WO2015165340A1 - Anti-enterovirus 71 thiadiazolidine derivative - Google Patents

Anti-enterovirus 71 thiadiazolidine derivative Download PDF

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Publication number
WO2015165340A1
WO2015165340A1 PCT/CN2015/077043 CN2015077043W WO2015165340A1 WO 2015165340 A1 WO2015165340 A1 WO 2015165340A1 CN 2015077043 W CN2015077043 W CN 2015077043W WO 2015165340 A1 WO2015165340 A1 WO 2015165340A1
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Prior art keywords
group
etoac
mmol
nmr
oxy
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PCT/CN2015/077043
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French (fr)
Chinese (zh)
Inventor
李鹏
贺海鹰
李宁
黎健
陈曙辉
杨百灵
沈旺
肖伟
Original Assignee
南京明德新药研发股份有限公司
江苏康缘药业股份有限公司
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Priority claimed from CN201410543064.6A external-priority patent/CN105085512A/en
Application filed by 南京明德新药研发股份有限公司, 江苏康缘药业股份有限公司 filed Critical 南京明德新药研发股份有限公司
Priority to JP2016565011A priority Critical patent/JP6389531B2/en
Priority to SG11201608710TA priority patent/SG11201608710TA/en
Priority to ES15786304T priority patent/ES2841418T3/en
Priority to EP15786304.4A priority patent/EP3138840B1/en
Priority to KR1020187016595A priority patent/KR101957178B1/en
Priority to US15/307,710 priority patent/US9988361B2/en
Priority to DK15786304.4T priority patent/DK3138840T3/en
Priority to KR1020167033211A priority patent/KR20160147010A/en
Priority to CN201580011272.4A priority patent/CN106661009B/en
Publication of WO2015165340A1 publication Critical patent/WO2015165340A1/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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel anti-enteric virus 71 (EV71) 1,2,5-thiadiazolidine-1,1-dioxide derivative or a pharmaceutically acceptable salt thereof, in particular to the formula (II) A compound or a pharmaceutically acceptable salt thereof.
  • Enterovirus 71 belongs to the family of small RNA viruses and is one of the most common sources of hand, foot and mouth disease. It can also cause a variety of neurological-related diseases such as herpes pharyngitis, aseptic meningitis, encephalitis, and polio-like paralytic diseases, which can be accompanied by severe central nervous system complications or neuroinflammation. Pulmonary Edema.
  • Hand, foot and mouth disease has the characteristics of high epidemic intensity, strong contagiousness and complicated transmission route. So far, there is no specific anti-enteric virus type 71 drug.
  • the present invention provides a compound of the formula (II) or a pharmaceutically acceptable salt thereof,
  • R 3 is selected from a 5-membered heterocyclic ring optionally substituted by R 01 , a C 6- 12 aryl group, a C 6- 12 aralkyl group, a C 5-12 heteroaryl ring or a C 5-12 heteroarylalkyl group;
  • L 2 are independently selected from
  • n 1 , m 2 are each independently selected from 0, 1 , 2 , 3, 4, 5 or 6;
  • R 4 is selected from a 5- to 14-membered cyclic hydrocarbon group or a heterocyclic hydrocarbon group
  • R d1 , R d2 are each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or a C 1-10 alkyl group optionally substituted by R 01 or a heteroalkyl group, a C 3-10 cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl;
  • R 01 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, R 02 ;
  • R 02 is selected from C 1-10 alkyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkoxy, C 1-10 alkanoyl, C 1 -10 alkoxycarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 cycloalkyl acyl, C 3-10 cycloalkoxycarbonyl, C 3-10 cycloalkylsulfonyl, C 3-10 cycloalkylsulfinyl;
  • R d3 - d7 are each independently selected from H, R 03 ;
  • R 03 is selected from C 1-10 alkyl, C 1-10 alkyl acyl, C 1-10 alkoxycarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 a cycloalkyl group, a C 3-10 cycloalkyl acyl group, a C 3-10 cycloalkoxycarbonyl group, a C 3-10 cycloalkylsulfonyl group, a C 3-10 cycloalkylsulfinyl group;
  • R 02 and R 03 are optionally substituted by R 001 ;
  • R 001 is selected from the group consisting of F, Cl, Br, I, CN, OH, N(CH 3 ) 2 , NH(CH 3 ), NH 2 , CHO, COOH, trifluoromethyl, aminomethyl, hydroxymethyl, A Base, methoxy, formyl, methoxycarbonyl, methylsulfonyl, methylsulfinyl;
  • R 01 , R 001 , hetero atom or hetero atomic group is independently selected from 0, 1, 2 or 3;
  • R d1 and R d2 are linked to each other to form a 3 or 4 membered carbocyclic or heterocyclic ring.
  • R 3 is selected from a 5 to 6 membered aryl or heteroaryl group which is optionally substituted.
  • R 3 is selected from R 01 is optionally substituted pyridyl, phenyl, furanyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrimidinyl, thienyl, R 01 is In the above definition, the number of R 01 is selected from 0, 1, 2 or 3.
  • R 01 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, Me,
  • R 3 is selected from the group consisting of
  • L 2 is selected from m 3 is 0, 1, or 2, and other variables are as defined above.
  • L 2 is selected from the group consisting of
  • R 4 is selected from T 4-7 are each independently selected from N or C(R t ),
  • n 2 is selected from 0, 1, 2 or 3,
  • n 3 is selected from 0, 1 or 2
  • R 5 , R 6 , R 7 , R t , R d1 , R d2 are each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or selected from the group consisting of a C 1-10 alkyl or heteroalkyl group substituted by R 01 , a C 3-10 cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl group ,
  • R 4 is selected from X 3 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or a C 1-10 alkyl or heteroalkyl group optionally substituted by R 01 , C 3-10 a cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl group.
  • R 5-7 are each independently selected from among them:
  • T 1-3 are each independently selected from N or C(R t );
  • R 8 , R 9 , R t are each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or C 1-10 selected from R 1 , optionally substituted by R 01 .
  • R 10 is selected from F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or a C 1-10 alkyl or heteroalkyl group optionally substituted by R 01 , C 3-10 a cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl group.
  • R 5-9 , R 01 , R t are each independently selected from F, Cl, Br, CF 3 , -C(C 2 H 5 )-, -C(OC 2 H 5 )-, methyl, ethyl, propyl, methoxy, ethoxy, propoxy,
  • R 4 is selected from the group consisting of
  • the invention is selected from the group consisting of:
  • C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ;
  • C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .
  • C 1-12 alkyl or heteroalkyl, C 3-12 cyclo or heterocycloalkyl, C 1-12 alkyl or heteroalkyl substituted by C 3-12 cycloalkyl or heterocycloalkyl includes, but is 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.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, 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 the addition of these compounds in free acid or base form in water or an organic solvent or a mixture of the two.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • 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 salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art.
  • the diastereomeric resolution is carried out by crystallization or chromatography, and then 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.
  • radiolabeled compounds can be used, 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 means a drug that is non-toxic but achieves the desired effect. Or a sufficient amount of the agent.
  • 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.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • 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. For example, a structural unit or It is indicated that it can be substituted at any position on the cyclohexyl or cyclodiene.
  • R', R", R"', R"" and R""' are each independently preferred Hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (eg substituted by 1 to 3 halogen aryl), substituted or unsubstituted alkyl, alkoxy, sulphur Alkoxy group or aralkyl group.
  • each R group is independently selected as if present Each of these groups of more than one R', R", R"', R"" and R""' groups.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they may be bonded to the nitrogen The atoms combine to form a 5-, 6- or 7-membered 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 hetero atom, which It may be saturated, partially unsaturated or unsaturated (aromatic) which comprises a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above is hetero
  • the ring may be fused to a benzene 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, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (preferably 1 to 3 rings) which 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.
  • aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, 5-
  • 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, pyridyl) Methyl or the like, including those wherein a carbon atom such as a methylene group has been replaced by, for example, an oxygen atom, such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl Wait.
  • 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 compound of the present invention is highly efficient, low in toxicity, and has achieved remarkable and unexpected progress in activity, half-life, solubility and pharmacokinetics, and is more suitable for pharmaceuticals.
  • Example 4A (5 g, 28.9 mmol) was dissolved in a mixed solvent of dichloromethane and N,N-dimethylformamide (50 ml / 5 ml), and the mixture was added dropwise to the mixed solution at 15 ° C. The sulfone (60 ml) was then raised to 40 ° C for 16 hours. After cooling to room temperature, pour ice water (200 ml), add 1 mol of aqueous sodium hydroxide solution to adjust the pH to 10, extract the aqueous layer with ethyl acetate (100 ml ⁇ 6), and combine the organic layer with brine (50 ml), EtOAc (EtOAc m.
  • EtOAc EtOAc
  • Example 6A To acetone (200 ml) Example 6A (20 g, 97.72 mmol) was added a solution of 1,5-dibromopentane (67 g, 293.2 mmol), K 2 CO 3 (27 g, 195.4 mmol) And KI (1.62 g, 9.77 mmol). After the addition was completed, the mixed solution was heated at 80 ° C for 12 hours. After the completion of the reaction, the reaction mixture was filtered, EtOAcjjjjjjjjjjj 75%).
  • Example 4F Sodium hydride (10 mg, 0.4 mmol, 60% content) was added to a solution of Example 4F (40 mg, 0.2 mmol) in N,N-dimethylformamide (10 ml) at 0 ° C
  • a solution of Example 6B 71 mg, 0.2 mmol of N,N-dimethylformamide (2 mL) was added.
  • the reaction was quenched with water and the aqueous layer was extracted with ethyl acetate.
  • Example 7A (1.0 g, 6.05 mmol), 1,5-dibromopentane (1.39 g, 6.05 mmol), potassium carbonate (1.67 g, 12.11 mmol) and potassium iodide (0.1 g, 0.605 mmol) It was mixed with acetone (100 ml) and heated under reflux for 10 hours. Filtration, EtOAc (EtOAc) m.
  • Example 4F Sodium hydrogen (10 mg, 250 mmol, 60%) was added in portions to a solution of Example 4F (60 mg, 301.2 mmol) in N,N-dimethylformamide (1 mL) After stirring for 1.5 hours, a solution of Example 7B (114 mg, 361.4 mmol) of N,N-dimethylformamide (0.5 ml) was added dropwise to the reaction mixture, and then the mixture was stirred at room temperature for 2 hr. In water (10 ml), EtOAc (3 mL,EtOAc) 30.7%).
  • Example 8A To a mixed solution of Example 8A (50 mg, 0.3 mmol) and water (5 mL), EtOAc (EtOAc, EtOAc (EtOAc) The mixed solution was heated at 80 ° C for 1 hour, and the aqueous layer was extracted with ethyl acetate (m. 1 H-NMR (CDCl 3 , 400 MHz) ⁇ 7.52-7.66 (m, 1H), 6.68-6.87 (m, 2H), 4.12-4.30 (m, 2H), 2.78-3.07 (m, 4H), 1.27- 1.41 (m, 3H).
  • Example 8B To a mixed solution of Example 8B (80 mg, 0.4 mmol) and acetone (5.0 mL) was added 1,5-dibromopentane (288 mg, 1.26 mmol, 3.0 eq.), potassium carbonate (578 mg, 4.18) Millimol, 10 equivalents) and potassium iodide (7 mg, 0.04 mmol, 0.1 eq.) were heated at 80 ° C for 5 hours. After the reaction mixture was filtered, EtOAcjjjjjjjjjj LCMS (ESI) m/z:
  • Example 9A To a solution of Example 9A (80 mg, 0.25 mmol), 1-ethylpyrazole-4-boronic acid succinate (55 mg, 0.25 mmol) and sodium carbonate (53 mg, The catalyst Pd(dppf)Cl 2 (9 mg, 12.4 ⁇ mol) was added to a mixed solution of 0.5 mmol of 1,4-dioxane (3 ml) and water (0.5 ml), and stirred at 80 ° C. After a few hours, water (10 ml), EtOAc (EtOAc m. White solid, 26 mg, yield 31%).
  • Pd(dppf)Cl 2 9 mg, 12.4 ⁇ mol
  • Example 10A To a solution of Example 10A (3 g, 19.57 mmol) in EtOAc (10 mL). After the addition was completed, the mixed solution was heated at 60 ° C for 1 hour. The reaction mixture was cooled to EtOAc.
  • LCMS m.
  • Example 10B To a solution of Example 10B (10 g, 52.58 mmol) of N,N-dimethylformamide (100 ml), EtOAc (3.26 g, 105.15 mmol) and 1,5-dibromopentane (36.27) Gram, 157.73 mmol). After the mixture was stirred at 10 ° C for 12 hours, the mixture was evaporated. EtOAcjjjjjjjjjjjj The title compound (white solid, 10 g, yield 56%).
  • Example 11B To Example 11B (1 g, 450 mmol) was added 10 mL of a solution of hydrogen bromide. The mixed solution was heated at 110 ° C for 24 hours. After cooling, the reaction mixture was evaporated.
  • Example 6A To a mixture of Example 6A (1 g, 4.89 mmol), potassium carbonate (1.35 g, 9.77 mmol) and potassium iodide (810 mg, 4.89 mmol) in acetone (15 mL) -Bromoethoxy)ethane (3.4 g, 14.66 mmol). After the mixture was stirred at 70 ° C for 3 hours, it was evaporated to dryness.
  • Example 7A A mixture of Example 7A (4.98 g, 30.17 mmol), Example 14A (11.7 g, 27.43 mmol), EtOAc (EtOAc) Ethyl acetate (50 ml) and water (50 ml) were evaporated. EtOAc (EtOAc) Purification gave the title compound (EtOAc m.
  • Example 16A (80 mg, 0.16 mmol), tert-butyl carbamate (74 mg, 0.63 mmol) and cesium carbonate (103 mg, 0.32 mmol) of dioxane/N, N under N2.
  • dimethylformamide 1.5 ml / 0.5 ml
  • Pd 2 (dba) 3 (20 mg, 0.03 mmol
  • Xant-Phos (10 mg, 0.03 mmol) were added, and the mixture was added after the addition.
  • the solution was stirred at 110 ° C for 16 hours. After the solvent was removed in vacuo, EtOAc m. .
  • Example 4E Sodium hydrogen (93 mg, 2.32 mmol) was added to a solution of Example 4E (271 mg, 1.16 mmol) of N, N-dimethylformamide. After stirring at 0<0>C for 0.5 h, EtOAc (EtOAc &lt The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 12 hours.
  • 1,5-Pentanediol 60 g, 0.57 mol
  • 3,4-dihydropyran 48.5 g, 0.57 mol
  • p-toluenesulfonic acid 50 mg
  • a potassium carbonate solution 200 ml
  • ethyl acetate 150 ml ⁇ 3
  • the combined organic phases were dried over anhydrous sodium sulfate and filtered and evaporated.
  • Example 19A 60 g, EtOAc.
  • Example 19B (7.5 g, 40.27 mmol), EtOAc (EtOAc:EtOAc.
  • Dichloromethane 50 ml
  • water 50 ml
  • the mixture was adjusted to pH 6 with dilute aqueous hydrochloric acid and the aqueous layer was extracted with dichloromethane (100 ml ⁇ 3).
  • Example 19C To a solution of Example 19C (2.5 g, 6.03 mmol) elute The reaction was carried out at 50 ° C for 3 hours. The solvent was evaporated to dryness EtOAc EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
  • Triethylphosphine (420 mg, 1.6 mmol) was slowly added to a mixture of Example 19E (500 mg, 1.6 mmol), tetrabromide (3.4 g, 10.3 mmol) in tetrahydrofuran (5 mL). The mixture was reacted at 60 ° C for 1 hour.
  • Example 19B (5.0 g, 29 mmol), 5'-bromo-2'-hydroxyacetophenone (6.37 g, 29 mmol) and piperidine (2.0 mL) were combined in ethanol (150 mL). After refluxing for 4 hours, the title compound was evaporated.
  • N-butyllithium (2.5 moles per liter, 1.8 milliliters, 4.6 millimoles) was slowly added dropwise to a solution of Example 20C (600 mg, 2.1 mmol) in anhydrous tetrahydrofuran (10.0 mL). ), continue to stir for 2 hours after the addition.
  • the reaction solution was again lowered to -78 ° C, and N,N-dimethylformamide (380 mg, 5.2 mmol) was slowly added dropwise. After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred overnight.
  • Example 21A To a solution of Example 21A (70 mg, 0.32 mmol) in water (2.0 mL), EtOAc (EtOAc, EtOAc. After heating for 3 hours, the reaction was stopped. The aqueous phase was extracted with ethyl acetate (5.0 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered and evaporated.
  • Example 2 The product of Example 2 was resolved using SFC to obtain two chiral isomers.
  • the conditions used for the split are as follows:
  • Example 22a is the first isomer with a retention time of 2.80 minutes;
  • Example 22b is the second isomer with a retention time of 4.04 minutes.
  • Example 23A (1.0 g, 6.1 mmol), 1,5-dibromopentane (1.4 g, 6.1 mmol), potassium carbonate (1.67 g, 12.1 mmol) and potassium iodide (0.1 g, 0.61 mmol)
  • the acetone (100 ml) solution was heated to reflux for 10 hours.
  • Example 4E 100 mg, 428 ⁇ mol
  • N,N-dimethylformamide 3 mL
  • EtOAc EtOAc
  • Example 23C (80 mg, 171.3 micromoles), tert-butyl carbamate (120 mg, 1.0 mmol) and Cs 2 CO 3 (112 mg, 343 ⁇ mol) of dioxane and N under N2.
  • Pd 2 (dba) 3 (30 mg, 33 ⁇ mol) and Xant-Phos (15 mg, 38 ⁇ mol)
  • N-dimethylformamide 3 ml
  • 1 ml N-dimethylformamide
  • Example 27A 120 mg, 0.24 mmol in N,N-dimethylformamide (1 mL), EtOAc ( 159 mg, 171 mg, 1.5 mmol). Pd 2 (dba) 3 (8.6 mg, 20 mmol), Xantphos (11.7 mg, 20 mmol) was added under nitrogen. After the reaction was stirred at 110 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated.
  • Example 8B A mixed solution of Example 8B (2.5 g, 13.1 mmol), 14A (6.1 g, 14.4 mmol) and potassium carbonate (3.6 g, 26.1 mmol) in acetonitrile (50 ml) was reacted at 80 ° C for 16 hours. Ethyl acetate (50 ml) and water (50 ml) were evaporated. The title compound (colorless liquid, 2.5 g, 39% yield).
  • Example 4E Slowly add sodium hydrogen (673 mg, 16.8 mmol) to a mixture of Example 4E (1.3 g, 4.8 mmol) of N,N-dimethylformamide (40 ml) at 0 ° C.
  • a mixture of Example 29A (2.5 g, 5.6 mmol) of N,N-dimethylformamide (40 ml) was obtained, and the mixture was reacted at 25 ° C for 12 hours.
  • Water (30 ml) was added to the reaction mixture, the aqueous layer was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj.
  • the title compound (yellow liquid, 2.1 g, 66% yield).
  • Example 29C by chiral separation (AD-H_3UM_3_60_3 ml_5MIN, Column: Chiralpak AD-350*4.6 mm ID, 3um mobile phase: 60% methanol (0.05% DEA) - CO 2 flow rate: 3 ml/min; wavelength: 220 nm; peak time: 1.334 min, 1.823 min) gave the title compound.
  • Example 30C 1.0 g, 2.3 mmol
  • EtOAc EtOAc
  • Example 31A (300 mg, 1.34 mmol) was added dropwise to a solution of lithium tetrahydroaluminum (102 mg, 2.68 mmol) in tetrahydrofuran (3 mL) at 0 ° C. Stir for 3 hours. Water (0.5 ml) and a 10% sodium hydroxide solution (0.5 ml) were added to the reaction mixture.
  • Example 31B To a solution of Example 31B (160 mg, 1.1 mmol), triphenylphosphine (1.79 g, 6.8 mmol) in THF (5 mL) After the addition was completed, the mixed solution was stirred at 60 ° C for 3 hours. Filtration, the filter cake was washed with EtOAc (EtOAc (EtOAc) (EtOAc) .
  • EtOAc EtOAc
  • Example 30C The preparation method of this example is referred to Example 30C.
  • Example 32C 550 mg, 2.5 mmol of N,N-dimethylformamide (8 mL). After stirring for 0.5 hours, a solution of 4-((5-bromophenyl)pentyl)benzaldehyde (671 mg, 2.5 mmol) in N,N-dimethylformamide (19 ml) was added dropwise. After stirring at 0 ° C for 0.5 hour, the reaction was terminated by TLC. The reaction was quenched with EtOAc (EtOAc (EtOAc)EtOAc. The title compound (white solid, 400 mg, 60%) was obtained.
  • EtOAc EtOAc
  • Trifluoroacetic acid (5 ml) was added to a solution of EtOAc (EtOAc)EtOAc. After the end of the reaction, the reaction mixture was purified by EtOAc EtOAc (EtOAc) (Colorless oil, 2.66 g, yield 88%), used directly in the next step.
  • Example 32F (130 mg, 366 ⁇ mol), 4-bromo-2-methylpyridine (189 mg, 1.1 mmol), Cs 2 CO 3 (179 mg, 549 ⁇ mol), Pd 2 A solution of (dba) 3 (34 mg, 37 ⁇ mol) and Xant-phos (21 mg, 37 ⁇ mol) in dioxane (2 mL) was heated to 100 ° C for 6 hours. TLC shows complete consumption of raw materials. After the reaction mixture was cooled to room temperature, ethyl acetate (20 ml) was evaporated. The title compound (white solid, 100 mg, yield 61%).
  • Acetyl chloride was added to a solution of 4-bromo-2-aminopyridine (1.0 g, 5.8 mmol) and triethylamine (1.75 g, 17 mmol) in dichloromethane (50 mL). 454 mg, 5.8 mmol). The reaction was quenched with EtOAc (EtOAc)EtOAc. The combined organic layers were dried with anhydrous sodium sulfate, filtered and evaporated.
  • Example 32F (60 mg, 169 ⁇ mol), 4-bromo-2-fluoro-pyridine (30 mg, 169 ⁇ mol) and cesium carbonate (83 mg, 253 ⁇ mol) of dioxane under nitrogen.
  • Pd 2 (dba) 3 (15 mg, 17 ⁇ mol) and Xant-Phos (10 mg, 17 ⁇ mol) were added, and the mixture was stirred and heated to 100 ° C for 4 hours. After the TLC detection reaction was completed, the solvent was concentrated and evaporated. Water (20 ml) was added, and EtOAc (EtOAc m. The title compound (white solid, 70 mg, 92%).
  • Example 39 To a solution of Example 39 (20 mg, 44 ⁇ mol) and 2-aminoethanol (27 mg, 444 ⁇ mol) in dimethyl sulfoxide (0.5 mL) was added triethylamine (27 mg, 266). Micromolar). The mixed solution was reacted at 100 ° C for 2 hours. After the reaction was completed by EtOAc (EtOAc) (EtOAc) The combined organic layers were dried with anhydrous sodium sulfate, filtered and evaporated.
  • EtOAc EtOAc
  • Example 32F 50 mg, 141 ⁇ mol
  • 4-fluorobenzonitrile 17 mg, 141 ⁇ mol
  • N,N-dimethylimide 1 mL
  • Potassium carbonate 39 mg, 281 ⁇ mol
  • the combined organic layers were dried with sodium sulfate, filtered and evaporated.
  • Example 32B Sodium hydrogen (17 mg, 428 micromoles) was added to a solution of Example 32B (100 mg, 428. After 1 hour, the mixed solution was added to a solution of 1,5-dibromopentane (98 mg, 428 ⁇ mol) in DMF (4 ml), and the mixture was stirred at 10 ° C for 10 hr. The aqueous phase was extracted with EtOAc (EtOAc (EtOAc)EtOAc. Purification of the title compound (yield: 50 mg, 38% yield).
  • Example 45A 100 mg, 269 ⁇ mol
  • Example 8B 52 mg, 269 ⁇ mol
  • N,N-dimethylformamide 1 mL
  • 808 micromolar 808 micromolar
  • the reaction mixture was stirred at 80 ° C for 10 hr.
  • EtOAc EtOAc
  • the organic layer was dried over anhydrous sodium sulfate, filtered and evaporated.
  • Example 45C (550 mg, 1.4 mmol), 4-bromo 2-aminopyridine (499 mg, 2.9 mmol), potassium carbonate (498 mg, 3.6 mmol), 8-hydroxyquinoline 209 mg, 1.4 mmol, (1R, 2R)-cyclohexanediamine (165 mg, 1.4 mmol) and cuprous iodide (275 mg, 1.4 mmol) in DMF (10 mL) at 120 ° C Heat for 10 hours. After completion of the reaction, water was added and the aqueous phase was extracted with ethyl acetate (10 ml).
  • Example 48A To a solution of Example 48A (50 mg, 98 ⁇ mol) in dioxane (1 mL) was added EtOAc EtOAc (EtOAc, EtOAc. Molar), Pd 2 (dba) 3 (9 mg, 9.8 ⁇ mol) and Xant-phos (6 mg, 10 ⁇ mol). The mixture was reacted at 110 ° C for 10 hours. TLC showed the reaction was quenched with EtOAc (EtOAc) The combined organic layers were dried with sodium sulfate, filtered and evaporated.
  • EtOAc EtOAc EtOAc, EtOAc. Molar
  • Pd 2 (dba) 3 9 mg, 9.8 ⁇ mol
  • Xant-phos 6 mg, 10 ⁇ mol
  • EtOAc EtOAc
  • Example 4E Sodium hydrogen (1.0 g, 27 mmol) was added to a solution of Example 4E (4.0 g, 17 mmol) in N,N-dimethylformamide (140 ml) at 10 ° C. The reaction was stirred for 1 hour. While maintaining this temperature, a solution of 1,5-dibromopentane (3.9 g, 17 mmol) in N,N-dimethylformamide (40 ml) was added dropwise, and then the reaction was continued for 1 hour. After the reaction was completed by thin layer chromatography, the reaction mixture was poured into ice water (100 ml) and ethyl acetate (100 ml).
  • Example 52B To a solution of Example 52B (110 mg, 0.25 mmol) of N,N-dimethylformamide (2 mL), EtOAc (EtOAc) Mg, 0.15 mmol). After the reaction was stirred at 50 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated. The combined organic phases were dried with EtOAc EtOAc. LCMS (ESI) m/z: 450 (21.
  • Example 52C To a solution of Example 52C (50 mg, 0.1 mmol) of N,N-dimethylformamide (1.5 ml), EtOAc (EtOAc, EtOAc, 23 mg, 0.2 mmol). After replacing the nitrogen, Pd 2 (dba) 3 (19 mg, 20 ⁇ mol), Xantphos (12 mg, 20 ⁇ mol) was added under nitrogen. After the reaction was stirred at 110 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated.
  • EtOAc EtOAc, 23 mg, 0.2 mmol
  • Example 55B To a solution of Example 55B (60 mg, 0.13 mmol),jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 18 mg, 0.15 mmol). After replacing the nitrogen, Pd 2 (dba) 3 (22 mg, 24 ⁇ mol), Xantphos (14 mg, 24 ⁇ mol) was added under nitrogen. After the reaction was stirred at 110 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated.
  • Example 52A (346 mg, 998 ⁇ mol), Example 56A (163 mg, 978 ⁇ mol) and potassium carbonate (276 mg, 2.0 mmol), potassium iodide (17 mg, 100 ⁇ mol) in acetone (5 ml) Heating to 70 ° C, reaction for 3 hours. Thin layer chromatography showed that the raw materials have been completely consumed. The reaction solution was cooled to room temperature, filtered, and evaporated to dryness.
  • Example 52A To a solution of Example 52A (2.0 g, 5.2 mmol) and 5-hydroxy-1-indolone (774 mg, 5.2 mmol) in acetone (30 mL) The reaction solution was heated to 70 ° C for 2 hours, and the starting material was completely reacted. The reaction mixture was cooled to EtOAc. The title compound (yellow solid, 1.3 g, 55% yield).
  • Example 57A 1.3 g, 2.9 mmol
  • hydroxyamine hydrochloride 603 mg, 8.7 mmol
  • the reaction mixture was concentrated, EtOAcjjjjjjjjjj ).
  • Example 59A (2.00 g, 7.35 mmol), bis-colonol borate (2.24 g, 8.82 mmol), potassium acetate (2.16 g, 22.05 mmol), Pd(dppf)Cl
  • a solution of 2 (537.80 mg, 735.00 ⁇ mol) in dioxane (5 ml) was heated to 50 ° C for 10 hours. The reaction solution was cooled to room temperature and then filtered, and the crude product was applied directly to the next.
  • Example 59B To a mixed solution of Example 59B (2.0 g, 6.6 mmol) of sodium hydroxide (2 mL, 2N) and THF (8 ml) was added hydrogen peroxide (2.3 g, 65.5 mmol). The mixed solution was stirred at 25 ° C for 10 minutes and then water (5.0 mL) was added. The mixed solution was extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate (mjjjjjjjj .
  • Example 59D (102 mg, 199 ⁇ mol), tert-butyl carbamate (222 mg, 1.9 mmol), Pd 2 (dba) 3 (18 mg, 20 ⁇ mol) of dioxane (5.0 ml) Xantphos (23 mg, 40 micromoles) and potassium carbonate (83 mg, 599 micromoles) were added to the solution.
  • Example 60 The preparation method of this example is referred to Example 60.

Abstract

Disclosed is a novel anti-enterovirus 71 (EV71) 1,2,5-thiadiazolidine-1,1-dioxide derivative or a pharmaceutically acceptable salt thereof, and specifically, a compound represented by formula (II) or a pharmaceutically acceptable salt thereof.

Description

抗肠病毒71噻二唑烷衍生物Anti-enteric virus 71 thiadiazolidine derivative 技术领域Technical field
本发明涉及新的抗肠道病毒71型(EV71)1,2,5-噻二唑烷-1,1-二氧化物衍生物或其药学上可接受的盐，具体涉及式(Ⅱ)所示化合物或其药学上可接受的盐。The present invention relates to a novel anti-enteric virus 71 (EV71) 1,2,5-thiadiazolidine-1,1-dioxide derivative or a pharmaceutically acceptable salt thereof, in particular to the formula (II) A compound or a pharmaceutically acceptable salt thereof.
背景技术Background technique
肠病毒71型属于小RNA病毒科，是最常见的手足口病致病源之一。此外还会引起孢疹性咽炎、无菌性脑膜炎、脑炎和脊髓灰质炎样的麻痹性疾病等多种与神经***相关的疾病，可伴有严重的中枢神经***并发症或神经炎性肺水肿。Enterovirus 71 belongs to the family of small RNA viruses and is one of the most common sources of hand, foot and mouth disease. It can also cause a variety of neurological-related diseases such as herpes pharyngitis, aseptic meningitis, encephalitis, and polio-like paralytic diseases, which can be accompanied by severe central nervous system complications or neuroinflammation. Pulmonary Edema.
手足口病具有流行强度大、传染性强、传播途径复杂等特点，迄今尚无特效的抗肠病毒71型的药物。Hand, foot and mouth disease has the characteristics of high epidemic intensity, strong contagiousness and complicated transmission route. So far, there is no specific anti-enteric virus type 71 drug.
虽然现有技术，比如US20030087936、US6706739、US20040116476、US20050267164、US20070049623等专利文献，公开了一系列结构，例如式(B-Ⅰ)所示结构，但是仍然亟须开发活性更好、更利于成药的新的化合物。Although the prior art, for example, the patent documents such as US20030087936, US6706739, US20040116476, US20050267164, US20070049623, etc., disclose a series of structures, such as the structure shown by formula (B-I), but there is still no need to develop new ones which are more active and more conducive to medicine. compound of.
Figure PCTCN2015077043-appb-000001
Figure PCTCN2015077043-appb-000001
发明内容Summary of the invention
本发明提供式(Ⅱ)所示化合物或其药学上可接受的盐，The present invention provides a compound of the formula (II) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2015077043-appb-000002
Figure PCTCN2015077043-appb-000002
其中，among them,
R3选自任选被R01取代的5元杂环、C6～12芳基、C6～12芳烷基、C5～12杂芳环或C5～12杂芳烷基；R 3 is selected from a 5-membered heterocyclic ring optionally substituted by R 01 , a C 6- 12 aryl group, a C 6- 12 aralkyl group, a C 5-12 heteroaryl ring or a C 5-12 heteroarylalkyl group;
L2分别独立地选自
Figure PCTCN2015077043-appb-000003
L 2 are independently selected from
Figure PCTCN2015077043-appb-000003
m1、m2分别独立地选自0、1、2、3、4、5或6；m 1 , m 2 are each independently selected from 0, 1 , 2 , 3, 4, 5 or 6;
X1、X2分别独立地选自单键、-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)-或-S(＝O)2-；X 1 and X 2 are each independently selected from a single bond, -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(= NR d5 )-, -S(=O) 2 N(R d6 )-, -S(=O)N(R d7 )-, -O-, -S-, -C(=O)O-,- C(=O)-, -C(=S)-, -S(=O)- or -S(=O) 2 -;
R4选自5～14元环烃基或杂环烃基； R 4 is selected from a 5- to 14-membered cyclic hydrocarbon group or a heterocyclic hydrocarbon group;
Rd1、Rd2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；R d1 , R d2 are each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or a C 1-10 alkyl group optionally substituted by R 01 or a heteroalkyl group, a C 3-10 cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl;
R01选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、R02；R 01 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, R 02 ;
R02选自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环烷氧羰基、C3-10环烷基磺酰基、C3-10环烷基亚磺酰基；R 02 is selected from C 1-10 alkyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkoxy, C 1-10 alkanoyl, C 1 -10 alkoxycarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 cycloalkyl acyl, C 3-10 cycloalkoxycarbonyl, C 3-10 cycloalkylsulfonyl, C 3-10 cycloalkylsulfinyl;
“杂”代表杂原子或杂原子团，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)-和/或-S(＝O)2-；"Heter" represents a hetero atom or a hetero atom selected from -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O) 2 N (R d6 )-, -S(=O)N(R d7 )-, -O-, -S-, =O, =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)- and/or -S(=O) 2 -;
Rd3-d7分别独立地选自H、R03；R d3 - d7 are each independently selected from H, R 03 ;
R03选自C1-10烷基、C1-10烷基酰基、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环烷基酰基、C3-10环烷氧羰基、C3-10环烷基磺酰基、C3-10环烷基亚磺酰基；R 03 is selected from C 1-10 alkyl, C 1-10 alkyl acyl, C 1-10 alkoxycarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 a cycloalkyl group, a C 3-10 cycloalkyl acyl group, a C 3-10 cycloalkoxycarbonyl group, a C 3-10 cycloalkylsulfonyl group, a C 3-10 cycloalkylsulfinyl group;
R02、R03任选地被R001取代；R 02 and R 03 are optionally substituted by R 001 ;
R001选自F、Cl、Br、I、CN、OH、N(CH3)2、NH(CH3)、NH2、CHO、COOH、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；R 001 is selected from the group consisting of F, Cl, Br, I, CN, OH, N(CH 3 ) 2 , NH(CH 3 ), NH 2 , CHO, COOH, trifluoromethyl, aminomethyl, hydroxymethyl, A Base, methoxy, formyl, methoxycarbonyl, methylsulfonyl, methylsulfinyl;
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；The number of R 01 , R 001 , hetero atom or hetero atomic group is independently selected from 0, 1, 2 or 3;
任选地，Rd1与Rd2相互连接形成一个3或4元碳环或杂环。Optionally, R d1 and R d2 are linked to each other to form a 3 or 4 membered carbocyclic or heterocyclic ring.
本发明的一些方案中，R3选自任选被取代的5～6元芳基或杂芳基。In some embodiments of the invention, R 3 is selected from a 5 to 6 membered aryl or heteroaryl group which is optionally substituted.
本发明的一些方案中，R3选自任选被R01取代的吡啶基、苯基、呋喃基、吡唑基、吡咯基、噻唑基、哒嗪基、嘧啶基、噻吩基，R01的上述定义，R01的数目选自0、1、2或3。Some aspects of the present invention, R 3 is selected from R 01 is optionally substituted pyridyl, phenyl, furanyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrimidinyl, thienyl, R 01 is In the above definition, the number of R 01 is selected from 0, 1, 2 or 3.
本发明的一些方案中，R01选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、Me、
Figure PCTCN2015077043-appb-000004
Figure PCTCN2015077043-appb-000005
In some embodiments of the invention, R 01 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, Me,
Figure PCTCN2015077043-appb-000004
Figure PCTCN2015077043-appb-000005
本发明的一些方案中，R3选自：In some aspects of the invention, R 3 is selected from the group consisting of
Figure PCTCN2015077043-appb-000006
Figure PCTCN2015077043-appb-000007
Figure PCTCN2015077043-appb-000006
Figure PCTCN2015077043-appb-000007
本发明的一些方案中，L2选自
Figure PCTCN2015077043-appb-000008
m3为0、1或2，其他变量如上述定义。In some embodiments of the invention, L 2 is selected from
Figure PCTCN2015077043-appb-000008
m 3 is 0, 1, or 2, and other variables are as defined above.
本发明的一些方案中，X1、X2分别独立地选自单键、-O-、-C(＝O)-、-CH(CH3)-、-C(CH3)2-、-CF2-、-CH(F)-、
Figure PCTCN2015077043-appb-000009
-CH(OH)、-CH2-、-NH-、-N(CH3)-。In some embodiments of the invention, X 1 and X 2 are each independently selected from the group consisting of a single bond, —O—, —C(=O)—, —CH(CH 3 )—, —C(CH 3 ) 2 —, CF 2 -, -CH(F)-,
Figure PCTCN2015077043-appb-000009
-CH(OH), -CH 2 -, -NH-, -N(CH 3 )-.
本发明的一些方案中，L2选自：
Figure PCTCN2015077043-appb-000010
Figure PCTCN2015077043-appb-000011
In some aspects of the invention, L 2 is selected from the group consisting of
Figure PCTCN2015077043-appb-000010
Figure PCTCN2015077043-appb-000011
本发明的一些方案中，R4选自
Figure PCTCN2015077043-appb-000012
Figure PCTCN2015077043-appb-000013
T4-7分别独立地选自N或C(Rt)，In some embodiments of the invention, R 4 is selected from
Figure PCTCN2015077043-appb-000012
Figure PCTCN2015077043-appb-000013
T 4-7 are each independently selected from N or C(R t ),
D1-3、D5、D6分别独立地选自单键、-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)-或-S(＝O)2-，D 1-3 , D 5 and D 6 are each independently selected from a single bond, -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )- , -C(=NR d5 )-, -S(=O) 2 N(R d6 )-, -S(=O)N(R d7 )-, -O-, -S-, -C(=O )O-, -C(=O)-, -C(=S)-, -S(=O)- or -S(=O) 2 -,
n2选自0、1、2或3，n 2 is selected from 0, 1, 2 or 3,
n3选自0、1或2，n 3 is selected from 0, 1 or 2,
R5、R6、R7、Rt、Rd1、Rd2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，R 5 , R 6 , R 7 , R t , R d1 , R d2 are each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or selected from the group consisting of a C 1-10 alkyl or heteroalkyl group substituted by R 01 , a C 3-10 cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl group ,
其他变量如权利要求1所定义。Other variables are as defined in claim 1.
本发明的一些方案中，R4选自
Figure PCTCN2015077043-appb-000014
Figure PCTCN2015077043-appb-000015
X3选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH，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。In some embodiments of the invention, R 4 is selected from
Figure PCTCN2015077043-appb-000014
Figure PCTCN2015077043-appb-000015
X 3 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or a C 1-10 alkyl or heteroalkyl group optionally substituted by R 01 , C 3-10 a cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl group.
本发明的一些方案中，R5-7分别独立地选自
Figure PCTCN2015077043-appb-000016
Figure PCTCN2015077043-appb-000017
其中：In some embodiments of the invention, R 5-7 are each independently selected from
Figure PCTCN2015077043-appb-000016
Figure PCTCN2015077043-appb-000017
among them:
T1-3分别独立地选自N或C(Rt)；T 1-3 are each independently selected from N or C(R t );
D4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)-或-S(＝O)2-；D 4 is selected from -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(= O) 2 N(R d6 )-, -S(=O)N(R d7 )-, -O-, -S-, -C(=O)O-, -C(=O)-, -C (=S)-, -S(=O)- or -S(=O) 2 -;
R8、R9、Rt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；R 8 , R 9 , R t are each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or C 1-10 selected from R 1 , optionally substituted by R 01 . An alkyl or heteroalkyl group, a C 3-10 cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl;
R10选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH，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.R 10 is selected from F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or a C 1-10 alkyl or heteroalkyl group optionally substituted by R 01 , C 3-10 a cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl group.
本发明的一些方案中，R5-9、R01、Rt分别独立地选自
Figure PCTCN2015077043-appb-000018
Figure PCTCN2015077043-appb-000019
F、Cl、Br、CF3、-C(C2H5)-、-C(OC2H5)-、甲基、乙基、丙基、甲 氧基、乙氧基、丙氧基、
Figure PCTCN2015077043-appb-000020
Figure PCTCN2015077043-appb-000021
In some embodiments of the invention, R 5-9 , R 01 , R t are each independently selected from
Figure PCTCN2015077043-appb-000018
Figure PCTCN2015077043-appb-000019
F, Cl, Br, CF 3 , -C(C 2 H 5 )-, -C(OC 2 H 5 )-, methyl, ethyl, propyl, methoxy, ethoxy, propoxy,
Figure PCTCN2015077043-appb-000020
Figure PCTCN2015077043-appb-000021
本发明的一些方案中，R4选自：In some embodiments of the invention, R 4 is selected from the group consisting of
Figure PCTCN2015077043-appb-000022
Figure PCTCN2015077043-appb-000022
具体地，本发明选自： In particular, the invention is selected from the group consisting of:
Figure PCTCN2015077043-appb-000023
Figure PCTCN2015077043-appb-000023
Figure PCTCN2015077043-appb-000024
Figure PCTCN2015077043-appb-000024
Figure PCTCN2015077043-appb-000025
Figure PCTCN2015077043-appb-000026
Figure PCTCN2015077043-appb-000025
Figure PCTCN2015077043-appb-000026
有关定义：Related definitions:
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。Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient.
C1-12选自C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11和C12；C3-12选自C3、C4、C5、C6、C7、C8、C9、C10、C11和C12。C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .
C1-12烷基或杂烷基、C3-12环基或杂环烃基、被C3-12环烃基或杂环烃基取代的C1-12烷基或杂烷基包括但不限于：C 1-12 alkyl or heteroalkyl, C 3-12 cyclo or heterocycloalkyl, C 1-12 alkyl or heteroalkyl substituted by C 3-12 cycloalkyl or heterocycloalkyl includes, but is not limited to:
C1-12烷基、C1-12烷氨基、N,N-二(C1-12烷基)氨基、C1-12烷氧基、C1-12烷酰基、C1-12烷氧羰基、C1-12 烷基磺酰基、C1-12烷基亚磺酰基、C3-12环烷基、C3-12环烷氨基、C3-12杂环烷氨基、C3-12环烷氧基、C3-12环烷基酰基、C3-12环烷基氧羰基、C3-12环烷基磺酰基、C3-12环烷基亚磺酰基、5～12元芳基或杂芳基、5～12元芳烷基或杂芳烷基；C 1-12 alkyl, C 1-12 alkylamino, N,N-di(C 1-12 alkyl)amino, C 1-12 alkoxy, C 1-12 alkanoyl, C 1-12 alkoxy Carbonyl, C 1-12 alkylsulfonyl, C 1-12 alkylsulfinyl, C 3-12 cycloalkyl, C 3-12 cycloalkylamino, C 3-12 heterocycloalkylamino, C 3-12 Cycloalkoxy, C 3-12 cycloalkyl acyl, C 3-12 cycloalkyloxycarbonyl, C 3-12 cycloalkylsulfonyl, C 3-12 cycloalkylsulfinyl, 5-12 aryl Or a heteroaryl group, a 5- to 12-membered aralkyl group or a heteroarylalkyl group;
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；Methyl, ethyl, n-propyl, isopropyl, -CH 2 C(CH 3 )(CH 3 )(OH), cyclopropyl, cyclobutyl, propylmethylene, cyclopropionyl, benzyloxy Base, trifluoromethyl, aminomethyl, hydroxymethyl, methoxy, formyl, methoxycarbonyl, methylsulfonyl, methylsulfinyl, ethoxy, acetyl, ethylsulfonyl, ethoxycarbonyl , dimethylamino, diethylamino, dimethylaminocarbonyl, diethylaminocarbonyl;
N(CH3)2,NH(CH3),-CH2CF3,-CH2CH2CF3,-CH2CH2F,-CH2CH2S(＝O)2CH3,-CH2CH2CN,
Figure PCTCN2015077043-appb-000027
Figure PCTCN2015077043-appb-000028
-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 PCTCN2015077043-appb-000029
Figure PCTCN2015077043-appb-000030
 N (CH 3) 2, NH (CH 3), - CH 2 CF 3, -CH2CH 2 CF 3, -CH 2 CH 2 F, -CH 2 CH 2 S (= O) 2 CH 3, -CH 2 CH 2 CN,
Figure PCTCN2015077043-appb-000027
Figure PCTCN2015077043-appb-000028
-CH 2 CH(OH)(CH3) 2 , -CH 2 CH(F)(CH 3 ) 2 , -CH 2 CH 2 F, -CH 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OCH 3 , -CH 2 CH 2 N(CH 3 ) 2 , -S(=O) 2 CH 3 , -CH 2 CH 2 S(=O) 2 CH 3 ,
Figure PCTCN2015077043-appb-000029
Figure PCTCN2015077043-appb-000030
Figure PCTCN2015077043-appb-000031
Figure PCTCN2015077043-appb-000032
Figure PCTCN2015077043-appb-000031
Figure PCTCN2015077043-appb-000032
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-***基、1,2,4-***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；Phenyl, thiazolyl, biphenyl, naphthyl, cyclopentyl, furyl, 3-pyrrolyl, pyrrolidinyl, 1,3-oxapentacyclyl, pyrazolyl, 2-pyrazolyl, Pyrazolidinyl, imidazolyl, oxazolyl, thiazolyl, 1,2,3-oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4- Thiadiazolyl, 4H-pyranyl, pyridyl, piperidinyl, 1,4-dioxolyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3 , 5-trithiazide, 1,3,5-triazinyl, benzofuranyl, benzothienyl, fluorenyl, benzimidazolyl, benzothiazolyl, fluorenyl, quinolinyl, iso a quinolyl group, a porphyrin group or a quinoxaline group;
Figure PCTCN2015077043-appb-000033
Figure PCTCN2015077043-appb-000034
Figure PCTCN2015077043-appb-000033
Figure PCTCN2015077043-appb-000034
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。The term "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.
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。The term "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. When a relatively acidic functional group is contained in the compound of the present invention, 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. When a relatively basic functional group is contained in the compound of the present invention, 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. Examples of 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 methanesulfonic acid; and salts of amino acids (such as arginine, etc.) And salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.
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。Preferably, 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.
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。As used herein, a "pharmaceutically acceptable salt" is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base. Examples of 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. Conventional 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, phosphoric acid, polygalacturaldehyde, propionic acid, salicylic acid, stearic acid, acrylic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, Tartaric acid and p-toluenesulfonic acid.
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。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. In general, such salts are prepared by the addition of these compounds in free acid or base form in water or an organic solvent or a mixture of the two. Prepared by stoichiometric reaction with a suitable base or acid. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
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。In addition to the form of the salt, 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. Furthermore, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。本发明的某些化合物可以以多晶或无定形形式存在。Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.
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。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.
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。Graphical representations of racemates, ambiscalemic and scalemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. 1985, 62: 114-120. The absolute configuration of a stereocenter is indicated by a wedge key and a dashed key unless otherwise stated. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.
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。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.
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分步结晶法或色谱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)。The 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. Alternatively, when a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art. The diastereomeric resolution is carried out by crystallization or chromatography, and then the pure enantiomer is recovered. Furthermore, 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).
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。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. For example, radiolabeled compounds can be used, 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.
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。The term "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.
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。The term "excipient" generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
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。The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacologically active agent means a drug that is non-toxic but achieves the desired effect. Or a sufficient amount of the agent. For oral dosage forms in the present invention, 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.
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。The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease or condition.
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。The term "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. . When the substituent is a keto group (ie, =0), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on the aryl group. The term "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.
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。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
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。例如，结构单元
Figure PCTCN2015077043-appb-000035
或
Figure PCTCN2015077043-appb-000036
表示其可在环己基或者环基二烯上的任意一个位置发生取代。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. When the recited 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. For example, a structural unit
Figure PCTCN2015077043-appb-000035
or
Figure PCTCN2015077043-appb-000036
It is indicated that it can be substituted at any position on the cyclohexyl or cyclodiene.
烷基和杂烷基原子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)。The substituents of the alkyl and heteroalkyl radicals are generally referred to as "alkyl substituents" and may be selected from one or more of the following groups: -R', -OR', =O, = NR', =N-OR', -NR'R", -SR', halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO 2 R' , -CONR'R", -OC(O)NR'R", -NR"C(O)R', NR'C(O)NR"R"', -NR"C(O) 2 R', -NR""'-C(NR'R"R"')=NR"", NR""C(NR'R")=NR"', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R", NR"SO 2 R', -CN, -NO 2 , -N 3 , -CH(Ph) 2 and fluoro(C 1 -C 4 )alkyl The number of substituents is 0 to (2m'+1), wherein m' is the total number of carbon atoms in such a group. R', R", R"', R"" and R""' are each independently preferred Hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (eg substituted by 1 to 3 halogen aryl), substituted or unsubstituted alkyl, alkoxy, sulphur Alkoxy group or aralkyl group. When the compound of the present invention includes more than one R group, for example, each R group is independently selected as if present Each of these groups of more than one R', R", R"', R"" and R""' groups. When R' and R" are attached to the same nitrogen atom, they may be bonded to the nitrogen The atoms combine to form a 5-, 6- or 7-membered ring. For example, -NR'R" is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. In light of the above discussion of substituents, those skilled in the art will appreciate that the term "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.).
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。Similar to the substituents of the alkyl group, the aryl and heteroaryl substituents are generally collectively referred to as "aryl substituents" and are selected, for example, from -R', -OR', -NR'R", -SR', - Halogen, -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) 2 R', -S(O) 2 NR'R", NR"SO 2 R', - CN, -NO 2 , -N 3 , -CH(Ph) 2 , fluorine (C 1 -C 4 ) alkoxy, and fluorine (C 1 -C 4 ) alkyl, etc., the number of substituents is 0 to an aromatic ring Between the total number of open valencies; wherein R', R", R"', R"" and R""' are independently preferred from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted a heteroalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group. When the compound of the present invention includes more than one R group, for example, each R group is independently added. Each of these groups is selected as when more than one R', R", R"', R"" and R"" group are present.
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。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. Alternatively, 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. Optionally, a single bond on the new ring thus formed can be replaced with a double bond. Alternatively, 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.
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。Unless otherwise specified, the term "halo" or "halogen", by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Further, the term "haloalkyl" is intended to include both monohaloalkyl and polyhaloalkyl. For example, the term "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.
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。Examples of 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. Examples of 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.
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
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)-。Unless otherwise specified, the term "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). ), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C (= O) O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) 2 -, and -C(=O) optionally substituted N(H)-, -N(H)-, -C(=NH)-, -S(=O) 2 N(H)- or -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。Unless otherwise specified, "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. Thus, "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. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.
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。Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a hetero atom, which It may be saturated, partially unsaturated or unsaturated (aromatic) which comprises a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above is hetero The ring may be fused to a benzene 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. The term "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.
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***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-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和呫吨基。还包括稠环和螺环化合物。Examples of 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, indanyl, mesoindolyl, fluorenyl, 3H-indole Sulfhydryl, isatino, isobenzofuranyl, pyran, isodecyl, isoindoline, isodecyl, decyl, isoquinolyl, isothiazolyl, isoxazolyl, Methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, isoxazolyl, oxindole , pyrimidinyl, phenanthryl, phenanthroline, phenazine, phenothiazine, benzoxanthyl, phenolzinyl, pyridazinyl, piperazinyl, piperidinyl, piperidinone, 4 -piperidone, piperonyl, pteridinyl, fluorenyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole , pyridothiazole, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, pyrazolyl, quinazolinyl, quinolyl, 4H-quinazinyl, quinoxalinyl , quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thioxyl, thiazolyl, isothiazolylthiophenyl, thienyl, thiophene And oxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazole Base, 1,3,4-triazolyl and xanthene. Also included are fused ring and spiro compounds.
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。Unless otherwise specified, the term "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. In some embodiments, the term "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. Examples of 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.
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。Unless otherwise specified, the term "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. In some embodiments, the term "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. In a typical embodiment, 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). Examples include, but are not limited to, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S -CH 2 -CH 3 , -CH 2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 , -CH=CH-O-CH 3 ,- CH 2 -CH=N-OCH 3 and -CH=CH-N(CH 3 )-CH 3 . Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
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。The terms "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.
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。Unless otherwise specified, the term "cycloalkyl", "heterocycloalkyl" or its subordinate concept (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl) A heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized "hydrocarbyl group" or "heterohydrocarbyl group", respectively. Further, in the case of a heterohydrocarbyl group or a heterocycloalkyl group (such as a heteroalkyl group or a heterocycloalkyl group), a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of 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.
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，可以是一价、二价或者多价，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。Unless otherwise specified, the term "aryl" denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (preferably 1 to 3 rings) which are fused together or covalently linked. The term "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 Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl, 1-isoquinolyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolinyl. The substituents of any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
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。For simplicity, aryl groups, when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridyl) Methyl or the like, including those wherein a carbon atom such as a methylene group has been replaced by, for example, an oxygen atom, such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl Wait.
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。The term "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). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
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。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "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-butyldimethylsilyl (TBS) and the like. The term "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.
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。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.
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并***-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；LDA代表二异丙基胺基锂；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；Pd2(dba)3代表三(二亚苄基丙酮)二钯；DAST代表二乙胺基三氟化硫；Pd(dppf)Cl2代表1,1'-双(二苯基膦)二茂铁；PCC代表氯铬酸吡啶鎓盐；TsCl代表对甲苯磺酰氯；Et3N代表三乙胺。All solvents used in the present invention are commercially available and can be used without further purification. 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 Carbonyldiimidazole; 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 acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for t-butylcarbonyl is an amine protecting group; HOAc for acetic acid; NaCNBH 3 for sodium cyanoborohydride ; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc 2 O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl 2 stands for chloride Sulfone; CS 2 represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; n-Bu 4 NF stands for tetrabutyl fluoride Ammonium; iPrOH represents 2-propanol; mp Representative mp; LDA lithium diisopropylamide Representative; Xantphos Representative xantphos; Pd 2 (dba 3 represents tris(dibenzylideneacetone)dipalladium; DAST represents diethylaminosulfur trifluoride; Pd(dppf)Cl2 represents 1,1'-bis(diphenylphosphino)ferrocene; PCC represents chlorine Pyridinium chromate; TsCl represents p-toluenesulfonyl chloride; Et 3 N represents triethylamine.
化合物经手工或者
Figure PCTCN2015077043-appb-000037
软件命名，市售化合物采用供应商目录名称。Compound by hand or
Figure PCTCN2015077043-appb-000037
Software naming, commercially available compounds using the supplier catalog name.
与现有技术相比，本发明化合物高效、低毒，在活性、半衰期、溶解度和药代动力学等方面均取得了显著甚至预料不到的进步，更适合于制药。Compared with the prior art, the compound of the present invention is highly efficient, low in toxicity, and has achieved remarkable and unexpected progress in activity, half-life, solubility and pharmacokinetics, and is more suitable for pharmaceuticals.
具体实施方式Detailed ways
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。 In order to explain the present invention in more detail, the following examples are given, but the scope of the invention is not limited thereto.
路线BRoute B
Figure PCTCN2015077043-appb-000038
Figure PCTCN2015077043-appb-000038
实施例4Example 4
2-(5-((4-氟苯氧基)戊基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(5-((4-fluorophenoxy)pentyl)-5-(pyridin-4-yl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000039
Figure PCTCN2015077043-appb-000039
实施例4AExample 4A
2-((2-氯吡啶-4-基)氨基)乙醇2-((2-chloropyridin-4-yl)amino)ethanol
Figure PCTCN2015077043-appb-000040
Figure PCTCN2015077043-appb-000040
2,4-二氯吡啶(100克，675.7毫摩尔)，三乙胺(136.7克，1.35摩尔)和2-氨基乙醇(41.3克，675.7毫摩尔)的乙醇(500毫升)溶液在100℃下搅拌72小时后旋转蒸发去除溶剂，残余物通过柱色谱纯化得到标题化合物(黄色油状，46克，产率40％)。1H-NMR(CDCl3,400MHz)δ7.90(d,J＝5.8Hz,1H),6.49(d,J＝2.0Hz,1H),6.41(dd,J＝5.8,2.0Hz,1H),5.17(brs,1H),3.87(t,J＝5.1Hz,2H),3.31(q,J＝5.0Hz,2H)；LCMS(ESI)m/z:173(M+1)。a solution of 2,4-dichloropyridine (100 g, 675.7 mmol), triethylamine (136.7 g, 1.35 mol) and 2-aminoethanol (41.3 g, 675.7 mmol) in ethanol (500 ml) at 100 ° C After stirring for 72 hours, the solvent was evaporated to dryness crystals crystals crystals 1 H-NMR (CDCl 3 , 400 MHz) δ 7.90 (d, J = 5.8 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 6.41 (dd, J = 5.8, 2.0 Hz, 1H), 5.17 (brs, 1H), 3.87 (t, J = 5.1 Hz, 2H), 3.31 (q, J = 5.0 Hz, 2H); LCMS (ESI) m/z: 173 (M+1).
实施例4BExample 4B
2-氯-N-(2-氯乙基)吡啶-4-胺2-chloro-N-(2-chloroethyl)pyridin-4-amine
Figure PCTCN2015077043-appb-000041
Figure PCTCN2015077043-appb-000041
实施例4A(5克，28.9毫摩尔)溶于二氯甲烷与N,N-二甲基甲酰胺(50毫升/5毫升)混合溶剂中，在15℃下向该混合溶液滴加氯化亚砜(60毫升)然后升至40℃反应16小时。冷却至室温后，倒入冰水(200毫升)，加入1摩尔每升的氢氧化钠水溶液调节pH值到10，水层用乙酸乙酯(100毫升×6)萃取，合并的有机层用盐水(50毫升)洗涤后，经硫酸钠干燥，过滤并蒸发，粗品通过柱色谱纯化得到标题化合物(白色固体，1.7克，产率45％)并回收原料(白色固体，2.0克)。LCMS(ESI)m/z:191(M+1).1H-NMR (CDCl3,400MHz)δ7.99(d,J＝6.0Hz,1H),6.38-6.55(m,2H),4.75(brs,1H),3.67-3.78(m,2H),3.55(q,J＝5.5Hz,2H)。Example 4A (5 g, 28.9 mmol) was dissolved in a mixed solvent of dichloromethane and N,N-dimethylformamide (50 ml / 5 ml), and the mixture was added dropwise to the mixed solution at 15 ° C. The sulfone (60 ml) was then raised to 40 ° C for 16 hours. After cooling to room temperature, pour ice water (200 ml), add 1 mol of aqueous sodium hydroxide solution to adjust the pH to 10, extract the aqueous layer with ethyl acetate (100 ml × 6), and combine the organic layer with brine (50 ml), EtOAc (EtOAc m. LCMS (ESI) m / z: . 191 (M + 1) 1 H-NMR (CDCl 3, 400MHz) δ7.99 (d, J = 6.0Hz, 1H), 6.38-6.55 (m, 2H), 4.75 ( Brs, 1H), 3.67-3.78 (m, 2H), 3.55 (q, J = 5.5 Hz, 2H).
实施例4CExample 4C
N-(2-氯乙基)-N-(2-氯吡啶-4-基)氨磺酰氨基甲酸叔丁酯N-(2-chloroethyl)-N-(2-chloropyridin-4-yl)sulfamoylcarbamic acid tert-butyl ester
Figure PCTCN2015077043-appb-000042
Figure PCTCN2015077043-appb-000042
0℃氮气保护下，向叔丁醇(3.4毫升)的二氯甲烷(27毫升)溶液中滴加氯磺酸异氰酸酯(2.7毫升)。滴加完逐渐升至室温继续搅拌30分钟，至澄清。将此溶液真空转移至恒压滴液漏斗与三乙胺(11.6毫升)混合，在0℃氮气保护下，将上述混合溶液滴加到实施例4B(1.7克，8.9毫摩尔)的二氯甲烷(20毫升)溶液中。滴加完毕后在12℃下搅拌48小时后，冰水淬灭，水相用二氯甲烷(50毫升×4)萃取。将合并的有机层用硫酸钠干燥，过滤并蒸发，提供标题化合物粗品(7克)可直接用于下一步骤而无需进一步纯化。1H-NMR(CDCl3,400MHz)δ8.45(d,J＝5.5Hz,1H),7.42(d,J＝1.5Hz,1H),7.34(dd,J＝5.3,1.8Hz,1H),4.32(t,J＝6.4Hz,2H),3.67(t,J＝6.3Hz,2H),1.49(s,9H)；LCMS(ESI)m/z:370(M+1)。To a solution of tert-butanol (3.4 ml) in dichloromethane (27 ml), m. After the addition was completed, the mixture was gradually warmed to room temperature and stirring was continued for 30 minutes until clarification. The solution was vacuum-transferred to a constant pressure dropping funnel and mixed with triethylamine (11.6 ml), and the mixture was added dropwise to a solution of Example 4B (1.7 g, 8.9 mmol) of dichloromethane at 0 ° C under nitrogen. (20 ml) in solution. After completion of the dropwise addition, the mixture was stirred at 12 ° C for 48 hours, then quenched with ice water, and the aqueous phase was extracted with dichloromethane (50 ml × 4). The combined organic layers were dried with EtOAc EtOAc EtOAc EtOAc 1 H-NMR (CDCl 3 , 400 MHz) δ 8.45 (d, J = 5.5 Hz, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.34 (dd, J = 5.3, 1.8 Hz, 1H), 4.32 (t, J = 6.4 Hz, 2H), 3.67 (t, J = 6.3 Hz, 2H), 1.49 (s, 9H); LCMS (ESI) m/z: 370 (M+1).
实施例4DExample 4D
5-(2-氯吡啶-4-基)-1,2,5-噻二唑烷-2-羧酸叔丁酯-1,1-二氧化物5-(2-chloropyridin-4-yl)-1,2,5-thiadiazolidine-2-carboxylic acid tert-butyl ester-1,1-dioxide
Figure PCTCN2015077043-appb-000043
Figure PCTCN2015077043-appb-000043
在15℃下，向实施例4C(7克，粗品)的二甲亚砜(30毫升)溶液中加入碳酸钾粉末(3.4克)搅拌3小时后，倒入1升水中，过滤得到白色固体，将固体溶于二氯甲烷中用硫酸钠干燥，过滤蒸发，得到标题化合物(2克，收率69％)。1H-NMR(CDCl3,400MHz)δ8.32(d,J＝6.0Hz,1H),7.06-7.21(m,2H),3.98-4.12(m,2H),3.79-3.92(m,2H),1.59(s,10H).LCMS(ESI)m/z:334(M+1)。Potassium carbonate powder (3.4 g) was added to a solution of Example 4C (7 g, crude) in dimethyl sulfoxide (30 ml) at 15 ° C for 3 hours, then poured into 1 liter of water and filtered to give a white solid. The solid was dissolved in EtOAc (EtOAc m. 1 H-NMR (CDCl 3 , 400 MHz) δ 8.32 (d, J = 6.0 Hz, 1H), 7.06-7.21 (m, 2H), 3.98-4.12 (m, 2H), 3.79-3.92 (m, 2H) , 1.59 (s, 10H). LCMS (ESI) m.
实施例4EExample 4E
2-(2-氯吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-chloropyridin-4-yl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000044
Figure PCTCN2015077043-appb-000044
向实施例4D(1.9克，5.69毫摩尔)的乙酸乙酯/甲醇(40毫升/4毫升)混合液中加入盐酸乙酸乙酯(4摩尔每升，40毫升)并在60℃下搅拌5小时。真空除去溶液后，残余物用饱和碳酸氢钠溶液调pH＝8，水层用乙酸乙酯(250毫升×3)萃取，合并有机层用硫酸钠干燥，过滤并蒸发，得到标题化合物(白色固体，1.2克，92％)。1H-NMR(CDCl3,400MHz)δ8.29(d,J＝5.8Hz,1H),7.05-7.09(m,1H),7.00(d,J＝2.0Hz,1H),3.95-3.99(m,2H),3.78-3.85(m,2H)；LCMS(ESI)m/z:234(M+1)。To a mixture of ethyl acetate / methanol (40 mL / 4 mL), EtOAc (EtOAc (EtOAc) . After the solution was removed in vacuo, EtOAc (EtOAc m. , 1.2 grams, 92%). 1 H-NMR (CDCl 3 , 400 MHz) δ 8.29 (d, J = 5.8 Hz, 1H), 7.05-7.09 (m, 1H), 7.00 (d, J = 2.0 Hz, 1H), 3.95 - 3.99 (m) , 2H), 3.78-3.85 (m, 2H); LCMS (ESI) m.
实施例4FExample 4F
2-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物 2-(pyridin-4-yl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000045
Figure PCTCN2015077043-appb-000045
实施例4E(1.3克，5.5毫摩尔)，Pd/C(100毫克)，三乙胺(2毫升)混合于甲醇(30毫升)中，将该混合物在25℃下搅拌12小时后过滤，真空除去溶剂后，得到标题化合物(3.8克，收率100％)可直接用于下一步骤而无需进一步纯化。1H-NMR(DMSO-d6，400MHz)8.75(s，br，1H)，8.68(d，J＝7.0Hz,2H),7.45(d,J＝7.0Hz,2H),4.08(t,J＝6.3Hz,2H),3.64(d,J＝6.3Hz,2H)；LCMS(ESI)m/z:200(M+1)。Example 4E (1.3 g, 5.5 mmol), Pd / C (100 mg), triethylamine (2 mL) The title compound (3.8 g, yield 100%) was obtained elute 1 H-NMR (DMSO-d 6 , 400 MHz) 8.75 (s, br, 1 H), 8.68 (d, J = 7.0 Hz, 2H), 7.45 (d, J = 7.0 Hz, 2H), 4.08 (t, J) = 6.3 Hz, 2H), 3.64 (d, J = 6.3 Hz, 2H); LCMS (ESI) m/z: 200 (M + 1).
实施例4GExample 4G
1-(5-溴代戊基)氧基-4-氟苯1-(5-bromopentyl)oxy-4-fluorobenzene
Figure PCTCN2015077043-appb-000046
Figure PCTCN2015077043-appb-000046
向对氟苯酚(4克，35.68毫摩尔)的丙酮(40毫升)溶液中加入碳酸钾(14.79克,107毫摩尔)，碘化钾(0.59克，3.6毫摩尔)和1,5-二溴戊烷(24.61克，107毫摩尔)。混合溶液在80℃下搅拌12小时后，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤蒸发后残余物用柱层层析纯化(石油醚：乙酸乙酯＝10：1)得到标题化合物(白色固体，6.6克，收率70.8％)。1H-NMR(CDCl3,400MHz)δ6.93-7.01(m,2H)6.79-6.86(m,2H)3.90-3.97(m,2H)3.45(t,J＝6.8Hz,2H)1.94(q,J＝7.2Hz,2H)1.76-1.86(m,2H)1.60-1.68(m,2H)。LCMS(ESI)m/z:262(M+1)。To a solution of p-fluorophenol (4 g, 35.68 mmol) in acetone (40 ml), potassium carbonate (14.79 g, 107 mmol), potassium iodide (0.59 g, 3.6 mmol) and 1,5-dibromopentane (24.61 g, 107 mmol). After the mixture was stirred at 80 ° C for 12 hours, it was extracted with EtOAc. EtOAc (EtOAc) The title compound (white solid, 6.6 g, yield 70.8%). 1 H-NMR (CDCl 3 , 400 MHz) δ 6.93-7.01 (m, 2H) 6.79-6.86 (m, 2H) 3.90-3.97 (m, 2H) 3.45 (t, J = 6.8 Hz, 2H) 1.94 (q) , J = 7.2 Hz, 2H) 1.76-1.86 (m, 2H) 1.60-1.68 (m, 2H). LCMS (ESI) m/z: 262 (21.
实施例4HExample 4H
2-(5-((4-氟苯氧基)戊基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(5-((4-fluorophenoxy)pentyl)-5-(pyridin-4-yl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000047
Figure PCTCN2015077043-appb-000047
0℃下，向实施例4F(30毫克，0.15毫摩尔)的N,N-二甲基甲酰胺(2毫升)溶液中加入氢化钠(6毫克，0.16毫摩尔，60％含量)。0℃下保持30分钟后，向上述混合溶液中加入实施例4G(39.3毫克，0.15毫摩尔)的N,N-二甲基甲酰胺(1毫升)溶液。15℃下搅拌反应6小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发后HPLC分离得到标题化合物(白色固体，28毫克，收率49％)。1H-NMR(400MHz,CDCl3)δ8.51(d,J＝6.0Hz,2H),7.05(d,J＝5.5Hz,2H),6.91-7.01(m,2H),6.82(dd,J＝9.0,4.0Hz,2H),3.93(t,J＝6.3Hz,2H),3.84(t,J＝6.5Hz,2H),3.54(t,J＝6.3Hz,2H),3.18(t,J＝7.0Hz,2H),1.72-1.87(m,5H),1.56-1.61(m,1H)。LCMS(ESI),m/z:380(M+1).Sodium hydride (6 mg, 0.16 mmol, 60% content) was added to a solution of EtOAc (EtOAc, EtOAc. After maintaining at 0 ° C for 30 minutes, a solution of Example 4G (39.3 mg, 0.15 mmol) of N,N-dimethylformamide (1 ml) was added to the mixture. After stirring the reaction at 15 ° C for 6 hours, the reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried with anhydrous sodium 1 H-NMR (400MHz, CDCl 3 ) δ 8.51 (d, J = 6.0 Hz, 2H), 7.05 (d, J = 5.5 Hz, 2H), 6.91-7.01 (m, 2H), 6.82 (dd, J = 9.0, 4.0 Hz, 2H), 3.93 (t, J = 6.3 Hz, 2H), 3.84 (t, J = 6.5 Hz, 2H), 3.54 (t, J = 6.3 Hz, 2H), 3.18 (t, J =7.0 Hz, 2H), 1.72-1.87 (m, 5H), 1.56-1.61 (m, 1H). LCMS (ESI), m/z: 380 (M+1).
实施例5Example 5
Figure PCTCN2015077043-appb-000048
Figure PCTCN2015077043-appb-000048
实施例5AExample 5A
1-(5-溴代戊基)氧基-4-三氟甲基苯 1-(5-bromopentyl)oxy-4-trifluoromethylbenzene
Figure PCTCN2015077043-appb-000049
Figure PCTCN2015077043-appb-000049
该实施例的制备方法参照实施例4G。1H-NMR(400MHz,CDCl3)δ7.54(d,J＝8.53Hz,2H),6.95(d,J＝8.53Hz,2H),4.01(t,J＝6.27Hz,2H),3.42-3.51(m,2H),1.95(quin,J＝7.15Hz,2H),1.76-1.89(m,2H),1.61-1.68(m,2H)。The preparation method of this example is referred to Example 4G. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.54 (d, J = 8.53 Hz, 2H), 6.95 (d, J = 8.53 Hz, 2H), 4.01 (t, J = 6.27 Hz, 2H), 3.42 3.51 (m, 2H), 1.95 (quin, J = 7.15 Hz, 2H), 1.76-1.89 (m, 2H), 1.61-1.68 (m, 2H).
实施例5BExample 5B
2-(吡啶-4-基)-5-(5-(4-三氟甲基苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(Pyridin-4-yl)-5-(5-(4-trifluoromethylphenoxy)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000050
Figure PCTCN2015077043-appb-000050
该实施例的制备方法参照实施例4H。1H-NMR(400MHz,CDCl3)δ8.53(d,J＝6.27Hz,2H),7.50-7.60(m,2H),7.07(d,J＝6.27Hz,2H),6.96(d,J＝8.78Hz,2H),4.04(t,J＝6.27Hz,2H),3.87(t,J＝6.40Hz,2H),3.57(t,J＝6.40Hz,2H),3.21(t,J＝7.15Hz,2H),1.86-1.94(m,2H),1.77-1.85(m,2H),1.60-1.68(m,2H)。The preparation method of this example is referred to Example 4H. 1 H-NMR (400MHz, CDCl 3 ) δ 8.53 (d, J = 6.27 Hz, 2H), 7.50-7.60 (m, 2H), 7.07 (d, J = 6.27 Hz, 2H), 6.96 (d, J) =8.78 Hz, 2H), 4.04 (t, J = 6.27 Hz, 2H), 3.87 (t, J = 6.40 Hz, 2H), 3.57 (t, J = 6.40 Hz, 2H), 3.21 (t, J = 7.15) Hz, 2H), 1.86-1.94 (m, 2H), 1.77-1.85 (m, 2H), 1.60-1.68 (m, 2H).
实施例6Example 6
2-(5-((4'-氯-[1,1'-联苯]-4-基)氧基)戊基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(5-((4'-Chloro-[1,1'-biphenyl]-4-yl)oxy)pentyl)-5-(pyridin-4-yl)-1,2,5-thia Diazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000051
Figure PCTCN2015077043-appb-000051
实施例6AExample 6A
4'-氯-[1,1'-联苯]-4-醇4'-chloro-[1,1'-biphenyl]-4-ol
Figure PCTCN2015077043-appb-000052
Figure PCTCN2015077043-appb-000052
将4-溴苯酚(62克,360毫摩尔)，4-氯苯硼酸(56克，360毫摩尔)，Pd(dppf)Cl2(10克，10毫摩尔)和Na2CO3(76克，720毫摩尔)混合于THF/H2O(600毫升/100毫升)中，将该混合物在氮气保护下70℃加热6小时。将反应混合物倒入水中，乙酸乙酯萃取，合并的有机相用无水硫酸钠干燥，过滤蒸发，残余物用柱层析纯化(石油醚：乙酸乙酯＝20：1)得到标题化合物(60克，收率80％)。LCMS(ESI)m/z:205(M+1)。4-bromophenol (62 g, 360 mmol), 4-chlorophenylboronic acid (56 g, 360 mmol), Pd(dppf)Cl 2 (10 g, 10 mmol) and Na 2 CO 3 (76 g) The mixture was mixed with THF/H 2 O (600 mL / 100 mL), and the mixture was heated at 70 ° C for 6 hours under nitrogen atmosphere. The reaction mixture was poured into water, EtOAc EtOAc (EtOAc m. Gram, yield 80%). LCMS (ESI) m/z:
实施例6BExample 6B
4-((5-溴代戊基)氧基)-4'-氯-1,1'-联苯4-((5-bromopentyl)oxy)-4'-chloro-1,1'-biphenyl
Figure PCTCN2015077043-appb-000053
Figure PCTCN2015077043-appb-000053
向实施例6A(20克，97.72毫摩尔)的丙酮(200毫升)溶液中加入1,5-二溴戊烷(67克，293.2毫摩尔)，K2CO3(27克，195.4毫摩尔)和KI(1.62克，9.77毫摩尔)。加完后将该混合溶液在80℃下加热12小时。反应完成后，将反应液过滤，将滤液浓缩，向残余物中加入石油醚(200毫升)，在0℃下继续搅拌2小时，过滤得到固体即为标题化合物(白色固体，25克，收率75％)。1H-NMR(400MHz,CDCl3)7.48(dd,J＝2.01,8.53Hz,4H),7.35-7.41(m,2H),6.91-7.00(m,2H),3.96-4.06(m,2H),3.41-3.50(m,2H),1.96(q,J＝7.15Hz,2H),1.80-1.90(m,2H),1.60-1.71(m,2H)。To acetone (200 ml) Example 6A (20 g, 97.72 mmol) was added a solution of 1,5-dibromopentane (67 g, 293.2 mmol), K 2 CO 3 (27 g, 195.4 mmol) And KI (1.62 g, 9.77 mmol). After the addition was completed, the mixed solution was heated at 80 ° C for 12 hours. After the completion of the reaction, the reaction mixture was filtered, EtOAcjjjjjjjjjjjj 75%). 1 H-NMR (400 MHz, CDCl 3 ) 7.48 (dd, J = 2.01, 8.35 Hz, 4H), 7.35-7.41 (m, 2H), 6.91-7.00 (m, 2H), 3.96-4.06 (m, 2H) , 3.41-3.50 (m, 2H), 1.96 (q, J = 7.15 Hz, 2H), 1.80-1.90 (m, 2H), 1.60-1.71 (m, 2H).
实施例6CExample 6C
2-(5-((4'-氯-[1,1'-联苯]-4-基)氧基)戊基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(5-((4'-Chloro-[1,1'-biphenyl]-4-yl)oxy)pentyl)-5-(pyridin-4-yl)-1,2,5-thia Diazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000054
Figure PCTCN2015077043-appb-000054
0℃下向实施例4F(40毫克，0.2毫摩尔)的N,N-二甲基甲酰胺(10毫升)溶液中加入氢化钠(10毫克，0.4毫摩尔，60％含量)，0℃下搅拌半小时后向上述溶液中加入实施例6B(71毫克，0.2毫摩尔)的N,N-二甲基甲酰胺(2毫升)溶液。继续在15℃下搅拌反应2小时后，加入水淬灭反应，水相用乙酸乙酯萃取。合并的有机相用无水硫酸钠干燥后蒸发，残余物用制备HPLC纯化得到标题化合物(白色固体，10毫克，收率11％)。1H-NMR(CDCl3,400MHz)δ8.51(d,J＝6.3Hz,2H),7.50-7.44(m,4H),7.41-7.34(m,2H),7.10-7.04(m,2H),6.95(d,J＝8.8Hz,2H),4.02(t,J＝6.3Hz,2H),3.89-3.81(m,2H),3.55(t,J＝6.4Hz,2H),3.19(t,J＝7.2Hz,2H),1.90-1.84(m,2H),1.82-1.78(m,2H),1.67-1.58(m,2H)，LCMS(ESI)m/z:472(M+1)。Sodium hydride (10 mg, 0.4 mmol, 60% content) was added to a solution of Example 4F (40 mg, 0.2 mmol) in N,N-dimethylformamide (10 ml) at 0 ° C After stirring for half an hour, a solution of Example 6B (71 mg, 0.2 mmol) of N,N-dimethylformamide (2 mL) was added. After the reaction was further stirred at 15 ° C for 2 hours, the reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried with EtOAc EtOAcjjjjjjjj 1 H-NMR (CDCl 3 , 400 MHz) δ 8.51 (d, J = 6.3 Hz, 2H), 7.50-7.44 (m, 4H), 7.41-7.34 (m, 2H), 7.10-7.04 (m, 2H) , 6.95 (d, J = 8.8 Hz, 2H), 4.02 (t, J = 6.3 Hz, 2H), 3.89 - 3.81 (m, 2H), 3.55 (t, J = 6.4 Hz, 2H), 3.19 (t, J = 7.2 Hz, 2H), 1.90-1.84 (m, 2H), 1.82-1.78 (m, 2H), 1.67-1.58 (m, 2H), LCMS (ESI) m/z: 472 (M+1).
实施例7Example 7
(E)-4-((5-(1,1-二氧代-5-(吡啶-4-基)-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基肟(E)-4-((5-(1,1-dioxo-5-(pyridin-4-yl)-1,2,5-thiadiazol-2-yl)pentyl)oxy) Benzaldehyde-oxy-ethyl hydrazine
Figure PCTCN2015077043-appb-000055
Figure PCTCN2015077043-appb-000055
实施例7AExample 7A
(E)-4-羟基苯甲醛-氧-乙基肟(E)-4-hydroxybenzaldehyde-oxy-ethylhydrazine
Figure PCTCN2015077043-appb-000056
Figure PCTCN2015077043-appb-000056
向对羟基苯甲醛(2.5克，20.47毫摩尔)，乙氧氨基盐酸盐(3.91克，40.94毫摩尔)的水(50毫升)溶液中加乙酸钠(3.36克，40.94毫摩尔)，混合物在80℃下搅拌4小时。乙酸乙酯(50毫升)加入反应体系，水层用乙酸乙酯(50毫升×3)萃取，将合并的有机层用无水硫酸钠干燥，过滤并蒸发得到标题化合物(棕色固体，3克，产率89％)。1H-NMR(CDCl3,400MHz)8.03(s,1H),7.46(d,J＝8.5Hz,2H),6.78-6.85(m,2H),4.20(q,J＝7.0Hz,2H),1.31(t,J＝7.0Hz,3H)。Add sodium acetate (3.36 g, 40.94 mmol) to a solution of p-hydroxybenzaldehyde (2.5 g, 20.47 mmol), EtOAc (3. Stir at 80 ° C for 4 hours. Ethyl acetate (50 ml) was added to EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Yield 89%). 1 H-NMR (CDCl 3 , 400 MHz) 8.03 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 6.78-6.85 (m, 2H), 4.20 (q, J = 7.0 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H).
实施例7B Example 7B
(E)-4-((5-溴代戊基)氧)苯甲醛-氧-乙基肟(E)-4-((5-bromopentyl)oxy)benzaldehyde-oxy-ethylhydrazine
Figure PCTCN2015077043-appb-000057
Figure PCTCN2015077043-appb-000057
将实施例7A(1.0克，6.05毫摩尔)，1,5-二溴戊烷(1.39克，6.05毫摩尔)，碳酸钾(1.67克，12.11毫摩尔)和碘化钾(0.1克，0.605毫摩尔)混合于丙酮(100毫升)中，加热回流10小时。过滤，滤液旋干，柱层析纯化，提供标题化合物(白色晶体，1.2克，63％)。1H-NMR(CDCl3,400MHz)δ8.01-8.05(m,1H),7.49-7.55(m,2H),6.86-6.91(m,2H),4.17-4.24(m,2H),3.96-4.01(m,2H),3.41-3.47(m,2H),1.89-1.99(m,2H),1.78-1.86(m,2H),1.60-1.68(m,2H),1.29-1.34(m,3H)。Example 7A (1.0 g, 6.05 mmol), 1,5-dibromopentane (1.39 g, 6.05 mmol), potassium carbonate (1.67 g, 12.11 mmol) and potassium iodide (0.1 g, 0.605 mmol) It was mixed with acetone (100 ml) and heated under reflux for 10 hours. Filtration, EtOAc (EtOAc) m. 1 H-NMR (CDCl 3 , 400 MHz) δ 8.01 - 8.05 (m, 1H), 7.49-7.55 (m, 2H), 6.86-6.91 (m, 2H), 4.17 - 4.24 (m, 2H), 3.96- 4.01 (m, 2H), 3.41-3.47 (m, 2H), 1.89-1.99 (m, 2H), 1.78-1.86 (m, 2H), 1.60-1.68 (m, 2H), 1.29-1.34 (m, 3H) ).
实施例7CExample 7C
(E)-4-((5-(1,1-二氧代-5-(吡啶-4-基)-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基肟(E)-4-((5-(1,1-dioxo-5-(pyridin-4-yl)-1,2,5-thiadiazol-2-yl)pentyl)oxy) Benzaldehyde-oxy-ethyl hydrazine
Figure PCTCN2015077043-appb-000058
Figure PCTCN2015077043-appb-000058
在0℃下，向实施例4F(60毫克，301.2毫摩尔)的N,N-二甲基甲酰胺(1毫升)溶液中，分批次加入钠氢(10毫克，250毫摩尔，60％含量)，搅拌1.5小时后，将实施例7B(114毫克，361.4毫摩尔)的N,N-二甲基甲酰胺(0.5毫升)溶液滴加入反应液中，然后升至室温搅拌2小时，倒入水(10毫升)中，用乙酸乙酯(3毫升×3)萃取，合并的有机相用无水硫酸钠干燥，旋干，制备HPLC纯化后得到标题化合物(白色固体，40毫克，收率30.7％)。1H-NMR(CDCl3,400MHz)δ8.53(d,J＝6.02Hz,1H),8.04(s,1H),7.53(d,J＝8.78Hz,2H),7.07(d,J＝6.27Hz,2H),6.89(d,J＝8.78Hz,2H),4.22(q,J＝7.03Hz,2H),4.02(t,J＝6.27Hz,2H),3.87(t,J＝6.40Hz,2H),3.56(t,J＝6.40Hz,2H),3.20(t,J＝7.15Hz,2H),1.85-1.93(m,2H),1.76-1.84(m,2H),1.67(br.s.,2H),1.34(t,J＝7.03Hz,3H)。LCMS(ESI)m/z:433(M+1)。Sodium hydrogen (10 mg, 250 mmol, 60%) was added in portions to a solution of Example 4F (60 mg, 301.2 mmol) in N,N-dimethylformamide (1 mL) After stirring for 1.5 hours, a solution of Example 7B (114 mg, 361.4 mmol) of N,N-dimethylformamide (0.5 ml) was added dropwise to the reaction mixture, and then the mixture was stirred at room temperature for 2 hr. In water (10 ml), EtOAc (3 mL,EtOAc) 30.7%). 1 H-NMR (CDCl 3 , 400 MHz) δ 8.53 (d, J = 6.02 Hz, 1H), 8.04 (s, 1H), 7.53 (d, J = 8.78 Hz, 2H), 7.07 (d, J = 6.27) Hz, 2H), 6.89 (d, J = 8.78 Hz, 2H), 4.22 (q, J = 7.03 Hz, 2H), 4.02 (t, J = 6.27 Hz, 2H), 3.87 (t, J = 6.40 Hz, 2H), 3.56 (t, J = 6.40 Hz, 2H), 3.20 (t, J = 7.15 Hz, 2H), 1.85-1.93 (m, 2H), 1.76-1.84 (m, 2H), 1.67 (br.s) .2H), 1.34 (t, J = 7.03 Hz, 3H). LCMS (ESI) m/z:
实施例8Example 8
Figure PCTCN2015077043-appb-000059
Figure PCTCN2015077043-appb-000059
实施例8AExample 8A
5-羟基-2,3-二氢-1H-茚-1-酮5-hydroxy-2,3-dihydro-1H-inden-1-one
Figure PCTCN2015077043-appb-000060
Figure PCTCN2015077043-appb-000060
氮气保护下，将5-溴-1-茚酮(1.0克,4.7毫摩尔)，N,N,N’,N’-四甲基乙二胺(210毫克,2.37毫摩尔),K3PO4(1.0毫克,4.74毫摩尔)和CuI(90毫克,0.47毫摩尔)混合于水(5.0毫升)中。用微波在120℃加热2小时，反应结束后，混合溶液用乙酸乙酯萃取(10毫升×3)。合并的有机相用无水硫酸钠干燥，过滤 浓缩后用薄层层析纯化得到标题化合物(白色固体，120毫克，收率17％)。1H-NMR(CDCl3,400MHz)δ7.71-7.69(m,1H),6.92-6.87(m,2H),3.11-3.09(m,2H),2.72-2.70(m,2H)。实施例8B(E)-5-羟基-2,3-二氢-1H-茚-1-酮-氧-乙基肟5-Bromo-1-indolone (1.0 g, 4.7 mmol), N,N,N',N'-tetramethylethylenediamine (210 mg, 2.37 mmol), K 3 PO under N2 4 (1.0 mg, 4.74 mmol) and CuI (90 mg, 0.47 mmol) were combined in water (5.0 mL). After heating at 120 ° C for 2 hours with a microwave, the mixture was extracted with ethyl acetate (10 ml × 3). The combined organic phases were dried with EtOAc EtOAcjjjjjjjjj 1 H-NMR (CDCl 3 , 400 MHz) δ 7.71 - 7.69 (m, 1H), 6.92 - 6.87 (m, 2H), 3.11-3.09 (m, 2H), 2.72 - 2.70 (m, 2H). Example 8B (E)-5-Hydroxy-2,3-dihydro-1H-inden-1-one-oxy-ethyl hydrazine
Figure PCTCN2015077043-appb-000061
Figure PCTCN2015077043-appb-000061
向实施例8A(50毫克，0.3毫摩尔)与水(5毫升)的混合溶液中加入乙氧氨基盐酸盐(65毫克，0.67毫摩尔)和醋酸钠(55毫克，0.67毫摩尔)。将该混合溶液在80℃下加热1小时，水相用乙酸乙酯萃取(5.0毫升×3)，合并的有机相用无水硫酸钠干燥，过滤浓缩后粗产物直接用于下一步反应。1H-NMR(CDCl3,400MHz)δ7.52-7.66(m,1H),6.68-6.87(m,2H),4.12-4.30(m,2H),2.78-3.07(m,4H),1.27-1.41(m,3H)。To a mixed solution of Example 8A (50 mg, 0.3 mmol) and water (5 mL), EtOAc (EtOAc, EtOAc (EtOAc) The mixed solution was heated at 80 ° C for 1 hour, and the aqueous layer was extracted with ethyl acetate (m. 1 H-NMR (CDCl 3 , 400 MHz) δ 7.52-7.66 (m, 1H), 6.68-6.87 (m, 2H), 4.12-4.30 (m, 2H), 2.78-3.07 (m, 4H), 1.27- 1.41 (m, 3H).
实施例8CExample 8C
(E)-5-((5-溴代戊基)氧)-2,3-二氢-1H-茚-1-酮-氧-乙基肟(E)-5-((5-bromopentyl)oxy)-2,3-dihydro-1H-inden-1-one-oxy-ethyl hydrazine
Figure PCTCN2015077043-appb-000062
Figure PCTCN2015077043-appb-000062
向实施例8B(80毫克，0.4毫摩尔)和丙酮(5.0毫升)的混合溶液中加入1,5-二溴戊烷(288毫克，1.26毫摩尔，3.0当量)，碳酸钾(578毫克，4.18毫摩尔，10当量)和碘化钾(7毫克，0.04毫摩尔，0.1当量)，将该混合溶液在80℃下加热5小时。将反应液过滤后，滤液浓缩，浓缩后的残留物用薄层层析纯化得到标题化合物(黄色固体，140毫克，收率98％)。LCMS(ESI)m/z:340(M+1)。To a mixed solution of Example 8B (80 mg, 0.4 mmol) and acetone (5.0 mL) was added 1,5-dibromopentane (288 mg, 1.26 mmol, 3.0 eq.), potassium carbonate (578 mg, 4.18) Millimol, 10 equivalents) and potassium iodide (7 mg, 0.04 mmol, 0.1 eq.) were heated at 80 ° C for 5 hours. After the reaction mixture was filtered, EtOAcjjjjjjjjjj LCMS (ESI) m/z:
实施例8DExample 8D
(E)-2-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy)pentyl)-5-(pyridine-4- 1,1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000063
Figure PCTCN2015077043-appb-000063
氮气保护下，向实施例4F(20毫克，0.10毫摩尔)的N,N-二甲基甲酰胺(1.0毫升)溶液中加入氢化钠(8毫克，0.2毫摩尔)。0℃下搅拌反应半小时后将实施例8C(34毫克，0.1毫摩尔)的N,N-二甲基甲酰胺(1.0毫升)溶液慢慢加入上述溶液中。15℃下搅拌反应过夜后，加入水(0.5毫升)淬灭，水相用二氯甲烷萃取，合并的有机相用无水硫酸钠干燥后，过滤蒸发，残留物用制备HPLC纯化得到标题化合物(17毫克，收率37％)。1H-NMR(CDCl3,400MHz)δ8.50(d,J＝5.0Hz,2H),7.59(d,J＝9.5Hz,1H),7.05(d,J＝5.5Hz,2H),6.74-6.82(m,2H),4.19(q,J＝7.0Hz,2H),3.96-4.08(m,2H),3.84(t,J＝5.8Hz,2H),3.50-3.58(m,2H),3.17(t,J＝7.0Hz,2H),2.94-3.11(m,2H),2.81-2.92(m,2H),1.72-1.94(m,4H),1.56-1.68(m,2H),1.22-1.40(m,3H)。LCMS(ESI)m/z:459(M+1)。 Sodium hydride (8 mg, 0.2 mmol) was added to a solution of EtOAc (EtOAc m. A solution of Example 8C (34 mg, 0.1 mmol) in N,N-dimethylformamide (1.0 mL) was slowly added to the solution. After the reaction was stirred at 15 ° C, EtOAc (EtOAc)EtOAc. 17 mg, yield 37%). 1 H-NMR (CDCl 3 , 400 MHz) δ 8.50 (d, J = 5.0 Hz, 2H), 7.59 (d, J = 9.5 Hz, 1H), 7.05 (d, J = 5.5 Hz, 2H), 6.74 6.82 (m, 2H), 4.19 (q, J = 7.0 Hz, 2H), 3.96-4.08 (m, 2H), 3.84 (t, J = 5.8 Hz, 2H), 3.50-3.58 (m, 2H), 3.17 (t, J = 7.0 Hz, 2H), 2.94 - 3.11 (m, 2H), 2.81-2.92 (m, 2H), 1.72-1.94 (m, 4H), 1.56-1.68 (m, 2H), 1.22-1.40 (m, 3H). LCMS (ESI) m/z: 459:
实施例9Example 9
Figure PCTCN2015077043-appb-000064
Figure PCTCN2015077043-appb-000064
实施例9AExample 9A
1-溴-4-((5-溴代戊基)氧)苯1-bromo-4-((5-bromopentyl)oxy)benzene
Figure PCTCN2015077043-appb-000065
Figure PCTCN2015077043-appb-000065
向4-溴苯酚(5克，28.9毫摩尔)的丙酮(50毫升)溶液中加入1,5-二溴戊烷(19.95克，86.7毫摩尔)，K2CO3(8克，57.8毫摩尔)和KI(0.4克，2.89毫摩尔)。加完后将该混合溶液在80℃下搅拌12小时。过滤后将滤液浓缩,向浓缩后的残留物中加入石油醚(100毫升)，0℃下搅拌1小时后过滤得到标题化合物(黄色固体，4克，收率43％)。1H-NMR(CDCl3,400MHz)δ7.37-7.39(m,1H),7.34-7.36(m,1H),6.77-6.79(m,1H),6.75-6.77(m,1H),3.93(t,J＝6.27Hz,2H),3.44(t,J＝6.78Hz,2H),1.90-1.99(m,2H),1.75-1.84(m,2H),1.58-1.67(m,2H)。LCMS(ESI)m/z:323(M+1)。To a solution of 4-bromophenol (5 g, 28.9 mmol) in acetone (50 mL) was added 1,5-dibromopentane (19.95 g, 86.7 mmol), K 2 CO 3 (8 g, 57.8 mmol) And KI (0.4 g, 2.89 mmol). After the addition was completed, the mixed solution was stirred at 80 ° C for 12 hours. After filtration, the filtrate was concentrated. EtOAc EtOAc m. 1 H-NMR (CDCl 3 , 400 MHz) δ 7.37-7.39 (m, 1H), 7.34-7.36 (m, 1H), 6.77-6.79 (m, 1H), 6.75-6.77 (m, 1H), 3.93 ( t, J = 6.27 Hz, 2H), 3.44 (t, J = 6.78 Hz, 2H), 1.90-1.99 (m, 2H), 1.75-1.84 (m, 2H), 1.58-1.67 (m, 2H). LCMS (ESI) m.
实施例9BExample 9B
4-(4-((5-溴代戊基)氧基)苯基)-1-乙基-1H-吡唑4-(4-((5-bromopentyl)oxy)phenyl)-1-ethyl-1H-pyrazole
Figure PCTCN2015077043-appb-000066
Figure PCTCN2015077043-appb-000066
25℃下，氮气保护下，向实施例9A(80毫克，0.25毫摩尔)，1-乙基吡唑-4-硼酸嚬哪醇酯(55毫克，0.25毫摩尔)和碳酸钠(53毫克，0.5毫摩尔)的1,4-二氧六环(3毫升)和水(0.5毫升)的混合溶液中加入催化剂Pd(dppf)Cl2(9毫克，12.4微摩尔)，在80℃下搅拌16小时后，加入水(10毫升)，水层用二氯甲烷(10毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发，残余物通过制备薄层板纯化得到标题化合物(白色固体，26毫克，收率31％)。1H-NMR(CDCl3,400MHz)δ7.70(s,1H),7.52-7.60(m,1H),7.38(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),4.20(q,J＝7.3Hz,2H),3.98(t,J＝6.4Hz,2H),3.45(t,J＝6.8Hz,2H),1.95(q,J＝7.2Hz,2H),1.77-1.86(m,2H),1.60-1.71(m,2H),1.49-1.54(m,3H)。To a solution of Example 9A (80 mg, 0.25 mmol), 1-ethylpyrazole-4-boronic acid succinate (55 mg, 0.25 mmol) and sodium carbonate (53 mg, The catalyst Pd(dppf)Cl 2 (9 mg, 12.4 μmol) was added to a mixed solution of 0.5 mmol of 1,4-dioxane (3 ml) and water (0.5 ml), and stirred at 80 ° C. After a few hours, water (10 ml), EtOAc (EtOAc m. White solid, 26 mg, yield 31%). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.70 (s, 1H), 7.52-7.60 (m, 1H), 7.38 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H) ), 4.20 (q, J = 7.3 Hz, 2H), 3.98 (t, J = 6.4 Hz, 2H), 3.45 (t, J = 6.8 Hz, 2H), 1.95 (q, J = 7.2 Hz, 2H), 1.77-1.86 (m, 2H), 1.60-1.71 (m, 2H), 1.49-1.54 (m, 3H).
实施例9CExample 9C
2-(5-(4-(1-乙基-1H-吡唑-4-基)苯氧基)戊基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(5-(4-(1-ethyl-1H-pyrazol-4-yl)phenoxy)pentyl)-5-(pyridin-4-yl)-1,2,5-thiadiazole Alkane-1,1-dioxide
Figure PCTCN2015077043-appb-000067
Figure PCTCN2015077043-appb-000067
该实施例的制备方法参照实施例8D。1H-NMR(CDCl3,400MHz)δ8.51(d,J＝6.5Hz,2H),7.70(s,1H),7.56(s,1H),7.38(d,J＝8.5Hz,2H),7.05(d,J＝6.3Hz,2H),6.89(d,J＝8.8Hz,2H),4.17-4.23(m,2H),3.99(t,J＝6.1Hz,2H),3.83-3.86(m,2H),3.53-3.56(m,2H),3.18(t,J＝7.2Hz,2H),1.70-1.99(m,4H),1.64(s,br.,2H),1.57-1.58(m,3H).LCMS(ESI)m/z:456(M+1)。 The preparation method of this example is referred to Example 8D. 1 H-NMR (CDCl 3 , 400 MHz) δ 8.51 (d, J = 6.5 Hz, 2H), 7.70 (s, 1H), 7.56 (s, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 6.3 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.17 - 4.23 (m, 2H), 3.99 (t, J = 6.1 Hz, 2H), 3.83 - 3.86 (m , 2H), 3.53-3.56 (m, 2H), 3.18 (t, J = 7.2 Hz, 2H), 1.70-1.99 (m, 4H), 1.64 (s, br., 2H), 1.57-1.58 (m, 3H). LCMS (ESI) m.
实施例10Example 10
Figure PCTCN2015077043-appb-000068
Figure PCTCN2015077043-appb-000068
实施例10AExample 10A
N',4-二羟基苯甲脒N',4-dihydroxybenzamide
Figure PCTCN2015077043-appb-000069
Figure PCTCN2015077043-appb-000069
向4-羟基苯氰(5克，42毫摩尔)的异丙醇(90毫升)溶液中加入DIPEA(42克，419毫摩尔)和NH2OH·HCl(29.1毫克，1.15毫摩尔)。将该混合溶液在80℃下加热4小时，冷却到室温后将溶液过滤得到固体即为标题化合物(4克，收率62.6％)。1H-NMR(CDCl3,400MHz)δ7.50(d,J＝8.5Hz,2H),6.82(d,J＝8.5Hz,2H)。LCMS(ESI)m/z:153(M+1)。The 4-hydroxyphenyl cyanide (5 g, 42 mmol) in isopropanol (90 ml) was added DIPEA (42 g, 419 mmol) and NH 2 OH · HCl (29.1 mg, 1.15 mmol). The mixed solution was heated at 80 ° C for 4 hours, and after cooling to room temperature, the solution was filtered to give the title compound (4 g, yield 62.6%). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.50 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H). LCMS (ESI) m/z:
实施例10BExample 10B
4-(5-乙基-1,2,4-噁二唑-3-基)苯酚4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenol
Figure PCTCN2015077043-appb-000070
Figure PCTCN2015077043-appb-000070
0℃下，向实施例10A(3克，19.57毫摩尔)的吡啶(10毫升)溶液中加入丙酸酐(2.57克，19.57毫摩尔)。加完后将该混合溶液在60℃下加热1小时。反应液冷却至室温后减压浓缩，柱层析纯化(石油醚：乙酸乙酯＝10：1)得到标题化合物(3克，收率80％)。1H-NMR(CDCl3,400MHz)δ7.97(d,J＝8.5Hz,2H),6.94(d,J＝8.5Hz,2H),2.99(q,J＝7.6Hz,2H),1.46(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:191(M+1)。To a solution of Example 10A (3 g, 19.57 mmol) in EtOAc (10 mL). After the addition was completed, the mixed solution was heated at 60 ° C for 1 hour. The reaction mixture was cooled to EtOAc. 1 H-NMR (CDCl 3 , 400 MHz) δ 7.97 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 2.99 (q, J = 7.6 Hz, 2H), 1.46 ( t, J = 7.5 Hz, 3H). LCMS (ESI) m.
实施例10CExample 10C
3-(4-((5-溴代戊基)氧基)苯基)-5-乙基-1,2,4-噁二唑3-(4-((5-bromopentyl)oxy)phenyl)-5-ethyl-1,2,4-oxadiazole
Figure PCTCN2015077043-appb-000071
Figure PCTCN2015077043-appb-000071
向实施例10B(10克，52.58毫摩尔)的N,N-二甲基甲酰胺(100毫升)溶液中加入碳酸铯(34.26克，105.15毫摩尔)和1，5-二溴戊烷(36.27克，157.73毫摩尔)。混合溶液在10℃下搅拌12小时后，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤蒸发后残余物用柱层层析纯化(石油醚：乙酸乙酯＝10：1)得到标题化合物(白色固体，10克，收率56％)。1H-NMR(CDCl3,400MHz)δ8.02(d,J＝8.5Hz,2H),6.95-7.03(m,2H),4.00-4.08(m,2H),3.41-3.51(m,2H),2.97(q,J＝7.6Hz,2H),1.92-2.01(m,2H),1.82-1.91(m,2H),1.64-1.71(m,2H),1.46(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:339(M+1)。 To a solution of Example 10B (10 g, 52.58 mmol) of N,N-dimethylformamide (100 ml), EtOAc (3.26 g, 105.15 mmol) and 1,5-dibromopentane (36.27) Gram, 157.73 mmol). After the mixture was stirred at 10 ° C for 12 hours, the mixture was evaporated. EtOAcjjjjjjjjjjjjj The title compound (white solid, 10 g, yield 56%). 1 H-NMR (CDCl 3 , 400 MHz) δ 8.02 (d, J = 8.5 Hz, 2H), 6.95-7.03 (m, 2H), 4.00-4.08 (m, 2H), 3.41-3.51 (m, 2H) , 2.97 (q, J = 7.6 Hz, 2H), 1.92-2.01 (m, 2H), 1.82-1.91 (m, 2H), 1.64-1.71 (m, 2H), 1.46 (t, J = 7.5 Hz, 3H) ). LCMS (ESI) m/z:
实施例10DExample 10D
2-(5-(4-(5-乙基-1,2,4-噁二唑-3-基)苯氧基)戊基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(5-(4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenoxy)pentyl)-5-(pyridin-4-yl)-1,2, 5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000072
Figure PCTCN2015077043-appb-000072
0℃下，向实施例4F(20毫克，0.1毫摩尔)的N,N-二甲基甲酰胺(5毫升)溶液中加入氢化钠(3.6毫克，0.15毫摩尔)。0℃下保持30分钟后，向上述混合溶液中加入实施例10C(34毫克，0.1毫摩尔)的N,N-二甲基甲酰胺(1毫升)溶液。15℃下搅拌反应4小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发得到标题化合物(白色固体，3毫克，收率7％)。1H-NMR(400MHz,CDCl3)δ8.51(d,J＝5.0Hz,2H),8.00(d,J＝9.0Hz,2H),7.05(d,J＝6.3Hz,2H),6.96(d,J＝8.8Hz,2H),4.04(t,J＝6.1Hz,2H),3.85(t,J＝6.4Hz,2H),3.54(t,J＝6.4Hz,2H),3.19(t,J＝7.3Hz,2H),2.96(q,J＝7.5Hz,2H),1.91-1.76(m,4H),1.68-1.62(m,2H),1.44(t,J＝7.7Hz,3H)。LCMS(ESI)m/z:458(M+1)。Sodium hydride (3.6 mg, 0.15 mmol) was added to a solution of EtOAc (EtOAc m. After maintaining for 30 minutes at 0 ° C, a solution of Example 10C (34 mg, 0.1 mmol) of N,N-dimethylformamide (1 ml) was added to the mixture. After stirring the reaction at 15 ° C for 4 hours, the reaction was quenched by water and the aqueous was extracted with ethyl acetate. The combined organic phases were dried with EtOAc EtOAc EtOAc 1 H-NMR (400 MHz, CDCl 3 ) δ 8.51 (d, J = 5.0 Hz, 2H), 8.00 (d, J = 9.0 Hz, 2H), 7.05 (d, J = 6.3 Hz, 2H), 6.96 ( d, J = 8.8 Hz, 2H), 4.04 (t, J = 6.1 Hz, 2H), 3.85 (t, J = 6.4 Hz, 2H), 3.54 (t, J = 6.4 Hz, 2H), 3.19 (t, J = 7.3 Hz, 2H), 2.96 (q, J = 7.5 Hz, 2H), 1.91-1.76 (m, 4H), 1.68-1.62 (m, 2H), 1.44 (t, J = 7.7 Hz, 3H). LCMS (ESI) m.
实施例11Example 11
Figure PCTCN2015077043-appb-000073
Figure PCTCN2015077043-appb-000073
实施例11AExample 11A
5-(4-甲氧基苯基)-1H-四氮唑5-(4-methoxyphenyl)-1H-tetrazole
Figure PCTCN2015077043-appb-000074
Figure PCTCN2015077043-appb-000074
向4-甲氧基苯氰(6克，450毫摩尔)的N,N-二甲基甲酰胺(60毫升)溶液中加入叠氮钠(3.2克，496毫摩尔)和NH4Cl(600毫克，11.2毫摩尔)。将该混合溶液在110℃下加热24小时，冷却到室温后加水，用二氯甲烷萃取，水相加入1摩尔每升盐酸调节pH到～8，将水相过滤得到固体即为标题化合物(白色固体，7克，收率88％)。1H-NMR(CDCl3,400MHz)δ7.96(d,J＝8.8Hz,2H)7.13(d,J＝8.8Hz,2H)3.90(s,3H)。LCMS(ESI)m/z:177(M+1)。Add sodium azide (3.2 g, 496 mmol) and NH 4 Cl (600 mg) to a solution of 4-methoxyphenyl cyanide (6 g, 450 mmol) in N,N-dimethylformamide (60 mL) Mg, 11.2 mmol). The mixed solution was heated at 110 ° C for 24 hours, cooled to room temperature, then added with water, extracted with dichloromethane, the aqueous phase was added with 1 mole of hydrochloric acid to adjust the pH to ~8, and the aqueous phase was filtered to give the title compound (white) Solid, 7 g, yield 88%). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.96 (d, J = 8.8 Hz, 2H) 7.13 (d, J = 8.8 Hz, 2H) 3.90 (s, 3H). LCMS (ESI) m/z:
实施例11BExample 11B
2-乙基-5-(4-甲氧基苯基)-2H-四氮唑2-ethyl-5-(4-methoxyphenyl)-2H-tetrazole
Figure PCTCN2015077043-appb-000075
Figure PCTCN2015077043-appb-000075
0℃下，向实施例11A(3克，17.07毫摩尔)的乙腈(30毫升)溶液中加入碳酸钾(4.71克，34.06毫摩尔)和碘乙烷(2.92克，18.73毫摩尔)。加完后将该混合溶液在100℃下加热5小时。反应液冷却至室温后减压浓缩，柱层析纯化(石油醚：乙酸乙酯＝10：1)得到标题化合物(白色固体，2.1克，收率60％)。1H-NMR(CDCl3,400MHz)δ8.08(d,J＝8.5Hz,2H)7.00(d,J＝8.5Hz,2H)4.68(q,J＝7.2Hz,2H)3.87(s,3H)1.68(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:205(M+1)。 Potassium carbonate (4.71 g, 34.06 mmol) and ethyl iodide (2.92 g, 18.73 mmol) were added to a solution of Example 11A (3 g, 17.07 mmol) in acetonitrile (30 mL). After the addition was completed, the mixed solution was heated at 100 ° C for 5 hours. The reaction mixture was cooled to EtOAc EtOAc m. 1 H-NMR (CDCl 3 , 400 MHz) δ 8.08 (d, J = 8.5 Hz, 2H) 7.00 (d, J = 8.5 Hz, 2H) 4.68 (q, J = 7.2 Hz, 2H) 3.87 (s, 3H) ) 1.68 (t, J = 7.5 Hz, 3H). LCMS (ESI) m/z:
实施例11CExample 11C
4-(2-乙基-2H-四氮唑-5-基)苯酚4-(2-ethyl-2H-tetrazol-5-yl)phenol
Figure PCTCN2015077043-appb-000076
Figure PCTCN2015077043-appb-000076
向实施例11B(1克，450毫摩尔)中加入10毫升溴化氢乙酸溶液。将该混合溶液在110℃下加热24小时，冷却后将反应液加入冰水中，将水相过滤得到固体即为标题化合物(白色固体，0.7克，收率75.2％)。1H-NMR(CDCl3,400MHz)δ8.08(d,J＝8.5Hz,2H),7.00(d,J＝8.5Hz,2H),4.68(q,J＝7.2Hz,2H),3.87(s,2H),1.68(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:191(M+1)。To Example 11B (1 g, 450 mmol) was added 10 mL of a solution of hydrogen bromide. The mixed solution was heated at 110 ° C for 24 hours. After cooling, the reaction mixture was evaporated. 1 H-NMR (CDCl 3 , 400 MHz) δ 8.08 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 4.68 (q, J = 7.2 Hz, 2H), 3.87 ( s, 2H), 1.68 (t, J = 7.5 Hz, 3H). LCMS (ESI) m.
实施例11DExample 11D
5-(4-((5-溴代戊基)氧基)苯基)-2-乙基-2H-四氮唑5-(4-((5-bromopentyl)oxy)phenyl)-2-ethyl-2H-tetrazole
Figure PCTCN2015077043-appb-000077
Figure PCTCN2015077043-appb-000077
向实施例11C(0.3克，1.58毫摩尔)的丙酮(5毫升)溶液中加入碳酸钾(0.653克，4.73毫摩尔)和1，5-二溴戊烷(1.09克，4.73毫摩尔)。混合溶液在80℃下搅拌12小时后，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤蒸发后残余物用柱层层析纯化(石油醚:乙酸乙酯＝10:1)得到标题化合物(白色固体，0.3克，收率56％)。1H-NMR(CDCl3,400MHz)δ8.08(d,J＝8.8Hz,2H),7.01(d,J＝8.8Hz,2H),4.70(q,J＝7.4Hz,2H),4.05(t,J＝6.4Hz,2H),3.44-3.52(m,2H),1.93-2.03(m,2H),1.83-1.91(m,2H),1.64-1.73(m,5H),LCMS(ESI)m/z:340(M+1)。To a solution of Example 11C (0.3 g, 1.58 mmol) in EtOAc (5 <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; After the mixture was stirred at 80 ° C for 12 hours, it was extracted with EtOAc. EtOAc (EtOAc) The title compound (white solid, 0.3 g, yield 56%). 1 H-NMR (CDCl 3 , 400 MHz) δ 8.08 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 4.70 (q, J = 7.4 Hz, 2H), 4.05 ( t, J=6.4 Hz, 2H), 3.44-3.52 (m, 2H), 1.93-2.03 (m, 2H), 1.83-1.91 (m, 2H), 1.64-1.73 (m, 5H), LCMS (ESI) m/z: 340 (M+1).
实施例11EExample 11E
2-(5-(4-(2-乙基-2H-四唑-5-基)苯氧基)戊基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(5-(4-(2-ethyl-2H-tetrazol-5-yl)phenoxy)pentyl)-5-(pyridin-4-yl)-1,2,5-thiadiazole Alkane-1,1-dioxide
Figure PCTCN2015077043-appb-000078
Figure PCTCN2015077043-appb-000078
0℃下，向实施例4F(30毫克，0.15毫摩尔)的N,N-二甲基甲酰胺(2毫升)溶液中加入氢化钠(7毫克，0.17毫摩尔，60％含量)。0℃下反应30分钟后，向上述混合溶液中加入实施例11D(51毫克，0.15毫摩尔)的N,N-二甲基甲酰胺(1毫升)溶液。15℃下搅拌反应6小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发得到标题化合物(白色固体，5毫克，收率7.26％)。1H-NMR(400MHz,CDCl3):δ8.51(d,J＝6.5Hz,2H),8.06(d,J＝8.5Hz,2H),7.05(d,J＝6.0Hz,2H),6.99(d,J＝9.0Hz,2H),4.68(q,J＝7.5Hz,2H),4.04(t,J＝6.0Hz,2H),3.85(t,J＝6.3Hz,2H),3.55(t,J＝6.3Hz,2H),3.19(t,J＝7.3Hz,2H),1.85-1.93(m,2H),1.75-1.82(m,2H),1.68(t,J＝7.5Hz,5H)。LCMS(ESI)m/z:458(M+1)。Sodium hydride (7 mg, 0.17 mmol, 60% content) was added to a solution of EtOAc (EtOAc, m. After reacting for 30 minutes at 0 ° C, a solution of Example 11D (51 mg, 0.15 mmol) of N,N-dimethylformamide (1 ml) was added to the mixture. After stirring the reaction at 15 ° C for 6 hours, the reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried with EtOAc EtOAcjjjjjj 1 H-NMR (400MHz, CDCl 3): δ8.51 (d, J = 6.5Hz, 2H), 8.06 (d, J = 8.5Hz, 2H), 7.05 (d, J = 6.0Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 4.68 (q, J = 7.5 Hz, 2H), 4.04 (t, J = 6.0 Hz, 2H), 3.85 (t, J = 6.3 Hz, 2H), 3.55 (t , J = 6.3 Hz, 2H), 3.19 (t, J = 7.3 Hz, 2H), 1.85-1.93 (m, 2H), 1.75-1.82 (m, 2H), 1.68 (t, J = 7.5 Hz, 5H) . LCMS (ESI) m.
实施例12 Example 12
Figure PCTCN2015077043-appb-000079
Figure PCTCN2015077043-appb-000079
实施例12AExample 12A
N,2-二羟基-4-甲氧基苯甲酰胺N,2-dihydroxy-4-methoxybenzamide
Figure PCTCN2015077043-appb-000080
Figure PCTCN2015077043-appb-000080
在磁力搅拌下，向羟胺盐酸盐(53克，766毫摩尔)的水溶液(500毫升)中缓慢滴加氢氧化钠(71克，1.78摩尔)的水溶液(250毫升)。氮气保护下，立刻将4-甲氧基水杨酸甲酯(93克，510毫摩尔)的二氧六环(250毫升)溶液缓慢的滴加到上述的溶液中，反应12小时。待反应结束后，将反应液缓慢的加入冰水中然后滴加浓盐酸至pH＝2，过滤得到标题化合物(84克，产率90％)。1H-NMR(400MHz,MeOD)δ7.57(d,J＝9.04Hz,1H),6.41-6.54(m,2H),3.75-3.87(m,3H)。LCMS(ESI)m/z:184(M+1)。Under a magnetic stirring, an aqueous solution (250 ml) of sodium hydroxide (71 g, 1.78 mol) was slowly added dropwise to an aqueous solution (500 ml) of hydroxylamine hydrochloride (53 g, 766 mmol). A solution of methyl 4-methoxysalicylate (93 g, 510 mmol) in dioxane (250 ml) was slowly added dropwise to the above solution under nitrogen atmosphere for 12 hours. After the reaction was completed, the reaction mixture was slowly added to ice water, and then concentrated hydrochloric acid was added dropwise to pH = 2, and the title compound (84 g, yield 90%) was obtained. 1 H-NMR (400 MHz, MeOD) δ 7.57 (d, J = 9.04 Hz, 1H), 6.41-6.54 (m, 2H), 3.75 - 3.87 (m, 3H). LCMS (ESI) m/z:
实施例12BExample 12B
6-甲氧基苯并[d]异噁唑-3(2H)-酮6-methoxybenzo[d]isoxazole-3(2H)-one
Figure PCTCN2015077043-appb-000081
Figure PCTCN2015077043-appb-000081
向羰基二咪唑(50克，031摩尔)的无水四氢呋喃(600毫升)溶液中滴加实施例12A(40克，0.22摩尔)，滴加完毕后，加热回流8小时。待反应完毕后，将反应液旋干，加入400毫升水，用柠檬酸调节pH＝6，过滤得到标题化合物(23克，产率63％)。1H-NMR(400MHz,MeOD)δ7.57(d,J＝8.53Hz,1H),6.97(d,J＝1.51Hz,1H),6.91(dd,J＝1.76,8.78Hz,1H),3.84-3.93(m,3H)。LCMS(ESI)m/z:166(M+1)。To a solution of carbonyldiimidazole (50 g, 031 mol) in anhydrous tetrahydrofuran (600 ml), mp. After the reaction was completed, the reaction mixture was evaporated to dryness. 1 H-NMR (400 MHz, MeOD) δ 7.57 (d, J = 8.53 Hz, 1H), 6.97 (d, J = 1.51 Hz, 1H), 6.91 (dd, J = 1.76, 8.78 Hz, 1H), 3.84 -3.93 (m, 3H). LCMS (ESI) m/z: 166
实施例12CExample 12C
3-乙氧基-6-甲氧基苯并[d]异噁唑3-ethoxy-6-methoxybenzo[d]isoxazole
Figure PCTCN2015077043-appb-000082
Figure PCTCN2015077043-appb-000082
在冰浴下，向实施例12B(10克，60毫摩尔)的无水四氢呋喃(200毫升)溶液中依次加入无水乙醇(3.5克，76毫摩尔)和三苯基膦(24克，90毫摩尔)。然后将DIAD(18毫升，90毫摩尔)缓慢的加入到上述溶液中，0℃下搅拌反应15分钟后，缓慢升至室温搅拌过夜，待反应结束后加入水(200毫升)淬灭，水层用乙酸乙酯(200毫升×2)萃取，将合并的有机层，用水和盐水依次洗涤，无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶柱色谱纯化得到标题化合物(5.6克，产率48％)。LCMS(ESI)m/z:194(M+1)。An absolute ethanol (3.5 g, 76 mmol) and triphenylphosphine (24 g, 90) were added sequentially to a solution of EtOAc (EtOAc m. Millimoles). Then DIAD (18 ml, 90 mmol) was slowly added to the above solution, and the reaction was stirred at 0 ° C for 15 minutes, then slowly warmed to room temperature and stirred overnight. After completion of the reaction, water (200 ml) was added to quench, water layer The mixture was extracted with EtOAc (EtOAc (EtOAc). 48%). LCMS (ESI) m/z:
实施例12DExample 12D
3-乙氧基苯并[d]异噁唑-6-醇 3-ethoxybenzo[d]isoxazole-6-ol
Figure PCTCN2015077043-appb-000083
Figure PCTCN2015077043-appb-000083
在氮气保护下，-78℃下，向实施例12C(810毫克，4.2毫摩尔)的二氯甲烷(10毫升)溶液中缓慢的滴加三溴化硼(4.2克，16.8毫摩尔)。待滴加完毕后，将反应液缓慢的升至室温并搅拌过夜。反应结束后，将反应液慢慢的滴加到冰水(100毫升)中淬灭，水层用乙酸乙酯(100毫升×2)萃取，将合并的有机层，用水、盐水洗涤，无水硫酸钠干燥，过滤并蒸发得到标题化合物化合物(650毫克，产率86.7％)。1H-NMR(CDCl3,400MHz)δ7.48(d,J＝8.53Hz,1H),6.90-7.08(m,2H),6.85(d,J＝8.03Hz,1H),4.47(q,J＝7.03Hz,2H),1.51(t,J＝7.03Hz,3H)。Boron tribromide (4.2 g, 16.8 mmol) was slowly added dropwise to a solution of Example 12C (810 mg, 4.2 mmol) in dichloromethane (10 mL). After the dropwise addition was completed, the reaction solution was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the reaction mixture was applied to EtOAc (EtOAc m. Dry over sodium sulfate, filtered and evaporated tolululu 1 H-NMR (CDCl 3 , 400 MHz) δ 7.48 (d, J = 8.53 Hz, 1H), 6.90-7.08 (m, 2H), 6.85 (d, J = 8.03 Hz, 1H), 4.47 (q, J) = 7.03 Hz, 2H), 1.51 (t, J = 7.03 Hz, 3H).
实施例12EExample 12E
6-((5-溴代戊基)氧基)-3-乙氧基并[d]异噁唑6-((5-bromopentyl)oxy)-3-ethoxy[d]isoxazole
Figure PCTCN2015077043-appb-000084
Figure PCTCN2015077043-appb-000084
0℃氮气保护下，向实施例12D(0.2克，1.12毫摩尔)的N,N-二甲基甲酰胺(20毫升)溶液中分批加入氢化钠(54毫克，1.34毫摩尔，60％含量)，加完后将该混合溶液在室温下搅拌1小时，然后将1，5-二溴戊烷(770毫克，2.33毫摩尔)的N,N-二甲基甲酰胺(10毫升)溶液加入到上述溶液中，继续在室温下搅拌反应10小时。将反应液倒入水中(100毫升)，水相用乙酸乙酯萃取(50毫升×3)，合并的有机相用无水硫酸钠干燥，过滤浓缩后得到标题化合物(黄色液体，0.2克，收率54.6％)。LCMS(ESI)m/z:328(M+1)。Sodium hydride (54 mg, 1.34 mmol, 60%) was added portionwise to a solution of EtOAc (EtOAc m. After the addition was completed, the mixed solution was stirred at room temperature for 1 hour, and then a solution of 1,5-dibromopentane (770 mg, 2.33 mmol) in N,N-dimethylformamide (10 ml) was added. Into the above solution, the reaction was further stirred at room temperature for 10 hours. The reaction mixture was poured into water (100 ml), EtOAc (EtOAc m. The rate is 54.6%). LCMS (ESI) m/z:
实施例12FExample 12F
2-(5-((3-乙氧基苯并[d]异噁唑-6-基)氧基)戊基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(5-((3-ethoxybenzo[d]isoxazole-6-yl)oxy)pentyl)-5-(pyridin-4-yl)-1,2,5-thiadi Azolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000085
Figure PCTCN2015077043-appb-000085
0℃氮气保护下，向实施例4F(60毫克，0.3毫摩尔)的N,N-二甲基甲酰胺(3毫升)溶液中加入钠氢(24毫克，0.6毫摩尔，60％含量)。在0℃下搅拌0.5小时后，逐滴加入实施例12E(100毫克，0.3毫摩尔)的N,N-二甲基甲酰胺溶液(1毫升)。反应混合物在0℃下搅拌1.5小时。反应混合物用饱和NH4Cl水溶液(5毫升)淬灭，用水稀释(50毫升)后，用乙酸乙酯萃取(15毫升×4)。合并的有机相后用饱和食盐水洗涤，无水硫酸钠干燥后过滤并旋干，残余物通过制备色谱纯化得到标题化合物(白色固体，60毫克，收率45％)。1H-NMR(400MHz,CDCl3)δ8.53(br.s.,1H),7.47(d,J＝8.5Hz,1H),7.27(s,1H),7.07(br.s.,2H),6.78-6.89(m,2H),4.46(q,J＝7.0Hz,2H),4.03(t,J＝6.2Hz,2H),3.85(t,J＝6.2Hz,2H),3.55(t,J＝6.27Hz,2H),3.19(t,J＝7.28Hz,2H),1.85-1.94(m,2H),1.80(q,J＝7.4Hz,2H),1.64-1.68(m,2H),1.50(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:447(M+1)。 Sodium hydrogen (24 mg, 0.6 mmol, 60% content) was added to a solution of Example 4F (60 mg, 0.3 mmol) of N,N-dimethylformamide (3 ml). After stirring at 0&lt;0&gt;C for 0.5 h, a solution <RTI ID=0.0></RTI></RTI><RTIgt; The reaction mixture was stirred at 0 ° C for 1.5 hours. The reaction mixture was washed with saturated aqueous NH 4 Cl (5 mL) was quenched, diluted with water (50 mL), extracted with ethyl acetate (15 mL × 4). The combined organics were washed with EtOAc EtOAc m. 1 H-NMR (400 MHz, CDCl 3 ) δ 8.53 (br.s., 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.27 (s, 1H), 7.07 (br.s., 2H) , 6.78-6.89 (m, 2H), 4.46 (q, J = 7.0 Hz, 2H), 4.03 (t, J = 6.2 Hz, 2H), 3.85 (t, J = 6.2 Hz, 2H), 3.55 (t, J = 6.27 Hz, 2H), 3.19 (t, J = 7.28 Hz, 2H), 1.85-1.94 (m, 2H), 1.80 (q, J = 7.4 Hz, 2H), 1.64-1.68 (m, 2H), 1.50 (t, J = 7.0 Hz, 3H). LCMS (ESI) m.
路线CRoute C
Figure PCTCN2015077043-appb-000086
Figure PCTCN2015077043-appb-000086
实施例13Example 13
2-(2-(2-((4'-氯-[1,1'-联苯]-4-基)氧基)乙氧基)乙基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-(2-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)ethoxy)ethyl)-5-(pyridin-4-yl)- 1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000087
Figure PCTCN2015077043-appb-000087
实施例13AExample 13A
4-(2-(2-溴乙氧基)乙氧基)-4'-氯-1,1'-联苯4-(2-(2-bromoethoxy)ethoxy)-4'-chloro-1,1'-biphenyl
Figure PCTCN2015077043-appb-000088
Figure PCTCN2015077043-appb-000088
向实施例6A(1克，4.89毫摩尔)，碳酸钾(1.35克，9.77毫摩尔)和碘化钾(810毫克，4.89毫摩尔)的丙酮(15毫升)混合物中加入1-溴-2-(2-溴乙氧基)乙烷(3.4克，14.66毫摩尔)。将混合物在70℃下搅拌3小时后旋干，向体系中加20毫升石油醚，过滤即得到标题化合物(1.5克，收率86％)。1H-NMR(CDCl3,400MHz)7.47(dd，J＝8.5,4.0Hz,4H),7.34-7.41(m,2H),6.99(d,J＝8.5Hz,2H),4.16-4.22(m,2H),3.85-3.96(m,4H),3.51(t,J＝6.3Hz,2H)。To a mixture of Example 6A (1 g, 4.89 mmol), potassium carbonate (1.35 g, 9.77 mmol) and potassium iodide (810 mg, 4.89 mmol) in acetone (15 mL) -Bromoethoxy)ethane (3.4 g, 14.66 mmol). After the mixture was stirred at 70 ° C for 3 hours, it was evaporated to dryness. 1 H-NMR (CDCl 3, 400 MHz) 7.47 (dd, J = 8.5, 4.0 Hz, 4H), 7.34 - 7.41 (m, 2H), 6.99 (d, J = 8.5 Hz, 2H), 4.16 - 4.22 (m) , 2H), 3.85-3.96 (m, 4H), 3.51 (t, J = 6.3 Hz, 2H).
实施例13BExample 13B
2-(2-(2-((4'-氯-[1,1'-联苯]-4-基)氧基)乙氧基)乙基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-(2-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)ethoxy)ethyl)-5-(pyridin-4-yl)- 1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000089
Figure PCTCN2015077043-appb-000089
本实施例制备方法参照实施例12F。1H-NMR(CDCl3,400MHz)8.48(d，J＝6.0Hz,2H),7.45-7.51(m,4H),7.36-7.41(m,2H),7.02(d,J＝6.3Hz,2H),6.98(d,J＝8.8Hz,2H),4.16-4.20(m,2H),3.88(q,J＝4.9Hz,4H),3.76(dd,J＝11.9,5.1Hz,4H),3.40(t,J＝4.9Hz,2H)。LCMS(ESI)m/z:474(M+1)。The preparation method of this example is referred to Example 12F. 1 H-NMR (CDCl 3, 400 MHz) 8.48 (d, J = 6.0 Hz, 2H), 7.45-7.51 (m, 4H), 7.36-7.41 (m, 2H), 7.02 (d, J = 6.3 Hz, 2H) ), 6.98 (d, J = 8.8 Hz, 2H), 4.16 - 4.20 (m, 2H), 3.88 (q, J = 4.9 Hz, 4H), 3.76 (dd, J = 11.9, 5.1 Hz, 4H), 3.40 (t, J = 4.9 Hz, 2H). LCMS (ESI) m/z:
路线D Route D
Figure PCTCN2015077043-appb-000090
Figure PCTCN2015077043-appb-000090
实施例14Example 14
(E)-4-((5-(1,1-二氧代-5-(吡啶-4-基)-1,2,5-噻二唑烷-2-基)-3-甲基戊基)氧基)苯甲醛-氧-乙基肟(E)-4-((5-(1,1-dioxo-5-(pyridin-4-yl)-1,2,5-thiadiazol-2-yl)-3-methylpentyl Benzyloxy-benzaldehyde-oxy-ethyl hydrazine
Figure PCTCN2015077043-appb-000091
Figure PCTCN2015077043-appb-000091
实施例14AExample 14A
3-甲基戊烷-1,5-二基双(4-甲基苯磺酰基)3-methylpentane-1,5-diylbis(4-methylphenylsulfonyl)
Figure PCTCN2015077043-appb-000092
Figure PCTCN2015077043-appb-000092
向3-甲基-1,5戊二醇(40克，338.5毫摩尔)的二氯甲烷(400毫升)溶液中加入三乙胺(160毫升)和对甲苯磺酰氯(258.1克,1.35摩尔)。混合溶液在20℃下搅拌12小时后，用乙酸乙酯萃取，合并的有机相用无水硫酸钠干燥，过滤蒸发后残余物用柱层层析纯化(石油醚:乙酸乙酯＝20:1)得到标题化合物(无色液体，80克,收率55％)。1H-NMR(CDCl3,400MHz)δ7.78(d,J＝8.0Hz,4H),7.37(d,J＝8.0Hz,4H),4.01(q,J＝6.0Hz,4H),2.46(s,6H)1.57-1.69(m,3H)1.43(dq,J＝13.4,6.7Hz,2H),0.78(d,J＝6.3Hz,3H)。LCMS(ESI)m/z:299(M+1)。To a solution of 3-methyl-1,5-pentanediol (40 g, 338.5 mmol) in dichloromethane <RTI ID=0.0>(</RTI><RTIgt; . After the mixture was stirred at 20 ° C for 12 hours, it was extracted with EtOAc. EtOAc EtOAc. The title compound (colorless liquid, 80 g, yield 55%) was obtained. 1 H-NMR (CDCl 3 , 400 MHz) δ 7.78 (d, J = 8.0 Hz, 4H), 7.37 (d, J = 8.0 Hz, 4H), 4.01 (q, J = 6.0 Hz, 4H), 2.46 ( s, 6H) 1.57-1.69 (m, 3H) 1.43 (dq, J = 13.4, 6.7 Hz, 2H), 0.78 (d, J = 6.3 Hz, 3H). LCMS (ESI) m/z: 299:
实施例14BExample 14B
(E)-5-(4-((乙氧基亚氨基)甲基)苯氧基)-3-甲基戊基-4-甲基苯磺酰(E)-5-(4-((ethoxyimino)methyl)phenoxy)-3-methylpentyl-4-methylbenzenesulfonyl
Figure PCTCN2015077043-appb-000093
Figure PCTCN2015077043-appb-000093
实施例7A(4.98克，30.17毫摩尔)，实施例14A(11.7克，27.43毫摩尔)，碳酸钾(7.58克，54.86毫摩尔)和乙腈(110毫升)的混合物在80℃下反应16小时。乙酸乙酯(50毫升)和水(50毫升)加入反应体系，水层用乙酸乙酯(100毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物(无色固体，3.7克，产率32％)。1H-NMR(CDCl3,400MHz)8.03(s,1H),7.46(d,J＝8.5Hz,2H),6.78-6.85(m,2H),4.20(q,J＝7.0Hz,2H),1.31(t,J＝7.0Hz,3H)。A mixture of Example 7A (4.98 g, 30.17 mmol), Example 14A (11.7 g, 27.43 mmol), EtOAc (EtOAc) Ethyl acetate (50 ml) and water (50 ml) were evaporated. EtOAc (EtOAc) Purification gave the title compound (EtOAc m. 1 H-NMR (CDCl 3 , 400 MHz) 8.03 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 6.78-6.85 (m, 2H), 4.20 (q, J = 7.0 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H).
实施例14CExample 14C
(E)-4-((5-(1,1-二氧代-5-(吡啶-4-基)-1,2,5-噻二唑烷-2-基)-3-甲基戊基)氧基)苯甲醛-氧-乙基肟(E)-4-((5-(1,1-dioxo-5-(pyridin-4-yl)-1,2,5-thiadiazol-2-yl)-3-methylpentyl Benzyloxy-benzaldehyde-oxy-ethyl hydrazine
Figure PCTCN2015077043-appb-000094
Figure PCTCN2015077043-appb-000094
本实施例的制备方法参照实施例12F。1H-NMR(CDCl3,400MHz)δ8.51(d,J＝5.5Hz,2H),8.02(s,1H), 7.50(d,J＝8.5Hz,2H),7.04(d,J＝6.0Hz,2H),6.87(d,J＝8.5Hz,2H),4.17-4.24(m,2H),3.98-4.07(m,2H),3.82(t,J＝6.5Hz,2H),3.48-3.55(m,2H),3.20(t,J＝7.5Hz,2H),1.79-1.93(m,3H),1.66-1.73(m,1H),1.56-1.61(m,1H),1.31(t,J＝7.0Hz,3H),1.03(d,J＝6.5Hz,3H)。LCMS(ESI)m/z:447(M+1)。The preparation method of this example is referred to Example 12F. 1 H-NMR (CDCl 3 , 400 MHz) δ 8.51 (d, J = 5.5 Hz, 2H), 8.02 (s, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 6.0) Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 4.17-4.24 (m, 2H), 3.98-4.07 (m, 2H), 3.82 (t, J = 6.5 Hz, 2H), 3.48-3.55 (m, 2H), 3.20 (t, J = 7.5 Hz, 2H), 1.79-1.93 (m, 3H), 1.66-1.73 (m, 1H), 1.56-1.61 (m, 1H), 1.31 (t, J =7.0 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H). LCMS (ESI) m.
实施例15Example 15
2-(5-((3-乙氧基苯并[d]异恶唑-6-基)氧基)-3-甲基戊基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(5-((3-ethoxybenzo[d]isoxazole-6-yl)oxy)-3-methylpentyl)-5-(pyridin-4-yl)-1,2 , 5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000095
Figure PCTCN2015077043-appb-000095
实施例15AExample 15A
5-((3-乙氧基苯并[d]异恶唑-6-基)氧基)-3-甲基戊基4-甲基苯磺酸酯5-((3-ethoxybenzo[d]isoxazole-6-yl)oxy)-3-methylpentyl 4-methylbenzenesulfonate
Figure PCTCN2015077043-appb-000096
Figure PCTCN2015077043-appb-000096
向实施例12D(0.3克，1.67毫摩尔)的N,N-二甲基甲酰胺(5毫升)溶液中加入碳酸钾(0.69克，5.0毫摩尔)和实施例14A(2.14克，5.0毫摩尔)。混合溶液在80℃下搅拌12小时后，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤蒸发后残余物用柱层层析纯化(石油醚：乙酸乙酯＝10：1)得到标题化合物(白色固体，0.3克，收率41.3％)。1H-NMR(CDCl3,400MHz)δ7.79(d,J＝8.0Hz,2H)7.46(d,J＝8.5Hz,1H)7.33(d,J＝8.0Hz,2H)6.78-6.84(m,2H)4.47(q,J＝7.0Hz,2H)4.07-4.15(m,2H)3.93-4.01(m,2H)2.43(s,3H)1.74-1.89(m,3H)1.60-1.66(m,1H)1.54-1.58(m,1H)1.51(t,J＝7.0Hz,3H)0.92(d,J＝6.5Hz,3H).LCMS(ESI)m/z:434(M+1)。Potassium carbonate (0.69 g, 5.0 mmol) and Example 14A (2.14 g, 5.0 mmol) were added to a solution of EtOAc (EtOAc, m. ). After the mixture was stirred at 80 ° C for 12 hours, it was extracted with EtOAc. EtOAc (EtOAc) The title compound (white solid, 0.3 g, yield 41.3%). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.79 (d, J = 8.0 Hz, 2H) 7.46 (d, J = 8.5 Hz, 1H) 7.33 (d, J = 8.0 Hz, 2H) 6.78-6.84 (m , 2H) 4.47 (q, J = 7.0 Hz, 2H) 4.07 - 4.15 (m, 2H) 3.93-4.01 (m, 2H) 2.43 (s, 3H) 1.74-1.89 (m, 3H) 1.60-1.66 (m, 1H) 1.54-1.58 (m, 1H) 1.51 (t, J = 7.0 Hz, 3H) 0.92 (d, J = 6.5 Hz, 3H). LCMS (ESI) m/z: 434 (M+1).
实施例15BExample 15B
2-(5-((3-乙氧基苯并[d]异恶唑-6-基)氧基)-3-甲基戊基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(5-((3-ethoxybenzo[d]isoxazole-6-yl)oxy)-3-methylpentyl)-5-(pyridin-4-yl)-1,2 , 5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000097
Figure PCTCN2015077043-appb-000097
0℃下，向实施例4F(30毫克，0.15毫摩尔)的N,N-二甲基甲酰胺(2毫升)溶液中加入氢化钠(6.62毫克,0.165毫摩尔)。0℃下搅拌30分钟后,向上述混合溶液中加入实施例15A(65毫克，0.15毫摩尔)的N,N-二甲基甲酰胺(1毫升)溶液。15℃下搅拌反应6小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发得到标题化合物(白色固体，18毫克，收率25.8％)。1H-NMR(400MHz,CDCl3)δ8.53(d,J＝6.0Hz,2H)7.46-7.51(m,1H)7.06(d,J＝6.3Hz,2H)6.86(dd,J＝4.3,2.5Hz,2H)4.48(q,J＝7.0Hz,2H)4.08(q,J＝5.7Hz,2H)3.86(t,J＝6.4Hz,2H)3.50-3.60(m,2H)3.24(t,J＝7.4Hz,2H)1.88-1.99(m,2H)1.77-1.87(m,1H)1.61-1.75(m,3H)1.52(t,J＝7.2Hz,3H)1.07(d,J＝6.3Hz,3H)。LCMS(ESI)m/z:461(M+1)。Sodium hydride (6.62 mg, 0.165 mmol) was added to a solution of EtOAc (EtOAc m. After stirring at 0 ° C for 30 minutes, a solution of Example 15A (65 mg, 0.15 mmol) of N, N-dimethylformamide (1 ml) was added to the mixture. After stirring the reaction at 15 ° C for 6 hours, the reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried with EtOAc EtOAcjjjjjj 1 H-NMR (400 MHz, CDCl 3 ) δ 8.53 (d, J = 6.0 Hz, 2H) 7.46-7.51 (m, 1H) 7.06 (d, J = 6.3 Hz, 2H) 6.86 (dd, J = 4.3, 2.5 Hz, 2H) 4.48 (q, J = 7.0 Hz, 2H) 4.08 (q, J = 5.7 Hz, 2H) 3.86 (t, J = 6.4 Hz, 2H) 3.50 - 3.60 (m, 2H) 3.24 (t, J = 7.4 Hz, 2H) 1.88-1.99 (m, 2H) 1.77-1.87 (m, 1H) 1.61-1.75 (m, 3H) 1.52 (t, J = 7.2 Hz, 3H) 1.07 (d, J = 6.3 Hz) , 3H). LCMS (ESI) m/z:
路线E Route E
Figure PCTCN2015077043-appb-000098
Figure PCTCN2015077043-appb-000098
实施例16Example 16
2-(2-氨基吡啶-4-基)-5-(5-((4'-氯-[1,1'-联苯]-4-基)氧基)戊基)-1,2,5-噻二唑烷1烷-1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(5-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)pentyl)-1,2, 5-thiadiazolidine 1-alkane-1,1-dioxide
Figure PCTCN2015077043-appb-000099
Figure PCTCN2015077043-appb-000099
实施例16AExample 16A
2-(5-((4'-氯-[1,1'-联苯]-4-基)氧基)戊基)-5-(2-氯吡啶-4-基)-1,2,5-噻二唑烷1烷-1,1-二氧化物2-(5-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)pentyl)-5-(2-chloropyridin-4-yl)-1,2, 5-thiadiazolidine 1-alkane-1,1-dioxide
Figure PCTCN2015077043-appb-000100
Figure PCTCN2015077043-appb-000100
在0℃，氮气保护下向实施例4E(200毫克，0.86毫摩尔)的N,N-二甲基甲酰胺(3毫升)溶液中分批加入NaH(68毫克，1.72毫摩尔，60％含量)。反应液在室温下搅拌0.5小时后，加入实施例6B(303毫克，0.86毫摩尔)的N,N-二甲基甲酰胺(5毫升)溶液，在室温下搅拌8小时。加水淬灭反应后，用乙酸乙酯(50毫升×3)萃取，合并有机层用硫酸钠干燥，过滤并蒸发，残余物以薄层层析板分离纯化得到标题化合物(80毫克，收率22％)。1H-NMR(CDCl3,400MHz)8.29(d，J＝5.8Hz,1H),7.48-7.52(m,4H),7.38-7.42(m,2H),7.09(dd,J＝5.8,2.3Hz,1H),7.01(d,J＝2.0Hz,1H),6.98(d,J＝8.8Hz,2H),4.05(t,J＝6.3Hz,2H),3.86(t,J＝6.4Hz,2H),3.58(t,J＝6.4Hz,2H),3.21(t,J＝7.2Hz,2H),1.76-1.95(m,4H),1.63-1.70(m,2H)。LCMS(ESI)m/z:506(M+1)。NaH (68 mg, 1.72 mmol, 60% content) was added portionwise to a solution of Example 4E (200 mg, 0.86 mmol) of N,N-dimethylformamide (3 ml). ). After the reaction mixture was stirred at room temperature for 0.5 hr, a solution of EtOAc (EtOAc, EtOAc. After quenching with water, EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ %). 1 H-NMR (CDCl 3 , 400 MHz) 8.29 (d, J = 5.8 Hz, 1H), 7.48-7.52 (m, 4H), 7.38-7.42 (m, 2H), 7.09 (dd, J = 5.8, 2.3 Hz) , 1H), 7.01 (d, J = 2.0 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 4.05 (t, J = 6.3 Hz, 2H), 3.86 (t, J = 6.4 Hz, 2H) ), 3.58 (t, J = 6.4 Hz, 2H), 3.21 (t, J = 7.2 Hz, 2H), 1.76-1.95 (m, 4H), 1.63-1.70 (m, 2H). LCMS (ESI) m/z:
实施例16BExample 16B
2-(2-氨基吡啶-4-基)-5-(5-((4'-氯-[1,1'-联苯]-4-基)氧基)戊基)-1,2,5-噻二唑烷1烷-1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(5-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)pentyl)-1,2, 5-thiadiazolidine 1-alkane-1,1-dioxide
Figure PCTCN2015077043-appb-000101
Figure PCTCN2015077043-appb-000101
在氮气保护下向实施例16A(80毫克，0.16毫摩尔)，氨基甲酸叔丁酯(74毫克，0.63毫摩尔)和碳酸铯(103毫克，0.32毫摩尔)的二氧六环/N,N-二甲基甲酰胺(1.5毫升/0.5毫升)混合溶液中加入Pd2(dba)3(20毫克，0.03毫摩尔)和Xant-Phos(10毫克，0.03毫摩尔)，加完后将该混合溶液在110℃下搅拌16小时。真空除去溶剂后，残余物用乙酸乙酯(250毫升×3)萃取，合并有机层用硫酸钠干燥，过滤并蒸发，残余物用制备HPLC纯化后获得标题化合物(30毫克，收率31％)。1H-NMR(CDCl3,400MHz):7.80(s br，1H)，7.48(dd,J＝8.8,3.3Hz,4H),7.35-7.41(m,2H),6.96(d,J＝8.5Hz,2H),6.58(s,br,1H),6.33(s,br,1H),4.02(t,J＝6.0Hz,2H),3.87(s,br,2H),3.55(t,J＝6.3Hz,2H),3.19(t,J＝7.3Hz,2H),1.85-1.90(m,2H),1.76-1.82(m,2H),1.63(d,J＝6.5Hz,2H)。LCMS(ESI)m/z:487(M+1)。Example 16A (80 mg, 0.16 mmol), tert-butyl carbamate (74 mg, 0.63 mmol) and cesium carbonate (103 mg, 0.32 mmol) of dioxane/N, N under N2. To a mixed solution of dimethylformamide (1.5 ml / 0.5 ml), Pd 2 (dba) 3 (20 mg, 0.03 mmol) and Xant-Phos (10 mg, 0.03 mmol) were added, and the mixture was added after the addition. The solution was stirred at 110 ° C for 16 hours. After the solvent was removed in vacuo, EtOAc m. . 1 H-NMR (CDCl 3 , 400 MHz): 7.80 (s br, 1H), 7.48 (dd, J = 8.8, 3.3 Hz, 4H), 7.35-7.41 (m, 2H), 6.96 (d, J = 8.5 Hz) , 2H), 6.58 (s, br, 1H), 6.33 (s, br, 1H), 4.02 (t, J = 6.0 Hz, 2H), 3.87 (s, br, 2H), 3.55 (t, J = 6.3) Hz, 2H), 3.19 (t, J = 7.3 Hz, 2H), 1.85-1.90 (m, 2H), 1.76-1.82 (m, 2H), 1.63 (d, J = 6.5 Hz, 2H). LCMS (ESI) m/z:
路线FRoute F
Figure PCTCN2015077043-appb-000102
Figure PCTCN2015077043-appb-000102
实施例17Example 17
(E)-4-((5-(5-(2-氨基吡啶-4-基)-1,1-二氧代-1,2,5-噻二唑烷-2-基)-3-甲基戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5-(5-(2-Aminopyridin-4-yl)-1,1-dioxo-1,2,5-thiadiazol-2-yl)-3- Methylpentyl)oxy)benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000103
Figure PCTCN2015077043-appb-000103
实施例17AExample 17A
(E)-4-((5-(5-(2-氯吡啶-4-基)-1,1-二氧代-1,2,5-噻二唑烷-2-基)-3-甲基戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5-(5-(2-chloropyridin-4-yl)-1,1-dioxo-1,2,5-thiadiazol-2-yl)-3- Methylpentyl)oxy)benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000104
Figure PCTCN2015077043-appb-000104
本实施例使用实施例16A中描述的方法制备。1H-NMR(CDCl3,400MHz)：8.29(d，J＝5.5Hz,1H),8.04(s,1H),7.53(d,J＝8.8Hz,2H),7.08(dd,J＝5.8,2.0Hz,1H),7.01(s,1H),6.90(d,J＝8.5Hz,2H),4.22(q,J＝7.0Hz,2H),4.01-4.12(m,2H),3.80-3.88(m,2H),3.50-3.61(m,2H),3.23(t,J＝7.5Hz,2H),1.60-1.98(m,5H),1.34(t,J＝7.0Hz,3H),1.06(d,J＝6.5Hz,3H)。LCMS(ESI)m/z:481(M+1)。This example was prepared using the method described in Example 16A. 1 H-NMR (CDCl 3 , 400 MHz): 8.29 (d, J = 5.5 Hz, 1H), 8.04 (s, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.08 (dd, J = 5.8, 2.0 Hz, 1H), 7.01 (s, 1H), 6.90 (d, J = 8.5 Hz, 2H), 4.22 (q, J = 7.0 Hz, 2H), 4.01-4.12 (m, 2H), 3.80-3.88 ( m, 2H), 3.50-3.61 (m, 2H), 3.23 (t, J = 7.5 Hz, 2H), 1.60-1.98 (m, 5H), 1.34 (t, J = 7.0 Hz, 3H), 1.06 (d) , J = 6.5 Hz, 3H). LCMS (ESI) m/z: 481 (21.
实施例17BExample 17B
(E)-4-((5-(5-(2-氨基吡啶-4-基)-1,1-二氧代-1,2,5-噻二唑烷-2-基)-3-甲基戊基)氧基)苯甲醛-氧-乙基酮肟 (E)-4-((5-(5-(2-Aminopyridin-4-yl)-1,1-dioxo-1,2,5-thiadiazol-2-yl)-3- Methylpentyl)oxy)benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000105
Figure PCTCN2015077043-appb-000105
本实施例的制备方法参照实施例16。1H-NMR(CDCl3，400MHz)8.03(s，1H)，7.89(d，J＝5.5Hz,1H),7.51(d,J＝8.5Hz,2H),6.88(d,J＝8.5Hz,2H),6.41(d,J＝6.0Hz,1H),6.29(s,1H),4.20(q,J＝7.2Hz,2H),4.01-4.09(m,2H),3.77(t,J＝6.3Hz,2H),3.43-3.55(m,2H),3.19(t,J＝7.5Hz,2H),1.63-1.95(m,5H),1.32(t,J＝7.0Hz,3H),1.03(d,J＝6.5Hz,3H)。LCMS(ESI)m/z:462(M+1)。The preparation method of this example is referred to Example 16. 1 H-NMR (CDCl 3 , 400 MHz) 8.03 (s, 1H), 7.89 (d, J = 5.5 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 6.41 (d, J = 6.0 Hz, 1H), 6.29 (s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.01-4.09 (m, 2H), 3.77 (t, J = 6.3) Hz, 2H), 3.43 - 3.55 (m, 2H), 3.19 (t, J = 7.5 Hz, 2H), 1.63-1.95 (m, 5H), 1.32 (t, J = 7.0 Hz, 3H), 1.03 (d , J = 6.5 Hz, 3H). LCMS (ESI) m.
路线GRoute G
Figure PCTCN2015077043-appb-000106
Figure PCTCN2015077043-appb-000106
实施例18Example 18
2-(5-((3-乙氧基苯并[d]异噁唑-6-)氧代)戊基)-5-(2-(甲氨基)吡啶-4-)-1,2,5-噻二唑啉-1,1-二氧化物2-(5-((3-ethoxybenzo[d]isoxazole-6-)oxy)pentyl)-5-(2-(methylamino)pyridine-4-)-1,2, 5-thiadiazoline-1,1-dioxide
Figure PCTCN2015077043-appb-000107
Figure PCTCN2015077043-appb-000107
实施例18AExample 18A
2-(2-氯吡啶-4-)-5-(5-((3-乙氧基苯并[d]异噁唑-6-)氧代)戊基)-1,2,5-噻二唑啉-1,1-二氧化物2-(2-Chloropyridin-4-)-5-(5-((3-ethoxybenzo[d]isoxazole-6-)oxy)pentyl)-1,2,5-thia Diazoline-1,1-dioxide
Figure PCTCN2015077043-appb-000108
Figure PCTCN2015077043-appb-000108
0℃氮气保护下，向实施例4E(271毫克，1.16毫摩尔)的N,N-二甲基甲酰胺溶液中加入钠氢(93毫克，2.32毫摩尔)。在0℃下搅拌0.5小时后，逐滴加入实施例12E(400毫克，1.22毫摩尔)的N,N-二甲基甲酰胺溶液(5毫升)。反应混合物在0℃下搅拌1小时，再在室温下搅拌12小时。反应混合物用饱和NH4Cl水溶液(5毫升)淬灭，大量水稀释(120毫升)后用乙酸乙酯萃取(30毫升×3)，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥后过滤并旋干，残余物通过柱色谱(二氯甲烷：甲醇＝20：1)纯化得到标题化合物(白色固体，210毫克，收率38％)。1H-NMR(400MHz,CDCl3)δ8.27(d,J＝6.0Hz,1H),7.47(d,J＝9.0Hz,1H),7.06(dd,J＝6.0,2.0Hz,1H),6.99(d,J＝2.0Hz,1H),6.81-6.87(m,2H),4.46(q,J＝7.0Hz,2H),4.02(t,J＝6.2Hz,2H),3.84(t,J＝6.2Hz,2H),3.56(t,J＝6.2Hz,2H),3.19(t,J＝7.0Hz,2H),1.85-1.93(m,2H),1.80(q,J＝7.4Hz,2H),1.50(t,J＝7.0Hz,3H),0.80-0.92(m,2H)。 LCMS(ESI)m/z:481(M+1)。Sodium hydrogen (93 mg, 2.32 mmol) was added to a solution of Example 4E (271 mg, 1.16 mmol) of N, N-dimethylformamide. After stirring at 0&lt;0&gt;C for 0.5 h, EtOAc (EtOAc &lt The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 12 hours. The reaction mixture was quenched with saturated aqueous NH 4 Cl (5 mL), diluted with a large amount of water (120 ml) and extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate After filtration, the residue was purified by mjjjjlililililililililililililili 1 H-NMR (400 MHz, CDCl 3 ) δ 8.27 (d, J = 6.0 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.06 (dd, J = 6.0, 2.0 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.81-6.87 (m, 2H), 4.46 (q, J = 7.0 Hz, 2H), 4.02 (t, J = 6.2 Hz, 2H), 3.84 (t, J) =6.2 Hz, 2H), 3.56 (t, J = 6.2 Hz, 2H), 3.19 (t, J = 7.0 Hz, 2H), 1.85-1.93 (m, 2H), 1.80 (q, J = 7.4 Hz, 2H) ), 1.50 (t, J = 7.0 Hz, 3H), 0.80-0.92 (m, 2H). LCMS (ESI) m/z: 481 (21.
实施例18BExample 18B
2-(5-((3-乙氧基苯并[d]异噁唑-6-)氧代)戊烷)-5-(2-(甲氨基)吡啶-4-)-1,2,5-噻二唑啉-1,1-二氧化物2-(5-((3-ethoxybenzo[d]isoxazole-6-)oxy)pentane)-5-(2-(methylamino)pyridine-4-)-1,2, 5-thiadiazoline-1,1-dioxide
Figure PCTCN2015077043-appb-000109
Figure PCTCN2015077043-appb-000109
向实施例18A(100毫克，0.2毫摩尔)的N-甲基吡咯烷酮溶液(8毫升)中加入甲胺的四氢呋喃溶液(5毫升，2摩尔每升，12.5毫摩尔)。混合物置于闷罐中在110℃搅拌反应72小时，反应混合物在真空下除去溶剂，残余物经制备色谱分离纯化得到标题化合物(黄色粉末，10毫克，收率10％)。1H-NMR(400MHz,CDCl3)δ8.02(br s,1H),7.48(br s,1H),6.85(br s,2H),6.38(br s,1H),6.16(br s,1H),4.49(br s,2H),4.04(br s,2H),3.84(br s,2H),3.52(br s,2H),3.19(br s,2H),2.94(br s,3H),1.91(br s,2H),1.81(br s,2H),1.69-1.75(m,2H),1.52(br s,3H)。LCMS(ESI)m/z:476(M+1)。A solution of methylamine in tetrahydrofuran (5 mL, 2 moles per liter, 12.5 mmol) was added to a solution of <RTI ID=0.0>#</RTI></RTI><RTIgt; The mixture was stirred in a sump, and the reaction was stirred at 110 ° C for 72 hr. 1 H-NMR (400MHz, CDCl 3 ) δ 8.02 (br s, 1H), 7.48 (br s, 1H), 6.85 (br s, 2H), 6.38 (br s, 1H), 6.16 (br s, 1H) ), 4.49 (br s, 2H), 4.04 (br s, 2H), 3.84 (br s, 2H), 3.52 (br s, 2H), 3.19 (br s, 2H), 2.94 (br s, 3H), 1.91 (br s, 2H), 1.81 (br s, 2H), 1.69-1.75 (m, 2H), 1.52 (br s, 3H). LCMS (ESI) m.
路线HRoute H
Figure PCTCN2015077043-appb-000110
Figure PCTCN2015077043-appb-000110
实施例19Example 19
2-(4-(6-(4-氯苯基)苯并二氢吡喃-2-基)丁基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(4-(6-(4-chlorophenyl) benzohydropyran-2-yl)butyl)-5-(pyridin-4-yl)-1,2,5-thiadiazolidine -1,1-dioxide
Figure PCTCN2015077043-appb-000111
Figure PCTCN2015077043-appb-000111
实施例19AExample 19A
5-((四氢-2H-吡喃-2-基)氧基)戊-1-醇5-((tetrahydro-2H-pyran-2-yl)oxy)pentan-1-ol
Figure PCTCN2015077043-appb-000112
Figure PCTCN2015077043-appb-000112
1，5-戊二醇(60克，0.57摩尔)，3，4-二氢吡喃(48.5克，0.57摩尔)和对甲苯磺酸(50毫克)在40℃下搅拌3小时。反应停止后加入碳酸钾溶液(200毫升)，水相用乙酸乙酯(150毫升×3)萃取。合并的有机相用无水硫酸钠干燥，过滤蒸干后残余物直接用于下一步反应。1H-NMR(CDCl3,400MHz)δ4.54(d,J＝3.5Hz,1H),3.78-3.89(m,1H),3.68-3.77(m,1H),3.60(br.s.,2H),3.43-3.52(m,1H),3.32-3.41(m,1H),2.02(br.s.,1H),1.80(m,1H),1.65-1.68(m,1H),1.39-1.70(m,10H)。1,5-Pentanediol (60 g, 0.57 mol), 3,4-dihydropyran (48.5 g, 0.57 mol) and p-toluenesulfonic acid (50 mg) were stirred at 40 ° C for 3 hours. After the reaction was stopped, a potassium carbonate solution (200 ml) was added, and the aqueous phase was extracted with ethyl acetate (150 ml × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered and evaporated. 1 H-NMR (CDCl 3 , 400 MHz) δ 4.54 (d, J = 3.5 Hz, 1H), 3.78-3.89 (m, 1H), 3.68-3.77 (m, 1H), 3.60 (br.s., 2H) ), 3.43 - 3.52 (m, 1H), 3.32-3.41 (m, 1H), 2.02 (br.s., 1H), 1.80 (m, 1H), 1.65-1.68 (m, 1H), 1.39-1.70 ( m, 10H).
实施例19BExample 19B
5-((四氢-2H-吡喃-2-基)氧基)戊醛5-((tetrahydro-2H-pyran-2-yl)oxy)pentanal
Figure PCTCN2015077043-appb-000113
Figure PCTCN2015077043-appb-000113
向实施例19A(60克，0.30摩尔)的二氯甲烷(400毫升)溶液中分批加入PCC(90克)，反应混合物在室温下搅拌5小时。过滤后滤液浓缩，柱层析纯化得标题化合物。1H-NMR(400MHz,CDCl3)δ9.62-9.79(m,1H),4.50(br.s.,1H),3.58-3.91(m,2H),3.25-3.53(m,2H),2.50-2.68(m,2H),2.42(dd,J＝1.25,3.51Hz,2H),1.48-1.79(m,8H)。To a solution of Example 19A (60 g, EtOAc. The filtrate was concentrated after filtration and purified by column chromatography toiel 1 H-NMR (400 MHz, CDCl 3 ) δ 9.62-9.79 (m, 1H), 4.50 (br.s., 1H), 3.58-3.91 (m, 2H), 3.25-3.53 (m, 2H), 2.50 - 2.68 (m, 2H), 2.42 (dd, J = 1.25, 3.51 Hz, 2H), 1.48-1.79 (m, 8H).
实施例19CExample 19C
6-(4-氯苯基)-2-(4-((四氢-2H-吡喃-2-基)氧基)丁基)苯并二氢吡喃-4-酮6-(4-chlorophenyl)-2-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)chroman-4-one
Figure PCTCN2015077043-appb-000114
Figure PCTCN2015077043-appb-000114
实施例19B(7.5克，40.27毫摩尔)，实施例1F(9.93克，40.27毫摩尔)和哌啶(3.43克，40.27毫摩尔)的乙醇(100毫升)混合物在85℃下搅拌3小时。二氯甲烷(50毫升)和水(50毫升)加入反应体系，反应体系用稀盐酸水溶液调pH至6，水层用二氯甲烷(100毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物(黄色液体，7克，产率42％)。1H-NMR(400MHz,CDCl3)δ8.05(d,J＝2.3Hz,1H),7.67(dd,J＝8.7,2.4Hz,1H),7.48(d,J＝8.5Hz,2H),7.38(d,J＝8.5Hz,2H),7.04(d,J＝8.5Hz,1H),4.58(d,J＝4.3Hz,1H),4.43-4.52(m,1H),3.86(td,J＝7.3,3.9Hz,1H),3.74-3.82(m,1H),3.47-3.54(m,1H),3.39-3.45(m,1H),2.67-2.76(m,2H),1.89-1.99(m,1H),1.76-1.86(m,2H),1.63-1.71(m,4H),1.49-1.59(m,5H)。Example 19B (7.5 g, 40.27 mmol), EtOAc (EtOAc:EtOAc. Dichloromethane (50 ml) and water (50 ml) were added to the reaction system. The mixture was adjusted to pH 6 with dilute aqueous hydrochloric acid and the aqueous layer was extracted with dichloromethane (100 ml × 3). Drying, filtration and evaporation, EtOAcqqqqqqq 1 H-NMR (400 MHz, CDCl 3 ) δ 8.05 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.7, 2.4 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.5 Hz, 1H), 4.58 (d, J = 4.3 Hz, 1H), 4.43-4.52 (m, 1H), 3.86 (td, J = 7.3, 3.9 Hz, 1H), 3.74-3.82 (m, 1H), 3.47-3.54 (m, 1H), 3.39-3.45 (m, 1H), 2.67-2.76 (m, 2H), 1.89-1.99 (m , 1H), 1.76-1.86 (m, 2H), 1.63-1.71 (m, 4H), 1.49-1.59 (m, 5H).
实施例19DExample 19D
4-(6-(4-氯苯基)苯并二氢吡喃-2-基)丁基-2,2,2-三氟乙酸酯4-(6-(4-chlorophenyl) benzochroman-2-yl)butyl-2,2,2-trifluoroacetate
Figure PCTCN2015077043-appb-000115
Figure PCTCN2015077043-appb-000115
向实施例19C(2.5克，6.03毫摩尔)的三氟乙酸(20毫升)溶液中加三乙基硅氢(10毫升)，混合物 在50℃下反应3小时。蒸干溶剂，乙酸乙酯(20毫升)和水(20毫升)加入反应体系，水层用乙酸乙酯(20毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发，提供标题化合物(黄色液体，2克，产率80％)。To a solution of Example 19C (2.5 g, 6.03 mmol) elute The reaction was carried out at 50 ° C for 3 hours. The solvent was evaporated to dryness EtOAc EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The title compound (yellow liquid, 2 g, yield 80%).
实施例19EExample 19E
4-(6-(4-氯苯基)苯并二氢吡喃-2-基)丁-1-醇4-(6-(4-chlorophenyl) benzohydropyran-2-yl)butan-1-ol
Figure PCTCN2015077043-appb-000116
Figure PCTCN2015077043-appb-000116
向实施例19D(500毫克，1.21毫摩尔)的1,4-二氧六环(5毫升)和水(2毫升)混合物中加氢氧化锂(29毫克，1.21毫摩尔)，混合物在25℃下反应3小时。乙酸乙酯(10毫升)和水(10毫升)加入反应体系，水层用乙酸乙酯(10毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物(无色固体，300毫克，产率78％)。1H-NMR(400MHz,CDCl3)δ7.43-7.47(m,2H),7.33-7.38(m,2H),7.26-7.30(m,2H),6.86(d,J＝8.3Hz,1H),4.03(br.s.,1H),3.70(t,J＝5.9Hz,2H),2.76-2.95(m,2H),1.98-2.08(m,1H),1.71-1.85(m,2H),1.58-1.70(m,5H)。Add lithium hydroxide (29 mg, 1.21 mmol) to a mixture of 1,4-dioxane (5 ml) and water (2 ml). The reaction was carried out for 3 hours. Ethyl acetate (10 ml) and water (10 ml) were added to the reaction mixture, the aqueous layer was extracted with ethyl acetate (10 ml × 3), and the combined organic layer was dried over sodium sulfate, filtered and evaporated. Purification afforded the title compound (m. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.43-7.47 (m, 2H), 7.33 - 7.38 (m, 2H), 7.26-7.30 (m, 2H), 6.86 (d, J = 8.3 Hz, 1H) , 4.03 (br.s., 1H), 3.70 (t, J = 5.9 Hz, 2H), 2.76-2.95 (m, 2H), 1.98-2.08 (m, 1H), 1.71-1.85 (m, 2H), 1.58-1.70 (m, 5H).
实施例19FExample 19F
2-(4-溴丁基)-6-(4-氯苯基)苯并二氢吡喃2-(4-bromobutyl)-6-(4-chlorophenyl)chroman
Figure PCTCN2015077043-appb-000117
Figure PCTCN2015077043-appb-000117
0℃下向实施例19E(500毫克，1.6毫摩尔)，四溴化碳(3.4克，10.3毫摩尔)的四氢呋喃(5毫升)混合物中慢慢加三苯基膦(420毫克，1.6毫摩尔)，混合物在60℃下反应1小时。减压浓缩反应液后，残余物通过柱色谱纯化得到标题化合物(黄色固体，658毫克，产率83％)。1H-NMR(400MHz,CDCl3)δ7.43-7.48(m,2H),7.34-7.38(m,2H),7.24-7.29(m,2H),6.86(d,J＝8.5Hz,1H),4.00-4.07(m,1H),3.45-3.49(m,2H),2.77-2.96(m,2H),1.90-2.02(m,3H),1.62-1.80(m,5H)。Triethylphosphine (420 mg, 1.6 mmol) was slowly added to a mixture of Example 19E (500 mg, 1.6 mmol), tetrabromide (3.4 g, 10.3 mmol) in tetrahydrofuran (5 mL). The mixture was reacted at 60 ° C for 1 hour. After the reaction mixture was evaporated, mjjjjlililililili 1 H-NMR (400MHz, CDCl 3 ) δ 7.43-7.48 (m, 2H), 7.34-7.38 (m, 2H), 7.24-7.29 (m, 2H), 6.86 (d, J = 8.5 Hz, 1H) , 4.00-4.07 (m, 1H), 3.45-3.49 (m, 2H), 2.77-2.96 (m, 2H), 1.90-2.02 (m, 3H), 1.62-1.80 (m, 5H).
实施例19GExample 19G
2-(4-(6-(4-氯苯基)苯并二氢吡喃-2-基)丁基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(4-(6-(4-chlorophenyl) benzohydropyran-2-yl)butyl)-5-(pyridin-4-yl)-1,2,5-thiadiazolidine -1,1-dioxide
Figure PCTCN2015077043-appb-000118
Figure PCTCN2015077043-appb-000118
本实施例中如实施例18A中描述的方法制备。1H-NMR(400MHz,CDCl3)δ8.51(d,J＝6.0Hz,2H),7.42-7.48(m,2H),7.33-7.40(m,2H),7.29(s,3H),7.05(d,J＝6.0Hz,2H),6.85(d,J＝8.5Hz,1H),4.03(br.s.,1H),3.86(t,J＝6.5Hz,2H),3.52-3.59(m,2H),3.20(t,J＝7.0Hz,2H),2.77-2.95(m,2H),2.03(d,J＝13.1Hz,1H),1.64-1.85(m,7H)。LCMS(ESI)m/z:498(M+1)。This example was prepared as described in Example 18A. 1 H-NMR (400MHz, CDCl 3 ) δ 8.51 (d, J = 6.0 Hz, 2H), 7.42-7.48 (m, 2H), 7.33-7.40 (m, 2H), 7.29 (s, 3H), 7.05 (d, J = 6.0 Hz, 2H), 6.85 (d, J = 8.5 Hz, 1H), 4.03 (br.s., 1H), 3.86 (t, J = 6.5 Hz, 2H), 3.52-3.59 (m , 2H), 3.20 (t, J = 7.0 Hz, 2H), 2.77-2.95 (m, 2H), 2.03 (d, J = 13.1 Hz, 1H), 1.64-1.85 (m, 7H). LCMS (ESI) m/z:
路线I Route I
Figure PCTCN2015077043-appb-000119
Figure PCTCN2015077043-appb-000119
实施例20Example 20
2-(4-(6-溴苯并二氢吡喃-2-基)丁基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(4-(6-Bromochroman-2-yl)butyl)-5-(pyridin-4-yl)-1,2,5-thiadiazolidine-1,1-di Oxide
Figure PCTCN2015077043-appb-000120
Figure PCTCN2015077043-appb-000120
实施例20AExample 20A
6-溴-2-(4-((四氢-2H-吡喃-2-基)氧基)丁基)苯并二氢吡喃-4-酮6-bromo-2-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)chroman-4-one
Figure PCTCN2015077043-appb-000121
Figure PCTCN2015077043-appb-000121
将实施例19B(5.0克，29毫摩尔)，5'-溴-2'-羟基苯乙酮(6.37克，29毫摩尔)和哌啶(2.0毫升)混合于乙醇(150毫升)中，加入回流4小时后，减压蒸干，所得残余物用柱层析纯化的标题化合物(黄色固体，6.5克，收率57％)。1H-NMR(CDCl3,400MHz)δ8.00(d,J＝2.3Hz,1H),7.56(dd,J＝8.8,2.3Hz,1H),6.90(d,J＝8.8Hz,1H),4.60(br.s.,1H),4.40-4.52(m,1H),3.72-3.95(m2H),3.37-3.59(m,2H),2.66-2.80(m,2H),1.48-2.01(m,12H)。Example 19B (5.0 g, 29 mmol), 5'-bromo-2'-hydroxyacetophenone (6.37 g, 29 mmol) and piperidine (2.0 mL) were combined in ethanol (150 mL). After refluxing for 4 hours, the title compound was evaporated. 1 H-NMR (CDCl 3 , 400 MHz) δ 8.00 (d, J = 2.3 Hz, 1H), 7.56 (dd, J = 8.8, 2.3 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 4.60 (br.s., 1H), 4.40-4.52 (m, 1H), 3.72-3.95 (m2H), 3.37-3.59 (m, 2H), 2.66-2.80 (m, 2H), 1.48-2.01 (m, 12H).
实施例20BExample 20B
4-(6-溴苯并二氢吡喃-2-基)丁基-2,2,2-三氟乙酸酯
Figure PCTCN2015077043-appb-000122
将实施例20A(1.0克，2.57毫摩尔)和三乙基硅氢(7.3克，62.8毫摩尔)混合在三氟乙酸中(20毫升)，60℃下加热5小时。减压浓缩后，粗产物直接用于下一步反应(5.8克，粗品收率97％)。1H-NMR(CDCl3,400MHz)δ7.17(d,J＝2.0Hz,2H),6.60-6.70(m,1H),4.30-4.47(m,2H),3.96(td,J＝7.8,2.0Hz,1H),2.67-2.90(m,2H),1.97(ddt,J＝13.5,5.6,2.8Hz,1H),1.48-1.89(m,8H)。4-(6-bromochroman-2-yl)butyl-2,2,2-trifluoroacetate
Figure PCTCN2015077043-appb-000122
Example 20A (1.0 g, 2.57 mmol) and triethylsilylhydrogen (7.3 g, 62.8 mmol) were combined in trifluoroacetic acid (20 ml) and heated at 60 ° C for 5 hours. After concentration under reduced pressure, the crude material was applied to the next step (y. 1 H-NMR (CDCl 3, 400MHz) δ7.17 (d, J = 2.0Hz, 2H), 6.60-6.70 (m, 1H), 4.30-4.47 (m, 2H), 3.96 (td, J = 7.8, 2.0 Hz, 1H), 2.67-2.90 (m, 2H), 1.97 (ddt, J = 13.5, 5.6, 2.8 Hz, 1H), 1.48-1.89 (m, 8H).
实施例20CExample 20C
4-(6-溴苯并二氢吡喃-2-基)丁-1-醇4-(6-bromochroman-2-yl)butan-1-ol
Figure PCTCN2015077043-appb-000123
Figure PCTCN2015077043-appb-000123
本实施例的制备方法参照实施例19E。1H-NMR(CDCl3,400MHz)δ7.11-7.24(m,1H),6.64-6.75(m,1H),3.99(d,J＝5.0Hz,1H),3.61-3.80(m,2H),2.66-2.91(m，2H),1.93-2.06(m,1H),1.47-1.84(m,10H)。The preparation method of this example is referred to Example 19E. 1 H-NMR (CDCl 3 , 400 MHz) δ 7.11 - 7.24 (m, 1H), 6.64 - 6.75 (m, 1H), 3.99 (d, J = 5.0 Hz, 1H), 3.61-3.80 (m, 2H) , 2.66-2.91 (m, 2H), 1.93-2.06 (m, 1H), 1.47-1.84 (m, 10H).
实施例20DExample 20D
4-(6-溴苯并二氢吡喃-2-基)丁基-4-甲基苯磺酸4-(6-bromochroman-2-yl)butyl-4-methylbenzenesulfonic acid
Figure PCTCN2015077043-appb-000124
Figure PCTCN2015077043-appb-000124
向实施例20C(71毫克，0.25毫摩尔)的二氯甲烷(5.0毫升)溶液中依次加入三乙胺(76毫克，0.75毫摩尔)和对甲苯磺酰氯(95毫克，0.5毫摩尔)。反应混合物在12℃下搅拌4小时，减压浓缩后，粗产物用薄层层析纯化得标题化合物(无色液体，60毫克，收率55％)。1H-NMR(CDCl3，400MHz)δ7.73-7.85(m，2H)，7.36(d，J＝8.0Hz，2H)，7.17(d，J＝4.8Hz，2H)，6.61-6.69(m，1H)，4.03-4.11(m，2H)，3.84-3.97(m，1H)，2.66-2.89(m，2H)，2.45(s，3H)，1.88-2.01(m，1H)，1.42-1.83(m,7H)。Triethylamine (76 mg, 0.75 mmol) and p-toluenesulfonyl chloride (95 mg, 0.5 mmol) were added sequentially to a solution of EtOAc. The reaction mixture was stirred at EtOAc (3 mL) 1 H-NMR (CDCl 3 , 400 MHz) δ 7.73 - 7.85 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 4.8 Hz, 2H), 6.61-6.69 (m) , 1H), 4.03-4.11 (m, 2H), 3.84-3.97 (m, 1H), 2.66-2.89 (m, 2H), 2.45 (s, 3H), 1.88-2.01 (m, 1H), 1.42-1.83 (m, 7H).
实施例20EExample 20E
2-(4-(6-溴苯并二氢吡喃-2-基)丁基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(4-(6-Bromochroman-2-yl)butyl)-5-(pyridin-4-yl)-1,2,5-thiadiazolidine-1,1-di Oxide
Figure PCTCN2015077043-appb-000125
Figure PCTCN2015077043-appb-000125
本实施例的制备方法参照实施例18A。1H-NMR(CDCl3,400MHz)δ8.52(d,J＝6.0Hz,2H),7.14-7.19(m,2H),7.06(d,J＝6.0Hz,2H),6.65-6.69(m,1H),3.97(s.,1H),3.86(t,J＝6.3Hz,2H),3.56(t,J＝6.5Hz,2H),3.19(t,J＝7.0Hz,2H),2.67-2.89(m,2H),1.94-2.04(m,1H),1.53-1.84(m,7H)。LCMS(ESI)m/z:466(M+1)。The preparation method of this example is referred to Example 18A. 1 H-NMR (CDCl 3 , 400 MHz) δ 8.52 (d, J = 6.0 Hz, 2H), 7.14 - 7.19 (m, 2H), 7.06 (d, J = 6.0 Hz, 2H), 6.65-6.69 (m) , 1H), 3.97 (s., 1H), 3.86 (t, J = 6.3 Hz, 2H), 3.56 (t, J = 6.5 Hz, 2H), 3.19 (t, J = 7.0 Hz, 2H), 2.67- 2.89 (m, 2H), 1.94-2.04 (m, 1H), 1.53-1.84 (m, 7H). LCMS (ESI) m/z:
路线JRoute J
Figure PCTCN2015077043-appb-000126
Figure PCTCN2015077043-appb-000126
实施例21Example 21
(E)-2-(4-(1,1-二氧代-5-(吡啶-4-基)-1,2,5-噻二唑烷-2-基)丁基)苯并二氢吡喃-6-甲醛-氧-乙基肟(E)-2-(4-(1,1-dioxo-5-(pyridin-4-yl)-1,2,5-thiadiazol-2-yl)butyl)benzodihydro Pyran-6-formaldehyde-oxy-ethyl hydrazine
Figure PCTCN2015077043-appb-000127
Figure PCTCN2015077043-appb-000127
实施例21AExample 21A
2-(4-羟丁基)苯并二氢吡喃-6-甲醛2-(4-hydroxybutyl) benzochroman-6-formaldehyde
Figure PCTCN2015077043-appb-000128
Figure PCTCN2015077043-appb-000128
氮气保护、-78℃下，向实施例20C(600毫克，2.1毫摩尔)的无水四氢呋喃(10.0毫升)溶液中慢慢滴加正丁基锂(2.5摩尔每升，1.8毫升，4.6毫摩尔)，加完后继续搅拌2小时。然后将反应液再次降低至-78℃，慢慢滴加入N,N-二甲基甲酰胺(380毫克，5.2毫摩尔)。加完后将反应液慢慢升至室温并搅拌过夜。加入水(5.0毫升)淬灭后，水相用乙酸乙酯萃取(10.0毫升×2)。合并的有机相用无水硫酸钠干燥后，过滤蒸发，残留物用薄层层析纯化得到标题化合物(无色液体，70.0毫克,收率15％)。1H-NMR(CDCl3,400MHz)δ9.83(s,1H),7.55-7.68(m,2H),6.83-6.92(m,1H),4.03-4.20(m,1H),3.71(t,J＝6.0Hz,2H),2.72-2.92(m,2H),2.00-2.13(m,1H),1.46-1.87(m,7H)。N-butyllithium (2.5 moles per liter, 1.8 milliliters, 4.6 millimoles) was slowly added dropwise to a solution of Example 20C (600 mg, 2.1 mmol) in anhydrous tetrahydrofuran (10.0 mL). ), continue to stir for 2 hours after the addition. The reaction solution was again lowered to -78 ° C, and N,N-dimethylformamide (380 mg, 5.2 mmol) was slowly added dropwise. After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred overnight. After quenching with water (5.0 mL), EtOAc (EtOAc) The combined organic phases were dried with EtOAc EtOAcjjjjjjjj 1 H-NMR (CDCl 3 , 400 MHz) δ 9.83 (s, 1H), 7.55-7.68 (m, 2H), 6.83-6.92 (m, 1H), 4.03-4.20 (m, 1H), 3.71 (t, J = 6.0 Hz, 2H), 2.72 - 2.92 (m, 2H), 2.00 - 2.13 (m, 1H), 1.46-1.87 (m, 7H).
实施例21BExample 21B
(E)-2-(4-羟丁基)苯并二氢吡喃-6-甲醛-氧-乙基肟(E)-2-(4-hydroxybutyl) chroman-6-formaldehyde-oxy-ethyl hydrazine
Figure PCTCN2015077043-appb-000129
Figure PCTCN2015077043-appb-000129
向实施例21A(70毫克，0.32毫摩尔)的水(2.0毫升)溶液中加入乙氧氨基盐酸盐(97毫克，1.6毫摩尔)和醋酸钠(130毫克，1.59毫摩尔)，60℃下加热3小时后，停止反应。水相用乙酸乙酯(5.0毫升×3)萃取。合并的有机相用无水硫酸钠干燥，过滤浓缩，粗产物可以直接用于下一步反应(70毫克，收率79％)。To a solution of Example 21A (70 mg, 0.32 mmol) in water (2.0 mL), EtOAc (EtOAc, EtOAc. After heating for 3 hours, the reaction was stopped. The aqueous phase was extracted with ethyl acetate (5.0 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and filtered and evaporated.
实施例21CExample 21C
(E)-4-(6-((乙氧基亚氨基)甲基)苯并二氢吡喃-2-基)丁基-4-甲基苯磺酸酯(E)-4-(6-((ethoxyimino)methyl)chroman-2-yl)butyl-4-methylbenzenesulfonate
Figure PCTCN2015077043-appb-000130
Figure PCTCN2015077043-appb-000130
向实施例21B(70毫克，0.25毫摩尔)的二氯甲烷(5.0毫升)溶液中依次加入三乙胺(76毫克，0.75毫摩尔)和对甲苯磺酰氯(95毫克，0.5毫摩尔)。反应混合物在12℃下搅拌4小时，减压浓缩后，粗产物用薄层层析纯化得标题化合物(无色液体，60毫克，收率55％)。1H-NMR(CDCl3,400MHz)δ7.98(s,1H),7.79(d,J＝8.0Hz,2H),7.24-7.39(m,2H),6.69-6.77(m,1H),4.12-4.23(m,2H),4.06(t,J＝6.3Hz,2H),3.92(br s,1H),2.68-2.87(m,2H),2.43(s,3H),1.89-1.99(m,1H),1.43-1.78(m,7H),1.26-1.37(m,3H)。Triethylamine (76 mg, 0.75 mmol) and p-toluenesulfonyl chloride (95 mg, 0.5 mmol) were added sequentially to a solution of EtOAc. The reaction mixture was stirred at EtOAc (3 mL) 1 H-NMR (CDCl 3 , 400 MHz) δ 7.98 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.24-7.39 (m, 2H), 6.69-6.77 (m, 1H), 4.12 -4.23 (m, 2H), 4.06 (t, J = 6.3 Hz, 2H), 3.92 (br s, 1H), 2.68-2.87 (m, 2H), 2.43 (s, 3H), 1.89-1.99 (m, 1H), 1.43-1.78 (m, 7H), 1.26-1.37 (m, 3H).
实施例21DExample 21D
(E)-2-(4-(1,1-二氧代-5-(吡啶-4-基)-1,2,5-噻二唑烷-2-基)丁基)苯并二氢吡喃-6-甲醛-氧-乙基肟(E)-2-(4-(1,1-dioxo-5-(pyridin-4-yl)-1,2,5-thiadiazol-2-yl)butyl)benzodihydro Pyran-6-formaldehyde-oxy-ethyl hydrazine
Figure PCTCN2015077043-appb-000131
Figure PCTCN2015077043-appb-000131
本实施例的制备方法参照实施例18A。1H-NMR(CDCl3,400MHz)8.52(br s，2H)，7.98(s，1H)，7.21-7.35(m,2H),7.07(d,J＝5.0Hz,2H),6.77(d,J＝9.0Hz,1H),4.15-4.28(m,2H),4.02(br s,1H),3.86(t,J＝6.5Hz,2H),3.52-3.61(m,2H),3.19(t,J＝7.0Hz,2H),2.72-2.90(m,2H),1.95-2.04(m,1H),1.57-1.84(m,8H),1.31(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:459(M+1)。The preparation method of this example is referred to Example 18A. 1 H-NMR (CDCl 3 , 400 MHz) 8.52 (br s, 2H), 7.98 (s, 1H), 7.21 - 7.35 (m, 2H), 7.07 (d, J = 5.0 Hz, 2H), 6.77 (d, J=9.0 Hz, 1H), 4.15-4.28 (m, 2H), 4.02 (br s, 1H), 3.86 (t, J = 6.5 Hz, 2H), 3.52-3.61 (m, 2H), 3.19 (t, J = 7.0 Hz, 2H), 2.72-2.90 (m, 2H), 1.95-2.04 (m, 1H), 1.57-1.84 (m, 8H), 1.31 (t, J = 7.0 Hz, 3H). LCMS (ESI) m/z: 459:
实施例22 Example 22
(R)-1-(4-(6-(4-氯苯基)苯并二氢吡喃-2-基)丁基)-3-(吡啶-4-基)咪唑烷酮(R)-1-(4-(6-(4-chlorophenyl) benzohydropyran-2-yl)butyl)-3-(pyridin-4-yl)imidazolidinone
Figure PCTCN2015077043-appb-000132
Figure PCTCN2015077043-appb-000132
(S)-1-(4-(6-(4-氯苯基)苯并二氢吡喃-2-基)丁基)-3-(吡啶-4-基)咪唑烷酮(S)-1-(4-(6-(4-chlorophenyl) benzohydropyran-2-yl)butyl)-3-(pyridin-4-yl)imidazolidinone
Figure PCTCN2015077043-appb-000133
Figure PCTCN2015077043-appb-000133
使用SFC将实施例2产物进行拆分，获得2个手性异构体。拆分所使用条件如下：The product of Example 2 was resolved using SFC to obtain two chiral isomers. The conditions used for the split are as follows:
方法：AS-H_S_5_40_3ML_8MIN_15CMMethod: AS-H_S_5_40_3ML_8MIN_15CM
色谱柱:Chiralpak AS-H 150*4.6mm I.D.,5umColumn: Chiralpak AS-H 150*4.6mm I.D., 5um
流动相:40％乙醇(0.05％DEA)-CO2Mobile phase: 40% ethanol (0.05% DEA)-CO2
流速:3mL/minFlow rate: 3mL/min
波长:220nm；Wavelength: 220 nm;
实施例22a为第一个异构体，保留时间为2.80分钟；实施例22b为第二个异构体，保留时间为4.04分钟。Example 22a is the first isomer with a retention time of 2.80 minutes; Example 22b is the second isomer with a retention time of 4.04 minutes.
流程KProcess K
Figure PCTCN2015077043-appb-000134
Figure PCTCN2015077043-appb-000134
实施例23Example 23
(E)-4-((5(5(2-氨基吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5(5(2-aminopyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl)oxy) Benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000135
Figure PCTCN2015077043-appb-000135
实施例23AExample 23A
(E)-4-羟基苯甲醛-氧-乙基肟(E)-4-hydroxybenzaldehyde-oxy-ethylhydrazine
Figure PCTCN2015077043-appb-000136
Figure PCTCN2015077043-appb-000136
向对羟基苯甲醛(2.5克，20.5毫摩尔)，乙氧氨基盐酸盐(3.9克，40.9毫摩尔)的水(50毫升)溶液中加乙酸钠(3.4克，40.9毫摩尔)，混合物在80下搅拌4小时。乙酸乙酯(50毫升)加入反应体系，水层用乙酸乙酯(50毫升×3)萃取，将合并的有机层用无水硫酸钠干燥，过滤并蒸发得到标题化合物(棕色固体，3克，产率89％)。1H NMR(CDCl3,400MHz)8.03(s,1H),7.46(d,J＝8.5Hz,2H),6.78-6.85 (m,2H),4.20(q,J＝7.0Hz,2H),1.31(t,J＝7.0Hz,3H)。Add sodium acetate (3.4 g, 40.9 mmol) to a solution of p-hydroxybenzaldehyde (2.5 g, 20.5 mmol), EtOAc (3 g, EtOAc) Stir at 80 for 4 hours. Ethyl acetate (50 ml) was added to EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Yield 89%). 1 H NMR (CDCl 3, 400 MHz) 8.03 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 6.78-6.85 (m, 2H), 4.20 (q, J = 7.0 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H).
实施例23BExample 23B
(E)-4-((6-溴己基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((6-bromohexyl)oxy)benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000137
Figure PCTCN2015077043-appb-000137
将实施例23A(1.0克，6.1毫摩尔)，1,5-二溴戊烷(1.4克，6.1毫摩尔)，碳酸钾(1.67克，12.1毫摩尔)和碘化钾(0.1克，0.61毫摩尔)的丙酮(100毫升)溶液加热回流10小时。反应液降至室温后，过滤，滤液旋干，柱层析纯化，提供标题化合物(白色晶体，1.2克，63％)。1H NMR(CDCl3,400MHz)δ8.01-8.05(m,1H),7.49-7.55(m,2H),6.86-6.91(m,2H),4.17-4.24(m,2H),3.96-4.01(m,2H),3.41-3.47(m,2H),1.89-1.99(m,2H),1.78-1.86(m,2H),1.60-1.68(m,2H),1.29-1.34(m,3H)。Example 23A (1.0 g, 6.1 mmol), 1,5-dibromopentane (1.4 g, 6.1 mmol), potassium carbonate (1.67 g, 12.1 mmol) and potassium iodide (0.1 g, 0.61 mmol) The acetone (100 ml) solution was heated to reflux for 10 hours. After the reaction mixture was cooled to room temperature, filtered, EtOAcjjjjjjjj 1 H NMR (CDCl 3 , 400 MHz) δ 8.01-8.05 (m, 1H), 7.49-7.55 (m, 2H), 6.86-6.91 (m, 2H), 4.17 - 4.24 (m, 2H), 3.96-4.01 (m, 2H), 3.41-3.47 (m, 2H), 1.89-1.99 (m, 2H), 1.78-1.86 (m, 2H), 1.60-1.68 (m, 2H), 1.29-1.34 (m, 3H) .
实施例23CExample 23C
(E)-4-((5-(5-(2-氯吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5-(5-(2-chloropyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl)oxy Benzoaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000138
Figure PCTCN2015077043-appb-000138
在10℃，氮气保护下，向实施例4E(100毫克,428微摩尔)的N,N-二甲基甲酰胺(3毫升)溶液中加入钠氢(51.4毫克，1.3毫摩尔)，反应液搅拌2小时后，向其中加入实施例23B(134.5毫克,428微摩尔)的N,N-二甲基甲酰胺(1毫升)溶液，然后在40℃下搅拌反应8小时。TLC检测反应结束后加入水(10毫升)淬灭反应，水层用乙酸乙酯(20毫升x 3)萃取，合并有机层并用无水硫酸钠干燥，过滤并蒸发，粗品用薄层色谱板分离(石油醚/乙酸乙酯＝1:1)得到标题化合物(白色固体，140毫克，产率：70％)。1H NMR(400MHz,CHLOROFORM-d)8.29(d,J＝5.77Hz,1H),8.05(s,1H),7.53(d,J＝9.03Hz,2H),7.09(dd,J＝2.01,5.77Hz,1H),7.01(d,J＝2.01Hz,1H),6.89(d,J＝8.78Hz,2H),4.22(q,J＝7.03Hz,2H),4.02(t,J＝6.15Hz,2H),3.86(t,J＝6.40Hz,2H),3.54-3.60(m,2H),3.20(t,J＝7.28Hz,2H),1.60-1.91(m,6H),1.34(t,J＝7.15Hz,3H)。LCMS(M+1):467。Add sodium hydrogen (51.4 mg, 1.3 mmol) to a solution of Example 4E (100 mg, 428 μmol) in N,N-dimethylformamide (3 mL). After stirring for 2 hours, a solution of Example 23B (134.5 mg, 428 m. After the end of the TLC reaction, the reaction was quenched with EtOAc (EtOAc)EtOAc. The title compound (white solid, 140 mg, yield: 70%). 1 H NMR (400MHz, CHLOROFORM- d) 8.29 (d, J = 5.77Hz, 1H), 8.05 (s, 1H), 7.53 (d, J = 9.03Hz, 2H), 7.09 (dd, J = 2.01,5.77 Hz, 1H), 7.01 (d, J = 2.01 Hz, 1H), 6.89 (d, J = 8.78 Hz, 2H), 4.22 (q, J = 7.03 Hz, 2H), 4.02 (t, J = 6.15 Hz, 2H), 3.86 (t, J = 6.40 Hz, 2H), 3.54-3.60 (m, 2H), 3.20 (t, J = 7.28 Hz, 2H), 1.60-1.91 (m, 6H), 1.34 (t, J) =7.15 Hz, 3H). LCMS (M+1): 467.
实施例23DExample 23D
(E)-4-((5-(5-(2-氨基吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5-(5-(2-Aminopyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl)oxy Benzoaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000139
Figure PCTCN2015077043-appb-000139
在氮气保护下向实施例23C(80毫克,171.3微摩尔)，氨基甲酸叔丁酯(120毫克,1.0毫摩尔)和Cs2CO3(112毫克,343微摩尔)的二氧六环和N,N-二甲基甲酰胺混合溶液(3毫升)/(1毫升)中加入Pd2(dba)3(30毫克,33微摩尔)和Xant-Phos(15毫克，38微摩尔)，搅拌均匀后升温到110℃下反应10小时。TLC(石油醚:乙酸乙酯＝2:1～二氯甲烷:甲醇＝20:1)检测反应结束后加入水(10毫升)淬灭，乙酸乙酯(30毫升x3)萃取，合并有机层用硫酸钠干燥，过滤并蒸发。粗品用制备HPLC分离(三氟乙酸)得到标题化合物(白色固体，20毫克，产率26％)。1H NMR(400MHz,CHLOROFORM-d)7.95-8.07(m,2H),7.51(d,J＝8.53Hz,2H),6.88(d,J＝8.53Hz,2H),6.42(dd,J＝2.01,5.52Hz,1H),6.29 (d,J＝2.01Hz,1H),4.52(br.s.,1H),4.20(q,J＝7.19Hz,2H),4.00(t,J＝6.27Hz,2H),3.80(t,J＝6.53Hz,2H),3.50(t,J＝6.27Hz,2H),3.16(t,J＝7.28Hz,2H),1.73-1.90(m,4H),1.62-1.65(m,2H),1.32(t,J＝7.03Hz,3H)。LCMS(M+1):448。Example 23C (80 mg, 171.3 micromoles), tert-butyl carbamate (120 mg, 1.0 mmol) and Cs 2 CO 3 (112 mg, 343 μmol) of dioxane and N under N2. Add Pd 2 (dba) 3 (30 mg, 33 μmol) and Xant-Phos (15 mg, 38 μmol) to a mixed solution of N-dimethylformamide (3 ml) / (1 ml), and mix well. Thereafter, the temperature was raised to 110 ° C for 10 hours. TLC (petroleum ether: ethyl acetate = 2:1 - methylene chloride:methanol = 20:1). After the reaction mixture was quenched with water (10 ml), ethyl acetate (30 ml x 3) Dry over sodium sulfate, filter and evaporate. The crude product was purified by EtOAcqqqqqq 1 H NMR (400MHz, CHLOROFORM- d) 7.95-8.07 (m, 2H), 7.51 (d, J = 8.53Hz, 2H), 6.88 (d, J = 8.53Hz, 2H), 6.42 (dd, J = 2.01 , 5.52 Hz, 1H), 6.29 (d, J = 2.01 Hz, 1H), 4.52 (br.s., 1H), 4.20 (q, J = 7.19 Hz, 2H), 4.00 (t, J = 6.27 Hz, 2H), 3.80 (t, J = 6.53 Hz, 2H), 3.50 (t, J = 6.27 Hz, 2H), 3.16 (t, J = 7.28 Hz, 2H), 1.73-1.90 (m, 4H), 1.62 1.65 (m, 2H), 1.32 (t, J = 7.03 Hz, 3H). LCMS (M+1): 448.
实施例24Example 24
4-((5-(5-(2-氨基吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛4-((5-(5-(2-Aminopyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl)oxy)benzaldehyde
Figure PCTCN2015077043-appb-000140
Figure PCTCN2015077043-appb-000140
将实施例23(30毫克，67微摩尔)和三氟乙酸(0.5毫升)的水(0.5毫升)及甲醇(0.5毫升)反应液在40℃下搅拌16小时。旋干，残余物通过制备HPLC分离得到标题化合物(2毫克，产率：7％)。1H NMR(CDCl3,400MHz)：7.75(d，J＝8.5Hz,2H),7.68(s,1H),6.96(d,J＝8.8Hz,2H),4.45(q,J＝7.4Hz,2H),3.84(s,3H),1.59(d,J＝3.8Hz,3H)。LCMS(ESI)m/z:405(M+1)。The reaction mixture of Example 23 (30 mg, 67 μmol) and trifluoroacetic acid (0.5 ml) in water (0.5 ml) and methanol (0.5 ml) was stirred at 40 ° C for 16 hours. The title compound (2 mg, yield: 7%) was obtained. 1 H NMR (CDCl 3 , 400 MHz): 7.75 (d, J = 8.5 Hz, 2H), 7.68 (s, 1H), 6.96 (d, J = 8.8 Hz, 2H), 4.45 (q, J = 7.4 Hz, 2H), 3.84 (s, 3H), 1.59 (d, J = 3.8 Hz, 3H). LCMS (ESI) m/z:
实施例25Example 25
(E)-4-((6-(5-(2-氨基吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)己基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((6-(5-(2-Aminopyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)hexyl)oxy Benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000141
Figure PCTCN2015077043-appb-000141
实施例25AExample 25A
Figure PCTCN2015077043-appb-000142
Figure PCTCN2015077043-appb-000142
(E)-4-((6-溴己基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((6-bromohexyl)oxy)benzaldehyde-oxy-ethyl ketone oxime
本实施例的制备方法参照实施例23B。1H NMR(400MHz,CHLOROFORM-d)8.04(d,J＝4.52Hz,1H),7.51(d,J＝4.52Hz,2H),6.88(d,J＝5.77Hz,2H),4.15-4.29(m,2H),3.99(d,J＝5.77Hz,2H),3.37-3.50(m,2H),1.74-2.00(m,4H),1.52(br.s.,4H),1.23-1.37(m,3H)。The preparation method of this example is referred to Example 23B. 1 H NMR (400MHz, CHLOROFORM- d) 8.04 (d, J = 4.52Hz, 1H), 7.51 (d, J = 4.52Hz, 2H), 6.88 (d, J = 5.77Hz, 2H), 4.15-4.29 ( m, 2H), 3.99 (d, J = 5.77 Hz, 2H), 3.37-3.50 (m, 2H), 1.74 - 2.00 (m, 4H), 1.52 (br.s., 4H), 1.23-1.37 (m , 3H).
实施例25BExample 25B
4-((6-(5-(2-氯吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)己基)氧基)苯甲醛-氧-乙基酮肟4-((6-(5-(2-Chloropyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)hexyl)oxy)benzaldehyde- Oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000143
Figure PCTCN2015077043-appb-000143
本实施例的制备方法参照实施例23C。1H NMR(400MHz,CHLOROFORM-d)8.28(d,J＝6.02Hz,1H),8.04(s,1H),7.52(d,J＝8.78Hz,2H),7.07(dd,J＝2.13,5.90Hz,1H),7.01(d,J＝2.01Hz,1H),6.89(d,J＝8.78Hz,2H),4.21(q,J＝7.03Hz,2H),4.00(t,J＝6.27Hz,2H),3.84(t,J＝6.40Hz,2H),3.55(t,J＝6.27Hz,2H),3.17(t,J＝7.28Hz,2H),1.79-1.87(m,2H),1.70-1.78(m,2H),1.49-1.58(m,4H),1.33(t,J＝7.03Hz,4H)。LCMS(ESI)m/z:480(M+1)。 The preparation method of this example is referred to Example 23C. 1 H NMR (400MHz, CHLOROFORM- d) 8.28 (d, J = 6.02Hz, 1H), 8.04 (s, 1H), 7.52 (d, J = 8.78Hz, 2H), 7.07 (dd, J = 2.13,5.90 Hz, 1H), 7.01 (d, J = 2.01 Hz, 1H), 6.89 (d, J = 8.78 Hz, 2H), 4.21 (q, J = 7.03 Hz, 2H), 4.00 (t, J = 6.27 Hz, 2H), 3.84 (t, J = 6.40 Hz, 2H), 3.55 (t, J = 6.27 Hz, 2H), 3.17 (t, J = 7.28 Hz, 2H), 1.79-1.87 (m, 2H), 1.70- 1.78 (m, 2H), 1.49-1.58 (m, 4H), 1.33 (t, J = 7.03 Hz, 4H). LCMS (ESI) m/z:
实施例25CExample 25C
(E)-4-((6-(5-(2-氨基吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)己基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((6-(5-(2-Aminopyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)hexyl)oxy Benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000144
Figure PCTCN2015077043-appb-000144
本实施例的制备方法参照实施例23。1H NMR(400MHz,CHLOROFORM-d)8.00-8.06(m,1H),7.93(d,J＝6.02Hz,1H),7.51(d,J＝9.03Hz,3H),6.87(d,J＝8.53Hz,3H),6.46(d,J＝4.52Hz,1H),6.28(s,1H),4.12-4.24(m,3H),3.98(t,J＝6.27Hz,3H),3.79(t,J＝6.27Hz,2H),3.49(t,J＝6.27Hz,2H),3.13(t,J＝7.03Hz,3H),1.77-1.85(m,2H),1.67-1.76(m,3H),1.51(t,J＝10.54Hz,5H),1.32(t,J＝7.03Hz,4H)。LCMS(ESI)m/z:462(M+1)。The preparation method of this example is referred to Example 23. 1 H NMR (400MHz, CHLOROFORM- d) 8.00-8.06 (m, 1H), 7.93 (d, J = 6.02Hz, 1H), 7.51 (d, J = 9.03Hz, 3H), 6.87 (d, J = 8.53 Hz, 3H), 6.46 (d, J = 4.52 Hz, 1H), 6.28 (s, 1H), 4.12-4.24 (m, 3H), 3.98 (t, J = 6.27 Hz, 3H), 3.79 (t, J =6.27Hz,2H), 3.49(t,J=6.27Hz,2H),3.13(t,J=7.03Hz,3H),1.77-1.85(m,2H),1.67-1.76(m,3H),1.51 (t, J = 10.54 Hz, 5H), 1.32 (t, J = 7.03 Hz, 4H). LCMS (ESI) m.
实施例26Example 26
(E)-4-(4-(5-(2-氨基吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)丁基)氧基)苯甲醛-氧-乙基酮肟(E)-4-(4-(5-(2-Aminopyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)butyl)oxy Benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000145
Figure PCTCN2015077043-appb-000145
本实施例的制备方法参照实施例25。1H NMR(400MHz,CHLOROFORM-d)8.05(s,1H),7.99(d,J＝5.77Hz,1H),7.53(d,J＝8.78Hz,2H),6.90(d,J＝8.78Hz,2H),6.43(d,J＝4.52Hz,1H),6.30(s,1H),4.56(br.s.,1H),4.22(q,J＝7.03Hz,2H),4.06(t,J＝5.14Hz,2H),3.77(t,J＝6.27Hz,2H),3.51(t,J＝6.27Hz,2H),3.22(t,J＝6.40Hz,2H),1.93(br.s.,5H),1.34(t,J＝7.15Hz,4H)。LCMS(ESI)m/z:434(M+1)。The preparation method of this example is referred to Example 25. 1 H NMR (400MHz, CHLOROFORM- d) 8.05 (s, 1H), 7.99 (d, J = 5.77Hz, 1H), 7.53 (d, J = 8.78Hz, 2H), 6.90 (d, J = 8.78Hz, 2H), 6.43 (d, J = 4.52 Hz, 1H), 6.30 (s, 1H), 4.56 (br.s., 1H), 4.22 (q, J = 7.03 Hz, 2H), 4.06 (t, J = 5.14 Hz, 2H), 3.77 (t, J = 6.27 Hz, 2H), 3.51 (t, J = 6.27 Hz, 2H), 3.22 (t, J = 6.40 Hz, 2H), 1.93 (br.s., 5H) ), 1.34 (t, J = 7.15 Hz, 4H). LCMS (ESI) m/z:
实施例27Example 27
4-(5-(5-(4-(2-乙基四唑-5-基)苯氧基)戊基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)吡啶-2-胺4-(5-(5-(4-(2-ethyltetrazol-5-yl)phenoxy)pentyl)-1,1-dioxy-1,2,5-thiadiazolidine-2 -yl)pyridin-2-amine
Figure PCTCN2015077043-appb-000146
Figure PCTCN2015077043-appb-000146
实施例27AExample 27A
2-(5-(4-(2-乙基四唑-5-基)苯氧基)戊基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(5-(4-(2-ethyltetrazol-5-yl)phenoxy)pentyl)-5-(pyridin-4-yl)-1,2,5-thiadiazolidine-1 , 1-dioxide
Figure PCTCN2015077043-appb-000147
Figure PCTCN2015077043-appb-000147
0℃下，向实施例4E(100毫克，0.43毫摩尔)的N,N-二甲基甲酰胺(3毫升)溶液中加入氢化钠(20毫克，0.85毫摩尔)。0℃下保持30分钟后，向上述混合溶液中加入实施例11D(51毫克,0.15毫摩尔) 的N,N-二甲基甲酰胺(1毫升)溶液。15℃下搅拌反应6小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发后柱分离(石油醚:乙酸乙酯＝1:1)得到标题化合物(白色固体，120毫克，收率57％)。1H NMR(CDCl3400MHz,)δ8.27(d,J＝6.0Hz,1H),8.07(d,J＝8.5Hz,2H),7.07(dd,J＝5.8,2.3Hz,1H),6.99-7.00(m,2H),4.69(q,J＝7.2Hz,2H),4.05(t,J＝6.3Hz,2H),3.84(t,J＝6.3Hz,2H),3.56(t,J＝6.3Hz,2H),3.19(t,J＝7.0Hz,2H),1.86-1.93(m,2H),1.76-1.83(m,2H),1.64-1.71(m,5H)。LCMS(ESI)m/z:492(M+1)。Sodium hydride (20 mg, 0.85 mmol) was added to a solution of EtOAc (EtOAc m. After maintaining for 30 minutes at 0 ° C, a solution of Example 11D (51 mg, 0.15 mmol) of N,N-dimethylformamide (1 ml) was added to the mixture. After stirring the reaction at 15 ° C for 6 hours, the reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried with EtOAc EtOAc EtOAcjjjjjjj 1 H NMR (CDCl 3 400 MHz,) δ 8.27 (d, J = 6.0 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.07 (dd, J = 5.8, 2.3 Hz, 1H), 6.99 -7.00 (m, 2H), 4.69 (q, J = 7.2 Hz, 2H), 4.05 (t, J = 6.3 Hz, 2H), 3.84 (t, J = 6.3 Hz, 2H), 3.56 (t, J = 6.3 Hz, 2H), 3.19 (t, J = 7.0 Hz, 2H), 1.86-1.93 (m, 2H), 1.76-1.83 (m, 2H), 1.64-1.71 (m, 5H). LCMS (ESI) m/z: 495 (21.
实施例27BExample 27B
4-(5-(5-(4-(2-基四唑-5-基)苯氧基)戊基)-1,1-氧化-1,2,5-噻二唑烷-2-基)吡啶-2-胺4-(5-(5-(4-(2-yltetrazol-5-yl)phenoxy)pentyl)-1,1-oxy-1,2,5-thiadiazol-2-yl Pyridin-2-amine
Figure PCTCN2015077043-appb-000148
Figure PCTCN2015077043-appb-000148
0℃下，向实施例27A(120毫克,0.24毫摩尔)的N,N-二甲基甲酰胺(1毫升)溶液中加入碳酸铯(159毫克,0.49毫摩尔)，氨基甲酸叔丁酯(171毫克,1.5毫摩尔)。在氮气保护下加入Pd2(dba)3(8.6毫克,20毫摩尔)，Xantphos(11.7毫克,20毫摩尔)。110℃下搅拌反应15小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发得到标题化合物(白色固体，15毫克，收率12％)。1H NMR(CDCl3400MHz,)δ8.51(d,J＝6.5Hz,2H)8.06(d,J＝8.5Hz,2H)7.05(d,J＝6.0Hz,2H)6.99(d,J＝9.0Hz,2H)4.68(q,J＝7.5Hz,2H)4.04(t,J＝6.0Hz,2H)3.85(t,J＝6.3Hz,2H)3.55(t,J＝6.3Hz,2H)3.19(t,J＝7.3Hz,2H)1.85-1.93(m,2H)1.76-1.83(m,2H)1.68(t,J＝7.5Hz,5H)。LCMS(ESI)m/z:473(M+1)。To a solution of Example 27A (120 mg, 0.24 mmol) in N,N-dimethylformamide (1 mL), EtOAc ( 159 mg, 171 mg, 1.5 mmol). Pd 2 (dba) 3 (8.6 mg, 20 mmol), Xantphos (11.7 mg, 20 mmol) was added under nitrogen. After the reaction was stirred at 110 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated. The combined organic phases were dried with EtOAcjjjjjjjj 1 H NMR (CDCl 3 400 MHz,) δ 8.51 (d, J = 6.5 Hz, 2H) 8.06 (d, J = 8.5 Hz, 2H) 7.05 (d, J = 6.0 Hz, 2H) 6.9 (d, J = 9.0 Hz, 2H) 4.68 (q, J = 7.5 Hz, 2H) 4.04 (t, J = 6.0 Hz, 2H) 3.85 (t, J = 6.3 Hz, 2H) 3.55 (t, J = 6.3 Hz, 2H) 3.19 (t, J = 7.3 Hz, 2H) 1.85-1.93 (m, 2H) 1.76-1.83 (m, 2H) 1.68 (t, J = 7.5 Hz, 5H). LCMS (ESI) m.
实施例28Example 28
4-(5-(5-((3-乙氧基-1,2-苯并唑-6-基)氧基)戊基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)吡啶-2-胺4-(5-(5-((3-ethoxy-1,2-benzoxazol-6-yl)oxy)pentyl)-1,1-dioxy-1,2,5-thiadi Oxazin-2-yl)pyridin-2-amine
Figure PCTCN2015077043-appb-000149
Figure PCTCN2015077043-appb-000149
实施例28AExample 28A
2-(2-氯-4-吡啶基)-5-(5-((3-乙氧基-1,2-苯并唑-6-基)氧基)戊基)-1,2,5-噻二唑烷1,1-二氧化物2-(2-Chloro-4-pyridyl)-5-(5-((3-ethoxy-1,2-benzoxazol-6-yl)oxy)pentyl)-1,2,5 -thiadiazolidine 1,1-dioxide
Figure PCTCN2015077043-appb-000150
Figure PCTCN2015077043-appb-000150
在0℃氮气保护下将钠氢(53.3毫克，2.2毫摩尔)分批加入实施例4E(500毫克，1.8毫摩尔)的N,N-二甲基甲酰胺(1毫升)溶液中，0℃下反应1小时后，再将实施例12E(911毫克,2.8毫摩尔)的N,N-二甲基甲酰(1毫升)的溶液滴加到上述体系中，升温至室温反应2小时，然后将反应液倒入水(10毫 升)中，用乙酸乙酯(10毫升×3)萃取，合并的有机相用无水硫酸钠干燥，过滤，旋转蒸发仪上除去溶剂后得到标题化合物(白色固体，50.00毫克,收率5.6％)。LCMS(ESI)m/z:481(M+1)。Sodium hydrogen (53.3 mg, 2.2 mmol) was added portionwise to a solution of EtOAc (EtOAc m. After 1 hour of the reaction, a solution of Example 12E (911 mg, 2.8 mmol) of N,N-dimethylformyl (1 ml) was added dropwise to the above system, and the mixture was warmed to room temperature for 2 hours, then Pour the reaction solution into water (10 m The title compound (white solid, 50.00 mg, yield 5.6%) was obtained from EtOAc (EtOAc) ). LCMS (ESI) m/z: 481 (21.
实施例28BExample 28B
4-(5-(5-((3-乙氧基-1,2-苯并唑-6-基)氧基)戊基)-1,1-二氧化1,2,5-噻二唑烷-2-基)吡啶-2-胺4-(5-(5-(3-ethoxy-1,2-benzoxazol-6-yl)oxy)pentyl)-1,1-dioxy 1,2,5-thiadiazole Alkan-2-yl)pyridin-2-amine
Figure PCTCN2015077043-appb-000151
Figure PCTCN2015077043-appb-000151
在氮气保护下将碳酸铯(339毫克，1.0毫摩尔)，Pd2(dba)3(47.6毫克,52微摩尔)，Xantphos(60.2毫克,0.1毫摩尔)加入实施例28A(250毫克，0.5毫摩尔)和氨基甲酸叔丁酯(61毫克，0.5毫摩尔)在二氧六环(2毫升)和N,N-二甲基甲酰胺(1毫升)的溶液中，将反应液升温到110℃下反应10小时。然后将反应液倒入水(150毫升)中用乙酸乙酯(100毫升×3)萃取。合并有机相，用饱和食盐水(100毫升×2)洗涤，无水硫酸钠干燥,过滤蒸发，残留物用制备HPLC纯化得到标题化合物(白色固体，25毫克,收率10.4％)。1H NMR(CDCl3,400MHz)δ7.98(d,J＝6.02Hz,1H),7.47(d,J＝9.54Hz,1H),6.81-6.87(m,2H),6.42(dd,J＝1.76,5.77Hz,1H),6.30(d,J＝1.51Hz,1H),4.53(br.s.,1H),4.47(q,J＝7.03Hz,2H),4.03(t,J＝6.02Hz,2H),3.81(t,J＝6.53Hz,2H),3.51(t,J＝6.53Hz,2H),3.17(t,J＝7.28Hz,2H),1.85-1.95(m,2H),1.79(quin,J＝7.40Hz,2H),1.65-1.68(m,2H),1.51(t,J＝7.28Hz,3H)。LCMS(ESI)m/z:462(M+1)。Cesium carbonate (339 mg, 1.0 mmol), Pd 2 (dba) 3 (47.6 mg, 52 μmol), Xantphos (60.2 mg, 0.1 mmol) was added under a nitrogen atmosphere to Example 28A (250 mg, 0.5 mM). Molar) and tert-butyl carbamate (61 mg, 0.5 mmol) in dioxane (2 ml) and N,N-dimethylformamide (1 ml), the mixture was warmed to 110 ° C The reaction was carried out for 10 hours. The reaction mixture was poured into water (150 ml) The combined organic phases were washed with EtOAc EtOAc m. 1 H NMR (CDCl 3 , 400 MHz) δ 7.98 (d, J = 6.02 Hz, 1H), 7.47 (d, J = 9.54 Hz, 1H), 6.81-6.87 (m, 2H), 6.42 (dd, J = 1.76, 5.77 Hz, 1H), 6.30 (d, J = 1.51 Hz, 1H), 4.53 (br.s., 1H), 4.47 (q, J = 7.03 Hz, 2H), 4.03 (t, J = 6.02 Hz) , 2H), 3.81 (t, J = 6.53 Hz, 2H), 3.51 (t, J = 6.53 Hz, 2H), 3.17 (t, J = 7.28 Hz, 2H), 1.85-1.95 (m, 2H), 1.79 (quin, J = 7.40 Hz, 2H), 1.65-1.68 (m, 2H), 1.51 (t, J = 7.28 Hz, 3H). LCMS (ESI) m.
流程LProcess L
Figure PCTCN2015077043-appb-000152
Figure PCTCN2015077043-appb-000152
实施例29Example 29
(S,E)-2-(2-氨基吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)-3-甲基戊基)-1,2,5-噻二唑烷-1,1-二氧化物(S,E)-2-(2-Aminopyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl) )oxy)-3-methylpentyl)-1,2,5-thiadiazolidine-1,1-dioxide
和(R,E)-2-(2-氨基吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧)-3-甲基戊基)-1,2,5-噻二唑烷-1,1-二氧化物And (R,E)-2-(2-aminopyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indole-5-) Oxy)-3-methylpentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000153
实施例29A
Figure PCTCN2015077043-appb-000153
Example 29A
(E)-5-羟基-2,3-二氢-1H-茚-1-氧-乙基酮肟 (E)-5-hydroxy-2,3-dihydro-1H-inden-1-oxo-ethyl ketone oxime
Figure PCTCN2015077043-appb-000154
Figure PCTCN2015077043-appb-000154
将实施例8B(2.5克，13.1毫摩尔)，14A(6.1克，14.4毫摩尔)和碳酸钾(3.6克，26.1毫摩尔)的乙腈(50毫升)混合溶液在80℃下反应16小时。将乙酸乙酯(50毫升)和水(50毫升)加入反应体系，水层用乙酸乙酯(50毫升×3)萃取，将合并的有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化(石油醚：乙酸乙酯＝20：1～5：1)得到标题化合物(无色液体，2.5克，39％产率)。1H-NMR(CDCl3,400MHz)7.79(d,J＝8.0Hz,2H),7.60(d,J＝9.0Hz,1H),7.34(d,J＝8.0Hz,2H),6.74-6.80(m,2H),4.20(q,J＝7.0Hz,2H),4.08-4.13(m,2H),3.91-4.01(m,2H),2.95-3.03(m,2H),2.85-2.93(m,2H),2.44(s,3H),1.72-1.87(m,3H),1.50-1.61(m,2H),1.33(t,J＝7.0Hz,3H),0.91(d,J＝6.5Hz,3H)。A mixed solution of Example 8B (2.5 g, 13.1 mmol), 14A (6.1 g, 14.4 mmol) and potassium carbonate (3.6 g, 26.1 mmol) in acetonitrile (50 ml) was reacted at 80 ° C for 16 hours. Ethyl acetate (50 ml) and water (50 ml) were evaporated. The title compound (colorless liquid, 2.5 g, 39% yield). 1 H-NMR (CDCl 3, 400 MHz) 7.79 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 6.74 - 6.80 ( m, 2H), 4.20 (q, J = 7.0 Hz, 2H), 4.08-4.13 (m, 2H), 3.91-4.01 (m, 2H), 2.95-3.03 (m, 2H), 2.85-2.93 (m, 2H), 2.44 (s, 3H), 1.72-1.87 (m, 3H), 1.50-1.61 (m, 2H), 1.33 (t, J = 7.0 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H) ).
实施例29BExample 29B
(E)-2-(2-氯吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)-3-甲基戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-chloropyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy) 3-methylpentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000155
Figure PCTCN2015077043-appb-000155
0℃下向实施例4E(1.3克，4.8毫摩尔)的N,N-二甲基甲酰胺(40毫升)的混合液慢慢加钠氢(673毫克，16.8毫摩尔)，30分钟后滴加实施例29A(2.5克，5.6毫摩尔)的N,N-二甲基甲酰胺(40毫升)的混合液，混合物在25℃下反应12小时。水(30毫升)加入反应体系，水层用二氯甲烷(40毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化(石油醚：乙酸乙酯＝5：1～1：1)得到标题化合物(黄色液体，2.1克，66％产率)。1H-NMR(CDCl3,400MHz)8.25(d,J＝6.0Hz,1H),7.55-7.61(m,1H),7.04(dd,J＝5.5,2.0Hz,1H),6.98(d,J＝2.0Hz,1H),6.75-6.80(m,2H),4.18(q,J＝7.0Hz,2H),4.11(q,J＝7.4Hz,1H),3.97-4.05(m,2H),3.80(t,J＝6.5Hz,2H),3.47-3.55(m,2H),3.19(t,J＝7.3Hz,2H),2.94-2.98(m,2H),2.86-2.90(m,2H),1.78-1.87(m,2H),1.53-1.71(m,2H),1.31(t,J＝7.0Hz,3H),1.02(d,J＝6.5Hz,3H)。LCMS(ESI)m/z:507(M+1)。Slowly add sodium hydrogen (673 mg, 16.8 mmol) to a mixture of Example 4E (1.3 g, 4.8 mmol) of N,N-dimethylformamide (40 ml) at 0 ° C. A mixture of Example 29A (2.5 g, 5.6 mmol) of N,N-dimethylformamide (40 ml) was obtained, and the mixture was reacted at 25 ° C for 12 hours. Water (30 ml) was added to the reaction mixture, the aqueous layer was evaporated, mjjjjjjjjjjjjjjjjjj The title compound (yellow liquid, 2.1 g, 66% yield). 1 H-NMR (CDCl 3 , 400 MHz) 8.25 (d, J = 6.0 Hz, 1H), 7.55 - 7.61 (m, 1H), 7.04 (dd, J = 5.5, 2.0 Hz, 1H), 6.98 (d, J) =2.0 Hz, 1H), 6.75-6.80 (m, 2H), 4.18 (q, J = 7.0 Hz, 2H), 4.11 (q, J = 7.4 Hz, 1H), 3.97-4.05 (m, 2H), 3.80 (t, J = 6.5 Hz, 2H), 3.47 - 3.55 (m, 2H), 3.19 (t, J = 7.3 Hz, 2H), 2.94 - 2.98 (m, 2H), 2.86 - 2.90 (m, 2H), 1.78-1.87 (m, 2H), 1.53-1.71 (m, 2H), 1.31 (t, J = 7.0 Hz, 3H), 1.02 (d, J = 6.5 Hz, 3H). LCMS (ESI) m/z:
实施例29CExample 29C
(E)-2-(2-氨基吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)-3-甲基戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-Aminopyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy) 3-methylpentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000156
Figure PCTCN2015077043-appb-000156
本实施例的制备方法参照实施例28。1H-NMR(CDCl3,400MHz)7.97(d,J＝5.8Hz,1H),7.53-7.68(m,1H),6.76-6.80(m,2H),6.41(dd,J＝5.8,2.0Hz,1H),6.27(d,J＝2.0Hz,1H),4.49(br.s.,2H),4.19(q,J＝7.0Hz,2H),4.03(q,J＝6.0Hz,2H),3.76(t,J＝6.4Hz,2H),3.44-3.50(m,2H),3.18(t,J＝7.5Hz,2H),2.95-3.00(m,2H),2.86-2.91(m,2H),1.68-1.92(m,5H),1.32(t,J＝7.0Hz,3H),1.03(d,J＝6.3Hz,3H)。 LCMS(ESI)m/z:488(M+1)。The preparation method of this example is referred to Example 28. 1 H-NMR (CDCl 3, 400 MHz) 7.97 (d, J = 5.8 Hz, 1H), 7.53 - 7.68 (m, 1H), 6.76 - 6.80 (m, 2H), 6.41 (dd, J = 5.8, 2.0 Hz , 1H), 6.27 (d, J = 2.0 Hz, 1H), 4.49 (br.s., 2H), 4.19 (q, J = 7.0 Hz, 2H), 4.03 (q, J = 6.0 Hz, 2H), 3.76 (t, J = 6.4 Hz, 2H), 3.44 - 3.50 (m, 2H), 3.18 (t, J = 7.5 Hz, 2H), 2.95 - 3.00 (m, 2H), 2.86 - 2.91 (m, 2H) , 1.68-1.92 (m, 5H), 1.32 (t, J = 7.0 Hz, 3H), 1.03 (d, J = 6.3 Hz, 3H). LCMS (ESI) m/z:
实施例29DExample 29D
(S,E)-2-(2-氨基吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧)-3-甲基戊基)-1,2,5-噻二唑烷-1,1-二氧化物(S,E)-2-(2-Aminopyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl) Oxy)-3-methylpentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000157
Figure PCTCN2015077043-appb-000157
(R,E)-2-(2-氨基吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧)-3-甲基戊基)-1,2,5-噻二唑烷-1,1-二氧化物(R,E)-2-(2-Aminopyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl) Oxy)-3-methylpentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000158
Figure PCTCN2015077043-appb-000158
实施例29C通过手性分离(AD-H_3UM_3_60_3毫升_5MIN,Column:Chiralpak AD-350*4.6mm I.D.,3um流动相:60％甲醇(0.05％DEA)-CO2流速:3毫升/分钟；波长：220nm；出峰时间：1.334min,1.823min)得到标题化合物。1H-NMR(CDCl3,400MHz)7.97(d,J＝6.0Hz,1H),7.56-7.63(m,1H),6.79(br.s.,2H),6.41(dd,J＝6.0,2.0Hz,1H),6.27(d,J＝1.8Hz,1H),4.51(br.s.,2H),4.17-4.23(m,2H),3.99-4.08(m,2H),3.76(t,J＝6.4Hz,2H),3.45-3.51(m,2H),3.18(t,J＝7.5Hz,2H),2.95-3.00(m,2H),2.86-2.91(m,2H),1.69-1.93(m,5H),1.32(t,J＝7.0Hz,3H),1.03(d,J＝6.5Hz,3H)。LCMS(ESI)m/z:488(M+1)。Example 29C by chiral separation (AD-H_3UM_3_60_3 ml_5MIN, Column: Chiralpak AD-350*4.6 mm ID, 3um mobile phase: 60% methanol (0.05% DEA) - CO 2 flow rate: 3 ml/min; wavelength: 220 nm; peak time: 1.334 min, 1.823 min) gave the title compound. 1 H-NMR (CDCl 3, 400 MHz) 7.97 (d, J = 6.0 Hz, 1H), 7.56-7.63 (m, 1H), 6.79 (br.s., 2H), 6.41 (dd, J = 6.0, 2.0 Hz, 1H), 6.27 (d, J = 1.8 Hz, 1H), 4.51 (br.s., 2H), 4.17-4.23 (m, 2H), 3.99-4.08 (m, 2H), 3.76 (t, J = 6.4 Hz, 2H), 3.45-3.51 (m, 2H), 3.18 (t, J = 7.5 Hz, 2H), 2.95-3.00 (m, 2H), 2.86-2.91 (m, 2H), 1.69-1.93 ( m, 5H), 1.32 (t, J = 7.0 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H). LCMS (ESI) m/z:
1H-NMR(CDCl3,400MHz)7.97(d,J＝5.8Hz,1H),7.53-7.68(m,1H),6.76-6.80(m,2H),6.41(dd,J＝5.8,2.0Hz,1H),6.27(d,J＝2.0Hz,1H),4.49(br.s.,2H),4.19(q,J＝7.0Hz,2H),4.03(q,J＝6.0Hz,2H),3.76(t,J＝6.4Hz,2H),3.44-3.50(m,2H),3.18(t,J＝7.5Hz,2H),2.95-3.00(m,2H),2.86-2.91(m,2H),1.68-1.92(m,5H),1.32(t,J＝7.0Hz,3H),1.03(d,J＝6.3Hz,3H)。LCMS(ESI)m/z:488(M+1)。 1 H-NMR (CDCl 3, 400 MHz) 7.97 (d, J = 5.8 Hz, 1H), 7.53 - 7.68 (m, 1H), 6.76 - 6.80 (m, 2H), 6.41 (dd, J = 5.8, 2.0 Hz , 1H), 6.27 (d, J = 2.0 Hz, 1H), 4.49 (br.s., 2H), 4.19 (q, J = 7.0 Hz, 2H), 4.03 (q, J = 6.0 Hz, 2H), 3.76 (t, J = 6.4 Hz, 2H), 3.44 - 3.50 (m, 2H), 3.18 (t, J = 7.5 Hz, 2H), 2.95 - 3.00 (m, 2H), 2.86 - 2.91 (m, 2H) , 1.68-1.92 (m, 5H), 1.32 (t, J = 7.0 Hz, 3H), 1.03 (d, J = 6.3 Hz, 3H). LCMS (ESI) m/z:
实施例30Example 30
(E)-2-(2-氨基吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)-3，3-二甲基戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-Aminopyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy) -3,3-dimethylpentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000159
Figure PCTCN2015077043-appb-000159
实施例30AExample 30A
3,3-二甲基戊烷-1,5-二醇3,3-dimethylpentane-1,5-diol
Figure PCTCN2015077043-appb-000160
Figure PCTCN2015077043-appb-000160
0℃下，氮气保护下，向4,4-二甲基戊二酸酐(500毫克，3.5毫摩尔)的四氢呋喃(20毫升)溶液中加入四氢铝锂(534毫克,14.1毫摩尔)。加完后混合物在80℃下搅拌12小时。将反应液降至室温后倒入冰水中(50毫升)搅拌10分钟。水相用乙酸乙酯(30毫升x 3)萃取，将合并的有机相用无水硫酸钠干燥，过滤浓缩得到标题化合物(黄色液体，300毫克,64％产率)。1H NMR(400MHz,CHLOROFORM-d)3.69(t,J＝7.15Hz,4H),3.25(br.s.,2H),1.49-1.63(m,4H),0.89-0.95(m,6H)。To a solution of 4,4-dimethylglutaric anhydride (500 mg, 3.5 mmol) in tetrahydrofuran (20 ml) was added EtOAc (m. After the addition was completed, the mixture was stirred at 80 ° C for 12 hours. The reaction solution was cooled to room temperature and poured into ice water (50 ml) and stirred for 10 min. The aqueous phase was extracted with EtOAc (EtOAc EtOAc. 1H NMR (400 MHz, CHLOROFORM-d) 3.69 (t, J = 7.15 Hz, 4H), 3.25 (br.s., 2H), 1.49-1.63 (m, 4H), 0.89 - 0.95 (m, 6H).
实施例30BExample 30B
3,3-二甲基戊烷-1,5-二基双(4-甲基苯磺酸)3,3-dimethylpentane-1,5-diylbis(4-methylbenzenesulfonic acid)
Figure PCTCN2015077043-appb-000161
Figure PCTCN2015077043-appb-000161
0℃下，向实施例30A(10克，75.6毫摩尔)的二氯甲烷(200毫升)溶液中加入对甲苯磺酰氯(43克，227毫摩尔)和三乙胺(23克，227毫摩尔)。加完后将上述混合溶液在25℃下搅拌12小时，原料消失后，将反应液倒入冰水(300毫升)中并搅拌20分钟。水相用二氯甲烷(50毫升x 4)萃取。将合并的有机相用饱和食盐水(50毫升)洗涤后用无水硫酸钠干燥，过滤浓缩，粗产物用柱层析纯化(石油醚:乙酸乙酯＝3:1)得到标题化合物(黄色液体，20克，60％产率)。1H NMR(400MHz,CHLOROFORM-d)7.77(d,J＝8.53Hz,2H),7.35(d,J＝8.03Hz,2H),4.02(t,J＝7.03Hz,2H),2.45(s,3H),1.55(t,J＝7.03Hz,2H),0.84(s,3H)。To a solution of Example 30A (10 g, 75.6 mmol) in dichloromethane <RTI ID=0.0>(</RTI> <RTIgt; <RTIgt; <RTIgt; <RTIgt; ). After the addition, the mixed solution was stirred at 25 ° C for 12 hours, and after the disappearance of the starting material, the reaction mixture was poured into ice water (300 ml) and stirred for 20 minutes. The aqueous phase was extracted with dichloromethane (50 mL x 4). The combined organic phase was washed with EtOAc EtOAc EtOAc. , 20 g, 60% yield). 1H NMR (400MHz, CHLOROFORM-d) 7.77 (d, J = 8.53 Hz, 2H), 7.35 (d, J = 8.03 Hz, 2H), 4.02 (t, J = 7.03 Hz, 2H), 2.45 (s, 3H) ), 1.55 (t, J = 7.03 Hz, 2H), 0.84 (s, 3H).
实施例30CExample 30C
(E)-5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)-3,3-二甲基戊基-4-甲基苯磺酸(E)-5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy)-3,3-dimethylpentyl-4-methyl Benzobenzenesulfonic acid
Figure PCTCN2015077043-appb-000162
Figure PCTCN2015077043-appb-000162
向实施例30C(1.0克，2.3毫摩尔)和实施例8B(173.6毫克，908微摩尔)的丙酮(20毫升)溶液中加入碳酸钾(627毫克，4.54毫摩尔)。反应液在70℃下搅拌12小时后冷却至室温，减压浓缩。向残余物中加入水(50毫升)，并用乙酸乙酯(30毫升x3)萃取。将合并的有机相用无水硫酸钠干燥，过滤浓缩并用柱层析纯化(石油醚：乙酸乙酯＝3：1)得到标题化合物(黄色固体，300毫克，72％产率)。1H NMR(400MHz,CHLOROFORM-d)7.77-7.82(m,2H),7.59(d,J＝8.53Hz,1H),7.33(d,J＝8.53Hz,2H),6.75(br.s.,2H),4.11-4.24(m,4H),3.97(t,J＝6.78Hz,2H),2.81-3.02(m,4H),2.38-2.46(m,4H),1.70(dt,J＝2.51,7.03Hz,4H),1.32(t,J＝7.03Hz,3H),0.96(s,6H)。To a solution of Example 30C (1.0 g, 2.3 mmol) and EtOAc (EtOAc) The reaction mixture was stirred at 70 ° C for 12 hr then cooled to room temperature and concentrated. Water (50 ml) was added to the residue and ethyl acetate (30 ml) The combined organic phases were dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1H NMR (400MHz, CHLOROFORM-d) 7.77-7.82 (m, 2H), 7.59 (d, J = 8.53 Hz, 1H), 7.33 (d, J = 8.53 Hz, 2H), 6.75 (br.s., 2H) ), 4.11-4.24 (m, 4H), 3.97 (t, J = 6.78 Hz, 2H), 2.81-3.02 (m, 4H), 2.38-2.46 (m, 4H), 1.70 (dt, J = 2.51, 7.03) Hz, 4H), 1.32 (t, J = 7.03 Hz, 3H), 0.96 (s, 6H).
实施例30DExample 30D
(E)-2-(2-氯吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)-3，3-二甲基戊基)-1,2-噻二唑烷-1,1-二氧化物(E)-2-(2-chloropyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy) -3,3-dimethylpentyl)-1,2-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000163
Figure PCTCN2015077043-appb-000163
0℃下，氮气保护下，向实施例4E(153毫克，653微摩尔)的N,N-二甲基甲酰胺(5毫升)溶液中加入钠氢(52毫克，1.3毫摩尔)。加完后室温搅拌反应30分钟。将实施例30C(300毫克，653微摩尔)加入上述溶液中并在室温下继续搅拌11小时。将反应液倒入冰水(30毫升)中，水相用乙酸乙酯(20毫升x 3)萃取。将合并的有机相用无水硫酸钠干燥，过滤浓缩，粗产物用柱层析纯化(石油醚：乙酸乙酯＝3：1)得到标题化合物(黄色固体，150毫克，44％产率)。1H NMR(400MHz,CHLOROFORM-d)8.27(d,J＝6.02Hz,1H),8.02(s,2H),7.60(d,J＝9.03Hz,1H),7.06(dd,J＝2.26,5.77Hz,1H),6.99(d,J＝2.01Hz,1H),6.77-6.82(m,2H),4.20(q,J＝7.03Hz,2H),4.05(t,J＝6.78Hz,2H),3.82(t,J＝6.27Hz,2H),3.54(t,J＝6.27Hz,2H),3.18-3.26(m,2H),2.97-3.03(m,2H),1.79(t,J＝6.53Hz,2H),1.68-1.76(m,2H),1.32(t,J＝7.03Hz,4H),1.06(s,6H)。LCMS(ESI)m/z:521(M+1)。Sodium hydrogen (52 mg, 1.3 mmol) was added to a solution of EtOAc (EtOAc m. After the addition was completed, the reaction was stirred at room temperature for 30 minutes. Example 30C (300 mg, 653 micromoles) was added to the above solution and stirring was continued at room temperature for 11 hours. The reaction solution was poured into ice water (30 mL) The combined organic phases were dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1H NMR (400MHz, CHLOROFORM-d) 8.27 (d, J = 6.02Hz, 1H), 8.02 (s, 2H), 7.60 (d, J = 9.03Hz, 1H), 7.06 (dd, J = 2.26, 5.77Hz) , 1H), 6.99 (d, J = 2.01 Hz, 1H), 6.77-6.82 (m, 2H), 4.20 (q, J = 7.03 Hz, 2H), 4.05 (t, J = 6.78 Hz, 2H), 3.82 (t, J = 6.27 Hz, 2H), 3.54 (t, J = 6.27 Hz, 2H), 3.18-3.26 (m, 2H), 2.97-3.03 (m, 2H), 1.79 (t, J = 6.53 Hz, 2H), 1.68-1.76 (m, 2H), 1.32 (t, J = 7.03 Hz, 4H), 1.06 (s, 6H). LCMS (ESI) m/z:
实施例30EExample 30E
(E)-2-(2-氨基吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)-3，3-二甲基戊基)-1,2-噻二唑烷-1,1-二氧化物(E)-2-(2-Aminopyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy) -3,3-dimethylpentyl)-1,2-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000164
Figure PCTCN2015077043-appb-000164
本实施例制备方法参照实施例29。1H NMR(400MHz,CHLOROFORM-d)7.82(br.s.,1H),7.61(d,J＝8.53Hz,1H),6.81(br.s.,2H),6.58(d,J＝4.02Hz,1H),6.36(br.s.,1H),4.21(d,J＝6.78Hz,2H),4.06(br.s.,2H),3.84(br.s.,2H),3.53(br.s.,2H),3.21(br.s.,2H),2.74-3.07(m,4H),1.58-1.85(m,4H),1.33(t,J＝6.53Hz,4H),1.06(br.s.,6H)。LCMS(ESI)m/z:502(M+1)。The preparation method of this example is referred to Example 29. 1 H NMR (400 MHz, CHLOROFORM-d) 7.82 (br.s., 1H), 7.61 (d, J = 8.53 Hz, 1H), 6.81 (br.s., 2H), 6.58 (d, J = 4.02 Hz , 1H), 6.36 (br.s., 1H), 4.21 (d, J = 6.78 Hz, 2H), 4.06 (br.s., 2H), 3.84 (br.s., 2H), 3.53 (br. s., 2H), 3.21 (br.s., 2H), 2.74-3.07 (m, 4H), 1.58-1.85 (m, 4H), 1.33 (t, J = 6.53 Hz, 4H), 1.06 (br. s., 6H). LCMS (ESI) m/z:
实施例31Example 31
(E)-2-(2-氨基吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)-3,3-二氟戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-Aminopyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy) -3,3-difluoropentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000165
Figure PCTCN2015077043-appb-000165
实施例31AExample 31A
二乙基-3,3-二氟戊烷二酸酯Diethyl-3,3-difluoropentane dicarboxylate
Figure PCTCN2015077043-appb-000166
Figure PCTCN2015077043-appb-000166
-65℃下向二溴海因(2.16克,7.56毫摩尔)，氢氟酸吡啶溶液(2.2毫升，1.8毫摩尔)的二氯甲烷(15毫升)溶液中慢慢加二乙基-2,2'-(1,3-二硫戊环-2,2-二基)二乙酸(501毫克,1.8毫摩尔)的二氯甲烷溶液，混合溶液在-65℃下继续搅拌5小时，升至25℃下搅拌3小时，水(10毫升)加入反应体系，体系用碳酸钠水溶液调至pH＝3-4，水层用二氯甲烷(20毫升×3)萃取，过滤旋干，残余物通过柱色谱(石油醚：乙酸乙酯＝10：1)纯化得到标题化合物(白色固体，210毫克，收率38％)得到标题化合物(黄 色液体，300毫克,收率74％)。1H NMR(CDCl3,400MHz)δ4.18(q,J＝7.0Hz,4H),3.24(t,J＝15.1Hz,4H),1.26-1.30(m,6H)。To a solution of dibromohydantoin (2.16 g, 7.56 mmol) in pyridine hydrofluoric acid (2.2 mL, 1.8 mmol) in dichloromethane (15 mL) 2'-(1,3-Dithiopenta-2,2-diyl)diacetic acid (501 mg, 1.8 mmol) in dichloromethane, the mixture was stirred at -65 ° C for 5 hours and then warmed to After stirring at 25 ° C for 3 hours, water (10 ml) was added to the reaction system, the system was adjusted to pH 3-4 with aqueous sodium carbonate solution, and the aqueous layer was extracted with dichloromethane (20 ml × 3), filtered, and dried. Column chromatography (petroleum ether: EtOAc = EtOAc) 1 H NMR (CDCl 3 , 400 MHz) δ 4.18 (q, J = 7.0 Hz, 4H), 3.24 (t,J = 15.1 Hz, 4H), 1.26-1.30 (m, 6H).
实施例31BExample 31B
3,3-二氟戊烷-1,5-二醇3,3-difluoropentane-1,5-diol
Figure PCTCN2015077043-appb-000167
Figure PCTCN2015077043-appb-000167
在0℃下向四氢铝锂(102毫克，2.68毫摩尔)的四氢呋喃(3毫升)溶液中滴加实施例31A(300毫克，1.34毫摩尔)，加完后将该混合溶液在25℃下搅拌3小时。水(0.5毫升)和10％的氢氧化钠溶液(0.5毫升)加入反应体系，体系用硫酸钠干燥，过滤并蒸发得到标题化合物(160毫克，收率72％)。1H NMR(CDCl3,400MHz)：3.77-3.90(m,4H),2.21(tt,J＝16.8,5.8Hz,4H)。Example 31A (300 mg, 1.34 mmol) was added dropwise to a solution of lithium tetrahydroaluminum (102 mg, 2.68 mmol) in tetrahydrofuran (3 mL) at 0 ° C. Stir for 3 hours. Water (0.5 ml) and a 10% sodium hydroxide solution (0.5 ml) were added to the reaction mixture. 1 H NMR (CDCl 3 , 400 MHz): 3.77 - 3.90 (m, 4H), 2.21. (t,J = 16.8, 5.8 Hz, 4H).
实施例31CExample 31C
1,5-二溴-3,3-二氟戊烷1,5-dibromo-3,3-difluoropentane
Figure PCTCN2015077043-appb-000168
Figure PCTCN2015077043-appb-000168
在0℃下向实施例31B(160毫克，1.1毫摩尔)，三苯基磷(1.79克，6.8毫摩尔)的四氢呋喃(5毫升)溶液中滴加四溴化碳(1.5克，4.6毫摩尔)，加完后将该混合溶液在60℃下搅拌3小时。过滤，滤饼用乙酸乙酯(300毫升×3)洗涤，旋干滤液，残余物通过柱色谱(石油醚：乙酸乙酯＝10：1)纯化得到标题化合物(200毫克，收率53％)。1H NMR(CDCl3,400MHz)：3.45-3.51(m,4H),2.48(tt,J＝16.2,7.9Hz,4H)。To a solution of Example 31B (160 mg, 1.1 mmol), triphenylphosphine (1.79 g, 6.8 mmol) in THF (5 mL) After the addition was completed, the mixed solution was stirred at 60 ° C for 3 hours. Filtration, the filter cake was washed with EtOAc (EtOAc (EtOAc) (EtOAc) . 1 H NMR (CDCl 3 , 400 MHz): 3.45-3.51 (m, 4H), 2.48 (t,J = 16.2, 7.9 Hz, 4H).
实施例31DExample 31D
(E)-5-((5-溴-3,3-二氟戊基)氧基)-2,3-二氢-1H-茚-1-酮-氧-乙基酮肟(E)-5-((5-Bromo-3,3-difluoropentyl)oxy)-2,3-dihydro-1H-inden-1-one-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000169
Figure PCTCN2015077043-appb-000169
本实施例的制备方法参照实施例30C。1H NMR(CDCl3)400MHz)：7.56-7.62(m,1H),6.76-6.83(m,2H),4.19(q,J＝6.9Hz,2H),4.01(t,J＝6.0Hz,2H),3.43-3.52(m,2H),2.95-3.02(m,2H),2.84-2.92(m,2H),2.03-2.12(m,2H),1.91-2.00(m,2H),1.32(t,J＝7.0Hz,3H)。The preparation method of this example is referred to Example 30C. 1 H NMR (CDCl 3 ) 400 MHz): 7.56-7.62 (m, 1H), 6.76-6.83 (m, 2H), 4.19 (q, J = 6.9 Hz, 2H), 4.01 (t, J = 6.0 Hz, 2H) ), 3.43-3.52 (m, 2H), 2.95-3.02 (m, 2H), 2.84-2.92 (m, 2H), 2.03-2.12 (m, 2H), 1.91-2.00 (m, 2H), 1.32 (t , J = 7.0 Hz, 3H).
实施例31EExample 31E
(E)-2-(2-氯吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)-3,3-二氟戊基)-1,2-噻二唑烷-1,1-二氧化物(E)-2-(2-chloropyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy) -3,3-difluoropentyl)-1,2-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000170
Figure PCTCN2015077043-appb-000170
本实施例的制备方法参照实施例30D。1H NMR(CDCl3,400MHz)：8.26(d，J＝5.8Hz,1H),7.60(d,J＝9.3Hz,1H),7.04(dd,J＝5.8,2.3Hz,1H),6.98(d,J＝2.0Hz,1H),6.73-6.86(m,3H),4.19(d,J＝7.0Hz,2H),4.00-4.05(m,2H),3.76-3.84(m,2H),3.55(t,J＝6.4Hz,2H),3.23(t,J＝6.1Hz,2H),2.96(d,J＝7.3Hz,2H),2.86-2.90(m,2H),1.86-1.96(m,4H),1.32(s,3H)。LCMS(ESI)m/z:529(M+1)。 The preparation method of this example is referred to Example 30D. 1 H NMR (CDCl 3, 400MHz ): 8.26 (d, J = 5.8Hz, 1H), 7.60 (d, J = 9.3Hz, 1H), 7.04 (dd, J = 5.8,2.3Hz, 1H), 6.98 ( d, J=2.0 Hz, 1H), 6.73-6.86 (m, 3H), 4.19 (d, J=7.0 Hz, 2H), 4.00-4.05 (m, 2H), 3.76-3.84 (m, 2H), 3.55 (t, J = 6.4 Hz, 2H), 3.23 (t, J = 6.1 Hz, 2H), 2.96 (d, J = 7.3 Hz, 2H), 2.86 - 2.90 (m, 2H), 1.86-1.96 (m, 4H), 1.32 (s, 3H). LCMS (ESI) m.
实施例31FExample 31F
(E)-2-(2-氨基吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)-3,3-二氟戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-Aminopyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy) -3,3-difluoropentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000171
Figure PCTCN2015077043-appb-000171
本实施例的制备方法参照实施例29。1H NMR(CDCl3,400MHz)：7.96(d，J＝5.8Hz,1H),7.51-7.64(m,1H),6.71-6.84(m,2H),6.40(dd,J＝5.8,1.8Hz,1H),6.24(d,J＝1.5Hz,1H),4.55(br.s.,2H),4.19(q,J＝7.0Hz,2H),4.04(t,J＝5.4Hz,2H),3.72(t,J＝6.4Hz,2H),3.42-3.55(m,2H),3.20(t,J＝6.5Hz,2H),2.92-3.00(m,2H),2.83-2.92(m,2H),1.86-1.95(m,4H),1.32(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:510(M+1)。The preparation method of this example is referred to Example 29. 1 H NMR (CDCl 3 , 400 MHz): 7.96 (d, J = 5.8 Hz, 1H), 7.51-7.64 (m, 1H), 6.71-6.84 (m, 2H), 6.40 (dd, J = 5.8, 1.8 Hz) , 1H), 6.24 (d, J = 1.5 Hz, 1H), 4.55 (br.s., 2H), 4.19 (q, J = 7.0 Hz, 2H), 4.04 (t, J = 5.4 Hz, 2H), 3.72 (t, J = 6.4 Hz, 2H), 3.42-3.55 (m, 2H), 3.20 (t, J = 6.5 Hz, 2H), 2.92-3.00 (m, 2H), 2.83 - 2.92 (m, 2H) , 1.86-1.95 (m, 4H), 1.32 (t, J = 7.0 Hz, 3H). LCMS (ESI) m/z:
流程MProcess M
Figure PCTCN2015077043-appb-000172
Figure PCTCN2015077043-appb-000172
实施例32Example 32
(E)-4-((5-(5-(2-甲基吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5-(5-(2-methylpyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl) Oxy)benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000173
Figure PCTCN2015077043-appb-000173
实施例32AExample 32A
N-叔丁基-N-(2-氯乙基)磺酰脲N-tert-butyl-N-(2-chloroethyl)sulfonylurea
Figure PCTCN2015077043-appb-000174
Figure PCTCN2015077043-appb-000174
0℃，氮气保护下，一小时内将N-(氧亚甲基)氨磺酰氯(244克，1.73摩尔)的二氯甲烷(1.0升)溶液逐滴加入至叔丁醇(453克，2.1摩尔)中。加完后混合溶液在25℃下搅拌1小时。将该混合溶液与三乙胺(872克，8.6摩尔)的混合液逐滴加入至2-氯乙胺(200克，1.73摩尔)的二氯甲烷(2升)溶液中，2小时加完。混合溶液在25℃下搅拌10小时候过滤，滤液浓缩后溶于2升水中，用4N的盐 酸调节pH＝5-6。大量固体析出，将固体过滤，并用石油醚(1升)洗涤得到标题化合物(白色固体，350克，产率78.5％)，直接用于下一步无需进一步纯化。A solution of N-(oxymethylene)sulfamoyl chloride (244 g, 1.73 mol) in dichloromethane (1.0 L) was added dropwise to a solution of tert-butanol (453 g, 2.1). Moore). After the addition was completed, the mixed solution was stirred at 25 ° C for 1 hour. A mixture of this mixed solution and triethylamine (872 g, 8.6 mol) was added dropwise to a solution of 2-chloroethylamine (200 g, 1.73 mol. The mixed solution was stirred at 25 ° C for 10 hours, and the filtrate was concentrated and dissolved in 2 liters of water with 4N of salt. The acid is adjusted to pH = 5-6. A large amount of solid was crystallized, crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
实施例32BExample 32B
叔丁基-1,2,5-噻二唑烷-2-羧酸叔丁酯-1,1-二氧化物Tert-butyl-1,2,5-thiadiazolidine-2-carboxylic acid tert-butyl ester-1,1-dioxide
Figure PCTCN2015077043-appb-000175
Figure PCTCN2015077043-appb-000175
室温下，向实施例32A(350克，1.35摩尔)的二甲亚砜(3升)溶液中加入碳酸钾(280克，2.03摩尔)混合溶液在室温下搅拌10小时候过滤。滤液倒入5升水中，用4N盐酸调节pH＝5-6，将固体过滤并用石油醚(1升)洗涤固体，将固体用(石油醚/乙酸乙酯＝1/1)(1升)重结晶得到标题化合物(白色固体，250克，84％产率)。To a solution of Example 32A (350 g, 1.35 mol) of dimethyl sulfoxide (3 liters), a mixture of potassium carbonate (280 g, 2.03 mol) was added and stirred at room temperature for 10 hours. The filtrate was poured into 5 liters of water, and the pH was adjusted to 5-6 with 4N hydrochloric acid. The solid was filtered and washed with petroleum ether (1 liter), and the solid was weighed ( petroleum ether/ethyl acetate = 1/1) (1 liter) Crystallization gave the title compound (m.
实施例32CExample 32C
4-((5-溴苯基)戊基)苯甲醛4-((5-bromophenyl)pentyl)benzaldehyde
Figure PCTCN2015077043-appb-000176
Figure PCTCN2015077043-appb-000176
本实施例的制备方法参照实施例4G。1H NMR(400MHz,CHLOROFORM-d)9.81-9.89(m,1H),7.81(d,J＝8.80Hz,2H),6.97-7.02(m,2H),4.04(t,J＝6.40Hz,2H),3.39-3.46(m,2H),1.94(t,J＝7.60Hz,2H),1.84(t,J＝7.20Hz,2H),1.61-1.65(m,2H)。The preparation method of this example is referred to Example 4G. 1 H NMR (400MHz, CHLOROFORM- d) 9.81-9.89 (m, 1H), 7.81 (d, J = 8.80Hz, 2H), 6.97-7.02 (m, 2H), 4.04 (t, J = 6.40Hz, 2H ), 3.39-3.46 (m, 2H), 1.94 (t, J = 7.60 Hz, 2H), 1.84 (t, J = 7.20 Hz, 2H), 1.61-1.65 (m, 2H).
实施例32DExample 32D
叔丁酯5(5(4-甲酰基苯氧基)戊基)-1,2,5-噻二唑烷-2-羧酸叔丁酯-1,1-二氧化物tert-Butyl ester 5(5(4-formylphenoxy)pentyl)-1,2,5-thiadiazolidine-2-carboxylic acid tert-butyl ester-1,1-dioxide
Figure PCTCN2015077043-appb-000177
Figure PCTCN2015077043-appb-000177
在0℃氮气保护下，向实施例32C(550毫克，2.5毫摩尔)的N,N-二甲基甲酰胺(8毫升)溶液中加入钠氢(81毫克，2.0毫摩尔)，0℃下搅拌0.5小时后向其中逐滴加入4-((5-溴苯基)戊基)苯甲醛(671毫克,2.5毫摩尔)的N,N-二甲基甲酰胺(19毫升)溶液。在0℃下搅拌0.5小时后TLC检测反应结束。加入水(10毫升)淬灭反应，水层用乙酸乙酯(10毫升x 3)萃取，合并有机层用硫酸钠干燥，过滤并蒸发，粗品用薄层色谱板分离(石油醚：乙酸乙酯＝3:1)得到标题化合物(白色固体，400毫克，60％)。1H NMR(400MHz,CHLOROFORM-d)9.88(s,1H),7.82(d,J＝8.53Hz,2H),6.98(d,J＝8.53Hz,2H),4.05(t,J＝6.27Hz,2H),3.79(t,J＝6.53Hz,2H),3.32(t,J＝6.27Hz,2H),3.08(t,J＝7.28Hz,2H),1.82-1.91(m,2H),1.72-1.79(m,2H),1.57-1.64(m,2H),1.54(s,10H)。Sodium hydrogen (81 mg, 2.0 mmol) was added to a solution of Example 32C (550 mg, 2.5 mmol) of N,N-dimethylformamide (8 mL). After stirring for 0.5 hours, a solution of 4-((5-bromophenyl)pentyl)benzaldehyde (671 mg, 2.5 mmol) in N,N-dimethylformamide (19 ml) was added dropwise. After stirring at 0 ° C for 0.5 hour, the reaction was terminated by TLC. The reaction was quenched with EtOAc (EtOAc (EtOAc)EtOAc. The title compound (white solid, 400 mg, 60%) was obtained. 1 H NMR (400MHz, CHLOROFORM- d) 9.88 (s, 1H), 7.82 (d, J = 8.53Hz, 2H), 6.98 (d, J = 8.53Hz, 2H), 4.05 (t, J = 6.27Hz, 2H), 3.79 (t, J = 6.53 Hz, 2H), 3.32 (t, J = 6.27 Hz, 2H), 3.08 (t, J = 7.28 Hz, 2H), 1.82-1.91 (m, 2H), 1.72 1.79 (m, 2H), 1.57-1.64 (m, 2H), 1.54 (s, 10H).
实施例32E Example 32E
4-((5-(1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛4-((5-(1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl)oxy)benzaldehyde
Figure PCTCN2015077043-appb-000178
Figure PCTCN2015077043-appb-000178
在0℃下向实施例32D(4克，9.7毫摩尔)的二氯甲烷(40毫升)溶液中加入三氟乙酸(5毫升)并在15℃下搅拌4小时。薄层色谱检测反应结束后，在0℃下用饱和碳酸氢钠溶液调节pH＝7并用二氯甲烷(30毫升x 2)萃取，合并有机层用硫酸钠干燥，过滤并蒸发，得到标题化合物粗品(无色油状，2.66克,产率88％)，直接用到下一步。Trifluoroacetic acid (5 ml) was added to a solution of EtOAc (EtOAc)EtOAc. After the end of the reaction, the reaction mixture was purified by EtOAc EtOAc (EtOAc) (Colorless oil, 2.66 g, yield 88%), used directly in the next step.
实施例32FExample 32F
(E)-4-((5-(1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5-(1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl)oxy)benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000179
Figure PCTCN2015077043-appb-000179
在氮气保护下向实施例32E(1.0克，3.2毫摩尔)的乙醇溶液(50毫升)中加入乙氧氨基盐酸盐(1.56克，16毫摩尔)和醋酸钠(1.31克，16毫摩尔)并且加热到60℃反应一个小时。薄层色谱检测反应结束后，浓缩蒸发溶剂后加入水(20毫升)，用乙酸乙酯(20毫升x 3)萃取，合并有机层用硫酸钠干燥，过滤并蒸发。粗产物经过柱层析纯化(石油醚：乙酸乙酯＝2:1)得到标题化合物(无色油状，1.1克，产率97％)，直接用于下一步反应。To a solution of Example 32E (1.0 g, 3.2 mmol) in ethanol (50 mL), EtOAc EtOAc (EtOAc, EtOAc. And heated to 60 ° C for one hour. After the end of the reaction, the mixture was evaporated, evaporated, evaporated, evaporated. The crude product was purified by EtOAcjjjjjjjjjj
实施例32GExample 32G
(E)-4-((5-(5-(2-甲基吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5-(5-(2-methylpyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl) Oxy)benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000180
Figure PCTCN2015077043-appb-000180
氮气保护下，将实施例32F(130毫克，366微摩尔)，4-溴-2-甲基吡啶(189毫克，1.1毫摩尔)，Cs2CO3(179毫克，549微摩尔)，Pd2(dba)3(34毫克，37微摩尔)和Xant-phos(21毫克，37微摩尔)的二氧六环(2毫升)溶液加热到100℃6个小时。TLC显示原料消耗完全。将反应液降至室温后，加入乙酸乙酯(20毫升)，并用饱和食盐水(30毫升)洗涤有机相，有机相用硫酸钠干燥，过滤浓缩后用制备薄层色谱纯化(二氯甲烷：甲醇＝30:1)得标题化合物(白色固体，100毫克,产率61％)。1H NMR(400MHz,CHLOROFORM-d)8.39(d，J＝5.52Hz,1H),8.02(s,1H),7.51(d,J＝8.53Hz,2H),6.95(s,1H),6.87(d,J＝8.53Hz,3H),4.20(q,J＝7.36Hz,2H),4.00(t,J＝6.27Hz,2H),3.84(t,J＝6.27Hz,2H),3.53(t,J＝6.27Hz,2H),3.18(t,J＝7.28Hz,2H),2.56(s,3H),1.82-1.90(m,2H),1.74-1.81(m,2H),1.62(br.s.,2H),1.25-1.36(m,3H)。LCMS(ESI)m/z:447(M+1)。Example 32F (130 mg, 366 μmol), 4-bromo-2-methylpyridine (189 mg, 1.1 mmol), Cs 2 CO 3 (179 mg, 549 μmol), Pd 2 A solution of (dba) 3 (34 mg, 37 μmol) and Xant-phos (21 mg, 37 μmol) in dioxane (2 mL) was heated to 100 ° C for 6 hours. TLC shows complete consumption of raw materials. After the reaction mixture was cooled to room temperature, ethyl acetate (20 ml) was evaporated. The title compound (white solid, 100 mg, yield 61%). 1 H NMR (400MHz, CHLOROFORM- d) 8.39 (d, J = 5.52Hz, 1H), 8.02 (s, 1H), 7.51 (d, J = 8.53Hz, 2H), 6.95 (s, 1H), 6.87 ( d, J = 8.53 Hz, 3H), 4.20 (q, J = 7.36 Hz, 2H), 4.00 (t, J = 6.27 Hz, 2H), 3.84 (t, J = 6.27 Hz, 2H), 3.53 (t, J = 6.27 Hz, 2H), 3.18 (t, J = 7.28 Hz, 2H), 2.56 (s, 3H), 1.82-1.90 (m, 2H), 1.74-1.81 (m, 2H), 1.62 (br.s) ., 2H), 1.25-1.36 (m, 3H). LCMS (ESI) m.
实施例33Example 33
(E)-4-((5-(5-(6-甲基哒嗪-3-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟 (E)-4-((5-(5-(6-methylpyridazin-3-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl )oxy)benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000181
Figure PCTCN2015077043-appb-000181
本实施例的制备方法参照实施例32。1H NMR(400MHz,CHLOROFORM-d)8.02(s，1H)，7.61(d，J＝9.03Hz,1H),7.51(d,J＝8.53Hz,2H),7.32(d,J＝9.54Hz,1H),6.87(d,J＝8.53Hz,2H),4.16-4.30(m,4H),4.00(t,J＝6.27Hz,2H),3.56(t,J＝6.27Hz,2H),3.19(t,J＝7.28Hz,2H),2.66(s,3H),1.75-1.91(m,4H),1.60-1.66(m,2H),1.32(t,J＝7.03Hz,3H)。LCMS(ESI)m/z:447(M+1)。The preparation method of this example is referred to Example 32. 1 H NMR (400MHz, CHLOROFORM- d) 8.02 (s, 1H), 7.61 (d, J = 9.03Hz, 1H), 7.51 (d, J = 8.53Hz, 2H), 7.32 (d, J = 9.54Hz, 1H), 6.87 (d, J = 8.53 Hz, 2H), 4.16-4.30 (m, 4H), 4.00 (t, J = 6.27 Hz, 2H), 3.56 (t, J = 6.27 Hz, 2H), 3.19 ( t, J = 7.28 Hz, 2H), 2.66 (s, 3H), 1.75-1.91 (m, 4H), 1.60-1.66 (m, 2H), 1.32 (t, J = 7.03 Hz, 3H). LCMS (ESI) m.
实施例34Example 34
(E)-4-((5-(5-(6-氯哒嗪-3-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5-(5-(6-chloropyridazin-3-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl) Oxy)benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000182
Figure PCTCN2015077043-appb-000182
本实施例的制备方法参照实施例32。1H NMR(400MHz,CHLOROFORM-d)d 8.02(s,1H),7.68(d,J＝9.03Hz,1H),7.45-7.54(m,1H),6.87(d,J＝8.53Hz,1H),4.15-4.29(m,5H),4.00(t,J＝6.02Hz,2H),3.57(t,J＝6.53Hz,2H),3.20(t,J＝7.28Hz,2H),1.75-1.91(m,4H),1.60-1.67(m,2H),1.32(t,J＝7.03Hz,3H)。LCMS(ESI)m/z:468(M+1)。For the preparation method of this example, refer to Example 32. 1H NMR (400 MHz, CHLOROFORM-d) d 8.02 (s, 1H), 7.68 (d, J = 9.03 Hz, 1H), 7.45-7.54 (m, 1H), 6.87 (d, J = 8.53 Hz, 1H), 4.15 - 4.29 (m, 5H), 4.00 (t, J = 6.02 Hz, 2H), 3.57 (t, J = 6.53 Hz, 2H), 3.20 (t, J = 7.28 Hz, 2H), 1.75-1.91 (m, 4H), 1.60-1.67 (m, 2H), 1.32 (t, J = 7.03 Hz, 3H). LCMS (ESI) m/z: 468
实施例35Example 35
(E)-4-((5-(1,1-二氧化-5(噻唑-2-基)-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5-(1,1-dioxy-5(thiazol-2-yl)-1,2,5-thiadiazol-2-yl)pentyl)oxy)benzaldehyde -oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000183
Figure PCTCN2015077043-appb-000183
本实施例的制备方法参照实施例32。1H NMR(400MHz,CHLOROFORM-d)d 8.02(s,1H),7.51(d,J＝8.53Hz,2H),7.43(d,J＝3.51Hz,1H),6.98(d,J＝3.51Hz,1H),6.87(d,J＝9.03Hz,2H),4.20(q,J＝7.03Hz,2H),4.12(t,J＝6.53Hz,2H),4.00(t,J＝6.27Hz,2H),3.56(t,J＝6.53Hz,2H),3.19(t,J＝7.28Hz,2H),1.82-1.89(m,2H),1.74-1.80(m,2H),1.58-1.65(m,2H),1.32(t,J＝7.03Hz,3H)。LCMS(ESI)m/z:439(M+1)。For the preparation method of this example, refer to Example 32. 1H NMR (400 MHz, CHLOROFORM-d) d 8.02 (s, 1H), 7.51 (d, J = 8.53 Hz, 2H), 7.43 (d, J = 3.51 Hz, 1H) ), 6.98 (d, J = 3.51 Hz, 1H), 6.87 (d, J = 9.03 Hz, 2H), 4.20 (q, J = 7.03 Hz, 2H), 4.12 (t, J = 6.53 Hz, 2H), 4.00 (t, J = 6.27 Hz, 2H), 3.56 (t, J = 6.53 Hz, 2H), 3.19 (t, J = 7.28 Hz, 2H), 1.82-1.89 (m, 2H), 1.74-1.80 (m , 2H), 1.58-1.65 (m, 2H), 1.32 (t, J = 7.03 Hz, 3H). LCMS (ESI) m/z:
实施例36Example 36
(E)-N-(4-(5-(5-(4-((乙氧基亚氨基)甲基)苯氧基)戊基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)吡啶-2-基)乙酰胺(E)-N-(4-(5-(5-(4-(4-ethoxyimino)methyl)phenoxy)pentyl)-1,1-dioxy-1,2,5- Thiadiazin-2-yl)pyridin-2-yl)acetamide
Figure PCTCN2015077043-appb-000184
Figure PCTCN2015077043-appb-000184
实施例36AExample 36A
N-(4-溴吡啶-2-基)乙酰胺 N-(4-bromopyridin-2-yl)acetamide
Figure PCTCN2015077043-appb-000185
Figure PCTCN2015077043-appb-000185
在0℃氮气保护下，向4-溴-2-氨基吡啶(1.0克，5.8毫摩尔)和三乙胺(1.75克，17毫摩尔)的二氯甲烷溶液(50毫升)中加入乙酰氯(454毫克，5.8毫摩尔)。室温下反应1小时，倒入冰水(50毫升)中淬灭，用二氯甲烷(20毫升)萃取。合并有机层用无水硫酸钠干燥，过滤并蒸发。粗品用柱层析分离纯化(石油醚：乙酸乙酯＝5：1)得到标题化合物(白色固体，400毫克，33％)。1H NMR(400MHz,CHLOROFORM-d)8.38-8.53(m,1H),8.08(d,J＝5.02Hz,1H),7.93(br.s.,1H),7.21(d,J＝4.52Hz,1H),2.22(s,3H)。Acetyl chloride was added to a solution of 4-bromo-2-aminopyridine (1.0 g, 5.8 mmol) and triethylamine (1.75 g, 17 mmol) in dichloromethane (50 mL). 454 mg, 5.8 mmol). The reaction was quenched with EtOAc (EtOAc)EtOAc. The combined organic layers were dried with anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by EtOAcjjjjjjjjj 1 H NMR (400MHz, CHLOROFORM- d) 8.38-8.53 (m, 1H), 8.08 (d, J = 5.02Hz, 1H), 7.93 (br.s., 1H), 7.21 (d, J = 4.52Hz, 1H), 2.22 (s, 3H).
实施例36BExample 36B
(E)-N-(4-(5-(5-(4-((乙氧基亚氨基)甲基)苯氧基)戊基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)吡啶-2-基)乙酰胺(E)-N-(4-(5-(5-(4-(4-ethoxyimino)methyl)phenoxy)pentyl)-1,1-dioxy-1,2,5- Thiadiazin-2-yl)pyridin-2-yl)acetamide
Figure PCTCN2015077043-appb-000186
Figure PCTCN2015077043-appb-000186
本实施例的制备方法参照实施例32。1H NMR(400MHz,CHLOROFORM-d)8.13(d，J＝5.52Hz,1H),8.02(s,1H),7.92(br.s.,1H),7.79(s,1H),7.51(d,J＝8.53Hz,2H),7.17(dd,J＝2.01,6.02Hz,1H),6.87(d,J＝8.53Hz,2H),4.13-4.28(m,2H),4.00(t,J＝6.27Hz,2H),3.90(t,J＝6.53Hz,2H),3.53(t,J＝6.53Hz,2H),3.18(t,J＝7.28Hz,2H),2.21(s,3H),1.73-1.92(m,4H),1.60-1.65(m,2H),1.28-1.40(m,3H)。LCMS(ESI)m/z:490(M+1)。The preparation method of this example is referred to Example 32. 1 H NMR (400MHz, CHLOROFORM- d) 8.13 (d, J = 5.52Hz, 1H), 8.02 (s, 1H), 7.92 (br.s., 1H), 7.79 (s, 1H), 7.51 (d, J = 8.53 Hz, 2H), 7.17 (dd, J = 2.01, 6.02 Hz, 1H), 6.87 (d, J = 8.53 Hz, 2H), 4.13-4.28 (m, 2H), 4.00 (t, J = 6.27) Hz, 2H), 3.90 (t, J = 6.53 Hz, 2H), 3.53 (t, J = 6.53 Hz, 2H), 3.18 (t, J = 7.28 Hz, 2H), 2.21 (s, 3H), 1.73 1.92 (m, 4H), 1.60-1.65 (m, 2H), 1.28-1.40 (m, 3H). LCMS (ESI) m/z:
实施例37Example 37
(E)-乙基4-(5-(5-(4-((乙氧亚氨基)甲基)苯氧基)戊基)-二氧化-1,2,5-噻二唑烷-2-基)吡啶-2-基甲酸甲酯(E)-ethyl 4-(5-(5-(4-((ethoxy)amino)methyl)phenoxy)pentyl)-dioxy-1,2,5-thiadiazolidine-2 Methyl-pyridin-2-ylcarboxylate
Figure PCTCN2015077043-appb-000187
Figure PCTCN2015077043-appb-000187
本实施例的制备方法参照实施例32。1H NMR(400MHz,CHLOROFORM-d)8.63(d，J＝5.77Hz，1H)，8.04(s,1H),7.75(d,J＝2.26Hz,1H),7.53(d,J＝8.78Hz,2H),7.40(dd,J＝2.38,5.65Hz,1H),6.89(d,J＝8.78Hz,2H),4.22(q,J＝7.03Hz,2H),4.00-4.06(m,5H),3.93(t,J＝6.40Hz,2H),3.59(t,J＝6.40Hz,2H),3.21(t,J＝7.28Hz,2H),1.77-1.93(m,4H),1.61-1.70(m,5H),1.33(t,J＝7.03Hz,3H)。LCMS(ESI)m/z:491(M+1)。The preparation method of this example is referred to Example 32. 1 H NMR (400MHz, CHLOROFORM- d) 8.63 (d, J = 5.77Hz, 1H), 8.04 (s, 1H), 7.75 (d, J = 2.26Hz, 1H), 7.53 (d, J = 8.78Hz, 2H), 7.40 (dd, J = 2.38, 5.65 Hz, 1H), 6.89 (d, J = 8.78 Hz, 2H), 4.22 (q, J = 7.03 Hz, 2H), 4.00 - 4.06 (m, 5H), 3.93 (t, J = 6.40 Hz, 2H), 3.59 (t, J = 6.40 Hz, 2H), 3.21 (t, J = 7.28 Hz, 2H), 1.77-1.93 (m, 4H), 1.61-1.70 (m , 5H), 1.33 (t, J = 7.03 Hz, 3H). LCMS (ESI) m/z: 495 (21.
实施例38Example 38
(E)-4-((5-(5-(6-氨基嘧啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟 (E)-4-((5-(5-(6-Aminopyrimidin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl)oxy Benzoaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000188
Figure PCTCN2015077043-appb-000188
实施例38AExample 38A
(E)-4-(5-(5-(6-氯嘧啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-(5-(5-(6-chloropyrimidin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl)oxy Benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000189
Figure PCTCN2015077043-appb-000189
本实施例的制备方法参照实施例32。LCMS(ESI)m/z:468(M+1)。The preparation method of this example is referred to Example 32. LCMS (ESI) m/z: 468
实施例38BExample 38B
(E)-4-((5-(5-(6-氨基嘧啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5-(5-(6-Aminopyrimidin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl)oxy Benzoaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000190
Figure PCTCN2015077043-appb-000190
本实施例的制备方法参照实施例28。1H NMR(CHLOROFORM-d,400MHz):8.33(s,1H),8.02(s,1H),7.51(d,J＝8.5Hz,2H),6.87(d,J＝8.5Hz,2H),6.34(s,1H),4.93(br.s.,2H),4.16-4.25(m,2H),4.05(t,J＝6.5Hz,2H),4.00(t,J＝6.3Hz,2H),3.44-3.50(m,2H),3.16(t,J＝7.3Hz,2H),1.82-1.90(m,2H),1.74-1.79(m,2H),1.55-1.60(m,2H),1.32(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:449(M+1)。The preparation method of this example is referred to Example 28. 1 H NMR (CHLOROFORM-d, 400MHz): 8.33 (s, 1H), 8.02 (s, 1H), 7.51 (d, J = 8.5Hz, 2H), 6.87 (d, J = 8.5Hz, 2H), 6.34 (s, 1H), 4.93 (br.s., 2H), 4.16-4.25 (m, 2H), 4.05 (t, J = 6.5 Hz, 2H), 4.00 (t, J = 6.3 Hz, 2H), 3.44 -3.50 (m, 2H), 3.16 (t, J = 7.3 Hz, 2H), 1.82-1.90 (m, 2H), 1.74-1.79 (m, 2H), 1.55-1.60 (m, 2H), 1.32 (t , J = 7.0 Hz, 3H). LCMS (ESI) m/z: 449
流程NProcess N
Figure PCTCN2015077043-appb-000191
Figure PCTCN2015077043-appb-000191
实施例39Example 39
(E)-4-((5-(5-(2-氟吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5-(5-(2-fluoropyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl)oxy Benzoaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000192
Figure PCTCN2015077043-appb-000192
在氮气保护下向实施例32F(60毫克，169微摩尔)，4-溴-2-氟-吡啶(30毫克，169微摩尔)和碳酸铯(83毫克，253微摩尔)的二氧六环溶液(2毫升)中加入Pd2(dba)3(15毫克，17微摩尔)和Xant-Phos(10毫克，17微摩尔)，搅拌均匀后升温到100℃反应4小时。TLC检测反应结束后浓缩蒸发溶剂。加入水(20毫升)并用乙酸乙酯(20毫升x 3)萃取，合并有机层用无水硫酸钠干燥， 过滤并蒸发，粗品用薄层色谱分离纯化(石油醚:乙酸乙酯＝2:1)得到标题化合物(白色固体，70毫克，92％)。1H NMR(400MHz,CHLOROFORM-d)8.12(d，J＝6.02Hz,1H),8.03(s,1H),7.51(d,J＝8.53Hz,2H),7.02(d,J＝5.52Hz,1H),6.82-6.93(m,2H),6.58(d,J＝2.01Hz,1H),4.20(q,J＝7.03Hz,2H),4.00(t,J＝6.02Hz,2H),3.85(t,J＝6.53Hz,2H),3.52-3.59(m,2H),3.19(t,J＝7.28Hz,2H),1.74-1.91(m,4H),1.59-1.67(m,2H),1.29-1.39(m,3H)。LCMS(M+1):451。Example 32F (60 mg, 169 μmol), 4-bromo-2-fluoro-pyridine (30 mg, 169 μmol) and cesium carbonate (83 mg, 253 μmol) of dioxane under nitrogen. To the solution (2 ml), Pd 2 (dba) 3 (15 mg, 17 μmol) and Xant-Phos (10 mg, 17 μmol) were added, and the mixture was stirred and heated to 100 ° C for 4 hours. After the TLC detection reaction was completed, the solvent was concentrated and evaporated. Water (20 ml) was added, and EtOAc (EtOAc m. The title compound (white solid, 70 mg, 92%). 1 H NMR (400MHz, CHLOROFORM- d) 8.12 (d, J = 6.02Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 8.53Hz, 2H), 7.02 (d, J = 5.52Hz, 1H), 6.82-6.93 (m, 2H), 6.58 (d, J = 2.01 Hz, 1H), 4.20 (q, J = 7.03 Hz, 2H), 4.00 (t, J = 6.02 Hz, 2H), 3.85 ( t, J = 6.53 Hz, 2H), 3.52-3.59 (m, 2H), 3.19 (t, J = 7.28 Hz, 2H), 1.74-1.91 (m, 4H), 1.59-1.67 (m, 2H), 1.29 -1.39 (m, 3H). LCMS (M+1): 451.
实施例40Example 40
(E)-4-((5-(5-(2-((2-羟基乙基)氨基)吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5-(5-(2-(2-hydroxyethyl)amino)pyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazolidine -2-yl)pentyl)oxy)benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000193
Figure PCTCN2015077043-appb-000193
在氮气保护下，向实施例39(20毫克，44微摩尔)和2-氨基乙醇(27毫克，444微摩尔)的二甲亚砜溶液(0.5毫升)中加入三乙胺(27毫克，266微摩尔)。混合溶液在100℃下反应2小时。薄层色谱检测反应结束后加水(5毫升)淬灭并用乙酸乙酯(10毫升)萃取。合并有机层用无水硫酸钠干燥，过滤并蒸发。粗品用薄层色谱分离纯化(二氯甲烷:甲醇＝20:1)得到标题化合物(无色油状液体，12毫克，55％)。1H NMR(400MHz,CHLOROFORM-d)8.02(s，1H)，7.84-7.95(m,1H),7.51(d,J＝8.53Hz,2H),6.85-6.93(m,2H),6.41(dd,J＝1.76,6.27Hz,1H),6.25(d,J＝1.51Hz,1H),5.47(br.s.,1H),4.15-4.29(m,2H),4.00(t,J＝6.27Hz,2H),3.81(t,J＝4.77Hz,4H),3.45-3.56(m,4H),3.16(t,J＝7.03Hz,2H),1.81-1.90(m,2H),1.72-1.81(m,2H),1.56-1.67(m,2H),1.27-1.40(m,3H).LCMS(ESI)m/z:492(M+1)。To a solution of Example 39 (20 mg, 44 μmol) and 2-aminoethanol (27 mg, 444 μmol) in dimethyl sulfoxide (0.5 mL) was added triethylamine (27 mg, 266). Micromolar). The mixed solution was reacted at 100 ° C for 2 hours. After the reaction was completed by EtOAc (EtOAc) (EtOAc) The combined organic layers were dried with anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by EtOAc EtOAcjjjjjjj 1 H NMR (400MHz, CHLOROFORM- d) 8.02 (s, 1H), 7.84-7.95 (m, 1H), 7.51 (d, J = 8.53Hz, 2H), 6.85-6.93 (m, 2H), 6.41 (dd , J = 1.76, 6.27 Hz, 1H), 6.25 (d, J = 1.51 Hz, 1H), 5.47 (br.s., 1H), 4.15-4.29 (m, 2H), 4.00 (t, J = 6.27 Hz) , 2H), 3.81 (t, J = 4.77 Hz, 4H), 3.45-3.56 (m, 4H), 3.16 (t, J = 7.03 Hz, 2H), 1.81-1.90 (m, 2H), 1.72-1.81 ( m, 2H), 1.56-1.67 (m, 2H), 1.27-1.40 (m, 3H). LCMS (ESI) m/z: 492 (M+1).
实施例41Example 41
(E)-4-((5-(5-(2-(甲基氨基)吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5-(5-(2-(methylamino)pyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl) Pentyl)oxy)benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000194
Figure PCTCN2015077043-appb-000194
本实施例的制备方法参照实施例40。1H NMR(400MHz,CHLOROFORM-d)7.97-8.05(m,2H),7.51(d,J＝8.53Hz,2H),6.87(d,J＝8.53Hz,2H),6.36(dd,J＝2.01,6.02Hz,1H),6.14(d,J＝2.01Hz,1H),4.64(br.s.,1H),4.20(q,J＝7.03Hz,2H),4.00(t,J＝6.27Hz,2H),3.82(t,J＝6.27Hz,2H),3.49(t,J＝6.27Hz,2H),3.16(t,J＝7.28Hz,2H),2.92(d,J＝5.02Hz,3H),1.73-1.91(m,4H),1.62-1.66(m,2H),1.28-1.39(m,3H)。LCMS(ESI)m/z:462(M+1)。The preparation method of this embodiment is referred to Example 40. 1 H NMR (400MHz, CHLOROFORM- d) 7.97-8.05 (m, 2H), 7.51 (d, J = 8.53Hz, 2H), 6.87 (d, J = 8.53Hz, 2H), 6.36 (dd, J = 2.01 , 6.02 Hz, 1H), 6.14 (d, J = 2.01 Hz, 1H), 4.64 (br.s., 1H), 4.20 (q, J = 7.03 Hz, 2H), 4.00 (t, J = 6.27 Hz, 2H), 3.82 (t, J = 6.27 Hz, 2H), 3.49 (t, J = 6.27 Hz, 2H), 3.16 (t, J = 7.28 Hz, 2H), 2.92 (d, J = 5.02 Hz, 3H) , 1.73-1.91 (m, 4H), 1.62-1.66 (m, 2H), 1.28-1.39 (m, 3H). LCMS (ESI) m.
实施例42Example 42
(E)-4-((5-(5-(2-(氮杂环丁烷-1-基)吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5-(5-(2-(azetidin-1-yl)pyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazole Alkan-2-yl)pentyl)oxy)benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000195
Figure PCTCN2015077043-appb-000195
本实施例的制备方法参照实施40。1H NMR(400MHz,CHLOROFORM-d)8.00-8.06(m,1H),7.50(d,J＝8.78Hz,1H),6.87(d,J＝8.78Hz,1H),6.40(dd,J＝2.01,5.77Hz,1H),5.92(d,J＝1.76Hz,1H),4.19(q,J＝7.03Hz,2H),4.05(t,J＝7.40Hz,4H),3.99(t,J＝6.27Hz,2H),3.80(t,J＝6.40Hz,2H),3.43-3.51(m,3H),3.15(t,J＝7.15Hz,2H),2.38(quin,J＝7.34Hz,2H),1.81-1.89(m,2H),1.72-1.79(m,2H),1.57-1.65(m,2H),1.31(t,J＝7.03Hz,3H)。LCMS(ESI)m/z:488(M+1)。The preparation method of this embodiment is referred to the implementation 40. 1 H NMR (400MHz, CHLOROFORM- d) 8.00-8.06 (m, 1H), 7.50 (d, J = 8.78Hz, 1H), 6.87 (d, J = 8.78Hz, 1H), 6.40 (dd, J = 2.01 , 5.77 Hz, 1H), 5.92 (d, J = 1.76 Hz, 1H), 4.19 (q, J = 7.03 Hz, 2H), 4.05 (t, J = 7.40 Hz, 4H), 3.99 (t, J = 6.27) Hz, 2H), 3.80 (t, J = 6.40 Hz, 2H), 3.43 - 3.51 (m, 3H), 3.15 (t, J = 7.15 Hz, 2H), 2.38 (quin, J = 7.34 Hz, 2H), 1.81-1.89 (m, 2H), 1.72-1.79 (m, 2H), 1.57-1.65 (m, 2H), 1.31 (t, J = 7.03 Hz, 3H). LCMS (ESI) m/z:
实施例43Example 43
(E)-4-((5-(5-(2-(二甲基氨基)吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-乙基酮肟(E)-4-((5-(5-(2-(Dimethylamino)pyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazolidine-2-yl Pentyl)oxy)benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000196
Figure PCTCN2015077043-appb-000196
本实施例的制备方法参照实施例40。1H NMR(400MHz,CHLOROFORM-d)8.09(d,J＝5.77Hz,1H),8.03(s,1H),7.52(d,J＝8.53Hz,2H),6.88(d,J＝8.78Hz,2H),6.38(dd,J＝1.88,5.90Hz,1H),6.26(d,J＝1.76Hz,1H),4.21(q,J＝7.03Hz,2H),3.97-4.04(m,2H),3.85(t,J＝6.27Hz,2H),3.51(t,J＝6.27Hz,2H),3.17(t,J＝7.15Hz,2H),3.12(s,5H),1.73-1.92(m,4H),1.58-1.67(m,2H),1.33(t,J＝7.03Hz,3H)。LCMS(ESI)m/z:476(M+1)。For the preparation method of this example, refer to Example 40. 1H NMR (400 MHz, CHLOROFORM-d) 8.09 (d, J = 5.77 Hz, 1H), 8.03 (s, 1H), 7.52 (d, J = 8.53 Hz, 2H) , 6.88 (d, J = 8.78 Hz, 2H), 6.38 (dd, J = 1.88, 5.90 Hz, 1H), 6.26 (d, J = 1.76 Hz, 1H), 4.21 (q, J = 7.03 Hz, 2H) , 3.97-4.04 (m, 2H), 3.85 (t, J = 6.27 Hz, 2H), 3.51 (t, J = 6.27 Hz, 2H), 3.17 (t, J = 7.15 Hz, 2H), 3.12 (s, 5H), 1.73-1.92 (m, 4H), 1.58-1.67 (m, 2H), 1.33 (t, J = 7.03 Hz, 3H). LCMS (ESI) m.
实施例44Example 44
(E)-4-(5-(5-(4-((乙氧基亚氨基)甲基)苯氧基)戊基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)苄腈(E)-4-(5-(5-(4-(ethyloxyimino)methyl)phenoxy)pentyl)-1,1-dioxy-1,2,5-thiadiazole Alkan-2-yl)benzonitrile
Figure PCTCN2015077043-appb-000197
Figure PCTCN2015077043-appb-000197
在0℃氮气保护下，向实施例32F(50毫克，141微摩尔)和4-氟苯腈(17毫克，141微摩尔)的N,N-二甲酰亚胺的溶液中(1毫升)，加入碳酸钾(39毫克，281微摩尔)，混合溶液在80℃下反应3小时。反应结束后倒入水中(40毫升)并用乙酸乙酯(20毫升)萃取。合并有机层用硫酸钠干燥，过滤并蒸发。粗品用薄层色谱分离纯化(石油醚：乙酸乙酯＝2：1)得到标题化合物(白色固体，30毫克，66％)。1H NMR(400MHz,CHLOROFORM-d)8.02(s，1H)，7.66(d,J＝8.53Hz,2H),7.51(d,J＝8.53Hz,2H),7.25(s,2H),6.82-6.93(m,2H),4.16-4.29(m,2H),4.00(t,J＝6.27Hz,2H),3.86(t,J＝6.53Hz,2H),3.54(t,J＝6.27Hz,2H),3.18(t,J＝7.28Hz,2H),1.74-1.90(m,4H),1.60-1.67(m,2H),1.29-1.40(m,3H)。LCMS(ESI)m/z:457(M+1)。To a solution of Example 32F (50 mg, 141 μmol) and 4-fluorobenzonitrile (17 mg, 141 μmol) in N,N-dimethylimide (1 mL) under N.sub.2 C. Potassium carbonate (39 mg, 281 μmol) was added, and the mixed solution was reacted at 80 ° C for 3 hours. After the reaction was poured into water (40 ml) The combined organic layers were dried with sodium sulfate, filtered and evaporated. The crude product was purified by EtOAcjjjjjjjjj 1 H NMR (400MHz, CHLOROFORM- d) 8.02 (s, 1H), 7.66 (d, J = 8.53Hz, 2H), 7.51 (d, J = 8.53Hz, 2H), 7.25 (s, 2H), 6.82- 6.93 (m, 2H), 4.16-4.29 (m, 2H), 4.00 (t, J = 6.27 Hz, 2H), 3.86 (t, J = 6.53 Hz, 2H), 3.54 (t, J = 6.27 Hz, 2H) ), 3.18 (t, J = 7.28 Hz, 2H), 1.74-1.90 (m, 4H), 1.60-1.67 (m, 2H), 1.29-1.40 (m, 3H). LCMS (ESI) m/z:
流程O Process O
Figure PCTCN2015077043-appb-000198
Figure PCTCN2015077043-appb-000198
实施例45Example 45
(E)-2-(2-氨基吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-Aminopyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy) Ethyl)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000199
Figure PCTCN2015077043-appb-000199
实施例45AExample 45A
叔丁基5(5-溴代戊基)-1,2,5-噻二唑烷-2–甲酸叔丁酯-1,1-二氧化物tert-Butyl 5(5-bromopentyl)-1,2,5-thiadiazolidine-2-carboxylic acid tert-butyl ester-1,1-dioxide
Figure PCTCN2015077043-appb-000200
Figure PCTCN2015077043-appb-000200
10℃，氮气保护下，向实施例32B(100毫克，428微摩尔)的DMF(8毫升)溶液中加入钠氢(17毫克，428微摩尔)。1小时后，将该混合溶液加入到1,5-二溴戊烷(98毫克，428微摩尔)的DMF(4毫升)溶液中，10℃下搅拌反应10小时后加入水将反应淬灭，水相用乙酸乙酯(20毫升x 3)萃取，合并的有机相用饱和食盐水(10毫升x 2)洗涤，无水硫酸钠干燥，过滤浓缩，粗产物用制备薄层色谱(二氯甲烷：甲醇＝20：1)纯化得到标题化合物(黄色液体，50毫克，38％产率)。1H NMR(400MHz,CHLOROFORM-d)3.82(t，J＝6.53Hz,2H),3.44(t,J＝6.65Hz,2H),3.34(t,J＝6.53Hz,2H),3.08(t,J＝7.15Hz,2H),1.92(quin,J＝7.09Hz,2H),1.66-1.79(m,2H),1.56-1.62(m,12H)。Sodium hydrogen (17 mg, 428 micromoles) was added to a solution of Example 32B (100 mg, 428. After 1 hour, the mixed solution was added to a solution of 1,5-dibromopentane (98 mg, 428 μmol) in DMF (4 ml), and the mixture was stirred at 10 ° C for 10 hr. The aqueous phase was extracted with EtOAc (EtOAc (EtOAc)EtOAc. Purification of the title compound (yield: 50 mg, 38% yield). 1 H NMR (400MHz, CHLOROFORM- d) 3.82 (t, J = 6.53Hz, 2H), 3.44 (t, J = 6.65Hz, 2H), 3.34 (t, J = 6.53Hz, 2H), 3.08 (t, J = 7.15 Hz, 2H), 1.92 (quin, J = 7.09 Hz, 2H), 1.66-1.79 (m, 2H), 1.56-1.62 (m, 12H).
实施例45BExample 45B
(E)-叔丁基-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-1,2,5-噻二唑烷-2-甲酸叔丁酯-1,1-二氧化物(E)-tert-Butyl-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy)pentyl)-1,2 , 5-thiadiazolidine-2-carboxylic acid tert-butyl ester-1,1-dioxide
Figure PCTCN2015077043-appb-000201
Figure PCTCN2015077043-appb-000201
在氮气保护下向实施例45A(100毫克，269微摩尔)和实施例8B(52毫克,269微摩尔)的N,N-二甲基甲酰胺(1毫升)溶液中加入碳酸钾(112毫克,808微摩尔)。反应液在80℃下反应10小时，薄层色谱显示反应结束后，加水(50毫升)淬灭，水相用乙酸乙酯(20毫升)萃取。有机层用无水硫酸钠干燥，过滤并蒸发。粗品用制备薄层色谱分离纯化(石油醚:乙酸乙酯＝2:1)得到标题化合物(白色固体，70毫克，54％)。1H NMR(400MHz,CHLOROFORM-d)7.54-7.64(m,1H),6.74-6.83(m,2H),4.20(q,J＝7.03Hz,2H),3.98(t,J＝6.27Hz,2H),3.80(t,J＝6.53Hz,2H),3.32(t,J＝6.53Hz,2H),3.08(t,J＝7.28Hz,2H),2.95-3.02(m,2H),2.85-2.93(m,2H),1.67-1.87(m,4H),1.51-1.59(m,11H),1.32(t,J＝7.03Hz,3H)。To a solution of Example 45A (100 mg, 269 μmol) and Example 8B (52 mg, 269 μmol) of N,N-dimethylformamide (1 mL) , 808 micromolar). The reaction mixture was stirred at 80 ° C for 10 hr. EtOAc (EtOAc) The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by EtOAcjjjjjjjj 1 H NMR 3.98 (t, J = 6.27Hz (400MHz, CHLOROFORM-d) 7.54-7.64 (m, 1H), 6.74-6.83 (m, 2H), 4.20 (q, J = 7.03Hz, 2H),, 2H ), 3.80 (t, J = 6.53 Hz, 2H), 3.32 (t, J = 6.53 Hz, 2H), 3.08 (t, J = 7.28 Hz, 2H), 2.95 - 3.02 (m, 2H), 2.85 - 2.93 (m, 2H), 1.67-1.87 (m, 4H), 1.51-1.59 (m, 11H), 1.32 (t, J = 7.03 Hz, 3H).
实施例45CExample 45C
(E)-2-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy)pentyl)-1,2,5-thia Diazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000202
Figure PCTCN2015077043-appb-000202
在氮气保护下向实施例45B(100毫克，208微摩尔)的甲醇溶液(1毫升)中加入碳酸钾(57毫克，415微摩尔)。反应液在50℃下反应72小时，薄层色谱显示反应结束后，浓缩蒸干溶剂，加入水(10毫升)，用乙酸乙酯(20毫升)萃取。合并有机层用硫酸钠干燥，过滤并蒸发。粗品用制备薄层色谱分离纯化(石油醚:乙酸乙酯＝2:1)得到标题化合物(白色固体，50毫克，63％)。1H NMR(400MHz,CHLOROFORM-d)8.09(d,J＝8.78Hz,2H),7.03(d,J＝8.78Hz,2H),4.40(s,3H),3.89(s,3H)。Potassium carbonate (57 mg, 415 micromoles) was added to a solution of EXAMPLE 45B (100 mg, 208. The reaction mixture was reacted at 50 ° C for 72 hours, and the mixture was evaporated to dryness. The combined organic layers were dried with sodium sulfate, filtered and evaporated. The crude product was purified by EtOAcjjjjjjjjj 1 H NMR (400 MHz, CHLOROFORM-d) 8.09 (d, J = 8.78 Hz, 2H), 7.03 (d, J = 8.78 Hz, 2H), 4.40 (s, 3H), 3.89 (s, 3H).
实施例45DExample 45D
(E)-2-(2-氨基吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-Aminopyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy) Ethyl)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000203
Figure PCTCN2015077043-appb-000203
氮气保护下，将实施例45C(550毫克，1.4毫摩尔)，4-溴2-氨基吡啶(499毫克,2.9毫摩尔)，碳酸钾(498毫克,3.6毫摩尔)，8-羟基喹啉(209毫克,1.4毫摩尔)，(1R,2R)-环己二胺(165毫克,1.4毫摩尔)和碘化亚铜(275毫克,1.4毫摩尔)的DMF(10毫升)溶液在120℃下加热10小时。反应结束后加水淬灭，水相用乙酸乙酯(10毫升x 3)萃取。有机相用饱和食盐水(5毫升)洗涤，无水硫酸钠干燥，浓缩，粗产物用制备薄层色谱纯化(二氯甲烷:甲醇＝30:1)得标题化合物(白色固体，350毫克，51％产率)。1H NMR(400MHz,DMSO-d6)8.09(d，J＝8.78Hz,1H),7.44(d,J＝8.53Hz,1H),6.92(s,1H),6.82(d,J＝8.53Hz,1H),6.34(br.s.,1H),6.15(br.s.,1H),4.09(q,J＝7.03Hz,2H),3.99(t,J＝6.40Hz,2H),3.79(t,J＝6.40Hz,2H),3.49(t,J＝ 6.40Hz,2H),3.04(t,J＝7.03Hz,2H),2.89-2.98(m,2H),2.69-2.82(m,2H),1.59-1.81(m,5H),1.40-1.54(m,2H),1.22(t,J＝7.03Hz,3H)。LCMS(ESI)m/z:474(M+1)。Example 45C (550 mg, 1.4 mmol), 4-bromo 2-aminopyridine (499 mg, 2.9 mmol), potassium carbonate (498 mg, 3.6 mmol), 8-hydroxyquinoline 209 mg, 1.4 mmol, (1R, 2R)-cyclohexanediamine (165 mg, 1.4 mmol) and cuprous iodide (275 mg, 1.4 mmol) in DMF (10 mL) at 120 ° C Heat for 10 hours. After completion of the reaction, water was added and the aqueous phase was extracted with ethyl acetate (10 ml). The organic phase was washed with EtOAcqqqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH %Yield). 1 H NMR (400 MHz, DMSO-d 6 ) 8.09 (d, J = 8.78 Hz, 1H), 7.44 (d, J = 8.53 Hz, 1H), 6.92 (s, 1H), 6.82 (d, J = 8.53 Hz) , 1H), 6.34 (br.s., 1H), 6.15 (br.s., 1H), 4.09 (q, J = 7.03 Hz, 2H), 3.99 (t, J = 6.40 Hz, 2H), 3.79 ( t, J = 6.40 Hz, 2H), 3.49 (t, J = 6.40 Hz, 2H), 3.04 (t, J = 7.03 Hz, 2H), 2.89-2.98 (m, 2H), 2.69-2.82 (m, 2H) ), 1.59-1.81 (m, 5H), 1.40-1.54 (m, 2H), 1.22 (t, J = 7.03 Hz, 3H). LCMS (ESI) m/z:
实施例46Example 46
(E)-2-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-5-(噻吩-3-基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy)pentyl)-5-(thiophene-3- 1,1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000204
Figure PCTCN2015077043-appb-000204
该实施例的制备方法参照实施例44。1H NMR(CDCl3 400MHz,)δ7.60(d，J＝9.5Hz，1H)7.35(dd,J＝5.0,3.0Hz,1H)7.18(dd,J＝5.5,1.0Hz,1H)6.76-6.85(m,3H)4.20(q,J＝7.0Hz,2H)3.99(t,J＝6.3Hz,2H)3.79(t,J＝6.3Hz,2H)3.49(t,J＝6.5Hz,2H)3.16(t,J＝7.3Hz,2H)2.95-3.02(m,2H)2.86-2.92(m,2H)1.81-1.89(m,2H)1.70-1.79(m,2H)1.64(br.s.,2H)1.32(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:464(M+1)。The preparation method of this example is referred to Example 44. 1 H NMR (CDCl 3 400 MHz,) δ 7.60 (d, J = 9.5 Hz, 1H) 7.35 (dd, J = 5.0, 3.0 Hz, 1H) 7.18 (dd, J = 5.5, 1.0 Hz, 1H) 6.76 - 6.85 (m, 3H) 4.20 (q, J = 7.0 Hz, 2H) 3.99 (t, J = 6.3 Hz, 2H) 3.79 (t, J = 6.3 Hz, 2H) 3.49 (t, J = 6.5 Hz, 2H) 3.16 (t, J = 7.3 Hz, 2H) 2.95 - 3.02 (m, 2H) 2.86 - 2.92 (m, 2H) 1.81-1.89 (m, 2H) 1.70-1.79 (m, 2H) 1.64 (br.s., 2H) ) 1.32 (t, J = 7.0 Hz, 3H). LCMS (ESI) m/z:
实施例47Example 47
(E)-2-(6-氨基吡啶-3-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(6-Aminopyridin-3-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy) Ethyl)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000205
Figure PCTCN2015077043-appb-000205
该实施例的制备方法参照实施例44。1H NMR(400MHz,CHLOROFORM-d)8.01(br.s.，1H)，7.59(dt，J＝3.26,6.02Hz,2H),6.76-6.85(m,2H),6.56(d,J＝9.03Hz,1H),4.20(q,J＝7.19Hz,2H),3.99(t,J＝6.27Hz,2H),3.74(t,J＝6.27Hz,2H),3.46(t,J＝6.40Hz,2H),3.15(t,J＝7.28Hz,2H),2.95-3.01(m,2H),2.86-2.92(m,2H),1.72-1.89(m,4H),1.56-1.60(m,2H),1.28-1.38(m,3H)。The preparation method of this example is referred to Example 44. 1 H NMR (400MHz, CHLOROFORM- d) 8.01 (br.s., 1H), 7.59 (dt, J = 3.26,6.02Hz, 2H), 6.76-6.85 (m, 2H), 6.56 (d, J = 9.03 Hz, 1H), 4.20 (q, J = 7.19 Hz, 2H), 3.99 (t, J = 6.27 Hz, 2H), 3.74 (t, J = 6.27 Hz, 2H), 3.46 (t, J = 6.40 Hz, 2H), 3.15 (t, J = 7.28 Hz, 2H), 2.95-3.01 (m, 2H), 2.86-2.92 (m, 2H), 1.72-1.89 (m, 4H), 1.56-1.60 (m, 2H) , 1.28-1.38 (m, 3H).
实施例48Example 48
(E)-2-(2-氨基-3-氟吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-Amino-3-fluoropyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indole-5) -yl)oxy)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000206
Figure PCTCN2015077043-appb-000206
实施例48AExample 48A
(E)-2-(2-氯-3-氟吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧)戊基)-1,2,5-噻二唑烷-1,1-二氧化物 (E)-2-(2-Chloro-3-fluoropyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indole-5) -yl)oxy)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000207
Figure PCTCN2015077043-appb-000207
在氮气保护下向实施例45C(100毫克,262微摩尔)的N,N-二甲基甲酰胺(3毫升)溶液中加入2-氯-5-氟-4-碘吡啶(101毫克,393微摩尔)，碳酸钾(54毫克,393微摩尔)，8-羟基喹啉(38毫克,262微摩尔)和碘化亚铜(25毫克,131微摩尔)。混合物在120℃下反应10小时。薄层色谱显示反应结束后，加水(10毫升)淬灭，乙酸乙酯(10毫升x 2)萃取。合并有机层用硫酸钠干燥，过滤并蒸发。粗品用薄层色谱板分离纯化(石油醚:乙酸乙酯＝2:1)得到标题化合物(白色固体，50毫克，37％)。1H NMR(400MHz,CHLOROFORM-d)8.21(d，J＝3.51Hz,1H),7.60(d,J＝9.03Hz,1H),7.46(d,J＝6.02Hz,1H),6.74-6.84(m,2H),4.20(q,J＝7.03Hz,2H),4.07(dt,J＝3.01,6.27Hz,2H),4.00(t,J＝6.27Hz,2H),3.54(t,J＝6.27Hz,2H),3.18(t,J＝7.28Hz,2H),2.95-3.02(m,2H),2.86-2.93(m,2H),1.73-1.91(m,4H),1.61-1.66(m,2H),1.32(t,J＝7.03Hz,3H)。To a solution of Example 45C (100 mg, 262 <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; Micromolar), potassium carbonate (54 mg, 393 micromoles), 8-hydroxyquinoline (38 mg, 262 micromoles) and cuprous iodide (25 mg, 131 micromoles). The mixture was reacted at 120 ° C for 10 hours. TLC showed the reaction was quenched with EtOAc (EtOAc) The combined organic layers were dried with sodium sulfate, filtered and evaporated. The crude product was purified with EtOAc EtOAcjjjjjjj 1 H NMR (400MHz, CHLOROFORM- d) 8.21 (d, J = 3.51Hz, 1H), 7.60 (d, J = 9.03Hz, 1H), 7.46 (d, J = 6.02Hz, 1H), 6.74-6.84 ( m, 2H), 4.20 (q, J = 7.03 Hz, 2H), 4.07 (dt, J = 3.01, 6.27 Hz, 2H), 4.00 (t, J = 6.27 Hz, 2H), 3.54 (t, J = 6.27) Hz, 2H), 3.18 (t, J = 7.28 Hz, 2H), 2.95-3.02 (m, 2H), 2.86-2.93 (m, 2H), 1.73-1.91 (m, 4H), 1.61-1.66 (m, 2H), 1.32 (t, J = 7.03 Hz, 3H).
实施例48BExample 48B
(E)-2-(2-氨基-3-氟吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-Amino-3-fluoropyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indole-5) -yl)oxy)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000208
Figure PCTCN2015077043-appb-000208
在氮气保护下向实施例48A(50毫克，98微摩尔)的二氧六环(1毫升)溶液中加入氨基甲酸叔丁酯(69毫克,587微摩尔)，碳酸铯(64毫克，196微摩尔)，Pd2(dba)3(9毫克，9.8微摩尔)和Xant-phos(6毫克，10微摩尔)。混合物在110℃下反应10小时。薄层色谱显示反应结束后，加水(10毫升)淬灭，乙酸乙酯(10毫升x 3)萃取。合并有机层用硫酸钠干燥，过滤并蒸发。粗品用薄层色谱板分离纯化(二氯甲烷：甲醇＝20:1)得到标题化合物，为白色固体(5毫克，10％)。1H NMR(400MHz,METHANOL-d4)7.97(d，J＝6.53Hz,1H),7.56(d,J＝8.53Hz,1H),6.91(s,1H),6.79-6.88(m,2H),4.05(t,J＝6.27Hz,2H),3.65(t,J＝6.27Hz,2H),3.22(t,J＝7.03Hz,2H),2.99-3.05(m,2H),2.86-2.92(m,2H),1.73-1.93(m,5H),1.58-1.70(m,2H),1.31(t,J＝7.03Hz,4H)。LCMS(ESI)m/z:492(M+1)。To a solution of Example 48A (50 mg, 98 μmol) in dioxane (1 mL) was added EtOAc EtOAc (EtOAc, EtOAc. Molar), Pd 2 (dba) 3 (9 mg, 9.8 μmol) and Xant-phos (6 mg, 10 μmol). The mixture was reacted at 110 ° C for 10 hours. TLC showed the reaction was quenched with EtOAc (EtOAc) The combined organic layers were dried with sodium sulfate, filtered and evaporated. The crude product was purified with EtOAc EtOAcjjjjjjj 1 H NMR (400MHz, METHANOL- d 4) 7.97 (d, J = 6.53Hz, 1H), 7.56 (d, J = 8.53Hz, 1H), 6.91 (s, 1H), 6.79-6.88 (m, 2H) , 4.05 (t, J = 6.27 Hz, 2H), 3.65 (t, J = 6.27 Hz, 2H), 3.22 (t, J = 7.03 Hz, 2H), 2.99 - 3.05 (m, 2H), 2.86 - 2.92 ( m, 2H), 1.73-1.93 (m, 5H), 1.58-1.70 (m, 2H), 1.31 (t, J = 7.03 Hz, 4H). LCMS (ESI) m/z: 495 (21.
实施例49Example 49
(E)-2-(2-氨基-5-氟吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物 (E)-2-(2-Amino-5-fluoropyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indole-5) -yl)oxy)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000209
Figure PCTCN2015077043-appb-000209
实施例49AExample 49A
(E)-2-(2-氯-5-氟吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-chloro-5-fluoropyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indole-5) -yl)oxy)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000210
Figure PCTCN2015077043-appb-000210
在氮气保护下向实施例45C(100毫克，262微摩尔)的N,N-二甲基甲酰胺(3毫升)溶液中加入2-氯-5-氟-4碘吡啶(101毫克，393微摩尔)，碳酸钾(54毫克，393微摩尔)，8-羟基喹啉(38毫克，262微摩尔)和碘化亚铜(25毫克，131微摩尔)。混合物在120℃下反应10小时。薄层色谱显示反应结束后，加水(10毫升)淬灭，乙酸乙酯(10毫升x 2)萃取。合并有机层用硫酸钠干燥，过滤并蒸发。粗品用薄层色谱板分离纯化(石油醚:乙酸乙酯＝2：1)得到标题化合物(白色固体，50毫克，37％)。1H NMR(400MHz,CHLOROFORM-d)8.21(d，J＝3.51Hz,1H),7.60(d,J＝9.03Hz,1H),7.46(d,J＝6.02Hz,1H),6.74-6.84(m,2H),4.20(q,J＝7.03Hz,2H),4.07(dt,J＝3.01,6.27Hz,2H),4.00(t,J＝6.27Hz,2H),3.54(t,J＝6.27Hz,2H),3.18(t,J＝7.28Hz,2H),2.95-3.02(m,2H),2.86-2.93(m,2H),1.73-1.91(m,4H),1.61-1.66(m,2H),1.32(t,J＝7.03Hz,3H)。To a solution of Example 45C (100 mg, 262 <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; Mole), potassium carbonate (54 mg, 393 μmol), 8-hydroxyquinoline (38 mg, 262 μmol) and cuprous iodide (25 mg, 131 μmol). The mixture was reacted at 120 ° C for 10 hours. TLC showed the reaction was quenched with EtOAc (EtOAc) The combined organic layers were dried with sodium sulfate, filtered and evaporated. The crude product was purified with EtOAc EtOAcjjjjjjj 1 H NMR (400MHz, CHLOROFORM- d) 8.21 (d, J = 3.51Hz, 1H), 7.60 (d, J = 9.03Hz, 1H), 7.46 (d, J = 6.02Hz, 1H), 6.74-6.84 ( m, 2H), 4.20 (q, J = 7.03 Hz, 2H), 4.07 (dt, J = 3.01, 6.27 Hz, 2H), 4.00 (t, J = 6.27 Hz, 2H), 3.54 (t, J = 6.27) Hz, 2H), 3.18 (t, J = 7.28 Hz, 2H), 2.95-3.02 (m, 2H), 2.86-2.93 (m, 2H), 1.73-1.91 (m, 4H), 1.61-1.66 (m, 2H), 1.32 (t, J = 7.03 Hz, 3H).
实施例49BExample 49B
(E)-2-(2-氨基-5-氟吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-Amino-5-fluoropyridin-4-yl)-5-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indole-5) -yl)oxy)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000211
Figure PCTCN2015077043-appb-000211
在氮气保护下向实施例49A(50毫克,98微摩尔)的二氧六环(1毫升)溶液中加入氨基甲酸叔丁酯(69毫克,587微摩尔),碳酸铯(64毫克,196微摩尔)，Pd2(dba)3(9毫克,9.8微摩尔)和Xant-phos(5.6毫克,9.8微摩尔)。混合物在110℃下反应10小时。薄层色谱显示反应结束后，加水(10毫升)淬灭，乙酸乙酯(10毫升x 3)萃取。合并有机层用硫酸钠干燥，过滤并蒸发。粗品用薄层色谱分离纯化(二氯甲烷:甲醇＝20:1)得到标题化合物，为白色固体(5毫克，10％)。1H NMR(400MHz,METHANOL-d4)7.97(d，J＝6.53Hz,1H),7.56(d,J＝8.53Hz,1H),6.91(s,1H),6.79-6.88(m,2H),4.05(t,J＝6.27Hz,2H),3.65(t,J＝6.27Hz,2H),3.22(t,J＝7.03Hz,2H),2.99-3.05(m,2H),2.86-2.92(m,2H),1.73-1.93(m,5H),1.58-1.70(m,2H),1.31(t,J＝7.03Hz,4H)。LCMS(ESI)m/z:492(M+1)。 To a solution of Example 49A (50 mg, 98 <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; Mole), Pd 2 (dba) 3 (9 mg, 9.8 μmol) and Xant-phos (5.6 mg, 9.8 μmol). The mixture was reacted at 110 ° C for 10 hours. TLC showed the reaction was quenched with EtOAc (EtOAc) The combined organic layers were dried with sodium sulfate, filtered and evaporated. The crude product was purified by EtOAcjjjjjjjj 1 H NMR (400MHz, METHANOL- d 4) 7.97 (d, J = 6.53Hz, 1H), 7.56 (d, J = 8.53Hz, 1H), 6.91 (s, 1H), 6.79-6.88 (m, 2H) , 4.05 (t, J = 6.27 Hz, 2H), 3.65 (t, J = 6.27 Hz, 2H), 3.22 (t, J = 7.03 Hz, 2H), 2.99 - 3.05 (m, 2H), 2.86 - 2.92 ( m, 2H), 1.73-1.93 (m, 5H), 1.58-1.70 (m, 2H), 1.31 (t, J = 7.03 Hz, 4H). LCMS (ESI) m/z: 495 (21.
流程PProcess P
Figure PCTCN2015077043-appb-000212
Figure PCTCN2015077043-appb-000212
实施例50Example 50
(E)-2-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-5-(2-(甲基氨基)吡啶-4-基)-1,2-噻二唑烷-1,1-二氧化物(E)-2-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy)pentyl)-5-(2-(A) Base amino)pyridin-4-yl)-1,2-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000213
Figure PCTCN2015077043-appb-000213
实施例50AExample 50A
(E)-2-(5-((1-(乙氧基亚氨基)-2,3-氢-1H-茚-5-基)氧)戊基)-5-(2-氟吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(5-((1-(ethoxyimino)-2,3-hydro-1H-indol-5-yl)oxy)pentyl)-5-(2-fluoropyridine-4 -yl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000214
Figure PCTCN2015077043-appb-000214
本实施例中如实施例50A中描述的方法制备。1H NMR(400MHz,CHLOROFORM-d)7.80(d,J＝5.5Hz,1H)7.62(d,J＝9.3Hz,1H)6.77-6.85(m,3H)4.65(br.s.,2H)4.22(q,J＝7.0Hz,2H)3.99-4.05(m,4H)3.52(t,J＝6.4Hz,2H)3.18(t,J＝7.2Hz,2H)2.97-3.04(m,2H)2.87-2.94(m,2H)1.75-1.91(m,4H)1.63-1.68(m,2H)1.34(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:474(M+1)。This example was prepared as described in Example 50A. 1 H NMR (400MHz, CHLOROFORM- d) 7.80 (d, J = 5.5Hz, 1H) 7.62 (d, J = 9.3Hz, 1H) 6.77-6.85 (m, 3H) 4.65 (br.s., 2H) 4.22 (q, J = 7.0 Hz, 2H) 3.99 - 4.05 (m, 4H) 3.52 (t, J = 6.4 Hz, 2H) 3.18 (t, J = 7.2 Hz, 2H) 2.97 - 3.04 (m, 2H) 2.87 - 2.94 (m, 2H) 1.75-1.91 (m, 4H) 1.63-1.68 (m, 2H) 1.34 (t, J = 7.0 Hz, 3H). LCMS (ESI) m/z:
实施例50BExample 50B
(E)-2-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-5-(2-(甲基氨基)吡啶-4-基)-1,2-噻二唑烷-1,1-二氧化物(E)-2-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy)pentyl)-5-(2-(A) Base amino)pyridin-4-yl)-1,2-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000215
Figure PCTCN2015077043-appb-000215
本实施例的制备方法参照实施例40。1H NMR(400MHz,METHANOL-d4)7.80(d，J＝7.53Hz,1H),7.56 (d,J＝8.53Hz,1H),6.81-6.93(m,3H),6.39(d,J＝2.01Hz,1H),4.17(q,J＝7.03Hz,2H),4.05(t,J＝6.15Hz,2H),3.99(t,J＝6.53Hz,2H),3.66(t,J＝6.53Hz,2H),3.22(t,J＝7.03Hz,2H),2.96-3.05(m,5H),2.84-2.92(m,2H),1.76-1.91(m,4H),1.58-1.71(m,2H),1.31(t,J＝7.03Hz,3H。LCMS(ESI)m/z:488(M+1)。The preparation method of this embodiment is referred to Example 40. 1 H NMR (400 MHz, METHANOL-d 4 ) 7.80 (d, J = 7.53 Hz, 1H), 7.56 (d, J = 8.53 Hz, 1H), 6.81-6.93 (m, 3H), 6.39 (d, J = 2.01 Hz, 1H), 4.17 (q, J = 7.03 Hz, 2H), 4.05 (t, J = 6.15 Hz, 2H), 3.99 (t, J = 6.53 Hz, 2H), 3.66 (t, J = 6.53 Hz) , 2H), 3.22 (t, J = 7.03 Hz, 2H), 2.96-3.05 (m, 5H), 2.84-2.92 (m, 2H), 1.76-1.91 (m, 4H), 1.58-1.71 (m, 2H) ), 1.31 (t, J = 7.03 Hz, 3H. LCMS (ESI) m/z: 488 (M+1).
实施例51Example 51
(E)-2-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-5-(2-((2-羟基乙基)氨基)吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy)pentyl)-5-(2-(( 2-hydroxyethyl)amino)pyridin-4-yl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000216
Figure PCTCN2015077043-appb-000216
本实施例的制备方法参照实施例40。1H NMR(400MHz,CHLOROFORM-d)7.84(d,J＝6.3Hz,1H),7.61(d,J＝9.0Hz,1H),6.74-6.85(m,2H),6.52(d,J＝5.3Hz,1H),6.27(s,1H),4.22(q,J＝7.0Hz,2H),4.01(t,J＝6.1Hz,2H),3.87(d,J＝4.8Hz,4H),2.86-3.62(m,10H),1.85-1.89(m,2H),1.76-1.82(m,2H),1.63(d,J＝7.0Hz,2H),1.34(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:518(M+1)。The preparation method of this embodiment is referred to Example 40. 1 H NMR (400MHz, CHLOROFORM- d) 7.84 (d, J = 6.3Hz, 1H), 7.61 (d, J = 9.0Hz, 1H), 6.74-6.85 (m, 2H), 6.52 (d, J = 5.3 Hz, 1H), 6.27 (s, 1H), 4.22 (q, J = 7.0 Hz, 2H), 4.01 (t, J = 6.1 Hz, 2H), 3.87 (d, J = 4.8 Hz, 4H), 2.86- 3.62 (m, 10H), 1.85-1.89 (m, 2H), 1.76-1.82 (m, 2H), 1.63 (d, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). LCMS (ESI) m/z:
流程QProcess Q
Figure PCTCN2015077043-appb-000217
Figure PCTCN2015077043-appb-000217
实施例52Example 52
4-(5-(2-(2-(4-((E)-乙氧基亚氨基甲基)苯氧基)乙氧基)乙基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)吡啶-2-胺4-(5-(2-(2-(4-((E)-ethoxyiminomethyl)phenoxy)ethoxy)ethyl)-1,1-dioxy-1,2, 5-thiadiazolidine-2-yl)pyridin-2-amine
Figure PCTCN2015077043-appb-000218
Figure PCTCN2015077043-appb-000218
实施例52AExample 52A
2-(5-溴代戊基)-5-(2-氯吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(5-bromopentyl)-5-(2-chloropyridin-4-yl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000219
Figure PCTCN2015077043-appb-000219
10℃下，向实施例4E(4.0克,17毫摩尔)的N,N-二甲基甲酰胺(140毫升)溶液中加入钠氢(1.0克,27毫摩尔)，加完后10℃下搅拌反应1小时。保持此温度向反应液中滴加1，5-二溴戊烷(3.9克,17 毫摩尔)的N,N-二甲基甲酰胺(40毫升)溶液，然后继续反应1小时。薄层色谱检测反应完全后，将反应液倒入冰水(100毫升)并用乙酸乙酯萃取(100毫升x 2)。取上层清液干燥，浓缩并通过柱色谱(石油醚:乙酸乙酯＝2:1)纯化得到标题化合物(白色固体，2.7克,41％产率)。1H NMR(400MHz,CHLOROFORM-d)8.27(d,J＝5.5Hz,1H),7.07(dd,J＝6.0,2.0Hz,1H),7.00(d,J＝1.5Hz,1H),3.85(t,J＝6.5Hz,2H),3.56(t,J＝6.3Hz,2H),3.44(t,J＝6.5Hz,2H),3.17(t,J＝7.0Hz,2H),1.88-1.98(m,2H),1.74(q,J＝7.4Hz,2H),1.58-1.64(m,2H)。Sodium hydrogen (1.0 g, 27 mmol) was added to a solution of Example 4E (4.0 g, 17 mmol) in N,N-dimethylformamide (140 ml) at 10 ° C. The reaction was stirred for 1 hour. While maintaining this temperature, a solution of 1,5-dibromopentane (3.9 g, 17 mmol) in N,N-dimethylformamide (40 ml) was added dropwise, and then the reaction was continued for 1 hour. After the reaction was completed by thin layer chromatography, the reaction mixture was poured into ice water (100 ml) and ethyl acetate (100 ml). The supernatant was dried, concentrated and purified title crystal crystal crystal crystal crystal 1 H NMR (400 MHz, CHLOROFORM-d) 8.27 (d, J = 5.5 Hz, 1H), 7.07 (dd, J = 6.0, 2.0 Hz, 1H), 7.00 (d, J = 1.5 Hz, 1H), 3.85 ( t, J = 6.5 Hz, 2H), 3.56 (t, J = 6.3 Hz, 2H), 3.44 (t, J = 6.5 Hz, 2H), 3.17 (t, J = 7.0 Hz, 2H), 1.88-1.98 ( m, 2H), 1.74 (q, J = 7.4 Hz, 2H), 1.58-1.64 (m, 2H).
实施例52BExample 52B
(E)-1-(4-(2-(2-(5-(2-氯-4-吡啶基)-1,1-二氧代-1,2,5-噻二唑烷-2-基)乙氧基)乙氧基)苯基)N-乙氧基甲亚胺(E)-1-(4-(2-(2-(5-(2-chloro-4-pyridyl)-1,1-dioxo-1,2,5-thiadiazolidine-2- Ethyl)ethoxy)phenyl)N-ethoxymethylimine
Figure PCTCN2015077043-appb-000220
Figure PCTCN2015077043-appb-000220
向实施例52A(0.1克，0.26毫摩尔)的N,N-二甲基甲酰胺(5毫升)溶液中加入碳酸钾(36毫克，0.26毫摩尔)，碘化钾(43毫克，0.26毫摩尔)和对氨羟基苯酚(43毫克,0.26毫摩尔)。混合溶液在80℃下搅拌15小时后，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤蒸发后残余物用柱层层析纯化(石油醚:乙酸乙酯＝2:1)得到标题化合物(白色固体，60毫克，收率49％)。LCMS(ESI)m/z:439(M+1)。Potassium carbonate (36 mg, 0.26 mmol), potassium iodide (43 mg, 0.26 mmol), and a solution of &lt;RTI ID=0.0&gt;0&gt; For aminohydroxyphenol (43 mg, 0.26 mmol). The mixed solution was stirred at 80 ° C for 15 hours, then extracted with EtOAc. EtOAc (EtOAc) The title compound (white solid, 60 mg, yield 49%). LCMS (ESI) m/z:
实施例52CExample 52C
(E)-1-(4-(5-(5-(2-氯-4-吡啶基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊氧基)苯基)-N-(环丙基)甲胺(E)-1-(4-(5-(5-(2-chloro-4-pyridyl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyloxy Phenyl)-N-(cyclopropyl)methylamine
Figure PCTCN2015077043-appb-000221
Figure PCTCN2015077043-appb-000221
0℃下，向实施例52B(110毫克，0.25毫摩尔)的N,N-二甲基甲酰胺(2毫升)溶液中加入环丙基溴(34毫克，0.25毫摩尔)和碳酸钾(35毫克，0.15毫摩尔)。50℃下搅拌反应15小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发溶剂后柱层析分离(石油醚:乙酸乙酯＝1：1)得到标题化合物(黄色固体，50毫克,收率40％)。LCMS(ESI)m/z:450(M+1)。1H NMR(400MHz,CDCl3)8.04(s,1H),7.63(d,J＝7.0Hz,1H),7.53(d,J＝8.5Hz,2H),6.90(d,J＝8.5Hz,2H),6.62(d,J＝7.5Hz,1H),6.10(s,1H),4.16-4.25(m,4H),3.82-3.88(m,4H),3.72(dd,J＝11.5,5.0Hz,4H),3.40(t,J＝4.8Hz,2H),1.32(t,J＝7.0Hz,3H)。To a solution of Example 52B (110 mg, 0.25 mmol) of N,N-dimethylformamide (2 mL), EtOAc (EtOAc) Mg, 0.15 mmol). After the reaction was stirred at 50 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated. The combined organic phases were dried with EtOAc EtOAc. LCMS (ESI) m/z: 450 (21. 1 H NMR (400MHz, CDCl 3 ) 8.04 (s, 1H), 7.63 (d, J = 7.0Hz, 1H), 7.53 (d, J = 8.5Hz, 2H), 6.90 (d, J = 8.5Hz, 2H ), 6.62 (d, J = 7.5 Hz, 1H), 6.10 (s, 1H), 4.16-4.25 (m, 4H), 3.82-3.88 (m, 4H), 3.72 (dd, J = 11.5, 5.0 Hz, 4H), 3.40 (t, J = 4.8 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H).
实施例52DExample 52D
4-(5-(2-(2-(4-((E)-乙氧基亚氨基甲基)苯氧基)乙氧基)乙基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)吡啶-2-胺 4-(5-(2-(2-(4-((E)-ethoxyiminomethyl)phenoxy)ethoxy)ethyl)-1,1-dioxy-1,2, 5-thiadiazolidine-2-yl)pyridin-2-amine
Figure PCTCN2015077043-appb-000222
Figure PCTCN2015077043-appb-000222
0℃下，向实施例52C(50毫克,0.1毫摩尔)的N,N-二甲基甲酰胺(1.5毫升)溶液中加入碳酸铯(66毫克,0.2毫摩尔)，氨基甲酸叔丁酯(23毫克,0.2毫摩尔)。置换完氮气后，在氮气保护下加入Pd2(dba)3(19毫克,20微摩尔)，Xantphos(12毫克,20微摩尔)。110℃下搅拌反应15小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发，制备HPLC纯化得到标题化合物(白色固体，5毫克,收率10％)。1H NMR(400MHz,CDCl3)8.08(s,1H),7.65(d,J＝7.0Hz,1H),7.53(d,J＝8.8Hz,2H),6.89(d,J＝8.5Hz,2H),6.70(d,J＝6.8Hz,1H),6.21(br.s.,1H),3.95-4.06(m,4H),3.83-3.90(m,2H),3.59(t,J＝6.1Hz,2H),3.21(t,J＝7.2Hz,2H),1.75-1.92(m,3H),1.57-1.69(m,3H),1.16-1.28(m,1H),0.57-0.64(m,2H),0.34(q,J＝4.9Hz,2H)。LCMS(ESI)m/z:474(M+1)。To a solution of Example 52C (50 mg, 0.1 mmol) of N,N-dimethylformamide (1.5 ml), EtOAc (EtOAc, EtOAc, 23 mg, 0.2 mmol). After replacing the nitrogen, Pd 2 (dba) 3 (19 mg, 20 μmol), Xantphos (12 mg, 20 μmol) was added under nitrogen. After the reaction was stirred at 110 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated. The combined organics were dried with EtOAc EtOAcjjjjjjj 1 H NMR (400MHz, CDCl 3 ) 8.08 (s, 1H), 7.65 (d, J = 7.0Hz, 1H), 7.53 (d, J = 8.8Hz, 2H), 6.89 (d, J = 8.5Hz, 2H ), 6.70 (d, J = 6.8 Hz, 1H), 6.21 (br.s., 1H), 3.95-4.06 (m, 4H), 3.83-3.90 (m, 2H), 3.59 (t, J = 6.1 Hz) , 2H), 3.21 (t, J = 7.2 Hz, 2H), 1.75-1.92 (m, 3H), 1.57-1.69 (m, 3H), 1.16-1.28 (m, 1H), 0.57-0.64 (m, 2H) ), 0.34 (q, J = 4.9 Hz, 2H). LCMS (ESI) m/z:
实施例53Example 53
(E)-4-((5(5(2-氨基吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)苯甲醛-氧-异丙基酮肟(E)-4-((5(5(2-aminopyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl)oxy) Benzaldehyde-oxy-isopropyl ketone oxime
Figure PCTCN2015077043-appb-000223
Figure PCTCN2015077043-appb-000223
本实施例的制备方法参照实施例52。1H NMR(400MHz,CHLOROFORM-d)8.00(s,1H),7.95(d,J＝6.0Hz,1H),7.50(d,J＝8.5Hz,2H),6.86(d,J＝9.0Hz,2H),6.43(d,J＝5.0Hz,1H),6.28(br.s.,1H),4.42(dt,J＝12.3,6.4Hz,1H),3.99(t,J＝6.3Hz,2H),3.80(t,J＝6.3Hz,2H),3.47-3.53(m,2H),3.15(t,J＝7.3Hz,2H),1.82-1.89(m,2H),1.73-1.80(m,4H),1.29(d,J＝6.0Hz,6H)。LCMS(ESI)m/z:462(M+1)。The preparation method of this example is referred to Example 52. 1 H NMR (400MHz, CHLOROFORM- d) 8.00 (s, 1H), 7.95 (d, J = 6.0Hz, 1H), 7.50 (d, J = 8.5Hz, 2H), 6.86 (d, J = 9.0Hz, 2H), 6.43 (d, J = 5.0 Hz, 1H), 6.28 (br.s., 1H), 4.42 (dt, J = 12.3, 6.4 Hz, 1H), 3.99 (t, J = 6.3 Hz, 2H) , 3.80 (t, J = 6.3 Hz, 2H), 3.47-3.53 (m, 2H), 3.15 (t, J = 7.3 Hz, 2H), 1.82-1.89 (m, 2H), 1.73-1.80 (m, 4H) ), 1.29 (d, J = 6.0 Hz, 6H). LCMS (ESI) m.
实施例54Example 54
(E)-2-(2-氨基吡啶-4-基)-5-(5-(4-(1-(乙氧基亚氨基)丙基)苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-Aminopyridin-4-yl)-5-(5-(4-(1-ethoxyimino)propyl)phenoxy)pentyl)-1,2, 5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000224
Figure PCTCN2015077043-appb-000224
实施例54AExample 54A
(E)-1-(4-羟基苯基)丙-1酮-氧-乙基酮肟(E)-1-(4-hydroxyphenyl)propan-1-one-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000225
Figure PCTCN2015077043-appb-000225
4-羟基苯丙酮(1克，6.7毫摩尔)，醋酸钠(1.1克，3.3毫摩尔)，乙氧基胺盐酸盐(814毫克，13.3毫摩尔)的乙醇(10毫升)混合溶液在80℃下搅拌2小时，水(10毫升)和乙酸乙酯(20毫升)加入 反应体系，水层用乙酸乙酯(20毫升×3)萃取，过滤蒸发得到标题化合物(棕色固体，1.28克,收率99％)。1H NMR(400MHz,CDCl3)7.48(d,J＝8.5Hz,2H),6.74-6.79(m,2H),4.20(q,J＝7.0Hz,2H),2.72(q,J＝7.7Hz,2H),1.30(t,J＝7.0Hz,3H),1.11(t,J＝7.5Hz,3H)。a mixture of 4-hydroxypropiophenone (1 g, 6.7 mmol), sodium acetate (1.1 g, 3.3 mmol), ethoxylated amine hydrochloride (814 mg, 13.3 mmol) in ethanol (10 ml) at 80 After stirring for 2 hours at rt EtOAc (EtOAc) (EtOAc m. Rate 99%). 1 H NMR (400 MHz, CDCl 3 ) 7.48 (d, J = 8.5 Hz, 2H), 6.74 - 6.79 (m, 2H), 4.20 (q, J = 7.0 Hz, 2H), 2.72 (q, J = 7.7 Hz) , 2H), 1.30 (t, J = 7.0 Hz, 3H), 1.11 (t, J = 7.5 Hz, 3H).
实施例54BExample 54B
(E)-2-(2-氯吡啶-4-基-5-(5-(4-(1-(乙氧基亚氨基)丙基)苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-chloropyridin-4-yl-5-(5-(4-(1-(ethoxyimino)propyl)phenoxy)pentyl)-1,2,5 -thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000226
Figure PCTCN2015077043-appb-000226
本实施例的制备方法参照实施例52C。1H NMR(400MHz,CDCl3)8.26(d,J＝5.8Hz,1H),7.57(d,J＝8.5Hz,2H),7.06(dd,J＝5.8,2.0Hz,1H),6.99(d,J＝1.8Hz,1H),6.86(d,J＝8.8Hz,2H),4.20(q,J＝7.0Hz,2H),3.99(t,J＝6.1Hz,2H),3.83(t,J＝6.4Hz,2H),3.54(t,J＝6.4Hz,2H),3.17(t,J＝7.3Hz,2H),2.72(q,J＝7.5Hz,2H),1.74-1.88(m,4H),1.61(d,J＝7.0Hz,2H),1.31(t,J＝7.0Hz,3H),1.12(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:495(M+1)。The preparation method of this example is referred to Example 52C. 1 H NMR (400MHz, CDCl 3 ) 8.26 (d, J = 5.8Hz, 1H), 7.57 (d, J = 8.5Hz, 2H), 7.06 (dd, J = 5.8,2.0Hz, 1H), 6.99 (d , J = 1.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 4.20 (q, J = 7.0 Hz, 2H), 3.99 (t, J = 6.1 Hz, 2H), 3.83 (t, J = 6.4 Hz, 2H), 3.54 (t, J = 6.4 Hz, 2H), 3.17 (t, J = 7.3 Hz, 2H), 2.72 (q, J = 7.5 Hz, 2H), 1.74-1.88 (m, 4H) ), 1.61 (d, J = 7.0 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H), 1.12 (t, J = 7.5 Hz, 3H). LCMS (ESI) m/z:495:
实施例54CExample 54C
(E)-2-(2-氨基吡啶-4-基)-5-(5-(4-(1-(乙氧基亚氨基)丙基)苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-Aminopyridin-4-yl)-5-(5-(4-(1-ethoxyimino)propyl)phenoxy)pentyl)-1,2, 5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000227
Figure PCTCN2015077043-appb-000227
本实施例的制备方法参照实施例52。1H NMR(400MHz,CDCl3)7.85(d，J＝6.0Hz,1H),7.57(d,J＝8.5Hz,2H),6.86(d,J＝9.0Hz,2H),6.52(d,J＝6.5Hz,1H),6.29(s,1H),5.58(br.s.,2H),4.20(q,J＝7.0Hz,2H),3.99(t,J＝6.0Hz,2H),3.80-3.85(m,2H),3.52(t,J＝6.3Hz,2H),3.17(t,J＝7.3Hz,2H),2.69-2.75(m,2H),1.85(d,J＝7.0Hz,2H),1.75(br.s.,2H),1.61(d,J＝7.0Hz,2H),1.31(t,J＝7.0Hz,3H),1.12(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:477(M+1)。The preparation method of this example is referred to Example 52. 1 H NMR (400 MHz, CDCl 3 ) 7.85 (d, J = 6.0 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 6.52 (d, J) = 6.5 Hz, 1H), 6.29 (s, 1H), 5.58 (br.s., 2H), 4.20 (q, J = 7.0 Hz, 2H), 3.99 (t, J = 6.0 Hz, 2H), 3.80- 3.85 (m, 2H), 3.52 (t, J = 6.3 Hz, 2H), 3.17 (t, J = 7.3 Hz, 2H), 2.69-2.75 (m, 2H), 1.85 (d, J = 7.0 Hz, 2H) ), 1.75 (br.s., 2H), 1.61 (d, J = 7.0 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H), 1.12 (t, J = 7.5 Hz, 3H). LCMS (ESI) m/z: 437
实施例55Example 55
(E)-4–(2-2-(5-(2-氨基吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)乙氧基)乙氧基)苯甲醛-氧-乙基酮肟(E)-4-(2-2-(5-(2-Aminopyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)ethoxy Ethoxy)benzaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000228
Figure PCTCN2015077043-appb-000228
实施例55AExample 55A
2-2-2(-溴乙氧基)乙基)-5-2-氯吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-2-2(-bromoethoxy)ethyl)-5-2-chloropyridin-4-yl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000229
Figure PCTCN2015077043-appb-000229
本实施例的制备方法参照实施52A。1H NMR(400MHz,CDCl3)8.29(d,J＝5.77Hz,1H),7.08(dd,J＝2.26,5.77Hz,1H),7.02(d,J＝2.26Hz,1H),3.78-3.92(m,8H),3.53(t,J＝5.52Hz,2H),3.42(t,J＝4.89Hz,2H)。The preparation method of this example is referred to the implementation 52A. 1 H NMR (400MHz, CDCl3) 8.29 (d, J = 5.77Hz, 1H), 7.08 (dd, J = 2.26,5.77Hz, 1H), 7.02 (d, J = 2.26Hz, 1H), 3.78-3.92 ( m, 8H), 3.53 (t, J = 5.52 Hz, 2H), 3.42 (t, J = 4.89 Hz, 2H).
实施例55BExample 55B
(E)-1-(4-(2-(2-(5-(2-氯-4-吡啶基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)乙氧基)乙氧基)苯基)-N-乙氧基甲亚胺(E)-1-(4-(2-(2-(5-(2-chloro-4-pyridyl)-1,1-dioxy-1,2,5-thiadiazol-2-yl) Ethoxy)ethoxy)phenyl)-N-ethoxymethylimine
Figure PCTCN2015077043-appb-000230
Figure PCTCN2015077043-appb-000230
向实施例55A(0.1克，0.26毫摩尔)的N,N-二甲基甲酰胺(2毫升)溶液中加入碳酸钾(72毫克，0.52毫摩尔)，碘化钾(8.6毫克，0.05毫摩尔)和实施例7A(47毫克，0.29毫摩尔)。混合溶液在80℃下搅拌12小时后，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤蒸发后残余物用柱层层析纯化(石油醚:乙酸乙酯＝1:1)得到标题化合物(白色固体，60毫克，收率49％)。LCMS(ESI)m/z:469(M+1)。Potassium carbonate (72 mg, 0.52 mmol), potassium iodide (8.6 mg, 0.05 mmol), and a solution of &lt;RTI ID=0.0&gt;0&gt; Example 7A (47 mg, 0.29 mmol). After the mixture was stirred at 80 ° C for 12 hours, it was extracted with EtOAc EtOAc. The title compound (white solid, 60 mg, yield 49%). LCMS (ESI) m/z: 469
实施例55CExample 55C
4-(5-(2-(2-(4-((E)-乙氧基亚氨基甲基)苯氧基)乙氧基)乙基)-1,1-二氧代-1,2,5-噻二唑烷-2-基)吡啶-2-胺4-(5-(2-(2-(4-((E)-ethoxyiminomethyl)phenoxy)ethoxy)ethyl)-1,1-dioxo-1,2 ,5-thiadiazolidine-2-yl)pyridin-2-amine
Figure PCTCN2015077043-appb-000231
Figure PCTCN2015077043-appb-000231
0℃下，向实施例55B(60毫克，0.13毫摩尔)的N,N-二甲基甲酰胺(1毫升)溶液中加入碳酸铯(84毫克，0.26毫摩尔)，氨基甲酸叔丁酯(18毫克，0.15毫摩尔)。置换完氮气后，在氮气保护下加入Pd2(dba)3(22毫克，24微摩尔)，Xantphos(14毫克，24微摩尔)。110℃下搅拌反应15小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发机分得到标题化合物(白色固体，5毫克,收率8.7％)。1H NMR(400MHz,CDCl3)8.04(s,1H),7.63(d,J＝7.0Hz,1H),7.53(d,J＝8.5Hz,2H),6.90(d,J＝8.5Hz,2H),6.62(d,J＝7.5Hz,1H),6.10(s,1H),4.16-4.25(m,4H),3.82-3.88(m,4H),3.72(dd,J＝11.5,5.0Hz,4H),3.40(t,J＝4.8Hz,2H),1.32(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:450(M+1)。To a solution of Example 55B (60 mg, 0.13 mmol),jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 18 mg, 0.15 mmol). After replacing the nitrogen, Pd 2 (dba) 3 (22 mg, 24 μmol), Xantphos (14 mg, 24 μmol) was added under nitrogen. After the reaction was stirred at 110 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated. The combined organic layers were dried with EtOAc EtOAcjjjjjj 1 H NMR (400MHz, CDCl 3 ) 8.04 (s, 1H), 7.63 (d, J = 7.0Hz, 1H), 7.53 (d, J = 8.5Hz, 2H), 6.90 (d, J = 8.5Hz, 2H ), 6.62 (d, J = 7.5 Hz, 1H), 6.10 (s, 1H), 4.16-4.25 (m, 4H), 3.82-3.88 (m, 4H), 3.72 (dd, J = 11.5, 5.0 Hz, 4H), 3.40 (t, J = 4.8 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H). LCMS (ESI) m/z: 450 (21.
实施例56Example 56
(E)-5-((5-(5-(2-氨基吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)甲基吡啶甲醛-氧-乙基酮肟(E)-5-((5-(5-(2-Aminopyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl)oxy Methylpyridine formaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000232
Figure PCTCN2015077043-appb-000232
实施例56AExample 56A
(E)-5-羟基吡啶醛-氧-乙基酮肟 (E)-5-hydroxypyridine aldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000233
Figure PCTCN2015077043-appb-000233
将乙氧氨基盐酸盐(244毫克，2.5毫摩尔)，5-羟基吡啶-2-醛(308毫克,2.5毫摩尔)，醋酸钠(410毫克,5.0毫摩尔)的水溶液(5毫升)加热到80℃搅拌2小时。薄层色谱显示原料消失，反应混合溶液用乙酸乙酯萃取(10毫升x 3)。将有机相合并，无水硫酸钠干燥，过滤浓缩后得标题化合物(白色固体，410毫克，99％产率)，无需纯化直接用于下一步。Heating ethoxylated amino acid hydrochloride (244 mg, 2.5 mmol), 5-hydroxypyridine-2-aldehyde (308 mg, 2.5 mmol), sodium acetate (410 mg, 5.0 mmol) (5 mL) Stir at 80 ° C for 2 hours. Thin layer chromatography showed the disappearance of the starting material, and the reaction mixture was extracted with ethyl acetate (10 ml x 3). The combined organics were dried with EtOAc EtOAcjjjjjjj
实施例56BExample 56B
(E)-5-((5-(5-(2-氯吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)甲基吡啶甲醛-氧-乙基酮肟(E)-5-((5-(5-(2-chloropyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl)oxy Methylpyridine formaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000234
Figure PCTCN2015077043-appb-000234
实施例52A(346毫克，998微摩尔)，实施例56A(163毫克，978微摩尔)和碳酸钾(276毫克,2.0毫摩尔)，碘化钾(17毫克,100微摩尔)的丙酮溶液(5毫升)加热到70℃，反应3个小时.薄层色谱显示原料已经消耗完全。将反应液冷却到室温后过滤，浓缩得粗产物。粗产物用制备薄层层析板纯化(石油醚：乙酸乙酯＝3:1)得标题化合物(白色固体，150毫克，产率：35％)。1H NMR(400MHz,CHLOROFORM-d)8.30-8.24(m,2H),8.12(s,1H),7.71(d,J＝9.0Hz,1H),7.18(dd,J＝2.8,8.8Hz,1H),7.05(dd,J＝2.0,5.5Hz,1H),6.99(d,J＝2.0Hz,1H),4.25(q,J＝7.0Hz,2H),4.04(t,J＝6.3Hz,2H),3.84(t,J＝6.5Hz,2H),3.55(t,J＝6.5Hz,2H),3.22-3.14(m,2H),1.92-1.83(m,2H),1.79(quin,J＝7.4Hz,2H),1.70-1.56(m,2H),1.33(t,J＝7.3Hz,3H)。Example 52A (346 mg, 998 μmol), Example 56A (163 mg, 978 μmol) and potassium carbonate (276 mg, 2.0 mmol), potassium iodide (17 mg, 100 μmol) in acetone (5 ml) Heating to 70 ° C, reaction for 3 hours. Thin layer chromatography showed that the raw materials have been completely consumed. The reaction solution was cooled to room temperature, filtered, and evaporated to dryness. The crude product was purified by EtOAcjjjjjjjj 1 H NMR (400MHz, CHLOROFORM- d) 8.30-8.24 (m, 2H), 8.12 (s, 1H), 7.71 (d, J = 9.0Hz, 1H), 7.18 (dd, J = 2.8,8.8Hz, 1H ), 7.05 (dd, J = 2.0, 5.5 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 4.04 (t, J = 6.3 Hz, 2H) ), 3.84 (t, J = 6.5 Hz, 2H), 3.55 (t, J = 6.5 Hz, 2H), 3.22-3.14 (m, 2H), 1.92-1.83 (m, 2H), 1.79 (quin, J = 7.4 Hz, 2H), 1.70-1.56 (m, 2H), 1.33 (t, J = 7.3 Hz, 3H).
实施例56CExample 56C
(E)-5-((5-(5-(2-氨基吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)甲基吡啶甲醛-氧-乙基酮肟(E)-5-((5-(5-(2-Aminopyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl)oxy Methylpyridine formaldehyde-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000235
Figure PCTCN2015077043-appb-000235
氮气保护下，将氨基甲酸叔丁酯(163毫克，1.4毫摩尔)和实施例56B(120毫克，278微摩尔)，Pd2(dba)3(25毫克,28微摩尔)，Xantphos(32毫克，56微摩尔)，碳酸铯(181毫克，556微摩尔)的二氧六环溶液(3毫升)加热到100℃6个小时。将反应热降至室温后，过滤浓缩，将所得粗产物用制备-HPLC(中性分离方法)纯化得标题化合物(白色固体，30毫克，产率26％)。1H NMR(400MHz,CHLOROFORM-d)8.27(d，J＝2.0Hz,1H),8.11(s,1H),7.97(d,J＝5.5Hz,1H),7.70(d,J＝8.8Hz,1H),7.18(dd,J＝2.3,8.5Hz,1H),6.41(d,J＝4.5Hz,1H),6.28(s,1H),4.49(br.s.,2H),4.25(q,J＝6.9Hz,2H),4.04(t,J＝6.0Hz,2H),3.79(t,J＝6.1Hz,2H),3.49(t,J＝6.3Hz,2H),3.15(t,J＝7.2Hz,2H),1.93-1.82(m,2H),1.82-1.67(m,2H),1.67-1.55(m,2H),1.33(t,J＝6.9Hz,3H)。LCMS(ESI)m/z:449(M+1)。tert-Butyl carbamate (163 mg, 1.4 mmol) and Example 56B (120 mg, 278 μmol), Pd 2 (dba) 3 (25 mg, 28 μmol), Xantphos (32 mg) under nitrogen. , 56 μmol), a solution of cesium carbonate (181 mg, 556 μmol) in dioxane (3 ml) was heated to 100 ° C for 6 hours. After the reaction heat was cooled to room temperature, the title compound was obtained (yield: white solid, 30 mg, yield 26%). 1 H NMR (400MHz, CHLOROFORM- d) 8.27 (d, J = 2.0Hz, 1H), 8.11 (s, 1H), 7.97 (d, J = 5.5Hz, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.18 (dd, J=2.3, 8.5 Hz, 1H), 6.41 (d, J=4.5 Hz, 1H), 6.28 (s, 1H), 4.49 (br.s., 2H), 4.25 (q, J = 6.9 Hz, 2H), 4.04 (t, J = 6.0 Hz, 2H), 3.79 (t, J = 6.1 Hz, 2H), 3.49 (t, J = 6.3 Hz, 2H), 3.15 (t, J = 7.2 Hz, 2H), 1.93-1.82 (m, 2H), 1.82-1.67 (m, 2H), 1.67-1.55 (m, 2H), 1.33 (t, J = 6.9 Hz, 3H). LCMS (ESI) m/z: 449
实施例57Example 57
(E)-2-(2-氨基吡啶-4-基)-5-(5-((1-(甲氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二 氧化物(E)-2-(2-Aminopyridin-4-yl)-5-(5-((1-(methoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy) Ethyl)pentyl)-1,2,5-thiadiazolidine-1,1-di Oxide
Figure PCTCN2015077043-appb-000236
Figure PCTCN2015077043-appb-000236
实施例57AExample 57A
5-((5-(5-(2-氯吡啶-4-基)-1,1-二氧化-1,2,5-噻二唑烷-2-基)戊基)氧基)-2,3-二氢-1H茚-1-酮5-((5-(5-(2-Chloropyridin-4-yl)-1,1-dioxy-1,2,5-thiadiazol-2-yl)pentyl)oxy)-2 ,3-dihydro-1H茚-1-one
Figure PCTCN2015077043-appb-000237
Figure PCTCN2015077043-appb-000237
室温下，向实施例52A(2.0克，5.2毫摩尔)和5-羟基-1-茚酮(774毫克，5.2毫摩尔)的丙酮(30毫升)溶液中加入碳酸钾(1.45克，10.5毫摩尔)，将反应液加热到70℃反应2小时，原料反应完全。将反应液冷却到室温浓缩后，残留物倒入水(50毫升)中，水相用乙酸乙酯(30毫升x 3)萃取，有机相用无水硫酸钠干燥，过滤浓缩，粗产物柱层析纯化(石油醚：乙酸乙酯＝2：1)得到标题化合物(黄色固体，1.3克，55％产率)。1H NMR(400MHz,CDCl3)8.28(d,J＝5.77Hz,1H),7.67-7.73(m,1H),7.08(dd,J＝2.01,5.77Hz,1H),7.01(d,J＝1.76Hz,1H),6.88-6.93(m,2H),4.07(t,J＝6.15Hz,2H),3.80-3.91(m,2H),3.58(t,J＝6.27Hz,2H),3.21(t,J＝7.28Hz,2H),3.04-3.13(m,3H),2.65-2.73(m,3H),1.87-1.96(m,2H),1.76-1.85(m,2H),1.57-1.68(m,2H)。To a solution of Example 52A (2.0 g, 5.2 mmol) and 5-hydroxy-1-indolone (774 mg, 5.2 mmol) in acetone (30 mL) The reaction solution was heated to 70 ° C for 2 hours, and the starting material was completely reacted. The reaction mixture was cooled to EtOAc. The title compound (yellow solid, 1.3 g, 55% yield). 1 H NMR (400MHz, CDCl 3 ) 8.28 (d, J = 5.77Hz, 1H), 7.67-7.73 (m, 1H), 7.08 (dd, J = 2.01,5.77Hz, 1H), 7.01 (d, J = 1.76 Hz, 1H), 6.88-6.93 (m, 2H), 4.07 (t, J = 6.15 Hz, 2H), 3.80-3.91 (m, 2H), 3.58 (t, J = 6.27 Hz, 2H), 3.21. t, J=7.28 Hz, 2H), 3.04-3.13 (m, 3H), 2.65-2.73 (m, 3H), 1.87-1.96 (m, 2H), 1.76-1.85 (m, 2H), 1.57-1.68 ( m, 2H).
实施例57BExample 57B
(E)-2-(2-氯吡啶-4-基)-5-(5-((1-(羟基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-chloropyridin-4-yl)-5-(5-((1-(hydroxyimino)-2,3-dihydro-1H-indol-5-yl)oxy) Pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000238
Figure PCTCN2015077043-appb-000238
室温下，氮气保护下，向实施例57A(1.3克，2.9毫摩尔)和羟胺盐酸盐(603毫克，8.7毫摩尔)的乙醇(30毫升)溶液中加入醋酸钠(711毫克，8.7毫摩尔)，反应液在70℃下反应2小时，原料反应完全。将反应液浓缩后倒入水中(50毫升)，用乙酸乙酯(30毫升x 3)萃取,有机相用无水硫酸钠干燥，过滤浓缩得到标题化合物(黄色固体，1.30克，97％产率)。1H NMR(400MHz,CDCl3)8.29(d,J＝5.77Hz,1H),7.53-7.58(m,1H),7.08(dd,J＝2.26,5.77Hz,1H),7.01(d,J＝2.01Hz,1H),6.82(d,J＝5.02Hz,2H),3.98-4.07(m,2H),3.86(t,J＝6.40Hz,2H),3.57(t,J＝6.40Hz,2H),3.20(t,J＝7.15Hz,2H),2.94-3.10(m,5H),1.75-1.94(m,4H),1.56-1.71(m,2H)。To a solution of Example 57A (1.3 g, 2.9 mmol) and hydroxyamine hydrochloride (603 mg, 8.7 mmol) in ethanol (30 mL) The reaction solution was reacted at 70 ° C for 2 hours, and the starting material was completely reacted. The reaction mixture was concentrated, EtOAcjjjjjjjjjjjjjj ). 1 H NMR (400 MHz, CDCl 3 ) 8.29 (d, J = 5.77 Hz, 1H), 7.53 - 7.58 (m, 1H), 7.08 (dd, J = 2.26, 5.77 Hz, 1H), 7.01 (d, J = 2.01 Hz, 1H), 6.82 (d, J = 5.02 Hz, 2H), 3.98-4.07 (m, 2H), 3.86 (t, J = 6.40 Hz, 2H), 3.57 (t, J = 6.40 Hz, 2H) , 3.20 (t, J = 7.15 Hz, 2H), 2.94-3.10 (m, 5H), 1.75-1.94 (m, 4H), 1.56-1.71 (m, 2H).
实施例57CExample 57C
(E)-2-(2-氨基吡啶-4-基)-5-(5-((1-(甲氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物 (E)-2-(2-Aminopyridin-4-yl)-5-(5-((1-(methoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy) Ethyl)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000239
Figure PCTCN2015077043-appb-000239
本实施例的制备方法参照实施例56。1H-NMR(400MHz,CDCl3)7.97(d,J＝5.8Hz,1H),7.59(d,J＝9.3Hz,1H),6.77-6.81(m,2H),6.42(dd,J＝5.9,1.9Hz,1H),6.29(d,J＝1.8Hz,1H),4.52(br.s.,2H),3.99(t,J＝6.3Hz,2H),3.96(s,3H),3.79(t,J＝6.4Hz,2H),3.47-3.52(m,2H),3.16(t,J＝7.2Hz,2H),2.96-3.01(m,2H),2.85-2.90(m,2H),1.65-1.93(m,4H),1.61-1.64(m,2H)。LCMS(ESI)m/z:460(M+1)。The preparation method of this example is referred to Example 56. 1 H-NMR (400 MHz, CDCl 3 ) 7.97 (d, J = 5.8 Hz, 1H), 7.59 (d, J = 9.3 Hz, 1H), 6.77-6.81 (m, 2H), 6.42 (dd, J = 5.9 , 1.9 Hz, 1H), 6.29 (d, J = 1.8 Hz, 1H), 4.52 (br.s., 2H), 3.99 (t, J = 6.3 Hz, 2H), 3.96 (s, 3H), 3.79 ( t, J = 6.4 Hz, 2H), 3.47-3.52 (m, 2H), 3.16 (t, J = 7.2 Hz, 2H), 2.96-3.01 (m, 2H), 2.85-2.90 (m, 2H), 1.65 -1.93 (m, 4H), 1.61-1.64 (m, 2H). LCMS (ESI) m/z:
实施例58Example 58
(E)-2-(2-氨基吡啶-4-基)-5-(5-(1-(异丙氧)-2,3-二氢-1H-茚-5-基)氧基)戊基)-1,2,5-噻二唑烷1,1-二氧化物(E)-2-(2-Aminopyridin-4-yl)-5-(5-(1-(isopropoxy)-2,3-dihydro-1H-indol-5-yl)oxy)pentane 1,1,2,5-thiadiazolidine 1,1-dioxide
Figure PCTCN2015077043-appb-000240
Figure PCTCN2015077043-appb-000240
本实施例的制备方法参照实施例56。1H-NMR(400MHz,CDCl3)7.80(br.s.,1H),7.58(d,J＝9.0Hz,1H),6.77(br.s.,2H),6.57(br.s.,1H),6.36(br.s.,1H),4.36-4.41(m,1H),3.96-4.00(m,2H),3.84(br.s.,2H),3.51(br.s.,2H),3.14(t,J＝6.9Hz,2H),2.93-2.98(m,2H),2.83-2.88(m,2H),1.80-1.85(m,2H),1.71-1.77(m,2H),1.59(d,J＝6.8Hz,2H),1.32(d,J＝6.0Hz,2H),1.24-1.28(m,6H)。LCMS(ESI)m/z:488(M+1)。The preparation method of this example is referred to Example 56. 1 H-NMR (400 MHz, CDCl 3 ) 7.80 (br.s., 1H), 7.58 (d, J = 9.0 Hz, 1H), 6.77 (br.s., 2H), 6.57 (br.s., 1H) ), 6.36 (br.s., 1H), 4.36-4.41 (m, 1H), 3.96-4.00 (m, 2H), 3.84 (br.s., 2H), 3.51 (br.s., 2H), 3.14 (t, J = 6.9 Hz, 2H), 2.93-2.98 (m, 2H), 2.83 - 2.88 (m, 2H), 1.80-1.85 (m, 2H), 1.71-1.77 (m, 2H), 1.59 ( d, J = 6.8 Hz, 2H), 1.32 (d, J = 6.0 Hz, 2H), 1.24-1.28 (m, 6H). LCMS (ESI) m/z:
实施例59Example 59
(E)-2-(2-氨基吡啶-4-基)-5-(5-((1-乙氧基亚氨基)-7-氟-2,3-二氢-1H-茚-5-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-Aminopyridin-4-yl)-5-(5-((1-ethoxyimino)-7-fluoro-2,3-dihydro-1H-indole-5- Ethyl)oxy)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
实施例59AExample 59A
5-溴-7-氟-茚满-1酮-氧-乙基酮肟5-bromo-7-fluoro-indan-1 keto-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000242
Figure PCTCN2015077043-appb-000242
将5-溴-7-氟-茚啶-1-酮(1.8克，7.9毫摩尔)和乙氧氨基盐酸盐(1.53克，15.7毫摩尔)，乙酸钠(1.29克，15.7毫摩尔)的乙醇溶液(10毫升)70℃下加热3小时。原料消失，加入水(20毫升)，水相用 乙酸乙酯(30毫升x 3)萃取，合并的有机相用无水硫酸钠干燥，过滤浓缩得到标题化合物(黄色固体，2.0克,94％产率)，直接用于下一步反应。5-Bromo-7-fluoro-acridin-1-one (1.8 g, 7.9 mmol) and ethoxyamino hydrochloride (1.53 g, 15.7 mmol), sodium acetate (1.29 g, 15.7 mmol) The ethanol solution (10 ml) was heated at 70 ° C for 3 hours. The raw material disappeared, water (20 ml) was added, and the water phase was used. Ethyl acetate (30 mL, EtOAc) was evaporated.
实施例59BExample 59B
(E)-7-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-2,3-二氢-1H-茚-1-酮-氧-乙基酮肟(E)-7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H- Indole-1-one-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000243
Figure PCTCN2015077043-appb-000243
氮气保护下，将实施例59A(2.00克,7.35毫尔)，双联嚬哪醇硼酸酯(2.24克,8.82毫摩尔)，乙酸钾(2.16克,22.05毫摩尔)，Pd(dppf)Cl2(537.80毫克,735.00微摩尔)的二氧六环(5毫升)溶液加热到50℃下反应10个小时。将反应液冷却到室温后过滤，粗产品直接用于下一步。Example 59A (2.00 g, 7.35 mmol), bis-colonol borate (2.24 g, 8.82 mmol), potassium acetate (2.16 g, 22.05 mmol), Pd(dppf)Cl A solution of 2 (537.80 mg, 735.00 μmol) in dioxane (5 ml) was heated to 50 ° C for 10 hours. The reaction solution was cooled to room temperature and then filtered, and the crude product was applied directly to the next.
实施例59CExample 59C
(E)-7-氟-5-羟基-2,3-二氢-1H-茚-1-酮-氧-乙基酮肟(E)-7-fluoro-5-hydroxy-2,3-dihydro-1H-inden-1-one-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000244
Figure PCTCN2015077043-appb-000244
向实施例59B(2.0克，6.6毫摩尔)的氢氧化钠溶液(2毫升，2N)和四氢呋喃(8毫升)混合溶液中加入双氧水(2.3克，65.5毫摩尔)。混合溶液在25℃下搅拌10分钟后加入水(5.0毫升)。将该混合溶液用乙酸乙酯萃取(10毫升x 3)。有机相用无水硫酸钠干燥，过滤浓缩得粗产物，粗产物用制备薄层色谱纯化(石油醚：乙酸乙酯＝2:1)得标题化合物(黄色固体，1.20克，产率88％)。To a mixed solution of Example 59B (2.0 g, 6.6 mmol) of sodium hydroxide (2 mL, 2N) and THF (8 ml) was added hydrogen peroxide (2.3 g, 65.5 mmol). The mixed solution was stirred at 25 ° C for 10 minutes and then water (5.0 mL) was added. The mixed solution was extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate (mjjjjjjjjjj .
1H NMR(400MHz,CDCl3)6.56(m,1H),6.48-6.46(m,1H),4.24-4.18(m,2H),4.14-4.09(m,2H),2.96-2.89(m,2H),1.31-1.23(m,3H)。 1 H NMR (400MHz, CDCl 3 ) 6.56 (m, 1H), 6.48-6.46 (m, 1H), 4.24-4.18 (m, 2H), 4.14-4.09 (m, 2H), 2.96-2.89 (m, 2H ), 1.31-1.23 (m, 3H).
实施例59DExample 59D
(E)-2-(2-氯吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-7-氟-2,3-二氢-1H-茚-5-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-chloropyridin-4-yl)-5-(5-((1-(ethoxyimino)-7-fluoro-2,3-dihydro-1H-indole-5) -yl)oxy)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000245
Figure PCTCN2015077043-appb-000245
向实施例52A(192毫克，502微摩尔)，实施例59C(105毫克,502微摩尔)的丙酮溶液(5毫升)中加入碘化钾(8毫克,50微摩尔)和碳酸钾(139毫克，1.0毫摩尔)。混合溶液在70℃下搅拌15小时候原料反应完全。加入水(5.0毫升)，用乙酸乙酯(10毫升x 3)萃取。有机相用无水硫酸钠干燥，过滤浓缩得到标题化合物(黄色固体，220毫克，86％产率)。LCMS(ESI)m/z:511(M+1)。 To a solution of Example 52A (192 mg, 502 <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; Millimoles). The mixed solution was stirred at 70 ° C for 15 hours and the starting material was completely reacted. Water (5.0 mL) was added and extracted with EtOAc EtOAc. The organic phase was dried with anhydrous sodium LCMS (ESI) m/z:
实施例59EExample 59E
(E)-2-(2-氨基吡啶-4-基)-5-(5-((1-(乙氧基亚氨基)-7-氟-2,3-二氢-1H-茚-5-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-Aminopyridin-4-yl)-5-(5-((1-(ethoxyimino)-7-fluoro-2,3-dihydro-1H-indole-5) -yl)oxy)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000246
Figure PCTCN2015077043-appb-000246
向实施例59D(102毫克，199微摩尔)，氨基甲酸叔丁酯(222毫克，1.9毫摩尔)，Pd2(dba)3(18毫克,20微摩尔)的二氧六环(5.0毫升)溶液中加入Xantphos(23毫克,40微摩尔)和碳酸钾(83毫克,599微摩尔)。将反应液在100℃下搅拌16小时，将反应液过滤浓缩后用制备HPLC(中性)纯化得到标题化合物(白色固体，52毫克，53％产率)。1H NMR(400MHz,CHLOROFORM-d)7.97(d,J＝6.0Hz,1H),6.60(s,1H),6.51(d,J＝11.5Hz,1H),6.42(d,J＝4.0Hz,1H),6.29(s,1H),4.56(br.s.,2H),4.23(q,J＝7.0Hz,2H),3.50(t,J＝6.5Hz,2H),3.16(t,J＝7.3Hz,2H),2.99(d,J＝8.0Hz,2H),2.93(d,J＝8.5Hz,2H),1.88-1.80(m,2H),1.80-1.72(m,2H),1.32(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:492(M+1)。Example 59D (102 mg, 199 μmol), tert-butyl carbamate (222 mg, 1.9 mmol), Pd 2 (dba) 3 (18 mg, 20 μmol) of dioxane (5.0 ml) Xantphos (23 mg, 40 micromoles) and potassium carbonate (83 mg, 599 micromoles) were added to the solution. The reaction was stirred at 100 ° C for 16 h then EtOAcqqqqm 1 H NMR (400MHz, CHLOROFORM- d) 7.97 (d, J = 6.0Hz, 1H), 6.60 (s, 1H), 6.51 (d, J = 11.5Hz, 1H), 6.42 (d, J = 4.0Hz, 1H), 6.29 (s, 1H), 4.56 (br.s., 2H), 4.23 (q, J = 7.0 Hz, 2H), 3.50 (t, J = 6.5 Hz, 2H), 3.16 (t, J = 7.3 Hz, 2H), 2.99 (d, J = 8.0 Hz, 2H), 2.93 (d, J = 8.5 Hz, 2H), 1.88-1.80 (m, 2H), 1.80 - 1.72 (m, 2H), 1.32 ( t, J = 7.0 Hz, 3H). LCMS (ESI) m/z: 495 (21.
实施例60Example 60
2-(2-氯-4-吡啶基)-5-(5-(4-(2-异丙基四唑-5-基)苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-chloro-4-pyridyl)-5-(5-(4-(2-isopropyltetrazol-5-yl)phenoxy)pentyl)-1,2,5-thiadi Azolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000247
Figure PCTCN2015077043-appb-000247
实施例60AExample 60A
2-异丙基-5-(4-甲氧基苯基)四唑2-isopropyl-5-(4-methoxyphenyl)tetrazole
Figure PCTCN2015077043-appb-000248
Figure PCTCN2015077043-appb-000248
0℃下，向实施例11A(3克，17毫摩尔)的乙腈(30毫升)溶液中加入碳酸钾(4.7克，34毫摩尔)和碘代异丙烷(2.92克，17毫摩尔)。加完后将该混合溶液在100℃下加热5小时。反应液冷却至室温后减压浓缩，柱层析纯化(石油醚:乙酸乙酯＝10:1)得到标题化合物(白色固体，2.1克，收率60％)。1H NMR(400MHz,CDCl3)8.08(d,J＝8.5Hz,2H),7.00(d,J＝8.5Hz,2H),4.68(q,J＝7.2Hz,2H),3.87(s,3H),1.68(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:205(M+1)。To a solution of Example 11A (3 g, 17 mmol) in EtOAc (30 <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; After the addition was completed, the mixed solution was heated at 100 ° C for 5 hours. The reaction mixture was cooled to EtOAc EtOAc m. 1 H NMR (400MHz, CDCl 3 ) 8.08 (d, J = 8.5Hz, 2H), 7.00 (d, J = 8.5Hz, 2H), 4.68 (q, J = 7.2Hz, 2H), 3.87 (s, 3H ), 1.68 (t, J = 7.5 Hz, 3H). LCMS (ESI) m/z:
实施例60BExample 60B
4-(2-异丙基-2H-四唑-5-基)苯酚 4-(2-isopropyl-2H-tetrazol-5-yl)phenol
Figure PCTCN2015077043-appb-000249
Figure PCTCN2015077043-appb-000249
向60A(1克,4.6毫摩尔)中加入溴化氢乙酸溶液(20毫升)。将该混合溶液在110℃下加热24小时，冷却到将反应液加入冰水中，将水相过滤得到固体即为标题化合物(白色固体,0.7克，收率75％)。1H NMR(400MHz,CDCl3)8.08(d,J＝8.5Hz,2H),7.00(d,J＝8.5Hz,2H),4.68(q,J＝7.2Hz,2H),3.87(s,2H),1.68(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:191(M+1)。To 60A (1 g, 4.6 mmol) was added a solution of hydrogen bromide acetic acid (20 mL). The mixed solution was heated at 110 ° C for 24 hours, and then cooled to give the title compound (yield: white solid, 0.7 g, yield 75%). 1 H NMR (400MHz, CDCl 3 ) 8.08 (d, J = 8.5Hz, 2H), 7.00 (d, J = 8.5Hz, 2H), 4.68 (q, J = 7.2Hz, 2H), 3.87 (s, 2H ), 1.68 (t, J = 7.5 Hz, 3H). LCMS (ESI) m.
实施例60CExample 60C
2-(2-氯-4-吡啶基)-5-(5-(4-(2-异丙基四唑-5-基)苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-chloro-4-pyridyl)-5-(5-(4-(2-isopropyltetrazol-5-yl)phenoxy)pentyl)-1,2,5-thiadi Azolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000250
Figure PCTCN2015077043-appb-000250
0℃下，向实施例52A(200毫克,0.52毫摩尔)的丙酮(3毫升)溶液中加入碳酸钾(270毫克,2毫摩尔)，碘化钾(81毫克,0.49毫摩尔)，向上述混合溶液中加入实施例60B(449毫克，2.2毫摩尔)。80℃下搅拌反应15小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发后机分得到标题化合物(白色固体，200毫克，收率74％)。1H NMR(400MHz,CDCl3)8.28(d,J＝6.0Hz,1H),8.09(d,J＝8.8Hz,2H),7.08(dd,J＝5.8,2.0Hz,1H),6.96-7.02(m,3H),5.10(dt,J＝13.5,6.7Hz,1H),4.06(t,J＝6.1Hz,2H),3.86(t,J＝6.3Hz,2H),3.57(t,J＝6.3Hz,2H),3.51(s,2H),3.21(t,J＝7.2Hz,2H),1.86-1.93(m,2H),1.78-1.84(m,2H),1.72(s,3H),1.70(s,3H)。LCMS(ESI)m/z:506(M+1)。Potassium carbonate (270 mg, 2 mmol), potassium iodide (81 mg, 0.49 mmol), was added to a solution of the mixture of the title compound (200 mg, 0.52 mmol) in acetone (3 ml). Example 60B (449 mg, 2.2 mmol) was added. After the reaction was stirred at 80 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated. The combined organic phases were dried with EtOAc EtOAcjjjjjjj 1 H NMR (400MHz, CDCl3) 8.28 (d, J = 6.0Hz, 1H), 8.09 (d, J = 8.8Hz, 2H), 7.08 (dd, J = 5.8,2.0Hz, 1H), 6.96-7.02 ( m, 3H), 5.10 (dt, J = 13.5, 6.7 Hz, 1H), 4.06 (t, J = 6.1 Hz, 2H), 3.86 (t, J = 6.3 Hz, 2H), 3.57 (t, J = 6.3) Hz, 2H), 3.51 (s, 2H), 3.21 (t, J = 7.2 Hz, 2H), 1.86-1.93 (m, 2H), 1.78-1.84 (m, 2H), 1.72 (s, 3H), 1.70 (s, 3H). LCMS (ESI) m/z:
实施例60DExample 60D
2-(2-氯-4-吡啶基)-5-(5-(4-(2-异丙基四唑-5-基)苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-chloro-4-pyridyl)-5-(5-(4-(2-isopropyltetrazol-5-yl)phenoxy)pentyl)-1,2,5-thiadi Azolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000251
Figure PCTCN2015077043-appb-000251
0℃下，向实施例60C(200毫克，0.40毫摩尔)的N,N-二甲基甲酰胺(1毫升)溶液中加入碳酸铯(386毫克，1.2毫摩尔)，氨基甲酸叔丁酯(93毫克，0.79毫摩尔)。在氮气保护下加入Pd2(dba)3(19毫克，20微摩尔)，Xantphos(12毫克，20微摩尔)。110℃下搅拌反应15小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发制备HPLC纯化得到标题化合物(白色固体，40毫克,收率20％)。1H NMR(400MHz,CDCl3)8.08(d,J＝8.5Hz,2H),7.99(d,J＝5.3Hz,1H),7.00(d,J＝8.8Hz,2H),6.44(d,J＝4.0Hz,1H),6.30(s,1H),5.10(dt,J＝13.4,6.7Hz,1H),4.54(br.s.,2H),4.05(t,J＝6.1Hz,2H),3.80(t,J＝6.3Hz,2H),3.47-3.54(m,2H),3.18(t,J＝7.2Hz,2H),1.88(d,J＝7.5Hz,2H),1.76-1.82(m,2H),1.71(d,J＝6.8Hz,6H),1.61-1.68(m,2H)。LCMS(ESI)m/z:487 (M+1)。To a solution of Example 60C (200 mg, 0.40 mmol),jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 93 mg, 0.79 mmol). Pd 2 (dba) 3 (19 mg, 20 μmol), Xantphos (12 mg, 20 μmol) was added under nitrogen. After the reaction was stirred at 110 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated. The combined organic phases were dried with EtOAc EtOAcjjjjjjj 1 H NMR (400MHz, CDCl 3 ) 8.08 (d, J = 8.5Hz, 2H), 7.99 (d, J = 5.3Hz, 1H), 7.00 (d, J = 8.8Hz, 2H), 6.44 (d, J =4.0 Hz, 1H), 6.30 (s, 1H), 5.10 (dt, J = 13.4, 6.7 Hz, 1H), 4.54 (br.s., 2H), 4.05 (t, J = 6.1 Hz, 2H), 3.80 (t, J = 6.3 Hz, 2H), 3.47-3.54 (m, 2H), 3.18 (t, J = 7.2 Hz, 2H), 1.88 (d, J = 7.5 Hz, 2H), 1.76-1.82 (m) , 2H), 1.71 (d, J = 6.8 Hz, 6H), 1.61-1.68 (m, 2H). LCMS (ESI) m/z: 495 (21.
实施例61Example 61
2-(2-氨基吡啶-4-基)-5-(5-(4-(2-甲基-2H-四唑-5-基)苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(5-(4-(2-methyl-2H-tetrazol-5-yl)phenoxy)pentyl)-1,2,5- Thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000252
Figure PCTCN2015077043-appb-000252
本实施例的制备方法参照实施例60。1H NMR(400MHz,DMSO-d6)7.95(d,J＝8.78Hz,2H),7.80-7.89(m,1H),7.09(d,J＝8.78Hz,2H),6.59(br.s.,2H),6.41(d,J＝4.27Hz,1H),6.25(s,1H),4.38(s,3H),4.04(t,J＝6.27Hz,2H),3.84(t,J＝6.40Hz,2H),3.52(t,J＝6.27Hz,2H),3.07(t,J＝7.03Hz,2H),1.62-1.83(m,4H),1.44-1.56(m,2H)。LCMS(ESI)m/z:459(M+1)。The preparation method of this example is referred to Example 60. 1 H NMR (400MHz, DMSO- d 6) 7.95 (d, J = 8.78Hz, 2H), 7.80-7.89 (m, 1H), 7.09 (d, J = 8.78Hz, 2H), 6.59 (br.s. , 2H), 6.41 (d, J = 4.27 Hz, 1H), 6.25 (s, 1H), 4.38 (s, 3H), 4.04 (t, J = 6.27 Hz, 2H), 3.84 (t, J = 6.40 Hz) , 2H), 3.52 (t, J = 6.27 Hz, 2H), 3.07 (t, J = 7.03 Hz, 2H), 1.62-1.83 (m, 4H), 1.44-1.56 (m, 2H). LCMS (ESI) m/z: 459:
实施例62Example 62
2-(2-氨基吡啶-4-基)-5-(5-((3-乙基苯并[d]异唑-6-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(5-((3-ethylbenzo[d]isoxazol-6-yl)oxy)pentyl)-1,2,5-thia Diazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000253
Figure PCTCN2015077043-appb-000253
实施例62AExample 62A
3-乙基苯并[d]异噁唑-6-醇3-ethylbenzo[d]isoxazole-6-ol
Figure PCTCN2015077043-appb-000254
Figure PCTCN2015077043-appb-000254
本实施例的制备方法参考Tetrahedron.Lett.2006，8247-8250。1H NMR(400MHz,CDCl3)7.50-7.48(m,1H),7.00(m,1H),6.85-6.82(m,1H),2.94(m,2H),1.45(t,J＝8.0Hz,3H)。The preparation method of this example is referred to Tetrahedron. Lett. 2006, 8247-8250. 1 H NMR (400MHz, CDCl3) 7.50-7.48 (m, 1H), 7.00 (m, 1H), 6.85-6.82 (m, 1H), 2.94 (m, 2H), 1.45 (t, J = 8.0Hz, 3H ).
实施例62BExample 62B
2-(2-氯吡啶-4-基)-5-(5-((3-乙基苯并[d]异唑-6-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Chloropyridin-4-yl)-5-(5-((3-ethylbenzo[d]isoxazol-6-yl)oxy)pentyl)-1,2,5-thia Diazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000255
Figure PCTCN2015077043-appb-000255
将碳酸钾(36毫克，0.26毫摩尔)和碘化钾(4.3毫克,0.026毫摩尔)加入实施例52A(100毫克,0.26毫摩尔)和实施例62A(42.6毫克,0.26毫摩尔)在丙酮(10毫升)的混合溶液中。然后在50℃反应10小时后。将反应液过滤蒸发，残留物用HPLC纯化得到标题化合物(白色固体，100毫克，收率82％)。1H NMR(400MHz,CDCl3)δ8.28(d,J＝5.77Hz,1H),7.54(d,J＝8.53Hz,1H),7.08(dd,J＝2.26,5.77Hz,1H),7.01(d,J＝2.01Hz,2H),6.89(dd,J＝2.38,8.66Hz,1H),4.02(t,J＝6.15Hz,2H),3.86(t,J＝6.40Hz,2H),3.57(t,J＝6.40Hz,2H),3.15-3.24(m,2H),2.91-2.97(m,2H),1.85-1.98(m,2H),1.74-1.84(m,2H),1.58-1.69(m, 2H),1.45(t,J＝7.65Hz,3H)。Potassium carbonate (36 mg, 0.26 mmol) and potassium iodide (4.3 mg, 0.026 mmol) were added to Example 52A (100 mg, 0.26 mmol) and Example 62A (42.6 mg, 0.26 mmol) in acetone (10 ml) ) in a mixed solution. Then, after reacting at 50 ° C for 10 hours. The reaction mixture was evaporated to dryness crystalljjjjjjjjj 1 H NMR (400MHz, CDCl 3 ) δ8.28 (d, J = 5.77Hz, 1H), 7.54 (d, J = 8.53Hz, 1H), 7.08 (dd, J = 2.26,5.77Hz, 1H), 7.01 (d, J = 2.01 Hz, 2H), 6.89 (dd, J = 2.38, 8.66 Hz, 1H), 4.02 (t, J = 6.15 Hz, 2H), 3.86 (t, J = 6.40 Hz, 2H), 3.57 (t, J = 6.40 Hz, 2H), 3.15-3.24 (m, 2H), 2.91-2.97 (m, 2H), 1.85-1.98 (m, 2H), 1.74-1.84 (m, 2H), 1.58-1.69 (m, 2H), 1.45 (t, J = 7.65 Hz, 3H).
实施例62CExample 62C
2-(2-氨基吡啶-4-基)-5-(5-((3-乙基苯并[d]异唑-6-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(5-((3-ethylbenzo[d]isoxazol-6-yl)oxy)pentyl)-1,2,5-thia Diazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000256
Figure PCTCN2015077043-appb-000256
在氮气保护下将碳酸铯(189毫克，0.58毫摩尔)，Xantphos(22毫克,0.038毫摩尔)和Pd2(dba)3(18毫克，0.019毫摩尔)加入实施例62B(90毫克,0.193毫摩尔)和氨基甲酸叔丁酯(136毫克,0.116毫摩尔)的二氧六环(2毫升)溶液中，然后在110℃下反应10小时后，将反应液倒入水中，用乙酸乙酯(100毫升×3)萃取，合并有机相，用硫酸钠干燥，过滤蒸发，残留物用制备HPLC纯化得到标题化合物(白色固体，20毫克，收率23％)。1H NMR(400MHz,CDCl3)7.98(d,J＝5.52Hz,1H),7.50-7.56(m,1H),7.00(d,J＝2.01Hz,1H),6.85-6.90(m,1H),6.42(d,J＝6.02Hz,1H),6.30(s,1H),4.01(t,J＝6.27Hz,2H),3.76-3.84(m,2H),3.51(t,J＝6.27Hz,2H),3.17(t,J＝7.28Hz,2H),2.93(d,J＝7.53Hz,2H),1.84-1.97(m,2H),1.79(t,J＝7.53Hz,2H),1.64(d,J＝7.03Hz,2H),1.43(t,J＝7.78Hz,3H)。LCMS(ESI)m/z:446(M+1)。Cesium carbonate (189 mg, 0.58 mmol), Xantphos (22 mg, 0.038 mmol) and Pd 2 (dba) 3 (18 mg, 0.019 mmol) were added under nitrogen to EXAMPLE 62B (90 mg, 0.193 m). Mole) and a solution of tert-butyl carbamate (136 mg, 0.116 mmol) in dioxane (2 ml), then reacted at 110 ° C for 10 hours, then poured into water with ethyl acetate ( The title compound (white solid, 20 mg, yield 23%) was obtained. 1 H NMR (400 MHz, CDCl 3 ) 7.98 (d, J = 5.52 Hz, 1H), 7.50-7.56 (m, 1H), 7.00 (d, J = 2.01 Hz, 1H), 6.85-6.90 (m, 1H) , 6.42 (d, J = 6.02 Hz, 1H), 6.30 (s, 1H), 4.01 (t, J = 6.27 Hz, 2H), 3.76-3.84 (m, 2H), 3.51 (t, J = 6.27 Hz, 2H), 3.17 (t, J = 7.28 Hz, 2H), 2.93 (d, J = 7.53 Hz, 2H), 1.84-1.97 (m, 2H), 1.79 (t, J = 7.53 Hz, 2H), 1.64 ( d, J = 7.03 Hz, 2H), 1.43 (t, J = 7.78 Hz, 3H). LCMS (ESI) m/z:
实施例63Example 63
4-(5-(5-(4-(5-乙基-1,3,4-恶二唑-2-基)苯氧基)戊基)-1,1-二氧代-1,2,5-噻二唑烷-2-基)吡啶-2-胺4-(5-(5-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenoxy)pentyl)-1,1-dioxo-1,2 ,5-thiadiazolidine-2-yl)pyridin-2-amine
Figure PCTCN2015077043-appb-000257
Figure PCTCN2015077043-appb-000257
实施例63AExample 63A
4-(5-乙基-1,3,4-恶二唑-2-基)苯酚4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenol
Figure PCTCN2015077043-appb-000258
Figure PCTCN2015077043-appb-000258
将甲基磺酸(63毫克658微摩尔)加入4-羟基苯甲酰肼(500毫克,3.3毫摩尔)和原甲酸三乙酯(579毫克,3.3毫摩尔)的二氧六环(10毫升)混合溶液中.然后在110℃下反应1小时。将反应体系过滤，滤液蒸发得到标题化合物(黄色固体150.00毫克,收率24％)。1H NMR(400MHz,CDCl3)7.79(d,J＝9.03Hz,2H),6.87(d,J＝8.53Hz,2H),2.87(q,J＝7.53Hz,2H),1.36(t,J＝7.53Hz,3H)。Methanesulfonic acid (63 mg 658 μmol) was added to 4-hydroxybenzoic acid hydrazide (500 mg, 3.3 mmol) and triethyl orthoformate (579 mg, 3.3 mmol) in dioxane (10 ml) The solution was mixed. Then, it was reacted at 110 ° C for 1 hour. The reaction system was filtered, and the filtrate was evaporated. 1 H NMR (400MHz, CDCl 3 ) 7.79 (d, J = 9.03Hz, 2H), 6.87 (d, J = 8.53Hz, 2H), 2.87 (q, J = 7.53Hz, 2H), 1.36 (t, J =7.53 Hz, 3H).
实施例63BExample 63B
2-(2-氯-4-吡啶基)-5-(5-(4-(5-乙基-1,3,4-恶二唑-2-基)苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Chloro-4-pyridyl)-5-(5-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenoxy)pentyl)-1 , 2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000259
Figure PCTCN2015077043-appb-000259
将碳酸钾(29毫克，0.02毫摩尔)，碘化钾(3.5毫克，2微摩尔)加入实施例52A(80毫克,0.02毫摩尔)和实施例63A(47.71毫克,0.25毫摩尔)的N,N-二甲基甲酰胺(2毫升)的混合液中。然后在80℃下反应10小时.然后将反应液倒入水(100毫升)中，用乙酸乙酯(100毫升×3)萃取。合并有机相，用硫酸钠干燥，过滤蒸发，残留物过柱得到标题化合物(黄色固体，100毫克,收率97％)。1H NMR(400MHz,CDCl3)8.22(d,J＝5.77Hz,1H),7.91(d,J＝8.78Hz,2H),7.02(dd,J＝2.26,5.77Hz,1H),6.98(d,J＝1.76Hz,1H),6.94(d,J＝9.03Hz,2H),3.95-4.04(m,2H),3.83(t,J＝6.40Hz,3H),3.54(t,J＝6.40Hz,3H),3.11-3.22(m,3H),2.87-2.90(m,2H),1.79-1.90(m,2H),1.69-1.79(m,2H),1.52-1.64(m,2H),1.39(t,J＝7.65Hz,3H)。Potassium carbonate (29 mg, 0.02 mmol), potassium iodide (3.5 mg, 2 micromol) was added to Example 52A (80 mg, 0.02 mmol) and Example 63A (47.71 mg, 0.25 mmol) of N,N- Mixture of dimethylformamide (2 ml). Then, it was reacted at 80 ° C for 10 hours. The reaction solution was poured into water (100 ml) and extracted with ethyl acetate (100 ml × 3). The combined organics were dried with EtOAc EtOAc EtOAc 1 H NMR (400MHz, CDCl3) 8.22 (d, J = 5.77Hz, 1H), 7.91 (d, J = 8.78Hz, 2H), 7.02 (dd, J = 2.26,5.77Hz, 1H), 6.98 (d, J = 1.76 Hz, 1H), 6.94 (d, J = 9.03 Hz, 2H), 3.95-4.04 (m, 2H), 3.83 (t, J = 6.40 Hz, 3H), 3.54 (t, J = 6.40 Hz, 3H), 3.11-3.22 (m, 3H), 2.87-2.90 (m, 2H), 1.79-1.90 (m, 2H), 1.69-1.79 (m, 2H), 1.52-1.64 (m, 2H), 1.39 ( t, J = 7.65 Hz, 3H).
实施例63CExample 63C
4-(5-(5-(4-(5-乙基-1,3,4-恶二唑-2-基)苯氧基)戊基)-1,1-二氧代-1,2,5-噻二唑烷-2-基)吡啶-2-胺4-(5-(5-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenoxy)pentyl)-1,1-dioxo-1,2 ,5-thiadiazolidine-2-yl)pyridin-2-amine
Figure PCTCN2015077043-appb-000260
Figure PCTCN2015077043-appb-000260
在氮气保护下将Pd2(dba)3(15毫克,0.016毫摩尔)，碳酸铯(106毫克,0.032摩尔)和Xantphos(19毫克，3微摩尔)加入实施例63B(80毫克,0.16毫摩尔)和氨基甲酸叔丁酯(114毫克,0.40毫摩尔)的二氧六环(1毫升)溶液中，然后在110℃下反应10小时。反应结束后，将反应液倒入入水(20毫升)中，用乙酸乙酯(10毫升×3)萃取，有机相用无水硫酸钠干燥，过滤蒸发，残留物用制备HPLC纯化得到标题化合物(白色固体，25毫克,收率33％)。1H NMR(400MHz,CDCl3)7.92-8.02(m,3H),6.98(d,J＝9.03Hz,2H),6.43(dd,J＝1.76,5.77Hz,1H),6.30(d,J＝1.51Hz,1H),4.57(br.s.,1H),4.05(t,J＝6.02Hz,2H),3.73-3.87(m,2H),3.51(t,J＝6.53Hz,2H),3.18(t,J＝7.28Hz,2H),2.95(q,J＝7.53Hz,2H),1.84-1.94(m,2H),1.75-1.83(m,2H),1.65-1.69(m,2H),1.44(t,J＝7.53Hz,3H)。LCMS(ESI)m/z:473(M+1)。Pd 2 (dba) 3 (15 mg, 0.016 mmol), cesium carbonate (106 mg, 0.032 mol) and Xantphos (19 mg, 3 μmol) were added under nitrogen to EXAMPLE 63B (80 mg, 0.16 mmol) And a solution of tert-butyl carbamate (114 mg, 0.40 mmol) in dioxane (1 ml), then reacted at 110 ° C for 10 hours. After the reaction was completed, the mixture was evaporated. mjjjjjj White solid, 25 mg, yield 33%). 1 H NMR (400MHz, CDCl 3 ) 7.92-8.02 (m, 3H), 6.98 (d, J = 9.03Hz, 2H), 6.43 (dd, J = 1.76,5.77Hz, 1H), 6.30 (d, J = 1.51 Hz, 1H), 4.57 (br.s., 1H), 4.05 (t, J = 6.02 Hz, 2H), 3.73-3.87 (m, 2H), 3.51 (t, J = 6.53 Hz, 2H), 3.18 (t, J = 7.28 Hz, 2H), 2.95 (q, J = 7.53 Hz, 2H), 1.84-1.94 (m, 2H), 1.75-1.83 (m, 2H), 1.65-1.69 (m, 2H), 1.44 (t, J = 7.53 Hz, 3H). LCMS (ESI) m.
实施例64Example 64
2-(2-氨基吡啶-4-基)-5-(5-(4-(2-乙基-2H-1,2,3-***-4-基)苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(5-(4-(2-ethyl-2H-1,2,3-triazol-4-yl)phenoxy)pentyl)- 1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000261
Figure PCTCN2015077043-appb-000261
实施例64AExample 64A
4-(4-甲氧基苯基)1,2,3-***4-(4-methoxyphenyl) 1,2,3-triazole
Figure PCTCN2015077043-appb-000262
Figure PCTCN2015077043-appb-000262
氮气保护下向碘化亚铜(144克，757毫摩尔)，4-甲氧基苯乙炔(2克，15.1毫摩尔)的N,N-二甲基甲酰胺(5.4毫升)和甲醇(0.6毫升)溶液中加入三甲基硅基叠氮(2.62克，22.7毫摩尔)。混合溶液在100℃下搅拌16小时后，过滤蒸发后残余物用柱层层析纯化(石油醚:乙酸乙酯＝10:1,石油醚:乙酸乙酯＝2:1) 得到标题化合物(黄色固体，2克,收率75％)。1H NMR(400MHz,CDCl3)7.88(s,1H),7.75(d,J＝8.5Hz,2H),6.98(d,J＝8.5Hz,2H),3.85(s,3H)。Under nitrogen, copper iodide (144 g, 757 mmol), 4-methoxyphenylacetylene (2 g, 15.1 mmol) of N,N-dimethylformamide (5.4 ml) and methanol (0.6) To the solution was added trimethylsilyl azide (2.62 g, 22.7 mmol). After the mixture was stirred at 100 ° C for 16 hours, the residue was purified by purified mjjjjjjjjjj Solid, 2 g, yield 75%). 1 H NMR (400 MHz, CDCl 3 ) 7.88 (s, 1 H), 7.75 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 3.85 (s, 3H).
实施例64BExample 64B
2-乙基-4(4-甲氧基苯基)-1,2,3-***2-ethyl-4(4-methoxyphenyl)-1,2,3-triazole
Figure PCTCN2015077043-appb-000263
Figure PCTCN2015077043-appb-000263
实施例64A(1克，5.71毫摩尔)，碘乙烷(2.67克，17.13毫摩尔)和碳酸钾(1.58克，11.42毫摩尔)的乙腈(10毫升)混合物在70℃下反应16小时。水(10毫升)加入反应体系，水层用乙酸乙酯(10毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化(石油醚：乙酸乙酯＝5:1)得到标题化合物(黄色液体，1克，产率86％)。1H NMR(400MHz,CDCl3)7.62-7.73(m,3H),6.92(d,J＝8.5Hz,2H),4.45(q,J＝7.5Hz,2H),3.81(s,3H),1.56(t,J＝7.3Hz,3H)。A mixture of Example 64A (1 g, 5.71 mmol), ethyl acetate (2.67 g, 17.13 mmol), and potassium carbonate (1. Water (10 ml) was added to the reaction mixture. EtOAc (EtOAc m. = 5:1) The title compound was obtained (yellow liquid, 1 g, yield 86%). 1 H NMR (400 MHz, CDCl 3 ) 7.62 - 7.73 (m, 3H), 6.92 (d, J = 8.5 Hz, 2H), 4.45 (q, J = 7.5 Hz, 2H), 3.81 (s, 3H), 1.56 (t, J = 7.3 Hz, 3H).
实施例64CExample 64C
4-(2-乙基-2H-1,2,3-***-4-基)-苯酚4-(2-ethyl-2H-1,2,3-triazol-4-yl)-phenol
Figure PCTCN2015077043-appb-000264
Figure PCTCN2015077043-appb-000264
-78℃下向实施例64B(200毫克,984微摩尔)二氯甲烷(5毫升)溶液中加入三溴化硼(986毫克，3.94毫摩尔)。混合物在25℃下反应1小时后，水(5毫升)加入反应体系，水层用二氯甲烷(10毫升×3)萃取，过滤蒸发后得到标题化合物(黄色固体，160毫克,收率86％)。1H NMR(400MHz,CDCl3)δ7.74(s,1H),7.66(d,J＝8.5Hz,2H),6.89(d,J＝8.5Hz,2H),4.46-4.52(m,2H),1.59(t,J＝7.3Hz,3H)。To a solution of Example 64B (200 mg, 984 mmol) dichloromethane (5 ml) After the mixture was reacted for 1 hour at 25 ° C, water (5 ml) was added to the reaction mixture, m~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ). 1 H NMR (400MHz, CDCl 3 ) δ 7.74 (s, 1H), 7.66 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 4.46-4.52 (m, 2H) , 1.59 (t, J = 7.3 Hz, 3H).
实施例64DExample 64D
2-(2-氯吡啶-4-基)-5-(5-(4-(2-乙基-2H-1,2,3-***-4-基)苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Chloropyridin-4-yl)-5-(5-(4-(2-ethyl-2H-1,2,3-triazol-4-yl)phenoxy)pentyl)- 1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000265
Figure PCTCN2015077043-appb-000265
本实施例的制备方法参照实施例63。1H NMR(400MHz,CDCl3)8.26(d，J＝6.0Hz,1H),7.74(s,1H),7.69(d,J＝9.0Hz,2H),7.06(dd,J＝5.5,2.0Hz,1H),6.99(d,J＝2.0Hz,1H),6.93(d,J＝8.5Hz,2H),4.49(q,J＝7.4Hz,2H),4.01(t,J＝6.3Hz,2H),3.83(t,J＝6.5Hz,2H),3.55(t,J＝6.5Hz,2H),3.18(t,J＝7.0Hz,2H),1.83-1.90(m,2H),1.75-1.82(m,2H),1.62-1.67(m,2H),1.61(d,J＝4.0Hz,3H)。LCMS(ESI)m/z:492(M+1)。The preparation method of this example is referred to Example 63. 1 H NMR (400MHz, CDCl 3 ) 8.26 (d, J = 6.0Hz, 1H), 7.74 (s, 1H), 7.69 (d, J = 9.0Hz, 2H), 7.06 (dd, J = 5.5,2.0Hz , 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 8.5 Hz, 2H), 4.49 (q, J = 7.4 Hz, 2H), 4.01 (t, J = 6.3 Hz, 2H) ), 3.83 (t, J = 6.5 Hz, 2H), 3.55 (t, J = 6.5 Hz, 2H), 3.18 (t, J = 7.0 Hz, 2H), 1.83-1.90 (m, 2H), 1.75-1.82 (m, 2H), 1.62-1.67 (m, 2H), 1.61 (d, J = 4.0 Hz, 3H). LCMS (ESI) m/z: 495 (21.
实施例64EExample 64E
2-(2-氨基吡啶-4-基)-5-(5-(4-(2-乙基-2H-[1,2,3]***-4-基)-苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(5-(4-(2-ethyl-2H-[1,2,3]triazol-4-yl)-phenoxy)pentyl )-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000266
Figure PCTCN2015077043-appb-000266
氮气保护下向实施例64D(80毫克,163微摩尔),氨基甲酸叔丁酯(115毫克,978微摩尔)，碳酸铯(106 毫克,326微摩尔)的二氧六环(3毫升)和N,N二甲基甲酰胺(0.5毫升)溶液中加入Xantphos(8毫克，13.8微摩尔)和Pd2(dba)3(9毫克，9.8微摩尔)。混合物在110℃下反应16小时后，水(10毫升)加入反应体系，水层用二氯甲烷(10毫升×3)萃取，过滤蒸发,残余物通过制备分离得到标题化合物(棕色固体，30毫克,收率39％)。1H NMR(400MHz,CDCl3)δ7.98(d,J＝6.0Hz,1H),7.74(s,1H),7.69(d,J＝8.5Hz,2H),6.94(d,J＝9.0Hz,2H),6.38-6.44(m,1H),6.29(s,1H),4.49(q,J＝7.5Hz,4H),4.01(t,J＝6.0Hz,2H),3.80(t,J＝6.5Hz,2H),3.47-3.53(m,2H),3.16(t,J＝7.3Hz,2H),1.84-1.91(m,2H),1.74-1.80(m,2H),1.64(br.s.,3H)。LCMS(ESI)m/z:472(M+1)。Example 64D (80 mg, 163 μmol), tert-butyl carbamate (115 mg, 978 μmol), cesium carbonate (106 mg, 326 μmol) in dioxane (3 mL) Xantphos (8 mg, 13.8 micromoles) and Pd 2 (dba) 3 (9 mg, 9.8 micromoles) were added to a solution of N,N-dimethylformamide (0.5 ml). After the mixture was reacted at 110 ° C for 16 hours, water (10 ml) was added to the reaction mixture. , yield 39%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (d, J = 6.0 Hz, 1H), 7.74 (s, 1H), 7.69 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 9.0 Hz) , 2H), 6.38-6.44 (m, 1H), 6.29 (s, 1H), 4.49 (q, J = 7.5 Hz, 4H), 4.01 (t, J = 6.0 Hz, 2H), 3.80 (t, J = 6.5 Hz, 2H), 3.47-3.53 (m, 2H), 3.16 (t, J = 7.3 Hz, 2H), 1.84-1.91 (m, 2H), 1.74-1.80 (m, 2H), 1.64 (br.s) ., 3H). LCMS (ESI) m.
实施例65Example 65
(E)-2-(2-氨基吡啶-4-基)-5-(5-((5(乙氧基亚氨基)-5,6,7,8-四氢萘-2-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-Aminopyridin-4-yl)-5-(5-((5(ethoxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl)oxy Ethyl)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000267
Figure PCTCN2015077043-appb-000267
实施例65AExample 65A
(E)-6-羟基-3,4-二氢萘-1(2H)-酮-氧-乙基酮肟(E)-6-hydroxy-3,4-dihydronaphthalene-1(2H)-one-oxy-ethyl ketone oxime
Figure PCTCN2015077043-appb-000268
Figure PCTCN2015077043-appb-000268
向6-羟基-1-四氢萘酮(1克,6.2毫摩尔)的水(10毫升)溶液中加入乙氧氨基盐酸盐(1.88克,30.9毫摩尔)和醋酸钠(2.5克,30.9毫摩尔)。混合溶液在80℃下搅拌2小时后，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤蒸发后得到标题化合物(黄色固体，0.8克,收率63％)。LCMS(ESI)m/z:206(M+1)。To a solution of 6-hydroxy-1-tetralone (1 g, 6.2 mmol) in water (10 mL), EtOAc (1. Millimoles). After the mixture was stirred at 80 ° C for 2 hr, EtOAc (EtOAc) LCMS (ESI) m/z:
实施例65BExample 65B
(E)-2-(2-氯吡啶-4-基)-5-(5-((5-(乙氧基亚氨基)-5,6,7,8-四氢萘-2-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-chloropyridin-4-yl)-5-(5-((5-(ethoxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl) Oxy)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000269
Figure PCTCN2015077043-appb-000269
向实施例52A(0.1克,0.26毫摩尔)的N,N二甲基甲酰胺(2毫升)溶液中加入碳酸钾(72毫克,0.52毫摩尔)，碘化钾(9毫克,0.05毫摩尔)和实施例64A(53.6毫克,0.26毫摩尔)。混合溶液在80℃下搅拌15小时后，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤蒸发后残余物用柱层层析纯化(石油醚:乙酸乙酯＝1:1)得到标题化合物(白色固体，60毫克,收率45％)。1H NMR(400MHz,CDCl3)8.28 (d,J＝5.8Hz,1H),7.92(d,J＝8.8Hz,1H),7.07(dd,J＝5.8,2.0Hz,1H),7.01(d,J＝2.0Hz,1H),6.74(dd,J＝8.8,2.5Hz,1H),6.63(d,J＝2.3Hz,1H),4.21(q,J＝7.0Hz,2H),3.99(t,J＝6.3Hz,2H),3.85(t,J＝6.3Hz,2H),3.56(t,J＝6.4Hz,2H),3.15-3.22(m,2H),2.67-2.77(m,4H),1.84(dt,J＝12.1,6.4Hz,6H),1.58-1.66(m,2H),1.33(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:507(M+1)。Potassium carbonate (72 mg, 0.52 mmol), potassium iodide (9 mg, 0.05 mmol), and a solution of &lt;RTI ID=0.0&gt;&gt; Example 64A (53.6 mg, 0.26 mmol). The mixture was stirred at 80 ° C for 15 hours, then extracted with EtOAc EtOAc. The title compound (white solid, 60 mg, yield 45%). 1 H NMR (400 MHz, CDCl 3 ) 8.28 (d, J = 5.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.07 (dd, J = 5.8, 2.0 Hz, 1H), 7.01 (d) , J=2.0 Hz, 1H), 6.74 (dd, J=8.8, 2.5 Hz, 1H), 6.63 (d, J=2.3 Hz, 1H), 4.21 (q, J=7.0 Hz, 2H), 3.99 (t , J = 6.3 Hz, 2H), 3.85 (t, J = 6.3 Hz, 2H), 3.56 (t, J = 6.4 Hz, 2H), 3.15 - 3.22 (m, 2H), 2.67-2.77 (m, 4H) , 1.84 (dt, J = 12.1, 6.4 Hz, 6H), 1.58-1.66 (m, 2H), 1.33 (t, J = 7.0 Hz, 3H). LCMS (ESI) m/z:
实施例65CExample 65C
(E)-2-(2-氨基吡啶-4-基)-5-(5-((5-(乙氧基亚氨基)-5,6,7,8-四氢萘-2-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(2-Aminopyridin-4-yl)-5-(5-((5-(ethoxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl) Oxy)pentyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000270
Figure PCTCN2015077043-appb-000270
0℃下，向实施例65B(60毫克,0.12毫摩尔)的N,N-二甲基甲酰胺(1毫升)溶液中加入碳酸铯(77毫克,0.24毫摩尔)，氨基甲酸叔丁酯(15毫克,0.13毫摩尔)，置换完氮气后，在氮气保护下加入Pd2(dba)3(22毫克,23.7毫摩尔)和Xantphos(14毫克,23.7毫摩尔)。在110℃下搅拌反应15小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发，制备HPLC纯化得到标题化合物(白色固体，15毫克,收率26％)。1H NMR(400MHz,CDCl3)7.91(d,J＝8.5Hz,1H),7.62(d,J＝7.0Hz,1H),6.68-6.75(m,2H),6.62(d,J＝2.0Hz,1H),6.18(s,1H),4.20(q,J＝7.0Hz,2H),3.98(t,J＝6.3Hz,2H),3.84(t,J＝6.3Hz,2H),3.57(t,J＝6.3Hz,2H),3.19(t,J＝7.0Hz,2H),2.65-2.76(m,4H),1.81-1.87(m,4H),1.76(d,J＝7.0Hz,2H),1.57-1.63(m,2H),1.32(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:488(M+1)。To a solution of Example 65B (60 mg, 0.12 mmol) of N,N-dimethylformamide (1 mL), EtOAc (EtOAc, 15 mg, 0.13 mmol), after replacing nitrogen, Pd 2 (dba) 3 (22 mg, 23.7 mmol) and Xantphos (14 mg, 23.7 mmol) were added under nitrogen. After the reaction was stirred at 110 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated. The combined organic phases were dried with EtOAc EtOAcjjjjjjj 1 H NMR (400 MHz, CDCl 3 ) 7.91 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 7.0 Hz, 1H), 6.68-6.75 (m, 2H), 6.62 (d, J = 2.0 Hz) , 1H), 6.18 (s, 1H), 4.20 (q, J = 7.0 Hz, 2H), 3.98 (t, J = 6.3 Hz, 2H), 3.84 (t, J = 6.3 Hz, 2H), 3.57 (t , J = 6.3 Hz, 2H), 3.19 (t, J = 7.0 Hz, 2H), 2.65-2.76 (m, 4H), 1.81-1.87 (m, 4H), 1.76 (d, J = 7.0 Hz, 2H) , 1.57-1.63 (m, 2H), 1.32 (t, J = 7.0 Hz, 3H). LCMS (ESI) m/z:
实施例66Example 66
2-(2-氨基吡啶-4-基)-5-(5-((2-丙基苯并[d]恶唑-6-基)氧基)戊基)-1,2,5-噻二唑烷1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(5-((2-propylbenzo[d]oxazol-6-yl)oxy)pentyl)-1,2,5-thia Diazolidine 1,1-dioxide
Figure PCTCN2015077043-appb-000271
Figure PCTCN2015077043-appb-000271
实施例66AExample 66A
2-丙基苯并[d]噁唑-6-醇2-propylbenzo[d]oxazole-6-ol
Figure PCTCN2015077043-appb-000272
Figure PCTCN2015077043-appb-000272
本实施例操作参考专利(WO 2005037814)LCMS(ESI)m/z:178(M+1)。This example is a reference to the patent (WO 2005037814) LCMS (ESI) m/z: 178 (M+1).
实施例66BExample 66B
2-(2-氯吡啶-4-基)-5-(5-((2-丙基苯并[d]恶唑-6-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Chloropyridin-4-yl)-5-(5-((2-propylbenzo[d]oxazole-6-yl)oxy)pentyl)-1,2,5-thia Diazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000273
Figure PCTCN2015077043-appb-000273
向实施例实施例52A(0.1克,0.26毫摩尔)的N,N-二甲基甲酰胺(2毫升)溶液中加入碳酸钾(72毫克,0.52毫摩尔),碘化钾(9毫克,0.05毫摩尔)和2-丙基6-羟基苯并恶唑(56毫克,0.3毫摩尔)。混合溶液在80℃下搅拌15小时后，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤蒸发后残余物用柱层层析纯化(石油醚:乙酸乙酯＝1:1)得到标题化合物(白色固体，50毫克,收率40％)。LCMS(ESI)m/z:479(M+1)。To a solution of Example 52A (0.1 g, 0.26 mmol),jjjjjjjjjjjjjjjjjjjjjj And 2-propyl 6-hydroxybenzoxazole (56 mg, 0.3 mmol). The mixture was stirred at 80 ° C for 15 hours, then extracted with EtOAc EtOAc. The title compound (white solid, 50 mg, yield 40%). LCMS (ESI) m.
实施例66CExample 66C
2-(2-氨基吡啶-4-基)-5-(5-((2-丙基苯并[d]恶唑-6-基)氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(5-((2-propylbenzo[d]oxazol-6-yl)oxy)pentyl)-1,2,5-thia Diazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000274
Figure PCTCN2015077043-appb-000274
0℃下，向实施例66B(50毫克,0.10毫摩尔)的N,N-二甲基甲酰胺(1毫升)溶液中加入碳酸铯(68毫克,0.21毫摩尔)，氨基甲酸叔丁酯(15毫克,0.13毫摩尔)，置换完氮气后，在氮气保护下加入Pd2(dba)3(19毫克,21微摩尔)和Xantphos(12毫克,20微摩尔)。在110℃下搅拌反应15小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发，制备HPLC纯化得到标题化合物(白色固体，8毫克,收率17％)。1H NMR(400MHz,CDCl3)7.92(d,J＝6.3Hz,1H),7.54(d,J＝8.5Hz,1H),7.02(d,J＝2.3Hz,1H),6.90(dd,J＝8.8,2.3Hz,1H),6.50(d,J＝5.8Hz,1H),6.33(s,1H),4.03(t,J＝6.3Hz,2H),3.85(t,J＝6.4Hz,2H),3.54(t,J＝6.3Hz,2H),3.19(t,J＝7.2Hz,2H),2.89(t,J＝7.5Hz,2H),1.87-1.94(m,4H),1.80(q,J＝7.3Hz,2H),1.61-1.70(m,2H),1.06(t,J＝7.4Hz,3H)。LCMS(ESI)m/z:460(M+1)。To a solution of Example 66B (50 mg, 0.10 mmol) in N,N-dimethylformamide (1 mL), EtOAc (EtOAc, m. 15 mg, 0.13 mmol), after replacement of nitrogen, Pd 2 (dba) 3 (19 mg, 21 μmol) and Xantphos (12 mg, 20 μmol) were added under nitrogen. After the reaction was stirred at 110 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated. The combined organic phases were dried with EtOAc EtOAcjjjjjjjj 1 H NMR (400 MHz, CDCl 3 ) 7.92 (d, J = 6.3 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H), 6.90 (dd, J = 8.8, 2.3 Hz, 1H), 6.50 (d, J = 5.8 Hz, 1H), 6.33 (s, 1H), 4.03 (t, J = 6.3 Hz, 2H), 3.85 (t, J = 6.4 Hz, 2H) ), 3.54 (t, J = 6.3 Hz, 2H), 3.19 (t, J = 7.2 Hz, 2H), 2.89 (t, J = 7.5 Hz, 2H), 1.87-1.94 (m, 4H), 1.80 (q) , J = 7.3 Hz, 2H), 1.61-1.70 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H). LCMS (ESI) m/z:
实施例67Example 67
2-(2-氨基吡啶-4-基)-5-(5-(4-(5-乙基异恶唑-3-基)苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(5-(4-(5-ethylisoxazol-3-yl)phenoxy)pentyl)-1,2,5-thiadi Azolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000275
Figure PCTCN2015077043-appb-000275
实施例67AExample 67A
(E)-4-羟基苯甲醛肟(E)-4-hydroxybenzaldehyde oxime
Figure PCTCN2015077043-appb-000276
Figure PCTCN2015077043-appb-000276
向4-羟基苯甲醛(10克,82毫摩尔)的乙醇(100毫升)溶液中加入醋酸钠(20克,246毫摩尔)和盐酸羟胺(17毫克，246毫摩尔)。将该混合溶液在70℃下加热15小时，冷却到室温后加水，用乙酸乙酯萃取，有机相旋干后，通过柱分离(石油醚:EA＝3:1)得到固体即为标题化合物(白色固体,7克,收率62％)。LCMS(ESI)m/z:138(M+1)。To a solution of 4-hydroxybenzaldehyde (10 g, 82 mmol) in ethanol (100 ml), sodium acetate (20 g, 246 mmol) and hydroxylamine hydrochloride (17 mg, 246 mmol). The mixed solution was heated at 70 ° C for 15 hours. After cooling to room temperature, water was added, and the mixture was combined with ethyl acetate. The organic phase was evaporated to dryness and then purified by column ( petroleum ether: EA = 3:1) White solid, 7 g, yield 62%). LCMS (ESI) m/z:
实施例67BExample 67B
4-(5-乙基异恶唑-3-基)苯酚 4-(5-ethylisoxazol-3-yl)phenol
Figure PCTCN2015077043-appb-000277
Figure PCTCN2015077043-appb-000277
0℃下，向实施例67A(3克,22毫摩尔)的1,2-二氯乙烷(30毫升)溶液中加入氯代丁二酰亚胺(2.9克,22毫摩尔)。室温下反应一个小时后，冰浴下加入1-丁炔(1.2克,22毫摩尔)，加完后将该混合溶液在20℃下加热2小时。再在冰浴下向反应液中加入三乙胺(2.2克,22毫摩尔)加完后将该混合溶液在20℃下加热15小时。反应液冷却至室温后减压浓缩，柱层析纯化(石油醚:乙酸乙酯＝10:1)得到标题化合物(白色固体,1克,收率24％)。LCMS(ESI)m/z:190(M+1)。Chlorobutyl succinimide (2.9 g, 22 mmol) was added to a solution of EtOAc (3 g, m. After reacting for one hour at room temperature, 1-butyne (1.2 g, 22 mmol) was added in an ice bath, and after the addition was completed, the mixture was heated at 20 ° C for 2 hours. Further, triethylamine (2.2 g, 22 mmol) was added to the reaction mixture under ice-cooling, and the mixture was heated at 20 ° C for 15 hr. The reaction mixture was cooled to EtOAc EtOAc m. LCMS (ESI) m/z:
实施例67CExample 67C
2-(2-氯吡啶-4-基)-5-(5-(4-(5-乙基异恶唑-3-基)苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Chloropyridin-4-yl)-5-(5-(4-(5-ethylisoxazol-3-yl)phenoxy)pentyl)-1,2,5-thiadi Azolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000278
Figure PCTCN2015077043-appb-000278
向实施例52A(0.1克,0.26毫摩尔)的N,N-二甲基甲酰胺(2毫升)溶液中加入碳酸钾(72毫克,0.5毫摩尔)，碘化钾(9毫克,0.05毫摩尔)和67B(59毫克,0.3毫摩尔)。混合溶液在80℃下搅拌15小时后，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤蒸发后残余物用柱层层析纯化(石油醚:乙酸乙酯＝2:1)得到标题化合物(白色固体，60毫克,收率49％)。LCMS(ESI)m/z:492(M+1)。Potassium carbonate (72 mg, 0.5 mmol), potassium iodide (9 mg, 0.05 mmol), and a solution of EtOAc (EtOAc, m. 67B (59 mg, 0.3 mmol). The mixed solution was stirred at 80 ° C for 15 hours, then extracted with EtOAc. EtOAc (EtOAc) The title compound (white solid, 60 mg, yield 49%). LCMS (ESI) m/z: 495 (21.
实施例67DExample 67D
2-(2-氨基吡啶-4-基)-5-(5-(4-(5-乙基异恶唑-3-基)苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(5-(4-(5-ethylisoxazol-3-yl)phenoxy)pentyl)-1,2,5-thiadi Azolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000279
Figure PCTCN2015077043-appb-000279
0℃下，向实施例67C(50毫克,0.101毫摩尔)的N,N-二甲基甲酰胺(1.5毫升)溶液中加入碳酸铯(66.36毫克,0.202毫摩尔)，氨基甲酸叔丁酯(23.26毫克,0.202毫摩尔)。置换完氮气后，在氮气保护下加入Pd2(dba)3(18.57毫克,20.28毫摩尔)/Xantphos(11.74毫克,20.28毫摩尔)。110℃下搅拌反应15小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发机分得到标题化合物(白色固体，3毫克,收率6.25％)。1H NMR(400MHz,CDCl3)7.98(d,J＝5.5Hz,1H),7.72(d,J＝8.5Hz,2H),6.95(d,J＝8.5Hz,2H),6.39-6.44(m,1H),6.29(s,1H),6.23(s,1H),4.48(br.s.,2H),4.03(t,J＝6.0Hz,2H),3.79(t,J＝6.5Hz,2H),3.50(t,J＝6.3Hz,2H),3.17(t,J＝7.3Hz,2H),2.81(q,J＝7.5Hz,2H),1.82-1.94(m,2H),1.70-1.82(m,2H),1.64(br.s.,2H),1.34(t,J＝7.8Hz,3H)。LCMS(ESI)m/z:472(M+1)。To a solution of EtOAc (m. 23.26 mg, 0.202 mmol). After replacing the nitrogen, Pd 2 (dba) 3 (18.57 mg, 20.28 mmol) / Xantphos (11.74 mg, 20.28 mmol) was added under a nitrogen atmosphere. After the reaction was stirred at 110 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated. The combined organic layers were dried with EtOAc EtOAcjjjjjj 1 H NMR (400 MHz, CDCl 3 ) 7.98 (d, J = 5.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 6.39-6.44 (m) , 1H), 6.29 (s, 1H), 6.23 (s, 1H), 4.48 (br.s., 2H), 4.03 (t, J = 6.0 Hz, 2H), 3.79 (t, J = 6.5 Hz, 2H) ), 3.50 (t, J = 6.3 Hz, 2H), 3.17 (t, J = 7.3 Hz, 2H), 2.81 (q, J = 7.5 Hz, 2H), 1.82-1.94 (m, 2H), 1.70-1.82 (m, 2H), 1.64 (br.s., 2H), 1.34 (t, J = 7.8 Hz, 3H). LCMS (ESI) m.
实施例68Example 68
2-(2-氨基吡啶-4-基)-5-(5-(4-(5(三氟甲基)-1,2,4-恶二唑-3-基)苯氧基)戊基)-1,2,5-噻二唑烷-1,1-二氧化物 2-(2-Aminopyridin-4-yl)-5-(5-(4-(5(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenoxy)pentyl )-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000280
Figure PCTCN2015077043-appb-000280
实施例68AExample 68A
4-(5-(5-(2-氯-4-吡啶基)-1,1-二氧代-1,2,5-噻二唑烷-2-基)-戊氧基)苄腈4-(5-(5-(2-chloro-4-pyridyl)-1,1-dioxo-1,2,5-thiadiazol-2-yl)-pentyloxy)benzonitrile
Figure PCTCN2015077043-appb-000281
Figure PCTCN2015077043-appb-000281
0℃下，向实施例52A(500毫克,1.31毫摩尔)的N,N-二甲基甲酰胺(5毫升)溶液中加入对氰基苯酚(187毫克,1.57毫摩尔)。向上述混合溶液中加入碳酸钾(362毫克,2.62毫摩尔).80℃下搅拌反应15小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发后柱分离(石油醚:乙酸乙酯＝2:1)得到标题化合物(白色固体，350毫克,收率63％)。LCMS(ESI)m/z:421(M+1)。To a solution of Example 52A (500 mg, 1. <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Potassium carbonate (362 mg, 2.62 mmol) was added to the above mixed solution. After the reaction was stirred at 80 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH LCMS (ESI) m/z:21.
实施例68BExample 68B
4-(5-(5-(2-氨基-4-吡啶基)-1,1-二氧代-1,2,5-噻二唑烷-2-基)-戊氧基)苄腈4-(5-(5-(2-Amino-4-pyridyl)-1,1-dioxo-1,2,5-thiadiazol-2-yl)-pentyloxy)benzonitrile
Figure PCTCN2015077043-appb-000282
Figure PCTCN2015077043-appb-000282
0℃下，向实施例68A(100毫克,0.24毫摩尔)的N,N-二甲基甲酰胺(1.5毫升)溶液中加入碳酸铯(154毫克,0.48毫摩尔)，氨基甲酸叔丁酯(42毫克,0.36毫摩尔)。在氮气保护下加入Pd2(dba)3(18.57毫克,20.28微摩尔)和Xantphos(11.7毫克，20微摩尔)。110℃下搅拌反应15小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发柱分离(二氯甲烷:甲醇＝10:1)得到标题化合物(白色固体，30毫克,收率31％)。LCMS(ESI)m/z:402(M+1)。To a solution of Example 68A (100 mg, 0.24 mmol) in N,N-dimethylformamide (1.5 ml), EtOAc ( EtOAc EtOAc 42 mg, 0.36 mmol). Pd 2 (dba) 3 (18.57 mg, 20.28 μmol) and Xantphos (11.7 mg, 20 μmol) were added under nitrogen. After the reaction was stirred at 110 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated. The combined organic phases were dried with EtOAc EtOAcjjjjjjjj LCMS (ESI) m/z: 402:
实施例68CExample 68C
N-(4-(5-(5-(4-氰基苯氧基)戊基)-1,1-二氧代-1,2,5-噻二唑烷-2-基)-2-吡啶基)氨基甲酸叔丁酯N-(4-(5-(5-(4-Cyanophenoxy)pentyl)-1,1-dioxo-1,2,5-thiadiazol-2-yl)-2- Tert-butyl pyridyl)carbamate
Figure PCTCN2015077043-appb-000283
Figure PCTCN2015077043-appb-000283
向68B(0.3克,0.75毫摩尔)的乙腈溶液中加入N,N-二甲基氨基吡啶(45毫克,0.37毫摩尔)和BOC酸酐(489毫克,2.2毫摩尔)。将该混合溶液在20℃下加热15小时，冷却到将反应液加入冰水中，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发柱分离(二氯甲烷:甲醇＝10：1)得到标题化合物(红色油状,0.2克,收率53％)。LCMS(ESI)m/z:502(M+1)。To a solution of 68B (0.3 g, 0.75 mmol) in acetonitrile, N,N-dimethylaminopyridine (45 mg, 0.37 mmol) and EtOAc. The mixed solution was heated at 20 ° C for 15 hours, cooled until the reaction solution was added to ice water, and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried with EtOAc EtOAc EtOAcjjjjjj LCMS (ESI) m/z:
实施例68DExample 68D
N-(4-(5-(5-(4-((Z)-N'-羟基脒基)苯氧基)戊基)-1,1-二氧代-1,2,5-噻二唑烷-2-基)-2-吡啶基)氨基甲酸叔丁 酯N-(4-(5-(5-(4-((Z)-N'-hydroxyindenyl)phenoxy)pentyl)-1,1-dioxo-1,2,5-thiadi Oxazol-2-yl)-2-pyridyl)carbamic acid tert-butyl ester
Figure PCTCN2015077043-appb-000284
Figure PCTCN2015077043-appb-000284
向实施例68C(0.1克,0.2毫摩尔)的异丙醇(2毫升)溶液中加入三乙胺(40毫克,0.4毫摩尔)和盐酸羟胺(27.8毫克,0.4毫摩尔)。混合溶液在80℃下搅拌5小时后，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤蒸发后得到标题化合物(白色固体，70毫克,收率66％)。LCMS(ESI)m/z:535(M+1)。To a solution of Example 68C (0.1 g, EtOAc) (EtOAc) After the mixture was stirred at 80 ° C for 5 hr, EtOAc (EtOAc) LCMS (ESI) m/z:
实施例68EExample 68E
2-(2-氨基吡啶-4-基)-5-(5-(4-(5(三氟甲基)-1,2,4-恶二唑-3-基)苯氧基)戊基)-1,2,5-噻二唑烷1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(5-(4-(5(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenoxy)pentyl )-1,2,5-thiadiazolidine 1,1-dioxide
Figure PCTCN2015077043-appb-000285
Figure PCTCN2015077043-appb-000285
0℃下，向实施例68D(60毫克,0.11毫摩尔)的吡啶(1毫升)溶液中加入TFAA(35毫克,0.17毫摩尔)。80℃下搅拌反应2小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发后机分得到标题化合物(白色固体，5毫克,收率7％)。1H NMR(400MHz,CDCl3)8.06(d,J＝8.8Hz,2H),8.00(d,J＝6.0Hz,1H),7.02(d,J＝8.8Hz,2H),6.44(dd,J＝5.8,2.0Hz,1H),6.31(d,J＝2.0Hz,1H),4.50(br.s.,2H),4.08(t,J＝6.3Hz,2H),3.83(t,J＝6.3Hz,2H),3.53(t,J＝6.4Hz,2H),3.19(t,J＝7.2Hz,2H),1.87-1.96(m,2H),1.81(quin,J＝7.4Hz,2H),1.65-1.70(m,2H)。LCMS(ESI)m/z:513(M+1)。To a solution of Example 68D (60 mg, 0.11 mmol) EtOAc (1 mL) After stirring the reaction at 80 ° C for 2 hours, the reaction was quenched by water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried with EtOAc EtOAcjjjjjjj 1 H NMR (400MHz, CDCl 3 ) 8.06 (d, J = 8.8Hz, 2H), 8.00 (d, J = 6.0Hz, 1H), 7.02 (d, J = 8.8Hz, 2H), 6.44 (dd, J = 5.8, 2.0 Hz, 1H), 6.31 (d, J = 2.0 Hz, 1H), 4.50 (br.s., 2H), 4.08 (t, J = 6.3 Hz, 2H), 3.83 (t, J = 6.3) Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 3.19 (t, J = 7.2 Hz, 2H), 1.87-1.96 (m, 2H), 1.81 (quin, J = 7.4 Hz, 2H), 1.65-1.70 (m, 2H). LCMS (ESI) m/z:
实施例69Example 69
2-(2-氨基吡啶-4-基)-5-(5-(4-(5-甲基-1,2,4-恶二唑-3-基)苯氧基)戊基-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(5-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy)pentyl-1, 2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000286
Figure PCTCN2015077043-appb-000286
本实施例的制备方法参照实施例68。1H NMR(400MHz,CDCl3)7.96(d,J＝8.78Hz,1H),7.79(d,J＝7.28Hz,1H),7.06(d,J＝8.78Hz,2H),6.80(dd,J＝2.51,7.28Hz,1H),6.47(d,J＝2.26Hz,1H),4.10(t,J＝6.15Hz,2H),3.97(t,J＝6.40Hz,2H),3.60-3.71(m,2H),3.22(t,J＝7.03Hz,2H),2.65(s,3H),1.85-1.94(m,2H),1.76-1.84(m,2H),1.60-1.70(m,2H)。LCMS(ESI)m/z:459(M+1)。The preparation method of this example is referred to Example 68. 1 H NMR (400MHz, CDCl3) 7.96 (d, J = 8.78Hz, 1H), 7.79 (d, J = 7.28Hz, 1H), 7.06 (d, J = 8.78Hz, 2H), 6.80 (dd, J = 2.51, 7.28 Hz, 1H), 6.47 (d, J = 2.26 Hz, 1H), 4.10 (t, J = 6.15 Hz, 2H), 3.97 (t, J = 6.40 Hz, 2H), 3.60-3.71 (m, 2H), 3.22 (t, J = 7.03 Hz, 2H), 2.65 (s, 3H), 1.85-1.94 (m, 2H), 1.76-1.84 (m, 2H), 1.60-1.70 (m, 2H). LCMS (ESI) m/z: 459:
流程R Process R
Figure PCTCN2015077043-appb-000287
Figure PCTCN2015077043-appb-000287
实施例70Example 70
(E)-2-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-5-(哒嗪-4-基)-1,2,5-噻二唑烷-1,1-二氧化物(E)-2-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy)pentyl)-5-(pyridazine-4 -yl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000288
Figure PCTCN2015077043-appb-000288
实施例70AExample 70A
5-(3,6-二氯哒-4-基)-1,2,5-噻二唑烷-2-羧酸叔丁酯-1,1-二氧化物5-(3,6-Dichloroindol-4-yl)-1,2,5-thiadiazolidine-2-carboxylic acid tert-butyl ester-1,1-dioxide
Figure PCTCN2015077043-appb-000289
Figure PCTCN2015077043-appb-000289
本实施例的制备方法参照实施例32G。1H NMR(400MHz,CDCl3)7.87(s，1H)，4.02-4.12(m,4H),1.58(s,10H)。LCMS(ESI)m/z:369(M+1)。The preparation method of this example is referred to Example 32G. 1 H NMR (400 MHz, CDCl 3 ) 7. 7. (s, 1H), 4.02-4.12 (m, 4H), 1.58 (s, 10H). LCMS (ESI) m/z:
实施例70BExample 70B
5-(哒嗪-4-基)-1,2,5-噻二唑烷-2-羧酸叔丁酯-1,1-二氧化物5-(pyridazin-4-yl)-1,2,5-thiadiazolidine-2-carboxylic acid tert-butyl ester-1,1-dioxide
Figure PCTCN2015077043-appb-000290
Figure PCTCN2015077043-appb-000290
在氮气保护下向实施例70A(890毫克,2.4毫摩尔)的甲醇(40毫升)溶液中加入醋酸钠(396毫克,4.8毫摩尔)和Pd/C(1克)。混合物在15℃下置换氢气后在15Psi反应5小时。薄层色谱显示反应结束后，将混合物过滤，滤液浓缩得到标题化合物，为黄色固体(520毫克，72％)。1H NMR(400MHz,CDCl3)9.13(d,J＝3.01Hz,1H),9.08(d,J＝6.02Hz,1H),7.35(dd,J＝3.01,6.02Hz,1H),4.06-4.12(m,2H),3.93-3.98(m,2H),1.59(s,9H)。LCMS(ESI)m/z:301(M+1)。To a solution of Example 70A (890 mg, 2.4 mmol) in methanol (40 mL) The mixture was replaced with hydrogen at 15 ° C and reacted at 15 Psi for 5 hours. TLC showed the mixture was evaporated. 1 H NMR (400 MHz, CDCl 3 ) 9.13 (d, J = 3.01 Hz, 1H), 9.08 (d, J = 6.02 Hz, 1H), 7.35 (dd, J = 3.01, 6.02 Hz, 1H), 4.06 - 4.12 (m, 2H), 3.93-3.98 (m, 2H), 1.59 (s, 9H). LCMS (ESI) m.
实施例70CExample 70C
2-(哒嗪-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(pyridazin-4-yl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000291
Figure PCTCN2015077043-appb-000291
本实施例的制备方法参照实施例32E。1H NMR(400MHz,DMSO-d6)9.07(d，J＝2.51Hz,1H),9.01(d,J＝6.02Hz,1H),8.26(br.s.,1H),7.26(dd,J＝3.01,6.02Hz,1H),3.96-4.00(m,2H),3.62(br.s.,2H)。The preparation method of this example is referred to Example 32E. 1 H NMR (400 MHz, DMSO-d 6 ) 9.07 (d, J = 2.51 Hz, 1H), 9.1 (d, J = 6.02 Hz, 1H), 8.26 (br.s., 1H), 7.26 (dd, J =3.01, 6.02 Hz, 1H), 3.96-4.00 (m, 2H), 3.62 (br.s., 2H).
实施例70DExample 70D
(E)-2-(5-((1-(乙氧基亚氨基)-2,3-二氢-1H-茚-5-基)氧基)戊基)-5-(哒嗪-4-基)-1,2,5-噻二唑烷-1,1-二氧化 物(E)-2-(5-((1-(ethoxyimino)-2,3-dihydro-1H-indol-5-yl)oxy)pentyl)-5-(pyridazine-4 -yl)-1,2,5-thiadiazolidine-1,1-dioxide Object
Figure PCTCN2015077043-appb-000292
Figure PCTCN2015077043-appb-000292
本实施例的制备方法参照实施例32D。1H NMR(400MHz,CDCl3)8.01(br.s.，1H)，7.59(dt，J＝3.26,6.02Hz,2H),6.76-6.85(m,2H),6.56(d,J＝9.03Hz,1H),4.20(q,J＝7.19Hz,2H),3.99(t,J＝6.27Hz,2H),3.74(t,J＝6.27Hz,2H),3.46(t,J＝6.40Hz,2H),3.15(t,J＝7.28Hz,2H),2.95-3.01(m,2H),2.86-2.92(m,2H),1.72-1.89(m,4H),1.56-1.60(m,2H),1.28-1.38(m,3H)。LCMS(ESI)m/z:474(M+1)。The preparation method of this example is referred to Example 32D. 1 H NMR (400MHz, CDCl 3 ) 8.01 (br.s., 1H), 7.59 (dt, J = 3.26,6.02Hz, 2H), 6.76-6.85 (m, 2H), 6.56 (d, J = 9.03Hz , 1H), 4.20 (q, J = 7.19 Hz, 2H), 3.99 (t, J = 6.27 Hz, 2H), 3.74 (t, J = 6.27 Hz, 2H), 3.46 (t, J = 6.40 Hz, 2H) ), 3.15 (t, J = 7.28 Hz, 2H), 2.95-3.01 (m, 2H), 2.86-2.92 (m, 2H), 1.72-1.89 (m, 4H), 1.56-1.60 (m, 2H), 1.28-1.38 (m, 3H). LCMS (ESI) m/z:
流程SProcess S
Figure PCTCN2015077043-appb-000293
Figure PCTCN2015077043-appb-000293
实施例71Example 71
2-(5-((3-乙氧基苯并[d]异唑-6-基)氧基)-3-氟戊基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(5-((3-ethoxybenzo[d]isoxazol-6-yl)oxy)-3-fluoropentyl)-5-(pyridin-4-yl)-1,2,5 -thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000294
Figure PCTCN2015077043-appb-000294
实施例71AExample 71A
1-(2-溴乙基)环丙醇1-(2-bromoethyl)cyclopropanol
Figure PCTCN2015077043-appb-000295
Figure PCTCN2015077043-appb-000295
0℃下向3-溴丙酸乙酯(10克，55毫摩尔)的四氢呋喃(250毫升)混合物中加入四异丙氧钛(7.9克，28毫摩尔)，然后在0℃下将乙基格氏试剂(14.7克，110毫摩尔)慢慢加到反应体系中，搅拌1小时后升至25℃下搅拌2小时，0℃下向体系加饱和氯化铵水溶液，用乙酸乙酯萃取，合并的有机相用无水硫酸钠干燥，过滤蒸发后残余物用柱层层析纯化(石油醚:乙酸乙酯＝10:1～石油醚:乙酸乙酯＝5:1)得到标题化合物(无色液体，4.9克,收率54％)。1H NMR(400MHz,CDCl3)3.61(t,J＝7.3Hz,2H),2.26(br. s.,1H),2.11(t,J＝7.3Hz,2H),0.78-0.82(m,2H),0.50-0.56(m,2H)。To a mixture of ethyl 3-bromopropionate (10 g, 55 mmol) in tetrahydrofuran (250 ml) was added to a mixture of tetraisopropoxide (7.9 g, 28 mmol) at 0 ° C, then ethyl ether at 0 ° C Grignard reagent (14.7 g, 110 mmol) was slowly added to the reaction system, stirred for 1 hour, and then stirred at 25 ° C for 2 hours. At 0 ° C, a saturated aqueous solution of ammonium chloride was added to the system, and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate (mjjjjjjj Color liquid, 4.9 g, yield 54%). 1 H NMR (400MHz, CDCl 3 ) 3.61 (t, J = 7.3Hz, 2H), 2.26 (br. S., 1H), 2.11 (t, J = 7.3Hz, 2H), 0.78-0.82 (m, 2H ), 0.50-0.56 (m, 2H).
实施例71BExample 71B
1,5-二溴戊烷-3酮1,5-dibromopentane-3one
Figure PCTCN2015077043-appb-000296
Figure PCTCN2015077043-appb-000296
0℃下向实施例71A(500毫克，3.0毫摩尔)的四氯化碳(8毫升)溶液中加N-溴代丁二酰亚胺(539毫克，3.0毫摩尔)，混合物在25℃下反应16小时。过滤并蒸发，残余物通过柱色谱纯化(石油醚:乙酸乙酯＝20:1～石油醚:乙酸乙酯＝10:1)得到标题化合物(黄色液体，500毫克，产率68％)。1H NMR(400MHz,CDCl3)3.56(t,J＝6.8Hz,2H),3.04(t,J＝6.8Hz,2H)。N-bromosuccinimide (539 mg, 3.0 mmol) was added to a solution of Example 71A (500 mg, 3.0 mmol) in carbonic acid (8 mL) at 0 ° C. The reaction was continued for 16 hours. Filtration and evaporation, and the~~~~~~~~~~~~~~~~~~~~~~~~ 1 H NMR (400 MHz, CDCl 3 ) 3.56 (t,J = 6.8 Hz, 2H), 3.04 (t,J = 6.8 Hz, 2H).
实施例71CExample 71C
1,5-二溴戊烷-3-醇1,5-dibromopentan-3-ol
Figure PCTCN2015077043-appb-000297
Figure PCTCN2015077043-appb-000297
0℃下向实施例71B(500毫克，2.1毫摩尔)的甲醇(5毫升)溶液中加硼氢化钠(155毫克，4.1毫摩尔)，混合物在25℃下反应3小时。水(5毫升)加入反应体系，水层用二氯甲烷(10毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发得到标题化合物(340毫克，67％产率)。1H NMR(400MHz,CDCl3)4.07(d,J＝4.6Hz,1H),3.51-3.57(m,4H),1.96-2.04(m,4H)。To a solution of Example 71B (500 mg, 2.1 mmol) in MeOH (5 mL) Water (5 ml) was added to EtOAcq. 1 H NMR (400 MHz, CDCl 3 ) 4.07 (d,J = 4.6 Hz, 1H), 3.51-3.57 (m, 4H), 1.96-2.04 (m, 4H).
实施例71DExample 71D
1-溴-5-((3-乙氧基苯并[d]异唑-6-基)氧基)戊-3-醇1-bromo-5-((3-ethoxybenzo[d]isoxazol-6-yl)oxy)pentan-3-ol
Figure PCTCN2015077043-appb-000298
Figure PCTCN2015077043-appb-000298
实施例71C(329毫克，1.34毫摩尔)，实施例12D(150毫克，837微摩尔)，碘化钾(14毫克，84微摩尔)的丙酮(5毫升)混合物在60℃下反应16小时。水(5毫升)和二氯甲烷(10毫升)加入反应体系，水层用二氯甲烷(10毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化(石油醚:乙酸乙酯＝2:1)得到标题化合物(无色固体，190毫克，66％产率)。1H NMR(400MHz,CDCl3)7.45-7.50(m,1H),6.83-6.88(m,2H),4.43-4.48(m,2H),4.11-4.32(m,3H),3.55-3.65(m,2H),1.94-2.09(m,4H),1.50(t,J＝7.2Hz,3H)。A mixture of Example 71C (329 mg, 1.34 mmol), EtOAc (EtOAc, EtOAc, m. Water (5 ml) and dichloromethane (10 ml) were added to the reaction mixture, the aqueous layer was extracted with dichloromethane (10 ml × 3), and the combined organic layer was dried over sodium sulfate, filtered and evaporated. Purification (petroleum ether: EtOAc = 2:1) 1 H NMR (400 MHz, CDCl 3 ) 7.45-7.50 (m, 1H), 6.83-6.88 (m, 2H), 4.43-4.48 (m, 2H), 4.11-4.32 (m, 3H), 3.55-3.65 (m) , 2H), 1.94-2.09 (m, 4H), 1.50 (t, J = 7.2 Hz, 3H).
实施例71EExample 71E
2-(5-((3-乙氧基苯并[d]异唑-6-基)氧基)-3-羟基戊基)-5-(吡啶-4-基)-1,2,5-噻二唑烷-1,1-二氧化物2-(5-((3-ethoxybenzo[d]isoxazol-6-yl)oxy)-3-hydroxypentyl)-5-(pyridin-4-yl)-1,2,5 -thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000299
Figure PCTCN2015077043-appb-000299
实施71D(20毫克，58微摩尔)，实施例4F(12毫克，58微摩尔)，碘化钾(1毫克，5.8微摩尔)的N,N-二甲基甲酰胺(3毫升)混合物在60℃下反应3小时。水(5毫升)和二氯甲烷(10毫升)加入反应体系，水层用二氯甲烷(10毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发，残余物通过制备分离纯化得到标题化合物(无色固体，8毫克，产率30％)。1H NMR(400MHz,CDCl3)8.64(d,J＝6.5Hz,2H), 7.48(d,J＝8.5Hz,1H),7.31(d,J＝6.5Hz,2H),6.86(d,J＝4.5Hz,2H),4.45-4.50(m,2H),4.11-4.27(m,2H),3.95-4.01(m,2H),3.71-3.75(m,4H),3.44(dt,J＝15.6,7.8Hz,2H),2.03(br.s.,4H),1.49-1.53(m,3H)。LCMS(ESI)m/z:463(M+1)。71D (20 mg, 58 μmol), a mixture of Example 4F (12 mg, 58 μmol), potassium iodide (1 mg, 5.8 μmol) of N,N-dimethylformamide (3 mL) at 60 ° C The reaction was carried out for 3 hours. Water (5 ml) and dichloromethane (10 ml) were added to the reaction mixture, the aqueous layer was extracted with methylene chloride (10 ml × 3), and the combined organic layer was dried over sodium sulfate, filtered and evaporated. Purification afforded the title compound (m. 1 H NMR (400MHz, CDCl 3 ) 8.64 (d, J = 6.5Hz, 2H), 7.48 (d, J = 8.5Hz, 1H), 7.31 (d, J = 6.5Hz, 2H), 6.86 (d, J =4.5 Hz, 2H), 4.45-4.50 (m, 2H), 4.11-4.27 (m, 2H), 3.95-4.01 (m, 2H), 3.71-3.75 (m, 4H), 3.44 (dt, J = 15.6) , 7.8 Hz, 2H), 2.03 (br.s., 4H), 1.49-1.53 (m, 3H). LCMS (ESI) m/z:
实施例72Example 72
2-(5-((3-乙氧基苯并[d]异唑-6-基)氧基)-3-氟戊基)-5-(吡啶-4-基)-1,2,5-噻二唑烷1,1-二氧化物2-(5-((3-ethoxybenzo[d]isoxazol-6-yl)oxy)-3-fluoropentyl)-5-(pyridin-4-yl)-1,2,5 -thiadiazolidine 1,1-dioxide
Figure PCTCN2015077043-appb-000300
Figure PCTCN2015077043-appb-000300
氮气保护，-78℃下向实施例71E(35毫克，76微摩尔)的二氯甲烷(2毫升)溶液中滴加DAST(37毫克，227毫摩尔)。混合溶液在20℃下搅拌1小时后,水(5毫升)加入反应体系，水层用二氯甲烷(10毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发，残余物通过制备分离纯化得到标题化合物(无色固体，35毫克，产率95％)。1H NMR(400MHz,CDCl3)8.53(d,J＝6.3Hz,2H),7.47(d,J＝9.3Hz,1H),7.07(d,J＝6.3Hz,2H),6.84-6.87(m,2H),4.83-5.12(m,1H),4.42-4.49(m,2H),4.06-4.19(m,2H),3.83-3.89(m,2H),3.57-3.62(m,2H),3.31-3.42(m,2H),1.98-2.29(m,4H),1.48-1.50(m,3H)。LCMS(ESI)m/z:465(M+1)。NAST (37 mg, 227 mmol) was added dropwise to a solution of EtOAc. After the mixed solution was stirred at 20 ° C for 1 hour, water (5 ml) was added to the reaction mixture, the aqueous layer was extracted with dichloromethane (10 ml × 3), and the combined organic layer was dried over sodium sulfate, filtered and evaporated. The title compound (colorless solid, 35 mg, yield 95%) 1 H NMR (400 MHz, CDCl 3 ) 8.53 (d, J = 6.3 Hz, 2H), 7.47 (d, J = 9.3 Hz, 1H), 7.07 (d, J = 6.3 Hz, 2H), 6.84-6.87 (m) , 2H), 4.83-5.12 (m, 1H), 4.42-4.49 (m, 2H), 4.06-4.19 (m, 2H), 3.83-3.89 (m, 2H), 3.57-3.62 (m, 2H), 3.31 -3.42 (m, 2H), 1.98-2.29 (m, 4H), 1.48-1.50 (m, 3H). LCMS (ESI) m/z:
流程TProcess T
Figure PCTCN2015077043-appb-000301
Figure PCTCN2015077043-appb-000301
实施例73Example 73
2-(2-氨基吡啶-4-基)-5-(2-(1-(2-(4-(2-乙基-2H-四唑-5-基)苯氧基)乙基)环丙基)乙基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(2-(1-(2-(4-(2-ethyl-2H-tetrazol-5-yl)phenoxy)ethyl)) Propyl)ethyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000302
Figure PCTCN2015077043-appb-000302
实施例73AExample 73A
二甲基2,2'-(环丙烷-1,1-二基)二乙酸Dimethyl 2,2'-(cyclopropane-1,1-diyl) diacetic acid
Figure PCTCN2015077043-appb-000303
Figure PCTCN2015077043-appb-000303
实施例8A的制备方法参照文献(Journal of Medicinal Chemistry,57(2),364-377；2014)The preparation method of Example 8A is referred to the literature (Journal of Medicinal Chemistry, 57(2), 364-377; 2014).
实施例73BExample 73B
2,2'-(环丙烷-1,1-二基)二乙醇2,2'-(cyclopropane-1,1-diyl)diethanol
Figure PCTCN2015077043-appb-000304
Figure PCTCN2015077043-appb-000304
在0℃下向四氢铝锂(102毫克，2.68毫摩尔)的四氢呋喃(3毫升)溶液中滴加实施例72A(249毫克，1.34毫摩尔)，加完后将该混合溶液在25℃下搅拌3小时。水(0.5毫升)和10％的氢氧化钠溶液(0.5毫升)加入反应体系，体系用硫酸钠干燥，过滤并蒸发得到标题化合物(122毫克，收率72％)。To a solution of lithium tetrahydroaluminum (102 mg, 2.68 mmol) in tetrahydrofuran (3 mL), EtOAc (EtOAc m. Stir for 3 hours. Water (0.5 ml) and a 10% sodium hydroxide solution (0.5 ml) were evaporated.
实施例73CExample 73C
2,2'-(环丙烷-1,1-二基)二乙基-4-甲基苯磺酸2,2'-(cyclopropane-1,1-diyl)diethyl-4-methylbenzenesulfonic acid
Figure PCTCN2015077043-appb-000305
Figure PCTCN2015077043-appb-000305
实施例73B(1克，7.9毫摩尔),对甲苯磺酰氯(5.9克，30.7毫摩尔)，三乙胺(3.1克，30.7毫摩尔)的二氯甲烷(80毫升)混合溶液在25℃下搅拌16小时，再在室温下搅拌12小时。水(40毫升)加入反应体系，水层用二氯甲烷(40毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化(石油醚：乙酸乙酯＝10：1～石油醚：乙酸乙酯＝5：1)得到标题化合物(黄色液体，730毫克，产率20％)。1H NMR(400MHz,CDCl3)δ7.78(s,4H),7.34(br.s.,4H),4.03-4.07(m,4H),2.45(s,6H),1.48-1.52(m,3H),0.25-0.34(m,4H)。Example 73B (1 g, 7.9 mmol), p-toluenesulfonyl chloride (5.9 g, 30.7 mmol), triethylamine (3.1 g, 30.7 mmol) in dichloromethane (80 mL) Stir for 16 hours and then at room temperature for 12 hours. Water (40 ml) was added to the reaction mixture, and the aqueous layer was evaporated, evaporated, evaporated, The title compound (yellow liquid, 730 mg, yield 20%) was obtained. 1 H NMR (400MHz, CDCl 3 ) δ7.78 (s, 4H), 7.34 (br.s., 4H), 4.03-4.07 (m, 4H), 2.45 (s, 6H), 1.48-1.52 (m, 3H), 0.25-0.34 (m, 4H).
实施例73DExample 73D
2-(1-(2-(4-(2-乙基-2H-四唑-5-基)苯氧基)乙基)环丙基)乙基-4-甲基苯磺酸2-(1-(2-(4-(2-ethyl-2H-tetrazol-5-yl)phenoxy)ethyl)cyclopropyl)ethyl-4-methylbenzenesulfonic acid
Figure PCTCN2015077043-appb-000306
Figure PCTCN2015077043-appb-000306
本实施例中如实施例29A中描述的方法制备。1H NMR(400MHz,CDCl3)8.04-8.07(m,4H),7.72-7.77(m,4H),7.36(br.s.,4H),6.91-7.00(m,4H),2.42(s,3H),1.49-1.55(m,3H),0.37(d,J＝9.5Hz,2H),0.28(s,2H)。LCMS(ESI)m/z:457(M+1)。This example was prepared as described in Example 29A. 1 H NMR (400MHz, CDCl 3 ) 8.04-8.07 (m, 4H), 7.72-7.77 (m, 4H), 7.36 (br.s., 4H), 6.91-7.00 (m, 4H), 2.42 (s, 3H), 1.49-1.55 (m, 3H), 0.37 (d, J = 9.5 Hz, 2H), 0.28 (s, 2H). LCMS (ESI) m/z:
实施例73EExample 73E
5(2-(1-(2-(4-(2-乙基-2H-四唑-5-基)苯氧基)乙基)环丙基氨基)乙基)-1,2-噻二唑烷-2-甲酸叔丁酯-1,1-二氧化物5(2-(1-(2-(4-(2-ethyl-2H-tetrazol-5-yl)phenoxy)ethyl)cyclopropylamino)ethyl)-1,2-thiadi Oxazolidin-2-carboxylic acid tert-butyl ester-1,1-dioxide
Figure PCTCN2015077043-appb-000307
Figure PCTCN2015077043-appb-000307
本实施例的制备方法参照实施例32D。LCMS(ESI)m/z:507(M+1)。The preparation method of this example is referred to Example 32D. LCMS (ESI) m/z:
实施例73FExample 73F
2-(2-(1-(2-(4-(2-乙基-2H-四唑-5-基)苯氧基)乙基)环丙基)乙基)-1,2,5-噻二唑烷-1,1-二氧化物 2-(2-(1-(2-(4-(2-ethyl-2H-tetrazol-5-yl)phenoxy)ethyl)cyclopropyl)ethyl)-1,2,5- Thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000308
Figure PCTCN2015077043-appb-000308
实施例73E(60毫克，0.18毫摩尔)，碳酸钾(82毫克，0.6毫摩尔)的甲醇溶液(2毫升)在60℃下搅拌反应4小时。旋干，水(5毫升)和二氯甲烷(10毫升)加入反应体系，水层用二氯甲烷(10毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发得到标题化合物(无色固体，40毫克，产率75％)。LCMS(ESI)m/z:407(M+1)。Example 73E (60 mg, 0.18 mmol), EtOAc (EtOAc) The mixture was stirred with EtOAc EtOAc (EtOAc m. (colorless solid, 40 mg, yield 75%). LCMS (ESI) m/z:
实施例73GExample 73G
2-(2-氨基吡啶-4-基)-5-(2-(1-(2-(4-(2-乙基-2H-四唑-5-基)苯氧基)乙基)环丙基)乙基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(2-(1-(2-(4-(2-ethyl-2H-tetrazol-5-yl)phenoxy)ethyl)) Propyl)ethyl)-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000309
Figure PCTCN2015077043-appb-000309
氮气保护下实施例73F(40毫克，988微摩尔)，碳酸钾(27毫克，0.2毫摩尔)，2-氨基-4-溴吡啶(26毫克，148微摩尔)的N,N-二甲基甲酰胺溶液(2毫升)加8-羟基喹啉(14毫克，98微摩尔)和碘化亚铜(2毫克，9.8微摩尔)。混合液在120℃下搅拌反应12小时。旋干，水(5毫升)加入反应体系，水层用二氯甲烷(10毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发，残余物经制备色谱分离纯化(二氯甲烷：甲醇＝20：1，二氯甲烷：乙酸乙酯＝1：2)得到标题化合物(无色固体，20毫克，产率39％)。1H NMR(400MHz,CDCl3)8.05-8.08(m,2H),7.91(d,J＝6.0Hz,1H),6.99-7.02(m,2H),6.45-6.47(m,1H),6.28(br.s.,1H),5.00(br.s.,2H),4.66-4.69(m,2H),4.11-4.17(m,2H),3.76-3.80(m,2H),3.50(t,J＝6.5Hz,2H),3.26-3.34(m,2H),1.80(t,J＝6.3Hz,2H),1.71-1.76(m,2H),1.68(s,3H),0.25-0.62(m,4H)。LCMS(ESI)m/z:499(M+1)。Example 73F (40 mg, 988 μmol), potassium carbonate (27 mg, 0.2 mmol), 2-amino-4-bromopyridine (26 mg, 148 μmol) of N,N-dimethyl Formamide solution (2 ml) was added 8-hydroxyquinoline (14 mg, 98 micromoles) and cuprous iodide (2 mg, 9.8 micromoles). The mixture was stirred at 120 ° C for 12 hours. The mixture was added to a methylene chloride (10 ml × 3). The combined organic layer was dried over sodium sulfate, filtered and evaporated. Methane: MeOH = 20:1, m. 1 H NMR (400MHz, CDCl 3 ) 8.05-8.08 (m, 2H), 7.91 (d, J = 6.0Hz, 1H), 6.99-7.02 (m, 2H), 6.45-6.47 (m, 1H), 6.28 ( Br.s.,1H),5.00(br.s.,2H),4.66-4.69(m,2H),4.11-4.17(m,2H),3.76-3.80(m,2H),3.50(t,J = 6.5 Hz, 2H), 3.26-3.34 (m, 2H), 1.80 (t, J = 6.3 Hz, 2H), 1.71-1.76 (m, 2H), 1.68 (s, 3H), 0.25-0.62 (m, 4H). LCMS (ESI) m/z: 499
流程UProcess U
Figure PCTCN2015077043-appb-000310
Figure PCTCN2015077043-appb-000310
实施例74Example 74
4-(5-(5-((5-(2-乙基四唑-5-基)-2-吡啶基)氧基)戊基)-1,1-二氧代-1,2,5-噻二唑烷-2-基)吡啶-2-胺4-(5-(5-((5-(2-ethyltetrazol-5-yl)-2-pyridyl)oxy)pentyl)-1,1-dioxo-1,2,5 -thiadiazolidine-2-yl)pyridin-2-amine
Figure PCTCN2015077043-appb-000311
Figure PCTCN2015077043-appb-000311
实施例74AExample 74A
5-(2-氨基-4-吡啶基)-1,1-二氧代-1,2,5-噻二唑烷-2-甲酸叔丁酯5-(2-Amino-4-pyridyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-carboxylic acid tert-butyl ester
Figure PCTCN2015077043-appb-000312
Figure PCTCN2015077043-appb-000312
4-溴-2-氨基吡啶(10克，57.8毫摩尔)，实施例32B(25.7克，115.6毫摩尔)，(1S,2S)-N1,N2-二甲基环己二胺(1.64克，11.6毫摩尔)，碳酸钾(24克，173毫摩尔)和碘化亚铜(16.5克，86.7毫摩尔)溶于N,N-二甲基甲酰胺(150毫升)。混合物在氮气保护下100℃下搅拌12小时。反应液倒入不断搅拌的冰水(300毫升)，氨水(100毫升)和乙酸乙酯(200毫升)的混合液中。用乙酸乙酯萃取，合并的有机相用无水硫酸钠干燥，过滤蒸发后残余物用甲醇重结晶，过滤即得到标题化合物(7.5克，收率70％)。1H NMR(400MHz,DMSO-d6)7.87(d,J＝5.0Hz,1H),6.40(d,J＝4.0Hz,1H),6.30(s,1H),6.09(br.s.,2H),3.99-3.89(m,2H),3.87-3.75(m,2H),1.50(s,9H)。4-bromo-2-aminopyridine (10 g, 57.8 mmol), Example 32B (25.7 g, 115.6 mmol), (1S, 2S) embodiment -N 1, N 2 - dimethyl-cyclohexanediamine (1.64 G, 11.6 mmol), potassium carbonate (24 g, 173 mmol) and cuprous iodide (16.5 g, 86.7 mmol) were dissolved in N,N-dimethylformamide (150 ml). The mixture was stirred at 100 ° C for 12 hours under a nitrogen atmosphere. The reaction mixture was poured into a mixture of ice water (300 ml), aqueous ammonia (100 ml) and ethyl acetate (200 ml). The title compound (7.5 g, yield 70%) was obtained. 1 H NMR (400MHz, DMSO- d6) 7.87 (d, J = 5.0Hz, 1H), 6.40 (d, J = 4.0Hz, 1H), 6.30 (s, 1H), 6.09 (br.s., 2H) , 3.99-3.89 (m, 2H), 3.87-3.75 (m, 2H), 1.50 (s, 9H).
实施例74BExample 74B
4-(1,1-二氧代-1,2,5-噻二唑烷-2-基)吡啶-2-胺4-(1,1-dioxo-1,2,5-thiadiazol-2-yl)pyridin-2-amine
Figure PCTCN2015077043-appb-000313
Figure PCTCN2015077043-appb-000313
0℃下，向实施例74A(5.0克，15.9毫摩尔)的乙酸乙酯(20毫升)溶液中加入氯化氢乙酸乙酯溶液(4摩尔/升)(50毫升)。混合物在25℃下反应2小时，旋干得到标题化合物的盐酸盐(3.95克，收率97％)。1H NMR(400MHz,DMSO-d6)8.44(t,J＝7.8Hz,1H),7.91(d,J＝7.3Hz,1H),7.82(br.s.,2H),6.63(dd,J＝2.3,7.3Hz,1H),6.41(d,J＝2.3Hz,1H),3.94(t,J＝6.3Hz,2H),3.59(q,J＝6.5Hz,2H)。To a solution of Example 74A (5.0 g, 15.9 mmol),EtOAc (EtOAc) The mixture was reacted at 25 ° C for 2 hours, and dried to give the title compound (3. 1 H NMR (400 MHz, DMSO-d6) 8.44 (t, J = 7.8 Hz, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.82 (br.s., 2H), 6.63 (dd, J = 2.3, 7.3 Hz, 1H), 6.41 (d, J = 2.3 Hz, 1H), 3.94 (t, J = 6.3 Hz, 2H), 3.59 (q, J = 6.5 Hz, 2H).
实施例74CExample 74C
6-(5-羟基戊氧基)吡啶-3-甲腈6-(5-hydroxypentyloxy)pyridine-3-carbonitrile
Figure PCTCN2015077043-appb-000314
Figure PCTCN2015077043-appb-000314
在0℃，氮气保护下向实施例1,5-戊二醇(11.3克，108.3毫摩尔)的N,N-二甲基甲酰胺(50毫升)溶液中分批加入钠氢(8.7克，216.5毫摩尔，60％)。反应液在0℃下搅拌0.5小时后，加入2-氯-5-氰基吡啶(5克，36.1毫摩尔)的N,N-二甲基甲酰胺(20毫升)溶液，在0℃下搅拌2小时。加水淬灭反应后，用乙酸乙酯(100毫升×3)萃取，合并有机层用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物(4.7克，收率63％)。1H NMR(400MHz,CDCl3)δ8.49(d,J＝2.0Hz,1H),7.78(dd,J＝2.3,8.5Hz,1H), 6.81(d,J＝8.5Hz,1H),4.46-4.33(m,2H),3.79-3.61(m,2H),1.84(quin,J＝7.2Hz,2H),1.71-1.45(m,4H)。LCMS(ESI)m/z:207(M+1)。To a solution of Example 1,5-pentanediol (11.3 g, 108.3 mmol) in N,N-dimethylformamide (50 mL) 216.5 mmol, 60%). After the reaction mixture was stirred at 0 ° C for 0.5 hr, a solution of 2-chloro-5-cyanopyridine (5 g, 36.1 mmol) in N,N-dimethylformamide (20 ml) 2 hours. After quenching with water, EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1 H NMR (400MHz, CDCl 3 ) δ8.49 (d, J = 2.0Hz, 1H), 7.78 (dd, J = 2.3,8.5Hz, 1H), 6.81 (d, J = 8.5Hz, 1H), 4.46 -4.33 (m, 2H), 3.79-3.61 (m, 2H), 1.84 (quin, J = 7.2 Hz, 2H), 1.71-1.45 (m, 4H). LCMS (ESI) m/z:
实施例74DExample 74D
5-((5(2H-四唑-5-基)-2-吡啶基)氧基)戊-1-醇5-((5(2H-tetrazol-5-yl)-2-pyridyl)oxy)pentan-1-ol
Figure PCTCN2015077043-appb-000315
Figure PCTCN2015077043-appb-000315
向实施例74C(2.00克,9.70毫摩尔)的N,N-二甲基甲酰胺(20.00毫升)中，加入叠氮钠(1.89克，29.09毫摩尔)和氯化铵(1.56克，29.09毫摩尔)。混合物在110℃下搅拌12小时后，加水淬灭，稀盐酸调pH＝3，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤蒸发后得到标题化合物(白色固体，2.3克,收率90％)。1H NMR(400MHz,CDCl3)8.81(d,J＝2.3Hz,1H),8.27(dd,J＝2.4,8.7Hz,1H),6.99(d,J＝8.8Hz,1H),4.52-4.29(m,2H),3.68-3.50(m,2H),1.86(quin,J＝7.0Hz,2H),1.75-1.47(m,4H)。LCMS(ESI)m/z:250(M+1)。To a solution of N-N-dimethylformamide (20.00 mL), EtOAc (tjjjjjjjjjjjjjj Moore). The mixture was stirred at 110 ° C for 12 hrs, EtOAc EtOAc (EtOAc m. Rate 90%). 1 H NMR (400 MHz, CDCl 3 ) 8.81 (d, J = 2.3 Hz, 1H), 8.27 (dd, J = 2.4, 8.7 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.52-4.29 (m, 2H), 3.68-3.50 (m, 2H), 1.86 (quin, J = 7.0 Hz, 2H), 1.75-1.47 (m, 4H). LCMS (ESI) m/z:
实施例74EExample 74E
5-((5-(2-乙基四唑-5-基)-2-吡啶基)氧基)戊-1-醇5-((5-(2-ethyltetrazol-5-yl)-2-pyridyl)oxy)pentan-1-ol
Figure PCTCN2015077043-appb-000316
Figure PCTCN2015077043-appb-000316
氮气保护下，向实施例74D(1克，4.01毫摩尔)和碳酸钾(2.77克，20.05毫摩尔)的乙腈(15毫升)溶液中加入碘乙烷(93毫克，2.32毫摩尔)。在25℃下搅拌4小时。反应混合物用水(50毫升)淬灭，用乙酸乙酯萃取(30毫升×3)，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥后过滤并旋干，残余物通过柱色谱(石油醚：乙酸乙酯＝3：1)纯化得到标题化合物(白色固体，700毫克，收率60％)。1H NMR(400MHz,CDCl3)8.93(d,J＝2.0Hz,1H),8.29(dd,J＝2.3,8.8Hz,1H),6.85(d,J＝8.5Hz,1H),4.72(q,J＝7.3Hz,2H),4.39(t,J＝6.7Hz,2H),3.81-3.62(m,2H),1.86(quin,J＝7.1Hz,2H),1.75-1.50(m,7H)。LCMS(ESI)m/z:278(M+1)。Ethyl iodide (93 mg, 2.32 mmol) was added to a solution of EtOAc (EtOAc, EtOAc. Stir at 25 ° C for 4 hours. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The title compound (white solid, 700 mg, yield 60%). 1 H NMR (400MHz, CDCl 3 ) 8.93 (d, J = 2.0Hz, 1H), 8.29 (dd, J = 2.3,8.8Hz, 1H), 6.85 (d, J = 8.5Hz, 1H), 4.72 (q , J = 7.3 Hz, 2H), 4.39 (t, J = 6.7 Hz, 2H), 3.81-3.62 (m, 2H), 1.86 (quin, J = 7.1 Hz, 2H), 1.75-1.50 (m, 7H) . LCMS (ESI) m/z: 278 (21.
实施例74FExample 74F
5-((5(2-乙基四唑-5-基)-2-吡啶基)氧基)戊基甲磺酸酯5-((5(2-ethyltetrazol-5-yl)-2-pyridyl)oxy)pentyl methanesulfonate
Figure PCTCN2015077043-appb-000317
Figure PCTCN2015077043-appb-000317
0℃氮气保护下，向实施例74E(0.1克，0.36毫摩尔)和三乙胺(146毫克，1.44毫摩尔)的四氢呋喃(8毫升)溶液中滴加入甲烷磺酰氯(83毫克，0.72毫摩尔)的四氢呋喃(1毫升)溶液。在0℃下搅拌2小时。反应混合物用水(20毫升)淬灭，用乙酸乙酯萃取(20毫升×3)，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥后过滤并旋干得到标题化合物(白色固体，120毫克，收率92.7％)。1H NMR(400MHz,CDCl3)δ8.93(d,J＝2.3Hz,1H),8.30(dd,J＝2.4,8.7Hz,1H),6.85(d,J＝8.8Hz,1H),4.72(q,J＝7.3Hz,2H),4.40(t,J＝6.5Hz,2H),4.33-4.23(m,2H),3.03(s,3H),1.98-1.67(m,9H)。LCMS(ESI)m/z:356(M+1)。 To a solution of Example 74E (0.1 g, 0.36 mmol) A solution of tetrahydrofuran (1 ml). Stir at 0 ° C for 2 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc) Mg, yield 92.7%). 1 H NMR (400MHz, CDCl 3 ) δ8.93 (d, J = 2.3Hz, 1H), 8.30 (dd, J = 2.4,8.7Hz, 1H), 6.85 (d, J = 8.8Hz, 1H), 4.72 (q, J = 7.3 Hz, 2H), 4.40 (t, J = 6.5 Hz, 2H), 4.33-4.23 (m, 2H), 3.03 (s, 3H), 1.98-1.67 (m, 9H). LCMS (ESI) m/z: 356:
实施例74GExample 74G
4-(5-(5-((5-(2-乙基四唑-5-基)-2-吡啶基)氧基)戊基)-1,1-二氧代-1,2,5-噻二唑烷-2-基)吡啶-2-胺4-(5-(5-((5-(2-ethyltetrazol-5-yl)-2-pyridyl)oxy)pentyl)-1,1-dioxo-1,2,5 -thiadiazolidine-2-yl)pyridin-2-amine
Figure PCTCN2015077043-appb-000318
Figure PCTCN2015077043-appb-000318
氮气保护下，向实施例74B(0.7克，1.97毫摩尔)和碳酸钾(0.54克，3.94毫摩尔)的N,N-二甲基甲酰胺(12毫升)溶液中加入实施例73F(422毫克，1.97毫摩尔)。在60℃下搅拌12小时。反应混合物用水(50毫升)淬灭，用乙酸乙酯萃取(30毫升×3)，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥后过滤并旋干，残余物通过柱色谱(石油醚：乙酸乙酯＝1：1)纯化得到标题化合物(白色固体，350毫克，收率36％)。1H NMR(400MHz,CDCl3)8.86(d,J＝2.0Hz,1H),8.32(dd,J＝2.3,8.8Hz,1H),7.80(d,J＝6.3Hz,1H),6.95(d,J＝8.8Hz,1H),6.52(dd,J＝2.0,6.0Hz,1H),6.31(d,J＝1.8Hz,1H),4.76(q,J＝7.3Hz,2H),4.41(t,J＝6.4Hz,2H),3.84(t,J＝6.4Hz,2H),3.56(t,J＝6.3Hz,2H),3.22-3.10(m,2H),1.97-1.76(m,4H),1.75-1.58(m,5H).。LCMS(ESI)m/z:474(M+1)。To a solution of Example 74B (0.7 g, 1.97 mmol) and potassium carbonate (0.54 g, 3. <RTI ID=0.0></RTI></RTI><RTIgt; , 1.97 mmol). Stir at 60 ° C for 12 hours. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The title compound (white solid, 350 mg, yield 36%) 1 H NMR (400MHz, CDCl 3 ) 8.86 (d, J = 2.0Hz, 1H), 8.32 (dd, J = 2.3,8.8Hz, 1H), 7.80 (d, J = 6.3Hz, 1H), 6.95 (d , J = 8.8 Hz, 1H), 6.52 (dd, J = 2.0, 6.0 Hz, 1H), 6.31 (d, J = 1.8 Hz, 1H), 4.76 (q, J = 7.3 Hz, 2H), 4.41 (t , J = 6.4 Hz, 2H), 3.84 (t, J = 6.4 Hz, 2H), 3.56 (t, J = 6.3 Hz, 2H), 3.22-3.10 (m, 2H), 1.97-1.76 (m, 4H) , 1.75-1.58 (m, 5H). LCMS (ESI) m/z:
实施例75Example 75
2-(2-氨基吡啶-4-基)-5-(5-(4-(2-乙基-2H-四唑-5-基)苯氧基)-3,3-二甲基戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(5-(4-(2-ethyl-2H-tetrazol-5-yl)phenoxy)-3,3-dimethylpentyl )-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000319
Figure PCTCN2015077043-appb-000319
实施例75AExample 75A
3,3-二甲基戊二醇3,3-dimethylpentanediol
Figure PCTCN2015077043-appb-000320
Figure PCTCN2015077043-appb-000320
在80℃下向四氢铝锂(50克，1.32摩尔)的四氢呋喃(1.3升)溶液中滴加3,3-二甲基戊二酸(50克，312毫摩尔)的四氢呋喃(200毫升)，加完后将该混合溶液在80℃下搅拌2小时。水(200毫升)加入反应体系，水层用乙酸乙酯(300毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发得到标题化合物(38克，收率92％)。1H NMR(400MHz,CDCl3)3.67(t，J＝7.03Hz,4H)，3.50(br.s.,1H),1.50-1.61(m,4H),0.92(s,6H)。To a solution of lithium tetrahydroaluminum (50 g, 1.32 mol) in tetrahydrofuran (1.3 L) was added dropwise 3,3-dimethylglutaric acid (50 g, 312 mmol) in tetrahydrofuran (200 mL). After the addition was completed, the mixed solution was stirred at 80 ° C for 2 hours. Water (200 ml) was added to EtOAc (EtOAc m. 1 H NMR (400 MHz, CDCl 3 ) 3.67 (t, J = 7.03 Hz, 4H), 3.50 (br.s., 1H), 1.50-1.61 (m, 4H), 0.92 (s, 6H).
实施例75BExample 75B
6-((5-羟基-3,3-二甲基戊基)氧基)烟腈6-((5-Hydroxy-3,3-dimethylpentyl)oxy)nicotinonitrile
Figure PCTCN2015077043-appb-000321
Figure PCTCN2015077043-appb-000321
本实施例的制备方法参照实施例74C。1H NMR(400MHz,CDCl3)8.47(d,J＝2.0Hz,1H),7.76(dd,J＝8.5,2.3Hz,1H),6.78(d,J＝8.8Hz,1H),4.44(t,J＝7.4Hz,2H),3.75(t,J＝7.4Hz,2H),1.75(t,J＝7.4Hz,2H),1.61(t,J＝7.4Hz,2H),1.01(s,6H)。 The preparation method of this example is referred to Example 74C. 1 H NMR (400MHz, CDCl 3 ) 8.47 (d, J = 2.0Hz, 1H), 7.76 (dd, J = 8.5,2.3Hz, 1H), 6.78 (d, J = 8.8Hz, 1H), 4.44 (t , J = 7.4 Hz, 2H), 3.75 (t, J = 7.4 Hz, 2H), 1.75 (t, J = 7.4 Hz, 2H), 1.61 (t, J = 7.4 Hz, 2H), 1.01 (s, 6H) ).
实施例75CExample 75C
5-((5-(2H-四唑-5-基)吡啶-2-基)氧基)-3,3-二甲基戊-1-醇5-((5-(2H-tetrazol-5-yl)pyridin-2-yl)oxy)-3,3-dimethylpentan-1-ol
Figure PCTCN2015077043-appb-000322
Figure PCTCN2015077043-appb-000322
本实施例的制备方法参照实施例74D。1H NMR(400MHz,CDCl3)8.81(d,J＝2.3Hz,1H),8.26(dd,J＝8.8,2.3Hz,1H),7.00(d,J＝8.8Hz,1H),4.39(t,J＝7.4Hz,2H),3.49(t,J＝7.4Hz,2H),1.68(t,J＝7.4Hz,2H),1.45(t,J＝7.4Hz,2H),0.92-0.97(m,6H)。The preparation method of this example is referred to Example 74D. 1 H NMR (400 MHz, CDCl 3 ) 8.81 (d, J = 2.3 Hz, 1H), 8.26 (dd, J = 8.8, 2.3 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 4.39 (t , J = 7.4 Hz, 2H), 3.49 (t, J = 7.4 Hz, 2H), 1.68 (t, J = 7.4 Hz, 2H), 1.45 (t, J = 7.4 Hz, 2H), 0.92-0.97 (m) , 6H).
实施例75DExample 75D
5-(4-(2-乙基-2H-四唑-5-基)苯氧基)-3,3-二甲基戊1-醇5-(4-(2-ethyl-2H-tetrazol-5-yl)phenoxy)-3,3-dimethylpentan-1-ol
Figure PCTCN2015077043-appb-000323
Figure PCTCN2015077043-appb-000323
本实施例的制备方法参照实施例74E。1H NMR(400MHz,CDCl3)8.92(d,J＝2.0Hz,1H),8.27(dd,J＝8.5,2.3Hz,1H),6.82(d,J＝8.8Hz,1H),4.70(q,J＝7.4Hz,2H),4.44(t,J＝7.4Hz,2H),3.77(t,J＝7.4Hz,2H),1.78(s,3H),1.64-1.71(m,4H),1.02(s,6H)。The preparation method of this example is referred to Example 74E. 1 H NMR (400 MHz, CDCl 3 ) 8.92 (d, J = 2.0 Hz, 1H), 8.27 (dd, J = 8.5, 2.3 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 4.70 (q) , J = 7.4 Hz, 2H), 4.44 (t, J = 7.4 Hz, 2H), 3.77 (t, J = 7.4 Hz, 2H), 1.78 (s, 3H), 1.64-1.71 (m, 4H), 1.02 (s, 6H).
实施例75EExample 75E
5-(4-(2-乙基-2H-四唑-5-基)苯氧基)-3,3-二甲基戊基甲磺酸酯5-(4-(2-ethyl-2H-tetrazol-5-yl)phenoxy)-3,3-dimethylpentyl methanesulfonate
Figure PCTCN2015077043-appb-000324
Figure PCTCN2015077043-appb-000324
本实施例的制备方法参照实施例74F。1H NMR(400MHz,CDCl3)8.92(d,J＝2.0Hz,1H),8.27(dd,J＝8.5,2.0Hz,1H),6.83(d,J＝9.0Hz,1H),4.66-4.73(m,2H),4.44(t,J＝7.0Hz,2H),4.37(t,J＝7.3Hz,2H),3.02(s,3H),1.80(dt,J＝14.2,7.2Hz,4H),1.69(t,J＝7.5Hz,3H),1.06(s,6H)。The preparation method of this example is referred to Example 74F. 1 H NMR (400 MHz, CDCl 3 ) 8.92 (d, J = 2.0 Hz, 1H), 8.27 (dd, J = 8.5, 2.0 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H), 4.66-4.73 (m, 2H), 4.44 (t, J = 7.0 Hz, 2H), 4.37 (t, J = 7.3 Hz, 2H), 3.02 (s, 3H), 1.80 (dt, J = 14.2, 7.2 Hz, 4H) , 1.69 (t, J = 7.5 Hz, 3H), 1.06 (s, 6H).
实施例75FExample 75F
2-(2-氨基吡啶-4-基)-5-(5-(4-(2-乙基-2H-四唑-5-基)苯氧基)-3,3-二甲基戊基)-1,2,5-噻二唑烷-1,1-二氧化物2-(2-Aminopyridin-4-yl)-5-(5-(4-(2-ethyl-2H-tetrazol-5-yl)phenoxy)-3,3-dimethylpentyl )-1,2,5-thiadiazolidine-1,1-dioxide
Figure PCTCN2015077043-appb-000325
Figure PCTCN2015077043-appb-000325
本实施例的制备方法参照实施例74G。1H NMR(400MHz,CDCl3)8.93(d,J＝2.0Hz,1H),8.28(dd,J＝8.8,2.3Hz,1H),7.97(d,J＝6.0Hz,1H),6.85(d,J＝8.5Hz,1H),6.43(dd,J＝5.8,2.3Hz,1H),6.30(d,J＝2.0Hz,1H),4.71(q,J＝7.4Hz,2H),4.58(br.s.,2H),4.45(t,J＝7.0Hz,2H),3.81(t,J＝6.5Hz,2H),3.50-3.56(m,2H),3.24(d,J＝8.5Hz,2H),1.81(t,J＝7.0Hz,2H),1.74(d,J＝8.5Hz,2H),1.67-1.71(m,3H),1.08(s,6H)。 LCMS(ESI)m/z:501(M+1)。The preparation method of this example is referred to Example 74G. 1 H NMR (400MHz, CDCl 3 ) 8.93 (d, J = 2.0Hz, 1H), 8.28 (dd, J = 8.8,2.3Hz, 1H), 7.97 (d, J = 6.0Hz, 1H), 6.85 (d , J = 8.5 Hz, 1H), 6.43 (dd, J = 5.8, 2.3 Hz, 1H), 6.30 (d, J = 2.0 Hz, 1H), 4.71 (q, J = 7.4 Hz, 2H), 4.58 (br .s., 2H), 4.45 (t, J = 7.0 Hz, 2H), 3.81 (t, J = 6.5 Hz, 2H), 3.50 - 3.56 (m, 2H), 3.24 (d, J = 8.5 Hz, 2H) ), 1.81 (t, J = 7.0 Hz, 2H), 1.74 (d, J = 8.5 Hz, 2H), 1.67-1.71 (m, 3H), 1.08 (s, 6H). LCMS (ESI) m/z:
流程VProcess V
Figure PCTCN2015077043-appb-000326
Figure PCTCN2015077043-appb-000326
实施例76Example 76
4-(5-(5-(4-(2-乙基四氮唑-5-基)苯氧基)-3,3-二甲基-戊基)-1,1-二氧-1,2,5-噻二唑-2-基)吡啶-2-胺4-(5-(5-(4-(2-ethyltetrazolyl-5-yl)phenoxy)-3,3-dimethyl-pentyl)-1,1-dioxo-1, 2,5-thiadiazol-2-yl)pyridin-2-amine
Figure PCTCN2015077043-appb-000327
Figure PCTCN2015077043-appb-000327
实施例76AExample 76A
3,3-二甲基戊基-1,5-二(4-甲基苯磺酸)酯3,3-dimethylpentyl-1,5-bis(4-methylbenzenesulfonate)
Figure PCTCN2015077043-appb-000328
Figure PCTCN2015077043-appb-000328
本实施例的制备方法参照实施例14A。1H NMR(400MHz,CDCl3)7.77(d,J＝8.53Hz,2H),7.35(d,J＝8.03Hz,2H),4.02(t,J＝7.03Hz,2H),2.45(s,3H),1.55(t,J＝7.03Hz,2H),0.84(s,3H)。The preparation method of this example is referred to Example 14A. 1 H NMR (400MHz, CDCl 3 ) 7.77 (d, J = 8.53Hz, 2H), 7.35 (d, J = 8.03Hz, 2H), 4.02 (t, J = 7.03Hz, 2H), 2.45 (s, 3H ), 1.55 (t, J = 7.03 Hz, 2H), 0.84 (s, 3H).
实施例76BExample 76B
5-(4-(2-乙基-2H-四氮唑-5-基)苯氧基)-3,3-二甲基戊基-4-甲基苯磺酸酯5-(4-(2-ethyl-2H-tetrazol-5-yl)phenoxy)-3,3-dimethylpentyl-4-methylbenzenesulfonate
Figure PCTCN2015077043-appb-000329
Figure PCTCN2015077043-appb-000329
向实施例76A(6克,31.55毫摩尔)，实施例11A(2.6克，31.55毫摩尔)的丙酮(100毫升)溶液中加入碳酸钾(8.72克,63.29毫摩尔)和碘化钾(5.24克,31.55毫摩尔)。混合溶液在80℃下搅拌12小时后，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤蒸发后残余物用柱层层析纯化(石油醚:乙酸乙酯＝10:1)得到标题化合物(白色固体，8.0克,收率56％)。1H NMR(400MHz,CDCl3)8.09(d,J＝8.5Hz,2H),7.00(d,J＝8.8Hz,2H),4.70(q,J＝7.3Hz,2H),4.38(t,J＝7.4Hz,2H),4.11(t,J＝6.8Hz,2H),3.0-3.04(m,3H),1.80-1.87(m,4H),1.70(t,J＝7.4Hz,3H),1.08(s,6H)。LCMS(ESI)m/z:459(M+1)。To a solution of Example 76A (6 g, 31.55 mmol), EtOAc (EtOAc, EtOAc (EtOAc) Millimoles). After the mixture was stirred at 80 ° C for 12 hours, it was extracted with EtOAc. EtOAc (EtOAc) The title compound (white solid, 8.0 g, yield 56%). 1 H NMR (400MHz, CDCl 3 ) 8.09 (d, J = 8.5Hz, 2H), 7.00 (d, J = 8.8Hz, 2H), 4.70 (q, J = 7.3Hz, 2H), 4.38 (t, J = 7.4 Hz, 2H), 4.11 (t, J = 6.8 Hz, 2H), 3.0-3.04 (m, 3H), 1.80-1.87 (m, 4H), 1.70 (t, J = 7.4 Hz, 3H), 1.08 (s, 6H). LCMS (ESI) m/z: 459:
实施例76CExample 76C
5-(4-(2-乙基-2H-四氮唑-5-基)苯氧基)-3,3-二甲基戊基-1,2,5-噻二唑-1,1-二氧化物 5-(4-(2-ethyl-2H-tetrazol-5-yl)phenoxy)-3,3-dimethylpentyl-1,2,5-thiadiazole-1,1- Dioxide
Figure PCTCN2015077043-appb-000330
Figure PCTCN2015077043-appb-000330
0℃下，向实施例76B(969毫克,4.4毫摩尔)的N,N-二甲基甲酰胺(5毫升)溶液中加入氢化钠(41.9毫克,1.7毫摩尔)。0℃下保持30分钟后,向上述混合溶液中加入实施例32B(400毫克,0.87毫摩尔)的N,N-二甲基甲酰胺(1毫升)溶液.20℃下搅拌反应2小时后，在反应液中加入碳酸钾(0.24毫克，1.7毫摩尔)加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发后柱分离(石油醚:乙酸乙酯＝1:1)得到标题化合物(黄色油状，100毫克,收率28％)。1H NMR(400MHz,CDCl3)7.56(d,J＝8.5Hz,2H),6.92(d,J＝9.0Hz,2H),4.00(t,J＝6.5Hz,2H),3.66-3.72(m,2H),3.47-3.52(m,2H),3.46(s,6H),3.35-3.41(m,2H),3.04(t,J＝7.3Hz,2H),1.79-1.88(m,2H),1.66-1.74(m,2H),1.52-1.60(m,2H),1.23(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:409(M+1)。Sodium hydride (41.9 mg, 1.7 mmol) was added <RTI ID=0.0># </RTI></RTI><RTIgt; After maintaining at 0 ° C for 30 minutes, a solution of Example 32B (400 mg, 0.87 mmol) of N,N-dimethylformamide (1 ml) was added to the mixture, and the reaction was stirred at 20 ° C for 2 hours. Potassium carbonate (0.24 mg, 1.7 mmol) was added to the reaction mixture, and the mixture was stirred and evaporated. The combined organic phases were dried with EtOAc EtOAc EtOAcjHHHHHHHHH 1 H NMR (400MHz, CDCl 3 ) 7.56 (d, J = 8.5Hz, 2H), 6.92 (d, J = 9.0Hz, 2H), 4.00 (t, J = 6.5Hz, 2H), 3.66-3.72 (m , 2H), 3.47-3.52 (m, 2H), 3.46 (s, 6H), 3.35-3.41 (m, 2H), 3.04 (t, J = 7.3 Hz, 2H), 1.79-1.88 (m, 2H), 1.66-1.74 (m, 2H), 1.52-1.60 (m, 2H), 1.23 (t, J = 7.0 Hz, 3H). LCMS (ESI) m.
实施例76DExample 76D
4-(5-(5-(4-(2-乙基四氮唑-5-基)苯氧基)-3,3-二甲基-戊基)-1,1-二氧-1,2,5-噻二唑-2-基)吡啶-2-胺4-(5-(5-(4-(2-ethyltetrazolyl-5-yl)phenoxy)-3,3-dimethyl-pentyl)-1,1-dioxo-1, 2,5-thiadiazol-2-yl)pyridin-2-amine
Figure PCTCN2015077043-appb-000331
Figure PCTCN2015077043-appb-000331
0℃下，向实施例76C(100毫克,0.24毫摩尔)的N,N-二甲基甲酰胺(2毫升)溶液中加入碳酸钾(67毫克,0.49毫摩尔)，2-氨基4-溴吡啶(85毫克,0.489毫摩尔)，8-羟基喹啉(35毫克,0.25毫摩尔)，碘化亚铜(23毫克,0.12毫摩尔)。置换氮气后加入环己二氨(14毫克,0.12毫摩尔)。110℃下搅拌反应15小时后，加入水淬灭反应，水相用乙酸乙酯萃取。将合并的有机相用无水硫酸钠干燥，过滤蒸发机分得到标题化合物(白色固体，35毫克,收率29％)。1H NMR(400MHz,CDCl3)8.07(d,J＝8.5Hz,1H),7.98(d,J＝5.5Hz,1H),6.99(d,J＝8.5Hz,2H),6.42(d,J＝4.5Hz,1H),6.29(s,1H),4.69(q,J＝7.5Hz,2H),4.48(br.s.,2H),4.11(t,J＝6.5Hz,2H),3.79(t,J＝6.0Hz,2H),3.46-3.53(m,2H),3.16-3.25(m,2H),1.83(t,J＝6.5Hz,2H),1.68-1.76(m,5H),1.07(s,6H)。LCMS(ESI)m/z:501(M+1)。Potassium carbonate (67 mg, 0.49 mmol), 2-amino 4-bromo, was added to a solution of EtOAc (EtOAc, m. Pyridine (85 mg, 0.489 mmol), 8-hydroxyquinoline (35 mg, 0.25 mmol), cuprous iodide (23 mg, 0.12 mmol). After replacing the nitrogen, cyclohexanediamine (14 mg, 0.12 mmol) was added. After the reaction was stirred at 110 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated. The combined organic phases were dried with EtOAc EtOAcjjjjjj 1 H NMR (400MHz, CDCl 3 ) 8.07 (d, J = 8.5Hz, 1H), 7.98 (d, J = 5.5Hz, 1H), 6.99 (d, J = 8.5Hz, 2H), 6.42 (d, J =4.5 Hz, 1H), 6.29 (s, 1H), 4.69 (q, J = 7.5 Hz, 2H), 4.48 (br.s., 2H), 4.11 (t, J = 6.5 Hz, 2H), 3.79 ( t, J=6.0 Hz, 2H), 3.46-3.53 (m, 2H), 3.16-3.25 (m, 2H), 1.83 (t, J = 6.5 Hz, 2H), 1.68-1.76 (m, 5H), 1.07 (s, 6H). LCMS (ESI) m/z:
实验例1：EV71体外细胞病变效应(CPE)测试Experimental Example 1: In vitro cytopathic effect (CPE) test of EV71
实验目的：Purpose:
通过细胞病变效应(CPE)实验检测化合物对手足口病病毒EV71的体外抗病毒活性及细胞毒性。The in vitro antiviral activity and cytotoxicity of the compound human foot disease virus EV71 were examined by cytopathic effect (CPE) assay.
实验材料:Experimental Materials:
1.病毒株:Shenzhen/120F1/091. Virus strain: Shenzhen/120F1/09
2.细胞系：人的横纹肌瘤RD细胞2. Cell line: human rhabdomyosarcoma RD cells
3.细胞培养基：DMEM培养基添加10％血清，Penicillin/Streptomycin和L-Glutamine(1×)3. Cell culture medium: 10% serum was added to DMEM medium, Penicillin/Streptomycin and L-Glutamine (1×)
4.检测试剂：细胞活性检测试剂CCK84. Detection reagent: cell activity detection reagent CCK8
实验方法： experimental method:
1.细胞接种：将RD细胞从贴壁状态消化下来，用培养基稀释密度为80000个/ml，接种100ul至96孔板的微孔中。1. Cell seeding: RD cells were digested from the adherent state, diluted to a density of 80,000 cells/ml in a medium, and inoculated into 100 microwells to microwells of a 96-well plate.
2.化合物稀释:2. Compound dilution:
第一步：将待测化合物的干粉制备为10mM的DMSO溶液。随后将化合物进行3倍，8个浓度点的稀释。参照化合物将以同样的方法稀释。First step: A dry powder of the test compound was prepared as a 10 mM DMSO solution. The compound was then diluted 3 times and diluted at 8 concentration points. The reference compound will be diluted in the same manner.
第二步：将化合物的DMSO稀释液用细胞培养基进一步稀释。每孔10ulDMSO溶液加入240ul培养基中。Second step: The DMSO dilution of the compound was further diluted with cell culture medium. 10 ul of DMSO solution per well was added to 240 ul of medium.
3.将化合物稀释液以每孔50ul体积加入接种有细胞的96孔板中，双复孔，DMSO终浓度1％。3. The compound dilution was added to the 96-well plate inoculated with cells at a volume of 50 ul per well, double wells, and the final concentration of DMSO was 1%.
4.病毒稀释：将EV71病毒液稀释10000倍，浓度为100TCID50/50ul。将病毒稀释液以每孔50ul体积加入96孔板。另准备一份以培养基替代病毒的96孔板，同样接种细胞，添加化合物用于检测化合物对细胞的毒性作用。4. Virus dilution: The EV71 virus solution was diluted 10,000 times at a concentration of 100 TCID 50 /50 ul. The virus dilution was added to a 96-well plate at a volume of 50 ul per well. Another 96-well plate was prepared by replacing the virus with a medium, and the cells were also inoculated, and a compound was added for detecting the toxic effect of the compound on the cells.
5.将96孔板于37℃,5％CO2条件下培养3天。5. The 96-well plate was incubated for 3 days at 37 ° C under 5% CO 2 .
6.EC50和CC50测试：将细胞活性检测试剂CCK8以20ul/孔加入微孔中。采用酶标仪读取波长450nm,630nm下的吸光度。6. EC50 and CC50 tests: The cell activity assay reagent CCK8 was added to the wells at 20 ul/well. The absorbance at a wavelength of 450 nm and 630 nm was read using a microplate reader.
7.分析数据:用Prism5.0来分析数据，计算化合物的抗病毒活性EC50值及细胞毒性CC50值。7. Analytical data: The data were analyzed using Prism 5.0 to calculate the anti-viral activity EC50 value and cytotoxic CC50 value of the compound.
实验结果见表1：The experimental results are shown in Table 1:
表1 EV71CPE检测EC50测试结果Table 1 EV71CPE test EC 50 test results
Figure PCTCN2015077043-appb-000332
Figure PCTCN2015077043-appb-000332
Figure PCTCN2015077043-appb-000333
Figure PCTCN2015077043-appb-000333
注：A≤50nM；50nM＜B≤100nM；100nM＜C≤500nM；500nM＜D≤1000nM。Note: A ≤ 50 nM; 50 nM < B ≤ 100 nM; 100 nM < C ≤ 500 nM; 500 nM < D ≤ 1000 nM.
结论：本发明化合物对EV71病毒在细胞水平上的抑制作用显著。 Conclusion: The compounds of the present invention have a significant inhibitory effect on the EV71 virus at the cellular level.

Claims (10)

  1. 式(Ⅱ)所示化合物或其药学上可接受的盐，a compound of the formula (II) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2015077043-appb-100001
    Figure PCTCN2015077043-appb-100001
    其中，among them,
    R3选自任选被R01取代的5元杂环、C6～12芳基、C6～12芳烷基、C5～12杂芳环或C5～12杂芳烷基；R 3 is selected from a 5-membered heterocyclic ring optionally substituted by R 01 , a C 6- 12 aryl group, a C 6- 12 aralkyl group, a C 5-12 heteroaryl ring or a C 5-12 heteroarylalkyl group;
    L2分别独立地选自
    Figure PCTCN2015077043-appb-100002
    L 2 are independently selected from
    Figure PCTCN2015077043-appb-100002
    m1、m2分别独立地选自0、1、2、3、4、5或6；m 1 , m 2 are each independently selected from 0, 1 , 2 , 3, 4, 5 or 6;
    X1、X2分别独立地选自单键、-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)-或-S(＝O)2-；X 1 and X 2 are each independently selected from a single bond, -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(= NR d5 )-, -S(=O) 2 N(R d6 )-, -S(=O)N(R d7 )-, -O-, -S-, -C(=O)O-,- C(=O)-, -C(=S)-, -S(=O)- or -S(=O) 2 -;
    R4选自5～14元环烃基或杂环烃基；R 4 is selected from a 5- to 14-membered cyclic hydrocarbon group or a heterocyclic hydrocarbon group;
    Rd1、Rd2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；R d1 , R d2 are each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or a C 1-10 alkyl group optionally substituted by R 01 or a heteroalkyl group, a C 3-10 cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl;
    R01选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、R02；R 01 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, R 02 ;
    R02选自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环烷氧羰基、C3-10环烷基磺酰基、C3-10环烷基亚磺酰基；R 02 is selected from C 1-10 alkyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkoxy, C 1-10 alkanoyl, C 1 -10 alkoxycarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 cycloalkyl acyl, C 3-10 cycloalkoxycarbonyl, C 3-10 cycloalkylsulfonyl, C 3-10 cycloalkylsulfinyl;
    “杂”代表杂原子或杂原子团，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)-和/或-S(＝O)2-；"Heter" represents a hetero atom or a hetero atom selected from -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O) 2 N (R d6 )-, -S(=O)N(R d7 )-, -O-, -S-, =O, =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)- and/or -S(=O) 2 -;
    Rd3-d7分别独立地选自H、R03；R d3-d7 are each independently selected from H, R 03 ;
    R03选自C1-10烷基、C1-10烷基酰基、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环烷基酰基、C3-10环烷氧羰基、C3-10环烷基磺酰基、C3-10环烷基亚磺酰基；R 03 is selected from C 1-10 alkyl, C 1-10 alkyl acyl, C 1-10 alkoxycarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 a cycloalkyl group, a C 3-10 cycloalkyl acyl group, a C 3-10 cycloalkoxycarbonyl group, a C 3-10 cycloalkylsulfonyl group, a C 3-10 cycloalkylsulfinyl group;
    R02、R03任选地被R001取代；R 02 and R 03 are optionally substituted by R 001 ;
    R001选自F、Cl、Br、I、CN、OH、N(CH3)2、NH(CH3)、NH2、CHO、COOH、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；R 001 is selected from the group consisting of F, Cl, Br, I, CN, OH, N(CH 3 ) 2 , NH(CH 3 ), NH 2 , CHO, COOH, trifluoromethyl, aminomethyl, hydroxymethyl, A Base, methoxy, formyl, methoxycarbonyl, methylsulfonyl, methylsulfinyl;
    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；The number of R 01 , R 001 , hetero atom or hetero atomic group is independently selected from 0, 1, 2 or 3;
    任选地，Rd1与Rd2相互连接形成一个3或4元碳环或杂环。Optionally, R d1 and R d2 are linked to each other to form a 3 or 4 membered carbocyclic or heterocyclic ring.
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R3选自任选被取代的5～6元芳基或杂芳基；The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from a 5- to 6-membered aryl or heteroaryl group which is optionally substituted;
    优选地，R3选自任选被R01取代的吡啶基、苯基、呋喃基、吡唑基、吡咯基、噻唑基、哒嗪基、嘧啶基、 噻吩基，R01的如权利要求1所定义，R01的数目选自0、1、2或3；Preferably, R 3 is selected from the group consisting of pyridyl, phenyl, furyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrimidinyl, thienyl, R 01 optionally substituted by R 01 Defined, the number of R 01 is selected from 0, 1, 2 or 3;
    优选地，R01选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、Me、
    Figure PCTCN2015077043-appb-100003
    Figure PCTCN2015077043-appb-100004
    Preferably, R 01 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, Me,
    Figure PCTCN2015077043-appb-100003
    Figure PCTCN2015077043-appb-100004
  3. 根据权利要求2所述的化合物或其药学上可接受的盐，其中R3选自：The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of:
    Figure PCTCN2015077043-appb-100005
    Figure PCTCN2015077043-appb-100005
  4. 根据权利要求1所述的化合物或其药学上可接受的盐，其中L2选自
    Figure PCTCN2015077043-appb-100006
    m3为0、1或2，其他变量如权利要求1所定义；    The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 2 is selected from
    Figure PCTCN2015077043-appb-100006
    m 3 is 0, 1 or 2, and other variables are as defined in claim 1;
    优选地，X1、X2分别独立地选自单键、-O-、-C(＝O)-、-CH(CH3)-、-C(CH3)2-、-CF2-、-CH(F)
    Figure PCTCN2015077043-appb-100007
    -CH(OH)、-CH2-、-NH-、-N(CH3)-；    Preferably, X 1 and X 2 are each independently selected from the group consisting of a single bond, -O-, -C(=O)-, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CF 2 -, -CH(F)
    Figure PCTCN2015077043-appb-100007
    -CH(OH), -CH 2 -, -NH-, -N(CH 3 )-;
    更优选地，L2选自：
    Figure PCTCN2015077043-appb-100008
    Figure PCTCN2015077043-appb-100009
    More preferably, L 2 is selected from the group consisting of:
    Figure PCTCN2015077043-appb-100008
    Figure PCTCN2015077043-appb-100009
    Figure PCTCN2015077043-appb-100010
    Figure PCTCN2015077043-appb-100010
  5. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R4选自
    Figure PCTCN2015077043-appb-100011
    Figure PCTCN2015077043-appb-100012
    T4-7分别独立地选自N或C(Rt)，    The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from
    Figure PCTCN2015077043-appb-100011
    Figure PCTCN2015077043-appb-100012
    T 4-7 are each independently selected from N or C(R t ),
    D1-3、D5、D6分别独立地选自单键、-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)-或-S(＝O)2-，D 1-3 , D 5 and D 6 are each independently selected from a single bond, -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )- , -C(=NR d5 )-, -S(=O) 2 N(R d6 )-, -S(=O)N(R d7 )-, -O-, -S-, -C(=O )O-, -C(=O)-, -C(=S)-, -S(=O)- or -S(=O) 2 -,
    n2选自0、1、2或3，n 2 is selected from 0, 1, 2 or 3,
    n3选自0、1或2，n 3 is selected from 0, 1 or 2,
    R5、R6、R7、Rt、Rd1、Rd2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，R 5 , R 6 , R 7 , R t , R d1 , R d2 are each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or selected from optional a C 1-10 alkyl or heteroalkyl group substituted by R 01 , a C 3-10 cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl group ,
    其他变量如权利要求1所定义。Other variables are as defined in claim 1.
  6. 根据权利要求5所述的化合物或其药学上可接受的盐，其中所述R4选自
    Figure PCTCN2015077043-appb-100013
    Figure PCTCN2015077043-appb-100014
    The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein said R 4 is selected from
    Figure PCTCN2015077043-appb-100013
    Figure PCTCN2015077043-appb-100014
    X3选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH，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。X 3 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or a C 1-10 alkyl or heteroalkyl group optionally substituted by R 01 , C 3-10 a cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl group.
  7. 根据权利要求5或6所述的化合物或其药学上可接受的盐，其中所述R5-7分别独立地选自 The compound according to claim 5 or 6, or a pharmaceutically acceptable salt thereof, wherein said R 5-7 are each independently selected from
    Figure PCTCN2015077043-appb-100015
    其中：
    Figure PCTCN2015077043-appb-100015
    among them:
    T1-3分别独立地选自N或C(Rt)；T 1-3 are each independently selected from N or C(R t );
    D4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)-或-S(＝O)2-；D 4 is selected from -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(= O) 2 N(R d6 )-, -S(=O)N(R d7 )-, -O-, -S-, -C(=O)O-, -C(=O)-, -C (=S)-, -S(=O)- or -S(=O) 2 -;
    R8、R9、Rt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；R 8 , R 9 , R t are each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or C 1-10 selected from R 1 , optionally substituted by R 01 . An alkyl or heteroalkyl group, a C 3-10 cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl;
    R10选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH，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.R 10 is selected from F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or a C 1-10 alkyl or heteroalkyl group optionally substituted by R 01 , C 3-10 a cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl group.
  8. 根据权利要求7所述的化合物或其药学上可接受的盐，其中：The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein:
    R5-9、R01、Rt分别独立地选自
    Figure PCTCN2015077043-appb-100016
    Figure PCTCN2015077043-appb-100017
    F、Cl、Br、CF3、-C(C2H5)-、-C(OC2H5)-、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、
    Figure PCTCN2015077043-appb-100018
    Figure PCTCN2015077043-appb-100019
    R 5-9 , R 01 and R t are each independently selected from
    Figure PCTCN2015077043-appb-100016
    Figure PCTCN2015077043-appb-100017
    F, Cl, Br, CF 3 , -C(C 2 H 5 )-, -C(OC 2 H 5 )-, methyl, ethyl, propyl, methoxy, ethoxy, propoxy,
    Figure PCTCN2015077043-appb-100018
    Figure PCTCN2015077043-appb-100019
  9. 根据权利要求8所述的化合物或其药学上可接受的盐，其中所述R4选自：The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein said R 4 is selected from the group consisting of:
    Figure PCTCN2015077043-appb-100020
    Figure PCTCN2015077043-appb-100020
    Figure PCTCN2015077043-appb-100021
    Figure PCTCN2015077043-appb-100021
  10. 根据权利要求1所述的化合物或其药学上可接受的盐，其选自：A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
    Figure PCTCN2015077043-appb-100022
    Figure PCTCN2015077043-appb-100022
    Figure PCTCN2015077043-appb-100023
    Figure PCTCN2015077043-appb-100023
    Figure PCTCN2015077043-appb-100024
    Figure PCTCN2015077043-appb-100024
    Figure PCTCN2015077043-appb-100025
    Figure PCTCN2015077043-appb-100025
    Figure PCTCN2015077043-appb-100026
    Figure PCTCN2015077043-appb-100026
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