TWI531564B - 胺甲酸六氟異丙酯衍生物、其製備及其治療應用 - Google Patents

胺甲酸六氟異丙酯衍生物、其製備及其治療應用 Download PDF

Info

Publication number
TWI531564B
TWI531564B TW100119659A TW100119659A TWI531564B TW I531564 B TWI531564 B TW I531564B TW 100119659 A TW100119659 A TW 100119659A TW 100119659 A TW100119659 A TW 100119659A TW I531564 B TWI531564 B TW I531564B
Authority
TW
Taiwan
Prior art keywords
group
trifluoromethyl
trifluoro
carboxylic acid
alkylene
Prior art date
Application number
TW100119659A
Other languages
English (en)
Other versions
TW201202198A (en
Inventor
巴次克 梨晶
朵洛希 卻瑞特
勒克 伊文
克里斯丁 豪奈特
珍 喬納西
法蘭克 瑪格特
Original Assignee
賽諾菲公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=43402192&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=TWI531564(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by 賽諾菲公司 filed Critical 賽諾菲公司
Publication of TW201202198A publication Critical patent/TW201202198A/zh
Application granted granted Critical
Publication of TWI531564B publication Critical patent/TWI531564B/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • 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
    • C07D211/54—Sulfur atoms
    • 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
    • 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Description

胺甲酸六氟異丙酯衍生物、其製備及其治療應用
本發明係關於胺甲酸六氟異丙酯衍生物、其製備及其治療應用。此等化合物對酶MGL(單醯基甘油脂肪酶)具有抑制活性。
WO 2009141238及WO 2010009207揭示GPR119受體促效劑，其可包含胺甲酸六氟異丙酯。
<<Characterization of the Tunable Piperidine and Piperazine Carbamates as Inhibitors of Endocannabinoid Hydrolases>>(J.Z. Long,X Jin,A. Adibekian,W.Li等人)描述酶MGL之抑制劑，該等抑制劑呈帶有胺甲酸酯之N-哌啶環形式。
WO 2009/052319揭示作為酶MGL之抑制劑的其他類型化合物。
本發明之一個標的物為式(I)化合物：
其中：R表示視情況經一或多個R2及/或R3基團取代之R1基團；R1表示芳基或雜芳基；R2表示鹵素原子或氰基、硝基、側氧基、(C1-C6)烷基、(C1-C6)烷氧基、羥基、(C1-C6)烷硫基、(C1-C6)鹵烷基、(C1-C6)鹵烷氧基、(C1-C6)鹵烷硫基、NR4R5、NR4COR5、NR4SO2R5、COR4、CO2R4、CONR4R5、SO2R4、SO2NR4R5、苯氧基或苯甲氧基；R3表示可經一或多個彼此相同或不同之R2基團取代之單環芳基或雜芳基；R4及R5彼此獨立地表示氫原子或(C1-C6)烷基，或與帶有其之氮原子或N-CO或N-SO2片段一起形成視情況經(C1-C6)烷基或苯甲基取代之雜環；Z表示一鍵、(C1-C6)伸烷基、(C2-C6)伸烯基、(C2-C6)伸炔基、O-(C1-C6)伸烷基或N(RA)-(C1-C6)伸烷基；A表示一鍵、氧原子、硫原子、N(RA)基團、N(RA)-(C1-C6)伸烷基、CON(RA)基團、CON(RA)-(C1-C6)伸烷基、SO2N(RA)基團、SO2N(RA)-(C1-C6)伸烷基、OCON(RA)基團、OCON(RA)-(C1-C6)伸烷基、N(RB)CON(RA)基團、N(RB)CON(RA)-(C1-C6)伸烷基、N(RB)SO2N(RA)基團、N(RB)SO2N(RA)-(C1-C6)伸烷基、O-(C1-C6)伸烷基、N(RB)CO2基團、N(RB)CO2-(C1-C6)伸烷基、S-(C1-C6)伸烷基、SO2基團、SO2-(C1-C6)伸烷基、N(RB)SO2基團、N(RB)SO2-(C1-C6)伸烷基、CO基團、CO-(C1-C6)伸烷基、N(RB)CO基團、N(RB)CO-(C1-C6)伸烷基、SO2N(RB)CO基團、SO2N(RB)CO-(C1-C6)伸烷基、SO2N(RB)CON(RA)基團或SO2N(RB)CON(RA)-(C1-C6)伸烷基；RA及RB彼此獨立地表示氫原子或(C1-C6)烷基；m及n彼此獨立地表示等於0或1之整數，該化合物呈鹼或與酸形成之加成鹽形式。
式(I)化合物可包含一或多個不對稱碳原子。其因此可以對映異構體或非對映異構體形式存在。此等對映異構體、非對映異構體及其混合物，包括外消旋混合物，處於本發明範圍內。
式(I)化合物可以鹼或與酸形成之加成鹽的形式存在。該等加成鹽處於本發明範圍內。
此等鹽可用醫藥學上可接受之酸來製備，但其他酸(例如可能用於純化或分離式(I)化合物之酸)之鹽亦處於本發明範圍內。
在本發明內容中：-　Ct-Cz，其中t及z之取值可為1至7，應理解為意謂可具有t至z個碳原子之碳鏈或碳環；例如C1-C3可表徵具有1至3個碳原子之碳鏈；-　鹵素應理解為意謂氟、氯、溴或碘；-　烷基應理解為意謂視情況經直鏈、分支鏈或環化飽和烷基取代之直鏈、分支鏈或環化飽和脂族基。舉例而言，可提及甲基、乙基、丙基、異丙基、丁基、異丁基、第三丁基、環丙基、環丁基、環戊基、環己基、甲基環丙基及環丙基甲基及其類似基團；-　伸烷基應理解為意謂直鏈、分支鏈或環化飽和二價脂族基。舉例而言，(C1-C6)伸烷基表示具有1至6個碳原子之直鏈、分支鏈或環化二價碳鏈，諸如亞甲基(-CH2-)、伸乙基(-CH2CH2-)、1-甲基伸乙基(-CH(CH3)CH2-)、伸丙基(-CH2CH2CH2-)、伸環丙基(-(c-prop))及其類似基團；-　烯基應理解為意謂包含例如一或兩個烯系不飽和度之單不飽和或多不飽和直鏈或分支鏈脂族基；-　炔基應理解為意謂包含例如一或兩個炔系不飽和度之單不飽和或多不飽和直鏈或分支鏈脂族基；-　烷氧基應理解為意謂-O-烷基，其中烷基如上文所定義；-　烷硫基應理解為意謂-S-烷基，其中烷基如上文所定義；-　鹵烷基應理解為意謂一或多個氫原子已被一或多個相同或不同之鹵素原子置換的烷基。舉例而言，可提及CF3、CH2CF3、CHF2及CCl3基團；-　鹵基(C1-C6)烷氧基應理解為意謂-O-烷基，其中烷基係如上文所定義且經一或多個相同或不同之鹵素原子取代。舉例而言，可提及-OCF3、-OCHF2及-OCCl3基團；-　芳基應理解為意謂包含6至10個碳原子之芳族環狀基團。作為芳基之實例，可提及苯基或萘基；此芳基亦可以部分不飽和之形式存在；作為實例，可提及茚基、二氫茚基或四氫萘基；-　雜芳基應理解為意謂包含5至10個原子(包括1至5個選自N、O及S之雜原子)的單環或雙環基團，此基團為芳族、不飽和或部分不飽和基團或部分經氧化。作為單環雜芳基之實例，可提及吡咯、呋喃、噻吩、吡唑、咪唑、***、四唑、噁唑、異噁唑、噁二唑、噻唑、異噻唑、噻二唑、吡啶、嘧啶、吡嗪、噠嗪或三嗪。作為雙環雜芳基之實例，可提及呋喃并呋喃、噻吩并噻吩、吡咯并吡咯、吡咯并咪唑、吡咯并吡唑、吡咯并***、咪唑并咪唑、咪唑并吡唑、呋喃并吡咯、呋喃并咪唑、呋喃并吡唑、呋喃并***、吡咯并噁唑、咪唑并噁唑、吡唑并噁唑、呋喃并噁唑、噁唑并噁唑、噁唑并異噁唑、吡咯并異噁唑、咪唑并異噁唑、吡唑并異噁唑、異噁唑并異噁唑、呋喃并異噁唑、異噁唑并噁二唑、吡咯并噁二唑、呋喃并噁二唑、異噁唑并噁二唑、噻吩并吡咯、噻吩并咪唑、噻吩并吡唑、噻吩并***、吡咯并噻唑、咪唑并噻唑、吡唑并噻唑、***并噻唑、呋喃并噻唑、噁唑并噻唑、噁唑并異噻唑、吡咯并異噻唑、咪唑并異噻唑、吡唑并異噻唑、異噁唑并異噻唑、呋喃并異噻唑、吡咯并噻二唑、咪唑并噻二唑、呋喃并噻二唑、異噁唑并噻二唑、噁唑并噻二唑、異噻唑并噻二唑、吲哚、異吲哚、苯并咪唑、吲唑、吲哚嗪、苯并呋喃、異苯并呋喃、苯并噻吩、吡咯并吡啶、咪唑并吡啶、吡唑并吡啶、***并吡啶、四唑并吡啶、吡咯并嘧啶、咪唑并嘧啶、吡唑并嘧啶、吡咯并吡嗪、咪唑并吡嗪、吡唑并吡嗪、吡咯并噠嗪、咪唑并噠嗪、吡唑并噠嗪、***并噠嗪、吡咯并三嗪、呋喃并吡啶、呋喃并嘧啶、呋喃并吡嗪、呋喃并噠嗪、呋喃并三嗪、噁唑并吡啶、噁唑并嘧啶、噁唑并吡嗪、噁唑并噠嗪、異噁唑并吡啶、異噁唑并嘧啶、異噁唑并吡嗪、異噁唑并噠嗪、噁二唑并吡啶、苯并噁唑、苯并異噁唑、苯并噁二唑、苯并噁嗪、苯并二氧雜環戊烯、苯并二氧雜環己烯、苯并二氧雜環庚烯(benzodioxepine)、噻吩并吡啶、噻吩并嘧啶、噻吩并吡嗪、噻吩并噠嗪、噻吩并三嗪、噻唑并吡啶、噻唑并嘧啶、噻唑并吡嗪、噻唑并噠嗪、異噻唑并吡啶、異噻唑并嘧啶、異噻唑并吡嗪、異噻唑并噠嗪、噻二唑并吡啶、噻二唑并嘧啶、苯并噻唑、苯并異噻唑、苯并噻二唑、喹啉、異喹啉、啉、酞嗪、喹喏啉、喹唑啉、啶、苯并三嗪、吡啶并嘧啶、吡啶并吡嗪、吡啶并噠嗪、吡啶并三嗪、嘧啶并嘧啶、嘧啶并吡嗪、嘧啶并噠嗪、吡嗪并吡嗪、吡嗪并噠嗪、吡嗪并三嗪或噠嗪并噠嗪。
此等基團可以不飽和或部分不飽和形式存在；舉例而言，可提及二氫苯并呋喃、二氫苯并噻吩、四氫喹啉、四氫異喹啉、吲哚啉、二氫苯并噁嗪或二氫苯并二噁烷。
-　雜環基團應理解為意謂包含1至4個選自N、O及S之雜原子的3至7員飽和環狀基團。舉例而言，可提及吡咯啶、哌啶、嗎啉、哌嗪、氮丙啶、氮雜環丁烷、氮呯、硫代嗎啉、N-甲基哌嗪、高哌嗪、氮雜環丁-2-酮、1,2-硫氮雜環丁烷1,1-二氧化物、吡咯啶-2-酮、1,2-異噻唑啶1,1-二氧化物、哌啶-2-酮、1,2-硫氮雜環己烷1,1-二氧化物、咪唑啶-2-酮、噁唑啶-2-酮、1,2,5-噻二唑啶1,1-二氧化物、1,2,3-氧雜噻唑啶2,2-二氧化物、四氫嘧啶-2-酮、1,3-氧氮雜環己-2-酮、1,2,6-硫二氮雜環己烷1,1-二氧化物、1,2,3-氧硫氮雜環己烷2,2-二氧化物、哌嗪-2-酮、嗎啉-3-酮、1,2,5-硫二氮雜環己烷1,1-二氧化物或1,3,4-氧硫氮雜環己烷3,3-二氧化物基團。
在本發明內容中，R、Z及A基團係自左向右閱讀：Z基團之左部分連接至「R」基團，且「Z」之右部分連接至「A」基團；同樣，「A」基團之左部分連接至「Z」基團且「A」之右部分連接至環系統：
在以下定義之各種基團中，當未定義A、Z、R、RA、RB、R1、R2或R3基團時，其具有與上文所提及者相同之定義。
在作為本發明標的物之式(I)化合物中，第一組化合物由以下化合物，其中：R1表示苯基、萘基、二氫茚基、苯并噁唑、苯并異噁唑、苯并咪唑、苯并***、噁二唑、吲唑、異噁唑、吡啶、吡嗪、嘧啶、噻吩基、噻唑、苯并噻吩、吲哚、二氫苯并二噁烷、苯并噻二唑、吡唑、二氫苯并噁嗪或吲哚啉基團；R2表示一或多個選自鹵素原子或甲基、三氟甲基、甲氧基、三氟甲氧基、氰基、側氧基、CH3NHCO、CH3SO2、NH2CO、NH2SO2或吡咯啶-SO2基團之基團；R3表示選自苯基或噁唑之基團；以及化合物4-{[3-(2-甲基嘧啶-4-基)苯磺醯基胺基]甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯構成。
在作為本發明標的物之式(I)化合物中，第二組化合物由以下式(I)化合物構成，其中：Z表示一鍵或CH2、(CH2)2、CH=CH、C≡C、OCH2或OC(CH3)2基團。
在作為本發明標的物之式(I)化合物中，第三組化合物由以下式(I)化合物構成，其中：A表示一鍵、氧原子、硫原子、OCH2基團、O(CH2)2基團、NH、NHCH2或NH(CH2)2基團、SO2或CO基團、CONH基團、CONHCH2或CONH(CH2)2基團、SO2NH基團、SO2NHCH2或SO2NH(CH2)2基團、SO2NHCO、SO2NHCONH或SO2NHCONHCH2基團、OCONH基團、NHCONH基團、NHCONHCH2基團、N(CH3)CONHCH2、NHCONH(CH2)2或N(CH3)CONH(CH2)2基團或SO2N(CH3)CH2基團。
在作為本發明標的物之式(I)化合物中，第四組化合物由以下式(I)化合物構成，其中：m及n表示1。
在作為本發明標的物之式(I)化合物中，第五組化合物由以下式(I)化合物構成，其中：m表示1且n表示0。
在作為本發明標的物之式(I)化合物中，第六組化合物由以下式(I)化合物構成，其中：m及n表示0。
在作為本發明標的物之式(I)化合物中，第七組化合物由以下式(I)化合物構成，其中：R1表示苯基、萘基、二氫茚基、苯并噁唑、苯并異噁唑、苯并咪唑、苯并***、噁二唑、吲唑、異噁唑、吡啶、吡嗪、嘧啶、塞吩基、噻唑、苯并噻吩、吲哚、二氫苯并二噁烷、苯并噻二唑、吡唑、二氫苯并噁嗪或吲哚啉基團；R2表示一或多個選自鹵素原子或甲基、三氟甲基、甲氧基、三氟甲氧基、氰基、側氧基、CH3NHCO、CH3SO2、NH2CO、NH2SO2或吡咯啶-SO2基團之基團；R3表示選自苯基或噁唑之基團；Z表示一鍵或CH2、(CH2)2、CH=CH、C≡C、OCH2或OC(CH3)2基團；A表示一鍵、氧原子、硫原子、OCH2基團、O(CH2)2基團、NH、NHCH2或NH(CH2)2基團、SO2或CO基團、CONH基團、CONHCH2或CONH(CH2)2基團、SO2NH基團、SO2NHCH2、SO2NH(CH2)2或SO2NHC[CH2]2基團、SO2NHCO、SO2NHCONH或SO2NHCONHCH2基團、OCONH基團、NHCONH基團、NHCONHCH2基團、N(CH3)CONHCH2、NHCONH(CH2)2或N(CH3)CONH(CH2)2基團或SO2N(CH3)CH2基團；m及n彼此獨立地表示等於0或1之整數；該化合物呈鹼或與酸形成之加成鹽形式。
如上文所定義之第一組至第七組之組合亦處於本發明範圍內。
在作為本發明標的物之式(I)化合物中，可特別提及以下化合物：‧4-(4-氯苯基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(間甲苯基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(2-(三氟甲基)苯基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(2-甲氧基苯基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-氰基苯基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-(甲基胺甲醯基)苯基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(萘-1-基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(苯并噁唑-2-基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(5-氟苯并[d]異噁唑-3-基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(6-氟苯并[d]異噁唑-3-基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(2-側氧基-2,3-二氫苯并咪唑-1-基)-哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(5-氯-2-側氧基-2,3-二氫苯并咪唑-1-基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(5-(三氟甲基)苯并***-1-基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[5-(4-氟苯基)-1,3,4-噁二唑-2-基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(6-氟-1H-吲唑-3-基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(苯甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(4-氯苯基)異噁唑-5-基甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(4-氯苯基)乙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-氯苯基乙炔基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-(4'-氟聯苯-3-基氧基)氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-(3'-氰基聯苯-3-基氧基)氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧(S)-3-(4'-氟聯苯-3-基氧基)吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧(R)-3-(4'-氟聯苯-3-基氧基)吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧(S)-3-(3'-氰基聯苯-3-基氧基)吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧(R)-3-(3'-氰基聯苯-3-基氧基)吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-氟苯氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-胺甲醯基苯氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(3'-氟聯苯-3-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4'-氟聯苯-3-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(3'-氯聯苯-3-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4'-氯聯苯-3-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(3'-氰基聯苯-3-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4'-氰基聯苯-3-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(3'-氰基聯苯-4-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4'-氰基聯苯-4-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(3'-甲氧基聯苯-3-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4'-甲氧基聯苯-3-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-氯萘-1-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(萘-2-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(6-氰基萘-2-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(6-甲氧基萘-2-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(7-甲氧基萘-2-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(吡啶-4-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[6-(3-氰基苯基)吡啶-2-基氧基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[5-(3-氰基苯基)吡啶-3-基氧基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[6-(3-氰基苯基)嘧啶-4-基氧基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[6-(4-氟苯基)吡嗪-2-基氧基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[6-(3-氰基苯基)吡嗪-2-基氧基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-氯萘-1-基氧基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(3'-氰基聯苯-3-基氧基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4'-氰基聯苯-3-基氧基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(3'-氰基聯苯-4-基氧基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4'-氰基聯苯-4-基氧基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(萘-2-基氧基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(6-甲氧基萘-2-基氧基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(7-甲氧基萘-2-基氧基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(6-氰基萘-2-基氧基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(聯苯-4-基氧基)乙基]-哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(4-氯萘-1-基氧基)乙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(6-溴吡啶-2-基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(5-氰基吡啶-2-基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(5-胺甲醯基吡啶-2-基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(5-(三氟甲基)吡啶-2-基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-三氟甲基嘧啶-2-基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(2-溴嘧啶-4-基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[6-(4-氟苯基)吡啶-2-基胺基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[6-(3-氰基苯基)吡啶-2-基胺基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(3-氰基苯基)嘧啶-4-基胺基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(6-氯吡啶-2-基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(吡啶-4-基硫基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(苯磺醯基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-氟苯甲醯基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-氯苯甲醯基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-氯苯甲醯基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-甲基苯甲醯基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(3-氯苯并[b]噻吩-2-羰基)胺基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(4-氯苯氧基)乙醯基胺基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[(E)-(3-苯基丙烯醯基)胺基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(E)-(3-苯基丙烯醯基)胺基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-氯苯甲醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{[(3-氯苯并[b]噻吩-2-羰基)胺基]甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{[2-(4-氯苯氧基)乙醯基胺基]甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{[2-(4-氯苯氧基)-2-甲基丙醯基胺基]甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-{[(E)-(3-苯基丙烯醯基)胺基]甲基}吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{[(E)-(3-苯基丙烯醯基)胺基]甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-{[2-(4-氯苯氧基)乙醯基胺基]甲基}吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-(2-(苯基乙醯基胺基)乙基)氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-{2-[2-(4-氯苯氧基)乙醯基胺基]乙基}氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-{2-[(E)-(3-苯基丙烯醯基)胺基]乙基}氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-(5-溴-2-甲氧基苯磺醯基胺基)氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-(4-溴-2-氟苯磺醯基胺基)氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-(二氫茚-5-磺醯基胺基)氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-(聯苯-4-磺醯基胺基)氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-(4-甲基萘-1-磺醯基胺基)氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-(5-氯噻吩-2-磺醯基胺基)氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-(5-溴噻吩-2-磺醯基胺基)氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[(苯并[b]噻吩-2-羰基)胺基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(3-氯苯磺醯基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-氯苯磺醯基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(5-溴-2-甲氧基苯磺醯基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(萘-1-磺醯基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(萘-2-磺醯基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-(苯基甲磺醯基胺基)氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(苯基甲磺醯基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[(4-氯苯磺醯基胺基)甲基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[(3-氯苯磺醯基胺基)甲基]吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[(4-氯苯磺醯基胺基)甲基]吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[(萘-1-磺醯基胺基)甲基]吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[(萘-2-磺醯基胺基)甲基]吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-((苯磺醯基胺基)甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-氟苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(2-氯苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(3-氯苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-氯苯磺醯基胺基)-甲基]-哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(甲苯-2-磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(甲苯-3-磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(甲苯-4-磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(3-(三氟甲基)苯磺醯基胺基)-甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-(三氟甲基)苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(3-甲氧基苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-甲氧基苯磺醯基-胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(3-{三氟甲氧基}苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-{三氟甲氧基}苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-氟-2-{三氟甲基}苯磺醯基-胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-氰基苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(3-氟-4-甲基苯磺醯基-胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(3,4--二氟苯磺醯基-胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧[(3,4-二氯苯磺醯基-胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(3-氯-4-甲基苯磺醯基-胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(3-氯-4-{三氟甲氧基}苯-磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(3,4-二甲基苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(3-氟-4-甲氧基苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-氟-3-甲基苯磺醯基-胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(3-氯-4-氟苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-氟-3-甲氧基苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-氟-3-{三氟甲基}苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-氯-3-{三氟甲基}苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-{甲磺醯基}苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{[4-(吡咯啶-1-磺醯基)苯磺醯基胺基]甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(聯苯-4-磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(萘-1-磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(萘-2-磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(3,5-二甲基異噁唑-4-磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-{噁唑-5-基}苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-氯苯基甲磺醯基胺基)-甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[1-(4-氯苯磺醯基胺基)環丙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[2-(3-氯苯磺醯基胺基)乙基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[2-(4-氯苯磺醯基胺基)乙基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[2-(萘-1-磺醯基胺基)乙基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[2-(萘-2-磺醯基胺基)乙基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(苯氧基羰基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(3-苯基脲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(3-氯苯基)脲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(4-氯苯基)脲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(3-氰基苯基)脲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(4-氰基苯基)脲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(2,4-二氟苯基)脲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(2,4-二氯苯基)脲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(2,5-二氯苯基)脲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(5-氯-2-甲氧基苯基)脲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(3-胺甲醯基苯基)脲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(3-苯甲基脲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[3-(4-氯苯基)脲基甲基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[3-(3-氯苯基)脲基甲基]吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[3-(4-氯苯基)脲基甲基]吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[3-(4-氰基苯基)脲基甲基]吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(4-氯苯基)脲基甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{3-[2-(4-{三氟甲基}苯基)噻唑-4-基]-脲基甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-(3-苯甲基脲基甲基)吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(3-苯甲基脲基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-(3-甲基-3-苯基脲基甲基)吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-{2-[3-(3-氯苯基)脲基]乙基}氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-{2-[3-(4-氯苯基)脲基]乙基}氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-{2-[3-(4-氰基苯基)脲基]乙基}氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[2-(3-甲基-3-苯基脲基)乙基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{2-[3-(4-氯苯基)脲基]乙基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[2-(3-苯甲基脲基)乙基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-氯苯磺醯基胺基-羰基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-({[(4-氯苯基)磺醯基]胺甲醯基}胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[({[(4-氯苯基)磺醯基]胺甲醯基}胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(3-胺甲醯基苯氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(3-胺甲醯基苯氧基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(吲哚-1-羰基)胺基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{[(吲哚-1-羰基)胺基]甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(2-氟苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(2-{三氟甲基}苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(2-甲氧基苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(3-氰基苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(3-氯-2-氟苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(苯并[b]噻吩-3-磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[1-(4-甲氧基苯磺醯基胺基)環丙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{2-[(1H-吲哚-1-基羰基)胺基]乙基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-({[3-(甲基磺醯基)苯基]胺甲醯基}胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{[(1H-苯并咪唑-5-基胺甲醯基)胺基]甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{[(1H-吲唑-6-基胺甲醯基)胺基]甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-胺甲醯基苯氧基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(3-胺甲醯基苯氧基)乙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(4-胺甲醯基苯氧基)乙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-(甲磺醯基)苯磺醯基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(吡啶-3-磺醯基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(2-{三氟甲氧基}苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(2-甲氧基-4-甲基苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(2,4-二甲氧基苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(2,5-二甲氧基苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(5-氟-2-甲氧基苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(5-甲磺醯基-2-甲氧基苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-氯-2,5-二甲基苯磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{[3-(5-甲基-1,3,4-噁二唑-2-基)苯磺醯基胺基]甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(2,3-二氫苯并[1,4]二氧雜環己烯-6-磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(苯并[1,2,5]噻二唑-4-磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-甲基-3,4-二氫-2H-苯并[1,4]噁嗪-7-磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{[3-(2-甲基嘧啶-4-基)苯磺醯基胺基]甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(5-氯-1,3-二甲基-1H-吡唑-4-磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(吡啶-3-磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(6-氯吡啶-3-磺醯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{[N-4-(氯苯磺醯基)-N-甲胺基]甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(4-(甲磺醯基)苯磺醯基胺基)乙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(吡啶-3-磺醯基胺基)乙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[1-(4-氯苯磺醯基胺基)環丙基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[1-(5-甲磺醯基-2-甲氧基苯磺醯基胺基)環丙基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[1-(吡啶-3-磺醯基胺基)環丙基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧3-[1-(4-{甲磺醯基}苯磺醯基胺基)環丙基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-{甲磺醯基}苯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-胺磺醯基苯基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(2-胺甲醯基吡啶-4-基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(4-胺甲醯基吡啶-2-基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(5-胺甲醯基吡啶-2-基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(6-胺甲醯基吡啶-2-基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(5-胺甲醯基吡嗪-2-基胺基)甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-(4-胺甲醯基吡唑-1-基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(5-胺甲醯基吡啶-2-基胺基)乙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(4-胺甲醯基嘧啶-2-基胺基)乙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(5-胺甲醯基吡嗪-2-基胺基)乙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(6-胺甲醯基吡嗪-2-基胺基)乙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[(2,3-二氫苯并[1,4]噁嗪-4-羰基)胺基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{[(2,3-二氫苯并[1,4]噁嗪-4-羰基)胺基]甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(3-{甲磺醯基}苯甲醯基胺基)乙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(4-{甲磺醯基}苯甲醯基胺基)乙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[2-(4-胺磺醯基苯甲醯基胺基)乙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{2-[(2,3-二氫苯并[1,4]噁嗪-4-羰基)胺基]乙基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(1H-苯并咪唑-5-基)脲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(1-甲磺醯基-2,3-二氫-1H-吲哚-5-基)脲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(1H-吲唑-6-基)脲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(5-甲磺醯基-2-甲氧基苯基)脲基甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-{3-[2-甲氧基-5-(吡咯啶-1-磺醯基)苯基]脲基甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯‧4-[3-(1-甲磺醯基-2,3-二氫-1H-吲哚-5-基)脲基甲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯接下來，術語「保護基Pg」應理解為意謂一方面在合成期間可保護諸如羥基或胺基之反應性官能基，另一方面在合成結束時可再生該反應性官能基的基團。「Protective Groups in Organic Synthesis」,Green等人，第2版(John Wiley & Sons Inc.,New York),1991中提供保護基以及保護及去保護方法之實例。
接下來，術語「離去基」應理解為意謂藉由***異質鍵(heterolytic bond)使電子對脫離而容易地自分子裂解之基團。因此在例如取代反應中，此基團可容易地被另一基團置換。
根據本發明，可根據以下方法製備通式(I)之化合物：用於製備本發明化合物之一般方法(流程1)在於使通式(II)之胺(呈鹼或鹽形式，其中m、n、A、Z及R如上文所定義)與通式(III)之衍生物(其中X表示離去基，諸如氯原子、4-硝基苯氧基、咪唑基、1,2,4-***基或N-氧基丁二醯亞胺基)反應。在諸如二氯甲烷、乙腈、N-甲基吡咯啶酮、二甲亞碸、二甲基甲醯胺之溶劑或此等溶劑之混合物中，視情況在諸如吡啶或二異丙基乙胺之鹼及諸如4-二甲胺基吡啶之催化劑存在下，在0至80℃之溫度下進行該反應。
流程1
通式(II)之化合物可購自市面，或描述於文獻中，或可根據文獻中所述之方法或熟習此項技術者已知的方法製備，如以下實例中所說明。
藉由視情況在諸如吡啶之鹼及諸如4-二甲胺基吡啶之催化劑存在下，在0至80℃之溫度下使醇1,1,1,3,3,3-六氟-2-丙醇與三光氣、氯甲酸4-硝基苯酯、羰基二咪唑、羰基二(1,2,4-***)或羰基二(N-氧基丁二醯亞胺)在諸如二氯甲烷、乙腈或N-甲基吡咯啶酮之溶劑中反應來製備通式(III)之化合物。一般就地製備並使用化合物(III)。一些通式(III)之化合物已報導於文獻中(X=氯，Synthesis,1993(1),103-106；X=咪唑，Tetrahedron Letters,1982,23(20),2113-2116；X=1,2,4-***，Chem. Pharm. Bull.,1983,31(12),4578-4581)。
或者，可藉由使通式(IV)之衍生物(其中W表示甲醯氯(COCl)、磺醯氯(SO2Cl)、異氰酸酯(NCO)、胺甲醯氯(N(RB)COCl)或氯甲酸酯(OCOCl)官能基)與通式(V)之衍生物(其中V表示胺HN(RA)或HN(RA)-(C1-C6)伸烷基官能基)反應(流程2)來製備通式(Ia)之化合物，其中A表示CON(RA)、CON(RA)-(C1-C6)伸烷基、SO2N(RA)、SO2N(RA)-(C1-C6)伸烷基、N(RB)CON(RA)、N(RB)CON(RA)-(C1-C6)伸烷基、OCON(RA)或OCON(RA)-(C1-C6)伸烷基且R、Z、m及n如上文所定義。此式(V)之衍生物可能為：-　哌啶-1-甲酸六氟異丙酯衍生物，當m及n表示1時；-　吡咯啶-1-甲酸六氟異丙酯衍生物，當m表示1且n表示0時；-　氮雜環丁烷-1-甲酸六氟異丙酯衍生物，當m及n表示0時。
流程2
在諸如二氯甲烷、乙腈或N-甲基吡咯啶酮之溶劑中，視情況在諸如吡啶或二異丙基乙胺之鹼及諸如4-二甲胺基吡啶之催化劑存在下，在0至80℃之溫度下進行該反應。
通式(IV)之化合物可購自市面，或描述於文獻中，或可根據文獻中所述之方法或熟習此項技術者已知的方法製備。
呈鹼或鹽形式之通式(V)化合物為新穎化合物且處於本發明範圍內。其係用作合成式(Ia)化合物之中間物且可如以下實例中所述來製備。
以下實例說明一些本發明化合物之製備。此等實例不具限制意義且僅用於說明本發明。微量分析、IR及NMR光譜及/或LC/MS分析證實所獲得之化合物的結構及純度。實例中之化合物之編號係指下表中所提供之編號，在該表中說明一些本發明化合物之化學結構及物理性質。
在d3-氯仿(CDCl3)、d6-(二甲亞碸)(DMSO)或d4-甲醇(CD3OD)中記錄200 MHz或400 MHz下之質子核磁共振(1H NMR)光譜(化學位移δ，ppm)。用於表徵信號之縮寫如下：s=單峰、m=多重峰、d=雙重峰、t=三重峰、q=四重峰、sept.=七重峰。
以下詳細描述LC/MS分析方法之實例。滯留時間(Rt)以分鐘表示。
方法A：
HPLC/阱(Trap)-5 mM乙酸銨/乙腈梯度
T0：100%A-T13至T16 min：100%B-T16.5至T20 min：100%A
路徑A：乙酸銨+3%乙腈；路徑B：乙腈
流速：0.5 ml/min-T°=40℃
管柱：Kromasil C18(50*2.1 mm；3.5 μm)
方法B：
HPLC/ZQ-水/乙腈/三氟乙酸梯度
T0：100%A-T13至T16 min：100%B-T16.5至T20 min：100%A
路徑A：水+0.05%三氟乙酸+3%乙腈；路徑B：乙腈+0.035%三氟乙酸
流速：0.5 ml/min-T°=40℃
管柱：Kromasil C18(50*2.1 mm；3.5 μm)
方法C：
HPLC/ZQ-5 mM乙酸銨/乙腈梯度
T0：100%A-T5.5至T7 min：100%B-T7.1至T10 min：100%A
路徑A：乙酸銨+3%乙腈；路徑B：乙腈
流速：0.8 ml/min-T°=40℃
管柱：Kromasil C18(50*2.1 mm；3.5 μm)
方法D：
UPLC/TOF-水/乙腈/三氟乙酸梯度
T0：98%A-T1.6至T2.1 min：100%B-T2.5至T3 min：98%A
路徑A：水+0.05%三氟乙酸；路徑B：乙腈+0.035%三氟乙酸
流速：1.0 ml/min-T°=40℃
管柱：Acquity BEH C18(50*2.1 mm；1.7 μm)
方法E：
HPLC/TOF-水/乙腈/三氟乙酸梯度
T0：95%A-T2.5 min：95%B
路徑A：水+0.05%三氟乙酸；路徑B：乙腈+0.05%三氟乙酸
流速：1.3 ml/min-環境溫度
管柱：YMC-Pack Jsphere H80(33*2.1 mm；4 μm)
實例1(第5號化合物)
4-(4-氰基苯基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
將0.604 g(3.6 mmol)1,1,1,3,3,3-三氟-2-丙醇、0.32 ml(3.96 mmol)吡啶及0.014 g(0.12 mmol)4-二甲胺基吡啶於9 ml二氯甲烷中之溶液逐滴添加至已冷卻至0℃且處於氬氣氛圍下的0.356 g(1.2 mmol)三光氣於8 ml二氯甲烷中之溶液中。在環境溫度下持續攪拌6小時。隨後添加0.670 g(3.6 mmol)4-(哌啶-4-基)苯甲腈及1.31 ml(7.92 mmol)二異丙基乙胺。攪拌混合物隔夜。添加23 ml二氯甲烷。用40 ml冰冷水洗滌有機相3次，經硫酸鈉乾燥並蒸發至乾燥。
藉由矽膠層析，用乙酸乙酯與環己烷之15:85混合物進行溶離來純化產物。自正己烷中結晶，從而獲得0.32 g(0.84 mmol)呈白色粉末形式之產物。
熔點(℃)：54-56
LC/MS(方法A): Rt 9.7 min,m/z 398(MNH4+)
IR(KBr,cm-1): 2226,1743
1H NMR(CDCl3,δ ppm,200 MHz): 7.65(d,2H),7.35(d,2H),5.8(七重峰,1H),4.35(m,2H),3.05(m,2H),2.8(m,1H),1.95(m,2H),1.8(m,2H)。
實例2(第10號化合物)
4-(6-氟苯并[d]異噁唑-3-基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
將0.342 g(1.7 mmol)氯甲酸4-硝基苯酯於6 ml二氯甲烷中之溶液逐滴添加至已冷卻至0℃且處於氬氣氛圍下的0.571 g(3.4 mmol)1,1,1,3,3,3-三氟-2-丙醇、0.28 ml(3.4 mmol)吡啶及0.011 g(0.1 mmol)4-二甲胺基吡啶於5 ml二氯甲烷中之溶液中。在環境溫度下攪拌混合物隔夜。相繼添加0.374 g(1.7 mmol)6-氟-3-(哌啶-4-基)苯并[d]異噁唑及0.74 ml(4.25 mmol)二異丙基乙胺。在環境溫度下攪拌混合物5小時。添加4 g二氧化矽並將混合物蒸發至乾燥。藉由矽膠層析，依序用乙酸乙酯與環己烷之10:90混合物及15:85混合物進行溶離來純化產物。在正己烷中進行結晶，從而獲得0.45 g(1.09 mmol)呈白色晶體形式之產物。
熔點(℃)：91-93
LC/MS(方法B): Rt 10.6 min,m/z 415(MH+)
IR(KBr,cm-1): 1741
1H NMR(DMSO,δ ppm,200 MHz): 8.0(d.d,1H),7.7(d.d,1H),7.3(d.t,1H),6.55(七重峰,1H),4.05(m,2H),3.5(m,1H),3.2(m,2H),2.1(m,2H),1.75(m,2H)。
實例3(第12號化合物)
4-(5-氯-2-側氧基-2,3-二氫苯并咪唑-1-基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
將0.328 g(2 mmol)羰基二(1,2,4-***)添加至0.6725 g(4 mmol)1,1,1,3,3,3-三氟-2-丙醇及0.012 g(0.1 mmol)4-二甲胺基吡啶於10 ml二氯甲烷中之溶液中。在環境溫度下攪拌混合物隔夜，接著添加0.503 g(2 mmol)5-氯-1-哌啶-4-基-1,3-二氫苯并咪唑-2-酮。在環境溫度下持續攪拌3小時，並在真空下蒸發二氯甲烷。使殘餘物溶解於50 ml乙酸乙酯與20 ml 1 N鹽酸水溶液之混合物中。藉由沈降分離有機相，接著依序用20 ml水(2次)及20 ml飽和氯化鈉水溶液洗滌。使有機相經硫酸鈉乾燥並在真空下蒸發。藉由矽膠層析，依序用乙酸乙酯與環己烷之30:70、40:60及50:50混合物進行溶離來純化產物。隨後在熱條件下自乙酸乙酯與環己烷之混合物中再結晶，從而獲得0.28 g(0.62 mmol)呈白色結晶粉末形式之產物。
熔點(℃)：231-233
LC/MS(方法B): Rt 9.3 min,m/z 446(MH+)
IR(KBr,cm-1): 1751,1697
1H NMR(CDCl3,δ ppm,200 MHz): 8.6(s,1H),7.15-6.95(m,3H),5.85(七重峰,1H),4.6-4.3(m,3H),3.1(m,2H),2.4(m,2H),1.95(m,2H)。
實例4(第75號化合物)
4-(4-氯苯甲醯基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
將0.512 g(2 mmol)羰基二(N-氧基丁二醯亞胺)及0.012 g(0.1 mmol)4-二甲胺基吡啶添加至0.504 g(3 mmol)1,1,1,3,3,3-三氟-2-丙醇於7 ml二氯甲烷中之溶液中。在環境溫度下攪拌混合物4小時。將其冷卻至0℃，且依序添加0.520 g(2 mmol)(4-氯-苯基)(哌啶-4-基)甲酮鹽酸鹽及1.04 ml(6 mmol)二異丙基乙胺。在環境溫度下攪拌混合物隔夜。添加20 ml冰冷水及50 ml冰冷二氯甲烷。藉由沈降分離有機相。依序用冰冷水(2次)及20 ml飽和氯化鈉水溶液洗滌。使有機相經硫酸鈉乾燥並蒸發至乾燥。藉由矽膠層析，依序用乙酸乙酯與環己烷之5:95及10:90混合物進行溶離而純化產物，從而獲得0.175 g(0.42 mmol)呈無色油形式之產物。
LC/MS(方法A): Rt 10.9 min,m/z 418(MH+)
IR(膜,cm-1): 1739,1684
1H NMR(CDCl3,δ ppm,200 MHz): 7.8(d,2H),7.4(d,2H),5.7(七重峰,1H),4.1(d,2H),3.5(m,1H),3.1(m,2H),1.9-1.6(m,4H)。
實例5(第33號化合物)
4-(3'-氰基聯苯-3-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
5.1.　4-(3'0氰基聯苯-7-基氧基)哌啶-1-甲酸第三丁酯
將1.210 g(5.99 mmol)偶氮二甲酸二異丙酯之溶液逐滴添加至已冷卻至0℃且處於氬氣氛圍下的0.974 g(4.99 mmol)3'-羥基聯苯-3-甲腈、1.205 g(5.99 mmol)4-羥基哌啶-1-甲酸第三丁酯及1.570 g(5.99 mmol)三苯膦於12 ml四氫呋喃中之溶液中。隨後在環境溫度下攪拌混合物隔夜。添加15 g二氧化矽並將混合物蒸發至乾燥。藉由矽膠層析，依序用乙酸乙酯與環己烷之10:90及15:85混合物進行溶離而純化產物，從而獲得1.538 g(4.06 mmol)呈無色油形式之產物。
5.2.　3'-(哌啶-4-基氧基)聯苯-3-甲腈
將1.508 g(3.98 mmol)階段5.1.中所獲得之4-(3'-氰基聯苯-3-基氧基)哌啶-1-甲酸第三丁酯溶解於13 ml二氯甲烷中。添加3.07 ml(39.84 mmol)三氟乙酸並在環境溫度下攪拌混合物4小時。蒸發至乾燥，接著與12 ml 1,2-二氯乙烷一起共同蒸發兩次。使殘餘物溶解於18 ml二氯甲烷與9 ml 1N氫氧化鈉水溶液之混合物中。藉由沈降分離有機相且用12 ml二氯甲烷萃取水相。依序用18 ml水及18 ml飽和氯化鈉水溶液洗滌有機相。使有機相經硫酸鈉乾燥並蒸發至乾燥，從而獲得1.026 g(3.68 mmol)呈橙色油形式之產物。
5.3.　4-(3'-氰基聯苯-3-基氧基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
將0.504 g(3 mmol)1,1,1,3,3,3-六氟-2-丙醇、0.27 ml(3 mmol)吡啶及0.012 g(0.1 mmol)4-二甲胺基吡啶於6 ml二氯甲烷中之溶液逐滴添加至已冷卻至0℃且處於氬氣氛圍下的0.296 g(1 mmol)三光氣於7 ml二氯甲烷中之溶液中。在環境溫度下攪拌混合物5小時。隨後依序添加0.835 g(3 mmol)階段5.2.中所獲得之3'-(哌啶-4-基氧基)聯苯-3-甲腈於4.9 ml二氯甲烷中之溶液及1.09 ml(6.6 mmol)二異丙基乙胺。在環境溫度下攪拌混合物隔夜。添加11 ml二氯甲烷且用25 ml冰冷水洗滌有機相三次。使有機相經硫酸鈉乾燥並蒸發至乾燥。藉由矽膠層析，用乙酸乙酯與環己烷之10:90混合物進行溶離來純化產物。隨後自正己烷中結晶，從而獲得0.635 g(1.34 mmol)呈白色固體形式之產物。
熔點(℃)：80-82
LC/MS(方法A): Rt 11.8 min,m/z 473(MH+)
IR(KBr,cm-1): 2235,1730
1H NMR(CDCl3,δ ppm,200 MHz): 7.85(m,2H),7.7-7.5(m,2H),7.4(t,1H),7.15(m,2H),7.0(d.d,1H),5.8(七重峰,1H),4.65(m,1H),3.85-3.55(m,4H),2.0(m,4H)。
實例6(第65號化合物)
4-(5-(三氟甲基)吡啶-2-基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯鹽酸鹽(1:1)
6.1.　4-(5-(三氟甲基)吡啶-2-基胺基)哌啶-1-甲酸第三丁酯
在100℃下將0.678 g(3 mmol)2-溴-5-(三氟甲基)吡啶、0.901 g(4.5 mmol)4-胺基哌啶-1-甲酸第三丁酯及0.829 g(6 mmol)碳酸鉀於5 ml二甲亞碸中之混合物加熱20小時。將混合物冷卻至環境溫度，接著添加50 ml乙酸乙酯及15 ml水。藉由沈降分離有機相，且依序用15 ml水及15 ml飽和氯化鈉水溶液洗滌兩次。使有機相經硫酸鈉乾燥並在真空下蒸發。藉由矽膠層析，依序用乙酸乙酯與環己烷之20:80及30:70混合物進行溶離而純化產物，從而獲得0.864 g(2.5 mmol)呈白色固體形式之產物。
熔點(℃)：152
6.2.(哌啶-4-基)(5-(三氟甲基)吡啶-2-基)胺
將0.860 g(2.49 mmol)階段6.1.中所獲得之4-(5-(三氟甲基)(吡啶-2-基胺基)哌啶-1-甲酸第三丁酯溶解於8.5 ml二氯甲烷中。添加1.91 ml三氟乙酸並在環境溫度下攪拌混合物4小時。蒸發二氯甲烷，接著將殘餘物與10 ml 1,2-二氯乙烷一起共同蒸發兩次。將殘餘物溶解於50 ml乙酸乙酯、10 ml 1 N氫氧化鈉水溶液及5 ml 33%氨水溶液之混合物中。藉由沈降分離有機相。依序用10 ml水(2次)及10 ml飽和氯化鈉水溶液洗滌。使有機相經硫酸鈉乾燥並蒸發至乾燥，產生0.572 g(2.33 mmol)呈灰白色固體形式之產物。
熔點(℃)：128
6.3.　4-(5-(三氟甲基)(吡啶-2-基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
將0.467 g(2.32 mmol)氯甲酸4-硝基苯酯於3 ml二氯甲烷中之溶液逐滴添加至已冷卻至0℃且處於氬氣氛圍下的0.781 g(4.64 mmol)1,1,1,3,3,3-六氟-2-丙醇、0.38 ml(4.64 mmol)吡啶及0.014 g(0.11 mmol)4-二甲胺基吡啶於1.5 ml二氯甲烷中之溶液中。使混合物處於環境溫度下隔夜，接著添加於5 ml二氯甲烷中之0.569 g(2.32 mmol)階段6.2.中所獲得之(哌啶-4-基)(5-(三氟甲基)吡啶-2-基)胺及1.22 ml(6.96 mmol)二異丙基乙胺。攪拌混合物5小時，接著蒸發。使殘餘物溶解於10 ml乙酸乙酯、50 ml***及20 ml水之混合物中。藉由沈降分離有機相，接著用20 ml 1M碳酸鉀水溶液洗滌三次。用20 ml***再萃取水相。依序用20 ml水及20 ml飽和氯化鈉水溶液洗滌有機相。使有機相經硫酸鈉乾燥並蒸發至乾燥。藉由矽膠層析，依序用乙酸乙酯與環己烷之15:85及20:80混合物進行溶離而純化產物，從而獲得0.766 g(1.74 mmol)呈白色固體形式之產物。
1H NMR(CDCl3,δ ppm,200 MHz): 8.3(s,1H),7.55(d.d,1H),6.25(d,1H),5.75(七重峰,1H),4.7(d,1H),4.1(m,3H),3.15(m,2H),2.15(m,2H),1.45(m,2H)。
6.4.　4-(5-(三氟甲基)(吡啶-2-基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯鹽酸鹽(1:1)
將0.75 g(1.71 mmol)階段6.3中所獲得之4-(5-(三氟甲基)吡啶-2-基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯溶解於15 ml二異丙醚中。添加0.68 ml鹽酸於異丙醇中之5 N溶液。將混合物蒸發至乾燥。使殘餘物在熱條件下自丙酮與二異丙醚之混合物中再結晶，從而獲得0.616 g(1.30 mmol)呈白色晶體形式之產物。
熔點(℃)：225-235(分解)
LC/MS(方法B): Rt 9 min,m/z 440(MH+)
1R(KBr,cm-1):1740,1673,1624
1H NMR(CD3OD,δ ppm,400 MHz):8.25(s,1H),8.05(d.d,1H),7.15(d,1H),6.15(七重峰,1H),4.2(m,2H),4.0(m,1H),3.2(m,2H),2.1(m,2H),1.6(m,2H)。
實例7(第120號化合物)
4-[(4-氯苯磺醯基胺基)甲基]-哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
7.1.　4-[(4-氯苯磺醯基胺基)甲基]哌啶-1-甲酸第三丁酯
將0.844 g(4 mmol)4-氯苯磺醯氯於5 ml二氯甲烷中之溶液逐滴添加至0.857 g(4 mmol)4-(胺基甲基)哌啶-1-甲酸第三丁酯、0.99 ml(6 mmol)二異丙基乙胺及0.024 g(0.2 mmol)4-二甲胺基吡啶於9 ml二氯甲烷中之溶液中。在環境溫度下攪拌混合物隔夜。依序用10 ml水、4 ml 1N鹽酸水溶液、14 ml水(2次)、14 ml 1N氫氧化鈉水溶液(2次)、14 ml水(3次)及14 ml飽和氯化鈉水溶液洗滌有機相。使有機相經硫酸鈉乾燥並蒸發至乾燥，從而獲得1.371 g(3.52 mmol)呈橙色糊狀物形式之產物，該產物依原樣用於下一階段。
7.2.　4-氯-N-(哌啶-4-基甲基)苯磺醯胺
將1.364 g(3.51 mmol)階段7.1.中所獲得之4-[(4-氯苯磺醯基胺基)甲基]哌啶-1-甲酸第三丁酯溶解於11 ml二氯甲烷中。添加2.7 ml(35 mmol)三氟乙酸。攪拌混合物4小時，接著蒸發至乾燥。將殘餘物溶解於11 ml 1 N鹽酸水溶液中。用11 ml***洗滌水相三次，接著添加1.6 ml 33%氫氧化鈉水溶液。用11 ml二氯甲烷萃取三次接著用15 ml氯仿萃取三次。使有機相經硫酸鈉乾燥並蒸發至乾燥，從而獲得0.847 g(2.93 mmol)呈白色固體形式之產物。
7.3.　4-[(4-氯苯磺醯基胺基)甲基]-哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
將0.59 g(2.93 mmol)氯甲酸4-硝基苯酯於6 ml二氯甲烷中之溶液逐滴添加至已冷卻至0℃且處於氬氣氛圍下的0.984 g(5.86 mmol)1,1,1,3,3,3-六氟-2-丙醇、0.48 ml(5.86 mmol)吡啶及0.015 g(0.17 mmol)4-二甲胺基吡啶於6 ml二氯甲烷中之溶液中。使混合物處於環境溫度下隔夜，接著添加0.846 g(2.93 mmol)階段7.2.中所獲得之4-氯-N-(哌啶-4-基甲基)苯磺醯胺及1.21 ml(7.33 mmol)二異丙基乙胺於9 ml二氯甲烷中之混合物。在環境溫度下攪拌混合物5小時，接著蒸發至乾燥。使殘餘物溶解於16 ml乙酸乙酯與56 ml***之混合物中。用50 ml水洗滌有機相4次，接著用70 ml 1M碳酸鈉水溶液、70 ml水及70 ml飽和氯化鈉水溶液洗滌有機相。使有機相經硫酸鈉乾燥並蒸發至乾燥。藉由矽膠層析，用乙酸乙酯與環己烷之25:75混合物進行溶離來純化殘餘物。自正己烷中結晶，從而獲得0.849g(1.75 mmol)呈白色固體形式之產物。
熔點(℃)：136-138
LC/MS(方法C): Rt 6.4 min,m/z 483(MH+)
IR(KBr,cm-1): 3272,1726
1H NMR(CDCl3,δ ppm,400 MHz): 7.85(d,2H),7.55(d,2H),5.75(七重峰,1H),4.50(m,1H),4.20(m,2H),2.90(m,4H),1.75(m,3H),1.15(m,2H)。
實例8(第166號化合物)
4-[3-(3-氯苯基)脲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
8.1.　4-(第三丁氧基羰基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
將3.02 g(15 mmol)氯甲酸4-硝基苯酯之溶液逐滴添加至已冷卻至0℃且處於氬氣氛圍下的3.15 ml(30 mmol)1,1,1,3,3,3-六氟-2-丙醇、2.42 ml(30 mmol)吡啶及0.091 g(0.75 mmol)4-二甲胺基吡啶於10 ml二氯甲烷中之溶液中。使混合物在環境溫度下反應隔夜。將其冷卻至0℃，並逐份添加3.00 g(15 mmol)(哌啶-4-基)胺甲酸第三丁酯，接著逐滴添加6.55 ml(37.5 mmol)二異丙基乙胺。在環境溫度下攪拌混合物5小時並蒸發。使殘餘物溶解於20 ml乙酸乙酯、30 ml水及60 ml***之混合物中。藉由沈降分離有機相。依序用30 ml水及30 ml 1 M碳酸鈉水溶液(4次)、30 ml水(2次)及30 ml飽和氯化鈉水溶液洗滌。使有機相經硫酸鈉乾燥並蒸發至乾燥，從而獲得5.18 g(13.1 mmol)呈灰白色固體形式之產物。
熔點(℃)：104-106
IR(KBr,cm-1): 1731,1678
1H NMR(CDCl3,δ ppm,200 MHz): 5.65(七重峰,1H),4.3(m,1H),4.0(m,2H),3.6(m,1H),2.95(m,2H),1.95(m,2H),1.4-1.2(m+s,11H)。
8.2.　4-胺基哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯鹽酸鹽
將5.10 g(12.93 mmol)階段8.1.中所獲得之4-(第三丁氧基羰基胺基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯溶解於18 ml二氯甲烷中，且隨攪拌添加5.2 ml鹽酸於異丙醇中之5N溶液。3小時後，再添加2.6 ml鹽酸溶液。在環境溫度下持續攪拌隔夜。將混合物蒸發至乾燥。添加50 ml二異丙醚。攪拌持續3小時。濾出固體，接著在五氧化二磷存在下在真空下乾燥，從而獲得4.27 g(12.9 mmol)呈灰白色粉末形式之產物。
熔點(℃)：204-206
IR(KBr,cm-1): 1731
1H NMR(DMSO,δ ppm,200 MHz): 8.2(m,3H),6.6(七重峰,1H),4.0(m,2H),3.4-2.9(m,3H),2.0(m,2H),1.45(m,2H)。
8.3.　4-[3-(3-氯苯基)脲基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
依序向0.545 g(1.65 mmol)階段8.2.中所獲得之4-胺基哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯鹽酸鹽於3 ml二氯甲烷中之懸浮液中添加0.30 ml(1.72 mmol)二異丙基乙胺及0.230 g(1.5 mmol)異氰酸3-氯苯酯於3 ml二氯甲烷中之溶液。在環境溫度下攪拌混合物隔夜。將混合物蒸發至乾燥。使殘餘物溶解於40 ml乙酸乙酯與10 ml水之混合物中。藉由沈降分離有機相。依序用10 ml水及10 ml 1 N鹽酸水溶液、10 ml水及10 ml飽和氯化鈉水溶液洗滌。使有機相經硫酸鈉乾燥並蒸發至乾燥。藉由矽膠層析，依序用乙酸乙酯與環己烷之30:70及40:60混合物進行溶離來純化產物。隨後在熱條件下自乙酸乙酯與正己烷之混合物中再結晶，從而獲得0.51 g(1.14 mmol)呈白色結晶粉末形式之產物。
熔點(℃)：204-206
LC/MS(方法D): Rt 1.27 min,m/z 448(MH+)
IR(KBr,cm-1): 1725,1683
1H NMR(DMSO,δ ppm,400 MHz): 8.55(s,1H),7.65(s,1H),7.25(m,2H),6.95(d.d,1H),6.55(七重峰,1H),6.35(d,1H),3.9(m,2H),3.75(m,1H),3.2(m,2H),1.9(m,2H),1.35(m,2H)。
實例9(第87號化合物)
4-{[2-(4-氯苯氧基)-2-甲基丙醯基胺基]-甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
9.1.　4-(胺基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯鹽酸鹽
如先前實例2、6.3.及7.3.中所述，使0.41 ml(3.91 mmol)1,1,1,3,3,3-六氟-2-丙醇、0.32 ml(3.91 mmol)吡啶、0.023 g(0.19 mmol)4-二甲胺基吡啶及0.75 g(3.72 mmol)氯甲酸4-硝基苯酯的混合物於13 ml二氯甲烷中之溶液在環境溫度下反應隔夜。添加0.84 g(3.90 mmol)(哌啶-4-基)甲基胺甲酸第三丁酯及2.1 ml(11.7 mmol)二異丙基乙胺。在環境溫度下攪拌混合物4小時。用25 ml 1 N氫氧化鈉水溶液洗滌有機相5次，接著用25 ml 1 N鹽酸水溶液洗滌2次。使有機相經硫酸鎂乾燥，從而獲得1.6 g呈油形式之產物。
將產物溶解於9.7 ml(39 mmol)鹽酸於二噁烷中之4 N溶液中。在環境溫度下攪拌混合物隔夜，接著蒸發至乾燥。將殘餘物溶解於***中並濾出產物，並且在真空下乾燥，從而獲得0.91 g(2.64 mmol)呈灰白色粉末狀形式之產物。
熔點(℃)：177-178
IR(KBr,cm-1): 1716
1H NMR(DMSO,δ ppm,200 MHz): 7.95(m,3H),6.55(七重峰,1H),4.0(m,2H),3.0(m,2H),2.75(m,2H),1.85(m,3H),1.15(m,2H)。
9.2.　4-{[2-(4-氯苯氧基)-2-甲基-丙醯基胺基]甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
將0.10 g(0.29 mmol)階段9.1.中所獲得之4-(胺基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯鹽酸鹽及0.071 g(0.29 mmol)2-(4-氯苯氧基)-2-甲基丙醯氯溶解於1.5 ml二氯甲烷中。添加0.13 ml(0.73 mmol)二異丙基乙胺。在環境溫度下攪拌混合物隔夜。添加1.5 ml二氯甲烷。用2 ml 1 N鹽酸水溶液洗滌有機相，接著過濾通過疏水性濾筒並蒸發至乾燥。藉由矽膠層析，在15分鐘內用10:90至40:60之乙酸乙酯與環己烷梯度進行溶離而純化產物，從而獲得0.089 g(0.176 mmol)呈白色粉末形式之產物。
熔點(℃)：77-78
LC/MS(方法D): Rt 1.44 min,m/z 505(MH+)
IR(KBr,cm-1): 1749,1655
1H NMR(DMSO,δ ppm,400 MHz): 8.2(t,1H),7.35(d,2H),6.9(d,2H),6.55(七重峰,1H),3.9(m,2H),3.0-2.85(m,4H),1.7(m,1H),1.55(d,2H),1.45(s,6H),1.0(m,2H)。
實例10(第191號化合物)
3-[2-(3-甲基-3-苯基脲基)乙基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
10.1.　3-(2-胺基乙基)氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯鹽酸鹽
如先前實例9.1.中所述，使1.65 ml(15.63 mmol)1,1,1,3,3,3-六氟-2-丙醇、1.27 ml(15.63 mmol)吡啶、0.090 g(0.74 mmol)4-二甲胺基吡啶及3.0 g(14.88 mmol)氯甲酸4-硝基苯酯的混合物於50 ml二氯甲烷中之溶液在環境溫度下反應隔夜。
抽取一半溶液。添加1.853 g(7.83 mmol)(2-(氮雜環丁-3-基)乙基)胺甲酸第三丁酯、4.19 ml(23.49 mmol)二異丙基乙胺及20 ml二氯甲烷。在環境溫度下攪拌混合物隔夜。隨後，依序用50 ml 1 N氫氧化鈉水溶液(3次)及50 ml 1 N鹽酸水溶液洗滌有機相。使有機相經硫酸鎂乾燥並蒸發至乾燥，從而獲得3.00 g產物。
將產物溶解於19 ml(76 mmol)鹽酸於二噁烷中之4 N溶液中。再添加20 ml二噁烷。在環境溫度下攪拌該混合物5小時。將其蒸發至乾燥，從而獲得2.50 g(7.56 mmol)呈油形式之產物，該產物固化。
熔點(℃)：116-117
IR(KBr,cm-1): 1731
1H NMR(DMSO,δ ppm,200 MHz): 8.0(m,3H),6.5(七重峰,1H),4.15(m,2H),3.75(m,2H),2.75(m,3H),1.9(m,2H)。
10.2.　3-[2-(3-甲基-3-苯基脲基)乙基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
將0.112 g(0.34 mmol)階段10.1.中所獲得之3-(2-胺基乙基)氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯鹽酸鹽溶解於2 ml二氯甲烷中。添加0.054 g(0.32 mmol)N-甲基-N苯基胺甲醯氯及0.15 ml(0.85 mmol)二異丙基乙胺。在環境溫度下攪拌混合物隔夜。用2 ml 1 N氫氧化鈉水溶液洗滌有機相三次，接著用2 ml 1 N鹽酸水溶液洗滌。藉由過濾通過疏水性濾筒來乾燥有機相，並蒸發至乾燥。藉由矽膠層析，在15分鐘內用15:85至45:55之乙酸乙酯與環己烷梯度進行溶離而純化產物，從而獲得0.06 g(0.14 mmol)呈白色粉末形式之產物。
熔點(℃)：101-102
LC/MS(方法D): Rt 1.2 min,m/z 428(MH+)
IR(KBr,cm-1): 3353,1738,1643
1H NMR(DMSO,δ ppm,400 MHz): 7.4(m,2H),7.25(m,3H),6.45(七重峰,1H),6.0(t,1H),4.1(m,2H),3.75(m,2H),3.15(s,3H),3.0(m,2H),2.65(m,1H),1.7(m,2H)。
實 例11(第113號化合物)
3-[(萘-1-磺醯基胺基)甲基]-吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
11.1.　3-(胺基甲基)吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯鹽酸鹽
該程序與實例10.1.中所述之程序相同，使用1.56 g(7.83 mmol)(吡咯啶-3-基甲基)胺甲酸第三丁酯(替代(2-(氮雜環丁-3-基)乙基)胺甲酸第三丁酯)，從而獲得1.51 g(4.56 mmol)呈油形式之產物，該產物依原樣用於下一階段。藉由自乙酸乙酯中濕磨獲得固體樣品。
熔點(℃)：190℃(分解)
IR(KBr,cm-1): 1732
1H NMR(DMSO,δ ppm,200 MHz): 7.90(m,3H),6.55(七重峰,1H),3.65(m,1H),3.55(m,1H),3.40(m,1H),3.15(m,1H),2.95(m,2H),2.50(m,1H),2.10(m,1H),1.75(m,1H)。
11.2.　3-[(萘-1-磺醯基胺基)甲基]-吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
該程序與實例10.2.中所述之程序相同，使用0.10 g(0.30 mmol)階段11.2中所獲得之3-(胺基甲基)吡咯啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯鹽酸鹽、0.066 g(0.29 mmol)萘-1-磺醯氯及0.13 ml(0.76 mmol)二異丙基乙胺，以便在藉由矽膠層析加以純化後獲得0.096 g(0.20 mmol)呈白色粉末形式之產物。
熔點(℃)：135-136
LC/MS(方法C): Rt 4.88 min,m/z 485(MH+)
IR(KBr,cm-1): 1732
1H NMR(DMSO,δ ppm,400 MHz): 8.65(d,1H),8.25(d,1H),8.15(m,3H),7.75-7.60(m,3H),6.45(七重峰,1H),3.45-3.20(m,3H),3.05(m,1H),2.85(m,2H),2.30(m,1H),1.85(m,1H),1.55(m,1H)。
實例12(第220號化合物)
3-[1-(4-氯苯磺醯基胺基)環丙基]-氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
12.1.　3-(1-胺基環丙基)氮雜環丁烷-1-甲酸第三丁酯
在氮氣氛圍下，向4.8 g(26.34 mmol)4-氰基氮雜環丁烷-1-甲酸第三丁酯於150 ml***中之溶液中添加10.5 ml(35 mmol)四異丙醇鈦(Ti(OiPr)4)，接著逐滴添加21 ml(63 mmol)乙基溴化鎂於***中之3 M溶液。攪拌混合物40分鐘，接著逐滴添加9 ml(71 mmol)醚合三氟化硼複合物(BF3.Et2O)。攪拌反應混合物5小時。添加100 ml 2 M氫氧化鈉水溶液及150 ml二氯甲烷。使混合物過濾通過矽藻土。藉由沈降分離有機相。使有機相經硫酸鈉乾燥並蒸發至乾燥。藉由矽膠層析，用二氯甲烷與甲醇之90:10混合物進行溶離而純化產物，從而獲得1.91 g(9.0 mmol)呈無色油形式之產物，該產物緩慢固化。
1H NMR(CDCl3,δ ppm,200 MHz): 3.65(t,2H),3.35(m,2H),2.30-2.20(m,1H),1.45(s,2H),1.15(s,9H),0.35(m,2H),0.20(m,2H)。
12.2.　3-[1-(4-氯苯磺醯基胺基)環丙基]氮雜環丁烷-1-甲酸第三丁酯
將0.35 g(1.65 mmol)階段12.1.中所獲得之3-(1-胺基環丙基)氮雜環丁烷-1-甲酸第三丁酯、0.6 ml(3.44 mmol)二異丙基乙胺及0.34 g(1.61 mmol)4-氯苯磺醯氯溶解於4 ml二氯甲烷中。在環境溫度下攪拌該混合物20小時。添加20 ml二氯甲烷，且用10 ml 1 N鹽酸水溶液進行洗滌，接著用10 ml 1 N氫氧化鈉水溶液及10 ml飽和氯化鈉水溶液進行洗滌。使有機相過濾通過疏水性濾筒並蒸發至乾燥。藉由矽膠層析，用二氯甲烷與甲醇之95:5混合物進行溶離而純化殘餘物，從而獲得0.30 g(0.77 mmol)呈白色固體形式之產物。
1H NMR(CDCl3,δ ppm,200 MHz): 7.85(m,2H),7.55(m,2H),5.55(s,1H),3.90(t,2H),3.50(m,2H),3.15-3.00(m,1H),1.50(s,9H),0.80(s,4H)。
12.3.N-(1-(氮雜環丁-3-基)環丙基)-4-氯苯磺醯胺鹽酸鹽
將0.30 g(0.78 mmol)階段12.2.中所獲得之3-[1-(4-氯苯磺醯基胺基)環丙基]-氮雜環丁烷-1-甲酸第三丁酯溶解於10 ml甲醇中。添加0.2 ml(1.58 mmol)三甲基氯矽烷。在環境溫度下攪拌混合物隔夜。再添加0.2 ml三甲基氯矽烷並持續攪拌4小時。在真空下濃縮混合物，接著將殘餘物溶解於乙酸乙酯中並蒸發至乾燥，從而獲得0.28 g呈白色固體形式之產物，該產物依原樣使用。
12.4.　3-[1-(4-氯苯磺醯基胺基)環丙基]氮雜環丁烷-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
將2.0 g(9.9 mmol)氯甲酸4-硝基苯酯於10 ml二氯甲烷中之溶液逐滴添加至2.50 g(14.9 mmol)1,1,1,3,3,3-六氟-2-丙醇及1.90 ml(23.5 mmol)吡啶於40 ml二氯甲烷中之溶液中。使混合物在環境溫度下反應隔夜。
抽取5 ml此溶液，且添加0.28 g(0.87 mmol)階段12.3.中所獲得之N-(1-氮雜環丁-3-基-環丙基)-4-氯苯磺醯胺鹽酸鹽及1.3 ml(7.46 mmol)二異丙基乙胺。攪拌混合物8小時。用10 ml 0.5 N鹽酸水溶液洗滌兩次，接著用10 ml飽和碳酸鈉水溶液洗滌三次。使有機相過濾通過疏水性濾筒並蒸發至乾燥。藉由矽膠層析，用二氯甲烷與甲醇之95:5混合物進行溶離而純化殘餘物，從而獲得0.32 g(0.66 mmol)呈白色粉末形式之產物。
熔點(℃)：108-109
LC/MS(方法C): Rt 4.97 min,m/z 481(MH+)
IR(KBr,cm-1): 1761,1736
1H NMR(DMSO,δ ppm,400 MHz): 8.55(s,1H),7.80(d,2H),7.70(d,2H),6.45(七重峰,1H),3.90(m,2H),3.70(m,2H),2.85(m,1H),0.65(m,2H),0.60(m,2H)。
實例13(第231號化合物)
4-(4-胺甲醯基吡唑-1-基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
13.1.　4-(4-胺甲醯基吡唑-1-基甲基)哌啶-1-甲酸第三丁酯
在氬氣氛圍下將2.15 g(10 mmol)4-(羥基甲基)哌啶-1-甲酸第三丁酯、2.11 ml(15 mmol)三乙胺及0.06 g(0.5 mmol)4-二甲胺基吡啶溶解於15 ml二氯甲烷中。用冰浴冷卻溶液，且逐滴添加1.60 g(14 mmol)甲磺醯氯於5 ml二氯甲烷中之溶液。在冰浴之溫度下攪拌混合物1小時，接著在環境溫度下攪拌2小時。添加20 ml水及20 ml二氯甲烷。藉由沈降分離有機相，且用20 ml 0.5 N鹽酸水溶液洗滌，接著用20 ml水及20 ml飽和氯化鈉水溶液洗滌兩次。使有機相經硫酸鈉乾燥，並蒸發至乾燥，從而獲得2.96 g(10 mmol)呈橙色油形式之甲磺酸酯。
將1.76 g(6 mmol)此產物再溶解於6 ml N,N-二甲基甲醯胺中。隨攪拌添加0.76 g(6.9 mmol)1H-吡唑-4-甲醯胺及1.24 g(9 mmol)碳酸鉀，且在70℃下加熱混合物隔夜。添加30 ml乙酸乙酯，且濾出固體並依序用6 ml N,N-二甲基甲醯胺與乙酸乙酯之1:5混合物及6 ml乙酸乙酯洗滌。將濾液蒸發至乾燥。將殘餘物溶解於50 ml氯仿與甲醇之95:5混合物中。濾出不溶性物質，且用氯仿與甲醇之95:5混合物洗滌兩次。將濾液蒸發至乾燥，並使殘餘物在熱條件下自乙酸乙酯中再結晶，從而獲得0.98 g(3.17 mmol)呈白色粉末形式之產物。
熔點(℃)：190-192
1H NMR(CDCl3,δ ppm,200 MHz): 7.80(s,1H),7.70(s,1H),5.55(m,2H),4.05(寬雙重峰,2H),3.95(d,2H),2.60(t,2H),2.00(m,1H),1.45(寬雙重峰,2H),1.80(s,9H),1.20-1.00(m,2H)。
13.2.　1-(哌啶-4-基甲基)-1H-吡唑-4-甲醯胺鹽酸鹽
將0.96 g(3.11 mmol)階段13.1.中所獲得之4-(4-胺甲醯基吡唑-1-基甲基)哌啶-1-甲酸第三丁酯於25 ml鹽酸(124 mmol)於異丙醇中之5 N溶液中的懸浮液攪拌隔夜。將其蒸發至乾燥，接著與25 ml乙酸乙酯一起共同蒸發兩次。使產物再懸浮於25 ml乙酸乙酯中。過濾，用10 ml乙酸乙酯洗滌兩次，並在真空下乾燥，從而獲得0.91 g(3.23 mmol)呈白色粉末形式之產物。
1H NMR(DMSO+D2O,δ ppm,200 MHz): 8.15(s,1H),7.85(s,1H),4.05(d,2H),3.25(寬雙重峰,2H),2,80(寬三重峰,2H),2.10(m,1H),1.60(寬雙重峰,2H),1.45-1.25(m,2H)。
13.3.　4-(4-胺甲醯基吡唑-1-基甲基)哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
將0.605 g(3 mmol)氯甲酸4-硝基苯酯於5 ml二氯甲烷中之溶液逐滴添加至1.00 g(6 mmol)1,1,1,3,3,3-六氟-2-丙醇、0.49 ml(6 mmol)吡啶及0.036 g(0.3 mmol)4-二甲胺基吡啶於5 ml二氯甲烷中之溶液中。使混合物在環境溫度下反應隔夜。
在氬氣氛圍下將此溶液逐滴添加至0.84 g(3 mmol)階段13.2.中所獲得之1-(哌啶-4-基甲基)-1H-吡唑-4-甲醯胺鹽酸鹽及2.2 ml(13 mmol)二異丙基乙胺於15 ml N,N-二甲基甲醯胺與7 ml二甲亞碸之混合物中的經冰浴冷卻之溶液中。隨後在環境溫度下攪拌反應混合物2小時並在真空下蒸發。將殘餘物溶解於50 ml乙酸乙酯中並向其中添加2.8 g(20 mmol)碳酸鉀。用力攪拌混合物2小時。濾出固體，並用25 ml乙酸乙酯洗滌兩次。隨後用10 ml半飽和氯化鈉水溶液洗滌濾液兩次，接著用10 ml飽和氯化鈉水溶液洗滌兩次。使濾液經硫酸鈉乾燥並蒸發至乾燥。藉由矽膠層析，依序用二氯甲烷與甲醇之97:3混合物、95:5混合物及92:8混合物進行溶離而純化產物，從而獲得1.0 g呈白色固體形式之產物，該產物被約3莫耳% 4-(4-胺甲醯基吡唑-1-基甲基)哌啶-1-甲酸4-硝基-苯酯污染。
將0.80 g此產物再溶解於15 ml乙酸乙酯中。向其中添加0.2 g 10%鈀/木炭，且在2巴氫氣氛圍下攪拌混合物3小時。隨後過濾通過矽藻土。用10 ml乙酸乙酯沖洗四次，並將濾液蒸發至乾燥。藉由矽膠層析，依序用二氯甲烷與甲醇之97:3混合物、95:5混合物及92:8混合物進行溶離而純化產物，從而獲得0.75 g呈白色固體形式之產物。在熱條件下自乙酸乙酯與二異丙醚之混合物中再結晶，從而獲得0.68 g(1.69 mmol)呈白色粉末形式之產物。
熔點(℃)：98-118
LC/MS(方法D): Rt 0.97 min,m/z 403(MH+)
IR(KBr,cm-1): 1722,1656
1H NMR(CDCl3,δ ppm,400 MHz): 7.90(s,1H),7.80(s,1H),5.75(七重峰1H),5.55(m,2H),4.20(寬三重峰,2H),4.05(d,2H),2.90(m,2H),2.20(m,1H),1.65(m,2H),1.25(m,2H)。
實例14(第234號化合物)
4-[2-(5-胺甲醯基吡嗪-2-基胺基)乙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
14.1.　4-[2-(5-胺甲醯基吡嗪-2-基胺基)乙基]哌啶-1-甲酸第三丁酯
在100℃下在氬氣氛圍下且隨攪拌加熱1.12 g(7.15 mmol)5-氯吡嗪-2-甲醯胺、1.95 g(8.58 mmol)4-(2-胺基乙基)哌啶-1-甲酸第三丁酯及1.18 g(8.58 mmol)碳酸鉀於1.4 ml二甲亞碸中之混合物。冷卻至環境溫度後，添加25 ml乙酸乙酯及25 ml水。藉由沈降分離有機相，且用25 ml水洗滌三次，接著用25 ml飽和氯化鈉水溶液洗滌。使有機相經硫酸鈉乾燥並蒸發至乾燥。藉由矽膠層析，依序用二氯甲烷與甲醇之97:3混合物、95:5混合物及93:7混合物進行溶離而純化殘餘物，從而獲得1.99 g(5.69 mmol)呈淡黃色糊狀物形式之產物。
1H NMR(CDCl3,δ ppm,200 MHz): 8.65(s,1H),8.10(s,1H),7.55(m,1H),5.75(m,1H),4.85(m,1H),4.15(m,2H),3.45(m,2H),2.75(t,2H),1.80-1.60(m,5H),1.50(s,9H),1.35-1.10(m,2H)。
14.2.　5-(2-(哌啶-4-基)乙胺基)吡嗪-2-甲醯胺二鹽酸鹽
將1.98 g(5.68 mmol)階段14.1.中所獲得之4-[2-(5-胺甲醯基吡嗪-2-基胺基)乙基]哌啶-1-甲酸第三丁酯溶解於20 ml二氯甲烷中。添加13 ml鹽酸於異丙醇中之5 N溶液，並攪拌混合物隔夜。將其蒸發至乾燥，接著與50 ml乙酸乙酯一起共同蒸發兩次。將殘餘物溶解於17 ml乙酸乙酯中並攪拌1小時。濾出固體，用5 ml乙酸乙酯洗滌兩次，且在真空下乾燥，從而獲得1.78 g(5.54 mmol)呈黃色固體形式之產物。
1H NMR(DMSO+D2O,δ ppm,200 MHz): 8.20(s,1H),8.10(s,1H),3.40(t,2H),3.25(寬雙重峰,2H),2.80(t,2H),1.90(寬雙重峰,2H),1.70-1.15(m,5H)。
14.3.　4-[2-(5-胺甲醯基吡嗪-2-基胺基)乙基]哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯
將1.01 g(5 mmol)氯甲酸4-硝基苯酯於8.5 ml二氯甲烷中之溶液逐滴添加至1.69 g(10 mmol)1,1,1,3,3,3-六氟-2-丙醇、0.82 ml(10 mmol)吡啶及0.030 g(0.25 mmol)4-二甲胺基吡啶於8.5 ml二氯甲烷中之在氬氣下經冰浴冷卻之溶液中。使混合物在環境溫度下反應隔夜。
在氬氣氛圍下且隨攪拌將此溶液逐滴添加至1.62 g(5.04 mmol)階段14.2.中所獲得之5-(2-(哌啶-4-基)乙胺基)吡嗪-2-甲醯胺二鹽酸鹽及3.75 ml(22 mmol)二異丙基乙胺於11 ml二甲亞碸中之經冷水浴冷卻之混合物中。隨後在環境溫度下攪拌反應混合物4小時並在真空下蒸發。將殘餘物溶解於110 ml乙酸乙酯中並向其中添加4.7 g(34 mmol)碳酸鉀。用力攪拌混合物4小時。濾出固體，並用30 ml乙酸乙酯洗滌兩次。隨後用16 ml半飽和氯化鈉水溶液洗滌濾液三次，接著用16 ml飽和氯化鈉水溶液洗滌三次。使濾液經硫酸鈉乾燥並蒸發至乾燥。藉由矽膠層析，用乙酸乙酯與環己烷之90:10混合物，接著用乙酸乙酯進行溶離而純化產物，從而獲得1.6 g產物。將其再溶解於90 ml乙酸乙酯中，且用7.5 ml 1 M碳酸鉀水溶液洗滌三次，接著用7.5 ml水洗滌兩次。使有機相經硫酸鈉乾燥並蒸發，從而獲得1.57 g產物。在熱條件下自乙酸乙酯與二異丙醚之混合物中再結晶，從而獲得1.31 g(2.95 mmol)呈淡黃色粉末形式之產物。
熔點(℃)：156-158
LC/MS(方法D): Rt 1.16 min,m/z 444(MH+)
IR(KBr,cm-1): 1725,1675
1H NMR(DMSO,δ ppm,400 MHz): 8.65(s,1H),8.10(s,1H),7.45(寬單峰,1H),5.75(七重峰,1H),5.55(寬單峰,1H),4,70(寬單峰,1H),4.15(寬三重峰,2H),3.50(寬單峰,2H),2.90(m,2H),1.80-1.20(m,7H)。
下表1中說明一些本發明化合物實例之化學結構及物理性質。在此表中：-　M.p.(℃)表示化合物之熔點(攝氏度)；-　(m/z)表示在質譜(LC/MS)中觀察到的分子態離子；-　(MH+)表示經質子化之分子態離子；-　((M-H)-)表示失去質子之分子態離子；-　(M+)表示失去電子之分子態離子；-　(MH+ACN)表示呈與乙腈之加合物形式的分子態離子；-　(MNH4+)表示呈與氨之加合物形式的分子態離子；-　(MACO2-)表示呈與乙酸根離子之加合物形式的分子態離子；-　在「Z」及「A」行中，「-」意謂不存在Z及/或A；-　在「鹽」行中，「-」表示呈游離鹼形式之化合物且「HCl」表示呈鹽酸鹽形式之化合物；-　「NC」表示氰基；-　「-(c-prop)」表示伸環丙基；-　「-NHC-(c-prop)-」表示基團：。
根據上述方法製備表1中所述之化合物。
表2中說明藉由LC/MS分析根據上述方法A、B、C、D或E之一所測得之數種表1化合物之滯留時間(Rt)。
表3中提供關於表1中之對映異構化合物22、23、24及25所獲得之旋光度([α]D)及量測[α]D之條件。
本發明化合物令人驚訝地展現對酶MGL(單醯基甘油脂肪酶)之抑制作用。酶MGL催化各種脂肪酸之單酸甘油酯之內源性衍生物之水解(FEBS Letters,1998,429,152-156)，且尤其催化2-二十碳四烯醯基甘油(2-arachidonoylglycerol；2-AG)及1(3)-二十碳四烯醯基甘油(1(3)-AG)之水解(J. Biol. Chem.,1987,272(48),27218-27223；Proc. Natl. Acad. Sci. USA,2002,99(16),10819-10824；Biochem. Pharmacol.,2004,67,1381-1387；Mol. Pharmacol.,2004,66(5),1260-1264)。2-AG及1(3)-AG衍生物尤其與類***酚受體相互作用(J. Biol. Chem.,1999,274(5),2794-2801；J. Biol. Chem.,2000,275(1),605-612；British J. Pharmacol.,2001,134,664-672)。
本發明化合物阻斷此分解路徑並增加此等衍生物(尤其2-AG及/或1(3)-AG)之組織含量。因此其可用於預防及治療牽涉(尤其)2-AG及/或1(3)-AG及/或由酶MGL代謝之任何其他受質的病變(Progress in Lipid Research,2006,45,405-446；Nature Reviews Drug Discovery,2008,7,438-455)。
本發明化合物已形成藥理學測試之標的，從而可測定其對酶MGL之抑制作用。
測試包括量測本發明化合物對酶MGL之活體外活性。
對MGL之抑制活性係以抑制50% MGL活性之濃度的形式提供。
在基於量測酶MGL水解2-油醯基甘油([3H]2-OG)之產物之放射酶學檢定中量測抑制活性。在甘油上經標記之[3H]2-OG之水解產物為油酸及[3H]甘油。酶MGL之來源為已移除小腦及延腦之小鼠腦部之組織勻漿。移出小鼠腦部且在-80℃下儲存直至使用，或立即使用Precellys裝置(Bertin)在5000 rpm下在10 mM Tris-HCl pH 8、150 mM NaCl、1 mM EDTA緩衝液中在4℃下均質化(兩次)5秒。隨後將組織勻漿之濃度調節至3.75 μg/μl。
由儲備溶液(20 mM，於100% DMSO中)製備化合物之稀釋系列。於100% DMSO中製備此系列之第一次稀釋液，接著在酶促反應緩衝液(50 mM磷酸酯，0.1% BSA)中製備第二次稀釋液，從而產生10倍濃縮濃度範圍的製劑。測試化合物在所選濃度下與小鼠腦部組織勻漿製劑一起預培育20分鐘。酶促反應中DMSO之最終濃度不超過0.1%。
在環境溫度下於96孔微量培養板中進行MGL活性檢定，最終反應體積為50 μl。簡而言之，將37.5 μg蛋白質稀釋於包含0.1% BSA之50 mM磷酸鹽緩衝液中。與測試化合物一起預培育20分鐘後，在50 μM 2-OG(每孔包含0.027 μCi之量之[3H]2-OG)存在下(比活性為20 Ci/mmol)培育蛋白質20分鐘。藉由每孔添加50 μl木炭懸浮液(6% Sigma活性木炭，參考C4386，呈於0.5 M HCl、1.5 M NaCl溶液中之懸浮液形式)停止反應。攪拌10分鐘後，藉由過濾將木炭不保留之[3H]甘油收集於每孔包含100 μl閃爍體(OptiPhase Supermix，Perkin-Elmer)之微量培養板中。藉由液體閃爍(Wallac 1450 MicroBeta)對各孔中所存在之放射性計數5分鐘。
在此等條件下，最具活性之本發明化合物展現0.0001至0.1 μM之IC50(抑制MGL之對照酶活性達50%的濃度)。
例如，第13號、第33號、第70號、第120號、第161號、第188號及第211號化合物分別顯示0.006 μM、0.0006 μM、0.005 μM、0.004 μM、0.0014 μM、0.0011 μM及0.007 μM之IC50。
因此，顯然本發明化合物對MGL具有抑制活性。
本發明化合物因此可用於製備藥物，詳言之作為酶MGL之抑制劑的藥物。
因此，根據本發明之另一態樣，本發明之一個標的物為包含式(I)化合物或其與醫藥學上可接受之酸形成之加成鹽或者式(I)化合物之水合物或溶劑合物的藥物。
詳言之，此等藥物在治療上用於治療及預防以下疾病：疼痛，尤其急性或慢性神經性類型疼痛：偏頭痛、神經痛，包括與疱疹病毒及糖尿病相關之形式；與發炎性疾病相關之急性或慢性疼痛：關節炎、類風濕性關節炎、骨關節炎、脊椎炎、痛風、血管炎、克羅恩氏病(Crohn's disease)、大腸急躁症；急性或慢性周邊性疼痛(peripheral pain)；頭腦昏沈、嘔吐、噁心，尤其由化學療法所致者；進食障礙，尤其厭食症及各種性質之惡病質；代謝症候群及其表現，包括肥胖症；異常血脂症及其表現，包括動脈粥樣硬化及冠狀動脈病；神經及精神病變：顫抖、運動障礙、肌張力障礙、痙攣狀態、強迫性-強制性行為、妥瑞症候群(Tourette's syndrome)、任何性質及起源之所有形式抑鬱症及焦慮症、情感障礙、精神病；急性或慢性神經退化性疾病：帕金森氏病(Parkinson's disease)、阿茲海默氏病(Alzheimer's disease)、老年癡呆、亨爾頓氏舞蹈病(Huntington's chorea)、與大腦局部缺血以及頭部及髓質外傷相關之病變、肌萎縮性側索硬化症；癲癇症；睡眠障礙，包括睡眠呼吸暫停；心血管疾病，尤其高血壓、心律不整、動脈硬化、心臟病發作、心肌缺血；腎缺血；癌症：良性皮膚腫瘤、腦瘤及乳頭狀瘤、***腫瘤、大腦瘤(神經膠母細胞瘤、髓上皮瘤(medulloepithelioma)、神經管母細胞瘤、神經母細胞瘤、胚胎來源之腫瘤、星形細胞瘤、星形母細胞瘤、室管膜瘤、少枝膠質瘤、叢腫瘤、神經上皮瘤、腦上體腫瘤(epiphyseal tumour)、室管膜母細胞瘤、惡性腦膜瘤、肉瘤、惡性黑素瘤、神經鞘瘤)；免疫系統病症，詳言之自體免疫疾病：牛皮癬、紅斑狼瘡、結締組織疾病或膠原蛋白疾病、修格林氏症候群(Sjgren's syndrome)、僵直性脊椎炎、未分化脊椎炎、***(Behcet's disease)、自體免疫性溶血性貧血、多發性硬化症、肌萎縮性側索硬化症、澱粉樣變性病、移植排斥、影響漿細胞株之疾病；過敏性疾病：速發型或遲發型過敏、過敏性鼻炎或結膜炎、接觸性皮炎；寄生蟲、病毒或細菌感染性疾病：AIDS、腦膜炎；發炎性疾病，詳言之關節病：關節炎、類風濕性關節炎、骨關節炎、脊椎炎、痛風、血管炎、克羅恩氏病、大腸急躁症；骨質疏鬆症；眼病：眼高壓、青光眼、視網膜神經節細胞及視網膜神經細胞之退化症及細胞凋亡；肺病：呼吸道疾病、支氣管痙攣、咳嗽、哮喘、慢性支氣管炎、慢性呼吸道阻塞、肺氣腫；胃腸疾病：大腸急躁症、發炎性腸道病症、潰瘍、腹瀉；尿失禁及膀胱炎。
根據本發明之另一態樣，本發明係關於包含本發明化合物作為活性成分之醫藥組合物。此等醫藥組合物包含有效劑量之至少一種本發明化合物，或該化合物之醫藥學上可接受之鹽或水合物或溶劑合物，以及至少一種醫藥學上可接受之賦形劑。
該等賦形劑係視所要醫藥形式及投藥方法而自熟習此項技術者已知的常用賦形劑中選擇。
在用於經口、舌下、皮下、肌肉內、靜脈內、表面(topical)、局部(local)、氣管內、鼻內、經皮或經直腸投藥之本發明醫藥組合物中，以上式(I)之活性成分或其視情況可選的鹽、溶劑合物或水合物可以單位投藥形式、呈與習知醫藥賦形劑之混合物形式投與動物及人類以用於預防或治療以上病症或疾病。
適當單位投藥形式包含諸如錠劑、軟明膠膠囊或硬明膠膠囊、散劑、顆粒劑及口服溶液或懸浮液之口服形式；用於經舌下、口腔、氣管內、眼內及鼻內投藥之形式或用於吸入投藥之形式；用於經表面、經皮、皮下、肌肉內或靜脈內投藥之形式；用於經直腸投藥之形式；及植入物。對於經表面應用，本發明化合物可以乳膏、凝膠、軟膏或洗劑之形式使用。
舉例而言，呈錠劑形式之本發明化合物之單位投藥形式可包含以下組分：
本發明化合物　50.0 mg
甘露糖醇　223.75 mg
交聯羧甲基纖維素鈉　6.0 mg
玉米澱粉　15.0 mg
羥丙基甲基纖維素　2.25 mg
硬脂酸鎂　3.0 mg
根據本發明之另一態樣，本發明亦係關於一種用於治療上文所指示之病變的方法，該方法包含投與患者有效劑量之本發明化合物，或其醫藥學上可接受之鹽或其水合物或其溶劑合物之一。

Claims (16)

  1. 一種對應於式(I)之化合物， 其中：R表示視情況經一或多個R2及/或R3基團取代之R1基團；R1表示苯基、萘基、二氫茚基、苯并噁唑、苯并異噁唑、苯并咪唑、苯并***、噁二唑、吲唑、異噁唑、吡啶、吡嗪、嘧啶、噻吩基、噻唑、苯并噻吩、吲哚、二氫苯并二噁烷、苯并噻二唑、吡唑、二氫苯并噁嗪或吲哚啉基團；R2表示一或多個選自鹵素原子或甲基、三氟甲基、甲氧基、三氟甲氧基、氰基、側氧基、CH3NHCO、CH3SO2、NH2CO、NH2SO2或吡咯啶-SO2基團之基團；R3表示選自苯基或噁唑之基團；Z表示一鍵或CH2、(CH2)2、CH=CH、C≡C、OCH2或OC(CH3)2基團；A表示一鍵、氧原子、硫原子、OCH2基團、O(CH2)2基團、NH、NHCH2或NH(CH2)2基團、SO2或CO基團、CONH基團、CONHCH2或CONH(CH2)2基團、SO2NH基團、SO2NHCH2或SO2NH(CH2)2基團、SO2NHCO、SO2NHCONH或SO2NHCONHCH2基團、OCONH基團、 NHCONH基團、NHCONHCH2基團、N(CH3)CONHCH2、NHCONH(CH2)2或N(CH3)CONH(CH2)2基團或SO2N(CH3)CH2基團；m及n彼此獨立地表示等於0或1之整數，該化合物呈鹼或與酸形成之加成鹽形式。
  2. 如請求項1之式(I)化合物，其特徵在於m及n表示1，該化合物呈鹼或與酸形成之加成鹽形式。
  3. 如請求項1之式(I)化合物，其特徵在於m表示1且n表示0，該化合物呈鹼或與酸形成之加成鹽形式。
  4. 如請求項1之式(I)化合物，其特徵在於m及n表示0，該化合物呈鹼或與酸形成之加成鹽形式。
  5. 一種4-{[3-(2-甲基嘧啶-4-基)苯磺醯基胺基]甲基}哌啶-1-甲酸2,2,2-三氟-1-(三氟甲基)乙酯之化合物，其呈鹼或與酸形成之加成鹽形式。
  6. 一種用於製備如請求項1至4中任一項之式(I)化合物之方法，其特徵在於使式(II)化合物： 其中A、Z、R、m及n如請求項1之通式(I)中所定義，與式(III)化合物反應： 其中X表示離去基。
  7. 如請求項6之方法，其中X表示氯原子、4-硝基苯氧基、 咪唑基、1,2,4-***基或N-氧基丁二醯亞胺基。
  8. 一種用於製備式(I)化合物之方法， 其中A表示CON(RA)、CON(RA)-(C1-C6)伸烷基、SO2N(RA)、SO2N(RA)-(C1-C6)伸烷基、N(RB)CON(RA)、N(RB)CON(RA)-(C1-C6)伸烷基、OCON(RA)或OCON(RA)-(C1-C6)伸烷基，其特徵在於使式(IV)化合物：R-Z-W (IV)其中R及Z如請求項1之通式(I)中所定義且W表示COCl、SO2Cl、NCO、OCOCl或N(RB)COCl官能基，且RA及RB彼此獨立地表示氫原子或(C1-C6)烷基，與式(V)化合物反應： 其中m及n如請求項1之通式(I)中所定義且V表示胺HN(RA)或HN(RA)-(C1-C6)伸烷基官能基。
  9. 一種式(V)化合物， 其中m及n如請求項1之通式(I)中所定義且V表示胺HN(RA)或HN(RA)-(C1-C6)伸烷基官能基，且RA表示氫原子或(C1-C6)烷基。
  10. 一種藥物，其特徵在於其包含如請求項1至5中任一項之化合物或此化合物與醫藥學上可接受之酸形成的加成鹽。
  11. 一種醫藥組合物，其特徵在於其包含如請求項1至5中任一項之化合物或醫藥學上可接受之鹽及至少一種醫藥學上可接受之賦形劑。
  12. 一種式(I)化合物之用途， 其中：R表示視情況經一或多個R2及/或R3基團取代之R1基團；R1表示芳基或雜芳基；R2表示鹵素原子或氰基、硝基、側氧基、(C1-C6)烷基、(C1-C6)烷氧基、羥基、(C1-C6)烷硫基、(C1-C6)鹵烷基、(C1-C6)鹵烷氧基、(C1-C6)鹵烷硫基、NR4R5、NR4COR5、NR4SO2R5、COR4、CO2R4、CONR4R5、SO2R4、SO2NR4R5、苯氧基或苯甲氧基；R3表示可能經一或多個彼此相同或不同的R2基團取代之單環芳基或雜芳基； R4及R5彼此獨立地表示氫原子或(C1-C6)烷基，或與帶有其之氮原子或N-CO或N-SO2片段一起形成視情況經(C1-C6)烷基或苯甲基取代之雜環；Z表示一鍵、(C1-C6)伸烷基、(C2-C6)伸烯基、(C2-C6)伸炔基、O-(C1-C6)伸烷基或N(RA)-(C1-C6)伸烷基；A表示一鍵、氧原子、硫原子、N(RA)基團、N(RA)-(C1-C6)伸烷基、CON(RA)基團、CON(RA)-(C1-C6)伸烷基、SO2N(RA)基團、SO2N(RA)-(C1-C6)伸烷基、OCON(RA)基團、OCON(RA)-(C1-C6)伸烷基、N(RB)CON(RA)基團、N(RB)CON(RA)-(C1-C6)伸烷基、N(RB)SO2N(RA)基團、N(RB)SO2N(RA)-(C1-C6)伸烷基、O-(C1-C6)伸烷基、N(RB)CO2基團、N(RB)CO2-(C1-C6)伸烷基、S-(C1-C6)伸烷基、SO2基團、SO2-(C1-C6)伸烷基、N(RB)SO2基團、N(RB)SO2-(C1-C6)伸烷基、CO基團、CO-(C1-C6)伸烷基、N(RB)CO基團、N(RB)CO-(C1-C6)伸烷基、SO2N(RB)CO基團、SO2N(RB)CO-(C1-C6)伸烷基、SO2N(RB)CON(RA)基團或SO2N(RB)CON(RA)-(C1-C6)伸烷基；RA及RB彼此獨立地表示氫原子或(C1-C6)烷基；m及n彼此獨立地表示等於0或1之整數，其中該芳基基團包含6至10個碳原子，且該雜芳基團為包含5至10個原子(包括1至5個選自N、O及S之雜原子)的單環或雙環基團，其係芳族、不飽和或部分不飽和基團或部分經氧化，該化合物呈鹼或與酸形成之加成鹽形式， 其係用於製備意欲用於治療及預防牽涉內源性2-二十碳四烯醯基甘油(2-arachidonoylglycerol；2-AG)及內源性1(3)-二十碳四烯醯基甘油及/或由酶單醯基甘油脂肪酶(MGL)代謝之任何其他受質之病變的藥物。
  13. 一種式(I)化合物之用途， 其中：R表示視情況經一或多個R2及/或R3基團取代之R1基團；R1表示芳基或雜芳基；R2表示鹵素原子或氰基、硝基、側氧基、(C1-C6)烷基、(C1-C6)烷氧基、羥基、(C1-C6)烷硫基、(C1-C6)鹵烷基、(C1-C6)鹵烷氧基、(C1-C6)鹵烷硫基、NR4R5、NR4COR5、NR4SO2R5、COR4、CO2R4、CONR4R5、SO2R4、SO2NR4R5、苯氧基或苯甲氧基；R3表示可能經一或多個彼此相同或不同的R2基團取代之單環芳基或雜芳基；R4及R5彼此獨立地表示氫原子或(C1-C6)烷基，或與帶有其之氮原子或N-CO或N-SO2片段一起形成視情況經(C1-C6)烷基或苯甲基取代之雜環；Z表示一鍵、(C1-C6)伸烷基、(C2-C6)伸烯基、(C2-C6)伸炔基、O-(C1-C6)伸烷基或N(RA)-(C1-C6)伸烷基； A表示一鍵、氧原子、硫原子、N(RA)基團、N(RA)-(C1-C6)伸烷基、CON(RA)基團、CON(RA)-(C1-C6)伸烷基、SO2N(RA)基團、SO2N(RA)-(C1-C6)伸烷基、OCON(RA)基團、OCON(RA)-(C1-C6)伸烷基、N(RB)CON(RA)基團、N(RB)CON(RA)-(C1-C6)伸烷基、N(RB)SO2N(RA)基團、N(RB)SO2N(RA)-(C1-C6)伸烷基、O-(C1-C6)伸烷基、N(RB)CO2基團、N(RB)CO2-(C1-C6)伸烷基、S-(C1-C6)伸烷基、SO2基團、SO2-(C1-C6)伸烷基、N(RB)SO2基團、N(RB)SO2-(C1-C6)伸烷基、CO基團、CO-(C1-C6)伸烷基、N(RB)CO基團、N(RB)CO-(C1-C6)伸烷基、SO2N(RB)CO基團、SO2N(RB)CO-(C1-C6)伸烷基、SO2N(RB)CON(RA)基團或SO2N(RB)CON(RA)-(C1-C6)伸烷基；RA及RB彼此獨立地表示氫原子或(C1-C6)烷基；m及n彼此獨立地表示等於0或1之整數，其中該芳基基團包含6至10個碳原子，且該雜芳基團為包含5至10個原子(包括1至5個選自N、O及S之雜原子)的單環或雙環基團，其係芳族、不飽和或部分不飽和基團或部分經氧化，該化合物呈鹼或醫藥學上可接受之鹽形式，其係用於製備意欲用於預防或治療以下疾病之藥物：急性或慢性疼痛、頭腦昏沈、嘔吐、噁心、進食障礙、異常血脂症、神經及精神病變、急性或慢性神經退化性疾病、癲癇症、睡眠障礙、腎缺血、癌症、免疫系統病症、過敏性疾病、寄生蟲、病毒或細菌感染性疾病、發 炎性疾病、骨質疏鬆症、眼病、肺病、胃腸疾病、尿失禁或膀胱炎。
  14. 如請求項1至5中任一項之化合物，其係用於製備意欲用於治療及預防牽涉內源性2-二十碳四烯醯基甘油(2-AG)及內源性1(3)-二十碳四烯醯基甘油及/或由酶MGL代謝之任何其他受質之病變的藥物。
  15. 如請求項1至5中任一項之化合物，其呈鹼或醫藥學上可接受之鹽形式，其係用於製備意欲用於預防或治療以下疾病之藥物：急性或慢性疼痛、頭腦昏沈、嘔吐、噁心、進食障礙、代謝症候群、異常血脂症、神經及精神病變、急性或慢性神經退化性疾病、癲癇症、睡眠障礙、心血管疾病、腎缺血、癌症、免疫系統病症、過敏性疾病、寄生蟲、病毒或細菌感染性疾病、發炎性疾病、骨質疏鬆症、眼病、肺病、胃腸疾病、尿失禁或膀胱炎。
  16. 一種如請求項1至5中任一項之化合物之用途，該化合物呈鹼或醫藥學上可接受之鹽形式，其係用於製備意欲用於預防或治療代謝症候群或心血管疾病之藥物。
TW100119659A 2010-06-04 2011-06-03 胺甲酸六氟異丙酯衍生物、其製備及其治療應用 TWI531564B (zh)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR1054411A FR2960875B1 (fr) 2010-06-04 2010-06-04 Derives de carbamates d'hexafluoroisopropyle, leur preparation et leur application en therapeutique

Publications (2)

Publication Number Publication Date
TW201202198A TW201202198A (en) 2012-01-16
TWI531564B true TWI531564B (zh) 2016-05-01

Family

ID=43402192

Family Applications (1)

Application Number Title Priority Date Filing Date
TW100119659A TWI531564B (zh) 2010-06-04 2011-06-03 胺甲酸六氟異丙酯衍生物、其製備及其治療應用

Country Status (35)

Country Link
US (1) US8835418B2 (zh)
EP (1) EP2576507B1 (zh)
JP (1) JP5913296B2 (zh)
KR (1) KR101753939B1 (zh)
CN (1) CN103068797B (zh)
AR (1) AR081578A1 (zh)
AU (1) AU2011262222B2 (zh)
BR (1) BR112012030906A2 (zh)
CA (1) CA2801405C (zh)
CL (1) CL2012003401A1 (zh)
CO (1) CO6640299A2 (zh)
CR (1) CR20120602A (zh)
DK (1) DK2576507T3 (zh)
DO (1) DOP2012000301A (zh)
EA (1) EA022076B1 (zh)
EC (1) ECSP12012323A (zh)
ES (1) ES2632136T3 (zh)
FR (1) FR2960875B1 (zh)
GT (1) GT201200322A (zh)
IL (1) IL223384A (zh)
MA (1) MA34359B1 (zh)
MX (1) MX336191B (zh)
MY (1) MY156938A (zh)
NI (1) NI201200174A (zh)
NZ (1) NZ603985A (zh)
PE (1) PE20130684A1 (zh)
PL (1) PL2576507T3 (zh)
PT (1) PT2576507T (zh)
SG (1) SG186145A1 (zh)
TN (1) TN2012000543A1 (zh)
TW (1) TWI531564B (zh)
UA (1) UA108240C2 (zh)
UY (1) UY33427A (zh)
WO (1) WO2011151808A1 (zh)
ZA (1) ZA201209145B (zh)

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3698782B1 (en) * 2012-01-06 2024-05-15 H. Lundbeck A/S Carbamate compounds for use in therapy
US10539870B2 (en) * 2013-05-31 2020-01-21 Rohm And Haas Electronic Materials Llc Photoresists comprising carbamate component
CA2979537C (en) 2015-03-18 2023-08-29 Abide Therapeutics, Inc. Piperazine carbamates and methods of making and using same
KR20180004263A (ko) 2015-05-11 2018-01-10 어바이드 테라퓨틱스, 인크. 염증 또는 신경병성 통증의 치료 방법
BR112018000041A2 (pt) 2015-07-31 2018-09-04 Pfizer Inc. Derivados de carbamato de 1,1,1-trifluoro-3- hidroxipropan-2-ila e derivados de carbamato de 1,1,1-trifluoro-4-hidroxibutan-2-ila como inibidores de magl
US10463753B2 (en) 2016-02-19 2019-11-05 Lundbeck La Jolla Research Center, Inc. Radiolabeled monoacylglycerol lipase occupancy probe
WO2017197192A1 (en) 2016-05-12 2017-11-16 Abide Therapeutics, Inc. Spirocycle compounds and methods of making and using same
JP7042804B2 (ja) 2016-09-19 2022-03-28 ルンドベック ラ ホーヤ リサーチ センター，インク． ピペラジンカルバメート、及びその製造と使用の方法
WO2018068296A1 (en) * 2016-10-14 2018-04-19 Merck Sharp & Dohme Corp. PIPERIDINE DERIVATIVES AS LIVER X RECEPTOR β AGONISTS, COMPOSITIONS, AND THEIR USE
WO2018068295A1 (en) * 2016-10-14 2018-04-19 Merck Sharp & Dohme Corp. ARYL AND HETEROARYL ETHER DERIVATIVES AS LIVER X RECEPTOR β AGONISTS, COMPOSITIONS, AND THEIR USE
JOP20190105A1 (ar) 2016-11-16 2019-05-09 Lundbeck La Jolla Research Center Inc مثبطات أحادي أسيل جليسرول ليباز (magl)
JOP20190106A1 (ar) * 2016-11-16 2019-05-09 Lundbeck La Jolla Research Center Inc مثبطات أحادي أسيل جليسرول ليباز (magl)
JOP20190107A1 (ar) 2016-11-16 2019-05-09 Lundbeck La Jolla Research Center Inc مثبطات أحادي أسيل جليسرول ليباز (magl)
WO2018134695A1 (en) 2017-01-20 2018-07-26 Pfizer Inc. 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives as magl inhibitors
BR112019014099A2 (pt) 2017-01-23 2020-02-11 Pfizer Inc. Compostos espiro-heterocíclico como inibidores de magl
MX2020002251A (es) * 2017-08-29 2020-07-20 Lundbeck La Jolla Research Center Inc Compuestos espirociclicos y sus metodos de preparacion y uso.
EA202090296A1 (ru) * 2017-08-29 2020-08-03 Лундбекк Ла-Хойя Рисерч Сентер, Инк. Спироциклические соединения и способы их получения и применения
EP3717477B1 (en) 2017-11-28 2022-07-20 F. Hoffmann-La Roche AG New heterocyclic compounds
TW201930300A (zh) * 2017-12-15 2019-08-01 瑞士商赫孚孟拉羅股份公司 新雜環化合物
US10570106B2 (en) 2018-05-15 2020-02-25 Lundbeck La Jolla Research Center, Inc. MAGL inhibitors
MX2021000549A (es) * 2018-07-19 2021-03-25 Pfizer Compuestos espiro heterociclicos como inhibidores de magl.
JP2023523219A (ja) 2020-04-21 2023-06-02 ハー・ルンドベック・アクチエゼルスカベット モノアシルグリセロールリパーゼ阻害剤の合成
US20230056935A1 (en) 2020-09-16 2023-02-23 Lg Chem, Ltd. Compound, Antimicrobial Deodorant Composition Comprising Same, and Method for Producing Same
US11141404B1 (en) 2020-11-18 2021-10-12 Anebulo Pharmaceuticals, Inc. Formulations and methods for treating acute cannabinoid overdose
CA3234167A1 (en) 2021-10-11 2023-04-20 Joseph Fenton Lawler Crystalline forms of a cannabinoid receptor type 1 (cb1) modulator and methods of use and preparation thereof

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69408873T2 (de) 1993-12-22 1998-07-09 Shell Int Research Verfahren zur herstellung von carbamaten
JP2002512626A (ja) 1997-06-05 2002-04-23 ハンツマン・アイシーアイ・ケミカルズ・エルエルシー カルバメート類の製造方法
EP1803453A1 (en) 2005-12-21 2007-07-04 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Carbamate antibiotics
JP2010519337A (ja) 2007-02-26 2010-06-03 コーサン バイオサイエンシーズ， インコーポレイテッド カルバメート化合物
EP2203412A4 (en) * 2007-10-16 2012-01-11 Univ Northeastern MONOACYLGLYCEROLLIPASE HEMMER FOR MODULATION OF CANNABINOIDACTIVITY
US8188098B2 (en) * 2008-05-19 2012-05-29 Hoffmann-La Roche Inc. GPR119 receptor agonists
US20110118286A1 (en) * 2008-07-16 2011-05-19 Santhosh Francis Neelamkavil Bicyclic heterocycle derivatives and their use as gpcr modulators
FR2938537B1 (fr) 2008-11-14 2012-10-26 Sanofi Aventis Derives de carbamates d'alkyl-heterocycles, leur preparation et leur application en therapeutique.
JP2011132138A (ja) * 2009-12-22 2011-07-07 Dainippon Sumitomo Pharma Co Ltd カルバメート誘導体またはその薬理学的に許容される塩
BR112012025592A2 (pt) * 2010-04-06 2019-09-24 Arena Pharm Inc moduladores do receptor de gpr119 e o tratamento de distúrbios relacionados com os mesmos

Also Published As

Publication number Publication date
CN103068797B (zh) 2015-03-11
KR101753939B1 (ko) 2017-07-04
AR081578A1 (es) 2012-10-03
US20130165422A1 (en) 2013-06-27
NZ603985A (en) 2015-02-27
SG186145A1 (en) 2013-01-30
UY33427A (es) 2011-12-30
AU2011262222A1 (en) 2013-01-10
ECSP12012323A (es) 2013-02-28
WO2011151808A1 (en) 2011-12-08
DK2576507T3 (en) 2017-07-10
IL223384A (en) 2016-07-31
GT201200322A (es) 2014-04-29
JP5913296B2 (ja) 2016-04-27
TN2012000543A1 (en) 2014-04-01
MY156938A (en) 2016-04-15
DOP2012000301A (es) 2013-06-30
PE20130684A1 (es) 2013-06-27
EA201291436A1 (ru) 2013-05-30
CL2012003401A1 (es) 2013-06-14
ES2632136T3 (es) 2017-09-11
CR20120602A (es) 2013-02-05
MA34359B1 (fr) 2013-07-03
CO6640299A2 (es) 2013-03-22
FR2960875A1 (fr) 2011-12-09
CA2801405C (en) 2018-05-22
EA022076B1 (ru) 2015-10-30
NI201200174A (es) 2013-02-05
EP2576507A1 (en) 2013-04-10
TW201202198A (en) 2012-01-16
CA2801405A1 (en) 2011-12-08
MX336191B (es) 2016-01-11
BR112012030906A2 (pt) 2016-11-08
MX2012014153A (es) 2013-02-07
UA108240C2 (uk) 2015-04-10
US8835418B2 (en) 2014-09-16
FR2960875B1 (fr) 2012-12-28
KR20130113408A (ko) 2013-10-15
PT2576507T (pt) 2017-07-12
ZA201209145B (en) 2014-02-26
JP2013527227A (ja) 2013-06-27
EP2576507B1 (en) 2017-04-05
IL223384A0 (en) 2013-03-05
AU2011262222B2 (en) 2015-08-13
PL2576507T3 (pl) 2017-10-31
CN103068797A (zh) 2013-04-24

Similar Documents

Publication Publication Date Title
TWI531564B (zh) 胺甲酸六氟異丙酯衍生物、其製備及其治療應用
US10442782B2 (en) Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
JP5140577B2 (ja) ヒドロキシステロイドデヒドロゲナーゼ阻害剤
AU2016299486A1 (en) 1,3,4-oxadiazole sulfamide derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
JP2011518142A (ja) Ｆａａｈ阻害剤として有用なエーテルベンジリデンピペリジン５員アリールカルボキサミド化合物
JP2011518145A (ja) Ｆａａｈ阻害剤として有用な４−［３−（アリールオキシ）ベンジリデン］−３−メチルピペリジン５員アリールカルボキサミド化合物
CA3125900A1 (en) 15-pgdh inhibitor
TW202208351A (zh) 作為組蛋白去乙醯酶6抑制劑之新穎化合物及包含其之醫藥組合物
JP2011518143A (ja) Ｆａａｈ阻害剤として有用なエーテルベンジリデンピペリジンアリールカルボキサミド化合物
US20240140933A1 (en) Oxoindoline compound for the treatment of inflammatory diseases or cancer
TW202045515A (zh) 酯化合物
TW202045506A (zh) 吡唑化合物
US11981686B2 (en) Urea compound having substituent
BR112021014539A2 (pt) Composto, ativador sirt6, composição farmacêutica, método para tratar e/ou prevenir uma doença inflamatória periférica e uso do composto
TW202246248A (zh) 羥基雜環烷-胺甲醯基衍生物
TW202043240A (zh) 胺基酸化合物
OA17933A (en) Hexafluoroisopropyl carbamate derivatives, their preparation and their therapeutic application
WO2007067904A2 (en) Peptide deformylase inhibitors

Legal Events

Date Code Title Description
MM4A Annulment or lapse of patent due to non-payment of fees