CN105693634B - Compound and application thereof - Google Patents

Compound and application thereof Download PDF

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CN105693634B
CN105693634B CN201610154581.3A CN201610154581A CN105693634B CN 105693634 B CN105693634 B CN 105693634B CN 201610154581 A CN201610154581 A CN 201610154581A CN 105693634 B CN105693634 B CN 105693634B
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nmr
dmso
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benzo
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CN105693634A (en
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刘刚
解希雷
于文俊
郭伟
张艳梅
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Tsinghua University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • 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
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms

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  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses compounds and application thereof, wherein and the compound is compound or the stereoisomer, pharmaceutically acceptable salt, solvate or prodrug of formula (I) compound represented shown in formula (I),

Description

Compound and application thereof
Technical field
The present invention relates to a kind of Isosorbide-5-Nitrae-benzodiazepine -2,5- cyclohexadione compounds and preparation method thereof and they Purposes in terms for the treatment of proliferative diseases especially cancer.
Background technique
In recent years, more and more researches show that, in same tumor tissues, tumour cell is in one-tenth knurl ability, differentiation journey It spends and there is heterogeneity on transfer ability, wherein only ability of the seldom a part of cell of quantity with initial tumor, this kind of Cell is referred to as tumor stem cell (Cancer stem cells, CSCs) or tumorigenesis cancer cell (Tumorigenic cancer cells)。
At present malignant tumour be difficult to the main reason for curing be transfer and recurrence.Recently there is scholar's proposition, CSCs may be The basic reason of metastases, and propose that CSCs is the viewpoint of metastases " seed " cell.CSCs has powerful proliferation Potential, they Yi Dan reach remote part clonal expansion can occur rapidly, even if rather than CSCs moves to remote part, also very Rare cell will form colony or clone.In addition to transfer ability, the root of CSCs or tumor recurrence, since CSCs can be with In opposing stationary dormant state, and it is often expressed as Teat pipette, therefore it is made to be not easy to be killed by chemicotherapy treatment.Simultaneously The extracellular matrix of hypoxemia tabernacle environment and surrounding that CSCs is in plays a protective role to it, its own efficient DNA repair machine System also results in tumor stem cell and generates tolerance to chemicotherapy to the selective activation of DNA damage reaction.
CSCs is mostly in dormant state, has lower division and proliferative capacity, and current chemicotherapy is mainly For the cell of high proliferation division stage, therefore it is unable to efficient targeting CSCs, eventually leads to tumor recurrence, transfer and treatment failure. Therefore, researching and developing has highly important meaning for the transfer and recurrence of anti-curing oncoma with the new drug for killing CSCs effect Justice.
Summary of the invention
The present invention is directed at least solve the problems, such as one of anti-tumor drug research and development existing in the prior art, such as to CSCs High inhibitory activity.For this purpose, an object of the present invention is to provide a kind of high activities with high antitumor and anti-CSCs Dominance structure 1,4- benzodiazepine -2,5- diketone (hereinafter referred to as BZD) class compound.
It is completed the present invention is based on the following work of inventor:
BZD analog derivative reported at present has lower anti-tumor activity more, still without report effect nucleotide The mechanism of action of protoenzyme subunit M2 (RRM2) and the activity of anti-CSCs, report is also different with the difference of substituent group, such as HDM2-p53 interaction antagonist (breast cancer tumor cells MCF-7:IC50=7.0 μM, Bioorg.Med.Chem.Lett.2006,16,3310-3314), DNA bonding agent (kidney tumor cell A498:GI50=0.51 μM, Bioorg.Med.Chem.2007,15,3041-3053.), Histone deacetylase inhibitor (human large cell lung cancer cell H661:IC50=6.0 μM, Bioorg.Med.Chem.Lett.2007,17,4819-4823), Wnt access antagonist (WO 2011/042145 A1), adjust reproduction cell nuclear factor (Modulate Germ Cell Nuclear Factor, WO 2007/ 095495 A2) inhibitor etc., show the characteristics of BZD skeleton is as " dominance structure ", i.e. the variation of substituent group can cause to act on The difference of target spot, thus, the purpose of the treatment clinical indication represented is also possible to difference.
The present invention Design and optimization and screening active ingredients through a large number of experiments, obtain a series of C7-, and the 1 of C8- substitutions, 4- benzodiazepine -2,5- derovatives, and these compounds are experimentally confirmed by effect RRM2, and have bright Aobvious antitumor and anti-CSCs activity.
Compound, its stereoisomer, pharmaceutically acceptable salt or the solvent that first aspect present invention is related to logical formula (I) close Object.
Compound, its stereoisomer, pharmaceutically acceptable salt or the solvent that second aspect of the present invention is related to logical formula (I) close The preparation method of object.
Third aspect present invention is related to the compound containing logical formula (I), its stereoisomer, pharmaceutically acceptable salt or molten The pharmaceutical composition of agent conjunction object.
Compound, its stereoisomer, pharmaceutically acceptable salt or the solvent that fourth aspect present invention is related to logical formula (I) close Object is used to prepare prevention or treats the application of the drug of cell Proliferation and cytothesis disease, especially cancer.
Specifically, it to be chemical combination shown in formula (I) that the present invention provides a kind of compounds in the first aspect of the present invention Stereoisomer, pharmaceutically acceptable salt, solvate or the prodrug of object or formula (I) compound represented,
Wherein:
X is optionally from-O-,-S-or-SO2–；
Y is optionally from-CO-,-SO2–、–CH2,-CONH-or-COO-, and respectively be connectedComposition
Z is optionally from O or S；
M represents 0,1,2 or 3；
N represents 0,1 or 2；
R1The C optionally replaced from hydrogen, optionally1–6Alkyl, the C optionally replaced2–6Alkenyl, the C optionally replaced3–6Naphthenic base is appointed The heterocycle choosing the phenyl in generation and optionally replacing, the substituted substituent group is selected from C1–6Alkyl, halogen or hydroxyl or cyanogen The C that base replaces1–6Alkyl, C3–6Naphthenic base, C1–6The C that alkoxy, halogen or hydroxyl or cyano replace1–6Alkoxy, nitro, ammonia Base, C1–6At least one of alkyl-substituted amino, halogen, cyano, hydroxyl and phenyl, and two adjacent substituent groups Five yuan or six-membered cyclic structure can be formed with atom is connect；
R2Optionally from-COOH ,-CONHNHCOR12、–COOR13、–CONR14R15、–COCH2P=O (OR17OR18) ,-COCH= CHR19, cyano or five yuan or hexa-atomic unsaturated heterocycle base, wherein R12、R13、R14、R15、R17、R18With R19It selects each independently From hydrogen, optionally the C replaced1–6Alkyl, the C optionally replaced2–6Alkenyl or the C optionally replaced2–7Alkynyl, the substituted substituent group For selected from least one of amino, hydroxyl, carbonyl, cyano, sulfonyl, halogen and phenyl, R14And R15Can together with hetero atom shape At quaternary, five yuan or hexa-atomic aliphatic heterocycle；
R3、R4、R5、R6And R7It is each independently selected from hydrogen, halogen, C1–6Alkyl-substituted amino, cyano, optionally takes hydroxyl The C in generation1–6Alkyl, the C optionally replaced1–6Alkoxy, the substituted substituent group be selected from halogen, cyano and phenyl at least One of, and R3、R4、R5、R6And R7Two groups of middle arbitrary neighborhood can be formed together five yuan with adjacent atoms and other hetero atoms Or six-membered cyclic structure；
R8、R9And R10It is each independently selected from hydrogen, C1–6Alkyl, C2–6Alkenyl, C2–6Alkynyl, C3–6Naphthenic base, benzyl；
R11Optionally from hydrogen atom, halogen.
It is surprisingly found by the inventors that the compound of the present invention shows extremely strong inhibition proliferative activity o f tumor, it can Inhibit tumor cell proliferation by effect RRM2, and inhibit the regeneration of tumor stem cell, so as to prevent effective for preparation Or the drug for the treatment of proliferative diseases, especially anti-tumor drug.
Some preferred embodiments according to the present invention, R1Optionally from hydrogen, methyl, cyclopropyl, Or it optionally takes The phenyl in generation, the substituted substituent group are selected from methyl, trifluoromethyl, hydroxymethyl, ethyl, isopropyl, methoxyl group, ammonia At least one of base, dimethylamino, halogen, cyano, hydroxyl and phenyl.
Some preferred embodiments according to the present invention, R2Optionally from-COOH ,-CONHNHCOR12、–COOR13、– CONR14R15、–COCH2P=O (OR17OR18) ,-COCH=CHR19, cyano, Wherein R16Optionally from hydrogen, C1–6Alkyl, methyl fluoride, difluoro first Base or trifluoromethyl.
Other embodiments according to the present invention, R12、R13It is each independently selected from methyl, ethyl, isopropyl, normal-butyl.
Some specific examples according to the present invention, R14、R15、R17、R18With R19Be each independently selected from hydrogen, methyl, ethyl, Propyl, normal-butyl,And R14And R15It can be with Hetero atom is formed together
Some preferred embodiments according to the present invention, R16Optionally from hydrogen, methyl, ethyl, trifluoromethyl.
Some preferred embodiments according to the present invention, R3、R4、R5、R6And R7It is each independently selected from hydrogen, halogen, methyl, first Oxygroup, difluoro-methoxy, hydroxyl, cyano, benzyloxy, and R3、R4、R5、R6And R7Two groups of middle arbitrary neighborhood can be interconnected mutually Connect composition
Some specific examples according to the present invention, R8、R9And R10Be each independently selected from hydrogen, methyl, ethyl, isopropyl, Benzyl,
Some preferred embodiments according to the present invention, the compound of structure shown in formula (I) or (IR) or (IS), its solid are different Structure body, pharmaceutically acceptable salt, solvate or prodrug final preferred embodiment are as follows:
Wherein, in formula (I) or (IR) or (IS):
X is selected from-O-,-S-and-SO2–；
Y is selected from-CO-,-SO2And-CH2–；
Z is optionally from O or S；
M=0,1,2 or 3；
N=0,1 or 2；
R1For hydrogen, methyl, cyclopropyl, phenyl,
R2For-COOH；Or-COOR13, wherein R13For methyl, ethyl, isopropyl or normal-butyl；Or cyano ,- CONH2、–CON(C2H5)2、–CONHCH3、–CON(CH3)2、–CON(CH2CH2CH3)2、–CON(CH2CH2CH2CH3)2、
R3、R4、R5、R6And R7It is each independently hydrogen, halogen, methyl, methoxyl group, difluoro-methoxy, hydroxyl, cyano or benzyl Oxygroup；Or R4With R5It connects and composes
R8And R9Be each independently hydrogen, methyl, ethyl, isopropyl, benzyl,
R10For hydrogen or methyl；
R11For hydrogen, F, Cl or Br.
Wherein, Y is selected from-CO-,-SO2–、–CH2,-CONH-or when-COO-, respectively be connectedComposition
Z is optionally from O or S；
It should be noted that " * " in structural formula represents link position herein.
According to an embodiment of the invention, most preferably, the compound is at least one of following compounds or described The stereoisomer of at least one of following compounds, pharmaceutically acceptable salt, solvate or prodrug:
" halogen " or " halo " of the present invention refers to the fluorine, chlorine, bromine or iodine as substituent group.It is taken when halogen atom is used as When for base, the number replaced is more than one, including one, two or three etc..
" C of the present invention1–6Alkyl " refers to be removed derived from a hydrogen atom on the alkane containing 1-6 carbon atom The alkyl of linear chain or branched chain.
" C of the present invention2–6Alkenyl " refers to the linear chain or branched chain or ring that the carbon atom number containing carbon-carbon double bond is 2-6 The alkenyl of shape.
" C of the present invention2–6Alkynyl " refers to that the carbon atom number containing carbon-carbon triple bond is the alkynes of 2-6 linear chain or branched chain Base, " C2–7Alkynyl " refers to that the carbon atom number containing carbon-carbon triple bond is the alkynyl of 2-7 linear chain or branched chain.
" C of the present invention3–6Naphthenic base " refers to all carbon atoms of ring atom, removes one hydrogen of company of carbon atom institute Cyclic alkyl radical derived from atom.
" C of the present invention1–6Alkoxy " refers to " C1–6Alkyl " is connected derivative base by-O-with other parts Group, C1–6Alkyl is as defined hereinabove.
" heterocycle " of the present invention refers to stable 4- to 7- unit monocycle, these heterocycles can be saturation or unsaturated , and formed by carbon atom and optionally from 1 to 4 hetero atom of N, O and S, nitrogen and sulfur heteroatom therein can be by selectively Oxidation, and nitrogen heteroatom can by selectively quaternized, preferably 5 yuan and 6 circle heterocyclic rings, such as furans, imidazoles, thiazole, thiadiazoles, Pyridine, piperidines, pyrazine, piperazine, morpholine, thiomorpholine etc..
" stereoisomer " of claimed formula (I) compound refers to asymmetric when existing in compound structure Whens carbon atom, carbon-carbon double bond etc., generate all enantiomters, diastereoisomer, raceme, cis-trans-isomer, mutually Tautomeric, geometric isomer, epimer and its mixture, are included in the present invention.
General formula compound can by it is other it is protected in the form of or derivative in the form of exist, these forms are to this field skill It is for art personnel it will be apparent that being intended to be limited solely by the scope of the present invention.
In the second aspect of the present invention, the present invention also provides the preparation methods of logical formula (I) compound.
Specifically, the compound of the present invention can be prepared by process 1-4.Wherein, process 1 is summarised containing 1, The universal synthesis method of the compound with structure shown in formula (I) of 4- benzodiazepine-2,5- diketone skeleton, process 2-4 Describe the method modified the substituent group on 1,4- benzodiazepine -2,5- diketone skeleton.
1, process 1:
In above formula, the definition of each symbol is the same as logical formula (I).
Above-mentioned process 1 summarise containing 1,4- benzodiazepine -2,5- diketone skeleton with structure shown in formula (I) The universal synthesis method of compound:
First step reaction (reaction a): the chloro- 2,4- dinitrobenzoic acid of 5- or the bromo- 2,4- dinitrobenzene first of the chloro- 6- of 5- are used Acid is starting material, carries out aromatic nucleophilic substitution reaction with the reagent with nucleophilie nucleus ability.Reactant is with the equivalent of molar ratio 1:1 It is reacted, while the alkali of at least twice equivalent is added.Alkali is selected according to specific nucleopilic reagent, predominantly bicarbonate Sodium, potassium hydroxide and sodium hydrogen, solvent are water, methanol or tetrahydrofuran, and reaction temperature is room temperature to solvent reflux temperature, when reaction Between according to specific response situation depending on.Such as when using phenol or substituted phenol for nucleopilic reagent, the preferred sodium bicarbonate of alkali, The preferred water of solvent, preferably 100 DEG C of reaction temperature, reaction time preferred 2h.
Second step reaction (reaction b): corresponding acyl chlorides is made with oxalyl chloride or thionyl chloride reaction first in intermediate 1-2. When using oxalyl chloride for chlorinating agent, react preferred methylene chloride be solvent, preferably 40 DEG C of reaction temperature；When using thionyl chloride When for chlorinating agent, reaction is suitable for carrying out under conditions of using thionyl chloride as solvent, the preferred reflux temperature of reaction temperature.It is obtained Acyl chlorides reacted again with amino-acid ester generate amide intermediate 1-3.Reaction be adapted so that with it is various not with the inertia of acyl chloride reaction Solvent such as methylene chloride, toluene, tetrahydrofuran, acetone etc. is at -10 DEG C to room temperature reaction, preferably 0 DEG C.In addition, amide intermediate 1-3 can also be prepared by intermediate 1-2 and amino-acid ester using method of condensing common in Peptide systhesis, and condensing agent N, N- are such as used The methods of diisopropylcarbodiimide (DIC).
Third step reaction (reaction c): for the committed step for constructing 1,4- benzodiazepine -2,5- diketone skeleton.This step Reaction first restores double nitros of intermediate 1-3, cyclization reaction occurs then to construct Isosorbide-5-Nitrae-benzodiazepine -2,5- bis- Ketone skeleton.Reaction system is the Plus acidic environment of reducing agent, and reducing agent is mainly active metal (iron, zinc, tin etc.) or transition metal (platinum, palladium, rhodium etc.), acidic environment can be provided by formic acid, acetic acid, p-methyl benzenesulfonic acid etc..It is reducing agent that this, which reacts preferred iron powder, It is reacted in glacial acetic acid, preferably 90 DEG C of reaction temperature, reaction time preferred 5h.
Four-step reaction (reaction d): reductive alkylation is carried out to 8- bit amino on skeleton.Using aldehydes such as formaldehyde, acetaldehyde Compound, using sodium cyanoborohydride or sodium triacetoxy borohydride as reducing agent, methylene chloride, tetrahydro furan is may be selected in solvent It mutters, methanol, ethyl alcohol, reaction temperature is room temperature to solvent reflux temperature.
5th step reaction (reaction e): 8- bit amino on skeleton is performed the derivatization.It mainly include reacting life with acyl chlorides or acid It at amide, is reacted with sulfonic acid chloride and generates sulfonamide, reductive alkylation reaction occurs with aldehyde, generate urea derivative and generate amino first Acid ester derivant.It is above the conventional chemical reaction of the field of chemical synthesis, details are not described herein, and method detailed can refer to implementation Example.
Six-step process (reaction f): N1- on skeleton are alkylated.It is examination with halides such as iodomethane, bromobenzyls Alkali is made in agent, preferably potassium carbonate, and n,N-Dimethylformamide is solvent, and reaction temperature is room temperature to 60 DEG C.
2, process 2:
In above formula, the definition of each symbol is the same as logical formula (I).
When the compound shown in formula (I) has 2-1 structure, i.e. X is-O-, m=1, R1When for phenyl, benzyl can be removed Intermediate 2-2 is obtained, Mitsunobu then occurs with multifarious alcohol and reacts, diversity is carried out to 7- bit substituent to reach The purpose of modification.Choosing multiple method removes benzyl, preferably uses Pd/C and hydrogen herein, is molten with tetrahydrofuran and methanol Agent removes under normal temperature and pressure conditions.Mitsunobu reaction herein, triphenylphosphine and diethyl azodiformate It (DEAD) is Mitsunobu reagent, the preferred tetrahydrofuran of reaction dissolvent, the preferred room temperature of reaction temperature.
3, process 3:
In above formula, the definition of each symbol is the same as logical formula (I).
As R in formula (I)2When for methyl esters group, the compound has 3-1 structure, can remove methyl esters to obtain sour derivative Object 3-2 is then condensed with multifarious alcohol or amine, and ester 3-3 or amide 3-4 is obtained.Preferred lithium hydroxide when hydrolyzing herein Make alkali, solvent, room temperature condition reaction, reaction time preferred 0.5h are mixed into tetrahydrofuran and water 1:1.Acid derivative 3-2 with The condensation reaction of alcohol or amine can be used a variety of methods and complete, and preferably with N, N- diisopropylcarbodiimide (DIC) is condensing agent, with N-hydroxysuccinimide (HOSu) reacts 12h using tetrahydrofuran as solvent for active ester at room temperature.
4, process 4:
In above formula, the definition of each symbol is the same as logical formula (I).
In addition:
(a) N, N- diisopropylcarbodiimide, n-hydroxysuccinimide, tetrahydrofuran, room temperature, corresponding azanol, 83% hydrazine hydrate or amine；(b) pyridine, reflux；(c) triethylamine, corresponding acid anhydrides, tetrahydrofuran, room temperature；(d) iodine, triphenylphosphine, Triethylamine, methylene chloride, room temperature；(e) carbonyl dimidazoles, triethylamine, tetrahydrofuran, 50 DEG C；(f) pyridine, trifluoroacetic anhydride, Tetrahydrofuran, room temperature；(g) hydroxylamine hydrochloride, triethylamine, ethyl alcohol, 90 DEG C；(h) pyridine, corresponding acid anhydrides, 90 DEG C；(i) N, N dimethyl Formamide, N,N-dimethylformamide dimethylacetal, room temperature；Glacial acetic acid, 40% methyl hydrazine, microwave, 50W；(j) Azide Sodium, ammonium chloride, triethylamine, glacial acetic acid, N, N-dimethylformamide, 90 DEG C；(k) pyridine, ethyl chloroformate, 90 DEG C；(l) trifluoro Methanesulfonic acid, methylene chloride, microwave, 200W.
When the compound shown in formula (I) has 4-1 structure, i.e. R2It, can be by multistep reaction by carboxylic acid when for carboxylic acid group Group transform a variety of five-membered unsaturated heterocycles as.Detailed reaction reagent and reaction condition are listed in process 4, are existing reality Technology is tested, details are not described herein, and detailed Examination on experimental operation can refer to embodiment.
The above reaction is because condition is milder, and the reaction time is shorter, stable yield, therefore is conducive to use and for example combine Chemical method carries out the synthesis of compound library, and this method using combinational chemistry synthesis compound library also belongs to the present invention Range.
Those skilled in the art can change above-mentioned steps to improve yield, they can be according to the basic knowledge of this field It determines the route of synthesis, such as selects reactant, solvent and temperature.Such change or variation are within the scope of the present invention.Also Can by using various GPF (General Protection False bases to avoid side reaction generation to improving yield.These conventional guard methods can See, for example, T.Greene, Protecting Groups in Organic Synthesis (The Fourth Edition, John Wiley&Sons, Inc.), by referring to be incorporated by herein.
In the third aspect of the present invention, the present invention provides a kind of pharmaceutical compositions.According to an embodiment of the invention, the medicine Compositions include mentioned-above compound.According to an embodiment of the invention, pharmaceutical composition of the invention can pass through effect It answers RRM2 to inhibit tumor cell proliferation, and inhibits the regeneration of tumor stem cell, it is living can also to significantly inhibit tumor cell proliferation Property, so as to prevent or treat the drug of proliferative diseases, especially anti-tumor drug effective for preparation.
According to some embodiments of the present invention, which further includes: being selected from pharmaceutically acceptable carrier With at least one of excipient.
According to an embodiment of the invention, the pharmaceutical composition is using the compound of the present invention as active ingredient.The medicine group Closing object can prepare according to method well known in the art.Can by by the compounds of this invention with it is one or more pharmaceutically acceptable Solid or liquid excipient and/or adjuvant combine, and any dosage form used suitable for human or animal is made.The compounds of this invention is at it Content in pharmaceutical composition is usually weight ratio 0.1% -99.9%.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be enteron aisle Or non-bowel, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, Vagina, rectum etc..
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution (including True solution and colloidal solution), emulsion (including o/w type, w/o type and emulsion), suspension, injection (including liquid drugs injection, powder-injection And infusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, lozenge, Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard capsule, soft capsule, capsulae enterosolubilis), granule, dissipate Agent, pellet, dripping pill, suppository, film, patch, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment, gel Agent, paste etc..
Ordinary preparation can be made in the compounds of this invention, may be made as sustained release preparation, controlled release preparation, targeting preparation and various Particulate delivery system.
In order to which tablet is made in the compounds of this invention, various excipient well known in the art can be widely used, including dilute Release agent, wetting agent, binder, disintegrating agent, lubricant, glidant.Diluent can be starch, dextrin, sucrose, glucose, cream Sugar, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, second Alcohol, isopropanol etc.；Binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, Arabic gum Slurry, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, card Wave nurse, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrating agent can be dried starch, microcrystalline cellulose, low substituted hydroxy-propyl fiber Element, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxy second Alkene sorbitan fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be talcum powder, silica, tristearin Hydrochlorate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double Synusia and multilayer tablet.
In order to which capsule is made in administration unit, effective component the compounds of this invention and diluent, glidant can be mixed It closes, mixture is placed directly in hard capsule or soft capsule.It can also effective component the compounds of this invention is first and diluent, bonding Particle or pellet is made in agent, disintegrating agent, then is placed in hard capsule or soft capsule.It is used to prepare each dilute of the compounds of this invention tablet Release agent, wetting agent, binder, disintegrating agent, glidant kind can also be used for preparing the capsule of the compounds of this invention.
In order to which injection is made in the compounds of this invention, water, ethyl alcohol, isopropanol, propylene glycol or their mixing can be used Object makees solvent and appropriate solubilizer commonly used in the art, cosolvent, pH adjustment agent, osmotic pressure regulator is added.Solubilizer helps Solvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjust agent can be phosphate, acetate, hydrochloric acid, Sodium hydroxide etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-drying Mannitol, glucose etc. can be also added as proppant in powder-injection.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation Agent.
In the fourth aspect of the present invention, the present invention also provides mentioned-above compounds or pharmaceutical composition to prepare Purposes in drug, the drug can be used for preventing or treating proliferative diseases.The drug prepared as a result, can effectively be shown It writes and inhibits proliferative activity o f tumor, and inhibit the regeneration of tumor stem cell, so as to effective for preventing or treating proliferation Property disease especially tumour.
Some specific examples according to the present invention, the proliferative diseases are cancer.
In other words, the present invention relates to use the compound and its pharmaceutical composition to prevent or treat cell Proliferation and cell Diseases of reproduction, specifically the present invention relates to use the compound and its pharmaceutical composition to prevent and treat the application of cancer.
In addition, including passing through effect Ribonucleoside- using the compound and its pharmaceutical composition Diphosphate reductase subunit M2 or ribonucleotide reductase small subunit (RRM2) disease prevented or treated, specifically the present invention relates to use the compound and its pharmaceutical composition to prevent and control Treat the application of cancer.
" disease " of the present invention, including but not limited to following disease:
Cancer, including bladder cancer, the cancer of the brain, breast cancer, colon and rectum carcinoma, kidney, liver cancer, lung cancer, oophoroma, cancer of pancreas, Adrenal, prostate cancer, gastric cancer, carcinoma of vagina, cervical carcinoma, carcinoma of endometrium, thyroid cancer and cutaneum carcinoma etc.；
Lymphohematological tumor, including acute lymphoblastic leukemia, B cell lymphoma and Burketts lymthoma etc.；
Marrow hemopoietic system tumor, including acute and chronic granulocytic leukemia and promyelocytic leukemia；
The tumor of mesenchymal derivation, including fibrosarcoma and rhabdomyosarcoma；
Other tumours, including melanoma, seminoma, teratoma, neuroblastoma, glioma etc..
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any The administration of prescription method.
The dosage of the compounds of this invention pharmaceutical composition is according to the property and serious journey to be prevented or be treated disease The individual instances of degree, patient or animal, administration route and dosage form etc. can have large-scale variation.In general, of the present inventionization Close object daily Suitable dosage ranges be 0.001-150mg/Kg weight, preferably 0.1-100mg/Kg weight, more preferably 1-60mg/Kg weight, most preferably 2-30mg/Kg weight.Above-mentioned dosage with a dosage unit or can be divided into several dosage lists Position administration, this depends on the clinical experience of doctor and includes the dosage regimen with other treatment means.
The compound of the present invention or composition can individually be taken, or merge use with other treatment drug or symptomatic drugs. When the compound of the present invention and other therapeutic agents, which exist, to act synergistically, its dosage should be adjusted according to the actual situation.
Term " stereoisomer " refers to identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.Stereoisomer includes that enantiomter, diastereoisomer, conformer (rotational isomer), geometry are different Structure body (cis/trans) isomers, atropisomer, etc..
Term " enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.
Term " diastereoisomer " refer to there are two or multiple chiral centers and its molecule not solid of mirror image each other Isomers.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral property and reactivity.Diastereo-isomerism Body mixture can be operated such as electrophoresis and chromatography, such as HPLC by high resolution analysis and be separated.
Term " chirality " be with its mirror image cannot be overlapped property molecule；And " achirality " refer to can be with its mirror image The molecule of overlapping.
Term " racemate " or " racemic mixture " be optically active two enantiomters of hypodactylia etc. rub That mixture.
Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc,New York,1994.Many organic compounds exist with optical active forms, i.e., they, which have, sends out the plane of polarised light The ability of raw rotation.When describing optically active compound, indicated using prefix D and L or R and S molecule about one or The absolute configuration of multiple chiral centers.Prefix d and l or (+) and (-) are rotated for linearly polarized light caused by appointed compound Symbol, wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.A kind of specific solid Isomers is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50:50 of enantiomter is mixed It closes object and is known as racemic mixture or racemic modification, when in chemical reaction or in the process without stereoselectivity or stereospecificity When, it may occur in which such case.
Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer It is excessive.
According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Chiral synthon or chiral reagent preparation can be used in optically active (R)-or (S)-isomers, or is torn open using routine techniques Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.
The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, can refer to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the recombination of some bonding electrons come The mutual inversion of phases carried out.The specific example of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyl are mutual The interconversion of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the interconversion of pure and mild pyridine -4 (1H) the -one tautomer of pyridine -4-.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.
Term " optional " or " optionally " refer to the event then described or situation can with but not necessarily occur, and this is retouched It states and includes the case where the case where wherein event or situation occur and wherein it does not occur.For example, " optional key " refers to The key may exist or can be not present, and the description includes singly-bound, double or triple bonds.
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.
One or more degrees of unsaturation are contained in term " unsaturation " or " unsaturated " expression part.
As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can be used interchangeably " optionally replacing " this term with " substituted or unsubstituted ".In general, art " substituted " the one or more hydrogen atoms indicated in given structure of language are replaced specific substituent group.Unless other aspect tables Bright, an optional substituent group can be replaced at various substitutable position of that group.When in given structural formula not Only a position can be replaced one or more substituent groups selected from specific group, then substituent group can identical or differently Replace at various locations.
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " ... it is each independently " it shall be understood in a broad sense, either referring among the different groups, expressed tool between the same symbol Do not influence mutually, can also be indicated in the same group between body option, between the same symbol expressed specific option it Between do not influence mutually.
It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-6Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
Unless explicitly recited, terminology used in the present invention " alkyl " or " alkyl group " indicate to contain 1 to 20 carbon original Son, the linear chain or branched chain univalent hydrocarbyl group of saturation, wherein the alkyl group can be optionally by one or more present invention Replaced the substituent group of description.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.One according to the present invention Embodiment, alkyl group contain 1-12 carbon atom；According to another embodiment of the invention, alkyl group contains 1-6 carbon Atom；According to one embodiment of present invention, alkyl group contains 1-4 carbon atom；According to another embodiment of the invention, Alkyl group contains 1-3 carbon atom.The example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,- CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,- CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tert-butyl (t- Bu、-C(CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl (- CH (CH3)CH2CH2CH3), 3- amyl (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl- 1- butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyl (- CH (CH3)CH2CH2CH2CH3), 3- hexyl (- CH (CH2CH3)(CH2CH2CH3)), 2- Methyl -2- amyl (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyl (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- penta Base (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- amyl (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3) C(CH3)3), n-heptyl, n-octyl, etc..
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.According to the present invention One embodiment, alkoxy base contains 1-6 carbon atom；According to one embodiment of present invention, alkoxy base contains 1-4 carbon atom；According to one embodiment of present invention, alkoxy base contains 1-3 carbon atom.The alkoxy base is appointed Replaced the substituent group that selection of land is described by one or more present invention.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), 1- amoxy (n- amoxy ,-OCH2CH2CH2CH2CH3), 2- amoxy (- OCH (CH3) CH2CH2CH3), 3- amoxy (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourth Oxygroup (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (- OCH2CH(CH3)CH2CH3), etc..
Term " ring " includes carbocyclic ring, heterocycle, aromatic ring, hetero-aromatic ring, etc., wherein the carbocyclic ring, heterocycle, aromatic ring, hetero-aromatic ring Group has meaning as described in the present invention.
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.About Being discussed in detail for pro-drug can refer to following documents: Higuchi et al., Pro-drugs as Novel Delivery Systems,Vol.14,A.C.S.Symposium Series；Roche et al.,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987； Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery,2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates, J.Med.Chem., 2008,51,2328-2345, every document are included herein by reference.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., Documented by J.Pharmaceutical Sciences, 66:1-19,1977.The salt that pharmaceutically acceptable nontoxic acid is formed It including, but is not limited to, inorganic acid salt formed by reacting with amino groups to form has a hydrochloride, hydrobromate, phosphate, sulfate, Perchlorate and acylate such as acetate, oxalates, maleate, tartrate, citrate, succinate, malonic acid Salt, or these salt are obtained by other methods described in the books or literature such as ion-exchange.Other are pharmaceutically acceptable Salt include adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, boric acid Salt, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonic acid Salt, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproic acid Salt, hydriodate, 2- hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malate, Malonate, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, mistake Sulfate, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, Undecylate, valerate, etc..Salt obtained by an appropriate base includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4 Salt.The compound that the present invention is also intended to contemplate the group of any included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or Dispersion product can be obtained by quaternization.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmacy Upper acceptable salt further comprises appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenation Object, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Sulphonic acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
When the solvent is water, term " hydrate " can be used.According to one embodiment of present invention, this hair Bright compound molecule can be combined with a hydrone, such as monohydrate；According to one embodiment of present invention, a sheet Invention compound molecule can be combined with more than one hydrone, such as dihydrate, an implementation according to the present invention Example, a compounds of this invention molecule can be combined with the hydrone less than one, such as semihydrate.It should be noted that this hair The bright hydrate remains with the biological effectiveness of the compound of nonhydrated form.
Any disease of term " treatment " or illness as used in the present invention, some embodiment middle fingers improve disease wherein Or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In further embodiments, it " controls Treat " refer to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.In other implementations Example in, " treatment " refer to from body (such as stablizing perceptible symptom) or physiologically (such as parameter of stable body) or on It states two aspects and adjusts disease or illness.In further embodiments, " treatment " refers to the breaking-out for preventing or delaying disease or illness, hair Raw or deterioration.
Term " prevention " refers to that the reduction for obtaining the risk of disease or obstacle (that is: makes at least one clinical symptoms of disease in main body Interior stopping development, the main body may be faced or are inclined in advance in face of this disease, but without the disease for undergoing or showing disease Shape).
A series of C7- of the invention, Isosorbide-5-Nitrae-benzodiazepine -2,5- derovatives of C8- substitutions are shown extremely strong Inhibition proliferative activity o f tumor, such compound can inhibit tumor cell proliferation by effect RRM2, and inhibit Tumor Stem The regeneration of cell, document have not been reported.
Isosorbide-5-Nitrae-benzodiazepine -2,5- dione compounds of C7- disclosed by the invention, C8- substitutions, relative to existing Technology has following features and advantage:
1. compound disclosed in this invention prevents tumor cell proliferation that it is made to stop at G2/M by effect RRM2 Phase；Meanwhile our first public such BZD compounds can with high activity inhibit the regeneration of tumor stem cell (CSCs), so that Such BZD be clearly distinguishable from terms of anti-tumor activity it has been reported that BZD analog, it is possible to provide a new class of antitumor Drug, to thoroughly remove tumour and tumor stem cell.
2. antitumor spectra is wide, activity is high.Growth inhibition effect, part are all had to 60 plants of human tumor cells of 9 kinds of cancers The average GI of compound50Value is less than 5nM, active highly significant.
3. the substituting group position for influencing BZD anti-tumor activity is different.Reported in literature influences the active group of BZD and all exists On the position N1-, C3-, N4-, and the C7- of BZD compound of the invention, C8- replace simultaneously, play main contributions to activity.
4. the further feature of BZD compound structure disclosed in this invention is, C3- substitutions need to be R- absolute configuration (can also be S- configuration), other configurations are without activity.
In conclusion BZD compound disclosed in this invention all has novelty in structurally and functionally mechanism, preventing Or in terms for the treatment of proliferative diseases especially cancer, with good application prospect.
Additional aspect and advantage of the invention will be set forth in part in the description, and will partially become from the following description Obviously, or practice through the invention is recognized.
Detailed description of the invention
Above-mentioned and/or additional aspect of the invention and advantage will become from the description of the embodiment in conjunction with the following figures Obviously and it is readily appreciated that, in which:
Fig. 1-Fig. 3 shows according to an embodiment of the present invention, Inhibition test of the compounds of this invention to tumor stem cell Result figure,
Wherein,
Fig. 1 is negative control (PTX), positive control (Salinomycin), sphere before untested compound (188) processing Form and quantity；Fig. 2 is negative control (PTX), positive control (Salinomycin), after untested compound (188) processing The form and quantity of sphere；Fig. 3 is through negative control (PTX), positive control (Salinomycin), untested compound (188) The form and quantity of treated sphere sphere after passage；
Fig. 4 and Fig. 5 shows compound according to an embodiment of the invention to human lung cancer H522 nude mouse xenograft The weight of nude mice influences the result of experiment, wherein abscissa indicates that number of days, ordinate indicate weight in Fig. 4；
Fig. 6 and Fig. 7 shows compound according to an embodiment of the invention to human lung cancer H522 nude mouse xenograft The inhibition assay result figure of the growth of tumor, wherein abscissa indicates that number of days, ordinate indicate gross tumor volume in Fig. 6；
Fig. 8-Figure 12 show embodiment 123 compound and embodiment 88 compound to the effect knot of ribonucleotide Fruit, wherein
Fig. 8 is that the compound of embodiment 88 and the compound of embodiment 123 are jointly processed by RNA survey after SUM59 tumour microballoon Sequence analysis as a result,
Fig. 9 is the expression that 123 compound of embodiment handles SUM159 microballoon RRM2,
Figure 10 shows RRM2T33A(mutant strain) can prevent SUM159 cell quilt under the processing of 123 compound of embodiment Fast degradation,
Figure 11 shows RRM2T33AMutation restores lethal effect and balling-up of 123 compound of embodiment to SUM159 cell The influence of ability,
Figure 12 shows RRM2T33AMutation restores 123 compound of embodiment to the lethal effect of SUM159 tumor stem cell.
Specific embodiment
The specific embodiment of form by the following examples makees further specifically above content of the invention It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.It is all to be based on above content of the present invention The technology realized all belongs to the scope of the present invention.
It tests agents useful for same unless otherwise instructed, is purchased from Beijing coupling Science and Technology Ltd., Beijing lark prestige science and technology has Limit company, Acros Organics, Alfa Aesar, Sigma-Aldrich and TCI, not purified direct use.Used in experiment Solvent is mainly purchased from Beijing Chemical Plant and Xilong Chemical Co., Ltd, except THF and DMF is through VAC company of the U.S. (Vacuum Atmospheres company) solvent purification system is further processed outer, remaining unprocessed direct use.GF254Thin layer Chromatographic silica gel plate, GF254Silica gel thickness prepares plate and column silica gel for chromatography powder (60-100 mesh, 160-200 mesh, 200-300 mesh) is equal Purchased from Haiyang Chemical Plant, Qingdao.
HPLC-MS analyzer: HPLC analyzer is Agilent 1100HPLC system, and Agilent G1312A is pumped, Agilent G1314A UV detector, Agilent G1313A autosampler, Agilent G1316A column oven and shunting Valve.Chromatographic column is Kromasil C18 analytical column (4.6 μm, 4.6mm × 50mm), is purchased from DIKMA company.Mobile phase be containing The acetonitrile and water of 0.05%HCOOH.Linear gradient elution 5:95 (v:v) acetonitrile-H2O to 95:5 (v:v) acetonitrile-H2O, time 5minutes, flow velocity 1mL/min.UV Detection wavelength 254nm.ThermoFinnigan LCQ- Advantage mass spectrograph, 5% in eluent is further separated into mass spectrograph, using cation or anion scanning mode, EFI Mist ion source (ESI).It is mainly used for the Preliminary Determination of reaction monitoring and compound purity.
UPLC-MS analyzer: the Acquity UPLC-MS system of Waters company, including binary solvent manager, sample Manager, chromatographic column manager, PDA detector and SQ mass detector.Chromatographic column is the Acquity of Waters companyBEH C18 column (1.7 μm, 2.1mm × 50mm).Mobile phase is acetonitrile and water containing 0.05%HCOOH.Linear ladder Degree elution 5:95 (v:v) acetonitrile-H2O to 95:5 (v:v) acetonitrile-H2O, time 3minutes, flow velocity 0.3mL/min.UV Detection wavelength 254nm.SQ mass spectrometer detector uses cation or anion scanning mode, electron spray ion Source (ESI).It is mainly used for the Preliminary Determination of reaction monitoring and compound purity.
HPLC analyzer: Agilent 1260HPLC system, Agilent G1311C quaternary pump, Agilent G4212B are purple External detector, Agilent G1367E high-performance autosampler, Agilent G1316A column oven.Chiral analysis column: AD-H, 250 × 4.6mm, 5 μM of DAICEL CHIRALPAK (Japanese Daicel company DAICEL production).Mobile phase is positive oneself Alkane/isopropanol, isocratic elution.UV Detection wavelength 254nm.It is mainly used for the optical purity analysis of target compound.
High-resolution mass spectrometer: Agilent LC/MSD TOF system.Chromatographic column: Agilent ZORBAX SB-C18 (Rapid resolution,3.5μm,2.1×30mm).Mobile phase: MeOH:H2O=75:25 (v:v) contains 5mmol/L first Acid, isocratic elution.Time 5min, flow velocity 0.40mL/min.Mass Spectrometer Method uses cation scanning mode, electric spray ion source (ESI).It is mainly used for measuring the accurate molecular masses of target compound.
Nuclear Magnetic Resonance: Varian Mercury 300MHz, 400MHz, 500MHz, 600MHz and Bruker Avance 400MHz, solvent CDCl3,DMSO-d6,acetone-d6or methanol-d4。
Melting point apparatus: the micro melting point apparatus of Yanaco, OptiMelt melting point apparatus.
Embodiment 1(S) -2- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -8- (3,4,5- trimethoxybenzoyl Amido) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 1)
The preparation of chloro- 2, the 4- dinitrobenzoic acid (intermediate 188) of 5-: being stirred at room temperature down, by 3- chlorobenzoic acid (10.0g, It 63.9mmol) is dissolved in the 120mL concentrated sulfuric acid, potassium nitrate (16.5g, 163.2mmol) is added portionwise in 15min.Reaction solution successively exists 80 DEG C of reactions 30min, 110 DEG C of reactions 2h, 120 DEG C of reaction 2h.Reaction solution is poured into 660g ice water, is filtered, gained white is solid The mixed solvent of body second alcohol and water recrystallizes, and obtains light yellow crystal 8.08g, yield 51.3%.1H NMR(400MHz,DMSO- d6)δ14.21(brs,1H),8.85(s,1H),8.28(s,1H).13C NMR(100MHz,DMSO-d6)δ163.78,147.95, 145.70,132.86,132.06,130.52,122.05.
The preparation of 5- (3,5- dimethyl phenoxy) -2,4- dinitrobenzoic acid (intermediate 189): by (intermediate 188) (4.93g, 20.0mmol), 3,5-dimethylphenol (2.59g, 21.2mmol) and sodium bicarbonate (3.57g, 42.4mmol) mixing In 20mL water, back flow reaction 2h.HPLC-MS monitoring reaction is completed, and 30mL water is added to dilute, hydrochloric acid tune pH value to acidity, filtering, It is dry, obtain pale solid 5.50g, yield 82.7%.1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),7.14(s, 1H),6.99(s,1H),6.89(s,2H),2.30(s,6H).13C NMR(100MHz,DMSO-d6)δ164.56,153.58, 153.56,140.60,140.38,139.33,135.32,127.78,122.66,118.76,117.64,20.78.
(S) -2- [5- (3,5- dimethyl phenoxy) -2,4- dinitrobenzamide base] dimethyl succinate (intermediate 190) preparation: being dissolved in 10mL DCM for (intermediate 189) (3.32g, 10.0mmol), sequentially adds 50 μ L of DMF, oxalyl chloride (2.58mL, 30.0mmol), back flow reaction 1h.Reaction solution is evaporated, DCM dissolved residue is added dropwise to by L-Aspartic acid diformazan In the mixed solution of ester hydrochloride (2.00g, 10.1mmol), triethylamine (3.06mL, 22.0mmol) and 20mL DCM composition, room Temperature reaction 15min.Add about 100mL DCM to dilute, successively use 1M dilute hydrochloric acid, saturated sodium bicarbonate solution, washing, point takes organic Phase is evaporated, and obtains rufous grease 4.23g, yield about 89.0%.1H NMR(400MHz,DMSO-d6) δ 9.31 (d, J= 7.9Hz, 1H), 8.84 (s, 1H), 7.00 (s, 1H), 6.97 (s, 1H), 6.90 (s, 2H), 4.74 (dd, J=13.7,7.1Hz, 1H), 3.61 (s, 3H), 3.55 (s, 3H), 2.88 (dd, J=16.5,5.7Hz, 1H), 2.80 (dd, J=16.5,7.3Hz, 1H),2.30(s,6H).
(S) -2- [8- amino -7- (3,5- dimethyl phenoxy) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 191) preparation: (intermediate 190) (2.38g, 5.0mmol) is dissolved in 80mL glacial acetic acid adds 6.0g iron powder, 90 DEG C of reaction 5h.Reaction solution adds DCM to dilute, and filtrate is evaporated, silica gel column chromatography by filtering, Petrol ether/ethyl acetate elution, obtains faint yellow solid 1.25g, yield about 65.0%.1H NMR(300MHz,DMSO-d6)δ 10.23 (s, 1H), 8.16 (d, J=5.0Hz, 1H), 7.00 (s, 1H), 6.74 (s, 1H), 6.59 (s, 2H), 6.42 (s, 1H), 5.75 (s, 2H), 4.04 (dt, J=8.8,5.5Hz, 1H), 3.58 (s, 3H), 2.85 (dd, J=17.0,8.8Hz, 1H), 2.68 (dd, J=17.0,5.6Hz, 1H), 2.23 (s, 6H)
Title compound (1): by (intermediate 191) (191.7mg, 0.5mmol) and 3,4,5- trimethoxy-benzoyl chloride (230.6mg, 1.0mmol) is mixed in 10mL THF, is added pyridine (120 μ L 1.5mmol), back flow reaction 1h.Silica gel column layer Analysis, DCM/MeOH elution, obtains faint yellow solid 274mg, yield 95.0%.Mp 128–130℃.1H NMR(300MHz,DMSO- d6) δ 10.56 (s, 1H), 9.87 (s, 1H), 8.60 (d, J=5.1Hz, 1H), 7.65 (s, 1H), 7.25 (s, 1H), 7.10 (s, 2H), 6.77 (s, 1H), 6.66 (s, 2H), 4.14 (dt, J=8.7,5.6Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.59 (s, 3H), 2.89 (dd, J=16.9,8.8Hz, 1H), 2.74 (dd, J=17.0,5.9Hz, 1H), 2.21 (s, 6H)13C NMR (100MHz,DMSO-d6)δ170.59,170.50,166.76,165.06,156.28,152.64,145.35,140.63, 139.41,133.23,132.59,129.18,125.31,123.23,120.07,117.45,115.78,105.35,60.14, 56.03,51.61,48.65,32.51,20.89.HRMS calcd.for C30H32N3O9(M+H+)578.21331；found 578.21265.
Embodiment 2(S) -2- [8- (3,5- dimethoxybenzamido) -7- (3,5- dimethyl phenoxy) -2,5- two Oxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 2)
According to 1 the method for embodiment, using intermediate 191 (191.7mg, 0.5mmol) and 3,5- dimethoxy benzene first Title compound (2) are prepared in acyl chlorides (200mg, 1.0mmol).Mp 137–139℃.1H NMR(300MHz,DMSO-d6)δ 10.54 (s, 1H), 9.87 (s, 1H), 8.60 (d, J=5.1Hz, 1H), 7.71 (s, 1H), 7.22 (s, 1H), 6.94 (d, J= 2.2Hz, 2H), 6.80 (s, 1H), 6.73-6.66 (m, 3H), 4.14 (dt, J=8.7,5.6Hz, 1H), 3.78 (s, 6H), 3.60 (s, 3H), 2.90 (dd, J=17.0,8.7Hz, 1H), 2.74 (dd, J=17.0,5.8Hz, 1H), 2.24 (s, 6H)13C NMR (100MHz,DMSO-d6)δ170.61,170.56,166.85,165.29,160.48,156.19,145.59,139.54, 136.18,132.97,132.43,125.58,123.19,119.62,117.31,116.23,105.71,103.79,55.52, 51.65,48.68,32.53,20.91.HRMS calcd.for C29H30N3O8(M+H+)548.2033；found 548.2027
Embodiment 3(S) -2- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -8- (2,3,4- trimethoxybenzoyl Amido) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 3)
According to 1 the method for embodiment, using intermediate 191 (191.7mg, 0.5mmol) and 2,3,4- trimethoxy-benzenes Title compound (3) are prepared in formyl chloride (230.6mg, 1.0mmol).Mp 136–138℃.1H NMR(300MHz,DMSO- d6) δ 10.96 (s, 1H), 10.53 (s, 1H), 8.55 (d, J=5.1Hz, 1H), 8.49 (s, 1H), 7.86 (d, J=9.0Hz, 1H), 7.10 (s, 1H), 7.05 (d, J=9.2Hz, 1H), 6.90 (s, 1H), 6.85 (s, 2H), 4.10 (dt, J=8.7, 5.5Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.77 (s, 3H), 3.59 (s, 3H), 2.89 (dd, J=17.0,8.8Hz, 1H), 2.72 (dd, J=17.0,5.8Hz, 1H), 2.30 (s, 6H)13C NMR(100MHz,DMSO-d6)δ170.63, 170.47,166.83,162.29,157.24,155.65,151.89,142.93,141.34,139.98,133.24,132.67, 126.45,126.34,120.91,117.52,117.39,116.83,112.34,108.54,61.97,60.61,56.19, 51.60,48.62,32.50,20.93.HRMS calcd.for C30H32N3O9(M+H+)578.2139；found 578.2116.
Embodiment 4(S) -2- [8- (4- benzyloxy -3,5- dimethoxybenzamido) -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 4)
According to 1 the method for embodiment, using intermediate 191 (191.7mg, 0.5mmol) and 4- benzyloxy -3,5- diformazan Title compound (4) are prepared in oxygroup chlorobenzoyl chloride (306.0mg, 1.0mmol).Mp 127–129℃.1H NMR (300MHz,DMSO-d6) δ 10.57 (s, 1H), 9.89 (s, 1H), 8.61 (d, J=5.0Hz, 1H), 7.66 (s, 1H), 7.45 (d, J=6.7Hz, 2H), 7.39-7.31 (m, 3H), 7.26 (s, 1H), 7.12 (s, 2H), 6.78 (s, 1H), 6.67 (s, 2H), 4.97 (s, 2H), 4.15 (dt, J=8.5,5.4Hz, 1H), 3.81 (s, 6H), 3.60 (s, 3H), 2.90 (dd, J=17.0, 8.7Hz, 1H), 2.75 (dd, J=16.9,5.7Hz, 1H), 2.23 (s, 6H) .HRMS calcd.for C36H36N3O9(M+H+) 654.2452；found 654.2442.
Embodiment 5(S) -2- [7- (3,5- dimethyl phenoxy) -8- (4- hydroxyl -3,5- dimethoxybenzamido) - 2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 5)
Compound 4 (131mg, 0.2mmol) and 10%Pd/C 50mg prepared by embodiment 4 are mixed in 5mL methanol, It is placed reaction liquid into atmosphere of hydrogen using hydrogen balloon, reacts at room temperature 5h.Solid, silica gel column chromatography are filtered out, DCM/MeOH is eluted, Obtain white solid 104mg, yield 92.0%.Mp 154–156℃.1H NMR(300MHz,DMSO-d6)δ10.55(s,1H), 9.69 (s, 1H), 9.12 (s, 1H), 8.59 (d, J=5.1Hz, 1H), 7.71 (s, 1H), 7.25 (s, 1H), 7.13 (s, 2H), 6.78 (s, 1H), 6.68 (s, 2H), 4.15 (dt, J=9.0,5.8Hz, 1H), 3.79 (s, 6H), 3.60 (s, 3H), 2.90 (dd, J=16.8,8.9Hz, 1H), 2.75 (dd, J=16.0,6.3Hz, 1H), 2.23 (s, 6H) .HRMS calcd.for C29H30N3O9(M+H+)564.1982；found 564.1955.
Embodiment 6(S) -2- [8- (the chloro- 3,4,5- trimethoxy-benzamide base of 2-) -7- (3,5- dimethyl phenoxy) - 2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 6)
According to 1 the method for embodiment, using intermediate 191 (191.7mg, 0.5mmol) and 2- chloro- 3,4,5- trimethoxies Title compound (6) are prepared in base chlorobenzoyl chloride (265.0mg, 1.0mmol).Mp 130–132℃.1H NMR(400MHz, DMSO-d6) δ 10.51 (s, 1H), 10.23 (s, 1H), 8.58 (d, J=4.9Hz, 1H), 8.02 (s, 1H), 7.17 (s, 1H), 6.84 (s, 1H), 6.82 (s, 1H), 6.68 (s, 2H), 4.12 (dt, J=9.2,5.6Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.60 (s, 3H), 2.88 (dd, J=17.0,8.7Hz, 1H), 2.73 (dd, J=16.9,5.6Hz, 1H),2.25(s,6H).13C NMR(100MHz,DMSO-d6)δ170.55,170.42,166.70,164.95,156.16, (151.92,149.32 d, J=5.4Hz), 144.35,143.91,139.37,132.84,132.42,131.59,125.45, 122.66,119.20,116.37,116.28,115.49,107.99,61.01,60.79,56.22,51.59,48.59, 32.48,20.87.HRMS calcd.for C30H31ClN3O9(M+H+)612.17433；found 612.17371.
Embodiment 7(S)-2- [7- (3,5- dimethyl phenoxy)-8- (4- fluorobenzoyl amido) dioxo-2,3-2,5-, 4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 7)
According to 1 the method for embodiment, using intermediate 191 (191.7mg, 0.5mmol) and 4- fluorobenzoyl chloride Title compound (7) are prepared in (158.5mg, 1.0mmol).Mp 138–140℃.1H NMR(300MHz,DMSO-d6)δ 10.52 (s, 1H), 9.99 (s, 1H), 8.60 (d, J=5.2Hz, 1H), 8.02-7.85 (m, 2H), 7.76 (s, 1H), 7.34 (t, J=8.9Hz, 2H), 7.18 (s, 1H), 6.81 (s, 1H), 6.72 (s, 2H), 4.13 (dt, J=8.7,5.6Hz, 1H), 3.60 (s, 3H), 2.89 (dd, J=17.0,8.6Hz, 1H), 2.74 (dd, J=17.0,5.8Hz, 1H), 2.25 (s, 6H)13C NMR (100MHz,DMSO-d6)δ170.56,170.45,166.75,165.53,164.58,163.04,155.95,145.82, (139.44,132.42 d, J=51.9Hz), 130.59,130.50,125.66,123.01,118.89,116.99,116.70, 115.43 (d, J=21.9Hz), 51.59,48.61,32.49,20.87.HRMS calcd.for C27H25FN3O6(M+H+) 506.1727；found 506.1722.
Embodiment 8(S)-2- [7- (3,5- dimethyl phenoxy)-8- (4- fluorobenzenesulfonamide base) dioxo-2,3-2,5-, 4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 8)
By intermediate (191) (115.0mg, 0.3mmol) and 3mL is mixed in fluorophenylsulfonyl chloride (175mg, 0.9mmol) In THF, add pyridine (73 μ L, 0.9mmol), back flow reaction 12h.Silica gel column chromatography, DCM/MeOH elution, obtains faint yellow solid 74.2mg, yield 45.7%.Mp 133–135℃.1H NMR(300MHz,DMSO-d6)δ10.53(s,1H),10.42(s,1H), 8.54 (d, J=5.0Hz, 1H), 7.90 (dd, J=8.8,5.2Hz, 2H), 7.38 (t, J=8.8Hz, 2H), 7.25 (s, 1H), 6.94 (s, 1H), 6.79 (s, 1H), 6.35 (s, 2H), 4.04 (dt, J=8.2,5.7Hz, 1H), 3.58 (s, 3H), 2.84 (dd, J=17.0,8.4Hz, 1H), 2.68 (dd, J=17.1,5.9Hz, 1H), 2.21 (s, 6H) .HRMS calcd.for C26H25FN3O7S(M+H+)542.13918；found 542.13873.
Embodiment 9(S)-2- [8- [(4- chlorobenzyl) amino]-7- (3,5- dimethyl phenoxy) dioxo-2,3-2,5-, 4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 9)
By intermediate (191) (76.7mg, 0.2mmol), p-chlorobenzaldehyde (56mg, 0.4mmol) and NaBH (OAc)3 (170mg, 0.8mmol) is mixed in 2mL DCM, 100 μ L of acetic acid on the rocks, and back flow reaction 12h, HPLC-MS monitoring reaction is completed. Silica gel column chromatography, DCM/MeOH elution, obtains yellow solid 35.4mg, yield 34.8%.Mp 279–281℃.1H NMR (300MHz,DMSO-d6) δ 10.15 (s, 1H), 8.13 (d, J=4.9Hz, 1H), 7.36 (q, J=8.7Hz, 4H), 6.99 (s, 1H), 6.78-6.74 (m, 2H), 6.64 (s, 2H), 6.21 (s, 1H), 4.33 (qd, J=16.4,6.3Hz, 2H), 4.00 (dt, J =8.5,5.6Hz, 1H), 3.56 (s, 3H), 2.82 (dd, J=17.0,8.6Hz, 1H), 2.65 (dd, J=17.0,5.8Hz, 1H),2.25(s,6H).13C NMR(100MHz,DMSO-d6)δ170.66,170.34,167.35,156.81,143.29, 140.00,139.23,138.36,134.27,131.30,128.81,128.33,124.90,119.29,115.66,112.84, 101.67,51.50,48.74,45.02,32.53,20.93.HRMS calcd.for C27H27ClN3O5(M+H+) 508.16338；found 508.16315.
Embodiment 10(S) -2- [8- [(benzo [d] [1,3] dioxolanes -5- ylmethyl) amino] -7- (3,5- dimethyl Phenoxy group) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 10)
According to 9 the method for embodiment, using intermediate 191 (76.7mg, 0.5mmol) and piperonal (3,4- methylene Dioxy benzaldehyde, 60.05mg, 0.4mmol) title compound (10) are prepared.Mp 124–126℃.1H NMR(400MHz, DMSO-d6) δ 10.21 (s, 1H), 8.15 (d, J=4.9Hz, 1H), 7.00 (s, 1H), 6.91-6.81 (m, 3H), 6.78 (s, 1H), 6.67 (t, J=6.2Hz, 1H), 6.63 (s, 2H), 6.28 (s, 1H), 5.98 (s, 2H), 4.29 (dd, J=15.7, 6.5Hz 1H), 4.19 (dd, J=15.8,6.2Hz, 1H), 4.02 (dt, J=8.6,5.5Hz, 1H), 3.57 (s, 3H), 2.84 (dd, J=17.0,8.7Hz, 1H), 2.67 (dd, J=17.0,5.8Hz, 1H), 2.26 (s, 6H)13C NMR(100MHz, DMSO-d6)δ170.68,170.39,167.39,156.88,147.36,146.10,143.42,139.85,139.21, 134.33,133.14,124.82,120.18,119.45,115.53,112.68,108.09,107.55,101.69,100.82, 51.52,48.76,45.41,32.55,20.93.HRMS calcd.for C28H28N3O7(M+H+)518.19218；found 518.19141.
Embodiment 11(S) -2- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -8- [(3,4,5- trimethoxy benzyl Base) amino] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 11)
According to 9 the method for embodiment, using intermediate 191 (76.7mg, 0.2mmol) and 3,4,5- trimethoxy-benzene first Title compound (11) are prepared in aldehyde (78.5mg, 0.4mmol).Mp 121–123℃.1H NMR(300MHz,DMSO-d6)δ 10.22 (s, 1H), 8.17 (d, J=4.9Hz, 1H), 7.02 (s, 1H), 6.77 (s, 1H), 6.69-6.63 (m, 5H), 6.31 (s, 1H), 4.37-4.15 (m, 2H), 4.02 (dt, J=8.6,5.5Hz, 1H), 3.73 (s, 6H), 3.63 (s, 3H), 3.57 (s, 3H), 2.84 (dd, J=17.0,8.6Hz, 1H), 2.67 (dd, J=17.1,5.8Hz, 1H), 2.25 (s, 6H)13C NMR (100MHz,DMSO-d6)δ170.69,170.44,167.41,157.12,152.93,143.78,139.83,139.23, 136.32,135.07,134.42,124.81,119.78,115.45,112.88,104.30,101.87,59.95,55.81, 51.52,48.77,46.03,32.58,20.92.HRMS calcd.for C30H34N3O8(M+H+)564.2346；found 564.2341.
Embodiment 12(R) -2- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -8- (3,4,5- trimethoxy-benzene first Amide groups) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 12)
According to 1 the method for embodiment, using intermediate 189 (3.32g, 10.0mmol) and D-Asp dimethyl ester salt Hydrochlorate (2.00g, 10.1mmol) be prepared (R) -2- [8- amino -7- (3,5- dimethyl phenoxy)-dioxo -2 2,5-, 3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 192).
1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.17(s,1H),7.02(s,1H),6.74(s,1H), 6.60 (s, 2H), 6.44 (s, 1H), 5.75 (s, 2H), 4.06 (brs, 1H), 3.59 (s, 3H), 2.87 (dd, J=16.8, 8.7Hz 1H), 2.69 (dd, J=16.9,4.3Hz, 1H), 2.24 (s, 6H)13C NMR(100MHz,DMSO-d6)δ170.68, 170.41,167.42,156.99,144.37,139.39,139.15,134.07,124.64,120.39,115.33,113.43, 105.47,51.52,48.74,40.15,39.94,39.73,39.52,39.31,39.10,38.89,32.59,20.94.
According to 1 the method for embodiment, using intermediate 192 (191.7mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (12): 134-136 DEG C of of Mp1H NMR(300MHz, DMSO-d6) δ 10.56 (s, 1H), 9.88 (s, 1H), 8.61 (d, J=5.2Hz, 1H), 7.67 (s, 1H), 7.26 (s, 1H), 7.12 (s, 2H), 6.78 (s, 1H), 6.67 (s, 2H), 4.15 (dt, J=8.7,5.5Hz, 1H), 3.81 (s, 6H), 3.71 (s, 3H), 3.60 (s, 3H), 2.90 (dd, J=16.9,8.7Hz, 1H), 2.75 (dd, J=17.0,5.7Hz, 1H), 2.23 (s, 6H).13C NMR(100MHz,DMSO-d6)δ170.56,170.48,166.72,165.03,156.26,152.61,145.34, 140.58,139.39,133.19,132.56,129.16,125.30,123.22,120.05,117.44,115.77,105.32, 60.12,56.01,51.59,48.61,32.49,20.88.HRMS calcd.for C30H32N3O9(M+H+)578.2139； found 578.2138.
Embodiment 137- (3,5- dimethyl phenoxy) -2,5- dioxo -8- (3,4,5- trimethoxy-benzamide Base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- Ethyl formate (compound 13)
According to 1 the method for embodiment, using intermediate 189 (3.32g, 10.0mmol) and 2- diethyl aminomalonate Hydrochloride (2.12g, 10.1mmol) is prepared 8- amino -7- (3,5- dimethyl phenoxy) -2,5- dioxo -2,3, and 4,5- Tetrahydro -1H- benzo [e] [1,4] diazepine -3- Ethyl formate (intermediate 193).
1H NMR(400MHz,DMSO-d6) δ 10.31 (s, 1H), 8.47 (d, J=4.5Hz, 1H), 6.98 (s, 1H), 6.73 (s, 1H), 6.52 (s, 2H), 6.39 (s, 1H), 5.76 (s, 2H), 4.57 (d, J=7.7Hz, 1H), 4.09-3.82 (m, 2H), 2.23 (s, 6H), 0.93 (t, J=6.7Hz, 3H)13C NMR(100MHz,DMSO-d6)δ168.25,167.20,166.77, 157.23,144.73,139.14,139.06,133.54,124.45,121.09,114.92,112.75,105.27,61.41, 58.79,20.93,13.75.
According to 1 the method for embodiment, using intermediate 193 (191.5mg, 0.5mmol) above-mentioned and 3,4,5- front threes Oxygroup chlorobenzoyl chloride (230.6mg, 1.0mmol) is prepared title compound (13): 138-140 DEG C of of Mp1H NMR (400MHz,DMSO-d6)δ10.62(s,1H),9.85(s,1H),8.95(s,1H),7.66(s,1H),7.22(s,1H),7.08 (s, 2H), 6.75 (s, 1H), 6.56 (s, 2H), 4.73 (d, J=7.8Hz, 1H), 4.06-3.86 (m, 2H), 3.79 (s, 6H), 3.70 (s, 3H), 2.20 (s, 6H), 0.94 (t, J=6.9Hz, 3H)13C NMR(100MHz,DMSO-d6)δ168.24, 166.59,166.44,164.94,156.51,152.58,145.01,140.56,139.30,133.68,131.97,129.06, 125.09,122.63,120.68,117.39,115.23,105.29,61.74,60.11,58.60,55.99,20.85, 13.76.HRMS calcd.for C30H32N3O9(M+H+)578.2139；found 578.2142.
Embodiment 14(R) -3- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -8- (3,4,5- trimethoxy-benzene first Amide groups) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl propionate (compound 14)
According to 1 the method for embodiment, using intermediate 189 (3.32g, 10.0mmol) and D-Glu diformazan ester hydrochloride Salt (2.12g, 10.1mmol) reaction, then with 3, target compound (14): Mp are prepared in 4,5- trimethoxy-benzoyl chlorides 122–124℃.1H NMR(400MHz,DMSO-d6) δ 10.49 (s, 1H), 9.85 (s, 1H), 8.50 (d, J=5.3Hz, 1H), 7.64(s,1H),7.25(s,1H),7.10(s,2H),6.77(s,1H),6.64(s,2H),3.83–3.76(m,7H),3.70 (s, 3H), 3.58 (s, 3H), 2.4-2.40 (m, 2H), 2.22 (s, 6H), 2.06 (td, J=15.3,7.2Hz, 1H), 1.85 (dt, J=14.5,7.8Hz, 1H) .HRMS calcd.for C31H34N3O9(M+H+)592.2295；found 592.2306.
Embodiment 15(S) -3- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -8- (3,4,5- trimethoxy-benzene first Amide groups) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl propionate (compound 15)
According to 1 the method for embodiment, using intermediate 189 (3.32g, 10.0mmol) and Pidolidone diformazan ester hydrochloride Salt (2.14g, 10.1mmol) reaction, then with 3, target compound (15) are prepared in 4,5- trimethoxy-benzoyl chlorides.Mp 119–121℃.1H NMR(300MHz,DMSO-d6) δ 10.49 (s, 1H), 9.85 (s, 1H), 8.51 (d, J=5.4Hz, 1H), 7.64(s,1H),7.25(s,1H),7.10(s,2H),6.77(s,1H),6.64(s,2H),3.80(m,7H),3.71(s,3H), 3.58 (s, 3H), 2.44 (t, J=7.5Hz, 2H), 2.22 (s, 6H), 2.14-1.98 (m, 1H), 1.92-1.77 (m, 1H)13C NMR(100MHz,DMSO-d6)δ172.91,171.12,166.88,164.99,156.30,152.60,145.12,140.56, 139.35,133.11,132.74,129.18,125.24,123.32,120.08,117.33,115.70,105.29,60.12, 56.00,51.35,50.99,29.74,23.22,20.88.HRMS calcd.for C31H34N3O9(M+H+)592.2295； found 592.2287.
Embodiment 16(S) -2- [7- (2,5- dimethyl phenoxy) -2,5- dioxo -8- (3,4,5- trimethoxy-benzene first Amide groups) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 16)
According to 1 the method for embodiment, using intermediate 188 (4.93g, 20.0mmol) and 2,5- xylenol (2.59g, 21.2mmol) prepares 5- (2,5- dimethyl phenoxy) -2,4- dinitrobenzoic acid (intermediate 194).
1H NMR(400MHz,DMSO-d6) δ 14.34 (brs, 1H), 8.83 (s, 1H), 7.31 (d, J=7.7Hz, 1H), 7.11 (d, J=7.7Hz, 1H), 7.05 (s, 1H), 7.00 (s, 1H), 2.30 (s, 3H), 2.11 (s, 3H)13C NMR (100MHz,DMSO-d6)δ164.52,153.40,150.98,140.30,139.04,138.00,134.07,131.91, 127.49,126.27,122.96,121.01,117.26,20.42,14.91.
(S) -2- [8- amino -7- (2,5- dimethyl phenoxy) -2,5- two is prepared according to 1 the method for embodiment Oxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 195).
According to 1 the method for embodiment, using intermediate 194 (191.7mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (16): 137-139 DEG C of of Mp1H NMR(300MHz, DMSO-d6) δ 10.53 (s, 1H), 9.89 (s, 1H), 8.59 (d, J=5.1Hz, 1H), 7.66 (s, 1H), 7.23-7.13 (m, 3H), 7.02 (s, 1H), 6.93 (d, J=7.6Hz, 1H), 6.76 (s, 1H), 4.11 (dt, J=12.7,6.3Hz, 1H), 3.82 (s, 6H), 3.72 (s, 3H), 3.60 (s, 3H), 2.89 (dd, J=17.0,8.7Hz, 1H), 2.73 (dd, J=17.0,5.7Hz, 1H),2.24(s,3H),2.17(s,3H).13C NMR(100MHz,DMSO-d6)δ170.57,170.48,166.78,165.19, 153.42,152.65,146.02,140.60,136.98,132.24,131.84,131.30,129.32,125.77,125.12, 123.19,119.32,117.50,105.37,60.14,56.04,51.59,48.62,32.48,20.61,15.44.HRMS calcd.for C30H32N3O9(M+H+)578.2139；found 578.2120.
Embodiment 17(S) -2- [8- (3,5- dimethoxybenzamido) -7- (2,5- dimethyl phenoxy) -2,5- two Oxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 17)
According to 1 the method for embodiment, using intermediate 195 (191.7mg, 0.5mmol) and 3,5- dimethoxy benzene first Acyl chlorides (200.6mg, 1.0mmol) is prepared title compound (17): 211-213 DEG C of of Mp1H NMR(400MHz,CDCl3)δ 8.78 (s, 1H), 8.59 (s, 1H), 8.55 (s, 1H), 7.22 (s, 1H), 7.16 (d, J=7.6Hz, 1H), 7.03-6.91 (m, 3H), 6.79 (s, 2H), 6.63 (s, 1H), 4.31 (dd, J=3.1,1.1Hz, 1H), 3.82 (s, 6H), 3.72 (s, 3H), 3.04 (dd, J=16.1,6.2Hz, 1H), 2.76 (dd, J=16.2,5.2Hz, 1H), 2.30 (s, 3H), 2.19 (s, 3H)13C NMR (100MHz,CDCl3)δ170.89,170.53,167.98,165.87,161.28,152.76,143.88,138.01, 136.41,132.90,131.87,131.81,126.48,126.39,120.58,116.78,112.43,105.26,104.49, 55.76,52.39,49.54,33.15,21.12,15.85.HRMS calcd.for C29H30N3O8(M+H+)548.20274； found 548.20184.
Embodiment 18(S) -2- [7- (2,5- dimethyl phenoxy) -2,5- dioxo -8- (2,3,4- trimethoxy-benzene first Amide groups) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 18)
According to 1 the method for embodiment, using intermediate 195 (191.7mg, 0.5mmol) and 2,3,4- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (18): 156-158 DEG C of of Mp1H NMR(400MHz, CDCl3)δ11.19(s,1H),8.68(s,1H),8.52(s,1H),8.06(s,1H),7.18(s,2H),6.96(s,1H), 6.81(brs,3H),4.36(brs,1H),3.92(s,6H),3.85(s,3H),3.72(s,3H),3.07(brs,1H),2.78 (brs,1H),2.31(s,3H),2.23(s,3H).13C NMR(100MHz,CDCl3)δ170.90,170.62,168.24, 163.53,157.49,153.28,152.65,144.17,141.75,137.89,133.95,131.94,131.70,127.49, 126.53,126.05,120.45,120.13,118.15,116.75,112.96,107.93,61.99,61.06,56.25, 52.38,49.60,33.29,21.16,15.82.HRMS calcd.for C30H32N3O9(M+H+)578.21331；found 578.21179.
Embodiment 19(S) -2- [8- (4- benzyloxy -3,5- dimethoxybenzamido) -7- (2,5- dimethyl benzene oxygen Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 19)
According to 1 the method for embodiment, using intermediate 195 (191.7mg, 0.5mmol) and 4- benzyloxy -3,5- diformazan Oxygroup chlorobenzoyl chloride (306.0mg, 1.0mmol) is prepared title compound (19): 223-225 DEG C of of Mp1H NMR (400MHz,DMSO-d6) δ 10.53 (s, 1H), 9.89 (s, 1H), 8.58 (d, J=5.0Hz, 1H), 7.65 (s, 1H), 7.45 (d, J=7.2Hz, 2H), 7.36 (t, J=7.2Hz, 2H), 7.34-7.28 (m, 1H), 7.18 (d, J=10.4Hz, 3H), 7.02 (s, 1H), 6.93 (d, J=7.6Hz, 1H), 6.77 (s, 1H), 4.98 (s, 2H), 4.12 (dt, J=8.9,5.6Hz, 1H), 3.82 (s, 6H), 3.60 (s, 3H), 2.89 (dd, J=16.9,8.7Hz, 1H), 2.73 (dd, J=16.9,5.6Hz, 1H), 2.24(s,3H),2.16(s,3H).HRMS calcd.for C36H36N3O9(M+H+)654.2452；found 654.24329.
Embodiment 20(S) -2- [7- (2,5- dimethyl phenoxy) -8- (4- hydroxyl -3,5- dimethoxybenzarnide Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 20)
According to 5 the method for embodiment, the title compound prepared by embodiment 19 (19) is prepared titled It closes object (20): 200-202 DEG C of of Mp1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),9.70(s,1H),9.09(s, 1H), 8.57 (d, J=3.9Hz, 1H), 7.69 (s, 1H), 7.20 (s, 1H), 7.17 (s, 2H), 7.01 (s, 1H), 6.93 (d, J =7.4Hz, 1H), 6.77 (s, 1H), 4.12 (dd, J=4.5,2.3Hz, 1H), 3.80 (s, 6H), 3.59 (s, 3H), 2.89 (dd, J=17.1,8.4Hz, 1H), 2.72 (dd, J=16.8,5.2Hz, 1H), 2.24 (s, 3H), 2.17 (s, 3H) .HRMS calcd.for C29H30N3O9(M+H+)564.19766；found 564.19659.
Embodiment 21(S) -2- [7- (4- bromobenzene oxygroup) -2,5- dioxo -8- (3,4,5- trimethoxy-benzamide Base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 21)
According to 1 the method for embodiment, using intermediate 188 (4.93g, 20.0mmol) and p bromophenol (3.67g, 5- (4- bromobenzene oxygroup) -2,4- dinitrobenzoic acid (intermediate 196) 21.2mmol) is prepared.
1H NMR(400MHz,DMSO-d6) δ 8.82 (s, 1H), 7.70 (d, J=8.8Hz, 2H), 7.33 (s, 1H), 7.27 (d, J=8.9Hz, 2H)13C NMR(100MHz,DMSO-d6)δ164.40,153.21,152.93,141.07,139.89, 134.47,133.52,122.87,122.34,119.57,118.32.
According to 1 the method for embodiment, using intermediate 196 (3.83g, 10.0mmol) and L-Aspartic acid dimethyl ester salt Hydrochlorate (2.00g, 10.1mmol) be prepared (S) -2- [8- amino -7- (4- bromobenzene oxygroup) -2,5- dioxo -2,3,4,5- Tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 197).
1H NMR(400MHz,DMSO-d6) δ 10.30 (s, 1H), 8.21 (s, 1H), 7.52 (d, J=8.2Hz, 2H), 7.10 (s, 1H), 6.93 (d, J=8.2Hz, 2H), 6.46 (s, 1H), 5.86 (s, 2H), 4.07 (brs, 1H), 3.59 (s, 3H), 2.87 (dd, J=16.8,8.9Hz, 1H), 2.70 (dd, J=16.6,4.4Hz, 1H)13C NMR(100MHz,DMSO-d6)δ 170.68,170.43,167.30,156.61,144.60,138.33,134.70,132.54,121.35,119.38,114.30, 113.55,105.66,51.55,48.75,32.59.
According to 1 the method for embodiment, using intermediate 197 (217.0mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (21): 143-145 DEG C of of Mp1H NMR(400MHz, DMSO-d6) δ 10.61 (s, 1H), 9.99 (s, 1H), 8.64 (d, J=5.2Hz, 1H), 7.65 (s, 1H), 7.54 (d, J= 8.9Hz, 2H), 7.35 (s, 1H), 7.05 (s, 2H), 7.00 (d, J=8.9Hz, 2H), 4.17 (dt, J=8.9,5.5Hz, 1H), 3.80 (s, 6H), 3.71 (s, 3H), 3.60 (s, 3H), 2.91 (dd, J=17.0,8.8Hz, 1H), 2.76 (dd, J=17.0, 5.7Hz,1H).13C NMR(100MHz,DMSO-d6)δ170.54,170.49,166.64,165.16,156.03,152.62, 144.61,140.62,133.56,133.29,132.71,129.03,123.52,121.10,119.83,117.82,115.06, 105.31,60.12,56.02,51.60,48.62,32.49.HRMS calcd.for C28H27BrN3O9(M+H+) 628.09252；found 628.09143.
Embodiment 22(S) -2- [7- (2,6- dimethyl phenoxy) -2,5- dioxo -8- (3,4,5- trimethoxy-benzene first Amide groups) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 22)
According to 1 the method for embodiment, using intermediate 188 (4.93g, 20.0mmol) and 2,6- xylenol (2.59g, 21.2mmol) prepares 5- (2,6- dimethyl phenoxy) -2,4- dinitrobenzoic acid (intermediate 198).
1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),7.30–7.21(m,3H),6.76(s,1H),2.09(s, 6H).13C NMR(100MHz,DMSO-d6)δ164.53,152.67,148.68,140.17,138.26,134.44,130.11, 129.77,127.08,123.19,115.09,15.48.
According to 1 the method for embodiment, using intermediate 198 (3.32g, 10.0mmol) and L-Aspartic acid dimethyl ester salt Hydrochlorate (2.00g, 10.1mmol) be prepared (S) -2- [8- amino -7- (2,6- dimethyl phenoxy)-dioxo -2 2,5-, 3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 199).
1H NMR(400MHz,DMSO-d6) δ 10.17 (s, 1H), 8.12 (d, J=4.4Hz, 1H), 7.17 (d, J= 7.2Hz, 2H), 7.13-7.06 (m, 1H), 6.43 (d, J=5.0Hz, 2H), 5.96 (s, 2H), 4.03-3.94 (m, 1H), 3.57 (s, 3H), 2.83 (dd, J=16.9,9.0Hz, 1H), 2.64 (dd, J=16.9,5.3Hz, 1H), 2.09 (s, 6H)13C NMR (100MHz,DMSO-d6)δ170.70,170.37,167.58,151.00,142.11,140.63,132.38,130.64, 129.12,125.19,112.82,112.32,104.94,51.51,48.70,32.57,15.76.
According to 1 the method for embodiment, using intermediate 199 (191.7mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (22): 154-156 DEG C of of Mp1H NMR(300MHz, DMSO-d6) δ 10.47 (s, 1H), 9.96 (s, 1H), 8.56 (d, J=5.2Hz, 1H), 7.69 (s, 1H), 7.28 (s, 2H), 7.24-7.09 (m, 3H), 6.64 (s, 1H), 4.06 (dt, J=9.1,5.6Hz, 1H), 3.87 (s, 6H), 3.74 (s, 3H), 3.58 (s, 3H), 2.86 (dd, J=16.9,8.8Hz, 1H), 2.69 (dd, J=17.0,5.6Hz, 1H), 2.12 (s, 6H)13C NMR(100MHz,DMSO-d6)δ170.55,170.44,166.84,165.46,152.70,150.21,145.85,140.69, 130.79,130.73,130.68,129.47,129.27,125.67,122.91,117.29,112.72,105.58,60.16, 56.11,51.57,48.59,32.45,15.85.HRMS calcd.for C30H32N3O9(M+H+)578.2139；found 578.2113.
Embodiment 23(S) -2- [2,5- dioxo -7- phenoxy group -8- (3,4,5- trimethoxy-benzamide base) -2,3, 4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 23)
According to 1 the method for embodiment, prepared using 188 (4.93g, 20.0mmol) and phenol (1.99g, 21.2mmol) 2,4- dinitro -5- phenoxy benzoic acid (intermediate 200).
According to 1 the method for embodiment, using intermediate 200 (3.04g, 10.0mmol) and L-Aspartic acid dimethyl ester salt (S) -2- [8- amino -2,5- dioxo -7- phenoxy group -2,3,4,5- tetrahydros-are prepared in hydrochlorate (2.00g, 10.1mmol) 1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 201).
1H NMR(400MHz,DMSO-d6) δ 10.25 (s, 1H), 8.17 (d, J=4.3Hz, 1H), 7.37 (t, J= 7.6Hz, 2H), 7.10 (t, J=7.2Hz, 1H), 7.05 (s, 1H), 6.99 (d, J=7.9Hz, 2H), 6.45 (s, 1H), 5.81 (s, 2H), 4.07 (dd, J=8.3,4.5Hz, 1H), 3.59 (s, 3H), 2.86 (dd, J=16.8,8.8Hz, 1H), 2.69 (dd, J=16.9,5.3Hz, 1H)13C NMR(100MHz,DMSO-d6)δ170.65,170.40,167.35,157.02,144.43, 139.13,134.20,129.85,122.94,120.49,117.59,113.44,105.50,51.51,48.72,32.57.
According to 1 the method for embodiment, using intermediate 201 (177.5mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (23): 137-139 DEG C of of Mp1H NMR(300MHz, DMSO-d6) δ 10.58 (s, 1H), 9.95 (s, 1H), 8.62 (d, J=5.2Hz, 1H), 7.69 (s, 1H), 7.39 (t, J= 7.9Hz, 2H), 7.30 (s, 1H), 7.18-7.01 (m, 5H), 4.16 (dt, J=8.9,5.6Hz, 1H), 3.80 (s, 6H), 3.70 (s, 3H), 3.60 (s, 3H), 2.90 (dd, J=17.0,8.7Hz, 1H), 2.75 (dd, J=17.0,5.7Hz, 1H)13C NMR (100MHz,DMSO-d6)δ170.55,170.50,166.74,165.08,156.49,152.64,145.08,140.57, 133.37,132.84,130.09,129.10,123.65,123.34,120.38,117.95,117.55,105.32,60.12, 56.05,51.60,48.62,32.49.HRMS calcd.for C28H28N3O9(M+H+)550.18201；found 550.18097.
Embodiment 24(S) -2- [7- [3- (dimethylamino) phenoxy group] -2,5- dioxo -8- (3,4,5- trimethoxy Benzamido) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 24)
According to 1 the method for embodiment, using intermediate 188 (4.93g, 20.0mmol) and 3- (dimethylamino) phenol (2.91g, 21.2mmol) prepares 5- [3- (dimethylamino) phenoxy group] -2,4- dinitrobenzoic acid (intermediate 202).
1H NMR(400MHz,DMSO-d6) δ 8.75 (s, 1H), 7.29 (t, J=8.2Hz, 1H), 7.11 (s, 1H), 6.67 (d, J=8.4Hz, 1H), 6.57 (s, 1H), 6.47 (d, J=7.8Hz, 1H), 2.91 (s, 6H)13C NMR(100MHz,DMSO- d6)δ164.71,154.37,154.12,152.31,140.18,138.91,135.07,130.82,122.71,118.14, 110.10,106.87,103.75,39.92.
According to 1 the method for embodiment, using 202 (1.12g, 10.0mmol) and L-Aspartic acid diformazan ester hydrochloride (2.00g, 10.1mmol) be prepared (S) -2- [8- amino -7- [3- (dimethylamino) phenoxy group]-dioxo -2 2,5-, 3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 203).
1H NMR(400MHz,DMSO-d6) δ 10.22 (s, 1H), 8.15 (d, J=4.6Hz, 1H), 7.13 (t, J= 8.1Hz, 1H), 7.02 (s, 1H), 6.48 (d, J=8.0Hz, 1H), 6.43 (s, 1H), 6.41 (s, 1H), 6.20 (d, J= 7.9Hz, 1H), 5.75 (s, 2H), 4.08-4.01 (m, 1H), 3.58 (s, 3H), 2.89 (s, 6H), 2.84 (dd, J=17.0, 8.9Hz, 1H), 2.69 (dd, J=16.9,5.3Hz, 1H)13C NMR(100MHz,DMSO-d6)δ170.68,170.41, 167.46,157.73,151.92,144.11,139.83,133.72,129.90,119.65,113.33,107.56,105.35, 105.17,102.44,51.53,48.74,40.05,32.58.
According to 1 the method for embodiment, using intermediate 203 (199.0mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (24): 131-133 DEG C of of Mp1H NMR(300MHz, DMSO-d6) δ 10.55 (s, 1H), 9.85 (s, 1H), 8.60 (d, J=5.1Hz, 1H), 7.68 (s, 1H), 7.28 (s, 1H), 7.20-7.08 (m, 3H), 6.49 (dd, J=8.3,1.9Hz, 1H), 6.42 (t, J=2.2Hz, 1H), 6.24 (dd, J=7.8, 1.8Hz, 1H), 4.14 (dt, J=8.6,5.6Hz, 1H), 3.80 (s, 6H), 3.71 (s, 3H), 3.60 (s, 3H), 2.95-2.82 (m, 7H), 2.74 (dd, J=17.0,5.8Hz, 1H)13C NMR(100MHz,DMSO-d6)δ170.56,170.49,166.77, 165.05,157.19,152.62,151.92,145.46,140.58,133.06,132.36,130.07,129.22,123.12, 119.76,117.26,107.94,105.31,105.26,102.35,60.13,56.04,51.59,48.63,32.49.HRMS calcd.for C30H33N4O9(M+H+)593.2248；found 593.2255.
Embodiment 25(S) -2- [2,5- dioxo -7- [4- (trifluoromethyl) phenoxy group] -8- (3,4,5- trimethoxy-benzene Formamido) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 25)
According to 1 the method for embodiment, using intermediate 188 (4.93g, 20.0mmol) and 4- (trifluoromethyl) phenol (3.43g, 21.2mmol) prepares 2,4- dinitro -5- [4- (trifluoromethyl) phenoxy group] benzoic acid (intermediate 204).
1H NMR(400MHz,DMSO-d6) δ 8.84 (s, 1H), 7.87 (d, J=8.7Hz, 2H), 7.53 (s, 1H), 7.46 (d, J=8.5Hz, 2H)
According to 1 the method for embodiment, using intermediate 204 (3.72g, 10.0mmol) and L-Aspartic acid dimethyl ester salt (S) -2- [8- amino -2,5- dioxo -7- [4- (trifluoromethyl) phenoxy group]-is prepared in hydrochlorate (2.00g, 10.1mmol) 2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 205).
1H NMR(400MHz,DMSO-d6) δ 10.34 (s, 1H), 8.24 (d, J=4.5Hz, 1H), 7.71 (d, J= 8.4Hz, 2H), 7.20 (s, 1H), 7.10 (d, J=8.3Hz, 2H), 6.49 (s, 1H), 5.90 (s, 2H), 4.15-4.05 (m, 1H), 3.59 (s, 3H), 2.88 (dd, J=16.9,8.9Hz, 1H), 2.72 (dd, J=16.9,5.3Hz, 1H)13C NMR (100MHz,DMSO-d6)δ170.68,170.45,167.24,160.51,144.89,137.15,135.25,127.23(d,J =3.6Hz), 123.05,122.56,116.91,113.73,105.83,51.54,48.76,32.59.
According to 1 the method for embodiment, using intermediate 205 (211.5mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (25): 141-143 DEG C of of Mp1H NMR(300MHz, DMSO-d6) δ 10.66 (s, 1H), 10.05 (s, 1H), 8.67 (d, J=5.1Hz, 1H), 7.72 (d, J=8.7Hz, 2H), 7.68 (s, 1H), 7.47 (s, 1H), 7.17 (d, J=8.5Hz, 2H), 7.00 (s, 2H), 4.20 (dt, J=8.9,5.5Hz, 1H), 3.76 (s, 6H), 3.69 (s, 3H), 3.61 (s, 3H), 2.92 (dd, J=16.8,8.7Hz, 1H), 2.77 (dd, J=16.8, 5.6Hz,1H).13C NMR(100MHz,DMSO-d6)δ170.60,170.56,166.58,165.23,159.90,152.59, 143.62,140.61,133.96,133.90,129.01,127.39,123.65,122.25,117.95,117.46,105.30, 60.14,55.98,51.61,48.63,32.50.HRMS calcd.for C29H27F3N3O9(M+H+)618.1699；found 618.1677.
Embodiment 26(S) -2- [7- (the fluoro- 5- methylphenoxy of 3-) -2,5- dioxo -8- (3,4,5- trimethoxy-benzene first Amide groups) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 26)
According to 1 the method for embodiment, using intermediate 188 (4.93g, 20.0mmol) and the fluoro- 5- methylphenol of 3- (2.67g, 21.2mmol) prepares 5- (the fluoro- 5- methylphenoxy of 3-) -2,4- dinitrobenzoic acid (intermediate 206).
1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),7.32(s,1H),7.09–7.01(m,2H),6.97(s, 1H),2.34(s,3H).13C NMR(100MHz,DMSO-d6) δ 164.45,163.88,161.44,154.72 (d, J= 12.1Hz), 152.66,142.73 (d, J=9.6Hz), 140.53 (d, J=157.8Hz), 135.48,122.70,119.87, 116.47 (d, J=2.8Hz), 113.51 (d, J=21.0Hz), 105.00 (d, J=25.3Hz), 20.87 (d, J=1.8Hz)
According to 1 the method for embodiment, using intermediate 206 (3.36g, 10.0mmol) and L-Aspartic acid dimethyl ester salt Hydrochlorate (2.00g, 10.1mmol) be prepared (S) -2- [8- amino -7- (the fluoro- 5- methylphenoxy of 3-)-dioxo -2 2,5-, 3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 207).
1H NMR(400MHz,DMSO-d6) δ 10.30 (s, 1H), 8.22 (d, J=2.4Hz, 1H), 7.12 (s, 1H), 6.76 (d, J=8.8Hz, 1H), 6.63-6.58 (m, 2H), 6.46 (s, 1H), 5.83 (s, 2H), 4.09 (d, J=4.3Hz, 1H), 3.59 (s, 3H), 2.87 (dd, J=16.6,8.8Hz, 1H), 2.70 (dd, J=16.7,4.4Hz, 1H), 2.28 (s, 3H)13C NMR(100MHz,DMSO-d6) δ 170.69,170.47,167.35,163.88,161.47,158.41 (d, J=11.7Hz), 144.62,141.49 (d, J=9.9Hz), 136.45 (d, J=335.1Hz), 121.63,113.60,113.54 (d, J= 2.3Hz), 110.13 (d, J=21.1Hz), 105.72,101.85 (d, J=25.0Hz), 51.55,48.76,32.61,21.04 (d, J=1.8Hz)
According to 1 the method for embodiment, using intermediate 207 (193.5mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6g, 1.0mmol) is prepared title compound (26): 132-134 DEG C of of Mp1H NMR(300MHz,DMSO- d6) δ 10.61 (s, 1H), 9.96 (s, 1H), 8.64 (d, J=5.1Hz, 1H), 7.65 (s, 1H), 7.38 (s, 1H), 7.07 (s, 2H), 6.80 (d, J=9.6Hz, 1H), 6.73-6.64 (m, 2H), 4.20 (dt, J=8.5,5.5Hz, 1H), 3.80 (s, 6H), (3.71 s, 3H), 3.61 (s, 3H), 2.91 (dd, J=17.0,8.8Hz, 1H), 2.75 (dd, J=17.0,5.6Hz, 1H), 2.26(s,3H).13C NMR(100MHz,DMSO-d6)δ170.57,170.55,166.68,165.13,163.86,161.42, (157.73,152.64,144.42,141.77,140.64,133.48 d, J=20.9Hz), 129.08,123.50,121.34, (117.85,114.11,110.79 d, J=20.5Hz), 105.34,102.37 (d, J=29.4Hz), 60.12,55.98, 51.60,48.60,32.50,20.95.HRMS calcd.for C29H29FN3O9(M+H+)582.1888；found 582.1866.
Embodiment 27(S) -2- [7- (3,5- dichlorophenoxy) -2,5- dioxo -8- (3,4,5- trimethoxybenzoyl Amido) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 27)
According to 1 the method for embodiment, using intermediate 188 (4.93g, 20.0mmol) and 3,5- chlorophenesic acid (3.46g, 21.2mmol) prepares 5- (3,5- dichlorophenoxy) -2,4- dinitrobenzoic acid (intermediate 208).
1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.57(s,1H),7.52(s,1H),7.47(s,1H), 7.47(s,1H).13C NMR(100MHz,DMSO-d6)δ164.37,155.73,151.85,141.97,140.16,135.83, 135.31,125.58,122.80,121.19,118.90.
According to 1 the method for embodiment, using intermediate 208 (3.73g, 10.0mmol) and L-Aspartic acid dimethyl ester salt Hydrochlorate (2.00g, 10.1mmol) be prepared (S) -2- [8- amino -7- (3,5- dichlorophenoxy) -2,5- dioxo -2,3, 4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 209).
1H NMR(400MHz,DMSO-d6) δ 10.33 (s, 1H), 8.25 (d, J=4.0Hz, 1H), 7.29 (s, 1H), 7.22 (s, 1H), 6.95 (s, 2H), 6.47 (s, 1H), 5.92 (s, 2H), 4.12 (dd, J=7.7,4.3Hz, 1H), 3.59 (s, 3H), 2.87 (dd, J=16.7,8.9Hz, 1H), 2.71 (dd, J=16.8,5.2Hz, 1H)13C NMR(100MHz,DMSO-d6)δ 170.66,170.48,167.23,158.97,144.74,136.76,135.50,134.68,122.77,122.19,115.55, 113.80,105.91,51.55,48.75,32.59.
According to 1 the method for embodiment, using intermediate 209 (212.0mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (27): 143-145 DEG C of of Mp1H NMR(300MHz, DMSO-d6) δ 10.65 (s, 1H), 10.05 (s, 1H), 8.67 (d, J=5.1Hz, 1H), 7.62 (s, 1H), 7.47 (s, 1H), 7.34 (t, J=1.7Hz, 1H), 7.06 (d, J=1.7Hz, 2H), 7.05 (s, 2H), 4.23 (dt, J=8.6,5.2Hz, 1H), 3.81 (s, 6H), 3.71 (s, 3H), 3.61 (s, 3H), 2.92 (dd, J=17.2,8.7Hz, 1H), 2.76 (dd, J=16.9, 5.5Hz,1H).13C NMR(100MHz,DMSO-d6)δ170.57,170.52,166.58,165.20,158.27,152.63, 143.60,140.66,134.85,134.04,133.70,128.94,123.86,122.96,122.21,118.18,116.35, (105.32,60.11,56.00 d, J=5.0Hz), 51.60,48.62,32.50.HRMS calcd.for C28H26Cl2N3O9(M +H+)618.10406；found 618.10291.
Embodiment 28(S) -2- [7- (4- fluorophenoxy) -2,5- dioxo -8- (3,4,5- trimethoxy-benzamide Base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 28)
According to 1 the method for embodiment, using intermediate 188 (4.93g, 20.0mmol) and p-fluorophenol (2.37g, 21.2mmol) prepare 5- (4- fluorophenoxy) -2,4- dinitrobenzoic acid (intermediate 210).
1H NMR(400MHz,DMSO-d6)δ14.43(brs,1H),8.83(s,1H),7.38(s,2H),7.37(s,2H), 7.23(s,1H).13C NMR(100MHz,DMSO-d6) δ 164.47,161.02,158.61,153.71,149.59 (d, J= 2.4Hz), 140.13 (d, J=106.9Hz), 133.97,122.90,122.45 (d, J=8.8Hz), 118.64,117.43 (d, J=23.8Hz)
According to 1 the method for embodiment, using intermediate 210 (3.22g, 10.0mmol) and L-Aspartic acid dimethyl ester salt Hydrochlorate (2.00g, 10.1mmol) be prepared (S) -2- [8- amino -7- (4- fluorophenoxy) -2,5- dioxo -2,3,4,5- Tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 211).
1H NMR(400MHz,DMSO-d6) δ 10.27 (s, 1H), 8.20 (d, J=4.2Hz, 1H), 7.20 (t, J= 8.6Hz, 2H), 7.03 (s, 3H), 6.45 (s, 1H), 5.86 (s, 2H), 4.06 (s, 1H), 3.58 (s, 3H), 2.86 (dd, J= 16.9,8.8Hz, 1H), 2.70 (dd, J=16.7,5.3Hz, 1H)13C NMR(100MHz,DMSO-d6)δ170.69, (170.43,167.38,159.09,156.72,153.12,141.96 d, J=471.5Hz), 134.23,120.11,119.40 (d, J=8.4Hz), 116.34 (d, J=23.4Hz), 113.42,105.53,51.54,48.75,32.59.
According to 1 the method for embodiment, using intermediate 211 (186.5mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (28): 136-138 DEG C of of Mp1H NMR(300MHz, DMSO-d6) δ 10.58 (s, 1H), 9.98 (s, 1H), 8.62 (d, J=5.1Hz, 1H), 7.64 (s, 1H), 7.26-7.20 (m, 3H), 7.17-7.05 (m, 4H), 4.15 (dt, J=8.6,5.4Hz, 1H), 3.81 (s, 6H), 3.71 (s, 3H), 3.60 (s, 3H), 2.90 (dd, J=17.0,8.7Hz, 1H), 2.75 (dd, J=16.9,5.6Hz, 1H) .HRMS calcd.for C28H27FN3O9(M+H+)568.17258；found 568.17139.
Embodiment 29(S) -2- [7- (3,4- dimethyl phenoxy) -2,5- dioxo -8- (3,4,5- trimethoxy-benzene first Amide groups) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 29)
According to 1 the method for embodiment, using intermediate 188 (4.93g, 20.0mmol) and 3,4- xylenol (2.59g, 21.2mmol) prepares 5- (3,4- dimethyl phenoxy) -2,4- dinitrobenzoic acid (intermediate 212).
1H NMR(400MHz,DMSO-d6) δ 8.81 (s, 1H), 7.28 (d, J=8.1Hz, 1H), 7.14 (s, 1H), 7.10 (s, 1H), 7.01 (dd, J=8.2,2.1Hz, 1H), 2.25 (s, 6H)13C NMR(100MHz,DMSO-d6)δ164.56, 154.00,151.31,140.40,139.46,139.27,134.66,133.87,131.34,122.86,121.13,118.40, 117.46,19.42,18.76.
According to 1 the method for embodiment, using intermediate 212 (3.32g, 10.0mmol) and L-Aspartic acid dimethyl ester salt Hydrochlorate (2.00g, 10.1mmol) be prepared (S) -2- [8- amino -7- (3,4- dimethyl phenoxy)-dioxo -2 2,5-, 3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 213).
1H NMR(400MHz,DMSO-d6) δ 10.22 (s, 1H), 8.15 (d, J=4.1Hz, 1H), 7.12 (d, J= 8.0Hz, 1H), 6.96 (s, 1H), 6.83 (s, 1H), 6.72 (d, J=7.3Hz, 1H), 6.43 (s, 1H), 5.76 (s, 2H), 4.08-4.00 (m, 1H), 3.58 (s, 3H), 2.86 (dd, J=16.9,8.7Hz, 1H), 2.68 (dd, J=16.9,5.2Hz, 1H),2.20(s,3H),2.18(s,3H).13C NMR(100MHz,DMSO-d6)δ170.66,170.38,167.42,154.61, 144.04,140.14,137.90,133.72,131.06,130.53,119.38,119.32,115.36,113.30,105.35, 51.51,48.71,32.57,19.54,18.60.
According to 1 the method for embodiment, using intermediate 213 (191.7mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (29): 136-138 DEG C of of Mp1H NMR(300MHz, DMSO-d6) δ 10.55 (s, 1H), 9.89 (s, 1H), 8.60 (d, J=5.1Hz, 1H), 7.67 (s, 1H), 7.21 (s, 1H), 7.18-7.09 (m, 3H), 6.90 (d, J=2.3Hz, 1H), 6.78 (dd, J=8.1,2.4Hz, 1H), 4.14 (dt, J=8.9, 5.6Hz, 1H), 3.81 (s, 6H), 3.71 (s, 3H), 3.60 (s, 3H), 2.90 (dd, J=17.0,8.7Hz, 1H), 2.74 (dd, J=16.9,5.7Hz, 1H), 2.19 (s, 3H), 2.18 (s, 3H)13C NMR(100MHz,DMSO-d6)δ170.56,170.48, 166.75,165.05,154.04,152.63,145.85,140.60,138.18,132.92,132.29,131.79,130.68, 129.18,123.13,119.66,119.32,117.34,115.67,105.34,60.13,56.03,51.59,48.62, 32.48,19.52,18.61.HRMS calcd.for C30H32N3O9(M+H+)578.2139；found 578.2119.
Embodiment 30(S) -2- [7- (4- ethyl phenoxy group) -2,5- dioxo -8- (3,4,5- trimethoxy-benzamide Base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 30)
According to 1 the method for embodiment, using intermediate 188 (4.93g, 20.0mmol) and 4- ethyl -phenol (2.59g, 21.2mmol) prepare 5- (4- ethyl phenoxy group) -2,4- dinitrobenzoic acid (intermediate 214).
1H NMR(400MHz,DMSO-d6) δ 8.81 (s, 1H), 7.36 (d, J=8.4Hz, 2H), 7.21 (d, J=8.4Hz, 2H), 7.16 (s, 1H), 2.66 (q, J=7.6Hz, 2H), 1.21 (t, J=7.6Hz, 3H)13C NMR(100MHz,DMSO-d6) δ164.53,153.81,151.43,142.03,140.53,139.55,134.04,129.95,122.86,120.18, 118.52,27.51,15.42.
According to 1 the method for embodiment, using intermediate 214 (3.32g, 10.0mmol) and L-Aspartic acid dimethyl ester salt Hydrochlorate (2.00g, 10.1mmol) be prepared (S) -2- [8- amino -7- (4- ethyl phenoxy group) -2,5- dioxo -2,3,4, 5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 215).
1H NMR(400MHz,DMSO-d6) δ 10.23 (s, 1H), 8.16 (d, J=4.7Hz, 1H), 7.20 (d, J= 8.2Hz, 2H), 7.01 (s, 1H), 6.92 (d, J=8.2Hz, 2H), 6.44 (s, 1H), 5.79 (s, 2H), 4.09-4.00 (m, 1H), 3.59 (s, 3H), 2.86 (dd, J=16.9,8.8Hz, 1H), 2.69 (dd, J=16.9,5.5Hz, 1H), 2.58 (q, J= 7.4Hz, 2H), 1.17 (t, J=7.5Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.66,170.40,167.40, 154.82,144.24,139.79,138.51,133.92,129.04,119.79,117.85,113.36,105.41,51.51, 48.73,32.58,27.42,15.78.
According to 1 the method for embodiment, using intermediate 215 (191.7g, 0.5mmol) and 3,4,5- trimethoxy-benzene first Acyl chlorides (230.6g, 1.0mmol) is prepared title compound (30): 132-134 DEG C of of Mp1H NMR(300MHz,DMSO-d6) δ 10.56 (s, 1H), 9.92 (s, 1H), 8.61 (d, J=5.1Hz, 1H), 7.68 (s, 1H), 7.27-7.18 (m, 3H), 7.13 (s, 2H), 6.99 (d, J=8.5Hz, 2H), 4.14 (dt, J=8.7,5.6Hz, 1H), 3.81 (s, 6H), 3.71 (s, 3H), 3.60 (s, 3H), 2.90 (dd, J=17.0,8.7Hz, 1H), 2.74 (dd, J=17.0,5.7Hz, 1H), 2.57 (q, J= 7.5Hz, 2H), 1.15 (t, J=7.6Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.54,170.48,166.77, 165.10,154.21,152.65,145.62,140.63,139.26,133.10,132.50,129.21,129.13,123.19, 119.67,118.23,117.45,105.34,60.11,56.04,51.59,48.63,32.49,27.41,15.68.HRMS calcd.for C30H32N3O9(M+H+)578.21331；found 578.21228.
Embodiment 31(S) -2- [7- [(2,3- dihydro -1H- indenes -5- base) oxygroup] -2,5- dioxo -8- (3,4,5- front three Oxybenzamide base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 31)
According to 1 the method for embodiment, using intermediate 188 (4.93g, 20.0mmol) and 2,3- dihydro -1H- indenes -5- Alcohol (2.84g, 21.2mmol) prepares 5- [(2,3- dihydro -1H- indenes -5- base) oxygroup] -2,4- dinitrobenzoic acid (216).
1H NMR(400MHz,DMSO-d6) δ 8.81 (s, 1H), 7.35 (d, J=8.1Hz, 1H), 7.15 (s, 2H), 7.03 (dd, J=8.0,1.9Hz, 1H), 2.89 (t, J=6.3Hz, 4H), 2.11-2.02 (m, 2H)13C NMR(100MHz,DMSO- d6)δ164.58,154.11,152.04,146.82,141.99,140.37,139.48,133.88,125.93,122.87, 118.42,118.10,116.41,32.49,31.73,25.31.
According to 1 the method for embodiment, using intermediate 216 (3.44g, 10.0mmol) and L-Aspartic acid dimethyl ester salt (S) -2- [8- amino -7- [(2,3- dihydro -1H- indenes -5- base) oxygroup] -2,5- is prepared in hydrochlorate (2.00g, 10.1mmol) Dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 217).
1H NMR(400MHz,DMSO-d6) δ 10.24 (s, 1H), 8.18 (d, J=2.9Hz, 1H), 7.19 (d, J= 7.8Hz, 1H), 6.99 (s, 1H), 6.86 (s, 1H), 6.77 (d, J=7.4Hz, 1H), 6.43 (s, 1H), 5.78 (s, 2H), 4.04 (brs, 1H), 3.58 (s, 3H), 2.89-2.81 (m, 5H), 2.69 (dd, J=16.7,4.5Hz, 1H), 2.07-1.96 (m,2H).13C NMR(100MHz,DMSO-d6)δ170.69,170.42,167.46,155.49,145.66,144.16, 140.18,138.46,133.82,125.08,119.60,116.11,114.14,113.36,105.40,51.53,48.74, 32.59,32.54,31.59,25.46.
According to 1 the method for embodiment, using intermediate 217 (197.5mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (31): 138-140 DEG C of of Mp1H NMR(300MHz, DMSO-d6) δ 10.55 (s, 1H), 9.90 (s, 1H), 8.60 (d, J=5.1Hz, 1H), 7.67 (s, 1H), 7.21 (d, J= 6.7Hz, 2H), 7.15 (s, 2H), 6.94 (d, J=1.3Hz, 1H), 6.83 (dd, J=8.1,2.1Hz, 1H), 4.14 (dt, J= 8.5,5.6Hz, 1H), 3.81 (s, 6H), 3.71 (s, 3H), 3.60 (s, 3H), 2.95-2.69 (m, 6H), 2.01 (p, J= 7.4Hz,2H).13C NMR(100MHz,DMSO-d6)δ170.55,170.47,166.80,165.07,154.89,152.67, 146.01,145.91,140.65,139.22,133.01,132.36,129.20,125.27,123.19,119.4,117.36, (116.48,114.67,105.38,60.12,56.05 d, J=5.4Hz), 51.63,48.61,32.49,31.58, 25.44.HRMS calcd.for C31H32N3O9(M+H+)590.2139；found 590.2127.
Embodiment 32(S) -2- [7- (benzo [d] [1,3] dioxole -5- base oxygroup) -2,5- dioxo -8- (3, 4,5- trimethoxy-benzamide base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (change Close object 32)
According to 1 the method for embodiment, using intermediate 188 (4.93g, 20.0mmol), 3,4- methylenedioxyphenols (2.93g, 21.2mmol) and L-Aspartic acid diformazan ester hydrochloride (4.00g, 20.2mmol) are prepared through three-step reaction (S) -2- [8- amino -7- (benzo [d] [1,3] dioxole -5- base oxygroup) -2,5- dioxo -2,3,4,5- tetrahydro - 1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 219).
1H NMR(400MHz,DMSO-d6) δ 10.23 (s, 1H), 8.18 (d, J=3.8Hz, 1H), 6.97 (s, 1H), 6.89 (d, J=8.3Hz, 1H), 6.71 (s, 1H), 6.46 (d, J=8.7Hz, 1H), 6.42 (s, 1H), 6.03 (s, 2H), 5.82 (s, 2H), 4.05 (brs, 1H), 3.58 (s, 3H), 2.85 (dd, J=16.6,8.8Hz, 1H), 2.68 (dd, J=16.8,5.3Hz, 1H).13C NMR(100MHz,DMSO-d6)δ170.69,170.44,167.48,151.29,148.10,143.85,143.28, 140.60,133.74,118.88,113.29,110.59,108.32,105.38,101.55,101.29,51.54,48.74, 32.59.
According to 1 the method for embodiment, using intermediate 219 (200.0mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (32): 145-147 DEG C of of Mp1H NMR(300MHz, DMSO-d6) δ 10.54 (s, 1H), 9.92 (s, 1H), 8.61 (d, J=5.1Hz, 1H), 7.64 (s, 1H), 7.21 (s, 1H), 7.18 (s, 2H), 6.91 (d, J=8.4Hz, 1H), 6.79 (d, J=2.4Hz, 1H), 6.53 (dd, J=8.4,2.4Hz, 1H), 6.03 (d, J=2.3Hz, 2H), 4.14 (dt, J=8.8,5.6Hz, 1H), 3.83 (s, 6H), 3.72 (s, 3H), 3.60 (s, 3H), 2.89 (dd, J=17.0,8.7Hz, 1H), 2.73 (dd, J=17.0,5.8Hz, 1H)13C NMR(100MHz,DMSO- d6)δ170.55,170.50,166.76,165.07,152.65,150.65,148.17,146.36,143.72,140.63, 132.63,132.25,129.13,123.19,118.93,117.44,111.14,108.41,105.37,101.69,101.54, 60.14,56.07,51.59,48.61,32.48.HRMS calcd.for C29H28N3O11(M+H+)594.1724；found 594.1718.
Embodiment 33(S) -2- [7- (2- phenylphenoxy) -2,5- dioxo -8- (3,4,5- trimethoxy-benzamide Base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 33)
According to 1 the method for embodiment, using intermediate 188 (4.93g, 20.0mmol) and 2- phenylphenol (3.60g, 21.2mmol) prepare 5- (2- phenylphenoxy) -2,4- dinitrobenzoic acid (intermediate 220).
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.63–7.28(m,9H),7.04(s,1H).13C NMR (100MHz,DMSO-d6)δ164.38,153.06,149.76,140.31,139.01,135.73,133.76,133.47, 131.80,130.00,128.68,128.49,127.92,127.34,122.80,121.51,117.75.
According to 1 the method for embodiment, using intermediate 220 (3.80g, 10.0mmol) and L-Aspartic acid dimethyl ester salt Hydrochlorate (2.00g, 10.1mmol) be prepared (S) -2- [7- (2- phenylphenoxy) -8- amino -2,5- dioxo -2,3,4, 5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 221).
1H NMR(400MHz,DMSO-d6) δ 10.23 (s, 1H), 8.16 (d, J=3.6Hz, 1H), 7.66-7.22 (m, 8H), 6.95 (d, J=7.8Hz, 1H), 6.88 (s, 1H), 6.40 (s, 1H), 5.86 (s, 2H), 4.01 (brs, 1H), 3.58 (s, 3H), 2.85 (dd, J=16.6,8.7Hz, 1H), 2.73-2.62 (m, 1H)13C NMR(100MHz,DMSO-d6)δ170.67, 170.39,167.39,153.30,143.94,140.40,137.30,133.66,132.42,131.07,129.11,128.89, 128.17,127.26,124.03,119.07,118.53,113.30,105.22,51.53,48.72,32.58.
According to 1 the method for embodiment, using intermediate 221 (216mg, 0.5mmol) and 3,4,5- trimethoxy-benzene first Title compound (33): Mp142-144 DEG C of are prepared in acyl chlorides (230.6mg, 1.0mmol)1H NMR(300MHz,DMSO-d6) δ 10.52 (s, 1H), 9.88 (s, 1H), 8.58 (d, J=5.1Hz, 1H), 7.69 (s, 1H), 7.56 (dd, J=7.8,1.4Hz, 2H), 7.49 (dd, J=7.6,1.6Hz, 1H), 7.45-7.26 (m, 5H), 7.17-7.09 (m, 4H), 4.08 (dt, J=8.6, 5.5Hz, 1H), 3.81 (s, 6H), 3.72 (s, 3H), 3.59 (s, 3H), 2.88 (dd, J=17.0,8.7Hz, 1H), 2.72 (dd, J=17.0,5.7Hz, 1H) .HRMS calcd.for C34H32N3O9(M+H+)626.2139；found 626.2130.
Embodiment 34(S) -2- [7- (4- methoxyphenoxy) -2,5- dioxo -8- (3,4,5- trimethoxybenzoyl Amido) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 34)
According to 1 the method for embodiment, using intermediate 188 (4.93g, 20.0mmol) and 4- metoxyphenol (2.63g, 21.2mmol) prepares 5- (4- methoxyphenoxy) -2,4- dinitrobenzoic acid (intermediate 222).
1H NMR(400MHz,DMSO-d6) δ 8.81 (s, 1H), 7.26 (d, J=9.0Hz, 2H), 7.10 (s, 1H), 7.07 (d, J=9.0Hz, 2H), 3.80 (s, 3H)13C NMR(100MHz,DMSO-d6)δ164.62,157.43,154.51, 146.48,140.18,133.89,122.91,121.84,117.81,115.71,114.60,55.54.
According to 1 the method for embodiment, using intermediate 222 (3.34g, 10.0mmol) and L-Aspartic acid dimethyl ester salt Hydrochlorate (2.00g, 10.1mmol) be prepared (S) -2- [8- amino -7- (4- methoxyphenoxy) -2,5- dioxo -2,3, 4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 223).
1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.16(s,1H),7.13–6.87(m,5H),6.42(s, 1H), 5.82 (s, 2H), 4.03 (brs, 1H), 3.74 (s, 3H), 3.58 (s, 3H), 2.84 (brs, 1H), 2.68 (dd, J= 13.7,0.7Hz,1H).13C NMR(100MHz,DMSO-d6)δ170.69,170.41,167.48,155.38,149.89, 143.78,141.04,133.48,119.90,118.28,114.97,113.21,105.28,55.41,51.53,48.74, 32.58.
According to 1 the method for embodiment, using intermediate 223 (192.5mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (34): 135-137 DEG C of of Mp1H NMR(300MHz, DMSO-d6) δ 10.53 (s, 1H), 9.93 (s, 1H), 8.59 (d, J=5.1Hz, 1H), 7.65 (s, 1H), 7.18 (s, 2H), 7.15 (s, 1H), 7.06 (d, J=9.1Hz, 2H), 6.97 (d, J=9.1Hz, 2H), 4.12 (dt, J=8.5,5.6Hz, 1H), 3.83 (s, 6H), 3.74 (s, 3H), 3.72 (s, 3H), 3.60 (s, 3H), 2.89 (dd, J=17.1,8.6Hz, 1H), 2.73 (dd, J=17.0,5.8Hz, 1H)13C NMR(100MHz,DMSO-d6)δ170.54,170.47,166.80,165.12, 155.82,152.68,149.31,146.74,140.65,132.50,132.00,129.22,123.14,120.30,118.36, 117.45,115.13,105.41,60.17,56.11,55.41,51.63,48.65,32.47.HRMS calcd.for C29H30N3O10(M+H+)580.1931；found 580.1925.
Embodiment 35(S) -2- [7- [3,5- bis- (trifluoromethyl) phenoxy group] -2,5- dioxo -8- (3,4,5- trimethoxy Yl-benzamide base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 35)
According to 1 the method for embodiment, using intermediate 188 (4.93g, 20.0mmol) and 3,5- bis- (trifluoromethyl) benzene Phenol (4.87g, 21.2mmol) prepares 5- [3,5- bis- (trifluoromethyl) phenoxy group] -2,4- dinitrobenzoic acid (intermediate 224).
1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.10(s,2H),8.06(s,1H),7.70s,1H).13C NMR(100MHz,DMSO-d6) δ 164.37,155.59,152.08,141.99,140.68,134.44,132.42 (q, J= 33.7Hz),124.13,123.07,121.43,121.24,119.25.
According to 1 the method for embodiment, using intermediate 224 (4.40g, 10.0mmol) and L-Aspartic acid dimethyl ester salt (S) -2- [8- amino -7- [3,5- bis- (trifluoromethyl) phenoxy group] -2,5- dioxy is prepared in hydrochlorate (2.00g, 10.1mmol) Generation -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 225).
1H NMR(400MHz,DMSO-d6) δ 10.35 (s, 1H), 8.25 (d, J=4.6Hz, 1H), 7.80 (s, 1H), 7.50 (s, 2H), 7.30 (s, 1H), 6.50 (s, 1H), 6.00 (s, 2H), 4.11 (dt, J=8.5,5.3Hz, 1H), 3.59 (s, 3H), 2.87 (dd, J=16.9,8.7Hz, 1H), 2.71 (dd, J=16.9,5.5Hz, 1H)13C NMR(100MHz,DMSO-d6)δ (170.62,170.42,167.11,158.56,144.78,136.03 d, J=58.2Hz), 132.30-130.90 (m), 124.30,123.02,121.59,116.96,115.65,113.90,105.98,51.50,48.75,32.55.
According to 1 the method for embodiment, using intermediate 225 (245.5mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (35): 138-140 DEG C of of Mp1H NMR(300MHz, DMSO-d6) δ 10.67 (s, 1H), 10.09 (s, 1H), 8.67 (d, J=5.0Hz, 1H), 7.80 (s, 1H), 7.66-7.45 (m, 4H), 6.99 (s, 2H), 4.20 (dt, J=6.7,5.7Hz, 1H), 3.75 (s, 6H), 3.68 (s, 3H), 3.60 (s, 3H), 2.91 (dd, J=16.8,8.3Hz, 1H), 2.76 (dd, J=17.2,5.9Hz, 1H)13C NMR(100MHz,DMSO-d6)δ 170.58,170.53,166.51,165.12,157.80,152.58,143.72,140.64 133.95 (d, J=51.4Hz), 131.81 (d, J=31.9Hz), 128.75,124.14 (d, J=13.3Hz), 122.33,121.48,118.52,118.05, 116.56,105.28,60.07,55.87,51.60,48.63,32.49.HRMS calcd.for C30H26F6N3O9(M+H+) 686.1573；found 686.1569.
Embodiment 36(S) -2- [7- (3,5- dimethyl phenoxy) -1- methyl -2,5- dioxo -8- (3,4,5- trimethoxy Yl-benzamide base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 36)
The title compound (1) (115.5g, 0.2mmol) that embodiment 1 prepares is dissolved in 2mL DMF, carbonic acid is added Potassium (55mg, 0.4mmol), iodomethane (28.4mg, 0.2mmol) react at room temperature 12h.Silica gel column chromatography, DCM/MeOH elution, Obtain white solid 87.5mg, yield 74.0%.Mp 117–119℃.1H NMR(400MHz,DMSO-d6)δ9.99(s,1H), 8.73 (d, J=5.4Hz, 1H), 7.91 (s, 1H), 7.17 (s, 2H), 7.16 (s, 1H), 6.81 (s, 1H), 6.71 (s, 2H), 4.18 (dt, J=8.8,5.7Hz, 1H), 3.81 (s, 6H), 3.72 (s, 3H), 3.59 (s, 3H), 3.33 (s, 3H), 2.92 (dd, J=16.9,8.8Hz, 1H), 2.76 (dd, J=16.9,5.5Hz, 1H), 2.24 (s, 6H)13C NMR(100MHz,DMSO-d6) δ170.60,169.72,166.53,165.16,155.86,152.64,146.73,140.64,139.48,135.99, 132.73,129.09,125.66,119.14,118.54,116.36,105.40,60.13,56.03,51.57,48.85, 35.32,32.85,20.86.HRMS calcd.for C31H34N3O9(M+H+)592.2295；found 592.2309.
Embodiment 37(S) -2- [1- benzyl -7- (3,5- dimethyl phenoxy) -2,5- dioxo -8- (3,4,5- trimethoxy Yl-benzamide base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 37)
According to 36 the method for embodiment, the title compound prepared using embodiment 1 (1) (115.5g, Title compound (37) 0.2mmol) are prepared with bromobenzyl (34.2mg, 0.2mmol).Mp 98–100℃.1H NMR (300MHz,DMSO-d6) δ 9.91 (s, 1H), 8.81 (d, J=5.4Hz, 1H), 7.92 (s, 1H), 7.31-7.16 (m, 3H), 7.13 (brs, 4H), 7.07 (s, 1H), 6.80 (s, 1H), 6.66 (s, 2H), 5.29 (d, J=16.4Hz, 1H), 4.94 (d, J= 15.7Hz, 1H), 4.29 (dt, J=10.1,3.3Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.59 (s, 3H), 2.97 (dd, J=16.8,8.7Hz, 1H), 2.79 (dd, J=16.9,5.3Hz, 1H), 2.22 (s, 6H)13C NMR(150MHz, DMSO-d6)δ170.50,169.39,166.36,165.01,155.51,152.56,147.17,140.55,139.46, 136.87,134.41,132.39,129.04,128.46,127.15,126.79,126.73,125.74,119.79,118.15, 116.49,105.35,60.11,56.02,51.61,50.36,48.80,32.78,20.84.HRMS calcd.for C37H38N3O9(M+H+)668.26026；found 668.25873.
Embodiment 38(S) -2- [7- methoxyl group -2,5- dioxo -8- (3,4,5- trimethoxy-benzamide base) -2,3, 4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 38)
The preparation of 5- methoxyl group -2,4- dinitrobenzoic acid (intermediate 226): by intermediate (188) (4.93g, It 20.0mmol) is mixed in 20mL MeOH with potassium hydroxide (2.47g, 44.0mmol), reacts at room temperature 12h.HPLC-MS monitoring Reaction is completed, and solvent is removed under reduced pressure, and 50mL water is added to dissolve, and hydrochloric acid tune pH value to acidity filters, dry, obtains white solid 4.10g, yield 84.7%.1H NMR(400MHz,DMSO-d6)δ14.35(brs,1H),8.71(s,1H),7.70(s,1H), 4.10(s,3H).13C NMR(100MHz,DMSO-d6)δ165.43,155.71,138.44,137.94,134.95,122.26, 114.71,58.32.
According to 1 the method for embodiment, by intermediate 226 (3.42g, 10.0mmol) and L-Aspartic acid diformazan ester hydrochloride (S) -2- [8- amino -7- methoxyl group -2,5- dioxo -2,3,4,5- tetrahydro -1H- are prepared in salt (2.00g, 10.1mmol) Benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 227).
1H NMR(400MHz,DMSO-d6) δ 10.10 (s, 1H), 8.15 (d, J=3.6Hz, 1H), 7.06 (s, 1H), 6.30 (s, 1H), 5.58 (s, 2H), 3.99 (brs, 1H), 3.78 (s, 3H), 3.58 (s, 3H), 2.87 (dd, J=16.7,8.4Hz, 1H), 2.69 (dd, J=16.7,5.1Hz, 1H)13C NMR(100MHz,DMSO-d6)δ170.75,170.43,168.01, 143.02,142.30,131.67,112.88,110.68,104.17,55.47,51.54,48.78,32.63.
According to 1 the method for embodiment, using intermediate 227 (146.5mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (38): 145-147 DEG C of of Mp1H NMR(400MHz, DMSO-d6) δ 10.40 (s, 1H), 9.57 (s, 1H), 8.58 (d, J=5.2Hz, 1H), 7.67 (s, 1H), 7.35 (s, 1H), 7.28 (s, 2H), 4.08 (dt, J=8.2,5.8Hz, 1H), 3.89 (s, 3H), 3.87 (s, 6H), 3.74 (s, 3H), 3.60 (s, 3H), 2.90 (dd, J=17.0,8.4Hz, 1H), 2.75 (dd, J=17.0,5.9Hz, 1H)13C NMR(100MHz,DMSO- d6) δ 170.55 (d, J=11.6Hz), 167.27,164.84,152.76,147.69,140.65,130.80,130.04, 129.33,122.58,116.19,111.60,105.28,60.16,56.14,51.59,48.67,40.15,39.94,39.73, 39.52,39.31,39.10,38.89,32.52.HRMS calcd.for C23H26N3O9(M+H+)488.1669；found 488.1670.
Embodiment 39(S) -2- [7- benzyloxy -2,5- dioxo -8- (3,4,5- trimethoxy-benzamide base) -2,3, 4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 39)
The preparation of 5- benzyloxy -2,4- dinitrobenzoic acid (intermediate 228): by intermediate (188) (4.93g, It 20.0mmol) is mixed in 20mL BnOH with potassium hydroxide (2.47g, 44.0mmol), reacts at room temperature 12h.HPLC-MS monitoring Reaction is completed, and into reaction solution plus 100mL DCM, filtering obtain yellow solid, be suspended in 50mL water, hydrochloric acid tune pH value To acidity, filter, it is dry, obtain faint yellow solid 5.37g, yield 84.4%.1H NMR(400MHz,DMSO-d6)δ14.42 (brs,1H),8.73(s,1H),7.81(s,1H),7.51–7.33(m,5H),5.51(s,2H).13C NMR(100MHz,DMSO- d6)δ165.40,154.63,138.75,138.13,134.97,134.88,128.63,128.46,127.66,122.33, 115.65,72.01.
According to 1 the method for embodiment, by 228 (3.18g, 10.0mmol) and L-Aspartic acid diformazan ester hydrochloride (2.00g, 10.1mmol) prepares (S) -2- [8- amino -7- benzyloxy -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzos [e] [1,4] diazepine -3- base] methyl acetate (intermediate 229).
1H NMR(400MHz,DMSO-d6) δ 10.11 (s, 1H), 8.13 (d, J=4.6Hz, 1H), 7.50 (d, J= 7.4Hz, 2H), 7.40 (t, J=7.3Hz, 2H), 7.36-7.29 (m, 1H), 7.17 (s, 1H), 6.35 (s, 1H), 5.60 (s, 2H), 5.12 (s, 2H), 4.00 (dd, J=12.9,5.6Hz, 1H), 3.58 (s, 3H), 2.87 (dd, J=16.9,8.6Hz, 1H), 2.69 (dd, J=16.9,5.6Hz, 1H)13C NMR(100MHz,DMSO-d6)δ170.70,170.39,167.85, 142.56,141.93,137.16,131.83,128.37,127.69,127.30,112.95,112.36,104.42,69.55, 51.50,48.74,32.60.
According to 1 the method for embodiment, using intermediate 229 (184.5mg, 0.5mmol) and 3,4,5- trimethoxy-benzenes Formyl chloride (230.6mg, 1.0mmol) is prepared title compound (39): 141-143 DEG C of of Mp1H NMR(400MHz, DMSO-d6) δ 10.44 (s, 1H), 9.54 (s, 1H), 8.58 (d, J=5.2Hz, 1H), 7.84 (s, 1H), 7.58 (d, J= 6.9Hz, 2H), 7.48 (s, 1H), 7.42-7.31 (m, 3H), 7.21 (s, 2H), 5.24 (s, 2H), 4.08 (dt, J=8.0, 5.8Hz, 1H), 3.80 (s, 6H), 3.73 (s, 3H), 3.60 (s, 3H), 2.91 (dd, J=17.0,8.3Hz, 1H), 2.75 (dd, J=17.0,5.9Hz, 1H)13C NMR(100MHz,DMSO-d6)δ170.60,170.48,167.20,164.45,152.78, 146.33,140.62,136.67,131.13,130.41,129.29,128.38,127.99,127.64,122.29,115.14, 112.93,104.93,70.40,60.15,55.98,51.58,48.67,32.5.HRMS calcd.for C29H30N3O9(M+H+)564.1982；found 564.1978.
Embodiment 40(S) -2- [7- hydroxyl -2,5- dioxo -8- (3,4,5- trimethoxy-benzamide base) -2,3,4, 5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 40)
The title compound (39) (1.13g, 2mmol) that embodiment 39 prepares is mixed in 10%Pd/C 500mg It in 10mL methanol, is placed reaction liquid into atmosphere of hydrogen using hydrogen balloon, reacts at room temperature 5h.Filter out solid, silica gel column chromatography, DCM/MeOH elution, obtains white solid 871mg, yield 92.0%.Mp 173–175℃.1H NMR(400MHz,DMSO-d6)δ 10.44 (s, 1H), 9.54 (s, 1H), 8.58 (d, J=5.2Hz, 1H), 7.84 (s, 1H), 7.58 (d, J=6.9Hz, 2H), 7.48 (s, 1H), 7.42-7.31 (m, 3H), 7.21 (s, 2H), 5.24 (s, 2H), 4.08 (dt, J=8.0,5.8Hz, 1H), 3.80 (s, 6H), 3.73 (s, 3H), 3.60 (s, 3H), 2.91 (dd, J=17.0,8.3Hz, 1H), 2.75 (dd, J=17.0, 5.9Hz,1H).13C NMR(100MHz,DMSO-d6)δ170.60,170.48,167.20,164.45,152.78,146.33, 140.62,136.67,131.13,130.41,129.29,128.38,127.99,127.64,122.29,115.14,112.93, 104.93,70.40,60.15,55.98,51.58,48.67,32.50.HRMS calcd.for C23H26N3O9(M+H+) 474.1513；found 474.1510.
Embodiment 41(S) -2- [2,5- dioxo -7- [2- (pyrrolidin-1-yl) ethyoxyl] -8- (3,4,5- trimethoxy Benzamido) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 41)
Title compound 40 (94.7mg, 0.2mmol) that embodiment 40 is prepared, triphenylphosphine (105mg, 0.4mmol) it is mixed in 2mL THF with 2- (pyrrolidin-1-yl) ethyl alcohol (100 μ L, 0.4mmol), dropwise addition DEAD (63 μ L, 0.4mmol), 0.5h is reacted at room temperature.Silica gel column chromatography, DCM/MeOH elution, obtains faint yellow solid 84.0mg, yield 73.6%. Mp 139–141℃.1H NMR(300MHz,DMSO-d6) δ 10.44 (s, 1H), 9.71 (s, 1H), 8.57 (d, J=5.2Hz, 1H), 7.94 (s, 1H), 7.42 (s, 1H), 7.21 (s, 2H), 4.31-4.15 (m, 2H), 4.08 (dt, J=8.2,5.9Hz, 1H), 3.87 (s, 6H), 3.74 (s, 3H), 3.60 (s, 3H), 2.90 (dd, J=16.9,8.5Hz, 1H), 2.81-2.71 (m, 3H),2.47(brs,4H),1.49(brs,4H).HRMS calcd.for C28H35N4O9(M+H+)571.2404；found 571.2414.
Embodiment 42(S) -2- [7- [(3- methyl but-2-ene -1- base) oxygroup] -2,5- dioxo -8- (3,4,5- front three Oxybenzamide base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 42)
According to 41 the method for embodiment, the title compound 40 prepared using embodiment 40 (94.7mg, Title compound (42) 0.2mmol) are prepared with 3- methyl but-2-ene -1- alcohol (34.4mg, 0.4mmol).Mp 128–130 ℃.1H NMR(300MHz,DMSO-d6) δ 10.39 (s, 1H), 9.44 (s, 1H), 8.55 (d, J=5.1Hz, 1H), 7.76 (s, 1H), 7.37 (s, 1H), 7.23 (s, 2H), 5.49 (t, J=6.9Hz, 1H), 4.66 (d, J=6.2Hz, 2H), 4.06 (dt, J= 7.8,5.9Hz, 1H), 3.86 (s, 6H), 3.73 (s, 3H), 3.59 (s, 3H), 2.89 (dd, J=16.9,8.3Hz, 1H), 2.73 (dd, J=17.0,6.0Hz, 1H), 1.72 (s, 6H) .HRMS calcd.for C27H32N3O9(M+H+)542.2139；found 542.2135.
Embodiment 43(S) -2- [7- (2- cyclopropylethoxy) -2,5- dioxo -8- (3,4,5- trimethoxybenzoyl Amido) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 43)
According to 41 the method for embodiment, the title compound 40 prepared using embodiment 40 (94.7mg, Title compound (43) 0.2mmol) are prepared with 2- cyclopropyl-ethanol (34.4mg, 0.4mmol).Mp 132–134℃.1H NMR(400MHz,DMSO-d6) δ 10.41 (s, 1H), 9.44 (s, 1H), 8.57 (d, J=5.1Hz, 1H), 7.83 (s, 1H), 7.35 (s, 1H), 7.25 (s, 2H), 4.19-4.12 (m, 2H), 4.08 (dt, J=8.3,5.8Hz, 1H), 3.87 (s, 6H), 3.74 (s, 3H), 3.60 (s, 3H), 2.90 (dd, J=17.0,8.5Hz, 1H), 2.74 (dd, J=17.0,5.8Hz, 1H), 1.70 (dd, J=12.9,6.3Hz, 2H), 0.98-0.87 (m, 1H), 0.40 (d, J=7.0Hz, 2H), 0.12 (q, J= 4.6Hz,2H).HRMS calcd.for C27H32N3O9(M+H+)542.2139；found 542.2134.
Embodiment 44(S) -2- [7- (2- morpholine base oxethyl) -2,5- dioxo -8- (3,4,5- trimethoxybenzoyl Amido) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 44)
According to 41 the method for embodiment, the title compound 40 prepared using embodiment 40 (94.7mg, Title compound (44) 0.2mmol) are prepared with 2- (morpholine -4- base) ethyl alcohol (52.4mg, 0.4mmol).Mp 117–119 ℃.1H NMR(400MHz,DMSO-d6) δ 10.43 (s, 1H), 9.50 (s, 1H), 8.57 (d, J=5.2Hz, 1H), 7.83 (s, 1H), 7.41 (s, 1H), 7.24 (s, 2H), 4.22 (td, J=10.0,5.0Hz, 2H), 4.07 (dt, J=7.5,5.6Hz, 1H), 3.87 (s, 6H), 3.74 (s, 3H), 3.60 (s, 3H), 3.45-3.39 (m, 4H), 2.90 (dd, J=17.0,8.5Hz, 1H), 2.79–2.70(m,3H),2.42(brs,4H).HRMS calcd.for C28H35N4O10(M+H+)587.2353；found 587.2357.
Embodiment 45(S) -2- [2,5- dioxo -7- [2- (thiophene -2- base) ethyoxyl] -8- (3,4,5- trimethoxy-benzene Formamido) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 45)
According to 41 the method for embodiment, the title compound 40 prepared using embodiment 40 (94.7mg, Title compound (45) 0.2mmol) are prepared with 2- (thiophene -2- base) ethyl alcohol (51.2mg, 0.4mmol).Mp 129–131 ℃.1H NMR(300MHz,DMSO-d6) δ 10.43 (s, 1H), 9.38 (s, 1H), 8.57 (d, J=5.3Hz, 1H), 7.89 (s, 1H), 7.37 (s, 1H), 7.27 (dd, J=5.1,1.1Hz, 1H), 7.24 (s, 2H), 6.97 (d, J=2.5Hz, 1H), 6.88 (dd, J=5.1,3.4Hz, 1H), 4.33 (t, J=6.0Hz, 2H), 4.08 (dt, J=8.3,5.7Hz, 1H), 3.84 (s, 6H), 3.75 (s, 3H), 3.59 (s, 3H), 3.37 (t, J=6.0Hz, 2H), 2.90 (dd, J=17.0,8.5Hz, 1H), 2.74 (dd, J =17.1,6.0Hz, 1H) .HRMS calcd.for C28H30N3O9S(M+H+)584.1703；found 584.1696.
Embodiment 46(S) -2- [7- [(3,5- dimethyl benzyl) oxygroup] -2,5- dioxo -8- (3,4,5- trimethoxy Benzamido) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 46)
According to 41 the method for embodiment, the title compound 40 prepared using embodiment 40 (94.7mg, Title compound (46) 0.2mmol) are prepared with 3,5- dimethylphenylcarbinol (54.4mg, 0.4mmol).Mp 135–137 ℃.1H NMR(300MHz,DMSO-d6) δ 10.44 (s, 1H), 9.53 (s, 1H), 8.59 (d, J=5.3Hz, 1H), 7.75 (s, 1H), 7.47 (s, 1H), 7.23 (s, 2H), 7.11 (s, 2H), 6.95 (s, 1H), 5.13 (s, 2H), 4.09 (dt, J=8.2, 5.8Hz, 1H), 3.79 (s, 6H), 3.73 (s, 3H), 3.60 (s, 3H), 2.91 (dd, J=17.0,8.4Hz, 1H), 2.75 (dd, J=17.0,6.1Hz, 1H), 2.22 (s, 6H)13C NMR(100MHz,DMSO-d6)δ170.61,170.50,167.22, 164.50,152.82,146.78,140.70,137.41,136.49,131.30,130.44,129.32,125.37,122.51, 115.56,113.29,105.04,70.69,60.17,56.01,51.61,48.69,32.51,20.82.HRMS calcd.for C31H34N3O9(M+H+)592.2295；found592.2288.
Embodiment 47(S) -2- [7- [2- (3,5- 3,5-dimethylphenyl) ethyoxyl] -2,5- dioxo -8- (3,4,5- front three Oxybenzamide base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 47)
According to 41 the method for embodiment, the title compound 40 prepared using embodiment 40 (94.7mg, Title compound (47) 0.2mmol) are prepared with 3,5- dimethyl benzene ethyl alcohol (60.0mg, 0.4mmol).Mp 120–122 ℃.1H NMR(300MHz,DMSO-d6) δ 10.41 (s, 1H), 9.33 (s, 1H), 8.57 (d, J=5.2Hz, 1H), 7.79 (s, 1H), 7.35 (s, 1H), 7.25 (s, 2H), 6.85 (s, 2H), 6.74 (s, 1H), 4.30 (t, J=6.3Hz, 2H), 4.06 (dt, J =8.2,5.6Hz, 1H), 3.86 (s, 6H), 3.75 (s, 3H), 3.59 (s, 3H), 3.02 (t, J=6.1Hz, 2H), 2.90 (dd, J=17.0,8.5Hz, 1H), 2.74 (dd, J=17.1,6.0Hz, 1H), 2.07 (s, 6H)13C NMR(100MHz,DMSO-d6) δ170.58,170.45,167.20,164.47,152.87,146.09,140.70,138.12,137.16,131.01, 130.21,129.37,127.65,126.58,122.21,114.91,112.53,105.00,69.41,60.12,56.08, 51.57,48.64,34.61,32.51,20.63.HRMS calcd.for C32H36N3O9(M+H+)606.2452；found 606.2444.
Embodiment 48(S) -2- [7- [3- (3,5- 3,5-dimethylphenyl) propoxyl group] -2,5- dioxo -8- (3,4,5- front three Oxybenzamide base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 48)
According to 41 the method for embodiment, the title compound 40 prepared using embodiment 40 (94.7mg, Title compound (48) 0.2mmol) are prepared with 3,5- dimethyl benzene propyl alcohol (65.6mg, 0.4mmol).Mp 116–118 ℃.1H NMR(300MHz,DMSO-d6) δ 10.42 (s, 1H), 9.53 (s, 1H), 8.57 (d, J=5.2Hz, 1H), 7.78 (s, 1H),7.31(s,1H),7.29(s,2H),6.78(s,1H),6.76(s,2H),4.11–4.05(m,3H),3.83(s,6H), 3.74 (s, 3H), 3.60 (s, 3H), 2.91 (dd, J=17.0,8.5Hz, 1H), 2.80-2.65 (m, 3H), 2.18 (s, 6H), 2.10–2.01(m,2H).13C NMR(100MHz,DMSO-d6)δ170.62,170.50,167.27,164.62,152.84, 146.72,141.22,140.66,137.19,131.15,130.16,129.39,127.24,126.05,122.39,115.32, 112.48,105.08,68.08,60.11,55.96,51.57,48.68,32.50,31.37,30.36,20.83.HRMS calcd.for C33H38N3O9(M+H+)620.2608；found620.2604.
Embodiment 49(S) -2- [7- [(4,6- dimethyl pyrimidine -2- base) oxygroup] -2,5- dioxo -8- (3,4,5- front three Oxybenzamide base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (compound 49)
Title compound (40) (94.7mg, 0.2mmol) that embodiment 40 is prepared, potassium carbonate (55mg, It 0.4mmol) is mixed in 2mL acetone with chloro- 4, the 6- dimethyl pyrimidine (114mg, 0.8mmol) of 2-, using CEM microwave synthesizer Reaction, reacts 30min by 100 DEG C, 150W.Silica gel column chromatography, DCM/MeOH elution, obtains white solid 27.2mg, yield 23.5%.Mp 169–171℃.1H NMR(300MHz,DMSO-d6) δ 10.61 (s, 1H), 9.21 (s, 1H), 8.52 (d, J= 5.1Hz, 1H), 7.93 (s, 1H), 7.57 (s, 1H), 7.30 (s, 2H), 6.61 (s, 1H), 4.14 (dt, J=8.2,5.8Hz, 1H), 3.82 (s, 6H), 3.76 (s, 3H), 3.60 (s, 3H), 2.91 (dd, J=17.1,8.5Hz, 1H), 2.76 (dd, J= 17.2,5.9Hz,1H),2.23(s,6H).HRMS calcd.for C28H30N5O9(M+H+)580.2044；found 580.2038.
Embodiment 50(S) -2- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -8- (3,4,5- trimethoxy-benzene first Amide groups) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] acetic acid (compound 50)
Title compound (1) (1.16g, 2.0mmol) that embodiment 1 is prepared and lithium hydroxide (143.7mg, It 6.0mmol) mixes, adds 20mL water and 20mL THF, react at room temperature 30min.It removes THF, 1M hydrochloric acid tune pH to acidity under reduced pressure, analyses It precipitates, filters out, it is dry, obtain white solid 1.08g, yield 95.6%.1H NMR(300MHz,DMSO-d6)δ12.40(brs, 1H), 10.52 (s, 1H), 9.87 (s, 1H), 8.60 (d, J=5.4Hz, 1H), 7.65 (s, 1H), 7.24 (s, 1H), 7.10 (s, 2H), 6.76 (s, 1H), 6.66 (s, 2H), 4.13-4.02 (m, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 2.83 (dd, J= 17.1,8.8Hz, 1H), 2.63 (dd, J=17.0,5.1Hz, 1H), 2.21 (s, 6H) .HRMS calcd.for C29H30N3O9(M +H+)564.19766；found 564.19696.
Embodiment 51(S) -2- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -8- (3,4,5- trimethoxy-benzene first Amide groups) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] isopropyl acetate (compound 51)
Title compound 50 (112.7mg, 0.2mmol) that embodiment 50 is prepared and DIC (63 μ L, 0.4mmol), HOSu (46mg, 0.4mmol) is mixed in 2mL THF, and isopropanol 1mL, back flow reaction 48h is added.Silica gel column chromatography, DCM/ MeOH elution, obtains faint yellow solid 62.5mg, yield 51.6%.Mp 103–105℃.1H NMR(300MHz,DMSO-d6)δ 10.55 (s, 1H), 9.87 (s, 1H), 8.62 (d, J=5.2Hz, 1H), 7.66 (s, 1H), 7.25 (s, 1H), 7.12 (s, 2H), 6.78 (s, 1H), 6.67 (s, 2H), 4.95-4.81 (m, 1H), 4.13 (dt, J=8.8,5.6Hz, 1H), 3.81 (s, 6H), 3.71 (s, 3H), 2.85 (dd, J=17.1,9.0Hz, 1H), 2.68 (dd, J=16.9,5.7Hz, 1H), 2.22 (s, 6H), 1.19(s,3H),1.17(s,3H).HRMS calcd.for C32H36N3O9(M+H+)606.2452；found 606.2442.
Embodiment 52(S) -2- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -8- (3,4,5- trimethoxy-benzene first Amide groups) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] n-butyl acetate (compound 52)
According to 51 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (52) 0.2mmol) are prepared with n-butanol 1mL.Mp 104–106℃.1H NMR(300MHz,DMSO-d6)δ 10.56 (s, 1H), 9.87 (s, 1H), 8.62 (d, J=5.1Hz, 1H), 7.66 (s, 1H), 7.25 (s, 1H), 7.11 (s, 2H), 6.78 (s, 1H), 6.66 (s, 2H), 4.14 (dt, J=8.4,5.7Hz, 1H), 4.02 (t, J=6.3Hz, 2H), 3.80 (s, 6H), 3.71 (s, 3H), 2.88 (dd, J=16.9,8.7Hz, 1H), 2.72 (dd, J=16.9,5.8Hz, 1H), 2.22 (s, 6H), 1.60-1.47 (m, 2H), 1.38-1.29 (m, 2H), 0.87 (t, J=7.3Hz, 3H)13C NMR(100MHz,DMSO- d6)δ170.54,170.08,166.78,165.06,156.30,152.65,145.35,140.62,139.42,133.19, 132.63,129.21,125.33,123.29,120.01,117.42,115.81,105.35,63.86,60.16,56.05, 48.64,32.72,30.17,20.86,18.57,13.53.HRMS calcd.for C33H38N3O9(M+H+)620.2608； found 620.2599.
Embodiment 53(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -2, 5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] (the change of -3,4,5- trimethoxy-benzamide Close object 53)
Title compound 50 (112.7mg, 0.2mmol) that embodiment 50 is prepared and DIC (63 μ L, 0.4mmol), HOSu (46mg, 0.4mmol) is mixed in 2mL THF, reacts at room temperature 12h.It is added diethylamine (62 μ L, 0.6mmol), continues anti- Answer 1h.Silica gel column chromatography, DCM/MeOH elution, obtains faint yellow solid 98.7mg, yield 79.8%.Mp 135–137℃.1H NMR(300MHz,DMSO-d6) δ 10.42 (s, 1H), 9.85 (s, 1H), 8.53 (d, J=5.3Hz, 1H), 7.65 (s, 1H), 7.24 (s, 1H), 7.10 (s, 2H), 6.76 (s, 1H), 6.66 (s, 2H), 4.20 (dt, J=8.1,5.1Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.38-3.15 (m, 4H), 2.99 (dd, J=16.2,8.3Hz, 1H), 2.61 (dd, J=16.4, 5.0Hz, 1H), 2.21 (s, 6H), 1.16 (t, J=6.9Hz, 3H), 0.98 (t, J=7.0Hz, 3H)13C NMR(100MHz, DMSO-d6)δ170.88,167.96,166.85,165.06,156.35,152.66,145.26,140.62,139.43, 133.13,132.79,129.25,125.32,123.49,120.03,117.40,115.79,105.37,60.17,56.06, 49.06,41.36,31.30,20.87,13.90,13.04.HRMS calcd.for C33H39N4O8(M+H+)619.27624； found 619.27423.
Embodiment 54(S)-N- [3- (2- amino -2- oxoethyl) -7- (3,5- dimethyl phenoxy) -2,5- dioxo - 2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzamide (compound 54)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (54) 0.2mmol) are prepared with ammonium hydroxide (21.0mg, 0.6mmol).Mp 269–271℃.1H NMR (400MHz,DMSO-d6) δ 10.45 (s, 1H), 9.86 (s, 1H), 8.59 (d, J=5.4Hz, 1H), 7.65 (s, 1H), 7.47 (s, 1H), 7.25 (s, 1H), 7.11 (s, 2H), 6.91 (s, 1H), 6.77 (s, 1H), 6.67 (s, 2H), 4.13 (dt, J=8.3, 5.5Hz, 1H), 3.80 (s, 6H), 3.71 (s, 3H), 2.78 (dd, J=15.9,8.5Hz, 1H), 2.43 (dd, J=16.0, 5.4Hz,1H),2.22(s,6H).13C NMR(100MHz,DMSO-d6)δ171.11,170.86,166.87,165.06, 156.29,152.65,145.20,140.56,139.43,133.08,132.79,129.20,125.31,123.36,120.05, 117.41,115.75,105.31,60.13,56.01,48.79,33.38,20.88.HRMS calcd.for C29H31N4O8(M+ H+)563.2142；found 563.2140.
Embodiment 55(S)-N- [7- (3,5- dimethyl phenoxy) -3- [2- (methylamino) -2- oxoethyl] -2,5- Dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzamide (chemical combination Object 55)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (55) 0.2mmol) are prepared with methylamine hydrochloride (40.5mg, 0.6mmol).Mp 151–153℃.1H NMR(300MHz,DMSO-d6) δ 10.45 (s, 1H), 9.87 (s, 1H), 8.59 (d, J=5.4Hz, 1H), 7.93 (d, J= 4.4Hz, 1H), 7.65 (s, 1H), 7.25 (s, 1H), 7.12 (s, 2H), 6.77 (s, 1H), 6.67 (s, 2H), 4.16 (dt, J= 8.0,5.7Hz, 1H), 3.81 (s, 6H), 3.71 (s, 3H), 3.08 (dd, J=14.2,7.7Hz, 1H), 2.76 (dd, J= 15.6,8.2Hz, 1H), 2.56 (d, J=4.5Hz, 3H), 2.23 (s, 6H) .HRMS calcd.for C30H33N4O8(M+H+) 577.2298；found 577.2293.
Embodiment 56(S)-N- [3- [2- (dimethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -2, 5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] (the change of -3,4,5- trimethoxy-benzamide Close object 56)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (56) 0.2mmol) are prepared with dimethylamine (27.0mg, 0.6mmol).Mp 130–132℃.1H NMR (300MHz,DMSO-d6) δ 10.44 (s, 1H), 9.85 (s, 1H), 8.52 (d, J=5.2Hz, 1H), 7.64 (s, 1H), 7.24 (s, 1H), 7.10 (s, 2H), 6.76 (s, 1H), 6.66 (s, 2H), 4.17 (dt, J=7.7,5.3Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.05-2.88 (m, 4H), 2.80 (s, 3H), 2.62 (dd, J=16.5,4.9Hz, 1H), 2.21 (s, 6H)13C NMR(150MHz,DMSO-d6)δ170.77,168.84,166.75,164.98,156.25,152.58,145.24,140.53, 139.36,133.05,132.74,129.16,125.25,123.40,119.94,117.42,115.74,105.29,60.11, 56.00,49.01,36.51,34.76,31.41,20.87.HRMS calcd.for C31H35N4O8(M+H+)591.2455； found 591.2468.
Embodiment 57(S)-N- [7- (3,5- dimethyl phenoxy) -3- [2- (dipropylamino) -2- oxoethyl] -2, 5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] (the change of -3,4,5- trimethoxy-benzamide Close object 57)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (57) 0.2mmol) are prepared with di-n-propylamine (60.6mg, 0.6mmol).Mp 108–110℃.1H NMR (300MHz,DMSO-d6) δ 10.42 (s, 1H), 9.85 (s, 1H), 8.54 (d, J=4.7Hz, 1H), 7.65 (s, 1H), 7.24 (s,1H),7.10(s,2H),6.76(s,1H),6.66(s,2H),4.27–4.13(m,1H),3.79(s,6H),3.70(s, 3H), 3.28-3.14 (m, 4H), 3.00 (dd, J=16.0,8.9Hz, 1H), 2.59 (dd, J=16.2,3.6Hz, 1H), 2.21 (s, 6H), 1.67-1.47 (m, 2H), 1.46-1.35 (m, 2H), 0.93 (t, J=6.9Hz, 3H), 0.84 (t, J=6.9Hz, 3H).HRMS calcd.for C35H43N4O8(M+H+)647.30754；found 647.30597.
Embodiment 58(S)-N- [3- [2- (dibutylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -2, 5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] (the change of -3,4,5- trimethoxy-benzamide Close object 58)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (58) 0.2mmol) are prepared with dibutyl amine (77.4mg, 0.6mmol).Mp 120–122℃.1H NMR (300MHz,DMSO-d6) δ 10.42 (s, 1H), 9.85 (s, 1H), 8.52 (d, J=5.2Hz, 1H), 7.64 (s, 1H), 7.24 (s, 1H), 7.10 (s, 2H), 6.76 (s, 1H), 6.65 (s, 2H), 4.19 (dt, J=8.3,5.0Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.25-3.12 (m, 4H), 3.01 (dd, J=16.1,8.4Hz, 1H), 2.60 (dd, J=16.2,4.4Hz, 1H), 2.21 (s, 6H), 1.59 (q, J=7.4Hz, 2H), 1.42 (q, J=7.4Hz, 2H), 0.89 (t, J=7.3Hz, 3H), 0.78 (t, J=7.3Hz, 3H)13C NMR(150MHz,DMSO-d6)δ170.77,168.46,166.76,164.99, 156.28,152.59,145.18,140.55,139.37,133.06,132.78,129.18,125.24,123.42,119.97, 117.39,115.71,105.30,60.12,56.01,49.09,48.87,46.84,31.38,21.60,20.88,20.57, 11.22,11.15.HRMS calcd.for C37H47N4O8(M+H+)675.33884；found 675.33777.
Embodiment 59N- [(3S) -7- (3,5- dimethyl phenoxy) -3- [2- (3,5- lupetidine -1- base) -2- oxygen For ethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 59)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (59) 0.2mmol) are prepared with 3,5- lupetidine (67.8mg, 0.6mmol).Mp 144–146℃ .1H NMR(400MHz,acetone-d6)δ9.52(s,1H),9.07(s,1H),8.34(s,1H),7.57(s,1H),7.41(s, 1H), 7.14 (s, 1H), 6.81 (s, 1H), 6.74 (s, 1H), 4.47 (d, J=7.1Hz, 1H), 3.92 (d, J=13.1Hz, 1H), 3.83 (s, 3H), 3.77 (s, 1H), 3.66-3.06 (m, 1H), 2.84 (s, 1H), 2.57 (dd, J=23.2,11.4Hz, 1H), 1.98 (t, J=11.7Hz, 1H), 1.87-1.62 (m, 1H), 1.47 (s, 1H), 0.91 (s, 1H), 0.85 (d, J= 6.4Hz,1H).HRMS calcd.for C36H43N4O8(M+H+)659.30754；found 659.30634.
Embodiment 60N- [(3S) -7- (3,5- dimethyl phenoxy) -2,5- dioxo -3- [2- oxo -2- [(1- phenyl Ethyl) amino] ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 60)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (60) 0.2mmol) are prepared with 1- phenyl ethyl amine (72.6mg, 0.6mmol).Mp 139–141℃.1H NMR(400MHz,acetone-d6) δ 9.56 (d, J=9.5Hz, 1H), 9.06 (s, 1H), 8.34 (dd, J=6.7,3.2Hz, 1H), 7.74 (dd, J=8.4,5.5Hz, 1H), 7.69 (dd, J=7.2,4.6Hz, 1H), 7.45-7.34 (m, 3H), 7.28 (t, J=7.5Hz, 2H), 7.19 (t, J=7.3Hz, 1H), 7.13 (d, J=2.0Hz, 2H), 6.81 (s, 1H), 6.73 (s, 2H), 5.15-5.00 (m, 1H), 4.42 (dd, J=10.5,6.1Hz, 1H), 3.82 (s, 6H), 3.77 (s, 3H), 2.98 (dd, J= 15.3,6.9Hz, 1H), 2.72 (dd, J=15.4,6.4Hz, 1H), 2.25 (d, J=2.5Hz, 6H), 1.43 (dd, J=7.0, 1.5Hz,3H).13C NMR(150MHz,acetone-d6)δ171.84,169.37,167.69,165.76,157.36, 154.23,145.31,143.76,142.55,140.78,134.66,134.08,130.45,129.05,127.46,126.93, 126.42,122.72,120.80,116.54,114.27,105.94,60.60,56.52,50.44,49.23,34.89, 22.65,21.25.HRMS calcd.for C37H39N4O8(M+H+)667.27624；found 667.27484.
Embodiment 61(S)-N- [7- (3,5- dimethyl phenoxy) -3- [2- (4- methylpiperazine-1-yl) -2- oxo second Base] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 61)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (61) 0.2mmol) are prepared with N methyl piperazine (60.0mg, 0.6mmol).Mp 154–156℃.1H NMR(400MHz,methanol-d4)δ8.10(s,1H),7.46(s,1H),7.06(s,2H),6.80(s,1H),6.70(s, 2H), 4.45 (dd, J=8.4,5.1Hz, 1H), 3.84 (s, 6H), 3.82 (s, 3H), 3.75-3.56 (m, 4H), 3.19 (dd, J =16.3,8.5Hz, 1H), 2.79 (dd, J=16.3,5.1Hz, 1H), 2.65 (brs, 2H), 2.54 (brs, 2H), 2.42 (s, 3H),2.27(s,6H).13C NMR(100MHz,DMSO-d6)δ171.17,167.97,167.25,165.46,156.72, 153.04,145.76,141.01,139.82,133.54,133.18,129.61,125.72,123.84,120.39,117.96, 116.20,105.76,60.57,56.46,54.67,54.40,49.42,45.69,44.83,41.16,31.62, 21.32.HRMS calcd.for C34H40N5O8(M+H+)646.2877；found 646.2880.
Embodiment 62(S)-N- [3- [2- [(2- amino-ethyl) (ethyl) amino] -2- oxoethyl] -7- (3,5- diformazan Phenoxyl) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 62)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, It 0.2mmol) reacts with [(ethylamino) methyl] t-butyl carbamate (52.8mg, 0.6mmol), is removed through trifluoroacetic acid Boc is protected and is obtained.Mp 157–158℃.1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.98(s,1H),8.58(s, 1H),7.62(s,1H),7.23(s,1H),7.14(s,2H),6.76(s,1H),6.66(s,2H),4.20(brs,1H),3.80 (s,6H),3.70(s,3H),3.30–3.09(m,5H),3.06–2.86(m,3H),2.78–2.69(m,1H),2.22(s,6H), 1.16 (t, J=6.9Hz, 1H), 0.98 (t, J=6.2Hz, 1H)13C NMR(100MHz,DMSO-d6)δ170.94,168.62, 166.92,165.06,156.31,152.63,145.64,140.59,139.42,133.12,132.79,129.20,125.32, 123.57,119.94,117.88,115.87,105.43,60.19,56.11,49.32,49.15,42.44,31.33,20.93, 13.80,12.90.HRMS calcd.for C33H40N5O8(M+H+)634.28714；found 634.28595.
Embodiment 63(S)-N- [7- (3,5- dimethyl phenoxy) -3- [2- [ethyl (2- hydroxyethyl) amino] -2- oxygen For ethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 63)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (63) 0.2mmol) are prepared with (2- hydroxyethyl) ethylamine (53.4mg, 0.6mmol).Mp 148–150 ℃.1H NMR(400MHz,DMSO-d6) δ 10.45 (s, 1H), 9.87 (s, 1H), 8.53 (dd, J=14.7,5.4Hz, 1H), 7.65 (s, 1H), 7.24 (s, 1H), 7.11 (s, 2H), 6.77 (s, 1H), 6.67 (s, 2H), 4.76 (dt, J=113.7, 5.2Hz,1H),4.25–4.15(m,1H),3.80(s,6H),3.70(s,3H),3.65–3.54(m,1H),3.46–3.34(m, 3H), 3.31-3.20 (m, 2H), 3.01 (ddd, J=13.7,7.8,5.4Hz, 1H), 2.67 (ddd, J=22.7,17.0, 6.4Hz, 1H), 2.22 (s, 6H), 1.17 (t, J=7.0Hz, 1H), 0.99 (t, J=7.0Hz, 2H) .HRMS calcd.for C33H39N4O9(M+H+)635.27116；found 635.27008.
Embodiment 64(S)-N- [3- [2- [(cyano methyl) (ethyl) amino] -2- oxoethyl] -7- (3,5- dimethyl Phenoxy group) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 64)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (64) 0.2mmol) are prepared with (2- cyano ethyl) ethylamine (50.4mg, 0.6mmol).Mp 153–154 ℃.1H NMR(400MHz,DMSO-d6) δ 10.50 (s, 1H), 9.88 (s, 1H), 8.58 (d, J=5.2Hz, 1H), 7.66 (s, 1H), 7.25 (s, 1H), 7.11 (s, 2H), 6.77 (s, 1H), 6.67 (s, 2H), 4.35 (q, J=17.3Hz, 2H), 4.22 (dt, J=7.7,5.4Hz, 1H), 3.80 (s, 6H), 3.71 (s, 3H), 3.48 (q, J=7.1Hz, 2H), 3.05 (dd, J=16.6, 8.0Hz, 1H), 2.75 (dd, J=16.7,5.5Hz, 1H), 2.22 (s, 6H), 1.23 (t, J=7.0Hz, 3H) .HRMS calcd.for C33H36N5O8(M+H+)630.25584；found 630.25500.
Embodiment 65(S)-N- [3- [2- (azetidine -1- base) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 65)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (65) 0.2mmol) are prepared with azetidine (34.2mg, 0.6mmol).Mp 163–165℃.1H NMR(300MHz,DMSO-d6) δ 10.48 (s, 1H), 9.88 (s, 1H), 8.55 (d, J=5.4Hz, 1H), 7.64 (s, 1H), 7.23 (s, 1H), 7.11 (s, 2H), 6.77 (s, 1H), 6.66 (s, 2H), 4.15 (dt, J=13.6,6.8Hz, 3H), 3.86- 3.77 (m, 8H), 3.70 (s, 3H), 2.64 (dd, J=16.0,7.6Hz, 1H), 2.38 (dd, J=16.1,6.3Hz, 1H), 2.23–2.12(m,8H).13C NMR(75MHz,DMSO-d6)δ170.74,168.86,166.77,165.01,156.25, 152.60,145.31,140.57,139.39,133.11,132.69,129.17,125.30,123.31,119.92,117.43, 115.79,105.32,60.13,56.02,49.55,48.75,47.50,29.22,20.87,14.73.HRMS calcd.for C32H35N4O8(M+H+)603.24494；found 603.24371.
Embodiment 66(S)-N- [3- [2- (3- cyano azetidine -1- base) -2- oxoethyl] -7- (3,5- dimethyl Phenoxy group) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 66)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (66) 0.2mmol) are prepared with 3- cyano azetidine (49.2mg, 0.6mmol).Mp 175–177 ℃.1H NMR(400MHz,DMSO-d6) δ 10.52 (d, J=10.4Hz, 1H), 9.88 (s, 1H), 8.60-8.49 (m, 1H), 7.65 (s, 1H), 7.24 (s, 1H), 7.11 (s, 2H), 6.77 (s, 1H), 6.66 (s, 2H), 4.46 (ddd, J=19.3,9.3, 5.8Hz, 2H), 4.18-4.08 (m, 2H), 4.00 (dd, J=12.6,6.5Hz, 1H), 3.86-3.76 (m, 7H), 3.70 (s, 3H),2.70–2.57(m,1H),2.48–2.37(m,1H),2.22(s,6H).HRMS calcd.for C33H34N5O8(M+H+) 628.24019；found 628.23907.
Embodiment 67(S)-N- [7- (3,5- dimethyl phenoxy)-3- (2- morpholine -2-oxoethyl)-2,5- dioxo- 2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzamide (compound 67)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (67) 0.2mmol) are prepared with morpholine (52.2mg, 0.6mmol).Mp>300℃.1H NMR(400MHz, DMSO-d6) δ 10.47 (s, 1H), 9.88 (s, 1H), 8.56 (d, J=5.2Hz, 1H), 7.65 (s, 1H), 7.25 (s, 1H), 7.11 (s, 2H), 6.77 (s, 1H), 6.66 (s, 2H), 4.20 (dt, J=7.6,5.8Hz, 1H), 3.80 (s, 6H), 3.70 (s, 3H), 3.62 (brs, 2H), 3.54 (brs, 2H), 3.44 (brs, 4H), 2.96 (dd, J=16.5,8.1Hz, 1H), 2.66 (dd, J=16.9,5.6Hz, 1H), 2.22 (s, 6H)13C NMR(100MHz,DMSO-d6)δ170.73,167.80,166.78, 165.01,156.27,152.59,145.28,140.55,139.37,133.09,132.73,129.17,125.27,123.37, 119.95,117.46,115.76,105.31,66.01,65.93,60.12,56.01,48.96,45.32,41.57,31.06, 20.88.HRMS calcd.for C33H37N4O9(M+H+)633.25551；found 633.25470.
Embodiment 68(S)-N- [7- (3,5- dimethyl phenoxy) -3- [2- (1,1- dioxothiomorpholin -4- base) -2- oxygen For ethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 68)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (68) 0.2mmol) are prepared with 1,1- dioxothiomorpholin (81.0mg, 0.6mmol).Mp 189–191 ℃.1H NMR(400MHz,DMSO-d6) δ 10.54 (s, 1H), 9.89 (s, 1H), 8.52 (d, J=4.7Hz, 1H), 7.66 (s, 1H), 7.25 (s, 1H), 7.11 (s, 2H), 6.78 (s, 1H), 6.66 (s, 2H), 4.20 (dd, J=11.8,6.1Hz, 1H), 4.05(s,1H),3.94(s,1H),3.80(s,7H),3.70(s,3H),3.63(s,1H),3.42(s,1H),3.30(s,1H), 3.10-3.00 (m, 3H), 2.75 (dd, J=16.6,6.5Hz, 1H), 2.22 (s, 6H) .HRMS calcd.for C33H37N4O10S(M+H+)681.22249；found 681.22119.
Embodiment 69(S)-N- [7- (3,5- dimethyl phenoxy) -3- [2- (4- hydroxy piperidine -1- base) -2- oxo second Base] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 69)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (69) 0.2mmol) are prepared with 4- hydroxy piperidine (60.6mg, 0.6mmol).Mp 165–167℃.1H NMR(300MHz,DMSO-d6)δ10.45(s,1H),9.88(s,1H),8.54(s,1H),7.64(s,1H),7.24(s,1H), 7.11 (s, 2H), 6.77 (s, 1H), 6.66 (s, 2H), 4.78 (d, J=3.7Hz, 1H), 4.19 (dt, J=7.7,5.3Hz, 1H),3.97–3.84(m,1H),3.80(s,6H),3.74–3.60(m,5H),3.17(brs,1H),2.96(brs,2H), 2.69–2.54(m,1H),2.22(s,6H),1.77(brs,1H),1.64(brs,1H),1.41(brs,1H),1.24(brs, 1H).HRMS calcd.for C34H39N4O9(M+H+)647.27116；found 647.26947.
Embodiment 70(S)-N- [3- [2- (4- amino piperidine -1- base) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 70)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, It 0.2mmol) is reacted with piperidin-4-yl t-butyl carbamate (60.0mg, 0.6mmol), through trifluoroacetic acid removing Boc protection Obtain title compound (70).Mp 258–260℃.1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.93(s,1H), 8.55(s,1H),7.64(s,1H),7.24(s,1H),7.12(s,2H),6.77(s,1H),6.66(s,2H),5.75(brs, 2H),4.27–4.14(m,2H),3.86–3.75(m,7H),3.70(s,3H),3.16–2.93(m,3H),2.74–2.59(m, 2H),2.22(s,6H),1.91–1.74(m,2H),1.41–1.11(m,2H).HRMS calcd.for C34H40N5O8(M+H+) 646.28714；found 646.28589.
Embodiment 71(S)-N- [7- (3,5- dimethyl phenoxy) -3- [2- [4- (methyl sulphonyl) piperidin-1-yl] -2- Oxoethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 71)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (71) 0.2mmol) are prepared with 4- (methyl sulphonyl) piperidines (97.8mg, 0.6mmol).Mp 172–173 ℃.1H NMR(400MHz,DMSO-d6) δ 10.48 (d, J=7.3Hz, 1H), 9.89 (s, 1H), 8.56 (dd, J=15.6, 4.9Hz,1H),7.64(s,1H),7.24(s,1H),7.11(s,2H),6.77(s,1H),6.66(s,2H),4.44(brs, 1H), 4.20 (brs, 1H), 3.96 (t, J=12.1Hz, 1H), 3.80 (s, 6H), 3.70 (s, 3H), 3.40-3.35 (m, 1H), 3.18-2.98 (m, 2H), 2.94 (s, 3H), 2.76-2.61 (m, 2H), 2.22 (s, 6H), 2.07 (dd, J=31.1,14.2Hz, 2H),1.65(brs,1H),1.39(brs,1H).HRMS calcd.for C35H41N4O10S(M+H+)709.25379； found 709.25311.
Embodiment 72(S)-N- [7- (3,5- dimethyl phenoxy) -3- [(3- methyl-1,2,4- oxadiazoles -5- base) first Base] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 72)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, 0.2mmol) corresponding intermediate is prepared with N- hydroxyl acetamidine (44.5mg, 0.6mmol).By above-mentioned intermediate (123.9mg, 0.2mmol) it is dissolved in 2mL pyridine, back flow reaction 5h.Silica gel column chromatography, DCM/MeOH elution, obtains faint yellow solid 33.9mg, receives Rate 28.2%.Mp 139–141℃.1H NMR(300MHz,DMSO-d6) δ 10.62 (s, 1H), 9.88 (s, 1H), 8.76 (d, J= 4.7Hz, 1H), 7.68 (s, 1H), 7.26 (s, 1H), 7.10 (s, 2H), 6.77 (s, 1H), 6.67 (s, 2H), 4.42 (dt, J= 6.9,5.9Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.43 (dd, J=17.1,7.9Hz, 1H), 3.26 (dd, J= 17.1,5.9Hz,1H),2.28(s,3H),2.22(s,6H).HRMS calcd.for C31H32N5O8(M+H+)602.2251； found 602.2240.
Embodiment 73(S)-N- [7- (3,5- dimethyl phenoxy) -3- [(3- ethyl -1,2,4- oxadiazoles -5- base) first Base] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 73)
According to 72 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (73) 0.2mmol) are prepared with the third amidine of N- hydroxyl (52.9mg, 0.6mmol).Mp 128–130℃.1H NMR(300MHz,DMSO-d6) δ 10.63 (s, 1H), 9.88 (s, 1H), 8.76 (d, J=4.9Hz, 1H), 7.68 (s, 1H), 7.26 (s, 1H), 7.11 (s, 2H), 6.77 (s, 1H), 6.67 (s, 2H), 4.42 (dt, J=6.9,5.9Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.44 (dd, J=16.6,7.6Hz, 1H), 3.26 (dd, J=17.1,5.9Hz, 1H), 2.66 (q, J= 7.4Hz, 2H), 2.22 (s, 6H), 1.17 (t, J=7.5Hz, 3H)13C NMR(100MHz,DMSO-d6)δ176.53, 170.94,169.98,166.63,165.05,156.21,152.60,145.44,140.59,139.39,133.25,132.49, 129.14,125.33,123.14,119.99,117.46,115.83,105.32,60.12,56.01,49.50,25.53, 20.87,18.99,11.12.HRMS calcd.for C32H34N5O8(M+H+)616.24019；found 616.23810.
Embodiment 74(S)-N- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -3- [(dihydro -1 5- oxo -4,5-, 3,4- oxadiazoles -2- base) methyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 74)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, (S)-N- [7- (3,5- dimethyl phenoxy) -3- (2- hydrazine 0.2mmol) is prepared with hydrazine hydrate (30.0mg, 0.6mmol) Base -2- oxoethyl) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- three Methoxy benzamide (intermediate 230).
Target compound (74): intermediate (230) (115.5mg, 0.2mmol) and CDI (162mg, 1.0mmol) is dissolved in 2mL THF is added triethylamine (139 μ L, 1.0mmol), 50 DEG C of reaction 1h.Silica gel column chromatography, DCM/MeOH elution, obtains white solid Body 41.8mg, yield 34.6%.Mp 265–267℃.1H NMR(300MHz,DMSO-d6)δ12.12(s,1H),10.61(s, 1H), 9.86 (s, 1H), 8.68 (d, J=5.4Hz, 1H), 7.67 (s, 1H), 7.24 (s, 1H), 7.10 (s, 2H), 6.77 (s, 1H), 6.66 (s, 2H), 4.23 (dt, J=7.0,6.0Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.11 (dd, J= 16.7,6.7Hz, 1H), 2.92 (dd, J=16.5,7.5Hz, 1H), 2.21 (s, 6H)13C NMR(150MHz,DMSO-d6)δ 169.93,166.61,164.99,156.16,154.79,154.27,152.57,145.36,140.55,139.36,133.19, 132.50,129.14,125.31,123.11,119.89,117.42,115.82,105.30,60.11,56.00,48.48, 25.12,20.87.HRMS calcd.for C30H30N5O9(M+H+)604.20380；found 604.20333.
Embodiment 75(S)-N- [3- [2- (2- acetyl group diazanyl) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) - 2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzamide (compound 75)
Intermediate (230) (231mg, 0.4mmol) is dissolved in 4mL THF, sequentially add acetic anhydride (76 μ L, 0.8mmol), Triethylamine (111 μ L, 0.8mmol) reacts at room temperature 3h.Silica gel column chromatography, DCM/MeOH elution, obtains faint yellow solid 187mg, receives Rate 73.9%.Mp 159–161℃.1H NMR(300MHz,DMSO-d6)δ10.49(s,1H),9.90(s,1H),9.86(s, 1H), 9.77 (s, 1H), 8.62 (d, J=5.4Hz, 1H), 7.65 (s, 1H), 7.25 (s, 1H), 7.11 (s, 2H), 6.77 (s, 1H), 6.67 (s, 2H), 4.18 (dt, J=7.6,5.6Hz, 1H), 3.80 (s, 6H), 3.71 (s, 3H), 2.86 (dd, J= 16.0,7.7Hz, 1H), 2.55 (dd, J=16.0,6.1Hz, 1H), 2.22 (s, 6H), 1.82 (s, 3H)13C NMR(100MHz, DMSO-d6)δ170.55,167.99,167.88,166.83,165.03,156.29,152.62,145.25,140.59, 139.41,133.16,132.73,129.19,125.29,123.33,120.04,117.39,115.76,105.32,60.15, 56.03,48.73,31.84,20.90.HRMS calcd.for C31H34N5O9(M+H+)620.23510；found 620.23267.
Embodiment 76(S)-N- [7- (3,5- dimethyl phenoxy)-3- [(5- Methyl-1,3,4-oxadiazole-2-2- base) first Base] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 76)
Iodine (127mg, 0.5mmol), triphenylphosphine (132mg, 0.5mmol) are dissolved in 1mL DCM, triethylamine (139 is added μ L, 1.0mmol), react at room temperature 5min.The title compound (75) (124mg, 0.2mmol) that embodiment 75 is prepared is molten In 2mL DCM, it is added dropwise to above-mentioned solution, reacts at room temperature 1h.Silica gel column chromatography, DCM/MeOH elution, obtains yellow solid 75.2mg, Yield 62.5%.Mp 136–138℃.1H NMR(300MHz,DMSO-d6)δ10.61(s,1H),9.87(s,1H),8.72(d,J =5.1Hz, 1H), 7.68 (s, 1H), 7.26 (s, 1H), 7.10 (s, 2H), 6.77 (s, 1H), 6.67 (s, 2H), 4.44-4.31 (m, 1H), 3.80 (s, 6H), 3.70 (s, 3H), 3.42-3.34 (m, 1H), 3.18 (dd, J=10.1,6.0Hz, 1H), 2.45 (s,3H),2.22(s,6H).13C NMR(151MHz,DMSO-d6)δ169.97,166.63,165.01,163.68,163.50, 156.17,152.58,145.36,140.56,139.37,133.20,132.52,129.14,125.31,123.17,119.94, 117.45,115.80,105.30,60.11,56.00,49.27,24.26,20.87,10.38.HRMS calcd.for C31H32N5O8(M+H+)602.22454；found 602.22290.
Embodiment 77(S)-N- [7- (3,5- dimethyl phenoxy) -3- [(5- ethyl -1,3,4- oxadiazoles -2- base) first Base] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 77)
According to 76 the method for embodiment 75 and embodiment, using intermediate 230 (231.0mg, 0.4mmol) and propionic andydride Title compound (77) are prepared in (104.1mg, 0.8mmol).Mp 132–134℃.1H NMR(300MHz,DMSO-d6)δ 10.61 (s, 1H), 9.87 (s, 1H), 8.72 (d, J=5.0Hz, 1H), 7.68 (s, 1H), 7.26 (s, 1H), 7.11 (s, 2H), 6.77(s,1H),6.67(s,2H),4.45–4.34(m,1H),3.80(s,6H),3.70(s,3H),3.42–3.34(m,1H), 3.17 (dd, J=16.4,7.2Hz, 1H), 2.81 (q, J=7.5Hz, 2H), 2.22 (s, 6H), 1.23 (t, J=7.6Hz, 3H) .HRMS calcd.for C32H34N5O8(M+H+)616.24019；found 616.23810.
Embodiment 78(S)-N- [3- (cyano methyl) -7- (3,5- dimethyl phenoxy) -2,5- dioxo -2,3,4,5- Tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzamide (compound 78)
The title compound (54) (1.13g, 2.0mmol) that embodiment 54 prepares is dissolved in 20mL THF, successively plus Enter pyridine (809 μ L, 10.0mmol), trifluoroacetic anhydride (1.41mL, 10.0mmol), reacts at room temperature 20min.Silica gel column chromatography, DCM/MeOH elution, obtains faint yellow solid 750mg, yield 68.9%.Mp 250–252℃.1H NMR(300MHz,DMSO-d6)δ 10.69 (s, 1H), 9.86 (s, 1H), 8.82 (d, J=5.3Hz, 1H), 7.69 (s, 1H), 7.26 (s, 1H), 7.09 (s, 2H), 6.76 (s, 1H), 6.64 (s, 2H), 4.29 (dt, J=8.5,5.5Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 2.95 (dd, J=16.8,5.7Hz, 1H), 2.82 (dd, J=16.8,8.7Hz, 1H), 2.21 (s, 6H)13C NMR(150MHz,DMSO-d6) δ169.52,166.61,164.97,156.24,152.56,145.14,140.56,139.34,133.36,132.49, 129.11,125.22,122.98,120.18,118.21,117.38,115.58,105.29,60.10,55.99,48.93, 20.87,17.13.HRMS calcd.for C29H29N4O7(M+H+)545.20308；found 545.20184.
Embodiment 79(S)-N- [7- (3,5- dimethyl phenoxy) -3- [(5- methyl-1,2,4- oxadiazoles -3- base) first Base] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 79)
(S, Z)-N- [3- [2- amino -2- (oxyimino) ethyl] -7- (3,5- dimethyl phenoxy) -2,5- dioxy Generation -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzamide (intermediate 231) preparation:
The title compound (78) (217.8mg, 0.4mmol) that embodiment 78 prepares is dissolved in 4mL ethyl alcohol, successively plus Hydroxylamine hydrochloride (30.6mg, 0.44mmol), triethylamine (61 μ L, 0.44mmol), back flow reaction 3h.Silica gel column chromatography, DCM- MeOH elution, obtains pale solid 209mg, yield 90.6%.Mp 160–162℃.1H NMR(300MHz,DMSO-d6)δ 10.48 (s, 1H), 9.87 (s, 1H), 9.15 (s, 1H), 8.44 (d, J=5.2Hz, 1H), 7.61 (s, 1H), 7.24 (s, 1H), 7.09(s,2H),6.76(s,1H),6.63(s,2H),5.75(s,2H),4.23–4.12(m,1H),3.79(s,6H),3.70 (s, 3H), 2.71 (dd, J=15.1,7.3Hz, 1H), 2.39 (dd, J=15.5,6.1Hz, 1H), 2.21 (s, 6H)13C NMR (150MHz,DMSO-d6)δ170.64,166.63,165.06,156.28,152.58,145.20,140.56,139.35, 133.05,132.77,129.11,125.24,123.45,120.08,117.54,115.66,105.30,60.11,56.01, 48.75,29.24,20.87.HRMS calcd.for C29H32N5O8(M+H+)578.22454；found 578.22272.
Target compound (79): (intermediate 231) (115.5mg, 0.2mmol) is dissolved in 2mL pyridine, acetic anhydride is added (21 μ L, 0.22mmol), 90 DEG C of reactions are for 24 hours.Silica gel column chromatography, DCM/MeOH elution, obtains red brown solid 48.5mg, yield 40.3%.Mp 132–134℃.1H NMR(300MHz,DMSO-d6) δ 10.56 (s, 1H), 9.87 (s, 1H), 8.70 (d, J= 5.3Hz, 1H), 7.66 (s, 1H), 7.24 (s, 1H), 7.10 (s, 2H), 6.77 (s, 1H), 6.66 (s, 2H), 4.31 (dt, J= 7.0,6.0Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.24 (dd, J=15.9,7.6Hz, 1H), 3.05 (dd, J= 16.2,6.7Hz,1H),2.53(s,3H),2.21(s,6H).HRMS calcd.for C31H32N5O8(M+H+)602.22454； found 602.22296.
Embodiment 80(S)-N- [7- (3,5- dimethyl phenoxy) -3- [(5- ethyl -1,2,4- oxadiazoles -3- base) first Base] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 80)
According to 79 the method for embodiment, using intermediate 231 (115.5mg, 0.2mmol) and propionic andydride (28.6mg, Title compound (80) 0.22mmol) are prepared.Mp 117–119℃.1H NMR(300MHz,DMSO-d6)δ10.57(s, 1H), 9.87 (s, 1H), 8.69 (d, J=5.5Hz, 1H), 7.66 (s, 1H), 7.24 (s, 1H), 7.10 (s, 2H), 6.77 (s, 1H), 6.66 (s, 2H), 4.31 (dt, J=7.0,6.0Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.27 (dd, J= 16.3,7.4Hz, 1H), 3.06 (dd, J=16.1,6.6Hz, 1H), 2.89 (q, J=7.6Hz, 2H), 2.21 (s, 6H), 1.23 (t, J=7.5Hz, 3H)13C NMR(150MHz,DMSO-d6)δ180.43,170.08,167.17,166.62,165.03, 156.19,152.59,145.39,140.57,139.37,133.16,132.57,129.14,125.31,123.27,119.91, 117.45,115.82,105.30,60.12,56.01,49.51,25.03,20.87,19.37,10.43.HRMS calcd.for C32H34N5O8(M+H+)616.24019；found 616.23773.
Embodiment 81(S)-N- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -3- [(5- Trifluoromethyl-1,2,4- Oxadiazoles -3- base) methyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene Formamide (compound 81)
According to 79 the method for embodiment, using intermediate 231 (115.5mg, 0.2mmol) and trifluoroacetic anhydride Title compound (81) are prepared in (46.0mg, 0.22mmol).Mp 129–131℃.1H NMR(300MHz,DMSO-d6)δ 10.64 (s, 1H), 9.87 (s, 1H), 8.75 (d, J=5.1Hz, 1H), 7.68 (s, 1H), 7.24 (s, 1H), 7.10 (s, 2H), 6.77 (s, 1H), 6.66 (s, 2H), 4.39 (q, J=6.8Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.46 (dd, J= 16.2,7.1Hz, 1H), 3.25 (dd, J=16.0,7.4Hz, 1H), 2.21 (s, 6H)13C NMR(150MHz,DMSO-d6)δ 169.93,168.75,166.65,165.03,156.17,152.58,145.42,140.57,139.37,133.22,132.48, 129.14,125.33,123.14,119.91,117.43,115.83,105.31,60.11,56.01,49.42,25.01, 20.85.HRMS calcd.for C31H29F3N5O8(M+H+)656.19627；found 656.19495.
Embodiment 82(S)-N- [7- (3,5- dimethyl phenoxy) -3- [(1- methyl-1 H-1,2,4- triazole -5- base) first Base] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 82)
The title compound (54) (112.5mg, 0.2mmol) that embodiment 54 prepares is dissolved in 2mL DMF, adds 2mL DMFDMA reacts at room temperature 1h.Reaction solution is evaporated, adds 5mL glacial acetic acid to dissolve, adds 40% methyl hydrazine solution, 240 μ L, CEM microwave Synthesizer reaction, reacts 10min by 70 DEG C, 50W.Silica gel column chromatography, DCM/MeOH elution, obtains faint yellow solid 41.2mg, yield 35.9%.Mp 144–146℃.1H NMR(300MHz,DMSO-d6) δ 10.54 (s, 1H), 9.87 (s, 1H), 8.64 (d, J= 4.7Hz,1H),7.75(s,1H),7.66(s,1H),7.25(s,1H),7.11(s,2H),6.77(s,1H),6.67(s,2H), 4.42 (q, J=6.3Hz, 1H), 3.81 (s, 3H), 3.79 (s, 6H), 3.70 (s, 3H), 3.25 (dd, J=16.2,7.1Hz, 1H), 3.06 (dd, J=16.1,7.0Hz, 1H), 2.22 (s, 6H)13C NMR(150MHz,DMSO-d6)δ170.42, 166.67,165.02,156.18,152.58,152.15,149.48,145.41,140.55,139.38,133.13,132.62, 129.15,125.34,123.23,119.86,117.48,115.87,105.30,60.11,56.01,50.27,34.90, 24.12,20.87.HRMS calcd.for C31H33N6O7(M+H+)601.24052；found 601.23938.
Embodiment 83(S)-N- [3- [(1H-TETRAZOLE -5- base) methyl] -7- (3,5- dimethyl phenoxy) -2,5- dioxy Generation -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzamide (compound 83)
40 μ L of glacial acetic acid is dissolved in 200 μ L DMF, adds 90 μ L triethylamines, 5min is stirred at room temperature.It prepared by embodiment 78 Title compound (78) (109mg, 0.2mmol), Sodium azide (78mg, 1.2mmol), the ammonium chloride (64mg, 1.2mmol) of acquisition It is mixed in 800 μ L DMF, is added dropwise to above-mentioned solution, 90 DEG C of reaction 18h.Silica gel column chromatography, DCM/HOAc elution, obtains faint yellow Solid 77.2mg, yield 65.7%.1H NMR(300MHz,DMSO-d6) δ 10.44 (s, 1H), 9.87 (s, 1H), 8.43 (d, J= 3.9Hz, 1H), 7.64 (s, 1H), 7.22 (s, 1H), 7.11 (s, 2H), 6.75 (s, 1H), 6.65 (s, 2H), 4.27 (dd, J= 12.2,6.9Hz, 1H), 3.79 (s, 6H), 3.69 (s, 3H), 3.21 (dd, J=15.6,6.4Hz, 1H), 2.98 (dd, J= 14.4,5.8Hz,1H),2.20(s,6H).HRMS calcd.for C29H30N7O7(M+H+)588.22012；found 588.21863.
Embodiment 84(S)-N- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -3- [(dihydro -1 5- oxo -4,5-, 2,4- oxadiazoles -3- base) methyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 84)
Intermediate (231) (115.5mg, 0.2mmol) is dissolved in 2mL pyridine, chlorination Ethyl formate (38 μ L, 0.4mmol), 90 DEG C of reaction 48h.Silica gel column chromatography, DCM/MeOH elution, obtains faint yellow solid 26.7mg, yield 22.1%.Mp 173–175 ℃.1H NMR(300MHz,DMSO-d6) δ 12.25 (brs, 1H), 10.62 (s, 1H), 9.87 (s, 1H), 8.71 (d, J= 4.9Hz, 1H), 7.66 (s, 1H), 7.25 (s, 1H), 7.10 (s, 2H), 6.77 (s, 1H), 6.65 (s, 2H), 4.26 (q, J= 7.1Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.10 (dd, J=16.3,7.0Hz, 1H), 2.91 (dd, J=16.0, 7.4Hz,1H),2.21(s,6H).13C NMR(150MHz,DMSO-d6)δ169.94,166.64,165.02,159.61, 157.29,156.17,152.58,145.40,140.57,139.37,133.20,132.46,129.13,125.32,123.21, 120.02,117.50,115.79,105.31,60.12,56.02,48.20,24.14,20.88.HRMS calcd.for C30H30N5O9(M+H+)604.20380；found 604.20215.
Embodiment 85(S)-N- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -3- [2- oxo -2- (propyl- 2- alkynes - 1- base amino) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 85)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (85) 0.2mmol) are prepared with allyl amine (54.9mg, 0.6mmol).Mp 143–145℃.1H NMR (300MHz,DMSO-d6) δ 10.46 (s, 1H), 9.86 (s, 1H), 8.60 (d, J=5.2Hz, 1H), 8.48 (t, J=4.8Hz, 1H), 7.65 (s, 1H), 7.25 (s, 1H), 7.11 (s, 2H), 6.77 (s, 1H), 6.67 (s, 2H), 4.17 (dt, J=7.8, 5.3Hz, 1H), 3.94-3.75 (m, 8H), 3.71 (s, 3H), 3.10 (s, 1H), 2.81 (dd, J=15.9,8.2Hz, 1H), 2.49–2.42(m,1H),2.22(s,6H).HRMS calcd.for C32H33N4O8(M+H+)601.22929；found 601.22772.
Embodiment 86(S)-N- [7- (3,5- dimethyl phenoxy) -3- [2- [(the amyl- 1- alkynes -3- base of 3- ethyl) amino] - 2- oxoethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- front three Oxybenzamide (compound 86)
According to 53 the method for embodiment, the title compound 50 prepared using embodiment 50 (112.7mg, Title compound (86) 0.2mmol) are prepared with 1,1- Diethyl Allylnime (66.7mg, 0.6mmol).Mp 130–132 ℃.1H NMR(300MHz,DMSO-d6) δ 10.45 (s, 1H), 9.86 (s, 1H), 8.60 (d, J=5.2Hz, 1H), 7.86 (s, 1H), 7.66 (s, 1H), 7.25 (s, 1H), 7.11 (s, 2H), 6.77 (s, 1H), 6.66 (s, 2H), 4.12 (dt, J=8.2, 6.1Hz, 1H), 3.80 (s, 6H), 3.71 (s, 3H), 3.16 (s, 1H), 2.86 (dd, J=14.5,7.3Hz, 1H), 2.47- 2.39(m,1H),2.22(s,6H),2.01–1.88(m,2H),1.76–1.59(m,2H),0.91–0.84(m,6H).HRMS calcd.for C36H41N4O8(M+H+)657.29189；found 657.29114.
Embodiment 87(S)-N- [3- [(4,4- diethyl -5- methylene -4,5- dihydro-oxazole -2- base) methyl] -7- (3, 5- dimethyl phenoxy) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- Trimethoxy-benzamide (compound 87)
The title compound (86) (131.3mg, 0.2mmol) that embodiment 86 prepares is dissolved in 2mL DCM, is added three Fluorine methanesulfonic acid (35 μ L, 0.4mmol), the reaction of CEM microwave synthesizer, react 40min by 70 DEG C, 200W.Silica gel column chromatography, DCM/ MeOH elution, obtains faint yellow solid 37.2mg, yield 28.3%.Mp 117–119℃.1H NMR(600MHz,DMSO-d6)δ 10.53 (s, 1H), 9.79 (s, 1H), 8.59 (d, J=5.4Hz, 1H), 7.59 (s, 1H), 7.18 (s, 1H), 7.06 (s, 2H), 6.72 (s, 1H), 6.62 (s, 2H), 4.65 (d, J=2.6Hz, 1H), 4.20 (dt, J=9.2,5.2Hz, 1H), 4.13 (d, J= 2.6Hz, 1H), 3.77 (s, 6H), 3.68 (s, 3H), 2.91 (dd, J=16.5,9.1Hz, 1H), 2.73 (dd, J=16.5, 5.0Hz, 1H), 2.20 (s, 6H), 1.64-1.58 (m, 2H), 1.43-1.37 (m, 2H), 0.62 (t, J=6.9Hz, 6H) .HRMS calcd.for C36H41N4O8(M+H+)657.29189；found 657.29065.
Embodiment 88(S) the bromo- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 88)
(S) -2- [8- amino -7- (3,5- dimethyl phenoxy) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base]-N, the preparation of N- diethyl acetamide (intermediate 232): by intermediate (191) (767mg, It 2.0mmol) is mixed with lithium hydroxide (144mg, 6.0mmol), adds 20mL water and 20mL THF, react at room temperature 30min.Decompression is steamed Except THF, 1M hydrochloric acid tune pH to acidity, precipitating is precipitated, filters, it is dry.By gained white solid and DIC (630 μ L, 4.0mmol), HOSu (460mg, 4.0mmol) is mixed in 20mL THF, reacts at room temperature 12h.It is added diethylamine (620 μ L, 6.0mmol), after Continuous reaction 1h.Silica gel column chromatography, DCM/MeOH elution, obtains faint yellow solid 508mg, yield 59.8%.1H NMR(400MHz, DMSO-d6) δ 10.11 (d, J=2.1Hz, 1H), 8.09 (s, 1H), 7.01 (d, J=3.5Hz, 1H), 6.74 (s, 1H), 6.60 (s, 2H), 6.43 (d, J=2.9Hz, 1H), 5.72 (s, 2H), 4.14 (dd, J=5.4,2.7Hz, 1H), 3.32-3.16 (m, 4H), 2.96 (dd, J=16.1,8.6Hz, 1H), 2.55 (dd, J=16.4,4.8Hz, 1H), 2.24 (s, 6H), 1.16 (t, J= 7.0Hz, 3H), 0.98 (t, J=7.0Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.79,168.09,167.54, 157.04,144.26,139.27,139.16,134.30,124.62,120.39,115.29,113.73,105.53,49.14, 41.37,31.35,20.96,13.94,13.06.
The preparation of the bromo- 3,4,5- trimethoxybenzoic acid (intermediate 233) of 2-: by 3,4,5- trimethoxybenzoic acid (2.12g, 10.0mmol) is dissolved in 100mL chloroform, is added bromine water (1.0mL, 20.0mmol), back flow reaction 5h.Reaction solution is successively With saturated sodium thiosulfate solution, washing, divides and organic phase is taken to be evaporated, water and ethyl alcohol recrystallization obtain white solid 2.74g, yield 94.2%.1H NMR(400MHz,DMSO-d6)δ13.31(brs,1H),7.17(s,1H),3.83(s,3H),3.82(s,3H), 3.78(s,3H).
Target compound (88): intermediate 233 (145.5mg, 0.5mmol) is dissolved in 5mL DCM, sequentially adds DMF 20 μ L, oxalyl chloride (129 μ L, 1.5mmol), 40 DEG C of reaction 1h.Reaction solution is evaporated, is recrystallized using 50mL petroleum ether.It will be above-mentioned Gained white solid and 232 (85mg, 0.2mmol), pyridine (49 μ L, 0.6mmol) are mixed in 2mL THF, back flow reaction 1h. Silica gel column chromatography, DCM/MeOH elution, obtains yellow oily liquid 119mg, yield 85.5%.Mp 148–150℃.1H NMR (400MHz,DMSO-d6) δ 10.38 (s, 1H), 10.22 (s, 1H), 8.52 (d, J=5.4Hz, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 6.82 (s, 1H), 6.68 (s, 2H), 4.19 (dt, J=9.4,5.2Hz, 1H), 3.80 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.31-3.13 (m, 4H), 2.99 (dd, J=16.2,8.6Hz, 1H), 2.60 (dd, J= 16.3,4.9Hz, 1H), 2.26 (s, 6H), 1.17 (t, J=7.0Hz, 3H), 0.99 (t, J=7.0Hz, 4H)13C NMR (100MHz,DMSO-d6)δ170.76,167.90,166.78,165.88,156.20,152.52,150.27,144.28, 143.59,139.33,133.94,132.74,132.61,125.37,122.90,119.10,116.37,115.52,108.29, 105.66,60.85,60.73,56.22,48.99,41.33,31.21,20.85,13.89,13.02.HRMS calcd.for C33H38BrN3O9(M+H+)697.18675；found 697.18378.
Embodiment 89(R) the bromo- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 89)
Then, according to 88 the method for embodiment, using intermediate 192 (76.7mg, 0.2mmol), diethylamine Title compound (89): Mp are prepared through three-step reaction in (43.8mg, 0.6mmol) and 233 (145.5mg, 0.5mmol) 146–148℃.1H NMR(400MHz,DMSO-d6) δ 10.38 (s, 1H), 10.21 (s, 1H), 8.51 (d, J=4.9Hz, 1H), 8.01 (s, 1H), 7.15 (s, 1H), 6.82 (s, 2H), 6.68 (s, 2H), 4.18 (dd, J=11.4,5.5Hz, 1H), 3.79 (s, 6H), 3.77 (s, 3H), 3.36-3.18 (m, 4H), 2.98 (dd, J=16.0,8.5Hz, 1H), 2.60 (dd, J=16.1, 3.5Hz, 1H), 2.25 (s, 6H), 1.17 (t, J=6.7Hz, 3H), 0.99 (t, J=6.8Hz, 3H)13C NMR(100MHz, DMSO-d6)δ170.77,167.91,166.79,165.89,156.21,152.53,150.29,144.29,143.61, 139.35,133.95,132.76,132.63,125.39,122.91,119.12,116.38,115.52,108.30,105.68, 60.86,60.73,56.22,49.00,41.34,31.22,20.85,13.89,13.02.HRMS calcd.for C33H38BrN4O8(M+H+)697.18675；found 697.18524.
Embodiment 90(S) the chloro- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] the fluoro- 3,4,5- trimethoxy of -6- Benzamide (compound 90)
The preparation of the fluoro- 3,4,5- trimethoxybenzoic acid (intermediate 235) of 2-: by 3,4,5- trimethoxy-benzoyl chloride (4.61g, 20.0mmol) is dissolved in 20mL methanol, is added triethylamine (4.17mL, 30.0mmol), reacts at room temperature 5h.Solvent is evaporated off, Add 200mL DCM to dissolve, successively use 1M hydrochloric acid, saturated sodium bicarbonate solution, washing, organic phase is concentrated, it is dry, obtain yellow solid 3.64g, yield 80.4%.Above-mentioned solid (2.26g, 10.0mmol) is dissolved in 100mL acetonitrile, adds selectfluor reagent (7.08g, 20.0mmol), argon gas protection, back flow reaction 1h.Silica gel column chromatography, DCM/MeOH elution, obtains pale yellow oily liquid 810mg, yield 33.2%.Above-mentioned oily liquids (488mg, 2.0mmol) and lithium hydroxide (144mg, 6.0mmol) is mixed in In 10mL water and 10mL THF, 30min is reacted at room temperature.THF, 1M hydrochloric acid tune pH value to acidity is evaporated off, DCM is extracted three times, merged Organic phase is evaporated to obtain brown solid 413mg, yield 89.6%.
The preparation of the fluoro- 3,4,5- trimethoxybenzoic acid (236) of the chloro- 6- of 2-: by intermediate (235) (460mg, It 2.0mmol) is dissolved in 20mL chloroform and 10mL glacial acetic acid with NCS (267mg, 2.0mmol), back flow reaction 12h.Reaction solution is steamed Dry, water and ethyl alcohol recrystallization obtain faint yellow solid 273mg, yield 51.6%.
Target compound (90): according to 88 the method for embodiment, using intermediate 232 (85.0mg, 0.2mmol) in Mesosome 236 (132.0mg, 0.5mmo) preparation.Mp 154–156℃.1H NMR(400MHz,DMSO-d6)δ10.67(s,1H), 10.31 (s, 1H), 8.49 (d, J=5.3Hz, 1H), 8.11 (s, 1H), 7.09 (s, 1H), 6.83 (s, 1H), 6.71 (s, 2H), 4.17 (dt, J=7.4,5.0Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.80 (s, 3H), 3.37-3.18 (m, 4H), 2.96 (dd, J=16.2,8.5Hz, 1H), 2.58 (dd, J=16.2,4.7Hz, 1H), 2.25 (s, 6H), 1.15 (t, J= 6.9Hz, 3H), 0.98 (t, J=6.9Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.71,167.87,166.70, (160.48,155.93,149.79,148.02 d, J=5.1Hz), 147.36,145.99 (d, J=3.2Hz), 144.46, 140.38 (d, J=13.1Hz), 139.41,132.22 (d, J=29.6Hz), 125.74,122.92,121.50 (d, J= 21.8Hz), 118.58 (d, J=8.0Hz), 118.40,117.10,114.88,61.73 (d, J=3.4Hz), 61.45, 61.09,48.96,41.33,31.20,20.82,13.88,13.01.HRMS calcd.for C33H37ClFN4O8(M+H+) 671.22785；found 671.22717.
Embodiment 91(S) the chloro- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 91)
The preparation of the chloro- 3,4,5- trimethoxybenzoic acid (intermediate 237) of 2-: by 3,4,5- trimethoxybenzoic acid (2.12g, 10.0mmol) is dissolved in 50mL chloroform and 25mL glacial acetic acid, is added NCS (1.34g, 10.0mmol), back flow reaction 5h. Reaction solution is evaporated, water and ethyl alcohol recrystallization, obtains white solid 1.80g, yield 73.1%.1H NMR(400MHz,DMSO-d6)δ 13.31(s,1H),7.20(s,1H),3.84(s,3H),3.83(s,3H),3.80(s,3H).13C NMR(100MHz,DMSO- d6)δ166.32,151.58,149.74,145.13,126.79,118.36,109.42,60.91,60.79,56.15.
Target compound (91) is according to 88 the method for embodiment, using intermediate 232 (85.0mg, 0.2mmol) in Mesosome 237 (123.0mg, 0.5mmol) preparation.Mp 142–143℃.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H), 10.22 (s, 1H), 8.52 (d, J=5.4Hz, 1H), 8.00 (s, 1H), 7.16 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), (6.68 s, 2H), 4.18 (dt, J=8.8,5.2Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.31- 3.16 (m, 4H), 2.98 (dd, J=16.2,8.5Hz, 1H), 2.60 (dd, J=16.3,4.8Hz, 1H), 2.25 (s, 6H), 1.17 (t, J=7.0Hz, 3H), 0.99 (t, J=7.0Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.76,167.91, 166.78,164.89,156.20,151.90,149.35,144.28,143.90,139.35,132.72,132.67,131.59, 125.39,122.95,119.17,116.31,115.58,107.99,61.00,60.77,56.21,49.01,41.35, 31.24,20.86,13.90,13.04.HRMS calcd.for C33H38ClN4O8(M+H+)653.23727；found 653.23596.
Embodiment 92(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -2, 5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3- (difluoro-methoxy) -4,5- dimethoxy Yl-benzamide (compound 92)
The preparation of 3- (difluoro-methoxy) -4,5- dimethoxybenzoic acid (intermediate 238): by 3- hydroxyl -4,5- diformazan P-methoxybenzoic acid (300mg, 1.52mmol) is dissolved in 20mL methanol, adds thionyl chloride 1mL, reacts at room temperature 12h.Reaction solution is steamed It is dry, add 50mL DCM to dissolve, successively with saturated sodium bicarbonate solution, washing, divides and take organic phase, be concentrated to give yellow solid 320mg, Yield 98.0%.Above-mentioned solid (320mg, 1.51mmol) is dissolved in 10mL acetonitrile and 10mL water, 2- chloro- 2,2- is sequentially added Difluoro acetophenone (1.4g, 7.55mmol), potassium carbonate (7.5g, 54.3mmol), back flow reaction 5h.Ethyl acetate extraction, merges Organic phase, concentration, silica gel column chromatography, petrol ether/ethyl acetate elution obtain yellow solid 327mg, yield 83%.It will be above-mentioned solid Body (327mg, 1.25mmol) is dissolved in 10mL THF and 2mL water, is added lithium hydroxide (120mg, 4.99mmol), room temperature reaction 30mim.Removing THF under reduced pressure, precipitating is precipitated in 1M hydrochloric acid tune pH value to acidity, filters, and it is dry, obtain white solid 100mg, yield 32%.1H NMR(300MHz,DMSO-d6) δ 13.24 (brs, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 7.22 (t, J= 73.8Hz,1H),3.88(s,3H),3.81(s,3H).
Target compound (92) is according to 88 the method for embodiment, using intermediate 232 (85.0mg, 0.2mmol) in Mesosome 238 (124.1mg, 0.5mmol) preparation.Mp 138–139℃.1H NMR(400MHz,DMSO-d6)δ10.44(s,1H), 10.02 (s, 1H), 8.56 (d, J=5.4Hz, 1H), 7.60 (s, 1H), 7.39 (d, J=1.9Hz, 1H), 7.31 (s, 1H), 7.23 (s, 1H), 7.17 (t, J=74.0Hz, 1H), 6.78 (s, 1H), 6.67 (s, 2H), 4.20 (dt, J=8.9,5.2Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.32-3.18 (m, 4H), 2.99 (dd, J=16.4,8.6Hz, 1H), 2.61 (dd, J =16.1,4.9Hz, 1H), 2.23 (s, 6H), 1.17 (t, J=7.1Hz, 3H), 0.99 (t, J=7.0Hz, 3H) .HRMS calcd.for C33H37F2N4O8(M+H+)655.25740；found 655.25623.
Embodiment 93(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -2, 5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -4- (difluoro-methoxy) -3,5- dimethoxy Yl-benzamide (compound 93)
The preparation of 4- (difluoro-methoxy) -3,5- dimethoxybenzoic acid (intermediate 239): according to side described in embodiment 92 Method, with the preparation of 4- hydroxyl -3,5- dimethoxybenzoic acid.1H NMR(400MHz,DMSO-d6)δ13.23(brs,1H),7.29 (s, 2H), 6.93 (t, J=74.9Hz, 1H), 3.86 (s, 6H)
Title compound (93) is according to 88 the method for embodiment, using intermediate 232 (85.0mg, 0.2mmol) in Mesosome 239 (124.1mg, 0.5mmol) preparation.Mp 149–150℃.1H NMR(400MHz,DMSO-d6)δ10.45(s,1H), 10.03 (s, 1H), 7.61 (s, 1H), 7.25 (s, 1H), 7.16 (s, 2H), 6.91 (t, J=74.8Hz, 1H), 6.77 (s, 1H), 6.66 (s, 2H), 4.21 (dt, J=8.6,5.2Hz, 1H), 3.84 (s, 6H), 3.32-3.15 (m, 4H), 2.99 (dd, J= 16.3,8.5Hz, 1H), 2.62 (dd, J=16.3,5.0Hz, 1H), 2.22 (s, 6H), 1.17 (t, J=7.1Hz, 3H), 0.99 (t, J=7.1Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.84,167.94,166.81,164.75,156.27, 152.26,145.48,139.40,132.85,132.78,132.25,125.29,123.76,120.03,117.77,117.07, 115.77,105.02,56.36,49.05,41.38,31.29,20.87,13.91,13.05.HRMS calcd.for C33H37F2N4O8(M+H+)655.25740；found 655.25629.
Embodiment 94(S) the chloro- N- of -4- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,5- dimethoxybenzoyl Amine (compound 94)
The preparation of the chloro- 3,5- dimethoxybenzoic acid (intermediate 240) of 4-: by 3,5- dihydroxy-benzoic acid (90.0g, It 0.58mol) is dissolved in 1000mL ethyl acetate, 65% nitric acid (45mL, 0.64mol) is added under the conditions of 0 DEG C, reacts 48h at room temperature. Reaction solution is washed with water, dry, concentration obtains dark oil object.Re-crystallizing in ethyl acetate obtains yellow solid 6.4g, yield 5.5%.Above-mentioned solid (5.4g, 0.027mol) is dissolved in 50mL DMF, adds potassium carbonate (5.59g, 0.04mol), iodomethane (19.3g, 0.136mol), 30 DEG C of reaction 12h.Reaction solution is diluted with water, ethyl acetate extraction, dry, and concentration obtains yellow solid 5.28g, yield 81.0%.Above-mentioned solid (2.0g, 8.3mmol) is dissolved in 20mL methanol and 20mL THF, adds Pd/C 100mg, Normal temperature and pressure catalysis hydrogenation.Solid is filtered out, yellow solid 1.75g, yield 99.0% are concentrated to give.By above-mentioned solid (200mg, It 0.95mmol) is dissolved in 3mL concentrated hydrochloric acid, under the conditions of 0 DEG C, adds sodium nitrite (78mg, 1.14mmol), the reaction was continued 30min.Chlorination Change cuprous (564mg, 5.7mmol), reacts at room temperature 1h.Reaction solution is diluted with water, ethyl acetate extraction, silica gel column chromatography, petroleum Ether/ethyl acetate elution, obtains yellow solid 140mg, yield 43%.It is hydrolyzed using method identical with preparation (238), obtains yellow Solid 100mg, yield 76%.1H NMR(400MHz,DMSO-d6)δ13.30(brs,1H),7.27(s,2H),3.90(s,6H).
Title compound (94) is according to 88 the method for embodiment, using intermediate 232 (85.0mg, 0.2mmol) in Mesosome 240 (108.3mg, 0.5mmol) preparation.Mp 162–163℃.1H NMR(400MHz,DMSO-d6)δ10.46(s,1H), 10.08 (s, 1H), 8.57 (d, J=5.5Hz, 1H), 7.60 (s, 1H), 7.25 (s, 1H), 7.15 (s, 2H), 6.77 (s, 1H), 6.66 (s, 2H), 4.21 (dt, J=8.6,5.2Hz, 1H), 3.88 (s, 6H), 3.33-3.17 (m, 4H), 2.99 (dd, J= 16.3,8.5Hz, 1H), 2.62 (dd, J=16.3,5.2Hz, 1H), 2.22 (s, 6H), 1.17 (t, J=7.1Hz, 3H), 0.99 (t, J=7.0Hz, 3H)13C NMR(100MHz,DMSO-d6)δ171.01,168.14,167.05,165.03,156.36, 155.55,145.71,139.60,133.60,132.95,132.89,125.47,123.94,120.21,118.05,115.89, 112.98,104.44,56.60,49.21,41.56,31.42,21.02,14.05,13.18.HRMS calcd.for C32H36ClN4O7(M+H+)623.22670；found 623.22656.
Embodiment 95(S) -4- cyano-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,5- dimethoxybenzoyl Amine (compound 95)
The preparation of 4- cyano -3,5- dimethoxybenzoic acid (intermediate 241): by 4- hydroxyl -3,5- dimethoxy benzene first Sour methyl esters (1.0g, 4.72mmol) is dissolved in 25mL DCM, sequentially adds triethylamine (1.64mL, 11.8mmol), trifluoromethanesulfonic acid Acid anhydride (1.99g, 7.1mmol) reacts at room temperature 12h.Silica gel column chromatography, petrol ether/ethyl acetate elution, obtains white solid 500mg, Yield 30.0%.Above-mentioned solid (320mg, 0.93mmol) is dissolved in 3mL DMF, successively plus zinc cyanide (218mg, 1.086mmol)、Pd(PPh3)4(500mg, 0.46mmol), nitrogen protection, 150 DEG C of reaction 3h.Silica gel column chromatography, petroleum ether/second Acetoacetic ester elution, obtains yellow solid 150mg, yield 50.0%.It is hydrolyzed using method same as described above, obtains yellow solid 140mg, yield 95.0%.
Title compound (95) is according to 88 the method for embodiment, using intermediate 232 (85.0mg, 0.2mmol) in Mesosome 241 (103.6mg, 0.5mmol) preparation.Mp 139–140℃.1H NMR(400MHz,DMSO-d6)δ10.47(s,1H), 10.25 (s, 1H), 8.58 (d, J=5.5Hz, 1H), 7.57 (s, 1H), 7.25 (s, 1H), 7.11 (s, 2H), 6.78 (s, 1H), 6.66 (s, 2H), 4.21 (dt, J=8.2,5.3Hz, 1H), 3.93 (s, 6H), 3.33-3.18 (m, 4H), 2.99 (dd, J= 16.4,8.6Hz, 1H), 2.62 (dd, J=16.2,5.1Hz, 1H), 2.22 (s, 6H), 1.17 (t, J=7.1Hz, 3H), 0.99 (t, J=7.1Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.84,167.91,166.75,164.42,161.90, 156.14,145.73,140.56,139.42,132.69,132.35,125.36,124.10,119.94,117.97,115.91, 113.36,103.52,92.26,56.73,49.03,41.37,31.27,20.86,13.91,13.05.HRMS calcd.for C33H36N5O7(M+H+)614.26092；found 614.25958.
Embodiment 96(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -2, 5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,5- dimethoxy-4 '-toluyl Amine (compound 96)
According to 88 the method for embodiment, using intermediate 232 (85.0mg, 0.2mmol) and 4- methyl -3,5- dimethoxy Yl benzoic acid (98.1mg, 0.5mmol) preparation.Mp 141–142℃.1H NMR(400MHz,DMSO-d6)δ10.45(s,1H), 9.88 (s, 1H), 8.56 (d, J=5.4Hz, 1H), 7.66 (s, 1H), 7.24 (d, J=8.7Hz, 1H), 7.04 (s, 2H), 6.77 (s, 1H), 6.67 (s, 2H), 4.21 (dt, J=10.5,5.2Hz, 1H), 3.80 (s, 6H), 3.33-3.15 (m, 4H), 2.99 (dd, J=16.2,8.6Hz, 1H), 2.62 (dd, J=16.3,5.1Hz, 1H), 2.22 (s, 6H), 2.02 (s, 3H), 1.17 (t, J=7.1Hz, 3H), 0.99 (t, J=7.1Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.80,167.90,166.78, 165.36,157.49,156.28,145.12,139.35,133.11,132.82,132.54,125.21,123.40,120.01, 117.37,117.24,115.65,103.12,55.71,49.02,41.34,31.26,20.86,13.89,13.03, 8.52.HRMS calcd.for C33H39N4O7(M+H+)603.28133；found 603.28040.
Embodiment 97(S) the bromo- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,5- dimethoxy-4 '-methyl Benzamide (compound 97)
The preparation of bromo- 3, the 5- dimethoxy-4 ' of 2--methyl benzoic acid (intermediate 242): according to 88 the method for embodiment, It is prepared by 4- methyl -3,5- dimethoxybenzoic acid.1H NMR(400MHz,DMSO-d6)δ13.34(brs,1H),7.07(s, 1H),3.82(s,3H),3.71(s,3H),2.14(s,3H).
Title compound (97) is according to 88 the method for embodiment, using intermediate 232 (85.0mg, 0.2mmol) in Mesosome 242 (137.5mg, 0.5mmol) preparation.Mp 157–158℃.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H), 10.22 (s, 1H), 8.53 (d, J=5.9Hz, 1H), 8.01 (s, 1H), 7.16 (s, 1H), 6.81 (s, 1H), 6.72 (s, 1H), 6.67 (s, 2H), 4.18 (dt, J=8.4,4.9Hz, 1H), 3.75 (s, 3H), 3.71 (s, 3H), 3.30-3.19 (m, 4H), 2.98 (dd, J=16.0,9.0Hz, 1H), 2.60 (dd, J=17.4,5.2Hz, 1H), 2.25 (s, 6H), 2.13 (s, 3H), 1.17 (t, J=7.0Hz, 3H), 0.99 (t, J=6.9Hz, 3H) .HRMS calcd.for C33H38BrN4O7(M+H+) 681.19184；found 681.19055.
Embodiment 98(S) the chloro- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,5- dimethoxy-4 '-methyl Benzamide (compound 98)
The preparation of chloro- 3, the 5- dimethoxy-4 ' of 2--methyl benzoic acid (intermediate 243): according to 91 the method for embodiment, It is prepared by 4- methyl -3,5- dimethoxybenzoic acid.
Title compound (98) is according to 88 the method for embodiment, using intermediate 232 (85.0mg, 0.2mmol) in Mesosome 243 (115.3mg, 0.5mmol) preparation.Mp 150–151℃.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H), 10.22 (s, 1H), 8.53 (d, J=5.5Hz, 1H), 7.99 (s, 1H), 7.17 (s, 1H), 6.81 (s, 1H), 6.75 (s, 1H), 6.68 (s, 2H), 4.19 (dt, J=8.5,5.2Hz, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.35-3.19 (m, 4H), 2.98 (dd, J=16.3,8.6Hz, 1H), 2.60 (dd, J=16.3,5.1Hz, 1H), 2.25 (s, 6H), 2.12 (s, 3H), 1.17 (t, J=7.1Hz, 3H), 0.99 (t, J=7.0Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.91,168.07, 166.97,165.30,156.58,156.31,154.33,144.42,139.51,134.76,132.88,132.80,125.50, 123.11,122.59,119.45,116.29,116.06,115.89,106.66,60.37,56.07,49.15,41.49, 31.35,20.98,14.01,13.14,9.55.HRMS calcd.for C33H38ClN4O7(M+H+)637.24235；found 637.24103.
Embodiment 99(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -2, 5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -7- methoxyl group benzo [d] [1,3] dioxy Heterocyclic pentene -5- formamide (compound 99)
According to 88 the method for embodiment, using intermediate 232 (85.0mg, 0.2mmol) and 7- methoxyl group benzo [d] [1,3] dioxole -5- carboxylic acid (98.1mg, 0.5mmol) preparation.Mp 136–137℃.1H NMR(400MHz,DMSO- d6) δ 10.41 (s, 1H), 9.77 (s, 1H), 8.54 (d, J=5.5Hz, 1H), 7.66 (s, 1H), 7.20 (s, 1H), 7.17 (d, J =1.4Hz, 1H), 7.07 (d, J=1.5Hz, 1H), 6.79 (s, 1H), 6.69 (s, 2H), 6.10 (s, 2H), 4.19 (dt, J= 10.2,5.1Hz, 1H), 3.85 (s, 3H), 3.30-3.18 (m, 4H), 2.98 (dd, J=16.2,8.4Hz, 1H), 2.61 (dd, J =16.2,5.0Hz, 1H), 2.23 (s, 6H), 1.17 (t, J=7.1Hz, 3H), 0.99 (t, J=7.1Hz, 3H)13C NMR (100MHz,DMSO-d6)δ170.78,167.90,166.80,164.45,162.29,156.13,148.36,145.39, 142.82,139.38,138.04,132.86,132.58,128.18,125.40,123.24,119.40,117.22,116.15, 108.54,102.18,101.75,56.39,49.01,41.34,35.77,31.25,20.85,13.89,13.03.HRMS calcd.for C32H35N4O8(M+H+)603.24494；found 603.24390.
Embodiment 100(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -2, 5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -8- methoxyl group -2,3- dihydrobenzo [b] [1,4] dioxine -6- formamide (compound 100)
According to 88 the method for embodiment, using intermediate 232 (85.0mg, 0.2mmol) and 8- methoxyl group -2,3- dihydro Benzo [b] [Isosorbide-5-Nitrae] dioxine -6- carboxylic acid (105.1mg, 0.5mmol) preparation.Mp 155–156℃.1H NMR (400MHz,DMSO-d6) δ 10.40 (s, 1H), 9.72 (s, 1H), 8.53 (d, J=5.4Hz, 1H), 7.69 (s, 1H), 7.20 (s, 1H), 7.04 (s, 2H), 6.79 (s, 1H), 6.69 (s, 2H), 4.27 (dd, J=8.0,4.7Hz, 4H), 4.19 (dt, J= 8.5,5.2Hz, 1H), 3.79 (s, 3H), 3.30-3.19 (m, 4H), 2.98 (dd, J=16.3,8.6Hz, 1H), 2.61 (dd, J =16.3,5.1Hz, 1H), 2.24 (s, 6H), 1.17 (t, J=7.1Hz, 3H), 0.99 (t, J=7.1Hz, 3H) .HRMS calcd.for C33H37N4O8(M+H+)617.26059；found 617.25934.
Embodiment 101(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -2, 5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -8- methoxyl group -4- methyl -3,4- dihydro - 2H- benzo [b] [1,4] oxazines -6- formamide (compound 101)
Prepare 8- methoxyl group -4- methyl -3,4- dihydro -2H- benzo [b] [1,4] oxazines -6- carboxylic acid (intermediate 244):
Vanillic acid (3.0g, 0.018mol) is dissolved in 20mL glacial acetic acid, add nitric acid (1.39g, 0.024mol), 1h is reacted at room temperature.Reaction solution is poured into ice water, solid is precipitated, is filtered, it is dry, obtain yellow solid 3.45g.It will Above-mentioned solid (3.45g, 0.016mol) is dissolved in 50mL methanol, and 4mL thionyl chloride is added, and reacts at room temperature 12h.Reaction solution is steamed Dry, DCM dissolution is washed, and dry, concentration obtains yellow solid 1.48g, yield 40%.Above-mentioned solid (1.0g, 4.4mmol) is molten In 20mL DMF, successively plus potassium carbonate (1.8g, 13.2mmol), 1,2- Bromofume (1.66g, 8.8mmol), 90 DEG C of reactions 3h.Filtering, silica gel column chromatography, petrol ether/ethyl acetate elution obtain yellow solid 1.2g, yield 82.0%.By above-mentioned solid (600mg, 1.8mmol) is dissolved in 10mL glacial acetic acid, adds iron powder (201mg, 3.59mmol), 90 DEG C of reaction 12h.Filtering, silicagel column Chromatography, petrol ether/ethyl acetate elution, obtains yellow solid 136mg, yield 33.0%.Methylation and methyl esters are successively carried out later Hydrolysis obtains 244.1H NMR(400MHz,DMSO-d6) δ 12.51 (brs, 1H), 6.97 (d, J=1.8Hz, 1H), 6.95 (d, J=1.8Hz, 1H), 4.30-4.24 (m, 2H), 3.74 (s, 3H), 3.26-3.21 (m, 2H), 2.85 (s, 3H)
Title compound (101) is according to 88 the method for embodiment, using intermediate 232 (85.0mg, 0.2mmol) in Mesosome 244 (111.5mg, 0.5mmol) preparation.Mp 143–144℃.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H), 9.59 (s, 1H), 8.52 (d, J=5.4Hz, 1H), 7.73 (s, 1H), 7.24 (s, 1H), 6.84 (d, J=1.4Hz, 2H), 6.77 (s,1H),6.67(s,2H),4.28–4.23(m,2H),4.23–4.17(m,1H),3.72(s,3H),3.35–3.19(m,6H), 2.99 (dd, J=16.3,8.5Hz, 1H), 2.83 (s, 3H), 2.61 (dd, J=16.3,4.9Hz, 1H), 2.22 (s, 6H), 1.17 (t, J=7.1Hz, 3H), 0.99 (t, J=7.0Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.80,167.91, 166.82,165.37,156.34,147.28,144.67,139.38,136.64,136.18,133.45,132.89,125.54, 125.23,122.95,119.98,116.78,115.56,105.41,102.03,64.49,55.70,49.02,47.91, 41.35,38.55,31.27,20.89,13.90,13.04.HRMS calcd.for C34H40N5O7(M+H+)630.29223； found 630.29089.
Embodiment 102(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -2, 5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -5- methoxyl group -4- methyl -3,4- dihydro - 2H- benzo [b] [1,4] oxazines -7- formamide (compound 102)
Prepare 5- methoxyl group -4- methyl -3,4- dihydro -2H- benzo [b] [1,4] oxazines -7- carboxylic acid (intermediate 245):
According to 101 the method for embodiment, prepared by raw material of 3- hydroxyl -4- nitro -5- methoxyl methyl benzoate.1H NMR(400MHz,DMSO-d6) δ 12.51 (brs, 1H), 7.04 (d, J=1.8Hz, 1H), 7.01 (d, J=1.8Hz, 1H), 4.10–4.05(m,2H),3.82(s,3H),3.11–3.06(m,2H),2.84(s,3H).
Title compound (102) is according to 88 the method for embodiment, using intermediate 232 (85.0mg, 0.2mmol) in Mesosome 245 (111.5mg, 0.5mmol) preparation.Mp 153–154℃.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H), 9.62 (s, 1H), 8.52 (d, J=5.3Hz, 1H), 7.74 (s, 1H), 7.19 (s, 1H), 6.99 (s, 2H), 6.79 (s, 1H), 6.70 (s, 2H), 4.19 (dt, J=8.5,5.2Hz, 1H), 4.08 (t, J=4.0Hz, 2H), 3.81 (s, 3H), 3.32-3.18 (m, 4H), 3.08 (t, J=4.0Hz, 2H), 2.98 (dd, J=16.3,8.4Hz, 1H), 2.82 (s, 3H), 2.60 (dd, J= 16.4,5.0Hz, 1H), 2.24 (s, 6H), 1.17 (t, J=7.1Hz, 3H), 0.99 (t, J=7.0Hz, 3H)13C NMR (100MHz,DMSO-d6)δ170.80,167.92,166.85,164.85,156.18,151.77,146.74,145.01, 139.43,133.12,132.67,129.21,125.84,125.45,122.87,119.36,116.63,116.10,109.58, 103.63,60.52,55.78,49.89,49.03,41.98,41.36,31.27,20.88,13.91,13.05.HRMS calcd.for C34H40N5O7(M+H+)630.29223；found 630.29102.
Embodiment 103(S) -2- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -8- (3,4,5- trimethoxy-benzene sulphur Amide groups) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base]-N, N- diethyl acetamide (compound 103)
According to 8 the method for embodiment, using intermediate 232 (85.0mg, 0.2mmol) and 3,4,5- trimethoxy-benzene sulphurs Acyl chlorides (133.4mg, 0.5mmol) preparation.Mp 159–161℃.1H NMR(400MHz,DMSO-d6)δ10.40(s,1H), 10.26(s,1H),8.49(s,1H),7.30(s,1H),7.12(s,2H),6.95(s,1H),6.78(s,1H),6.38(s, 2H), 4.09 (dt, J=8.9,5.5Hz, 1H), 3.71 (s, 6H), 3.70 (s, 3H), 3.30-3.15 (m, 4H), 2.94 (dd, J =16.3,8.3Hz, 1H), 2.56 (dd, J=16.4,5.5Hz, 1H), 2.21 (s, 6H), 1.15 (t, J=7.1Hz, 3H), 0.98 (t, J=7.0Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.78,167.88,166.70,156.04, 152.73,145.04,140.81,139.26,132.60,125.40,118.94,116.31,114.90,104.28,60.16, 56.18,49.00,41.36,31.20,20.83,13.90,13.03.HRMS calcd.for C32H39N4O9S(M+H+) 655.24323；found 655.24286.
Embodiment 104(S) -2- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -8- [3- (3,4,5- trimethoxy Phenyl) urea] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base]-N, N- diethyl acetamide (compound 104)
Triphosgene 1.3g is dissolved in 35mL DCM, the DCM dissolved with 3,4,5- trimethoxy-aniline of 500mg is slowly added dropwise Solution 15mL reacts at room temperature 1h, white solid is concentrated under reduced pressure to obtain.Above-mentioned white solid 400mg and (232) 150mg are dissolved in 20mL toluene adds triethylamine 0.5mL, back flow reaction 16h.Silica gel column chromatography, DCM/MeOH elution, obtains faint yellow solid 98mg, Yield 43%.Mp 191–193℃.1H NMR(300MHz,DMSO-d6)δ10.27(s,1H),9.46(s,1H),8.75(s, 1H), 8.40 (d, J=4.4Hz, 1H), 8.21 (s, 1H), 7.04 (s, 1H), 6.86 (s, 1H), 6.78 (s, 2H), 6.76 (s, 2H), 4.13 (brs, 1H), 3.75 (s, 6H), 3.61 (s, 3H), 3.29-3.13 (m, 4H), 2.96 (dd, J=17.0,9.5Hz, 1H), 2.58 (dd, J=16.4,5.5Hz, 1H), 2.29 (s, 6H), 1.16 (t, J=6.0Hz, 3H), 0.98 (t, J=6.8Hz, 3H).13C NMR(100MHz,DMSO-d6)δ170.70,168.01,167.01,156.14,152.93,152.00,141.98, 139.59,135.48,134.54,133.01,132.69,125.74,119.36,117.99,116.63,110.70,95.86, 60.12,55.66,49.04,41.36,31.25,20.88,13.89,13.03.HRMS calcd.for C33H40N5O8(M+H+) 634.28714；found 634.28601.
Embodiment 105(S)-[3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -2,5- Dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] carbamic acid (3,4,5- trimethoxyphenyl) Ester (compound 105)
Intermediate 232100mg is dissolved in 5mL pyridine, adds 3,4,5- trimethoxyphenyl phosgene 200mg, 80 DEG C of reactions 4h.Silica gel column chromatography, DCM/MeOH elution, obtains white solid 17mg, yield 11.4%.Mp 158–159℃.1H NMR (400MHz,DMSO-d6) δ 10.38 (s, 1H), 9.86 (s, 1H), 8.50 (d, J=5.7Hz, 1H), 7.70 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 6.72 (s, 2H), 6.53 (s, 2H), 4.15 (dt, J=8.1,5.1Hz, 1H), 3.75 (s, 6H), 3.65 (s, 3H), 3.31 (dd, J=14.3,7.3Hz, 2H), 3.23 (dt, J=13.7,6.6Hz, 2H), 2.97 (dd, J= 16.3,8.5Hz, 1H), 2.58 (dd, J=16.1,4.9Hz, 1H), 2.28 (s, 6H), 1.16 (t, J=7.1Hz, 3H), 0.97 (t, J=7.0Hz, 3H) .HRMS calcd.for C33H39N4O9(M+H+)635.27116；found 635.27051.
Embodiment 106(S) the bromo- N- of -2- [3- [2- (dimethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 106)
Preparation (S) -2- [8- (the bromo- 3,4,5- trimethoxy-benzamide base of 2-) -7- (3,5- dimethyl phenoxy) -2, 5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 246):
According to 88 the method for embodiment, using intermediate 191 (767.0mg, 2.0mmol) and intermediate 233 (1.45g, 5.0mmol) prepare.1H NMR(400MHz,DMSO-d6) δ 10.51 (s, 1H), 10.23 (s, 1H), 8.58 (d, J=5.1Hz, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.12 (dt, J=8.9, 5.7Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.60 (s, 3H), 2.88 (dd, J=17.0,8.8Hz, 1H), 2.73 (dd, J=17.0,5.7Hz, 1H), 2.25 (s, 6H)13C NMR(100MHz,DMSO-d6)δ170.51, 170.38,166.68,165.88,156.15,152.52,150.27,144.34,143.61,139.33,133.89,132.86, 132.38,125.40,122.62,119.16,116.39,115.47,108.33,105.65,60.85,60.73,56.22, 51.55,48.58,32.46,20.85.
Title compound (106) is mixed by intermediate 246 (131mg, 0.2mmol) and lithium hydroxide (14.4mg, 0.6mmol) It closes, adds 2mL water and 2mL THF, react at room temperature 30min.It removes THF, 1M hydrochloric acid tune pH to acidity under reduced pressure, precipitating is precipitated, filter, It is dry.Gained white solid and DIC (63 μ L, 0.4mmol), HOSu (46mg, 0.4mmol) are mixed in 2mL THF, room temperature React 12h.It is added dimethylamine (422 μ L, 2M in THF, 0.6mmol), the reaction was continued 1h.Silica gel column chromatography, DCM/MeOH are washed It is de-, obtain faint yellow solid 81mg, yield 60.6%.Mp 160–162℃.1H NMR(400MHz,DMSO-d6)δ10.40(s, 1H), 10.22 (s, 1H), 8.51 (d, J=4.5Hz, 1H), 8.02 (s, 1H), 7.15 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H),6.68(s,2H),4.16(brs,1H),3.80(s,3H),3.79(s,3H),3.77(s,3H),2.99(s,3H),2.94 (dd, J=12.3,4.3Hz, 1H), 2.81 (s, 3H), 2.62 (dd, J=16.3,4.4Hz, 1H), 2.25 (s, 6H)13C NMR (100MHz,DMSO-d6)δ171.21,169.33,167.24,166.37,156.66,152.99,150.75,144.78, 144.05,139.82,134.44,133.23,133.07,125.88,123.33,119.55,116.90,116.02,108.76, 106.14,61.34,61.22,56.69,49.47,36.98,35.22,31.85,21.33.HRMS calcd.for C31H34BrN4O8(M+H+)669.1560；found 669.1532.
Embodiment 107(S)-N- [3- [2- (azetidine -1- base) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] the bromo- 3,4,5- trimethoxy of -2- Benzamide (compound 107)
According to 106 the method for embodiment, using intermediate 246 (131.0mg, 0.2mmol) and azetidine (34.2mg, 0.6mmol) preparation.Mp 135–136℃.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),10.24(s, 1H), 8.52 (d, J=5.5Hz, 1H), 8.02 (s, 1H), 7.14 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.17 (t, J=7.8Hz, 2H), 4.10 (dt, J=7.7,6.3Hz, 1H), 3.84 (brs, 1H), 3.82 (brs, 1H), 3.79 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 2.62 (dd, J=15.9,7.9Hz, 1H), 2.36 (dd, J=16.0, 6.1Hz, 1H), 2.25 (s, 6H), 2.19 (dd, J=15.3,7.7Hz, 2H) .HRMS calcd.for C32H34BrN4O8(M+H+)681.15545；found 681.15405.
Embodiment 108(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -3- [2- oxo -2- (pyrrole Cough up alkane -1- base) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 108)
According to 106 the method for embodiment, using intermediate 246 (131.0mg, 0.2mmol) and nafoxidine (42.6mg, 0.6mmol) preparation.Mp 155–157℃.1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),10.21(s, 1H), 8.52 (d, J=5.2Hz, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.17 (dd, J=12.4,5.9Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.45 (t, J= 6.6Hz, 2H), 3.25 (t, J=6.7Hz, 2H), 2.87 (dd, J=16.4,8.0Hz, 1H), 2.58 (dd, J=16.4, 5.4Hz,1H),2.25(s,6H),1.94–1.87(m,2H),1.83–1.69(m,2H).13C NMR(100MHz,DMSO-d6)δ 170.76,167.19,166.77,165.88,156.17,152.52,150.27,144.31,143.59,139.34,133.94, 132.76,132.59,125.41,122.83,119.05,116.42,115.50,108.30,105.66,60.86,60.74, 56.22,48.78,45.81,45.30,32.61,25.52,23.94,20.85.HRMS calcd.for C33H36BrN4O8(M+H+)695.17110；found 695.17004.
Embodiment 109(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -3- [2- oxo -2- (piperazine Pyridine -1- base) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxybenzoyl Amine (compound 109)
According to 106 the method for embodiment, using intermediate 246 (131.0mg, 0.2mmol) and piperidines (51.0mg, 0.6mmol) prepare.Mp 153–155℃.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),10.21(s,1H),8.50 (d, J=5.3Hz, 1H), 8.01 (s, 1H), 7.15 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.16 (dt, J=8.3,5.3Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.47-3.34 (m, 4H), 2.96 (dd, J=16.4,8.4Hz, 1H), 2.60 (dd, J=16.4,4.9Hz, 1H), 2.25 (s, 6H), 1.56 (brs, 4H), 1.40 (brs,2H).13C NMR(100MHz,DMSO-d6)δ170.71,167.03,166.77,165.88,156.20,152.52, 150.27,144.27,143.58,139.33,133.94,132.75,132.60,125.37,122.87,119.10,116.38, 115.51,108.29,105.66,60.85,60.73,56.21,48.96,45.78,42.02,31.15,25.72,25.19, 23.99,20.85.HRMS calcd.for C34H38BrN4O8(M+H+)709.18675；found 709.18610.
Embodiment 110(S) the bromo- N- of-2- [7- (3,5- dimethyl phenoxy)-3- (2- morpholine -2-oxoethyl)-2,5- Dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzamide (chemical combination Object 110)
According to 106 the method for embodiment, using intermediate 246 (131.0mg, 0.2mmol) and morpholine (52.3mg, 0.6mmol) prepare.Mp 157–159℃.1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),10.21(s,1H),8.52 (d, J=5.2Hz, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.18 (dd, J=12.9,5.6Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.62 (brs, 2H), 3.53 (brs, 2H), 3.48-3.36 (m, 4H), 2.95 (dd, J=16.4,8.0Hz, 1H), 2.64 (dd, J=16.4,5.3Hz, 1H), 2.25 (s,6H).13C NMR(100MHz,DMSO-d6)δ170.69,167.80,166.78,165.91,156.19,152.53, 150.28,144.31,143.59,139.35,133.96,132.79,132.59,125.42,122.82,119.09,116.42, 115.52,108.30,105.67,66.00,65.92,60.88,60.75,56.22,48.94,45.30,41.55,31.03, 20.87.HRMS calcd.for C33H36BrN4O9(M+H+)711.16602；found 711.16571.
Embodiment 111(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -3- [2- (4- methylpiperazine-1-yl) -2- oxygen For ethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 111)
According to 106 the method for embodiment, using intermediate 246 (131.0mg, 0.2mmol) and N methyl piperazine (60.1mg, 0.6mmol) preparation.Mp 167–169℃.1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),10.21(s, 1H), 8.51 (d, J=5.0Hz, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.17 (dd, J=12.3,5.2Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.46 (brs, 4H), 2.96 (dd, J=16.3,8.1Hz, 1H), 2.63 (dd, J=16.4,5.2Hz, 1H), 2.44 (brs, 2H), 2.33 (brs, 2H),2.25(s,9H).13C NMR(100MHz,DMSO-d6)δ170.69,167.51,166.78,165.91,156.20, 152.53,150.28,144.30,143.59,139.35,133.96,132.78,132.59,125.41,122.83,119.10, 116.41,115.52,108.30,105.67,60.88,60.75,56.22,54.23,53.95,48.94,45.28,44.38, 40.70,31.14,20.87.HRMS calcd.for C34H39BrN5O8(M+H+)724.19765；found 724.19727.
Embodiment 112(S) [(2- oxo -2- is thio by 7- (3,5- dimethyl phenoxy) -2,5- dioxo -3- by the bromo- N- of -2- Morpholinyl ethyl) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzamide (compound 112)
According to 106 the method for embodiment, using intermediate 246 (131.0mg, 0.2mmol) and thiomorpholine (61.8mg, 0.6mmol) preparation.Mp 158–160℃.1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),10.21(s, 1H), 8.51 (d, J=5.1Hz, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.18 (dd, J=12.8,5.5Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.76-3.55 (m, 4H), 2.96 (dd, J=16.4,8.0Hz, 1H), 2.73 (dd, J=12.8,5.8Hz, 1H), 2.63 (dd, J=16.5, 5.5Hz,2H),2.51(brs,2H),2.25(s,6H).13C NMR(100MHz,DMSO-d6)δ170.74,167.57, 166.78,165.91,156.18,152.53,150.27,144.33,143.58,139.35,133.96,132.77,132.56, 125.42,122.84,119.05,116.43,115.52,108.29,105.67,60.87,60.75,56.22,48.98, 47.79,43.93,31.31,26.54,26.39,20.87.HRMS calcd.for C33H36BrN4O8S(M+H+) 727.14317；found 727.14240.
Embodiment 113(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -3- [2- oxo -2- (4- Oxo-piperidine -1- base) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 113)
According to 106 the method for embodiment, using intermediate 246 (131.0mg, 0.2mmol) and 4- oxo-piperidine (59.4mg, 0.6mmol) preparation.Mp 168–170℃.1H NMR(400MHz,methanol-d4)δ8.22(s,1H),7.37 (s, 1H), 6.81 (s, 2H), 6.66 (s, 2H), 4.49 (dd, J=8.8,4.8Hz, 1H), 4.00-3.87 (m, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.77-3.66 (m, 1H), 3.25 (dd, J=16.2,8.9Hz, 1H), 2.80 (dd, J =16.2,4.8Hz, 1H), 2.72-2.38 (m, 4H), 2.27 (s, 6H) .HRMS calcd.for C34H36BrN4O9(M+H+) 723.16607；found 723.16504.
Embodiment 114(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -3- [2- (4- fluorine resources -1- base) -2- oxo Ethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene Formamide (compound 114)
According to 106 the method for embodiment, using intermediate 246 (131.0mg, 0.2mmol) and 4- fluorine resources (61.8mg, 0.6mmol) preparation.Mp 130–131℃.1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),10.24(s, 1H), 8.53 (d, J=3.8Hz, 1H), 8.02 (s, 1H), 7.15 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.88 (d, J=47.7Hz, 1H), 4.16 (dt, J=8.1,5.5Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.61-3.36 (m, 4H), 2.98 (dd, J=16.4,7.8Hz, 1H), 2.65 (dd, J=15.9,4.7Hz, 1H), 2.25(s,6H),1.99(brs,1H),1.76(brs,2H),1.59(brs,1H).13C NMR(100MHz,DMSO-d6)δ 170.73,167.46,166.77,165.88,156.19,152.52,150.28,144.30,143.60,139.34,133.93, 132.78,132.59,125.39,122.84,119.10,116.38,115.52,108.31,105.67,60.86,60.74, 56.22,49.02,41.24,37.51,31.04,30.66,20.85.HRMS calcd.for C34H37BrFN4O8(M+H+) 727.17733；found 727.17676.
Embodiment 115(S) the bromo- N- of -2- [3- [2- (4,4- difluoropiperdin -1- base) -2- oxoethyl] -7- (3,5- diformazan Phenoxyl) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 115)
According to 106 the method for embodiment, using intermediate 246 (131.0mg, 0.2mmol) and 4,4- difluoropiperdin (72.6mg, 0.6mmol) preparation.Mp 273–274℃.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),10.22(s, 1H), 8.51 (d, J=5.0Hz, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 6.82 (s, 2H), 6.68 (s, 2H), 4.17 (dd, J =12.3,5.7Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.67-3.42 (m, 5H), 3.01 (dd, J= 16.4,7.9Hz, 1H), 2.70 (dd, J=16.3,6.1Hz, 1H), 2.25 (s, 6H), 2.09 (brs, 2H), 1.88 (brs, 2H).13C NMR(100MHz,DMSO-d6)δ170.75,167.79,166.77,165.88,156.17,152.52,150.27, 144.33,143.60,139.34,133.92,132.79,132.55,125.40,122.78,119.07,116.40,115.52, 108.31,105.66,60.86,60.74,56.22,49.07,41.85,38.22,33.19,30.99,20.85.HRMS calcd.for C34H36BrF2N4O8(M+H+)745.16791；found 745.16736.
Embodiment 116(S) the chloro- N- of -2- [7- (3,5- dimethyl phenoxy) -3- [2- (4- methylpiperazine-1-yl) -2- oxygen For ethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 116)
According to 106 the method for embodiment, the title compound 6 prepared using embodiment 6 (122.4mg, 0.2mmol) prepared with N methyl piperazine (60.1mg, 0.6mmol).Mp 151–152℃.1H NMR(400MHz,DMSO-d6)δ 10.41 (s, 1H), 10.24 (s, 1H), 8.52 (d, J=5.2Hz, 1H), 8.00 (s, 1H), 7.16 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.16 (dt, J=7.5,5.5Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.46 (brs, 4H), 2.96 (dd, J=16.6,8.2Hz, 1H), 2.64 (dd, J=16.4,5.3Hz, 1H), 2.34- 2.20(m,10H).HRMS calcd.for C34H39ClN5O8(M+H+)680.24817；found 680.24786.
Embodiment 117(S) the chloro- N- of -2- [3- [2- (4,4- difluoropiperdin -1- base) -2- oxoethyl] -7- (3,5- diformazan Phenoxyl) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 117)
According to 106 the method for embodiment, the title compound 6 prepared using embodiment 6 (122.4mg, 0.2mmol) prepared with 4,4- difluoropiperdin (72.6mg, 0.6mmol).Mp 155–156℃.1H NMR(400MHz,DMSO-d6) δ 10.44 (s, 1H), 10.24 (s, 1H), 8.52 (d, J=5.2Hz, 1H), 8.01 (s, 1H), 7.16 (s, 1H), 6.84 (s, 1H), 6.82 (s, 1H), 6.68 (s, 2H), 4.17 (dd, J=12.9,5.6Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.68-3.41 (m, 4H), 3.01 (dd, J=16.4,7.8Hz, 1H), 2.70 (dd, J=16.4,5.6Hz, 1H),2.25(s,6H),2.09(brs,2H),1.88(brs,2H).HRMS calcd.for C34H36ClF2N4O8(M+H+) 701.21842；found 701.21796.
Embodiment 118(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -3- [2- (4- methylpiperazine-1-yl) -2- oxygen For ethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,5- dimethoxy-4 ' - Methyl benzamide (compound 118)
According to 106 the method for embodiment, using intermediate 191 (191.7mg, 0.5mmol) and intermediate 242 (343.7mg, 1.25mmol) is prepared through two-step reaction.Mp 128–129℃.1H NMR(400MHz,DMSO-d6)δ10.41(s, 1H), 10.22 (s, 1H), 8.52 (d, J=5.3Hz, 1H), 8.01 (s, 1H), 7.16 (s, 1H), 6.81 (s, 1H), 6.73 (s, 1H), 6.67 (s, 2H), 4.16 (dt, J=8.0,5.3Hz, 1H), 3.75 (s, 3H), 3.71 (s, 3H), 3.44 (brs, 4H), 2.96 (dd, J=16.4,8.1Hz, 1H), 2.63 (dd, J=16.3,5.3Hz, 1H), 2.40 (brs, 2H), 2.31-2.22 (m, 11H),2.13(s,3H).HRMS calcd.for C34H39BrN5O7(M+H+)708.20274；found 708.20209.
Embodiment 119(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -1- Methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 119)
According to 36 the method for embodiment, the title compound 53 prepared using embodiment 53 (123.6mg, 0.2mmol) prepared with iodomethane (28.4mg, 0.2mmol).Mp 109–111℃.1H NMR(400MHz,acetone-d6)δ 9.16 (s, 1H), 8.53 (d, J=3.6Hz, 1H), 7.75 (d, J=5.4Hz, 1H), 7.30 (s, 1H), 7.18 (s, 2H), 6.84 (s, 1H), 6.77 (s, 2H), 4.46 (dt, J=8.5,4.3Hz, 1H), 3.85 (s, 6H), 3.78 (s, 3H), 3.51-3.23 (m, 7H), 3.17 (dd, J=16.0,8.5Hz, 1H), 2.74 (dd, J=16.0,4.5Hz, 1H), 2.28 (s, 6H), 1.25 (t, J= 7.1Hz, 3H), 1.03 (t, J=7.1Hz, 3H)13C NMR(150MHz,acetone-d6)δ171.19,169.10,167.48, 165.93,157.07,154.30,144.72,142.64,140.89,138.23,134.20,130.48,126.73,125.42, 119.42,117.04,115.75,106.05,60.66,56.60,50.64,42.53,40.63,35.88,32.71,21.29, 14.42,13.39.HRMS calcd.for C34H3241N4O8(M+H+)633.29189；found 633.29114.
Embodiment 120(S)-N- [1- (Cvclopropvlmethvl) -3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- Dimethyl phenoxy) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- three Methoxy benzamide (compound 120)
According to 36 the method for embodiment, the title compound 53 prepared using embodiment 53 (123.6mg, 0.2mmol) prepared with bromomethyl cyclopropane (27.0mg, 0.2mmol).Mp 100–102℃.1H NMR(400MHz, acetone-d6) δ 9.16 (s, 1H), 8.61 (d, J=3.8Hz, 1H), 7.73 (d, J=5.7Hz, 1H), 7.29 (s, 1H), 7.19 (d, J=0.7Hz, 2H), 6.85 (s, 1H), 6.77 (s, 2H), 4.44 (dt, J=8.8,4.2Hz, 1H), 4.10 (dd, J =14.3,7.3Hz, 1H), 3.85 (s, 6H), 3.78 (s, 3H), 3.67 (dd, J=14.2,6.5Hz, 1H), 3.52-3.24 (m, 4H), 3.19 (dd, J=16.0,9.0Hz, 1H), 2.80 (d, J=13.4Hz, 1H), 2.70 (dd, J=15.9,4.4Hz, 1H), 2.28 (s, 6H), 1.24 (t, J=7.1Hz, 3H), 1.03 (t, J=7.0Hz, 4H), 0.41 (q, J=4.7Hz, 2H), 0.34- 0.21(m,2H).13C NMR(150MHz,acetone-d6)δ170.69,169.07,167.48,165.97,156.97, 154.30,145.13,142.62,140.90,137.04,133.95,130.53,126.83,126.79,119.13,117.28, 117.17,106.06,60.66,56.61,52.79,50.75,42.53,40.62,32.75,21.30,14.43,13.40, 10.94,4.41,3.94.HRMS calcd.for C37H45N4O8(M+H+)673.32319；found 673.32172.
Embodiment 121(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -2, 5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-N- methylbenzene first Amide (compound 121)
Prepare (S) -2- [7- (3,5- dimethyl phenoxy) -8- methylamino -2,5- dioxo -2,3,4,5- tetrahydro - 1H- benzo [e] [1,4] diazepine -3- base]-N, N- diethyl acetamide (intermediate 247):
Intermediate 232 (148.6mg, 0.35mmol) is dissolved in 3.5mL DCE, 37%formalin (63 μ are sequentially added L, 1.05mmol), 175 μ L of glacial acetic acid, react at room temperature 2h.NaBH is added3CN (110mg, 1.75mmol), the reaction was continued 1h.Silicon Plastic column chromatography, DCM/MeOH elution, obtains faint yellow solid 130mg, yield 85.0%.1H NMR(400MHz,DMSO-d6)δ 10.10 (s, 1H), 8.09 (d, J=5.2Hz, 1H), 6.97 (s, 1H), 6.76 (s, 1H), 6.61 (s, 2H), 6.27 (s, 1H), 6.07 (brs, 1H), 4.20-4.09 (m, 1H), 3.33-3.16 (m, 4H), 2.97 (dd, J=16.3,8.7Hz, 1H), 2.74 (s, 3H), 2.54 (dd, J=16.4,5.0Hz, 1H), 2.24 (s, 6H), 1.16 (t, J=7.1Hz, 3H), 0.98 (t, J= 7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ170.76,168.05,167.59,156.85,144.58,139.18, 134.65,124.82,118.81,115.62,112.99,112.45,100.93,49.18,41.37,31.33,29.30, 20.92,13.93,13.03.
Title compound (121): according to 1 the method for embodiment, using intermediate 247 (219.0mg, 0.5mmol) with 3,4,5- trimethoxy-benzoyl chlorides (230.6mg, 1.0mmol) preparation.Mp 146–148℃.1H NMR(400MHz,DMSO- d6) δ 10.39 (s, 1H), 8.59 (d, J=5.4Hz, 1H), 7.33 (s, 1H), 6.89 (s, 1H), 6.82 (s, 1H), 6.57 (s, 2H), 6.23 (s, 2H), 4.11 (brs, 1H), 3.66 (s, 3H), 3.53 (s, 6H), 3.32-3.16 (m, 7H), 2.97 (dd, J= 16.3,8.9Hz 1H), 2.58 (dd, J=16.3,4.5Hz, 1H), 2.20 (s, 6H), 1.15 (t, J=7.0Hz, 3H), 0.99 (t, J=7.0Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.54,169.22,167.77,166.37,154.63, 152.01,148.66,139.51,138.99,138.42,132.27,130.11,126.02,121.68,118.10,116.70, 106.29,60.12,55.82,48.91,41.35,37.52,31.18,20.75,13.89,13.02.HRMS calcd.for C34H41N4O8(M+H+)633.29189；found 633.28900.
Embodiment 122(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -4- Methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 122)
Prepare (S) -2- [5- (3,5- dimethyl phenoxy)-N- methyl -2,4- dinitrobenzamide base] succinic acid two Methyl esters (intermediate 248):
Intermediate 190 (2.38g, 5.0mmol) is dissolved in 10mL DMF, potassium carbonate (1.73g, 12.5mmol), iodine are added Methane (1.56mL, 25.0mmol), 30 DEG C of reactions are for 24 hours.Filtering, is evaporated off DMF, silica gel column chromatography, petrol ether/ethyl acetate is washed It is de-, obtain faint yellow solid 1.99g, yield 81.3%.1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),7.01(s,1H), 6.93 (s, 2H), 6.83 (s, 1H), 5.03 (t, J=7.1Hz, 1H), 3.58 (s, 3H), 3.53 (s, 3H), 3.05 (dd, J= 16.5,6.6Hz, 1H), 2.95 (dd, J=16.7,7.5Hz, 1H), 2.78 (s, 3H), 2.30 (s, 6H)13C NMR(100MHz, DMSO-d6)δ170.50,169.27,165.08,154.90,153.45,140.41,139.09,137.93,137.16, 127.78,123.86,117.50,116.86,55.02,52.23,51.50,35.36,32.60,20.72.
Prepare (S) -2- [8- amino -7- (3,5- dimethyl phenoxy) -4- methyl -2,5- dioxo -2,3,4,5- four Hydrogen -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 249):
According to the preparation method of intermediate described in embodiment 1 (191), made using intermediate 248 (2.45g, 5.0mmol) It is standby.1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),7.02(s,1H),6.74(s,1H),6.60(s,2H),6.44(s, 1H), 5.75 (brs, 2H), 4.41-4.32 (m, 1H), 3.60 (s, 3H), 3.10 (dd, J=19.2,6.0Hz, 1H), 2.97 (dd, J=15.8,0.8Hz, 1H), 2.84 (s, 3H), 2.24 (s, 6H)13C NMR(100MHz,DMSO-d6)δ170.69, 169.09,167.12,156.94,144.22,139.31,139.12,134.07,124.60,120.67,115.25,114.06, 105.04,52.03,51.74,30.92,29.02,20.94.
(S) -2- [8- amino -7- (3,5- dimethyl phenoxy) -4- methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- Benzo [e] [1,4] diazepine -3- base]-N, N- diethyl acetamide (intermediate 250)
According to the preparation method of intermediate described in embodiment 88 (232), made using intermediate 249 (1.59g, 4.0mmol) It is standby.1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),7.01(s,1H),6.74(s,1H),6.60(s,2H),6.42(s, 1H), 5.71 (s, 2H), 4.44 (dd, J=9.9,4.1Hz, 1H), 3.40 (d, J=6.7Hz, 3H), 3.29-3.09 (m, 4H), 2.87 (s, 3H), 2.81 (dd, J=16.3,3.7Hz, 1H), 2.24 (s, 6H), 1.16 (t, J=5.9Hz, 3H), 0.97 (t, J =6.9Hz, 3H)13C NMR(100MHz,DMSO-d6)δ169.49,167.79,167.23,157.01,144.05,139.11, 134.30,124.55,120.66,117.02,115.18,114.46,105.15,52.50,41.19,29.78,29.37, 20.93,13.95,12.97.
Title compound (122) is according to 1 the method for embodiment, using intermediate 250 (438.5mg, 1.0mmol) and 3, 4,5- trimethoxy-benzoyl chlorides (461.2mg, 2.0mmol) preparation.Mp 129–131℃.1H NMR(300MHz,DMSO-d6)δ 10.49(s,1H),9.85(s,1H),7.65(s,1H),7.25(s,1H),7.10(s,2H),6.76(s,1H),6.66(s, 2H), 4.48 (dd, J=9.7,4.1Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.40 (d, J=6.7Hz, 2H), 3.28- 3.04 (m, 3H), 2.93-2.85 (m, 4H), 2.21 (s, 6H), 1.17 (t, J=7.2Hz, 3H), 0.97 (t, J=7.0Hz, 3H).13C NMR(100MHz,DMSO-d6)δ169.50,167.69,166.46,165.03,156.24,152.61,145.12, 140.59,139.37,132.87,132.80,129.21,125.25,124.06,120.22,116.97,115.70,105.32, 60.12,56.02,52.44,41.19,29.75,29.52,20.86,13.95,12.97.HRMS calcd.for C31H41N4O8 (M+H+)633.29189；found 633.28973.
Embodiment 123(S) the bromo- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -4- methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 123)
According to 88 the method for embodiment, using intermediate 250 (87.6mg, 0.2mmol) and intermediate 233 (145.5mg, 0.5mmol) preparation.Mp 135–137℃.1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),10.20(s, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.47 (dd, J=9.7, 3.5Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.41 (d, J=6.6Hz, 2H), 3.25 (dd, J= 14.2,7.4Hz, 1H), 3.22-3.12 (m, 2H), 2.92 (s, 3H), 2.86 (dd, J=15.9,3.1Hz, 1H), 1.17 (t, J =6.9Hz, 3H), 0.97 (t, J=7.0Hz, 3H)13C NMR(100MHz,DMSO-d6)δ169.44,167.69,166.46, 165.92,156.14,152.54,150.29,144.19,143.60,139.34,133.97,132.63,132.55,125.39, 123.53,119.32,116.36,115.15,108.30,105.66,60.88,60.76,56.23,52.42,41.20, 29.73,29.51,20.86,13.96,12.97.HRMS calcd.for C34H40BrN4O8(M+H+)711.20240；found 711.20264.
Embodiment 124(R) the bromo- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -4- methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 124)
According to 88 the method for embodiment, using intermediate 250 (87.6mg, 0.2mmol) and intermediate 233 (145.5mg, 0.5mmol) preparation.Mp 135–137℃.1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),10.22(s, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.46 (dd, J=9.9, 3.5Hz,1H),3.80(s,3H),3.79(s,3H),3.77(s,3H),3.43–3.38(m,2H),3.30–3.12(m,3H), 2.92 (s, 3H), 2.86 (dd, J=16.3,3.3Hz, 1H), 2.25 (s, 6H), 1.17 (t, J=6.8Hz, 3H), 0.97 (t, J =7.0Hz, 3H)13C NMR(100MHz,DMSO-d6)δ169.43,167.68,166.44,165.91,156.13,152.53, 150.28,144.17,143.58,139.33,133.97,132.63,132.55,125.38,123.50,119.30,116.36, 115.11,108.29,105.66,60.86,60.74,56.22,52.41,41.19,29.72,29.49,20.85,13.95, 12.97.HRMS calcd.for C34H40BrN4O8(M+H+)711.20240；found 711.20172.
Embodiment 125(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -4- Methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] the fluoro- 3,4,5- trimethoxy of -2- Yl-benzamide (compound 125)
According to 88 the method for embodiment, using intermediate 250 (87.6mg, 0.2mmol) and intermediate 235 (115.0mg, 0.5mmol) preparation.Mp 125–127℃.1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.87(d,J =7.3Hz, 1H), 8.11 (s, 1H), 7.15 (s, 1H), 7.05 (d, J=6.4Hz, 1H), 6.85 (s, 1H), 6.75 (s, 2H), 4.46 (dd, J=9.8,3.7Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.43-3.37 (m, 2H), 3.27 (dd, J=13.8,7.1Hz, 1H), 3.23-3.13 (m, 2H), 2.92 (s, 3H), 2.87 (dd, J=16.1,3.8Hz, 1H), 2.27 (s, 6H), 1.17 (t, J=6.9Hz, 3H), 0.97 (t, J=7.0Hz, 3H) .HRMS calcd.for C34H40FN4O8(M+H+)651.28247；found 651.28125.
Embodiment 126(S) the chloro- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -4- methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 126)
According to 88 the method for embodiment, using intermediate 250 (87.6mg, 0.2mmol) and intermediate 237 (123.0mg, 0.5mmol) preparation.Mp 117–119℃.1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),10.23(s, 1H),8.01(s,1H),7.16(s,1H),6.84(s,1H),6.81(s,1H),6.68(s,2H),4.53–4.41(m,1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.29-3.12 (m, 5H), 2.92 (s, 3H), 2.87 (dd, J=17.2, 4.4Hz, 1H), 2.25 (s, 6H), 1.17 (t, J=6.3Hz, 3H), 0.97 (t, J=6.7Hz, 3H)13C NMR(100MHz, DMSO-d6)δ169.43,167.68,166.43,164.93,156.12,151.90,149.33,144.18,143.88, 139.34,132.64,132.50,131.63,125.39,123.54,119.34,116.31,116.26,115.14,107.96, 60.99,60.77,56.20,52.40,41.18,29.72,29.49,20.85,13.94,12.96.HRMS calcd.for C34H40ClN4O8(M+H+)667.25292；found 667.25250.
Embodiment 127(S) the chloro- N- of the bromo- 6- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl Phenoxy group) -4- methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- three Methoxy benzamide (compound 127)
Prepare the chloro- 3,4,5- trimethoxybenzoic acid (intermediate 251) of the bromo- 6- of 2-:
Intermediate 237 (, 493mg, 2.0mmol) is mixed in 20mL chloroform with silver trifluoroacetate (883mg, 4.0mmol), It is stirred at room temperature down, the chloroformic solution of bromine (205 μ L, 4.0mmol) is slowly added dropwise.Precipitating is filtered out, it is successively molten with saturated sodium bicarbonate Liquid, washing are concentrated organic phase, water and ethyl alcohol recrystallization, obtain faint yellow solid 613mg, yield 94.1%.
Title compound (127) according to 88 the method for embodiment, using intermediate 250 (87.6mg, 0.2mmol) with 251 (162.5mg, 0.5mmol) preparation.Mp 136–138℃.1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),10.39 (s, 1H), 8.19 (s, 1H), 7.11 (s, 1H), 6.82 (s, 1H), 6.70 (s, 2H), 4.45 (dd, J=9.7,3.5Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.48-3.35 (m, 2H), 3.28-3.13 (m, 2H), 3.06 (dd, J= 13.4,6.4Hz, 1H), 2.91 (s, 3H), 2.85 (dd, J=15.8,3.2Hz, 1H), 2.25 (s, 6H), 1.17 (t, J= 6.6Hz, 3H), 0.97 (t, J=6.9Hz, 3H)13C NMR(100MHz,DMSO-d6)δ169.35,167.67,166.39, 163.54,156.05,149.76,149.21,147.78,144.23,139.35,134.03,132.43,132.24,125.62, 123.34,120.23,118.75,117.02,114.35,109.76,61.29,61.03,60.93,52.37,45.68, 41.16,29.68,29.47,20.82,13.92,12.95.HRMS calcd.for C34H39BrClN4O8(M+H+) 745.16343；found 745.16290.
Embodiment 128(S) the bromo- N- of -2- [3- [2- (dimethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -4- methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 128)
Prepare (S) -2- [8- (the bromo- 3,4,5- trimethoxy-benzamide base of 2-) -7- (3,5- dimethyl phenoxy) -4- Methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 252):
According to 88 the method for embodiment, using intermediate 249 (794.0mg, 2.0mmol) and intermediate 233 (1.46g, 5.0mmol) prepare.1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),10.22(s,1H),8.05(s,1H),7.17(s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.40 (dd, J=8.8,5.8Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.60 (s, 3H), 3.13 (dd, J=15.9,9.8Hz, 1H), 3.01 (dd, J=16.5,3.1Hz, 1H),2.89(s,3H),2.25(s,6H).13C NMR(100MHz,DMSO-d6)δ170.84,169.33,166.67,166.21, 156.28,152.76,150.52,144.56,143.86,139.64,134.02,132.93,132.57,125.67,123.46, 119.72,116.50,115.42,108.48,105.84,61.12,61.00,56.42,52.16,52.05,30.99,29.39, 21.06.
Title compound (128) according to 106 the method for embodiment, using intermediate 252 (134.0mg, 0.2mmol) with Dimethylamine (27.0mg, 0.6mmol) preparation.Mp 209–211℃.1H NMR(400MHz,DMSO-d6)δ10.46(s,1H), 10.21(s,1H),8.03(s,1H),7.16(s,1H),6.83(s,1H),6.81(s,1H),6.68(s,2H),4.42(dd,J =9.9,3.5Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.18 (dd, J=15.8,10.1Hz, 1H), 3.05 (s, 3H), 2.92 (s, 3H), 2.87 (dd, J=16.0,3.1Hz, 1H), 2.79 (s, 3H), 2.25 (s, 6H)13C NMR (100MHz,DMSO-d6)δ169.35,168.64,166.41,165.88,156.15,152.50,150.25,144.12, 143.56,139.29,133.94,132.61,132.57,125.33,123.46,119.34,116.31,115.08,108.29, 105.64,60.84,60.72,56.20,52.42,45.57,34.68,29.88,29.48,20.83.HRMS calcd.for C32H36BrN4O8(M+H+)683.1717；found 683.1694.
Embodiment 129(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -4- methyl -2,5- dioxo -3- [2- oxygen Generation -2- (pyrrolidin-1-yl) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- front three Oxybenzamide (compound 129)
According to 106 the method for embodiment, using intermediate 252 (134.0mg, 0.2mmol) and nafoxidine (42.6mg, 0.6mmol) preparation.Mp 149–151℃.1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),10.20(s, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.44 (dd, J=9.7, 3.8Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.52 (dd, J=16.2,7.1Hz, 2H), 3.23 (t, J =6.5Hz, 2H), 3.09 (dd, J=16.0,10.0Hz, 1H), 2.91 (s, 3H), 2.84 (dd, J=15.8,3.4Hz, 1H), 2.25 (s, 6H), 1.89 (dt, J=11.4,5.7Hz, 2H), 1.77 (dt, J=12.3,6.1Hz, 2H)13C NMR(100MHz, DMSO-d6)δ169.32,166.92,166.40,165.88,156.13,152.50,150.25,144.14,143.57, 139.30,133.95,132.59,125.35,123.42,119.33,116.33,115.08,108.29,105.64,60.84, 60.72,56.21,52.16,45.81,45.25,31.04,29.40,25.47,23.90,20.84.HRMS calcd.for C34H38BrN4O8(M+H+)709.18675；found 709.18616.
Embodiment 130(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -4- methyl -2,5- dioxo -3- [2- oxygen Generation -2- (piperidin-1-yl) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 130)
According to 106 the method for embodiment, using intermediate 252 (134.0mg, 0.2mmol) and piperidines (51.0mg, 0.6mmol) prepare.Mp 144–146℃.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),10.20(s,1H),8.02 (s, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.45 (dd, J=9.7,3.2Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.58-3.39 (m, 3H), 3.27 (d, J=4.5Hz, 1H), 3.20 (dd, J=15.9,10.8Hz, 1H), 2.92 (s, 3H), 2.85 (dd, J=15.6,1.8Hz, 1H), 2.25 (s, 6H), 1.58 (s, 4H),1.39(s,2H).13C NMR(100MHz,DMSO-d6)δ169.38,166.92,166.43,165.88,156.16, 152.51,150.26,144.11,143.57,139.30,133.96,132.63,132.54,125.33,123.51,119.34, 116.31,115.09,108.28,105.64,60.84,60.72,56.20,52.38,45.67,42.01,29.71,29.52, 25.94,25.22,23.96,20.83.HRMS calcd.for C35H40BrN4O8(M+H+)723.20240；found 723.20148.
Embodiment 131The bromo- N- of 2- [(3S) -7- (3,5- dimethyl phenoxy) -3- [2- (3,5- lupetidine -1- Base) -2- oxoethyl] -4- methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] - 3,4,5- trimethoxy-benzamide (compound 131)
According to 106 the method for embodiment, using intermediate 252 (134.0mg, 0.2mmol) and 3,5- lupetidine (267.8mg, 0.6mmol) preparation.Mp 148–150℃.1H NMR(400MHz,DMSO-d6) δ 10.44 (d, J=7.9Hz, 1H),10.21(s,1H),8.03(s,1H),7.17(s,1H),6.83(s,1H),6.82(s,1H),6.69(s,2H),4.46 (dd, J=9.7,3.9Hz, 1H), 4.27 (d, J=11.2Hz, 1H), 4.03-3.91 (m, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.41 (brs, 2H), 3.29-3.09 (m, 1H), 2.94 (s, 3H), 2.85 (dd, J=21.8,6.2Hz, 1H), 2.26 (s, 6H), 1.99 (q, J=11.7Hz, 1H), 1.76 (t, J=13.0Hz, 1H), 1.59 (d, J=37.6Hz, 1H), 1.36 (brs, 1H), 0.91 (t, J=7.2Hz, 3H), 0.83 (t, J=5.5Hz, 3H) .HRMS calcd.for C37H44BrN4O8(M+H+)751.23370；found 751.23328.
Embodiment 132(S) the bromo- N- of-2- [7- (3,5- dimethyl phenoxy)-4- methyl-3- (2- morpholine -2-oxo second Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 132)
According to 106 the method for embodiment, using intermediate 252 (134.0mg, 0.2mmol) and morpholine (52.3mg, 0.6mmol) prepare.Mp 154–156℃.1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),10.20(s,1H),8.03 (s, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.67 (s, 2H), 4.45 (dd, J=9.8,3.1Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.64-3.30 (m, 8H), 3.22 (dd, J=15.8,10.2Hz, 1H), 2.95–2.85(m,4H),2.25(s,6H).13C NMR(100MHz,DMSO-d6)δ169.32,167.67,166.44, 165.91,156.17,152.52,150.27,144.15,143.59,139.32,133.95,132.61,125.35,123.48, 119.39,116.30,115.12,108.30,105.65,66.09,66.03,60.87,60.75,56.22,52.36,45.23, 41.57,29.64,29.54,20.86.HRMS calcd.for C34H38BrN4O9(M+H+)725.18167；found 725.18152.
Embodiment 133(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -4- methyl -2,5- dioxo -3- (2- oxygen Generation -2- thio-morpholinyl ethyl) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 133)
According to 106 the method for embodiment, using intermediate 252 (134.0mg, 0.2mmol) and thiomorpholine (61.8mg, 0.6mmol) preparation.Mp 154–156℃.1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),10.21(s, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.45 (dd, J=9.9, 3.3Hz,1H),3.89–3.85(m,1H),3.80(s,3H),3.79(s,3H),3.77(brs,5H),3.63–3.51(m,1H), 3.22 (dd, J=16.0,10.5Hz, 1H), 2.93 (s, 3H), 2.88 (dd, J=16.7,2.9Hz, 1H), 2.66 (brs, 2H), 2.47(brs,2H),2.25(s,6H).13C NMR(100MHz,DMSO-d6)δ169.37,167.55,166.42,165.90, 156.14,152.51,150.26,144.16,143.57,139.31,133.95,132.59,132.56,125.35,123.47, 119.30,116.33,115.09,108.29,105.64,60.84,60.72,56.21,52.40,47.62,43.87,29.89, 29.57,26.91,26.41,20.83.HRMS calcd.for C34H38BrN4O8S(M+H+)741.15882；found 741.15729.
Embodiment 134(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -4- methyl -2,5- dioxo -3- [2- oxygen Generation -2- (4- oxo-piperidine -1- base) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- Trimethoxy-benzamide (compound 134)
According to 106 the method for embodiment, using intermediate 252 (134.0mg, 0.2mmol) and 4- oxo-piperidine (59.4mg, 0.6mmol) preparation.Mp 146–148℃.1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),10.23(s, 1H), 8.04 (s, 1H), 7.17 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.47 (dd, J=10.1, 3.6Hz, 1H), 3.94-3.82 (m, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.59 (dt, J=12.9, 6.4Hz, 1H), 3.38-3.28 (m, 1H), 3.00 (dd, J=16.1,3.5Hz, 1H), 2.95 (s, 3H), 2.47 (brs, 2H), 2.31 (t, J=6.2Hz, 2H), 2.25 (s, 6H)13C NMR(100MHz,DMSO-d6)δ207.23,169.38,168.01, 166.43,165.91,156.14,152.51,150.26,144.17,143.56,139.31,133.96,132.60,125.36, 123.45,119.33,116.33,115.12,108.28,105.64,60.86,60.74,56.21,52.44,42.87, 40.57,29.74,29.60,20.85.HRMS calcd.for C35H38BrN4O9(M+H+)737.1822；found 737.1800.
Embodiment 135(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -4- methyl -3- [2- (4- methyl piperazine -1- Base) -2- oxoethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- Trimethoxy-benzamide (compound 135)
According to 106 the method for embodiment, using intermediate 252 (134.0mg, 0.2mmol) and 4- methyl piperazine (60.1mg, 0.6mmol) preparation.Mp 165–167℃.1H NMR(400MHz,methanol-d4)δ8.21(s,1H),7.35 (s, 1H), 6.81 (s, 2H), 6.64 (s, 2H), 4.68 (dd, J=9.7,3.6Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.77-3.44 (m, 5H), 3.04 (s, 3H), 2.85 (dd, J=16.2,3.2Hz, 1H), 2.63 (s, 2H), 2.51(s,2H),2.41(s,3H),2.26(s,6H).13C NMR(100MHz,DMSO-d6)δ169.29,167.39,166.40, 165.88,156.15,152.50,150.25,144.12,143.56,139.29,133.94,132.60,132.57,125.33, 123.46,119.36,116.29,115.08,108.28,105.63,60.84,60.72,56.20,54.41,53.98, 52.34,45.22,44.24,40.70,29.71,29.53,20.84.HRMS calcd.for C35H41BrN5O8(M+H+) 738.21330；found 738.21259.
Embodiment 136(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -4- methyl -2,5- dioxo -3- [2- oxygen Generation -2- (piperazine -1- base) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 136)
According to 106 the method for embodiment, using intermediate 252 (134.0mg, 0.2mmol) and piperazine (51.6mg, 0.6mmol) prepare.Mp 155–157℃.1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),10.21(s,1H),8.02 (s, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.45 (dd, J=10.0,3.6Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.55-3.27 (m, 5H), 3.19 (dd, J=16.0,10.5Hz, 1H), (2.92 s, 3H), 2.86 (dd, J=16.0,3.2Hz, 1H), 2.79-2.54 (m, 4H), 2.25 (s, 6H)13C NMR (100MHz,CDCl3)δ170.08,167.74,167.63,165.27,155.62,153.28,151.17,145.43, 143.44,140.20,132.59,132.32,132.20,126.53,122.54,118.77,117.04,111.75,109.32, 106.46,61.23,61.21,56.46,53.11,46.52,45.96,45.50,42.70,30.21,30.12,21.37.HRMS calcd.for C34H39BrN5O8(M+H+)724.1982；found 724.1956.
Embodiment 137(S) the chloro- N- of -2- [7- (3,5- dimethyl phenoxy) -4- methyl -3- [2- (4- methyl piperazine -1- Base) -2- oxoethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- Trimethoxy-benzamide (compound 137)
Prepare (S) -2- [8- (the chloro- 3,4,5- trimethoxy-benzamide base of 2-) -7- (3,5- dimethyl phenoxy) -4- Methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 253):
According to 88 the method for embodiment, using intermediate 249 (397.4mg, 1.0mmol) and intermediate 237 (615.0mg, 2.5mmol) preparation.1H NMR(400MHz,DMSO)δ10.61(s,1H),10.26(s,1H),8.04(s,1H), 7.17 (s, 1H), 6.85 (s, 1H), 6.82 (s, 1H), 6.68 (s, 2H), 4.40 (dd, J=9.4,5.6Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.60 (s, 3H), 3.13 (dd, J=16.4,9.5Hz, 1H), 3.02 (dd, J= 17.1,4.8Hz,1H),2.89(s,3H),2.25(s,6H).
According to 106 the method for embodiment, using intermediate 253 (125.2mg, 0.2mmol) and 4- methyl piperazine (60.1mg, 0.6mmol) preparation.Mp 144–145℃.1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),10.23(s, 1H), 8.01 (s, 1H), 7.16 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.67 (s, 2H), 4.44 (dd, J=9.7, 3.8Hz,1H),3.81(s,3H),3.79(s,3H),3.77(s,3H),3.54(brs,2H),3.42(brs,2H),3.21(dd, J=16.1,10.4Hz, 1H), 2.95-2.84 (m, 4H), 2.37-2.16 (m, 13H) .HRMS calcd.for C35H41ClN5O8 (M+H+)694.26382；found 694.26318.
Embodiment 138(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -4- methyl -3- [2- (4- methyl piperazine -1- Base) -2- oxoethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,5- two Methoxyl group -4- methyl benzamide (compound 138)
According to 106 the method for embodiment, using intermediate 249 (397.4mg, 1.0mmol) and intermediate 242 (687.5g, 2.5mmol) is prepared through two-step reaction.Mp 134–135℃.1H NMR(400MHz,methanol-d4)δ8.19(s, 1H), 7.37 (s, 1H), 6.81 (s, 1H), 6.69 (s, 1H), 6.66 (s, 2H), 4.68 (dd, J=9.8,4.1Hz, 1H), 3.84-3.56 (m, 10H), 3.38 (dd, J=11.9,5.6Hz, 1H), 3.06 (s, 3H), 2.92 (brs, 1H), 2.81 (brs, 2H),2.69(brs,2H),2.53(s,3H),2.27(s,6H),2.19(s,3H).HRMS calcd.for C35H41BrN5O7(M +H+)722.21839；found 722.21655.
Embodiment 139(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -2, 5- dioxo -4- (propyl- 2- alkynes -1- base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- three Methoxy benzamide (compound 139)
Prepare (S) -2- (propyl- 2- alkynes -1- base amino) dimethyl succinate (intermediate 254):
L-Aspartic acid diformazan ester hydrochloride (4.94g, 25.0mmol) is dissolved in 25mL DMF, sequentially adds 3- propargyl bromide (2.05mL, 26.25mmol), potassium carbonate (7.25g, 52.5mmol) reacts at room temperature 12h.Filter out insoluble matter, silica gel column chromatography, DCM/MeOH elution, obtains yellow oily liquid 2.40g, yield 48.2%.1H NMR(400MHz,CDCl3) δ 3.84 (t, J= 5.9Hz,1H),3.76(s,3H),3.70(s,3H),3.52(s,2H),2.84–2.70(m,2H),2.51(s,1H),2.23(s, 1H).13C NMR(100MHz,CDCl3)δ173.47,171.26,81.01,72.24,56.24,52.45,52.06,37.55, 36.99.
Preparation (S) -2- [8- amino -7- (3,5- dimethyl phenoxy) -2,5- dioxo -4- (propyl- 2- alkynes -1- base) -2, 3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 256):
According to 1 the method for embodiment, using intermediate 189 (3.32g, 10.0mmol) and intermediate 254 (2.01g, 10.1mmol) prepared through two-step reaction.1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),7.02(s,1H),6.75(s, 1H),6.61(s,2H),6.43(s,1H),5.83(s,2H),4.52–4.34(m,2H),4.10–3.96(m,1H),3.59(s, 3H),3.30–3.04(m,3H),2.24(s,6H).13C NMR(100MHz,DMSO-d6)δ170.50,169.16,166.79, 156.89,144.59,139.37,139.15,134.33,124.67,120.73,115.32,113.07,104.94,79.86, 73.92,51.96,51.77,31.48,30.69,20.94.
Preparation (S) -2- [8- amino -7- (3,5- dimethyl phenoxy) -2,5- dioxo -4- (propyl- 2- alkynes -1- base) -2, 3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base]-N, N- diethyl acetamide (intermediate 257):
According to the preparation method of intermediate 232 described in embodiment 88, using intermediate 256 (421.0mg, 1.0mmol) It is prepared with diethylamine (219.0mg, 3.0mmol).1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),7.02(s,1H), 6.74 (s, 1H), 6.61 (s, 2H), 6.43 (s, 1H), 5.79 (s, 2H), 4.51 (d, J=7.7Hz, 1H), 4.43 (d, J= 18.0Hz, 1H), 4.06 (d, J=17.7Hz, 1H), 3.38 (dd, J=15.7,5.3Hz, 2H), 3.29-3.04 (m, 4H), 2.91 (d, J=15.4Hz, 1H), 2.24 (s, 6H), 1.18 (t, J=6.8Hz, 3H), 0.98 (t, J=6.6Hz, 3H)13C NMR(100MHz,DMSO-d6)δ169.42,167.66,166.90,156.95,144.45,139.18,139.12,134.54, 124.61,120.71,115.25,113.35,105.00,80.19,73.68,52.44,45.65,41.26,31.84,29.47, 20.93,13.94,12.98.
Title compound (139) is according to 1 the method for embodiment, using intermediate 257 (231.3mg, 0.5mmol) and 3, 4,5- trimethoxy-benzoyl chlorides (230.6mg, 1.0mmol) preparation.Mp 132–134℃.1H NMR(400MHz,DMSO-d6)δ 10.52(s,1H),9.87(s,1H),7.70(s,1H),7.28(s,1H),7.11(s,2H),6.77(s,1H),6.68(s, 2H), 4.58 (d, J=7.0Hz, 1H), 4.51 (d, J=18.0Hz, 1H), 4.13 (d, J=17.8Hz, 1H), 3.80 (s, 6H), 3.71 (s, 3H), 3.43-3.37 (m, 3H), 3.30-3.15 (m, 3H), 2.97 (d, J=13.1Hz, 1H), 2.22 (s, 6H), 1.19 (t, J=6.6Hz, 3H), 0.98 (t, J=6.7Hz, 3H)13C NMR(100MHz,DMSO-d6)δ169.44,167.54, 166.24,165.03,156.22,152.60,145.03,140.59,139.38,133.28,133.03,129.18,125.28, 123.08,120.35,116.83,115.71,105.31,79.67,74.03,60.11,56.00,52.39,41.25,32.06, 29.48,20.86,13.93,12.97.HRMS calcd.for C36H41N4O8(M+H+)657.29189；found 657.29053.
Embodiment 140(S) the bromo- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -4- (propyl- 2- alkynes -1- base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3, 4,5- trimethoxy-benzamide (compound 140)
According to 88 the method for embodiment, using intermediate 257 (92.4mg, 0.2mmol) and intermediate 233 (145.5mg, 0.5mmol) preparation.Mp 136–138℃.1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),10.24(s, 1H), 8.06 (s, 1H), 7.17 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.69 (s, 2H), 4.54 (d, J=7.6Hz, 1H), 4.48 (d, J=18.1Hz, 1H), 4.11 (d, J=17.8Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.42-3.35 (m, 3H), 3.30-3.15 (m, 3H), 2.94 (d, J=13.5Hz, 1H), 2.25 (s, 6H), 1.19 (t, J =6.7Hz, 3H), 0.98 (t, J=6.8Hz, 3H)13C NMR(100MHz,DMSO-d6)δ169.39,167.54,166.21, 165.95,156.11,152.53,150.27,144.13,143.59,139.35,133.97,132.95,132.85,125.44, 122.51,119.37,116.42,114.96,108.31,105.66,79.66,74.01,60.86,60.73,56.22, 52.37,41.26,32.02,29.44,20.85,13.92,12.97.HRMS calcd.for C36H40BrN4O8(M+H+) 735.20240；found 735.20087.
Embodiment 141(S) the chloro- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -4- (propyl- 2- alkynes -1- base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3, 4,5- trimethoxy-benzamide (compound 141)
According to 88 the method for embodiment, using intermediate 257 (92.4mg, 0.2mmol) and intermediate 237 (123.0mg, 0.5mmol) preparation.Mp 120–121℃.1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),10.26(s, 1H), 8.04 (s, 1H), 7.17 (s, 1H), 6.85 (s, 1H), 6.81 (s, 1H), 6.69 (s, 2H), 4.53 (dd, J=10.2, 3.7Hz, 1H), 4.48 (dd, J=17.7,2.0Hz, 1H), 4.11 (dd, J=17.5,1.6Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.40 (dt, J=12.9,6.5Hz, 3H), 3.30-3.20 (m, 2H), 3.18 (s, 1H), 2.95 (dd, J=15.9,3.6Hz, 1H), 2.25 (s, 6H), 1.18 (t, J=7.0Hz, 3H), 0.98 (t, J=7.0Hz, 3H)13C NMR(100MHz,DMSO-d6)δ169.37,167.52,166.19,164.94,156.10,151.89,149.32,144.11, 143.89,139.35,132.89,131.60,125.43,122.55,119.42,116.34,116.26,114.99,107.99, 79.64,74.00,60.98,60.75,56.20,52.37,41.26,32.01,29.45,20.84,13.92,12.96.HRMS calcd.for C36H40ClN4O8(M+H+)691.25292；found 691.25275.
Embodiment 142(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -3- [2- (4- methylpiperazine-1-yl) -2- oxygen For ethyl] -2,5- dioxo -4- (propyl- 2- alkynes -1- base) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- Base] -3,4,5- trimethoxy-benzamide (compound 142)
According to 106 the method for embodiment, using intermediate 256 (84.3mg, 0.2mmol) and intermediate 233 (145.5g, 0.5mmol) is prepared through two-step reaction.Mp 152–153℃.1H NMR(400MHz,DMSO-d6)δ10.47(s, 1H),10.25(s,1H),8.05(s,1H),7.16(s,1H),6.84(s,1H),6.81(s,1H),6.68(s,2H),4.51 (dd, J=10.3,3.2Hz, 1H), 4.46 (dd, J=17.9,2.5Hz, 1H), 4.13 (dd, J=17.9,2.1Hz, 1H), 3.80(s,3H),3.79(s,3H),3.77(s,3H),3.56(brs,2H),3.42–3.37(m,3H),3.15(s,1H),2.92 (d, J=13.0Hz, 1H), 2.41-2.16 (m, 13H) .HRMS calcd.for C37H41BrN5O8(M+H+)762.21330； found 762.21161.
Embodiment 143(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -4- Ethyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 143)
Prepare (S) -2- (ethylamino) dimethyl succinate (intermediate 258):
L-Aspartic acid diformazan ester hydrochloride (2.96g, 15.0mmol) is dissolved in 30mL methanol, sequentially adds triethylamine (2.5mL, 18.0mmol), 40% acetaldehyde solution (3.03mL, 30.0mmol) reacts at room temperature 5h.10%Pd/C 1.5g is added, Normal temperature and pressure hydrogenation 12h.Pd/C, silica gel column chromatography are filtered out, DCM/MeOH elution obtains yellow oily liquid 1.34g, yield 47.2%.1H NMR(400MHz,CDCl3)δ3.75(s,3H),3.73–3.64(m,4H),2.82–2.53(m,4H),2.20 (brs, 1H), 1.11 (t, J=7.1Hz, 3H)13C NMR(100MHz,CDCl3)δ174.24,171.46,57.63,52.24, 51.98,42.52,37.89,15.28.
Prepare (S) -2- [8- amino -7- (3,5- dimethyl phenoxy) -4- ethyl -2,5- dioxo -2,3,4,5- four Hydrogen -1H- benzo [e] [1,4] diazepine -3- base]-N, N- diethyl acetamide (intermediate 259):
According to the preparation method of intermediate described in embodiment 139 (257), using intermediate 189 (3.32g, 10.0mmol) prepared with intermediate 258 (1.91g, 10.1mmol) through three-step reaction.1H NMR(400MHz,DMSO-d6)δ 10.13(s,1H),6.99(s,1H),6.74(s,1H),6.60(s,2H),6.41(s,1H),5.70(s,2H),4.48(dd,J =10.2,3.7Hz, 1H), 3.41 (dd, J=14.1,6.9Hz, 2H), 3.30-3.08 (m, 5H), 2.76 (dd, J=15.7, 3.8Hz, 1H), 2.24 (s, 6H), 1.17 (t, J=7.0Hz, 3H), 0.99 (dt, J=13.9,7.1Hz, 6H)13C NMR (100MHz,DMSO-d6)δ170.67,167.77,166.94,157.03,143.97,139.16,139.11,134.30, 124.55,120.56,115.20,114.83,105.05,52.30,41.21,37.46,29.67,20.93,14.16,13.92, 12.97.
Title compound (143) is according to 1 the method for embodiment, using intermediate 259 (90.4mg, 0.2mmol) and 3, 4,5- trimethoxy-benzoyl chlorides (92.2mg, 0.4mmol) preparation.Mp 128–130℃.1H NMR(400MHz,DMSO-d6)δ 10.47(s,1H),9.86(s,1H),7.64(s,1H),7.24(s,1H),7.11(s,2H),6.77(s,1H),6.67(s, 2H), 4.53 (dd, J=9.9,3.5Hz, 1H), 3.80 (s, 6H), 3.71 (s, 3H), 3.49-3.37 (m, 2H), 3.30-3.11 (m, 4H), 2.84 (dd, J=15.7,3.3Hz, 1H), 2.58 (dd, J=18.6,5.1Hz, 1H), 2.22 (s, 6H), 1.18 (t, J=6.9Hz, 3H), 1.04 (t, J=6.8Hz, 3H), 0.98 (t, J=6.9Hz, 3H)13C NMR(100MHz,DMSO-d6)δ 170.67,167.65,166.17,165.00,156.27,152.59,145.13,140.56,139.35,132.81,129.22, 125.23,124.42,120.12,116.84,115.70,115.38,105.30,60.10,55.99,52.26,41.18, 37.76,29.60,20.85,13.91,12.96.HRMS calcd.for C35H43N4O8(M+H+)647.30754；found 647.30609.
Embodiment 144(S) the bromo- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -4- ethyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 144)
According to 88 the method for embodiment, using intermediate 259 (90.4mg, 0.2mmol) and intermediate 233 (145.5mg, 0.5mmol) preparation.Mp 127–129℃.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),10.22(s, 1H), 8.02 (s, 1H), 7.14 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.50 (dd, J=9.3, 1.8Hz, 1H), 3.79 (s, 6H), 3.77 (s, 3H), 3.43 (brs, 2H), 3.30-3.14 (m, 4H), 2.82 (dd, J=15.2, 2.5Hz, 1H), 2.59 (dd, J=12.6,6.4Hz, 1H), 2.25 (s, 6H), 1.17 (t, J=6.5Hz, 3H), 1.03 (t, J= 6.6Hz, 3H), 0.97 (t, J=6.6Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.60,167.65,166.15, 165.89,156.18,152.52,150.26,144.16,143.57,139.31,133.98,132.65,132.48,125.36, 123.85,119.21,116.35,115.95,114.95,108.29,105.65,60.84,60.72,56.21,52.23, 41.18,37.74,29.57,20.84,13.92,12.95.HRMS calcd.for C35H42BrN4O8(M+H+)725.21805； found 725.21814.
Embodiment 145(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -4- Isopropyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene Formamide (compound 145)
Prepare (S) -2- (isopropylamino) dimethyl succinate (intermediate 260):
According to the preparation method of intermediate described in embodiment 143 (258), using L-Aspartic acid diformazan ester hydrochloride It is prepared by (2.96g, 15.0mmol) and acetone (1.74g, 30.0mmol).1H NMR(400MHz,CDCl3)δ3.76–3.70(m, 4H), 3.69 (s, 3H), 2.81 (dt, J=12.4,6.2Hz, 1H), 2.67 (qd, J=15.8,6.4Hz, 2H), 1.84 (s, 1H), 1.06 (d, J=6.3Hz, 3H), 1.02 (d, J=6.1Hz, 3H)13C NMR(100MHz,CDCl3)δ174.80, 171.42,55.40,52.27,51.96,47.34,38.67,23.63,22.21.
Title compound (145) is intermediate using intermediate 189 (3.32g, 10.0mmol) according to 1 the method for embodiment Body 260 (2.05g, 10.1mmol) and 3,4,5- trimethoxy-benzoyl chlorides (4.61g, 20.0mmol) are prepared through four-step reaction. Mp 124–126℃.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),9.84(s,1H),7.70(s,1H),7.34(s, 1H), 7.08 (s, 2H), 6.75 (s, 1H), 6.60 (s, 2H), 4.85 (dt, J=13.7,6.8Hz, 1H), 4.62 (t, J= 6.8Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.41 (dd, J=15.2,8.0Hz, 1H), 3.23 (ddd, J=19.9, 14.2,7.2Hz 3H), 3.01 (q, J=6.9Hz, 1H), 2.52 (s, 1H), 2.20 (s, 6H), 1.16 (d, J=6.8Hz, 3H), 1.09 (d, J=6.6Hz, 3H), 0.97 (t, J=7.0Hz, 3H), 0.85 (t, J=7.0Hz, 3H) .HRMS calcd.for C36H45N4O8(M+H+)661.32319；found 661.32190.
Embodiment 146(S) the bromo- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene oxygen Base) -4- isopropyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- front three Oxybenzamide (compound 146)
According to 88 the method for embodiment, using intermediate 261 (93.3mg, 0.2mmol) and intermediate 233 (145.5mg, 0.5mmol) preparation.Mp 121–123℃.1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),10.19(s, 1H), 8.04 (s, 1H), 7.24 (s, 1H), 6.79 (s, 1H), 6.77 (s, 1H), 6.65 (d, J=30.9Hz, 2H), 4.83 (dt, J=13.5,6.7Hz, 1H), 4.58 (t, J=6.7Hz, 1H), 3.79 (s, 6H), 3.75 (s, 3H), 3.41 (dt, J=10.6, 7.1Hz, 1H), 3.30-2.94 (m, 4H), 2.47 (brs, 1H), 2.23 (s, 6H), 1.14 (d, J=6.6Hz, 3H), 1.07 (d, J=6.7Hz, 3H), 0.96 (t, J=7.0Hz, 3H), 0.84 (t, J=7.0Hz, 3H) .HRMS calcd.for C36H44BrN4O8(M+H+)739.23370；found 739.23328.
Embodiment 147N- [(3S) -3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) - 4- (2- methyl amyl) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- three Methoxy benzamide (compound 147)
According to method described in embodiment 143, using L-Aspartic acid diformazan ester hydrochloride (2.96g, 15.0mmol), third Aldehyde (1.74g, 30.0mmol) and 3,4,5- trimethoxy-benzoyl chlorides (6.92g, 30.0mmol) are prepared through four-step reaction.Mp 111–113℃.1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),9.88(s,1H),7.66(s,1H),7.28(s,1H), 7.12 (s, 2H), 6.77 (s, 1H), 6.67 (s, 2H), 4.55 (dd, J=11.8,7.4Hz, 1H), 3.91 (dd, J=24.6, 12.6Hz, 1H), 3.81 (s, 6H), 3.71 (s, 3H), 3.41 (qd, J=15.4,7.8Hz, 2H), 3.31-3.02 (m, 3H), 3.02-2.79 (m, 2H), 2.22 (s, 6H), 1.77 (brs, 1H), 1.38-1.08 (m, 6H), 0.98 (t, J=7.2Hz, 3H), 0.93–0.65(m,7H).HRMS calcd.for C39H51N4O8(M+H+)703.37014；found 703.36902.
Embodiment 148The bromo- N- of 2- [(3S) -3- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl benzene Oxygroup) -4- (2- methyl amyl) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3, 4,5- trimethoxy-benzamide (compound 148)
According to method described in embodiment 143, L-Aspartic acid diformazan ester hydrochloride (1.00g, 5.0mmol), propionic aldehyde (0.58g, 10.0mmol) and intermediate 233 (3.64g, 12.5mmol) is prepared through four-step reaction.Mp 128–130℃.1H NMR (400MHz,DMSO-d6)δ10.50(s,1H),10.22(s,1H),8.01(s,1H),7.17(s,1H),6.82(s,1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.58-4.44 (m, 1H), 3.89 (dd, J=20.4,8.9Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.41 (ddd, J=17.5,15.8,7.6Hz, 2H), 3.31-3.00 (m, 3H), 2.98- 2.78 (m, 2H), 2.25 (s, 6H), 1.74 (s, 1H), 1.38-1.08 (m, 6H), 0.97 (t, J=7.1Hz, 3H), 0.91- 0.64(m,7H).HRMS calcd.for C39H50BrN4O8(M+H+)781.28065；found 781.28009.
Embodiment 149(S)-N- [7- (the bromo- 5- methylphenoxy of 3-) -3- [2- (diethylamino) -2- oxoethyl] - 2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzamide (compound 149)
Prepare 5- (the bromo- 5- methylphenoxy of 3-) -2,4- dinitrobenzoic acid (intermediate 262): according to institute in embodiment 1 Method is stated, is prepared using intermediate 188 (2.46g, 10.0mmol) and the bromo- 5- methylphenol (1.98g, 10.6mmol) of 3-.
1H NMR(400MHz,DMSO-d6)δ14.61(brs,1H),8.74(s,1H),7.39(s,1H),7.36(s,1H), 7.26(s,1H),7.14(s,1H),2.33(s,3H).
Prepare (S) -2- [8- amino -7- (the bromo- 5- methylphenoxy of 3-) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzene And [e] [Isosorbide-5-Nitrae] diazepine -3- base] methyl acetate (intermediate 263): according to method described in embodiment 1, using intermediate It is prepared by 262 (1.99g, 5.0mmol) and L-Aspartic acid diformazan ester hydrochloride (1.00g, 5.05mmol).
1H NMR(300MHz,DMSO-d6) δ 10.29 (s, 1H), 8.22 (d, J=5.0Hz, 1H), 7.14 (s, 1H), 7.10 (s,1H),6.90(s,1H),6.80(s,1H),6.45(s,1H),5.85(s,2H),4.13–4.05(m,1H),3.59(s, 3H), 2.86 (dd, J=17.0,8.7Hz, 1H), 2.70 (dd, J=17.0,5.7Hz, 1H), 2.28 (s, 3H)
Prepare (S) -2- [8- amino -7- (the bromo- 5- methylphenoxy of 3-) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzene And [e] [Isosorbide-5-Nitrae] diazepine -3- base]-N, N- diethyl acetamide (intermediate 264): according to method described in embodiment 88, It is prepared using intermediate 263 (896.0mg, 2.0mmol) and diethylamine (438.8mg, 6.0mmol).
1H NMR(400MHz,DMSO-d6) δ 10.16 (s, 1H), 8.14 (d, J=5.2Hz, 1H), 7.13 (s, 1H), 7.10 (s,1H),6.90(s,1H),6.79(s,1H),6.44(s,1H),5.82(s,2H),4.19–4.12(m,1H),3.32–3.14 (m, 4H), 2.96 (dd, J=16.3,8.7Hz, 1H), 2.56 (dd, J=16.3,4.8Hz, 1H), 2.28 (s, 3H), 1.16 (t, J=7.0Hz, 3H), 0.98 (t, J=7.0Hz, 3H)
Prepare title compound (149): according to method described in embodiment 88, using intermediate 264 (97.8mg, 0.2mmol) prepared with intermediate 233 (145.5mg, 0.5mmol).Mp 159–161℃.1H NMR(400MHz,DMSO-d6)δ 10.49 (s, 1H), 9.97 (s, 1H), 8.59 (d, J=5.3Hz, 1H), 7.62 (s, 1H), 7.35 (s, 1H), 7.15 (s, 1H), 7.07 (s, 2H), 7.00 (s, 1H), 6.85 (s, 1H), 4.24 (dt, J=9.0,5.3Hz, 1H), 3.80 (s, 6H), 3.70 (s, 3H), 3.32-3.18 (m, 4H), 3.00 (dd, J=16.3,8.5Hz, 1H), 2.63 (dd, J=16.3,4.9Hz, 1H), 2.24 (s, 3H), 1.17 (t, J=7.0Hz, 3H), 0.99 (t, J=7.0Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.83, 167.89,166.67,165.07,157.35,152.57,144.32,141.97,140.56,133.57,133.39,129.05, 126.83,123.76,121.80,121.14,117.84,117.61,117.26,105.29,60.12,56.01,49.02, 41.36,31.28,20.60,13.91,13.05.HRMS calcd.for C32H36BrN4O8(M+H+)683.17110；found 683.17065.
Embodiment 150(S)-N- [7- (3- cyano -5- methylphenoxy) -3- [2- (diethylamino) -2- oxo second Base] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 150)
Prepare (S) -2- [8- amino -7- (3- cyano -5- methylphenoxy) -2,5- dioxo -2,3,4,5- tetrahydro -1H- Benzo [e] [Isosorbide-5-Nitrae] diazepine -3- base] methyl acetate (intermediate 265): according to method described in embodiment 1, using centre Body 8 (2.46g, 10.0mmol), 3- cyano -5- methylphenol (1.41g, 10.6mmol), L-Aspartic acid diformazan ester hydrochloride (2.00g, 10.1mmol) is prepared through three-step reaction.
1H NMR(400MHz,DMSO-d6) δ 10.30 (s, 1H), 8.22 (d, J=4.8Hz, 1H), 7.39 (s, 1H), 7.19 (s,1H),7.12(s,2H),6.46(s,1H),5.88(s,2H),4.14–4.06(m,1H),3.59(s,3H),2.86(dd,J =16.9,9.0Hz, 1H), 2.70 (dd, J=17.0,5.6Hz, 1H), 2.33 (s, 3H)
Prepare (S) -2- [7- (3- cyano -5- methylphenoxy) -2,5- dioxo -8- (3,4,5- trimethoxybenzoyl Amido) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 266): according to implementation Method described in example 1, using intermediate 265 (78.8mg, 0.5mmol) and 3,4,5- trimethoxy-benzoyl chlorides (230.6mg, 1.0mmol) prepare.
1H NMR(300MHz,DMSO-d6) δ 10.63 (s, 1H), 10.01 (s, 1H), 8.65 (d, J=5.1Hz, 1H), 7.61 (s, 1H), 7.41 (s, 1H), 7.39 (s, 1H), 7.26 (s, 1H), 7.20 (s, 1H), 7.04 (s, 2H), 4.22 (dt, J= 8.7,5.6Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.61 (s, 3H), 2.91 (dd, J=16.8,9.0Hz, 1H), 2.76 (dd, J=17.2,5.8Hz, 1H), 2.29 (s, 3H)
Prepare title compound (compound 150): (specific using intermediate 266 according to method described in embodiment 106 It is 117.6mg, 0.2mmol) it is prepared with diethylamine (43.8mg, 0.6mmol).Mp 146–148℃.1H NMR(400MHz, DMSO-d6) δ 10.50 (s, 1H), 10.00 (s, 1H), 8.59 (d, J=5.3Hz, 1H), 7.59 (s, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 7.27 (s, 1H), 7.19 (s, 1H), 7.05 (s, 2H), 4.26 (dt, J=9.2,5.2Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.32-3.17 (m, 4H), 3.01 (dd, J=16.2,8.6Hz, 1H), 2.62 (dd, J=16.5, 4.8Hz, 1H), 2.29 (s, 3H), 1.17 (t, J=7.0Hz, 3H), 0.99 (t, J=7.0Hz, 3H) .HRMS calcd.for C33H36N5O8(M+H+)630.25584；found 630.25513.
Embodiment 151(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3- isopropyl -5- methylenedioxy phenoxy Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 151)
Prepare 5- (3- isopropyl -5- methylphenoxy) -2,4- dinitrobenzoic acid (intermediate 267): according to embodiment 1 Described in method, using intermediate 188 (2.46g, 10.0mmol) with (3- isopropyl -5- methylphenol (1.59g, 10.6mmol) preparation.
1H NMR(400MHz,DMSO-d6)δ14.65(brs,1H),8.74(s,1H),7.11(s,1H),7.06(s,1H), 6.96 (s, 1H), 6.90 (s, 1H), 2.89 (dt, J=13.7,6.8Hz, 1H), 2.32 (s, 3H), 1.20 (s, 3H), 1.18 (s, 3H).
Prepare (S) -2- [8- amino -7- (3- isopropyl -5- methylphenoxy) -2,5- dioxo -2,3,4,5- tetrahydro - 1H- benzo [e] [Isosorbide-5-Nitrae] diazepine -3- base] methyl acetate (intermediate 268): according to method described in embodiment 1, in It is prepared by mesosome 267 (1.80g, 5.0mmol) and L-Aspartic acid diformazan ester hydrochloride (1.00g, 5.05mmol).
1H NMR(400MHz,CDCl3) δ 8.46 (brs, 1H), 7.40 (s, 1H), 6.88 (d, J=8.6Hz, 1H), 6.80 (s, 1H), 6.72 (s, 1H), 6.60 (s, 1H), 6.36 (s, 1H), 4.36-4.30 (m, 1H), 4.12 (q, J=7.1Hz, 1H), 3.73 (s, 3H), 3.06 (dd, J=16.4,8.0Hz, 1H), 2.73 (dd, J=16.5,5.6Hz, 1H), 2.30 (s, 3H), 1.23(s,3H),1.22(s,3H).
Prepare (S) -2- [8- amino -7- (3- isopropyl -5- methylphenoxy) -2,5- dioxo -2,3,4,5- tetrahydro - 1H- benzo [e] [1,4] diazepine -3- base]-N, N- diethyl acetamide (intermediate 269): according to described in embodiment 88 Method is prepared using intermediate 268 (822.0mg, 2.0mmol) and diethylamine (438.8mg, 6.0mmol).
1H NMR(400MHz,DMSO-d6) δ 10.11 (s, 1H), 8.09 (d, J=5.3Hz, 1H), 7.00 (s, 1H), 6.81 (s,1H),6.71(s,1H),6.56(s,1H),6.42(s,1H),5.75(s,2H),4.19–4.09(m,1H),3.32–3.15 (m, 5H), 2.96 (dd, J=16.3,8.7Hz, 1H), 2.58-2.52 (m, 1H), 2.25 (s, 3H), 1.19-1.14 (m, 9H), 0.98 (t, J=7.0Hz, 3H)
Prepare title compound (151): according to method described in embodiment 88, using intermediate 269 (226.3mg, 0.5mmol) prepared with 3,4,5- trimethoxy-benzoyl chlorides (230.6mg, 1.0mmol).Mp 142–144℃.1H NMR (400MHz,DMSO-d6) δ 10.44 (s, 1H), 9.89 (s, 1H), 8.54 (d, J=5.4Hz, 1H), 7.61 (s, 1H), 7.27 (s, 1H), 7.10 (s, 2H), 6.83 (s, 1H), 6.70 (s, 1H), 6.65 (s, 1H), 4.21 (dt, J=7.8,5.3Hz, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.32-3.18 (m, 4H), 3.00 (dd, J=16.5,8.5Hz, 1H), 2.83-2.74 (m, 1H), 2.62 (dd, J=16.1,4.7Hz, 1H), 2.24 (s, 3H), 1.17 (t, J=7.0Hz, 3H), 1.12 (d, J=2.4Hz, 3H), 1.10 (d, J=2.4Hz, 3H), 0.99 (t, J=7.0Hz, 3H) .HRMS calcd.for C35H41N4O8(M+H+) 647.3081；found 647.30754.
Embodiment 152(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- [3- methyl -5- (trifluoromethyl) Phenoxy group] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 152)
Prepare 5- [3- methyl -5- (trifluoromethyl) phenoxy group] -2,4- dinitrobenzoic acid (intermediate 270): according to reality Method described in example 1 is applied, using intermediate 188 (2.46g, 10.0mmol) and [3- methyl -5- (trifluoromethyl) phenol (1.87g, 10.6mmol) preparation.
1H NMR(400MHz,DMSO-d6)δ14.49(brs,1H),8.84(s,1H),7.54(s,1H),7.51(s,1H), 7.45(s,1H),7.41(s,1H),2.42(s,3H).
Prepare (S) -2- [8- amino -7- [3- methyl -5- (trifluoromethyl) phenoxy group] -2,5- dioxo -2,3,4,5- four Hydrogen -1H- benzo [e] [Isosorbide-5-Nitrae] diazepine -3- base] methyl acetate (intermediate 271): according to method described in embodiment 1, adopt It is prepared with intermediate 270 (1.93g, 5.0mmol) and L-Aspartic acid diformazan ester hydrochloride (1.00g, 5.05mmol).
1H NMR(400MHz,DMSO-d6) δ 10.30 (s, 1H), 8.21 (d, J=4.9Hz, 1H), 7.27 (s, 1H), 7.13 (s,1H),7.04(s,2H),6.46(s,1H),5.89(s,2H),4.11–4.05(m,1H),3.59(s,3H),2.86(dd,J =16.9,8.9Hz, 1H), 2.70 (dd, J=17.0,5.6Hz, 1H), 2.37 (s, 3H)
Prepare (S) -2- [7- [3- methyl -5- (trifluoromethyl) phenoxy group] -2,5- dioxo -8- (3,4,5- trimethoxy Benzamido) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 272): according to According to method described in embodiment 1, using 3,4,5- trimethoxy-benzoyl chloride of intermediate 271 (218.5mg, 0.5mmol) (230.6mg, 1.0mmol) preparation.
1H NMR(400MHz,DMSO-d6) δ 10.64 (s, 1H), 10.03 (s, 1H), 8.66 (d, J=5.3Hz, 1H), 7.62(s,1H),7.38(s,1H),7.30(s,1H),7.12(s,2H),7.04(s,2H),4.21–4.15(m,1H),3.77 (s, 6H), 3.69 (s, 3H), 3.60 (s, 3H), 2.90 (dd, J=17.0,8.8Hz, 1H), 2.76 (dd, J=16.9,5.7Hz, 1H),2.34(s,3H).
Prepare title compound (152): according to method described in embodiment 106, using intermediate 272 (126.2mg, 0.2mmol) prepared with diethylamine (438.8mg, 6.0mmol).Mp 146–147℃.1H NMR(400MHz,DMSO-d6)δ 10.51 (s, 1H), 10.01 (s, 1H), 8.59 (d, J=5.4Hz, 1H), 7.61 (s, 1H), 7.38 (s, 1H), 7.29 (s, 1H), 7.12 (s, 2H), 7.04 (s, 2H), 4.24 (dt, J=8.5,5.2Hz, 1H), 3.77 (s, 6H), 3.69 (s, 3H), 3.32- 3.14 (m, 4H), 3.00 (dd, J=16.4,8.8Hz, 1H), 2.63 (dd, J=16.1,4.9Hz, 1H), 2.33 (s, 3H), 1.17 (t, J=7.0Hz, 3H), 0.99 (t, J=7.0Hz, 3H) .HRMS calcd.for C33H36F3N4O8(M+H+) 673.24798；found 673.24677.
Embodiment 153(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- [(3,5- 3,5-dimethylphenyl) sulphur Base] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 153)
Prepare 5- [(3,5- 3,5-dimethylphenyl) sulfenyl] -2,4- dinitrobenzoic acid (intermediate 273): according to embodiment 1 Described in method, made using intermediate 188 (2.46g, 10.0mmol) and 3,5- thiophenol dimethyl benzene (1.46g, 10.6mmol) It is standby.
1H NMR(400MHz,DMSO-d6)δ14.40(brs,1H),8.83(s,1H),7.33(s,2H),7.28(s,1H), 7.07(s,1H),2.33(s,6H).
Prepare (S) -2- [8- amino -7- [(3,5- 3,5-dimethylphenyl) sulfenyl] -2,5- dioxo -2,3,4,5- tetrahydro - 1H- benzo [e] [Isosorbide-5-Nitrae] diazepine -3- base] methyl acetate (intermediate 274): according to method described in embodiment 1, in It is prepared by mesosome 273 (1.74g, 5.0mmol) and L-Aspartic acid diformazan ester hydrochloride (1.00g, 5.05mmol).
1H NMR(400MHz,DMSO-d6) δ 10.41 (s, 1H), 8.23 (d, J=5.0Hz, 1H), 7.71 (s, 1H), 6.81 (s, 1H), 6.74 (s, 2H), 6.42 (s, 1H), 6.07 (s, 2H), 4.09 (dt, J=8.7,5.6Hz, 1H), 3.59 (s, 3H), 2.86 (dd, J=17.0,8.7Hz, 1H), 2.71 (dd, J=17.0,5.8Hz, 1H), 2.19 (s, 6H)
Prepare (S) -2- [7- [(3,5- 3,5-dimethylphenyl) sulfenyl] -2,5- dioxo -8- (3,4,5- trimethoxy-benzene first Amide groups) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 275): according to reality Method described in example 1 is applied, intermediate is using 274 (200.0mg, 0.5mmol) and 3,4,5- trimethoxy-benzoyl chlorides (230.6mg, 1.0mmol) preparation.
1H NMR(400MHz,DMSO-d6) δ 10.74 (s, 1H), 9.88 (s, 1H), 8.64 (d, J=5.2Hz, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.14 (s, 2H), 6.88 (s, 1H), 6.87 (s, 2H), 4.15 (dt, J=8.4,5.7Hz, 1H), 3.81 (s, 6H), 3.72 (s, 3H), 3.60 (s, 3H), 2.90 (dd, J=17.0,8.5Hz, 1H), 2.75 (dd, J=17.0, 5.9Hz,1H),2.18(s,6H).
Prepare title compound (153): according to method described in embodiment 106, using intermediate 275 (118.6mg, Mmol it) is prepared with diethylamine (438.8mg, 6.0mmol).Mp 144–146℃.1H NMR(400MHz,DMSO-d6)δ10.62 (s, 1H), 9.87 (s, 1H), 8.58 (d, J=5.4Hz, 1H), 7.75 (s, 1H), 7.61 (s, 1H), 7.14 (s, 2H), 6.87 (s, 3H), 4.21 (brs, 1H), 3.81 (s, 6H), 3.72 (s, 3H), 3.33-3.19 (m, 4H), 2.99 (dd, J=16.2, 8.4Hz, 1H), 2.63 (dd, J=16.6,5.3Hz, 1H), 2.17 (s, 6H), 1.17 (t, J=7.1Hz, 3H), 0.99 (t, J= 7.0Hz,3H).HRMS calcd.for C33H39N4O7S(M+H+)635.25340；found 635.25238.
Embodiment 154(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- [(3,5- 3,5-dimethylphenyl) sulphonyl Base] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 154)
Intermediate 153 (150mg, 0.24mmol) is dissolved in 5mL DCM, under the conditions of 0 DEG C, add 85%mCPBA (144mg, 0.79mmol), 3h is reacted at room temperature.Silica gel column chromatography, DCM/MeOH elution, obtains white solid 80mg, yield 51.0%.Mp 160–161℃.1H NMR(400MHz,DMSO-d6) δ 10.92 (s, 1H), 10.35 (s, 1H), 8.77 (d, J=5.4Hz, 1H), 8.41(s,1H),7.93(s,1H),7.40(s,2H),7.29(s,1H),7.29(s,2H),4.28–4.17(m,1H),3.90 (s, 6H), 3.78 (s, 3H), 3.31-3.18 (m, 4H), 2.98 (dd, J=16.4,8.6Hz, 1H), 2.64 (dd, J=16.5, 5.2Hz, 1H), 2.16 (s, 6H), 1.16 (t, J=7.0Hz, 3H), 0.98 (t, J=7.1Hz, 3H)13C NMR(100MHz, DMSO-d6)δ170.66,167.70,166.04,163.86,153.08,142.26,141.22,139.90,139.52, 138.92,135.63,133.20,128.44,125.66,124.30,122.35,115.70,104.81,60.25,56.19, 49.10,41.35,31.21,20.49,13.87,13.01.HRMS calcd.for C33H39N4O9S(M+H+)667.24323； found 667.24268.
Embodiment 155(S)-N- [7- (the chloro- 5- methylphenoxy of 3-) -3- [2- (diethylamino) -2- oxoethyl] - 2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzamide (compound 155)
Prepare 5- (the chloro- 5- methylphenoxy of 3-) -2,4- dinitrobenzoic acid (intermediate 276): according to institute in embodiment 1 Method is stated, is prepared using intermediate 188 (2.46g, 10.0mmol) and the chloro- 5- methylphenol (1.50g, 10.6mmol) of 3-.
1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),7.28(s,1H),7.23(s,2H),7.09(s,1H), 2.33(s,3H).13C NMR(100MHz,DMSO-d6)δ164.45,154.64,152.62,142.55,141.34,139.59, 136.18,134.04,126.55,122.62,119.88,119.22,117.20,20.63.
Prepare (S) -2- [8- amino -7- (the chloro- 5- methylphenoxy of 3-) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzene And [e] [Isosorbide-5-Nitrae] diazepine -3- base] methyl acetate (intermediate 277): according to method described in embodiment 1, using intermediate It is prepared by 276 (1.76g, 5.0mmol) and L-Aspartic acid diformazan ester hydrochloride (1.00g, 5.05mmol).
1H NMR(400MHz,DMSO-d6) δ 10.28 (s, 1H), 8.20 (d, J=4.9Hz, 1H), 7.11 (s, 1H), 6.99 (s,1H),6.78(s,1H),6.76(s,1H),6.45(s,1H),5.84(s,2H),4.11–4.04(m,1H),3.59(s, 3H), 2.86 (dd, J=17.0,8.9Hz, 1H), 2.70 (dd, J=16.9,5.5Hz, 1H), 2.28 (s, 3H)13C NMR (100MHz,DMSO-d6)δ170.66,170.43,167.30,158.08,144.64,141.45,137.96,134.85, 133.40,123.25,121.77,116.30,114.12,113.62,105.72,51.52,48.75,32.59,20.78.
Prepare (S) -2- [8- amino -7- (the chloro- 5- methylphenoxy of 3-) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzene And [e] [Isosorbide-5-Nitrae] diazepine -3- base]-N, N- diethyl acetamide (intermediate 278): according to method described in embodiment 88, It is prepared using intermediate 277 (80.6mg, 0.2mmol) and diethylamine (43.8mg, 0.6mmol).
1H NMR(400MHz,DMSO-d6) δ 10.16 (s, 1H), 8.14 (d, J=5.3Hz, 1H), 7.10 (s, 1H), 6.99 (s,1H),6.77(s,1H),6.75(s,1H),6.44(s,1H),5.82(s,2H),4.19–4.12(m,1H),3.31–3.18 (m, 4H), 2.96 (dd, J=16.3,8.6Hz, 1H), 2.56 (dd, J=16.3,4.8Hz, 1H), 2.28 (s, 3H), 1.16 (t, J=7.0Hz, 3H), 0.98 (t, J=7.0Hz, 3H)
Prepare title compound (155): according to method described in embodiment 1, using intermediate 278 (222.5mg, 0.5mmol) prepared with 3,4,5- trimethoxy-benzoyl chlorides (230.6mg, 1.0mmol).Mp 156–158℃.1H NMR (400MHz,DMSO-d6) δ 10.49 (s, 1H), 9.97 (s, 1H), 8.59 (d, J=5.0Hz, 1H), 7.62 (s, 1H), 7.35 (s, 1H), 7.07 (s, 2H), 7.02 (s, 1H), 6.88 (s, 1H), 6.81 (s, 1H), 4.24 (dt, J=7.8,5.1Hz, 1H), 3.80 (s, 6H), 3.70 (s, 3H), 3.32-3.18 (m, 4H), 3.00 (dd, J=16.6,8.9Hz, 1H), 2.62 (dd, J= 16.4,5.0Hz, 1H), 2.25 (s, 3H), 1.17 (t, J=7.0Hz, 3H), 0.99 (t, J=6.9Hz, 3H)13C NMR (100MHz,DMSO-d6)δ170.82,167.88,166.67,165.05,157.33,152.57,144.28,141.65, 140.58,133.57,133.50,133.40,129.03,123.92,123.73,121.15,117.82,116.82,114.79, 105.31,60.10,55.99,49.03,41.35,31.28,20.68,13.90,13.03.HRMS calcd.for C32H36ClN4O8(M+H+)639.22162；found 639.22070.
Embodiment 156(S) the bromo- N- of -2- [7- (the chloro- 5- methylphenoxy of 3-) -3- [2- (diethylamino) -2- oxo second Base] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 156)
According to 88 the method for embodiment, using intermediate 278 (88.9mg, 0.2mmol) and intermediate 233 (145.5mg, 0.5mmol) preparation.Mp 146–147℃.1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),10.31(s, 1H), 8.57 (d, J=5.5Hz, 1H), 7.98 (s, 1H), 7.27 (s, 1H), 7.06 (s, 1H), 6.89 (s, 1H), 6.82 (s, 1H), 6.77 (s, 1H), 4.21 (dt, J=9.3,5.1Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.32-3.15 (m, 4H), 2.99 (dd, J=16.4,8.6Hz, 1H), 2.60 (dd, J=16.4,4.8Hz, 1H), 2.28 (s, 3H), 1.17 (t, J=7.1Hz, 3H), 0.99 (t, J=7.1Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.81, 167.94,166.71,165.92,157.45,152.58,150.35,143.65,143.19,141.64,133.88,133.54, 133.49,133.21,124.00,123.29,120.62,117.30,116.08,115.34,108.20,105.65,60.90, 60.78,56.23,49.05,41.40,31.28,20.73,13.93,13.06.HRMS calcd.for C32H35BrClN4O8(M +H+)717.13213；found 717.13184.
Embodiment 157(S) the chloro- N- of -2- [7- (the chloro- 5- methylphenoxy of 3-) -3- [2- (diethylamino) -2- oxo second Base] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,5- dimethoxy-4 '-methyl Benzamide (compound 157)
According to 88 the method for embodiment, using intermediate 278 (88.9mg, 0.2mmol) and intermediate 243 (115.3mg, 0.5mmol) preparation.Mp 146–147℃.1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),10.29(s, 1H), 8.57 (d, J=5.5Hz, 1H), 7.96 (s, 1H), 7.28 (s, 1H), 7.06 (s, 1H), 6.89 (s, 1H), 6.82 (s, 1H), 6.70 (s, 1H), 4.22 (dt, J=8.6,5.2Hz, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.36-3.30 (m, 2H), 3.25 (dt, J=13.9,6.7Hz, 2H), 2.99 (dd, J=16.3,8.7Hz, 1H), 2.61 (dd, J=16.1, 4.8Hz 1H), 2.28 (s, 3H), 2.11 (s, 3H), 1.17 (t, J=7.1Hz, 3H), 0.99 (t, J=7.1Hz, 3H) .HRMS calcd.for C32H35Cl2N4O7(M+H+)657.18773；found 657.18671.
Embodiment 158(S) the chloro- N- of -2- [7- (the chloro- 5- methylphenoxy of 3-) -3- [2- (4- methylpiperazine-1-yl) -2- Oxoethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,5- dimethoxy - 4- methyl benzamide (compound 158)
According to 106 the method for embodiment, using intermediate 277 (80.6mg, 0.2mmol)), intermediate 243 (115.3mg, 0.5mmol) and N methyl piperazine (60.1mg, 0.6mmol) is prepared through three-step reaction.Mp 163–164℃.1H NMR(400MHz,DMSO-d6) δ 10.46 (s, 1H), 10.29 (s, 1H), 8.56 (d, J=5.3Hz, 1H), 7.96 (s, 1H), 7.28 (s, 1H), 7.06 (s, 1H), 6.88 (s, 1H), 6.82 (s, 1H), 6.70 (s, 1H), 4.20 (dt, J=8.3,5.4Hz, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.44 (brs, 4H), 2.97 (dd, J=16.4,8.3Hz, 1H), 2.64 (dd, J= 16.4,5.2Hz,1H),2.45–2.25(m,7H),2.21(s,3H),2.11(s,3H).HRMS calcd.for C33H36Cl2N5O7(M+H+)684.19863；found 684.19775.
Embodiment 159(S) the bromo- N- of -2- [7- (the chloro- 5- methylphenoxy of 3-) -2,5- dioxo -3- [2- oxo -2- (piperazine Pyridine -1- base) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxybenzoyl Amine (compound 159)
(S) -8- amino -7- (the chloro- 5- methylphenoxy of 3-) -3- [2- oxo -2- (piperidin-1-yl) ethyl] -3 is prepared, 4- dihydro -1H- benzo [e] [Isosorbide-5-Nitrae] diazepine -2,5- diketone (intermediate 279): it according to 88 the method for embodiment, uses It is prepared by intermediate 277 (80.6mg, 0.2mmol) and piperidines (51.0mg, 0.6mmol).
1H NMR(400MHz,DMSO-d6) δ 10.16 (s, 1H), 8.12 (d, J=5.1Hz, 1H), 7.10 (s, 1H), 6.99 (s,1H),6.77(s,1H),6.75(s,1H),6.44(s,1H),5.81(s,2H),4.19–4.08(m,1H),3.49–3.33 (m, 4H), 2.95 (dd, J=16.3,8.6Hz, 1H), 2.56 (dd, J=16.5,4.8Hz, 1H), 2.28 (s, 3H), 1.56 (brs,4H),1.40(brs,2H).13C NMR(100MHz,DMSO-d6)δ170.73,167.37,167.16,158.13, 144.53,141.42,137.80,135.06,133.38,123.18,121.72,116.22,114.06,113.85,105.74, 49.11,45.79,42.02,31.28,25.73,25.20,24.01,20.77.
Prepare title compound (159): according to 88 the method for embodiment, using intermediate 279 (91.2mg, 0.2mmol) prepared with intermediate 233 (145.5mg, 0.5mmol).Mp 151–153℃.1H NMR(400MHz,DMSO-d6)δ 10.44 (s, 1H), 10.29 (s, 1H), 8.55 (d, J=5.3Hz, 1H), 7.99 (s, 1H), 7.27 (s, 1H), 7.06 (s, 1H), 6.89 (s, 1H), 6.82 (s, 1H), 6.78 (s, 1H), 4.19 (dt, J=8.9,5.2Hz, 1H), 3.79 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.47-3.35 (m, 4H), 2.97 (dd, J=16.3,8.6Hz, 1H), 2.61 (dd, J=16.3, 4.9Hz,1H),2.28(s,3H),1.57(brs,4H),1.40(brs,2H).13C NMR(100MHz,DMSO-d6)δ170.72, 167.01,166.65,165.88,157.42,152.54,150.30,143.61,143.13,141.59,133.86,133.50, 133.45,133.19,123.97,123.21,120.55,117.29,115.99,115.33,108.18,105.61,60.86, 60.74,56.20,48.98,45.80,42.03,31.18,25.74,25.21,24.01,20.70.HRMS calcd.for C33H35BrClN4O8(M+H+)729.1327；found 729.1302.
Embodiment 160(S) the chloro- N- of -2- [7- (the chloro- 5- methylphenoxy of 3-) -2,5- dioxo -3- [2- oxo -2- (piperazine Pyridine -1- base) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxybenzoyl Amine (compound 160)
According to 88 the method for embodiment, using intermediate 279 (91.2mg, 0.2mmol) and intermediate 237 (123.3mg, 0.5mmol) preparation.Mp 155–157℃.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),10.29(s, 1H), 8.55 (d, J=5.3Hz, 1H), 7.97 (s, 1H), 7.27 (s, 1H), 7.06 (s, 1H), 6.89 (s, 1H), 6.82 (s, 1H), 6.79 (s, 1H), 4.20 (dt, J=8.5,5.1Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.47-3.35 (m, 4H), 2.97 (dd, J=16.3,8.5Hz, 1H), 2.61 (dd, J=16.4,5.0Hz, 1H), 2.28 (s, 3H),1.57(brs,4H),1.40(brs,2H).13C NMR(100MHz,DMSO-d6)δ170.72,167.01,166.63, 164.91,157.41,151.91,149.36,143.90,143.13,141.60,133.52,133.45,133.14,131.54, 123.98,123.23,120.58,117.24,116.25,115.99,115.28,107.85,60.98,60.76,56.18, 48.98,45.80,42.03,31.19,25.74,25.21,24.00,20.69.HRMS calcd.for C33H35Cl2N4O8(M+ H+)685.1832；found 685.1813.
Embodiment 161(S) the bromo- N- of -2- [7- (the chloro- 5- methylphenoxy of 3-) -4- methyl -2,5- dioxo -3- [2- oxygen Generation -2- (piperidin-1-yl) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 161)
Prepare (S) -2- [8- amino -7- (the chloro- 5- methylphenoxy of 3-) -4- methyl -2,5- dioxo -2,3,4,5- four Hydrogen -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 280): according to embodiment 1 and 122 institute of embodiment The method stated, using intermediate 276 (3.52g, 10.0mmol), L-Aspartic acid diformazan ester hydrochloride (2.00g, 10.1mmol), iodomethane (7.10g, 50.0mmol) is prepared through three-step reaction.
1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),7.11(s,1H),6.99(s,1H),6.77(s,2H), 6.45 (s, 1H), 5.84 (s, 2H), 4.39 (dd, J=8.7,5.2Hz, 1H), 3.60 (s, 3H), 3.10 (dd, J=15.2, 9.7Hz, 1H), 2.98 (dd, J=16.3,3.8Hz, 1H), 2.85 (s, 3H), 2.28 (s, 3H)13C NMR(100MHz,DMSO- d6)δ170.64,169.08,167.00,158.04,144.48,141.42,137.89,134.85,133.38,123.21, 122.06,116.24,114.26,114.02,105.29,52.04,51.72,30.92,29.03,20.76.
Prepare (S) -8- amino -7- (the chloro- 5- methylphenoxy of 3-) -4- methyl -3- [2- oxo -2- (piperidin-1-yl) second Base] -3,4- dihydro -1H- benzo [e] [1,4] diazepine -2,5- diketone (intermediate 281): according to side described in embodiment 88 Method is prepared using intermediate 280 (83.4mg, 0.2mmol) and piperidines (51.0mg, 0.6mmol).
1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),7.10(s,1H),6.99(s,1H),6.76(s,2H), 6.44 (s, 1H), 5.80 (s, 2H), 4.44 (dd, J=8.1,0.6Hz, 1H), 3.63-3.40 (m, 4H), 3.16 (dd, J= 15.4,10.9Hz, 1H), 2.88 (s, 3H), 2.81 (dd, J=15.7,1.2Hz, 1H), 2.28 (s, 3H), 1.57 (brs, 4H), 1.38(brs,2H).13C NMR(100MHz,DMSO-d6)δ169.46,167.11,167.04,158.13,144.32, 141.41,137.68,135.09,133.37,123.15,122.02,116.16,114.64,113.95,105.39,52.52, 45.69,42.02,29.79,29.44,25.94,25.25,23.99,20.77.
Prepare title compound (161): according to 88 the method for embodiment, using intermediate 281 (83.6mg, 0.2mmol) prepared with 233 (145.5mg, 0.5mmol).Mp 141–143℃.1H NMR(400MHz,DMSO-d6)δ10.49 (s,1H),10.29(s,1H),8.00(s,1H),7.27(s,1H),7.06(s,1H),6.88(s,1H),6.82(s,1H), 6.78 (s, 1H), 4.47 (dd, J=9.9,3.4Hz, 1H), 3.79 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.65- 3.39 (m, 4H), 3.20 (dd, J=16.0,10.7Hz, 1H), 2.94 (s, 3H), 2.87 (dd, J=15.7,3.0Hz, 2H), 2.28(s,3H),1.58(s,4H),1.39(s,2H).13C NMR(100MHz,DMSO-d6)δ169.38,166.90,166.31, 165.89,157.37,152.53,150.29,143.59,142.99,141.56,133.88,133.51,133.43,132.97, 123.94,123.85,120.78,117.24,115.55,115.26,108.17,105.59,60.85,60.72,56.19, 52.41,45.68,42.03,29.74,29.56,25.95,25.24,23.98,20.68.HRMS calcd.for C34H37BrClN4O8(M+H+)743.1483；found 743.1463.
Embodiment 162(S) the chloro- N- of -2- [7- (the chloro- 5- methylphenoxy of 3-) -4- methyl -2,5- dioxo -3- [2- oxygen Generation -2- (piperidin-1-yl) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 162)
According to 88 the method for embodiment, using intermediate 281 (83.6mg, 0.2mmol) and intermediate 237 (123.3mg, 0.5mmol) preparation.Mp 144–146℃.1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),10.29(s, 1H),7.98(s,1H),7.28(s,1H),7.06(s,1H),6.88(s,1H),6.83(s,1H),6.80(s,1H),4.52– 4.41(m,1H),3.81(s,3H),3.79(s,3H),3.77(s,3H),3.61–3.39(m,3H),3.30–3.25(m,1H), 3.20 (dd, J=15.8,10.9Hz, 1H), 2.94 (s, 3H), 2.87 (dd, J=15.9,1.7Hz, 1H), 2.28 (s, 3H), 1.58(brs,4H),1.39(brs,2H).13C NMR(100MHz,DMSO-d6)δ169.39,166.90,166.30,164.92, 157.36,151.90,149.35,143.88,143.00,141.57,133.53,133.44,132.92,131.56,123.95, 123.88,120.81,117.19,116.23,115.56,115.21,107.84,60.97,60.75,56.17,52.41, 45.68,42.02,29.74,29.55,25.94,25.24,23.97,20.68.HRMS calcd.for C34H37Cl2N4O8(M+ H+)699.1988；found 699.1961.
Embodiment 163(S) the bromo- N- of -2- [7- (the chloro- 5- methylphenoxy of 3-) -4- methyl -2,5- dioxo -3- (2- oxygen Generation -2- thio-morpholinyl ethyl) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 163)
Prepare (S) -8- amino -7- (the chloro- 5- methylphenoxy of 3-) -4- methyl -3- (2- oxo -2- thio-morpholinyl second Base) -3,4- dihydro -1H- benzo [e] [1,4] diazepine -2,5- diketone (intermediate 282): according to side described in embodiment 88 Method is prepared using intermediate 280 (83.4mg, 0.2mmol) and morpholine (52.3mg, 0.6mmol).
1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),7.10(s,1H),6.99(s,1H),6.76(s,2H), 6.44 (s, 1H), 5.81 (s, 2H), 4.44 (dd, J=9.8,3.2Hz, 1H), 3.90-3.74 (m, 3H), 3.60-3.51 (m, 1H), 3.19 (dd, J=16.0,10.7Hz, 1H), 2.96-2.80 (m, 5H), 2.66 (brs, 3H), 2.28 (s, 3H)13C NMR (100MHz,DMSO-d6)δ169.46,167.66,167.10,158.12,144.35,141.43,137.72,135.06, 133.37,123.18,122.00,116.20,114.57,113.99,105.36,52.52,47.64,43.88,29.98, 29.52,26.92,26.44,20.79.
Prepare title compound (163): according to 88 the method for embodiment, using intermediate 282 (97.6mg, 0.2mmol) prepared with intermediate 233 (145.5mg, 0.5mmol).Mp 152–154℃.1H NMR(400MHz,methanol- d4)δ8.17(s,1H),7.44(s,1H),7.00(s,1H),6.85(s,1H),6.77(s,1H),6.75(s,1H),4.71 (dd, J=9.7,3.9Hz, 1H), 4.00-3.87 (m, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.74- 3.64 (m, 1H), 3.39-3.33 (m, 1H), 3.07 (s, 3H), 2.92 (dd, J=15.9,3.3Hz, 1H), 2.82-2.48 (m, 4H),2.30(s,3H).13C NMR(100MHz,DMSO-d6)δ169.40,167.55,166.32,165.93,157.37, 152.55,150.31,143.59,143.04,141.60,133.90,133.49,133.45,133.01,123.98,123.82, 120.79,117.29,115.56,115.30,108.17,105.61,60.88,60.75,56.21,52.44,47.65, 43.89,29.94,29.65,26.96,26.46,20.71.HRMS calcd.for C33H35BrClN4O8S(M+H+) 761.1048；found 761.1014.
Embodiment 164(S) the chloro- N- of -2- [7- (the chloro- 5- methylphenoxy of 3-) -4- methyl -2,5- dioxo -3- (2- oxygen Generation -2- thio-morpholinyl ethyl) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Yl-benzamide (compound 164)
According to 88 the method for embodiment, using intermediate 282 (97.6mg, 0.2mmol) and intermediate 237 (123.3mg, 0.5mmol) preparation.Mp 149–151℃.1H NMR(400MHz,methanol-d4)δ8.19(s,1H),7.44 (s, 1H), 7.00 (s, 1H), 6.86 (s, 1H), 6.82 (s, 1H), 6.78 (s, 1H), 4.71 (dd, J=9.9,4.1Hz, 1H), 4.02–3.88(m,3H),3.87(s,3H),3.86(s,3H),3.81(s,3H),3.76–3.66(m,1H),3.39–3.34(m, 1H), 3.08 (s, 3H), 2.95 (dd, J=16.1,3.5Hz, 1H), 2.84-2.49 (m, 4H), 2.31 (s, 3H)13C NMR (100MHz,DMSO-d6)δ169.41,167.54,166.31,164.97,157.36,151.92,149.36,143.88, 143.05,141.61,133.51,133.46,132.96,131.59,124.00,123.85,120.82,117.25,116.23, 115.58,115.24,107.83,61.00,60.78,56.19,52.43,47.64,43.89,29.95,29.65,26.95, 26.46,20.71.HRMS calcd.for C33H35Cl2N4O8S(M+H+)717.1553；found 717.1532.
Embodiment 165(S) the bromo- N- of -2- [7- (the chloro- 5- methylphenoxy of 3-) -2,5- dioxo -3- (2- oxo -2- sulphur For morpholinyl ethyl) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxybenzoyl Amine (compound 165)
According to 88 the method for embodiment, using intermediate 278 (80.6mg, 0.2mmol), morpholine (52.3mg, 0.6mmol) prepared with intermediate 233 (145.5mg, 0.5mmol) through three-step reaction.Mp 168–170℃.1H NMR (400MHz,DMSO-d6) δ 10.47 (s, 1H), 10.29 (s, 1H), 8.56 (d, J=5.1Hz, 1H), 8.00 (s, 1H), 7.28 (s,1H),7.06(s,1H),6.89(s,1H),6.83(s,1H),6.78(s,1H),4.24–4.19(m,1H),3.80(s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.76-3.54 (m, 4H), 2.97 (dd, J=16.3,8.1Hz, 1H), 2.74 (dd, J =18.2,6.9Hz, 1H), 2.65 (dd, J=16.4,5.1Hz, 2H), 2.51 (brs, 2H), 2.29 (s, 3H)13C NMR (100MHz,DMSO-d6)δ171.21,168.02,167.11,166.36,157.87,153.01,150.77,144.07, 143.65,142.07,134.33,133.91,133.66,124.46,123.64,120.98,117.80,116.46,115.83, 108.65,106.08,61.33,61.21,56.68,49.46,48.26,44.40,31.79,27.02,26.87,21.17.
Embodiment 166(S)-N- [3- [2- (diethylamino) -2- oxoethyl] -7- (3- methoxyl group -5- methylenedioxy phenoxy Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 166)
Prepare 5- (3- methoxyl group -5- methylphenoxy) -2,4- dinitrobenzoic acid (intermediate 283): according to embodiment 1 The method is made using intermediate 188 (4.93g, 20.0mmol) and 3- methoxyl group -5- methylphenol (2.93g, 21.2mmol) It is standby.
1H NMR(400MHz,DMSO-d6)δ14.45(brs,1H),8.81(s,1H),7.24(s,1H),6.76(s,1H), 6.71(s,1H),6.67(s,1H),3.75(s,3H),2.31(s,3H).
Prepare (S) -2- [8- amino -7- (3- methoxyl group -5- methylphenoxy) -2,5- dioxo -2,3,4,5- tetrahydro - 1H- benzo [e] [Isosorbide-5-Nitrae] diazepine -3- base] methyl acetate (intermediate 284): according to 1 the method for embodiment, using centre It is prepared by body 283 (3.48g, 10.0mmol) and L-Aspartic acid diformazan ester hydrochloride (2.00g, 10.1mmol).
1H NMR(400MHz,DMSO-d6) δ 10.25 (s, 1H), 8.18 (d, J=4.9Hz, 1H), 7.04 (s, 1H), 6.52 (s, 1H), 6.43 (s, 1H), 6.37 (s, 1H), 6.35 (s, 1H), 5.77 (s, 2H), 4.05 (dt, J=4.5,3.8Hz, 1H), 3.72 (s, 3H), 3.58 (s, 3H), 2.85 (dd, J=17.0,8.9Hz, 1H), 2.69 (dd, J=17.0,5.5Hz, 1H), 2.24(s,3H).
Prepare title compound (166): according to 88 the method for embodiment, using intermediate 284 (79.9mg, 0.2mmol), diethylamine (43.8mg, 0.6mmol) and 3,4,5- trimethoxy-benzoyl chlorides (92.3mg, 0.4mmol) are through three steps Reaction preparation.Mp 141–143℃.1H NMR(400MHz,DMSO-d6) δ 10.45 (s, 1H), 9.89 (s, 1H), 8.56 (d, J= 5.3Hz, 1H), 7.65 (s, 1H), 7.30 (s, 1H), 7.10 (s, 2H), 6.54 (s, 1H), 6.41 (s, 2H), 4.22 (dt, J= 9.0,5.8Hz, 1H), 3.80 (s, 6H), 3.70 (s, 3H), 3.68 (s, 3H), 3.32-3.19 (m, 4H), 2.99 (dd, J= 16.5,8.6Hz, 1H), 2.62 (dd, J=16.4,4.9Hz, 1H), 2.22 (s, 3H), 1.17 (t, J=7.0Hz, 3H), 0.99 (t, J=7.0Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.84,167.90,166.77,165.02,160.42, 157.37,152.60,144.87,140.56,140.51,133.19,133.02,129.16,123.52,120.41,117.51, 110.56,109.71,105.31,101.53,60.12,56.01,55.19,49.03,41.35,31.27,21.24,13.91, 13.05.HRMS calcd.for C33H39N4O9(M+H+)635.27116；found 635.26984.
Embodiment 167(S) the bromo- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3- methoxyl group -5- methyl Phenoxy group) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 167)
According to 88 the method for embodiment, using intermediate 284 (79.9mg, 0.2mmol), diethylamine (43.8mg, 0.6mmol) prepared with intermediate 233 (145.5mg, 0.5mmol) through three-step reaction.Mp 120–121℃.1H NMR (400MHz,DMSO-d6) δ 10.40 (s, 1H), 10.24 (s, 1H), 8.54 (d, J=5.6Hz, 1H), 7.98 (s, 1H), 7.20 (s, 1H), 6.79 (s, 1H), 6.58 (s, 1H), 6.43 (s, 2H), 4.18 (dt, J=8.7,5.2Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.71 (s, 3H), 3.32-3.18 (m, 4H), 2.98 (dd, J=16.3,8.7Hz, 1H), 2.60 (dd, J=16.3,4.8Hz, 1H), 2.25 (s, 3H), 1.17 (t, J=7.1Hz, 3H), 0.99 (t, J=7.0Hz, 3H) .13C NMR(100MHz,DMSO-d6)δ170.78,167.91,166.77,165.85,160.41,157.29,152.52, 150.30,144.01,143.61,140.46,133.90,132.84,132.81,123.04,119.55,115.77,111.20, 109.98,108.26,105.69,102.06,60.87,60.75,56.21,55.26,49.01,41.35,31.23,21.22, 13.90,13.04.HRMS calcd.for C33H38BrN4O9(M+H+)713.18167；found 713.18140.
Embodiment 168(S) the chloro- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3- methoxyl group -5- methyl Phenoxy group) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 168)
According to 88 the method for embodiment, using intermediate 284 (79.9mg, 0.2mmol), diethylamine (43.8mg, 0.6mmol) prepared with intermediate 237 (123.3mg, 0.5mmol) through three-step reaction.Mp 149–150℃.1H NMR (400MHz,DMSO-d6) δ 10.39 (s, 1H), 10.24 (s, 1H), 8.54 (d, J=5.4Hz, 1H), 7.97 (s, 1H), 7.21 (s, 1H), 6.81 (s, 1H), 6.58 (s, 1H), 6.43 (s, 2H), 4.19 (dt, J=8.6,5.2Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.71 (s, 3H), 3.35-3.19 (m, 4H), 2.98 (dd, J=16.2,8.5Hz, 1H), 2.60 (dd, J=16.3,5.0Hz, 1H), 2.25 (s, 3H), 1.17 (t, J=7.1Hz, 3H), 0.99 (t, J=7.0Hz, 3H) .HRMS calcd.for C33H38ClN4O9(M+H+)669.23218；found 669.23169.
Embodiment 169(S) the bromo- 3,4,5- trimethoxy-N- of -2- [7- (3- methoxyl group -5- methylphenoxy) -3- [2- (4- methylpiperazine-1-yl) -2- oxoethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diaza Zhuo -8- base] benzamide (compound 169)
Prepare (S) -8- amino -7- (3- methoxyl group -5- methylphenoxy) -3- [2- (4- methylpiperazine-1-yl) -2- oxygen For ethyl] -3,4- dihydro -1H- benzo [e] [1,4] diazepine -2,5- diketone (intermediate 285): according to described in embodiment 88 Method is prepared using intermediate 284 (79.9mg, 0.2mmol) and N methyl piperazine (60.1mg, 0.6mmol).
1H NMR(400MHz,DMSO-d6) δ 10.15 (s, 1H), 8.10 (d, J=5.1Hz, 1H), 7.04 (s, 1H), 6.52 (s, 1H), 6.42 (s, 1H), 6.36 (t, J=2.0Hz, 1H), 6.34 (s, 1H), 5.75 (brs, 2H), 4.12 (dt, J=8.2, 5.3Hz, 1H), 3.71 (s, 3H), 3.44 (brs, 4H), 2.93 (dd, J=16.6,8.4Hz, 1H), 2.59 (dd, J=16.4, 5.3Hz,1H),2.43(brs,2H),2.32(brs,2H),2.24(s,6H).
Prepare title compound (169): according to 88 the method for embodiment, using intermediate 285 (93.5mg, 0.2mmol) prepared with 233 (145.5mg, 0.5mmol).Mp 138–139℃.1H NMR(400MHz,CDCl3)δ8.75(s, 1H), 8.46 (s, 1H), 8.11 (d, J=3.6Hz, 1H), 7.45 (s, 1H), 7.05 (s, 1H), 6.53 (s, 1H), 6.43 (s, 1H),6.41(s,1H),4.49(s,1H),3.92(s,3H),3.89(s,3H),3.87(s,3H),3.85(brs,2H),3.75 (s,3H),3.06–2.75(m,6H),2.58(s,3H),2.30(s,3H).HRMS calcd.for C34H39BrN5O9(M+H+) 740.19257；found 740.19238.
Embodiment 170(S) the chloro- 3,4,5- trimethoxy-N- of -2- [7- (3- methoxyl group -5- methylphenoxy) -3- [2- (4- methylpiperazine-1-yl) -2- oxoethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diaza Zhuo -8- base] benzamide formates (compound 170)
According to 88 the method for embodiment, using intermediate 285 (93.5mg, 0.2mmol), intermediate 237 (123.3mg, 0.5mmol) prepared with formic acid solution through two-step reaction.Mp 141–142℃.1H NMR(400MHz,DMSO-d6)δ10.42(s, 1H), 10.25 (s, 1H), 8.54 (d, J=5.3Hz, 1H), 8.32 (s, 1H), 7.98 (s, 1H), 7.21 (s, 1H), 6.81 (s, 1H), 6.58 (s, 1H), 6.42 (s, 2H), 4.17 (dt, J=8.1,5.3Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.71 (s, 3H), 3.42 (brs, 4H), 2.95 (dd, J=16.4,8.2Hz, 1H), 2.63 (dd, J=16.4, 5.2Hz,1H),2.34(brs,2H),2.25(s,3H),2.24–2.20(m,2H),2.18(s,3H).HRMS calcd.for C34H39ClN5O9(M+H+)696.24308；found 696.24194.
Embodiment 171(S) the bromo- 3,4,5- trimethoxy-N- of -2- [7- (3- methoxyl group -5- methylphenoxy) -4- methyl - 3- [2- (4- methylpiperazine-1-yl) -2- oxoethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] two Azatropylidene -8- base] benzamide (compound 171)
Prepare title compound (171): according to method described in embodiment 1 and embodiment 122, using intermediate 283 (1.74g, 5.0mmol), L-Aspartic acid diformazan ester hydrochloride (1.00g, 5.05mmol), iodomethane (3.60g, 25.0mmol), N methyl piperazine (1.50g, 15.0mmol) and intermediate 233 (3.64g, 12.5mmol) are through six-step process system It is standby.Mp 159–161℃.1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),10.23(s,1H),7.99(s,1H),7.21 (s, 1H), 6.80 (s, 1H), 6.58 (s, 1H), 6.42 (s, 2H), 4.44 (dd, J=10.2,3.8Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.71 (s, 3H), 3.55 (brs, 2H), 3.42 (brs, 2H), 3.21 (dd, J=16.0, 10.3Hz, 1H), 2.93 (s, 3H), 2.88 (dd, J=16.0,3.6Hz, 1H), 2.42-2.15 (m, 10H)13C NMR (100MHz,DMSO-d6)δ169.33,167.36,166.42,165.86,160.40,157.27,152.52,150.29, 143.87,143.60,140.43,133.90,132.85,132.66,123.65,119.86,115.39,111.12,109.92, 108.28,105.66,101.98,60.87,60.75,56.21,55.25,54.57,54.12,52.38,45.46,44.46, 40.89,29.75,29.55,21.21.HRMS calcd.for C35H41BrN5O9(M+H+)754.20822；found 754.20648.
Embodiment 172(S) the bromo- 3,5- dimethoxy-N- of -2- [7- (3- methoxyl group -5- methylphenoxy) -4- methyl -3- [2- (4- methylpiperazine-1-yl) -2- oxoethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] phenodiazine Miscellaneous Zhuo -8- base] -4- methyl benzamide (compound 172)
According to method described in embodiment 1 and embodiment 122, using intermediate 283 (1.74g, 5.0mmol), L- asparagus fern Propylhomoserin diformazan ester hydrochloride (1.00g, 5.05mmol), iodomethane (3.60g, 25.0mmol), N methyl piperazine (1.50g, 15.0mmol) prepared with 242 (3.44g, 12.5mmol) through six-step process.Mp 146–147℃.1H NMR(400MHz, methanol-d4)δ8.16(s,1H),7.42(s,1H),6.66(s,1H),6.55(s,1H),6.41(s,2H),4.69(dd,J =9.9,4.4Hz, 1H), 3.76 (s, 6H), 3.73 (s, 3H), 3.58 (brs, 4H), 3.37 (dd, J=16.3,10.2Hz, 1H), 3.07 (s, 3H), 2.93 (d, J=12.6Hz, 1H), 2.82 (brs, 2H), 2.69 (brs, 2H), 2.54 (s, 3H), 2.27 (s,3H),2.19(s,3H).HRMS calcd.for C35H41BrN5O8(M+H+)738.21330；found 738.21246.
Embodiment 173(S) the chloro- 3,5- dimethoxy-N- of -2- [7- (3- methoxyl group -5- methylphenoxy) -4- methyl -3- [2- (4- methylpiperazine-1-yl) -2- oxoethyl] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] phenodiazine Miscellaneous Zhuo -8- base] -4- methyl benzamide (compound 173)
According to method described in embodiment 1 and embodiment 122, using intermediate 283 (1.74g, 5.0mmol), L- asparagus fern Propylhomoserin diformazan ester hydrochloride (1.00g, 5.05mmol), iodomethane (3.60g, 25.0mmol), N methyl piperazine (1.50g, 15.0mmol) prepared with 243 (2.88g, 12.5mmol) through six-step process.Mp 134–135℃.1H NMR(400MHz,DMSO- d6)δ10.48(s,1H),10.23(s,1H),7.98(s,1H),7.23(s,1H),6.73(s,1H),6.57(s,1H),6.42 (s, 2H), 4.45 (dd, J=10.0,3.9Hz, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 3.70 (s, 3H), 3.59 (brs, 2H), 3.45 (brs, 2H), 3.22 (dd, J=16.3,10.1Hz, 1H), 2.96-2.86 (m, 4H), 2.26 (brs, 4H), 2.24 (s,3H),2.11(s,3H).HRMS calcd.for C35H41ClN5O8(M+H+)694.26382；found 694.26245.
Embodiment 174(S) the bromo- 3,4,5- trimethoxy-N- of -2- [7- (3- methoxyl group -5- methylphenoxy) -3- [2- (4- methylpiperazine-1-yl) -2- oxoethyl] -2,5- dioxo -4- (propyl- 2- alkynes -1- base) -2,3,4,5- tetrahydro -1H- benzene And [e] [1,4] diazepine -8- base] benzamide (compound 174)
Title compound (174): according to 1 the method for embodiment, using intermediate 283 (1.74g, 5.0mmol), 254 (1.01g, 5.05mmol), N methyl piperazine (1.50g, 15.0mmol) and 233 (3.64g, 12.5mmol) are reacted through five steps to be made It is standby.Mp 142–143℃.1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),10.25(s,1H),8.03(s,1H),7.21 (s, 1H), 6.81 (s, 1H), 6.58 (s, 1H), 6.43 (s, 2H), 4.52 (dd, J=10.4,3.7Hz, 1H), 4.47 (dd, J= 18.5,1.5Hz, 1H), 4.13 (dd, J=18.1,1.8Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.71 (s, 3H), 3.56 (brs, 2H), 3.38 (dd, J=15.9,10.4Hz, 3H), 3.15 (s, 1H), 2.93 (d, J= 13.5Hz,1H),2.40–2.12(m,10H).HRMS calcd.for C37H41BrN5O9(M+H+)778.20822；found 778.20654.
Embodiment 175(S)-N- [7- (the bromo- 3,5- dimethyl phenoxy of 4-) -3- [2- (diethylamino) -2- oxo second Base] -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 175)
The preparation of the bromo- 3,5- xylenol (intermediate 292) of 4-: by 3,5- xylenol (2.44g, 20.0mmol) It is dissolved in 20mL chloroform, bromine (1.0mL, 21.0mmol) is dissolved in 10mL chloroform, is slowly dropped into above-mentioned solution, reacts at room temperature 1h.According to Secondary hypo solution, washing, divide and take organic phase, and silica gel column chromatography, petrol ether/ethyl acetate elution obtains white solid 800mg, yield 20.0%.1H NMR(400MHz,CDCl3)δ6.59(s,2H),4.58(brs,1H),2.36(s,6H).
Title compound (175): according to method described in embodiment 1 and embodiment 88, using intermediate 188 (1.23g, 5.0mmol), 286 (1.06g, 5.3mmol), L-Aspartic acid diformazan ester hydrochloride (1.00g, 5.05mmol), diethylamine (1.10g, 15.0mmol) and 3,4,5- trimethoxy-benzoyl chlorides (2.31g, 10.0mmol) are prepared through six-step process.Mp 152–154℃.1H NMR(400MHz,DMSO-d6) δ 10.49 (s, 1H), 10.05 (s, 1H), 8.57 (d, J=5.1Hz, 1H), 7.58 (s, 1H), 7.27 (s, 1H), 7.12 (s, 2H), 6.89 (s, 2H), 4.22 (d, J=8.0Hz, 1H), 3.80 (s, 6H), 3.70 (s, 3H), 3.36-3.20 (m, 4H), 3.00 (dd, J=16.1,8.3Hz, 1H), 2.62 (dd, J=16.2,4.7Hz, 1H), 2.29 (s, 6H), 1.17 (t, J=6.9Hz, 3H), 0.99 (t, J=7.0Hz, 3H)13C NMR(100MHz,DMSO-d6) δ170.75,167.91,166.74,164.97,154.98,152.53,145.32,140.50,139.25,133.10, 133.05,129.04,123.74,120.61,120.24,118.19,118.03,105.37,60.10,56.02,49.01, 41.35,31.27,23.41,13.91,13.04.HRMS calcd.for C33H38BrN4O8(M+H+)697.18675；found 697.18439.
Embodiment 176(S) the chloro- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (fluoro- 3,5- dimethyl of 4- Phenoxy group) -4- methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- three Methoxy benzamide (compound 176)
The preparation fluoro- 3,5-dimethylphenol of 4- (287): it using 3,5-dimethylphenol as raw material, is prepared using literature method (specific method refers to: Yamada, S.；Gavryushin,A.；Knochel,P.Convenient electrophilic fluorination of functionalized aryl and heteroaryl magnesium Reagents.Angew.Chem.Int.Ed.2010,49,2215-2218, by referring to be incorporated by herein).
Preparation (S)-2- [8- amino-7- (the fluoro- 3,5- dimethyl phenoxy of 4-) dioxo-2,3,4-4- methyl-2,5-, 5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (intermediate 288): according to embodiment 1 and embodiment 122 the methods, using intermediate 188 (1.23g, 5.0mmol), intermediate 287 (742.7mg, 5.3mmol), L- asparagus fern ammonia Dimethyl phthalate hydrochloride (1.00g, 5.05mmol) and iodomethane (3.60g, 25.0mmol) are prepared through four-step reaction.
1H NMR(400MHz,DMSO-d6) δ 10.32 (s, 1H), 6.99 (s, 1H), 6.75 (d, J=5.3Hz, 2H), 6.44 (s, 1H), 5.79 (s, 2H), 4.36 (dd, J=8.9,4.9Hz, 1H), 3.59 (s, 3H), 3.16-3.04 (m, 1H), 2.97 (d, J=14.3Hz, 1H), 2.84 (s, 3H), 2.19 (s, 6H)13C NMR(100MHz,DMSO-d6)δ170.68,169.09, (167.12,156.37,154.01,151.90,141.98 d, J=400.0Hz), 133.95,125.16 (d, J=19.7Hz), 119.91,118.12,114.01,105.04,52.03,51.73,30.93,29.03,14.4 1 (d, J=3.5Hz)
Prepare (S) -2- [8- (the chloro- 3,4,5- trimethoxy-benzamide base of 2-) -7- (fluoro- 3,5- dimethyl benzene oxygen of 4- Base) -4- methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] methyl acetate (centre Body 289): according to 106 the method for embodiment, using intermediate 288 (83.1mg, 0.2mmol) with 237 (123.3mg, 0.5mmol) prepare.
1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),10.27(s,1H),8.05(s,1H),7.12(s,1H), (6.91 s, 1H), 6.85 (d, J=5.6Hz, 2H), 4.39 (dd, J=9.2,5.5Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.60 (s, 3H), 3.13 (dd, J=16.7,9.6Hz, 1H), 3.01 (dd, J=17.4,4.4Hz, 1H),2.89(s,3H),2.20(s,6H).
Prepare title compound (176): according to 106 the method for embodiment, using intermediate 289 (128.1mg, 0.2mmol) prepared with diethylamine (43.8mg, 0.6mmol).Mp 130–132℃.1H NMR(400MHz,DMSO-d6)δ10.42 (s, 1H), 10.22 (s, 1H), 8.01 (s, 1H), 7.11 (s, 1H), 6.89 (s, 1H), 6.84 (d, J=5.4Hz, 2H), 4.44 (dd, J=9.7,3.4Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.40 (d, J=6.2Hz, 2H), 3.26 (dd, J=13.4,6.8Hz, 1H), 3.16 (dd, J=15.6,9.3Hz, 2H), 2.91 (s, 3H), 2.85 (dd, J= 16.1,3.0Hz, 1H), 2.19 (s, 6H), 1.16 (t, J=6.7Hz, 3H), 0.96 (t, J=6.9Hz, 3H)13C NMR (100MHz,DMSO-d6)δ169.40,167.65,166.40,164.95,156.80,154.43,151.91,151.06, (149.32,144.64,143.87,132.32 d, J=33.8Hz), 131.66,125.37 (d, J=19.8Hz), 123.42, 119.30 (d, J=4.6Hz), 118.54,116.23,114.97,107.99,60.98,60.75,56.19,52.37,41.1 6, (29.70,29.47,14.32 d, J=3.5Hz), 13.93,12.94.HRMS calcd.for C34H39ClFN4O8(M+H+) 685.24350；found 685.24274.
Embodiment 177(S) the chloro- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (fluoro- 3,5- dimethyl of 4- Phenoxy group) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 177)
According to 88 the method for embodiment, using intermediate 188 (1.23g, 5.0mmol), intermediate 287 (742.7mg, 5.3mmol), L-Aspartic acid diformazan ester hydrochloride (1.00g, 5.05mmol), diethylamine (1.10g, 15.0mmol) and centre Body 237 (3.08g, 12.5mmol) is prepared through six-step process.Mp 146–148℃.1H NMR(400MHz,DMSO-d6)δ10.36 (s, 1H), 10.22 (s, 1H), 8.50 (d, J=4.9Hz, 1H), 8.00 (s, 1H), 7.11 (s, 1H), 6.88 (s, 1H), 6.84 (d, J=5.5Hz, 2H), 4.16 (dt, J=7.4,5.2Hz, 1H), 3.81 (s, 3H), 3.79 (s, 6H), 3.31-3.18 (m, 4H), 2.97 (dd, J=16.4,8.6Hz, 1H), 2.58 (dd, J=16.2,4.5Hz, 1H), 2.20 (s, 6H), 1.16 (t, J= 6.8Hz, 3H), 0.98 (t, J=6.9Hz, 3H)13C NMR(100MHz,DMSO-d6)δ170.75,167.88,166.75, 164.93,156.81,154.44,151.91,151.15,149.33,144.72,143.89 132.44 (d, J=13.1Hz), 131.63,125.39 (d, J=19.8Hz), 122.83,119.28 (d, J=4.7Hz), 118.40,116.26,115.41, (107.99,60.99,60.76,56.19,48.97,41.33,31.21,14.33 d, J=3.5Hz), 13.88,13.02.HRMS calcd.for C33H37ClFN4O8(M+H+)671.22785；found 671.22687.
Embodiment 178(S) the bromo- N- of -2- [3- [2- (diethylamino) -2- oxoethyl] -7- (3- hydroxy-5-methyl base benzene Oxygroup) -4- methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- front three Oxybenzamide (compound 178)
Prepare (S) -2- [8- amino -7- (3- hydroxy-5-methyl phenoxyl) -4- methyl -2,5- dioxo -2,3,4,5- Tetrahydro -1H- benzo [e] [1,4] diazepine -3- base]-N, N- diethyl acetamide (intermediate 290): according to embodiment 1 with 122 the method for embodiment, using intermediate 188 (1.23g, 5.0mmol), 3- hydroxy-5-methyl base phenol (657.7mg, 5.3mmol), L-Aspartic acid diformazan ester hydrochloride (1.00g, 5.05mmol), iodomethane (3.60g, 25.0mmol) and diethyl Amine (1.10g, 15.0mmol) is reacted through five steps to be prepared.
1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.46(s,1H),7.04(s,1H),6.42(s,1H), 6.31 (s, 1H), 6.26 (s, 1H), 6.13 (s, 1H), 5.70 (s, 2H), 4.44 (dd, J=9.7,3.9Hz, 1H), 3.44- (3.36 m, 2H), 3.29-3.11 (m, 3H), 2.87 (s, 3H), 2.82 (dd, J=15.8,2.3Hz, 1H), 2.18 (s, 3H), 1.16 (t, J=6.6Hz, 3H), 0.97 (t, J=6.8Hz, 3H)13C NMR(100MHz,DMSO-d6)δ169.52,167.83, 167.26,158.50,158.14,144.21,139.96,138.75,134.46,121.25,114.53,110.78,108.75, 105.21,101.50,52.55,41.22,29.81,29.41,21.20,13.97,12.99.
Prepare title compound (178): according to 88 the method for embodiment, using intermediate 290 (88.1mg, 0.2mmol) prepared with intermediate 233 (145.5mg, 0.5mmol).Mp 180–182℃.1H NMR(400MHz,DMSO-d6)δ 10.45(s,1H),10.20(s,1H),9.52(s,1H),7.99(s,1H),7.21(s,1H),6.79(s,1H),6.36(s, 1H), 6.29 (s, 1H), 6.20 (s, 1H), 4.45 (dd, J=9.8,3.6Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H), 3.50-3.35 (m, 4H), 3.29-3.11 (m, 3H), 2.92 (s, 3H), 2.86 (dd, J=16.2,3.6Hz, 1H), 2.18 (s, 3H), 1.16 (t, J=6.8Hz, 3H), 0.96 (t, J=7.0Hz, 3H)13C NMR(100MHz,DMSO-d6)δ 169.46,167.71,166.46,165.89,158.52,157.35,152.54,150.31,143.87,143.60,140.19, 133.96,132.83,132.76,123.62,120.05,115.25,111.52,109.66,108.26,105.69,102.68, 60.89,60.77,56.23,52.45,41.21,29.74,29.54,21.13,13.97,12.99.HRMS calcd.for C33H38BrN4O9(M+H+)713.18167；found 713.18140.
Embodiment 179(S) the bromo- N- of -2- [7- (3- hydroxy-5-methyl phenoxyl) -4- methyl -2,5- dioxo -3- [2- Oxo -2- (piperidin-1-yl) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- front three Oxybenzamide (compound 179)
According to embodiment 1 and 122 the method for embodiment, using intermediate 188 (1.23g, 5.0mmol), 3- hydroxyl -5- Methylphenol (657.7mg, 5.3mmol), L-Aspartic acid diformazan ester hydrochloride (1.00g, 5.05mmol), iodomethane (3.60g, 25.0mmol), piperidines (1.28g, 15.0mmol) and intermediate 233 (3.64g, 12.5mmol) are reacted through seven steps and are made It is standby.Mp 151–153℃.1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),10.20(s,1H),9.52(s,1H),8.00 (s, 1H), 7.22 (s, 1H), 6.79 (s, 1H), 6.37 (s, 1H), 6.30 (s, 1H), 6.20 (s, 1H), 4.44 (dd, J=9.7, 2.9Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.55-3.44 (m, 4H), 3.20 (dd, J=15.9, 10.4Hz, 1H), 2.93 (s, 3H), 2.87 (d, J=17.3Hz, 1H), 2.19 (s, 3H), 1.58 (brs, 4H), 1.38 (brs, 2H).HRMS calcd.for C34H38BrN4O9(M+H+)725.1822；found 725.1798.
Embodiment 180(S) the bromo- N- of -2- [7- [3- (dimethylamino) phenoxy group] -4- methyl -2,5- dioxo -3- [2- Oxo -2- (piperidin-1-yl) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- front three Oxybenzamide (compound 180)
Title compound (180): according to embodiment 1 and 122 the method for embodiment, using intermediate 188 (1.23g, 5.0mmol), 3- (dimethylamino) phenol (727.0mg, 5.3mmol), L-Aspartic acid diformazan ester hydrochloride (1.00g, 5.05mmol), iodomethane (3.60g, 25.0mmol), piperidines (1.28g, 15.0mmol) and intermediate 233 (3.64g, It 12.5mmol) reacts and prepares through seven steps.Mp 142–144℃.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),10.19 (s, 1H), 8.01 (s, 1H), 7.19-7.15 (m, 2H), 6.83 (s, 1H), 6.52 (dd, J=8.4,1.6Hz, 1H), 6.42 (s, 1H), 6.24 (d, J=7.8Hz, 1H), 4.44 (dd, J=10.0,3.5Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.62-3.34 (m, 4H), 3.28 (dd, J=8.0,3.6Hz, 1H), 3.19 (dd, J=15.9,10.4Hz, 1H), 2.92(s,3H),2.87(s,6H),1.57(brs,4H),1.38(brs,2H).13C NMR(100MHz,DMSO-d6)δ 169.41,166.92,166.50,165.86,157.09,152.52,151.91,150.28,144.33,143.59,133.95, 132.43,132.37,130.00,123.49,119.09,115.06,108.31,107.99,105.82,105.69,102.86, 60.86,60.74,56.25,52.42,45.69,42.04,39.94,29.71,29.51,25.95,25.25,23.99.HRMS calcd.for C35H41BrN5O8(M+H+)738.2139；found 738.2106.
Compound is prepared using following route in embodiment 181-186:
Embodiment 181(S) the bromo- N- of -2- [3- [2- (dimethylamino) -2- oxoethyl] -7- (3- methylol -5- methyl Phenoxy group) -4- methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- three Methoxy benzamide (compound 181)
Mp 148–150℃.1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),10.23(s,1H),8.04(s, 1H), 7.16 (s, 1H), 6.92 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.76 (s, 1H), 5.21 (t, J=5.7Hz, 1H), 4.44 (d, J=5.6Hz, 2H), 4.41 (d, J=3.5Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.17 (dd, J=10.5,5.4Hz, 1H), 3.05 (s, 3H), 2.92 (s, 3H), 2.90-2.84 (m, 1H), 2.79 (s, 3H), 2.28(s,3H).13C NMR(100MHz,DMSO-d6)δ169.38,168.67,166.44,165.92,156.17,152.54, 150.27,144.71,144.16,143.59,139.22,133.97,132.64,123.43,122.45,119.35,117.55, 115.03,113.62,108.32,105.65,62.41,60.86,60.73,56.25,52.45,36.49,34.71,29.90, 29.50,20.94.
Embodiment 182(S) the bromo- N- of -2- [7- (3- methylol -5- methylphenoxy) -4- methyl -2,5- dioxo -3- [2- oxo -2- (piperidin-1-yl) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- Trimethoxy-benzamide (compound 182)
Mp 149–151℃.1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),10.23(s,1H),8.04(s, 1H), 7.16 (s, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.76 (s, 1H), 5.21 (t, J=5.4Hz, 1H), 4.44 (d, J=5.1Hz, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.57-3.43 (m, 4H), 3.20 (dd, J=15.9,10.4Hz, 1H), 2.92 (s, 3H), 2.86 (dd, J=15.7,3.1Hz, 1H), 2.28 (s, 3H), 1.58 (brs,4H),1.38(brs,2H).13C NMR(100MHz,DMSO-d6)δ169.37,166.93,166.44,165.90, 156.16,152.52,150.25,144.70,144.14,143.57,139.20,133.96,132.64,132.58,123.47, 122.43,119.31,117.53,115.03,113.61,108.30,105.63,62.39,60.85,60.72,56.24, 52.41,45.68,42.03,29.70,29.53,25.94,25.24,23.97,20.93.HRMS calcd.for C35H40BrN4O9(M+H+)739.1979；found 739.1946.
Embodiment 183(S) the bromo- N- of -2- [7- (3- methylol -5- methylphenoxy) -4- methyl -2,5- dioxo -3- (2- oxo -2- thio-morpholinyl ethyl) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- three Methoxy benzamide (compound 183)
Mp 158–160℃.1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),10.23(s,1H),8.04(s, 1H), 7.16 (s, 1H), 6.92 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.76 (s, 1H), 5.21 (t, J=5.7Hz, 1H), 4.46 (brs, 1H), 4.44 (d, J=5.7Hz, 2H), 3.91-3.72 (m, 12H), 3.61-3.52 (m, 1H), 3.22 (dd, J=16.1,10.4Hz, 1H), 2.98-2.83 (m, 4H), 2.66 (brs, 4H), 2.28 (s, 3H)13C NMR(100MHz, DMSO-d6)δ169.36,167.54,166.43,165.91,156.13,152.52,150.26,144.70,144.17, 143.58,139.21,133.95,132.60,123.42,122.45,119.28,117.55,115.02,113.63,108.31, 105.64,62.39,60.84,60.72,56.24,52.42,47.63,43.88,29.89,29.58,26.91,26.43, 20.93.HRMS calcd.for C34H38BrN4O9S(M+H+)757.1543；found 757.1514.
Embodiment 184(S) the bromo- N- of -2- [7- (3- methylol -5- methylphenoxy) -2,5- dioxo -3- [2- oxo - 2- (piperidin-1-yl) ethyl] -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 184)
Mp 271–273℃.1H NMR(400MHz,DMSO-d6) δ 10.39 (s, 1H), 10.25 (s, 1H), 8.51 (d, J= 5.3Hz,1H),8.03(s,1H),7.15(s,1H),6.93(s,1H),6.83(s,1H),6.80(s,1H),6.76(s,1H), 5.23 (t, J=5.7Hz, 1H), 4.44 (d, J=5.7Hz, 2H), 4.22-4.10 (m, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.47-3.34 (m, 4H), 2.96 (dd, J=16.3,8.4Hz, 1H), 2.60 (dd, J=16.4, 5.0Hz,1H),2.28(s,3H),1.58(brs,4H),1.40(brs,2H).13C NMR(100MHz,DMSO-d6)δ170.72, 167.04,166.79,165.92,156.22,152.54,150.27,144.75,144.29,143.59,139.25,133.97, 132.81,132.63,122.84,122.47,119.10,117.61,115.46,113.67,108.32,105.67,62.40, 60.87,60.75,56.26,48.99,45.81,42.04,31.17,25.74,25.22,24.02,20.96.HRMS calcd.for C34H38BrN4O9(M+H+)725.1822；found 725.1787.
Embodiment 185(S) the bromo- N- of -2- [3- [2- (dimethylamino) -2- oxoethyl] -7- (3- methylol -5- methyl Phenoxy group) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 185)
Mp 160–162℃.1H NMR(400MHz,DMSO-d6) δ 10.41 (s, 1H), 10.25 (s, 1H), 8.52 (d, J= 5.3Hz,1H),8.03(s,1H),7.15(s,1H),6.93(s,1H),6.83(s,1H),6.81(s,1H),6.76(s,1H), 5.23 (t, J=5.6Hz, 1H), 4.44 (d, J=5.5Hz, 2H), 4.14 (dt, J=7.6,5.4Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.76 (s, 3H), 2.99 (s, 3H), 2.94 (dd, J=16.5,8.4Hz, 1H), 2.80 (s, 3H), 2.61 (dd, J=16.5,5.1Hz, 1H), 2.28 (s, 3H)13C NMR(100MHz,DMSO-d6)δ170.75,168.88,166.79, 165.93,156.20,152.55,150.28,144.76,144.33,143.59,139.27,133.97,132.81,132.63, 122.83,122.49,119.08,117.65,115.47,113.70,108.32,105.68,62.41,60.88,60.76, 56.26,49.03,36.52,34.77,31.39,20.97.HRMS calcd.for C33H32BrN4O9(M+H+)685.1509； found 685.1478.
Embodiment 186(S) the bromo- N- of -2- [7- (3- methylol -5- methylphenoxy) -2,5- dioxo -3- (2- oxo - 2- thio-morpholinyl ethyl) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene Formamide (compound 186)
Mp 287–289℃.1H NMR(400MHz,DMSO-d6) δ 10.42 (s, 1H), 10.24 (s, 1H), 8.51 (d, J= 5.2Hz,1H),8.04(s,1H),7.16(s,1H),6.93(s,1H),6.83(s,1H),6.81(s,1H),6.76(s,1H), 5.22 (t, J=5.6Hz, 1H), 4.44 (d, J=5.1Hz, 2H), 4.17 (dt, J=7.5,5.5Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.74-3.56 (m, 4H), 2.96 (dd, J=16.4,8.0Hz, 1H), 2.74 (dd, J= 12.4,7.8Hz,1H),2.68–2.52(m,4H),2.28(s,3H).13C NMR(100MHz,DMSO-d6)δ170.73, 167.57,166.78,165.91,156.19,152.53,150.27,144.75,144.33,143.60,139.25,133.94, 132.81,132.59,122.79,122.48,119.06,117.63,115.45,113.68,108.32,105.67,62.40, 60.87,60.74,56.26,49.00,47.80,43.95,31.31,26.55,26.40,20.95.HRMS calcd.for C33H36BrN4O9S(M+H+)743.1386；found 743.1351.
Embodiment 187(S) the bromo- N- of -2- [the bromo- 3- of 6- [2- (diethylamino) -2- oxoethyl] -7- (3,5- dimethyl Phenoxy group) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 187)
The preparation of the chloro- 4,6- dinitrobenzoic acid (intermediate 291) of the bromo- 3- of 2-: by the chloro- 2,4-DNT of 5- (0.463mmol) uses concentrated sulfuric acid dissolution, is heated with stirring to 60 DEG C, and after solution clarification, NBS is added portionwise in 20min (0.556mmol) reacts 2.5h at 60 DEG C.Reaction solution is poured slowly into ice water, room temperature is placed, removes supernatant, will precipitate With ether dissolution, saturated sodium thiosulfate solution is successively used, saturated sodium bicarbonate solution, washing divide and take organic phase, anhydrous slufuric acid Sodium is dry, is concentrated to give crude product 100mg, yield 73.5%.By above-mentioned crude product (3.40mmol) with 10ml concentrated sulfuric acid dissolution, under stirring Sodium dichromate (4.58mmol) is added portionwise in 1h, reacts at room temperature 2h after adding.Reaction solution is poured slowly into ice water, holding chamber Temperature, ethyl acetate extraction, divides and takes organic phase, and anhydrous sodium sulfate is dry, is evaporated, obtains object 938mg, yield 85.2%.1H NMR(400MHz,DMSO-d6)δ9.02(s,1H).13C NMR(100MHz,DMSO-d6)δ164.00,148.13,143.25, 136.32,133.31,123.77,121.10.
Prepare the bromo- 3- of 2- (3,5- dimethyl phenoxy) -4,6- dinitrobenzoic acid (intermediate 292): according to embodiment 1 Described in method, prepared using intermediate 188 (2.46g, 10.0mmol) and intermediate 291 (1.29g, 10.6mmol).
1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),6.78(s,1H),6.59(s,2H),2.23(s,6H).13C NMR(100MHz,DMSO-d6)δ163.99,156.04,149.33,143.09,141.26,139.65,138.20,20.81.
Prepare (S) -2- [the bromo- 7- of 8- amino -6- (3,5- dimethyl phenoxy) -2,5- dioxo -2,3,4,5- tetrahydro - 1H- benzo [e] [1,4] diazepine -3- base]-N, N- diethyl acetamide (intermediate 293): according to described in embodiment 88 Method, using intermediate 291 (2.06g, 5.0mmol), L-Aspartic acid diformazan ester hydrochloride (1.00g, 5.5mmol) and diethyl Amine (2.18g, 30.0mmol) is prepared through four-step reaction.
1H NMR(400MHz,DMSO-d6) δ 10.16 (s, 1H), 8.39 (d, J=7.5Hz, 1H), 6.67 (s, 1H), 6.46 (s, 1H), 6.44 (s, 2H), 5.73 (s, 2H), 4.23 (dt, J=8.6,4.4Hz, 1H), 3.43-3.13 (m, 4H), 2.99 (dd, J=16.2,9.2Hz, 1H), 2.57 (dd, J=16.2,4.2Hz, 1H), 2.22 (s, 6H), 0.98 (t, J=7.0Hz, 3H).
Prepare title compound (187): according to method described in embodiment 88, using intermediate 293 (100.7mg, 0.2mmol) prepared with 233 (145.5mg, 0.5mmol).1H NMR(400MHz,CDCl3)δ8.52(s,1H),8.51(s,1H), 8.29 (s, 1H), 7.55 (d, J=7.7Hz, 1H), 6.93 (s, 1H), 6.70 (s, 1H), 6.50 (s, 2H), 4.59 (td, J= 8.0,3.7Hz 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.76 (s, 3H), 3.49-3.29 (m, 4H), 3.09 (dd, J= 15.6,8.3Hz, 1H), 2.74 (dd, J=15.5,3.4Hz, 1H), 2.26 (s, 6H), 1.25 (t, J=6.5Hz, 3H), 1.12 (t, J=7.0Hz, 3H)
Embodiment 188(S) the bromo- N- of -2- [3- [2- (methylethylamine) -2- oxoethyl] -7- (3,5- dimethyl benzene Oxygroup) -4- methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- front three Oxybenzamide (compound 188)
Title compound (188): according to method described in embodiment 106, using intermediate 252 (134.0mg, 0.2mmol) prepared with N- methyl ethylamine hydrochloride (35.5mg, 0.6mmol).Mp 141–143℃.1H NMR(400MHz, DMSO-d6)δ10.46(s,1H),10.23(s,1H),8.04(s,1H),7.17(s,1H),6.84(s,1H),6.82(s,1H), 6.69 (s, 2H), 4.45 (dt, J=10.4,3.7Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.44 (m, 1H),3.30–3.11(m,2H),3.04(s,1.5H,-NCH3), 2.93 (s, 3H), 2.87 (dd, J=15.9Hz 3.1Hz, 1H),2.77(s,1.5H,-NCH3), 2.26 (s, 6H), 1.16 (t, J=6.9Hz, 1.5H ,-NCH2CH3), 0.97 (t, J= 7.1Hz,1.5H,-NCH2CH3).13C NMR(100MHz,DMSO-d6)δ169.87(s),168.65(s),168.54(s), 166.90(s),166.38(s),156.61(s),152.98(s),150.73(s),144.61(s),144.02(s),139.79 (s),134.43(s),133.07(s),125.83(s),123.94(s),119.79(s),116.79(s),115.58(s), 108.72(s),106.11(s),61.33(s),61.21(s),56.67(s),52.87(s),43.86(s,-NCH2CH3), 42.02(s,-NCH2CH3),34.51(s,-NCH3),32.51(s,-NCH3),30.57(s),29.96(s),21.32(s), 13.55(s,-NCH2CH3),12.61(s,-NCH2CH3).
Embodiment 189(S)-N- [3- [2- (dimethylamino) -2- oxoethyl] -7- (3,5- dimethyl phenoxy) -2- Oxygen -5- sulphur -- 2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] (the change of -3,4,5- trimethoxy-benzamide Close object 189)
Title compound (189) is prepared by following route:
1H NMR(400MHz,DMSO-d6) δ 10.81 (d, J=6.0Hz, 1H), 10.67 (s, 1H), 9.89 (s, 1H), 7.66 (s, 1H), 7.64 (s, 1H), 7.10 (s, 2H), 6.76 (s, 1H), 6.67 (s, 2H), 4.33 (d, J=6.8Hz, 1H), 3.80 (s, 6H), 3.71 (s, 3H), 3.05 (d, J=7.8Hz, 1H), 3.02 (s, 3H), 2.88 (d, J=5.8Hz, 1H), 2.83 (d, J=7.3Hz, 3H), 2.22 (s, 6H)
Embodiment 190(S)-dimethyl (3- [8- (the bromo- 3,4,5- trimethoxy-benzamide of 2-) -7- (3,5- dimethyl Phenoxy group) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] -2- propiono) phosphate (compound 190)
Title compound (190) is prepared by following route:
1H NMR(400MHz,DMSO-d6) δ 10.46 (s, 1H), 10.22 (s, 1H), 8.55 (d, J=5.1Hz, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.11 (dd, J=13.2,5.4Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.67 (d, J=3.2Hz, 3H), 3.64 (d, J=3.2Hz, 3H), 3.49-3.34 (m, 2H), 3.26 (dd, J=18.6,8.4Hz, 1H), 2.93 (dd, J=18.3,5.4Hz, 1H), 2.25 (s, 6H).
Embodiment 191The bromo- N- of (S, E) -2- [7- (3,5- dimethyl phenoxy) -2,5- dioxo -3- (- 3 alkene of 2- carbonyl - 1- yl) -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzamide (chemical combination Object 191)
Title compound (191): it uses compound 190 (170.0mg, 0.2mmol), potassium carbonate (50.0mg, 0.3mmol) With propionic aldehyde (100 μ l, 1.4mmol), preparation overnight is reacted using acetonitrile as solvent, at 50 DEG C.1H NMR(400MHz,CDCl3)δ 8.80 (s, 1H), 8.51 (s, 1H), 8.49 (s, 1H), 7.45 (s, 1H), 7.26 (s, 1H), 7.10 (s, 1H), 6.99 (dt, J= 15.7,6.2Hz, 1H), 6.79 (s, 1H), 6.66 (s, 2H), 6.16 (d, J=16.0Hz, 1H), 4.47 (s, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.39 (dd, J=16.9,7.3Hz, 1H), 2.93 (dd, J=16.9,4.4Hz, 1H), 2.29 (s, 6H), 2.24 (d, J=7.1Hz, 2H), 1.07 (t, J=7.4Hz, 3H)
Embodiment 192(S)-(3- [8- (the bromo- 3,4,5- trimethoxy-benzamide base of 2-) -7- (3,5- dimethyl benzene oxygen Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] -2- propiono) phosphoric acid (chemical combination Object 192)
Title compound (192): it uses compound 190 (100.0mg, 0.12mmol), allyl trimethyl silane (170.0 μ l, 1.0mmol) and bromotrimethylsilane (90.0 μ l, 0.6mmol), using methylene chloride as solvent, reacted at room temperature Night preparation.1H NMR(400MHz,DMSO-d6) δ 10.47 (s, 1H), 10.22 (s, 1H), 8.52 (d, J=5.0Hz, 1H), 8.04 (s, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.09 (dd, J=12.5,5.9Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.06 (dddd, J=47.7,34.7,20.1,10.2Hz, 4H), 2.25 (s,6H).
Embodiment 193(S)-dimethyl-[4- (8- (the bromo- 3,4,5- trimethoxy-benzamide of 2-) -7- (3,5- dimethyl Phenoxy group) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -3- base] -2- methyl -3- butyryl - 2- yl) phosphate (compound 193)
Title compound (193) is prepared by following route:
1HNMR(400MHz,DMSO-d6) δ 10.44 (s, 1H), 10.22 (s, 1H), 8.51 (d, J=5.1Hz, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.82 (d, J=4.4Hz, 2H), 6.68 (s, 2H), 4.24-4.03 (m, 1H), 3.80 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.70 (d, J=3.4Hz, 3H), 3.67 (d, J=3.4Hz, 3H), 3.42 (dd, J= 18.5,8.4Hz, 1H), 2.98 (dd, J=18.3,4.7Hz, 1H), 2.26 (s, 6H), 1.39 (d, J=16.6Hz, 3H), 1.34 (d, J=16.4Hz, 3H)
Embodiment 194(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -3- (2- (methoxymethylamino group) -2- oxygen For ethyl) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy Benzamide (compound 194)
According to 106 the method for embodiment, using intermediate 246 (160.0mg, 0.25mmol) and methylmethoxyamino Hydrochloride (100mg, 1.0mmol) preparation.1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),10.22(s,1H),8.51 (d, J=5.1Hz, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.82 (d, J=4.4Hz, 2H), 6.68 (s, 2H), 4.24- 4.03 (m, 1H), 3.80 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.70 (d, J=3.4Hz, 3H), 3.67 (d, J= 3.4Hz, 3H), 3.42 (dd, J=18.5,8.4Hz, 1H), 2.98 (dd, J=18.3,4.7Hz, 1H), 2.26 (s, 6H), 1.39 (d, J=16.6Hz, 3H), 1.34 (d, J=16.4Hz, 3H)
Embodiment 195(S)-N- [3- (2- (dimethylamino) -2- oxoethyl) -7- (3,5- dimethyl phenoxy) -2, 5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy -2- trifluoromethyl Benzamide (compound 195)
Following route is pressed in the preparation of 3,4,5- trimethoxy -2- trifluoromethylbenzoic acid (intermediate 294):
According to 88 the method for embodiment, using intermediate 232 (70.0mg, 0.16mmol) and intermediate 294 (70.0mg, 0.25mmol) preparation.1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),10.37(s,1H),8.52(d,J =5.3Hz, 1H), 8.00 (s, 1H), 7.16 (s, 1H), 6.81 (s, 1H), 6.72 (s, 1H), 6.67 (s, 2H), 4.17 (s, 1H), 3.88 (s, 3H), 3.80 (s, 6H), 3.32-3.14 (m, 4H), 2.98 (dd, J=16.1,8.5Hz, 1H), 2.60 (dd, J =16.2,4.6Hz, 1H), 2.25 (s, 6H), 1.17 (t, J=6.9Hz, 3H), 0.99 (t, J=6.9Hz, 3H)
Embodiment 196(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -3- (2- (Methoxyamino) -2- oxo second Base) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- trimethoxy-benzene first Amide (compound 196)
According to 106 the method for embodiment, using intermediate 246 (80.0mg, 0.12mmol) and Methoxyamino hydrochloric acid Salt (32mg, 0.37mmol) preparation.1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),10.44(s,1H),10.23(s, 1H),8.61(s,1H),8.03(s,1H),7.16(s,1H),6.83(s,1H),6.82(s,1H),6.69(s,2H),4.14(s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.56 (s, 3H), 2.70-2.57 (m, 1H), 2.36 (d, J= 12.2Hz,1H),2.25(s,6H).
Embodiment 197(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -3- (2- (methoxymethylamino group) -2- oxygen For ethyl) -4- methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- three Methoxy benzamide (compound 197)
According to 106 the method for embodiment, using intermediate 252 (80.0mg, 0.12mmol) and methylmethoxyamino Hydrochloride (47.5mg, 0.48mmol) preparation.1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),10.23(s,1H), 8.04(s,1H),7.17(s,1H),6.83(s,1H),6.81(s,1H),6.68(s,2H),4.43(s,1H),3.80(s,3H), 3.79 (s, 3H), 3.77 (s, 6H), 3.26 (s, 1H), 3.08 (s, 3H), 3.00 (d, J=17.0Hz, 1H), 2.92 (s, 3H), 2.25(s,6H).
Embodiment 198(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -4- methyl -3- (2- (4- methyl piperazine -1- Base) -2- oxoethyl) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- Trimethoxy-benzamide fumarate (compound 198)
It is prepared using compound 135 (50.0mg, 0.06mmol) and fumaric acid (8.0mg, 0.06mmol).1H NMR (400MHz,DMSO-d6)δ10.47(s,1H),10.24(s,1H),8.03(s,1H),7.16(s,1H),6.83(s,1H), 6.81 (s, 1H), 6.68 (s, 2H), 6.62 (s, 1H), 6.62 (s, 1H), 4.44 (d, J=9.2Hz, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.73 (s, 3H), 3.57 (s, 2H), 3.41 (d, J=24.4Hz, 2H), 3.29-3.14 (m, 1H), 2.92 (s, 3H),2.88(s,1H),2.48–2.42(m,2H),2.33(s,2H),2.25(s,6H),2.21(s,3H).
Embodiment 199(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -4- methyl -3- (2- (4- methyl piperazine -1- Base) -2- oxoethyl) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- Trimethoxy-benzamide citrate (compound 199) uses compound 135 (50.0mg, 0.06mmol) and citric acid (13.0mg, 0.06mmol) preparation.1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),10.24(s,1H),8.03(s, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.44 (dd, J=9.8,3.4Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.64 (s, 2H), 3.50 (s, 1H), 3.43 (s, 1H), 3.23 (dd, J= 16.1,10.3Hz, 2H), 2.93 (s, 3H), 2.89 (s, 1H), 2.64 (dd, J=36.9,15.3Hz, 5H), 2.47-2.43 (m, 1H),2.38(s,3H),2.25(s,6H).
Embodiment 200(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -4- methyl -3- (2- (4- methyl piperazine -1- Base) -2- oxoethyl) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- Trimethoxy-benzamide succinate (compound 200) uses compound 135 (50.0mg, 0.06mmol) and succinic acid (8.0mg, 0.06mmol) preparation.1H NMR(400MHz,DMSO-d6)δ12.29(s,2H),10.46(s,1H),10.24(s, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.44 (d, J=6.7Hz, 1H),3.80(s,3H),3.79(s,3H),3.77(s,3H),3.56(s,2H),3.43(s,1H),3.37(s,1H),3.26– 3.16(m,1H),2.92(s,3H),2.87(s,1H),2.41(s,4H),2.25(s,6H),2.20(s,4H).
Embodiment 201(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -4- methyl -3- (2- (4- methyl piperazine -1- Base) -2- oxoethyl) -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- Trimethoxy-benzamide maleate (compound 201)
It is prepared using compound 135 (50.0mg, 0.06mmol) and malonic acid (7.5mg, 0.06mmol).1H NMR (400MHz,DMSO-d6)δ10.48(s,1H),10.24(s,1H),8.03(s,1H),7.17(s,1H),6.82(s,1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.44 (d, J=6.6Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.66 (s, 2H), 3.49 (d, J=32.6Hz, 2H), 3.24 (dd, J=15.8,9.8Hz, 1H), 3.06 (s, 2H), 2.93 (s, 3H),2.90(s,1H),2.76–2.59(m,2H),2.44(s,2H),2.25(s,6H).
Embodiment 202(S) the bromo- N- of -2- [7- (3,5- dimethyl phenoxy) -3- (2- (hydroxymethyl amino) -2- oxo Ethyl) -4- methyl -2,5- dioxo -2,3,4,5- tetrahydro -1H- benzo [e] [1,4] diazepine -8- base] -3,4,5- front three Oxybenzamide (compound 202)
According to 106 the method for embodiment, using intermediate 252 (80.0mg, 0.12mmol) and methylhydroxylamino salt Hydrochlorate (41.0mg, 0.48mmol) preparation.1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),10.23(s,1H),10.07 (s,1H),8.03(s,1H),7.17(s,1H),6.83(s,1H),6.81(s,1H),6.68(s,2H),4.42(s,1H),3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.20 (d, J=9.2Hz, 1H), 3.07 (s, 3H), 2.95 (s, 1H), 2.90 (s,3H),2.25(s,6H).
Embodiment 203The anti-tumor activity of 1,4- benzodiazepine -2,5- cyclohexadione compounds of the invention
The present embodiment is using the evaluation method of national cancer institute (NCI) to embodiment compound in the present invention Antitumor activity is evaluated.Part of compounds uses 60 kinds of human tumor cell lines and carries out activity rating, participates in the 60 of screening Kind human tumor cell line is respectively from leukaemia, lung cancer in non-cellule type, colon cancer, central nerve neuroma, black 9 kinds of plain tumor, oophoroma, kidney, prostate cancer and breast cancer cancers.Remaining compound has chosen 9 kinds of representativeness cell strains and carries out Activity rating, including A549 (lung cancer in non-cellule type), HCT116 (colon cancer), SF295 (central nerve neuroma), LOX- IMVI (melanoma), 786-0 (kidney), K562 (leukaemia), PC-3 (prostate cancer), OVCAR-3 (oophoroma), HS 578T (breast cancer).Detailed method of operation in relation to active appraisal experiment please refers to the website NCI http: // Www.dtp.nci.nih.gov or relevant survey article[33,34]。
Evaluation result is shown: most of embodiment compound has the significant work for inhibiting growth of tumour cell in the present invention Property.
Table 1 is that the title compound 1 prepared in previous embodiment, 53,88,123,130 and 177 are (i.e. of the invention Compound) it is directed to the antitumor spectra of 60 kinds of tumor cell lines, table 2 lists title compound that 188 embodiments prepare to 5 kinds The inhibitory activity of representative tumor cell line.Wherein GI50Value indicates " 50% growth inhibition ratio ", can inhibit cell 50% The concentration of untested compound when growth；AVE value indicates compound to the average GI of 60 kinds of tumor cell lines50Value；"-" indicates not Measurement.
Table 1
Table 2
Embodiment 204The compounds of this invention can kill breast carcinoma stem cell and inhibit its self-renewal capacity
A series of embodiment compounds according to the present invention can not only effectively inhibit growth of tumour cell, demonstrate,prove through experiment It is real, moreover it is possible to which that the proliferation for inhibiting tumor stem cell in vivo and in vitro is expected to be developed into while inhibiting Common tumors cell and Tumor Stem The difunctional drug of cell.
Tumor stem cell can form sphere under suitable condition of in vitro culture, and Common tumors cell does not have this Kind ability, the effect that can be separated under in vitro conditions tumor stem cell accordingly and it is proliferated, is broken up to evaluate drug.With Experimentation and result of the lower illustrated embodiments compound to the breast cancer cell line SUM159sphere inhibiting effect formed.
1. test method:
Breast cancer cell line SUM159sphere is cultivated in ultralow absorption plate with serum free medium, basal medium DMEM/F12 (without phenol red, without phenol red), addition B27 (without vitamin A is free of vitamin A) (1x), EGF (20ng/ml), bFGF (20ng/ml), insulin (insulin, 5 μ g/ml).
The cell of common normal adhere-wall culture, is passed on when growth conditions are preferable, taken after cell count appropriate kind to ultralow Adsorb 24 orifice plates.The growth conditions of cell directly affect the formational situation of sphere.When state is preferable, SUM159sphere at Ball rate is about 0.5%, and the inoculating cell quantity in the every hole of 24 orifice plates should be at 4000 or so.The shape of sphere is observed after inoculation daily At situation, can suitably be blown and beaten with pipette tips if any adhesion.Generally it can clearly be seen that sphere was formed at culture 2-3 days, it 4-5 days can To carry out drug-treated experiment, normally it can pass on or collect within 7-8 days cell extraction RNA or albumen progress molecular water is plain It tests.
The drug-treated of Sphere is tested:
Every hole is inoculated with equivalent (4000) SUM159 cell to 24 plates of ultralow absorption, carries out after culture 4-5 days to sphere It takes pictures counting, replaces fresh culture, carry out drug-treated respectively by a certain concentration.This experiment does blank, Japanese yew using DMSO Alcohol (PTX-50nM) does negative control, and salinomycin (Salinomycin-8uM) does positive control, the embodiment compound evaluated 5nM, two concentration processing of 50nM are respectively taken respectively.It is observed that within drug-treated 3 days or so its influence effect to sphere phenotype Fruit.Counting of taking pictures is carried out to sphere again after drug-treated 5 days, then carries out the passage of sphere.Sphere secondary culture 5 It takes pictures again after it counting.
Count and compare three different phases and take pictures the difference of counting, by the difference of sphere forming quantity after passage and The difference of sphere phenotype evaluates untested compound to the lethal effect of SUM159sphere, to reflect different compounds to cream The inhibiting effect of gland cancer stem cell.
2. experimental result and conclusion:
Through embodiment 188 to be measured compound handle 5 days after, through processed SUM159sphere compared with DMSO blank group with Taxol negative control group is obviously loose, cannot substantially form complete sphere.Reason may be compound directly or Connecing leads to cell ageing apoptosis.Through -8 μM of SUM159sphere handled with embodiment compound 188-50nM of salinomycin after passage Forming quantity significantly reduces, and the compound -50nM group effect of embodiment 188 is better than -8 μM of groups of salinomycin.Specific sphere cell Number and form see Fig. 1-Fig. 3.
Experimental result shows that the compound effects concentration of embodiment 188, cannot after SUM159sphere passage in 50nM Sphere is re-formed, this compound has stronger lethal effect to SUM159sphere, it is made to lose the energy of self-renewing Power.By the experimental results showed that the compound of embodiment 188 all has stronger lethal effect to breast carcinoma stem cell in vitro.
In addition, using it is above-mentioned it is experimentally confirmed that test embodiment 88,106,115,123,128,135,165,129,130, 131,132,133 compound can inhibition of breast carcinoma stem cell and and its self-renewal capacity, show that such compound has Kill the effect of tumor stem cell.
Embodiment 205Inhibiting effect (Fig. 4-figure that embodiment compound grows human lung cancer H522 nude mouse xenograft tumor 7)
The compound of embodiment 123 according to the present invention is verified by experiments, and is able to suppress human lung cancer H522 bare mouse different species The growth of transplantable tumor is expected to be developed into the drug for inhibiting tumour.
1. tested material:
The compound of embodiment 123 is configured to 40 × DMSO stock solution, before use with containing 2.5% Tween 80 (Tween80) physiology salt
Water is diluted to administration concentration；Paclitaxel injection (lot number: 140401, specification: 5mL:30mg)
2. experimental animal and tumor strain:
Male BALB/c nu mouse, 4~5 week old are purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., license Card SCXK (capital) 2012-0001, mouse are raised in Tsinghua University SPF grades of Experimental Animal Center.Test tumor strain used are as follows: people's lung Cancer H522 transplanted tumor in nude mice builds strain by this laboratory and passes on preservation.
3. test method:
Tumour growth and the good tumor animal of overall health of patients are selected, cervical dislocation is put to death.Tumor mass is taken out under aseptic condition, It is cut into the tumor mass that diameter is 2-3mm with scalpel, trochar is inoculated in after nude mouse armpit subcutaneously.Tumour is grown naturally, to tumor The bulk grows to 130mm3Random grouping afterwards, if grouping administration day is D0.
Test sets 5 groups altogether, is respectively as follows: 1. vehicle control group；2. positive controls: taxol (PTX) 24mg/kg；3. real Apply the compound 50mg/kg group of example 123；4. the compound 25mg/kg group of embodiment 123；5. the compound of embodiment 123 12.5mg/kg group；Every group of 10 animals reopen administration of beginning by animal body respectively from this very day.Positive control PTX 24mg/kg group is dynamic Object is injected intravenously weekly 1 time, is administered 4 times altogether.It is injected intravenously within remaining groups of animals every 6 days 1 time, is administered 4 times altogether.In administration process The long and short diameter of every 2-3 days measurement animal tumors and weight, with formula: (1/2) × major diameter × (minor axis)2Calculate tumor size, grouping End in the 21st day (D21) is tested afterwards.Animal cervical dislocation is put to death at the end of experiment, removes tumour, claims knurl weight, calculates drug pair Inhibition rate of tumor growth.Calculate gross tumor volume (TV) and relative tumour volume (RTV).Compare groups of animals tumour with t method of inspection The other statistical significance of the index errors such as weight, gross tumor volume, RTV.
Calculation formula is as follows:
Gross tumor volume (TV)=(long × wide2)/2。
(measurement gained TV, Vt are to survey every time later to relative tumour volume (RTV)=Vt/Vo when wherein Vo is sub-cage administration TV when amount).
The evaluation index of anti-tumor activity is Relative tumor proliferation rate T/C (%):
The standard of curative effect evaluation: T/C (%) > 40 is invalid；
T/C (%)≤40, and it is effective for being statistically analyzed P < 0.05.
4. test result and discussion:
Experimental result is shown in Fig. 4-Fig. 7, table 3.
By tumor growth curve (Fig. 6) and photo (Fig. 7) as it can be seen that each treatment group mouse knurl of the compound of embodiment 123 Long-pending growth rate slows down compared with vehicle control group, and curative effect enhances with the raising of dosage.When off-test, embodiment The T/C value of high, medium and low three dosage of 123 compounds is respectively 13.2%, 36.3%, 62.6%, and tumour inhibiting rate is respectively 88.7%, 62.4%, 41.6%, knurl weight and RTV are reduced compared with the control group, wherein high, middle dose group has statistical significance (table 1). The knurl weight of positive controls (PTX 24mg/kg) animal, RTV are remarkably decreased compared with the control group, and have statistical significance (p<0.001,p<0.001).In this test, compound 25mg/kg, the 50mg/kg dosage group and PTX of embodiment 123 It is effective that 24mg/kg group, which can be evaluated,.The compound low dose group mouse weight amplification of embodiment 123 is suitable with control group, about 10%, it is about 7% that 123 compound middle dose group weight amplification of embodiment, which is about 8%, PTX 24mg/kg group mouse weight amplification, (see Fig. 4 and Fig. 5).The compound high dose group mouse weight decline about 2% of embodiment 123, and dead 1 at D20 days.Remaining Each dosage group has no animal dead.
5. conclusion:
With the dosage of compound 12.5mg/kg, 25mg/kg, 50mg/kg of embodiment 123 to human lung cancer H522 mice with tumor Intravenous injection, 6 days primary, totally 4 times, significantly inhibits to tumour growth, tumor killing effect is related to dosage.Its Middle 50mg/kg, 25mg/kg dosage group tumor-like hyperplasia at the end of experiment is respectively 88.7%, 62.4%, Relative tumor proliferation Rate 13.2%, 36.3% has statistical difference compared with negative control group, and it is effective for can be evaluated.
Embodiment 206: effect of the embodiment compound to ribonucleotide reductase
Ribonucleoside-diphosphate reductase subunit M2 or ribonucleotide Reductase small subunit (RRM2) is a subunit of ribonucleotide reductase (RR), and RR is unique catalysis core Ribotide is reduced into the enzyme of deoxyribonucleotide, is the rate-limiting enzyme of DNA synthesis and reparation.RR includes RRM1 and RRM2 two Subunit, wherein the catalytic activity of RR is mainly by the regulation of RRM2 expression.Research shows that RRM2 all high table in many tumours It reaches, the high expression of RRM2 and drug resistance, transfer and the poor prognosis of tumour are closely related, and therefore, RRM2 is likely to treatment tumour Potential target spot.
The compound processing group of 1.RNAseq comparative example 123 and the difference expression gene of DMSO control group
One of feature of tumor stem cell is exactly that can form tumour ball under low adsorption plate condition of culture in vitro.We are logical It crosses after handling SUM159 microballoon 48h with 123 compound of embodiment of 25nM and the like 88 compound of embodiment, extracts total RNA is prepared into double-stranded cDNA library, is used for transcript profile sequence rna-Seq.Sequencing result (Fig. 8) obtains embodiment 123 and implements Common difference expression gene 135 relative to DMSO control group of 88 compound group of example, RRM2 gene is in two drug-treated groups It is all significant to lower.
2. verifying the variation of RRM2 transcriptional level and protein expression level under the compound processing of embodiment 123
Using without phenol red DMEM/F12 (1XB27,20ng/mL EGF, 20ng/mL FGF and 5ng/mL insulin) By SUM159 breast cancer cell culture 5 days in sphere cultivating system, when microsphere diameter is greater than 50 μm, with final concentration of 5nM The compound of embodiment 123 handle SUM159sphere 2 hours, be then divided into two parts, portion passes through q- for extracting RNA The variation of PCR detection RRM2 transcriptional level；Another is digested to individual cells by pancreatin, then passes through cell inner dyeing The expression of (intracellular staining) flow cytometer detection RRM2 protein level.As shown in the results, it is compareed relative to DMSO Group, 123 compound processing group of embodiment, the mRNA level in-site and protein level of RRM2 have conspicuousness to reduce (see Fig. 9).Wherein, In Fig. 9, A:q-PCR verifies the expression of RRM2mRNA；The table of B:intracellular dyeing verifying RRM2 protein level It reaches.
3.RRM2T33AMutation can block killing of the compound of embodiment 123 to SUM159 cell and tumor stem cell Effect
Studies have shown that RRM2T33AMutation can prevent the combination of RRM2 and cyclinF, so that its ubiquitination be blocked to degrade Approach.By RRM2 and RRM2T33AMutation is connected in viral packaging plasmid, and packaging virus simultaneously infects SUM159 cell line, is established Stable RRM2 is overexpressed and RRM2T33ASUM159 cell line.Using DMSO processing as control, with the implementation of final concentration of 5nM 123 compound of example handles normal SUM159, RRM2 overexpression group and RRM2 respectivelyT33AThe cell of mutation group 10 hours；Then RIPA extracts total protein of cell, the variation (Figure 10) of western blotting Germicidal efficacy RRM2 protein expression.Relative to Overexpression group of the RRM2 without mutation, the expression of either endogenous or external source RRM2 are handled in the compound of embodiment 123 Under, all not reductions of conspicuousness, i.e. RRM2T33APrevent the degradation of RRM2.
Further by 1*105A adherent SUM159 cell is incubated for, film recording, then using the processing of compound 123 5 It, (see Figure 11-A, the processing of 123 compound of embodiment is normal, RRM2 is overexpressed and RRM2 for film recordingT33AMutation Cellular morphology after SUM159 attached cell 5 days), continue to be incubated for, cell balling-up, take a picture, counts.As a result (see Figure 11-B, RRM2T33AThe balling-up situation of remaining cell after SUM159 [123] is handled 5 days) display, it is overexpressed in normal SUM159, RRM2 Group and RRM2T33AIn three groups of experiments, only RRM2T33AThe cell of group still has part thin after 123 compound of embodiment is handled 5 days Born of the same parents' survival, and the cell survived shows stronger balling-up ability in balling-up experiment.
Further experiment is by normal SUM159, RRM2 overexpression group and RRM2T33ASUM159 cell sphere culture 4 It, is then handled microballoon 5 days with the compound of the embodiment 123 of 5nM, observes microballoon form.Experimental result (such as Figure 12-A, RRM2T33ALethal effect of the mutation rescue embodiment compound 123 to SUM159 tumour microballoon) show only RRM2T33AGroup Tumour cell microballoon still has the survival of part cell microsphere, remaining DMSO group and RRM2 overexpression group after the processing of compound 123 Sphere all after processing 5 days apoptosis, and with RRM2T33ARemaining microballoon is thin after the compound of embodiment 123 is handled 5 days Born of the same parents are passed on, and the balling-up ability of cell after detection processing, discovery also only has RRM2T33AThe sphere of group is in 123 compound of embodiment Continuous passage (such as Figure 12-B, with RRM2 still is able to after processingT33ARemaining bead cell after 123 compound of embodiment is handled 5 days Passage, the balling-up ability of cell after detection processing, figure are the balling-up situation that the second generation is passed to after drug-treated).
By conclusions it may be concluded that blocking the degradation of RRM2 can be done with part blocks breast cancer cell and breast cancer Cell is not killed after the processing of 123 compound of COMPOUNDS EXAMPLE.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or spy described in conjunction with this embodiment or example Point is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are not Centainly refer to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be any One or more embodiment or examples in can be combined in any suitable manner.
Although an embodiment of the present invention has been shown and described, it will be understood by those skilled in the art that: not A variety of change, modification, replacement and modification can be carried out to these embodiments in the case where being detached from the principle of the present invention and objective, this The range of invention is defined by the claims and their equivalents.

Claims (10)

1. a kind of compound is compound or the pharmaceutically acceptable salt of formula (I) compound represented shown in formula (I), and Compound shown in formula (I) is S configuration,
Wherein:
X is optionally from-O-or-S-；
Y is selected from-CO-, and be connectedComposition
Z is optionally from O or S；
M represents 0,1 or 2；
N represents 1 or 2；
R1Optionally certainly
At least one of；
R2Optionally from-COOR13、–CONR14R15、–COCH2P=O (OR17OR18) ,-COCH=CHR19, cyano, Wherein R13、R14、R15、R17、R18And R19It is each independently selected from amino, hydroxyl, the C optionally replaced1–6 Alkyl, the C optionally replaced2–6Alkenyl or the C optionally replaced2–7Alkynyl, the substituted substituent group are selected from amino, hydroxyl, cyanogen At least one of base, halogen and phenyl, R14And R15Quaternary, five yuan or hexa-atomic aliphatic heterocycle can be formed together with hetero atom；Or R14、R15、R17、R18And R19It is each independently selected from hydrogen；R16 is selected from C1-6Alkyl, methyl fluoride, difluoromethyl or trifluoromethyl；
R3And R7It is each independently selected from hydrogen or halogen, R4And R6It is each independently methoxyl group, R5Selected from methyl or methoxy；
R8And R10It is each independently hydrogen；R9Selected from hydrogen, C1–6Alkyl, C2–6Alkenyl, C2–6Alkynyl, C3–6Naphthenic base, benzyl；
R11For hydrogen atom.
2. compound according to claim 1, which is characterized in that
R13Selected from methyl, ethyl, isopropyl, normal-butyl.
3. compound according to claim 1, which is characterized in that R14、R15、R17、R18、R19It selects each independently From hydrogen, methyl, ethyl, propyl, normal-butyl, hydroxyl, methylol, amino, aminomethyl, And R14And R15It can be formed together with hetero atom
4. compound according to claim 1, which is characterized in that R16Optionally from methyl, ethyl, trifluoromethyl.
5. compound according to claim 1, which is characterized in that
R8And R10It is each independently hydrogen, R9Selected from hydrogen, methyl, ethyl, isopropyl, benzyl,
6. a kind of compound, which is characterized in that the compound is at least one of following compounds:
Or the pharmaceutically acceptable salt of at least one of described above compound.
7. a kind of pharmaceutical composition, which is characterized in that include the described in any item compounds of claim 1-6.
8. pharmaceutical composition according to claim 7, which is characterized in that further include: selected from pharmaceutically acceptable At least one of carrier and excipient.
9. the purposes of the described in any item compounds of claim 1-6 in medicine preparation, the drug can be used for preventing or controlling Treat proliferative diseases.
10. purposes according to claim 9, which is characterized in that the proliferative diseases are cancer.
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CN106831614B (en) * 2017-01-09 2020-07-28 清华大学 Substituted benzodiazacyclo compound and its preparation method and use
AU2021382771B2 (en) * 2020-11-17 2024-07-11 Ningbo Combireg Pharmaceutical Technology Co., Ltd. Deuterated 1,4-benzodiazepine-2,5-dione compound and use thereof
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