CN102464654B - Antiviral compound - Google Patents

Antiviral compound Download PDF

Info

Publication number
CN102464654B
CN102464654B CN201010541329.0A CN201010541329A CN102464654B CN 102464654 B CN102464654 B CN 102464654B CN 201010541329 A CN201010541329 A CN 201010541329A CN 102464654 B CN102464654 B CN 102464654B
Authority
CN
China
Prior art keywords
methyl
400mhz
hnmr
base
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201010541329.0A
Other languages
Chinese (zh)
Other versions
CN102464654A (en
Inventor
陈平
周鼎
大卫·普莱德
安德鲁·贝尔
李涛
贺志良
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Hongbo Shangyi Pharmaceutical Technology Co ltd
Original Assignee
PHARMARESOURCES (SHANGHAI) CO Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by PHARMARESOURCES (SHANGHAI) CO Ltd filed Critical PHARMARESOURCES (SHANGHAI) CO Ltd
Priority to CN201010541329.0A priority Critical patent/CN102464654B/en
Priority to PCT/US2011/060370 priority patent/WO2012065062A1/en
Publication of CN102464654A publication Critical patent/CN102464654A/en
Application granted granted Critical
Publication of CN102464654B publication Critical patent/CN102464654B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/10—Radicals substituted by halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

The present invention relates to the compound of structure as shown in general formula I,

Description

Antiviral compound
Technical field
The present invention relates to and can be applied to treatment as Novel antivirus compound of HIV, HBV and HCV virus and preparation method thereof; Also comprise containing these compounds drug regimen and apply the method for these compounds.Technical background
Although the exploitation of the various multiple antiretroviral drugs being target with membranin, reversed transcriptive enzyme (RT), intergrase (IN) and proteolytic enzyme (PR) achieves significant achievement to prevention acquired immune deficiency syndrome (AIDS) spreading in HIV person, but the resistance thereupon occurred, side effect and and existing methods for the treatment of between the problem such as incompatible limit it and widely use, for acquired immune deficiency syndrome (AIDS) brand-new, the treatment plan of safety remains the current problem being badly in need of solving.In the medicine of more than 20 infection of the HIV-1 in treatment in the market, 19 is for target with in two viral enzymes, i.e. reversed transcriptive enzyme (RT) or proteolytic enzyme (PR), granted Drug-resistant virus strain finally there is the selectivity and the validity that reduce treatment plan.Therefore, still there is urgent demand in treating AIDS field to the newtype drug that exploitation has unique mechanism of action and efficient disease-resistance cytotoxic activity.
Cross resistance can not be produced with existing medicine with the newtype drug of brand-new mechanism of action inhibiting HIV replicative cycle, the research and development of this kind of medicine bring very large hope to the patient carrying anti HIV-1 virus varient, also helpful to novel combination treatment.In addition, because the treatment standard-required that acquired immune deficiency syndrome (AIDS) is current is that virus infection person carries life long treatment, exploitation is efficient, low toxicity and have the newtype drug of good safety (improving safe treatment window), will all provide more help for AIDS patient carrier, no matter it carries wild-type or mutant/multidrug resistant disease strain.
The structure of viruses molecule is that single virus is formed by multiple relatively weak non-covalent interaction, and from this treatment thoughts of antiviral intervention, the assembling stoping viruses molecule is a very attractive method.But, owing to lacking the understanding to aspects such as virus structure and each subunit combinations, add there is no suitable screening method, only have the virus assembly inhibitor of only a few to be found up to now.
Virus of AIDS is released with non-maturation, noninfectious virion from the cell infected, and these particles contain the globular protein shell wearing about 5000 Gag molecules under viromembrane.Discharging incident with virus is the Gag polyprotein fractional hydrolysis process produced by viral lytic enzyme, formation that result in single maturation, that have infective virus.A cone containment structure is comprised in this virus, and with structural protein such as stromatin (MA), shell (CA), core shell (NC) and p6, additional SP1 and SP2 bis-interval polypeptide.Significantly, the hydrolysis of the final key of CA-SP1 protein polypeptide is split and can be produced into a ripe p24CA albumen step by step, and the latter can form the high-sequential mixture containing ripe viral core.Lack this ripe mechanism, virion will keep it non-infectious.
The antiviral of the some new mechanisms using the maturation of virus as target enters clinical experimental stage at present 1-6.Also there is report with the inhibitor that HIV-1 coat protein is target, comprising: helical peptides enzyme inhibitors (CAI) 7-9, two micromolecular inhibitor CAP-1 and CAP-2 10with the inhibitor based on several thiocarbamide 11.In addition, the application of the compound patent acting on HIV coat protein is also had to appear in the newspapers 12-16.Brief summary of the invention
On the one hand, compound structure provided by the invention as shown in general formula I, or its enantiomorph, diastereomer, tautomer, or pharmacy acceptable salt or solvate, wherein: W can be optionally with substituent 8-10 unit dicyclic compound, comprises carbocyclic ring or heterocycle; R 1and R 2any one can independently represent hydrogen or (C 1-C 4) alkyl, hydroxyl, fluorine or NR br c, or R 1and R 2(C can be formed together 3-C 5) cycloalkyl or replace (C 3-C 5) cycloalkyl; R 3it is the heterocyclic aryl of phenyl, the phenyl of replacement, heterocyclic aryl or replacement; R 4hydrogen, (C 1-C 4) alkyl or replace (C 1-C 4) alkyl, (C 3-C 7) cycloalkyl or replace (C 3-C 7) cycloalkyl; R 5(CR 8r 9) q-cycloalkyl, (CR 8r 9) qthe cycloalkyl, (CR of-replacement 8r 9) q-aryl, (CR 8r 9) qthe aryl, (CR of-replacement 8r 9) q-heterocycle or (CR 8r 9) qthe heterocycle of-replacement; R 8and R 9any one can independently represent hydrogen or (C 1-C 4) alkyl, hydroxyl, fluorine or NR br c, R band R cany one alkyl that independently can represent hydrogen, alkyl or replace, or described R band R cthe heterocycle of heterocycle or replacement optionally can be formed together with the atom N that they combine; Each q independently represents 0,1,2,3 or 4; And n is 1 or 2.
On the other hand, the invention provides pharmaceutical composition and comprise the compound described at least one the application, and pharmaceutically acceptable carrier.
Again on the one hand, the invention provides the method for the treatment of or prevention certain viral infection in mammalian species in need, its method comprises and gives to treat at least one compound described in the application of effective dose to this mammalian species.
Again on the one hand, the invention provides the method for the treatment of or prophylactic treatment HIV in mammalian species in need, its method comprises and gives to treat at least one compound described in the application of effective dose to this mammalian species.That invents further illustrates definition
Following be in this specification sheets use the definition of term.Unless otherwise noted, the initial definition of group provided herein or term be applicable to this specification sheets in the whole text in independent appearance or this group occurred as a part for other group or term.
Term " alkyl " refers to straight or branched alkyl (alkyl), and it comprises 1-12 carbon atom, preferably 1-6 carbon atom.The example of " alkyl " comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, isohexyl, heptyl, 4,4-dimethyl amyl groups, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl etc.Term " (C 1-C 4) alkyl " referring to straight or branched alkyl (alkyl), it comprises 1-4 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl and isobutyl-." substituted alkyl " refers to that the one or more positions in alkyl are substituted, preferably 1-4 substituting group, can replace on any combinable position.Substituent example includes but not limited to one or more following group: hydrogen, and (such as, single halogenic substituent or many halogenic substituents, the latter is formed as trifluoromethyl or comprises Cl halogen 3alkyl), itrile group, nitro, oxygen (namely=O), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, aryl, OR a, SR a, S (=O) R e, S (=O) 2r e, P (=O) 2r e, S (=O) 2oR e, P (=O) 2oR e, NR br c, NR bs (=O) 2r e, NR bp (=O) 2r e, S (=O) 2nR br c, P (=O) 2nR br c, C (=O) OR d, C (=O) R a, C (=O) NR br c, OC (=O) R a, OC (=O) NR br c, NR bc (=O) OR e, NR dc (=O) NR br c, NR ds (=O) 2nR br c, NR dp (=O) 2nR br c, NR bc (=O) R a, or NR bp (=O) 2r e, wherein at each R that this occurs acan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aryl, at each R that this occurs b, R cand R dcan independently represent hydrogen, alkyl, cycloalkyl, heterocycle or aryl, or described R band R coptionally heterocycle is formed together with the atom N that they combine; At each R that this occurs ecan independently represent alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aryl.Above-mentioned substituent example, as alkyl, cycloalkyl, thiazolinyl, alkynyl, cycloalkenyl group, heterocycle and aryl also can optionally be substituted itself.
The straight or branched hydrocarbon-based that refers to term " thiazolinyl " contains 2-12 carbon atom and at least one carbon-carbon double bond.The example of such group comprises vinyl or allyl group.Term " C 2-C 6thiazolinyl " refer to straight or branched containing 2-6 carbon atom and the alkyl having a carbon-carbon double bond at least, as vinyl, propenyl, 2-propenyl, (E)-crotyl, (Z)-crotyl, (E)-2-methyl-2-butene base, (Z)-2-methyl-2-butene base, 2, 3-dimethyl-crotyl, (Z)-pentenyl, (E)-1-pentenyl, (Z)-1-hexenyl, (E)-pentenyl, (Z)-2-hexenyl, (E)-2-hexenyl, (Z)-1-hexenyl, (E)-1-hexenyl, (Z)-3-hexenyl, (E)-3-hexenyl and (E)-1, 3-hexadienyl." substituted alkenyl " refers to the thiazolinyl replaced by one or more substituting group, preferably 1-4 substituting group, can replace on any combinable position.Substituent example includes but not limited to one or more following group: hydrogen, and (such as, single halogenic substituent or many halogenic substituents, the latter is formed as trifluoromethyl or comprises Cl halogen 3alkyl), itrile group, nitro, oxygen (that is ,=O), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, aryl, OR a, SR a, S (=O) R e, S (=O) 2r e, P (=O) 2r e, S (=O) 2oR e, P (=O) 2oR e, NR br c, NR bs (=O) 2r e, NR bp (=O) 2r e, S (=O) 2nR br c, P (=O) 2nR br c, C (=O) OR d, C (=O) R a, C (=O) NR br c, OC (=O) R a, OC (=O) NR br c, NR bc (=O) OR e, NR dc (=O) NR br c, NR ds (=O) 2nR br c, NR dp (=O) 2nR br c, NR bc (=O) R a, or NR bp (=O) 2r e, wherein at each R that this occurs acan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aryl, at each R that this occurs b, R cand R dcan independently represent hydrogen, alkyl, cycloalkyl, heterocycle or aryl, or described R band R coptionally heterocycle is formed together with the atom N that they combine; At each R that this occurs ecan independently represent alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aryl.The above-mentioned substituting group exemplified can optionally be substituted himself.
Term " alkynyl " refers to straight or branched alkyl, and it contains 2-12 carbon atom and at least one carbon carbon triple bond.The example of such group comprises ethynyl.Term " C 2-C 6alkynyl " refer to straight or branched containing 2-6 carbon atom and the hydrocarbyl group having a carbon carbon triple bond at least, as ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 1-pentynyl, valerylene base, 1-hexin base, 2-hexin base, 3-hexin base." substituted alkynyl " refers to the alkynyl replaced by one or more substituting group, preferably 1-4 substituting group, can replace on any combinable position.Substituent example includes but not limited to one or more following group: hydrogen, and (such as, single halogenic substituent or many halogenic substituents, the latter is formed as trifluoromethyl or comprises Cl halogen 3alkyl), itrile group, nitro, oxygen (that is ,=O), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, aryl, OR a, SR a, S (=O) R e, S (=O) 2r e, P (=O) 2r e, S (=O) 2oR e, P (=O) 2oR e, NR br c, NR bs (=O) 2r e, NR bp (=O) 2r e, S (=O) 2nR br c, P (=O) 2nR br c, C (=O) OR d, C (=O) R a, C (=O) NR br c, OC (=O) R a, OC (=O) NR br c, NR bc (=O) OR e, NR dc (=O) NR br c, NR ds (=O) 2nR br c, NR dp (=O) 2nR br c, NR bc (=O) R a, or NR bp (=O) 2r e, wherein at each R that this occurs acan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aryl, at each R that this occurs b, R cand R dcan independently represent hydrogen, alkyl, cycloalkyl, heterocycle or aryl, or described R band R coptionally heterocycle is formed together with the atom N that they combine; At each R that this occurs ecan independently represent alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aryl.Described substituent example can optionally be substituted himself.
Term " cycloalkyl " refers to completely saturated cyclic hydrocarbon compounds group, comprises 1-4 ring, containing 3-8 carbon atom in each ring." (C 3-C 7) cycloalkyl " be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl." substituted cycloalkyl " refers to that the one or more positions in cycloalkyl are substituted, especially 1-4 substituting group, can replace on any position.Substituent example includes but not limited to one or more following group: as hydrogen, and (such as, single halogenic substituent or many halogenic substituents, the latter is as trifluoromethyl or comprise Cl for halogen 3alkyl), itrile group, nitro, oxygen (as=O), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, aryl, OR a, SR a, S (=O) R e, S (=O) 2r e, P (=O) 2r e, S (=O) 2oR e, P (=O) 2oR e, NR br c, NR bs (=O) 2r e, NR bp (=O) 2r e, S (=O) 2nR br c, P (=O) 2nR br c, C (=O) OR d, C (=O) R a, C (=O) NR br c, OC (=O) R a, OC (=O) NR br c, NR bc (=O) OR e, NR dc (=O) NR br c, NR ds (=O) 2nR br c, NR dp (=O) 2nR br c, NR bc (=O) R a, or NR bp (=O) 2r e, wherein at each R that this occurs acan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aryl, at each R that this occurs b, R cand R dcan independently represent hydrogen, alkyl, cycloalkyl, heterocycle or aryl, or described R band R cheterocycle can be formed together with the atom N that they combine; At each R that this occurs ecan independently represent alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aryl.Above-mentioned substituent example can optionally be substituted himself.Substituent example also comprises ring substituents that is that volution connects or that condense, especially the heterocycle (not comprising heteroaryl) that the cycloalkenyl group that volution connects cycloalkyl, volution connect, volution connect, the cycloalkyl condensed, the cycloalkenyl group condensed, the heterocyclic radical condensed or the aryl condensed, wherein above-mentioned cycloalkyl, cycloalkenyl group, heterocyclic radical and aryl substituent can optionally be substituted himself.
Term " cycloalkenyl group " refers to the undersaturated cyclic hydrocarbon group of part, and it comprises 1-4 ring, containing 3-8 carbon atom in each ring.The example of such group comprises cyclobutene base, cyclopentenyl, cyclohexenyl etc." substituted cycloalkenyl " refers to the cycloalkenyl group replaced by one or more substituting group, preferably 1-4 substituting group, can replace on any combinable position.Substituent example includes but not limited to one or more following group: hydrogen, and (such as, single halogenic substituent or many halogenic substituents, the latter is formed as trifluoromethyl or comprises Cl halogen 3alkyl), itrile group, nitro, oxygen (that is ,=O), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, aryl, OR a, SR a, S (=O) R e, S (=O) 2r e, P (=O) 2r e, S (=O) 2oR e, P (=O) 2oR e, NR br c, NR bs (=O) 2r e, NR bp (=O) 2r e, S (=O) 2nR br c, P (=O) 2nR br c, C (=O) OR d, C (=O) R a, C (=O) NR br c, OC (=O) R a, OC (=O) NR br c, NR bc (=O) OR e, NR dc (=O) NR br c, NR ds (=O) 2nR br c, NR dp (=O) 2nR br c, NR bc (=O) R a, or NR bp (=O) 2r e, wherein at each R that this occurs acan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aryl, at each R that this occurs b, R cand R dcan independently represent hydrogen, alkyl, cycloalkyl, heterocycle or aryl, or described R band R coptionally heterocycle is formed together with the atom N that they combine; At each R that this occurs ecan independently represent alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aryl.Above-mentioned substituent example can optionally be substituted himself.Substituent example also comprises ring substituents that is that volution connects or that condense, especially volution connect cycloalkyl, volution connect cycloalkenyl group, volution connect heterocycle (not comprising heteroaryl), the cycloalkyl condensed, thick and cycloalkenyl group, the heterocyclic radical condensed or the aryl condensed, wherein above-mentioned cycloalkyl, cycloalkenyl group, heterocyclic radical and aryl substituent can optionally be substituted himself.
Term " aryl " refers to aromatic ring-shaped alkyl, has 1-5 aromatic nucleus, especially monocycle and bicyclic radicals, as phenyl, xenyl or naphthyl.When containing two or more aromatic nucleus (dicyclo etc.), the aromatic nucleus of aromatic yl group can be connected (as biphenyl) by singly-bound, or condenses (as naphthalene, anthracene etc.)." substituted aryl " refers to the aryl replaced by one or more substituting group, preferably 1-3 substituting group, can replace on any combinable position.Substituent example includes but not limited to one or more following group: hydrogen, and (such as, single halogenic substituent or many halogenic substituents, the latter is formed as trifluoromethyl or comprises Cl halogen 3alkyl), itrile group, nitro, oxygen (that is ,=O), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, aryl, OR a, SR a, S (=O) R e, S (=O) 2r e, P (=O) 2r e, S (=O) 2oR e, P (=O) 2oR e, NR br c, NR bs (=O) 2r e, NR bp (=O) 2r e, S (=O) 2nR br c, P (=O) 2nR br c, C (=O) OR d, C (=O) R a, C (=O) NR br c, OC (=O) R a, OC (=O) NR br c, NR bc (=O) OR e, NR dc (=O) NR br c, NR ds (=O) 2nR br c, NR dp (=O) 2nR br c, NR bc (=O) R a, or NR bp (=O) 2r e, wherein at each R that this occurs acan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aryl, at each R that this occurs b, R cand R dcan independently represent hydrogen, alkyl, cycloalkyl, heterocycle or aryl, or described R band R coptionally heterocycle is formed together with the atom N that they combine; At each R that this occurs ecan independently represent alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aryl.Above-mentioned substituent example can optionally be substituted.Substituent example also comprises the ring substituents condensed, especially the cycloalkyl condensed, the cycloalkenyl group condensed, the ring heterocyclic radical condensed or the aryl condensed, wherein above-mentioned cycloalkyl, cycloalkenyl group, heterocyclic radical and aryl substituent can optionally be substituted himself.
Term " carbocyclic ring " refers to cyclic hydrocarbon group that is completely saturated or fractional saturation, comprises 1-4 ring, containing 3-8 carbon atom in each ring, or aromatic ring-shaped alkyl, there is 1-5 aromatic nucleus, especially monocycle or bicyclic radicals, as phenyl, xenyl or naphthyl.Term " carbocyclic ring " comprises cycloalkyl, cycloalkenyl group, cycloalkynyl radical and aryl defined above.The carbon ring group that term " replacement carbocyclic ring " refers to carbocyclic ring or replaced by one or more substituting group, preferably 1-4 substituting group, can replace on any combinable position.Substituent example includes but not limited to above-described group: substituted cycloalkyl, substituted cycloalkenyl, substituted ring alkynyl and substituted aryl.That the substituent example volution be also included on any combinable position connects or condense ring substituents, especially the heterocycle (not comprising heteroaryl) that the cycloalkenyl group that volution connects cycloalkyl, volution connect, volution connect, the cycloalkyl condensed, the cycloalkenyl group condensed, the heterocyclic radical condensed or the aryl condensed, wherein above-mentioned cycloalkyl, cycloalkenyl group, heterocyclic radical and aryl substituent can optionally be substituted himself.
Term " heterocycle " or " heterocycle " refer to completely saturated or part is undersaturated or completely undersaturatedly comprise fragrance (namely, " heteroaryl ") cyclic group (as 4-7 unit monocycle, 7-11 unit dicyclo, or 8-16 unit three-loop system), wherein have at least a heteroatoms to be present in and have one at least containing in the ring of carbon atom.Each ring containing heteroatomic heterocyclic group can with 1,2,3 or 4 heteroatoms, and these heteroatomss are selected from nitrogen-atoms, Sauerstoffatom/or sulphur atom, and wherein nitrogen-atoms and sulphur atom can be optionally oxidized, and nitrogen-atoms also can be optionally quaternized.(term " heteroaryl ion " refers to the also therefore positively charged heteroaryl groups containing quaternary nitrogen atoms.) heterocyclic group can be connected at any heteroatoms of ring or loop systems or carbon atom place with the other parts of this molecule.The example of monocyclic heterocycles comprises azetidinyl, pyrrolidyl, pyrryl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidyl, oxazolyl, oxazolidinyl, isoxazole alkyl, isoxazolyl, thiazolyl, thiadiazolyl group, thiazolidyl, isothiazolyl, isothiazole alkyl, furyl, tetrahydrofuran base, thienyl, oxadiazolyl, piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo azepines base, azepines base, hexahydroazepine base, 4-piperidone base, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, three nitrogen piperazine bases, triazol radical, tetrazole base, THP trtrahydropyranyl, morpholine base, thio-morpholine group, sulfo-morpholine sulfoxide group, sulfo-morpholine sulfuryl, 1, 3-alkyl dioxin and tetrahydrochysene-1, 1-dioxy thiophene etc.The example of bicyclic heterocycle comprises indyl, pseudoindoyl, benzothiazolyl, benzoxazolyl, benzo oxygen di azoly, benzothienyl, benzo [d] [1, 3] two oxyalkyls, 2, 3-dihydrobenzo [b] [1, 4] two oxyalkyls, quinine base, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl-, benzopyranyl, indolinyl, benzofuryl, coumaran base, chromanyl, tonka bean camphor base, benzopyranyl, cinnolines base, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridyl is (as furo [2, 3-c] pyridyl, furo [3, 2-b] pyridyl or furo [2, 3-b] pyridine), dihydro-iso indolyl, dihydroquinazoline base is (as 3, 4-dihydro-4-oxoquinazolin base), three azepine azepines bases, tetrahydric quinoline group etc.The example of tricyclic heterocyclic comprises carbazyl, benzindole, phenanthroline base, acridyl, phenanthridinyl, xanthyl etc.
" substituted heterocycle " and " substituted heterocycle " (as " substituted heteroaryl ") refers to the heterocycle or heterocyclic group that are replaced by one or more substituting group, preferably 1-4 substituting group, can replace on any combinable position.Substituent example includes but not limited to one or more following group: hydrogen, and (such as, single halogenic substituent or many halogenic substituents, the latter is formed as trifluoromethyl or comprises Cl halogen 3alkyl), itrile group, nitro, oxygen (that is ,=O), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, aryl, OR a, SR a, S (=O) R e, S (=O) 2r e, P (=O) 2r e, S (=O) 2oR e, P (=O) 2oR e, NR br c, NR bs (=O) 2r e, NR bp (=O) 2r e, S (=O) 2nR br c, P (=O) 2nR br c, C (=O) OR d, C (=O) R a, C (=O) NR br c, OC (=O) R a, OC (=O) NR br c, NR bc (=O) OR e, NR dc (=O) NR br c, NR ds (=O) 2nR br c, NR dp (=O) 2nR br c, NR bc (=O) R a, or NR bp (=O) 2r e, wherein at each R that this occurs acan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aryl, at each R that this occurs b, R cand R dcan independently represent hydrogen, alkyl, cycloalkyl, heterocycle or aryl, or described R band R cheterocycle can be formed together with the atom N that they combine; At each R that this occurs ecan independently represent alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aryl.Above-mentioned substituent example can optionally be substituted himself.That the substituent example volution be also included on any combinable position connects or condense ring substituents, especially the ring heterocyclic radical that the cycloalkenyl group that volution connects cycloalkyl, volution connect, volution connect or the cycloalkyl that condenses, the cycloalkenyl group condensed, the heterocyclic radical condensed, the aryl condensed, above-mentioned cycloalkyl, cycloalkenyl group, heterocyclic radical and aryl substituent can optionally be substituted himself.
Term " alkyl amine group " refers to the group of-NHR ' with structure, and wherein R ' refers to the cycloalkyl of halogen, the alkyl of alkyl or replacement, cycloalkyl or replacement, as in the application define.The example of alkyl amine group includes but not limited to methylamino, ethylamino-, Tri N-Propyl Amine base, isopropylamine base, cyclopropyl amino, n-butylamine-based, TERTIARY BUTYL AMINE base, neopentyl amine base, n-amylamine base, hexylamine base, cyclohexylamino etc.
Term " dialkyl amino " refers to the group of-NRR ' with structure, wherein R and R ' each independently can represent the heterocycle of the alkyl of alkyl or replacement, the cycloalkyl of cycloalkyl or replacement, the cycloalkenyl group of cycloalkenyl group or replacement, the aryl of aryl or replacement, heterocycle or replacement, as in the application define.R and R ' can be identical or different in dialkylamine fragment.The example of dialkyl amino includes but not limited to, dimethylin, methylethyl amido, diethylin, methyl-propyl amido, two (n-propyl) amido, two (sec.-propyl) amido, two (cyclopropyl) amido, two (normal-butyl) amido, two (tertiary butyl) amido, two (neo-pentyl) amido, two (n-pentyl) amido, two (hexyl) amido, two (cyclohexyl) amido etc.In some instances, R and R ' connects together formation ring texture.Consequent ring texture can be aromatic nucleus or non-aromatic ring.The example of cyclic dialkyl amido includes but not limited to, aziridinyl, pyrrolinyl, piperidyl, morpholinyl, pyrryl, imidazolyl, 1,3,4-triazol radical and tetrazole base.
Term " halogen " or " halogen " refer to chlorine, bromine, fluorine or iodine.
Unless otherwise indicated, assuming that the heteroatoms of any discontented valence state has enough hydrogen atoms to supplement its valence state.
The salt that compound in the present invention can be formed also is within the scope of this invention.Except as otherwise noted, the compound in the present invention is understood to include its esters.Term " salt (class) ", refers to the salt of acid and/or the alkali formula formed with inorganic and/or organic bronsted lowry acids and bases bronsted lowry as used herein.In addition, when the compound in the present invention is containing a basic moiety, such as but not limited to pyridine or imidazoles, and during containing an acidic moiety, such as but not limited to carboxylic acid, its zwitter-ion that may be formed (" inner salt ") is also contained in the scope of term " salt (class) ".Preferably pharmaceutically acceptable (namely nontoxic, physiology is acceptable) salt, although other salts are also useful, such as, can be used in the isolated or purified step that may adopt in preparation process.Compound of the present invention can form salt, such as, Compound I and a certain amount of acid as equivalent or alkali reaction, in media as well salify, such as one can saltout in medium, or in an aqueous medium again through lyophilize salify.
The compound of the basic moiety contained in the present invention, includes but not limited to amine or pyridine or imidazole ring, can form salt with multiple organic and mineral acid.The example of acid salt comprises acetate (as with acetic acid or three halogenated acetic acids, as the salt that trifluoroacetic acid is formed), adipate, alginate, ascorbate salt, aspartate, benzoate, benzene sulfonate, hydrosulfate, borate, butyrates, Citrate trianion, camphor salt, camsilate, cyclopentane propionate, glycol ether hydrochlorate, dodecyl sulfate, ethane sulfonate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, isethionate (e.g., 2-isethionate), lactic acid salt, maleate, mesylate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectate, persulphate, phenpropionate (as 3-phenpropionate), phosphoric acid salt, picrate, Pivalate, propionic salt, salicylate, succinate, vitriol (as formed with sulfuric acid), sulfonate, tartrate, thiocyanate-, mesylate is as tosilate, dodecanoate etc.
The acidic moiety that compound of the present invention contains, includes but not limited to carboxylic acid, can form salt with multiple organic and mineral alkali.The example of base addition salt comprises ammonium salt, an alkali metal salt as sodium, lithium, sylvite, alkaline earth salt is as calcium, magnesium salts, with the salt (as organic amine) that organic bases is formed, if benzyl star, dicyclohexylamine, sea bar amine are (with N, the salt that N-bis-(dehydroabietyl) quadrol is formed), N-methyl-D-glucosamine, N-methyl-D-glucamides, tert-butylamine, and and the salt that formed as arginine, Methionin etc. of amino acid.Basic nitrogen-containing groups can form quaternary ammonium salt with Cucumber, as lower alkyl halogenide (as the muriate of methyl, ethyl, propyl group and butyl, bromide and iodide), dialkyl sulfate (as, methyl-sulfate, diethyl ester, dibutylester and diamyl ester), long chain halide (as the muriate of decyl, dodecyl, tetradecyl and tetradecyl, bromide and iodide), aralkyl halide (as benzyl and phenylethyl bromide) etc.
In the present invention, the prodrug of compound and solvate are also within the scope contained.Term " prodrug " refers to a kind of compound herein, after delivering medicine to an object, through the chemical conversion of metabolism or chemical process and the compound produced in the present invention or salt and/or solvate.The solvate of compound of the present invention comprises, as hydrate.
, (such as acid amides or imines ether) can be there is with tautomeric form in the compound in the present invention and salt or solvate.All these tautomers are all parts of the present invention.
All steric isomers (such as, those steric isomers that may exist due to the unsymmetrical carbon on multiple substituting group) of the compound in the application, comprise its enantiomeric form and diastereomeric forms, all belong to scope of the present invention.Compound in the present invention independently steric isomer is passable, such as, in fact without other isomer (such as, pure or be in fact pure optical isomer as one, it has specific activity), or can be also mixture, as raceme, or the mixture formed with every other or other steric isomers selected.Chiral centre of the present invention can have S or R two kinds of configurations, as in International Union of Pure and Applied Chemistry (IUPAC) suggestion in 1974 define.Racemic form splits by physical method, such as fractional crystallization, is separated or carries out crystallization to diastereomer derivative, or being separated by chiral column chromatography.Single optical isomer is obtained by racemic modification by any suitable method, includes but not limited to traditional method, such as with optical activity acid salify after recrystallize.
Compound in the present invention after the production, a composition is obtained preferably by abstraction and purification, it contains the described compound that weight content is equal to or greater than 90%, such as, be equal to or greater than 95%, be equal to or greater than 99% (compound of " pure in fact "), its then as described in the present application such used or preparation.The compound of the present invention of " pure in fact " is like this also as a part of the present invention.
No matter all configurational isomer of compound of the present invention, all within the scope contained, is mixture, pure or pure in fact form.Cis (Z) and trans (E) two kinds of olefin isomers are comprised in the definition of the compounds of this invention, and the cis of cyclic hydrocarbon or heterocycle and trans-isomer(ide).
In whole specification sheets, group and substituting group can be selected to provide stable fragment and compound.
Particular functional group and technical term of chemistry definition are all described in detail as follows.In order of the present invention, chemical element and PeriodicTableoftheElements, CASversion, HandbookofChemistryandPhysics, 75 thed. in, definition is consistent.The definition of particular functional group also describes wherein.In addition, vitochemical fundamental principle and particular functional group are with reactive at " OrganicChemistry ", and ThomasSorrell, UniversityScienceBooks, Sausalito:1999, also have explanation, and its full content includes the row of reference in.
Some compound of the present invention may be present in specific geometry or stereoisomer form.All these compounds are contained in the present invention, comprise its cis and trans-isomer(ide), R and S enantiomer, diastereomer, (D) type isomer, (L) type isomer, racemic mixture and other mixture, all within the scope of the invention.Other unsymmetrical carbon can be present in certain substituting group, as alkyl.All isomer and their mixture, all forgive in the present invention.
The isomer mixture containing any isomer proportion can be used according to the present invention.Such as, when only having two isomer mixing, containing 50: 50,60: 40,70: 30,80: 20,90: 10,95: 5,96: 4,97: 3,98: 2,99: 1, or all mixtures of the isomer proportion of 100: 0 are all within the scope of the invention.Those skilled in the art's easy understand in this specialty, the similar ratio in more complicated isomer mixture is also within the scope of the invention.
The present invention also comprises isotope-labeled compound, and it is equal to compound disclosed herein, and except one or more atom is replaced by an atom, the nucleidic mass of this atom or total mass number are different from the nucleidic mass or total mass number that occurring in nature finds usually.The isotopic example that can add in compound of the present invention comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine isotope, respectively as 2h, 3h, 13c, 11c, 14c, 15n, 18o, 17o, 31p, 32p, 35s, 18f and 36cl.Containing the compound in other isotopic the present invention of above-mentioned isotropic substance and/or other atoms, or enantiomorph, diastereomer, tautomer, or pharmacy acceptable salt or solvate, all within the scope of the present invention.Some compound isotopically labelled in the present invention, such as those add radio isotope as 3h and 14the compound of C, can be used in the tissue distribution experiment of medicine and/or substrate.Preferred coordination have tritium, namely 3h and carbon-14, namely 14c, because their preparation and determination methods ratio is easier to.In addition, in some cases can preferably with heavier isotropic substance as deuterium, namely 2h replaces, because thus its good metabolic stability can provide some treatment advantage, such as, increases transformation period or the consumption needed for minimizing in vivo.Isotope-labeled compound can be prepared by the step in the scheme that hereafter discloses and/or example usually, replaces non isotopic reagent with the isotope labeling reagent be easy to get.
If such as, need the specific enantiomorph of a compound of the present invention, it can be prepared by asymmetric synthesis, or uses chiral auxiliaries derivatize, is separated by produced mixture of diastereomers, then cuts off chiral auxiliaries and obtain pure required enantiomorph.In addition, if containing a basic functionality in molecule, as amino, or acidic functionality, as carboxyl, diastereomeric salt can be formed with it with suitable optically active acid or alkali, then be split by the means well known in the art such as fractional crystallization or chromatogram, then obtain pure enantiomer.
As described herein, the compound in the present invention can be replaced by any amount of substituting group or functional group.Usually, whether term " replacement " is no matter there is term " optionally " before it, and the substituting group contained in chemical formula of the present invention, refers in specified structure with a specific substituting group replacement hydroperoxyl radical.When the more than one position in any specified structure can be replaced by more than one specified substituent, can be identical or different at the described substituting group of each position.Term used herein " replacement " includes the substituting group of all permissions of organic compounds.In broad terms, the substituting group of permission include the acyclic of organic compounds and ring-type, side chain with non-branched, carbocyclic ring with heterocycle, fragrance with non-aromatic substituting group.In the present invention, heteroatoms such as nitrogen can have the substituting group of the organic compound of any permission as described in hydrogen substituting group and/or the application to carry out its valence state supplementary.In addition, the substituting group of the organic compound of described permission can not limit the present invention by any way.Preferably those cause the combination forming stable compound in the combination of the substituting group that the present invention is susceptible to and variable groups, and these stable compounds can be used for disease therapy, such as transmissible disease or proliferative disease.In the application, term " is stablized " and is preferably referred to that compound has enough stability and is enough to allow it to produce, and being enough in the time detected, preferably in the time being enough to be used in the purposes that the application describes in detail, maintains the integrity of compound structure. compound
On the one hand, compound structure provided by the invention as shown in general formula I, or its enantiomorph, diastereomer, tautomer, or pharmacy acceptable salt or solvate, wherein: W can be optionally with substituent 8-10 unit dicyclic compound, comprises carbocyclic ring or heterocycle; R 1and R 2any one can independently represent hydrogen, (C 1-C 4) alkyl, hydroxyl, fluorine or NR br c, or R 1and R 2(C can be formed together 3-C 5) cycloalkyl or replace (C 3-C 5) cycloalkyl; R 3it is the heteroaryl of phenyl, the phenyl of replacement, heteroaryl or replacement; R 4hydrogen, (C 1-C 4) alkyl or replace (C 1-C 4) alkyl, (C 3-C 7) cycloalkyl or replace (C 3-C 7) cycloalkyl; R 5(CR 8r 9) q-cycloalkyl, (CR 8r 9) qthe cycloalkyl, (CR of-replacement 8r 9) q-aryl, (CR 8r 9) qthe aryl, (CR of-replacement 8r 9) q-heterocycle or (CR 8r 9) qthe heterocycle R of-replacement 8and R 9any one can independently represent hydrogen or (C 1-C 4) alkyl, hydroxyl, fluorine or NR br c; R band R cany one alkyl that independently can represent hydrogen, alkyl or replace, or described R band R cthe heterocycle of heterocycle or replacement can be formed together with the atom N that they combine; Each q independently represents 0,1,2,3 or 4; And n is 1 or 2.
In some example, W can choose from following structure: wherein: in general formula (Ia) and (Ib) refer to or general formula (Id) refer to double bond or singly-bound; Z 1, Z 2, Z 3, Z 4, Z 5, Z 6, Z 7, Z 8, and Z 9any one can independently represent carbon or nitrogen, and Z 5, Z 6, Z 7, and Z 8in at least one is carbon; X 1, X 2, X 3, X 4, X 5, X 6, X 7and X 8any one can independently represent carbon or nitrogen, and X 1, X 2, X 3and X 4in at least one is carbon, X 5, X 6, X 7and X 8in at least one is carbon; J is nitrogen or carbon; L is nitrogen or oxygen; Q is nitrogen, oxygen or sulphur; R 1and R 2any one can independently represent hydrogen or (C 1-C 4) alkyl; R 3it is the heteroaryl of phenyl, the phenyl of replacement, heteroaryl or replacement; R 4hydrogen, (C 1-C 4) alkyl or replace (C 1-C 4) alkyl, (C 3-C 7) cycloalkyl or replace (C 3-C 7) cycloalkyl; R 5(CR 8r 9) q-cycloalkyl, (CR 8r 9) qthe cycloalkyl, (CR of-replacement 8r 9) q-aryl, (CR 8r 9) qthe aryl, (CR of-replacement 8r 9) q-heteroaryl or (CR 8r 9) qthe heteroaryl of-replacement; Each R 6independently can represent aryl, the OR of hydrogen, halogen, itrile group, nitro, trifluoromethyl, trifluoromethoxy, the alkyl of alkyl or replacement, the thiazolinyl of thiazolinyl or replacement, the alkynyl of alkynyl or replacement, the cycloalkyl of cycloalkyl or replacement, the cycloalkenyl group of cycloalkenyl group or replacement, the heterocycle of heterocycle or replacement, aryl or replacement a, SR a, S (=O) R a, S (=O) 2r a, S (=O) 2oR a, NR br c, C (=O) OR a, C (=O) R a, C (=O) NR br c, OC (=O) R a, OC (=O) NR br c, NR bc (=O) OR a, NR ac (=O) NR br c, NR bc (=O) R a, (CR 8r 9) q-OH, (CR 8r 9) q-O-(C 1-C 4) alkyl, (CR 8r 9) q-NR br c, (CR 8r 9) q-cycloalkyl, (CR 8r 9) qthe cycloalkyl, (CR of-replacement 8r 9) q-phenyl or (CR 8r 9) qthe phenyl, (CR of-replacement 8r 9) q-heteroaryl or (CR 8r 9) qthe heteroaryl of-replacement; Each R 7independently can represent the aryl, (CR of hydrogen, halogen, itrile group, nitro, azido-, trifluoromethyl, the alkyl of alkyl or replacement, the thiazolinyl of thiazolinyl or replacement, the alkynyl of alkynyl or replacement, the cycloalkyl of cycloalkyl or replacement, the cycloalkenyl group of cycloalkenyl group or replacement, the heterocycle of heterocycle or replacement, aryl or replacement 8r 9) q-OH, (CR 8r 9) q-O-(C 1-C 4) alkyl, (CR 8r 9) q-NR br c, (CR 8r 9) q-NR bc (=O) R a, (CH 2) q-cycloalkyl, (CR 8r 9) qthe cycloalkyl, (CR of-replacement 8r 9) q-phenyl or (CR 8r 9) qthe phenyl, (CR of-replacement 8r 9) q-heteroaryl or (CR 8r 9) qthe heteroaryl of-replacement; Each R 8and R 9can independently represent hydrogen or (C 1-C 4) alkyl; At each R that this occurs a, R band R cindependently can represent the aryl of hydrogen, the alkyl of alkyl or replacement, the thiazolinyl of thiazolinyl or replacement, the alkynyl of alkynyl or replacement, the cycloalkyl of cycloalkyl or replacement, the cycloalkenyl group of cycloalkenyl group or replacement, the heterocycle of heterocycle or replacement, aryl or replacement, or described R band R cthe heterocycle of heterocycle or replacement is optionally formed together with the atom N that they combine; Any one of m and q can independently represent 0,1,2,3 or 4; N is 1 or 2; And p is 0,1 or 2.
At some in other specific example, the compound with general formula (I) can be expressed as the structure of general formula (II): wherein W, R 1, R 2, R 3, R 4and R 5above defining in the application.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (III): wherein Z 1, Z 2, Z 3, Z 4, Z 5, Z 6, Z 7, Z 8, Z 9, R 1, R 2, R 3, R 4, R 5, R 6, R 7, m and p above defining in the application.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (IV): wherein Z 1, Z 2, Z 3, Z 4, Z 5, Z 6, Z 7, Z 8, Z 9, R 1, R 2, R 3, R 4, R 5, R 6, R 7with p above defining in the application, m is 0,1,2 or 3.
In other specific example, the compound with general formula (I) can be expressed as the structure of logical formula V: wherein Z 1, Z 2, Z 3, R 1, R 2, R 3, R 4, R 5, R 6, R 7with p above defining in the application, m is 0,1,2 or 3.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (VI): wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7with p above defining in the application, m is 1,2 or 3.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (VIa): wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7above defining in the application, m is 1,2 or 3.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (VII): wherein Z 1, Z 2, Z 3, Z 4, Z 5, Z 6, Z 7, Z 8, Z 9, R 1, R 2, R 3, R 4, R 5, R 6, R 7, m and p above defining in the application.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (VIII): wherein Z 2, Z 3, Z 5, Z 6, Z 7, Z 8, R 1, R 2, R 3, R 4, R 5, R 6, R 7with m above defining in the application, p is 1 or 2.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (IX): wherein Z 5, Z 6, Z 7, Z 8, R 1, R 2, R 3, R 4, R 5, R 6, R 7with m above defining in the application, p is 1 or 2.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (XI): wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7with m above defining in the application, p is 1 or 2.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (Xa): wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7with m above defining in the application.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (XI): wherein Z 5, Z 6, Z 7, Z 8, R 1, R 2, R 3, R 4, R 5, R 6, R 7with m above defining in the application, p is 1 or 2.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (XII): wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7with m above defining in the application, p is 1 or 2.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (XIII): wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7define hereinbefore with m.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (XIV): wherein Z 5, Z 6, Z 7, Z 8, R 1, R 2, R 3, R 4, R 5, R 6, R 7define hereinbefore with m.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (XV): wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7above define with m.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (XVI): wherein Z 5, Z 6, Z 7, Z 8, R 1, R 2, R 3, R 4, R 5, R 6, R 7define hereinbefore with m.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (XVII): wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7define hereinbefore with m.
In other specific example, the compound with general formula (I) can be expressed as the structure of general formula (XVIII): wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7define hereinbefore with m.
In some example, W refers to carbocyclic ring or the heterocycle of the dicyclo of 8-10 unit, and wherein with 1 to 6 substituting groups, these substituting groups are selected from hydrogen, halogen, itrile group, nitro, trifluoromethyl, trifluoromethoxy, (C 1-C 4) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, (C 3-C 7) cycloalkyl, (C 3-C 7) cycloalkenyl group, the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen, phenyl, naphthyl, OR a, SR a, S (=O) R a, S (=O) 2r a, S (=O) 2oR a, NR br c, C (=O) OR a, C (=O) R a, C (=O) NR br c, OC (=O) R a, OC (=O) NR br c, NR bc (=O) OR a, NR ac (=O) NR br c, NR bc (=O) R a, (CR 8r 9) q-OH, (CR 8r 9) q-O-(C 1-C 4) alkyl, (CR 8r 9) q-NR br c, (CR 8r 9) q-cycloalkyl, (CR 8r 9) q-phenyl and (CR 8r 9) q-heteroaryl; Wherein R 8and R 9any one can independently represent hydrogen or (C 1-C 4) alkyl; At each R that this occurs a, R band R ccan independently represent hydrogen, (C 1-C 4) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, (C 3-C 7) cycloalkyl, (C 3-C 7) cycloalkenyl group, heterocycle or aryl, or described R band R coptionally can form heterocycle together with the atom N that they combine, described heterocycle refers to the monocycle of 3-10 unit or the heterocycle of dicyclo, and wherein at least containing a heteroatoms be selected among nitrogen, sulphur and oxygen, each q can independently represent 0,1,2,3 or 4.
In some example, R 1and R 2any one independently can represent hydrogen, in some other example, R 1and R 2any one can independently represent (C 1-C 4) alkyl, also have in some examples, R 1and R 2any one can independently representation hydroxy or fluorine, also have in some examples, R 1and R 2any one independently can represent NR br c, wherein R band R cany one alkyl that independently can represent hydrogen, alkyl or replace, or described R band R cthe heterocycle of heterocycle or replacement optionally can be formed together with the atom N that they combine.Also have in some examples, R 1and R 2(C can be formed together 3-C 5) cycloalkyl or replace (C 3-C 5) cycloalkyl.Also have in some examples, R 1and R 2cyclopropyl can be formed together.
In some example, R 3represent phenyl.In some other example, R 3the phenyl that representative replaces.Also have in some examples, R 3represent heteroaryl.Also have in some examples, R 3the heteroaryl that representative replaces.Also have in some examples, R 3represent pyridyl.Also have in some examples, R 3the pyridyl that representative replaces.In some example, R 3represent aryl (as phenyl) or heteroaryl (as pyridyl), with 1-4 substituting group, these substituting groups are selected from hydrogen, halogen, itrile group, nitro, trifluoromethyl, trifluoromethoxy, (C 1-C 4) alkyl, (C 3-C 7) cycloalkyl, the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen, phenyl, naphthyl, (CH 2) q-OH, (CH 2) q-O-(C 1-C 4) alkyl, (CH 2) q-NR br c, (CH 2) q-(C 3-C 7) cycloalkyl, (CH 2) q(the C of-replacement 3-C 7) cycloalkyl, (CH 2) q-phenyl or (CH 2) qthe phenyl, (CH of-replacement 2) q-heteroaryl and (CH 2) qthe heteroaryl of-replacement, wherein q can represent 0,1,2,3 or 4, each R herein occurred band R ccan independently represent hydrogen, (C 1-C 4) alkyl, (C 3-C 7) cycloalkyl, the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen or aryl, or described R band R cthe heterocycle of heterocycle or replacement optionally can be formed together with the atom N that they combine.
In some example, R 4represent hydrogen.In some other example, R 4representative (C 1-C 4) alkyl.Also have in some examples, R 4represent methyl.Also have in some examples, R 4represent ethyl.
In some example, R 5representative (CH 2) q-cycloalkyl, (CH 2) qthe cycloalkyl, (CH of-replacement 2) q-aryl, (CH 2) qthe aryl, (CH of-replacement 2) q-heteroaryl, (CH 2) qthe heteroaryl of-replacement, wherein q is 0 or 1.In some other example, R 5represent the heteroaryl of aryl, the aryl of replacement, heteroaryl, replacement.Also have in some examples, R 5represent the phenyl of phenyl or replacement.Also have in some examples, R 5represent the pyridyl of pyridyl or replacement.
Also have in some examples, R 5represent aryl (as phenyl) or heteroaryl (as pyridyl), wherein with 1 to 4 substituting groups, these substituting groups are selected from hydrogen, halogen, itrile group, nitro, trifluoromethyl, trifluoromethoxy, (C 1-C 4) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, (C 3-C 7) cycloalkyl, (C 3-C 7) cycloalkenyl group, the monocycle of 3-10 unit or the heterocycle of dicyclo, it contains at least one and is selected from heteroatoms among nitrogen, sulphur and oxygen, phenyl, naphthyl, OR a, SR a, S (=O) R a, S (=O) 2r a, S (=O) 2oR a, NR br c, C (=O) OR a, C (=O) R a, C (=O) NR br c, OC (=O) R a, OC (=O) NR br c, NR bc (=O) OR a, NR ac (=O) NR br c, NR bc (=O) R a, (CR 8r 9) q-OH, (CR 8r 9) q-O-(C 1-C 4) alkyl, (CR 8r 9) q-NR br c, (CR 8r 9) q-cycloalkyl, (CR 8r 9) q-phenyl and (CR 8r 9) q-heteroaryl; Wherein R 8and R 9any one can independently represent hydrogen or (C 1-C 4) alkyl; At each R that this occurs a, R band R ccan independently represent hydrogen, (C 1-C 4) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, (C 3-C 7) cycloalkyl, (C 3-C 7) cycloalkenyl group, heterocycle or aryl, or described R band R coptionally heterocycle can be formed together with the atom N that they combine; Wherein said heterocycle be the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen, each q can independently represent 0,1,2,3 or 4.
Also have in some examples, R 5represent phenyl or pyridyl, wherein with 1 to 4 substituting groups, these substituting groups are selected from hydrogen, halogen, itrile group, nitro, trifluoromethyl, trifluoromethoxy, (C 1-C 4) alkyl, (C 3-C 7) cycloalkyl, (C 3-C 7) cycloalkenyl group, the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen, phenyl, naphthyl, (CH 2) q-OH, (CH 2) q-O-(C 1-C 4) alkyl, (CH 2) q-NR br c, (CH 2) q-(C 3-C 7) cycloalkyl, (CH 2) q-phenyl and (CH 2) q-heteroaryl; At each R that this occurs band R ccan independently represent hydrogen, (C 1-C 4) alkyl, (C 3-C 7) cycloalkyl, the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen or aryl, or described R band R coptionally heterocycle can be formed together with the atom N that they combine; Wherein said heterocycle be the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen, q can independently represent 0,1,2,3 or 4.
In some example, each R 6can independently represent hydrogen, halogen, itrile group, nitro, trifluoromethyl, trifluoromethoxy, (C 1-C 4) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, (C 3-C 7) cycloalkyl, (C 3-C 7) cycloalkenyl group, the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen, phenyl, naphthyl, OR a, SR a, S (=O) R a, S (=O) 2r a, S (=O) 2oR a, NR br c, C (=O) OR a, C (=O) R a, C (=O) NR br c, OC (=O) R a, OC (=O) NR br c, NR bc (=O) OR a, NR ac (=O) NR br c, NR bc (=O) R a, (CR 8r 9) q-OH, (CR 8r 9) q-O-(C 1-C 4) alkyl, (CR 8r 9) q-NR br c, (CR 8r 9) q-cycloalkyl, (CR 8r 9) q-phenyl or (CR 8r 9) q-heteroaryl; R 8and R 9any one can independently represent hydrogen or (C 1-C 4) alkyl; At each R that this occurs a, R band R ccan independently represent hydrogen, (C 1-C 4) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, (C 3-C 7) cycloalkyl, (C 3-C 7) cycloalkenyl group, heterocycle or aryl, or described R band R coptionally can form heterocycle together with the atom N that they combine, wherein said heterocycle be the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen; Each q can independently represent 0,1,2,3 or 4.
In some other example, each R 6can independently represent hydrogen, halogen, itrile group, nitro, trifluoromethyl, trifluoromethoxy, (C 1-C 4) alkyl, (C 3-C 7) cycloalkyl, the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen, phenyl, naphthyl, (CH 2) q-OH, (CH 2) q-O-(C 1-C 4) alkyl, (CH 2) q-NR br c, (CH 2) q-(C 3-C 7) cycloalkyl, (CH 2) q-phenyl or (CH 2) q-heteroaryl; At each R that this occurs band R ccan independently represent hydrogen, (C 1-C 4) alkyl, (C 3-C 7) cycloalkyl, the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen or aryl, or described R band R coptionally can form heterocycle together with the atom N that they combine, wherein said heterocycle be the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen; Each q can independently represent 0,1,2,3 or 4.
In some example, each R 7can independently represent halogen, itrile group, nitro, azido-, trifluoromethyl, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, heterocycle, aryl, (CR 8r 9) q-OH, (CR 8r 9) q-O-(C 1-C 4) alkyl, (CR 8r 9) q-NR br c, (CR 8r 9) q-NR bc (=O) R a, (CH 2) q-cycloalkyl, (CR 8r 9) q-phenyl or (CR 8r 9) q-heteroaryl; R 8and R 9any one can independently represent hydrogen or (C 1-C 4) alkyl; At each R that this occurs a, R band R ccan independently represent hydrogen, (C 1-C 4) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, (C 3-C 7) cycloalkyl, (C 3-C 7) cycloalkenyl group, heterocycle, or aryl, or described R band R coptionally can form heterocycle together with the atom N that they combine, wherein said heterocycle be the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen; Each q can independently represent 0,1,2,3 or 4.
In some other example, each R 7can independently represent hydrogen, halogen, itrile group, nitro, azido-, trifluoromethyl, (C 1-C 4) alkyl, (C 3-C 7) cycloalkyl, the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen or aryl, (CH 2) q-OH, (CH 2) q-O-(C 1-C 4) alkyl, (CH 2) q-NR br c, (CH 2) q-NR bc (=O) R a, (CH 2) q-(C 3-C 7) cycloalkyl, (CH 2) q-phenyl or (CH 2) q-heteroaryl; At each R that this occurs a, R band R ccan independently represent hydrogen, (C 1-C 4) alkyl, (C 3-C 7) cycloalkyl, the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen or aryl, or described R band R coptionally can form heterocycle together with the atom N that they combine, wherein said heterocycle be the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen; Each q can independently represent 0,1,2,3 or 4.
In some other example, each R 7can independently represent halogen, itrile group, nitro, azido-, trifluoromethyl, (C 1-C 4) alkyl, (C 3-C 7) cycloalkyl, the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen or aryl, (CH 2) q-OH, (CH 2) q-O-(C 1-C 4) alkyl, (CH 2) q-NR br c, (CH 2) q-NR bc (=O) R a, (CH 2) q-(C 3-C 7) cycloalkyl, (CH 2) q-phenyl or (CH 2) q-heteroaryl; At each R that this occurs a, R band R ccan independently represent hydrogen, (C 1-C 4) alkyl, (C 3-C 7) cycloalkyl, the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen or aryl, or described R band R coptionally can form heterocycle together with the atom N that they combine, wherein said heterocycle be the monocycle of 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen; Each q can independently represent 0,1,2,3 or 4.
Also have in some examples, each R 7can independently represent (C 1-C 4) alkyl.Also have in some examples, R 7can independently represent (CR 8r 9) 2-NR bc (=O) R a; At each each R occurred at this that this occurs aand R bcan independently represent hydrogen, (C 1-C 4) alkyl, (C 3-C 7) cycloalkyl, the monocycle of aryl or 3-10 unit or dicyclo heterocycle its contain at least one and be selected from heteroatoms among nitrogen, sulphur and oxygen.In some example, R 8and R 9any one independently can represent hydrogen.
In some example, at each R that this occurs band R ccan independently represent hydrogen or (C 1-C 4) alkyl, or described R band R cit contains at least one and is selected from heteroatoms among nitrogen, sulphur and oxygen optionally can to form 3-8 unit heterocycle together with the atom N that they combine.
In some other example ,-NR br crefer to these optionally with 1 to 3 substituting groups, can be selected from (C 1-C 4) alkyl, OH, (C 1-C 4alkyl)-OH and-O-(C 1-C 4) alkyl.
On the one hand, the invention provides a compound, it is selected from example 1 to 218, as described herein.
On the other hand, the invention provides a pharmaceutical composition, it comprises at least one compound described herein and pharmaceutically acceptable carrier or thinner.
Again on the one hand, the invention provides a kind of method that treatment or prevention mammalian virus infect, the method comprises at least one compound described herein is delivered medicine to Mammals to treat effective dose.In some example, the infection of described virus infection HIV virus.In some other example, described virus infection is HBV virus infection.Also have in some examples, described virus infection is HCV virus infection.Also have in some examples, described virus infection is that influenza A infects, and severe acute respiratory syndrome coronavirus infects or vaccinia virus infection.
Again on the one hand, the invention provides a kind of HIV viral infectious process for the treatment of or prevention in Mammals, the method comprises at least one compound described herein is delivered medicine to Mammals to treat effective dose. shorteningsaCN acetonitrile EA ethyl acetate DMFN, dinethylformamide PE sherwood oil DCM methylene dichloride THF tetrahydrofuran (THF) HOBt1-hydroxy benzo triazole EDCI1-ethyl-3-(3-dimethylamino-propyl) carbimide HBTU2-(1H-benzotriazole-1-base)-1,1,3,3-tetramethyl-urea hexafluorophosphate HATU2-(7-azo benzotriazole)-N, N, N ', two (2-oxo-3-oxazolidinyl) secondary phosphoryl chloride BOP benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate TEA triethylamine DIPEA diisopropyl ethyl amine DMAPN of N '-tetramethyl-urea hexafluorophosphate PyBOP1H-benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus hexafluorophosphate BOPCl, N-dimethyl-4-amido pyridine PCC Pyridinium chlorochromate on silica gel PDC pyridinium dichromate NBSN-bromo-succinimide NCSN-chlorosuccinimide NISN-N-iodosuccinimide 9-BBN9-boron dicyclo (3,3,1)-nonane TsOH tosic acid TFA triethylamine CDIN, N '-carbonyl dimidazoles TLC thin layer plate chromatography TsOH p-methyl benzenesulfonic acid NMPN-methyl-2-pyrrolidone Boc tertbutyloxycarbonyl DME glycol dimethyl ether preparation method
It is below the general synthetic schemes preparing the compounds of this invention.These schemes are descriptive, do not represent that the method that restriction those skilled in the art uses other possible synthesizes compound disclosed herein.Various method is all obvious for a person skilled in the art.In addition, the multiple steps in synthesis can be carried out according to other order or order thus obtain required compound.Be incorporated to all by way of reference herein at these all documents quoted.Such as, reaction formula is below descriptive, does not limit some raw material used herein and example.
Scheme 1-10 describes the different methods of these intermediates of synthesis, and these methods can in the preparation of compound of the present invention.Those skilled in the art can be realized and similar result described below contriver by the various modifications of these methods.
Intermediate indole acid V ' can be prepared shown in scheme 1.Scheme 1 step 1
The nitro-compound I ' replaced as in methyl alcohol, ethanol, with Ranney nickel and hydrazine hydrate reaction, obtains the aniline compound II ' replaced at alcoholic solvent.Step 2
The aniline compound II ' replaced, under the existence of sour example hydrochloric acid etc., reacts with Sodium Nitrite, then under the existence of sour example hydrochloric acid etc., reacts with tin protochloride, obtains the phenylhydrazine compound III ' replaced.Step 3
Phenylhydrazine compound III ' and 4-oxopentanoie acid ester, at alkali, as reacted under the existence of sodium bicarbonate etc., and then reacting, obtaining the benzazolyl compounds IV ' replaced under Lewis acid is as the existence such as zinc chloride, acetic acid.Step 4
Under the effect of alkali as sodium hydride, salt of wormwood etc., intermediate compound IV ' elder generation and halogenide, as the reaction such as methyl iodide, monobromethane, then add another kind of alkali, as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium hydroxide etc., obtain indolic acid V '.
Intermediate indole acid compound VIII ' can by being prepared as shown in scheme 2.Scheme 2 step 1
II ' and keto ester compound, as ethyl 4-oxopentanoie acid methyl esters, at alkali, as reacted under the existence of sodium bicarbonate etc., and then in Lewis acid as the reaction such as zinc chloride, acetic acid, obtain benzazolyl compounds VI '.Step 2
Under the existence of alkali as sodium hydride, sodium hydroxide etc., benzazolyl compounds VI ' and halogen acetonyl ester, as reactions such as ethyl bromoacetate, then use alkali, as reactions such as lithium hydroxide, sodium hydroxide, potassium hydroxide, obtain intermediate VII '.Step 3
If R in VI ' 2group is halogen atom, as Cl or Br etc., and compound VI ' react with reductive agent, as Lithium Aluminium Hydride, by palladium carbon catalytic hydrogenation, just halogen atom can be reduced to hydrogen atom; R 4such as ester also can be reduced into R 4' such as alcohol, finally obtain mono-substituted indoles VIII '.
The preparation of intermediate indole acid compound XIV ' is as shown in Scheme 3: scheme 3 step 1
At aprotic solvent as in tetrahydrofuran (THF), ether or dioxane, aldehyde X ' and Grignard reagent, as methyl-magnesium-bromide, ethyl phosphonium bromide reactive magnesium, obtain alcohol XI '.Step 2
Alcohol XI ', in acetone, DCM or DMF, with oxygenant, as PCC, PDC, Jones reagent react, obtains ketone intermediate X II '.Step 3
Ketone intermediate X II ' reacts with hydrazine hydrate in the solvent of such as DME, THF or ethylene dichloride, obtains indazole intermediate XIII '.Step 4
Under the existence of alkali as sodium hydride, sodium hydroxide etc., indazole compound XIII ' and halogen acetonyl ester, as reactions such as ethyl bromoacetate, then use alkali, as reactions such as lithium hydroxide, sodium hydroxide or potassium hydroxide, obtain intermediate X IV '.
The preparation of intermediate indazole acid compound XIV ' is as shown in Scheme 4: scheme 4 step 1
Aldehyde X ' reacts with hydrazine hydrate in such as DME, THF or ethylene dichloride equal solvent, obtains indazole intermediate XV '.Step 2
In DMF or THF, indazole intermediate XV ' and halide reagent, as reactions such as NBS, NCS, iodine or bromines, obtain halogenide XVI '.Step 3
Under the existence of alkali as DIPEA, TEA etc., halogenide XVI ' and Acetyl Chloride 98Min. or acetic anhydride, obtain intermediate X VII '.Step 4
In such as THF, DMF or DME equal solvent, intermediate X VII ' and vinyl coupling reagent, as reactions such as boric acid, organotin reagent, Grignard reagent or organic zinc reagents, under the existence of the catalyzer such as such as palladium reagent, obtain coupled product XVIII '.Step 5
In such as THF, DME equal solvent, intermediate X VIII ' and borane reagent such as borine or 9-BBN react, and then under the existence of alkali as sodium hydroxide or potassium hydroxide, react, obtain product X IX ' with hydrogen peroxide.Step 6
Under the effect of alkali as sodium hydride, sodium hydroxide etc., indazole compound XIX ' and halogen acetonyl ester, as reactions such as ethyl bromoacetate, then use alkali, as reactions such as lithium hydroxide, sodium hydroxide or potassium hydroxide, obtain intermediate X X '.
The preparation of intermediate azaindole acid XXV ' is as shown in scheme 5: scheme 5 step 1
At aprotic solvent as in THF, ether or dioxane, starting raw material XXI ' and highly basic, as n-Butyl Lithium, s-butyl lithium, tert-butyl lithium reaction, then add another reactant, as DMF, DMA or acetic acid ethyl reaction, obtain azaindole intermediate XXII '.Step 2
In DMF or THF equal solvent, azaindole intermediate XXII ' and halide reagent, as reactions such as NBS, NCS, NIS, iodine or bromines, obtain intermediate X XIII '.Step 3
In THF, DMF or DME equal solvent, intermediate X XIII ' and coupling reagent, as reactions such as boric acid, organotin reagent, Grignard reagent or organic zinc reagents, at catalyzer as under the existence of palladium reagent, obtain coupled product XXIV '.Step 4
Under the existence of the alkali such as sodium hydride, sodium hydroxide, indazole compound XXIV ' and halogen acetonyl ester, as reactions such as ethyl bromoacetate, then use alkali, as reactions such as lithium hydroxide, sodium hydroxide or potassium hydroxide, obtain intermediate X XV '.
The preparation of intermediate azaindole acid XXIX ' is as shown in scheme 6: scheme 6 step 1
Under the existence of alkali as sodium hydride, sodium hydroxide etc., azaindole XXII ' and halogenide, as reactions such as monobromethane, methyl iodide or bromine isopropyl alkane, obtain intermediate X XVI '.Step 2
Under the existence of alkali as TEA, DIPEA etc., intermediate X XII ' and oxalyl chloride react, and then with alcohol, as the quencher such as methyl alcohol or ethanol, obtain intermediate X XVII '.Step 3
Intermediate X XII ' under catalyzer is as the existence of palladium carbon with H-H reaction, obtain intermediate X XVIII '.Step 4
Intermediate X XVIII ' basic hydrolysis, as lithium hydroxide, sodium hydroxide, potassium hydroxide etc., obtains azaindole acid XXIX '.
The preparation of intermediate benzoglyoxaline acid XXV ' is as shown in scheme 7: scheme 7 step 1
Oil of mirbane or amino benzenes compounds XXX ' as the vitriol oil and concentrated nitric acid process, obtain two nitro intermediate XXXI ' with nitration mixture.Step 2
The dinitro compound XXXI ' replaced as in methyl alcohol, ethanol, with Ranney nickel and hydrazine or hydrogen and the reaction of palladium carbon, obtains the aniline compound XXXII ' replaced at alcoholic solvent.Step 3
Aniline compound XXXII ' and carboxylic acid, as reactions such as formic acid, acetic acid or trifluoroacetic acids, obtain benzoglyoxaline intermediate X XXIII '.Step 4
At alkali as under the existence of the alkali such as sodium hydride, sodium hydroxide, benzimidazole compound XXXIII ' and halogen acetonyl ester, as reactions such as ethyl bromoacetate, then use alkali, as process such as lithium hydroxide, sodium hydroxide or potassium hydroxide, obtains benzoglyoxaline acid XXXIV '.
The preparation of intermediate benzoglyoxaline acid compound XXXVIII ' is as shown in scheme 8: scheme 8 step 1
In THF, DME or DMF equal solvent, aniline compound XXXII ' and the reaction such as CDI or triphosgene, obtain benzoglyoxaline intermediate X XXV '.Step 2
By benzoglyoxaline intermediate X XXV ' and chlorination reagent, as reactions such as phosphorus oxychloride, phosphorus pentachloride or thionyl chlorides, obtain intermediate X XXVI '.Step 3
At alkali as under the existence of sodium hydride, sodium hydroxide, benzimidazole compound XXXVI ' and halogen acetonyl ester, as reactions such as ethyl bromoacetate, and then with diluted acid, as the process such as dilute hydrochloric acid, dilute sulphuric acid, obtain benzoglyoxaline acid XXXVII '.Step 4
At alkali as under the existence of the alkali such as sodium hydride, sodium hydroxide, benzoglyoxaline acid XXXVII ' and halogenide, as reactions such as monobromethane, methyl iodide or bromine isopropyl alkane, obtain intermediate X XXVIII '.
The preparation of intermediate amine XLII ' is as shown in scheme 9: scheme 9 step 1
Take alcohol as solvent, primary amine XXXIX ' and aldehyde as the reaction such as paraformaldehyde, acetaldehyde, and then with reductive agent as NaBH 4, NaBH 3cNorNaBH 3oAc process, obtains secondary amine XL '.Step 2
With DCM, DMF, THF etc. for solvent, amine XL ' at condensing agent if HOBt/EDCI, HATU, HBTU, PyBOP, BOPCl or bop reagent and alkali are as under the existence of TEA, DIPEA or DMAP etc., react with N-Boc-Phenylalanine analogue, obtain aminated compounds XLI '.Step 3
Intermediate X LI ' is joined in hydrochloric acid soln, the methanol solution of example hydrochloric acid, the tetrahydrofuran solution etc. of hydrochloric acid, obtain amine midbody compound XLII '.
The preparation of compounds X LIV ' is as shown in scheme 10: scheme 10 step 1
With DCM, DMF or THF etc. for solvent, acid XLIII ' at coupling agent if HOBT/EDCI, HATU, HBTU, PyBOP, BOPCl or bop reagent and alkali are as under the existence of TEA, DIPEA or DMAP etc., react with amine XLII ', obtain amide compound XLIV '.
In addition, other can be prepared by the knowledge of persons skilled in the art as the compound of general formula I.Example in addition provides other preparation method of compound in the present invention.
Present the present invention will further describe enforcement example, and this is preferred embodiment of the present invention.These examples just describe instead of method are limited within this.Be appreciated that also have other embodiment also drop on as appended claim in the spirit and scope of the present invention that define. pharmaceutical composition
The present invention also provides a kind of pharmaceutical composition, comprises at least one compound described herein or pharmaceutically acceptable salt or solvate, and pharmaceutically acceptable carrier.
Here phrase " pharmaceutically acceptable carrier " used refers to material, composition or medium that pharmacy accepts, as liquid or solid filler, thinner, auxiliary material, solvent or packaged material, comprise and carry or transport main body pharmaceutical agents certain part to another organ or health from certain part of an organ or health.Each carrier must be " can accept ", can other compositions in compatible preparation and not damaging patient.Some examples that can be used as pharmaceutically acceptable carrier comprise: sugar, as lactose, dextrose plus saccharose sugar; Starch, as wheat starch and yam starch; Cellulose and its derivates, as Xylo-Mucine, ethyl cellulose, cellulose acetate, powdery two tragacanth gum, Fructus Hordei Germinatus, gelatin, talcum powder; Auxiliary material, as cocoa butter and suppository wax; Oil, as peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil; Glycol, as butyleneglycol; Polyvalent alcohol, as glycerine, sorbyl alcohol, N.F,USP MANNITOL and polyoxyethylene glycol; Ester, as ethyl oleate and Laurate ethyl; Agar; Buffer reagent, as magnesium hydroxide and aluminium hydroxide; Lalgine; Apirogen water; Physiological saline; Ringer's solution; Ethanol; Phosphate buffered saline buffer, and other nontoxic be applied in pharmaceutical preparation can compatible material.
As described above, some example of this drug substance can be presented as the form of pharmaceutically acceptable salt.In this respect, term in the present invention " salt that pharmacy accepts ", refer to the relative nontoxic of the compounds of this invention, the organic acid of compound and inorganic acid addition salt.These salts in the present invention can be in the end isolation and purification compound time on-the-spot to produce, or in the present invention in single reaction by the suitable organic or inorganic acid-respons of the free alkali form of the compound of purifying, thus be separated and form salt.The example of salt comprises hydrobromate, hydrochloride, vitriol, hydrosulfate, phosphoric acid salt, nitrate, acetate, valerate, oleate, palmitate, stearate, lauroleate, benzoate, lactic acid salt, tosilate, Citrate trianion, maleate, fumarate, succinate, tartrate, naphtholate, mesylate, gluceptate, Lactobionate and dodecane sulfonate etc.(example see Bergeetal., (1977) " PharmaceuticalSalts ", J.Pharm.Sci.66:1-19.)
The pharmacy acceptable salt of host compound comprises traditional non-toxic salt or the quaternary ammonium salt of described compound, as sour from nontoxic organic or inorganic.Such as, the salt of this conventional non-toxic comprises the salt derived from mineral acid, example hydrochloric acid salt, hydrobromate, vitriol, sulfamate, phosphoric acid salt, nitrate etc.; And from salt prepared by organic acid, as acetate, butyrates, succinate, glycol hydrochlorate, stearate, lactic acid salt, malate, tartrate, Citrate trianion, ascorbate salt, palmitate, maleate, hydroxymaleic acid salt, phenylacetate, glutaminate, benzoate, salicylate, sulfanilate, Aspirin salt, fumarate, tosylate, methane sulfonates, ethane disulfonic acid hydrogen salt, oxalate, isethionate etc.
In other cases, compound of the present invention may comprise one or more acidic functionalities, therefore can be formed and pharmacy acceptable salt with pharmaceutically acceptable alkali.Term " pharmacy acceptable salt " refers to the inorganic of the relative nontoxic of the compounds of this invention and organic base addition salts in this case.These salt in the present invention can be equally in the end isolation and purification compound time on-the-spot to produce, or in single reaction, in the present invention, use the free acid form of the compound of purifying and suitable organic or inorganic alkali to be formed, as the oxyhydroxide of metallic cation, carbonate or supercarbonate that pharmacy accepts, or organic primary amine, secondary amine or tertiary amine that ammoniacal liquor, pharmacy accept.The example of an alkali metal salt or alkaline earth salt comprises lithium salts, sodium salt, sylvite, calcium salt, magnesium salts, aluminium salt etc.Example for the formation of the organic amine of base addition salt comprises ethamine, diethylamine, quadrol, thanomin, diethanolamine, piperazine etc.((example is see Bergeetal., supra.)
Wetting agent, emulsifying agent and lubricant, as the multipolymer of sodium lauryl sulphate, Magnesium Stearate, polyethylene oxide and polybutylene oxide thing, and tinting material, releasing agent, coating-forming agent, sweeting agent, stir taste agent and flavouring agent, sanitas and antioxidant also may reside among described composition.
Preparation of the present invention comprises the preparation that those are applicable to oral cavity, nasal cavity, external application (comprise oral cavity and sublingual), rectum, vagina and/or intravenously administrable.This formula can provide with unit dosage form easily, and can by pharmaceutically any known method preparation.Can be combined with a solid support material amount of the active ingredient producing single dose, can because of carry out treating host, the difference of specific administration pattern and different.The amount of the effective ingredient producing single dose that can combine with solid support material is generally the dosage that this compound produces result for the treatment of.In general, in the scope of 100%, the active ingredient of this dose is between about 1%-about between 99%, and preferably from about 5%-about 70%, optimum is about 10%-about 30%.
The method preparing these preparations or composition in the present invention comprises compound of the present invention and carrier and optionally, the step that one or more assistant agent composition is associated.In the ordinary course of things, undertaken associating uniformly with closely, then, if necessary again by product shaping by compound of the present invention and liquid vehicle or solid smalls carrier or both are had both at the same time.
Applicable oral preparation of the present invention can have following form, as capsule, cachet, pill, tablet, lozenge (normally sucrose and Acacia or tragakanta, have certain taste), pulvis, granule, or as a solution or be suspended in water or non-aqueous liquid, or as water-in-oil or oil-in-water emulsion liquid, or as elixir or syrup, or granularly (use such as gelatin and glycerine, the inert base of sucrose and Acacia) and/or collutory and so on, eachly comprise the predetermined dose of the compounds of this invention as active ingredient.The compounds of this invention also can be used as bolus, paste or plaster.
At the oral solid formulation (capsule, tablet, pill, drageeing, powder, particle etc.) of invention, its effective ingredient mixes with one or more pharmaceutically acceptable carrier, as Trisodium Citrate or secondary calcium phosphate, and/or any following content: filler or weighting agent, as starch, lactose, sucrose, glucose, N.F,USP MANNITOL; And/or silicic acid, tackiness agent such as, Xylo-Mucine, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or Sudan Gum-arabic, wetting Agent for Printing Inks, as glycerine; Disintegrating agent, as agar, calcium carbonate, potato or tapioca (flour), alginic acid, some silicate, sodium carbonate, Vivastar P 5000; Separate retardant, as paraffin, absorption enhancer, as quarternary ammonium salt compound; Wetting agent, as hexadecanol, Zerol and polyethylene oxide-polybutylene oxide composition copolymer; Absorption agent, as kaolin clay, wilkinite, lubricant, as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and composition thereof; And tinting material.When capsule, tablet, pill, pharmaceutical composition also may comprise buffer reagent.Similar solids versions composition can as weighting agent in soft filling and hard filled capsules, uses as lactose or milk carbohydrate, and the weighting material of High molecular weight polyethylene ethylene glycol and so on.
Tablet can be prepared, optionally with one or more auxiliary ingredients by compressing tablet or pressing mold.The tablet of compressing tablet can be prepared with binding agent (as gelatin or HBMC), lubricant, inert diluent, sanitas, disintegrating agent (as Vivastar P 5000 or croscarmellose sodium), surfactivity or dispersion agent.The tablet of pressing mold can by the mixture of the powdered compounds with inert liq diluent humidification, and the pressing mold on a suitable machine forms.
Other solid preparations of tablet and pharmaceutical composition of the present invention, as drageeing, capsule, pill, granule, optionally can use dressing and shell preparation or moulding, as enteric coating, and other dressings known in field of pharmaceutical preparations.Also may provide slow or the preparation of the active ingredient of Co ntrolled release, such as, use HBMC to provide required release profiles in different situations, other polymeric matrixs, liposome and/or microballoon.They can be sterilized, and such as, by a filter bacteria gear strainer, or anti-microbial agents joins in aseptic solid composite, and it can be dissolved in sterilized water before use, or in other sterile injectable medium.These compositions also optionally can contain opacifying agent, can be only or preferential at some part GI release of active agent in a delayed fashion.Embed the operable material of composition and comprise polymkeric substance and wax.Active substance can also be the form of the micro-encapsulating with one or more above-mentioned auxiliary materials.
Pharmaceutically acceptable emulsion is comprised, microemulsion, solution, suspension to compound oral liquid dosage forms of the present invention, syrup and elixir.Except activeconstituents, liquid dosage form can containing pharmaceutically conventional inert diluent, such as water or other solvents, solvating agent and emulsifying agent, as ethanol, isopropylcarbinol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, methyltrimethylene glycol, 1,3-butyleneglycol, oil (particularly Oleum Gossypii semen, peanut oil, Fructus Maydis oil, sweet oil, Viscotrol C, sesame oil), glycerine, tetrahydrofuran (THF) alcohol, polyoxyethylene glycol and fatty acid ester sorbyl alcohol and composition thereof.In addition, cyclodextrin, as hydroxyl butyl-beta-cyclodextrin, also can be used for dissolved compound.
Except inert diluent, oral composition can also comprise as wetting agent, emulsifying agent and suspension agent, and sweeting agent stirs taste agent, pigment, the auxiliary material such as flavouring agent and sanitas.
Except active compound, suspension can contain suspension agent, such as Unimac 5680 ethyl ester, polyoxyethylene sorbitol and sorbitol ester, Microcrystalline Cellulose, aluminum metal oxyhydroxide, wilkinite, agar and tragakanta and composition thereof.
The present invention treats rectum or intravaginal drug composite preparation can be suppository, it can be mixed with one or more suitable nonirritant excipient or carrier by one or more compound of the present invention, comprise, such as, theobroma oil, polyoxyethylene glycol, one suppository wax or Whitfield's ointment, it is at room temperature solid, but is liquid under body temperature, therefore, rectum or vaginal canal and release active pharmaceutical ingredient of the present invention will be melted in.
Be suitable for the preparation of the present invention for the treatment of vagina class disease, also comprise pessary, cotton balls, paste, gel, paste, foam or spray agent.
Pulvis is comprised, sprays, ointment, ointment, face cream, emulsion, gel, solution for the local of the compounds of this invention or the formulation of transdermal administration, plaster and inhalation.At the carrier that active compound can aseptically accept with pharmacy, and any sanitas that may need or buffer reagent mixing.
Except the active ingredient beyond the region of objective existence in the present invention, ointment, ointment, auxiliary material can be comprised as animal and plant fat, oil, wax in ointment and gel, paraffin, starch, tragakanta, derivatived cellulose, polyoxyethylene glycol, organosilicon, organobentonite active compound, silicic acid, talcum powder, zinc oxide, or their mixture.
Except the compound in the present invention, the auxiliary material that powder and spray can comprise as lactose, talcum powder, silicic acid, aluminium hydroxide, calcium-silicate and Silon, or the mixture of these materials.Spray additionally can contain conventional propelling agent, if fluorochlorohydrocarbon and volatility are without the hydrocarbon polymer replaced, as butane and butylene.
Transdermal patch has extra benefit to compound in the present invention to the controlled delivery in body.This formulation is formed by being dissolved or dispersed in buffer medium by drug substance.Absorption enhancer also can be used for increasing drug substance in the present invention to the amount of penetrating of skin.The speed of this amount of penetrating can be controlled, by providing rate controlling membranes or being dispersed in polymeric matrix or gel by compound.
Ophthalmic preparation, spongaion, powder, solution etc., also belongs within scope of the present invention.
The pharmaceutical composition of the present invention being applicable to parenterai administration comprises one or more compound of the present invention and one or more pharmaceutically acceptable sterile physiological aqueous solution or non-aqueous solution, dispersion agent, suspension agent or emulsion, or sterilized powder, they can be recombinated with sterile injectable solution or dispersion agent before use, and it can contain antioxidant, buffer reagent, fungistat, can make the solute that the blood of preparation and target receiver is isotonic, or suspension agent or thickening material.
In some cases, in order to extend drug effect, preferably delay medicine from absorption that is subcutaneous or intramuscular injection.This can come by using the suspension liquid of the low crystal of water solubility or amorphous substance.Its dissolution rate is then depended on to the absorption rate of medicine, depends on grain-size and crystal formation possibly conversely simultaneously.In addition, the delay of the pharmaceutical dosage form of parenterai administration absorbs by medicine dissolution or be suspended in oily medium being realized.Wherein one of storage type injection strategy comprises use polyethylene oxide-polybutylene oxide composition copolymer, and the medium wherein used is fluid in room temperature, solidifies when body temperature.
By by host compound at Biodegradable polymeric, make storage type injection type as formed microcapsule in poly-glue ester-polyglycolic acid glue ester.According to the ratio of medicine and polymkeric substance, and the special property of the polymkeric substance used, can Drug controlled release speed.The example of other biological degradation polymer comprises POE and poly acid anhydrides.Storage type injection type can also by being embedded in liposome or microemulsion and preparing by pharmaceutical pack, this and tissue are compatible.
When compound of the present invention carries out administration as medicament to human and animal, they can directly administration or with pharmaceutical composition administration, pharmaceutical composition contains, such as, and the activeconstituents of 0.1%-99.5% (more preferably 0.5%-90%) and pharmaceutically acceptable carrier.
Compound in the present invention and pharmaceutical composition can be applied to combination treatment, namely compound and pharmaceutical composition can with one or more medicine needed for other or medical procedure administration simultaneously, or before it or afterwards.The particular combination of the therapy (treatment or program) used in treatment plan will consider the compatibility of required therapy and/or program and the result for the treatment of needing to reach.The therapy of preferred use can equal extent ground realize required for effect (such as, compound of the present invention can with the administration simultaneously of another HCV-Ab IgG material), or they can reach different effects (as controlled any untoward reaction).
Compound of the present invention by intravenous injection, intramuscular injection, abdominal injection, subcutaneous injection, external application, oral, or other acceptable ways carry out disease therapy.These compounds can Mammals (such as, the mankind, domestic animal and domestic animal), birds, lizard, and anyly in the other biological of these compounds compatible, can be used for the treatment of arthritic states.
Present invention also offers drug packaging or external member, comprise one or more containers, one or more compositions of the pharmaceutical composition in the present invention are housed.With optional the associating thing and can have specification sheets of this kind of container, meet the form of government organs' defined of supervision medicine or the production of biological products, use or sale, described specification sheets has reacted described mechanism to the approval for the production of mankind's administration, use or sale. similar description
Representational example is intended to help to set forth the present invention below, instead of has a mind to or be construed as limiting the scope of the invention.In fact, according to the full content of presents, comprise following Examples, and the scientific literature quoted herein and patent, except occurring in this article except those and describing, can be all obvious to amendment multiple in the present invention and many further examples to those skilled in the art.It is also understood that these reference quoted all are incorporated by reference herein, contribute to the level that this area is described.Example below contains important side information, example and guidance, can adapt to amendment according to embodiment various in the present invention and analogue. examples Example 1
(S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(1-ethyl-2,4,7-trimethylammonium-1H-indol-3-yl) acetamido)-N-methyl-3-Phenylpropionamide the preparation of example 1A.2,5-xylidine
At 0 DEG C, Ranney nickel (1.0mL, suspension liquid) be added to 2,5-dimethyl nitrobenzene (5.0g, 33.1mmol, 1.0eq) in methyl alcohol (50mL) solution, then hydrazine hydrate (2.0mL, 53.1mmol, 1.8eq, 85% aqueous solution) dropwise add, at reaction solution 0 DEG C, stirring two is little complete up to TLC detection display raw material consumption.Solids removed by filtration, be dissolved into after filtrate is concentrated also with water and salt washing in ethyl acetate, anhydrous sodium sulfate drying, solvent evaporated, obtains product 2,5-xylidine (3.81g, 31.5mmol, productive rate: 95%), LC/MS:m/zM ++ 1=122.The preparation of example 1B.1-(2,5-3,5-dimethylphenyl) hydrazine
2,5-xylidine (20.0g, 165mmol, 1.0eq) is dissolved in 50%HCl (180mL) solution, and ice-water bath is chilled to 0 DEG C.When temperature keeps below 5 DEG C, NaNO 2(11.4g, 165mmol, 1.0eq, 88mL) aqueous solution dropwise adds, and adding rear solution is glassy yellow transparent liquid, continues stirring and in the time of 40 minutes, add SnCl in 0 DEG C after one hour in same temperature 2(46.8g, 248mmol, 1.5eq) concentrated hydrochloric acid solution (120mL).Reaction solution is warming up to stirred overnight at room temperature and separates out to solid, filter, filter residue washing (150mL), filtrate adds NaOH at 0 DEG C and regulates PH to alkalescence, and ethyl acetate (200mL) extracts, merge organic layer, concentrated, obtain crude product (14g, purity: 90%, productive rate: 64%), LC/MS:m/zM ++ 1=137.The preparation of example 1C.2-(2,4,7-trimethylammonium-1H-indol-3-yl) ethyl acetate
Saturated NaHCO 3(11mL) solution adds 1-(2 with vigorous stirring, 5-3,5-dimethylphenyl) hydrazine (2.0g, 11.6mmol, in dichloromethane solution 1.0eq) (11mL), then ethyl levulinate (1.68g, 11.6mmol, 1.0eq) be added to above-mentioned solution and stirring at room temperature 3 hours, TLC (PE: EA=5: 1) display reaction terminates.Then add water, and with DCM (10mL) extraction, wash with water repeatedly, the anhydrous MgSO of organic extraction 4drying, concentrated give light yellow oil.The ZnCl of this intermediate and fresh dried 2be blended in 140 DEG C of dry combustion methods to spend the night, water and methyl alcohol add cancellation reaction, and mixture is through dichloromethane extraction, after normal process steps, silica gel column chromatography (PE: EA=15: 1) purifying crude, product (560mg, productive rate: 21.5%), LC/MS:m/zM ++ 1=246.The preparation of example 1D.2-(1-ethyl 2,4,7-trimethylammonium-1H-indol-3-yl) acetic acid
At room temperature by NaH (122mg, 3.05mmol, 2.5eq) be added to 2-(2,4,7-trimethylammonium-1H-indol-3-yl) ethyl acetate (300mg, 1.22mmol, in DMF (3mL) solution 1.0eq), monobromethane (0.18mL, 2.44mmol after 10 minutes, 2.0eq) add in this reaction solution, stirred at ambient temperature 30 minutes is until raw material reaction is complete.At 0 DEG C, add water and NaOH (2M, the 3mL) aqueous solution subsequently, and stir 4 hours at 50 DEG C, then HCl adds adjustment PH=5.Have solid to separate out, namely solid collected by filtration obtains product (210mg, productive rate: 70%) .LC/MS:m/zM ++ 1=246.The preparation of example 1E.N-methyl benzo [d] [1,3] dioxane-5-amine
At 0 DEG C and N 2under protection in the time of 20 minutes by n-Butyl Lithium (7.65mL; 15.3mmol) slowly add benzo [d] [1; 3] dioxane-5-amine (2.1g; 15.3mmol; in tetrahydrofuran solution (17mL) 1.0eq); MeI (0.95mL after 10 minutes; 15.3mmol; 1.0eq) slowly add in the time of 20 minutes at 0 DEG C; TLC (PE: EA=6: 1) detects to reacting end; the cancellation that adds water is reacted, vacuum removing organic solvent.Ethyl acetate (2x30mL) extracts, and salt washing (3x40mL), purification by silica gel column chromatography, obtains product (950mg, productive rate: 41.3%), LC/MS:m/zM ++ 1=152.The preparation of example 1F. (S)-(benzo [d] [1,3] dioxane-5-base (methylamino)-1-oxo-3-phenylpropyl alcohol-2-base) amidocarbonic acid tert-butyl ester
To (S)-2-(tertiary butyl manthanoate)-3-phenylalanine (2.17g be dissolved in DMF (20mL), 8.18mmol, 1.3eq), N-methyl benzo [d] [1, 3] dioxane-5-amido (950mg, 6.29mmol, EDCI (1.8g is added 1.0eq), 9.43mmol, 1.5eq), HOBt (1.7g, 12.6mmol, 2.0eq) with DIPEA (1.62g, 12.6mmol, 2.0eq), the mixture room temperature for overnight obtained, EA extraction after washing, water lithium chloride solution washing (3x40mL), organic layer concentrates, concentrated, silica column purification is carried out with PE and EA, obtain product (2.2g, productive rate: 88%), LC/MS:m/zM ++ 1=399.The preparation of example 1G. (S)-N-(benzo [d] [1,3] dioxane-5-base)-N-methyl-3-hydrocinnamamide-2-amido hydrochloride
(S)-(benzo [d] [1,3] dioxane-5-base (methylamino)-1-oxo-3-phenylpropyl alcohol-2-base t-butyl formate (2.2g, 5.52mmol, 1.0eq) be dissolved in MeOH/HCl (1M, 6mL) in solution, stirred at ambient temperature one hour is until TLC indicates raw material reaction complete, and removal of solvent under reduced pressure obtains crude product (2.2g, productive rate: 98%), LC/MS:m/zM ++ 1=299.The preparation of example 1H. (S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(1-ethyl-2,4,7-trimethylammonium-1H-indol-3-yl) acetamido)-N-methyl-3-hydrocinnamamide
To (S)-N-(benzo [d] [1,3] dioxane-5-base)-N-methyl-3-phenylpropyl alcohol acyl 2-amido hydrochloride (73mg, 0.245mmol, 2-(1-ethyl-2 is added in DCM (1.5mL) solution 1.2eq), 4,7-trimethylammonium-1H-indol-3-yl) acetic acid (50mg, 0.2mmol, 1.0eq), EDCI (97mg, 0.5mmol, 2.5eq), HOBt (55mg, 0.41mg, 2.0eq) with DMAP (5mg), room temperature for overnight.Reaction solution use water, NaHCO 3wash respectively with the HCl aqueous solution, organic layer in vacuo is concentrated, mixture first alcohol and water is prepared HPLC purifying, obtain product (40mg, productive rate: 50%), LC/MS:m/zM ++ 1=526, HPLC retention time=3.43min (10-90% acetonitrile and the aqueous solution, containing 0.1%TFA).
1HNMR(400MHz，DMSO)δ7.88(d，J＝8.1Hz，1H)，7.21-7.12(m，3H)，6.92(d，J＝8.3Hz，1H)，6.86-6.81(m，2H)，6.79(s，1H)，6.72(d，J＝8.2Hz，1H)，6.62(d，J＝7.3Hz，1H)，6.51(d，J＝7.3Hz，1H)，6.06(d，J＝4.5Hz，2H)，4.46(s，1H)，4.25(q，J＝7.2Hz，2H)，3.59(s，2H)，3.08(s，3H)，2.84(dd，J＝13.4，4.5Hz，1H)，2.70-2.57(m，4H)，2.38(s，3H)，2.17(s，3H)，1.17(t，J＝7.1Hz，3H).
Compound 2-70 uses the preparation method similar to example 1, with corresponding acid and amine for raw material is obtained.Example 2 to 70
(example 2): 1hNMR (400MHz, DMSO) δ 8.46 (d, J=7.9Hz, 1H), 8.04 (s, 1H), 7.48 (d, J=8.9Hz, 1H), 7.26 (ddd, J=18.0, 14.8, 7.1Hz, 7H), 7.18-7.08 (m, 3H), 6.99 (t, J=7.7Hz, 1H), 6.88 (t, J=7.5Hz, 3H), 6.81 (d, J=8.7Hz, 1H), 4.26 (s, 1H), 4.07 (t, J=7.4Hz, 2H), 3.83 (s, 3H), 3.44 (d, J=20.4Hz, 2H), 3.10 (s, 3H), 2.94-2.83 (m, 1H), 2.75-2.60 (m, 3H), 2.23 (s, 3H), 1.98-1.85 (m, 2H).
(example 3): 1hNMR (400MHz, DMSO) δ 8.49 (d, J=7.7Hz, 1H), 8.04 (s, 1H), 7.48 (d, J=7.8Hz, 1H), 7.32 (dd, J=10.6, 8.1Hz, 2H), 7.24-7.06 (m, 3H), 7.01 (t, J=7.3Hz, 1H), 6.96-6.55 (m, 4H), 4.25 (dd, J=13.0, 9.0Hz, 1H), 4.10 (q, J=7.0Hz, 2H), 3.84 (s, 3H), 3.62-3.39 (m, 2H), 3.11 (s, 3H), 2.88 (dd, J=13.4, 4.7Hz, 1H), 2.72 (dd, J=13.5, 9.5Hz, 1H), 2.27 (s, 3H), 1.18 (t, J=7.1Hz, 3H).
(example 4): 1hNMR (400MHz, DMSO) δ 8.50 (d, J=7.6Hz, 1H), 8.05 (s, 1H), 7.49 (d, J=9.0Hz, 1H), 7.36 (d, J=7.7Hz, 1H), 7.34-7.22 (m, 4H), 7.21-7.08 (m, 3H), 6.94 (dt, J=13.6, 8.8Hz, 6H), 6.82 (d, J=8.8Hz, 1H), 5.35 (s, 2H), 4.29 (s, 1H), 3.84 (s, 3H), 3.58-3.43 (m, 2H), 3.11 (s, 3H), 2.95-2.85 (m, 1H), 2.71 (dd, J=13.5, 9.7Hz, 1H), 2.23 (s, 3H).
(example 5): 1hNMR (400MHz, DMSO) δ 8.51 (dd, J=12.0, 6.3Hz, 2H), 8.04 (s, 1H), 7.67 (dd, J=9.4, 7.7Hz, 1H), 7.49 (d, J=7.0Hz, 1H), 7.38-7.23 (m, 3H), 7.23-7.03 (m, 3H), 6.94 (dt, J=29.9, 6.1Hz, 4H), 6.79 (dd, J=21.5, 8.4Hz, 2H), 5.41 (s, 2H), 4.28 (d, J=4.3Hz, 1H), 3.84 (s, 3H), 3.49 (d, J=20.7Hz, 2H), 3.11 (s, 3H), 2.88 (dd, J=13.4, 4.7Hz, 1H), 2.75-2.66 (m, 1H), 2.27 (s, 3H).
(example 6): 1hNMR (400MHz, CDCl 3) δ 8.44 (d, J=5.6Hz, 2H), 8.39 (d, J=8.1Hz, 1H), 7.46-7.33 (m, 4H), 7.27 (t, J=8.0Hz, 3H), 7.08 (d, J=6.6Hz, 3H), 6.99 (t, J=7.4Hz, 1H), 6.90 (dd, J=17.2, 6.6Hz, 3H), 6.78 (d, J=5.6Hz, 2H), 5.41 (s, 2H), 4.41 (s, 1H), 3.52 (s, 2H), 3.16 (s, 3H), 2.83 (d, J=9.8Hz, 1H), 2.73-2.62 (m, 1H), 2.19 (s, 3H).
(example 7): 1hNMR (400MHz, CDCl 3) δ 8.42 (d, J=10.7Hz, 2H), 8.31 (s, 1H), 7.40 (t, J=8.9Hz, 3H), 7.34 (d, J=8.4Hz, 2H), 7.28 (s, 4H), 7.09 (d, J=6.9Hz, 3H), 7.00 (t, J=7.6Hz, 1H), 6.90 (t, J=7.4Hz, 1H), 6.77 (d, J=6.1Hz, 2H), 5.41 (s, 2H), 4.40 (s, 1H), 3.54 (s, 2H), 3.16 (s, 3H), 2.82 (d, J=9.1Hz, 1H), 2.72-2.61 (m, 1H), 2.24 (s, 3H).
(example 8): 1hNMR (400MHz, CDCl 3) δ 8.52 (d, J=4.7Hz, 1H), 8.38 (d, J=7.8Hz, 1H), 7.66 (d, J=7.7Hz, 1H), 7.42 (d, J=7.5Hz, 3H), 7.29 (dt, J=28.2, 9.8Hz, 5H), 7.09 (d, J=6.6Hz, 3H), 6.98 (t, J=7.6Hz, 1H), 6.89 (t, J=7.3Hz, 1H), 6.77 (t, J=7.0Hz, 3H), 5.40 (s, 2H), 4.40 (s, 1H), 3.54 (s, 2H), 3.15 (s, 3H), 2.83 (d, J=13.3Hz, 1H), 2.67 (s, 1H), 2.25 (s, 3H).
(example 9): 1hNMR (400MHz, DMSO) δ 7.94 (d, J=7.4Hz, 1H), 7.43 (d, J=7.3Hz, 3H), 7.29 (d, J=7.0Hz, 2H), 7.13 (s, 3H), 6.72 (s, 2H), 6.62 (d, J=7.0Hz, 1H), 6.50 (d, J=6.9Hz, 1H), 4.44 (s, 1H), 4.25 (d, J=7.0Hz, 2H), 3.58 (s, 2H), 3.15 (s, 3H), 2.77 (s, 1H), 2.61 (s, 4H), 2.37 (s, 3H), 2.17 (s, 3H), 1.16 (t, J=7.0Hz, 3H).
(example 10): 1hNMR (400MHz, DMSO) δ 8.40 (s, 1H), 7.41 (d, J=8.2Hz, 3H), 7.28 (s, 4H), 7.13 (s, 3H), 6.99 (s, 1H), 6.87 (s, 1H), 6.79 (s, 2H), 4.38 (s, 1H), 4.22 (s, 2H), 3.53 (s, 2H), 3.46 (s, 2H), 3.17 (d, J=11.5Hz, 6H), 2.81 (s, 1H), 2.68 (s, 1H), 2.26 (s, 3H).
(example 11): 1hNMR (400MHz, DMSO) δ 8.35 (d, J=7.7Hz, 1H), 7.41 (d, J=7.4Hz, 3H), 7.34-7.25 (m, 5H), 7.22 (s, 4H), 7.09 (s, 3H), 6.98 (d, J=7.9Hz, 1H), 6.87 (d, J=7.3Hz, 1H), 6.76 (s, 2H), 4.37 (s, 1H), 4.06 (s, 2H), 3.50 (s, 2H), 3.15 (s, 3H), 2.80 (s, 1H), 2.64 (d, J=7.9Hz, 3H), 2.21 (s, 3H), 1.89 (s, 2H).
(example 12): 1hNMR (400MHz, DMSO) δ 8.39 (d, J=7.4Hz, 1H), 7.40 (t, J=9.1Hz, 3H), 7.37-7.24 (m, 6H), 7.22 (d, J=7.1Hz, 1H), 7.09 (d, J=6.5Hz, 3H), 6.98 (t, J=8.6Hz, 3H), 6.90 (d, J=7.7Hz, 1H), 6.77 (d, J=6.6Hz, 2H), 5.35 (s, 2H), 4.40 (s, 1H), 3.51 (s, 2H), 3.15 (s, 3H), 2.83 (d, J=13.6Hz, 1H), 2.73-2.61 (m, 1H), 2.22 (s, 3H).
(example 13): 1hNMR (400MHz, DMSO) δ 8.39 (d, J=7.6Hz, 1H), 8.22 (s, 1H), 7.41 (d, J=7.5Hz, 3H), 7.29 (t, J=8.0Hz, 3H), 7.12 (s, 3H), 6.99 (d, J=7.8Hz, 1H), 6.88 (d, J=7.5Hz, 1H), 6.79 (s, 2H), 4.38 (s, 1H), 4.09 (d, J=7.8Hz, 2H), 3.50 (s, 2H), 3.15 (s, 3H), 2.81 (s, 1H), 2.67 (s, 1H), 2.26 (s, 3H), 1.04 (d, J=6.5Hz, 3H).
(example 14): 1hNMR (400MHz, DMSO) δ 8.38 (s, 1H), 7.41 (d, J=7.7Hz, 3H), 7.29 (d, J=7.9Hz, 3H), 7.12 (s, 3H), 7.01 (s, 1H), 6.87 (s, 1H), 6.79 (s, 2H), 4.37 (s, 1H), 3.60 (s, 3H), 3.45 (d, J=16.8Hz, 2H), 3.15 (s, 3H), 2.80 (s, 1H), 2.67 (s, 1H), 2.25 (s, 3H).
(example 15): 1hNMR (400MHz, DMSO) δ 7.93 (d, J=8.1Hz, 1H), 7.36 (dd, J=59.7,7.6Hz, 5H), 7.14 (s, 3H), 6.73 (s, 2H), 6.59 (d, J=6.9Hz, 1H), 6.47 (d, J=7.2Hz, 1H), 4.47-4.37 (m, 1H), 3.84 (s, 3H), 3.57 (s, 2H), 3.15 (s, 3H), 2.85-2.75 (m, 1H), 2.66 (s, 4H), 2.35 (s, 3H), 2.15 (s, 3H).
(example 16): 1hNMR (400MHz, DMSO) δ 8.47 (d, J=7.5Hz, 1H), 8.03 (s, 1H), 7.45 (s, 1H), 7.31 (dd, J=14.6, 8.1Hz, 2H), 7.16 (d, J=3.5Hz, 2H), 7.02 (t, J=7.6Hz, 1H), 6.87 (dd, J=21.6, 13.6Hz, 4H), 4.25 (s, 1H), 3.84 (s, 3H), 3.60 (s, 3H), 3.49 (d, J=15.0Hz, 2H), 3.10 (s, 3H), 2.90 (s, 1H), 2.73 (d, J=7.7Hz, 1H), 2.26 (s, 3H).
(example 17): 1hNMR (400MHz, DMSO) δ 8.10-7.95 (m, 2H), 7.46 (s, 1H), 7.25-7.11 (m, 3H), 6.84 (d, J=8.8Hz, 3H), 6.59 (d, J=7.3Hz, 1H), 6.48 (d, J=7.1Hz, 1H), 4.30 (s, 1H), 3.85 (d, J=2.6Hz, 6H), 3.58 (s, 2H), 3.10 (s, 3H), 2.91-2.79 (m, 1H), 2.68 (d, J=20.4Hz, 4H), 2.38 (s, 3H), 2.16 (s, 3H).
(example 18): 1hNMR (400MHz, DMSO) δ 8.49 (d, J=7.7Hz, 1H), 8.03 (s, 1H), 7.47 (d, J=8.3Hz, 1H), 7.31 (t, J=7.4Hz, 2H), 7.26-7.09 (m, 3H), 7.00 (t, J=8.0Hz, 1H), 6.89 (dd, J=14.3, 6.5Hz, 3H), 6.81 (d, J=8.8Hz, 1H), 4.23 (t, J=5.5Hz, 3H), 3.84 (s, 3H), 3.52 (dd, J=19.8, 14.3Hz, 4H), 3.19 (s, 3H), 3.11 (s, 3H), 2.88 (dd, J=13.4, 5.0Hz, 1H), 2.71 (dd, J=13.8, 9.4Hz, 1H), 2.27 (s, 3H).
(example 19): 1hNMR (400MHz, DMSO) δ 8.16-7.87 (m, 2H), 7.48 (d, J=7.2Hz, 1H), 7.24-7.09 (m, 3H), 6.85 (t, J=6.3Hz, 3H), 6.62 (d, J=7.3Hz, 1H), 6.51 (d, J=7.2Hz, 1H), 4.43-4.19 (m, 3H), 3.85 (s, 3H), 3.59 (s, 2H), 3.10 (s, 3H), 2.85 (dd, J=13.6, 4.9Hz, 1H), 2.77-2.56 (m, 4H), 2.42 (d, J=23.9Hz, 3H), 2.18 (s, 3H), 1.17 (t, J=7.1Hz, 3H).
(example 20): 1hNMR (400MHz, DMSO) δ 8.51 (d, J=7.8Hz, 1H), 8.48-8.39 (m, 1H), 8.31 (s, 1H), 8.04 (s, 1H), 7.49 (d, J=8.9Hz, 1H), 7.42-7.31 (m, 2H), 7.28 (s, 2H), 7.14 (dd, J=5.0, 1.9Hz, 3H), 7.01 (t, J=7.5Hz, 1H), 6.91 (dd, J=12.9, 7.6Hz, 3H), 6.82 (d, J=8.8Hz, 1H), 5.42 (s, 2H), 4.41-4.21 (m, 1H), 3.84 (s, 3H), 3.49 (d, J=21.1Hz, 2H), 3.11 (s, 3H), 2.88 (dd, J=13.4, 4.9Hz, 1H), 2.71 (dd, J=13.7, 9.7Hz, 1H), 2.25 (s, 3H).
(example 21): 1hNMR (400MHz, DMSO) δ 8.50 (d, J=7.8Hz, 1H), 8.45 (d, J=5.9Hz, 2H), 8.05 (s, 1H), 7.50 (d, J=7.0Hz, 1H), 7.39 (d, J=7.8Hz, 1H), 7.27 (d, J=8.0Hz, 1H), 7.21-7.07 (m, 3H), 7.00 (t, J=7.5Hz, 1H), 6.96-6.77 (m, 6H), 5.42 (s, 2H), 4.39-4.20 (m, 1H), 3.85 (s, 3H), 3.53 (s, 2H), 3.11 (s, 3H), 2.88 (dd, J=13.5, 4.6Hz, 1H), 2.72 (dd, J=13.3, 9.5Hz, 1H), 2.20 (s, 3H).
(example 22): 1hNMR (400MHz, DMSO) δ 8.05 (s, 2H), 7.49 (d, J=7.9Hz, 1H), 7.27 (ddd, J=22.9, 15.4, 7.3Hz, 5H), 7.16 (dd, J=11.5, 8.2Hz, 3H), 7.01-6.67 (m, 3H), 6.59 (d, J=7.3Hz, 1H), 6.49 (d, J=7.3Hz, 1H), 4.31 (dd, J=13.4, 8.9Hz, 1H), 4.26-4.12 (m, 2H), 3.84 (s, 3H), 3.58 (s, 2H), 3.09 (s, 3H), 2.84 (dd, J=13.8, 4.9Hz, 1H), 2.73-2.61 (m, 3H), 2.46 (s, 3H), 2.39 (s, 3H), 2.12 (s, 3H), 1.80 (s, 2H).
(example 23): 1hNMR (400MHz, DMSO) δ 8.06 (d, J=10.1Hz, 2H), 7.48 (d, J=7.3Hz, 1H), 7.19 (t, J=10.8Hz, 3H), 6.84 (d, J=8.7Hz, 3H), 6.62 (d, J=7.1Hz, 1H), 6.51 (d, J=7.2Hz, 1H), 4.48-4.10 (m, 3H), 3.85 (s, 3H), 3.59 (s, 2H), 3.33-3.30 (m, 2H), 3.26 (s, 3H), 3.10 (s, 3H), 2.85 (dd, J=13.5, 5.0Hz, 1H), 2.74-2.64 (m, 1H), 2.60 (s, 3H), 2.39 (s, 3H), 2.18 (s, 3H), 1.75 (s, 2H).
(example 24): 1hNMR (400MHz, DMSO) δ 8.05 (d, J=7.9Hz, 2H), 7.48 (d, J=7.4Hz, 1H), 7.25-7.07 (m, 3H), 6.84 (dd, J=9.1, 3.1Hz, 3H), 6.62 (d, J=7.3Hz, 1H), 6.51 (d, J=7.4Hz, 1H), 4.41 (t, J=6.0Hz, 2H), 4.32 (dd, J=12.9, 9.0Hz, 1H), 3.85 (s, 3H), 3.59 (s, 2H), 3.50 (t, J=6.0Hz, 2H), 3.20 (s, 3H), 3.10 (s, 3H), 2.85 (dd, J=13.7, 4.9Hz, 1H), 2.67 (dd, J=13.4, 9.2Hz, 1H), 2.59 (s, 3H), 2.39 (s, 3H), 2.20 (s, 3H).
(example 25): 1hNMR (400MHz, DMSO) δ 8.46 (d, J=5.6Hz, 2H), 8.07 (d, J=7.7Hz, 2H), 7.49 (d, 1H), 7.14 (s, 3H), 6.82 (dd, J=33.1, 7.1Hz, 5H), 6.58 (dd, J=15.0, 7.2Hz, 2H), 5.58 (s, 2H), 4.45-4.29 (m, 1H), 3.86 (s, 3H), 3.67 (s, 2H), 3.11 (s, 3H), 2.93-2.79 (m, J=9.0Hz, 1H), 2.72-2.63 (m, 1H), 2.44 (s, 3H), 2.35 (s, 3H), 2.10 (s, 3H).
(example 26): 1hNMR (400MHz, DMSO) δ 8.44 (d, J=4.5Hz, 1H), 8.09 (t, J=13.6Hz, 3H), 7.48 (s, 1H), 7.30 (dd, J=7.9, 4.6Hz, 1H), 7.26-7.11 (m, 3H), 7.06 (d, J=8.1Hz, 1H), 6.86 (d, J=8.7Hz, 3H), 6.58 (dd, J=17.3, 7.3Hz, 2H), 5.60 (s, 2H), 4.36 (d, J=4.1Hz, 1H), 3.86 (s, 3H), 3.66 (s, 2H), 3.11 (s, 3H), 2.86 (dd, J=13.2, 5.2Hz, 1H), 2.69 (dd, J=13.7, 9.1Hz, 1H), 2.55 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H), 2.12 (s, 3H).
(example 27): 1hNMR (400MHz, DMSO) δ 7.92 (d, J=7.7Hz, 1H), 7.53-7.34 (m, 3H), 7.28 (d, J=7.1Hz, 2H), 7.13 (d, J=6.2Hz, 3H), 6.71 (d, J=5.1Hz, 2H), 6.62 (d, J=7.3Hz, 1H), 6.51 (d, J=7.2Hz, 1H), 4.41 (t, J=6.0Hz, 3H), 3.58 (s, 2H), 3.50 (t, J=6.0Hz, 2H), 3.23-3.10 (m, 6H), 2.79 (d, J=9.4Hz, 1H), 2.59 (s, 3H), 2.37 (s, 3H), 2.19 (s, 3H).
(example 28): 1hNMR (400MHz, DMSO) δ 7.91 (d, J=7.9Hz, 1H), 7.41 (dd, J=13.3, 7.1Hz, 3H), 7.35-7.15 (m, 7H), 7.10 (s, 3H), 6.69 (s, 2H), 6.59 (d, J=7.3Hz, 1H), 6.49 (d, J=7.1Hz, 1H), 4.44 (s, 1H), 4.26-4.08 (m, 2H), 3.57 (s, 2H), 3.14 (s, 3H), 2.77 (d, J=9.4Hz, 1H), 2.64 (dt, J=22.6, 10.4Hz, 3H), 2.46 (s, 3H), 2.37 (s, 3H), 2.10 (s, 3H), 1.80 (s, 2H).
(example 29): 1hNMR (400MHz, DMSO) δ 7.92 (s, 1H), 7.43 (d, J=6.6Hz, 2H), 7.29 (s, 2H), 7.13 (s, 3H), 6.72 (s, 2H), 6.60 (s, 1H), 6.51 (s, 1H), 4.43 (s, 1H), 4.26 (s, 2H), 3.58 (s, 2H), 3.32-3.30 (m, 2H), 3.25 (s, 3H), 3.14 (s, 3H), 2.76 (s, 1H), 2.60 (s, 4H), 2.36 (s, 3H), 2.16 (s, 3H), 1.73 (s, 2H).
(example 30): 1hNMR (400MHz, DMSO) δ 8.45 (d, J=4.5Hz, 2H), 7.93 (d, J=7.6Hz, 1H), 7.43 (dd, J=14.5, 7.2Hz, 3H), 7.29 (d, J=7.5Hz, 2H), 7.09 (s, 3H), 6.90-6.66 (m, 4H), 6.58 (dd, J=16.5, 7.4Hz, 2H), 5.58 (s, 2H), 4.50 (s, 1H), 3.66 (s, 2H), 3.15 (s, 3H), 2.79 (d, J=8.8Hz, 1H), 2.70-2.60 (m, 1H), 2.39 (d, J=27.3Hz, 6H), 2.09 (s, 3H).
(example 31): 1hNMR (400MHz, DMSO) δ 8.44 (s, 1H), 8.10 (s, 1H), 7.97 (d, J=7.8Hz, 1H), 7.49-7.35 (m, 3H), 7.28 (d, J=7.6Hz, 3H), 7.08 (d, J=14.6Hz, 4H), 6.72 (s, 2H), 6.57 (dd, J=18.6, 7.3Hz, 2H), 5.59 (s, 2H), 4.47 (s, 1H), 3.64 (s, 2H), 3.15 (s, 3H), 2.78 (s, 1H), 2.64 (d, J=9.9Hz, 1H), 2.39 (d, J=7.4Hz, 6H), 2.11 (s, 3H).
(example 32): 1hNMR (400MHz, DMSO) δ 8.55 (d, J=4.8Hz, 1H), 7.90 (d, J=7.6Hz, 1H), 7.65 (s, 1H), 7.43 (dd, J=14.5, 7.4Hz, 3H), 7.29 (d, J=7.2Hz, 3H), 7.10 (s, 3H), 6.72 (s, 2H), 6.56 (dd, J=16.7, 7.4Hz, 2H), 6.41 (d, J=7.8Hz, 1H), 5.60 (s, 2H), 4.49 (s, 1H), 3.65 (s, 2H), 3.15 (s, 3H), 2.78 (s, 1H), 2.64 (d, J=8.9Hz, 1H), 2.39 (d, J=16.0Hz, 6H), 2.12 (s, 3H).
(example 33): 1hNMR (400MHz, DMSO) δ 8.55 (d, J=4.4Hz, 1H), 8.05 (d, J=7.5Hz, 2H), 7.66 (t, J=6.8Hz, 1H), 7.49 (d, J=7.5Hz, 1H), 7.28-7.13 (m, 4H), 6.86 (d, J=8.7Hz, 3H), 6.56 (dd, J=15.2, 7.2Hz, 2H), 6.41 (d, J=7.8Hz, 1H), 5.60 (s, 2H), 4.36 (d, J=5.2Hz, 1H), 3.86 (s, 3H), 3.66 (s, 2H), 3.10 (s, 3H), 2.85 (dd, J=13.4, 4.7Hz, 1H), 2.68 (dd, J=13.2, 9.4Hz, 1H), 2.43 (s, 3H), 2.37 (s, 3H), 2.13 (s, 3H).
(example 34): 1hNMR (400MHz, DMSO) δ 8.52 (d, J=8.0Hz, 1H), 8.04 (s, 1H), 7.48 (d, J=8.4Hz, 1H), 7.33 (d, J=8.5Hz, 2H), 7.21-7.12 (m, 3H), 7.00 (t, J=7.7Hz, 1H), 6.88 (dd, J=14.4, 6.7Hz, 3H), 6.81 (d, J=8.8Hz, 1H), 4.30-4.20 (m, 1H), 3.98 (d, J=6.7Hz, 2H), 3.84 (s, 3H), 3.53-3.41 (m, 2H), 3.11 (s, 3H), 2.88 (dd, J=13.2, 4.8Hz, 1H), 2.77-2.66 (m, 1H), 2.29 (s, 3H), 1.10 (dt, J=12.2, 6.2Hz, 1H), 0.47-0.39 (m, 2H), 0.37-0.30 (m, 2H).
(example 35): 1hNMR (400MHz, DMSO) δ 8.49 (d, J=7.7Hz, 1H), 8.04 (s, 1H), 7.48 (d, J=8.1Hz, 1H), 7.31 (dd, J=14.5, 8.0Hz, 2H), 7.20-7.13 (m, 3H), 7.02 (t, J=7.7Hz, 1H), 6.89 (t, J=7.3Hz, 3H), 6.81 (d, J=8.7Hz, 1H), 4.28-4.23 (m, 1H), 4.18-4.12 (m, 2H), 3.84 (s, 3H), 3.58 (s, 3H), 3.45 (dd, J=34.7, 14.8Hz, 5H), 3.11 (s, 3H), 2.88 (dd, J=13.8, 5.0Hz, 1H), 2.71 (dd, J=13.6, 9.5Hz, 1H), 2.47 (d, J=7.1Hz, 2H), 2.28 (s, 3H), 2.26 (s, 6H).
(example 36): 1hNMR (400MHz, DMSO) δ 8.47 (d, J=7.8Hz, 1H), 8.04 (s, 1H), 7.47 (d, J=6.2Hz, 1H), 7.32 (t, J=8.4Hz, 2H), 7.16 (s, 3H), 7.01 (t, J=7.4Hz, 1H), 6.88 (dd, J=13.0, 5.3Hz, 3H), 6.81 (d, J=8.6Hz, 1H), 4.26 (dd, J=13.8, 7.3Hz, 1H), 4.07 (t, J=7.0Hz, 2H), 3.84 (s, 3H), 3.52-3.42 (m, 3H), 3.10 (s, 3H), 2.88 (dd, J=13.5, 4.9Hz, 1H), 2.71 (dd, J=13.5, 10.3Hz, 1H), 2.28 (s, 3H), 2.20 (t, J=6.4Hz, 2H), 2.14 (s, 6H), 1.77-1.68 (m, 2H).
(example 37): 1hNMR (400MHz, DMSO) δ 8.47 (d, J=7.9Hz, 1H), 8.04 (s, 1H), 7.48 (d, J=6.4Hz, 1H), 7.31 (dd, J=10.7, 8.2Hz, 2H), 7.19-7.12 (m, 3H), 7.00 (t, J=7.5Hz, 1H), 6.89 (t, J=6.3Hz, 3H), 6.81 (d, J=8.7Hz, 1H), 4.26 (td, J=9.2, 6.0Hz, 1H), 4.06 (t, J=7.1Hz, 2H), 3.84 (s, 3H), 3.53-3.42 (m, 2H), 3.31 (t, J=6.2Hz, 2H), 3.20 (s, 3H), 3.11 (s, 3H), 2.88 (dd, J=13.5, 4.9Hz, 1H), 2.71 (dd, J=13.3, 9.8Hz, 1H), 2.26 (s, 3H), 1.66-1.58 (m, 2H), 1.50 (dt, J=14.3, 7.0Hz, 2H).
(example 38): 1hNMR (400MHz, DMSO) δ 8.46 (d, J=5.7Hz, 2H), 8.41 (d, J=4.7Hz, 1H), 8.04 (s, 1H), 7.65 (d, J=7.8Hz, 1H), 7.48 (dd, J=9.2, 1.9Hz, 1H), 7.34-7.26 (m, 3H), 7.15-7.10 (m, 3H), 7.00 (t, J=7.5Hz, 1H), 6.89 (t, J=6.5Hz, 3H), 6.81 (d, J=8.8Hz, 1H), 4.29-4.21 (m, 1H), 4.11-4.06 (m, 2H), 3.83 (s, 3H), 3.52-3.41 (m, 9H), 3.10 (s, 3H), 2.87 (dd, J=13.4, 4.7Hz, 1H), 2.74-2.64 (m, 3H), 2.24 (s, 3H), 1.95-1.87 (m, 2H).
(example 39): 1hNMR (400MHz, DMSO) δ 8.16 (s, 1H), 8.11-8.04 (m, 1H), 7.48 (d, J=8.5Hz, 1H), 7.21-7.14 (m, 3H), 6.84 (d, J=8.8Hz, 3H), 6.63 (d, J=7.3Hz, 1H), 6.52 (d, J=7.1Hz, 1H), 4.39-4.29 (m, 3H), 3.85 (s, 3H), 3.59 (s, 4H), 3.10 (s, 3H), 2.85 (dd, J=13.7, 5.1Hz, 1H), 2.72-2.66 (m, 1H), 2.63 (s, 3H), 2.39 (s, 3H), 2.33 (s, 6H), 2.21 (s, 3H).
(example 40): 1hNMR (400MHz, DMSO) δ 8.46 (d, J=7.6Hz, 1H), 8.04 (s, 1H), 7.47 (d, J=7.8Hz, 1H), 7.31 (dd, J=11.8, 7.9Hz, 2H), 7.19-7.13 (m, 3H), 7.00 (t, J=7.4Hz, 1H), 6.89 (dd, J=14.0, 6.8Hz, 3H), 6.81 (d, J=8.8Hz, 1H), 4.88 (s, 1H), 4.29-4.22 (m, 1H), 4.11 (t, J=5.9Hz, 2H), 3.84 (s, 3H), 3.60 (s, 2H), 3.51-3.42 (m, 2H), 3.10 (s, 3H), 2.88 (dd, J=13.5, 4.8Hz, 1H), 2.72 (dd, J=13.6, 9.5Hz, 1H), 2.28 (s, 3H).
(example 41): 1hNMR (400MHz, DMSO) δ 8.16 (s, 1H), 8.10 (d, J=7.7Hz, 1H), 7.48 (d, J=8.6Hz, 1H), 7.19-7.17 (m, 3H), 6.85 (dd, J=11.4, 7.6Hz, 4H), 6.63 (d, J=7.1Hz, 1H), 6.52 (d, J=7.1Hz, 1H), 4.35-4.30 (m, 1H), 4.25-4.20 (m, 2H), 3.85 (s, 3H), 3.60 (s, 2H), 3.10 (s, 3H), 2.88-2.83 (m, 1H), 2.71-2.60 (m, 6H), 2.40 (d, J=13.2Hz, 9H), 2.20 (s, 3H), 1.79-1.73 (m, 2H).
(example 42): 1hNMR (400MHz, CDCl 3) δ 8.11-7.96 (m, 2H), 7.48 (s, 1H), 7.18 (s, 3H), 6.84 (d, J=8.4Hz, 3H), 6.61 (d, J=7.1Hz, 1H), 6.51 (d, J=6.9Hz, 1H), 4.97 (s, 1H), 4.30 (s, 3H), 3.85 (s, 3H), 3.63-3.50 (m, 4H), 3.10 (s, 3H), 2.84 (d, J=9.1Hz, 1H), 2.73-2.63 (m, 1H), 2.61 (s, 3H), 2.39 (s, 3H), 2.20 (s, 3H).
(example 43): 1hNMR (400MHz, CDCl 3) δ 8.50 (s, 1H), 8.43 (d, J=4.9Hz, 1H), 8.08-8.00 (m, 2H), 7.69 (d, J=7.8Hz, 1H), 7.48 (d, J=5.2Hz, 1H), 7.33 (dd, J=7.6, 4.8Hz, 1H), 7.20-7.11 (m, 3H), 6.84 (d, J=8.8Hz, 3H), 6.60 (d, J=7.4Hz, 1H), 6.50 (d, J=7.2Hz, 1H), 4.31 (dt, J=12.5, 6.8Hz, 1H), 4.20 (dd, J=9.2, 7.1Hz, 2H), 3.84 (s, 3H), 3.58 (s, 2H), 3.09 (s, 3H), 2.83 (dd, J=12.8, 4.1Hz, 1H), 2.68 (dd, J=19.3, 12.4Hz, 3H), 2.47 (s, 3H), 2.38 (s, 3H), 2.13 (s, 3H), 1.87-1.77 (m, 2H).
(example 44): 1hNMR (400MHz, DMSO) δ 8.41 (d, J=7.6Hz, 1H), 7.43-7.35 (m, 3H), 7.30 (dd, J=16.6, 8.0Hz, 4H), 7.12 (d, J=3.5Hz, 3H), 6.99 (t, J=7.3Hz, 1H), 6.86 (t, J=7.2Hz, 1H), 6.81-6.74 (m, 2H), 4.40-4.34 (m, 1H), 3.97 (d, J=6.9Hz, 2H), 3.55-3.47 (m, 4H), 3.15 (s, 3H), 2.82 (dd, J=14.8, 3.9Hz, 1H), 2.68 (dd, J=7.0, 5.0Hz, 1H), 2.28 (s, 3H), 1.13-1.05 (m, 1H), 0.47-0.40 (m, 2H), 0.36-0.31 (m, 2H).
(example 45): 1hNMR (400MHz, CDCl 3) δ 7.94 (d, J=7.8Hz, 1H), 7.48-7.37 (m, 3H), 7.29 (d, J=7.5Hz, 2H), 7.12 (d, J=5.2Hz, 3H), 6.71 (d, J=7.2Hz, 2H), 6.63 (d, J=7.0Hz, 1H), 6.51 (d, J=7.1Hz, 1H), 4.48-4.40 (m, 1H), 4.22 (dd, J=10.1, 4.2Hz, 2H), 3.59 (s, 2H), 3.15 (s, 3H), 2.79 (dd, J=8.6, 7.7Hz, 1H), 2.65 (s, 3H), 2.59 (dd, J=9.4, 2.0Hz, 1H), 2.37 (s, 3H), 2.17 (s, 3H), 1.05-0.95 (m, 1H), 0.41 (d, J=8.3Hz, 2H), 0.20 (d, J=3.9Hz, 2H).
(example 46): 1hNMR (400MHz, DMSO) δ 8.45 (s, 1H), 8.41 (d, J=4.1Hz, 1H), 8.34 (d, J=7.7Hz, 1H), 7.64 (d, J=7.7Hz, 1H), 7.45-7.34 (m, 3H), 7.29 (dt, J=13.4, 6.1Hz, 5H), 7.12-7.04 (m, 3H), 7.00 (t, J=7.9Hz, 1H), 6.87 (t, J=7.5Hz, 1H), 6.79-6.73 (m, 2H), 4.41-4.33 (m, 1H), 4.08 (t, J=7.1Hz, 2H), 3.60 (s, 2H), 3.15 (s, 3H), 2.81 (dd, J=13.6, 4.6Hz, 1H), 2.66 (dd, J=14.7, 7.1Hz, 3H), 2.23 (s, 3H), 1.95-1.85 (m, 2H).
(example 47): 1hNMR (400MHz, DMSO) δ 8.39 (d, J=8.1Hz, 1H), 7.45-7.34 (m, 3H), 7.29 (t, J=8.3Hz, 4H), 7.12 (dd, J=4.9, 1.5Hz, 3H), 7.01 (t, J=7.5Hz, 1H), 6.87 (t, J=7.4Hz, 1H), 6.80-6.73 (m, 2H), 4.41-4.33 (m, 1H), 4.13 (t, J=7.2Hz, 2H), 3.56 (s, 2H), 3.15 (s, 3H), 2.82 (dd, J=13.5, 3.8Hz, 1H), 2.70-2.63 (m, 1H), 2.44 (t, J=7.1Hz, 2H), 2.27 (s, 3H), 2.22 (s, 6H).
(example 48): 1hNMR (400MHz, DMSO) δ 7.95 (d, J=8.1Hz, 1H), 7.48-7.37 (m, 3H), 7.29 (d, J=7.5Hz, 2H), 7.13 (d, J=4.8Hz, 3H), 6.75-6.68 (m, 2H), 6.62 (d, J=7.3Hz, 1H), 6.51 (d, J=7.6Hz, 1H), 4.48-4.40 (m, 1H), 4.31 (dd, J=9.4, 6.5Hz, 2H), 3.58 (s, 2H), 3.15 (s, 3H), 2.79 (dd, J=13.8, 4.6Hz, 1H), 2.62 (s, 4H), 2.37 (s, 5H), 2.24 (s, 6H), 2.18 (s, 3H).
(example 49): 1hNMR (400MHz, DMSO) δ 8.37 (d, J=7.7Hz, 1H), 7.44-7.35 (m, 3H), 7.29 (t, J=8.1Hz, 4H), 7.11 (d, J=3.5Hz, 3H), 7.00 (t, J=7.5Hz, 1H), 6.86 (t, J=7.6Hz, 1H), 6.80-6.75 (m, 2H), 4.41-4.34 (m, 1H), 4.06 (t, J=7.1Hz, 2H), 3.50-3.42 (m, 2H), 3.30 (t, J=6.3Hz, 3H), 3.20 (s, 3H), 3.15 (s, 3H), 2.82 (dd, J=15.3, 6.0Hz, 1H), 2.71-2.62 (m, 1H), 2.25 (s, 3H), 1.66-1.56 (m, 2H), 1.54-1.45 (m, 2H).
(example 50): 1hNMR (400MHz, DMSO) δ 7.89 (d, J=7.9Hz, 1H), 7.48-7.37 (m, 3H), 7.30 (d, J=7.0Hz, 2H), 7.12 (d, J=5.5Hz, 3H), 6.74-6.66 (m, 2H), 6.61 (d, J=7.4Hz, 1H), 6.50 (d, J=7.1Hz, 1H), 4.96 (t, J=5.4Hz, 1H), 4.49-4.38 (m, 1H), 4.29 (dd, J=7.4, 5.2Hz, 2H), 3.63-3.47 (m, 4H), 3.15 (s, 3H), 2.78 (dd, J=12.8, 4.4Hz, 1H), 2.60 (s, 4H), 2.37 (s, 3H), 2.18 (s, 3H).
(example 51): 1hNMR (400MHz, DMSO) δ 8.49 (s, 1H), 8.43 (d, J=3.7Hz, 1H), 7.92 (d, J=7.7Hz, 1H), 7.69 (d, J=7.8Hz, 1H), 7.48-7.36 (m, 3H), 7.36-7.24 (m, 3H), 7.13-7.03 (m, 3H), 6.70 (dd, J=6.8, 3.4Hz, 2H), 6.60 (d, J=7.4Hz, 1H), 6.49 (d, J=7.4Hz, 1H), 4.43 (ddd, J=11.6, 7.4, 3.9Hz, 1H), 4.24-4.16 (m, 2H), 3.57 (s, 2H), 3.14 (s, 3H), 2.81-2.73 (m, 1H), 2.69 (t, J=7.4Hz, 2H), 2.65-2.56 (m, 1H), 2.47 (s, 3H), 2.37 (s, 3H), 2.12 (s, 3H), 1.87-1.77 (m, 2H).
(example 52): 1hNMR (400MHz, DMSO) δ 8.28 (s, 1H), 8.06 (d, J=7.7Hz, 1H), 7.45 (s, 1H), 7.29 (d, J=8.5Hz, 1H), 7.18 (s, 3H), 6.83 (s, 2H), 6.63 (d, J=7.2Hz, 1H), 6.52 (d, J=7.2Hz, 1H), 4.35-4.19 (m, 3H), 3.60 (s, 2H), 3.12 (s, 3H), 2.84 (d, J=8.5Hz, 1H), 2.68 (s, 1H), 2.62 (s, 3H), 2.48 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H), 1.18 (t, J=7.0Hz, 3H).
(example 53): 1hNMR (400MHz, DMSO) δ 8.06 (d, J=7.4Hz, 2H), 7.48 (s, 1H), 7.22-7.15 (m, 3H), 6.85 (d, J=8.5Hz, 3H), 6.62 (d, J=7.5Hz, 1H), 6.51 (d, J=7.0Hz, 1H), 4.32 (s, 1H), 4.26-4.12 (m, 2H), 3.86 (s, 3H), 3.60 (s, 2H), 3.11 (s, 3H), 2.85 (d, J=8.3Hz, 1H), 2.68 (t, J=11.4Hz, 1H), 2.60 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H), 1.51 (s, 2H), 1.35 (dd, J=14.8, 7.3Hz, 2H), 0.93 (t, J=7.2Hz, 3H).
(example 54): 1hNMR (400MHz, DMSO) δ 8.06 (d, J=7.6Hz, 2H), 7.49 (d, J=8.0Hz, 1H), 7.22-7.14 (m, 3H), 6.85 (d, J=8.5Hz, 3H), 6.62 (d, J=7.4Hz, 1H), 6.51 (d, J=7.3Hz, 1H), 4.33 (dd, J=13.7, 8.7Hz, 1H), 4.19-4.07 (m, 2H), 3.86 (s, 3H), 3.60 (s, 2H), 3.11 (s, 3H), 2.85 (dd, J=13.5, 5.0Hz, 1H), 2.68 (dd, J=13.6, 9.2Hz, 1H), 2.60 (s, 3H), 2.39 (s, 3H), 2.19 (s, 3H), 1.55 (dd, J=15.6, 7.8Hz, 2H), 0.90 (t, J=7.3Hz, 3H).
(example 55): 1hNMR (400MHz, CDCl 3) δ 8.27 (d, J=7.6Hz, 1H), 8.06 (s, 1H), 7.50 (d, J=7.2Hz, 1H), 7.23-7.14 (m, 3H), 6.95-6.81 (m, 4H), 6.63 (d, J=7.9Hz, 1H), 4.45 (q, J=7.3Hz, 2H), 4.33 (dd, J=13.0, 9.0Hz, 1H), 3.86 (s, 3H), 3.69-3.55 (m, 2H), 3.12 (s, 3H), 2.88 (dd, J=13.6, 4.9Hz, 1H), 2.71 (dd, J=13.4, 9.3Hz, 1H), 2.43 (s, 3H), 2.22 (s, 3H), 1.24 (t, J=7.0Hz, 3H).
(example 56): 1hNMR (400MHz, DMSO) δ 8.55 (d, J=7.8Hz, 1H), 8.05 (d, J=2.0Hz, 1H), 7.49 (d, J=8.7Hz, 1H), 7.30 (d, J=7.6Hz, 1H), 7.20-7.12 (m, 3H), 7.02 (d, J=7.4Hz, 1H), 6.87 (ddd, J=20.7, 9.9, 6.2Hz, 4H), 4.42 (q, J=6.9Hz, 2H), 4.26 (td, J=9.3, 4.7Hz, 1H), 3.84 (s, 3H), 3.46 (dd, J=31.1, 15.1Hz, 2H), 3.11 (s, 3H), 2.96-2.83 (m, 1H), 2.71 (dd, J=13.5, 9.6Hz, 1H), 2.28 (s, 3H), 1.24 (t, J=7.0Hz, 3H).
(example 57): 1hNMR (400MHz, DMSO) δ 8.49 (d, J=7.8Hz, 1H), 7.33 (d, J=7.2Hz, 1H), 7.25-7.16 (m, 3H), 7.06 (d, J=6.9Hz, 1H), 6.92 (ddd, J=17.4, 13.6, 7.9Hz, 4H), 6.84 (s, 1H), 6.81-6.73 (m, 1H), 6.09 (d, J=7.2Hz, 2H), 4.55-4.34 (m, 3H), 3.53 (t, J=10.3Hz, 1H), 3.13 (s, 3H), 2.92 (dd, J=13.5, 4.2Hz, 1H), 2.73 (dd, J=13.4, 10.0Hz, 1H), 2.31 (s, 3H), 1.28 (t, J=7.0Hz, 3H).
(example 58): 1hNMR (400MHz, DMSO) δ 8.03 (s, 1H), 7.97 (d, J=7.5Hz, 1H), 7.47 (s, 1H), 7.22-7.14 (m, 3H), 6.85 (d, J=8.8Hz, 3H), 6.63 (d, J=7.6Hz, 1H), 6.53 (d, J=7.2Hz, 1H), 4.34 (s, 1H), 4.05 (s, 2H), 3.86 (s, 3H), 3.61 (s, 2H), 3.10 (s, 3H), 2.90-2.79 (m, 1H), 2.70-2.61 (m, 2H), 2.57 (s, 3H), 2.39 (s, 3H), 2.20 (s, 3H), 1.85 (s, 1H), 0.78 (t, J=6.3Hz, 6H).
(example 59): 1hNMR (400MHz, CDCl 3) δ 7.87 (s, 1H), 7.27 (d, J=7.1Hz, 1H), 7.23-7.07 (m, 6H), 6.97 (t, J=7.7Hz, 1H), 6.73 (d, J=7.1Hz, 2H), 6.07 (d, J=8.2Hz, 1H), 4.66-4.44 (m, 3H), 3.65-3.50 (m, 2H), 3.13 (s, 3H), 2.72 (dd, J=13.2,7.9Hz, 1H), 2.63-2.48 (m, 4H), 2.30 (s, 3H), 1.38 (t, J=7.1Hz, 3H).
(example 60): 1hNMR (400MHz, CDCl 3) δ 7.36 (q, J=6.1Hz, 3H), 7.24 (s, 1H), 7.13 (d, J=7.7Hz, 2H), 7.05 (t, J=7.4Hz, 2H), 6.96 (t, J=7.7Hz, 3H), 6.62 (d, J=7.3Hz, 2H), 6.07 (d, J=8.5Hz, 1H), 4.76 (dd, J=15.1, 7.2Hz, 1H), 4.60-4.45 (m, 2H), 3.57 (q, J=17.3Hz, 2H), 3.18 (s, 3H), 2.71 (dd, J=13.4, 6.7Hz, 1H), 2.50 (dd, J=13.3, 7.3Hz, 1H), 2.28 (s, 3H), 1.37 (t, J=7.1Hz, 3H).
(example 61): 1hNMR (400MHz, CDCl 3) δ 8.10 (d, J=7.3Hz, 1H), 7.17 (s, 3H), 6.96-6.88 (m, 2H), 6.85 (d, J=7.3Hz, 2H), 6.80 (s, 1H), 6.73 (d, J=7.5Hz, 1H), 6.62 (d, J=7.8Hz, 1H), 6.06 (d, J=4.6Hz, 2H), 4.44 (d, J=7.1Hz, 3H), 3.61 (s, 2H), 3.09 (s, 3H), 2.86 (d, J=13.6Hz, 1H), 2.67 (t, J=11.7Hz, 1H), 2.41 (s, 3H), 2.20 (s, 3H), 1.23 (t, J=7.0Hz, 3H).
(example 62): 1hNMR (400MHz, CDCl 3) δ 8.11 (d, J=7.8Hz, 1H), 7.42 (dd, J=13.4, 7.5Hz, 3H), 7.29 (d, J=7.1Hz, 2H), 7.13 (s, 3H), 6.90 (d, J=7.7Hz, 1H), 6.73 (d, J=3.6Hz, 2H), 6.62 (d, J=7.6Hz, 1H), 4.44 (d, J=7.0Hz, 3H), 3.61 (s, 2H), 3.15 (s, 3H), 2.81 (d, J=13.7Hz, 1H), 2.71-2.57 (m, 1H), 2.39 (s, 3H), 2.20 (s, 3H), 1.23 (t, J=7.0Hz, 3H).
(example 63): 1hNMR (400MHz, DMSO) δ 8.39 (d, J=7.8Hz, 1H), 8.26 (s, 1H), 7.44 (d, J=8.1Hz, 1H), 7.29-7.12 (m, 5H), 6.87 (d, J=3.2Hz, 2H), 6.80-6.72 (m, 2H), 4.24 (t, J=6.5Hz, 3H), 3.52-3.39 (m, 2H), 3.12 (s, 3H), 2.87 (dd, J=13.5, 4.8Hz, 1H), 2.75-2.66 (m, 1H), 2.64 (s, 3H), 2.46 (s, 3H), 2.25 (s, 3H), 1.19 (t, J=7.1Hz, 3H).
(example 64): 1hNMR (400MHz, DMSO) δ 8.41 (d, J=7.4Hz, 1H), 8.03 (s, 1H), 7.47 (d, J=7.4Hz, 1H), 7.17 (s, 4H), 6.91 (s, 2H), 6.85-6.69 (m, 3H), 4.25 (d, J=7.0Hz, 3H), 3.84 (s, 3H), 3.51-3.39 (m, 2H), 3.10 (s, 3H), 2.93-2.82 (m, 1H), 2.72 (d, J=9.5Hz, 1H), 2.64 (s, 3H), 2.25 (s, 3H), 1.19 (t, J=6.9Hz, 3H).
(example 65): 1hNMR (400MHz, DMSO) δ 8.29 (d, J=7.8Hz, 1H), 7.16 (d, J=4.7Hz, 4H), 6.90 (d, J=7.1Hz, 3H), 6.84-6.67 (m, 4H), 6.05 (d, J=8.7Hz, 2H), 4.37 (s, 1H), 4.25 (d, J=7.2Hz, 2H), 3.52-3.39 (m, 2H), 3.09 (s, 3H), 2.87 (d, J=9.0Hz, 1H), 2.70 (d, J=10.1Hz, 1H), 2.64 (s, 3H), 2.24 (s, 3H), 1.19 (t, J=7.0Hz, 3H).
(example 66): 1hNMR (400MHz, DMSO) δ 8.40 (d, J=7.8Hz, 1H), 7.32 (dd, J=8.7, 4.6Hz, 1H), 7.21 (dd, J=10.2, 2.3Hz, 1H), 7.13 (d, J=3.5Hz, 3H), 6.94-6.86 (m, 3H), 6.83 (dd, J=8.9, 1.8Hz, 1H), 6.78 (s, 1H), 6.71 (d, J=8.4Hz, 1H), 6.05 (d, J=7.9Hz, 2H), 4.37 (s, 1H), 4.10 (d, J=7.0Hz, 2H), 3.47 (d, J=14.8Hz, 2H), 3.09 (s, 3H), 2.87 (dd, J=14.5, 5.5Hz, 1H), 2.69 (dd, J=13.2, 9.6Hz, 1H), 2.27 (s, J=67.4Hz, 3H), 1.18 (t, J=7.0Hz, 3H).
(example 67): 1hNMR (400MHz, DMSO) δ 8.38 (d, J=7.9Hz, 1H), 7.30 (dd, J=8.7, 4.5Hz, 1H), 7.19 (dd, J=10.2, 2.6Hz, 1H), 7.17-7.10 (m, 3H), 6.90 (dd, J=7.7, 3.4Hz, 3H), 6.86-6.80 (m, 1H), 6.77 (s, 1H), 6.71 (d, J=8.3Hz, 1H), 6.05 (d, J=7.4Hz, 2H), 4.87 (t, J=5.4Hz, 1H), 4.37 (s, 1H), 4.11 (t, J=5.7Hz, 2H), 3.63-3.56 (m, 2H), 3.46 (d, J=14.7Hz, 2H), 3.09 (s, 3H), 2.87 (dd, J=13.3, 4.4Hz, 1H), 2.68 (dd, J=13.5, 12.1Hz, 1H), 2.27 (s, 3H).
(example 68): 1hNMR (400MHz, DMSO) δ 8.27 (dd, J=13.7, 7.4Hz, 1H), 7.16 (d, J=3.8Hz, 4H), 6.93-6.86 (m, 3H), 6.80-6.65 (m, 4H), 6.05 (d, J=8.2Hz, 2H), 4.38 (dd, J=10.4, 4.3Hz, 2H), 4.29 (t, J=5.1Hz, 1H), 3.63-3.54 (m, 2H), 3.45 (d, J=1.7Hz, 2H), 3.09 (s, 3H), 2.87 (dd, J=14.9, 6.6Hz, 1H), 2.69 (dd, J=8.2, 6.4Hz, 1H), 2.63 (d, J=1.7Hz, 3H), 2.26 (d, J=4.2Hz, 3H).
(example 69): 1hNMR (400MHz, CDCl 3) δ 7.41 (d, J=7.8Hz, 1H), 7.25 (s, 1H), 7.21-7.13 (m, 2H), 7.10 (t, J=7.2Hz, 3H), 6.74 (dd, J=14.9, 7.6Hz, 3H), 6.16 (d, J=8.2Hz, 1H), 6.01 (s, 2H), 5.94 (tdd, J=14.9, 10.2, 4.6Hz, 1H), 5.12 (dd, J=10.3, 1.1Hz, 1H), 4.83-4.67 (m, 4H), 3.71-3.56 (m, 2H), 3.09 (s, 3H), 2.74 (dd, J=13.2, 7.5Hz, 1H), 2.58 (dd, J=13.2, 6.7Hz, 1H), 2.28 (s, 3H).
(example 70): 1hNMR (400MHz, CDCl 3) δ 7.35 (d, J=7.1Hz, 1H), 7.25-7.16 (m, 3H), 7.17-7.12 (m, 2H), 7.10 (d, J=3.6Hz, 1H), 7.07 (d, J=7.7Hz, 1H), 6.81-6.74 (m, 3H), 6.23 (d, J=8.6Hz, 1H), 6.04 (s, 2H), 5.60 (d, J=26.2Hz, 2H), 5.19 (s, 2H), 4.82 (dd, J=14.7, 6.9Hz, 1H), 3.61 (d, J=9.9Hz, 2H), 3.10 (s, J=6.1Hz, 3H), 2.78 (dd, J=13.5, 7.0Hz, 1H), 2.63 (dd, J=13.4, 6.6Hz, 1H), 2.28 (s, 3H).
(example 71): 1hNMR (400MHz, DMSO) δ 7.47-7.39 (m, 1H), 7.37-7.30 (m, 1H), 7.24-7.07 (m, 5H), 6.87-6.77 (m, 2H), 6.74 (d, J=8.0Hz, 1H), 6.51-6.29 (m, 2H), 6.02 (t, J=4.2Hz, 2H), 4.81 (dt, J=13.9, 7.0Hz, 1H), 4.24-4.11 (m, 2H), 4.07-3.89 (m, 1H), 3.67-3.60 (m, 2H), 3.60-3.28 (m, 2H), 3.07 (d, J=3.8Hz, 3H), 2.83-2.57 (m, 2H), 2.32 (d, J=3.3Hz, 3H).
(example 72): 1hNMR (400MHz, CDCl 3) δ 7.33 (dd, J=7.8, 1.0Hz, 1H), 7.23-7.10 (m, 4H), 7.04 (t, J=7.7Hz, 1H), 6.84-6.78 (m, 2H), 6.73 (d, J=8.2Hz, 1H), 6.22 (d, J=8.5Hz, 1H), 6.03 (s, 2H), 4.86-4.56 (m, 3H), 3.97 (t, J=5.0Hz, 2H), 3.59 (d, J=17.6Hz, 2H), 3.06 (s, 3H), 2.73 (dd, J=13.3, 7.7Hz, 1H), 2.62 (dd, J=13.2, 6.2Hz, 1H), 2.40 (s, 3H).
(example 73): 1hNMR (400MHz, CDCl 3) δ 7.35 (d, J=7.7Hz, 1H), 7.10 (ddd, J=21.4, 20.1, 7.6Hz, 5H), 6.76 (d, J=6.8Hz, 3H), 6.16 (d, J=8.2Hz, 1H), 6.04 (s, 2H), 4.89 (d, J=14.6Hz, 1H), 4.79 (d, J=7.7Hz, 1H), 4.21 (s, 1H), 4.06 (d, J=14.6Hz, 1H), 3.62 (dd, J=35.0, 17.5Hz, 2H), 3.10 (d, J=11.9Hz, 3H), 2.62 (ddd, J=19.6, 13.3, 7.0Hz, 2H), 2.46-2.34 (m, 3H), 1.33 (d, J=6.2Hz, 3H). example 74
(S)-2-(2-(chloro-2, the 7-dimethyl-1H-indol-3-yls of 4-) acetamido)-N-methyl-N, 3-diphenylpropanamide the preparation of example 74A.2-(chloro-2, the 7-dimethyl-1H-indol-3-yls of 4-) acetic acid
2-(4-chloro-2,7-dimethyl-1H-indol-3-yl) synthesis of acetic acid (327mg, 1.26mmol, 1.0eq) is the same with the building-up process of 1A, 1B and 1C, be dissolved in 10mL methyl alcohol, then add the NaOH aqueous solution (2N, 3mL) and stir 4h at 50 DEG C, add HCl solution after reaction terminates and regulate PH=5, filter to obtain precipitation, collect solid and namely obtain product (210mg, productive rate: 70%), LC/MS:m/zM ++ 1=238.Example 74B. (S)-2-(2-(chloro-2, the 7-dimethyl-1H-indol-3-yls of 4-) acetamido)-N-methyl-N, the preparation of 3-diphenylpropanamide
The building-up process of this compound is the same with 1H, with corresponding acid and amine condensation gained, and LC/MS:m/zM ++ 1=474, HPLC retention time=3.10min (10-90% acetonitrile and the aqueous solution, containing 0.1%TFA).
1HNMR(400MHz，DMSO)δ11.00(s，1H)，7.77(d，J＝7.9Hz，1H)，7.40(d，J＝7.6Hz，3H)，7.21(d，J＝7.0Hz，2H)，7.12(d，J＝6.3Hz，3H)，6.76(q，J＝7.7Hz，4H)，4.48(d，J＝4.7Hz，1H)，3.67(s，2H)，3.13(s，3H)，2.78(dd，J＝13.1，4.4Hz，1H)，2.70-2.57(m，1H)，2.39(s，3H)，2.20(s，3H).
Compound 75-93 uses the preparation method similar to example 74, with corresponding acid and amine for raw material is obtained.Example 75 to 93
(example 75): 1hNMR (400MHz, CDCl 3) δ 10.99 (s, 1H), 8.04-7.91 (m, 2H), 7.42 (s, 1H), 7.22-7.14 (m, 3H), 6.89 (d, J=3.5Hz, 2H), 6.85-6.69 (m, 3H), 4.36 (d, J=5.7Hz, 1H), 3.84 (s, 3H), 3.66 (s, 2H), 3.09 (s, 3H), 2.84 (dd, J=13.1,5.5Hz, 1H), 2.69 (dd, J=13.7,8.2Hz, 1H), 2.39 (s, 3H), 2.21 (s, 3H).
(example 76): 1hNMR (400MHz, DMSO) δ 10.57 (s, 1H), 7.77 (d, J=7.9Hz, 1H), 7.41 (dd, J=12.3, 7.2Hz, 3H), 7.26 (d, J=7.0Hz, 2H), 7.12 (d, J=6.3Hz, 3H), 6.71 (d, J=5.7Hz, 2H), 6.62 (d, J=7.2Hz, 1H), 6.50 (d, J=7.2Hz, 1H), 4.46 (s, 1H), 3.54 (s, 2H), 3.14 (s, 3H), 2.77 (d, J=9.3Hz, 1H), 2.64-2.56 (m, 1H), 2.35 (s, 6H), 2.20 (s, 3H).
(example 77): 1hNMR (400MHz, CDCl 3) δ 10.58 (s, 1H), 8.07-7.96 (m, 2H), 7.48 (d, J=10.5Hz, 1H), 7.18 (s, 3H), 6.84 (d, J=8.5Hz, 3H), 6.61 (d, J=7.3Hz, 1H), 6.50 (d, J=7.0Hz, 1H), 4.32 (dd, J=13.4,8.4Hz, 1H), 3.85 (s, 3H), 3.54 (s, 2H), 3.10 (s, 3H), 2.84 (d, J=9.0Hz, 1H), 2.73-2.61 (m, 1H), 2.36 (d, J=10.6Hz, 6H), 2.21 (s, 3H).
(example 78): 1hNMR (400MHz, CDCl 3) δ 10.58 (s, 1H), 7.94 (d, J=7.7Hz, 2H), 7.41-7.28 (m, 1H), 7.19 (d, J=2.5Hz, 3H), 6.94-6.77 (m, 3H), 6.62 (d, J=7.0Hz, 1H), 6.50 (d, J=6.9Hz, 1H), 4.25 (d, 1H), 3.85 (s, 3H), 3.55 (s, 4H), 2.89-2.83 (m, 1H), 2.70-2.66 (m, 1H), 2.36 (d, J=10.7Hz, 6H), 2.21 (s, 3H), 0.95 (t, J=7.1Hz, 3H).
(example 79): 1hNMR (400MHz, CDCl 3) δ 10.57 (s, 1H), 8.26 (s, 1H), 7.96 (d, J=8.8Hz, 1H), 7.45 (d, J=9.7Hz, 1H), 7.28 (d, J=8.6Hz, 1H), 7.17 (s, 3H), 6.82 (s, 2H), 6.62 (d, J=7.3Hz, 1H), 6.50 (d, J=7.1Hz, 1H), 4.31 (s, 1H), 3.54 (s, 2H), 3.11 (s, 3H), 2.85-2.83 (m, 1H), 2.68 (s, 1H), 2.48 (s, 3H), 2.35 (t, J=6.8Hz, 6H), 2.21 (s, 3H).
(example 80): 1hNMR (400MHz, CDCl 3) δ 10.57 (s, 1H), 7.84 (d, J=7.7Hz, 1H), 7.22-7.13 (m, 3H), 6.93 (d, J=8.2Hz, 1H), 6.82 (dd, J=12.4, 9.1Hz, 3H), 6.55 (dd, J=49.2, 7.2Hz, 2H), 6.07 (d, J=4.7Hz, 2H), 4.45 (s, 1H), 3.54 (s, 2H), 3.08 (s, 3H), 2.83 (dd, J=13.6, 4.6Hz, 1H), 2.64 (dd, J=13.5, 9.4Hz, 1H), 2.36 (d, J=6.5Hz, 6H), 2.20 (s, 3H).
(example 81): 1hNMR (400MHz, CDCl 3) δ 10.65 (s, 1H), 8.22 (d, J=7.5Hz, 1H), 7.36 (t, J=8.5Hz, 3H), 7.23 (t, J=8.0Hz, 3H), 7.18-7.01 (m, 4H), (6.90 t, J=7.4Hz, 1H), 6.79 (dd, J=17.1,9.7Hz, 3H), 4.54-4.15 (m, 1H), 3.11 (s, 3H), 2.78 (d, J=9.8Hz, 1H), 2.73-2.57 (m, 1H), 2.20 (s, 3H).
(example 82): 1hNMR (400MHz, CDCl 3) δ 10.58 (s, 1H), 7.77 (d, J=7.9Hz, 1H), 7.15 (d, J=2.6Hz, 3H), 6.94 (d, J=8.6Hz, 1H), 6.86 (s, 1H), 6.79 (s, 3H), 6.62 (d, J=7.1Hz, 1H), 6.50 (d, J=7.5Hz, 1H), 4.52 (s, 1H), 3.76 (s, 3H), 3.66 (s, 3H), 3.54 (s, 2H), 3.11 (s, 3H), 2.83 (d, J=13.1Hz, 1H), 2.64 (d, J=9.8Hz, 1H), 2.36 (d, J=9.0Hz, 6H), 2.21 (s, 3H).
(example 83): 1hNMR (400MHz, DMSO) δ 11.00 (s, 1H), 8.27 (s, 1H), 8.16 (d, J=7.7Hz, 1H), 7.44 (s, 1H), 7.28 (d, J=8.3Hz, 1H), 7.18 (s, 3H), 6.89 (d, J=7.7Hz, 1H), 6.83 (s, 2H), 6.61 (d, J=7.7Hz, 1H), 4.30 (s, 1H), 3.55 (s, 2H), 3.11 (s, 3H), 2.84 (dd, J=15.7, 5.4Hz, 1H), 2.69 (dd, J=13.3, 8.3Hz, 2H), 2.48 (s, 3H), 2.39 (s, 3H), 2.23 (s, 3H).
(example 84): 1hNMR (400MHz, CDCl 3) δ 10.99 (s, 1H), 8.20 (s, 1H), 7.98 (d, J=7.7Hz, 1H), 7.39 (d, J=6.7Hz, 1H), 7.26 (d, J=8.2Hz, 1H), 7.18 (s, 3H), 6.86 (d, J=3.7Hz, 2H), 6.78-6.71 (m, 2H), 4.34 (d, J=6.0Hz, 1H), 3.66 (s, 2H), 3.10 (s, 3H), 2.83 (dd, J=13.5, 5.4Hz, 1H), 2.68 (d, J=1.8Hz, 1H), 2.47 (s, 3H), 2.39 (s, 3H), 2.21 (s, 3H).
(example 85): 1hNMR (400MHz, DMSO) δ 11.49-11.43 (m, 1H), 8.22-7.38 (m, 7H), 7.26 (d, J=8.5Hz, 1H), 7.22-7.12 (m, 3H), 7.03 (d, J=8.3Hz, 1H), 6.94-6.80 (m, 3H), 4.32 (s, J=12.5Hz, 1H), 3.66 (s, 2H), 3.11 (s, 3H), 2.85 (dd, J=13.2,5.9Hz, 1H), 2.70 (dd, J=10.4,3.6Hz, 1H), 2.47 (s, 3H), 2.23 (s, 3H).
(example 86): 1hNMR (400MHz, DMSO) δ 11.44 (s, 1H), 8.12 (d, J=7.8Hz, 1H), 7.98 (s, 1H), 7.41 (d, J=7.5Hz, 1H), 7.26-7.15 (m, 3H), 7.02 (d, J=8.1Hz, 1H), 6.89 (d, J=8.1Hz, 3H), 6.81 (d, J=8.7Hz, 1H), 4.41-4.32 (m, 1H), 3.85 (s, 3H), 3.67 (s, 2H), 3.09 (s, 3H), 2.92-2.80 (m, 1H), 2.75-2.65 (m, 1H), 2.23 (s, 3H).
(example 87): 1hNMR (400MHz, CDCl 3) δ 11.44 (s, 1H), 8.02 (d, J=7.9Hz, 1H), 7.40 (t, J=8.7Hz, 3H), 7.23 (d, J=7.3Hz, 2H), 7.13 (s, 3H), 7.02 (d, J=8.1Hz, 1H), (6.89 d, J=8.1Hz, 1H), 6.78 (s, 1H), 4.47 (s, 1H), 3.66 (s, 2H), 3.14 (s, 3H), 2.80 (d, J=8.6Hz, 1H), 2.71-2.60 (m, 1H), 2.22 (s, 3H).
(example 88): 1hNMR (400MHz, DMSO) δ 11.00 (s, 1H), 8.07 (d, J=7.4Hz, 1H), 7.50-7.35 (m, 3H), 7.29 (d, J=6.7Hz, 2H), 7.13 (s, 3H), 6.88 (d, J=7.6Hz, 1H), 6.73 (s, 2H), 6.60 (d, J=7.9Hz, 1H), 4.44 (s, 1H), 3.55 (s, 2H), 3.15 (s, 3H), 2.80 (d, J=9.8Hz, 1H), 2.66 (d, J=10.2Hz, 1H), 2.37 (s, 3H), 2.21 (s, 3H).
(example 89): 1hNMR (400MHz, DMSO) δ 11.00 (s, 1H), 8.19 (d, J=7.7Hz, 1H), 8.04 (s, 1H), 7.47 (s, 1H), 7.22-7.14 (m, 3H), 6.86 (dd, J=17.8, 8.2Hz, 4H), 6.60 (d, J=7.9Hz, 1H), 4.32 (d, J=4.3Hz, 1H), 3.85 (s, 3H), 3.55 (s, 2H), 3.10 (s, 3H), 2.86 (dd, J=13.3, 4.7Hz, 1H), 2.69 (dd, J=13.6, 9.1Hz, 1H), 2.39 (s, 3H), 2.23 (s, 3H).
(example 90): 1hNMR (400MHz, DMSO) δ 10.61 (s, 1H), 10.02 (s, 1H), 7.66 (d, J=8.3Hz, 1H), 7.27-7.07 (m, 6H), 6.89 (dt, J=23.3, 5.2Hz, 2H), 6.63 (d, J=7.3Hz, 1H), 6.51 (d, J=7.4Hz, 1H), 5.98 (d, J=1.4Hz, 2H), 4.65 (td, J=8.5, 5.2Hz, 1H), 3.60 (s, 2H), 2.98 (dd, J=13.6, 5.0Hz, 1H), 2.86 (dd, J=13.6, 9.1Hz, 1H), 2.37 (d, J=5.1Hz, 6H), 2.22 (s, 3H).
(example 91): 1hNMR (400MHz, CDCl 3) δ 8.34 (s, 1H), 7.40-7.12 (m, 4H), 7.04 (dd, J=21.6, 7.4Hz, 2H), 6.82 (d, J=7.1Hz, 2H), 6.73 (d, J=8.0Hz, 1H), 6.31 (d, J=8.3Hz, 1H), 5.98 (t, J=15.0Hz, 2H), 4.83 (dd, J=14.7, 7.2Hz, 1H), 3.62 (s, 2H), 3.12 (s, 3H), 2.82 (dt, J=14.2, 7.6Hz, 3H), 2.65 (dd, J=13.2, 6.5Hz, 1H), 2.30 (s, 3H), 1.38 (t, J=7.6Hz, 3H).
(example 92): 1hNMR (400MHz, DMSO) δ 10.56 (s, 1H), 8.25 (d, J=7.7Hz, 1H), 7.22-7.06 (m, 4H), 6.89 (dd, J=7.5, 3.4Hz, 3H), 6.81-6.59 (m, 4H), 6.05 (d, J=7.5Hz, 2H), 4.38 (td, J=8.9, 4.6Hz, 1H), 3.52-3.37 (m, 2H), 3.08 (s, 3H), 2.86 (dd, J=13.5, 4.5Hz, 1H), 2.78-2.59 (m, 3H), 2.25 (s, 3H), 1.72-1.55 (m, 2H), 0.93 (t, J=7.3Hz, 3H).
(example 93): 1hNMR (400MHz, CDCl 3) δ 10.81 (s, 1H), 8.34 (d, J=7.8Hz, 1H), 7.22-7.08 (m, 5H), 6.95-6.84 (m, 3H), 6.77 (td, J=9.4,2.6Hz, 2H), 6.70 (d, J=7.8Hz, 1H), 6.11-5.98 (m, 2H), 4.38 (s, 1H), (3.43 d, J=14.8Hz, 2H), 3.09 (s, 3H), 2.87 (dd, J=13.5,4.5Hz, 1H), 2.68 (dd, J=13.4,9.6Hz, 1H), 2.24 (s, 3H). example 94
(S)-N-(benzo [d] [1,3] dioxane-5-base)-N-methyl-2-(2-(2-methyl-7-vinyl-1H-indol-3-yl) kharophen)-3-hydrocinnamamide example 94A.2-(the bromo-2-Methyl-1H-indole of 7--3-base) ethyl acetate
Do raw material with 2 bromo phenyl hydrazine, 94A building-up process and 1C similar, LC/MS:m/zM ++ 1=296.The preparation of example 94B.2-(the bromo-2-Methyl-1H-indole of 1-ethanoyl-7--3-base) ethyl acetate
Triethylamine (4.2mL, 17.2mmol, 3.0eq) join 2-(the bromo-2-Methyl-1H-indole of 7--3-base) ethyl acetate (3.0g, 10.1mmol, in dichloromethane solution 1.0eq), then instill Acetyl Chloride 98Min. (1.57g, 11.6mmol, 2.0eq), reaction is at room temperature stirred and is spent the night.The cancellation that adds water is reacted; dichloromethane extraction (2x15mL); evaporate to dryness organic extraction; namely 2-(the bromo-2-Methyl-1H-indole of 1-ethanoyl-7--3-base) ethyl acetate (2.89g is obtained with silica gel chromatography (PE: EA=10: 1); 8.6mmol; productive rate: 85%), LC/MS:m/zM ++ 1=338.Example 94C.2-(2-methyl-7-vinyl-1H-indol-3-yl) ethyl acetate
Tributylvinyl tin (1.9g, 6.4mmol, 4.0eq) and Pd (PPh 3) 4(0.05g, 10%) adds in DMF (10mL) solution of 2-(the bromo-2-Methyl-1H-indole of 1-ethanoyl-7--3-base) ethyl acetate (540mg, 1.6mmol, 1.0eq), at N 2protection flows through night next time; until TLC (PE: EA=3: 1) Indicator Reaction terminates; add water cancellation (10mL); after being cooled to room temperature, reaction solution EA extracts (2x20mL); organic extraction evaporate to dryness silica gel chromatography (PE: EA=5: 1) namely obtains 2-(2-methyl-7-vinyl-1H-indol-3-yl) ethyl acetate (291mg; 1.2mmol, productive rate: 75%), LC/MS:m/zM ++ 1=244.Example 94D.2-(2-methyl-7-vinyl-1H-indol-3-yl) acetic acid
Make raw material with 2-(2-methyl-7-vinyl-1H-indol-3-yl) ethyl acetate, building-up process and 71A similar, LC/MS:m/zM ++ 1=216.Example 94E. (S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(7-(2-hydroxyethyl)-2-Methyl-1H-indole-3-base) kharophen)-N-methyl-3-hydrocinnamamide
With corresponding acid and amine for raw material, synthetic method and 1H similar, LC/MS:m/zM ++ 1=496, HPLC retention time=3.07min (10-90% acetonitrile and the aqueous solution, comprise 0.1%TFA).
1hNMR (400MHz, DMSO) δ 10.77 (s, 1H), 8.27 (d, J=7.7Hz, 1H), 7.25-7.12 (m, 6H), 6.91-6.83 (m, 4H), 6.77 (s, 1H), 6.70 (d, J=7.7Hz, 1H), 6.05 (d, J=7.5Hz, 2H), 5.86 (d, J=17.6Hz, 1H), 5.32 (d, J=11.3Hz, 1H), 4.39 (td, J=8.1, 4.3Hz, 1H), 3.46 (d, J=15.1Hz, 2H), 3.08 (s, 3H), 2.86 (dd, J=13.5, 4.6Hz, 1H), 2.68 (dd, J=13.3, 9.8Hz, 1H), 2.27 (s, 3H). example 95
(S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(7-(2-hydroxyethyl)-2-Methyl-1H-indole-3-base) kharophen)-N-methyl-3-hydrocinnamamide example 95A.2-(7-(2-hydroxyethyl)-2-Methyl-1H-indole-3-base) acetic acid
(2-(2-methyl-7-vinyl-1H-indol-3-yl) acetic acid (200mg, 0.93mmol, 1.0eq) be added to 9-BBN (0.5M, in tetrahydrofuran solution 5mL), stirred at ambient temperature two is little to be terminated up to the reaction of TLC (PE: EA=2: 1) detection display.Methyl alcohol (5mL) adds this reaction of cancellation, after solvent evaporated, adds H in residuum 2o 2(3mL, 30%) and NaOH (2mL, the 50%) aqueous solution, this reaction solution stirred at ambient temperature five hours, EA extracts.Organic extraction evaporate to dryness obtains residuum, purifies and obtain product 2-(7-(2-hydroxyethyl)-2-Methyl-1H-indole-3-base) acetic acid (91mg, 0.39mmol, isolated yield: 42%), LC/MS:m/zM with preparative HPLC ++ 1=234.Example 95B. (S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(7-(2-hydroxyethyl)-2-Methyl-1H-indole-3-base) kharophen)-N-methyl-3-hydrocinnamamide
With corresponding acid and amine for raw material, reaction process and 1H similar, obtain this product, LC/MS:m/zM ++ 1=514, HPLC retention time=3.23min (10-90% acetonitrile and the aqueous solution, comprise 0.1%TFA).
1hNMR (400MHz, CDCl 3) δ 8.91 (s, 1H), 7.30 (s, 1H), 7.17 (dt, J=14.1, 6.8Hz, 3H), 7.06 (t, J=7.5Hz, 1H), 6.97 (d, J=7.1Hz, 1H), 6.83 (d, J=6.9Hz, 2H), 6.73 (d, J=8.2Hz, 1H), 6.27 (d, J=8.2Hz, 1H), 6.02 (s, 2H), 4.82 (dd, J=15.0, 7.4Hz, 1H), 4.15 (q, J=7.2Hz, 1H), 4.02 (t, J=5.7Hz, 2H), 3.60 (d, J=1.5Hz, 2H), 3.09 (d, J=8.3Hz, 5H), 2.79 (dd, J=13.1, 7.6Hz, 1H), 2.64 (dd, J=13.2, 6.5Hz, 1H), 2.34 (s, 3H). example 96
(S)-2-(2-(the chloro-1-Ethyl-2-Methyl of 7--1H-indol-3-yl) kharophen)-N, 3-diphenylpropanamide
With corresponding acid and amine for raw material, building-up process and example 1 similar, LC/MS:m/zM ++ 1=474, HPLC retention time=3.50min (10-90% acetonitrile and the aqueous solution, comprise 0.1%TFA).
1HNMR(400MHz，DMSO)δ10.11(s，1H)，8.33(d，J＝8.2Hz，1H)，7.56(d，J＝7.6Hz，2H)，7.26(tdd，J＝11.1，8.0，5.8Hz，8H)，7.05(dd，J＝12.3，7.4Hz，2H)，6.87(t，J＝7.7Hz，1H)，4.64(td，J＝9.3，4.6Hz，1H)，4.43(dd，J＝8.2，6.4Hz，2H)，3.52(d，J＝5.1Hz，2H)，3.02(d，J＝4.7Hz，1H)，2.89(dd，J＝13.4，9.8Hz，1H)，2.27(s，3H)，1.25(t，J＝7.0Hz，3H).
Make raw material with corresponding acid and amine, compound 97-103 building-up process is similar with example 96.Example 97 to 103
(example 97): 1hNMR (400MHz, DMSO) δ 10.15 (s, 1H), 8.29 (d, J=2.6Hz, 1H), 7.84 (dd, J=8.9, 2.7Hz, 1H), 7.80 (d, J=8.1Hz, 1H), 7.29-7.13 (m, 5H), 6.80 (d, J=8.8Hz, 1H), 6.63 (d, J=7.3Hz, 1H), 6.52 (d, J=7.4Hz, 1H), 4.72-4.60 (m, 1H), 4.27 (q, J=7.1Hz, 2H), 3.81 (s, 3H), 3.65 (s, 2H), 3.02 (dd, J=13.6, 5.0Hz, 1H), 2.88 (dd, J=13.7, 9.2Hz, 1H), 2.62 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H), 1.17 (t, J=7.1Hz, 3H).
(example 98): 1hNMR (400MHz, CDCl 3) δ 10.01 (s, 1H), 7.70 (d, J=8.2Hz, 1H), 7.30-7.08 (m, 6H), 6.92 (dd, J=8.4, 2.0Hz, 1H), 6.85 (d, J=8.4Hz, 1H), 6.64 (d, J=7.2Hz, 1H), 6.52 (d, J=7.2Hz, 1H), 6.03-5.92 (m, 2H), 4.69-4.56 (m, 1H), 4.27 (q, J=7.0Hz, 2H), 3.65 (s, 2H), 2.99 (dd, J=13.6, 5.0Hz, 1H), 2.86 (dd, J=13.6, 9.1Hz, 1H), 2.62 (s, 3H), 2.39 (s, 3H), 2.18 (d, J=10.0Hz, 3H), 1.17 (t, J=7.0Hz, 3H).
(example 99): 1hNMR (400MHz, DMSO) δ 10.03 (s, 1H), 8.32 (d, J=8.4Hz, 1H), 7.33 (d, J=7.8Hz, 1H), 7.29-7.14 (m, 6H), 7.04 (d, J=7.5Hz, 1H), 6.93 (dd, J=8.4, 1.9Hz, 1H), 6.91-6.81 (m, 2H), 6.04-5.92 (m, 2H), 4.59 (dd, J=13.3, 8.8Hz, 1H), 4.44 (d, J=7.1Hz, 2H), 3.52 (d, J=4.3Hz, 2H), 3.02 (dd, J=13.6, 4.8Hz, 1H), 2.87 (dd, J=13.7, 9.8Hz, 1H), 2.28 (s, 3H), 1.25-1.19 (m, 3H).
(example 100): 1hNMR (400MHz, CDCl 3) δ 10.02 (s, 1H), 7.93 (d, J=8.4Hz, 1H), 7.26-7.19 (m, 5H), 6.98-6.88 (m, 2H), 6.85 (d, J=8.4Hz, 1H), 6.63 (d, J=8.3Hz, 1H), 5.98 (d, J=1.2Hz, 2H), 4.69-4.59 (m, 1H), 4.46 (q, J=7.1Hz, 2H), 3.67 (s, 2H), 3.01 (dd, J=13.5, 4.9Hz, 1H), 2.87 (dd, J=13.5, 9.6Hz, 1H), 2.41 (s, 3H), 2.22 (s, 3H), 1.24 (t, J=7.0Hz, 3H).
(example 101): 1hNMR (400MHz, DMSO) δ 10.11 (s, 1H), 7.94 (d, J=8.2Hz, 1H), 7.56 (d, J=7.6Hz, 2H), 7.31 (t, J=7.9Hz, 2H), 7.26-7.15 (m, 5H), 7.06 (t, J=7.4Hz, 1H), 6.91 (d, J=7.7Hz, 1H), 6.63 (d, J=7.7Hz, 1H), 4.73-4.64 (m, 1H), 4.46 (q, J=7.1Hz, 2H), 3.67 (s, 2H), 3.04 (dd, J=13.7, 4.9Hz, 1H), 2.88 (dd, J=13.8, 9.4Hz, 1H), 2.41 (s, 3H), 2.21 (s, 3H), 1.24 (t, J=7.0Hz, 3H).
(example 102): 1hNMR (400MHz, DMSO) δ 10.16 (s, 1H), 8.31 (s, 1H), 8.00 (d, J=7.6Hz, 1H), 7.85 (d, J=7.9Hz, 1H), 7.22 (s, 5H), 6.92 (d, J=7.7Hz, 1H), 6.81 (d, J=8.6Hz, 1H), 6.63 (d, J=7.6Hz, 1H), 4.68 (s, 1H), 4.46 (d, J=6.7Hz, 2H), 3.82 (s, 3H), 3.68 (s, 2H), 3.05 (d, J=9.5Hz, 1H), 2.96-2.85 (m, 1H), 2.42 (s, 3H), 2.22 (s, 3H), 1.24 (s, 3H).
(example 103): 1hNMR (400MHz, DMSO) δ 10.14 (s, 1H), 8.36 (d, J=8.2Hz, 1H), 8.31 (d, J=2.6Hz, 1H), 7.85 (dd, J=8.9, 2.6Hz, 1H), 7.34 (d, J=7.8Hz, 1H), 7.29-7.14 (m, 5H), 7.04 (d, J=7.6Hz, 1H), 6.87 (t, J=7.7Hz, 1H), 6.80 (d, J=8.9Hz, 1H), 4.62 (dd, J=13.6, 9.1Hz, 1H), 4.44 (d, J=7.0Hz, 2H), 3.82 (s, 3H), 3.52 (d, J=4.4Hz, 2H), 3.04 (dd, J=13.5, 4.9Hz, 1H), 2.89 (dd, J=13.4, 9.7Hz, 1H), 2.28 (s, 3H), 1.25 (t, J=6.9Hz, 3H). example 104
(S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(1-ethyl-2,4,7-trimethylammonium-1H-indol-3-yl) acetamido)-N-methyl-3-(pyridin-4-yl) propionic acid amide example 104A. (S)-2-amido-N-(benzo [d] [1,3] dioxane-5-base)-N-methyl-3-(pyridin-4-yl) propionic acid amide
To (S)-2-(tertiary butyl manthanoate) amido)-3-(pyridin-4-yl) propionic acid (500mg, 3.0mmol, 1.0eq), with N-methyl benzo [d] [1,3] dioxane-5-amine (549mg, 3.6mmol, 1.2eq) DCM (10mL) mixed solution in, add EDCI (864mg, 4.5mmol, 1.5eq), HOBt (810mg, 6.0mmol, 2.0eq) with DIPEA (1mL, 6.0mmol, 2.0eq), at N 2stirred overnight at room temperature under the condition of protection.Reaction solution washes three times with water, namely dry, concentrated, column chromatography purification obtains (S)-(1-(benzo [d] [1,3] dioxane-5-methylamino)-1-oxo-3-(pyridin-4-yl) propyl group-2-base) the amidocarbonic acid tert-butyl ester (450mg, 1.13mmol, productive rate: 37.7%), LC/MS:m/zM ++ 1=400.The preparation of example 104B. (S)-2-amido-N-(benzo [d] [1,3] dioxane-5-base)-N-methyl-3-(pyridin-4-yl) propionic acid amide
To (S)-(1-(benzo [d] [1,3] dioxane-5-methylamino)-1-oxo-3-(pyridin-4-yl) propyl group-2-base) the amidocarbonic acid tert-butyl ester (450mg, 1.13mmol, in MeOH solution 1.0eq), at 0 DEG C, add the MeOH solution of Acetyl Chloride 98Min. (3mL).Reaction solution stirring at room temperature two hours, solvent removed in vacuo, obtains crude product (330mg, 1.10mmol, 97.3%), LC/MS:m/zM ++ 1=300.Example 104C. (S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(1-ethyl-2,4,7-trimethylammonium-1H-indol-3-yl) acetamido) preparation of-N-methyl-3-(pyridin-4-yl) hydrocinnamamide
Make raw material with corresponding acid and amine, building-up process and 1H similar, LC/MS:m/zM ++ 1=527, HPLC retention time=3.60min (10-90% acetonitrile and the aqueous solution, comprise 0.1%TFA).
1HNMR(400MHz，DMSO)δ8.34(d，J＝5.7Hz，2H)，7.94(d，J＝8.0Hz，1H)，6.93(dd，J＝17.4，5.0Hz，2H)，6.87-6.76(m，3H)，6.62(d，J＝7.3Hz，1H)，6.50(d，J＝7.2Hz，1H)，6.07(d，J＝2.5Hz，2H)，4.52(s，1H)，4.25(q，J＝7.0Hz，2H)，3.58(s，2H)，3.10(s，3H)，2.86(dd，J＝13.6，3.9Hz，1H)，2.75-2.64(m，1H)，2.61(s，3H)，2.34(s，3H)，2.17(s，3H)，1.16(t，J＝6.9Hz，3H).
Compound 105-107 is raw material preparation with corresponding acid and amine, and process is similar with example 104.Example 105 to 107
(example 105): 1hNMR (400MHz, DMSO) δ 6.81 (dd, J=7.6, 4.7Hz, 2H), 6.73 (dd, J=10.0, 7.5Hz, 3H), 6.61 (dd, J=8.6, 5.4Hz, 2H), 6.51 (s, 1H), 6.09 (d, J=8.5Hz, 1H), 6.05 (dd, J=2.9, 1.3Hz, 2H), 4.81 (dd, J=15.1, 7.1Hz, 1H), 4.46-4.28 (m, 2H), 3.77 (q, J=18.1Hz, 2H), 3.14 (s, 3H), 2.75 (s, 3H), 2.70 (dd, J=13.5, 6.8Hz, 1H), 2.53 (dd, J=13.6, 7.1Hz, 1H), 2.45 (s, 3H), 2.30 (s, 3H), 1.31 (t, J=7.1Hz, 3H).
(example 106): 1hNMR (400MHz, CDCl 3) δ 8.05 (d, J=4.1Hz, 1H), 7.30 (s, 2H), 7.03-6.96 (m, 1H), 6.81 (dd, J=13.4, 7.7Hz, 2H), 6.67 (d, J=7.2Hz, 1H), 6.61 (t, J=7.8Hz, 2H), 6.05 (d, J=1.7Hz, 2H), 4.89 (dd, J=13.8, 7.6Hz, 1H), 4.42-4.34 (m, 2H), 3.78 (q, J=18.0Hz, 2H), 3.17 (s, 3H), 2.89 (dd, J=13.2, 5.5Hz, 1H), 2.81-2.68 (m, 4H), 2.45 (s, 3H), 2.33 (s, 4H), 1.31 (t, J=7.2Hz, 10H).
(example 107): 1hNMR (400MHz, DMSO) δ 8.42 (s, 1H), 8.05 (d, J=10.3Hz, 1H), 6.95 (t, J=3.2Hz, 2H), 6.81 (dd, J=7.7, 5.1Hz, 2H), 6.72 (d, J=7.4Hz, 1H), 6.18 (d, J=8.4Hz, 1H), 6.06 (s, 2H), 4.87 (dd, J=15.2, 7.2Hz, 1H), 4.43-4.32 (m, 2H), 3.84-3.72 (m, 2H), 3.14 (s, 3H), 2.78 (d, J=6.6Hz, 1H), 2.74 (d, J=4.8Hz, 3H), 2.57 (dd, J=13.7, 7.2Hz, 1H), 2.47 (s, 3H), 2.30 (s, 3H), 1.32 (t, J=7.1Hz, 4H). example 108
(S)-2-(2-(3-Ethyl-2-Methyl-1H-indoles-1-base) acetamido)-N-methyl-N, the preparation of 3-diphenylpropanamide the preparation of example 108A. phenylhydrazine
-5 DEG C time, NaNO 2(4.5g, 64.5mmol, 1.2eq) aqueous solution is added to the aniline (10.0g of stirring, 53.8mmol, 1.0eq) HCl (180mL, 6M) solution in, until solution becomes clarification, then maintain the temperature between-5 DEG C to 5 DEG C, add SnCl 2(16.9g, 75.3mmol, 1.4eq) HCl (90mL, 6M) solution, filter after stirring 10min, filtrate is adjusted to pH > 11, EA with the saturated NaOH aqueous solution and extracts, washes with water, dried over sodium sulfate, under low pressure concentrate and obtain crude product phenylhydrazine (2.0g, 18.5mmol, productive rate: 34.5%), LC/MS:m/zM ++ 1=109.Example 108B.3-Ethyl-2-Methyl-1H-indoles
Saturated NaHCO is added to phenylhydrazine (2.0g, 18.5mmol, 1.0eq) and penta being dissolved in the mixed solution of DCM of-2-ketone (2.4g, 27.3mmol, 1.5eq) 3the aqueous solution (1: 1), stirred at ambient temperature 3h.Reaction solution DCM extracts, organic extraction washes with water, anhydrous Na 2sO 4dry, low-press thick is reduced to dry intermediate.This intermediate and anhydrous ZnCl 2(3.0g, 22.2mmol) is mixed and heated to 140 DEG C and spends the night.The crude product solution that MeOH dissolves is filtered, and low-press thick is reduced to dry crude product, and purification by silica gel column chromatography (PE: EA=5: 1) namely obtains 3-Ethyl-2-Methyl-1H indoles (500mg, 3.1mmol, productive rate: 17.0%), LC/MS:m/zM ++ 1=160.Example 108C.2-(3-Ethyl-2-Methyl-1H-indoles-1-base) acetic acid
By NaH (310mg, 7.8mmol, 2.5eq) slowly add in the tetrahydrofuran solution of 3-Ethyl-2-Methyl-1H-indoles (500mg, 3.1mmol, 1.0eq), after 20min, 2-ethyl bromoacetate (617.9mg, 3.7mmol, 1.2eq) is added dropwise in the time of 30 minutes, reaction solution 0 DEG C stirs 30min, terminates to the reaction of TLC (DCM: MeOH=10: 1) detection display.Water (15mL) adds cancellation reaction, then adds NaOH (1.2g, 31mmol, 10eq), at room temperature continue to stir 30min, then add HCl (2M) and regulate PH=4, collecting by filtration gained precipitates, washing, 50 DEG C of dryings, obtain 2-(3-Ethyl-2-Methyl-1H-indoles-1-base) acetic acid (400mg, 1.8mmol, productive rate: 58.7%), LC/MS:m/zM ++ 1=218.Example 108D. (S)-2-(2-(3-Ethyl-2-Methyl-1H-indoles-1-base) acetamido)-N-methyl-N, 3-diphenylpropanamide
To 2-(3-Ethyl-2-Methyl-1H-indoles-1-base) acetic acid (50mg, 0.2mmol, 1.0eq), (S)-2-amido-N-methyl-N, 3-diphenylpropanamide (76.2mg, 0.3mmol, 1.5eq) the mixed solution (2.0mL) being dissolved in DCM in, add EDCI (57.3mg, 0.3mmol, 1.5eq), HOBt (54mg, 0.4mmol, 2.0eq) with DIPEA (51.6mg, 0.4mmol, 2.0eq), at N 2stirred overnight at room temperature under the condition of protection.Reaction solution washes 3 times with water, dry and concentrated, namely residuum preparative HPLC purifying obtains (S)-2-(2-(3-Ethyl-2-Methyl-1H-indoles-1-base) acetamido)-N-methyl-N, 3-diphenylpropanamide (25mg, 0.06mmol, productive rate: 24%), LC/MS:m/zM++1=454, HPLC retention time=3.48min (10-90% acetonitrile and the aqueous solution, containing 0.1%TFA).
1HNMR(400MHz，CDCl 3)δ8.68(d，J＝8.2Hz，1H)，7.48-7.33(m，4H)，7.26(d，J＝7.4Hz，2H)，7.15(d，J＝2.4Hz，3H)，7.10(d，J＝7.0Hz，1H)，7.00-6.87(m，2H)，6.79(s，2H)，4.68(q，J＝16.6Hz，2H)，4.45(s，1H)，3.16(s，3H)，2.93-2.79(m，1H)，2.69(d，J＝10.4Hz，1H)，2.62(dd，J＝14.8，7.3Hz，2H)，2.13(s，3H)，1.11(t，J＝7.5Hz，3H).
So that acid and amine are for raw material accordingly, compound 109-119 building-up process is similar with example 108.Example 109 to 119
(example 109): 1hNMR (400MHz, CDCl 3) δ 10.21 (s, 1H), 8.63 (d, J=8.4Hz, 1H), 8.31 (d, J=2.5Hz, 1H), 7.86 (dd, J=8.8, 2.7Hz, 1H), 7.40 (d, J=7.1Hz, 1H), 7.28 (d, J=4.3Hz, 4H), 7.22 (dd, J=8.9, 4.3Hz, 1H), 7.15 (d, J=7.3Hz, 1H), 7.03-6.90 (m, 2H), 6.81 (d, J=8.8Hz, 1H), 4.84-4.62 (m, 3H), 3.82 (s, 3H), 3.09 (dd, J=13.8, 5.0Hz, 1H), 2.90 (dd, J=13.6, 9.5Hz, 1H), 2.63 (q, J=7.4Hz, 2H), 2.13 (d, J=12.6Hz, 3H), 1.11 (t, J=7.5Hz, 3H).
(example 110): 1hNMR (400MHz, DMSO) δ 8.78 (d, J=7.9Hz, 1H), 8.02 (s, 1H), 7.47 (d, J=8.0Hz, 1H), 7.39 (d, J=7.2Hz, 1H), 7.21 (s, 3H), 7.12 (d, J=7.6Hz, 1H), 7.02-6.89 (m, 4H), 6.82 (d, J=8.7Hz, 1H), 4.69 (q, J=16.8Hz, 2H), 4.42-4.24 (m, 1H), 3.84 (s, 3H), 3.12 (s, 3H), 2.93 (dd, J=13.3, 4.6Hz, 1H), 2.82-2.69 (m, 1H), 2.63 (q, J=7.5Hz, 2H), 2.15 (s, 3H), 1.11 (t, J=7.4Hz, 3H).
(example 111): 1hNMR (400MHz, CDCl 3) δ 8.67 (d, J=7.7Hz, 1H), 7.39 (d, J=7.0Hz, 1H), 7.19 (t, J=6.6Hz, 3H), 7.11 (d, J=7.0Hz, 1H), 6.93 (dt, J=17.1, 4.9Hz, 5H), 6.77 (s, 1H), 6.71 (d, J=8.0Hz, 1H), 6.05 (d, J=5.3Hz, 2H), 4.76-4.59 (m, 2H), 4.46 (s, 1H), 3.09 (s, 3H), 2.92 (dd, J=13.5, 4.4Hz, 1H), 2.70 (dd, J=13.5, 9.8Hz, 1H), 2.62 (q, J=7.6Hz, 2H), 2.14 (s, 3H), 1.11 (t, J=7.5Hz, 3H).
(example 112): 1hNMR (400MHz, CDCl 3) δ 8.76 (d, J=7.8Hz, 1H), 8.24 (s, 1H), 7.48-7.35 (m, 2H), 7.26 (d, J=8.2Hz, 1H), 7.20 (d, J=3.6Hz, 3H), 7.12 (d, J=7.5Hz, 1H), 6.96 (dd, J=14.0, 7.1Hz, 2H), 6.92-6.82 (m, 2H), 4.68 (q, J=16.8Hz, 2H), 4.32 (dd, J=13.4, 8.2Hz, 1H), 3.12 (s, 3H), 2.92 (dd, J=13.4, 5.0Hz, 1H), 2.72 (dd, J=13.3, 9.3Hz, 1H), 2.62 (q, J=7.4Hz, 2H), 2.46 (s, 3H), 2.14 (s, 3H), 1.11 (t, J=7.5Hz, 3H).
(example 113): 1hNMR (400MHz, DMSO) δ 8.75 (d, J=7.9Hz, 1H), 7.95 (d, J=8.4Hz, 2H), 7.80 (d, J=7.2Hz, 1H), 7.63 (s, 1H), 7.56 (dd, J=17.5, 13.6Hz, 2H), 7.35 (dd, J=17.1, 7.8Hz, 2H), 7.14 (dd, J=18.6, 7.6Hz, 4H), 6.96 (dt, J=14.8, 7.3Hz, 2H), 6.80 (d, J=7.1Hz, 2H), 6.14 (s, 1H), 4.73 (q, J=16.9Hz, 2H), 4.49 (dd, J=13.1, 8.5Hz, 1H), 3.24 (s, 3H), 2.99 (dd, J=12.9, 5.3Hz, 1H), 2.85-2.66 (m, 1H), 2.22 (s, 3H).
(example 114): 1hNMR (400MHz, DMSO) δ 7.60-7.56 (m, 2H), 7.48-7.41 (m, 2H), 7.39-7.31 (m, 1H), 7.21-6.97 (m, 15H), 6.86 (td, J=7.6, 1.2Hz, 1H), 6.69 (d, J=6.9Hz, 2H), 6.53 (dd, J=7.7, 1.6Hz, 1H), 6.38 (dd, J=15.1, 10.5Hz, 4H), 5.94 (dd, J=125.8, 8.7Hz, 2H), 4.79-4.55 (m, 6H), 3.82 (d, J=37.6Hz, 6H), 3.15 (d, J=37.6Hz, 6H), 2.79-2.49 (m, 3H), 2.32 (dd, J=30.7, 0.7Hz, 6H).
(example 115): 1hNMR (400MHz, CDCl 3) δ 7.59 (dd, J=5.2, 2.5Hz, 4H), 7.38-7.33 (m, 8H), 7.20-7.01 (m, 26H), 6.66 (d, J=7.7Hz, 3H), 6.55 (d, J=7.2Hz, 5H), 6.39 (dd, J=16.0, 6.3Hz, 6H), 5.78 (dd, J=62.4, 8.3Hz, 4H), 4.68-4.53 (m, 8H), 4.47 (td, J=8.5, 5.7Hz, 3H), 3.17 (d, J=7.8Hz, 11H), 2.84-2.60 (m, 4H), 2.52-2.34 (m, 4H), 2.30 (d, J=5.0Hz, 12H), 2.28 (d, J=9.8Hz, 11H).
(example 116): 1hNMR (400MHz, CDCl 3) δ 8.99 (d, J=2.8Hz, 1H), 8.12 (t, J=8.3Hz, 2H), 7.58 (dt, J=16.0, 8.1Hz, 1H), 7.48 (dd, J=8.3, 4.3Hz, 1H), 7.42-7.29 (m, 2H), 7.23-7.11 (m, 4H), 7.07 (t, J=7.6Hz, 2H), 6.57 (d, J=7.3Hz, 2H), 6.37 (d, J=9.9Hz, 1H), 5.87 (d, J=7.8Hz, 1H), 4.83-4.58 (m, 3H), 3.28 (s, 3H), 2.74 (dd, J=13.2, 7.3Hz, 1H), 2.49 (dd, J=13.3, 7.5Hz, 1H), 2.36 (s, 3H).
(example 117): 1hNMR (400MHz, CDCl 3) δ 8.86 (dd, J=72.8, 2.7Hz, 1H), 8.23 (dd, J=38.5, 7.6Hz, 1H), 7.92 (dd, J=22.0, 7.8Hz, 1H), 7.83-7.63 (m, 9H), 7.56 (d, J=5.8Hz, 1H), 7.51-7.39 (m, 2H), 7.34 (dd, J=14.9, 7.4Hz, 1H), 7.23-7.08 (m, 3H), 7.06-6.94 (m, 1H), 6.84 (dd, J=19.6, 7.4Hz, 2H), 6.34 (d, J=15.7Hz, 1H), 6.25 (d, J=6.4Hz, 0.5H), 6.10 (d, J=6.9Hz, 1H), 5.79 (d, J=7.8Hz, 0.5H), 4.76-4.44 (m, 3H), 3.53-3.18 (m, 3H), 2.83-2.52 (m, 2H), 2.32 (d, J=52.6Hz, 3H).
(example 118): 1hNMR (400MHz, DMSO) δ 7.49-6.86 (m, 9H), 6.18 (s, 1H), 5.05-4.86 (m, 1H), 4.75 (s, 2H), 3.52 (s, 1H), 3.05-2.80 (m, 2H), 2.67 (s, 3H), 2.27 (s, 3H), 1.40 (ddd, J=101.4,87.8,50.7Hz, 10H).
(example 119): 1hNMR (400MHz, CDCl 3) δ 7.58 (d, J=7.3Hz, 1H), 7.24-7.11 (m, 5H), 7.00-6.94 (m, 1H), 6.93-6.86 (m, 1H), 6.37 (d, J=4.9Hz, 1H), 6.27 (s, 1H), 5.16 (ddd, J=68.6, 15.1, 7.2Hz, 1H), 4.68 (t, J=9.0Hz, 2H), 4.89-4.05 (m, 1H), 2.83 (dtd, J=34.8, 13.6, 6.9Hz, 2H), 2.65 (d, J=55.1Hz, 3H), 2.36 (d, J=6.1Hz, 3H), 1.74-1.50 (m, 8H). example 120
(S)-2-(2-(3-ethyl-2,4-dimethyl-1H-indoles-1-base) acetamido)-N-(6-methoxypyridine-3-base)-N-methyl-3-hydrocinnamamide the bromo-5-monomethylaniline of example 120A.2-
Ranney nickel (2mL) is joined bromo-4-methyl-2-oil of mirbane (5g, 23.3mmol, in MeOH solution 1.0eq), hydrazine hydrate (2.33g is instilled after stirring 15min, 46.6mmol, 2eq), filter after reaction solution stirred at ambient temperature 2h, filter vacuum concentrates after washing (2x30mL), and EA extracts (2x20mL), merges organic extract, namely evaporate to dryness obtains the bromo-5-monomethylaniline of 2-(4.2g, 22.7mmol, productive rate: 97.4%), LC/MS:m/zM ++ 1=186.Example 120B.1-(the bromo-5-aminomethyl phenyl of 2-) hydrazine
At-5 DEG C, by NaNO 2the HCl (80mL, 6M) that (1.9g, 27.2mmol, 1.2eq) aqueous solution is added to the bromo-5-monomethylaniline (4.2g, 22.7mmol, 1.0eq) of 2-stirs in liquid, clarifies to reaction solution.Then maintenance temperature of reaction is at-5 DEG C to 5 DEG C, adds SnCl 2(7.2g, 31.8mmol, 1.4eq) HCl (50mL, 6M) solution, reaction solution filters after stirring 10min, filtrate regulates pH > 11, EA to extract after washing, anhydrous sodium sulfate drying with the NaOH aqueous solution, namely concentrating under reduced pressure obtains the bromo-5-methyl-phenyl hydrazine of 2-(3.0g, 15.0mmol, productive rate: 66.1%), LC/MS:m/zM ++ 1=201.Example 120C.7-bromo-3-ethyl-2,4-dimethyl-1H-indoles
Saturated NaHCO is added to 1-(2-bromo-5-aminomethyl phenyl) hydrazine (3.0g, 15.0mmol, 1.0eq) and being dissolved in the mixing solutions of DCM of diacetylmethane (1.94g, 22.5mmol, 1.5eq) 3solution (1: 1), stirred at ambient temperature 3h.Reaction solution DCM extracts, and the organic layers with water after merging is washed, anhydrous sodium sulfate drying, filters, is evaporated to and is drying to obtain intermediate, then intermediate and anhydrous ZnCl 2(2.4g, 18.0mmol, 1.2eq) is mixed and heated to 140 DEG C and spends the night.The crude product that MeOH dissolves filters, be evaporated to dry crude product, purification by silica gel column chromatography (PE: EA=5: 1) namely obtains 7-bromo-3-ethyl-2,4-dimethyl-1H-indoles (800mg, 3.2mmol. productive rate: 21.3%), LC/MS:m/zM ++ 1=252.Example 120D.3-ethyl-2,4-dimethyl-1H-indoles
Lithium Aluminium Hydride (384.0mg, 9.6mmol, anhydrous tetrahydro furan (8mL) stirred at ambient temperature 3.0eq) 20 minutes, then the bromo-3-ethyl-2 of 7-is added dropwise to, 4-dimethyl-1H-indoles (800mg, 3.2mmol, 1.0eq) solution, reaction solution room temperature for overnight.Filter after frozen water cancellation reaction, filter vacuum is dry, and EA extracts (2x50mL), and namely organic extract evaporate to dryness obtains 3-ethyl-2,4-dimethyl-1H-indoles (300mg, 1.73mmol, productive rate: 54.1%).Example 120E.2-(3-ethyl-2,4-dimethyl-1H-indoles-1-base) acetic acid
By NaH (124.6mg, 5.2mmol, 3eq) slowly add 3-ethyl-2,4-dimethyl-1H-indoles (300mg, 1.73mmol, in DMF solution 1.0eq), after 20min, in the time of 30 minutes, be added dropwise to 2-ethyl bromoacetate (346.5mg, 2.1mmol, 1.2eq), reaction solution stirs 1h at 0 DEG C, until the reaction of TLC (DCM: MeOH=10: 1) detection display terminates.Add 15mL shrend to go out reaction, then add NaOH (700mg, 17.3mmol, 10eq), stirred at ambient temperature 30min, then adds HCl (2M) and regulates PH to 4, form precipitation, collected by filtration, washing, is drying to obtain 2-(3-ethyl-2 at 50 DEG C, 4-dimethyl-1H-indoles-1-base) acetic acid (250mg, 1.1mmol, productive rate: 63.6%), LC/MS:m/zM ++ 1=232.Example 120F. (S)-2-(2-(3-ethyl-2,4-dimethyl-1H-indoles-1-base) acetamido)-N-(6-methoxypyridine-3-base)-N-methyl-3-hydrocinnamamide
To 2-(3-ethyl-2,4-dimethyl-1H-indoles-1-base) acetic acid (80mg, 0.35mmol, 1.0eq), (S)-2-amido-N-(6-methoxypyridine-3-base)-N-methyl-3-hydrocinnamamide (125.2mg, 0.42mmol, 1.2eq) the mixed solution (3.0mL) being dissolved in DCM in, add EDCI (101.2mg, 0.53mmol, 1.5eq), HOBt (94.5mg, 0.7mmol, 2.0eq) with DIPEA (90.3mg, 0.7mmol, 2.0eq), reaction solution is at N 2the lower stirred overnight at room temperature of protection.Reaction solution washes three times, dry concentrated, purify with preparative HPLC and obtain (S)-2-(2-(3-ethyl-2,4-dimethyl-1H-indoles-1-base) acetamido)-N-(6-methoxypyridine-3-base)-N-methyl-3-hydrocinnamamide (23.6mg, 0.05mmol, isolated productive rate: 14.3%), LC/MS:m/zM ++ 1=499, HPLC retention time=3.48min (10-90% acetonitrile and the aqueous solution, comprise 0.1%TFA).
1HNMR(400MHz，DMSO)δ8.73(d，J＝7.6Hz，1H)，8.01(s，1H)，7.46(d，J＝9.6Hz，1H)，7.21(d，J＝5.9Hz，3H)，6.93(t，J＝7.5Hz，3H)，6.88-6.78(m，2H)，6.67(d，J＝6.9Hz，1H)，4.67(q，J＝16.9Hz，2H)，4.35(dd，J＝13.5，8.3Hz，1H)，3.84(s，3H)，3.11(s，3H)，2.92(dd，J＝13.7，4.8Hz，1H)，2.73(t，J＝10.3Hz，3H)，2.58(s，3H)，2.14(s，3H)，1.10(t，J＝7.4Hz，3H).
Make raw material with corresponding acid and amine, the building-up process of compound 121-126 is similar with example 120.Example 121 to 126
(example 121): 1hNMR (400MHz, DMSO) δ 7.10 (ddd, J=30.0, 16.8, 7.6Hz, 5H), 6.94 (d, J=8.2Hz, 1H), 6.89 (d, J=7.1Hz, 1H), 6.79 (d, J=8.5Hz, 1H), 6.66 (d, J=7.2Hz, 2H), 6.05 (s, 2H), 5.80 (d, J=8.0Hz, 1H), 4.74 (d, J=6.4Hz, 1H), 4.61 (q, J=18.0Hz, 2H), 3.15 (s, 3H), 2.89 (q, J=7.6Hz, 2H), 2.80-2.69 (m, 4H), 2.49 (dd, J=13.5, 7.7Hz, 1H), 2.24 (s, 3H), 1.23 (t, J=7.5Hz, 3H).
(example 122): 1hNMR (400MHz, CDCl 3) δ 8.01 (s, 1H), 7.27-7.10 (m, 5H), 7.08-7.01 (m, 1H), 6.95 (d, J=8.1Hz, 1H), 6.89 (d, J=7.0Hz, 1H), 6.66 (d, J=7.5Hz, 2H), 5.79 (d, J=7.8Hz, 1H), 4.72-4.53 (m, 3H), 3.17 (d, J=7.0Hz, 3H), 2.89 (q, J=7.5Hz, 2H), 2.75 (s, 3H), 2.73-2.66 (m, 1H), 2.61 (s, 3H), 2.51 (dd, J=13.4, 7.6Hz, 1H), 2.25 (s, 3H), 1.24 (t, J=7.5Hz, 3H).
(example 123): 1hNMR (400MHz, DMSO) δ 8.73 (d, J=8.0Hz, 1H), 7.21 (q, J=6.3Hz, 3H), 7.10 (dd, J=6.8, 2.2Hz, 1H), 6.98-6.87 (m, 5H), 6.77 (s, 1H), 6.71 (d, J=8.1Hz, 1H), 6.06 (d, J=4.3Hz, 2H), 4.72 (q, J=16.8Hz, 2H), 4.48 (s, 1H), 3.10 (s, 3H), 2.93 (dd, J=13.4, 4.3Hz, 1H), 2.82 (q, J=7.4Hz, 2H), 2.70 (dd, J=13.3, 9.7Hz, 1H), 2.15 (s, 3H), 1.12 (t, J=7.4Hz, 3H).
(example 124): 1hNMR (400MHz, DMSO) δ 8.72 (d, J=7.5Hz, 2H), 8.24 (s, 2H), 7.43 (d, J=7.8Hz, 2H), 7.30-7.16 (m, 9H), 6.98-6.79 (m, 8H), 6.67 (d, J=6.5Hz, 2H), 4.67 (d, J=7.9Hz, 6H), 4.33 (s, 2H), 3.45 (s, 4H), 3.13 (s, 6H), 2.91 (s, 6H), 2.71 (d, J=13.2Hz, 3H), 2.59 (s, 6H), 2.47 (s, 6H), 2.14 (s, 6H).
(example 125): 1hNMR (400MHz, CDCl 3) δ 8.62 (d, J=8.0Hz, 1H), 7.21 (q, J=5.7Hz, 3H), 6.92 (t, J=10.0Hz, 4H), 6.82 (t, J=7.6Hz, 1H), 6.76 (s, 1H), 6.68 (dd, J=13.8, 7.6Hz, 2H), 6.06 (d, J=4.7Hz, 2H), 4.66 (d, J=6.4Hz, 3H), 4.47 (s, 1H), 3.46 (d, J=7.5Hz, 2H), 3.10 (s, 3H), 2.91 (dd, J=14.9, 7.7Hz, 3H), 2.73 (s, 1H), 2.58 (s, 3H), 2.14 (s, 3H).
(example 126): 1hNMR (400MHz, DMSO) δ 8.71 (d, J=7.9Hz, 1H), 7.20 (t, J=6.6Hz, 3H), 7.11 (dd, J=7.0, 2.0Hz, 1H), 6.93 (dd, J=13.1, 7.0Hz, 5H), 6.77 (s, 1H), 6.71 (d, J=8.2Hz, 1H), 6.06 (d, J=4.1Hz, 2H), 4.72 (q, J=16.8Hz, 2H), 4.59 (s, 1H), 4.48 (s, 1H), 3.51 (s, 2H), 3.10 (s, 3H), 3.04-2.87 (m, 3H), 2.70 (dd, J=13.4, 9.5Hz, 1H), 2.15 (s, 3H). example 127
(S)-N-([1,3] dioxane [4,5-b] pyridine-5-base) preparation (PR-001243) of-2-(2-(the chloro-3-of 4-(2-hydroxyethyl)-2-Methyl-1H-indole-1-base) acetamido)-N-methyl-3-Phenylpropionamide the preparation of example 127A. [1,3] dioxane [4,5-b] pyridine
By CH 2br 2(7.83g, 45.0mmol, 1.0eq) is added in the 50mLNMP solution of 2,3-dihydroxy-pyridine (5.0g, 45.0mmol, 1.0eq), is then heated to 120 DEG C of reaction 48h.The NMP that decompression removing is unnecessary, is dissolved into resistates in EA, with water and salt washing, dry, concentrates and obtain [1,3] dioxane [4,5-b] pyridine (1.0g, 8.1mmol, productive rate: 18.0%), LC/MS:m/zM ++ 1=124.The preparation of example 127B.5-nitro-[1,3] dioxane [4,5-b] pyridine
The vitriol oil (5mL) and concentrated nitric acid (4mL) are made into nitration mixture, then instill the dense H of [1,3] dioxane [4,5-b] pyridine (200mg, 1.62mmol, 1.0eq) 2sO 4solution (1mL), temperature of reaction remains between 35 DEG C-40 DEG C, stirs 2h at this temperature, terminates to the reaction of TLC detection display.Reaction solution is poured cancellation in ice into and is alkalized to PH=10, EA extraction (3x10mL), the organic extract water merged and salt washing, dry and concentratedly to obtain product 5-nitro-[1,3] dioxane [4,5-b] pyridine (120mg, 0.71mmol, productive rate: 44.1%), LC/MS:m/zM ++ 1=169.The preparation of example 127C. [1,3] dioxane [4,5-b] pyridin-5-amine
At 0 DEG C, Ranney nickel (0.5mL is suspended in water) is added to 5-nitro-[1,3] dioxane [4,5-b] pyridine (1.0g, 5.95mmol, 1.0eq) 20mL methanol solution in, be then cooled to 0 DEG C, then by hydrazine hydrate (0.5mL, 26.6mmol, 4.5eq, 85% aqueous solution) be slowly added dropwise to reaction system, reaction solution stirs 2h at 0 DEG C, reacts completely to TLC detection display raw material.Solids removed by filtration, filtrate concentrates and is dissolved in EA, with water and salt washing, organic extraction anhydrous sodium sulfate drying, namely product [1,3] dioxane [4,5-b] pyridin-5-amine (756mg is obtained after filtering and concentrating, 5.48mmol, productive rate: 92%), LC/MS:m/zM ++ 1=139.The preparation of example 127D.N-methyl-[1,3] dioxane [4,5-b] pyridin-5-amine
Paraformaldehyde (1.64g is added in the 20mL methanol solution of sodium methylate (1.48g, 27.4mmol, 5.0eq), 54.8mmol, 10.0eq) and [1,3] dioxane [4,5-b] pyridin-5-amine (756mg, 5.48mmol, 1.0eq).At room temperature stir 24h, detect raw material reaction to TLC and terminate.Then NaBH 4(625mg, 16.5mmol, 3.0eq) slowly adds system, reaction solution continues to stir 3h at 40 DEG C, is dissolved in EA after reaction solution is concentrated, with water and salt washing, anhydrous sodium sulfate drying, after filtering and concentrating, namely residuum silica gel chromatography column purification obtains product N-methyl-[1,3] dioxane [4,5-b] pyridin-5-amine (816mg, 5.37mmol, productive rate: 98%), LC/MS:m/zM ++ 1=153.Example 127E. (S)-N-([1,3] dioxane [4,5-b] pyridine-5-base)-2-amido-N-methyl-3-hydrocinnamamide
Make raw material with N-methyl-[1,3] dioxane [4,5-b] pyridin-5-amine, the building-up process of 127E is similar to 102A with 102B, LC/MS:m/zM ++ 1=300.Example 127F. (S)-N-([1,3] dioxane [4,5-b] pyridine-5-base)-2-(2-(the chloro-3-of 4-(2-hydroxyethyl)-2-Methyl-1H-indole-1-base) acetamido)-N-methyl-3-hydrocinnamamide
To 2-(the chloro-3-ethyl of 4--2-dimethyl-1H-indoles-1-base) acetic acid (80mg; 0.35mmol; 1.0eq); (S)-2-amido-N-methyl-N; 3-diphenylpropanamide (125.2mg; 0.42mmol, 1.2eq) mixed solution in, add EDCI (101.2mg; 0.53mmol; 1.5eq), HOBt (94.5mg, 0.7mmol; 2.0eq) with DIPEA (90.3mg; 0.7mmol, 2.0eq), reaction solution is stirred overnight at room temperature under N2 protection.Reaction solution washes three times, organic extraction carries out drying and concentrates, residuum preparative HPLC is purified, obtain product (S)-N-([1,3] dioxane [4,5-b] pyridine-5-base)-2-(2-(3-ethyl-2,4-dimethyl-1H-indoles-1-base) acetamido)-N-methyl-3-hydrocinnamamide (23.6mg, 0.05mmol, productive rate: 14.3%), LC/MS:m/zM ++ 1=549, HPLC retention time=2.79min (10-90% acetonitrile and the aqueous solution, comprise 0.1%TFA).
1hNMR (400MHz, DMSO) (400MHz, CDCl 3) δ 7.22-6.99 (m, 6H), 6.66 (d, J=6.7Hz, 2H), 6.58 (d, J=8.0Hz, 1H), 6.17 (s, 2H), 5.79 (s, 1H), 4.94 (s, 1H), 4.75-4.57 (m, 2H), 3.90 (t, J=10.6Hz, 2H), 3.43-3.28 (m, 1H), 3.18 (d, J=15.2Hz, 3H), 3.17-3.05 (m, 1H), 2.82 (d, J=8.9Hz, 1H), 2.55 (s, 1H), 2.29 (s, 3H). example 128
(S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(3-(2-hydroxyethyl)-2,4,7-trimethylammonium-1H-indoles-1-base) acetamido)-N-methyl-3-(pyridin-4-yl) propionic acid amide example 128A. (S)-2-amido-N-(benzo [d] [1,3] dioxane-5-base)-N-methyl-3-(pyridin-4-yl) propionic acid amide
To (S)-2-(amine t-butyl formate)-3-(pyridin-4-yl) propionic acid (500mg, 3.0mmol, 1.0eq), N-methyl benzo [d] [1,3] dioxane-5-amine (549mg, 3.6mmol, 1.2eq) be dissolved in the mixed solution of DCM, add EDCI (864mg, 4.5mmol, 1.5eq), HOBt (810mg, 6.0mmol, 2.0eq) with DIPEA (1mL, 6.0mmol, 2.0eq), reaction solution is at N 2the lower stirred overnight at room temperature of protection.Reaction solution wash three times, dry and concentrated, namely residuum column chromatography purification obtains product (S)-(1-(benzo [d] [1,3] dioxane-5-methylamino)-1-oxo-3-(pyridin-4-yl) propyl group-2-base) amine t-butyl formate (450mg, 1.13mmol, productive rate: 37.7%), LC/MS:m/zM ++ 1=400.Example 128B. (S)-2-amido-N-(benzo [d] [1,3] dioxane-5-base)-N-methyl-3-(pyridin-4-yl) propionic acid amide
At 0 DEG C, to (S)-(1-(benzo [d] [1,3] dioxane-5-methylamino)-1-oxo-3-(pyridin-4-yl) propyl group-2-base) amine t-butyl formate (450mg, 1.13mmol, the MeOH solution of Acetyl Chloride 98Min. (3mL) is added, reaction solution stirring at room temperature 2h in MeOH solution 1.0eq).Miscellany concentrates and obtains crude product (330mg, 1.10mmol, productive rate: 97.3%), LC/MS:m/zM ++ 1=300.Example 128C. (S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(3-(2-hydroxyethyl)-2,4,7-trimethylammonium-1H-indoles-1-base) acetamido)-N-methyl-3-(pyridin-4-yl) propionic acid amide
Make raw material with corresponding acid and amine, building-up process and the 1H of 128C are similar, LC/MS:m/zM ++ 1=543, HPLC retention time=2.47min (10-90% acetonitrile and the aqueous solution, comprise 0.1%TFA).
1HNMR(400MHz，MeOD)δ8.49(t，J＝3.2Hz，1H)，8.14(s，1H)，8.03(s，1H)，7.19-7.09(m，2H)，6.94(d，J＝8.7Hz，1H)，6.76(dt，J＝16.2，8.0Hz，3H)，6.02(s，2H)，4.81(dd，J＝15.7，7.4Hz，1H)，3.88(dd，J＝44.5，15.4Hz，2H)，3.78-3.69(m，1H)，3.62(dd，J＝15.9，7.0Hz，1H)，3.27-3.07(m，5H)，2.74(dd，J＝13.5，7.7Hz，1H)，2.67(s，3H)，2.48(s，3H)，2.45(dd，J＝13.5，7.7Hz，1H)，2.43(s，1H).
Make raw material with corresponding acid and amine, compound 129-130 building-up process is similar to example 128.Example 129 to 130
(example 129): 1hNMR (400MHz, CDCl 3) δ 8.50 (s, 1H), 8.01 (s, 1H), 7.55 (s, 1H), 7.50-7.09 (m, 4H), 6.89 (d, J=7.2Hz, 1H), 6.77 (d, J=11.7Hz, 3H), 6.02 (s, 2H), 4.96 (d, J=6.7Hz, 1H), 3.89 (dd, J=34.3,15.3Hz, 2H), 3.77-3.57 (m, 2H), 3.19 (s, 3H), 3.00 (s, 1H), 2.80 (s, 1H), 2.66 (s, 3H), 2.47 (s, 3H), 2.42 (s, 3H).
(example 130): 1hNMR (400MHz, CDCl 3) δ 8.41 (d, J=5.1Hz, 2H), 8.21 (d, J=9.4Hz, 1H), 6.90 (d, J=8.9Hz, 1H), 6.77 (dt, J=11.8, 6.0Hz, 5H), 6.35 (s, 1H), 6.03 (s, 2H), 4.86 (dd, J=15.8, 7.5Hz, 1H), 3.93 (d, J=15.6Hz, 1H), 3.76 (dd, J=15.1, 7.5Hz, 2H), 3.63-3.53 (m, 1H), 3.51 (s, 2H), 3.18 (s, 3H), 3.27-3.07 (m, 2H), 2.73 (dd, J=13.3, 7.0Hz, 1H), 2.66 (s, 3H), 2.45 (s, 3H), 2.41-2.36 (m, 1H). example 131
(S)-2-(2-(the chloro-3-ethyl of 4--1H-indazole-1-base) acetamido)-N-(6-methoxypyridine-3-base)-N-methyl-3-hydrocinnamamide example 131A.1-(the chloro-6-fluorophenyl of 2-) propyl group-1-alcohol
At 0 DEG C and N 2under the condition of protection, THF (63mL, 63.0mmol, 2.0eq, the 1M) dropwise of ethylmagnesium bromide is added in the THF solution of the chloro-6-fluorobenzaldehyde (5.0g, 31.6mmol, 1.0eq) of 2-, reaction solution stirred at ambient temperature 2h.Add saturated NH 4the cancellation of Cl solution is reacted, and reaction solution EA extracts, evaporate to dryness organic phase, residuum silica gel column chromatography (PE: EA=10: 1) purifying obtains 1-(the chloro-6-fluorophenyl of 2-) propyl group-1-alcohol (2.5g, 13.3mmol, productive rate: 43%), LC/MS:m/zM ++ 1=189.Example 131B.1-(the chloro-6-fluorophenyl of 2-) propyl group-1-ketone
Jones reagent dropwise is entered in the acetone soln of 1-(the chloro-6-fluorophenyl of 2-) propyl group-1-alcohol (2.5g, 13.3mmol, 1.0eq), terminate to the reaction of TLC (PE: EA=5: 1) detection display.Virahol adds cancellation reaction, then water is added, miscellany EA extracts, evaporate to dryness organic phase obtains residuum, with purification by silica gel column chromatography (PE: EA=10: 1), obtain 1-(the chloro-6-fluorophenyl of 2-) propyl group-1-ketone (2.2g, 11.8mmol, productive rate: 89%), LC/MS:m/zM ++ 1=187.The chloro-3-ethyl of example 131C.4--1H-indazole
Hydrazine hydrate (85%, 20mL) is added in the time of 10 minutes in DME (20mL) solution of 1-(the chloro-6-fluorophenyl of 2-) propyl group-1-ketone (2.2g, 11.8mmol, 1.0eq).Reaction backflow is spent the night, and vacuum concentration, to about 20mL, adds water (20mL), the precipitation that collecting by filtration obtains, is drying to obtain the chloro-3-ethyl of 4--1H-indazole (1.8g, 10mmol, productive rate: 85%), LC/MS:m/zM ++ 1=181.Example 131D.2-(the chloro-3-ethyl of 4--1H-indazole-1-base) acetic acid
By NaH (264mg, 6.6mmol, 1.5eq) slowly add the chloro-3-ethyl of 4--1H-indazole (800mg, 4.4mmol, in DMF solution 1.0eq), again by 2-ethyl bromoacetate (0.76mL, 6.6mmol after 30min, 1.5eq) instill, reaction solution continues to stir the reaction of 30min to TLC (PE: EA=10: 1) detection display and terminates at 0 DEG C.10mL water adds cancellation reaction, add NaOH (176mg, 4.4mmol, 1.0eq) again, stirred at ambient temperature 30min, then with EA extraction (2x30mL), the organic layer washed with brine (2x10mL) of merging, then uses anhydrous sodium sulfate drying, concentrate and obtain 2-(the chloro-3-ethyl of 4--1H-indazole-1-base) acetic acid (380mg, 1.3mmol, productive rate: 36%), LC/MS:m/zM ++ 1=239.Example 131E. (S)-N-([1,3] dioxane [4,5-b] pyridine-5-base)-2-(2-(the chloro-3-of 4-(2-hydroxyethyl)-2-Methyl-1H-indole-1-base) acetamido)-N-methyl-3-hydrocinnamamide
Make raw material with corresponding acid and amine, 131E building-up process and 1H similar.LC/MS:m/zM ++ 1=506, HPLC retention time=3.28min (10-90% acetonitrile and the aqueous solution, comprise 0.1%TFA).
1HNMR(400MHz，DMSO)δ7.67(s，1H)，7.27(s，1H)，7.23-7.11(m，5H)，6.82(d，J＝7.0Hz，2H)，6.66(t，J＝8.2Hz，2H)，4.92(q，J＝17.1Hz，2H)，4.69(dd，J＝14.7，7.9Hz，1H)，3.96(s，3H)，3.27(d，J＝7.5Hz，2H)，3.14(s，3H)，2.83(dd，J＝13.2，8.0Hz，1H)，2.67(dd，J＝13.2，6.6Hz，1H)，1.45(t，J＝7.5Hz，3H).
Raw material is made in compound 132-133 corresponding acid and amine, and building-up process is similar with example 131.Example 129 to 130
(example 132): 1hNMR (400MHz, DMSO) δ 7.86 (s, 1H), 7.27-7.09 (m, 7H), 6.81 (d, J=7.0Hz, 2H), 6.72 (d, J=8.0Hz, 1H), 4.92 (q, J=17.1Hz, 2H), 4.65 (dd, J=14.7,8.0Hz, 1H), 3.25 (q, J=7.5Hz, 2H), 3.16 (s, 3H), 2.83 (dd, J=13.1,8.1Hz, 1H), 2.68 (dd, J=13.1,6.5Hz, 1H), 2.59 (s, 3H), 1.45 (t, J=7.5Hz, 3H).
(example 133): 1hNMR (400MHz, DMSO) δ 7.32-7.24 (m, 2H), 7.23-7.07 (m, 5H), 6.82 (d, J=7.0Hz, 2H), 6.73 (d, J=8.2Hz, 1H), 6.65 (d, J=8.2Hz, 1H), 6.03 (s, 2H), 4.91 (q, J=17.1Hz, 2H), 4.80 (dd, J=14.9, 7.5Hz, 1H), 3.24 (q, J=7.5Hz, 2H), 3.14 (s, 3H), 2.84 (dd, J=13.2, 7.5Hz, 1H), 2.67 (dd, J=13.3, 6.7Hz, 1H), 1.44 (t, J=7.5Hz, 3H). example 134
(S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(the chloro-3-of 4-(2-hydroxyethyl)-1H-indazole-1-base) acetamido)-N-methyl-3-hydrocinnamamide the chloro-1H-indazole of example 134A.4-
Be added to by hydrazine hydrate (85%, 50mL) in DME (50mL) solution of the chloro-6-fluorobenzaldehyde (5.0g, 31.6mmol, 1.0eq) of 2-in the time of 10 minutes, reaction solution backflow is spent the night.Vacuum concentration, to about 50mL, adds water (50mL), the solid that collecting by filtration obtains, is drying to obtain the chloro-1H-indazole of product 4-(2.5g, 16.4mmol, productive rate: 52%), LC/MS:m/zM ++ 1=153.The iodo-1H-indazole of the chloro-3-of example 134B.4-
By KOH (1.25g, 22.4mmol, 2.0eq) be added to the chloro-1H-indazole of 4-(1.7g, 11.2mmol, in DMF (20mL) solution 1.0eq), after reaction solution stirring at room temperature 30min, add iodine (5.64g, 22.4mmol in 0 DEG C, 2.0eq), room temperature for overnight is reacted.It is complete that LC-MS shows raw material reaction.Reaction solution poured into frozen water cancellation and extract (50mLx2) with EA, the saturated Na of organic extraction of merging 2sO 3(2x20mL) wash, salt solution (2x20mL) washs, and anhydrous sodium sulfate drying, concentrates and obtain the iodo-1H-indazole of the chloro-3-of 4-(2.7g, 9.7mmol, productive rate: 87%), LC/MS:m/zM ++ 1=279.Example 134C.1-(the iodo-1H-indazole of the chloro-3-of 4--1-base) ethyl ketone
By triethylamine (2.4mL, 17.2mmol, 3eq) add the iodo-1H-indazole of the chloro-3-of 4-(1.6g, 5.8mmol, in DCM (15mL) solution 1.0eq), then add Acetyl Chloride 98Min. (0.9g, 11.6mmol, 2.0eq), reaction solution room temperature for overnight.Add water (10mL) cancellation reaction, DCM (15mLx2) extracts, evaporate to dryness organic phase obtains residuum, namely product 1-(the iodo-1H-indazole of the chloro-3-of 4--1-base) ethyl ketone (1.4g is obtained with purification by silica gel column chromatography (PE: EA=10: 1), 4.3mmol, productive rate: 76%), LC/MS:m/zM ++ 1=321.The chloro-3-vinyl of example 134D.4--1H-indazole
By tributylvinyl tin (1.9g, 6.4mmol, 4.0eq) and Pd (PPh 3) 4(0.05g, 10%) is added in DMF (10mL) solution of 1-(the iodo-1H-indazole of the chloro-3-of 4--1-base) ethyl ketone (500mg, 1.6mmol, 1.0eq), and reaction solution is at N 2the lower refluxed overnight of protection, TLC (PE/EA3: 1) detection display raw material reaction is complete.Add the rear cool to room temperature of water (10mL) cancellation reaction, EA extraction (2x20mL), evaporate to dryness organic phase obtain residuum, namely obtain the chloro-3-vinyl of 4--1H-indazole (210mg with purification by silica gel column chromatography (PE: EA=5: 1), 1.2mmol, productive rate: 75%), LC/MS:m/zM ++ 1=179.Example 134E.2-(the chloro-3-vinyl of 4--1H-indazole-1-base) acetic acid
To salt of wormwood (662mg, 4.8,4.0eq) with the chloro-3-vinyl of 4--1H-indazole (210mg, 1.2mmol, 1.0eq) DMF (5mL) solution in, instillation 2-ethyl bromoacetate (0.26mL, 2.4mmol, 2.0eq), reaction solution stirred at ambient temperature 50min is complete to TLC (PE: EA=1: 1) detection display raw material reaction.NaOH (48mg, 1.2mmol, 1.0eq) is added again after adding water (10mL) cancellation reaction.And at room temperature continue to stir 30min, then the organic layer washed with brine of EA extraction (2x10mL), merging is washed (2x10mL), anhydrous sodium sulfate drying, concentrate and obtain product 2-(the chloro-3-vinyl of 4--1H-indazole-1-base) acetic acid (200mg, 0.85mmol, productive rate: 72%), LC/MS:m/zM ++ 1=237.Example 134F. (S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(the chloro-3-vinyl of 4--1H-indazole-1-base) acetamido)-N-methyl-3-hydrocinnamamide
To 2-(the chloro-3-vinyl of 4--1H-indazole-1-base) acetic acid (80mg, 0.34mmol, 1.0eq), (S)-2-amido-N-(benzo [d] [1,3] dioxane-5-base)-N-methyl-3-hydrocinnamamide (101mg, 0.34mmol, in DCM (3mL) solution 1.0eq), add EDCI (129mg, 0.68mmol, 2.0eq), HOBt (91mg, 0.68mmol, 2.0eq) and DIPEA (0.45mL, 1.3mmol, 4.0eq), reaction solution is at N 2the lower stirred overnight at room temperature of protection.Reaction solution washing (3mLx2), drying concentrate, namely residuum preparative HPLC purifying obtains product (S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(the chloro-3-vinyl of 4--1H-indazole-1-base) acetamido)-N-methyl-3-hydrocinnamamide (130mg, 0.25mmol, productive rate: 28%), LC/MS:m/zM ++ 1=517.Example 134G. (S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(the chloro-3-vinyl of 4--1H-indazole-1-base) acetamido)-N-methyl-3-hydrocinnamamide
By (S)-N-(benzo [d] [1,3] dioxy 1-5-yl)-2-(2-(the chloro-3-vinyl of 4--1H-indazole-1-base) acetamido)-N-methyl-3-hydrocinnamamide (130mg, 0.25mmol, 1.0eq) add the THF (0.5M of 9-BBN, 5mL) in solution, reaction solution stirred at ambient temperature 2h to TLC (PE: EA=2: 1) detection display raw material reaction is complete.With methyl alcohol (5mL) cancellation reaction, after evaporate to dryness, add H 2o 2(3mL, 30%) and NaOH (2mL, the 50%) aqueous solution.Reaction solution continues stirred at ambient temperature 5h, then EA extraction, evaporate to dryness organic extraction obtain residuum, purify with preparative HPLC and obtain product (S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(the chloro-3-of 4-(2-hydroxyethyl)-1H-indazole-1-base) acetamido)-N-methyl-3-hydrocinnamamide (50mg, 0.09mmol, isolated productive rate: 37%), LC/MS:m/zM++1=535, HPLC retention time=2.82min (10-90% acetonitrile and the aqueous solution, comprise 0.1%TFA).
1hNMR (400MHz, DMSO) δ 8.71 (d, J=7.9Hz, 1H), 7.30-7.19 (m, 5H), 7.13 (dd, J=5.1, 3.0Hz, 1H), 7.00-6.80 (m, 3H), 6.66 (d, J=19.5Hz, 2H), 6.05 (d, J=3.3Hz, 2H), 5.00 (q, J=16.6Hz, 2H), 4.74 (t, J=5.5Hz, 1H), 4.47 (dd, J=13.5, 8.4Hz, 1H), 3.75 (dd, J=12.8, 7.4Hz, 2H), 3.21 (t, J=7.5Hz, 2H), 3.09 (s, 3H), 2.93 (dd, J=13.4, 5.0Hz, 1H), 2.71 (dd, J=13.4, 9.1Hz, 1H). example 135
(S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(3-Ethyl-2-Methyl-1H-pyrroles [2,3-b] pyridine-1-base) acetamido)-N-methyl-3-hydrocinnamamide example 135A. (3-picoline-2-base) the amidocarbonic acid tert-butyl ester
In the EA (30mL) and PE (120mL) mixing solutions of 3-picoline-2-amine (15g, 0.14mol, 1.0eq), add Boc 2o (48.5g, 0.55mol, 1.6eq), reaction solution stirred at ambient temperature 4h, TLC (PE/EA3: 1) detection display raw material reaction is complete.Reaction solution vacuum concentration obtains crude product, namely obtains product (3-picoline-2-base) the amidocarbonic acid tert-butyl ester (20g, 0.096mmol, productive rate: 68.6%), LC/MS:m/zM with purification by silica gel column chromatography ++ 1=209.Example 135B.2-methyl isophthalic acid H-pyrroles [2,3-b] pyridine
By n-Butyl Lithium (2.5M at-78 DEG C, 19.4mL, 50.4mmol, 7eq) be added drop-wise in anhydrous THF (50mL) solution of (3-picoline-2-base) the amidocarbonic acid tert-butyl ester (1.5g, 7.2mmol, 1eq), reaction solution reacts 2h at such a temperature, then instill DMA (3g, 36mmol, 5eq) and keep this temperature to continue reaction 2h.TLC (PE/EA=10: 1) detection display raw material reaction is complete. and water (10mL) adds cancellation reaction, is separated organic layer.Water layer EA extraction (2x30mL), organic extraction salt solution (15mL) washing merged, anhydrous sodium sulfate drying, vacuum concentration, be dissolved in residuum in dense HCl (15mL), and the 12h that refluxes.EA extraction after reaction solution cool to room temperature, namely water layer vacuum concentration obtains product 2-methyl isophthalic acid H-pyrroles [2,3-b] pyridine (0.3g, 2.27mmol, productive rate: 31.5%), LC/MS:m/zM ++ 1=133.Example 135C.3-iodo-2-methyl isophthalic acid H-azaindole
Join in DMF (20mL) solution of 2-methyl isophthalic acid H-azaindole (1g, 7.58mmol, 1eq) by KOH (0.42g, 7.58mmol, 1eq) at 0 DEG C, reaction adds I at 0 DEG C after at room temperature stirring 30min 2(3.85g, 15.16mmol, 2eq), reaction room temperature for overnight, TLC (PE/EA1: 1) detection display raw material reaction is complete.Reaction solution pours cancellation in frozen water into and the saturated Na of organic extraction extracting (2x80mL) with EA, merge 2sO 3(2x10mL) solution washing, salt water washing (2x10mL), anhydrous sodium sulfate drying, concentrate and obtain product 3-iodo-2-methyl isophthalic acid H-pyrroles [2,3-b] pyridine (1.0g, 3.86mmol, productive rate: 51.5%), LC/MS:m/zM ++ 1=259.Example 135D.2-(3-iodo-2-methyl isophthalic acid H-azaindole-1-base) tert.-butyl acetate
By NaH (70mg, 1.74mmol, 1.5eq) slowly join 3-iodo-2-methyl isophthalic acid H-azaindole (0.3g, 1.16mmol, in DMF solution 1eq), after 20min, be added dropwise to 2-bromo-acetic acid tert-butyl (0.23g, 1.16mmol, 1eq), miscellany is complete at 0 DEG C of stirring 30min to TLC (PE/EA1: 1) detection display raw material reaction.(30mLx2) is extracted with EA after adding water (15mL) cancellation reaction, the organic extraction merged salt washing (10mLx2), dried over sodium sulfate, concentrate and obtain product 2-(3-iodo-2-methyl isophthalic acid H-azaindole-1-base) tert.-butyl acetate (0.20g, 0.53mmol, productive rate: 46%), LC/MS:m/zM ++ 1=373.Example 135E.2-(2-methyl-3-vinyl-1H-azaindole-1-base) tert.-butyl acetate
At N 2by Pd (PPh under the condition of protection 3) 4(0.03g) 2-(3-iodo-2-methyl isophthalic acid H-azaindole-1-base) tert.-butyl acetate (0.3g is joined, 0.8mmol, 1eq) with tributylvinyl tin (1g, 3.2mmol, in DMF (10mL) solution 4eq), reaction backflow is spent the night, and TLC (PE/EA1: 1) detection display raw material reaction is complete.Reaction cool to room temperature filters, wet that filter cake EA (20mL) washs, filter vacuum concentrates to obtain residuum, namely purification by silica gel column chromatography obtains product 2-(2-methyl-3-vinyl-1H-azaindole-1-base) tert.-butyl acetate (0.15g, 0.55mmol, productive rate: 69%), LC/MS:m/zM ++ 1=273.Example 135F.2-(2-methyl-3-vinyl-1H-azaindole-1-base) acetic acid
By the H of NaOH (88mg, 2.2mmol, 2eq) 2o (15mL) solution and 2-(2-methyl-3-vinyl-1H-azaindole-1-base) ethyl acetate (0.3g, 1.1mmol, the mixing solutions stirred at ambient temperature 3h of MeOH (10mL) solution 1eq), the reaction of TLC (PE/EA1: 1) detection display terminates.Concentrated removing MeOH, residuum is acidified to PH to 6-7, EA (20mLx2) extraction, THF (10mLx2) extraction, the organic extraction merged washs with salt solution (10mL), dried over sodium sulfate, concentrate and obtain product 2-(2-methyl-3-vinyl-1H-azaindole-1-base) acetic acid (0.2g, 3.86mmol, productive rate: 84%), LC/MS:m/zM ++ 1=217.Example 135G. (S)-N-(benzo [d] [1,3] dioxane-5-base)-N-methyl-2-(2-(2-methyl-3-vinyl-1H-azaindole-1-base) acetamido)-3-hydrocinnamamide
At 2-(2-methyl-3-vinyl-1H-azaindole-1-base) acetic acid (100mg, 0.46mmol, 1eq), (S)-2-amido-N-(benzo [d] [1,3] dioxane-5-base)-N-methyl-3-hydrocinnamamide (137mg, 0.46mmol, in 5.0mLDCM mixing solutions 1.0eq), add EDCI (132mg, 0.69mmol, 1.5eq), HOBt (124mg, 0.92mmol, 2.0eq) and DIPEA (118mg, 0.92mmol, 2.0eq), reaction solution is at N 2the lower stirred overnight at room temperature of protection.Reaction solution wash three times, dry and concentrated, residuum preparative HPLC is purified, obtain product ((S)-N-(benzo [d] [1,3] dioxane-5-base)-N-methyl-2-(2-(2-methyl-3-vinyl-1H-azaindole-1-base) acetamido)-3-hydrocinnamamide (40mg, 80mmol, productive rate: 17%), LC/MS:m/zM ++ 1=497.Example 135H. (S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(3-Ethyl-2-Methyl-1H-azaindole-1-base) acetamido)-N-methyl-3-hydrocinnamamide
By Pd/C (10mg, 25%) ((S)-N-(benzo [d] [1 is joined, 3] dioxane-5-base)-N-methyl-2-(2-(2-methyl-3-vinyl-1H-azaindole-1-base) acetamido)-3-hydrocinnamamide (40mg, 0.08mmol, in MeOH (20mL) solution 1eq), and remove gas under vacuo, use H 2replace three times, reaction solution is at room temperature and H 2(55psi) stir 12h under pressure, TLC (PE/EA=1: 1) detection display raw material reaction is complete.Reacting liquid filtering, filter vacuum concentrates, obtain residuum, purify with preparative HPLC and obtain product (S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(3-Ethyl-2-Methyl-1H-pyrazoles [2,3-b] pyridine-1-base) kharophen)-N-methyl-3-hydrocinnamamide (16mg, 0.026mmol, productive rate: 33.4%), LC/MS:m/zM ++ 1=499, HPLC retention time=3.13min (10-90% acetonitrile and the aqueous solution, comprise 0.1%TFA).
1hNMR (400MHz, CDCl 3) δ 8.24 (dd, J=4.8, 1.4Hz, 1H), 7.87 (dd, J=7.8, 1.4Hz, 1H), 7.28 (s, 1H), 7.12 (ddd, J=12.6, 10.9, 6.0Hz, 4H), 6.75 (dd, J=16.5, 7.5Hz, 3H), 6.66 (d, J=7.3Hz, 1H), 6.02 (s, 2H), 5.32 (s, 1H), 4.97-4.80 (m, 2H), 4.76 (q, J=7.4Hz, 1H), 3.17-3.10 (m, 3H), 2.83 (dd, J=13.2, 7.3Hz, 1H), 2.74 (q, J=7.6Hz, 2H), 2.63 (dd, J=13.3, 7.2Hz, 1H), 2.29 (d, J=4.6Hz, 3H), 1.25 (t, J=7.6Hz, 3H). example 136
(S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(3-(2-hydroxyethyl)-2-methyl isophthalic acid H-azaindole-1-base) acetamido)-N-methyl-3-hydrocinnamamide at ((S)-N-(benzo [d] [1,3] dioxane-5-base)-N-methyl-2-(2-(2-methyl-3-vinyl-1H-pyrroles [2,3-b] pyridine-1-base) acetamido)-3-hydrocinnamamide (130mg, 0.25mmol, THF solution (the 5mL of 9-BBN is added in solution 1.0eq), 0.5M), reaction at room temperature stirs 2h, complete to TLC (PE: EA=2: 1) detection display raw material reaction.Add methyl alcohol (5mL) cancellation reaction, obtain residuum after evaporate to dryness, add H 2o 2(3mL, 30%) and NaOH (2mL, 50%) aqueous solution, continue at room temperature to stir 5h, then EA extraction (10mL), organic extraction evaporate to dryness obtains residuum, purify with preparative HPLC and obtain product (S)-N-(benzo [d] [1, 3] dioxane-5-base)-2-(2-(3-(2-hydroxyethyl)-2-methyl isophthalic acid H-azaindole-1-base) acetamido)-N-methyl-3-hydrocinnamamide (50mg, 0.09mmol, isolated yield: 37%), LC/MS:m/zM++1=515, HPLC retention time=2.52min (10-90% acetonitrile and the aqueous solution, comprise 0.1%TFA).
1hNMR (400MHz, CDCl 3) δ 8.28 (d, J=4.8Hz, 1H), 7.86 (d, J=7.8Hz, 1H), 7.47 (d, J=7.4Hz, 1H), 7.34 (d, J=7.2Hz, 2H), 7.22-7.04 (m, 4H), 6.75 (dd, J=14.0, 7.6Hz, 3H), 6.29 (d, J=8.0Hz, 1H), 6.02 (s, 2H), 5.01 (d, J=16.9Hz, 1H), 4.92-4.75 (m, 2H), 3.93-3.80 (m, 2H), 3.10 (s, 3H), 2.98 (t, J=5.9Hz, 2H), 2.77-2.71 (m, 1H), 2.61 (dd, J=13.3, 6.6Hz, 1H), 2.33 (s, 3H). example 137
(S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(1-Ethyl-2-Methyl-1H-pyrrolo-[2,3-c] pyridin-3-yl) acetamido)-N-methyl-3-Phenylpropionamide the preparation of example 137A.2-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine
At-78 DEG C, by s-butyl lithium (1.3M, 50mL, 65mmol, 2.4eq) slowly instill 4-picoline-3-amine (3.0g, 27mmol, 1.0eq) anhydrous tetrahydro furan (50mL) solution in, drip ethyl acetate (9.75g at the same temperature stir 2h at-78 DEG C after, 108mmol, 4eq), reaction solution continuation stirring 3h, TLC detection display raw material reaction is complete.Add water (15mL) cancellation reaction, be separated organic layer, by ethyl acetate (30mLx2) aqueous layer extracted, the organic phase merged is through salt solution (500mL) washing, anhydrous sodium sulfate drying, vacuum concentration, residuum is dissolved in concentrated hydrochloric acid (15mL), backflow 12h.With ethyl acetate washing after reaction solution cool to room temperature, by aqueous phase vacuum concentration, residuum pH is neutralized to 7,2-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine (1.2g, 10mmol is obtained with silica gel column chromatography separating purification, productive rate: 33.6%), LC/MS:m/zM ++ 1=133.The preparation of example 137B.1-Ethyl-2-Methyl-1H-pyrrolo-[2,3-c] pyridine
At 2-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine (0.2g, 1.51mmol, 1eq) DMF solution in, slowly add sodium hydride (90mg, 2.26mmol, 1.5eq), dropwise add monobromethane (0.16g after 20 minutes, 1.51mmol, 1eq), reaction solution continues stirring at room temperature 30min, complete to TLC detection display raw material reaction.Add 15mL shrend to go out reaction, extraction into ethyl acetate (2x30mL), the organic phase merged concentrates to obtain residuum through salt solution (2x10mL) washing, anhydrous sodium sulfate drying final vacuum, purification by silica gel column chromatography obtains 1-Ethyl-2-Methyl-1H-pyrrolo-[2,3-c] pyridine (0.15g, 0.9mmol, productive rate: 62.5%), LC/MS:m/zM ++ 1=161.The preparation of example 137C.2-(1-Ethyl-2-Methyl-1H-pyrrolo-[2,3-c] pyridin-3-yl)-2-oxoacetic acid methyl ester
To 1-Ethyl-2-Methyl-1H-pyrrolo-[2, 3-c] pyridine (0.1g, 0.625mmol, oxalyl chloride (0.078g is dropwise added in tetrahydrofuran solution 1eq), 0.625mmol, 1eq), 30min is stirred under 0 DEG C of condition, until TLC (PE/EA1: 1) detection display raw material reaction adds 15mL methyl alcohol completely in reaction system, reaction solution is concentrated after continuing to stir 30min, residue obtains 2-(1-Ethyl-2-Methyl-1H-pyrrolo-[2 through purification by silica gel column chromatography, 3-c] pyridin-3-yl)-2-oxoacetic acid methyl ester (0.1g, 0.4mmol, productive rate: 65%), LC/MS:m/zM ++ 1=247.The preparation of example 137D.2-(1-Ethyl-2-Methyl-1H-pyrrolo-[2,3-c] pyridin-3-yl) methyl acetate
At 2-(1-Ethyl-2-Methyl-1H-pyrrolo-[2,3-c] pyridin-3-yl)-2-oxoacetic acid methyl ester (0.1g, 0.4mmol, 1eq) and in tetrahydrofuran (THF) (10mL) solution of trifluoroacetic acid (0.5mL) dropwise add triethyl silicane (0.09g, 0.8mmol, 2eq), reaction solution stirs 3 hours under 55 DEG C of conditions, and TLC (PE/EA3: 1) detection display raw material reaction is complete.Concentrated by reaction solution, residue obtains 2-(1-Ethyl-2-Methyl-1H-pyrrolo-[2,3-c] pyridin-3-yl) methyl acetate (0.08g, 0.34mmol, productive rate: 86%), LC/MS:m/zM through column chromatography purification ++ 1=233.The preparation of example 137E.2-(1-Ethyl-2-Methyl-1H-pyrrolo-[2,3-c] pyridin-3-yl) acetic acid
By 2-(1-Ethyl-2-Methyl-1H-pyrrolo-[2, 3-c] pyridin-3-yl) methyl acetate (0.08g, 0.34mmol, 1eq) with sodium hydroxide (27mg, 0.68mmol, 2eq) be dissolved in the mixed solvent of methyl alcohol (10mL) and water (15mL), stirring at room temperature 3h, it is complete that TLC (PE/EA1: 1) shows raw material reaction, concentrated miscellany is to remove methyl alcohol, residuum is acidified to pH6-7, use ethyl acetate (20mLx2) and tetrahydrofuran (THF) (10mLx2) extraction respectively, the organic phase merged is washed with salt solution (10mL), 2-(1-Ethyl-2-Methyl-1H-pyrrolo-[2 is obtained after concentrated after anhydrous sodium sulfate drying, 3-c] pyridin-3-yl) acetic acid (0.01g, 0.045mmol, productive rate: 13.5%), LC/MS:m/zM ++ 1=219.Example 137F.2 (S)-N-(benzo [d] [1,3] dioxane-5-base) preparation of-2-(2-(1-Ethyl-2-Methyl-1H-pyrrolo-[2,3-c] pyridin-3-yl) acetamido)-N-methyl-3-Phenylpropionamide
At 2-(1-Ethyl-2-Methyl-1H-pyrrolo-[2, 3-c] pyridin-3-yl) acetic acid (10mg, 0.045mmol, 1eq), (S)-2-amino-N-(benzo [d] [1, 3] dioxane-5-base)-N-methyl-3-Phenylpropionamide (13.4mg, 0.045mmol, in DMF (5mL) mixed solution 1.0eq), add EDCI (66.24mg, 0.35mmol, 1.5eq), HOBt (62mg, 0.46mmol, 2.0eq) with DIPEA (59mg, 0.46mmol, 2.0eq), reaction solution is stirred overnight at room temperature under nitrogen protection.Reaction solution washes three times with water, dry and concentrated, residuum preparative HPLC purifying obtains (S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(1-Ethyl-2-Methyl-1H-pyrrolo-[2,3-c] pyridin-3-yl) acetamido)-N-methyl-3-phenyl (2mg, 0.004mmol, productive rate: 8.9%), LC/MS:m/zM ++ 1=499, HPLC retention time=3.32min (10-90% acetonitrile and the aqueous solution, comprise 0.1%TFA).
1hNMR (400MHz, CDCl 3) δ 8.82 (s, 1H), 8.23 (d, J=5.7Hz, 1H), 7.48 (s, 1H), 7.34 (d, J=8.3Hz, 2H), 7.15 (dt, J=14.6, 7.2Hz, 3H), 6.76 (dd, J=12.6, 7.7Hz, 3H), 6.11 (d, J=7.7Hz, 1H), 6.03 (s, 2H), 4.81 (d, J=7.9Hz, 1H), 4.24 (q, J=7.0Hz, 2H), 3.58 (s, 2H), 3.15 (s, 3H), 2.81 (dd, J=13.4, 7.1Hz, 1H), 2.64 (d, J=7.0Hz, 1H), 2.37 (s, 3H), 1.41 (d, J=7.2Hz, 3H). example 138
(S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(1-Ethyl-2-Methyl-1H-pyrrolo-[2,3-b] pyridin-3-yl) kharophen)-N-methyl-3-hydrocinnamamide the preparation of this compound is similar to example 137, and raw material is prepared by the method for example 135B.LC/MS:m/zM ++ 1=506, HPLC retention time=3.28min (10-90% acetonitrile and water, containing 0.1%TFA).
1hNMR (400MHz, DMSO) δ 7.67 (s, 1H), 7.27 (s, 1H), 7.23-7.11 (m, 5H), 6.82 (d, J=7.0Hz, 2H), 6.66 (t, J=8.2Hz, 2H), 4.92 (q, J=17.1Hz, 2H), 4.69 (dd, J=14.7, 7.9Hz, 1H), 3.96 (s, 3H), 3.27 (d, J=7.5Hz, 2H), 3.14 (s, 3H), 2.83 (dd, J=13.2, 8.0Hz, 1H), 2.67 (dd, J=13.2, 6.6Hz, 1H), 1.45 (t, J=7.5Hz, 3H). example 139
(S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(1-ethyl-1H-indol-3-yl)-2-oxoaGetamide base)-N-methyl-3-hydrocinnamamide the preparation of example 139A.2-(2-Methyl-1H-indole-3-base 1)-2-oxoacetic acid methyl ester
By oxalyl chloride (1.94g, 15.2mmol, 1.0eq) be dropwise added to 2 methyl indole (2.0g, 15.2mmol, in tetrahydrofuran solution 1.0eq), reaction solution stirs 30min under 0 DEG C of condition, until TLC (PE/EA1: 1) detection display raw material reaction completely after, 15mL methyl alcohol is added in reaction solution, obtain residuum by concentrated for reaction solution after continuing to stir 30min, purification by silica gel column chromatography obtains 2-(2-Methyl-1H-indole-3-base 1)-2-oxoacetic acid methyl ester (2.42g, 11.1mmol, productive rate: 73%), LC/MS:m/zM ++ 1=218.Example 139B.2-(1-Ethyl-2-Methyl-1H-indol-3-yl)-2-Oxoacetic Acid
At 0 DEG C, by sodium hydride (110mg, 2.76mmol, 1.5eq) slowly join 2-(2-Methyl-1H-indole-3-base 1)-2-oxoacetic acid methyl ester (400mg, 1.84mmol, N 1.0eq), in dinethylformamide solution, after 20 minutes, more dropwise add monobromethane (0.20mL, 2.76mmol, 1.5eq).Reaction solution stirs 2 hours at 0 DEG C, add 5mL frozen water cancellation reaction, pH to 4 is regulated with HCl, then extraction into ethyl acetate obtains 2-(1-Ethyl-2-Methyl-1H-indol-3-yl)-2-Oxoacetic Acid (245mg with sherwood oil recrystallization, 1.13mmol, productive rate: 61.4%), LC/MS:m/zM ++ 1=232.Example 139C. (S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(1-ethyl-1H-indol-3-yl)-2-oxoaGetamide base)-N-methyl-3-hydrocinnamamide
To 2-(1-Ethyl-2-Methyl-1H-indol-3-yl)-2-Oxoacetic Acid (150mg; 0.69mmol; 1.0eq), (S)-2-amino-N-(benzo [d] [1; 3] dioxane-5-base)-N-methyl-3-Phenylpropionamide (247mg; 0.83mmol; in DCM (5mL) mixed solution 1.2eq); add EDCI (198.7mg; 1.04mmol, 1.5eq), HOBt (186.3mg, 1.38mmol; 2.0eq) with DIPEA (178mg; 1.38mmol, 2.0eq), reaction solution is stirred overnight at room temperature under nitrogen protection.Wash three times with water, dry concentrated, residuum preparative HPLC purifying obtains (S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(1-ethyl-1H-indol-3-yl)-2-oxoaGetamide base)-N-methyl-3-benzamide (110mg, 0.22mmol, productive rate: 32%), LC/MS:m/zM ++ 1=512, retention time=3.10min (10-90% acetonitrile and water, containing 0.1%TFA).
1HNMR(400MHz，CDCl 3)δ9.13(d，J＝7.8Hz，1H)，7.76(d，J＝7.9Hz，1H)，7.55(d，J＝8.2Hz，1H)，7.39(dd，J＝16.3，8.0Hz，1H)，7.29-7.15(m，4H)，7.10(t，J＝7.5Hz，1H)，7.07-6.90(m，4H)，6.12(d，J＝5.6Hz，2H)，4.67(dd，J＝12.7，8.9Hz，1H)，4.23(q，J＝7.3Hz，2H)，4.15(q，J＝7.2Hz，1H)，3.16(d，J＝5.7Hz，3H)，3.00(dd，J＝13.6，4.9Hz，1H)，2.81(dd，J＝13.5，9.6Hz，1H)，2.31(s，3H)，1.24(t，J＝7.1Hz，4H).
Utilize corresponding acid and amine, obtain compound 140-141 example 140 to 141 by the reactions steps of similar example 139
(example 140): 1hNMR (400MHz, DMSO) δ 12.06 (s, 1H), 9.23 (d, J=7.7Hz, 1H), 8.07 (s, 1H), 7.82 (d, J=7.7Hz, 1H), 7.52 (s, 1H), 7.37 (d, J=7.9Hz, 1H), 7.28-7.20 (m, 3H), 7.16 (dd, J=11.0, 4.1Hz, 1H), 7.10 (t, J=7.1Hz, 1H), 6.95 (dd, J=12.0, 6.3Hz, 3H), 4.54 (dd, J=13.3, 8.8Hz, 1H), 3.92 (s, 3H), 3.18 (s, 3H), 3.00 (dd, J=13.6, 5.3Hz, 1H), 2.83 (dd, J=13.5, 9.3Hz, 1H), 2.21 (s, 3H).
(example 141): 1hNMR (400MHz, CDCl 3) δ 7.94 (dd, J=6.1, 2.8Hz, 1H), 7.63 (s, 1H), 7.45 (d, J=8.4Hz, 1H), 7.31 (dd, J=4.0, 2.4Hz, 5H), 7.27-7.21 (m, 2H), 7.15-7.08 (m, 2H), 6.68 (d, J=8.6Hz, 1H), 4.88 (td, J=8.5, 6.5Hz, 1H), 4.20 (q, J=7.3Hz, 2H), 3.97 (s, 3H), 3.20 (s, 3H), 3.10 (dd, J=17.5, 8.9Hz, 1H), 2.97 (dd, J=13.0, 6.4Hz, 1H), 2.65 (s, 3H), 1.40 (t, J=7.2Hz, 3H). example 142
(2S)-N-(benzo [d] [1,3] dioxane-5-base)-2-(2-(1-Ethyl-2-Methyl-1H-indol-3-yl)-2-hydroxyacetamido)-N-methyl-3-hydrocinnamamide to (S)-N-(benzo [d] [1, 3] dioxane-5-base)-2-(2-(1-Ethyl-2-Methyl-1H-indol-3-yl)-2-oxo kharophen)-N-methyl-3-benzamide (50mg, 0.10mmol, in methanol solution 1.0eq), sodium borohydride (6mg is slowly added under 0 DEG C of condition, 0.15mmol, 1.5eq), methyl alcohol removed after 2 hours by stirring at room temperature in a vacuum, residue with Ethyl acetate extracts, purify with preparative HPLC and obtain target product (38mg, 0.08mmol, productive rate: 80%), LC/MS:m/zM ++ 1=514, HPLC retention time=3.00min (10-90% acetonitrile and water, containing 0.1%TFA).
1hNMR (400MHz, DMSO) δ 8.01 (d, J=8.0Hz, 1H), 7.57 (d, J=8.0Hz, 1H), 7.41 (d, J=8.2Hz, 1H), 7.26 (dd, J=5.1, 1.8Hz, 3H), 7.10 (t, J=7.1Hz, 1H), 7.04-6.96 (m, 3H), 6.89 (d, J=8.2Hz, 1H), 6.54 (s, 2H), 6.10 (d, J=1.2Hz, 2H), 5.88 (d, J=3.9Hz, 1H), 5.18 (d, J=3.9Hz, 1H), 4.61 (d, J=6.8Hz, 1H), 4.19 (t, J=6.2Hz, 2H), 3.16 (s, 3H), 2.97 (dd, J=13.4, 6.2Hz, 1H), 2.86 (dd, J=13.5, 8.0Hz, 1H), 2.41 (s, 3H), 1.30 (t, J=8.4Hz, 3H). example 143
(S)-2-(2-(4,7-dimethyl-1H-benzo [d] imidazoles-1-base) kharophen)-N-methyl-N-(6-picoline-3-base)-3-hydrocinnamamide the preparation of example 143A.1,4-methyl-2,3-dinitrobenzene
By Isosorbide-5-Nitrae-dimethyl-2-oil of mirbane (9.0g, 59.0mmol, 1.0eq) is dissolved in concentrated nitric acid at 0 DEG C, drips the vitriol oil wherein at 0 DEG C, reaction solution stirs 2 hours at 0 DEG C until TLC display raw material reaction is complete.Slowly poured in frozen water by reaction solution, stir 30 minutes at 0 DEG C, solid collected by filtration, washes final vacuum drying with water and obtains Isosorbide-5-Nitrae-methyl-2,3-dinitrobenzene (10.0g crude product, 51.3mmol, productive rate: 86.9%), LC/MS:m/zM ++ 1=197.The preparation of example 143B.3,6-dimethyl benzene-1,2-diamines
To in the 30mL methyl alcohol of Isosorbide-5-Nitrae-methyl-2,3-dinitrobenzene (10.0g crude product, 51.3mmol, 1.0eq), slowly add Pd/C (1.5g, 15%) under nitrogen protection, reaction solution 40 DEG C of stirrings under the atmosphere of hydrogen are spent the night.Cross after reacting completely and filter Pd/C, filtrate concentrates to obtain 3,6-dimethyl benzene-1,2-diamines (6.0g crude product, 44.1mmol, productive rate 86.5%), LC/MS:m/zM ++ 1=137.The preparation of example 143C.4,7-dimethyl-1H-benzo [d] imidazoles
By 3,6-dimethyl benzene-1,2-diamines (3.0g, 22.1mmol, 1.0eq) be dissolved in 6mL acetic acid, heated overnight at reflux, after reacting completely, regulate pH to 8 with the sodium hydroxide solution of 3M, collected by filtration, filtration cakes torrefaction obtains 4,7-dimethyl-1H-benzo [d] imidazoles (3.0g, 20.7mmol, productive rate: 94%), LC/MS:m/zM ++ 1=147.The preparation of example 143D.2-(4,7-dimethyl-1H-benzo [d] imidazoles-1-base) acetic acid
At 0 DEG C, in the tetrahydrofuran (THF) of 4,7-dimethyl-1H-benzo [d] imidazoles (1.0g, 6.8mmol, 1.0eq), slowly add sodium hydride (408mg, 10.2mmol, 1.5eq).After 20 minutes, dropwise ethyl bromoacetate (0.9mL is added again in the time of 30 minutes, 8.2mmol, 1.2eq), mixed solution 0 DEG C continue stirring 30 minutes until TLC (DCM: MeOH=10: 1) show raw material reaction completely after add 15mL shrend and to go out reaction, then sodium hydroxide (100mg is added, 2.5mmol, 0.37eq), reaction solution stirring at room temperature adds hydrochloric acid (2N) and regulates pH to 4 after 30 minutes, there is precipitation and solid collected by filtration, washing and 75 DEG C of dryings, obtain product 2-(4, 7-dimethyl-1H-benzo [d] imidazoles-1-base) acetic acid (600mg, 3.1mmol, productive rate: 46%), LC/MS:m/zM ++ 1=205.The preparation of example 143E. (S)-2-(2-(4,7-dimethyl-1H-benzo [d] imidazoles-1-base) kharophen)-N-methyl-N-(6-picoline-3-base)-3-Phenylpropionamide
To (R)-2-Amino-N-methyl-N-(6-picoline-3-base)-3-phenylpropionyl amine hydrochlorate (64.5mg, 0.24mmol, 1.2eq), 2-(4, 7-dimethyl-1H-benzo [d] imidazoles-1-base) acetic acid (40mg, 0.2mmol, in DCM (1.5mL) mixed solution 1.0eq), add EDCI (57.3mg, 0.3mmol, 1.5eq), HOBt (54mg, 0.4mmol, 2.0eq) with DIPEA (51.6mg, 0.4mmol, 2.0eq), reaction solution is stirred overnight at room temperature under nitrogen protection, mixed solution washes 3 times with water, dry concentrated, residuum preparative HPLC purifying obtains (S)-2-(2-(4, 7-dimethyl-1H-benzo [d] imidazoles-1-base) kharophen)-N-methyl-N-(6-picoline-3-base)-3-Phenylpropionamide (30mg, 0.07mmol, productive rate: 33%), LC/MS:m/zM ++ 1=456, HPLC retention time=2.15min (10-90% acetonitrile and water, containing 0.1%TFA).
1HNMR(400MHz，DMSO)δ8.93(d，J＝7.6Hz，3H)，8.22(d，J＝14.7Hz，5H)，7.97(s，3H)，7.40(d，J＝7.4Hz，3H)，7.35-7.17(m，13H)，6.99-6.69(m，12H)，5.03(dd，J＝35.9，17.2Hz，7H)，4.34(dd，J＝13.7，8.8Hz，4H)，3.12(s，10H)，2.94(d，J＝8.1Hz，4H)，2.74(dd，J＝13.8，9.7Hz，3H)，2.46(s，20H)，2.24(s，9H).
So that acid and amine, for raw material, can prepare 144-171 example 144 to 171 by the preparation method being similar to 143 accordingly
(example 144): 1hNMR (400MHz, CDCl 3) δ 8.92 (d, J=8.3Hz, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 7.60 (s, 1H), 7.41 (d, J=7.7Hz, 3H), 7.27-7.04 (m, 5H), 6.81 (s, 2H), 4.93 (q, J=16.2Hz, 2H), 4.48 (s, 1H), 3.17 (s, 3H), 2.90 (d, J=9.0Hz, 1H), 2.73-2.61 (m, 1H).
(example 145): 1hNMR (400MHz, DMSO) δ 8.85 (d, J=7.9Hz, 1H), 7.97 (s, 1H), 7.49-7.34 (m, 3H), 7.27-7.14 (m, 5H), 6.85-6.70 (m, 4H), 5.02 (dd, J=40.7,17.3Hz, 2H), 4.46 (s, 1H), 3.15 (s, 3H), 2.90 (d, J=14.1Hz, 1H), 2.68 (d, J=13.3Hz, 1H), 2.45 (s, 3H), 2.21 (s, 3H).
(example 146): 1hNMR (400MHz, DMSO) δ 8.94 (s, 1H), 7.97 (s, 2H), 7.42 (s, 1H), 7.22 (s, 3H), 6.99-6.69 (m, 5H), 5.13-4.90 (m, 2H), 4.37 (s, 1H), 3.84 (s, 3H), 3.11 (s, 3H), 2.95 (d, J=13.7Hz, 1H), 2.74 (t, J=15.1Hz, 1H), 2.46 (s, 3H), (2.24 s, 3H).
(example 147): 1hNMR (400MHz, DMSO) δ 8.82 (d, J=8.0Hz, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.22 (d, J=6.4Hz, 3H), 6.90 (d, J=7.9Hz, 3H), 6.83 (d, J=7.3Hz, 1H), 6.76-6.63 (m, 3H), 6.05 (s, 2H), 5.02 (q, J=17.4Hz, 2H), 4.48 (s, 1H), 3.09 (s, 4H), 2.94 (d, J=9.4Hz, 1H), 2.75-2.67 (m, 1H), 2.45 (s, 3H), 2.22 (s, 3H).
(example 148): 1hNMR (400MHz, DMSO) δ 8.98 (d, J=8.1Hz, 1H), 8.20 (s, 1H), 7.94 (d, J=7.3Hz, 2H), 7.62 (s, 1H), 7.41 (s, 1H), 7.20 (d, J=4.1Hz, 3H), 6.92 (d, J=4.3Hz, 2H), 6.81 (d, J=8.7Hz, 1H), 4.93 (q, J=16.6Hz, 2H), 4.38 (d, J=5.6Hz, 1H), 3.83 (s, 3H), 3.11 (s, 3H), 2.94 (d, J=8.4Hz, 1H), 2.76-2.65 (m, 1H).
(example 149): 1hNMR (400MHz, DMSO) δ 8.82 (d, J=8.2Hz, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.19 (s, 3H), 6.93 (d, J=8.5Hz, 1H), 6.84 (dd, J=13.2, 7.8Hz, 4H), 6.74 (d, J=7.3Hz, 1H), 5.02 (dd, J=38.2, 17.3Hz, 2H), 4.55 (s, 1H), 3.75 (s, 6H), 3.13 (s, 3H), 2.95 (d, J=13.5Hz, 1H), 2.76-2.65 (m, 1H), 2.45 (s, 3H), 2.24 (s, 3H).
(example 150): 1hNMR (400MHz, DMSO) δ 8.97 (d, J=8.0Hz, 1H), 7.94 (d, J=15.2Hz, 2H), 7.39 (s, 2H), 7.22 (d, J=5.7Hz, 3H), 7.01-6.90 (m, 3H), 6.81 (d, J=8.6Hz, 1H), 4.83 (dd, J=37.9, 16.4Hz, 2H), 4.37 (dd, J=13.8, 8.3Hz, 1H), 3.83 (s, 3H), 3.11 (s, 3H), 2.95 (dd, J=13.5, 5.4Hz, 1H), 2.75 (dd, J=13.5, 9.2Hz, 1H), 2.28 (s, 6H).
(example 151): 1hNMR (400MHz, DMSO) δ 8.90 (d, J=7.9Hz, 1H), 7.92 (s, 1H), 7.49-7.31 (m, 4H), 7.19 (dd, J=13.2,5.2Hz, 5H), 6.96 (s, 1H), 6.83 (s, 2H), 4.82 (dd, J=40.9,16.4Hz, 2H), 4.47 (s, 1H), 3.16 (s, 3H), 2.96-2.85 (m, 1H), 2.76-2.63 (m, 1H), 2.28 (d, J=3.2Hz, 6H).
(example 152): 1hNMR (400MHz, DMSO) δ 9.02 (d, J=7.7Hz, 1H), 8.20 (d, J=12.9Hz, 2H), 7.45-7.35 (m, 2H), 7.23 (dd, J=13.4, 6.1Hz, 4H), 7.04 (s, 1H), 6.91 (d, J=4.1Hz, 2H), 4.89 (dd, J=35.9, 16.4Hz, 2H), 4.34 (d, J=5.3Hz, 1H), 3.12 (s, 3H), 2.94 (dd, J=13.5, 5.2Hz, 1H), 2.79-2.70 (m, 1H), 2.45 (s, 3H), 2.30 (d, J=2.8Hz, 6H).
(example 153): 1hNMR (400MHz, DMSO) δ 8.97 (d, J=8.4Hz, 1H), 8.27-8.11 (m, 2H), 7.92 (s, 1H), 7.61 (s, 1H), 7.38 (d, J=7.8Hz, 1H), 7.22 (dd, J=23.7,5.8Hz, 4H), 6.89 (d, J=4.0Hz, 2H), 4.93 (q, J=16.5Hz, 2H), 4.36 (d, J=5.4Hz, 1H), 3.13 (s, 3H), 2.93 (dd, J=13.5,5.6Hz, 1H), 2.77-2.65 (m, 1H), 2.46 (s, 3H).
(example 154): 1hNMR (400MHz, CDCl 3) δ 8.95 (d, J=7.8Hz, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.43 (d, J=8.7Hz, 1H), 7.22 (dd, J=4.8, 1.7Hz, 3H), 7.12 (d, J=7.8Hz, 1H), 6.93-6.86 (m, 3H), 6.83 (d, J=8.7Hz, 1H), 5.07 (dd, J=36.1, 17.5Hz, 2H), 4.42-4.34 (m, 1H), 3.84 (s, 3H), 3.11 (s, 3H), 2.95 (dd, J=13.5, 5.1Hz, 1H), 2.74 (dd, J=13.5, 9.3Hz, 1H), 2.25 (s, 3H).
(example 155): 1hNMR (400MHz, CDCl 3) δ 8.89 (d, J=8.1Hz, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.38 (s, 1H), 7.22 (dd, J=4.7,1.4Hz, 3H), 7.04 (d, J=7.8Hz, 1H), 7.00-6.92 (m, 3H), 6.80 (d, J=9.0Hz, 1H), 5.12 (s, 2H), 4.38 (dd, J=14.4,9.2Hz, 1H), 3.83 (s, 3H), 3.11 (s, 3H), 2.94 (dd, J=8.0,7.1Hz, 1H), 2.76-2.72 (m, 1H), 2.49 (s, 3H).
(example 156): 1hNMR (400MHz, DMSO) δ 8.95 (d, J=7.9Hz, 1H), 7.55 (s, 1H), 7.39 (d, J=7.7Hz, 3H), 7.30 (s, 1H), 7.17 (dd, J=9.8,5.1Hz, 5H), 6.82 (s, 2H), 4.99 (dd, J=37.0,18.0Hz, 2H), 4.47 (s, 1H), 3.16 (s, 3H), 2.90 (dd, J=14.2,5.2Hz, 1H), 2.72-2.66 (m, 1H), 2.34 (s, 3H), 2.33 (s, 3H).
(example 157): 1hNMR (400MHz, DMSO) δ 9.01 (d, J=8.1Hz, 1H), 7.91 (s, 1H), 7.56 (s, 1H), 7.34 (s, 1H), 7.31 (s, 1H), 7.26-7.19 (m, 3H), 6.97-6.89 (m, 2H), 6.79 (d, J=8.7Hz, 1H), 4.99 (q, J=17.5Hz, 2H), 4.45-4.31 (m, 1H), 3.82 (s, 3H), 3.11 (s, 3H), 2.95 (dd, J=13.3, 5.5Hz, 1H), 2.73 (dd, J=13.4, 8.7Hz, 1H), 2.35 (s, 3H), 2.33 (s, 3H).
(example 158): 1hNMR (400MHz, DMSO) δ 8.95 (d, J=8.2Hz, 1H), 7.46-7.34 (m, 3H), 7.24-7.12 (m, 5H), 7.01 (q, J=7.2Hz, 2H), 6.78 (dd, J=6.5,2.2Hz, 22H), 5.10 (d, J=42.7Hz, 2H), 4.50 (s, 1H), 3.16 (s, 3H), 2.90 (dd, J=13.5,4.5Hz, 1H), 2.70-2.66 (m, 1H), 2.33 (d, J=1.9Hz, 6H).
(example 159): 1hNMR (400MHz, CDCl 3) δ 8.98 (d, J=7.7Hz, 1H), 7.91 (s, 1H), 7.35 (d, J=7.6Hz, 1H), 7.22 (dd, J=5.0, 1.7Hz, 3H), 7.01 (q, J=7.3Hz, 2H), 6.91 (dd, J=6.7, 2.5Hz, 2H), 6.81 (d, J=8.8Hz, 1H), 5.10 (dd, J=42.6, 9.2Hz, 2H), 4.42 (dd, J=16.0, 8.1Hz, 1H), 3.83 (s, 3H), 3.11 (s, 3H), 2.94 (dd, J=13.5, 5.6Hz, 1H), 2.72 (dd, J=15.8, 6.7Hz, 1H), 2.36 (s, 3H).
(example 160): 1hNMR (400MHz, DMSO) δ 8.91 (d, J=8.1Hz, 1H), 8.12 (s, 1H), 7.46-7.34 (m, 3H), 7.24 (d, J=6.9Hz, 2H), 7.21-7.14 (m, 3H), 7.11 (d, J=7.8Hz, 1H), 6.86 (d, J=7.6Hz, 1H), 6.81-6.75 (m, 2H), 5.06 (dd, J=42.3, 17.6Hz, 2H), 4.47 (s, 1H), 3.16 (s, 3H), 2.90 (dd, J=13.9, 4.3Hz, 1H), 2.70 (dd, J=13.6, 3.7Hz, 1H), 2.22 (s, 3H).
(example 161): 1hNMR (400MHz, DMSO) δ 8.84 (d, J=7.9Hz, 1H), 8.13 (s, 1H), 7.43-7.36 (m, 3H), 7.22-7.14 (m, 5H), 7.02 (d, J=7.9Hz, 1H), 6.96 (d, J=8.1Hz, 1H), 6.86-6.78 (m, 2H), 5.16-5.05 (m, 2H), 4.47 (s, 1H), 3.15 (s, 3H), 2.89 (dd, J=13.7,4.1Hz, 1H), 2.68 (dd, J=6.2,3.0Hz, 1H), 2.48 (s, 3H).
(example 162): 1hNMR (400MHz, DMSO) δ 8.91 (d, J=8.1Hz, 1H), 7.53 (s, 1H), 7.27 (s, 1H), 7.24-7.17 (m, 3H), 6.91 (dd, J=7.7, 1.5Hz, 2H), 6.86 (d, J=8.3Hz, 1H), 6.61 (d, J=16.4Hz, 2H), 6.02 (d, J=4.6Hz, 2H), 4.96 (q, J=17.6Hz, 2H), 4.51-4.43 (m, 1H), 3.07 (s, 3H), 2.92 (dd, J=13.6, 5.0Hz, 1H), 2.68 (dd, J=13.6, 9.2Hz, 1H), 2.32 (s, 3H), 2.31 (s, 3H).
(example 163): 1hNMR (400MHz, DMSO) δ 9.00 (d, J=8.2Hz, 1H), 8.11 (s, 1H), 7.54 (s, 1H), 7.29 (t, J=5.2Hz, 3H), 7.23-7.17 (m, 3H), 6.93-6.84 (m, 2H), 4.98 (q, J=18.0Hz, 2H), 4.39-4.30 (m, 1H), 3.10 (s, 3H), 2.92 (dd, J=13.5,6.9Hz, 1H), 2.71 (dd, J=14.2,9.2Hz, 1H), 2.42 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H).
(example 164): 1hNMR (400MHz, CDCl 3) δ 8.30 (s, 1H), 7.89 (d, J=8.5Hz, 2H), 7.74 (t, J=12.2Hz, 2H), 7.59-7.51 (m, 2H), 7.32-7.28 (m, 2H), 7.27-7.08 (m, 5H), 6.67 (d, J=7.5Hz, 38H), 4.88 (q, J=7.7Hz, 1H), (4.68 d, J=3.3Hz, 2H), 3.32 (s, 3H), 2.90 (dd, J=13.6,6.7Hz, 1H), 2.64 (dd, J=13.4,7.9Hz, 1H), 3.52 (s, 3H).
(example 165): 1hNMR (400MHz, CDCl 3) δ 8.26 (s, 1H), 7.75 (d, J=7.3Hz, 1H), 7.49-7.29 (m, 3H), 7.27-7.02 (m, 7H), 6.97-6.78 (m, 3H), 6.55 (ddd, J=16.2,15.0,7.6Hz, 2H), 4.90-4.58 (m, 4H), (3.75 d, J=106.0Hz, 4H), (3.20 d, J=28.6Hz, 4H), 2.95-2.63 (m, 2H), 2.47 (dd, J=24.7,13.7Hz, 4H).
(example 166): 1hNMR (400MHz, CDCl 3) δ 7.88 (dd, J=20.6,13.5Hz, 2H), 7.45 (t, J=8.0Hz, 1H), 7.40-7.29 (m, 3H), 7.27-7.02 (m, 5H), 6.98-6.79 (m, 2H), 6.55 (dd, J=43.5,7.6Hz, 2H), 4.94-4.64 (m, 3H), 3.75 (d, J=102.4Hz, 3H), 3.19 (d, J=32.7Hz, 3H), 2.83 (ddd, J=18.1,13.5,5.5Hz, 1H), 2.57 (ddd, J=22.9,13.6,7.7Hz, 1H).
(example 167): 1hNMR (400MHz, CDCl 3) δ 8.24 (s, 1H), 7.77 (s, 1H), 7.43-7.30 (m, 4H), 7.27-7.03 (m, 6H), 6.69 (dd, J=19.6,7.4Hz, 2H), 4.74-4.49 (m, 3H), 3.21 (d, J=3.6Hz, 3H), 2.93 (dd, J=13.7,5.6Hz, 1H), 2.65 (ddd, J=22.4,13.7,6.4Hz, 1H), 2.47 (s, 3H), 2.22 (d, J=13.4Hz, 3H).
(example 168): 1hNMR (400MHz, CDCl 3) δ 7.98 (s, 1H), 7.87 (d, J=8.2Hz, 3H), 7.74 (d, J=5.7Hz, 1H), 7.59-7.50 (m, 2H), 7.34 (dd, J=13.2, 6.4Hz, 3H), 7.27-7.16 (m, 3H), 7.13 (t, J=7.4Hz, 3H), 6.72 (d, J=7.5Hz, 2H), 4.88 (dt, J=14.3, 7.0Hz, 1H), 4.79 (d, J=6.8Hz, 2H), 3.30 (s, 3H), 2.90 (dd, J=13.2, 7.3Hz, 1H), 2.68 (dd, J=13.1, 7.3Hz, 1H).
(example 169): 1hNMR (400MHz, CDCl 3) δ 8.31 (d, J=40.9Hz, 2H), 8.13 (d, J=8.5Hz, 1H), 7.85-7.73 (m, 2H), 7.70 (d, J=8.1Hz, 1H), 7.60 (t, J=7.5Hz, 1H), 7.48-7.30 (m, 5H), 7.20 (t, J=7.5Hz, 2H), 6.82 (d, J=7.2Hz, 2H), 4.94 (s, 2H), 4.71 (dd, J=14.6,7.9Hz, 1H), 3.27 (s, 3H), 2.93 (dd, J=12.7,9.2Hz, 1H), 2.78-2.74 (m, 1H).
(example 170): 1hNMR (400MHz, CDCl 3) δ 7.79-7.71 (m, 1H), 7.28-7.26 (m, 1H), 7.26-7.22 (m, 3H), 7.22-7.18 (m, 1H), 7.12-7.04 (m, 2H), 7.00-6.90 (m, 1H), 5.18 (ddd, J=34.4,14.6,7.4Hz, 1H), 4.73 (d, J=3.0Hz, 2H), 4.42-4.19 (m, 1H), 3.49-3.35 (m, 2H), 3.04-2.86 (m, 2H), 2.70 (d, J=64.0Hz, 3H), 2.56 (s, 3H), 1.78-1.04 (m, 10H).
(example 171): 1hNMR (400MHz, CDCl 3) δ 7.93 (d, J=40.9Hz, 2H), 7.40-7.29 (m, 3H), 7.28-7.19 (m, 3H), 7.14-6.99 (m, 2H), 6.87 (s, 1H), 5.16 (dt, J=22.2,7.2Hz, 1H), (4.82 t, J=3.2Hz, 2H), (3.74 q, J=7.0Hz, 1H), 3.04-2.85 (m, 2H), 2.67 (d, J=76.7Hz, 3H), 1.47-0.95 (m, 10H). example 172
(S)-2-(2-(4,7-dimethyl-1H-benzo [d] imidazoles-1-base) kharophen)-N-ethyl-N-(6-methoxypyridine-3-base)-3-Phenylpropionamide the preparation method of this compound is similar to (S)-2-(2-(4,7-dimethyl-1H-benzo [d] imidazoles-1-base) kharophen) preparation of-N-methyl-N-(6-methoxypyridine-3-base)-3-Phenylpropionamide, obtain solid chemical compound (productive rate: 30%), LC/MS:m/zM ++ 1=468, HPLC retention time=2.54min (10-90% acetonitrile and water, containing 0.1%TFA).
1hNMR (400MHz, DMSO) δ 8.89 (d, J=7.8Hz, 1H), 7.97 (s, 1H), 7.91-7.76 (m, 1H), 7.32-7.19 (m, 3H), 7.04-6.62 (m, 5H), 5.03 (dd, J=34.7, 17.3Hz, 2H), 4.27 (dd, J=12.2, 7.3Hz, 1H), 3.83 (s, 3H), 2.95 (dd, J=13.7, 5.9Hz, 1H), 2.77-2.64 (m, 1H), 2.45 (s, 3H), 2.23 (s, 3H), 1.24 (s, 1H), 0.98 (dd, J=32.4, 25.4Hz, 3H). example 173
(S)-N-(benzo [d] [1,3] dioxy-5-base)-2-(2-(3-ethyl-4,7-dimethyl-2-oxo-2,3-dihydrobenzo [d] imidazoles-1-base) kharophen)-N-methyl-3-Phenylpropionamide (PR-001014) the preparation of example 173A.4,7-dimethyl-1H-benzo [d] imidazoles-2 (3H)-one
Be dissolved in 10mL tetrahydrofuran (THF) to 3,6-dimethyl benzene-1,2-diamines (1.0g, 7.35mmol, 1.0eq) and CDI (1.1eq), reaction solution stirred overnight at room temperature.Remove excessive solvent, add water in residuum, be extracted with ethyl acetate, 4,7-dimethyl-1H-benzo [d] imidazoles-2 (3H)-one (760mg, 4.69mmol is obtained with sherwood oil recrystallization, productive rate: 63.9%), LC/MS:m/zM ++ 1=163.The preparation of chloro-4,7-dimethyl-1H-benzo [d] imidazoles of example 173B.2-
By 4, the mixing solutions reflux of 7-dimethyl-1H-benzo [d] imidazoles-2 (3H)-one (400mg, 2.47mmol, 1.0eq) and phosphorus oxychloride, careful for reaction solution is joined in frozen water, adding sodium hydroxide solution will regulate pH to 8, extraction into ethyl acetate, and column chromatography purification obtains 2-chloro-4,7-dimethyl-1H-benzo [d] imidazoles (170mg, 0.94mmol, productive rate: 38.2%), LC/MS:m/zM ++ 1=181.The preparation of example 173C.2-(4,7-dimethyl-2-oxo-2,3-dihydro 1H-benzo [d] imidazoles-1-base) acetic acid
At 2-chloro-4, the N of 7-dimethyl-1H-benzo [d] imidazoles (170g, 0.94mmol, 1.0eq), in dinethylformamide solution, NaH (56.4mg, 1.41mmol, 1.5eq) is slowly added at 0 DEG C, ethyl bromoacetate (0.16mL is dropwise added after 20 minutes, 1.41mmol, 1.5eq), reaction solution at 0 DEG C, continues stirring 50 minutes until TLC (PE: EA=5: 1) display raw material reaction is complete.The pH adding the rear hydrochloric acid conditioning solution of 5mL frozen water cancellation reaction is 2, after normal procedure, obtain crude material 2-(4,7-dimethyl-2-oxo-2,3-dihydro 1H-benzo [d] imidazoles-1-base) acetic acid (180mg, 0.81mmol, productive rate: 87.0%), LC/MS:m/zM ++ 1=221.The preparation of example 173D.2-(3-ethyl-4,7-dimethyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazoles-1-base) acetic acid
To 2-(4,7-dimethyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazoles-1-base) acetic acid (100mg, 0.45mmol, in DMF solution 1.0eq), NaH (27.3mg, 0.68mmol, 1.5eq) is slowly added at 0 DEG C, monobromethane (0.05mL is dropwise added after 20 minutes, 0.68mmol, 1.5eq), react 0 DEG C and stir 2 hours.Add 5mL frozen water cancellation reaction, add hydrochloric acid by the pH regulator of solution to 4, extraction into ethyl acetate, concentrated after obtain crude material 2-(3-ethyl-4,7-dimethyl-2-oxygen-2,3-dihydro-1H-benzo [d] imidazoles-1-base) acetic acid (60mg, 0.24mmol, productive rate: 53.8%), LC/MS:m/zM ++ 1=249.Example 173E. (S)-N-(benzo [d] [1,3] dioxy-5-base)-2-(2-(3-ethyl-4,7-dimethyl-2-oxo-2,3-dihydrobenzo [d] imidazoles-1-base) kharophen) preparation of-N-methyl-3-Phenylpropionamide
To 2-(3-ethyl-4, 7-dimethyl-2-oxygen-2, 3-dihydro-1H-benzo [d] imidazoles-1-base) acetic acid (60mg, 0.24mmol, 1.0eq), (S)-2-amino-N-(benzo [d] [1, 3] dioxy-5-base)-N-methyl-3-Phenylpropionamide (86mg, 0.29mmol, in DCM (5mL) mixed solution 1.2eq), add EDCI (68.7mg, 0.36mmol, 1.5eq), HOBt (65mg, 0.48mmol, 2.0eq) with DIPEA (62mg, 0.48mmol, 2.0eq), stirred overnight at room temperature under nitrogen protection, reaction solution washes three times with water, dry concentrated, residuum preparative HPLC purifying obtains (S)-N-(benzo [d] [1, 3] dioxy-5-base)-2-(2-(3-ethyl-4, 7-dimethyl-2-oxo-2, 3-dihydrobenzo [d] imidazoles-1-base) kharophen)-N-methyl-3-Phenylpropionamide (30mg, 0.06mmol, yield: 25%), LC/MS:m/zM ++ 1=529, HPLC retention time=3.05min (10-90% acetonitrile and water, containing 0.1%TFA).
1HNMR(400MHz，DMSO)δ8.69(d，J＝7.8Hz，1H)，7.20(t，J＝5.8Hz，3H)，6.91(t，J＝8.1Hz，3H)，6.73(s，1H)，6.68(d，J＝7.8Hz，2H)，6.58(d，J＝7.9Hz，1H)，6.06(d，J＝1.0Hz，2H)，4.58(dd，J＝51.6，17.6Hz，2H)，4.49(m，1H)，4.01(q，J＝7.1Hz，2H)，3.10(s，3H)，2.93(dd，J＝13.3，4.6Hz，1H)，2.69(dd，J＝13.7，9.6Hz，1H)，2.49(s，3H)，2.05(s，3H)，1.18(t，J＝7.0Hz，3H).
Compound 174-175 can by similar and 173 preparation method, with corresponding acid and amine for raw material prepares and obtain.Example 170 to 171
(example 174): 1hNMR (400MHz, DMSO) δ 10.95 (s, 1H), 8.84 (d, J=7.8Hz, 1H), 7.94 (d, J=42.7Hz, 1H), 7.44 (s, 1H), 7.22 (d, J=3.8Hz, 3H), 6.91 (d, J=3.8Hz, 2H), 6.84 (d, J=8.7Hz, 1H), 6.65 (d, J=7.7Hz, 1H), 6.55 (d, J=8.0Hz, 1H), 4.53 (dd, J=47.7, 17.6Hz, 2H), 4.42-4.28 (m, 1H), 3.86 (s, 3H), 3.12 (s, 3H), 2.92 (dd, J=13.3, 4.8Hz, 1H), 2.81-2.67 (m, 1H), 2.22 (s, 3H), 2.05 (s, 3H).
(example 175): 1hNMR (400MHz, DMSO) δ 10.89 (s, 1H), 8.67 (d, J=7.9Hz, 1H), 7.21 (d, J=6.7Hz, 3H), 6.91 (t, J=7.1Hz, 3H), 6.76-6.61 (m, 3H), 6.54 (d, J=7.8Hz, 1H), 6.07 (s, 2H), 4.57 (d, J=17.6Hz, 1H), 4.45 (d, J=17.5Hz, 2H), 3.10 (s, 3H), 2.92 (dd, J=13.2, 4.8Hz, 1H), 2.75-2.63 (m, 1H), 2.21 (s, 3H), 2.03 (s, 3H). example 176
(S)-N-(benzo [d] [1,3] dioxane-5-base)-N-methyl-2-(2-(1-Methyl-1H-indole-4-base) kharophen)-3-Phenylpropionamide the preparation of example 176A.1-methyl-6,7-dihydro-1H-indoles-4 (5H)-one
At cyclohexyl-1,3-diketone (10g, 89mmol, 2 are added in toluene (150mL) solution 1eq), 2-Dimethoxy-N-methyl ethamine (16g, 134mmol, 1.5eq) and tosic acid (0.8g, 4.65mmol, 0.05eq), reaction solution stirring and refluxing 12 hours, after TLC (PE/EA0: 1) detection display reacts completely, by reaction mixture vacuum concentration, residue purification by silica gel column chromatography obtains 1-methyl-6,7-dihydro-1H-indoles-4 (5H)-one (3g, 20.1mmol, productive rate: 22.47%), LC/MS:m/zM ++ 1=150.The preparation of example 176B. (E)-2-(1-methyl-6,7-dihydro-1H-indoles-4 (5H)-subunit) acetonitrile
To 1-methyl-6,7-dihydro-1H-indoles-4 (5H)-one (2.7g, 18.1mmol, sodium hydride (2.1g, 54.3mmol, 3eq) is slowly added in tetrahydrofuran solution 1eq), stir after 40 minutes, dropwise add cyanogen methyl-phosphoric acid dimethyl ester ((2.1g, 54.3mmol, 3eq) again.Reaction solution backflow is spent the night, after TLC (PE/EA1: 1) detection display raw material reaction is complete, add 30mL shrend to go out reaction, extraction into ethyl acetate (50mLx2), organic phase after merging is concentrated after salt solution (20mLx2) washing, anhydrous sodium sulfate drying obtains (E)-2-(1-methyl-6,7-dihydro-1H-indoles-4 (5H)-subunit) acetonitrile (2g, 11.6mmol, productive rate: 64.2%), LC/MS:m/zM ++ 1=173.The preparation of example 176C.2-(1-Methyl-1H-indole-4-base) acetonitrile
By Pd/C (0.5g, 50%) and (E)-2-(1-methyl-6,7-dihydro-1H-indoles-4 (5H)-subunit) acetonitrile (1.0g, 5.81mmol, 1eq) 1,2-diethyl ethane solution (3mL), stir 3 hours under 200 DEG C of conditions, after TLC (PE/EA3: 1) detection display reacts completely, reaction solution is cooled to room temperature, filter, wet cake 30mL washed with dichloromethane.Obtain residuum after filter vacuum is concentrated, purification by silica gel column chromatography obtains 2-(1-Methyl-1H-indole-4-base) acetonitrile (0.6g, 3.53mmoL, productive rate: 60%), LC/MS:m/zM ++ 1=171.The preparation of example 176D.2-(1-Methyl-1H-indole-4-base) acetic acid
Be dissolved in 10mL concentrated hydrochloric acid by 2-(1-Methyl-1H-indole-4-base) acetonitrile (0.3g, 1.76mmol, 1eq), reflux 12 hours, TLC (PE/EA1: 1) detection display raw material reaction is complete.Concentration response mixed solution removing hydrochloric acid, residue sodium hydroxide solution regulates the rear washed with diethylether of pH to 10 (20mLx2), adjust aqueous phase pH to 4 again, extraction into ethyl acetate (30mLx2), organic phase after merging is concentrated after salt solution (20mL) washing, anhydrous sodium sulfate drying obtains 2-(1-Methyl-1H-indole-4-base) acetic acid (0.2g, 1mmoL, productive rate: 60%), LC/MS:m/zM ++ 1=190.The preparation of example 176E. (S)-N-(benzo [d] [1,3] dioxane-5-base)-N-methyl-2-(2-(1-Methyl-1H-indole-4-base) kharophen)-3-Phenylpropionamide
To 2-(1-Methyl-1H-indole-4-base) acetic acid (30mg, 0.16mmol, 1eq), (S)-2-amino-N-(benzo [d] [1, 3] dioxane-5-yl)-N-methyl-3-Phenylpropionamide (48mg, 0.16mmol, in DMF (5mL) mixed solution 1.0eq), add EDCI (46mg, 0.24mmol, 1.5eq), HOBt (43mg, 0.32mmol, 2.0eq) with DIPEA (41.3mg, 0.32mmol, 2.0eq), reaction solution is stirred overnight at room temperature under nitrogen protection, wash three times with water, dry, concentrated, residuum preparative HPLC purifying obtains (S)-N-(benzo [d] [1, 3] dioxane-5-base)-N-methyl-2-(2-(1-Methyl-1H-indole-4-base) kharophen)-3-Phenylpropionamide (33mg, 0.07mmoL, productive rate: 44%), LC/MS:m/zM ++ 1=470, HPLC retention time=2.94min (10-90% acetonitrile and water, containing 0.1%TFA).
1HNMR(400MHz，CDCl 3)δ7.28(s，2H)，7.26-7.11(m，4H)，7.08(d，J＝3.1Hz，1H)，6.96(d，J＝7.0Hz，1H)，6.80(d，J＝7.1Hz，2H)，6.71(d，J＝8.0Hz，1H)，6.46(d，J＝3.1Hz，1H)，6.12(d，J＝8.6Hz，1H)，6.02(s，2H)，4.79(dd，J＝14.7，7.8Hz，1H)，3.83(d，J＝8.5Hz，5H)，3.09(s，3H)，2.75(dd，J＝13.2，7.9Hz，1H)，2.62(dd，J＝13.1，6.3Hz，1H).
So that acid and amine, for raw material, can obtain compound 177-180 example 177 to 180 by the preparation method being similar to 176 accordingly
(example 177): 1hNMR (400MHz, CDCl 3) δ 7.92-7.80 (m, 2H), 7.70 (s, 1H), 7.61-7.50 (m, 2H), 7.32-7.29 (m, 3H), 7.27-7.18 (m, 2H), 7.10 (dd, J=14.8, 5.4Hz, 3H), 6.98 (d, J=6.7Hz, 1H), 6.73 (d, J=7.6Hz, 2H), 6.47 (d, J=3.0Hz, 1H), 6.12 (d, J=8.3Hz, 1H), 4.83 (dd, J=14.5, 8.1Hz, 1H), 3.89-3.78 (m, 5H), 3.23 (s, 3H), 2.75 (dd, J=13.2, 8.1Hz, 1H), 2.59 (dd, J=13.0, 6.1Hz, 1H).
(example 178): 1hNMR (400MHz, CDCl 3) δ 7.45-7.30 (m, 2H), 7.25-6.96 (m, 6H), 6.94-6.71 (m, 3H), 6.57 (d, J=7.4Hz, 1H), 6.45 (dd, J=31.6,3.0Hz, 1H), 6.35-6.04 (m, 2H), 4.73 (dd, J=79.5,5.3Hz, 1H), 3.81 (dd, J=20.9,6.0Hz, 6H), (3.59 d, J=63.8Hz, 2H), (3.11 d, J=45.4Hz, 3H), 2.71-2.63 (m, 1H), 2.38 (dd, J=14.0,7.8Hz, 1H).
(example 179): 1hNMR (400MHz, CDCl 3) δ 8.22 (s, 1H), 8.13 (d, J=8.3Hz, 1H), 7.76 (dd, J=16.8, 8.4Hz, 2H), 7.60 (t, J=7.4Hz, 1H), 7.34-7.28 (m, 4H), 7.21 (dt, J=19.2, 7.3Hz, 3H), 7.10 (d, J=3.2Hz, 1H), 7.00 (d, J=7.0Hz, 1H), 6.81 (d, J=7.7Hz, 1H), 6.49 (d, J=3.2Hz, 1H), 6.10 (d, J=8.6Hz, 1H), 4.70 (dd, J=14.9, 8.5Hz, 1H), 3.85 (d, J=4.9Hz, 5H), 3.22 (s, 3H), 2.83-2.69 (m, 1H), 2.62 (dd, J=12.9, 5.8Hz, 1H).
(example 180): 1hNMR (400MHz, CDCl 3) δ 7.26-7.11 (m, 5H), 7.07 (d, J=2.8Hz, 1H), 7.03-6.79 (m, 3H), 6.55-6.46 (m, 1H), 6.42 (d, J=8.2Hz, 1H), 5.12 (ddd, J=38.1,13.7,8.0Hz, 1H), 3.83 (s, 1H), 3.81 (s, 3H), (3.50 d, J=105.4Hz, 1H), 2.94-2.76 (m, 2H), 2.58 (d, J=76.9Hz, 3H), 1.81-1.64 (m, 2H), 1.62-0.76 (m, 10H). example 181
(S)-2-(2-(5,8-dimethyl-1-carbonyl isoquinoline 99.9-2 (1H)-Ji) kharophen)-N-methyl-N, 3-diphenylpropanamide this compound by being similar to the preparation method of 1H, with corresponding acid and amine for prepared by raw material.LC/MS:m/zM ++ 1=468, HPLC retention time=3.71min (10-90% acetonitrile and water, containing 0.1%TFA).
1HNMR(400MHz，CDCl 3)δ8.68(d，J＝7.7Hz，1H)，7.37(dd，J＝12.3，7.4Hz，4H)，7.27(d，J＝7.6Hz，1H)，7.23-7.09(m，6H)，6.87(d，J＝3.8Hz，2H)，6.52(d，J＝7.5Hz，1H)，4.54(dd，J＝39.0，15.9Hz，2H)，4.44(d，J＝5.7Hz，1H)，3.14(s，3H)，2.88(dd，J＝13.3，5.1Hz，1H)，2.74-2.64(m，4H)，2.42(s，3H).
Compound 182-184 can by being similar to the preparation method of example 181, with corresponding acid and amine for raw material prepares and obtain.Example 182 to 184
(example 182): 1hNMR (400MHz, CDCl 3) δ 8.68 (d, J=7.5Hz, 1H), 7.92 (s, 1H), 7.38 (dd, J=15.4,8.0Hz, 4H), 7.23-7.10 (m, 6H), 6.89-6.78 (m, 2H), 6.45 (d, J=7.3Hz, 1H), 4.56 (dd, J=60.1,16.0Hz, 2H), 4.46-4.38 (m, 1H), 3.14 (s, 3H), 2.87 (dd, J=13.5,5.4Hz, 1H), 2.68 (dd, J=13.2,9.3Hz, 1H), 2.35 (d, J=1.8Hz, 6H).
(example 183): 1hNMR (400MHz, DMSO) δ 8.75 (d, J=7.6Hz, 1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.41 (s, 1H), 7.31-7.19 (m, 4H), 7.16 (d, J=7.3Hz, 1H), 7.00-6.92 (m, 2H), 6.76 (d, J=8.8Hz, 1H), 6.46 (d, J=7.3Hz, 1H), 4.62 (d, J=16.0Hz, 1H), 4.51 (d, J=16.0Hz, 1H), 4.34 (dd, J=14.3, 7.5Hz, 1H), 3.82 (s, 3H), 3.08 (s, 3H), 2.92 (dd, J=13.3, 6.2Hz, 1H), 2.73 (dd, J=13.1, 7.9Hz, 1H), 2.36 (s, 6H).
(example 184): 1hNMR (400MHz, DMSO) δ 8.65 (d, J=7.8Hz, 1H), 7.92 (s, 1H), 7.41 (s, 1H), 7.28-7.18 (m, 3H), 7.14 (d, J=7.3Hz, 1H), 6.95 (d, J=7.7Hz, 2H), 6.87 (d, J=8.2Hz, 1H), 6.60 (s, 2H), 6.45 (d, J=7.4Hz, 1H), 6.04 (d, J=4.9Hz, 2H), 4.62 (d, J=15.9Hz, 1H), 4.48 (dd, J=17.5, 10.9Hz, 2H), 3.07 (s, 3H), 2.91 (dd, J=13.1, 5.5Hz, 1H), 2.71 (dd, J=13.3, 8.7Hz, 1H), 2.36 (s, 6H).
Example 185-218 below can be prepared by method similar in above example. bioexperiment
MT2 copies experiment: precipitation be resuspended in appropriate RPMI1640 (10%FBS) after MT2 cell centrifugation, make cell density be about 1.34 × 10 5/ ml.In above-mentioned MT2 cell, add HIV-1 (NL4-3) virus of appropriate volume, make its MOI be about 0.01TCID50/ cell.In containing Antiviral breeding 384 orifice plate of compound, add 90ul/ hole MT reconnaissance 2 cells/HIV-1 mixture, in containing cytotoxicity experiment 384 orifice plate of compound, add 45ul/ hole MT2 cell (1.34 × 10 5/ ml, does not add virus).Place 384 cell plate in 37 DEG C, 5%CO 23 days are hatched in incubator.MT2 cell infection, after 3 days, produces 10ul/ hole supernatant to 384 new plates, adds 40ul/ hole JC53BL cell (0.4 × 10 in the plate from Antiviral breeding 384 plate 6/ ml).β-Gal is detected by the following method active after 24 hours.30ul/ hole FluorAce solution is added in brassboard, in 37 DEG C, 5% (v/v) CO 2cultivate after 2 hours in incubator, add 10ul/ hole reaction terminating liquid, use PEVictor3 instrument to read plate under umbelliferone frequency range.MT2 plating cells is after 3 days, and detect cytotoxicity experiment result under the condition using CellTiter-Glo test kit to recommend at Promega, the add-on of CellTiter-Glo reagent changes 10ul/ hole into.The calculating of IC50 and CC50 adopts GraphPadPrism5.00 (four-parameterlogisticequation).
Here is the bioassay data of example 1-218, records with above-described biological detecting method.
Instance number EC50(nM) CC50(nM)
1 9.8 ＞20,000
2 8,300 ＞20,000
3 170 ＞20,000
4 5,200 ＞20,000
5 6,200 ＞20,000
6 2,500 ＞20,000
7 5,500 ＞20,000
8 9,500 ＞20,000
9 39 ＞20,000
10 1,800 ＞20,000
11 20,000 ＞20,000
12 6,400 ＞20,000
13 210 ＞20,000
14 220 ＞20,000
15 70 ＞20,000
16 250 ＞20,000
17 28 ＞20,000
18 1,500 ＞20,000
19 8 ＞20,000
20 4,700 ＞20,000
21 3,200 ＞20,000
22 8,300 ＞20,000
23 2,700 ＞20,000
24 910 ＞20,000
25 2,800 ＞20,000
26 3,500 ＞20,000
27 1,700 ＞20,000
28 15,000 ＞20,000
29 17,000 ＞20,000
30 8,700 ＞20,000
31 4,800 ＞20,000
32 9,300 ＞20,000
33 6,000 ＞20,000
34 540 ＞20,000
35 8,700 ＞20,000
36 6,900 ＞20,000
37 3,300 ＞20,000
38 700 ＞20,000
39 2,800 ＞20,000
40 28 ＞20,000
41 2,800 ＞20,000
42 21 ＞20,000
43 950 ＞20,000
44 660 ＞20,000
45 510 ＞20,000
46 1,100 ＞20,000
47 7,800 ＞20,000
48 2,500 ＞20,000
49 4,000 ＞20,000
50 100 ＞20,000
51 7,000 ＞20,000
52 5 ＞20,000
53 2,400 ＞20,000
54 460 ＞20,000
55 38 ＞20,000
56 34 ＞20,000
57 44 7,300
58 2,900 ＞20,000
59 13 ＞20,000
60 160 ＞20,000
61 310 ＞20,000
62 460 ＞20,000
63 4.4 ＞20,000
64 6.3 ＞20,000
65 3.7 ＞20,000
66 450 ＞20,000
67 51 ＞20,000
68 10 ＞20,000
69 270 ＞20,000
70 330 ＞20,000
71 1,000 ＞20,000
72 12 ＞20,000
73 260 ＞20,000
74 620 ＞20,000
75 320 ＞20,000
76 240 ＞20,000
77 79 ＞20,000
78 150 ＞20,000
79 66 ＞20,000
80 130 ＞20,000
81 540 ＞20,000
82 190 ＞20,000
83 85 ＞20,000
84 480 ＞20,000
85 130 ＞20,000
86 250 ＞20,000
87 620 ＞20,000
88 190 ＞20,000
89 63 ＞20,000
90 20,000 ＞20,000
91 160 ＞20,000
92 630 ＞20,000
93 82 ＞20,000
94 240 ＞20,000
95 110 ＞20,000
96 20,000 ＞20,000
97 20,000 ＞20,000
98 20,000 ＞20,000
99 20,000 ＞20,000
100 20,000 ＞20,000
101 20,000 ＞20,000
102 20,000 ＞20,000
103 20,000 ＞20,000
104 950 ＞20,000
105 990 ＞20,000
106 2,800 ＞20,000
107 160 ＞20,000
108 310 ＞20,000
109 20,000 ＞20,000
110 170 ＞20,000
111 220 ＞20,000
112 130 ＞20,000
113 880 ＞20,000
114 2,000 ＞20,000
115 520 ＞20,000
116 230 ＞20,000
117 460 ＞20,000
118 7,000 ＞20,000
119 ＞20,000 ＞20,000
120 16 ＞20,000
121 24 ＞20,000
122 11 ＞20,000
123 120 ＞20,000
124 6.6 ＞20,000
125 2.2 ＞20,000
126 8.4 ＞20,000
127 44 ＞20,000
128 16,000 ＞20,000
129 16,000 ＞20,000
130 16,000 ＞20,000
131 410 ＞20,000
132 320 ＞20,000
133 620 ＞20,000
134 310 ＞20,000
135 470 ＞20,000
136 180 ＞20,000
137 920 ＞20,000
138 1,100 ＞20,000
139 7,100 ＞20,000
140 9,600 ＞20,000
141 4,300 ＞20,000
142 950 ＞20,000
143 80 ＞20,000
144 7,100 ＞20,000
145 440 ＞20,000
146 260 ＞20,000
147 180 ＞20,000
148 6,200 ＞20,000
149 480 ＞20,000
150 180 ＞20,000
151 140 ＞20,000
152 170 ＞20,000
153 5,700 ＞20,000
154 160 ＞20,000
155 240 ＞20,000
156 330 ＞20,000
157 620 ＞20,000
158 1,600 ＞20,000
159 820 ＞20,000
160 180 ＞20,000
161 510 ＞20,000
162 610 ＞20,000
163 330 ＞20,000
164 640 ＞20,000
165 1,400 ＞20,000
166 1,700 ＞20,000
167 880 ＞20,000
168 370 ＞20,000
169 1,700 ＞20,000
170 3,000 ＞20,000
171 20,000 ＞20,000
172 14,000 ＞20,000
173 880 ＞20,000
174 1,400 ＞20,000
175 600 ＞20,000
176 145 ＞20,000
177 290 ＞20,000
178 1,400 ＞20,000
179 300 ＞20,000
180 14,000 ＞20,000
181 3,500 ＞20,000
182 20,000 ＞20,000
183 10,000 ＞20,000
184 3,300 ＞20,000
185 850 100,000
186 1,020 100,000
187 737 20,000
188 847 20,000
189 3,710 20,000
190 6,040 20,000
191 6,350 20,000
192 4,300 100,000
193 4,840 20,000
194 490 35,000
195 4,500 61,000
196 387 20,000
197 497 20,000
198 650 32,000
199 333 20,000
200 7,060 14,200
201 1,130 20,000
202 4,000 4,000
203 5,550 20,000
204 3,450 20,000
205 6,330 20,000
206 8,820 20,000
207 1,930 20,000
208 4,220 20,000
209 6,270 8,540
210 8,130 20,000
211 8,300 20,000
212 4,090 20,000
213 4,200 100,000
214 3,220 20,000
215 1,810 20,000
216 2,490 20,000
217 3,210 20,000
218 4,430 20,000
Reference: 1) Salzwedel, K., D.E.Matin, andM.Sakalian, " Maturationinhibitors:anewtherapeuticclasstargetsthevirus structure ", 2007, AIDSRev.9,162-172, 2) Smith, P.E., A.Ogundele, A.Forrest, J.Wilton, K.Salzwedel, J.Doto, G.P.Allaway, andD.E.Martin, " PhaseIandIIstudyofthesafety, virologiceffect, andpharmacokinetics/pharmacodynamicsofsingle-dose3-O-(3, 3 '-dimethylsuccinyl) betulinicacid (bevirimat) againsthumanimmunodeficiencyvirusinfection ", Antimacrob.AgentsChemother.2007, 51, 3574-3581, 3) Baichwal, V., H.Austin, B.Brown, R.McKinnon, K.Yager, V.Kumar, D.Gerrish, M.Anderson, andR.Carlson, " Anti-viralcharacterizationinvitroofanovelmaturationinhib itor, MPC-9055, " 2009, Poster561,16 thconf.Retrovir.Opport.Infect., Montreal, Canada, 4) Beelen, A., J.Otto, M.Fidler, E.Sanguinetti, P.Smiley, A.Balch, M.Medlock, M.Jackson, andE.Swabb, " Phase-1singleascendingoraldosestudyofthesafety, tolerability, andpharmacokineticsofanovelHIV-1maturationinhibitorinHIV negative, healthyvolunteers ", 2009, Poster570,16 thconf.Retrovir.Opport.Infect., Montreal, Canada, 5) Li, F., R.Goila-Gaur, K.Salzwedel, N.R.Kilgore, M.Reddick, C.Matallana, A.Castillo, D.Zoumplis, D.E.Martin, J.M.Orenstein, G.P.Allaway, E.O.Freed, andC.T.Wild, " PA-457:apotentHIVinhibitorthatdisruptscorecondensationby targetingalatestepinGagprocessing ", 2003, Proc.Natl.Acad.Sci., USA100,13555-13560, 6) Martin, D., J.Jacobson, D.Schurmann, E.Osswald, J.Doto, C.Wild, andG.P.Allaway, " PA-457:thefirst-in-classmaturationinhibitor, exhibitsantiviralactivityollowingasingleoraldoseinHIV-1i nfectedpatients ", 2005, Oralpresentation159,12 thconf.Retrovir.Opport.Infect., Boston, MA, USA, 7) Ganser-Pornillos, B.K., Cheng, A., Yeager, M., Cell2007,131,70, 8) Sundquist, W.I., Hill, P.C., Cell2007,131,17, 9) Ternois, F., Sticht, J., Duquerroy, S., Krausslich, H.G., Rey, F.A., Nat.Struct.Mol.Biol.2005,12,678, 10) Tang, C., Loeliger, E., Kinde, I., Kyere, S., Mayo, K., Barklis, E., Sun, Y., Huang, M., Summers, M.F.J.Mol, Biol., 2003,327,1013, 11) Li, J., Tan, Z., Tang, S., Hewlett, I., Pang, R., He, M., He, S., Tian, B.Chen, K., Yang, M.Bioorg.Med.Chem.2009,17,3177-3188, 12) Prevelige, P.Jr., " SmallmoleculeinhibitorsofHIV-1capsidassembly ", PCTInt.Appl.2007, WO2007048042A2, 13) Yang, M., He, S., Yuan, D., " Preparationofphenylthioureaderivativesascapsidproteininh ibitorsfortreatmentofHIV ", FamingZhuanliShenqingGongkaiShuomingshu, 2006, CN1793120A, 14) Summers, M.F., Agarwal, A., Chen, X., Deshpande, M.F. " PreparationofthiazolederevativesasinhibitorsofHIV-1capsi dformation ", U.S.Pat.Appl.Publ.2006, US2006100232A1, 15) Salzwedel, K., Li, F., Wild, C.T., Allaway, G.P., Freed, E.O., " InhibitionofHIV-1replicationbydisruptionoftheprocessingo ftheviralcapsid-spacerpeptide1protein ", PCTInt.Appl.2005, WO2005113059A2, 16) Summers, M.F., Tang, C., Huang, M., " Antiviralinhibitionsofcapsidproteins ", PCTInt.Appl.2003, Wo2003089615A2,

Claims (2)

1. a compound, this compound is selected from the compound of following structural formula:
2. a pharmaceutical composition, containing at least one compound as claimed in claim 1 and pharmaceutically acceptable carrier or thinner.
CN201010541329.0A 2010-11-12 2010-11-12 Antiviral compound Active CN102464654B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201010541329.0A CN102464654B (en) 2010-11-12 2010-11-12 Antiviral compound
PCT/US2011/060370 WO2012065062A1 (en) 2010-11-12 2011-11-11 Novel antiviral compounds

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201010541329.0A CN102464654B (en) 2010-11-12 2010-11-12 Antiviral compound

Publications (2)

Publication Number Publication Date
CN102464654A CN102464654A (en) 2012-05-23
CN102464654B true CN102464654B (en) 2016-01-13

Family

ID=46051317

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201010541329.0A Active CN102464654B (en) 2010-11-12 2010-11-12 Antiviral compound

Country Status (2)

Country Link
CN (1) CN102464654B (en)
WO (1) WO2012065062A1 (en)

Families Citing this family (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6205354B2 (en) 2011-07-06 2017-09-27 ギリアード サイエンシーズ， インコーポレイテッド Compounds for the treatment of HIV
GB201213087D0 (en) * 2012-07-24 2012-09-05 Medical Res Council Inhibition of HIV-1 infection
TWI706945B (en) 2013-03-01 2020-10-11 美商基利科學股份有限公司 Therapeutic compounds for treating a retroviridae viral infection
CN103788020B (en) * 2014-01-22 2015-11-04 苏州明锐医药科技有限公司 The fertile preparation method for Xi Ting
US10202353B2 (en) 2014-02-28 2019-02-12 Gilead Sciences, Inc. Therapeutic compounds
WO2015130966A1 (en) * 2014-02-28 2015-09-03 Gilead Sciences, Inc. Antiviral agents
TWI747873B (en) * 2016-02-01 2021-12-01 美商百歐克斯製藥公司 Benzopyrazole compounds and analogues thereof
KR102180740B1 (en) 2016-08-19 2020-11-20 길리애드 사이언시즈, 인코포레이티드 Therapeutic compounds useful for prophylactic or curative treatment of HIV viral infection
UY37710A (en) 2017-05-02 2018-11-30 Viiv Healthcare Uk No 5 Ltd INHIBITORS OF THE HUMAN IMMUNODEFICIENCY VIRUS REPLICATION
AR112412A1 (en) 2017-08-17 2019-10-23 Gilead Sciences Inc CHOLINE SALT FORMS OF AN HIV CAPSID INHIBITOR
AR112413A1 (en) 2017-08-17 2019-10-23 Gilead Sciences Inc SOLID FORMS OF AN HIV CAPSID INHIBITOR
CA3089590C (en) 2018-02-15 2022-12-06 Gilead Sciences, Inc. Pyridine derivatives and their use for treating hiv infection
AR114631A1 (en) 2018-02-16 2020-09-30 Gilead Sciences Inc METHODS AND INTERMEDIATES FOR PREPARING PYRIDINE COMPOUNDS
WO2019198024A1 (en) 2018-04-11 2019-10-17 VIIV Healthcare UK (No.5) Limited 4-oxo-3,4-dihydroquinazoline compounds as inhibitors of human immunodeficiency virus replication
WO2019246545A1 (en) * 2018-06-21 2019-12-26 Drexel University Small-molecule hiv-1 capsid protein inhibitors and methods using same
KR20210033492A (en) 2018-07-16 2021-03-26 길리애드 사이언시즈, 인코포레이티드 Capsid inhibitors for the treatment of HIV
JP7386230B2 (en) 2018-08-09 2023-11-24 ヴィーブ ヘルスケア ユーケー（ナンバー５）リミテッド Inhibitor of human immunodeficiency virus replication
WO2020053811A1 (en) 2018-09-14 2020-03-19 VIIV Healthcare UK (No.5) Limited Inhibitors of human immunodeficiency virus replication
EP3853228A1 (en) 2018-09-20 2021-07-28 VIIV Healthcare UK (No.5) Limited Inhibitors of human immunodeficiency virus replication
WO2020084491A1 (en) 2018-10-24 2020-04-30 VIIV Healthcare UK (No.5) Limited Inhibitors of human immunodeficiency virus replication
AR116798A1 (en) 2018-10-24 2021-06-16 VIIV HEALTHCARE UK Nº 5 LTD HUMAN IMMUNODEFICIENCY VIRUS REPLICATION INHIBITORS
JP2022505597A (en) 2018-10-25 2022-01-14 ヴィーブ ヘルスケア ユーケー（ナンバー５）リミテッド Inhibitor of human immunodeficiency virus replication
EP3873607B1 (en) 2018-10-29 2023-11-29 VIIV Healthcare UK (No.5) Limited Quinazolinyl-indazole derivatives and their use as inhibitors of human immunodeficiency virus replication
JP2022509919A (en) 2018-11-05 2022-01-25 ヴィーブ ヘルスケア ユーケー（ナンバー５）リミテッド Inhibitor of human immunodeficiency virus replication
JP2022506399A (en) 2018-11-05 2022-01-17 ヴィーブ ヘルスケア ユーケー（ナンバー５）リミテッド Inhibitor of human immunodeficiency virus replication
CN110128422B (en) * 2019-01-04 2022-03-18 金凯(辽宁)生命科技股份有限公司 Synthesis method of 5-methoxy-7-azaindole
UY38559A (en) 2019-02-01 2020-07-31 Viiv Healthcare Uk No 5 Ltd HUMAN IMMUNODEFICIENCY VIRUS REPLICATION INHIBITORS
WO2020222108A1 (en) 2019-04-30 2020-11-05 VIIV Healthcare UK (No.5) Limited Inhibitors of human immunodeficiency virus replication
SI3986561T1 (en) 2019-06-19 2024-04-30 VIIV Healthcare UK (No.5) Limited Pyrido(2,3-d)pyrimidine derivatives as inhibitors of human immunodeficiency virus replication
WO2021064571A1 (en) 2019-10-01 2021-04-08 VIIV Healthcare UK (No.5) Limited N-substituted-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl derivatives as inhibitors of the human immunodeficiency virus replication
JP2022551256A (en) 2019-10-01 2022-12-08 ビーブ、ヘルスケア、ユーケー、（ナンバー５）、リミテッド Replication inhibitor of human immunodeficiency virus
TW202128648A (en) 2019-10-04 2021-08-01 英商Ｖｉｉｖ醫療保健英國(Ｎｏ 5)有限公司 Inhibitors of human immunodeficiency virus replication
JP2022551691A (en) 2019-10-08 2022-12-13 ビーブ、ヘルスケア、ユーケー、（ナンバー５）、リミテッド Replication inhibitor of human immunodeficiency virus
JP2023502530A (en) 2019-11-26 2023-01-24 ギリアード サイエンシーズ， インコーポレイテッド Capsid inhibitors for HIV prevention
JPWO2021107066A1 (en) 2019-11-28 2021-06-03
WO2021176367A1 (en) 2020-03-06 2021-09-10 VIIV Healthcare UK (No.5) Limited Inhibitors of human immunodeficiency virus replication
BR112022017832A2 (en) 2020-03-06 2022-11-01 Viiv Healthcare Uk No 5 Ltd HUMAN IMMUNODEFICIENCY VIRUS REPLICATION INHIBITORS
MX2022012881A (en) 2020-04-15 2022-11-08 Viiv Healthcare Uk No 5 Ltd Inhibitors of human immunodeficiency virus replication.
WO2021262990A1 (en) 2020-06-25 2021-12-30 Gilead Sciences, Inc. Capsid inhibitors for the treatment of hiv
KR102513463B1 (en) 2020-11-26 2023-03-29 주식회사 에스앤케이테라퓨틱스 New Small Molecule Compounds that Control Endosomal Toll-like receptors and Autoimmune Disease Treatment Using the same
CN113912544B (en) * 2021-11-29 2023-03-17 沧州普瑞东方科技有限公司 Preparation method of 5-bromo-1-methylindazole
US11787825B2 (en) 2021-12-03 2023-10-17 Gilead Sciences, Inc. Therapeutic compounds for HIV virus infection

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0030303D0 (en) * 2000-12-13 2001-01-24 Lilly Co Eli Compounds
WO2010065799A2 (en) * 2008-12-04 2010-06-10 Palatin Technologies, Inc. Amine substituted piperidine melanocortin receptor-specific compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Infection by Virus Capsid Destabilization;Jiong Shi等;《JOURNAL OF VIROLOGY》;20101020;第85卷;542-549 *

Also Published As

Publication number Publication date
CN102464654A (en) 2012-05-23
WO2012065062A1 (en) 2012-05-18

Similar Documents

Publication Publication Date Title
CN102464654B (en) Antiviral compound
CN102863512B (en) Antiviral compound
CA3124898C (en) Heterocyclic compound, intermediate, preparation method therefor and application thereof
CN101891680B (en) Modulators of ATP-binding cassette transporters
CN101535276B (en) Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-MET inhibitors
CN101861307B (en) Certain substituted amides, method of making, and method of use thereof
CN105121432A (en) Heterocyclic amides as kinase inhibitors
AU2006259474B2 (en) Androgen receptor modulator compounds and methods
WO2007005887A2 (en) Androgen receptor modulator compounds, compositions and uses thereof
CN109890797A (en) It can be used as the substituted carbon nucleoside derivates of anticancer agent
CN105209468A (en) Substituted 7-azabicycles and their use as orexin receptor modulators
CN105228997A (en) CARM1 inhibitor and uses thereof
CN109661396A (en) Spiro-condensed ring-type urea as ROCK inhibitor
CN104507916A (en) 4 - substituted 1, 3 - dihydro - 2h - benzimidazol - 2 - one derivatives substituted with benzimidazoles as respiratory syncytial virus antiviral agents
CN108779114A (en) naphthyridine compounds as integrin antagonists
CN106536491B (en) Benzoxazine keto-amide as mineralcorticoid receptor regulator
KR20080038369A (en) Caspase inhibitor prodrugs
JP6811233B2 (en) Cyclic compounds useful as modifiers of TNF alpha
CN108137542A (en) Pyridone diformamide as bromine structural domain inhibitor
RU2233278C9 (en) Pyrimidinone compounds, method for their preparing and pharmaceutical composition
CN102070618B (en) Compound and crystals thereof
CN102197031A (en) Substituted 5-aminopyrazoles and use thereof
KR102556482B1 (en) Tetrahydroisoquinoline-based compound, method for preparing the same, drug composition containing the tetrahydroisoquinoline-based compound and use thereof
WO2024040768A1 (en) 5-pyridine-1h-indazole compound, pharmaceutical composition, and use
CN114667289A (en) Heteroaryl plasma kallikrein inhibitors

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C56 Change in the name or address of the patentee
CP03 Change of name, title or address

Address after: 201201 Shanghai City, Pudong New Area Ruiqinglu No. 528 Building 9, No. 2

Patentee after: PHARMARESOURCES (SHANGHAI) CO.,LTD.

Address before: 201201 Shanghai City, Pudong New Area Ruiqinglu No. 528 Building 1 B two floor

Patentee before: PHARMA RESOURCES (SHANGHAI) Co.,Ltd.

TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20240108

Address after: 200120, Zone C, 1st Floor, Building 1, No. 178 Renqing Road, Pudong New Area, Shanghai

Patentee after: Shanghai Hongbo Shangyi Pharmaceutical Technology Co.,Ltd.

Address before: 201201 2nd Floor, Building A, No. 528 Ruiqing Road, Pudong New Area, Shanghai

Patentee before: PHARMARESOURCES (SHANGHAI) CO.,LTD.