基或1,3,5-三嗪基；其中各环C独立地未被取代或被1、2、3或4个R y所取代。
  3. 根据权利要求1或2所述的化合物，其中：
    所述各R y独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、C 2-4烯基、C 2-4炔基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、四氢噻吩基、四氢吡喃基、二氧六环基、吗啉基、哌啶基、哌嗪基、六氢嘧啶基、苯基、萘基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基或1,3,5-三嗪基；其中各R y独立地未被取代或被1、2、3或4个R d所取代；
    所述各R d独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-S(＝O) 2R f、C 1-4卤代烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、C 2-4烯基、C 2-4炔基、C 3-10环烷基、3-10个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基。
  4. 根据权利要求1-3任意一项所述的化合物，其中：
    所述各R y独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、正丁基、 异丁基、叔丁基、仲丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、三氟甲基、N-甲氨基、N-乙氨基、甲硫基、乙硫基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、四氢噻吩基、四氢吡喃基、二氧六环基、吗啉基、哌啶基、哌嗪基、六氢嘧啶基、苯基、萘基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基或1,3,5-三嗪基；其中各R y独立地未被取代或被1、2、3或4个R d所取代；
    所述各R d独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-S(＝O) 2R f、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、三氟甲基、二氟甲基、一氟甲基、三氟甲氧基、二氟甲氧基、一氟甲氧基、N-甲氨基、N-乙氨基、甲硫基、乙硫基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、氮杂环戊基、苯基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻唑烷基、吡唑烷基、恶唑烷基、咪唑烷基、异恶唑烷基、哌啶基、哌嗪基、吗啉基、吡咯基、呋喃基、噻吩基、噻唑基、吡唑基、吡啶基或嘧啶基。
  5. 根据权利要求1-4任意一项所述的化合物，其中：
    L选自键、-NR x-、-O-、-C(O)-、*-C(O)-CH 2-、*-CH 2-C(O)-、-S(O) 2-、*-S(O) 2-CH 2-、*-CH 2-S(O) 2-、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-或-CH 2CH 2CH 2CH 2-；其中*表示与环A连接。
  6. 根据权利要求1-5任意一项所述的化合物，其中：
    R 1选自H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟甲基、二氟甲基、一氟甲基、2,2,2-三氟乙基、1,1-二氟乙基、2,2-二氟乙基、1-氟乙基、2-氟乙基、甲氧基、乙氧基、丙氧基、甲硫基、乙硫基、N-甲氨基、N-乙氨基、N’N-二甲基氨基、C 1-4卤代烷氧基、环丙基、环丁基、环戊基、环氧乙烷基、氧杂环丁基或四氢呋喃基，其中各R 1独立地未被取代或被1、2、3或4个R e所取代；
    R 2选自F、Cl、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟甲基、二氟甲基、一氟甲基、2,2,2-三氟乙基、1,1-二氟乙基、2,2-二氟乙基、1-氟乙基、2-氟乙基、甲氧基、乙氧基、丙氧基、甲硫基、乙硫基、N-甲氨基、N-乙氨基、N’N-二甲基氨基、C 1-4卤代烷氧基、环丙基、环丁基、环戊基、环氧乙烷基、氧杂环丁基或四氢呋喃基，其中各R 2独立地未被取代或被1、2、3或4个R e所取代；
    各R 3独立地选自氘、F、Cl、Br、I、-CN、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、-S(＝O) 2-CH 3、-S(＝O) 2-CH 2CH 3或-S(＝O) 2-CH 2CH 2CH 3；
    各R 4独立地选自H、氘、F、Cl、Br、I、-CN、-OH、-NR aR b、-C(＝O)OR f、-C(＝O)R f、-C(＝O)NR aR b、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟甲基、二氟甲基、一氟甲基、2,2,2- 三氟乙基、1,1-二氟乙基、2,2-二氟乙基、1-氟乙基、2-氟乙基、甲氧基、乙氧基、丙氧基、甲硫基、乙硫基、N-甲氨基、N-乙氨基、N’N-二甲基氨基、C 1-4卤代烷氧基、C 2-4烯基或C 2-4炔基；其中各R 4独立地未被取代或被1、2、3或4个R c所取代。
  7. 根据权利要求1-6任意一项所述的化合物，其中所述化合物具有如式(II)所示结构：
    Figure PCTCN2020141222-appb-100007
    其中，Z 1为CH或N；s为0、1、2、3或4。
  8. 根据权利要求1-7任意一项所述的化合物，其中所述化合物具有如式(III)或式(IV)所示结构：
    Figure PCTCN2020141222-appb-100008
    其中，Z 1为CH或N；s为0、1、2、3或4。
  9. 根据权利要求1-8任意一项所述的化合物，其具有以下其中之一的结构：
    Figure PCTCN2020141222-appb-100009
    Figure PCTCN2020141222-appb-100010
    Figure PCTCN2020141222-appb-100011
    Figure PCTCN2020141222-appb-100012
    或它的立体异构体、互变异构体、氮化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药。
  10. 一种药物组合物，其包含权利要求1-9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。
  11. 权利要求1-9任意一项所述的化合物或权利要求10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、自身免疫性眼病、银屑病、系统性红斑狼疮、多发性硬化症、炎性肠病、炎性肠综合征、结肠炎、细菌感染、真菌感染、强直性脊柱炎、哮喘、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。
PCT/CN2020/141222 2019-12-31 2020-12-30 具有双环结构的酰胺类化合物及其在药物中的应用 Ceased WO2021136339A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201911411802.0 2019-12-31
CN201911411802 2019-12-31

Publications (1)

Publication Number Publication Date
WO2021136339A1 true WO2021136339A1 (zh) 2021-07-08

Family

ID=76685869

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/141222 Ceased WO2021136339A1 (zh) 2019-12-31 2020-12-30 具有双环结构的酰胺类化合物及其在药物中的应用

Country Status (2)

Country Link
CN (1) CN113121463A (zh)
WO (1) WO2021136339A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106232582A (zh) * 2014-04-16 2016-12-14 格兰马克药品股份有限公司 作为RORγ调节剂的芳基和杂芳基醚化合物
EP3192791A1 (en) * 2014-09-11 2017-07-19 Takeda Pharmaceutical Company Limited Heterocyclic compound
WO2018030550A1 (en) * 2016-08-09 2018-02-15 Takeda Pharmaceutical Company Limited Heterocyclic compounds with an ror(gamma)t modulating activity
CN108026045A (zh) * 2015-05-15 2018-05-11 奥瑞基尼探索技术有限公司 用作RORγ调节剂的经过取代的四氢喹啉酮化合物
CN108689942A (zh) * 2017-04-11 2018-10-23 广东东阳光药业有限公司 含氮双环化合物及其制备方法和用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10919867B2 (en) * 2015-07-07 2021-02-16 3M Innovative Properties Company Substituted benzotriazole phenols

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106232582A (zh) * 2014-04-16 2016-12-14 格兰马克药品股份有限公司 作为RORγ调节剂的芳基和杂芳基醚化合物
EP3192791A1 (en) * 2014-09-11 2017-07-19 Takeda Pharmaceutical Company Limited Heterocyclic compound
CN108026045A (zh) * 2015-05-15 2018-05-11 奥瑞基尼探索技术有限公司 用作RORγ调节剂的经过取代的四氢喹啉酮化合物
WO2018030550A1 (en) * 2016-08-09 2018-02-15 Takeda Pharmaceutical Company Limited Heterocyclic compounds with an ror(gamma)t modulating activity
CN108689942A (zh) * 2017-04-11 2018-10-23 广东东阳光药业有限公司 含氮双环化合物及其制备方法和用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SUN NANNAN, GUO HUIMIN, WANG YONGHUI: "Retinoic acid receptor-related orphan receptor gamma-t (RORγt) inhibitors in clinical development for the treatment of autoimmune diseases: a patent review (2016-present)", EXPERT OPINION ON THERAPEUTIC PATENTS, TAYLOR & FRANCIS, GB, vol. 29, no. 9, 2 September 2019 (2019-09-02), GB, pages 663 - 674, XP055825830, ISSN: 1354-3776, DOI: 10.1080/13543776.2019.1655541 *

Also Published As

Publication number Publication date
CN113121463A (zh) 2021-07-16

Similar Documents

Publication Publication Date Title
CN111788193B (zh) Pd-1/pd-l1类小分子抑制剂及其在药物中的应用
CN105884758B (zh) 三环化合物及其在药物中的应用
CN109563071B (zh) 作为atf4途径抑制剂的化学化合物
CN110770233B (zh) 稠合双环类化合物及其在药物中的应用
CN102015705B (zh) 稠合的杂环衍生物及其用途
CN108689942B (zh) 含氮双环化合物及其制备方法和用途
CN107686486A (zh) 含氮三环化合物及其在药物中的应用
TW201609726A (zh) 作為ｌｓｄ１抑制劑之咪唑并吡啶及咪唑并吡嗪
WO2020103897A1 (zh) 杂环稠合嘧啶衍生物、其药物组合物及应用
WO2023280254A1 (zh) 一种tead抑制剂
CN107406427A (zh) 炔基醇及其使用方法
CN112513021B (zh) RORγ拮抗剂及其在药物中的应用
TW202128642A (zh) 用於疾病治療之雙白胺酸拉鍊（dlk）激酶的雙環[1.1.1]戊烷抑制劑
JP2024521141A (ja) Ｋａｔ６ａ阻害剤としての縮合イソオキサゾリル化合物
WO2020083264A1 (zh) 胍类衍生物及其用途
CN112028891B (zh) 腺苷受体拮抗剂
CN109863142B (zh) 2-氮杂双环[3.1.0]己烷-3-酮衍生物及使用方法
WO2024175121A1 (zh) α，β-不饱和酰胺类化合物及其应用
WO2021136339A1 (zh) 具有双环结构的酰胺类化合物及其在药物中的应用
WO2024131827A1 (zh) 一种kras g12d抑制剂及其应用
WO2024199524A1 (zh) 作为pkmyt1抑制剂的化合物
CN111793077B (zh) Pd-1/pd-l1小分子抑制剂及其在药物中的应用
CN113121393B (zh) 芳香酰胺类化合物及其在药物中的应用
WO2023274396A1 (zh) 苯并氮杂环类化合物及其在药物中的应用
CN116836167A (zh) 咪唑并[1,2-a]吡嗪或吡唑并[1,5-a]嘧啶衍生物及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20909342

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20909342

Country of ref document: EP

Kind code of ref document: A1