WO2016124129A1 - 二氮杂-苯并荧蒽类化合物 - Google Patents

二氮杂-苯并荧蒽类化合物 Download PDF

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Publication number
WO2016124129A1
WO2016124129A1 PCT/CN2016/073143 CN2016073143W WO2016124129A1 WO 2016124129 A1 WO2016124129 A1 WO 2016124129A1 CN 2016073143 W CN2016073143 W CN 2016073143W WO 2016124129 A1 WO2016124129 A1 WO 2016124129A1
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Prior art keywords
group
ethyl
pyridine
mmol
indole
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PCT/CN2016/073143
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English (en)
French (fr)
Inventor
罗云富
杨纯道
Original Assignee
南京明德新药研发股份有限公司
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Priority claimed from CN201510058257.7A external-priority patent/CN105985333A/zh
Priority to KR1020177024794A priority Critical patent/KR101998011B1/ko
Priority to EP16746124.3A priority patent/EP3255044B1/en
Priority to UAA201708745A priority patent/UA121882C2/uk
Priority to RU2017130595A priority patent/RU2697513C9/ru
Priority to AU2016214802A priority patent/AU2016214802B2/en
Priority to CN201680015258.6A priority patent/CN107614498B/zh
Priority to ES16746124T priority patent/ES2802526T3/es
Application filed by 南京明德新药研发股份有限公司 filed Critical 南京明德新药研发股份有限公司
Priority to US15/548,776 priority patent/US10017507B2/en
Priority to JP2017559752A priority patent/JP6434170B2/ja
Priority to BR112017016819-7A priority patent/BR112017016819B1/pt
Publication of WO2016124129A1 publication Critical patent/WO2016124129A1/zh
Priority to IL253813A priority patent/IL253813B/en
Priority to PH12017501404A priority patent/PH12017501404A1/en
Priority to ZA2017/06005A priority patent/ZA201706005B/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a series of diaza-benzofluoranthene compounds, in particular to a compound of formula (I), a pharmaceutically acceptable salt thereof or a tautomer thereof.
  • Vinpocetine which has the structure as shown in formula (B-I)
  • Vinpocetine which has the structure as shown in formula (B-I)
  • the brain tissue has a higher concentration distribution and exerts therapeutic effects.
  • Developed by Gedeon Richter of Hungary it was launched in 1978 and has a history of more than 30 years in Europe. It is mainly used to "improve various symptoms induced by sequelae of cerebral infarction, sequelae of cerebral hemorrhage, and cerebral arteriosclerosis.” Since its listing, it has become a routine treatment for cardiovascular and cerebrovascular diseases. In recent years, it has further discovered other physiological activities, improving senile memory impairment and mental activity in healthy people. In addition, there are certain effects on confusion, inattention, irritability, visual and auditory abnormalities, and mood swings.
  • Stroke has a high incidence and disability rate in China and has become a serious burden on China's health care system.
  • vinpocetine has a wide range of applications in the treatment of stroke and related diseases, and is an important treatment for improving the prognosis of stroke, but its exact efficacy is doubtful, and the bioavailability of tablets is low.
  • Epilepsy is a chronic recurrent transient brain dysfunction syndrome. It is characterized by repeated epileptic seizures caused by abnormal discharge of brain neurons. Epilepsy is one of the common diseases of the nervous system, and its prevalence is second only to stroke.
  • R 2 is selected from a 5- to 6-membered unsaturated cyclic hydrocarbon group or a heterocycloalkyl group optionally substituted by R 01 ,
  • R 02 is selected from C 1-10 alkyl or heteroalkyl, C 3-10 cycloalkyl or heterocycloalkyl, aminoacyl, 5- to 12-membered unsaturated heterocyclic;
  • R d3 - d9 are each independently selected from H, NH 2 , R 02 ;
  • R 02 is optionally substituted by R 001 ;
  • R 01 , R 001 , heteroatoms or heteroatoms is independently selected from 0, 1, 2 or 3.
  • R 1 and R 3 are each independently selected from H, R 105 , R 101-105 are each independently selected from a C 1-6 alkyl or heteroalkyl group optionally substituted by R 001 ; or from 5 to 6 members substituted with 0, 1, 2 or 3 R 01 Unsaturated cyclic hydrocarbon or heterocycloalkyl,
  • R 101-105 are each independently selected from H,
  • R 1 and R 3 are each independently selected from H,
  • R 2 are independently selected from the group consisting of among them,
  • T 21-23 are each independently selected from N, and the rest are selected from C(R t );
  • T 24 is selected from N or C(R t );
  • T 25-29 are each independently selected from N, and the rest are selected from C(R t );
  • any two of each R t , R d1-d9 are joined to the same atom or group of atoms to form 1 or 2 3-8-membered rings;
  • R 2 are independently selected from the group consisting of
  • A each independently represents a 3 to 8 membered saturated or unsaturated carbocyclic or heterocyclic ring optionally substituted with 0, 1, 2 or 3 R t .
  • R 2 are independently selected from the group consisting of
  • R t , R d1 - d9 are each independently selected from H, NH 2 , CN, C 1-6 alkyl or heteroalkyl optionally substituted by R 001 , C 3-6 ring
  • R t and R d1-d2 may be independently selected from the group consisting of F, Cl, Br, and I.
  • R t , R d1 - d9 are each independently selected from C 1-6 alkylamino, N,N-di(C 1-3 alkyl)amino optionally substituted by R 001 , C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 3-6 cycloalkyl , C 3-6 cycloalkylamino, C 3-6 heterocycloalkylamino, C 3-6 cycloalkoxy, C 3-6 cycloalkyl acyl, C 3-6 cycloalkoxycarbonyl, C 3-6 ring Alkylsulfonyl group, C 3-6 cycloalkylsulfinyl group, aminoacyl group, 5- to 6-membered unsaturated heterocyclic group.
  • said R t , R d1-d9 are each independently selected from a 5- to 6-membered aryl or heteroaryl group optionally substituted by R 001 .
  • R t , R d1-d9 are each independently selected from the group consisting of phenyl, pyridyl and thienyl optionally substituted by R 001 .
  • R t , R d1 - d9 are each independently selected from the group consisting of H, F, Cl, Br, I, NH 2 , CH 3 , CN,
  • R 1-3 are each independently selected from:
  • the above pharmaceutically acceptable salt or tautomer thereof is selected from the group consisting of:
  • the present invention also provides the use of the above compound, a pharmaceutically acceptable salt thereof or a tautomer thereof for the preparation of a medicament for treating stroke or epilepsy.
  • C 1-10 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10 ;
  • C 3-10 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10 .
  • C 1-10 alkyl or heteroalkyl, C 3-10 cyclo or heterocycloalkyl, C 1-10 alkyl or heteroalkyl substituted by C 3-10 cycloalkyl or heterocycloalkyl include, but are not limited to:
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • 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.
  • “Pharmaceutically acceptable salt” as used herein is a derivative of the compound of the present invention, wherein the salt is formed by salt formation with an acid or with a base.
  • the parent compound is modified.
  • 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, glycolic 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, phen
  • 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 have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then resolved by art.
  • a suitable optically active acid or base e.g., an amino group
  • an acidic functional group e.g., a carboxyl group
  • the diastereomer is resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • the compound may be labeled with a radioisotope, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • 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 the substituted 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.
  • substituents When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
  • substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • alkyl and heteroalkyl radicals (including what are commonly referred to as alkylene, alkenyl, heteroalkyl, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl)
  • R', R", R"', R"" and R""' are each independently preferably hydrogen, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group (for example, an aryl group substituted by 1 to 3 halogens), a substituted or unsubstituted alkyl group, an alkoxy group, or a thioalkyl group Oxyl a group or an aralkyl group.
  • each R group is independently selected, as when more than one R', R", R"' Each of these groups, R"" and R""' groups.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can form a 5-, 6- or 7-member with the nitrogen atom. ring.
  • -NR'R is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is intended to include carbon.
  • a group bonded to a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
  • a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
  • Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -TC(O)-(CRR')qU-, wherein T and U are independently selected From -NR-, -O-, CRR'- or a single bond, q is an integer from 0 to 3.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein A and B are independently selected From -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) 2 -, -S(O) 2 NR'- or a single bond, r is 1 to 4 The integer.
  • a single bond on the new ring thus formed can be replaced with a double bond.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein s and d are each independently An integer selected from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) 2 - or -S(O) 2 NR'-.
  • the substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C 1 -C 6 )alkyl.
  • 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.
  • haloalkyl groups 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.
  • the 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups.
  • 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 or halogen refers to fluoro, chloro, bromo and iodo.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • N nitrogen
  • S sulfur
  • Si silicon
  • Ge germanium
  • Al aluminum
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, 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.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one.
  • Bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • 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, mono- or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (methine), may include a divalent or polyvalent radical having the specified number of carbon atoms (e.g., C 1 -C 10 represents 1 to 10 carbons).
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • alkyl refers to a straight or branched chain 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.
  • 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.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • 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 can be located at any internal position of the heterohydrocarbyl group (including 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 and “alkylthio” (or thioalkoxy) are customary expressions and refer to those alkane which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Base group alkoxy
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • 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.
  • 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. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and 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 Azolyl, 2-imidazolyl, 4- Imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridine , 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, fluorenyl, 2-benzimidazolyl, 5-indenyl, 1-is
  • 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.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent 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.
  • Representative 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-
  • 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
  • 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 synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for carbonyl Diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl and is an amine protecting group; BOC
  • the compounds of the invention can be prepared by the following scheme:
  • the present invention finds a compound which is superior to vinpocetine and has higher oral bioavailability in treating stroke.
  • This intermediate amide (205 mg, 0.45 mmol) was dissolved in toluene (15 ml), then potassium t-butoxide (167 mg, 1.49 mmol), and the mixture was warmed to reflux and stirred overnight. The mixture was cooled to 15 ° C, and the mixture was evaporated.
  • This example was prepared in the same manner as in Example 23.
  • This example was prepared in the same manner as in Example 23.
  • This example was prepared in the same manner as in Example 23.
  • This example was prepared in the same manner as in Example 23.
  • This example was prepared in the same manner as in Example 23.
  • This example was prepared in the same manner as in Example 29.
  • This example was prepared in the same manner as in Example 29.
  • This example was prepared in the same manner as in Example 29.
  • This example was prepared in the same manner as in Example 29.
  • This example was prepared in the same manner as in Example 29.
  • This example was prepared in the same manner as in Example 29.
  • reaction solution is poured into a sodium carbonate solution and the pH is adjusted to 8 and extracted with dichloromethane.
  • the combined extracts are washed with water, brine, dried over anhydrous sodium sulfate, and the solvent is concentrated in vacuo.
  • the title compound (30 mg, yield 32%) was obtained.
  • reaction solution is poured into a sodium carbonate solution and the pH is adjusted to 8 and extracted with dichloromethane.
  • the combined extracts are washed with water, brine, dried over anhydrous sodium sulfate, and the solvent is concentrated in vacuo.
  • the title compound (50 mg, yield 25%) was obtained.
  • reaction solution was poured into a sodium carbonate solution and the pH was adjusted to 8 and extracted with dichloromethane (3 ⁇ 10 ml), and the combined extracts were washed with water (10 ml) and brine (10 ml). After drying over anhydrous sodium sulfate, the solvent was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Embodiments 68B, 68C The operation of this embodiment is the same as that of Embodiments 68B, 68C.
  • Embodiments 68B, 68C The operation of this embodiment is the same as that of Embodiments 68B, 68C.
  • Embodiments 68B, 68C The operation of this embodiment is the same as that of Embodiments 68B, 68C.
  • Embodiments 68B, 68C The operation of this embodiment is the same as that of Embodiments 68B, 68C.
  • Embodiments 68B, 68C The operation of this embodiment is the same as that of Embodiments 68B, 68C.
  • Embodiments 68A, 68B, and 68C The operation of this embodiment is the same as that of Embodiments 68A, 68B, and 68C.
  • Embodiments 68A, 68B, and 68C The operation of this embodiment is the same as that of Embodiments 68A, 68B, and 68C.
  • Embodiments 68A, 68B, and 68C The operation of this embodiment is the same as that of Embodiments 68A, 68B, and 68C.
  • Embodiments 68A, 68B, and 68C The operation of this embodiment is the same as that of Embodiments 68A, 68B, and 68C.
  • Embodiments 68A, 68B, and 68C The operation of this embodiment is the same as that of Embodiments 68A, 68B, and 68C.
  • Embodiments 68A, 68B, and 68C The operation of this embodiment is the same as that of Embodiments 68A, 68B, and 68C.
  • Embodiments 68A, 68B, and 68C The operation of this embodiment is the same as that of Embodiments 68A, 68B, and 68C.
  • Embodiments 68A, 68B, and 68C The operation of this embodiment is the same as that of Embodiments 68A, 68B, and 68C.
  • Embodiments 68A, 68B, and 68C The operation of this embodiment is the same as that of Embodiments 68A, 68B, and 68C.
  • the assay measures PDE1A enzyme activity based on fluorescence polarization detection of AMP/GMP production by the combination of AlexaFluor 633 labeled AMP/GMP to AMP/GMP binding to the antibody.

Abstract

本发明公开了一系列二氮杂-苯并荧蒽类化合物，具体涉及式(Ⅰ)所示化合物、其药学上可接受的盐或其互变异构体。

Description

二氮杂-苯并荧蒽类化合物 技术领域
本发明涉及一系列二氮杂-苯并荧蒽类化合物，具体涉及式(Ⅰ)所示化合物、其药学上可接受的盐或其互变异构体。
背景技术
据世界卫生组织WHO调查显示，脑卒中已经成为继缺血性心脏疾病之后导致人类死亡的第二大原因，并且是因病致畸、致残的主要原因，严重影响患者个人和其家庭的生活质量和幸福指数。因此改善脑卒中患者的肢体致残状况以最大限度的恢复机体功能和劳动能力，方能改善患者的预后和生活质量，最终减轻个人和社会负担。
长春西汀，其结构如式(B-Ⅰ)所示，是一种从夹竹桃科小蔓长春花中提取出的吲哚类生物碱，具有高脂溶性，易通过血脑屏障，从而在脑组织有较高的浓度分布而发挥疗效。由匈牙利Gedeon Richter公司开发，1978年上市，在欧洲有超过30年的应用历史，主要用于“改善脑梗死后遗症、脑出血后遗症、脑动脉硬化症等诱发的各种症状”。上市以来，已成为治疗心脑血管疾病常规用药，近年来还进一步发现了其他生理活性，改善老年性记忆障碍和和健康人群的精神活动。另外，对思维混乱、注意力不集中、易怒、视觉和听觉异常、情绪波动等都有一定效果。
Figure PCTCN2016073143-appb-000001
脑卒中在中国有着极高的发病率和致残率，已经成为中国医疗体系的严重负担。在中国长春西汀在脑卒中以及相关疾病治疗过程中有着广泛的应用，是改善脑卒中预后重要的治疗手段，但其确切疗效存疑，且片剂的生物利用度较低。
癫痫是慢性反复发作性短暂脑功能失调综合征。以脑神经元异常放电引起反复痫性发作为特征。癫痫是神经系统常见疾病之一，患病率仅次于脑卒中。
发明内容
本发明的目的在于提供式(Ⅰ)所示化合物、其药学上可接受的盐或其互变异构体，
Figure PCTCN2016073143-appb-000002
其中，
R1、R3分别独立地选自H、F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH，或选自任选被R01取代的：C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、C1-10烷基或杂烷基、C3-10环烃基或杂环烃基、被C3-10环烃基或杂环烃基取代的C1-10烷基或杂烷基、C1-10烯基或杂烯基；
R2选自任选被R01取代的5～6元不饱和环烃基或杂环烃基、
Figure PCTCN2016073143-appb-000003
Figure PCTCN2016073143-appb-000004
R01选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、R02；
R02选自C1-10烷基或杂烷基、C3-10环烷基或杂环烷基、氨基酰基、5～12元不饱和杂环基；
“杂”表示杂原子或杂原子团，选自-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7)-、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-和/或-N(Rd8)C(＝O)N(Rd9)-；
Rd3-d9分别独立地选自H、NH2、R02；
R02任选地被R001取代；
R001选自F、Cl、Br、I、CN、OH、N(CH3)2、NH(CH3)、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、三氟甲基、氨甲基、羟甲基、甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基；
R01、R001、杂原子或杂原子团的数目分别独立地选自0、1、2或3。
本发明的一个方案中，上述R1、R3分别独立地选自H、
Figure PCTCN2016073143-appb-000005
R105，R101-105分别独立地选自任选被R001取代的C1-6烷基或杂烷基；或选自被0、1、2或3个R01取代的5～6元不饱和环烃基或杂环烃基、
Figure PCTCN2016073143-appb-000006
Figure PCTCN2016073143-appb-000007
本发明的一个方案中，上述R101-105分别独立地选自H、
Figure PCTCN2016073143-appb-000008
Figure PCTCN2016073143-appb-000009
本发明的一个方案中，上述R1、R3分别独立地选自H、
Figure PCTCN2016073143-appb-000010
Figure PCTCN2016073143-appb-000011
本发明的一个方案中，上述R2分别独立地选自
Figure PCTCN2016073143-appb-000012
Figure PCTCN2016073143-appb-000013
Figure PCTCN2016073143-appb-000014
其中，
T21-23中的0～2个分别独立地选自N，其余选自C(Rt)；
D21选自-C(Rd1)(Rd2)-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(Rd8)C(＝O)N(Rd9)-；
T24选自N或C(Rt)；
D22-24分别独立地选自-C(Rd1)(Rd2)-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(Rd8)C(＝O)N(Rd9)-；
T25-29中的0～2个分别独立地选自N，其余选自C(Rt)；
任选地，各个Rt、Rd1-d9中的任意两个共同连接到同一个原子或原子团上形成1或2个3～8元环；
Rt、Rd1、Rd2分别独立地选自H、F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2，或选自任选被R01取代的C1-10烷基或杂烷基、C3-10环烃基或杂环烃基、被C3-10环烃基或杂环烃基取代的C1-10烷基或杂烷基、C1-10烯基或杂烯基。
本发明的一个方案中，上述R2分别独立地选自
Figure PCTCN2016073143-appb-000015
其中A分别独立地代表任选被0、1、2或3个Rt取代的3～8元饱和或不饱和的碳环或杂环。
本发明的一个方案中，上述R2分别独立地选自
Figure PCTCN2016073143-appb-000016
本发明的一个方案中，上述Rt、Rd1-d9分别独立地选自H、NH2、CN、任选被R001取代的C1-6烷基或杂烷基、C3-6环烷基或杂环烷基、吡啶基、苯基、5～6元不饱和杂环基、氨基酰基；Rt、Rd1-d2还可以分别独立地选自F、Cl、Br、I。
在本发明的一个方案中，上述Rt、Rd1-d9分别独立地选自任选被R001取代的：C1-6烷氨基、N,N-二(C1-3烷基)氨基、C1-6烷氧基、C1-6烷酰基、C1-6烷氧羰基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C3-6环烷基、C3-6环烷氨基、C3-6杂环烷氨基、C3-6环烷氧基、C3-6环烷基酰基、C3-6环烷氧羰基、C3-6环烷 基磺酰基、C3-6环烷基亚磺酰基、氨基酰基、5～6元不饱和杂环基。
在本发明的一个方案中，上述Rt、Rd1-d9分别独立地选自任选被R001取代的5～6元芳基或杂芳基。
在本发明的一个方案中，上述Rt、Rd1-d9分别独立地选自任选被R001取代的苯基、吡啶基、噻吩基。
本发明的一个方案中，上述杂原子或原子团选自O、N、S、-C(＝O)O-、
Figure PCTCN2016073143-appb-000017
本发明的一个方案中，上述Rt、Rd1-d9分别独立地选自H、F、Cl、Br、I、NH2、CH3、CN、
Figure PCTCN2016073143-appb-000018
Figure PCTCN2016073143-appb-000019
本发明的一个方案中，上述R1-3分别独立地选自：
Figure PCTCN2016073143-appb-000020
Figure PCTCN2016073143-appb-000021
Figure PCTCN2016073143-appb-000022
本发明的一个方案中，上述药学上可接受的盐或其互变异构体选自：
Figure PCTCN2016073143-appb-000023
Figure PCTCN2016073143-appb-000024
Figure PCTCN2016073143-appb-000025
本发明还提供了上述化合物、其药学上可接受的盐或其互变异构体，在制备治疗脑卒中或癫痫的药物中的应用。
有关定义：
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
C1-10选自C1、C2、C3、C4、C5、C6、C7、C8、C9和C10；C3-10选自C3、C4、C5、C6、C7、C8、C9和C10。
C1-10烷基或杂烷基、C3-10环基或杂环烃基、被C3-10环烃基或杂环烃基取代的C1-10烷基或杂烷基包 括但不限于：
C1-10烷基、C1-10烷氨基、N,N-二(C1-10烷基)氨基、C1-10烷氧基、C1-10烷酰基、C1-10烷氧羰基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基、C3-10环烷氨基、C3-10杂环烷氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷基氧羰基、C3-10环烷基磺酰基、C3-10环烷基亚磺酰基；
甲基、乙基、正丙基、异丙基、-CH2C(CH3)(CH3)(OH)、环丙基、环丁基、丙基亚甲基、环丙酰基、苄氧基、三氟甲基、氨甲基、羟甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基、乙氧基、乙酰基、乙磺酰基、乙氧羰基、二甲基氨基、二乙基氨基、二甲基氨基羰基、二乙基氨基羰基；
N(CH3)2,NH(CH3),-CH2CF3,-CH2CH2CF3,-CH2CH2F,-CH2CH2S(＝O)2CH3,-CH2CH2CN,
Figure PCTCN2016073143-appb-000026
Figure PCTCN2016073143-appb-000027
-CH2CH(OH)(CH3)2,-CH2CH(F)(CH3)2,-CH2CH2F,-CH2CF3,-CH2CH2CF3,-CH2CH2NH2,-CH2CH2OH,-CH2CH2OCH3,-CH2CH2CH2OCH3,-CH2CH2N(CH3)2,-S(＝O)2CH3,-CH2CH2S(＝O)2CH3,
Figure PCTCN2016073143-appb-000028
Figure PCTCN2016073143-appb-000029
Figure PCTCN2016073143-appb-000030
Figure PCTCN2016073143-appb-000031
苯基、噻唑基、联苯基、萘基、环戊基、呋喃基、3-吡咯啉基、吡咯烷基、1,3-氧五环基、吡唑基、2-吡唑啉基、吡唑烷基、咪唑基、恶唑基、噻唑基、1,2,3-唑基、1,2,3-三唑基、1,2,4-三唑基、1,3,4-噻二唑基、4H-吡喃基、吡啶基、哌啶基、1,4-二氧六环基、吗啉基、哒嗪基、嘧啶基、吡嗪基、哌嗪基、1,3,5-三噻烷基、1,3,5-三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、嘌呤基、喹啉基、异喹啉基、噌啉基或喹喔啉基；
Figure PCTCN2016073143-appb-000032
Figure PCTCN2016073143-appb-000033
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
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。
本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。1985年，62：114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的拆分方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可 用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
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。
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。
当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当所列举的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，这种取代基可以通过其任何原子相键合。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。
烷基和杂烷基原子团(包括通常被称为亚烷基、链烯基、亚杂烷基、杂烯基、炔基、环烷基、杂环烷基、环烯基和杂环烯基的那些基团)的取代基一般被称为“烷基取代基”，它们可以选自但不限于下列基团中的一个或多个：-R’、-OR’、＝O、＝NR’、＝N-OR’、-NR’R”、-SR’、卤素、-SiR’R”R”’、OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R’”)＝NR””、NR””C(NR’R”)＝NR’”、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2和氟代(C1-C4)烷基,取代基的数目为0～(2m’+1),其中m’是这类原子团中碳原子的总数。R'、R”、R”'、R””和R””’各自独立地优选氢、被取代或未被取代的杂烷基、被取代或未被取代的芳基(例如被1～3个卤素取代芳基)、被取代或未被取代的烷基、烷氧基、硫代烷氧基基团或芳烷基。当本发明的化合物包括一个以上的R基团时，例如，每一个R基团是独立地加以选择的，如同 当存在一个以上的R'、R”、R”'、R””和R””’基团时的每个这些基团。当R'和R”附着于同一个氮原子时，它们可与该氮原子结合形成5-，6-或7-元环。例如，-NR'R“意在包括但不仅限于1-吡咯烷基和4-吗啉基。根据上述关于取代基的讨论中，本领域技术人员可以理解，术语“烷基”意在包括碳原子键合于非氢基团所构成的基团，如卤代烷基(例如-CF3、-CH2CF3)和酰基(例如-C(O)CH3、-C(O)CF3、-C(O)CH2OCH3等)。
与烷基原子团所述取代基相似，芳基和杂芳基取代基一般统称为“芳基取代基”，选自例如-R’、-OR’、-NR’R”、-SR’、-卤素,-SiR’R”R”’、OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R’”)＝NR””、NR””C(NR’R”)＝NR’”、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2、氟(C1-C4)烷氧基和氟(C1-C4)烷基等，取代基的数量为0到芳香环上开放化合价的总数之间；其中R’、R”、R”’、R””和R””’独立地优选自氢、被取代或未被取代的烷基、被取代或未被取代的杂烷基、被取代或未被取代的芳基和被取代或未被取代的杂芳基。当本发明的化合物包括一个以上的R基团时，例如，每个R基团是独立地加以选择的，如同当存在一个以上R’、R”、R”’、R””和R””’基团时的每个这些基团。
芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–T-C(O)-(CRR’)q-U-的取代基所取代，其中T和U独立地选自-NR-、-O-、CRR'-或单键，q是0到3的整数。作为替代选择，芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–A(CH2)r B-的取代基所取代，其中A和B独立的选自–CRR’-、-O-、-NR-、-S-、-S(O)-、S(O)2-、-S(O)2NR’-或单键，r是1～4的整数。任选地，由此形成的新环上的一个单键可以替换为双键。作为替代选择，芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–A(CH2)r B-的取代基所取代，其中s和d分别独立的选自0～3的整数，X是–O-、-NR’、-S-、-S(O)-、-S(O)2-或–S(O)2NR’-。取代基R、R’、R”和R”’分别独立地优选自氢和被取代或未被取代的(C1-C6)烷基。
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。
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。
术语“卤”或“卤素”是指氟、氯、溴和碘。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-，以及任选被被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。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，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，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。氮和硫杂原子可任选被氧化(即NO和S(O)p)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
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，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，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，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)。“烃基”包括但不限于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，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“杂烷基”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(包括该烃基附着于分子其余部分的位置)。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。
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”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。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“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。
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。
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。
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。
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。
本发明所使用的溶剂可经市售获得。
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；TMSCF3代表(三氟甲基)三甲基硅烷；TCDI代表1,1'-硫代碳酰基二咪唑；Py代表吡啶；HOBt代表1-羟基苯并 三唑；DIEA代表N,N-二异丙基乙胺；MsCl代表甲基磺酰氯；TosMIC代表对甲苯磺酰甲基异氰；TBTU代表O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸；MW代表微波反应；DAST代表二乙氨基三氟化硫；DMA-DMA代表N,N-二甲基乙酰胺二甲基缩醛；LAH代表铝锂氢；PhIO代表亚碘酰苯；DCE代表二氯乙烷；EDCI代表1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；NMO代表N-甲基吗啉氧化物。
化合物经手工或者
Figure PCTCN2016073143-appb-000034
软件命名，市售化合物采用供应商目录名称。
本发明的化合物可以通过下述流程制备：
流程A
Figure PCTCN2016073143-appb-000035
流程A1
Figure PCTCN2016073143-appb-000036
流程A2
Figure PCTCN2016073143-appb-000037
流程A3
Figure PCTCN2016073143-appb-000038
流程A4
Figure PCTCN2016073143-appb-000039
流程A5
Figure PCTCN2016073143-appb-000040
流程B
Figure PCTCN2016073143-appb-000041
流程B1
Figure PCTCN2016073143-appb-000042
流程B2
Figure PCTCN2016073143-appb-000043
流程B3
Figure PCTCN2016073143-appb-000044
流程B4
Figure PCTCN2016073143-appb-000045
流程B5
Figure PCTCN2016073143-appb-000046
流程B6
Figure PCTCN2016073143-appb-000047
流程B7
Figure PCTCN2016073143-appb-000048
流程B8
Figure PCTCN2016073143-appb-000049
流程B9
Figure PCTCN2016073143-appb-000050
流程B10
Figure PCTCN2016073143-appb-000051
流程B11
Figure PCTCN2016073143-appb-000052
流程B12
Figure PCTCN2016073143-appb-000053
流程B13
Figure PCTCN2016073143-appb-000054
流程B14
Figure PCTCN2016073143-appb-000055
流程B15
Figure PCTCN2016073143-appb-000056
流程B16
Figure PCTCN2016073143-appb-000057
流程B17
Figure PCTCN2016073143-appb-000058
流程B18
Figure PCTCN2016073143-appb-000059
流程B19
Figure PCTCN2016073143-appb-000060
流程B20
Figure PCTCN2016073143-appb-000061
通过对长春西汀进行结构改造，经过体内外药效模型筛选，本发明找到对脑卒中治疗作用明显优于长春西汀、口服生物利用度更高的化合物。
具体实施方式
为了更详细地说明本发明，给出下列实例，但本发明的范围并非限定于此。
流程A
Figure PCTCN2016073143-appb-000062
实施例1
1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-2,2,2-三氟乙醇
Figure PCTCN2016073143-appb-000063
实施例1A
((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)甲醇
Figure PCTCN2016073143-appb-000064
在0-5℃下向长春西汀(10克，28.6毫摩尔)溶于四氢呋喃(400毫升)的溶液中分批加入铝锂氢(3.2克，85.7毫摩尔)，反应混合物在室温、氮气保护下搅拌30分钟。反应结束后，用5毫升水将反应淬灭，再向反应混合物中加入4毫升2M氢氧化钠溶液和4毫升水，滤掉固体，滤液浓缩后加入水并用乙酸乙酯萃取。萃取液干燥、浓缩后得到标题化合物(白色固体，7.8克，收率89％)。
1H NMR(400MHz,CHLOROFORM-d)δppm 0.98(t,J＝7.53Hz,3H),1.08-1.17(m,1H),1.38-1.48(m,2H),1.65-1.82(m,2H),1.86-1.96(m,1H),2.51(ddd,J＝16.00,4.96,1.88Hz,1H),2.62-2.76(m,2H),2.98-3.09(m,1H),3.20-3.29(m,1H),3.32-3.39(m,1H),4.16(br.s.,1H),4.61(d,J＝13.30Hz,1H),4.83(d,J＝13.30Hz,1H),5.11(s,1H),7.10-7.15(m,1H),7.20(td,J＝7.72,1.38Hz,1H),7.47(d,J＝7.78Hz,1H),7.67(d,J＝8.53Hz,1H).
实施例1B
(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲醛
Figure PCTCN2016073143-appb-000065
向((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)甲醇(1.8克，5.84毫摩尔)溶于二氯甲烷(20毫升)的溶液中加入活性二氧化锰(5.07克，58.4毫摩尔)，将反应混合物加热并搅拌过夜。过滤，将滤液浓缩干，残留物用石油醚/乙酸乙酯为10/1的混合溶液作为洗脱液 过柱得到标题化合物(无色油状物，1.2克，收率67.1％)。
实施例1C
1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-2,2,2-三氟乙醇
Figure PCTCN2016073143-appb-000066
在0℃下向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲醛(200毫克，0.652毫摩尔)溶于无水四氢呋喃(5毫升)的溶液中分别加入氟化铯(148.73毫克，0.979毫摩尔)和(三氟甲基)三甲基硅烷(139.2毫克，0.979毫摩尔)，反应混合物在0℃下搅拌1小时，然后加入四丁基氟化铵(248毫克)，在室温下搅拌1小时后浓缩，残留物通过制备高效液相色谱分离得到标题化合物(100毫克，收率40.8％)。
1H NMR(CD3OD,400MHz)δ7.59(d,J＝8.0Hz,1H),7.43(d,J＝8.0Hz,1H),7.13～7.17(m,1H),7.05～7.09(m,1H),5.54～5.61(m,2H),4.18(s,1H),3.24～3.28(m,2H),2.96～2.98(m,1H),2.53～2.67(m,3H),1.75～1.98(m,1H),1.70～1.74(m,2H),1.44～1.51(m,2H),0.99～1.08(m,4H).LCMS(ESI)m/z:377(M+1)
流程A1
Figure PCTCN2016073143-appb-000067
实施例2
(41S,13aS,Z)-13a-乙基-N-甲氧基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-异氰酸基氰化物
Figure PCTCN2016073143-appb-000068
实施例2A
Figure PCTCN2016073143-appb-000069
((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)甲基磺酸甲酯在0-5℃、氮气保护下向((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)甲醇(3.8克，12.3毫摩尔)溶于四氢呋喃(80毫升)的溶液中依次加入三乙胺(1.9克，18.5毫摩尔)和甲磺酰氯(1.1毫升，14.8毫摩尔)，反应混合物升到室温并搅拌1小时。反应完全后，向反应混合物中加入氯化铵溶液，用乙酸乙酯萃取，萃取液干燥并浓缩后得到标题化合物(黄色固体，5克，粗品，直接用于下一步)。
实施例2B
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)乙腈
Figure PCTCN2016073143-appb-000070
将上一步的粗品(5克，12.9毫摩尔)溶于二甲亚砜(40毫升)，然后加入氰化钠(3.2克，64.8毫摩尔)，反应混合物在室温下搅拌过夜。反应完成后将混合物倒入150毫升水中，滤出析出的固体并干燥得到标题化合物(黄色固体，3.6克，收率88％)。
1H NMR(400MHz,CHLOROFORM-d)δppm 0.94-1.02(m,4H),1.38-1.50(m,2H),1.69-1.80(m,2H),2.03(dq,J＝14.62,7.51Hz,1H),2.37-2.45(m,1H),2.48-2.62(m,3H),2.88-2.98(m,1H),3.11(d,J＝15.06Hz,1H),3.20-3.36(m,2H),3.98(s,1H),5.62(d,J＝1.76Hz,1H),7.25-7.33(m,2H),7.47-7.52(m,1H),7.65(d,J＝7.53Hz,1H).
实施例2C
(41S,13aS,Z)-13a-乙基-N-甲氧基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-异氰酸基氰化物
Figure PCTCN2016073143-appb-000071
向2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)乙腈(300毫克，0.95毫摩尔)溶于四氢呋喃(20毫升)的溶液中依次加入亚硝酸异戊酯(332毫克，0.95毫摩尔)和叔丁醇钾(424毫克，3.8毫摩尔)，反应混合物在氮气保护下室温搅拌1小时。
向反应混合物中加入碘化钾(538毫克，3.8毫摩尔)，继续搅拌3小时。反应完全后，向反应混合物中加入水并用乙酸乙酯萃取，萃取液干燥后浓缩，残留物通过制备高效液相色谱分离得到标题化合物(100毫克，收率29％)。
1H NMR(400MHz,CHLOROFORM-d)δppm 1.07-1.30(m,4H),1.62-1.73(m,2H),2.17-2.35(m,3H),2.90-3.20(m,3H),3.31(br.s.,1H),3.58-3.84(m,2H),4.22(s,3H),4.72(br.s.,1H),5.75(s,1H),7.20-7.26(m,2H),7.28-7.33(m,1H),7.47-7.56(m,1H).
流程A2
Figure PCTCN2016073143-appb-000072
实施例3
(41S,13aS)-13a-乙基-12-(1H-咪唑-2-yl)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶
Figure PCTCN2016073143-appb-000073
向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲醛(300毫克，0.97毫摩尔)溶于无水乙醇(5毫升)的溶液中分别加入乙二醛(568毫克，0.97毫摩尔)和氨水(343毫克，9.79毫摩尔)，将反应混合物加热并回流3天。反应混合物浓缩后，残留物通过制备高效液相色谱分离得到标题化合物(50毫克，收率14.8％)。
1H NMR(CD3OD,400MHz)δppm 7.75(s,2H),7.64(d,J＝8.0Hz,1H),7.14～7.24(m,2H),6.11(d,J＝8.0Hz,1H),5.98(s,1H),5.16(s,1H),3.86～3.96(m,2H),3.35～3.38(m,2H),3.16～3.27(m,2H),1.96～2.04(m,3H),1.79～1.87(m,2H),1.38(m,1H),1.12(t,J＝9.8Hz,3H).
LCMS(ESI)m/z:345(M+1)
流程A3
Figure PCTCN2016073143-appb-000074
实施例4
5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)恶唑
Figure PCTCN2016073143-appb-000075
室温下向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲醛(500毫克，1.63毫摩尔)溶于甲醇(6毫升)的溶液中依次加入甲醇钠(450毫克，8.15毫摩尔)和对甲苯磺酰甲基异氰(390毫克，2毫摩尔)，反应混合物回流过夜。冷却后将混合物浓缩，残留物用碳酸氢钠溶液处理，并用乙酸乙酯萃取，有机层用无水硫酸钠干燥后过滤，滤液浓缩，粗品过硅胶柱得到标题化合物(200毫克，收率35.6％)。
1H NMR(400MHz,DMSO)δppm 8.58(s,1H),7.59-7.35(m,2H),7.09-6.85(m,2H),6.12(d,J＝8.1Hz,1H),5.52(s,1H),4.10(q,J＝5.1Hz,1H),3.20-3.09(m,3H),2.94(br.s.,1H),1.94-1.73(m,2H),1.59(br.s.,1H),1.50(d,J＝13.0Hz,1H),1.38(br.s.,1H),0.97-0.85(m,3H).
LCMS(ESI)m/z:346(M+1)
流程A4
Figure PCTCN2016073143-appb-000076
实施例5
(E)-3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)丙烯酸
Figure PCTCN2016073143-appb-000077
用冰水浴将膦酰基乙酸三乙酯(293毫克，1.3毫摩尔)溶于2毫升四氢呋喃的溶液冷却到0℃，向其中加入钠氢(60％，80毫克，2毫摩尔)，大约小时后将(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲醛(200毫克，0.65毫摩尔)溶于2毫升四氢呋喃的溶液加入，反应混合物缓慢升至室温并搅拌过夜。TLC检测反应结束后，将溶剂蒸去，残留物溶于2毫升二甲亚砜后用制备高效液相色谱分离得到标题化合物(17毫克，收率7.56％)。
1H NMR(400MHz,METHANOL-d4)δppm 7.71-7.60(m,1H),7.52(t,J＝7.9Hz,2H),7.28-7.13(m,2H),6.38(d,J＝15.6Hz,1H),5.51(s,1H),3.73(d,J＝7.0Hz,3H),3.09(br.s.,6H),2.17-1.89(m,3H),1.69(d,J＝12.3Hz,2H),1.31-1.16(m,2H),1.10(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:349(M+1)
实施例6
(E)-乙基-3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)丙烯酸酯
Figure PCTCN2016073143-appb-000078
向(E)-3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)丙烯酸(200毫克，0.573毫摩尔)溶于5毫升四氢呋喃的溶液中分别加入碳酸钾(158毫克，1.14毫摩尔)和碘乙烷(88毫克，0.57毫摩尔)，反应混合物在室温下搅拌过夜。TLC检测反应结束后，将溶剂蒸去，残留物溶于2毫升二甲亚砜后用制备高效液相色谱分离得到标题化合物。
1H NMR(400MHz,METHANOL-d4)δppm 7.67(d,J＝15.6Hz,1H),7.44-7.24(m,2H),7.15-6.96(m,2H),6.28(d,J＝15.8Hz,1H),5.52(s,1H),4.27(d,J＝7.0Hz,2H),3.85(br.s.,1H),3.24-3.11(m,1H),3.08-2.79(m,2H),2.55-2.32(m,3H),1.90-1.67(m,2H),1.67-1.51(m,1H),1.46-1.22(m,5H),0.98(t,J＝7.4Hz,3H),0.90-0.77(m,1H).
LCMS(ESI)m/z:377(M+1)
流程A5
Figure PCTCN2016073143-appb-000079
实施例7
(E)-3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)丙烯酰胺
Figure PCTCN2016073143-appb-000080
向(E)-3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)丙烯酸(200毫克，0.57毫摩尔)、氯化铵(36毫克，0.688毫摩尔)和5毫升四氢呋喃的混合物中分别加入三乙胺(69毫克，0.68毫摩尔)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(217毫克，0.57毫摩尔)，反应混合物在室温下搅拌1小时，然后升温到60℃过夜。TLC检测反应结束后，将溶剂蒸去，残留物溶于2毫升二甲亚砜后用制备高效液相色谱分离得到标题化合物。
1H NMR(400MHz,MeOD)δppm 7.66(d,J＝15.3Hz,1H),7.43(dd,J＝7.9,12.7Hz,2H),7.25-6.99(m,2H),6.49(d,J＝15.6Hz,1H),5.53(s,1H),4.17(br.s.,1H),3.27-3.16(m,1H),3.03(br.s.,1H),2.72-2.49(m,3H),2.04-1.64(m,3H),1.57-1.36(m,2H),1.04(t,J＝7.3Hz,4H).
LCMS(ESI)m/z:348(M+1)
流程B
Figure PCTCN2016073143-appb-000081
实施例8
(41S,13aS)-13a-乙基-12-(4-甲基嘧啶-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶
Figure PCTCN2016073143-appb-000082
实施例8A
(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-羧酸
Figure PCTCN2016073143-appb-000083
80℃下，向氢氧化钠(137毫克，3.43毫摩尔)和无水二氧六环(14毫升)的混合物中加入长春西汀(1克，2.86毫摩尔)，混合物在该温度下继续反应2小时。TLC检测长春西汀反应完毕，将混合物浓缩干，加水重新溶解，溶液用2M盐酸调至pH等于3，用二氯甲烷/异丙醇10/1的混合溶剂萃取，萃取液干燥、 浓缩后得到标题化合物(直接用于下一步反应，900毫克，收率98％)。
LCMS(ESI)m/z:323(M+1)
实施例8B
(41S,13aS)-13a-乙基-12-(4-甲基嘧啶-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶
Figure PCTCN2016073143-appb-000084
在微波管中加入(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-羧酸(300毫克，0.93毫摩尔)、2-氯-4-甲基嘧啶(180毫克，1.396毫摩尔)、碳酸铯(363毫克，1.117毫摩尔)和1,10-邻菲啰啉(8.4毫克，0.047毫摩尔)，用N-甲基吡咯烷酮(3毫升)混合均匀后，氮气置换3次，再加入碘化亚铜(8.9毫克，0.047毫摩尔)和乙酰丙酮钯(II)(14毫克，0.047毫摩尔)，密封好后微波加热到170℃反应30分钟。反应混合物倒入20毫升水中，过滤，滤饼通过制备高效液相色谱分离得到标题化合物(100毫克，收率29％)。
1H NMR(400MHz,METHANOL-d4)δppm 8.77(d,J＝5.3Hz,1H),7.60(d,J＝7.8Hz,1H),7.53(d,J＝5.3Hz,1H),7.15(t,J＝7.5Hz,1H),7.07-7.01(m,1H),6.21(d,J＝8.3Hz,1H),5.90(s,1H),5.15(s,1H),3.99-3.90(m,1H),3.90-3.83(m,1H),3.36(d,J＝3.5Hz,1H),3.31-3.26(m,1H),3.23-3.15(m,1H),2.61(s,3H),2.09-1.91(m,3H),1.90-1.77(m,2H),1.36(dt,J＝3.1,13.7Hz,1H),1.13(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:371(M+1)
实施例9
(41S,13aS)-13a-乙基-12-(6-甲基哒嗪-3-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶
Figure PCTCN2016073143-appb-000085
该实施例的方法同实施例8B。
1H NMR(400MHz,METHANOL-d4)δppm 8.57-8.51(m,1H),8.50-8.45(m,1H),7.63(d,J＝7.5Hz,1H),7.21-7.15(m,1H),7.13-7.08(m,1H),6.50(d,J＝8.3Hz,1H),6.02(s,1H),5.19(s,1H),3.97-3.82(m,2H),3.38-3.33(m,1H),3.28-3.14(m,2H),3.01(s,3H),2.13-1.95(m,3H),1.91-1.77(m,2H),1.36(dt,J＝3.3,13.8Hz,1H),1.13(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:371(M+1)
实施例10
(41S,13aS)-13a-乙基-12-(6-甲基吡嗪-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶
Figure PCTCN2016073143-appb-000086
该实施例的方法同实施例8B。
1H NMR(400MHz,METHANOL-d4)δppm 8.67(d,J＝11.8Hz,2H),7.61(d,J＝7.8Hz,1H),7.15(t,J＝7.5Hz,1H),7.06-6.97(m,1H),6.13(d,J＝8.3Hz,1H),5.67(s,1H),5.18(s,1H),4.00-3.91(m,1H),3.90-3.84(m,1H),3.38-3.34(m,1H),3.31-3.27(m,1H),3.24-3.16(m,1H),2.60(s,3H),2.08-1.91(m,3H),1.90-1.78(m,2H),1.46-1.36(m,1H),1.14(t,J＝7.4Hz,3H).
LCMS(ESI)m/z:371(M+1)
实施例11
(41S,13aS)-13a-乙基-12-(吡啶-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶
Figure PCTCN2016073143-appb-000087
该实施例的方法同实施例8B。
1H NMR(400MHz,METHANOL-d4)δppm 8.99(d,J＝5.3Hz,1H),8.79(t,J＝7.7Hz,1H),8.31-8.23(m,2H),7.68(d,J＝7.8Hz,1H),7.23(t,J＝7.5Hz,1H),7.12(t,J＝7.5Hz,1H),6.22(d,J＝8.3Hz,1H),6.07(s,1H),5.23(br.s.,1H),4.02-3.93(m,1H),3.92-3.86(m,1H),3.42-3.34(m,2H),3.30-3.19(m,2H),2.14-1.99(m,3H),1.92(d,J＝14.3Hz,1H),1.84(d,J＝14.3Hz,1H),1.40(dt,J＝3.4,13.9Hz,1H),1.17(t,J＝7.4Hz,3H).
LCMS(ESI)m/z:356(M+1)
实施例12
(41S,13aS)-13a-乙基-12-(6-甲基吡啶-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶
Figure PCTCN2016073143-appb-000088
该实施例的方法同实施例8B。
1H NMR(400MHz,METHANOL-d4)δppm 8.57(t,J＝8.0Hz,1H),8.10-7.95(m,2H),7.65(d,J＝7.8Hz,1H),7.20(t,J＝7.3Hz,1H),7.13-7.06(m,1H),6.21(d,J＝8.3Hz,1H),6.00(s,1H),5.21(s,1H),4.00-3.91(m,1H),3.90-3.82(m,1H),3.41-3.32(m,2H),3.30-3.24(m,1H),3.24-3.17(m,1H),2.86(s,3H),2.16-1.95(m,3H),1.94-1.77(m,2H),1.40(dt,J＝3.3,13.9Hz,1H),1.15(t,J＝7.4Hz,3H).
LCMS(ESI)m/z:370(M+1)
实施例13
(41S,13aS)-13a-乙基-12-(3-甲基吡啶-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶
Figure PCTCN2016073143-appb-000089
该实施例的方法同实施例8B。
1H NMR(400MHz,METHANOL-d4)δppm 8.95(d,J＝5.5Hz,1H),8.62(d,J＝8.0Hz,1H),8.27-8.18(m,1H),7.64(d,J＝7.8Hz,1H),7.22-7.14(m,1H),7.08-6.99(m,1H),6.00(d,J＝8.5Hz,0.67H),5.90-5.82 (m,1H),5.73(d,J＝8.3Hz,0.33H),5.38-5.24(m,1H),4.02-3.84(m,2H),3.43-3.32(m,2H),3.30-3.26(m,1H),3.24-3.16(m,1H),2.69(s,1H),2.21(s,2H),2.17-2.08(m,1H),2.07-1.81(m,4H),1.60-1.45(m,1H),1.14(t,J＝7.4Hz,3H).
LCMS(ESI)m/z:370(M+1)
实施例14
(41S,13aS)-12-(5,6-二甲基吡嗪-2-基)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘
啶
Figure PCTCN2016073143-appb-000090
该实施例的方法同实施例8B。
1H NMR(400MHz,METHANOL-d4)δppm 8.69(s,1H),7.61(d,J＝7.8Hz,1H),7.19-7.12(m,1H),7.04(t,J＝7.8Hz,1H),6.30(d,J＝8.3Hz,1H),5.75(s,1H),5.17(br.s.,1H),3.99-3.83(m,2H),3.40-3.16(m,4H),2.78(s,3H),2.67(s,3H),2.12-1.95(m,3H),1.90-1.79(m,2H),1.39(t,J＝12.5Hz,1H),1.14(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:385(M+1)
流程B1
Figure PCTCN2016073143-appb-000091
实施例15
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,3,4-恶二唑
Figure PCTCN2016073143-appb-000092
实施例15A
(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-酰肼
Figure PCTCN2016073143-appb-000093
0℃下，向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-羧酸(1.8克，5.58毫摩尔)和DMF(1毫升)溶于氯仿(15毫升)的溶液中滴加氯化亚砜(20毫升)，加毕，反应体系加热至回流并保持3小时，降到室温后，将反应混合物倒入25％水合肼(1.4克，27.9毫摩尔)中，再搅拌2小时。混合物加水稀释，用二氯甲烷萃取，萃取液用无水硫酸钠干燥后浓缩得到标题化合物(黄色固体，1.7克，收率89％)。
实施例15B
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,3,4-恶二唑
Figure PCTCN2016073143-appb-000094
(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-酰肼(400毫克，1.2毫摩尔)和原甲酸三甲酯(5毫升)的混合物用微波加热至160℃反应半小时，浓缩至干后粗品通过制备高效液相色谱分离得到标题化合物(50毫克，收率12％)。
1H NMR(400MHz,CDCl3)δppm 1.02(t,J＝7.28Hz,3H),1.17(td,J＝13.55,3.51Hz,1H),1.26(s,1H),1.45(d,J＝13.05Hz,1H),1.60(d,J＝14.05Hz,1H),1.69-1.79(m,1H),1.90-2.01(m,2H),2.54(d,J＝16.31,3.26Hz,1H),2.63-2.69(m,2H),2.99-3.11(m,1H),3.26-3.41(m,2H),4.25(s,1H),5.99(s,1H),6.52(d,J＝8.53Hz,1H),7.03-7.15(m,2H),7.49(d,J＝7.53Hz,1H),8.57(s,1H).
LCMS(ESI)m/z:346(M+1)
实施例16
5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-yl)-1,3,4-恶二唑-2(3H)-酮
Figure PCTCN2016073143-appb-000095
向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-酰肼(170毫克，0.5毫摩尔)溶于二氧六环(7毫升)的溶液中加入羰基二咪唑(98毫克，0.6毫摩尔)，混合物加热回流45分钟，浓缩后，残留物通过制备高效液相色谱分离得到标题化合物(42毫克，收率23％)。
1H NMR(400MHz,CDCl3)δppm 0.90(t,J＝7.21Hz,3H),1.40(d,J＝13.69Hz,1H),1.50(d,J＝13.69Hz,1H),1.77-1.96(m,4H),2.11(s,1H),2.56(t,J＝11.00Hz,1H),2.68(s,1H),2.76(d,J＝10.27Hz,1H),3.23(d,J＝6.36Hz,2H),4.37(br.s.,1H),5.23(s,1H),5.81(s,1H),7.13(d,J＝3.67Hz,1H),7.17-7.22(m,1H),7.31-7.36(m,1H).
LCMS(ESI)m/z:362(M+1)
实施例17
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-5-甲基-1,3,4-恶二唑
Figure PCTCN2016073143-appb-000096
在50毫升圆底瓶中加入(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-酰肼(500毫克，1.5毫摩尔)、原乙酸三乙酯(487毫克，3毫摩尔)和醋酸(5毫升)，反应混合物回流约30分钟。LC-MS检测反应结束后，蒸去溶剂，残留物溶于2毫升二甲亚砜后制备分离得到标题化合物(200毫克，收率31.1％)。
1H NMR(400MHz,METHANOL-d4)δppm 1.12(t,J＝7.28Hz,3H),1.24-1.37(m,1H),1.70-1.85(m,2H),1.89-2.12(m,3H),2.56-2.74(m,5H),3.08-3.29(m,3H),3.84(d,J＝5.27Hz,2H),5.14(br.s.,1H),6.08(s,1H),6.78(d,J＝8.78Hz,1H),7.1-7.28(m,2H),7.55-7.68(m,1H).
LCMS(ESI)m/z:363(M+1)
流程B2
Figure PCTCN2016073143-appb-000097
实施例18
3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑
-5(4H)-酮
Figure PCTCN2016073143-appb-000098
实施例18A
(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-酰胺
Figure PCTCN2016073143-appb-000099
0℃下，向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-羧酸(4克，12.4毫摩尔)和DMF(0.1毫升)溶于氯仿(40毫升)的溶液中滴加氯化亚砜(5毫升)，加毕，反应体系加热至回流并保持3小时，降到室温后，将反应混合物倒入25％氨水(40毫升)中，再搅拌2小时。混合物加水稀释，用二氯甲烷萃取，萃取液用无水硫酸钠干燥后浓缩得到标题化合物(黄色固体，3.8克，收率95％)。
1H NMR(400MHz,CDCl3)δppm 7.44(d,J＝6.8Hz,1H),7.36(d,J＝8.0Hz,1H),7.09～7.15(m,2H),5.91～6.10(m,2H),5.84(s,1H),4.14(s,1H),3.32～3.41(m,1H),3.19～3.31(m,1H),2.89～3.09(m,1H),2.58～2.68(m,2H),2.44～2.55(m,1H),1.84～1.96(m,3H),1.65～1.77(m,1H),1.47～1.50(m,1H),1.39～1.42(m,1H),1.01(t,J＝8.0Hz,3H).
LCMS(ESI)m/z:322(M+1)
实施例18B
(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-腈
Figure PCTCN2016073143-appb-000100
0℃下，向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-酰胺(3.8克，11.8毫摩尔)溶于氯仿(50毫升)的溶液中滴入三氯氧磷，混合物加热回流4小时后冷却至室温，倒入冰水中并用40％氢氧化钠溶液调至中性。分出有机层，水层用二氯甲烷萃取，合并的有机层用碳酸氢钠溶液清洗后，用无水硫酸钠干燥。过滤并浓缩，粗品用异丙醇/水1/1的混合溶剂重结晶得到标题化合物(黄色固体，2.0克，收率56％)。
1H NMR(400MHz,CDCl3)δppm 7.94(d,J＝8.0Hz,1H),7.40(d,J＝8.0Hz,1H),7.17～7.21(m,1H),7.10～7.13(m,1H),5.86(s,1H),4.16(s,1H),3.27～3.32(m,1H),3.14～3.23(m,1H),2.91～2.98(m,1H),2.61(d,J＝4.0Hz,2H),2.42～2.47(m,1H),1.87～1.99(m,1H),1.70～1.81(m,2H),1.39～1.48(m,2H),1.01～1.09(m,1H),0.95(t,J＝8.0Hz,3H).
LCMS(ESI)m/z:304(M+1)
实施例18C
(41S,13aS,Z)-13a-乙基-N'-羟基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-脒
Figure PCTCN2016073143-appb-000101
向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-腈(300毫克，1毫摩尔)溶于甲醇(8毫升)的溶液中分别加入盐酸羟胺(350毫克，5毫摩尔)和二异丙基乙胺(323毫克，2.5毫摩尔)，反应混合物在室温下搅拌2小时后，再加入盐酸羟胺(175毫克，2.5毫摩尔)，再搅拌5小时，再加入盐酸羟胺(175毫克，2.5毫摩尔)，最后反应混合物在室温下搅拌17小时。反应结束后，向混合物中加入少量水，过滤，固体用乙酸乙酯清洗，然后溶于甲醇，蒸去溶剂得到纯的标题化合物(白色固体，300毫克，收率89％)。
1H NMR(400MHz,MeOD)δppm 1.10(t,J＝7.39Hz,3H),1.21-1.33(m,2H),1.34-1.39(m,1H),1.73(d,J＝11.69Hz,3H),1.85-1.92(m,2H),1.98(dt,J＝14.55,7.28Hz,2H),3.06-3.13(m,1H),3.21-3.26(m,2H),3.34(s,1H),3.79-3.85(m,2H),5.03(br.s.,1H),5.49(s,1H),7.13-7.19(m,1H),7.22(t,J＝7.28Hz,1H),7.38(d,J＝8.38Hz,1H),7.54(d,J＝7.72Hz,1H).
实施例18D
3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑-5(4H)-酮
Figure PCTCN2016073143-appb-000102
向(41S,13aS,Z)-13a-乙基-N'-羟基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-脒(200毫克，0.6毫摩尔)溶于二氧六环(10毫升)的溶液中加入羰基二咪唑(482毫克，3.0毫摩尔)，反应混合物加热回流45分钟，溶剂蒸干后，残留物通过制备高效液相色谱分离得到纯的标题化合物(127毫克，收率58％)。
1H NMR(400MHz,CDCl3)δppm 1.00(s,3H),1.26(d,J＝13.55Hz,1H),1.72(d,J＝15.06Hz,2H),1.92(s,4H),3.06(s,3H),3.26(s,1H),3.47(s,1H),3.60(s,1H),4.86(s,1H),5.85(s,1H),7.08(d,J＝7.53Hz,1H),7.16-7.25(m,2H),7.40-7.55(m,1H).
LCMS(ESI)m/z:362(M+1)
实施例19
3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-硫二唑-5(4H)-酮
Figure PCTCN2016073143-appb-000103
将(41S,13aS,Z)-13a-乙基-N'-羟基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-脒(200 毫克，0.6毫摩尔)和硫羰基二咪唑溶于四氢呋喃(15毫升)的溶液加热到60℃并搅拌1.5小时。反应液浓缩后残留物经制备高效液相色谱分离得到标题化合物(69毫克，收率31％)。
1H NMR(400MHz,CDCl3)δppm 1.02(br.s.,3H),1.14-1.31(m,2H),1.58(d,J＝14.11Hz,1H),1.72(d,J＝13.45Hz,1H),2.03(br.s.,1H),2.90(d,J＝11.03Hz,2H),3.14(br.s.,2H),3.47(d,J＝2.43Hz,1H),3.56(br.s.,1H),4.85(br.s.,1H),5.77(br.s.,1H),6.81(br.s.,1H),7.15(br.s.,2H),7.41(br.s.,1H).
LCMS(ESI)m/z:378(M+1)
实施例20
3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-5-甲基-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000104
在50毫升圆底瓶中分别加入(41S,13aS,Z)-13a-乙基-N'-羟基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-脒(150毫克，0.45毫摩尔)、乙酸酐(136.6毫克，0.134毫摩尔)和乙酸(10毫升)，反应混合物在110℃下搅拌约1小时。浓缩后残留物溶于1毫升N，N-二甲基甲酰胺，经制备分离得到标题化合物(17毫克，收率10.7％)。
1H NMR(400MHz,METHANOL-d4)δppm 7.61-7.55(m,1H),7.20-7.10(m,2H),6.87-6.78(m,1H),5.95(s,1H),5.14(s,1H),3.94-3.76(m,2H),3.29-3.23(m,2H),3.19-3.11(m,1H),2.71(s,3H),2.06-1.99(m,1H),1.99-1.91(m,2H),1.83-1.74(m,2H),1.37-1.29(m,2H),1.11(t,J＝7.4Hz,3H).
LCMS(ESI)m/z:361(M+1)
实施例21
3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-5-(三氟甲基)-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000105
0℃下，向(41S,13aS,Z)-13a-乙基-N'-羟基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-脒(700毫克，2.083毫摩尔)溶于四氢呋喃(20毫升)的溶液中分别加入吡啶(822.92毫克，10.417毫摩尔)和三氟乙酸酐(2177.08毫克，10.417毫摩尔)，反应混合物在10℃下搅拌约3小时。反应完全后减压除去溶剂，残留物加水用乙酸乙酯提取，萃取液浓缩后，粗品通过制备高效液相色谱分离得到标题化合物(400毫克，收率46.4％)。
1H NMR(400MHz,Methanol-d4)δppm 7.63-7.59(m,1H),7.21-7.19(m,2H),7.01-6.99(m,1H),6.20(s,1H),5.10(s,1H),3.84-3.82(m,2H),3.32-3.16(m,4H),2.08-2.00(m,3H),1.98-1.79(m,2H),1.30-1.15(m,1H),1.13-1.11(m,3H).
LCMS(ESI)m/z:415(M+1)
实施例22
5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-3-(三氟甲基)-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000106
向3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-5-(三氟甲基)-1,2,4-恶二唑(300毫克，0.725毫摩尔)溶于N，N-二甲基甲酰胺的溶液中分别加入盐酸羟胺(150毫克，2.174毫摩尔)和叔丁醇钾(243.93毫克，2.174毫摩尔)，反应混合物在40℃下搅拌5小时。过滤，再向滤液中加入叔丁醇钾(150.62毫克，1.342毫摩尔)，将混合物升温至100℃搅拌1小时。冷却到室温后，加水稀释，用乙酸乙酯萃取三次，合并的萃取液用盐水洗，浓缩后，残留物通过制备高效液相色谱分离得到标题化合物(30毫克，收率10％)。
1H NMR(400MHz,Methanol-d4)δppm 7.65-7.63(m,1H),7.27-7.21(m,2H),6.92-6.90(m,1H),6.51(s,1H),5.16(s,1H),3.94-3.85(m,2H),3.33-3.16(m,4H),2.12-2.03(m,3H),1.99-1.84(m,2H),1.33-1.17(m,1H),1.15-1.14(m,3H).
LCMS(ESI)m/z:415(M+1)
流程B3
Figure PCTCN2016073143-appb-000107
实施例23
3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-5-(四氢-2H-吡喃-4-基)-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000108
将二异丙基乙胺(288毫克，2.23毫摩尔)、四氢吡喃-4-甲酸(116毫克，0.89毫摩尔)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(340毫克，1.78毫摩尔)、1-羟基苯并三唑(120毫克，0.89毫摩尔)和N，N-二甲基甲酰胺(4毫升)的混合物在15℃下搅拌1小时，然后加入(41S,13aS,Z)-13a-乙基-N'-羟基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-脒(250毫克，0.74毫摩尔)，加毕，将混合物继续搅拌16小时，反应混合物用二氯甲烷/甲醇10/1的混合液萃取，萃取液浓缩，残留物通过制备薄层色谱(二氯甲烷/甲醇10/1的混合液作为展开剂)分离得到中间体酰胺(白色固体，205毫克，收率62％)。
将该中间体酰胺(205毫克，0.45毫摩尔)溶于甲苯(15毫升)，然后加入叔丁醇钾(167毫克，1.49毫摩尔)，将该混合物加热到回流并搅拌过夜。冷却到15℃，将混合物浓缩，残留物通过制备高效液相色谱分离得到标题化合物(70毫克，收率36％)。
1H NMR(CDCl3,400MHz)δppm 12.00(br.s.,1H),7.66-8.09(m,2H),7.49(d,J＝7.0Hz,1H),7.17(q,J＝6.9Hz,2H),6.78(d,J＝7.8Hz,1H),5.85-5.98(m,1H),4.95(br.s.,1H),4.06(d,J＝11.7Hz,2H),3.74-3.87(m,2H),3.58(t,J＝11.3Hz,2H),3.45(d,J＝11.3Hz,1H),3.26-3.36(m,1H),3.01-3.22(m,3H),1.94-2.15(m,7H),1.63-1.81(m,2H),1.25-1.39(m,1H),1.04(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:431(M+1)
实施例24
3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-5-(吡啶-4-基)-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000109
该实施例的制备方法同实施例23。
1H NMR(CDCl3,400MHz)δppm 11.54(br.s.,1H),9.00(d,J＝5.1Hz,2H),8.35(d,J＝5.5Hz,2H),7.43-7.57(m,1H),7.13-7.18(m,2H),6.83(d,J＝8.2Hz,1H),6.04(s,1H),4.99(br.s.,1H),3.71-3.89(m,2H),3.46(d,J＝11.0Hz,1H),3.03-3.21(m,3H),1.90-2.13(m,3H),1.64-1.81(m,2H),1.27-1.40(m,1H),1.02(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:424(M+1)
实施例25
2-(3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑-5-基)丙-2-醇
Figure PCTCN2016073143-appb-000110
该实施例的制备方法同实施例23。
1H NMR(MeOD,400MHz)δppm 7.46(d,J＝8.0Hz,1H),6.97-7.15(m,2H),6.65(d,J＝8.5Hz,1H),5.87(s,1H),4.33(br.s.,1H),3.03-3.15(m,1H),2.53-2.77(m,3H),1.87-2.05(m,2H),1.69-1.83(m,7H),1.49-1.66(m,2H),1.10-1.20(m,2H),1.05(t,J＝7.5Hz,3H).
LCMS(ESI)m/z:405(M+1)
实施例26
叔丁基-4-(3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑-5-基)哌啶-1-羧酸酯
Figure PCTCN2016073143-appb-000111
该实施例的制备方法同实施例23。
1H NMR(MeOD,400MHz)δppm 7.46(d,J＝7.5Hz,1H),6.95-7.13(m,2H),6.64(d,J＝8.0Hz,1H),5.85 (s,1H),4.32(br.s.,1H),4.07-4.14(m,2H),3.35-3.45(m,2H),3.07(d,J＝7.0Hz,3H),2.57-2.75(m,3H),2.15(d,J＝14.1Hz,2H),1.72-2.01(m,5H),1.63(d,J＝13.6Hz,1H),1.01-1.19(m,4H).
LCMS(ESI)m/z:530(M+1)
实施例27
3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-5-(4-氟苯)-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000112
该实施例的制备方法同实施例23。
1H NMR(MeOD,400MHz)δppm 8.24(dd,J＝5.3,8.8Hz,2H),7.28-7.50(m,3H),6.93-7.11(m,2H),6.76(d,J＝8.2Hz,1H),5.94(s,1H),4.40(br.s.,1H),3.39(d,J＝5.5Hz,2H),3.04-3.14(m,1H),2.61-2.79(m,3H),1.89-2.01(m,2H),1.77(d,J＝12.9Hz,1H),1.65(d,J＝13.7Hz,1H),1.51(d,J＝13.3Hz,1H),1.16(d,J＝3.1Hz,1H),1.04(t,J＝7.4Hz,3H).
LCMS(ESI)m/z:441(M+1)
实施例28
3-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-5-(噻吩-2-基)-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000113
该实施例的制备方法同实施例23。
1H NMR(MeOD,400MHz,)δppm 8.06(d,J＝3.5Hz,1H),7.94(d,J＝5.0Hz,1H),7.47(d,J＝7.5Hz,1H),7.33(t,J＝4.3Hz,1H),6.98-7.11(m,2H),6.80(d,J＝8.0Hz,1H),5.95(s,1H),4.34(br.s.,1H),3.03-3.18(m,1H),2.56-2.77(m,3H),1.87-2.08(m,2H),1.78(d,J＝14.1Hz,1H),1.65(d,J＝14.1Hz,1H),1.50(d,J＝13.6Hz,1H),1.11-1.21(m,1H),1.06(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:429(M+1)
流程B4
Figure PCTCN2016073143-appb-000114
实施例29
5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-3-甲基-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000115
向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-羧酸(14克，43.4毫摩尔)、1-羟基苯并三唑(300毫克，2.17毫摩尔)和三乙胺(31毫升，217毫摩尔)溶于N，N-二甲基甲酰胺(200毫升)的溶液里分别加入O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(14.6克，45.6毫摩尔)和N-羟基乙脒盐酸盐(5.28克，47.8毫摩尔)，反应混合物在室温下搅拌过夜，加入盐水并过滤，滤液加水稀释，用二氯甲烷萃取，萃取液用无水硫酸钠干燥后蒸去低沸点溶剂，残留的粗品的N，N-二甲基甲酰胺溶液直接用微波加热到160℃反应50分钟。粗品通过碱性制备高效液相色谱分离得到标题化合物(4.0克，收率25％)。
1H NMR(CDCl3,400MHz)δppm 7.46(d,J＝6.8Hz,1H),7.13-7.06(m,2H),6.73(d,J＝8.0Hz,1H),6.08(s,1H),4.23(s,1H),3.38-3.34(m,2H),3.29-3.28(m,2H),2.65～2.63(m,2H),2.55～2.51(m,1H),2.51(s,3H),1.97～1.92(m,2H),1.59-1.55(m,2H),1.45-1.41(m,1H),1.11-1.10(m,1H),1.00(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:361(M+1)
实施例30
5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-3-苯基-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000116
该实施例的制备方法同实施例29。
1H NMR(CDCl3,400MHz)δppm 8.19-8.13(m,2H),7.55-7.47(m,4H),7.17-7.04(m,2H),6.88(d,J＝7.94Hz,1H),6.19(s,1H),4.26(br.s.,1H),3.43-3.25(m,2H),3.13-3.00(m,1H),2.71-2.60(m,2H),2.55(dd,J＝16.21,2.98Hz,1H),2.06-1.87(m,3H),1.85-1.68(m,1H),1.62(d,J＝13.45Hz,1H),1.52-1.38(m,1H),1.17(td,J＝13.67,3.53Hz,1H),1.04(t,J＝7.50Hz,3H).
LCMS(ESI)m/z:423(M+1)
实施例31
5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-3-(吡啶-4-基)-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000117
该实施例的制备方法同实施例29。
1H NMR(400MHz,CDCl3)δppm 8.83(d,J＝4.02Hz,2H),8.02(d,J＝6.02Hz,2H),7.54(d,J＝7.53Hz,1H),7.16-7.24(m,1H),6.87(d,J＝7.53Hz,1H),6.26(s,1H),5.30(s,1H),4.69(br.s.,1H),3.62(br.s., 1H),3.22-3.06(m,2H),2.89(d,J＝11.04Hz,2H),2.03(td,J＝14.68,6.78Hz,2H),1.75(d,J＝14.05Hz,1H),1.62(d,J＝13.55Hz,1H),1.23-1.32(m,2H),1.09(t,J＝7.28Hz,3H).
LCMS(ESI)m/z:424(M+1)
实施例32
5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-3-(4-氟苯)-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000118
该实施例的制备方法同实施例29。
1H NMR(400MHz,CDCl3)δppm 8.16(d,J＝8.71,5.40Hz,2H),7.50(d,J＝7.50Hz,1H),7.15-7.23(m,2H),7.07-7.15(m,2H),6.87(d,J＝7.94Hz,1H),6.19(s,1H),4.26(br.s.,1H),3.36-3.43(m,1H),3.26-3.35(m,1H),3.00-3.12(m,1H),2.67(d,J＝6.39Hz,2H),2.52-2.59(m,1H),1.91-2.03(m,2H),1.71-1.81(m,1H),1.62(d,J＝13.67Hz,2H),1.46(d,J＝13.23Hz,1H),1.10-1.26(m,2H),1.04(t,J＝7.39Hz,3H).
LCMS(ESI)m/z:440(M+1)
实施例33
3-乙基-5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000119
该实施例的制备方法同实施例29。
1H NMR(400MHz,Methanol-d4)δppm 7.61-7.59(d,J＝8.0Hz,1H),7.23-7.16(m,2H),6.75-6.73(d,J＝8.0Hz,1H),6.22(s,1H),5.05(s,1H),3.80(m,2H),3.30-3.13(m,4H),2.89-2.85(m,2H),2.09-1.98(m,3H),1.77(m,2H),1.41-1.37(m,1H),1.36-1.25(m,1H),1.14-1.10(m,3H).
实施例34
5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-3-异丙基-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000120
该实施例的制备方法同实施例29。
1H NMR(400MHz,Methanol-d4)δppm 7.63-7.61(d,J＝8.0Hz,1H),7.24-7.17(m,2H),6.74-6.72(d,J＝8.0Hz,1H),6.24(s,1H),5.14(s,1H),3.93-3.85(m,2H),3.32-3.20(m,5H),2.07-1.99(m,3H),1.83-1.79(m, 2H),1.43-1.40(m,6H),1.32-1.30(m,1H),1.16-1.12(m,3H).
实施例35
3-环丙基-5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000121
该实施例的制备方法同实施例29。
1H NMR(400MHz,MeOD-d4)δppm 7.61(d,J＝6.5Hz,1H),7.26-7.16(m,2H),6.77-6.65(m,1H),6.21(s,1H),5.12(br.s.,1H),3.85(d,J＝5.0Hz,2H),3.29-3.12(m,3H),2.30-2.21(m,1H),2.12-1.94(m,3H),1.86-1.73(m,2H),1.58-0.78(m,9H).
LCMS(ESI)m/z:387(M+1)
流程B5
Figure PCTCN2016073143-appb-000122
实施例36
3-(二氟甲基)-5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000123
实施例36A
2,2-二乙氧基-N'-羟基乙脒
Figure PCTCN2016073143-appb-000124
在0℃下，将盐酸羟胺(2.674克，38.76毫摩尔)和甲醇钠(2.093克，38.76毫摩尔)在甲醇(20毫升)中的混合物搅拌半小时，再升温至25℃搅半小时，加入二乙氧基乙腈(1克，7.752毫摩尔)，混合物升温至40℃搅拌过夜。溶剂减压除去后，残留物加水稀释并用乙酸乙酯萃取(3×20毫升)，萃取液合并后用盐水清洗，经无水硫酸钠干燥后，浓缩得到标题化合物的粗品(无色油状物，900毫克，收率71.6％)。
实施例36B
(41S,13aS)-N-(-2,2-二乙氧基-1-(肟基)乙基)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺
Figure PCTCN2016073143-appb-000125
向2,2-二乙氧基-N'-羟基乙脒(600毫克，3.529毫摩尔)溶于四氢呋喃(20毫升)的溶液中加入(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-酰氯(1克，2.941毫摩尔，用实施例21A的方法制备，并蒸除过量的氯化亚砜)，反应完全后，蒸除低沸点组分得到标题化合物的粗品(黄色固体，1.6克，收率～100％)。
LCMS(ESI)m/z:467(M+1)
实施例36C
3-(二乙氧甲基)-5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000126
将(41S,13aS)-N-(-2,2-二乙氧基-1-(肟基)乙基)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺(1.2克，2.79毫摩尔)和叔丁醇钾(469毫克，4.185毫摩尔)在N,N-二甲基甲酰胺中的混合物加热到110℃2小时，冷却后加水20毫升，用乙酸乙酯萃取(3×50毫升)，合并的萃取液用盐水洗，真空浓缩后得到标题化合物的粗品(黄色固体，900毫克，71.9％)
LCMS(ESI)m/z:449(M+1)
实施例36D
5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑-3-甲醛
Figure PCTCN2016073143-appb-000127
向盐酸(1.613克，44.2毫摩尔)和水(0.8克，44.2毫摩尔)中加入3-(二乙氧甲基)-5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑(200毫克，0.446毫摩尔)，反应混合物加热回流1小时，LC-MS鉴测反应完全后，将混合物缓慢倒入水中，再用乙酸乙酯萃取(3×20毫升)，合并的萃取液用盐水清洗、无水硫酸钠干燥后，真空浓缩得标题化合物的粗品(黄色固体，100毫克，收率59.9％)。
LCMS(ESI)m/z:393(M+1)
实施例36E
3-(二氟甲基)-5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑
Figure PCTCN2016073143-appb-000128
0℃、氮气保护下向5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑-3-甲醛(100毫克，0.267毫摩尔)溶于无水二氯甲烷(10毫升)的溶液中加入二乙氨基三氟化硫(644.72毫克，1.070毫摩尔)，加毕升温到15℃继续搅拌10小时。将混合物倒入饱和碳酸氢钠溶液，用二氯甲烷萃取(3×15毫升)，合并的萃取液盐水洗后浓缩，粗品通过制备高效液相色谱分离得到标题化合物(15毫克，收率14.2％)。
1H NMR(400MHz,Methanol-d4)δppm 7.65-7.63(m,1H),7.25-7.05(m,1H),7.25-7.22(m,2H),6.84-6.82(m,1H),6.44(s,1H),5.20(s,1H),3.97-3.85(m,2H),2.07-1.98(m,3H),1.97-1.85(m,2H),1.36-1.35(m,2H),1.17-1.14(m,3H).
LCMS(ESI)m/z:397(M+1)
流程B6
Figure PCTCN2016073143-appb-000129
实施例37
2-(5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑-3-基)丙-2-醇
Figure PCTCN2016073143-appb-000130
实施例37A
乙基-2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺基)-2-(肟基)乙酸
Figure PCTCN2016073143-appb-000131
将(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-羧酸(2.0克，6.20毫摩尔)和氯化亚砜(10.0毫升)的混合物加热回流2小时，减压浓缩后粗品溶于二氯甲烷(30毫升)，0℃下向其中加入乙基-2-氨基-2-(肟基)乙酸(1.0克，7.58毫摩尔)溶于四氢呋喃(30毫升)的溶液，反应混合物搅拌过夜，反应完全后将混合物浓缩得到标题化合物(黄色固体，2.71克，收率100％)。
1H NMR(DMSO_d6,400MHz)δppm 7.59(d,J＝7.5Hz,1H),7.24-7.14(m,3H),6.51(s,1H),5.05(br.s.,1H),4.33(q,J＝7.2Hz,2H),3.25-2.94(m,4H),2.23-2.12(m,1H),1.97-1.82(m,2H),1.76(td,J＝3.3,6.5Hz,3H),1.63(d,J＝12.3Hz,2H),1.32(t,J＝7.2Hz,3H),1.03(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:437(M+1)
实施例37B
乙基-5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑-3-羧酸酯
Figure PCTCN2016073143-appb-000132
向乙基-2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺基)-2-(肟基)乙酸(2.71克，6.2毫摩尔)溶于甲苯(250毫升)的溶液中加入碳酸铯(4.03克，12.4毫摩尔)，反应混合物在110℃下搅拌1小时。反应结束后，将甲苯浓缩掉，向残留物中加入水(100毫升)，用二氯甲烷萃取(3×100毫升)，合并后的萃取液用200毫升盐水清洗、无水硫酸钠干燥后浓缩，粗品通过制备高效液相色谱分离得到标题化合物(黄色固体，400毫克，收率15％)。
1H NMR(400MHz,MeOD)δppm 7.51(d,J＝7.0Hz,1H),7.18-7.05(m,2H),6.72(d,J＝8.0Hz,1H),6.32(s,1H),4.53(q,J＝7.0Hz,2H),4.32(s.,1H),3.43-3.35(m,2H),3.10(td,J＝7.8,15.9Hz,1H),2.70-2.58(m,3H),2.10-1.91(m,2H),1.80-1.62(m,2H),1.51(d,J＝13.6Hz,1H),1.46(t,J＝7.3Hz,3H),1.12-1.03(m,4H).
LCMS(ESI)m/z:419(M+1)
实施例37C
2-(5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑-3-基)丙-2-醇
Figure PCTCN2016073143-appb-000133
0℃下，向乙基-5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-1,2,4-恶二唑-3-羧酸酯(200毫克，0.48毫摩尔)溶于四氢呋喃(5毫升)的溶液中滴加甲基溴化镁(3M， 0.5毫升，1.5毫摩尔)，反应混合物在0℃下搅拌1小时。反应结束后，向混合物中加入10毫升水，用二氯甲烷萃取(3×20毫升)，合并的萃取液用盐水清洗、无水硫酸钠干燥后浓缩，粗品通过制备高效液相色谱分离得到标题化合物(30毫克，收率15.4％)。
1H NMR(400MHz,MeOD)δppm 7.50(d,J＝7.5Hz,1H),7.20-7.00(m,2H),6.67(d,J＝8.5Hz,1H),6.1(s,1H),4.34(s.,1H),3.36(s.,1H),3.08(d,J＝8.0Hz,1H),2.77-2.52(m,3H),2.13-1.87(m,2H),1.85-1.61(m,9H),1.51(d,J＝12.0Hz,1H),1.18-1.10(m,1H),1.07(t,J＝7.5Hz,3H).
LCMS(ESI)m/z:405(M+1)
流程B7
Figure PCTCN2016073143-appb-000134
实施例38
(S)-2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基-4,5-二氢恶唑
Figure PCTCN2016073143-appb-000135
实施例38A
(41S,13aS)-13a-乙基-N-((S)-1-羟基丙-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺
Figure PCTCN2016073143-appb-000136
向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-羧酸(500毫克，1.552毫摩尔)溶于二氯甲烷(7.8毫升)的溶液中分别加入O-(7-氮杂苯并三氮唑-1-YL)-N,N,N',N'-四甲基脲六氟膦盐(707.7毫克，1.862毫摩尔)和二异丙基乙胺(240.25毫克，1.862毫摩尔)，混合物搅拌1小时，再加入L-氨基丙醇(233.01毫克，3.104毫摩尔)，反应混合物继续搅拌4小时。加水稀释后，反应混合物用二氯甲烷萃取，萃取液经水和盐水清洗后用无水硫酸钠干燥，真空浓缩后残留物用二氯甲烷/甲醇20/1作为洗脱液过硅胶柱得到标题化合物(570毫克，收率96％)。
1H NMR(400MHz,CHLOROFORM-d)δppm 0.94-1.07(m,4H),1.29(d,J＝7.03Hz,3H),1.36-1.57(m,3H),1.65-1.80(m,1H),1.81-2.00(m,2H),2.52(d,J＝14.05Hz,1H),2.58-2.71(m,2H),2.96-3.10(m,1H),3.19-3.30(m,1H),3.31-3.41(m,1H),3.61-3.70(m,1H),3.80(d,J＝10.54Hz,1H),4.18(br.s.,1H),4.30(br.s.,1H),5.72(s,1H),6.26(br.s.,1H),7.08-7.20(m,2H),7.32(d,J＝8.03Hz,1H),7.46(d,J＝7.53Hz,1H).
实施例38B
(S)-2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基-4,5-二氢恶唑
Figure PCTCN2016073143-appb-000137
氮气保护下，将(41S,13aS)-13a-乙基-N-((S)-1-羟基丙-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺(200毫克，0.527毫摩尔)溶于三氟化硼乙醚的溶液加热到120℃搅拌20小时，反应结束后，反应混合物加水稀释并用氢氧化钠溶液将pH调至8，再用二氯甲烷萃取，萃取液经水和盐水清洗后用无水硫酸钠干燥，真空浓缩后残留物通过制备高效液相色谱分离得到标题化合物(白色固体，60毫克，收率31％)。
1H NMR(400MHz,METHANOL-d4)δppm 7.42(d,J＝8.03Hz,1H),7.25(d,J＝8.03Hz,1H),7.03-7.16(m,2H),5.87(s,1H),4.54-4.67(m,1H),4.43(dt,J＝9.16,6.71Hz,1H),4.06-4.21(m,2H),3.12-3.31(m,2H),2.88-3.05(m,1H),2.41-2.63(m,3H),1.77-1.97(m,2H),1.58-1.75(m,1H),1.52(d,J＝13.55Hz,1H),1.38(d,J＝6.53Hz,4H),0.86-1.08(m,4H).
流程B8
Figure PCTCN2016073143-appb-000138
实施例39
5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-3-甲基-1,2,4-噻二唑
Figure PCTCN2016073143-appb-000139
实施例39A
(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-硫代酰胺
Figure PCTCN2016073143-appb-000140
向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-腈(2克，6.6毫摩尔)溶于N,N-二甲基甲酰胺(20毫升)的溶液中分别加入乙硫酰胺(1.48克，19.8毫摩尔)和4N的盐酸二氧六环溶液(8毫升，33毫摩尔)，反应混合物在120℃下搅拌过夜。冷却后混合物用碳酸氢钠水溶液调至中性，用乙酸乙酯萃取，萃取液干燥并浓缩，残留物用二氯甲烷/四氢呋喃20/1作为洗脱液过硅胶柱得到标题化合物(黄色固体，580毫克，收率26％)。
1H NMR(400MHz,CHLOROFORM-d)δppm 0.93-1.05(m,4H),1.35-1.42(m,1H),1.55(d,J＝13.80Hz,1H),1.63-1.76(m,1H),1.88-1.95(m,2H),2.47-2.64(m,3H),2.99-3.08(m,1H),3.20-3.30(m,1H),3.32-3.40(m,1H),4.13(s,1H),6.12(br.s.,1H),7.08(br.s.,1H),7.12-7.20(m,2H),7.35-7.40(m,1H),7.47-7.51(m,1H),7.90(br.s.,1H).
实施例39B
(41S,13aS)-N-(1-(二甲氨基)亚乙基)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-硫代酰胺
Figure PCTCN2016073143-appb-000141
将(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-硫代酰胺(560毫克，1.7毫摩尔)和N,N-二甲基乙酰胺二甲基缩醛(3毫升)的混合物在室温下搅拌3.5小时，溶剂蒸去后，残留物用二氯甲烷/四氢呋喃10/1作为洗脱液过硅胶柱得到标题化合物(橙色固体，800毫克，粗品)。
LCMS(ESI)m/z:407(M+1)
实施例39C
5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-3-甲基-1,2,4-噻二唑
Figure PCTCN2016073143-appb-000142
向(41S,13aS)-N-(1-(二甲氨基)亚乙基)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘 啶-12-硫代酰胺(400毫克，0.98毫摩尔)溶于乙醇/甲醇(12毫升/6毫升)的溶液中分别加入羟胺-O-磺酸(156毫克，1.4毫摩尔)和吡啶(311毫克，3.9毫摩尔)，混合物在60℃下搅拌过夜。反应结束后，加水稀释，并用乙酸乙酯萃取，萃取液干燥并浓缩，残留物通过制备高效液相色谱分离得到标题化合物(100毫克，收率27％)。
1H NMR(400MHz,CHLOROFORM-d)δppm 1.12(t,J＝7.15Hz,3H),1.29-1.39(m,1H),1.68-1.86(m,2H),2.21-2.35(m,3H),2.79(s,3H),2.98-3.22(m,3H),3.36(d,J＝6.78Hz,1H),3.63-3.87(m,2H),4.80(br.s.,1H),5.77(s,1H),6.51(d,J＝8.28Hz,1H),7.09-7.17(m,1H),7.18-7.25(m,1H),7.53(d,J＝7.78Hz,1H).
实施例40
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4,5-二甲基噻唑
Figure PCTCN2016073143-appb-000143
将(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-硫代酰胺(200毫克，0.59毫摩尔)和3-氯丁-2-酮(9.47克，88.89毫摩尔)装入封管，在130℃下反应20小时。冷却到20℃，加入10毫升乙酸乙酯和20毫升水，水层用乙酸乙酯萃取(2×20毫升)，合并的萃取液用10毫升盐水清洗、无水硫酸钠干燥、真空浓缩后，粗品通过制备高效液相色谱分离得到标题化合物(40毫克，收率15.84％)。
1H NMR(400MHz,METHANOL-d4)δppm 7.60(d,J＝7.5Hz,1H),7.20-7.15(m,1H),7.13-7.08(m,1H),6.37(d,J＝8.3Hz,1H),5.80(s,1H),5.16(br.s.,1H),3.96-3.80(m,2H),3.33-3.12(m,4H),2.55(s,3H),2.44(s,3H),2.09-1.91(m,3H),1.84-1.73(m,2H),1.38-1.28(m,1H),1.12(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:390(M+1)
流程B9
Figure PCTCN2016073143-appb-000144
实施例41
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-5-甲氧基-4-甲基恶唑
Figure PCTCN2016073143-appb-000145
实施例41A
(S)-甲基-2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺基)丙酸乙酯
Figure PCTCN2016073143-appb-000146
向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-羧酸(500毫克，1.552毫摩尔)溶于二氯甲烷(7.7毫升)的溶液中分别加入O-(7-氮杂苯并三氮唑-1-YL)-N,N,N',N'-四甲基脲六氟膦盐(707.7毫克，1.862毫摩尔)和二异丙基乙胺(600.6毫克，4.656毫摩尔)，该混合物搅拌1小时后，加入(S)-丙氨酸甲酯盐酸盐(431.6毫克，3.104毫摩尔)，反应混合物继续搅拌4小时。加水稀释后用二氯甲烷萃取，萃取液经水洗、盐水洗后用无水硫酸钠干燥，真空浓缩，残留物用二氯甲烷/甲醇20/1过硅胶柱得到标题化合物(白色固体，600毫克，收率95％)。
LCMS(ESI)m/z:408(M+1)
实施例41B
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-5-甲氧基-4-甲基恶唑
Figure PCTCN2016073143-appb-000147
向三苯基膦(514.93毫克，1.96毫摩尔)和碘(498.28毫克，1.96毫摩尔)溶于无水二氯甲烷(10毫升)的溶液中滴入三乙胺(397.31毫克，3.93毫摩尔)，混合物搅拌约10分钟逐渐变成红黑色，再向其中加入(S)-甲基-2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺基)丙酸乙酯(200毫克，0.49毫摩尔)溶于二氯甲烷(2.5毫升)的溶液，所得混合物搅拌24小时直到通过薄层色谱检测反应完全。反应混合物用二氯甲烷稀释，饱和碳酸氢钠溶液、盐水清洗，无水硫酸钠干燥，过滤，滤液真空浓缩后，残留物用石油醚/四氢呋喃5/1过硅胶柱得到标题化合物(40毫克，收率20.9％)。
1H NMR(400MHz,METHANOL-d4)δppm 1.13(t,J＝7.03Hz,3H)1.22-1.35(m,1H)1.79(br.s.,2H)1.88-2.09(m,3H)2.11-2.16(s,3H)3.10-3.32(m,4H)3.76-4.01(m,5H)5.13(br.s.,1H)5.82(s,1H)6.59(dd,J＝5.77,2.76Hz,1H)7.20(dd,J＝5.52,2.51Hz,2H)7.60(d,J＝5.02Hz,1H).
流程B10
Figure PCTCN2016073143-appb-000148
实施例42
(41S,13aS)-13a-乙基-12-(咪唑[1,2-a]吡啶-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶
Figure PCTCN2016073143-appb-000149
实施例42A
(41S,13aS)-13a-乙基-N-甲氧基-N-甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺
Figure PCTCN2016073143-appb-000150
室温下向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-羧酸(18克，56毫摩尔)溶于N,N-二甲基甲酰胺的溶液中分别加入N,O-二甲基羟胺盐酸盐(11.3克，112毫摩尔)、O-(7-氮杂苯并三氮唑-1-YL)-N,N,N',N'-四甲基脲六氟膦盐(22克，56毫摩尔)和三乙胺(10.6克，112毫摩尔)，反应混合物搅拌过夜。将反应混合物加水稀释，用乙酸乙酯萃取，萃取液用无水硫酸钠干燥，过滤并浓缩后得到标题化合物(固体，18克，收率90％)。
LCMS(ESI)m/z:366(M+1)
实施例42B
1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)乙酮
Figure PCTCN2016073143-appb-000151
0℃下向(41S,13aS)-13a-乙基-N-甲氧基-N-甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺(17克，49毫摩尔)溶于四氢呋喃(170毫升)的溶液中滴入甲基溴化镁(50毫升，150毫摩尔)，混合物在该温度下继续搅拌4小时。将混合物倒入氯化铵溶液中，用二氯甲烷萃取，硫酸钠干燥，过滤并浓缩得到标题化合物(固体，11克，收率70.5％)。
LCMS(ESI)m/z:321(M+1)
实施例42C
2-溴-1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)乙酮
Figure PCTCN2016073143-appb-000152
向1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)乙酮(7克，21.8毫摩尔)溶于二氯甲烷的溶液中分批加入液溴(3.47克，21.8毫摩尔)，混合物在室温下搅拌4小时。将混合物倒入水中，并用二氯甲烷萃取，萃取液经无水硫酸钠干燥，过滤并浓缩后得到标题化合物的粗品(5克，收率57.6％)，该粗品直接用于下面的反应。
实施例42D
(41S,13aS)-13a-乙基-12-(咪唑[1,2-a]吡啶-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶
Figure PCTCN2016073143-appb-000153
将2-溴-1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)乙酮(400毫克，1毫摩尔)和2-氨基吡啶(92毫克，1毫摩尔)溶于乙醇(3毫升)的混合物加热到70℃反应8小时，滤出产生的固体用乙酸乙酯清洗，并通过制备高效液相色谱分离得到标题化合物(100毫克，收率25.3％)。
1H NMR(CD3OD,400MHz)δppm 8.11(d,J＝6.6Hz,1H),7.69-7.59(m,2H),7.46(d,J＝7.9Hz,1H),7.23(d,J＝7.9Hz,1H),7.04(t,J＝7.5Hz,1H),6.95-6.80(m,3H),6.64(d,J＝8.4Hz,1H),5.60(s,1H),4.31(br.s.,1H),3.48-3.27(m,2H),3.15-3.01(m,1H),2.76-2.53(m,3H),2.02-1.86(m,2H),1.60(d,J＝13.7Hz,1H),1.43(d,J＝13.2Hz,1H),1.29-1.15(m,1H),1.01(t,J＝7.5Hz,3H).
LCMS(ESI)m/z:395(M+1)
实施例43
4-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)噻唑-2-氨
Figure PCTCN2016073143-appb-000154
将2-溴-1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)乙酮(400毫克，1毫摩尔)和硫脲(92毫克，1毫摩尔)溶于乙醇(3毫升)的混合物加热到80℃反应2小时，冷却后倒入水中并用二氯甲烷萃取，萃取液浓缩后粗品通过制备高效液相色谱分离得到标题化合物(10毫克，收率50％)。
1H NMR(CD3OD,400MHz)δppm 7.45(d,J＝7.5Hz,1H),7.10-6.96(m,2H),6.70-6.55(m,2H),5.39(s,1H),5.04(s,2H),4.23(br.s.,1H),3.42-3.21(m,2H),3.11-2.98(m,1H),2.70-2.45(m,3H),1.96-1.81(m,2H),1.58-1.34(m,2H),1.18-0.90(m,3H).
LCMS(ESI)m/z:377(M+1)
实施例44
(41S,13aS)-13a-乙基-12-(7-(三氟甲基)咪唑[1,2-a]吡啶-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶
Figure PCTCN2016073143-appb-000155
将2-溴-1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)乙酮(400毫克，1毫摩尔)和2-氨基-4-三氟甲基吡啶(162毫克，1毫摩尔)溶于乙醇(3毫升)的混合物加热到回流反应12小时，将混合物浓缩，粗品通过制备高效液相色谱分离得到标题化合物(100毫克，收率22％)。
1H NMR(CD3OD,400MHz)δppm 8.24(d,J＝7.0Hz,1H),7.98(s,1H),7.76(s,1H),7.53-7.43(m,1H),7.10-6.99(m,2H),6.93(t,J＝7.8Hz,1H),6.58(d,J＝8.5Hz,1H),5.64(s,1H),4.31(br.s.,1H),3.50-3.28(m,2H),3.17-3.00(m,1H),2.79-2.52(m,3H),2.06-1.72(m,4H),1.49-1.35(m,1H),1.30-1.13(m,1H),1.02(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:463(M+1)
流程B11
Figure PCTCN2016073143-appb-000156
实施例45
5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)异恶唑
Figure PCTCN2016073143-appb-000157
实施例45A
(E)-3-(二甲氨基)-1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)丙-2-烯-1-酮
Figure PCTCN2016073143-appb-000158
将1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)乙酮(800毫克，2.5毫摩尔)和N,N-二甲基甲酰胺二甲基缩醛(8毫升)的混合物加热回流到原料消失，降低沸点组分减压浓缩干得到标题化合物(700毫克，收率74.7％)，该产品直接用于下一步的反应。
LCMS(ESI)m/z:376(M+1)
实施例45B
5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)异恶唑
Figure PCTCN2016073143-appb-000159
向(E)-3-(二甲氨基)-1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)丙-2-烯-1-酮(350毫克，0.93毫摩尔)溶于N,N-二甲基甲酰胺(3毫升)的溶液中加入盐酸羟胺(100毫克，1.4毫摩尔)，反应混合物用微波加热到120℃反应2小时，真空浓缩后残留物通过制备高效液相色谱分离得到标题化合物(60毫克，收率18.7％)。
1H NMR(CD3OD,400MHz)δppm 8.53(s,1H),7.48(d,J＝8.0Hz,1H),7.15-6.96(m,3H),6.67(d,J＝8.5Hz,1H),6.45(s,1H),5.58(s,1H),3.07(br.s.,1H),2.70(br.s.,1H),2.05-1.84(m,2H),1.48(br.s.,1H),1.30-1.12(m,2H),1.02(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:346(M+1)
实施例46
(41S,13aS)-13a-乙基-12-(1-甲基-1H-吡唑-3-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶和(41S,13aS)-13a-乙基-12-(1-甲基-1H-吡唑-5-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶
Figure PCTCN2016073143-appb-000160
向(E)-3-(二甲氨基)-1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶 -12-基)丙-2-烯-1-酮(200毫克，0.53毫摩尔)溶于醋酸(2毫升)的溶液中加入甲基肼(46毫克，1毫摩尔)，混合物回流4小时后倒入水中，用二氯甲烷萃取，无水硫酸钠干燥，过滤并浓缩，残留物经超临界流体色谱分离得到两个标题化合物，(41S,13aS)-13a-乙基-12-(1-甲基-1H-吡唑-3-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶(20毫克，收率10.5％)，
1H NMR(CD3OD,400MHz)δppm 7.51-7.41(m,2H),7.10-6.91(m,2H),6.62(d,J＝8.5Hz,1H),6.30(d,J＝2.0Hz,1H),5.38(s,1H),4.00(s,3H),3.53-3.28(m,2H),3.08(t,J＝15.8Hz,1H),2.84-2.55(m,3H),1.95(br.s.,2H),1.61(d,J＝13.1Hz,5H),1.45(d,J＝13.1Hz,2H),1.34-1.11(m,2H),1.02(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:359(M+1)
和(41S,13aS)-13a-乙基-12-(1-甲基-1H-吡唑-5-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶(30毫克，收率15.8％)。
1H NMR(CD3OD,400MHz)δppm 7.61(s,1H),7.45(d,J＝7.5Hz,1H),7.11-6.87(m,2H),6.41(br.s.,1H),5.89(d,J＝8.5Hz,1H),5.20(br.s.,1H),4.37(br.s.,1H),3.72-3.27(m,5H),3.14-3.00(m,1H),2.84-2.48(m,3H),2.09-1.93(m,1H),1.86(dd,J＝6.8,13.8Hz,3H),1.59(d,J＝12.5Hz,5H),1.35-1.15(m,3H),1.02(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:359(M+1)
实施例47
5-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-3-甲基异恶唑
Figure PCTCN2016073143-appb-000161
将1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)乙酮(80毫克，0.25毫摩尔)溶于2毫升N,N-二甲基乙酰胺二甲基缩醛的溶液加热回流2小时，低沸点组分真空除去后残留物溶于5毫升乙腈，分别加入盐酸羟胺(20毫克，0.3毫摩尔)和三氯氧磷(100毫克)，反应混合物加热回流1小时。冷却到室温后，倒入碳酸氢钠溶液，用二氯甲烷萃取，盐水洗，无水硫酸钠干燥，真空除去溶剂，残留物通过制备高效液相色谱分离得到标题化合物。
1H NMR(400MHz,METHANOL-d4)δppm 7.40(d,J＝7.5Hz,1H),7.08-6.91(m,2H),6.52(s,1H),6.39(d,J＝8.3Hz,1H),5.57(s,1H),4.21(br.s.,1H),3.38-3.36(m,1H),3.31-3.15(m,2H),3.07-2.91(m,1H),2.65-2.44(m,3H),2.39(s,3H),2.03(s,4H),1.58-1.34(m,2H),1.00(t,J＝7.4Hz,4H).
LCMS(ESI)m/z:360(M+1)
流程B12
Figure PCTCN2016073143-appb-000162
实施例48
1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)丁-1-酮-O-甲基肟
Figure PCTCN2016073143-appb-000163
实施例48A
1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)丁-1-酮
Figure PCTCN2016073143-appb-000164
0℃、氮气保护下，向(41S,13aS)-13a-乙基-N-甲氧基-N-甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺(200毫克，0.55毫摩尔)溶于四氢呋喃(2毫升)的溶液中缓慢滴入正丙基溴化镁(2M溶于四氢呋喃，0.825毫升，1.65毫摩尔)，加毕，反应混合物在该条件下继续搅拌4小时。向混合物中加入饱和氯化铵溶液(20毫升)，再用40毫升乙酸乙酯萃取，萃取液经盐水洗，硫酸钠干燥后，过滤并浓缩，残留物通过制备高效液相色谱分离得到标题化合物。
1H NMR(400MHz,MeOD)δppm 7.52-7.61(m,1H),7.16-7.28(m,2H),7.00-7.06(m,1H),6.30(s,1H),3.58-3.77(m,2H),3.23-3.30(m,1H),3.11-3.23(m,2H),2.98-3.08(m,1H),2.84-2.96(m,2H),2.01-2.15(m,1H),1.94(dt,J＝14.68,7.47Hz,2H),1.70-1.88(m,4H),1.03-1.24(m,7H).
LCMS(ESI)m/z:349(M+1)
实施例48B
1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)丁-1-酮-O-甲基肟
Figure PCTCN2016073143-appb-000165
将1-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)丁-1-酮(200毫克，0.55毫摩尔)、甲氧基胺盐酸盐(455毫克，5.5毫摩尔)、醋酸钠(445毫克，5.5毫摩尔)和乙醇(10毫升)的混合物回流搅拌过夜。混合物加水(20毫升)稀释，再用40毫升二氯甲烷萃取，萃取液经盐水洗，无水硫酸钠干燥，过滤并浓缩后，粗品通过制备高效液相色谱和超临界流体色谱分离得到标题化合物。
超临界流体色谱方法：
"柱:Chiralpak AD-H 250×4.6mm I.D.,5um；流动相:异丙醇(0.05％DEA)，CO25％～40％；流速：2.35mL/min；波长:220nm"
1H NMR(400MHz,METHANOL-d4)δppm 7.55(d,J＝7.53Hz,1H),7.11-7.24(m,3H),5.28(s,1H),4.01(s,3H),3.64-3.79(m,2H),2.95-3.25(m,5H),2.23(s,1H),1.97-2.12(m,2H),1.77-1.97(m,2H),1.67(d,J＝11.04Hz,2H),1.51(dt,J＝15.18,7.72Hz,2H),1.42(s,3H),1.17-1.33(m,2H),1.10(t,J＝7.53Hz,3H),0.91(t,J＝7.28Hz,3H).
LCMS(ESI)m/z:378(M+1)
实施例49
4-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)庚-4-醇
Figure PCTCN2016073143-appb-000166
0℃、氮气保护下，向长春西汀(300毫克，0.86毫摩尔)溶于四氢呋喃(2毫升)的溶液中缓缓滴加正丙基溴化镁(2M溶于四氢呋喃，2.14毫升，4.29毫摩尔)，加毕，混合物在该条件下继续搅拌4小时，向混合物中加入饱和氯化铵溶液(20毫升)，用40毫升乙酸乙酯萃取，萃取液经盐水洗，无水硫酸钠干燥，过滤并浓缩后，残留物通过制备高效液相色谱分离得到标题化合物。
1H NMR(400MHz,MeOD)δppm 8.51-8.63(m,1H),7.34-7.44(m,1H),7.00-7.14(m,2H),5.30(s,1H),4.09(br.s.,1H),3.20-3.31(m,2H),2.99-3.13(m,1H),2.52-2.71(m,3H),1.95(br.s.,4H),1.43(br.s.,8H),0.96-1.14(m,8H),0.72(t,J＝7.28Hz,3H).
LCMS(ESI)m/z:393(M+1)
流程B13
Figure PCTCN2016073143-appb-000167
实施例50
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑
Figure PCTCN2016073143-appb-000168
实施例50A
(41S,13aS)-13a-乙基-N-((S)-1-(甲氧基(甲基)氨基)-1-氧丙-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺
Figure PCTCN2016073143-appb-000169
在0℃下，向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-羧酸(500毫克，1.552毫摩尔)和催化量的N,N-二甲基甲酰胺(0.075毫升)溶于无水二氯甲烷(7.5毫升)的溶液中滴入草酰氯(590.98毫克，4.656毫摩尔)，反应混合物在该温度下继续搅拌1小时，减压蒸去溶剂，所得粗品立即溶于二氯甲烷(7.5毫升)，然后分别加入二异丙基乙胺(600.61毫克，4.656毫摩尔)和(S)-2-氨基-N-甲氧基-N-甲基丙酰胺(307.5毫克，2.328毫摩尔)，反应混合物在室温下搅拌2小时，加入水并用二氯甲烷萃取，萃取液经水洗，盐水洗，无水硫酸钠干燥，溶剂真空浓缩后，残留物用二氯甲烷/甲醇20/1的混合溶剂作为洗脱剂过硅胶柱得到标题化合物(白色固体，460毫克，收率68％)。LCMS(ESI)m/z:437(M+1)
实施例50B
(41S,13aS)-13a-乙基-N-((S)-1-氧丙-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺
Figure PCTCN2016073143-appb-000170
在氮气保护、-78℃下向(41S,13aS)-13a-乙基-N-((S)-1-(甲氧基(甲基)氨基)-1-氧丙-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺溶于四氢呋喃的溶液中加入铝锂氢(32.66毫克，0.86毫摩尔)，加毕将干冰丙酮浴换成冰浴，反应温度升至0℃，搅拌20分钟后，在降温到-78℃，迅速加入硫酸氢钾溶液将反应淬灭。混合物升至室温后，滤掉固体滤液用乙酸乙酯萃取，合并的萃取液经盐水洗后，用无水硫酸钠干燥，过滤并蒸去溶剂得到标题化合物的粗品(直接用于下一步，190毫克，收率88％)。
LCMS(ESI)m/z:378(M+1)
实施例50C
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑
Figure PCTCN2016073143-appb-000171
向(41S,13aS)-13a-乙基-N-((S)-1-氧丙-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺(190毫克，0.504毫摩尔)溶于无水乙腈(5毫升)的溶液中加入催化量的N,N-二甲基甲酰胺(0.025毫升)和三氯氧磷(386.59毫克，2.518毫摩尔)，将反应混合物加热至90℃，氮气保护下搅拌3小时。反应完全后，将反应液倒入碳酸钠溶液并将pH调至8，用二氯甲烷萃取，合并的萃取液经水洗，盐水洗，无水硫酸钠干燥，溶剂真空浓缩后，粗品通过制备高效液相色谱分离得到标题化合物(30毫克，收率32％)。
1H NMR(400MHz,METHANOL-d4)δppm 1.13(t,J＝6.27Hz,3H),1.24-1.47(m,2H),1.70-1.86(m,2H),1.91-2.14(m,3H),2.30(s,3H),2.72(s,2H),3.11-3.22(m,1H),3.78-3.96(m,2H),5.14(br.s.,1H),5.90(s,1H),6.45(d,J＝8.03Hz,1H),7.08-7.24(m,2H),7.60(d,J＝7.03Hz,1H),7.87(s,1H).
LCMS(ESI)m/z:360(M+1)
流程B14
Figure PCTCN2016073143-appb-000172
实施例51
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-5-甲基恶唑
Figure PCTCN2016073143-appb-000173
实施例51A
(41S,13aS)-13a-乙基-N-(2-氧丙)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺
Figure PCTCN2016073143-appb-000174
向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-羧酸(200毫克，0.621毫摩尔)溶于二氯甲烷(3.1毫升)的溶液中加入O-(7-氮杂苯并三氮唑-1-YL)-N,N,N',N'-四甲基脲六氟膦盐(283.08毫克，0.745毫摩尔)和二异丙基乙胺(240.25毫克，1.862毫摩尔)，混合物搅拌1小时后，再加入氨基丙酮盐酸盐(135.37毫克，1.242毫摩尔)，继续搅拌约4小时。混合物中加入水，并用二氯甲烷萃取，合并的萃取液经水洗，盐水洗，无水硫酸钠干燥后，有机层真空浓缩，残留物用二氯甲烷/甲醇20/1的混合溶剂作为洗脱剂过硅胶柱得到标题化合物(白色固体，210毫克，收率89％)。
1H NMR(400MHz,CHLOROFORM-d)δppm 0.98-1.15(m,4H),1.50-1.55(m,1H),1.59(d,J＝13.55 Hz,1H),1.81-2.11(m,3H),2.30(s,3H),2.62-2.93(m,3H),3.00-3.15(m,1H),3.31-3.43(m,1H),3.44-3.56(m,1H),4.27-4.40(m,2H),4.43-4.54(m,1H),5.69-5.75(m,1H),6.78(br.s.,1H),7.16(quin,J＝6.71Hz,2H),7.21-7.26(m,1H),7.47(d,J＝7.03Hz,1H).
实施例51B
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-5-甲基恶唑
Figure PCTCN2016073143-appb-000175
向(41S,13aS)-13a-乙基-N-(2-氧丙)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺(210毫克，0.557毫摩尔)溶于无水乙腈(2.8毫升)的溶液中加入催化量的N,N-二甲基甲酰胺(0.028毫升)和三氯氧磷(854.56毫克，5.567毫摩尔)，将反应混合物加热至90℃，氮气保护下搅拌3小时。反应完全后，将反应液倒入碳酸钠溶液并将pH调至8，用二氯甲烷萃取，合并的萃取液经水洗，盐水洗，无水硫酸钠干燥，溶剂真空浓缩后，粗品通过制备高效液相色谱分离得到标题化合物(50毫克，收率25％)。
1H NMR(400MHz,METHANOL-d4)δppm 1.12(t,J＝6.78Hz,3H),1.23-1.36(m,1H),1.79(t,J＝12.55Hz,2H),1.90-2.12(m,3H),2.45(s,3H),3.12(d,J＝16.06Hz,1H),3.25(d,J＝12.05Hz,2H),3.37(s,1H),3.75-4.00(m,2H),5.14(br.s.,1H),5.88(s,1H),6.53(d,J＝8.03Hz,1H),7.05-7.26(m,3H),7.60(d,J＝7.03Hz,1H).
实施例52
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4,5-二甲基恶唑
Figure PCTCN2016073143-appb-000176
该实施例的操作同实施例51。
1H NMR(400MHz,CHLOROFORM-d)δppm 1.09(t,J＝7.40Hz,3H),1.24(td,J＝13.93,3.26Hz,1H),1.63(d,J＝14.56Hz,1H),1.73(d,J＝14.05Hz,1H),2.08-2.26(m,6H),2.32(s,3H),2.90-3.07(m,2H),3.08-3.20(m,1H),3.26(d,J＝11.04Hz,1H),3.64(td,J＝12.67,5.77Hz,1H),3.73-3.84(m,1H),4.73(br.s.,1H),5.79(s,1H),6.56-6.64(m,1H),7.11-7.22(m,2H),7.46-7.55(m,1H).
实施例53
5-乙基-2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑
Figure PCTCN2016073143-appb-000177
该实施例的操作同实施例51。
1H NMR(400MHz,CHLOROFORM-d)δppm 1.11(t,J＝7.28Hz,3H),1.17-1.34(m,4H),1.60-1.81(m,2H),2.14-2.38(m,6H),2.58-2.78(m,2H),2.91-3.22(m,3H),3.31(d,J＝10.04Hz,1H),3.65(br.s.,1H),3.80(d,J＝11.04Hz,1H),4.76(br.s.,1H),5.83(s,1H),6.52(d,J＝8.03Hz,1H),7.17(quin,J＝7.03Hz,2H),7.50(d,J＝7.03Hz,1H),13.07(br.s.,1H).
实施例54
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-5-异丙基-4-甲基恶唑
Figure PCTCN2016073143-appb-000178
该实施例的操作同实施例51。
1H NMR(400MHz,CHLOROFORM-d)δppm 1.12(t,J＝7.03Hz,3H),1.18-1.35(m,7H),1.66(d,J＝14.05Hz,1H),1.79(d,J＝14.05Hz,1H),2.13-2.38(m,6H),2.94-3.23(m,4H),3.32(d,J＝9.54Hz,1H),3.66(br.s.,1H),3.80(d,J＝10.54Hz,1H),4.78(br.s.,1H),5.91(s,1H),6.43(d,J＝8.03Hz,1H),7.10-7.24(m,2H),7.51(d,J＝7.53Hz,1H).
实施例55
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4,5,6,7-四氢苯并[d]恶唑
Figure PCTCN2016073143-appb-000179
该实施例的操作同实施例51。
1H NMR(400MHz,CHLOROFORM-d)δppm 7.52(dd,J＝6.27,2.76Hz,1H),7.15-7.25(m,2H),6.65-6.76(m,1H),5.91(s,1H),4.77(br.s.,1H),3.81(d,J＝11.29Hz,1H),3.33(d,J＝9.79Hz,1H),3.15(br.s.,1H),3.02(d,J＝10.54Hz,1H),2.58-2.77(m,4H),2.17-2.39(m,4H),1.87-2.05(m,4H),1.80(d,J＝14.05Hz,1H),1.68(d,J＝14.31Hz,1H),1.21-1.38(m,1H),1.13(t,J＝7.28Hz,3H).
实施例56
4-乙基-2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-5-甲基恶唑
Figure PCTCN2016073143-appb-000180
该实施例的操作同实施例51。
1H NMR(400MHz,METHANOL-d4)δppm 1.06-1.17(m,3H),1.28(t,J＝7.53Hz,4H),1.70-1.84(m,2H),1.91-2.15(m,4H),2.38(s,3H),2.54-2.65(m,2H),3.09-3.30(m,3H),3.76-3.96(m,2H),5.12(br.s.,1H),5.85(s,1H),6.54(d,J＝7.53Hz,1H),7.16(quin,J＝7.03Hz,2H),7.59(d,J＝7.53Hz,1H).
实施例57
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-异丙基-5-甲基恶唑
Figure PCTCN2016073143-appb-000181
该实施例的操作同实施例51。
1H NMR(400MHz,METHANOL-d4)δppm 1.13(t,J＝7.28Hz,3H),1.29(dd,J＝9.91,6.90Hz,7H),1.70-1.83(m,2H),1.92-2.14(m,3H),2.38(s,3H),2.96-3.07(m,1H),3.10-3.35(m,5H),3.74-3.96(m,2H),5.12(br.s.,1H),5.84(s,1H),6.53(d,J＝7.78Hz,1H),7.09-7.21(m,2H),7.58(d,J＝7.53Hz,1H).
流程B15
Figure PCTCN2016073143-appb-000182
实施例58
5-环丙基-2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑
Figure PCTCN2016073143-appb-000183
实施例58A
(S)-2-氨基-N-甲氧基-N-甲基丙酰胺盐酸盐
Figure PCTCN2016073143-appb-000184
将(S)-叔丁基-(1-(甲氧基(甲基)氨基)-1-氧丙-2-基)氨基甲酸酯(20.0克，106.82毫摩尔)溶于4M盐酸乙酸乙酯(100毫升)，混合物在20℃下搅拌2小时，低沸点组分蒸除后得标题化合物(12.0克，收率90.9％)。
1H NMR(400MHz,CHLOROFORM-d)δppm 1.54-1.71(m,3H),3.23(s,1H),3.82(s,1H),3.93-4.28(m,2H),4.53(br.s.,1H),8.39(br.s.,3H).
实施例58B
(41S,13aS)-13a-乙基-N-((S)-1-(甲氧基(甲基)氨基)-1-氧丙-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺
Figure PCTCN2016073143-appb-000185
向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-羧酸(5.0克，15.51毫摩尔)溶于二氯甲烷(80毫升)的溶液中分别加入O-(7-氮杂苯并三氮唑-1-YL)-N,N,N',N'-四甲基脲六氟膦盐(7.08克，18.61毫摩尔)和N,N-二异丙基乙胺(3.01克，23.26毫摩尔)，混合物在20℃下搅拌1小时，然后再加入N,N-二异丙基乙胺(4.01克，31.02毫摩尔)和(S)-2-氨基-N-甲氧基-N-甲基丙酰胺盐酸盐(2.11克，17.06毫摩尔)，反应混合物继续搅拌约14小时。加入水，并用二氯甲烷萃取(3×10毫升)，合并后的萃取液经水(10毫升)洗，盐水(10毫升)洗，无水硫酸钠干燥，溶剂真空浓缩后，残留物用二氯甲烷/甲醇20/1的混合溶剂作为洗脱剂过硅胶柱得到标题化合物(淡黄色胶状物，5.5克，收率90.58％)。
LCMS(ESI)m/z:437(M+1)
实施例58C
(41S,13aS)-N-((S)-1-环丙基-1-氧丙-2-基)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺
Figure PCTCN2016073143-appb-000186
在0℃下向(41S,13aS)-13a-乙基-N-((S)-1-(甲氧基(甲基)氨基)-1-氧丙-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺(2.24克，5.13毫摩尔)的固体上直接滴加环丙基溴化镁(0.5M，307.8毫升，153.9毫摩尔)，用时超过60分钟，滴加完毕反应混合物升温至20℃继续搅拌18小时。再降温到0℃，加入饱和氯化铵溶液，用乙酸乙酯萃取(3×30毫升)，合并后的萃取液经水(30毫升)洗，盐水(30毫升)洗，无水硫酸钠干燥，溶剂真空浓缩后，残留物用二氯甲烷/甲醇20/1的混合溶剂作为洗脱剂过硅胶柱得到标题化合物(淡黄色胶状物，1.7克，收率79.37％)。
LCMS(ESI)m/z:418(M+1)
实施例58D
5-环丙基-2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑
Figure PCTCN2016073143-appb-000187
向(41S,13aS)-N-((S)-1-环丙基-1-氧丙-2-基)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺(200毫克，0.479毫摩尔)溶于无水乙腈(2.8毫升)的溶液中加入催化量的N,N-二甲基甲酰胺(17.5毫克)和三氯氧磷(367.22毫克，2.39毫摩尔)，将反应混合物加热至90℃，氮气保护下搅拌15小时。反应完全后，将反应液倒入碳酸钠溶液并将pH调至8，用二氯甲烷萃取(3×10毫升)，合并的萃取液经水(10毫升)洗，盐水(10毫升)洗，无水硫酸钠干燥，溶剂真空浓缩后，残留物用石油醚/四氢呋喃5/1的混合溶剂作为洗脱剂过硅胶柱得到标题化合物(淡黄色固体，100毫克，收率52.25％)。
1H NMR(400MHz,CHLOROFORM-d)δppm 0.71-0.88(m,2H),0.91-1.03(m,2H),1.12(t,J＝7.28Hz,3H),1.27(td,J＝13.99,2.89Hz,1H),1.67(d,J＝14.05Hz,1H),1.78(d,J＝14.31Hz,1H),1.86-1.96(m,1H),2.15-2.34(m,6H),2.93-3.25(m,3H),3.32(d,J＝10.29Hz,1H),3.65(br.s.,1H),3.81(d,J＝11.29Hz,1H),4.76(br.s.,1H),5.82(s,1H),6.45-6.54(m,1H),7.14-7.24(m,2H),7.47-7.56(m,1H).
流程B16
Figure PCTCN2016073143-appb-000188
实施例59
2-(2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-基)丙-2-醇
Figure PCTCN2016073143-appb-000189
实施例59A
(41S,13aS)-3-氨基-1-甲氧基-1-氧丁-2-烯-2-基13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-碳酸酯
Figure PCTCN2016073143-appb-000190
20℃下，向3-氨基巴豆酸甲酯(1.5克，13.03毫摩尔)和亚碘酰苯(3.44克，15.63毫摩尔)悬浮于二氯乙烷(75毫升)的混合物中加入(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-羧酸(5.04克，15.63毫摩尔)，反应混合物在该温度下搅拌20小时。加入饱和碳酸氢钠(150毫升)淬灭反应，并用二氯甲烷萃取(3×100毫升)，合并的萃取液用无水硫酸钠干燥，溶剂蒸干后，残留物用四氢呋喃/石油醚(1/10～1/2)的混合溶剂作为洗脱液过硅胶柱得到标题化合物(白色固体，1.5克，收率26.4％)。
1H NMR(400MHz,CHLOROFORM-d)δppm 7.49-7.44(m,1H),7.40-7.34(m,1H),7.18-7.09(m,2H),6.39(br.s.,1H),4.21(br.s.,1H),3.85-3.68(m,3H),3.40-3.33(m,1H),3.32-3.21(m,1H),3.10-2.98(m,1H),2.68-2.61(m,2H),2.52(dd,J＝2.9,16.2Hz,1H),2.02(br.s.,3H),1.87-1.72(m,2H),1.52(br.s.,1H),1.47-1.40(m,1H),1.12-0.98(m,5H).
实施例59B
甲基-2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-碳酸酯
Figure PCTCN2016073143-appb-000191
将(41S,13aS)-3-氨基-1-甲氧基-1-氧丁-2-烯-2-基13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-碳酸酯(1.5克，3.44毫摩尔)加到醋酸(20毫升)中，升温到120℃搅拌20小时。溶剂蒸干，残留物加入二氯甲烷(50毫升)和水(30毫升)处理，分出的水层用二氯甲烷萃取(2×50毫升)，合并的有机相用30毫升盐水清洗，无水硫酸钠干燥，过滤，滤液浓缩后，粗品用四氢呋喃/石油醚(0～2/5)的混合溶剂作为洗脱液过硅胶柱得到标题化合物(580毫克，收率40.38％)。
1H NMR(400MHz,METHANOL-d4)δppm 7.61(dd,J＝2.0,6.5Hz,1H),7.25-7.13(m,2H),6.79-6.67(m,1H),6.12(s,1H),5.13(s,1H),3.97-3.79(m,5H),3.37-3.34(m,0.5H),3.32-3.13(m,3.5H),2.56(s,3H),2.08-1.91(m,3H),1.87-1.74(m,2H),1.35-1.24(m,1H),1.13(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:418(M+1)
实施例60
2-(2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-基)丙-2-醇
Figure PCTCN2016073143-appb-000192
在-70℃、氮气保护下，向甲基-2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-碳酸酯(100毫克，0.24毫摩尔)溶于无水四氢呋喃(2毫升)的溶液中加入甲基溴化镁(3M，0.4毫升，1.2毫摩尔)，反应混合物在-70～20℃下搅拌16小时。在-78～0℃下，加入2毫升饱和氯化铵溶液将反应淬灭，并用乙酸乙酯萃取(3×10毫升)，合并的萃取液用盐水(10毫升)清洗，无水硫酸钠干燥，过滤，滤液浓缩后，残留物通过制备高效液相色谱分离得到标题化合物(52.0毫克，收率52.0％)。
1H NMR(400MHz,METHANOL-d4)δppm 7.59(d,J＝7.3Hz,1H),7.24-7.08(m,2H),6.42(d,J＝7.8Hz,1H),5.86(s,1H),5.14(br.s.,1H),3.96-3.77(m,2H),3.38-3.07(m,4H),2.40(s,3H),2.09-1.91(m,3H),1.86-1.72(m,2H),1.53(d,J＝14.1Hz,6H),1.35-1.25(m,1H),1.12(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:418(M+1)
实施例61
(2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-基)甲醇
Figure PCTCN2016073143-appb-000193
在-70℃下，向甲基-2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-碳酸酯(100毫克，0.24毫摩尔)溶于无水二氯甲烷(8毫升)的溶液中加入二丁基氢化铝(1M，0.527毫升，0.527毫摩尔)，反应混合物在-70～15℃下搅拌2小时。在-78～0℃下，缓缓加入饱和氯化铵(5毫升)将反应淬灭，再用乙酸乙酯萃取(3×30毫升)，合并的萃取液用盐水(20毫升)清洗，无水硫酸钠干燥，过滤，滤液浓缩后，粗品通过制备高效液相色谱分离得到标题化合物(50.0毫克，收率53.6％)。
1H NMR(400MHz,METHANOL-d4)δppm 7.60(d,J＝7.5Hz,1H),7.24-7.12(m,2H),6.60(d,J＝7.8Hz,1H),5.93(s,1H),5.14(br.s.,1H),4.64(s,2H),3.99-3.74(m,2H),3.36-3.09(m,4H),2.31(s,3H),2.10- 1.91(m,3H),1.86-1.73(m,2H),1.35-1.24(m,1H),1.13(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:390(M+1)
流程B17
Figure PCTCN2016073143-appb-000194
实施例62
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-腈
Figure PCTCN2016073143-appb-000195
实施例62A
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-羧酸
Figure PCTCN2016073143-appb-000196
搅拌下，向向甲基-2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-碳酸酯(1.80克，4.31毫摩尔)溶于甲醇(10毫升)的溶液中滴入氢氧化钠(330.0毫克，8.25毫摩尔)溶于水(10毫升)的溶液，混合物搅拌约16小时。反应完全后，蒸去低沸点组分，再用乙酸乙酯清洗(3×30毫升)，水相用6M盐酸酸化，将析出的固体过滤，并用水(3×20毫升)清洗滤饼，然后再溶于甲醇(20毫升)，用无水硫酸钠干燥，过滤并浓缩得到标题化合物(1.20克，收率69.01％)。LCMS(ESI)m/z:404(M+1)
实施例62B
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-甲酰胺
Figure PCTCN2016073143-appb-000197
向2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-羧酸(100毫克，0.248毫摩尔)、1-羟基苯并三唑(50毫克，0.372毫摩尔)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(71毫克，0.372毫摩尔)溶于N，N-二甲基甲酰胺(5毫升)的溶液中分别加入三乙胺(75毫克，0.744毫摩尔)和氯化铵(40毫克，0.744毫摩尔)，反应混合物搅拌约16小时。反应完全后，将混合物倒入5倍体积的水中，用乙酸乙酯萃取(5×30毫升)，合并的萃取液用无水硫酸钠干燥，过滤并浓缩后，粗品通过制备高效液相色谱分离得到标题化合物(白色固体，50毫克，收率50.12％)。1H NMR(400MHz,METHANOL-d4)δppm 7.72-7.55(m,1H),7.31-7.13(m,2H),6.83-6.59(m,1H),6.18(s,1H),5.14(br.s.,1H),3.99-3.76(m,2H),3.30-3.09(m,3H),2.56(s,3H),2.19-1.93(m,3H),1.88-1.65(m,2H),1.43-1.25(m,1H),1.16(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:403(M+1)
实施例63
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-腈
Figure PCTCN2016073143-appb-000198
搅拌下向2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-甲酰胺(150毫克)溶于氯仿(10毫升)的溶液中加入三氯氧磷(571毫克，3.73毫摩尔)，反应混合物加热到50℃并搅拌6小时。冷却后，将混合物小心倒入水(10毫升)中，用饱和碳酸氢钠溶液将pH调至7-8，再用二氯甲烷萃取(3×20毫升)，合并的萃取液浓缩，残留物通过制备高效液相色谱分离得到标题化合物(80毫克，收率55.83％)。
1H NMR(400MHz,METHANOL-d4)δppm 7.63(dd,J＝2.5,6.3Hz,1H),7.32-7.18(m,2H),6.90-6.70(m,1H),6.19(s,1H),5.15(br.s.,1H),4.07-3.78(m,2H),3.32-3.13(m,4H),2.47(s,3H),2.13-1.92(m,3H),1.88-1.71(m,2H),1.40-1.24(m,1H),1.14(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:385(M+1)
实施例64
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-N,4-二甲基恶唑-5-甲酰胺
Figure PCTCN2016073143-appb-000199
向2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-羧酸(100毫克，0.248毫摩尔)、1-羟基苯并三唑(50毫克，0.37毫摩尔)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(72毫克，0.376毫摩尔)溶于N，N-二甲基甲酰胺(5毫升)的溶液中分别加入三乙胺(75毫克，0.744毫摩尔)和甲胺溶于四氢呋喃的溶液(1M，0.74毫升，0.74毫摩尔)，反应混合物搅拌约16小时。反应完全后，将混合物倒入5倍体积的水中，用乙酸乙酯萃取(5×30毫升)，合并的萃取液用无水硫酸钠干燥，过滤并浓缩后，粗品通过制备高效液相色谱分离得到标题化合物(20毫克，收率19.37％)。
1H NMR(400MHz,METHANOL-d4)δppm 7.78-7.54(m,1H),7.30-7.16(m,2H),6.87-6.65(m,1H),6.16(s,1H),5.15(br.s.,1H),4.08-3.77(m,2H),3.31-3.23(m,2H),3.21(d,J＝5.0Hz,1H),2.87(s,3H),2.57(s,3H),2.01(dd,J＝7.5,10.0Hz,3H),1.82(br.s.,2H),1.32(br.s.,1H),1.16(t,J＝7.5Hz,3H).
LCMS(ESI)m/z:417(M+1)
实施例65
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-N,N,4-三甲基恶唑-5-甲酰胺
Figure PCTCN2016073143-appb-000200
向2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-羧酸(100毫克，0.248毫摩尔)、1-羟基苯并三唑(50毫克，0.37毫摩尔)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(72毫克，0.376毫摩尔)溶于N，N-二甲基甲酰胺(5毫升)的溶液中分别加入三乙胺(75毫克，0.744毫摩尔)和二甲胺盐酸盐(60毫升，0.744毫摩尔)，反应混合物搅拌约16小时。反应完全后，将混合物倒入5倍体积的水中，用乙酸乙酯萃取(5×30毫升)，合并的萃取液用无水硫酸钠干燥，过滤并浓缩后，粗品通过制备高效液相色谱分离得到标题化合物(50毫克，收率46.86％)。 1H NMR(400MHz,METHANOL-d4)δppm 7.75-7.55(m,1H),7.32-7.10(m,2H),6.76-6.51(m,1H),6.07(s,1H),5.18(br.s.,1H),4.03-3.76(m,2H),3.30-3.16(m,2H),3.16-2.96(m,6H),2.48(s,3H),2.15-1.90(m,3H),1.82(br.s.,2H),1.32(br.s.,1H),1.15(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:431(M+1)
流程B18
Figure PCTCN2016073143-appb-000201
实施例66
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-6,7-二氢-4H-吡喃酮[3,4-d]恶唑
Figure PCTCN2016073143-appb-000202
实施例66A
4，4-二甲氧基四氢-2H-吡喃-3-醇
Figure PCTCN2016073143-appb-000203
在0-5℃下，向氢氧化钾(15.82克，240毫摩尔)溶于210毫升甲醇的溶液中加入四氢吡喃-4-酮(10克，99.88毫摩尔)，大约5-10分钟后再用超过1.5小时的时间向其中加入碘(27.89克，109.87毫摩尔)溶于185毫升甲醇的溶液，加毕，混合物逐渐升至室温。将混合物浓缩，再加入50毫升甲苯并过滤，滤液蒸干后残留物用石油醚/乙酸乙酯1/1作为洗脱液过硅胶柱得到标题化合物(黄色液体，10.0克，收率61.73％)。
1H NMR(400MHz,CDCl3-d)δppm 4.13(q,J＝7.03Hz,1H),3.77-3.90(m,2H),3.65-3.74(m,2H),3.50(td,J＝11.67,2.51Hz,1H),3.27(d,J＝7.28Hz,6H),2.31(br.s.,1H),2.05(s,1H),1.95(ddd,J＝14.31,11.80,4.77Hz,1H),1.71-1.83(m,2H),1.27(t,J＝7.03Hz,1H).
实施例66B
4,4-二甲氧基二氢-2H-吡喃-3(4H)-酮
Figure PCTCN2016073143-appb-000204
在20℃下，向4,4-二甲氧基四氢-2H-吡喃-3-醇(2.0克，12.33毫摩尔)溶于二氯甲烷(30毫升)的溶液里加入4A分子筛(5.0克，12.33毫摩尔)、N-甲基吗啉氧化物(3.64克，31.08毫摩尔)和四丙基过钌酸铵(200毫克，0.569毫摩尔)，反应混合物搅拌约30分钟。过滤，滤液浓缩后，残留物用石油醚/乙酸乙酯10/1作为洗脱液过硅胶柱得到标题化合物(黄色液体，1.2克，收率60.76％)。
1H NMR(400MHz,CDCl3-d)δppm 4.05(s,2H),3.90-3.98(m,2H),3.66-3.72(m,1H),3.19-3.27(m,6H),2.27(s,1H),2.16-2.23(m,2H).
实施例66C
4,4-二甲氧基四氢-2H-吡喃-3-氨
Figure PCTCN2016073143-appb-000205
在20℃、氮气保护下向4,4-二甲氧基二氢-2H-吡喃-3(4H)-酮(1.2克，7.49毫摩尔)溶于甲醇(30毫升)的溶液中分别加入钯碳(50毫克)和甲酸胺(4.72克，74.9毫摩尔)，混合物在20℃下搅拌过夜。过滤，滤液浓缩得到标题化合物的粗品(直接用于下一步反应，800毫克)。
实施例66D
(41S,13aS)-N-(4,4-二甲氧基四氢-2H-吡喃-3-基)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺
Figure PCTCN2016073143-appb-000206
在0℃下，向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-羧酸(300毫克，0.93毫摩尔)溶于二氯甲烷(20毫升)的溶液中加入两滴N,N-二甲基甲酰胺，再向其中缓慢滴入草酰氯(236.22毫克，1.86毫摩尔)，反应混合物在0℃、氮气保护下搅拌1小时。混合物真空浓缩后，残留物溶于二氯甲烷(20毫升)，然后在0℃下向其中加入二异丙基乙胺(240.52毫克，1.86毫摩尔)和4,4-二甲氧基四氢-2H-吡喃-3-氨(100毫克，0.62毫摩尔)，混合物在室温下搅拌1小时，向其中加入水(50毫升)和二氯甲烷(50毫升)，二氯甲烷层经水(2×50毫升)洗，盐水(50毫升)洗，无水硫酸钠干燥，过滤，滤液浓缩后的粗品用二氯甲烷/四氢呋喃2/1作为洗脱液过硅胶柱得到标题化合物(无色油状物，220毫克，收率76.17％)。
LCMS(ESI)m/z:420(M+1)
实施例66E
2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-6,7-二氢-4H-吡喃酮[3,4-d]恶唑
Figure PCTCN2016073143-appb-000207
氮气保护下，向(41S,13aS)-N-(4,4-二甲氧基四氢-2H-吡喃-3-基)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺(120毫克，0.258毫摩尔)溶于乙腈(10毫升)的溶液中加入两滴N,N-二甲基甲酰胺，再向其中缓慢加入三氯氧磷(350毫克，2.28毫摩尔)，反应混合物加热到80-90℃、搅拌4小时。反应混合物浓缩后，残留物通过制备高效液相色谱分离得到标题化合物(40毫克，收率35％)。
1H NMR(400MHz,MeOD-d4)δppm 7.57-7.64(m,1H),7.13-7.24(m,2H),6.57-6.64(m,1H),5.93(s,1H),5.16(s,1H),4.69(s,2H),3.99-4.17(m,2H),3.79-3.99(m,2H),3.13-3.30(m,3H),2.90(t,J＝5.27Hz,2H),1.89-2.11(m,3H),1.74-1.89(m,2H),1.32(td,J＝14.12,3.89Hz,1H),1.14(t,J＝7.40Hz,3H).
LCMS(ESI)m/z:402(M+1)
流程B19
Figure PCTCN2016073143-appb-000208
实施例67
4-(2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-基)吗啡啉
Figure PCTCN2016073143-appb-000209
实施例67A
叔丁基-(1-吗啡啉基-1-氧丙-2-基)-氨基甲酸酯
Figure PCTCN2016073143-appb-000210
氮气保护下，向2-(叔丁氧羰基氨基)-丙酸(2.0克，10.57毫摩尔)和吗啡啉(1.11克，12.68毫摩尔) 溶于二氯甲烷(30毫升)的溶液中一次性加入O-(7-氮杂苯并三氮唑-1-yl)-N,N,N',N'-四甲基脲六氟膦盐(4.82克，12.68毫摩尔)，然后加入二异丙基乙胺(3.01克，23.25毫摩尔)，反应混合物在室温下搅拌15小时。向混合物中加水20毫升，水相再用乙酸乙酯萃取(3×50毫升)，合并的有机相经饱和盐水(20毫升)洗，无水硫酸钠干燥，过滤，滤液真空浓缩后，残留物用四氢呋喃/石油醚(0-1/2)作为洗脱液过硅胶柱得到标题化合物(无色油状物，2.5克，收率91.56％)。
1H NMR(400MHz,DMSO-d6)δppm 6.97(d,J＝7.8Hz,1H),4.40(quin,J＝7.2Hz,1H),3.54(d,J＝4.3Hz,4H),3.45(td,J＝4.6,13.4Hz,4H),1.36(s,9H),1.12(d,J＝6.8Hz,3H).
实施例67B
2-氨基-1-吗啡啉丙基-1-酮
Figure PCTCN2016073143-appb-000211
氮气保护下，向叔丁基-(1-吗啡啉基-1-氧丙-2-基)-氨基甲酸酯(900毫克，3.48毫摩尔)溶于二氯甲烷(15毫升)的溶液中加入三氟乙酸(5毫升)，混合物在15℃下反应2小时。将混合物控制在40℃下减压浓缩，残留物用20毫升碳酸氢钠溶液稀释，水相再用二氯甲烷萃取(3×30毫升)，合并的有机相用饱和盐水(20毫升)清洗，无水硫酸钠干燥，过滤并真空浓缩得到标题化合物(淡黄色液体，400毫克，收率72.66％)。1H NMR(400MHz,DMSO-d6)δppm 3.75(q,J＝6.6Hz,1H),3.60-3.52(m,1H),3.50-3.40(m,4H),1.07(d,J＝6.8Hz,3H).
实施例67C
(41S,13aS)-13a-乙基-N-(1-吗啡啉基-1-氧丙-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺
Figure PCTCN2016073143-appb-000212
氮气保护下，向(41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-羧酸(800毫克，2.48毫摩尔)和2-氨基-1-吗啡啉丙基-1-酮(400.18毫克，2.53毫摩尔)溶于二氯甲烷(20毫升)的溶液中分别加入O-(7-氮杂苯并三氮唑-1-YL)-N,N,N',N'-四甲基脲六氟膦盐(1.13克，2.98毫摩尔)和三乙胺(552.09毫克，5.46毫摩尔)，反应混合物在20℃下搅拌15小时。向混合物中加水20毫升，水相再用乙酸乙酯萃取(3×50毫升)，合并的有机相经饱和盐水(20毫升)洗，无水硫酸钠干燥，过滤，滤液真空浓缩后，残留物用四氢呋喃/石油醚(1/5-4/5)作为洗脱液过硅胶柱得到标题化合物(黄色固体，350毫克，收率30.51％)。
1H NMR(400MHz,CHLOROFORM-d)δppm 7.49-7.43(m,1H),7.24-7.18(m,1H),7.15-7.08(m,2H),7.05(d,J＝7.3Hz,1H),5.69(s,1H),5.11(quin,J＝6.9Hz,1H),4.15(s,1H),3.82-3.52(m,8H),3.39-3.31(m,1H),3.30-3.20(m,1H),3.08-2.96(m,1H),2.66-2.60(m,2H),2.51(dd,J＝2.9,16.2Hz,1H),1.97-1.81(m,3H),1.78-1.63(m,1H),1.55-1.45(m,4H),1.39(br.s.,1H),1.07-0.95(m,4H).
实施例67D
4-(2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4-甲基恶唑-5-基)吗啡啉
Figure PCTCN2016073143-appb-000213
向三苯基膦(210.93毫克，0.804毫摩尔)溶于二氯甲烷(10毫升)的溶液中滴入液溴(128.52毫克，0.804毫摩尔)溶于二氯甲烷(2毫升)的溶液，搅拌30分钟后，分别加入三乙胺(203.44毫克，2.01毫摩尔)和(41S,13aS)-13a-乙基-N-(1-吗啡啉基-1-氧丙-2-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-甲酰胺(310毫克，0.67毫摩尔)溶于二氯甲烷(8毫升)的溶液，反应混合物在氮气保护下回流30分钟，并在20℃下保持超过12小时。混合物用石油醚(50毫升)稀释，滤除析出的三乙胺的氢溴酸盐，滤液减压蒸干，残留物通过碱性制备高效液相色谱分离得到标题化合物(100毫克，收率33.57％)。
1H NMR(400MHz,METHANOL-d4)δppm 7.45(d,J＝7.0Hz,1H),7.11-6.98(m,2H),6.34(d,J＝7.8Hz,1H),5.72(s,1H),4.28(s,1H),3.78-3.70(m,4H),3.37-3.24(m,1H),3.11-2.98(m,5H),2.68-2.53(m,3H),2.21(s,3H),2.04-1.82(m,2H),1.79-1.66(m,1H),1.60(d,J＝13.8Hz,1H),1.50-1.40(m,1H),1.12-0.99(m,4H).
LCMS(ESI)m/z:445(M+1)
流程B20
Figure PCTCN2016073143-appb-000214
实施例68
(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N-甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-9-磺酰胺
Figure PCTCN2016073143-appb-000215
实施例68A
(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N-甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-9-磺酸
Figure PCTCN2016073143-appb-000216
在0-5℃下，用10-15分钟的时间向2-((41S,13aS)-13a-乙基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-12-基)-4,5-二甲基恶唑(1.5克，4.02毫摩尔)溶于氯仿(40毫升)的溶液中滴入氯磺酸(2.0克，17.21毫摩尔)，加毕，反应混合物升到20℃搅拌0.5小时，再向其中加入30毫升氯仿，将混合物倒入冰水中，用三乙胺将pH调至8，加入50毫升二氯甲烷萃取，有机相经水(50毫升)洗，无水硫酸钠干燥并浓缩后，残留物通过制备高效液相色谱分离得到标题化合物(黄色固体，600毫克，收率32.91％)，同时得到(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N-甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-8-磺酸(黄色固体，600毫克，收率32.91％)和(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N-甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-7-磺酸(210毫克，收率11.52％)。
1H NMR(400MHz,DMSO-d6)δppm 0.97(t,J＝7.28Hz,3H),1.06-1.14(m,1H),1.57-1.83(m,4H),1.87-1.98(m,1H),2.13(s,3H),2.30(s,3H),2.95-3.11(m,3H),3.21(d,J＝11.29Hz,1H),3.68-3.88(m,2H),5.17(br.s.,1H),5.81(s,1H),7.02(s,1H),7.41-7.46(m,1H),7.48-7.51(m,1H),10.49(br.s.,1H).
(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N-甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-8-磺酸
Figure PCTCN2016073143-appb-000217
1H NMR(400MHz,DMSO-d6)δppm 0.97(t,J＝7.03Hz,3H),1.06-1.21(m,1H),1.54-1.83(m,4H),1.88-1.98(m,1H),2.13(s,3H),2.30(s,3H),3.11(br.s.,3H),3.22(d,J＝11.54Hz,1H),3.72-3.86(m,2H),5.17(br.s.,1H),5.80(s,1H),6.47(d,J＝8.78Hz,1H),7.39(d,J＝8.78Hz,1H),7.82(s,1H),10.47(br.s.,1H).
(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N-甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-7-磺酸
Figure PCTCN2016073143-appb-000218
1H NMR(400MHz,DMSO-d6)δppm 0.98(t,J＝7.28Hz,3H),1.11-1.21(m,1H),1.58-1.85(m,4H),1.92(dq,J＝14.37,7.26Hz,1H),2.13(s,3H),2.28(s,3H),2.93-3.04(m,1H),3.25(d,J＝11.54Hz,1H),3.37-3.50(m,1H),3.69(br.s.,3H),5.17(br.s.,1H),5.79(s,1H),6.34(d,J＝8.53Hz,1H),7.02(t,J＝7.91Hz,1H),7.48(d,J＝7.28Hz,1H),10.31(d,J＝7.53Hz,1H).
实施例68B
(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N-甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-9-磺酰氯
Figure PCTCN2016073143-appb-000219
向(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N-甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-9-磺酸(300毫克，0.66毫摩尔)溶于氯仿(10毫升)的溶液中加入氯化亚砜(236毫克，1.98毫摩尔)和N,N-二甲基甲酰胺(95毫克，1.3毫摩尔)，反应混合物加热到55℃并搅拌2小时，低沸点组分浓缩干后，所得黄色油状物直接用于下一步的反应。
实施例68C
(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N-甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-9-磺酰胺
Figure PCTCN2016073143-appb-000220
向(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N-甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-9-磺酰氯(100毫克，0.212毫摩尔)溶于氯仿(3毫升)的溶液中分别加入三乙胺(60毫克，0.632毫摩尔)和甲胺溶于四氢呋喃的溶液(1M，0.426毫升，0.426毫摩尔)，反应混合物在20℃下搅拌1小时。加入二氯甲烷(30毫升)和水(20毫升)处理，分出的有机层用无水硫酸钠干燥后浓缩，残留物通过制备高效液相色谱分离得到标题化合物。
1H NMR(400MHz,METHANOL-d4)δppm 1.15(t,J＝7.40Hz,3H),1.28-1.38(m,1H),1.77-1.88(m,2H),1.94-2.13(m,3H),2.23(s,3H),2.39(s,3H),2.48(s,3H),3.19-3.30(m,2H),3.38(br.s.,2H),3.83-3.99(m,2H),5.22(br.s.,1H),6.04(s,1H),7.29(s,1H),7.64(d,J＝8.28Hz,1H),7.80(d,J＝8.28Hz,1H).
实施例69
(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N,N-二甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-9-磺酰胺
Figure PCTCN2016073143-appb-000221
该实施例的操作过程同实施例68C。
1H NMR(400MHz,METHANOL-d4)δppm 1.15(t,J＝7.40Hz,3H),1.34(td,J＝14.18,4.02Hz,1H),1.77-1.88(m,2H),1.94-2.13(m,3H),2.20(s,3H),2.39(s,3H),2.65(s,6H),3.19-3.31(m,2H),3.33-3.41(m,2H),3.85-4.00(m,2H),5.24(s,1H),6.04(s,1H),7.20(s,1H),7.58(dd,J＝8.28,1.25Hz,1H),7.83(d,J＝8.28Hz,1H).
实施例70
(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N-(3-甲氧基丙基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-9-磺酰胺
Figure PCTCN2016073143-appb-000222
该实施例的操作过程同实施例68C。
1H NMR(400MHz,METHANOL-d4)δppm 1.15(t,J＝7.28Hz,3H),1.28-1.37(m,1H),1.65(quin,J＝6.46Hz,2H),1.76-1.87(m,2H),1.96-2.15(m,3H),2.24(s,3H),2.40(s,3H),2.77-2.94(m,2H),3.18-3.32(m,6H),3.34-3.40(m,3H),3.84-3.99(m,2H),5.22(s,1H),6.04(s,1H),7.29(s,1H),7.65(dd,J＝8.28,1.25Hz,1H),7.79(d,J＝8.53Hz,1H).
实施例71
(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N,N-二甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-8-磺酰胺
Figure PCTCN2016073143-appb-000223
该实施例的操作过程同实施例68B、68C。
1H NMR(400MHz,METHANOL-d4)δppm 1.14(t,J＝7.28Hz,3H),1.26-1.38(m,1H),1.76-1.87(m,2H),1.95-2.15(m,3H),2.23(s,3H),2.39(s,3H),2.68(s,6H),3.22-3.30(m,2H),3.33-3.43(m,2H),3.84-4.00(m,2H),5.22(s,1H),6.04(s,1H),6.87(d,J＝8.78Hz,1H),7.57(dd,J＝8.91,1.38Hz,1H),8.06(d,J＝1.00Hz,1H).
实施例72
(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N-(3-甲氧基丙基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-9-磺酰胺
Figure PCTCN2016073143-appb-000224
该实施例的操作过程同实施例68B、68C。
1H NMR(400MHz,METHANOL-d4)δppm 1.14(t,J＝7.28Hz,3H),1.27-1.37(m,1H),1.70(quin,J＝6.40Hz,2H),1.75-1.87(m,2H),1.94-2.13(m,3H),2.22(s,3H),2.38(s,3H),2.90(t,J＝6.90Hz,2H),3.20-3.32(m,6H),3.39(t,J＝6.02Hz,3H),3.84-4.01(m,2H),5.20(br.s.,1H),6.02(s,1H),6.82(d,J＝9.03Hz,1H),7.64(dd,J＝8.78,1.25Hz,1H),8.14(s,1H).
实施例73
(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N-甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-7-磺酰胺
Figure PCTCN2016073143-appb-000225
该实施例的操作过程同实施例68B、68C。
1H NMR(400MHz,METHANOL-d4)δppm 1.14(t,J＝7.28Hz,3H),1.31(td,J＝14.05,3.51Hz,1H),1.75-1.87(m,2H),1.93-2.12(m,3H),2.22(s,3H),2.37(s,3H),2.68-2.74(m,3H),3.20-3.30(m,1H),3.34-3.40(m,1H),3.52-3.69(m,2H),3.80-3.91(m,2H),5.22(s,1H),6.04(s,1H),6.81(d,J＝8.28Hz,1H),7.29(t,J＝8.03Hz,1H),7.68(d,J＝7.53Hz,1H).
实施例74
(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N,N-二甲基-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-7-磺酰胺
Figure PCTCN2016073143-appb-000226
该实施例的操作过程同实施例68B、68C。
1H NMR(400MHz,METHANOL-d4)δppm 1.14(t,J＝7.28Hz,3H),1.31(td,J＝13.99,3.64Hz,1H),1.76-1.86(m,2H),1.95-2.11(m,3H),2.23(s,3H),2.37(s,3H),2.92(s,6H),3.19-3.29(m,1H),3.34-3.40 (m,1H),3.49-3.61(m,2H),3.81-3.92(m,2H),5.22(s,1H),6.07(s,1H),6.87(d,J＝8.53Hz,1H),7.31(t,J＝8.16Hz,1H),7.64(d,J＝7.53Hz,1H).
实施例75
(41S,13aS)-12-(4,5-二甲基恶唑-2-基)-13a-乙基-N-(3-甲氧基丙基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-7-磺酰胺
Figure PCTCN2016073143-appb-000227
该实施例的操作过程同实施例68B、68C。
1H NMR(400MHz,METHANOL-d4)δppm 1.14(t,J＝7.28Hz,3H),1.31(td,J＝13.93,3.76Hz,1H),1.73-1.87(m,4H),1.93-2.09(m,3H),2.22(s,3H),2.36(s,3H),3.11-3.17(m,2H),3.22-3.31(m,4H),3.36(br.s.,1H),3.41(t,J＝6.02Hz,2H),3.54-3.70(m,2H),3.79-3.93(m,2H),5.23(br.s.,1H),6.04(s,1H),6.80(d,J＝8.28Hz,1H),7.29(t,J＝8.03Hz,1H),7.70(d,J＝7.53Hz,1H).
实施例76
(41S,13aS)-13a-乙基-N-甲基-12-(3-甲基-1,2,4-恶二唑-5-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-9-磺酰胺
Figure PCTCN2016073143-appb-000228
该实施例的操作过程同实施例68A、68B、68C。
1H NMR(400MHz,CD3OD)δppm8.10(s,1H),7.62(dd,J＝1.1,8.9Hz,1H),7.04(d,J＝9.0Hz,1H),6.41(s,1H),5.23(br.s.,1H),4.06-3.78(m,2H),3.32-3.16(m,3H),2.60-2.42(m,7H),2.22-1.93(m,3H),1.87-1.70(m,2H),1.42-1.25(m,1H),1.15(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:444(M+1)
实施例77
(41S,13aS)-13a-乙基-N,N-二甲基-12-(3-甲基-1,2,4-恶二唑-5-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-9-磺酰胺
Figure PCTCN2016073143-appb-000229
该实施例的操作过程同实施例68A、68B、68C。
1H NMR(400MHz,CD3OD)δppm 8.07(d,J＝1.3Hz,1H),7.60(dd,J＝1.5,9.0Hz,1H),7.11(d,J＝9.0Hz,1H),6.44(s,1H),5.25(br.s.,1H),4.07-3.82(m,2H),3.29-3.16(m,2H),2.78-2.65(m,7H),2.54(s,3H),2.21-1.96(m,3H),1.91-1.75(m,2H),1.43-1.30(m,3H),1.16(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:468(M+1)
实施例78
(41S,13aS)-13a-乙基-N-(3-甲氧基丙基)-12-(3-甲基-1,2,4-恶二唑-5-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-9-磺酰胺
Figure PCTCN2016073143-appb-000230
该实施例的操作过程同实施例68A、68B、68C。
1H NMR(400MHz,CD3OD)δppm 8.12(d,J＝1.0Hz,1H),7.65(dd,J＝1.5,8.8Hz,1H),7.05(d,J＝9.0Hz,1H),6.42(s,1H),5.23(br.s.,1H),4.04-3.82(m,2H),3.41-3.35(m,3H),3.29-3.19(m,5H),2.90(t,J＝6.9Hz,2H),2.53(s,3H),2.23-1.98(m,3H),1.90-1.77(m,2H),1.69(quin,J＝6.5Hz,2H),1.40-1.26(m,2H),1.15(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:502(M+1)
实施例79
(41S,13aS)-13a-乙基-N-甲基-12-(3-甲基-1,2,4-恶二唑-5-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-8-磺酰胺
Figure PCTCN2016073143-appb-000231
该实施例的操作过程同实施例68A、68B、68C。
1H NMR(400MHz,CD3OD)δppm 7.80(d,J＝8.3Hz,1H),7.67(d,J＝8.3Hz,1H),7.51(s,1H),6.45(s,1H),5.25(s,1H),4.08-3.81(m,2H),3.31-3.17(m,3H),2.63-2.44(m,7H),2.20-1.96(m,3H),1.92-1.73(m,2H),1.47-1.28(m,2H),1.16(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:444(M+1)
实施例80
(41S,13aS)-13a-乙基-N,N-二甲基-12-(3-甲基-1,2,4-恶二唑-5-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-8-磺酰胺
Figure PCTCN2016073143-appb-000232
该实施例的操作过程同实施例68A、68B、68C。
1H NMR(400MHz,CD3OD)δppm 7.86(d,J＝8.3Hz,1H),7.63(d,J＝8.3Hz,1H),7.44(s,1H),6.48(s,1H),5.26(br.s.,1H),4.01-3.86(m,2H),3.32-3.21(m,4H),2.67(s,6H),2.51(s,3H),2.17-1.92(m,3H),1.91-1.78(m,2H),1.44-1.32(m,1H),1.16(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:468(M+1)
实施例81
(41S,13aS)-13a-乙基-N-(3-甲氧基丙基)-12-(3-甲基-1,2,4-恶二唑-5-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-8-磺酰胺
Figure PCTCN2016073143-appb-000233
该实施例的操作过程同实施例68A、68B、68C。
1H NMR(400MHz,CD3OD)δppm 7.80(d,J＝8.5Hz,1H),7.69(dd,J＝1.0,8.5Hz,1H),7.52(s,1H),6.44(s,1H),5.25(s,1H),4.02-3.84(m,2H),3.37(t,J＝6.0Hz,3H),3.32-3.19(m,6H),2.99-2.79(m,2H),2.53(s,3H),2.16-1.94(m,3H),1.90-1.77(m,2H),1.67(quin,J＝6.5Hz,2H),1.42-1.29(m,1H),1.16(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:502(M+1)
实施例82
(41S,13aS)-13a-乙基-N-甲基-12-(3-甲基-1,2,4-恶二唑-5-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-7-磺酰胺
Figure PCTCN2016073143-appb-000234
该实施例的操作过程同实施例68A、68B、68C。
1H NMR(400MHz,CD3OD)δppm 7.71(d,J＝7.5Hz,1H),7.32(t,J＝8.2Hz,1H),7.06(d,J＝8.5Hz,1H),6.43(s,1H),5.24(s,1H),3.93-3.79(m,2H),3.71-3.49(m,2H),3.33-3.24(m,2H),2.72(s,3H),2.52(s,3H),2.14-1.94(m,3H),1.90-1.76(m,2H),1.34(dt,J＝3.8,14.1Hz,1H),1.15(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:444(M+1)
实施例83
(41S,13aS)-13a-乙基-N,N-二甲基-12-(3-甲基-1,2,4-恶二唑-5-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-7-磺酰胺
Figure PCTCN2016073143-appb-000235
该实施例的操作过程同实施例68A、68B、68C。
1H NMR(400MHz,CD3OD)δppm 7.66(d,J＝7.8Hz,1H),7.34(t,J＝8.2Hz,1H),7.10(d,J＝8.5Hz,1H), 6.45(s,1H),5.24(s,1H),3.93-3.80(m,2H),3.64-3.47(m,2H),3.43-3.35(m,1H),3.30-3.19(m,2H),2.93(s,6H),2.72(s,1H),2.52(s,3H),2.16-1.94(m,3H),1.90-1.77(m,2H),1.40-1.28(m,3H),1.15(t,J＝7.3Hz,3H).
LCMS(ESI)m/z:468(M+1)
实施例84
(41S,13aS)-13a-乙基-N-(3-甲氧基丙基)-12-(3-甲基-1,2,4-恶二唑-5-基)-2,3,41,5,6,13a-六氢-1H-吲哚[3,2,1-de]吡啶[3,2,1-ij][1,5]萘啶-7-磺酰胺
Figure PCTCN2016073143-appb-000236
该实施例的操作过程同实施例68A、68B、68C。
1H NMR(400MHz,CD3OD)δppm 7.72(d,J＝7.8Hz,1H),7.32(t,J＝8.2Hz,1H),7.06(d,J＝8.5Hz,1H),6.44(s,1H),5.26(s,1H),3.97-3.81(m,2H),3.72-3.51(m,3H),3.45-3.36(m,4H),3.30-3.24(m,4H),3.16(t,J＝6.8Hz,2H),3.06(t,J＝6.9Hz,1H),2.52(s,3H),2.13-1.74(m,8H),1.41-1.27(m,1H),1.15(t,J＝7.4Hz,3H).
LCMS(ESI)m/z:502(M+1)
实验例1：磷酸二酯酶(PDE)体外检测
实验原理：
该测定基于荧光偏振检测AMP/GMP产生来测定PDE1A酶活性,反应原理是由AlexaFluor 633标记的AMP/GMP取代AMP/GMP与之抗体的结合。
实验试剂：
反应缓冲液：10mM的Tris-HCl，pH值7.5，5mM的氯化镁，0.01％的Brij 35，1mM的DTT
和1％DMSO
酶底物：1McAMP或cGMP(Ca2+-钙调蛋白作为PDE1A的辅因子)
检测试剂：
Figure PCTCN2016073143-appb-000237
AMP2/GMP2抗体
AMP2/GMP2AlexaFluor 633标记物
实验步骤和方法:
1、用新鲜配制的反应缓冲液稀释制待测人源酶(从SignalChem购买)和底物
2、将酶溶液(浓度为3pM)加入反应板孔中
3、使用Echo550将若干100％DMSO的化合物溶液，按照所需浓度加入含有酶溶液的微孔板中，室温孵育10分钟
4、加底物溶液至含有酶和化合物溶液的微孔板中，从而起始反应中
5、室温孵育1小时，同时震荡微孔板
6、加入检测混合物(示踪和抗体中的终止缓冲液)从而使酶反应停止，并孵育90分钟，同时震荡微孔板。
7、用设备EnVision(PerkinElmer),Cy5FP Ex FP 620,Em S-pol 688/P-pol 688,FP mirror D658fp/D688检测，用Ex/Em 620/688检测荧光偏振。
数据分析：
在Excel表中用DMSO作对照在AMP/GMP标准曲线上找出FP信号相对应的酶活性，并转换成nM产物浓度。使用GraphPad Prism进行分析并计算IC50值。
实验结果见表1：
表1PDE1检测IC50测试结果
Figure PCTCN2016073143-appb-000238
Figure PCTCN2016073143-appb-000239
注：A≤1uM；1uM＜B≤20uM；20uM＜C≤100uM；D>100uM
实验例2：比格犬药代动力学对比
本研究选用雄性比格犬为受试动物，应用LC/MS/MS法定量测定了比格犬分别静脉注射或口服给予实施例和参比化合物长春西汀后不同时间点的血浆中的药物浓度，以评价这两个受试药物在比格犬体内的药代动力学特征。
选择健康成年比格犬(体重范围7.0-10.83kg)共8只，购自北京玛斯生物技术有限公司。静脉注射组制剂均为DMSO:PEG400:water＝5:20:75，精确称量适量受试药物，加入适量溶媒后，通过涡旋振荡和超声使得到终浓度为1.0mg/mL的澄清溶液。用0.22μm的滤膜过滤，并保存于室温待用。口服组制剂均为PEG400:Tween80:H2O＝40:10:50。精确称量适量受试药物，加入适量溶媒，通过涡旋和超声后得到终浓度为1.5mg/mL的澄清溶液。静注给药制剂和口服给药制剂均为给药当天配制。静脉注射剂量为1.0mg/kg，口服组给药剂量为3.0mg/kg。各给药组在给药后0.083(仅静脉注射组)、0.25、0.5、1、2、4、6、8和24小时分别采集全血。全血离心(3000g,15分钟，4度)制备血浆。用LC/MS/MS法测定各血浆样品的药物浓度，用WinNonlinTMVersion 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型对血浆药物浓度数据进行处理。使用线性对数梯形法计算相关药代动力学参数。
表2实施例29标题化合物和长春西汀在比格犬中的药代动力学参数对比
Figure PCTCN2016073143-appb-000240
验结果表明，实施例29化合物的血浆清除率是长春西汀15％左右，半衰期比长春西汀延长56％；口服生物利用度是长春西汀的3.1倍。在非啮齿动物比格犬中，实施例29的药代动力学显著优于长春西汀。
实验例3：对戊四唑点燃食蟹猴癫痫模型的抑制作用
本试验选用了6只雄性食蟹猴，每只猴通过鼻饲灌胃。分别给予如下药物(戊四唑除外，采用皮下注射)实施例29化合物及卡马西平连续给药8天，首次给药前分别给予一次溶媒，最后一次给药后立即皮下注射戊四唑，两次供试品给药间隔约为10天；并在首次实施例29给药前给予一次戊四唑用于诱发癫痫。给药量基于动物的最新体重，首次给药日定为Day 1。
手术过程：动物在动物饲养设施中适应性饲养至少一周后，按照公司标准要求进行麻醉及术前准备。手术主要操作如下：剪开头部皮肤，充分暴露颅骨，剥离骨膜，干脱脂棉擦至头骨表面干洁。用颅骨钻 在食蟹猴头骨处钻2孔，植入脑电电极，用牙科水泥固定。然后将2根肌电电极埋入食蟹猴颈部肌肉内，眼电点击埋置于双侧提眼肌，植入子主体固定在腹部肌肉层。术后护理按照公司标准执行。
原始数据由DSI系统的Ponemah采集，由Neuronscore进行分析修正。
实验数据由平均值±标准误差(Mean±SEM)表示，采用t-检验和ANOVA进行统计分析，P<0.05表示有显著性差异，P<0.01表示有非常显著性差异，P<0.001表示有极显著性差异。
为比较实施例29和卡马西平对戊四唑点燃食蟹猴癫痫的药效学抑制作用，首先对戊四唑点燃癫痫的脑电放电特征和脑电能量进行观察分析，然后比较了实施例29和卡马西平对戊四唑点燃食蟹猴癫痫首次发作的潜伏期、阵挛性惊厥和强直性惊厥发作次数及发作时长。
利用DSI无线遥感信号记录系统，首先检测了食蟹猴在背部皮下注射40mg/kg的戊四唑后点燃癫痫样行为的脑电、肌电和自主活动情况。注射戊四唑后食蟹猴出现了特征化的癫痫样脑电和肌电活动。根据癫痫发生的状态我们将之分成阵发性活动、阵挛性惊厥和强直性惊厥。
分析统计注射戊四唑后24小时内食蟹猴癫痫发作时4-24Hz波段脑电能量的变化。结果显示，戊四唑点燃癫痫发生时4-24Hz波段脑电的能量明显增强。
为了评价实施例29和卡马西平对戊四唑点燃食蟹猴癫痫首次发作的潜伏期的影响，统计了注射戊四唑后癫痫首次发作的潜伏期。结果显示，实施例29和卡马西平显著延长了癫痫首次发作的潜伏期，连续给药8天后，各组对戊四唑点燃癫痫首次发作的潜伏期分别为：Vehicle组为24.86±3.97分钟；卡马西平组为45.20±9.11分钟；实施例29组为64.10±13.21分钟。实施例29组和卡马西平组与溶剂对照组相比均有显著性差异(P<0.05)。卡马西平组相较于Vehicle组延长20.34min，相对延长81％；实施例29相较于Vehicle组延长39.24min，相对延长约为160％；实施例29较卡马西平延长18.9min，相对延长约为42％。
因此在相同剂量下(10mg/kg)，实施例29与卡马西平都展现出显著延长癫痫首次发作潜伏期的作用，而且实施例29延长癫痫首次发作潜伏期的作用效果明显优于卡马西平约为42％。
此外实施例29和卡马西平能够显著减少戊四唑给药后24小时内的阵挛性惊厥和强直性惊厥的发生次数。阵挛性惊厥和强直性惊厥的发作次数：Vehicle组为107.50±15.60次；卡马西平组为39.20±14.92次；实施例29组为25.7±7.07次。相比于Vehicle对照组：实施例29组和卡马西平组均具有非常显著性差异(P<0.01)。卡马西平组相较于Vehicle组平均减少约68次，相对减少63％；而实施例29组相较于Vehicle组平均减少约82次，相对减少76％。最后实施例29较卡马西平减少约14次，相对减少36％。
因此在相同剂量下(10mg/kg)，实施例29和卡马西平都非常显著地减少了阵挛性惊厥和强直性惊厥的发作次数，而且实施例29减少发作次数的作用效果优于卡马西平约36％。
最后检测实施例29和卡马西平对阵挛性惊厥和强直性惊厥发生时长的影响。结果显示，实施例29和卡马西平明显抑制戊四唑点燃食蟹猴阵挛性惊厥和强直性惊厥的发作时长。阵挛性惊厥和强直性惊厥时长分别为：Vehicle组为11.68±3.15分钟；卡马西平组为4.71±2.35分钟；实施例29组为2.61±0.99分钟。相比于Vehicle对照组：实施例29组和卡马西平组均具有显著性差异(P<0.05)。卡马西平相较于Vehicle平均减少6.97分钟，相对缩短60％；实施例29较Vehicle组减少9.07分钟，相对缩短78％。实 施例29组相较于卡马西平组平均减少约2.1分钟，相对缩短45％。
因此在相同剂量下(10mg/kg)，实施例29和卡马西平都显著缩短阵挛性惊厥和强直性惊厥的发作时长，而且实施例29缩短阵挛性惊厥和强直性惊厥发作时长的作用效果优于卡马西平约45％。
综上所述本实验结果显示：皮下注射戊四唑后6只雄性食蟹猴均产生了癫痫样脑电波及惊厥和强直性肌放电。实施例29化合物和卡马西平不仅能够显著延长戊四唑点燃食蟹猴首次癫痫发作的潜伏期，还能够显著减少戊四唑给药后24小时内阵挛性惊厥和强直性惊厥的发作次数和发作时长。数据表明：实施例29在这三项抗癫痫作用的关键指标中均优于卡马西平。

Claims (13)

  1. 式(Ⅰ)所示化合物、其药学上可接受的盐或其互变异构体，
    Figure PCTCN2016073143-appb-100001
    其中，
    R1、R3分别独立地选自H、F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH，或选自任选被R01取代的：C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、C1-10烷基或杂烷基、C3-10环烃基或杂环烃基、被C3-10环烃基或杂环烃基取代的C1-10烷基或杂烷基、C1-10烯基或杂烯基；
    R2选自任选被R01取代的5～6元不饱和环烃基或杂环烃基、
    Figure PCTCN2016073143-appb-100002
    Figure PCTCN2016073143-appb-100003
    R01选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、R02；
    R02选自C1-10烷基或杂烷基、C3-10环烷基或杂环烷基、氨基酰基、5～12元不饱和杂环基、；
    “杂”表示杂原子或杂原子团，选自-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7)-、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-和/或-N(Rd8)C(＝O)N(Rd9)-；
    Rd3-d9分别独立地选自H、NH2、R02；
    R02任选地被R001取代；
    R001选自F、Cl、Br、I、CN、OH、N(CH3)2、NH(CH3)、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、三氟甲基、氨甲基、羟甲基、甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基；
    R01、R001、杂原子或杂原子团的数目分别独立地选自0、1、2、3或4。
  2. 根据权利要求1所述化合物、其药学上可接受的盐或其互变异构体，其中R1、R3分别独立地选自H、
    Figure PCTCN2016073143-appb-100004
    R105，R101-105分别独立地选自任选被R001取代的C1-6烷基或杂烷基；或R1、R3分别独立地选自被0、1、2或3个R01取代的5～6元不饱和环烃基或杂环烃基、
    Figure PCTCN2016073143-appb-100005
    Figure PCTCN2016073143-appb-100006
  3. 根据权利要求2所述化合物、其药学上可接受的盐或其互变异构体，其中R101-105分别独立地选自H、
    Figure PCTCN2016073143-appb-100007
  4. 根据权利要求3所述化合物或其药学上可接受的盐，其中R1、R3分别独立地选自H、
    Figure PCTCN2016073143-appb-100008
    Figure PCTCN2016073143-appb-100009
  5. 根据权利要求1～2所述化合物、其药学上可接受的盐或其互变异构体，其中R2选自
    Figure PCTCN2016073143-appb-100010
    Figure PCTCN2016073143-appb-100011
    Figure PCTCN2016073143-appb-100012
    其中，
    T21-23中的0～2个分别独立地选自N，其余选自C(Rt)；
    D21选自-C(Rd1)(Rd2)-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(Rd8)C(＝O)N(Rd9)-；
    T24选自N或C(Rt)；
    D22-24分别独立地选自-C(Rd1)(Rd2)-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(Rd8)C(＝O)N(Rd9)-；
    T25-29中的0～2个分别独立地选自N，其余选自C(Rt)；
    任选地，各个Rt、Rd1-d9中的任意两个共同连接到同一个原子或原子团上形成1或2个3～8元环；
    Rt、Rd1、Rd2分别独立地选自H、F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2，或选自任选被R01取代的C1-10烷基或杂烷基、C3-10环烃基或杂环烃基、被C3-10环烃基或杂环烃基取代的C1-10烷基或杂烷基、C1-10烯基或杂烯基；
    其他变量如权利要求1所定义。
  6. 根据权利要求5所述化合物、其药学上可接受的盐或其互变异构体，其中R2分别独立地选自
    Figure PCTCN2016073143-appb-100013
    其中A分别独立地代表任选被0、1、2或3个Rt取代的3～8元饱和或不饱和的碳环或杂环。
  7. 根据权利要求6所述化合物、其药学上可接受的盐或其互变异构体，其中R2分别独立地选自
    Figure PCTCN2016073143-appb-100014
  8. 根据权利要求5所述化合物、其药学上可接受的盐或其互变异构体，其中Rt、Rd1-d9分别独立地选自H、NH2、CN、任选被R001取代的：C1-6烷基或杂烷基、C3-6环烷基或杂环烷基、5～6元不饱和杂环基、氨基酰基；
    Rt、Rd1-d2还可以分别独立地选自F、Cl、Br、I；
    优选地，Rt、Rd1-d9分别独立地选自任选被R001取代的：C1-6烷氨基、N,N-二(C1-3烷基)氨基、C1-6烷氧基、C1-6烷酰基、C1-6烷氧羰基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C3-6环烷基、C3-6环烷氨基、C3-6杂环烷氨基、C3-6环烷氧基、C3-6环烷基酰基、C3-6环烷氧羰基、C3-6环烷基磺酰基、C3-6环烷基亚磺酰基、氨基酰基、5～6元不饱和杂环基；
    更优选地，Rt、Rd1-d9分别独立地选自任选被R001取代的5～6元芳基或杂芳基；
    更优选地，Rt、Rd1-d9分别独立地选自任选被R001取代的苯基、吡啶基、噻吩基。
  9. 根据权利要求8所述化合物、其药学上可接受的盐或其互变异构体，其中杂原子或原子团选自O、N、S、-C(＝O)O-、
    Figure PCTCN2016073143-appb-100015
  10. 根据权利要求9所述化合物、其药学上可接受的盐或其互变异构体，其中Rt、Rd1-d9分别独立地选自H、F、Cl、Br、I、NH2、CH3、CN、
    Figure PCTCN2016073143-appb-100016
    Figure PCTCN2016073143-appb-100017
  11. 根据权利要求10所述化合物、其药学上可接受的盐或其互变异构体，其中R1-3分别独立地选自：
    Figure PCTCN2016073143-appb-100018
    Figure PCTCN2016073143-appb-100019
  12. 根据权利要求1所述化合物、其药学上可接受的盐或其互变异构体，其选自：
    Figure PCTCN2016073143-appb-100020
    Figure PCTCN2016073143-appb-100021
    Figure PCTCN2016073143-appb-100022
    Figure PCTCN2016073143-appb-100023
  13. 根据权利要求1～12任意一项所述的化合物、其药学上可接受的盐或其互变异构体，在制备治疗脑卒中或癫痫的药物中的应用。
PCT/CN2016/073143 2015-02-04 2016-02-02 二氮杂-苯并荧蒽类化合物 WO2016124129A1 (zh)

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