WO2018192461A1 - Piperidine ampk agonist and medical application thereof - Google Patents

Piperidine ampk agonist and medical application thereof Download PDF

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Publication number
WO2018192461A1
WO2018192461A1 PCT/CN2018/083267 CN2018083267W WO2018192461A1 WO 2018192461 A1 WO2018192461 A1 WO 2018192461A1 CN 2018083267 W CN2018083267 W CN 2018083267W WO 2018192461 A1 WO2018192461 A1 WO 2018192461A1
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Prior art keywords
sulfonyl
piperidin
dimethylphenoxy
compound
dimethyl
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PCT/CN2018/083267
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French (fr)
Chinese (zh)
Inventor
孙宏斌
汪鹏飞
刘耐欣
张佳
晏顶霏
孙更
黄亚平
姚智颖
冯志奇
程亚龙
韩立帅
吴文珍
刘胜杰
赵星
秦鹿柘
李明雷
张翔鹰
喻生琪
陈辉
赵文峰
王锦政
尤燕平
孙恒之
戴量
张艳春
袁浩亮
陈彩萍
许庆龙
温小安
柳军
Original Assignee
中国药科大学
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Priority claimed from CN201810336935.5A external-priority patent/CN108727250A/en
Application filed by 中国药科大学 filed Critical 中国药科大学
Publication of WO2018192461A1 publication Critical patent/WO2018192461A1/en

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4

Definitions

  • the present invention relates to the field of biomedicine, and in particular to a piperidine compound having AMPK agonistic activity, and to a process for the preparation of such a compound and its use as an AMPK agonist.
  • AMPK adenylate-activated protein kinase
  • AMPK adenylate-activated protein kinase
  • Its phosphorylation activation can overcome insulin resistance, lower blood sugar, lower blood fat (by inhibiting the synthesis of fatty acids and cholesterol), anti-inflammatory, anti-aging Death, anti-fibrosis, promotion of mitochondrial synthesis, enhancement of mitochondrial oxidative metabolism, anti-aging and anti-tumor (Physiol. Rev. 2009, 89, 1025).
  • AMPK adenylate-activated protein kinase
  • the broad-spectrum ⁇ - ⁇ subunit agonist MK-8722 although it can lower blood glucose, has found irreversible cardiac hypertrophy in animal hearts in rats and monkeys. iSciencelOll, 357, 507).
  • the selective ⁇ - ⁇ subunit agonist PF-249 only lowers blood lipids but does not have hypoglycemic activity (Ce//Meto6.2017, 25, 1 147 ).
  • adiponectin is an important cytokine secreted by adipocytes that activates the AMPK signaling pathway by activating adiponectin receptor 1 (AdipoRl) (Nat. Med 2002, 8, 1288).
  • AdipoRl adiponectin receptor 1
  • small molecule adiponectin receptor agonists can mimic the biological effects of adiponectin in vivo, improve insulin resistance, lower blood sugar, and prolong the lifespan of high-fat diet mice (Blood re2013, 503, 493).
  • no small molecule adiponectin receptor agonists have entered the clinical research phase.
  • Another object of the invention is to provide a pharmaceutical use of the piperidines as AMPK agonists. These compounds have significant agonistic activity on AMPK in vitro biochemical levels and cell levels, and may activate AMPK signaling pathway by activating adiponectin receptors, and thus can be used to prepare drugs for preventing or treating AMPK-mediated diseases.
  • I 1 , R 2 , R 3 , R 6 , R 7 and R 8 are each H, R, OR, SR, S(0)R, S(0) 2 R, C(0)R , C(0)OH, C(0)OR, OC(0)R, HR, N(R) 2 , C(0) H 2 , C(0) HR, C(0)N(R) 2 , H(CO)R, R(CO)R, H(CO)OR, R(CO)OR, H(CO) H 2 , H(CO) HR, H(CO)N(R) 2 , R(CO ) HR, R(CO)N(R) 2 , S0 2 H 2 , S0 2 HR, S0 2 engraving) 2 , NHS0 2 R, RS0 2 R, HS0 2 HR, HS0 2 N(R) 2 , RS0 2 HR, RS0 2 N(R) 2 , C(0) HNOH, C(0) HNOR, C(0) HS0 2 R, C( H) H 2 , C( H( H) H 2
  • R is phenyl, heteroaryl, cyclodecyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, indenyl, alkenyl, or alkynyl; wherein said phenyl is unfused or fused R 9, R 9 is a phenyl, hetero aromatic, hydrocarbon embankment, cycloalkene, heterocycle, or heterocycle embankment hydrocarbon olefin; said heteroaryl group is not bonded or fused fused with R 1Q, R 1Q benzene a heteroaromatic hydrocarbon, a cycloalkylene hydrocarbon, a cyclic olefin, a heterocyclic anthracene or a heterocycloalkene; said cyclodecyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group each of which is unfused or with R 11 fused, R 11 is benzene, a heteroaren
  • R 12 is a 2 to 5 carbon spiro group, each of which is unsubstituted or is OH, (0), CN, H 2 , F, Cl, Br, I, CF 3 , CF 2 CF 3 , H (CH 3 ) or N(CH 3 ) 2 substituted;
  • R 13 and R 14 are independently selected indenyl groups, or N to which they are attached are aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine -1-yl, each having an unsubstituted or being 0, C(0), CNOH, CH 2 moiety substituted by CNOCH 3 , S, S(0) S(0) 2 or NH;
  • R 15 is phenyl, heteroaryl, cyclodecyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, indenyl, alkenyl or alkynyl; wherein said phenyl is unfused or fused R 16, R 16 is benzene, heteroarene, embankment hydrocarbon ring, cycloalkene, heterocycle, or heterocycle embankment hydrocarbon olefin; said heteroaryl is unfused or fused with R 17, R 17 is a phenyl a heteroaromatic hydrocarbon, a cycloalkylene hydrocarbon, a cyclic olefin, a heterocyclic anthracene or a heterocycloalkene; said cyclodecyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group each of which is unfused or with R 18 fused, R 18 is benzene, heteroarene,
  • R 19 is phenyl, heteroaryl, cyclodecyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, indenyl, alkenyl or alkynyl; wherein said phenyl is unfused or R 2Q fused, R 2Q benzene, heteroarene, embankment hydrocarbon ring, cycloalkene, heterocycle, or heterocycle embankment hydrocarbon olefin; said heteroaryl is unfused or fused with R 21, R 21 is a phenyl a heteroaromatic hydrocarbon, a cycloalkylene hydrocarbon, a cyclic olefin, a heterocyclic anthracene or a heterocycloalkene; said cyclodecyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group each of which is unfused or with R 22 fused, R 22 is a benzene, a
  • n 0 ⁇ 10;
  • R 4 and R 5 are each H, F or a fluorenyl group of 1 to 6 carbons; or R 4 and R 5 together with the atom to which they are attached form a substituted or unsubstituted cycloterpene hydrocarbon ring, substituted or unsubstituted a heterocyclic anthracene ring or a substituted or unsubstituted heterocyclic olefin ring;
  • X is S(0) 2 , C(0) or CH 2 ;
  • P, Q, W, Y and Z are each CH, N or C substituted by one of R 6 , R 7 and R 8 , and at least three of ⁇ , Q, W, Y and Z are not N;
  • R 1 ' is 11, thiol, 0H, CN, NH 2 , H(CH 3 ), N(CH 3 ) 2 or a thiol group of 1 to 6 carbons, and R' may be a 4-amino alpha in the piperidine ring. Substituting a carbon or a carbon at the beta position; and when R' is not a purine, the compound may act as a diastereomer or a mixture or diastereomer and/or enantiomer of the enantiomer The form of enrichment of the body is provided.
  • the enantiomerically enriched form of the compound of the invention is embodied in diastereomeric excess (de) 3 ⁇ 4 70-100%, preferably 90-100%, more preferably 95 to 100%, most preferably 98 100%; the enriched form of the enantiomer of the compound of the present invention is expressed in enantiomeric excess (ee) 3 ⁇ 4 70-100%, preferably 90-100 % is more preferably 95 to 100%, and most preferably 98 to 100%.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or ester or solvate thereof, of the invention :
  • RR 2 , R 3 , R 6 , R 7 and R 8 are each H, R, OR, SR, S(O)R, S(0) 2 R, C(0)R, C(0)OH,
  • R is phenyl, heteroaryl or fluorenyl; wherein the fluorenyl group is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of: OH, F, CF 3 , CF 2 CF 3 , OR 15 , SR 15 , S(0)R 15 , S(0) 2 R 15 , HR 15 , N(R 15 ) 2 , C(0)R 15 , C(0) H 2 , C (0) HR 15 , C(0)N(R 15 ) 2 , HC(0)R 15 , R 15 C(0)R 15 , HS0 2 R 15 , HC(0)OR 15 , S0 2 HR 15 , S0 2 N(R 15 ) 2 , HC(0) H 2 , HC(0) HR 15 , HC(0)CH(CH 3 ) HC(0)CH(CH 3 ) H 2 or HC(0)CH( CH 3 ) HC(0)CH(CH 3 ) HR 15 ;
  • R 15 is a fluorenyl group, and the fluorenyl group is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of OR 19 , SR 19 , S(0)R 19 , S( 0) 2 R 19 , HR 19 , N(R 19 ) 2 , C(0)R 19 , C(0) H 2 , C(0) HR 19 , C(O) Zun 19 ) 2 , HC(0) R 19 , R 19 C(0)R 19 , HS0 2 R 19 , HC(0)OR 19 , S0 2 HR 19 , S0 2 N(R 19 ) 2 , HC(0) H 2 , HC(0) HR 19 , OH, (0), C(0)OH, CN, H 2 , F, CF 3 or CF 2 CF 3; wherein R 19 is a fluorenyl group;
  • n 0 ⁇ 6;
  • R 4 and R 5 are each H, F or methyl
  • P, Q, W, Y and Z are each CH, N or C substituted by one of R 6 , R 7 and R 8 , and at least four of ⁇ , Q, W, Y and Z are not N;
  • R' is H, F or a fluorenyl group of 1 to 6 carbons, and R' may be substituted on the ex or carbon of the 4-amino group in the piperidine ring; and when R' is not hydrazine, the compound It may be provided as a diastereomer or a mixture of enantiomers or as an enriched form of diastereomers and/or enantiomers.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or ester or solvate thereof, of the invention :
  • RR 2 , R 3 , R 6 , R 7 and R 8 are each H, R, OR, SR, S(O)R, S(0) 2 R, C(0)R, C(0)OH,
  • R is phenyl, heteroaryl or fluorenyl; wherein the fluorenyl group is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of: OH, F, CF 3 , CF 2 CF 3 , OR 15 , SR 15 , S(0)R 15 , S(0) 2 R 15 , HR 15 , N(R 15 ) 2 , C(0)R 15 , C(0) H 2 , C (0) HR 15 , C(0)N(R 15 ) 2 , HC(0)R 15 , R 15 C(0)R 15 , HS0 2 R 15 , HC(0)OR 15 , S0 2 HR 15 , S0 2 N(R 15 ) 2 , NHC(0) H 2 , HC(0) HR 15 ;
  • R 15 is a fluorenyl group, and the fluorenyl group is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of OR 19 , SR 19 , S(0)R 19 , S( 0) 2 R 19 , HR 19 , N(R 19 ) 2 , C(0)R 19 , C(0) H 2 , C(0) HR 19 , C(O) Zun 19 ) 2 , HC(0) R 19 , R 19 C(0)R 19 , HS0 2 R 19 , HC(0)OR 19 , S0 2 HR 19 , S0 2 N(R 19 ) 2 , HC(0) H 2 , HC(0) HR 19 , OH, (0), C(0)OH, CN, H 2 , F, CF 3 or CF 2 CF 3; wherein R 19 is a fluorenyl group;
  • n 0 ⁇ 5;
  • R 4 and R 5 are each H or methyl
  • X is S(0) 2 , C(O) or CH 2;
  • P, Q, W, Y and Z are each CH, N or C substituted by one of R 6 , R 7 and R 8 , and at least four of ⁇ , Q, W, Y and Z are not N;
  • R' is H, F or methyl, and R' may be substituted on the alpha or carbon of the 4-amino group of the piperidine ring; and when R' is not , the compound may act as a diastereomer
  • the mixture or mixture of enantiomers or enriched forms of diastereomers and/or enantiomers is provided.
  • the compound has a diastereomeric purity greater than 98%.
  • the compound can be a diastereomerically pure cis compound or a diastereomerically pure trans compound.
  • the compound has an enantiomeric purity greater than 98%.
  • the compound of the invention is a compound of Table 1, or a pharmaceutically acceptable salt or ester or solvate thereof:
  • the compounds of the present invention are also useful as pharmaceutically acceptable salts.
  • the salt may be an acid salt of at least one of the following acids: galactose diacid, D-glucuronic acid, glycerophosphoric acid, hippuric acid, isethionic acid, lactobionic acid, maleic acid, 1,5-naphthalene Disulfonic acid, naphthalene-2-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecylsulfuric acid, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, Malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, hydrobromic acid,
  • the salt may be a salt of a compound of the invention with a metal (including sodium, potassium, calcium, etc.) ion or a pharmaceutically acceptable amine (including ethylenediamine, tromethamine, etc.) or an ammonium ion.
  • a metal including sodium, potassium, calcium, etc.
  • a pharmaceutically acceptable amine including ethylenediamine, tromethamine, etc.
  • ammonium ion e.g., compound 596.
  • the compounds of the present invention may also constitute a pharmaceutical composition in the form of an ester, a prodrug, an N-oxide or a solvate thereof.
  • a pharmaceutical composition in the form of an ester, a prodrug, an N-oxide or a solvate thereof.
  • the compound of the present invention is a carboxylic acid (e.g., compounds 119, 411, 415, and 467, etc.)
  • a suitable alcohol e.g., N-(2-hydroxyethyl)acetamide, etc.
  • the compound of formula (I) or a pharmaceutically acceptable salt or ester or solvate thereof of the present invention is a novel AMPK agonist which may activate the AMPK signaling pathway by activating adiponectin receptors and thus may be used for the preparation of prophylaxis or A drug that treats a variety of diseases as follows.
  • the compounds of the present invention are useful for preventing or treating a variety of metabolic abnormalities or cardiovascular and cerebrovascular diseases, including: insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, atherosclerosis, Myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, cardiac hypertrophy, myocarditis, diabetes Symptoms (including diabetic cardiomyopathy, diabetic nephropathy, retinopathy, neuropathy and delayed wound healing), nonalcoholic fatty liver, nonalcoholic steatohepatitis, alcoholic fatty liver, cirrhosis, hyperuricemia, gout, Osteoporosis, stroke or cerebral infarction.
  • diabetes Symptoms including diabetic cardiomyopathy, diabetic nephropathy, retinopathy, neuropathy and delayed wound healing
  • nonalcoholic fatty liver nonalcoholic steatohepatitis
  • alcoholic fatty liver cirrhosis
  • hyperuricemia gout, Ost
  • the compound of the present invention can be used for the prevention or treatment of various inflammatory diseases, autoimmune diseases, organ fibrosis diseases, nerve damage diseases or secondary diseases caused by pathogen infections, for example, pneumonia, tuberculosis, inflammatory bowel disease
  • the compounds of the invention are useful for the treatment or modulation of mitochondrial dysfunction and disorders, including: myasthenia gravis, myoclonus, exercise intolerance, Carnes-Syle syndrome, chronic fatigue syndrome, Rees' syndrome, mitochondria Myopathy - encephalopathy - hyperlactosis, stroke syndrome or stroke-like episodes.
  • the compounds of the invention may also be used to treat myasthenia dystrophies, such as Duchenne muscular dystrophy, shell muscle dystrophy or Fleetid's ataxia.
  • the compounds of the invention have anti-tumor effects.
  • tumors include, but are not limited to, bone cancer, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, Huo Chikin's lymphoma, non-Hodgkin's lymphoma, hemangioma, granuloma, xanthoma, meningosarcoma, glioma, astrocytoma, medulloblastoma, ependymoma, germ cell tumor (pineal tumor), pleomorphic glioblastoma, oligodendroglioma, schwannomas, retinoblastoma, fibrosarcoma, sarcoma, esophageal cancer, gastric cancer, pancreatic cancer, colorec
  • the pharmaceutical composition for preventing or treating the above-mentioned diseases according to the present invention which comprises a therapeutically effective amount of the compound of the formula (I) or a pharmaceutically acceptable salt or ester or solvate thereof as an active ingredient and a pharmaceutically acceptable adjuvant.
  • the excipients which may be optionally mixed may vary depending on the dosage form, administration form and the like. Examples of the excipients include excipients, binders, disintegrators, lubricants, flavoring agents, flavoring agents, coloring agents or sweeteners, and the like.
  • the pharmaceutical composition may be in the form of a pharmaceutically acceptable preparation such as a capsule, a powder, a tablet, a granule, a pill, an injection, a syrup, an oral solution, an inhalation, an ointment, a suppository or a patch.
  • a pharmaceutically acceptable preparation such as a capsule, a powder, a tablet, a granule, a pill, an injection, a syrup, an oral solution, an inhalation, an ointment, a suppository or a patch.
  • the compounds of the invention may be combined with one or more other types of agents for the prevention or treatment of the above disorders, including but not limited to the following combinations.
  • prophylactic or therapeutic agents that may be selected for use in combination with the compounds of the invention may be one or more anti-diabetic agents, including metformin, sulfonylureas, such as glibenclamide and glimepiride.
  • anti-diabetic agents including metformin, sulfonylureas, such as glibenclamide and glimepiride.
  • glucose Glycosidase inhibitors such as acarbose and miglitol
  • PPAR Y agonists such as pioglitazone and rosiglitazone
  • PPARot/ ⁇ dual agonists dipeptidyl peptidase IV (DPP-IV) Inhibitors (such as sitagliptin, saxagliptin, alogliptin, and linagliptin), glinide-type hypoglycemic agents (such as repaglinide and nateglinide, etc.), SGLT2 inhibitors (eg, cangliflozin, dapagliflozin, nglipepsin, iglegide, rugliflozin, and togliflozin), glucokinase agonists (eg, HMS5552, etc.), insulin, glucagon Peptide-l (GLP-1) drugs (such as exenatide, liragluti
  • prophylactic or therapeutic agents may be one or more weight-loss drugs, including lorcaserin, orlistat, and glucagon-like peptide-1 (GLP-l Classes of drugs (such as exenatide, liraglutide, risnatide, duraglutide, benaglutide, and albendide, etc.).
  • weight-loss drugs including lorcaserin, orlistat, and glucagon-like peptide-1 (GLP-l Classes of drugs (such as exenatide, liraglutide, risnatide, duraglutide, benaglutide, and albendide, etc.).
  • prophylactic or therapeutic agents may be one or more anti-alcoholic fatty liver disease drugs, including: AMPK agonists (e.g., metformin), farnesyl X receptor ( FXR) agonists (eg, oleic acid, GS-9674, EDP-305, and LJN452, etc.), acetyl-CoA carboxylase (ACC) inhibitors (eg, GS-0976, etc.), apoptosis signal-regulated kinase-1 ( ASK1) inhibitors (eg Rhythmsertib, etc.), PPAR agonists (eg Elafibranor, Saroglitazar, IVA337 and MSDC-0602K, etc.), caspase inhibitors (eg Emricasan, etc.), stearoyl-CoA desaturation Enzyme 1 (SCD1) inhibitors (eg Aramchol et al), long-acting
  • AMPK agonists e.g., metform
  • prophylactic or therapeutic agents may be one or more hypolipidemic drugs, including niacin, statins (eg, lovastatin, simvastatin, pravastatin, Mevastatin, fluvastatin, atorvastatin, cerivastatin, lovastatin and pitavastatin), cholesterol absorption inhibitors (eg ezetimibe, etc.), fibrates (eg clofibrate, benzal) Bet, fenofibrate, etc.), PCSK9 inhibitors (such as Evolocumab and Alirobumab, etc.), CETP inhibitors (such as anacetrapib, etc.), AMPK agonists and ACC inhibitors (such as GS-0976, etc.).
  • statins eg, lovastatin, simvastatin, pravastatin, Mevastatin, fluvastatin, atorvastatin, cerivastatin, lovastatin and pitavastatin
  • RR 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R′ are identical to those defined in the above formula (I); m is 0, 1, 2 , 3, 4, 5, 6, 7, 8, or 9.
  • the compound prepared by the present invention has a structure of the formula (I) having significant AMPK agonistic activity, and the present invention
  • the agonistic activity of the compound to AMPK is adiponectin 1 (AdipoRl)-dependent, a specific adiponectin receptor agonist, and the compound having the structure of the formula (I) of the present invention can be applied to the preparation of AMPK in an organism.
  • Drugs related to the disease for example, can be used to prevent diabetes and its complications, hyperlipidemia and nonalcoholic fatty liver disease, cardiomyopathy and heart failure.
  • Figure 1 is a graph showing the effect of compounds on the phosphorylation of AMPK in C2C12 cells
  • Figure 2 is a graph showing the effect of compounds on AMPK phosphorylation of AdipoRl wild type or AdipoRl knockout HEK293T cells;
  • Figure 3 is a graph showing the effect of the calcium chelator EGTA on the agonistic activity of the compound AMPK;
  • Figure 4 is a time-FBG relationship diagram of hypoglycemia of Compounds 111 and 119;
  • Fig. 5 is a graph showing the levels of TG, LDL, HDL and liver TG in serum after oral administration of compound 119 in mice;
  • Fig. 6 is a diagram showing HE staining of liver after oral administration of compound 119 in mice;
  • Figure 7 is a graph showing liver oil red staining after oral administration of Compound 119 in mice.
  • Figure 8 is a graph showing the levels of ALT and AST in serum after oral administration of Compound 119 in mice;
  • Figure 9 is a graph showing the effect of Compound 119 on the SD rat heart failure model.
  • the invention discloses a compound, a preparation method thereof, an intermediate of the compound and a preparation method thereof, and an application of the compound as an AMPK agonist, and those skilled in the art can learn from the contents of the present invention and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
  • the compound 1-6 (200 mg, 0.6275 mmol) was dissolved in anhydrous DMF (1 mL), and 1,1-carbonyldiimidazole (CDI) (117 mg, 0.7216 mmol) was added and heated at 70 ° C for 1 h. N-Boc-4-aminopiperidine (126 mg, 0.6275 mmol) was added and the reaction was continued for 2 hours.
  • CDI 1,1-carbonyldiimidazole
  • ESI-MS m/z 451.2 [M+Na] + .
  • Gemfibrozil (II-l) 250 mg, 1 mmol was dissolved in anhydrous DMF (2 mL), CDI (186 mg, 1.149 mmol) was added, and stirred at 70 ° C for 1 h, then N-Boc-4 was added -Aminopiperidine (200 mg, 1 mmol), reacted for 2 h.
  • Example 74 2-(4-Benzoylphenoxy)-N-(1-benzylpiperidin-4-yl)-2-methylpropanamide (Compound 74)
  • ESI-MS m/z 479.1 [M+Na] +
  • ESI-MS m/z 443.3 [M+H] + .
  • the compound ⁇ -2 (160 mg, 0.45 mmoL) was dissolved in DCM (5 mL), triethylamine (0.095 mL) and p-cyanobenzenesulfonyl chloride (92 mg, 0.46 mmoL).
  • ee 99.8% (Chiral HPLC analysis conditions: Chiralpak IC 4.6 mm X 250 mm, column temperature: 25 ° C; mobile phase: 70% hexane/ 30% isopropanol; flow rate: l mL/min; detection wavelength: UV254 nm ; retention time: 16.0 min).
  • the ee value was detected using the similar conditions as described above unless otherwise specified.
  • ESI-MS m/z 540.2 [M+Na] + .
  • ESI-MS m/z 579.3 [M+Na] + .
  • ESI-MS m/z 489.3 [M+Na] + .
  • ESI-MS m/z 539.3 [M+Na].
  • Compound IV-1 (1.1 mL, 10 mmoL) was dissolved in DMF (20 mL).
  • Compound IV-2 (2.23 g, lOmmoL) and potassium carbonate (2.07 g, 15 mmoL) were added in sequence, and heated to reflux under N 2 protection. . After about 8 h of reaction, it was cooled to room temperature, then added with aq. NaOH (60 mL) and ethyl acetate (60 mL ⁇ 3).
  • ESI-MS m/z 522.2 [M+Na] + .
  • ESI-MS m/z 591.3 [M+Na] + .
  • ESI-MS m/z 560.1 [M+Na] + .
  • ESI-MS m/z 528.2 [M+Na] + .
  • ESI-MS m/z 525.4 [M+H] + .

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Abstract

Disclosed in the present invention are a piperidine compound having an AMPK agonistic activity, a method for preparing the compound, a medical application of the compound, which has a structural formula as represent by formula (I), and pharmaceutically acceptable salts, or esters, or prodrugs, or N-oxides, or solvates of the compound. The compound as represent by formula (I) provided by the present invention may activate an AMPK signaling pathway by activating an adiponectin receptor, and thus may be used in preparation of medicaments for preventing or treating AMPK-mediated diseases.

Description

哌啶类 AMPK激动剂及其医药用途 技术领域  Piperidine AMPK agonist and its medical use
本发明涉及生物医药领域， 特别涉及一种具有 AMPK激动活性的哌啶类化合物， 本 发明还涉及该类化合物的制备方法及其作为 AMPK激动剂的医药用途。  The present invention relates to the field of biomedicine, and in particular to a piperidine compound having AMPK agonistic activity, and to a process for the preparation of such a compound and its use as an AMPK agonist.
本专利申请要求中国专利申请 （申请号 201710269119.2， 申请日： 2017年 4月 18 日， 发明创造名称： 具有 AMPK活化作用的哌啶类化合物、 其制备方法及医药用途） 的优先权。  This patent application claims priority to Chinese patent application (Application No. 201710269119.2, filing date: April 18, 2017, name of the invention: piperidine compound having AMPK activation, its preparation method and medical use).
背景技术 Background technique
AMPK (腺苷酸活化蛋白激酶） 是调控机体能量代谢及炎症反应的关键激酶， 其磷 酸化激活可克服胰岛素抵抗、 降血糖、 降血脂 （通过抑制脂肪酸及胆固醇的合成）、 抗 炎、 抗凋亡、 抗纤维化、 促进线粒体合成、 增强线粒体的氧化代谢、 抗衰老和抗肿瘤等 (Physiol. Rev. 2009, 89, 1025 )。 然而， 由于安全性或有效性的原因， 在研的 AMPK激 动剂进入临床研究的化合物寥寥无几。 例如， 广谱 ΑΜΡΚ-β亚基激动剂 MK-8722尽管 可以降血糖， 但在大鼠和猴子实验中发现动物心脏发生不可逆性心肌肥厚副作用 iSciencelOll, 357, 507)。 而选择性的 ΑΜΡΚ-βΙ亚基激动剂 PF-249则只降血脂， 但不 具备降血糖活性 （Ce//Meto6.2017, 25, 1 147 ) 。  AMPK (adenylate-activated protein kinase) is a key kinase regulating energy metabolism and inflammatory response in the body. Its phosphorylation activation can overcome insulin resistance, lower blood sugar, lower blood fat (by inhibiting the synthesis of fatty acids and cholesterol), anti-inflammatory, anti-aging Death, anti-fibrosis, promotion of mitochondrial synthesis, enhancement of mitochondrial oxidative metabolism, anti-aging and anti-tumor (Physiol. Rev. 2009, 89, 1025). However, due to safety or efficacy, there are very few compounds that have entered the clinical study of AMPK agonists. For example, the broad-spectrum ΑΜΡΚ-β subunit agonist MK-8722, although it can lower blood glucose, has found irreversible cardiac hypertrophy in animal hearts in rats and monkeys. iSciencelOll, 357, 507). The selective ΑΜΡΚ-βΙ subunit agonist PF-249 only lowers blood lipids but does not have hypoglycemic activity (Ce//Meto6.2017, 25, 1 147 ).
另一方面， 脂联素是一种由脂肪细胞分泌的重要的细胞因子， 其通过激活脂联素受 体 1 ( AdipoRl ) 而激活 AMPK信号通路 （Nat. Med 2002, 8, 1288)。 研究发现， 小分子 脂联素受体激动剂能很好地模拟脂联素在体内的生物学作用， 可改善胰岛素抵抗， 降血 糖， 且能够延长高脂饮食小鼠的寿命（Μ血 re2013, 503, 493 )。然而， 迄今尚未有任何小 分子脂联素受体激动剂进入临床研究阶段。  On the other hand, adiponectin is an important cytokine secreted by adipocytes that activates the AMPK signaling pathway by activating adiponectin receptor 1 (AdipoRl) (Nat. Med 2002, 8, 1288). The study found that small molecule adiponectin receptor agonists can mimic the biological effects of adiponectin in vivo, improve insulin resistance, lower blood sugar, and prolong the lifespan of high-fat diet mice (Blood re2013, 503, 493). However, to date no small molecule adiponectin receptor agonists have entered the clinical research phase.
综上所述， 临床上亟需开发活性高、 毒副作用小的新型 AMPK激动剂。  In summary, it is urgent to develop a novel AMPK agonist with high activity and small toxic side effects.
发明内容 Summary of the invention
本发明的目的是提供一种具有 AMPK激动活性的哌啶类化合物。  It is an object of the present invention to provide a piperidine compound having AMPK agonistic activity.
本发明的另一个目的是提供所述哌啶类化合物作为 AMPK激动剂的医药用途。 该 类化合物在体外生化水平和细胞水平均对 AMPK具有显著的激动活性， 可能通过激活 脂联素受体而激活 AMPK信号通路， 因而可用于制备预防或治疗 AMPK介导的多种疾 病的药物。  Another object of the invention is to provide a pharmaceutical use of the piperidines as AMPK agonists. These compounds have significant agonistic activity on AMPK in vitro biochemical levels and cell levels, and may activate AMPK signaling pathway by activating adiponectin receptors, and thus can be used to prepare drugs for preventing or treating AMPK-mediated diseases.
为实现目的， 本发明的技术方案如下：  For the purpose of realization, the technical solution of the present invention is as follows:
本发明所述的如下式 （I) 所示的化合物、 其药学上可接受的盐或酯或溶剂化物：
Figure imgf000004_0001
A compound represented by the following formula (I), a pharmaceutically acceptable salt or ester or solvate thereof:
Figure imgf000004_0001
(I) 其中， I 1、 R2、 R3、 R6、 R7和 R8各自是 H、 R、 OR、 SR、 S(0)R、 S(0)2R、 C(0)R、 C(0)OH、 C(0)OR、 OC(0)R、 HR、 N(R)2、 C(0) H2、 C(0) HR、 C(0)N(R)2、 H(CO)R、 R(CO)R、 H(CO)OR、 R(CO)OR、 H(CO) H2、 H(CO) HR、 H(CO)N(R)2、 R(CO) HR、 R(CO)N(R)2、 S02 H2、 S02 HR、 S02雕 )2、 NHS02R、 RS02R、 HS02 HR、 HS02N(R)2、 RS02 HR、 RS02N(R)2、 C(0) HNOH、 C(0) HNOR、 C(0) HS02R、 C( H) H2、 C( H) HR、 C(NH)N(R)2、 F、 Cl、 Br、 I、 CN、 N02、 H2、 OH、 CF3、 CF2CF3、 OCF3或 OCF2CF3; 或者， I 1、 R2和 R3之中每两个与它们所连接到 的原子一起形成取代或非取代的苯环、 取代或非取代的杂芳环、 取代或非取代的环垸烃 环、 取代或非取代的杂环垸烃环或取代或非取代的杂环烯烃环； 或者， R6、 R7和 R8之 中每两个与它们所连接到的原子一起形成取代或非取代的苯环、 取代或非取代的杂芳 环、 取代或非取代的环垸烃环、 取代或非取代的杂环垸烃环或取代或非取代的杂环烯烃 环； 其中， 所述的取代基选自： F、 Cl、 Br、 I、 CN、 N02、 NH2、 OH、 OR、 COOH、 COOR、 CF3、 CF2CF3、 OCF3或 OCF2CF3; (I) wherein, I 1 , R 2 , R 3 , R 6 , R 7 and R 8 are each H, R, OR, SR, S(0)R, S(0) 2 R, C(0)R , C(0)OH, C(0)OR, OC(0)R, HR, N(R) 2 , C(0) H 2 , C(0) HR, C(0)N(R) 2 , H(CO)R, R(CO)R, H(CO)OR, R(CO)OR, H(CO) H 2 , H(CO) HR, H(CO)N(R) 2 , R(CO ) HR, R(CO)N(R) 2 , S0 2 H 2 , S0 2 HR, S0 2 engraving) 2 , NHS0 2 R, RS0 2 R, HS0 2 HR, HS0 2 N(R) 2 , RS0 2 HR, RS0 2 N(R) 2 , C(0) HNOH, C(0) HNOR, C(0) HS0 2 R, C( H) H 2 , C( H) HR, C(NH)N(R 2 , F, Cl, Br, I, CN, N0 2 , H 2 , OH, CF 3 , CF 2 CF 3 , OCF 3 or OCF 2 CF 3 ; or, each of I 1 , R 2 and R 3 Two together with the atom to which they are attached form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloterpene ring, a substituted or unsubstituted heterocyclic hydrocarbon ring or a substituent olefins or unsubstituted heterocyclic ring; or, R 6, form a substituted or unsubstituted benzene ring R 7 and R 8 in each of the two atoms to which they are connected together, substituted An unsubstituted heteroaryl ring, a substituted or unsubstituted cycloterpene hydrocarbon ring, a substituted or unsubstituted heterocyclic anthracene ring or a substituted or unsubstituted heterocyclic olefin ring; wherein the substituent is selected from the group consisting of: F, Cl, Br, I, CN, N0 2 , NH 2 , OH, OR, COOH, COOR, CF 3 , CF 2 CF 3 , OCF 3 or OCF 2 CF 3 ;
R是苯基、 杂芳基、 环垸基、 环烯基、 杂环垸基、 杂环烯基、 垸基、 烯基、 或炔基; 其中， 所述苯基是未稠合的或与 R9稠合， R9是苯、 杂芳烃、 环垸烃、 环烯烃、 杂环垸 烃或杂环烯烃； 所述杂芳基是未稠合的或与 R1Q稠合， R1Q是苯、 杂芳烃、 环垸烃、 环烯 烃、 杂环垸烃或杂环烯烃； 所述环垸基、 环烯基、 杂环垸基或杂环烯基其每个是未稠合 的或与 R11稠合， R11是苯、杂芳烃、环垸烃、环烯烃、杂环垸烃或杂环烯烃； 所述垸基、 烯基或炔基其每个是未取代的或被一或两个或三个独立地选自下列的取代基所取代： R12、 OH、 （0)、 C(0)OH、 CN、 H2、 F、 Cl、 Br、 I、 CF3、 CF2CF3、 NC(R13)(R14)、 R15、 OR15、 SR15、 S(0)R15、 S(0)2R15、 HR15、 尊 15)2、 C(0)R15、 C(0) H2、 C(0) HR15、 C(O)尊 15)2、 HC(0)R15、 R15C(0)R15、 HS02R15、 HC(0)OR15、 S02 HR15、 S02N(R15)2、 HC(0) H2、 HC(0) HR15、 HC(0)CH(CH3) HC(0)CH(CH3) H2或 HC(0)CH(CH3) HC(0) -CH(CH3) HR15; R is phenyl, heteroaryl, cyclodecyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, indenyl, alkenyl, or alkynyl; wherein said phenyl is unfused or fused R 9, R 9 is a phenyl, hetero aromatic, hydrocarbon embankment, cycloalkene, heterocycle, or heterocycle embankment hydrocarbon olefin; said heteroaryl group is not bonded or fused fused with R 1Q, R 1Q benzene a heteroaromatic hydrocarbon, a cycloalkylene hydrocarbon, a cyclic olefin, a heterocyclic anthracene or a heterocycloalkene; said cyclodecyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group each of which is unfused or with R 11 fused, R 11 is benzene, a heteroarene, a cyclononene, a cycloalkene, a heterocyclic anthracene or a heterocycloalkene; the fluorenyl, alkenyl or alkynyl group each being unsubstituted or one or two And one or three substituents independently selected from the group consisting of: R 12 , OH, (0), C(0)OH, CN, H 2 , F, Cl, Br, I, CF 3 , CF 2 CF 3 , NC(R 13 )(R 14 ), R 15 , OR 15 , SR 15 , S(0)R 15 , S(0) 2 R 15 , HR 15 , 尊15 ) 2 , C(0)R 15 , C(0) H 2 , C(0) HR 15 , C(O) Respect 15 ) 2 , HC(0)R 15 , R 15 C(0)R 15 , HS0 2 R 15 , HC(0)OR 15 , S0 2 HR 15 , S0 2 N(R 15 ) 2 , HC(0) H 2 , HC(0) HR 15 , HC(0)CH(CH 3 ) HC(0)CH( CH 3 ) H 2 or HC(0)CH(CH 3 ) HC(0) -CH(CH 3 ) HR 15 ;
R12是 2~5个碳的螺垸基， 其每个是未取代的或被 OH、 (0), CN、 H2、 F、 Cl、 Br、 I、 CF3、 CF2CF3、 H(CH3)或 N(CH3)2取代； R 12 is a 2 to 5 carbon spiro group, each of which is unsubstituted or is OH, (0), CN, H 2 , F, Cl, Br, I, CF 3 , CF 2 CF 3 , H (CH 3 ) or N(CH 3 ) 2 substituted;
R13和 R14是独立选择的垸基， 或者与它们所连接到的 N—起是氮丙啶 -1-基、 氮杂 环丁垸 -1-基、吡咯垸 -1-基或哌啶 -1-基，每个具有一个未被替代的或被 0、 C(0), CNOH、 CNOCH3、 S、 S(0) S(0)2或 NH替代的 CH2部分； R 13 and R 14 are independently selected indenyl groups, or N to which they are attached are aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine -1-yl, each having an unsubstituted or being 0, C(0), CNOH, CH 2 moiety substituted by CNOCH 3 , S, S(0) S(0) 2 or NH;
R15是苯基、 杂芳基、 环垸基、 环烯基、 杂环垸基、 杂环烯基、 垸基、 烯基或炔基； 其中， 所述苯基是未稠合的或与 R16稠合， R16是苯、 杂芳烃、 环垸烃、 环烯烃、 杂环垸 烃或杂环烯烃； 所述杂芳基是未稠合的或与 R17稠合， R17是苯、 杂芳烃、 环垸烃、 环烯 烃、 杂环垸烃或杂环烯烃； 所述环垸基、 环烯基、 杂环垸基或杂环烯基其每个是未稠合 的或与 R18稠合， R18是苯、杂芳烃、环垸烃、环烯烃、杂环垸烃或杂环烯烃； 所述垸基、 烯基或炔基其每个是未取代的或被一或两个或三个独立地选自下列的取代基所取代： R19、 OR19、 SR19、 S(0)R19、 S(0)2R19、 HR19、 N(R19)2、 C(0)R19、 C(0) H2、 C(0) HR19、 C(O)尊 19)2、 HC(0)R19、 R19C(0)R19、 HS02R19、 HC(0)OR19、 S02 HR19、 S02N(R19)2、 HC(0) H2、 HC(0) HR19、 OH、 （0)、 C(0)OH、 CN、 H2、 F、 Cl、 Br、 I、 CF3或 CF2CF3; R 15 is phenyl, heteroaryl, cyclodecyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, indenyl, alkenyl or alkynyl; wherein said phenyl is unfused or fused R 16, R 16 is benzene, heteroarene, embankment hydrocarbon ring, cycloalkene, heterocycle, or heterocycle embankment hydrocarbon olefin; said heteroaryl is unfused or fused with R 17, R 17 is a phenyl a heteroaromatic hydrocarbon, a cycloalkylene hydrocarbon, a cyclic olefin, a heterocyclic anthracene or a heterocycloalkene; said cyclodecyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group each of which is unfused or with R 18 fused, R 18 is benzene, heteroarene, cyclononene, cycloalkene, heterocycloalkyl or heterocycloalkene; the fluorenyl, alkenyl or alkynyl group each being unsubstituted or one or two Substituted by three or three substituents independently selected from: R 19 , OR 19 , SR 19 , S(0)R 19 , S(0) 2 R 19 , HR 19 , N(R 19 ) 2 , C (0) R 19 , C(0) H 2 , C(0) HR 19 , C(O) Zun 19 ) 2 , HC(0)R 19 , R 19 C(0)R 19 , HS0 2 R 19 , HC (0) OR 19, S0 2 HR 19, S0 2 N (R 19) 2, HC (0) H 2, HC (0) HR 19, OH, (0), C (0) OH, CN H 2, F, Cl, Br , I, CF 3 or CF 2 CF 3;
R19是苯基、 杂芳基、 环垸基、 环烯基、 杂环垸基、 杂环烯基、 垸基、 烯基或炔基； 其中， 所述苯基是未稠合的或与 R2Q稠合， R2Q是苯、 杂芳烃、 环垸烃、 环烯烃、 杂环垸 烃或杂环烯烃； 所述杂芳基是未稠合的或与 R21稠合， R21是苯、 杂芳烃、 环垸烃、 环烯 烃、 杂环垸烃或杂环烯烃； 所述环垸基、 环烯基、 杂环垸基或杂环烯基其每个是未稠合 的或与 R22稠合， R22是苯、 杂芳烃、 环垸烃、 环烯烃、 杂环垸烃或杂环烯烃； R 19 is phenyl, heteroaryl, cyclodecyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, indenyl, alkenyl or alkynyl; wherein said phenyl is unfused or R 2Q fused, R 2Q benzene, heteroarene, embankment hydrocarbon ring, cycloalkene, heterocycle, or heterocycle embankment hydrocarbon olefin; said heteroaryl is unfused or fused with R 21, R 21 is a phenyl a heteroaromatic hydrocarbon, a cycloalkylene hydrocarbon, a cyclic olefin, a heterocyclic anthracene or a heterocycloalkene; said cyclodecyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group each of which is unfused or with R 22 fused, R 22 is a benzene, a heteroarene, a cyclononene, a cyclic olefin, a heterocyclic anthracene or a heterocycloalkene;
n=0~10;  n=0~10;
R4和 R5各自是 H、 F或 1~6个碳的垸基； 或者， R4和 R5与它们所连接到的原子一 起形成取代或非取代的环垸烃环、取代或非取代的杂环垸烃环或取代或非取代的杂环烯 烃环； R 4 and R 5 are each H, F or a fluorenyl group of 1 to 6 carbons; or R 4 and R 5 together with the atom to which they are attached form a substituted or unsubstituted cycloterpene hydrocarbon ring, substituted or unsubstituted a heterocyclic anthracene ring or a substituted or unsubstituted heterocyclic olefin ring;
X是 S(0)2、 C(0)或 CH2 ; X is S(0) 2 , C(0) or CH 2 ;
P、 Q、 W、 Y和 Z各自是 CH、 N或被 R6、 R7和 R8中的一个所取代的 C， 且卩、 Q、 W、 Y和 Z中至少有三个不是 N; P, Q, W, Y and Z are each CH, N or C substituted by one of R 6 , R 7 and R 8 , and at least three of 卩, Q, W, Y and Z are not N;
1 '是11、 F、 0H、 CN、 NH2、 H(CH3)、 N(CH3)2或 1~6个碳的垸基， 且 R'可在哌 啶环中 4-氨基的 α位碳或 β位碳上取代； 且当 R'不是 Η时， 所述化合物可作为非对映异 构体或者对映异构体的混合物或者非对映异构体和 /或者对映异构体的富集形式来提供。 1 'is 11, thiol, 0H, CN, NH 2 , H(CH 3 ), N(CH 3 ) 2 or a thiol group of 1 to 6 carbons, and R' may be a 4-amino alpha in the piperidine ring. Substituting a carbon or a carbon at the beta position; and when R' is not a purine, the compound may act as a diastereomer or a mixture or diastereomer and/or enantiomer of the enantiomer The form of enrichment of the body is provided.
在某些实施方案中， 本发明的化合物其非对映异构体的富集形式体现在非对映体过 量 (diastereomeric excess, de) ¾ 70-100%, 优选为 90~100%， 更优选为 95~100%， 最 优选为 98 100% ; 本发明的化合物其对映异构体的富集形式体现在对映体过量 (enantiomeric excess, ee) ¾ 70-100%, 优选为 90~100%， 更优选为 95~100%， 最优选 为 98~100%。  In certain embodiments, the enantiomerically enriched form of the compound of the invention is embodied in diastereomeric excess (de) 3⁄4 70-100%, preferably 90-100%, more preferably 95 to 100%, most preferably 98 100%; the enriched form of the enantiomer of the compound of the present invention is expressed in enantiomeric excess (ee) 3⁄4 70-100%, preferably 90-100 % is more preferably 95 to 100%, and most preferably 98 to 100%.
在某些实施方案中，本发明的式（I)化合物或其药学上可接受的盐或酯或溶剂化物: In certain embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt or ester or solvate thereof, of the invention:
R R2、 R3、 R6、 R7和 R8各自是 H、 R、 OR、 SR、 S(O)R、 S(0)2R、 C(0)R、 C(0)OH、RR 2 , R 3 , R 6 , R 7 and R 8 are each H, R, OR, SR, S(O)R, S(0) 2 R, C(0)R, C(0)OH,
C(0)OR、 OC(0)R、 HR、 N(R)2、 C(0) H2、 C(0) HR、 C(0)N(R)2、 H(CO)R、 R(CO)R、 H(CO)OR、 R(CO)OR、 H(CO) H2、 H(CO) HR、 H(CO)N(R)2、 R(CO) HR、 R(CO)N(R)2、 S02 H2、 S02 HR、 S02N(R)2、 HS02R、 RS02R、 HS02 HR、 HS02N(R)2、 RS02 HR、 RS02N(R)2、 C(0) HNOH、 C(0) HNOR、 C(0) HS02R、 C( H) H2、 C( H) HR、 C(NH)N(R)2、 F、 Cl、 Br、 I、 CN、 N02、 H2、 OH、 CF3、 CF2CF3、 OCF3或 OCF2CF3; 或者， R1 R2和 R3 之中每两个与它们所连接到的原子一 起形成取代或非取代的苯环或取代或非取代的杂芳环； 或者， R6、 R7和 R8 之中每两个 与它们所连接到的原子一起形成取代或非取代的苯环或取代或非取代的杂芳环； 其中， 所述的取代基选自： F、 Cl、 Br、 CN、 OR、 COOH、 COOR、 CF3、 CF2CF3、 OCF3或 OCF2CF3; C(0)OR, OC(0)R, HR, N(R) 2 , C(0) H 2 , C(0) HR, C(0)N(R) 2 , H(CO)R, R (CO)R, H(CO)OR, R(CO)OR, H(CO) H 2 , H(CO) HR, H(CO)N(R) 2 , R(CO) HR, R(CO)N(R) 2 , S0 2 H 2 , S0 2 HR, S0 2 N(R) 2 , HS0 2 R, RS0 2 R, HS0 2 HR, HS0 2 N(R) 2 , RS0 2 HR, RS0 2 N(R) 2 , C(0) HNOH, C(0) HNOR, C(0) HS0 2 R, C(H) H 2 , C( H) HR, C(NH)N(R) 2 , F, Cl, Br, I , CN, N0 2 , H 2 , OH, CF 3 , CF 2 CF 3 , OCF 3 or OCF 2 CF 3 ; or, each of R 1 R 2 and R 3 together with the atom to which they are attached a substituted or unsubstituted benzene ring or a substituted or unsubstituted heteroaryl ring; or, each of two of R 6 , R 7 and R 8 together with the atom to which they are attached form a substituted or unsubstituted benzene ring or a substituent Or an unsubstituted heteroaryl ring; wherein the substituent is selected from the group consisting of: F, Cl, Br, CN, OR, COOH, COOR, CF 3 , CF 2 CF 3 , OCF 3 or OCF 2 CF 3 ;
R是苯基、 杂芳基或垸基； 其中， 所述垸基是未取代的或被一或两个或三个独立地 选自下列的取代基所取代： OH、 F、 CF3、 CF2CF3、 OR15、 SR15、 S(0)R15、 S(0)2R15、 HR15、N(R15)2、 C(0)R15、 C(0) H2、 C(0) HR15、 C(0)N(R15)2、 HC(0)R15、 R15C(0)R15、 HS02R15、 HC(0)OR15、 S02 HR15、 S02N(R15)2、 HC(0) H2、 HC(0) HR15、 HC(0)CH(CH3) HC(0)CH(CH3) H2或 HC(0)CH(CH3) HC(0)CH(CH3) HR15;R is phenyl, heteroaryl or fluorenyl; wherein the fluorenyl group is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of: OH, F, CF 3 , CF 2 CF 3 , OR 15 , SR 15 , S(0)R 15 , S(0) 2 R 15 , HR 15 , N(R 15 ) 2 , C(0)R 15 , C(0) H 2 , C (0) HR 15 , C(0)N(R 15 ) 2 , HC(0)R 15 , R 15 C(0)R 15 , HS0 2 R 15 , HC(0)OR 15 , S0 2 HR 15 , S0 2 N(R 15 ) 2 , HC(0) H 2 , HC(0) HR 15 , HC(0)CH(CH 3 ) HC(0)CH(CH 3 ) H 2 or HC(0)CH( CH 3 ) HC(0)CH(CH 3 ) HR 15 ;
R15是垸基，且所述垸基是未取代的或被一或两个或三个独立地选自下列的取代基所 取代： OR19、 SR19、 S(0)R19、 S(0)2R19、 HR19、 N(R19)2、 C(0)R19、 C(0) H2、 C(0) HR19、 C(O)尊 19)2、 HC(0)R19、 R19C(0)R19、 HS02R19、 HC(0)OR19、 S02 HR19、 S02N(R19)2、 HC(0) H2、 HC(0) HR19、 OH、 （0)、 C(0)OH、 CN、 H2、 F、 CF3或 CF2CF3; 其中， R19是垸基； R 15 is a fluorenyl group, and the fluorenyl group is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of OR 19 , SR 19 , S(0)R 19 , S( 0) 2 R 19 , HR 19 , N(R 19 ) 2 , C(0)R 19 , C(0) H 2 , C(0) HR 19 , C(O) Zun 19 ) 2 , HC(0) R 19 , R 19 C(0)R 19 , HS0 2 R 19 , HC(0)OR 19 , S0 2 HR 19 , S0 2 N(R 19 ) 2 , HC(0) H 2 , HC(0) HR 19 , OH, (0), C(0)OH, CN, H 2 , F, CF 3 or CF 2 CF 3; wherein R 19 is a fluorenyl group;
n=0~6;  n=0~6;
R4和 R5各自是 H、 F或甲基； R 4 and R 5 are each H, F or methyl;
X是 S(0)2、 C(O)或 CH2; X is S(0) 2 , C(O) or CH 2;
P、 Q、 W、 Y和 Z各自是 CH、 N或被 R6、 R7和 R8中的一个所取代的 C， 且卩、 Q、 W、 Y和 Z中至少有四个不是 N; P, Q, W, Y and Z are each CH, N or C substituted by one of R 6 , R 7 and R 8 , and at least four of 卩, Q, W, Y and Z are not N;
R'是 H、 F或 1~6个碳的垸基， 且 R'可在哌啶环中 4-氨基的 ex位碳或 β位碳上取代； 且当 R'不是 Η时， 所述化合物可作为非对映异构体或者对映异构体的混合物或者非对 映异构体和 /或者对映异构体的富集形式来提供。  R' is H, F or a fluorenyl group of 1 to 6 carbons, and R' may be substituted on the ex or carbon of the 4-amino group in the piperidine ring; and when R' is not hydrazine, the compound It may be provided as a diastereomer or a mixture of enantiomers or as an enriched form of diastereomers and/or enantiomers.
在某些实施方案中，本发明的式（I)化合物或其药学上可接受的盐或酯或溶剂化物： In certain embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt or ester or solvate thereof, of the invention:
R R2、 R3、 R6、 R7和 R8各自是 H、 R、 OR、 SR、 S(O)R、 S(0)2R、 C(0)R、 C(0)OH、RR 2 , R 3 , R 6 , R 7 and R 8 are each H, R, OR, SR, S(O)R, S(0) 2 R, C(0)R, C(0)OH,
C(0)OR、 OC(0)R、 HR、 N(R)2、 C(0) H2、 C(0) HR、 C(0)N(R)2、 H(CO)R、 R(CO)R、 H(CO)OR、 R(CO)OR、 H(CO) H2、 H(CO) HR、 H(CO)N(R)2、 R(CO) HR、 R(CO)N(R)2、 S02 H2、 S02 HR、 S02N(R)2、 HS02R、 RS02R、 HS02 HR、 HS02N(R)2、 RS02 HR、 RS02N(R)2、 C(0) HNOH、 C(0) HNOR、 C(0) HS02R、 C( H) H2、 C( H) HR、 C(NH)N(R)2、 F、 Cl、 Br、 I、 CN、 N02、 H2、 OH、 CF3、 CF2CF3、 OCF3或 OCF2CF3; 或者， R1 R2和 R3 之中每两个与它们所连接到的原子一 起形成取代或非取代的苯环或取代或非取代的杂芳环； 或者， R6、 R7和 R8 之中每两个 与它们所连接到的原子一起形成取代或非取代的苯环或取代或非取代的杂芳环； 其中， 所述的取代基选自： F、 Cl、 Br、 CN、 OR、 COOH、 COOR、 CF3、 CF2CF3、 OCF3或 OCF2CF3; C(0)OR, OC(0)R, HR, N(R) 2 , C(0) H 2 , C(0) HR, C(0)N(R) 2 , H(CO)R, R (CO)R, H(CO)OR, R(CO)OR, H(CO) H 2 , H(CO) HR, H(CO)N(R) 2 , R(CO) HR, R(CO) N(R) 2 , S0 2 H 2 , S0 2 HR, S0 2 N(R) 2 , HS0 2 R, RS0 2 R, HS0 2 HR, HS0 2 N(R) 2 , RS0 2 HR, RS0 2 N (R) 2 , C(0) HNOH, C(0) HNOR, C(0) HS0 2 R, C(H) H 2 , C( H) HR, C(NH)N(R) 2 , F, Cl, Br, I, CN, N0 2 , H 2 , OH, CF 3 , CF 2 CF 3 , OCF 3 or OCF 2 CF 3; or, each of R 1 R 2 and R 3 together with the atom to which they are attached form a substituted or unsubstituted benzene ring or a substituted or unsubstituted hetero Or an aromatic ring; or, each of R 6 , R 7 and R 8 together with the atom to which they are attached form a substituted or unsubstituted benzene ring or a substituted or unsubstituted heteroaryl ring; wherein the substitution The base is selected from the group consisting of: F, Cl, Br, CN, OR, COOH, COOR, CF 3 , CF 2 CF 3 , OCF 3 or OCF 2 CF 3 ;
R是苯基、 杂芳基或垸基； 其中， 所述垸基是未取代的或被一或两个或三个独立地 选自下列的取代基所取代： OH、 F、 CF3、 CF2CF3、 OR15、 SR15、 S(0)R15、 S(0)2R15、 HR15、N(R15)2、 C(0)R15、 C(0) H2、 C(0) HR15、 C(0)N(R15)2、 HC(0)R15、 R15C(0)R15、 HS02R15、 HC(0)OR15、 S02 HR15、 S02N(R15)2、 NHC(0) H2、 HC(0) HR15;R is phenyl, heteroaryl or fluorenyl; wherein the fluorenyl group is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of: OH, F, CF 3 , CF 2 CF 3 , OR 15 , SR 15 , S(0)R 15 , S(0) 2 R 15 , HR 15 , N(R 15 ) 2 , C(0)R 15 , C(0) H 2 , C (0) HR 15 , C(0)N(R 15 ) 2 , HC(0)R 15 , R 15 C(0)R 15 , HS0 2 R 15 , HC(0)OR 15 , S0 2 HR 15 , S0 2 N(R 15 ) 2 , NHC(0) H 2 , HC(0) HR 15 ;
R15是垸基，且所述垸基是未取代的或被一或两个或三个独立地选自下列的取代基所 取代： OR19、 SR19、 S(0)R19、 S(0)2R19、 HR19、 N(R19)2、 C(0)R19、 C(0) H2、 C(0) HR19、 C(O)尊 19)2、 HC(0)R19、 R19C(0)R19、 HS02R19、 HC(0)OR19、 S02 HR19、 S02N(R19)2、 HC(0) H2、 HC(0) HR19、 OH、 （0)、 C(0)OH、 CN、 H2、 F、 CF3或 CF2CF3; 其中， R19是垸基； R 15 is a fluorenyl group, and the fluorenyl group is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of OR 19 , SR 19 , S(0)R 19 , S( 0) 2 R 19 , HR 19 , N(R 19 ) 2 , C(0)R 19 , C(0) H 2 , C(0) HR 19 , C(O) Zun 19 ) 2 , HC(0) R 19 , R 19 C(0)R 19 , HS0 2 R 19 , HC(0)OR 19 , S0 2 HR 19 , S0 2 N(R 19 ) 2 , HC(0) H 2 , HC(0) HR 19 , OH, (0), C(0)OH, CN, H 2 , F, CF 3 or CF 2 CF 3; wherein R 19 is a fluorenyl group;
n=0~5；  n=0~5;
R4和 R5各自是 H或甲基； R 4 and R 5 are each H or methyl;
X是 S(0)2、 C(O)或 CH2; X is S(0) 2 , C(O) or CH 2;
P、 Q、 W、 Y和 Z各自是 CH、 N或被 R6、 R7和 R8中的一个所取代的 C， 且卩、 Q、 W、 Y和 Z中至少有四个不是 N; P, Q, W, Y and Z are each CH, N or C substituted by one of R 6 , R 7 and R 8 , and at least four of 卩, Q, W, Y and Z are not N;
R'是 H、 F或甲基， 且 R'可在哌啶环中 4-氨基的 α位碳或 β位碳上取代； 且当 R'不是 Η 时， 所述化合物可作为非对映异构体或者对映异构体的混合物或者非对映异构体和 / 或者对映异构体的富集形式来提供。在某些实施方案中， 所述化合物具有大于 98%的非 对映异构体纯度。 例如， 所述化合物可以是非对映异构纯的顺式化合物或者非对映异构 纯的反式化合物。 在某些实施方案中， 所述化合物具有大于 98%的对映异构体纯度。  R' is H, F or methyl, and R' may be substituted on the alpha or carbon of the 4-amino group of the piperidine ring; and when R' is not ,, the compound may act as a diastereomer The mixture or mixture of enantiomers or enriched forms of diastereomers and/or enantiomers is provided. In certain embodiments, the compound has a diastereomeric purity greater than 98%. For example, the compound can be a diastereomerically pure cis compound or a diastereomerically pure trans compound. In certain embodiments, the compound has an enantiomeric purity greater than 98%.
在某些实施方案中， 本发明的化合物是表 1所示的化合物或其药学上可接受的盐或 酯或溶剂化物：  In certain embodiments, the compound of the invention is a compound of Table 1, or a pharmaceutically acceptable salt or ester or solvate thereof:
表 1、 化合 ί吻的结构与命名  Table 1. Structure and naming of ί kiss
化合物  Compound
化合物结构 命名 编号  Compound structure nomenclature
ο N- (1-苄基哌啶 -4-基) -2- (4- (4-氯苯甲酰基) 苯 ο N-(1-Benzylpiperidin-4-yl)-2-(4-(4-chlorobenzoyl)benzene
1 氧基） -2-甲基丙酰胺 1 oxy)-2-methylpropionamide
N- (1-苄基哌啶 -4-基） -5- (2,5-二甲基苯氧基) -2,2-N-(1-Benzylpiperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-
2 二甲基戊酰胺
Figure imgf000008_0001
N- (1- (2-氯 -4-氟苄基) 哌啶 -4-基) -2- (4- (4-氯 苄基） 苯氧基） -2-甲基丙酰胺 2 dimethyl pentamide
Figure imgf000008_0001
N-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-2-(4-(4-chlorobenzyl)phenoxy)-2-methylpropanamide
N- (1- (4-氰基苄基） 哌啶 -4-基） -5- (2,5-二甲基 苯氧基） -2,2-二甲基戊酰胺 N-(1-(4-Cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- (1- (4- (三 氟甲基） 苄基） 哌啶 -4-基） 戊酰胺 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)pentanamide
5- (2,5-二甲基苯氧基） -N- (1- (4-甲氧基苄基） 哌啶 -4-基） -2,2-二甲基戊酰胺5-(2,5-Dimethylphenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)-2,2-dimethylpentanamide
Figure imgf000009_0001
Figure imgf000009_0001
N- (1- (2-氯 -4-氟苄基) 哌啶 -4-基) -5- (2,5-二甲 基苯氧基） -2,2-二甲基戊酰胺  N-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide
N- (1- (4-氯苯甲酰基) 哌啶 -4-基） -5- (2,5-二甲 基苯氧基） -2,2-二甲基戊酰胺N-(1-(4-Chlorobenzoyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide
Figure imgf000009_0002
Figure imgf000009_0002
N- (1-苯甲酰哌啶 -4-基) -2- (4-氯苯氧基) -2-甲基 丙酰胺  N-(1-benzoylpiperidin-4-yl)-2-(4-chlorophenoxy)-2-methylpropanamide
O  O
N- (1- (4-氯苯甲酰基） 哌啶 -4-基） -2- (4-氯苯氧 基） -2-甲基丙酰胺  N-(1-(4-chlorobenzoyl)piperidin-4-yl)-2-(4-chlorophenoxy)-2-methylpropionamide
o  o
2- (4-氯苯氧基) -2-甲基 -N- (1- ((4-甲基苯基)磺 酰基） 哌啶 -4-基） 丙酰胺  2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-methylphenyl)sulfonyl)piperidin-4-yl)propanamide
2- (4-氯苯氧基） -N- (1-异烟酰基哌啶 -4-基） -2- 甲基丙酰胺 2-(4-Chlorophenoxy)-N-(1-isonicotinylpiperidin-4-yl)-2-methylpropanamide
0  0
2- (4-氯苯氧基） -2-甲基 -N- (1-烟酰基哌啶 -4-基） 丙酰胺 2-(4-Chlorophenoxy)-2-methyl-N-(1-nicotinopiperidin-4-yl)propanamide
Figure imgf000009_0003
Figure imgf000009_0003
N- (1-苄基哌啶 -4-基） -2- (2,5-二甲基苯氧基) -2- 甲基丙酰胺  N-(1-Benzylpiperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropanamide
^ Ύ Ό  ^ Ύ Ό
N- (1-苯甲酰基哌啶 -4-基） -2- (2,5-二甲基苯氧基） -2-甲基丙酰胺  N-(1-benzoylpiperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropanamide
0  0
N- (1- (4-氯苯甲酰基) 哌啶 -4-基） -2- (2,5-二甲 基苯氧基） -2-甲基丙酰胺  N-(1-(4-chlorobenzoyl)piperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropanamide
0
Figure imgf000010_0001
N- (1- (4-氰基苄基） 哌啶 -4-基） -2,2-二甲基 -5-苯0
Figure imgf000010_0001
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2,2-dimethyl-5-benzene
47 47
氧基戊酰胺  Oxyvaleramide
N- (1- (3-氰基苄基) 哌啶 -4-基） -2,2-二甲基 -5-苯 N-(1-(3-Cyanobenzyl)piperidin-4-yl)-2,2-dimethyl-5-benzene
48 48
氧基戊酰胺  Oxyvaleramide
N- (1- (2-氰基苄基) 哌啶 -4-基) -2,2-二甲基 -5-苯 N-(1-(2-cyanobenzyl)piperidin-4-yl)-2,2-dimethyl-5-benzene
49 氧基戊酰胺 49 oxyvaleramide
N- (1- (4-氰基苄基) 哌啶 -4-基) -5- (2,5-二氯苯N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(2,5-dichlorobenzene
50 氧基） -2,2-二甲基戊酰胺 50 oxy) -2,2-dimethyl pentamide
« 1/ N- (1- (3-氰基苄基) 哌啶 -4-基) -5- (2,5-二氯苯« 1/ N- (1- (3-Cyanobenzyl) piperidin-4-yl) -5- (2,5-dichlorobenzene
51 氧基） -2,2-二甲基戊酰胺 51 oxy) -2,2-dimethyl pentamide
N- (1- (2-氰基苄基) 哌啶 -4-基) -5- (2,5-二氯苯N-(1-(2-cyanobenzyl)piperidin-4-yl)-5-(2,5-dichlorobenzene
52 氧基） -2,2-二甲基戊酰胺 52 oxy) -2,2-dimethyl pentamide
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- (1- (4-丙酰5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-propionyl)
53 基苯甲酰基） 哌啶 -4-基） 戊酰胺 53-benzoyl) piperidine-4-yl) pentanoamide
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- (1-甲苯基5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-tolyl
54 哌啶 -4-基） 戊酰胺 54 piperidine-4-yl) pentanoamide
N- (1-苯甲酰基哌啶 -4-基） -5- (2,5-二甲基苯氧基）N-(1-benzoylpiperidin-4-yl)-5-(2,5-dimethylphenoxy)
55 -2,2-二甲基戊酰胺 55 -2,2-dimethylpentanamide
N- (1- (2-氯苄基) 哌啶 -4-基) -5- (2,5-二甲基苯N-(1-(2-chlorobenzyl)piperidin-4-yl)-5-(2,5-dimethylbenzene
56 氧基） -2,2-二甲基戊酰胺56 oxy) -2,2-dimethyl pentamide
Figure imgf000011_0001
Figure imgf000011_0001
N- (1- (2-氰基苄基) 哌啶 -4-基） -5- (2,5-二甲基 N-(1-(2-cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethyl
57 苯氧基） -2,2-二甲基戊酰胺 57 phenoxy) -2,2-dimethylpentanamide
N- (1- (3-氰基苄基) 哌啶 -4-基） -5- (2,5-二甲基N-(1-(3-Cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethyl
58 苯氧基） -2,2-二甲基戊酰胺 58 phenoxy) -2,2-dimethylpentanamide
N- (1-苄基哌啶 -4-基) -4- (2,5-二甲基苯氧基) 丁N-(1-Benzylpiperidin-4-yl)-4-(2,5-dimethylphenoxy) butyl
59 59
酰胺  Amide
N- (1- (4-氰基苄基) 哌啶 -4-基) -4- (2,5-二甲基 N-(1-(4-cyanobenzyl)piperidin-4-yl)-4-(2,5-dimethyl
60 苯氧基） 丁酰胺 60 phenoxy)butanamide
N- (1- (2-氰基苄基) 哌啶 -4-基） -4- (2,5-二甲基N-(1-(2-cyanobenzyl)piperidin-4-yl)-4-(2,5-dimethyl
61 苯氧基） 丁酰胺 61 phenoxy)butanamide
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- ( 1- ( (4-
Figure imgf000014_0001
5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N- ( 1- ( 4-
(三氟甲氧基）苯基）磺酰基） 哌啶 -4-基）戊酰胺 (trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)pentanamide
N- (2- (二甲基氨基） 乙基） -4 - ( (4- (5- (2,5- 二甲基苯氧基） -2,2-二甲基戊酰胺基） 哌啶 -1-基） 磺酰基） 苯甲酰胺 N-(2-(Dimethylamino)ethyl)-4-(-(4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl)piperidine -1-yl)sulfonyl)benzamide
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- ( 1- ( (4- φ οο== (4-甲基哌嗪 -1-羰基） 苯基）磺酰基） 哌啶 -4-基） 戊酰胺  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-( 1-((4- φ οο== (4-methylpiperazine-1-carbonyl)phenyl Sulfonyl)piperidin-4-yl)pentanamide
o  o
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- ( 1- (萘 -2- 基磺酰基） 哌啶 -4-基） 戊酰胺  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(naphthalen-2-ylsulfonyl)piperidin-4-yl)pentanamide
N- ( 1- (4-氰基苯甲酰基) 哌啶 -4-基） -5- (2,5-二 甲基苯氧基） -2,2-二甲基戊酰胺N-(1-(4-Cyanobenzoyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide
Figure imgf000015_0001
Figure imgf000015_0001
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- ( 1- (4- (三 氟甲基） 苯甲酰基） 哌啶 -4-基） 戊酰胺  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)pentanamide
5- (2,5-二甲基苯氧基） -N- ( 1- (4-甲氧基苯甲酰 基） 哌啶 -4-基） -2,2-二甲基戊酰胺 5-(2,5-Dimethylphenoxy)-N-(1-(4-methoxybenzoyl)piperidin-4-yl)-2,2-dimethylpentanamide
5- (2,5-二甲基苯氧基） -N- ( 1- (4-氟苯甲酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 5-(2,5-Dimethylphenoxy)-N-(1-(4-fluorobenzoyl)piperidin-4-yl)-2,2-dimethylpentanamide
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- (4-硝基 苯甲酰基） 哌啶 -4-基） 戊酰胺 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-nitrobenzoyl)piperidin-4-yl)pentanamide
4- (4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰氨 L 基） 哌啶 -1-羰基） 苯甲酸甲酯 4-(4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoylamino L-) piperidine-1-carbonyl) methyl benzoate
o  o
N- ( 1- (2-萘甲酰基) 哌啶 -4-基） -5- (2,5-二甲基 苯氧基） - 2,2-二甲基戊酰胺  N-(1-(2-Naphthoyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide
4- (4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺 基） 哌啶 -1-羰基） 苯甲酸 4-(4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanamide)piperidine-1-carbonyl)benzoic acid
4- (4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺 基） 哌啶 -1-羰基） 苯甲酰胺 4-(4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanamide)piperidine-1-carbonyl)benzamide
4- (4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺 基） 哌啶 -1-羰基） -N N-二甲基苯甲酰胺 N- (1- (苯并 [d][l,3]二氧杂环戊烯 -5-羰基）哌啶 -4- 基） -5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺
Figure imgf000016_0001
4-(4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoyl)piperidine-1-carbonyl)-N N-dimethylbenzamide N-(1-(Benzo[d][l,3]dioxol-5-carbonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)- 2,2-dimethyl pentamide
Figure imgf000016_0001
N-(l- (2,2-二氟苯并 [d] [1,3]二氧杂环戊烯 -5-羰基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基） -2,2-二甲基戊 N-(l-(2,2-difluorobenzo[d][1,3]dioxol-5-carbonyl)piperidin-4-yl)-5-(2,5-dimethyl Phenoxy group -2,2-dimethyl pentyl
1 酰胺 1 amide
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- (1- (喹啉 -6- 羰基） 哌啶 -4-基） 戊酰胺 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(quinolin-6-carbonyl)piperidin-4-yl)pentanamide
Figure imgf000016_0002
Figure imgf000016_0002
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- (1- (吡嗪 -2- 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(pyrazine-2-
V NYV 羰基） 哌啶 -4-基） 戊酰胺 V N YV carbonyl) piperidin-4-yl) pentamide
1  1
2- (4-苯甲酰基苯氧基） -N- (1- (苯基磺酰基） 哌 啶 -4-基) 乙酰胺  2-(4-Benzoylphenoxy)-N-(1-(phenylsulfonyl)piperidin-4-yl)acetamide
U " X¾ ) U " X3⁄4 )
N- (1- (4-氰基苯磺酰基) 哌啶 -4-基) -5- (2-甲氧 基苯氧基） -2,2-二甲基戊酰胺  N-(1-(4-Cyanobenzenesulfonyl)piperidin-4-yl)-5-(2-methoxyphenoxy)-2,2-dimethylpentanamide
N- (1- (4-氰基苯磺酰基） 哌啶 -4-基） -5- (4-甲氧 基苯氧基） -2,2-二甲基戊酰胺 N-(1-(4-Cyanobenzenesulfonyl)piperidin-4-yl)-5-(4-methoxyphenoxy)-2,2-dimethylpentanamide
o  o
N- (1- (4-氰基苯磺酰基） 哌啶 -4-基） -2,2-二甲基 -5-苯氧基戊酰胺  N-(1-(4-cyanobenzenesulfonyl)piperidin-4-yl)-2,2-dimethyl-5-phenoxypentanamide
ό  ό
N- (1- (4-氰基苯磺酰基） 哌啶 -4-基） -5- (2,5-二 甲基苯氧基） 戊酰胺 N-(1-(4-Cyanobenzenesulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)pentanamide
Figure imgf000016_0003
Figure imgf000016_0003
2 - ((4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰 氨基） 哌啶 -1-基） 甲基） 苯甲酰胺  2-((4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)methyl)benzamide
C NH2 C NH 2
4 - ((4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰 氨基） 哌啶 -1-基） 甲基） 苯甲酰胺  4-((4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)methyl)benzamide
4 - ((4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰 o 人人 J 氨基） 哌啶 -1-基） 甲基） 苯甲酸甲酯 4-((4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoyl), human J, amino)piperidin-1-yl)methyl)benzoic acid Ester
4 - ((4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰 胺基） 哌啶 -1-基） 甲基） 苯甲酸4-((4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)methyl)benzoic acid
Figure imgf000016_0004
Figure imgf000016_0004
4 - ((4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰 。 OJO 3 氨基） 哌啶 -1-基） 甲基） -N-甲基苯甲酰胺 5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- (1- (4- (甲 基磺酰基） 苄基） 哌啶 -4-基） 戊酰胺 4-((4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoyl) OJO 3 amino)piperidin-1-yl)methyl)-N-A Benzoylamide 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-(methylsulfonyl)benzyl)piperidin-4-yl)pentanamide
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- (1- (4-硝基 苄基） 哌啶 -4-基） 戊酰胺 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-nitrobenzyl)piperidin-4-yl)pentanamide
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- (1- (4- (三 rr0CF3 氟甲氧基） 苄基） 哌啶 -4-基） 戊酰胺 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-( trirr 0CF3fluoromethoxy )benzyl)piperidin-4-yl) Valeramide
2- (4-苯甲酰基苯氧基) -N- (1- (吡啶 -3-基磺酰基) 哌啶 -4-基） 乙酰胺 2-(4-Benzophenoxy)-N-(1-(pyridine-3-ylsulfonyl)piperidin-4-yl)acetamide
6  6
N- (1-苄基哌啶 -4-基） -2- (4- (苯基磺酰基） 苯氧 基） 乙酰胺  N-(1-Benzylpiperidin-4-yl)-2-(4-(phenylsulfonyl)phenoxy)acetamide
N- (1-苄基哌啶 -4-基） -2- (4- (苯基亚磺酰基）苯 氧基） 乙酰胺 N-(1-Benzylpiperidin-4-yl)-2-(4-(phenylsulfinyl)phenoxy)acetamide
N- (1-苄基哌啶 -4-基） -2- (4- (苯硫基） 苯氧基） 乙酰胺 N-(1-Benzylpiperidin-4-yl)-2-(4-(phenylthio)phenoxy)acetamide
N- (1-苄基哌啶 -4-基) -2 - ((5-氧代 -5,6,7,8-四氢 萘 -2-基） 氧） 乙酰胺 N-(1-Benzylpiperidin-4-yl)-2-((5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)oxy)acetamide
5- (4-氯苯氧基） -N- (1- ((4-氰基苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 5-(4-Chlorophenoxy)-N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
N- (1 - ((4-氰基苯基） 磺酰基） 哌啶 -4-基） -2,2- 二甲基 -5- (3,4,5- 三甲氧基苯氧基） 戊酰胺N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(3,4,5-trimethoxyphenoxy)pentane Amide
、 ,
N- (1 - ((4-氯苯基） 磺酰基） 哌啶 -4-基） -2,2-二 甲基 -5- (3,4,5- 三甲氧基苯氧基） 戊酰胺  N-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(3,4,5-trimethoxyphenoxy)pentanamide
。 。 c,  . . c,
反式 -5- (2,5-二甲基苯氧基) -N-0-M-1- (吡啶 -3- 基磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 反式 -4- ((4- (5- (2,5-二甲基苯氧基) -2,2-二甲基 戊酰胺基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 6  Trans-5-(2,5-Dimethylphenoxy)-N-0-M-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2,2-dimethyl Valeramide trans-4-((4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl)-3-fluoropiperidin-1-yl) sulfonate Acyl) benzoic acid 6
5- (2,5-二甲基苯氧基) -N- ((3S,4S) -3-氟小 (吡 啶 -3-基磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 4- (((3S,4S) -4- (5- (2,5-二甲基苯氧基) -2,2-二 甲基戊酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 5-(2,5-Dimethylphenoxy)-N-((3S,4S)-3-fluorosuccinyl(pyridin-3-ylsulfonyl)piperidin-4-yl)-2,2-di Methyl pentamide 4-(((3S,4S)-4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl) Sulfonyl) benzoic acid
2- (4- (4-氯苯甲酰基）苯氧基） -N- (1- ((4-氰基 苯基） 磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 2-(4-(4-Chlorobenzoyl)phenoxy)-N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide
N- (1- ((4- (1H-四唑 -5-基） 苯基） 磺酰基） 哌啶 -4-基) -5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺
Figure imgf000018_0001
N-(1-((4-(1H-tetrazol-5-yl)phenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2, 2-dimethylpentanamide
Figure imgf000018_0001
N- (1 - ( (4-氰基苯基） 磺酰基） 哌啶 -4-基） -5- (2,5-二氯苯氧基） -2,2-二甲基戊酰胺  N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- (1- ( (4-5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N- (1- ( 4-
(甲基磺酰基）苯基）磺酰基） 哌啶 -4-基）戊酰胺
Figure imgf000018_0002
(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)pentanamide
Figure imgf000018_0002
N- (1 - ((4-氰基苯基） 磺酰基） 哌啶 -4-基） -2,2- 二甲基 5- (4- (甲基磺酰基） 苯氧基） 戊酰胺  N-(1-((4-Cyanophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanamide
2 - ((4-氧代 -3-苯基 -4H-色烯 -7-基) 氧基） -N- (1-2-((4-oxo-3-phenyl-4H-chromen-7-yl)oxy)-N- (1-
(吡啶 -3-基磺酰基） 哌啶 -4-基） 乙酰胺
Figure imgf000018_0003
(pyridin-3-ylsulfonyl)piperidin-4-yl)acetamide
Figure imgf000018_0003
2 - ((4-氧代 -2-苯基 -4H-色烯 -7-基) 氧基） -N- (1- 2-((4-oxo-2-phenyl-4H-chromen-7-yl)oxy)-N- (1-
[1 II Ί (吡啶 -3-基磺酰基） 哌啶 -4-基） 乙酰胺 [1 II Ί (pyridine-3-ylsulfonyl) piperidin-4-yl) acetamide
N- (1 - ((4-氯苯基）磺酰基） 哌啶 -4-基） -5- (2,6- 二氟苯氧基） -2,2-二甲基戊酰胺 N-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-5-(2,6-difluorophenoxy)-2,2-dimethylpentanamide
ί I H ί I H
2,2-二甲基 -5-苯氧基 -N- (1- (吡啶 -3-磺酰基) 哌啶 -4-基） 戊酰胺  2,2-Dimethyl-5-phenoxy-N-(1-(pyridine-3-sulfonyl)piperidin-4-yl)pentanamide
5- (2,6-二氟苯氧基） -2,2-二甲基 -N- (1- (吡啶 -3- 磺酰基） 哌啶 -4-基） 戊酰胺 5-(2,6-Difluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-3-sulfonyl)piperidin-4-yl)pentanamide
2,2-二甲基 -5- (4- (甲基磺酰基） 苯氧基） -N- (1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 戊酰胺 2,2-Dimethyl-5-(4-(methylsulfonyl)phenoxy)-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide
4- ((4- (2,2-二甲基 -5- (4- (甲基磺酰基)苯氧基） 戊酰氨基） 哌啶 -1-基）磺酰基） 苯甲酸 。
Figure imgf000019_0001
2- (2,5-二甲基苯氧基) -2-甲基 -Ν- (1- ((4- (三氟 甲基） 苯基）磺酰基） 哌啶 -4-基） 丙酰胺 4-((4-(2,2-Dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid.
Figure imgf000019_0001
2-(2,5-Dimethylphenoxy)-2-methyl-indole-(1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-yl)propanamide
0  0
2- (2,5-二甲基苯氧基) -2-甲基 -Ν- (1- (吡啶 -3-基 磺酰基） 哌啶 -4-基） 丙酰胺  2-(2,5-Dimethylphenoxy)-2-methyl-indole-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)propanamide
0  0
4- ((4- (2- (2,5-二甲基苯氧基) -2-甲基丙酰氨基) 哌啶 -1-基） 磺酰基） 苯甲酸  4-((4-(2-(2,5-Dimethylphenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid
0  0
2- (2,5-二甲基苯氧基) -Ν- ((3S,4S) -3-氟 -1- (吡 啶 -3-基磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 2-(2,5-Dimethylphenoxy)-indole-((3S,4S)-3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-yl Propionamide
0 0
反式 -2- (2,5-二甲基苯氧基) -N- (3-氟 -1- (吡啶 -3- 基磺酰基） 哌啶 -4-基） -2-甲基丙酰胺  Trans-2-(2,5-Dimethylphenoxy)-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methylpropanamide
0  0
2- (2,5-二甲基苯氧基） -2-甲基 -N- (1- ((4- (甲基 磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 2-(2,5-Dimethylphenoxy)-2-methyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide
0 0
5- (2,5-二甲基苯氧基） -N - ( (3S,4S) -3-氟 -1 - ( (4- 氟苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 5-(2,5-Dimethylphenoxy)-N-((3S,4S)-3-fluoro-1 -((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2 2-dimethylpentanamide
1 ο 1 ο
反式 -5- (2,5-二甲基苯氧基) -N - (3-氟 -1 - ( (4- 氟苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺
Figure imgf000020_0001
Trans-5-(2,5-dimethylphenoxy)-N-(3-fluoro-1 -((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2- Dimethylpentanamide
Figure imgf000020_0001
4- ( ( (3S,4S) -4- (5- (2,5-二氯苯氧基) -2,2-二 甲基戊酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 4-((3S,4S)-4-(5-(2,5-Dichlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl) sulfonate Acyl) benzoic acid
CI ο CI ο
反式 -4- ( (4- (5- (3,4-二氟苯氧基） -2,2-二甲基戊 Trans-4-((4-(5-(3,4-difluorophenoxy)-2,2-dimethylpentyl)
F Λ π Λ 丄 ^\ ^COOH F Λ π Λ丄^\ ^COOH
酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸 δ  Amido)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid δ
反式 -N- (1 - ((3,4-二氟苯基）磺酰基） -3-氟哌啶 -4-基) -5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺
Figure imgf000020_0002
trans-N-(1 - ((3,4-difluorophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-5-(2,5-dimethylphenoxy)-2 2-dimethylpentanamide
Figure imgf000020_0002
5- (3-氟苯氧基) -2,2-二甲基 -N- (1- (吡啶 -3-基磺 酰基） 哌啶 -4-基） 戊酰胺  5-(3-Fluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-3-ylsulfonyl)piperidin-4-yl)pentanamide
5- (2-氟苯氧基) -2,2-二甲基 -N- (1- (吡啶 -3-基磺 酰基） 哌啶 -4-基） 戊酰胺 5-(2-Fluorophenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide
0  0
4 - ((4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰 胺基） 哌啶 -1-基） 磺酰基） 苯甲酸- (乙酰氨基） - ό 乙酯 5- (3,4-二氟苯氧基) -2,2-二甲基 -N- ( 1- (吡啶 -3- 基磺酰基） 哌啶 -4-基） 戊酰胺4-((4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanyl)piperidin-1-yl)sulfonyl)benzoic acid-(acetylamino) - ό ethyl ester 5-(3,4-Difluorophenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide
Figure imgf000021_0001
Figure imgf000021_0001
反式 -5- (2,6-二氟苯氧基） -N - (3-氟 -1- (吡啶 -3- o  Trans-5-(2,6-difluorophenoxy)-N-(3-fluoro-1-(pyridine-3-o)
基磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺  Sulfonyl) piperidine-4-yl)-2,2-dimethylpentanamide
0  0
I 5- (2,6-二氟苯氧基） -N- ( OS, 4S ) -3-氟 -1- (吡 I 5-(2,6-difluorophenoxy)-N-( OS, 4S ) -3-fluoro-1-(pyridyl)
0 0
啶 -3-基磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 0 o  Pyridin-3-ylsulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide 0 o
o  o
5- (2,4-二氟苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (甲 基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 戊酰胺
Figure imgf000021_0002
5-(2,4-Difluorophenoxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valeramide
Figure imgf000021_0002
4 - ( (4- (5- (2,4-二氟苯氧基) -2,2-二甲基戊酰氨 4-(-(5-(2,4-Difluorophenoxy)-2,2-dimethylpentanoylamide
A^^ ^ A^^ ^
基） 哌啶 -1-基） 磺酰基） 苯甲酸  Piperidin-1-yl)sulfonyl)benzoic acid
0  0
反式 -4- ( 5- (2,5-二氯苯氧基） -2,2-二甲基戊酰氨 基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸  Trans-4-(5-(2,5-dichlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid
5- (2-甲氧基苯氧基) -N - ((3S,4S) -1 - ( (4-氰基 苯基）磺酰基） -3-氟哌啶 -4-基） -2,2-二甲基戊酰胺 5-(2-Methoxyphenoxy)-N-((3S,4S) -1 - ((4-cyanophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-2, 2-dimethylpentanamide
5- (2-甲氧基苯氧基) -N - ((3S,4S) -1 - ( (3-氰基 苯基）磺酰基） -3-氟哌啶 -4-基） -2,2-二甲基戊酰胺 、、 5-(2-Methoxyphenoxy)-N-((3S,4S) -1 - ((3-cyanophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-2, 2-dimethylpentanamide,
、^^乂 H 5- (2,5-二氯苯氧基) -2,2-二甲基 -N- ( 1- (吡啶 -3- 基磺酰基） 哌啶 -4-基） 戊酰胺 ,^^乂H 5-(2,5-Dichlorophenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide
0  0
反式 -5- (2,4-二氟苯氧基) -N- (3 氟小 (吡啶 -3- 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺  Trans-5-(2,4-difluorophenoxy)-N-(3 fluorosuccinic (pyridine-3-sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- ( 1- ( (2,4,5- 三氟苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-((2,4,5-trifluorophenyl)sulfonyl)piperidin-4-yl Valentamide
N- ( 1 - ( (5-氯 -2,4-二氟苯基）磺酰基） 哌啶 -4-基) -5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 N-( 1 - ( (5-chloro-2,4-difluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2- Dimethylpentanamide
N- ( 1 - ( (3-氯 -4-氟苯基)磺酰基） 哌啶 -4-基) -5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 N-( 1 - ( (3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl) -5-(2,5-dimethylphenoxy) -2,2-dimethyl Valeramide
N- ( 1 - ( (2-氯 -4-氟苯基)磺酰基） 哌啶 -4-基) -5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺
Figure imgf000022_0001
4- (2,5-二甲基苯氧基) -N- ( 1- (吡啶 -3-基磺酰基) 哌啶 -4-基） 丁酰胺N-( 1 - ( (2-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethyl Valeramide
Figure imgf000022_0001
4-(2,5-Dimethylphenoxy)-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)butanamide
Figure imgf000023_0001
Figure imgf000023_0001
反式 -5-(4-氯 -2-氟苯氧基) -N-(3-氟 -1-((4- (甲基磺酰 基)苯基)磺酰基)哌啶 -4-基) -2 2-二甲基戊酰胺 ό  Trans-5-(4-chloro-2-fluorophenoxy)-N-(3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) -2 2-Dimethylpentanamide oxime
反式 -5-(4-氯 -2-氟苯氧基) -N-(3-氟 -1- (吡啶 -3-磺酰 基)哌啶 -4-基) -2,2-二甲基戊酰胺  Trans-5-(4-chloro-2-fluorophenoxy)-N-(3-fluoro-1-(pyridine-3-sulfonyl)piperidin-4-yl)-2,2-dimethyl Valeramide
0  0
5- (2,5-二氯苯氧基) -2,2-二甲基 -N- ( 1- ( (3- (甲 基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 5-(2,5-Dichlorophenoxy)-2,2-dimethyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valeramide
CI o o CI o o
5- (2,5-二 (三氟甲基)苯氧基） -2,2-二甲基 -N- ( 1- ( (3- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 5-(2,5-bis(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidine -4-base)
CF3 0 0 戊酰胺 CF 3 0 0 pentamide
5- (4-氟苯氧基) -2,2-二甲基 -N- ( 1- (吡啶 -3-基磺 酰基） 哌啶 -4-基） 戊酰胺  5-(4-Fluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-3-ylsulfonyl)piperidin-4-yl)pentanamide
3- (2,5-二甲基苯氧基) -N- ( 1- ( (4-氟苯基） 磺酰 基） 哌啶 -4-基丙酰胺 3-(2,5-Dimethylphenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-ylpropanamide
0 0
3- (2,5-二甲基苯氧基) -N- ( 1- (吡啶 -3-基磺酰基) 哌啶 -4-基） 丙酰胺  3-(2,5-Dimethylphenoxy)-N-(1-(pyridine-3-ylsulfonyl)piperidin-4-yl)propanamide
0 0
3- (2,5-二甲基苯氧基） -N- ( 1- ( (4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺  3-(2,5-Dimethylphenoxy)-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide
5- (2,4-二氟苯氧基） -N- ( 1- ( (4-氟苯基)磺酰基）5-(2,4-difluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)
Fjar¾ 、 T 哌啶 -4-基） -2,2-二甲基戊酰胺 F jar3⁄4 , T piperidin-4-yl) -2,2-dimethylpentanamide
5- (4-溴 -2,6-二氟苯氧基） -2,2-二甲基 -N- ( 1- (口比 啶 -3-基磺酰基） 哌啶 -4-基） 戊酰胺 5-(4-Bromo-2,6-difluorophenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)penta Amide
ό  ό
反式 -N- ( 1 - ( (2,4-二氟苯基） 磺酰基） -3-氟哌啶 -4-基) -5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺
Figure imgf000023_0002
trans-N-(1 - ((2,4-difluorophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-5-(2,5-dimethylphenoxy)-2 2-dimethylpentanamide
Figure imgf000023_0002
反式 -5- (2,6-二氟苯氧基） -N- 3-氟小 (吡啶 -3-基 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺  Trans-5-(2,6-Difluorophenoxy)-N- 3-fluoro small (pyridine-3-ylsulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
l I H 反式 -5- (2,6-二氟苯氧基） -^3-氟-1 - ((4-氟苯基) 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 l I H Trans-5-(2,6-difluorophenoxy)-^3-fluoro-1 -((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Valeramide
ί T  ί T
反式 -5- (2,6-二氟苯氧基） -^3-氟-1- ((4- (甲基 磺酰基）苯基）磺酰基） 哌啶 -4-基） -2,2-二甲基戊 ί I Η ό 酰胺 Trans-5-(2,6-difluorophenoxy)-^3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-2, 2-dimethylpentyl I Η amide
Ν- ((3S,4S) -3-氟 -1- ((4-氟苯基）磺酰基） 哌啶 -4-基) -5- (2-甲氧基苯氧基） -2,2-二甲基戊酰胺 ό  Ν-((3S,4S)-3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-5-(2-methoxyphenoxy)-2,2 - dimethyl pentanoamide
5-(4-氯苯基 )-2,2-二甲基 -N-(l-((4- (甲磺酰基)苯基） 磺酰基)哌啶 -4-基)戊酰胺  5-(4-Chlorophenyl)-2,2-dimethyl-N-(l-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)pentanamide
ο  ο
5-(4-氯苯基）-Ν-(1-((4-氟苯基）磺酰基）哌啶 -4- αΐ5^ 基) -2,2-二甲基戊酰胺 5-(4-chlorophenyl)-indole-(1-((4-fluorophenyl)sulfonyl)piperidin-4- α ΐ5^yl)-2,2-dimethylpentanamide
5-(4-氯苯基 )-2,2-二甲基 -N-(l- (吡啶 -3-基磺酰基)哌 ¾-4-¾) 戊酰胺 5-(4-Chlorophenyl)-2,2-dimethyl-N-(l-(pyridine-3-ylsulfonyl)piped 3⁄4-4-3⁄4) pentanamide
ο  ο
N- (1 - ((4-氟苯基) 磺酰基） 哌啶 -4-基) -2,2-二 甲基 -5- (4- (甲基磺酰基） 苯氧基） 戊酰胺  N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanamide
5- (2,4-二氟苯氧基） -N- ((3S,4S) -3-氟 -1- (吡啶 -3-基磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 5-(2,4-Difluorophenoxy)-N-((3S,4S)-3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2,2- Dimethylpentanamide
N- (1- ( (3,4-二氟苯基) 磺酰基） 哌啶 -4-基) -5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺N-(1-((3,4-difluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentyl Amide
Figure imgf000024_0001
Figure imgf000024_0001
2- (3,4-二氟苯氧基） -2-甲基 -N- (1- ((3- (甲基磺 2-(3,4-difluorophenoxy)-2-methyl-N- (1-((3-(methyl))
FI O 酰基） 苯基）磺酰基） 哌啶 -4-基） 丙酰胺 FI O acyl) phenyl)sulfonyl) piperidin-4-yl)propionamide
ο ο  ο ο
反式 -2- (3,4-二氟苯氧基) -N- (3-氟小 (吡啶 -3- Trans-2-(3,4-difluorophenoxy)-N-(3-fluorosodium (pyridine-3-
^ο^γ-,。 基磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 反式 -2- (3,4-二氟苯氧基) -N- (3-氟 -1 - ( (4- (甲 基磺酰基）苯基）磺酰基）哌啶 -4-基） -2-甲基丙酰 胺 ^ο^γ-,. Sulfonyl)piperidin-4-yl)-2-methylpropionamide trans-2-(3,4-difluorophenoxy)-N-(3-fluoro-1 - (4-4- Sulfonyl)phenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide
反式 -N- (3- -1- (吡啶 -3-基磺酰基） 哌啶 -4-基） Trans-N-(3- -1-(pyridin-3-ylsulfonyl)piperidin-4-yl)
^^ο Η 。 -2-甲基 -2- (3- (三氟甲基） 苯氧基） 丙酰胺 反式 -N- (3-氟 -1 - ((4- (甲基磺酰基）苯基）磺酰 基）哌啶 -4-基) -2-甲基 -2- (3- (三氟甲基)苯氧基） ό 丙酰胺 2- (4-氯苯氧基) -2-甲基 -Ν- (1 - ((4- (甲基磺酰^^ο Η . -2-methyl-2-(3-(trifluoromethyl)phenoxy)propanamide trans-N-(3-fluoro-1 -((4-(methylsulfonyl)phenyl)sulfonyl) Piperidin-4-yl)-2-methyl-2-(3-(trifluoromethyl)phenoxy) hydrazine 2-(4-Chlorophenoxy)-2-methyl-indole-(1 - ((4-(methylsulfonyl))
348 基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 反式 -2- (4-氯 -2-氟苯氧基) -Ν- (3-氟-1 - ((4- (甲348 phenyl)sulfonyl)piperidin-4-yl)propanamide trans-2-(4-chloro-2-fluorophenoxy)-indole-(3-fluoro-1 - ((4- A
349 基磺酰基）苯基）磺酰基） 哌啶 -4-基） -2-甲基丙酰 胺 349 sulfamoyl)phenyl)sulfonyl)piperidin-4-yl)-2-methylpropionylamine
反式 -2- (4-氯 -2-氟苯氧基) -Ν- (3-氟 -1 - ((4-氟苯 Trans-2-(4-chloro-2-fluorophenoxy)-indole-(3-fluoro-1 - ((4-fluorobenzene)
350 基） 磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 反式 -2- (4-氯 -2-氟苯氧基) -Ν- (3-氟 -1- (吡啶 -3-350-based) sulfonyl)piperidin-4-yl)-2-methylpropionamide trans-2-(4-chloro-2-fluorophenoxy)-indole-(3-fluoro-1-(pyridine- 3-
351 基磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 351 sulfamoyl) piperidin-4-yl)-2-methylpropionamide
2- (2,5-二甲基苯氧基） -Ν- (1- ((4-氟苯基） 磺酰2-(2,5-Dimethylphenoxy)-indole-(1-((4-fluorophenyl)sulfonyl)
352 基） 哌啶 -4-基） -2-甲基丙酰胺 反式 -2- (2,5-二甲基苯氧基) -Ν- (3-氟 -1 - ((4- (甲 基磺酰基）苯基）磺酰基） 哌啶 -4-基） -2-甲基丙酰352 yl) piperidin-4-yl)-2-methylpropionamide trans-2-(2,5-dimethylphenoxy)-indole-(3-fluoro-1 - ((4-) Sulfamoyl)phenyl)sulfonyl)piperidin-4-yl)-2-methylpropionyl
353 353
胺  Amine
2- (2,5-二甲基苯氧基) -Ν - ((3S,4S) -3-氟 -1 - ((4-2-(2,5-Dimethylphenoxy)-indole - ((3S,4S)-3-fluoro -1 - ((4-
354 (甲基磺酰基）苯基）磺酰基） 哌啶 -4-基） -2-甲基 丙酰胺 354 (methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide
5- (4-氯 -2-氟苯氧基） -N- (1- ((4-氟苯基）磺酰基） 5-(4-Chloro-2-fluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)
355 哌啶 -4-基） -2,2-二甲基戊酰胺 355 piperidin-4-yl)-2,2-dimethylpentanamide
5- (4-氟 -3- (三氟甲基) 苯氧基） -N- (1- ((4-氟苯5-(4-Fluoro-3-(trifluoromethyl)phenoxy)-N-(1-((4-fluorobenzene)
356 基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 356 base) sulfonyl) piperidine-4-yl)-2,2-dimethylpentanamide
N- (1 - ((3- (甲基磺酰基）苯基）磺酰基） 哌啶 -4-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidine-4-
357 基） -4- (3- (三氟甲基） 苯氧基） 丁酰胺 357 base) -4- (3-(trifluoromethyl)phenoxy)butanamide
5- (2,3-二氟 -4-甲基苯氧基） -N- (1- ((4-氟苯基）5-(2,3-Difluoro-4-methylphenoxy)-N-(1-((4-fluorophenyl))
360 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 360 sulfonyl) piperidine-4-yl)-2,2-dimethylpentanamide
1  1
5- (2,3-二氟 -4-甲基苯氧基） -N- (1- ((3-氟苯基) 5-(2,3-Difluoro-4-methylphenoxy)-N-(1-((3-fluorophenyl))
361 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 361 sulfonyl) piperidine-4-yl)-2,2-dimethylpentanamide
5- (2,3-二氟 -4-甲基苯氧基） -2,2-二甲基 -N- (1- ((4-5-(2,3-Difluoro-4-methylphenoxy)-2,2-dimethyl-N- (1- ((4-
362 (三氟甲氧基） 苯基）磺酰基） 哌啶 -4-基） 戊酰胺 反式 -5- (2,5-二氯苯氧基) -N- (3-氟 -1 - ( (4- (甲362 (trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)pentanamide trans-5-(2,5-dichlorophenoxy)-N-(3-fluoro-1 - ( (4- (A
367 基磺酰基） 苯基）磺酰基） 哌啶 -4-基） -2,2-二甲基 戊酰胺 反式 -5- (2,5-二氯苯氧基) -Ν- (3-氟 -1 - ( (3- (甲 基磺酰基）苯基）磺酰基） 哌啶 -4-基） -2,2-二甲基 6 戊酰胺 367 sulfamoyl)phenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide Trans-5-(2,5-Dichlorophenoxy)-indole-(3-fluoro-1 -((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) - 2,2-dimethyl 6 pentamide
反式 -5- (2,5-二氯苯氧基) -Ν - (3-氟 -1 - ( (4-氟 苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 ό  Trans-5-(2,5-dichlorophenoxy)-indole-(3-fluoro-1 -((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-di Methyl pentanoamide
2- (4- (4-氯苯甲酰基） 苯氧基） -Ν- (1- ( (4-氟 ΐΛΧ 苯基） 磺酰基） 哌啶 -4-基） -2-甲基丙酰胺  2-(4-(4-Chlorobenzoyl)phenoxy)-indole-(1-((4-fluorophenyl)phenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide
ό  ό
5- (2,6-二氟苯氧基） -2,2-二甲基 -Ν- (1- ((3- (甲 基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 戊酰胺  5-(2,6-Difluorophenoxy)-2,2-dimethyl-indole-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valeramide
Ν- (1- ((4-氟苯基） 磺酰基） 哌啶 -4-基） -3- (3-Ν-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-3-(3-
(三氟甲基） 苯氧基） 丙酰胺(trifluoromethyl) phenoxy) propionamide
Figure imgf000026_0001
Figure imgf000026_0001
Ν- (1- ((4- (甲磺酰基） 苯基） 磺酰基） 哌啶 -4- 基） -3- (3- (三氟甲基） 苯氧基） 丙酰胺  Ν-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-3-(3-(trifluoromethyl)phenoxy)propanamide
2,2-二甲基 -Ν- (1- (吡啶 -3-基磺酰基） 哌啶 -4-基） -5- (2,4,6-三氟苯氧基） 戊酰胺 2,2-Dimethyl-indole-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-5-(2,4,6-trifluorophenoxy)pentanamide
5- (2,5-二 （三氟甲基） 苯氧基） -Ν- (1- ( (4-氟 苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 5-(2,5-bis(trifluoromethyl)phenoxy)-indole-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Valeramide
5- (4-氟 -3- (三氟甲基） 苯氧基） -2,2-二甲基 -Ν- (1- ((4- (甲基磺酰基） 苯基） 磺酰基） -哌啶 -4- ό 基） 戊酰胺 5-(4-Fluoro-3-(trifluoromethyl)phenoxy)-2,2-dimethyl-indole-(1-((4-(methylsulfonyl)phenyl)sulfonyl) Piperidine-4-mercapto)pentanamide
5- (4-氟 -3- (三氟甲基） 苯氧基） -2,2-二甲基 -Ν- (1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 戊酰胺 ό  5-(4-Fluoro-3-(trifluoromethyl)phenoxy)-2,2-dimethyl-indole-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)penta Amide oxime
5- (4-氟 -3- (三氟甲基） 苯氧基） -2,2-二甲基 -Ν- (1- ((4- (三氟甲氧基） 苯基） 磺酰基） 哌啶 -4- 5-(4-Fluoro-3-(trifluoromethyl)phenoxy)-2,2-dimethyl-indole-(1-((4-(trifluoromethoxy)phenyl)sulfonyl) Piperidine-4-
。 基） 戊酰胺 . Ethyl amide
Ν- (1 - ((4-氟苯基) 磺酰基） 哌啶 -4-基) -4- (3- Ν-(1 - ((4-fluorophenyl)sulfonyl)piperidin-4-yl)-4-(3-
(三氟甲基） 苯氧基） 丁酰胺(trifluoromethyl) phenoxy) butanamide
Figure imgf000026_0002
Figure imgf000026_0002
反式 -2- (2,4-二氟苯氧基) -Ν- (3-氟 -1- ((3- (甲 基磺酰基）苯基）磺酰基）哌啶 -4-基） -2-甲基丙酰 ο 胺  Trans-2-(2,4-difluorophenoxy)-indole-(3-fluoro-1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)- 2-methylpropionylamine
2- (2,4-二氟苯氧基） -2-甲基 -Ν- (1- ((3- (甲基磺 禽 酰基） 苯基）磺酰基） 哌啶 -4-基） 丙酰胺 ό N- (1- ((4- (甲基磺酰基）苯基）磺酰基）哌啶 -4- 基） -4- (3- (三氟甲基） 苯氧基） 丁酰胺 2-(2,4-Difluorophenoxy)-2-methyl-indole-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide ό N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) -4- (3-(trifluoromethyl)phenoxy)butanamide
N- (1- (吡啶 -3-基磺酰基) 哌啶 -4-基） -4- (3- (三 氟甲基） 苯氧基） 丁酰胺 N-(1-(Pyridin-3-ylsulfonyl)piperidin-4-yl)-4-(3-(trifluoromethyl)phenoxy)butanamide
5- (2,3-二氟苯氧基） -N- (1- ( (4-氟苯基） 磺酰 基） 哌啶 -4-基） -2,2-二甲基戊酰胺 5-(2,3-Difluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
2,2-二甲基 -N- (1- ( (4- (甲基磺酰基） 苯基） 磺2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl) sulfonate
:x^ 酰基） 哌啶 -4-基) -5- (3,4,5-三氟苯氧基) 戊酰胺 :x^ acyl) piperidine-4-yl)-5-(3,4,5-trifluorophenoxy)pentanamide
N- (1- ( (4-氟苯基）磺酰基） 哌啶 -4-基） -2,2-二 甲基 -5- (3,4,5-三氟苯氧基) 戊酰胺 N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(3,4,5-trifluorophenoxy)pentanamide
2,2-二甲基 -N- (1- (吡啶 -3-基磺酰基） 哌啶 -4-基） -5- (2,3 ,4-三氟苯氧基） 戊酰胺 2,2-Dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-5-(2,3,4-trifluorophenoxy)pentanamide
N- (1- ( (4-氟苯基）磺酰基） 哌啶 -4-基） -2,2-二 甲基 -5- (2,3 ,4-三氟苯氧基） 戊酰胺 ^^J 2,2-二甲基 -N- (1- (吡啶 -3-基磺酰基） 哌啶 -4-基） N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(2,3,4-trifluorophenoxy)pentanamide^ ^J 2,2-Dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)
-5- (2- (三氟甲基） 苯氧基） 戊酰胺  -5-(2-(trifluoromethyl)phenoxy)pentanamide
N- (1- ( (4-氟苯基）磺酰基） 哌啶 -4-基） -2,2-二 甲基 -5- (2- (三氟甲基） 苯氧基） 戊酰胺 N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(2-(trifluoromethyl)phenoxy)pentanamide
5- (4-氟 -2- (三氟甲基） 苯氧基） -2,2-二甲基 -N- (1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 戊酰胺 5-(4-Fluoro-2-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)penta Amide
6  6
5- (4-氟 -2- (三氟甲基) 苯氧基） -N- (1- ( (4-氟 苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺  5-(4-Fluoro-2-(trifluoromethyl)phenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Pentamide
5- (4-氯苯氧基） -N- ((3R,4R) -3-氟 -1- ((4-氟苯 基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 5-(4-Chlorophenoxy)-N-((3R,4R)-3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-di Methyl pentamide
4- (((3R,4R) -4- (5- (4-氯苯氧基） -2,2-二甲基戊 酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸 4-(((3R,4R)-4-(5-(4-chlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Formic acid
N- (1- (吡啶 -3-磺酰基) 哌啶 -4-基) -3- (3- (三氟 甲基） 苯氧基） 丙酰胺 反式—4- ((4- (5- (4-氯苯氧基) -2,2-二甲基戊酰胺） -3-氟哌啶 -1-基）磺酰基） 苯甲酸 反式 -5-(4-氯苯氧基) -N- (3-氟 -1- ((4-氟苯基)磺酰 基） 哌啶 -4-基） -2 2-二甲基戊酰胺 N-(1-(pyridine-3-sulfonyl)piperidin-4-yl)-3-(3-(trifluoromethyl)phenoxy)propanamide Trans-4-((4-(5-(4-chlorophenoxy)-2,2-dimethylvaleramide)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid trans- 5-(4-Chlorophenoxy)-N-(3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-2-dimethylpentanamide
a J 。 a J .
反式—4- ((4- (2- (3,4-二氟苯氧基) -2-甲基丙酰氨 基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 反式—4- ((4- (2- (3,4-二氟苯氧基) -2-甲基丙酰氨 基） -3-氟哌啶 -1-基）磺酰基）苯甲酸 2-乙酰氨基乙 酯  Trans-4-((4-(2-(3,4-difluorophenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid trans —4-((4-(2-(3,4-Difluorophenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid 2-acetamido Ethyl ester
5- (2,5-二 (三氟甲基) 苯氧基） -N- (1- ((3-氟苯 基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺  5-(2,5-bis(trifluoromethyl)phenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Valeramide
N- (1 - ((4-氟苯基) 磺酰基） 哌啶 -4-基) -2,2-二 甲基 -5- (萘 -2-基氧基） 戊酰胺 N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(naphthalen-2-yloxy)pentanamide
N- (1 - ((4-氟苯基) 磺酰基） 哌啶 -4-基) -2,2-二 甲基 -5- (萘 -1-基氧基） 戊酰胺 N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(naphthalen-1-yloxy)pentanamide
Ό I  Ό I
反式 -4- ((4- (5- (4-氯苯氧基） -2 2-二甲基戊酰 胺基） -3-氟哌啶 -1-基）磺酰基）苯甲酸 2-乙酰氨基 乙酯  Trans-4-((4-(5-(4-chlorophenoxy)-2-2-2-dimethylpentanyl)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid 2-acetyl Aminoethyl ester
I  I
顺式 -5- (4-氯苯氧基） -N- (3-氟 -1- ((4-氟苯基） 磺酰基） 哌啶 -4-基） -2 2-二甲基戊酰胺  Cis-5-(4-chlorophenoxy)-N-(3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-2-dimethylpentanamide
5- (4-氯 -2-氟苯氧基) -2,2-二甲基 -N- (1- ((4- (甲 基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 5-(4-Chloro-2-fluorophenoxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl Valentamide
顺式—4- ((4- (5- (4-氯苯氧基) -2,2-二甲基戊酰胺 基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸Cis- 4-((4-(5-(4-chlorophenoxy)-2,2-dimethylpentanyl)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid
Figure imgf000028_0001
Figure imgf000028_0001
4- ((4- (2- (4- (4-氯苯甲酰基） 苯氧基） -2-甲基 α Λ 丙酰氨基） 哌啶 -1-基）磺酰基） 苯甲酸 反式 -4- ((4- (5- (2,5-二氟苯氧基） -2,2-二甲基戊 ίτ。^ τ。Η 酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸
Figure imgf000029_0001
4- (((3R,4R) -4- (5- (2,5-二氟苯氧基) -2,2-二甲 基戊酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 o 4- ((4- (2- (4- (4-chlorobenzoyl) phenoxy) -2-methyl-α Λ propionylamino) piperidin-1-yl) sulfonyl) benzoic acid trans - 4- ((4- (5- (2,5-difluorophenoxy) -2,2-dimethyl-pentyl ίτ. ^ τ. Η) -3- fluoropiperidin-l-yl) sulfonamide Acyl) benzoic acid
Figure imgf000029_0001
4-(((3R,4R)-4-(5-(2,5-Difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl) sulfonate Acyl) benzoic acid
4- (((3S,4S) -4- (5- (2,5-二氟苯氧基) -2,2-二甲 基戊酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸  4-(((3S,4S)-4-(5-(2,5-Difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl) sulfonate Acyl) benzoic acid
2- (4- (4-氯苯甲酰基)苯氧基） -N- ((3R,4R) -3- 氟 -1 - ((4-氟苯基）磺酰基） 哌啶 -4-基） -2-甲基丙2-(4-(4-Chlorobenzoyl)phenoxy)-N-((3R,4R)-3-fluoro-1 -((4-fluorophenyl)sulfonyl)piperidin-4-yl -2-methylpropane
6 酰胺 6 amide
o  o
5- (2,5-二氯苯氧基) -2,2-二甲基 -N- (1- ((4- (甲 基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 反式 -2- (4-氯苯氧基) -N- (3-氟 -1 - ((4-氟苯基) 磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 反式—4- ((4- (2- (4-氯苯氧基） -2-甲基丙酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸 反式 -2- (4- (4-氯苯甲酰基）苯氧基） -N- (3-氟 -1 - ((4-氟苯基）磺酰基） 哌啶 -4-基） -2-甲基丙酰胺  5-(2,5-Dichlorophenoxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valeramide trans-2-(4-chlorophenoxy)-N-(3-fluoro-1 -((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide Trans-4-((4-(2-(4-chlorophenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid trans-2- (4-(4-Chlorobenzoyl)phenoxy)-N-(3-fluoro-1 -((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide
4- (((3R,4R) -4- (5- (2,6-二氟苯氧基） -2,2-二甲 基戊酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 4-(((3R,4R)-4-(5-(2,6-Difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl) sulfonate Acyl) benzoic acid
4- (((3R,4R) -4- (5- (4-氯 -2-氟苯氧基) -2,2-二甲 基戊酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 4-(((3R,4R)-4-(5-(4-Chloro-2-fluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl) Sulfonyl) benzoic acid
2- (4-氯 -2-氟苯氧基) -2-甲基 -N- (1- ( (4- (三氟 甲氧基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 2-(4-Chloro-2-fluorophenoxy)-2-methyl-N-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)propane Amide
2- (3,4-二氟苯氧基） -2-甲基 -N- (1- ( (4- (三氟 甲氧基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 2-(3,4-Difluorophenoxy)-2-methyl-N-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)propanamide
N- (1 - ( (3-氰基苯基） 磺酰基） 哌啶 -4-基） -5- 丫 (2,5- 、。 二氯苯氧基） -2,2-二甲基戊酰胺 N-(1-(3-cyanophenyl)sulfonyl)piperidin-4-yl)-5-indole (2,5-, dichlorophenoxy)-2,2-dimethylpentyl Amide
CI o  CI o
2- (2,3-二氟苯氧基) -2-甲基 -N- (1- ((4- (甲基磺 酰基） 苯基）磺酰基） 哌啶 -4-基） 丙酰胺  2-(2,3-Difluorophenoxy)-2-methyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide
2- (2,3-二氟苯氧基） -2-甲基 -N- (1- ((3- (甲基磺 酰基） 苯基）磺酰基） 哌啶 -4-基） 丙酰胺 o o" 2- (4-氟苯氧基） -N- (1- ((4-氟苯基）磺酰基） 哌 啶 -4-基） -2-甲基丙酰胺2-(2,3-Difluorophenoxy)-2-methyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide oo " 2-(4-Fluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide
Figure imgf000031_0001
Figure imgf000031_0001
、 ( 4- ((4- (2- (4- (4-氯苯甲酰基) 苯氧基） -2-甲基 丙酰氨基） 哌啶 -1-基）磺酰基） 苯甲酸 ^^ 〇 6 , (4-((4-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid ^^ 〇 6
工  Work
2- (4-氯苯氧基） -2-甲基 -N- (1- ((4- (吗啡啉 -4- ^==  2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-(morpholine-4-^==)
。 羰基） 苯基）磺酰基） 哌啶 -4-基） 丙酰胺 工  . Carbonyl)phenyl)sulfonyl)piperidin-4-yl)propionamide
N-(l -((3-氰基苯基）磺酰基）哌啶 -4-基） -5- (2,4- 二氟苯氧基） -2,2-二甲基戊酰胺  N-(l-((3-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,4-difluorophenoxy)-2,2-dimethylpentanamide
5- (2,4-二氟苯氧基） -N- (1- ((3-氟苯基)磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 5-(2,4-Difluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
Figure imgf000031_0002
Figure imgf000031_0002
5- (4-氯 -2-氟苯氧基） -N- (1- ((3-氟苯基）磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺  5-(4-Chloro-2-fluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
3 - ((4- (5- (2,4-二氟苯氧基） -2,2-二甲基戊酰氨 基） 哌啶 -1-基） 磺酰基） 苯甲酸 反式—4- ((4- (2- (4- (4-氯苯甲酰基)苯氧基） -2- 甲基丙酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 3-((4-(5-(2,4-Difluorophenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid trans-4-( (4-(2-(4-(4-Chlorobenzoyl)phenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid
5- (2,4-二氟苯氧基） -2,2-二甲基 -N- (1- ((3- (甲 基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 戊酰胺
Figure imgf000031_0003
5-(2,4-Difluorophenoxy)-2,2-dimethyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valeramide
Figure imgf000031_0003
反式 -4- ((4- (5- (2,4-二氟苯氧基) -2,2-二甲基戊 酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸甲酯 ί T S  Trans-4-((4-(5-(2,4-difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Methyl formate ί TS
反式 -4- ((4- (5- (2,4-二氟苯氧基) -2,2-二甲基戊 酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸 反式 -4- ((4- (5- (2,4-二氟苯氧基) -2,2-二甲基戊 酰氨基） -3-氟哌啶 -1-基）磺酰基）苯甲酸（2-乙酰 氨基） 乙酯  Trans-4-((4-(5-(2,4-difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Formic acid trans-4-((4-(5-(2,4-difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl) Benzoic acid (2-acetamido) ethyl ester
4-((4-(5-(4-氟苯氧基) -2,2-二甲基戊酰氨基)哌啶 -1- 基)磺酰基)苯甲酸  4-((4-(5-(4-fluorophenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid
5-(4-氟苯氧基) -N-(l-((3-氟苯基）磺酰基）哌啶 -4- 基) -2,2-二甲基戊酰胺 5-(4-氟苯氧基) -N-(l-((4-氟苯基）磺酰基）哌啶 -4- 基) -2,2-二甲基戊酰胺 5-(4-fluorophenoxy)-N-(l-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide 5-(4-Fluorophenoxy)-N-(l-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
5-(4-氟苯氧基) -2,2-二甲基 -N-(l-((3- (甲基磺酰基）5-(4-fluorophenoxy)-2,2-dimethyl-N-(l-((3-(methylsulfonyl))
〇 〇
苯基)磺酰基)哌啶 -4-基)戊酰胺 Phenyl)sulfonyl)piperidin-4-yl)pentanamide
Figure imgf000032_0001
Figure imgf000032_0001
工  Work
工 4 - ( (4- (5- (2,4-二氟苯氧基） -2,2-二甲基戊酰胺 基） 哌啶 -1-基） 磺酰基） 苯甲酸 2-乙酰氨基乙酯  4-(4-(5-(2,4-Difluorophenoxy)-2,2-dimethylpentanoyl)piperidin-1-yl)sulfonyl) 2-acetamidoethylbenzoate Ester
4- ( (4- (2- (4-氟苯氧基） -2-甲基丙酰氨基） 哌啶 o 4-( (4-(2-(4-fluorophenoxy)-2-methylpropionylamino)piperidine o
。 -1-基） 磺酰基） 苯甲酸  . -1-yl)sulfonyl)benzoic acid
。 t  . t
4-((4-(5-(4-氯苯氧基) -2,2-二甲基戊酰胺)哌啶 -1-基） 磺酰基)苯甲酸 4-((4-(5-(4-chlorophenoxy)-2,2-dimethylvaleramide)piperidin-1-yl)sulfonyl)benzoic acid
Figure imgf000032_0002
Figure imgf000032_0002
4- ( ( (3R,4R) -4- (2- (4- (4-氯苯甲酰基)苯氧基） -2-甲基丙酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲 酸  4-(((3R,4R)-4-(2-(4-(4-Chlorobenzoyl)phenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl) Sulfonyl) benzoic acid
4- ( ( (3R,4R) -4- (2- (4- (4-氯苯甲酰基)苯氧基） -2-甲基丙酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲4-(((3R,4R)-4-(2-(4-(4-Chlorobenzoyl)phenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl) Sulfonyl)
6 酸甲酯 6 acid methyl ester
4-((4-(5-(4-氯苯氧基) -2,2-二甲基戊酰胺)哌啶 -1-基） 4-((4-(5-(4-Chlorophenoxy)-2,2-dimethylvaleramide)piperidin-1-yl)
。 。^ 。〜 磺酰基)苯甲酸 2-乙酰氨基乙酯 . . ^. ~ Sulfonyl)benzoic acid 2-acetamidoethyl ester
4-((4-(2-(4-氯苯氧基) -2-甲基丙酰胺)哌啶 -1-基)磺 酰基)苯甲酸 -2- (乙酰氨基) -乙酯4-((4-(2-(4-Chlorophenoxy)-2-methylpropionamide) piperidin-1-yl)sulfonyl)benzoic acid-2-(acetylamino)-ethyl ester
Figure imgf000032_0003
Figure imgf000032_0003
4 - ( (4- (5- (3,4-二氟苯氧基) -2,2-二甲基戊酰胺 基） 哌啶 -1-基） 磺酰基） 苯甲酸  4-((4-(5-(3,4-Difluorophenoxy)-2,2-dimethylpentanyl)piperidin-1-yl)sulfonyl)benzoic acid
6  6
3 - ( (4- (5- (3,4-二氟苯氧基) -2,2-二甲基戊酰氨 基） 哌啶 -1-基） 磺酰基） 苯甲酸  3-((4-(5-(3,4-Difluorophenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid
5- (3,4-二氟苯氧基） -N- ( 1- ( (3-氟苯基）磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 5-(3,4-Difluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
5- (3,4-二氟苯氧基) -N- ( 1- ( (4-氟苯基)磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 5-(3,4-Difluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
5- (4-氯苯氧基） -2,2-二甲基 -N- (1- ((4- (吗啉 -4- 羰基） 苯基）磺酰基） 哌啶 -4-基） 戊酰胺
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholin-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)penta Amide
5-(4-氯苯氧基) -N- (1- ( (4-(N-环丙基磺酰胺) -苯 基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰 5-(4-Chlorophenoxy)-N-(1-((4-(N-cyclopropylsulfonamide)-phenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Pentoyl
2-(4-氯苯氧基) -N- (1- ( (4-(N-环丙基磺酰胺) -苯 f"、'lds"。 基） 磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 αΧΧ'Λ 2-(4-Chlorophenoxy)-N-(1-((4-(N-cyclopropylsulfonamide)-benzene f", 'ld s ".))sulfonyl)piperidin-4-yl -2-methylpropionamide αΧΧ'Λ
( ( (3R,4R) -4- (5- (2,5-二氯苯氧基) -2,2-二甲 基戊酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 反式 -3- ( (4- (5- (2,5-二氯苯氧基） -2,2-二甲基戊 酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸
Figure imgf000036_0001
((3R,4R)-4-(5-(2,5-Dichlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl) Benzoic acid trans-3-((4-(5-(2,5-dichlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl Benzoic acid
Figure imgf000036_0001
3- ( ( (3R,4R) -4- (5- (2,5-二氯苯氧基) -2,2-二 甲基戊酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 γ  3-((3R,4R)-4-(5-(2,5-Dichlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl) sulfonate Acyl) benzoic acid γ
2- (4-氟苯氧基) -2-甲基 -N- (1- ( (4- (甲基磺酰 基） 苯基）磺酰基） 哌啶 -4-基） 丙酰胺
Figure imgf000036_0002
2-(4-Fluorophenoxy)-2-methyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide
Figure imgf000036_0002
2- (4-氟苯氧基) -N- (1- ( (3-氟苯基) 磺酰基） o i。 哌啶 -4-基） -2-甲基丙酰胺  2-(4-Fluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl) o i. Piperidin-4-yl)-2-methylpropionamide
° ¾ F ° 3⁄4 F
。广 反式 -5- (2,5-二氯苯氧基） -N- (3-氟 -1 - ((3-氟苯 基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺  .广-trans-5-(2,5-dichlorophenoxy)-N-(3-fluoro-1 -((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2- Dimethylpentanamide
5- (4-氟苯氧基） -2,2-二甲基 -N- (1- (喹啉 -8-基磺 酰基） 哌啶 -4-基） 戊酰胺 5-(4-Fluorophenoxy)-2,2-dimethyl-N-(1-(quinolin-8-ylsulfonyl)piperidin-4-yl)pentanamide
5- (4-氯苯氧基） -2,2-二甲基 -N- (1- (喹啉 -8-基磺 酰基） 哌啶 -4-基） 戊酰胺5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-(quinolin-8-ylsulfonyl)piperidin-4-yl)pentanamide
Figure imgf000036_0003
Figure imgf000036_0003
4- ((4- (2- (4-氟苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 (2-乙酰氨基)乙酯 3- ((4- (2- (4-氟苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 '、(、(、 \、 。 。 4- (((3R,4R) -3-氟 -4- (2- (4-氟苯氧基） -2-甲基 o rrc。。H 丙酰氨基） 哌啶 -1-基）磺酰基） 苯甲酸 4-((4-(2-(4-Fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (2-acetamido)ethyl ester 3-((4-(2-(4-fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid ', (, (, \, . . 4- (((3R,4R)-3-fluoro-4-(2-(4-fluorophenoxy)-2-methylo rr c . H propionylamino)piperidin-1-yl)sulfonyl) benzoic acid
N- ((3R,4R) -3-氟 -1 - ((4- (甲基磺酰基) 苯基） 磺酰基）哌啶 -4-基） -2- (4-氟苯氧基） -2-甲基丙酰 胺 N-((3R,4R)-3-fluoro-1 -((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-2-(4-fluorophenoxy)- 2-methylpropionamide
3- (((3R,4R) -3-氟 -4- (2- (4-氟苯氧基） -2-甲基 丙酰氨基） 哌啶 -1-基）磺酰基） 苯甲酸 3-(((3R,4R)-3-fluoro-4-(2-(4-fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid
FjCr。 ^ F jCr. ^
5- (4-氟苯氧基） -2,2-二甲基 -N- (1- ((4- (吗啉 -4- 羰基） 苯基）磺酰基） 哌啶 -4-基） 戊酰胺  5-(4-Fluorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholin-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)penta Amide
4- ((4- (2-甲基 -2- (4- (甲基磺酰基) 苯氧基） 丙 酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 (2-乙酰氨基） 乙酯 反式 -4- ((3-氟 -4- (2-甲基 -2- (4- (甲基磺酰基) 苯氧基） 丙酰氨基） 哌啶 -1-基）磺酰基） 苯甲酸4-((4-(2-methyl-2-(4-(methylsulfonyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzoic acid (2-acetylamino) Ester trans-4-((3-fluoro-4-(2-methyl-2-(4-(methylsulfonyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzene Formic acid
。Ά 。 . Oh.
。 ¾  . 3⁄4
反式 -4- ((3-氟 -4- (2-甲基 -2- (4- (甲基磺酰基) 苯氧基）丙酰氨基）哌啶 -1-基）磺酰基）苯甲酸（2- 乙酰氨基） 乙酯  Trans-4-((3-fluoro-4-(2-methyl-2-(4-(methylsulfonyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzoic acid (2-acetylamino)ethyl ester
。Ί  . Ί
反式 -N- (3-氟 -1 - ( (4- (吗啉 -4-羰基）苯基）磺 酰基）哌啶 -4-基） -2-甲基 -2- (4- (甲基磺酰基）苯 氧基） 丙酰胺  trans-N-(3-Fluoro-1 - ((4-(morpholine-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)-2-methyl-2- (4- (A Sulfonyl)phenoxy)propionamide
2-甲基 -2- (4- (甲基磺酰基)苯氧基） -N- (1- ( (4-2-methyl-2-(4-(methylsulfonyl)phenoxy)-N- (1- ( 4-
°^° r^。 (吗啉 -4-羰基）苯基）磺酰基）哌啶 -4-基）丙酰胺°^° r^. (morpholine-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide
° T ° T
4 - ( ( (3R,4R) -4- (2- (4-氯苯氧基） -2-甲基丙 酰胺基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸 4-((3R,4R)-4-(2-(4-Chlorophenoxy)-2-methylpropionamido)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid
6 5- (4-氯苯氧基） -2,2-二甲基 -N- (1- ( (4-氨磺酰 基苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 6 5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-((4-sulfamoylphenyl)sulfonyl)piperidin-4-yl)pentanamide
5- (4-氯苯氧基） -2,2-二甲基 -N- (1- (吡啶 -4-磺酰 o 基） 哌啶 -4-基） 戊酰胺 5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-(pyridine-4-sulfonyl)pyridin-4-yl)pentanamide
2- (4-氯苯氧基） -2-甲基 -N- (1- (吡啶 -4-磺酰基） 哌啶 -4-基） 丙酰胺 2-(4-Chlorophenoxy)-2-methyl-N-(1-(pyridine-4-sulfonyl)piperidin-4-yl)propanamide
。 .
5- (4-氟苯氧基） -2,2-二甲基 -N- (1- (吡啶 -4-磺酰 基） 哌啶 -4-基） 戊酰胺  5-(4-Fluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-4-sulfonyl)piperidin-4-yl)pentanamide
2- (4-氟苯氧基） -2-甲基 -N- (1- (吡啶 -4-磺酰基） 哌啶 -4-基） 丙酰胺 2-(4-Fluorophenoxy)-2-methyl-N-(1-(pyridine-4-sulfonyl)piperidin-4-yl)propanamide
。  .
5- (4-氯苯氧基） -2,2-二甲基 -N- (1- (吡啶 -2-磺酰 基） 哌啶 -4-基） 戊酰胺  5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-(pyridine-2-sulfonyl)piperidin-4-yl)pentanamide
o  o
2- (4-氯苯氧基） -2-甲基 -N- (1- (吡啶 -2-磺酰基） 哌啶 -4-基） 丙酰胺  2-(4-Chlorophenoxy)-2-methyl-N-(1-(pyridine-2-sulfonyl)piperidin-4-yl)propanamide
。  .
5- (4-氟苯氧基） -2,2-二甲基 -N- (1- (吡啶 -2-磺酰 基） 哌啶 -4-基） 戊酰胺  5-(4-Fluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-2-sulfonyl)piperidin-4-yl)pentanamide
2- (4-氟苯氧基） -2-甲基 -N- (1- (吡啶 -2-磺酰基） 。 。 哌啶 -4-基） 丙酰胺 2-(4-Fluorophenoxy)-2-methyl-N-(1-(pyridine-2-sulfonyl). Piperidin-4-yl)propanamide
。 ^  . ^
5- ((7-溴萘 -2-基) 氧基） -2,2-二甲基 -N- (1- ((4- 5-((7-bromonaphthalen-2-yl)oxy)-2,2-dimethyl-N- (1- ((4-
(甲基磺酰基） 苯基）磺酰基） 哌啶 -4-基） 戊酰胺 Xx _- 、- -X、八、7S。 (Methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)pentanamide Xx _-, -X, VIII, 7 S.
2,2-二甲基 -N- (1- ((4- (甲基磺酰基） 苯基） 磺酰 基） 哌啶 -4-基） -5- (喹啉 -6-基氧基） 戊酰胺
Figure imgf000038_0001
2,2-Dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-5-(quinolin-6-yloxy)pentane Amide
Figure imgf000038_0001
5- ((5,7-二溴喹啉 -8-基）氧基） -2,2-二甲基 -N- (1- o. jfT%° ((4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基）5-((5,7-Dibromoquinolin-8-yl)oxy)-2,2-dimethyl-N- (1-o. jfT % ° ((4-(methylsulfonyl))benzene Base) sulfonyl) piperidin-4-yl)
ΒΓΥΥΒΓ ° r h 戊酰胺 ΒΓ ΥΥ ΒΓ ° rh pentamide
I  I
5- ((7-溴萘 -2-基） 氧基） -2,2-二甲基 -N- (1- ((4- 羧基苯基） 磺酰基） 哌啶 -4-基） 戊酰胺  5-((7-bromonaphthalen-2-yl)oxy)-2,2-dimethyl-N-(1-((4-carboxyphenyl)sulfonyl)piperidin-4-yl)pentanamide
。 2,2-二甲基 -N- (1- ((4-羧基苯基)磺酰基）哌啶 -4- 基） -5- (喹啉 -6-基氧基） 戊酰胺 . 2,2-Dimethyl-N-(1-((4-carboxyphenyl)sulfonyl)piperidin-4-yl)-5-(quinolin-6-yloxy)pentanamide
2- (4-氟苯氧基） -N- (1- ((4-甲氧苯基） 磺酰基） 哌啶 -4-基） -2-甲基丙酰胺2-(4-Fluorophenoxy)-N-(1-((4-methoxyphenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide
Figure imgf000039_0001
Figure imgf000039_0001
2- (4-氟苯氧基） -2-甲基 -N- (1- ( (4- (吗啡啉 -4- 羰基） 苯基）磺酰基） 哌啶 -4-基） 丙酰胺  2-(4-Fluorophenoxy)-2-methyl-N-(1-((4-(morpholine-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide
2- (4-氯苯氧基） -2-甲基 -N- (1- ((4- (4-甲基 -1， 4-二氮杂环庚垸 -1-羰基） 苯基） 磺酰基） 哌啶 -4- 基） 丙酰胺 反式 -5- (2， 4-二氟苯氧基) -N- (1- ((2， 3-二氢 苯并呋喃 -5-基） 磺酰基） -3-氟哌啶 -4-基） -2， 2- 二甲基戊酰胺 2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-(4-methyl-1, 4-diazacycloheptan-1-yl)phenyl) sulfonate Acyl) piperidin-4-yl)propionamide trans-5-(2,4-difluorophenoxy)-N-(1-((2,3-dihydrobenzofuran-5-yl)sulfonate Acyl)-3-fluoropiperidin-4-yl)-2,2-dimethylpentanamide
反式 -5- (3， 4-二氟苯氧基) -N- (1- ((2， 3-二氢 苯并呋喃 -5-基） 磺酰基） -3-氟哌啶 -4-基） -2， 2-
Figure imgf000039_0002
二甲基戊酰胺 Trans-5-(3,4-difluorophenoxy)-N-(1-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-3-fluoropiperidin-4- Base) -2, 2-
Figure imgf000039_0002
Dimethylpentanamide
2- (4-氯苯氧基） -2-甲基 -N- (1- ( (4- (4-甲基哌 2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-(4-methyl)
0 k 啶 -1-羰基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 0 k pyridine-1-carbonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide
5- (3， 4-二氟苯氧基） -2， 2-二甲基 -N- (1- ((4- (吗啡啉 -4-羰基）苯基）磺酰基）哌啶 -4-基）戊酰 胺 5-(3,4-Difluorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholine- 4- carbonyl)phenyl)sulfonyl)piperidin-4- Pentamide
5- (2， 4-二氟苯氧基） -2， 2-二甲基 -N- (1- ( (4-5-(2,4-Difluorophenoxy)-2,2-dimethyl-N- (1- ( 4-
(吗啡啉 -4-羰基）苯基）磺酰基）哌啶 -4-基）戊酰 胺 (morpholine- 4- carbonyl)phenyl)sulfonyl)piperidin-4-yl)pentanamide
N- (1- ((3-氯 -4-氟苯基） 磺酰基） 哌啶 -4-基) -2-N-(1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-
(4-氯苯氧基） -2-甲基丙酰胺
Figure imgf000039_0003
(4-chlorophenoxy)-2-methylpropionamide
Figure imgf000039_0003
N- (1- ( (2， 6-二氟苯基磺酰基） 哌啶 -4-基） -5- (4-氟苯氧基） -2， 2-二甲基戊酰胺  N-(1-((2,6-Difluorophenylsulfonyl)piperidin-4-yl)-5-(4-fluorophenoxy)-2,2-dimethylpentanamide
2- (4-氯苯氧基) -2-甲基 -N- (1- ((4- (N-甲基氨 磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-(N-methylsulfamoyl)phenyl)sulfonyl)piperidin-4-yl)propanamide
Figure imgf000040_0001
4-((4-(2-(4-氯苯氧基) -2-甲基丙酰氨基） 哌啶 -1-基） o 磺酰基）苯磺酸 2-乙酰氨基乙酯
Figure imgf000040_0001
4-((4-(2-(4-chlorophenoxy)-2-methylpropionylamino)piperidin-1-yl) o sulfonyl)benzenesulfonate 2-acetamidoethyl ester
4-((4-(5-(4-氯苯氧基) -2,2-二甲基戊酰胺基） 哌啶 -1- 基）磺酰基） 苯磺酸 2-乙酰氨基乙酯 4-((4-(5-(4-chlorophenoxy)-2,2-dimethylpentanyl)piperidin-1-yl)sulfonyl)benzenesulfonic acid 2-acetamidoethyl ester
0  0
0 4- ( (4- (2-甲基 -2- (3- (三氟甲基） 苯氧基） 丙酰 ^yo^^^ 。ΧΧ。。Η 氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 o工 31 4- ( (4- (2-甲基 -2- (3- (三氟甲基） 苯氧基） 丙酰 氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 （2-乙酰氨基）
Figure imgf000041_0001
乙酯 04- ((4- (2-methyl-2- (3- (trifluoromethyl) phenoxy) propionyl ^ yo ^^^ .ΧΧ .. Η amino) piperidin-1-yl) sulfonamide Acyl) benzoic acid o- 31 4-((4-(2-methyl-2-(3-(trifluoromethyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzoic acid (2-acetylamino)
Figure imgf000041_0001
Ethyl ester
2- (4-氯苯氧基） -2-甲基 -N- ( 1- ( (4-氨磺酰基苯基） 磺酰基） 哌啶 -4-基） 丙酰胺  2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-sulfamoylphenyl)sulfonyl)piperidin-4-yl)propanamide
。 KA  . KA
d'XX。  D'XX.
0、 5 - ( ( 1-溴萘 -2-基) 氧基） -N- ( 1- ( (4-氟苯基)磺 酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺  0,5-((1-Butonaphthalen-2-yl)oxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Valeramide
o  o
N- ( 1 - ( (4-氟苯基） 磺酰基） 哌啶 -4-基） -5- (异 喹啉 -5-基氧基） -2,2-二甲基戊酰胺 N-( 1 - ( (4-fluorophenyl)sulfonyl) piperidin-4-yl) -5-(isoquinoline-5-yloxy)-2,2-dimethylpentanamide
Figure imgf000041_0002
Figure imgf000041_0002
4 - ( (4- ( 5- (异喹啉 -5-基氧基) -2,2-二甲基戊酰胺 基） 哌啶 -1-基） 磺酰基） 苯甲酸  4-((4-(5-(isoquinoline-5-yloxy)-2,2-dimethylpentanyl)piperidin-1-yl)sulfonyl)benzoic acid
4- ( (4- (2,2-二甲基 -5- (4- (甲基磺酰基)苯氧基） 戊酰氨基）哌啶 -1-基）磺酰基）苯甲酸 2-乙酰氨基4-((4-(2,2-Dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid 2-acetamido
0 0 0 0
乙酯  Ethyl ester
4- ( (4- (2,2-二甲基 -5- (4- (甲基磺酰基)苯氧基） 戊酰氨基） 哌啶 -1-基）磺酰基） 苯甲酸钠  4-((4-(2,2-Dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanoylamino)piperidin-1-yl)sulfonyl) benzoate
4-((4-(5-(3,4-二氟苯氧基) -2,2-二甲基戊酰胺基）哌 啶 -1-基)磺酰基)苯甲酸 2-乙酰氨基乙酯 2-((4-(5-(3,4-difluorophenoxy)-2,2-dimethylpentanyl)piperidin-1-yl)sulfonyl)benzoic acid 2-acetamidoethyl ester
o' Y  o' Y
。  .
。人  . People
。丫 4-((4-(5-(4-氟苯氧基) -2,2-二甲基戊酰胺基)哌啶 -1- 基)磺酰基)苯甲酸 2-乙酰氨基乙酯 5- ( 4-氯苯氧基） -2,2-二甲基 -N- ( 1- ( ( 4- (N-甲. 2-((4-(5-(4-Fluorophenoxy)-2,2-dimethylpentanyl)piperidin-1-yl)sulfonyl)benzoic acid 2-acetamidoethyl ester 5-(4-Chlorophenoxy)-2,2-dimethyl-N- ( 1- ( ( 4- (N-A)
599 基氨磺酰基） 苯基）磺酰基） 哌啶 -4-基） 戊酰胺 反式—4- ( (4- (2,2-二甲基 -5- (4- (甲基磺酰基)苯599 sulfamoyl)phenyl)sulfonyl)piperidin-4-yl)pentanamide trans-4-((4-(2,2-dimethyl-5-(4-(methylsulfonyl)) benzene
600 氧基）戊酰氨基） -3-氟哌啶 -1-基）磺酰基）苯甲酸 工工 反式 -N- (3-氟 -1- ( (4- (甲基磺酰基） 苯基）磺酰600 oxy)pentanoylamino)-3-fluoropiperidin-1-ylsulfonyl)benzoic acid engineering trans-N-(3-fluoro-1-((4-(methylsulfonyl))phenyl) Sulfonyl
601 基） 哌啶 -4-基) -2,2-二甲基 -5- (4- (甲基磺酰基)601 base) piperidin-4-yl)-2,2-dimethyl-5-(4-(methylsulfonyl)
。。 . .
苯氧基） 戊酰胺  Phenoxy) pentamide
4-((4-(2,2-二甲基 -5-(3- (三氟甲基） 苯氧基）戊酰胺 工  4-((4-(2,2-dimethyl-5-(3-(trifluoromethyl)phenoxy)pentanamide)
602 基） 哌啶 -1-基） 磺酰基） 苯甲酸  602 base) piperidine-1-yl)sulfonyl)benzoic acid
。 ΧΛ  . ΧΛ
4-((4-(5-(4-氟 -3- (三氟甲基）苯氧基 )-2,2-二甲基戊 4-((4-(5-(4-fluoro-3-)trifluoromethyl)phenoxy)-2,2-dimethylpentyl
603 酰胺基） 哌啶 -1-基）磺酰基） 苯甲酸 本发明的化合物也可作为药用盐。 该盐可为下列酸中的至少一种的酸盐： 半乳糖二 酸、 D-葡糖醛酸、 甘油磷酸、 马尿酸、 羟乙磺酸、 乳糖酸、 马来酸、 1,5-萘二磺酸、 萘 -2-磺酸、 新戊酸、 对苯二甲酸、 硫氰酸、 胆酸、 正十二垸基硫酸、 苯磺酸、 柠檬酸、 D-葡萄糖， 乙醇酸、 乳酸、 苹果酸、 丙二酸、 扁桃酸、 磷酸、 丙酸、 盐酸、 硫酸、 酒石 酸、 琥珀酸、 甲酸、 氢碘酸、 氢溴酸、 甲垸磺酸、 烟酸、 硝酸、 乳清酸、 草酸、 苦味酸、 L-焦谷氨酸、 糖精酸、 水杨酸、 龙胆酸、 对甲苯磺酸、 戊酸、 棕榈酸、 葵二酸、 硬脂酸、 月桂酸、 乙酸、 己二酸、 碳酸、 4-苯磺酸、 乙垸二磺酸、 乙基琥珀酸、 富马酸、 3-羟基 萘 -2-甲酸、 1-羟基萘 -2-甲酸、 油酸、 十一碳烯酸、 抗坏血酸、 樟脑酸、 樟脑磺酸、 二氯 乙酸、 乙垸磺酸。 另一方面， 该盐也可以是本发明的化合物与金属（包括钠、钾、钙等） 离子或药学上可接受的胺 （包括乙二胺、 氨丁三醇等）或铵离子形成的盐。 例如， 化合 物 239可制成钠盐 （化合物 596)。 603 Amido)piperidin-1-ylsulfonyl)benzoic acid The compounds of the present invention are also useful as pharmaceutically acceptable salts. The salt may be an acid salt of at least one of the following acids: galactose diacid, D-glucuronic acid, glycerophosphoric acid, hippuric acid, isethionic acid, lactobionic acid, maleic acid, 1,5-naphthalene Disulfonic acid, naphthalene-2-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecylsulfuric acid, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, Malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, hydrobromic acid, formamidinesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, Picric acid, L-pyroglutamic acid, saccharin acid, salicylic acid, gentisic acid, p-toluenesulfonic acid, valeric acid, palmitic acid, azelaic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid , 4-benzenesulfonic acid, acetamidine disulfonic acid, ethyl succinic acid, fumaric acid, 3-hydroxynaphthalene-2-carboxylic acid, 1-hydroxynaphthalene-2-carboxylic acid, oleic acid, undecylenic acid, ascorbic acid , camphoric acid, camphorsulfonic acid, dichloroacetic acid, acetamidine sulfonic acid. Alternatively, the salt may be a salt of a compound of the invention with a metal (including sodium, potassium, calcium, etc.) ion or a pharmaceutically acceptable amine (including ethylenediamine, tromethamine, etc.) or an ammonium ion. . For example, compound 239 can be made into a sodium salt (compound 596).
本发明的化合物也可以按酯、 前药形式、 N-氧化物或其溶剂化物组成药物组合物。 例如， 本发明的化合物如果是羧酸 （如化合物 119、 411、 415和 467等）， 它们可以与 适当的醇 （如 N- (2-羟基乙基） 乙酰胺等） 形成酯类前药 （如化合物 272、 424、 416和 468等）。  The compounds of the present invention may also constitute a pharmaceutical composition in the form of an ester, a prodrug, an N-oxide or a solvate thereof. For example, if the compound of the present invention is a carboxylic acid (e.g., compounds 119, 411, 415, and 467, etc.), they may form an ester prodrug with a suitable alcohol (e.g., N-(2-hydroxyethyl)acetamide, etc.) Such as compounds 272, 424, 416 and 468, etc.).
本发明所述的式 （I) 化合物或其药学上可接受的盐或酯或溶剂化物是新型 AMPK 激动剂， 其可能通过激活脂联素受体而激活 AMPK信号通路， 因而可用于制备预防或 治疗以下多种疾病的药物。  The compound of formula (I) or a pharmaceutically acceptable salt or ester or solvate thereof of the present invention is a novel AMPK agonist which may activate the AMPK signaling pathway by activating adiponectin receptors and thus may be used for the preparation of prophylaxis or A drug that treats a variety of diseases as follows.
本发明的化合物可用于预防或治疗多种代谢异常相关疾病或心脑血管疾病， 包括： 胰岛素抵抗、 代谢综合征、 1型或 2型糖尿病、 高脂血症、 肥胖症、 动脉粥样硬化、 心 肌缺血、 心肌梗死、 心律失常、 冠心病、 高血压、 心衰、 心肌肥大、 心肌炎、 糖尿病并 发症 （包括糖尿病心肌病、 糖尿病肾病、 视网膜病变、 神经病和伤口愈合延迟等）、 非 酒精性脂肪肝、 非酒精性脂肪性肝炎、 酒精性脂肪肝、 肝硬化、 高尿酸血症、 痛风、 骨 质疏松、 中风或脑梗死等。 The compounds of the present invention are useful for preventing or treating a variety of metabolic abnormalities or cardiovascular and cerebrovascular diseases, including: insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, atherosclerosis, Myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, cardiac hypertrophy, myocarditis, diabetes Symptoms (including diabetic cardiomyopathy, diabetic nephropathy, retinopathy, neuropathy and delayed wound healing), nonalcoholic fatty liver, nonalcoholic steatohepatitis, alcoholic fatty liver, cirrhosis, hyperuricemia, gout, Osteoporosis, stroke or cerebral infarction.
本发明的化合物可用于预防或治疗各种炎症疾病、 自身免疫性疾病、 器官纤维化疾 病、 神经损伤性疾病或病原体感染所致的继发性疾病， 例如， 肺炎、 肺结核、 炎性肠病 The compound of the present invention can be used for the prevention or treatment of various inflammatory diseases, autoimmune diseases, organ fibrosis diseases, nerve damage diseases or secondary diseases caused by pathogen infections, for example, pneumonia, tuberculosis, inflammatory bowel disease
(如克罗恩病和溃疡性结肠炎）、 白塞氏病、 哮喘、 慢性阻塞性肺病、 慢性支气管炎、 肺气肿、 闭塞性细支气管炎、系统性红斑狼疮、类风湿关节炎、脊椎关节炎、骨关节炎、 滑膜炎、 肌腱炎、 血栓闭塞性脉管炎、 静脉炎、 间歇性跛行、 瘢痕瘤、 银屑病、 鱼鳞癣、 大疱性类天疱疮、 皮炎、 接触性皮炎、 胰腺炎、 慢性肾炎、 膀胱炎、 脑膜炎、 胃炎、 败 血症、 坏疽性脓皮症、 葡萄膜炎、 特发性肺纤维化、 囊性纤维化、 帕金森病、 阿尔茨海 默病、 （X-共核蛋白病、 抑郁症、 多发性硬化症、 肌萎缩侧索硬化病、 纤维肌痛综合症、 神经痛、 唐氏综合征、 哈勒沃登-施帕病、 亨廷顿舞蹈病或威尔逊病等。 (such as Crohn's disease and ulcerative colitis), Behcet's disease, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiolitis obliterans, systemic lupus erythematosus, rheumatoid arthritis, spine Arthritis, osteoarthritis, synovitis, tendonitis, thromboangiitis obliterans, phlebitis, intermittent claudication, keloids, psoriasis, ichthyosis, bullous pemphigoid, dermatitis, contact Dermatitis, pancreatitis, chronic nephritis, cystitis, meningitis, gastritis, sepsis, gangrenous pyoderma, uveitis, idiopathic pulmonary fibrosis, cystic fibrosis, Parkinson's disease, Alzheimer's disease, (X-synucleinopathy, depression, multiple sclerosis, amyotrophic lateral sclerosis, fibromyalgia syndrome, neuralgia, Down's syndrome, Hallerwalden-Sparta disease, Huntington's disease or Wilson's disease and so on.
本发明的化合物可用于治疗或调节线粒体功能障碍和紊乱疾病， 包括： 肌无力、 肌 阵挛、 运动不耐受、 卡恩斯-赛尔综合征、 慢性疲乏综合征、 利氏综合征、 线粒体肌病- 脑病-高乳酸血症、 中风综合征或中风样发作。 同样， 本发明的化合物也可用于治疗肌 肉营养不良状态， 例如， 杜氏肌营养不良、 贝壳肌营养不良或弗立德希氏共济失调。  The compounds of the invention are useful for the treatment or modulation of mitochondrial dysfunction and disorders, including: myasthenia gravis, myoclonus, exercise intolerance, Carnes-Syle syndrome, chronic fatigue syndrome, Rees' syndrome, mitochondria Myopathy - encephalopathy - hyperlactosis, stroke syndrome or stroke-like episodes. Likewise, the compounds of the invention may also be used to treat myasthenia dystrophies, such as Duchenne muscular dystrophy, shell muscle dystrophy or Fleetid's ataxia.
本发明的化合物具有抗肿瘤作用。 所述肿瘤包括但不限于： 骨癌、 急性骨髓性白血 病、 慢性骨髓性白血病、 急性淋巴细胞系白血病、 慢性淋巴细胞系白血病、 骨髓增生性 疾病、 多发性骨髓瘤、 骨髓增生异常综合征、 霍奇金氏淋巴瘤、 非霍奇金氏淋巴瘤、 血 管瘤、 肉芽瘤、 黄瘤、 脑膜肉瘤、 神经胶质瘤、 星形细胞瘤、 成神经管细胞瘤、 室管膜 瘤、 生殖细胞瘤 （松果体瘤）、 多形性成胶质细胞瘤、 少突神经胶质细胞瘤、 神经鞘瘤、 成视网膜细胞瘤、 纤维神经瘤、 肉瘤、 食道癌、 胃癌、 胰腺癌、 大肠癌、 结肠癌、 直肠 癌、 肾癌、 前列腺癌、 淋巴癌、 睾丸癌、 间质细胞癌、 肺癌、 肝癌、 皮肤癌、 恶性黑素 瘤或基底细胞癌等。  The compounds of the invention have anti-tumor effects. Such tumors include, but are not limited to, bone cancer, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, Huo Chikin's lymphoma, non-Hodgkin's lymphoma, hemangioma, granuloma, xanthoma, meningosarcoma, glioma, astrocytoma, medulloblastoma, ependymoma, germ cell tumor (pineal tumor), pleomorphic glioblastoma, oligodendroglioma, schwannomas, retinoblastoma, fibrosarcoma, sarcoma, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, Colon cancer, rectal cancer, kidney cancer, prostate cancer, lymphoma, testicular cancer, stromal cell carcinoma, lung cancer, liver cancer, skin cancer, malignant melanoma or basal cell carcinoma.
本发明所述的预防或治疗上述疾病的药物组合物， 其中含有治疗有效量的式（I)化 合物或其药学上可接受的盐或酯或溶剂化物作为活性成份和药学上可接受的辅料。可任 意混合的辅料根据剂型、 给药形式等可以改变。 辅料的例子包括赋形剂、 粘合剂、 崩解 剂、 润滑剂、 矫味剂、 香味剂、 着色剂或甜味剂等。 所述药物组合物可以是胶囊剂、 散 剂、 片剂、 颗粒剂、 丸剂、 注射剂、 糖浆剂、 口服液、 吸入剂、 软膏剂、 栓剂或贴剂等 制剂学上常规的制剂形式。  The pharmaceutical composition for preventing or treating the above-mentioned diseases according to the present invention, which comprises a therapeutically effective amount of the compound of the formula (I) or a pharmaceutically acceptable salt or ester or solvate thereof as an active ingredient and a pharmaceutically acceptable adjuvant. The excipients which may be optionally mixed may vary depending on the dosage form, administration form and the like. Examples of the excipients include excipients, binders, disintegrators, lubricants, flavoring agents, flavoring agents, coloring agents or sweeteners, and the like. The pharmaceutical composition may be in the form of a pharmaceutically acceptable preparation such as a capsule, a powder, a tablet, a granule, a pill, an injection, a syrup, an oral solution, an inhalation, an ointment, a suppository or a patch.
如果需要， 本发明的化合物可与一种或多种其他类型的预防或治疗上述疾病的药物 联合使用， 包括但不限于以下几种联合用药的情形。  If desired, the compounds of the invention may be combined with one or more other types of agents for the prevention or treatment of the above disorders, including but not limited to the following combinations.
可选择与本发明的化合物联合使用的其他类型的预防或治疗药物可以是一种或多种 抗糖尿病药物， 包括二甲双胍、 磺酰脲类降糖药 （如格列苯脲和格列美脲等）、 葡萄糖 苷酶抑制剂 （如阿卡波糖和米格列醇等）、 PPARY激动剂 (如吡格列酮和罗格列酮）、 PPARot/γ双重激动剂、 二肽基肽酶 IV (DPP-IV)抑制剂（如西格列汀、 沙格列汀、 阿格 列汀和利格列汀等）、 格列奈类降糖药（如瑞格列奈和那格列奈等）、 SGLT2抑制剂（如 坎格列净、 达格列净、 恩格列净、 依格列净、 鲁格列净和托格列净等）、 葡萄糖激酶激 动剂 （如 HMS5552等）、 胰岛素、 胰高血糖素样肽 -l(GLP-l) 类药物 （如埃塞那肽、 利 拉鲁肽、 利司那肽、 杜拉鲁肽、 贝那鲁肽和阿必鲁肽等）、 PTP1B抑制剂、 糖原磷酸化 酶抑制剂、 葡萄糖 -6-磷酸酶抑制剂、 AMPK激动剂、 GPR40激动剂或 GPR120激动剂。 Other types of prophylactic or therapeutic agents that may be selected for use in combination with the compounds of the invention may be one or more anti-diabetic agents, including metformin, sulfonylureas, such as glibenclamide and glimepiride. ), glucose Glycosidase inhibitors (such as acarbose and miglitol), PPAR Y agonists (such as pioglitazone and rosiglitazone), PPARot/γ dual agonists, dipeptidyl peptidase IV (DPP-IV) Inhibitors (such as sitagliptin, saxagliptin, alogliptin, and linagliptin), glinide-type hypoglycemic agents (such as repaglinide and nateglinide, etc.), SGLT2 inhibitors (eg, cangliflozin, dapagliflozin, nglipepsin, iglegide, rugliflozin, and togliflozin), glucokinase agonists (eg, HMS5552, etc.), insulin, glucagon Peptide-l (GLP-1) drugs (such as exenatide, liraglutide, risnatide, duraglutide, benaglutide, and abiglutide), PTP1B inhibitors, sugars Pro-phosphorylase inhibitor, glucose-6-phosphatase inhibitor, AMPK agonist, GPR40 agonist or GPR120 agonist.
可选择与本发明的化合物联合使用的其他类型的预防或治疗药物可以是一种或多种 减肥药物， 包括氯卡色林、 奥利司他和胰高血糖素样肽 -l(GLP-l) 类药物（如埃塞那肽、 利拉鲁肽、 利司那肽、 杜拉鲁肽、 贝那鲁肽和阿必鲁肽等） 等。  Other types of prophylactic or therapeutic agents that may be selected for use in combination with the compounds of the invention may be one or more weight-loss drugs, including lorcaserin, orlistat, and glucagon-like peptide-1 (GLP-l Classes of drugs (such as exenatide, liraglutide, risnatide, duraglutide, benaglutide, and albendide, etc.).
可选择与本发明的化合物联合使用的其他类型的预防或治疗药物可以是一种或多种 抗非酒精性脂肪性肝病药物， 包括： AMPK激动剂（如二甲双胍）、法尼酯 X受体 (FXR) 激动剂 （如奥贝胆酸、 GS-9674、 EDP-305和 LJN452等）、 乙酰辅酶 A羧化酶 （ACC) 抑制剂 （如 GS-0976等）、 凋亡信号调节激酶 -1 (ASK1 ) 抑制剂 （如 Selonsertib等）、 PPAR激动剂 （如 Elafibranor、 Saroglitazar、 IVA337和 MSDC-0602K等）、 半胱天冬酶 (caspase)抑制剂（如 Emricasan等）、 硬脂酰辅酶 A去饱和酶 1 ( SCD1 )抑制剂（如 Aramchol等）、 长效胰高血糖素样肽 -1 (GLP-1 ) 受体激动剂 （如 Semaglutide等）、 顶 端钠依赖性胆盐转运体 (ASBT) 抑制剂 （如 Volixibat等）、 血管粘附蛋白 1 (VAP-1 ) 抑 制剂（如 BI 1467335等）、 CCR5R阻断剂（如 Cenicriviroc等）和甲状腺激素受体 p(THR-p) 激动剂 （如 MGL-3196等） 等。  Other types of prophylactic or therapeutic agents that may be selected for use in combination with the compounds of the invention may be one or more anti-alcoholic fatty liver disease drugs, including: AMPK agonists (e.g., metformin), farnesyl X receptor ( FXR) agonists (eg, oleic acid, GS-9674, EDP-305, and LJN452, etc.), acetyl-CoA carboxylase (ACC) inhibitors (eg, GS-0976, etc.), apoptosis signal-regulated kinase-1 ( ASK1) inhibitors (eg Selonsertib, etc.), PPAR agonists (eg Elafibranor, Saroglitazar, IVA337 and MSDC-0602K, etc.), caspase inhibitors (eg Emricasan, etc.), stearoyl-CoA desaturation Enzyme 1 (SCD1) inhibitors (eg Aramchol et al), long-acting glucagon-like peptide-1 (GLP-1) receptor agonists (eg Semaglutide, etc.), apical sodium-dependent bile salt transporter (ASBT) inhibition Agents (eg, Volixibat, etc.), vascular adhesion protein 1 (VAP-1) inhibitors (eg, BI 1467335, etc.), CCR5R blockers (eg, Cenicriviroc, etc.), and thyroid hormone receptor p (THR-p) agonists (eg, MGL-3196, etc.).
可选择与本发明的化合物联合使用的其他类型的预防或治疗药物可以是一种或多种 降血脂药物， 包括烟酸、 他汀类药物 （如洛伐他丁、 辛伐他汀、 普伐他汀、 美伐他汀、 氟伐他汀、 阿托伐他汀、 西立伐他汀、罗伐他汀和 pitavastatin)、胆固醇吸收抑制剂（如 依折麦布等）、 贝特类药物 （如氯贝特、 苯扎贝特、 非诺贝特等）、 PCSK9 抑制剂 （如 Evolocumab和 Alirocumab等）、 CETP抑制剂（如 anacetrapib等）、 AMPK激动剂和 ACC 抑制剂 （如 GS-0976等） 等。  Other types of prophylactic or therapeutic agents that may be selected for use in combination with the compounds of the invention may be one or more hypolipidemic drugs, including niacin, statins (eg, lovastatin, simvastatin, pravastatin, Mevastatin, fluvastatin, atorvastatin, cerivastatin, lovastatin and pitavastatin), cholesterol absorption inhibitors (eg ezetimibe, etc.), fibrates (eg clofibrate, benzal) Bet, fenofibrate, etc.), PCSK9 inhibitors (such as Evolocumab and Alirobumab, etc.), CETP inhibitors (such as anacetrapib, etc.), AMPK agonists and ACC inhibitors (such as GS-0976, etc.).
本发明的化合物的制备可参照以下合成路线或改进的方法进行。 The preparation of the compounds of the invention can be carried out with reference to the following synthetic routes or modified methods.
、 oos== , oos==
合成路线 2. Synthetic route 2.
Figure imgf000045_0001
Figure imgf000045_0001
合成路线 3. Synthetic route 3.
Figure imgf000045_0002
Figure imgf000045_0002
合成 4. Synthesis 4.
Figure imgf000045_0003
Figure imgf000045_0003
(CICO)2, DMF Et3N, DCM (CICO) 2 , DMF Et 3 N, DCM
R3 R 3
'  '
o  o
R8 合成路线 5. R 8 Synthetic route 5.
Figure imgf000046_0001
Figure imgf000046_0001
合成路线  synthetic route
Figure imgf000046_0002
Figure imgf000046_0002
合成路线 8.  Synthetic route 8.
Figure imgf000046_0003
在上述合成路线中， R R2、 R3、 R4、 R5、 R6、 R7、 R8和 R'的定义与上述式 （I) 化合物中的定义一致； m为 0、 1、 2、 3、 4、 5、 6、 7、 8或 9。
Figure imgf000046_0003
In the above synthetic route, the definitions of RR 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R′ are identical to those defined in the above formula (I); m is 0, 1, 2 , 3, 4, 5, 6, 7, 8, or 9.
本发明制备的结构如式 （I) 所示的化合物具有显著的 AMPK激动活性， 并且本发 明的化合物对 AMPK的激动活性是脂联素受体 1 (AdipoRl ) 依赖的， 是特异性的脂联 素受体激动剂， 本发明具有式 （I) 结构的化合物可应用于制备有机体中 AMPK相关疾 病的药物， 例如， 可用于防治糖尿病及其并发症、 高血脂症及非酒精性脂肪性肝病、 心 肌病和心力衰竭等。 The compound prepared by the present invention has a structure of the formula (I) having significant AMPK agonistic activity, and the present invention The agonistic activity of the compound to AMPK is adiponectin 1 (AdipoRl)-dependent, a specific adiponectin receptor agonist, and the compound having the structure of the formula (I) of the present invention can be applied to the preparation of AMPK in an organism. Drugs related to the disease, for example, can be used to prevent diabetes and its complications, hyperlipidemia and nonalcoholic fatty liver disease, cardiomyopathy and heart failure.
附图说明 DRAWINGS
图 1为化合物对 C2C12细胞 AMPK磷酸化的影响图；  Figure 1 is a graph showing the effect of compounds on the phosphorylation of AMPK in C2C12 cells;
图 2为化合物对 AdipoRl野生型或 AdipoRl敲除 HEK293T细胞 AMPK磷酸化的影 响图；  Figure 2 is a graph showing the effect of compounds on AMPK phosphorylation of AdipoRl wild type or AdipoRl knockout HEK293T cells;
图 3为钙螯合剂 EGTA对化合物 AMPK激动活性的影响图；  Figure 3 is a graph showing the effect of the calcium chelator EGTA on the agonistic activity of the compound AMPK;
图 4为化合物 111和 119降血糖的时间 -FBG关系图；  Figure 4 is a time-FBG relationship diagram of hypoglycemia of Compounds 111 and 119;
图 5为小鼠口服化合物 119后血清中 TC、 LDL、 HDL及肝脏组织内 TG水平图； 图 6为小鼠口服化合物 119后的肝脏 HE染色图；  Fig. 5 is a graph showing the levels of TG, LDL, HDL and liver TG in serum after oral administration of compound 119 in mice; Fig. 6 is a diagram showing HE staining of liver after oral administration of compound 119 in mice;
图 7为小鼠口服化合物 119后的肝脏油红染色图；  Figure 7 is a graph showing liver oil red staining after oral administration of Compound 119 in mice;
图 8为小鼠口服化合物 119后血清中 ALT和 AST水平图；  Figure 8 is a graph showing the levels of ALT and AST in serum after oral administration of Compound 119 in mice;
图 9为化合物 119对 SD大鼠心力衰竭模型的影响图。  Figure 9 is a graph showing the effect of Compound 119 on the SD rat heart failure model.
具体实施方式 Detailed ways
本发明公开了一种化合物及其制备方法、 该化合物的中间体及其制备方法， 以及该 化合物作为 AMPK激动剂的应用， 本领域技术人员可以借鉴本文内容， 适当改进工艺 参数实现。 特别需要指出的是， 所有类似的替换和改动对本领域技术人员来说是显而易 见的， 它们都被视为包括在本发明。 本发明的方法及应用已经通过较佳实施例进行了描 述， 相关人员明显能在不脱离本发明内容、 精神和范围内对本文所述的方法和应用进行 改动或适当变更与组合， 来实现和应用本发明技术。  The invention discloses a compound, a preparation method thereof, an intermediate of the compound and a preparation method thereof, and an application of the compound as an AMPK agonist, and those skilled in the art can learn from the contents of the present invention and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
实施例 1  Example 1
N- ( 1-苄基哌啶 -4-基） -2- (4- (4-氯苯甲酰基）苯氧基） -2-甲基丙酰胺（化合物 1 )  N-(1-Benzylpiperidin-4-yl)-2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamide (Compound 1)
Figure imgf000047_0001
取苯酚（5 g， 53.1 mmol)和对氯苯甲酰氯（9.76 g， 55.8 mmol)溶于二氯甲垸（DCM)
Figure imgf000047_0001
Phenol (5 g, 53.1 mmol) and p-chlorobenzoyl chloride (9.76 g, 55.8 mmol) in dichloromethane (DCM)
(50 mL) 中， 加入三乙胺 （7.4 mL)， 室温条件下搅拌过夜， 用饱和碳酸钠 （10 mL) 淬灭， 水相使用 DCM (10 mLx 3) 萃取， 饱和食盐水 （10 mk3) 洗涤， 无水硫酸钠干 燥， 旋干， 得到白色固体化合物 1-3 (11.88 g， 收率 95%)。取化合物 1-3 (7 g， 30 mmol) 和 A1C13 ( 12 g， 90 mmol)于反应瓶中， 140。C条件下加热搅拌 2小时， 用水 ( 100 mL) 淬灭反应， 水相用 DCM (50 mLx3) 萃取， 饱和食盐水 （10 ml x3) 洗涤， 无水硫酸钠 干燥， 减压蒸除溶剂， 残余物经柱层析 （洗脱剂： 石油醚 /乙酸乙酯 = 30:1) 纯化， 得 化合物 1-4 (黄色固体， 4.7 g， 收率 67%)。 (50 mL), add triethylamine (7.4 mL), stir at room temperature overnight, quench with saturated sodium carbonate (10 mL), and elute with DCM (10 mL×3) with saturated brine (10 mk3) The organic layer was dried (MgSO.sub.4). Compound 1-3 (7 g, 30 mmol) and A1C1 3 (12 g, 90 mmol) were taken in a reaction flask, 140. The mixture was heated and stirred for 2 hours, and the reaction was quenched with water (100 mL). EtOAc (EtOAc m. Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 30:1) gave Compound 1-4 (yellow solid, 4.7 g, yield 67%).
取化合物 1-4 (l g， 4.3 mmol)和碳酸钾 （1.78 g， 12.89 mmol)溶于 Ν,Ν-二甲基甲 酰胺 (DMF) (30 mL)中， 室温条件下搅拌半小时， 然后滴加 2-溴 -2-甲基丙酸乙酯（1.89 mDo 70°C条件下反应 5 h，冷却至室温，加入水（50 mL)，水相用乙酸乙酯（30 mLx3) 萃取， 有机相用饱和食盐水 （10 mLx3) 洗涤， 无水硫酸钠干燥， 减压蒸除溶剂， 残余 物经柱层析（洗脱剂： 石油醚 /乙酸乙酯 = 10: 1)纯化， 得化合物 1-5 (白色固体， 1.3 g， 收率 90%)。  Compound 1-4 (lg, 4.3 mmol) and potassium carbonate (1.78 g, 12.89 mmol) were dissolved in hydrazine, hydrazine-dimethylformamide (DMF) (30 mL), stirred at room temperature for half an hour, then drip Add 2-bromo-2-methylpropionic acid ethyl ester (1.89 mDo at 70 ° C for 5 h, cool to room temperature, add water (50 mL), the aqueous phase is extracted with ethyl acetate (30 mL×3), organic phase The mixture was washed with brine (10 mL×3), dried over anhydrous sodium sulfate. 5 (white solid, 1.3 g, yield 90%).
取化合物 1-5 (1.3 g) 溶于 THF (20 mL) 禾 P CH3OH (2 mL) 的混合溶液， 加入 5wt%NaOH水溶液 （10 mL), 加热回流。 反应完毕后， 减压蒸除溶剂， 残余物用乙酸 乙酯 （10 mL) 溶解， 用 1NHC1调节 pH至酸性， 乙酸乙酯 （30 mLx3) 萃取。 有机相 用饱和食盐水洗涤， 无水硫酸钠干燥， 减压蒸除溶剂， 得化合物 1-6 (白色固体， 1.13 g， 收率 94%)。 Solution of compound 1-5 (1.3 g) was dissolved in THF (20 mL) Wo P CH 3 OH (2 mL) mixed solution was added 5wt% NaOH solution (10 mL), heated to reflux. After completion of the reaction, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjjjjj The organic layer was washed with brine, dried over anhydrous sodium sulfate sulfate
取化合物 1-6 (200 mg， 0.6275 mmol) 溶于无水 DMF (1 mL), 加入 1,1-羰基二咪 唑（CDI) (117 mg， 0.7216 mmol), 70°C条件下加热 lh后，加入 N-Boc-4-氨基哌啶（ 126 mg， 0.6275 mmol), 继续反应 2小时。 冷却至室温， 加入水（10 mL)， 水相用乙酸乙酯 (10 mL x3) 萃取， 有机相用饱和食盐水 （10 mLx3) 洗涤， 无水硫酸钠干燥， 减压蒸 除溶剂， 残余物经柱层析 （洗脱剂： 石油醚 /乙酸乙酯 = 2:1) 纯化， 得化合物 1-7 (白 色固体， 260 mg， 收率 83%)。  The compound 1-6 (200 mg, 0.6275 mmol) was dissolved in anhydrous DMF (1 mL), and 1,1-carbonyldiimidazole (CDI) (117 mg, 0.7216 mmol) was added and heated at 70 ° C for 1 h. N-Boc-4-aminopiperidine (126 mg, 0.6275 mmol) was added and the reaction was continued for 2 hours. After cooling to room temperature, water (10 mL) was added, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated brine (10 mL×3), dried over anhydrous sodium sulfate Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) gave Compound 1-7 (white solid, 260 mg, yield 83%).
取化合物 1-7 (211 mg, 0.42 mmol) 溶于 DCM ( 10 mL) 中， 冰浴条件下加入三氟醋 酸 （2 mL)， 反应过夜， 旋干， 加入 DCM (10 mL)， 用饱和碳酸氢钠调节 pH至碱性， 水相用 DCM (10 mLx3)萃取， 有机相用饱和食盐水（10 mLx3)洗涤， 无水硫酸钠干 燥， 减压蒸除溶剂， 得化合物 1-8 (白色固体， 174 mg， 收率 98%)。  Compound 1-7 (211 mg, 0.42 mmol) was dissolved in DCM (10 mL). EtOAc (2 mL) The sodium hydroxide was adjusted to pH, and the aqueous phase was extracted with DCM (10 mL×3). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous sodium sulfate and evaporated. , 174 mg, yield 98%).
取化合物 1-8 (90 mg, 0.225 mmol) 溶于 DMF (lmL) ， 加入碳酸钾 （47mg) 和 溴苄 （0.03 mL) ， 室温下搅拌过夜。 减压蒸除溶剂， 残余物经柱层析 （洗脱剂： 石油 醚 /乙酸乙酯 =2:1) 纯化， 得化合物 1 (白色固体， 87 mg， 收率 80%) ： 1H MR(300 MHz, CDCI3) δ 7.73 (t, J = 8.7 Hz, 4H), 7.46 (d, J = 8.4 Hz, 2H), 7.28 (m, 5H), 6.95 (d, J =Compound 1-8 (90 mg, 0.225 mmol) was dissolved in DMF (1 mL), EtOAc (EtOAc) The solvent was evaporated under reduced pressure. EtOAc mjjjjjjjjjj MHz, CDCI3) δ 7.73 (t, J = 8.7 Hz, 4H), 7.46 (d, J = 8.4 Hz, 2H), 7.28 (m, 5H), 6.95 (d, J =
8.7 Hz, 2H), 6.28 (d, J= 8.1 Hz, 1H), 3.95 - 3.73 (m, 1H)， 3.47 (s, 2H), 2.77 (d, J= 11.8 Hz, 2H), 2.12 (t, J= 10.8 Hz, 2H), 1.88 (d, J= 11.5 Hz, 2H), 1.59 (s, 6H), 1.40 (dd, J= 11.5, 9.3 Hz,2H). ESI-MS: m/z 492.2 [M+H]+. 8.7 Hz, 2H), 6.28 (d, J= 8.1 Hz, 1H), 3.95 - 3.73 (m, 1H), 3.47 (s, 2H), 2.77 (d, J= 11.8 Hz, 2H), 2.12 (t, J = 10.8 Hz, 2H), 1.88 (d, J = 11.5 Hz, 2H), 1.59 (s, 6H), 1.40 (dd, J = 11.5, 9.3 Hz, 2H). ESI-MS: m/z 492.2 [ M+H] + .
实施例 2  Example 2
2- (4- (4-氯苯甲酰基） 苯氧基） -N- ( 1- (4-氯苯甲酰基） 哌啶 -4-基） -2-甲基丙酰 胺 （化合物 5 )  2-(4-(4-Chlorobenzoyl)phenoxy)-N-(1-(4-chlorobenzoyl)piperidin-4-yl)-2-methylpropionylamide (Compound 5)
取化合物 1-8 (实施例 1， 220 mg， 0.55 mmol)和对氯苯甲酰氯（106 mg， 0.60 mmol) 溶于 DCM (5 mL)， 室温条件下加入三乙胺 (56 mg， 0.55 mmol), 反应 2小时后， 减压蒸 除溶剂， 残余物经柱层析（洗脱剂： 石油醚 /乙酸乙酯 = 2: 1 )纯化， 得化合物 5 (白色固 体， 150 mg): 1H MR (300 MHz, d6-OMSO) δ 7.93 (d, J= 8.2 Hz, 1H), 7.67 - 7.57 (m, 4H), 7.56 - 7.48 (m, 2H), 7.43 - 7.34 (m, 2H), 7.28 - 7.19 (m, 2H), 6.87 (d, J= 8.8 Hz, 2H), 4.24 (dt, J= 18.2, 9.5 Hz, 1H), 3.95 - 3.72 (m, 1H), 3.59 - 3.27 (m, 1H), 3.07 - 2.92 (m, 1H), 2.85 - 2.72 (m, 1H), 1.71 - 1.47 (m, 2H), 1.43 (s, 6H), 1.36 - 1.23 (m, 2H). ESI-MS: m/z 562.1 [M+Na]+. Compounds 1-8 (Example 1, 220 mg, 0.55 mmol) and p-chlorobenzoyl chloride (106 mg, 0.60 mmol) were dissolved in DCM (5 mL) and triethylamine (56 mg, 0.55 mmol) After reacting for 2 hours, the solvent was evaporated under reduced pressure and the residue was purified eluted elut elut elut elut elut elut elut elut elut elut (300 MHz, d 6 -OMSO) δ 7.93 (d, J = 8.2 Hz, 1H), 7.67 - 7.57 (m, 4H), 7.56 - 7.48 (m, 2H), 7.43 - 7.34 (m, 2H), 7.28 - 7.19 (m, 2H), 6.87 (d, J= 8.8 Hz, 2H), 4.24 (dt, J= 18.2, 9.5 Hz, 1H), 3.95 - 3.72 (m, 1H), 3.59 - 3.27 (m, 1H) ), 3.07 - 2.92 (m, 1H), 2.85 - 2.72 (m, 1H), 1.71 - 1.47 (m, 2H), 1.43 (s, 6H), 1.36 - 1.23 (m, 2H). ESI-MS: m /z 562.1 [M+Na] + .
实施例 3  Example 3
2- (4- (4-氯苯甲酰基） 苯氧基） -N- ( 1- (4-氰基苄基） 哌啶 -4-基） -2-甲基丙酰胺 (化合物 6)  2-(4-(4-Chlorobenzoyl)phenoxy)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-methylpropanamide (Compound 6)
参照实施例 1的方法制得化合物 6: 1H MR (300 MHz, CDC13) δ 7.74 (d, J= 9.0 Hz, 2H), 7.71 (d, J = 9.2 Hz, 2H), 7.58 (d, J= 7.7 Hz, 2H), 7.45 (d, J= 8.3 Hz, 2H), 7.40 (d, J =Compound 6 was prepared by the method of Example 1: 1H MR (300 MHz, CDC1 3 ) δ 7.74 (d, J = 9.0 Hz, 2H), 7.71 (d, J = 9.2 Hz, 2H), 7.58 (d, J = 7.7 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.40 (d, J =
7.8 Hz, 2H), 6.95 (d, J = 8.2 Hz, 2H), 6.32 (d, J = 7.7 Hz, 1H), 3.95 - 3.69 (m, 1H), 3.50 (s, 2H), 2.72 (d, J = 10.6 Hz, 2H), 2.15 (t, J= 10.8 Hz, 2H), 1.88 (d, J = 10.3 Hz, 2H), 1.59 (s, 6H), 1.37-1.47 (m, 2H). ESI-MS: m/z 539.3 [M+Na]+. 7.8 Hz, 2H), 6.95 (d, J = 8.2 Hz, 2H), 6.32 (d, J = 7.7 Hz, 1H), 3.95 - 3.69 (m, 1H), 3.50 (s, 2H), 2.72 (d, J = 10.6 Hz, 2H), 2.15 (t, J = 10.8 Hz, 2H), 1.88 (d, J = 10.3 Hz, 2H), 1.59 (s, 6H), 1.37-1.47 (m, 2H). ESI- MS: m/z 539.3 [M+Na] + .
实施例 4  Example 4
2- (4- (4-氯苯甲酰基）苯氧基） -2-甲基 -N- ( 1- (4- (三氟甲基）苄基） 哌啶 -4-基） 丙酰胺 （化合物 7)  2-(4-(4-Chlorobenzoyl)phenoxy)-2-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)propanamide ( Compound 7)
参照实施例 1的方法制得化合物 7: 1H NMR (300 MHz, CDC13) δ 7.76 (s, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 7.9 Hz, 2H), 7.45 (d, J= 8.4 Hz, 2H), 7.44 - 7.37 (m, 2H), 6.95 (d, J = 8.5 Hz, 2H), 6.32 (d, J= 7.8 Hz, 1H), 3.82 (s, 1H), 3.51 (s, 2H), 2.74 (d, J= 11.3 Hz, 2H), 2.14 (t, J = 11.0 Hz, 2H), 1.88 (d, J = 10.8 Hz, 2H), 1.59 (s, 6H), 1.37-1.47 (m, 2H). ESI-MS: m/z 582.3 [M+Na]+. Compound 7 was obtained by the method of Example 1: 1H NMR (300 MHz, CDC1 3 ) δ 7.76 (s, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 7.9 Hz, 2H ), 7.45 (d, J = 8.4 Hz, 2H), 7.44 - 7.37 (m, 2H), 6.95 (d, J = 8.5 Hz, 2H), 6.32 (d, J = 7.8 Hz, 1H), 3.82 (s , 1H), 3.51 (s, 2H), 2.74 (d, J = 11.3 Hz, 2H), 2.14 (t, J = 11.0 Hz, 2H), 1.88 (d, J = 10.8 Hz, 2H), 1.59 (s , 6H), 1.37-1.47 (m, 2H). ESI-MS: m/z 582.3 [M+Na] + .
实施例 5  Example 5
2- (4- (4-氯苯甲酰基） 苯氧基） -N- ( 1- (4-甲氧基苄基） 哌啶 -4-基） -2-甲基丙酰 胺 (化合物 8) 参照实施例 1的方法制得化合物 8: 1H NMR (300 MHz, CDC13) δ 7.73 (d, J= 8.1 Hz, 2H), 7.70 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 7.4 Hz, 2H), 7.17 (d, J = 7.3 Hz, 2H), 6.94 (d, J = 7.5 Hz, 2H), 6.82 (d, J= 7.3 Hz, 2H), 6.30 (d, J= 6.3 Hz, 1H), 3.80 (s, 1H), 3.78 (s, 3H), 3.40 (s, 2H), 2.91 - 2.61 (m, 2H), 2.09 (t, J = 10.2 Hz, 2H), 1.87 (d, J= 10.2 Hz, 2H), 1.59 (s, 6H), 1.37-1.47 (m, 2H). ESI-MS: m/z 544.3 [M+Na]+. 2-(4-(4-Chlorobenzoyl)phenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)-2-methylpropanamide (Compound 8) Compound 8 was obtained by the method of Example 1: 1H NMR (300 MHz, CDC1 3 ) δ 7.73 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 7.4 Hz, 2H), 7.17 (d, J = 7.3 Hz, 2H), 6.94 (d, J = 7.5 Hz, 2H), 6.82 (d, J = 7.3 Hz, 2H), 6.30 (d, J= 6.3 Hz, 1H), 3.80 (s, 1H), 3.78 (s, 3H), 3.40 (s, 2H), 2.91 - 2.61 (m, 2H), 2.09 (t, J = 10.2 Hz, 2H), 1.87 (d , J = 10.2 Hz, 2H), 1.59 (s, 6H), 1.37-1.47 (m, 2H). ESI-MS: m/z 544.3 [M+Na] + .
实施例 6  Example 6
N- ( 1- (2-氯 -4-氟苄基) 哌啶 -4-基） -2- (4- (4-氯苯甲酰基) 苯氧基） -2-甲基丙酰 胺 （化合物 9)  N-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamide (compound) 9)
参照实施例 1的方法制得化合物 9: 1H MR (300 MHz, d6-OMSO) δ 7.91 (d, J = 7.9 Hz, 1H), 7.70 (dd, J= 8.6, 3.6 Hz, 4H), 7.60 (d, J= 8.4 Hz, 2H), 7.51 - 7.29 (m, 2H), 7.18 (td, J = 8.4, 2.3 Hz, 1H), 6.96 (d, J= 8.7 Hz, 2H), 3.64 (s, 1H), 3.47 (s, 2H), 2.72 (d, J = 11.1 Hz, 2H), 2.06 (t, J = 11.0 Hz, 2H), 1.60 (d, J = 12.1 Hz, 2H), 1.52 (s, 6H), 1.40 - 1.50 (m, 2H). ESI-MS: m/z 567.1 [M+Na]+. Compound 9 was prepared by the method of Example 1: 1H MR (300 MHz, d 6 -OMSO) δ 7.91 (d, J = 7.9 Hz, 1H), 7.70 (dd, J = 8.6, 3.6 Hz, 4H), 7.60 (d, J = 8.4 Hz, 2H), 7.51 - 7.29 (m, 2H), 7.18 (td, J = 8.4, 2.3 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 3.64 (s, 1H), 3.47 (s, 2H), 2.72 (d, J = 11.1 Hz, 2H), 2.06 (t, J = 11.0 Hz, 2H), 1.60 (d, J = 12.1 Hz, 2H), 1.52 (s, 6H), 1.40 - 1.50 (m, 2H). ESI-MS: m/z 567.1 [M+Na] + .
实施例 7  Example 7
2- (4-氯苯氧基） -N- ( 1- (4-氰基苄基） 哌啶 -4-基） -2-甲基丙酰胺 (化合物 3) 参照实施例 1的方法制得化合物 3 : 1H MR (300 MHz, d6-OMSO) δ 7.89 (d, J = 8.0 Hz, 1H), 7.77 (d, J= 7.7 Hz, 2H), 7.47 (d, J= 7.7 Hz, 2H), 7.31 (d, J= 8.4 Hz, 2H), 6.87 (d, J = 8.1 Hz, 2H), 3.75 - 3.55 (m, 1H), 3.53 (s, 2H), 2.71 (d, J = 11.4 Hz, 2H), 2.00 (t, J = 11.0 Hz, 2H), 1.59 (t, J= 10.5 Hz, 2H), 1.49 (dd, J = 12.1, 1.8 Hz, 2H), 1.41 (s, 6H). ESI-MS: m/z 413.3 [M+H]+. 2-(4-Chlorophenoxy)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-methylpropanamide (Compound 3) was obtained by the method of Example 1. Compound 3: 1H MR (300 MHz, d 6 -OMSO) δ 7.89 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 7.7 Hz, 2H), 7.47 (d, J = 7.7 Hz, 2H) , 7.31 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.1 Hz, 2H), 3.75 - 3.55 (m, 1H), 3.53 (s, 2H), 2.71 (d, J = 11.4 Hz, 2H), 2.00 (t, J = 11.0 Hz, 2H), 1.59 (t, J = 10.5 Hz, 2H), 1.49 (dd, J = 12.1, 1.8 Hz, 2H), 1.41 (s, 6H). ESI- MS: m/z 413.3 [M+H] + .
实施例 8  Example 8
N- ( 1-苄基哌啶 -4-基） -2- (4-氯苯氧基） -2-甲基丙酰胺 （化合物 10)  N-( 1-Benzylpiperidin-4-yl)-2-(4-chlorophenoxy)-2-methylpropanamide (Compound 10)
参照实施例 1的方法制得化合物 10: 1H MR (300 MHz, d6-OM O) δ 7.85 (d, J= 6.8 Hz, 1H), 7.30 (s, 2H), 7.30 - 7.10 (dd, J = 11.2, 4.5 Hz, 5H), 6.84 (d, J = 8.3 Hz, 2H), 3.59 (dd, J = 17.6, 7.1 Hz, 1H), 3.41 (s, 2H), 2.71 (d, J = 11.8 Hz, 2H), 2.08 - 1.81 (m, 2H), 1.57 (d, J= 10.8 Hz, 2H), 1.55 - 1.43 (m, 2H), 1.38 (s, 6H). ESI-MS: m/z 409.2 [M+Na]+. Compound 10 was prepared by the method of Example 1: 1H MR (300 MHz, d 6 -OM O) δ 7.85 (d, J = 6.8 Hz, 1H), 7.30 (s, 2H), 7.30 - 7.10 (dd, J = 11.2, 4.5 Hz, 5H), 6.84 (d, J = 8.3 Hz, 2H), 3.59 (dd, J = 17.6, 7.1 Hz, 1H), 3.41 (s, 2H), 2.71 (d, J = 11.8 Hz , 2H), 2.08 - 1.81 (m, 2H), 1.57 (d, J = 10.8 Hz, 2H), 1.55 - 1.43 (m, 2H), 1.38 (s, 6H). ESI-MS: m/z 409.2 [ M+Na] + .
实施例 9  Example 9
2- (4-氯苯氧基） -2-甲基 -N- ( 1- (4- (三氟甲基） 苄基） 哌啶 -4-基） 丙酰胺 （化合 物 11 )  2-(4-Chlorophenoxy)-2-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)propanamide (Compound 11)
参照实施例 1的方法制得化合物 11 : 1H MR (300 MHz, 6-DMSO) δ 7.90 (d, J = 7.9 Hz, 1H), 7.67 (d, J= 7.8 Hz, 2H), 7.50 (d, J= 7.8 Hz, 2H), 7.31 (d, J= 7.6 Hz, 2H), 6.87 (dd, J = 8.1, 0.5 Hz, 2H), 3.61 (dd, J = 17.1, 12.0 Hz, 1H), 3.54 (d, J = 13.4 Hz, 2H), 2.72 (d, J = 10.7 Hz, 2H), 2.00 (t, J= 11.1 Hz, 2H), 1.59 (t, J= 10.5 Hz, 2H), 1.55 - 1.44 (m, 2H), 1.41 (s, 6H). ESI-MS: m/z 475.3 [M+Na]+. 实施例 10 Compound 11 was prepared by the method of Example 1 : 1H MR (300 MHz, 6 -DMSO) δ 7.90 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.8 Hz, 2H), 7.50 (d, J = 7.8 Hz, 2H), 7.31 (d, J = 7.6 Hz, 2H), 6.87 (dd, J = 8.1, 0.5 Hz, 2H), 3.61 (dd, J = 17.1, 12.0 Hz, 1H), 3.54 ( d, J = 13.4 Hz, 2H), 2.72 (d, J = 10.7 Hz, 2H), 2.00 (t, J = 11.1 Hz, 2H), 1.59 (t, J = 10.5 Hz, 2H), 1.55 - 1.44 ( m, 2H), 1.41 (s, 6H). ESI-MS: m/z 475.3 [M+Na] + . Example 10
2- (4-氯苯氧基） -2-甲基 -N- ( 1- (4- (三氟甲基） 苄基） 哌啶 -4-基） 丙酰胺 （化合 物 12)  2-(4-Chlorophenoxy)-2-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)propanamide (Compound 12)
参照实施例 1的方法制得化合物 12: 1H MR (300 MHz, d6-OMSO) δ 7.86 (d, J= 7.9 Hz, 1H), 7.31 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 6.86 (dd, J = 7.6, 1.2 Hz, 4H), 3.72 (s, 3H), 3.59 (dd, J= 7.3, 4.3 Hz, 1H), 3.35 (s, 2H), 2.72 (d, J= 11.0 Hz, 2H), 1.92 (d, J = 8.3 Hz, 2H), 1.59 (d, J = 10.1 Hz, 2H), 1.53 - 1.44 (m, 2H), 1.41 (s, 6H). ESI-MS: m/z 440.2 [M+Na]+. Compound 12 was prepared by the method of Example 1: 1H MR (300 MHz, d 6 -OMSO) δ 7.86 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 8.6 Hz, 2H), 7.17 (d , J = 7.9 Hz, 2H), 6.86 (dd, J = 7.6, 1.2 Hz, 4H), 3.72 (s, 3H), 3.59 (dd, J= 7.3, 4.3 Hz, 1H), 3.35 (s, 2H) , 2.72 (d, J = 11.0 Hz, 2H), 1.92 (d, J = 8.3 Hz, 2H), 1.59 (d, J = 10.1 Hz, 2H), 1.53 - 1.44 (m, 2H), 1.41 (s, 6H). ESI-MS: m/z 440.2 [M+Na] + .
实施例 11  Example 11
N- ( 1- (2-氯 -4-氟苄基） 哌啶 -4-基） -2- (4-氯苯氧基） -2-甲基丙酰胺 （化合物 13 ) 参照实施例 1的方法制得化合物 13 : 1H MR (300 MHz, 6-DMSO) δ 7.87 (d, J= 7.9 Hz, 1H), 7.65 - 7.43 (m, 1H), 7.38 (dd, J = 8.7, 1.9 Hz, 1H), 7.31 (d, J = 8.7 Hz, 2H), 7.20 (dd, J= 11.5, 5.2 Hz, 1H), 6.87 (d, J= 8.7 Hz, 2H), 3.73 - 3.55 (m, 1H), 3.48 (s, 2H), 2.74 (d, J= 10.7 Hz, 2H), 2.06 (t, J = 10.6 Hz, 2H), 1.61 (d, J= 9.4 Hz, 2H), 1.52 (d, J= 11.1 Hz, 2H), 1.43 (s, 6H). ESI-MS: m/z 463.0 [M+Na]+. N-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-2-(4-chlorophenoxy)-2-methylpropanamide (Compound 13) Referring to Example 1 Method to prepare compound 13 : 1H MR (300 MHz, 6 -DMSO) δ 7.87 (d, J = 7.9 Hz, 1H), 7.65 - 7.43 (m, 1H), 7.38 (dd, J = 8.7, 1.9 Hz, 1H ), 7.31 (d, J = 8.7 Hz, 2H), 7.20 (dd, J= 11.5, 5.2 Hz, 1H), 6.87 (d, J= 8.7 Hz, 2H), 3.73 - 3.55 (m, 1H), 3.48 (s, 2H), 2.74 (d, J = 10.7 Hz, 2H), 2.06 (t, J = 10.6 Hz, 2H), 1.61 (d, J = 9.4 Hz, 2H), 1.52 (d, J = 11.1 Hz , 2H), 1.43 (s, 6H). ESI-MS: m/z 463.0 [M+Na] + .
实施例 12  Example 12
N- ( 1-苯甲酰哌啶 -4-基） -2- (4-氯苯氧基） -2-甲基丙酰胺 （化合物 23 )  N-(1-benzoylpiperidin-4-yl)-2-(4-chlorophenoxy)-2-methylpropanamide (Compound 23)
参照实施例 2的方法制得化合物 23 : 1H MR (300 MHz, CDC13) δ 7.42 (dd, J= 7.0, 3.0 Hz, 5H), 7.31 - 7.24 (m, 2H), 6.86 (d, J = 8.9 Hz, 2H), 6.63 (d, J = 8.0 Hz, 1H), 4.81 - 4.50 (m, 1H), 4.16 - 3.97 (m, 1H), 3.97 - 3.56 (m, 1H), 3.34 - 2.86 (m, 2H), 2.07 - 1.87 (m, 2H) ,1.50 (s, 7H), 1.41 - 1.28 (m, 2H). ESI-MS: m/z 423.2 [M+Na]+. Compound 23 was prepared by the method of Example 2: 1H MR (300 MHz, CDC1 3 ) δ 7.42 (dd, J = 7.0, 3.0 Hz, 5H), 7.31 - 7.24 (m, 2H), 6.86 (d, J = 8.9 Hz, 2H), 6.63 (d, J = 8.0 Hz, 1H), 4.81 - 4.50 (m, 1H), 4.16 - 3.97 (m, 1H), 3.97 - 3.56 (m, 1H), 3.34 - 2.86 (m , 2H), 2.07 - 1.87 (m, 2H), 1.50 (s, 7H), 1.41 - 1.28 (m, 2H). ESI-MS: m/z 423.2 [M+Na] + .
实施例 13  Example 13
N- ( 1- (4-氯苯甲酰基） 哌啶 -4-基） -2- (4-氯苯氧基） -2-甲基丙酰胺 （化合物 24) 参照实施例 2的方法制得化合物 24: 1H NMR (300 MHz, CDC13) δ 7.30 (q, J= 8.5 Hz, 4H), 7.22 - 7.17 (m, 2H), 6.79 (d, J= 8.8 Hz, 2H), 6.53 (d, J= 7.9 Hz, 1H), 4.53 (dd, J= 56.8, 30.4 Hz, 1H), 4.12 - 3.96 (m, 1H), 3.91 - 3.48 (m, 1H), 3.16 - 2.81 (m, 2H), 2.04 - 1.84 (m, 2H), 1.43 (s, 6H), 1.50 - 1.35 (m, 2H). ESI-MS: m/z 458.1 [M+Na]+. N-(1-(4-Chlorobenzoyl)piperidin-4-yl)-2-(4-chlorophenoxy)-2-methylpropanamide (Compound 24) was obtained according to the method of Example 2. compound 24: 1H NMR (300 MHz, CDC1 3) δ 7.30 (q, J = 8.5 Hz, 4H), 7.22 - 7.17 (m, 2H), 6.79 (d, J = 8.8 Hz, 2H), 6.53 (d, J= 7.9 Hz, 1H), 4.53 (dd, J= 56.8, 30.4 Hz, 1H), 4.12 - 3.96 (m, 1H), 3.91 - 3.48 (m, 1H), 3.16 - 2.81 (m, 2H), 2.04 - 1.84 (m, 2H), 1.43 (s, 6H), 1.50 - 1.35 (m, 2H). ESI-MS: m/z 458.1 [M+Na] + .
实施例 14  Example 14
2- (4-氯苯氧基） -2-甲基 -N- ( 1- ( (4-甲基苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 （化 合物 25 )  2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-methylphenyl)sulfonyl)piperidin-4-yl)propanamide (Compound 25)
将 2-(4-氯苯氧基) -2-甲基 -N- (哌啶 -4-基)丙酰胺 （lOO mg, 0.337 mmol) 和对甲苯磺 酰氯 （64 mg， 0.34 mmol) 溶于 DCM ( lO mL) 中， 加入三乙胺 （300 μί) ， 室温下搅 拌一夜， 减压蒸除溶剂， 残余物经柱层析 （洗脱剂： 石油醚 /乙酸乙酯 = 1 : 1 ) 纯化， 得 化合物 25(白色固体， 100 mg): 1H NMR (300 MHz, CDC13) δ 7.65 (d, J= 8.1 Hz, 2H), 7.35 (d, J= 8.0 Hz, 2H), 7.25 (d, J= 8.8 Hz, 2H), 6.83 (d, J= 8.8 Hz, 2H), 6.54 (d, J= 8.1 Hz, 1H): 3.80 - 3.65 (m, 3H), 2.46 (s, 3H), 2.42 (s, 2H), 1.98 (d, J = 10.5 Hz, 2H), 1.55 (dd, J = 12.5, 3.8 Hz, 2H), 1.47 (s, 6H). ESI-MS: m/z 474.1 [M+Na]+. Dissolve 2-(4-chlorophenoxy)-2-methyl-N-(piperidin-4-yl)propanamide (100 mg, 0.337 mmol) and p-toluenesulfonyl chloride (64 mg, 0.34 mmol) Triethylamine (300 μί) was added to DCM (10 mL), and stirred at room temperature overnight. The solvent was evaporated evaporated evaporated. Compound 25 (white solid, 100 mg): 1H NMR (300 MHz, CDC13) δ 7.65 (d, J = 8.1 Hz, 2H), 7.35 (d, J= 8.0 Hz, 2H), 7.25 (d, J= 8.8 Hz, 2H), 6.83 (d, J= 8.8 Hz, 2H), 6.54 (d, J= 8.1 Hz, 1H): 3.80 - 3.65 (m, 3H), 2.46 (s, 3H), 2.42 (s, 2H), 1.98 (d, J = 10.5 Hz, 2H), 1.55 (dd, J = 12.5, 3.8 Hz, 2H), 1.47 (s, 6H). ESI-MS: m/z 474.1 [M+Na] + .
实施例 15  Example 15
2- (4-氯苯氧基） -N- ( 1-异烟酰基哌啶 -4-基） -2-甲基丙酰胺 （化合物 26) 参照实施例 2的方法制得化合物 26: 1H NMR (300 MHz, CDC13) δ 8.63 (d, J= 5.5 Hz, 2H), 7.35 -7.15 (m,3H), 6.79 (d, J = 8.7 Hz, 2H), 6.55 (d, J= 7.3 Hz, 1H), 4.59 (d, J = 11.6 Hz, 1H), 3.99 (dd, J = 16.3, 11.7 Hz, 1H), 3.56 (d, J = 12.5 Hz, 1H), 3.12 (dd, J = 19.9, 9.2 Hz, 1H), 2.98 - 2.83 (m, 1H), 1.93 (dd, J= 19.0, 7.6 Hz, 2H), 1.43 (s, 6H), 1.26 (dd, J= 14.6, 8.6 Hz, 2H). ESI-MS: m/z 425.2 [M+Na]+. 2-(4-Chlorophenoxy)-N-(1-isonicotinylpiperidin-4-yl)-2-methylpropanamide (Compound 26) Compound 26 was obtained by the procedure of Example 2: 1H NMR (300 MHz, CDC1 3 ) δ 8.63 (d, J = 5.5 Hz, 2H), 7.35 -7.15 (m, 3H), 6.79 (d, J = 8.7 Hz, 2H), 6.55 (d, J = 7.3 Hz, 1H), 4.59 (d, J = 11.6 Hz, 1H), 3.99 (dd, J = 16.3, 11.7 Hz, 1H), 3.56 (d, J = 12.5 Hz, 1H), 3.12 (dd, J = 19.9, 9.2 Hz, 1H), 2.98 - 2.83 (m, 1H), 1.93 (dd, J= 19.0, 7.6 Hz, 2H), 1.43 (s, 6H), 1.26 (dd, J= 14.6, 8.6 Hz, 2H). ESI -MS: m/z 425.2 [M+Na] + .
实施例 16  Example 16
2- (4-氯苯氧基） -2-甲基 -N- ( 1-烟酰基哌啶 -4-基） 丙酰胺 （化合物 27)  2-(4-Chlorophenoxy)-2-methyl-N-( 1-nicotinopiperidin-4-yl)propanamide (Compound 27)
参照实施例 2的方法制得化合物 27: 1H MR (300 MHz, CDC13) δ 8.59 (s, 2H), 7.67 (d, J= 7.6 Hz, 1H), 7.35 - 7.22 (m, 1H), 7.25 - 7.12 (m, 2H), 6.78 (d, J= 8.3 Hz, 2H), 6.56 (d J = 7.4 Hz, 1H), 4.73 - 4.40 (m, 1H), 4.11 - 3.92 (m, 1H), 3.80 - 3.45 (m, 1H), 3.27 - 2.81 (m, 2H), 2.07 - 1.79 (m, 2H), 1.43 (s, 6H), 1.35 - 1.15 (m, 2H). ESI-MS: m/z 424.2 [M+Na]+. 实施例 17 Compound 27 was prepared by the method of Example 2: 1H MR (300 MHz, CDC1 3 ) δ 8.59 (s, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.35 - 7.22 (m, 1H), 7.25 - 7.12 (m, 2H), 6.78 (d, J = 8.3 Hz, 2H), 6.56 (d J = 7.4 Hz, 1H), 4.73 - 4.40 (m, 1H), 4.11 - 3.92 (m, 1H), 3.80 - 3.45 (m, 1H), 3.27 - 2.81 (m, 2H), 2.07 - 1.79 (m, 2H), 1.43 (s, 6H), 1.35 - 1.15 (m, 2H). ESI-MS: m/z 424.2 [M+Na] + . Example 17
N- ( 1-苄基哌啶 -4-基） -2- (2,5-二甲基苯氧基） -2-甲基丙酰胺 （化合物 28) 参照实施例 1的方法制得化合物 28: 1H NMR (300 MHz, CDC13) δ 7.35 - 7.25 (m, 5H), 7.04 (d, J= 7.5 Hz, 1H), 6.75 (d, J= 7.9 Hz, 1H), 6.67 (d, J= 8.2 Hz, 1H), 6.63 (s, 1H), 3.91 - 3.79 (m, 1H), 3.48 (s, 2H), 2.79 (d, J= 11.1 Hz, 2H), 2.23 (s, 3H), 2.18 (s, 3H), 2.12 (d, J = 11.3 Hz, 2H), 1.92 (d, J= 9.9 Hz, 2H), 1.58 - 1.37 (m, 8H). ESI-MS: m/z 381.3 [M+H]+. 实施例 18 N-(1-Benzylpiperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropanamide (Compound 28) Compound 28 was obtained by the procedure of Example 1. : 1H NMR (300 MHz, CDC1 3 ) δ 7.35 - 7.25 (m, 5H), 7.04 (d, J = 7.5 Hz, 1H), 6.75 (d, J = 7.9 Hz, 1H), 6.67 (d, J= 8.2 Hz, 1H), 6.63 (s, 1H), 3.91 - 3.79 (m, 1H), 3.48 (s, 2H), 2.79 (d, J= 11.1 Hz, 2H), 2.23 (s, 3H), 2.18 ( s, 3H), 2.12 (d, J = 11.3 Hz, 2H), 1.92 (d, J = 9.9 Hz, 2H), 1.58 - 1.37 (m, 8H). ESI-MS: m/z 381.3 [M+H ] + . Example 18
N- ( 1-苯甲酰基哌啶 -4-基） -2- (2,5-二甲基苯氧基） -2-甲基丙酰胺 （化合物 29) 参照实施例 2的方法制得化合物 29: 1H NMR (300 MHz, CDC13) δ 7.53 - 7.28 (m, 5H): 7.06 (d, J = 7.6 Hz, 1H), 6.76 (dd, J = 12.6, 8.0 Hz, 2H), 6.61 (s, 1H), 4.71 - 4.47 (m, 1H), 4.16 - 4.04 (m, 1H), 3.82 - 3.57 (m, 1H), 3.20 - 3.00(m, 2H), 2.25 (s, 3H), 2.19 (s, 3H), 2.10 - 1.92 (m, 2H), 1.51 (s, 6H), 1.46 - 1.30 (m, 2H). ESI-MS: m/z 417.5 [M+Na]+. N-(1-benzoylpiperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropanamide (Compound 29) Compound obtained according to the method of Example 2 29: 1H NMR (300 MHz, CDC1 3 ) δ 7.53 - 7.28 (m, 5H): 7.06 (d, J = 7.6 Hz, 1H), 6.76 (dd, J = 12.6, 8.0 Hz, 2H), 6.61 (s , 1H), 4.71 - 4.47 (m, 1H), 4.16 - 4.04 (m, 1H), 3.82 - 3.57 (m, 1H), 3.20 - 3.00(m, 2H), 2.25 (s, 3H), 2.19 (s , 3H), 2.10 - 1.92 (m, 2H), 1.51 (s, 6H), 1.46 - 1.30 (m, 2H). ESI-MS: m/z 417.5 [M+Na] + .
实施例 19  Example 19
N- ( 1- (4-氯苯甲酰基） 哌啶 -4-基） -2- (2,5-二甲基苯氧基） -2-甲基丙酰胺 （化合 物 30)  N-(1-(4-Chlorobenzoyl)piperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropanamide (Compound 30)
参照实施例 2的方法制得化合物 30: 1H NMR (300 MHz, CDC13) δ 7.51 - 7.28 (m, 4H): 7.06 (d, J = 7.6 Hz, 1H), 6.76 (dd, J = 14.2, 8.0 Hz, 2H), 6.61 (s, 1H), 4.78 - 4.46 (m, 1H), 4.21 - 4.02 (m, 1H), 3.86 - 3.55 (m, 1H), 3.26 - 2.95 (m, 2H), 2.25 (s, 3H), 2.19 (s, 3H), 2.09 - 1.91 (m, 2H), 1.51 (s, 6H), 1.45 - 1.29 (m, 2H). ESI-MS: m/z 451.2 [M+Na]+. The compound 30 was obtained by the method of Example 2: 1H NMR (300 MHz, CDC1 3 ) δ 7.51 - 7.28 (m, 4H): 7.06 (d, J = 7.6 Hz, 1H), 6.76 (dd, J = 14.2, 8.0 Hz, 2H), 6.61 (s, 1H), 4.78 - 4.46 (m, 1H), 4.21 - 4.02 (m, 1H), 3.86 - 3.55 (m, 1H), 3.26 - 2.95 (m, 2H), 2.25 (s, 3H), 2.19 (s, 3H), 2.09 - 1.91 (m, 2H), 1.51 (s, 6H), 1.45 - 1.29 (m, 2H). ESI-MS: m/z 451.2 [M+Na] + .
实施例 20  Example 20
2- (2,5-二甲基苯氧基） -N- ( 1-异烟酰基哌啶 -4-基） -2-甲基丙酰胺 （化合物 31 ) 参照实施例 2的方法制得化合物 31： 1H NMR (300 MHz, CDC13) δ 8.69 (d, J= 5.9 Hz, 2H), 7.25 (s, 1H), 7.13 - 7.00 (m, 2H), 6.78 (d, J= 7.5 Hz, 2H), 6.60 (s, 1H), 4.63 (d, J= 14.7 Hz, 1H), 4.14 - 4.10 (m, 1H), 3.63 - 3.50 (m, 1H), 3.21 - 3.16 (m, 1H), 3.04 - 2.92 (m, 1H), 2.25 (s, 3H), 2.19 (s, 3H), 2.09 - 1.98 (m, 2H), 1.51 (s, 6H), 1.42 - 1.30 (m, 2H). ESI-MS: m/z 418.2 [M+Na]+. 2-(2,5-Dimethylphenoxy)-N-(1-isonicotinylpiperidin-4-yl)-2-methylpropanamide (Compound 31) Compound obtained according to the method of Example 2 31: 1H NMR (300 MHz, CDC1 3 ) δ 8.69 (d, J = 5.9 Hz, 2H), 7.25 (s, 1H), 7.13 - 7.00 (m, 2H), 6.78 (d, J = 7.5 Hz, 2H ), 6.60 (s, 1H), 4.63 (d, J = 14.7 Hz, 1H), 4.14 - 4.10 (m, 1H), 3.63 - 3.50 (m, 1H), 3.21 - 3.16 (m, 1H), 3.04 - 2.92 (m, 1H), 2.25 (s, 3H), 2.19 (s, 3H), 2.09 - 1.98 (m, 2H), 1.51 (s, 6H), 1.42 - 1.30 (m, 2H). ESI-MS: m/z 418.2 [M+Na] + .
实施例 21  Example 21
(2,5-二甲基苯氧基） -2-甲基 -N- ( 1-烟酰基哌啶 -4-基） 丙酰胺 （化合物 32) 参照实施例 2的方法制得化合物 32: 1H NMR (300 MHz, CDC13) δ 8.78 - 8.53 (m, 2H): 7.74 (dt, J= 7.8, 1.9 Hz, 1H), 7.36 (dd, J= 7.5, 5.2 Hz, 1H), 7.06 (d, J= 7.6 Hz, 1H), 6.76 (t, J = 8.2 Hz, 2H), 6.60 (s, 1H), 4.79 - 4.48 (m, 1H), 4.14 (tt, J = 6.5, 3.8 Hz, 1H), 3.89 - 3.58 (m, 1H), 3.42 - 3.00 (m, 2H), 2.25 (s, 3H), 2.19 (s, 3H), 2.02 (s, 2H), 1.51 (s, 6H), 1.31 (d, J = 10.4 Hz, 2H). ESI-MS: m/z 418.2 [M+Na]+. (2,5-Dimethylphenoxy)-2-methyl-N-( 1-nicotinopiperidin-4-yl)propanamide (Compound 32) Compound 32 was obtained according to the procedure of Example 2: 1H NMR (300 MHz, CDC1 3 ) δ 8.78 - 8.53 (m, 2H) : 7.74 (dt, J = 7.8, 1.9 Hz, 1H), 7.36 (dd, J = 7.5, 5.2 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.76 (t, J = 8.2 Hz, 2H), 6.60 (s, 1H), 4.79 - 4.48 (m, 1H), 4.14 (tt, J = 6.5, 3.8 Hz, 1H), 3.89 - 3.58 (m, 1H), 3.42 - 3.00 (m, 2H), 2.25 (s, 3H), 2.19 (s, 3H), 2.02 (s, 2H), 1.51 (s, 6H), 1.31 (d, J = 10.4 Hz, 2H). ESI-MS: m/z 418.2 [M+Na] + .
实施例 22  Example 22
(2,5-二甲基苯氧基） -N- ( 1- (4-氟苄基） 哌啶 -4-基） -2-甲基丙酰胺 （化合物 33 ) 参照实施例 1的方法制得化合物 33： 1H NMR (300 MHz, CDC13) δ 7.26 (t, J= 4.1 Hz, 2H), 7.14 - 6.84 (m, 3H), 6.76 (d, J= 7.5 Hz, 1H), 6.68 (d, J= 8.3 Hz, 1H), 6.64 (s, 1H), 3.94 - 3.78 (m, 1H), 3.44 (s, 2H), 2.76 (d, J= 11.6 Hz, 2H), 2.24 (s, 3H), 2.18 (s, 3H), 2.18 - 2.08 (m, 2H), 2.00 - 1.88 (m, 2H), 1.51 (s, 6H), 1.50 - 1.32 (m, 2H). ESI-MS: m/z 421.3 [M+Na]+. 实施例 23 (2,5-Dimethylphenoxy)-N-(1-(4-fluorobenzyl)piperidin-4-yl)-2-methylpropanamide (Compound 33) Prepared by the method of Example 1. Compound 33: 1H NMR (300 MHz, CDC1 3 ) δ 7.26 (t, J = 4.1 Hz, 2H), 7.14 - 6.84 (m, 3H), 6.76 (d, J = 7.5 Hz, 1H), 6.68 (d , J= 8.3 Hz, 1H), 6.64 (s, 1H), 3.94 - 3.78 (m, 1H), 3.44 (s, 2H), 2.76 (d, J= 11.6 Hz, 2H), 2.24 (s, 3H) , 2.18 (s, 3H), 2.18 - 2.08 (m, 2H), 2.00 - 1.88 (m, 2H), 1.51 (s, 6H), 1.50 - 1.32 (m, 2H). ESI-MS: m/z 421.3 [M+Na] + . Example 23
(2- (2,5-二甲基苯氧基） -2-甲基 -N- ( 1- (4- (三氟甲基） 苄基） 哌啶 -4-基） 丙酰 胺 （化合物 34)  (2-(2,5-Dimethylphenoxy)-2-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)propanamide (Compound 34 )
参照实施例 1的方法制得化合物 34: 1H NMR (300 MHz, CDC13) δ 7.60 (d, J= 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.05 (d, J= 7.6 Hz, 1H), 6.77 (d, J= 7.8 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 6.64 (s, 1H), 3.95 - 3.84 (m, 1H), 3.52 (s, 2H), 2.75 (d, J= 11.8 Hz, 2H), 2.25 (s, 3H), 2.19 (s, 4H), 2.19 (s, 2H), 1.94 (dd, J = 12.5, 2.6 Hz, 2H), 1.51 (s, 6H), 1.50 - 1.39 (m, 2H). ESI-MS: m/z 447.2 [M-H]". Compound 34 was obtained by the method of Example 1: 1H NMR (300 MHz, CDC1 3 ) δ 7.60 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.77 (d, J= 7.8 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 6.64 (s, 1H), 3.95 - 3.84 (m, 1H), 3.52 (s , 2H), 2.75 (d, J= 11.8 Hz, 2H), 2.25 (s, 3H), 2.19 (s, 4H), 2.19 (s, 2H), 1.94 (dd, J = 12.5, 2.6 Hz, 2H) , 1.51 (s, 6H), 1.50 - 1.39 (m, 2H). ESI-MS: m/z 447.2 [MH]".
实施例 24  Example 24
N- ( 1- (4-氰基苄基） 哌啶 -4-基） -2- (2,5-二甲基苯氧基） -2-甲基丙酰胺 （化合物 N-( 1-(4-cyanobenzyl)piperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropanamide (compound
35 ) 参照实施例 1的方法制得化合物 35: 1H NMR (300 MHz, CDC13) δ 7.60 (d, J= 8.2 Hz, 2H), 7.42 (d, J= 8.2 Hz, 2H), 7.05 (d, J= 7.6 Hz, 1H), 6.77 (d, J= 7.8 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 6.64 (s, 1H), 3.95 - 3.84 (m, 1H), 3.52 (s, 2H), 2.75 (d,J= 11.8 Hz, 2H), 2.25 (s, 3H), 2.19 (s, 4H), 2.19 (s, 2H), 1.94 (dd, J= 12.5, 2.6 Hz, 2H), 1.51 (s, 6H), 1.50 - 1.39 (m, 2H). ESI-MS: m/z 443.2 [M+K]+. 35 ) Compound 35 was obtained by the method of Example 1: 1H NMR (300 MHz, CDC1 3 ) δ 7.60 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.77 (d, J= 7.8 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 6.64 (s, 1H), 3.95 - 3.84 (m, 1H), 3.52 (s , 2H), 2.75 (d, J = 11.8 Hz, 2H), 2.25 (s, 3H), 2.19 (s, 4H), 2.19 (s, 2H), 1.94 (dd, J= 12.5, 2.6 Hz, 2H) , 1.51 (s, 6H), 1.50 - 1.39 (m, 2H). ESI-MS: m/z 443.2 [M+K] + .
实施例 25  Example 25
(2,5-二甲基苯氧基） -N- (1- (4-甲氧基苄基） 哌啶 -4-基） -2-甲基丙酰胺 （化合物 (2,5-Dimethylphenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)-2-methylpropanamide (compound
36) 36)
参照实施例 1的方法制得化合物 36: 1H NMR (300 MHz, CDC13) δ 7.20 (d, J= 8.5 Hz, 2H), 7.04 (d, J= 7.7 Hz, 1H), 6.84 (d, J= 8.6 Hz, 2H), 6.76 (d, J= 7.6 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.63 (s, 1H), 3.97 - 3.83 (m, 1H), 3.80 (s, 3H), 3.42 (s, 2H), 2.78 (d, J= 10.6 Hz, 2H), 2.24 (s, 3H), 2.18 (s, 3H), 2.11 (d, J= 10.8 Hz, 2H), 2.00 - 1.82 (m, 2H), 1.50 (s, 6H), 1.49 - 1.37 (m, 2H). ESI-MS: m/z 433.5 [M+Na]+. Compound 36 was prepared by the method of Example 1: 1H NMR (300 MHz, CDC1 3 ) δ 7.20 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 7.7 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.76 (d, J= 7.6 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.63 (s, 1H), 3.97 - 3.83 (m, 1H), 3.80 (s , 3H), 3.42 (s, 2H), 2.78 (d, J = 10.6 Hz, 2H), 2.24 (s, 3H), 2.18 (s, 3H), 2.11 (d, J= 10.8 Hz, 2H), 2.00 - 1.82 (m, 2H), 1.50 (s, 6H), 1.49 - 1.37 (m, 2H). ESI-MS: m/z 433.5 [M+Na] + .
实施例 26  Example 26
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- (1- (4- (三氟甲基） 苄基） 哌啶 -4-基） 戊 酰胺 （化合物 19)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)pentanamide ( Compound 19)
Figure imgf000054_0001
取吉非罗齐（II-l)(250mg, 1 mmol)溶于无水 DMF(2mL)，加入 CDI(186mg, 1.149 mmol)， 于 70 °C下搅拌 1 h， 然后加入 N-Boc-4-氨基哌啶 (200 mg, 1 mmol), 反应 2 h。 冷却至室温， 加入水（10mL)， 乙酸乙酯萃取（20mLx3)， 有机相用饱和 NaHC03 (10 mLx3) 洗涤， 无水硫酸钠干燥， 减压蒸除溶剂， 残余物经柱层析 （洗脱剂： 石油醚 /乙 酸乙酯 =2:1) 纯化， 得化合物 Π-2 (白色固体， 340 mg， 收率 79%)。
Figure imgf000054_0001
Gemfibrozil (II-l) (250 mg, 1 mmol) was dissolved in anhydrous DMF (2 mL), CDI (186 mg, 1.149 mmol) was added, and stirred at 70 ° C for 1 h, then N-Boc-4 was added -Aminopiperidine (200 mg, 1 mmol), reacted for 2 h. Cooled to room temperature, water (10 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was washed with saturated NaHC0 3 (10 mLx3), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (eluting Deprotection: Petroleum ether / ethyl acetate = 2:1) Purified to give the compound y-2 (white solid, 340 mg, yield 79%).
取化合物 Π-2 (340 mg) 溶于二氯甲垸 （10mL) ， 冰浴下加入三氟乙酸 （lmL) ， 室温搅拌过夜。 减压蒸除溶剂， 用饱和碳酸氢钠调节 pH至碱性， 乙酸乙酯 （30mLx3) 萃取， 饱和 NaCl (10mLx3)洗涤， 无水硫酸钠干燥， 减压蒸除溶剂， 得化合物 Π-3 (无 色液体， 260 mg, 收率 99%) 。  The compound Π-2 (340 mg) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was then evaporated. The solvent was evaporated under reduced pressure. EtOAc (3 mL, EtOAc, EtOAc (EtOAc) Colorless liquid, 260 mg, yield 99%).
以化合物 Π-3为原料，参照实施例 1的方法制得化合物 19(收率 78%): 1H MR(300 MHz, d6-OMSO) δ 7.67 (d, J= 8.1 Hz, 2H), 7.51 (d, J= 7.9 Hz, 2H), 7.13 (d, J= 7.8 Hz, 1H), 6.96 (d, J= 7.6 Hz, 1H), 6.68 (s, 1H), 6.60 (d, J= 7.3 Hz, 1H), 3.88 (s, 2H), 3.59 (s, 1H), 3.53 (s, 2H), 2.75 (d, J= 10.8 Hz, 2H), 2.22 (s, 3H), 2.08 (s, 3H), 2.00 (t, J= 11.4 Hz, 2H), 1.60 (s, 2H), 1.59 (s, 4H), 1.56-1.41 (m, 2H), 1.09 (s, 6H). ESI-MS: m/z 513.3 [M+Na]+. Using compound Π-3 as a starting material, compound 19 was obtained by the method of Example 1 (yield 78%): 1H MR (300) MHz, d 6 -OMSO) δ 7.67 (d, J= 8.1 Hz, 2H), 7.51 (d, J= 7.9 Hz, 2H), 7.13 (d, J= 7.8 Hz, 1H), 6.96 (d, J= 7.6 Hz, 1H), 6.68 (s, 1H), 6.60 (d, J= 7.3 Hz, 1H), 3.88 (s, 2H), 3.59 (s, 1H), 3.53 (s, 2H), 2.75 (d, J= 10.8 Hz, 2H), 2.22 (s, 3H), 2.08 (s, 3H), 2.00 (t, J= 11.4 Hz, 2H), 1.60 (s, 2H), 1.59 (s, 4H), 1.56- 1.41 (m, 2H), 1.09 (s, 6H). ESI-MS: m/z 513.3 [M+Na] + .
实施例 27  Example 27
N- ( 1-苄基哌啶 -4-基） -2,2-二甲基 -5-苯氧基戊酰胺 （化合物 38)  N-( 1-Benzylpiperidin-4-yl)-2,2-dimethyl-5-phenoxypentanamide (Compound 38)
参照合成路线 5及实施例 1的方法制得化合物 38: 1H MR (300 MHz, CDC13) δ 7.38 - 7.27 (m, 5H), 6.90 (dd, J= 18.4, 7.7 Hz, 3H), 5.49 (s, 1H), 3.93 (t, J = 5.6 Hz, 2H), 3.89 - 3.75 (m, 1H), 3.49 (s, 2H), 2.79 (d, J= 12.0 Hz, 2H), 2.14 (t, J= 10.8 Hz, 2H), 2.00 - 1.81 (m, 4H), 1.76 - 1.69 (m, 2H), 1.51 - 1.36 (m, 2H), 1.19 (s, 6H). ESI-MS: m/z 417.3 [M+Na]+. 实施例 28 Compound 38 was prepared by the method of Synthesis Scheme 5 and Example 1: 1H MR (300 MHz, CDC1 3 ) δ 7.38 - 7.27 (m, 5H), 6.90 (dd, J = 18.4, 7.7 Hz, 3H), 5.49 ( s, 1H), 3.93 (t, J = 5.6 Hz, 2H), 3.89 - 3.75 (m, 1H), 3.49 (s, 2H), 2.79 (d, J = 12.0 Hz, 2H), 2.14 (t, J = 10.8 Hz, 2H), 2.00 - 1.81 (m, 4H), 1.76 - 1.69 (m, 2H), 1.51 - 1.36 (m, 2H), 1.19 (s, 6H). ESI-MS: m/z 417.3 [ M+Na] + . Example 28
N- ( 1-苄基哌啶 -4-基） -5- (4-氯苯氧基） -2,2-二甲基戊酰胺 （化合物 39) 参照合成路线 5及实施例 1的方法制得化合物 39: 1H NMR (300 MHz, CDC13) δ 7.37 - 7.29 (m, 4H), 7.21 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 5.48 (d, J= 7.8 Hz, 1H), 3.89 (t, J= 5.1 Hz, 2H), 3.85 - 3.73 (m, 1H), 3.49 (s, 2H), 2.79 (d, J= 11.6 Hz, 2H), 2.13 (t, J = 11.2 Hz, 2H), 1.89 (d, J = 11.0 Hz, 2H), 1.80 - 1.64 (m, 4H), 1.52 - 1.38 (m, 2H), 1.19 (s, 6H). ESI-MS: m/z 429.1 [M+H]+. N-(1-Benzylpiperidin-4-yl)-5-(4-chlorophenoxy)-2,2-dimethylpentanamide (Compound 39) Manufactured by the method of Synthesis Scheme 5 and Example 1. Compound 39: 1H NMR (300 MHz, CDC1 3 ) δ 7.37 - 7.29 (m, 4H), 7.21 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 5.48 (d , J = 7.8 Hz, 1H), 3.89 (t, J = 5.1 Hz, 2H), 3.85 - 3.73 (m, 1H), 3.49 (s, 2H), 2.79 (d, J = 11.6 Hz, 2H), 2.13 (t, J = 11.2 Hz, 2H), 1.89 (d, J = 11.0 Hz, 2H), 1.80 - 1.64 (m, 4H), 1.52 - 1.38 (m, 2H), 1.19 (s, 6H). ESI- MS: m/z 429.1 [M+H] + .
实施例 29  Example 29
N- ( 1-苄基哌啶 -4-基） -5- (2,5-二氯苯氧基） -2,2-二甲基戊酰胺 （化合物 40) 参照合成路线 5及实施例 1的方法制得化合物 40: 1H NMR (300 MHz, CDC13) δ 7.32 (d, J = 3.8 Hz, 3H), 7.27 (d, J = 4.5 Hz, 3H), 6.95 - 6.83 (m, 2H), 5.51 (d, J = 7.3 Hz, 1H), 3.99 (t, J= 5.6 Hz, 2H), 3.88 - 3.74 (m, 1H), 3.50 (s, 2H), 2.80 (d, J= 11.6 Hz, 2H), 2.14 (t, J = 10.7 Hz, 2H), 1.91 (d, J = 9.8 Hz, 2H), 1.82 - 1.66 (m, 4H), 1.51 - 1.35 (m, 2H), 1.21 (s, 6H). ESI-MS: m/z 463.0 [M+H]+. N-(1-Benzylpiperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide (Compound 40) Referring to Synthesis Scheme 5 and Example 1 Method 40: 1H NMR (300 MHz, CDC1 3 ) δ 7.32 (d, J = 3.8 Hz, 3H), 7.27 (d, J = 4.5 Hz, 3H), 6.95 - 6.83 (m, 2H), 5.51 (d, J = 7.3 Hz, 1H), 3.99 (t, J= 5.6 Hz, 2H), 3.88 - 3.74 (m, 1H), 3.50 (s, 2H), 2.80 (d, J= 11.6 Hz, 2H ), 2.14 (t, J = 10.7 Hz, 2H), 1.91 (d, J = 9.8 Hz, 2H), 1.82 - 1.66 (m, 4H), 1.51 - 1.35 (m, 2H), 1.21 (s, 6H) ESI-MS: m/z 463.0 [M+H] + .
实施例 30  Example 30
N- ( 1-苄基哌啶 -4-基） -5- (4-甲氧基苯氧基） -2,2-二甲基戊酰胺 （化合物 41 ) 参照合成路线 5及实施例 1的方法制得化合物 41： 1H NMR (300 MHz, CDC13) δ 7.37 - 7.29 (m, 4H), 6.83 (s, 4H), 5.52 (d, J= 7.2 Hz, 1H), 3.90 (t, J= 8.8 Hz, 2H), 3.86 - 3.79 (m, 1H), 3.78 (s, 3H), 3.51 (s, 2H), 2.80 (d, J= 11.7 Hz, 2H), 2.14 (t, J= 11.4 Hz, 2H), 1.90 (d, J = 11.4 Hz, 2H), 1.75 - 1.66 (m, 4H), 1.51 - 1.38 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 447.2 [M+Na]+. N-(1-Benzylpiperidin-4-yl)-5-(4-methoxyphenoxy)-2,2-dimethylpentanamide (Compound 41) Referring to Synthesis Scheme 5 and Example 1 Method Compound 41: 1H NMR (300 MHz, CDC1 3 ) δ 7.37 - 7.29 (m, 4H), 6.83 (s, 4H), 5.52 (d, J = 7.2 Hz, 1H), 3.90 (t, J = 8.8 Hz, 2H), 3.86 - 3.79 (m, 1H), 3.78 (s, 3H), 3.51 (s, 2H), 2.80 (d, J = 11.7 Hz, 2H), 2.14 (t, J = 11.4 Hz, 2H), 1.90 (d, J = 11.4 Hz, 2H), 1.75 - 1.66 (m, 4H), 1.51 - 1.38 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 447.2 [M +Na] + .
实施例 31  Example 31
N- ( 1-苄基哌啶 -4-基） -2,2-二甲基 -5- (对甲苯基氧基） 戊酰胺 （化合物 42) 参照合成路线 5及实施例 1的方法制得化合物 42: 1H NMR (300 MHz, CDC13) δ 7.38 - 7.29 (m, 5H), 7.08 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 5.51 (d, J= 7.3 Hz, 1H), 3.91 (t, J= 5.7 Hz, 2H), 3.89 - 3.79 (m, 1H), 3.51 (s, 2H), 2.80 (d, J= 11.9 Hz, 2H), 2.29 (s, 3H), 2.15 (t, J= 10.5 Hz, 2H), 1.91 (d, J= 12.6 Hz, 2H), 1.69 (d, J= 3.8 Hz, 4H), 1.50 - 1.40 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 410.2 [M+H]+. N-(1-Benzylpiperidin-4-yl)-2,2-dimethyl-5-(p-tolyloxy)pentanamide (Compound 42) Compound 42 was prepared according to the procedure of Scheme 5 and Example 1. 1H NMR (300 MHz, CDC1 3 ) δ 7.38 - 7.29 (m, 5H), 7.08 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 5.51 (d, J = 7.3 Hz, 1H), 3.91 (t, J = 5.7 Hz, 2H), 3.89 - 3.79 (m, 1H), 3.51 (s, 2H), 2.80 ( d, J = 11.9 Hz, 2H), 2.29 (s, 3H), 2.15 (t, J = 10.5 Hz, 2H), 1.91 (d, J = 12.6 Hz, 2H), 1.69 (d, J = 3.8 Hz, 4H), 1.50 - 1.40 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 410.2 [M+H] + .
实施例 32  Example 32
N- ( 1-苄基哌啶 -4-基） -5- ( 5-异丙基 -2-甲基苯氧基） -2,2-二甲基戊酰胺 （化合物 N-( 1-Benzylpiperidin-4-yl)-5-(5-isopropyl-2-methylphenoxy)-2,2-dimethylpentanamide (compound)
43 ) 43 )
参照合成路线 5及实施例 1的方法制得化合物 43 : 1H NMR (300 MHz, CDC13) δ 7.37 - 7.26 (m, 5H), 7.04 (d, J = 7.5 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 6.65 (s, 1H), 5.47 (d, J = 6.6 Hz, 1H), 3.93 (t, J = 5.4 Hz, 2H), 3.88 - 3.76 (m, 1H)， 3.49 (s, 2H), 2.96 - 2.82 (m, 1H), 2.82 - 2.69 (m, 2H), 2.27 - 2.17 (m, 3H), 2.17 - 2.04 (m, 2H), 1.94 - 1.84 (m, 2H), 1.82 - 1.68 (m, 4H), 1.52 - 1.38 (m, 2H), 1.27 - 1.17 (m, 12H). ESI-MS: m/z 451.2 [M+H]+. Compound 43 was prepared by the method of Synthesis Scheme 5 and Example 1 : 1H NMR (300 MHz, CDC1 3 ) δ 7.37 - 7.26 (m, 5H), 7.04 (d, J = 7.5 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 6.65 (s, 1H), 5.47 (d, J = 6.6 Hz, 1H), 3.93 (t, J = 5.4 Hz, 2H), 3.88 - 3.76 (m, 1H), 3.49 ( s, 2H), 2.96 - 2.82 (m, 1H), 2.82 - 2.69 (m, 2H), 2.27 - 2.17 (m, 3H), 2.17 - 2.04 (m, 2H), 1.94 - 1.84 (m, 2H), 1.82 - 1.68 (m, 4H), 1.52 - 1.38 (m, 2H), 1.27 - 1.17 (m, 12H). ESI-MS: m/z 451.2 [M+H] + .
实施例 33  Example 33
N- ( 1-苄基哌啶 -4-基） -5- (3,5-二甲基苯氧基） -2,2-二甲基戊酰胺 （化合物 44) 参照合成路线 5及实施例 1的方法制得化合物 44: 1H NMR (300 MHz, CDC13) δ 7.36 - 7.29 (m, 4H), 7.28 - 7.24 (m, 1H), 6.60 (s, 1H), 6.52 (s, 2H), 5.51 (d, J= 7.5 Hz, 1H), 3.91 (t, J= 5.7 Hz, 2H), 3.86 - 3.74 (m, 1H), 3.51 (s, 2H), 2.80 (d, J= 11.9 Hz, 2H), 2.29 (s, 6H), 2.15 (t, J= 10.6 Hz, 2H), 1.91 (d, J= 10.7 Hz, 2H), 1.78 - 1.68 (m, 4H), 1.53 - 1.40 (m, 2H), 1.23 (d, J= 16.7 Hz, 6H). ESI-MS: m/z 423.1 [M+H]+. N-(1-Benzylpiperidin-4-yl)-5-(3,5-dimethylphenoxy)-2,2-dimethylpentanamide (Compound 44) Referring to Scheme 5 and Examples Method 1 to give compound 44: 1H NMR (300 MHz, CDC1 3 ) δ 7.36 - 7.29 (m, 4H), 7.28 - 7.24 (m, 1H), 6.60 (s, 1H), 6.52 (s, 2H), 5.51 (d, J= 7.5 Hz, 1H), 3.91 (t, J= 5.7 Hz, 2H), 3.86 - 3.74 (m, 1H), 3.51 (s, 2H), 2.80 (d, J= 11.9 Hz, 2H ), 2.29 (s, 6H), 2.15 (t, J= 10.6 Hz, 2H), 1.91 (d, J= 10.7 Hz, 2H), 1.78 - 1.68 (m, 4H), 1.53 - 1.40 (m, 2H) , 1.23 (d, J = 16.7 Hz, 6H). ESI-MS: m/z 423.1 [M+H] + .
实施例 34  Example 34
N- ( 1-苄基哌啶 -4-基） -2,2-二甲基 -5- (邻甲苯氧基） 戊酰胺 （化合物 45 )  N-(1-Benzylpiperidin-4-yl)-2,2-dimethyl-5-(o-tolyloxy)pentanamide (Compound 45)
参照合成路线 5及实施例 1的方法制得化合物 45: 1H NMR (300 MHz, CDC13) δ 7.40 - 7.23 (m, 5H), 7.19 - 7.05 (m, 2H), 6.94 - 6.68 (m, 2H), 5.47 (d, J = 5.7 Hz, 1H), 3.92 (d, J = 5.0 Hz, 2H), 3.87 - 3.70 (m, 1H), 3.49 (s, 2H), 2.79 (d, J = 10.7 Hz, 2H), 2.33 - 2.07 (m, 5H), 1.90 (d, J = 11.7 Hz, 2H), 1.70 (s, 4H), 1.54 - 1.34(m, 2H), 1.20 (s, 6H). ESI-MS: m/z 409.2 [M+H]+. Compound 45 was obtained by the procedure of Synthesis Scheme 5 and Example 1 : 1H NMR (300 MHz, CDC1 3 ) δ 7.40 - 7.23 (m, 5H), 7.19 - 7.05 (m, 2H), 6.94 - 6.68 (m, 2H ), 5.47 (d, J = 5.7 Hz, 1H), 3.92 (d, J = 5.0 Hz, 2H), 3.87 - 3.70 (m, 1H), 3.49 (s, 2H), 2.79 (d, J = 10.7 Hz) , 2H), 2.33 - 2.07 (m, 5H), 1.90 (d, J = 11.7 Hz, 2H), 1.70 (s, 4H), 1.54 - 1.34(m, 2H), 1.20 (s, 6H). ESI- MS: m/z 409.2 [M+H] + .
实施例 35  Example 35
N- ( 1-苄基哌啶 -4-基） -2,2-二甲基 -5- (3,4,5-三甲氧基苯氧基）戊酰胺（化合物 46) 参照合成路线 5及实施例 1的方法制得化合物 46: 1H NMR (300 MHz, CDC13) δ 7.30 (d, J = 3.6 Hz, 5H), 6.13 (s, 2H), 5.50 (d, J = 7.5 Hz, 1H), 3.89 (t, J = 5.5 Hz, 2H), 3.83 (s, 6H), 3.78 (s, 1H), 3.77 (s, 3H), 3.48 (s, 2H), 2.79 (d, J = 11.9 Hz, 2H), 2.12 (t, J = 10.8 Hz, 2H), 1.90 (d, J = 11.6 Hz, 2H), 1.66 (d, J = 9.1 Hz, 4H), 1.54 - 1.40 (m, 2H), 1.19 (s, 6H). ESI-MS: m/z 485.1 [M+H]+. 实施例 36 N-(1-Benzylpiperidin-4-yl)-2,2-dimethyl-5-(3,4,5-trimethoxyphenoxy)pentanamide (Compound 46) Referring to Scheme 5 and Compound 46 was prepared by the method of Example 1: 1H NMR (300 MHz, CDC1 3 ) δ 7.30 (d, J = 3.6 Hz, 5H), 6.13 (s, 2H), 5.50 (d, J = 7.5 Hz, 1H) , 3.89 (t, J = 5.5 Hz, 2H), 3.83 (s, 6H), 3.78 (s, 1H), 3.77 (s, 3H), 3.48 (s, 2H), 2.79 (d, J = 11.9 Hz, 2H), 2.12 (t, J = 10.8 Hz, 2H), 1.90 (d, J = 11.6 Hz, 2H), 1.66 (d, J = 9.1 Hz, 4H), 1.54 - 1.40 (m, 2H), 1.19 ( s, 6H). ESI-MS: m/z 485.1 [M+H] + . Example 36
N- ( 1- (4-氰基苄基） 哌啶 -4-基） -2,2-二甲基 -5-苯氧基戊酰胺 （化合物 47) 参照合成路线 5及实施例 1的方法制得化合物 47: 1H NMR (300 MHz, CDC13) δ 7.62 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.31 (s, 2H), 6.93 (dd, J = 20.1, 7.7 Hz, 3H), 5.53 (d, J= 7.4 Hz, 1H), 3.95 (t, J= 5.5 Hz, 2H), 3.89 - 3.78 (m, 1H), 3.55 (s, 2H), 2.77 (d, J = 11.6 Hz, 2H), 2.18 (t, J= 11.0 Hz, 2H), 1.92 (d, J= 12.1 Hz, 2H), 1.78 - 1.66 (m, 4H), 1.49 - 1.37 (m, 2H), 1.21 (s, 6H). ESI-MS: m/z 442.2 [M+Na]+. N-(1-(4-Cyanobenzyl)piperidin-4-yl)-2,2-dimethyl-5-phenoxyvaleramide (Compound 47) Referring to the method of Synthesis Scheme 5 and Example 1 Compound 47: 1H NMR (300 MHz, CDC1 3 ) δ 7.62 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.31 (s, 2H), 6.93 (dd, J = 20.1, 7.7 Hz, 3H), 5.53 (d, J = 7.4 Hz, 1H), 3.95 (t, J = 5.5 Hz, 2H), 3.89 - 3.78 (m, 1H), 3.55 (s, 2H), 2.77 (d, J = 11.6 Hz, 2H), 2.18 (t, J = 11.0 Hz, 2H), 1.92 (d, J = 12.1 Hz, 2H), 1.78 - 1.66 (m, 4H), 1.49 - 1.37 (m , 2H), 1.21 (s, 6H). ESI-MS: m/z 442.2 [M+Na] + .
实施例 37  Example 37
N- ( 1- (3-氰基苄基） 哌啶 -4-基） -2,2-二甲基 -5-苯氧基戊酰胺 （化合物 48) 参照合成路线 5及实施例 1的方法制得化合物 48: 1H NMR (300 MHz, CDC13) δ 7.68 - 7.63 (m, 1H), 7.58 - 7.50 (m, 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.33 - 7.27 (m, 2H), 6.98 - 6.84 (m, 3H), 5.51 (d, J= 7.1 Hz, 1H), 3.94 (t, J= 5.6 Hz, 2H), 3.86 - 3.78 (m, 1H), 3.51 (s, 2H), 2.76 (d, J = 12.1 Hz, 2H), 2.18 (d, J = 12.8 Hz, 2H), 1.91 (d, J = 14.0 Hz, 2H), 1.82 - 1.68 (m, 4H), 1.55 - 1.35 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 442.2 [M+Na]+. N-(1-(3-Cyanobenzyl)piperidin-4-yl)-2,2-dimethyl-5-phenoxypentanamide (Compound 48) Referring to the scheme of Synthesis Scheme 5 and Example 1 Compound 48: 1H NMR (300 MHz, CDC1 3 ) δ 7.68 - 7.63 (m, 1H), 7.58 - 7.50 (m, 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.33 - 7.27 (m , 2H), 6.98 - 6.84 (m, 3H), 5.51 (d, J= 7.1 Hz, 1H), 3.94 (t, J= 5.6 Hz, 2H), 3.86 - 3.78 (m, 1H), 3.51 (s, 2H), 2.76 (d, J = 12.1 Hz, 2H), 2.18 (d, J = 12.8 Hz, 2H), 1.91 (d, J = 14.0 Hz, 2H), 1.82 - 1.68 (m, 4H), 1.55 - 1.35 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 442.2 [M+Na] + .
实施例 38  Example 38
N- ( 1- (2-氰基苄基） 哌啶 -4-基） -2,2-二甲基 -5-苯氧基戊酰胺 （化合物 49) 参照合成路线 5及实施例 1的方法制得化合物 49: 1H NMR (300 MHz, CDC13) δ 7.65 (d, J = 7.8 Hz, 1H), 7.58 - 7.48 (m, 2H), 7.36 (d, J = 7.0 Hz, 1H), 7.25 (d, J= 5.8 Hz, 2H), 6.90 (dd, J= 16.8, 8.0 Hz, 3H), 5.51 (d, J= 8.0 Hz, 1H), 3.93 (t, J= 5.5 Hz, 2H), 3.89 - 3.77 (m, 1H), 3.68 (s, 2H), 2.79 (d, J = 11.5 Hz, 2H), 2.26 (t, J = 11.4 Hz, 2H), 1.90 (d, J = 13.1 Hz, 2H), 1.79 - 1.65 (m, 4H), 1.54 - 1.43 (m, 2H), 1.19 (s, 6H). ESI-MS: m/z 442.1 [M+Na]+. N-(1-(2-Cyanobenzyl)piperidin-4-yl)-2,2-dimethyl-5-phenoxyvaleramide (Compound 49) Referring to the method of Synthesis Scheme 5 and Example 1 Compound 49: 1H NMR (300 MHz, CDC1 3 ) δ 7.65 (d, J = 7.8 Hz, 1H), 7.58 - 7.48 (m, 2H), 7.36 (d, J = 7.0 Hz, 1H), 7.25 ( d, J= 5.8 Hz, 2H), 6.90 (dd, J= 16.8, 8.0 Hz, 3H), 5.51 (d, J= 8.0 Hz, 1H), 3.93 (t, J= 5.5 Hz, 2H), 3.89 - 3.77 (m, 1H), 3.68 (s, 2H), 2.79 (d, J = 11.5 Hz, 2H), 2.26 (t, J = 11.4 Hz, 2H), 1.90 (d, J = 13.1 Hz, 2H), 1.79 - 1.65 (m, 4H), 1.54 - 1.43 (m, 2H), 1.19 (s, 6H). ESI-MS: m/z 442.1 [M+Na] + .
实施例 39  Example 39
N- ( 1- (4-氰基苄基) 哌啶 -4-基） -5- (2,5-二氯苯氧基) -2,2-二甲基戊酰胺 （化合 物 50)  N-(1-(4-Cyanobenzyl)piperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide (Compound 50)
参照合成路线 5及实施例 1的方法制得化合物 50: 1H NMR (300 MHz, CDC13) δ 7.68 (s, 1H), 7.55 (d, J= 7.2 Hz, 2H), 7.48 - 7.37 (m, 1H), 7.29 (d, J= 7.4 Hz, 2H), 6.89 (s, 2H), 5.53 (d, J= 7.2 Hz, 1H), 4.00 (t, J= 5.2 Hz, 2H), 3.83 (tdd, J= 15.4, 8.0, 3.1 Hz, 1H), 3.52 (s, 2H), 2.77 (d, J = 10.5 Hz, 2H), 2.17 (t, J = 11.1 Hz, 2H), 1.90 (t, J = 12.2 Hz, 2H), 1.88 - 1.68 (m, 4H), 1.57 - 1.37(m, 2H), 1.22 (s, 6H). ESI-MS: m/z 512.1 [M+Na]+. Compound 50 was prepared by the method of Synthesis Scheme 5 and Example 1. 1H NMR (300 MHz, CDC1 3 ) δ 7.68 (s, 1H), 7.55 (d, J = 7.2 Hz, 2H), 7.48 - 7.37 (m, 1H), 7.29 (d, J= 7.4 Hz, 2H), 6.89 (s, 2H), 5.53 (d, J= 7.2 Hz, 1H), 4.00 (t, J= 5.2 Hz, 2H), 3.83 (tdd, J= 15.4, 8.0, 3.1 Hz, 1H), 3.52 (s, 2H), 2.77 (d, J = 10.5 Hz, 2H), 2.17 (t, J = 11.1 Hz, 2H), 1.90 (t, J = 12.2 Hz, 2H), 1.88 - 1.68 (m, 4H), 1.57 - 1.37 (m, 2H), 1.22 (s, 6H). ESI-MS: m/z 512.1 [M+Na] + .
实施例 40  Example 40
N- ( 1- (3-氰基苄基） 哌啶 -4-基） -5- (2,5-二氯苯氧基） -2,2-二甲基戊酰胺 （化合 物 51 ) 参照合成路线 5及实施例 1的方法制得化合物 51： 1H NMR (300 MHz, CDC13) δ 7.60 (d, J= 8.2 Hz, 2H), 7.43 (d, J= 8.0 Hz, 2H), 7.25 (s, 1H), 6.87 (d, J= 3.2 Hz, 2H), 5.51 (d, J = 7.9 Hz, 1H), 3.84 (d, J = 6.5 Hz, 2H), 3.83 (s, 1H), 3.52 (s, 2H), 2.75 (d, J= 11.4 Hz, 2H), 2.16 (t, J= 11.6 Hz, 2H), 1.98 - 1.89 (m, 2H), 1.83 - 1.73 (m, 4H), 1.52 - 1.39 (m, 2H), 1.22 (s, 6H). ESI-MS: m/z 512.1 [M+Na]+. N-(1-(3-Cyanobenzyl)piperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide (Compound 51) Compound 51 was prepared according to the procedure of Scheme 5 and Example 1. 1H NMR (300 MHz, CDC1 3 ) δ 7.60 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.25 (s, 1H), 6.87 (d, J = 3.2 Hz, 2H), 5.51 (d, J = 7.9 Hz, 1H), 3.84 (d, J = 6.5 Hz, 2H), 3.83 (s, 1H), 3.52 (s, 2H), 2.75 (d, J = 11.4 Hz, 2H), 2.16 (t, J = 11.6 Hz, 2H), 1.98 - 1.89 (m, 2H), 1.83 - 1.73 (m, 4H), 1.52 - 1.39 (m, 2H), 1.22 (s, 6H). ESI-MS: m/z 512.1 [M+Na] + .
实施例 41  Example 41
N- ( 1- (2-氰基苄基） 哌啶 -4-基） -5- (2,5-二氯苯氧基） -2,2-二甲基戊酰胺 （化合 物 52)  N-(1-(2-Cyanobenzyl)piperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide (Compound 52)
参照合成路线 5及实施例 1的方法制得化合物 52: 1H NMR (300 MHz, CDC13) δ 7.64 (d, J= 7.5 Hz, 1H), 7.59 - 7.43 (m, 2H), 7.35 (t, J= 7.8 Hz, 1H), 7.26 (s, 1H), 6.97 - 6.77 (m, 2H), 5.51 (d, J = 6.6 Hz, 1H), 3.96 (dd, J= 15.0, 8.8 Hz, 2H), 3.82 (dt, J= 15.1, 7.6 Hz, 1H), 3.71 (d, J = 18.4 Hz, 2H), 2.80 (d, J = 10.9 Hz, 2H), 2.27 (t, J = 11.4 Hz, 2H), 1.90 (d, J = 12.0 Hz, 2H), 1.83 - 1.69 (m, 4H), 1.53 - 1.42 (m, 2H), 1.20 (s, 6H). ESI-MS: M/Z m/z 487.3 [M-H]". Compound 52 was prepared according to the procedure of Scheme 5 and Example 1. 1H NMR (300 MHz, CDC1 3 ) δ 7.64 (d, J = 7.5 Hz, 1H), 7.59 - 7.43 (m, 2H), 7.35 (t, J = 7.8 Hz, 1H), 7.26 (s, 1H), 6.97 - 6.77 (m, 2H), 5.51 (d, J = 6.6 Hz, 1H), 3.96 (dd, J = 15.0, 8.8 Hz, 2H), 3.82 (dt, J= 15.1, 7.6 Hz, 1H), 3.71 (d, J = 18.4 Hz, 2H), 2.80 (d, J = 10.9 Hz, 2H), 2.27 (t, J = 11.4 Hz, 2H), 1.90 (d, J = 12.0 Hz, 2H), 1.83 - 1.69 (m, 4H), 1.53 - 1.42 (m, 2H), 1.20 (s, 6H). ESI-MS: M/Z m/z 487.3 [MH ]".
实施例 42  Example 42
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- (4-丙酰基苯甲酰基） 哌啶 -4-基） 戊酰 胺 （化合物 53 )  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-propanoylbenzoyl)piperidin-4-yl)pentanamide (Compound 53)
参照合成路线 5及实施例 2的方法制得化合物 53： 1H NMR (300 MHz, CDC13) δ 7.32 (d, J= 7.8 Hz, 2H), 7.23 (d, J= 7.7 Hz, 2H), 7.01 (d, J= 7.4 Hz, 1H), 6.66 (d, J= 7.3 Hz, 1H), 6.61 (s, 1H), 5.69 (d, J = 7.5 Hz, 1H), 4.14 - 3.99 (m, 1H), 3.95 - 3.83 (m, 2H), 3.20 - 2.89 (m, 2H), 2.68 (q, J= 7.5 Hz, 2H), 2.31 (s, 3H), 2.18 (s, 3H), 2.04 - 1.86 (m, 2H), 1.71 (s, 4H), 1.28 (s, 2H), 1.21 (s, 6H). ESI-MS: m/z 493.1 [M+H]+. Compound 53 was obtained by the method of Synthesis Scheme 5 and Example 2: 1H NMR (300 MHz, CDC1 3 ) δ 7.32 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 7.7 Hz, 2H), 7.01 (d, J = 7.4 Hz, 1H), 6.66 (d, J = 7.3 Hz, 1H), 6.61 (s, 1H), 5.69 (d, J = 7.5 Hz, 1H), 4.14 - 3.99 (m, 1H) , 3.95 - 3.83 (m, 2H), 3.20 - 2.89 (m, 2H), 2.68 (q, J= 7.5 Hz, 2H), 2.31 (s, 3H), 2.18 (s, 3H), 2.04 - 1.86 (m , 2H), 1.71 (s, 4H), 1.28 (s, 2H), 1.21 (s, 6H). ESI-MS: m/z 493.1 [M+H] + .
实施例 43  Example 43
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1-甲苯基哌啶 -4-基） 戊酰胺 （化合物 54)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-tolylpiperidin-4-yl)pentanamide (Compound 54)
Figure imgf000058_0001
Figure imgf000058_0001
将化合物 Π-3 (买施例 26) (260 mg， 0.78 mmol) 和三乙胺 （305 μL 溶于二氯 甲垸（15 mL)，冰浴下滴加对甲苯磺酰氯（180 mg， 0.95 mmol)的二氯甲垸溶液（2 mL)， 自然升温至室温， 搅拌过夜。 将反应液减压浓缩， 加饱和碳酸钠水溶液 （20 mL) ， 二 氯甲垸 （3 x 30 mL) 萃取。 有机相依次用饱和碳酸氢钠水溶液 （lO mL) 、 水 （lO mL) 和饱和氯化钠水溶液 （10 mL) 洗， 无水硫酸钠干燥， 减压蒸除溶剂。 残余物经柱层析 (洗脱剂： 二氯甲焼 /甲醇 =150: 1 )纯化，得化合物 54 (白色固体， 320 mg, 收率 85%) ： 1H MR (300 MHz, CDC13) δ 7.64 (d, J= 8.1 Hz, 2H), 7.34 (d, J= 7.9 Hz, 2H), 7.01 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.60 (s, 1H), 5.57 (d, J = 7.4 Hz, 1H), 3.91 (t, J = 5.0 Hz, 2H), 3.84 - 3.75 (m, 2H), 3.75 - 3.67 (m, 1H), 2.46 (s, 3H), 2.39 (d, J = 11.6 Hz, 2H), 2.31 (s, 3H), 2.18 (s, 3H), 1.95 (d, J = 12.3 Hz, 2H), 1.67 (m, 4H), 1.55 (td, J = 12.1, 3.7 Hz, 2H), 1.19 (s, 6H). ESI-MS: m/z 509.2 [M+Na]+. The compound Π-3 (Buy Example 26) (260 mg, 0.78 mmol) and triethylamine (305 μL in dichloromethane (15 mL) were added dropwise p-toluenesulfonyl chloride (180 mg, 0.95). A solution of methylene chloride in EtOAc (2 mL), EtOAc (EtOAc)EtOAc. The organic phase was sequentially saturated aqueous sodium hydrogencarbonate (10 mL), water (10 mL) It was washed with a saturated aqueous solution of sodium chloride (10 mL) and dried over anhydrous sodium sulfate. The residue was purified by column chromatography (eluent: methylene firing / methanol = 150: 1) to give Compound 54 (white solid, 320 mg, yield 85%): 1H MR (300 MHz, CDC1 3) δ 7.64 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 7.01 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.60 ( s, 1H), 5.57 (d, J = 7.4 Hz, 1H), 3.91 (t, J = 5.0 Hz, 2H), 3.84 - 3.75 (m, 2H), 3.75 - 3.67 (m, 1H), 2.46 (s , 3H), 2.39 (d, J = 11.6 Hz, 2H), 2.31 (s, 3H), 2.18 (s, 3H), 1.95 (d, J = 12.3 Hz, 2H), 1.67 (m, 4H), 1.55 (td, J = 12.1, 3.7 Hz, 2H), 1.19 (s, 6H). ESI-MS: m/z 509.2 [M+Na] + .
实施例 44  Example 44
N- ( 1-苯甲酰基哌啶 -4-基） -5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 （化合物 55 ) 参照实施例 2和 43的方法制得化合物 55: 1H NMR (300 MHz, CDC13) 5 7.38 - 7.26 (m, 5H), 7.01 (d, J= 7.4 Hz, 1H), 6.67 (d, J= 7.6 Hz, 1H), 6.62 (s, 1H), 3.94 (s, 2H), 3.67 (d, J =N-(1-benzoylpiperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (Compound 55) Refer to Examples 2 and 43 Method 55: 1H NMR (300 MHz, CDC1 3 ) 5 7.38 - 7.26 (m, 5H), 7.01 (d, J = 7.4 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.62 (s, 1H), 3.94 (s, 2H), 3.67 (d, J =
4.4 Hz, 3H), 3.47 (s, 2H), 2.42 (d, J = 4.7 Hz, 4H), 2.31 (s, 3H), 2.16 (s, 3H), 1.79 (s, 4H), 1.29 (s, 6H)。 ESI-MS: m/z 437.1 [M+H]+. 4.4 Hz, 3H), 3.47 (s, 2H), 2.42 (d, J = 4.7 Hz, 4H), 2.31 (s, 3H), 2.16 (s, 3H), 1.79 (s, 4H), 1.29 (s, 6H). ESI-MS: m/z 437.1 [M+H] + .
实施例 45  Example 45
N- ( 1- (2-氯苄基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 (化合物 N-(1-(2-chlorobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (compound)
56) 56)
参照实施例 1的方法制得化合物 56: 1H NMR (300 MHz, CDC13) δ 7.44 (d, J= 7.0 Hz, 1H), 7.30 (dd, J= 7.5, 1.6 Hz, 1H), 7.20 - 7.11 (m, 2H), 6.94 (d, J= 7.5 Hz, 1H), 6.59 (d, J =Compound 56 was obtained by the method of Example 1: 1H NMR (300 MHz, CDC1 3 ) δ 7.44 (d, J = 7.0 Hz, 1H), 7.30 (dd, J = 7.5, 1.6 Hz, 1H), 7.20 - 7.11 (m, 2H), 6.94 (d, J= 7.5 Hz, 1H), 6.59 (d, J =
7.5 Hz, 1H), 6.54 (s, 1H), 5.48 (d, J = 7.7 Hz, 1H), 3.85 (t, J = 5.5 Hz, 2H), 3.81 - 3.73 (m, 1H), 3.61 (s, 2H), 2.83 (d, J = 11.3 Hz, 2H), 2.30 - 2.24 (m, 2H), 2.24 (s, 3H), 2.11 (s, 3H), 1.91 - 1.81 (m, 4H), 1.79 - 1.70 (m, 2H), 1.46 (d, J = 10.9 Hz, 2H), 1.14 (s, 6H). ESI-MS: m/z 458.2 [M+H]+. 7.5 Hz, 1H), 6.54 (s, 1H), 5.48 (d, J = 7.7 Hz, 1H), 3.85 (t, J = 5.5 Hz, 2H), 3.81 - 3.73 (m, 1H), 3.61 (s, 2H), 2.83 (d, J = 11.3 Hz, 2H), 2.30 - 2.24 (m, 2H), 2.24 (s, 3H), 2.11 (s, 3H), 1.91 - 1.81 (m, 4H), 1.79 - 1.70 (m, 2H), 1.46 (d, J = 10.9 Hz, 2H), 1.14 (s, 6H). ESI-MS: m/z 458.2 [M+H] + .
实施例 46  Example 46
N- ( 1- (2-氰基苄基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 （化合 物 57)  N-(1-(2-Cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (Compound 57)
参照实施例 1的方法制得化合物 57: 1H NMR (300 MHz, CDC13) δ 7.44 (d, J= 7.0 Hz, 1H), 7.30 (dd, J= 7.5, 1.6 Hz, 1H), 7.20 - 7.11 (m, 2H), 6.94 (d, J= 7.5 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 6.54 (s, 1H), 5.48 (d, J = 7.7 Hz, 1H), 3.85 (t, J = 5.5 Hz, 2H), 3.81 - 3.73 (m, 1H), 3.61 (s, 2H), 2.83 (d, J = 11.3 Hz, 2H), 2.30 - 2.24 (m, 2H), 2.24 (s, 3H), 2.11 (s, 3H), 1.91 - 1.81 (m, 4H), 1.79 - 1.70 (m, 2H), 1.46 (d, J = 10.9 Hz, 2H), 1.14 (s, 6H). ESI-MS: m/z 448.1 [M+H]+. Compound 57 was obtained by the method of Example 1: 1H NMR (300 MHz, CDC1 3 ) δ 7.44 (d, J = 7.0 Hz, 1H), 7.30 (dd, J = 7.5, 1.6 Hz, 1H), 7.20 - 7.11 (m, 2H), 6.94 (d, J = 7.5 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 6.54 (s, 1H), 5.48 (d, J = 7.7 Hz, 1H), 3.85 (t, J = 5.5 Hz, 2H), 3.81 - 3.73 (m, 1H), 3.61 (s, 2H), 2.83 (d, J = 11.3 Hz, 2H), 2.30 - 2.24 (m, 2H), 2.24 ( s, 3H), 2.11 (s, 3H), 1.91 - 1.81 (m, 4H), 1.79 - 1.70 (m, 2H), 1.46 (d, J = 10.9 Hz, 2H), 1.14 (s, 6H). ESI -MS: m/z 448.1 [M+H] + .
实施例 47  Example 47
N- ( 1- (3-氰基苄基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 （化合 参照实施例 1的方法制得化合物 58: 1H NMR (300 MHz, CDC13) δ 7.44 (d, J= 7.0 Hz, 1H), 7.30 (dd, J= 7.5, 1.6 Hz, 1H), 7.20 - 7.11 (m, 2H), 6.94 (d, J= 7.5 Hz, 1H), 6.59 (d, J =N-(1-(3-Cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (combination Compound 58 was prepared by the method of Example 1: 1H NMR (300 MHz, CDC1 3 ) δ 7.44 (d, J = 7.0 Hz, 1H), 7.30 (dd, J = 7.5, 1.6 Hz, 1H), 7.20 - 7.11 (m, 2H), 6.94 (d, J= 7.5 Hz, 1H), 6.59 (d, J =
7.5 Hz, 1H), 6.54 (s, 1H), 5.48 (d, J = 7.7 Hz, 1H), 3.85 (t, J = 5.5 Hz, 2H), 3.81 - 3.73 (m, 1H), 3.61 (s, 2H), 2.83 (d, J = 11.3 Hz, 2H), 2.30 - 2.24 (m, 2H), 2.24 (s, 3H), 2.11 (s, 3H), 1.91 - 1.81 (m, 4H), 1.79 - 1.70 (m, 2H), 1.46 (d, J = 10.9 Hz, 2H), 1.14 (s, 6H). ESI-MS: m/z 448.1 [M+H]+. 7.5 Hz, 1H), 6.54 (s, 1H), 5.48 (d, J = 7.7 Hz, 1H), 3.85 (t, J = 5.5 Hz, 2H), 3.81 - 3.73 (m, 1H), 3.61 (s, 2H), 2.83 (d, J = 11.3 Hz, 2H), 2.30 - 2.24 (m, 2H), 2.24 (s, 3H), 2.11 (s, 3H), 1.91 - 1.81 (m, 4H), 1.79 - 1.70 (m, 2H), 1.46 (d, J = 10.9 Hz, 2H), 1.14 (s, 6H). ESI-MS: m/z 448.1 [M+H] + .
实施例 48  Example 48
N- ( 1-苄基哌啶 -4-基） -4- (2,5-二甲基苯氧基） 丁酰胺 （化合物 59)  N-( 1-Benzylpiperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide (Compound 59)
参照合成路线 5和实施例 1的方法制得化合物 59: 1H NMR (300 MHz, CDC13) δ 7.37 - 7.28 (m, 5H), 7.03 (d, J = 7.5 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 6.64 (s, 1H), 5.37 (d, J =Compound 59 was prepared according to the procedure of Scheme 5 and Example 1. 1H NMR (300 MHz, CDC1 3 ) δ 7.37 - 7.28 (m, 5H), 7.03 (d, J = 7.5 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 6.64 (s, 1H), 5.37 (d, J =
7.6 Hz, 1H), 4.01 (t, J= 5.9 Hz, 2H), 3.93 - 3.75 (m, 1H), 3.50 (s, 2H), 2.79 (d, J= 11.8 Hz, 2H), 2.40 (t, J= 7.3 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.14 (t, J= 10.1 Hz, 4H), 1.94 - 1.85 (m, 2H), 1.51 - 1.37 (m, 2H). ESI-MS: m/z 381.2 [M+H]+. 7.6 Hz, 1H), 4.01 (t, J= 5.9 Hz, 2H), 3.93 - 3.75 (m, 1H), 3.50 (s, 2H), 2.79 (d, J= 11.8 Hz, 2H), 2.40 (t, J= 7.3 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.14 (t, J= 10.1 Hz, 4H), 1.94 - 1.85 (m, 2H), 1.51 - 1.37 (m, 2H) ESI-MS: m/z 381.2 [M+H] + .
实施例 49  Example 49
N- ( 1- (4-氰基苄基） 哌啶 -4-基） -4- (2,5-二甲基苯氧基） 丁酰胺 （化合物 60) 参照合成路线 5和实施例 1的方法制得化合物 60: 1H NMR (300 MHz, CDC13) δ 7.62 (d, J= 8.1 Hz, 2H), 7.44 (d, J= 8.1 Hz, 2H), 7.03 (d, J= 7.5 Hz, 1H), 6.69 (d, J= 7.4 Hz, 1H): 6.64 (s, 1H), 5.36 (d, J = 7.8 Hz, 1H), 4.01 (t, J = 5.9 Hz, 2H), 3.89 - 3.77 (m, 1H), 3.52 (s, 2H), 2.74 (d, J = 11.7 Hz, 2H), 2.40 (t, J = 7.3 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.16 (m, 2H), 2.15 - 2.07 (m, 2H), 1.97 - 1.86 (m, 2H), 1.49 - 1.37 (m, 2H). ESI-MS: m/z 406.4 [M+H]+. N-(1-(4-Cyanobenzyl)piperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide (Compound 60) Referring to Synthesis Scheme 5 and Example 1 Method Compound 60: 1H NMR (300 MHz, CDC1 3 ) δ 7.62 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 7.5 Hz, 1H ), 6.69 (d, J= 7.4 Hz, 1H): 6.64 (s, 1H), 5.36 (d, J = 7.8 Hz, 1H), 4.01 (t, J = 5.9 Hz, 2H), 3.89 - 3.77 (m , 1H), 3.52 (s, 2H), 2.74 (d, J = 11.7 Hz, 2H), 2.40 (t, J = 7.3 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.16 (m, 2H), 2.15 - 2.07 (m, 2H), 1.97 - 1.86 (m, 2H), 1.49 - 1.37 (m, 2H). ESI-MS: m/z 406.4 [M+H] + .
实施例 50  Example 50
N- ( 1- (4-氰基苄基） 哌啶 -4-基） -4- (2,5-二甲基苯氧基） 丁酰胺 （化合物 61 ) 参照合成路线 5和实施例 1的方法制得化合物 61： 1H NMR (300 MHz, CDC13) δ 7.65 (d, J= 7.5 Hz, 1H), 7.59 - 7.48 (m, 2H), 7.40 - 7.32 (m, 1H), 7.02 (d, J= 7.5 Hz, 1H), 6.73 - 6.60 (m, 2H), 5.40 (d, J= 7.5 Hz, 1H), 4.01 (t, J= 5.9 Hz, 2H), 3.91 - 3.78 (m, 1H), 3.68 (s, 2H), 2.78 (d, J = 11.9 Hz, 2H), 2.40 (t, J= 7.3 Hz, 2H), 2.31 (s, 3H), 2.25 (dd, J = 11.5, 2.1 Hz, 2H), 2.20 (s, 3H), 2.14 (dd, J = 13.3, 7.0 Hz, 2H), 1.96 - 1.85 (m, 2H), 1.53 - 1.38 (m, 2H). ESI-MS: m/z 428.1 [M+Na]+. N-(1-(4-Cyanobenzyl)piperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide (Compound 61) Referring to Scheme 5 and Example 1, Method Compound 61: 1H NMR (300 MHz, CDC1 3 ) δ 7.65 (d, J = 7.5 Hz, 1H), 7.59 - 7.48 (m, 2H), 7.40 - 7.32 (m, 1H), 7.02 (d, J= 7.5 Hz, 1H), 6.73 - 6.60 (m, 2H), 5.40 (d, J= 7.5 Hz, 1H), 4.01 (t, J= 5.9 Hz, 2H), 3.91 - 3.78 (m, 1H), 3.68 (s, 2H), 2.78 (d, J = 11.9 Hz, 2H), 2.40 (t, J = 7.3 Hz, 2H), 2.31 (s, 3H), 2.25 (dd, J = 11.5, 2.1 Hz, 2H ), 2.20 (s, 3H), 2.14 (dd, J = 13.3, 7.0 Hz, 2H), 1.96 - 1.85 (m, 2H), 1.53 - 1.38 (m, 2H). ESI-MS: m/z 428.1 [ M+Na] + .
实施例 51  Example 51
N- ( 1- (3-氰基苄基） 哌啶 -4-基） -4- (2,5-二甲基苯氧基） 丁酰胺 （化合物 62) 参照合成路线 5和实施例 1的方法制得化合物 62: 1H NMR (300 MHz, CDC13) δ 7.66 (s, 1H), 7.60 - 7.50 (m, 2H), 7.43 (t, J= 7.7 Hz, 1H), 7.03 (d, J= 7.4 Hz, 1H), 6.70 (d, J= 7.5 Hz, 1H), 6.65 (s, 1H), 5.49 (d, J= 7.9 Hz, 1H), 4.01 (t, J= 5.9 Hz, 2H), 3.90 - 3.76 (m, 1H), 3.50 (s, 2H), 2.75 (d, J = 11.6 Hz, 2H), 2.42 (t, J = 7.3 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.15 (m,4H), 1.91 (d, J= 10.6 Hz, 2H), 1.51 - 1.37 (m, 2H). ESI-MS: m/z 428.2 [M+Na]+. 实施例 52 N-(1-(3-Cyanobenzyl)piperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide (Compound 62) Referring to Synthesis Scheme 5 and Example 1 Method Compound 62: 1H NMR (300 MHz, CDC1 3 ) δ 7.66 (s, 1H), 7.60 - 7.50 (m, 2H), 7.43 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.70 (d, J= 7.5 Hz, 1H), 6.65 (s, 1H), 5.49 (d, J= 7.9 Hz, 1H), 4.01 (t, J= 5.9 Hz, 2H), 3.90 - 3.76 (m, 1H), 3.50 (s, 2H), 2.75 (d, J = 11.6 Hz, 2H), 2.42 (t, J = 7.3 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.15 (m, 4H) ), 1.91 (d, J = 10.6 Hz, 2H), 1.51 - 1.37 (m, 2H). ESI-MS: m/z 428.2 [M+Na] + .
N- ( 1- (4-氯苄基） 哌啶 -4-基） -4- (2,5-二甲基苯氧基） 丁酰胺 （化合物 63 ) 参照合成路线 5和实施例 1的方法制得化合物 63 : 1H NMR (300 MHz, CDC13) δ 7.34 - 7.22 (m, 5H), 7.03 (d, J = 7.5 Hz, 1H), 6.70 (d, J = 7.5 Hz, 1H), 6.65 (s, 1H), 5.38 (d, J = 7.8 Hz, 1H), 4.01 (t, J= 5.9 Hz, 2H), 3.89 - 3.76 (m, 1H), 3.45 (s, 2H), 2.76 (d, J= 11.8 Hz, 2H), 2.40 (t, J = 7.3 Hz, 2H), 2.33 (s, 3H), 2.20 (s, 3H), 2.18 - 2.14 (m, 2H), 2.12 (m, 2H), 1.95 _ 1.85 (m, 2H), 1.49 - 1.37 (m, 2H). ESI-MS: m/z 415.2 [M+H]+. N-(1-(4-Chlorobenzyl)piperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide (Compound 63) Referring to the scheme of Synthesis Scheme 5 and Example 1 Compound 63: 1H NMR (300 MHz, CDC1 3 ) δ 7.34 - 7.22 (m, 5H), 7.03 (d, J = 7.5 Hz, 1H), 6.70 (d, J = 7.5 Hz, 1H), 6.65 ( s, 1H), 5.38 (d, J = 7.8 Hz, 1H), 4.01 (t, J= 5.9 Hz, 2H), 3.89 - 3.76 (m, 1H), 3.45 (s, 2H), 2.76 (d, J = 11.8 Hz, 2H), 2.40 (t, J = 7.3 Hz, 2H), 2.33 (s, 3H), 2.20 (s, 3H), 2.18 - 2.14 (m, 2H), 2.12 (m, 2H), 1.95 _ 1.85 (m, 2H), 1.49 - 1.37 (m, 2H). ESI-MS: m/z 415.2 [M+H] + .
实施例 53  Example 53
4- (2,5-二甲基苯氧基） -N- ( 1- (4- (三氟甲基） 苄基） 哌啶 -4-基） 丁酰胺 (化合物 4-(2,5-Dimethylphenoxy)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)butanamide (compound)
64) 64)
参照合成路线 5和实施例 1的方法制得化合物 64: 1H NMR (300 MHz, CDC13) δ 7.58 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 7.4 Hz, 1H), 6.75 - 6.61 (m, 2H), 5.35 (d, J= 7.7 Hz, 1H), 3.98 (s, 2H), 3.92 - 3.76 (m, 1H)， 3.55 (s, 2H), 2.79 (d, J= 11.7 Hz, 2H), 2.32 (s, 3H), 2.26 (t, J = 7.0 Hz, 2H), 2.19 (s, 3H), 2.16 (m, 2H), 1.93 (m, 4H), 1.53 -Compound 64 was prepared by the procedure of Scheme 5 and Example 1: 1H NMR (300 MHz, CDC1 3 ) δ 7.58 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 7.4 Hz, 1H), 6.75 - 6.61 (m, 2H), 5.35 (d, J = 7.7 Hz, 1H), 3.98 (s, 2H), 3.92 - 3.76 (m, 1H), 3.55 ( s, 2H), 2.79 (d, J = 11.7 Hz, 2H), 2.32 (s, 3H), 2.26 (t, J = 7.0 Hz, 2H), 2.19 (s, 3H), 2.16 (m, 2H), 1.93 (m, 4H), 1.53 -
1.39 (m, 2H). ESI-MS: m/z 449.2 [M+H]+. 1.39 (m, 2H). ESI-MS: m/z 449.2 [M+H] + .
实施例 54  Example 54
4- (2,5-二甲基苯氧基) -N- ( 1- (4-氟苄基) 哌啶 -4-基） 丁酰胺 (化合物 65) 参照合成路线 5和实施例 1的方法制得化合物 65: 1H NMR (300 MHz, CDC13) δ 7.28 (s, 2H), 7.01 (t, J= 8.8 Hz, 3H), 6.69 (d, J = 7.5 Hz, 1H), 6.64 (s, 1H), 5.35 (d, J = 7.4 Hz, 1H), 4.01 (t, J = 5.8 Hz, 2H), 3.89 - 3.77 (m, 1H), 3.44 (s, 2H), 2.76 (d, J = 11.4 Hz, 2H),4-(2,5-Dimethylphenoxy)-N-(1-(4-fluorobenzyl)piperidin-4-yl)butanamide (Compound 65) Referring to the scheme of Synthesis Scheme 5 and Example 1 Compound 65: 1H NMR (300 MHz, CDC1 3 ) δ 7.28 (s, 2H), 7.01 (t, J = 8.8 Hz, 3H), 6.69 (d, J = 7.5 Hz, 1H), 6.64 (s, 1H), 5.35 (d, J = 7.4 Hz, 1H), 4.01 (t, J = 5.8 Hz, 2H), 3.89 - 3.77 (m, 1H), 3.44 (s, 2H), 2.76 (d, J = 11.4 Hz, 2H),
2.40 (t, J= 7.3 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.18 - 2.08 (m, 4H), 1.90 (d, J= 12.4 Hz, 2H), 1.49 - 1.37 (m, 2H). ESI-MS: m/z 397.7 [M-H]". 2.40 (t, J= 7.3 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.18 - 2.08 (m, 4H), 1.90 (d, J= 12.4 Hz, 2H), 1.49 - 1.37 (m, 2H). ESI-MS: m/z 397.7 [MH]".
实施例 55  Example 55
4- (2,5-二甲基苯氧基） -N- ( 1- (2-甲基苄基） 哌啶 -4-基） 丁酰胺 （化合物 66) 参照合成路线 5和实施例 1的方法制得化合物 66: 1H NMR (300 MHz, CDC13) δ 7.26 (dd, J = 9.4, 4.3 Hz, 2H), 7.17 (m, 2H), 7.02 (d, J = 7.5 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 6.64 (s, 1H), 5.35 (d, J = 7.7 Hz, 1H), 4.01 (t, J = 5.7 Hz, 2H), 3.93 - 3.76 (m, 1H), 3.44 (s, 2H), 2.77 (d, J= 8.7 Hz, 2H), 2.41 (d, J= 7.3 Hz, 2H), 2.36 (s, 3H), 2.32 (s, 3H), 2.20 (s, 3H), 2.14 (m, 4H), 1.89 (d, J= 10.8 Hz, 2H), 1.48 - 1.33 (m, 2H). ESI-MS: m/z 417.2 [M+Na]+. 实施例 56 4-(2,5-Dimethylphenoxy)-N-(1-(2-methylbenzyl)piperidin-4-yl)butanamide (Compound 66) Referring to Scheme 5 and Example 1 Method Compound 66: 1H NMR (300 MHz, CDC1 3 ) δ 7.26 (dd, J = 9.4, 4.3 Hz, 2H), 7.17 (m, 2H), 7.02 (d, J = 7.5 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 6.64 (s, 1H), 5.35 (d, J = 7.7 Hz, 1H), 4.01 (t, J = 5.7 Hz, 2H), 3.93 - 3.76 (m, 1H) , 3.44 (s, 2H), 2.77 (d, J = 8.7 Hz, 2H), 2.41 (d, J = 7.3 Hz, 2H), 2.36 (s, 3H), 2.32 (s, 3H), 2.20 (s, 3H), 2.14 (m, 4H), 1.89 (d, J = 10.8 Hz, 2H), 1.48 - 1.33 (m, 2H). ESI-MS: m/z 417.2 [M+Na] + .
N- ( 1-苯甲酰基哌啶 -4-基） -4- (2,5-二甲基苯氧基） 丁酰胺 （化合物 67) 参照合成路线 5和实施例 2的方法制得化合物 67: 1H NMR (300 MHz, CDC13) δ 7.41 (m, 5H), 7.03 (d, J = 7.5 Hz, 1H), 6.69 (d, J = 7.4 Hz, 1H), 6.64 (s, 1H), 5.50 (d, J= 7.4 Hz, 1H), 4.78 - 4.50 (m, 1H), 4.04 (ddd, J = 20.4, 9.2, 4.4 Hz, 3H), 3.91 - 3.58 (m, 1H), 3.19 - 2.87 (m, 2H), 2.41 (t, J = 7.2 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.17 - 2.10 (m, 2H), 2.03 - 1.89 (m, 2H), 1.48 - 1.30 (m, 2H). ESI-MS: m/z 417.2 [M+Na]+. N-(1-benzoylpiperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide (Compound 67) Compound 67 was prepared by the procedure of Scheme 5 and Example 2: 1H NMR (300 MHz, CDC1 3 ) δ 7.41 (m, 5H), 7.03 (d, J = 7.5 Hz, 1H), 6.69 (d, J = 7.4 Hz, 1H), 6.64 (s, 1H), 5.50 (d, J= 7.4 Hz, 1H), 4.78 - 4.50 (m, 1H), 4.04 (ddd, J = 20.4, 9.2, 4.4 Hz, 3H), 3.91 - 3.58 (m, 1H), 3.19 - 2.87 (m, 2H), 2.41 (t, J = 7.2 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.17 - 2.10 (m, 2H), 2.03 - 1.89 (m, 2H), 1.48 - 1.30 (m, 2H). ESI-MS: m/z 417.2 [M+Na] + .
实施例 57  Example 57
4- (2,5-二甲基苯氧基） -N- ( 1-烟酰基哌啶 -4-基） 丁酰胺 （化合物 68)  4-(2,5-Dimethylphenoxy)-N-( 1-nicotinopiperidin-4-yl)butanamide (Compound 68)
参照合成路线 5和实施例 2的方法制得化合物 68: 1H NMR (300 MHz, CDC13) δ 8.73 - 8.62 (m, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.40 (dd, J= 7.6, 5.0 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.70 (d, J= 7.6 Hz, 1H), 6.64 (s, 1H), 5.68 (d, J= 6.7 Hz, 1H), 4.76 - 4.55 (m, 1H), 4.16 - 4.04 (m, 1H), 4.03 - 3.94 (m, 2H), 3.79 - 3.60 (m, 1H), 3.29 - 3.09 (m, 1H), 3.08 - 2.87 (m, 1H), 2.42 (t, J= 7.2 Hz, 2H), 2.32 (s, 3H), 2.19 (s, 3H), 2.16 - 2.09 (m, 2H), 2.09 - 1.91 (m, 2H), 1.55 - 1.33 (m, 2H). ESI-MS: m/z 419.1 [M+H]+. Compound 68 was prepared by the procedure of Scheme 5 and Example 2: 1H NMR (300 MHz, CDC1 3 ) δ 8.73 - 8.62 (m, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.40 (dd, J= 7.6, 5.0 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.70 (d, J= 7.6 Hz, 1H), 6.64 (s, 1H), 5.68 (d, J= 6.7 Hz, 1H), 4.76 - 4.55 (m, 1H), 4.16 - 4.04 (m, 1H), 4.03 - 3.94 (m, 2H), 3.79 - 3.60 (m, 1H), 3.29 - 3.09 (m, 1H), 3.08 - 2.87 (m, 1H), 2.42 (t, J= 7.2 Hz, 2H), 2.32 (s, 3H), 2.19 (s, 3H), 2.16 - 2.09 (m, 2H), 2.09 - 1.91 (m, 2H) , 1.55 - 1.33 (m, 2H). ESI-MS: m/z 419.1 [M+H] + .
实施例 58  Example 58
N- ( 1-苄基哌啶 -4-基) -5- (2,5-二甲基苯氧基) 戊酰胺 (化合物 69)  N-(1-Benzylpiperidin-4-yl)-5-(2,5-dimethylphenoxy)pentanamide (Compound 69)
参照合成路线 5和实施例 1的方法制得化合物 69: 1H NMR (300 MHz, CDC13) δ 7.33 (m 5H), 7.02 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 6.64 (s, 1H), 5.34 (d, J = 7.5 Hz, 1H), 3.98 (s, 2H), 3.90 - 3.75 (m, 1H), 3.51 (s, 2H), 2.82 (d, J = 11.6 Hz, 2H), 2.32 (s, 3H), 2.26 (m, 2H), 2.19 (s, 3H), 2.13 (d, J = 11.3 Hz, 2H), 1.94 - 1.81 (m, 6H), 1.54 - 1.37 (m, 2H). ESI-MS: m/z 395.3 [M+H]+. Compound 69 was prepared according to the procedure of Scheme 5 and Example 1. 1H NMR (300 MHz, CDC1 3 ) δ 7.33 (m 5H), 7.02 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 6.64 (s, 1H), 5.34 (d, J = 7.5 Hz, 1H), 3.98 (s, 2H), 3.90 - 3.75 (m, 1H), 3.51 (s, 2H), 2.82 (d , J = 11.6 Hz, 2H), 2.32 (s, 3H), 2.26 (m, 2H), 2.19 (s, 3H), 2.13 (d, J = 11.3 Hz, 2H), 1.94 - 1.81 (m, 6H) , 1.54 - 1.37 (m, 2H). ESI-MS: m/z 395.3 [M+H] + .
实施例 59  Example 59
N- ( 1- (4-氰基苄基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基） 戊酰胺 （化合物 70) 参照合成路线 5和实施例 1的方法制得化合物 70: 1H NMR (300 MHz, CDC13) δ 7.62 (d, J= 8.1 Hz, 2H), 7.45 (d, J= 8.0 Hz, 2H), 7.02 (d, J= 7.4 Hz, 1H), 6.68 (d, J= 7.7 Hz, 1H)， 6.64 (s, 1H), 5.33 (d, J= 7.4 Hz, 1H), 3.98 (s, 2H), 3.92 - 3.74 (m, 1H), 3.54 (s, 2H), 2.77 (d, J= 11.8 Hz, 2H), 2.32 (s, 3H), 2.26 (t, J = 6.6 Hz, 2H), 2.19 (s, 3H), 2.14 (d, J= 12.0 Hz, 2H), 1.98 - 1.83 (m, 6H), 1.47 (td, J= 11.7, 3.1 Hz, 2H). ESI-MS: m/z 442.2 [M+Na]+. N-(1-(4-Cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)pentanamide (Compound 70) Referring to Synthesis Scheme 5 and Example 1 Method Compound 70: 1H NMR (300 MHz, CDC1 3 ) δ 7.62 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 7.4 Hz, 1H ), 6.68 (d, J= 7.7 Hz, 1H), 6.64 (s, 1H), 5.33 (d, J= 7.4 Hz, 1H), 3.98 (s, 2H), 3.92 - 3.74 (m, 1H), 3.54 (s, 2H), 2.77 (d, J = 11.8 Hz, 2H), 2.32 (s, 3H), 2.26 (t, J = 6.6 Hz, 2H), 2.19 (s, 3H), 2.14 (d, J= 12.0 Hz, 2H), 1.98 - 1.83 (m, 6H), 1.47 (td, J = 11.7, 3.1 Hz, 2H). ESI-MS: m/z 442.2 [M+Na] + .
实施例 60  Example 60
5- (2,5-二甲基苯氧基） -N- ( 1- (4- (三氟甲基） 苄基） 哌啶 -4-基）戊酰胺 （化合物 5-(2,5-Dimethylphenoxy)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)pentanamide (compound)
71 ) 71)
参照合成路线 5和实施例 1的方法制得化合物 71： 1H NMR (300 MHz, CDC13) δ 7.58 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 7.4 Hz, 1H), 6.75 - 6.61 (m, 2H), 5.35 (d, J= 7.7 Hz, 1H), 3.98 (s, 2H), 3.92 - 3.76 (m, 1H)， 3.55 (s, 2H), 2.79 (d, J= 11.7 Hz, 2H), 2.32 (s, 3H), 2.26 (t, J = 7.0 Hz, 2H), 2.19 (s, 3H), 2.16 (s, 2H), 1.99 - 1.83 (m, 6H), 1.53 - 1.39 (m, 2H). ESI-MS: m/z 485.3 [M+Na]+. Compound 71 was prepared according to the procedure of Scheme 5 and Example 1. 1H NMR (300 MHz, CDC1 3 ) δ 7.58 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 7.4 Hz, 1H), 6.75 - 6.61 (m, 2H), 5.35 (d, J = 7.7 Hz, 1H), 3.98 (s, 2H), 3.92 - 3.76 (m, 1H), 3.55 ( s, 2H), 2.79 (d, J = 11.7 Hz, 2H), 2.32 (s, 3H), 2.26 (t, J = 7.0 Hz, 2H), 2.19 (s, 3H), 2.16 (s, 2H), 1.99 - 1.83 (m, 6H), 1.53 - 1.39 (m , 2H). ESI-MS: m/z 485.3 [M+Na] + .
实施例 61  Example 61
N- ( 1- (2-氰基苄基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基） 戊酰胺 （化合物 72) 参照合成路线 5和实施例 1的方法制得化合物 72: 1H NMR (300 MHz, CDC13) δ 7.66 (d, J = 7.7 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.01 (d, J = 7.4 Hz, 1H), 6.72 - 6.61 (m, 2H), 5.37 (d, J = 7.6 Hz, 1H), 3.98 (d, J = 5.1 Hz, 2H), 3.91 - 3.76 (m, 1H), 3.69 (s, 2H), 2.81 (d, J= 11.7 Hz, 2H), 2.32 (s, 3H), 2.27 (m, 2H), 2.25 (m, 2H), 2.19 (s, 3H), 1.94 - 1.81 (m, 6H), 1.54 - 1.40 (m, 2H). ESI-MS: m/z 442.1 [M+Na]+. N-(1-(2-Cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)pentanamide (Compound 72) Referring to Synthesis Scheme 5 and Example 1 Method Compound 72: 1H NMR (300 MHz, CDC1 3 ) δ 7.66 (d, J = 7.7 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.01 (d, J = 7.4 Hz, 1H), 6.72 - 6.61 (m, 2H), 5.37 (d, J = 7.6 Hz, 1H), 3.98 (d, J = 5.1 Hz, 2H), 3.91 - 3.76 (m, 1H), 3.69 (s, 2H), 2.81 (d, J = 11.7 Hz, 2H), 2.32 (s, 3H), 2.27 (m, 2H), 2.25 (m, 2H), 2.19 (s, 3H), 1.94 - 1.81 (m, 6H), 1.54 - 1.40 (m, 2H). ESI-MS: m/z 442.1 [M+Na] + .
实施例 62  Example 62
N- ( 1- (3-氰基苄基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基） 戊酰胺 (化合物 73) 参照合成路线 5和实施例 1的方法制得化合物 73 : 1H NMR (300 MHz, CDC13) δ 7.67 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.71 - 6.60 (m, 2H), 5.36 (d, J= 7.8 Hz, 1H), 3.98 (t, J= 5.4 Hz, 2H), 3.92 - 3.77 (m, 1H), 3.52 (s, 2H), 2.78 (d, J= 11.8 Hz, 2H), 2.32 (s, 3H), 2.27 (t, J= 7.0 Hz, 2H), 2.19 (s, 3H), 2.19 - 2.12 (m, 2H), 1.90 (m, 6H), 1.52 - 1.42 (m, 2H). ESI-MS: m/z 442.2 [M+Na]+. N-(1-(3-Cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)pentanamide (Compound 73) Referring to Synthesis Scheme 5 and Example 1 Method Compound 73: 1H NMR (300 MHz, CDC1 3 ) δ 7.67 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.02 (d , J = 7.4 Hz, 1H), 6.71 - 6.60 (m, 2H), 5.36 (d, J = 7.8 Hz, 1H), 3.98 (t, J = 5.4 Hz, 2H), 3.92 - 3.77 (m, 1H) , 3.52 (s, 2H), 2.78 (d, J = 11.8 Hz, 2H), 2.32 (s, 3H), 2.27 (t, J = 7.0 Hz, 2H), 2.19 (s, 3H), 2.19 - 2.12 ( m, 2H), 1.90 (m, 6H), 1.52 - 1.42 (m, 2H). ESI-MS: m/z 442.2 [M+Na] + .
实施例 63  Example 63
N- ( 1-苄基哌啶 -4-基） -5- (2,5-二异丙基苯氧基） -2,2-二甲基戊酰胺 （化合物 37) 参照合成路线 5和实施例 1的方法制得化合物 37: 1H NMR (300 MHz, CDC13) δ 7.44 - 7.27 (m, 5H), 7.14 - 7.06 (m, 3H), 5.57 (d, J= 8.8 Hz, 1H), 3.89 - 3.79 (m, 1H), 3.72 (dt, J = 10.7, 3.6 Hz, 2H), 3.48 (s, 2H), 3.29 (dd, J= 17.3, 10.5 Hz, 2H), 2.79 (d, J= 11.3 Hz, 2H), 2.14 (t, J= 11.1 Hz, 2H), 1.91 (d, J = 9.1 Hz, 2H), 1.73 (s, 4H), 1.51 - 1.40 (m, 2H), 1.27 - 1.18 (m, 18H). ESI-MS: m/z 479.2 [M+H]+. N-(1-Benzylpiperidin-4-yl)-5-(2,5-diisopropylphenoxy)-2,2-dimethylpentanamide (Compound 37) Referring to Scheme 5 and carrying out Compound 37 was obtained by the method of Example 1: 1H NMR (300 MHz, CDC1 3 ) δ 7.44 - 7.27 (m, 5H), 7.14 - 7.06 (m, 3H), 5.57 (d, J = 8.8 Hz, 1H), 3.89 - 3.79 (m, 1H), 3.72 (dt, J = 10.7, 3.6 Hz, 2H), 3.48 (s, 2H), 3.29 (dd, J= 17.3, 10.5 Hz, 2H), 2.79 (d, J= 11.3 Hz, 2H), 2.14 (t, J= 11.1 Hz, 2H), 1.91 (d, J = 9.1 Hz, 2H), 1.73 (s, 4H), 1.51 - 1.40 (m, 2H), 1.27 - 1.18 (m , 18H). ESI-MS: m/z 479.2 [M+H] + .
实施例 64  Example 64
N- ( 1-苄基哌啶 -4-基） -5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 （化合物 2) 参照实施例 1和 43的方法制得化合物 2: 1H MR (300 MHz, CDC13) δ 7.38-7.24 (s, 5H), 6.99 (d, J= 7.3 Hz, 1H), 6.65 (d, J= 7.4 Hz, 1H), 6.60 (s, 1H), 5.55 (d, J= 7.4 Hz, 1H), 3.90 (s, 2H), 3.80 (s, 1H), 3.54 (s, 2H), 2.85 (d, J = 11.2 Hz, 2H), 2.26 (d, J= 15.7 Hz, 3H), 2.21-2.11 (m, 5H), 1.89 (d, J = 11.6 Hz, 2H), 1.68 (s, 4H), 1.58-1.38 (m, 2H), 1.19 (s, 6H). ESI-MS: m/z 423.3 [M+H]+. N-(1-Benzylpiperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (Compound 2) Referring to Examples 1 and 43 Method 2: 1H MR (300 MHz, CDC1 3 ) δ 7.38-7.24 (s, 5H), 6.99 (d, J = 7.3 Hz, 1H), 6.65 (d, J = 7.4 Hz, 1H), 6.60 (s, 1H), 5.55 (d, J = 7.4 Hz, 1H), 3.90 (s, 2H), 3.80 (s, 1H), 3.54 (s, 2H), 2.85 (d, J = 11.2 Hz, 2H) , 2.26 (d, J = 15.7 Hz, 3H), 2.21-2.11 (m, 5H), 1.89 (d, J = 11.6 Hz, 2H), 1.68 (s, 4H), 1.58-1.38 (m, 2H), 1.19 (s, 6H). ESI-MS: m/z 423.3 [M+H] + .
实施例 65  Example 65
N- ( 1- (4-氰基苄基) 哌啶 -4-基） -5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺 （化 合物 18)  N-(1-(4-Cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (Compound 18)
参照实施例 1和 43的方法制得化合物 18: 1H NMR (300 MHz, 6-DMSO) δ 7.78 (d, J = 4.6 Hz, 2H), 7.49 (d, J= 4.1 Hz, 2H), 7.16-7.00 (m, 2H), 6.64 (d, J= 20.2 Hz, 2H), 3.88 (s, 2H), 3.55 (s, 1H), 3.53 (s, 2H), 2.73 (d, J = 6.2 Hz, 2H), 2.23 (s, 3H), 2.08 (s, 3H), 2.10-1.90 (m, 2H), 1.58 (s, 4H), 1.60-1.40 (m, 2H), 1.36-1.16 (m, 2H), 1.09 (s, 6H). ESI-MS: m/z 470.3 [M+Na]+. Compound 18 was prepared by the methods of Examples 1 and 43: 1H NMR (300 MHz, 6 -DMSO) δ 7.78 (d, J = 4.6 Hz, 2H), 7.49 (d, J= 4.1 Hz, 2H), 7.16-7.00 (m, 2H), 6.64 (d, J= 20.2 Hz, 2H), 3.88 (s, 2H), 3.55 (s , 1H), 3.53 (s, 2H), 2.73 (d, J = 6.2 Hz, 2H), 2.23 (s, 3H), 2.08 (s, 3H), 2.10-1.90 (m, 2H), 1.58 (s, 4H), 1.60-1.40 (m, 2H), 1.36-1.16 (m, 2H), 1.09 (s, 6H). ESI-MS: m/z 470.3 [M+Na] + .
实施例 66  Example 66
5- (2,5-二甲基苯氧基) -N- ( 1- (4-甲氧基苄基)哌啶 -4-基） -2,2-二甲基戊酰胺（化 合物 20)  5-(2,5-Dimethylphenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)-2,2-dimethylpentanamide (Compound 20)
参照实施例 1和 43的方法制得化合物 20: 1H MR (300 MHz, CDC13) δ 7.20 (d, J = 8.2 Hz, 2H), 6.99 (d, J= 7.3 Hz, 1H), 6.84 (d, J= 8.3 Hz, 2H), 6.64 (d, J= 7.4 Hz, 1H), 6.59 (s, 1H), 5.48 (d, J= 7.6 Hz, 1H), 3.89 (d, J = 5.4 Hz, 2H), 3.79 (s, 3H), 3.78 - 3.74 (m, 1H), 3.42 (s, 2H), 2.77 (d, J= 11.4 Hz, 2H), 2.29 (s, 3H), 2.16 (s, 3H), 2.10 - 1.98 (d, J= 11.1 Hz, 2H), 1.87 (s, 4H), 1.65 (s, 2H), 1.51 - 1.31 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 475.3 [M+Na]+. Compound 20 was prepared by the methods of Examples 1 and 43: 1H MR (300 MHz, CDC1 3 ) δ 7.20 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 7.3 Hz, 1H), 6.84 (d , J= 8.3 Hz, 2H), 6.64 (d, J= 7.4 Hz, 1H), 6.59 (s, 1H), 5.48 (d, J= 7.6 Hz, 1H), 3.89 (d, J = 5.4 Hz, 2H ), 3.79 (s, 3H), 3.78 - 3.74 (m, 1H), 3.42 (s, 2H), 2.77 (d, J= 11.4 Hz, 2H), 2.29 (s, 3H), 2.16 (s, 3H) , 2.10 - 1.98 (d, J = 11.1 Hz, 2H), 1.87 (s, 4H), 1.65 (s, 2H), 1.51 - 1.31 (m, 2H), 1.18 (s, 6H). ESI-MS: m /z 475.3 [M+Na] + .
实施例 67  Example 67
N- ( 1- (2-氯 -4-氟苄基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺 （化 合物 21 )  N-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (compound twenty one )
参照实施例 1和 43的方法制得化合物 21： 1H NMR (300 MHz, CDC13) δ 7.54 - 7.38 (m, 1H), 7.12 (dd, J= 8.5, 2.5 Hz, 1H), 7.06 - 6.94 (m, 2H), 6.67 (d, J= 7.4 Hz, 1H), 6.62 (s, 1H), 5.50 (d, J= 7.7 Hz, 1H), 3.94 (t, J= 5.5 Hz, 2H), 3.89 - 3.74 (m, 1H), 3.57 (s, 2H), 2.81 (d, J = 11.9 Hz, 2H), 2.31 (d, J= 6.3 Hz, 3H), 2.25 (s, 2H), 2.19 (s, 3H), 1.92 (d, J= 11.0 Hz, 2H), 1.72 (s, 4H), 1.55 - 1.36 (m, 3H), 1.22 (s, 6H). ESI-MS: m/z 475.3 [M+H]+. Compound 21 was obtained by the methods of Examples 1 and 43: 1H NMR (300 MHz, CDC1 3 ) δ 7.54 - 7.38 (m, 1H), 7.12 (dd, J = 8.5, 2.5 Hz, 1H), 7.06 - 6.94 ( m, 2H), 6.67 (d, J = 7.4 Hz, 1H), 6.62 (s, 1H), 5.50 (d, J = 7.7 Hz, 1H), 3.94 (t, J = 5.5 Hz, 2H), 3.89 - 3.74 (m, 1H), 3.57 (s, 2H), 2.81 (d, J = 11.9 Hz, 2H), 2.31 (d, J = 6.3 Hz, 3H), 2.25 (s, 2H), 2.19 (s, 3H) ), 1.92 (d, J = 11.0 Hz, 2H), 1.72 (s, 4H), 1.55 - 1.36 (m, 3H), 1.22 (s, 6H). ESI-MS: m/z 475.3 [M+H] + .
实施例 68  Example 68
N- ( 1- (4-氯苯甲酰基)哌啶 -4-基） -5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺（化 合物 22)  N-(1-(4-Chlorobenzoyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (Compound 22)
参照实施例 2和 43的方法制得化合物 22: 1H MR (300 MHz, DMSO- d6) δ 7.52 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 7.6 Hz, 1H), 6.96 (d, J= 7.4 Hz, 1H), 6.67 (s, 1H), 6.59 (d, J = 7.5 Hz, 1H), 3.94 - 3.77 (m, 3H), 3.61 - 3.38 (m, 1H), 3.18 - 2.99 (m, 1H), 2.93-2.70 (m, 2H), 2.22 (s, 3H), 2.07 (s, 3H), 1.78-1.61 (m, 2H), 1.58 (s, 4H), 1.45-1.30 (m, 2H), 1.08 (s, 6H). ESI-MS: m/z 494.1 [M+Na]+. Compound 22 was prepared by the methods of Examples 2 and 43: 1H MR (300 MHz, DMSO-d 6 ) δ 7.52 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.67 (s, 1H), 6.59 (d, J = 7.5 Hz, 1H), 3.94 - 3.77 (m, 3H) , 3.61 - 3.38 (m, 1H), 3.18 - 2.99 (m, 1H), 2.93-2.70 (m, 2H), 2.22 (s, 3H), 2.07 (s, 3H), 1.78-1.61 (m, 2H) , 1.58 (s, 4H), 1.45-1.30 (m, 2H), 1.08 (s, 6H). ESI-MS: m/z 494.1 [M+Na] + .
实施例 69  Example 69
2- (4- (4-氯苄基） 苯氧基） -N- ( 1- (4-氰基苄基） 哌啶 -4-基） -2-甲基丙酰胺 （化 合物 14)  2-(4-(4-Chlorobenzyl)phenoxy)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-methylpropanamide (Compound 14)
参照合成路线 1和实施例 1的方法制得化合物 14: 1H MR (300 MHz, DMSO- d6) δ 7.78 (d, J= 7.6 Hz, 3H), 7.49 (d, J= 7.7 Hz, 2H), 7.31 (d, J= 8.2 Hz, 2H), 7.21 (d, J= 8.2 Hz, 2H), 7.10 (d, J= 8.3 Hz, 2H), 6.79 (d, J= 8.3 Hz, 2H), 3.85 (s, 2H), 3.70 -3.50 (m, 3H), 2.72 (d, J = 8.8 Hz, 2H), 2.21 - 1.96 (m, 2H), 1.69 - 1.56 (m, 2H), 1.56 - 1.40 (m, 2H), 1.40 (s, 6H). ESI-MS: m/z 503.1 [M+H]+. Compound 14 was prepared by the method of Synthesis Scheme 1 and Example 1: 1H MR (300 MHz, DMSO-d 6 ) δ 7.78 (d, J = 7.6 Hz, 3H), 7.49 (d, J = 7.7 Hz, 2H) , 7.31 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 7.10 (d, J= 8.3 Hz, 2H), 6.79 (d, J= 8.3 Hz, 2H), 3.85 (s, 2H), 3.70 -3.50 (m, 3H), 2.72 (d, J = 8.8 Hz, 2H), 2.21 - 1.96 (m, 2H), 1.69 - 1.56 (m, 2H), 1.56 - 1.40 (m, 2H), 1.40 (s, 6H). ESI-MS: m/z 503.1 [M+ H] + .
实施例 70  Example 70
N- ( 1-苄基哌啶 -4-基） -2- (4- (4-氯苄基） 苯氧基） -2-甲基丙酰胺 （化合物 4) 参照合成路线 1和实施例 1的方法制得化合物 4: 1H MR (300 MHz, DMSO- 6) δ 7.78 (d, J = 7.7 Hz, 1H), 7.37-7.26(m, 5H), 7.26 - 7.18 (m, 4H), 7.09 (d, J = 8.0 Hz, 2H), 6.80 (d, J= 8.1 Hz, 2H), 3.85 (s, 2H), 3.61 (ddd, J = 8.2, 7.0, 2.9 Hz, 1H), 3.41 (s, 2H), 2.71 (d, J= 10.4 Hz, 2H), 1.95 (t, J= 10.8 Hz, 2H), 1.59 (d, J= 8.9 Hz, 2H), 1.47 (d, J= 11.4 Hz, 2H), 1.38 , 6H). ESI-MS: m/z 475.3 [M-H]". N-(1-Benzylpiperidin-4-yl)-2-(4-(4-chlorobenzyl)phenoxy)-2-methylpropanamide (Compound 4) Referring to Synthesis Scheme 1 and Example 1 Method 4: 1H MR (300 MHz, DMSO- 6 ) δ 7.78 (d, J = 7.7 Hz, 1H), 7.37-7.26 (m, 5H), 7.26 - 7.18 (m, 4H), 7.09 ( d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.1 Hz, 2H), 3.85 (s, 2H), 3.61 (ddd, J = 8.2, 7.0, 2.9 Hz, 1H), 3.41 (s, 2H ), 2.71 (d, J= 10.4 Hz, 2H), 1.95 (t, J= 10.8 Hz, 2H), 1.59 (d, J= 8.9 Hz, 2H), 1.47 (d, J= 11.4 Hz, 2H), 1.38, 6H). ESI-MS: m/z 475.3 [MH]".
实施例 71  Example 71
N- ( 1- (2-氯 -4-氟苄基） 哌啶 -4-基） -2- (4-氯苯氧基） -2-甲基丙酰胺 （化合物 17) 参照合成路线 1和实施例 1的方法制得化合物 17: 1H NMR (300 MHz, CDC13) δ 7.48 - 7.33 (m, 1H), 7.24 (d, J= 8.8 Hz, 2H), 7.07 (dd, J= 14.0, 8.2 Hz, 4H), 6.94 (td, J= 8.4, 2.4 Hz, 1H), 6.82 (d, J= 8.4 Hz, 2H), 6.60 (d, J= 7.7 Hz, 1H), 3.89 (s, 2H), 3.86 - 3.77 (m, 1H), 3.54 (s, 2H), 2.78 (d, J = 11.6 Hz, 2H), 2.24 (t, J = 10.7 Hz, 2H), 1.91 (d, J = 10.9 Hz, 2H), 1.47 (s, 6H), 1.46 - 1.33 (m, 2H). ESI-MS: m/z 529.2 [M+H]+. N-(1-(2-Chloro-4-fluorobenzyl)piperidin-4-yl)-2-(4-chlorophenoxy)-2-methylpropanamide (Compound 17) Referring to Scheme 1 and Compound 17 was obtained by the method of Example 1: 1H NMR (300 MHz, CDC1 3 ) δ 7.48 - 7.33 (m, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.07 (dd, J = 14.0, 8.2 Hz, 4H), 6.94 (td, J= 8.4, 2.4 Hz, 1H), 6.82 (d, J= 8.4 Hz, 2H), 6.60 (d, J= 7.7 Hz, 1H), 3.89 (s, 2H), 3.86 - 3.77 (m, 1H), 3.54 (s, 2H), 2.78 (d, J = 11.6 Hz, 2H), 2.24 (t, J = 10.7 Hz, 2H), 1.91 (d, J = 10.9 Hz, 2H ), 1.47 (s, 6H), 1.46 - 1.33 (m, 2H). ESI-MS: m/z 529.2 [M+H] + .
实施例 72  Example 72
2- (4- (4-氯苄基） 苯氧基） -2-甲基 -N- ( 1- (4- (三氟甲基） 苄基） 哌啶 -4-基） 丙 酰胺 （化合物 15 )  2-(4-(4-Chlorobenzyl)phenoxy)-2-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)propanamide (compound) 15)
参照合成路线 1和实施例 1的方法制得化合物 15: 1H NMR (300 MHz, CDC13) δ 7.58 (d, J= 8.0 Hz, 2H), 7.44 (d, J= 8.0 Hz, 2H), 7.26 (d, J= 8.3 Hz, 2H), 7.09 (dd, J= 13.1, 8.4 Hz, 4H), 6.85 (d, J= 8.4 Hz, 2H), 6.63 (d, J= 8.0 Hz, 1H), 3.91 (s, 2H), 3.88 - 3.77 (m, 1H), 3.54 (s, 2H), 2.78 (d, J = 11.7 Hz, 2H), 2.17 (t, J = 11.3 Hz, 2H), 1.93 (d, J = 10.8 Hz, 2H), 1.49 (s, 6H), 1.48 - 1.39 (m, 2H). ESI-MS: m/z 546.1 [M+H]+. Compound 15 was prepared by the method of Synthesis Scheme 1 and Example 1: 1H NMR (300 MHz, CDC1 3 ) δ 7.58 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.26 (d, J= 8.3 Hz, 2H), 7.09 (dd, J= 13.1, 8.4 Hz, 4H), 6.85 (d, J= 8.4 Hz, 2H), 6.63 (d, J= 8.0 Hz, 1H), 3.91 (s, 2H), 3.88 - 3.77 (m, 1H), 3.54 (s, 2H), 2.78 (d, J = 11.7 Hz, 2H), 2.17 (t, J = 11.3 Hz, 2H), 1.93 (d, J = 10.8 Hz, 2H), 1.49 (s, 6H), 1.48 - 1.39 (m, 2H). ESI-MS: m/z 546.1 [M+H] + .
实施例 73  Example 73
2- (4- (4-氯苄基）苯氧基） -N- ( 1- (4-甲氧基苄基）哌啶 -4-基） -2-甲基丙酰胺（化 合物 16)  2-(4-(4-Chlorobenzyl)phenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)-2-methylpropanamide (Compound 16)
参照合成路线 1和实施例 1的方法制得化合物 16: 1H NMR (300 MHz, CDC13) δ 7.22 (dd, J= 13.8, 8.5 Hz, 4H), 7.06 (dd, J= 16.1, 8.3 Hz, 4H), 6.83 (t, J= 8.0 Hz, 4H), 6.58 (d, J = 8.0 Hz, 1H), 3.89 (s, 2H), 3.83 (s, 1H), 3.79 (s, 3H), 3.42 (s, 2H), 2.77 (d, J= 11.6 Hz, 2H), 2.11 (t, J= 10.7 Hz, 2H), 1.89 (d, J= 12.3 Hz, 2H), 1.47 (s, 6H), 1.50 - 1.30(m, 2H). ESI-MS: m/z 507.3 [M+H]+. Compound 16 was prepared by the method of Synthesis Scheme 1 and Example 1 : 1H NMR (300 MHz, CDC1 3 ) δ 7.22 (dd, J = 13.8, 8.5 Hz, 4H), 7.06 (dd, J = 16.1, 8.3 Hz, 4H), 6.83 (t, J= 8.0 Hz, 4H), 6.58 (d, J = 8.0 Hz, 1H), 3.89 (s, 2H), 3.83 (s, 1H), 3.79 (s, 3H), 3.42 ( s, 2H), 2.77 (d, J= 11.6 Hz, 2H), 2.11 (t, J= 10.7 Hz, 2H), 1.89 (d, J= 12.3 Hz, 2H), 1.47 (s, 6H), 1.50 - 1.30 (m, 2H). ESI-MS: m/z 507.3 [M+H] + .
实施例 74 2- (4-苯甲酰基苯氧基） -N- ( 1-苄基哌啶 -4-基） -2-甲基丙酰胺 （化合物 74) 参照实施例 1的方法制得化合物 74: 1H NMR (300 MHz, CDC13) δ 7.81 -7.50 (m,5H), 7.46 (d, J = 8.4 Hz, 2H), 7.28 - 7.10 (m, 5H), 7.01 (d, J = 8.7 Hz, 2H), 6.10 (d, J = 8.1 Hz, 1H), 3.95 - 3.73 (m, 1H), 3.47 (s, 2H), 2.65 (d, J= 11.8 Hz, 2H), 2.20 (t, J = 10.8 Hz, 2H), 1.88 (d, J= 11.5 Hz, 2H), 1.45 (s, 6H), 1.45-1.20 (m,2H)。 ESI-MS: m/z 479.1 [M+Na]+. 实施例 75 Example 74 2-(4-Benzoylphenoxy)-N-(1-benzylpiperidin-4-yl)-2-methylpropanamide (Compound 74) Compound 74 was obtained according to the procedure of Example 1: 1H NMR (300 MHz, CDC1 3 ) δ 7.81 -7.50 (m, 5H), 7.46 (d, J = 8.4 Hz, 2H), 7.28 - 7.10 (m, 5H), 7.01 (d, J = 8.7 Hz, 2H) , 6.10 (d, J = 8.1 Hz, 1H), 3.95 - 3.73 (m, 1H), 3.47 (s, 2H), 2.65 (d, J = 11.8 Hz, 2H), 2.20 (t, J = 10.8 Hz, 2H), 1.88 (d, J = 11.5 Hz, 2H), 1.45 (s, 6H), 1.45-1.20 (m, 2H). ESI-MS: m/z 479.1 [M+Na] + .
2- (4-苯甲酰基苯氧基） -N- ( 1-苯甲酰哌啶 -4-基） 乙酰胺 （化合物 96)  2-(4-Benzoylphenoxy)-N-(1-benzoylpiperidine-4-yl)acetamide (Compound 96)
参照实施例 2的方法制得化合物 96: 1H NMR (300 MHz, CDC13) δ 7.85 (d, J= 8.7 Hz, 2H), 7.76 (d, J= 7.0 Hz, 2H), 7.63 - 7.53 (m, 1H), 7.53 - 7.44 (m, 2H), 7.43 - 7.33 (m, 5H), 7.00 (d, J = 8.7 Hz, 2H), 6.45 (d, J = 7.5 Hz, 1H), 4.80 - 4.49 (m, 3H), 4.24 - 4.07 (m, 1H), 3.99 - 3.67 (m, 1H), 3.24 - 2.85 (m, 2H), 2.16 - 1.86 (m, 2H), 1.53 - 1.19 (m, 2H). ESI-MS: m/z 443.3 [M+H]+. The compound 96 was obtained by the method of Example 2: 1H NMR (300 MHz, CDC1 3 ) δ 7.85 (d, J = 8.7 Hz, 2H), 7.76 (d, J = 7.0 Hz, 2H), 7.63 - 7.53 (m , 1H), 7.53 - 7.44 (m, 2H), 7.43 - 7.33 (m, 5H), 7.00 (d, J = 8.7 Hz, 2H), 6.45 (d, J = 7.5 Hz, 1H), 4.80 - 4.49 ( m, 3H), 4.24 - 4.07 (m, 1H), 3.99 - 3.67 (m, 1H), 3.24 - 2.85 (m, 2H), 2.16 - 1.86 (m, 2H), 1.53 - 1.19 (m, 2H). ESI-MS: m/z 443.3 [M+H] + .
实施例 76  Example 76
2- (4-苯甲酰基苯氧基） -N- ( 1- ( (4-氰基苯基）磺酰基） 哌啶 -4-基） 乙酰胺 （化合 物 97)  2-(4-Benzophenoxy)-N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)acetamide (Compound 97)
参照合成路线 2和实施例 43的方法制得化合物 97: 1H MR (300 MHz, DMSO- 6) δ 8.15 (d, J = 8.5 Hz, 3H), 7.93 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.72 - 7.62 (m, 3H), 7.60 - 7.52 (m, 2H), 7.07 (d, J = 8.8 Hz, 2H), 4.57 (s, 2H), 3.76 - 3.64 (m, 1H), 3.63 - 3.50 (m, 2H), 2.61 - 2.52 (m, 2H), 1.84 - 1.72 (m, 2H), 1.59 - 1.42 (m, 2H). ESI-MS: m/z 526.1 [M+Na]+. Compound 97 was prepared by the method of Synthesis Scheme 2 and Example 43: 1H MR (300 MHz, DMSO- 6 ) δ 8.15 (d, J = 8.5 Hz, 3H), 7.93 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.72 - 7.62 (m, 3H), 7.60 - 7.52 (m, 2H), 7.07 (d, J = 8.8 Hz, 2H), 4.57 (s, 2H), 3.76 - 3.64 (m, 1H), 3.63 - 3.50 (m, 2H), 2.61 - 2.52 (m, 2H), 1.84 - 1.72 (m, 2H), 1.59 - 1.42 (m, 2H). ESI-MS: m/ z 526.1 [M+Na] + .
实施例 77  Example 77
N - ( (3S,4S) -1 - ( (4-氰基苯基)磺酰基） -3-氟哌啶 -4-基) -5- (2,5-二甲基苯氧基) -2,2-二甲  N - ((3S,4S) -1 - ((4-cyanophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-5-(2,5-dimethylphenoxy) - 2,2-dimethyl
Figure imgf000066_0001
Figure imgf000066_0001
取化合物 II-1 (200 mg， 0.8 mmoL) 置于反应瓶中， 加入 0-(7-氮杂苯并三氮唑 -1- 基) -Ν,Ν,Ν',Ν'-四甲基脲六氟磷酸酯 （HATU) (456 mg， 1.2 mmoL)， 氮气保护下， 加入 无水 DMF ( 5 mL)， 室温搅拌溶解后， 加入 Ν,Ν-二异丙基乙胺 （DIPEA) (0.66 mL)， 室温搅拌 0.5 h。将光学纯的（3S,4S ) -4-氨基 -3-氟哌啶 -1-甲酸叔丁酯（175 mg, 0.8 mmoL) 溶于无水 DMF (2 mL)后，用注射器滴加入反应瓶中，继续室温搅拌 4 h。加水（20 mL) 稀释反应液， 乙酸乙酯萃取（10 mL x3 )。 有机相用水（20 mL)和饱和氯化钠 （20 mL) 洗涤， 无水硫酸钠干燥， 过滤， 旋干。残余物经柱层析（洗脱剂： 石油醚 /乙酸乙酯 =5: 1 ) 纯化， 得化合物 III-1 (淡黄色液体， 250 mg， 收率 69%)。 Take compound II-1 (200 mg, 0.8 mmoL) in a reaction flask and add 0-(7-azabenzotriazol-1-yl)-indole, hydrazine, Ν', Ν'-tetramethyl Urea hexafluorophosphate (HATU) (456 mg, 1.2 mmoL), under anhydrous nitrogen, add anhydrous DMF (5 mL), stir at room temperature, add hydrazine, hydrazine-diisopropylethylamine (DIPEA) (0.66 mL), Stir at room temperature for 0.5 h. The optically pure (3S,4S )-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (175 mg, 0.8 mmoL) was dissolved in anhydrous DMF (2 mL) and added to the reaction vial with a syringe. In the middle, continue stirring at room temperature for 4 h. The reaction was diluted with water (20 mL) and EtOAc (EtOAc) The organic phase was washed with water (20 mL) EtOAc. The residue was purified by EtOAc EtOAcjjjjjjj
取化合物 III-1 (250 mg, 0.56 mmoL) 溶于二氯甲垸 （5 mL)， 冰浴下加入三氟乙酸 (3 mL)， 室温搅拌过夜。 旋干， 饱和碳酸氢钠调节 pH至碱性， 乙酸乙酯 （10 mL x3 ) 萃取， 饱和 NaCl (20 mL)洗涤， 无水硫酸钠干燥， 旋干， 得化合物 ΠΙ-2 (淡黄色液体， 160 mg, 收率 82%)。  Compound III-1 (250 mg, 0.56 mmoL) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL). Cyclohexane, saturated sodium bicarbonate, adjusted to pH, extracted with ethyl acetate (10 mL×3), washed with saturated NaCI (20 mL), dried over anhydrous sodium sulfate and dried. 160 mg, yield 82%).
取化合物 ΙΠ-2 ( 160 mg, 0.45 mmoL) 溶于 DCM ( 5 mL), 加入三乙胺 （0.095 mL) 和对氰基苯磺酰氯 （92 mg, 0.46 mmoL)， 室温搅拌 4 h。 旋干， 残余物经柱层析 （洗脱 剂：石油醚 /乙酸乙酯 =3: 1 )纯化，得化合物 98 (白色固体， 200 mg，收率 85%): 1H MR (300 MHz, CDC13) δ 8.01 - 7.85 (m, 4H), 7.04 (d, J = 7.4 Hz, 1H), 6.71 (d, J = 7.4 Hz, 1H), 6.64 (s, 1H), 5.68 (d, J = 7.1 Hz, 1H), 4.61 - 4.33 (m, 1H), 4.16 - 4.04 (m, 1H), 3.95 (t, J = 4.2Hz, 3H), 3.81 - 3.70 (m, 1H), 2.66 - 2.54 (m, 2H), 2.34 (s, 3H), 2.20 (s, 3H), 2.19 - 2.11 (m, 1H), 1.80 - 1.70 (m, 4H), 1.61 - 1.52 (m, 1H), 1.24 (s, 6H). ESI-MS: m/z 538.3 [M+Na]+. ee=99.8% (手性 HPLC分析条件： Chiralpak IC4.6 mmX 250 mm， 柱温： 25°C ; 流动相： 70%正己垸 /30%异丙醇； 流速： l mL/min; 检测波长： UV254 nm; 保留时间： 16.0 min)。 在以下的实施例中， 如无特殊说明， ee值的检测均采用上述类似的条件。 The compound ΙΠ-2 (160 mg, 0.45 mmoL) was dissolved in DCM (5 mL), triethylamine (0.095 mL) and p-cyanobenzenesulfonyl chloride (92 mg, 0.46 mmoL). The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: 3 ) δ 8.01 - 7.85 (m, 4H), 7.04 (d, J = 7.4 Hz, 1H), 6.71 (d, J = 7.4 Hz, 1H), 6.64 (s, 1H), 5.68 (d, J = 7.1 Hz, 1H), 4.61 - 4.33 (m, 1H), 4.16 - 4.04 (m, 1H), 3.95 (t, J = 4.2Hz, 3H), 3.81 - 3.70 (m, 1H), 2.66 - 2.54 (m, 2H), 2.34 (s, 3H), 2.20 (s, 3H), 2.19 - 2.11 (m, 1H), 1.80 - 1.70 (m, 4H), 1.61 - 1.52 (m, 1H), 1.24 (s, 6H) ESI-MS: m/z 538.3 [M+Na] + . ee=99.8% (Chiral HPLC analysis conditions: Chiralpak IC 4.6 mm X 250 mm, column temperature: 25 ° C; mobile phase: 70% hexane/ 30% isopropanol; flow rate: l mL/min; detection wavelength: UV254 nm ; retention time: 16.0 min). In the following examples, the ee value was detected using the similar conditions as described above unless otherwise specified.
实施例 78  Example 78
4- (2,5-二甲基苯氧基） -N- ( 1- (4-甲氧基苄基） 哌啶 -4-基） 丁酰胺 （化合物 101 ) 参照实施例 1的方法制得化合物 101： 1H NMR (300 MHz, CDC13) δ 7.22 (d, J= 8.5 Hz, 2H), 7.03 (d, J= 7.4 Hz, 1H), 6.69 (d, J= 7.5 Hz, 1H), 6.64 (s, 1H), 5.39 (d, J= 7.7 Hz, 1H), 4.01 (t, J= 5.9 Hz, 2H), 3.82 (s, 4H), 3.43 (s, 2H), 2.77 (d, J = 11.6 Hz, 2H), 2.39 (t, J= 7.3 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.11 (dd, J= 14.5, 8.3 Hz, 4H), 1.90 (d, J= 13.1 Hz, 3H), 1.49 - 1.35 (m, 2H). ESI-MS: m/z 411.0 [M+H]+. 4-(2,5-Dimethylphenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)butanamide (Compound 101) was obtained by the method of Example 1. Compound 101: 1H NMR (300 MHz, CDC1 3 ) δ 7.22 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 7.4 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 6.64 (s, 1H), 5.39 (d, J= 7.7 Hz, 1H), 4.01 (t, J= 5.9 Hz, 2H), 3.82 (s, 4H), 3.43 (s, 2H), 2.77 (d, J = 11.6 Hz, 2H), 2.39 (t, J= 7.3 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.11 (dd, J= 14.5, 8.3 Hz, 4H), 1.90 (d, J = 13.1 Hz, 3H), 1.49 - 1.35 (m, 2H). ESI-MS: m/z 411.0 [M+H] + .
实施例 79  Example 79
4- (2,5-二甲基苯氧基） -N- ( 1- (3-甲氧基苄基） 哌啶 -4-基） 丁酰胺 （化合物 102) 参照实施例 1的方法制得化合物 102: 1H MR (300 MHz, CDC13) δ 7.24 (dd, J= 8.0 Hz, 1H), 7.03 (d, J= 7.4 Hz, 1H), 6.90 (d, J= 4.5 Hz, 2H), 6.82 (dd, J= 8.2 Hz, 1H), 6.69 (d, J= 7.5 Hz, 1H), 6.64 (s, 1H), 5.39 (d, J= 7.6 Hz, 1H), 4.01 (t, J= 5.9 Hz, 2H), 3.88 - 3.76 (m, 4H), 3.47 (s, 2H), 2.85 - 2.71 (m, 2H), 2.40 (t, J = 7.3 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.18 - 2.07 (m, 4H), 1.93 - 1.83 (m, 2H), 1.51 - 1.38 (m, 2H). ESI-MS: m/z 411.1 [M+H]+. 实施例 80 4- (2,5-二甲基苯氧基） -N- ( 1- (苯基磺酰基） 哌啶 -4-基） 丁酰胺 （化合物 103 ) 参照实施例 43的方法制得化合物 103 : 1H NMR (300 MHz, CDC13) δ 7.79 - 7.69 (m, 2H), 7.65 - 7.50 (m, 3H), 6.99 (d, J= 7.5 Hz, 1H), 6.66 (d, J= 7.6 Hz, 1H), 6.60 (s, 1H), 5.46 (d, J= 8.0 Hz, 1H), 3.96 (t, J = 5.9 Hz, 2H), 3.80 - 3.64 (m, 3H), 2.45 - 2.31 (m, 4H), 2.29 (s, 3H), 2.15 (s, 3H), 2.12 - 2.03 (m, 2H), 2.00 - 1.89 (m, 2H), 1.48 (ddd, J= 22.7, 11.4, 3.2 Hz, 2H). ESI-MS: m/z 453.2 [M+Na]+. 4-(2,5-Dimethylphenoxy)-N-(1-(3-methoxybenzyl)piperidin-4-yl)butanamide (Compound 102) was obtained by the method of Example 1. Compound 102: 1H MR (300 MHz, CDC1 3 ) δ 7.24 (dd, J = 8.0 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.90 (d, J = 4.5 Hz, 2H), 6.82 (dd, J= 8.2 Hz, 1H), 6.69 (d, J= 7.5 Hz, 1H), 6.64 (s, 1H), 5.39 (d, J= 7.6 Hz, 1H), 4.01 (t, J= 5.9 Hz , 2H), 3.88 - 3.76 (m, 4H), 3.47 (s, 2H), 2.85 - 2.71 (m, 2H), 2.40 (t, J = 7.3 Hz, 2H), 2.32 (s, 3H), 2.20 ( s, 3H), 2.18 - 2.07 (m, 4H), 1.93 - 1.83 (m, 2H), 1.51 - 1.38 (m, 2H). ESI-MS: m/z 411.1 [M+H] + . 4-(2,5-Dimethylphenoxy)-N-(1-(phenylsulfonyl)piperidin-4-yl)butanamide (Compound 103) Compound 103 was obtained according to the procedure of Example 43: 1H NMR (300 MHz, CDC1 3 ) δ 7.79 - 7.69 (m, 2H), 7.65 - 7.50 (m, 3H), 6.99 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H ), 6.60 (s, 1H), 5.46 (d, J = 8.0 Hz, 1H), 3.96 (t, J = 5.9 Hz, 2H), 3.80 - 3.64 (m, 3H), 2.45 - 2.31 (m, 4H) , 2.29 (s, 3H), 2.15 (s, 3H), 2.12 - 2.03 (m, 2H), 2.00 - 1.89 (m, 2H), 1.48 (ddd, J= 22.7, 11.4, 3.2 Hz, 2H). ESI -MS: m/z 453.2 [M+Na] + .
实施例 81  Example 81
N- ( 1-苄基哌啶 -4-基） -4- ( 5-异丙基 -2-甲基苯氧基） 丁酰胺 (化合物 104) 参照实施例 1的方法制得化合物 104: 1H MR (300 MHz, CDC13) δ 7.39 - 7.27 (m, 5H), 7.10 (d, J= 7.6 Hz, 1H), 6.78 (d, J= 7.6 Hz, 1H), 6.72 (s, 1H), 5.45 (d, J= 7.7 Hz, 1H), 4.05 (t, J = 5.8 Hz, 2H), 3.93 - 3.78 (m, 1H), 3.51 (s, 2H), 2.93 - 2.85 (m, 1H), 2.85 - 2.76 (m, 2H), 2.43 (t, J= 7.2 Hz, 2H), 2.23 (s, 3H), 2.20 - 2.09 (m, 4H), 1.97 - 1.86 (m, 2H), 1.53 - 1.36 (m, 2H), 1.27 (d, J= 6.9 Hz, 6H). ESI-MS: m/z 409.0 [M+H]+. N-(1-Benzylpiperidin-4-yl)-4-(5-isopropyl-2-methylphenoxy)butanamide (Compound 104) Compound 104 was obtained according to the procedure of Example 1: 1H MR (300 MHz, CDC1 3 ) δ 7.39 - 7.27 (m, 5H), 7.10 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 5.45 (d, J = 7.7 Hz, 1H), 4.05 (t, J = 5.8 Hz, 2H), 3.93 - 3.78 (m, 1H), 3.51 (s, 2H), 2.93 - 2.85 (m, 1H), 2.85 - 2.76 (m, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.23 (s, 3H), 2.20 - 2.09 (m, 4H), 1.97 - 1.86 (m, 2H), 1.53 - 1.36 (m, 2H), 1.27 (d, J = 6.9 Hz, 6H). ESI-MS: m/z 409.0 [M+H] + .
实施例 82  Example 82
N- ( 1- (4-氰基苄基）哌啶 -4-基） -4- ( 5-异丙基 -2-甲基苯氧基）丁酰胺 (化合物 105) 参照实施例 1的方法制得化合物 105: 1H NMR (300 MHz, CDC13) δ 7.63 (d, J= 8.2 Hz, 2H), 7.46 (d, J= 8.0 Hz, 2H), 7.09 (d, J= 7.5 Hz, 1H), 6.78 (d, J= 7.6 Hz, 1H), 6.71 (s, 1H), 5.43 (d, J = 7.7 Hz, 1H), 4.05 (t, J = 5.8 Hz, 2H), 3.95 - 3.78 (m, 1H), 3.54 (s, 2H), 2.94 - 2.82 (m, 1H), 2.8-2.7 (m, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.23 (s, 3H), 2.25-2.15 (m, 4H), 1.97-1.87 (m, 2H), 1.50 - 1.37 (m, 2H), 1.26 (d, J= 6.9 Hz, 6H). ESI-MS: m/z 434.2 [M+H]+. 实施例 83 N-(1-(4-Cyanobenzyl)piperidin-4-yl)-4-(5-isopropyl-2-methylphenoxy)butanamide (Compound 105) Refer to the method of Example 1. Compound 105: 1H NMR (300 MHz, CDC1 3 ) δ 7.63 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 7.5 Hz, 1H) , 6.78 (d, J= 7.6 Hz, 1H), 6.71 (s, 1H), 5.43 (d, J = 7.7 Hz, 1H), 4.05 (t, J = 5.8 Hz, 2H), 3.95 - 3.78 (m, 1H), 3.54 (s, 2H), 2.94 - 2.82 (m, 1H), 2.8-2.7 (m, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.23 (s, 3H), 2.25-2.15 (m, 4H), 1.97-1.87 (m, 2H), 1.50 - 1.37 (m, 2H), 1.26 (d, J = 6.9 Hz, 6H). ESI-MS: m/z 434.2 [M+H] + Example 83
4- ( 5-异丙基 -2-甲基苯氧基） -N- ( 1- (4-甲氧基苄基） 哌啶 -4-基） 丁酰胺 （化合物 106)  4-(5-isopropyl-2-methylphenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)butanamide (Compound 106)
参照实施例 1的方法制得化合物 106: 1H NMR (300 MHz, CDC13) δ 7.24 (d, J= 8.6 Hz, 2H), 7.09 (d, J= 7.6 Hz, 1H), 6.89 (d, J= 8.7 Hz, 2H), 6.78 (dd,J= 7.5Hz,1.5Hz,lH), 6.71 (d, 1H), 5.40 (d, J= 7.8 Hz, 1H), 4.05 (t, J= 5.9 Hz, 2H), 3.89 - 3.80 (m, 4H), 3.44 (s, 2H), 2.95 - 2.85 (m, 1H), 2.83 - 2.73 (m, 2H), 2.42 (t, J = 7.3 Hz, 2H), 2.23 (s, 3H), 2.21 - 2.06 (m, 4H), 1.97 - 1.83 (m, 3H), 1.49 - 1.37 (m, 2H), 1.27 (d, J= 6.9 Hz, 6H). ESI-MS: m/z 439.2 [M+H]+. Compound 106 was prepared by the method of Example 1: 1H NMR (300 MHz, CDC1 3 ) δ 7.24 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 6.78 (dd, J = 7.5 Hz, 1.5 Hz, lH), 6.71 (d, 1H), 5.40 (d, J = 7.8 Hz, 1H), 4.05 (t, J = 5.9 Hz, 2H), 3.89 - 3.80 (m, 4H), 3.44 (s, 2H), 2.95 - 2.85 (m, 1H), 2.83 - 2.73 (m, 2H), 2.42 (t, J = 7.3 Hz, 2H), 2.23 (s, 3H), 2.21 - 2.06 (m, 4H), 1.97 - 1.83 (m, 3H), 1.49 - 1.37 (m, 2H), 1.27 (d, J = 6.9 Hz, 6H). ESI-MS: m /z 439.2 [M+H] + .
实施例 84  Example 84
N- ( 1- (4-氰基苄基） 哌啶 -4-基） -4- (2,5-二氯苯氧基） 丁酰胺 （化合物 107) 参照实施例 1的方法制得化合物 107: 1H NMR (300 MHz, CDC13) δ 7.60 (d, J= 8.2 Hz, 2H), 7.42 (d, J= 8.2 Hz, 2H), 7.29 (d, J= 5.1 Hz, 1H), 6.91 (s, 1H), 6.88 (d, J = 2.2 Hz, 1H), 5.48 (d, J = 7.5 Hz, 1H), 4.06 (t, J = 5.8 Hz, 2H), 3.89 - 3.70 (m, 1H), 3.50 (s, 2H), 2.78 - 2.67 (m, 2H), 2.42 (t, J = 7.1 Hz, 2H), 2.22 - 2.09 (m, 4H), 1.92 - 1.81 (m, 2H), 1.43 - 1.31 (m, 2H). ESI-MS: m/z 446.3 [M+H]+. N-(1-(4-Cyanobenzyl)piperidin-4-yl)-4-(2,5-dichlorophenoxy)butanamide (Compound 107) Compound 107 was obtained by the procedure of Example 1. : 1H NMR (300 MHz, CDC1 3 ) δ 7.60 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 5.1 Hz, 1H), 6.91 (s , 1H), 6.88 (d, J = 2.2 Hz, 1H), 5.48 (d, J = 7.5 Hz, 1H), 4.06 (t, J = 5.8 Hz, 2H), 3.89 - 3.70 (m, 1H), 3.50 (s, 2H), 2.78 - 2.67 (m, 2H), 2.42 (t, J = 7.1 Hz, 2H), 2.22 - 2.09 (m, 4H), 1.92 - 1.81 (m, 2H), 1.43 - 1.31 (m, 2H). ESI-MS: m/z 446.3 [M+H] + .
实施例 85  Example 85
4- (2,5-二氯苯氧基） -N- ( 1- (4-甲氧基苄基） 哌啶 -4-基） 丁酰胺 （化合物 99) 参照实施例 1的方法制得化合物 99: 1H NMR (300 MHz, CDC13) δ 7.28 (d, J= 6.5 Hz, 2H), 7.20 (d, J= 8.6 Hz, 2H), 6.90 (s, 1H), 6.88 - 6.82 (m, 2H), 5.46 (d, J= 7.9 Hz, 1H), 4.05 (t, J = 5.8 Hz, 2H), 3.85 - 3.73 (m, 4H), 3.40 (s, 2H), 2.80 - 2.70 (m, 2H) 2.41 (t, J= 7.0 Hz, 2H), 2.23 - 2.14 (m, 2H), 1.90 - 1.73 (m, 4H), 1.43 - 1.33 (m, 2H). ESI-MS: m/z 451.2 [M+H]+. 4-(2,5-Dichlorophenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)butanamide (Compound 99) Compound obtained according to the procedure of Example 1 99: 1H NMR (300 MHz, CDC1 3 ) δ 7.28 (d, J = 6.5 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 6.90 (s, 1H), 6.88 - 6.82 (m, 2H ), 5.46 (d, J = 7.9 Hz, 1H), 4.05 (t, J = 5.8 Hz, 2H), 3.85 - 3.73 (m, 4H), 3.40 (s, 2H), 2.80 - 2.70 (m, 2H) 2.41 (t, J = 7.0 Hz, 2H), 2.23 - 2.14 (m, 2H), 1.90 - 1.73 (m, 4H), 1.43 - 1.33 (m, 2H). ESI-MS: m/z 451.2 [M+ H] + .
实施例 86  Example 86
4 - ( (4- ( 5- (2,5-二甲基苯氧基） 戊基） 哌啶 -1-基） 甲基） 苯甲酰胺 （化合物 100) 参照实施例 1的方法制得化合物 100: 1H MR (300 MHz, OMSO-d6) δ 7.88 (s, 1H),4-((4-(5-(2,5-Dimethylphenoxy)pentyl)piperidin-1-yl)methyl)benzamide (Compound 100) The compound was obtained by the method of Example 1 100: 1H MR (300 MHz, OMSO-d 6 ) δ 7.88 (s, 1H),
7.80 (d, J = 7.5 Hz, 2H), 7.68 (d, J = 7.3 Hz, 1H), 7.32 (d, J = 7.3 Hz, 2H), 7.25 (s, 1H), 6.95 (d,J=7.5Hz, 1H), 6.69 (s, 1H), 6.59 (d, J= 7.4 Hz, 1H), 3.90 (t,J=6.0Hz, 2H), 3.56 - 3.42 (m, 3H), 2.75 - 2.64 (m, 2H), 2.22 (s, 3H), 2.13 - 1.91 (m, 7H), 1.71 - 1.56 (m, 6H), 1.39 - 1.29 (m, 2H). ESI-MS: m/z 438.2 [M+H]+. 7.80 (d, J = 7.5 Hz, 2H), 7.68 (d, J = 7.3 Hz, 1H), 7.32 (d, J = 7.3 Hz, 2H), 7.25 (s, 1H), 6.95 (d, J=7.5 Hz, 1H), 6.69 (s, 1H), 6.59 (d, J= 7.4 Hz, 1H), 3.90 (t, J=6.0Hz, 2H), 3.56 - 3.42 (m, 3H), 2.75 - 2.64 (m , 2H), 2.22 (s, 3H), 2.13 - 1.91 (m, 7H), 1.71 - 1.56 (m, 6H), 1.39 - 1.29 (m, 2H). ESI-MS: m/z 438.2 [M+H ] + .
实施例 87  Example 87
5- ( 2,5-二甲基苯氧基） -N- ( 1- ( ( 4-氟苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊 酰胺 （化合物 108 )  5-(2,5-Dimethylphenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound) 108)
参照实施例 43的方法制得化合物 108: 1H MR (300 MHz, CDC13) δ 7.77 (m, 2H), 7.21 (dd, J = 8.6 Hz, 8.6 Hz, 2H), 7.00 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 6.59 (s, 1H), 5.44 (d, J= 8.1 Hz, 1H), 3.90 (t, J= 5.1 Hz, 2H), 3.80 - 3.67 (m, 3H), 2.40 (m, 2H), 2.29 (s, 3H), 2.16 (s, 3H), 2.01 - 1.91 (m, 2H), 1.73 - 1.65 (m, 4H), 1.52 - 1.41 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 529.2 [M+K]+. Compound 108 was prepared by the method of Example 43: 1H MR (300 MHz, CDC1 3 ) δ 7.77 (m, 2H), 7.21 (dd, J = 8.6 Hz, 8.6 Hz, 2H), 7.00 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 6.59 (s, 1H), 5.44 (d, J = 8.1 Hz, 1H), 3.90 (t, J = 5.1 Hz, 2H), 3.80 - 3.67 (m, 3H), 2.40 (m, 2H), 2.29 (s, 3H), 2.16 (s, 3H), 2.01 - 1.91 (m, 2H), 1.73 - 1.65 (m, 4H), 1.52 - 1.41 ( m, 2H), 1.17 (s, 6H). ESI-MS: m/z 529.2 [M+K] + .
实施例 88  Example 88
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- ( (4-硝基苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 （化合物 109)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-((4-nitrophenyl)sulfonyl)piperidin-4-yl)pentanamide ( Compound 109)
参照实施例 43的方法制得化合物 109: 1H NMR (300 MHz, CDC13) δ 8.41 (d, J= 8.8 Hz, 2H), 7.97 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 7.4 Hz, 1H), 6.69 (d, J = 7.4 Hz, 1H), 6.62 (s, 1H), 5.51 (d, J = 7.2 Hz, 1H), 3.97 - 3.72 (m, 5H), 2.58 - 2.44 (m, 2H), 2.32 (s, 3H), 2.19 (s, 3H), 2.01 (d, J = 12.2 Hz, 2H), 1.77 - 1.66 (m, 4H), 1.56 - 1.44 (m, 2H), 1.21 (s, 6H). ESI-MS: m/z 540.2 [M+Na]+. The compound 109 was obtained by the method of Example 43: 1H NMR (300 MHz, CDC1 3 ) δ 8.41 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 7.4 Hz, 1H), 6.69 (d, J = 7.4 Hz, 1H), 6.62 (s, 1H), 5.51 (d, J = 7.2 Hz, 1H), 3.97 - 3.72 (m, 5H), 2.58 - 2.44 (m, 2H), 2.32 (s, 3H), 2.19 (s, 3H), 2.01 (d, J = 12.2 Hz, 2H), 1.77 - 1.66 (m, 4H), 1.56 - 1.44 (m, 2H), 1.21 (s, 6H). ESI-MS: m/z 540.2 [M+Na] + .
实施例 89  Example 89
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- (苯基磺酰基） 哌啶 -4-基） 戊酰胺 （化 合物 110) 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(phenylsulfonyl)piperidin-4-yl)pentanamide Compound 110)
参照实施例 43的方法制得化合物 110: 1H NMR (300 MHz, CDC13) δ 7.78 (d, J= 8.1 Hz, 2H), 7.67 - 7.53 (m, 3H), 7.03 (d, J = 7.3 Hz, 1H), 6.69 (d, J= 7.2 Hz, 1H), 6.62 (s, 1H), 5.51 (d, J = 7.6 Hz, 1H), 3.92 (t, J = 5.3 Hz, 2H), 3.83 - 3.68 (m, 3H), 2.48 - 2.35 (m, 2H),2.32 (s, 3H), 2.19 (s, 3H), 2.03 - 1.91 (m, 2H), 1.76 - 1.64 (m, 4H), 1.55 - 1.44 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 473.2 [M+H]+. The compound 110 was obtained by the method of Example 43: 1H NMR (300 MHz, CDC1 3 ) δ 7.78 (d, J = 8.1 Hz, 2H), 7.67 - 7.53 (m, 3H), 7.03 (d, J = 7.3 Hz , 1H), 6.69 (d, J= 7.2 Hz, 1H), 6.62 (s, 1H), 5.51 (d, J = 7.6 Hz, 1H), 3.92 (t, J = 5.3 Hz, 2H), 3.83 - 3.68 (m, 3H), 2.48 - 2.35 (m, 2H), 2.32 (s, 3H), 2.19 (s, 3H), 2.03 - 1.91 (m, 2H), 1.76 - 1.64 (m, 4H), 1.55 - 1.44 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 473.2 [M+H] + .
实施例 90  Example 90
N- ( 1 - ( (4-氰基苯基） 磺酰基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基） -2,2-二甲基 戊酰胺 （化合物 111 )  N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide Compound 111)
参照实施例 43的方法制得化合物 111： 1H NMR (300 MHz, CDC13) δ 7.91 - 7.81 (m, 4H), 7.02 (d, J= 7.4 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 6.61 (s, 1H), 5.49 (d, J = 7.5 Hz, 1H), 3.92 (t, J = 5.1 Hz, 2H), 3.85 - 3.71 (m, 3H), 2.57 - 2.43 (m, 2H), 2.31 (s, 3H), 2.18 (s, 3H), 2.04 - 1.94 (m, 2H), 1.76 - 1.65 (m, 4H), 1.55 - 1.43 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 520.2 [M+Na]+. The compound 111 was obtained by the method of Example 43: 1H NMR (300 MHz, CDC1 3 ) δ 7.91 - 7.81 (m, 4H), 7.02 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 7.5 Hz , 1H), 6.61 (s, 1H), 5.49 (d, J = 7.5 Hz, 1H), 3.92 (t, J = 5.1 Hz, 2H), 3.85 - 3.71 (m, 3H), 2.57 - 2.43 (m, 2H), 2.31 (s, 3H), 2.18 (s, 3H), 2.04 - 1.94 (m, 2H), 1.76 - 1.65 (m, 4H), 1.55 - 1.43 (m, 2H), 1.20 (s, 6H) ESI-MS: m/z 520.2 [M+Na] + .
实施例 91  Example 91
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (三氟甲基） 苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 （化合物 112)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-yl Pentanoamide (Compound 112)
参照实施例 43的方法制得化合物 112: 1H NMR (300 MHz, CDC13) δ 7.88 (d, J= 8.0 Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 7.4 Hz, 1H), 6.66 (d, J = 7.2 Hz, 1H), 6.58 (s, 1H), 5.45 (d, J= 7.4 Hz, 1H), 3.90 (t, J=6.0Hz, 2H), 3.85 - 3.67 (m, 3H), 2.51 - 2.38 (m, 2Ά), 2.29 (s, 3H), 2.16 (s, 3H), 2.02 - 1.91 (m, 2H), 1.73 - 1.61 (m, 4H), 1.51 - 1.39 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 563.2 [M+Na]+. The compound 112 was obtained by the method of Example 43: 1H NMR (300 MHz, CDC1 3 ) δ 7.88 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 7.4 Hz, 1H), 6.66 (d, J = 7.2 Hz, 1H), 6.58 (s, 1H), 5.45 (d, J = 7.4 Hz, 1H), 3.90 (t, J=6.0Hz, 2H), 3.85 - 3.67 (m, 3H), 2.51 - 2.38 (m, 2Ά), 2.29 (s, 3H), 2.16 (s, 3H), 2.02 - 1.91 (m, 2H), 1.73 - 1.61 (m, 4H), 1.51 - 1.39 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 563.2 [M+Na] + .
实施例 92  Example 92
5- (2,5-二甲基苯氧基) -N- ( 1- ( (4-甲氧基苯基)磺酰基） 哌啶 -4-基） -2,2-二甲基 戊酰胺 （化合物 113 )  5-(2,5-Dimethylphenoxy)-N-(1-((4-methoxyphenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 113)
参照实施例 43的方法制得化合物 113 : 1H NMR (300 MHz, CDC13) δ 7.64 (d, J= 8.8 Hz, 2H), 6.96 (d, J = 8.6 Hz, 3H), 6.62 (d, J = 7.5 Hz, 1H), 6.55 (s, 1H), 5.49 (d, J = 7.8 Hz, 1H), 3.88 - 3.82 (m, 5H), 3.75 - 3.60 (m, 3H), 2.38 - 2.27 (m, 2H), 2.25 (s, 3H), 2.12 (s, 3H), 1.95 - 1.84 (m, 2H), 1.71 - 1.61 (m, 4H), 1.53 - 1.39 (m, 2H), 1.13 (s, 6H). ESI-MS: m/z 525.2 [M+Na]+. The compound 113 was obtained by the method of Example 43: 1H NMR (300 MHz, CDC1 3 ) δ 7.64 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.6 Hz, 3H), 6.62 (d, J = 7.5 Hz, 1H), 6.55 (s, 1H), 5.49 (d, J = 7.8 Hz, 1H), 3.88 - 3.82 (m, 5H), 3.75 - 3.60 (m, 3H), 2.38 - 2.27 (m, 2H), 2.25 (s, 3H), 2.12 (s, 3H), 1.95 - 1.84 (m, 2H), 1.71 - 1.61 (m, 4H), 1.53 - 1.39 (m, 2H), 1.13 (s, 6H) ESI-MS: m/z 525.2 [M+Na] + .
实施例 93  Example 93
N- ( 1- ( (4-氯苯基)磺酰基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰 胺 （化合物 114)  N-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (compound) 114)
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Z.9ZC80/8T0ZN3/X3d I9^6l/810Z OAV J = 7.5 Hz, 1H), 3.97 (s, 3H), 3.89 (t, J = 5.2 Hz, 2H), 3.84 - 3.76 (m, 2H), 3.74 - 3.63 (m, 1H), 2.49 - 2.37 (m, 2H), 2.29 (s, 3H), 2.16 (s, 3H), 2.02 - 1.91 (m, 2H), 1.74 - 1.62 (m, 4H), 1.51 - 1.38 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 553.3 [M+Na]+. Z.9ZC80/8T0ZN3/X3d I9^6l/810Z OAV J = 7.5 Hz, 1H), 3.97 (s, 3H), 3.89 (t, J = 5.2 Hz, 2H), 3.84 - 3.76 (m, 2H), 3.74 - 3.63 (m, 1H), 2.49 - 2.37 (m , 2H), 2.29 (s, 3H), 2.16 (s, 3H), 2.02 - 1.91 (m, 2H), 1.74 - 1.62 (m, 4H), 1.51 - 1.38 (m, 2H), 1.17 (s, 6H ESI-MS: m/z 553.3 [M+Na] + .
实施例 98  Example 98
4 - ( (4- ( 5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰氨基） 哌啶 -1-基） 磺酰基） 苯甲 酸 （化合物 119)  4-((4-(5,5-Dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 119)
取化合物 118 (400 mg, 0.75 mmoL) 溶于甲醇和四氢呋喃 （5: 1， 24 mL), 加入 IN NaOH (2 mL), 室温搅拌过夜。 减压蒸除溶剂， 加 IN HC1调至酸性， 有白色固体 析出， 过滤， 水洗， 收集白色固体， 加 20 mL石油醚搅拌 2h， 抽滤， 真空干燥， 得化 合物 119 (白色固体， 380 mg， 收率 98%): 1H NMR (300 MHz, CDC13) δ 13.47 (br s, 1H), 8.17 (d, J= 8.3 Hz, 2H), 7.86 (d, J= 8.2 Hz, 2H), 7.22 (d, J= 7.6 Hz, 1H), 6.98 (d, J= 7.4 Hz, 1H), 6.69 (s, 1H), 6.63 (d, J= 7.5 Hz, 1H), 3.87 (t, J= 6.0Hz, 2H), 3.67 - 3.51 (m, 3H), 2.47 - 2.34 (m, 2H), 2.24 (s, 3H), 2.09 (s, 3H), 1.76-1.67 (m, 2H), 1.61 - 1.41 (m, 6H), 1.07 (s, 6H). ESI-MS: m/z 539.2 [M+Na]+. Compound 118 (400 mg, 0.75 mmol) was dissolved in methanol and THF (5:1, 24 mL). The solvent was evaporated under reduced pressure. EtOAc EtOAc (EtOAc: EtOAc, EtOAc, EtOAc Yield 98%): 1H NMR (300 MHz, CDC1 3 ) δ 13.47 (br s, 1H), 8.17 (d, J = 8.3 Hz, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.22 ( d, J= 7.6 Hz, 1H), 6.98 (d, J= 7.4 Hz, 1H), 6.69 (s, 1H), 6.63 (d, J= 7.5 Hz, 1H), 3.87 (t, J= 6.0Hz, 2H), 3.67 - 3.51 (m, 3H), 2.47 - 2.34 (m, 2H), 2.24 (s, 3H), 2.09 (s, 3H), 1.76-1.67 (m, 2H), 1.61 - 1.41 (m, 6H), 1.07 (s, 6H). ESI-MS: m/z 539.2 [M+Na] + .
实施例 99  Example 99
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 戊酰胺 (化合物 120)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide (Compound 120)
参照实施例 43的方法制得化合物 120: 1H NMR (300 MHz, CDC13) δ 9.01 (d, J= 1.5 Hz, 1H), 8.85 (dd, J = 5.1, 1.5 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.51 (dd, J = 7.8, 5.1 Hz, 1H), 7.02 (d, J= 7.5 Hz, 1H), 6.68 (d, J= 7.4 Hz, 1H), 6.61 (s, 1H), 5.48 (d, J= 7.4 Hz, 1H), 3.91 (t, J= 5.2 Hz, 2H), 3.90-3.65 (m, 3H), 2.49 (m, 2H), 2.31 (s, 3H), 2.18 (s, 3H), 2.00 (m, 2H), 1.76 - 1.66 (m, 4H), 1.58 - 1.44 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 474.2 [M+H]+. 实施例 100 Compound 120 was prepared by the method of Example 43: 1H NMR (300 MHz, CDC1 3 ) δ 9.01 (d, J = 1.5 Hz, 1H), 8.85 (dd, J = 5.1, 1.5 Hz, 1H), 8.06 (d , J = 8.0 Hz, 1H), 7.51 (dd, J = 7.8, 5.1 Hz, 1H), 7.02 (d, J= 7.5 Hz, 1H), 6.68 (d, J= 7.4 Hz, 1H), 6.61 (s , 1H), 5.48 (d, J= 7.4 Hz, 1H), 3.91 (t, J= 5.2 Hz, 2H), 3.90-3.65 (m, 3H), 2.49 (m, 2H), 2.31 (s, 3H) , 2.18 (s, 3H), 2.00 (m, 2H), 1.76 - 1.66 (m, 4H), 1.58 - 1.44 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 474.2 [M +H] + . Example 100
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (三氟甲氧基） 苯基） 磺酰基） 哌啶—4-基） 戊酰胺 （化合物 121 )  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)piperidine- 4- Ethyl pentamide (compound 121)
参照实施例 43的方法制得化合物 121： 1H NMR (300 MHz, CDC13) δ 7.84 (d, J= 8.7 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 7.04 (d, J= 7.4 Hz, 1H), 6.70 (d, J= 7.5 Hz, 1H), 6.63 (s, 1H), 5.57 (d, J= 7.5 Hz, 1H), 3.94 (t, J = 4.9 Hz, 2H), 3.88 - 3.72 (m, 3H), 2.53 - 2.40 (m, 2H), 2.33 (s, 3H), 2.20 (s, 3H), 2.06 - 1.96 (m, 2H), 1.77 - 1.68 (m, 4H), 1.63 - 1.47 (m, 2H), 1.21 (s, 6H). ESI-MS: m/z 579.3 [M+Na]+. The compound 121 was obtained by the method of Example 43: 1H NMR (300 MHz, CDC1 3 ) δ 7.84 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 7.04 (d, J = 7.4 Hz, 1H), 6.70 (d, J= 7.5 Hz, 1H), 6.63 (s, 1H), 5.57 (d, J= 7.5 Hz, 1H), 3.94 (t, J = 4.9 Hz, 2H), 3.88 - 3.72 (m, 3H), 2.53 - 2.40 (m, 2H), 2.33 (s, 3H), 2.20 (s, 3H), 2.06 - 1.96 (m, 2H), 1.77 - 1.68 (m, 4H), 1.63 - 1.47 (m, 2H), 1.21 (s, 6H). ESI-MS: m/z 579.3 [M+Na] + .
实施例 101  Example 101
N- (2- (二甲基氨基） 乙基） -4 - ( (4- ( 5- (2,5-二甲基苯氧基） -2,2- 二甲基戊酰 胺基） 哌啶 -1-基） 磺酰基） 苯甲酰胺 （化合物 122)  N-(2-(Dimethylamino)ethyl)-4-(-(4-(5,5-dimethylphenoxy)-2,2-dimethylpentanoyl)piperidine -1-yl)sulfonyl)benzamide (Compound 122)
将化合物 119 (100 mg, 0.19 mmoL)、HATU (111 mg, 0.29 mmoL)禾口 DIPEA(0.16 mL) 溶于无水 DMF ( 5 mL)， 室温搅拌 30 min， 加入 Ν,Ν-二甲基二乙胺 （0.032 mL)， 室温 搅拌 4 ho加水（20 mL)淬灭反应， 乙酸乙酯 （10 mL x3)萃取，有机相用饱和氯化钠（20 mL) 和水 (20 mL)洗涤， 无水硫酸钠干燥， 过滤， 减压蒸除溶剂。 残余物经柱层析 （洗 脱剂： 二氯甲焼 /甲醇 /三乙胺 =50: 1 : 1 )纯化， 所得油状物加入盐酸-乙醇饱和溶液， 搅拌 30 min。 减压蒸除溶剂， 残余物用甲醇 -乙醚结晶， 得化合物 122的盐酸盐 （白色固体， 70 mg， 收率 63%): 1H MR (300 MHz, CDC13) δ 7.98 (d, J= 8.3 Hz, 2H), 7.81 (d, J= 8.3 Hz, 2H), 7.21 (br s, 1H), 7.00 (d, J= 7.4 Hz, 1H), 6.66 (d, J= 7.5 Hz, 1H), 6.59 (s, 1H), 5.52 (d, J = 7.8 Hz, 1H), 3.89 (t, J = 5.3 Hz, 2H), 3.83 - 3.75 (m, 2H), 3.74 - 3.65 (m, 1H), 3.58 (dd, J= 11.0, 5.2 Hz, 2H), 2.63 (t, J= 5.7 Hz, 2H), 2.49 - 2.38 (m, 2H), 2.38 - 2.32 (m, 6H), 2.29 (s, 3H), 2.16 (s, 3H), 1.99 - 1.90 (m, 2H), 1.76 - 1.61 (m, 4H), 1.55 - 1.41 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 587.3 [M+H]+. Compound 119 (100 mg, 0.19 mmoL), HATU (111 mg, 0.29 mmoL) and DIPEA (0.16 mL) Dissolve in anhydrous DMF (5 mL), stir at room temperature for 30 min, add hydrazine, dimethyl-dimethyldiethylamine (0.032 mL), stir at room temperature 4 hr with water (20 mL), ethyl acetate (10 mL) The extract was washed with saturated sodium chloride (20 mL) and water (20 mL). The residue was purified by column chromatography (EtOAc:EtOAc:EtOAc:EtOAc The solvent was distilled off under reduced pressure, the residue was treated with methanol - crystallized from diethyl ether to afford the hydrochloride salt of compound 122 (white solid, 70 mg, yield 63%): 1H MR (300 MHz, CDC1 3) δ 7.98 (d, J = 8.3 Hz, 2H), 7.81 (d, J= 8.3 Hz, 2H), 7.21 (br s, 1H), 7.00 (d, J= 7.4 Hz, 1H), 6.66 (d, J= 7.5 Hz, 1H), 6.59 (s, 1H), 5.52 (d, J = 7.8 Hz, 1H), 3.89 (t, J = 5.3 Hz, 2H), 3.83 - 3.75 (m, 2H), 3.74 - 3.65 (m, 1H), 3.58 (dd, J = 11.0, 5.2 Hz, 2H), 2.63 (t, J = 5.7 Hz, 2H), 2.49 - 2.38 (m, 2H), 2.38 - 2.32 (m, 6H), 2.29 (s, 3H), 2.16 (s, 3H), 1.99 - 1.90 (m, 2H), 1.76 - 1.61 (m, 4H), 1.55 - 1.41 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 587.3 [ M+H] + .
实施例 102  Example 102
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (4-甲基哌嗪 -1-羰基） 苯基） 磺 酰基） 哌啶 -4-基） 戊酰胺 （化合物 123 )  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-((4-(4-methylpiperazin-1-carbonyl)phenyl)sulfonyl) Piperidin-4-yl)pentanamide (compound 123)
参照实施例 101的方法制得化合物 123的盐酸盐： 1H NMR (300 MHz, CDC13) δ 13.75 (s, 1H), 7.84 (d, J= 7.8 Hz, 2H), 7.60 (d, J= 7.8 Hz, 2H), 7.00 (d,J=7.3Hz , 1H), 6.66 (d, J = 7.3 Hz, 1H), 6.59 (s, 1H), 5.49 (d, J = 7.6 Hz, 1H), 3.89 (t, J = 4.8 Hz, 2H), 3.85 - 3.77 (m, 2H), 3.76 - 3.66 (m, 1H), 3.48 (s, 3H), 2.84 (s, 4H), 2.52 - 2.39 (m, 2H), 2.29 (s, 3H), 2.22 - 2.10 (m, 7H), 2.01 - 1.92 (m, 2H), 1.75 - 1.63 (m, 4H), 1.55 - 1.44 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 621.2 [M+Na]+. The hydrochloride salt of Compound 123 was obtained by the method of Example 101: 1H NMR (300 MHz, CDC1 3 ) δ 13.75 (s, 1H), 7.84 (d, J = 7.8 Hz, 2H), 7.60 (d, J = 7.8 Hz, 2H), 7.00 (d, J = 7.3 Hz, 1H), 6.66 (d, J = 7.3 Hz, 1H), 6.59 (s, 1H), 5.49 (d, J = 7.6 Hz, 1H), 3.89 (t, J = 4.8 Hz, 2H), 3.85 - 3.77 (m, 2H), 3.76 - 3.66 (m, 1H), 3.48 (s, 3H), 2.84 (s, 4H), 2.52 - 2.39 (m, 2H ), 2.29 (s, 3H), 2.22 - 2.10 (m, 7H), 2.01 - 1.92 (m, 2H), 1.75 - 1.63 (m, 4H), 1.55 - 1.44 (m, 2H), 1.18 (s, 6H ESI-MS: m/z 621.2 [M+Na] + .
实施例 103  Example 103
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- (萘 -2-基磺酰基）哌啶 -4-基）戊酰胺（化 合物 124)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(naphthalen-2-ylsulfonyl)piperidin-4-yl)pentanamide (Compound 124)
参照实施例 43的方法制得化合物 124: 1H MR (300 MHz, CDC13) δ 8.33 (s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.92 (d, J = 7.7 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.70 - 7.59 (m, 2H), 6.99 (d, J= 7.4 Hz, 1H), 6.65 (d, J= 7.4 Hz, 1H), 6.57 (s, 1H), 5.46 (d, J= 7.4 Hz, 1H), 3.92 - 3.79 (m, 4H), 3.78 - 3.62 (m, 1H), 2.55 - 2.41 (m, 2H), 2.28 (s, 3H), 2.15 (s, 3H), 2.00 - 1.89 (m, 2H), 1.72 - 1.60 (m, 4H), 1.55 - 1.41 (m, 2H), 1.16 (s, 6H). ESI-MS: m/z 545.3 [M+Na]+. Compound 124 was prepared by the method of Example 43: 1H MR (300 MHz, CDC1 3 ) δ 8.33 (s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.92 (d, J = 7.7 Hz, 1H ), 7.73 (d, J = 8.7 Hz, 1H), 7.70 - 7.59 (m, 2H), 6.99 (d, J = 7.4 Hz, 1H), 6.65 (d, J = 7.4 Hz, 1H), 6.57 (s , 1H), 5.46 (d, J = 7.4 Hz, 1H), 3.92 - 3.79 (m, 4H), 3.78 - 3.62 (m, 1H), 2.55 - 2.41 (m, 2H), 2.28 (s, 3H), 2.15 (s, 3H), 2.00 - 1.89 (m, 2H), 1.72 - 1.60 (m, 4H), 1.55 - 1.41 (m, 2H), 1.16 (s, 6H). ESI-MS: m/z 545.3 [ M+Na] + .
实施例 104  Example 104
N- ( 1- (4-氰基苯甲酰基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 (化合物 125 )
Figure imgf000074_0001
取 4-氰基苯甲酸 （80 mg， 0.54 mmol) 加二氯甲垸 （5 mL) 溶解， 冰浴下滴加草酰 氯 （54 μί， 0.63 mmol), 再加两滴 DMF， 自然升温至室温。 搅拌 5 h后再次冰浴冷却， 加入三乙胺 ( 125 μί)， 搅拌 5分钟后加入化合物 ΙΙ-3 (实施例 26， 150 mg, 0.45 mmol), 自然升温至室温。 待反应完全后， 将反应液浓缩， 加饱和碳酸钠水溶液（10 mL)， 二氯 甲垸 （3x10 mL) 萃取。 有机相依次用饱和碳酸氢钠 （10 mL)、 水 （5 mL) 和饱和氯化 钠溶液 （5 mL)洗涤， 无水硫酸钠干燥。 减压蒸除溶剂， 残余物经柱层析 （洗脱剂： 二 氯甲垸 /甲醇 =50: 1 )纯化，得化合物 125 (白色固体， 154 mg， 收率 74%): 1H MR (300 MHz, CDC13) δ 7.71 (d, J = 7.5 Hz, 2H), 7.48 (d, J = 7.5 Hz, 2H), 7.00 (d, J= 6.9 Hz, 1H), 6.66 (d, J = 7.0 Hz, 1H), 6.60 (s, 1H), 5.52 (d, J = 6.1 Hz, 1H), 4.76 - 4.52 (m, 1H), 4.13 - 3.97 (m, 1H), 3.98 - 3.85 (m, 2H), 3.71 - 3.42 (m, 1H), 3.24 - 2.80 (m, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.09 - 1.86 (m, 2H), 1.81 - 1.64 (m, 4H), 1.50 - 1.28 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 484.2 [M+Na]+. N-(1-(4-Cyanobenzoyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (Compound 125)
Figure imgf000074_0001
Dissolve 4-cyanobenzoic acid (80 mg, 0.54 mmol) with dichloromethane (5 mL), add oxalyl chloride (54 μί, 0.63 mmol), and add two » ́DMF, and warm to room temperature. . After stirring for 5 h, it was cooled again in an ice bath, triethylamine (125 μί) was added, and after stirring for 5 minutes, the compound hydrazine-3 (actually 26, 150 mg, 0.45 mmol) was added, and the temperature was raised to room temperature. After the reaction was completed, the reaction mixture was concentrated, and then evaporated and evaporated. The organic phase was washed successively with aq. sodium hydrogen sulfate (10 mL), water (5 mL) The solvent was evaporated under reduced pressure and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MHz, CDC1 3 ) δ 7.71 (d, J = 7.5 Hz, 2H), 7.48 (d, J = 7.5 Hz, 2H), 7.00 (d, J = 6.9 Hz, 1H), 6.66 (d, J = 7.0 Hz , 1H), 6.60 (s, 1H), 5.52 (d, J = 6.1 Hz, 1H), 4.76 - 4.52 (m, 1H), 4.13 - 3.97 (m, 1H), 3.98 - 3.85 (m, 2H), 3.71 - 3.42 (m, 1H), 3.24 - 2.80 (m, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.09 - 1.86 (m, 2H), 1.81 - 1.64 (m, 4H), 1.50 - 1.28 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 484.2 [M+Na] + .
实施例 105  Example 105
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- (4- (三氟甲基） 苯甲酰基） 哌啶 -4-基） 戊酰胺 （化合物 126)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)pentanamide (Compound 126)
参照实施例 104的方法制得化合物 126: 1H MR (300 MHz, DMSO- 6) δ 7.83 (d, J = 8.0 Hz, 2H), 7.57 (d, J= 7.9 Hz, 2H), 7.23 (d, J= 7.7 Hz, 1H), 6.96 (d, J= 7.4 Hz, 1H), 6.68 (s, 1H), 6.59 (d, J = 7.4 Hz, 1H), 4.53 - 4.33 (m, 1H), 3.96 - 3.77 (m, 3H), 3.52 - 3.38 (m, 1H), 3.20 - 3.02 (m, 1H), 2.99 - 2.81 (m, 1H), 2.22 (s, 3H), 2.08 (s, 3H), 1.86 - 1.24 (m, 8H), 1.09 (s, 6H). ESI-MS: m/z 527.2 [M+Na]+. Compound 126 was prepared by the method of Example 104: 1H MR (300 MHz, DMSO- 6 ) δ 7.83 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 7.7 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.68 (s, 1H), 6.59 (d, J = 7.4 Hz, 1H), 4.53 - 4.33 (m, 1H), 3.96 - 3.77 (m, 3H), 3.52 - 3.38 (m, 1H), 3.20 - 3.02 (m, 1H), 2.99 - 2.81 (m, 1H), 2.22 (s, 3H), 2.08 (s, 3H), 1.86 - 1.24 (m, 8H), 1.09 (s, 6H). ESI-MS: m/z 527.2 [M+Na] + .
实施例 106  Example 106
5- (2,5-二甲基苯氧基） -N- ( 1- (4-甲氧基苯甲酰基） 哌啶 -4-基） -2,2-二甲基戊酰 胺 （化合物 127)  5-(2,5-Dimethylphenoxy)-N-(1-(4-methoxybenzoyl)piperidin-4-yl)-2,2-dimethylpentanamide (Compound 127 )
参照实施例 104的方法制得化合物 127: 1H MR (300 MHz, DMSO- 6) δ 7.32 (d, J = 8.4 Hz, 2H), 7.22 (d, J= 7.9 Hz, 1H), 7.00 (d, J= 8.4 Hz, 2H), 6.96 (d, J= 7.2 Hz, 1H), 6.68 (s, 1H), 6.60 (d, J= 7.4 Hz, 1H), 4.47 - 3.59 (m, 8H), 3.14 - 2.85 (m, 2H), 2.22 (s, 3H), 2.08 (s, 3H), 1.76 - 1.62 (m, 2H), 1.58 (s, 4H), 1.47 - 1.31 (m, 2H), 1.09 (s, 6H). ESI-MS: m/z 489.3 [M+Na]+. Compound 127 was prepared by the method of Example 104: 1H MR (300 MHz, DMSO- 6 ) δ 7.32 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 7.9 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 7.2 Hz, 1H), 6.68 (s, 1H), 6.60 (d, J = 7.4 Hz, 1H), 4.47 - 3.59 (m, 8H), 3.14 - 2.85 (m, 2H), 2.22 (s, 3H), 2.08 (s, 3H), 1.76 - 1.62 (m, 2H), 1.58 (s, 4H), 1.47 - 1.31 (m, 2H), 1.09 (s, 6H). ESI-MS: m/z 489.3 [M+Na] + .
实施例 107  Example 107
5- (2,5-二甲基苯氧基) -N- ( 1- (4-氟苯甲酰基)哌啶 -4-基） -2,2-二甲基戊酰胺（化 合物 128) 5-(2,5-Dimethylphenoxy)-N-(1-(4-fluorobenzoyl)piperidin-4-yl)-2,2-dimethylpentanamide Compound 128)
参照实施例 104的方法制得化合物 128: 1H MR (300 MHz, DMSO- 6) δ 7.48 - 7.36 (m, 2H), 7.34 - 7.24 (m, 2H), 7.21 (d, J= 8.0 Hz, 1H), 6.96 (d, J= 7.5 Hz, 1H), 6.68 (s, 1H), 6.59 (d, J= 7.3 Hz, 1H), 4.51 - 4.25 (m, 1H), 3.96 - 3.78 (m, 3H), 3.67 - 3.44 (m, 1H), 3.18 - 2.74 (m, 2H), 2.22 (s, 3H), 2.08 (s, 3H), 1.78 - 1.52 (m, 6H), 1.50 - 1.26 (m, 2H), 1.09 (s, 6H). ESI-MS: m/z 477.3 [M+Na]+. Compound 128 was prepared by the method of Example 104: 1H MR (300 MHz, DMSO- 6 ) δ 7.48 - 7.36 (m, 2H), 7.34 - 7.24 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H ), 6.96 (d, J= 7.5 Hz, 1H), 6.68 (s, 1H), 6.59 (d, J= 7.3 Hz, 1H), 4.51 - 4.25 (m, 1H), 3.96 - 3.78 (m, 3H) , 3.67 - 3.44 (m, 1H), 3.18 - 2.74 (m, 2H), 2.22 (s, 3H), 2.08 (s, 3H), 1.78 - 1.52 (m, 6H), 1.50 - 1.26 (m, 2H) , 1.09 (s, 6H). ESI-MS: m/z 477.3 [M+Na] + .
实施例 108  Example 108
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- (4-硝基苯甲酰基）哌啶 -4-基）戊酰胺 (化 合物 129)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-nitrobenzoyl)piperidin-4-yl)pentanamide (Compound 129)
参照实施例 104的方法制得化合物 129: 1H NMR (300 MHz, CDC13) δ 8.27 (d, J= 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.00 (d, J= 7.4 Hz, 1H), 6.66 (d, J= 7.7 Hz, 1H), 6.60 (s, 1H), 5.52 (d, J = 7.3 Hz, 1H), 4.82 - 4.54 (m, 1H), 4.17 - 3.98 (m, 1H), 3.92 (t, 2H), 3.70 - 3.43 (m, 1H), 3.26 - 2.81 (m, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.09 - 1.89 (m, 2H), 1.79 - 1.63 (m, 4H), 1.49 - 1.25 (m, 2H), 1.21 (s, 6H). ESI-MS: m/z 504.3 [M+Na]+. Compound 129 was obtained by the method of Example 104: 1H NMR (300 MHz, CDC1 3 ) δ 8.27 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 7.4 Hz, 1H), 6.66 (d, J= 7.7 Hz, 1H), 6.60 (s, 1H), 5.52 (d, J = 7.3 Hz, 1H), 4.82 - 4.54 (m, 1H), 4.17 - 3.98 (m, 1H), 3.92 (t, 2H), 3.70 - 3.43 (m, 1H), 3.26 - 2.81 (m, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.09 - 1.89 (m , 2H), 1.79 - 1.63 (m, 4H), 1.49 - 1.25 (m, 2H), 1.21 (s, 6H). ESI-MS: m/z 504.3 [M+Na] + .
实施例 109  Example 109
4- (4- ( 5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰氨基）哌啶 -1-羰基）苯甲酸甲酯 (化 合物 130)  4-(4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidine-1-carbonyl)benzoic acid methyl ester (Compound 130)
参照实施例 104的方法制得化合物 130: 1H NMR (300 MHz, CDC13) δ 8.08 (d, J= 8.0 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.00 (d, J = 7.4 Hz, 1H), 6.78 - 6.53 (m, 2H), 5.53 (d, J = 7.4 Hz, 1H), 4.80 - 4.55 (m, 1H), 4.12 - 3.99 (m, 1H), 3.99 - 3.86 (m, 5H), 3.74 - 3.46 (m, 1H), 3.24 - 2.82 (m, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.10 - 1.83 (m, 2H), 1.81 - 1.65 (m, 4H), 1.56 - 1.29 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 517.2 [M+Na]+. The compound 130 was obtained by the method of Example 104: 1H NMR (300 MHz, CDC1 3 ) δ 8.08 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.00 (d, J = 7.4 Hz, 1H), 6.78 - 6.53 (m, 2H), 5.53 (d, J = 7.4 Hz, 1H), 4.80 - 4.55 (m, 1H), 4.12 - 3.99 (m, 1H), 3.99 - 3.86 ( m, 5H), 3.74 - 3.46 (m, 1H), 3.24 - 2.82 (m, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.10 - 1.83 (m, 2H), 1.81 - 1.65 ( m, 4H), 1.56 - 1.29 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 517.2 [M+Na] + .
实施例 110  Example 110
N- ( 1- (2-萘甲酰基) 哌啶 -4-基） -5- (2,5-二甲基苯氧基) - 2,2-二甲基戊酰胺 (化合 物 131)  N-(1-(2-Naphthoyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (Compound 131)
参照实施例 104的方法制得化合物 131 : 1H MR (300 MHz, DMSO- 6) δ 8.04 - 7.89 (m, 4H), 7.65 - 7.54 (m, 2H), 7.47 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 6.68 (s, 1H), 6.57 (d, J= 7.4 Hz, 1H), 4.63 - 4.29 (m, 1H), 3.98 - 3.76 (m, 3H), 3.73 - 3.49 (m, 1H), 3.21 - 2.77 (m, 2H), 2.21 (s, 3H), 2.08 (s, 3H), 1.86 - 1.29 (m, 8H), 1.10 (s, 6H). ESI-MS: m/z 509.3 [M+Na]+. Compound 131 was prepared by the method of Example 104: 1H MR (300 MHz, DMSO- 6 ) δ 8.04 - 7.89 (m, 4H), 7.65 - 7.54 (m, 2H), 7.47 (d, J = 8.3 Hz, 1H ), 7.24 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 6.68 (s, 1H), 6.57 (d, J= 7.4 Hz, 1H), 4.63 - 4.29 (m , 1H), 3.98 - 3.76 (m, 3H), 3.73 - 3.49 (m, 1H), 3.21 - 2.77 (m, 2H), 2.21 (s, 3H), 2.08 (s, 3H), 1.86 - 1.29 (m , 8H), 1.10 (s, 6H). ESI-MS: m/z 509.3 [M+Na] + .
实施例 111  Example 111
4- (4- ( 5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺基）哌啶 -1-羰基）苯甲酸 (化合物 132)  4-(4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanyl)piperidine-1-carbonyl)benzoic acid (Compound 132)
参照实施例 98的方法， 将化合物 130水解， 制得化合物 132: 1H MR (300 MHz, DMSO- e) δ 13.12 (brs, 1H), 8.01 (d, J= 8.1 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.68 (s, 1H), 6.59 (d, J = 7.5 Hz, 1H), 4.55 - 4.34 (m, 1H), 3.98 - 3.76 (m, 3H), 3.55 - 3.40 (m, 1H), 3.18 - 2.77 (m, 2H), 2.22 (s, 3H), 2.08 (s, 3H), 1.84 - 1.32 (m, 8H), 1.09 (s, 6H). ESI-MS: m/z 503.2 [M+Na]+. Compound 130 was hydrolyzed by the method of Example 98 to give compound 132: 1H MR (300 MHz, DMSO-e) δ 13.12 (brs, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 7.8 Hz, 1H), 6.96 ( d, J = 7.4 Hz, 1H), 6.68 (s, 1H), 6.59 (d, J = 7.5 Hz, 1H), 4.55 - 4.34 (m, 1H), 3.98 - 3.76 (m, 3H), 3.55 - 3.40 (m, 1H), 3.18 - 2.77 (m, 2H), 2.22 (s, 3H), 2.08 (s, 3H), 1.84 - 1.32 (m, 8H), 1.09 (s, 6H). ESI-MS: m /z 503.2 [M+Na] + .
实施例 112  Example 112
4- (4- ( 5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺基）哌啶 -1-羰基）苯甲酰胺 (化合 物 133)  4-(4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanyl)piperidine-1-carbonyl)benzamide (Compound 133)
参照实施例 104的方法制得化合物 133 : 1H MR (300 MHz, DMSO- 6) δ 8.07 (brs, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.49 (brs, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 7.9 Hz, 1H), 6.96 (d, J= 7.5 Hz, 1H), 6.68 (s, 1H), 6.59 (d, J= 7.3 Hz, 1H), 4.50 - 4.35 (m, 1H), 3.96 - 3.77 (m, 3H), 3.54 - 3.40 (m, 1H), 3.17 - 3.03 (m, 1H), 2.93 - 2.78 (m, 1H), 2.22 (s, 3H),Compound 133 was prepared by the method of Example 104: 1H MR (300 MHz, DMSO- 6 ) δ 8.07 (brs, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.49 (brs, 1H), 7.41 ( d, J = 8.0 Hz, 2H), 7.26 (d, J = 7.9 Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.68 (s, 1H), 6.59 (d, J = 7.3 Hz, 1H), 4.50 - 4.35 (m, 1H), 3.96 - 3.77 (m, 3H), 3.54 - 3.40 (m, 1H), 3.17 - 3.03 (m, 1H), 2.93 - 2.78 (m, 1H), 2.22 ( s, 3H),
2.08 (s, 3H), 1.82 - 1.30 (m, 8H), 1.09 (s, 6H). ESI-MS: m/z 502.3 [M+Na]+. 2.08 (s, 3H), 1.82 - 1.30 (m, 8H), 1.09 (s, 6H). ESI-MS: m/z 502.3 [M+Na] + .
实施例 113  Example 113
4- (4- ( 5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺基）哌啶 -1-羰基） -Ν,Ν-二甲基苯 甲酰胺 (化合物 134)  4-(4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoyl)piperidine-1-carbonyl)-indole, hydrazine-dimethylbenzamide (Compound 134)
参照实施例 104的方法制得化合物 134: 1H NMR (300 MHz, CDC13) δ 7.51 - 7.36 (m, 4H), 7.00 (d, J= 7.4 Hz, 1H), 6.65 (d, J= 7.5 Hz, 1H), 6.60 (s, 1H), 5.52 (d, J= 7.6 Hz, 1H), 4.83 - 4.44 (m, 1H), 4.11 - 3.96 (m, 1H), 3.92 (t, J= 4.9 Hz, 2H), 3.83 - 3.56 (m, 1H), 3.25 - 2.79 (m, 8H), 2.29 (s, 3H), 2.17 (s, 3H), 2.06 - 1.85 (m, 2H), 1.79 - 1.64 (m, 4H), 1.53 - 1.27 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 530.3 [M+Na]+. The compound 134 was obtained by the method of Example 104: 1H NMR (300 MHz, CDC1 3 ) δ 7.51 - 7.36 (m, 4H), 7.00 (d, J = 7.4 Hz, 1H), 6.65 (d, J = 7.5 Hz , 1H), 6.60 (s, 1H), 5.52 (d, J= 7.6 Hz, 1H), 4.83 - 4.44 (m, 1H), 4.11 - 3.96 (m, 1H), 3.92 (t, J= 4.9 Hz, 2H), 3.83 - 3.56 (m, 1H), 3.25 - 2.79 (m, 8H), 2.29 (s, 3H), 2.17 (s, 3H), 2.06 - 1.85 (m, 2H), 1.79 - 1.64 (m, 4H), 1.53 - 1.27 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 530.3 [M+Na] + .
实施例 114  Example 114
N- ( 1- (苯并 [d][l,3]二氧杂环戊烯 -5-羰基）哌啶 -4-基） -5- (2,5-二甲基苯氧基） -2,2- 二甲基戊酰胺 (化合物 135)  N-(1-(Benzo[d][l,3]dioxol-5-carbonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)- 2,2-dimethylpentanamide (compound 135)
参照实施例 104的方法制得化合物 135 : 1H MR (300 MHz, DMSO- 6) δ 7.20 (d, J =Compound 135 was prepared by the method of Example 104: 1H MR (300 MHz, DMSO- 6 ) δ 7.20 (d, J =
7.9 Hz, 1H), 7.05 - 6.82 (m, 4H), 6.68 (s, 1H), 6.60 (d, J = 7.5 Hz, 1H), 6.08 (s, 2H), 4.46 - 3.58 (m, 5H), 3.08 - 2.80 (m, 2H), 2.22 (s, 3H), 2.08 (s, 3H), 1.76 - 1.51 (m, 6H), 1.49 - 1.27 (m, 2H), 1.09 (s, 6H). ESI-MS: m/z 503.3 [M+Na]+. 7.9 Hz, 1H), 7.05 - 6.82 (m, 4H), 6.68 (s, 1H), 6.60 (d, J = 7.5 Hz, 1H), 6.08 (s, 2H), 4.46 - 3.58 (m, 5H), 3.08 - 2.80 (m, 2H), 2.22 (s, 3H), 2.08 (s, 3H), 1.76 - 1.51 (m, 6H), 1.49 - 1.27 (m, 2H), 1.09 (s, 6H). ESI- MS: m/z 503.3 [M+Na] + .
实施例 115  Example 115
N- ( 1- (2,2-二氟苯并 [d] [1,3]二氧杂环戊烯 -5-羰基） 哌啶 -4-基） -5- (2,5-二甲基苯 氧基） -2,2-二甲基戊酰胺 (化合物 136)  N-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-carbonyl)piperidin-4-yl)-5-(2,5-dimethyl Phenoxy group -2,2-dimethyl pentamide (compound 136)
参照实施例 104的方法制得化合物 136: 1H MR (300 MHz, DMSO- 6) δ 7.48 (d, J = 8.2 Hz, 1H), 7.43 (s, 1H), 7.21 (d, J= 8.1 Hz, 2H), 6.96 (d, J= 7.4 Hz, 1H), 6.68 (s, 1H), 6.59 (d, J = 7.3 Hz, 1H), 4.55 - 4.19 (m, 1H), 3.99 - 3.77 (m, 3H), 3.74 - 3.46 (m, 1H), 3.18 - 2.77 (m, 2H), 2.22 (s, 3H), 2.08 (s, 3H), 1.80 - 1.51 (m, 6H), 1.49 - 1.27 (m, 2H), 1.09 (s, 6H). ESI-MS: m/z 539.3 [M+Na] . Compound 136 was prepared by the method of Example 104: 1H MR (300 MHz, DMSO- 6 ) δ 7.48 (d, J = 8.2 Hz, 1H), 7.43 (s, 1H), 7.21 (d, J = 8.1 Hz, 2H), 6.96 (d, J= 7.4 Hz, 1H), 6.68 (s, 1H), 6.59 (d, J = 7.3 Hz, 1H), 4.55 - 4.19 (m, 1H), 3.99 - 3.77 (m, 3H) ), 3.74 - 3.46 (m, 1H), 3.18 - 2.77 (m, 2H), 2.22 (s, 3H), 2.08 (s, 3H), 1.80 - 1.51 (m, 6H), 1.49 - 1.27 (m, 2H) ), 1.09 (s, 6H). ESI-MS: m/z 539.3 [M+Na].
实施例 116  Example 116
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- ( 1- (喹啉 -6-羰基) 哌啶 -4-基） 戊酰胺 （化 合物 137)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(quinolin-6-carbonyl)piperidin-4-yl)pentanamide (compound 137)
参照实施例 104的方法制得化合物 137: 1H MR (300 MHz, DMSO- 6) δ 8.97 (d, J = 2.8 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.00 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 8.2, 4.2 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 6.67 (s, 1H), 6.57 (d, J = 7.3 Hz, 1H), 4.58 - 4.30 (m, 1H), 3.97 - 3.79 (m, 3H), 3.72 - 3.49 (m, 1H), 3.23 - 2.83 (m, 2H), 2.21 (s, 3H), 2.07 (s, 3H), 1.87 - 1.31 (m, 8H), 1.10 (s, 6H). ESI-MS: m/z 510.3 [M+Na]+. Compound 137 was prepared by the method of Example 104: 1H MR (300 MHz, DMSO- 6 ) δ 8.97 (d, J = 2.8 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.00 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 8.2, 4.2 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 6.67 (s, 1H), 6.57 (d, J = 7.3 Hz, 1H), 4.58 - 4.30 (m, 1H), 3.97 - 3.79 (m, 3H) ), 3.72 - 3.49 (m, 1H), 3.23 - 2.83 (m, 2H), 2.21 (s, 3H), 2.07 (s, 3H), 1.87 - 1.31 (m, 8H), 1.10 (s, 6H). ESI-MS: m/z 510.3 [M+Na] + .
实施例 117  Example 117
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- (吡嗪 -2-羰基） 哌啶 -4-基） 戊酰胺 （化 合物 138)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(pyrazine-2-carbonyl)piperidin-4-yl)pentanamide (compound 138)
参照实施例 104的方法制得化合物 138: 1H MR (300 MHz, DMSO- 6) δ 8.84 - 8.78 (m, 1H), 8.75 (d, J = 2.5 Hz, 1H), 8.70 - 8.62 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.68 (s, 1H), 6.59 (d, J= 7.4 Hz, 1H), 4.52 - 4.33 (m, 1H), 3.98 - 3.79 (m, 3H), 3.69 - 3.56 (m, 1H), 3.19 - 3.05 (m, 1H), 2.98 - 2.83 (m, 1H), 2.22 (s, 3H), 2.07 (s, 3H), 1.83 - 1.72 (m, 1H), 1.68 - 1.39 (m, 7H), 1.08 (s, 6H). ESI-MS: m/z 461.2 [M+Na]+. Compound 138 was prepared by the method of Example 104: 1H MR (300 MHz, DMSO- 6 ) δ 8.84 - 8.78 (m, 1H), 8.75 (d, J = 2.5 Hz, 1H), 8.70 - 8.62 (m, 1H) ), 7.30 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.68 (s, 1H), 6.59 (d, J = 7.4 Hz, 1H), 4.52 - 4.33 (m , 1H), 3.98 - 3.79 (m, 3H), 3.69 - 3.56 (m, 1H), 3.19 - 3.05 (m, 1H), 2.98 - 2.83 (m, 1H), 2.22 (s, 3H), 2.07 (s , 3H), 1.83 - 1.72 (m, 1H), 1.68 - 1.39 (m, 7H), 1.08 (s, 6H). ESI-MS: m/z 461.2 [M+Na] + .
实施例 118  Example 118
2- (4-苯甲酰基苯氧基） -N- ( 1- (苯基磺酰基） 哌啶 -4-基） 乙酰胺 （化合物 139) 参照合成路线 1和实施例 43的方法制得化合物 139: 1H MR (300 MHz, CDC13) δ 7.84 (d, J = 8.6 Hz, 2H), 7.80 - 7.71 (m, 4H), 7.68 - 7.40 (m, 6H), 6.97 (d, J = 8.6 Hz, 2H), 6.43 (d, J = 8.2 Hz, 1H), 4.52 (s, 2H), 3.92 - 3.73 (m, 3H), 2.52 - 2.37 (m, 2H), 2.09 - 1.95 (m, 2H), 1.72 - 1.59 (m, 2H). ESI-MS: m/z 479.2 [M+H]+. 2-(4-Benzoylphenoxy)-N-(1-(phenylsulfonyl)piperidin-4-yl)acetamide (Compound 139) The compound was obtained by the procedure of Synthesis Scheme 1 and Example 43 139: 1H MR (300 MHz, CDC1 3 ) δ 7.84 (d, J = 8.6 Hz, 2H), 7.80 - 7.71 (m, 4H), 7.68 - 7.40 (m, 6H), 6.97 (d, J = 8.6 Hz , 2H), 6.43 (d, J = 8.2 Hz, 1H), 4.52 (s, 2H), 3.92 - 3.73 (m, 3H), 2.52 - 2.37 (m, 2H), 2.09 - 1.95 (m, 2H), 1.72 - 1.59 (m, 2H). ESI-MS: m/z 479.2 [M+H] + .
实施例 119  Example 119
N- ( 1- (4-氰基苯磺酰基）哌啶 -4-基） -5- (2-甲氧基苯氧基） -2,2-二甲基戊酰胺（化 合物 140) N-(1-(4-Cyanobenzenesulfonyl)piperidin-4-yl)-5-(2-methoxyphenoxy)-2,2-dimethylpentanamide (Compound 140)
Figure imgf000078_0001
取化合物 IV- 1 (1.1 mL, 10 mmoL)溶于 DMF (20 mL)， 依次加入化合物 IV-2 (2.23 g, lOmmoL)和碳酸钾 （2.07g, 15 mmoL)， N2保护下加热至回流。 反应约 8 h后， 冷却 至室温， 加入 INNaOH溶液（60mL)， 乙酸乙酯萃取（60mLx3)。 有机相依次用饱和 碳酸钠（60mLx2)、 水（20mLx2)和饱和食盐水（60mLx2)洗涤， 无水硫酸钠干燥， 减压旋干溶剂。残余物经柱层析（洗脱剂： 石油醚 /乙酸乙酯 =75:1)纯化， 得化合物 IV-3
Figure imgf000078_0001
Compound IV-1 (1.1 mL, 10 mmoL) was dissolved in DMF (20 mL). Compound IV-2 (2.23 g, lOmmoL) and potassium carbonate (2.07 g, 15 mmoL) were added in sequence, and heated to reflux under N 2 protection. . After about 8 h of reaction, it was cooled to room temperature, then added with aq. NaOH (60 mL) and ethyl acetate (60 mL×3). The organic phase was washed with saturated sodium sulfate (60 mL×2), EtOAc (EtOAc) The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate=75:1) to give compound IV-3
(黄色油， 1.741 g， 收率 66%)。 (Yellow oil, 1.741 g, yield 66%).
取化合物 IV-3 (532 mg, 2 mmoL) 溶于甲醇 （10mL) 禾 P THF (10 mL) 中， 加入 2N氢氧化钠水溶液 （2mL)， 加热回流 6h， 冷却至室温。 减压浓缩反应液， 加适量水 稀释， 用盐酸调节水相 pH至 2-3左右， 乙酸乙酯萃取 （30mLx3)。 有机相用饱和食盐 水洗涤 （20mLx2)， 无水硫酸钠干燥， 减压蒸除溶剂， 得化合物 IV-4 (白色固体， 460 mg, 收率 91%)。  The compound IV-3 (532 mg, 2 mmol) was dissolved in MeOH (10 mL) EtOAc (EtOAc)EtOAc. The reaction mixture was concentrated under reduced pressure, diluted with water, and the aqueous phase was adjusted to pH 2-3 with hydrochloric acid and extracted with ethyl acetate (30mL×3). The organic phase was washed with EtOAc (EtOAc) (EtOAc)
取化合物 IV-5 (2 g, 10 mmoL)溶于二氯甲垸（60 mL),加入化合物 IV-6 (2.62 g, 13 mmoL) 和三乙胺 （2.78 mL, 20 mmoL)， 室温反应 10 h。 加二氯甲垸 （60 mL) 稀释反 应液， 有机相用水 （60mLx3) 和饱和食盐水 （60mLx2) 洗涤， 无水硫酸钠干燥。 减 压蒸除溶剂， 残余物用乙酸乙酯洗涤， 抽滤， 得化合物 IV-7 (3.297 g， 收率 90%)。  Compound IV-5 (2 g, 10 mmoL) was dissolved in dichloromethane (60 mL), and compound IV-6 (2.62 g, 13 mmoL) and triethylamine (2.78 mL, 20 mmoL) were added. h. The reaction mixture was diluted with chloroform (60 mL). The organic phase was washed with water (60 mL×3) and brine (60 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. EtOAc mjjjjjj
取化合物 IV-7 (3.297 g, 9mmoL)混悬于二氯甲垸（30mL)， 冰浴下滴加三氟乙酸 (6.7 mL， 90mmol)。 室温反应 6h， 减压蒸除溶剂和三氟乙酸。 加水 （lOOmL) 稀释， 用 IN NaOH水溶液调节 pH至碱性， 有大暈白色固体析出， 抽滤， 得化合物 IV-8 (白 色固体， 2.175 g， 收率 91%)。  Compound IV-7 (3.297 g, 9 mmoL) was suspended in dichloromethane (30 mL), and trifluoroacetic acid (6.7 mL, 90 mmol) was added dropwise. After reacting at room temperature for 6 hours, the solvent and trifluoroacetic acid were evaporated under reduced pressure. Add water (100 mL) to dilute, adjust the pH to alkaline with IN NaOH aqueous solution, precipitate with a large white solid, and suction to give compound IV-8 (white solid, 2.175 g, yield 91%).
取化合物 IV-4 (163 mg, 0.64 mmol) 溶于无水二氯甲垸 （5 mL)， 冰浴下滴加草酰 氯 （108 μί, 1.28 mmol) 和 2滴 DMF， 室温反应 5h。 减压蒸除二氯甲垸及未反应的草 酰氯制得酰氯。 取化合物 IV-8 (188mg, 0.71 mmoL) 溶于无水二氯甲垸 （3 mL)， 依次 加入上述制备好的酰氯和三乙胺（178μί, 1.28mmoL)， 室温搅拌过夜。 加入 DCM (20 mL)稀释反应液， 用水（10 mL x3 )和饱和食盐水（10 mL x2)洗涤， 无水硫酸钠干燥， 减压旋干溶剂。残余物经柱层析（洗脱剂： 石油醚 /乙酸乙酯 =2: 1 )纯化， 得化合物 140 (白色固体， 138 mg， 收率 43%): 1H NMR (300 MHz, CDC13) δ 7.90 - 7.78 (m, 4H), 6.97 - 6.82 (m, 4H), 5.68 (d, J= 7.3 Hz, 1H), 3.96 (t, J= 5.9 Hz, 2H), 3.87 (s, 3H), 3.82 - 3.65 (m, 3H), 2.51 - 2.39 (m, 2H), 2.01 - 1.90 (m, 2H), 1.80 - 1.64 (m, 4H), 1.58 - 1.42 (m, 2H), 1.16 (s, 6H). ESI-MS: m/z 522.2 [M+Na]+. Compound IV-4 (163 mg, 0.64 mmol) was dissolved in anhydrous dichloromethane (5 mL). oxalyl chloride (108 μί, 1.28 mmol) and 2 drops of DMF were added dropwise in an ice bath and allowed to react at room temperature for 5 h. The acid chloride is obtained by distilling off methylene chloride and unreacted oxalyl chloride under reduced pressure. The compound IV-8 (188 mg, 0.71 mmol) was dissolved in anhydrous dichloromethane (3 mL), and the acid chloride and triethylamine (178 μί, 1. Join DCM (20 The reaction solution was diluted with water (10 mL×3) and brine (10 mL×2) and dried over anhydrous sodium sulfate. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 2: 1) to give compound 140 (white solid, 138 mg, yield 43%): 1H NMR (300 MHz, CDC1 3) δ 7.90 - 7.78 (m, 4H), 6.97 - 6.82 (m, 4H), 5.68 (d, J= 7.3 Hz, 1H), 3.96 (t, J= 5.9 Hz, 2H), 3.87 (s, 3H), 3.82 - 3.65 (m, 3H), 2.51 - 2.39 (m, 2H), 2.01 - 1.90 (m, 2H), 1.80 - 1.64 (m, 4H), 1.58 - 1.42 (m, 2H), 1.16 (s, 6H) ESI-MS: m/z 522.2 [M+Na] + .
实施例 120  Example 120
N- ( 1- (4-氰基苯磺酰基）哌啶 -4-基） -5- (4-甲氧基苯氧基） -2,2-二甲基戊酰胺（化 合物 141 )  N-(1-(4-cyanobenzenesulfonyl)piperidin-4-yl)-5-(4-methoxyphenoxy)-2,2-dimethylpentanamide (compound 141)
参照实施例 119的方法制得化合物 141： 1H NMR (300 MHz, CDC13) δ 7.91 - 7.78 (m, 4H), 6.87 - 6.74 (m, 4H), 5.54 (d, J = 7.4 Hz, 1H), 3.90 - 3.66 (m, 5H), 3.77 (s, 3H) , 2.52 - 2.40 (m, 2H), 2.04 - 1.91 (m, 2H), 1.70 - 1.62 (m, 4H), 1.58 - 1.41 (m, 2H), 1.17 (s, 6H).ESI-MS: m/z 522.2 [M+Na]+. The compound 141 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.91 - 7.78 (m, 4H), 6.87 - 6.74 (m, 4H), 5.54 (d, J = 7.4 Hz, 1H) , 3.90 - 3.66 (m, 5H), 3.77 (s, 3H) , 2.52 - 2.40 (m, 2H), 2.04 - 1.91 (m, 2H), 1.70 - 1.62 (m, 4H), 1.58 - 1.41 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 522.2 [M+Na] + .
实施例 121  Example 121
N- ( 1- (4-氰基苯磺酰基） 哌啶 -4-基） -2,2-二甲基 -5-苯氧基戊酰胺 (142) 参照实施例 119的方法制得化合物 142: 1H NMR (300 MHz, CDC13) δ 7.91 - 7.79 (m, 4H), 7.33 - 7.23 (m, 2H), 7.00 - 6.91 (m, 1H), 6.86 (d, J = 8.0 Hz, 2H), 5.52 (d, J = 7.5 Hz, 1H), 3.91 (t, J = 5.3 Hz, 2H), 3.84 - 3.66 (m, 3H), 2.52 - 2.40 (m, 2H), 2.03 - 1.93 (m, 2H), 1.77 - 1.62 (m, 4H), 1.57 - 1.35 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 492.2 [M+Na]+. N-(1-(4-Cyanobenzenesulfonyl)piperidin-4-yl)-2,2-dimethyl-5-phenoxypentanamide (142) Compound 142 was obtained according to the procedure of Example 119. : 1H NMR (300 MHz, CDC1 3 ) δ 7.91 - 7.79 (m, 4H), 7.33 - 7.23 (m, 2H), 7.00 - 6.91 (m, 1H), 6.86 (d, J = 8.0 Hz, 2H), 5.52 (d, J = 7.5 Hz, 1H), 3.91 (t, J = 5.3 Hz, 2H), 3.84 - 3.66 (m, 3H), 2.52 - 2.40 (m, 2H), 2.03 - 1.93 (m, 2H) , 1.77 - 1.62 (m, 4H), 1.57 - 1.35 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 492.2 [M+Na] + .
实施例 122  Example 122
N- ( 1- (4-氰基苯磺酰基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基）戊酰胺 (化合物 143) 参照实施例 119的方法制得化合物 143 : 1H MR (300 MHz, DMSO- 6) δ 8.13 (d, J = 7.8 Hz, 2H), 7.92 (d, J = 7.9 Hz, 2H), 7.75 (d, J = 7.0 Hz, 1H), 6.97 (d, J = 7.3 Hz, 1H), 6.70 (s, 1H), 6.62 (d, J= 7.0 Hz, 1H), 3.91 (t, J= 5.7 Hz, 2H), 3.67 - 3.46 (m, 3H), 2.65 - 2.52 (m, 2H), 2.24 (s, 3H), 2.13 - 2.02 (m, 5H), 1.82 - 1.56 (m, 6H), 1.44 - 1.28 (m, 2H). ESI-MS: m/z 470.2 [M+H]+. N-(1-(4-Cyanobenzenesulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)pentanamide (Compound 143) was obtained according to the procedure of Example 119. Compound 143 : 1H MR (300 MHz, DMSO- 6 ) δ 8.13 (d, J = 7.8 Hz, 2H), 7.92 (d, J = 7.9 Hz, 2H), 7.75 (d, J = 7.0 Hz, 1H), 6.97 (d, J = 7.3 Hz, 1H), 6.70 (s, 1H), 6.62 (d, J= 7.0 Hz, 1H), 3.91 (t, J= 5.7 Hz, 2H), 3.67 - 3.46 (m, 3H) ), 2.65 - 2.52 (m, 2H), 2.24 (s, 3H), 2.13 - 2.02 (m, 5H), 1.82 - 1.56 (m, 6H), 1.44 - 1.28 (m, 2H). ESI-MS: m /z 470.2 [M+H] + .
实施例 123  Example 123
2 - ( (4- ( 5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰氨基） 哌啶 -1-基） 甲基） 苯甲酰 胺 （化合物 147)  2-((4-(5,5-Dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)methyl)benzamide (Compound 147)
参照实施例 26 的方法制得化合物 147 : 1H MR (300 MHz, OMSO-d6) δ 8.87 (s, lH),7.59(dd, J=7.5Hz, 1.3Hz, 1H), 7.45 - 7.29 (m, 4H), 7.15 (d, J = 7.9 Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.67 (s, 1H), 6.59 (d, J= 7.4 Hz, 1H), 3.87 (t, 2H), 3.65-3.55 (m, 1H), 3.54 (s, 2H), 2.80 - 2.70 (m, 2H), 2.22 (s, 3H), 2.11 - 1.99 (m, 5H), 1.68 - 1.52 (m, 6H), 1.49 - 1.35 (m, 2H), 1.07 (s, 6H). ESI-MS: m/z 466.2 [M+H]+. 实施例 124 Compound 147 was prepared by the method of Example 26: 1H MR (300 MHz, OMSO-d 6 ) δ 8.87 (s, lH), 7.59 (dd, J = 7.5 Hz, 1.3 Hz, 1H), 7.45 - 7.29 (m , 4H), 7.15 (d, J = 7.9 Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.67 (s, 1H), 6.59 (d, J = 7.4 Hz, 1H), 3.87 (t , 2,,,,, , 6H), 1.49 - 1.35 (m, 2H), 1.07 (s, 6H). ESI-MS: m/z 466.2 [M+H] + . Example 124
4 - ( (4- ( 5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰氨基） 哌啶 -1-基） 甲基） 苯甲酰 胺 （化合物 148)  4-((4-(5,5-Dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)methyl)benzamide (Compound 148)
参照实施例 26 的方法制得化合物 148: 1H MR (300 MHz, DMSO- 6) δ 7.91 (s, 1H), 7.82 (d, J= 8.1 Hz, 2H), 7.35 (d, J= 8.1 Hz, 2H), 7.29 (s, 1H), 7.14 (d, J= 7.9 Hz, 1H), 6.97 (d, J= 7.5 Hz, 1H), 6.68 (s, 1H), 6.60 (d, J= 7.4 Hz, 1H), 3.88 (s, 2H), 3.56 (d, J= 7.5 Hz, 1H), 3.48 (s, 2H), 2.75 (d, J= 11.3 Hz, 2H), 2.23 (s, 3H), 2.08 (s, 3H), 1.97 (dd, J = 14.0, 7.5 Hz, 2H), 1.60 (d, J= 14.9 Hz, 6H), 1.49 (d, J= 9.1 Hz, 2H), 1.08 (s, 6H). ESI-MS: m/z 466.2 [M+H]+. Compound 148 was prepared by the method of Example 26: 1H MR (300 MHz, DMSO- 6 ) δ 7.91 (s, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.29 (s, 1H), 7.14 (d, J= 7.9 Hz, 1H), 6.97 (d, J= 7.5 Hz, 1H), 6.68 (s, 1H), 6.60 (d, J= 7.4 Hz, 1H), 3.88 (s, 2H), 3.56 (d, J= 7.5 Hz, 1H), 3.48 (s, 2H), 2.75 (d, J= 11.3 Hz, 2H), 2.23 (s, 3H), 2.08 ( s, 3H), 1.97 (dd, J = 14.0, 7.5 Hz, 2H), 1.60 (d, J= 14.9 Hz, 6H), 1.49 (d, J= 9.1 Hz, 2H), 1.08 (s, 6H). ESI-MS: m/z 466.2 [M+H] + .
实施例 125  Example 125
4- ( (4- ( 5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰氨基） 哌啶 -1-基） 甲基） 苯甲酸 甲酯 （化合物 149)  4-((4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)methyl)benzoic acid methyl ester (compound 149 )
参照实施例 26的方法制得化合物 149: 1H MR (300 MHz, CDC13) δ 7.98 (d, J= 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 6.99 (d, J= 7.4 Hz, 1H), 6.65 (d, J= 7.5 Hz, 1H), 6.60 (s, 1H), 5.49 (d, J = 7.6 Hz, 1H), 3.96 - 3.87 (m, 5H), 3.86 - 3.74 (m, 1H), 3.53 (s, 2H), 2.83 - 2.70 (m, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.16 - 2.09 (m, 2H), 1.97 - 1.83 (m, 2H), 1.73 - 1.64 (m, 4H), 1.50 - 1.39 (m, 2H), 1.19 (s, 6H). ESI-MS: m/z 481.2 [M+H]+. Compound 149 was prepared by the method of Example 26: 1H MR (300 MHz, CDC1 3 ) δ 7.98 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 7.4 Hz, 1H), 6.65 (d, J= 7.5 Hz, 1H), 6.60 (s, 1H), 5.49 (d, J = 7.6 Hz, 1H), 3.96 - 3.87 (m, 5H), 3.86 - 3.74 (m, 1H), 3.53 (s, 2H), 2.83 - 2.70 (m, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.16 - 2.09 (m, 2H), 1.97 - 1.83 (m , 2H), 1.73 - 1.64 (m, 4H), 1.50 - 1.39 (m, 2H), 1.19 (s, 6H). ESI-MS: m/z 481.2 [M+H] + .
实施例 126  Example 126
4 - ( (4- ( 5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺基） 哌啶 -1-基） 甲基） 苯甲酸 (化合物 150)  4-((4-(5,5-Dimethylphenoxy)-2,2-dimethylpentanyl)piperidin-1-yl)methyl)benzoic acid (Compound 150)
参照实施例 98的方法， 将化合物 149水解， 制得化合物 150: 1H MR (300 MHz, DMSO-i ) δ 13.18 (br s, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 7.9 Hz, 2H), 7.59 (d, J = Compound 149 was hydrolyzed by the method of Example 98 to give compound 150: 1H MR (300 MHz, DMSO-i) δ 13.18 (br s, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.78 ( d, J = 7.9 Hz, 2H), 7.59 (d, J =
7.0 Hz, 1H), 6.97 (d, J= 7.5 Hz, 1H), 6.68 (s, 1H), 6.60 (d, J= 7.3 Hz, 1H), 4.30 (s, 2H), 3.87 (t, J= 6.0Hz,2H), 3.83 - 3.71 (m, 1H), 3.32 - 3.22 (m, 2H), 3.04 - 2.90 (m, 2H), 2.23 (s, 3H), 2.08 (s, 3H), 1.96 - 1.76 (m, 4H), 1.65 - 1.51 (m, 4H), 1.08 (s, 6H). ESI-MS: m/z 467.2 [M+H]+. 7.0 Hz, 1H), 6.97 (d, J= 7.5 Hz, 1H), 6.68 (s, 1H), 6.60 (d, J= 7.3 Hz, 1H), 4.30 (s, 2H), 3.87 (t, J= 6.0Hz, 2H), 3.83 - 3.71 (m, 1H), 3.32 - 3.22 (m, 2H), 3.04 - 2.90 (m, 2H), 2.23 (s, 3H), 2.08 (s, 3H), 1.96 - 1.76 (m, 4H), 1.65 - 1.51 (m, 4H), 1.08 (s, 6H). ESI-MS: m/z 467.2 [M+H] + .
实施例 127  Example 127
4 - ( (4- ( 5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰氨基） 哌啶 -1-基） 甲基） -N-甲基 苯甲酰胺 （化合物 151 )  4-((4-(5,5-Dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)methyl)-N-methylbenzamide Amide (compound 151)
参照实施例 26的方法制得化合物 151 : 1H MR (300 MHz, OM O-d6) δ 8.33 (q, J = 4.4 Hz, 1H), 7.76 (d, J= 8.1 Hz, 2H), 7.33 (d, J= 8.1 Hz, 2H), 7.09 (d, J= 7.9 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 6.66 (s, 1H), 6.58 (d, J = 7.4 Hz, 1H), 3.86 (t, J=6.0Hz, 2H), 3.59 - 3.50 (m, 1H), 3.46 (s, 2H), 2.75 (d, J= 4.5 Hz, 3H), 2.74 - 2.68 (m, 2H), 2.20 (s, 3H), 2.06 (s, 3H),Compound 151 was prepared by the method of Example 26: 1H MR (300 MHz, OM Od 6 ) δ 8.33 (q, J = 4.4 Hz, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 7.9 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 6.66 (s, 1H), 6.58 (d, J = 7.4 Hz, 1H) , 3.86 (t, J=6.0Hz, 2H), 3.59 - 3.50 (m, 1H), 3.46 (s, 2H), 2.75 (d, J= 4.5 Hz, 3H), 2.74 - 2.68 (m, 2H), 2.20 (s, 3H), 2.06 (s, 3H),
2.01 - 1.88 (m, 2H), 1.63 - 1.53 (m, 6H), 1.51 - 1.40 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 480.3 [M+H] . 2.01 - 1.88 (m, 2H), 1.63 - 1.53 (m, 6H), 1.51 - 1.40 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 480.3 [M+H] .
实施例 128  Example 128
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- (4- (甲基磺酰基） 苄基） 哌啶 -4-基） 戊酰胺 （化合物 152)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-(methylsulfonyl)benzyl)piperidin-4-yl)pentanamide ( Compound 152)
参照实施例 26的方法制得化合物 152: 1H MR (300 MHz, CDC13) δ 7.89 (d, J= 8.1 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.00 (d, J= 7.4 Hz, 1H), 6.66 (d, J= 7.5 Hz, 1H), 6.60 (s, 1H), 5.49 (d, J= 7.6 Hz, 1H), 3.92 (t, J= 5.3 Hz, 2H), 3.87 - 3.74 (m, 1H), 3.57 (s, 2H), 3.05 (s, 3H), 2.83 - 2.71 (m, 2H), 2.30 (s, 3H), 2.23 - 2.11 (m, 5H), 1.95 - 1.86 (m, 2H), 1.76 - 1.68 (m, 4H), 1.52 - 1.40 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 501.3 [M+H]+. Compound 152 was prepared by the method of Example 26: 1H MR (300 MHz, CDC1 3 ) δ 7.89 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 7.4 Hz, 1H), 6.66 (d, J= 7.5 Hz, 1H), 6.60 (s, 1H), 5.49 (d, J= 7.6 Hz, 1H), 3.92 (t, J= 5.3 Hz, 2H), 3.87 - 3.74 (m, 1H), 3.57 (s, 2H), 3.05 (s, 3H), 2.83 - 2.71 (m, 2H), 2.30 (s, 3H), 2.23 - 2.11 (m, 5H), 1.95 - 1.86 (m, 2H), 1.76 - 1.68 (m, 4H), 1.52 - 1.40 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 501.3 [M+H] + .
实施例 129  Example 129
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- (4-硝基苄基） 哌啶 -4-基） 戊酰胺 （化 合物 153 )  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-nitrobenzyl)piperidin-4-yl)pentanamide (compound 153)
参照实施例 26的方法制得化合物 153 : 1H MR (300 MHz, CDC13) δ 8.20 (d, J= 8.5 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.03 (d, J= 7.4 Hz, 1H), 6.69 (d, J= 7.5 Hz, 1H), 6.64 (s, 1H), 5.58 (d, J= 7.6 Hz, 1H), 3.95 (t, J= 5.4 Hz, 2H), 3.91 - 3.80 (m, 1H), 3.63 (s, 2H), 2.88 - 2.76 (m, 2H), 2.33 (s, 3H), 2.28 - 2.18 (m, 5H), 2.01 - 1.90 (m, 2H), 1.80 - 1.68 (m, 4H), 1.60 - 1.44 (m, 2H), 1.24 (s, 6H). ESI-MS: m/z 468.2 [M+H]+. Compound 153 was prepared by the method of Example 26: 1H MR (300 MHz, CDC1 3 ) δ 8.20 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 7.4 Hz, 1H), 6.69 (d, J= 7.5 Hz, 1H), 6.64 (s, 1H), 5.58 (d, J= 7.6 Hz, 1H), 3.95 (t, J= 5.4 Hz, 2H), 3.91 - 3.80 (m, 1H), 3.63 (s, 2H), 2.88 - 2.76 (m, 2H), 2.33 (s, 3H), 2.28 - 2.18 (m, 5H), 2.01 - 1.90 (m, 2H), 1.80 - 1.68 (m, 4H), 1.60 - 1.44 (m, 2H), 1.24 (s, 6H). ESI-MS: m/z 468.2 [M+H] + .
实施例 130  Example 130
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- (4- (三氟甲氧基） 苄基） 哌啶 -4-基） 戊酰胺 （化合物 154)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)pentanamide (compound 154)
参照实施例 26的方法制得化合物 154: 1H MR (300 MHz, CDC13) δ 7.32 (d, J= 8.5 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 6.99 (d, J= 7.4 Hz, 1H), 6.65 (d, J= 7.5 Hz, 1H), 6.60 (s, 1H), 5.48 (d, J= 7.6 Hz, 1H), 3.91 (t, J= 5.5 Hz, 2H), 3.85 - 3.72 (m, 1H), 3.46 (s, 2H), 2.81 - 2.70 (m, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.15 - 2.07 (m, 2H), 1.95 - 1.84 (m, 2H), 1.76 - 1.63 (m, 4H), 1.49 - 1.35 (m, 3H), 1.19 (s, 6H). ESI-MS: m/z 507.2 [M+H]+. Compound 154 was prepared by the method of Example 26: 1H MR (300 MHz, CDC1 3 ) δ 7.32 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 7.4 Hz, 1H), 6.65 (d, J= 7.5 Hz, 1H), 6.60 (s, 1H), 5.48 (d, J= 7.6 Hz, 1H), 3.91 (t, J= 5.5 Hz, 2H), 3.85 - 3.72 (m, 1H), 3.46 (s, 2H), 2.81 - 2.70 (m, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.15 - 2.07 (m, 2H), 1.95 - 1.84 (m, 2H), 1.76 - 1.63 (m, 4H), 1.49 - 1.35 (m, 3H), 1.19 (s, 6H). ESI-MS: m/z 507.2 [M+H] + .
实施例 131  Example 131
2- (4-苯甲酰基苯氧基） -N- ( 1- (吡啶 -3-基磺酰基）哌啶 -4-基）乙酰胺（化合物 196) 参照合成路线 1和实施例 14的方法制得化合物 196: 1H MR (300 MHz, DMSO- 6) δ 8.94 - 8.87 (m, 2H), 8.21 - 8.04 (m, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.72 - 7.62 (m, 4H), 7.60 - 7.52 (m, 2H), 7.07 (d, J = 8.8 Hz, 2H), 4.57 (s, 2H), 3.77 - 3.65 (m, 1H), 3.64 - 3.54 (m, 2H), 2.68 - 2.53 (m, 2H), 1.90 - 1.74 (m, 2H), 1.63 - 1.44 (m, 2H). ESI-MS: m/z 480.2 [M+H]+. 2-(4-Benzoylphenoxy)-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)acetamide (Compound 196) Referring to the methods of Synthesis Scheme 1 and Example 14 Compound 196: 1H MR (300 MHz, DMSO- 6 ) δ 8.94 - 8.87 (m, 2H), 8.21 - 8.04 (m, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.72 - 7.62 ( m, 4H), 7.60 - 7.52 (m, 2H), 7.07 (d, J = 8.8 Hz, 2H), 4.57 (s, 2H), 3.77 - 3.65 (m, 1H), 3.64 - 3.54 (m, 2H) , 2.68 - 2.53 (m, 2H), 1.90 - 1.74 (m, 2H), 1.63 - 1.44 (m, 2H). ESI-MS: m/z 480.2 [M+H] + .
实施例 132  Example 132
N- ( 1-苄基哌啶 -4-基） -2- (4- (苯基磺酰基） 苯氧基） 乙酰胺 （化合物 216) 参照合成路线 1和实施例 1的方法制得化合物 216: 1H MR (300 MHz, CDC13) δ 7.99 - 7.87 (m, 4H), 7.60 - 7.46 (m, 3H), 7.41 (d, J = 9.8 Hz, 2H), 7.36 (d, J = 6.0 Hz, 2H), 7.01 (d, J= 8.8 Hz, 2H), 6.48 (d, J= 7.9 Hz, 1H), 4.48 (s, 2H), 3.99 (s, 1H), 3.77 (s, 2H), 3.07 (s, 2H), 2.40 (s, 2H), 1.96 (s, 4H). ESI-MS: m/z 465.0 [M+H]+. N-(1-Benzylpiperidin-4-yl)-2-(4-(phenylsulfonyl)phenoxy)acetamide (Compound 216) Compound 216 was prepared by the method of Synthesis Scheme 1 and Example 1 : 1H MR (300 MHz, CDC1 3 ) δ 7.99 - 7.87 (m, 4H), 7.60 - 7.46 (m, 3H), 7.41 (d, J = 9.8 Hz, 2H), 7.36 (d, J = 6.0 Hz, 2H), 7.01 (d, J= 8.8 Hz, 2H), 6.48 (d, J= 7.9 Hz, 1H), 4.48 (s, 2H), 3.99 ( s, 1H), 3.77 (s, 2H), 3.07 (s, 2H), 2.40 (s, 2H), 1.96 (s, 4H). ESI-MS: m/z 465.0 [M+H] + .
实施例 133  Example 133
N- ( 1-苄基哌啶 -4-基） -2- (4- (苯基亚磺酰基） 苯氧基） 乙酰胺 （化合物 217) 参照合成路线 1和实施例 1的方法制得化合物 217: 1H MR (300 MHz, CDC13) δ 7.54 (d, J= 3.6 Hz, 2H), 7.39 (dd, J= 16.6, 7.7 Hz, 7H), 7.22 (d, J= 10.4 Hz, 1H), 7.05 (d, J= 8.5 Hz, 2H), 6.92 (d, J= 8.7 Hz, 2H), 6.75 (d, J= 7.8 Hz, 1H), 4.46 (s, 2H), 4.03 (s, 1H), 4.00 (s, 2H), 3.31 (d, J= 10.2 Hz, 2H), 2.64 (t, J= 11.0 Hz, 2H), 2.21 (d, J= 10.8 Hz, 2H), 2.05 (d, J = 12.8 Hz, 2H). ESI-MS: m/z 449.3 [M+H]+. N-(1-Benzylpiperidin-4-yl)-2-(4-(phenylsulfinyl)phenoxy)acetamide (Compound 217) Compounds were prepared according to the procedures of Synthesis Scheme 1 and Example 1. 217: 1H MR (300 MHz, CDC1 3 ) δ 7.54 (d, J = 3.6 Hz, 2H), 7.39 (dd, J = 16.6, 7.7 Hz, 7H), 7.22 (d, J = 10.4 Hz, 1H), 7.05 (d, J= 8.5 Hz, 2H), 6.92 (d, J= 8.7 Hz, 2H), 6.75 (d, J= 7.8 Hz, 1H), 4.46 (s, 2H), 4.03 (s, 1H), 4.00 (s, 2H), 3.31 (d, J = 10.2 Hz, 2H), 2.64 (t, J = 11.0 Hz, 2H), 2.21 (d, J = 10.8 Hz, 2H), 2.05 (d, J = 12.8 Hz, 2H). ESI-MS: m/z 449.3 [M+H] + .
实施例 134  Example 134
N- ( 1-苄基哌啶 -4-基） -2- (4- (苯硫基） 苯氧基） 乙酰胺 （化合物 218)  N-(1-Benzylpiperidin-4-yl)-2-(4-(phenylthio)phenoxy)acetamide (Compound 218)
参照合成路线 1和实施例 1的方法制得化合物 218: 1H MR (300 MHz, CDC13) δ 7.45 - 7.36 (m, 2H), 7.35 - 7.27 (m, 5H), 7.19 (ddd, J= 9.4, 7.8, 4.8 Hz, 5H), 6.94 - 6.83 (m, 2H), 6.38 (d, J= 7.9 Hz, 1H), 4.46 (s, 2H), 3.99 - 3.84 (m, 1H), 3.49 (s, 2H), 2.79 (d, J= 11.9 Hz, 2H), 2.14 (t, J = 11.4 Hz, 2H), 1.91 (d, J = 10.1 Hz, 2H), 1.51 (td, J = 14.6, 3.6 Hz, 2H). ESI-MS: m/z 433.2 [M+H]+. Compound 218 was prepared by the method of Synthesis Scheme 1 and Example 1: 1H MR (300 MHz, CDC1 3 ) δ 7.45 - 7.36 (m, 2H), 7.35 - 7.27 (m, 5H), 7.19 (ddd, J = 9.4 , 7.8, 4.8 Hz, 5H), 6.94 - 6.83 (m, 2H), 6.38 (d, J = 7.9 Hz, 1H), 4.46 (s, 2H), 3.99 - 3.84 (m, 1H), 3.49 (s, 2H), 2.79 (d, J = 11.9 Hz, 2H), 2.14 (t, J = 11.4 Hz, 2H), 1.91 (d, J = 10.1 Hz, 2H), 1.51 (td, J = 14.6, 3.6 Hz, 2H). ESI-MS: m/z 433.2 [M+H] + .
实施例 135  Example 135
N- ( 1-苄基哌啶 -4-基） -2 - ( ( 5-氧代 -5,6,7,8-四氢萘 -2-基）氧） 乙酰胺（化合物 219) 将 7-甲氧基 -1-萘满酮 （176 mg, l.O mmol)和三氯化铝 (330 mg, 2.5 mmol) 溶于甲 苯 （5 mL) 中， 加热回流过夜。 冷至室温， 加入 1N盐酸， 用乙酸乙酯 （20 mL x 3 ) 萃 取， 有机相用饱和食盐水 （10 mL x 2) 洗涤， 无水硫酸钠干燥， 过滤， 滤液减压浓缩， 粗品经硅胶柱层析（洗脱剂： 石油醚 /乙酸乙酯 =5: 1 )纯化， 得 6-羟基 -3,4-二氢萘 -1(2H)- 酮 （白色固体， 147 mg)。 以 6-羟基 -3,4-二氢萘 -1(2H)-酮为原料， 参照合成路线 1和实 施例 1的方法制得化合物 219: 1H MR (300 MHz, CDC13) δ 8.03 (d, J= 8.7 Hz, 1H), 7.35 - 7.27 (m, 5H), 6.84 (dd, J = 8.7, 2.5 Hz, 1H), 6.72 (d, J = 2.3 Hz, 1H), 6.34 (d, J = 7.9 Hz, 1H), 4.51 (s, 2H), 3.98 - 3.81 (m, 1H), 3.49 (s, 2H), 2.93 (t, J= 6.0 Hz, 2H), 2.80 (d, J= 11.9 Hz, 2H), 2.70 - 2.56 (m, 2H), 2.20 - 2.07 (m, 4H), 1.92 (d, J = 9.7 Hz, 2H), 1.59 - 1.43 (m, 2H). ESI-MS: m/z 393.2 [M+H]+. N-(1-Benzylpiperidin-4-yl)-2-(-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)oxy)acetamide (Compound 219) Methoxy-1-tetralinone (176 mg, 10 mmol) and aluminum trichloride (330 mg, 2.5 mmol) were dissolved in toluene (5 mL) and heated to reflux overnight. After cooling to room temperature, 1N hydrochloric acid was added, and ethyl acetate (20 mL×3) was evaporated. Column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) afforded 6-hydroxy-3,4-dihydronaphthalene-1 (2H)-one (white solid, 147 mg). Starting from 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one, compound 219 was prepared by the method of Synthesis Scheme 1 and Example 1 : 1H MR (300 MHz, CDC1 3 ) δ 8.03 (d , J = 8.7 Hz, 1H), 7.35 - 7.27 (m, 5H), 6.84 (dd, J = 8.7, 2.5 Hz, 1H), 6.72 (d, J = 2.3 Hz, 1H), 6.34 (d, J = 7.9 Hz, 1H), 4.51 (s, 2H), 3.98 - 3.81 (m, 1H), 3.49 (s, 2H), 2.93 (t, J = 6.0 Hz, 2H), 2.80 (d, J = 11.9 Hz, 2H), 2.70 - 2.56 (m, 2H), 2.20 - 2.07 (m, 4H), 1.92 (d, J = 9.7 Hz, 2H), 1.59 - 1.43 (m, 2H). ESI-MS: m/z 393.2 [M+H] + .
实施例 136  Example 136
5- (4-氯苯氧基） -N- ( 1- ( (4-氰基苯基）磺酰基）哌啶 -4-基） -2,2-二甲基戊酰胺 (化 合物 221)  5-(4-Chlorophenoxy)-N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (Compound 221)
参照实施例 119的方法制得化合物 221： 1H NMR (300 MHz, CDC13) δ 7.91 - 7.83 (m, 4H), 7.22 (d, J = 8.9 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H), 5.57 (d, J= 7.9 Hz, 1H), 3.92 - 3.79 (m, 4H), 3.77 - 3.66 (m, 1H), 2.48 - 2.35 (m, 2H), 2.04 - 1.93 (m, 2H), 1.75 - 1.62 (m, 4H), 1.59 - 1.44 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 526.2 [M+Na]+. Compound 221 was prepared by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.91 - 7.83 (m, 4H), 7.22 (d, J = 8.9 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H), 5.57 (d, J = 7.9 Hz, 1H), 3.92 - 3.79 (m, 4H), 3.77 - 3.66 (m, 1H), 2.48 - 2.35 (m, 2H), 2.04 - 1.93 (m, 2H), 1.75 - 1.62 (m, 4H), 1.59 - 1.44 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 526.2 [M+Na] + .
实施例 137  Example 137
N- ( 1 - ( (4-氰基苯基）磺酰基）哌啶 -4-基） -2,2-二甲基 -5- ( 3,4,5-三甲氧基苯氧基） 戊酰胺 (化合物 222)  N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(3,4,5-trimethoxyphenoxy)pentane Amide (compound 222)
参照实施例 119的方法制得化合物 222: 1H NMR (300 MHz, CDC13) δ 7.90 - 7.81 (m, 4H), 6.12 (s, 2H), 5.52 (d, J= 7.7 Hz, 1H), 3.92 - 3.66 (m, 14H), 2.52 - 2.40 (m, 2H), 2.05 - 1.95 (m, 2H), 1.72 - 1.61 (m, 4H), 1.56 - 1.44 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 582.3 [M+Na]+. Compound 222 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.90 - 7.81 (m, 4H), 6.12 (s, 2H), 5.52 (d, J = 7.7 Hz, 1H), 3.92 - 3.66 (m, 14H), 2.52 - 2.40 (m, 2H), 2.05 - 1.95 (m, 2H), 1.72 - 1.61 (m, 4H), 1.56 - 1.44 (m, 2H), 1.18 (s, 6H) ESI-MS: m/z 582.3 [M+Na] + .
实施例 138  Example 138
N- ( 1 - ( (4-氯苯基) 磺酰基） 哌啶 -4-基） -2,2-二甲基 -5- ( 3,4,5-三甲氧基苯氧基) 戊酰胺 （化合物 223 )  N-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(3,4,5-trimethoxyphenoxy)pentanamide (compound 223)
参照实施例 119的方法制得化合物 223 : 1H NMR (300 MHz, CDC13) δ 7.69 (d, J= 8.5 Hz, 2H), 7.52 (d, J= 8.5 Hz, 2H), 6.12 (s, 2H), 5.51 (d, J= 7.3 Hz, 1H), 3.92 - 3.63 (m, 14H), 2.48 - 2.35 (m, 2H), 2.03 - 1.93 (m, 2H), 1.74 - 1.62 (m, 4H), 1.54 - 1.43 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 591.3 [M+Na]+. The compound 223 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.69 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 6.12 (s, 2H) ), 5.51 (d, J = 7.3 Hz, 1H), 3.92 - 3.63 (m, 14H), 2.48 - 2.35 (m, 2H), 2.03 - 1.93 (m, 2H), 1.74 - 1.62 (m, 4H), 1.54 - 1.43 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 591.3 [M+Na] + .
实施例 139  Example 139
反式 -N - ( 1 . ( (4-氰基苯基）磺酰基） -3-氟哌啶 -4-基） -5- (2,5-二甲基苯氧基） -2,2- 二甲基戊酰胺 （化合物 78 ) Trans- N- (1.((4-cyanophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2 - Dimethylpentylamide (Compound 78)
参照实施例 77 的方法， 将 （3S,4S ) -4-氨基 -3-氟哌啶 -1-甲酸叔丁酯替换成 （士） - 反式 -4-氨基 -3-氟哌啶 -1-甲酸叔丁酯， 制得化合物 78: 1H NMR (300 MHz, CDC13) δ 7.93 - 7.76 (m, 4H), 7.00 (d, J = 7.1 Hz, 1H), 6.66 (d, J = 7.0 Hz, 1H), 6.59 (s, 1H), 5.73 (d, J = 6.7 Hz, 1H), 4.58 - 4.30 (m, 1H), 4.11 - 4.00 (m, 1H), 3.98 - 3.86 (m, 3H), 3.77 - 3.64 (m, 1H), 2.62 - 2.42 (m, 2H), 2.29 (s, 3H), 2.21 - 2.07 (m, 4H), 1.75 - 1.64 (m, 4H), 1.61 - 1.52 (m, 1H), 1.20 (s, 6H). ESI-MS: m/z 538.3 [M+Na]+. Following the procedure of Example 77, tert-butyl (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylate was replaced with (s)-trans-4-amino-3-fluoropiperidine-1 - tert-butyl formate, compound 78: 1H NMR (300 MHz, CDC1 3 ) δ 7.93 - 7.76 (m, 4H), 7.00 (d, J = 7.1 Hz, 1H), 6.66 (d, J = 7.0 Hz , 1H), 6.59 (s, 1H), 5.73 (d, J = 6.7 Hz, 1H), 4.58 - 4.30 (m, 1H), 4.11 - 4.00 (m, 1H), 3.98 - 3.86 (m, 3H), 3.77 - 3.64 (m, 1H), 2.62 - 2.42 (m, 2H), 2.29 (s, 3H), 2.21 - 2.07 (m, 4H), 1.75 - 1.64 (m, 4H), 1.61 - 1.52 (m, 1H) ), 1.20 (s, 6H). ESI-MS: m/z 538.3 [M+Na] + .
实施例 140  Example 140
反式 -5- (2,5-二甲基苯氧基） -N - ( 3-氟 -1- (吡啶 -3-基磺酰基） 哌啶 -4-基） -2,2-二 甲基戊酰胺 （化合物 224)  Trans-5-(2,5-dimethylphenoxy)-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2,2-dimethyl Kevalamide (compound 224)
参照实施例 139 的方法制得化合物 224: 1H MR (300 MHz, CDC13) δ 9.01 (d, J=1.7Hz, lH), 8.88 (dd, J= 4.7 Hz, 1.3Hz, lH), 8.07 (d, J= 8.0 Hz, 1H), 7.53 (dd, J= 8.0, 4.9 Hz, 1H), 7.01 (d, J = 7.5 Hz, 1H), 6.67 (d, J= 7.6 Hz, 1H), 6.60 (s, 1H), 5.65 (d, J= 7.1 Hz, 1H), 4.52 - 4.33 (m, 1H), 4.15 - 4.05 (m, 1H), 3.97 - 3.86 (m, 3H), 3.79 - 3.70 (m, 1H), 2.58 - 2.46 (m, 2H), 2.30 (s, 3H), 2.16 (s, 3H), 1.76 - 1.65 (m, 4H), 1.62 - 1.48 (m, 2H), 1.21 (s, 6H). ESI-MS: m/z 514.2 [M+Na] . Compound 224 was prepared by the method of Example 139: 1H MR (300 MHz, CDC1 3 ) δ 9.01 (d, J = 1.7 Hz, lH), 8.88 (dd, J = 4.7 Hz, 1.3 Hz, lH), 8.07 ( d, J= 8.0 Hz, 1H), 7.53 (dd, J= 8.0, 4.9 Hz, 1H), 7.01 (d, J = 7.5 Hz, 1H), 6.67 (d, J= 7.6 Hz, 1H), 6.60 ( s, 1H), 5.65 (d, J= 7.1 Hz, 1H), 4.52 - 4.33 (m, 1H), 4.15 - 4.05 (m, 1H), 3.97 - 3.86 (m, 3H), 3.79 - 3.70 (m, 1H), 2.58 - 2.46 (m, 2H), 2.30 (s, 3H), 2.16 (s, 3H), 1.76 - 1.65 (m, 4H), 1.62 - 1.48 (m, 2H), 1.21 (s, 6H). ESI-MS: m/z 514.2 [M+Na].
实施例 141  Example 141
反式—4- ((4- (5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺基） -3-氟哌啶 -1-基） 磺酰 基） 苯甲酸 （化合物 225)  Trans-4-((4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl)-3-fluoropiperidin-1-yl)sulfonyl) Benzoic acid (compound 225)
参照实施例 139的方法制得化合物 225: 1H MR (300 MHz, OMSO-d6) δ 13.54 (s, 1H), 8.14 (d, J= 8.2 Hz, 2H), 7.88 (d,J= 8.2 Hz, 2H), 7.45 (d, J= 7.7 Hz, 1H), 6.95 (d,J= 7.3 Hz, 1H), 6.66 (s, 1H), 6.59 (d, J= 7.5 Hz, 1H), 4.64 - 4.42 (m, 1H), 3.92 - 3.73 (m, 4H), 3.55 - 3.42 (m, 1H), 2.68 - 2.55 (m, 2H), 2.21 (s, 3H), 2.04 (s, 3H), 1.77 - 1.67 (m, 1H), 1.61 - 1.45 (m, 5H), 1.05 (s, 5H). ESI-MS: m/z 557.3 [M+Na]+. Compound 225 was prepared by the method of Example 139: 1H MR (300 MHz, OMSO-d 6 ) δ 13.54 (s, 1H), 8.14 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 8.2 Hz , 2H), 7.45 (d, J = 7.7 Hz, 1H), 6.95 (d, J = 7.3 Hz, 1H), 6.66 (s, 1H), 6.59 (d, J = 7.5 Hz, 1H), 4.64 - 4.42 (m, 1H), 3.92 - 3.73 (m, 4H), 3.55 - 3.42 (m, 1H), 2.68 - 2.55 (m, 2H), 2.21 (s, 3H), 2.04 (s, 3H), 1.77 - 1.67 (m, 1H), 1.61 - 1.45 (m, 5H), 1.05 (s, 5H). ESI-MS: m/z 557.3 [M+Na] + .
实施例 142  Example 142
5- (2,5-二甲基苯氧基) -N- ((3S,4S) -3-氟 -1- (吡啶 -3-基磺酰基) 哌啶 -4-基） -2,2- 二甲基戊酰胺 （化合物 226)  5-(2,5-Dimethylphenoxy)-N-((3S,4S)-3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2,2 - Dimethyl valeramide (Compound 226)
参照实施例 77的方法制得化合物 226: ee>99%; 1HNMR (300 MHz, CDC13) δ 9.00 (s, 1Η), 8.86 (d, J= 4.1 Hz, 1H), 8.05 (d, J= 7.9 Hz, 1H), 7.51 (dd, J= 7.7, 5.0 Hz, 1H), 7.00 (d, J= 7.4 Hz, 1H), 6.66 (d, J= 7.4 Hz, 1H), 6.59 (s, 1H), 5.68 (d, J= 7.3 Hz, 1H), 4.58 - 4.30 (m, 1H), 4.13 - 4.03 (m, 1H), 3.98 - 3.86 (m, 3H), 3.78 - 3.68 (m, 1H), 2.60 - 2.48 (m, 2H), 2.30 (s, 3H), 2.20 - 2.09 (m, 4H), 1.76 - 1.66 (m, 4H), 1.64 - 1.50 (m, 1H), 1.20 (s, 6H). ESI-MS: m/z 514.3 [M+Na]+. Compound 226 was prepared by the method of Example 77: ee >99%; 1HNMR (300 MHz, CDC1 3 ) δ 9.00 (s, 1 Η), 8.86 (d, J = 4.1 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.51 (dd, J= 7.7, 5.0 Hz, 1H), 7.00 (d, J= 7.4 Hz, 1H), 6.66 (d, J= 7.4 Hz, 1H), 6.59 (s, 1H) , 5.68 (d, J = 7.3 Hz, 1H), 4.58 - 4.30 (m, 1H), 4.13 - 4.03 (m, 1H), 3.98 - 3.86 (m, 3H), 3.78 - 3.68 (m, 1H), 2.60 - 2.48 (m, 2H), 2.30 (s, 3H), 2.20 - 2.09 (m, 4H), 1.76 - 1.66 (m, 4H), 1.64 - 1.50 (m, 1H), 1.20 (s, 6H). ESI -MS: m/z 514.3 [M+Na] + .
实施例 143  Example 143
4- (((3S,4S) -4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰氨基) -3-氟哌啶小基） 磺酰基） 苯甲酸 （化合物 227)  4-(((3S,4S)-4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidinyl)sulfonyl Benzoic acid (compound 227)
参照实施例 77的方法制得化合物 227: ee>99%; 1H NMR (300 MHz, OMSO-d6) 58.13 (d, J= 8.0 Hz, 2H), 7.83 (d,J= 8.0 Hz, 2H), 7.44 (d, J= 7.9 Hz, 1H), 6.97 (d,J= 7.3 Hz, 1H), 6.68 (s, 1H), 6.61 (d,J= 7.2 Hz, 1H), 4.70-4.43 (m, 1H), 3.96-3.77 (m, 4H), 3.55-3.43 (m, 1H), 2.69 - 2.56 (m, 2H), 2.24 (s, 3H), 2.07 (s, 3H), 1.81 - 1.70 (m, 1H), 1.63 - 1.49 (m, 5H), 1.08 (s, 6H). ESI-MS: m/z 557.2 [M+Na]+. Compound 227 was obtained by the method of Example 77: ee >99%; 1H NMR (300 MHz, OMSO-d 6 ) 58.13 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H) , 7.44 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 7.3 Hz, 1H), 6.68 (s, 1H), 6.61 (d, J = 7.2 Hz, 1H), 4.70-4.43 (m, 1H), 3.96-3.77 (m, 4H), 3.55-3.43 (m, 1H), 2.69 - 2.56 (m, 2H), 2.24 (s, 3H), 2.07 (s, 3H), 1.81 - 1.70 (m, 1H), 1.63 - 1.49 (m, 5H), 1.08 (s, 6H). ESI-MS: m/z 557.2 [M+Na] + .
实施例 144  Example 144
2- (4- (4-氯苯甲酰基） 苯氧基） -N- (1- - ((4-氰基苯基） 磺酰基） 哌啶 -4-基） -2- 甲基丙酰胺 （化合物 228)  2-(4-(4-Chlorobenzoyl)phenoxy)-N-(1- -((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (Compound 228)
参照实施例 14的方法制得化合物 228: 1H MR (300 MHz, CDC13) δ 7.91 - 7.82 (m, 4H), 7.79 - 7.69 (m, 4H), 7.47 (d, J= 7.9 Hz, 2H), 6.93 (d, J= 8.1 Hz, 2H), 6.34 (d, J= 7.9 Hz, 1H), 3.83 - 3.70 (m, 3H), 2.59 - 2.44 (m, 2H), 2.03 - 1.93 (m, 2H), 1.57 (s, 6H), 1.55 - 1.42 (m, 2H). ESI-MS: m/z 566.2 [M+H]+. Compound 228 was prepared by the method of Example 14: 1H MR (300 MHz, CDC1 3 ) δ 7.91 - 7.82 (m, 4H), 7.79 - 7.69 (m, 4H), 7.47 (d, J = 7.9 Hz, 2H) , 6.93 (d, J= 8.1 Hz, 2H), 6.34 (d, J= 7.9 Hz, 1H), 3.83 - 3.70 (m, 3H), 2.59 - 2.44 (m, 2H), 2.03 - 1.93 (m, 2H) ), 1.57 (s, 6H), 1.55 - 1.42 (m, 2H). ESI-MS: m/z 566.2 [M+H] + .
实施例 145 N- (1 - ((4- (1H-四唑 -5-基） 苯基） 磺酰基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 （化合物 229 ) Example 145 N-(1 - ((4-(1H-tetrazol-5-yl)phenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2, 2-dimethylpentanamide (compound 229)
将化合物 111 (200 mg)、 叠氮化钠 （53 mg)、 氯化铵 （44 mg) 溶于 DMF (5 mL) 中， 油浴 125°C加热搅拌 24h。 冷却至室温， 加水 （20mL)， 乙酸乙酯 （10mLx3) 萃 取， 有机相依次用盐水 （20 mL)、 水 （20 mL) 和盐水 （20 mL) 洗涤， 无水硫酸钠干 燥， 将溶剂减压浓缩。 残余物经柱层析 （洗脱剂： 二氯甲焼 /甲醇 /冰醋酸 =400: 20： 1) 纯化，得化合物 229(白色固体， 160 mg, 收率 74%): 1H MR(300 MHz, OMSO-d6) δ 8.29 (d, J= 8.3 Hz, 2H), 7.95 (d,J= 8.3 Hz, 2H), 7.21 (d, J= 7.6 Hz, 1H), 6.97 (d,J= 7.4 Hz, 1H)， 6.67 (s, 1H), 6.61 (d, J= 7.5 Hz, 1H), 3.86 (t, J= 5.4Hz, 2H), 3.71 - 3.61 (m, 2H), 3.60 - 3.49 (m, 1H), 2.48 - 2.37 (m, 2H), 2.23 (s, 3H), 2.07 (s, 3H), 1.78 - 1.67 (m, 2H), 1.61 - 1.53 (m, 4H), 1.53 - 1.44 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 539.2 [M-H]". Compound 111 (200 mg), sodium azide (53 mg), ammonium chloride (44 mg) were dissolved in DMF (5 mL). After cooling to room temperature, water (20 mL), ethyl acetate (10 mL×3) was evaporated. The organic phase was washed with brine (20 mL), water (20 mL) and brine (20 mL) concentrate. The residue was purified by column chromatography eluting elut elut elut elut elut elut elut elut elut elut , OMSO-d 6 ) δ 8.29 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 7.4 Hz, 1H), 6.67 (s, 1H), 6.61 (d, J= 7.5 Hz, 1H), 3.86 (t, J= 5.4Hz, 2H), 3.71 - 3.61 (m, 2H), 3.60 - 3.49 (m , 1H), 2.48 - 2.37 (m, 2H), 2.23 (s, 3H), 2.07 (s, 3H), 1.78 - 1.67 (m, 2H), 1.61 - 1.53 (m, 4H), 1.53 - 1.44 (m , 2H), 1.06 (s, 6H). ESI-MS: m/z 539.2 [MH]".
实施例 146  Example 146
N- ( 1 - ( (4-氰基苯基） 磺酰基） 哌啶 -4-基） -5- (2,5-二氯苯氧基） -2,2-二甲基戊 酰胺 （化合物 230)  N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide (compound) 230)
参照实施例 119的方法制得化合物 230: 1H NMR (300 MHz, CDC13) δ 7.94 - 7.79 (m, 4H), 7.29 (d, 1H), 6.93 - 6.84 (m, 2H), 5.51 (d, J= 7.3 Hz, 1H), 3.97 (t, J= 5.4 Hz, 2H), 3.87 -3.76 (m, 2H), 3.76-3.67 (m, 1H), 2.53 -2.39 (m, 2H), 2.08-1.91 (m, 2H), 1.83 - 1.61 (m, 4H), 1.54 - 1.42 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 560.1 [M+Na]+. The compound 230 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.94 - 7.79 (m, 4H), 7.29 (d, 1H), 6.93 - 6.84 (m, 2H), 5.51 (d, J= 7.3 Hz, 1H), 3.97 (t, J= 5.4 Hz, 2H), 3.87 -3.76 (m, 2H), 3.76-3.67 (m, 1H), 2.53 -2.39 (m, 2H), 2.08-1.91 (m, 2H), 1.83 - 1.61 (m, 4H), 1.54 - 1.42 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 560.1 [M+Na] + .
实施例 147  Example 147
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- (1- ((4- (甲基磺酰基） 苯基） 磺酰基） 哌 啶 -4-基） 戊酰胺 （化合物 231)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl ) pentanoamide (compound 231)
参照实施例 43的方法制得化合物 231： 1H MR (300 MHz, DMSO- 6) δ 8.18 (d, J = 8.3 Hz, 2H), 7.99 (d, J= 8.3 Hz, 2H), 7.22 (d, J= 7.7 Hz, 1H), 6.97 (d, J= 7.4 Hz, 1H), 6.68 (s, 1H), 6.62 (d, J= 7.3 Hz, 1H), 3.93 - 3.80 (m, 2H), 3.73 - 3.60 (m, 2H), 3.59 - 3.49 (m, 1H), 3.31 (s, 3H), 2.47 - 2.38 (m, 2H), 2.24 (s, 3H), 2.08 (s, 3H), 1.77 - 1.65 (m, 2H), 1.62 - 1.53 (m, 4H), 1.53 - 1.41 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 573.2 [M+Na]+. Compound 231 was prepared by the method of Example 43: 1H MR (300 MHz, DMSO- 6 ) δ 8.18 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 8.3 Hz, 2H), 7.22 (d, J= 7.7 Hz, 1H), 6.97 (d, J= 7.4 Hz, 1H), 6.68 (s, 1H), 6.62 (d, J= 7.3 Hz, 1H), 3.93 - 3.80 (m, 2H), 3.73 - 3.60 (m, 2H), 3.59 - 3.49 (m, 1H), 3.31 (s, 3H), 2.47 - 2.38 (m, 2H), 2.24 (s, 3H), 2.08 (s, 3H), 1.77 - 1.65 ( m, 2H), 1.62 - 1.53 (m, 4H), 1.53 - 1.41 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 573.2 [M+Na] + .
实施例 148  Example 148
N- (1 - ((4-氰基苯基）磺酰基） 哌啶 -4-基） -2,2-二甲基 5- (4- (甲基磺酰基）苯氧 基） 戊酰胺 （化合物 232)  N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanamide Compound 232)
参照实施例 119的方法制得化合物 232: 1H MR (300 MHz, DMSO- 6) δ 8.12 (d, J = 8.2 Hz, 2H), 7.91 (d, J= 8.2 Hz, 2H), 7.82 (d,J= 8.7 Hz, 2H), 7.23 (d, J= 7.9 Hz, 1H), 7.11 (d, J= 8.7 Hz, 2H), 4.07 - 3.96 (m, 2H), 3.70 - 3.58 (m, 2H), 3.58 - 3.50 (m, 1H), 3.15 (s, 3H), 2.48 - 2.37 (m, 2H), 1.75 - 1.64 (m, 2H), 1.62 - 1.52 (m, 4H), 1.52 - 1.40 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 570.4 [M+Na]+. 实施例 149 Compound 232 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.12 (d, J = 8.2 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H), 7.82 (d, J= 8.7 Hz, 2H), 7.23 (d, J= 7.9 Hz, 1H), 7.11 (d, J= 8.7 Hz, 2H), 4.07 - 3.96 (m, 2H), 3.70 - 3.58 (m, 2H), 3.58 - 3.50 (m, 1H), 3.15 (s, 3H), 2.48 - 2.37 (m, 2H), 1.75 - 1.64 (m, 2H), 1.62 - 1.52 (m, 4H), 1.52 - 1.40 (m, 2H) ), 1.06 (s, 6H). ESI-MS: m/z 570.4 [M+Na] + . Example 149
2 - ( (4-氧代 -3-苯基 -4H-色烯 -7-基） 氧基） -N- ( 1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 乙酰胺 （化合物 233 )  2-((4-Oxo-3-phenyl-4H-chromen-7-yl)oxy)-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)acetamide (compound 233)
参照合成路线 1和实施例 14的方法制得化合物 233 : 1H MR (300 MHz, DMSO- 6) δ 8.92 (d, J = 1.9 Hz, 1H), 8.89 (d, J = 4.9 Hz, 1H), 8.47 (s, 1H), 8.16 (d, J = 8.0 Hz, 2H), 8.06 (d, J= 8.5 Hz, 1H), 7.69 (dd, J= 7.9, 4.8 Hz, 1H), 7.58 (d, J= 6.7 Hz, 2H), 7.41 (dq, J = 14.1, 7.0 Hz, 3H), 7.17 - 7.09 (m, 2H), 4.64 (s, 2H), 3.70 (s, 1H), 3.65 - 3.55 (m, 2H), 2.57 (dd, J = 20.3, 8.9 Hz, 2H), 1.82 (d, J = 10.4 Hz, 2H), 1.54 (dd, J = 20.1, 11.0 Hz, 2H). ESI-MS: m/z 520.1 [M+H]+. Compound 233 was prepared by the method of Synthesis Scheme 1 and Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 8.92 (d, J = 1.9 Hz, 1H), 8.89 (d, J = 4.9 Hz, 1H), 8.47 (s, 1H), 8.16 (d, J = 8.0 Hz, 2H), 8.06 (d, J = 8.5 Hz, 1H), 7.69 (dd, J= 7.9, 4.8 Hz, 1H), 7.58 (d, J = 6.7 Hz, 2H), 7.41 (dq, J = 14.1, 7.0 Hz, 3H), 7.17 - 7.09 (m, 2H), 4.64 (s, 2H), 3.70 (s, 1H), 3.65 - 3.55 (m, 2H), 2.57 (dd, J = 20.3, 8.9 Hz, 2H), 1.82 (d, J = 10.4 Hz, 2H), 1.54 (dd, J = 20.1, 11.0 Hz, 2H). ESI-MS: m/z 520.1 [M+H] + .
实施例 150  Example 150
2 - ( (4-氧代 -2-苯基 -4H-色烯 -7-基） 氧基） -N- ( 1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 乙酰胺 （化合物 234)  2-((4-oxo-2-phenyl-4H-chromen-7-yl)oxy)-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)acetamide (Compound 234)
参照合成路线 1和实施例 14的方法制得化合物 234: 1H MR (300 MHz, DMSO-d) δ 8.91 (d, J= 2.1 Hz, 1H), 8.89 (d, J= 4.9 Hz, 1H), 8.16 (d, J= 8.0 Hz, 2H), 8.08 (d, J= 5.5 Hz, 2H), 7.97 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 7.9, 4.9 Hz, 1H), 7.60 (d, J = 6.0 Hz, 3H), 7.28 (d, J= 2.0 Hz, 1H), 7.12 (d, J= 8.8 Hz, 1H), 6.97 (s, 1H), 4.65 (s, 2H), 3.70 (s, 1H), 3.60 (d, J= 15.2 Hz, 2H), 2.58 (t, J= 11.6 Hz, 2H), 1.82 (d, J= 10.5 Hz, 2H), 1.63 - 1.46 (m, 2H). ESI-MS: m/z 520.2 [M+H]+. Compound 234 was prepared by the method of Synthesis Scheme 1 and Example 14: 1H MR (300 MHz, DMSO-d) δ 8.91 (d, J = 2.1 Hz, 1H), 8.89 (d, J = 4.9 Hz, 1H), 8.16 (d, J = 8.0 Hz, 2H), 8.08 (d, J = 5.5 Hz, 2H), 7.97 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 7.9, 4.9 Hz, 1H), 7.60 (d, J = 6.0 Hz, 3H), 7.28 (d, J = 2.0 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.97 (s, 1H), 4.65 (s, 2H), 3.70 (s, 1H), 3.60 (d, J = 15.2 Hz, 2H), 2.58 (t, J = 11.6 Hz, 2H), 1.82 (d, J = 10.5 Hz, 2H), 1.63 - 1.46 (m, 2H) ESI-MS: m/z 520.2 [M+H] + .
实施例 151  Example 151
N- ( 1 - ( (4-氯苯基)磺酰基） 哌啶 -4-基） -5- (2,6-二氟苯氧基) -2,2-二甲基戊酰胺 (化合物 235 )  N-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-5-(2,6-difluorophenoxy)-2,2-dimethylpentanamide (Compound 235 )
参照实施例 119的方法制得化合物 235: 1H NMR (300 MHz, CDC13) δ 7.68 (d, J= 8.3 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.02 - 6.82 (m, 3H), 5.58 (d, J = 7.1 Hz, 1H), 4.14 - 4.02 (m, 2H), 3.80 - 3.65 (m, 3H), 2.50 - 2.35 (m, 2H), 2.02 - 1.90 (m, 2H), 1.73 - 1.61 (m, 4H), 1.53 - 1.41 (m, 2H), 1.16 (s, 6H). ESI-MS: m/z 537.2 [M+Na]+. Compound 235 was prepared by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.68 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.02 - 6.82 (m , 3H), 5.58 (d, J = 7.1 Hz, 1H), 4.14 - 4.02 (m, 2H), 3.80 - 3.65 (m, 3H), 2.50 - 2.35 (m, 2H), 2.02 - 1.90 (m, 2H ), 1.73 - 1.61 (m, 4H), 1.53 - 1.41 (m, 2H), 1.16 (s, 6H). ESI-MS: m/z 537.2 [M+Na] + .
实施例 152  Example 152
2,2-二甲基 -5-苯氧基 -N- ( 1- (吡啶 -3-磺酰基） 哌啶 -4-基） 戊酰胺 （化合物 236) 参照实施例 119的方法制得化合物 236: 1H MR (300 MHz, CDC13) δ 8.99 (s, 1H), 8.83 (d, J = 4.4 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.53 - 7.44 (m, 1H), 7.32 - 7.22 (m, 2H), 6.98 - 6.90 (m, 1H), 6.86 (d, J = 7.9 Hz, 2H), 5.50 (d, J = 7.4 Hz, 1H), 3.91 (t, J = 5.1 Hz, 2H), 3.87 - 3.65 (m, 3H), 2.54 - 2.39 (m, 2H), 2.03 - 1.91 (m, 2H), 1.75 - 1.62 (m, 4H), 1.56 - 1.39 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 468.2 [M+Na]+. 2,2-Dimethyl-5-phenoxy-N-(1-(pyridine-3-sulfonyl)piperidin-4-yl)pentanamide (Compound 236) Compound 236 was obtained according to the procedure of Example 119. : 1H MR (300 MHz, CDC1 3 ) δ 8.99 (s, 1H), 8.83 (d, J = 4.4 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.53 - 7.44 (m, 1H) , 7.32 - 7.22 (m, 2H), 6.98 - 6.90 (m, 1H), 6.86 (d, J = 7.9 Hz, 2H), 5.50 (d, J = 7.4 Hz, 1H), 3.91 (t, J = 5.1 Hz, 2H), 3.87 - 3.65 (m, 3H), 2.54 - 2.39 (m, 2H), 2.03 - 1.91 (m, 2H), 1.75 - 1.62 (m, 4H), 1.56 - 1.39 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 468.2 [M+Na] + .
实施例 153  Example 153
5- (2,6-二氟苯氧基） -2,2-二甲基 -N- ( 1- (吡啶 -3-磺酰基） 哌啶 -4-基） 戊酰胺 （化 合物 237) 5-(2,6-Difluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-3-sulfonyl)piperidin-4-yl)pentanamide Compound 237)
参照实施例 119的方法制得化合物 237: 1H MR (300 MHz, CDC13) δ 8.99 (s, 1H), 8.83 (d, J = 4.0 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.54 - 7.45 (m, 1H), 7.02 - 6.84 (m, 3H), 5.61 (d, J= 7.0 Hz, 1H), 4.14 - 4.03 (m, 2H), 3.88 - 3.68 (m, 3H), 2.54 - 2.42 (m, 2H), 2.07 - 1.93 (m, 2H), 1.74 - 1.64 (m, 4H), 1.58 - 1.42 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 504.2 [M+Na]+. Compound 237 was prepared by the method of Example 119: 1H MR (300 MHz, CDC1 3 ) δ 8.99 (s, 1H), 8.83 (d, J = 4.0 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H ), 7.54 - 7.45 (m, 1H), 7.02 - 6.84 (m, 3H), 5.61 (d, J = 7.0 Hz, 1H), 4.14 - 4.03 (m, 2H), 3.88 - 3.68 (m, 3H), 2.54 - 2.42 (m, 2H), 2.07 - 1.93 (m, 2H), 1.74 - 1.64 (m, 4H), 1.58 - 1.42 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 504.2 [M+Na] + .
实施例 154  Example 154
2,2-二甲基 -5- (4- (甲基磺酰基) 苯氧基） -N- ( 1- (吡啶 -3-基磺酰基) 哌啶 -4-基） 戊酰胺 （化合物 238)  2,2-Dimethyl-5-(4-(methylsulfonyl)phenoxy)-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide (compound 238 )
参照实施例 119的方法制得化合物 238: 1H MR (300 MHz, DMSO- 6) δ 8.95 - 8.85 (m, 2H), 8.15 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.69 (dd, J = 7.7, 4.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 8.5 Hz, 2H), 4.06 - 3.96 (m, 2H), 3.70 - 3.59 (m, 2H), 3.59 - 3.50 (m, 1H), 3.15 (s, 3H), 2.47 - 2.35 (m, 2H), 1.77 - 1.64 (m, 2H), 1.63 - 1.53 (m, 4H), 1.53 - 1.41 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 524.1 [M+H]+. Compound 238 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.95 - 8.85 (m, 2H), 8.15 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.69 (dd, J = 7.7, 4.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 8.5 Hz, 2H), 4.06 - 3.96 (m, 2H) ), 3.70 - 3.59 (m, 2H), 3.59 - 3.50 (m, 1H), 3.15 (s, 3H), 2.47 - 2.35 (m, 2H), 1.77 - 1.64 (m, 2H), 1.63 - 1.53 (m , 4H), 1.53 - 1.41 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 524.1 [M+H] + .
实施例 155  Example 155
4 - ( (4- (2,2-二甲基 -5- (4- (甲基磺酰基）苯氧基）戊酰氨基）哌啶 -1-基）磺酰基） 苯甲酸 （化合物 239)  4-((4-(2,2-Dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 239)
参照实施例 119的方法制得化合物 239: 1H MR (300 MHz, DMSO- 6) δ 13.47 (brs, 1H), 8.15 (dd, J= 8.4, 2.2 Hz, 2H), 7.90 - 7.77 (m, 4H), 7.22 (d, J= 7.7 Hz, 1H), 7.11 (dd, J = 8.9, 2.2 Hz, 2H), 4.09 - 3.92 (m, 2H), 3.68 - 3.57 (m, 2H), 3.56 - 3.47 (m, 1H), 3.14 (s, 3H), 2.46 - 2.33 (m, 2H), 1.75 - 1.63 (m, 2H), 1.62 - 1.52 (m, 4H), 1.52 - 1.40 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 567.2 [M+H]+. Compound 239 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 13.47 (brs, 1H), 8.15 (dd, J = 8.4, 2.2 Hz, 2H), 7.90 - 7.77 (m, 4H) ), 7.22 (d, J = 7.7 Hz, 1H), 7.11 (dd, J = 8.9, 2.2 Hz, 2H), 4.09 - 3.92 (m, 2H), 3.68 - 3.57 (m, 2H), 3.56 - 3.47 ( m, 1H), 3.14 (s, 3H), 2.46 - 2.33 (m, 2H), 1.75 - 1.63 (m, 2H), 1.62 - 1.52 (m, 4H), 1.52 - 1.40 (m, 2H), 1.06 ( s, 6H). ESI-MS: m/z 567.2 [M+H] + .
实施例 156  Example 156
N- ( 1 - ( (4-氰基苯基）磺酰基） 哌啶 -4-基） -2-甲基 -2- (4- (甲基磺酰基） 苯氧基） 丙酰胺 （化合物 240)  N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2-methyl-2-(4-(methylsulfonyl)phenoxy)propanamide (compound 240 )
参照实施例 14的方法制得化合物 240: 1H MR (300 MHz, DMSO- 6) δ 8.12 (d, J = 8.2 Hz, 2H), 8.03 (d, J= 6.8 Hz, 1H), 7.88 (d, J= 8.4 Hz, 2H), 7.81 (d, J= 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.73 - 3.60 (m, 1H), 3.60 - 3.46 (m, 2H), 3.17 (s, 3H), 2.49 - 2.40 (m, 2H), 1.73 - 1.60 (m, 2H), 1.56 - 1.37 (m, 8H). ESI-MS: m/z 528.2 [M+Na]+. Compound 240 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 8.12 (d, J = 8.2 Hz, 2H), 8.03 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.73 - 3.60 (m, 1H), 3.60 - 3.46 (m, 2H), 3.17 (s, 3H), 2.49 - 2.40 (m, 2H), 1.73 - 1.60 (m, 2H), 1.56 - 1.37 (m, 8H). ESI-MS: m/z 528.2 [M+Na] + .
实施例 157  Example 157
N- ( 1- (吡啶 -3-基磺酰基） 哌啶 -4-基） -2-甲基 -2- (4- (甲基磺酰基） 苯氧基） 丙酰 胺 （化合物 241 )  N-(1-(Pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methyl-2-(4-(methylsulfonyl)phenoxy)propionylamine (Compound 241)
参照实施例 14的方法制得化合物 241 : 1H MR (300 MHz, DMSO- 6) δ 8.96 - 8.79 (m, 2H), 8.12 (d, J= 8.0 Hz, 1H), 8.06 (d, J= 8.0 Hz, 1H), 7.81 (d, J= 8.6 Hz, 2H), 7.68 (dd, J= 7.8, 4.9 Hz, 1H), 6.97 (d, J= 8.6 Hz, 2H), 3.73-3.61 (m, 1H), 3.60-3.47 (m, 2H), 3.17 (s, 3H), 2.48 - 2.40 (m, 2H), 1.67 (d, J= 10.5 Hz, 2H), 1.57 - 1.36 (m, 8H). ESI-MS: m/z 482.2 [M+H]+. Compound 241 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 8.96 - 8.79 (m, 2H), 8.12 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.81 (d, J= 8.6 Hz, 2H), 7.68 (dd, J= 7.8, 4.9 Hz, 1H), 6.97 (d, J= 8.6 Hz, 2H), 3.73-3.61 (m, 1H), 3.60-3.47 (m, 2H), 3.17 (s, 3H), 2.48 - 2.40 (m, 2H), 1.67 (d, J = 10.5 Hz, 2H), 1.57 - 1.36 (m, 8H). ESI-MS: m/z 482.2 [M+H] + .
实施例 158  Example 158
4- ((4- (2-甲基 -2- (4- (甲基磺酰基） 苯氧基） 丙酰氨基） 哌啶 -1-基）磺酰基） 苯 甲酸 （化合物 242)  4-((4-(2-methyl-2-(4-(methylsulfonyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 242)
参照实施例 14的方法制得化合物 242: 1H MR (300 MHz, DMSO- 6) δ 13.48 (brs, 1H), 8.15 (d, J= 8.2 Hz, 2H), 8.03 (d, J= 7.7 Hz, 1H), 7.88 - 7.74 (m, 4H), 6.97 (d, J= 8.7 Hz, 2H), 3.66 - 3.46 (m, 3H), 3.16 (s, 3H), 2.48 - 2.35 (m, 2H), 1.72 - 1.59 (m, 2H), 1.58 - 1.33 (m, 8H). ESI-MS: m/z 525.4 [M+H]+. Compound 242 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 13.48 (brs, 1H), 8.15 (d, J = 8.2 Hz, 2H), 8.03 (d, J = 7.7 Hz, 1H), 7.88 - 7.74 (m, 4H), 6.97 (d, J= 8.7 Hz, 2H), 3.66 - 3.46 (m, 3H), 3.16 (s, 3H), 2.48 - 2.35 (m, 2H), 1.72 - 1.59 (m, 2H), 1.58 - 1.33 (m, 8H). ESI-MS: m/z 525.4 [M+H] + .
实施例 159  Example 159
2- (4-氯苯氧基) -N- ((3S,4S) -3-氟 -1- (吡啶 -3-基磺酰基) 哌啶 -4-基） -2-甲基丙 酰胺 （化合物 243)  2-(4-Chlorophenoxy)-N-((3S,4S)-3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methylpropanamide ( Compound 243)
以 2-(4-氯苯氧基; )-2-甲基丙酸为原料， 参照实施例 77 的方法制得化合物 243: ee>99%; 1H NMR (300 MHz, OMSO-d6) δ 8.93 (s, 1H), 8.90 (d, J= 4.1 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.18 (d, J= 8.1 Hz, 1H), 7.69 (dd,J= 7.8, 4.9 Hz, 1H), 7.30 (d,J= 8.7 Hz, 2H), 6.86 (d, J= 8.7 Hz, 2H), 4.71 - 4.44 (m, 1H), 4.02 - 3.88 (m, 1H), 3.86 - 3.74 (m, 1H), 3.56 - 3.45 (m, 1H), 2.79 - 2.61 (m, 2H), 1.82 - 1.71 (m, 1H), 1.63 - 1.50 (m, 1H), 1.40 (s, 3H), 1.39 (s, 3H). ESI-MS: m/z 478.1 [M+Na]+. Starting from 2-(4-chlorophenoxy;)-2-methylpropionic acid, the compound 243 was obtained according to the procedure of Example 77: ee >99%; 1H NMR (300 MHz, OMSO-d 6 ) δ 8.93 (s, 1H), 8.90 (d, J = 4.1 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.69 (dd, J = 7.8 , 4.9 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.71 - 4.44 (m, 1H), 4.02 - 3.88 (m, 1H), 3.86 - 3.74 (m, 1H), 3.56 - 3.45 (m, 1H), 2.79 - 2.61 (m, 2H), 1.82 - 1.71 (m, 1H), 1.63 - 1.50 (m, 1H), 1.40 (s, 3H) , 1.39 (s, 3H). ESI-MS: m/z 478.1 [M+Na] + .
实施例 160  Example 160
反式 -2- (4-氯苯氧基） -N- (3-氟 -1- (吡啶 -3-基磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 (化合物 244)  Trans-2-(4-chlorophenoxy)-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methylpropanamide (compound 244)
参照实施例 14和 139的方法制得化合物 244: 1H MR (300 MHz, CDC13) δ 9.00 (s, 1H), 8.86 (d, J= 4.7 Hz, 1H), 8.06 (d, J= 8.0 Hz, 1H), 7.51 (dd, J= 7.6, 5.1 Hz, 1H), 7.24 (d, J= 8.9 Hz, 2H), 6.84 (d,J= 8.8 Hz, 2H), 6.70 (d, J= 7.7 Hz, 1H), 4.61 - 4.33 (m, 1H), 4.12 - 3.88 (m, 2H), 3.80 - 3.69 (m, 1H), 2.67 - 2.53 (m, 2H), 2.22 - 2.08 (m, 1H), 1.72 - 1.62 (m, 1H), 1.48 (s, 3H), 1.46 (s, 3H). ESI-MS: m/z 478.1 [M+Na]+. Compound 244 was prepared by the methods of Examples 14 and 139: 1H MR (300 MHz, CDC1 3 ) δ 9.00 (s, 1H), 8.86 (d, J = 4.7 Hz, 1H), 8.06 (d, J = 8.0 Hz , 1H), 7.51 (dd, J= 7.6, 5.1 Hz, 1H), 7.24 (d, J= 8.9 Hz, 2H), 6.84 (d, J= 8.8 Hz, 2H), 6.70 (d, J= 7.7 Hz , 1H), 4.61 - 4.33 (m, 1H), 4.12 - 3.88 (m, 2H), 3.80 - 3.69 (m, 1H), 2.67 - 2.53 (m, 2H), 2.22 - 2.08 (m, 1H), 1.72 - 1.62 (m, 1H), 1.48 (s, 3H), 1.46 (s, 3H). ESI-MS: m/z 478.1 [M+Na] + .
实施例 161  Example 161
N- ((3S,4S) -1- ((3-氰基苯基) 磺酰基） -3-氟哌啶 -4-基) -5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺 （化合物 245)  N-((3S,4S)-1-((3-cyanophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-5-(2,5-dimethylphenoxy) - 2,2-dimethylvaleramide (compound 245)
参照实施例 77的方法得到化合物 245: 1H MR (300 MHz, OMSO-d6) δ 8.09 (s, 1H), 8.02 (d,J= 7.9 Hz, 1H), 7.93 (d, J= 7.7 Hz, 1H), 7.74 (dd,J= 7.8 Hz,7.8 Hz, 1H), 7.03 (d, J = 7.3 Hz, 1H), 6.69 (d,J= 7.3 Hz, 1H), 6.62 (s, 1H), 5.67 (d, J= 7.3 Hz, 1H), 4.61 - 4.33 (m, 1H), 4.15 - 4.04 (m, 1H), 4.02 - 3.88 (m, 3H), 3.80 - 3.69 (m, 1H), 2.66 - 2.50 (m, 2H), 2.32 (s, 3H), 2.24-2.13 (m, 4H), 1.83 - 1.68 (m, 4H), 1.59 - 1.50 (m, 1H), 1.23 (s, 6H). ESI-MS: m/z 538.3 [M+Na]+. Compound 245 was obtained by the method of Example 77: 1H MR (300 MHz, OMSO-d 6 ) δ 8.09 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.74 (dd, J = 7.8 Hz, 7.8 Hz, 1H), 7.03 (d, J = 7.3 Hz, 1H), 6.69 (d, J = 7.3 Hz, 1H), 6.62 (s, 1H), 5.67 (d, J = 7.3 Hz, 1H), 4.61 - 4.33 (m, 1H), 4.15 - 4.04 (m, 1H), 4.02 - 3.88 (m, 3H), 3.80 - 3.69 (m, 1H), 2.66 - 2.50 (m, 2H), 2.32 (s, 3H), 2.24-2.13 (m, 4H), 1.83 - 1.68 (m, 4H), 1.59 - 1.50 (m, 1H), 1.23 (s, 6H). ESI-MS: m/z 538.3 [M +Na] + .
实施例 162  Example 162
2- (4- (4-氯苯甲酰基) 苯氧基） -2-甲基 -N- (1- (吡啶 -3-基磺酰基) 哌啶 -4-基） 丙 酰胺 （化合物 246)  2-(4-(4-Chlorobenzoyl)phenoxy)-2-methyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)propanamide (Compound 246)
参照实施例 14的方法制得化合物 246: 1H MR (300 MHz, CDC13) δ 8.98 (d, J= 1.8 Hz, 1H), 8.84 (dd, J=4.8, 1.4 Hz, 1H), 8.04 (d, J= 8.1 Hz, 1H), 7.80 - 7.68 (m, 4H), 7.54 -Compound 246 was prepared by the method of Example 14: 1H MR (300 MHz, CDC1 3 ) δ 8.98 (d, J = 1.8 Hz, 1H), 8.84 (dd, J = 4.8, 1.4 Hz, 1H), 8.04 (d , J= 8.1 Hz, 1H), 7.80 - 7.68 (m, 4H), 7.54 -
7.43 (m, 3H), 6.93 (d, J= 8.7 Hz, 2H), 6.35 (d, J= 7.9 Hz, 1H), 3.89 - 3.72 (m, 3H), 2.58 -7.43 (m, 3H), 6.93 (d, J = 8.7 Hz, 2H), 6.35 (d, J = 7.9 Hz, 1H), 3.89 - 3.72 (m, 3H), 2.58 -
2.44 (m, 2H), 2.07 - 1.93 (m, 2H), 1.60 (s, 6H), 1.55 - 1.47 (m, 2H). ESI-MS: m/z 564.2 [M+Na]+. 2.44 (m, 2H), 2.07 - 1.93 (m, 2H), 1.60 (s, 6H), 1.55 - 1.47 (m, 2H). ESI-MS: m/z 564.2 [M+Na] + .
实施例 163  Example 163
反式 -N - (1 - ((4- (1H-四唑 -5-基） 苯基） 磺酰基） -3-氟哌啶 -4-基) -5- (2,5-二甲 基苯氧基） -2， 2-二甲基戊酰胺 （化合物 247)  trans-N-(1 - ((4-(1H-tetrazol-5-yl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)-5-(2,5-dimethyl Phenoxy)-2,2-dimethylvaleramide (compound 247)
参照实施例 139和 145的方法制得化合物 247: 1H MR(300 MHz, OMSO-d6) δ 8.28 (d, J= 7.8 Hz, 2H), 7.99 (d,J= 7.8 Hz, 2H), 7.41 (d, J= 7.9 Hz, 1H), 6.95 (d,J= 7.2 Hz, 1H), 6.66 (s, 1H), 6.60 (d, J= 7.3 Hz, 1H), 4.71 - 4.42 (m, 1H), 3.95 - 3.77 (m, 4H), 3.59 - 3.47 (m, 1H), 2.74 - 2.57 (m, 2H), 2.22 (s, 3H), 2.05 (s, 3H), 1.83 - 1.67 (m, 1H), 1.62 - 1.45 (m, 5H), 1.06 (s, 6H). ESI-MS: m/z 557.2 [M-H]". Compound 247 was prepared by the methods of Examples 139 and 145: 1H MR (300 MHz, OMSO-d 6 ) δ 8.28 (d, J = 7.8 Hz, 2H), 7.99 (d, J = 7.8 Hz, 2H), 7.41 (d, J = 7.9 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 6.66 (s, 1H), 6.60 (d, J = 7.3 Hz, 1H), 4.71 - 4.42 (m, 1H) , 3.95 - 3.77 (m, 4H), 3.59 - 3.47 (m, 1H), 2.74 - 2.57 (m, 2H), 2.22 (s, 3H), 2.05 (s, 3H), 1.83 - 1.67 (m, 1H) , 1.62 - 1.45 (m, 5H), 1.06 (s, 6H). ESI-MS: m/z 557.2 [MH]".
实施例 164  Example 164
2- (4-氯苯氧基） -N- (1- ((4-氰基苯基） 磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 （化 合物 248)  2-(4-Chlorophenoxy)-N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (Compound 248)
参照实施例 14的方法制得化合物 248: 1H NMR (300 MHz, CDC13) δ 7.90 - 7.82 (m, 4H), 7.24 (d, J= 8.7 Hz, 2H), 6.81 (d, J= 8.7 Hz, 2H), 6.54 (d, J= 8.6 Hz, 1H), 3.82 - 3.70 (m, 3H), 2.57 - 2.44 (m, 2H), 2.05 - 1.94 (m, 2H), 1.58 - 1.54 (m, 1H), 1.54 -1.50 (m, 1H), 1.46 (s, 6H). ESI-MS: m/z 484.1 [M+Na]+. Compound 248 was obtained by the method of Example 14: 1H NMR (300 MHz, CDC1 3 ) δ 7.90 - 7.82 (m, 4H), 7.24 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz , 2H), 6.54 (d, J= 8.6 Hz, 1H), 3.82 - 3.70 (m, 3H), 2.57 - 2.44 (m, 2H), 2.05 - 1.94 (m, 2H), 1.58 - 1.54 (m, 1H) ), 1.54 - 1.50 (m, 1H), 1.46 (s, 6H). ESI-MS: m/z 484.1 [M+Na] + .
实施例 165  Example 165
2- (4-氯苯氧基） -N- (1- ((4-氯苯基） 磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 （化合 物 249)  2-(4-Chlorophenoxy)-N-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (Compound 249)
参照实施例 14的方法制得化合物 249: 1H MR (300 MHz, CDC13) δ 7.69 (d, J= 8.5 Hz, 2H), 7.52 (d, J= 8.5 Hz, 2H), 7.23 (d, J= 8.8 Hz, 2H), 6.81 (d,J= 8.8 Hz, 2H), 6.54 (d, J = 7.9 Hz, 1H), 3.83 - 3.66 (m, 3H), 2.54 - 2.37 (m, 2H), 2.04 - 1.92 (m, 2H), 1.61 - 1.49 (m, 2H), 1.45 (s, 6H). ESI-MS: m/z 493.0 [M+Na]+. Compound 249 was prepared by the method of Example 14: 1H MR (300 MHz, CDC1 3 ) δ 7.69 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 7.9 Hz, 1H), 3.83 - 3.66 (m, 3H), 2.54 - 2.37 (m, 2H), 2.04 - 1.92 (m, 2H), 1.61 - 1.49 (m, 2H), 1.45 (s, 6H). ESI-MS: m/z 493.0 [M+Na] + .
实施例 166  Example 166
2- (4-氯苯氧基） -2-甲基 -N- (1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 丙酰胺 （化合物 250) 2-(4-Chlorophenoxy)-2-methyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)propanamide (compound) 250)
参照实施例 14的方法制得化合物 250： 1H MR (300 MHz, CDC13) δ 9.01 (d, J= 1.6 Hz, 1H), 8.86 (dd, J = 4.7, 1.2 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.52 (dd, J = 7.9, 4.9 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.56 (d, J= 7.7 Hz, 1H), 3.88 - 3.71 (m, 3H), 2.62 - 2.47 (m, 2H), 2.08 - 1.95 (m, 2H), 1.61 -1.50 (m, 2H), 1.48 (s, 6H). ESI-MS: m/z 460.2 [M+Na]+. Compound 250 was prepared by the method of Example 14: 1H MR (300 MHz, CDC1 3 ) δ 9.01 (d, J = 1.6 Hz, 1H), 8.86 (dd, J = 4.7, 1.2 Hz, 1H), 8.06 (d , J = 8.0 Hz, 1H), 7.52 (dd, J = 7.9, 4.9 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.56 (d , J= 7.7 Hz, 1H), 3.88 - 3.71 (m, 3H), 2.62 - 2.47 (m, 2H), 2.08 - 1.95 (m, 2H), 1.61 -1.50 (m, 2H), 1.48 (s, 6H ESI-MS: m/z 460.2 [M+Na] + .
实施例 167  Example 167
4 - ( ( 4- ( 2- ( 4-氯苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 （化 合物 251 )  4-((4-(2-(4-chlorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 251)
参照实施例 14的方法制得化合物 251 : 1H MR (300 MHz, OMSO-d6) δ 13.45 (br s, 1H), 8.14 (d, J = 8.2 Hz, 2H), 7.97 (d, J= 7.7 Hz, 1H), 7.81 (d, J= 8.2 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 3.70 - 3.58 (m, 1H), 3.58 - 3.47 (m, 2H), 2.46 - 2.37 (m, 2H), 1.73 - 1.63 (m, 2H), 1.61 - 1.45 (m, 2H), 1.39 (s, 6H).ESI-MS: m/z 479.2 [M-H]". 实施例 168 Compound 251 was prepared by the method of Example 14: 1H MR (300 MHz, OMSO-d 6 ) δ 13.45 (br s, 1H), 8.14 (d, J = 8.2 Hz, 2H), 7.97 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 3.70 - 3.58 (m, 1H), 3.58 - 3.47 (m, 2H), 2.46 - 2.37 (m, 2H), 1.73 - 1.63 (m, 2H), 1.61 - 1.45 (m, 2H), 1.39 (s, 6H).ESI-MS: m/z 479.2 [MH]". Example 168
N- ( 1 - ( (4-氯苯基） 磺酰基） 哌啶 -4-基） -2- (2,5-二甲基苯氧基） -2-甲基丙酰胺 (化合物 252)  N-( 1 - ( (4-chlorophenyl)sulfonyl) piperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropanamide (compound 252)
参照实施例 14的方法制得化合物 252: 1H MR (300 MHz, CDC13) δ 7.70 (d, J= 8.3 Hz, 2H), 7.53 (d, J= 8.4 Hz, 2H), 7.06 (d, J= 7.4 Hz, 1H), 6.79 (d, J= 7.6 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.58 (s, 1H), 3.89 - 3.76 (m, 1H), 3.70 (d, J = 12.1 Hz, 2H), 2.52 (t, J = 10.7 Hz, 2H), 2.26 (s, 3H), 2.16 (s, 3H), 2.02 (d, J = 11.5 Hz, 3H), 1.64 - 1.54 (m, 2H), 1.50 (s, 6H). ESI-MS: m/z 487.2 [M+Na]+. Compound 252 was prepared by the method of Example 14: 1H MR (300 MHz, CDC1 3 ) δ 7.70 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 7.4 Hz, 1H), 6.79 (d, J= 7.6 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.58 (s, 1H), 3.89 - 3.76 (m, 1H), 3.70 (d , J = 12.1 Hz, 2H), 2.52 (t, J = 10.7 Hz, 2H), 2.26 (s, 3H), 2.16 (s, 3H), 2.02 (d, J = 11.5 Hz, 3H), 1.64 - 1.54 (m, 2H), 1.50 (s, 6H). ESI-MS: m/z 487.2 [M+Na] + .
实施例 169  Example 169
N- ( 1 - ( (4-氰基苯基） 磺酰基） 哌啶 -4-基） -2- (2,5-二甲基苯氧基） -2-甲基丙酰 胺 （化合物 253 )  N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropanamide (compound 253)
参照实施例 14的方法制得化合物 253 : 1H NMR (300 MHz, CDC13) δ 7.86 (dd, 4H), 7.05 (d, J= 7.2 Hz, 1H), 6.78 (d, J= 7.5 Hz, 1H), 6.68 (d, J= 8.5 Hz, 1H), 6.56 (s, 1H), 3.90 - 3.78 (m, 1H), 3.74 (d, J= 11.8 Hz, 2H), 2.55 (t, J= 11.8 Hz, 2H), 2.24 (s, 3H), 2.16 (s, 3H), 2.02 (d, J = 15.0 Hz, 2H), 1.54 (d, J = 4.1 Hz, 2H), 1.48 (s, 6H). ESI-MS: m/z 478.2 [M+Na]+. The compound 253 was obtained by the method of Example 14: 1H NMR (300 MHz, CDC1 3 ) δ 7.86 (dd, 4H), 7.05 (d, J = 7.2 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H ), 6.68 (d, J= 8.5 Hz, 1H), 6.56 (s, 1H), 3.90 - 3.78 (m, 1H), 3.74 (d, J= 11.8 Hz, 2H), 2.55 (t, J= 11.8 Hz) , 2H), 2.24 (s, 3H), 2.16 (s, 3H), 2.02 (d, J = 15.0 Hz, 2H), 1.54 (d, J = 4.1 Hz, 2H), 1.48 (s, 6H). ESI -MS: m/z 478.2 [M+Na] + .
实施例 170  Example 170
2- (2,5-二甲基苯氧基） -2-甲基 -N- ( 1- ( (4- (三氟甲基） 苯基） 磺酰基） 哌啶 -4- 基） 丙酰胺 （化合物 254)  2-(2,5-Dimethylphenoxy)-2-methyl-N-(1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-yl)propanamide (compound 254)
参照实施例 14的方法制得化合物 254: 1H MR (300 MHz, CDC13) δ 7.90 (d, J= 8.1 Hz, 2H), 7.83 (d, J= 8.4 Hz, 2H), 7.06 (d, J= 7.6 Hz, 1H), 6.79 (d, J= 7.6 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.58 (s, 1H), 3.90 - 3.79 (m, 1H), 3.74 (d, J = 12.9 Hz, 2H), 2.56 (t, J = 10.9 Hz, 2H), 2.26 (s, 3H), 2.16 (s, 3H), 2.04 (d, J= 10.9 Hz, 2H), 1.59 (dd, J= 12.4, 3.4 Hz, 2H),Compound 254 was prepared by the method of Example 14: 1H MR (300 MHz, CDC1 3 ) δ 7.90 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 7.6 Hz, 1H), 6.79 (d, J= 7.6 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.58 (s, 1H), 3.90 - 3.79 (m, 1H), 3.74 (d, J = 12.9 Hz, 2H), 2.56 (t, J = 10.9 Hz, 2H), 2.26 (s , 3H), 2.16 (s, 3H), 2.04 (d, J= 10.9 Hz, 2H), 1.59 (dd, J= 12.4, 3.4 Hz, 2H),
I.50 (s, 6H). ESI-MS: m/z 521.2 [M+Na]+. I.50 (s, 6H). ESI-MS: m/z 521.2 [M+Na] + .
实施例 171  Example 171
2- (2,5-二甲基苯氧基） -2-甲基 -N- ( 1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 丙酰胺 （化 合物 255 )  2-(2,5-Dimethylphenoxy)-2-methyl-N-(1-(pyridine-3-ylsulfonyl)piperidin-4-yl)propanamide (Compound 255)
参照实施例 14的方法制得化合物 255: 1H MR (300 MHz, DMSO- 6) δ 9.01 (s, 1Η), 8.86 (d, J= 4.5 Hz, 1H), 8.06 (dd, J= 8.0, 1.5 Hz, 1H), 7.51 (dd, J= 7.9, 4.9 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.70 (d, J = 7.9 Hz, 1H), 6.59 (s, 1H), 3.93 - 3.83 (m, 1H), 3.78 (d, J= 12.0 Hz, 2H), 2.58 (t, J = 11.6 Hz, 2H), 2.26 (s, 3H), 2.17 (s, 3H), 2.04 (d, J= 9.8 Hz, 2H), 1.66 - 1.55 (m, 2H), 1.50 (s, 6H). ESI-MS: m/z 454.2 [M+Na]+. Compound 255 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 9.01 (s, 1 Η), 8.86 (d, J = 4.5 Hz, 1H), 8.06 (dd, J = 8.0, 1.5 Hz, 1H), 7.51 (dd, J= 7.9, 4.9 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.70 (d, J = 7.9 Hz, 1H), 6.59 (s, 1H), 3.93 - 3.83 (m, 1H), 3.78 (d, J = 12.0 Hz, 2H), 2.58 (t, J = 11.6 Hz, 2H), 2.26 (s, 3H) ), 2.17 (s, 3H), 2.04 (d, J = 9.8 Hz, 2H), 1.66 - 1.55 (m, 2H), 1.50 (s, 6H). ESI-MS: m/z 454.2 [M+Na] + .
实施例 172  Example 172
4 - ( (4- (2- (2,5-二甲基苯氧基） -2-甲基丙酰氨基）哌啶 -1-基）磺酰基）苯甲酸（化 合物 256)  4-((4-(2-(2,5-Dimethylphenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 256)
参照实施例 14的方法制得化合物 256: 1H MR (300 MHz, DMSO- 6) δ 13.41 (s, 1H), 8.15 (d, J= 8.2 Hz, 2H), 7.89 (d, J= 8.0 Hz, 1H), 7.82 (d, J= 8.2 Hz, 2H), 7.01 (d, J= 7.6 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 6.51 (s, 1H), 3.68 (ddd, J= 14.3, 6.7, 3.7 Hz, 1H), 3.52 (d, J = 12.2 Hz, 2H), 2.44 (s, 2H), 2.17 (s, 3H), 2.10 (s, 3H), 1.73 (d, J= 14.6 Hz, 2H), 1.58 (dd, J = 21.9, 11.7 Hz, 2H), 1.36 (s, 6H). ESI-MS: m/z 497.2 [M+Na]+. Compound 256 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 13.41 (s, 1H), 8.15 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.0 Hz, 1H), 7.82 (d, J= 8.2 Hz, 2H), 7.01 (d, J= 7.6 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 6.51 (s, 1H), 3.68 (ddd, J= 14.3, 6.7, 3.7 Hz, 1H), 3.52 (d, J = 12.2 Hz, 2H), 2.44 (s, 2H), 2.17 (s, 3H), 2.10 (s, 3H), 1.73 (d, J = 14.6 Hz, 2H), 1.58 (dd, J = 21.9, 11.7 Hz, 2H), 1.36 (s, 6H). ESI-MS: m/z 497.2 [M+Na] + .
实施例 173  Example 173
2- (2,5-二甲基苯氧基) -N - ( (3S,4S) -3-氟 -1- (吡啶 -3-基磺酰基) 哌啶 -4-基） -2- 甲基丙酰胺 (化合物 257)  2-(2,5-Dimethylphenoxy)-N-((3S,4S)-3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methyl Propionamide (compound 257)
参照实施例 14和 77的方法制得化合物 257: 1H NMR (300 MHz, CDC13) δ 9.03 (s, 1H), 8.88 (d, J = 4.6 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 7.58 - 7.48 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.81 (t, J= 9.1 Hz, 2H), 6.64 (s, 1H), 4.50 (dtd, J= 48.8, 9.1, 5.1 Hz, 1H), 4.06 (dd, J =Compound 257 was obtained by the methods of Examples 14 and 77: 1H NMR (300 MHz, CDC1 3 ) δ 9.03 (s, 1H), 8.88 (d, J = 4.6 Hz, 1H), 8.08 (d, J = 7.9 Hz , 1H), 7.58 - 7.48 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.81 (t, J= 9.1 Hz, 2H), 6.64 (s, 1H), 4.50 (dtd, J= 48.8, 9.1, 5.1 Hz, 1H), 4.06 (dd, J =
II .1, 6.0 Hz, 2H), 3.74 (d, J = 12.3 Hz, 1H), 2.65 (t, J = 10.6 Hz, 2H), 2.26 (s, 3H), 2.19 (s, 4H), 1.74 - 1.57 (m, 3H), 1.52 (d, J= 13.0 Hz, 6H). ESI-MS: m/z 472.2 [M+Na]+. II .1, 6.0 Hz, 2H), 3.74 (d, J = 12.3 Hz, 1H), 2.65 (t, J = 10.6 Hz, 2H), 2.26 (s, 3H), 2.19 (s, 4H), 1.74 - 1.57 (m, 3H), 1.52 (d, J = 13.0 Hz, 6H). ESI-MS: m/z 472.2 [M+Na] + .
实施例 174  Example 174
反式 -2- (2,5-二甲基苯氧基） -N - (3-氟 -1- (吡啶 -3-基磺酰基） 哌啶 -4-基） -2-甲基 丙酰胺 （化合物 258)  Trans-2-(2,5-Dimethylphenoxy)-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methylpropanamide (Compound 258)
参照实施例 14和 139的方法制得化合物 258: 1H MR (300 MHz, CDC13) δ 9.03 (s, 1H), 8.89 (d, J= 4.4 Hz, 1H), 8.08 (d, J= 8.1 Hz, 1H), 7.54 (dd, J= 7.8, 4.9 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.81 (t, J = 7.5 Hz, 2H), 6.64 (s, 1H), 4.64 - 4.36 (m, 2H), 4.13 - 3.95 (m, 2H), 3.75 (d, J = 12.0 Hz, 1H), 2.65 (t, J = 10.6 Hz, 2H), 2.26 (s, 3H), 2.19 (s, 4H), 1.75 - 1.60 (m, 2H), 1.52 (d, J= 13.1 Hz, 6H). ESI-MS: m/z 472.2 [M+Na] . Compound 258 was prepared by the methods of Examples 14 and 139: 1H MR (300 MHz, CDC1 3 ) δ 9.03 (s, 1H), 8.89 (d, J = 4.4 Hz, 1H), 8.08 (d, J = 8.1 Hz , 1H), 7.54 (dd, J= 7.8, 4.9 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.81 (t, J = 7.5 Hz, 2H), 6.64 (s, 1H), 4.64 - 4.36 (m, 2H), 4.13 - 3.95 (m, 2H), 3.75 (d, J = 12.0 Hz, 1H), 2.65 (t, J = 10.6 Hz, 2H), 2.26 (s, 3H), 2.19 ( s, 4H), 1.75 - 1.60 (m, 2H), 1.52 (d, J = 13.1 Hz, 6H). ESI-MS: m/z 472.2 [M+Na].
实施例 175  Example 175
2- (2,5-二甲基苯氧基） -2-甲基 -N- ( 1- ( (4- (甲基磺酰基） 苯基）磺酰基） 哌啶 -4- 基） 丙酰胺 （化合物 259)  2-(2,5-Dimethylphenoxy)-2-methyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide (compound 259)
参照实施例 14的方法制得化合物 259: 1H MR (300 MHz, CDC13) δ 8.12 (d, J= 8.4 Hz, 2H), 7.95 (d, J= 8.4 Hz, 2H), 7.05 (d, J= 7.5 Hz, 1H), 6.77 (d, J= 7.4 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 6.57 (s, 1H), 3.84 (ddd, J = 9.2, 4.3, 2.2 Hz, 1H), 3.75 (d, J = 11.7 Hz, 2H), 3.11 (s, 3H), 2.59 (t, J = 10.9 Hz, 2H), 2.24 (s, 3H), 2.15 (s, 3H), 2.03 (d, J = 9.4 Hz, 2H),Compound 259 was prepared by the method of Example 14: 1H MR (300 MHz, CDC1 3 ) δ 8.12 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 7.5 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 6.57 (s, 1H), 3.84 (ddd, J = 9.2, 4.3, 2.2 Hz , 1H), 3.75 (d, J = 11.7 Hz, 2H), 3.11 (s, 3H), 2.59 (t, J = 10.9 Hz, 2H), 2.24 (s, 3H), 2.15 (s, 3H), 2.03 (d, J = 9.4 Hz, 2H),
1.61 (dd, J= 10.8, 4.2 Hz, 2H), 1.48 (s, 6H). ESI-MS: m/z 531.2 [M+Na]+. 1.61 (dd, J= 10.8, 4.2 Hz, 2H), 1.48 (s, 6H). ESI-MS: m/z 531.2 [M+Na] + .
实施例 176  Example 176
5- (2,5-二甲基苯氧基) -N - ( (3S,4S ) -3-氟 -1 - ( (4-氟苯基)磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 （化合物 260)  5-(2,5-Dimethylphenoxy)-N-((3S,4S)-3-fluoro-1 -((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2 ,2-dimethylpentanamide (compound 260)
参照实施例 77的方法制得化合物 260: ee>99%; 1H NMR (300 MHz, CDC13) δ 7.79 (dd, J = 7.2, 5.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.00 (d, J = 7.3 Hz, 1H), 6.66 (d, J = 7.3 Hz, 1H), 6.59 (s, 1H), 5.61 (d, J = 6.9 Hz, 1H), 4.56 -4.27 (m, 1H), 4.11— 4.00 (m, 1H), 3.98 -3.82 (m, 3H), 3.75 -3.64 (m, 1H), 2.52 -2.38 (m, 2H), 2.30 (s, 3H), 2.22 -2.07 (m, 4H), 1.76 -1.63 (m, 4H), 1.53 - 1.46 (m, 1H), 1.20 (s, 6H).ESI-MS: m/z 531.3 [M+Na]+. Compound 260 was prepared by the method of Example 77: ee >99%; 1H NMR (300 MHz, CDC1 3 ) δ 7.79 (dd, J = 7.2, 5.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H ), 7.00 (d, J = 7.3 Hz, 1H), 6.66 (d, J = 7.3 Hz, 1H), 6.59 (s, 1H), 5.61 (d, J = 6.9 Hz, 1H), 4.56 - 4.27 (m , 1H), 4.11— 4.00 (m, 1H), 3.98 -3.82 (m, 3H), 3.75 -3.64 (m, 1H), 2.52 -2.38 (m, 2H), 2.30 (s, 3H), 2.22 -2.07 (m, 4H), 1.76 - 1.63 (m, 4H), 1.53 - 1.46 (m, 1H), 1.20 (s, 6H). ESI-MS: m/z 531.3 [M+Na] + .
实施例 177  Example 177
反式 -5- (2,5-二甲基苯氧基) -N - (3-氟 -1 - ( (4-氟苯基)磺酰基） 哌啶 -4-基） -2,2- 二甲基戊酰胺 （化合物 261 )  Trans-5-(2,5-dimethylphenoxy)-N-(3-fluoro-1 -((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2- Dimethyl valeramide (compound 261)
参照实施例 139的方法制得化合物 261： 1H NMR (300 MHz, CDC13) δ 7.85 - 7.74 (m, 2H), 7.23 (d, J= 8.4 Hz, 2H), 7.00 (d, J= 7.4 Hz, 1H), 6.66 (d, J= 7.2 Hz, 1H), 6.59 (s, 1H),Compound 261 was obtained by the method of Example 139: 1H NMR (300 MHz, CDC1 3 ) δ 7.85 - 7.74 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 7.4 Hz , 1H), 6.66 (d, J= 7.2 Hz, 1H), 6.59 (s, 1H),
5.62 (d, J= 7.3 Hz, 1H), 4.57 - 4.30 (m, 1H), 4.10 - 4.01 (m, 1H), 3.96-3.84 (m, 3H), 3.70 (d, J = 11.9 Hz, 1H), 2.45 (t, J = 10.9 Hz, 2H), 2.30 (s, 3H), 2.22-2.09 (m, 4H), 1.78-1.64 (m, 4H), 1.52 (s, 1H), 1.16 (s, 6H). ESI-MS: m/z 531.3 [M+Na]+. 5.62 (d, J = 7.3 Hz, 1H), 4.57 - 4.30 (m, 1H), 4.10 - 4.01 (m, 1H), 3.96-3.84 (m, 3H), 3.70 (d, J = 11.9 Hz, 1H) , 2.45 (t, J = 10.9 Hz, 2H), 2.30 (s, 3H), 2.22-2.09 (m, 4H), 1.78-1.64 (m, 4H), 1.52 (s, 1H), 1.16 (s, 6H) ESI-MS: m/z 531.3 [M+Na] + .
实施例 178  Example 178
4- ( ( (3S,4S ) -4- ( 5- (2,5-二氯苯氧基) -2,2-二甲基戊酰氨基) -3-氟哌啶 -1-基) 磺酰基） 苯甲酸 （化合物 262)  4-((3S,4S)-4-(5-(2,5-Dichlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl) sulfonate Acyl) benzoic acid (compound 262)
参照实施例 77的方法制得化合物 262: ee>99%; 1H NMR (300 MHz, DMSO- 6) δ 13.47 (s, 1H), 8.16 (d, J= 8.3 Hz, 2H), 7.90 (d, J= 8.4 Hz, 2H), 7.43 (d, J= 8.5 Hz, 2H), 7.19 (d, J= 2.0 Hz, 1H), 7.03 - 6.98 (m, 1H), 4.434.68 (m, 1H), 4.07-3.97 (m, 2H), 3.93-3.77 (m, 2H), 3.58-3.45(m, 1H), 2.72 - 2.55 (m, 2H), 1.81-1.69 (m, 1H), 1.63-1.49 (m, 5H), 1.08 (s, 6H). ESI-MS: m/z 575.1 [M+H]+. Compound 262 was obtained by the method of Example 77: ee >99%; 1H NMR (300 MHz, DMSO- 6 ) δ 13.47 (s, 1H), 8.16 (d, J = 8.3 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 2.0 Hz, 1H), 7.03 - 6.98 (m, 1H), 4.434.68 (m, 1H), 4.07-3.97 (m, 2H), 3.93-3.77 (m, 2H), 3.58-3.45 (m, 1H), 2.72 - 2.55 (m, 2H), 1.81-1.69 (m, 1H), 1.63-1.49 (m , 5H), 1.08 (s, 6H). ESI-MS: m/z 575.1 [M+H] + .
实施例 179 反式—4- ( (4- ( 5- (3,4-二氟苯氧基） -2,2-二甲基戊酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸 （化合物 265 ) Example 179 Trans-4-((4-(5-(3,4-difluorophenoxy)-2,2-dimethylpentanoyl)-3-fluoropiperidin-1-yl)sulfonyl)benzene Formic acid (compound 265)
参照实施例 119和 139的方法制得化合物 265: 1H NMR (300 MHz, DMSO- 6) δ 13.55 - 13.22 (m, IH), 8.16 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 8.3 Hz, 2H), 7.47 - 7.24 (m, 2H), 7.06-6.92 (m, IH), 6.78-6.63 (m, IH), 4..43-4.67 (m, IH), 3.95-3.75 (m, 4H), 3.56-3.45 (m, IH), 2.75 - 2.57 (m, 2H), 1.46-1.80 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 543.2 [M+H]+. Compound 265 was prepared by the method of Examples 119 and 139: 1H NMR (300 MHz, DMSO- 6 ) δ 13.55 - 13.22 (m, IH), 8.16 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 8.3 Hz, 2H), 7.47 - 7.24 (m, 2H), 7.06-6.92 (m, IH), 6.78-6.63 (m, IH), 4..43-4.67 (m, IH), 3.95-3.75 ( m, 4H), 3.56-3.45 (m, IH), 2.75 - 2.57 (m, 2H), 1.46-1.80 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 543.2 [M+ H] + .
实施例 180  Example 180
反式 -N - ( 1 - ( (3,4-二氟苯基） 磺酰基） -3-氟哌啶 -4-基) -5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺 （化合物 268)  trans-N-(1 - ((3,4-difluorophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-5-(2,5-dimethylphenoxy)-2 ,2-Dimethylpentanamide (Compound 268)
参照实施例 139的方法制得化合物 268: 1H MR (300 MHz, DMSO- 6) δ 7.93 (t, J = 8.1 Hz, IH), 7.82- 7.63(m, 2H), 7.42 (d, J= 8.3 Hz, IH), 6.97 (d, J= 7.5 Hz, IH), 6.73 - 6.56 (m, 2H), 4.67- 4.43 (m, IH), 3.92- 3.77 (m, 4H), 3.50 (d, J = 12.0 Hz, IH), 2.72 - 2.58 (m, 2H), 2.24 (s, 3H), 2.07 (s, 3H), 1.49- 1.79 (m, 6H), 1.08 (s, 6H). ESI-MS: m/z 549.2 [M+Na]+. Compound 268 was prepared by the method of Example 139: 1H MR (300 MHz, DMSO- 6 ) δ 7.93 (t, J = 8.1 Hz, IH), 7.82 - 7.63 (m, 2H), 7.42 (d, J = 8.3 Hz, IH), 6.97 (d, J= 7.5 Hz, IH), 6.73 - 6.56 (m, 2H), 4.67- 4.43 (m, IH), 3.92- 3.77 (m, 4H), 3.50 (d, J = 12.0 Hz, IH), 2.72 - 2.58 (m, 2H), 2.24 (s, 3H), 2.07 (s, 3H), 1.49- 1.79 (m, 6H), 1.08 (s, 6H). ESI-MS: m /z 549.2 [M+Na] + .
实施例 181  Example 181
5- (3-氟苯氧基） -2,2-二甲基 -N- ( 1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 戊酰胺 （化合 物 270)  5-(3-Fluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-3-ylsulfonyl)piperidin-4-yl)pentanamide (Compound 270)
参照实施例 119的方法制得化合物 270: 1H MR (300 MHz, DMSO- 6) δ 8.88 (dd, J = 5.7, 3.5 Hz, 2H), 8.21 - 8.07 (m, IH), 7.67 (dd, J = 8.1, 4.8 Hz, IH), 7.35 - 7.12 (m, 2H), 6.80 - 6.65 (m, 3H), 3.89 (d, J= 4.5 Hz, 2H), 3.61 (t, J= 10.0 Hz, 3H), 2.46 - 2.35 (m, 2H), 1.76 - 1.60 (m, 2H), 1.61 - 1.37 (m, 6H), 1.04 (s, 6H). ESI-MS: m/z 486.2 [M+Na]+. Compound 270 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.88 (dd, J = 5.7, 3.5 Hz, 2H), 8.21 - 8.07 (m, IH), 7.67 (dd, J = 8.1, 4.8 Hz, IH), 7.35 - 7.12 (m, 2H), 6.80 - 6.65 (m, 3H), 3.89 (d, J= 4.5 Hz, 2H), 3.61 (t, J= 10.0 Hz, 3H) , 2.46 - 2.35 (m, 2H), 1.76 - 1.60 (m, 2H), 1.61 - 1.37 (m, 6H), 1.04 (s, 6H). ESI-MS: m/z 486.2 [M+Na] + .
实施例 182  Example 182
5- (2-氟苯氧基） -2,2-二甲基 -N- ( 1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 戊酰胺 （化合 物 271 )  5-(2-Fluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-3-ylsulfonyl)piperidin-4-yl)pentanamide (Compound 271)
参照实施例 119的方法制得化合物 271： 1H MR (300 MHz, DMSO- 6) δ 8.89 (d, J = 6.1 Hz, 2H), 8.15 (d, J= 8.1 Hz, IH), 7.69 (dd, J= 8.1, 4.8 Hz, IH), 7.38 - 6.99 (m, 4H), 6.91 (d, J= 7.9 Hz, IH), 3.97 (m, 2H), 3.63 (d, J= 12.2 Hz, 2H), 3.50 - 3.39 (m, IH), 2.42 (d, J = 12.4 Hz, 2H), 1.78 - 1.63 (m, 2H), 1.62 - 1.34 (m, 6H), 1.06 (s,6H). ESI-MS: m/z 486.2 [M+Na]+. Compound 271 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.89 (d, J = 6.1 Hz, 2H), 8.15 (d, J = 8.1 Hz, IH), 7.69 (dd, J= 8.1, 4.8 Hz, IH), 7.38 - 6.99 (m, 4H), 6.91 (d, J= 7.9 Hz, IH), 3.97 (m, 2H), 3.63 (d, J= 12.2 Hz, 2H), 3.50 - 3.39 (m, IH), 2.42 (d, J = 12.4 Hz, 2H), 1.78 - 1.63 (m, 2H), 1.62 - 1.34 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 486.2 [M+Na] + .
实施例 183  Example 183
4- ( (4- ( 5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺基） 哌啶 -1-基） 磺酰基） 苯甲 酸- (乙酰氨基） -乙酯 （化合物 272)  4-((4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanyl)piperidin-1-yl)sulfonyl)benzoic acid-(acetylamino) -ethyl ester (compound 272)
取化合物 119 ( 100 mg， 0.19 mmol)溶于二氯甲垸（3 mL)， 冰浴下滴加草酰氯（22 μί) 和 DMF (2滴；)。 反应约 5小时后， 减压蒸除溶剂及未反应的草酰氯制得酰氯。 取 N- (2-羟基乙基） 乙酰胺 (19μί， 0.19 mmol)溶于二氯甲垸 （2 mL)， 冰浴下加入上述制 备的酰氯及三乙胺 （40μί， 0.29 mmol), 反应 12小时。 加入二氯甲垸 （5 mL) 稀释反 应液， 有机相用水 （5mLx3) 和饱和食盐水 （5mLx2) 洗涤， 无水硫酸钠干燥， 减压 蒸除溶剂， 残余物经柱层析 （洗脱剂： 二氯甲焼 /甲醇 =100:1) 纯化， 得化合物 272 (白 色固体， 48 mg): 1H MR (300 MHz, DMSO- 6) δ 8.20 (d, J= 8.2 Hz, 2H),8.16-8.06 (m, 1H)， 7.88 (d, J= 8.2 Hz, 2H), 7.23 (d, J= 7.5 Hz, 1H), 6.97 (d, J= 7.4 Hz, 1H), 6.71 - 6.57 (m, 2H), 4.30 (t, J = 5.2 Hz, 2H), 3.86 (s, 2H), 3.69-3.5 (m, 3H), 3.43 (d,J= 5.3 Hz, 2H), 2.33 - 2.44 (m , 2H), 2.23 (s, 3H), 2.07 (s, 3H), 1.83 (s, 3H), 1.75 - 1.49 (m, 8H), 1.06 (s, 6H). ESI-MS: m/z 624.3 [M+Na]+. Compound 119 (100 mg, 0.19 mmol) was dissolved in dichloromethane (3 mL) and oxalyl chloride (22 μί) and DMF (2 drops; After reacting for about 5 hours, the solvent and the unreacted oxalyl chloride were evaporated under reduced pressure to give an acid chloride. take N-(2-hydroxyethyl)acetamide (19 μί, 0.19 mmol) was dissolved in dichloromethane (2 mL), and the acid chloride and triethylamine (40 μί, 0.29 mmol) prepared above were added to the mixture for 12 hours. . The reaction mixture was diluted with chloroform (5 mL). : Dichloromethane/methanol = 100:1) Purified to give compound 272 (white solid, 48 mg): 1H MR (300 MHz, DMSO- 6 ) δ 8.20 (d, J = 8.2 Hz, 2H), 8.16- 8.06 (m, 1H), 7.88 (d, J= 8.2 Hz, 2H), 7.23 (d, J= 7.5 Hz, 1H), 6.97 (d, J= 7.4 Hz, 1H), 6.71 - 6.57 (m, 2H) ), 4.30 (t, J = 5.2 Hz, 2H), 3.86 (s, 2H), 3.69-3.5 (m, 3H), 3.43 (d, J = 5.3 Hz, 2H), 2.33 - 2.44 (m , 2H) , 2.23 (s, 3H), 2.07 (s, 3H), 1.83 (s, 3H), 1.75 - 1.49 (m, 8H), 1.06 (s, 6H). ESI-MS: m/z 624.3 [M+Na ] + .
实施例 184  Example 184
5- (3,4-二氟苯氧基） -2,2-二甲基 -N- (1- (吡啶 -3-基磺酰基）哌啶 -4-基）戊酰胺（化 合物 273)  5-(3,4-Difluorophenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide (compound 273)
参照实施例 119的方法制得化合物 273: 1H MR(300 MHz, DMSO- 6) δ 9.02 - 8.75 (m, 2H), 8.24 - 8.04 (m, 1H), 7.69 (dd,J= 8.1, 4.8 Hz, 1H), 7.41 - 7.25 (m, 1H), 7.22 (d,J = 7.8 Hz, 1H), 7.10 - 6.87 (m, 1H), 6.83 - 6.58 (m, 1H), 3.89 (m, 2H), 3.72 - 3.49 (m, 3H), 2.48 - 2.24 (m, 2H), 1.84 - 1.62 (m, 2H), 1.62 - 1.35 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 504.2 [M+Na]+. Compound 273 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 9.02 - 8.75 (m, 2H), 8.24 - 8.04 (m, 1H), 7.69 (dd, J = 8.1, 4.8 Hz , 1H), 7.41 - 7.25 (m, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.10 - 6.87 (m, 1H), 6.83 - 6.58 (m, 1H), 3.89 (m, 2H), 3.72 - 3.49 (m, 3H), 2.48 - 2.24 (m, 2H), 1.84 - 1.62 (m, 2H), 1.62 - 1.35 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 504.2 [M+Na] + .
实施例 185  Example 185
反式 -5- (2,6-二氟苯氧基） -N - (3-氟 -1- (吡啶 -3-基磺酰基） 哌啶 -4-基） -2,2-二甲 基戊酰胺 （化合物 274)  Trans-5-(2,6-difluorophenoxy)-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2,2-dimethyl Valentamide (compound 274)
参照实施例 119和 139的方法制得化合物 274: 1H MR(300 MHz, DMSO- 6) δ 9.02 -8.81 (m, 2Η), 8.20 (d,J= 8.0 Hz, 1H), 7.74-7.63 (m, 1H), 7.42 (d,J= 8.0 Hz, 1H), 7.12 (d J= 9.3 Hz, 3H), 4.42-4.68 (m, 1H), 4.00 (s, 2H), 3.83 (s, 2H), 3.52 (d,J= 11.9 Hz, 1H), 2.80 - 2.63 (m, 2H), 1.45-1.76 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 522.2 [M+Na]+. Compound 274 was prepared by the methods of Examples 119 and 139: 1H MR (300 MHz, DMSO- 6 ) δ 9.02 - 8.81 (m, 2 Η), 8.20 (d, J = 8.0 Hz, 1H), 7.74-7.63 (m , 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.12 (d J = 9.3 Hz, 3H), 4.42-4.68 (m, 1H), 4.00 (s, 2H), 3.83 (s, 2H), 3.52 (d, J = 11.9 Hz, 1H), 2.80 - 2.63 (m, 2H), 1.45-1.76 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 522.2 [M+Na] + .
实施例 186  Example 186
5- (2,6-二氟苯氧基) -N- ((3S,4S) -3-氟 -1- (吡啶 -3-基磺酰基) 哌啶 -4-基） -2,2- 二甲基戊酰胺 （化合物 276)  5-(2,6-Difluorophenoxy)-N-((3S,4S)-3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2,2- Dimethyl valeramide (compound 276)
参照实施例 119和 77的方法制得化合物 276: ee>99%; 1H NMR (300 MHz, DMSO- 6) δ 9.00 - 8.85 (m, 2H), 8.20 (d,J= 7.9 Hz, 1H), 7.72 - 7.66 (m, 1H), 7.42 (d,J= 7.9 Hz, 1H), 7.20 - 7.04 (m, 3H), 4.69 - 4.43 (m, 1H), 4.01 (s, 2H), 3.84 (s, 2H), 3.58- 3.47 (m, 1H), 2.82 - 2.63 (m, 2H), 1.49-1.76 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 522.2 [M+Na]+. Compound 276 was prepared according to the methods of Examples 119 and 77: ee >99%; 1H NMR (300 MHz, DMSO- 6 ) δ 9.00 - 8.85 (m, 2H), 8.20 (d, J = 7.9 Hz, 1H), 7.72 - 7.66 (m, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.20 - 7.04 (m, 3H), 4.69 - 4.43 (m, 1H), 4.01 (s, 2H), 3.84 (s, 2H), 3.58- 3.47 (m, 1H), 2.82 - 2.63 (m, 2H), 1.49-1.76 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 522.2 [M+Na] + .
实施例 187  Example 187
5- (2,4-二氟苯氧基） -2,2-二甲基 -N- (1- ((4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 （化合物 277) 参照实施例 119的方法制得化合物 277: 1H MR (300 MHz, DMSO- 6) δ 8.18 (d, J =5-(2,4-Difluorophenoxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valentamide (Compound 277) Compound 277 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.18 (d, J =
8.4 Hz, 2H), 8.00 (d, J= 8.2 Hz, 2H), 7.31 - 7.19 (m, 2H), 7.17 - 7.10 (m, 1H), 7.04 - 6.94 (m, 1H), 3.96 (t, J= 4.0, 3.3 Hz, 2H), 3.71 - 3.57 (m, 2H), 3.49 - 3.36 (m, 1H), 3.32 (s, 3H), 2.49 - 2.32 (m, 2H), 1.81 - 1.64 (m, 2H), 1.63 - 1.33 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 581.3 [M+Na]+. 8.4 Hz, 2H), 8.00 (d, J = 8.2 Hz, 2H), 7.31 - 7.19 (m, 2H), 7.17 - 7.10 (m, 1H), 7.04 - 6.94 (m, 1H), 3.96 (t, J = 4.0, 3.3 Hz, 2H), 3.71 - 3.57 (m, 2H), 3.49 - 3.36 (m, 1H), 3.32 (s, 3H), 2.49 - 2.32 (m, 2H), 1.81 - 1.64 (m, 2H ), 1.63 - 1.33 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 581.3 [M+Na] + .
实施例 188  Example 188
2- (4-苯甲酰基苯氧基） -N- (1- ((4-氰基苯基） 磺酰基） 哌啶 -4-基） -2-甲基丙酰 胺 (化合物 75)  2-(4-Benzophenoxy)-N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide (Compound 75)
参照实施例 1禾卩 14的方法制得化合物 75: 'HNMRPOO MHz, DMSO-t/6) δ 8.10 (d,J= 8.4 Hz, 2H), 8.02 (d,J=7.7 Hz, 1H), 7.88 (d,J= 8.4 Hz, 2H), 7.75 - 7.62 (m, 5H), 7.61 - 7.51 (m, 2H), 6.93 (d, J = 8.7 Hz, 2H), 3.71 - 3.61 (m, 1H), 3.60 - 3.48 (m, 2H), 2.49 - 2.42 (m, 2H), 1.74 - 1.59 (m, 2H), 1.49 (s, 6H), 1.48 - 1.39 (m, 2H). ESI-MS: m/z 532.2 [M+H]+. Compound 75 was prepared by the method of Example 1 and Example 14: 'HNMRPOO MHz, DMSO-t/ 6 δ 8.10 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.75 - 7.62 (m, 5H), 7.61 - 7.51 (m, 2H), 6.93 (d, J = 8.7 Hz, 2H), 3.71 - 3.61 (m, 1H), 3.60 - 3.48 (m, 2H), 2.49 - 2.42 (m, 2H), 1.74 - 1.59 (m, 2H), 1.49 (s, 6H), 1.48 - 1.39 (m, 2H). ESI-MS: m/z 532.2 [M+H] + .
实施例 189  Example 189
2- (4-苯甲酰基苯氧基） -N- (1- ((3-氰基苯基）磺酰基） 哌啶 -4-基） 乙酰胺 （化合 物 76)  2-(4-Benzophenoxy)-N-(1-((3-cyanophenyl)sulfonyl)piperidin-4-yl)acetamide (Compound 76)
参照实施例 1禾卩 14的方法制得化合物 76: ¾ NMR (300 MHz, DMSO-t/6) δ 8.23 - 8.17 (m, 2H), 8.10 (d,J= 7.6 Hz, 1H), 8.06 (d,J= 7.9 Hz, 1H), 7.90 - 7.81 (m, 1H), 7.74 (d,J= 8.7 Hz, 2H), 7.71 - 7.62 (m, 3H), 7.59 - 7.51 (m, 2H), 7.07 (d,J= 8.6 Hz, 2H), 4.60 - 4.53 (s, 2H), 3.77 - 3.64 (m, 1H), 3.65 - 3.53 (m, 2H), 2.65 - 2.54 (m, 2H), 1.87 - 1.70 (m, 2H), 1.59 - 1.45 (m, 2H). ESI-MS: m/z 504.2 [M+H]+. The compound 76 was obtained by the method of Example 1 and Example 14: 3⁄4 NMR (300 MHz, DMSO-t/ 6 ) δ 8.23 - 8.17 (m, 2H), 8.10 (d, J = 7.6 Hz, 1H), 8.06 ( d, J = 7.9 Hz, 1H), 7.90 - 7.81 (m, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.71 - 7.62 (m, 3H), 7.59 - 7.51 (m, 2H), 7.07 (d, J = 8.6 Hz, 2H), 4.60 - 4.53 (s, 2H), 3.77 - 3.64 (m, 1H), 3.65 - 3.53 (m, 2H), 2.65 - 2.54 (m, 2H), 1.87 - 1.70 (m, 2H), 1.59 - 1.45 (m, 2H). ESI-MS: m/z 504.2 [M+H] + .
实施例 190  Example 190
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- (1- ((3- (甲基磺酰基） 苯基） 磺酰基） 哌 啶 -4-基） 戊酰胺 （化合物 77)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl Pentanoamide (Compound 77)
参照实施例 43的方法制得化合物 77: ¾ NMR (300 MHz, DMSO-t/6) δ 8.28 (d,J= 7.6 Hz, 1H), 8.15 (s, 1H), 8.08 (d,J= 8.0 Hz, 1H), 7.98 - 7.89 (m, 1H), 7.22 (d,J=7.5 Hz, 1H), 6.97 (d,J=7.5 Hz, 1H), 6.68 (s, 1H), 6.62 (d,J= 7.4 Hz, 1H), 3.92 - 3.80 (m, 2H), 3.72 - 3.49 (m, 3H), 3.34 (s, 3H), 2.47 - 2.35 (m, 2H), 2.23 (s, 3H), 2.08 (s, 3H), 1.77 - 1.66 (m, 2H), 1.62 - 1.53 (m, 4H), 1.53 - 1.42 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 573.2 [M+Na]+. Compound 77 was prepared by the method of Example 43: NMR (300 MHz, DMSO-t/ 6 ) δ 8.28 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.98 - 7.89 (m, 1H), 7.22 (d, J=7.5 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.68 (s, 1H), 6.62 (d, J = 7.4 Hz, 1H), 3.92 - 3.80 (m, 2H), 3.72 - 3.49 (m, 3H), 3.34 (s, 3H), 2.47 - 2.35 (m, 2H), 2.23 (s, 3H), 2.08 ( s, 3H), 1.77 - 1.66 (m, 2H), 1.62 - 1.53 (m, 4H), 1.53 - 1.42 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 573.2 [M+ Na] + .
实施例 191  Example 191
4 - ( (4- (5- (2,4-二氟苯氧基） -2,2-二甲基戊酰氨基） 哌啶 -1-基）磺酰基） 苯甲酸 (化合物 278)  4-((4-(5-(2,4-Difluorophenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 278)
参照实施例 119的方法制得化合物 278: 1H MR (300 MHz, DMSO- 6) δ 13.49 (s, 1H)， 8.16 (d, J= 8.0 Hz, 2H), 7.85 (d, J= 8.0 Hz, 2H), 7.33 - 7.06 (m, 3H), 7.05 - 6.93 (m, 1H),Compound 278 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 13.49 (s, 1H), 8.16 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.33 - 7.06 (m, 3H), 7.05 - 6.93 (m, 1H),
4.05 - 3.77 (m, 2H), 3.72 - 3.44 (m, 3H), 2.46 - 2.31 (m, 2H), 1.82 - 1.39 (m, 8H), 1.05 (s, 6H). ESI-MS: m/z 523.2 [M-H] -. 4.05 - 3.77 (m, 2H), 3.72 - 3.44 (m, 3H), 2.46 - 2.31 (m, 2H), 1.82 - 1.39 (m, 8H), 1.05 (s, 6H). ESI-MS: m/z 523.2 [MH] -.
实施例 192  Example 192
反式—4- ( 5- (2,5-二氯苯氧基） -2,2-二甲基戊酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯 甲酸 （化合物 280)  Trans-4-(5(5,5-Dichlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (compound 280 )
参照实施例 119和 139的方法制得化合物 280: 1H NMR (300 MHz, DMSO- 6) δ 13.49 (s, IH), 8.15 (d, J= 8.1 Hz, 2H), 7.88 (d, J= 8.2 Hz, 2H), 7.48 - 7.32 (m, 2H), 7.18 (d, J= 2.4 Hz, IH), 7.03 - 6.95 (m, IH), 4.71 - 4.41 (m, IH), 4.00 (t, J = 5.3 Hz, 2H), 3.93 - 3.74 (m, 2H), 3.58 - 3.44 (m, IH), 2.72 - 2.54 (m, 2H), 1.82 - 1.67 (m, IH), 1.66 - 1.47 (m, 5H), 1.06 (s， 6H). ESI-MS: m/z 575.1 [M+H]+. Compound 280 was obtained by the method of Examples 119 and 139: 1H NMR (300 MHz, DMSO- 6 ) δ 13.49 (s, IH), 8.15 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.2 Hz, 2H), 7.48 - 7.32 (m, 2H), 7.18 (d, J = 2.4 Hz, IH), 7.03 - 6.95 (m, IH), 4.71 - 4.41 (m, IH), 4.00 (t, J = 5.3 Hz, 2H), 3.93 - 3.74 (m, 2H), 3.58 - 3.44 (m, IH), 2.72 - 2.54 (m, 2H), 1.82 - 1.67 (m, IH), 1.66 - 1.47 (m, 5H) , 1.06 (s, 6H). ESI-MS: m/z 575.1 [M+H] + .
实施例 193  Example 193
5- (2-甲氧基苯氧基) -N - ( (3S,4S) -1 - ( (4-氰基苯基) 磺酰基） -3-氟哌啶 -4-基) -2,2-二甲基戊酰胺 （化合物 284 )  5-(2-Methoxyphenoxy)-N-((3S,4S) -1 - ((4-cyanophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-2, 2-dimethylpentanamide (compound 284)
参照实施例 119和 77的方法制得化合物 284: 1H NMR (300 MHz, CDC13) δ 7.90 - 7.79 (m, 4H), 6.99 - 6.83 (m, 4H), 5.95 (d, J = 7.5 Hz, IH), 4.61 - 4.34 (m, IH), 4.08 - 3.93 (m, 4H), 3.87 (s, 3H), 3.73 - 3.63 (m, IH), 2.61 - 2.49 (m, 2H), 2.17 - 2.05 (m, IH), 1.82 - 1.67 (m, 4H), 1.57 - 1.48 (m, IH), 1.19 (s, 6H). ESI-MS: m/z 540.1 [M+Na]+. Compound 284 was obtained by the methods of Examples 119 and 77: 1H NMR (300 MHz, CDC1 3 ) δ 7.90 - 7.79 (m, 4H), 6.99 - 6.83 (m, 4H), 5.95 (d, J = 7.5 Hz, IH), 4.61 - 4.34 (m, IH), 4.08 - 3.93 (m, 4H), 3.87 (s, 3H), 3.73 - 3.63 (m, IH), 2.61 - 2.49 (m, 2H), 2.17 - 2.05 ( m, IH), 1.82 - 1.67 (m, 4H), 1.57 - 1.48 (m, IH), 1.19 (s, 6H). ESI-MS: m/z 540.1 [M+Na] + .
实施例 194  Example 194
5- (2-甲氧基苯氧基) -N - ( (3S,4S) -1 - ( (3-氰基苯基) 磺酰基） -3-氟哌啶 -4-基) -2,2-二甲基戊酰胺 （化合物 285 )  5-(2-Methoxyphenoxy)-N-((3S,4S) -1 - ((3-cyanophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-2, 2-dimethylpentanamide (compound 285)
参照实施例 119和 77的方法制得化合物 285: 1H NMR (300 MHz, CDC13) δ 8.06 (s, IH), 7.98 (d, J = 7.9 Hz, IH), 7.89 (d, J = 7.7 Hz, IH), 7.72 - 7.66 (m, IH), 6.97 - 6.85 (m, 4H), 5.95 (d, J= 7.5 Hz, IH), 4.62 - 4.34 (m, IH), 4.10 - 4.02 (m, IH), 4.03 - 3.96 (m, 3H), 3.87 (s, 3H), 3.74 - 3.65 (m, IH), 2.60 - 2.49 (m, 2H), 2.17 - 2.03 (m, IH), 1.81 - 1.67 (m, 4H), 1.58 - 1.48 (m, IH), 1.19 (s, 6H). ESI-MS: m/z 540.1 [M+Na]+. Compound 285 was prepared by the methods of Examples 119 and 77: 1H NMR (300 MHz, CDC1 3 ) δ 8.06 (s, IH), 7.98 (d, J = 7.9 Hz, IH), 7.89 (d, J = 7.7 Hz , IH), 7.72 - 7.66 (m, IH), 6.97 - 6.85 (m, 4H), 5.95 (d, J = 7.5 Hz, IH), 4.62 - 4.34 (m, IH), 4.10 - 4.02 (m, IH ), 4.03 - 3.96 (m, 3H), 3.87 (s, 3H), 3.74 - 3.65 (m, IH), 2.60 - 2.49 (m, 2H), 2.17 - 2.03 (m, IH), 1.81 - 1.67 (m , 4H), 1.58 - 1.48 (m, IH), 1.19 (s, 6H). ESI-MS: m/z 540.1 [M+Na] + .
实施例 195  Example 195
5- (2,5-二氯苯氧基） -2,2-二甲基 -N- ( 1- (吡啶 -3-基磺酰基）哌啶 -4-基）戊酰胺（化 合物 287)  5-(2,5-Dichlorophenoxy)-2,2-dimethyl-N-(1-(pyridine-3-ylsulfonyl)piperidin-4-yl)pentanamide (compound 287)
参照实施例 119的方法制得化合物 287: 1H MR (300 MHz, DMSO- 6) δ 8.95 - 8.83 (m, 2H), 8.15 (d, J = 7.9 Hz, IH), 7.69 (dd, J = 8.1, 4.8 Hz, IH), 7.44 (d, J = 8.4 Hz, IH), 7.27 - 7.15 (m, 2H), 7.01 (dd, J= 8.5, 2.3 Hz, IH), 4.12 - 3.96 (m, 2H), 3.70 - 3.60 (m, 2H), 3.60 - 3.50 (m, IH), 2.48 - 2.37 (m, 2H), 1.78 - 1.66 (m, 2H), 1.64 - 1.54 (m, 4H), 1.53 - 1.42 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 536.2 [M+Na]+. Compound 287 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.95 - 8.83 (m, 2H), 8.15 (d, J = 7.9 Hz, IH), 7.69 (dd, J = 8.1 , 4.8 Hz, IH), 7.44 (d, J = 8.4 Hz, IH), 7.27 - 7.15 (m, 2H), 7.01 (dd, J= 8.5, 2.3 Hz, IH), 4.12 - 3.96 (m, 2H) , 3.70 - 3.60 (m, 2H), 3.60 - 3.50 (m, IH), 2.48 - 2.37 (m, 2H), 1.78 - 1.66 (m, 2H), 1.64 - 1.54 (m, 4H), 1.53 - 1.42 ( m, 2H), 1.06 (s, 6H). ESI-MS: m/z 536.2 [M+Na] + .
实施例 196  Example 196
反式 -5— (2,4-二氟苯氧基） -N- (3氟 -1- (吡啶 -3-磺酰基） 哌啶 -4-基） -2,2-二甲基戊 酰胺 （化合物 289) Trans-5-(2,4-difluorophenoxy)-N-(3fluoro-1-(pyridine-3-sulfonyl)piperidin-4-yl)-2,2-dimethylpentyl Amide (compound 289)
参照实施例 119和 139的方法制得化合物 289: 1H MR (300 MHz, DMSO- 6) δ 9.00 (s, 1Η), 8.86 (d, J= 4.1 Hz, 1H), 8.06 (d, J= 7.9 Hz, 1H), 7.51 (dd, J= 7.7, 4.9 Hz, 1H), 6.98 - 6.68 (m, 3H), 5.80 (d, J= 7.4 Hz, 1H), 4.68 - 4.34 (m, 1H), 4.17 - 3.85 (m, 4H), 3.74 (d, J = 11.9 Hz, 1H), 2.56 (dd, J = 13.8, 11.6 Hz, 2H), 2.13 (d, J = 13.4 Hz, 1H), 1.88 - 1.53 (m, 6H), 1.19 (s, 6H). ESI-MS: m/z 500.2 [M+H]+. Compound 289 was prepared by the methods of Examples 119 and 139: 1H MR (300 MHz, DMSO- 6 ) δ 9.00 (s, 1 Η), 8.86 (d, J = 4.1 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.51 (dd, J= 7.7, 4.9 Hz, 1H), 6.98 - 6.68 (m, 3H), 5.80 (d, J= 7.4 Hz, 1H), 4.68 - 4.34 (m, 1H), 4.17 - 3.85 (m, 4H), 3.74 (d, J = 11.9 Hz, 1H), 2.56 (dd, J = 13.8, 11.6 Hz, 2H), 2.13 (d, J = 13.4 Hz, 1H), 1.88 - 1.53 ( m, 6H), 1.19 (s, 6H). ESI-MS: m/z 500.2 [M+H] + .
实施例 197  Example 197
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- ( 1- ( (2,4,5-三氟苯基）磺酰基）哌啶 -4-基） 戊酰胺 （化合物 290)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-((2,4,5-trifluorophenyl)sulfonyl)piperidin-4-yl Pentanoamide (compound 290)
参照实施例 43的方法制得化合物 290: 1H NMR (300 MHz, CDC13) δ 7.80 - 7.69 (m, 1H), 7.18 - 7.07 (m, 1H), 7.04 (d, J= 7.4 Hz, 1H), 6.70 (d, J= 7.3 Hz, 1H), 6.63 (s, 1H), 5.52 (d, J= 7.5 Hz, 1H), 4.02 - 3.77 (m, 5H), 2.84 - 2.69 (m, 2H), 2.33 (s, 3H), 2.20 (s, 3H), 2.09 - 1.95 (m, 2H), 1.80 - 1.66 (m, 4H), 1.54 - 1.45 (m, 2H), 1.23 (s, 6H). ESI-MS: m/z 549.3 [M+Na]+. The compound 290 was obtained by the method of Example 43: 1H NMR (300 MHz, CDC1 3 ) δ 7.80 - 7.69 (m, 1H), 7.18 - 7.07 (m, 1H), 7.04 (d, J = 7.4 Hz, 1H) , 6.70 (d, J= 7.3 Hz, 1H), 6.63 (s, 1H), 5.52 (d, J= 7.5 Hz, 1H), 4.02 - 3.77 (m, 5H), 2.84 - 2.69 (m, 2H), 2.33 (s, 3H), 2.20 (s, 3H), 2.09 - 1.95 (m, 2H), 1.80 - 1.66 (m, 4H), 1.54 - 1.45 (m, 2H), 1.23 (s, 6H). ESI- MS: m/z 549.3 [M+Na] + .
实施例 198  Example 198
N- ( 1 - ( ( 5-氯 -2,4-二氟苯基) 磺酰基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基) -2,2- 二甲基戊酰胺 （化合物 291 )  N-( 1 - ( ( 5-chloro-2,4-difluorophenyl)sulfonyl)piperidin-4-yl) -5-(2,5-dimethylphenoxy) -2,2- Dimethyl valeramide (compound 291)
参照实施例 43的方法制得化合物 291： 1H NMR (300 MHz, CDC13) δ 7.99 - 7.87 (m, 1H), 7.13 - 7.03 (m, 1H), 7.00 (d, J= 7.4 Hz, 1H), 6.66 (d, J= 7.3 Hz, 1H), 6.59 (s, 1H), 5.49 (d, J= 7.2 Hz, 1H), 3.97 - 3.77 (m, 5H), 2.81 - 2.64 (m, 2H), 2.30 (s, 3H), 2.16 (s, 3H), 2.07 - 1.93 (m, 2H), 1.80 - 1.64 (m, 4H), 1.51 - 1.42 (m, 2H), 1.19 (s, 6H). ESI-MS: m/z 565.2 [M+Na]+. Compound 291 was obtained by the method of Example 43: 1H NMR (300 MHz, CDC1 3 ) δ 7.99 - 7.87 (m, 1H), 7.13 - 7.03 (m, 1H), 7.00 (d, J = 7.4 Hz, 1H) , 6.66 (d, J = 7.3 Hz, 1H), 6.59 (s, 1H), 5.49 (d, J = 7.2 Hz, 1H), 3.97 - 3.77 (m, 5H), 2.81 - 2.64 (m, 2H), 2.30 (s, 3H), 2.16 (s, 3H), 2.07 - 1.93 (m, 2H), 1.80 - 1.64 (m, 4H), 1.51 - 1.42 (m, 2H), 1.19 (s, 6H). ESI- MS: m/z 565.2 [M+Na] + .
实施例 199  Example 199
N- ( 1 - ( (3-氯 -4-氟苯基) 磺酰基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基) -2,2-二甲 基戊酰胺 （化合物 292)  N-( 1 - ((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethyl Valentamide (compound 292)
参照实施例 43的方法制得化合物 292: 1H NMR (300 MHz, CDC13) δ 7.83 (dd, J= 6.4, 1.5 Hz, 1H), 7.70 - 7.59 (m, 1H), 7.34 - 7.27 (m, 1H), 7.00 (d, J = 7.4 Hz, 1H), 6.66 (d, J = 7.4 Hz, 1H), 6.59 (s, 1H), 5.48 (d, J = 7.4 Hz, 1H), 3.89 (t, J = 5.1 Hz, 2H), 3.84 - 3.70 (m, 3H), 2.51 - 2.36 (m, 2H), 2.29 (s, 3H), 2.16 (s, 3H), 2.03 - 1.91 (m, 2H), 1.76 - 1.62 (m, 4H), 1.54 - 1.41 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 547.2 [M+Na]+. The compound 292 was obtained by the method of Example 43: 1H NMR (300 MHz, CDC1 3 ) δ 7.83 (dd, J = 6.4, 1.5 Hz, 1H), 7.70 - 7.59 (m, 1H), 7.34 - 7.27 (m, 1H), 7.00 (d, J = 7.4 Hz, 1H), 6.66 (d, J = 7.4 Hz, 1H), 6.59 (s, 1H), 5.48 (d, J = 7.4 Hz, 1H), 3.89 (t, J = 5.1 Hz, 2H), 3.84 - 3.70 (m, 3H), 2.51 - 2.36 (m, 2H), 2.29 (s, 3H), 2.16 (s, 3H), 2.03 - 1.91 (m, 2H), 1.76 - 1.62 (m, 4H), 1.54 - 1.41 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 547.2 [M+Na] + .
实施例 200  Example 200
N- ( 1 - ( (2-氯 -4-氟苯基） 磺酰基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基) -2,2-二甲 基戊酰胺 （化合物 293 )  N-( 1 - ( (2-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl) -5-(2,5-dimethylphenoxy) -2,2-dimethyl Valentamide (compound 293)
参照实施例 43的方法制得化合物 293 : 1H NMR (300 MHz, CDC13) δ 8.17 - 8.05 (m, 1H), 7.32 - 7.26 (m, 1H), 7.18 - 7.07 (m, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.69 (d, J= 7.4 Hz, 1H), 6.63 (s, 1H), 5.53 (d, J= 7.5 Hz, 1H), 4.03 - 3.75 (m, 5H), 2.99 - 2.79 (m, 2H), 2.33 (s, 3H), 2.20 (s, 3H), 2.03 - 1.93 (m, 2H), 1.81 - 1.65 (m, 4H), 1.54 - 1.40 (m, 2H), 1.23 (s, 6H). ESI-MS: m/z 547.2 [M+Na]+. Compound 293 was obtained by the method of Example 43: 1H NMR (300 MHz, CDC1 3 ) δ 8.17 - 8.05 (m, 1H), 7.32 - 7.26 (m, 1H), 7.18 - 7.07 (m, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.69 (d, J = 7.4 Hz, 1H), 6.63 (s, 1H) ), 5.53 (d, J= 7.5 Hz, 1H), 4.03 - 3.75 (m, 5H), 2.99 - 2.79 (m, 2H), 2.33 (s, 3H), 2.20 (s, 3H), 2.03 - 1.93 ( m, 2H), 1.81 - 1.65 (m, 4H), 1.54 - 1.40 (m, 2H), 1.23 (s, 6H). ESI-MS: m/z 547.2 [M+Na] + .
实施例 201  Example 201
N- ( 1 - ( (3,5-二氟苯基） 磺酰基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基） -2,2-二甲 基戊酰胺 （化合物 294)  N-( 1 - ( (3,5-difluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentyl Amide (compound 294)
参照实施例 43的方法制得化合物 294: 1H MR (300 MHz, CDC13) δ 7.32 (d, J= 4.1 Hz, 2H), 7.07 (dd, J = 21.0, 7.9 Hz, 2H), 6.70 (d, J = 7.3 Hz, 1H), 6.63 (s, 1H), 5.51 (d, J = 7.2 Hz, 1H), 3.98 - 3.90 (m, 2H), 3.82 (d, J= 12.1 Hz, 2H), 3.78 - 3.72 (m, 1H), 2.52 (t, J = 11.6 Hz, 2H), 2.33 (s, 3H), 2.20 (s, 3H), 2.02 (d, J = 11.6 Hz, 2H), 1.71 (s, 4H), 1.59 - 1.46 (m, 2H), 1.22 (s, 6H). ESI-MS: m/z 531.3 [M+Na]+. Compound 294 was prepared by the method of Example 43: 1H MR (300 MHz, CDC 13) δ 7.32 (d, J = 4.1 Hz, 2H), 7.07 (dd, J = 21.0, 7.9 Hz, 2H), 6.70 (d, J = 7.3 Hz, 1H), 6.63 (s, 1H), 5.51 (d, J = 7.2 Hz, 1H), 3.98 - 3.90 (m, 2H), 3.82 (d, J = 12.1 Hz, 2H), 3.78 - 3.72 (m, 1H), 2.52 (t, J = 11.6 Hz, 2H), 2.33 (s, 3H), 2.20 (s, 3H), 2.02 (d, J = 11.6 Hz, 2H), 1.71 (s, 4H) ), 1.59 - 1.46 (m, 2H), 1.22 (s, 6H). ESI-MS: m/z 531.3 [M+Na] + .
实施例 202  Example 202
N- ( 1 - ( (2,4-二氟苯基） 磺酰基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基) -2,2-二甲基 戊酰胺 （化合物 295 )  N-( 1 - ( (2,4-difluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentyl Amide (compound 295)
参照实施例 43的方法制得化合物 295: MR (300 MHz, CDC13) δ 7.88 (dd, J= 14.7,Compound 295 was prepared by the method of Example 43: MR (300 MHz, CDC1 3 ) δ 7.88 (dd, J = 14.7,
8.1 Hz, 1H), 6.99 (dd, J= 16.1, 8.1 Hz, 3H), 6.68 (d, J= 7.4 Hz, 1H), 6.61 (s, 1H), 5.49 (d, J = 7.1 Hz, 1H), 3.92 (d, J = 5.3 Hz, 2H), 3.86 (d, J= 12.7 Hz, 3H), 2.70 (t, J = 12.1 Hz, 2H), 2.32 (s, 3H), 2.18 (s, 3H), 2.00 (d, J = 12.7 Hz, 2H), 1.70 (s, 4H), 1.48 (ddd, J = 15.7, 12.6, 3.7 Hz, 2H), 1.21 (s, 6H). ESI-MS: m/z 531.3 [M+Na]+. 8.1 Hz, 1H), 6.99 (dd, J= 16.1, 8.1 Hz, 3H), 6.68 (d, J= 7.4 Hz, 1H), 6.61 (s, 1H), 5.49 (d, J = 7.1 Hz, 1H) , 3.92 (d, J = 5.3 Hz, 2H), 3.86 (d, J = 12.7 Hz, 3H), 2.70 (t, J = 12.1 Hz, 2H), 2.32 (s, 3H), 2.18 (s, 3H) , 2.00 (d, J = 12.7 Hz, 2H), 1.70 (s, 4H), 1.48 (ddd, J = 15.7, 12.6, 3.7 Hz, 2H), 1.21 (s, 6H). ESI-MS: m/z 531.3 [M+Na] + .
实施例 203  Example 203
N- ( 1 - ( ( 5-氯 -2-氟苯基) 磺酰基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基) -2,2-二甲 基戊酰胺 （化合物 296)  N-( 1 - ( ( 5-chloro-2-fluorophenyl)sulfonyl)piperidin-4-yl) -5-(2,5-dimethylphenoxy) -2,2-dimethyl Valentamide (compound 296)
参照实施例 43的方法制得化合物 296: 1H MR (300 MHz, CDC13) δ 7.32 (d, J= 4.1 Hz, 2H), 7.07 (dd, J = 21.0, 7.9 Hz, 2H), 6.70 (d, J = 7.3 Hz, 1H), 6.63 (s, 1H), 5.51 (d, J = Compound 296 was prepared by the method of Example 43: 1H MR (300 MHz, CDC13) δ 7.32 (d, J = 4.1 Hz, 2H), 7.07 (dd, J = 21.0, 7.9 Hz, 2H), 6.70 (d, J = 7.3 Hz, 1H), 6.63 (s, 1H), 5.51 (d, J =
7.2 Hz, 1H), 3.98 - 3.90 (m, 2H), 3.82 (d, J= 12.1 Hz, 2H), 3.78 - 3.72 (m, 1H), 2.52 (t, J = 11.6 Hz, 2H), 2.33 (s, 3H), 2.20 (s, 3H), 2.02 (d, J = 11.6 Hz, 2H), 1.71 (s, 4H), 1.59 - 1.46 (m, 2H), 1.22 (s, 6H). ESI-MS: m/z 547.3 [M+Na]+. 7.2 Hz, 1H), 3.98 - 3.90 (m, 2H), 3.82 (d, J = 12.1 Hz, 2H), 3.78 - 3.72 (m, 1H), 2.52 (t, J = 11.6 Hz, 2H), 2.33 ( s, 3H), 2.20 (s, 3H), 2.02 (d, J = 11.6 Hz, 2H), 1.71 (s, 4H), 1.59 - 1.46 (m, 2H), 1.22 (s, 6H). ESI-MS : m/z 547.3 [M+Na] + .
实施例 204  Example 204
N- ( 1 - ( (2,6-二氟苯基） 磺酰基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基） -2,2-二甲 基戊酰胺 （化合物 297)  N-( 1 - ( (2,6-difluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentyl Amide (compound 297)
参照实施例 43的方法制得化合物 297: 1H MR (300 MHz, OMSO-d6) δ 7.82 - 7.72 (m, 1H), 7.38 - 7.25 (m, 3H), 6.97 (d, J = 7.6 Hz, 1H), 6.72 - 6.66 (m, 1H), 6.61 (d, J = 7.3 Hz, 1H), 3.89 - 3.83 (m, 2H), 3.74 - 3.62 (m, 3H), 2.76 - 2.66 (m, 2H), 2.24 (s, 3H), 2.08 (s, 3H), 1.77 - 1.69 (m, 2H), 1.59 - 1.54 (m, 4H), 1.52 - 1.44 (m, 2H), 1.07 (s, 6H). ESI-MS: m/z 531.3 [M+Na]+. Compound 297 was prepared by the method of Example 43: 1H MR (300 MHz, OMSO-d 6 ) δ 7.82 - 7.72 (m, 1H), 7.38 - 7.25 (m, 3H), 6.97 (d, J = 7.6 Hz, 1H), 6.72 - 6.66 (m, 1H), 6.61 (d, J = 7.3 Hz, 1H), 3.89 - 3.83 (m, 2H), 3.74 - 3.62 (m, 3H), 2.76 - 2.66 (m, 2H) , 2.24 (s, 3H), 2.08 (s, 3H), 1.77 - 1.69 (m, 2H), 1.59 - 1.54 (m, 4H), 1.52 - 1.44 (m, 2H), 1.07 (s, 6H). ESI-MS: m/z 531.3 [M+Na] + .
实施例 205  Example 205
5- (2,5-二甲基苯氧基) -N- ( 1- - ( (4-氟 -3- (三氟甲基） 苯基)磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 （化合物 298 )  5-(2,5-Dimethylphenoxy)-N-(1-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-yl)-2 ,2-dimethylpentanamide (compound 298)
参照实施例 43的方法制得化合物 298: 1H MR (300 MHz, OMSO-d6) δ 8.20 - 8.10 (m, 1H), 8.03 - 7.93 (m, 1H), 7.88 - 7.77 (m, 1H), 7.25 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.68 (s, 1H), 6.62 (d, J= 7.6 Hz, 1H), 3.85 (t, J= 10.6 Hz, 2H), 3.68 - 3.55 (m, 3H), 2.48 - 2.39 (m, 2H), 2.23 (s, 3H), 2.08 (s, 3H), 1.76 - 1.64 (m, 2H), 1.61 - 1.53 (m, 4H), 1.52 - 1.42 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 581.3 [M+Na]+. Compound 298 was prepared by the method of Example 43: 1H MR (300 MHz, OMSO-d 6 ) δ 8.20 - 8.10 (m, 1H), 8.03 - 7.93 (m, 1H), 7.88 - 7.77 (m, 1H), 7.25 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.68 (s, 1H), 6.62 (d, J= 7.6 Hz, 1H), 3.85 (t, J= 10.6 Hz, 2H), 3.68 - 3.55 (m, 3H), 2.48 - 2.39 (m, 2H), 2.23 (s, 3H), 2.08 (s, 3H), 1.76 - 1.64 (m, 2H), 1.61 - 1.53 ( m, 4H), 1.52 - 1.42 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 581.3 [M+Na] + .
实施例 206  Example 206
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- ( 1- (喹啉 -8-基磺酰基) 哌啶 -4-基） 戊酰胺 (化合物 299)  5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(quinolin-8-ylsulfonyl)piperidin-4-yl)pentanamide (compound 299 )
参照实施例 43的方法制得化合物 299: 1H MR (300 MHz, CDC13) δ 9.06 (d, J = 2.8 Hz, 1H), 8.49 (d, J = 7.2 Hz, 1H), 8.25 (d, J= 8.2 Hz, 1H)， 8.04 (d, J = 8.1 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.54 (dd, J = 8.2, 4.1 Hz, 1H), 7.01 (d, J = 7.4 Hz, 1H), 6.67 (d, J = 7.4 Hz, 1H), 6.61 (s, 1H), 5.55 (d, J= 7.6 Hz, 1H), 4.11 (d, J= 12.9 Hz, 2H), 3.90 (t, J= 5.3 Hz, 2H), 3.87 - 3.73 (m, 1H), 2.92 (t, J = 12.1 Hz, 2H), 2.31 (s, 3H), 2.17 (s, 3H), 1.96 (d, J= 11.0 Hz, 2H), 1.69 (s, 4H), 1.52 (ddd, J = 15.3, 12.1, 3.7 Hz, 2H), 1.19 (s, 6H). ESI-MS: m/z 546.3 [M+Na]+. Compound 299 was prepared by the method of Example 43: 1H MR (300 MHz, CDC1 3 ) δ 9.06 (d, J = 2.8 Hz, 1H), 8.49 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 8.2 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.54 (dd, J = 8.2, 4.1 Hz, 1H), 7.01 (d, J = 7.4 Hz, 1H), 6.67 (d, J = 7.4 Hz, 1H), 6.61 (s, 1H), 5.55 (d, J= 7.6 Hz, 1H), 4.11 (d, J= 12.9 Hz, 2H), 3.90 (t, J= 5.3 Hz, 2H), 3.87 - 3.73 (m, 1H), 2.92 (t, J = 12.1 Hz, 2H), 2.31 (s, 3H), 2.17 (s, 3H), 1.96 (d , J = 11.0 Hz, 2H), 1.69 (s, 4H), 1.52 (ddd, J = 15.3, 12.1, 3.7 Hz, 2H), 1.19 (s, 6H). ESI-MS: m/z 546.3 [M+ Na] + .
实施例 207  Example 207
反式 -2- (2,4-二氟苯氧基） -N - ( 3-氟 -1- (吡啶 -3-基磺酰基） 哌啶 -4-基） -2-甲基丙 酰胺 （化合物 300)  Trans-2-(2,4-difluorophenoxy)-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methylpropanamide ( Compound 300)
参照实施例 14和 139的方法制得化合物 300: 1H MR (300 MHz, OMSO-d6) δ 9.00 - 8.86 (m, 2H), 8.32 (d, J = 8.3 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.74 - 7.62 (m, 1H), 7.38 - 7.22 (m, 1H), 7.14 - 6.92 (m, 2H), 4.79 - 4.50 (m, 1H), 4.04 - 3.80 (m, 2H), 3.61 - 3.50 (m, 1H), 2.81 - 2.62 (m, 2H), 1.89 - 1.73 (m, 1H), 1.73 - 1.55 (m, 1H), 1.37 (s, 3H), 1.35 (s, 3H). ESI-MS :m/z 480.1 [M+Na]+. Compound 300 was prepared by the methods of Examples 14 and 139: 1H MR (300 MHz, OMSO-d 6 ) δ 9.00 - 8.86 (m, 2H), 8.32 (d, J = 8.3 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.74 - 7.62 (m, 1H), 7.38 - 7.22 (m, 1H), 7.14 - 6.92 (m, 2H), 4.79 - 4.50 (m, 1H), 4.04 - 3.80 (m, 2H), 3.61 - 3.50 (m, 1H), 2.81 - 2.62 (m, 2H), 1.89 - 1.73 (m, 1H), 1.73 - 1.55 (m, 1H), 1.37 (s, 3H), 1.35 (s, 3H). ESI-MS: m/z 480.1 [M+Na] + .
实施例 208  Example 208
反式 -2- (2,4-二氟苯氧基） -N - ( 3-氟 -1 - ( (4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 —4-基） -2-甲基丙酰胺 （化合物 301 )  Trans-2-(2,4-difluorophenoxy)-N-(3-fluoro-1 -((4-(methylsulfonyl)phenyl)sulfonyl)piperidine-4-yl)- 2-methylpropionamide (compound 301)
参照实施例 14和 139的方法制得化合物 301 : iH MR (300 MHz, OMSO-d6) δ 8.38 - 8.28 (m, 1H), 8.19 (d, J = 8.2 Hz, 2H), 8.05 (d, J = 8.2 Hz, 2H), 7.36 - 7.23 (m, 1H), 7.12 - 6.93 (m, 2H), 4.76 - 4.54 (m, 1H), 3.95 - 3.78 (m, 2H), 3.60 - 3.47 (m, 1H), 3.32 (s, 3H), 2.76 - 2.60 (m, 2H), 1.88 - 1.76 (m, 1H), 1.72 - 1.58 (m, 1H), 1.37 (s, 3H), 1.35 (s, 3H). ESI-MS: m/z 557.1 [M+Na]+. Compound 301 was prepared by the methods of Examples 14 and 139: iH MR (300 MHz, OMSO-d 6 ) δ 8.38 - 8.28 (m, 1H), 8.19 (d, J = 8.2 Hz, 2H), 8.05 (d, J = 8.2 Hz, 2H), 7.36 - 7.23 (m, 1H), 7.12 - 6.93 (m, 2H), 4.76 - 4.54 (m, 1H), 3.95 - 3.78 (m, 2H), 3.60 - 3.47 (m, 1H), 3.32 (s, 3H), 2.76 - 2.60 (m, 2H), 1.88 - 1.76 (m, 1H), 1.72 - 1.58 (m, 1H), 1.37 (s, 3H), 1.35 (s, 3H). ESI-MS: m/z 557.1 [ M+Na] + .
实施例 209  Example 209
2- (2,3-二氟 -4-甲基苯氧基） -2-甲基 -N- ( 1- ( (4- (甲基磺酰基） 苯基）磺酰基） 哌 啶 -4-基） 丙酰胺 （化合物 302)  2-(2,3-Difluoro-4-methylphenoxy)-2-methyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4- Base) propionamide (compound 302)
参照实施例 14的方法制得化合物 302: 1H MR (300 MHz, DMSO- 6) δ 8.20 (d, J = 2.8 Hz, 2H), 8.07 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 5.1 Hz, 2H), 7.03 - 6.93 (m, 1H), 6.74 - 6.64 (m, 1H), 3.63 (d, J= 11.9 Hz, 1H),3.65-3.63 (m, 2H), 3.31 (s, 3H), 2.60 - 2.52 (m, 2H), 2.21 (s, 3H), 1.79 - 1.68 (m, 2H), 1.61 - 1.52 (m, 2H), 1.38 (s, 6H). ESI-MS: m/z 553.3 [M+Na]+. Compound 302 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 8.20 (d, J = 2.8 Hz, 2H), 8.07 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 5.1 Hz, 2H), 7.03 - 6.93 (m, 1H), 6.74 - 6.64 (m, 1H), 3.63 (d, J = 11.9 Hz, 1H), 3.65-3.63 (m, 2H), 3.31 (s , 3H), 2.60 - 2.52 (m, 2H), 2.21 (s, 3H), 1.79 - 1.68 (m, 2H), 1.61 - 1.52 (m, 2H), 1.38 (s, 6H). ESI-MS: m /z 553.3 [M+Na] + .
实施例 210  Example 210
4- (2,3-二氟 -4-甲基苯氧基） -N- ( 1- ( (4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4- 基） 丁酰胺 （化合物 303 )  4-(2,3-Difluoro-4-methylphenoxy)-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)butanamide Compound 303)
参照实施例 119的方法制得化合物 303 : 1H MR (300 MHz, DMSO- 6) δ 8.22 - 8.15 (m, 2Η), 8.05 - 7.96 (m, 2H), 7.82 (d, J = 7.5 Hz, 1H), 7.03 - 6.93 (m, 1H), 6.91 - 6.83 (m, 1H), 4.01 (t, J= 6.3 Hz, 2H), 3.71 - 3.61 (m, 1H), 3.59 - 3.48 (m, 2H), 3.32 (s, 3H), 2.59 (t, J = 12.2 Hz, 2H), 2.51 - 2.49 (m, 2H), 2.19 (s, 3H), 1.95 - 1.86 (m, 2H), 1.83 - 1.74 (m, 2H), 1.48 - 1.31 (m, 2H). ESI-MS: m/z 553.3 [M+Na]+. Compound 303 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.22 - 8.15 (m, 2 Η), 8.05 - 7.96 (m, 2H), 7.82 (d, J = 7.5 Hz, 1H ), 7.03 - 6.93 (m, 1H), 6.91 - 6.83 (m, 1H), 4.01 (t, J = 6.3 Hz, 2H), 3.71 - 3.61 (m, 1H), 3.59 - 3.48 (m, 2H), 3.32 (s, 3H), 2.59 (t, J = 12.2 Hz, 2H), 2.51 - 2.49 (m, 2H), 2.19 (s, 3H), 1.95 - 1.86 (m, 2H), 1.83 - 1.74 (m, 2H), 1.48 - 1.31 (m, 2H). ESI-MS: m/z 553.3 [M+Na] + .
实施例 211  Example 211
5- (2,3-二氟 -4-甲基苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (甲基磺酰基）苯基）磺酰基） 哌啶—4-基） 戊酰胺 （化合物 304)  5-(2,3-Difluoro-4-methylphenoxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidine —4-yl) pentanoamide (compound 304)
参照实施例 119的方法制得化合物 304: 1H MR (300 MHz, DMSO- 6) δ 8.21 - 8.14 (m, 2H), 8.00 (d, J = 9 Hz, 1H), 7.97 (d, J = 9 Hz, 1H), 7.20 (d, J= 7.7 Hz, 1H), 7.02 - 6.92 (m, 1H), 6.89 - 6.81 (m, 1H), 3.97 (t, J= 6 Hz ,2H), 3.64 (d, 1H), 3.29 - 3.24 (m, 2H), 2.49 (s, 3H), 2.47 - 2.36 (m, 2H), 2.18 (s, 3H), 1.74 - 1.64 (m, 2H), 1.59 - 1.50 (m, 4H), 1.50 - 1.36 (m, 2H), 1.04 (s, 6H). ESI-MS: m/z 595.3 [M+Na]+. Compound 304 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.21 - 8.14 (m, 2H), 8.00 (d, J = 9 Hz, 1H), 7.97 (d, J = 9 Hz, 1H), 7.20 (d, J= 7.7 Hz, 1H), 7.02 - 6.92 (m, 1H), 6.89 - 6.81 (m, 1H), 3.97 (t, J= 6 Hz , 2H), 3.64 (d , 1H), 3.29 - 3.24 (m, 2H), 2.49 (s, 3H), 2.47 - 2.36 (m, 2H), 2.18 (s, 3H), 1.74 - 1.64 (m, 2H), 1.59 - 1.50 (m , 4H), 1.50 - 1.36 (m, 2H), 1.04 (s, 6H). ESI-MS: m/z 595.3 [M+Na] + .
实施例 212  Example 212
5- (2,3-二氟 -4-甲基苯氧基） -2,2-二甲基 -N- ( 1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 戊 酰胺 （化合物 305 )  5-(2,3-Difluoro-4-methylphenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide (compound 305)
参照实施例 119的方法制得化合物 305: 1H NMR (300 MHz, CDC13) δ 9.11 - 8.72 (m, 2H), 8.04 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 6.5 Hz, 1H), 6.87 - 6.70 (m, 1H), 6.69 - 6.51 (m, 1H), 5.58 (d, J = 6.8 Hz, 1H), 3.96 (t, J = 12 Hz, 1H), 3.92 - 3.82 (m, 1H), 3.84 - 3.70 (m, 2H), 2.23 (s, 3H), 2.13 - 2.03 (m, 2H), 2.03 - 1.92 (m, 2H), 1.81 - 1.58 (m, 4H), 1.57 - 1.46 (m, 2H), 1.16 (s, 6H). ESI-MS: m/z 518.2 [M+Na]+. 实施例 213 Compound 305 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 9.11 - 8.72 (m, 2H), 8.04 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 6.5 Hz , 1H), 6.87 - 6.70 (m, 1H), 6.69 - 6.51 (m, 1H), 5.58 (d, J = 6.8 Hz, 1H), 3.96 (t, J = 12 Hz, 1H), 3.92 - 3.82 ( m, 1H), 3.84 - 3.70 (m, 2H), 2.23 (s, 3H), 2.13 - 2.03 (m, 2H), 2.03 - 1.92 (m, 2H), 1.81 - 1.58 (m, 4H), 1.57 - 1.46 (m, 2H), 1.16 (s, 6H). ESI-MS: m/z 518.2 [M+Na] + . Example 213
4- (2,5-二甲基苯氧基） -N- ( 1- ( (4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 丁 酰胺 （化合物 306)  4-(2,5-Dimethylphenoxy)-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)butanamide (Compound 306)
参照实施例 119的方法制得化合物 306: 1H MR (300 MHz, DMSO- 6) δ 8.16 (d, J = 8.1 Hz, 2H), 7.99 (d, J= 8.2 Hz, 2H), 7.79 (d, J= 7.4 Hz, 1H), 6.96 (d, J= 7.4 Hz, 1H), 6.67 (s, 1H), 6.60 (d, J = 7.5 Hz, 1H), 3.89 (t, J= 6.2 Hz, 2H), 3.53 (d, J = 12.7 Hz, 3H), 3.29 (s, 1H), 2.57 (t, J= 11.4 Hz, 2H), 2.21 (d, J= 7.3 Hz, 5H), 2.06 (s, 3H), 1.89 (q, J= 6.8 Hz, 2H), 1.77 (d, J= 11.4 Hz, 2H), 1.49 - 1.10 (m, 4H). ESI-MS: m/z 531.2 [M+Na]+. Compound 306 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.16 (d, J = 8.1 Hz, 2H), 7.99 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 7.4 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.67 (s, 1H), 6.60 (d, J = 7.5 Hz, 1H), 3.89 (t, J = 6.2 Hz, 2H) , 3.53 (d, J = 12.7 Hz, 3H), 3.29 (s, 1H), 2.57 (t, J = 11.4 Hz, 2H), 2.21 (d, J = 7.3 Hz, 5H), 2.06 (s, 3H) , 1.89 (q, J = 6.8 Hz, 2H), 1.77 (d, J = 11.4 Hz, 2H), 1.49 - 1.10 (m, 4H). ESI-MS: m/z 531.2 [M+Na] + .
实施例 214  Example 214
4- (2,5-二甲基苯氧基） -N- ( 1- ( (4-氟苯基）磺酰基） 哌啶 -4-基） 丁酰胺 （化合物 307)  4-(2,5-Dimethylphenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)butanamide (Compound 307)
参照实施例 119的方法制得化合物 307: 1H NMR (300 MHz, Chloroform- ) δ 7.76 (dd, J= 8.5, 5.0 Hz, 2H), 7.23 (dd, J= 14.5, 6.5 Hz, 3H), 7.00 (d, J= 7.4 Hz, 1H), 6.67 (d, J= 7.6 Hz, 1H), 6.60 (s, 1H), 5.43 (d, J= 8.0 Hz, 1H), 3.96 (t, J= 5.9 Hz, 2H), 3.74 (d, J= 11.7 Hz, 3H), 2.49 - 2.32 (m, 4H), 2.29 (s, 3H), 2.15 (s, 4H), 2.11 (d, J= 9.2 Hz, 3H), 1.96 (d, J= 12.1 Hz, 2H), 1.59 (s, 1H), 1.48 (qd, J= 12.0, 4.1 Hz, 2H). ESI-MS: m/z 471.3 [M+Na]+. The compound 307 was obtained by the method of Example 119: 1H NMR (300 MHz, chloroform) δ 7.76 (dd, J = 8.5, 5.0 Hz, 2H), 7.23 (dd, J = 14.5, 6.5 Hz, 3H), 7.00 (d, J= 7.4 Hz, 1H), 6.67 (d, J= 7.6 Hz, 1H), 6.60 (s, 1H), 5.43 (d, J= 8.0 Hz, 1H), 3.96 (t, J= 5.9 Hz , 2H), 3.74 (d, J = 11.7 Hz, 3H), 2.49 - 2.32 (m, 4H), 2.29 (s, 3H), 2.15 (s, 4H), 2.11 (d, J = 9.2 Hz, 3H) , 1.96 (d, J = 12.1 Hz, 2H), 1.59 (s, 1H), 1.48 (qd, J = 12.0, 4.1 Hz, 2H). ESI-MS: m/z 471.3 [M+Na] + .
实施例 215  Example 215
4- (2,5-二甲基苯氧基） -N- ( 1- (吡啶 -3-基磺酰基）哌啶 -4-基）丁酰胺（化合物 308) 参照实施例 119的方法制得化合物 308: 1H NMR (300 MHz, Chloroform- ) δ 9.00 (d, J= 2.3 Hz, 1H), 8.86 (dd, J= 4.9, 1.6 Hz, 1H), 8.05 (dt, J= 8.0, 2.0 Hz, 1H), 7.51 (dd, J= 8.0, 4.8 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 6.62 (s, 1H), 5.45 (d, J = 8.0 Hz, 1H), 3.98 (t, J= 5.8 Hz, 2H), 3.80 (dt, J= 8.9, 4.3 Hz, 3H), 2.58 - 2.43 (m, 2H), 2.39 (t, J = 7.3 Hz, 2H), 2.31 (s, 3H), 2.17 (s, 3H), 2.13 (d, J = 7.0 Hz, 2H), 2.00 (d, J= 12.9 Hz, 2H), 1.50 (qd, J= 12.0, 3.9 Hz, 2H). ESI-MS: m/z 454.2 [M+Na]+. 4-(2,5-Dimethylphenoxy)-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)butanamide (Compound 308) was obtained according to the procedure of Example 119. Compound 308: 1H NMR (300 MHz, Chloroform-) δ 9.00 (d, J = 2.3 Hz, 1H), 8.86 (dd, J = 4.9, 1.6 Hz, 1H), 8.05 (dt, J = 8.0, 2.0 Hz, 1H), 7.51 (dd, J= 8.0, 4.8 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 6.62 (s, 1H), 5.45 ( d, J = 8.0 Hz, 1H), 3.98 (t, J = 5.8 Hz, 2H), 3.80 (dt, J= 8.9, 4.3 Hz, 3H), 2.58 - 2.43 (m, 2H), 2.39 (t, J = 7.3 Hz, 2H), 2.31 (s, 3H), 2.17 (s, 3H), 2.13 (d, J = 7.0 Hz, 2H), 2.00 (d, J= 12.9 Hz, 2H), 1.50 (qd, J = 12.0, 3.9 Hz, 2H). ESI-MS: m/z 454.2 [M+Na] + .
实施例 216  Example 216
反式 -5-(4-氯 -2-氟苯氧基) -N-(3-氟 -l-((4- (甲基磺酰基)苯基)磺酰基)哌啶 -4-基) -2， 2- 二甲基戊酰胺 （化合物 309)  Trans-5-(4-chloro-2-fluorophenoxy)-N-(3-fluoro-l-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) -2, 2-dimethylpentanamide (compound 309)
参照实施例 119和 139的方法制得化合物 309: 1H MR (300 MHz, OMSO-d6) δ 8.19 (d, J= 8.2 Hz, 2H), 8.05 (d, J= 8.3 Hz, 2H), 7.52 - 7.37 (m, 2H), 7.24 - 7.07 (m, 2H), 4.75 - 4.36 (m, 1H), 4.12 - 3.74 (m, 4H), 3.62 - 3.46 (m, 1H), 3.33 (s, 3H), 2.81 - 2.57 (m, 2H), 1.83 - 1.67 (m, 1H), 1.67 - 1.43 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 615.2 [M+Na]+. Compound 309 was prepared by the methods of Examples 119 and 139: 1H MR (300 MHz, OMSO-d 6 ) δ 8.19 (d, J = 8.2 Hz, 2H), 8.05 (d, J = 8.3 Hz, 2H), 7.52 - 7.37 (m, 2H), 7.24 - 7.07 (m, 2H), 4.75 - 4.36 (m, 1H), 4.12 - 3.74 (m, 4H), 3.62 - 3.46 (m, 1H), 3.33 (s, 3H) , 2.81 - 2.57 (m, 2H), 1.83 - 1.67 (m, 1H), 1.67 - 1.43 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 615.2 [M+Na] + .
实施例 217  Example 217
反式 -5-(4-氯 -2-氟苯氧基) -N-(3-氟 -1- (吡啶 -3-磺酰基;)哌啶 -4-基) -2,2-二甲基戊酰胺 (化合物 310) 参照实施例 119和 139的方法制得化合物 310: 1H MR(300 MHz, OMSO-d6) δ 9.01 -8.93 (m, 1Η), 8.93 -8.84 (m, 1H), 8.31-8.11 (m, 1H), 7.78-7.65 (m, 1H), 7.52-7.34 (m, 2H), 7.27 - 7.08 (m, 2H), 4.70 - 4.40 (m, 1H), 4.06 - 3.76 (m, 4H), 3.65 - 3.45 (m, 1H), 2.82 - 2.60 (m, 2H), 1.86 - 1.65 (m, 1H), 1.65 - 1.43 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 538.2 [M+Na]+. Trans-5-(4-chloro-2-fluorophenoxy)-N-(3-fluoro-1-(pyridine-3-sulfonyl;)piperidin-4-yl)-2,2-dimethyl Radicotamide (Compound 310) Compound 310 was prepared by the methods of Examples 119 and 139: 1H MR (300 MHz, OMSO-d 6 ) δ 9.01 -8.93 (m, 1 Η), 8.93 -8.84 (m, 1H), 8.31-8.11 (m, 1H ), 7.78-7.65 (m, 1H), 7.52-7.34 (m, 2H), 7.27 - 7.08 (m, 2H), 4.70 - 4.40 (m, 1H), 4.06 - 3.76 (m, 4H), 3.65 - 3.45 (m, 1H), 2.82 - 2.60 (m, 2H), 1.86 - 1.65 (m, 1H), 1.65 - 1.43 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 538.2 [M +Na] + .
实施例 218  Example 218
5- (2,5-二氯苯氧基） -2,2-二甲基 -N- (1- ((3- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 （化合物 312)  5-(2,5-Dichlorophenoxy)-2,2-dimethyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valentamide (compound 312)
参照实施例 119的方法制得化合物 312: 1H MR(300 MHz, DMSO- 6) δ 8.32 - 8.21 (m, 1H), 8.20 - 8.12 (m, 1H), 8.12 - 8.03 (m, 1H), 7.94 (t, J= 7.8 Hz, 1H), 7.49 - 7.39 (m, 1H), 7.29 - 7.16 (m, 2H), 7.06 - 6.96 (m, 1H), 4.09 - 3.95 (m, 2H), 3.73 - 3.48 (m, 3H), 3.35 (s, 3H), 2.42 (t, J = 11.7 Hz, 2H), 1.78 - 1.65 (m, 2H), 1.60 - 1.43 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 613.3 [M+Na]+. Compound 312 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.32 - 8.21 (m, 1H), 8.20 - 8.12 (m, 1H), 8.12 - 8.03 (m, 1H), 7.94 (t, J = 7.8 Hz, 1H), 7.49 - 7.39 (m, 1H), 7.29 - 7.16 (m, 2H), 7.06 - 6.96 (m, 1H), 4.09 - 3.95 (m, 2H), 3.73 - 3.48 (m, 3H), 3.35 (s, 3H), 2.42 (t, J = 11.7 Hz, 2H), 1.78 - 1.65 (m, 2H), 1.60 - 1.43 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 613.3 [M+Na] + .
实施例 219  Example 219
5- (2,5-二 （三氟甲基） 苯氧基） -2,2-二甲基 -N- (1- ((3- (甲基磺酰基） 苯基） 磺 酰基） 哌啶 -4-基） 戊酰胺 （化合物 313)  5-(2,5-bis(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidine -4-yl) pentanoamide (compound 313)
参照实施例 119的方法制得化合物 313: 1H MR (300 MHz, CDC13) δ 8.33 (s, 1H), 8.19 (d,J=7.9Hz, 1H), 8.04 (d,J=7.8Hz, 1H), 7.80 (app t, J= 7.8 Hz, 1H), 7.69 (d,J=7.9 Hz, 1H), 7.28 (d, J= 6.9 Hz, 1H), 7.16 (s, 1H), 5.50 (d, J= 7.6 Hz, 1H), 4.06 (t, J= 5.2 Hz, 2H), 3.88 - 3.78 (m, 2H), 3.78 - 3.68 (m, 1H), 3.12 (s, 3H), 2.54 - 2.38 (m, 2H), 2.05 - 1.90 (m, 2H), 1.80 - 1.64 (m, 4H), 1.56 - 1.43 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 681.2 [M+Na]+. 实施例 220 Compound 313 was prepared by the method of Example 119: 1H MR (300 MHz, CDC1 3 ) δ 8.33 (s, 1H), 8.19 (d, J = 7.9 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H ), 7.80 (app t, J= 7.8 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.28 (d, J= 6.9 Hz, 1H), 7.16 (s, 1H), 5.50 (d, J= 7.6 Hz, 1H), 4.06 (t, J= 5.2 Hz, 2H), 3.88 - 3.78 (m, 2H), 3.78 - 3.68 (m, 1H), 3.12 (s, 3H), 2.54 - 2.38 (m , 2H), 2.05 - 1.90 (m, 2H), 1.80 - 1.64 (m, 4H), 1.56 - 1.43 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 681.2 [M+Na ] + . Example 220
5- (4-氟苯氧基） -2,2-二甲基 -N- (1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 戊酰胺 （化合 物 314)  5-(4-Fluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-3-ylsulfonyl)piperidin-4-yl)pentanamide (Compound 314)
参照实施例 119的方法制得化合物 314: 1H MR(300 MHz, DMSO- 6) δ 8.93 - 8.87 (m, 2H), 8.17 - 8.13 (m, 1H), 7.69 (dd, J = 7.9, 4.9 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.09 (t, J = 8.8 Hz, 2H), 6.94 - 6.87 (m, 2H), 3.90 - 3.83 (m, 2H), 3.69 - 3.52 (m, 3H), 2.49 - 2.38 (m， 2H), 1.77 - 1.66 (m, 2H), 1.54 (s, 6H). ESI-MS: m/z 486.2 [M+Na]+. Compound 314 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.93 - 8.87 (m, 2H), 8.17 - 8.13 (m, 1H), 7.69 (dd, J = 7.9, 4.9 Hz , 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.09 (t, J = 8.8 Hz, 2H), 6.94 - 6.87 (m, 2H), 3.90 - 3.83 (m, 2H), 3.69 - 3.52 ( m, 3H), 2.49 - 2.38 (m, 2H), 1.77 - 1.66 (m, 2H), 1.54 (s, 6H). ESI-MS: m/z 486.2 [M+Na] + .
实施例 221  Example 221
3- (2,5-二甲基苯氧基） -N- (1- ((4-氟苯基）磺酰基）哌啶 -4-基丙酰胺（化合物 315) 参照实施例 119的方法制得化合物 315: 1H NMR (300 MHz, CDC13) δ 7.86 - 7.57 (m, 1H), 7.21 (t, J= 8.3 Hz, 1H), 7.00 (d, J= 7.4 Hz, 1H), 6.68 (d, J= 7.3 Hz, 1H), 6.62 (s, 1H), 6.29 (s, 1H), 4.17 (t,J= 5.6 Hz, 1H), 3.74 (d,J= 11.1 Hz, 1H), 2.61 (t, J= 5.5 Hz, 1H), 2.38 (t, J= 11.5 Hz, 1H), 2.29 (s, 1H), 2.12 (s, 1H), 1.98 (d, J= 12.1 Hz, 1H), 1.55 (dd, J= 21.0, 11.1 Hz, 1H). ESI-MS: m/z 457.2 [M+Na] . 3-(2,5-Dimethylphenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-ylpropanamide (Compound 315) was prepared according to the method of Example 119 Compound 315: 1H NMR (300 MHz, CDC1 3 ) δ 7.86 - 7.57 (m, 1H), 7.21 (t, J = 8.3 Hz, 1H), 7.00 (d, J = 7.4 Hz, 1H), 6.68 (d , J = 7.3 Hz, 1H), 6.62 (s, 1H), 6.29 (s, 1H), 4.17 (t, J = 5.6 Hz, 1H), 3.74 (d, J = 11.1 Hz, 1H), 2.61 (t , J= 5.5 Hz, 1H), 2.38 (t, J= 11.5 Hz, 1H), 2.29 (s, 1H), 2.12 (s, 1H), 1.98 (d, J= 12.1 Hz, 1H), 1.55 (dd , J= 21.0, 11.1 Hz, 1H). ESI-MS: m/z 457.2 [M+Na].
实施例 222  Example 222
3- (2,5-二甲基苯氧基） -N- ( 1- (吡啶 -3-基磺酰基）哌啶 -4-基）丙酰胺（化合物 317) 参照实施例 119的方法制得化合物 317: 1H MR (300 MHz, CDC13) δ 8.97 (s, 1H), 8.87 - 8.80 (m, 1H), 8.03 (d, J= 8.0 Hz, 1H), 7.49 (dd, J = 7.7, 4.9 Hz, 1H), 7.01 (d, J= 7.5 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 6.63 (s, 1H), 6.09 (d, J= 7.7 Hz, 1H), 4.19 (t, J= 5.7 Hz, 2H), 3.79 (d, J= 11.7 Hz, 3H), 2.63 (t, J= 5.7 Hz, 2H), 2.46 (t, J= 11.7 Hz, 2H), 2.30 (s, 3H), 2.13 (s, 3H), 2.02 (d, J= 15.2 Hz, 3H), 1.62 - 1.37 (m, 4H). ESI-MS: m/z 440.2 [M+Na]+. 实施例 223 3-(2,5-Dimethylphenoxy)-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)propanamide (Compound 317) was obtained according to the procedure of Example 119. Compound 317: 1H MR (300 MHz, CDC1 3 ) δ 8.97 (s, 1H), 8.87 - 8.80 (m, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 7.7, 4.9 Hz, 1H), 7.01 (d, J= 7.5 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 6.63 (s, 1H), 6.09 (d, J= 7.7 Hz, 1H), 4.19 ( t, J = 5.7 Hz, 2H), 3.79 (d, J = 11.7 Hz, 3H), 2.63 (t, J = 5.7 Hz, 2H), 2.46 (t, J = 11.7 Hz, 2H), 2.30 (s, 3H), 2.13 (s, 3H), 2.02 (d, J = 15.2 Hz, 3H), 1.62 - 1.37 (m, 4H). ESI-MS: m/z 440.2 [M+Na] + .
3- (2,5-二甲基苯氧基） -N- ( 1- ( (4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 丙 酰胺 （化合物 319)  3-(2,5-Dimethylphenoxy)-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide (Compound 319)
参照实施例 119的方法制得化合物 319: 1H MR (300 MHz, DMSO- 6) δ 8.19 (d, J = 8.2 Hz, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.97 (d, J= 7.5 Hz, 1H), 6.97 (d, J= 7.4 Hz, 1H), 6.72 (s, 1H), 6.63 (d, J = 7.4 Hz, 1H), 5.76 (s, 1H), 4.12 (t, J = 5.8 Hz, 1H), 3.68 - 3.58 (m, 1H), 3.54 (d, J = 11.9 Hz, 1H), 3.32 (s, 3H), 2.63 (t, J = 10.6 Hz, 1H), 2.48 (d, J = 5.9 Hz, 2H), 2.24 (s, 2H), 2.02 (s, 2H), 1.81 (d, J= 10.5 Hz, 1H), 1.43 (dd, J= 20.1, 9.8 Hz, 1H), 1.27 (d, J = 6.8 Hz, 2H). ESI-MS: m/z 517.1 [M+Na]+. Compound 319 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.19 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.97 (d, J= 7.5 Hz, 1H), 6.97 (d, J= 7.4 Hz, 1H), 6.72 (s, 1H), 6.63 (d, J = 7.4 Hz, 1H), 5.76 (s, 1H), 4.12 (t, J = 5.8 Hz, 1H), 3.68 - 3.58 (m, 1H), 3.54 (d, J = 11.9 Hz, 1H), 3.32 (s, 3H), 2.63 (t, J = 10.6 Hz, 1H), 2.48 ( d, J = 5.9 Hz, 2H), 2.24 (s, 2H), 2.02 (s, 2H), 1.81 (d, J = 10.5 Hz, 1H), 1.43 (dd, J= 20.1, 9.8 Hz, 1H), 1.27 (d, J = 6.8 Hz, 2H). ESI-MS: m/z 517.1 [M+Na] + .
实施例 224  Example 224
5- (2,4-二氟苯氧基） -N- ( 1- ( (4-氟苯基) 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 (化合物 320)  5-(2,4-Difluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (Compound 320 )
参照实施例 119的方法制得化合物 320: 1H MR (300 MHz, DMSO- 6) δ 7.81 (dd, J = 8.7, 5.2 Hz, 2H), 7.48 (dd, J= 8.7 Hz, 2H), 7.32 - 7.08 (m, 3H), 6.98 (d, J= 8.8 Hz, 1H), 3.95 (m, 2H), 3.66 - 3.46 (m, 3H), 2.43 - 2.26 (m, 2H), 1.81 - 1.64 (m, 2H), 1.60 - 1.39 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 521.1 [M+Na]+. Compound 320 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 7.81 (dd, J = 8.7, 5.2 Hz, 2H), 7.48 (dd, J = 8.7 Hz, 2H), 7.32 - 7.08 (m, 3H), 6.98 (d, J= 8.8 Hz, 1H), 3.95 (m, 2H), 3.66 - 3.46 (m, 3H), 2.43 - 2.26 (m, 2H), 1.81 - 1.64 (m, 2H), 1.60 - 1.39 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 521.1 [M+Na] + .
实施例 225  Example 225
5- (4-溴 -2,6-二氟苯氧基） -2,2-二甲基 -N- ( 1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 戊酰 胺 （化合物 321 )  5-(4-Bromo-2,6-difluorophenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide Compound 321 )
参照实施例 119的方法制得化合物 321 : 1H MR (300 MHz, DMSO- 6) δ 9.16 - 8.75 (m, 2Η), 8.15 (d, J = 8.1 Hz, 1H), 7.69 (dd, J = 8.0, 4.8 Hz, 1H), 7.50 (d, J = 7.7 Hz, 2H), 7.21 (d, J = 7.8 Hz, 1H), 4.03 (t, J = 5.1 Hz, 2H), 3.72 - 3.51 (m, 3H), 2.48 - 2.35 (m, 2H), 1.76 - 1.63 (m, 2H), 1.59 - 1.40 (m, 6H), 1.04 (s, 6H). ESI-MS: m/z 582.0 [M+Na]+. Compound 321 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 9.16 - 8.75 (m, 2 Η), 8.15 (d, J = 8.1 Hz, 1H), 7.69 (dd, J = 8.0 , 4.8 Hz, 1H), 7.50 (d, J = 7.7 Hz, 2H), 7.21 (d, J = 7.8 Hz, 1H), 4.03 (t, J = 5.1 Hz, 2H), 3.72 - 3.51 (m, 3H) ), 2.48 - 2.35 (m, 2H), 1.76 - 1.63 (m, 2H), 1.59 - 1.40 (m, 6H), 1.04 (s, 6H). ESI-MS: m/z 582.0 [M+Na] + .
实施例 226  Example 226
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COT COT
Z.9ZC80/8T0ZN3/X3d I9^6l/810Z OAV 2.15 - 2.03 (m, 1H), 1.85 - 1.65 (m, 4H), 1.59 - 1.48 (m, 1H), 1.19 (s, 6H). ESI-MS: m/z 533.1 [M+Na]+. Z.9ZC80/8T0ZN3/X3d I9^6l/810Z OAV 2.15 - 2.03 (m, 1H), 1.85 - 1.65 (m, 4H), 1.59 - 1.48 (m, 1H), 1.19 (s, 6H). ESI-MS: m/z 533.1 [M+Na] + .
实施例 231  Example 231
5-(4-氯苯基 )-2,2-二甲基 -N-(l-((4- (甲磺酰基)苯基)磺酰基)哌啶 -4-基；)戊酰胺（化合物 329)  5-(4-chlorophenyl)-2,2-dimethyl-N-(l-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl;)pentanamide (compound) 329)
参照实施例 119的方法制得化合物 329: 1H MR (300 MHz, DMSO- 6) δ 8.18 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 3.95 - 3.82 (m, 2H), 3.72 - 3.49 (m, 3H), 3.33 (s, 3H), 2.43 (t, J = 11.1 Hz, 2H), 1.70 (d, J = 11.0 Hz, 2H), 1.61— 1.40 (m, 6H), 1.05 (s, 3H). ESI-MS: m/z 579.1 [M+Na]+. Compound 329 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.18 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 3.95 - 3.82 (m, 2H), 3.72 - 3.49 (m, 3H), 3.33 (s, 3H), 2.43 (t, J = 11.1 Hz, 2H), 1.70 (d, J = 11.0 Hz, 2H), 1.61— 1.40 (m, 6H), 1.05 (s, 3H). ESI-MS : m/z 579.1 [M+Na] + .
实施例 232  Example 232
5-(4-氯苯基) -N-(l-((4-氟苯基)磺酰基)哌啶 -4-基) -2,2-二甲基戊酰胺 （化合物 330) 参照实施例 119的方法制得化合物 330: 1H MR (300 MHz, DMSO- 6) δ 7.80 (dd, J = 8.4, 5.3 Hz, 2H), 7.48 (t, J = 8.7 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 3.95 - 3.83 (m, 2H), 3.65 - 3.48 (m, 3H), 2.35 (t, J = 11.3 Hz, 2H),5-(4-Chlorophenyl)-N-(l-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (Compound 330) Reference Example Compound 175 was prepared by the method of 119: 1H MR (300 MHz, DMSO- 6 ) δ 7.80 (dd, J = 8.4, 5.3 Hz, 2H), 7.48 (t, J = 8.7 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 3.95 - 3.83 (m, 2H), 3.65 - 3.48 (m, 3H), 2.35 (t, J = 11.3 Hz, 2H),
I .69 (d, J = 10.6 Hz,2H), 1.60 - 1.40 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 519.1 [M+Na]+. 实施例 233 I.69 (d, J = 10.6 Hz, 2H), 1.60 - 1.40 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 519.1 [M+Na] + .
5-(4-氯苯基 )-2,2-二甲基 -N-(l- (吡啶 -3-基磺酰基)哌啶 -4-基） 戊酰胺 （化合物 331 ) 参照实施例 119的方法制得化合物 331 : iH NMR (300 MHz, DMSO- 6) δ 8.89 (m, 2Η)， 8.15 (d, J = 8.1 Hz, 1H), 7.69 (dd, J = 7.6, 4.9 Hz, 1H), 7.30 (d, J = 8.9 Hz, 2H), 7.21 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 8.9 Hz, 2H), 3.94 - 3.83 (m, 2H), 3.70 - 3.54 (m, 3H), 2.44 (t, J =5-(4-Chlorophenyl)-2,2-dimethyl-N-(l-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide (Compound 331) Method 331: iH NMR (300 MHz, DMSO- 6 ) δ 8.89 (m, 2 Η), 8.15 (d, J = 8.1 Hz, 1H), 7.69 (dd, J = 7.6, 4.9 Hz, 1H), 7.30 (d, J = 8.9 Hz, 2H), 7.21 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 8.9 Hz, 2H), 3.94 - 3.83 (m, 2H), 3.70 - 3.54 (m , 3H), 2.44 (t, J =
I I .6 Hz, 2H), 1.70 (d, J = 10.4 Hz, 2H), 1.59 - 1.42 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 502.1 [M+Na]+. II .6 Hz, 2H), 1.70 (d, J = 10.4 Hz, 2H), 1.59 - 1.42 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 502.1 [M+Na] + .
实施例 234  Example 234
N- ( 1 - ( (4-氟苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基 -5- (4- (甲基磺酰基） 苯氧 基） 戊酰胺 （化合物 332)  N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanamide Compound 332)
参照实施例 119的方法制得化合物 332: 1H MR (300 MHz, OMSO-d6) δ 7.88 - 7.75 (m, 4H), 7.56 - 7.40 (m, 2H), 7.25 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 4.10 - 3.92 (m, 2H), 3.65 - 3.47 (m, 3H), 3.15 (s, 3H), 2.40 - 2.26 (m, 2H), 1.77 - 1.62 (m, 2H), 1.62 - 1.40 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 541.4 [M+H]+. Compound 332 was prepared by the method of Example 119: 1H MR (300 MHz, OMSO-d 6 ) δ 7.88 - 7.75 (m, 4H), 7.56 - 7.40 (m, 2H), 7.25 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 4.10 - 3.92 (m, 2H), 3.65 - 3.47 (m, 3H), 3.15 (s, 3H), 2.40 - 2.26 (m, 2H), 1.77 - 1.62 (m, 2H), 1.62 - 1.40 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 541.4 [M+H] + .
实施例 235  Example 235
5- (2,4-二氟苯氧基) -N - ( ( 3S,4S ) -3-氟 -1- (吡啶 -3-基磺酰基) 哌啶 -4-基） -2,2- 二甲基戊酰胺 （化合物 334)  5-(2,4-Difluorophenoxy)-N-((3S,4S)-3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2,2- Dimethyl valeramide (compound 334)
参照实施例 119和 77的方法制得化合物 334: ee>99%; 1H NMR (300 MHz, DMSO- 6) δ 8.95 (s, 1H), 8.90 (d, J = 4.0 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.69 (dd, J = 7.8, 4.9 Hz, 1H), 7.44 (d, J= 8.0 Hz, 1H), 7.31 - 6.91 (m, 3H), 4.71 - 4.39 (m, 1H), 4.04 - 3.77 (m, 4H), 3.63 - 3.46 (m, 1H), 2.83 - 2.60 (m, 2H), 1.85 - 1.45 (m, 6H), 1.07 (s, 6H). ESI-MS: m/z 522.2 [M+Na]+. Compound 334 was prepared by the methods of Examples 119 and 77: ee >99%; 1H NMR (300 MHz, DMSO- 6 ) δ 8.95 (s, 1H), 8.90 (d, J = 4.0 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.69 (dd, J = 7.8, 4.9 Hz, 1H), 7.44 (d, J= 8.0 Hz, 1H), 7.31 - 6.91 (m, 3H), 4.71 - 4.39 (m, 1H), 4.04 - 3.77 (m, 4H), 3.63 - 3.46 (m, 1H), 2.83 - 2.60 (m, 2H), 1.85 - 1.45 (m, 6H), 1.07 (s, 6H). ESI-MS: m/z 522.2 [M+Na] + .
实施例 236  Example 236
N- ( 1- ( (3,4-二氟苯基)磺酰基） 哌啶 -4-基） -5- (2,5-二甲基苯氧基) -2,2-二甲基 戊酰胺 （化合物 341 )  N-(1-((3,4-difluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentyl Amide (compound 341)
参照实施例 43的方法制得化合物 341： 1H NMR (300 MHz, CDC13) δ 7.67 - 7.50 (m, 2H), 7.41 - 7.30 (m, 1H), 7.02 (d, J= 7.4 Hz, 1H), 6.68 (d, J= 7.3 Hz, 1H), 6.61 (s, 1H), 5.50 (d, J= 7.3 Hz, 1H), 3.92 (t, J= 4.9 Hz, 2H), 3.85 - 3.72 (m, 3H), 2.53 - 2.40 (m, 2H), 2.32 (s, 3H), 2.18 (s, 3H), 2.05 - 1.94 (m, 2H), 1.75 - 1.66 (m, 4H), 1.57 - 1.46 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 509.3 [M+H]+. Compound 341 was obtained by the method of Example 43: 1H NMR (300 MHz, CDC1 3 ) δ 7.67 - 7.50 (m, 2H), 7.41 - 7.30 (m, 1H), 7.02 (d, J = 7.4 Hz, 1H) , 6.68 (d, J= 7.3 Hz, 1H), 6.61 (s, 1H), 5.50 (d, J= 7.3 Hz, 1H), 3.92 (t, J= 4.9 Hz, 2H), 3.85 - 3.72 (m, 3H), 2.53 - 2.40 (m, 2H), 2.32 (s, 3H), 2.18 (s, 3H), 2.05 - 1.94 (m, 2H), 1.75 - 1.66 (m, 4H), 1.57 - 1.46 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 509.3 [M+H] + .
实施例 237  Example 237
2- ( 3,4-二氟苯氧基） -2-甲基 -N- ( 1- ( ( 3- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4- 基） 丙酰胺 （化合物 342)  2-(3,4-Difluorophenoxy)-2-methyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide ( Compound 342)
参照实施例 14的方法制得化合物 342: 1H MR (300 MHz, CDC13) δ 8.32 (s, 1H), 8.19 (d, J= 7.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.06 (dd, J= 18.8, 9.2 Hz, 1H), 6.74 (ddd, J = 11.2, 6.7, 2.8 Hz, 1H), 6.61 (dt, J= 4.3, 3.9 Hz, 1H), 6.52 (d, J = 7.7 Hz, 1H), 3.80 (m, 3H), 3.11 (s, 3H), 2.55 (t, J= 11.8 Hz, 2H), 2.02 (d, J= 12.6 Hz, 2H), 1.63 - 1.52 (m, 2H), 1.45 (s, 6H). ESI-MS: m/z 539.1 [M+Na]+. Compound 342 was prepared by the method of Example 14: 1H MR (300 MHz, CDC1 3 ) δ 8.32 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H ), 7.79 (t, J = 7.8 Hz, 1H), 7.06 (dd, J= 18.8, 9.2 Hz, 1H), 6.74 (ddd, J = 11.2, 6.7, 2.8 Hz, 1H), 6.61 (dt, J= 4.3, 3.9 Hz, 1H), 6.52 (d, J = 7.7 Hz, 1H), 3.80 (m, 3H), 3.11 (s, 3H), 2.55 (t, J = 11.8 Hz, 2H), 2.02 (d, J = 12.6 Hz, 2H), 1.63 - 1.52 (m, 2H), 1.45 (s, 6H). ESI-MS: m/z 539.1 [M+Na] + .
实施例 238  Example 238
反式—2- ( 3,4-二氟苯氧基） -N- ( 3-氟 -1- (吡啶 -3-基磺酰基） 哌啶 -4-基） -2-甲基丙 酰胺 （化合物 343 )  Trans-2-(3,4-difluorophenoxy)-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methylpropanamide ( Compound 343 )
参照实施例 14和 139的方法制得化合物 343 : 1H MR (300 MHz, CDC13) δ 9.01 (s, 1H), 8.87 (d, J = 4.1 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.53 (dd, J = 7.7, 5.0 Hz, 1H), 7.07 (dd, J = 18.7, 9.2 Hz, 1H), 6.84 - 6.73 (m, 1H), 6.72 - 6.59 (m, 2H), 4.63 - 4.35 (m, 1H), 4.17 - 4.05 (m, 1H), 4.03 - 3.89 (m, 1H), 3.78 (dd, J= 12.3, 1.2 Hz, 1H), 2.65 - 2.51 (m, 2H): 2.25 - 2.10 (m, 1H), 1.74 - 1.61 (m, 1H), 1.48 (s, 3H), 1.46 (s, 3H). ESI-MS: m/z 558.1 [M+H]+ Compound 343 was prepared by the methods of Examples 14 and 139: 1H MR (300 MHz, CDC1 3 ) δ 9.01 (s, 1H), 8.87 (d, J = 4.1 Hz, 1H), 8.07 (d, J = 8.0 Hz , 1H), 7.53 (dd, J = 7.7, 5.0 Hz, 1H), 7.07 (dd, J = 18.7, 9.2 Hz, 1H), 6.84 - 6.73 (m, 1H), 6.72 - 6.59 (m, 2H), 4.63 - 4.35 (m, 1H), 4.17 - 4.05 (m, 1H), 4.03 - 3.89 (m, 1H), 3.78 (dd, J= 12.3, 1.2 Hz, 1H), 2.65 - 2.51 (m, 2H) : 2.25 - 2.10 (m, 1H), 1.74 - 1.61 (m, 1H), 1.48 (s, 3H), 1.46 (s, 3H). ESI-MS: m/z 558.1 [M+H] +
实施例 239  Example 239
反式—2- (3,4-二氟苯氧基） -N - (3-氟 -1 - ( (4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 —4-基） -2-甲基丙酰胺 （化合物 344)  Trans-2-(3,4-difluorophenoxy)-N-(3-fluoro-1 -((4-(methylsulfonyl)phenyl)sulfonyl)piperidine-4-yl)- 2-methylpropionamide (compound 344)
参照实施例 14和 139的方法制得化合物 344: 1H MR (300 MHz, DMSO- 6) δ 8.29 (d, J= 8.4 Hz, 1H), 8.17 (d, J= 8.2 Hz, 2H), 8.03 (d, J= 8.3 Hz, 2H), 7.32 (dd, J= 19.6, 9.6 Hz, 1H), 6.94 (ddd, J= 12.0, 6.8, 2.7 Hz, 1H), 6.71 (d, J= 8.9 Hz, 1H), 4.74 - 4.42 (m, 1H), 4.01 - 3.83 (m, 2H), 3.54 (d, J= 11.6 Hz, 1H), 3.29 (s, 3H), 2.66 (dd, J= 24.9, 11.5 Hz, 2H), 1.82 - 1.69 (m, 1H), 1.67 - 1.48 (m, 1H), 1.40 (s, 3H), 1.37 (s, 3H). ESI-MS: m/z 533.2 [M-H]". 实施例 240 Compound 344 was prepared by the methods of Examples 14 and 139: 1H MR (300 MHz, DMSO- 6 ) δ 8.29 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.2 Hz, 2H), 8.03 ( d, J = 8.3 Hz, 2H), 7.32 (dd, J= 19.6, 9.6 Hz, 1H), 6.94 (ddd, J= 12.0, 6.8, 2.7 Hz, 1H), 6.71 (d, J= 8.9 Hz, 1H), 4.74 - 4.42 (m, 1H), 4.01 - 3.83 (m, 2H), 3.54 (d, J = 11.6 Hz, 1H), 3.29 (s, 3H), 2.66 (dd, J= 24.9, 11.5 Hz, 2H), 1.82 - 1.69 (m, 1H), 1.67 - 1.48 (m, 1H), 1.40 (s, 3H), 1.37 (s, 3H). ESI-MS: m/z 533.2 [MH]". Example 240
反式 -N - (3-氟 -1- (吡啶 -3-基磺酰基) 哌啶 -4-基） -2-甲基 -2- (3- (三氟甲基) 苯氧 基） 丙酰胺 （化合物 346)  trans-N-(3-Fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methyl-2-(3-(trifluoromethyl)phenoxy)propane Amide (compound 346)
参照实施例 14和 139的方法制得化合物 346: 1H MR (300 MHz, CDC13) δ 9.03 (s, 1H), 8.89 (s, 1H), 8.08 (d, J= 8.0 Hz, 1H), 7.53 (dd, J= 7.8, 4.8 Hz, 1H), 7.48 - 7.34 (m, 2H), 7.18 (s, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 4.49 (ddd, J = 13.4, 9.3, 4.7 Hz, 1H), 4.22 - 3.90 (m, 3H), 3.77 (d, J= 11.3 Hz, 1H), 2.62 (t, J = 12.9 Hz, 2H), 2.17 (d, J = 13.2 Hz, 1H), 1.73 (ddd, J = 16.0, 12.2, 4.8 Hz, 2H), 1.54 (d, J= 4.7 Hz, 6H). ESI-MS: m/z 513.2 [M+Na]+. Compound 346 was prepared by the methods of Examples 14 and 139: 1H MR (300 MHz, CDC1 3 ) δ 9.03 (s, 1H), 8.89 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.53 (dd, J= 7.8, 4.8 Hz, 1H), 7.48 - 7.34 (m, 2H), 7.18 (s, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 4.49 (ddd, J = 13.4, 9.3, 4.7 Hz, 1H), 4.22 - 3.90 (m, 3H), 3.77 (d, J = 11.3 Hz, 1H), 2.62 (t, J = 12.9 Hz, 2H ), 2.17 (d, J = 13.2 Hz, 1H), 1.73 (ddd, J = 16.0, 12.2, 4.8 Hz, 2H), 1.54 (d, J = 4.7 Hz, 6H). ESI-MS: m/z 513.2 [M+Na] + .
实施例 241  Example 241
反式 -N - (3-氟 -1 - ( (4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） -2-甲基 -2- (3- (三氟甲基） 苯氧基） 丙酰胺 （化合物 347)  trans-N-(3-fluoro-1 -((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-2-methyl-2-(3-(trifluoromethyl) Phenoxy) propionamide (compound 347)
参照实施例 14和 139的方法制得化合物 347: 1H MR (300 MHz, DMSO- 6) δ 8.30 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.3 Hz, 2H), 8.01 (d, J = 8.3 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 7.8 Hz, 2H), 4.67 - 4.43 (m, 1H), 3.98 - 3.87 (m, 1H), 3.87 - 3.74 (m, 1H), 3.56 - 3.44 (m, 1H), 2.74 - 2.56 (m, 2H), 1.75 (dd, J = 14.7, 10.7 Hz, 1H), 1.58 (dd, J= 17.1, 8.7 Hz, 1H), 1.44 (s, 3H), 1.41 (s, 3H). ESI-MS: m/z 589.3 [M+Na]+. 实施例 242 Compound 347 was prepared by the methods of Examples 14 and 139: 1H MR (300 MHz, DMSO- 6 ) δ 8.30 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.3 Hz, 2H), 8.01 ( d, J = 8.3 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 7.8 Hz, 2H), 4.67 - 4.43 ( m, 1H), 3.98 - 3.87 (m, 1H), 3.87 - 3.74 (m, 1H), 3.56 - 3.44 (m, 1H), 2.74 - 2.56 (m, 2H), 1.75 (dd, J = 14.7, 10.7 Hz, 1H), 1.58 (dd, J= 17.1, 8.7 Hz, 1H), 1.44 (s, 3H), 1.41 (s, 3H). ESI-MS: m/z 589.3 [M+Na] + . 242
2- (4-氯苯氧基） -2-甲基 -N- ( 1 - ( (4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 （化合物 348)  2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide (Compound 348)
参照实施例 14的方法制得化合物 348: 1H MR (300 MHz, CDC13) δ 8.16 (d, J= 8.0 Hz, 2H), 7.98 (d, J= 8.4 Hz, 2H), 7.25 (d,J= 8.8 Hz ,2H), 6.84 (d, J= 8.8 Hz, 2H), 6.54 (d, J = 8.3 Hz, 1H), 3.81 (d, J = 11.3 Hz, 3H), 3.14 (s, 3H), 2.58 (t, J = 11.0 Hz, 2H), 2.07 - 1.99 (m, 2H), 1.65 - 1.57 (m, 2H), 1.48 (s, 6H). ESI-MS: m/z 537.2 [M+Na]+. Compound 348 was prepared by the method of Example 14: 1H MR (300 MHz, CDC1 3 ) δ 8.16 (d, J = 8.0 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.8 Hz , 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 8.3 Hz, 1H), 3.81 (d, J = 11.3 Hz, 3H), 3.14 (s, 3H), 2.58 (t, J = 11.0 Hz, 2H), 2.07 - 1.99 (m, 2H), 1.65 - 1.57 (m, 2H), 1.48 (s, 6H). ESI-MS: m/z 537.2 [M+Na] + .
实施例 243  Example 243
反式 -2- (4-氯 -2-氟苯氧基） -N - (3-氟 -1 - ( (4- (甲基磺酰基） 苯基）磺酰基） 哌啶 —4-基） -2-甲基丙酰胺 （化合物 349)  Trans-2-(4-chloro-2-fluorophenoxy)-N-(3-fluoro-1 -((4-(methylsulfonyl)phenyl)sulfonyl)piperidine-4-yl) -2-methylpropionamide (compound 349)
参照实施例 14和 139的方法制得化合物 349: 1H MR (300 MHz, DMSO- 6) δ 8.35 (d, J= 8.2 Hz, 1H), 8.18 (d, J= 8.4 Hz, 2H), 8.03 (d, J= 8.3 Hz, 2H), 7.47 (d, J= 12.8 Hz, 1H), 7.16 (d, J= 7.5 Hz, 1H), 6.95 (t, J = 8.8 Hz, 1H), 4.60 (d, J = 52.1 Ηζ,ΙΗ), 3.95 (d, J = 20.0 Hz, 1H), 3.87 - 3.77 (m, 1H), 3.51 (dd, J = 10.9, 4.0 Hz, 1H), 3.33 (s, 3H), 2.65 (t, J = 13.2 Hz, 2H), 1.85 - 1.70 (m, 1H), 1.66 - 1.56 (m, 1H), 1.38 (s, 3H), 1.37 (s, 3H). ESI-MS: m/z 573.2 [M+Na]+. Compound 349 was prepared by the methods of Examples 14 and 139: 1H MR (300 MHz, DMSO- 6 ) δ 8.35 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 8.4 Hz, 2H), 8.03 ( d, J = 8.3 Hz, 2H), 7.47 (d, J = 12.8 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 6.95 (t, J = 8.8 Hz, 1H), 4.60 (d, J = 52.1 Ηζ, ΙΗ), 3.95 (d, J = 20.0 Hz, 1H), 3.87 - 3.77 (m, 1H), 3.51 (dd, J = 10.9, 4.0 Hz, 1H), 3.33 (s, 3H), 2.65 (t, J = 13.2 Hz, 2H), 1.85 - 1.70 (m, 1H), 1.66 - 1.56 (m, 1H), 1.38 (s, 3H), 1.37 (s, 3H). ESI-MS: m/z 573.2 [M+Na] + .
实施例 244  Example 244
反式 -2- (4-氯 -2-氟苯氧基) -N - (3-氟 -1 - ( (4-氟苯基) 磺酰基） 哌啶 -4-基） -2-甲 基丙酰胺 （化合物 350)  Trans-2-(4-chloro-2-fluorophenoxy)-N-(3-fluoro-1 -((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methyl Propionamide (compound 350)
参照实施例 14和 139的方法制得化合物 350: 1H NMR (300 MHz, CDC13) δ 7.82 (dd, J = 8.6, 5.0 Hz, 2H), 7.32 - 7.25 (m, 2H), 7.16 (dd, J = 10.2, 2.2 Hz, 1H), 7.03 (dt, J = 16.9, 9.2 Hz, 3H), 4.54 (dtd, J = 48.7, 9.2, 5.0 Hz, 1H), 4.09 - 3.86 (m, 2H), 3.69 (d, J= 11.9 Hz, 1H), 2.61 (dt, J = 15.5, 8.0 Hz, 2H), 2.19 (d, J= 13.4 Hz, 1H), 1.79 - 1.66 (m, 1H), 1.49 (s, 3H), 1.47 (s, 3H). ESI-MS: m/z 513.1 [M+Na]+. Compound 350 was prepared by the methods of Examples 14 and 139: 1H NMR (300 MHz, CDC1 3 ) δ 7.82 (dd, J = 8.6, 5.0 Hz, 2H), 7.32 - 7.25 (m, 2H), 7.16 (dd, J = 10.2, 2.2 Hz, 1H), 7.03 (dt, J = 16.9, 9.2 Hz, 3H), 4.54 (dtd, J = 48.7, 9.2, 5.0 Hz, 1H), 4.09 - 3.86 (m, 2H), 3.69 (d, J = 11.9 Hz, 1H), 2.61 (dt, J = 15.5, 8.0 Hz, 2H), 2.19 (d, J = 13.4 Hz, 1H), 1.79 - 1.66 (m, 1H), 1.49 (s, 3H), 1.47 (s, 3H). ESI-MS: m/z 513.1 [M+Na] + .
实施例 245  Example 245
反式 -2- (4-氯 -2-氟苯氧基） -N - (3-氟 -1- (吡啶 -3-基磺酰基） 哌啶 -4-基） -2-甲基丙 酰胺 （化合物 351 )  Trans-2-(4-chloro-2-fluorophenoxy)-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methylpropanamide (compound 351)
参照实施例 14和 139的方法制得化合物 351 : iH MR (300 MHz, OMSO-d6) δ 8.93 (s, 1Η), 8.89 (d, J = 4.7 Hz, 1H), 8.33 (d, J= 8.4 Hz, 1H), 8.18 (d, J= 8.1 Hz, 1H), 7.68 (dd, J = 7.9, 4.8 Hz, 1H), 7.46 (dd, J= 10.7, 2.3 Hz, 1H), 7.16 (d, J= 8.6 Hz, 1H), 6.96 (t, J= 8.9 Hz, 1H), 4.59 (dtd, J= 13.8, 8.9, 4.2 Hz, 1H), 4.02 - 3.77 (m, 2H), 3.51 (d, J= 12.1 Hz, 1H), 2.69 (dd, J = 23.5, 12.3 Hz, 2H), 1.81 - 1.54 (m, 2H), 1.39 (s, 3H), 1.37 (s, 3H). ESI-MS: m/z 496.2 [M+Na]+. Compound 351 was prepared by the methods of Examples 14 and 139: iH MR (300 MHz, OMSO-d 6 ) δ 8.93 (s, 1 Η), 8.89 (d, J = 4.7 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.18 (d, J= 8.1 Hz, 1H), 7.68 (dd, J = 7.9, 4.8 Hz, 1H), 7.46 (dd, J= 10.7, 2.3 Hz, 1H), 7.16 (d, J= 8.6 Hz, 1H), 6.96 (t, J= 8.9 Hz, 1H), 4.59 (dtd, J= 13.8, 8.9, 4.2 Hz, 1H), 4.02 - 3.77 (m, 2H), 3.51 (d, J = 12.1 Hz, 1H), 2.69 (dd, J = 23.5, 12.3 Hz, 2H), 1.81 - 1.54 (m, 2H), 1.39 (s, 3H), 1.37 (s, 3H). ESI-MS: m/ z 496.2 [M+Na] + .
实施例 246  Example 246
2- (2,5-二甲基苯氧基） -N- ( 1- ( (4-氟苯基）磺酰基）哌啶 -4-基） -2-甲基丙酰胺（化 合物 352)  2-(2,5-Dimethylphenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (compound 352)
参照实施例 14的方法制得化合物 352: 1H MR (300 MHz, CDC13) δ 7.79 (dd, J= 8.6, 5.1 Hz, 2H), 7.24 (t, J = 8.5 Hz, 2H), 7.07 (d, J= 7.6 Hz, 1H), 6.80 (d, J= 7.6 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 6.60 (s, 1H), 3.89 - 3.77 (m, 1H), 3.72 (d, J = 12.0 Hz, 2H), 2.53 (t, J = 10.7 Hz, 2H), 2.27 (s, 3H), 2.18 (s, 3H), 2.03 (d, J= 11.9 Hz, 2H),1.58 (m, 2H), 1.51 (s, 6H). ESI-MS: m/z 471.2 [M+Na]+. Compound 352 was prepared by the method of Example 14: 1H MR (300 MHz, CDC1 3 ) δ 7.79 (dd, J = 8.6, 5.1 Hz, 2H), 7.24 (t, J = 8.5 Hz, 2H), 7.07 (d , J = 7.6 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 6.60 (s, 1H), 3.89 - 3.77 (m, 1H), 3.72 (d, J = 12.0 Hz, 2H), 2.53 (t, J = 10.7 Hz, 2H), 2.27 (s, 3H), 2.18 (s, 3H), 2.03 (d, J = 11.9 Hz, 2H), 1.58 (m, 2H), 1.51 (s, 6H). ESI-MS: m/z 471.2 [M+Na] + .
实施例 247  Example 247
反式 -2- (2,5-二甲基苯氧基） -N - 3-氟 -1 - ( (4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 —4-基） -2-甲基丙酰胺 （化合物 353 )  Trans-2-(2,5-Dimethylphenoxy)-N-3-fluoro-1 -((4-(methylsulfonyl)phenyl)sulfonyl)piperidine-4-yl)- 2-methylpropionamide (compound 353)
参照实施例 14和 139的方法制得化合物 353 : 1H NMR (300 MHz, CDC13) δ 8.17 (d, J = 8.4 Hz, 2H), 8.17 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 6.82 (t, J = 10.1 Hz, 2H), 6.82 (t, J = 10.1 Hz, 2H), 6.64 (s, 1H), 6.64 (s, 1H), 4.66 - 4.35 (m, 1H), 4.04 (s, 2H), 3.73 (d, J = 12.5 Hz, 1H), 3.14 (s, 3H), 2.67 (t, J = 10.8 Hz, 2H), 2.26 (s, 3H), 2.19 (s, 3H), 1.72 - 1.64 (m, 1H), 1.52 (d, J= 12.9 Hz, 6H). ESI-MS: m/z 525.4 [M-H]+. Compound 353 was obtained by the methods of Examples 14 and 139: 1H NMR (300 MHz, CDC1 3 ) δ 8.17 (d, J = 8.4 Hz, 2H), 8.17 (d, J = 8.4 Hz, 2H), 8.00 (d , J = 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 6.82 (t, J = 10.1 Hz, 2H), 6.82 (t, J = 10.1 Hz, 2H), 6.64 (s, 1H), 6.64 (s, 1H), 4.66 - 4.35 (m, 1H), 4.04 (s, 2H), 3.73 (d, J = 12.5 Hz, 1H), 3.14 (s, 3H), 2.67 (t, J = 10.8 Hz, 2H), 2.26 (s, 3H), 2.19 (s, 3H), 1.72 - 1.64 (m, 1H), 1.52 (d, J = 12.9 Hz, 6H). ESI-MS: m/z 525.4 [MH] + .
实施例 248  Example 248
2- (2,5-二甲基苯氧基） -N - ( (3S,4S) -3-氟 -1 - ( (4- (甲基磺酰基） 苯基）磺酰基） 哌啶—4-基） -2-甲基丙酰胺 （化合物 354)  2-(2,5-Dimethylphenoxy)-N-((3S,4S)-3-fluoro-1 -((4-(methylsulfonyl)phenyl)sulfonyl)piperidine-4 -yl)-2-methylpropionamide (compound 354)
参照实施例 14和 77的方法制得化合物 354: ee>99%; 1H NMR (300 MHz, CDC13) δ 8.16 (d, J= 8.2 Hz, 2H), 7.99 (d, J= 8.2 Hz, 2H), 7.07 (d, J= 7.6 Hz, 1H), 6.82 (dd, J= 15.9,Compound 354 was prepared by the methods of Examples 14 and 77: ee >99%; 1H NMR (300 MHz, CDC1 3 ) δ 8.16 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 8.2 Hz, 2H ), 7.07 (d, J= 7.6 Hz, 1H), 6.82 (dd, J= 15.9,
8.0 Hz, 2H), 6.64 (s, 1H), 4.66 - 4.37 (m, 1H), 4.04 (s, 2H), 3.73 (d, J= 12.2 Hz, 1H), 3.13 (s, 3H), 2.67 (t, J = 10.7 Hz, 2H), 2.26 (s, 3H), 2.19 (s, 3H), 1.76 - 1.64 (m, 1H), 1.52 (d, J = 12.9 Hz, 6H). ESI-MS: M/Z 549.2 [M+Na]+. 8.0 Hz, 2H), 6.64 (s, 1H), 4.66 - 4.37 (m, 1H), 4.04 (s, 2H), 3.73 (d, J= 12.2 Hz, 1H), 3.13 (s, 3H), 2.67 ( t, J = 10.7 Hz, 2H), 2.26 (s, 3H), 2.19 (s, 3H), 1.76 - 1.64 (m, 1H), 1.52 (d, J = 12.9 Hz, 6H). ESI-MS: M /Z 549.2 [M+Na] + .
实施例 249  Example 249
5- (4-氯 -2-氟苯氧基） -N- ( 1- ( (4-氟苯基）磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 (化合物 355 )  5-(4-Chloro-2-fluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound) 355 )
参照实施例 119的方法制得化合物 355: 1H NMR (300 MHz, DMSO- 6) δ 7.94 - 7.69 (m, 2H), 7.61 - 7.33 (m, 3H), 7.33 - 7.02 (m, 3H), 4.10 - 3.88 (m, 2H), 3.67 - 3.41 (m, 3H), 2.41 - 2.22 (m, 2H), 1.78 - 1.62 (m, 2H), 1.62 - 1.37 (m, 6H), 1.05 (s, 6H).ESI-MS: m/z 537.3 [M+Na]+. Compound 355 was obtained by the method of Example 119: 1H NMR (300 MHz, DMSO-6) δ 7.94 - 7.69 (m, 2H), 7.61 - 7.33 (m, 3H), 7.33 - 7.02 (m, 3H), 4.10 - 3.88 (m, 2H), 3.67 - 3.41 (m, 3H), 2.41 - 2.22 (m, 2H), 1.78 - 1.62 (m, 2H), 1.62 - 1.37 (m, 6H), 1.05 (s, 6H) .ESI-MS: m/z 537.3 [M+Na] + .
实施例 250  Example 250
5- (4-氟 -3- (三氟甲基) 苯氧基） -N- ( 1- ( (4-氟苯基) 磺酰基） 哌啶 -4-基） -2,2- 二甲基戊酰胺 （化合物 356)  5-(4-Fluoro-3-(trifluoromethyl)phenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Radicotamide (Compound 356)
参照实施例 119的方法制得化合物 356: 1H NMR (300 MHz, CDC13) δ 7.77 (dd, J= 8.5:Compound 356 was prepared by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.77 (dd, J = 8.5:
5.1 Hz, 2H), 7.23 (dd, J = 14.5, 5.9 Hz, 2H), 7.12 - 6.72 (m, 3H), 5.56 (d, J = 7.5 Hz, 1H), 3.90 (t, J = 5.3 Hz, 2H), 3.85 - 3.59 (m, 3H), 2.39 (t, J = 11.6 Hz, 2H), 1.97 (d, J= 11.4 Hz, 2H), 1.80 - 1.43 (m, 6H), 1.18 (s, 6H). ESI-MS: m/z 571.2 [M+Na]+. 5.1 Hz, 2H), 7.23 (dd, J = 14.5, 5.9 Hz, 2H), 7.12 - 6.72 (m, 3H), 5.56 (d, J = 7.5 Hz, 1H), 3.90 (t, J = 5.3 Hz, 2H), 3.85 - 3.59 (m, 3H), 2.39 (t, J = 11.6 Hz, 2H), 1.97 (d, J = 11.4 Hz, 2H), 1.80 - 1.43 (m, 6H), 1.18 (s, 6H ESI-MS: m/z 571.2 [M+Na] + .
实施例 251  Example 251
N- ( 1 - ( (3- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） -4- (3- (三氟甲基） 苯氧 基） 丁酰胺 （化合物 357)  N-( 1 - ( (3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-4-(3-(trifluoromethyl)phenoxy)butanamide (compound 357)
参照实施例 119的方法制得化合物 357: 1H MR (300 MHz, CDC13) δ 8.32 (s, 1H), 8.19 (d, J= 7.8 Hz, 1H), 8.03 (d, J= 7.6 Hz, 1H), 7.79 (t, J= 7.8 Hz, 1H), 7.37 (t, J= 8.0 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.10 - 6.99 (m, 2H), 5.52 (d, J= 7.8 Hz, 1H), 4.01 (t, J = 5.9 Hz, 2H), 3.78 (d, J= 11.7 Hz, 3H), 3.12 (s, 3H), 2.50 (t, J= 11.3 Hz, 2H), 2.36 (t, J= 7.2 Hz, 2H), 2.21 - 2.05 (m, 2H), 2.02 (dd, J= 20.6, 8.6 Hz, 2H), 1.65 - 1.34 (m, 2H). ESI-MS: m/z 571.1 [M+Na]+. Compound 357 was prepared by the method of Example 119: 1H MR (300 MHz, CDC1 3 ) δ 8.32 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.03 (d, J = 7.6 Hz, 1H ), 7.79 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.10 - 6.99 (m, 2H), 5.52 (d , J= 7.8 Hz, 1H), 4.01 (t, J = 5.9 Hz, 2H), 3.78 (d, J= 11.7 Hz, 3H), 3.12 (s, 3H), 2.50 (t, J= 11.3 Hz, 2H ), 2.36 (t, J = 7.2 Hz, 2H), 2.21 - 2.05 (m, 2H), 2.02 (dd, J = 20.6, 8.6 Hz, 2H), 1.65 - 1.34 (m, 2H). ESI-MS: m/z 571.1 [M+Na] + .
实施例 252 5- (2,3-二氟 -4-甲基苯氧基） -N- ( 1- ( (4-氟苯基)磺酰基） 哌啶 -4-基） -2,2-二甲基 戊酰胺 （化合物 360) Example 252 5-(2,3-Difluoro-4-methylphenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Valentamide (Compound 360)
参照实施例 119的方法制得化合物 360: 1H NMR (300 MHz, CDC13) δ 7.86 - 7.69 (m, 2H), 7.33 - 7.16 (m, 2H), 6.86 - 6.74 (m, 1H), 6.66 - 6.53 (m, 1H), 5.75 (d, J= 8.1 Hz, 1H), 3.98 (t, J = 5.3 Hz, 2H), 3.89 - 3.78 (m, 1H), 3.78 - 3.61 (m, 2H), 2.43 - 2.34 (m, 2H), 2.24 (s, 3H), 2.04 - 1.89 (m, 2H), 1.76 - 1.62 (m, 4H), 1.62 - 1.50 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 535.2 [M+Na]+. The compound 360 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.86 - 7.69 (m, 2H), 7.33 - 7.16 (m, 2H), 6.86 - 6.74 (m, 1H), 6.66 - 6.53 (m, 1H), 5.75 (d, J = 8.1 Hz, 1H), 3.98 (t, J = 5.3 Hz, 2H), 3.89 - 3.78 (m, 1H), 3.78 - 3.61 (m, 2H), 2.43 - 2.34 (m, 2H), 2.24 (s, 3H), 2.04 - 1.89 (m, 2H), 1.76 - 1.62 (m, 4H), 1.62 - 1.50 (m, 2H), 1.18 (s, 6H). ESI -MS: m/z 535.2 [M+Na] + .
实施例 253  Example 253
5- (2,3-二氟 -4-甲基苯氧基） -N- ( 1- ( (3-氟苯基）磺酰基） 哌啶 -4-基） -2,2-二甲基 戊酰胺 （化合物 361 )  5-(2,3-Difluoro-4-methylphenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Valentamide (compound 361)
参照实施例 119的方法制得化合物 361： 1H NMR (300 MHz, CDC13) δ 7.62 - 7.50 (m, 2H), 7.51 - 7.41 (m, 1H), 7.38 - 7.29 (m, 1H), 6.88 - 6.72 (m, 1H), 6.69 - 6.51 (m, 1H), 5.56 (d, J= 7.6 Hz, 2H), 3.96 (t, J= 5.5 Hz, 2H), 3.86 - 3.76 (m, 1H), 3.77 - 3.63 (m, 2H), 2.56 - 2.36 (m, 2H), 2.23 (s, 3H), 2.07 - 1.87 (m, 2H), 1.79 - 1.60 (m, 4H), 1.55 - 1.44 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 535.2 [M+Na]+. The compound 361 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.62 - 7.50 (m, 2H), 7.51 - 7.41 (m, 1H), 7.38 - 7.29 (m, 1H), 6.88 - 6.72 (m, 1H), 6.69 - 6.51 (m, 1H), 5.56 (d, J= 7.6 Hz, 2H), 3.96 (t, J= 5.5 Hz, 2H), 3.86 - 3.76 (m, 1H), 3.77 - 3.63 (m, 2H), 2.56 - 2.36 (m, 2H), 2.23 (s, 3H), 2.07 - 1.87 (m, 2H), 1.79 - 1.60 (m, 4H), 1.55 - 1.44 (m, 2H) , 1.17 (s, 6H). ESI-MS: m/z 535.2 [M+Na] + .
实施例 254  Example 254
5- (2,3-二氟 -4-甲基苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (三氟甲氧基)苯基）磺酰基） 哌啶—4-基） 戊酰胺 （化合物 362)  5-(2,3-Difluoro-4-methylphenoxy)-2,2-dimethyl-N-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)piperidyl Pyridine- 4-yl) pentanoamide (compound 362)
参照实施例 119的方法制得化合物 362: 1H NMR (300 MHz, CDC13) δ 7.88 - 7.75 (m, 2H), 7.43 - 7.32 (m, 2H), 6.89 - 6.70 (m, 1H), 6.66 - 6.52 (m, 1H), 5.59 (d, J= 7.8 Hz, 1H), 3.96 (t, J = 5.3 Hz, 2H), 3.85 - 3.76 (m, 1H), 3.77 - 3.62 (m, 2H), 2.56 - 2.37 (m, 2H), 2.23 (s, 3H), 2.06 - 1.88 (m, 2H), 1.81 - 1.58 (m, 4H), 1.59 - 1.46 (m, 2H), 1.25 - 1.04 (m, 6H). ESI-MS: m/z 601.2 [M+Na]+. Compound 362 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.88 - 7.75 (m, 2H), 7.43 - 7.32 (m, 2H), 6.89 - 6.70 (m, 1H), 6.66 - 6.52 (m, 1H), 5.59 (d, J = 7.8 Hz, 1H), 3.96 (t, J = 5.3 Hz, 2H), 3.85 - 3.76 (m, 1H), 3.77 - 3.62 (m, 2H), 2.56 - 2.37 (m, 2H), 2.23 (s, 3H), 2.06 - 1.88 (m, 2H), 1.81 - 1.58 (m, 4H), 1.59 - 1.46 (m, 2H), 1.25 - 1.04 (m, 6H) ESI-MS: m/z 601.2 [M+Na] + .
实施例 255  Example 255
反式 -5- (2,5-二氯苯氧基） -N - (3-氟 -1 - ( (4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 （化合物 367)  Trans-5-(2,5-Dichlorophenoxy)-N-(3-fluoro-1 -((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) - 2,2-dimethylvaleramide (compound 367)
参照实施例 119和 139的方法制得化合物 367: 1H NMR (300 MHz, CDC13) δ 8.18 (d, J = 8.3 Hz, 2H), 8.05 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.19 (d, J= 1.9 Hz, 1H), 7.01 (dd, J= 8.5, 1.9 Hz, 1H), 4.74 - 4.43 (m, 1H), 4.08 - 3.96 (m, 2H), 3.96 - 3.80 (m, 2H), 3.59 - 3.49 (m, 1H), 3.32 (s, 3H), 2.82 - 2.59 (m, 2H), 1.87 - 1.67 (m, 1H), 1.69 - 1.44 (m, 5H), 1.08 (s, 6H). ESI-MS: m/z 631.2 [M+Na]+. Compound 367 was prepared by the methods of Examples 119 and 139: 1H NMR (300 MHz, CDC1 3 ) δ 8.18 (d, J = 8.3 Hz, 2H), 8.05 (d, J = 8.3 Hz, 2H), 7.44 (d , J = 8.4 Hz, 2H), 7.19 (d, J = 1.9 Hz, 1H), 7.01 (dd, J= 8.5, 1.9 Hz, 1H), 4.74 - 4.43 (m, 1H), 4.08 - 3.96 (m, 2H), 3.96 - 3.80 (m, 2H), 3.59 - 3.49 (m, 1H), 3.32 (s, 3H), 2.82 - 2.59 (m, 2H), 1.87 - 1.67 (m, 1H), 1.69 - 1.44 ( m, 5H), 1.08 (s, 6H). ESI-MS: m/z 631.2 [M+Na] + .
实施例 256  Example 256
反式 -5- (2,5-二氯苯氧基） -N - (3-氟 -1 - ( (3- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 （化合物 368) 参照实施例 119和 139的方法制得化合物 368: 1H NMR (300 MHz, CD3CN) δ 8.27 - 8.16 (m, 2H), 8.08 (d, J = 8.0 Hz, 1H), 7.92 - 7.81 (m, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.94 (dd, J= 8.5, 2.4 Hz, 1H), 6.27 (d, J = 8.3 Hz, 1H), 4.70 - 4.37 (m, 1H), 4.00 (t, J = 5.8 Hz, 2H), 3.97 - 3.82 (m, 2H), 3.65 - 3.51 (m, 1H), 3.13 (s, 3H), 2.78 - 2.59 (m, 2H), 1.91 - 1.81 (m, 1H), 1.75 - 1.53 (m, 5H), 1.12 (s, 6H). ESI-MS: m/z 631.2 [M+Na]+. 实施例 257 Trans-5-(2,5-dichlorophenoxy)-N-(3-fluoro-1 -((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) - 2,2-dimethylvaleramide (compound 368) Compound 368 was obtained by the methods of Examples 119 and 139: 1H NMR (300 MHz, CD 3 CN) δ 8.27 - 8.16 (m, 2H), 8.08 (d, J = 8.0 Hz, 1H), 7.92 - 7.81 (m , 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.94 (dd, J= 8.5, 2.4 Hz, 1H), 6.27 (d, J = 8.3 Hz , 1H), 4.70 - 4.37 (m, 1H), 4.00 (t, J = 5.8 Hz, 2H), 3.97 - 3.82 (m, 2H), 3.65 - 3.51 (m, 1H), 3.13 (s, 3H), 2.78 - 2.59 (m, 2H), 1.91 - 1.81 (m, 1H), 1.75 - 1.53 (m, 5H), 1.12 (s, 6H). ESI-MS: m/z 631.2 [M+Na] + . Example 257
反式 -5- (2,5-二氯苯氧基) -N - ( 3-氟 -1 - ( (4-氟苯基) 磺酰基） 哌啶 -4-基） -2,2-二 甲基戊酰胺 （化合物 369)  Trans-5-(2,5-dichlorophenoxy)-N-(3-fluoro-1 -((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-di Methyl pentamide (compound 369)
参照实施例 119和 139的方法制得化合物 369: 1H MR (300 MHz, DMSO- 6) δ 7.92 - 7.81(m, 2H), 7.56 - 7.38 (m, 4H), 7.19 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.5, 2.3 Hz, 1H), 4.73 - 4.43 (m, 1H), 4.10 - 3.95 (m, 2H), 3.94 - 3.73 (m, 2H), 3.55 - 3.41 (m, 1H), 2.66 - 2.53 (m, 2H), 1.86 - 1.68 (m, 1H), 1.67 - 1.44 (m, 5H), 1.08 (s, 6H). ESI-MS: m/z 571.2 [M+Na]+. Compound 369 was prepared by the methods of Examples 119 and 139: 1H MR (300 MHz, DMSO- 6 ) δ 7.92 - 7.81 (m, 2H), 7.56 - 7.38 (m, 4H), 7.19 (d, J = 2.0 Hz , 1H), 7.01 (dd, J = 8.5, 2.3 Hz, 1H), 4.73 - 4.43 (m, 1H), 4.10 - 3.95 (m, 2H), 3.94 - 3.73 (m, 2H), 3.55 - 3.41 (m , 1H), 2.66 - 2.53 (m, 2H), 1.86 - 1.68 (m, 1H), 1.67 - 1.44 (m, 5H), 1.08 (s, 6H). ESI-MS: m/z 571.2 [M+Na ] + .
实施例 258  Example 258
2- (4- (4-氯苯甲酰基） 苯氧基） -N- ( 1- ( (4-氟苯基）磺酰基） 哌啶 -4-基） -2-甲基 丙酰胺 （化合物 370)  2-(4-(4-Chlorobenzoyl)phenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (compound) 370)
参照实施例 14的方法制得化合物 370: 1H MR (300 MHz, DMSO- 6) δ 8.01 (d, J = 7.8 Hz, 1H), 7.85 - 7.66 (m, 6H), 7.62 (d, J = 8.2 Hz, 2H), 7.53 - 7.39 (m, 2H), 6.93 (d, J = 8.6 Hz, 2H), 3.71 - 3.56 (m, 1H), 3.56 - 3.44 (m, 2H), 2.45 - 2.32 (m, 2H), 1.75 - 1.60 (m, 2H), 1.59 - 1.35 (m, 8H). ESI-MS: m/z 581.2 [M+Na]+. Compound 370 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 8.01 (d, J = 7.8 Hz, 1H), 7.85 - 7.66 (m, 6H), 7.62 (d, J = 8.2 Hz, 2H), 7.53 - 7.39 (m, 2H), 6.93 (d, J = 8.6 Hz, 2H), 3.71 - 3.56 (m, 1H), 3.56 - 3.44 (m, 2H), 2.45 - 2.32 (m, 2H), 1.75 - 1.60 (m, 2H), 1.59 - 1.35 (m, 8H). ESI-MS: m/z 581.2 [M+Na] + .
实施例 259  Example 259
5- (2,6-二氟苯氧基） -2,2-二甲基 -N- ( 1- ( ( 3- (甲基磺酰基） 苯基）磺酰基） 哌啶 -4-基） 戊酰胺 （化合物 373 )  5-(2,6-Difluorophenoxy)-2,2-dimethyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valentamide (compound 373)
参照实施例 119的方法制得化合物 373 : 1H MR (300 MHz, DMSO- 6) δ 8.33 - 8.25 (m, 1H), 8.19 - 8.14 (m, 1H), 8.12 - 8.06 (m, 1H), 7.99 - 7.90 (m, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.16 - 7.08 (m, 3H), 4.02 (t, J = 5.3 Hz, 2H), 3.73 - 3.50 (m, 3H), 3.35 (s, 3H), 2.48 - 2.36 (m, 2H), 1.77 - 1.60 (m, 2H), 1.60 - 1.41 (m, 6H), 1.04 (s, 6H). ESI-MS: m/z 581.1 [M+Na]+. Compound 373 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.33 - 8.25 (m, 1H), 8.19 - 8.14 (m, 1H), 8.12 - 8.06 (m, 1H), 7.99 - 7.90 (m, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.16 - 7.08 (m, 3H), 4.02 (t, J = 5.3 Hz, 2H), 3.73 - 3.50 (m, 3H), 3.35 (s, 3H), 2.48 - 2.36 (m, 2H), 1.77 - 1.60 (m, 2H), 1.60 - 1.41 (m, 6H), 1.04 (s, 6H). ESI-MS: m/z 581.1 [ M+Na] + .
实施例 260  Example 260
N- ( 1- ( (4-氟苯基）磺酰基） 哌啶 -4-基） -3- (3- (三氟甲基） 苯氧基） 丙酰胺 （化 合物 375 )  N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-3-(3-(trifluoromethyl)phenoxy)propanamide (compound 375)
参照实施例 119的方法制得化合物 375 : 1H NMR (300 MHz, CDC13) δ 7.87 - 7.68 (m, 2H), 7.46 - 7.33 (m, 1H), 7.26 - 7.15 (m, 3H), 7.11 - 6.94 (m, 2H), 5.67 (d, J = 7.0 Hz, 1H), 4.27 (t, J = 5.9 Hz, 2H), 3.90 - 3.65 (m, 3H), 2.62 (t, J = 5.9 Hz, 2H), 2.51 - 2.31 (m, 2H), 2.11 - 1.86 (m, 2H), 1.60 - 1.54 (m, 2H). ESI-MS: m/z 497.3 [M+Na] . Compound 375 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.87 - 7.68 (m, 2H), 7.46 - 7.33 (m, 1H), 7.26 - 7.15 (m, 3H), 7.11 - 6.94 (m, 2H), 5.67 (d, J = 7.0 Hz, 1H), 4.27 (t, J = 5.9 Hz, 2H), 3.90 - 3.65 (m, 3H), 2.62 (t, J = 5.9 Hz, 2H ), 2.51 - 2.31 (m, 2H), 2.11 - 1.86 (m, 2H), 1.60 - 1.54 (m, 2H). ESI-MS: m/z 497.3 [M+Na].
实施例 261  Example 261
N- ( 1- ( (4- (甲磺酰基） 苯基） 磺酰基） 哌啶 -4-基） -3- (3- (三氟甲基） 苯氧基） 丙酰胺 （化合物 376)  N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-3-(3-(trifluoromethyl)phenoxy)propanamide (Compound 376)
参照实施例 119的方法制得化合物 376: 1H NMR (300 MHz, CD3OD-i¾) δ 8.21 (d, J = 8.3 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 7.53 - 7.39 (m, 1H), 7.29 - 7.10 (m, 3H), 4.29 (t, J = 5.8 Hz, 2H), 3.84 - 3.68 (m, 3H), 3.21 (s, 3H), 2.70 - 2.56 (m, 4H), 1.98 - 1.85 (m, 2H), 1.65 - 1.50 (m, 2H).ESI-MS: m/z 557.3 [M+Na]+. Compound 376 was prepared by the method of Example 119: 1H NMR (300 MHz, CD 3 OD-i3⁄4) δ 8.21. (d, J = 8.3 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 7.53 - 7.39 (m, 1H), 7.29 - 7.10 (m, 3H), 4.29 (t, J = 5.8 Hz, 2H), 3.84 - 3.68 (m, 3H), 3.21 (s, 3H), 2.70 - 2.56 (m, 4H), 1.98 - 1.85 (m, 2H), 1.65 - 1.50 (m, 2H). ESI-MS: m/z 557.3 [M+Na] + .
实施例 262  Example 262
2,2-二甲基 -N- ( 1- (吡啶 -3-基磺酰基） 哌啶 -4-基） -5- (2,4,6-三氟苯氧基） 戊酰胺 (化合物 377)  2,2-Dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-5-(2,4,6-trifluorophenoxy)pentanamide (Compound 377 )
参照实施例 119的方法制得化合物 377: 1H MR (300 MHz, DMSO- 6) δ 9.03 - 8.80 (m, 2H), 8.26 - 8.09 (m, 1H), 7.69 (dd, J= 8.1, 4.8 Hz, 1H), 7.35 - 7.06 (m, 3H), 3.97 (d, J = 5.5 Hz, 2H), 3.61 (t, J = 14.8 Hz, 3H), 2.49 - 2.33 (m, 2H), 1.70 (d, J= 11.0 Hz, 2H), 1.59 - 1.39 (m, 6H), 1.04 (s, 6H). ESI-MS: m/z 522.1 [M+Na]+. Compound 377 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 9.03 - 8.80 (m, 2H), 8.26 - 8.09 (m, 1H), 7.69 (dd, J = 8.1, 4.8 Hz , 1H), 7.35 - 7.06 (m, 3H), 3.97 (d, J = 5.5 Hz, 2H), 3.61 (t, J = 14.8 Hz, 3H), 2.49 - 2.33 (m, 2H), 1.70 (d, J = 11.0 Hz, 2H), 1.59 - 1.39 (m, 6H), 1.04 (s, 6H). ESI-MS: m/z 522.1 [M+Na] + .
实施例 263  Example 263
5- (2,5-二 （三氟甲基） 苯氧基） -N- ( 1- ( (4-氟苯基） 磺酰基） 哌啶 -4-基） -2,2-二 甲基戊酰胺 （化合物 379)  5-(2,5-bis(trifluoromethyl)phenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Valentamide (compound 379)
参照实施例 119的方法制得化合物 379: 1H NMR (300 MHz, CDC13) δ 7.82 - 7.73 (m, 2H), 7.69 (d, J= 8.0 Hz, 1H), 7.30 - 7.19 (m, 3H), 7.15 (s, 1H), 5.53 (d, J= 7.7 Hz, 1H), 4.06 (t, J= 5.3 Hz, 2H), 3.82 - 3.68 (m, 3H), 2.45 - 2.30 (m, 2H), 2.02 - 1.88 (m, 2H), 1.81 - 1.64 (m, 4H), 1.55 - 1.43 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 621.3 [M+Na]+. Compound 379 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.82 - 7.73 (m, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.30 - 7.19 (m, 3H) , 7.15 (s, 1H), 5.53 (d, J = 7.7 Hz, 1H), 4.06 (t, J = 5.3 Hz, 2H), 3.82 - 3.68 (m, 3H), 2.45 - 2.30 (m, 2H), 2.02 - 1.88 (m, 2H), 1.81 - 1.64 (m, 4H), 1.55 - 1.43 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 621.3 [M+Na] + .
实施例 264  Example 264
5- (4-氟 -3- (三氟甲基） 苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (甲基磺酰基） 苯基） 磺 酰基） -哌啶 -4-基） 戊酰胺 （化合物 380)  5-(4-Fluoro-3-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl) Piperidin-4-yl)pentanamide (compound 380)
参照实施例 119的方法制得化合物 380: 1H NMR (300 MHz, CDC13) δ 8.13 (d, J= 7.8 Hz, 2H), 7.96 (d, J = 7.9 Hz, 2H), 7.18 - 6.94 (m, 3H), 5.46 (d, J = 6.0 Hz, 1H), 3.97 - 3.64 (m, 6H), 3.11 (s, 3H), 2.50 (t, J = 11.6 Hz, 2H), 2.08 - 1.92 (m, 2H), 1.54 - 1.40 (m, 3H), 1.31 - 1.21 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 631.3 [M+Na]+. The compound 380 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 8.13 (d, J = 7.8 Hz, 2H), 7.96 (d, J = 7.9 Hz, 2H), 7.18 - 6.94 (m , 3H), 5.46 (d, J = 6.0 Hz, 1H), 3.97 - 3.64 (m, 6H), 3.11 (s, 3H), 2.50 (t, J = 11.6 Hz, 2H), 2.08 - 1.92 (m, 2H), 1.54 - 1.40 (m, 3H), 1.31 - 1.21 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 631.3 [M+Na] + .
实施例 265  Example 265
5- (4-氟 -3- (三氟甲基) 苯氧基） -2,2-二甲基 -N- ( 1- (吡啶 -3-基磺酰基) 哌啶 -4- 基） 戊酰胺 （化合物 381 )  5-(4-Fluoro-3-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)penta Amide (compound 381)
参照实施例 119的方法制得化合物 381 : 1H MR (300 MHz, CDC13) δ 8.99 (s, 1H), 8.84 (d, J = 4.0 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.57 - 7.41 (m, 1H), 7.06 (dd, J = 23.3, 13.4 Hz, 3H), 5.65 (d, J= 7.3 Hz, 1H), 3.99 - 3.64 (m, 5H), 2.46 (t, J= 11.4 Hz, 2H), 1.99 (d, J= 11.5 Hz, 2H), 1.79 - 1.45 (m, 6H), 1.26 - 1.07 (m, 6H). ESI-MS: m/z 554.2 [M+Na]+. 实施例 266 Compound 381 was prepared by the method of Example 119: 1H MR (300 MHz, CDC1 3 ) δ 8.99 (s, 1H), 8.84 (d, J = 4.0 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H ), 7.57 - 7.41 (m, 1H), 7.06 (dd, J = 23.3, 13.4 Hz, 3H), 5.65 (d, J= 7.3 Hz, 1H), 3.99 - 3.64 (m, 5H), 2.46 (t, J= 11.4 Hz, 2H), 1.99 (d, J= 11.5 Hz, 2H) , 1.79 - 1.45 (m, 6H), 1.26 - 1.07 (m, 6H). ESI-MS: m/z 554.2 [M+Na] + . Example 266
5- (4-氟 -3- (三氟甲基） 苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (三氟甲氧基） 苯基） 磺 酰基） 哌啶 -4-基） 戊酰胺 （化合物 382)  5-(4-Fluoro-3-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-((4-(trifluoromethoxy)phenyl)sulfonyl) Piperidin-4-yl)pentanamide (compound 382)
参照实施例 119的方法制得化合物 382: 1H NMR (300 MHz, CDC13) δ 7.80 (d, J= 8.7 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.14 - 6.93 (m, 3H), 5.80 (d, J = 7.7 Hz, 1H), 3.97 - 3.67 (m, 5H), 2.41 (t, J = 11.4 Hz, 2H), 1.97 (d, J= 12.2 Hz, 2H), 1.50-1.80 (m, 6H), 1.17 (s, 6H). ESI-MS: m/z 637.1 [M+Na]+. Compound 382 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.80 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.14 - 6.93 (m , 3H), 5.80 (d, J = 7.7 Hz, 1H), 3.97 - 3.67 (m, 5H), 2.41 (t, J = 11.4 Hz, 2H), 1.97 (d, J = 12.2 Hz, 2H), 1.50 -1.80 (m, 6H), 1.17 (s, 6H). ESI-MS: m/z 637.1 [M+Na] + .
实施例 267  Example 267
N- ( 1 - ( (4-氟苯基）磺酰基） 哌啶 -4-基） -4- (3- (三氟甲基）苯氧基）丁酰胺 （化 合物 383 )  N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-4-(3-(trifluoromethyl)phenoxy)butanamide (compound 383)
参照实施例 119的方法制得化合物 383 : 1H NMR (300 MHz, CDC13) δ 7.76 (dd, J= 8.4， 5.1 Hz, 2H), 7.37 (t, J = 7.9 Hz, 1H), 7.33 - 7.15 (m, 3H), 7.12 - 6.97 (m, 2H), 5.57 (d, J =The compound 383 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.76 (dd, J = 8.4, 5.1 Hz, 2H), 7.37 (t, J = 7.9 Hz, 1H), 7.33 - 7.15 (m, 3H), 7.12 - 6.97 (m, 2H), 5.57 (d, J =
7.5 Hz, 1H), 4.01 (t, J= 5.8 Hz, 2H), 3.86 - 3.65 (m ,3H), 2.49 - 2.26 (m, 4H), 2.18 - 2.05 (m, 2H), 2.04 - 1.86 (m, 2H), 1.61 - 1.42 (m, 2H). ESI-MS: m/z 511.2 [M+Na]+. 7.5 Hz, 1H), 4.01 (t, J= 5.8 Hz, 2H), 3.86 - 3.65 (m , 3H), 2.49 - 2.26 (m, 4H), 2.18 - 2.05 (m, 2H), 2.04 - 1.86 (m , 2H), 1.61 - 1.42 (m, 2H). ESI-MS: m/z 511.2 [M+Na] + .
实施例 268  Example 268
反式 -2- (2,4-二氟苯氧基） -N - ( 3-氟 -1 - ( ( 3- (甲基磺酰基） 苯基） 磺酰基） 哌啶 —4-基） -2-甲基丙酰胺 （化合物 391 )  Trans-2-(2,4-difluorophenoxy)-N-(3-fluoro-1 -((3-(methylsulfonyl)phenyl)sulfonyl)piperidine-4-yl)- 2-methylpropionamide (compound 391)
参照实施例 14和 139的方法制得化合物 391 : iH MR (300 MHz, OMSO-d6) δ 8.39 - 8.25 (m, 2H), 8.19 (s, 1H), 8.14 (d, J= 7.7 Hz, 1H), 8.01 - 7.89 (m, 1H), 7.37 - 7.24 (m, 1H), 7.10 - 6.92 (m, 2H), 4.77 - 4.52 (m, 1H), 4.02 - 3.84 (m, 2H), 3.62 - 3.52 (m, 1H), 3.35 (s, 3H), 2.74 - 2.59 (m, 2H), 1.88 - 1.76 (m, 1H), 1.73 - 1.60 (m, 1H), 1.37 (s, 3H), 1.35 (s, 3H). ESI-MS: m/z 557.2 [M+Na]+. Compound 391 was prepared by the methods of Examples 14 and 139: iH MR (300 MHz, OMSO-d 6 ) δ 8.39 - 8.25 (m, 2H), 8.19 (s, 1H), 8.14 (d, J = 7.7 Hz, 1H), 8.01 - 7.89 (m, 1H), 7.37 - 7.24 (m, 1H), 7.10 - 6.92 (m, 2H), 4.77 - 4.52 (m, 1H), 4.02 - 3.84 (m, 2H), 3.62 - 3.52 (m, 1H), 3.35 (s, 3H), 2.74 - 2.59 (m, 2H), 1.88 - 1.76 (m, 1H), 1.73 - 1.60 (m, 1H), 1.37 (s, 3H), 1.35 ( s, 3H). ESI-MS: m/z 557.2 [M+Na] + .
实施例 269  Example 269
2- ( 2,4-二氟苯氧基） -2-甲基 -N- ( 1- ( ( 3- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4- 基） 丙酰胺 （化合物 392)  2-(2,4-Difluorophenoxy)-2-methyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide ( Compound 392)
参照实施例 14的方法制得化合物 392: 1H MR (300 MHz, OMSO-d6) δ 8.28 (d, J =Compound 392 was prepared by the method of Example 14: 1H MR (300 MHz, OMSO-d 6 ) δ 8.28 (d, J =
7.6 Hz, 1H), 8.15 (s, 1H), 8.13 - 8.00 (m, 2H), 8.00 - 7.89 (m, 1H), 7.35 - 7.23 (m, 1H), 7.09 - 6.93 (m, 2H), 3.72 - 3.57 (m, 3H), 3.30 (s, 3H), 2.48 - 2.37 (m, 2H), 1.81 - 1.68 (m, 2H), 1.69 - 1.51 (m, 2H), 1.35 (s, 6H). ESI-MS: m/z 539.1 [M+Na]+. 7.6 Hz, 1H), 8.15 (s, 1H), 8.13 - 8.00 (m, 2H), 8.00 - 7.89 (m, 1H), 7.35 - 7.23 (m, 1H), 7.09 - 6.93 (m, 2H), 3.72 - 3.57 (m, 3H), 3.30 (s, 3H), 2.48 - 2.37 (m, 2H), 1.81 - 1.68 (m, 2H), 1.69 - 1.51 (m, 2H), 1.35 (s, 6H). ESI -MS: m/z 539.1 [M+Na] + .
实施例 270  Example 270
N- ( 1 - ( (4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） -4- ( 3- (三氟甲基） 苯氧 基） 丁酰胺 （化合物 394) 参照实施例 119的方法制得化合物 394: 1H MR (300 MHz, DMSO- 6) δ 8.27 - 8.11 (m, 2Η), 8.08 - 7.94 (m, 2H), 7.89 - 7.77 (m, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.33 - 7.14 (m, 3H), 4.03 (t, J= 6.1 Hz, 2H), 3.70 - 3.46 (m, 3H), 3.32 (s, 3H), 2.60 (t, J= 11.0 Hz, 2H), 2.21 (t, J = 7.2 Hz, 2H), 2.00 - 1.85 (m, 2H), 1.85 - 1.72 (m, 2H), 1.50 - 1.29 (m, 2H). ESI-MS: m/z 571.3 [M+Na]+. N-( 1 - ( (4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-4-(3-(trifluoromethyl)phenoxy)butanamide (compound 394) Compound 394 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.27 - 8.11 (m, 2 Η), 8.08 - 7.94 (m, 2H), 7.89 - 7.77 (m, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.33 - 7.14 (m, 3H), 4.03 (t, J = 6.1 Hz, 2H), 3.70 - 3.46 (m, 3H), 3.32 (s, 3H), 2.60 ( t, J = 11.0 Hz, 2H), 2.21 (t, J = 7.2 Hz, 2H), 2.00 - 1.85 (m, 2H), 1.85 - 1.72 (m, 2H), 1.50 - 1.29 (m, 2H). ESI -MS: m/z 571.3 [M+Na] + .
实施例 271  Example 271
N- ( 1- (吡啶 -3-基磺酰基） 哌啶 -4-基） -4- (3- (三氟甲基） 苯氧基） 丁酰胺 （化合 物 395 )  N-(1-(Pyridin-3-ylsulfonyl)piperidin-4-yl)-4-(3-(trifluoromethyl)phenoxy)butanamide (Compound 395)
参照实施例 119的方法制得化合物 395: 1H MR (300 MHz, DMSO- 6) δ 8.96 - 8.85 (m, 2H), 8.20 - 8.11 (m, 1H), 7.87 - 7.77 (m, 1H), 7.74 - 7.64 (m, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.32 - 7.15 (m, 3H), 4.02 (t, J = 6.3 Hz, 2H), 3.68 - 3.46 (m, 3H), 2.59 (t, J= 10.4 Hz, 2H), 2.21 (t, J = 7.3 Hz, 2H), 2.01 - 1.85 (m, 2H), 1.85 - 1.73 (m, 2H), 1.48 - 1.29 (m, 2H). ESI-MS: m/z 494.3 [M+Na]+. Compound 395 was obtained by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.96 - 8.85 (m, 2H), 8.20 - 8.11 (m, 1H), 7.87 - 7.77 (m, 1H), 7.74 - 7.64 (m, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.32 - 7.15 (m, 3H), 4.02 (t, J = 6.3 Hz, 2H), 3.68 - 3.46 (m, 3H), 2.59 (t, J= 10.4 Hz, 2H), 2.21 (t, J = 7.3 Hz, 2H), 2.01 - 1.85 (m, 2H), 1.85 - 1.73 (m, 2H), 1.48 - 1.29 (m, 2H) ESI-MS: m/z 494.3 [M+Na] + .
实施例 272  Example 272
5- (2,3-二氟苯氧基） -N- ( 1- ( (4-氟苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 (化合物 396)  5-(2,3-Difluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (Compound 396 )
参照实施例 119的方法制得化合物 396: 1H MR (300 MHz, DMSO- 6) δ 7.87 - 7.74 (m, 2H), 7.54 - 7.42 (m, 2H), 7.23 (d, J = 7.2 Hz, 1H), 7.17 - 7.04 (m, 1H), 7.04 - 6.90 (m, 2H), 4.11 - 3.94 (m, 2H), 3.69 - 3.45 (m, 3H), 2.35 (t, J= 11.3 Hz, 2H), 1.78 - 1.64 (m, 2H), 1.64 - 1.40 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 521.3 [M+Na]+. Compound 396 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 7.87 - 7.74 (m, 2H), 7.54 - 7.42 (m, 2H), 7.23 (d, J = 7.2 Hz, 1H ), 7.17 - 7.04 (m, 1H), 7.04 - 6.90 (m, 2H), 4.11 - 3.94 (m, 2H), 3.69 - 3.45 (m, 3H), 2.35 (t, J = 11.3 Hz, 2H), 1.78 - 1.64 (m, 2H), 1.64 - 1.40 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 521.3 [M+Na] + .
实施例 273  Example 273
2,2-二甲基 -N- ( 1- ( (4- (甲基磺酰基) 苯基） 磺酰基） 哌啶 -4-基） -5- (3,4,5-三氟 苯氧基） 戊酰胺 （化合物 397)  2,2-Dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-5-(3,4,5-trifluorophenoxy Ethyl pentamide (compound 397)
参照实施例 119的方法制得化合物 397: 1H MR (300 MHz, DMSO- 6) δ 8.18 (d, J = 8.2 Hz, 2H), 8.00 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 1.1 Hz, 1H), 6.98 - 6.84 (m, 2H), 4.02 - 3.85 (m, 2H), 3.73 - 3.49 (m, 3H), 3.32 (s, 3H), 2.49 - 2.37 (m, 2H), 1.81 - 1.63 (m, 2H), 1.63 - 1.38 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 599.4 [M+Na]+. Compound 397 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.18 (d, J = 8.2 Hz, 2H), 8.00 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 1.1 Hz, 1H), 6.98 - 6.84 (m, 2H), 4.02 - 3.85 (m, 2H), 3.73 - 3.49 (m, 3H), 3.32 (s, 3H), 2.49 - 2.37 (m, 2H) , 1.81 - 1.63 (m, 2H), 1.63 - 1.38 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 599.4 [M+Na] + .
实施例 274  Example 274
N- ( 1 - ( (4-氟苯基) 磺酰基） 哌啶 -4-基） -2,2-二甲基 -5- (3,4,5-三氟苯氧基） 戊酰 胺 （化合物 398)  N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(3,4,5-trifluorophenoxy)pentanamide ( Compound 398)
参照实施例 119的方法制得化合物 398: 1H MR (300 MHz, DMSO- 6) δ 7.87 - 7.76 (m, 2H), 7.49 (t, J = 8.7 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 6.98 - 6.85 (m, 2H), 3.97 - 3.86 (m, 2H), 3.66 - 3.48 (m, 3H), 2.36 (t, J= 11.3 Hz, 2H), 1.77 - 1.64 (m, 2H), 1.61 - 1.41 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 539.3 [M+Na]+. 实施例 275 Compound 398 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 7.87 - 7.76 (m, 2H), 7.49 (t, J = 8.7 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 6.98 - 6.85 (m, 2H), 3.97 - 3.86 (m, 2H), 3.66 - 3.48 (m, 3H), 2.36 (t, J= 11.3 Hz, 2H), 1.77 - 1.64 (m, 2H), 1.61 - 1.41 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 539.3 [M+Na] + . Example 275
2,2-二甲基 -N- ( 1- (吡啶 -3-基磺酰基) 哌啶 -4-基） -5- (2,3,4-三氟苯氧基） 戊酰胺 (化合物 399)  2,2-Dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-5-(2,3,4-trifluorophenoxy)pentanamide (Compound 399 )
参照实施例 119的方法制得化合物 399: 1H NMR (300 MHz, CDC13) δ 9.05 - 8.93 (m, 1H), 8.91 - 8.78 (m, 1H), 8.11-7.99 (m, 1H), 7.57 - 7.45 (m, 1H), 6.91 - 6.72 (m, 2H), 5.74 (d, J= 7.1 Hz, 1H), 4.20 - 4.05 (m, 2H), 3.92 - 3.67 (m, 3H), 2.47 (t, J= 11.4 Hz, 2H), 2.03 - 1.95 (m, 2H), 1.78- 1.64 (m, 4H), 1.64- 1.47 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 522.3 [M+Na]+. Compound 399 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 9.05 - 8.93 (m, 1H), 8.91 - 8.78 (m, 1H), 8.11-7.99 (m, 1H), 7.57 - 7.45 (m, 1H), 6.91 - 6.72 (m, 2H), 5.74 (d, J = 7.1 Hz, 1H), 4.20 - 4.05 (m, 2H), 3.92 - 3.67 (m, 3H), 2.47 (t, J= 11.4 Hz, 2H), 2.03 - 1.95 (m, 2H), 1.78- 1.64 (m, 4H), 1.64- 1.47 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 522.3 [M+Na] + .
实施例 276  Example 276
N- ( 1 - ( (4-氟苯基) 磺酰基） 哌啶 -4-基） -2,2-二甲基 -5- (2,3,4-三氟苯氧基） 戊酰 胺 （化合物 400)  N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(2,3,4-trifluorophenoxy)pentanamide Compound 400)
参照实施例 119的方法制得化合物 400: 1H NMR (300 MHz, CDC13) δ 7.82 - 7.72 (m, 2H), 7.22 (t, J = 8.4 Hz, 2H), 6.90 - 6.73 (m, 2H), 5.78 (d, J = 7.7 Hz, 1H), 4.22 - 4.03 (m, 2H), 3.85 - 3.68 (m, 3H), 2.39 (t, J= 11.7 Hz, 2H), 2.05 - 1.90 (m, 2H), 1.74 - 1.61 (m, 4H),Compound 400 was prepared by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.82 - 7.72 (m, 2H), 7.22 (t, J = 8.4 Hz, 2H), 6.90 - 6.73 (m, 2H) , 5.78 (d, J = 7.7 Hz, 1H), 4.22 - 4.03 (m, 2H), 3.85 - 3.68 (m, 3H), 2.39 (t, J = 11.7 Hz, 2H), 2.05 - 1.90 (m, 2H) ), 1.74 - 1.61 (m, 4H),
I.62 - 1.49 (m, 2H), 1.16 (s, 6H). ESI-MS: m/z 539.3 [M+Na]+. I.62 - 1.49 (m, 2H), 1.16 (s, 6H). ESI-MS: m/z 539.3 [M+Na] + .
实施例 277  Example 277
2,2-二甲基 -N- ( 1- (吡啶 -3-基磺酰基) 哌啶 -4-基） -5- (2- (三氟甲基) 苯氧基） 戊 酰胺 （化合物 401 )  2,2-Dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-5-(2-(trifluoromethyl)phenoxy)pentanamide (Compound 401 )
参照实施例 119的方法制得化合物 401： 1H NMR (300 MHz, CDC13) δ 9.04 - 8.93 (m, 1H), 8.88 - 8.78 (m, 1H), 8.10 - 7.98 (m, 1H), 7.61 - 7.53 (m, 1H), 7.52 - 7.39 (m, 2H), 7.05 - 6.88 (m, 2H), 5.65 (d, J= 7.5 Hz, 1H), 4.10 - 3.91 (m, 2H), 3.90 - 3.63 (m, 3H), 2.46 (t, J =The compound 401 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 9.04 - 8.93 (m, 1H), 8.88 - 8.78 (m, 1H), 8.10 - 7.98 (m, 1H), 7.61 - 7.53 (m, 1H), 7.52 - 7.39 (m, 2H), 7.05 - 6.88 (m, 2H), 5.65 (d, J = 7.5 Hz, 1H), 4.10 - 3.91 (m, 2H), 3.90 - 3.63 ( m, 3H), 2.46 (t, J =
II.8 Hz, 2H), 2.02 - 1.91 (m, 2H), 1.80 - 1.62 (m, 4H), 1.62 - 1.43 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 536.3 [M+Na]+. II.8 Hz, 2H), 2.02 - 1.91 (m, 2H), 1.80 - 1.62 (m, 4H), 1.62 - 1.43 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 536.3 [M+Na] + .
实施例 278  Example 278
N- ( 1 - ( (4-氟苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基 -5- (2- (三氟甲基） 苯氧基） 戊酰胺 （化合物 402)  N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(2-(trifluoromethyl)phenoxy)pentanamide ( Compound 402)
参照实施例 119的方法制得化合物 402: 1H NMR (300 MHz, CDC13) δ 7.85 - 7.68 (m, 2H), 7.64 - 7.51 (m, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.21 (t, J = 8.5 Hz, 2H), 7.07 - 6.87 (m, 2H), 5.67 (d, J= 7.7 Hz, 1H), 4.07 - 3.95 (m, 2H), 3.84 - 3.65 (m, 3H), 2.39 (t, J= 11.1 Hz, 2H), 2.01 - 1.87 (m, 2H), 1.79 - 1.61 (m, 4H), 1.61 - 1.45 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 553.3 [M+Na]+. Compound 402 was prepared by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.85 - 7.68 (m, 2H), 7.64 - 7.51 (m, 1H), 7.45 (t, J = 7.8 Hz, 1H) , 7.21 (t, J = 8.5 Hz, 2H), 7.07 - 6.87 (m, 2H), 5.67 (d, J = 7.7 Hz, 1H), 4.07 - 3.95 (m, 2H), 3.84 - 3.65 (m, 3H) ), 2.39 (t, J = 11.1 Hz, 2H), 2.01 - 1.87 (m, 2H), 1.79 - 1.61 (m, 4H), 1.61 - 1.45 (m, 2H), 1.17 (s, 6H). ESI- MS: m/z 553.3 [M+Na] + .
实施例 279  Example 279
5- (4-氟 -2- (三氟甲基) 苯氧基） -2,2-二甲基 -N- ( 1- (吡啶 -3-基磺酰基) 哌啶 -4- 基） 戊酰胺 （化合物 403 ) 参照实施例 119的方法制得化合物 403 : 1H NMR (300 MHz, CDC13) δ 9.04 - 8.93 (m, 1H), 8.90 - 8.78 (m, 1H), 8.11— 8.00 (m, 1H), 7.55 - 7.46 (m, 1H), 7.32 - 7.24 (m, 1H), 7.21 - 7.10 (m, 1H), 6.94 - 6.84 (m, 1H), 5.64 (d, J = 7.5 Hz, 1H), 4.04 - 3.91 (m, 2H), 3.90 - 3.69 (m, 3H), 2.47 (t, J = 11.7 Hz, 2H), 2.05 - 1.93 (m, 2H), 1.80 - 1.62 (m, 4H), 1.60 - 1.48 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 554.3 [M+Na]+. 5-(4-Fluoro-2-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)penta Amide (compound 403) Compound 403 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 9.04 - 8.93 (m, 1H), 8.90 - 8.78 (m, 1H), 8.11 - 8.00 (m, 1H), 7.55 - 7.46 (m, 1H), 7.32 - 7.24 (m, 1H), 7.21 - 7.10 (m, 1H), 6.94 - 6.84 (m, 1H), 5.64 (d, J = 7.5 Hz, 1H), 4.04 - 3.91 ( m, 2H), 3.90 - 3.69 (m, 3H), 2.47 (t, J = 11.7 Hz, 2H), 2.05 - 1.93 (m, 2H), 1.80 - 1.62 (m, 4H), 1.60 - 1.48 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 554.3 [M+Na] + .
实施例 280  Example 280
5- ( 4善 2- (三氟甲基) 苯氧基） -N- ( 1- ( ( 4-氟苯基) 磺酰基） 哌啶 -4-基） -2,2- 二甲基戊酰胺 （化合物 404)  5-( 4 good 2-(trifluoromethyl)phenoxy)-N-( 1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpenta Amide (compound 404)
参照实施例 119的方法制得化合物 404: 1H NMR (300 MHz, CDC13) δ 7.85 - 7.70 (m, 2H), 7.34 - 7.10 (m, 4H), 6.96 - 6.84 (m, 1H), 5.68 (d, J = 7.7 Hz, 1H), 4.05 - 3.89 (m, 2H), 3.87 - 3.64 (m, 3H), 2.40 (t, J = 11.4 Hz, 2H), 2.03 - 1.88 (m, 2H), 1.76 - 1.61 (m, 4H), 1.61 - 1.46 (m, 2H), 1.22 - 1.08 (s, 6H). ESI-MS: m/z 571.3 [M+Na]+. The compound 404 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.85 - 7.70 (m, 2H), 7.34 - 7.10 (m, 4H), 6.96 - 6.84 (m, 1H), 5.68 ( d, J = 7.7 Hz, 1H), 4.05 - 3.89 (m, 2H), 3.87 - 3.64 (m, 3H), 2.40 (t, J = 11.4 Hz, 2H), 2.03 - 1.88 (m, 2H), 1.76 - 1.61 (m, 4H), 1.61 - 1.46 (m, 2H), 1.22 - 1.08 (s, 6H). ESI-MS: m/z 571.3 [M+Na] + .
实施例 281  Example 281
5- (4-氯苯氧基) -N- ( ( 3R,4R) -3-氟 -1- ( (4-氟苯基) 磺酰基） 哌啶 -4-基） -2,2-二 甲基戊酰胺 （化合物 408 )  5-(4-Chlorophenoxy)-N-((3R,4R)-3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-di Methyl pentamide (compound 408)
参照实施例 77的方法， 以 5-(4-氯苯氧基) -2,2-二甲基戊酸和光学纯的 （3R,4R) -4- 氨基 -3-氟哌啶 -1-甲酸叔丁酯为原料， 制得化合物 408: ee>99% (手性 HPLC分析条件： Chiralpak IC4.6 mmX 250 mm, 柱温： 25 °C ; 流动相： 60%正己垸 /40%异丙醇； 流速： 1 mL/min;检测波长： UV254 nm;保留时间： 18.1 min) ; 1H NMR (300 MHz, CDC13) δ 7.76 - 7.67 (m, 2H), 7.19 - 7.09 (m, 4H), 6.71 (d, J= 8.9 Hz, 2H), 5.59 (d, J = 7.2 Hz, 1H), 4.53 - 4.24 (m, 1H), 4.06 - 3.95 (m, 1H), 3.92 - 3.74 (m, 3H), 3.70 - 3.59 (m, 1H), 2.44 - 2.30 (m, 2H), 2.12 - 1.99 (m, 1H), 1.65 - 1.57 (m, 3H), 1.54 - 1.41 (m, 2H), 1.12 (s, 6H). ESI-MS: m/z 537.2 [M+Na]+. Referring to the method of Example 77, 5-(4-chlorophenoxy)-2,2-dimethylpentanoic acid and optically pure (3R,4R)-4-amino-3-fluoropiperidin-1- Starting from tert-butyl formate, compound 408: ee>99% (Chiral HPLC analysis conditions: Chiralpak IC 4.6 mm X 250 mm, column temperature: 25 ° C; mobile phase: 60% hexane/40% isopropyl Alcohol; flow rate: 1 mL/min; detection wavelength: UV254 nm ; retention time: 18.1 min); 1H NMR (300 MHz, CDC1 3 ) δ 7.76 - 7.67 (m, 2H), 7.19 - 7.09 (m, 4H), 6.71 (d, J= 8.9 Hz, 2H), 5.59 (d, J = 7.2 Hz, 1H), 4.53 - 4.24 (m, 1H), 4.06 - 3.95 (m, 1H), 3.92 - 3.74 (m, 3H) , 3.70 - 3.59 (m, 1H), 2.44 - 2.30 (m, 2H), 2.12 - 1.99 (m, 1H), 1.65 - 1.57 (m, 3H), 1.54 - 1.41 (m, 2H), 1.12 (s, 6H). ESI-MS: m/z 537.2 [M+Na] + .
实施例 282  Example 282
4- ( ( ( 3R,4R) -4- ( 5- (4-氯苯氧基） -2,2-二甲基戊酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸 （化合物 409)  4-((3R,4R)-4-(5-(4-Chlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Formic acid (compound 409)
参照实施例 281的方法制得化合物 409: ee>99%; 1H NMR (300 MHz, OMSO-d6) δ 13.43 (s, 1H), 8.16 (d, J= 8.1 Hz, 2H), 7.90 (d, J= 8.1 Hz, 2H), 7.43 (d, J= 8.1 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 4.69 - 4.41 (m, 1H), 3.98 - 3.70 (m, 4H), 3.57 - 3.41 (m, 1H), 2.75 - 2.55 (m, 2H), 1.83 - 1.66 (m, 1H), 1.63 - 1.41 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 563.2 [M+Na]+. Compound 409 was obtained by the method of Example 281: ee >99%; 1H NMR (300 MHz, OMSO-d 6 ) δ 13.43 (s, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.90 (d , J= 8.1 Hz, 2H), 7.43 (d, J= 8.1 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 4.69 - 4.41 (m , 1H), 3.98 - 3.70 (m, 4H), 3.57 - 3.41 (m, 1H), 2.75 - 2.55 (m, 2H), 1.83 - 1.66 (m, 1H), 1.63 - 1.41 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 563.2 [M+Na] + .
实施例 283  Example 283
N- ( 1- (吡啶 -3-磺酰基） 哌啶 -4-基） -3- ( 3- (三氟甲基） 苯氧基） 丙酰胺 （化合物 410) 参照实施例 119的方法制得化合物 410: 1H MR (300 MHz, CDC13) δ 9.01 (s, 1H), 8.93 - 8.79 (m, 1H), 8.23 - 7.95 (m, 1H), 7.64 - 7.46 (m, 1H), 7.46 - 7.34 (m, 1H), 7.27 - 7.20 (m, 1H), 7.16 - 6.98 (m, 2H), 5.72 (d, J = 7.1 Hz, 1H), 4.29 (t, J = 5.8 Hz, 2H), 3.95 - 3.77 (m, 3H), 2.64 (t, J = 5.8 Hz, 2H), 2.59 - 2.42 (m, 2H), 2.21 - 1.94 (m, 2H), 1.75 - 1.61 (m, 2H). ESI-MS: m/z 480.2 [M+Na]+. N-(1-(pyridine-3-sulfonyl)piperidin-4-yl)-3-(3-(trifluoromethyl)phenoxy)propanamide (compound 410) Compound 410 was prepared by the method of Example 119: 1H MR (300 MHz, CDC1 3 ) δ 9.01 (s, 1H), 8.93 - 8.79 (m, 1H), 8.23 - 7.95 (m, 1H), 7.64 - 7.46 ( m, 1H), 7.46 - 7.34 (m, 1H), 7.27 - 7.20 (m, 1H), 7.16 - 6.98 (m, 2H), 5.72 (d, J = 7.1 Hz, 1H), 4.29 (t, J = 5.8 Hz, 2H), 3.95 - 3.77 (m, 3H), 2.64 (t, J = 5.8 Hz, 2H), 2.59 - 2.42 (m, 2H), 2.21 - 1.94 (m, 2H), 1.75 - 1.61 (m , 2H). ESI-MS: m/z 480.2 [M+Na] + .
实施例 284  Example 284
反式—4- ( (4- ( 5- (4-氯苯氧基) -2,2-二甲基戊酰胺) -3-氟哌啶 -1-基)磺酰基）苯甲 酸 （化合物 411 )  Trans-4-((4-(5-(4-chlorophenoxy)-2,2-dimethylvaleramide)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (Compound 411 )
参照实施例 119和 139的方法制得化合物 411： NMR (300 MHz, OMSO-d6) δ 13.49 (s, 1H), 8.16 (d, J = 8.3 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.2Hz, 1H), 7.30 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 4.73 - 4.40 (m, 1H), 3.97 - 3.75 (m, 4H), 3.59 - 3.43 (m, 1H), 2.79 - 2.55 (m, 2H), 1.84 - 1.65 (m, 1H), 1.61 - 1.42 (m, 5H), 1.06 (s, 6H). ESI-MS: m/z 563.2 [M+Na]+. Compound 411 was prepared by the methods of Examples 119 and 139: NMR (300 MHz, OMSO-d 6 ) δ 13.49 (s, 1H), 8.16 (d, J = 8.3 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.2Hz, 1H), 7.30 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 4.73 - 4.40 (m, 1H), 3.97 - 3.75 (m, 4H), 3.59 - 3.43 (m, 1H), 2.79 - 2.55 (m, 2H), 1.84 - 1.65 (m, 1H), 1.61 - 1.42 (m, 5H), 1.06 (s, 6H) ESI-MS: m/z 563.2 [M+Na] + .
实施例 285  Example 285
反式 -5-(4-氯苯氧基) -N- ( 3-氟 -1- ( (4-氟苯基）磺酰基） 哌啶 -4-基） -2， 2-二甲基戊 酰胺 （化合物 412) Trans- 5- (4-chlorophenoxy)-N-(3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpenta Amide (compound 412)
参照实施例 119和 139的方法制得化合物 412: 1H MR (300 MHz, CDC13) δ 7.86 - 7.72 (m, 2H), 7.30 - 7.25 (m, 1H), 7.24 - 7.15 (m, 3H), 6.83 - 6.73 (m, 2H), 5.80 - 5.55 (m, 1H), 4.63 - 4.23 (m, 1H), 4.18 - 3.99 (m, 1H), 3.99 - 3.79 (m, 3H), 3.79 - 3.63 (m, 1H), 2.56 - 2.36 (m, 2H), 2.23 - 2.06 (m, 1H), 1.76 - 1.61 (m, 5H), 1.19 (s, 6H). ESI-MS: m/z 537.2 [M+Na]+. Compound 412 was prepared by the methods of Examples 119 and 139: 1H MR (300 MHz, CDC1 3 ) δ 7.86 - 7.72 (m, 2H), 7.30 - 7.25 (m, 1H), 7.24 - 7.15 (m, 3H), 6.83 - 6.73 (m, 2H), 5.80 - 5.55 (m, 1H), 4.63 - 4.23 (m, 1H), 4.18 - 3.99 (m, 1H), 3.99 - 3.79 (m, 3H), 3.79 - 3.63 (m , 1H), 2.56 - 2.36 (m, 2H), 2.23 - 2.06 (m, 1H), 1.76 - 1.61 (m, 5H), 1.19 (s, 6H). ESI-MS: m/z 537.2 [M+Na ] + .
实施例 286  Example 286
反式—4- ( (4- (2- ( 3,4-二氟苯氧基) -2-甲基丙酰氨基) -3-氟哌啶 -1-基)磺酰基）苯 甲酸 （化合物 415 )  Trans-4-((4-(2-(3,4-difluorophenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (compound) 415 )
参照实施例 14和 139的方法制得化合物 415 : 1H NMR (300 MHz, DMSO- 6) δ 13.46 (s, 1Η), 8.29 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.32 (dd, J = 19.6, 9.6 Hz, 1H), 6.94 (ddd, J = 12.1, 6.8, 2.6 Hz, 1H), 6.77 - 6.65 (m, 1H), 4.75 - 4.40 (m, 1H), 4.06 - 3.71 (m, 2H), 3.51 (d, J = 11.3 Hz, 1H), 3.32 (s, 1H), 2.70 - 2.55 (m, 2H), 1.82 - 1.70 (m, 1H), 1.70 - 1.50 (m, 1H), 1.39 (d, j = 10.1 Hz, 6H). ESI-MS: m/z 499.1 [M-H]". 实施例 287 Compound 415 was obtained by the method of Examples 14 and 139: 1H NMR (300 MHz, DMSO- 6 ) δ 13.46 (s, 1 Η), 8.29 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.32 (dd, J = 19.6, 9.6 Hz, 1H), 6.94 (ddd, J = 12.1, 6.8, 2.6 Hz, 1H), 6.77 - 6.65 (m, 1H), 4.75 - 4.40 (m, 1H), 4.06 - 3.71 (m, 2H), 3.51 (d, J = 11.3 Hz, 1H), 3.32 (s, 1H), 2.70 - 2.55 (m, 2H ), 1.82 - 1.70 (m, 1H), 1.70 - 1.50 (m, 1H), 1.39 (d, j = 10.1 Hz, 6H). ESI-MS: m/z 499.1 [MH]". Example 287
反式—4- ( (4- (2- ( 3,4-二氟苯氧基) -2-甲基丙酰氨基) -3-氟哌啶 -1-基) 磺酰基） 苯甲酸 2-乙酰氨基乙酯 （化合物 416)  Trans-4-((4-(2-(3,4-difluorophenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid 2- Acetylaminoethyl ester (compound 416)
以化合物 415 (实施例 286)为原料，参照实施例 183的方法制得化合物 416: 1H MR (300 MHz, CDCI3) δ 8.23 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 7.07 (dd, J = 18.7, 9.3 Hz, 1H), 6.84 - 6.58 (m, 3H), 5.83 (s, 1H), 4.71 - 4.32 (m, 3H), 4. 16 - 4.04 (m, 1H), 4.00 - 3.86 (m, 1H), 3.83 -3.61 (dt, 3H), 2.64 - 2.46 (m, 2H), 2.24 - 2.09 (m, 1H), 2.03 (s, 3H), 1.75 - 1.62 (m, 1H), 1.48 (d, J = 6.8 Hz, 6H). ESI-MS: m/z 608.2 [M+Na]+. Using Compound 415 (Example 286) as a starting material, Compound 416 was obtained by the procedure of Example 183: 1H MR (300 MHz, CDCI3) δ 8.23 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 7.07 (dd, J = 18.7, 9.3 Hz, 1H), 6.84 - 6.58 (m, 3H), 5.83 (s, 1H), 4.71 - 4.32 (m, 3H), 4. 16 - 4.04 (m, 1H), 4.00 - 3.86 (m, 1H), 3.83 -3.61 (dt, 3H), 2.64 - 2.46 (m, 2H), 2.24 - 2.09 (m, 1H), 2.03 (s, 3H), 1.75 - 1.62 (m, 1H), 1.48 (d, J = 6.8 Hz, 6H). ESI-MS: m/z 608.2 [M+Na] + .
实施例 288  Example 288
5- ( 2,5-二 （三氟甲基） 苯氧基） -N- ( 1- ( ( 3-氟苯基） 磺酰基） 哌啶 -4-基） -2,2- 二甲基戊酰胺 （化合物 417 )  5-(2,5-bis(trifluoromethyl)phenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Valentamide (compound 417)
参照实施例 119的方法制得化合物 417: 1H MR (300 MHz, CDC13) δ 7.71 (d, J = 8.0 Hz, 1H), 7.55 (m, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.34 (m, 2H), 7.18 (s, 1H), 5.49 (d, J = 7.6 Hz: 1H), 4.08 (t, J = 5.4 Hz, 2H), 3.87 - 3.66 (m, 3H), 2.46 (t, J = 1 1.4 Hz, 2H), 1.98 (d, J = 1 1.3 Hz, 2H), 1.85 - 1.63 (m, 4H), 1.57 - 1.44 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 621.3
Figure imgf000118_0001
Compound 417 was obtained by the method of Example 119: 1H MR (300 MHz, CDC13) δ 7.71 (d, J = 8.0 Hz, 1H), 7.55 (m, 2H), 7.49 (d, J = 7.8 Hz, 1H) , 7.34 (m, 2H), 7.18 (s, 1H), 5.49 (d, J = 7.6 Hz: 1H), 4.08 (t, J = 5.4 Hz, 2H), 3.87 - 3.66 (m, 3H), 2.46 ( t, J = 1 1.4 Hz, 2H), 1.98 (d, J = 1 1.3 Hz, 2H), 1.85 - 1.63 (m, 4H), 1.57 - 1.44 (m, 2H), 1.20 (s, 6H). ESI -MS: m/z 621.3
Figure imgf000118_0001
实施例 289  Example 289
N- ( 1 - ( ( 4-氟苯基）磺酰基）哌啶 -4-基） -2,2-二甲基 -5- (萘 -2-基氧基）戊酰胺（化 合物 418 )  N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(naphthalen-2-yloxy)pentanamide (compound 418)
参照实施例 119的方法制得化合物 418 : 1H MR (300 MHz, OMSO-d6) δ 7.86 - 7.73 (m, 5H), 7.54 - 7.40 (m, 3H), 7.39 - 7.29 (m, 1H), 7.29 - 7.20 (m, 2H), 7.18 - 7.09 (m, 1H), 4.10 - 3.97 (m, 3H), 3.62 - 3.45 (m, 4H), 2.37 - 2.24 (m, 2H), 1.67 - 1.59 (m, 4H), 1.55 - 1.42 (m, 2H), 1.08 (s, 6H). ESI-MS: m/z 535.2 [M+Na]+. The compound 418 was obtained by the method of Example 119: 1H MR (300 MHz, OMSO-d 6 ) δ 7.86 - 7.73 (m, 5H), 7.54 - 7.40 (m, 3H), 7.39 - 7.29 (m, 1H), 7.29 - 7.20 (m, 2H), 7.18 - 7.09 (m, 1H), 4.10 - 3.97 (m, 3H), 3.62 - 3.45 (m, 4H), 2.37 - 2.24 (m, 2H), 1.67 - 1.59 (m , 4H), 1.55 - 1.42 (m, 2H), 1.08 (s, 6H). ESI-MS: m/z 535.2 [M+Na] + .
实施例 290  Example 290
N- ( 1 - ( ( 4-氟苯基）磺酰基）哌啶 -4-基） -2,2-二甲基 -5- (萘 -1-基氧基）戊酰胺（化 合物 419 )  N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(naphthalen-1-yloxy)pentanamide (compound 419)
参照实施例 119的方法制得化合物 419: 1H MR (300 MHz, OMSO-d6) δ 8.16 (d, J = 7.9 Hz, 1H), 7.90 - 7.75 (m, 3H), 7.57 - 7.34 (m, 6H), 7.28 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 7.1 Hz, 1H), 4.16 - 4.01 (m, 2H), 3.67 - 3.48 (m, 3H), 2.42 - 2.27 (m, 2H), 1.80 - 1.62 (m, 6H), 1.59 - 1.45 (m, 2H), 1.10 (s, 6H). ESI-MS: m/z 535.2 [M+Na]+ . Compound 419 was prepared by the method of Example 119: 1H MR (300 MHz, OMSO-d 6 ) δ 8.16 (d, J = 7.9 Hz, 1H), 7.90 - 7.75 (m, 3H), 7.57 - 7.34 (m, 6H), 7.28 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 7.1 Hz, 1H), 4.16 - 4.01 (m, 2H), 3.67 - 3.48 (m, 3H), 2.42 - 2.27 (m , 2H), 1.80 - 1.62 (m, 6H), 1.59 - 1.45 (m, 2H), 1.10 (s, 6H). ESI-MS: m/z 535.2 [M+Na] + .
实施例 291  Example 291
反式—4- ( ( 4- ( 5- ( 4-氯苯氧基) -2, 2-二甲基戊酰胺基) -3-氟哌啶 -1-基) 磺酰基） 苯甲酸 2-乙酰氨基乙酯 （化合物 424 )  Trans-4-((4-(5-(4-chlorophenoxy)-2,2-dimethylpentanoyl)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid 2- Acetylaminoethyl ester (compound 424)
以化合物 41 1 (实施例 284 )为原料，参照实施例 183的方法制得化合物 424: 1H MR (300 MHz, CDC13) δ 8.22 (d, J = 7.6 Hz, 2H), 7.85 (d, J = 7.7 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 5.92 - 5.57 (m, 2H), 4.68 - 4.30 (m, 3H), 4.20 - 3.81 (m, 4H), 3.81 - 3.57 (m, 3H), 2.60 - 2.38 (m, 2H), 2.27 - 1.94 (m, 4H), 1.68 - 1.52 (m, 5H), 1.23 (s, 6H). ESI-MS: m/z 648.2 [M+Na]+. Using Compound 41 1 (Example 284) as a starting material, Compound 424 was obtained by the procedure of Example 183: 1H MR (300 MHz, CDC1 3 ) δ 8.22 (d, J = 7.6 Hz, 2H), 7.85 (d, J = 7.7 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 5.92 - 5.57 (m, 2H), 4.68 - 4.30 (m, 3H), 4.20 - 3.81 (m, 4H), 3.81 - 3.57 (m, 3H), 2.60 - 2.38 (m, 2H), 2.27 - 1.94 (m, 4H), 1.68 - 1.52 (m, 5H), 1.23 (s, 6H) ESI-MS: m/z 648.2 [M+Na] + .
实施例 292 顺式—5- ( 4-氯苯氧基) -N- ( 3-氟 -1- ( ( 4-氟苯基) 磺酰基） 哌啶 -4-基） -2, 2-二甲 基戊酰胺 （化合物 425 ) Example 292 Cis-5-(4-chlorophenoxy)-N-(3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentyl Amide (compound 425)
参照实施例 139的方法， 以 5-(4-氯苯氧基) -2,2-二甲基戊酸和 （±) -顺式 -4-氨基 -3- 氟哌啶 -1-甲酸叔丁酯为原料， 制得化合物 425 : 1H NMR (300 MHz, CDC13) δ 7.89 - 7.75 (m, 2H), 7.25 - 7.09 (m, 4H), 6.78 (d, J = 8.8 Hz, 2H), 5.87 (d, J = 7.6 Hz, 1H), 4.87 - 4.50 (m, 1H), 4.25 - 4.07 (m, 1H), 4.07 - 3.74 (m, 4H), 2.80 - 2.48 (m, 2H), 1.94 - 1.74 (m, 2H), 1.66 - 1.52 (m, 3H), 1.19 (s, 6H). ESI-MS: m/z 537.1 [M+Na]+. Referring to the method of Example 139, 5-(4-chlorophenoxy)-2,2-dimethylvaleric acid and (±)-cis-4-amino-3-fluoropiperidin-1-carboxylic acid Starting from butyl ester, compound 425 : 1H NMR (300 MHz, CDC1 3 ) δ 7.89 - 7.75 (m, 2H), 7.25 - 7.09 (m, 4H), 6.78 (d, J = 8.8 Hz, 2H), 5.87 (d, J = 7.6 Hz, 1H), 4.87 - 4.50 (m, 1H), 4.25 - 4.07 (m, 1H), 4.07 - 3.74 (m, 4H), 2.80 - 2.48 (m, 2H), 1.94 - 1.74 (m, 2H), 1.66 - 1.52 (m, 3H), 1.19 (s, 6H). ESI-MS: m/z 537.1 [M+Na] + .
实施例 293  Example 293
5- (4-氯 -2-氟苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (甲基磺酰基） 苯基）磺酰基） 哌啶 -4-基） 戊酰胺 （化合物 426)  5-(4-Chloro-2-fluorophenoxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl ) pentanoamide (compound 426)
参照实施例 119的方法制得化合物 426: 1H NMR (300 MHz, CDC13) δ 8.23 - 8.03 (m, 2H), 8.04 - 7.88 (m, 2H), 7.10 (dd, J = 10.8, 2.5 Hz, OH), 7.07 - 6.98 (m, 1H), 6.91 - 6.75 (m, 1H), 5.56 (d, J = 7.7 Hz, 1H), 3.95 (t, J = 5.6 Hz, 1H), 3.89 - 3.82 (m, 1H), 3.81 - 3.68 (m, 2H), 3.11 (s, 3H), 2.59 - 2.41 (m, 2H), 2.04 - 1.89 (m, 2H), 1.76 - 1.62 (m, 4H), 1.58 - 1.45 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 597.1 [M+Na]+. Compound 426 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 8.23 - 8.03 (m, 2H), 8.04 - 7.88 (m, 2H), 7.10 (dd, J = 10.8, 2.5 Hz, OH), 7.07 - 6.98 (m, 1H), 6.91 - 6.75 (m, 1H), 5.56 (d, J = 7.7 Hz, 1H), 3.95 (t, J = 5.6 Hz, 1H), 3.89 - 3.82 (m , 1H), 3.81 - 3.68 (m, 2H), 3.11 (s, 3H), 2.59 - 2.41 (m, 2H), 2.04 - 1.89 (m, 2H), 1.76 - 1.62 (m, 4H), 1.58 - 1.45 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 597.1 [M+Na] + .
实施例 294  Example 294
顺式—4- ( (4- ( 5- (4-氯苯氧基) -2,2-二甲基戊酰胺基) -3-氟哌啶 -1-基)磺酰基）苯 甲酸 （化合物 427)  Cis- 4-((4-(5-(4-chlorophenoxy)-2,2-dimethylpentanoyl)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (compound) 427)
参照实施例 292的方法制得化合物 427: 1H NMR (300 MHz, OMSO-d6) δ 13.51 (s, 1H), 8.15 (d, J= 8.2 Hz, 2H), 7.86 (d, J= 8.2 Hz, 2H), 7.38 (d, J= 7.4 Hz, 1H), 7.30 (d, J= 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 4.80 - 4.55 (m, 1H), 3.99 - 3.63 (m, 5H), 2.89 - 2.53 (m, 2H), 1.96 - 1.71 (m, 1H), 1.64 - 1.43 (m, 5H), 1.08 (d, J = 3.4 Hz, 6H). ESI-MS: m/z 563.2 [M+Na]+. Compound 427 was obtained by the method of Example 292: 1H NMR (300 MHz, OMSO-d 6 ) δ 13.51 (s, 1H), 8.15 (d, J = 8.2 Hz, 2H), 7.86 (d, J = 8.2 Hz , 2H), 7.38 (d, J= 7.4 Hz, 1H), 7.30 (d, J= 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 4.80 - 4.55 (m, 1H), 3.99 - 3.63 (m, 5H), 2.89 - 2.53 (m, 2H), 1.96 - 1.71 (m, 1H), 1.64 - 1.43 (m, 5H), 1.08 (d, J = 3.4 Hz, 6H). ESI-MS : m/z 563.2 [M+Na] + .
实施例 295  Example 295
4 - ( (4- (2- (4- (4-氯苯甲酰基） 苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 （化合物 428 )  4-((4-(2-(4-(4-Chlorobenzoyl)phenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 428)
参照实施例 14的方法制得化合物 428: 1H MR (300 MHz, DMSO- 6) δ 13.48 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 8.02 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.76 - 7.66 (m, 4H), 7.62 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 3.71 - 3.59 (m, 1H), 3.59 - 3.46 (m, 2H), 2.56 - 2.45 (m, 4H), 1.68 (d, J = 10.9 Hz, 2H), 1.49 (s, 6H). ESI-MS: m/z 607.3 [M+Na]+. Compound 428 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 13.48 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 8.02 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.76 - 7.66 (m, 4H), 7.62 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 3.71 - 3.59 (m, 1H), 3.59 - 3.46 (m, 2H), 2.56 - 2.45 (m, 4H), 1.68 (d, J = 10.9 Hz, 2H), 1.49 (s, 6H). ESI-MS: m/ z 607.3 [M+Na] + .
实施例 296  Example 296
反式—4- ( (4- ( 5- (2,5-二氟苯氧基） -2,2-二甲基戊酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸 （化合物 429) 参照实施例 139的方法制得化合物 429: 1H MR (300 MHz, DMSO- 6) δ 13.49 (s, 1Η), 8.24 - 8.10 (m, 2H), 8.01 - 7.79 (m, 2H), 7.45 (d, J = 8.2 Hz, 1H), 7.23 (ddd, J = 11.5, 9.0, 5.5 Hz, 1H), 7.06 (ddd, J = 10.3, 6.9, 3.0 Hz, 1H), 6.82 - 6.64 (m, 1H), 4.74 - 4.39 (m, 1H), 3.97 (t, 2H), 3.94 - 3.74 (m, 2H), 3.51 (d, J = 12.1 Hz, 1H), 2.73 - 2.54 (m, 2H), 1.86 - 1.44 (m, 6H), 1.07 (s, 6H). ESI-MS: m/z 565.2 [M+Na]+. Trans-4-((4-(5-(2,5-difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Formic acid (compound 429) Compound 429 was prepared by the method of Example 139: 1H MR (300 MHz, DMSO- 6 ) δ 13.49 (s, 1 Η), 8.24 - 8.10 (m, 2H), 8.01 - 7.79 (m, 2H), 7.45 (d , J = 8.2 Hz, 1H), 7.23 (ddd, J = 11.5, 9.0, 5.5 Hz, 1H), 7.06 (ddd, J = 10.3, 6.9, 3.0 Hz, 1H), 6.82 - 6.64 (m, 1H), 4.74 - 4.39 (m, 1H), 3.97 (t, 2H), 3.94 - 3.74 (m, 2H), 3.51 (d, J = 12.1 Hz, 1H), 2.73 - 2.54 (m, 2H), 1.86 - 1.44 ( m, 6H), 1.07 (s, 6H). ESI-MS: m/z 565.2 [M+Na] + .
实施例 297  Example 297
4 - ( (4- (2- (4- (4-氯苯甲酰基） 苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸甲酯 （化合物 430)  4-((4-(2-(4-(4-Chlorobenzoyl)phenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid methyl ester (compound 430 )
参照实施例 14的方法制得化合物 430: 1H MR (300 MHz, DMSO- 6) δ 8.14 (d, J = 8.1 Hz, 2H), 8.02 (d, J= 7.9 Hz, 1H), 7.82 (d, J= 8.2 Hz, 2H), 7.76 - 7.46 (m, 6H), 6.90 (d, J = 8.4 Hz, 2H), 3.88 (s, 3H), 3.68 - 3.43 (m, 3H), 2.40 (d, J= 11.5 Hz, 2H), 1.66 (d, J = 12.9 Hz, 2H), 1.55 - 1.38 (m, 8H). ESI-MS: m/z 621.1 [M+Na]+. Compound 430 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 8.14 (d, J = 8.1 Hz, 2H), 8.02 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.76 - 7.46 (m, 6H), 6.90 (d, J = 8.4 Hz, 2H), 3.88 (s, 3H), 3.68 - 3.43 (m, 3H), 2.40 (d, J = 11.5 Hz, 2H), 1.66 (d, J = 12.9 Hz, 2H), 1.55 - 1.38 (m, 8H). ESI-MS: m/z 621.1 [M+Na] + .
实施例 298  Example 298
反式 -2-(4-氯苯氧基) -N - (3-氟 -1 - ((3-氟苯基;)磺酰基;)哌啶 -4-基;) -2-甲基丙酰胺（化合 物 431 ) Trans- 2- (4-chlorophenoxy)-N-(3-fluoro-1 -((3-fluorophenyl))sulfonyl;)piperidin-4-yl;)-2-methylpropane Amide (compound 431)
参照实施例 14和 139的方法制得化合物 431： 1H NMR (300 MHz, CDC13) δ 7.63-7.53 (m, 2H), 7.62 - 7.36 (m, 1H), 7.51 - 7.22 (m, 1H), 7.27 (d, J = 5.3 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.3 Hz, 1H), 4.71 - 4.24 (m, 1H), 4.20 - 3.61 (m, 4H), 2.70 - 2.40 (m, 2H), 1.74-1.62 (m, 1H), 1.50 (s, 3H), 1.48 (s, 3H). ESI-MS: m/z 495.2 [M+Na]+. The compound 431 was obtained by the method of Example 14 and 139: 1H NMR (300 MHz, CDC1 3 ) δ 7.63-7.53 (m, 2H), 7.62 - 7.36 (m, 1H), 7.51 - 7.22 (m, 1H), 7.27 (d, J = 5.3 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.3 Hz, 1H), 4.71 - 4.24 (m, 1H), 4.20 - 3.61 (m , 4H), 2.70 - 2.40 (m, 2H), 1.74-1.62 (m, 1H), 1.50 (s, 3H), 1.48 (s, 3H). ESI-MS: m/z 495.2 [M+Na] + .
实施例 299  Example 299
2-(4-氯苯氧基) -N - 3R,4R)-3-氟 -1 - 3-氟苯基)磺酰基)哌啶 -4-基;) -2-甲基丙酰胺 (化合物 432)  2-(4-Chlorophenoxy)-N-3R,4R)-3-fluoro-1-trifluorophenyl)sulfonyl)piperidin-4-yl;)-2-methylpropanamide (compound) 432)
参照实施例 14和 281的方法， 以光学纯的 （3R,4R) -4-氨基 -3-氟哌啶 -1-甲酸叔丁 酯为原料，制得化合物 432: ee>99%; 1H NMR (300 MHz, CDC13) δ 7.63-7.53 (m, 2Η), 7.62 - 7.36 (m, 1H), 7.51 - 7.22 (m, 1H), 7.27 (d, J= 5.3 Hz, 2H), 6.85 (d, J= 8.4 Hz, 2H), 6.73 (d, J= 8.3 Hz, 1H), 4.71 - 4.24 (m, 1H), 4.20 - 3.61 (m, 4H), 2.70 - 2.40 (m, 2H), 1.74-1.62 (m, 1H), 1.50 (s, 3H), 1.48 (s, 3H). ESI-MS: m/z 495.2 [M+Na]+. The compound 432 was prepared by optically pure tert-butyl (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylate according to the methods of Examples 14 and 281: ee>99%; 1H NMR (300 MHz, CDC1 3 ) δ 7.63-7.53 (m, 2Η), 7.62 - 7.36 (m, 1H), 7.51 - 7.22 (m, 1H), 7.27 (d, J= 5.3 Hz, 2H), 6.85 (d , J= 8.4 Hz, 2H), 6.73 (d, J= 8.3 Hz, 1H), 4.71 - 4.24 (m, 1H), 4.20 - 3.61 (m, 4H), 2.70 - 2.40 (m, 2H), 1.74- 1.62 (m, 1H), 1.50 (s, 3H), 1.48 (s, 3H). ESI-MS: m/z 495.2 [M+Na] + .
实施例 300  Example 300
反式 -3-((4-(2-(4-氯苯氧基; )-2-甲基丙酰氨基 )-3-氟哌啶 -1-基;)磺酰基；)苯甲酸 （化合物 Trans-3-((4-(2-(4-chlorophenoxy))-2-methylpropionylamino)-3-fluoropiperidin-1-yl;)sulfonyl;)benzoic acid (compound
433 ) 433 )
参照实施例 14和 139的方法制得化合物 433： 1H NMR (300 MHz, CD3OD) δ 8.38 (s, 1H), 8.33 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.79 - 4.33 (m, 1H), 4.12 - 3.84 (m, 2H), 3.79 - 3.58 (m, 1H), 2.75 - 2.39 (m, 2H), 2.04 - 1.84 (m, 1H), 1.82 - 1.59 (m, 1H), 1.49 (s, 3H), 1.46 (s, 3H). ESI-MS: m/z 497.2 [M-H]". Compound 433 was prepared by the method of Examples 14 and 139: 1H NMR (300 MHz, CD 3 OD) δ 8.38 (s, 1H), 8.33 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.79 - 4.33 (m, 1H), 4.12 - 3.84 (m, 2H), 3.79 - 3.58 (m, 1H), 2.75 - 2.39 (m, 2H), 2.04 - 1.84 (m, 1H), 1.82 - 1.59 (m, 1H), 1.49 (s, 3H ), 1.46 (s, 3H). ESI-MS: m/z 497.2 [MH]".
实施例 301  Example 301
3-(((3¾4R)-4-(2-(4-氯苯氧基) -2-甲基丙酰氨基 )-3-氟哌啶 -1-基)磺酰基)苯甲酸（化合 物 434)  3-(((33⁄44R)-4-(2-(4-Chlorophenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (Compound 434)
参照实施例 281的方法制得化合物 434: ee>99%; 1H NMR (300 MHz, Methanol-i¾) δ 8.38 (s, 1Η), 8.33 (d, J= 7.9 Hz, 1H), 8.02 (d, J= 7.8 Hz, 1H), 7.77 (t, J= 7.8 Hz, 1H), 7.24 (d, J= 8.4 Hz, 2H), 6.89 (d, J= 8.4 Hz, 2H), 4.79 - 4.33 (m, 1H), 4.12 - 3.84 (m, 2H), 3.79 - 3.58 (m, 1H), 2.75 - 2.39 (m, 2H), 2.04 - 1.84 (m, 1H), 1.82 - 1.59 (m, 1H), 1.49 (s, 3H), 1.46 (s, 3H). ESI-MS: m/z 497.2 [M-H]".  Compound 434 was prepared by the method of Example 281: ee > 99%; 1H NMR (300 MHz, Methanol-i3⁄4) δ 8.38 (s, 1 Η), 8.33 (d, J = 7.9 Hz, 1H), 8.02 (d, J= 7.8 Hz, 1H), 7.77 (t, J= 7.8 Hz, 1H), 7.24 (d, J= 8.4 Hz, 2H), 6.89 (d, J= 8.4 Hz, 2H), 4.79 - 4.33 (m, 1H), 4.12 - 3.84 (m, 2H), 3.79 - 3.58 (m, 1H), 2.75 - 2.39 (m, 2H), 2.04 - 1.84 (m, 1H), 1.82 - 1.59 (m, 1H), 1.49 ( s, 3H), 1.46 (s, 3H). ESI-MS: m/z 497.2 [MH]".
实施例 302  Example 302
反式 -2-(4-氯苯氧基) -N - (4-氟 -1 - ((3-氟苯基;)磺酰基;)哌啶 -4-基;) -2-甲基丙酰胺（化合 物 435 ) Trans- 2- (4-chlorophenoxy)-N-(4-fluoro-1 -((3-fluorophenyl))sulfonyl;)piperidin-4-yl;)-2-methylpropane Amide (compound 435)
参照实施例 14和 139的方法制得化合物 435: 1H NMR (300 MHz, CDC13) δ 7.80 (dd, J = 8.6, 5.0 Hz, 2H), 7.40 - 7.12 (m, 4H), 6.85 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.3 Hz, 1H), 4.71 - 4.24 (m, 1H), 4.19 - 3.86 (m, 2H), 3.85 - 3.58 (m, 1H), 2.67 - 2.36 (m, 2H), 2.29 - 1.99 (m, 1H), 1.81 - 1.50 (m, 1H), 1.50 (s, 3H), 1.48 (s, 3H). ESI-MS: m/z 495.2 [M+Na]+. 实施例 303 Compound 435 was prepared by the methods of Examples 14 and 139: 1H NMR (300 MHz, CDC1 3 ) δ 7.80 (dd, J = 8.6, 5.0 Hz, 2H), 7.40 - 7.12 (m, 4H), 6.85 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.3 Hz, 1H), 4.71 - 4.24 (m, 1H), 4.19 - 3.86 (m, 2H), 3.85 - 3.58 (m, 1H), 2.67 - 2.36 (m, 2H), 2.29 - 1.99 (m, 1H), 1.81 - 1.50 (m, 1H), 1.50 (s, 3H), 1.48 (s, 3H). ESI-MS: m/z 495.2 [M+Na ] + . Example 303
2-(4-氯苯氧基) -N-((3R,4R)-3-氟 -l-((4-氟苯基)磺酰基)哌啶 -4-基) -2-甲基丙酰胺 （化 合物 436)  2-(4-Chlorophenoxy)-N-((3R,4R)-3-fluoro-l-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropane Amide (compound 436)
参照实施例 281的方法制得化合物 436: ee>99%; 1H NMR (300 MHz, CDC13) δ 7.80 (dd, J = 8.6, 5.0 Hz, 2H), 7.40 - 7.12 (m, 4H), 6.85 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.3 Hz, 1H), 4.71 - 4.24 (m, 1H), 4.19 - 3.86 (m, 2H), 3.85 - 3.58 (m, 1H), 2.67 - 2.36 (m, 2H), 2.29 - 1.99 (m, 1H), 1.81 - 1.50 (m, 1H), 1.50 (s, 3H), 1.48 (s, 3H). ESI-MS: m/z 495.2 [M+Na]+. 实施例 304 Compound 436 was prepared by the method of Example 281: ee >99%; 1H NMR (300 MHz, CDC1 3 ) δ 7.80 (dd, J = 8.6, 5.0 Hz, 2H), 7.40 - 7.12 (m, 4H), 6.85 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.3 Hz, 1H), 4.71 - 4.24 (m, 1H), 4.19 - 3.86 (m, 2H), 3.85 - 3.58 (m, 1H), 2.67 - 2.36 (m, 2H), 2.29 - 1.99 (m, 1H), 1.81 - 1.50 (m, 1H), 1.50 (s, 3H), 1.48 (s, 3H). ESI-MS: m/z 495.2 [ M+Na] + . Example 304
2- (4-氯 -2-氟苯氧基) -N- ( 1- ( (4-氟苯基)磺酰基）哌啶 -4-基） -2-甲基丙酰胺（化 合物 437)  2-(4-Chloro-2-fluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (compound 437)
参照实施例 14的方法制得化合物 437: 1H MR (300 MHz, DMSO- 6) δ 7.80 (s, 2Η), 7.28 - 7.21 (m, 2H), 7.16 (d, J = 10.1 Hz, 1H), 7.06 (s, 1H), 6.97 (t, J = 8.3 Hz, 1H), 6.88 (dd, J = 4.3, 2.6 Hz, 1H), 3.73 (d, J = 10.8 Hz, 3H), 2.55 (t, J = 11.1 Hz, 2H), 2.04 (d, J = 10.9 Hz, 2H), 1.62 (s, 3H), 1.29 (t, J = 19.4 Hz, 6H). ESI-MS: m/z 495.1 [M+Na]+. Compound 437 was obtained by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 7.80 (s, 2 Η), 7.28 - 7.21 (m, 2H), 7.16 (d, J = 10.1 Hz, 1H), 7.06 (s, 1H), 6.97 (t, J = 8.3 Hz, 1H), 6.88 (dd, J = 4.3, 2.6 Hz, 1H), 3.73 (d, J = 10.8 Hz, 3H), 2.55 (t, J = 11.1 Hz, 2H), 2.04 (d, J = 10.9 Hz, 2H), 1.62 (s, 3H), 1.29 (t, J = 19.4 Hz, 6H). ESI-MS: m/z 495.1 [M+Na ] + .
实施例 305  Example 305
2- (4-氯 -2-氟苯氧基） -N- ( 1- ( (3-氟苯基）磺酰基）哌啶 -4-基） -2-甲基丙酰胺（化 合物 438)  2-(4-Chloro-2-fluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (compound 438)
参照实施例 14的方法制得化合物 438: 1H MR (300 MHz, DMSO- 6) δ 7.57 (t, J = 4.8 Hz, 2H), 7.50 (dd, J = 8.1, 1.0 Hz, 1H), 7.34 (ddd, J = 9.4, 7.0, 2.6 Hz, 1H), 7.16 (dd, J = 10.2, 2.4 Hz, 1H), 7.11 - 7.04 (m, 1H), 6.97 (t, J = 8.6 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 3.88 - 3.70 (m, 3H), 2.58 (t, J = 11.7 Hz, 2H), 2.05 (d, J = 10.0 Hz, 2H), 1.68 - 1.57 (m, 3H), 1.46 (s, 6H). ESI-MS: m/z 495.2 [M+Na]+. Compound 438 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 7.57 (t, J = 4.8 Hz, 2H), 7.50 (dd, J = 8.1, 1.0 Hz, 1H), 7.34 (ddd, J = 9.4, 7.0, 2.6 Hz, 1H), 7.16 (dd, J = 10.2, 2.4 Hz, 1H), 7.11 - 7.04 (m, 1H), 6.97 (t, J = 8.6 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 3.88 - 3.70 (m, 3H), 2.58 (t, J = 11.7 Hz , 2H), 2.05 (d, J = 10.0 Hz, 2H), 1.68 - 1.57 (m, 3H), 1.46 (s, 6H). ESI-MS: m/z 495.2 [M+Na] + .
实施例 306  Example 306
2- (2,5-二甲基苯氧基） -2-甲基 -N- ( 1- (苯基磺酰基） 哌啶 -4-基） 丙酰胺 （化合物 2-(2,5-Dimethylphenoxy)-2-methyl-N-(1-(phenylsulfonyl)piperidin-4-yl)propanamide (compound)
439) 439)
参照实施例 14的方法制得化合物 439: 1H MR (300 MHz, CDC13) δ 7.78 (d, J = 7.7 Hz, 2H), 7.65 - 7.60 (m, 1H), 7.56 (dd, J = 9.8, 4.8 Hz, 2H), 7.06 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 6.70 - 6.63 (m, 1H), 6.60 (s, 1H), 3.77 (t, J = 11.8 Hz, 3H), 2.52 (t, J = 10.8 Hz, 3H), 2.27 (s, 3H), 2.17 (s, 3H), 2.01 (d, J = 12.7 Hz, 3H), 1.59 - 1.53 (m, 2H), 1.50 (s, 6H). ESI-MS: m/z 453.2 [M+Na]+. Compound 439 was prepared by the method of Example 14: 1H MR (300 MHz, CDC13) δ 7.78 (d, J = 7.7 Hz, 2H), 7.65 - 7.60 (m, 1H), 7.56 (dd, J = 9.8, 4.8 Hz, 2H), 7.06 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 6.70 - 6.63 (m, 1H), 6.60 (s, 1H), 3.77 (t, J = 11.8 Hz, 3H), 2.52 (t, J = 10.8 Hz, 3H), 2.27 (s, 3H), 2.17 (s, 3H), 2.01 (d, J = 12.7 Hz, 3H), 1.59 - 1.53 (m , 2H), 1.50 (s, 6H). ESI-MS: m/z 453.2 [M+Na] + .
实施例 307  Example 307
2- (2,5-二甲基苯氧基） -2-甲基 -N- ( 1- ( ( 3- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 （化合物 440)  2-(2,5-Dimethylphenoxy)-2-methyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide (Compound 440)
参照实施例 14的方法制得化合物 440: 1H NMR (300 MHz, DMSO- 6) δ 8.29 (d, J =Compound 440 was prepared by the method of Example 14: 1H NMR (300 MHz, DMSO- 6 ) δ 8.29 (d, J =
7.6 Hz, 1H), 8.15 (s, 1H), 8.08 (d, J = 7.5 Hz, 1H), 7.95 (t, J = 8.0 Hz, 2H), 7.03 (d, J = 7.4 Hz, 1H), 6.71 (d, J = 7.5 Hz, 1H), 6.52 (s, 1H), 4.04 (dd, J = 14.3, 7.2 Hz, 1H), 3.68 - 3.57 (m, 2H), 3.35 (s, 3H), 2.46 (dd, J = 11.6, 3.0 Hz, 2H), 2.18 (s, 3H), 2.12 (s, 3H), 1.74 (d, J = 12.9 Hz, 2H), 1.59 (dt, J = 9.2, 7.4 Hz, 2H), 1.37 (s, 6H). ESI-MS: m/z 531.2 [M+Na]+. 7.6 Hz, 1H), 8.15 (s, 1H), 8.08 (d, J = 7.5 Hz, 1H), 7.95 (t, J = 8.0 Hz, 2H), 7.03 (d, J = 7.4 Hz, 1H), 6.71 (d, J = 7.5 Hz, 1H), 6.52 (s, 1H), 4.04 (dd, J = 14.3, 7.2 Hz, 1H), 3.68 - 3.57 (m, 2H), 3.35 (s, 3H), 2.46 ( Dd, J = 11.6, 3.0 Hz, 2H), 2.18 (s, 3H), 2.12 (s, 3H), 1.74 (d, J = 12.9 Hz, 2H), 1.59 (dt, J = 9.2, 7.4 Hz, 2H ), 1.37 (s, 6H). ESI-MS: m/z 531.2 [M+Na] + .
实施例 308  Example 308
2- (4-氯 -2-氟苯氧基） -2-甲基 -N- ( 1- ( (4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4- 基） 丙酰胺 （化合物 441 )  2-(4-Chloro-2-fluorophenoxy)-2-methyl-N-( 1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide (Compound 441)
参照实施例 14的方法制得化合物 441 : 1H MR (300 MHz, OMSO-d6) δ 8.17 (d, J =Compound 441 was prepared by the method of Example 14 : 1H MR (300 MHz, OMSO-d 6 ) δ 8.17 (d, J =
8.4 Hz, 2H), 8.07 (m, 1H), 7.97 (d, J= 8.3 Hz, 2H), 7.45 (m, 1H), 7.17 (m, 1H), 6.94 (m, 1H), 3.59 (m, 3H), 3.31 (s, 3H), 2.44 (s, 2H), 1.72 (m, 2H), 1.54 (m, 2H), 1.37 (s, 6H). ESI-MS: m/z 555.1 [M+Na]+. 8.4 Hz, 2H), 8.07 (m, 1H), 7.97 (d, J= 8.3 Hz, 2H), 7.45 (m, 1H), 7.17 (m, 1H), 6.94 (m, 1H), 3.59 (m, 3H), 3.31 (s, 3H), 2.44 (s, 2H), 1.72 (m, 2H), 1.54 (m, 2H), 1.37 (s, 6H). ESI-MS: m/z 555.1 [M+Na ] + .
实施例 309  Example 309
2- (4-氯 -2-氟苯氧基） -2-甲基 -N- ( 1- ( ( 3- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4- 基） 丙酰胺 （化合物 442)  2-(4-Chloro-2-fluorophenoxy)-2-methyl-N-( 1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide (Compound 442)
参照实施例 14的方法制得化合物 442: 1H MR (300 MHz, OMSO-d6) δ 8.27 (d, J =Compound 442 was prepared by the method of Example 14: 1H MR (300 MHz, OMSO-d 6 ) δ 8.27 (d, J =
7.7 Hz, 1H), 8.13 (m, 1H), 8.06 (d, J = 7.9 Hz, 2H), 7.98 - 7.88 (m, 1H), 7.45 (dd, J = 10.8,7.7 Hz, 1H), 8.13 (m, 1H), 8.06 (d, J = 7.9 Hz, 2H), 7.98 - 7.88 (m, 1H), 7.45 (dd, J = 10.8,
2.5 Hz, 1H), 7.21 - 7.10 (m, 1H), 6.99 - 6.88 (m, 1H), 3.68 - 3.55 (m, 3H), 3.33 (s, 3H), 2.44 - 2.35 (m, 2H), 1.78 - 1.65 (m, 2H), 1.62 - 1.47 (m, 2H), 1.36 (s, 6H). ESI-MS: m/z 555.1 [M+Na]+. 2.5 Hz, 1H), 7.21 - 7.10 (m, 1H), 6.99 - 6.88 (m, 1H), 3.68 - 3.55 (m, 3H), 3.33 (s, 3H), 2.44 - 2.35 (m, 2H), 1.78 - 1.65 (m, 2H), 1.62 - 1.47 (m, 2H), 1.36 (s, 6H). ESI-MS: m/z 555.1 [M+Na] + .
实施例 310  Example 310
4- (((3R,4R) -4- (5- (2,5-二氟苯氧基) -2,2-二甲基戊酰氨基) -3-氟哌啶 -1-基) 磺 酰基） 苯甲酸 （化合物 443)  4-(((3R,4R)-4-(5-(2,5-Difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl) sulfonate Acyl) benzoic acid (compound 443)
参照实施例 281的方法制得化合物 443: ee>99%; 1H MR (300 MHz, DMSO- 6) δ 13.54 (s, 1Η), 8.17 (d, J= 8.3 Hz, 2H), 7.90 (d,J= 8.3 Hz, 2H), 7.46 (d, J= 8.1 Hz, 1H), 7.31 -7.15 (m, 1H), 7.12-7.00 (m, 1H), 6.81 -6.66 (m, 1H), 4.71-4.42 (m, 1H), 4.01-3.95 (m, 2H), 3.93 -3.77 (m, 2H), 3.51 (d,J= 11.8 Hz, 1H), 2.72-2.55 (m, 2H), 1.84- 1.69 (m, 1H),Compound 443 was prepared by the method of Example 281: ee >99%; 1H MR (300 MHz, DMSO- 6 ) δ 13.54 (s, 1 Η), 8.17 (d, J = 8.3 Hz, 2H), 7.90 (d, J= 8.3 Hz, 2H), 7.46 (d, J= 8.1 Hz, 1H), 7.31 -7.15 (m, 1H), 7.12-7.00 (m, 1H), 6.81 -6.66 (m, 1H), 4.71-4.42 (m, 1H), 4.01-3.95 (m, 2H), 3.93 -3.77 (m, 2H), 3.51 (d, J = 11.8 Hz, 1H), 2.72-2.55 (m, 2H), 1.84- 1.69 (m , 1H),
1.65 - 1.46 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 565.2 [M+Na]+. 1.65 - 1.46 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 565.2 [M+Na] + .
实施例 311  Example 311
4- (((3S， 4S) -4- (5- (2,5-二氟苯氧基) -2,2-二甲基戊酰氨基) -3-氟哌啶 -1-基) 磺酰基） 苯甲酸 （化合物 444)  4-(((3S, 4S)-4-(5-(2,5-Difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl) sulfonate Acyl) benzoic acid (compound 444)
参照实施例 77的方法制得化合物 444: ee>99%; 1H NMR (300 MHz, DMSO- 6) δ 13.52 (s, 1H), 8.17 (d, J= 8.2 Hz, 2H), 7.90 (d,J= 8.3 Hz, 2H), 7.46 (d, J= 8.2 Hz, 1H), 7.31 -7.17(m, 1H), 7.13-6.99 (m, 1H), 6.78 - 6.67 (m, 1H), 4.68-4.43 (m, 1H), 4.03 -3.94 (m, 2H), 3.93 -3.76 (m, 2H), 3.51 (d,J= 11.8 Hz, 1H), 2.73 -2.54 (m, 2H), 1.83 - 1.71 (m, 1H),Compound 444 was prepared according to the method of Example 77: ee >99%; 1H NMR (300 MHz, DMSO- 6 ) δ 13.52 (s, 1H), 8.17 (d, J = 8.2 Hz, 2H), 7.90 (d, J= 8.3 Hz, 2H), 7.46 (d, J= 8.2 Hz, 1H), 7.31 -7.17(m, 1H), 7.13-6.99 (m, 1H), 6.78 - 6.67 (m, 1H), 4.68-4.43 (m, 1H), 4.03 -3.94 (m, 2H), 3.93 -3.76 (m, 2H), 3.51 (d, J = 11.8 Hz, 1H), 2.73 -2.54 (m, 2H), 1.83 - 1.71 (m , 1H),
1.66 - 1.47 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 565.2 [M+Na]+. 1.66 - 1.47 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 565.2 [M+Na] + .
实施例 312  Example 312
2- (4- (4-氯苯甲酰基） 苯氧基） -N- ((3R,4R) -3-氟 -1 - ((4-氟苯基） 磺酰基） 哌 啶—4-基） -2-甲基丙酰胺 （化合物 445)  2-(4-(4-Chlorobenzoyl)phenoxy)-N-((3R,4R)-3-fluoro-1 -((4-fluorophenyl)sulfonyl)piperidine-4-yl )-2-methylpropionamide (compound 445)
参照实施例 14和 281的方法制得化合物 445: ee>99%; 1H NMR (300 MHz, CDC13) δ 7.85 - 7.67 (m, 6H), 7.54 - 7.43 (m, 2H), 7.27 - 7.19 (m, 2H), 7.02 - 6.90 (m,2H), 6.53 (d, J = 7.9 Hz, 1H), 4.58 - 4.27 (m, 1H), 4.12 - 3.89 (m, 2H), 3.81 - 3.64 (m, 1H), 2.58 - 2.39 (m, 2H), 2.18-2.01 (m, 1H), 1.70- 1.57 (m, 7H). ESI-MS: m/z 599.2 [M+Na]+. Compound 445 was prepared by the methods of Examples 14 and 281: ee >99%; 1H NMR (300 MHz, CDC1 3 ) δ 7.85 - 7.67 (m, 6H), 7.54 - 7.43 (m, 2H), 7.27 - 7.19 ( m, 2H), 7.02 - 6.90 (m, 2H), 6.53 (d, J = 7.9 Hz, 1H), 4.58 - 4.27 (m, 1H), 4.12 - 3.89 (m, 2H), 3.81 - 3.64 (m, 1H), 2.58 - 2.39 (m, 2H), 2.18-2.01 (m, 1H), 1.70- 1.57 (m, 7H). ESI-MS: m/z 599.2 [M+Na] + .
实施例 313  Example 313
5- (2,5-二氯苯氧基） -2,2-二甲基 -N- (1- ((4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 （化合物 446)  5-(2,5-Dichlorophenoxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valentamide (Compound 446)
参照实施例 119的方法制得化合物 446: 1H MR(300 MHz, DMSO- 6) δ 8.25 - 8.12 (m, 2H), 8.06 - 7.95 (m, 2H), 7.49 - 7.41 (m, 1H), 7.30 - 7.16 (m, 2H), 7.06 - 6.98 (m, 1H), 4.15 - 3.94 (m, 2H), 3.72 - 3.50 (m, 3H), 3.33 (s, 3H), 2.49 - 2.37 (m, 2H), 1.80 - 1.64 (m, 2H), 1.64 - 1.41 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 613.1 [M+Na]+. Compound 446 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.25 - 8.12 (m, 2H), 8.06 - 7.95 (m, 2H), 7.49 - 7.41 (m, 1H), 7.30 - 7.16 (m, 2H), 7.06 - 6.98 (m, 1H), 4.15 - 3.94 (m, 2H), 3.72 - 3.50 (m, 3H), 3.33 (s, 3H), 2.49 - 2.37 (m, 2H) , 1.80 - 1.64 (m, 2H), 1.64 - 1.41 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 613.1 [M+Na] + .
实施例 314  Example 314
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实施例 319  Example 319
2- (4-氯 -2-氟苯氧基） -2-甲基 -N- ( 1- ( (4- (三氟甲氧基） 苯基） 磺酰基） 哌啶 -4- 基） 丙酰胺 （化合物 452)  2-(4-Chloro-2-fluorophenoxy)-2-methyl-N-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)propane Amide (compound 452)
参照实施例 14的方法制得化合物 452: 1H MR (300 MHz, CDC13) δ 7.85 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H), 7.16 (dd, J = 10.2, 1.2 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H),Compound 452 was prepared by the method of Example 14: 1H MR (300 MHz, CDC1 3 ) δ 7.85 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H), 7.16 (dd, J = 10.2, 1.2 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H),
6.97 (t, J = 8.5 Hz, 1H), 6.88 (d, J = 9.0 Hz, 1H), 3.85 - 3.69 (m, 3H), 2.66 - 2.48 (m, 2H), 2.05 (dd, J = 11.6, 1.4 Hz, 2H), 1.71 - 1.61 (m, 2H), 1.46 (s, 6H). ESI-MS: m/z 561.2 [M+Na]+. 6.97 (t, J = 8.5 Hz, 1H), 6.88 (d, J = 9.0 Hz, 1H), 3.85 - 3.69 (m, 3H), 2.66 - 2.48 (m, 2H), 2.05 (dd, J = 11.6, 1.4 Hz, 2H), 1.71 - 1.61 (m, 2H), 1.46 (s, 6H). ESI-MS: m/z 561.2 [M+Na] + .
实施例 320  Example 320
2- ( 3,4-二氟苯氧基） -2-甲基 -N- ( 1- ( (4- (三氟甲氧基） 苯基） 磺酰基） 哌啶 -4- 基） 丙酰胺 （化合物 453 )  2-(3,4-Difluorophenoxy)-2-methyl-N-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)propanamide (compound 453)
参照实施例 14的方法制得化合物 453 : 1H MR (300 MHz, CDC13) δ 7.83 (d, J = 8.6 Hz, 2H), 7.39 (d, J= 8.2 Hz, 2H), 7.08 (dd, J = 18.7, 9.3 Hz, 1H), 6.82 - 6.71 (m, 1H), 6.68 - 6.60 (m, 1H), 6.56 (d, J= 7.4 Hz, 1H), 3.79 (d, J= 11.5 Hz, 2H), 3.76 - 3.70 (m, 1H), 2.50 (t, J = 11.4 Hz, 2H), 2.02 (d, J = 11.7 Hz, 2H), 1.63 - 1.54 (m, J = 11.8, 2.8 Hz, 2H), 1.47 (s, 6H). ESI-MS: m/z 545.2 [M+Na]+. Compound 453 was prepared by the method of Example 14: 1H MR (300 MHz, CDC1 3 ) δ 7.83 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.08 (dd, J = 18.7, 9.3 Hz, 1H), 6.82 - 6.71 (m, 1H), 6.68 - 6.60 (m, 1H), 6.56 (d, J= 7.4 Hz, 1H), 3.79 (d, J= 11.5 Hz, 2H) , 3.76 - 3.70 (m, 1H), 2.50 (t, J = 11.4 Hz, 2H), 2.02 (d, J = 11.7 Hz, 2H), 1.63 - 1.54 (m, J = 11.8, 2.8 Hz, 2H), 1.47 (s, 6H). ESI-MS: m/z 545.2 [M+Na] + .
实施例 321  Example 321
N- ( 1 - ( ( 3-氰基苯基） 磺酰基） 哌啶 -4-基） -5- (2,5-二氯苯氧基） -2,2-二甲基戊 酰胺 （化合物 454)  N-(1-((3-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide (compound) 454)
参照实施例 119的方法制得化合物 454: 1H MR (300 MHz, CDC13) δ 8.05 (s, 1H),Compound 454 was prepared by the method of Example 119: 1H MR (300 MHz, CDC1 3 ) δ 8.05 (s, 1H),
7.98 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.73 - 7.66 (m, 1H), 7.28 (d, J = 9.1 Hz, 1H), 6.92 - 6.85 (m, 2H), 5.53 (d, J = 7.1 Hz, 1H), 3.97 (t, J = 5.5 Hz, 2H), 3.86 - 3.69 (m, 3H), 2.54 - 2.40 (m, 2H), 2.04 - 1.93 (m, 2H), 1.80 - 1.69 (m, 4H), 1.59 - 1.50 (m, 2H), 1.19 (s, 6H). ESI-MS: m/z 560.2 [M+Na]+. 7.98 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.73 - 7.66 (m, 1H), 7.28 (d, J = 9.1 Hz, 1H), 6.92 - 6.85 (m , 2H), 5.53 (d, J = 7.1 Hz, 1H), 3.97 (t, J = 5.5 Hz, 2H), 3.86 - 3.69 (m, 3H), 2.54 - 2.40 (m, 2H), 2.04 - 1.93 ( m, 2H), 1.80 - 1.69 (m, 4H), 1.59 - 1.50 (m, 2H), 1.19 (s, 6H). ESI-MS: m/z 560.2 [M+Na] + .
实施例 322  Example 322
2- (2,3-二氟苯氧基） -2-甲基 -N- ( 1- ( (4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4- 基） 丙酰胺 （化合物 455 )  2-(2,3-Difluorophenoxy)-2-methyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide Compound 455)
参照实施例 14的方法制得化合物 455 : 1H MR (300 MHz, OMSO-d6) δ 8.18 (d, J = 8.3 Hz, 2H), 8.06 - 7.94 (m, 3H), 7.33 (dd, J = 19.7, 9.6 Hz, 1H), 6.99 - 6.87 (m, 1H), 6.74 -Compound 455 was prepared by the method of Example 14: 1H MR (300 MHz, OMSO-d 6 ) δ 8.18 (d, J = 8.3 Hz, 2H), 8.06 - 7.94 (m, 3H), 7.33 (dd, J = 19.7, 9.6 Hz, 1H), 6.99 - 6.87 (m, 1H), 6.74 -
6.63 (m, 1H), 3.72 - 3.53 (m, 3H), 3.31 (s, 3H), 2.47 - 2.32 (m, 2H), 1.78 - 1.65 (m, 2H),6.63 (m, 1H), 3.72 - 3.53 (m, 3H), 3.31 (s, 3H), 2.47 - 2.32 (m, 2H), 1.78 - 1.65 (m, 2H),
1.64 - 1.48 (m, 2H), 1.39 (s, 6H). ESI-MS: m/z 539.2 [M+Na]+. 1.64 - 1.48 (m, 2H), 1.39 (s, 6H). ESI-MS: m/z 539.2 [M+Na] + .
实施例 323  Example 323
2- (2,3-二氟苯氧基） -2-甲基 -N- ( 1- ( ( 3- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4- 基） 丙酰胺 （化合物 456) 2-(2,3-Difluorophenoxy)-2-methyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4- Base) propionamide (compound 456)
参照实施例 14的方法制得化合物 456: 1H MR (300 MHz, OMSO-d6) δ 8.28 (d, J = 7.8 Hz, 1H), 8.15 (s, 1H), 8.11 - 7.99 (m, 2H), 7.98 - 7.89 (m, 1H), 7.33 (dd, J= 19.6, 9.7 Hz, 1H), 6.99 - 6.86 (m, 1H), 6.75 - 6.62 (m, 1H), 3.72 - 3.57 (m, 3H), 3.34 (s, 3H), 2.46 - 2.34 (m, 2H), 1.80 - 1.63 (m, 2H), 1.63 - 1.46 (m, 2H), 1.39 (s, 6H). ESI-MS: m/z 539.2 [M+Na]+. 实施例 324 Compound 456 was prepared by the method of Example 14: 1H MR (300 MHz, OMSO-d 6 ) δ 8.28 (d, J = 7.8 Hz, 1H), 8.15 (s, 1H), 8.11 - 7.99 (m, 2H) , 7.98 - 7.89 (m, 1H), 7.33 (dd, J= 19.6, 9.7 Hz, 1H), 6.99 - 6.86 (m, 1H), 6.75 - 6.62 (m, 1H), 3.72 - 3.57 (m, 3H) , 3.34 (s, 3H), 2.46 - 2.34 (m, 2H), 1.80 - 1.63 (m, 2H), 1.63 - 1.46 (m, 2H), 1.39 (s, 6H). ESI-MS: m/z 539.2 [M+Na] + . Example 324
2- ( 4-氟苯氧基） -N- ( 1- ( ( 4-氟苯基） 磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 （化合 物 457)  2-(4-Fluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (Compound 457)
参照实施例 14的方法制得化合物 457: 1H NMR (300 MHz, CDC13) δ 7.90 - 7.64 (m, 2H), 7.32 - 7.25 (m, 1H), 7.23 - 7.15 (m, 1H), 7.04 - 6.75 (m, 4H), 6.63 (d, J = 7.5 Hz, 1H), 3.88 - 3.62 (m, 3H), 2.59 - 2.37 (m, 2H), 2.12 - 1.86 (m, 2H), 1.59 - 1.47 (m, 3H), 1.43 (s, 6H). ESI-MS: m/z 461.2 [M+Na]+. Compound 457 was obtained by the method of Example 14: 1H NMR (300 MHz, CDC1 3 ) δ 7.90 - 7.64 (m, 2H), 7.32 - 7.25 (m, 1H), 7.23 - 7.15 (m, 1H), 7.04 - 6.75 (m, 4H), 6.63 (d, J = 7.5 Hz, 1H), 3.88 - 3.62 (m, 3H), 2.59 - 2.37 (m, 2H), 2.12 - 1.86 (m, 2H), 1.59 - 1.47 ( m, 3H), 1.43 (s, 6H). ESI-MS: m/z 461.2 [M+Na] + .
实施例 325  Example 325
4 - ( (4- (2- (4- (4-氯苯甲酰基） 苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 （化合物 458 )  4-((4-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 458)
参照实施例 14的方法制得化合物 458: 1H MR (300 MHz, DMSO- 6) δ 13.48 (s, 1H), 8.20 - 8.09 (m, 2H), 8.02 (d, J = 7.9 Hz, 1H), 7.87 - 7.76 (m, 2H), 7.76 - 7.66 (m, 4H), 7.62 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 3.62 (d, 1H), 3.53 (d, J = 11.9 Hz, 2H), 2.41 (d, J = 11.9 Hz, 2H), 1.67 (d, J = 10.9 Hz, 2H), 1.58 - 1.40 (m, 8H). ESI-MS: m/z 607.3 [M+Na]+. Compound 458 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 13.48 (s, 1H), 8.20 - 8.09 (m, 2H), 8.02 (d, J = 7.9 Hz, 1H), 7.87 - 7.76 (m, 2H), 7.76 - 7.66 (m, 4H), 7.62 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 3.62 (d, 1H), 3.53 (d, J = 11.9 Hz, 2H), 2.41 (d, J = 11.9 Hz, 2H), 1.67 (d, J = 10.9 Hz, 2H), 1.58 - 1.40 (m, 8H). ESI-MS: m/ z 607.3 [M+Na] + .
实施例 326  Example 326
2- (4-氯苯氧基) -2-甲基 -N- ( 1- ( (4- (吗啡啉 -4-羰基) 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 （化合物 459)  2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-(morpholine-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide (compound) 459)
参照实施例 14的方法制得化合物 459: 1H NMR (300 MHz, CDC13) δ 7.95 - 7.75 (d, J = 7.9 Ηζ,, 2Η), 7.57 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.53 (d, J = 7.6 Hz, 1H), 4.02 - 3.55 (m, 9H), 3.52 - 3.17 (m, 2H), 2.62 - 2.40 (m, 2H), 2.12 - 1.89 (m, 2H), 1.57 - 1.50 (m, 2H), 1.44 (s, 6H). ESI-MS: m/z 572.3 [M+Na]+. Compound 459 was prepared by the method of Example 14: 1H NMR (300 MHz, CDC1 3 ) δ 7.95 - 7.75 (d, J = 7.9 Ηζ, 2 Η), 7.57 (d, J = 7.9 Hz, 2H), 7.23 ( d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.53 (d, J = 7.6 Hz, 1H), 4.02 - 3.55 (m, 9H), 3.52 - 3.17 (m, 2H) ), 2.62 - 2.40 (m, 2H), 2.12 - 1.89 (m, 2H), 1.57 - 1.50 (m, 2H), 1.44 (s, 6H). ESI-MS: m/z 572.3 [M+Na] + .
实施例 327  Example 327
N- ( 1 - ( ( 3-氰基苯基)磺酰基） 哌啶 -4-基） -5- (2,4-二氟苯氧基） -2,2-二甲基戊酰 胺 (化合物 460)  N-(1-((3-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,4-difluorophenoxy)-2,2-dimethylpentanamide (compound) 460)
参照实施例 119的方法制得化合物 460: 1H NMR (300 MHz, CDC13) δ 8.10 - 8.02 (m, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.75 - 7.64 (m, 1H), 6.94 - 6.81 (m, 2H), 6.81 - 6.71 (m, 1H), 5.67 (d, J = 8.0 Hz, 1H), 3.94 (t, J = 5.4 Hz, 2H), 3.88 - 3.81 (m, 1H), 3.82 - 3.67 (m, 2H), 2.55 - 2.38 (m, 2H), 2.07 - 1.91 (m, 2H), 1.78 - 1.60 (m, 4H), 1.59 - 1.47 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 528.2 [M+Na] . Compound 460 was prepared by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 8.10 - 8.02 (m, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 7.7 Hz , 1H), 7.75 - 7.64 (m, 1H), 6.94 - 6.81 (m, 2H), 6.81 - 6.71 (m, 1H), 5.67 (d, J = 8.0 Hz, 1H), 3.94 (t, J = 5.4 Hz, 2H), 3.88 - 3.81 (m, 1H), 3.82 - 3.67 (m, 2H), 2.55 - 2.38 (m, 2H), 2.07 - 1.91 (m, 2H), 1.78 - 1.60 (m, 4H), 1.59 - 1.47 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 528.2 [M+Na].
实施例 328  Example 328
5- (2,4-二氟苯氧基） -N- ( 1- ( (3-氟苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 (化合物 461 )  5-(2,4-Difluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (Compound 461 )
参照实施例 119的方法制得化合物 461 : 1H NMR (300 MHz, CDC13) δ 7.60 - 7.51 (m, 2Η), 7.50 - 7.40 (m, 1H), 7.38 - 7.28 (m, 1H), 6.95 - 6.81 (m, 2H), 6.81 - 6.70 (m, 1H), 5.57 (d, J= 7.8 Hz, 1H), 3.94 (t, J= 5.4 Hz, 2H), 3.84 - 3.65 (m, 3H), 2.58 - 2.33 (m, 2H), 2.07 - 1.86 (m, 2H), 1.74 - 1.60 (m, 4H), 1.52 (dd, J= 12.1, 3.9 Hz, 2H), 1.17 (s, 6H). ESI-MS: m/z 521.2 [M+Na]+. Compound 461 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.60 - 7.51 (m, 2 Η), 7.50 - 7.40 (m, 1H), 7.38 - 7.28 (m, 1H), 6.95 - 6.81 (m, 2H), 6.81 - 6.70 (m, 1H), 5.57 (d, J = 7.8 Hz, 1H), 3.94 (t, J = 5.4 Hz, 2H), 3.84 - 3.65 (m, 3H), 2.58 - 2.33 (m, 2H), 2.07 - 1.86 (m, 2H), 1.74 - 1.60 (m, 4H), 1.52 (dd, J= 12.1, 3.9 Hz, 2H), 1.17 (s, 6H). ESI-MS : m/z 521.2 [M+Na] + .
实施例 329  Example 329
5- (4-氯 -2-氟苯氧基） -N- ( 1- ( (3-氟苯基）磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 (化合物 462)  5-(4-Chloro-2-fluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound) 462)
参照实施例 119的方法制得化合物 462: 1H NMR (300 MHz, Chloroform- ) δ 7.59 - 7.51 (m, 2H), 7.51 - 7.43 (m, 1H), 7.37 - 7.28 (m, 1H), 7.10 (dd, J = 10.8, 2.5 Hz, 1H), 7.07 - 6.98 (m, 1H), 6.91 - 6.78 (m, 1H), 5.56 (d, J= 7.8 Hz, 1H), 3.95 (t, J= 5.7 Hz, 2H), 3.84 - 3.62 (m, 3H), 2.53 - 2.32 (m, 2H), 2.03 - 1.91 (m, 2H), 1.81 - 1.60 (m, 4H), 1.56 - 1.47 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 537.2 [M+Na]+. The compound 462 was obtained by the method of Example 119: 1H NMR (300 MHz, chloroform) δ 7.59 - 7.51 (m, 2H), 7.51 - 7.43 (m, 1H), 7.37 - 7.28 (m, 1H), 7.10 ( Dd, J = 10.8, 2.5 Hz, 1H), 7.07 - 6.98 (m, 1H), 6.91 - 6.78 (m, 1H), 5.56 (d, J = 7.8 Hz, 1H), 3.95 (t, J = 5.7 Hz , 2,,,,,,,,, (s, 6H). ESI-MS: m/z 537.2 [M+Na] + .
实施例 330  Example 330
3 - ( (4- ( 5- (2,4-二氟苯氧基） -2,2-二甲基戊酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 (化合物 463 )  3-(4-(5-(2,4-Difluorophenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 463)
参照实施例 119的方法制得化合物 463 : iH MR (300 MHz, DMSO- 6) δ 13.52 (s, 1Η)， 8.24 (d, J = 7.8 Hz, 1H), 8.21 - 8.16 (m, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.85 - 7.72 (m, 1H), 7.32 - 7.17 (m, 2H), 7.16 - 7.08 (m, 1H), 7.05 - 6.91 (m, 1H), 3.95 (t, J= 5.4 Hz, 2H), 3.68 - 3.60 (m, 1H), 3.61 - 3.45 (m, 2H), 2.46 - 2.29 (m, 2H), 1.76 - 1.64 (m, 2H), 1.59 - 1.49 (m, 4H), 1.50 - 1.39 (m, 2H), 1.05 (s, 6H). ESI-MS: m/z 547.2 [M+Na]+. Compound 463 was prepared by the method of Example 119: iH MR (300 MHz, DMSO- 6 ) δ 13.52 (s, 1 Η), 8.24 (d, J = 7.8 Hz, 1H), 8.21 - 8.16 (m, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.85 - 7.72 (m, 1H), 7.32 - 7.17 (m, 2H), 7.16 - 7.08 (m, 1H), 7.05 - 6.91 (m, 1H), 3.95 ( t, J= 5.4 Hz, 2H), 3.68 - 3.60 (m, 1H), 3.61 - 3.45 (m, 2H), 2.46 - 2.29 (m, 2H), 1.76 - 1.64 (m, 2H), 1.59 - 1.49 ( m, 4H), 1.50 - 1.39 (m, 2H), 1.05 (s, 6H). ESI-MS: m/z 547.2 [M+Na] + .
实施例 331  Example 331
反式—4- ( (4- (2- (4- (4-氯苯甲酰基) 苯氧基） -2-甲基丙酰氨基) -3-氟哌啶 -1-基) 磺酰基） 苯甲酸 （化合物 464)  Trans-4-((4-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl) Benzoic acid (Compound 464)
参照实施例 14和 139的方法制得化合物 464: 1H NMR (300 MHz, CDC13) δ 13.52 (s, 1H), 8.28 (d, J= 8.4 Hz, 1H), 8.15 (d, J= 8.2 Hz, 2H), 7.86 (d, J= 8.2 Hz, 2H), 7.71 (dd, J = 8.3, 4.7 Hz, 4H), 7.62 (d, J= 8.4 Hz, 2H), 6.94 (d, J= 8.6 Hz, 2H), 4.71 - 4.39 (m, 1H), 4.02 - 3.65 (m, 2H), 3.50 - 3.37 (m, 1H), 2.74 - 2.57 (m, 2H), 1.85 - 1.66 (m, 1H), 1.61 - 1.53 (m, 1H), 1.50 (s, 6H). ESI-MS: m/z 601.2 [M-H]". Compound 464 was obtained by the methods of Examples 14 and 139: 1H NMR (300 MHz, CDC1 3 ) δ 13.52 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.2 Hz , 2H), 7.86 (d, J= 8.2 Hz, 2H), 7.71 (dd, J = 8.3, 4.7 Hz, 4H), 7.62 (d, J= 8.4 Hz, 2H), 6.94 (d, J= 8.6 Hz , 2H), 4.71 - 4.39 (m, 1H), 4.02 - 3.65 (m, 2H), 3.50 - 3.37 (m, 1H), 2.74 - 2.57 (m, 2H), 1.85 - 1.66 (m, 1H), 1.61 - 1.53 (m, 1H), 1.50 (s, 6H). ESI-MS: m/z 601.2 [MH]".
实施例 332 5- (2,4-二氟苯氧基） -2,2-二甲基 -N- ( 1- ( (3- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基) 戊酰胺 (化合物 465 ) Example 332 5-(2,4-Difluorophenoxy)-2,2-dimethyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valentamide (compound 465)
参照实施例 119的方法制得化合物 465: 1H MR (300 MHz, CDC13) δ 8.33 (s, 1H), 8.19 (d, J = 7.1 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.79 (dd, J = 7.5 Hz, 7.1 Hz, 1H), 6.95 - 6.71 (m, 3H), 5.59 (d, J= 6.9 Hz, 1H), 4.02 - 3.90 (m, 2H), 3.88 - 3.64 (m, 3H), 3.12 (s, 3H), 2.57 - 2.41 (m, 2H), 2.07 - 1.92 (m, 2H), 1.79 - 1.60 (m, 6H), 1.17 (s, 6H). ESI-MS: m/z 581.2 [M+Na] +. Compound 465 was prepared by the method of Example 119: 1H MR (300 MHz, CDC1 3 ) δ 8.33 (s, 1H), 8.19 (d, J = 7.1 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H ), 7.79 (dd, J = 7.5 Hz, 7.1 Hz, 1H), 6.95 - 6.71 (m, 3H), 5.59 (d, J= 6.9 Hz, 1H), 4.02 - 3.90 (m, 2H), 3.88 - 3.64 (m, 3H), 3.12 (s, 3H), 2.57 - 2.41 (m, 2H), 2.07 - 1.92 (m, 2H), 1.79 - 1.60 (m, 6H), 1.17 (s, 6H). ESI-MS : m/z 581.2 [M+Na] + .
实施例 333  Example 333
反式—4- ( (4- ( 5- (2,4-二氟苯氧基） -2,2-二甲基戊酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸甲酯 （化合物 466)  Trans-4-((4-(5-(2,4-difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Methyl formate (Compound 466)
参照实施例 119和 139的方法制得化合物 466: 1H MR (300 MHz, DMSO- 6) δ 8.18 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.1 Hz, 1H), 7.34 - 6.90 (m, 3H), 4.71 - 4.41 (m, 1H), 4.06 - 3.93 (m, 2H), 3.91 (s, 3H), 3.88 - 3.77 (m, 2H), 3.58 - 3.45 (m, 1H), 2.75 - 2.55 (m, 2H), 1.82 - 1.69 (m, 1H), 1.61 - 1.51 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 579.2 [M+Na] +. Compound 466 was prepared by the methods of Examples 119 and 139: 1H MR (300 MHz, DMSO- 6 ) δ 8.18 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.43 ( d, J = 8.1 Hz, 1H), 7.34 - 6.90 (m, 3H), 4.71 - 4.41 (m, 1H), 4.06 - 3.93 (m, 2H), 3.91 (s, 3H), 3.88 - 3.77 (m, 2H), 3.58 - 3.45 (m, 1H), 2.75 - 2.55 (m, 2H), 1.82 - 1.69 (m, 1H), 1.61 - 1.51 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 579.2 [M+Na] + .
实施例 334  Example 334
反式—4- ( (4- ( 5- (2,4-二氟苯氧基） -2,2-二甲基戊酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸 （化合物 467)  Trans-4-((4-(5-(2,4-difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Formic acid (compound 467)
参照实施例 119和 139的方法制得化合物 467: 1H NMR (300 MHz, DMSO- 6) δ 13.49 (s, 1H), 8.16 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 - 6.91 (m, 3H), 4.73 - 4.40 (m, 1H), 4.01 - 3.90 (m, 2H), 3.89 - 3.75 (m, 2H), 3.57 - 3.44 (m, 1H), 2.77 - 2.55 (m, 2H), 1.83 - 1.69 (m, 1H), 1.63 - 1.47 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 541.2 [M-H] -. Compound 467 was obtained by the methods of Examples 119 and 139: 1H NMR (300 MHz, DMSO- 6 ) δ 13.49 (s, 1H), 8.16 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 - 6.91 (m, 3H), 4.73 - 4.40 (m, 1H), 4.01 - 3.90 (m, 2H), 3.89 - 3.75 (m, 2H), 3.57 - 3.44 (m, 1H), 2.77 - 2.55 (m, 2H), 1.83 - 1.69 (m, 1H), 1.63 - 1.47 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 541.2 [MH] -.
实施例 335  Example 335
反式—4- ( (4- ( 5- (2,4-二氟苯氧基） -2,2-二甲基戊酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸 （2-乙酰氨基） 乙酯 （化合物 468)  Trans-4-((4-(5-(2,4-difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene (2-acetamido) ethyl formate (compound 468)
以化合物 467(实施例 334)为原料，参照实施例 183的方法制得化合物 468: 1H MR (300 MHz, DMSO- e) δ 8.21 (d, J = 8.3 Hz, 2H), 8.15 - 8.06 (m, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.32 - 6.90 (m, 3H), 4.70 - 4.39 (m, 1H), 4.31 (t, J = 5.4 Hz, 2H), 4.06 - 3.90 (m, 2H), 3.90 - 3.75 (m, 2H), 3.61 - 3.49 (m, 1H), 3.48 - 3.38 (m, 2H), 2.72 - 2.57 (m, 2H), 1.83 (s, 3H), 1.77 - 1.70 (m, 1H), 1.64 - 1.48 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 650.1 [M+Na] +. Using Compound 467 (Example 334) as a starting material, compound 468 was obtained by the procedure of Example 183: 1H MR (300 MHz, DMSO-e) δ 8.21 (d, J = 8.3 Hz, 2H), 8.15 - 8.06 (m , 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.32 - 6.90 (m, 3H), 4.70 - 4.39 (m, 1H), 4.31 (t, J = 5.4 Hz, 2H), 4.06 - 3.90 (m, 2H), 3.90 - 3.75 (m, 2H), 3.61 - 3.49 (m, 1H), 3.48 - 3.38 (m, 2H), 2.72 - 2.57 (m, 2H), 1.83 (s, 3H), 1.77 - 1.70 (m, 1H), 1.64 - 1.48 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 650.1 [M+Na] + .
实施例 336  Example 336
4-((4-(5-(4-氟苯氧基) -2,2-二甲基戊酰氨基)哌啶 -1-基;)磺酰基)苯甲酸 （化合物 469) 参照实施例 119的方法制得化合物 469: 1H MR (300 MHz, DMSO- 6) δ 8.16 (d, J = 8.0 Hz, 2H), 7.85 (d, J= 8.0 Hz, 2H), 7.22 (d, J = 7.8 Hz, 1H), 7.09 (t, J= 8.7 Hz, 2H), 6.90 (p, J = 4.2 Hz, 2H), 3.91 - 3.82 (m, 2H), 3.67 - 3.56 (m, 3H), 2.48 - 2.33 (m, 2H), 1.76 - 1.64 (m, 2H), 1.59 - 1.43 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 505.2 [M-H]". 4-((4-(5-(4-fluorophenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl;)sulfonyl)benzoic acid (Compound 469) Compound 469 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.16 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 7.8 Hz, 1H), 7.09 (t, J = 8.7 Hz, 2H), 6.90 (p, J = 4.2 Hz, 2H), 3.91 - 3.82 (m, 2H), 3.67 - 3.56 (m, 3H), 2.48 - 2.33 (m, 2H), 1.76 - 1.64 (m, 2H), 1.59 - 1.43 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 505.2 [MH]".
实施例 337  Example 337
5-(4-氟苯氧基) -N-(l-((3-氟苯基)磺酰基)哌啶 -4-基) -2,2-二甲基戊酰胺 （化合物 470) 参照实施例 119的方法制得化合物 470: 1H NMR (300 MHz, CDC13) δ 7.54 (d, J= 3.9 Hz, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.39 - 7.27 (m, 1H), 6.95 (t, J = 8.6 Hz, 2H), 6.86 - 6.71 (m, 2H), 5.53 (d, J= 7.8 Hz, 1H), 3.96 - 3.58 (m, 5H), 2.44 (t, J= 11.9 Hz, 2H), 2.07 - 1.85 (m, 2H), 1.75 - 1.46 (m, 6H), 1.17 (s, 6H). ESI-MS: m/z 503.2 [M+Na]+. 5-(4-fluorophenoxy)-N-(l-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (Compound 470) Compound 470: 1H NMR (300 MHz, CDC1 3 ) δ 7.54 (d, J = 3.9 Hz, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.39 - 7.27 (m, 1H) ), 6.95 (t, J = 8.6 Hz, 2H), 6.86 - 6.71 (m, 2H), 5.53 (d, J = 7.8 Hz, 1H), 3.96 - 3.58 (m, 5H), 2.44 (t, J= 11.9 Hz, 2H), 2.07 - 1.85 (m, 2H), 1.75 - 1.46 (m, 6H), 1.17 (s, 6H). ESI-MS: m/z 503.2 [M+Na] + .
实施例 338  Example 338
5-(4-氟苯氧基) -N-(l-((4-氟苯基)磺酰基)哌啶 -4-基) -2,2-二甲基戊酰胺 （化合物 471 ) 参照实施例 119的方法制得化合物 471： 1H NMR (300 MHz, CDC13) δ 7.77 (dd, J= 8.7， 5.0 Hz, 2H), 7.33 - 7.13 (m,2H), 7.03 - 6.87 (m, 2H), 6.79 (dd, J= 9.1, 4.2 Hz, 2H), 5.53 (d, J = 7.8 Hz, 1H), 3.97 - 3.62 (m, 5H), 2.49 - 2.25 (m, 2H), 2.05 - 1.85 (m, 2H), 1.77 - 1.42 (m, 6H), 1.17 (s, 6H). ESI-MS: m/z 503.2 [M+Na]+. 5-(4-fluorophenoxy)-N-(l-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (Compound 471) Compound 471: 1H NMR (300 MHz, CDC1 3 ) δ 7.77 (dd, J = 8.7, 5.0 Hz, 2H), 7.33 - 7.13 (m, 2H), 7.03 - 6.87 (m, 2H) , 6.79 (dd, J= 9.1, 4.2 Hz, 2H), 5.53 (d, J = 7.8 Hz, 1H), 3.97 - 3.62 (m, 5H), 2.49 - 2.25 (m, 2H), 2.05 - 1.85 (m , 2H), 1.77 - 1.42 (m, 6H), 1.17 (s, 6H). ESI-MS: m/z 503.2 [M+Na] + .
实施例 339  Example 339
5-(4-氟苯氧基) -2,2-二甲基 -N-(l-((3- (甲基磺酰基)苯基)磺酰基)哌啶 -4-基；)戊酰胺（化 合物 472)  5-(4-fluorophenoxy)-2,2-dimethyl-N-(l-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl;) pentanamide (Compound 472)
参照实施例 119的方法制得化合物 472: 1H MR (300 MHz, CDC13) δ 8.33 (s, 1H), 8.19 (d, J= 7.8 Hz, 1H), 8.04 (d, J= 7.8 Hz, 1H), 7.79 (t, J= 7.8 Hz, 1H), 6.95 (t, J= 8.4 Hz, 2H), 6.79 (dd, J= 9.0, 4.4 Hz, 2H), 5.54 (d, J= 7.6 Hz, 1H), 4.01 - 3.64 (m, 5H), 3.12 (s, 3H)， 2.49 (t, J= 11.9 Hz, 2H), 2.12 - 1.88 (m, 2H), 1.80 - 1.42 (m, 6H), 1.17 (s, 6H). ESI-MS: m/z 563.2 [M+Na]+. Compound 472 was prepared by the method of Example 119: 1H MR (300 MHz, CDC1 3 ) δ 8.33 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H ), 7.79 (t, J= 7.8 Hz, 1H), 6.95 (t, J= 8.4 Hz, 2H), 6.79 (dd, J= 9.0, 4.4 Hz, 2H), 5.54 (d, J= 7.6 Hz, 1H ), 4.01 - 3.64 (m, 5H), 3.12 (s, 3H), 2.49 (t, J = 11.9 Hz, 2H), 2.12 - 1.88 (m, 2H), 1.80 - 1.42 (m, 6H), 1.17 ( s, 6H). ESI-MS: m/z 563.2 [M+Na] + .
实施例 340  Example 340
4- ( (4- ( 5- (2,4-二氟苯氧基） -2,2-二甲基戊酰胺基） 哌啶 -1-基） 磺酰基） 苯甲酸 2-乙酰氨基乙酯 （化合物 473 )  4-((4-(5-(2,4-Difluorophenoxy)-2,2-dimethylpentanyl)piperidin-1-yl)sulfonyl) 2-acetamidoethyl benzoate (compound 473)
以化合物 278(实施例 191 )为原料，参照实施例 183的方法制得化合物 473 : 1H MR (300 MHz, CDCI3) δ 8.19 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.1 Hz, 2H), 6.94 - 6.72 (m, 3H), 5.85 (br s, 1H), 5.57 (d, J = 7.7 Hz, 1H), 4.47 (t, J = 5.2 Hz, 2H), 3.94 (t, J = 5.0 Hz, 2H), 3.87 - 3.75 (m, 2H), 3.75 - 3.61 (m, 3H), 2.51 - 2.36 (m, 2H), 2.01 (s, 3H), 1.99 - 1.91 (m, 2H), 1.77 - 1.64 (m, 4H), 1.57 - 1.43 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 632.2 [M+Na]+. 实施例 341 Using Compound 278 (Example 191) as a starting material, Compound 473 was obtained by the method of Example 183: 1H MR (300 MHz, CDCI3) δ 8.19 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.1 Hz, 2H), 6.94 - 6.72 (m, 3H), 5.85 (br s, 1H), 5.57 (d, J = 7.7 Hz, 1H), 4.47 (t, J = 5.2 Hz, 2H), 3.94 (t, J = 5.0 Hz, 2H), 3.87 - 3.75 (m, 2H), 3.75 - 3.61 (m, 3H), 2.51 - 2.36 (m, 2H), 2.01 (s, 3H), 1.99 - 1.91 (m, 2H) , 1.77 - 1.64 (m, 4H), 1.57 - 1.43 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 632.2 [M+Na] + . Example 341
4- ( (4- (2- (4-氟苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 （化合物 474) 4-((4-(2-(4-fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound) 474)
参照实施例 14的方法制得化合物 474: 1H MR (300 MHz, DMSO- 6) δ 13.48 (s, 1H),Compound 474 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 13.48 (s, 1H),
8.20 - 8.11 (m, 2H), 7.98 (d, J= 7.9 Hz, 1H), 7.88 - 7.79 (m, 2H), 7.18— 7.02 (m, 2H), 6.93 - 6.81 (m, 2H), 3.69 - 3.51 (m, 3H), 2.49 - 2.37 (m, 2H), 1.79 - 1.66 (m, 2H), 1.62 - 1.47 (m, 2H), 1.35 (s, 6H). ESI-MS: m/z 487.1 [M+Na]+. 8.20 - 8.11 (m, 2H), 7.98 (d, J = 7.9 Hz, 1H), 7.88 - 7.79 (m, 2H), 7.18 - 7.02 (m, 2H), 6.93 - 6.81 (m, 2H), 3.69 - 3.51 (m, 3H), 2.49 - 2.37 (m, 2H), 1.79 - 1.66 (m, 2H), 1.62 - 1.47 (m, 2H), 1.35 (s, 6H). ESI-MS: m/z 487.1 [ M+Na] + .
实施例 342  Example 342
4-((4-(5-(4-氯苯氧基; )-2,2-二甲基戊酰胺;)哌啶 -1-基;)磺酰基；)苯甲酸 （化合物 475 ) 参照实施例 119的方法制得化合物 475: 1H MR (300 MHz, DMSO- 6) δ 13.47 (s, 1H), 8.16 (d, J= 8.3 Hz, 2H), 7.85 (d, J= 8.2 Hz, 2H), 7.30 (d, J= 8.8 Hz, 2H), 7.21 (d, J= 7.8 Hz, 1H), 6.91 (d, J= 8.9 Hz, 2H), 3.96 - 3.83 (m, 2H), 3.70 - 3.50 (m, 3H), 2.47 - 2.34 (m, 2H), 1.77 - 1.61 (m, 2H), 1.60 - 1.39 (m, 6H), 1.08 (s, 6H). ESI-MS: m/z 545.2 [M+Na]+. 4-((4-(5-(4-chlorophenoxy))-2,2-dimethylvaleramide;)piperidin-1-yl;)sulfonyl;)benzoic acid (compound 475) Compound 475 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 13.47 (s, 1H), 8.16 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H) , 7.30 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 8.9 Hz, 2H), 3.96 - 3.83 (m, 2H), 3.70 - 3.50 ( m, 3H), 2.47 - 2.34 (m, 2H), 1.77 - 1.61 (m, 2H), 1.60 - 1.39 (m, 6H), 1.08 (s, 6H). ESI-MS: m/z 545.2 [M+ Na] + .
实施例 343  Example 343
4- ( ( (3R,4R) -4- (2- (4- (4-氯苯甲酰基)苯氧基） -2-甲基丙酰氨基) -3-氟哌啶 -1- 基） 磺酰基） 苯甲酸 （化合物 476)  4-((3R,4R)-4-(2-(4-(4-Chlorobenzoyl)phenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl) Sulfonyl) benzoic acid (compound 476)
参照实施例 14和 281的方法制得化合物 476: ee>99%; 1H NMR (300 MHz, DMSO- 6) δ 13.52 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.19 - 8.09 (m, 2H), 7.92 - 7.79 (m, 2H), 7.77 - 7.66 (m, 4H), 7.66 - 7.58 (m, 2H), 6.99 - 6.89 (m, 2H), 4.68 - 4.40 (m, 1H), 4.01 - 3.68 (m, 2H), 3.55 - 3.35 (m, 2H), 2.76 - 2.56 (m, 2H), 1.87 - 1.66 (m, 1H), 1.50 (s, 6H). ESI-MS: m/z 601.1 [M-H]". Compound 476 was prepared by the methods of Examples 14 and 281: ee >99%; 1H NMR (300 MHz, DMSO- 6 ) δ 13.52 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.19 - 8.09 (m, 2H), 7.92 - 7.79 (m, 2H), 7.77 - 7.66 (m, 4H), 7.66 - 7.58 (m, 2H), 6.99 - 6.89 (m, 2H), 4.68 - 4.40 (m, 1H ), 4.01 - 3.68 (m, 2H), 3.55 - 3.35 (m, 2H), 2.76 - 2.56 (m, 2H), 1.87 - 1.66 (m, 1H), 1.50 (s, 6H). ESI-MS: m /z 601.1 [MH]".
实施例 344  Example 344
4- ( ( (3R,4R) -4- (2- (4- (4-氯苯甲酰基)苯氧基） -2-甲基丙酰氨基) -3-氟哌啶 -1- 基） 磺酰基） 苯甲酸甲酯 （化合物 477)  4-((3R,4R)-4-(2-(4-(4-Chlorobenzoyl)phenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl) Sulfonyl) methyl benzoate (compound 477)
参照实施例 14和 281的方法制得化合物 477: ee>99%; 1H NMR (300 MHz, CDC13) δCompound 477 was prepared by the methods of Examples 14 and 281: ee >99%; 1H NMR (300 MHz, CDC1 3 ) δ
8.21 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H), 7.79 - 7.67 (m, 4H), 7.47 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 6.53 (d, J = 8.4 Hz, 1H), 4.57 - 4.27 (m, 1H), 4.13 - 3.88 (m, 5H), 3.80 - 3.67 (m, 1H), 2.57 - 2.42 (m, 2H), 2.20 - 2.03 (m, 1H), 1.69 - 1.57 (m, 7H). ESI-MS: m/z 639.2 [M+Na]+. 8.21 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H), 7.79 - 7.67 (m, 4H), 7.47 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 6.53 (d, J = 8.4 Hz, 1H), 4.57 - 4.27 (m, 1H), 4.13 - 3.88 (m, 5H), 3.80 - 3.67 (m, 1H), 2.57 - 2.42 ( m, 2H), 2.20 - 2.03 (m, 1H), 1.69 - 1.57 (m, 7H). ESI-MS: m/z 639.2 [M+Na] + .
实施例 345  Example 345
4-((4-(5-(4-氯苯氧基; )-2,2-二甲基戊酰胺;)哌啶 -1-基)磺酰基；)苯甲酸 2-乙酰氨基乙酯 (化合物 478)  4-((4-(5-(4-chlorophenoxy))-2,2-dimethylvaleramide;)piperidin-1-yl)sulfonyl;) 2-acetamidoethyl benzoate Compound 478)
以化合物 475 (实施例 342)为原料，参照实施例 183的方法制得化合物 478: 1H MR (300 MHz, DMSO- e) δ 8.19 (d, J= 8.3 Hz, 2H), 8.08 (s, 1H), 7.87 (d, J= 8.3 Hz, 2H), 7.29 (d, J= 8.8 Hz, 2H), 7.21 (d, J= 7.0 Hz, 1H), 6.90 (d, J= 8.9 Hz, 2H), 4.29 (t, J= 5.1 Hz, 2H), 3.93 - 3.81 (m, 2H), 3.70 - 3.49 (m, 3H), 3.45 - 3.35 (m, 2H), 2.44 - 2.29 (m, 2H), 1.81 (s, 3H), 1.74 - 1.61 (m, 2H), 1.59 - 1.38 (m, 6H), 1.03 (s, 6H). ESI-MS: m/z 630.2 [M+Na] . 实施例 346 Using Compound 475 (Example 342) as a starting material, Compound 478 was obtained by the procedure of Example 183: 1H MR (300 MHz, DMSO-e) δ 8.19 (d, J = 8.3 Hz, 2H), 8.08 (s, 1H) ), 7.87 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 7.0 Hz, 1H), 6.90 (d, J = 8.9 Hz, 2H), 4.29 (t, J = 5.1 Hz, 2H), 3.93 - 3.81 (m, 2H), 3.70 - 3.49 (m, 3H), 3.45 - 3.35 (m, 2H), 2.44 - 2.29 (m, 2H), 1.81 ( s, 3H), 1.74 - 1.61 (m, 2H), 1.59 - 1.38 (m, 6H), 1.03 (s, 6H). ESI-MS: m/z 630.2 [M+Na] .
4- ((4-(2-(4-氯苯氧基; )-2-甲基丙酰胺)哌啶 -1-基;)磺酰基；)苯甲酸 -2- (乙酰氨基) -乙酯（化 合物 479)  4-((4-(2-(4-chlorophenoxy))-2-methylpropionamide)piperidin-1-yl;)sulfonyl;)benzoic acid-2-(acetylamino)-ethyl ester (Compound 479)
以化合物 251 (实施例 167)为原料，参照实施例 183的方法制得化合物 479: 1H MR (300 MHz, DMSO- e) δ 8.19 (d, J= 8.1 Hz, 2H), 8.09 (s, IH), 7.99 (d, J= 7.7 Hz, IH), 7.86 (d, J= 8.1 Hz, 2H), 7.30 (d, J= 8.6 Hz, 2H), 6.83 (d, J= 8.7 Hz, 2H), 4.31 (t, J= 5.2 Hz, 2H), 3.68 - 3.50 (m, 3H), 3.44 (q, J = 5.4 Hz, 2H), 2.47 - 2.35 (m, 2H), 1.83 (s, 3H), 1.74 - 1.62 (m, 2H), 1.61 - 1.45 (m, 2H), 1.39 (s, 6H). ESI-MS: m/z 588.2 [M+Na]+. Using Compound 251 (Example 167) as a starting material, Compound 479 was obtained by the procedure of Example 183: 1H MR (300 MHz, DMSO-e) δ 8.19 (d, J = 8.1 Hz, 2H), 8.09 (s, IH ), 7.99 (d, J = 7.7 Hz, IH), 7.86 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 4.31 (t, J = 5.2 Hz, 2H), 3.68 - 3.50 (m, 3H), 3.44 (q, J = 5.4 Hz, 2H), 2.47 - 2.35 (m, 2H), 1.83 (s, 3H), 1.74 - 1.62 (m, 2H), 1.61 - 1.45 (m, 2H), 1.39 (s, 6H). ESI-MS: m/z 588.2 [M+Na] + .
实施例 347  Example 347
4 - ( (4- ( 5- (3,4-二氟苯氧基） -2,2-二甲基戊酰胺基） 哌啶 -1-基） 磺酰基） 苯甲酸 (化合物 480)  4-((4-(5-(3,4-Difluorophenoxy)-2,2-dimethylpentanyl)piperidin-1-yl)sulfonyl)benzoic acid (Compound 480)
参照实施例 119的方法制得化合物 480: 1H MR (300 MHz, DMSO- 6) δ 13.44 (s, 1H): 8.16 (d, J= 8.0 Hz, 2H), 7.84 (d, J = 8.1 Hz, 2H), 7.42 - 7.25 (d, IH), 7.25 - 7.17 (m, IH), 7.09 - 6.93 (m, IH), 6.81 - 6.62 (m, IH), 3.88 (m, 2H), 3.72 - 3.50 (m, 2H), 3.38 - 3.24 (m, IH), 2.40 (m, 2H), 1.82 - 1.61 (m, 2H), 1.64 - 1.39 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 547.2 [M+Na]+. Compound 480 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 13.44 (s, 1H): 8.16 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.1 Hz, 2H), 7.42 - 7.25 (d, IH), 7.25 - 7.17 (m, IH), 7.09 - 6.93 (m, IH), 6.81 - 6.62 (m, IH), 3.88 (m, 2H), 3.72 - 3.50 ( m, 2H), 3.38 - 3.24 (m, IH), 2.40 (m, 2H), 1.82 - 1.61 (m, 2H), 1.64 - 1.39 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 547.2 [M+Na] + .
实施例 348  Example 348
3 - ( (4- ( 5- (3,4-二氟苯氧基） -2,2-二甲基戊酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 (化合物 481 )  3-(4-(5-(3,4-Difluorophenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 481)
参照实施例 119的方法制得化合物 481： NMR (300 MHz, DMSO- 6) δ 12.80 (s, 1H): 8.24 (d, J = 7.8 Hz, IH), 8.19 (s, IH), 7.97 (d, J = 7.8 Hz, IH), 7.86 - 7.70 (m, IH), 7.50 - 7.24 (m, IH), 7.20 (d, J= 7.7 Hz, IH), 7.10 - 6.91 (m, IH), 6.82 - 6.63 (m, IH), 3.88 (m, 2H)， 3.72 - 3.45 (m, 2H), 3.41 - 3.16 (m, IH), 2.46 - 2.32 (m, 2H), 1.79 - 1.64 (m, 2H), 1.63 - 1.41 (m, 6H), 1.05 (s, 6H).ESI-MS: m/z 547.2 [M+Na]+. Compound 481 was obtained by the method of Example 119: NMR (300 MHz, DMSO- 6 ) δ 12.80 (s, 1H): 8.24 (d, J = 7.8 Hz, IH), 8.19 (s, IH), 7.97 (d , J = 7.8 Hz, IH), 7.86 - 7.70 (m, IH), 7.50 - 7.24 (m, IH), 7.20 (d, J = 7.7 Hz, IH), 7.10 - 6.91 (m, IH), 6.82 - 6.63 (m, IH), 3.88 (m, 2H), 3.72 - 3.45 (m, 2H), 3.41 - 3.16 (m, IH), 2.46 - 2.32 (m, 2H), 1.79 - 1.64 (m, 2H), 1.63 - 1.41 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 547.2 [M+Na] + .
实施例 349  Example 349
5- (3,4-二氟苯氧基） -N- ( 1- ( (3-氟苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 (化合物 482)  5-(3,4-Difluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (Compound 482 )
参照实施例 119的方法制得化合物 482: 1H MR (300 MHz, DMSO- 6) δ 7.77 - 7.65 (m, IH), 7.63 - 7.51 (m, 3H), 7.39 - 7.26 (m, IH), 7.23 (d, J = 7.7 Hz, IH), 7.12 - 6.93 (m, IH), 6.84 - 6.62 (m, IH), 3.89 (t, 2H), 3.71 - 3.46 (m, 3H), 2.48 - 2.23 (m, 2H), 1.81 - 1.61 (m, 2H), 1.61 - 1.37 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 521.2 [M+Na]+. Compound 482 was obtained by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 7.77 - 7.65 (m, IH), 7.63 - 7.51 (m, 3H), 7.39 - 7.26 (m, IH), 7.23 (d, J = 7.7 Hz, IH), 7.12 - 6.93 (m, IH), 6.84 - 6.62 (m, IH), 3.89 (t, 2H), 3.71 - 3.46 (m, 3H), 2.48 - 2.23 (m , 2H), 1.81 - 1.61 (m, 2H), 1.61 - 1.37 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 521.2 [M+Na] + .
实施例 350  Example 350
5- (3,4-二氟苯氧基) -N- ( 1- ( (4-氟苯基) 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 (化合物 483 ) 5-(3,4-Difluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (Compound 483)
参照实施例 119的方法制得化合物 483 : 1H MR (300 MHz, DMSO- 6) δ 7.86 - 7.72 (m, 2H), 7.57 - 7.41 (m, 2H), 7.40 - 7.25 (m, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.08 - 6.91 (m, 1H), 6.72 (d, J = 9.1 Hz, 1H), 3.88 (m, 2H), 3.70 - 3.44 (m, 3H), 2.46 - 2.23 (m, 2H), 1.80 - 1.61 (m, 2H), 1.62 - 1.35 (m, 6H), 1.05 (s, 6H).ESI-MS: m/z 521.2 [M+Na]+. Compound 483 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 7.86 - 7.72 (m, 2H), 7.57 - 7.41 (m, 2H), 7.40 - 7.25 (m, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.08 - 6.91 (m, 1H), 6.72 (d, J = 9.1 Hz, 1H), 3.88 (m, 2H), 3.70 - 3.44 (m, 3H), 2.46 - 2.23 (m, 2H), 1.80 - 1.61 (m, 2H), 1.62 - 1.35 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 521.2 [M+Na] + .
实施例 351  Example 351
2- ( 3,4-二氟苯氧基） -N- ( 1- ( ( 3-氟苯基）磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 （化 合物 484)  2-(3,4-Difluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (Compound 484)
参照实施例 14的方法制得化合物 484: 1H NMR (300 MHz, CDC13) δ 7.64 - 7.51 (m, 2H), 7.51 - 7.41 (m, 1H), 7.40 - 7.28 (m, 1H), 7.15 - 6.98 (m, 1H), 6.82 - 6.69 (m, 1H), 6.68 - 6.58 (m, 1H), 6.57 - 6.47 (m, 1H), 3.90 - 3.67 (m, 3H), 2.63 - 2.41 (m, 2H), 2.13 - 1.91 (m, 2H), 1.64 - 1.56 (m, 2H), 1.45 (s, 6H). ESI-MS:m/z 479.1 [M+Na]+. Compound 484 was obtained by the method of Example 14: 1H NMR (300 MHz, CDC1 3 ) δ 7.64 - 7.51 (m, 2H), 7.51 - 7.41 (m, 1H), 7.40 - 7.28 (m, 1H), 7.15 - 6.98 (m, 1H), 6.82 - 6.69 (m, 1H), 6.68 - 6.58 (m, 1H), 6.57 - 6.47 (m, 1H), 3.90 - 3.67 (m, 3H), 2.63 - 2.41 (m, 2H) ), 2.13 - 1.91 (m, 2H), 1.64 - 1.56 (m, 2H), 1.45 (s, 6H). ESI-MS: m/z 479.1 [M+Na] + .
实施例 352  Example 352
2- ( 3,4-二氟苯氧基) -N- ( 1- ( (4-氟苯基)磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 （化 合物 485 )  2-(3,4-Difluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (Compound 485)
参照实施例 14的方法制得化合物 485 : 1H NMR (300 MHz, CDC13) δ 7.82 - 7.68 (m, 2H), 7.25 - 7.14 (m, 2H), 7.10 - 6.95 (m, 1H), 6.79 - 6.66 (m, 1H), 6.65 - 6.49 (m, 2H), 3.87 - 3.62 (m, 3H), 2.52 - 2.34 (m, 2H), 2.06 - 1.90 (m, 2H), 1.65 - 1.48 (m, 2H), 1.44 (s, 6H). ESI-MS: m/z 479.1 [M+Na]+. The compound 485 was obtained by the method of Example 14: 1H NMR (300 MHz, CDC1 3 ) δ 7.82 - 7.68 (m, 2H), 7.25 - 7.14 (m, 2H), 7.10 - 6.95 (m, 1H), 6.79 - 6.66 (m, 1H), 6.65 - 6.49 (m, 2H), 3.87 - 3.62 (m, 3H), 2.52 - 2.34 (m, 2H), 2.06 - 1.90 (m, 2H), 1.65 - 1.48 (m, 2H ), 1.44 (s, 6H). ESI-MS: m/z 479.1 [M+Na] + .
实施例 353  Example 353
反式—5- ( 3， 4-二氟苯氧基) -N- ( 3-氟 -1- ( (4-氟苯基) 磺酰基） 哌啶 -4-基） -2, 2- 二甲基戊酰胺 （化合物 486)  Trans-5-(3,4-difluorophenoxy)-N-(3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2- Methyl pentamide (compound 486)
参照实施例 139的方法制得化合物 486: 1H NMR (300 MHz, CDC13) δ 7.79 (dd, J= 8.4, 5.0 Hz, 2H), 7.25 (dd, J = 10.4, 6.1 Hz, 2H), 7.03 (dd, J = 18.8, 9.3 Hz, 1H), 6.79 - 6.60 (m, 1H), 6.55 (d, J = 9.0 Hz, 1H), 5.68 (d, J = 7.4 Hz, 1H), 4.67 - 4.30 (m, 1H), 4.19 - 4.02 (m, 1H), 3.99 - 3.79 (m, 3H), 3.79 - 3.65 (m, 1H), 2.60 - 2.33 (m, 2H), 2.26 - 2.05 (m, 1H), 1.66 (s, 5H), 1.20 (s, 6H). ESI-MS: m/z 539.2 [M+Na]+. Compound 486 was obtained by the method of Example 139: 1H NMR (300 MHz, CDC1 3 ) δ 7.79 (dd, J = 8.4, 5.0 Hz, 2H), 7.25 (dd, J = 10.4, 6.1 Hz, 2H), 7.03 (dd, J = 18.8, 9.3 Hz, 1H), 6.79 - 6.60 (m, 1H), 6.55 (d, J = 9.0 Hz, 1H), 5.68 (d, J = 7.4 Hz, 1H), 4.67 - 4.30 ( m, 1H), 4.19 - 4.02 (m, 1H), 3.99 - 3.79 (m, 3H), 3.79 - 3.65 (m, 1H), 2.60 - 2.33 (m, 2H), 2.26 - 2.05 (m, 1H), 1.66 (s, 5H), 1.20 (s, 6H). ESI-MS: m/z 539.2 [M+Na] + .
实施例 354  Example 354
5- (4-氯苯氧基） -N- ( ( 3R,4R) -3-氟 -1- ( (4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 （化合物 487)  5-(4-Chlorophenoxy)-N-((3R,4R)-3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) - 2,2-dimethylvaleramide (compound 487)
参照实施例 281的方法制得化合物 487: ee>99%; 1H NMR (300 MHz, OMSO-d6) δ 8.19 (d, J= 8.4 Hz, 2H), 8.05 (d, J= 8.4 Hz, 2H), 7.44 (d, J= 8.3 Hz, 1H), 7.30 (d, J= 8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 4.72 - 4.41 (m, 1H), 3.97 - 3.77 (m, 4H), 3.59 - 3.46 (m, 1H), 3.31 (s, 3H), 2.76 - 2.60 (m, 2H), 1.82 - 1.69 (m, 1H), 1.63 - 1.45 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 597.1 [M+Na] . Compound 487 was prepared according to the method of Example 281: ee >99%; 1H NMR (300 MHz, OMSO-d 6 ) δ 8.19 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H ), 7.44 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 4.72 - 4.41 (m, 1H), 3.97 - 3.77 (m, 4H), 3.59 - 3.46 (m, 1H), 3.31 (s, 3H), 2.76 - 2.60 (m, 2H), 1.82 - 1.69 (m, 1H), 1.63 - 1.45 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 597.1 [M+Na].
实施例 355  Example 355
5- (4-氯苯氧基） -N- ((3R,4R) -3-氟 -1- ((4- (三氟甲氧基） 苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 （化合物 488)  5-(4-Chlorophenoxy)-N-((3R,4R)-3-fluoro-1-((4-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl) -2,2-dimethylvaleramide (compound 488)
参照实施例 281的方法制得化合物 488: ee>99%; 1H NMR (300 MHz, CDC13) δ 7.83 (d, J= 8.7 Hz, 2H), 7.39 (d,J= 8.4 Hz, 2H), 7.21 (d, J= 8.9 Hz, 2H), 6.78 (d,J= 8.9 Hz, 2H)， 5.66 (d, J= 7.4 Hz, 1H), 4.60 - 4.32 (m, 1H), 4.15 - 4.03 (m, 1H), 3.98 - 3.91 (m, 1H), 3.88 (t,J= 5.1 Hz, 2H), 3.79-3.67 (m, 1H), 2.56-2.42 (m, 2H), 2.23 -2.09 (m, 1H), 1.70-1.65 (m, 3H), 1.61 - 1.54 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 603.2 [M+Na]+. Compound 488 was obtained by the method of Example 281: ee >99%; 1H NMR (300 MHz, CDC1 3 ) δ 7.83 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.21 (d, J= 8.9 Hz, 2H), 6.78 (d, J= 8.9 Hz, 2H), 5.66 (d, J= 7.4 Hz, 1H), 4.60 - 4.32 (m, 1H), 4.15 - 4.03 (m , 1H), 3.98 - 3.91 (m, 1H), 3.88 (t, J = 5.1 Hz, 2H), 3.79-3.67 (m, 1H), 2.56-2.42 (m, 2H), 2.23 -2.09 (m, 1H) ), 1.70-1.65 (m, 3H), 1.61 - 1.54 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 603.2 [M+Na] + .
实施例 356  Example 356
5- (4-氯苯氧基) -N- ((3R,4R) -1- ((4-氰基苯基) 磺酰基） -3-氟哌啶 -4-基) -2,2- 二甲基戊酰胺 （化合物 489)  5-(4-Chlorophenoxy)-N-((3R,4R)-1-((4-cyanophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-2,2- Dimethyl valeramide (compound 489)
参照实施例 281的方法制得化合物 489: ee>99%; 1H NMR (300 MHz, CDC13) δ 7.91 - 7.83 (m, 4H), 7.21 (d, J= 8.8 Hz, 2H), 6.78 (d, J= 8.8 Hz, 2H), 5.65 (d, J= 7.2 Hz, 1H), 4.60 - 4.32 (m, 1H), 4.15 - 4.02 (m, 1H), 3.99 - 3.92 (m, 1H), 3.88 (d, J= 5.0 Hz, 2H), 3.79 - 3.66 (m, 1H), 2.62-2.48 (m, 2H), 2.22-2.08 (m, 1H), 1.69 - 1.65 (m, 3H), 1.60 - 1.52 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 544.2 [M+Na]+. Compound 489 was obtained by the method of Example 281: ee >99%; 1H NMR (300 MHz, CDC1 3 ) δ 7.91 - 7.83 (m, 4H), 7.21 (d, J = 8.8 Hz, 2H), 6.78 (d , J= 8.8 Hz, 2H), 5.65 (d, J= 7.2 Hz, 1H), 4.60 - 4.32 (m, 1H), 4.15 - 4.02 (m, 1H), 3.99 - 3.92 (m, 1H), 3.88 ( d, J= 5.0 Hz, 2H), 3.79 - 3.66 (m, 1H), 2.62-2.48 (m, 2H), 2.22-2.08 (m, 1H), 1.69 - 1.65 (m, 3H), 1.60 - 1.52 ( m, 2H), 1.20 (s, 6H). ESI-MS: m/z 544.2 [M+Na] + .
实施例 357  Example 357
3- (((3R,4R) -4- (5- (4-氯苯氧基) -2,2-二甲基戊酰氨基) -3-氟哌啶 -1-基)磺酰基） 苯甲酸 （化合物 490)  3-(((3R,4R)-4-(5-(4-chlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Formic acid (compound 490)
参照实施例 281的方法制得化合物 490: ee>99%; 1H NMR (300 MHz, DMSO- 6) δ 13.40 (s, 1H), 8.37 (s, 1H), 8.30 (d, J= 7.9 Hz, 1H), 8.01 (d, J= 7.8 Hz, 1H), 7.77 (t, J= 7.8 Hz, 1H), 7.41 (d, J= 8.1 Hz, 1H), 7.30 (d, J= 8.6 Hz, 2H), 6.91 (d, J= 8.7 Hz, 2H), 4.69 - 4.41 (m, 1H), 3.88 (s, 4H), 3.51 (d, J= 12.0 Hz, 1H), 2.75 - 2.55 (m, 2H), 1.83 - 1.66 (m, 1H), 1.55 (s, 5H), 1.07 (s, 6H). ESI-MS: m/z 563.2 [M+Na]+. Compound 490 was obtained by the method of Example 281: ee >99%; 1H NMR (300 MHz, DMSO- 6 ) δ 13.40 (s, 1H), 8.37 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H), 8.01 (d, J= 7.8 Hz, 1H), 7.77 (t, J= 7.8 Hz, 1H), 7.41 (d, J= 8.1 Hz, 1H), 7.30 (d, J= 8.6 Hz, 2H) , 6.91 (d, J = 8.7 Hz, 2H), 4.69 - 4.41 (m, 1H), 3.88 (s, 4H), 3.51 (d, J = 12.0 Hz, 1H), 2.75 - 2.55 (m, 2H), 1.83 - 1.66 (m, 1H), 1.55 (s, 5H), 1.07 (s, 6H). ESI-MS: m/z 563.2 [M+Na] + .
实施例 358  Example 358
4- ((4- (5- (2,5-双 （三氟甲基） 苯氧基） -2,2-二甲基戊酰氨基） 哌啶 -1-基） 磺酰 基） 苯甲酸 （化合物 491)  4-((4-(5-(2,5-bis(trifluoromethyl)phenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid ( Compound 491)
参照实施例 119的方法制得化合物 491: 1H MR (300 MHz, OMSO-d6) δ 13.47 (s, 1H), 8.16 (d, J= 8.3 Hz, 2H), 7.85 (d, J= 8.2 Hz, 3H), 7.52 (s, 1H), 7.44 (d, J= 8.0 Hz, 1H), 7.20 (d, J= 7.6 Hz, 1H), 4.14 (dd, J= 10.7, 3.4 Hz, 2H), 3.62 (dd, J= 7.1, 4.6 Hz, 2H), 3.57- 3.49 (m, 1H), 2.39 (t, J= 11.3 Hz, 2H), 1.70 (d, J= 14.5 Hz, 2H), 1.60 - 1.54 (m, 4H), 1.52 - 1.39 (m, 2H), 1.05 (s, 6H). ESI-MS: m/z 647.4 [M+Na]+. Compound 491 was prepared by the method of Example 119: 1H MR (300 MHz, OMSO-d6) δ 13.47 (s, 1H), 8.16 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.2 Hz, 3H), 7.52 (s, 1H), 7.44 (d, J= 8.0 Hz, 1H), 7.20 (d, J= 7.6 Hz, 1H), 4.14 (dd, J= 10.7, 3.4 Hz, 2H), 3.62 ( Dd, J= 7.1, 4.6 Hz, 2H), 3.57- 3.49 (m, 1H), 2.39 (t, J= 11.3 Hz, 2H), 1.70 (d, J= 14.5 Hz, 2H), 1.60 - 1.54 (m , 4H), 1.52 - 1.39 (m, 2H), 1.05 (s, 6H). ESI-MS: m/z 647.4 [M+Na] + .
实施例 359 5- (2,5-二甲基苯氧基） -N- ( 1- ( (3-氟苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰 胺 (化合物 492) Example 359 5-(2,5-Dimethylphenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound) 492)
参照实施例 43的方法制得化合物 492: 1H MR (300 MHz, CDC13) δ 7.53 (d, J= 5.6 Hz, 2H), 7.46 (d, J = 7.4 Hz, 1H), 7.36 - 7.28 (m, 1H), 7.00 (d, J= 7.4 Hz, 1H), 6.66 (d, J = 7.4 Hz, 1H), 6.59 (s, 1H), 5.50 (d, J = 7.5 Hz, 1H), 3.89 (t, J = 5.1 Hz, 2H), 3.82 - 3.75 (m, 2H), 3.74 - 3.63 (m, 1H), 2.43 (t, J = 11.4 Hz, 2H), 2.29 (s, 3H), 2.16 (s, 3H), 1.96 (d, J = 11.0 Hz, 2H), 1.73 - 1.65 (m, 4H), 1.49 (ddd, J = 23.5, 11.9, 3.6 Hz, 2H), 1.18 (s, 6H). ESI-MS: m/z 513.2 [M+Na]+. Compound 492 was prepared by the method of Example 43: 1H MR (300 MHz, CDC1 3 ) δ 7.53 (d, J = 5.6 Hz, 2H), 7.46 (d, J = 7.4 Hz, 1H), 7.36 - 7.28 (m , 1H), 7.00 (d, J= 7.4 Hz, 1H), 6.66 (d, J = 7.4 Hz, 1H), 6.59 (s, 1H), 5.50 (d, J = 7.5 Hz, 1H), 3.89 (t , J = 5.1 Hz, 2H), 3.82 - 3.75 (m, 2H), 3.74 - 3.63 (m, 1H), 2.43 (t, J = 11.4 Hz, 2H), 2.29 (s, 3H), 2.16 (s, 3H), 1.96 (d, J = 11.0 Hz, 2H), 1.73 - 1.65 (m, 4H), 1.49 (ddd, J = 23.5, 11.9, 3.6 Hz, 2H), 1.18 (s, 6H). ESI-MS : m/z 513.2 [M+Na] + .
实施例 360  Example 360
N- ( 1 - ( (3-氰基苯基）磺酰基） 哌啶 -4-基） -5- (2,5-二氯苯氧基） -2,2-二甲基戊酰 胺 （化合物 493 )  N-(1-((3-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide (compound) 493 )
参照实施例 119的方法制得化合物 493 : 1H MR (300 MHz, CDC13) δ 8.05 (s, 1H), 7.98 (d, J= 7.8 Hz, 1H), 7.89 (d, J= 7.7 Hz, 1H), 7.70 (t, J= 7.9 Hz, 1H), 7.30 (s, 1H), 6.91 (d, J= 2.1 Hz, 1H), 6.87 (s, 1H), 5.53 (d, J= 7.1 Hz, 1H), 3.97 (t, J= 5.5 Hz, 2H), 3.86 - 3.78 (m, 2H), 3.77 - 3.67 (m, 1H), 2.46 (t, J= 11.1 Hz, 2H), 1.99 (d, J= 12.0 Hz, 2H), 1.78 - 1.66 (m, 4H), 1.60 - 1.48 (m, 2H), 1.19 (s, 6H). ESI-MS: m/z 560.2 [M+Na]+. Compound 493 was obtained by the method of Example 119: 1H MR (300 MHz, CDC1 3 ) δ 8.05 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H ), 7.70 (t, J= 7.9 Hz, 1H), 7.30 (s, 1H), 6.91 (d, J= 2.1 Hz, 1H), 6.87 (s, 1H), 5.53 (d, J= 7.1 Hz, 1H ), 3.97 (t, J= 5.5 Hz, 2H), 3.86 - 3.78 (m, 2H), 3.77 - 3.67 (m, 1H), 2.46 (t, J= 11.1 Hz, 2H), 1.99 (d, J= 12.0 Hz, 2H), 1.78 - 1.66 (m, 4H), 1.60 - 1.48 (m, 2H), 1.19 (s, 6H). ESI-MS: m/z 560.2 [M+Na] + .
实施例 361  Example 361
5- (2,5-二 （三氟甲基） 苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (三氟甲氧基） 苯基）磺 酰基） 哌啶 -4-基） 戊酰胺 （化合物 494)  5-(2,5-bis(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)piperidyl Pyridin-4-yl)pentanamide (compound 494)
参照实施例 119的方法制得化合物 494: 1H NMR (300 MHz, CDC13) δ 7.83 (d, J= 8.7 Hz, 2H), 7.71 (d, J= 8.1 Hz, 1H), 7.39 (d, J= 8.4 Hz, 2H), 7.31 (s, 1H), 7.18 (s, 1H), 5.56 (d, J= 7.7 Hz, 1H), 4.08 (t, J= 5.4 Hz, 2H), 3.81 (d, J= 12.1 Hz, 2H), 3.75 - 3.68 (m, 1H), 2.45 (t, J= 11.1 Hz, 2H), 1.98 (d, J= 10.9 Hz, 2H), 1.84 - 1.67 (m, 4H), 1.54 (qd, J= 12.3, 3.8 Hz, 2H), 1.20 (s, 6H). ESI-MS: m/z 687.1 [M+Na]+. Compound 494 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.83 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.31 (s, 1H), 7.18 (s, 1H), 5.56 (d, J= 7.7 Hz, 1H), 4.08 (t, J= 5.4 Hz, 2H), 3.81 (d, J = 12.1 Hz, 2H), 3.75 - 3.68 (m, 1H), 2.45 (t, J= 11.1 Hz, 2H), 1.98 (d, J= 10.9 Hz, 2H), 1.84 - 1.67 (m, 4H), 1.54 (qd, J = 12.3, 3.8 Hz, 2H), 1.20 (s, 6H). ESI-MS: m/z 687.1 [M+Na] + .
实施例 362  Example 362
5- (2,3-二氟苯氧基） -N- ( 1- ( (3-氟苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 (化合物 495 )  5-(2,3-Difluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (Compound 495 )
参照实施例 119的方法制得化合物 495: 1H NMR (300 MHz, CDC13) δ 7.62 - 7.40 (m, 3H), 7.39 - 7.27 (m, 1H), 7.03 - 6.89 (m, 1H), 6.82 - 6.64 (m, 2H), 5.53 (d, J= 6.8 Hz, 1H), 4.08 - 3.92 (m, 2H), 3.85 - 3.63 (m, 3H), 2.45 (t, J= 11.0 Hz, 2H), 2.07 - 1.88 (m, 2H), 1.81 - 1.60 (m, 4H), 1.55 - 1.43 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 521.2 [M+Na]+. The compound 495 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.62 - 7.40 (m, 3H), 7.39 - 7.27 (m, 1H), 7.03 - 6.89 (m, 1H), 6.82 - 6.64 (m, 2H), 5.53 (d, J = 6.8 Hz, 1H), 4.08 - 3.92 (m, 2H), 3.85 - 3.63 (m, 3H), 2.45 (t, J = 11.0 Hz, 2H), 2.07 - 1.88 (m, 2H), 1.81 - 1.60 (m, 4H), 1.55 - 1.43 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 521.2 [M+Na] + .
实施例 363  Example 363
反式 -5-(3,4-二氟苯氧基) -N- ( ( 3R,4R) -3-氟 -1- ( (3-氟苯基) 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 （化合物 496) 参照实施例 139的方法制得化合物 496: 1H NMR (300 MHz, CDC13) δ 7.56 (s, 2H), 7.48 (d,J=7.5Hz, 1H), 7.35 (s, 1H), 7.03 (q,J=9.4Hz, 1H), 6.66 (dd,J= 11.8, 6.6 Hz, 1H): 6.55 (d,J= 8.9 Hz, 1H), 5.69 (d, J= 7.3 Hz, 1H), 4.47 (ddd,J=49.3, 14.4, 9.4 Hz, 1H), 4.18 - 4.02 (m, 1H), 4.02 - 3.79 (m, 3H), 3.79 - 3.66 (m, 1H), 2.50 (dd, J = 14.1, 7.5 Hz, 2H), 2.24-2.10 (m, 1H), 1.77 - 1.59 (m, 5H), 1.20 (s, 6H). ESI-MS: m/z 539.2 [M+Na]+. Trans-5-(3,4-difluorophenoxy)-N-((3R,4R)-3-fluoro-1-((3-fluorophenyl)sulfonyl)piperidin-4-yl) -2,2-dimethylvaleramide (compound 496) Compound 496 was obtained by the method of Example 139: 1H NMR (300 MHz, CDC1 3 ) δ 7.56 (s, 2H), 7.48 (d, J = 7.5 Hz, 1H), 7.35 (s, 1H), 7.03 (q , J=9.4Hz, 1H), 6.66 (dd, J= 11.8, 6.6 Hz, 1H) : 6.55 (d, J= 8.9 Hz, 1H), 5.69 (d, J= 7.3 Hz, 1H), 4.47 (ddd , J=49.3, 14.4, 9.4 Hz, 1H), 4.18 - 4.02 (m, 1H), 4.02 - 3.79 (m, 3H), 3.79 - 3.66 (m, 1H), 2.50 (dd, J = 14.1, 7.5 Hz , 2H), 2.24-2.10 (m, 1H), 1.77 - 1.59 (m, 5H), 1.20 (s, 6H). ESI-MS: m/z 539.2 [M+Na] + .
实施例 364  Example 364
反式 -4-((4-(5-(4-氯苯氧基; )-2,2-二甲基戊酰胺基; )-2-甲基哌啶 -1-基；)磺酰基；)苯甲酸 (化合 497)  Trans-4-((4-(5-(4-chlorophenoxy))-2,2-dimethylpentanamide;)-2-methylpiperidin-1-yl;)sulfonyl; Benzoic acid (Chemical 497)
Figure imgf000135_0001
取化合物 V-l (256 mg, 1 mmol) 溶于无水 DMF (2 mL)， 加入 CDI (186 mg, 1.149 mmol)，于 70 °C下搅拌 1 h，然后加入（士） -反式 - 4-氨基 -2-甲基哌啶 -1-甲酸叔丁酯 （214 mg, 1 mmol), 反应 2 h。 冷却至室温， 加入水 （10mL)， 乙酸乙酯萃取 （20mLx3)， 有机相用饱和 NaHC03 (10mLx3) 洗涤， 无水硫酸钠干燥， 减压蒸除溶剂， 残余物经 柱层析 （洗脱剂： 石油醚 /乙酸乙酯 =2:1) 纯化， 得化合物 V-2 (白色固体， 366 mg， 收率 81%)。
Figure imgf000135_0001
The compound Vl (256 mg, 1 mmol) was dissolved in anhydrous DMF (2 mL), CDI (186 mg, 1.149 mmol) was added, and the mixture was stirred at 70 ° C for 1 h, then added (Shi)-trans- 4- Amino-2-methylpiperidine-1-carboxylic acid tert-butyl ester (214 mg, 1 mmol) was reacted for 2 h. Cooled to room temperature, water (10 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was washed with saturated NaHC0 3 (10mLx3), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (eluting Preparation: Petroleum ether / ethyl acetate = 2:1) Purified to give Compound V-2 (white solid, 366 mg, yield 81%).
取化合物 V-2 (366 mg) 溶于二氯甲垸 （10mL) ， 冰浴下加入三氟乙酸 （lmL) ， 室温搅拌过夜。 减压蒸除溶剂， 用饱和碳酸氢钠调节 pH至碱性， 乙酸乙酯 （30mLx3) 萃取， 饱和 NaCl (10 mL x3) 洗涤， 无水硫酸钠干燥， 减压蒸除溶剂， 得化合物 V-3 (无色液体， 279 mg， 收率 98%) 。  Compound V-2 (366 mg) was dissolved in dichloromethane (10 mL). The solvent was evaporated under reduced pressure, and the mixture was evaporated to dryness eluted with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc 3 (colorless liquid, 279 mg, yield 98%).
取化合物 V-3 (158 mg, 0.45 mmoL) 溶于 DCM (5 mL), 加入三乙胺 （0.095 mL) 和氯磺酰基苯甲酸甲酯（115 mg, 0.46 mmoL)，室温搅拌 4 h。旋干，残余物经柱层析（洗 脱剂： 石油醚 /乙酸乙酯 =3:1) 纯化， 得化合物 V-4 (186 mg， 收率 75%)。  Compound V-3 (158 mg, 0.45 mmoL) was dissolved in DCM (5 mL), triethylamine (0.095 mL) and methyl chlorosulfonylbenzoate (115 mg, 0.46 mmoL). After spin-drying, the residue was purified by EtOAc EtOAcjjjjjjj
取化合物 V-4 (186 mg, 0.34 mmoL)溶于甲醇和四氢呋喃（5: 1， 20 mL), 加入 IN NaOH (2 mL), 室温搅拌过夜。减压蒸除溶剂， 加 1N HC1调至酸性， 有白色固体析出， 过滤， 水洗， 收集白色固体， 加 20 mL石油醚搅拌 2h， 抽滤， 真空干燥， 得化合物 497 (白色固体， 176 mg， 收率 97%): 1H MR (300 MHz, DMSO- 6) δ 13.47 (s, 1H), 8.16 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.21 (d, J= 7.8 Hz, 1H), 6.91 (d, J= 8.9 Hz, 2H), 3.88 (t, 2H), 3.70 - 3.50 (m, 3H), 2.40 (m, 1H), 1.69 (m, 2H), 1.60 -Compound V-4 (186 mg, 0.34 mmoL) was dissolved in methanol and tetrahydrofuran (5: 1, 20 mL), and added to IN. NaOH (2 mL), stir at room temperature overnight. The solvent was evaporated under reduced pressure. EtOAc EtOAc (EtOAc md. Yield 97%): 1H MR (300 MHz, DMSO- 6 ) δ 13.47 (s, 1H), 8.16 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 7.30 ( d, J = 8.8 Hz, 2H), 7.21 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 8.9 Hz, 2H), 3.88 (t, 2H), 3.70 - 3.50 (m, 3H), 2.40 (m, 1H), 1.69 (m, 2H), 1.60 -
1.39 (m, 6H), 1.16 (s, 6H), 1.06 (d, J= 6.8 Hz, 3H). ESI-MS: m/z 560.2 [M+Na]+. 1.39 (m, 6H), 1.16 (s, 6H), 1.06 (d, J = 6.8 Hz, 3H). ESI-MS: m/z 560.2 [M+Na] + .
实施例 365  Example 365
反式 -5-(4-氯苯氧基) -N-(l-((4-氟苯基） 磺酰基 )-2-甲基哌啶 -4-基) -2,2-二甲基戊酰胺 (化合物 498)  Trans-5-(4-chlorophenoxy)-N-(l-((4-fluorophenyl)sulfonyl)-2-methylpiperidin-4-yl)-2,2-dimethyl Valentamide (compound 498)
参照实施例 364的方法制得化合物 498: 1H MR (300 MHz, DMSO- 6) δ 7.80 (dd, J = 8.4, 5.3 Hz, 2H), 7.48 (t, J = 8.7 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 3.95 - 3.83 (m, 2H), 3.65 - 3.48 (m, 3H), 2.35 (m, 1H), 1.69 (m, 2H): 1.60 - 1.40 (m, 6H), 1.15 (s, 6H), 1.08 (d, J= 6.8 Hz, 3H). ESI-MS: m/z 560.2 [M+Na]+. 实施例 366 Compound 498 was prepared by the method of Example 364: 1H MR (300 MHz, DMSO- 6 ) δ 7.80 (dd, J = 8.4, 5.3 Hz, 2H), 7.48 (t, J = 8.7 Hz, 2H), 7.30 ( d, J = 8.8 Hz, 2H), 7.21 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 3.95 - 3.83 (m, 2H), 3.65 - 3.48 (m, 3H ), 2.35 (m, 1H), 1.69 (m, 2H) : 1.60 - 1.40 (m, 6H), 1.15 (s, 6H), 1.08 (d, J = 6.8 Hz, 3H). ESI-MS: m/ z 560.2 [M+Na] + . Example 366
反式 -5-(4-氯苯氧基) -N-(l-((3-氟苯基） 磺酰基 )-2-甲基哌啶 -4-基;) -2,2-二甲基戊酰胺 (化合物 499) Trans- 5- (4-chlorophenoxy)-N-(l-((3-fluorophenyl)sulfonyl)-2-methylpiperidin-4-yl;) -2,2-dimethyl Radicotamide (Compound 499)
参照实施例 364的方法制得化合物 499: 1H NMR (300 MHz, DMSO- 6) δ 7.79 (m, 1H), 7.58-7.60 (m, 2H), 7.47 (m, 1H), 7.21 (d, J= 7.6 Hz, 2H), 6.91 (d, J= 8.8 Hz, 2H), 3.93 - 3.81 (m, 2H), 3.64 - 3.47 (m, 3H), 2.34 (m, 1H), 1.68 (m, 2H), 1.60 - 1.40 (m, 6H), 1.15 (s, 6H), 1.08 (d, J= 6.8 Hz, 3H). ESI-MS: m/z 560.2 [M+Na]+. Compound 499 was prepared by the method of Example 364: 1H NMR (300 MHz, DMSO- 6 ) δ 7.79 (m, 1H), 7.58-7.60 (m, 2H), 7.47 (m, 1H), 7.21 (d, J = 7.6 Hz, 2H), 6.91 (d, J= 8.8 Hz, 2H), 3.93 - 3.81 (m, 2H), 3.64 - 3.47 (m, 3H), 2.34 (m, 1H), 1.68 (m, 2H) , 1.60 - 1.40 (m, 6H), 1.15 (s, 6H), 1.08 (d, J = 6.8 Hz, 3H). ESI-MS: m/z 560.2 [M+Na] + .
实施例 367  Example 367
反式 -5-(4-氯苯氧基) -2,2-二甲基 -N-(2-甲基 -1- (吡啶 -3-基磺酰基)哌啶 -4-基；） 戊酰胺 (化合物 500)  Trans-5-(4-chlorophenoxy)-2,2-dimethyl-N-(2-methyl-1-(pyridin-3-ylsulfonyl)piperidin-4-yl;) pentyl Amide (compound 500)
参照实施例 364的方法制得化合物 500: 1H NMR (300 MHz, DMSO- 6) δ 8.88 (m, 2H), 8.16 (d, j = 8.1 Hz, 1H), 7.68 (dd, J = 7.6, 4.9 Hz, 1H), 7.21 (d, J= 7.6 Hz, 2H), 6.91 (d, J= 8.8 Hz, 2H), 3.93 - 3.81 (m, 2H), 3.64 - 3.47 (m, 3H), 2.34 (m, 1H), 1.68 (m, 2H), 1.60 -Compound 500 was prepared by the method of Example 364: 1H NMR (300 MHz, DMSO- 6 ) δ 8.88 (m, 2H), 8.16 (d, j = 8.1 Hz, 1H), 7.68 (dd, J = 7.6, 4.9 Hz, 1H), 7.21 (d, J= 7.6 Hz, 2H), 6.91 (d, J= 8.8 Hz, 2H), 3.93 - 3.81 (m, 2H), 3.64 - 3.47 (m, 3H), 2.34 (m , 1H), 1.68 (m, 2H), 1.60 -
1.40 (m, 6H), 1.15 (s, 6H), 1.08 (d, J= 6.8 Hz, 3H). ESI-MS: m/z 517.1 [M+Na]+. 1.40 (m, 6H), 1.15 (s, 6H), 1.08 (d, J = 6.8 Hz, 3H). ESI-MS: m/z 517.1 [M+Na] + .
实施例 368  Example 368
反式 -4-((4-(5-(4-氟苯氧基) -2,2-二甲基戊酰胺基) -2-甲基哌啶 -1-基；） 磺酰基；） 苯甲酸 (化合物 501 )  Trans-4-((4-(5-(4-fluorophenoxy)-2,2-dimethylpentanyl)-2-methylpiperidin-1-yl;)sulfonyl;) Benzene Formic acid (compound 501)
参照实施例 364的方法制得化合物 501 : 1H NMR (300 MHz, DMSO- 6) δ 13.47 (s, 1H), 8.16 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 7.8 Hz, 1H), 7.09 (t, J = 8.7 Hz, 2H), 6.90 (p, J= 4.2 Hz, 2H), 3.88 (t, 2H), 3.70 - 3.50 (m, 3H), 2.40 (m, 1H), 1.69 (m， 2H), 1.60 - 1.39 (m, 6H), 1.16 (s, 6H), 1.06 (d, J= 6.8 Hz, 3H). ESI-MS: m/z 543.2 [M+Na]+. 实施例 369 Compound 501 was obtained by the method of Example 364: 1H NMR (300 MHz, DMSO- 6 ) δ 13.47 (s, 1H), 8.16 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 7.8 Hz, 1H), 7.09 (t, J = 8.7 Hz, 2H), 6.90 (p, J = 4.2 Hz, 2H), 3.88 (t, 2H), 3.70 - 3.50 ( m, 3H), 2.40 (m, 1H), 1.69 (m, 2H), 1.60 - 1.39 (m, 6H), 1.16 (s, 6H), 1.06 (d, J = 6.8 Hz, 3H). ESI-MS : m/z 543.2 [M+Na] + . Example 369
反式 -5-(4-氟苯氧基) -N-(l-((4-氟苯基） 磺酰基 )-2-甲基哌啶 -4-基；) -2,2-二甲基戊酰胺 (化合物 502 ) Trans- 5- (4-fluorophenoxy)-N-(l-((4-fluorophenyl)sulfonyl)-2-methylpiperidin-4-yl;) -2,2-dimethyl Kefalamide (compound 502)
参照实施例 364的方法制得化合物 502: 1H NMR (300 MHz, CDC13) δ 7.77 (dd, J = 8.7: 5.0 Hz, 2H), 7.33 - 7.13 (m,2H), 7.03 - 6.87 (m, 2H), 6.79 (dd, J = 9.1, 4.2 Hz, 2H), 5.53 (d, J = 7.8 Hz, 1H), 3.87 (t, 2H), 3.71 - 3.51 (m, 3H), 2.40 (m, 1H), 1.68 (m, 2H), 1.60 - 1.39 (m, 6H), 1.16 (s, 6H), 1.06 (d, J = 6.8 Hz, 3H). ESI-MS: m/z 517.2 [M+Na]+. The compound 502 was obtained by the method of Example 364: 1H NMR (300 MHz, CDC1 3 ) δ 7.77 (dd, J = 8.7: 5.0 Hz, 2H), 7.33 - 7.13 (m, 2H), 7.03 - 6.87 (m, 2H), 6.79 (dd, J = 9.1, 4.2 Hz, 2H), 5.53 (d, J = 7.8 Hz, 1H), 3.87 (t, 2H), 3.71 - 3.51 (m, 3H), 2.40 (m, 1H) ), 1.68 (m, 2H), 1.60 - 1.39 (m, 6H), 1.16 (s, 6H), 1.06 (d, J = 6.8 Hz, 3H). ESI-MS: m/z 517.2 [M+Na] + .
实施例 370  Example 370
反式 -5-(2,4-二氟苯氧基) -N-(l-((4-氟苯基；） 磺酰基 )-2-甲基哌啶 -4-基) -2,2-二甲基戊 酰胺 （化合物 503 )  Trans-5-(2,4-difluorophenoxy)-N-(l-((4-fluorophenyl))sulfonyl)-2-methylpiperidin-4-yl)-2,2 - dimethyl valeramide (compound 503)
参照实施例 364的方法制得化合物 503 : iH MR (300 MHz, DMSO- 6) δ 7.81 (dd, J = 8.7, 5.2 Hz, 2H), 7.48 (t, J = 8.7 Hz, 2H), 7.32 - 7.08 (m, 3H), 6.98 (t, J = 8.8 Hz, 1H), 3.95 (m, 2H), 3.59 (m, 3H), 2.35 (m, 1H), 1.70 (m, 2H), 1.60 - 1.39 (m, 6H), 1.05 (s, 6H), 1.06 (d, J = 6.8 Hz, 3H). ESI-MS: m/z 535.1 [M+Na]+. Compound 503 was prepared by the method of Example 364: iH MR (300 MHz, DMSO- 6 ) δ 7.81 (dd, J = 8.7, 5.2 Hz, 2H), 7.48 (t, J = 8.7 Hz, 2H), 7.32 - 7.08 (m, 3H), 6.98 (t, J = 8.8 Hz, 1H), 3.95 (m, 2H), 3.59 (m, 3H), 2.35 (m, 1H), 1.70 (m, 2H), 1.60 - 1.39 (m, 6H), 1.05 (s, 6H), 1.06 (d, J = 6.8 Hz, 3H). ESI-MS: m/z 535.1 [M+Na] + .
实施例 371  Example 371
反式 -5-(2,4-二氟苯氧基) -2,2-二甲基 -N-(2-甲基 -1- (吡啶 -3-基磺酰基)哌啶 -4-基；） 戊 酰胺 （化合物 504 )  Trans-5-(2,4-difluorophenoxy)-2,2-dimethyl-N-(2-methyl-1-(pyridin-3-ylsulfonyl)piperidin-4-yl ;) pentanoamide (compound 504)
参照实施例 364的方法制得化合物 504: 1H MR (300 MHz, CDC13) δ 9.04 (m, 1H), 8.90 (m, 1H), 8.11- 8.00 (m, 1H), 7.55 - 7.46 (m, 1H), 7.32 - 7.24 (m, 1H), 7.21 - 7.10 (m, 1H), 6.94 - 6.84 (m, 1H), 5.64 (d, J = 7.5 Hz, 1H), 3.92 (m, 2H), 3.90 - 3.69 (m, 3H), 2.47 (m， 2H), 2.05 - 1.93 (m, 1H), 1.80 - 1.62 (m, 4H), 1.60 - 1.48 (m, 2H), 1. 17 (s, 6H), 1.06 (d, J = 6.8 Hz, 3H). ESI-MS: m/z 518.3 [M+Na]+. Compound 504 was prepared by the method of Example 364: 1H MR (300 MHz, CDC1 3 ) δ 9.04 (m, 1H), 8.90 (m, 1H), 8.11-8.00 (m, 1H), 7.55 - 7.46 (m, 1H), 7.32 - 7.24 (m, 1H), 7.21 - 7.10 (m, 1H), 6.94 - 6.84 (m, 1H), 5.64 (d, J = 7.5 Hz, 1H), 3.92 (m, 2H), 3.90 - 3.69 (m, 3H), 2.47 (m, 2H), 2.05 - 1.93 (m, 1H), 1.80 - 1.62 (m, 4H), 1.60 - 1.48 (m, 2H), 1. 17 (s, 6H) , 1.06 (d, J = 6.8 Hz, 3H). ESI-MS: m/z 518.3 [M+Na] + .
实施例 372  Example 372
5-(2,4-二氟苯氧基) -2,2-二甲基 -N-(l-((4-甲基吡啶 -3-基） 磺酰基） 哌啶 -4-基） 戊酰胺 (化合物 505 )  5-(2,4-difluorophenoxy)-2,2-dimethyl-N-(l-((4-methylpyridin-3-yl)sulfonyl)piperidin-4-yl)penta Amide (compound 505)
参照实施例 119的方法制得化合物 505 : 1H MR (300 MHz, CDC13) δ 9.05 (m, 1H), 8.88 (m, 1H), 7.50 (m, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 6.88 (m, 1H), 5.63 (d, J = 7.5 Hz, 1H), 4.03 - 3.90 (m, 2H), 3.90 - 3.69 (m, 3H), 2.45 (m, 2H), 2.36 (s, 3H), 2.04 - 1.92 (m, 2H): 1.80 - 1.61 (m, 4H), 1.61 - 1.50 (m, 2H), 1.16 (s, 6H). ESI-MS: m/z 518.2 [M+Na]+. Compound 505 was obtained by the method of Example 119: 1H MR (300 MHz, CDC1 3 ) δ 9.05 (m, 1H), 8.88 (m, 1H), 7.50 (m, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 6.88 (m, 1H), 5.63 (d, J = 7.5 Hz, 1H), 4.03 - 3.90 (m, 2H), 3.90 - 3.69 (m, 3H), 2.45 (m, 2H), 2.36 (s, 3H), 2.04 - 1.92 (m, 2H) : 1.80 - 1.61 (m, 4H), 1.61 - 1.50 (m, 2H), 1.16 (s, 6H). ESI-MS: m/z 518.2 [ M+Na] + .
实施例 373  Example 373
5-(2,4-二氟苯氧基) -2,2-二甲基 -N-(l-((2-甲基吡啶 -3-基） 磺酰基） 哌啶 -4-基） 戊酰胺 (化合物 506 )  5-(2,4-difluorophenoxy)-2,2-dimethyl-N-(l-((2-methylpyridin-3-yl)sulfonyl)piperidin-4-yl)penta Amide (compound 506)
参照实施例 119的方法制得化合物 506: 1H MR (300 MHz, CDC13) δ 8.88 (m, 1H), 8.45 (m, 1H), 7.50 (m, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 6.88 (m, 1H), 5.62 (d, J = 7.5 Hz, 1H), 4.02 - 3.91 (m, 2H), 3.89 - 3.70 (m, 3H), 2.50 (s, 3H), 2.44 (m, 2H), 2.03 - 1.90 (m, 2H): 1.80 - 1.62 (m, 4H), 1.60 - 1.52 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 518.2 [M+Na]+. Compound 506 was prepared by the method of Example 119: 1H MR (300 MHz, CDC1 3 ) δ 8.88 (m, 1H), 8.45 (m, 1H), 7.50 (m, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 6.88 (m, 1H), 5.62 (d, J = 7.5 Hz, 1H), 4.02 - 3.91 (m, 2H), 3.89 - 3.70 (m, 3H), 2.50 (s, 3H), 2.44 (m, 2H), 2.03 - 1.90 (m, 2H) : 1.80 - 1.62 (m, 4H), 1.60 - 1.52 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 518.2 [M+Na] + .
实施例 374  Example 374
反式 -2-(3,4-二氟苯氧基) -2-甲基 -N-(2-甲基 -1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 丙酰胺 (化合物 507)  Trans-2-(3,4-difluorophenoxy)-2-methyl-N-(2-methyl-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)propanamide (Compound 507)
参照实施例 364的方法制得化合物 507: 1H MR (300 MHz, DMSO-d6) δ 9.03 (m, 1Η): 8.90 (m, 1Η), 8.10 (m, 1H), 7.54 - 7.47 (m, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.09 (m, 1H), 6.82 - 6.70 (m, 1H), 6.69- 6.57 (m, 1H), 3.60-3.38 (m, 3H), 2.80 (m, 1H), 1.64 - 1.56 (m, 4H), 1.45 (s, 6H), 1.06 (d, J= 6.8 Hz, 3H). ESI-MS: m/z 476.1 [M+Na]+. Compound 507 was prepared by the method of Example 364: 1H MR (300 MHz, DMSO-d 6 ) δ 9.03 (m, 1 Η) : 8.90 (m, 1 Η), 8.10 (m, 1H), 7.54 - 7.47 (m, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.09 (m, 1H), 6.82 - 6.70 (m, 1H), 6.69- 6.57 (m, 1H), 3.60-3.38 (m, 3H), 2.80 (m, 1H), 1.64 - 1.56 (m, 4H), 1.45 (s, 6H), 1.06 (d, J = 6.8 Hz, 3H). ESI-MS: m/z 476.1 [M+Na] + .
实施例 375  Example 375
反式 -N-(l-((4-氟苯基） 磺酰基 )-2-甲基哌啶 -4-基) -2,2-二甲基 -5-(4- (甲磺酰基） 苯氧 基） 戊酰胺 （化合物 508 )  trans-N-(l-((4-fluorophenyl)sulfonyl)-2-methylpiperidin-4-yl)-2,2-dimethyl-5-(4-(methylsulfonyl) Phenoxy) pentanoamide (compound 508)
参照实施例 364的方法制得化合物 508: 1H MR (300 MHz, OMSO-d6) δ 7.88 - 7.75 (m, 4H), 7.56 - 7.40 (m, 2H), 7.25 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 4.10 - 3.92 (m, 2H), 3.65 - 3.47 (m, 3H), 3.15 (s, 3H), 2.40 (m, 1H), 1.77 - 1.62 (m, 2H), 1.62 - 1.40 (m, 6H), 1.10 (s, 6H). 1.06 (d, J= 6.8 Hz, 3H). ESI-MS: m/z 577.4 [M+Na]+. Compound 508 was prepared by the method of Example 364: 1H MR (300 MHz, OMSO-d 6 ) δ 7.88 - 7.75 (m, 4H), 7.56 - 7.40 (m, 2H), 7.25 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 4.10 - 3.92 (m, 2H), 3.65 - 3.47 (m, 3H), 3.15 (s, 3H), 2.40 (m, 1H), 1.77 - 1.62 (m, 2H), 1.62 - 1.40 (m, 6H), 1.10 (s, 6H). 1.06 (d, J = 6.8 Hz, 3H). ESI-MS: m/z 577.4 [M+Na] + .
实施例 376  Example 376
反式 -5-(4-氯苯氧基) -2,2-二甲基 -N-(2-甲基 -l-((4- (甲磺酰基；） 苯基；） 磺酰基；） 哌啶 -4- 基） 丙酰胺 （化合物 509) Trans- 5- (4-chlorophenoxy)-2,2-dimethyl-N-(2-methyl-l-((4-(methylsulfonyl))phenyl;)sulfonyl;) Piperidin-4-yl)propanamide (compound 509)
参照实施例 364的方法制得化合物 509: 1H MR (300 MHz, DMSO- 6) δ 8.18 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 3.95 - 3.82 (m, 2H), 3.72 - 3.49 (m, 3H), 3.33 (s, 3H), 2.42 (m, 1H), 1.70 (m, 2H), 1.61 - 1.40 (m, 6H), 1.10 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H). ESI-MS: m/z 572.2 [M+H]+. Compound 509 was prepared by the method of Example 364: 1H MR (300 MHz, DMSO- 6 ) δ 8.18 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 3.95 - 3.82 (m, 2H), 3.72 - 3.49 (m, 3H), 3.33 (s, 3H), 2.42 (m, 1H), 1.70 (m, 2H), 1.61 - 1.40 (m, 6H), 1.10 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H). ESI -MS: m/z 572.2 [M+H] + .
实施例 377  Example 377
反式 -2-(4-氯苯氧基) -2-甲基 -N-(2-甲基 -1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 丙酰胺 （化 合物 510)  Trans-2-(4-chlorophenoxy)-2-methyl-N-(2-methyl-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)propanamide (compound 510 )
参照实施例 364的方法制得化合物 510: 1H MR (300 MHz, DMSO- 6) δ 9.01 (d, J = 1.6 Hz, 1H), 8.86 (d, J= 3.5 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.52 (dd, J= 7.9, 4.9 Hz, 1H), 7.25 (d, J= 8.8 Hz, 2H), 6.83 (d, J= 8.8 Hz, 2H), 6.56 (d, J= 7.7 Hz, 1H), 3.80 (m, 3H), 2.54 (t, J = 11.2 Hz, 2H), 2.02 (m, 1H), 1.61 - 1.50 (m, 2H), 1.48 (s, 6H), 1.06 (d, J= 6.8 Hz, 3H). ESI-MS: m/z 474.2 [M+Na]+. Compound 510 was prepared by the method of Example 364: 1H MR (300 MHz, DMSO- 6 ) δ 9.01 (d, J = 1.6 Hz, 1H), 8.86 (d, J = 3.5 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.52 (dd, J= 7.9, 4.9 Hz, 1H), 7.25 (d, J= 8.8 Hz, 2H), 6.83 (d, J= 8.8 Hz, 2H), 6.56 (d, J = 7.7 Hz, 1H), 3.80 (m, 3H), 2.54 (t, J = 11.2 Hz, 2H), 2.02 (m, 1H), 1.61 - 1.50 (m, 2H), 1.48 (s, 6H), 1.06 (d, J = 6.8 Hz, 3H). ESI-MS: m/z 474.2 [M+Na] + .
实施例 378  Example 378
2-(4-氯苯氧基) -2-甲基 -N-(l-((4-甲基吡啶 -3-基；）磺酰基；） 哌啶 -4-基；） 丙酰胺（化合物 511 ) 2-(4-Chlorophenoxy)-2-methyl-N-(l-((4-methylpyridin-3-yl))sulfonyl;)piperidin-4-yl;)propionamide (compound) 511)
参照实施例 14的方法制得化合物 511 : 1H MR (300 MHz, DMSO- 6) δ 8.90 (s, 1H), 8.51 (m, 1H), 7.48 (m, 1H), 7.25 (d, J= 8.8 Hz, 2H), 6.83 (d, J= 8.8 Hz, 2H), 6.56 (d, J= 7.7 Hz, 1H), 3.80 (m, 3H), 2.55 (t, J= 11.2 Hz, 2H), 2.36 (s, 3H), 2.02 (d, J= 12.1 Hz, 2H), 1.61 - 1.50 (m, 2H), 1.48 (s, 6H). ESI-MS: m/z 452.2 [M+H]+. Compound 511 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 8.90 (s, 1H), 8.51 (m, 1H), 7.48 (m, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.83 (d, J= 8.8 Hz, 2H), 6.56 (d, J= 7.7 Hz, 1H), 3.80 (m, 3H), 2.55 (t, J= 11.2 Hz, 2H), 2.36 ( s, 3H), 2.02 (d, J = 12.1 Hz, 2H), 1.61 - 1.50 (m, 2H), 1.48 (s, 6H). ESI-MS: m/z 452.2 [M+H] + .
实施例 379  Example 379
2-(4-氯苯氧基) -2-甲基 -N-(l-((2-甲基吡啶 -3-基；）磺酰基；） 哌啶 -4-基；） 丙酰胺（化合物 512)  2-(4-Chlorophenoxy)-2-methyl-N-(l-((2-methylpyridin-3-yl))sulfonyl;)piperidin-4-yl;)propionamide (compound) 512)
参照实施例 14的方法制得化合物 512: 1H MR (300 MHz, DMSO- 6) δ 8.82 (m, 1Η), 8.45 (m, 1H), 7.68 (m, 1H), 7.25 (d, J= 8.8 Hz, 2H), 6.82 (d, J= 8.8 Hz, 2H), 6.54 (d, J= 7.6 Hz, 1H), 3.80 (m, 3H), 2.54 (t, J= 11.2 Hz, 2H), 2.42 (s, 3H), 2.01 (d, J= 12.1 Hz, 2H), 1.60 - 1.51 (m, 2H), 1.45 (s, 6H). ESI-MS: m/z 452.2 [M+H]+. Compound 512 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 8.82 (m, 1 Η), 8.45 (m, 1H), 7.68 (m, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.82 (d, J= 8.8 Hz, 2H), 6.54 (d, J= 7.6 Hz, 1H), 3.80 (m, 3H), 2.54 (t, J= 11.2 Hz, 2H), 2.42 ( s, 3H), 2.01 (d, J = 12.1 Hz, 2H), 1.60 - 1.51 (m, 2H), 1.45 (s, 6H). ESI-MS: m/z 452.2 [M+H] + .
实施例 380  Example 380
2-(4-氟苯氧基) -2-甲基 -N-(l-((4-甲基吡啶 -3-基；）磺酰基；） 哌啶 -4-基；） 丙酰胺（化合物 513 )  2-(4-Fluorophenoxy)-2-methyl-N-(l-((4-methylpyridin-3-yl))sulfonyl;)piperidin-4-yl;)propanamide (compound) 513 )
参照实施例 14的方法制得化合物 513 : 1H MR (300 MHz, DMSO- 6) δ 8.88 (s, 1Η),Compound 513 was prepared by the method of Example 14 : 1H MR (300 MHz, DMSO- 6 ) δ 8.88 (s, 1 Η),
8.45 (m, 1H), 7.46 (m, 1H), 7.15 (d, J= 8.8 Hz, 2H), 6.63 (d, J= 8.8 Hz, 2H), 6.45 (d, J= 7.6 Hz, 1H), 3.67 (m, 3H), 2.51 (t, J= 11.2 Hz, 2H), 2.35 (s, 3H), 2.01 (d, J= 12.1 Hz, 2H), 1.60 - 1.50 (m, 2H), 1.42 (s, 6H). ESI-MS: m/z 436.2 [M+H]+. 8.45 (m, 1H), 7.46 (m, 1H), 7.15 (d, J= 8.8 Hz, 2H), 6.63 (d, J= 8.8 Hz, 2H), 6.45 (d, J= 7.6 Hz, 1H), 3.67 (m, 3H), 2.51 (t, J= 11.2 Hz, 2H), 2.35 (s, 3H), 2.01 (d, J= 12.1 Hz, 2H), 1.60 - 1.50 (m, 2H), 1.42 (s , 6H). ESI-MS: m/z 436.2 [M+H] + .
实施例 381  Example 381
2-(4-氟苯氧基) -2-甲基 -N-(l-((2-甲基吡啶 -3-基；）磺酰基；） 哌啶 -4-基；） 丙酰胺（化合物 514)  2-(4-Fluorophenoxy)-2-methyl-N-(l-((2-methylpyridin-3-yl))sulfonyl;)piperidin-4-yl;)propionamide (compound) 514)
参照实施例 14的方法制得化合物 514: 1H MR (300 MHz, DMSO- 6) δ 8.80 (m, 1Η), 8.41 (m, 1H), 7.62 (m, 1H), 7.16 (d, J= 8.8 Hz, 2H), 6.62 (d, J= 8.8 Hz, 2H), 6.43 (d, J= 7.6 Hz, 1H), 3.66 (m, 3H), 2.50 (t, J= 11.2 Hz, 2H), 2.41 (s, 3H), 2.02 (d, J= 12.1 Hz, 2H), 1.60 - 1.50 (m, 2H), 1.42 (s, 6H). ESI-MS: m/z 436.2 [M+H]+. Compound 514 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 8.80 (m, 1 Η), 8.41 (m, 1H), 7.62 (m, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6.62 (d, J= 8.8 Hz, 2H), 6.43 (d, J= 7.6 Hz, 1H), 3.66 (m, 3H), 2.50 (t, J= 11.2 Hz, 2H), 2.41 ( s, 3H), 2.02 (d, J = 12.1 Hz, 2H), 1.60 - 1.50 (m, 2H), 1.42 (s, 6H). ESI-MS: m/z 436.2 [M+H] + .
实施例 382  Example 382
5-(3,4-二氟苯氧基) -2,2-二甲基 -N-(l-((4-甲基吡啶 -3-基） 磺酰基） 哌啶 -4-基） 戊酰胺 (化合物 515 )  5-(3,4-Difluorophenoxy)-2,2-dimethyl-N-(l-((4-methylpyridin-3-yl)sulfonyl)piperidin-4-yl)penta Amide (compound 515)
参照实施例 119的方法制得化合物 515: 1H MR (300 MHz, DMSO- 6) δ 8.90 (s, 1Η),Compound 515 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.90 (s, 1 Η),
8.46 (m, 1H), 7.46 (m, 1H), 7.29 (m, 2H), 7.01 (m, 1H), 6.72 (d, J = 7.6 Hz, 1H), 3.89 (m, 2H), 3.64 (m, 3H), 2.50 (m, 2H), 2.36 (s, 3H), 1.84 - 1.62 (m, 2H), 1.53 (s, 6H), 1.05 (s, 6H). ESI-MS: m/z 396.2 [M+H]+. 8.46 (m, 1H), 7.46 (m, 1H), 7.29 (m, 2H), 7.01 (m, 1H), 6.72 (d, J = 7.6 Hz, 1H), 3.89 (m, 2H), 3.64 (m , 3H), 2.50 (m, 2H), 2.36 (s, 3H), 1.84 - 1.62 (m, 2H), 1.53 (s, 6H), 1.05 (s, 6H). ESI-MS: m/z 396.2 [ M+H] + .
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反式 -3-((4-(5-(2,4-二氟苯氧基) -2,2-二甲基戊酰胺基) -2-甲基哌啶 -1-基；） 磺酰基)苯甲 酸 （化合物 521 )  Trans-3-((4-(5-(2,4-difluorophenoxy)-2,2-dimethylpentanyl)-2-methylpiperidin-1-yl;) sulfonyl Benzoic acid (compound 521)
参照实施例 364的方法制得化合物 521： 1H MR (300 MHz, DMSO- 6) δ 13.52 (s, 1H): 8.28 (m, IH), 8.19 (m, IH), 8.02 - 7.93 (m, IH), 7.79 (t, J= 7.8 Hz, IH), 7.31 (m, IH), 7.12 (dd, J= 9.4, 5.5 Hz, IH), 6.98 (t, J= 8.9 Hz, IH), 3.94 (m, 2H), 3.67 - 3.48 (m, 3H), 2.39 (m, IH), 1.70 (d, J = 12.6 Hz, 2H), 1.61 - 1.40 (m, 6H), 1.10 (s, 6H), 1.06 (d, J = 6.8 Hz, 3H). ESI-MS: m/z 561.2 [M+Na]+. Compound 521 was prepared by the method of Example 364: 1H MR (300 MHz, DMSO- 6 ) δ 13.52 (s, 1H): 8.28 (m, IH), 8.19 (m, IH), 8.02 - 7.93 (m, IH ), 7.79 (t, J= 7.8 Hz, IH), 7.31 (m, IH), 7.12 (dd, J= 9.4, 5.5 Hz, IH), 6.98 (t, J= 8.9 Hz, IH), 3.94 (m , 2,,,,, d, J = 6.8 Hz, 3H). ESI-MS: m/z 561.2 [M+Na] + .
实施例 389  Example 389
反式 -3-((4-(5-(3,4-二氟苯氧基) -2,2-二甲基戊酰胺基) -2-甲基哌啶 -1-基；） 磺酰基)苯甲 酸 （化合物 522)  Trans-3-((4-(5-(3,4-difluorophenoxy)-2,2-dimethylpentanoyl)-2-methylpiperidin-1-yl;) sulfonyl Benzoic acid (compound 522)
参照实施例 364的方法制得化合物 522: 1H MR (300 MHz, DMSO- 6) δ 12.80 (s, 1H): 8.33 (m, 2H), 7.84 (d, J = 8.1 Hz, 2H), 7.68 (m, 2H), 7.40 (m, IH), 6.88 (m, IH), 3.88 (m, 2H), 3.62 (d, J= 12.0 Hz, 2H), 3.37 (d, J= 37.2 Hz, IH), 2.40 (m, IH), 1.70 (d, J= 10.5 Hz, 2H), 1.62 - 1.41 (m, 6H), 1.10 (s, 6H), 1.06 (d, J= 6.8 Hz, 3H). ESI-MS: m/z 561.2 [M+Na]+. 实施例 390 Compound 522 was obtained by the method of Example 364: 1H MR (300 MHz, DMSO- 6 ) δ 12.80 (s, 1H): 8.33 (m, 2H), 7.84 (d, J = 8.1 Hz, 2H), 7.68 ( m, 2H), 7.40 (m, IH), 6.88 (m, IH), 3.88 (m, 2H), 3.62 (d, J = 12.0 Hz, 2H), 3.37 (d, J = 37.2 Hz, IH), 2.40 (m, IH), 1.70 (d, J = 10.5 Hz, 2H), 1.62 - 1.41 (m, 6H), 1.10 (s, 6H), 1.06 (d, J = 6.8 Hz, 3H). ESI-MS : m/z 561.2 [M+Na] + . Example 390
反式—4- ( (3善 4- ( 5- (4-氟苯氧基) -2,2-二甲基戊酰氨基) 哌啶 -1-基）磺酰基）苯 甲酸 （化合物 523 )  Trans-4-((3 good 4-(5-(4-fluorophenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 523)
参照实施例 139的方法制得化合物 523： 1H MR (300 MHz, DMSO- 6) δ 13.49 (s, 1H): 8.16 (d, J= 8.1 Hz, 2H), 7.90 (d, J= 8.1 Hz, 2H), 7.43 (d, J= 8.2 Hz, IH), 7.09 (t, J= 8.8 Hz, 2H), 6.95 - 6.85 (m, 2H), 4.71 - 4.43 (m, IH), 3.98 - 3.74 (m, 4H), 3.55 - 3.45 (m, IH), 2.76 - 2.56 (m, 2H), 1.84 - 1.69 (m, IH), 1.65 - 1.44 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 547.2 [M+Na]+. Compound 523 was obtained by the method of Example 139: 1H MR (300 MHz, DMSO- 6 ) δ 13.49 (s, 1H): 8.16 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 8.1 Hz, 2H), 7.43 (d, J= 8.2 Hz, IH), 7.09 (t, J= 8.8 Hz, 2H), 6.95 - 6.85 (m, 2H), 4.71 - 4.43 (m, IH), 3.98 - 3.74 (m , 4H), 3.55 - 3.45 (m, IH), 2.76 - 2.56 (m, 2H), 1.84 - 1.69 (m, IH), 1.65 - 1.44 (m, 5H), 1.07 (s, 6H). ESI-MS : m/z 547.2 [M+Na] + .
实施例 391  Example 391
反式—4- ( (3善 4- ( 5- (4-氟苯氧基) -2,2-二甲基戊酰胺基) 哌啶 -1-基）磺酰基）苯 甲酸 2-乙酰氨基乙酯 （化合物 524)  Trans-4-((3,4-(5-(4-fluorophenoxy)-2,2-dimethylpentanyl)piperidin-1-yl)sulfonyl)benzoic acid 2-acetamido Ethyl ester (compound 524)
以化合物 523 (实施例 390)为原料，参照实施例 183的方法制得化合物 524: 1H MR (300 MHz, DMSO- e) δ 8.20 (d, J= 8.2 Hz, 2H), 8.08 (t, J= 4.9 Hz, IH), 7.93 (d, J= 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, IH), 7.13 - 7.03 (m, 2H), 6.94 - 6.85 (m, 2H), 4.70 - 4.43 (m, IH), 4.31 (t, J = 5.5 Hz, 2H), 3.94 - 3.78 (m, 4H), 3.58 - 3.48 (m, IH), 3.48 - 3.38 (m, 2H), 2.74 - 2.56 (m, 2H), 1.83 (s, 3H), 1.79 - 1.69 (m, IH), 1.63 - 1.47 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 632.2 [M+Na]+. Using Compound 523 (Example 390) as a starting material, Compound 524 was obtained by the procedure of Example 183: 1H MR (300 MHz, DMSO-e) δ 8.20 (d, J = 8.2 Hz, 2H), 8.08 (t, J = 4.9 Hz, IH), 7.93 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, IH), 7.13 - 7.03 (m, 2H), 6.94 - 6.85 (m, 2H), 4.70 - 4.43 (m, IH), 4.31 (t, J = 5.5 Hz, 2H), 3.94 - 3.78 (m, 4H), 3.58 - 3.48 (m, IH), 3.48 - 3.38 (m, 2H), 2.74 - 2.56 (m, 2H), 1.83 (s, 3H), 1.79 - 1.69 (m, IH), 1.63 - 1.47 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 632.2 [M+Na ] + .
实施例 392 5- (4-氯苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (吗啉 -4-羰基） 苯基） 磺酰基） 哌啶 -4- 基） 戊酰胺 （化合物 525 ) Example 392 5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholin-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)penta Amide (compound 525)
以化合物 475 (实施例 342)为原料，参照实施例 101的方法制得化合物 525: 1H MR (300 MHz, CDCI3-6 δ 7.81 (d, J= 8.0 Hz, 2H), 7.56 (d, J= 8.0 Hz, 2H), 7.24 - 7.19 (m, 2H), 6.85 - 6.72 (m, 2H), 5.50 (d, J = 7.7 Hz, 1H), 3.88 (t, J = 5.4 Hz, 2H), 3.84 - 3.55 (m, 9H), 3.51 - 3.29 (m, 2H), 2.55 - 2.38 (m, 2H), 2.02 - 1.89 (m, 2H), 1.73 - 1.62 (m, 4H), 1.49 (dd, J = 12.0, 3.9 Hz, 2H), 1.17 (s, 6H). ESI-MS: m/z 614.3 [M+Na]+. Using compound 475 (Example 342) as a starting material, compound 525 was obtained by the method of Example 101: 1H MR (300 MHz, CDCI3-6 δ 7.81 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.24 - 7.19 (m, 2H), 6.85 - 6.72 (m, 2H), 5.50 (d, J = 7.7 Hz, 1H), 3.88 (t, J = 5.4 Hz, 2H), 3.84 - 3.55 (m, 9H), 3.51 - 3.29 (m, 2H), 2.55 - 2.38 (m, 2H), 2.02 - 1.89 (m, 2H), 1.73 - 1.62 (m, 4H), 1.49 (dd, J = 12.0 , 3.9 Hz, 2H), 1.17 (s, 6H). ESI-MS: m/z 614.3 [M+Na] + .
实施例 393  Example 393
5-(4-氯苯氧基) -N- ( 1- ( (4-(N-环丙基磺酰胺)-苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲 基戊酰胺 （化合物 526) 5- (4-Chlorophenoxy)-N-(1-((4-(N-cyclopropylsulfonamide)-phenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Radicotamide (Compound 526)
参照实施例 119的方法制得化合物 526: 1H MR (300 MHz, DMSO- 6) δ 8.22 - 8.09 (m, 1H), 8.03 (d, J = 8.2 Hz, 2H), 7.95 (d, J= 8.3 Hz, 2H), 7.35 - 7.25 (m, 2H), 7.21 (d, J =Compound 526 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.22 - 8.09 (m, 1H), 8.03 (d, J = 8.2 Hz, 2H), 7.95 (d, J = 8.3 Hz, 2H), 7.35 - 7.25 (m, 2H), 7.21 (d, J =
7.7 Hz, 1H), 6.96 - 6.84 (m, 2H), 3.87 (t, J = 8.3 Hz, 2H), 3.69 - 3.46 (m, 3H), 2.42 (t, J = 12.6 Hz, 2H), 2.16 (dq, J = 7.0, 3.5 Hz, 1H), 1.69 (m, 2H), 1.60 - 1.38 (m, 6H), 1.04 (s, 6H), 0.48 (dd, J= 7.1, 4.6 Hz, 2H), 0.37 (dd, J= 3.9 Hz, 2H). ESI-MS: m/z 620.2 [M+Na]+. 7.7 Hz, 1H), 6.96 - 6.84 (m, 2H), 3.87 (t, J = 8.3 Hz, 2H), 3.69 - 3.46 (m, 3H), 2.42 (t, J = 12.6 Hz, 2H), 2.16 ( Dq, J = 7.0, 3.5 Hz, 1H), 1.69 (m, 2H), 1.60 - 1.38 (m, 6H), 1.04 (s, 6H), 0.48 (dd, J= 7.1, 4.6 Hz, 2H), 0.37 (dd, J = 3.9 Hz, 2H). ESI-MS: m/z 620.2 [M+Na] + .
实施例 394  Example 394
2-(4-氯苯氧基) -N- ( 1- ( (4-(N-环丙基磺酰胺)-苯基） 磺酰基） 哌啶 -4-基） -2-甲基 丙酰胺 （化合物 527) 2- (4-Chlorophenoxy)-N-(1-((4-(N-cyclopropylsulfonamide)-phenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide (Compound 527)
参照实施例 14的方法制得化合物 527: 1H MR (300 MHz, DMSO- 6) δ 8.16 (d, J =Compound 527 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 8.16 (d, J =
2.8 Hz, 1H), 8.06 - 7.94 (m, 4H), 7.92 (s, 1H), 7.29 (d, J = 8.8 Hz, 2H), 6.83 (d, J= 8.8 Hz, 2H), 3.69 - 3.50 (m, 3H), 2.43 (d, J= 11.9 Hz, 2H), 2.21 - 2.10 (m, 1H), 1.69 (d, J= 12.5 Hz, 2H), 1.54 (t, J = 11.3 Hz, 2H), 1.38 (s, 6H), 0.48 (dd, J = 7.2, 4.8 Hz, 2H), 0.37 (dd, J = 3.6 Hz, 2H). ESI-MS: m/z 578.2 [M+Na]+. 2.8 Hz, 1H), 8.06 - 7.94 (m, 4H), 7.92 (s, 1H), 7.29 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 3.69 - 3.50 ( m, 3H), 2.43 (d, J = 11.9 Hz, 2H), 2.21 - 2.10 (m, 1H), 1.69 (d, J = 12.5 Hz, 2H), 1.54 (t, J = 11.3 Hz, 2H), 1.38 (s, 6H), 0.48 (dd, J = 7.2, 4.8 Hz, 2H), 0.37 (dd, J = 3.6 Hz, 2H). ESI-MS: m/z 578.2 [M+Na] + .
实施例 395  Example 395
( ( (3R,4R) -4- ( 5- (2,5-二氯苯氧基) -2,2-二甲基戊酰氨基) -3-氟哌啶小基）磺 酰基） 苯甲酸 （化合物 528)  ((3R,4R)-4-(5-(2,5-Dichlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidinyl)sulfonyl)benzoic acid (compound 528)
参照实施例 281的方法制得化合物 528: ee>99%; 1H NMR (300 MHz, DMSO- 6) δ 13.47 (s, 1H), 8.16 (d, J= 8.1 Hz, 2H), 7.90 (d, J= 8.2 Hz, 2H), 7.43 (d, J= 8.4 Hz, 2H), 7.19 (s, 1H), 7.04 - 6.96 (m, 1H), 4.71 - 4.44 (m, 1H), 4.07 - 3.97 (m, 2H), 3.92 - 3.77 (m, 2H), 3.58 - 3.45 ( m, 1H), 2.57 - 2.34 (m, 2H), 1.81 - 1.70 (m, 1H), 1.57 (s, 5H), 1.08 (s, 6H). ESI-MS: m/z 597.3 [M+Na]+. Compound 528 was obtained by the method of Example 281: ee >99%; 1H NMR (300 MHz, DMSO- 6 ) δ 13.47 (s, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.19 (s, 1H), 7.04 - 6.96 (m, 1H), 4.71 - 4.44 (m, 1H), 4.07 - 3.97 (m , 2,,,,,,,,, , 6H). ESI-MS: m/z 597.3 [M+Na] + .
实施例 396  Example 396
反式—3- ( (4- ( 5- (2,5-二氯苯氧基) -2,2-二甲基戊酰氨基) -3-氟哌啶 -1-基) 磺酰 基） 苯甲酸 （化合物 529) 参照实施例 139的方法制得化合物 529: 1H MR (300 MHz, DMSO- 6) δ 8.29 - 8.16 (m, 2H), 8.03 (d, J = 7.9 Hz, 1H), 7.84 - 7.75 (m, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.23 - 7.16 (m, 1H), 7.06-6.97 (m, 1H), 4.70 - 4.46 (m, 1H), 4.08-3.98 (m, 2H), 3.92 - 3.76 (m, 2H), 3.56 - 3.41 (m, 1H) , 2.75 - 2.55 (m, 2H), 1.82 - 1.71 (m, 1H)， 1.66 - 1.49 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 597.1 [M+Na]+. Trans-3-((4-(5-(2,5-dichlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Formic acid (compound 529) Compound 529 was prepared by the method of Example 139: 1H MR (300 MHz, DMSO- 6 ) δ 8.29 - 8.16 (m, 2H), 8.03 (d, J = 7.9 Hz, 1H), 7.84 - 7.75 (m, 1H) ), 7.43 (d, J = 8.4 Hz, 2H), 7.23 - 7.16 (m, 1H), 7.06-6.97 (m, 1H), 4.70 - 4.46 (m, 1H), 4.08-3.98 (m, 2H), 3.92 - 3.76 (m, 2H), 3.56 - 3.41 (m, 1H), 2.75 - 2.55 (m, 2H), 1.82 - 1.71 (m, 1H), 1.66 - 1.49 (m, 5H), 1.07 (s, 6H ESI-MS: m/z 597.1 [M+Na] + .
实施例 397  Example 397
3- ( ( (3R,4R) -4- ( 5- (2,5-二氯苯氧基) -2,2-二甲基戊酰氨基) -3-氟哌啶 -1-基) 磺 酰基） 苯甲酸 （化合物 530)  3-((3R,4R)-4-(5-(2,5-Dichlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl) sulfonate Acyl) benzoic acid (compound 530)
参照实施例 281的方法制得化合物 530: ee>99%; 1H NMR (300 MHz, DMSO- 6) δ 13.52 (s, 1H), 8.31 - 8.18 (m, 2H), 8.02 (d, J= 7.6 Hz, 1H), 7.85 - 7.75 (m, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.24 - 7.16 (m, 1H), 7.01 (d, J = 8.4 Hz, 1H), 4.72 - 4.45 (m, 1H), 4.10 - 3.97 (m, 2H), 3.93 - 3.75 (m, 2H), 3.56 - 3.45 (m, 1H), 2.75 - 2.56 (m, 2H), 1.83 - 1.71 (m, 1H),Compound 530 was obtained by the method of Example 281: ee >99%; 1H NMR (300 MHz, DMSO- 6 ) δ 13.52 (s, 1H), 8.31 - 8.18 (m, 2H), 8.02 (d, J = 7.6 Hz, 1H), 7.85 - 7.75 (m, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.24 - 7.16 (m, 1H), 7.01 (d, J = 8.4 Hz, 1H), 4.72 - 4.45 (m, 1H), 4.10 - 3.97 (m, 2H), 3.93 - 3.75 (m, 2H), 3.56 - 3.45 (m, 1H), 2.75 - 2.56 (m, 2H), 1.83 - 1.71 (m, 1H) ,
1.66 - 1.46 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 597.2 [M+Na]+. 1.66 - 1.46 (m, 5H), 1.07 (s, 6H). ESI-MS: m/z 597.2 [M+Na] + .
实施例 398  Example 398
2- (4-氟苯氧基） -2-甲基 -N- ( 1- ( (4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 （化合物 531 )  2-(4-Fluorophenoxy)-2-methyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide (Compound 531)
参照实施例 14的方法制得化合物 531 : 1H MR (300 MHz, DMSO- 6) δ 8.22 - 8.14 (m, 2H), 8.04 - 7.94 (m, 3H), 7.15 - 7.04 (m, 2H), 6.93 - 6.83 (m, 2H), 3.71 - 3.55 (m, 3H), 3.31 (s, 3H), 2.49 - 2.43 (m, 2H), 1.79 - 1.65 (m, 2H), 1.65 - 1.47 (m, 2H), 1.36 (s, 6H). ESI-MS: m/z 521.2 [M+Na]+. Compound 531 was obtained by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 8.22 - 8.14 (m, 2H), 8.04 - 7.94 (m, 3H), 7.15 - 7.04 (m, 2H), 6.93 - 6.83 (m, 2H), 3.71 - 3.55 (m, 3H), 3.31 (s, 3H), 2.49 - 2.43 (m, 2H), 1.79 - 1.65 (m, 2H), 1.65 - 1.47 (m, 2H) , 1.36 (s, 6H). ESI-MS: m/z 521.2 [M+Na] + .
实施例 399  Example 399
2- (4-氟苯氧基） -N- ( 1- ( ( 3-氟苯基） 磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 （化合 物 532)  2-(4-Fluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (Compound 532)
参照实施例 14的方法制得化合物 532: 1H NMR (300 MHz, CDC13) δ 7.59 - 7.50 (m, 2H), 7.50 - 7.43 (m, 1H), 7.38 - 7.27 (m, 1H), 7.02 - 6.91 (m, 2H), 6.90 - 6.81 (m, 2H), 6.63 (d, J = 8.1 Hz, 1H), 3.85 - 3.71 (m, 3H), 2.60 - 2.46 (m, 2H), 2.07 - 1.95 (m, 2H), 1.64 - 1.48 (m, 2H), 1.43 (s, 6H). ESI-MS: m/z 461.2 [M+Na]+. Compound 532 was obtained by the method of Example 14: 1H NMR (300 MHz, CDC1 3 ) δ 7.59 - 7.50 (m, 2H), 7.50 - 7.43 (m, 1H), 7.38 - 7.27 (m, 1H), 7.02 - 6.91 (m, 2H), 6.90 - 6.81 (m, 2H), 6.63 (d, J = 8.1 Hz, 1H), 3.85 - 3.71 (m, 3H), 2.60 - 2.46 (m, 2H), 2.07 - 1.95 ( m, 2H), 1.64 - 1.48 (m, 2H), 1.43 (s, 6H). ESI-MS: m/z 461.2 [M+Na] + .
实施例 400  Example 400
反式 -5- (2,5-二氯苯氧基） -N - (3-氟 -1 - ( (3-氟苯基） 磺酰基） 哌啶 -4-基） -2,2-二 甲基戊酰胺 （化合物 533 )  Trans-5-(2,5-dichlorophenoxy)-N-(3-fluoro-1 -((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-di Methyl pentamide (compound 533)
参照实施例 139的方法制得化合物 533 : 1H NMR (300 MHz, CDC13) δ 7.59 - 7.53 (m, 2H), 7.51 - 7.45 (m, 1H), 7.39 - 7.31 (m, 1H), 7.30 - 7.26 (m, 1H), 6.91 - 6.85 (m, 2H), 5.69 (d, J = 7.5 Hz, 1H), 4.60 - 4.32 (m, 1H), 4.14 - 4.03 (m, 1H), 4.01 - 3.92 (m, 3H), 3.77 -Compound 533 was obtained by the method of Example 139: 1H NMR (300 MHz, CDC1 3 ) δ 7.59 - 7.53 (m, 2H), 7.51 - 7.45 (m, 1H), 7.39 - 7.31 (m, 1H), 7.30 - 7.26 (m, 1H), 6.91 - 6.85 (m, 2H), 5.69 (d, J = 7.5 Hz, 1H), 4.60 - 4.32 (m, 1H), 4.14 - 4.03 (m, 1H), 4.01 - 3.92 ( m, 3H), 3.77 -
3.67 (m, 1H), 2.56 - 2.43 (m, 2H), 2.19 - 2.07 (m, 1H), 1.79 - 1.69 (m, 4H), 1.29 - 1.23 (m, 1H), 1.21 (s, 6H). ESI-MS: m/z 571.2 [M+Na] . 3.67 (m, 1H), 2.56 - 2.43 (m, 2H), 2.19 - 2.07 (m, 1H), 1.79 - 1.69 (m, 4H), 1.29 - 1.23 (m, 1H), 1.21 (s, 6H). ESI-MS: m/z 571.2 [M+Na].
实施例 401  Example 401
5- (4-氟苯氧基） -2,2-二甲基 -N- ( 1- (喹啉 -8-基磺酰基） 哌啶 -4-基） 戊酰胺 （化合 物 534)  5-(4-Fluorophenoxy)-2,2-dimethyl-N-(1-(quinolin-8-ylsulfonyl)piperidin-4-yl)pentanamide (Compound 534)
参照实施例 119的方法制得化合物 534: 1H NMR (300 MHz, CDC13) δ 9.08 - 9.01 (m, 1H), 8.52 - 8.43 (m, 1H), 8.27 - 8.20 (m, 1H), 8.07 - 7.99 (m, 1H), 7.68 - 7.57 (m, 1H), 7.57 - 7.48 (m, 1H), 7.01 - 6.89 (m, 2H), 6.84 - 6.74 (m, 2H), 5.55 (d, J = 7.6 Hz, 1H), 4.18 -Compound 534 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 9.08 - 9.01 (m, 1H), 8.52 - 8.43 (m, 1H), 8.27 - 8.20 (m, 1H), 8.07 - 7.99 (m, 1H), 7.68 - 7.57 (m, 1H), 7.57 - 7.48 (m, 1H), 7.01 - 6.89 (m, 2H), 6.84 - 6.74 (m, 2H), 5.55 (d, J = 7.6 Hz, 1H), 4.18 -
4.02 (m, 2H), 3.94 - 3.74 (m, 3H), 2.98 - 2.83 (m, 2H), 2.03 - 1.88 (m, 2H), 1.74 - 1.59 (m, 4H), 1.56 - 1.43 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 536.3 [M+Na]+. 4.02 (m, 2H), 3.94 - 3.74 (m, 3H), 2.98 - 2.83 (m, 2H), 2.03 - 1.88 (m, 2H), 1.74 - 1.59 (m, 4H), 1.56 - 1.43 (m, 2H ), 1.17 (s, 6H). ESI-MS: m/z 536.3 [M+Na] + .
实施例 402  Example 402
5- (4-氯苯氧基） -2,2-二甲基 -N- ( 1- (喹啉 -8-基磺酰基） 哌啶 -4-基） 戊酰胺 （化合 物 535 )  5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-(quinolin-8-ylsulfonyl)piperidin-4-yl)pentanamide (Compound 535)
参照实施例 119的方法制得化合物 535: 1H NMR (300 MHz, CDC13) δ 9.08 - 9.02 (m, 1H), 8.50 - 8.44 (m, 1H), 8.27 - 8.21 (m, 1H), 8.06 - 8.00 (m, 1H), 7.67 - 7.57 (m, 1H), 7.56 - 7.49 (m, 1H), 7.24 - 7.15 (m, 2H), 6.82 - 6.72 (m, 2H), 5.53 (d, J = 7.4 Hz, 1H), 4.16 - 4.04 (m, 2H), 3.94 - 3.77 (m, 3H), 2.98 - 2.84 (m, 2H), 2.01 - 1.88 (m, 2H), 1.75 - 1.61 (m, 4H), 1.55 - 1.45 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 552.2 [M+Na]+. Compound 535 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 9.08 - 9.02 (m, 1H), 8.50 - 8.44 (m, 1H), 8.27 - 8.21 (m, 1H), 8.06 - 8.00 (m, 1H), 7.67 - 7.57 (m, 1H), 7.56 - 7.49 (m, 1H), 7.24 - 7.15 (m, 2H), 6.82 - 6.72 (m, 2H), 5.53 (d, J = 7.4 Hz, 1H), 4.16 - 4.04 (m, 2H), 3.94 - 3.77 (m, 3H), 2.98 - 2.84 (m, 2H), 2.01 - 1.88 (m, 2H), 1.75 - 1.61 (m, 4H), 1.55 - 1.45 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 552.2 [M+Na] + .
实施例 403  Example 403
4- ( (4- (2- (4-氟苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基）磺酰基） 苯甲酸 (2-乙酰氨 基)乙酯 （化合物 536)  4-((4-(2-(4-Fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (2-acetamido)ethyl ester (Compound 536)
参照实施例 14和 183的方法制得化合物 536: 1H MR (300 MHz, CDC13) δ 8.25 - 8.15 (m, 2H), 7.90 - 7.79 (m, 2H), 7.01 - 6.91 (m, 2H), 6.90 - 6.80 (m, 2H), 6.63 (d, J = 7.3 Hz, 1H), 5.88 - 5.74 (m, 1H), 4.53 - 4.43 (m, 2H), 3.83 - 3.72 (m, 3H), 3.72 - 3.63 (m, 2H), 2.58 - 2.44 (m, 2H), 2.01 (s, 3H), 2.00 - 1.95 (m, 2H), 1.58 - 1.50 (m, 2H), 1.43 (s, 6H). ESI-MS: m/z 572.3 [M+Na]+. Compound 536 was prepared by the methods of Examples 14 and 183: 1H MR (300 MHz, CDC1 3 ) δ 8.25 - 8.15 (m, 2H), 7.90 - 7.79 (m, 2H), 7.01 - 6.91 (m, 2H), 6.90 - 6.80 (m, 2H), 6.63 (d, J = 7.3 Hz, 1H), 5.88 - 5.74 (m, 1H), 4.53 - 4.43 (m, 2H), 3.83 - 3.72 (m, 3H), 3.72 - 3.63 (m, 2H), 2.58 - 2.44 (m, 2H), 2.01 (s, 3H), 2.00 - 1.95 (m, 2H), 1.58 - 1.50 (m, 2H), 1.43 (s, 6H). ESI- MS: m/z 572.3 [M+Na] + .
实施例 404  Example 404
3- ( (4- (2- (4-氟苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 （化合物 537)  3-((4-(2-(4-Fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 537)
参照实施例 14的方法制得化合物 537: 1H MR (300 MHz, DMSO- 6) δ 13.32 (s, 1H), 8.28 - 8.22 (m, 1H), 8.21 - 8.16 (m, 1H), 8.01 - 7.91 (m, 2H), 7.83 - 7.74 (m, 1H), 7.13 -Compound 537 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 13.32 (s, 1H), 8.28 - 8.22 (m, 1H), 8.21 - 8.16 (m, 1H), 8.01 - 7.91 (m, 2H), 7.83 - 7.74 (m, 1H), 7.13 -
7.03 (m, 2H), 6.92 - 6.82 (m, 2H), 3.69 - 3.52 (m, 3H), 2.47 - 2.37 (m, 2H), 1.80 - 1.66 (m, 2H), 1.65 - 1.48 (m, 2H), 1.35 (s, 6H). ESI-MS: m/z 463.1 [M-H]". 7.03 (m, 2H), 6.92 - 6.82 (m, 2H), 3.69 - 3.52 (m, 3H), 2.47 - 2.37 (m, 2H), 1.80 - 1.66 (m, 2H), 1.65 - 1.48 (m, 2H ), 1.35 (s, 6H). ESI-MS: m/z 463.1 [MH]".
实施例 405  Example 405
4- ( ( (3R,4R) -3-氟 -4- (2- (4-氟苯氧基) -2-甲基丙酰氨基) 哌啶 -1-基） 磺酰基） 苯甲酸 （化合物 538) 4-((3R,4R)-3-fluoro-4-(2-(4-fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl) Benzoic acid (compound 538)
参照实施例 14和 281的方法制得化合物 538: 1H NMR (300 MHz, DMSO- 6) δ 13.48 (s, 1Η), 8.29 - 8.21 (m, 1H), 8.19 - 8.12 (m, 2H), 7.93 - 7.85 (m, 2H), 7.13 - 7.03 (m, 2H),The compound 538 was obtained by the method of Example 14 and 281: 1H NMR (300 MHz, DMSO- 6 ) δ 13.48 (s, 1 Η), 8.29 - 8.21 (m, 1H), 8.19 - 8.12 (m, 2H), 7.93 - 7.85 (m, 2H), 7.13 - 7.03 (m, 2H),
6.94 - 6.84 (m, 2H), 4.75 - 4.48 (m, 1H), 4.01 - 3.74 (m, 2H), 3.55 - 3.42 (m, 1H), 2.76 - 2.57 (m, 2H), 1.86 - 1.71 (m, 1H), 1.70 - 1.51 (m, 1H), 1.40 - 1.32 (m, 6H). ESI-MS: m/z 481.1 [M-H]". 6.94 - 6.84 (m, 2H), 4.75 - 4.48 (m, 1H), 4.01 - 3.74 (m, 2H), 3.55 - 3.42 (m, 1H), 2.76 - 2.57 (m, 2H), 1.86 - 1.71 (m , 1H), 1.70 - 1.51 (m, 1H), 1.40 - 1.32 (m, 6H). ESI-MS: m/z 481.1 [MH]".
实施例 406  Example 406
N- ( (3R,4R) -3-氟 -1 - ( (4- (甲基磺酰基） 苯基）磺酰基） 哌啶 -4-基） -2- (4-氟苯 氧基） -2-甲基丙酰胺 （化合物 539)  N-((3R,4R)-3-fluoro-1 -((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-2-(4-fluorophenoxy)- 2-methylpropionamide (compound 539)
参照实施例 14和 281的方法制得化合物 539: 1H MR (300 MHz, DMSO- 6) δ 8.30 - 8.23 (m, 1H), 8.22 - 8.15 (m, 2H), 8.08 - 8.01 (m, 2H), 7.14 - 7.05 (m, 2H), 6.96 - 6.85 (m, 2H), 4.76 - 4.50 (m, 1H), 4.03 - 3.78 (m, 2H), 3.58 - 3.44 (m, 1H), 3.32 (s, 3H), 2.79 - 2.60 (m, 2H), 1.84 - 1.72 (m, 1H), 1.71 - 1.51 (m, 1H), 1.41 - 1.30 (m, 6H). ESI-MS: m/z 539.2 [M+Na]+. Compound 539 was prepared by the methods of Examples 14 and 281: 1H MR (300 MHz, DMSO- 6 ) δ 8.30 - 8.23 (m, 1H), 8.22 - 8.15 (m, 2H), 8.08 - 8.01 (m, 2H) , 7.14 - 7.05 (m, 2H), 6.96 - 6.85 (m, 2H), 4.76 - 4.50 (m, 1H), 4.03 - 3.78 (m, 2H), 3.58 - 3.44 (m, 1H), 3.32 (s, 3H), 2.79 - 2.60 (m, 2H), 1.84 - 1.72 (m, 1H), 1.71 - 1.51 (m, 1H), 1.41 - 1.30 (m, 6H). ESI-MS: m/z 539.2 [M+ Na] + .
实施例 407  Example 407
3- ( ( (3R, 4R) -3-氟 -4- (2- (4-氟苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 （化合物 540)  3-(((3R, 4R)-3-fluoro-4-(2-(4-fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound) 540)
参照实施例 14和 281的方法制得化合物 540: 1H NMR (300 MHz, DMSO- 6) δ 13.56 (s, 1Η), 8.31 - 8.16 (m, 3H), 8.04 - 7.98 (m, 1H), 7.83 - 7.75 (m, 1H), 7.15 - 7.02 (m, 2H),The compound 540 was obtained by the method of Example 14 and 281: 1H NMR (300 MHz, DMSO- 6 ) δ 13.56 (s, 1 Η), 8.31 - 8.16 (m, 3H), 8.04 - 7.98 (m, 1H), 7.83 - 7.75 (m, 1H), 7.15 - 7.02 (m, 2H),
6.95 - 6.83 (m, 2H), 4.76 - 4.48 (m, 1H), 4.02 - 3.72 (m, 2H), 3.58 - 3.42 (m, 1H), 2.73 - 2.55 (m, 2H), 1.86 - 1.71 (m, 1H), 1.71 - 1.51 (m, 1H), 1.43 - 1.30 (m, 6H). ESI-MS: m/z 481.1 [M-H]". 6.95 - 6.83 (m, 2H), 4.76 - 4.48 (m, 1H), 4.02 - 3.72 (m, 2H), 3.58 - 3.42 (m, 1H), 2.73 - 2.55 (m, 2H), 1.86 - 1.71 (m , 1H), 1.71 - 1.51 (m, 1H), 1.43 - 1.30 (m, 6H). ESI-MS: m/z 481.1 [MH]".
实施例 408  Example 408
5- (4-氟苯氧基) -2,2-二甲基 -N- ( 1- ( (4- (吗啉 -4-羰基) 苯基） 磺酰基） 哌啶 -4- 基） 戊酰胺 （化合物 541 )  5-(4-fluorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholin-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)penta Amide (compound 541)
参照实施例 101的方法制得化合物 541 : 1H NMR (300 MHz, CDC13- ) δ 7.81 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.01 - 6.90 (m, 2H), 6.84 - 6.74 (m, 2H), 5.51 (d, J = 7.7 Hz, 1H), 3.87 (t, J = 5.2 Hz, 2H), 3.84 - 3.50 (m, 9H), 3.50 - 3.23 (m, 2H), 2.46 (td, J = 12.2, 1.7 Hz 2H), 2.03 - 1.90 (m, 2H), 1.75 - 1.60 (m, 4H), 1.54 - 1.41 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 598.3 [M+Na]+. The compound 541 was obtained by the method of Example 101: 1H NMR (300 MHz, CDC1 3 - ) δ 7.81 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.01 - 6.90 ( m, 2H), 6.84 - 6.74 (m, 2H), 5.51 (d, J = 7.7 Hz, 1H), 3.87 (t, J = 5.2 Hz, 2H), 3.84 - 3.50 (m, 9H), 3.50 - 3.23 (m, 2H), 2.46 (td, J = 12.2, 1.7 Hz 2H), 2.03 - 1.90 (m, 2H), 1.75 - 1.60 (m, 4H), 1.54 - 1.41 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 598.3 [M+Na] + .
实施例 409  Example 409
4- ( (4- (2-甲基 -2- (4- (甲基磺酰基） 苯氧基） 丙酰氨基） 哌啶 -1-基） 磺酰基） 苯 甲酸 (2-乙酰氨基；)乙酯 （化合物 542)  4-((4-(2-methyl-2-(4-(methylsulfonyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzoic acid (2-acetylamino;) Ethyl ester (compound 542)
参照实施例 14和 183的方法制得化合物 542: 1H MR (300 MHz, DMSO- 6) δ 8.19 (d, LZ 9 XUZ 'ZH 1·8 =Γ 'ρ) 869 UZ ¾i 6' L =Γ 'Ρ) L9'L XUZ ¾i Γ8 =Γ 'P) 08'乙 UZ ¾ 9.8 = riV) 1787.9 (P-HDQD '^H i 00 ε)霸 N HT :9 i#^ p$?^^ 101 P ¾$Sti Compound 542 was prepared by the methods of Examples 14 and 183: 1H MR (300 MHz, DMSO- 6 ) δ 8.19 (d, LZ 9 XUZ 'ZH 1·8 =Γ 'ρ) 869 UZ 3⁄4i 6' L =Γ 'Ρ) L9'L XUZ 3⁄4i Γ8 =Γ 'P) 08'B UZ 3⁄4 9.8 = r i V) 1787.9 (P- HDQD '^H i 00 ε) PA NH T : 9 i#^ p$?^^ 101 P 3⁄4$Sti
(9 (  (9 (
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Z.9ZC80/8T0ZN3/X3d I9^6l/810Z OAV (d, J= 8.0 Hz, 1H), 3.90 - 3.55 (m, 9H), 3.51 - 3.30 (m, 2H), 3.05 (s, 3H), 2.60 - 2.43 (m, 2H), 2.01 - 1.87 (m, 2H), 1.56 (s, 6H), 1.52 - 1.44 (m, 2H). ESI-MS: m/z 616.2 [M+Na]+. Z.9ZC80/8T0ZN3/X3d I9^6l/810Z OAV (d, J= 8.0 Hz, 1H), 3.90 - 3.55 (m, 9H), 3.51 - 3.30 (m, 2H), 3.05 (s, 3H), 2.60 - 2.43 (m, 2H), 2.01 - 1.87 (m , 2H), 1.56 (s, 6H), 1.52 - 1.44 (m, 2H). ESI-MS: m/z 616.2 [M+Na] + .
实施例 414  Example 414
4 - ( ( (3R,4R) -4- (2- (4-氯苯氧基) -2-甲基丙酰胺基) -3-氟哌啶 -1-基) 磺酰基） 苯甲酸 （化合物 547)  4-((3R,4R)-4-(2-(4-Chlorophenoxy)-2-methylpropionamido)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (compound) 547)
参照实施例 14和 281的方法制得化合物 547: ¾ NMR (300 MHz, DMSO-t/6) δ 13.50 (s, 1H), 8.25 (d, J= 8.5 Hz, 1H), 8.16 (d, J= 8.0 Hz, 2H), 7.87 (d, J= 8.1 Hz, 2H), 7.29 (d, J= 8.6 Hz, 2H), 6.85 (d, J= 8.5 Hz, 2H), 4.73 - 4.42 (m, 1H), 4.06 - 3.84 (m, 1H), 3.83 - 3.68 (m, 1H), 3.56 - 3.39 (m, 1H), 2.79 - 2.57 (m, 2H), 1.88 - 1.68 (m, 1H), 1.66 - 1.47 (m, 1H), 1.39 (d, J = 4.6 Hz, 6H). ESI-MS: m/z 497.1 [M-H]". Compound 547 was obtained by the method of Examples 14 and 281: 3⁄4 NMR (300 MHz, DMSO-t/ 6 ) δ 13.50 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 8.0 Hz, 2H), 7.87 (d, J= 8.1 Hz, 2H), 7.29 (d, J= 8.6 Hz, 2H), 6.85 (d, J= 8.5 Hz, 2H), 4.73 - 4.42 (m, 1H ), 4.06 - 3.84 (m, 1H), 3.83 - 3.68 (m, 1H), 3.56 - 3.39 (m, 1H), 2.79 - 2.57 (m, 2H), 1.88 - 1.68 (m, 1H), 1.66 - 1.47 (m, 1H), 1.39 (d, J = 4.6 Hz, 6H). ESI-MS: m/z 497.1 [MH]".
实施例 415  Example 415
5- (4-氯苯氧基） -2,2-二甲基 -N- ( 1- ( (4-氨磺酰基苯基）磺酰基） 哌啶 -4-基）戊酰 胺 （化合物 548)  5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-((4-sulfamoylphenyl)sulfonyl)piperidin-4-yl)pentanamide (Compound 548)
参照实施例 119的方法制得化合物 548: 1H MR (300 MHz, DMSO- 6) δ 8.05 (d, J = 8.3 Hz, 2H), 7.94 (d, J= 8.3 Hz, 2H), 7.63 (brs, 2H), 7.30 (d, J= 8.9 Hz, 2H), 7.24 (d, J= 7.8 Hz, 1H), 6.91 (d, J = 8.9 Hz, 2H), 3.98 - 3.80 (m, 2H), 3.70 - 3.59 (m, 2H), 3.59 - 3.48 (m, 1H), 2.47 - 2.34 (m, 2H), 1.79 - 1.64 (m, 2H), 1.62 - 1.39 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 580.2 [M+Na]+. Compound 548 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.05 (d, J = 8.3 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.63 (brs, 2H), 7.30 (d, J= 8.9 Hz, 2H), 7.24 (d, J= 7.8 Hz, 1H), 6.91 (d, J = 8.9 Hz, 2H), 3.98 - 3.80 (m, 2H), 3.70 - 3.59 (m, 2H), 3.59 - 3.48 (m, 1H), 2.47 - 2.34 (m, 2H), 1.79 - 1.64 (m, 2H), 1.62 - 1.39 (m, 6H), 1.05 (s, 6H). ESI-MS: m/z 580.2 [M+Na] + .
实施例 416  Example 416
5- (4-氯苯氧基） -2,2-二甲基 -N- ( 1- (吡啶 -4-磺酰基） 哌啶 -4-基） 戊酰胺 （化合物 549)  5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-(pyridine-4-sulfonyl)piperidin-4-yl)pentanamide (Compound 549)
参照实施例 119的方法制得化合物 549: 1H NMR (300 MHz, CDC13) δ 8.89 (d, J= 5.4 Hz, 2H), 7.69 - 7.53 (m, 2H), 7.23 (d, J = 8.9 Hz, 2H), 6.80 (d, J = 8.9 Hz, 2H), 5.56 (d, J = 7.8 Hz, 1H), 4.02 - 3.67 (m, 5H), 2.51 (td, J = 12.2, 2.6 Hz, 2H), 1.99 (dd, J = 13.3, 3.7 Hz, 2H), 1.62 -1.24 (m, 6H), 1.19 (s, 6H). ESI-MS: m/z 502.2 [M+Na]+. Compound 549 was prepared by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 8.89 (d, J = 5.4 Hz, 2H), 7.69 - 7.53 (m, 2H), 7.23 (d, J = 8.9 Hz , 2H), 6.80 (d, J = 8.9 Hz, 2H), 5.56 (d, J = 7.8 Hz, 1H), 4.02 - 3.67 (m, 5H), 2.51 (td, J = 12.2, 2.6 Hz, 2H) , 1.99 (dd, J = 13.3, 3.7 Hz, 2H), 1.62 - 1.24 (m, 6H), 1.19 (s, 6H). ESI-MS: m/z 502.2 [M+Na] + .
实施例 417  Example 417
2- (4-氯苯氧基） -2-甲基 -N- ( 1- (吡啶 -4-磺酰基）哌啶 -4-基）丙酰胺（化合物 550) 参照实施例 14的方法制得化合物 550: 1H MR (300 MHz, CDC13) δ 8.89 (d, J = 5.6 Hz, 2H), 7.61 (d, J= 5.7 Hz, 2H), 7.25 (d, J= 8.8 Hz, 2H), 6.83 (d, J= 8.8 Hz, 2H), 6.56 (d, J = 7.8 Hz, 1H), 3.90 - 3.70 (m, 3H), 2.58 (td, J = 12.2, 2.6 Hz, 2H), 2.02 (d, J= 12.7 Hz, 2H), 1.63 - 1.52 (m, 2H), 1.47 (s, 6H). ESI-MS: m/z 460.1 [M+Na]+. 2-(4-Chlorophenoxy)-2-methyl-N-(1-(pyridine-4-sulfonyl)piperidin-4-yl)propanamide (Compound 550) was obtained according to the method of Example 14. Compound 550: 1H MR (300 MHz, CDC1 3 ) δ 8.89 (d, J = 5.6 Hz, 2H), 7.61 (d, J = 5.7 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 7.8 Hz, 1H), 3.90 - 3.70 (m, 3H), 2.58 (td, J = 12.2, 2.6 Hz, 2H), 2.02 (d, J = 12.7 Hz, 2H), 1.63 - 1.52 (m, 2H), 1.47 (s, 6H). ESI-MS: m/z 460.1 [M+Na] + .
实施例 418  Example 418
5- (4-氟苯氧基） -2,2-二甲基 -N- ( 1- (吡啶 -4-磺酰基） 哌啶 -4-基） 戊酰胺 （化合物 551 ) 参照实施例 119的方法制得化合物 551 : 1H NMR (300 MHz, CDC13) δ 8.88 (d, J= 5.2 Hz, 2H), 7.67 - 7.51 (m, 2H), 7.09 - 6.87 (m, 2H), 6.79 (dd, J= 9.2, 4.2 Hz, 2H), 5.64 (d, J = 7.8 Hz, 1H), 4.02 - 3.62 (m, 5H), 2.49 (td, J= 12.1, 2.6 Hz, 2H), 2.09 - 1.87 (m, 2H), 1.64 - 1.22 (m, 6H), 1.17 (s, 6H). ESI-MS: m/z 486.2 [M+Na]+. 5-(4-Fluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-4-sulfonyl)piperidin-4-yl)pentanamide (Compound 551) Compound 551 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 8.88 (d, J = 5.2 Hz, 2H), 7.67 - 7.51 (m, 2H), 7.09 - 6.87 (m, 2H) , 6.79 (dd, J= 9.2, 4.2 Hz, 2H), 5.64 (d, J = 7.8 Hz, 1H), 4.02 - 3.62 (m, 5H), 2.49 (td, J= 12.1, 2.6 Hz, 2H), 2.09 - 1.87 (m, 2H), 1.64 - 1.22 (m, 6H), 1.17 (s, 6H). ESI-MS: m/z 486.2 [M+Na] + .
实施例 419  Example 419
2- (4-氟苯氧基） -2-甲基 -N- ( 1- (吡啶 -4-磺酰基）哌啶 -4-基）丙酰胺（化合物 552) 参照实施例 14的方法制得化合物 552: 1H MR (300 MHz, CDC13) δ 8.87 (d, J= 5.9 Hz, 2H), 7.60 (d, J = 6.0 Hz, 2H), 7.05 - 6.93 (m, 2H), 6.91 - 6.77 (m, 2H), 6.69 (d, J = 8.1 Hz, 1H), 3.96 - 3.64 (m, 3H), 2.56 (td, J= 12.0, 2.6 Hz, 2H), 2.02 (dd, J= 13.2, 3.7 Hz, 2H), 1.69 - 1.51 (m, 2H), 1.43 (s, 6H). ESI-MS: m/z 444.2 [M+Na]+. 2-(4-Fluorophenoxy)-2-methyl-N-(1-(pyridine-4-sulfonyl)piperidin-4-yl)propanamide (Compound 552) was obtained according to the method of Example 14. Compound 552: 1H MR (300 MHz, CDC1 3 ) δ 8.87 (d, J = 5.9 Hz, 2H), 7.60 (d, J = 6.0 Hz, 2H), 7.05 - 6.93 (m, 2H), 6.91 - 6.77 ( m, 2H), 6.69 (d, J = 8.1 Hz, 1H), 3.96 - 3.64 (m, 3H), 2.56 (td, J = 12.0, 2.6 Hz, 2H), 2.02 (dd, J= 13.2, 3.7 Hz , 2H), 1.69 - 1.51 (m, 2H), 1.43 (s, 6H). ESI-MS: m/z 444.2 [M+Na] + .
实施例 420  Example 420
5- (4-氯苯氧基） -2,2-二甲基 -N- ( 1- (吡啶 -2-磺酰基） 哌啶 -4-基） 戊酰胺 （化合物 553 )  5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-(pyridine-2-sulfonyl)piperidin-4-yl)pentanamide (Compound 553)
参照实施例 119的方法制得化合物 553 : 1H NMR (300 MHz, CDC13) δ 8.81 - 8.61 (m, 1H), 8.03 - 7.79 (m, 2H), 7.50 (dd, J= 4.6 Hz, 1H), 7.20 (d, J= 8.9 Hz, 2H), 6.78 (d, J= 8.9 Hz, 2H), 5.74 (d, J= 7.9 Hz, 1H), 4.15— 3.69 (m, 5H), 2.99 - 2.67 (m, 2H), 1.96 (dd, J= 12.9， 3.7 Hz, 2H), 1.77 - 1.45 (m, 6H), 1.18 (s, 6H). ESI-MS: m/z 502.2 [M+Na]+. Compound 553 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 8.81 - 8.61 (m, 1H), 8.03 - 7.79 (m, 2H), 7.50 (dd, J = 4.6 Hz, 1H) , 7.20 (d, J= 8.9 Hz, 2H), 6.78 (d, J= 8.9 Hz, 2H), 5.74 (d, J= 7.9 Hz, 1H), 4.15— 3.69 (m, 5H), 2.99 - 2.67 ( m, 2H), 1.96 (dd, J = 12.9, 3.7 Hz, 2H), 1.77 - 1.45 (m, 6H), 1.18 (s, 6H). ESI-MS: m/z 502.2 [M+Na] + .
实施例 421  Example 421
2- (4-氯苯氧基） -2-甲基 -N- ( 1- (吡啶 -2-磺酰基）哌啶 -4-基）丙酰胺（化合物 554) 参照实施例 14的方法制得化合物 554: 1H NMR (300 MHz, CDC13) δ 8.78 - 8.66 (m, 1H), 7.95 (dd, J= 3.9, 1.6 Hz, 2H), 7.61 - 7.43 (m, 1H), 7.25 (d, J= 8.8 Hz, 2H), 6.92 - 6.77 (m, 2H), 6.60 (d, J= 8.1 Hz, 1H), 4.02 - 3.80 (m, 3H), 2.95 (td, J= 12.2, 2.6 Hz, 2H), 2.13 - 1.86 (m, 2H), 1.63 - 1.53 (m, 2H), 1.50 (s, 6H). ESI-MS: m/z 460.1 [M+Na]+. 2-(4-Chlorophenoxy)-2-methyl-N-(1-(pyridine-2-sulfonyl)piperidin-4-yl)propanamide (Compound 554) was obtained according to the method of Example 14. Compound 554: 1H NMR (300 MHz, CDC1 3 ) δ 8.78 - 8.66 (m, 1H), 7.95 (dd, J = 3.9, 1.6 Hz, 2H), 7.61 - 7.43 (m, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.92 - 6.77 (m, 2H), 6.60 (d, J= 8.1 Hz, 1H), 4.02 - 3.80 (m, 3H), 2.95 (td, J= 12.2, 2.6 Hz, 2H) , 2.13 - 1.86 (m, 2H), 1.63 - 1.53 (m, 2H), 1.50 (s, 6H). ESI-MS: m/z 460.1 [M+Na] + .
实施例 422  Example 422
5- (4-氟苯氧基） -2,2-二甲基 -N- ( 1- (吡啶 -2-磺酰基） 哌啶 -4-基） 戊酰胺 （化合物 555 )  5-(4-Fluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-2-sulfonyl)piperidin-4-yl)pentanamide (Compound 555)
参照实施例 119的方法制得化合物 555: 1H NMR (300 MHz, CDC13) δ 8.82 - 8.62 (m, 1H), 8.05 - 7.83 (m, 2H), 7.51 (dd, J= 4.5 Hz, 1H), 7.06 - 6.88 (m, 2H), 6.88 - 6.69 (m, 2H), 5.80 (d, J = 7.9 Hz, 1H), 4.10 - 3.70 (m, 5H), 2.85 (td, J= 12.3, 2.5 Hz, 2H), 1.97 (dd, J = 12.9, 3.7 Hz, 2H), 1.65 - 1.25 (m, 6H), 1.19 (s, 6H). ESI-MS: m/z 486.2 [M+Na]+. Compound 555 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 8.82 - 8.62 (m, 1H), 8.05 - 7.83 (m, 2H), 7.51 (dd, J = 4.5 Hz, 1H) , 7.06 - 6.88 (m, 2H), 6.88 - 6.69 (m, 2H), 5.80 (d, J = 7.9 Hz, 1H), 4.10 - 3.70 (m, 5H), 2.85 (td, J= 12.3, 2.5 Hz , 2H), 1.97 (dd, J = 12.9, 3.7 Hz, 2H), 1.65 - 1.25 (m, 6H), 1.19 (s, 6H). ESI-MS: m/z 486.2 [M+Na] + .
实施例 423  Example 423
2- (4-氟苯氧基） -2-甲基 -N- ( 1- (吡啶 -2-磺酰基）哌啶 -4-基）丙酰胺（化合物 556) 参照实施例 14的方法制得化合物 556: 1H MR (300 MHz, CDC13) δ 8.72 (d, J= 4.7 Hz, 1H), 8.03 - 7.86 (m, 2H), 7.62 - 7.46 (m, 1H), 7.07 - 6.94 (m, 2H), 6.89 (dd, J= 9.0, 4.5 Hz, 2H), 6.71 (d, J= 8.1 Hz, 1H), 4.16 - 3.70 (m, 3H), 3.13 - 2.73 (m, 2H), 2.19 - 1.89 (m, 2H), 1.69 - 1.52 (m, 2H), 1.47 (s, 6H). ESI-MS: m/z 444.1 [M+Na]+. 2-(4-Fluorophenoxy)-2-methyl-N-(1-(pyridine-2-sulfonyl)piperidin-4-yl)propanamide (Compound 556) was obtained according to the method of Example 14. Compound 556: 1H MR (300 MHz, CDC1 3 ) δ 8.72 (d, J = 4.7 Hz, 1H), 8.03 - 7.86 (m, 2H), 7.62 - 7.46 (m, 1H), 7.07 - 6.94 (m, 2H) ), 6.89 (dd, J= 9.0, 4.5 Hz, 2H), 6.71 (d, J= 8.1 Hz, 1H), 4.16 - 3.70 (m, 3H), 3.13 - 2.73 (m, 2H), 2.19 - 1.89 (m, 2H), 1.69 - 1.52 (m, 2H), 1.47 (s, 6H). ESI-MS: m/z 444.1 [M+Na] + .
实施例 424  Example 424
5- ((7-溴萘 -2-基） 氧基） -2,2-二甲基 -N- (1- ((4- (甲基磺酰基） 苯基） 磺酰基） 哌啶—4-基） 戊酰胺 （化合物 557)  5-((7-bromonaphthalen-2-yl)oxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidine-4 -yl) pentanoamide (compound 557)
参照实施例 119的方法制得化合物 557: 1H MR (300 MHz, OMSO-d6) δ 8.16 (d, J = 8.2 Hz, 2H), 8.02 (d, J= 2.0 Hz, 1H), 7.96 (d, J= 8.2 Hz, 2H), 7.79 (dd, J= 13.8, 8.8 Hz, 2H), 7.43 (dd, J= 8.7, 2.0 Hz, 1H), 7.33 - 7.20 (m, 2H), 7.15 (dd, J= 8.9, 2.5 Hz, 1H), 4.13 - 3.91 (m, 2H), 3.67 - 3.45 (m, 3H), 3.29 (s, 3H), 2.45 - 2.31 (m, 2H), 1.77 - 1.37 (m, 8H), 1.05 (s, 6H). ESI-MS: m/z 673.1 [M+Na]+. Compound 557 was prepared by the method of Example 119: 1H MR (300 MHz, OMSO-d 6 ) δ 8.16 (d, J = 8.2 Hz, 2H), 8.02 (d, J = 2.0 Hz, 1H), 7.96 (d , J= 8.2 Hz, 2H), 7.79 (dd, J= 13.8, 8.8 Hz, 2H), 7.43 (dd, J= 8.7, 2.0 Hz, 1H), 7.33 - 7.20 (m, 2H), 7.15 (dd, J= 8.9, 2.5 Hz, 1H), 4.13 - 3.91 (m, 2H), 3.67 - 3.45 (m, 3H), 3.29 (s, 3H), 2.45 - 2.31 (m, 2H), 1.77 - 1.37 (m, 8H), 1.05 (s, 6H). ESI-MS: m/z 673.1 [M+Na] + .
实施例 425  Example 425
2,2-二甲基 -N- (1- ((4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） -5- (喹啉 -6-基 氧基） 戊酰胺 （化合物 558)  2,2-Dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-5-(quinolin-6-yloxy)pentane Amide (compound 558)
参照实施例 119的方法制得化合物 558: 1H NMR (500 MHz, DMSO- 6) δ 8.76 (d, J = 4.1 Hz, 1H), 8.33 - 8.13 (m, 3H), 8.01 (d,J= 8.0 Hz, 2H), 7.94 (d, J=9.1 Hz, 1H), 7.48 (dd, J= 8.3, 4.2 Hz, 1H), 7.39 (d, J= 9.2 Hz, 1H), 7.35 (s, 1H), 7.26 (d,J= 7.7 Hz, 1H), 4.09 (d, J = 5.4 Hz, 2H), 3.73 - 3.51 (m, 3H), 3.34 (s, 3H), 2.46 (t, J= 12.1 Hz, 2H), 1.79 - 1.45 (m, 8H), 1.11 , 6H). ESI-MS: m/z 596.3 [M+Na]+. Compound 558 was obtained by the method of Example 119: 1H NMR (500 MHz, DMSO- 6 ) δ 8.76 (d, J = 4.1 Hz, 1H), 8.33 - 8.13 (m, 3H), 8.01 (d, J = 8.0 Hz, 2H), 7.94 (d, J=9.1 Hz, 1H), 7.48 (dd, J= 8.3, 4.2 Hz, 1H), 7.39 (d, J= 9.2 Hz, 1H), 7.35 (s, 1H), 7.26 (d, J = 7.7 Hz, 1H), 4.09 (d, J = 5.4 Hz, 2H), 3.73 - 3.51 (m, 3H), 3.34 (s, 3H), 2.46 (t, J = 12.1 Hz, 2H ), 1.79 - 1.45 (m, 8H), 1.11, 6H). ESI-MS: m/z 596.3 [M+Na] + .
实施例 426  Example 426
5- ((5,7-二溴喹啉 -8-基） 氧基） -2,2-二甲基 -N- (1- ((4- (甲基磺酰基） 苯基） 磺 酰基） 哌啶 -4-基） 戊酰胺 （化合物 559)  5-((5,7-Dibromoquinolin-8-yl)oxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl) Piperidin-4-yl)pentanamide (Compound 559)
参照实施例 119的方法制得化合物 559: 1H MR(300 MHz, OMSO-d6) δ 8.99 (dd, J = 4.2, 1.6 Hz, 1H), 8.48 (dd, J= 8.6, 1.6 Hz, 1H), 8.36 - 8.07 (m, 3H), 7.98 (d, J= 8.2 Hz, 2H), 7.74 (dd,J= 8.6, 4.1 Hz, 1H), 7.22 (d, J= 7.8 Hz, 1H), 4.41 - 4.21 (m, 2H), 3.70 - 3.43 (m, 3H), 3.30 (s, 3H), 2.44-2.33 (m, 2H), 1.80- 1.54 (m, 6H), 1.54-1.31 (m, 2H), 1.05 (s, 6H). ESI-MS: m/z 754.0 [M+Na]+. Compound 559 was prepared by the method of Example 119: 1H MR (300 MHz, OMSO-d 6 ) δ 8.99 (dd, J = 4.2, 1.6 Hz, 1H), 8.48 (dd, J = 8.6, 1.6 Hz, 1H) , 8.36 - 8.07 (m, 3H), 7.98 (d, J = 8.2 Hz, 2H), 7.74 (dd, J = 8.6, 4.1 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 4.41 - 4.21 (m, 2H), 3.70 - 3.43 (m, 3H), 3.30 (s, 3H), 2.44-2.33 (m, 2H), 1.80- 1.54 (m, 6H), 1.54-1.31 (m, 2H), 1.05 (s, 6H). ESI-MS: m/z 754.0 [M+Na] + .
实施例 427  Example 427
5- ((7-溴萘 -2-基） 氧基） -2,2-二甲基 -N- (1- ((4-羧基苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 （化合物 560)  5-((7-bromonaphthalen-2-yl)oxy)-2,2-dimethyl-N-(1-((4-carboxyphenyl)sulfonyl)piperidin-4-yl)pentanamide (Compound 560)
参照实施例 119的方法制得化合物 560: 1H MR (300 MHz, DMSO- 6) δ 13.50 (s, 1H), 8.15 (d,J= 8.2 Hz, 2H), 8.02 (d, J= 2.0 Hz, 1H), 7.94 - 7.72 (m, 4H), 7.43 (dd, J= 8.7, 2.0 Hz, 1H), 7.31 - 7.20 (m, 2H), 7.15 (dd,J= 9.0, 2.4 Hz, 1H), 4.10-3.91 (m, 2H), 3.65-3.45 (m, 3H), 2.32 (t, J = 11.6 Hz, 2H), 1.80 - 1.30 (m, 8H), 1.05 (s, 6H). ESI-MS: m/z 615.1 [M-H]". 实施例 428 Compound 560 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 13.50 (s, 1H), 8.15 (d, J = 8.2 Hz, 2H), 8.02 (d, J = 2.0 Hz, 1H), 7.94 - 7.72 (m, 4H), 7.43 (dd, J= 8.7, 2.0 Hz, 1H), 7.31 - 7.20 (m, 2H), 7.15 (dd, J= 9.0, 2.4 Hz, 1H), 4.10 -3.91 (m, 2H), 3.65-3.45 (m, 3H), 2.32 (t, J = 11.6 Hz, 2H), 1.80 - 1.30 (m, 8H), 1.05 (s, 6H). ESI-MS: m /z 615.1 [MH]". Example 428
2,2-二甲基 -N- ( 1- ( (4-羧基苯基） 磺酰基） 哌啶 -4-基） -5- (喹啉 -6-基氧基） 戊酰 胺 （化合物 561 )  2,2-Dimethyl-N-(1-((4-carboxyphenyl)sulfonyl)piperidin-4-yl)-5-(quinolin-6-yloxy)pentanamide (Compound 561)
参照实施例 119的方法制得化合物 561： 1H MR (300 MHz, DMSO- 6) δ 13.49 (s, 1H), 8.72 (dd, J= 4.1, 1.7 Hz, 1H), 8.18 (dd, J = 19.2, 8.2 Hz, 3H), 7.97 - 7.77 (m, 3H), 7.45 (dd, J= 8.4, 4.2 Hz, 1H), 7.39 - 7.19 (m, 3H), 4.09 - 3.97 (m, 2H), 3.67 - 3.44 (m, 3H), 2.33 (t, J = 11.7 Hz, 2H), 1.72 - 1.37 (m, 8H), 1.06 (s, 6H). ESI-MS: m/z 540.3 [M+H]+. Compound 561 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 13.49 (s, 1H), 8.72 (dd, J = 4.1, 1.7 Hz, 1H), 8.18 (dd, J = 19.2 , 8.2 Hz, 3H), 7.97 - 7.77 (m, 3H), 7.45 (dd, J= 8.4, 4.2 Hz, 1H), 7.39 - 7.19 (m, 3H), 4.09 - 3.97 (m, 2H), 3.67 - 3.44 (m, 3H), 2.33 (t, J = 11.7 Hz, 2H), 1.72 - 1.37 (m, 8H), 1.06 (s, 6H). ESI-MS: m/z 540.3 [M+H] + .
实施例 429  Example 429
2- (4-氟苯氧基） -N- ( 1- ( (4-甲氧苯基） 磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 （化 合物 562)  2-(4-Fluorophenoxy)-N-(1-((4-methoxyphenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (Compound 562)
参照实施例 14的方法制得化合物 562: 1H MR (300 MHz, CDC13) δ 7.69 (d, J= 8.8 Hz, 2H), 7.07 - 6.89 (m, 4H), 6.89 - 6.78 (m, 2H), 6.62 (d, J= 7.9 Hz, 1H), 3.88 (s, 3H), 3.81 - 3.63 (m, 3H), 2.54 - 2.32 (m, 2H), 2.07 - 1.87 (m, 2H), 1.68 - 1.56 (m, 2H), 1.43 (s, 6H). ESI-MS: m/z 473.2 [M+Na]+. Compound 562 was obtained by the method of Example 14: 1H MR (300 MHz, CDC1 3 ) δ 7.69 (d, J = 8.8 Hz, 2H), 7.07 - 6.89 (m, 4H), 6.89 - 6.78 (m, 2H) , 6.62 (d, J = 7.9 Hz, 1H), 3.88 (s, 3H), 3.81 - 3.63 (m, 3H), 2.54 - 2.32 (m, 2H), 2.07 - 1.87 (m, 2H), 1.68 - 1.56 (m, 2H), 1.43 (s, 6H). ESI-MS: m/z 473.2 [M+Na] + .
实施例 430  Example 430
2- (4-氟苯氧基) -2-甲基 -N- ( 1- ( (4- (吗啡啉 -4-羰基) 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 （化合物 563 )  2-(4-Fluorophenoxy)-2-methyl-N-(1-((4-(morpholine-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide (compound) 563 )
参照实施例 14和 101的方法制得化合物 563 : 1H NMR (300 MHz, CDC13) δ 7.82 (d, J = 7.8 Hz, 2H), 7.57 (d, J= 7.8 Hz, 2H), 7.03 - 6.91 (m, 2H), 6.91 - 6.80 (m, 2H), 6.64 (d, J = 7.9 Hz, 1H), 4.00 - 3.54 (m, 9H), 3.51 - 3.23 (m, 2H), 2.59 - 2.40 (m, 2H), 2.09 - 1.90 (m, 2H), 1.58 - 1.49 (m, 2H), 1.43 (s, 6H). ESI-MS: m/z 556.2 [M+Na]+. Compound 563 was obtained by the methods of Examples 14 and 101: 1H NMR (300 MHz, CDC1 3 ) δ 7.82 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H), 7.03 - 6.91 (m, 2H), 6.91 - 6.80 (m, 2H), 6.64 (d, J = 7.9 Hz, 1H), 4.00 - 3.54 (m, 9H), 3.51 - 3.23 (m, 2H), 2.59 - 2.40 (m , 2H), 2.09 - 1.90 (m, 2H), 1.58 - 1.49 (m, 2H), 1.43 (s, 6H). ESI-MS: m/z 556.2 [M+Na] + .
实施例 431  Example 431
2- (4-氯苯氧基） -2-甲基 -N- ( 1- ( (4- (4-甲基 -1， 4-二氮杂环庚垸 -1-羰基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 （化合物 564)  2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-(4-methyl-1,4-diazepan-1-yl)phenyl) sulfonate Acyl) piperidin-4-yl)propanamide (compound 564)
参照实施例 14和 101的方法制得化合物 564: 1H NMR (300 MHz, CDC13) δ 7.80 (d, J = 7.7 Hz, 2H), 7.61 (d, J = 7.7 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 6.54 (d, J= 8.0 Hz, 1H), 4.08 - 3.94 (m, 1H), 3.89 - 3.65 (m, 4H), 3.65 - 3.38 (m, 2H), 2.93 - 2.63 (m, 4H), 2.59 - 2.39 (m, 4H), 2.37 - 2.07 (m, 3H), 2.06 - 1.90 (m, 3H), 1.65 - 1.47 (m, 2H), 1.44 (s, 6H). ESI-MS: m/z 577.3 [M+H]+. Compound 564 was obtained by the methods of Examples 14 and 101: 1H NMR (300 MHz, CDC1 3 ) δ 7.80 (d, J = 7.7 Hz, 2H), 7.61 (d, J = 7.7 Hz, 2H), 7.22 (d , J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 6.54 (d, J = 8.0 Hz, 1H), 4.08 - 3.94 (m, 1H), 3.89 - 3.65 (m, 4H) , 3.65 - 3.38 (m, 2H), 2.93 - 2.63 (m, 4H), 2.59 - 2.39 (m, 4H), 2.37 - 2.07 (m, 3H), 2.06 - 1.90 (m, 3H), 1.65 - 1.47 ( m, 2H), 1.44 (s, 6H). ESI-MS: m/z 577.3 [M+H] + .
实施例 432  Example 432
反式—5- (2， 4-二氟苯氧基) -N- ( 1- ( (2， 3-二氢苯并呋喃 -5-基) 磺酰基） -3-氟哌 啶—4-基） -2， 2-二甲基戊酰胺 （化合物 565 )  Trans-5-(2,4-difluorophenoxy)-N-(1-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-3-fluoropiperidine- 4- -2,2-dimethylvaleramide (compound 565)
参照实施例 139的方法制得化合物 565: 1H NMR (300 MHz, CDC13) δ 7.61 - 7.50 (m, 2H), 7.11— 6.95 (m, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.73 - 6.61 (m, 1H), 6.59 - 6.48 (m, 1H), 5.86 (d, J = 7.5 Hz, 1H), 4.71 (t, J = 8.8 Hz, 2H), 4.63 - 4.32 (m, 1H), 4.12 - 4.02 (m, 1H), 4.00 - 3.89 (m, 1H), 3.85 (t, J = 5.3 Hz, 2H), 3.76 - 3.64 (m, 1H), 3.29 (t, J = 8.7 Hz, 2H), 2.45 - 2.25 (m, 2H), 2.18 - 2.05 (m, 1H), 1.79 - 1.61 (m, 5H), 1.19 (s, 6H). ESI-MS: m/z 563.3 [M+Na]+. Compound 565 was obtained by the method of Example 139: 1H NMR (300 MHz, CDC1 3 ) δ 7.61 - 7.50 (m, 2H), 7.11 - 6.95 (m, 1H), 6.88 (d, J = 8.2 Hz, 1H) , 6.73 - 6.61 (m, 1H), 6.59 - 6.48 (m, 1H), 5.86 (d, J = 7.5 Hz, 1H), 4.71 (t, J = 8.8 Hz, 2H), 4.63 - 4.32 (m, 1H), 4.12 - 4.02 (m, 1H), 4.00 - 3.89 (m, 1H) , 3.85 (t, J = 5.3 Hz, 2H), 3.76 - 3.64 (m, 1H), 3.29 (t, J = 8.7 Hz, 2H), 2.45 - 2.25 (m, 2H), 2.18 - 2.05 (m, 1H ), 1.79 - 1.61 (m, 5H), 1.19 (s, 6H). ESI-MS: m/z 563.3 [M+Na] + .
实施例 433  Example 433
反式—5- (3， 4-二氟苯氧基) -N- ( 1- ( (2， 3-二氢苯并呋喃 -5-基) 磺酰基） -3-氟哌 啶—4-基） -2， 2-二甲基戊酰胺 （化合物 566)  Trans-5-(3,4-difluorophenoxy)-N-(1-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-3-fluoropiperidine- 4- -2,2-Dimethylpentanamide (Compound 566)
参照实施例 139的方法制得化合物 566: 1H NMR (300 MHz, CDC13) δ 7.64 - 7.49 (m, 2H), 6.94 - 6.79 (m, 3H), 6.79 - 6.71 (m, 1H), 5.78 (d, J= 7.5 Hz, 1H), 4.70 (t, J = 8.8 Hz, 2H), 4.62 - 4.30 (m, 1H), 4.10 - 4.00 (m, 1H), 4.00 - 3.83 (m, 3H), 3.76 - 3.61 (m, 1H), 3.29 (t, J = 8.8 Hz, 2H), 2.49 - 2.31 (m, 2H), 2.18 - 2.05 (m, 1H), 1.80 - 1.60 (m, 5H), 1.19 (s, 6H). ESI-MS: m/z 563.3 [M+Na]+. Compound 566 was obtained by the method of Example 139: 1H NMR (300 MHz, CDC1 3 ) δ 7.64 - 7.49 (m, 2H), 6.94 - 6.79 (m, 3H), 6.79 - 6.71 (m, 1H), 5.78 ( d, J = 7.5 Hz, 1H), 4.70 (t, J = 8.8 Hz, 2H), 4.62 - 4.30 (m, 1H), 4.10 - 4.00 (m, 1H), 4.00 - 3.83 (m, 3H), 3.76 - 3.61 (m, 1H), 3.29 (t, J = 8.8 Hz, 2H), 2.49 - 2.31 (m, 2H), 2.18 - 2.05 (m, 1H), 1.80 - 1.60 (m, 5H), 1.19 (s , 6H). ESI-MS: m/z 563.3 [M+Na] + .
实施例 434  Example 434
2- (4-氯苯氧基） -2-甲基 -N- ( 1- ( (4- (4-甲基哌啶 -1-羰基）苯基）磺酰基） 哌啶 -4- 基） 丙酰胺 （化合物 567)  2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-(4-methylpiperidin-1-carbonyl)phenyl)sulfonyl)piperidin-4-yl) Propionamide (Compound 567)
参照实施例 14和 101的方法制得化合物 567: 1H NMR (300 MHz, CDC13) δ 7.80 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.52 (d, J= 7.9 Hz, 1H), 3.93 - 3.64 (m, 5H), 3.55 - 3.26 (m, 2H), 2.64 - 2.44 (m, 4H), 2.43 - 2.25 (m, 5H), 2.06 - 1.92 (m, 2H), 1.61 - 1.49 (m, 2H), 1.46 (s, 6H). ESI-MS: m/z 563.3 [M+H]+. Compound 567 was prepared by the methods of Examples 14 and 101: 1H NMR (300 MHz, CDC1 3 ) δ 7.80 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.23 (d , J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 7.9 Hz, 1H), 3.93 - 3.64 (m, 5H), 3.55 - 3.26 (m, 2H) , 2.64 - 2.44 (m, 4H), 2.43 - 2.25 (m, 5H), 2.06 - 1.92 (m, 2H), 1.61 - 1.49 (m, 2H), 1.46 (s, 6H). ESI-MS: m/ z 563.3 [M+H] + .
实施例 435  Example 435
5- (3， 4-二氟苯氧基） -2， 2-二甲基 -N- ( 1- ( (4- (吗啡啉 -4-羰基） 苯基） 磺酰基） 哌啶—4-基） 戊酰胺 （化合物 568)  5-(3,4-Difluorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholine-4-carbonyl)phenyl)sulfonyl)piperidine- 4- Ethyl pentamide (compound 568)
参照实施例 119和 101的方法制得化合物 568: 1H NMR (300 MHz, CDC13) δ 7.82 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.11 - 6.95 (m, 1H), 6.75 - 6.61 (m, 1H), 6.61 - 6.48 (m, 1H), 5.52 (d, J= 7.7 Hz, 1H), 4.00 - 3.54 (m, 11H), 3.53 - 3.23 (m, 2H), 2.46 (t, J = 11.1 Hz, 2H), 2.10 - 1.87 (m, 2H), 1.78 - 1.63 (m, 4H), 1.55 - 1.40 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 616.3 [M+Na]+. Compound 568 was prepared by the methods of Examples 119 and 101: 1H NMR (300 MHz, CDC1 3 ) δ 7.82 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.11 - 6.95 (m, 1H), 6.75 - 6.61 (m, 1H), 6.61 - 6.48 (m, 1H), 5.52 (d, J= 7.7 Hz, 1H), 4.00 - 3.54 (m, 11H), 3.53 - 3.23 (m , 2H), 2.46 (t, J = 11.1 Hz, 2H), 2.10 - 1.87 (m, 2H), 1.78 - 1.63 (m, 4H), 1.55 - 1.40 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 616.3 [M+Na] + .
实施例 436  Example 436
5- (2， 4-二氟苯氧基） -2， 2-二甲基 -N- ( 1- ( (4- (吗啡啉 -4-羰基） 苯基） 磺酰基） 哌啶—4-基） 戊酰胺 （化合物 569)  5-(2,4-Difluorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholine-4-carbonyl)phenyl)sulfonyl)piperidine- 4- Ethyl pentamide (compound 569)
参照实施例 119和 101的方法制得化合物 569: 1H NMR (300 MHz, CDC13) δ 7.81 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 6.98 - 6.67 (m, 3H), 5.55 (d, J= 7.6 Hz, 1H), 3.93 (t, J= 5.4 Hz, 2H), 3.88 - 3.54 (m, 9H), 3.51 - 3.23 (m, 2H), 2.46 (t, J= 11.5 Hz, 2H), 2.06 - 1.88 (m, 2H), 1.77 - 1.61 (m, 4H), 1.55 - 1.42 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 616.3 [M+Na]+. Compound 569 was obtained by the methods of Examples 119 and 101: 1H NMR (300 MHz, CDC1 3 ) δ 7.81 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 6.98 - 6.67 (m, 3H), 5.55 (d, J= 7.6 Hz, 1H), 3.93 (t, J= 5.4 Hz, 2H), 3.88 - 3.54 (m, 9H), 3.51 - 3.23 (m, 2H), 2.46 ( t, J = 11.5 Hz, 2H), 2.06 - 1.88 (m, 2H), 1.77 - 1.61 (m, 4H), 1.55 - 1.42 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 616.3 [M+Na] + .
实施例 437  Example 437
N- ( 1- ( ( 3-氯 -4-氟苯基）磺酰基）哌啶 -4-基） -2- (4-氯苯氧基) -2-甲基丙酰胺（化 合物 570)  N-(1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-(4-chlorophenoxy)-2-methylpropanamide (compound 570)
参照实施例 14的方法制得化合物 570: 1H NMR (300 MHz, CDC13) δ 8.13 - 7.99 (m, 1H), 7.30 - 7.23 (m, 2H), 7.23 - 7.19 (m, 1H), 7.17 - 7.02 (m, 1H), 6.90 - 6.76 (m, 2H), 6.55 (d, J= 7.6 Hz, 1H), 4.03 - 3.87 (m, 1H), 3.87 - 3.70 (m, 2H), 3.04 - 2.82 (m, 2H), 2.11 - 1.87 (m, 2H), 1.56 - 1.51 (m, 2H), 1.47 (s, 6H). ESI-MS: m/z 511.1 [M+Na]+. The compound 570 was obtained by the method of Example 14: 1H NMR (300 MHz, CDC1 3 ) δ 8.13 - 7.99 (m, 1H), 7.30 - 7.23 (m, 2H), 7.23 - 7.19 (m, 1H), 7.17 - 7.02 (m, 1H), 6.90 - 6.76 (m, 2H), 6.55 (d, J= 7.6 Hz, 1H), 4.03 - 3.87 (m, 1H), 3.87 - 3.70 (m, 2H), 3.04 - 2.82 ( m, 2H), 2.11 - 1.87 (m, 2H), 1.56 - 1.51 (m, 2H), 1.47 (s, 6H). ESI-MS: m/z 511.1 [M+Na] + .
实施例 438  Example 438
N- ( 1- ( (2， 6-二氟苯基磺酰基） 哌啶 -4-基） -5- ( 4-氟苯氧基） -2， 2-二甲基戊酰 胺 （化合物 571 )  N-(1-((2,6-Difluorophenylsulfonyl)piperidin-4-yl)-5-(4-fluorophenoxy)-2,2-dimethylpentanamide (Compound 571)
参照实施例 119的方法制得化合物 571： 1H NMR (300 MHz, CDC13) δ 7.60 - 7.43 (m, 1H), 7.14 - 6.89 (m, 4H), 6.85 - 6.73 (m, 2H), 5.55 (d, J = 7.9 Hz, 1H), 4.02 - 3.72 (m, 5H), 2.84 - 2.65 (m, 2H), 2.08 - 1.90 (m, 2H), 1.74 - 1.62 (m, 4H), 1.56 - 1.44 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 521.2 [M+Na]+. Compound 571 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.60 - 7.43 (m, 1H), 7.14 - 6.89 (m, 4H), 6.85 - 6.73 (m, 2H), 5.55 ( d, J = 7.9 Hz, 1H), 4.02 - 3.72 (m, 5H), 2.84 - 2.65 (m, 2H), 2.08 - 1.90 (m, 2H), 1.74 - 1.62 (m, 4H), 1.56 - 1.44 ( m, 2H), 1.18 (s, 6H). ESI-MS: m/z 521.2 [M+Na] + .
实施例 439  Example 439
2- ( 4-氯苯氧基） -2-甲基 -N- ( 1- ( ( 4- (N-甲基氨磺酰基） 苯基） 磺酰基） 哌啶 -4- 基） 丙酰胺 （化合物 572)  2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-(N-methylsulfamoyl)phenyl)sulfonyl)piperidin-4-yl)propanamide Compound 572)
参照实施例 14的方法制得化合物 572: 1H MR (300 MHz, CDC13) δ 8.03 (d, J = 8.4 Hz, 2H), 7.90 (d, J= 8.4 Hz, 2H), 7.22 (d, J= 8.8 Hz, 2H), 6.81 (d, J= 8.8 Hz, 2H), 6.52 (d, J = 7.3 Hz, 1H), 4.50 - 4.39 (m, 1H), 3.86 - 3.69 (m, 3H), 2.73 (d, J = 5.3 Hz, 3H), 2.62 - 2.46 (m, 2H), 2.06 - 1.94 (m, 2H), 1.58 - 1.54 (m, 2H), 1.46 (s, 6H). ESI-MS: m/z 552.1 [M+Na]+. 实施例 440 Compound 572 was prepared by the method of Example 14: 1H MR (300 MHz, CDC1 3 ) δ 8.03 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 7.3 Hz, 1H), 4.50 - 4.39 (m, 1H), 3.86 - 3.69 (m, 3H), 2.73 (d, J = 5.3 Hz, 3H), 2.62 - 2.46 (m, 2H), 2.06 - 1.94 (m, 2H), 1.58 - 1.54 (m, 2H), 1.46 (s, 6H). ESI-MS: m /z 552.1 [M+Na] + . Example 440
4 - ( (4- (2- ( 3,4-二氟苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 （化 合物 573 )  4-((4-(2-(3,4-Difluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 573)
参照实施例 14的方法制得化合物 573 : 1H MR (300 MHz, OMSO-d6) δ 13.41 (s, 1H), 8.15 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.38 - 7.25 (m, 1H), 6.97 - 6.87 (m, 1H), 6.72 - 6.63 (m, 1H), 3.65 - 3.54 (m, 3H), 2.48 - 2.38 (m, 2H), 1.75 - 1.65 (m, 2H), 1.61 - 1.47 (m, 2H), 1.39 (s, 6H). ESI-MS: m/z 481.1 [M-H]". Compound 573 was prepared by the method of Example 14: 1H MR (300 MHz, OMSO-d 6 ) δ 13.41 (s, 1H), 8.15 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 7.9 Hz , 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.38 - 7.25 (m, 1H), 6.97 - 6.87 (m, 1H), 6.72 - 6.63 (m, 1H), 3.65 - 3.54 (m, 3H) ), 2.48 - 2.38 (m, 2H), 1.75 - 1.65 (m, 2H), 1.61 - 1.47 (m, 2H), 1.39 (s, 6H). ESI-MS: m/z 481.1 [MH]".
实施例 441  Example 441
4- ( (4- (2- ( 3,4-二氟苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 -2-乙 酰氨基乙酯 （化合物 574)  4-((4-(2-(3,4-Difluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)-2-acetamidoethyl benzoate (compound) 574)
参照实施例 14和 183的方法制得化合物 574: 1H NMR (300 MHz, CDC13) δ 8.19 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.1 Hz, 2H), 7.12 - 6.99 (m, 1H), 6.78 - 6.67 (m, 1H), 6.67 - 6.57 (m, 1H), 6.57 - 6.44 (m, 1H), 5.85 (s, 1H), 4.47 (t, J = 4.7 Hz, 2H), 3.84 - 3.63 (m, 5H), 2.57 - 2.43 (m, 2H), 2.01 (s, 3H), 2.00 - 1.93 (m, 2H), 1.61 - 1.53 (m, 2H), 1.45 (s, 6H). ESI-MS: m/z 590.2 [M+Na]+. Compound 574 was prepared by the methods of Examples 14 and 183: 1H NMR (300 MHz, CDC1 3 ) δ 8.19 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.1 Hz, 2H), 7.12 - 6.99 (m, 1H), 6.78 - 6.67 (m, 1H), 6.67 - 6.57 (m, 1H), 6.57 - 6.44 ( m, 1H), 5.85 (s, 1H), 4.47 (t, J = 4.7 Hz, 2H), 3.84 - 3.63 (m, 5H), 2.57 - 2.43 (m, 2H), 2.01 (s, 3H), 2.00 - 1.93 (m, 2H), 1.61 - 1.53 (m, 2H), 1.45 (s, 6H). ESI-MS: m/z 590.2 [M+Na] + .
实施例 442  Example 442
4 - ( (4- (2- (2,4-二氟苯氧基） -2-甲基丙酰氨基）哌啶 -1-基）磺酰基）苯甲酸（化 合物 575 )  4-((4-(2-(2,4-Difluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 575)
参照实施例 14的方法制得化合物 575 : 1H MR (300 MHz, OMSO-d6) δ 13.42 (s, 1H), 8.14 (d, J = 8.3 Hz, 2H), 8.00 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.30 - 7.21 (m, 1H), 7.06 - 6.92 (m, 2H), 3.68 - 3.51 (m, 3H), 2.46 - 2.35 (m, 2H), 1.79 - 1.67 (m, 2H), 1.65 - 1.48 (m, 2H), 1.33 (s, 6H). ESI-MS: m/z 481.2 [M-H]". Compound 575 was prepared by the method of Example 14 : 1H MR (300 MHz, OMSO-d 6 ) δ 13.42 (s, 1H), 8.14 (d, J = 8.3 Hz, 2H), 8.00 (d, J = 7.9 Hz , 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.30 - 7.21 (m, 1H), 7.06 - 6.92 (m, 2H), 3.68 - 3.51 (m, 3H), 2.46 - 2.35 (m, 2H) ), 1.79 - 1.67 (m, 2H), 1.65 - 1.48 (m, 2H), 1.33 (s, 6H). ESI-MS: m/z 481.2 [MH]".
实施例 443  Example 443
4- ( (4- (2- (2,4-二氟苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 -2-乙 酰氨基乙酯 （化合物 576)  4-((4-(2-(2,4-Difluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)-2-acetamidoethyl benzoate (compound) 576)
参照实施例 14和 183的方法制得化合物 576: 1H NMR (300 MHz, CDC13) δ 8.23 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.08 - 6.77 (m, 4H), 5.89 (br s, 1H), 4.50 (t, J = 4.7 Hz, 2H), 3.87 - 3.63 (m, 5H), 2.68 - 2.52 (m, 2H), 2.15 - 2.05 (m, 2H), 2.04 (s, 3H), 1.72 - 1.57 (m, 2H), 1.45 (s, 6H). ESI-MS: m/z 590.2 [M+Na]+. Compound 576 was obtained by the methods of Examples 14 and 183: 1H NMR (300 MHz, CDC1 3 ) δ 8.23 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.08 - 6.77 (m, 4H), 5.89 (br s, 1H), 4.50 (t, J = 4.7 Hz, 2H), 3.87 - 3.63 (m, 5H), 2.68 - 2.52 (m, 2H), 2.15 - 2.05 (m, 2H), 2.04 (s, 3H), 1.72 - 1.57 (m, 2H), 1.45 (s, 6H). ESI-MS: m/z 590.2 [M+Na] + .
实施例 444  Example 444
5- (4-氯苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (吗啉代） 苯基） 磺酰基） 哌啶 -4-基） 戊 酰胺 （化合物 577)  5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholino)phenyl)sulfonyl)piperidin-4-yl)pentanamide (compound) 577)
参照实施例 119的方法制得化合物 577: 1H NMR (300 MHz, CDC13) δ 7.96 - 7.87 (m, 4H), 7.22 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H), 5.51 - 5.43 (m, 1H), 3.88 (t, J = 5.6 Hz, 2H), 3.85 - 3.77 (m, 3H), 3.78 - 3.72 (m, 4H), 3.11 - 2.99 (m, 4H), 2.58 - 2.45 (m, 2H), 2.06 - 1.92 (m, 2H), 1.72 - 1.61 (m, 4H), 1.53 - 1.44 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 650.2 [M+Na]+. Compound 577 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 7.96 - 7.87 (m, 4H), 7.22 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 8.9 Hz , 2H), 5.51 - 5.43 (m, 1H), 3.88 (t, J = 5.6 Hz, 2H), 3.85 - 3.77 (m, 3H), 3.78 - 3.72 (m, 4H), 3.11 - 2.99 (m, 4H ), 2.58 - 2.45 (m, 2H), 2.06 - 1.92 (m, 2H), 1.72 - 1.61 (m, 4H), 1.53 - 1.44 (m, 2H), 1.17 (s, 6H). ESI-MS: m /z 650.2 [M+Na] + .
实施例 445  Example 445
5- (4-氟苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (吗啉代） 苯基） 磺酰基） 哌啶 -4-基） 戊 酰胺 （化合物 578 )  5-(4-fluorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholino)phenyl)sulfonyl)piperidin-4-yl)pentanamide (compound) 578 )
参照实施例 119的方法制得化合物 578: 1H NMR (300 MHz, CDC13) δ 8.06 - 7.84 (m, 4H), 7.02 - 6.90 (m, 2H), 6.87 - 6.74 (m, 2H), 5.53 - 5.47 (m, 1H), 3.98 - 3.59 (m, 9H), 3.12 - 2.96 (m, 4H), 2.56 - 2.45 (m, 2H), 2.04 - 1.95 (m, 2H), 1.74 - 1.59 (m, 4H), 1.54 - 1.46 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 634.2 [M+Na]+. The compound 578 was obtained by the method of Example 119: 1H NMR (300 MHz, CDC1 3 ) δ 8.06 - 7.84 (m, 4H), 7.02 - 6.90 (m, 2H), 6.87 - 6.74 (m, 2H), 5.53 - 5.47 (m, 1H), 3.98 - 3.59 (m, 9H), 3.12 - 2.96 (m, 4H), 2.56 - 2.45 (m, 2H), 2.04 - 1.95 (m, 2H), 1.74 - 1.59 (m, 4H ), 1.54 - 1.46 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 634.2 [M+Na] + .
实施例 446 2- (4-氟苯氧基） -2-甲基 -N- ( 1- ( (4- (吗啉代） 苯基） 磺酰基） 哌啶 -4-基） 丙酰 胺 （化合物 579) Example 446 2-(4-Fluorophenoxy)-2-methyl-N-(1-((4-(morpholino)phenyl)sulfonyl)piperidin-4-yl)propanamide (Compound 579)
参照实施例 14的方法制得化合物 579: 1H NMR (300 MHz, CDC13) δ 8.02 - 7.86 (m, 4H), 7.02 - 6.92 (m, 2H), 6.90 - 6.81 (m, 2H), 6.69 - 6.62 (m, 1H), 3.86 - 3.79 (m, 2H), 3.80 - 3.74 (m, 4H), 3.11 - 2.97 (m, 4H), 2.64 - 2.46 (m, 3H), 2.05 - 1.98 (m, 2H), 1.56 - 1.48 (m, 2H), 1.43 (s, 6H). ESI-MS: m/z 570.2 [M+H]+. Compound 579 was obtained by the method of Example 14: 1H NMR (300 MHz, CDC1 3 ) δ 8.02 - 7.86 (m, 4H), 7.02 - 6.92 (m, 2H), 6.90 - 6.81 (m, 2H), 6.69 - 6.62 (m, 1H), 3.86 - 3.79 (m, 2H), 3.80 - 3.74 (m, 4H), 3.11 - 2.97 (m, 4H), 2.64 - 2.46 (m, 3H), 2.05 - 1.98 (m, 2H) ), 1.56 - 1.48 (m, 2H), 1.43 (s, 6H). ESI-MS: m/z 570.2 [M+H] + .
实施例 447  Example 447
2- (4-氯苯氧基） -2-甲基 -N- ( 1 - ( (4- (吗啉代） 苯基） 磺酰基） 哌啶 -4-基） 丙酰 胺 （化合物 580)  2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-(morpholino)phenyl)sulfonyl)piperidin-4-yl)propionylamine (Compound 580)
参照实施例 14的方法制得化合物 580: 1H NMR (300 MHz, CDC13) δ 8.02 - 7.86 (m, 4H), 7.30 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.69 (m, 1H), 3.86 - 3.79 (m, 2H), 3.80 - 3.74 (m, 4H), 3.11 - 2.97 (m, 4H), 2.64 - 2.46 (m, 3H), 2.05 - 1.98 (m, 2H), 1.56 - 1.48 (m, 2H), 1.43 (s, 6H). ESI-MS: m/z 587.2 [M+H]+. Compound 580 was obtained by the method of Example 14: 1H NMR (300 MHz, CDC1 3 ) δ 8.02 - 7.86 (m, 4H), 7.30 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz , 2,,,,,,,,,,,,,, (m, 2H), 1.56 - 1.48 (m, 2H), 1.43 (s, 6H). ESI-MS: m/z 587.2 [M+H] + .
实施例 448  Example 448
顺式 -2- (4-氯苯氧基) -N - (3-氟 -1 - ( (4-氟苯基) 磺酰基） 哌啶 -4-基） -2-甲基丙 酰胺 （化合物 581 )  Cis-2-(4-chlorophenoxy)-N-(3-fluoro-1 -((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (compound) 581 )
参照实施例 14和 292的方法制得化合物 581 : 1H MR (300 MHz, CDC13) δ 7.85 - 7.77 (m, 2H), 7.25 - 7.17 (m, 3H), 6.91 (d, J = 8.2 Hz, 1H), 6.86 - 6.78 (m, 2H), 4.82 - 4.56 (m, 1H), 4.24 - 4.09 (m, 1H), 4.08 - 3.78 (m, 2H), 2.87 - 2.65 (m, 1H), 2.66 - 2.53 (m, 2H), 1.93 - 1.70 (m, 1H), 1.46 (s, 6H). ESI-MS: m/z 573.2 [M+H]+. Compound 581 was prepared by the methods of Examples 14 and 292: 1H MR (300 MHz, CDC1 3 ) δ 7.85 - 7.77 (m, 2H), 7.25 - 7.17 (m, 3H), 6.91 (d, J = 8.2 Hz, 1H), 6.86 - 6.78 (m, 2H), 4.82 - 4.56 (m, 1H), 4.24 - 4.09 (m, 1H), 4.08 - 3.78 (m, 2H), 2.87 - 2.65 (m, 1H), 2.66 - 2.53 (m, 2H), 1.93 - 1.70 (m, 1H), 1.46 (s, 6H). ESI-MS: m/z 573.2 [M+H] + .
实施例 449  Example 449
顺式—4- ( (-4- (2- (4-氯苯氧基) -2-甲基丙酰氨基) -3-氟哌啶 -1-基) 磺酰基） 苯甲 酸 （化合物 582)  Cis-4-((-4-(2-(4-chlorophenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (compound 582)
参照实施例 14和 292的方法制得化合物 582: 'H NMR (300 MHz, DMSO- δ 8.15 (d, J = 8.2 Hz, 2H), 7.99 (d, J= 7.6 Hz, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.88 - 4.58 (m, 1H), 4.03 - 3.77 (m, 2H), 3.77 - 3.65 (m, 1H), 2.92 - 2.69 (m, 1H), 2.67 - 2.53 (m, 1H), 1.99 - 1.74 (m, 1H), 1.65 - 1.48 (m, 1H), 1.42 (s, 3H), 1.40 (s, 3H). ESI-MS: m/z 499.2 [M+H]+. 实施例 450 Compound 582 was prepared by the method of Examples 14 and 292: 'H NMR (300 MHz, DMSO - δ 8.15 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 7.6 Hz, 1H), 7.86 (d , J = 8.2 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.88 - 4.58 (m, 1H), 4.03 - 3.77 (m, 2H) , 3.77 - 3.65 (m, 1H), 2.92 - 2.69 (m, 1H), 2.67 - 2.53 (m, 1H), 1.99 - 1.74 (m, 1H), 1.65 - 1.48 (m, 1H), 1.42 (s, 3H), 1.40 (s, 3H). ESI-MS: m/z 499.2 [M+H] + .
5- ( ( 5,7-二溴喹啉 -8-基）氧基） -2,2-二甲基 -N- ( 1- ( (4-羧基苯基）磺酰基）哌啶 -4- 基） 戊酰胺 （化合物 583 )  5-((5,7-Dibromoquinolin-8-yl)oxy)-2,2-dimethyl-N-(1-((4-carboxyphenyl)sulfonyl)piperidin-4- Ethyl pentamide (compound 583)
参照实施例 119的方法制得化合物 583 : iH MR (300 MHz, DMSO- 6) δ 13.56 (s, 1H): 8.99 (dd, J= 4.1, 1.7 Hz, 1H), 8.48 (dd, J= 8.6, 1.6 Hz, 1H), 8.32 - 8.06 (m, 3H), 7.99 - 7.67 (m, 3H), 7.23 (d, J= 7.8 Hz, 1H), 4.34 - 4.17 (m, 2H), 3.66 - 3.44 (m, 3H), 2.35 (t, J = 11.8 Hz, 2H), 1.77 - 1.31 (m, 8H), 1.04 (s, 6H). ESI-MS: m/z 696.0 [M-H]". 实施例 451 Compound 583 was prepared by the method of Example 119: iH MR (300 MHz, DMSO- 6 ) δ 13.56 (s, 1H): 8.99 (dd, J = 4.1, 1.7 Hz, 1H), 8.48 (dd, J = 8.6 , 1.6 Hz, 1H), 8.32 - 8.06 (m, 3H), 7.99 - 7.67 (m, 3H), 7.23 (d, J = 7.8 Hz, 1H), 4.34 - 4.17 (m, 2H), 3.66 - 3.44 ( m, 3H), 2.35 (t, J = 11.8 Hz, 2H), 1.77 - 1.31 (m, 8H), 1.04 (s, 6H). ESI-MS: m/z 696.0 [MH]". Example 451
反式- ( (—4- ( 3- (2,5-二甲基苯氧基） 丙酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 (化合物 584)  Trans-((4-(3-(2,5-dimethylphenoxy)propionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (compound 584)
参照实施例 139的方法制得化合物 584: 1H MR (300 MHz, OMSO-d6) δ 13.52 (s, 1H), 8.18 (d, J= 8.1 Hz, 2H), 8.10 (d, J= 7.7 Hz, 1H), 7.91 (d, J= 8.1 Hz, 2H), 6.96 (d, J= 7.4 Hz, 1H), 6.72 (s, 1H), 6.62 (d, J= 7.3 Hz, 1H), 4.66 - 4.30 (m, 1H), 4.23 - 4.01 (m, 2H), 3.92 (m, 1H), 3.68 - 3.47 (m, 1H), 3.43 - 3.22 (m, 1H), 3.10 - 2.98 (m, 1H), 2.98 - 2.80 (m, 1H), 2.52 (m, 2H), 2.24 (s, 3H), 2.00 (s, 3H), 1.89 (m, 1H), 1.60 - 1.38 (m, 1H). ESI-MS: m/z 477.3 [M-H]". Compound 584 was prepared by the method of Example 139: 1H MR (300 MHz, OMSO-d 6 ) δ 13.52 (s, 1H), 8.18 (d, J = 8.1 Hz, 2H), 8.10 (d, J = 7.7 Hz , 1H), 7.91 (d, J= 8.1 Hz, 2H), 6.96 (d, J= 7.4 Hz, 1H), 6.72 (s, 1H), 6.62 (d, J= 7.3 Hz, 1H), 4.66 - 4.30 (m, 1H), 4.23 - 4.01 (m, 2H), 3.92 (m, 1H), 3.68 - 3.47 (m, 1H), 3.43 - 3.22 (m, 1H), 3.10 - 2.98 (m, 1H), 2.98 - 2.80 (m, 1H), 2.52 (m, 2H), 2.24 (s, 3H), 2.00 (s, 3H), 1.89 (m, 1H), 1.60 - 1.38 (m, 1H). ESI-MS: m /z 477.3 [MH]".
实施例 452  Example 452
4-((4-(2-(4-氟苯氧基) -2-甲基丙酰氨基） 哌啶 -1-基）磺酰基） 苯磺酸 2-乙酰氨基乙酯 (化合物 585 )  4-((4-(2-(4-fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzenesulfonic acid 2-acetamidoethyl ester (compound 585)
参照实施例 14的方法制得化合物 585 : 1H MR (300 MHz, DMSO- 6) δ 8.25 - 8.16 (m, 1H), 8.07 - 7.97 (m, 3H), 7.94 (d, J = 8.3 Hz, 2H), 7.15 - 7.04 (m, 2H), 6.92 - 6.84 (m, 2H), 3.94 (t, J= 5.5 Hz, 2H), 3.57 (d, 1H), 3.14 - 3.06 (m, 4H), 3.03 (d, J= 7.3 Hz, 2H), 1.93 (s, 3H), 1.79 - 1.66 (m, 2H), 1.63 - 1.47 (m, 2H), 1.36 (s, 6H). ESI-MS: m/z 608.2 [M+Na]+. 实施例 453 Compound 585 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 8.25 - 8.16 (m, 1H), 8.07 - 7.97 (m, 3H), 7.94 (d, J = 8.3 Hz, 2H ), 7.15 - 7.04 (m, 2H), 6.92 - 6.84 (m, 2H), 3.94 (t, J = 5.5 Hz, 2H), 3.57 (d, 1H), 3.14 - 3.06 (m, 4H), 3.03 ( d, J = 7.3 Hz, 2H), 1.93 (s, 3H), 1.79 - 1.66 (m, 2H), 1.63 - 1.47 (m, 2H), 1.36 (s, 6H). ESI-MS: m/z 608.2 [M+Na] + . Example 453
4-((4-(5-(4-氟苯氧基) -2,2-二甲基戊酰胺基） 哌啶 -1-基） 磺酰基） 苯磺酸 2-乙酰氨基 乙酯 (化合物 586)  4-((4-(5-(4-fluorophenoxy)-2,2-dimethylpentanoyl)piperidin-1-yl)sulfonyl) 2-acetamidoethyl benzenesulfonate (compound) 586)
参照实施例 119的方法制得化合物 586: 1H MR (300 MHz, DMSO- 6) δ 8.12 (t, J = 5.7 Hz, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 7.8 Hz, 1H), 7.12 - 6.98 (m, 2H), 6.93 - 6.79 (m, 2H), 3.90 (t, J= 5.5 Hz, 2H), 3.86 - 3.77 (m, 2H), 3.67 - 3.47 (m, 3H), 3.13 - 2.97 (m, 2H), 2.39 (d, J = 12.1 Hz, 2H), 1.89 (s, 3H), 1.68 (d, J = 12.2 Hz, 2H), 1.56 - 1.46 (m, 4H), 1.46 - 1.38 (m, 2H), 1.02 (s, 6H). ESI-MS: m/z 626.2 [M-H]". Compound 586 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.12 (t, J = 5.7 Hz, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 7.8 Hz, 1H), 7.12 - 6.98 (m, 2H), 6.93 - 6.79 (m, 2H), 3.90 (t, J = 5.5 Hz, 2H), 3.86 - 3.77 (m, 2H), 3.67 - 3.47 (m, 3H), 3.13 - 2.97 (m, 2H), 2.39 (d, J = 12.1 Hz, 2H), 1.89 (s, 3H), 1.68 (d, J = 12.2 Hz, 2H), 1.56 - 1.46 (m, 4H), 1.46 - 1.38 (m, 2H), 1.02 (s, 6H). ESI-MS: m/z 626.2 [MH]".
实施例 454  Example 454
4-((4-(2-(4-氯苯氧基) -2-甲基丙酰氨基） 哌啶 -1-基）磺酰基） 苯磺酸 2-乙酰氨基乙酯 (化合物 587)  4-((4-(2-(4-Chlorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzenesulfonic acid 2-acetamidoethyl ester (compound 587)
参照实施例 14的方法制得化合物 587: 1H MR (300 MHz, DMSO- 6) δ 8.26 - 8.14 (m, 1H), 8.11— 7.97 (m, 3H), 7.93 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 3.94 (t, J = 5.5 Hz, 2H), 3.56 (d, J = 12.0 Hz, 1H), 3.17 - 3.05 (m, 4H), 3.06 - 2.97 (m, 2H), 1.93 (s, 3H), 1.77 - 1.64 (m, 2H), 1.61 - 1.46 (m, 2H), 1.39 (s, 6H). ESI-MS: m/z 624.2 [M+Na]+. Compound 587 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 8.26 - 8.14 (m, 1H), 8.11 - 7.97 (m, 3H), 7.93 (d, J = 8.2 Hz, 2H ), 7.31 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 3.94 (t, J = 5.5 Hz, 2H), 3.56 (d, J = 12.0 Hz, 1H), 3.17 - 3.05 (m, 4H), 3.06 - 2.97 (m, 2H), 1.93 (s, 3H), 1.77 - 1.64 (m, 2H), 1.61 - 1.46 (m, 2H), 1.39 (s, 6H). ESI-MS: m/z 624.2 [M+Na] + .
实施例 455  Example 455
4-((4-(5-(4-氯苯氧基) -2,2-二甲基戊酰胺基） 哌啶 -1-基） 磺酰基） 苯磺酸 2-乙酰氨基 乙酯 （化合物 588) 4-((4-(5-(4-chlorophenoxy)-2,2-dimethylpentanoyl)piperidin-1-yl)sulfonyl) 2-acetamidobenzenesulfonate Ethyl ester (compound 588)
参照实施例 119的方法制得化合物 588: 1H MR (300 MHz, DMSO- 6) δ 8.26 - 8.16 (m, 1H), 8.04 (d, J= 8.2 Hz, 2H), 7.95 (d, J= 8.2 Hz, 2H), 7.31 (d, J= 2.5 Hz, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 6.94 (d, J = 4.0 Hz, 1H), 6.90 (d, J = 1.8 Hz, 1H), 3.94 (t, J = 5.5 Hz, 2H), 3.92 - 3.82 (m, 2H), 3.68 - 3.51 (m, 3H), 3.13 - 3.00 (m, 4H), 1.93 (s, 3H), 1.78 - 1.64 (m, 2H), 1.60 - 1.50 (m, 4H), 1.50 - 1.42 (m, 2H), 1.05 (s, 6H). ESI-MS: m/z 642.2 [M-H]". Compound 588 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.26 - 8.16 (m, 1H), 8.04 (d, J = 8.2 Hz, 2H), 7.95 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 2.5 Hz, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 6.94 (d, J = 4.0 Hz, (1, H) , 4H), 1.93 (s, 3H), 1.78 - 1.64 (m, 2H), 1.60 - 1.50 (m, 4H), 1.50 - 1.42 (m, 2H), 1.05 (s, 6H). ESI-MS: m /z 642.2 [MH]".
实施例 456  Example 456
4- ( (4- (2-甲基 -2- (3- (三氟甲基） 苯氧基） 丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲 酸 （化合物 489)  4-((4-(2-methyl-2-(3-(trifluoromethyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 489)
参照实施例 14的方法制得化合物 589: 1H MR (300 MHz, DMSO- 6) δ 13.48 (s, 1H), 8.14 (d, J = 8.2 Hz, 2H), 8.06 (d, J = 7.7 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.49 (dd, 1H), 7.34 (d, J= 7.6 Hz, 1H), 7.17 - 7.05 (m, 2H), 3.72 - 3.57 (m, 1H), 3.57 - 3.48 (m, 2H), 2.47 - 2.35 (m, 2H), 1.72 - 1.61 (m, 2H), 1.59 - 1.49 (m, 2H), 1.44 (s, 6H). ESI-MS: m/z 513.1 [M-H] -. Compound 589 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 13.48 (s, 1H), 8.14 (d, J = 8.2 Hz, 2H), 8.06 (d, J = 7.7 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.49 (dd, 1H), 7.34 (d, J= 7.6 Hz, 1H), 7.17 - 7.05 (m, 2H), 3.72 - 3.57 (m, 1H) ), 3.57 - 3.48 (m, 2H), 2.47 - 2.35 (m, 2H), 1.72 - 1.61 (m, 2H), 1.59 - 1.49 (m, 2H), 1.44 (s, 6H). ESI-MS: m /z 513.1 [MH] -.
实施例 457  Example 457
4- ( (4- (2-甲基 -2- (3- (三氟甲基） 苯氧基） 丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲 酸 （2-乙酰氨基） 乙酯 （化合物 590)  4-((4-(2-methyl-2-(3-(trifluoromethyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzoic acid (2-acetylamino) Ester (compound 590)
参照实施例 14和 183的方法制得化合物 590: 1H NMR (300 MHz, CDC13) δ 8.19 (d, J = 8.0 Hz, 2H), 7.82 (d, J= 8.0 Hz, 2H), 7.47 - 7.30 (m, 2H), 7.12 (s, 1H), 7.05 (d, J= 7.6 Hz, 1H), 6.46 (d, J = 7.4 Hz, 1H), 5.90 - 5.76 (m, 1H), 4.47 (t, J = 4.8 Hz, 2H), 3.91 - 3.59 (m, 5H), 2.59 - 2.37 (m, 2H), 2.12 - 1.87 (m, 2H), 2.10(s, 3H), 1.65 - 1.55 (m, 2H), 1.50 (s, 6H). ESI-MS: m/z 622.2 [M+Na] +. Compound 590 was prepared by the methods of Examples 14 and 183: 1H NMR (300 MHz, CDC1 3 ) δ 8.19 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.47 - 7.30 (m, 2H), 7.12 (s, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.46 (d, J = 7.4 Hz, 1H), 5.90 - 5.76 (m, 1H), 4.47 (t, J = 4.8 Hz, 2H), 3.91 - 3.59 (m, 5H), 2.59 - 2.37 (m, 2H), 2.12 - 1.87 (m, 2H), 2.10(s, 3H), 1.65 - 1.55 (m, 2H) , 1.50 (s, 6H). ESI-MS: m/z 622.2 [M+Na] + .
实施例 458  Example 458
2- (4-氯苯氧基） -2-甲基 -N- ( 1- ( (4-氨磺酰基苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 (化合物 591 )  2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-sulfamoylphenyl)sulfonyl)piperidin-4-yl)propanamide (Compound 591)
参照实施例 14的方法制得化合物 591 : 1H MR (300 MHz, DMSO- 6) δ 8.05 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.62 (s, 2H), 7.31 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 3.77 - 3.44 (m, 3H), 2.48 - 2.36 (m, 2H), 1.77 - 1.62 (m, 2H), 1.62 - 1.45 (m, 2H), 1.39 (s, 6H). ESI-MS: m/z 538.1 [M+Na]+. Compound 591 was prepared by the method of Example 14: 1H MR (300 MHz, DMSO- 6 ) δ 8.05 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.62 (s, 2H), 7.31 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 3.77 - 3.44 (m, 3H), 2.48 - 2.36 (m, 2H), 1.77 - 1.62 (m, 2H), 1.62 - 1.45 (m, 2H), 1.39 (s, 6H). ESI-MS: m/z 538.1 [M+Na] + .
实施例 459  Example 459
5 - ( ( 1-溴萘 -2-基） 氧基） -N- ( 1- ( (4-氟苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊 酰胺 （化合物 592)  5-((1-Bromonaphthalen-2-yl)oxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (Compound 592)
参照实施例 119的方法制得化合物 592: 1H MR (300 MHz, DMSO- 6) δ 8.18 (d, J = 8.4 Hz, 2H), 8.08 (d, J= 8.5 Hz, 1H), 7.99 - 7.88 (m, 4H), 7.67 - 7.58 (m, 1H), 7.51 - 7.41 (m, 2H), 7.21 (d,J= 7.9 Hz, 1H), 4.19-4.11 (m, 2H), 3.66-3.54 (m, 3H), 3.31 (s, 3H), 2.45 - 2.37 (m, 2H), 1.71 - 1.60 (m, 6H), 1.52 - 1.42 (m, 2H), 1.07 (s, 6H). ESI-MS: m/z 652.2 [M+H] +. Compound 592 was prepared by the method of Example 119: 1H MR (300 MHz, DMSO- 6 ) δ 8.18 (d, J = 8.4 Hz, 2H), 8.08 (d, J= 8.5 Hz, 1H), 7.99 - 7.88 (m, 4H), 7.67 - 7.58 (m, 1H), 7.51 - 7.41 (m, 2H), 7.21 (d, J = 7.9 Hz, 1H), 4.19-4.11 (m, 2H), 3.66-3.54 (m, 3H), 3.31 (s, 3H), 2.45 - 2.37 (m, 2H), 1.71 - 1.60 (m, 6H), 1.52 - 1.42 (m, 2H), 1.07 (s, 6H). ESI-MS: m/z 652.2 [M+H] + .
实施例 460  Example 460
N- (1 - ((4-氟苯基） 磺酰基） 哌啶 -4-基） -5- (异喹啉 -5-基氧基） -2,2-二甲基戊酰 胺 （化合物 593)  N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-5-(isoquinolin-5-yloxy)-2,2-dimethylpentanamide (compound 593 )
参照实施例 119的方法制得化合物 593: iH MR (300 MHz, OMSO-d6) δ 9.25 (s, 1Η),Compound 593 was prepared by the method of Example 119: iH MR (300 MHz, OMSO-d 6 ) δ 9.25 (s, 1 Η),
8.49 (d, J= 5.8 Hz, 1H), 7.97 - 7.92 (m, 1H), 7.83 - 7.74 (m, 2H), 7.66 - 7.61 (m, 1H), 7.60 -7.52 (m, 1H), 7.52-7.41 (m, 2H), 7.29-7.21 (m, 1H), 7.20 -7.12 (m, 1H), 4.16-4.05 (m, 2H), 3.65 - 3.47 (m, 3H), 3.27 - 3.22 (m, 2H), 2.39 - 2.23 (m, 2H), 1.79 - 1.61 (m, 4H), 1.55 - 1.43 (m, 2H), 1.23 (s, 3H), 1.09 (s, 3H). ESI-MS: m/z 536.2 [M+Na]+. 8.49 (d, J = 5.8 Hz, 1H), 7.97 - 7.92 (m, 1H), 7.83 - 7.74 (m, 2H), 7.66 - 7.61 (m, 1H), 7.60 -7.52 (m, 1H), 7.52- 7.41 (m, 2H), 7.29-7.21 (m, 1H), 7.20 -7.12 (m, 1H), 4.16-4.05 (m, 2H), 3.65 - 3.47 (m, 3H), 3.27 - 3.22 (m, 2H) ), 2.39 - 2.23 (m, 2H), 1.79 - 1.61 (m, 4H), 1.55 - 1.43 (m, 2H), 1.23 (s, 3H), 1.09 (s, 3H). ESI-MS: m/z 536.2 [M+Na] + .
实施例 461  Example 461
4- ((4- (5- (异喹啉 -5-基氧基） -2,2-二甲基戊酰胺基） 哌啶 -1-基）磺酰基）苯甲酸 (化合物 594)  4-((4-(5-(Isoquinoline-5-yloxy)-2,2-dimethylpentanyl)piperidin-1-yl)sulfonyl)benzoic acid (Compound 594)
参照实施例 119的方法制得化合物 594: 1H MR(300 MHz, OMSO-d6) δ 9.26 (s, 1Η),Compound 594 was prepared by the method of Example 119: 1H MR (300 MHz, OMSO-d 6 ) δ 9.26 (s, 1 Η),
8.50 (d, J= 5.8 Hz, 1H), 8.10 (d, J= 8.0 Hz, 2H), 7.95 (d, J= 5.9 Hz, 1H), 7.74 - 7.52 (m, 4H), 7.34-7.24 (m, 2H), 7.18 (d, J=7.9Hz, 1H), 4.16-4.07 (m, 2H), 3.66-3.51 (m, 3H), 2.33 - 2.24 (m, 2H), 1.80 - 1.66 (m, 6H), 1.57 - 1.46 (m, 2H), 1.24 (s, 3H), 1.10 (s, 3H). ESI-MS: m/z 540.2 [M+H]+. 8.50 (d, J = 5.8 Hz, 1H), 8.10 (d, J = 8.0 Hz, 2H), 7.95 (d, J = 5.9 Hz, 1H), 7.74 - 7.52 (m, 4H), 7.34-7.24 (m , 2H), 7.18 (d, J=7.9Hz, 1H), 4.16-4.07 (m, 2H), 3.66-3.51 (m, 3H), 2.33 - 2.24 (m, 2H), 1.80 - 1.66 (m, 6H ), 1.57 - 1.46 (m, 2H), 1.24 (s, 3H), 1.10 (s, 3H). ESI-MS: m/z 540.2 [M+H] + .
实施例 462  Example 462
4- ((4- (2,2-二甲基 -5- (4- (甲基磺酰基） 苯氧基）戊酰氨基） 哌啶 -1-基）磺酰基） 苯甲酸 2-乙酰氨基乙酯 （化合物 595)  4-((4-(2,2-Dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanoylamino)piperidin-1-yl)sulfonyl)-2-acetamidobenzoate Ethyl ester (compound 595)
参照实施例 119和 183的方法制得化合物 595: 1H NMR (300 MHz, CDC13) δ 8.20 (d, J= 8.3 Hz, 2H), 7.84 (d, J= 3.5 Hz, 2H), 7.82 (d, J= 3.0 Hz, 2H), 6.97 (d, J= 8.7 Hz, 2H), 5.90 (br s, 1H), 5.55 (d, J= 7.8 Hz, 1H), 4.46 (t, J= 5.2 Hz, 2H), 3.99 (t, J= 5.6 Hz, 2H), 3.88 - 3.77 (m, 2H), 3.76 - 3.62 (m, 3H), 3.03 (s, 3H), 2.48 - 2.34 (m, 2H), 2.01 (s, 3H), 1.99 - 1.90 (m, 2H), 1.79 - 1.64 (m, 4H), 1.56 - 1.45 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 674.3 [M+Na]+. Compound 595 was obtained by the methods of Examples 119 and 183: 1H NMR (300 MHz, CDC1 3 ) δ 8.20 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 3.5 Hz, 2H), 7.82 (d , J= 3.0 Hz, 2H), 6.97 (d, J= 8.7 Hz, 2H), 5.90 (br s, 1H), 5.55 (d, J= 7.8 Hz, 1H), 4.46 (t, J= 5.2 Hz, 2H), 3.99 (t, J= 5.6 Hz, 2H), 3.88 - 3.77 (m, 2H), 3.76 - 3.62 (m, 3H), 3.03 (s, 3H), 2.48 - 2.34 (m, 2H), 2.01 (s, 3H), 1.99 - 1.90 (m, 2H), 1.79 - 1.64 (m, 4H), 1.56 - 1.45 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 674.3 [M +Na] + .
实施例 463  Example 463
4- ((4- (2,2-二甲基 -5- (4- (甲基磺酰基） 苯氧基）戊酰氨基） 哌啶 -1-基）磺酰基） 苯甲酸钠 （化合物 596)  4-((4-(2,2-Dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanoylamino)piperidin-1-yl)sulfonyl) sodium benzoate (Compound 596)
将化合物 239 (实施例 155)制成钠盐，得化合物 596: 1H MR(300 MHz, OMSO-d6) δ 8.03 (d, J= 8.1 Hz, 2H), 7.82 (d, J= 8.7 Hz, 2H), 7.61 (d, J= 8.1 Hz, 2H), 7.24 (d, J= 7.5 Hz, 1H), 7.11 (d, J= 8.7 Hz, 2H), 4.07 - 3.94 (m, 2H), 3.64 - 3.43 (m, 3H), 3.15 (s, 3H), 2.39 - 2.23 (m, 2H), 1.74 - 1.63 (m, 2H), 1.59 - 1.54 (m, 3H), 1.54 - 1.45 (m, 2H), 1.05 (s, 6H). ESI-MS: m/z 611.2 [M+Na]+. Compound 239 (Example 155) was prepared as the sodium salt to give compound 596: 1H MR (300 MHz, OMSO-d 6 ) δ 8.03 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 8.7 Hz, 2H), 7.61 (d, J= 8.1 Hz, 2H), 7.24 (d, J= 7.5 Hz, 1H), 7.11 (d, J= 8.7 Hz, 2H), 4.07 - 3.94 (m, 2H), 3.64 - 3.43 (m, 3H), 3.15 (s, 3H), 2.39 - 2.23 (m, 2H) , 1.74 - 1.63 (m, 2H), 1.59 - 1.54 (m, 3H), 1.54 - 1.45 (m, 2H), 1.05 (s, 6H). ESI-MS: m/z 611.2 [M+Na] + .
实施例 464  Example 464
4-((4-(5-(3,4-二氟苯氧基; )-2,2-二甲基戊酰胺基;)哌啶 -1-基;)磺酰基；)苯甲酸 2-乙酰氨基 乙酯 （化合物 597)  4-((4-(5-(3,4-difluorophenoxy))-2,2-dimethylpentanamide;)piperidin-1-yl;)sulfonyl;)benzoic acid 2- Acetylaminoethyl ester (compound 597)
参照实施例 183的方法制得化合物 597: 1H NMR (300 MHz, CDC13) δ 8.19 (d, J= 8.1 Hz, 2H), 7.83 (d, J = 8.1 Hz, 2H), 7.13 - 6.95 (m, 1H), 6.74 - 6.60 (m, 1H), 6.57 - 6.50 (m, 1H), 5.92 - 5.77 (m, 1H), 5.51 (d, J = 7.8 Hz, 1H), 4.62 - 4.35 (m, 2H), 3.98 - 3.73 (m, 4H), 3.73 - 3.57 (m, 3H), 2.64 - 2.27 (m, 2H), 2.17 - 1.90 (m, 4H), 1.73 - 1.38 (m, 7H), 1.17 (s, 6H). ESI-MS: m/z 632.3 [M+Na]+. Compound 597 was obtained by the method of Example 183: 1H NMR (300 MHz, CDC1 3 ) δ 8.19 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.1 Hz, 2H), 7.13 - 6.95 (m , 1H), 6.74 - 6.60 (m, 1H), 6.57 - 6.50 (m, 1H), 5.92 - 5.77 (m, 1H), 5.51 (d, J = 7.8 Hz, 1H), 4.62 - 4.35 (m, 2H ), 3.98 - 3.73 (m, 4H), 3.73 - 3.57 (m, 3H), 2.64 - 2.27 (m, 2H), 2.17 - 1.90 (m, 4H), 1.73 - 1.38 (m, 7H), 1.17 (s , 6H). ESI-MS: m/z 632.3 [M+Na] + .
实施例 465  Example 465
4- ((4-(5-(4-氟苯氧基; )-2,2-二甲基戊酰胺基)哌啶 -1-基;)磺酰基；)苯甲酸 2-乙酰氨基乙 酯 （化合物 598 )  4-((4-(5-(4-fluorophenoxy))-2,2-dimethylpentanoyl)piperidin-1-yl;)sulfonyl;) 2-acetamidoethyl benzoate (compound 598)
参照实施例 183的方法制得化合物 598 : 1H NMR (300 MHz, CDC13) δ 8.19 (d, J= 8.3 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.03 - 6.89 (m, 2H), 6.86 - 6.72 (m, 2H), 5.95 - 5.77 (m, 1H), 5.53 (d, J = 7.8 Hz, 1H), 4.46 (t, J = 5.3 Hz, 2H), 3.95 - 3.60 (m, 7H), 2.50 - 2.34 (m, 2H), 2.1 1 - 1.91 (m, 5H), 1.59 - 1.27 (m, 6H), 1.17 (s, 6H). ESI-MS: m/z 592.2 [M+H]+. 实施例 466 Compound 598 was obtained by the method of Example 183: 1H NMR (300 MHz, CDC1 3 ) δ 8.19 (d, J = 8.3 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.03 - 6.89 (m , 2H), 6.86 - 6.72 (m, 2H), 5.95 - 5.77 (m, 1H), 5.53 (d, J = 7.8 Hz, 1H), 4.46 (t, J = 5.3 Hz, 2H), 3.95 - 3.60 ( m, 7H), 2.50 - 2.34 (m, 2H), 2.1 1 - 1.91 (m, 5H), 1.59 - 1.27 (m, 6H), 1.17 (s, 6H). ESI-MS: m/z 592.2 [M +H] + . Example 466
5- (4-氯苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (N-甲基氨磺酰基） 苯基）磺酰基） 哌啶 -4-基） 戊酰胺 （化合物 599)  5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-((4-(N-methylsulfamoyl)phenyl)sulfonyl)piperidin-4-yl) Valentamide (compound 599)
参照实施例 119的方法制得化合物 599: 1H MR (300 MHz, OMSO-d6) δ 8.01 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.73 (s, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 6.91 (d, J= 8.8 Hz, 2H), 3.93 - 3.84 (m, 2H), 3.66 - 3.51 (m, 3H), 2.47 (s, 3H), 2.45 - 2.37 (m, 2H), 1.70 (d, J = 10.7 Hz, 2H), 1.56 - 1.51 (m, 4H), 1.51 - 1.41 (m, 2H), 1.05 (s, 6H). ESI-MS: m/z 594.1 [M+Na]+. Compound 599 was prepared by the method of Example 119: 1H MR (300 MHz, OMSO-d 6 ) δ 8.01 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.73 (s , 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 3.93 - 3.84 (m, 2H), 3.66 - 3.51 (m, 3H), 2.47 (s, 3H), 2.45 - 2.37 (m, 2H), 1.70 (d, J = 10.7 Hz, 2H), 1.56 - 1.51 (m, 4H), 1.51 - 1.41 (m , 2H), 1.05 (s, 6H). ESI-MS: m/z 594.1 [M+Na] + .
实施例 467  Example 467
反式—4- ( ( 4- ( 2,2-二甲基 -5- ( 4- (甲基磺酰基） 苯氧基） 戊酰氨基） -3-氟哌啶 -1- 基） 磺酰基） 苯甲酸 （化合物 600)  Trans-4-((4-(2,2-Dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl Benzoic acid (compound 600)
参照实施例 139的方法制得化合物 600: 1H NMR (300 MHz, OMSO-d6) δ 13.49 (s, 1H), 8.15 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 4.69 - 4.42 (m, 1H), 4.00 (t, J = 5.2 Hz, 2H), 3.93 - 3.75 (m, 2H), 3.58 - 3.45 (m, 1H), 3.14 (s, 3H), 2.71 - 2.54 (m, 2H), 1.81 - 1.68 (m, 1H), 1.65 - 1.54 (m, 4H), 1.54 - 1.46 (m, 1H), 1.07 (s, 6H). ESI-MS: m/z 607.2 [M+Na]+. 实施例 468 The compound 600 was obtained by the method of Example 139: 1H NMR (300 MHz, OMSO-d 6 ) δ 13.49 (s, 1H), 8.15 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz , 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 4.69 - 4.42 (m, 1H), 4.00 (t, J = 5.2 Hz, 2H), 3.93 - 3.75 (m, 2H), 3.58 - 3.45 (m, 1H), 3.14 (s, 3H), 2.71 - 2.54 (m, 2H), 1.81 - 1.68 (m , 1H), 1.65 - 1.54 (m, 4H), 1.54 - 1.46 (m, 1H), 1.07 (s, 6H). ESI-MS: m/z 607.2 [M+Na] + . Example 468
反式 -N- ( 3-氟-1- ( ( 4- (甲基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基 -5- (4- (甲基磺酰基） 苯氧基） 戊酰胺 （化合物 601 )  trans-N-(3-Fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5- (4- Methylsulfonyl) phenoxy) pentanoamide (compound 601)
参照实施例 139的方法制得化合物 601 : 1H MR (300 MHz, OMSO-d6) δ 8.19 (d, J = 8.3 Hz, 2H), 8.05 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 8.7 Hz, 2H), 4.71 - 4.44 (m, 1H), 4.01 (t, J = 5.2 Hz, 2H), 3.93 - 3.82 (m, 2H), 3.60 - 3.48 (m, 1H), 3.32 (s, 3H), 3.15 (s, 3H), 2.77 - 2.60 (m, 2H), 1.82 - 1.70 (m, 1H), 1.65 - 1.56 (m, 4H), 1.56 - 1.47 (m, 1H), 1.08 (s, 6H). ESI-MS: m/z 641.2 [M+Na]+. Compound 601 was prepared by the method of Example 139: 1H MR (300 MHz, OMSO-d 6 ) δ 8.19 (d, J = 8.3 Hz, 2H), 8.05 (d, J = 8.3 Hz, 2H), 7.82 (d , J = 8.6 Hz, 2H), 7.45 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 8.7 Hz, 2H), 4.71 - 4.44 (m, 1H), 4.01 (t, J = 5.2 Hz , 2H), 3.93 - 3.82 (m, 2H), 3.60 - 3.48 (m, 1H), 3.32 (s, 3H), 3.15 (s, 3H), 2.77 - 2.60 (m, 2H), 1.82 - 1.70 (m , 1H), 1.65 - 1.56 (m, 4H), 1.56 - 1.47 (m, 1H), 1.08 (s, 6H). ESI-MS: m/z 641.2 [M+Na] + .
实施例 469  Example 469
4-((4-(2,2-二甲基 -5-(3- (三氟甲基） 苯氧基） 戊酰胺基） 哌啶 -1-基） 磺酰基） 苯甲酸 (化合物 602)  4-((4-(2,2-Dimethyl-5-(3-(trifluoromethyl)phenoxy)pentanamide)piperidin-1-yl)sulfonyl)benzoic acid (Compound 602)
参照实施例 119的方法制得化合物 602: 1H NMR (300 MHz, DMSO- 6) δ 13.47 (s, 1H), 8.15 (d, J= 8.3 Hz, 2H), 7.84 (d, J= 8.2 Hz, 2H), 7.25 (m, 1H), 7.21 (d, J= 7.8 Hz, 1H), 7.18 (m, 1H), 7.13 (m, 1H), 6.90 (m, 1H), 3.96 - 3.83 (m, 2H), 3.70 - 3.50 (m, 3H), 2.47 - 2.34 (m, 2H), 1.77 - 1.61 (m, 2H), 1.60 - 1.39 (m, 6H), 1.08 (s, 6H). ESI-MS: m/z 555.2 [M-H]". Compound 602 was obtained by the method of Example 119: 1H NMR (300 MHz, DMSO- 6 ) δ 13.47 (s, 1H), 8.15 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.25 (m, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.18 (m, 1H), 7.13 (m, 1H), 6.90 (m, 1H), 3.96 - 3.83 (m, 2H) ), 3.70 - 3.50 (m, 3H), 2.47 - 2.34 (m, 2H), 1.77 - 1.61 (m, 2H), 1.60 - 1.39 (m, 6H), 1.08 (s, 6H). ESI-MS: m /z 555.2 [MH]".
实施例 470  Example 470
4-((4-(5-(4-氟 -3- (三氟甲基） 苯氧基 )-2,2-二甲基戊酰胺基） 哌啶 -1-基） 磺酰基） 苯 甲酸 （化合物 603 )  4-((4-(5-(4-fluoro-3-(trifluoromethyl)phenoxy)-2,2-dimethylpentanyl)piperidin-1-yl)sulfonyl)benzoic acid (compound 603)
参照实施例 119的方法制得化合物 603 : 1H NMR (300 MHz, DMSO- 6) δ 13.41 (s, 1H), 8.14 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.25 - 6.98 (m, 3H), 3.95 - 3.82 (m, 2H), 3.69 - 3.51 (m, 3H), 2.46 - 2.35 (m, 2H), 1.76 - 1.62 (m, 2H), 1.60 - 1.39 (m, 6H), 1.08 (s, 6H). ESI-MS: m/z 573.2 [M-H]". The compound 603 was obtained by the method of Example 119: 1H NMR (300 MHz, DMSO- 6 ) δ 13.41 (s, 1H), 8.14 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.25 - 6.98 (m, 3H), 3.95 - 3.82 (m, 2H), 3.69 - 3.51 (m, 3H), 2.46 - 2.35 (m, 2H) , 1.76 - 1.62 (m, 2H), 1.60 - 1.39 (m, 6H), 1.08 (s, 6H). ESI-MS: m/z 573.2 [MH]".
实施例 471  Example 471
化合物促进 C2C12细胞 AMPK ( Thrl72) 磷酸化激活能力的测试  Compounds promote C2C12 cell AMPK ( Thrl72) phosphorylation activation ability test
将 C2C12细胞铺板于 12孔板中， 用含 10%牛血清的培养基促进细胞生长至密为 70-80%, 更换含 2.0%马血清的培养基， 每日更换培养基， 诱导细胞分化。 分化完全后， 饥饿 6-8小时。 将受试化合物 （10 μΜ) 添加于 12孔板中， 0.1% DMSO组设为阴性对 照， AICAR ( ΙΟΟ μΜ) 组设为阳性对照。 给药 2h后， 丢弃培养基， 预冷的 PBS洗涤 2 次， 每孔加入 100 μΐ的裂解液， 收集裂解液。采用 Western Blot技术检测 AMPK磷酸化 情况， 然后进行灰度扫描， 阴性对照组 pAMPK/AMPK 的比值定义为 1， 受试化合物 pAMPK/AMPK的比值为阴性对照组的相对比值。 pAMPK/AMPK的比值反映化合物促 进 AMPK磷酸化激活的能力。 实验结果见表 2和图 1。  C2C12 cells were plated in a 12-well plate, and the cells were grown to a 70-80% density with a medium containing 10% bovine serum. The medium containing 2.0% horse serum was replaced, and the medium was changed daily to induce cell differentiation. After the differentiation is complete, starvation is 6-8 hours. The test compound (10 μΜ) was added to a 12-well plate, the 0.1% DMSO group was set as a negative control, and the AICAR (ΙΟΟ μΜ) group was set as a positive control. After 2 h of administration, the medium was discarded, washed twice with pre-cooled PBS, and 100 μM of lysate was added to each well to collect the lysate. Western blotting was used to detect AMPK phosphorylation, followed by grayscale scanning. The ratio of pAMPK/AMPK in the negative control group was defined as 1. The ratio of the test compound pAMPK/AMPK was the relative ratio of the negative control group. The ratio of pAMPK/AMPK reflects the ability of the compound to promote AMPK phosphorylation activation. The experimental results are shown in Table 2 and Figure 1.
表 2、 化合物促进 C2C12细胞 AMPK磷酸化激动的活性 化合物编号 pAMPK/AMPK 化合物编号 pAMPK/AMPK 化合物编号 pAMPK/AMPKTable 2. Compounds promote AMPK phosphorylation agonistic activity in C2C12 cells Compound number pAMPK/AMPK Compound number pAMPK/AMPK Compound number pAMPK/AMPK
DMSO 1.00 152 1.75 381 2.55DMSO 1.00 152 1.75 381 2.55
AICAR 1.43 153 1.83 382 2.90AICAR 1.43 153 1.83 382 2.90
1 1.88 154 1.69 383 3.271 1.88 154 1.69 383 3.27
2 1.51 196 1.90 391 1.562 1.51 196 1.90 391 1.56
3 1.80 216 1.50 392 1.793 1.80 216 1.50 392 1.79
4 1.55 217 1.45 394 1.874 1.55 217 1.45 394 1.87
5 1.91 218 1.44 395 1.985 1.91 218 1.44 395 1.98
6 1.58 219 1.53 396 1.886 1.58 219 1.53 396 1.88
7 1.62 221 1.68 397 1.697 1.62 221 1.68 397 1.69
8 1.77 222 1.99 398 1.828 1.77 222 1.99 398 1.82
9 1.70 223 2.02 399 2.079 1.70 223 2.02 399 2.07
10 1.63 224 1.84 400 1.6810 1.63 224 1.84 400 1.68
11 1.57 225 1.57 401 2.1111 1.57 225 1.57 401 2.11
12 1.69 226 1.69 402 1.9712 1.69 226 1.69 402 1.97
13 1.85 227 1.62 403 1.9213 1.85 227 1.62 403 1.92
14 1.59 228 1.75 404 1.7514 1.59 228 1.75 404 1.75
15 1.51 229 1.63 408 1.8015 1.51 229 1.63 408 1.80
16 1.52 230 1.84 409 1.8916 1.52 230 1.84 409 1.89
17 1.49 231 1.53 410 1.8417 1.49 231 1.53 410 1.84
18 1.61 232 1.62 411 1.9018 1.61 232 1.62 411 1.90
19 1.62 233 1.65 412 1.8319 1.62 233 1.65 412 1.83
20 1.38 234 1.57 415 1.9620 1.38 234 1.57 415 1.96
21 1.47 235 1.65 416 1.7021 1.47 235 1.65 416 1.70
22 1.64 236 1.84 417 1.7322 1.64 236 1.84 417 1.73
23 1.69 237 2.08 418 1.7023 1.69 237 2.08 418 1.70
24 1.80 238 2.14 419 1.5124 1.80 238 2.14 419 1.51
25 1.69 239 2.02 424 1.6925 1.69 239 2.02 424 1.69
26 1.63 240 1.67 425 1.8026 1.63 240 1.67 425 1.80
27 1.75 241 1.95 426 1.8627 1.75 241 1.95 426 1.86
28 1.54 242 1.81 427 1.9528 1.54 242 1.81 427 1.95
29 1.58 243 2.15 428 1.5929 1.58 243 2.15 428 1.59
30 1.64 244 1.90 429 1.9030 1.64 244 1.90 429 1.90
31 1.73 245 1.82 430 1.6731 1.73 245 1.82 430 1.67
32 1.69 246 1.74 431 1.7132 1.69 246 1.74 431 1.71
33 1.47 247 1.67 432 1.9033 1.47 247 1.67 432 1.90
34 1.50 248 1.86 433 1.6334 1.50 248 1.86 433 1.63
35 1.56 249 1.71 434 1.8435 1.56 249 1.71 434 1.84
36 1.42 250 1.97 435 1.7636 1.42 250 1.97 435 1.76
37 1.48 251 1.83 436 1.8337 1.48 251 1.83 436 1.83
38 1.60 252 1.54 437 1.9038 1.60 252 1.54 437 1.90
39 1.82 253 1.69 438 1.68 1.65 254 1.80 439 1.5439 1.82 253 1.69 438 1.68 1.65 254 1.80 439 1.54
1.53 255 1.91 440 1.961.53 255 1.91 440 1.96
1.51 256 1.66 441 1.741.51 256 1.66 441 1.74
1.45 257 1.82 442 1.871.45 257 1.82 442 1.87
1.56 258 1.69 443 1.751.56 258 1.69 443 1.75
1.59 259 1.58 444 1.781.59 259 1.58 444 1.78
3.01 260 1.71 445 1.573.01 260 1.71 445 1.57
1.48 261 1.86 446 1.761.48 261 1.86 446 1.76
1.75 262 1.98 447 1.821.75 262 1.98 447 1.82
1.61 265 2.37 448 1.741.61 265 2.37 448 1.74
1.80 268 1.81 449 1.631.80 268 1.81 449 1.63
1.67 270 1.96 450 1.691.67 270 1.96 450 1.69
1.84 271 1.87 451 1.951.84 271 1.87 451 1.95
1.95 272 1.68 452 1.581.95 272 1.68 452 1.58
1.73 273 1.92 453 1.691.73 273 1.92 453 1.69
1.72 274 1.84 454 1.851.72 274 1.84 454 1.85
1.60 276 1.92 455 1.701.60 276 1.92 455 1.70
1.72 277 2.03 456 1.781.72 277 2.03 456 1.78
1.63 278 2.45 457 1.931.63 278 2.45 457 1.93
1.42 280 1.70 458 1.811.42 280 1.70 458 1.81
1.60 284 1.79 459 1.861.60 284 1.79 459 1.86
1.45 285 1.91 460 1.921.45 285 1.91 460 1.92
1.57 287 2.15 461 1.711.57 287 2.15 461 1.71
1.52 289 1.95 462 1.891.52 289 1.95 462 1.89
1.48 290 1.80 463 1.841.48 290 1.80 463 1.84
1.44 291 1.78 464 1.701.44 291 1.78 464 1.70
1.50 292 2.02 465 1.861.50 292 2.02 465 1.86
1.47 293 1.86 466 1.701.47 293 1.86 466 1.70
1.55 294 1.51 467 1.831.55 294 1.51 467 1.83
1.46 295 1.87 468 1.741.46 295 1.87 468 1.74
1.72 296 1.65 469 2.931.72 296 1.65 469 2.93
1.58 297 1.80 470 2.281.58 297 1.80 470 2.28
1.62 298 1.84 471 2.051.62 298 1.84 471 2.05
1.54 299 1.69 472 1.861.54 299 1.69 472 1.86
1.49 300 1.85 473 1.791.49 300 1.85 473 1.79
1.57 301 1.78 474 1.881.57 301 1.78 474 1.88
1.61 302 1.47 475 1.971.61 302 1.47 475 1.97
1.79 303 1.52 476 1.761.79 303 1.52 476 1.76
1.84 304 1.63 477 1.681.84 304 1.63 477 1.68
1.49 305 1.85 478 1.851.49 305 1.85 478 1.85
1.64 306 1.65 479 1.711.64 306 1.65 479 1.71
1.80 307 1.58 480 3.03 99 1.48 308 1.73 481 3.271.80 307 1.58 480 3.03 99 1.48 308 1.73 481 3.27
100 1.63 309 1.74 482 1.85100 1.63 309 1.74 482 1.85
101 1.52 310 2.04 483 1.66101 1.52 310 2.04 483 1.66
102 1.44 312 1.85 484 1.58102 1.44 312 1.85 484 1.58
103 1.68 313 1.79 485 1.69103 1.68 313 1.79 485 1.69
104 1.52 314 1.88 486 1.86104 1.52 314 1.88 486 1.86
105 1.72 315 1.52 487 1.73105 1.72 315 1.52 487 1.73
106 1.67 317 1.69 488 1.90106 1.67 317 1.69 488 1.90
107 1.83 319 1.64 489 1.81107 1.83 319 1.64 489 1.81
108 1.82 320 2.10 490 1.67108 1.82 320 2.10 490 1.67
109 1.80 321 1.63 491 1.85109 1.80 321 1.63 491 1.85
110 1.57 322 1.78 492 1.74110 1.57 322 1.78 492 1.74
111 2.02 323 1.90 493 1.81111 2.02 323 1.90 493 1.81
112 1.69 324 1.81 494 1.94112 1.69 324 1.81 494 1.94
113 1.47 325 1.72 495 1.68113 1.47 325 1.72 495 1.68
114 1.53 328 1.69 496 1.77114 1.53 328 1.69 496 1.77
115 1.85 329 1.92 497 1.93115 1.85 329 1.92 497 1.93
116 1.90 330 1.88 498 1.85116 1.90 330 1.88 498 1.85
117 1.65 331 1.78 499 1.92117 1.65 331 1.78 499 1.92
118 1.60 332 2.01 500 2.15118 1.60 332 2.01 500 2.15
119 1.98 334 1.84 501 1.97119 1.98 334 1.84 501 1.97
120 1.83 341 1.80 502 1.85120 1.83 341 1.80 502 1.85
121 1.66 342 1.75 503 1.93121 1.66 342 1.75 503 1.93
122 1.54 343 1.82 504 2.17122 1.54 343 1.82 504 2.17
123 1.73 344 1.66 505 2.23123 1.73 344 1.66 505 2.23
124 1.61 346 1.75 506 2.05124 1.61 346 1.75 506 2.05
125 1.56 347 1.58 507 2.16125 1.56 347 1.58 507 2.16
126 1.64 348 1.74 508 1.73126 1.64 348 1.74 508 1.73
127 1.51 349 1.82 509 1.82127 1.51 349 1.82 509 1.82
128 1.58 350 1.95 510 1.95128 1.58 350 1.95 510 1.95
129 1.88 351 1.81 511 1.83129 1.88 351 1.81 511 1.83
130 1.48 352 1.70 512 1.79130 1.48 352 1.70 512 1.79
131 1.69 353 1.61 513 1.90131 1.69 353 1.61 513 1.90
132 1.62 354 1.66 514 2.01132 1.62 354 1.66 514 2.01
133 1.45 355 1.88 515 1.99133 1.45 355 1.88 515 1.99
134 1.66 356 2.01 516 1.87134 1.66 356 2.01 516 1.87
135 1.52 357 1.73 517 1.98135 1.52 357 1.73 517 1.98
136 1.59 360 1.68 518 1.85136 1.59 360 1.68 518 1.85
137 1.57 361 1.79 519 1.80137 1.57 361 1.79 519 1.80
138 1.68 362 1.60 520 1.96138 1.68 362 1.60 520 1.96
139 1.53 367 1.53 521 2.06139 1.53 367 1.53 521 2.06
140 2.01 368 1.64 522 2.10 141 1.65 369 1.79 523 1.96140 2.01 368 1.64 522 2.10 141 1.65 369 1.79 523 1.96
142 1.54 370 1.61 524 1.75142 1.54 370 1.61 524 1.75
143 1.70 373 1.80 525 1.76143 1.70 373 1.80 525 1.76
147 1.51 375 1.66 526 2.28147 1.51 375 1.66 526 2.28
148 1.60 376 1.87 527 1.83148 1.60 376 1.87 527 1.83
149 1.55 377 1.83 528 1.89149 1.55 377 1.83 528 1.89
150 1.58 379 1.77 529 2.01150 1.58 379 1.77 529 2.01
151 1.61 380 3.40 530 1.86151 1.61 380 3.40 530 1.86
531 1.57 553 1.78 575 2.04531 1.57 553 1.78 575 2.04
532 1.68 554 2.11 576 1.85532 1.68 554 2.11 576 1.85
533 1.90 555 2.50 577 1.96533 1.90 555 2.50 577 1.96
534 1.84 556 2.34 578 1.88534 1.84 556 2.34 578 1.88
535 1.75 557 1.82 579 1.90535 1.75 557 1.82 579 1.90
536 1.69 558 1.65 580 1.91536 1.69 558 1.65 580 1.91
537 1.81 559 1.70 581 1.73537 1.81 559 1.70 581 1.73
538 1.98 560 1.77 582 2.65538 1.98 560 1.77 582 2.65
539 1.69 561 1.61 583 2.21539 1.69 561 1.61 583 2.21
540 1.78 562 1.69 584 2.40540 1.78 562 1.69 584 2.40
541 1.75 563 1.78 585 1.89541 1.75 563 1.78 585 1.89
542 1.62 564 1.81 586 1.71542 1.62 564 1.81 586 1.71
543 1.81 565 1.88 587 2.01543 1.81 565 1.88 587 2.01
544 1.67 566 1.82 588 1.87544 1.67 566 1.82 588 1.87
545 1.69 567 2.11 589 1.91545 1.69 567 2.11 589 1.91
546 1.73 568 1.93 590 1.86546 1.73 568 1.93 590 1.86
547 2.10 569 1.89 591 2.30547 2.10 569 1.89 591 2.30
548 1.85 570 2.14 592 1.76548 1.85 570 2.14 592 1.76
549 1.97 571 2.10 593 1.55549 1.97 571 2.10 593 1.55
550 1.80 572 1.85 594 1.76550 1.80 572 1.85 594 1.76
551 1.91 573 2.06 595 1.98551 1.91 573 2.06 595 1.98
552 1.72 574 1.87 596 2.43552 1.72 574 1.87 596 2.43
597 2.31 598 2.17 599 2.01597 2.31 598 2.17 599 2.01
600 1.83 601 1.94 602 3.11600 1.83 601 1.94 602 3.11
603 3.03 图 1为化合物对 C2C12细胞 AMPK磷酸化的影响图： （ay(c)为不同浓度化合物 111 剌激 C2C12细胞 2小时后 pAMPK和 AMPK表达情况； （b)/(d)为不同浓度化合物 119 剌激 C2C12细胞 2小时后 pAMPK和 AMPK表达情况。 实验结果表明， 本发明的化合 物具有显著的 AMPK激动活性（表 2) 。 例如， 化合物 111和 119分别剂量依赖性地促 进 C2C12细胞 AMPK的磷酸化（图 1 )。以上结果表明本发明的化合物是明确的 AMPK 激动剂。 603 3.03 Figure 1 shows the effect of compounds on AMPK phosphorylation in C2C12 cells: (ay(c) is the expression of pAMPK and AMPK after 2 hours of C2C12 cells stimulated by different concentrations of compound 111; (b)/(d) are compounds of different concentrations 119 Expression of pAMPK and AMPK after 2 hours of stimulation of C2C12 cells. The results of the experiments showed that the compounds of the present invention have significant AMPK agonistic activity (Table 2). For example, Compounds 111 and 119 promote the phosphoric acid of AMPK in C2C12 cells, respectively, in a dose-dependent manner. (Fig. 1) The above results indicate that the compound of the present invention is a well-defined AMPK agonist.
实施例 472 化合物对 AdipoRl敲除细胞 AMPK磷酸化的影响 Example 472 Effect of Compounds on Phosphorylation of AMPK in AdipoRl Knockout Cells
为了确证本发明的化合物是否是通过脂联素受体 1 (AdipoRl ) 而激活 AMPK, 构 建了 AdipoRl敲除的 HEK293T细胞系， 并检测受试化合物对其 AMPK磷酸化的效应。  To confirm whether the compound of the present invention activates AMPK via adiponectin receptor 1 (AdipoRl), an AdipoRl knockout HEK293T cell line was constructed and the effect of the test compound on its AMPK phosphorylation was examined.
将野生型 HEK293T和 AdipoRl敲除 HEK293T细胞铺于 6孔板中， 用含 10%牛血 清的培养基培养， 长满后， 1%血清饥饿 6小时。 将受试化合物 （ 1,5,10,30,50 μΜ)加入 6孔板中， 0.1% DMSO组设为阴性对照。 2小时后， 丢弃培养基， 用预冷的 PB S洗涤 2 次， 每孔加入 150 μΐ的裂解液， 收集裂解液， 采用 Western Blot技术检测下游 AMPK和 pAMPK表达情况。 实验结果见图 2。  Wild type HEK293T and AdipoRl knockout HEK293T cells were plated in 6-well plates and cultured in medium containing 10% bovine serum. After completion, 1% serum was starved for 6 hours. The test compound (1, 5, 10, 30, 50 μΜ) was added to a 6-well plate, and the 0.1% DMSO group was set as a negative control. After 2 hours, the medium was discarded, washed twice with pre-cooled PB S, 150 μM of lysate was added to each well, and the lysate was collected, and the expression of downstream AMPK and pAMPK was detected by Western Blot. The experimental results are shown in Figure 2.
图 2为化合物对 AdipoRl野生型或 AdipoRl敲除 HEK293T细胞 AMPK磷酸化的 影响图： 不同浓度的化合物 119处理野生型或 AdipoRl敲除 HEK293T细胞 2小时后 pAMPK和 AMPK表达情况。 实验结果表明， 化合物 119对野生型 HEK293T细胞具有 显著的 AMPK磷酸化激动活性，而即使在高浓度下化合物 119也没有显示出对 AdipoRl 敲除细胞 AMPK的磷酸化激动活性。 以上结果说明本发明的化合物对 AMPK的激动活 性是 AdipoRl依赖的， 即本发明的化合物是特异性的脂联素受体激动剂。  Figure 2 is a graph showing the effect of compounds on AMPK phosphorylation of AdipoR1 wild-type or AdipoRl knockout HEK293T cells: expression of pAMPK and AMPK after 2 hours of treatment with wild-type or AdipoR1 knockout HEK293T cells at different concentrations of compound 119. The results showed that Compound 119 had significant AMPK phosphorylation agonistic activity against wild-type HEK293T cells, and Compound 119 showed no phosphorylation agonistic activity against AdipoR1 knockout cells AMPK even at high concentrations. The above results indicate that the agonistic activity of the compound of the present invention against AMPK is AdipoRl dependent, i.e., the compound of the present invention is a specific adiponectin receptor agonist.
实施例 473  Example 473
钙螯合剂 EGTA对化合物 AMPK激动活性的拮抗作用  Antagonism of chelating agent EGTA on agonistic activity of compound AMPK
脂联素激活细胞内 AMPK主要依赖于促进细胞外钙离子内流， 激活 AMPK的上游 激酶 CaMKK。 而 EGTA可以络合细胞外钙离子， 进而拮抗脂联素或小分子脂联素受体 激动剂介导的 AMPK激活作用。  Adiponectin activates intracellular AMPK mainly by promoting extracellular calcium influx and activating the upstream kinase CaMKK of AMPK. EGTA can complex extracellular calcium ions to antagonize AMPK activation mediated by adiponectin or small adiponectin receptor agonists.
在给予化合物 119剌激 C2C12细胞前，将 EGTA( 5 mM)与 C2C12细胞孵育 20min， 然后给药两小时， 采用 Western Blot技术检测下游 AMPK和 pAMPK表达情况。 实验结 果见图 3。  EGTA (5 mM) was incubated with C2C12 cells for 20 min before administration of compound 119 stimulating C2C12 cells, followed by two hours of administration, and the expression of downstream AMPK and pAMPK was detected by Western Blot. The experimental results are shown in Figure 3.
图 3为钙螯合剂 EGTA对化合物 AMPK激动活性的影响图： 在 EGTA ( 5mM) 存 在或不存在的情况下， 10 μΜ和 30 μΜ化合物 119剌激 C2C12细胞 2小时后 pAMPK 和 AMPK表达情况。 实验结果表明， 在不用 EGTA预处理细胞的情况下， 化合物 119 可显著激活 AMPK。 而在用 EGTA预处理细胞的情况下， EGTA完全拮抗了化合物 119 的 AMPK激动作用， 即使将化合物 119的浓度增加， EGTA也同样阻止了化合物 119对 C2C12细胞 AMPK的激动作用。 以上结果说明本发明的化合物对 AMPK的激动作用是 细胞外钙离子依赖的， 这与脂联素或小分子脂联素受体激动剂的行为一致。  Figure 3 is a graph showing the effect of EGTA on the agonistic activity of AMPK: in the presence or absence of EGTA (5 mM), 10 μΜ and 30 μΜ of compound 119 stimulate C2C12 cells to express pAMPK and AMPK after 2 hours. The experimental results showed that Compound 119 significantly activated AMPK without pretreatment of cells with EGTA. In the case of pretreatment of cells with EGTA, EGTA completely antagonized the AMPK agonism of compound 119. Even with the increase of the concentration of compound 119, EGTA also prevented the agonistic effect of compound 119 on AMPK of C2C12 cells. The above results indicate that the agonistic effect of the compounds of the present invention on AMPK is extracellular calcium-dependent, which is consistent with the behavior of adiponectin or small molecule adiponectin receptor agonists.
实施例 474  Example 474
化合物的体内降血糖活性评价  Evaluation of in vivo hypoglycemic activity of compounds
实验动物： C57B1/6J小鼠， 雄性， 8周， 购自于北京维通利华实验动物技术有限公 司。  Experimental animals: C57B1/6J mice, male, 8 weeks, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
试剂和仪器： 血糖仪 （罗氏， 卓越精采型） ， 灌胃针， 剪刀。 药物及配置： 化合物 111、 119 和阳性药罗格列酮 （购自于 Sigma) 在用时用 0.5%CMC-Na配成混悬液。 Reagents and instruments: Blood glucose meter (Roche, excellent and brilliant), gavage needle, scissors. Drugs and configuration: Compound 111, 119 and the positive drug rosiglitazone (purchased from Sigma) were formulated with 0.5% CMC-Na as a suspension.
实验方法： 8 周龄雄性 C57B1/6J小鼠适应性喂养一周后， 随机分组， 阴性对照组 (control: 0.5%CMCNa) ， 阳性对照组 （罗格列酮， 10 mg/Kg) ， 待测化合物组 1 (化 合物 111， 10 mg/Kg) ， 待测化合物组 2 (化合物 119， 10 mg/Kg) ， 每组 6只， 实验 前禁食不禁水 6小时。 在给予小鼠高血糖剌激 60min之前（记录为 -60 min) ， 剪尾取血 测定血糖水平， 并立即给药； 给药 60min后 （记录为 Omin) ， 再剪尾取血测定血糖水 平， 并立即腹腔注射 2g/Kg葡萄糖水溶液； 之后， 依次测定 20、 40、 60和 90min的小 鼠血糖水平。 收集血糖测试结果， 绘制各组血糖水平随时间变化曲线。化合物 111、 119 和罗格列酮在动物体内各时间点的血糖值变化见表 3和图 4。 表 3、 化合物对正常小鼠糖耐量的影响 （*p < 0.05,**p < 0.01 vs control) 组别 血糖水平  Experimental methods: Eight weeks old male C57B1/6J mice were fed ad libitum for one week, randomized, negative control group (control: 0.5% CMCNa), positive control group (rosiglitazone, 10 mg/Kg), test compound Group 1 (Compound 111, 10 mg/Kg), test compound group 2 (Compound 119, 10 mg/Kg), 6 rats in each group, fasted for 6 hours before the experiment. Before the mice were given hyperglycemia for 60 minutes (recorded as -60 min), the blood was collected from the tail and the blood glucose level was measured and administered immediately. After 60 minutes of administration (recorded as Omin), the blood was measured by tail-cutting. Immediately, a 2 g/Kg aqueous glucose solution was intraperitoneally injected; thereafter, blood glucose levels of the mice at 20, 40, 60, and 90 min were sequentially measured. Collect blood glucose test results and plot the blood glucose levels over time for each group. The changes in blood glucose levels of compounds 111, 119 and rosiglitazone at various time points in animals are shown in Table 3 and Figure 4. Table 3. Effect of compounds on glucose tolerance in normal mice (*p < 0.05, **p < 0.01 vs control) Group Blood glucose levels
-6 Omin Omin 20min 40min 60min 90min  -6 Omin Omin 20min 40min 60min 90min
(mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L) control 6.6±0.9 7.0±1.7 24.6±1.6 20.9±3.6 16.4±1.4 10.5±1.5 (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L) control 6.6±0.9 7.0±1.7 24.6±1.6 20.9±3.6 16.4±1.4 10.5±1.5
111 6.5±1.3 6.9±1.5 19.1±2.7* 17.7±3.6 11.8±2.3* 9.8±1.3 111 6.5±1.3 6.9±1.5 19.1±2.7* 17.7±3.6 11.8±2.3* 9.8±1.3
119 6.8±0.9 7.0±0.8 20.9±1.4* 13.9±1.0* 11.2±1.1 9.7±0.3 罗格列酮 7.1±0.5 7.7±0.7 21.1±1.3* 17.9±1.6 12.8±1.2* 10.5±1.2 实验结果表明： 正常小鼠腹腔注射 2g/Kg葡萄糖后， 血糖在 20、 40和 60min显著 升高。 给予化合物 119能够显著降低小鼠 20、 40和 60min的血糖水平， 而化合物 111 和罗格列酮能够显著降低 20和 60min的血糖水平。 以上结果说明， 本发明化合物具有 显著的降血糖活性， 因而可用于防治糖尿病及其并发症。  119 6.8±0.9 7.0±0.8 20.9±1.4* 13.9±1.0* 11.2±1.1 9.7±0.3 Rosiglitazone 7.1±0.5 7.7±0.7 21.1±1.3* 17.9±1.6 12.8±1.2* 10.5±1.2 Experimental results show: Normal After intraperitoneal injection of 2 g/Kg of glucose in mice, blood glucose was significantly increased at 20, 40 and 60 min. Administration of Compound 119 significantly reduced blood glucose levels in mice at 20, 40, and 60 min, while Compound 111 and rosiglitazone significantly reduced blood glucose levels at 20 and 60 min. The above results indicate that the compound of the present invention has remarkable hypoglycemic activity and thus can be used for the prevention and treatment of diabetes and its complications.
实施例 475  Example 475
化合物的降血脂及抗非酒精性脂肪肝作用活性评价  Evaluation of the hypolipidemic and anti-alcoholic fatty liver activity of the compound
动物： 雄性 C57BL/J6小鼠 32只， SPF级， 8周龄， 体重 20g, 购于北京维通利华。 所有动物保持 12小时交替的昼夜节律， 自由饮食。  Animals: Male C57BL/J6 mice 32, SPF grade, 8 weeks old, weighing 20 g, purchased from Beijing Vital Lihua. All animals maintained a 12-hour alternating circadian rhythm and a free diet.
奥贝胆酸 （OCA) ： 购自江苏维凯尔医药科技有限公司。  Obecholic acid (OCA): purchased from Jiangsu Weikaier Pharmaceutical Technology Co., Ltd.
小鼠高脂饲料： 购自 Research Diets (D 12492, 60 kcal%) 。  Mouse high fat diet: purchased from Research Diets (D 12492, 60 kcal%).
小鼠标准饲料： 购自 Research Diets (D12450B, 10 kcal%) 。  Standard feed for mice: purchased from Research Diets (D12450B, 10 kcal%).
动物分组及造模： 小鼠按照体重随机分成 4组： 正常饲料对照组（CHOW) 、 高脂 饲料模型组（HFD)、阳性药奥贝胆酸（5mg/Kg)组（HFD+OCA)和化合物 119 ( 10 mg/kg) 组 （HFD+119) 。 对照组喂以正常对照饲料， 其余各组给以高脂饲料造模 20周。  Animal grouping and modeling: Mice were randomly divided into 4 groups according to body weight: normal feed control group (CHOW), high fat diet model group (HFD), positive drug oleic acid (5 mg/Kg) group (HFD+OCA) and Compound 119 (10 mg/kg) group (HFD+119). The control group was fed normal control feed, and the other groups were given a high-fat diet for 20 weeks.
实验方法： 造模 20周后， 对照组及高脂饲料模型组每日灌胃予以 0.5% CMC-Na, OCA组每日灌胃予以 OCA 的 CMC-Na混悬液， 119 组每日灌胃予以化合物 119 的 CMC-Na 混悬液。给药 4周， 这期间正常饲料对照组给予正常饲料， 其余三组给予高脂 饲料。 每日对各组小鼠称重， 仔细观察并记录其体重、 毛发、 粪便及活动情况。 Experimental methods: After 20 weeks of modeling, the control group and the high-fat diet model group were intragastrically administered with 0.5% CMC-Na daily. The OCA group was intragastrically administered with CMC-Na suspension of OCA, and 119 groups were intragastrically administered daily. Compound 119 CMC-Na suspension. The drug was administered for 4 weeks, during which the normal feed control group was given normal feed, and the other three groups were given high fat feed. Each group of mice was weighed daily and carefully observed and recorded for weight, hair, feces and activity.
取材及检测： 给药 4周后， 提前 12小时禁食不禁水， 次日上午眼球取血， 处死取 肝脏。 肝脏右小叶组织用 4%多聚甲醛固定， 用于组织切片。 将全血室温静置 2小时， 3000 rpm离心 15分钟，收集血清。取肝脏组织 100 mg，用 0.9 mL预冷的生理盐水匀浆， 匀浆液 4 °C, 3000 rpm离心 15分钟， 取上清液。将样品送江苏省中西医结合医院病理科 全自动生化分析仪测定血清中 TG、 TC、 LDL、 HDL, AST禾 P ALT的水平， 测定肝脏 组织匀浆上清液中 TG水平。 将预处理好的组织送谷歌生物技术有限公司制作 HE染色 切片、 油红染色切片。 实验结果见图 5-8。  Materials and tests: After 4 weeks of administration, the water was fasted for 12 hours in advance, and the blood was taken from the eyeball the next morning, and the liver was sacrificed. Liver right lobular tissue was fixed with 4% paraformaldehyde for tissue sectioning. The whole blood was allowed to stand at room temperature for 2 hours, centrifuged at 3000 rpm for 15 minutes, and serum was collected. The liver tissue was taken up to 100 mg, homogenized with 0.9 mL of pre-cooled physiological saline, and the homogenate was centrifuged at 3000 ° C for 15 minutes at 4 ° C, and the supernatant was taken. The samples were sent to the Department of Pathology, Jiangsu Provincial Hospital of Integrated Traditional Chinese and Western Medicine. The levels of TG, TC, LDL, HDL, AST and P ALT in serum were determined by automatic biochemical analyzer. The level of TG in the supernatant of liver tissue homogenate was determined. The pretreated tissue was sent to Google Biotechnology Co., Ltd. to produce HE stained sections and oil red stained sections. The experimental results are shown in Figure 5-8.
图 5显示了化合物 1 19的降血脂及抗脂肪肝作用： 小鼠血清中 TC、 LDL、 HDL及 肝脏组织内 TG水平。 图 6显示了化合物 1 19的抗脂肪肝作用： HE染色图。 图 7显示 了化合物 1 19的抗脂肪肝作用： 油红染色图。 图 8显示了化合物 1 19的抗脂肪肝炎症作 用： 小鼠血清中 ALT和 AST水平。  Figure 5 shows the hypolipidemic and anti-fatty liver effects of Compound 1 19: TC, LDL, HDL and TG levels in liver tissue in mouse serum. Figure 6 shows the anti-fatty liver effect of Compound 1 19: HE staining. Figure 7 shows the anti-fatty liver effect of Compound 1 19: Oil red staining. Figure 8 shows the anti-fatty liver inflammation effect of Compound 1 19: ALT and AST levels in mouse serum.
实验结果表明： 与正常饮食的对照组相比， 发现高脂饮食显著增加血清中总胆固醇 The results of the experiment showed that the high-fat diet significantly increased the total cholesterol in the serum compared with the control group of the normal diet.
( TC ) 、 低密度脂蛋白 （LDL)及高密度脂蛋白 （HDL)水平， 同时肝脏组织内甘油三 酯（TG)也显著增加。与高脂饮食模型组比较， 奥贝胆酸组（HFD+OCA)和化合物 1 19 组 （HFD+1 19 ) 均能明显下调血清 TC、 LDL, HDL及肝脏组织内 TG水平 （图 5 ) 。 高脂模型组小鼠肝脏呈土黄色， 边缘不明显。 HE染色镜下观察 （图 6 ) ， 肝细胞内有 明显的脂质空泡， 细胞核位于细胞边缘， 肝细胞肿胀、 气球样病变， 细胞间边缘不清。 油红染色显示模型组肝脏内脂肪堆积明显。 油红染色结果 （图 7 ) 显示， 给药 1 19组的 脂质堆积比模型组明显减少， 肝细胞组织形态更加完整， 细胞间边缘清楚。 此外， 与正 常对照组相比， 高脂饮食模型组的血清中谷丙转氨酶 （ALT) 和谷草转氨酶 （AST ) 的 水平明显上升， 而给予化合物 1 19之后， 相比模型组血清 ALT和 AST水平有明显下降(TC), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels, as well as a significant increase in triglyceride (TG) in liver tissue. Compared with the high-fat diet model group, the oleic acid group (HFD+OCA) and the compound 1 19 group (HFD+1 19) significantly down-regulated serum TC, LDL, HDL and liver tissue TG levels (Fig. 5). In the high-fat model group, the liver of the mice was yellowish in color and the edges were not obvious. Under HE staining (Fig. 6), there were obvious lipid vacuoles in the liver cells, the nucleus was located at the edge of the cells, the hepatocytes were swollen, balloon-like lesions, and the intercellular edges were unclear. Oil red staining showed significant accumulation of fat in the liver of the model group. The oil red staining results (Fig. 7) showed that the lipid accumulation in the 19-19 group was significantly reduced compared with the model group, the hepatocyte tissue morphology was more complete, and the intercellular edges were clear. In addition, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly increased in the high-fat diet model group compared with the normal control group, whereas after administration of compound 1 19, serum ALT and AST levels were compared with the model group. Significant decline
(图 8 )。 以上结果表明， 本发明化合物可用于高血脂症及非酒精性脂肪性肝病的防治。 (Figure 8). The above results indicate that the compound of the present invention can be used for the prevention and treatment of hyperlipemia and nonalcoholic fatty liver disease.
实施例 476  Example 476
化合物对 SD大鼠心力衰竭模型的改善作用  Effect of compound on SD rat heart failure model
实验动物： SD大鼠， 雄性， 8周， 购自于北京维通利华实验动物技术有限公司。 试剂和仪器： 脑钠素 (B P)检测试剂盒购自于武汉优尔生贸易有限公司， 动物细胞 / 组织线粒体粗提分离试剂盒和线粒体损伤 /氧化荧光测定试剂盒购自于上海杰美基因医 药科技有限公司。  Experimental animals: SD rats, male, 8 weeks, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. Reagents and instruments: Brain Natriuretic Peptide (BP) detection kit was purchased from Wuhan Youersheng Trading Co., Ltd., animal cell/tissue mitochondrial crude extraction kit and mitochondrial damage/oxidative fluorescence assay kit were purchased from Shanghai Jiemei Gene. Pharmaceutical Technology Co., Ltd.
药物及配置： 取 250 mg异丙肾上腺素 （购自于 Sigma) 溶于 lOOmL的 0.09%的生 理盐水中制成终浓度为 2.5 mg/kg, 每次使用时新鲜配制。 化合物 119 (口服剂量： 10 mg/kg) 溶于 0.5%的羧甲基纤维素钠中制成终浓度为 1 mg/mL。  DRUGS AND CONFIGURATION: 250 mg isoproterenol (purchased from Sigma) was dissolved in 100 mL of 0.09% physiological saline to a final concentration of 2.5 mg/kg, freshly prepared for each use. Compound 119 (oral dose: 10 mg/kg) was dissolved in 0.5% sodium carboxymethylcellulose to a final concentration of 1 mg/mL.
心衰模型建立： 40只 8周龄雄性 SD大鼠适应性喂养一周后， 随机分为 4组， 空白 组 （n = 10)， 每天腹腔注射等体积生理盐水； 模型组每天腹腔注射 2.5 mg/Kg异丙肾上 腺素， 持续四周后， 大鼠出现毛发变黄， 体重降低， 且伴有气喘等早期心衰症状。 Establishment of heart failure model: 40 8-week-old male SD rats were randomly divided into 4 groups, blank after one week of adaptive feeding. Group (n = 10), intraperitoneal injection of the same volume of normal saline per day; model group daily intraperitoneal injection of 2.5 mg / Kg isoproterenol, after four weeks, the rat appeared yellow hair, weight loss, accompanied by early heart such as asthma Symptoms of aging.
实验方法： 1 ) 空白组 （Control, n=10): 每日腹腔注射等体积生理盐水， 灌胃等体 积 0.5%羧甲基纤维素钠； 2) 模型组 （Model, n=15 ): 每日腹腔注射 2.5 mg/kg异丙肾 上腺素， 灌胃等体积 0.5%羧甲基纤维素钠， 持续 4周； 3 )给药组（化合物 119， n=15 ): 每日腹腔注射 2.5 mg/kg异丙肾上腺素后， 立即灌胃化合物 119 ( 10 mg/kg)， 持续 4周。  Experimental methods: 1) blank group (Control, n=10): daily intraperitoneal injection of equal volume of normal saline, intragastric administration of an equal volume of 0.5% sodium carboxymethylcellulose; 2) model group (Model, n=15): per Daily intraperitoneal injection of 2.5 mg/kg isoproterenol, an equal volume of 0.5% sodium carboxymethylcellulose for 4 weeks; 3) Administration group (compound 119, n=15): daily intraperitoneal injection of 2.5 mg/ Immediately after kg of isoproterenol, compound 119 (10 mg/kg) was administered for 4 weeks.
彩色超声心动图评估动物心力衰竭： 4周末， 大鼠采用麻醉剂麻醉剂， 于大鼠胸骨 旁左侧长轴切面行超声心动图检测心脏功能。 检测指标主要有： 射血分数 (EF)、 缩短分 数 (FS)， 舒张末期室间隔厚度 (IVSd)、 收缩末期室间隔厚度 (IVSd)、 舒张末期左室后壁 厚度 (LVPWd；)、 舒张末左室内径 (LVEDd；)、 收缩期左室后壁厚度 (LVPWs；)、 收缩末左室 内径 (LVEDs；)、 舒张期左室重量（LV Mass;d)， 收缩期左室重量（LV mass;s)， 舒张期左 室体积 （LWol;d)， 收缩期左室体积 （LWol;s)。  Color echocardiography was used to assess heart failure in animals: At 4 weeks, rats were anesthetized with anesthetic anesthesia and echocardiography was performed on the left long axis of the sternum. The main indicators are: ejection fraction (EF), shortening fraction (FS), end-diastolic interventricular septal thickness (IVSd), end-systolic septal thickness (IVSd), end-diastolic left ventricular posterior wall thickness (LVPWd;), end diastolic Left ventricular diameter (LVEDd;), systolic left ventricular posterior wall thickness (LVPWs;), end-systolic left ventricular diameter (LVEDs;), diastolic left ventricular mass (LV Mass; d), systolic left ventricular mass (LV mass) ;s), diastolic left ventricular volume (LWol; d), systolic left ventricular volume (LWol; s).
大鼠心脏处理： 4周末， 给大鼠称重 （Body Weight, BW)， 眼眶取血， 断颈处死， 取心， 生理盐水洗净， 滤纸吸干， 称取全心重量（Heart Weight, HW)， 左心重量 （Left ventricle weight, LVW) o 每组取左心组织， 分为三份， 置于组织固定液固定， 用于石蜡 包埋做组织切片； 余下两份在液氮中速冻， 保存于 -80°C冰箱， 用于 Western Blot和 PCR 检测等。 大鼠心体比计算： 心脏指数=心脏重量 /体重， 左心室指数 =左心室重量 /体重。  Rat heart treatment: 4 weeks, the rats were weighed (Body Weight, BW), the eyelids were taken, the neck was sacrificed, the heart was taken, the saline was washed, the filter paper was blotted, and the whole weight was weighed (Heart Weight, HW ), Left ventricle weight (LVW) o Each group takes left heart tissue, divided into three parts, placed in tissue fixative, used for paraffin embedding for tissue section; the remaining two parts are frozen in liquid nitrogen, Store in a -80 ° C refrigerator for Western Blot and PCR detection. Rat heart-to-body ratio calculation: Cardiac index = heart weight / body weight, left ventricular index = left ventricular weight / body weight.
实验结果见图 9和表 4。  The experimental results are shown in Figure 9 and Table 4.
表 4、 SD大鼠心脏参数  Table 4. SD rat heart parameters
Control Model 119  Control Model 119
BW (g) 345.3±18.3 313.6±18.1 315.1±17.6 BW (g) 345.3±18.3 313.6±18.1 315.1±17.6
HW (g) 1.00±0.077 1.26±0.139 1.14±0.10HW (g) 1.00±0.077 1.26±0.139 1.14±0.10
HW BW(mg/g) 2.92±0.179 4.03±0.458 3.62±0.187# HW BW(mg/g) 2.92±0.179 4.03±0.458 3.62±0.187 #
LVW BW(mg/g) 0.402±0.056 0.768±0.013* 0.574±0.095# 图 9为化合物 119对 SD大鼠心力衰竭模型的影响图： （a)全心重与体重比； （b)左心 室重与体重比。 实验结果表明： 大鼠腹腔注射 2.5 mg/Kg异丙肾上腺素 （ISO) 后， 模 型组死亡只数为 7只， 存活率为 53%; 化合物 119给药组死亡只数为 2只， 存活率为 87%， 说明， 化合物 119可以延缓 ISO造模引起的动物死亡。 与正常组相比， ISO造模 后， 模型组 SD大鼠全心和体重比， 以及左心室重量和体重比， 显著增加， 发生严重心 肌肥厚。 与模型组相比， 化合物 119给药组大鼠全心和体重比， 以及左心室重量和体重 比， 均显著降低。 LVW BW (mg / g) 0.402 ± 0.056 0.768 ± 0.013 * 0.574 ± 0.095 # Compound 119 in FIG. 9 is a model of heart failure SD rats FIG effect: (a) ratio of heart weight to body weight; (b) LVH Compared with weight. The experimental results showed that: rats injected intraperitoneally with 2.5 mg/Kg isoproterenol (ISO), the number of deaths in the model group was only 7 and the survival rate was 53%; the number of deaths in the compound 119 group was only 2, the survival rate At 87%, it is indicated that Compound 119 can delay animal death caused by ISO modeling. Compared with the normal group, after the ISO model, the whole heart and body weight ratio of the model group SD rats, as well as the left ventricular weight and body weight ratio, increased significantly, and severe cardiac hypertrophy occurred. Compared with the model group, the whole heart and body weight ratio, as well as the left ventricular weight and body weight ratio, were significantly lower in the compound 119 administration group.
以上结果说明， 本发明的化合物可以显著改善心衰动物模型的射血分数， 改善心肌 肥厚。 其可通过激活 AMPK而改善心脏脂质堆积、 改善心脏能量代谢、 抗炎、 抗凋亡， 进而发挥心肌保护作用， 因而可用于防治心肌病和心力衰竭。 实施例 477 The above results indicate that the compound of the present invention can significantly improve the ejection fraction of an animal model of heart failure and improve cardiac hypertrophy. It can be used to prevent cardiomyopathy and heart failure by activating AMPK to improve cardiac lipid accumulation, improve cardiac energy metabolism, anti-inflammatory, and anti-apoptosis, thereby exerting myocardial protection. Example 477
片剂  Tablet
将实施例 98中制得的化合物 119(50g)、羟丙甲基纤维素 E( 150 g)、淀粉（200 g)、 聚维酮 K30适量和硬脂酸镁 （lg) 混合， 制粒， 压片。  Compound 119 (50 g) obtained in Example 98, hydroxypropylmethylcellulose E (150 g), starch (200 g), povidone K30 and magnesium stearate (lg) were mixed and granulated. Tableting.

Claims

1、 如式 （I) 所示的化合物、 其药学上可接受的盐或酯或溶剂化物: A compound represented by the formula (I), a pharmaceutically acceptable salt or ester or solvate thereof:
Figure imgf000169_0001
Figure imgf000169_0001
(I)  (I)
R R2、 R3、 R6、 R7和 R8各自是 H、 R、 OR、 SR、 S(O)R、 S(0)2R、 C(0)R、 C(0)OH、RR 2 , R 3 , R 6 , R 7 and R 8 are each H, R, OR, SR, S(O)R, S(0) 2 R, C(0)R, C(0)OH,
C(0)OR、 OC(0)R、 HR、 N(R)2、 C(0) H2、 C(0) HR、 C(0)N(R)2、 H(CO)R、 R(CO)R、 H(CO)OR、 R(CO)OR、 H(CO) H2、 H(CO) HR、 H(CO)N(R)2、 R(CO) HR、 R(CO)N(R)2、 S02 H2、 S02 HR、 S02N(R)2、 HS02R、 RS02R、 HS02 HR、 HS02N(R)2、 RS02 HR、 RS02N(R)2、 C(0) HNOH、 C(0) HNOR、 C(0) HS02R、 C( H) H2、 C( H) HR、 C(NH)N(R)2、 F、 Cl、 Br、 I、 CN、 N02、 H2、 OH、 CF3、 CF2CF3、 OCF3或 OCF2CF3; 或者， R1 R2和 R3 之中每两个与它们所连接到的原子一 起形成取代或非取代的苯环、 取代或非取代的杂芳环、 取代或非取代的环垸烃环、 取代 或非取代的杂环垸烃环或取代或非取代的杂环烯烃环； 或者， R6、 R7和 R8 之中每两个 与它们所连接到的原子一起形成取代或非取代的苯环、 取代或非取代的杂芳环、 取代或 非取代的环垸烃环、 取代或非取代的杂环垸烃环或取代或非取代的杂环烯烃环； C(0)OR, OC(0)R, HR, N(R) 2 , C(0) H 2 , C(0) HR, C(0)N(R) 2 , H(CO)R, R (CO)R, H(CO)OR, R(CO)OR, H(CO) H 2 , H(CO) HR, H(CO)N(R) 2 , R(CO) HR, R(CO) N(R) 2 , S0 2 H 2 , S0 2 HR, S0 2 N(R) 2 , HS0 2 R, RS0 2 R, HS0 2 HR, HS0 2 N(R) 2 , RS0 2 HR, RS0 2 N (R) 2 , C(0) HNOH, C(0) HNOR, C(0) HS0 2 R, C(H) H 2 , C( H) HR, C(NH)N(R) 2 , F, Cl, Br, I, CN, N0 2 , H 2 , OH, CF 3 , CF 2 CF 3 , OCF 3 or OCF 2 CF 3; or, each of R 1 R 2 and R 3 is connected to them The resulting atoms together form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloterpene hydrocarbon ring, a substituted or unsubstituted heterocyclic anthracene ring or a substituted or unsubstituted heterocyclic ring. Or an olefin ring; or, each of two of R 6 , R 7 and R 8 together with the atom to which they are attached form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted ring Anthracene ring, substituted or unsubstituted heterocyclic anthracene ring or substituted or unsubstituted heterocyclic ring Hydrocarbon ring;
R是苯基、 杂芳基、 环垸基、 环烯基、 杂环垸基、 杂环烯基、 垸基、 烯基、 或炔基； 其中， 所述苯基是未稠合的或与 R9稠合， R9是苯、 杂芳烃、 环垸烃、 环烯烃、 杂环垸 烃或杂环烯烃； 所述杂芳基是未稠合的或与 R1Q稠合， R1Q是苯、 杂芳烃、 环垸烃、 环烯 烃、 杂环垸烃或杂环烯烃； 所述环垸基、 环烯基、 杂环垸基或杂环烯基其每个是未稠合 的或与 R11稠合， R11是苯、杂芳烃、环垸烃、环烯烃、杂环垸烃或杂环烯烃； 所述垸基、 烯基或炔基其每个是未取代的或被一或两个或三个独立地选自下列的取代基所取代： R12、 OH、 （0)、 C(0)OH、 CN、 H2、 F、 Cl、 Br、 I、 CF3、 CF2CF3、 NC(R13)(R14)、 R15、 OR15、 SR15、 S(0)R15、 S(0)2R15、 HR15、 尊 15)2、 C(0)R15、 C(0) H2、 C(0) HR15、 C(O)尊 15)2、 HC(0)R15、 R15C(0)R15、 HS02R15、 HC(0)OR15、 S02 HR15、 S02N(R15)2、 HC(0) H2、 HC(0) HR15、 HC(0)CH(CH3) HC(0)CH(CH3) H2或 HC(0)CH(CH3) HC(0) -CH(CH3) HR15; R is phenyl, heteroaryl, cyclodecyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, indenyl, alkenyl, or alkynyl; wherein said phenyl is unfused or fused R 9, R 9 is a phenyl, hetero aromatic, hydrocarbon embankment, cycloalkene, heterocycle, or heterocycle embankment hydrocarbon olefin; said heteroaryl group is not bonded or fused fused with R 1Q, R 1Q benzene a heteroaromatic hydrocarbon, a cycloalkylene hydrocarbon, a cyclic olefin, a heterocyclic anthracene or a heterocycloalkene; said cyclodecyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group each of which is unfused or with R 11 fused, R 11 is benzene, a heteroarene, a cyclononene, a cycloalkene, a heterocyclic anthracene or a heterocycloalkene; the fluorenyl, alkenyl or alkynyl group each being unsubstituted or one or two And one or three substituents independently selected from the group consisting of: R 12 , OH, (0), C(0)OH, CN, H 2 , F, Cl, Br, I, CF 3 , CF 2 CF 3 , NC(R 13 )(R 14 ), R 15 , OR 15 , SR 15 , S(0)R 15 , S(0) 2 R 15 , HR 15 , 尊15 ) 2 , C(0)R 15 , C (0) H 2, C (0) HR 15, C (O) SIM 15) 2, HC (0) R 15, R 15 C (0) R 15, HS0 2 R 15 HC (0) OR 15, S0 2 HR 15, S0 2 N (R 15) 2, HC (0) H 2, HC (0) HR 15, HC (0) CH (CH 3) HC (0) CH ( CH 3 ) H 2 or HC(0)CH(CH 3 ) HC(0) -CH(CH 3 ) HR 15 ;
R12是 2~5个碳的螺烷基， 其每个是未取代的或被 OH、 (0), CN、 H2、 F、 Cl、 Br、 I、 CF3、 CF2CF3、 H(CH3)或 N(CH3)2取代; R 12 is a 2 to 5 carbon spiroalkyl group, each of which is unsubstituted or is OH, (0), CN, H 2 , F, Cl, Br, I, CF 3 , CF 2 CF 3 , H (CH 3 ) or N(CH 3 ) 2 substituted;
R13和 R14是独立选择的垸基， 或者与它们所连接到的 N—起是氮丙啶 -1-基、 氮杂 环丁垸 -1-基、吡咯垸 -1-基或哌啶 -1-基，每个具有一个未被替代的或被 0、 C(0), CNOH、 CNOCH3、 S、 S(0) S(0)2或 NH替代的 CH2部分； R 13 and R 14 are independently selected indenyl groups, or N to which they are attached are aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine -1-yl, each having a CH 2 moiety that is unsubstituted or replaced by 0, C(0), CNOH, CNOCH 3 , S, S(0) S(0) 2 or NH;
R15是苯基、 杂芳基、 环垸基、 环烯基、 杂环垸基、 杂环烯基、 垸基、 烯基或炔基； 其中， 所述苯基是未稠合的或与 R16稠合， R16是苯、 杂芳烃、 环垸烃、 环烯烃、 杂环垸 烃或杂环烯烃； 所述杂芳基是未稠合的或与 R17稠合， R17是苯、 杂芳烃、 环垸烃、 环烯 烃、 杂环垸烃或杂环烯烃； 所述环垸基、 环烯基、 杂环垸基或杂环烯基其每个是未稠合 的或与 R18稠合， R18是苯、杂芳烃、环垸烃、环烯烃、杂环垸烃或杂环烯烃； 所述垸基、 烯基或炔基其每个是未取代的或被一或两个或三个独立地选自下列的取代基所取代： R19、 OR19、 SR19、 S(0)R19、 S(0)2R19、 HR19、 N(R19)2、 C(0)R19、 C(0) H2、 C(0) HR19、 C(O)尊 19)2、 HC(0)R19、 R19C(0)R19、 HS02R19、 HC(0)OR19、 S02 HR19、 S02N(R19)2、 HC(0) H2、 HC(0) HR19、 OH、 （0)、 C(0)OH、 CN、 H2、 F、 Cl、 Br、 I、 CF3或 CF2CF3; R 15 is phenyl, heteroaryl, cyclodecyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, indenyl, alkenyl or alkynyl; Wherein said phenyl is non-fused or fused with R 16, R 16 is benzene, heteroarene, embankment hydrocarbon ring, cycloalkene, heterocycle, or heterocycle embankment hydrocarbon olefin; said heteroaryl is unsubstituted condensed bonded or fused with R 17, R 17 is benzene, heteroarene, embankment hydrocarbon ring, cycloalkene, heterocycle, or heterocyclic hydrocarbon olefin embankment; alkyl with the ring, cycloalkenyl group, heterocyclyl group or heterocyclic embankment alkenyl, each of which is unfused or fused with R 18, R 18 is benzene, heteroarene, embankment hydrocarbon ring, cycloalkene, heterocycle, or heterocycle embankment hydrocarbon olefin; the embankment, alkenyl or alkynyl Each of which is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of: R 19 , OR 19 , SR 19 , S(0)R 19 , S(0) 2 R 19 , HR 19 , N(R 19 ) 2 , C(0)R 19 , C(0) H 2 , C(0) HR 19 , C(O) Zun 19 ) 2 , HC(0)R 19 , R 19 C(0)R 19 , HS0 2 R 19 , HC(0)OR 19 , S0 2 HR 19 , S0 2 N(R 19 ) 2 , HC(0) H 2 , HC(0) HR 19 , OH, (0), C(0)OH, CN, H 2 , F, Cl, Br, I, CF 3 or CF 2 CF 3 ;
R19是苯基、 杂芳基、 环垸基、 环烯基、 杂环垸基、 杂环烯基、 垸基、 烯基或炔基; 其中， 所述苯基是未稠合的或与 R2Q稠合， R2Q是苯、 杂芳烃、 环垸烃、 环烯烃、 杂环垸 烃或杂环烯烃； 所述杂芳基是未稠合的或与 R21稠合， R21是苯、 杂芳烃、 环垸烃、 环烯 烃、 杂环垸烃或杂环烯烃； 所述环垸基、 环烯基、 杂环垸基或杂环烯基其每个是未稠合 的或与 R22稠合， R22是苯、 杂芳烃、 环垸烃、 环烯烃、 杂环垸烃或杂环烯烃； R 19 is phenyl, heteroaryl, cyclodecyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, indenyl, alkenyl or alkynyl; wherein said phenyl is unfused or R 2Q fused, R 2Q benzene, heteroarene, embankment hydrocarbon ring, cycloalkene, heterocycle, or heterocycle embankment hydrocarbon olefin; said heteroaryl is unfused or fused with R 21, R 21 is a phenyl a heteroaromatic hydrocarbon, a cycloalkylene hydrocarbon, a cyclic olefin, a heterocyclic anthracene or a heterocycloalkene; said cyclodecyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group each of which is unfused or with R 22 fused, R 22 is a benzene, a heteroarene, a cyclononene, a cyclic olefin, a heterocyclic anthracene or a heterocycloalkene;
n=0~10;  n=0~10;
R4和 R5各自是 H、 F或 1~6个碳的垸基； 或者， R4和 R5与它们所连接到的原子一 起形成取代或非取代的环垸烃环、取代或非取代的杂环垸烃环或取代或非取代的杂环烯 烃环； R 4 and R 5 are each H, F or a fluorenyl group of 1 to 6 carbons; or R 4 and R 5 together with the atom to which they are attached form a substituted or unsubstituted cycloterpene hydrocarbon ring, substituted or unsubstituted a heterocyclic anthracene ring or a substituted or unsubstituted heterocyclic olefin ring;
X是 S(0)2、 C(0)或 CH2; X is S(0) 2 , C(0) or CH 2;
P、 Q、 W、 Y禾 PZ各自是 CH、 N或被 R6、 R7和 R8中的一个所取代的 C， 且卩、 Q、 W、 Y和 Z中至少有三个不是 N; P, Q, W, Y and PZ are each CH, N or C substituted by one of R 6 , R 7 and R 8 , and at least three of 卩, Q, W, Y and Z are not N;
R'^H^ F、 0H、 CN、 H2、 H(CH3)、 N(CH3)2或 1~6个碳的垸基， 且 R'可在哌 啶环中 4-氨基的 α位碳或 β位碳上取代。 R'^H^ F, 0H, CN, H 2 , H(CH 3 ), N(CH 3 ) 2 or a fluorenyl group of 1 to 6 carbons, and R' may be a 4-amino group in the piperidine ring Substituted on carbon or beta carbon.
2、 如权利要求 1所述的化合物， 其特征在于： I 1、 R2、 R3、 R6、 R7和 R8各自是 H、 R、 0R、 SR、 S(0)R、 S(0)2R、 C(0)R、 C(0)OH、 C(0)OR、 OC(0)R、 HR、 N(R)2、 C(0) H2、 C(0) HR、 C(0)N(R)2、 H(CO)R、 R(CO)R、 H(CO)OR、 R(CO)OR、 H(CO) H2、 H(CO) HR、 H(CO)N(R)2、 R(CO)NHR、 R(CO)N(R)2、 S02 H2、 S02 HR、 S02N(R)2、 HS02R、 RS02R、 HS02 HR、 HS02N(R)2、 RS02 HR、 RS02N(R)2、 C(0) HNOH、 C(0) HNOR、 C(0) HS02R、 C( H) H2、 C( H) HR、 C(NH)尊 )2、 F、 Cl、 Br、 I、 CN、 N02、 H2、 0H、 CF3、 CF2CF3、 OCF3或 OCF2CF3; 或者， R R2和 R3 之中每两个与它们所连接到的原子一起形成取代或非取代的苯环或 取代或非取代的杂芳环； 或者， R6、 R7和 R8 之中每两个与它们所连接到的原子一起形 成取代或非取代的苯环或取代或非取代的杂芳环； The compound according to claim 1, wherein: I 1 , R 2 , R 3 , R 6 , R 7 and R 8 are each H, R, 0R, SR, S(0)R, S ( 0) 2 R, C(0)R, C(0)OH, C(0)OR, OC(0)R, HR, N(R) 2 , C(0) H 2 , C(0) HR, C(0)N(R) 2 , H(CO)R, R(CO)R, H(CO)OR, R(CO)OR, H(CO) H 2 , H(CO) HR, H(CO N(R) 2 , R(CO)NHR, R(CO)N(R) 2 , S0 2 H 2 , S0 2 HR, S0 2 N(R) 2 , HS0 2 R, RS0 2 R, HS0 2 HR, HS0 2 N(R) 2 , RS0 2 HR, RS0 2 N(R) 2 , C(0) HNOH, C(0) HNOR, C(0) HS0 2 R, C( H) H 2 , C (H) HR, C(NH)) 2 , F, Cl, Br, I, CN, N0 2 , H 2 , 0H, CF 3 , CF 2 CF 3 , OCF 3 or OCF 2 CF 3 ; or, RR Each of 2 and R 3 together with the atom to which they are attached form a substituted or unsubstituted benzene ring or a substituted or unsubstituted heteroaryl ring; or, each of R 6 , R 7 and R 8 Forming a substituted or unsubstituted benzene ring or a substituted or unsubstituted heteroaryl ring together with the atom to which they are attached;
R是苯基、 杂芳基或垸基； 其中， 所述垸基是未取代的或被一或两个或三个独立地 选自下列的取代基所取代： OH、 F、 CF3、 CF2CF3、 OR15、 SR15、 S(0)R15、 S(0)2R15、 HR15、N(R15)2、 C(0)R15、 C(0) H2、 C(0) HR15、 C(0)N(R15)2、 HC(0)R15、 R15C(0)R15、 HS02R15、 HC(0)OR15、 S02 HR15、 S02N(R15)2、 HC(0) H2、 HC(0) HR15、 HC(0)CH(CH3) HC(0)CH(CH3) H2或 HC(0)CH(CH3) HC(0)CH(CH3) HR15; R is phenyl, heteroaryl or anthracenyl; wherein the fluorenyl group is unsubstituted or is independently or one or two or three independently Substituted by a substituent selected from the group consisting of: OH, F, CF 3 , CF 2 CF 3 , OR 15 , SR 15 , S(0)R 15 , S(0) 2 R 15 , HR 15 , N(R 15 ) 2 , C(0)R 15 , C(0) H 2 , C(0) HR 15 , C(0)N(R 15 ) 2 , HC(0)R 15 , R 15 C(0)R 15 , HS0 2 R 15 , HC(0)OR 15 , S0 2 HR 15 , S0 2 N(R 15 ) 2 , HC(0) H 2 , HC(0) HR 15 , HC(0)CH(CH 3 ) HC (0) CH(CH 3 ) H 2 or HC(0)CH(CH 3 ) HC(0)CH(CH 3 ) HR 15 ;
R15是垸基， 且所述垸基是未取代的或被一或两个或三个独立地选自下列的取代基 所取代： OR19、 SR19、 S(0)R19、 S(0)2R19、 HR19、N(R19)2、C(0)R19、C(0) H2、C(0) HR19、 C(O)尊 19)2、 HC(0)R19、 R19C(0)R19、 HS02R19、 HC(0)OR19、 S02 HR19、 S02N(R19)2、 HC(0) H2、 HC(0) HR19、 OH、 （0)、 C(0)OH、 CN、 H2、 F、 CF3或 CF2CF3; 其中， R19是垸基； R 15 is an indenyl group, and the fluorenyl group is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of: OR 19 , SR 19 , S(0)R 19 , S( 0) 2 R 19 , HR 19 , N(R 19 ) 2 , C(0)R 19 , C(0) H 2 , C(0) HR 19 , C(O) Zun 19 ) 2 , HC(0) R 19 , R 19 C(0)R 19 , HS0 2 R 19 , HC(0)OR 19 , S0 2 HR 19 , S0 2 N(R 19 ) 2 , HC(0) H 2 , HC(0) HR 19 , OH, (0), C(0)OH, CN, H 2 , F, CF 3 or CF 2 CF 3; wherein R 19 is a fluorenyl group;
n=0~6;  n=0~6;
R4和 R5各自是 H、 F或甲基； R 4 and R 5 are each H, F or methyl;
X是 S(0)2、 C(O) 或 CH2; X is S(0) 2 , C(O) or CH 2;
P、 Q、 W、 Y和 Z各自是 CH、 N或被 R6、 R7和 R8中的一个所取代的 C， 且卩、 Q、 W、 Y和 Z中至少有四个不是 N; P, Q, W, Y and Z are each CH, N or C substituted by one of R 6 , R 7 and R 8 , and at least four of 卩, Q, W, Y and Z are not N;
R'是 H、 F或 1~6个碳的垸基， 且 R'可在哌啶环中 4-氨基的 α位碳或 β位碳上取代。 R' is H, F or a fluorenyl group of 1 to 6 carbons, and R' may be substituted on the ?-position carbon or the ?-position carbon of the 4-amino group in the piperidine ring.
3、 如权利要求 1所述的化合物， 其特征在于： I 1、 R2、 R3、 R6、 R7和 R8各自是 H、 R、 OR、 SR、 S(0)R、 S(0)2R、 C(0)R、 C(0)OH、 C(0)OR、 OC(0)R、 HR、 N(R)2、 C(0) H2、 C(0) HR、 C(0)N(R)2、 H(CO)R、 R(CO)R、 H(CO)OR、 R(CO)OR、 H(CO) H2、 H(CO) HR、 H(CO)N(R)2、 R(CO)NHR、 R(CO)N(R)2、 S02 H2、 S02 HR、 S02N(R)2、 HS02R、 RS02R、 HS02 HR、 HS02N(R)2、 RS02 HR、 RS02N(R)2、 C(0) HNOH、 C(0) HNOR、 C(0) HS02R、 C( H) H2、 C( H) HR、 C(NH)尊 )2、 F、 Cl、 Br、 I、 CN、 N02、 H2、 OH、 CF3、 CF2CF3、 OCF3或 OCF2CF3; 或者， R R2和 R3 之中每两个与它们所连接到的原子一起形成取代或非取代的苯环或 取代或非取代的杂芳环； 或者， R6、 R7和 R8 之中每两个与它们所连接到的原子一起形 成取代或非取代的苯环或取代或非取代的杂芳环； 3. The compound according to claim 1, wherein: I 1 , R 2 , R 3 , R 6 , R 7 and R 8 are each H, R, OR, SR, S(0)R, S ( 0) 2 R, C(0)R, C(0)OH, C(0)OR, OC(0)R, HR, N(R) 2 , C(0) H 2 , C(0) HR, C(0)N(R) 2 , H(CO)R, R(CO)R, H(CO)OR, R(CO)OR, H(CO) H 2 , H(CO) HR, H(CO N(R) 2 , R(CO)NHR, R(CO)N(R) 2 , S0 2 H 2 , S0 2 HR, S0 2 N(R) 2 , HS0 2 R, RS0 2 R, HS0 2 HR, HS0 2 N(R) 2 , RS0 2 HR, RS0 2 N(R) 2 , C(0) HNOH, C(0) HNOR, C(0) HS0 2 R, C( H) H 2 , C (H) HR, C(NH)) 2 , F, Cl, Br, I, CN, N0 2 , H 2 , OH, CF 3 , CF 2 CF 3 , OCF 3 or OCF 2 CF 3 ; or, RR Each of 2 and R 3 together with the atom to which they are attached form a substituted or unsubstituted benzene ring or a substituted or unsubstituted heteroaryl ring; or, each of R 6 , R 7 and R 8 Forming a substituted or unsubstituted benzene ring or a substituted or unsubstituted heteroaryl ring together with the atom to which they are attached;
R是苯基、 杂芳基或垸基； 其中， 所述垸基是未取代的或被一或两个或三个独立地 选自下列的取代基所取代： OH、 F、 CF3、 CF2CF3、 OR15、 SR15、 S(0)R15、 S(0)2R15、 HR15、N(R15)2、 C(0)R15、 C(0) H2、 C(0) HR15、 C(0)N(R15)2、 HC(0)R15、 R15C(0)R15、 HS02R15、 HC(0)OR15、 S02 HR15、 S02N(R15)2、 NHC(0) H2、 HC(0) HR15; R is phenyl, heteroaryl or fluorenyl; wherein the fluorenyl group is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of: OH, F, CF 3 , CF 2 CF 3 , OR 15 , SR 15 , S(0)R 15 , S(0) 2 R 15 , HR 15 , N(R 15 ) 2 , C(0)R 15 , C(0) H 2 , C (0) HR 15 , C(0)N(R 15 ) 2 , HC(0)R 15 , R 15 C(0)R 15 , HS0 2 R 15 , HC(0)OR 15 , S0 2 HR 15 , S0 2 N(R 15 ) 2 , NHC(0) H 2 , HC(0) HR 15 ;
R15是垸基， 且所述垸基是未取代的或被一或两个或三个独立地选自下列的取代基 所取代： OR19、 SR19、 S(0)R19、 S(0)2R19、 HR19、N(R19)2、C(0)R19、C(0) H2、C(0) HR19、 C(O)尊 19)2、 HC(0)R19、 R19C(0)R19、 HS02R19、 HC(0)OR19、 S02 HR19、 S02N(R19)2、 HC(0) H2、 HC(0) HR19、 OH、 （0)、 C(0)OH、 CN、 H2、 F、 CF3或 CF2CF3; 其中， R19是垸基； n=0~5； R 15 is an indenyl group, and the fluorenyl group is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of: OR 19 , SR 19 , S(0)R 19 , S( 0) 2 R 19 , HR 19 , N(R 19 ) 2 , C(0)R 19 , C(0) H 2 , C(0) HR 19 , C(O) Zun 19 ) 2 , HC(0) R 19 , R 19 C(0)R 19 , HS0 2 R 19 , HC(0)OR 19 , S0 2 HR 19 , S0 2 N(R 19 ) 2 , HC(0) H 2 , HC(0) HR 19 , OH, (0), C(0)OH, CN, H 2 , F, CF 3 or CF 2 CF 3; wherein R 19 is a fluorenyl group; n=0~5;
R4和 R5各自是 H或甲基； R 4 and R 5 are each H or methyl;
X是 S(0)2 C(O) 或 CH2 ; X is S(0) 2 C(O) or CH 2 ;
P Q W Y和 Z各自是 CH N或被 R6 R7和 R8中的一个所取代的 C， 且卩、 Q W Y和 Z中至少有四个不是 N; PQWY and Z are each CH N or C substituted by one of R 6 R 7 and R 8 , and at least four of 卩, QWY and Z are not N;
1 '是11 F或甲基， 且 R'可在哌啶环中 4-氨基的 α位碳或 β位碳上取代。  1 'is 11 F or methyl, and R' may be substituted on the alpha or carbon of the 4-amino group of the piperidine ring.
4、 如权利要求 1所述的化合物， 其特征在于： 当 R'不是 Η时， 所述化合物可作 为非对映异构体或者对映异构体的混合物或者非对映异构体和 /或者对映异构体的富集 形式来提供。  4. A compound according to claim 1, wherein: when R' is not hydrazine, the compound may act as a diastereomer or a mixture or diastereomer of enantiomers and/or Or enriched forms of enantiomers are provided.
5、 如权利要求 1所述的化合物， 其特征在于， 所述化合物或其药学上可接受的盐 或酯或溶剂化合物选自:  The compound according to claim 1, wherein the compound or a pharmaceutically acceptable salt or ester or solvent compound thereof is selected from the group consisting of:
Figure imgf000172_0001
Figure imgf000173_0001
N- (1- (4-氯苯甲酰基） 哌啶 -4-基） -2- (4-氯苯氧 基） -2-甲基丙酰胺
Figure imgf000172_0001
Figure imgf000173_0001
N-(1-(4-chlorobenzoyl)piperidin-4-yl)-2-(4-chlorophenoxy)-2-methylpropanamide
o  o
2- (4-氯苯氧基) -2-甲基 -N- (1- ((4-甲基苯基)磺 酰基） 哌啶 -4-基） 丙酰胺  2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-methylphenyl)sulfonyl)piperidin-4-yl)propanamide
2- (4-氯苯氧基） -N- (1-异烟酰基哌啶 -4-基） -2- 甲基丙酰胺 2-(4-Chlorophenoxy)-N-(1-isonicotinylpiperidin-4-yl)-2-methylpropanamide
2- (4-氯苯氧基） -2-甲基 -N- (1-烟酰基哌啶 -4-基） L J 丙酰胺 2-(4-Chlorophenoxy)-2-methyl-N-(1-nicotinopiperidin-4-yl) L J propionamide
N- (1-苄基哌啶 -4-基） -2- (2,5-二甲基苯氧基) -2- 甲基丙酰胺 N-(1-Benzylpiperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropanamide
N- (1-苯甲酰基哌啶 -4-基） -2- (2,5-二甲基苯氧基） -2-甲基丙酰胺 N-(1-benzoylpiperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropanamide
N- (1- (4-氯苯甲酰基) 哌啶 -4-基） -2- (2,5-二甲 基苯氧基） -2-甲基丙酰胺 N-(1-(4-chlorobenzoyl)piperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropanamide
2- (2,5-二甲基苯氧基） -N- (1-异烟酰基哌啶 -4-基） -2-甲基丙酰胺 2-(2,5-Dimethylphenoxy)-N-(1-isonicotinylpiperidin-4-yl)-2-methylpropanamide
(2,5-二甲基苯氧基） -2-甲基 -N- ( 1-烟酰基哌啶 -4- 基） 丙酰胺 (2,5-Dimethylphenoxy)-2-methyl-N-( 1-nicotinopiperidin-4-yl)propanamide
k k
(2,5-二甲基苯氧基) -N- (1- (4-氟苄基) 哌啶 -4- 基） -2-甲基丙酰胺 (2,5-Dimethylphenoxy)-N-(1-(4-fluorobenzyl)piperidin-4-yl)-2-methylpropanamide
(2- (2,5-二甲基苯氧基) -2-甲基 -N- (1- (4- (三 氟甲基） 苄基） 哌啶 -4-基） 丙酰胺 (2-(2,5-Dimethylphenoxy)-2-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)propanamide
N- (1- (4-氰基苄基) 哌啶 -4-基) -2- (2,5-二甲基 苯氧基） -2-甲基丙酰胺 N-(1-(4-Cyanobenzyl)piperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropanamide
(2,5-二甲基苯氧基） -N- (1- (4-甲氧基苄基） 哌 啶 -4-基） -2-甲基丙酰胺 (2,5-Dimethylphenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)-2-methylpropanamide
N- (1-苄基哌啶 -4-基） -5- (2,5-二异丙基苯氧基） -2,2-二甲基戊酰胺 N- (1-苄基哌啶 -4-基） -2,2-二甲基 -5-苯氧基戊酰胺 N-(1-Benzylpiperidin-4-yl)-5-(2,5-diisopropylphenoxy)-2,2-dimethylpentanamide N-(1-Benzylpiperidin-4-yl)-2,2-dimethyl-5-phenoxyvaleramide
N- (1-苄基哌啶 -4-基） -5- (4-氯苯氧基） -2,2-二甲 基戊酰胺 N-(1-Benzylpiperidin-4-yl)-5-(4-chlorophenoxy)-2,2-dimethylpentanamide
? 1/ N- (1-苄基哌啶 -4-基） -5- (2,5-二氯苯氧基) -2,2- 二甲基戊酰胺  ? 1/ N-(1-Benzylpiperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide
N- (1-苄基哌啶 -4-基） -5- (4-甲氧基苯氧基) -2,2- 二甲基戊酰胺 N-(1-Benzylpiperidin-4-yl)-5-(4-methoxyphenoxy)-2,2-dimethylpentanamide
N- (1-苄基哌啶 -4-基) -2,2-二甲基 -5- (对甲苯基氧 基） 戊酰胺  N-(1-Benzylpiperidin-4-yl)-2,2-dimethyl-5-(p-tolyloxy)pentanamide
N- (1-苄基哌啶 -4-基） -5- (5-异丙基 -2-甲基苯氧基） -2,2-二甲基戊酰胺  N-(1-Benzylpiperidin-4-yl)-5-(5-isopropyl-2-methylphenoxy)-2,2-dimethylpentanamide
N- (1-苄基哌啶 -4-基） -5- (3,5-二甲基苯氧基） -2,2- 二甲基戊酰胺 N-(1-Benzylpiperidin-4-yl)-5-(3,5-dimethylphenoxy)-2,2-dimethylpentanamide
N- (1-苄基哌啶 -4-基) -2,2-二甲基 -5- (邻甲苯氧基) 戊酰胺 N-(1-Benzylpiperidin-4-yl)-2,2-dimethyl-5-(o-tolyloxy)pentanamide
1 I . N- (1-苄基哌啶 -4-基) -2,2-二甲基 -5- (3,4,5-三甲 氧基苯氧基） 戊酰胺  1 I . N-(1-Benzylpiperidin-4-yl)-2,2-dimethyl-5-(3,4,5-trimethoxyphenoxy)pentanamide
11
N- (1- (4-氰基苄基） 哌啶 -4-基） -2,2-二甲基 -5-苯 氧基戊酰胺  N-(1-(4-Cyanobenzyl)piperidin-4-yl)-2,2-dimethyl-5-phenyloxypentanamide
N- (1- (3-氰基苄基) 哌啶 -4-基） -2,2-二甲基 -5-苯 氧基戊酰胺  N-(1-(3-Cyanobenzyl)piperidin-4-yl)-2,2-dimethyl-5-phenyloxypentanamide
N- (1- (2-氰基苄基) 哌啶 -4-基) -2,2-二甲基 -5-苯 氧基戊酰胺  N-(1-(2-Cyanobenzyl)piperidin-4-yl)-2,2-dimethyl-5-phenoxypentanamide
N- (1- (4-氰基苄基) 哌啶 -4-基) -5- (2,5-二氯苯 氧基） -2,2-二甲基戊酰胺 N-(1-(4-Cyanobenzyl)piperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide
« 1/ N- (1- (3-氰基苄基) 哌啶 -4-基) -5- (2,5-二氯苯 氧基） -2,2-二甲基戊酰胺 « 1/ N- (1-(3-Cyanobenzyl)piperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide
N- (1- (2-氰基苄基） 哌啶 -4-基） -5- (2,5-一.氯苯 氧基） -2,2-二甲基戊酰胺 N-(1-(2-Cyanobenzyl)piperidin-4-yl)-5-(2,5-monochlorophenoxy)-2,2-dimethylpentanamide
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- (1- (4-丙酰 基苯甲酰基） 哌啶 -4-基） 戊酰胺 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-propionylbenzoyl)piperidin-4-yl)pentanamide
1 5- (2,5-二甲基苯氧基） -2,2-二甲基 -Ν- ( 1-甲苯基 哌啶 -4-基） 戊酰胺 1 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-indole-(1-tolylpiperidin-4-yl)pentanamide
Ν- ( 1-苯甲酰基哌啶 -4-基） -5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 Ν-( 1-benzoylpiperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide
Ν- ( 1- (2-氯苄基) 哌啶 -4-基) -5- (2,5-二甲基苯 氧基） -2,2-二甲基戊酰胺Ν-( 1-(2-chlorobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide
Figure imgf000176_0001
Figure imgf000176_0001
Ν- ( 1- (2-氰基苄基) 哌啶 -4-基） -5- (2,5-二甲基 苯氧基） -2,2-二甲基戊酰胺  Ν-( 1-(2-Cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide
Ν- ( 1- (3-氰基苄基) 哌啶 -4-基） -5- (2,5-二甲基 苯氧基） -2,2-二甲基戊酰胺 Ν-( 1-(3-Cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide
Ν- ( 1-苄基哌啶 -4-基) -4- (2,5-二甲基苯氧基) 丁 酰胺 Ν-( 1-Benzylpiperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide
Ν- ( 1- (4-氰基苄基) 哌啶 -4-基) -4- (2,5-二甲基 苯氧基） 丁酰胺  Ν-( 1-(4-Cyanobenzyl)piperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide
Ν- ( 1- (2-氰基苄基) 哌啶 -4-基） -4- (2,5-二甲基 苯氧基） 丁酰胺 Ν-( 1-(2-Cyanobenzyl)piperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide
Ν- ( 1- (3-氰基苄基) 哌啶 -4-基) -4- (2,5-二甲基 x 苯氧基） 丁酰胺 Ν-( 1-(3-Cyanobenzyl)piperidin-4-yl)-4-(2,5-dimethyl x phenoxy)butanamide
。 J . J
Ν- ( 1- (4-氯苄基) 哌啶 -4-基) -4- (2,5-二甲基苯 Ν-( 1-(4-chlorobenzyl)piperidin-4-yl)-4-(2,5-dimethylbenzene
1 氧基） 丁酰胺 1 oxy) butanamide
4- (2,5-二甲基苯氧基) -Ν- ( 1- (4- (三氟甲基) 苄基） 哌啶 -4-基） 丁酰胺 4-(2,5-Dimethylphenoxy)-indole-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)butanamide
4- (2,5-二甲基苯氧基) -Ν- ( 1- (4-氟苄基）哌啶 -4-4-(2,5-Dimethylphenoxy)-indole-(1-(4-fluorobenzyl)piperidine-4-
V H 基） 丁酰胺 V H group) butanamide
4- (2,5-二甲基苯氧基） -Ν- ( 1- (2-甲基苄基） 哌 啶 -4-基） 丁酰胺 4-(2,5-Dimethylphenoxy)-indole-(1-(2-methylbenzyl)piperidin-4-yl)butanamide
Ν- ( 1-苯甲酰基哌啶 -4-基） -4- (2,5-二甲基苯氧基） 丁酰胺 Ν-( 1-benzoylpiperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide
Figure imgf000177_0001
4- (2,5-二氯苯氧基） -N- (1- (4-甲氧基苄基） 哌
Figure imgf000177_0001
4-(2,5-Dichlorophenoxy)-N-(1-(4-methoxybenzyl)piperidin
99 啶 -4-基） 丁酰胺99 pyridine-4-yl)butanamide
Figure imgf000178_0001
Figure imgf000178_0001
4- ((4- (5- (2,5-二甲基苯氧基)戊基） 哌啶 -1-基) 4-((4-(5-(2,5-Dimethylphenoxy)pentyl)piperidin-1-yl)
100 甲基） 苯甲酰胺 100 methyl) benzamide
4- (2,5-二甲基苯氧基） -N- (1- (4-甲氧基苄基）4-(2,5-Dimethylphenoxy)-N-(1-(4-methoxybenzyl)
101 、 1、^ 哌啶 -4-基） 丁酰胺 101, 1, ^ piperidin-4-yl) butanamide
4- (2,5-二甲基苯氧基） -N- (1- (3-甲氧基苄基）4-(2,5-Dimethylphenoxy)-N-(1-(3-methoxybenzyl)
102 1 哌啶 -4-基） 丁酰胺 102 1 piperidine-4-yl)butanamide
4- (2,5-二甲基苯氧基） -N- (1- (苯基磺酰基） 哌4-(2,5-Dimethylphenoxy)-N-(1-(phenylsulfonyl)piperidin
103 啶 -4-基） 丁酰胺 103 pyridine-4-yl)butanamide
N- (1-苄基哌啶 -4-基） -4- (5-异丙基 -2-甲基苯氧基）N-(1-benzylpiperidin-4-yl)-4-(5-isopropyl-2-methylphenoxy)
104 丁酰胺 104 butanamide
N- (1- (4-氰基苄基） 哌啶 -4-基） -4- ( 5-异丙基 -2-N-(1-(4-cyanobenzyl)piperidin-4-yl)-4-(5-isopropyl-2-
105 甲基苯氧基） 丁酰胺 105 methylphenoxy)butanamide
4- (5-异丙基 -2-甲基苯氧基) -N- (1- (4-甲氧基苄4-(5-isopropyl-2-methylphenoxy)-N-(1-(4-methoxybenzyl)
106 基） 哌啶 -4-基） 丁酰胺 106 base) piperidine-4-yl)butanamide
N- (1- (4-氰基苄基) 哌啶 -4-基) -4- (2,5-二氯苯N-(1-(4-cyanobenzyl)piperidin-4-yl)-4-(2,5-dichlorobenzene
107 氧基） 丁酰胺107 oxy) butanamide
Figure imgf000178_0002
Figure imgf000178_0002
5- (2,5-二甲基苯氧基) -N- (1- ( (4-氟苯基） 磺 5-(2,5-Dimethylphenoxy)-N-(1-((4-fluorophenyl)sulfonate
108 酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 108 acyl) piperidine-4-yl)-2,2-dimethylpentanamide
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- (1- ( (4-5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N- (1- ( 4-
109 硝基苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 109 nitrophenyl)sulfonyl)piperidin-4-yl)pentanamide
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- (1- (苯基5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N- (1-(phenyl)
110 磺酰基） 哌啶 -4-基） 戊酰胺 110 sulfonyl) piperidine-4-yl) pentanoamide
N-(l -((4-氰基苯基）磺酰基）哌啶 -4-基） -5- (2,5-N-(l-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-
111 二甲基苯氧基） -2,2-二甲基戊酰胺111 dimethylphenoxy)-2,2-dimethylpentanamide
Figure imgf000178_0003
Figure imgf000178_0003
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- (1- ((4- (三 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N- (1- ((4-)
112 氟甲基） 苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 112 fluoromethyl)phenyl)sulfonyl)piperidin-4-yl)pentanamide
1 5- (2,5-二甲基苯氧基) -N- (1- ((4-甲氧基苯基)1 5-(2,5-Dimethylphenoxy)-N-(1-((4-methoxyphenyl))
113 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 113 sulfonyl) piperidine-4-yl)-2,2-dimethylpentanamide
N- (1 - ((4-氯苯基）磺酰基） 哌啶 -4-基） -5- (2,5-N-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-
114 二甲基苯氧基） -2,2-二甲基戊酰胺 114 dimethylphenoxy)-2,2-dimethylpentanamide
N-(l -((2-氰基苯基）磺酰基）哌啶 -4-基） -5- (2,5-N-(l-((2-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-
115 二甲基苯氧基） -2,2-二甲基戊酰胺 115 dimethylphenoxy)-2,2-dimethylpentanamide
N-(l -((3-氰基苯基）磺酰基）哌啶 -4-基） -5- (2,5-N-(l-((3-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-
116 二甲基苯氧基） -2,2-二甲基戊酰胺116 dimethylphenoxy)-2,2-dimethylpentanamide
Figure imgf000179_0001
Figure imgf000179_0001
4- ( (4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰 4-( (4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoyl)
117 氨基） 哌啶 -1-基） 磺酰基） 苯甲酰胺 117 amino) piperidine-1-yl)sulfonyl)benzamide
4- ( (4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰4-( (4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoyl)
118 氨基） 哌啶 -1-基） 磺酰基） 苯甲酸甲酯 118 amino (amino) piperidine-1-yl)sulfonyl) methyl benzoate
4- ( (4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰4-( (4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoyl)
119 氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 119 amino) piperidine-1-yl)sulfonyl)benzoic acid
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- (1- (吡啶 -3-5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(pyridine-3-
120 基磺酰基） 哌啶 -4-基） 戊酰胺 120 sulfamoyl) piperidine-4-yl) pentanoamide
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- (1- ( (4-5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N- (1- ( 4-
121 (三氟甲氧基） 苯基）磺酰基） 哌啶 -4-基） 戊酰胺121 (trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)pentanamide
Figure imgf000179_0002
Figure imgf000179_0002
N- (2- (二甲基氨基） 乙基） -4 - ( (4- (5- (2,5- N- (2-(dimethylamino)ethyl) -4 - ( (4- (5- (2,5-)
122 二甲基苯氧基） -2,2-二甲基戊酰胺基） 哌啶 -1-基） 122 dimethylphenoxy) -2,2-dimethylpentanoyl)piperidin-1-yl)
1 磺酰基） 苯甲酰胺  1 sulfonyl) benzamide
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- (1- ( (4- 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N- (1- ( 4-
123 (4-甲基哌嗪 -1-羰基） 苯基） 磺酰基） 哌啶 -4-基） 123 (4-Methylpiperazine-1-carbonyl)phenyl)sulfonyl)piperidin-4-yl)
1 戊酰胺  1 pentamide
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- (1- (萘 -2- 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N- (1-(naphthalene-2-)
124 基磺酰基） 哌啶 -4-基） 戊酰胺 124 sulfamoyl) piperidine-4-yl) pentanoamide
N- (1- (4-氰基苯甲酰基) 哌啶 -4-基） -5- (2,5-二N-(1-(4-cyanobenzoyl)piperidin-4-yl)-5-(2,5-di
125 甲基苯氧基） -2,2-二甲基戊酰胺125 methylphenoxy)-2,2-dimethylpentanamide
Figure imgf000179_0003
Figure imgf000179_0003
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- (1- (4- (三 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N- (1- (4- (three
126 氟甲基） 苯甲酰基） 哌啶 -4-基） 戊酰胺 126 fluoromethyl)benzoyl) piperidine-4-yl)pentanamide
1 5- (2,5-二甲基苯氧基） -N- ( 1- (4-甲氧基苯甲酰1 5-(2,5-Dimethylphenoxy)-N-(1-(4-methoxybenzoyl)
127 基） 哌啶 -4-基） -2,2-二甲基戊酰胺 127 base) piperidine-4-yl)-2,2-dimethylpentanamide
5- (2,5-二甲基苯氧基） -N- ( 1- (4-氟苯甲酰基）5-(2,5-Dimethylphenoxy)-N-(1-(4-fluorobenzoyl)
128 哌啶 -4-基） -2,2-二甲基戊酰胺128 piperidine-4-yl)-2,2-dimethylpentanamide
Figure imgf000180_0001
Figure imgf000180_0001
5- (2,5-二甲基苯氧基） -2,2-二甲基 -N- ( 1- (4-硝基 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N- (1-(4-nitro)
129 苯甲酰基） 哌啶 -4-基） 戊酰胺 129 benzoyl) piperidine-4-yl) pentanoamide
4- (4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰氨4-(4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoylamide
130 基） 哌啶 -1-羰基） 苯甲酸甲酯 130 base) piperidine-1-carbonyl) methyl benzoate
N- ( 1- (2-萘甲酰基) 哌啶 -4-基） -5- (2,5-二甲基N-(1-(2-naphthoyl)piperidin-4-yl)-5-(2,5-dimethyl
131 苯氧基） - 2,2-二甲基戊酰胺131 phenoxy) - 2,2-dimethylvaleramide
Figure imgf000180_0002
Figure imgf000180_0002
4- (4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺 4-(4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanamide
132 基） 哌啶 -1-羰基） 苯甲酸 132 base) piperidine-1-carbonyl) benzoic acid
1  1
4- (4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺 4-(4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanamide
133 基） 哌啶 -1-羰基） 苯甲酰胺133 base) piperidine-1-carbonyl) benzamide
Figure imgf000180_0003
Figure imgf000180_0003
4- (4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺 4-(4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanamide
134 基） 哌啶 -1-羰基） -N， N-二甲基苯甲酰胺 134 base) piperidine-1-carbonyl)-N, N-dimethylbenzamide
1  1
N- ( 1- (苯并 [d][l,3]二氧杂环戊烯 -5-羰基）哌啶 -4- N-( 1-(benzo[d][l,3]dioxol-5-carbonyl)piperidine-4-
135 基） -5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺
Figure imgf000180_0004
135 base) -5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide
Figure imgf000180_0004
N- ( l- (2,2-二氟苯并 [d] [1,3]二氧杂环戊烯 -5-羰基） N-( l-(2,2-difluorobenzo[d] [1,3]dioxol-5-carbonyl)
136 哌啶 -4-基） -5- (2,5-二甲基苯氧基） -2,2-二甲基戊 136 piperidine-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentyl
1  1
酰胺  Amide
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- ( 1- (喹啉 -6- 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(quinoline-6-)
137 羰基） 哌啶 -4-基） 戊酰胺137 carbonyl) piperidine-4-yl) pentanoamide
Figure imgf000180_0005
Figure imgf000180_0005
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- ( 1- (吡嗪 -2- 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N- ( 1-(pyrazine-2-
138 V 。 NYV 羰基） 哌啶 -4-基） 戊酰胺 138 V. N YV carbonyl) piperidin-4-yl) pentanoamide
1  1
2- (4-苯甲酰基苯氧基） -N- ( 1- (苯基磺酰基） 哌 啶 -4-基) 乙酰胺  2-(4-benzoylphenoxy)-N-(1-(phenylsulfonyl)piperidin-4-yl)acetamide
139  139
U " X¾ ) U " X3⁄4 )
N- ( 1- (4-氰基苯磺酰基) 哌啶 -4-基) -5- (2-甲氧 N-( 1-(4-cyanobenzenesulfonyl)piperidin-4-yl)-5-(2-methoxy
140 基苯氧基） -2,2-二甲基戊酰胺
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
2- (4- (4-氯苯甲酰基)苯氧基） -2-甲基 -Ν- (1- (吡140 phenoxy) -2,2-dimethylpentanamide
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
2-(4-(4-chlorobenzoyl)phenoxy)-2-methyl-indole- (1- (pyridyl)
246 啶 -3-基磺酰基） 哌啶 -4-基） 丙酰胺 反式 -Ν- (1- ((4- (1H-四唑 -5-基) 苯基）磺酰基）246 pyridine-3-ylsulfonyl)piperidin-4-yl)propanamide trans-hydrazine-(1-((4-(1H-tetrazol-5-yl)phenyl)sulfonyl)
247 -3-氟哌啶 -4-基) -5- (2,5-二甲基苯氧基) -2， 2-二 甲基戊酰胺 247-3-Fluoropiperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide
2- (4-氯苯氧基） -Ν- (1- ((4-氰基苯基） 磺酰基） 2-(4-Chlorophenoxy)-indole-(1-((4-cyanophenyl)sulfonyl)
248 哌啶 -4-基） -2-甲基丙酰胺 248 piperidine-4-yl)-2-methylpropionamide
2- (4-氯苯氧基） -Ν- (1- ((4-氯苯基） 磺酰基） 哌2-(4-Chlorophenoxy)-indole-(1-((4-chlorophenyl)sulfonyl)piperidin
249 啶 -4-基） -2-甲基丙酰胺 249 pyridine-4-yl)-2-methylpropionamide
6  6
2- (4-氯苯氧基) -2-甲基 -Ν- (1- (吡啶 -3-基磺酰基) 2-(4-Chlorophenoxy)-2-methyl-indole-(1-(pyridine-3-ylsulfonyl)
250 哌啶 -4-基） 丙酰胺 250 piperidine-4-yl)propanamide
〇  〇
4- ((4- (2- (4-氯苯氧基） -2-甲基丙酰氨基） 哌啶 4-((4-(2-(4-Chlorophenoxy)-2-methylpropionylamino)piperidine
251 -1-基） 磺酰基） 苯甲酸 251 -1-yl)sulfonyl)benzoic acid
6  6
Ν- (1 - ((4-氯苯基)磺酰基） 哌啶 -4-基） -2- (2,5- Ν-(1 - ((4-chlorophenyl)sulfonyl)piperidin-4-yl)-2-(2,5-
252 二甲基苯氧基） -2-甲基丙酰胺 252 dimethylphenoxy)-2-methylpropionamide
6  6
N-(l - ((4-氰基苯基）磺酰基）哌啶 -4-基） -2- (2,5- N-(l-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2-(2,5-
253 二甲基苯氧基） -2-甲基丙酰胺 253 dimethylphenoxy)-2-methylpropionamide
2- (2,5-二甲基苯氧基) -2-甲基 -Ν- (1- ((4- (三氟2-(2,5-Dimethylphenoxy)-2-methyl-indole-(1-((4-(trifluoro))
254 甲基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 254 methyl) phenyl) sulfonyl) piperidine-4-yl) propionamide
2- (2,5-二甲基苯氧基) -2-甲基 -Ν- (1- (吡啶 -3-基2-(2,5-Dimethylphenoxy)-2-methyl-indole-(1-(pyridin-3-yl)
255 磺酰基） 哌啶 -4-基） 丙酰胺 255 sulfonyl) piperidine-4-yl) propionamide
4- ((4- (2- (2,5-二甲基苯氧基) -2-甲基丙酰氨基)4-((4-(2-(2,5-Dimethylphenoxy)-2-methylpropionylamino)
256 哌啶 -1-基） 磺酰基） 苯甲酸 256 piperidine-1-yl)sulfonyl)benzoic acid
2- (2,5-二甲基苯氧基) -Ν- ((3S,4S) -3-氟 -1- (吡2-(2,5-Dimethylphenoxy)-indole-((3S,4S)-3-fluoro-1-(pyridyl)
257 啶 -3-基磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 反式 -2- (2,5-二甲基苯氧基) -N- (3-氟 -1- (吡啶 -3-257 pyridine-3-ylsulfonyl)piperidin-4-yl)-2-methylpropionamide trans-2-(2,5-dimethylphenoxy)-N- (3-fluoro-1- (pyridine-3-
258 基磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 258 sulfamoyl)piperidin-4-yl)-2-methylpropionamide
2- (2,5-二甲基苯氧基） -2-甲基 -N- (1- ((4- (甲基2-(2,5-Dimethylphenoxy)-2-methyl-N- (1-((4-(methyl))
259 磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 5- (2,5-二甲基苯氧基） -N - ( (3S,4S) -3-氟 -1 - ( (4-259 sulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide 5-(2,5-Dimethylphenoxy)-N - ( (3S,4S)-3-fluoro-1 - ( (4-
260 氟苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺260 fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
1 o 1 o
反式 -5- (2,5-二甲基苯氧基) -N - (3-氟 -1 - ( (4- Trans -5- (2,5-dimethylphenoxy) -N - (3-fluoro -1 - (4-
261 氟苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺
Figure imgf000185_0001
261 fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
Figure imgf000185_0001
4- ( ( (3S,4S) -4- ( 5- (2,5-二氯苯氧基) -2,2-二 4-( ( (3S,4S) -4- ( 5- (2,5-dichlorophenoxy) -2,2-di
262 甲基戊酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 262-methylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid
CI ο  CI ο
反式 -4- ( (4- (5- (3,4-二氟苯氧基） -2,2-二甲基戊 π Λ 丄 ^\ Trans-4-( (4-(5-(3,4-difluorophenoxy)-2,2-dimethylpentanium Λ丄^\
265 酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸 反式 -N - ( 1 - ( (3,4-二氟苯基）磺酰基） -3-氟哌啶 265 acylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid trans-N-(1 - ((3,4-difluorophenyl)sulfonyl)-3-fluoropiperidine
268 -4-基) -5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺
Figure imgf000185_0002
268 -4-yl) -5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide
Figure imgf000185_0002
5- (3-氟苯氧基) -2,2-二甲基 -N- ( 1- (吡啶 -3-基磺 5-(3-Fluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-3-ylsulfonate)
270 酰基） 哌啶 -4-基） 戊酰胺 270 acyl) piperidine-4-yl) pentanoamide
5- (2-氟苯氧基) -2,2-二甲基 -N- ( 1- (吡啶 -3-基磺5-(2-fluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-3-ylsulfonate)
271 酰基） 哌啶 -4-基） 戊酰胺 271 acyl) piperidine-4-yl) pentanoamide
4 - ( (4- (5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰4-((4-(5-(2,5-Dimethylphenoxy)-2,2-dimethylvaleryl)
272 胺基） 哌啶 -1-基） 磺酰基） 苯甲酸- (乙酰氨基） -272 amino) piperidine-1-yl)sulfonyl)benzoic acid-(acetylamino)-
1 乙酯 1 ethyl ester
5- (3,4-二氟苯氧基) -2,2-二甲基 -N- ( 1- (吡啶 -3- 5-(3,4-Difluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-3-
273 基磺酰基） 哌啶 -4-基） 戊酰胺 反式 -5- (2,6-二氟苯氧基） -N - (3-氟 -1- (吡啶 -3-273 sulfamoyl) piperidine-4-yl) pentanoamide trans -5-(2,6-difluorophenoxy)-N - (3-fluoro-1-(pyridine-3-
274 基磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 274 sulfamoyl) piperidin-4-yl)-2,2-dimethylpentanamide
5- (2,6-二氟苯氧基） -N- ( OS, 4S ) -3-氟 -1- (吡5-(2,6-difluorophenoxy)-N-( OS, 4S ) -3-fluoro-1-(pyridyl)
276 啶 -3-基磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 276 pyridine-3-ylsulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
5- (2,4-二氟苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (甲5-(2,4-difluorophenoxy)-2,2-dimethyl-N- ( 1- ( (4-)
277 基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 277 sulfonyl)phenyl)sulfonyl)piperidin-4-yl)pentanamide
4 - ( (4- (5- (2,4-二氟苯氧基) -2,2-二甲基戊酰氨4-(-(5-(2,4-Difluorophenoxy)-2,2-dimethylpentanoylamide
A^^ ^ A^^ ^
278 基） 哌啶 -1-基） 磺酰基） 苯甲酸 反式 -4- ( 5- (2,5-二氯苯氧基） -2,2-二甲基戊酰氨 278 base) piperidine-1-yl)sulfonyl)benzoic acid trans-4-(5-(2,5-dichlorophenoxy)-2,2-dimethylpentanoylamide
280 基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 5- (2-甲氧基苯氧基) -N - ( (3S,4S ) -1 - ( (4-氰基280-based)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid 5-(2-Methoxyphenoxy)-N - ( (3S,4S ) -1 - ( (4-cyano)
284 苯基）磺酰基） -3-氟哌啶 -4-基） -2,2-二甲基戊酰胺284 phenyl)sulfonyl)-3-fluoropiperidin-4-yl)-2,2-dimethylpentanamide
Figure imgf000186_0001
Figure imgf000186_0001
5- (2-甲氧基苯氧基) -N - ( (3S,4S ) -1 - ( (3-氰基 5-(2-Methoxyphenoxy)-N - ( (3S,4S ) -1 - ( (3-cyano)
285 苯基）磺酰基） -3-氟哌啶 -4-基） -2,2-二甲基戊酰胺 285 phenyl)sulfonyl)-3-fluoropiperidin-4-yl)-2,2-dimethylpentanamide
/、.、 H  /,.,H
CI 、^^乂 H 5- (2,5-二氯苯氧基) -2,2-二甲基 -N- ( 1- (吡啶 -3-CI, ^^乂H 5-(2,5-dichlorophenoxy)-2,2-dimethyl-N-(1-(pyridine-3-
287 基磺酰基） 哌啶 -4-基） 戊酰胺 287 sulfamoyl) piperidine-4-yl) pentanoamide
CI 0  CI 0
反式 -5- (2,4-二氟苯氧基) -N- ( 3 氟小 (吡啶 -3- Trans-5-(2,4-difluorophenoxy)-N- (3 fluoro small (pyridine-3-
289 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 289 sulfonyl) piperidine-4-yl)-2,2-dimethylpentanamide
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- ( 1- ( (2,4,5-5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N- ( 1-( (2,4,5-)
290 三氟苯基） 磺酰基） 哌啶 -4-基） 戊酰胺290 trifluorophenyl)sulfonyl)piperidin-4-yl)pentanamide
Figure imgf000186_0002
Figure imgf000186_0002
N- ( 1 - ( ( 5-氯 -2,4-二氟苯基）磺酰基） 哌啶 -4-基) N-( 1 - ((5-chloro-2,4-difluorophenyl)sulfonyl)piperidin-4-yl)
291 -5- (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 291 -5- (2,5-Dimethylphenoxy)-2,2-dimethylpentanamide
O F  O F
N- ( 1 - ( (3-氯 -4-氟苯基)磺酰基） 哌啶 -4-基) -5- N-( 1 - ( (3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl) -5-
292 (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 292 (2,5-Dimethylphenoxy)-2,2-dimethylpentanamide
0  0
N- ( 1 - ( (2-氯 -4-氟苯基)磺酰基） 哌啶 -4-基) -5- N-( 1 - ( (2-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl) -5-
293 (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 293 (2,5-Dimethylphenoxy)-2,2-dimethylpentanamide
N- ( 1 - ( (3,5-二氟苯基） 磺酰基） 哌啶 -4-基） -5-N-( 1 - ( (3,5-difluorophenyl)sulfonyl)piperidin-4-yl) -5-
294 (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 294 (2,5-Dimethylphenoxy)-2,2-dimethylpentanamide
N- ( 1 - ( (2,4-二氟苯基） 磺酰基） 哌啶 -4-基) -5-N-( 1 - ( (2,4-difluorophenyl)sulfonyl)piperidin-4-yl) -5-
295 (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 295 (2,5-Dimethylphenoxy)-2,2-dimethylpentanamide
N- ( 1 - ( ( 5-氯 -2-氟苯基)磺酰基） 哌啶 -4-基) -5-N-( 1 - ( ( 5-chloro-2-fluorophenyl)sulfonyl) piperidin-4-yl) -5-
296 (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 296 (2,5-Dimethylphenoxy)-2,2-dimethylpentanamide
N- ( 1 - ( (2,6-二氟苯基） 磺酰基） 哌啶 -4-基) -5-N-( 1 - ( (2,6-difluorophenyl)sulfonyl)piperidin-4-yl) -5-
297 (2,5-二甲基苯氧基） -2,2-二甲基戊酰胺 297 (2,5-Dimethylphenoxy)-2,2-dimethylpentanamide
5- (2,5-二甲基苯氧基) -N- ( 1- - ( (4-氟 -3- (三氟5-(2,5-Dimethylphenoxy)-N-( 1- - (4-fluoro-3-(trifluoro)
298 甲基） 苯基）磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰298 methyl)phenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanoyl
Figure imgf000186_0003
胺
Figure imgf000186_0003
amine
5- (2,5-二甲基苯氧基) -2,2-二甲基 -N- ( 1- (喹啉 -8- 5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(quinoline-8-)
299 基磺酰基） 哌啶 -4-基） 戊酰胺 299 sulfamoyl) piperidine-4-yl) pentanoamide
O N^J
Figure imgf000187_0001
3- (2,5-二甲基苯氧基) -N- (1- ((4-氟苯基） 磺酰ON^J
Figure imgf000187_0001
3-(2,5-Dimethylphenoxy)-N-(1-((4-fluorophenyl)sulfonyl)
315 基） 哌啶 -4-基丙酰胺 315 base) piperidine-4-ylpropanamide
0 0
3- (2,5-二甲基苯氧基) -N- (1- (吡啶 -3-基磺酰基) 3-(2,5-Dimethylphenoxy)-N-(1-(pyridine-3-ylsulfonyl)
317 哌啶 -4-基） 丙酰胺 317 piperidine-4-yl)propionamide
0 0
3- (2,5-二甲基苯氧基） -N- (1- ((4- (甲基磺酰基） 3-(2,5-Dimethylphenoxy)-N-(1-((4-(methylsulfonyl))
319 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 319 phenyl)sulfonyl)piperidin-4-yl)propanamide
5- (2,4-二氟苯氧基） -N- (1- ((4-氟苯基)磺酰基）5-(2,4-difluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)
320 Fjar¾、 T 哌啶 -4-基） -2,2-二甲基戊酰胺 320 F jar3⁄4, T piperidin-4-yl)-2,2-dimethylpentanamide
5- (4-溴 -2,6-二氟苯氧基） -2,2-二甲基 -N- (1- (口比5-(4-Bromo-2,6-difluorophenoxy)-2,2-dimethyl-N- (1- (mouth ratio)
321 啶 -3-基磺酰基） 哌啶 -4-基） 戊酰胺 321 pyridine-3-ylsulfonyl)piperidin-4-yl)pentanamide
ό  ό
反式 -N- (1 - ((2,4-二氟苯基） 磺酰基） -3-氟哌啶 trans-N-(1 - ((2,4-difluorophenyl)sulfonyl)-3-fluoropiperidine
322 -4-基) -5- (2,5-二甲基苯氧基) -2,2-二甲基戊酰胺 反式 -5- (2,6-二氟苯氧基） -N- 3-氟小 (吡啶 -3-基322 -4-yl) -5-(2,5-dimethylphenoxy)-2,2-dimethylvaleramide trans-5-(2,6-difluorophenoxy)-N- 3-fluoro small (pyridin-3-yl)
323 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 323 sulfonyl) piperidine-4-yl)-2,2-dimethylpentanamide
Ϊ I H Ϊ I H
0 反式 -5- (2,6-二氟苯氧基） -N-3-氟 -1 - ((4-氟苯基) 0 trans -5-(2,6-difluorophenoxy)-N-3-fluoro-1 - ((4-fluorophenyl)
324 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 324 sulfonyl) piperidine-4-yl)-2,2-dimethylpentanamide
ί T  ί T
反式 -5- (2,6-二氟苯氧基） -^3-氟-1- ((4- (甲基 Trans-5-(2,6-difluorophenoxy)-^3-fluoro-1-((4-(methyl)
325 磺酰基）苯基）磺酰基） 哌啶 -4-基） -2,2-二甲基戊 ί I H ό 酰胺 325 sulfonyl)phenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentyl I H oxime
N- ((3S,4S) -3-氟 -1- ((4-氟苯基）磺酰基） 哌啶 N-((3S,4S)-3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidine
328 -4-基) -5- (2-甲氧基苯氧基） -2,2-二甲基戊酰胺 ό 328 -4-yl) -5-(2-methoxyphenoxy)-2,2-dimethylpentanamide ό
5-(4-氯苯基 )-2,2-二甲基 -N-(l-((4- (甲磺酰基)苯基） 5-(4-chlorophenyl)-2,2-dimethyl-N-(l-((4-(methylsulfonyl)phenyl))
329 磺酰基)哌啶 -4-基)戊酰胺 329 sulfonyl)piperidin-4-yl)pentanamide
o  o
5-(4-氯苯基）-Ν-(1-((4-氟苯基）磺酰基）哌啶 -4- 5-(4-chlorophenyl)-indole-(1-((4-fluorophenyl)sulfonyl)piperidine-4-
330 基) -2,2-二甲基戊酰胺 330 base) -2,2-dimethylpentanamide
0  0
5-(4-氯苯基 )-2,2-二甲基 -N-(l- (吡啶 -3-基磺酰基)哌 5-(4-chlorophenyl)-2,2-dimethyl-N-(l-(pyridine-3-ylsulfonyl)per
331 ¾-4-¾) 戊酰胺 331 3⁄4-4-3⁄4) pentanoamide
o  o
N- (1 - ((4-氟苯基) 磺酰基） 哌啶 -4-基) -2,2-二 N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-di
332 甲基 -5- (4- (甲基磺酰基） 苯氧基） 戊酰胺 332 methyl-5-(4-(methylsulfonyl)phenoxy)pentanamide
·'。■ 0
Figure imgf000189_0001
5- (4-氯 -2-氟苯氧基） -Ν- (1- ((4-氟苯基）磺酰基）·'. ■ 0
Figure imgf000189_0001
5-(4-Chloro-2-fluorophenoxy)-indole-(1-((4-fluorophenyl)sulfonyl)
355 哌啶 -4-基） -2,2-二甲基戊酰胺 355 piperidin-4-yl)-2,2-dimethylpentanamide
5- (4-氟 -3- (三氟甲基)苯氧基） -Ν- (1- ((4-氟苯5-(4-Fluoro-3-(trifluoromethyl)phenoxy)-indole-(1-((4-fluorobenzene)
356 基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 356 base) sulfonyl) piperidine-4-yl)-2,2-dimethylpentanamide
Ν- (1 - ((3- (甲基磺酰基）苯基）磺酰基）哌啶 -4-Ν-(1 - ((3-(methylsulfonyl)phenyl)sulfonyl)piperidine -4-
357 基） -4- (3- (三氟甲基） 苯氧基） 丁酰胺 357 base) -4- (3-(trifluoromethyl)phenoxy)butanamide
5- (2,3-二氟 -4-甲基苯氧基） -Ν- (1- ((4-氟苯基）5-(2,3-Difluoro-4-methylphenoxy)-indole-(1-((4-fluorophenyl))
360 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 360 sulfonyl) piperidine-4-yl)-2,2-dimethylpentanamide
1  1
5- (2,3-二氟 -4-甲基苯氧基） -Ν- (1- ((3-氟苯基) 5-(2,3-Difluoro-4-methylphenoxy)-indole-(1-((3-fluorophenyl))
361 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 361 sulfonyl) piperidine-4-yl)-2,2-dimethylpentanamide
5- (2,3-二氟 -4-甲基苯氧基） -2,2-二甲基 -Ν- (1- ((4-5-(2,3-Difluoro-4-methylphenoxy)-2,2-dimethyl-indole- (1- ((4-
362 (三氟甲氧基）苯基）磺酰基） 哌啶 -4-基）戊酰胺 反式 -5- (2,5-二氯苯氧基) -Ν- (3-氟 -1 - ( (4- (甲362 (trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)pentanamide trans-5-(2,5-dichlorophenoxy)-indole-(3-fluoro-1 - ( (4- (A
367 基磺酰基）苯基）磺酰基） 哌啶 -4-基） -2,2-二甲基 戊酰胺 367 sulfamoyl)phenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
反式 -5- (2,5-二氯苯氧基) -Ν- (3-氟 -1 - ( (3- (甲 Trans-5-(2,5-Dichlorophenoxy)-indole-(3-fluoro-1 - (3-(A)
368 基磺酰基）苯基）磺酰基） 哌啶 -4-基） -2,2-二甲基 a 6 6 戊酰胺 368 sulfonyl)phenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl a 6 6 pentamide
反式 -5- (2,5-二氯苯氧基) -Ν - (3-氟 -1 - ( (4-氟 Trans-5-(2,5-Dichlorophenoxy)-indole-(3-fluoro-1 - (4-fluoro
369 苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 369 phenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
2- (4- (4-氯苯甲酰基） 苯氧基） -Ν- (1- ( (4-氟2-(4-(4-chlorobenzoyl)phenoxy)-indole-(1-((4-fluoro)
370 ΐΛΧ 苯基） 磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 370 ΐΛΧphenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide
5- (2,6-二氟苯氧基） -2,2-二甲基 -Ν- (1- ((3- (甲5-(2,6-difluorophenoxy)-2,2-dimethyl-indole-(1-((3-))
373 基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 373 sulfamoyl)phenyl)sulfonyl)piperidin-4-yl)pentanamide
Ν- (1- ((4-氟苯基） 磺酰基） 哌啶 -4-基） -3- (3-Ν-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-3-(3-
375 (三氟甲基） 苯氧基） 丙酰胺375 (trifluoromethyl) phenoxy) propionamide
Figure imgf000190_0001
Figure imgf000190_0001
Ν- (1- ((4- (甲磺酰基） 苯基） 磺酰基） 哌啶 -4- Ν-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidine-4-
376 基） -3- (3- (三氟甲基） 苯氧基） 丙酰胺 376 base) -3- (3-(trifluoromethyl)phenoxy)propanamide
2,2-二甲基 -Ν- (1- (吡啶 -3-基磺酰基） 哌啶 -4-基）2,2-Dimethyl-indole-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)
377 -5- (2,4,6-三氟苯氧基） 戊酰胺 5- (2,5-二 （三氟甲基） 苯氧基） -N- (1- ( (4-氟377 -5- (2,4,6-trifluorophenoxy) pentamide 5-(2,5-bis(trifluoromethyl)phenoxy)-N-(1-((4-fluoro)
379 苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 379 phenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
5- (4-氟 -3- (三氟甲基） 苯氧基） -2,2-二甲基 -N-5-(4-Fluoro-3-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-
〇 〇
380 (1- ((4- (甲基磺酰基） 苯基） 磺酰基） -哌啶 -4- 380 (1-((4-(methylsulfonyl)phenyl)sulfonyl)-piperidine-4-
0 基） 戊酰胺 0 base) pentamide
5- (4-氟 -3- (三氟甲基） 苯氧基） -2,2-二甲基 -N- 5-(4-Fluoro-3-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-
381 (1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 戊酰胺 381 (1-(Pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide
0  0
5- (4-氟 -3- (三氟甲基） 苯氧基） -2,2-二甲基 -N- 5-(4-Fluoro-3-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-
382 (1- ((4- (三氟甲氧基） 苯基） 磺酰基） 哌啶 -4-
Figure imgf000191_0001
基） 戊酰胺 382 (1-((4-(Trifluoromethoxy)phenyl)sulfonyl)piperidin-4-
Figure imgf000191_0001
Ethyl amide
0 N- (1 - ((4-氟苯基) 磺酰基） 哌啶 -4-基) -4- (3- 0 N-(1 - ((4-fluorophenyl)sulfonyl)piperidin-4-yl)-4- (3-
383 (三氟甲基） 苯氧基） 丁酰胺 反式 -2- (2,4-二氟苯氧基) -N- (3-氟 -1- ((3- (甲383 (trifluoromethyl)phenoxy)butanamide trans-2-(2,4-difluorophenoxy)-N- (3-fluoro-1-((3-)
391 基磺酰基）苯基）磺酰基）哌啶 -4-基） -2-甲基丙酰 391 sulfamoyl)phenyl)sulfonyl)piperidin-4-yl)-2-methylpropionyl
0 o 胺  0 o amine
2- (2,4-二氟苯氧基） -2-甲基 -N- (1- ((3- (甲基磺 2-(2,4-difluorophenoxy)-2-methyl-N- (1-((3-(methyl))
392 禽 酰基） 苯基）磺酰基） 哌啶 -4-基） 丙酰胺 392 avian acyl) phenyl)sulfonyl) piperidine-4-yl) propionamide
ό o  ό o
0 N- (1- ((4- (甲基磺酰基）苯基）磺酰基）哌啶 -4- 0 N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidine -4-
394 基） -4- (3- (三氟甲基） 苯氧基） 丁酰胺 394 base) -4- (3-(trifluoromethyl)phenoxy)butanamide
0 N- (1- (吡啶 -3-基磺酰基) 哌啶 -4-基） -4- (3- (三0 N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-4-(3- (three
395 氟甲基） 苯氧基） 丁酰胺 395 fluoromethyl) phenoxy) butanamide
5- (2,3-二氟苯氧基） -N- (1- ( (4-氟苯基） 磺酰5-(2,3-difluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)
396 基） 哌啶 -4-基） -2,2-二甲基戊酰胺 396 base) piperidine-4-yl)-2,2-dimethylpentanamide
0  0
2,2-二甲基 -N- (1- ( (4- (甲基磺酰基） 苯基） 磺 2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl) sulfonate
397 :x 酰基） 哌啶 -4-基) -5- (3,4,5-三氟苯氧基) 戊酰胺 397 : x acyl) piperidin-4-yl) -5-(3,4,5-trifluorophenoxy)pentanamide
F^ 0  F^ 0
N- (1- ( (4-氟苯基）磺酰基） 哌啶 -4-基） -2,2-二 N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-di
398 甲基 -5- (3,4,5-三氟苯氧基) 戊酰胺 398 methyl-5-(3,4,5-trifluorophenoxy)pentanamide
F O  F O
2,2-二甲基 -N- (1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 2,2-Dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)
399 -5- (2,3 ,4-三氟苯氧基） 戊酰胺 399 -5- (2,3,4-trifluorophenoxy)pentanamide
0  0
N- (1- ( (4-氟苯基）磺酰基） 哌啶 -4-基） -2,2-二 N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-di
400 甲基 -5- (2,3 ,4-三氟苯氧基） 戊酰胺 400 methyl-5-(2,3,4-trifluorophenoxy)pentanamide
o 2,2-二甲基 -N- (1- (吡啶 -3-基磺酰基） 哌啶 -4-基）o 2,2-Dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)
401 -5- (2- (三氟甲基） 苯氧基） 戊酰胺 401 -5- (2-(Trifluoromethyl)phenoxy)pentanamide
N- (1- ( (4-氟苯基）磺酰基） 哌啶 -4-基） -2,2-二N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-di
402 甲基 -5- (2- (三氟甲基） 苯氧基） 戊酰胺 402 methyl 5-(2-(trifluoromethyl)phenoxy)pentanamide
6  6
5- (4-氟 -2- (三氟甲基） 苯氧基） -2,2-二甲基 -N- 5-(4-Fluoro-2-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-
403 (1- (吡啶 -3-基磺酰基） 哌啶 -4-基） 戊酰胺 403 (1-(Pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide
6  6
5- (4-氟 -2- (三氟甲基) 苯氧基） -N- (1- ( (4-氟 5-(4-Fluoro-2-(trifluoromethyl)phenoxy)-N-(1-((4-fluoro)
404 苯基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 404 phenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
5- (4-氯苯氧基） -N- ((3R,4R) -3-氟 -1- ((4-氟苯5-(4-Chlorophenoxy)-N-((3R,4R)-3-fluoro-1-((4-fluorobenzene)
408 基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 408 base) sulfonyl) piperidine-4-yl)-2,2-dimethylpentanamide
o  o
4- (((3R,4R) -4- (5- (4-氯苯氧基） -2,2-二甲基戊 4-(((3R,4R)-4-(5-(4-chlorophenoxy)-2,2-dimethylpentyl)
409 酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸 409 acylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid
N- (1- (吡啶 -3-磺酰基) 哌啶 -4-基) -3- (3- (三氟N-(1-(pyridine-3-sulfonyl)piperidin-4-yl)-3-(3-(trifluoro)
410 甲基） 苯氧基） 丙酰胺 反式—4- ((4- (5- (4-氯苯氧基) -2,2-二甲基戊酰胺）410 methyl) phenoxy) propionamide trans-4-((4-(5-(4-chlorophenoxy)-2,2-dimethylpentanamide)
411 -3-氟哌啶 -1-基）磺酰基） 苯甲酸 411 -3-fluoropiperidin-1-yl)sulfonyl)benzoic acid
00
反式 -5-(4-氯苯氧基) -N- (3-氟 -1- ((4-氟苯基)磺酰 Trans-5-(4-chlorophenoxy)-N-(3-fluoro-1-((4-fluorophenyl)sulfonyl)
412 基） 哌啶 -4-基） -2， 2-二甲基戊酰胺 412 base) piperidine-4-yl)-2,2-dimethylpentanamide
a J 。 a J .
反式—4- ((4- (2- (3,4-二氟苯氧基) -2-甲基丙酰氨 Trans-4-((4-(2-(3,4-difluorophenoxy)-2-methylpropionylamide)
415 基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 反式—4- ((4- (2- (3,4-二氟苯氧基) -2-甲基丙酰氨415 yl)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid trans-4-((4-(2-(3,4-difluorophenoxy)-2-methylpropanoylamino)
416 基） -3-氟哌啶 -1-基）磺酰基）苯甲酸 2-乙酰氨基乙 酯 416-based)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid 2-acetamidoethyl ester
5- (2,5-二 (三氟甲基) 苯氧基） -N- (1- ((3-氟苯 5-(2,5-bis(trifluoromethyl)phenoxy)-N-(1-((3-fluorobenzene)
417 基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 417 base) sulfonyl) piperidine-4-yl)-2,2-dimethylpentanamide
N- (1 - ((4-氟苯基) 磺酰基） 哌啶 -4-基) -2,2-二N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-di
418 甲基 -5- (萘 -2-基氧基） 戊酰胺 418 methyl -5-(naphthalen-2-yloxy)pentanamide
、 o  , o
N- (1 - ((4-氟苯基) 磺酰基） 哌啶 -4-基) -2,2-二 N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-di
419 甲基 -5- (萘 -1-基氧基） 戊酰胺 419 methyl -5-(naphthalen-1-yloxy)pentanamide
丁 1 "
Figure imgf000193_0001
2-(4-氯苯氧基) -N-((3R,4R)-3-氟 -l-((4-氟苯基)磺酰 Ding 1 "
Figure imgf000193_0001
2-(4-chlorophenoxy)-N-((3R,4R)-3-fluoro-l-((4-fluorophenyl)sulfonyl
o ff  o ff
基)哌啶 -4-基) -2-甲基丙酰胺  Piperidin-4-yl)-2-methylpropionamide
436  436
2- (4-氯 -2-氟苯氧基） -N- (1- ((4-氟苯基）磺酰基）2-(4-Chloro-2-fluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)
437 哌啶 -4-基） -2-甲基丙酰胺 437 piperidine-4-yl)-2-methylpropionamide
2- (4-氯 -2-氟苯氧基） -N- (1- ((3-氟苯基）磺酰基）2-(4-Chloro-2-fluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)
438 哌啶 -4-基） -2-甲基丙酰胺 438 piperidine-4-yl)-2-methylpropionamide
2- (2,5-二甲基苯氧基) -2-甲基 -N- (1- (苯基磺酰2-(2,5-Dimethylphenoxy)-2-methyl-N-(1-(phenylsulfonyl)
439 基） 哌啶 -4-基） 丙酰胺 439 base) piperidine-4-yl) propionamide
2- (2,5-二甲基苯氧基) -2-甲基 -N- (1- ((3- (甲2-(2,5-Dimethylphenoxy)-2-methyl-N- (1- ((3-)
440 Ά 基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 440 Ά sulfonyl) phenyl) sulfonyl) piperidine-4-yl) propionamide
2- (4-氯 -2-氟苯氧基) -2-甲基 -N- (1- ((4- (甲基2-(4-Chloro-2-fluorophenoxy)-2-methyl-N- (1-((4-(methyl))
441 磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 441 sulfonyl)phenyl)sulfonyl)piperidin-4-yl)propionamide
2- (4-氯 -2-氟苯氧基) -2-甲基 -N- (1- ((3- (甲基2-(4-Chloro-2-fluorophenoxy)-2-methyl-N- (1-((3-(methyl))
442 磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 丙酰胺 442 sulfonyl)phenyl)sulfonyl)piperidin-4-yl)propionamide
4- (((3R,4R) -4- (5- (2,5-二氟苯氧基) -2,2-二甲4-(((3R,4R)-4-(5-(2,5-Difluorophenoxy)-2,2-dimethyl
443 基戊酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 443 valerylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid
4- (((3S,4S) -4- (5- (2,5-二氟苯氧基) -2,2-二甲4-(((3S,4S)-4-(5-(2,5-Difluorophenoxy)-2,2-dimethyl
444 基戊酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 444 valerylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid
2- (4- (4-氯苯甲酰基)苯氧基） -N- ((3R,4R) -3-2-(4-(4-Chlorobenzoyl)phenoxy)-N- ((3R,4R) -3-
445 氟 -1- ((4-氟苯基）磺酰基） 哌啶 -4-基） -2-甲基丙 酰胺 445 fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide
5- (2,5-二氯苯氧基) -2,2-二甲基 -N- (1- ((4- (甲 5-(2,5-Dichlorophenoxy)-2,2-dimethyl-N- (1- ((4-)
446 基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 反式 -2- (4-氯苯氧基) -N- (3-氟 -1- ((4-氟苯基)446 sulfonyl)phenyl)sulfonyl)piperidin-4-yl)pentanamide trans-2-(4-chlorophenoxy)-N-(3-fluoro-1-((4-fluorophenyl) )
447 磺酰基） 哌啶 -4-基） -2-甲基丙酰胺 反式—4- ((4- (2- (4-氯苯氧基） -2-甲基丙酰氨基）447 sulfonyl) piperidine-4-yl)-2-methylpropionamide trans-4-((4-(2-(4-chlorophenoxy)-2-methylpropanoylamino)
448 -3-氟哌啶 -1-基）磺酰基） 苯甲酸 反式 -2- (4- (4-氯苯甲酰基）苯氧基） -N- (3-氟 -1448 -3-fluoropiperidin-1-yl)sulfonyl)benzoic acid trans-2-(4-(4-chlorobenzoyl)phenoxy)-N-(3-fluoro-1
449 - ((4-氟苯基）磺酰基） 哌啶 -4-基） -2-甲基丙酰胺
Figure imgf000195_0001
0 反式—4- ( (4- (2- (4- (4-氯苯甲酰基)苯氧基） -2- 甲基丙酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 o 449 - ((4-Fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide
Figure imgf000195_0001
0 trans-4-( (4-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl Benzoic acid o
0  0
5- (2,4-二氟苯氧基） -2,2-二甲基 -N- ( 1- ( (3- (甲 基磺酰基） 苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 Λ H  5-(2,4-Difluorophenoxy)-2,2-dimethyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valentamide Λ H
0 反式 -4- ( (4- ( 5- (2,4-二氟苯氧基) -2,2-二甲基戊 ^ O O==  0 trans -4- ( (4- ( 5- (2,4-difluorophenoxy) -2,2-dimethylpentyl] O O==
酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸甲酯 ί T H S  Amido)-3-fluoropiperidin-1-yl)sulfonyl) benzoic acid methyl ester ί T H S
0 反式 -4- ( (4- ( 5- (2,4-二氟苯氧基) -2,2-二甲基戊 工 o  0 trans -4- ( (4- ( 5- (2,4-difluorophenoxy) -2,2-dimethylpentene o
酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸 反式 -4- ( (4- ( 5- (2,4-二氟苯氧基) -2,2-二甲基戊 酰氨基） -3-氟哌啶 -1-基）磺酰基）苯甲酸（2-乙酰 氨基） 乙酯  Amido)-3-fluoropiperidin-1-yl)sulfonyl) benzoic acid trans-4-((4-(5-(2,4-difluorophenoxy)-2,2-dimethyl) (pentylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (2-acetylamino)ethyl ester
4-((4-(5-(4-氟苯氧基) -2,2-二甲基戊酰氨基)哌啶 -1- 基)磺酰基)苯甲酸 4-((4-(5-(4-fluorophenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid
Figure imgf000196_0001
Figure imgf000196_0001
5-(4-氟苯氧基) -N-(l-((3-氟苯基）磺酰基）哌啶 -4- 基) -2,2-二甲基戊酰胺  5-(4-Fluorophenoxy)-N-(l-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
/、、 H  /,,H
5-(4-氟苯氧基) -N-(l-((4-氟苯基）磺酰基）哌啶 -4- 基) -2,2-二甲基戊酰胺  5-(4-Fluorophenoxy)-N-(l-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide
5-(4-氟苯氧基) -2,2-二甲基 -N-(l-((3- (甲基磺酰基） 苯基)磺酰基)哌啶 -4-基)戊酰胺5-(4-Fluorophenoxy)-2,2-dimethyl-N-(l-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)pentanamide
Figure imgf000196_0002
Figure imgf000196_0002
4 - ( (4- ( 5- (2,4-二氟苯氧基） -2,2-二甲基戊酰胺 基） 哌啶 -1-基） 磺酰基） 苯甲酸 2-乙酰氨基乙酯 4-(4-(5-(2,4-Difluorophenoxy)-2,2-dimethylpentanyl)piperidin-1-yl)sulfonyl)benzoic acid 2-acetamidoethyl ester
0 0
4- ( (4- (2- (4-氟苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸
Figure imgf000196_0003
4-((4-(2-(4-fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid
Figure imgf000196_0003
4-((4-(5-(4-氯苯氧基) -2,2-二甲基戊酰胺)哌啶 -1-基） 磺酰基)苯甲酸  4-((4-(5-(4-chlorophenoxy)-2,2-dimethylvaleramide)piperidin-1-yl)sulfonyl)benzoic acid
0 4- ( ( (3R,4R) -4- (2- (4- (4-氯苯甲酰基)苯氧基） 0 4- ( (3R,4R) -4- (2- (4-(4-chlorobenzoyl)phenoxy)
-2-甲基丙酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲 酸  -2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid
0
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
反式 -2-(2,4-二氟苯氧基）-2-甲基 -N-(2-甲基0
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Trans-2-(2,4-difluorophenoxy)-2-methyl-N-(2-methyl
519 ¾ ¾禽 -1-((3- (甲磺酰基)苯基） 磺酰基） 哌啶 -4-基） 丙酰 ό 0 胺 519 3⁄4 3⁄4 Avian-1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propionylhydrazone 0 Amine
ο V w 、 反式 -5-(2,4-二氟苯氧基 )-2,2-二甲基 -N-(2-甲基 ο V w , trans -5-(2,4-difluorophenoxy)-2,2-dimethyl-N-(2-methyl
520 -1-((3- (甲磺酰基)苯基） 磺酰基） 哌啶 -4-基） 戊酰 o 胺 520-1-((3-(Methanesulfonyl)phenyl)sulfonyl)piperidin-4-yl)pentanoyl oamine
反式 -3-((4-(5-(2,4-二氟苯氧基) -2,2-二甲基戊酰胺 、  Trans-3-((4-(5-(2,4-difluorophenoxy)-2,2-dimethylpentanamide,
521 Χ ^ΛΧΙ 基) -2-甲基哌啶 -1-基）磺酰基)苯甲酸 反式 -3-((4-(5-(3,4-二氟苯氧基) -2,2-二甲基戊酰胺 521 Χ ^ΛΧΙyl)-2-methylpiperidin-1-ylsulfonyl)benzoic acid trans-3-((4-(5-(3,4-difluorophenoxy))-2,2 - dimethyl pentamide
522 基) -2-甲基哌啶 -1-基）磺酰基)苯甲酸 522-based)-2-methylpiperidin-1-ylsulfonyl)benzoic acid
ΰ  ΰ
反式 -4- ( (3-氟 -4- (5- (4-氟苯氧基) -2,2-二甲基戊 Trans-4-((3-fluoro-4-(5-(4-fluorophenoxy)-2,2-dimethylpentyl)
523 酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸523 acylamino) piperidine-1-yl)sulfonyl)benzoic acid
Figure imgf000200_0001
Figure imgf000200_0001
反式 -4- ( (3-氟 -4- (5- (4-氟苯氧基) -2,2-二甲基戊 Trans-4-((3-fluoro-4-(5-(4-fluorophenoxy)-2,2-dimethylpentyl)
524 。 酰胺基）哌啶 -1-基）磺酰基）苯甲酸 2-乙酰氨基乙 酯 524. Amido)piperidin-1-ylsulfonyl)benzoic acid 2-acetamidoethyl ester
5- (4-氯苯氧基） -2,2-二甲基 -N- ( 1- ( (4- (吗啉 -4- 羰基） 苯基）磺酰基） 哌啶 -4-基） 戊酰胺  5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholin-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)penta Amide
525  525
0  0
5-(4-氯苯氧基) -N- ( 1- ( (4-(N-环丙基磺酰胺) -苯 5-(4-chlorophenoxy)-N-(1-((4-(N-cyclopropylsulfonamide))-benzene
526 αΧΤ ^Χ 、 基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰 526 α ΧΤ ^Χ , yl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanoyl
0  0
0 2-(4-氯苯氧基) -N- ( 1- ( (4-(N-环丙基磺酰胺) -苯 ο  0 2-(4-Chlorophenoxy)-N-( 1-((4-(N-cyclopropylsulfonamide)-benzene ο
527 f"、'l ds" 527 f", 'ld s "
αΧΧ'Λ 基） 磺酰基） 哌啶 -4-基） -2-甲基丙酰胺  αΧΧ'Λ group)sulfonyl)piperidin-4-yl)-2-methylpropionamide
( ( (3R,4R) -4- (5- (2,5-二氯苯氧基) -2,2-二甲((3R,4R)-4-(5-(2,5-Dichlorophenoxy)-2,2-dimethyl
528 基戊酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 528-valerylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid
CI ό  CI ό
反式 -3- ( (4- (5- (2,5-二氯苯氧基） -2,2-二甲基戊 Trans-3-(4-(5-(2,5-dichlorophenoxy)-2,2-dimethylpentyl
529 酰氨基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸529 acylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid
Figure imgf000200_0002
Figure imgf000200_0002
3- ( ( (3R,4R) -4- (5- (2,5-二氯苯氧基) -2,2-二 3- ( (3R,4R) -4- (5- (2,5-Dichlorophenoxy) -2,2-di
530 甲基戊酰氨基） -3-氟哌啶 -1-基） 磺酰基） 苯甲酸 530 methylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid
γ s cooH  γ s cooH
CI o  CI o
2- (4-氟苯氧基) -2-甲基 -N- ( 1- ( (4- (甲基磺酰 基） 苯基）磺酰基） 哌啶 -4-基） 丙酰胺  2-(4-Fluorophenoxy)-2-methyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide
531  531
6' 2- (4-氟苯氧基) -Ν- (1- ( (3-氟苯基) 磺酰基）6' 2-(4-fluorophenoxy)-indole-(1-((3-fluorophenyl)sulfonyl)
532 o i。 哌啶 -4-基） -2-甲基丙酰胺 532 o i. Piperidine-4-yl)-2-methylpropionamide
° ¾ F ° 3⁄4 F
'、(、(、 \、 。 。 。广 反式 -5- (2,5-二氯苯氧基) -Ν- (3-氟 -1 - ((3-氟苯 基） 磺酰基） 哌啶 -4-基） -2,2-二甲基戊酰胺 ', (, (, \, . . . wide trans-5-(2,5-dichlorophenoxy)-Ν-(3-fluoro-1 -((3-fluorophenyl)sulfonyl)piperidin Pyridin-4-yl)-2,2-dimethylpentanamide
533 533
5- (4-氟苯氧基） -2,2-二甲基 -Ν- (1- (喹啉 -8-基磺 o 5-(4-fluorophenoxy)-2,2-dimethyl-indole-(1-(quinolin-8-ylsulfonyl)
534 酰基） 哌啶 -4-基） 戊酰胺  534 acyl) piperidine-4-yl) pentanoamide
5- (4-氯苯氧基） -2,2-二甲基 -Ν- (1- (喹啉 -8-基磺5-(4-Chlorophenoxy)-2,2-dimethyl-indole-(1-(quinoline-8-yl)
535 酰基） 哌啶 -4-基） 戊酰胺535 acyl) piperidine-4-yl) pentanoamide
Figure imgf000201_0001
Figure imgf000201_0001
4- ((4- (2- (4-氟苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 (2-乙酰氨基)乙酯 4-((4-(2-(4-Fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (2-acetamido)ethyl ester
536 536
3- ((4- (2- (4-氟苯氧基） -2-甲基丙酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 3-((4-(2-(4-fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid
537 - (((3R,4R) -3-氟 -4- (2- (4-氟苯氧基） -2-甲基 o rrc。。H 4 537 - (((3R,4R)-3-fluoro-4-(2-(4-fluorophenoxy)-2-methylo rr c .. H 4
丙酰氨基） 哌啶 -1-基）磺酰基） 苯甲酸 Propionylamino) piperidine-1-yl)sulfonyl)benzoic acid
538 538
N- ((3R,4R) -3-氟 -1 - ((4- (甲基磺酰基) 苯基） 磺酰基）哌啶 -4-基） -2- (4-氟苯氧基） -2-甲基丙酰N-((3R,4R)-3-fluoro-1 -((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-2-(4-fluorophenoxy)- 2-methylpropionyl
539 539
胺  Amine
3- (((3R,4R) -3-氟 -4- (2- (4-氟苯氧基） -2-甲基3-(((3R,4R)-3-fluoro-4-(2-(4-fluorophenoxy)-2-methyl)
540 丙酰氨基） 哌啶 -1-基）磺酰基） 苯甲酸 540 propionylamino) piperidine-1-yl)sulfonyl)benzoic acid
FjCr。 ^ F jCr. ^
5- (4-氟苯氧基） -2,2-二甲基 -N- (1- ((4- (吗啉 -4- 5-(4-fluorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholine-4-)
541 羰基） 苯基）磺酰基） 哌啶 -4-基） 戊酰胺 541 carbonyl)phenyl)sulfonyl)piperidin-4-yl)pentanamide
4- ((4- (2-甲基 -2- (4- (甲基磺酰基) 苯氧基） 丙 酰氨基） 哌啶 -1-基） 磺酰基） 苯甲酸 (2-乙酰氨基）4-((4-(2-methyl-2-(4-(methylsulfonyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzoic acid (2-acetylamino)
542 542
乙酯  Ethyl ester
。Ί Λ 0 反式 -4- ((3-氟 -4- (2-甲基 -2- (4- (甲基磺酰基) 苯氧基） 丙酰氨基） 哌啶 -1-基）磺酰基） 苯甲酸. Ί Λ 0 trans-4-((3-fluoro-4-(2-methyl-2-(4-(methylsulfonyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzene Formic acid
。Ά 。 . Oh.
o  o
。 ¾  . 3⁄4
反式 -4- ((3-氟 -4- (2-甲基 -2- (4- (甲基磺酰基) 苯氧基）丙酰氨基）哌啶 -1-基）磺酰基）苯甲酸（2- 乙酰氨基） 乙酯  Trans-4-((3-fluoro-4-(2-methyl-2-(4-(methylsulfonyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzoic acid (2-acetylamino)ethyl ester
。Ί  . Ί
反式 -N- (3-氟 -1 - ( (4- (吗啉 -4-羰基) 苯基）磺 o  Trans-N-(3-fluoro-1 -((4-(morpholine-4-carbonyl)phenyl)sulfonate o
酰基）哌啶 -4-基） -2-甲基 -2- (4- (甲基磺酰基）苯 氧基） 丙酰胺  Acyl)piperidin-4-yl)-2-methyl-2-(4-(methylsulfonyl)phenoxy)propanamide
0  0
- 0  - 0
2-甲基 -2- (4- (甲基磺酰基)苯氧基） -N- (1- ( (4- 2-methyl-2-(4-(methylsulfonyl)phenoxy)-N- (1- ( 4-
。' 。 x^。 (吗啉 -4-羰基）苯基）磺酰基）哌啶 -4-基）丙酰胺. ' . x^. (morpholine-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide
° T ° T
0  0
4 - ( ( (3R,4R) -4- (2- (4-氯苯氧基） -2-甲基丙 酰胺基） -3-氟哌啶 -1-基）磺酰基） 苯甲酸  4-((3R,4R)-4-(2-(4-Chlorophenoxy)-2-methylpropionamido)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid
5- (4-氯苯氧基） -2,2-二甲基 -N- (1- ( (4-氨磺酰 基苯基） 磺酰基） 哌啶 -4-基） 戊酰胺 5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-((4-sulfamoylphenyl)sulfonyl)piperidin-4-yl)pentanamide
0  0
5- (4-氯苯氧基） -2,2-二甲基 -N- (1- (吡啶 -4-磺酰 基） 哌啶 -4-基） 戊酰胺  5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-(pyridine-4-sulfonyl)piperidin-4-yl)pentanamide
o  o
2- (4-氯苯氧基） -2-甲基 -N- (1- (吡啶 -4-磺酰基） 哌啶 -4-基） 丙酰胺  2-(4-Chlorophenoxy)-2-methyl-N-(1-(pyridine-4-sulfonyl)piperidin-4-yl)propanamide
。 .
5- (4-氟苯氧基） -2,2-二甲基 -N- (1- (吡啶 -4-磺酰 基） 哌啶 -4-基） 戊酰胺 5-(4-Fluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-4-sulfonyl)piperidin-4-yl)pentanamide
Figure imgf000202_0001
Figure imgf000202_0001
2- (4-氟苯氧基） -2-甲基 -N- (1- (吡啶 -4-磺酰基） 哌啶 -4-基） 丙酰胺  2-(4-Fluorophenoxy)-2-methyl-N-(1-(pyridine-4-sulfonyl)piperidin-4-yl)propanamide
。  .
5- (4-氯苯氧基） -2,2-二甲基 -N- (1- (吡啶 -2-磺酰 基） 哌啶 -4-基） 戊酰胺  5-(4-Chlorophenoxy)-2,2-dimethyl-N-(1-(pyridine-2-sulfonyl)piperidin-4-yl)pentanamide
o  o
2- (4-氯苯氧基） -2-甲基 -N- (1- (吡啶 -2-磺酰基） 哌啶 -4-基） 丙酰胺  2-(4-Chlorophenoxy)-2-methyl-N-(1-(pyridine-2-sulfonyl)piperidin-4-yl)propanamide
。
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
4 - ( (4- ( 5- (异喹啉 -5-基氧基) -2,2-二甲基戊酰胺.
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
4-((4-(isoquinolin-5-yloxy)-2,2-dimethylvaleramide
594 基） 哌啶 -1-基） 磺酰基） 苯甲酸594 base) piperidine-1-yl)sulfonyl)benzoic acid
Figure imgf000206_0001
Figure imgf000206_0001
4- ( (4- (2,2-二甲基 -5- (4- (甲基磺酰基)苯氧基） o  4-( (4-(2,2-Dimethyl-5-(4-(methylsulfonyl)phenoxy) o)
595 戊酰氨基）哌啶 -1-基）磺酰基）苯甲酸 2-乙酰氨基 乙酯  595 pentamamido) piperidine-1-yl)sulfonyl)benzoic acid 2-acetamidoethyl ester
工 4- ( (4- (2,2-二甲基 -5- (4- (甲基磺酰基)苯氧基） 4-((4-(2,2-Dimethyl-5-(4-(methylsulfonyl)phenoxy))
596 戊酰氨基） 哌啶 -1-基）磺酰基） 苯甲酸钠596 valerylamino) piperidine-1-yl)sulfonyl) sodium benzoate
ώ=  ώ=
4-((4-(5-(3,4-二氟苯氧基) -2,2-二甲基戊酰胺基）哌 工 4-((4-(5-(3,4-difluorophenoxy)-2,2-dimethylpentanoyl)pipeper
啶 -1-基)磺酰基)苯甲酸 2-乙酰氨基乙酯  Pyridin-1-yl)sulfonyl)benzoic acid 2-acetamidoethyl ester
o' Y i  o' Y i
597  597
。  .
。人  . People
。丫 4-((4-(5-(4-氟苯氧基) -2,2-二甲基戊酰胺基)哌啶 -1- 基)磺酰基)苯甲酸 2-乙酰氨基乙酯.  . 4- 4-((4-(5-(4-fluorophenoxy)-2,2-dimethylpentanyl)piperidin-1-yl)sulfonyl)benzoic acid 2-acetamidoethyl ester.
598  598
5- ( 4-氯苯氧基） -2,2-二甲基 -N- ( 1- ( ( 4- (N-甲5-(4-Chlorophenoxy)-2,2-dimethyl-N- ( 1- ( ( 4- (N-A)
599 基氨磺酰基） 苯基）磺酰基） 哌啶 -4-基） 戊酰胺 反式—4- ( (4- (2,2-二甲基 -5- (4- (甲基磺酰基)苯599 sulfamoyl)phenyl)sulfonyl)piperidin-4-yl)pentanamide trans-4-((4-(2,2-dimethyl-5-(4-(methylsulfonyl)) benzene
600 氧基）戊酰氨基） -3-氟哌啶 -1-基）磺酰基）苯甲酸 反式 -N- (3-氟 -1- ( (4- (甲基磺酰基） 苯基）磺酰600 oxy)pentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid trans-N-(3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonate Acyl
601 基） 哌啶 -4-基) -2,2-二甲基 -5- (4- (甲基磺酰基) 苯氧基） 戊酰胺 601 base) piperidin-4-yl)-2,2-dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanamide
4-((4-(2,2-二甲基 -5-(3- (三氟甲基） 苯氧基）戊酰胺 4-((4-(2,2-Dimethyl-5-(3-(trifluoromethyl)phenoxy)pentanamide)
602 基） 哌啶 -1-基） 磺酰基） 苯甲酸 602 base) piperidine-1-yl)sulfonyl)benzoic acid
。 ΧΛ  . ΧΛ
4-((4-(5-(4-氟 -3- (三氟甲基）苯氧基 )-2,2-二甲基戊 4-((4-(5-(4-fluoro-3-)trifluoromethyl)phenoxy)-2,2-dimethylpentyl
603 酰胺基） 哌啶 -1-基）磺酰基） 苯甲酸 603 amide) piperidine-1-yl)sulfonyl)benzoic acid
。 Λ  . Λ
6、 一种药物组合物， 其包含如权利要求 1~5任一项所述的化合物作为活性成分， 和药学上可接受的辅料。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 as an active ingredient, and a pharmaceutically acceptable adjuvant.
7、 如权利要求 6所述的药物组合物， 其特征在于， 所述药物组合物是胶囊剂、 散 剂、 片剂、 颗粒剂、 丸剂、 注射剂、 糖浆剂、 口服液、 吸入剂、 软膏剂、 栓剂或贴剂。  The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is a capsule, a powder, a tablet, a granule, a pill, an injection, a syrup, an oral solution, an inhalant, an ointment, Suppositories or patches.
8、 权利要求 1~5任一项所述的化合物在制备预防或治疗代谢异常相关疾病、 心脑 血管疾病、 炎症疾病、 自身免疫性疾病、 器官纤维化疾病、 神经损伤性疾病、 病原体感 染所致的继发性疾病或肿瘤的药物中的用途。 The compound according to any one of claims 1 to 5, which is useful for the preparation of a medicament for preventing or treating metabolic abnormalities, cardiovascular and cerebrovascular diseases, inflammatory diseases, autoimmune diseases, organ fibrotic diseases, nerve damage diseases, pathogenic sensations. Use in drugs for secondary diseases or tumors caused by infection.
9、权利要求 1~5任一项所述的化合物在制备预防或治疗 AMPK介导的病症药物方 面的应用。  Use of a compound according to any one of claims 1 to 5 for the preparation of a medicament for preventing or treating AMPK-mediated disorders.
PCT/CN2018/083267 2017-04-18 2018-04-17 Piperidine ampk agonist and medical application thereof WO2018192461A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020146876A3 (en) * 2019-01-11 2020-09-03 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Anti-cancer compositions and methods of use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1934099A (en) * 2004-03-22 2007-03-21 阿斯利康(瑞典)有限公司 N-piperidine derivates as CCR3 modulators
EP3053911A1 (en) * 2013-09-30 2016-08-10 The University of Tokyo Adiponectin receptor-activating compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1934099A (en) * 2004-03-22 2007-03-21 阿斯利康(瑞典)有限公司 N-piperidine derivates as CCR3 modulators
EP3053911A1 (en) * 2013-09-30 2016-08-10 The University of Tokyo Adiponectin receptor-activating compound

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020146876A3 (en) * 2019-01-11 2020-09-03 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Anti-cancer compositions and methods of use

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