WO2015131773A1 - 作为食欲素受体拮抗剂的哌啶衍生物 - Google Patents

作为食欲素受体拮抗剂的哌啶衍生物 Download PDF

Info

Publication number
WO2015131773A1
WO2015131773A1 PCT/CN2015/073330 CN2015073330W WO2015131773A1 WO 2015131773 A1 WO2015131773 A1 WO 2015131773A1 CN 2015073330 W CN2015073330 W CN 2015073330W WO 2015131773 A1 WO2015131773 A1 WO 2015131773A1
Authority
WO
WIPO (PCT)
Prior art keywords
unsubstituted
group
cycloalkane
heteroatoms
hydroxy
Prior art date
Application number
PCT/CN2015/073330
Other languages
English (en)
French (fr)
Inventor
贺海鹰
吴松亮
张杨
马彪
陈远
王玉贺
陈曙辉
吕强
兰炯
刘星
Original Assignee
上海海雁医药科技有限公司
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=54054589&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2015131773(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to EP15758792.4A priority Critical patent/EP3115362B1/en
Priority to SG11201607183PA priority patent/SG11201607183PA/en
Priority to KR1020167027668A priority patent/KR101920472B1/ko
Priority to NZ723671A priority patent/NZ723671A/en
Priority to JP2016572879A priority patent/JP6262885B2/ja
Priority to MX2016011549A priority patent/MX2016011549A/es
Priority to CA2941663A priority patent/CA2941663C/en
Application filed by 上海海雁医药科技有限公司 filed Critical 上海海雁医药科技有限公司
Priority to CN201580012396.4A priority patent/CN106414439B/zh
Priority to AU2015226679A priority patent/AU2015226679B2/en
Priority to US15/123,014 priority patent/US10100047B2/en
Priority to RU2016130937A priority patent/RU2669701C2/ru
Publication of WO2015131773A1 publication Critical patent/WO2015131773A1/zh
Priority to IL247584A priority patent/IL247584A0/en
Priority to ZA2016/06141A priority patent/ZA201606141B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • 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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D401/14—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 three or more hetero rings

Definitions

  • the present invention relates to piperidine derivatives and their compositions as orexin receptor antagonists, and to the preparation thereof for the treatment of insomnia, chronic obstructive pulmonary disease, obstructive sleep apnea, lethargy, anxiety, coercion, panic, nicotine dependence or The application of drugs in the application of dietary disorders disorders.
  • Orexin includes two neuropeptides produced in the hypothalamus: orexin A (OX-A) (33 amino acid peptide) and orexin B (OX-B) (28 amino acid peptide) ( Sakurai T. et al., Cell, 1998, 92, 573-585). It has been found that orexin stimulates food consumption in rats, suggesting that these peptides have a physiological role as a mediator in a central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573-585). . Orexin regulates the state of sleep and insomnia, potentially suggesting new ways to treat patients with narcolepsy or insomnia (Chemelli R. M.
  • Orexin also plays a role in arousal, motivation, learning and memory (Harris, et al., Trends Neurosc1., 2006, 29(10), 571-577).
  • two orexin receptors have been cloned and characterized. They belong to the superfamily of G-protein coupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585):
  • the orexin-1 receptor (0X or 0X1R) is selective for OX-A, orexin-2
  • the receptor (OX2 or OX2R) is capable of binding to OX-A and OX-B. It is believed that the physiological role involved in the hypothesis of orexin is expressed by one or both of the OXI receptor and OX 2 (as two subtypes of the orexin receptor).
  • Orexin receptors can be found in the brains of warm-blooded animals and have many implications in, for example, depression: anxiety; addiction; compulsive mandatory disorders; affective neurosis; depressive neurosis; anxiety Neurosis; depressive disorder; behavioral disorder; mood disorder; sexual dysfunction; sexual psychological dysfunction; gender disorder; schizophrenia; manic depression; mental disorder; dementia; severe mental retardation and dyskinesia, for example Huntington's disease and pruritus; eating disorders such as anorexia, bulimia, cachexia and obesity; addictive feeding behavior; feeding behavior of madness; cardiovascular disease; diabetes; appetite/taste Disorder; vomiting, vomiting, nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophilic adenoma; prolactinoma; hyperprolactinemia; pituitary tumor/adenomas; Thalamic disease; inflammatory bowel disease; gastric dysfunction; gastric ulcer; obesity genital degeneration; pituitary disease; pituitary disease; glandular hypofunction
  • WO2008147518 (CN101679366 B) discloses the structure shown by the formula (B-I) and MK6096 on the basis of the above patent:
  • r 1 , r 3 are each independently selected from 0, 1 or 2, r 2 is selected from 0 or 1, and r 1 , r 2 and r 3 are 0 at the same time, and X is a single bond which only serves as a linking;
  • T is selected from C or a single bond which acts only as a linkage, and when T is selected from a single bond, R 2 and R 3 are absent;
  • M is selected from C(Y)(R 1a ), wherein Q is selected from C(R 1b )(R 1c ), or M is selected from C(R 1b )(R 1c ), where Q is selected from C(Y) )(R 1a );
  • Y is selected from -(CH 2 ) r4 (G) r5 (CH 2 ) r6 -Y 1
  • Y 1 is selected from the group consisting of -OE or the formula (Y 2 ).
  • r 4 , r 6 are each independently selected from 0, 1 or 2, r 5 is selected from 0 or 1, and r 4 , r 5 and r 6 are 0 at the same time, meaning that the corresponding structure is a single bond which only serves as a linking;
  • the compound or a pharmaceutically acceptable salt thereof contains one or more chiral centers.
  • n 4 is selected from 0, 1, 2, 3, 4;
  • n 6 is selected from 0, 1, 2, and 3.
  • the above compound or a pharmaceutically acceptable salt thereof wherein the structural unit Selected from phenyl or pyridyl, It is selected from a furyl group, a thienyl group or a thiazolyl group.
  • V 1 , V 2 , V 3 , V 4 , V 5 , R 6 , R 7 , and n 6 are as defined in the formula (A 2 ).
  • R 6 and R 7 are as defined in the formula (A 2 ); and n 6a is selected from 0, 1 or 2.
  • the above compound or a pharmaceutically acceptable salt thereof wherein the 5- to 6-membered cycloalkyl or heterocyclic group in R 5 and R 7 are each independently selected from a phenyl group, a pyridyl group, a furyl group, a thienyl group, Thiazolyl, pyrimidinyl, pyrazolyl, 1,2,3-triazolyl or 1,2,5-triazolyl.
  • the above compound or a pharmaceutically acceptable salt thereof, wherein said A is selected from the group consisting of:
  • Y 2a , Y 2b , Y 2c , Y 2d , Y 2e , Y 2f , Y 2g are as defined in the formula (I).
  • the above compound or a pharmaceutically acceptable salt thereof wherein the formula (Y 21 ) is selected from the structure represented by the formula (Y 22 ) which is optionally substituted:
  • the above compound or a pharmaceutically acceptable salt thereof wherein Y is selected from -CH 2 -OE or -OE, wherein E is as defined in formula (I).
  • E is selected from the structural unit represented by the formula (E a ):
  • E 1 , E 2 , E 3 , and E 4 are each independently selected from halo or hydroxy or amine or unsubstituted CH, N;
  • the above compound or a pharmaceutically acceptable salt thereof wherein the structural unit It is defined as a phenyl or pyridyl group, or it is replaced with a thienyl or furyl group.
  • the above compound or a pharmaceutically acceptable salt thereof wherein U, X, and G are each independently selected from NH or N(C 1-6 alkyl).
  • R 1a , R 1b , R 1c are each independently selected from H, methyl or fluorine.
  • R 2 and R 3 are each independently selected from H, methyl, fluoro or cyclopropyl.
  • the benzyl or hexyl group is optionally cyclized or partially cyclized.
  • the above compound or a pharmaceutically acceptable salt thereof has the following structure:
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another object of the present invention is to provide a therapeutic compound for the treatment of insomnia, chronic obstructive pulmonary disease, obstructive sleep apnea, lethargy, anxiety, obsessive-compulsiveness, panic disorder, nicotine dependence, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the application of drugs for eating disorders is to provide a therapeutic compound for the treatment of insomnia, chronic obstructive pulmonary disease, obstructive sleep apnea, lethargy, anxiety, obsessive-compulsiveness, panic disorder, nicotine dependence, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, ethanol Acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, Oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and after substitution The compound is stable.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a group or a bond of a substituent may be cross-linked to two atoms on a ring, such a group or substituent may be bonded to any atom on the ring.
  • a group or substituent does not indicate which atom is attached to a compound included in the chemical structural formula, but not specifically mentioned, such a group or substituent may be bonded through any of its atoms.
  • Combinations of groups or substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclodiene.
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic
  • the hydrocarbon radical or a combination thereof may be fully saturated, unitary or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may include divalent or polyvalent radicals having a specified number of carbon atoms (eg, C1 ) -C 10 represents 1 to 10 carbons).
  • the hydrocarbon group includes an aliphatic hydrocarbon group including an chain hydrocarbon group and a cyclic hydrocarbon group, and includes, but not limited to, an alkyl group, an alkenyl group, and an alkynyl group, and the aromatic hydrocarbon group includes, but not limited to, a 6-12 member aromatic hydrocarbon group.
  • alkyl refers to a straight or branched or cyclic group of atoms or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and Structure.
  • heteroalkyl, heterocyclyl, hydrocarbyl, cyclohetero, heteroalkylhetero, heterocyclylhetero group means a hetero atom or a hetero atom group, a hetero atom or a hetero atom group on a specific group.
  • the so-called heterohydrocarbyl, heterocyclic group is connected to the rest of the molecule through carbon atoms , that is, a hetero atom may be located at any internal position of the group (except that the group is attached to the rest of the molecule); the so-called hydrocarbon heterocycle, cyclohetero is attached to the rest of the molecule through a hetero atom, ie, The atom is located at a position where the group is attached to the rest of the molecule; the so-called heteroalkylhetero, heterocyclyl is attached to the remainder of the molecule through a heteroatom, wherein the heteroatom can be located at any internal position of the group (including This group is attached to the rest of the molecule).
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and the like), by itself or in combination with another term, means a stable straight chain.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroatoms B, O, N and S may be located at any internal position of the heterohydrocarbyl group (except where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • alkoxy alkylamino
  • alkylthio or thioalkoxy
  • cycloalkyl Unless otherwise specified, the terms “cycloalkyl”, “heterocycloalkyl”, “cyclohetero” or subordinates thereof (such as aryl, heteroaryl, aryl, cycloalkyl, heterocycloalkyl, ring) Alkyl, cycloalkenyl, heterocycloalkenyl, cycloalkenyl, cycloalkynyl, heterocycloalkynyl, cycloalkynyl, and the like, by themselves or in combination with other terms, respectively denote a cyclized “hydrocarbyl group", Heterohydrocarbyl” or “hydrocarbyl”.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • halo or halogen
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, which may be monocyclic or polycyclic (preferably 1 to 3 rings), They are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms.
  • the hetero atom is selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxygenated The nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl
  • aryl groups when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • ring means substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted hetero Aryl.
  • the so-called ring includes a fused ring.
  • the number of atoms on the ring is usually defined as the number of elements of the ring.
  • “5 to 7-membered ring” means 5 to 7 atoms arranged in a circle.
  • the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenylpyridine and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • hetero atom as used herein, unless otherwise specified, includes atoms other than carbon (C) and hydrogen (H), including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), antimony ( Ge), aluminum (Al) and boron (B).
  • leaving group refers to a functional group or atom that can be substituted by another functional group or atom by a substitution reaction (eg, an affinity substitution reaction).
  • a substitution reaction eg, an affinity substitution reaction
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, “amino protecting group”, “hydroxy protecting group” or “thiol protecting group.”
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like.
  • acyl such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxy
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • haloalkyl examples include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl. 3-7 cycloalkyl includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
  • halo refers to fluoro, chloro, bromo and iodo.
  • heterocycle or “heterocyclyl” means a stable monocyclic or bicyclic or bicyclic heterocyclic ring which may be saturated, partially unsaturated or unsaturated (aromatic), which A carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocyclic rings may be fused to a phenyl ring to form a bicyclic ring.
  • heterocyclic compounds include, but are not limited to, acridinyl, anthracycline, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazole , benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH -carbazolyl, porphyrinyl, chromanyl, chromene, porphyrinyldecahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuran[2 ,3-b]tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl
  • fused ring and spiro compounds are also included.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthesis methods, and techniques of the art. Preferred embodiments are well known to those skilled in the art, and preferred embodiments include, but are not limited to, embodiments of the invention.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and liquid phase mass spectrometry (LCMS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methyl silane
  • the absolute configuration is determined by conventional methods of single crystal X-ray diffraction.
  • the absolute configuration of compound 1-16 is used as an example.
  • the instrument used is a Bruker APEX-II CCD with a temperature of 296K.
  • the radiation wavelength was 1.54178 and the radiation type was Cu-Ka.
  • the test results are shown in Figure 1.
  • liquid phase mass spectrometry LCMS was measured using agilent 1200 (Xtimate C182.1*30 mm column) and mass spectrometry section using Agilent 6110 (ion source: ESI).
  • HPLC measurements were performed using a Shimadzu LC10AD high pressure liquid chromatograph (Xtimate C182.1*30 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, and the silica gel plate used for thin layer chromatography (TLC) adopts the specification of 0.15mm ⁇ 0.2mm.
  • the specification is 0.4mm to 0.5mm.
  • column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, TCI, Alfa, Suiyuan Chemical Accela ChemBio Inc., Beijing Coupling and other companies.
  • the examples can be carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified in the examples.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • a hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon having a volume of about 1 liter.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX type hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • microwave reaction used a CEM Discover-S Model 908860 or Biotage Initiator 60 microwave reactor.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • TLC thin layer chromatography
  • the column chromatography eluent system and the thin layer chromatography developer system used for the purification of the compound include: A: dichloromethane and methanol systems, B: petroleum ether and ethyl acetate systems, C: In the dichloromethane and acetone systems, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.
  • the instrument used for HPLC separation was Shimadzu LC-8A Prep.; the separation column model was Phenomenex Luna C18 250*50 mm, 10 ⁇ m; the fluidity was: A: Water (0.2% FA), B: CH3CN; The polarity of the sample was determined by the mobile phase gradient: 0 to 100% B; the separation time was 25 min; the flow rate was 90 mL/min; and the detection wavelength was 220/254 nm.
  • the invention employs the following abbreviations: aq for water; HATU for O-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, etc.
  • CDI carbonyl diimidazole
  • DCM dichloromethane
  • PE petroleum ether
  • DIAD diisopropyl azodicarboxylate
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • EtOAc stands for ethyl acetate
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • CBz stands for benzyloxycarbonyl, an amine protecting group
  • BOC stands for t-butylcarbonyl is an amine protecting group
  • HOAc stands for acetic acid
  • NaCNBH 3 stands for cyanide Sodium borohydride
  • rt stands for room temperature
  • O/N stands for overnight
  • THF stands for tetrahydrofuran
  • Boc 2 O stands for di-tert-butyldicarbonate
  • TFA trifluoroacetic acid
  • DIPEA stands for diisopropylethylamine
  • the compound is either by hand or Software naming, commercially available compounds using the supplier catalog name.
  • the compound of the invention Compared with the prior art, the compound of the invention has high efficiency, low toxicity, and has obtained in terms of activity, half-life, solubility and pharmacokinetics. Significant and even unexpected advances are more suitable for pharmaceuticals.
  • a wavy key indicates that the key may be facing up or down and is not affected by other groups (the same below).
  • the first step (synthesis of 1-3)
  • the crude compound 1-4 (1.4 g) was dissolved in 40 mL of dichloromethane, and then triethylamine (1.01 g, 10 mmol) and methanesulfonyl chloride (1.12 g, 9.86 mmol). It was allowed to warm to room temperature and stirred at room temperature for 10 hours. The reaction mixture was poured into water and extracted with dichloromethane (100 mL ⁇ 3). The organic phase was combined, washed with water (100 mL ⁇ 2), saturated sodium chloride solution (100 mL ⁇ 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the product 1-5.
  • the crude compound 1-5 (about 600 mg) was dissolved in 10 mL of DMF, and DBU (4 g, 16 mmol) was added, and the mixture was stirred at 100 ° C for 16 hours.
  • the reaction solution was cooled to room temperature, and 50 mL of water was added, and ethyl acetate (20 mL ⁇ 2) was added, and the organic phase was combined and washed successively with water (20 mL ⁇ 2), saturated sodium chloride solution (20 mL ⁇ 2), and anhydrous sodium sulfate The organic layer was dried, filtered, and the filtrate was evaporated. mjjjjjjj 30%).
  • the seventh step (synthesis of 1-10)
  • the compound racemic product 1-15 (28 mg) was separated via SFC (isolation method: instrument model: MG II preparative SFC; separation column: phenomenex Lux C2, 250 x 30 mm I.D.; mobile phase: A: CO 2 , B: Ethanol (0.1% ammonia); Gradient: B40%; Flow rate: 50 mL/min; Back pressure: 100 bar; Column temperature: 38 ° C; UV wavelength: 220 nm) to obtain optically pure compound 1-16 (10 mg, white solid) Yield: 71%) and optically pure compound 2-1 (10 mg, white solid, yield: 71%).
  • the absolute structure of 1-16 was confirmed by single crystal X-ray.
  • the compound 1-12 (100 mg) was dissolved in 4 mL of ethyl acetate. ethyl acetate (4 mL, 4M) was evaporated. The product was directly subjected to the next reaction without purification.
  • the compound racemic product 3-2 (30 mg) was separated via SFC (isolation method: instrument model: MG II preparative SFC; separation column: ChiralPak IC, 250 x 30 mm I.D.; mobile phase: A: CO 2 , B: ethanol (0.1% aqueous ammonia); gradient: B 50%; flow rate: 45 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm) to obtain optically pure compound 3-3 (12 mg, white solid, Yield: 80%) and optically pure compound 4-1 (12 mg, white solid, yield: 80%).
  • SFC isolation method: instrument model: MG II preparative SFC; separation column: ChiralPak IC, 250 x 30 mm I.D.; mobile phase: A: CO 2 , B: ethanol (0.1% aqueous ammonia); gradient: B 50%; flow rate: 45 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm
  • (3-3 and 4-1 are a pair of enantiomers, the relative structure of which is a hypothetical structure, and the absolute structure is not confirmed).
  • the compound racemic product 5-2 (24 mg) was separated via SFC (isolation method: instrument model: MG II preparative SFC; separation column: ChiralPak IC, 250 x 30 mm I.D.; mobile phase: A: CO 2 , B: ethanol (0.1% aqueous ammonia); gradient: B 45%; flow rate: 40 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm) to obtain optically pure compound 5-3 (8 mg, white solid) And 6-1 (8 mg, white solid), total yield of two compounds: 67%.
  • SFC isolation method: instrument model: MG II preparative SFC; separation column: ChiralPak IC, 250 x 30 mm I.D.; mobile phase: A: CO 2 , B: ethanol (0.1% aqueous ammonia); gradient: B 45%; flow rate: 40 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm) to obtain optical
  • the compound racemic product 7-1 (30 mg) was separated via SFC (isolation method: instrument model: MG II preparative SFC; separation column: ChiralPak AS, 250 x 30 mm I.D.; mobile phase: A: CO2, B : ethanol (0.1% ammonia); gradient: B 15%; flow rate: 60 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm) to obtain optically pure compound 7-2 (12 mg, white solid, produced Rate: 80%) and optically pure compound 8-1 (12 mg, white solid, yield: 80%).
  • SFC isolation method: instrument model: MG II preparative SFC; separation column: ChiralPak AS, 250 x 30 mm I.D.; mobile phase: A: CO2, B : ethanol (0.1% ammonia); gradient: B 15%; flow rate: 60 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm
  • the compound racemic product 1-11 (280 mg) was separated via SFC (isolation method: instrument model: MG II preparative SFC (SFC-1); separation column: ChiralPak AD, 250 x 30 mm I.D.; mobile phase: A: CO2, B: ethanol (0.1% ammonia); gradient: B 25%; flow rate: 60 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm) to obtain optically pure compound 9-1 (100 mg) , white solid, yield: 71%).
  • SFC isolation method: instrument model: MG II preparative SFC (SFC-1); separation column: ChiralPak AD, 250 x 30 mm I.D.; mobile phase: A: CO2, B: ethanol (0.1% ammonia); gradient: B 25%; flow rate: 60 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm) to obtain optically pure compound 9-1 (100 mg) , white solid, yield: 71%
  • the compound 9-1 (120 mg) was dissolved in 4 mL of ethyl acetate. ethyl acetate (4 mL, 4M) was evaporated. The product was directly subjected to the next reaction without purification.
  • Example 11 Referring to the synthetic route of Example 10, the reagent 10-1 used was replaced by 11-1: Purification by preparative HPLC gave the product 11-2 (24 mg, white solid, yield: 25%).
  • Example 12 refers to the synthetic route of Example 10, in which reagent 10-1 is replaced by 12-1: Purification by preparative HPLC gave the product 12-2 (8 mg, white solid.
  • Example 13 refers to the synthetic route of Example 10, in which reagent 10-1 is replaced by 13-1: Purification by preparative HPLC gave the product 13-2 (37 mg, white.
  • Example 14 Referring to the synthetic route of Example 10, the reagent 10-1 used was replaced by 14-1: Purification by preparative HPLC gave the product 14-2 (19 mg, pale yellow solid, yield: 20%).
  • Example 15 Referring to the synthetic route of Example 10, the reagent 10-1 used was changed to 15-1: Purification by preparative HPLC gave the product 15-2 (17 mg, pale yellow solid, yield: 18%).
  • Example 16 refers to the synthetic route of Example 10, in which reagent 10-1 is replaced by 16-1: Purification by preparative HPLC gave the product 16-2 (6.5 mg, m.
  • Example 17 Referring to the synthetic route of Example 10, the reagent 10-1 used was replaced by 17-1: Purification by preparative HPLC gave the product 17-2 (4.3 mg, white.
  • Example 18 refers to the synthetic route of Example 10, in which reagent 10-1 is replaced by 18-1: Purification by preparative HPLC gave the product 18-2 (4.3 mg, white.
  • Example 19 Referring to the synthetic route of Example 10, the reagent 10-1 used was changed to 19-1: Purification by preparative HPLC gave the product 19-2 (29 mg, white solid.
  • Example 20 refers to the synthetic route of Example 10, in which reagent 10-1 is replaced by 20-1: Purification by preparative HPLC gave product 20-2 (51 mg, m.
  • the compound 1-7 (48 g) was dissolved in 50 mL of ethyl acetate. ethyl acetate (150 mL, 4M) was evaporated. The product was directly subjected to the next reaction without purification.
  • Example 25 Referring to the synthetic route of Example 24, the reagent 24-1 used was changed to 25-1: Purification via TLC plate gave product 25-2 (33.72 mg, white solid, yield: 22%).
  • the compound 26-3 (150 mg) was dissolved in 4 mL of ethyl acetate. ethyl acetate (4 mL, 4M). The product was directly subjected to the next reaction without purification.
  • the compound 23-5 (190 mg) was dissolved in 10 mL of THF, and 10 mL of a 0.48% aqueous solution of LiOH was added thereto, and the mixture was heated to reflux for 3 hours, diluted hydrochloric acid was added dropwise to weakly acidic, and extracted with ethyl acetate. 1 (160 mg, 94%), the product was taken to the next step without purification.
  • Compound 23-5 (5 g) was separated via SFC (isolation method: instrument model: MG II preparative SFC (SFC-1); separation column: ChiralPak OD, 250 x 30 mm I.D.; mobile phase: A: CO2, B :ethanol (0.1% aqueous ammonia); gradient: B 30%; flow rate: 55 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm) to give chiral pure compound 29-1 (2 g, white solid, Yield: 80%).
  • SFC isolation method: instrument model: MG II preparative SFC (SFC-1); separation column: ChiralPak OD, 250 x 30 mm I.D.; mobile phase: A: CO2, B :ethanol (0.1% aqueous ammonia); gradient: B 30%; flow rate: 55 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm) to give chiral pure compound 29-1 (2 g, white
  • Example 31 Referring to the synthetic route of Example 30, the reagent 30-1 used was changed to 31-1: Purification by preparative HPLC gave the product 31-2 (5.
  • Example 31 Referring to the synthetic route of Example 30, the reagent 30-1 used was changed to 32-1: Purification by preparative HPLC gave the product 32-2 (7.32 g, white.
  • Example 33 Referring to the synthetic route of Example 10, the reagent 10-1 used was changed to 33-1: Purification by preparative HPLC gave the product 33-2 (25 mg, m.
  • Example 34 refers to the synthetic route of Example 10, in which reagent 10-1 is replaced by 34-1: Purification by preparative HPLC gave the product 34-2 (30 mg, m.
  • Example 35 Referring to the synthetic route of Example 10, the reagent 10-1 used was changed to 35-1: Purification by preparative HPLC gave the product 35-2 (4.47 mg, white.
  • Example 36 Referring to the synthetic route of Example 10, the reagent 10-1 used was changed to 36-1: Purification by preparative HPLC gave the product 36-2 (25.32 mg, white solid, yield: 34.4%).
  • Example 37 Referring to the synthetic route of Example 10, the reagent 10-1 used was changed to 37-1: Purification by preparative HPLC gave product 37-2 (29.63 mg, m.
  • OX1 and OX2GPCR receptors were evaluated by FLIPR to detect intracellular calcium signal changes and IC50 values of the compounds as indicators.
  • Cell line HEK293-OX1 and OX2 stable cell lines
  • HEK293-OX1 cell culture medium (DMEM, Invitrogen #11960-044, 10% serum Gibco #10099141, L-Glutamine 1 ⁇ , Gibco #25030, sodium pyruvate 1 ⁇ , Gibco #11360, Geneticin 300 ⁇ g/ml, Gibco #10131)
  • HEK293-OX2 cell culture medium (DMEM, Invitrogen #11960-044, 10% serum Gibco #10099141, L-Glutamine 1 ⁇ , Gibco #25030, sodium pyruvate 1 ⁇ , Gibco #11360, Geneticin 300 ⁇ g/ml, Gibco #10131, Blasticin 2 ⁇ g/ml, Invitrogen#R21001)
  • Each T150 was suspended with 10-15 mL of medium, centrifuged at 800 rpm for 5 minutes, resuspended in 10 mL of medium, and 1 mL of the cell suspension was aspirated and counted with Vi-cell;
  • the exemplified compounds of the present invention have significant inhibitory effects on OX1 and OX2 GPCR receptors, with some of the exemplified compounds having more excellent activity than the positive controls. Furthermore, it was found that for some of the exemplified compounds, the difference in stereoconfiguration has a greater effect on the inhibition of OX1 and OX2 GPCR receptors.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Anesthesiology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

本发明公开了一系列作为食欲素受体拮抗剂的哌啶衍生物及其组合物，并涉及其在制备治疗失眠、慢性阻塞性肺病、阻塞性睡眠呼吸暂停、嗜睡、焦虑、强迫、恐慌、尼古丁依赖或饮食混乱障碍的药物中的应用。

Description

作为食欲素受体拮抗剂的哌啶衍生物 技术领域
本发明涉及作为食欲素受体拮抗剂的哌啶衍生物及其组合物，并涉及其在制备治疗失眠、慢性阻塞性肺病、阻塞性睡眠呼吸暂停、嗜睡、焦虑、强迫、恐慌、尼古丁依赖或饮食混乱障碍的药物中的应用药物中的应用。
背景技术
食欲素(食欲肽)包括下丘脑中所产生的两种神经肽:食欲素A(OX-A)(33个氨基酸的肽)和食欲素B(OX-B)(28个氨基酸的肽)(SakuraiT.等人，Cell,1998,92,573-585)。人们发现，食欲素能够在大鼠中刺激食物消耗，这说明，在调节摄食行为的中心反馈机制中，这些肽具有作为介质的生理学作用(Sakurai T.等人，Cell,1998,92,573-585)。食欲素能够调节睡眠和失眠的状态，潜在地提出了治疗发作性睡眠或失眠症患者的新方法(Chemelli R.M.等人，Cell,1999,98,437-451)。食欲素还在觉醒、激励、学习和记忆中起一定作用(Harris，等人，Trends Neurosc1.，2006，29(10)，571-577)。在哺乳动物中，已经克隆和表征了两种食欲素受体。它们属于G蛋白偶联受体的超科(Sakurai T.等人，Cell,1998,92,573-585):食欲素-1受体(0X或0X1R)对OX-A具有选择性，食欲素-2受体(OX2或OX2R)能够与OX-A以及OX-B结合。人们认为，假定食欲素所参与的生理作用是通过OXI受体和OX 2(作为食欲素受体的两个亚型)的其中一个或两个来表达的。
在温血动物脑中可以发现食欲素受体，并且在例如下列病变中具有许多牵连：忧郁症；焦虑症；成瘾；强迫性的强制病症；情感性神经症；抑郁性神经症；焦虑性神经症；精神抑郁病症；行为失常；心情病症；性功能紊乱；性心理的功能紊乱；性别病症；精神分裂症；躁狂性忧郁症；精神错乱；痴呆；严重的智力迟钝和运动障碍，例如亨丁顿舞蹈症和妥瑞症；进食障碍，例如厌食，贪食症，恶病体质和肥胖症；上瘾性摄食行为；狂吃狂泻的摄食行为；心血管性疾病；糖尿病；食欲/味觉失调；呕吐，呕，恶心；哮喘；癌症；帕金森氏症；库兴氏综合症/疾病；嗜碱细胞腺瘤；泌乳素瘤；高催乳素血症；脑下垂体肿瘤/腺瘤；下丘脑疾病；炎症性肠病；胃机能障碍；胃溃疡；肥胖性生殖器退化；腺垂体疾病；脑下垂体疾病；腺垂体机能减退；腺垂体机能亢进；下丘脑的性腺机能减退；卡尔曼氏综合症(嗅觉缺失，嗅觉减退)；功能性或心因性闭经；垂体机能减退；下丘脑的甲状腺机能减退；下丘脑-肾上腺功能紊乱；突发性的高催乳素血症；下丘脑病的生长激素缺乏；突发性的生长缺乏；侏儒症；巨人症；肢端肥大症；受到干扰的生物和昼夜节律；与疾病例如神经错乱、神经性疼痛和多动腿综合征相关的睡眠障碍；心脏和肺疾病，急性和充血性心力衰竭；低血压；高血压症；尿储留；骨质疏松症；心绞痛；急性心肌梗死；缺血性或出血性中风；蛛网膜出血；溃疡；变态反应；良性前列腺肥大；慢性肾衰竭；肾病；葡糖耐量削弱；偏头痛；痛觉过敏；疼痛；对疼痛敏感性增强或夸张，例如痛觉过敏、灼痛和触摸痛；急性疼痛；灼伤性疼痛；非典型性的面部疼痛；神经性疼痛；背痛；复合区域疼痛综合症I和II；关节炎疼痛；运动创伤疼痛；与感染例如HIV相关的疼痛，化疗后疼痛；中风后的疼痛；手术后的疼 痛；神经痛；呕吐，恶心，呕；与内脏疼痛相关的病症，例如过敏性肠综合症和心绞痛；偏头痛；膀胱失禁，例如急迫性尿失禁；对麻醉剂或戒除麻醉剂的耐受性；睡眠障碍；睡眠呼吸暂停；嗜眠病；失眠；深眠状态；时差综合症；和神经变性的病症，包括疾病分类实体，例如抑制解除-痴呆-震颤性麻痹-肌萎缩综合征；癫痫；癫痫发作病症及其它与普通食欲素系统功能紊乱相关的疾病。
某些食欲素受体拮抗剂公开在下列专利中：W099/09024，WO 99/58533，WO 00/47576,WO 00/47577,WO 00/47580,WO 01/68609,W001/85693,WO 01/96302，WO 2002/044172，WO 2002/051232，WO 2002/051838，W02002/089800,WO 2002/090355，WO 2003/002559,WO 2003/002561,WO 2003/032991,W02003/037847,WO 2003/041711,WO 2003/051368,WO 2003/051872,WO 2003/051873,W02004/004733,WO 2004/026866,WO 2004/033418,WO 2004/041807,WO 2004/041816,W02004/052876,WO 2004/083218,WO 2004/085403,WO 2004/096780,WO 2005/060959,W02005/075458,W02005/118548,WO 2006/067224,WO 2006/110626,WO 2006/127550,W02007/019234,WO 2007/025069,WO 2007/061763,WO 2007/116374,WO 2007/122591,W02007/126934,WO 2007/126935,WO2008/008517，WO 2008/008518，WO 2008/008551，W02008/020405,WO 2008//026149,WO2008/038251。
另外，WO2008147518(CN101679366 B)在上述专利的基础上公开了式(B-Ⅰ)所示结构以及MK6096：
Figure PCTCN2015073330-appb-000001
其活性、溶解性、药代动力学、半衰期等方面的效果有待改善。
发明内容
本发明的目的在于提供式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2015073330-appb-000002
其中，
A选自任选被取代的3～12元环烃基或杂环烃基或环烃杂基，所述环烃基或杂环烃基或环烃杂基可以单环、联环、螺环、并环或稠环形式存在，取代基选自F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的；
B选自C(＝O)、S(＝O)或S(＝O)2；
X选自任选被取代的(CH2)r1(U)r2(CH2)r3，取代基选自F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的；
r1、r3分别独立地选自0、1或2，r2选自0或1，r1、r2和r3同时为0表示X为仅起连接作用的单键；
U选自卤代或羟代或胺代或未被取代的CH2、C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基的数目在化学上可稳定实现的前提下是任意的；
D、L分别独立地选自任选被取代的CH2，取代基选自F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的；
T选自C或者仅起连接作用的单键，当T选自单键时R2、R3不存在；
M选自C(Y)(R1a)，此时Q选自C(R1b)(R1c)，或者，M选自C(R1b)(R1c)，此时Q选自C(Y)(R1a)；
Y选自-(CH2)r4(G)r5(CH2)r6-Y1，Y1选自-O-E或式(Y2)所示结构，
Figure PCTCN2015073330-appb-000003
G选自卤代或羟代或胺代或未被取代的CH2、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、S(＝O)、S(＝O)2、C(＝O)或C(＝S)，取代基的数目在化学上可稳定实现的前提下是任意的；
r4、r6分别独立地选自0、1或2，r5选自0或1，r4、r5和r6同时为0表示相应结构为仅起连接作用的单键；
E选自任选被取代的5～6元环烃基或杂环基，取代基选自F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的；
Y2a、Y2b、Y2c、Y2d、Y2e、Y2f、Y2g选自任选被取代的CH2、CH、NH、或选自N、O、S、S(＝O)、S(＝O)2、C(＝O)或C(＝S),且Y2a、Y2b、Y2c、Y2d、Y2e、Y2f、Y2g至少一项为任选被取代的CH、CH2或NH，取代基选自F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的；
Figure PCTCN2015073330-appb-000004
代表单键或双键；
R1a、R1b、R1c、R2、R3分别独立地选自H、F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的，或者任选地R2、R3连接成环；和
该化合物或其药学上可接受的盐包含一个或多个手性中心。
优选地，上述化合物或其药学上可接受的盐，其中A选自式(A1)或(A2)所示结构单元：
Figure PCTCN2015073330-appb-000005
其中，
Z1、Z2、Z3、Z4、Z5分别独立地选自卤代或羟代或胺代或未被取代的CH或CH2、或C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH或NH、C＝N、N、O、S、S(＝O)、S(＝O)2、C(＝O)O、C(＝O)或C(＝S)，取代基的数目在化学上可稳定实现的前提下是任意的；
V1、V2、V3、V4、V5分别独立地选自卤代或羟代或胺代或未被取代的CH或CH2、C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH或NH、C＝N、C、N、O、S、S(＝O)、S(＝O)2、C(＝O)O、C(＝O)或C(＝S)，且V1-5至少一项为C或N，取代基的数目在化学上可稳定实现的前提下是任意的；
Figure PCTCN2015073330-appb-000006
代表单键或双键；
R4、R6分别独立地选自H、F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的；
R5、R7分别独立地选自任选被取代的5～6元环烃基或杂环基，取代基选自F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的；
n4选自0、1、2、3、4；和
n6选自0、1、2、3。
优选地，上述化合物或其药学上可接受的盐，其中结构单元
Figure PCTCN2015073330-appb-000007
选自苯基或吡啶基，
Figure PCTCN2015073330-appb-000008
选自呋喃基、噻吩基或噻唑基。
优选地，上述化合物或其药学上可接受的盐，其中式(A2)选自式(A21)所示结构：
Figure PCTCN2015073330-appb-000009
式中，V1、V2、V3、V4、V5、R6、R7、n6如式(A2)中所定义。
优选地，上述化合物或其药学上可接受的盐，其中A选自式(A22)所示结构单元：
Figure PCTCN2015073330-appb-000010
其中，R6、R7如式(A2)中所定义；n6a选自0、1或2。
优选地，上述化合物或其药学上可接受的盐，其中所述R5、R7中5～6元环烃基或杂环基分别独立地选自苯基、吡啶基、呋喃基、噻吩基、噻唑基、嘧啶基、吡唑基、1,2,3-三唑基或1,2,5-三唑基。
优选地，上述化合物或其药学上可接受的盐，其中所述A选自：
Figure PCTCN2015073330-appb-000011
Figure PCTCN2015073330-appb-000012
优选地，上述化合物或其药学上可接受的盐，其中式(Y2)选自式(Y21)所示结构：
Figure PCTCN2015073330-appb-000013
式中，Y2a、Y2b、Y2c、Y2d、Y2e、Y2f、Y2g如式(I)中所定义。
优选地，上述化合物或其药学上可接受的盐，其中式(Y21)选自任选被取代的式(Y22)所示结构：
Figure PCTCN2015073330-appb-000014
其中，取代基选自F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的。
优选地，上述化合物或其药学上可接受的盐，其中Y选自任选被取代的
Figure PCTCN2015073330-appb-000015
优选地，上述化合物或其药学上可接受的盐，其中Y选自-CH2-O-E或-O-E，其中，E如式(I)中所定义。
优选地，上述化合物或其药学上可接受的盐，其中E选自式(Ea)所示结构单元：
Figure PCTCN2015073330-appb-000016
其中，
E1、E2、E3、E4分别独立地选自卤代或羟代或胺代或未被取代的CH、N；和
R8、R9分别独立地选自H、F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的。
优选地，上述化合物或其药学上可接受的盐，其中将结构单元
Figure PCTCN2015073330-appb-000017
限定为苯基或者吡啶基，或将其替换为噻吩基或呋喃基。
优选地，上述化合物或其药学上可接受的盐，其中Y选自：
Figure PCTCN2015073330-appb-000018
优选地，上述化合物或其药学上可接受的盐，其中U、X、G分别独立地选自NH或N(C1-6烷基)。
优选地，上述化合物或其药学上可接受的盐，其中R1a、R1b、R1c分别独立地选自H、甲基或氟。
优选地，上述化合物或其药学上可接受的盐，其中R2、R3分别独立地选自H、甲基、氟或环丙基。
优选地，上述化合物或其药学上可接受的盐，其中R2、R3连接成3～8元环烷基。
优选地，上述化合物或其药学上可接受的盐，其中R2、R3连接成环丙基。
优选地，上述化合物或其药学上可接受的盐，其中C1-6烷基选自甲基、乙基、丙基、丁基、戊基、己基，其中所述丙基、丁基、戊基、己基任选地环化或部分环化。
优选地，上述化合物或其药学上可接受的盐，其具有如下结构：
Figure PCTCN2015073330-appb-000019
Figure PCTCN2015073330-appb-000020
本发明的另一目的在于提供一种药物组合物，包括治疗有效量的上述化合物或其药学上可接受的盐以及药学上可接受的载体。
本发明的另一目的在于上述化合物或其药学上可接受的盐或上述药物组合物在制备治疗治疗失眠、慢性阻塞性肺病、阻塞性睡眠呼吸暂停、嗜睡、焦虑、强迫、恐慌、尼古丁依赖或饮食混乱障碍的药物中的应用。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇 酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。本发明的某些化合物可以以多晶或无定形形式存在。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
除非另有规定，术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
除非另有规定，当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
除非另有规定，当一个基团或者取代基的键可以交叉连接到一个环上的两个原子时，这种基团或者取代基可以与这个环上的任意原子相键合。当所列举的基团或者取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种基团或者取代基可以通过其任何原子相键合。基团或者取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。例如，结构单元
Figure PCTCN2015073330-appb-000021
表示其可在环己基或者环基二烯上的任意一个位置发生取代。除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、苯基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的、单元或多元不饱和的，可以是单取代、二取代或多取代的，可以包括二价或多价原子团，具有指定数量的碳原子(如C1-C10表示1至10个碳)。所述烃基包括脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烷基”表示直链的或支链或环状的原子团或它们的组合，可以是完全饱和的、单元或 多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烷基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，所述杂烃基、杂环基、烃杂基、环杂基、杂烃基杂基、杂环基杂基是指特定基团上含有杂原子或杂原子团，杂原子或杂原子团包括但不限于N、NH、被取代或者被保护的NH、O、S、S(＝O)、S(＝O)2，所谓杂烃基、杂环基是通过碳原子与分子其余部分相连接，即杂原子可以位于该基团的任何内部位置(除该基团附着于分子其余部分的位置之外)；所谓烃杂基、环杂基是通过杂原子与分子其余部分相连接，即杂原子位于该基团附着于分子其余部分的位置上；所谓杂烃基杂基、杂环基杂基是通过杂原子与分子其余部分相连接，其中杂原子可以位于该基团的任何内部位置(包括该基团附着于分子其余部分的位置)。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子B、O、N和S可以位于杂烃基的任何内部位置(除该烃基附着于分子其余部分的位置之外)。实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3和–CH＝CH-N(CH3)-CH3。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。
除非另有规定，术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。
除非另有规定，术语“环烃基”、“杂环烃基”、“环烃杂基”或者其下位概念(比如芳基、杂芳基、芳杂基、环烷基、杂环烷基、环烷杂基、环烯基、杂环烯基、环烯杂基、环炔基、杂环炔基、环炔杂基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”或“烃杂基”。环烷基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C1-C4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代、二取代或多取代的，它可以是单环或多环(优选1至3个环)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧 化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，为简便起见，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
除非另有规定，“环”表示被取代或未被取代的环烷基、被取代或未被取代的杂环烷基、被取代或未被取代的芳基或被取代或未被取代的杂芳基。所谓的环包括稠环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，本文所用术语“杂原子”包括碳(C)和氢(H)以外的原子，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)和硼(B)等。
除非另有规定，术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
除非另有规定，术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基。C1-6烷氧基包括C1、C2、C3、C4、C5和C6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。“环烷基”包括饱和环基，如环丙基、环丁基或环戊基。3-7 环烷基包括C3、C4、C5、C6和C7环烷基。“链烯基”包括直链或支链构型的烃链，其中该链上任何的稳定位点上存在一个或多个碳-碳双键，例如乙烯基和丙烯基。
除非另有规定，术语“卤”或“卤素”是指氟、氯、溴和碘。
除非另有规定，术语“杂环”或“杂环基”意指稳定的单环或双环或双环杂环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。
除非另有规定，杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、isatino基、异苯并呋喃基、吡喃、异吲哚基、异二氢吲哚基、异吲哚基、吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、异恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、吡唑基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。还包括稠环和螺环化合物。除非另有规定，本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
除非另有规定，化合物的结构是通过核磁共振(NMR)或/和液相质谱(LCMS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
除非另有规定，绝对构型的测定是通过单晶X-Ray衍射的常规方法测定，以化合物1-16的绝对构型的测定为例，所用仪器为Bruker APEX-II CCD，温度为296K，辐射波长为1.54178，辐射类型为Cu-Ka，测试结果如附图1所示。
除非另有规定，液相质谱LCMS的测定液相部分用安捷伦1200(Xtimate C182.1*30mm色谱柱)和质谱部分用安捷伦6110(离子源:ESI)。
除非另有规定，HPLC的测定使用岛津LC10AD高压液相色谱仪(Xtimate C182.1*30mm色谱柱)。
除非另有规定，薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
除非另有规定，柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
除非另有规定，本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，TCI，Alfa，韶远化学科技(Accela ChemBio Inc)、北京偶合等公司。
除非另有规定，实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
除非另有规定，氢气氛是指反应瓶连接一个约1L容积的氢气气球。
除非另有规定，加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。氢化反应通常抽真空，充入氢气，反复操作3次。
除非另有规定，微波反应使用CEM Discover-S 908860型或Biotage Initiator 60微波反应器。
除非另有规定，实施例中无特殊说明，溶液是指水溶液。
除非另有规定，实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
除非另有规定，实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。
除非另有规定，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：石油醚和乙酸乙酯体系，C：二氯甲烷和丙酮体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
除非另有规定，HPLC分离使用的仪器为Shimadzu LC-8A Prep.；分离柱子型号为Phenomenex Luna C18 250*50mm,10μm；流动性分别为：A:Water(0.2％FA),B:CH3CN；根据样品极性确定流动相梯度：0～100％B；分离时间为25min；流速为90mL/min；检测波长为：220/254nm。
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。
除非另有规定，本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。
除非另有规定，本发明采用下述缩略词：aq代表水；HATU代表O-7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点。
除非另有规定，化合物经手工或者
Figure PCTCN2015073330-appb-000022
软件命名，市售化合物采用供应商目录名称。
与现有技术相比，本发明化合物高效、低毒，在活性、半衰期、溶解度和药代动力学等方面均取得 了显著甚至预料不到的进步，更适合于制药。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1，2
Figure PCTCN2015073330-appb-000023
波浪形键表示该键可能朝上或朝下，并不受其它基团影响(下同)。
第一步(1-3的合成)
将化合物1-1(10.0g,44.4mmol)溶于55mL四氢呋喃中，在-78℃下，慢慢滴加LDA(24.4mL,0.0488mol)，在-78℃下，搅拌1小时。温度保持在-78℃，将化合物1-2滴加入反应中，加完之后，温度慢慢升到室温，室温下将反应搅拌过夜。将反应液倒入氯化胺水溶液(50mL)中，减压浓缩得粗品。向其中加入50mL饱和氯化钠水溶液，用乙酸乙酯(100mL×3)萃取，合并有机相，依次用水(100mL×2)、饱和氯化钠溶液(100mL×2)洗涤，用无水硫酸钠干燥、过滤、经柱层析(石油醚：乙酸乙酯＝50:1)纯化得到产物1-3为黄色液体,产率：80％。(冷却放置后有固体析出)。
LC/MS：198.0(M-Boc+H+)
第二步(1-4的合成)
将化合物1-3(1.5g,5.05mmol)溶于15mL甲醇，加入NaBH4(192mg,5.05mmol)。反应液于室温下搅拌12小时。往反应液中加入20mL水淬灭，混合物浓缩后用乙酸乙酯(20mL×3)萃取，合并有机相，依次用水(100mL×2)、饱和氯化钠溶液(100mL×2)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，得产物1-4，产物不经纯化直接进行下一步反应。
第三步(1-5的合成)
将粗品化合物1-4(1.4g)溶于40mL二氯甲烷中，在0℃下，加入三乙胺(1.01g,10mmol)和甲烷磺酰氯(1.12g,9.86mmol)，搅拌30分钟后，升到室温，室温搅拌10小时。将反应液倒入水中并用二氯甲烷(100mL×3)萃取，合并有机相，依次用水(100mL×2)、饱和氯化钠溶液(100mL×2)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，得产物1-5，产物不经纯化直接进行下一步反应。
第四步(1-6的合成)
将粗品化合物1-5(约600mg)溶于10mL DMF中，加入DBU(4g,16mmol),加热至100℃搅拌16小时。将反应液冷却至室温，加入50mL水，乙酸乙酯萃取(20mL×2)，合并有机相，依次用水(20mL×2)、饱和氯化钠溶液(20mL×2)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，经柱层析(石油醚：乙酸乙酯＝50:1)纯化得到280mg的产物1-6(黄色液体，冷却放置后有固体析出，三步总产率：30％)。
LC/MS：182.0(M-Boc+H+)，226.0(M-56+H+)，304.0(M+Na+)
1H NMR(400MHz,CDCl3)δ6.75(s,1H),4.34～4.32(m,1H),4.10～4.02(m,2H),2.96～2.90(m,1H),2.08～2.02(m,2H),1.97～1.91(m,2H),1.63～1.55(m,2H),1.45(s,9H),1.42～1.28(m,3H)。
第五步(1-7的合成)
将化合物1-6(300mg,1.06mmol)溶于20mL甲醇，加入湿Pd(OH)2(50mg,5％)，在氢气氛围中搅拌16小时。反应液经过虑，滤液浓缩得产物1-7(无色油状物)，产物无需纯化直接进行下一步反应。
第六步(1-8的合成)
将化合物1-7(300mg,1.06mmol)溶于30mL四氢呋喃中，在0℃下，少量多次的加入LAH(80mg,2mmol)，加完后撤掉冰浴慢慢升到室温，室温反应4小时。反应液依次加入0.08mL水，0.08mL的15％氢氧化钠的水溶液和0.24mL水，加入少量的硫酸镁，搅拌10分钟后过滤，滤液旋干得到产物1-8，产物不经纯化直接进行下一步反应。
LC/MS:237.0(M-Boc+H+)，337.1(M+H+)
第七步(1-10的合成)
将化合物1-8(280mg,1.16mmol)溶于14mL的DMF中，在0℃下，少量多次的加入NaH(139mg,3.48mmol)，保持温度不变，搅拌30分钟后，慢慢滴加化合物1-9，加完后升到室温，室温反应10小时，反应液倒入30mL水中，并向其中加入10mL饱和氯化钠水溶液，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL×2)、饱和氯化钠溶液(10mL×2)洗涤，用无水硫酸钠干燥，过滤、浓缩得到粗品；粗品经柱纯化(石油醚：乙酸乙酯＝50:1)得到产物1-10(150mg，三步产率：42％)。
第八步(1-11的合成)
将化合物1-10(300mg)经制备HPLC分离得到外消旋体产物1-11(120mg,80％)，同时可以得到外消旋体产物1-12(100mg,67％)。
第九步(1-13的合成)
将化合物1-11(120mg)溶于4mL的乙酸乙酯，冰浴条件下滴加氯化氢乙酸乙酯溶液(4mL，4M),搅拌2小时，减压浓缩得到产物1-13(盐酸盐形式)，产物不经纯化直接进行下一步反应。
第十步(1-15的合成)
将化合物1-13(120mg,0.32mmol),化合物1-14(77mg,0.38mmol),HATU(182mg,0.48mmol)和DIEA(124mg,0.96mmol)溶于5mL的DMF中，室温下搅拌3小时，反应液倒入食盐水溶液中并用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL×2)、饱和氯化钠溶液(10mL×2)洗涤，旋干得到产品1-15(28mg，白色固体，产率：16％)。
1H NMR(400MHz,MeOD)δ8.01(s,1H),7.93～7.88(m,2H),7.75～7.73(m,1H),7.52～7.45(m,2H),7.41～7.36(m,1H),6.86(s,br,0.5H),6.41～6.38(m,0.5H),4.75～4.66(m,1H),4.48～4.33(m,1H),4.14～4.04(m,1H),3.77～3.72(m,1H),2.45～2.42(m,1H),2.30～225(m,1H),1.94(s,3H),1.87～1.83(m,4H),1.67～1.46(m,3H).
第十一步(1-16及2-1的合成)
将化合物外消旋体产物1-15(28mg)经由SFC分离(分离方法为：仪器型号:MG Ⅱ preparative SFC；分离柱:phenomenex Lux C2,250×30mmI.D.；流动相：A：CO2，B：乙醇(0.1％氨水)；梯度：B40％；流速：50mL/min；背压：100bar；柱温：38℃；检测紫外波长：220nm)得到光学纯化合物1-16(10mg,白色固体，产率：71％)和光学纯化合物2-1(10mg,白色固体，产率：71％)。1-16的绝对结构经单晶X-ray确证。
实施例3，4
Figure PCTCN2015073330-appb-000024
Figure PCTCN2015073330-appb-000025
第一步(3-1的合成)
将化合物1-12(100mg)溶于4mL的乙酸乙酯，冰浴条件下滴加氯化氢乙酸乙酯(4mL，4M),搅拌2小时，减压浓缩得到产物3-1(盐酸盐形式)，产物不经纯化直接进行下一步反应。
第二步(3-2的合成)
将化合物3-1(100mg,0.26mmol),化合物1-14(58mg,0.28mmol),HATU(150mg,0.39mmol)和DIEA(124mg,0.96mmol)溶于5mL的DMF中，室温下搅拌3小时，反应液倒入食盐水溶液中并用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL×2)、饱和氯化钠溶液洗(10mL×2)洗涤、干燥、过滤、浓缩得到粗品。粗品经制备HPLC分离得到化合物3-2(30mg，白色固体，产率：20％)。
1H NMR(400MHz,MeOD)δ＝8.14(br.s.,1H),8.00-7.61(m,4H),7.49(br.s.,0.5H),7.33(dd,J＝8.0,17.8Hz,1H),7.12(br.s.,1H),6.56(br.s.,0.5H),5.00-4.83(m,1H),4.48(br.s.,3H),3.88-3.62(m,1H),2.45-2.34(m,3H),2.05-1.56(m,5H),1.42-1.35(m,3H)
第三步(3-3及4-1的合成)
将化合物外消旋体产物3-2(30mg)经由SFC分离(分离方法为：仪器型号:MG Ⅱ preparative SFC；分离柱:ChiralPak IC,250×30mmI.D.；流动相：A：CO2，B：乙醇(0.1％氨水)；梯度:B 50％；流速：45mL/min；背压：100bar；柱温:38℃；检测波长:220nm)得到光学纯化合物3-3(12mg,白色固体，产率：80％)和光学纯化合物4-1(12mg,白色固体，产率：80％)。
(3-3和4-1为一对对映异构体，其相对结构为假设结构，绝对结构未经确认)。
实施例5,6
Figure PCTCN2015073330-appb-000026
Figure PCTCN2015073330-appb-000027
第一步(5-2的合成)
将化合物1-12(120mg,0.32mmol),化合物5-1(77mg,0.38mmol),HATU(182mg,0.48mmol)和DIEA(124mg,0.96mmol)溶于5mL的DMF中，室温下搅拌3小时，反应液倒入食盐水溶液中并用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL×2)、饱和氯化钠溶液(10mL×2)洗涤，用无水硫酸钠干燥，过滤，粗品经制备HPLC纯化得到产物5-2(24mg，白色固体，产率：14％)。
1H NMR(400MHz,METHANOL-d4)＝8.83(br.s.,2H),8.17-8.01(m,2H),7.49-7.33(m,3H),6.86(dd,J＝3.5,9.0Hz,1H),6.41(br.s.,1H),4.63(br.s.,1H),4.43(br.s.,1H),4.11(br.s,1H),3.79(br.s.,1H),2.52-2.48(m,2H),2.35-2.11(m,1H),2.01-1.95(m,3H),1.90-1.67(m,3H),1.63-1.43(m,1H),1.29-1.20(m,2H)
第二步(5-3及6-1的合成)
将化合物外消旋体产物5-2(24mg)经由SFC分离(分离方法为：仪器型号:MG Ⅱ preparative SFC；分离柱:ChiralPak IC,250×30mmI.D.；流动相：A：CO2，B：乙醇(0.1％氨水)；梯度:B 45％；流速：40mL/min；背压：100bar；柱温:38℃；检测波长:220nm)得到光学纯化合物5-3(8mg,白色固体)和6-1(8mg,白色固体)，两个化合物总产率：67％。
实施例7，8
Figure PCTCN2015073330-appb-000028
第一步(7-1的合成)
将化合物3-1(100mg,0.26mmol),化合物3-1(58mg,0.28mmol),HATU(150mg,0.39mmol)和DIEA(124mg,0.96mmol)溶于5mL的DMF中，室温下搅拌3小时，反应液倒入食盐水溶液中并用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL×2)、饱和氯化钠溶液洗(10mL×2)洗涤、干 燥、过滤、浓缩得到粗品。粗品经制备HPLC分离得到化合物7-1(30mg，白色固体，产率：20％)。
1H NMR(400MHz,MeOD)δ＝8.78(dd,J＝4.9,9.7Hz,2H),8.17(d,J＝8.2Hz,0.5H),8.11(d,J＝7.9Hz,0.5H),8.01(d,J＝3.1Hz,0.5H),7.75(br.s.,0.5H),7.57-7.50(m,0.5H),7.43(d,J＝8.2Hz,0.5H),7.38-7.31(m,2H),7.26(s,0.4H),7.13(s,0.6H),6.86(dd,J＝3.5,9.0Hz,0.5H),6.36(dd,J＝3.5,9.0Hz,0.5H),4.77-4.72(m,0.5H),4.21-4.11(m,1.5H),3.78(br.s.,1H),2.52(br.s.,1H),2.46(s,1.5H),2.35(s,1.5H),2.09-1.95(m,2H),1.91-1.37(m,7H)
第三步(7-2及8-1的合成)
将化合物外消旋体产物7-1(30mg)经由SFC分离(分离方法为：仪器型号:MG Ⅱ preparative SFC；分离柱:ChiralPak AS,250×30mmI.D.；流动相：A：CO2，B：乙醇(0.1％氨水)；梯度:B 15％；流速：60mL/min；背压：100bar；柱温:38℃；检测波长:220nm)得到光学纯化合物7-2(12mg,白色固体，产率：80％)和光学纯化合物8-1(12mg，白色固体，产率：80％)。
(7-2和8-1为一对对映异构体，其相对应结构为假设结构，绝对结构未经确认)
实施例9
Figure PCTCN2015073330-appb-000029
第一步(9-1的合成)
将化合物外消旋体产物1-11(280mg)经由SFC分离(分离方法为：仪器型号:MG Ⅱ preparative SFC(SFC-1)；分离柱:ChiralPak AD,250×30mmI.D.；流动相：A：CO2，B：乙醇(0.1％氨水)；梯度:B 25％；流速：60mL/min；背压：100bar；柱温:38℃；检测波长:220nm)得到光学纯化合物9-1(100mg,白色固体，产率：71％)。
第二步(9-2的合成)
将化合物9-1(120mg)溶于4mL的乙酸乙酯，冰浴条件下滴加氯化氢乙酸乙酯(4mL，4M),搅拌2小时，减压浓缩得到产物9-2(盐酸盐形式)，产物不经纯化直接进行下一步反应。
第三步(9-4的合成)
将化合物9-2(120mg,0.32mmol),化合物9-3(77mg,0.38mmol),HATU(182mg,0.48mmol)和DIEA(124mg,0.96mmol)溶于5mL的DMF中，室温下搅拌3小时，反应液倒入食盐水溶液中并用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL×2)、饱和氯化钠溶液(10mL×2)洗涤，用无水硫 酸钠干燥、过滤、浓缩得到粗品，粗品经制备HPLC纯化得到产物9-4(22mg，白色固体，产率：21％)。
1H NMR(400MHz,MeOD)δ＝8.20-7.98(m,3H),7.85-7.72(m,1H),7.71-7.50(m,2H),7.48-7.17(m,1H),7.03-6.75(m,1H),4.87-4.66(m,1H),4.54-4.36(m,1H),4.31-4.05(m,1H),3.86-3.55(m,1H),2.14(br.s.,1H),2.08-1.95(m,1H),1.88(td,J＝7.2,19.8Hz,2H),1.77(dd,J＝11.3,18.1Hz,2H),1.68-1.54(m,1H),1.53-1.32(m,2H)
实施例10
Figure PCTCN2015073330-appb-000030
第一步(10-2的合成)
将化合物9-2(120mg,0.32mmol),化合物10-1(77mg,0.38mmol),HATU(182mg,0.48mmol)和DIEA(124mg,0.96mmol)溶于5mL的DMF中，室温下搅拌3小时，反应液倒入食盐水溶液中并用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL×2)、饱和氯化钠溶液(10mL×2)洗涤，用无水硫酸钠干燥、过滤、浓缩得到粗品，粗品经制备HPLC纯化得到产物10-2(41mg，白色固体，产率：42％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.11-7.90(m,1H),7.81-7.56(m,2H),7.49-7.38(m,2H),7.35(d,J＝8.8Hz,1H),6.77(br.s.,1H),6.42(d,J＝6.0Hz,1H),4.97(br.s.,0.3H),4.82(br.s.,0.7H),4.40(br.s.,0.5H),4.14(br.s.,1H),4.06(br.s.,0.6H),4.00(d,J＝10.3Hz,0.5H),3.74(br.s.,0.4H),2.76(br.s.,1H),2.12(br.s.,0.5H),2.06-1.86(m,2.5H),1.85-1.67(m,2H),1.62(br.s.,1H),1.65-1.56(m,2H),1.45(br.s.,1H),1.12(br.s.,1H),0.67(d,J＝6.3Hz,1H)
实施例11
Figure PCTCN2015073330-appb-000031
实施例11参考实施例10的合成路线，其所用试剂10-1换为11-1：
Figure PCTCN2015073330-appb-000032
经制备HPLC纯化得到产物11-2(24mg，白色固体，产率：25％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.55(br.s.,1H),8.42(br.s.,0.5H),8.03-7.85(m,1H),7.80-7.63(m,2H),7.57(d,J＝7.5Hz,1H),7.41(d,J＝8.0Hz,1H),7.34-7.28(m,1.5H),7.23(d,J＝5.0Hz,1H),6.84-6.63(m,1H),4.50(t,J＝9.5Hz,1H),4.32(dd,J＝5.8,10.8Hz,1H),3.89(br.s.,2H),2.40(s,3H),2.20-1.93(m,4H),1.84(dt,J＝7.3,13.4Hz,1H),1.72(d,J＝8.5Hz,2H),1.52(d,J＝11.5Hz,1H),1.48-1.35(m,1H)
实施例12
Figure PCTCN2015073330-appb-000033
实施例12参考实施例10的合成路线，其所用试剂10-1换为12-1：
Figure PCTCN2015073330-appb-000034
经由制备HPLC纯化得到产物12-2(8mg，白色固体，产率：9％)。
1H NMR(400MHz,CHLOROFORM-d)＝7.96(d,J＝2.5Hz,1H),7.57-7.43(m,2H),7.42-7.30(m,3H),7.30-7.23(m,2.5H),7.20(s,1H),7.09(d,J＝8.0Hz,1H),6.26(dd,J＝3.5,9.0Hz,0.5H),4.94-4.71(m,1H),4.09-3.97(m,1H),3.96-3.79(m,1H),3.61(d,J＝7.0Hz,1H),2.40(s,1H),1.99-1.89(m,2.5H),1.86-1.59(m,2.5H),1.57-1.24(m,4H),1.23-1.09(m,1H),0.99-0.87(m,1H)
实施例13
Figure PCTCN2015073330-appb-000035
实施例13参考实施例10的合成路线，其所用试剂10-1换为13-1：
Figure PCTCN2015073330-appb-000036
经由制备HPLC纯化得到产物13-2(37mg，白色固体，产率：32％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.64(br.s.,2H),8.13-7.85(m,1H),7.85-7.53(m,2H),7.40-7.33(m,1.5H),7.40-7.29(m,0.5H),7.24(br.s.,1H),7.17(d,J＝7.5Hz,1H),6.76(dd,J＝3.5,9.0Hz,0.5H),6.27(dd,J＝3.5,9.0Hz,0.5H),4.95-4.74(m,1H),4.12-3.87(m,2H),3.64-3.44(m,1H),2.44(s,1H),2.11(d,J＝6.5Hz,1H),2.07-1.88(m,2H),1.88-1.72(m,2H),1.72-1.63(m,1H),1.62-1.42(m,3H),1.41-1.29(m,1H),1.29-0.98(m,1H)
实施例14
Figure PCTCN2015073330-appb-000037
实施例14参考实施例10的合成路线，其所用试剂10-1换为14-1：
Figure PCTCN2015073330-appb-000038
经由制备HPLC纯化得到产物14-2(19mg，淡黄色固体，产率：20％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.04-7.90(m,1H),7.89-7.63(m,2H),7.34-7.26(m,1H),7.23(d,J＝8.0Hz,1.5H),7.15-6.93(m,1.5H),6.80-6.76(m,0.5H),6.32-6.30(m,0.5H),4.99-4.90(m,1H),4.49-4.35(m,1H),4.19-4.03(m,1H)3.87-3.68(m,1H),2.01-1.86(m,6H),1.70-1.38(m,2.5H),1.36-1.05(m,0.5H)
实施例15
Figure PCTCN2015073330-appb-000039
实施例15参考实施例10的合成路线，其所用试剂10-1换为15-1：
Figure PCTCN2015073330-appb-000040
经由制备HPLC纯化得到产物15-2(17mg，淡黄色固体，产率：18％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.01(br.s.,1H),7.94-7.70(m,2H),7.64(d,J＝8.0Hz,1H),7.42-7.23(m,2H),6.77(d,J＝6.3Hz,1H),6.59-6.24(m,1H),4.99(d,J＝17.1Hz,1H),4.52-4.32(m,1H),4.25-4.04(m,1H),3.92-3.44(m,1H),2.53-2.10(m,1H),2.09-1.76(m,4H),1.68(br.s.,1H),1.61-1.38(m,2H),1.37-0.62(m,1H)
实施例16
Figure PCTCN2015073330-appb-000041
实施例16参考实施例10的合成路线，其所用试剂10-1换为16-1：
Figure PCTCN2015073330-appb-000042
经由制备HPLC纯化得到产物16-2(6.5mg，白色固体，产率：1.5％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.30-7.72(m,2H),7.71-7.52(m,1H),7.52-7.37(m,1H),7.35-7.14(m,3H),6.78-6.38(m,1H),4.94-4.66(m,1H),4.53-4.21(m,1H),4.08(br.s.,1H),3.83-3.58(m,1H),2.53-2.40(m,0.5H),1.90-1.82(m,1.5H),1.81-1.45(m,5.5H),1.27(br.s.,0.5H),1.0-0.91(m,1H)
实施例17
Figure PCTCN2015073330-appb-000043
实施例17参考实施例10的合成路线，其所用试剂10-1换为17-1：
Figure PCTCN2015073330-appb-000044
经由制备HPLC 纯化得到产物17-2(4.3mg，白色固体，产率：3.5％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.76(d,J＝4.5Hz,1.5H),8.39-8.12(m,1H),7.96(br.s.,1H),7.34(t,J＝6.7Hz,0.5H),7.30-7.26(m,1H),7.19(br.s.,1H),7.16-6.84(m,2H),6.74(d,J＝5.8Hz,0.5H),6.29(br.s.,0.5H),5.08-4.83(m,1H),4.48-4.15(m,1.5H),4.14-4.04(m,0.5H),3.89(br.s.,0.5H),3.78-3.63(m,0.5H),2.27-2.06(m,2H),2.03-1.93(m,1H),1.92-1.81(m,1.5H),1.79-1.59(m,2H),1.57-1.41(m,1.5H),1.25(br.s.,1H)
实施例18
Figure PCTCN2015073330-appb-000045
实施例18参考实施例10的合成路线，其所用试剂10-1换为18-1：
Figure PCTCN2015073330-appb-000046
经由制备HPLC纯化得到产物18-2(4.3mg，白色固体，产率：9.5％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.94-8.74(m,1H),8.65(br.s.,1H),8.39-8.26(m,1.5H),7.70-7.42(m,0.5H),7.36-7.25(m,1H),7.14(br.s.,1H),6.92-6.8(m,0.5H),6.79(d,J＝19.3Hz,1H),5.98(br.s.,0.5H),5.15-4.97(m,1H),4.70-4.38(m,1H),4.26-4.07(m,1.6H),3.80(br.s.,0.4H),2.52-2.32(m,1H),2.29-2.18(m,2H),2.11-1.92(m,1H),1.91-1.81(m,2H),1.62-1.35(m,3H)
实施例19
Figure PCTCN2015073330-appb-000047
实施例19参考实施例10的合成路线，其所用试剂10-1换为19-1：
Figure PCTCN2015073330-appb-000048
经由制备HPLC纯化得到产物19-2(29mg，白色固体，产率：7％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.28-7.90(m,1H),7.85-7.69(m,1H),7.64-7.47(m,1.5H),7.46-7.38(m,1H),7.36-7.28(m,1H),7.25-7.21(m,1.5H),6.76(dd,J＝3.3,9.0Hz,0.5H),6.36(dd,J＝3.4,8.9Hz,0.5H),4.85-4.69(m,1H),4.57-4.20(m,1H),4.06(d,J＝4.5Hz,1H),3.77-3.57(m,1H),2.24-1.99(m,1H),1.97-1.78(m,2.5H),1.76-1.52(m,4H),1.46(d,J＝8.0Hz,1.5H)
实施例20
Figure PCTCN2015073330-appb-000049
实施例20参考实施例10的合成路线，其所用试剂10-1换为20-1：
Figure PCTCN2015073330-appb-000050
经由制备HPLC纯化得到产物20-2(51mg，白色固体，产率：55％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.08-7.93(m,1H),7.87-7.60(m,2H),7.56-7.42(m,1H),7.34-7.24(m,2H),7.22-7.16(m,1H),6.79(d,J＝5.3Hz,0.4H),6.42-6.27(m,1.6H),4.97-4.73(m,1H),4.50-3.91(m,2H),3.77(d,J＝6.0Hz,0.6H),3.58(br.s.,0.4H),2.43(br.s.,1H),2.26-2.03(m,1H),2.00-1.88(m,3H),1.85-1.65(m,3H),1.59(d,J＝6.0Hz,2H),1.51-1.37(m,2H)
实施例21
Figure PCTCN2015073330-appb-000051
第一步(21-2的合成)
将化合物9-2(50mg,0.18mmol)溶于2mL二氯甲烷中，加入三乙胺(56mg,0.55mmol)和化合物21-1(48mg,0.28mmol)。室温下搅拌2小时后，旋干去除溶剂得到粗品；粗品经制备HPLC纯化得到产物21-2(31mg，黄色固体，产率：9％)。
1H NMR(400MHz,CHLOROFORM-d)＝7.96(br.s.,1H),7.50-7.18(m,3H),7.16-6.94(m,2H),6.78-6.19(m,1H),5.14-4.80(m,1H),4.69-4.23(m,1.5H),4.20-3.86(m,1.5H),2.39(br.s.,1H),2.28-2.09(m, 3H),2.09-1.92(m,3H),1.85(br.s.,1H),1.75(br.s.,1H),1.64(s,1H),1.52(br.s.,1H),1.44-1.08(m,1H)
实施例22
Figure PCTCN2015073330-appb-000052
将化合物9-2(50mg,0.18mmol)溶于2mL二氯甲烷中，加入三乙胺(56mg,0.55mmol)和化合物22-1(53mg,0.28mmol)。室温下搅拌2小时后，旋干去除溶剂得到粗品。粗品经制备HPLC纯化得到产物22-2(60mg，白色固体，产率：87％)。
1H NMR(400MHz,CHLOROFORM-d)＝7.96(d,J＝2.8Hz,1H),7.78-7.54(m,2H),7.34-7.19(m,3H),6.63(dd,J＝3.4,8.9Hz,1H),4.48-4.24(m,3H),4.21-4.07(m,1H),2.35(s,3H),2.03(d,J＝6.0Hz,1H),1.97-1.69(m,4H),1.68-1.60(m,2.6H),1.54-1.45(m,1.5H)
实施例23
Figure PCTCN2015073330-appb-000053
Figure PCTCN2015073330-appb-000054
第一步(23-1的合成)
将化合物1-7(48g)溶于50mL的乙酸乙酯，冰浴条件下滴加氯化氢乙酸乙酯(150mL，4M),搅拌2小时，减压浓缩得到产物23-1(盐酸盐形式)，产物不经纯化直接进行下一步反应。
第二步(23-2的合成)
将化合物23-1(33g,150mmol)溶于300mL二氯甲烷，冰浴条件下依次加入TEA(62.7mL,450mmol)和CbzCl(21.3mL,150mmol)。半小时后反应液升到室温，搅拌过夜。将反应液倒入水中用二氯甲烷(300mL×3)萃取，合并有机相，依次用水(100mL×2)、饱和氯化钠溶液(100mL×2)洗涤，用无水硫酸钠干燥、过滤、浓缩得到粗品，粗品经由柱纯化(石油醚：乙酸乙酯＝50:1)纯化得到产物23-2(35g，黄色液体，冷却放置后有固体析出，产率：74％)。
第三步(23-3的合成)
将化合物23-2(35g)经制备HPLC分离得到产物23-3(22g,62.8％)。
第四步(23-4的合成)
将化合物23-3(5g,15.75mmol)溶于100mL甲醇，加入湿Pd(OH)2(500mg,5％，)，在氢气氛围中搅拌16小时。反应液经过滤，浓缩得产物产物23-4(2.7g，94％)(无色油状物)，产物无需纯化直接进行下一步反应。
第五步(23-5的合成)
将化合物23-4(8g,43.7mmol),化合物5-1(11.2g,52.4mmol),HATU(24.9g,65.6mmol)和DIEA(16.9g,131.1mmol)溶于200mL的THF中，室温下搅拌16小时，反应液倒入食盐水溶液中并用乙酸乙酯(100mL×3)萃取，合并有机相，依次用水(50mL×2)、饱和氯化钠溶液(50mL×2)洗涤，用无水硫酸钠干燥、过滤、滤液减压浓缩得到粗品，粗品经柱(石油醚：乙酸乙酯＝1:2)纯化得到产物23-5(13g，淡黄色固体，产率：78％)。
第六步(23-6的合成)
将化合物23-5(950mg，2.5mmol)溶于25mL THF中，冰乙醇浴条件下加入LAH(100mg，2.5mmol)。反应液于当前温度下搅拌1小时。加入20mL无水THF稀释，依次滴加0.1mL水、0.1mL15％的氢氧化钠溶液和0.3mL水淬灭反应，再加入无水硫酸钠干燥，过滤，滤液减压浓缩，得产物23-6(800mg，淡黄固体，产率：96％)，产物不经纯化直接进行下一步反应。
第七步(23-8的合成)
将化合物23-6(80mg，0.237mmol)溶于5mL DMF中，冰浴条件下加入NaH(38mg，60％，0.984mmol)。反应液于当前温度下搅拌0.5小时后加入化合物23-7(46mg，0.474mmol)。反应液室温下搅拌16小时，倒入食盐水溶液中并用乙酸乙酯(20mL×3)萃取，合并有机相，依次用水(10mL×2)、饱和氯化钠溶液(10mL×2)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，经制备TLC板纯化得到产物23-8(23.24mg，白色固体，产率：23.7％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.75(br.s.,2H),8.22-8.06(m,2H),7.58-7.46(m,1H),7.28(d,J＝8.0Hz,1H),7.23-7.05(m,2H),6.88-6.76(m,1H),6.34(br.s.,1H),5.01(d,J＝6.5Hz,1H),4.65-4.37(m,1H),4.16(d,J＝6.3Hz,1H),3.94-3.75(m,1H),2.41(s,1H),2.21(d,J＝7.0Hz,1H),1.96-1.77(m,5H),1.54-1.45(m,2H),1.33-0.77(m,3H)
实施例24
Figure PCTCN2015073330-appb-000055
第一步(24-2的合成)
将化合物23-6(80mg，0.237mmol)溶于5mL DMF中，冰浴条件下加入NaH(38mg，60％，0.984mmol)。反应液于当前温度下搅拌0.5小时后加入化合物24-1(53mg，0.474mmol)。反应液室温下搅拌16小时，倒入食盐水溶液中并用乙酸乙酯(20mL×3)萃取，合并有机相，依次用水(10mL×2)、饱和氯化钠溶液(10mL×2)洗涤，用无水硫酸钠干燥、过滤、滤液减压浓缩得到粗品，经制备TLC板纯化得到产物24-2(17.6mg，白色固体，产率：19％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.75(br.s.,2H),8.20-8.07(m,1H),7.98-7.88(m,1H),7.41-7.28(m,1H),7.23-7.08(m,3H),6.71-6.25(m,1H),5.01(d,J＝6.3Hz,1H),4.64-4.30(m,1H),4.12(d,J＝6.8Hz,1H),3.92-3.75(m,1H),2.41(s,1.5H),2.29-2.16(m,4H),2.01-1.75(m,6H),1.56-1.44(m, 1.5H),1.30-1.21(m,1.5H),0.98(d,J＝6.8Hz,0.5H)
实施例25
Figure PCTCN2015073330-appb-000056
第一步(25-2的合成)
实施例25参考实施例24的合成路线，其所用试剂24-1换为25-1：
Figure PCTCN2015073330-appb-000057
经由TLC板纯化得到产物25-2(33.72mg，白色固体，产率：22％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.74(br.s.,2H),8.16(dd,J＝7.7,18.2Hz,1H),7.89(br.s.,1H),7.37-7.25(m,2H),7.24-7.12(m,2H),5.01(br.s.,1H),4.84-4.36(m,1H),4.21(br.s.,1H),3.80(d,J＝19.8Hz,1H),2.42(br.s.,2H),2.09(br.s.,2H),1.86-1.8(m,3H),1.68-1.60(m,1H),1.60-1.43(m,2H),1.35-1.13(m,2H),
实施例26
Figure PCTCN2015073330-appb-000058
第一步(26-1的合成)
将化合物1-7(4.0g,14.13mmol)溶于30mL四氢呋喃中，在0℃下，慢慢滴加LDA(14.4mL,28.26mmol)，在0℃下，搅拌1小时。温度保持在0℃，将化合物NFSI(5.3g,16.96mmol)加入反应中，加完之后，温度慢慢升到室温，室温下将反应搅拌过夜。将反应液倒入氯化胺水溶液(30mL)中，减压浓缩，得粗品加入20mL饱和氯化钠水溶液，用乙酸乙酯(40mL×3)萃取，合并有机相，依次用水(40mL×2)、饱和氯化钠溶液(40mL×2)洗涤，用无水硫酸钠干燥、过滤、浓缩得到粗品，经由柱层析(石油醚：乙酸乙酯＝60:1～20:1)纯化得到产物26-1(1.5g，黄色油状液体，产率：40％)
LC/MS：245.9(M-56+H+)，323.9(M+Na+)
第二步(26-2的合成)
将化合物26-1(1.8g,6.0mmol)溶于30mL四氢呋喃中，在0℃下，少量多次的加入LAH(500mg,13.15mmol)，加完后升到室温，室温反应过夜。反应液中依次加入0.5mL水，0.5mL的15％氢氧化钠的水溶液和1.5mL水，加入少量的硫酸镁，搅拌10分钟后，过滤，滤液旋干得到产物26-2，产物不经纯化直接进行下一步反应。
第三步(26-3的合成)
将化合物26-2(1.5g,5.88mmol)溶于20mL的DMF中，在0℃下，少量多次的加入NaH(800mg,20.0mmol)，保持温度不变，搅拌30分钟后，滴加化合物1-9(676mg,5.88mmol)，加完后升到室温，室温反应10小时，反应液倒入30mL水中，并向其中加入30mL饱和氯化钠水溶液，用乙酸乙酯(30mL×3)萃取，合并有机相，依次用水(30mL×2)、饱和氯化钠溶液(30mL×2)洗涤，用无水硫酸钠干燥、过滤、经柱层析(石油醚：乙酸乙酯＝50:1)纯化得到产物26-3(500mg，三步产率：25％)。
LC/MS：254.9(M-56+H+)，254.9(M-Boc+H+),354.9(M+H+)
第四步(26-4的合成)
将化合物26-3(150mg)溶于4mL的乙酸乙酯，冰浴条件下滴加氯化氢乙酸乙酯(4mL，4M),搅拌2小时，减压浓缩得到产物26-4(盐酸盐形式)，产物不经纯化直接进行下一步反应。
第五步(26-5的合成)
将化合物26-4(120mg,0.37mmol),化合物5-1(94mg,0.38mmol),HATU(209mg,0.55mmol)和DIEA(143mg,0.96mmol)溶于5mL的DMF中，室温下搅拌3小时，反应液倒入食盐水溶液中并用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL×2)、饱和氯化钠溶液(10mL×2)洗涤，用无水硫酸钠干燥、过滤、浓缩得到粗品，经由制备HPLC纯化得到产物26-5(14mg，产率：7.8％)。
1H NMR(400MHz,METHANOL-d4)＝8.91-8.78(m,2H),8.21-8.00(m,2H),7.59-7.40(m,2H),7.38-7.17(m,2H),6.92(dd,J＝3.8,9.3Hz,1H),5.17-5.01(m,1H),4.81-4.58(m,2H),4.34(br.s.,1H),2.64-2.36(m,3H),2.29-2.09(m,2H),2.01-1.67(m,6H)
实施例27
Figure PCTCN2015073330-appb-000059
Figure PCTCN2015073330-appb-000060
第一步(27-1的合成)
将化合物23-5(190mg)溶于10mL的THF，加入10mL 0.48％的LiOH水溶液,加热回流3小时，滴加稀盐酸至弱酸性，用乙酸乙酯萃取，有机相减压浓缩得到产物27-1(160mg,94％)，产物不经纯化直接进行下一步反应。
第二步(27-3的合成)
将化合物27-1(105.4mg,0.3mmol),化合物23-2(65.5mg,0.6mmol),HATU(171mg,0.45mmol)和DIEA(0.157mL,0.9mmol)溶于5mL的THF中，室温下搅拌16小时，反应液倒入食盐水溶液中并用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(5mL×2)、饱和氯化钠溶液(5mL×2)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，经由制备TLC板纯化得到产物100mg的27-3(100mg，淡黄色固体)。
1H NMR(400MHz,CHLOROFORM-d)＝10.63(br.s.,0.5H),9.23(br.s.,1H),8.76(br.s.,0.5H),8.38(br.s.,1H),8.20(br.s.,1H),7.35(d,J＝8.0Hz,1.5H),7.14-6.92(m,5H),6.76-6.54(m,1.5H),5.36-5.22(m,1H),3.99(br.s.,0.5H),3.83(br.s.,0.5H),2.80(s,5H),2.46-2.42(m,3H),2.23(d,J＝7.5Hz,1H),2.11-1.96(m,3H)
实施例28
Figure PCTCN2015073330-appb-000061
第一步(28-1的合成)
将化合物27-3(88mg，0.2mmol)和三苯基膦(52.4mg,0.2mmol)溶于25mL THF中，氮气保护下用注射器加入2mL DIAD(40.4mg，0.2mmol)的THF溶液。反应液加热回流3小时，倒入食盐水溶液中并用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL×2)、饱和氯化钠溶液(10mL×2)洗涤，用无水硫酸钠干燥、过滤、滤液浓缩得到粗品，粗品经由制备TLC板纯化得产物28-1(11.7mg，白色固体，产率：13.37％)。
1H NMR(400MHz,CHLOROFORM-d)＝10.51(br.s.,0.4H),10.03(br.s.,0.1H),9.15(s,1H),8.74(br.s.,1H),8.39(br.s.,1H),8.26-8.10(m,1H),7.41-7.30(m,1.5H),7.05(br.s.,1.5H),6.92(d,J＝8.5Hz,1.5H),6.74(br.s.,1H),5.24(br.s.,1H),4.99-4.81(m,2H),4.01(br.s.,0.6H),3.78(br.s.,0.4H),2.78(br.s.,1H),2.43(br.s.,4H),2.25(br.s.,1H),2.11-1.93(m,3H),1.81(br.s.,1H)
实施例29
Figure PCTCN2015073330-appb-000062
第一步(29-1的合成)
将化合物23-5(5g)经由SFC分离(分离方法为：仪器型号:MG Ⅱ preparative SFC(SFC-1)；分离柱:ChiralPak OD,250×30mmI.D.；流动相：A：CO2，B：乙醇(0.1％氨水)；梯度:B 30％；流速：55mL/min；背压：100bar；柱温:38℃；检测波长:220nm)得到手性纯化合物29-1(2g,白色固体，产率：80％)。
第二步(29-2的合成)
将化合物29-1(1.3g,3.426mmol)溶于25mL THF中，冰乙醇浴条件下慢慢加入LAH(100mg，2.5mmol)。反应液于当前温度下搅拌1小时。加入20mL无水THF稀释，依次滴加0.1mL水、0.1mL 15％的氢氧化钠溶液和0.3mL水淬灭反应，再加入无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物29-2(1.1g，淡黄色固体，产率：96％)，产物不经纯化直接进行下一步反应。
第三步(29-3的合成)
将化合物29-2(200mg,0.6mmol)溶于10mL DCM中，依次加入三乙胺(152mg，1.5mmol)和MsCl(103mg，0.9mmol)。反应液室温下搅拌2小时，倒入食盐水溶液中并用二氯甲烷(10mL×3)萃取，合并有机相，依次用水(10mL×2)、饱和氯化钠溶液(10mL×2)洗涤，用无水硫酸钠干燥、过滤、，滤液减压浓缩得产物29-3(244mg，产率：98％)，产物不经纯化直接进行下一步反应。
第四步(29-5的合成)
将化合物29-3(98mg,0.237mmol)和化合物29-4(53mg,0.474mmol)溶于5mL DMF中，室温下加入碳酸铯(196mg,0.6mmol)。反应液80℃下搅拌16小时，倒入食盐水溶液中并用乙酸乙酯(20mL×3)萃取，合并有机相，依次用水(10mL×2)、饱和氯化钠溶液(10mL×2)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，经由制备HPLC纯化得产物29-5(5.45mg，白色固体，产率：5.3％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.76(d,J＝4.3Hz,1H),8.70(br.s.,1H),8.16(d,J＝8.0Hz,0.5H),8.10(d,J＝8.0Hz,0.5H),7.31(d,J＝8.0Hz,0.5H),7.17(d,J＝7.3Hz,1.5H),7.10(br.s.,1H),6.98-6.88(m,3H),6.57(br.s.,1H),5.00(d,J＝7.3Hz,0.6H),4.92(br.s.,0.4H),4.26(br.s.,0.6H),4.04(br.s.,0.4H),3.84(br.s.,1.5H),3.66(dd,J＝6.0,8.5Hz,0.5H),2.41(s,2H),2.17(br.s.,0.5H),1.98-1.73(m,7H),1.52(d,J＝8.5Hz,1.5H),1.25(br.s.,1H)
实施例30
Figure PCTCN2015073330-appb-000063
第一步(30-2的合成)
将化合物29-3(98mg,0.237mmol)和化合物30-1(63mg,0.474mmol)溶于5mL DMF中，室温下加入碳酸铯(196mg,0.6mmol)。反应液80℃下搅拌16小时，倒入食盐水溶液中并用乙酸乙酯(20mL×3)萃取，合并有机相，依次用水(10mL×2)、饱和氯化钠溶液(10mL×2)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，经由制备HPLC纯化得产物30-2(19.63mg，白色固体，产率：18.4％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.75(d,J＝3.8Hz,1H),8.70(br.s.,1H),8.17(d,J＝8.0Hz,0.6H),8.12(d,J＝7.8Hz,0.4H),7.31(d,J＝7.8Hz,0.5H),7.21(d,J＝8.0Hz,0.5H),7.18-7.05(m,2.5H),6.91-6.82(m,1H),6.79(br.s.,1.5H),5.01(d,J＝6.5Hz,0.5H),4.92(br.s.,0.5H),4.32(br.s.,0.6H),4.12(br.s.,0.4H),4.03-3.68(m,2H),2.41(s,2H),2.21(br.s.,1H),2.02(d,J＝11.5Hz,2H),1.94-1.78(m,4H),1.61-1.48(m,2H),1.25(br.s.,1H)
实施例31
Figure PCTCN2015073330-appb-000064
实施例31参考实施例30的合成路线，其所用试剂30-1换为31-1：
Figure PCTCN2015073330-appb-000065
经制备HPLC纯化得到产物31-2(5.79mg，白色固体，产率：5.9％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.84-8.61(m,2H),8.47-8.26(m,1H),8.18(d,J＝8.0Hz,1H),8.12-8.06(m,0.5H),8.02(br.s.,0.5H),7.37(dd,J＝1.5,8.5Hz,0.5H),7.33-7.27(m,1.5H),7.22-7.04(m,3H),5.02(d,J＝6.5Hz,1H),4.40(br.s.,0.5H),4.17-4.06(m,0.5H),3.92(br.s.,1H),3.80(br.s.,0.5H),3.74(dd,J＝5.5,8.5Hz,0.5H),2.41(s,1.5H),2.26-2.21(m,0.5H),1.99-1.73(m,6H),1.67(br.s.,1.5H),1.51(d,J＝9.5Hz,1.5H),0.98-0.79(m,1H)
实施例32
Figure PCTCN2015073330-appb-000066
实施例31参考实施例30的合成路线，其所用试剂30-1换为32-1：
Figure PCTCN2015073330-appb-000067
经制备HPLC纯化得到产物32-2(7.32mg，白色固体，产率：7.46％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.75(d,J＝4.5Hz,2H),8.26(d,J＝6.8Hz,1H),7.87(br.s.,2H),7.36(d,J＝8.0Hz,1H),7.20(br.s.,2H),6.60(br.s.,2H),4.75(d,J＝5.5Hz,1H),4.29(br.s.,1H),3.90(br.s.,2H),2.45(s,3.5H),2.07(br.s.,3.5H),1.77(br.s.,1H),1.63(br.s.,2H),1.52(d,J＝12.8Hz,1H),1.34(br.s.,1H)
实施例33
Figure PCTCN2015073330-appb-000068
实施例33参考实施例10的合成路线，其所用试剂10-1换为33-1：
Figure PCTCN2015073330-appb-000069
经由制备HPLC纯化得到产物33-2(25mg，淡黄色固体，产率：29％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.87-8.68(m,1H),8.68-8.48(m,1H),8.30-7.89(m,2H),7.58-7.40(m,1H),7.34(s,1H),7.33-7.22(m,2H),7.18(d,J＝7.8Hz,1H),6.77(dd,J＝3.0,8.8Hz,0.4H), 6.30(dd,J＝3.1,8.9Hz,0.6H),4.95-4.71(m,1H),4.07-3.92(m,1H),3.71-3.49(m,1H),3.38(br.s.,1H),2.44(s,1H),2.29-2.04(m,1H),2.04-1.93(m,2H),1.93-1.70(m,2H),1.66-1.52(m,1H),1.59-1.20(m,5H)
实施例34
Figure PCTCN2015073330-appb-000070
实施例34参考实施例10的合成路线，其所用试剂10-1换为34-1：
Figure PCTCN2015073330-appb-000071
经由制备HPLC纯化得到产物34-2(30mg，淡黄色固体，产率：34.5％)。
1H NMR(400MHz,CHLOROFORM-d)＝9.31-9.12(m,1H),9.06-8.74(m,2H),8.07-7.88(m,1H),7.43-7.10(m,4H),6.78(dd,J＝3.4,8.9Hz,0.4H),6.28(dd,J＝3.4,8.9Hz,0.6H),4.98-4.73(m,1H),4.41(br.s.,1H),4.13-3.85(m,1H),3.69-3.44(m,1H),2.45(s,1H),2.33-2.06(m,1H),2.04-1.93(m,3H),1.93-1.73(m,2H),1.68(br.s.,1H),1.60-1.51(m,1H),1.50-1.23(m,3H)
实施例35
Figure PCTCN2015073330-appb-000072
实施例35参考实施例10的合成路线，其所用试剂10-1换为35-1：
Figure PCTCN2015073330-appb-000073
经由制备HPLC纯化得到产物35-2(4.47mg，白色固体，产率：4.6％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.80(br.s.,2H),8.52-8.25(m,1H),7.86-7.63(m,2H),7.31(t,J＝8.2Hz,1H),7.26-7.18(m,2H),6.75(dd,J＝3.5,9.0Hz,0.5H),6.26(br.s.,0.5H),5.02(br.s.,1H),4.65-4.38(m,1H),4.28-3.98(m,1H),3.78(br.s.,1H),2.27-2.10(m,1H),2.06-1.79(m,3H),1.59-1.56(m,4H),1.25(br.s.,1H)
实施例36
Figure PCTCN2015073330-appb-000074
实施例36参考实施例10的合成路线，其所用试剂10-1换为36-1：
Figure PCTCN2015073330-appb-000075
经由制备HPLC纯化得到产物36-2(25.32mg，白色固体，产率：34.4％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.06-7.79(m,1H),7.38-7.27(m,1H),7.12-7.02(m,1H),6.95-6.77(m,2H),6.29(br.s.,1H),5.09-4.93(m,1H),4.54(dd,J＝7.8,10.5Hz,0.5H),4.34(dd,J＝7.7,10.4Hz,0.5H),4.22-4.14(m,0.5H),4.06(br.s.,1H),3.73(br.s.,0.5H),2.44-2.19(m,3H),2.19-2.05(m,3H),2.04-1.87(m,3H),1.87-1.60(m,3H),1.60-0.90(m,3H)
实施例37
Figure PCTCN2015073330-appb-000076
实施例37参考实施例10的合成路线，其所用试剂10-1换为37-1：
Figure PCTCN2015073330-appb-000077
经由制备HPLC纯化得到产物37-2(29.63mg，米黄色固体，产率：33.9％)。
1H NMR(400MHz,CHLOROFORM-d)＝8.30-7.93(m,1H),7.92-7.78(m,1H),7.77-7.54(m,1H),7.46-6.95(m,4H),6.79(dd,J＝3.5,9.0Hz,0.5H),6.33(d,J＝6.3Hz,0.5H),5.11-4.76(m,1H),4.69-4.24(m,1H),4.16-3.97(m,1H),3.89-3.55(m,1H),2.42(s,1H),2.27-1.94(m,3H),1.92-1.70(m,3H),1.63(br.s.,1H),1.56-1.39(m,2H),1.27-0.80(m,2H)
实验例1：OX1/2R体外测试
实验目的：
通过FLIPR检测细胞内钙信号变化,以化合物的IC50值为指标，来评价化合物对OX1和OX2GPCR受体的抑制作用。
实验材料:
细胞系：HEK293-OX1和OX2稳转细胞株
HEK293-OX1细胞培养基(DMEM,Invitrogen#11960-044,10％血清Gibco#10099141,L-Glutamine1×，Gibco#25030，丙酮酸钠1×,Gibco#11360，Geneticin 300μg/ml，Gibco#10131)
HEK293-OX2细胞培养基(DMEM,Invitrogen#11960-044,10％血清Gibco#10099141,L-Glutamine1×，Gibco#25030，丙酮酸钠1×,Gibco#11360，Geneticin 300μg/ml，Gibco#10131,Blasticin 2μg/ml,Invitrogen#R21001)
胰酶(Invitrogen,#25200-072)
DPBS(Hyclone,#SH30028.01B)
Fluo-4AM，Invitrogen#F14202
F-127，Invitrogen#P3000MP
Probenecid，Sigma#P8761
384细胞板，Greiner#781946
384化合物板，Greiner#781280
CO2培养箱，Thermo#371
离心机，Eppendorf#5810R
Vi-cell细胞计数仪，Beckman Coulter
POD 810 Plate Assembler全自动微孔板预处理系统
Labcyte FLIPR，Molecular Device。
实验步骤和方法：
a)细胞接种(HEK293-OX1和HEK293-OX2细胞)
1)37℃水浴预热培养基、胰酶、DPBS。吸掉细胞培养的培养基，用10mLD PBS清洗；
2)加入预热过的胰酶到培养瓶中，旋转培养瓶使胰酶均匀覆盖培养瓶,放到37℃、5％CO2培养箱中消化1-2分钟；
3)每个T150用10-15mL培养基垂悬细胞，800rpm离心5分钟，用10mL培养基重悬细胞，吸取1mL细胞重悬液，用Vi-cell计数；
4)用培养基稀释OX1细胞到5×105/mL,OX2细胞到4×105/mL，用排枪将稀释好的细胞加入到384板(Greiner.781946)(50μL/孔,OX1细胞25000cells/孔，OX2细胞20000cells/孔)。将细胞板放置于37℃、5％CO2培养箱过夜。
b)化合物加样:
1)用DMSO将化合物稀释成20mM，3倍稀释，8个梯度，双复孔，用Echo声波移液设备(Echo liquid handler)加到化合物板中。然后再加20μL缓冲液，保证DMSO终浓度为0.1％；
c)FLIPR实验：
1)用真空泵洗掉384板中的细胞培养基，加入30μL Fluo4AM荧光染料，37℃、5％CO2培养箱孵育1小时，室温再平衡10分钟。
2)EC50测试：在冰上手动稀释Orexin A,3倍稀释，8个梯度，双复孔。再准备DMSO板，使DMSO浓度为0.5％。分别把细胞板、OrexinA板，以及DMSO板放入FLIPR中，读取荧光值。
3)通过Orexin A的EC50值，计算出EC70值，准备5×EC70溶液，用排枪加到384化合物板中，放到冰上保存。
4)在FLIPR中，依次放入化合物板，5×EC70板，细胞板，FLIPR枪头，运行程序，读取荧光值。
d)分析数据:用Prism5.0来分析数据，计算化合物的IC50值。
实验结果见表1：
表1 FLIPR检测IC50测试结果
Figure PCTCN2015073330-appb-000078
Figure PCTCN2015073330-appb-000079
结论：从表1可以看出，本发明的示例化合物对OX1和OX2GPCR受体具有明显的抑制作用，其中部分示例化合物较阳性对照物具有更加优异的活性。并且研究发现对于部分示例化合物，立体构型的不同对OX1和OX2 GPCR受体的抑制作用影响较大。

Claims (22)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2015073330-appb-100001
    其中，
    A选自任选被取代的3～12元环烃基或杂环烃基或环烃杂基，所述环烃基或杂环烃基或环烃杂基可以单环、联环、螺环、并环或稠环形式存在，取代基选自F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的；
    B选自C(＝O)、S(＝O)或S(＝O)2；
    X选自任选被取代的(CH2)r1(U)r2(CH2)r3，取代基选自F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的；
    r1、r3分别独立地选自0、1或2，r2选自0或1，r1、r2和r3同时为0表示X为仅起连接作用的单键；U选自卤代或羟代或胺代或未被取代的CH2、C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基的数目在化学上可稳定实现的前提下是任意的；
    D、L分别独立地选自任选被取代的CH2，取代基选自F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的；
    T选自C或者仅起连接作用的单键，当T选自单键时R2、R3不存在；
    M选自C(Y)(R1a)，此时Q选自C(R1b)(R1c)，或者，M选自C(R1b)(R1c)，此时Q选自C(Y)(R1a)；
    Y选自-(CH2)r4(G)r5(CH2)r6-Y1，Y1选自-O-E或式(Y2)所示结构，
    Figure PCTCN2015073330-appb-100002
    G选自卤代或羟代或胺代或未被取代的CH2、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、S(＝O)、S(＝O)2、C(＝O)或C(＝S)，取代基的数目在化学上可稳定实现的前提下是任意的；
    r4、r6分别独立地选自0、1或2，r5选自0或1，r4、r5和r6同时为0表示相应结构为仅起连接作用的单键；
    E选自任选被取代的5～6元环烃基或杂环基，取代基选自F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的；
    Y2a、Y2b、Y2c、Y2d、Y2e、Y2f、Y2g选自任选被取代的CH2、CH、NH、或选自N、O、S、S(＝O)、S(＝O)2、C(＝O)或C(＝S),且Y2a、Y2b、Y2c、Y2d、Y2e、Y2f、Y2g至少一项为任选被取代的CH、CH2或NH，取代基选自F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的；
    Figure PCTCN2015073330-appb-100003
    代表单键或双键；
    R1a、R1b、R1c、R2、R3分别独立地选自H、F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的，或者任选地R2、R3连接成环；和
    该化合物或其药学上可接受的盐包含一个或多个手性中心。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中A选自式(A1)或(A2)所示结构单元：
    Figure PCTCN2015073330-appb-100004
    其中，
    Z1、Z2、Z3、Z4、Z5分别独立地选自卤代或羟代或胺代或未被取代的CH或CH2、或C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH或NH、C＝N、N、O、S、S(＝O)、S(＝O)2、C(＝O)O、C(＝O)或C(＝S)，取代基的数目在化学上可稳定实现的前提下是任意的；
    V1、V2、V3、V4、V5分别独立地选自卤代或羟代或胺代或未被取代的CH或CH2、C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH或NH、C＝N、C、N、O、S、S(＝O)、S(＝O)2、C(＝O)O、C(＝O)或C(＝S)，且V1-5至少一项为C或N，取代基的数目在化学上可稳定实现的前提下是任意的；
    Figure PCTCN2015073330-appb-100005
    代表单键或双键；
    R4、R6分别独立地选自H、F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的；
    R5、R7分别独立地选自任选被取代的5～6元环烃基或杂环基，取代基选自F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的；
    n4选自0、1、2、3、4；和
    n6选自0、1、2、3。
  3. 根据权利要求2所述的化合物或其药学上可接受的盐，其中结构单元
    Figure PCTCN2015073330-appb-100006
    选自苯基或吡啶基，
    Figure PCTCN2015073330-appb-100007
    选自呋喃基、噻吩基或噻唑基。
  4. 根据权利要求2或3所述的化合物或其药学上可接受的盐，其中式(A2)选自式(A21)所示结构：
    Figure PCTCN2015073330-appb-100008
    式中，V1、V2、V3、V4、V5、R6、R7、n6如权利要求2中所定义。
  5. 根据权利要求4所述的化合物或其药学上可接受的盐，其中A选自式(A22)所示结构单元：
    Figure PCTCN2015073330-appb-100009
    其中，R6、R7如权利要求2中所定义；n6a选自0、1或2。
  6. 根据权利要求2、3、4或5所述的化合物或其药学上可接受的盐，其中所述R5或R7中5～6元环烃基或杂环基分别独立地选自苯基、吡啶基、呋喃基、噻吩基、噻唑基、嘧啶基、吡唑基、1,2,3-三唑基或1,2,5-三唑基。
  7. 根据权利要求1、2、3、4或5所述的化合物或其药学上可接受的盐，其中所述A选自：
    Figure PCTCN2015073330-appb-100010
    Figure PCTCN2015073330-appb-100011
  8. 根据权利要求1所述的化合物或其药学上可接受的盐，其中式(Y2)选自式(Y21)所示结构：
    Figure PCTCN2015073330-appb-100012
    式中，Y2a、Y2b、Y2c、Y2d、Y2e、Y2f、Y2g如权利要求1中所定义。
  9. 根据权利要求8所述的化合物或其药学上可接受的盐，其中式(Y21)选自任选被取代的式(Y22)所示结构：
    Figure PCTCN2015073330-appb-100013
    其中，取代基选自F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的。
  10. 根据权利要求9所述的化合物或其药学上可接受的盐，其中Y选自任选被取代的
    Figure PCTCN2015073330-appb-100014
  11. 根据权利要求1所述的化合物或其药学上可接受的盐，其中Y选自-CH2-O-E或-O-E，其中，E如权利要求1中所定义。
  12. 根据权利要求1或11所述的化合物或其药学上可接受的盐，其中E选自式(Ea)所示结构单元：
    Figure PCTCN2015073330-appb-100015
    其中，
    E1、E2、E3、E4分别独立地选自卤代或羟代或胺代或未被取代的CH、N；和
    R8、R9分别独立地选自H、F、Cl、Br、I、CN、＝O、＝S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基，杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(＝O)NH、C(＝O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C＝NH、C＝O、C＝S、S(＝O)和/或S(＝O)2，取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的。
  13. 根据权利要求12所述的化合物或其药学上可接受的盐，其中将结构单元
    Figure PCTCN2015073330-appb-100016
    限定为苯基或者吡啶基，或将其替换为噻吩基或呋喃基。
  14. 根据权利要求12所述的化合物或其药学上可接受的盐，其中Y选自：
    Figure PCTCN2015073330-appb-100017
  15. 根据权利要求1所述的化合物或其药学上可接受的盐，其中U、X、G分别独立地选自NH或N-C1-6烷基。
  16. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R1a、R1b、R1c分别独立地选自H、甲基或氟。
  17. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R2、R3分别独立地选自H、甲基、氟或环丙基。
  18. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R2、R3连接成3～8元环烷基；
    具体地，R2、R3连接成环丙基。
  19. 根据权利要求1～18任意一项所述的化合物或其药学上可接受的盐，其中C1-6烷基选自甲基、乙基、丙基、丁基、戊基、己基，其中所述丙基、丁基、戊基、己基任选地环化或部分环化。
  20. 根据权利要求1所述的化合物或其药学上可接受的盐，其具有如下结构：
    Figure PCTCN2015073330-appb-100018
    Figure PCTCN2015073330-appb-100019
  21. 一种药物组合物，包括治疗有效量的根据权利要求1～20任意一项所述的化合物或其药学上可接受的盐，以及药学上可接受的载体。
  22. 根据权利要求1～20任意一项所述的化合物或其药学上可接受的盐或根据权利要求21所述的药物组合物在制备治疗失眠、慢性阻塞性肺病、阻塞性睡眠呼吸暂停、嗜睡、焦虑、强迫、恐慌、尼古丁依赖或饮食混乱障碍的药物中的应用。
PCT/CN2015/073330 2014-03-06 2015-02-27 作为食欲素受体拮抗剂的哌啶衍生物 WO2015131773A1 (zh)

Priority Applications (13)

Application Number Priority Date Filing Date Title
RU2016130937A RU2669701C2 (ru) 2014-03-06 2015-02-27 Производные пиперидина в качестве антагонистов рецептора орексина
CA2941663A CA2941663C (en) 2014-03-06 2015-02-27 Piperidine derivatives as orexin receptor antagonist
KR1020167027668A KR101920472B1 (ko) 2014-03-06 2015-02-27 오렉신 수용체 길항제로서의 피페리딘 유도체
NZ723671A NZ723671A (en) 2014-03-06 2015-02-27 Piperidine derivatives as orexin receptor antagonist
JP2016572879A JP6262885B2 (ja) 2014-03-06 2015-02-27 オレキシン受容体拮抗剤としてのピペリジン誘導体
MX2016011549A MX2016011549A (es) 2014-03-06 2015-02-27 Derivados de piperidina como antagonistas de receptores de orexina.
CN201580012396.4A CN106414439B (zh) 2014-03-06 2015-02-27 作为食欲素受体拮抗剂的哌啶衍生物
EP15758792.4A EP3115362B1 (en) 2014-03-06 2015-02-27 Piperidine derivatives as orexin receptor antagonist
SG11201607183PA SG11201607183PA (en) 2014-03-06 2015-02-27 Piperidine derivatives as orexin receptor antagonist
AU2015226679A AU2015226679B2 (en) 2014-03-06 2015-02-27 Piperidine derivatives as orexin receptor antagonist
US15/123,014 US10100047B2 (en) 2014-03-06 2015-02-27 Piperidine derivatives as orexin receptor antagonist
IL247584A IL247584A0 (en) 2014-03-06 2016-08-31 Pepridine derivatives as orexin receptor blockers
ZA2016/06141A ZA201606141B (en) 2014-03-06 2016-09-05 Piperidine derivatives as orexin receptor antagonist

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410081220 2014-03-06
CN201410081220.1 2014-03-06

Publications (1)

Publication Number Publication Date
WO2015131773A1 true WO2015131773A1 (zh) 2015-09-11

Family

ID=54054589

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/073330 WO2015131773A1 (zh) 2014-03-06 2015-02-27 作为食欲素受体拮抗剂的哌啶衍生物

Country Status (16)

Country Link
US (1) US10100047B2 (zh)
EP (1) EP3115362B1 (zh)
JP (1) JP6262885B2 (zh)
KR (1) KR101920472B1 (zh)
CN (1) CN106414439B (zh)
AU (1) AU2015226679B2 (zh)
CA (1) CA2941663C (zh)
CL (1) CL2016002240A1 (zh)
IL (1) IL247584A0 (zh)
MX (1) MX2016011549A (zh)
NZ (1) NZ723671A (zh)
PE (1) PE20170184A1 (zh)
RU (1) RU2669701C2 (zh)
SG (2) SG10201900536TA (zh)
WO (1) WO2015131773A1 (zh)
ZA (1) ZA201606141B (zh)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017028732A1 (zh) * 2015-08-14 2017-02-23 上海海雁医药科技有限公司 食欲素受体拮抗剂化合物的晶型及其制备方法和应用
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
CN112480107A (zh) * 2020-11-30 2021-03-12 上海海雁医药科技有限公司 取代的氮杂双环辛烷化合物及其中间体和制备方法
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
WO2021208976A1 (zh) * 2020-04-17 2021-10-21 上海海雁医药科技有限公司 固体药物制剂及其制备方法和用途

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2016295693B2 (en) 2015-07-17 2020-05-21 Sunshine Lake Pharma Co., Ltd. Substituted quinazoline compounds and preparation and uses thereof
CA3005918C (en) 2015-11-23 2023-10-17 Sunshine Lake Pharma Co., Ltd. Octahydropyrrolo[3,4-c]pyrrole derivatives and uses thereof
ES2907373T3 (es) 2016-02-04 2022-04-25 Takeda Pharmaceuticals Co Compuesto de piperidina sustituida y uso de la misma

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008147518A1 (en) * 2007-05-23 2008-12-04 Merck & Co., Inc. Pyridyl piperidine orexin receptor antagonists
WO2014159591A1 (en) * 2013-03-13 2014-10-02 Janssen Pharmaceutica Nv Substituted 7-azabicycles and their use as orexin receptor modulators
WO2014165070A1 (en) * 2013-03-13 2014-10-09 Janssen Pharmaceutica Nv Substituted 2-azabicycles and their use as orexin receptor modulators

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7368457B2 (en) * 2003-05-13 2008-05-06 Schering Corporation Bridged N-arylsulfonylpiperidines as gamma-secretase inhibitors
WO2008024284A2 (en) * 2006-08-21 2008-02-28 Merck & Co., Inc. Sulfonylated piperazines as cannabinoid-1 receptor modulators
EP2150114A4 (en) * 2007-05-18 2012-01-18 Merck Sharp & Dohme OXO-BRIDGED DIAZEPANOREXINE RECEPTOR ANTAGONISTS
EP2150115B1 (en) * 2007-05-23 2013-09-18 Merck Sharp & Dohme Corp. Cyclopropyl pyrrolidine orexin receptor antagonists
US8188280B2 (en) * 2008-02-06 2012-05-29 Msd K.K. 3-substituted sulfonyl piperidine derivative
RU2010138640A (ru) * 2008-02-21 2012-03-27 Актелион Фармасьютиклз Лтд (Ch) Производные 2-аза-бицикло [2.2.1] гептана
AU2009307918A1 (en) * 2008-10-21 2010-04-29 Merck Sharp & Dohme Corp. 2,4-disubstituted pyrrolidine orexin receptor antagonists
JP2012506375A (ja) * 2008-10-21 2012-03-15 メルク・シャープ・エンド・ドーム・コーポレイション ２，５−二置換ピペリジンオレキシン受容体アンタゴニスト
EP2350061B1 (en) * 2008-10-21 2013-08-14 Merck Sharp & Dohme Corp. 2,3-disubstituted piperidine orexin receptor antagonists
EP2350066B1 (en) * 2008-10-21 2013-08-28 Merck Sharp & Dohme Corp. 2,5-disubstituted piperidine orexin receptor antagonists
EP2563780B1 (en) * 2010-04-29 2015-05-06 The University Of Edinburgh 3,3-disubstituted-(8-aza-bicyclo[3.2.1]oct-8-yl)-[5-(1h-pyrazol-4-yl)-thiophen-3-yl]-methanones as inhibitors of 11(beta)-hsd1
ES2823350T3 (es) * 2010-07-29 2021-05-06 Rigel Pharmaceuticals Inc Compuestos heterocíclicos que activan AMPK y métodos de uso de los mismos
TW201315730A (zh) * 2011-07-05 2013-04-16 大正製藥股份有限公司 甲基哌啶衍生物
AR088352A1 (es) * 2011-10-19 2014-05-28 Merck Sharp & Dohme Antagonistas del receptor de 2-piridiloxi-4-nitrilo orexina
JP6099051B2 (ja) * 2011-10-25 2017-03-22 塩野義製薬株式会社 Ｐｇｄ２受容体アンタゴニスト活性を有するへテロ環誘導体
JOP20130213B1 (ar) * 2012-07-17 2021-08-17 Takeda Pharmaceuticals Co معارضات لمستقبلht3-5
WO2014075392A1 (en) 2012-11-16 2014-05-22 Merck Sharp & Dohme Corp. Purine inhibitors of human phosphatidylinositol 3-kinase delta

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008147518A1 (en) * 2007-05-23 2008-12-04 Merck & Co., Inc. Pyridyl piperidine orexin receptor antagonists
WO2014159591A1 (en) * 2013-03-13 2014-10-02 Janssen Pharmaceutica Nv Substituted 7-azabicycles and their use as orexin receptor modulators
WO2014165070A1 (en) * 2013-03-13 2014-10-09 Janssen Pharmaceutica Nv Substituted 2-azabicycles and their use as orexin receptor modulators

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3115362A4 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
WO2017028732A1 (zh) * 2015-08-14 2017-02-23 上海海雁医药科技有限公司 食欲素受体拮抗剂化合物的晶型及其制备方法和应用
US10668066B2 (en) 2015-08-14 2020-06-02 Shanghai Haiyan Pharmaceutical Technology Co., Ltd. Crystal form of orexin receptor antagonist compound, and preparation method and application thereof
US10874674B2 (en) 2015-08-14 2020-12-29 Shanghai Haiyan Pharmaceutical Technology Co., Ltd. Crystal form of orexin receptor antagonist compound, and preparation method and application thereof
US10898486B2 (en) 2015-08-14 2021-01-26 Shanghai Haiyan Pharmaceutical Technology Co., Ltd. Crystal form of orexin receptor antagonist compound, and preparation method and application thereof
US10912775B2 (en) 2015-08-14 2021-02-09 Shanghai Haiyan Pharmaceutical Technology Co., Ltd. Crystal form of orexin receptor antagonist compound, and preparation method and application thereof
WO2021208976A1 (zh) * 2020-04-17 2021-10-21 上海海雁医药科技有限公司 固体药物制剂及其制备方法和用途
CN112480107A (zh) * 2020-11-30 2021-03-12 上海海雁医药科技有限公司 取代的氮杂双环辛烷化合物及其中间体和制备方法
CN112480107B (zh) * 2020-11-30 2022-08-16 上海海雁医药科技有限公司 取代的氮杂双环辛烷化合物及其中间体和制备方法

Also Published As

Publication number Publication date
EP3115362A4 (en) 2017-08-16
MX2016011549A (es) 2017-05-08
KR20160143668A (ko) 2016-12-14
EP3115362B1 (en) 2019-06-12
RU2669701C2 (ru) 2018-10-15
PE20170184A1 (es) 2017-04-07
CN106414439A (zh) 2017-02-15
CA2941663C (en) 2020-02-18
CN106414439B (zh) 2017-12-08
KR101920472B1 (ko) 2019-02-08
AU2015226679A1 (en) 2016-09-15
US10100047B2 (en) 2018-10-16
RU2016130937A (ru) 2018-04-09
SG10201900536TA (en) 2019-02-27
NZ723671A (en) 2017-05-26
US20170233385A1 (en) 2017-08-17
ZA201606141B (en) 2017-05-31
CA2941663A1 (en) 2015-09-11
AU2015226679B2 (en) 2017-05-25
JP2017507185A (ja) 2017-03-16
CL2016002240A1 (es) 2017-02-17
JP6262885B2 (ja) 2018-01-17
EP3115362A1 (en) 2017-01-11
SG11201607183PA (en) 2016-10-28
IL247584A0 (en) 2016-11-30

Similar Documents

Publication Publication Date Title
WO2015131773A1 (zh) 作为食欲素受体拮抗剂的哌啶衍生物
JP7311228B2 (ja) Ｒｈｏ－関連プロテインキナーゼ阻害剤、それを含む医薬組成物並びにその調製方法及び使用
JP6754505B2 (ja) Ａｓｋ１阻害剤、その調製方法および使用
CN109071509B (zh) 作为ROR-γ的调节剂的苯并咪唑衍生物
AU2015237788B2 (en) ROR-gamma modulators and uses thereof
CA3005658A1 (en) Modulators of ror-gamma
WO2009077533A1 (en) Fluoroalkyl substituted benzimidazole cannabinoid agonists
CN102123999B (zh) 制备食欲素受体拮抗剂的方法
JP6568855B2 (ja) ピラゾール誘導体の製造方法
EP2632924A1 (en) Diaza-spiro[5.5]undecanes useful as orexin receptor antagonists
WO2015018289A1 (zh) 一种合成阿哌沙班重要中间体的新方法
TWI631122B (zh) 食慾素受體阻抗劑受體化合物的製備方法及其中間體和晶型
TWI631120B (zh) Acridine derivative as an appetite hormone receptor antagonist
WO2022228413A1 (zh) 一种抑制细胞程序性死亡的化合物及其制备方法
JP2015059118A (ja) テトラヒドロピラゾロピラジン誘導体

Legal Events

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

Ref document number: 15758792

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 247584

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 15123014

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2016572879

Country of ref document: JP

Kind code of ref document: A

Ref document number: 2941663

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 001578-2016

Country of ref document: PE

Ref document number: MX/A/2016/011549

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2015226679

Country of ref document: AU

Date of ref document: 20150227

Kind code of ref document: A

REEP Request for entry into the european phase

Ref document number: 2015758792

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2015758792

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 20167027668

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: NC2016/0002714

Country of ref document: CO

ENP Entry into the national phase

Ref document number: 2016130937

Country of ref document: RU

Kind code of ref document: A